Copper-catalyzed highly enantioselective 1,4-conjugate addition of trimethylaluminum to 2-cyclohexenone

Article abstract of DOI:10.1016/S0957-4166(02)00361-0

New bidentate phosphites were prepared starting from BINOL and H₈-BINOL. Utilization of these ligands in the copper-catalyzed enantioselective conjugate addition of trimethylaluminum to 2-cyclohexenone afforded 3-methylcyclohexanone with up to

Full text of DOI:10.1016/S0957-4166(02)00361-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1393–1396
Copper-catalyzed highly enantioselective 1,4-conjugate addition
of trimethylaluminum to 2-cyclohexenone
Liang Lianga,b and Albert S. C. Chana,*
aOpen Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis† and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
bFaculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, China
Received 10 June 2002; accepted 2 July 2002
Abstract—New bidentate phosphites were prepared starting from BINOL and H8-BINOL. Utilization of these ligands in the
copper-catalyzed enantioselective conjugate addition of trimethylaluminum to 2-cyclohexenone afforded 3-methylcyclohexanone
with up to 96% e.e. The scope of this process using various copper sources was investigated. © 2002 Published by Elsevier Science
Ltd.
1. Introduction
organometallic reagents to cyclic enones have been
widely studied in the last decade, very little attention
has been paid to the 1,4-additions of trialkylaluminum
reagents. Since trialkylaluminums are produced on
industrial scales, new chemistry using these reagents
may generate more practical applications. Recently,
Dieguez et al reported an effective phosphine–phosphite
ligand that gave 62% e.e. in the reaction of triethylalu-
minum with 2-cyclohexenones.11 Herein, we report an
effective catalytic enantioselective conjugate addition of
trimethylaluminum to 2-cyclohexenone.
The 1,4-conjugate addition of organometallic reagents
to a,b-unsaturated ketones is a useful method for the
introduction of a hydrocarbon unit to the b-position of
a carbonyl function.1 In recent years considerable pro-
gress has been achieved in the development of the
copper-mediated catalytic versions of the enantioselec-
tive 1,4-addition of organozinc reagents to enones.2–4
Among the different chiral ligands used for this pur-
pose, phosphoramidites,5 peptide-based phosphines,6
BINOL-based diphosphites,7 phosphites,8 TADDOL-
derivatives,9 and oxazoline–phosphites10 have proven to
be effective chirality sources in the reaction of dialkyl-
zinc compounds with cyclic enones and acyclic enones.
However, the development of effective ligands for the
asymmetric conjugate addition to enones, in particular
using trialkylaluminum reagents is still a challenge.
Although the asymmetric 1,4-additions of many
2. Results and discussion
A new family of chiral aryl diphosphite ligands, 1–3,
were prepared in our studies of diphosphite ligands
containing binaphthyl and H8-binaphthyl moieties (Fig.
1).
Figure 1.
* Corresponding author. E-mail: bcachan@polyu.edu.hk
† A University Grants Committee Areas of Excellent Scheme in Hong Kong.
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00361-0

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L. Liang, A. S. C. Chan / Tetrahedron: Asymmetry 13 (2002) 1393–1396
These new ligands were synthesized in a one-step
reaction from the chlorophosphite of (S)-H8-BINOL
with (R)- or (S)-BINOL or (S)-H8-BINOL. As a
model reaction, the copper-catalyzed 1,4-conjugate
addition of trimethylaluminum to 2-cyclohexenone 4
was examined by using ligands 1–3 with a number of
copper sources including Cu(OTf)2, (CuOTf)2·C6H6
and Cu(CH3CN)4·BF4 as catalyst precursor. All reac-
tions were carried out at 0°C in the presence of 1
mol% of CuX and 2 mol% of ligand under nitrogen
was dominated by the end groups of the chiral lig-
and.
Table 2 shows more detailed results from the experi-
ments under various conditions by using ligand 1.
The influence of different copper sources was
observed in the reaction (entries 2, 6 and 7). For
example, when [Cu(CH3CN)4] BF4 was used as the
copper source the reaction proceeded smoothly with
high enantioselectivity. The highest e.e. value of 5
96% was obtained using copper(II) triflate. The effect
of the solvent on the enantioselectivity of the reaction
atmosphere. Table
1 summarized the preliminary
results obtained by using (CuOTf)2·C6H6 with 1–3 in
the 1,4-addition of trimethylaluminum to 2-cyclo-
hexenone in dichloromethane. The results indicated
that 1–3 were effective ligands in the 1,4-addition
reaction. Ligand 1 was particularly effective, giving
the desired product in 91% e.e. at 83% yield (entry
1). It was obvious from Table 1 that the bridging
moiety profoundly affected the enantioselectivity of
the asymmetric catalytic reaction: when the configura-
tion of the bridging moiety of the ligand was changed
from S to R (entries 1 and 3, from ligand 1 to ligand
3), the catalyst exhibited higher enantioselectivity
(91% e.e.) in the catalytic reaction. This result was
consistent with the expectation that the alkylation
reaction with trimethylaluminum was sensitive to the
steric properties of the ligand. The experimental
results also indicated that the asymmetric induction
was
also
examined
(entries
2–5).
Toluene,
dichloromethane and diethyl ether were found to give
good results (>90% e.e.) while the use of a more
polar solvent such as tetrahydrofuran gave less satis-
factory results (entry 5, 62% e.e.).
3. Conclusion
In conclusion, the present investigation reveals that
the application of a new diphosphite ligand in the
copper-catalyzed 1,4-conjugate addition of trimethyl-
aluminum to 2-cyclohexenone induces high enantiose-
lectivity. To the best of our knowledge, the new
catalyst system gives the best e.e. value achieved to
date in this reaction.
Table 1. The effect of ligands 1–3 on the 1,4-addition of trimethylaluminum to 2-cyclohexenones
Entry
(CuOTf)2·C6H6 (mol%)
Ligands (mol%)
Yielda,b,c of 1,4-product (%)
E.e. (%)/configurationd
1
2
3
1
1
1
(S,R,S)-1 (2)
(S,R,S)-2 (2)
(S,S,S)-3 (2)
83
85
83
91 (−)/S
68 (−)/S
69 (−)/S
a The reaction of 2-cyclohexenone (0.5 mmol) and AlMe3 (0.5 mmol) was performed in CH2Cl2 at 0°C for 6 h (the molar ratio of 2-cyclohexenone,
trimethylaluminum, and (CuOTf)2·C6H6 was 100: 100:1).
b The yields and e.e. values were determined by GC with a Chiraldex A-TA column (50 m×0.25 mm) using dodecane as an internal standard.
c A trace amount of the 1,2-product was formed.
d The absolute configuration was determined by the specific rotation (Ref. 13).
Table 2. The effect of solvents and copper source on the 1,4-addition of trimethylaluminum to 2-cyclohexenone
Entry
Catalyst (mol%)
(S,R,S)-1 (mol%)
Solvents
Yielda,b (%) (1,4-product)
E.e. (%)/configuration
1
2
3
4
5
6
7
[Cu(CH3CN)4]·BF4 (1)
[Cu(CH3CN)4]·BF4 (1)
[Cu(CH3CN)4]·BF4 (1)
[Cu(CH3CN)4]·BF4 (1)
[Cu(CH3CN)4]·BF4 (1)
(CuOTf)2·C6H6 (1)
Cu(OTf)2 (1)
–
2
2
2
2
2
2
CH2Cl2
CH2Cl2
Toluene
Et2O
THF
CH2Cl2
CH2Cl2
48
81
56
64
69
83
60
rac
96 (−)/S
91 (−)/S
91 (−)/S
62 (−)/S
91 (−)/S
95 (−)/S
a The reactions were performed at 0°C for 6 h.
b Trace 1,2-product was formed.

L. Liang, A. S. C. Chan / Tetrahedron: Asymmetry 13 (2002) 1393–1396
1395
4. Experimental
23.02, 23.09, 27.62, 27.79, 27.85, 29.18, 29.27, 29.76,
117.90, 118.91, 119.17, 127.82, 128.27, 129.04, 129.33,
129.53, 133.82, 133.99, 135.05, 137.21, 138.04, 138.58,
145.70, 146.16, 147.25 ppm; [h]2D0=+91.1 (c 1.0, tolu-
ene); HRMS calcd for C60H60O6P2: 938.3865, found:
938.4191.
4.1. General
Unless otherwise indicated, all experiments were carried
out under dry N2 atmosphere. Toluene and diethyl
ether were distilled from sodium and dichloromethane
was distilled from CaH2. 2-Cyclohexenone 4 (ACROS)
and PCl3 were distilled before use. BINOL was dried by
toluene azeotrope before use. The following substances
were from commercial sources and were used without
further purification: (CuOTf)2·C6H6, Cu(OTf)2, AlMe3
(97%, Aldrich).
1
(S,S,S)-3: 31P NMR (CD2Cl2): l 138.39 ppm; H NMR
(CD2Cl2): l 8.09–8.07 (d, 2H), 7.99–7.97 (d, 2H), 7.56–
7.55 (d, 2H), 7.45–7.44 (t, 2H), 7.32–7.20 (m, 6H),
7.01–7.00 (d, 2H), 6.85–6.83 (d, 2H), 6.03–6.02 (d, 2H),
2.82–2.60 (m, 8H), 2.57–2.53 (m, 4H), 2.16–2.07 (m,
4H), 1.80–1.66 (m, 12H), 1.49–1.42 (m, 4H); 13C NMR
(CD2Cl2): l 22.48, 22.67, 27.72, 29.14, 118.65, 118.89,
120.03, 122.58, 125.21, 125.91, 126.97, 127.64, 128.20,
128.25, 129.11, 129.27, 130.09, 130.98, 134.06, 134.19,
135.08, 137.56, 138.50, 145.52, 145.86; [h]2D0=+98.0 (c
1.0, toluene); HRMS calcd for C60H52O6P2: 930.3241,
found: 930.3161.
31P, 1H and 13C NMR spectra were recorded on a
Varian AS500 spectrometer. E.e. values were deter-
mined by chiral GC analysis (Chiraldex A-TA column
50 m×0.25 mm) in comparison with authentic materials
(3-methylcyclohexanone, ACROS). High-resolution
mass spectrometry was performed using a Finnigan
MAT 95S model spectrometer. Optical rotations were
measured on a Perkin–Elmer 241 MC (at 20°C). GC
analyses were performed on an HP 5890 apparatus
equipped with FID.
4.4. General procedure for the reaction of 2-cyclo-
hexenone with trimethylaluminum
12
A solution of [Cu(CH3CN)4]·BF4 (0.005 mmol) and 1
(0.01 mmol) in CH2Cl2 (5 mL) was stirred under a
nitrogen atmosphere at ambient temperature for 0.5 h
The resulting mixture was then treated with 2-cyclo-
hexenone (0.5 mmol). The reaction mixture was cooled
to 0°C and trimethylaluminum (97%, 0.6 mmol) was
added via gas-tight syringe. The stirring was continued
at 0°C for 6 h and the reaction mixture was quenched
by adding saturated of NH4Cl solution (2 mL). After
extraction with Et2O (3×2.0 mL), the organic layers
were combined. The solvent was removed under
reduced pressure after the solution was dried with
MgSO4. Purification by flash column chromatography
afforded the pure product as a clear oil. [h]2D0=−12.7 (c
0.7, CHCl3). The e.e. values of the resulting (S)-(−)-5
were determined by chiral GC (Chiraldex A-TA chiral
capillary column, 50 m×0.25 mm, 80°C, 165 kPa, N2,
tR=26.4 (S), 27.2 min (R), internal standard dodecane
tR=35.3 min).
4.2. Synthesis of (S,R,S)-1
A solution of (S)-H8-BINOL (882 mg, 3 mmol) in
toluene (25 mL) at ambient temperature was added to a
cooled solution (−60°C) of PCl3 (270 mL, 3 mmol) and
Et3N (860 mL, 6 mmol), in toluene (5 mL) over 5 min.
The reaction mixture was stirred for 2 h, warmed to
room temperature, and filtered. The filtrate was treated
with a solution of Et3N (290 mL, 2.9 mmol), (R)-
BINOL (400 mg, 1.4 mmol), and 40 mg DMAP in
toluene (25 mL) at 0°C and the temperature of the
mixture was allowed to rise to ambient temperature.
After 6 h at room temperature, the reaction mixture
was filtered, concentrated, and purified by chromatog-
raphy (silica gel, hexane/EA: 3/1) to give the pure
product, (S,R,S)-1 (85% yield): 31P NMR (CDCl3): l
1
138.3 ppm; H NMR (500 MHz, CD2Cl2): l 8.05–8.04
(d, 2H), 8.00–7.99 (d, 2H), 7.49–7.47 (m, 4H), 7.30–7.28
(t, 2H), 7.20–7.18 (m, 2H), 6.95–6.94 (d, 2H), 6.73–6.72
(d, 2H), 6.42–6.41 (d, 2H), 5.3–5.28 (d, 2H), 2.71–2.47
(m, 12H), 2.09–2.04 (m, 4H), 1.69–1.61 (m, 12H), 1.45–
1.41 (m, 4H); 13C NMR (CD2Cl2): l 22.45, 22.51,
22.65, 22.68, 27.67, 27.75, 29.07, 29.13, 118.50, 118.79,
123.11, 125.31, 126.11, 127.10, 127.48, 128.23, 128.78,
129.07, 129.29, 130.28, 121.38, 131.24, 134.00, 134.21,
135.16, 137.14, 138.06, 138.54, 145.82, 148.37 ppm; mp
167°C; [h]2D0=+87.9 (c 1.0, toluene); HRMS calcd for
C60H52O6P2: 930.3241, found: 930.3306.
Acknowledgements
We thank The Hong Kong Polytechnic University ASD
Fund and The Hong Kong Research Grants Council
(Project Number Polyu 5152/98P) for financial support
of this study.
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