TETRAHEDRON:
ASYMMETRY
Pergamon Tetrahedron: Asymmetry 11 (2000) 4163–4169
Titanium catalysed enantioselective addition of
allyltributyltin to aldehydes: a simple and easily
reproducible procedure
Henri Doucet* and Maurice Santelli
Laboratoire de Synthèse Organique associé au CNRS, Faculté des Sciences de Saint Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 3 September 2000; accepted 15 September 2000
Abstract
We describe here an extremely simple procedure for the enantioselective addition of allyltributyltin to
aldehydes in the presence of a binaphthol–titanium complex. In toluene or pentane, the reaction can be
performed at room temperature in the absence of molecular sieves without a decrease in the enantioselec-
tivity. Enantiomeric excesses of up to 99% can be obtained in the most favourable cases. © 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Chiral homoallylic alcohols are useful but not easily accessible compounds. They are difficult
to obtain by enantioselective reduction of enones;1 enantioselective allylation of aldehydes
remains the most attractive method for the preparation of such compounds.2–4 The Lewis acid-
promoted addition of allyltributyltin to aldehydes is the most common procedure to perform
this reaction.5 The general conditions used to carry out the titanium catalysed allylation are to
employ dichloromethane as a solvent in the presence of 4 A, molecular sieves at low temperature
(−78°C).6 If the reaction is conducted by skillful operators, with dry dichloromethane and 4 A,
molecular sieves oven dried at 250°C for 12 hours at 0.1 Torr, high enantiomeric excesses can
be obtained.6a,b But this binaphthol–titanium complex seems to be extremely water-sensitive and,
in dichloromethane, even under dry conditions, the catalyst decomposes after a few hours. We
have also observed that, if the solvent and the sieves are not perfectly dry, much lower
enantiomeric excesses and lower yields are obtained. Despite many attempts, we have not been
able to obtain reproducible results with these operating conditions. Moreover, to the best of our
knowledge, the ability of this titanium catalyst to give very high enantiomeric excesses at room
* Corresponding author. Fax: 04 91 98 38 65; e-mail: henri.doucet@lso.u-3mrs.fr; m.santelli@lso.u-3mrs.fr
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S 0 9 5 7 - 4 1 6 6 ( 0 0 ) 0 0 3 7 4 - 8
4164 H. Doucet, M. Santelli / Tetrahedron: Asymmetry 11 (2000) 4163–4169
temperature has never been demonstrated.7 Our objective was to find a simpler procedure to
perform this reaction that can be easily reproduced by any synthetic organic chemist. We
decided to study the influence of three parameters for this reaction: the solvent, the temperature
and the importance of the molecular sieves.
2. Results and discussion
We began by investigating the influence of the solvent and the temperature and found that the
most suitable solvents for the reaction are toluene or pentane. In these solvents the stability of
the active catalytic titanium species is much higher than in dichloromethane and the reaction can
be performed at room temperature without decomposition of the catalyst and without loss of
enantioselectivity. The addition of allyltributyltin to 4-trifluoromethylbenzaldehyde in the
presence of 10% ((R)-binaphthol)Ti(OiPr)2 in pentane or toluene at 25°C led to complete
conversion after 20 hours and to 92 and 94% ees, respectively (Scheme 1).
The second problem for the reproducibility of this reaction is the presence of the molecular
sieves. It is generally very difficult to know the exact dryness of the sieves and even storing dry
sieves in a desiccator with P2O5 results in progressive degradation of their performance.6b In
order to simplify the procedure we decided to study the influence of the sieves in toluene and
pentane at room temperature on the reaction rate and on the ees. We observed that, under these
conditions, 4 A, molecular sieves have almost no influence on the reaction rate and on the ees.
With 10% catalyst, complete conversions are observed in the absence or presence of molecular
sieves. Moreover, the ees observed in toluene in the absence and presence of molecular sieves are
95 and 94%, respectively. In the presence of 5% catalyst in toluene or pentane, the ees are even
slightly higher in the absence of molecular sieves (Table 1).
Scheme 1.
We next examined various aldehydes using these conditions: room temperature, toluene and
absence of molecular sieves (Scheme 2). Aldehydes bearing an electron withdrawing, para or
meta aryl substituent gave good yields of addition products, and excellent enantiomeric excesses.
4-Trifluoromethylbenzaldehyde 1a, 3-trifluoromethylbenzaldehyde 1b and 4-fluorobenzaldehyde
1e gave 97% ees and 96–100% yields. The di-ortho-substituted 3,5-bistrifluoromethyl 1d and
3,5-difluorobenzaldehyde 1g led to lower ees: 91 and 90%, respectively. Pentafluorobenzalde-
hyde 1h gave a moderate yield but an excellent ee of 99%. Conversely the reaction rate was
dramatically decreased when an aldehyde with electron-releasing aryl para-substituent was
employed. With 4-methoxybenzaldehyde, only a trace of coupling product was observed. A
significant steric effect was also observed with the ortho-substituted aldehydes 1c, 1f or 1k,
which gave lower enantiomeric excesses and only a small amount of adducts 2c and 2k. In the
case of 2,4-dimethoxybenzaldehyde, no trace of the coupling product was observed. Addition to
decanal gave the addition product 2m in good yield and excellent ee: 98%. In all cases, similar
H. Doucet, M. Santelli / Tetrahedron: Asymmetry 11 (2000) 4163–4169 4165
Table 1
Addition to 4-trifluoromethylbenzaldehyde 1a: influence of the solvent and of the molecular sievesa
Solvent Catalyst (%) Conversionc (%) ee (%)
CH2Cl2 10 95 20–82d
CH2Cl2 5b 58 41
Toluene 50 100 90
Toluene 50b 100 97
Toluene 10 100 94
Toluene 10b 100 95
Toluene 5 68 68
Toluene 5b 99 76
Pentane 10b 100 92
Pentane 5 100 78
Pentane 5b 100 84
a
Conditions: 4-trifluoromethylbenzaldehyde (2 mmol), allyltributyltin (2.2 mmol), ((R)-binaphthol)Ti(iPrO)2,
solvent 5 mL, molecular sieves 4 A, , 25°C, 20 h.
b
Reaction without molecular sieves.
c
Conversion determined by GC and NMR.
d
Not reproducible ees.
or higher enantiomeric excesses were obtained at room temperature in toluene without molecu-
lar sieves than at −78°C in dichloromethane in the presence of molecular sieves. The results are
summarised in Table 2.
Scheme 2.
Finally we tried to clarify the difference in reaction rates between electron-withdrawing and
electron-releasing substituted benzaldehydes. The slow reaction rate observed with 4-methoxy-
benzaldehyde could be due either to poisoning of the catalyst by coordination of the methoxy
function to the complex or to an electronic effect. The addition of allyltributyltin to an
equimolar mixture of 4-methoxybenzaldehyde and 4-trifluoromethylbenzaldehyde in the pres-
ence of (binaphthol)Ti(OiPr)2 led exclusively to 1-(4-trifluoromethylphenyl)-3-buten-1-ol 2a
(Scheme 3). The same tendency was observed in the presence of an equimolar mixture of
4-fluorobenzaldehyde and 4-trifluoromethylbenzaldehyde. A higher conversion of 4-tri-
fluoromethylbenzaldehyde was observed. These results indicate that the difference in reaction
rate does not come from poisoning, but more probably from electronic factors.
4166 H. Doucet, M. Santelli / Tetrahedron: Asymmetry 11 (2000) 4163–4169
Table 2
Titanium catalysed allylation: influence of the aldehyde
Scheme 3.
3. Conclusion
We report here an extremely simple procedure for the enantioselective addition of allyl-
tributyltin to aldehydes in the presence of a titanium catalyst. We observed that in toluene or
H. Doucet, M. Santelli / Tetrahedron: Asymmetry 11 (2000) 4163–4169 4167
pentane the stability of the active catalytic titanium species is much higher than in
dichloromethane, the solvent generally used for this reaction. In these solvents the reaction can
be performed at room temperature in the absence of molecular sieves without decrease of the
enantioselectivity. We have also observed important effects of the electronic and steric factors on
the rate of the addition.
4. Experimental
4.1. General
Reactions were conducted under a dry argon atmosphere, using standard vacuum line
techniques. NMR spectra were recorded on a Varian Gemini 200 and a Bruker AC200 or AMX
400 spectrometer. Gas chromatography analyses were performed on a Hewlett Packard HP
4890A. Reactions were carried out in solvents distilled from standard drying agents. Aldehydes
were distilled under reduced pressure before use.
4.2. Preparation of [( R) -(+) -1,1 %-bi(2 -naphthol)]titanium isopropoxide complex
In a Schlenk tube, 2 mL of degassed toluene was added to 60 mg (0.21 mmol) of
(R)-(+)-1,1%-bi(2-naphthol), then 59 mL (0.20 mmol) of titanium tetraisopropoxide was added.
After stirring for 1 hour, the solvent was removed. These complexes are not air stable and were
stored in Schlenk tubes under argon. For the catalytic allylation reactions the complexes were
prepared just before use.
4.3. Catalytic allylation, general procedure
To 0.2 mmol of a solution of [(R)-(+)-1,1%-bi(2-naphthol)]titanium isopropoxide complex in
toluene in a Schlenk tube were added 0.4 mmol of aldehyde and 0.45 mmol of allyltributyltin.
The solution was stirred at 20°C over 20 hours, quenched with 1 mL of water, 10 mL of ether
was added to the mixture, then the organic layer was washed with water and was dried over
MgSO4. After evaporation of the solvent, the product was purified by chromatography on silica
gel (pentane/ether).
4.4. 1H NMR (200 MHz, CDCl3) spectra of the products
1-(4-Trifluoromethylphenyl)-3-buten-1-ol 2a: l=7.58 (d, 3J(H,H)=8.2 Hz, 2H), 7.43 (d,
3
J(H,H)=8.2 Hz, 2H), 5.75 (m, 1H), 5.2–5.0 (m, 2H), 4.75 (t, 3J(H,H)=5.4 Hz, 1H), 2.50 (m,
3H); 1-(3-trifluoromethylphenyl)-3-buten-1-ol 2b: l 7.65–7.35 (m, 4H), 5.75 (m, 1H), 5.2–5.0 (m,
2H), 4.75 (t, 3J(H,H)=5.4 Hz, 1H), 2.47 (m, 2H); 1-(2-trifluoromethylphenyl)-3-buten-1-ol 2c:
l=7.9–7.3 (m, 4H), 5.86 (m, 1H), 5.2–4.9 (m, 2H), 4.88 (t, 3J(H,H)=5.4 Hz, 1H), 2.50 (m, 3H);
1-(3,5-bistrifluoromethylphenyl)-3-buten-1-ol 2d: l=7.9–7.5 (m, 3H), 5.77 (m, 1H), 5.20–4.80
(m, 3H), 2.50 (m, 3H); 1-(4-fluorophenyl)-3-buten-1-ol 2e: l=7.3 (m, 2H), 7.0 (m, 2H), 5.78
(ddt, 3J(H,H)=16.0, 7.4 and 5.4 Hz, 1H), 5.15 (d, 3J(H,H)=7.4 Hz, 1H), 5.14 (d, 3J(H,H)=
16.0 Hz, 1H), 4.72 (t, 3J(H,H)=6.2 Hz, 1H), 2.50 (m, 2H); 1-(2-fluorophenyl)-3-buten-1-ol 2f:
4168 H. Doucet, M. Santelli / Tetrahedron: Asymmetry 11 (2000) 4163–4169
l=7.5–6.9 (m, 4H), 5.75 (ddt, 3J(H,H)=15.7, 9.2 and 6.0 Hz, 1H), 5.13 (d, 3J(H,H)=15.7 Hz,
1H), 5.0 (m, 1H), 4.70 (d, 3J(H,H)=6.0 Hz, 1H), 2.50 (m, 2H); 1-(3,5-difluorophenyl)-3-buten-1-
ol 2g: l=7.00 (m, 2H), 6.75 (m, 1H), 5.77 (m, 1H), 5.3–5.0 (m, 2H), 4.72 (t, 3J(H,H)=7.0 Hz,
1H), 2.50 (m, 2H); 1-(pentafluorophenyl)-3-buten-1-ol 2h: l=5.75 (ddt, 3J(H,H)=15.5, 7.8 and
7.0 Hz, 1H), 5.20 (d, 3J(H,H)=7.8 Hz, 1H), 5.19 (d, 3J(H,H)=15.5 Hz, 1H), 5.18 (m, 1H), 2.45
(m, 2H); 1-(4-chlorophenyl)-3-buten-1-ol 2i: l=7.95 (d, 3J(H,H)=8.3 Hz, 2H), 7.30 (d,
3
J(H,H)=8.3 Hz, 2H), 5.75 (ddt, 3J(H,H)=16.0, 8.0 and 6.3 Hz, 1H), 5.15 (d, 3J(H,H)=16.0
Hz, 1H), 5.13 (d, 3J(H,H)=8.0 Hz, 1H), 4.72 (t, 3J(H,H)=6.2 Hz, 1H), 2.50 (m, 2H);
1-(4-methoxyphenyl)-3-buten-1-ol 2l: l=7.27 (d, 3J(H,H)=7.5 Hz, 2H), 6.82 (d, 3J(H,H)=7.5
Hz, 2H), 5.79 (ddt, 3J(H,H)=17.4, 7.7 and 6.3 Hz, 1H), 5.14 (d, 3J(H,H)=7.7 Hz, 1H), 5.13 (d,
3
J(H,H)=17.4 Hz, 1H), 4.72 (t, 3J(H,H)=6.4 Hz, 1H), 3.90 (s, 3H), 2.50 (m, 2H).
4.5. Determination of enantiomeric excesses (Table 3)
Table 3
Determination of enantiomeric excesses by gas chromatographya
Alcohol Oven temp. Retention time of the enantiomers (min)b
(°C)
1-(4-Trifluoromethylphenyl)but-3-en-1-ol 140 14.7 16.1
1-(3-Trifluoromethylphenyl)but-3-en-1-ol 130 18.9 20.2
1-(2-Trifluoromethylphenyl)but-3-en-1-ol 130 15.2 15.9
1-(3,5-Bistrifluoromethylphenyl)but-3-en-1-ol 110 35.7 37.0
1-(4-Fluorophenyl)but-3-en-1-ol 120 35.0 37.0
1-(2-Fluorophenyl)but-3-en-1-ol 130 17.2 18.3
1-(3,5-Difluorophenyl)but-3-en-1-ol 115 46.0 48.0
1-(2,3,4,5,6-Pentafluorophenyl)but-3-en-1-ol 120 15.8 18.0
1-(4-Chlorophenyl)but-3-en-1-ol 130 24.0 25.0
1-(4-Bromophenyl)but-3-en-1-ol 150 32.6 34.5
1-(4-Methoxyphenyl)but-3-en-1-ol 135 44.0 46.0
1-(2-Methylphenyl)but-3-en-1-ol 125 38.8 39.9
Tridec-1-en-3-ol 130 35.4 37.0
a
Using a column Chrompack WCOT Fused Silica, CP-Chirasil-DEX CB, 25 meters, injector temperature: 200°C,
detector temperature: 250°C, inlet pressure 13 psi.
b
Times in bold represent the major peaks obtained with [(R)-(+)-1,1%-bi(2-naphthol)]titanium isopropoxide
complex as catalyst and should be R in all cases.
Acknowledgements
We thank the CNRS for providing financial support.
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