The Dissertation Committee for David Frederic Cauble, Jr. certifies that this is the approved version of the following dissertation: TRANSITION METAL AND ORGANO-CATALYZED CYCLIZATIONS, CYCLOADDITIONS AND COUPLINGS Committee: Michael Krische, Supervisor Eric Anslyn Stephen Martin Philip Magnus Christian Whitman
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The Dissertation Committee for David Frederic Cauble, Jr. certifies that this is
the approved version of the following dissertation:
TRANSITION METAL AND ORGANO-CATALYZED CYCLIZATIONS, CYCLOADDITIONS AND COUPLINGS
Committee:
Michael Krische, Supervisor
Eric Anslyn
Stephen Martin
Philip Magnus
Christian Whitman
TRANSITION METAL AND ORGANO-CATALYZED CYCLIZATIONS, CYCLOADDITIONS AND COUPLINGS
David Frederic Cauble, Jr., B.S
by
DissertationPresented to the Faculty of the Graduate School of
the University of Texas at Austinin Partial Fulfillment of the Requirements
for the Degree ofDoctor of Philosophy
The University of Texas at AustinDecember 2004
UMI Number: 3150558
31505582005
UMI MicroformCopyright
All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code.
ProQuest Information and Learning Company 300 North Zeeb Road
P.O. Box 1346 Ann Arbor, MI 48106-1346
by ProQuest Information and Learning Company.
Dedication
To my parents, David and Alice Cauble, whose support and encouragement have made
all the difference.
Acknowledgements
I am grateful to my mentor, Professor Michael J. Krische, for his support and
guidance and for providing a challenging environment within which to grow personally
and intellectually. I am indebted also to the members of the Krische group, with whom I
spent much time and from whom I learned a great deal. Finally, special thanks are due to
those who helped proof-read this dissertation: Alice Cauble, Diane Lam, Wendy Mariner,
Susan Garner and Pablo Mauleon.
iv
TRANSITION METAL AND ORGANO-CATALYZED CYCLIZATIONS, CYCLOADDITIONS AND COUPLINGS
Publication No.
David Frederic Cauble, Jr., Ph.D.The University of Texas at Austin, 2004
Supervisor: Michael J. Krische Transition metal-catalyzed carbon-carbon bond-forming reactions are attractive
methodological targets, as they enable the rapid build-up of molecular complexity.
Herein is described research directed toward the development of highly practical,
efficient and selective transition metal-catalyzed processes that facilitate the succinct,
sequential formation of multiple chemical bonds: i. Catalysts derived from rhodium and
copper are featured in tandem conjugate addition-electrophilic trapping reactions (tandem
vicinal difunctionalization), leading to products of formal aldol, Dieckmann and Blaise
cyclizations. In this context, the use of diastereotopic 1,3-dione electrophilic acceptors is
examined. ii. Related rhodium catalysts are employed successfully in the catalytic
reductive arylation of 1,3-cyclohexadiene. iii. The classical Gilman reagent
(dimethyllithium cuprate-lithium iodide) is shown to catalyze the [2+2]cycloaddition of
v
bis(enone) substrates in high yield. Effective partitioning between the 1,4-addition and
cycloaddition manifolds is showcased and discussed.
Finally, a strategy for the enantioselective catalysis of photo-mediated reactions in
solution is described, involving the use of chiral molecular receptors possessing
appendant triplet sensitizing moieties. Energy transfer is selectively directed to bound
substrate as a consequence of the distance dependence of triplet-triplet energy transfer.
This effect, which is equivalent to a binding induced rate enhancement, enables
substoichiometric chirality transfer from the receptor template to the substrate, as
observed in the intramolecular enone-olefin photo[2+2]cycloaddition of a quinolone
substrate.
vi
Table of Contents
List of Schemes xiv
List of Tables xviii
List of Figures xix
Glossary xx
Chapter I. Tandem Vicinal Difunctionalization of α,β-Unsaturated Carbonyl
Compounds: Catalytic Tandem Conjugate Addition-Electrophilic Trapping
Reactions
Part 1. Recent Advances 1
A. Introduction 1
B. Reactions Proceeding via Copper Catalysis 4
i. Addition of Grignard Pronucleophiles: The Kharasch Reaction 4
a. Mechanistic Features 4
b. Application to Lycopodine and Prostanoid Syntheses 5
c. Tandem Conjugate Addition-Claisen Rearrangement 6
d. Tandem Conjugate Addition-Intramolecular Alkylation 7
ii. Addition of Organozirconium Pronucleophiles 7
a. Organozirconium Pronucleophiles via Hydrozirconation of Alkynes 7
b. Zirconocyclopentene Pronucleophiles via Oxidative Cyclization 9
c. Organozirconium Pronucleophiles via Hydrozirconation of Alkenes 10
iii. Addition of Organozinc Pronucleophiles 13
a. Mechanistic Features 13
b. Zinc Homoenolate Pronucleophiles 15
c. Organozincate Pronucleophiles 16
d. Diorganozinc Pronucleophiles 18
vii
C. Reactions Proceeding via Rhodium Catalysis 22
i. Additions of Organoboronic Acid and Organoboronate Pronucleophiles 22
a. Background and Mechanistic Features 22
ii. Tandem Reactions Employing Organoborane Pronucleophiles 24
iii. Tandem Reactions Employing Organotitanium and Organozinc 26
D. Reactions Proceeding via Nickel Catalysis 27
i. Additions of Organozinc Pronucleophiles: Background and Mechanistic Features 27
ii. Tandem Reactions Employing Organozinc Pronucleophiles 28
iii. Tandem Reactions Employing Aryl Iodide Pronucleophiles 29
E. Conclusion 30
Part 2: Graduate Research: Metal-Catalyzed Conjugate Addition-Electrophilic Trapping Reactions 32
A. Background: Conjugate Reduction-Electrophilic Trapping Reactions Developed by the Krische Group 32
i. Cobalt-Catalyzed Reductive Aldol and Reductive Michael Cyclizations 32
ii. Cobalt-Catalyzed Intramolecular [2+2] Cycloaddition 33
iii. Borane-Mediated Reductive Aldol Cyclizations 34
iv. Hydrogenative Rhodium-Catalyzed Aldol Cyclizations 35
B. Metal-Catalyzed Conjugate Addition-Aldol, Blaise, Dieckmann and Darzens Condensation Sequences 39
i. Respective Contributions 39
ii. Rhodium-Catalyzed Conjugate Addition-Aldol Cyclizations 39
a. Mono-Enone Mono-Methyl Ketone Substrates 39
b. Conjugate Addition-Aldol Cyclizations Using Symmetrical Dione Acceptors 41
c. Application Towards the Synthesis of Steroidal Ring Systems 42
d. Parallel Kinetic Resolution 43
iii. Cu-Catalyzed Conjugate Addition-Aldol, Dieckmann 43
and Blaise Cyclizations 43
viii
iv. Higher-Order Tandem Reactions 47
a. Latent Functionality and Chemoselectivity 47
b. Cu-Catalyzed Conjugate Addition-Darzens Condensation 48
c. Cu-Catalyzed Conjugate Addition-Aziridination 49
Part 3. References 50
Part 4. Experimental Section 57
A. Synthetic Procedures 57
i. General 57
ii. Representative procedure for the preparation of I-2.7 – I-2.10 58
iii. Representative procedure for the preparation of I-2.11 – I-2.14 58
iv. Representative procedure for the preparation of I-2.1 – I-2.4 59
v. Procedures for the preparation of I-2.19 – I-2.21 59
vi. Procedures for the synthesis of substrates I-2.22 – I-2.24 59
vii. Procedure for Yandem CA-Dieckmann cyclization of I-2.7 and I-2.9 61
viii.Procedure for Tandem CA-Dieckmann cyclization of I-2.8 and I-2.10 61
ix. Procedure for Tandem CA-Blaise cyclization of substrates I-2.11 – I-2.14 62
x. Procedure for Cu-Catalyzed Aldol Cyclizations 62
xi. Procedure for the Preparation of Product I-2.1e 63
xii. Procedure for the Preparation of Products I-2.21, I-2.22 and I-2.25 63
xiii.Procedure for the Preparation of Product I-2.24 64
xiv.Procedure for the Preparation of Substrate I-2.6 64
xv.General procedure for Rh-Catalyzed Aldol Cylizations 64
B. Spectroscopic and Crystallographic Characterization Data 66
ix
Chapter II. Rhodium-Catalyzed Additions to Conjugated Dienes: Reductive Arylation of 1,3-Cyclohexadiene Part 1. Introduction: Metal-Catalyzed Additions to Conjugated Dienes 119
A. Reactions Involving Electrophilic π-Allyl Complexes 119
i. Electrophilic π-Allyl Complexes Derived from Palladium(II) 119
ii. Electrophilic π-Allyl Complexes Derived from Palladium(0) 120
B. Reactions Involving Neutral π-Allyl Complexes 120
i. Mechanistic Features 120
C. Reactions Involving Nucleophilic π-Allyl Complexes 121
i. Tandem Hydrometallation-Aldehyde Additions 121
ii. Carbocyclizations Involving Oxametallocycle Intermediates 122
iii. Carboxylative Processes 123
iv. Coupling of Dienes and Glyoxals Under Catalytic Hydrogenation Conditions 124
Part 2. Rhodium-Catalyzed Reductive Arylation of 1,3-Cyclohexadiene 125
A. Background and Objective 125
B. Results and Discussion 127
i. Initial Results and Mechanistic Hypothesis 127
ii. Optimization 128
a. Counter-ion Effects 128
b. Additive/Solvent/Reaction Time 129
c. Ligand Effects 130
d. Summary 130
iii. Alternative Subtrates 130
a. α-Terpinene and α-Phellandrene 133
b. 2,3-Dimethyl-1,3-Butadiene 133
c. Acyclic Dienes Incorporating Electrophilic (Ketone) Traps 134
d. 2-Phenyl-1,3-cyclohexadiene 134
e. ortho-Acetyl-phenylboronic acid 134
iv. Revised Mechanistic Hypothesis 135
x
Part 3. Conclusion 137
Part 4. References 138
Part 5. Experimental Section 140
A. Synthetic Procedures and Product Characterization 140
i. General 140
ii. Representative procedure for the Rh-catalyzed reductive
arylation of 1,3- cyclohexadiene 140
iii. 4-Phenylcyclohexene 141
iv. 4-Methoxybiphenyl 141
v. Preparation of substrate II-1.1 141
Chapter III: Recent Developments in Catalytic [2+2]Cycloadditions
Part 1. Anion Radical [2+2]Cycloaddition as a Mechanistic Probe: Stoichiometry
and Concentration-Dependant Partitioning of Electron-Transfer (ET) and
Alkylation Pathways in the Reaction of the Gilman Reagent Me2CuLi•LiI
with bis(Enones) 142
A. Introduction and Background 142
i. Early Observations Attributed to Electron Transfer in Gilman Alkylations 142
ii. Accepted Mechanistic Features of Gilman Alkylation 143
iii. Conjugated- bis(Enones) as Mechanistic Probes 144
B. Results and Discussion 146
i. The Anion Radical Probe Reaction 146
ii. Organocuprate Catalyzed [2+2]Cycloaddition 147
a. Partitioning of Reactivity as a Function of Catalyst Loading 147
b. Partitioning of Reactivity as a Function of Catalyst Concentration 147
c. Exploration of Substrate Scope 149
d. Kinetic Studies 149
iii. Mechanistic Proposal 150
a. Concentration-Dependant Speciation 150
xi
b. Role of Lithium Iodide 151
c. Anion Radical Chain Cycloaddition vs. Oxidative Cyclization- Reductive Elimination 152
d. Concentration-Dependant Speciation 153
C. Conclusion 154
D. References 156
E. Experimental Section 158
i. Synthetic Procedures 158
a. General 158
b. Preparation of bis(enone) substrates III-1.1a – III-1.e 159
c. Preparation of dimethyllithium cuprate-lithium iodide (Me2CuLi-LiI) reagent 159
ii. Experimental Procedures 159
a. Procedure for data reported in Table III-1.1 159
b. Procedure for data reported in Table III-1.2 160
c. Procedure for data reported in Table III-1.3 160
iii. Spectroscopic and Crystallographic Data 160
a. Spectroscopic data for cyclobutane products III-1.3a – III-1.3e 160
b. Spectroscopic data for cyclobutane products III-1.2a – III-1.2e 161
c. Crystallographic data for cyclization product III-1.2e 166
Part 2. Studies on the Enantioselective Catalysis of Photochemically Promoted Transformations: “Sensitizing Receptors” as Chiral Catalysts 167
A. Introduction 167
i. Stoichiometric Chirality Transfer in Photo[2+2]cycloadditions 167
ii. Substoichiometric Chirality Transfer 168
B. Sensitizing Molecular Receptors as Enantioselective Catalysts 168
i. Hydrogen Bond-Mediated Host-Guest Complex 168
ii. Triplet Sensitization as Basis for Binding-Induced Rate Enhancement 169
iii. Synthesis of Sensitizing Receptor R (III-2.8) 170
C. Proposed Catalytic Mechanism: Receptor-Directed Energy Transfer 171
xii
D. Evaluation of Organic Chromophore-Mediated Energy Transfer 172
i. Comparison of Exogenous and Receptor-Based Chromophores 172
ii. Identification of the Quenching Chromophore 173
iii. Incorporation of a Non-Quenching Scaffold 174
a. Kinetic Studies 174
E. Characterization of Host-Guest Binding Interactions 176
F. Enantioselective Catalytic Photocycloaddition 176
G. Second-Generation Receptor Design and Synthesis 178
i. Conformational Analysis 178
ii. Incorporation of a tertiary-Butyl Residue 179
iii. Characterization of Host-Guest Binding Interactions 180
H. Conclusion and Outlook 181
I. References 182
J. Experimental Section 186
i. Synthetic Procedures 186
a. General 186
b. Synthesis and Characterization of Cycloaddition Substrate S and Cycloadduct P 187
Figure III-2.1: X-Ray crystal structure of mandelamide (R,S) III-2.4 171
Figure III-2.2: Rates of Cycloaddition in the Presence of RT versus Benzophenone 175
Figure III-2.3: Stoichiometry Determination 176
Figure II-2.4: 1H NMR Titration Plot 176
Figure III-2.5: Conformational Basis of Enantiodiscrimination 179
Figure III-2.6: Possible Dimerization Equilibrium 181
xix
xx
Glossary
For questions pertaining to acronyms or abbreviations, see: “The Use of
Acronyms in Organic Chemistry,” Daub, G. H.; Daub, G. W.; Walker, S. B. Aldrichimica
Acta, 1984, 17, 13.
For questions pertaining to chemical nomenclature, see: ‘Systematic
Nomenclature of Organic Chemistry: A Directory to Comprehension and Application of
its Basic Principles,” Hellwinkel, D., Springer-Verlag, Berlin, 2001.
Chapter I: Tandem Vicinal Difunctionalization of α,β-Unsaturated Carbonyl Compounds: Catalytic Tandem Conjugate Addition-Electrophilic Trapping Reactions Part 1. Recent Advances
A. Introduction
Tandem carbon-carbon bond formations are attractive methodological targets as
they enable the rapid build-up of molecular complexity. This is due to the efficiency with
which the reactive potentials of reaction parteners are matched. Central to the
development of highly efficient, sequential processes is the notion of latent functionality,
wherein reaction at one site of a molecule confers reactivity upon another site. Among
functional groups amenable to this technique, conjugated enones (and ynones) represent
versatile platforms for the design of tandem processes involving initial conjugate addition
(CA) and subsequent trapping of the nucleophilic adduct. The first reported instance of
this strategy is a Kharasch-type 1,4-addition/alkylation sequence,1 found in Stork’s
synthesis of Lycopodine (Scheme I-1.2).2 In the following years, as the technologies of
metal-mediated and metal-catalyzed conjugate addition matured, so did the attendant
applications in tandem vicinal difunctionalization. Taylor’s detailed 1985 review3 of
organocopper-based CA/trapping cites instances of catalytically-generated metallo-
enolate and stabilized enolate derivatives trapped with classical (alkyl halide,4
carbonyl,5,6,7 acyl,8,9 Michael,10 oxocarbenium,11 and iminium12) electrophiles. Despite
these developments, greater synthetic versatility and higher yields were, at the time,
associated with the use of stoichiometric cuprate reagents, and this general preference
was reflected by the relatively few instances of catalytic processes in Hulce and
1
Chapdelaine’s 1990 Organic Reactions survey.13 A subsequent mini-review14 in 1994
focused entirely on the use of stoichiometric cuprate reagents. Noyori explains that
“although the combination of Grignard reagents and copper catalysts is often the first
choice, lithium diorganocuprates and higher order cuprates have been used more widely
in view of the higher efficiency, selectivity and reproducibility of the conjugate addition
reactions.”14 For many tandem processes, however, it is conceded that “the utility is
greatly enhanced if the 1,4-addition sequence is made catalytic in such a way as to form a
well-defined, single-metal enolate.”15 From the standpoint of economics and waste
management, furthermore, the benefits of “downsizing”16 the role of metals are obvious.
Ultimately, the most compelling incentive to develop catalytic variants may reside in the
prospect of ligand-mediated, substoichiometric chirality transfer and amplification. To
these ends, catalytic conjugate addition methodologies have unquestionably dominated
the developmental field for the past decade, and the Krische group has been among those
to develop and explore an emergent family of catalytic, tandem carbon-carbon bond-
forming reactions.
The goal of the first part of Chapter I is to review developments in catalytic
tandem vicinal difunctionalization over the past ten years, and in this way contextualize
the author’s research. With regard to the topics reviewed, the intended focus is primarily
the diversity of molecular structures acessible via a wide range of catalysis systems, and
secondarily the evolution of these systems in terms of operational convenience. General
mechanistic features and detailed examples of each catalysis system are presented.
Across the range of systems, yields, selectivites, and substrate/functional group
2
tolerances vary greatly, and as such, do not constitute a basis for the evaluation of relative
merit.
Reactions under consideration are those that i) involve the catalytic 1,4-addition
of organometallic nucleophiles to α,β-unsaturated carbonyls, resulting in the formation of
products embodying both a new β carbon-carbon bond and an enolate or derivative, and
ii) parlay this nascent enolate species (and frequently its associated chirality) into the
formation of new α C-R (R=C,O,N,X) bond. Excluded from consideration are related
cascade Mukaiyama-Michael sequences,17,18 represented also by Shibasaki’s asymmetric
syntheses using heterobimetallic catalysis,19 as well as tandem vicinal
difunctionalizations proceeding from the catalyzed addition of organic radicals, recently
exemplified in the work of Sibi.20
Finally, this section has been organized, primarily with respect to the catalytic
metal, and secondarily with respect to the pronucleophilic organometallic reagent. Within
this framework, an effort has been made to provide relevant background and furthermore,
to partition sections on the basis of terminal electrophiles employed in a given catalytic
system. Most often, the presentation corresponds to the chronology of discovery. The
emphasis, however, is on technological continuity and for this reason some minor
anachronisms may appear.
3
B. Reactions Proceeding via Copper Catalysis
i. Addition of Grignard Pronucleophiles: The Kharasch Reaction
a. Mechanistic Features
Conjugate addition reactions catalyzed by copper(I) are the oldest and most
extensively developed subgroup. First reported by Kharasch1 in the context of Grignard
alkylations, the utility of this chemistry derives from the ability of copper to efficiently
transmetallate a large number of (pro)nucleophilic organometallics,21 thereby promoting
selective 1,4-addition, among other things.22 As the mechanism responsible for classical
Gilman alkylations has begun to yield to extensive theoretical and empirical analysis,23 so
the details of related catalytic cycles have become more clear. A Kharasch 1,4-addition
cycle is depicted in Scheme I-1.1.
Scheme I-1.1: Kharasch-Type 1,4-Addition Cycle
RCu(I)
R2Cu(I)MgX2RMgX + Cu(I)X
RMgX
O
Cu(I)R2
MgX
X2Mg
O
O
Cu(III)R2
MgX
MgX2
O
R
MgX
This simplified cycle involves the formation of magnesium diorganocuprate species,
followed by a “trap-and-bite” π-complexation/oxidative addition sequence resulting in a
β-cuprio(III) intermediate. Reductive elimination results in the β-alkyl magnesium
enolate product and liberates the catalytic alkylcopper(I) residue. In contrast, the
exhaustive mechanism is undoubtedly more complex. Nonlinear effects observed in
4
conjunction with the use of chiral ligands implicate the involvement of copper(I)
aggregates.24
b. Application to Lycopodine and Prostanoid Syntheses
The evolution of the tandem electrophilic trapping implementation began in 1968
(Scheme I-1.2) with Stork’s lycopodine synthesis,2 and to a large extent developed in the
context of prostanoid-related “three-component couplings.”25
Scheme I-1.2: Stork’s Synthesis of Lycopodine
O
H3C
OMgX
H3C
OCH3 O
H3C
OCH3
NH
CH3
OH
N O
H3CH
H
Scheme I-1.3: Prostanoid Synthesis: Tandem 1,4-Addition-Aldol Condensation
7
O
TBSO
1. TBSO(CH2)7MgBr CuI (10 mol %)
Et2O
2. Octanal
O
TBSOOTBS
OH
-H2OCH3
4
7
O
TBSOOTBS
CH3
4
34% Whereas the direct interception of magnesium enolate intermediates is the most
concise approach (Schemes I-1.3),26 it may be advantageous in certain instances to
proceed via a one-pot sequence involving the corresponding silyl enol ether or enol
acetate (Scheme I-1.4).27
5
Scheme I-1.4: Prostanoid Sythesis: Tandem 1,4-Addition-Aldol Condensation via Enolate Derivative
O
O
O
1. n-OctMgBr CuBr-Me2S (0.05 mol%) THF
2. Ac2O
OAc
O
OCH3
7
O
O
OCH3
7
1. MeLi 2. ZnCl2
3. RCHO -H2O
CO2Me
88% 83%
A strategy entailing tandem conjugate addition-Peterson olefination was explored
toward the synthesis of a PG-A2 analogue (Scheme I-1.5),28 currently in pre-clinical trials
as an anticancer agent.29
Scheme I-1.5: Tandem Conjugate Addition-Peterson Olefination O
Me3SiH
H
1. RMgBr CuI (10 mol%) Et2O
2. i PrCHO
OH
HR
R = Me; 86% E:Z - 75:25
R = iPr; 81% E:Z - 58:42R = Vinyl; 94% E:Z - 93:7
2. PhCHO
OH
HR
H3C
CH3
R = Me; 83% E:Z - 30:70R = Vinyl; 88% E:Z - 52:48
O
MeO2C
PG-A2 Analogue
1. RMgBr CuI (10 mol%) Et2O
For a given substrate, considerable differences (in some cases inversions) in olefin
geometry selectivity were observed when comparing Kharasch (catalytic) and Gilman
(stoichiometric) additions of identical alkyl units.
c. Tandem Conjugate Addition-Claisen Rearrangement
Though representing a quantum technological leap in many regards, copper-
catalyzed Grignard additions are liable to suffer from competitive, uncatalyzed 1,2-
addition and may require the presence of stoichiometric additives such as HMPA or
trialkyl chlorosilanes to proceed in high yield. In the latter case, the use of silylating
agents can open the door to new reactivity manifolds. In a unique tandem process, silyl
6
ketene acetals generated in this manner are trapped via [3,3]-sigmatropic rearrangement
(Scheme I-1.6).30
Scheme I-1.6: Tandem Conjugate Addition-Claisen Rearrangement
H3C
O
O
CH3
MeMgBr (150 mol%)TMS-Cl (300 mol%) H3C
OTMS
O
CH3
CH3
H3C
O
OH
CH3
CH3
1. 50 °C
87%
O
N O
NCu
iPr
iPr
CuL2 =
2. H+CuL2 (1 mol%)THF-Et2O
d. Tandem Conjugate Addition-Intramolecular Alkylation
Intramolecular alkylation has been used to access the triquinane subergorgic acid
skeleton (Scheme I-1.7).31 For less reactive halide leaving groups, the use of HMPA or
DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) was found to be necessary.
Scheme I-1.7 Tandem Conjugate Addition-Intramolecular Alkylation
O
OCH3
CH3
O
HO
O CH3
CH3O
H
Cl
MgBr
CuBr-Me2S (14 mol%)then DMPU (200 mol%)
81%
THF-Et2O
ii. Addition of Organozirconium Reagents
a. Organozirconium Pronucleophiles via Hydrozirconation of Alkynes
The combination of facile hydrozirconation with Cp2Zr(H)Cl32 and
transmetallation from zirconium to copper was reported by Schwartz to provide an
efficient and direct method for the catalytic β-vinylation of enones, starting with terminal
alkynes as pronucleophiles.33 An elegant catalytic implementation by Lipshutz34
7
employed the higher-order cuprate Me2Cu(CN)Li2, and involved initial transmetallation
between the catalyst and a methyl vinylzirconocene, followed by 1,4-addition and a final
transmetallative ligand exchange between the intermediate copper(I) enolate and added
Me3ZnLi (Scheme I-1.8). Notably, at -78 °C, the lithium trimethylzincate does not
compete with the vinyl cuprate as a nucleophile, but is subordinated to the role of a soft
MeLi surrogate. Derivative tandem sequences afforded good yields of structurally
Table I-2.3: Tandem 1,4-Addition Dieckmann, Blaise and Aldol Cyclizations
Substrate Product
87%
Yield (%)
93%
O
PhO OCH3
O
Ph
O
OCH3
O
R'
O
R'
Et
90%
O
H3CO OCH3
O
H3C
R
O
Et
O
O
O
Ph
O
Ph
O
Ph
O
Ph
84%91%87%
Et
O
H3C
O
H3C
O
H3C
O
H3C
Et
R
X
Et
NH2
NH2
NH2
N
N
N
N
X=NH2X=OH
Substrate Product
98%
Yield (%)
96%
99%
96%
(d.r.)*
(2.2:1)
(2:1)
(10:1)**
(>95:1)(>95:1)(>95:1)
(>95:1)
(>95:1)
84% (8:1)
94% (>95:1)
O
PhO CH3
O
Ph
O
CH3
O
R'
O
R'
83%81%91%
Et
O
H3CO CH3
O
H3C
OH3C
OHOPh
Et
R'
OO
OH3C
O
OH3C
OPh
R'
OO
OH3C
OH
H3C O
Et
R'O
OH
H3C O
R'O
Et
OH
H3C O
OPhO
OH3C
OPh
99%
78% (3:1)
R
OH
R
CH3
OHCH3
OHCH3
R=MeR=EtR=nBu
Et
* Reflects ratio of syn-aldol to anti-aldol product; ** Reflects ratio of cis-fused to trans-fused hydrindane
R'=PhR'=Me
R'=PhR'=Me
Procedure: To solution of substrate (0.5 mmol), CuOTf2 (0.0125 mmol) and P(OEt)3 (0.025 mmol) in DCM (0.5 ml) wasadded R2Zn (0.75 mmol). Reaction was stirred at -20 °C for 24h.
Entry Entry
8
9
10
11
12
13
14
I-2.8 I-2.8a
I-2.9 R'=Ph I-2.9aI-2.10 R'=Me I-2.10a
I-2.11 R=Me R=Et R=nBut
I-2.11aI-2.11bI-2.11c
93%88%88%
I-2.7 R=Me I-2.7a R=Et I-2.7b R=nBut I-2.7c
73%I-2.13 I-2.13a
98%I-2.12 I-2.12a
85%I-2.14 I-2.14a
I-2.1 I-2.1bI-2.1cI-2.1d
77% (3:1)I-2.4 I-2.4b
I-2.2I-2.3
I-2.2cI-2.3c
R'=PhR'=Me
I-2.15I-2.16
I-2.15aI-2.16a
I-2.17 I-2.17a
I-2.18 I-2.18aI-2.19 I-2.19a
I-2.20 I-2.20a
1
2
3
4
5
6
7
46
Finally, under copper catalysis, isopropyl Grignard reagents were found to add
selectively to enones with appendant carbonyl functionality. Trapping of the intermediate
magnesium enolate leads to products representing aldol cyclizations in high yield and
diastereoselectivity (Scheme I-2.14).109
Scheme I-2.14: Tandem Kharasch Addition- Aldol Cyclization
O
PhO CH3
O
Ph
76% (95:1)
i Pr
OHCH3CuCl (3 mol%)
Me3SiCl (120 mol%)i PrMgCl (104 mol%)THF
I-2.1 I-2.1e
iv. Higher-Order Tandem Reactions
a. Latent Functionality and Chemoselectivity
The tandem vicinal difunctionalization of activated carbon-carbon double bonds
is possible in virtue of their primary electrophilicity and latent, or secondary
nucleophilicity. The incorporation of a secondary C=X (X = C,N,O) electrophile (itself
inert to the action of the primary organometallic nucleophile) likewise leads directly to
the formation of tertiary nucleophile, and so on. Strategies for the programmed formation
of multiple chemical bonds and stereogenic centers, therefore, are feasible to the extent
that the sequenced unmasking of latent functionality occurs chemoselectively. From this
point of view, the evolution of catalytic conjugate addition technology can be demarcated
in terms of the efficiency with which it employs its own reactive intermediates in situ.
47
b. Cu-Catalyzed Conjugate Addition-Darzens Condensation
An approach to the catalytic conjugate addition-Darzens condensation that
embodies this notion of efficiency has been developed by the author.110 By endowing the
α-carbon of an olefin (cyclohexenone) with both latent nucleophilicity and latent
electrophilicity, the reactive potential of the substrate complements the reactive potential
of an aldehyde or ketone partner (Figure I-2.3).
Figure I-2.3: Chemoselectivity and Latent Functionality
O
Electrophile
O
R
PrimaryElectrophile
Secondary/Terminal Electrophile
H
O O
R
OH
R"+R'
O
R"
Latent Nucleophile
Latent Nucleophile
Secondary/TerminalNucleophile
OX
Latent Nucleophile
PrimaryElectrophile
Terminal Electrophle
R' R"
X
1. M R
2. H
1. M R
2. H
M R
SecondaryElectrophile
SecondaryNucleophile
+
O
R
O R'
R"
Conjugate Addition Three Component Coupling
Higher-Order Tandem Processes
OR
O
R
N R'
R"
Z
α-Tosyloxycyclohexenone, an air/moisture stable, crystalline solid is obtained in good
yield from the corresponding vicinal dione. In the presence of diethylzinc, copper-
catalyzed conjugate addition precedes inter- or intramolecular trapping with an aldehyde
or ketone and Darzens-type epoxidation (Scheme I-2.15). Isolated yields are good;
diastereoselectivity is modest, but somewhat erratic at this stage of development.
48
Notably, under the present conditions unactivated aromatic aldehydes such as
benzaldehyde fail to react. The intramolecular process is viable and offers the advantages
of being operationally more simple and more diastereoselective. In the latter case, the
absence of HMPA results in the formation chlorohydrin only – no epoxide is obtained.
1 Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308. 2 Stork, G. Pure Appl. Chem. 1968, 17, 383. 3 Taylor, R. J. K. Synthesis 1985, 364. 4 (a) Naf, F.; Decorzant, R. Helv. Chim. Acta. 1974, 57, 1317; (b) Bornack, W. K.;
Bhagwat, S. S.; Ponton, J.; Helquist, P. J. Am. Chem. Soc. 1981, 103, 4647; (c) Ito, Y.;
Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1982, 104, 7609. 5 Tandem CA-intermolecular aldehyde trapping: a. Stork, G.; d’Angelo, J. J. Am. Chem.
Soc. 1974, 96, 7114; (b) Johnson, C. R.; Meanwell, N. A. J. Am. Chem. Soc. 1981, 103,
7667; (c) Piers, E.; Lau, C. K. Synth. Commun. 1977, 7, 495; (d) See also Ref. 4a. 6 Tandem CA-intramolecular ketone trapping: (a) Alexakis, A.; Chapdelaine, M. J.;
Posner, G. H.; Runquist, A. W. Tetrahedron Lett. 1978, 19, 4205. 7 For Ni-catalyzed Conjugate Addition of vinylzirconocenes followed by carbonyl
addition: Schwartz, J; Loots, M. J. J. Am. Chem. Soc. 1980, 102, 1333. 8 Tandem CA-intermolecular enolate acylation: (a) Beck, A. K.; Hoekstra, M. S.;
Seebach, D. Tetrahedron Lett. 1977, 18, 1187; (b) Marshall, J. A.; Jochstetler, A. R. J.
Am. Chem. Soc. 1969, 91, 648; (c) Danishefsky, S.; Kahn, M.; Sivestri, M.
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Trans. 1, 1981, 1516; (e) Salomon, R. G.; Salomon, M. F. J. Org. Chem. 1975, 40,
1488. 9 Tandem CA-intramolecular enolate acylation (Dieckmann): Pearson, A.J. Tetrahedron
Lett. 1980, 21, 3929. 10 Kretchmer, R.A.; Mihelich, E. D.; Waldron, J. J. J. Org. Chem., 1972, 37, 4483; and
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51
14Suzuki, M.; Noyori, R. “Conjugate Addition-Enolate Trapping Reactions” in
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52
31 Dragojlovic, V. Molecules, 2000, 5, 674. 32 Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 679. 33 Yoshifuji, M.; Loots, M. J.; Schwartz, J. Tetrahedron Lett. 1977, 18, 1303. 34 (a) Lipshutz, B. H.; Wood, M. R. J. Am. Chem. Soc. 1993, 115, 12625; (b) Lipshutz, B.
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Kerk, G. J. M. J. Organomet. Chem. 1978, 144, 255. 46 House, H. O. J. Org. Chem. 1966, 31, 3128. 47 Yamamoto, Y. Angew. Chem. Int. Ed. 1986, 25, 947, and references therein. 48 Bergdahl, M.; Nilsson, M.; Olsson, T. J. Organomet. Chem. 1990, 391, C19-C22. 49 Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc., 1987,
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53
53 (a) Knochel, P.; Yeh, M. C. P.; Berk, S.; Talbert, J. J. Org. Chem. 1988, 53, 2390; (b)
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Int. Ed. 1997, 36, 2620. 60 Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123,
5841. 61 Pineschi, M.; Del Moro, F.; Gini, F.; Minnaard, A. J.; Feringa, B. L. Chem. Commun.
2004, 1244. 62 Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358. 63 Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835. 64 Alexakis, A.; March, S. J. Org. Chem. 2002, 67, 8753. 65 (a) Mizutani, H.; Degrado, S.; Hoveyda, A. J. Am. Chem. Soc. 2001, 124, 779; (b)
Degrado, S.; Mizutani, H.; Hoveyda, A. J. Am. Chem. Soc. 2001, 124, 755. 66 Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229. 67 Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579. 68 Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc., 2001, 124,
5052. 69 Mori, A.; Danda, Y.; Fujii, T.; Hirabayashi, K.; Osakada, K. J. Am. Chem. Soc. 2001,
123, 10774. 70 Zou, G.; Wang, Z.; Zhu, J.; Tang, J. Chem. Commun. 2003, 19, 2438. 71 Yoshida, K., Ogasawara, M., Hayashi, T. J. Am. Chem. Soc. 2002, 124, 10984. 72 Yoshida, K., Ogasawara, M., Hayashi, T. J. Org. Chem. 2003, 68, 1901.
54
73 Hayashi, T., Tokunaga, N., Yoshida, K., Han, J-H. J. Am. Chem. Soc. 2002, 124,
12102. 74 Shintani, R., Tokunaga, N., Doi, H., Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240. 75 Diaz, S., Cuesta, J., Gonzalez, A., Bonjoch, J. J. Org. Chem. 2003, 68, 7400. 76 Savchenko, A.V., Montgomery, J. J. Org. Chem. 1996, 61, 1562. 77 Montgomery, J., Oblinger, E., Savchenko, A.V. J. Am. Chem. Soc. 1997, 119, 4911. 78 Subburaj, K., Montgomery, J. J. Am. Chem. Soc. 2003, 125, 11210. 79 (a) Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc. 1961, 83, 2965. (b) Stork,
G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. J. Am. Chem. Soc. 1965, 87, 275. 80 For catalytic reductive aldol processes, see: (a) Revis, A.; Hilty, T. K. Tetrahedron
Lett. 1987, 28, 4809. (b) Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron Lett. 1990,
31, 5331. (c) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 2005. (d) Kiyooka, S.;
Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39, 5237. (e) Ooi, T.; Doda, K.; Sakai,
D.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2133. (f) Taylor, S. J.; Morken, J. P. J.
Am. Chem. Soc. 1999, 121, 12202. (g) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J.
Am. Chem. Soc. 2000, 122, 4528. (h) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.;
Morken, J. P. Org. Lett. 2001, 3, 1829. 81 (a) Baik, T-G.; Luis, A. L.; Wang, L-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123,
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448. 82 For examples of Co-cat. acrylate hydrodimerization see: (a) Kanai, H.; Okada, M.
Chem. Lett. 1975, 167. (b) Kanai, H.; Ishii, K. Bull. Chem. Soc. Jpn. 1981, 54, 1015. 83 For examples of cobalt catalyzed enone hydrodimerization see: Kanai, H. J. Mol. Cat.
1981, 12, 231. 84 Baik, T-G.; Luis, A. L.; Wang, L-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 6716. 85 Roh, Y.; Jang, H-Y.; Lynch, V.; Krische, M. J.; Bauld, N. L. Org. Lett., 2002, 4, 611. 86 Huddleston, R. H.; Cauble, D. F.; Krische, M. J. J. Org. Chem. 2003, 68, 11.
55
87 For the first example of catalytic homogeneous hydrogenation, see: M. Calvin,
Homogeneous Catalytic Hydrogenation. Trans. Faraday Soc. 1938, 34, 1181-1191. 88 For early examples of catalytic heterogeneous hydrogenation, see: (a) Loew, O.
Darstellung Eines Sehr Wirksamen Platinmohrs. Ber. 1890, 23, 289-290. (b) Sabatier,
P. Senderens, J.-B.. C. R. Acad. Sci. Paris 1897, 124, 1358-1361. 89 For the first practical heterogeneous catalyst system for hydrogenation at ambient
temperature, see: Voorhees, V.; Adams, R. J. Am. Chem. Soc. 1922, 44, 1397-1405. 90 For recent reviews on alkene hydroformylation, see: (a) Breit, B. Acc. Chem. Res.
2003, 36, 264-275. (b) Breit, B.; Seiche, W. Synthesis 2001, 1-36. 91 For reviews on the Fischer-Tropsch reaction, see: (a) Herrmann, W. A. Angew. Chem.,
474. 92 For a Recent Review, see: Jang, H-Y.; Krische, M. J. Acc. Chem. Res. 2004, 9, 653. 93 Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 15156-
15157. 94 Arnett, E. M.; Fisher, F. J.; Nichols, M. A.; Ribeiro, A. A. J. Am. Chem. Soc. 1989,
111, 748-749. 95 Lack of reactivity of tris(dialkylamino)sulfonium enolates: (a) Noyori, R.; Sakata, J.;
Nishizawa, M. J. Am. Chem. Soc. 1980, 102, 1223-1225. (b) Noyori, R.; Nishida, I.;
Sakata, J. J. Am. Chem. Soc. 1981, 103, 2106-2108. (c) Noyori, R.; Nishida, I.;
Sakata, J. Synthesis, Structure, and Reactions. J. Am. Chem. Soc. 1983, 105, 1598-
1608. 96 Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143-1146. 97 (a) Heathcock, C. H. in Comprehensive Organic Synthesis: Additions to C-X Bonds
Part 2.; Trost, B. M.; Fleming, I.; Heathcock, C. H., Ed. Pergamon Press: New York.,
p. 181-238. (b) Alcaide, B.; Almendros, P. The Direct Catalytic Asymmetric Cross-
98 Marriner, G. A.; Garner, S. A.; Jang, H.-Y.; Krische, M. J. J. Org. Chem. 2004, 69,
1380. 99 Yachi, K.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 1999, 121, 9465-9466. 100 Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691. 101 Monohydride formation by deprotonation of a dihydride intermediate is known for
cationic Rh-complexes: (a) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98,
2134-2143. (b) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 2143-2147.
(c) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 4450-4455. 102 Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110. 103 Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. 104 Bocknack, B. M.; Wang, L. -C.; Krische, M. J. Proc. Nat. Acad. Sci. 2004, 101, 5421. 105 Uson, R.; Oro, L. A. Inorg. Synth. 1985, 23, 126. 106 Aronson, J.K “An Account of the Foxglove and Its Medicinal Uses: 1785-1985”
Oxford Univ. Press: London, 1985. 107 a) Dehli H.R., Gotor, V. Chem. Soc. Rev. 2002, 31, 365; b) Martin, S.F., Spaller, M.
R., Liras, S., Hartmann, B. J. Am. Chem. Soc. 1994, 116, 4493; c) Vedejs, E., Chen,
X. J. J. Am. Chem. Soc. 1997, 119, 2584; d) Cardona, F., Valenza, S., Goti, A.,
Brandi, A. Eur. J. Org. Chem. 1999, 1319; e) Pederson, T. M., Jensen, J. F., Humble,
R. E., Rein, T., Tanner, D., Bodmann, K., Reiser, O. Org. Lett. 2000, 2, 535; f)
Bertozzi, F., Crotti, P., Macchia, F., Pineschi, M., Feringa, B. Angew. Chem. Int. Ed.
2001, 40, 930; g) Vedejs, E., Rozners, E. J. Am. Chem. Soc. 2001, 123, 2428; h) Al-
Sehemi, A. G., Atkinson, R. S., Meades, C. K. Chem. Commun. 2001, 2684; i) Dehli,
J. R., Gotor, V. J. Org. Chem. 2002, 67, 1716; j) Tanaka, K., Fu, G. C. J. Am. Chem.
Soc. 2003, 125, 8078. 108 Feringa, B. L. Acc. Chem. Res. 2000, 33, 346, and references therein. 109 Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4528. 110 Unpublished results
Part 4. Experimental A. Synthetic Procedures
i. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator.
Analytical thin-layer chromatography (TLC) was carried out using 0.2 mm
commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254). Preparative column
chromatography employing silica gel was performed according to the method of Still.1
Melting points were determined on a Thomas-Hoover melting point apparatus in sealed
capillaries and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1420
spectrometer. High-resolution mass spectra (HRMS) were obtained on a Karatos MS9
and are reported as m/e (relative intensity). Accurate masses are reported for the
molecular ion (M+1).
Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra
were recorded with a Varian Gemini (300 MHz) spectrometer or a Mercury (400 MHz)
spectrometer. Chemical Shifts are reported in delta (δ) units, parts per million (ppm)
downfield from trimethylsilane. Coupling constants are reported in Hertz (Hz). Carbon-
13 nuclear magnetic resonance (13C NMR) spectra were recorded with a Varian Gemini
300 (75 MHz) spectrometer and a Mercury 400 (100 MHz) spectrometer. Chemical shifts
are reported in delta (δ ) units, parts per million (ppm) relative to the center of the triplet
57
at 77.0 ppm for deuteriochloroform. 13C NMR spectra were routinely run with broad
brand decoupling.
ii. Representative procedure for the preparation of I-2.7 – I-2.10. Cyclization substrates were prepared via Wittig olefination of the corresponding
aldehydes (Fleming, I.; Kilburn, J.D. J. Chem. Soc. Perkins Trans. 1, 1998, 17, 2663.) in
refluxing chloroform. Reaction mixtures were concentrated onto silica gel and purified by
chromatography, eluting over silica gel with ethyl acetate/hexanes to afford product in
greater than 80% yield. Characterization data for substrate I-2.10 was consistent with that
reported in the literature. See: Durman, J.; Elliot, J.; McElroy, A.B.; Warren, S. J. Chem.
Soc., Perkin Trans. 1, 1985, 1237.
iii. Representative procedure for the preparation of I-2.11 – I-2.14. Cyclization substrates were prepared via tandem ozonolytic cleavage – Wittig
olefination of the corresponding unsaturated nitriles. Accordingly, ozone was bubbled
through a solution of 4-pentenonitrile (1 g, 12.0 mmol, 100 mol%) in dichloromethane
(60 ml) at –78 ºC. Upon consumption of 4-pentenonitrile, nitrogen was bubbled though
the mixture followed by the addition of triphenylphosphine (3.15 g, 12.0 mmol, 100
mol%). The mixture was gradually warmed to room temperature and allowed to stir for
1h. The Wittig reagent, 1-phenyl-2-(triphenyl-λ5-phosphanylidene)-ethanone (2.64 g,
6.93 mmol, 200 mol%), was added and the reaction mixture was allowed to stir under
gentle reflux for 16h. The solvent was removed in vacuo and the crude product was
58
subjected to chromatography over silica gel with 10% ethyl acetate in hexanes to give I-
2.5 as a dark red solid (1.58 g, 71%).
iv. Representative procedure for the preparation of I-2.1 – I-2.4.
Cyclization substrates were prepared via tandem ozonolytic cleavage – Wittig
olefination of the corresponding unsaturated methyl ketones as described in the literature.
Spectroscopic characterization data was found to be consistent with reported values. See:
Huddlesston, R. R.; Cauble, D. F.; Krische, M. J. J. Org. Chem. 2003, 68, 11.
v. Procedures for the preparation of I-2.15 – I-2.17.
(Mono)enone-tethered 1,3-cyclopentandione substrates I-2.15 – I-2.17 were
prepared according to literature procedures. Spectroscopic characterization was found to
be consistent with reported values. See: Huddleston, R. R.; Jang,H.-Y.; Krische, M. J. J.
Am. Chem. Soc. 2003, 125, 11488.
vi. Procedures for the synthesis of substrates I-2.18 – I-2.20.
59
2-Methyl-2-(4-oxo-4-phenyl-but-2-enyl)-indan-1,3-dione (I-2.18): Ozone was
bubbled through a solution of 2-allyl-2-methyl-1,3-indandione (Bloch, R.; Orvane, P.
Chapter II. Rhodium-Catalyzed Additions to Conjugated Dienes: Reductive Arylation of 1,3-Cyclohexadiene Part 1. Introduction: Metal-Catalyzed Additions to Conjugated Dienes
Conjugated-dienes are reactive substrates for metal-catalyzed/mediated formation
of carbon-metal, carbon-hydrogen or carbon-carbon bonds. Known reactions occur via
several distinct mechanisms, but most involve the intermediacy of a (π-allyl)metal
complex. For this reason, regiochemical issues figure prominently.1 The nature of the
coupling partners, furthermore, is determined by the reactivity of the π-allyl intermediate.
An analysis on the basis of reactivity involves partitioning reaction types into three broad
categories – those in which the π-allyl is nucleophilic, electrophilic, or neutral. The latter
two groups encompass a huge number of reactions – too many to enumerate here. The
subject has been extensively reviewed elsewhere,2 so only a cursory outline follows.
A. Reactions Involving Electrophilic π-Allyl Complexes
The most common representatives of the electrophilic family involve (π-
allyl)palladium intermediates. Generally speaking, this family of reactions can be
partitioned into i) those in which the active catalyst has an oxidation state of (II), and ii)
those for which the active catalyst is zerovalent.
i. Electrophilic π-Allyl Complexes Derived from Palladium(II)
In the first class, a palladium(II) complex first coordinates, then oxidizes the
diene. Reoxidation of the catalyst to its +2 state by a stoichiometric additive completes
the cycle. Examples of this category include diacyloxylations and dialkoxylations
119
(Scheme II-1.1).2b In the case of mono-ene substrates, this manifold constitutes the basis
of the Wacker process.3
Scheme II-1.1: Electrophilic π-Allyl Complexes Derived from Palladium(II)
R = Alkyl, Carbonyl
ROPdII X
RO ORPdX2, ROH ROH RO
RO
ii. Electrophilic π-Allyl Complexes Derived from Palladium(0)
The other type of palladium-catalyzed coupling involves initial oxidative addition
of Pd(0) into an RX bond. Insertion of the diene leads to formation of a (π-
allyl)palladium intermediate, which reacts with a nucleophile to form the product and
regenerate the zerovalent palladium catalyst. Reactions of this category involve three-
component couplings of aryl and vinyl halides, and nitrogen, oxygen, or stabilized carbon
nucleophiles (Scheme II-1.2).2b
SchemeII-1.2: Electrophilic π-Allyl Complexes Derived from Palladium(0)
R = Aryl, Vinyl; Nuc = NR2, OR, CZ2
RPdII X
NucR Nuc
R-PdII-XR
Nuc
B. Reactions Involving Neutral π-Allyl Complexes
i. Mechanistic Features
A second category of reactions involves (π-allyl)metal species that behave as
neither nucleophiles or electrophiles. In this regard, they can be considered neutral,
although certainly not unreactive. Reactions involve formation of a catalytically active
hydrido-metal species (Scheme II-1.3) by oxidative addition of the metal pre-catalyst to
an appropriate metal-hydrogen or carbon-hydrogen σ-bond. Hydrometallation yields a (π-
120
allyl)metal complex; finally, reductive elimination occurs to afford the mono-unsaturated
coupling product. Most examples of this category involve palladium-catalysis:
hydrosilation, hydrostannation, hydroboration, and additions across active carbon-
hydrogen bonds.2b
Scheme II-1.3: Addition to Conjugated Dienes via Neutral (π-Allyl)Palladium Complexes PdII HNuc
H NucH
PdII-NucH
Nuc
Recently, complementary rhodium-catalyzed procedures, such as Mori’s
intramolecular hydroacylation of 4,6-dienals, have been reported.4 In this work, seven-
membered unsaturated alkenones are generated along with small amounts of isomeric
cyclopentanones via a common (π-allyl)rhodium intermediate (Scheme II-1.4).
Scheme II-1.4: Intramolecular Hydroacylation of Conjugated Dienes
OR O
R[Rh(dppe)]ClO4
OR
R
O
Rh
R
O
H
R = PhCH2CH2-
10 mol %65 °C, 18h
62% 13% 6%
C. Reactions Involving Nucleophilic π-Allyl Complexes
i. Tandem Hydrometallation-Aldehyde Additions
A final category of diene functionalizations proceeds via nucleophilic (π-
allyl)metal species. This subset is currently under rapid development and, as it constitutes
the context of current Krische group research, will be examined in greater detail. Mori’s
nickel-catalyzed reductive cyclizations and allylations exemplify this reaction manifold,5
in which conjugated dienes undergo regioselective6 hydrometallation followed by
electrophilic trapping with appendant (Scheme II-1.5, Eqn. 1) or exogenous (Scheme II-
121
1.5, Eqn. 2) aldehydes or ketones. In these reactions, the catalytically active species is
nickel(II).
Scheme II-1.5: Nickel-Catalyzed Reductive Couplings of Conjugated-Dienes and Carbonyls
O OM
NiII HM
ONi
Mcat.
R
Ni(COD)2 (20 mol%)PPh3 (40 mol%)
Et3SiH (500 mol%)R
OSiEt3
Ph
Eqn. 1
Eqn. 2RNi
Et3Si
M-H
PhCHO (100 mol%)R = MOM-CH2-Ph- 84%
ii. Carbocyclizations Involving Oxametallocycle Intermediates
Related studies from the same group focus on intramolecular, nickel(0)-catalyzed
oxidative cyclizations, wherein turnover derives from a β-elimination/O-H reductive
elimination sequence (Scheme II-1.6).7
Scheme II-1.6: Nickel-Catalyzed Oxidative Cyclizations of Conjugated Diene-Tethered Aldehydes
Ocat. Ni(COD)2
PPh3
ONi OH OH
O O O O O O O O
91% (1:3.8)
2.5h, 50 °C
Ketone/aldehyde allylation and homoallylation chemistry developed by Tamaru8
(Scheme II-1.7 Eqn. 1) and extended by Loh9 to incorporate cyclohexadiene (Scheme II-
1.7 Eqn. 2) involves formation of a hydrido(π-allyl)nickel(II) species that reductively
eliminates to afford either of two unsaturated alcohol isomers.
122
Scheme II-1.7: Nickel-Catalyzed Bimolecular Oxidative Cyclizations of 1,3-Dienes and Aldehydes
Ni(acac)
OH
Ph
PhCHO
O
Ph
NiOH
Ph
+OMEtn
Ph
NiH
+
Ni(acac)2 (10 mol%)
ZnEt2
EtZnO R
NiII
HO R
+ H
Eqn. 1
Eqn. 2
(2.5 mol%)RT
77%
13%
Et3B
(240 mol%)
PhCHO
(400 mol%)72% syn28% anti62%
iii. Carboxylative Processes
Bimolecular oxidative coupling and transmetallative carbon-carbon bond-forming
manifolds are paired in an impressive tandem manipulation reported by Mori.10 In her
procedure, stoichiometric zerovalent nickel promotes an oxidative cyclization involving a
diene substrate and carbon dioxide. The resulting (π-allyl)nickel(II)carboxylate
undergoes transmetallation with an diarylzinc(II) species followed in one instance by
reductive elimination to afford, regio- and stereoselectively, the syn 1,4-addition product.
Alternatively, if the diarylzinc(II) reagent is replaced with dimethylzinc, products of anti
1 A 200 500 - 0.2 M D 95 2 25 2 A 200 0 - 0.2 M D 95 2 0 3 A 200 250 - 0.2 M D 95 2 24 4 A 200 2800 - 0.4 M D 95 2 12 5 A 200 500 - 0.2 M Tol 95 2 0 6 A 200 500 - 0.2 M DCE 95 2 0 7 A 200 500 10 KOH 0.2 M D 95 2 25 8 A 200 500 10 KOH 0.2 MTol 95 2 0 9 B 200 500 - 0.2 M D 95 2 27
10 B 200 2800 - 0.2 M D 95 2 16 11 B 200 500 - 0.2 M D 95 14 28 12 B 200 500 - 0.2 M D 65 13 22 13 B 200 500 - 0.2 M D 95 2 22 14 B 3 x 100 500 - 0.2 M D 95 16 15 15 C 200 2800 - 0.2 M D 95 2 11 16 C 200 500 - 0.2 M D 65 2 27 17 C 200 500 1000 TEA 0.2 M D 65 2 0 18 C 200 500 10 KHCO3 0.2 M D 95 2 12 19 C 200 500 2000 MEK 0.2 M D 95 2 11 20 C 200 500 100 KOH 0.2 M D 95 2 11 21 D 200 500 - 0.2 M D 95 2 0 22 E 200 500 - 0.2 M D 95 2 0 23 E 200 Ph 0 500 MeOH 0.2 M DCE 95 2 0 24 F 200 Ph 500 - 0.2 M D 95 2 0 25 G 200 Ph 500 - 0.2 M D 65 2 0 26 C 200 Ph 0 500 TFE 0.2 M D 95 4 trace
(a) For detailed procedure see experimental section; (b) Unless otherwise indicated all reactions employ racemic BINAP (7.5 mol%); (c) Catalysts (5 mol% w.r.t. Rh): A = [Rh(COD)Cl]2; B = [Rh(COD)OMe]2; C = [Rh(COD)OH]2; D = [Rh(C2H4)Cl]2; E = Rh(COD)2OTf; F = Rh(COD)(IMes)OTf; G = [Rh(CO)2Cl]2; (d) Solvents: D = 1,4-dioxane; Tol = toluene; DCE = 1,2-dichloroethane
27 C 15 PPh3 200 - 65 2 0 28 C 15 PBu3 200 - 65 2 0 29 C 7.5 dppf 200 - 65 2 0 30 C 7.5 dppPh 200 - 65 16 14 31 B 7.5 dppb 200 - 95 14 trace 32 C 7.5 dppe 200 - 65 2 trace 33 C 7.5 dppp 200 - 65 2 13 34 C 7.5 (R)-Phanephos 200 - 65 2 trace 35 C 7.5 (R)-Quinap 200 - 65 2 trace 36 C 7.5 (S,S)-NT 200 - 65 2 trace 37 C 5 IMes 150 5 Cs2C03 65 2 trace 38g C 5 IMes 150 5 Cs2C03 65 2 0 39 A 5 IMes 200 5 KOtBu 95 4 trace 40 C 7.5 Biphep 200 - 65 16 23 41 C 7.5 Biphep 200 - 65 2 32 42 C 7.5 Biphep 200 - 95 2 8 43h C 7.5 Biphep 200 - 65 2 trace 44e C 7.5 Biphep 100 - 65 2 31 45e C 7.5 Biphep 100 - 65 2 29 46 C 7.5 Biphep 200 100 KHCO3 95 2 0 47 A 7.5 Biphep 200 4 Ag2CO3 95 2 0 48 A 7.5 Biphep 200 7.5 AgBF4 95 2 0 49g C 7.5 Biphep 200 500 PhOH 65 2 0 50g C 7.5 Biphep 200 1000 MeOH 65 2 14 51g C 7.5 Biphep 200 o-AcPh - 65 12 0
(e) 1M dioxane was used instead of 0.2M dioxane; (f) Ligands: dppf = 1,1’-bis(diphenylphosphino)ferrocene; dppPh = 1,2-bis(diphenylphosphino)benzene; dppb = 1,4-bis(diphenylphosphino)butane; dppe = 1,2-bis(diphenylphosphino)ethane; dppp = 1,3-bis(diphenylphosphino)propane; Imes = N,N-dimesitylimidazolium chloride; (S,S)-NT = (S,S)-Napthyl Trost Ligand; BIPHEP = 2,2’-bis(diphenylphosphino)biphenyl; (g) No water was used in these reactions; (h) 2800 mol% water was used in this reaction
132
iii. Alternative Substrates
a. α-Terpinene and α-Phellandrene
It was clear, qualitatively (by smell and by GC-MS), that much of the diene was
not being consumed during the reaction. By contrast, complete consumption of
phenylboronic acid was always observed by TLC. Due to difficulties attendant to the
quantification of residual diene, two higher-boiling alternatives were assayed: α-terpinene
and α-phellandrene (Scheme II-2.7). Unfortunately, under the optimized conditions,
neither substrate underwent arylation detectable by NMR or TLC.
Scheme II-2.7: Attempted Arylation of α-Terpinene and α-Phellandrene
alpha-Terpinene
Standard Conditions Standard ConditionsNR
alpha-Phellandrene
b. 2,3-Dimethyl-1,3-Butadiene
It is reasonable to expect that strong pre-coordination in virtue of the S-cis diene
configuration of 1,3-cyclohexadiene plays a role in the observed reactivity. Supporting
this notion is the observation that 2,3-dimethyl-1,3-butadiene (Scheme II-2.8) fails to
react under standard conditions.
Scheme II-2.8: Attempted Arylation of 2,3-Dimethyl-1,3-Butadiene StandardConditions
NR
2,3-Dimethyl-1,3-Butadiene
133
c. Acyclic Dienes Incorporating Electrophilic (Ketone) Traps
End-functionalized acyclic diene II-1.1 could be expected to easily adopt the
requisite conformation (Scheme II-2.9). Substrate II-1.1, furthermore, was designed to
incorporate a third point of chelation. Despite these features, the substrate was unreactive
under standard conditions.
Scheme II-2.9: Attempted Cyclization of Diene-Ketone II-1.1
PhII-1.1
StandardConditions
O
H3C Ph
Ph
RhI O CH3
Ph
Ph
H3CHO
d. 2-Phenyl-1,3-cyclohexadiene
2-Phenyl-1,3-cyclohexadiene (Scheme II-2.10), underwent dehydrogenation to
yield biphenyl, and was the only other diene found to react under standard conditions.
Scheme II-2.10: Dehydrogenation of 2-Phenyl-1,3-Cyclohexadiene
Ph
StandardConditions
Ph
2-phenyl-1,3-cyclohexadiene biphenyl
e. ortho-Acetyl-phenylboronic acid
In an effort to substantiate the proposed mechanism, ortho-acetyl phenylboronic
was employed using standard conditions (Table II-2.1, Entry 51). The expected product
(Scheme II-2.11) was not obtained. Rather, the boronic acid underwent decomposition to
acetophenone.
134
Scheme II-2.11: Attempted Coupling of 1,3-Cyclohexadiene and o-Acetyl Phenylboronic Acid
(OH)2BO
CH3
Standard Conditions
(OH)2BO
CH3
Standard Conditions
H3C
HOO
CH3
+
In a related experiment, the effect of added methyl ethyl ketone was investigated
(Table II-2.1, Entry 19). In this reaction, a low (11%) yield of 4-phenylcyclohexene was
produced, although no product resulting from carbonyl addition was observed (Scheme
II-2.12).
Scheme II-2.12: Attempted Trapping of (π-Allyl)Rhodium Intermediate with Methyl Ethyl Ketone
PhB(OH)2(200 mol%)+
[Rh(COD)Cl]2 (2.5 mol%)(rac)-Binap (7.5 mol%)
Dioxane/H2O (500 mol%)95 °C Ph
11%
O+
Ph
OH
0%
(2000 mol%)
iv. Revised Mechanistic Hypothesis
In terms of substrate scope, these restrictions severely limited applicability and
ultimately provided little incentive to continue the project. Within the narrow framework
of the most successful reaction, however, we were confounded by the apparent “ceiling”
of 32% yield. A hypothesis follows, which accounts for some product formation as well
as the persistence of unconsumed diene across a range of conditions (Figure II-2.1).
Tamaru, Y. Tetrahedron Lett., 2000, 41, 6789; (d) Shibata, K.; Kimura, M.; Shimizu,
M.; Tamaru, Y. Org. Lett., 2001, 3, 2181; (e) Kimura, M.; Ezoe, A.; Tanaka, S.;
Tamaru, Y. Angew. Chem. Int. Ed., 2001, 40, 3600. 9 Loh, T. -P.; Song, H. -Y.; Zhou, Y. Org. Lett., 2002, 4, 2715. 10 Takimoto, M.; Mori, M. J. Am. Chem. Soc., 2001, 123, 2895. 11 Jang, H. -Y.; Huddleston, R. R.; Krische, M.J Angew. Chem. Int. Ed., 2003, 42, 4074.
139
12 Sato, Y.; Takimoto, M.; Mori, M. Tetrahedron Lett., 1996, 37, 887. 13 Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229. 14 Hayashi, T.; Takahashi, M.; Takaya, Y., Ogasawara, M. J. Am. Chem. Soc., 2001, 124,
5052, and references therein. See also Ref. 13. 15 Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110. 16 Bocknack, B. M.; Wang, L. -C.; Krische, M. J. Proc. Nat. Acad. Sci., 2004, 101, 5421.
Part 5. Experimental Section
A. Synthetic Procedures and Product Characterization
i. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator.
Analytical thin-layer chromatography (TLC) was carried out using 0.2-mm
commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254). Preparative column
chromatography employing silica gel was performed according to the method of Still.*
Melting points were determined on a Thomas-Hoover melting point apparatus in sealed
capillaries and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1420
spectrometer. High-resolution mass spectra (HRMS) were obtained on a Karatos MS9
and are reported as m/e (relative intensity). Accurate masses are reported for the
molecular ion (M+1).
Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra
were recorded with a Varian Gemini (300 MHz) spectrometer or a Mercury (400 MHz)
spectrometer.
ii. Representative procedure for the Rh-catalyzed reductive arylation of 1,3- cyclohexadiene
A 25 ml tube was flame dried and allowed to cool in a drybox. Thereupon, the
tube was charged with [Rh(OH)COD]2 (14.3 mg, 0.313 mmol, 2.5 mol%), BIPHEP (49
500 mol%). The tube was sealed and the contents were allowed to stir at room
temperature until homogeneous – typically ca. 30 minutes. PhB(OH)2 (305 mg, 2.5
mmol, 200 mol%), and 1,3-cyclohexadiene (119 µl, 1.25 mmol, 100 mol%) were added
and the tube was quickly purged with Ar, resealed, and heated in an oil bath for 2h. After
the allotted time, the tube was allowed to cool to room temperature. The contents were
either analyzed directly via GC-MS or evaporated onto silica gel. Purification by silica
gel chromotagraphy, eluting with a mixture of ethyl acetate and hexanes, yielded the
desired product.
iii. 4-Phenylcyclohexene
4-Phenylcyclohexene was identified by comparison of 1HNMR spectroscopic
data to reported values: Kamigata, N.; Fukushima, T.; Satoh, A.; Kameyama, M. J.
Chem. Soc. Perkin Trans. 1 1990, 549.
iv. 4-Methoxybiphenyl
4-Methoxybiphenyl was identified by comparison of 1HNMR spectroscopic data
to reported values: Spivey, A. C.; Diaper, C. M.; Adams, H.; Rudge, A. J. J. Org. Chem.
2000, 65, 5253.
v. Preparation of substrate II-1.1
Diene-tethered methyl ketone substrate II-1.1 was prepared in accordance with a
literature procedure. Spectroscopic data was consistent with values reported therein. See:
Murakami, M.; Ubukata, M.; Ito, Y. Tetrahedron Lett. 1998, 39, 7361.
Chapter III: Recent Developments in Catalytic [2+2]Cycloadditions Part 1: Anion Radical [2+2]Cycloaddition as a Mechanistic Probe: Stoichiometry and Concentration-Dependant Partitioning of Electron-Transfer (ET) and Alkylation Pathways in the Reaction of the Gilman Reagent Me2CuLi•LiI with bis(Enones) A. Introduction and Background
i. Early Observations Attributed to Electron Transfer in Gilman Alkylations
An electron transfer (ET) mechanism was originally proposed for the alkylation
of conjugated enones by Gilman reagents (formally lithium dialkylcuprates).1 However,
much of the data once believed to support the intermediacy of enone anion radicals in the
Gilman conjugate addition has been subject to debate and in some instances refuted.2 For
example: (a) E/Z isomerization of enones upon exposure to Me2CuLi•LiI, initially
attributed to the formation of anion radical intermediates, is catalyzed by lithium iodide at
temperatures as low as -78 °C.3 (b) Although a correlation between enone reduction
potential and the ability to undergo conjugate addition using Me2CuLi•LiI has been
made,4 subsequent studies reveal this correlation to be superficial, thus disqualifying rate-
determining electron transfer.5 (c) A large number of studies involving the use of
chemical probes were considered to corroborate the intermediacy of anion radicals.7-9
Specifically, upon exposure to Gilman reagents, enones possessing γ-heteroatom
substitution afford products of elimination,6 enones possessing leaving groups at the δ-
position afford products of internal substitution,6a,7 and γ,δ-cyclopropyl enones are
subject to alkylative ring opening.8 While products of ring cleavage potentially could
arise via the intermediacy of a cyclopropylcarbinyl radical, the nucleophilic ring opening
of cyclopropyl esters and ketones using Gilman reagents is known.9 Moreover, elegant
142
studies by Casey demonstrate stereospecific alkylative ring opening, which appears
incompatible with anion radical intermediates.10 Initially, this result was interpreted as
evidence for direct nucleophilic addition to the cyclopropane. Related studies by Bertz
suggest that alkylative ring opening actually occurs through stereospecific rearrangement
of an initially formed β-cuprio adduct.11 Indeed, for all the aforementioned chemical
probes, reactivity once deemed “diagnostic” of the presence of anion radicals is perhaps
better attributed to the action of β-cuprio intermediates. (d) Finally, attempted
spectroscopic detection of anion radicals using electron spin resonance (ESR) and
chemically induced dynamic nuclear polarization (CIDNP) was unsuccessful.12
ii. Accepted Mechanistic Features of Gilman 1,4-Addition
It is now generally believed that the reaction of the Gilman reagent Me2CuLi•LiI
with conjugated enones involves reversible formation of a copper-complexed
intermediate followed by rate-determining carbon-carbon reductive elimination (Scheme
III-1.1). Rate-determining reductive elimination is supported by kinetic isotope effects.13
Additionally, kinetic studies performed by Krauss and Smith reveal reversible formation
of an intermediate that is subject to irreversible rate-determining conversion to product.14
While copper-complexed enone intermediates have been directly observed using low
temperature NMR spectroscopically,15 the precise nature of such enone complexes is the
The available theoretical data suggest their structure resides between the limiting,
and perhaps mesomeric, forms represented by unsymmetrical π-complexes and oxy- π -
allyls, enyls(σ+π) and β-cuprio adducts.16 Studies by Boche suggest the copper-
complexed intermediate is a contact ion pair (CIP), rather than a solvent separated ion
pair (SSIP), even in cases when the latter predominates in solution.17
Despite strong evidence against the intermediacy of enone anion radicals in many
Gilman type conjugate additions, the ET properties of Gilman reagents have been clearly
demonstrated in cases involving easily reduced substrates. These include: (a) additions to
doubly activated olefins,18 (b) addition to bromonaphthoquinone,19 (c) polyaddition to
fullerenes, as well as the (d) ketyl anion radical formation and pinacolization of
fluorenone.20 Hence, the formation of anion radicals in a pre-equilibrium preceding the
rate-determining step of the Gilman reaction remains a possibility, especially for easily
reduced systems.
iii. Conjugated bis(Enones) as Mechanistic Probes
Our recent observation that easily reduced bis(enones) are subject to
intramolecular [2+2]cycloaddition upon cathodic reduction or chemically promoted ET
provides a hitherto unavailable means of detecting anion radical intermediates.21 As such,
we became interested in utilizing these anion radical probes in an examination of the
mechanism of the Gilman alkylation of conjugated enones.
144
THF, 0 oCHH
O
R
O
R
III-1.1a-e III-1.3a-eIII-1.2a-e
O
R
O
R(CH3)2CuLi-LiI
H3C
RR
OO
a. R=4-Biphenylyl; b. R = 2-Naphthyl; c. R = 4-Chlorophenyl; d. R = 3,4-Dichlorophenyl; e. R = Phenyl
Eqn. III-1.1
To this end, our investigations have established that exposure of aromatic bis(enones)
III-1.1a-e to the methyl Gilman reagent (Me2CuLi•LiI) at 0 oC in THF results in the
formation of both the products of tandem conjugate addition-Michael cyclization III-
1.2a-e and [2+2]cycloaddition III-1.3a-e. Partitioning of these reaction pathways is
achieved by modulating the concentration and loading of the Gilman reagent. While the
aggregate(s) present at higher concentration induce typical Gilman alkylation en route to
products III-1.2a-e, the aggregate(s) present at lower concentration provide products of
catalytic [2+2]cycloaddition III-1.3a-e. These studies suggest a concentration-dependent
speciation of the Gilman reagent and differential reactivity of the aggregates present at
higher and lower concentrations. Based on these data, along with our prior studies
involving chemically and electrochemically induced anion radical cyclobutanation of the
very same bis(enones),21 the [2+2]cycloadducts III-1.3a-e arising under Gilman
conditions appear to be products of anion radical chain cyclobutanation that derive via
electron transfer (ET) from the Me2CuLi•LiI aggregate(s) present at low concentration
(Scheme III-1.2).
145
Scheme III-1.2: Partitioning of Electron Transfer and Alkylation Pathways
R R
O O
O
R
O
R
O
R
O
R
H3C
HH
R = ArylTHF, 0 oC
(CH3)2CuLi-LiI
200 mol% CuprateHigh Concentration
Fast Addition
25 mol% CuprateLow Concentration
Slow Addition
Electrochemical ReductionET from Arene Anion Radicals
B. Results and Discussion
i. The Anion Radical Probe Reaction
In connection with ongoing studies toward the development of catalysts for
alkene [2+2]cycloaddition,21,22 the belief that Gilman reagents might serve as ET agents
prompted us to examine their capacity to induce anion radical chain cyclobutanation of
bis(enone) substrates. The bis(enone) substrates III-1.1a-e have been shown in this
laboratory to undergo intramolecular cyclobutanation via enone anion radical
intermediates formed initially either by ET from the chrysene anion radical or by
cathodic reduction.21 The available evidence strongly supports a stepwise cycloaddition
mechanism involving the formation of a distonic anion radical intermediate which then
cyclizes to form the anion radical of the cyclobutane product III-1.3, which should be
localized upon the aroyl moiety. Exergonic ET to the more easily reducible substrate III-
1.1 then initiates an anion radical chain reaction (Scheme III-1.3). Since the 4-biphenoyl
moiety of III-1.1a more effectively stabilizes the anion radical moiety than does the
benzoyl moiety of III-1.1e, the former has been found to be a substantially more efficient
146
anion radical probe than the latter. Consequently, bis(enone) III-1.1a was used in the
most extensive series of probe experiments in the present work. The prototypical Gilman
reagent Me2CuLi•LiI, generated through the addition of methyl lithium to a THF solution
of copper(I) iodide, was selected as the specific Gilman reagent for this study.
Scheme III-1.3: Postulated Stepwise Mechanism for Anion Radical Chain Cyclobutanation
O ROR
e-
O ROR O RORO
R
O
R
O
R
O
R
Distonic Anion Radical
III-1.1a-e III-1.3a-e
a. R=4-Biphenylyl; b. R = 2-Naphthyl; c. R = 4-Chlorophenyl; d. R = 3,4-Dichlorophenyl; e. R= Phenyl
ii. Organocuprate-Catalyzed [2+2]Cycloaddition
a. Partitioning of Reactivity as a Function of Catalyst Loading
Toward this end, variable quantities of the methyl Gilman reagent were added to a
THF solution (0.01 M) of the 4-biphenylyl substituted bis(enone) III-1.1a at 0 oC. Using
two equivalents of the Gilman reagent, an 85% yield of the tandem conjugate addition-
Michael cyclization product III-1.2a is obtained (Table III-1.1, Entry 1). Upon use of one
equivalent of the methyl Gilman reagent, both III-1.2a and the [2+2]cycloadduct III-1.3a
are obtained in 64% and 13% yields, respectively (Entry 2). Further decrease in the
loading of Gilman reagent was found to favor the cycloaddition pathway. Using 0.5
equivalents of the Gilman reagent, III-1.2a and the [2+2]cycloadduct III-1.3a are
produced in 38% and 40% yields, respectively (Entry 3), and upon use of 0.25
equivalents of the Gilman reagent, III-1.2a and the [2+2]cycloadduct III-1.3a are
produced in 13% and 84% yields, respectively (Entry 4). Notably, when 0.25 equivalents
of the Gilman reagent is added more slowly (60 sec), the cyclobutanation manifold is 147
favored to the exclusion of III-1.2a, providing the cycloadduct III-1.3a in 91% yield as a
single diastereomer (Entry 5). A further decrease in loading of the Gilman reagent results
in incomplete consumption of III-1.1a (Entry 6).
b. Partitioning of Reactivity as a Function of Catalyst Concentration
Finally, use of one equivalent Gilman reagent at 0.00125 M rather than 0.01 M
concentration inverts the proportion of alkylation product III-1.2a and cyclobutanation
product III-1.3a. The yields of III-1.2a and III-1.3a change from 64% and 13%, to 10%
and 60%, respectively (Table III-1.1, Entry 7). These results demonstrate that, when
suitably dilute, the Gilman reagent becomes ineffective at methylation, and instead serves
as a catalyst for cyclobutanation.
Table III-1.1: Effect of Cuprate-Loading, Concentration and Order of Addition
THF, 0 oCHH
O
R
O
R
1aR = 4-Biphenylyl 3a2a
Entry 3a (Yield)c2a (Yield)c
1234567
200 mol%a
100 mol%a
50 mol%a
25 mol%a
25 mol%b
10 mol%a
100 mol%a
---13%40%84%91%72%60%
85%64%38%13%---7%
10%
O
R
O
R(CH3)2CuLi-LiI
H3C
RR
OO
0.01 M0.01 M0.01 M0.01 M0.01 M0.01 M1.25 mM
Conc. 1a(CH3)2CuLi 1a (Recov.)c
5%5%------
3%16%---
(a) A 0.5 M solution of the Gilman reagent in THF is added over 5 seconds. (b) A 0.5 M solution of the Gilman reagent in THF is added over 60 seconds. (c) Isolated yields afterchromatographic separation.
148
c. Exploration of Substrate Scope
To explore the scope of this partitioning phenomenon, optimum Gilman
alkylation and anion radical cyclobutanation conditions were applied to related
bis(enones) (Table III-1.2). Gratifyingly, complete partitioning of the alkylation and
cyclobutanation manifolds was achieved in most cases. Interestingly, the parent phenyl-
substituted bis(enone) III-1.1e is more resistant to cyclobutanation, suggesting the
Gilman reagent catalyzes only the cycloaddition of easily reduced bis(enones).
Table III-1.2: Partitioning of Mechanistic Pathways Across a Range of Substrates
Substrate III-1.3 (Yield)bIII-1.2 (Yield)b
III-1.1a
III-1.1b
III-1.1c
III-1.1d
III-1.1e
ABABABABAB
---91%
---90%
---80%
---70%
---43%
91%---
89%---
93%---
85%4%
90%12%
Conditions
R = 4-Biphenylyl
R = 2-Naphthyl
R = 4-Chlorophenyl
R = 3,4-Dichlorophenyl
R = Phenyl
R
THF, 0 oCHH
O
R
O
R
III-1.1a-e III-1.3a-eIII-1.2a-e
O
R
O
R(CH3)2CuLi-LiI
H3C
RR
OO
(a) Conditions A for tandem conjugate addition-Michael cyclization employ rapid addition (5 sec)of Me2Culi (200 mol%) to a solution of substrate (100 mol%) in THF at 0 oC. Conditions B foranion radical cyclobutanation employ slow addition (60 sec) of Me2Culi (25 mol%) to a solution of substrate (100 mol%) in THF at 0 oC. (b) Isolated yields after chromatographic separation. Theratio of cis:trans diastereomers for 3a, 3b, 3c, 3d and 3e is >99:1, 44:1, 9:1, 13:1 and 17:1respectively.
d. Kinetic Studies
Reaction kinetics experiments are described in Table III-1.3. With a starting
concentration of the cuprate reagent of 0.01 M, which is injected rapidly to the substrate
solution, and using 25 mol% of the Gilman reagent, III-1.2a is formed almost exclusively
during the initial stages of reaction. However, after the majority of the Gilman reagent is
149
consumed through the conversion of III-1.1a to III-1.2a, the formation of III-1.3a begins
and continues to develop, ultimately becoming the dominant reaction pathway. The
implications of these results will be discussed (vide infra).
Table III-1.3: Reaction Kinetics Experiments
THF, 0 oC(Fast Addition)
HH
O
R
O
R
III-1.1aR = 4-Biphenylyl III-1.3aIII-1.2a
Entry III-1.3a (mol%)aIII-1.2a (mol%)aTime (sec)
1234567
0103060
180480
1200
05.1
11.712.733.243.254.7
016.319.020.318.620.222.0
O
R
O
R(CH3)2CuLi-LiI(25 mol%)
H3C
RR
OO
III-1.1a (mol%)a
10076.366.763.442.033.424.3
(a) Conversion was determined by 1H NMR analysis and the values given are the average of two runs. Total values are under 100 mol% as small quantities of hetero-Diels-Aldercycloadduct are produced.
iii. Mechanistic Proposal
a. Concentration-Dependent Speciation
It is evident from the results presented in Table III-1.1 that the cyclobutanation
reaction is indeed a catalytic or chain process, but that the chain lengths are rather short
(ca. 2-3). These experiments also suggest a concentration-dependent speciation of the
Gilman reagent, as demonstrated by differential reactivity at high and low concentration.
The aggregates present at high concentration favor alkylation, while the aggregates
present at low concentration favor cycloaddition. A corollary to this hypothesis requires
that variation of concentration at constant loading of Gilman reagent should modulate the
ratio of alkylation and cyclobutanation products. Indeed, the yields of III-1.2a and III-
150
1.3a change from 64% and 13%, to 10% and 60%, respectively, when one equivalent
Gilman reagent is used at 0.00125 M rather than 0.01 M concentration (Table III-1.1).
Studies of the time-evolution of products III-1.2a and III-1.3a provide further
insights into the mechanistic dichotomy observed in this work (Table III-1.3). The
alkylation product III-1.2a is formed rapidly early in the reaction, whereas only small
amounts of III-1.3a are generated at this stage. However, after the concentration of
Gilman reagent is lowered through its consumption, the cycloaddition pathway becomes
dominant. These results again suggest that the composition of the Gilman reagent is
concentration-dependent and that the species present at low concentration are relatively
ineffective methyl transfer agents, but are effective agents for chain cycloaddition in the
case of easily reduced bis(enones).
b. Role of Lithium Iodide
A further important consequence of the kinetic studies is the conclusion that
lithium iodide, which is present at constant concentration throughout the reaction period,
is not differentially involved in the competition between methylation and
cyclobutanation. This conclusion is further substantiated by carrying out a reaction in
which 100 mol % of lithium iodide is included with the substrate and 100 mol % of the
Gilman reagent is added in the slow fashion. Instead of favoring the methylation, the
results are essentially the same as when the lithium iodide is omitted. The nature of the
termination step of the anion radical chain process is not currently known, but coupling
of two anion radicals is a possibility.
151
c. Anion Radical Chain Cycloaddition vs. Oxidative Cyclization-Reductive Elimination
A paramount question relates to whether the cycloadducts III-1.3a-e are products
of anion radical chain cycloaddition or instead derive from copper(I)-catalyzed oxidative
cyclization-reductive elimination (Scheme III-1.4). In the latter case, the Gilman
intermediate, be it a π-complex, oxy- π -allyl, enyl(σ+π) or β-cuprio adduct, is required to
insert into the appendant enone. Here, it is especially noteworthy that the biphenoyl
derived bis(enone) III-1.1a is much more efficiently converted to III-1.3a than the
related benzoyl substituted bis(enone) III-1.1e is to III-1.3e. This same reactivity order
has been observed in authenticated anion radical reactions involving ET from chrysene
anion radical,21 and is attributable to the more facile generation of the 4-biphenoyl-type
anion radical moiety, as opposed to a benzoyl-type anion radical moiety, in the second
cyclization step to close the cyclobutane ring. Since the comparison of III-1.1a and III-
1.1e should not involve a significant difference in polar effects (phenyl vs. 4-biphenyl),
the enhancement associated with III-1.1b is presumed to be a conjugative effect, such as
would be present in the delocalization of an anion radical moiety. Further, authenticated
anion radical cyclobutanations involving cathodic reduction typically proceed through
short chains, in the same manner as the currently-observed cyclobutanations. Finally,
when the same solvent (THF) is involved, chemically initiated anion radical
cyclobutanation of substrate III-1.1a affords exclusively the exo,cis-cyclobutane product
III-1.3a, as observed in the present work. The high levels of stereoselectivity suggest the
anion radical intermediates derived from III-1.1a exist as CIPs.
152
Scheme III-1.4: Alternative Cyclobutanation Pathways
HH
O
R
O
RElectronTransferRR
OO O ROR
Anion Radical Chain Cycloaddition
HH
O
R
O
RCu(I)LnRR
OO
Oxidative Cyclization - Reductive Elimination
e
Cu(I)Ln
HH
CuIIIO O
RR
Ln
Eqn. 1
Eqn. 2
d. Concentration-Dependent Speciation
A second important question concerns the composition of the reactive species at
high and low concentration. It has been established that, in THF solution, the methyl
Gilman reagent exists primarily as solvent-separated ion pairs (Li+ // CuMe2־), which are
in rapid equilibrium with the cyclic dimer of lithium dimethylcuprate ([Me2CuLi]2).17
Extensive evidence suggests that the latter dimer is much more reactive than the former
with respect to Gilman methylation. Neither monomer nor dimer is intimately associated
with the lithium halide, which is consistent with our own observation that the product
distribution is insensitive to added lithium iodide (Scheme III-1.5).
Scheme III-1.5: Equilibrium Between Solvent-Separated Ion Pairs and Contact Ion Pair Dimer Me MeCu
Me MeCu
Li Li2 Me2CuLiTHF
(Dimeric CIP)
(Monomeric SSIPs)
Since the equilibrium between the dimer and the monomer would be shifted even
further to the monomer upon dilution, it is reasonable to suggest that the monomeric
solvent-separated ion pairs, which are known to be relatively unreactive toward
153
methylation, may be the species responsible for the initiating electron transfer, while the
dimer is the species which is responsible for methylation. This proposal would explain
why electron transfer chemistry appears to dominate when the Gilman reagent is very
dilute, but methylation dominates when the reagent is more concentrated. Because
products derived via anion radical intermediates may be formed to the exclusion of
methylation products, it appears that these anion radical intermediates are not subject to
Gilman methylation. Hence, the Gilman alkylation and cycloaddition pathways are
mechanistically distinct.
The possibility that small amounts of extraneous impurities could be responsible
for the initiation of the anion radical chemistry observed in the present work has been
extensively considered. The following reagents (acting alone, under the typical conditions
of the reaction) have been shown not to initiate anion radical chemistry in the case of III-
1.1a, or in any of the substrates of this study: MeLi, MeCu, and LiI. Further, the reagent
lithium trimethyldicuprate reacts in essentially the same manner as lithium
dimethylcuprate. This reagent was specifically considered because it could be generated
from lithium dimethylcuprate and methylcopper, which is released upon Gilman
methylation.
C. Conclusion
The now well-established intramolecular anion radical chain cyclobutanation
reactions of 1,7-bis(aroyl)-1,6-heptadienes have been employed as anion radical probes in
the reactions of these enones with the Gilman reagent. When the Gilman reagent is
present in the reaction solution at low concentrations, either via slow addition of the
154
reagent to a solution of the bis(enone), or by use of a sub-stoichiometric amount of the
reagent (25 mol%), the intramolecular [2 + 2] cycloaddition products are formed in good
yield. In contrast, when a stoichiometric (or greater) amount of the reagent is added
rapidly to a solution of the enone, tandem Gilman methylation-intramolecular Michael
addition occurs in high yield. Under suitable conditions, complete partitioning of the
anion radical and conventional Gilman methylation pathways is observed. These results
indicate that anion radical intermediates are generated in competition with Gilman
methylation products, and that the anion radical mechanism is independent of the
methylation mechanism. That is, under ideal anion radical conditions (low concentration
of the Gilman reagent), no methylation is observed; conversely, under ideal methylation
conditions (high concentration and an excess of the Gilman reagent), no anion radical
products are formed. The powerful dependence of the competition between ET chemistry
and Gilman methylation upon the concentration of the Gilman reagent, coupled with the
generally acknowledged greater methylation reactivity of the dimeric, rather than
monomeric, Gilman reagent, suggests that the species responsible for methylation is
probably the CIP dimer, while the species responsible for electron transfer is probably the
Gilman monomer, which is present in tetrahydrofuran solutions as the solvent-separated
ion pair.
155
156
D. References
1 For a review, see: House, H. O. Acc. Chem. Res. 1976, 9, 59. 2 For reviews covering the mechanism of the Gilman conjugate addition, see: (a)
Nakamura, E.; Mori, S. Angew. Chem. Int. Ed. 2000, 39, 3750. (b) R. A. J. Smith, A.
S. Vellekoop in Advances in Detailed Reaction Mechanisms, Vol. 3 (Ed.: J. M.
Coxon), JAI: Greenville, CT, 1994, pp. 79-130. (c) Perlmutter, P., in Conjugate
Addition Reactions in Organic Synthesis (Baldwin, J. E. and Magnus, P. D., Eds),
Pergamon Press, Oxford, 1992, pp 10-13. 3 Corey, E. J.; Hannon, F. J.; Boaz, N. W. Tetrahedron 1989, 45, 545. 4 House, H. O. Umen, M. J. J. Am. Chem. Soc. 1972, 94, 5495. 5 Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141. 6 (a) Ruden, R. A. Litterer, W. E. Tetrahedron Lett. 1975, 16, 2043. (b) Logusch, U. W.
Tetrahedron Lett. 1979, 20, 3365. (c) Ibuka, T.; Chu, G.-N.; Yoneda, F. Tetrahedron Lett. 1984, 25, 3247.
7 (a) Hannah, D. J.; Smith, R. A. J.; Teoh, I.; Weavers, R. T. Aust. J. Chem. 1981, 34,
181. (b) Smith, R. A. J.; Vellekoop, A. S. Tetrahedron 1989, 49, 517. 8 (a) Marshall, J. A.; Ruden, R. A. J. Org. Chem. 1972, 37, 659. (b) House, H. O.;
Snoble, K. A. J. Org. Chem. 1976, 41, 3076. 9 For classic examples, see: (a) Corey, E. J.; Fuchs, P. L. J. Am. Chem. Soc. 1972, 94,
4014. (b) Daviaud, G.; Miginiac, P. Tetrahedron Lett. 1972, 13, 997. (c) Grieco, P. A.;
Finkelhor, R. J. Org. Chem. 1973, 38, 2100. (d) Miyaura, M.; Itoh, M.; Sasaki, N.;
Suzuki, A. Synthesis 1975, 317. (e) House, H. O.; Prabhu, A. V.; Wilkins, J. M.; Lee.
L. F. J. Org. Chem. 1976, 41, 3067. (f) House, H. O.; McDaniel, W. C.; Sieloff, R. F.;
Vanderveer, D. J. Org. Chem. 1978, 43, 4316. 10 Casey, C. P.; Cesa, M. C. J. Am. Chem. Soc. 1979, 101, 4236. 11 Bertz, S. H.; Honkan, V. J. Org. Chem. 1984, 49, 1739. 12 (a) Hannah, D. J.; Smith, R. A. J. Tetrahedron Lett. 1975, 16, 187. (b) Smith, R. A. J.;
Mannah, D. J. Tetrahedron 1979, 35, 1138. 13 Frantz, D. E.; Singleton, D. A. Snyder, J. P. J. Am. Chem. Soc. 1997, 119, 3383.
157
14 Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141. 15 (a) Bertz, S. H.; Carlin, C. M.; Deadwyler, D. A.; Murphy, M. D.; Ogle, C. A.;
Seagle, P. H. J. Am. Chem. Soc. 2002, 124, 13650. (b) Vellekoop, A. S.; Smith, R. A.
J. J. Am. Chem. Soc. 1994, 116, 2902. (c) Bertz, S. H.; Smith, R. A. J. Am. Chem. Soc. 1989, 111, 8276. (d) Ullenius, C.; Christianson, B. Pure Appl. Chem. 1988, 60,
57. 16 (a) Snyder, J. P. J. Am. Chem. Soc. 1995, 117, 11025. (b) Snyder, J. P.; Bertz, S. H. J.
Org. Chem. 1995, 60, 4312. (c) Nakamura, E.; Mori, S.; Morokuma, K.; J. Am .Chem. Soc. 1997, 119, 4900. (d) Mori, S.; Nakamura, E. Chem. Eur. J. 1999, 5, 1534. (e)
Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941. (f) Yamanaka, M.;
Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 6287. 17 John, M.; Auel, C.; Behrens, C.; Marsch, M.; Harms, K.; Bosold, F.; Gschwind, R. M.;
Rajamohanan, P. R.; Boche, G. Chem. Eur. J. 2000, 6, 3060. 18 (a) Chounan, Y.; Ibuka, T.; Yamamoto, Y. J. Chem. Soc. Chem. Commun. 1994, 2003.
(b) Yamamoto, Y.; Nishii, S.; Ibuka, Y. J. Am. Chem. Soc. 1988, 110, 617. 19 (a) Chounan, Y.; Horino, H.; Ibuka, T.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 1997, 50,
1953. (b) Wigal, C. T.; Grunwell, J. R.; Hershberger, J. J. Org. Chem. 1991, 56, 3759.
(c) Anderson, S. J.; Hopkins, W. T.; Wigal, C. T. J. Org. Chem. 1992, 57, 4304. 20 House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128. 21 (a) Roh, Y.; Jang, H.-Y.; Lynch, V.; Bauld, N. L.; Krische, M. J. Org. Lett. 2002, 4,
611. (b) Yang, J.; Felton, G.; Bauld, N. L.; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 1634. 22 (a) Baik, T.-G.; Wang, L.-C.; Luiz, A.-L.; Krische, M. J. J. Am. Chem. Soc. 2001, 123,
6716. (b) Wang, L. -C.; Jang, H.-Y.; Roh, Y.; Schultz, A. J.; Wang, X.; Lynch, V.;
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448.
E. Experimental Section
i. Synthetic Procedures
a. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator.
CuI (99.999%) was obtained from Strem chemical company. Tetrahydrofuran was
distilled from sodium benzophenone ketyl immediately prior to use. All reactions were
conducted in oven-dried glassware, under an inert atmosphere of Argon.
Analytical thin-layer chromatography (TLC) was carried out using 0.2-mm
commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254). Preparative column
chromatography employing silica gel was performed according to the method of Still.*
Melting points were determined on a Thomas-Hoover melting point apparatus in sealed
capillaries and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1420
spectrometer. High-resolution mass spectra (HRMS) were obtained on a Karatos MS9
and are reported as m/e (relative intensity). Accurate masses are reported for the
molecular ion (M+1).
158
Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra
were recorded with a Varian Gemini (300 MHz) spectrometer or a Mercury (400 MHz)
spectrometer. Chemical Shifts are reported in delta (δ) units, parts per million (ppm)
downfield from trimethylsilane. Coupling constants are reported in Hertz (Hz). Carbon-
13 nuclear magnetic resonance (13C NMR) spectra were recorded with a Bruker
spectrometer (63 MHz). Chemical shifts are reported in delta (δ ) units, parts per million
(ppm) relative to the center of the triplet at 77.0 ppm for deuteriochloroform. 13C NMR
spectra were routinely run with broad brand decoupling.
b. Preparation of bis(enone) substrates III-1.1a – III-1.e
Cyclization/cycloaddition substrates III-1.1a – III-1.e were prepared according to
literature procedures. Sprectroscopic data was consistent with reported values. See: Yang,
J.; Felton, G.; Bauld, N. L.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 1634.
c. Preparation of dimethyllithium cuprate-lithium iodide (Me2CuLi-LiI) reagent
Dimethyllithium cuprate-lithium iodide (Me2CuLi-LiI) reagent was prepared by
adding 200 mol% MeLi (1.6 M in Et2O) to a suspension of 100 mol% CuI in 0 °C THF.
Stirring for approximately 30 minutes at 0°C resulted in a homogeneous solution. The
reagent solution was used immediately.
ii. Experimental Procedures
a. Procedure for data reported in Table III-1.1
Data was obtained using the following procedure: Me2CuLi-LiI reagent solution
(0.5 M in Et2O/THF) was added at the indicated rate to a solution of (bis)enone substrate
(0.25 mmol) in 25 ml 0 °C THF. The reaction was stirred at 0 °C for 25 minutes, and then
quenched with several drops of saturated aqueous NH4Cl solution. The residue was
concentrated and purified via silica gel chromatography, eluting with a mixture of ethyl
acetate and hexane.
159
b. Procedure for data reported in Table III-1.2
Data was obtained using the following representative procedures:
(A) Me2CuLi-LiI (15.7 ml; 0.0032 M in Et2O/THF; 200 mol%) was added over 5s to a solution of
substrate (0.26 mmol; 100 mol%) in 5 ml 0 °C THF. Stirring was maintained for 25 minutes and
then was worked up and purified as described above.
(B) Me2CuLi-LiI (0.125 ml; 0.5 M in Et2O/THF; 25 mol%) was added over 60s to a solution of
substrate (0.25 mmol; 100 mol%) in 25 ml 0 °C THF. Stirring was maintained for 25 minutes and
then was worked up and purified as described above.
c. Procedure for data reported in Table III-1.3
Data represents measurements from separate, parallel reactions conducted using the
following procedure: Me2CuLi-LiI (0.98 mL; 0.034 M in Et2O/THF; 25 mol%) was added over
5s to a solution of substrate (0.1316 mmol; 100 mol%) in 3.5 ml 0 °C THF. Stirring was
maintained for the indicated time before work up and purification as described above.
iii. Spectroscopic and Crystallographic Data
a. Spectroscopic data for cyclobutane products III-1.3a – III-1.3e
1HNMR data for cyclobutane products III-1.3a – III-1.3e was consistent with
values reported in the literature. See: Yang, J.; Felton, G.; Bauld, N. L.; Krische, M. J. J.
Am. Chem. Soc. 2004, 126, 1634.
160
b. Spectroscopic data for cyclobutane products III-1.2a – III-1.2e
c. Crystallographic data for cyclization product III-1.2e
View of molecule III-1.2e showing the atom labeling scheme. Displacement
ellipsoids are scaled to the 50% probability level.
166
Part 2. Studies on the Enantioselective Catalysis of Photochemically Promoted Transformations: “Sensitizing Receptors” as Chiral Catalysts A. Introduction
i. Stoichiometric Chirality Transfer in Photo[2+2]cycloadditions
Many important classes of chemical transformations exist for which catalytic
enantioselective variants do not exist or have not been optimally developed.
Photocycloadditions represent a powerful means of stereogenic carbon-carbon and
carbon-oxygen bond formation that have found extensive use in synthesis,1 yet generally
effective strategies for catalytic asymmetric induction in photochemically mediated
transformations are largely undeveloped.2 Thus far, methods affording useful
enantiomeric excess have been restricted to stoichiometric chirality transfer from
preexisting stereocenters in the substrate3 and the use of chiral auxiliaries4 (i.e.
diastereoselection), solid-state photochemical transformations5 including clathrates,6 and
unimolecular photochemical reactions in chirally modified zeolites.7 Most recently, chiral
molecular receptors have been shown to serve as highly effective “noncovalent chiral
auxiliaries” for enantioselective photo[2+2]cycloadditions.8
The use of asymmetric media (e.g. chiral solvents,9 chiral liquid crystalline
phases,10 and chiral polymer matrices11) embodies another approach to stoichiometric
chirality transfer in photo-mediated transformations.12 However, in contrast to
photochemical reactions that take place in the well-defined chiral microenvironment of
non-centrosymmetric crystal lattices13 and synthetic host-guest complexes,8 the “loose”
asymmetric environment of chiral solvents and liquid crystals confers low levels of
enantioselection.
167
ii. Substoichiometric Chirality Transfer
Methods for substoichiometric chirality transfer have met with limited success.
The use of circularly polarized lasers (i.e. so-called absolute asymmetric synthesis) gives
disappointing enantiomeric enrichments.14 Chiral photosensitizers provide modest
enantiomeric enrichments for a limited range of substrates.15 The asymmetric protonation
of dienols generated via photodeconjugation of γ,γ-disubstituted enones or enoates in the
presence of sub-stoichiometric amounts of chiral aminoalcohols proceeds with
synthetically-useful enantioinduction.16 For this process, enantiodiscrimination does not
occur in the excited state, but in the tautomerization of the photochemically produced
ground-state dienol.
B. Sensitizing Molecular Receptors as Enantioselective Catalysts
As for any catalytic enantioselective process, a generally effective approach to the
enantioselective catalysis of photo-mediated transformations in solution will require: i.
that the substrate be placed in a well-defined chiral microenvironment upon binding to
the template and, ii. that substrate-template binding confer a kinetic advantage to the
transformation of interest. In principle, chiral molecular receptors that incorporate triplet-
sensitizing residues meet these requirements.
i. Hydrogen Bond-Mediated Host-Guest Complex
With regard to the first requirement, the high levels of asymmetric induction
observed for solution state photo[2+2]cycloadditions in synthetic host-guest systems
strongly suggest that cycloaddition proceeds in a well-defined chiral microenvironment.8 168
In such a system, hydrogen-bond formation dictates the orientation of the substrate with
respect to the chiral receptor template in a distinct and predictable fashion. In general, the
use of hydrogen-bond interactions as stereochemical control elements in photochemical
cycloadditions is well documented.17
ii. Triplet Sensitization as Basis for Binding-Induced Rate Enhancement
The second requirement is met through the incorporation of a triplet-sensitizing
moiety. The lifetime of the triplet sensitizer, in relation to the rates of diffusion and
sensitization, defines a highly-localized sphere of sensitization within which energy
transfer occurs via intermediacy of a triplet exciplex.18 The stringent distance dependence
of energy transfer is equivalent to a binding-induced rate enhancement, i.e. excitation of
bound substrate should be favored over excitation of exogenous, untemplated substrate. If
the lifetime of the exciplex is comparable to the rate of cyclization, exciplex formation
can be enantiodiscriminating.
Predicated on this simple analysis, “sensitizing receptor” R (III-2.8) is proposed.
The binding motif embodied by R derives from structurally related carboxylic acid
receptors.19 The proposed substrate, 4-butenyloxy-2-quinolone S, embodies an identical
array of hydrogen-bond donor-acceptor sites with respect to carboxylic acid guests and
undergoes quantitative photo[2+2]cycloaddition, making it a suitable test substrate. A
binding-induced rate enhancement is engineered by equipping receptor R with a triplet-
sensitizing moiety in the form of a benzophenone residue. While modeling of the host-
guest complex indicates this first generation receptor R does not optimally obscure an
169
enantiotopic π-face of the bound quinolone, exceptionally high levels of enantiofacial
bias are not necessary to illustrate proof of concept.
iii. Synthesis of Sensitizing Receptor R (III-2.8)
The synthesis of receptor R (III-2.8) is straightforward and involves the modular
introduction of sensitizing and binding residues via amide bond formation. The
sensitizing moiety, optically pure 4-(1-aminoethyl)-benzophenone III-2.3, is prepared
from 4-ethyl-benzophenone as outlined in Scheme III-2.1. Resolution of the racemic
amine is achieved through conversion to the (R)-mandelic acid amide III-2.4, followed
by chromatographic separation of the diastereomers and subsequent amide hydrolysis.
Coupling of the resolved sensitizing amine fragment to the indicated mono-amide mono-
acid III-2.7 provides the sensitizing receptor R (Scheme III-2.1).
Scheme III-2.1: Synthesis of Sensitizing Molecular Receptor R (III-2.8)
(a) Conditions: [S] = 0.075 M. Irradiations were performed in CDCl3 for 15 minutes using a medium pressure Hg vapor lamp. (b) Reactions were periodically monitored by 1HNMR, which enabled a determination of the percent conversion. The formation of byproducts was not observed by 1HNMR. (c) Enantiomeric excess was determined by chiral stationary phase HPLC analysis using a Chiracel OD column.
177
The persistence of the observed 20% enantiomeric excess across a range of
receptor stoichiometries strongly suggests that the observed level of asymmetric
induction results from the intrinsic enantiofacial bias conferred by the association of
quinolone S to the sensitizing receptor R. In order to support this contention, a control
experiment was performed. Irradiation of S was carried out under conditions identical to
those described in Table III-2.1, but in the presence of receptor fragment RF for which
the binding site has been deleted. Quantitative conversion to cycloadduct P was observed,
but without any detectable asymmetric induction. Collectively, these results establish
substoichiometric chirality transfer from a receptor template to the prochiral substrate
(Scheme III-2.6).
Scheme III-2.6: Control Experiment - Irradiation of quinolone S in the presence of receptor Ra,b
HN
O
O
HN
O
O
hv NH
O
OR or RF
-70oC
O O
CH3O NH
CH3
OC6H13
OBinding SiteDeleted
2 Equivalents of Receptor RF, 0% ee2 Equivalents of Receptor R, 21% ee
O O
N N
NH H
CH3
R
OC6H13
O
RF
Binding SitePresent
(a) Conditions: [7] = 0.075 M, [Additive] = 0.15 M. Irradiations were performed in CDCl3 for 15 minutes using a medium pressure Hg vapor lamp. (b) Enantiomeric excess was determined by chiral stationary phase HPLC analysis using a Chiracel OD column.
S
G. Second-Generation Receptor Design and Synthesis
i. Conformational Analysis
A qualitative analysis of competitive diastereomeric transition states en route to
each enantiomeric cycloadduct reveals differentiation on the basis of the host
conformation relative to the guest. The lowest energy duplex results when the substrate is
distal to the benzylic methyl (Figure III-2.5). The disfavored conformation involves
binding of the guest proximally with respect to the methyl.
178
Figure III-2.5: Conformational Basis of Enantiodiscrimination
O
O
O
CH3
BPH
H
CH3BP
BP H
CH3 ii. Incorporation of a tertiary-Butyl Residue
Based on this analysis, it is reasonable to presume that a more sterically
demanding antipode to hydrogen would shift the conformational equilibrium further to
the left. To this end, receptor RtB (III-2.16) was conceived and synthesized per Scheme
III-2.7.
Scheme III-2.7: Retrosynthesis of t-Butyl Sensitizing Receptor RtB
O
OO
NH HN
N
O
O
OO
NH
N
OH
+
H2N
O
RtB III-2.16 III-2.7 III-2.15
Synthesis of primary amine III-2.15 began with a regioselective acylation of
commercially available neopentylbenzene to afford benzophenone derivative III-2.12.
Benzylic bromination, yielding III-2.13, was initially followed by an unsuccessful
179
attempt at substitution with a homochiral benzylic amine. Ultimately, the corresponding
azide III-2.14 was employed. Reduction of the organic azide under Staudinger conditions
was not successful in this case; instead, catalytic hydrogenation led to good yields of the
racemic base (Scheme III-2.8).
Scheme III-2.8: Synthesis of Sensitizing Amine III-2.15
BzCl, AlCl3, CS2
O
NBS, (BzO)2, CCl4
0-25 °C, 16h, 88%
Br
O
77 °C, 5h, 70%
NH2
NH2
MeO
NR
NR
1. NaN3, DMF
80 °C, 28h, 100%
2. H2, Pd/C 25 °C, 20h, 80%
H2N
O
VI
Neopentylbenzene III-2.12 III-2.13
III-2.15
iii. Characterization of Host-Guest Binding Interactions
1H NMR titration experiments were undertaken to quantify RtB:S binding affinity.
Unfortunately, the observed shift behavior was not consistent with the anticipated mode
of association (did not produce a characteristic curve). A reasonable interpretation of the
data is that very weak binding, or alternatively, unexpected modes of association,
including homodimerization of RtB (Figure III-2.6), predominate under the conditions of
the titration.
180
Figure III-2.6: Possible Dimerization Equilibrium
OO
HN
O
NON
H
OO
NH
O
NO N
H
O
OO
NH HN
N
O
RtB
H. Conclusion and Outlook While the use of transition metal templates in conjunction with chiral ligands has
proven successful for myriad reaction types,24 application of this approach to
photochemical reactions is complicated by two factors: i. most metals possess intense
charge transfer bands in the spectral region of interest for organic photochemistry, and ii.
photochemically-promoted ligand loss is often a consequence of such absorptions, which
disrupts the chiral microenvironment of the metal template at the crucial moment of bond
formation. As supported by the collective results reported herein, a potentially general
strategy for the enantioselective catalysis of photo-mediated transformations involves the
use of molecular receptors equipped with appendant chiral sensitizing moieties. Future
studies will focus on the development and optimization of receptor-sensitizer templates
that confer heightened levels of enantiodiscrimination.
181
182
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Alibes, R.; Bourdelande, J. L.; Font, J.; Gregori, A.; Parella, T. Tetrahedron 1996, 52,
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Taylor, N. J.; Lange, G. L. J. Am. Chem. Soc. 1994, 116, 3312. 4 For representative examples of chiral auxiliaries in photochemical transformations, see:
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Yamaguchi, T.; Uchida, K.; Irie, M. J. Am. Chem. Soc. 1997, 119, 6066. (d) Faure, S.;
Piva-Le Blanc, S.; Piva, O.; Pete, J.-P. Tetrahedron Lett. 1997, 38, 1045. 5 For selected examples of enantioselective solid state photochemistry, see: (a)
Takahashi, M.; Sekine, N.; Fujita, T.; Watanabe, S.; Yamaguchi, K.; Sakamoto, M. J.
Am. Chem. Soc. 1998, 120, 12770. (b) Leibovitch, M.; Olovsson, G.; Scheffer, J. R.;
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Leibovitch, M.; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203. 6 For selected examples of enantioselective photochemistry in clathrates, see: (a) Toda,
F.; Miyamoto, H.; Tamashima, T.; Kondo, M.; Ohashi, Y. J. Org. Chem. 1999, 64,
2690. (b) Toda, F. Acc. Chem. Res. 1995, 28, 480.
183
7 For selected examples of enantioselective photochemistry in zeolites, see: (a) Sen, S. E.;
Smith, S. M.; Sullivan, K. A. Tetrahedron 1999, 55, 12657. (b) Joy, A.; Scheffer, J. R.;
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references therein. 9 For selected examples of photochemical reactions in chiral solvents, see: (a) Boyd, D.
R.; Campbell, R. M.; Coulter, P. B.; Grimshaw, J.; Neill, D. C.; Jennings, W. B. J.
(b) Hilbert, M.; Solladie, G. J. Org. Chem. 1980, 45, 5393. (c) Eskanazi, C.; Nicoud, J.
F.; Kagan, H. B. 1979, 44, 995-999. (d) Nakazaki, M.; Yamamoto, K.; Fujiwara, K.;
Maeda, M. J. Chem. Soc., Chem. Commun. 1979, 1086. (e) Nakazaki, M.; Yamamoto,
K.; Fujiwara, K.; Chem. Lett. 1978, 863. 11 For selected examples of photochemical reactions in chiral polymer matrices, see:
Tazuke, S.; Miyamoto, Y.; Ikeda, T.; Tachibana, K. Chem. Lett. 1986, 953. 12 For selected reviews on photochemistry in organized media, see: (a) Weiss, R. G.
Photochemistry in Organized and Constrained Media; Ramamurthy, V., Ed.; VCH
Publishers: New York, 1991; Chapter 14. (b) Ganapathy, S.; Weiss, R. G.; Organic
Phototransformations in Non-homogeneous Media; Fox, M. A., Ed., American
Chemical Society: Washington, DC, 1985; Chapter 10. 13 Obata, T.; Tetsuro, S.; Yasutake, M.; Shinmyozu, T.; Kawaminami, M.; Yoshida, R.;
Somekawa, K. Tetrahedron, 2001, 57, 1531 and references therein.
184
14 For selected examples of enantioselective photochemistry via circularly polarized
lasers, see: (a) Feringa, B. L.; van Delden, R. A. Angew. Chem. Int. Ed. 1999, 38,
3418. (b) Salam, A.; Meath, W. J. J. Chem. Phys. 1997, 106, 7865. (c) Salam, A.;
Meath, W. J. Chem. Phys. Lett. 1997, 277, 199. (d) Shimizu, Y. J. Chem. Soc., Perkin
Trans. 1 1997, 1275. (e) Moradpour, A.; Kagan, H.; Baes, M.; Morren, G.; Martin, R.
H. Tetrahedron 1975, 31, 2139. 15 For selected examples of enantioselective photochemistry via chiral photosensitizers,
see: (a) Asaoka, S.; Kitazawa, T.; Wada, T.; Inoue, Y. J. Am. Chem. Soc. 1999, 121,
8486. (b) Inoue, Y.; Matsushima, E.; Takehiko, W. J. Am. Chem. Soc. 1998, 120,
10687. (c) “Optically Active (E/Z)-1,3-Cyclooctadiene: First Enantioselective
Synthesis through Asymmetric Photosensitization and Chirotopical Properties,” Inoue,
Y.; Tsuneishi, H.; Hakushi, T.; Tai, A. J. Am. Chem. Soc. 1997, 119, 472. (d) Inoue,
Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J. Org. Chem. 1993, 58, 1011. (e) Inoue, Y.;
Yamasaki, N.; Yokoyama, T.; Tai, A. J. Org. Chem. 1992, 57, 1332. (f) Inoue, Y.;
Yokoyama, T.; Yamasaki, N.; Tai, A. J. Am. Chem. Soc. 1989, 111, 6480. 16 For asymmetric photodeconjugation, see: (a) Piva, O.; Mortezaei, R.; Henin, F.;
Piva, O. Pure Appl. Chem. 1986, 58, 1257. 17 “Solvent Effects on Diastereoselective Intramolecular [2 + 2] Photocycloadditions:
Reversal of Selectivity through Intramolecular Hydrogen Bonding,” Crimmins, M. T.;
Choy, A. L. J. Am. Chem. Soc. 1997, 119, 10237 and references therein. 18 Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570. 19 Bilz, A.; Stork, T.; Helmchen, G.; Tetrahedron: Asymmetry 1997, 24, 3999. 20 See Turro, N. “Comparison of the Theoretical Distance Dependencies of Energy-
Transfer Rates and Efficiencies,” in Modern Molecular Photochemistry; University
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185
23 CHEM-EQUILI is a computer program for the calculation of equilibrium constant and
related values from many types of experimental data (IR, NMR, UV/Vis, and
fluorescence spectrophotometry, potentiometry, calorimetry, conductometry, etc.). It is
possible to use any combination of such kinds of methods simultaneously for reliable
calculations of equilibrium constants. For a detailed description see: (a) Solov’ev, V.
P.; Vnuk, E. A.; Strakhova, N. N.; Raevsky, O. A., “Thermodynamic of complexation
of the macrocyclic polyethers with salts of alkali and alkaline-earth metals” VINTI:
Moscow, 1991. (b) Solov’ev, V. P.; Baulin, V. W.; Strakhova, N. N.;Kazachenko, V.
P.; Belsky, V. K.; Varnek, A. A.; Volkova, T. A.; Wipff, G., J. Chem. Soc. Perkin
Trans. 2 1998, 1489. 24 For an authoritative account, see: Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999.
I. Experimental Section
i. Synthetic Procedures
a. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator. Analytical thin-layer chromatography (TLC) was carried out
using 0.2-mm commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254).
Preparative column chromatography employing silica gel was performed according to the
method of Still.* Melting points were determined on a Thomas-Hoover melting point
apparatus in sealed capillaries and are uncorrected. Infrared spectra were recorded on a
Perkin-Elmer 1420 spectrometer. High-resolution mass spectra were obtained on a
Karatos MS9 and are reported as m/e (relative intensity). Accurate masses are reported
for the molecular ion (M+1). Unless otherwise noted, proton nuclear magnetic resonance
(1H NMR) spectra were recorded with a Varian Gemini (300 MHz) spectrometer or a
Mercury (400 MHz) spectrometer. Chemical Shifts are reported in delta (δ) units, parts
per million (ppm) downfield from trimethylsilane. Coupling constants are reported in
Hertz (Hz). Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded
with a Varian Gemini 300 (75 MHz) spectrometer and a Mercury 400 (100 MHz)
spectrometer. Chemical shifts are reported in delta (δ ) units, parts per million (ppm)
relative to the center of the triplet at 77.0 ppm for deuteriochloroform. Enantiomeric
purity of sensitizing amines (R)-III-2.3 and (S)-III-2.3 was determined using a Varian
Pro Star HPLC equipped with a Chiracel OD column, eluting with 20% ethanol in
186
hexane. Enantiomeric ratios of photocycloaddition products were likewise determined
using a Chiracel OD column, eluting with 10% isopropanol in hexane.
b. Synthesis and Characterization of Cycloaddition Substrate S and Cycloadduct P
The quinolone photocycloaddition substrate S was prepared in accordance with a
literature procedure. Spectroscopic data for this comound, and photocycloaddition
product P were consitent with reported values. See: Kaneko, C. et al. J. Chem Soc. Chem.