Novel recyclable aminoalcohol salts in catalytic asymmetric inductions. The addition of diethylzinc to aromatic aldehydes

Article abstract of DOI:10.1055/s-1999-2541

Novel recyclable benzyloxyalkyl norephedrine salts have been used as efficient catalysts for the addition of diethylzinc to aromatic aldehydes to give the corresponding secondary alcohols in up to 82% ee.

Full text of DOI:10.1055/s-1999-2541

LETTER
105
Novel Recyclable Aminoalcohol Salts in Catalytic Asymmetric Inductions.
The Addition of Diethylzinc to Aromatic Aldehydes
Helen C. Hailes* and James Madden
Department of Chemistry, University College London, London WC1H OAJ, U.K.
Fax +44-171-380 7463; E-mail: h.c.hailes@ucl.ac.uk
Received 28 October 1998
Abstract: Novel recyclable benzyloxyalkyl norephedrine salts
have been used as efficient catalysts for the addition of diethylzinc
to aromatic aldehydes to give the corresponding secondary alcohols
in up to 82% ee.
Key words: diethylzinc, aromatic aldehydes, asymmetric catalysis,
reverse micellar salts, recyclable salts
Carbon-carbon bond formation is a fundamental opera-
tion used in the construction of organic molecules. The
addition of organometallic reagents to carbonyl com-
pounds is among the most common reaction for this pur-
pose and is a reliable method for the synthesis of alcohols.
Typically, for the enantioselective addition of diorga-
nozinc compounds to aldehydes, chiral amines such as al-
kaloids and b-amino alcohols have been utilised.1 To date,
the issue of catalyst recyclability has received little atten-
tion other than with the synthesis of polymer bound b-
amino alcohols and their derivatives2, however such solid
supported catalyst reactions do not always proceed in the
was required. To this end the alkyl chain and benzyloxy
group were present. In the absence of the benzyloxy group
the salt behaves like a conventional surfactant with corre-
sponding water solubility. However, the introduction of
the benzyloxy group introduces both a polar functionality
and a large bulky group that will have a tendency to inhibit
micelle formation and consequently effect its solubility in
water. Since the reaction is quenched with dilute hydro-
chloric acid, with concomitant salt formation we used the
salt as our catalyst and deprotonated it in situ . In addition,
as mentioned above, it was envisaged that dissolution of 1
in the organic reaction solvent may lead to the formation
of reverse micellar aggregates, which could influence the
selectivities or yields.
same way as the analogous reaction in solution3,4. That
said, on the basis of Soai’s elegant work on the synthesis
and use of polymer supported amines (and their benzy-
loxy solution analogues) and also his use of an unusual
solid phase quaternary ammonium salt5, we elected to
study the behaviour of the salt catalyst 1. Our decision to
use a trialkyl ammonium salt was based primarily on con-
sideration of its solubility properties, and recyclability. It
was also in view of the fact that the use of such a catalyst
precursor could lead to the formation of reverse micellar
aggregates, and would generate zinc chloride in situ with
unknown consequences for aggregation phenomena. In
this letter we therefore discuss the synthesis and applica-
tion of a new non-polymer bound recoverable salt catalyst
1 in the asymmetric alkylation of aromatic aldehydes with
diethylzinc.
With the salt 1 in hand we tested its efficiency as an enan-
tioselective catalyst in the alkylation of aromatic alde-
hydes using diethylzinc, as shown in table 1. Initial
experiments using benzaldehyde (entries 1 and 2) showed
reasonable levels of enantioinduction with selection for
the formation of the S isomer, which is consistent with
previous results using (1S,2R)-norephedrine based cata-
lysts.4,7 Reactions were performed at room temperature
and at 70 °C and in the latter case higher yields and enan-
tioselectivities were observed. Other amino alcohol cata-
lysts such as prolinol have shown similar temperature
effects.8
Our catalyst 1 was prepared utilising Saoi’s route as out-
lined below in scheme 1.4,6 We selected norephedrine as
the chiral promoter, since it has been successfully used as
the chiral moiety in several systems.4,7 The ether 2 was
formed by reacting benzyl chloride with 1,12-dode-
canediol which was then iodinated, via the chloride, to
give 3. The alkylation of N-butyl norephedrine with 3 gen-
erated, after purification, the free amine 1a which was
subsequently converted into the hydrochloride salt 1.
In order to enable straightforward recycling of the cata-
lyst, limited solubility in water and mixed water systems
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106
H. C. Hailes, J. Madden
LETTER
Not only was it found that the salt 1 was sparingly soluble
in water but it also had a low solubility in the reaction sol-
vent hexane where 4 mol% was normally used. Upon ad- In summary, we have synthesised a new reusable salt cat-
dition of dilute hydrochloric acid at the end of the alyst that is deprotonated in situ and is successfully used
reaction, the surfactant was found to precipitate out of so- as an enantioselective catalyst in the alkylation of aromat-
lution, and was then available for collection and reuse.
ic aldehydes using diethylzinc.
With the aldehydes 4-methyl- and 4-methoxybenzalde-
hyde (entries 3-6) high yields and good selectivities were
again observed at the higher reaction temperature. Other
aromatic aldehydes gave similar results (entries 7-9), al-
though notably 4-nhexyloxybenzaldehyde gave the high-
est yield at ambient temperature and the best
enantioselectivity.
Acknowledgement
We thank Dr. Neil Harris, Rhône-Poulenc Rorer Ltd (for an Indu-
strial CASE Studentship to J.M.) and the EPSRC for financial sup-
port of this research.
References and Notes
Several researchers have investigated the catalytic cycle
of the diethylzinc reaction with aldehydes, and key inter-
mediates have been postulated.10 From these, the higher
yield with 4-nhexyloxybenzaldehyde could be attributed
to the favourable aggregation of a zinc complex, an exam-
ple of which is given in figure 1. If the alkyl chains are di-
rected out into the organic phase and the charged entities
are at the centre of the aggregate then interactions be-
tween the solvent and charged intermediates would be
minimised.
†
In each case a negative rotation was obtained, indicating that
the selectivity was for the (S)-enantiomer in agreement with
reported work (ref. 11,12). For entries 8 and 9 the configurati-
ons are tentatively assumed.
Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl., 1991,
30, 49.
Soai, K.; Niwa, S; Watanabe, M. J. Chem. Soc., Perkin Trans.
I, 1989, 109, Soai, K.; Watanabe, M.; Yamamoto, A. J. Org.
Chem., 1990, 55, 4832.
1
2
3
4
Hodge, P. Chem. Soc. Rev., 1997, 26, 417.
Watanabe, M.; Soai, K. Chem. Soc., Perkin Trans. I, 1994,
837.
5
6
Watanabe, M.; Soai, K. J.Chem. Soc., Chem Commun., 1990,
43.
We also tested the catalytic capability of the free amine 1a
which was available as an intermediate from the synthesis
of 1. For the standard room temperature reaction with ben-
zaldehyde, although an ee of 65% (for the S-isomer) was
observed, the yield was much lower at 9%. This can be
compared with Soai’s work4,5 and suggests that norephe-
drine derived free amines may have reversed temperature
and yield dependencies compared to the salts. We also
prepared the quaternary salt of 1, via methylation using
methyl iodide in a sealed tube, in order to highlight the re-
quirement for nitrogen complexation. We found that with
benzaldehyde the reaction did proceed albeit in lower
yield (15%), and that the R-isomer was the major enanti-
omer that was formed although the enantioselectivity was
small (approximately 6%).
All yields cited herein are of isolated, purified materials which
gave satisfactory 1H,13C NMR and IR spectra, and showed
low resolution MS and either elemental analysis or high reso-
lution MS characteristics in accord with the assigned struc-
tures.
Chaloner, P. A.; Perera, S. A. R. Tetrahedron Lett., 1987, 28,
3013. Fréchet, J. M. J.; Itsuno, S. J. Org. Chem., 1987, 52,
4140.
7
8
9
Muchow, G.; Vannoorenberghe, Y.; Buono, G. Tetrahedron
Lett., 1987, 28, 6163.
Typical experimental procedure (for R=C6H5): Surfactant 1
(25 mg, 49 mmol) was dissolved in dry hexane (12 ml) and stir-
red at 0 °C prior to the addition of redistilled benzaldehyde
(0.12 ml, 1.18 mmol). This mixture was stirred for a further 10
minutes before the dropwise addition of diethylzinc (1.0 M in
hexanes; 2.55 ml, 2.55 mmol). The reaction was then stirred
Synlett 1999, No. 1, 105–107 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Recyclable Aminoalcohol Salts in Catalytic Asymmetric Inductions
107
for 48 h at 25 °C. The reaction was quenched by the dropwise
addition of 1.5 M hydrochloric acid. The organic layer was se-
128.34: (Found; M+, 136.0891. C9H12O requires: M,
136.0880).
parated and the aqueous layer extracted with diethyl ether (2 x
15 ml). The combined organic extracts were dried over anhy-
drous sodium sulphate and concentrated in vacuo to afford the
crude product. This was purified by flash column chromato-
graphy (petroleum ether 40-60/ethyl acetate, 4:1) to give the
product as a colourless oil.
For the Chiral HPLC a Chiralcel OD column was used, 2 %
iso-propanol in hexane, 1.0 ml/min. Retention time R 12.0
min, S -17.0 min.
10 Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc., 1989, 111, 4028.
11 Nakamura, K.; Kawasaki, M.; Ohno, A. Bull. Chem. Soc. Jpn.,
1996, 69, 1079.
12 Pickard, R. H.; Kenyon, J. J. Chem. Soc., 1914, 1115, Prasad,
K. R. K.; Joshi, N. N. J. Org. Chem., 1997, 62, 3770, Kitamu-
ra, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc.,
1986, 108, 6071.
[a]D20 -18 ° (c 1.25, CHCl3 for compound with 62% ee as deter-
mined by HPLC)11; IR (neat) 3300, 3010, 2850, 1100 cm-1; 1H
NMR (400 MHz, CDCl3) d 0.86 (3H, t, J 6.8 Hz, CH3), 1.80
(2H, m, CH2), 2.12 (1H, br s, OH), 4.59 (1H, dt, J 6.7 and 2.0
Hz, CHOH), and 7.38 (5H, m, Ph), 13C NMR (100 MHz,
CDCl3) d 10.11, 31.85, 75.97. 125.92, 127.37, 127.44, and
Synlett 1999, No. 1, 105–107 ISSN 0936-5214 © Thieme Stuttgart · New York