Enantioselective addition of diethylzinc to aldehydes induced by a new chiral Ti(IV) catalyst

Article abstract of DOI:10.1016/S0957-4166(98)00415-7

A new chiral titanium reagent, derived from optically active trans-1,2- dicamphorsulfonamidocyclohexane 2a and Ti(O(i)Pr)₄, was found to promote the enantioselective addition of diethylzinc to various aldehydes giving rise to the corresponding

Full text of DOI:10.1016/S0957-4166(98)00415-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3979–3984
Enantioselective addition of diethylzinc to aldehydes induced by
a new chiral Ti(IV) catalyst
Chyuan-Der Hwang and Biing-Jiun Uang ∗
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300
Received 19 August 1998; accepted 5 October 1998
Abstract
A new chiral titanium reagent, derived from optically active trans-1,2-dicamphorsulfonamidocyclohexane 2a
and Ti(OiPr)4, was found to promote the enantioselective addition of diethylzinc to various aldehydes giving rise to
the corresponding alcohols in high yields with moderate to high selectivity. © 1998 Published by Elsevier Science
Ltd. All rights reserved.
1. Introduction
In recent years, there has been a great deal of interest in the development of metal catalyzed asymmetric
reactions1 and also the synthesis of ligands2 that result in high enantioselectivity. To design efficient
asymmetric catalysts, particularly in the case of nucleophilic addition of an alkyl metal on aldehyde,
we became interested in developing a much simpler and readily available ligand possessing electron-
withdrawing groups that feature a deep chiral pocket after complexation with Ti(OiPr)4.3–5 In such a
modified Lewis acid, the chiral ligand will not only provide a chiral environment but also increase the
Lewis acidity of the catalyst which we believe to be crucial in order to realize an efficient catalytic
process.
2. Results and discussion
2.1. Preparation of ligands 2a and 2b
Based on the above considerations, we have developed potentially useful C2-symmetrical trans-1,2-
biscamphorsulfonamidocyclohexane 2a, 2b ligands for used in a catalytic enantioselective alkylation of
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00415-7

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aldehydes by the disulfonamide–Ti(OiPr)4–dialkylzinc system.3–5 Compound 2a and 2b were synthesi-
zed respectively from (+)- and (−)-trans-1,2-diaminocyclohexane by reacting with 2 equiv. of (1S)-(+)-
10-camphorsulfonyl chloride in the presence of triethylamine. Alternatively, by treating (ꢀ)-trans-1,2-
diaminocyclohexane under the same conditions mentioned above (Scheme 1), 2a and 2b can be isolated
by selective crystallization (vide infra).
Scheme 1.
2.2. Enantioselective addition of diethylzinc to aldehydes catalyzed by 2/Ti(OiPr)4 complex
After the synthesis of 2a and 2b, we started a study of the diethylzinc addition reaction catalyzed by
a complex conveniently prepared by mixing small amounts of 2a or 2b with Ti(OiPr)4. The catalyst was
found to be highly effective for the enantioselective addition of diethylzinc to a variety of aldehydes
(Eq. 1). Since benzaldehyde has been extensively studied,6,7 we focused our efforts on the diethylzinc
addition to benzaldehyde in our initial study so that the results can be easily compared with those from
previous studies.3–7 The reaction was found to be quite clean with essentially no byproduct observed
(Table 1). By using hexane, dichloromethane and toluene as solvents and 20 mol% of chiral ligand 2a at
−20°C, the addition products were isolated in 96–99% yield with 73–81% enantiomeric excess (ee) in
favor of the S isomer. However, in THF solution at 27°C the addition product was obtained in 89% yield
with 91% ee (entry 5). When ligand 2b was applied to the same reaction conditions as 2a using hexane
as solvent, the addition product was isolated in 99% yield with 57% ee in favor of the R isomer (entry
2). Although, using THF as solvent gave the best enantioselectivity in the case of benzaldehyde, it was
not the best solvent for other aldehydes since a slower reaction rate and inferior enantioselectivity was
observed; for instance, p-methoxybenzaldehyde gave 28% yield and 68% ee of the addition product after
reaction at 30°C for 16 h.
(1)
The applicability of the present catalytic system to the diethylzinc addition reaction with various
substituted aldehydes was then examined using hexane as the solvent at −20°C. The results are summa-
rized in Table 2. From Table 2, it can be observed that for para-substituted benzaldehydes, an electron-
donating substituent (e.g. a methoxy group, entry 1) was found to increase the enantioselectivity of the
reaction while an electron-withdrawing substituent (e.g. a chloride group, entry 2) was found to decrease
it. For the ortho-substituted benzaldehyde, significantly lower enantioselectivity was observed. This is
probably due to the strong steric interaction between ortho-substituent and chiral ligand thus weakening
the coordination of the substrate to the chiral catalyst. This would effectively reduce the influence
of the chiral environment of the catalyst on the orientation of the substrate, and consequently lower

C.-D. Hwang, B.-J. Uang / Tetrahedron: Asymmetry 9 (1998) 3979–3984
3981
Table 1
Enantioselective addition of diethylzinc to benzaldehyde (3a) catalyzed by 2/Ti(OiPr)4 complexa
Table 2
Enantioselective addition of diethylzinc to aldehydes catalyzed by 2a/Ti(OiPr)4 complexa
enantioselectivity was observed for the alkylation of 2-methoxybenzaldehyde (entry 3). In comparison
with benzaldehyde, the sterically more demanding 2-naphthaldehyde gave better enantioselectivity (entry
4). Additionally, (E)-cinnamaldehyde and 3-phenylpropionaldehyde gave addition products in 88 and
76% ee respectively. All addition products are in the S configuration by comparison of the [α]D value
with literature data.
In conclusion, a new chiral ligand has been developed and has been shown to catalyze the addition of
diethylzinc to a variety of aldehydes with moderate to high enantioselectivity after complexation with
Ti(OiPr)4. Further modification of the ligand and the exploration of potential asymmetric catalysis in
other reactions are in progress.
3. Experimental section
3.1. General
All melting points were uncorrected. 1H and 13C NMR were measured on Varian GEMINI-300, Varian
UNITY-400 or Bruker AC-300 MHz NMR spectrometers. HRMS analyses were measured on a JEOL
JMS-HX110 mass spectrometer. HPLC analysis were performed on a HITACHI L-6200 chromatography
system with L-4200 UV detector at 254 nm. Chiralcel OD column was purchased from Daicel Chemical
Industries, Ltd. Optical rotations were measured with a DIP-1000 polarimeter. CH2Cl2 was distilled from

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CaH2. THF was distilled from potassium. Hexane and toluene were distilled from sodium. Ti(OiPr)4 was
purchased from Aldrich. Et2Zn was purchased from STREM.
3.2. (1R,2R)-N,N0-Bis[(1S,4R)-7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptylmethanesulfonyl]-1,2-cyclo-
hexyldiamine 2a and (1S,2S)-N,N0-bis[(1S,4R)-7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptylmethane-
sulfonyl]-1,2-cyclohexyldiamine 2b
(1S)-(+)-10-Camphorsulfonyl chloride 1 (5.20 g, 20.8 mmol) in CH2Cl2 (25 mL) was added to a stirred
solution of triethylamine (3 g, 42 mmol) and racemic trans-1,2-diaminocyclohexane (1.14 g, 10 mmol) in
CH2Cl2 (5 mL) at 0°C over a 1 h period. The reaction was then allowed to come to room temperature and
stirred for an additional hour. The reaction was quenched by pouring into saturated NaHCO3 solution
(20 mL) then the pH value was adjusted to 7 and the aqueous phase was extracted with CH2Cl2. The
combined organic phase was washed with brine, dried with Na2SO4, then evaporated to give a mixture
of 2a and 2b (5.37 g, 99%). About 10% of the diastereomer 2a was crystallized and collected when
a boiling solution of ethyl acetate saturated with the mixture of 2a and 2b was cooled to 25°C. The
remaining solution was added with hexane to the cloudy point. After standing for 12 h, about 10% of the
diastereomer 2b was crystallized and collected. The remaining solution was concentrated and the above
procedure was repeated. Thus, about 75% of 2a and 2b were separated into pure form by repeating the
aforementioned procedure five times. 2a: mp 242°C; [α]D +26.2 (c 1.0, CHCl3); 1H NMR (400 MHz,
26
CDCl3): δ 0.88 (s, 6H), 1.01 (s, 6H), 1.25–1.45 (m, 6H), 1.65–1.75 (m, 2H), 1.86–2.39 (m, 14H), 2.97
(d, J=15 Hz, 2H), 3.15 (m, 2H), 3.47 (d, J=15 Hz, 2H), 5.55 (d, J=6 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 185.23, 58.71, 57.29, 50.53, 48.29, 42.61, 42.39, 33.54, 26.79, 25.80, 24.16, 19.52, 19.34;
HRMS (M+) calcd for C26H42O6N2S2 542.2484, found 542.2457; IR (KBr) 3362, 1750, 1636 cm−1. 2b:
26
1
mp 227°C; [α]D +41.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3): δ 0.85 (s, 6H), 1.03 (s, 6H),
1.30–1.45 (m, 6H), 1.56–2.10 (m, 10H), 2.20–2.30 (m, 2H), 2.30–2.42 (m, 4H), 2.98 (d, J=15 Hz, 2H),
3.20–3.23 (m, 2H), 3.51 (d, J=15 Hz, 2H), 5.49 (d, J=6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 185.33,
58.87, 56.56, 51.24, 48.36, 42.73 (2C), 33.89, 26.85, 25.46, 24.27, 19.74, 19.63; HRMS (M+H)+ calcd
for C26H43O6N2S2 543.2563, found 543.2570; IR (KBr) 3362, 1750, 1636 cm−1
.
3.3. General procedure for the enantioselective addition of diethylzinc to aldehydes
To a stirred solution of compound 2a (0.11 g, 0.20 mmol) in dichloromethane (5 mL) was added
titanium tetraisopropoxide (0.42 mL, 1.4 mmol) under Ar at room temperature. After stirring for 1 h, the
mixture was cooled to −78°C and diethylzinc9 (0.30 mL, 3.0 mmol) was added. The resulting mixture
was stirred for 0.5 h, then benzaldehyde (0.1 mL, 1 mmol) was added. The mixture was stirred at −78°C
for an additional 0.5 h then warmed to −20°C. The disappearance of the aldehyde was monitored by thin
layer chromatography (ethyl acetate/hexane=1/5). The reaction mixture was quenched with 1 N HCl (10
mL), filtered, and the filtrate was extracted with ethyl acetate (3×5 mL). The combined organic extracts
were washed with brine and dried over anhydrous MgSO4, then concentrated in vacuo. The residue was
distilled under reduced pressure (100°C/0.3 mmHg) to afford (S)-1-phenylpronpanol 135 mg (99%).
3.4. Determination of enantiomeric excess (ee) of the corresponding alcohol
3.4.1. 1-Phenylpropanol 4a
Crude product was purified by bulb to bulb distillation (100°C/0.3 mmHg) to give S-enriched product
(99%): [α]D −36.6 (c 0.99, CHCl3) [lit.8 [α]D −47.6 (c 6.11, CHCl3) for S enantiomer in 98% ee].
24
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C.-D. Hwang, B.-J. Uang / Tetrahedron: Asymmetry 9 (1998) 3979–3984
3983
The product was determined as 81% ee by HPLC analysis. The tR of the R isomer is 14.1 min and that
for the S isomer is 16.6 min [hexane/2-propanol (97.5/2.5), 1.0 mL/min].
3.4.2. 1-(4-Methoxyphenyl)propanol 4b
Crude product was purified by bulb to bulb distillation (150°C/0.3 mmHg) to give S-enriched product
(91%): [α]D −28.3 (c 2.20, C6H6) [lit.8 [α]D −32.1 (c 1.25, C6H6) for S enantiomer in 93% ee]. The
product was determined as 87.1% ee by HPLC analysis. The tR of the R isomer is 17.99 min and that for
the S isomer is 20.0 min [hexane/2-propanol (97.5/2.5), 1.0 mL/min].
24
22
3.4.3. 1-(4-Chlorophenyl)propanol 4c
Crude product was purified by bulb to bulb distillation (120°C/0.3 mmHg) to give S-enriched product
(95%): [α]D −19.55 (c 1.0, C6H6) [lit.8 [α]D −23.5 (c 0.82, C6H6) for S enantiomer in 93% ee]. The
24
22
product was determined as 77% ee by comparison of the [α]D value with that in the literature.8
3.4.4. 1-(2-Methoxyphenyl)propanol 4d
Crude product was purified by bulb to bulb distillation (150°C/0.3 mmHg) to give S-enriched product
24
(95%): [α]D −36.0 (c 0.71, C6H5CH3) [lit.10 [α]D22 +37.6 (c 3.02, C6H5CH3) in 73% ee]. The product
was determined as 59% ee by HPLC analysis. The tR of the R isomer is 32.83 min and that for the S isomer
is 30.35 min [hexane/2-propanol (100/0.8), 1.0 mL/min].
3.4.5. 1-(2-Naphthyl)propanol 4e
Crude product was purified by bulb to bulb distillation (150°C/0.3 mmHg) to give S-enriched product
(99%): [α]D −19.2 (c 1.79, C6H6) [lit.11 [α]D −26.6 (c 3.35, C6H6) for S enantiomer in 97% ee].
The product was determined as 90.7% ee by HPLC analysis. The tR of the R isomer is 33.92 min and
that for the S isomer is 29.35 min [hexane/2-propanol (97.5/2.5), 1.0 mL/min].
24
22
3.4.6. trans-1-Phenyl-1-penten-3-ol 4f
Crude product was purified by bulb to bulb distillation (110°C/0.3 mmHg) to give S-enriched product
(91%): [α]D −6.3 (c 1.73, CHCl3) [lit.8 [α]D −5.7 (c 100, CHCl3) for S enantiomer in 96% ee]. The
product was determined as 87.6% ee by HPLC analysis. The tR of the R isomer is 8.96 min and that for
the S isomer is 13.02 min [hexane/2-propanol (9/1), 1.0 mL/min].
24
22
3.4.7. 1-Phenyl-3-pentanol 4g
Crude product was purified by bulb to bulb distillation (110°C/0.3 mmHg) to give S-enriched product
(94%): [α]D +16.8 (c 1.2, EtOH) [lit.8 [α]D +23.9 (c 1.44, EtOH) for S enantiomer in 90% ee]. The
product was determined as 76% ee by HPLC analysis. The tR of the R isomer is 21.55 min and that for
the S isomer is 23.83 min [hexane/2-propanol (97.5/2.5), 1.0 mL/min].
24
22
Acknowledgements
We are grateful to the National Science Council, Republic of China for support of this work.

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