· General Methods S2 . General Procedures for the Copper-Catalyzed Allylic Alkylation of S3. Allylic Halides with Organolithium Reagents . Optimization Study: Additional Data S5.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
S1
Supplementary Information
for:
Catalyst-Controlled Reverse Selectivity in C-C Bond Formation:
NHC-Cu-Catalyzed α-Selective Allylic Alkylation with Organolithium Reagents
Stefano F. Pizzolato, Massimo Giannerini, Pieter H. Bos, Martín Fañanás-Mastral*
and Ben L. Feringa*
Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm.
Components were visualized by UV light (254 nm) and/or phosphomolybdic acid or potassium
permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC,
HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies 19091s-433, Palo Alto,
CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI) or a LTQ Orbitrap
XL (APCI; ESI). 1H NMR and 13C NMR were recorded on a Varian AMX400 (400 and 100.59
MHz, respectively) or a Varian VXR200 (200 and 50 MHz, respectively) using CDCl3 as solvent.
Chemical shift values are reported in ppm with the solvent resonance as the internal standard
(CHCl3: δ = 7.26 ppm for 1H, δ = 77.0 ppm for 13C). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet, sept = septet, br =
broad, m = multiplet), coupling constants (Hz) and integration (nH). All reactions were carried out
under a nitrogen atmosphere using oven dried glassware or using standard Schlenk techniques.
CH2Cl2 was dried and distilled over calcium hydride; toluene was dried and distilled over sodium; nhexane was dried over molecular sieves. Cinnamyl bromide (1a), cinnamyl chloride (1j), NatOBu,
KtOBu and all copper-salts (CuCl CuSCN, CuTC [Copper(I)-thiophene-2-carboxylate] and
CuBr.SMe2) were purchased from Sigma-Aldrich and used without further purification. Allyl
bromides 1b-k were prepared following literature procedures (1b1, 1c2, 1d1, 1e1, 1f3, 1g4, 1h5, 1i6,
1k3). Organolithium reagents were purchased from Sigma-Aldrich (MeLi (1.6 M in diethyl ether),
EtLi (0.5 M in benzene/cyclohexane 9:1), nHexLi (2.3 M in nhexane), secBuLi (1.4 M in
cyclohexane), PhLi (1.8 M in dibutyl ether)) or from Acros (nBuLi (1.6 M in nhexane), isoBuLi (1.6
M in nheptane)). Ligands L1-2-3-6-8 were purchased from Sigma-Aldrich. Ligands L4,7 L5,8 L77
and L99 were prepared as reported in the literature.
S3
General Procedures for the Copper-Catalyzed Allylic Alkylation of Allylic Halides with
Organolithium Reagents
General Procedure (A) for Cu-NHC catalyzed allylic alkylation of allylic halides with
organolithium reagents (preformation of the catalyst by addition of NaOtBu or KOtBu).
A flame-dried Schlenk tube equipped with septum and stirring bar under nitrogen atmosphere is
charged with copper salt (0.015 mmol, 5 mol%), NHC ligand salt (0.0165 mmol, 5.5 mol%) (the
copper and ligand salts used in each experiment are reported in the optimization and scope tables)
and solid base (NaOtBu or KOtBu as reported) (0.0165 mmol, 5.5 mol%). The tube is evacuated and
backfilled with nitrogen three times, then dry CH2Cl2 (1 mL) is added and the solution is stirred
under nitrogen at r.t. for 30 min. The solution is cooled down (at the reported temperature) and
stirred over 10 min. The allylic halide (0.3 mmol) is dissolved in dry CH2Cl2 (1 mL), injected in the
mixture under stirring and stirred over 10 min. In a separate flame-dried Schlenk tube, the
organolithium reagent (reported equivalents) is diluted to a combined volume of 1 mL with dry
hexane (dry toluene was employed in the case of MeLi due to gelation) under nitrogen and slowly
injected dropwise in the reaction mixture (over the reported time) using a syringe pump. The flow of
inert gas was turned off during the addition to prevent the drops of organolithium reagent from
drying on the tip of the needle. Once the addition is complete, the mixture is stirred for 2 h. The
reaction is quenched with NH4Cl sat. (2 mL), the mixture is warmed up to r.t., diluted with CH2Cl2
(5 mL) and the layers are separated. The aqueous layer is extracted with CH2Cl2 (3 x 5 mL) and the
combined organic layers are dried over Na2SO4, filtered and the solvent is evaporated in vacuo.
Purification is performed by column chromatography on silica gel using different mixtures of
pentane:Et2O as eluent. Note: Gas chromatography analysis is carried out to determine the
SN2:SN2’:homocoupling ratio on a sample obtained after work up, which has been passed through a
short plug of silica gel to remove transition metal residues.
General Procedure (B) for Cu-NHC catalyzed allylic alkylation of allylic halides with
organolithium reagents (preformation of the catalyst by addition of nBuLi).
A flame-dried Schlenk tube equipped with septum and stirring bar under nitrogen atmosphere is
charged with CuBr.SMe2 (0.015 mmol, 5 mol%) and NHC ligand salt (0.0165 mmol, 5.5 mol%) (the
ligand salt used in each experiment are reported in the optimization and scope tables). The tube is
evacuated and backfilled with nitrogen three times, then dry CH2Cl2 (1 mL) is added and the
solution is stirred under nitrogen at r.t. for 10 min. The solution is cooled down to -80 °C, then 2
drops of nBuLi (0.0165 mmol, 5.5 mol%, 1.6 M) are injected in the mixture and stirred over 15 min.
The addition of allylic halide and organolithium reagent, work up of the reaction and analysis are
performed as previously described in Procedure (A).
S4
General Procedure (C) for Cu-NHC catalyzed allylic alkylation of allylic halides with
organolithium reagents (without preformation of the catalyst).
A flame-dried Schlenk tube equipped with septum and stirring bar under nitrogen atmosphere is
charged with CuBr.SMe2 (0.015 mmol, 5 mol%) and NHC ligand salt (0.0165 mmol, 5.5 mol%) (the
ligand salt used in each experiment are reported in the optimization and scope tables). The tube is
evacuated and backfilled with nitrogen three times, then dry CH2Cl2 (1 mL) is added and the
solution is stirred under nitrogen at r.t. for 10 min. The solution is cooled down to -80 °C and stirred
over 10 min. The addition of allylic halide and organolithium reagent, work up of the reaction and
analysis are performed as previously described in Procedure (A).
S5
Optimization Study: Additional Data
A. Blank reactions in different solvents
Ph Br + nBuLiSolvent , T
Ph Ph+nBu
nBu
α−product γ−product
Ph+
Ph
1a
2a 3a Ph
Ph
homocoupling products
Allylic substitutionproducts
4
Table S1
Entrya Solvent Addition time Temperature Conversion (%)b 2a:3a:4 (%)b
1 CH2Cl2 3 h -80 °C 83 48:16:36
2 CH2Cl2 3 h r.t. full 47:19:34
3 CH2Cl2 direct r.t. full 48:21:31
4 toluene 3 h -80 °C 50 57:15:28
5 toluene 3 h 0 °C full 50:21:29
6 toluene 3 h r.t. full 49:25:26
7 toluene direct r.t. full 54:23:23
8 THF 3 h -80 °C full 21:5:74
9 MTBE 3 h -80 °C full 53:17:30
a Reaction conditions: 0.3 mmol of 1a in 2 mL of dry solvent. nBuLi (0.45 mmol, 1.6 M in hexane) diluted with dry hexane (final
conc. 0.45 M) added over 3h. Reaction mixture was further stirred for 2 h at -80 oC. b Determined by GC and 1H NMR.
Preliminary results obtained by addition of to a solution of cinnamyl bromide in CH2Cl2 at -80 °C
over 3 hours showed incomplete conversion, low selectivity and large amount of homocoupling
products (Table S1, entry 1). Performing the reaction at room temperature with long or short time of
addition of nBuLi afforded full conversion without any improvement in regioselectivity (entries 2-3).
The use of toluene afforded similar results in all the previous conditions (entries 4-7). The use of a
coordinating solvent as THF afforded full conversion unfortunately with large quantities of
homocoupling products (entry 8). The use of MTBE yielded result comparable to CH2Cl2 (entry 9).
Reaction conditions: General Procedure (C). 0.015 mmol (5.0 mol%) of CuBr·SMe2 and 0.0165 mmol (5.0 mol%) of L2 in 1 mL of dry CH2Cl2 cooled at -80 C̊. 0.3 mmol of substrate dissolved in 1 mL of dry CH2Cl2 and added to the cooled mixture. nBuLi (0.36 mmol, 1.6 M in hexane) diluted with dry hexane (final conc. 0.36 M) added over 3 h. Reaction mixture stirred for 2 h at -80 oC. Ratios determined by GC and 1H NMR.
S12
Product Characterization
(E)-Hept-1-enylbenzene (2a)
Synthesized according to General Procedure C. Colorless oil obtained
as a 98:2 mixture of 2a and 3a after column chromatography (SiO2,
pentane), [78% yield] from 1a as starting material and nBuLi. A 94:6
mixture of 2a and 3a was obtained after column chromatography (SiO2, pentane), [85% yield] from
1j as starting material and nBuLi. The physical data were identical in all respects to those previously
14.4. One 13C signal is missing or overlapping (C=C double bond). LRMS (ESI) m/z (abundance%,
ion label): 55(99), 69(100), 83(76), 97(66), 111(26), 125(8), 210(20, M+).
(Z)-Hept-1-enylbenzene (2o)
Synthesized according to General Procedure C from 1k (Z:E ratio = 94:6)
as starting material and nBuLi. Colorless oil obtained as a 94:6 mixture of
2o (Z:E ratio = 94:6) and 3o after column chromatography (SiO2, pentane),
[77% yield]. The physical data were identical in all respects to those previously reported.15 (Z)-2o: 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.38-7.28 (m, 4H), 7.25-7.23 (m, 1H), 6.43 (d, J = 11.7 Hz,