1 R3 2 H* 3 1 n 3 1 3 R O N Ruthenium-Hydride and N 2 N R ... · Lansiumamide B Fruits of Clausena Lansium Leaves of Clausena Lansium 3rd EuCheMS 2010 Chemistry Congress 29.08 –
Post on 25-Sep-2020
1 Views
Preview:
Transcript
NH
O
Ru
PnBu
3
Ru
H
PnBu
3
N
O
PnBu
3
PnBu
3Ru
H
N
nBu
3P
PnBu
3
PnBu
3
O
Ru
H
NP
nBu
3
PnBu
3
O
nBu
3P
DMAPRu
H
N
DMAPP
nBu
3
PnBu
3
O
Ru
H
NP
nBu
3
PnBu
3
O
DMAP
DMAP
PnBu3
DMAP
toluene
T
[Ru0(PnBu3)xDMAPy]
ox. addition
red. ligandexchange ?
duplet/triplet quartet quartet triplet triplet
Literature and Further Reading (see also www.chemie.uni-kl.de/goossen)
(1) a) L. J. Gooßen, J. E. Rauhaus, D. Deng, Angew. Chem. Int. Ed. 2005, 44, 4042; b) L. J. Gooßen, K. S. M. Salih, M. Blanchot, Angew. Chem. Int. Ed. 2008, 47, 8492, c) L. J. Gooßen, M. Arndt, M.
Blanchot, F. Rudolphi, F. Menges, G. Niedner-Schatteburg, Adv. Synth. Cat. 2008, 350, 2701.
(2) L. J. Gooßen, M. Blanchot, M. Arndt, K. S. M. Salih, Synlett 2010, 1685.
(3) a) Yet, L. Chem. Rev. 2003, 103, 4283; b) Stefanuti, I.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 3735; c) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2004, 67, 1064.
(4) a) L. J. Gooßen, M. Blanchot, C. Brinkmann, K. Gooßen, R. Karch, A. Rivas-Nass, J. Org. Chem. 2006, 71, 9506; b) L. J. Gooßen, M. Blanchot, K. S. M. Salih, K. Gooßen, Synthesis 2009, 2283; c) L. J.
Gooßen, M. Blanchot, K. S. M. Salih, R. Karch, A. Rivas-Nass, Org. Lett. 2008, 10, 4497; d) A. E. Buba, M. Arndt, L. J. Gooßen J. Organomet. Chem. 2010, in press.
(5) Unpublished results.
(6) M. Tokunaga, T. Suzuki, N. Koga, T. Fukushima, A. Horiuchi, Y. Wakatsuki, J. Am. Chem. Soc. 2001, 123, 11917.
(7) M. Oliván, E. Clot, O. Eisenstein, K. G. Caulton, Organometallics 1998, 17, 3091.
Ruthenium-Hydride and –Vinylidene
Species as key Intermediates
in Hydroamidation Reactions
Abstract: The enamide moiety is an important motif often encountered in biologically active compounds and synthetic drugs. We have previously developed ruthenium-
based complexes as effective catalysts for the anti-Markovnikov addition of amides, imides, and thioamides to terminal alkynes.1 This method proved to be suitable for
the synthesis of several natural products, namely botryllamides C and E, lansamide I, lansiumamides A and B. These new reaction pathways proceed in only one to
three steps and yield the products in 57 to 98%, starting from cheap and easily available compounds.2
Comprehensive mechanistic studies were performed with the goal of getting a better understanding of the catalytic cycle. In this context the reaction mixture was
investigated in situ by NMR (1H, 1H{P}, 2H, 31P, 31P{H}, PP-COSY, HP-HMQC), ESI-MS/ -MS-MS and IR spectroscopy. Complemental deuterium labelling experiments
and kinetic studies were carried out and lead to the conclusion that a redox neutral mechanism must be excluded for the hydroamidation. The new findings support a
catalytic cycle starting from a ruthenium(0) species. Oxidative addition of the N-H nucleophile results in the formation of a ruthenium-amide-hydride species. The alkyne
then inserts into the ruthenium-hydride bond generating a ruthenium-vinyl species, which in the rate-determining step rearranges to a ruthenium-vinylidene-hydride
intermediate. This mechanism explains the anti-Markovnikov selectivity of such hydroamidation reactions and their restriction to terminal alkyne substrates.
The Enamide Functionality
The enamide moiety is an important substructure often found in natural products and synthetic
drugs.3 Enamides and their derivatives are also versatile synthetic intermediates,
e. g. for the preparation of heterocycles, chiral amines or amino acids.
Matthias Arndt, Mathieu Blanchot, Kifah S. M. Salih, Annette E. Buba, Lukas J. Gooßen*
“Dream Reactions”: Addition of Amides, Imides and Thioamides to Terminal Alkynes1,4
Traditional syntheses of enamides require harsh conditions, lead to the formation of mixtures of
E/Z products or suffer from the limited availability of the starting materials.
A much more attractive synthetic access is the Ru-catalyzed addition of amides to alkynes:
Institut für Organische Chemie, TU Kaiserslautern, Erwin-Schrödinger-Straße-54, 67663 Kaiserslautern,
Tel.: (+49) 0631 205 2046, goossen@chemie.uni-kl.de
Synthesis of Natural Products via Hydroamidation2
Following the protocol for the addition of primary amides to terminal alkynes the natural
products botryllamides C and E, lansiumamides A and B, and lansamide I could be synthesized
in 1-3 steps and 57-98% overall yield.
Mechanistic Investigations5
NH
O
Ph
NH
O
N
O
nBu
EtO
N
O
O
nBu
NH
O
nBu
Ph
O
N
nBu
NO
OnBu
N
SnBu
N
O
SiMe3 N
OtBu
N
O
CO2Me
N
O
N
O
(CH2)OMe
80%, Z/E = 1:3
96%, E/Z = 1: 22
90%, E/Z = 2:1
96%, E/Z = 40: 1
93%, E/Z = 40: 1
98%, E/Z = 1: 8
94%, E/Z = 1: 18
97%, E/Z = 8:1
99%, E/Z = 24: 1
99%, E/Z = 40: 1
99%, E/Z = 40: 1
94% ,E/Z = 22: 1
Chondria atropurpurea
NH
NH
O
NH
Chondriamide C
N
O
Lansamide I
N
O
Lansiumamide A
N
O
Lansiumamide B
Fruits of Clausena Lansium Leaves of Clausena Lansium
3rd EuCheMS 2010 Chemistry Congress
29.08 – 02.09.2010 Nürnberg / Germany
Marine ascidian Botryllus Schlosseri
OHO
O
N
O
Br Botryllamide C
OHO
O
N
O
Botryllamide E
1.0
0
0.8
7
0.8
9
0.4
1
0.9
0
[ppm]5 0 - 5 - 10 - 15 - 20 [ppm]5 0 - 5 - 10 - 15 - 20
-8.4
1-8
.45
-8.5
0
-8.5
9-8
.63
-8.6
8
-18.5
9-1
8.6
3
-18.6
8-1
8.7
2
-22.7
0-2
2.7
4-2
2.7
9-2
2.8
3
-11.4
4-1
1.5
0-1
1.5
5
-12.4
7-1
2.5
1-1
2.5
4
-8.3
5
-8.5
5
-8.7
4
-11.5
1
-11.6
3
-12.5
2
-18.6
6
-22.7
7b)
a)
1H-NMR experiments with 2-pyrrolidinone after heating
to 100°C for 5 min. a) 1H-NMR (C6D6, 600 MHz, 298 K),
b) 1H{31P}-NMR (C6D6, .400 MHz, 298 K).
P,P-COSY and H,P-HMQC experiments with 2-pyrroli-
dinone; spectra measured at 298 K after 5 min at 100°C.
[ppm]100 50 0
1.0
3
2.2
6
2.2
2
1.0
0
-7.9
8-8
.42
13.8
613.7
713.6
8
19.3
719.2
619.1
5
52.7
552.6
3
a)
13.8
313.7
613.7
1
19.3
619.2
819.2
419.1
6
-7.9
2-8
.02
-8.1
8
-8.2
7-8
.22
52.8
752.7
552.6
4
b)
31P-NMR experiments: with 2-pyrrolidinone after heating
to 100°C for 5 min. a) 31P-NMR (C6D6, 243 MHz, 298
K), b) 31P{1H}-NMR (C6D6, 243 MHz, 298 K).
593.28675.38
716.38
757.48
798.46
833.53
921.71
1003.80
1085.92
0
2
4
6
8
x104
Intens.
400 500 600 700 800 900 1000 1100 1200 m/z
631.2
712.3792.4
0
1
2
3
x104
Intens.
400 500 600 700 800 900 1000 1100 1200m/z
675.3
691.3 757.4
839.5
921.6
0
50
100
150
200 Intens.
400 500 600 700 800 900 1000 1100 1200 m/z
501.1 549.2
596.2 716.4
757.5
798.5
833.5
880.5921.7
0
1
2
3
4
x105
Intens.
400 500 600 700 800 900 1000 1100 1200 m/z
a) b)
c) d)
ESI-MS spectra for the hydroamidation of 2-pyrolidinone and
1-hexyne. a) 100°C for 5 min without 1-hexyne; b) with
1-hexyne 5 min at 100°C; c) 40 min; d) 150 min.
M+H+ = 918.58
[Ru(PC12H27)2(C7H10N2)2(C4H6NO)1(C6H10)1H]
M+H+ = 751.45
[Ru(PC12H27)2(C7H10N2)2]
M+H+ = 836.50
[Ru(PC12H27)2(C7H10N2)2(C4H6NO)1H]
[Ru(PC12H27)2(C7H10N2)2(C6H10)1H]+
M+H+ = 877.50
[Ru(PC12H27)3(C4H6NO)2]
dimerisation species:
M+H+ = 798.45
[Ru(PC12H27)1(C7H10N2)2(C4H6NO)1(C6H10)2H]
827.53828.54 829.55
830.54
831.54
832.54
833.53
834.53
835.53
836.54
837.55 838.58
827.53828.54 829.53
830.53
831.53
832.53
833.53
834.53
835.53
836.53
837.54
828 830 832 834 836 838 m/z
792.47793.48 794.52
795.49
796.47
797.47
798.46
799.48
800.47
801.48
802.49
792.48793.48 794.48
795.48
796.48
797.48
798.48
799.48
800.48
801.48
802.48
792 794 796 798 800 802 m/z
[Ru(PC12H27)1(C7H10N2)2(C4H6NO)1(C6H10)1H]+H+
593.28675.38
716.38
757.48
798.46
833.53
1003.80
1085.92
0
2
4
6
8
4x10
Intens.
400 500 600 700 800 900 1000 1100 1200 m/z
921.71
successful assignment of 7 different Ru intermediates and
detection of [PnBu3C4H7+]-fragments (not displayed) →
evidence for PnBu3 mediated reductive ligand exchange
R1
R2
N
O
H*R
3
N
R1
R2
OH
H* LnRu
LnRu
H*
N R1
R2
O
H
R3
LnRu
NR
1
R2
O
H
R3
H*
Ln-1
Ru
H*
NR
1
R2
O
H
R3
Ln-1
Ru
H
NR
1
R2
O
R3
H*
LnRu
H
N
R3
H*
R2O
R1
L
L = phosphine and/or additive
LL
L
a
b
cd
e
f
In situ NMR-
experiments
Kinetic Isotope Effects via NMR
competition hydroamidation reactions:
In situ NMR-Experiments
In situ ESI-MS Experiments
kH/kD= 1.5-2.3 → primary KIE → cleavage
of the C(sp)-H bond of the alkyne in the
rate-determining step → involvement of Ru-
vinylidene species very likely → vinylidene
formation see Wakatsuki6 and Caulton7
a) oxidative addition of an amide
b) coordination of an alkyne
to the resulting Ru-H-amide
intermediate
c) insertion of the p-coordinated
alkyne into Ru-H bond
d) rearrangement to a Ru-H-
vinylidene species
e) selective attack of the amide in
a-C position
f) reductive elimination of the
product and regeneration of
the active Ru(0) species
Mechanism for the Ru-catalyzed Hydroamidation
• no 1,2-proton shifts → confirmed via deuterium-labeling experiments
• formation of E-enamides with sterically less hindered ligands (e.g.
PnBu3, PnOc3) → thermodynamically favored product
• formation of Z-enamides with bulky, bidentate ligands (e.g. dcypm,
dcypb) → repulsion of R3 and ligands (Ru-H-vinylidene species)
N
nBu
H
H
R1
O
R2
N
nBu
H
D
R1
O
R2
NR1
O
R2
H
H
nBu
D
nBu
2 eq.
2 eq.
+kH /kD = 1.5-2.3
1 eq.[Ru]-cat.
R1
N
O
R2
R3
R1
N
S
R3
R2
R1
N
S
R3
R2
R1
N
O
R3
R4
O
R1
N
O
R3
R4
O
R1
N
O
R3
H
R1
N
O
R3
H
R1
N
O
R2
R3
R1
N
O
R2
R3
R1
N
O
R2
R3
R1
N
X
R2
H
R3
enamide, X=O
thioenamide, X=S
sec. enamide, X=O
enimide, X=O(cod)Ru(met)2
(cod)Ru(met)2
PnBu3
Sc(OTf)3
PiPr3
Sc(OTf)3
NEt3
PnBu3/DMAP
K2CO3/H2O
PnOc3
3Å MS
dcypmKOtBu
up to 98% yield20/1 E/Z
up to 78% yield1/8 E/Z
up to 99% yield40/1 E/Z
up to 99% yield1/40 E/Z
up to 92% yield20/1 E/Z
up to 98% yield1/20 Z/E
up to 78% yield15/1 E/Z
up to 99% yield1/8 E/Z
dcypm, H2O
up to 92% yield1/20 E/Z
dcypb/Yb(OTf)3
up to 99% yield20/1 E/Z
PnBu3/DMAP
(cod)Ru(met)2
(cod)Ru(met)2
RuCl3.3 H2O
+
R2=C(O)R3
R2=H
dcypb, Yb(OTf)3
enamide, X=O
Assig
nm
en
t PhNH
O
Ph
Ph
N
O
Ph
Ph
NH2
O
Ph
N
O
PhPh
+
MeI, NaH, 85%
Lansiumamide A98%, E/Z = 1 : 20
Lansiumamide B, E/Z = 20 : 178% overall yield
Lansamide I, E/Z = 20 : 172% overall yield
Ru/Yb dcypb
1. Ru/Yb, dcypb2. MS, NEt3, 85%
3. MeI, NaH, 85%
OHOMe
O
NH
R
OMe
OHOMe
NH2
O OMe
R
R = Br: botryllamide C(59% overall yield)
R = H: botryllamide E(57% overall yield)
R = Br, 88%, E/Z = 20:1R = H, 85%, E/Z = 20:1
1. Ru/Yb dcypb2. MS, NEt3
accessible in 67% yield
F2 [ppm] 40 20 0 - -20 F1 [ppm] 5 0 -5 -15 -10
F1 [
pp
m]
40
20
0
-20
F1 [
pp
m]
40
20
0
- 20
Simulated pattern:
Simulated pattern:
top related