Enantioselective cyanoformylation of aldehydes mediated by BINOLAM-AlCl as a monometallic bifunctional catalyst

Article abstract of DOI:10.1016/S0957-4166(02)00824-8

BINOLAM-AlCl's, binaphthoxide aluminium chloride species generated in situ from either (R)- or (S)-3,3′-bis(diethylaminomethyl)-2,2′-dihydroxy-1,1′- binaphthalene (BINOLAM) behave as Lewis acid-Lewis base (LA-LB) catalysts in the enantioselective addition of methyl cyanoformate to aldehydes at room temperature, thereby leading to the asymmetric synthesis of (S)- or (R)-O-methoxycarbonyl cyanohydrins, respectively.

Full text of DOI:10.1016/S0957-4166(02)00824-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 197–200
Enantioselective cyanoformylation of aldehydes mediated by
BINOLAM–AlCl as a monometallic bifunctional catalyst
a
a
a
a,
b,
Jes u´ s Casas, Alejandro Baeza, Jos e´ M. Sansano, Carmen N a´ jera * and Jos e´ M. Sa a´ *
a
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
b
Departament de Qu ´ı mica, Universitat de les Illes Balears, 07071 Palma de Mallorca, Spain
Received 20 November 2002; accepted 2 December 2002
Abstract—BINOLAM–AlCl’s, binaphthoxide aluminium chloride species generated in situ from either (R)- or (S)-3,3%-bis(diethyl-
aminomethyl)-2,2%-dihydroxy-1,1%-binaphthalene (BINOLAM) behave as Lewis acid–Lewis base (LA-LB) catalysts in the enan-
tioselective addition of methyl cyanoformate to aldehydes at room temperature, thereby leading to the asymmetric synthesis of
(
S)- or (R)-O-methoxycarbonyl cyanohydrins, respectively. © 2003 Elsevier Science Ltd. All rights reserved.
Asymmetric catalysis, based on chiral bifunctional cata-
lysts is a conceptually relevant new strategy for enantiose-
requires a cyanoformate as reagent and tri-n-butyltin
7 8 9
cyanide as catalyst, or either organic or inorganic bases.
1
,2
lective synthesis.
These catalysts bear two
The first enantioselective cyanoformylation of ketones
(only) has recently been reported by Tian and Deng for
which purpose they employ Cinchona alkaloid-derived
non-annihilating centres capable of acting as Lewis or
Br o¨ nsted acid or base, in order to activate both elec-
trophilic and nucleophilic reagents simultaneously.
10
tertiary amines as chiral catalysts. During the prepara-
tion of this manuscript, the first asymmetric cyanoformyl-
ation of aldehydes with ethyl cyanoformate has been
2
a–c
Shibasaki et al.
ric, monometallic, bifunctional Lewis acid–Lewis base
LA-LB) catalysts 1, derived from 3,3%-diphenylphos-
have recently developed a C symmet-
2
11
(
described by Shibasaki et al. The reaction is best
performed with a sophisticated catalyst derived from the
phane oxide-substituted BINOL (2,2%-dihydroxy-1,1%-
binaphthalene) attached to an aluminium atom.
According to Shibasaki, in this system the aluminium
atom acts as Lewis acid while the diphenylphosphane
oxide arm works as Lewis base activating the electrophile
and the nucleophile, respectively. These catalysts have
been proved to be highly efficient for the enantioselective
3
addition of trimethylsilyl cyanide to aldehydes, or imines
4
(
Strecker reaction), as well as to quinolines and isoquino-
5
lines (Reissert-type reaction). On our side, we have
recently found that (S)- or (R)-3,3%-bis(diethylamino-
methyl)-1,1%-bi-2-naphthol (BINOLAM) 2 form alu-
minium complexes 3, which are efficient catalysts for the
enantioselective addition of trimethylsilyl cyanide to
aldehydes at −20 to −40°C in the presence of triphenyl-
phosphine oxide and wet 4 A molecular sieves as addi-
,
6
tives. While the precise role of the amino group of our
catalysts in this reaction (either as Lewis or Bronsted base)
is still under study, the aluminium centre worked as Lewis
acid. As an additional bonus, we showed that the chiral
ligand BINOLAM could be recycled after recovery by
simple acid–base extractive work-up.
A much less studied cyanation methodology is the
cyanoformylation of carbonyl compounds, which
*
Corresponding authors. E-mail: cnajera@ua.es; jmsaa@uib.es
0
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00824-8

1
98
J. Casas et al. / Tetrahedron: Asymmetry 14 (2003) 197–200
ytrium heterobimetallic complex [YLi {tris(binaphth-
ascribed to their capacity to liberate a certain amount of
12
3
oxide)}] (10 mol%) in the presence of water (30 mol%),
tris(2,6-dimethoxyphenyl)phosphane oxide (10 mol%)
and butyllithium (10 mol%) in THF at −78°C. Herein,
we described the use of BINOLAM–AlCl species 3,
derived in situ from (R)- and (S)-2, as efficient
monometallic, bifunctional catalysts for the enantioselec-
tive cyanoformylation of aldehydes.
water into the reaction medium. Other additives such
as triphenylphosphane oxide were examined but did not
lead to further improvement of the enantiomeric ratio
such as was observed in the cyanosilylation of alde-
6,13
hydes. The use of toluene and dichloromethane (Table
1, entries 8 and 9) gave similar er, the former being selected
as the optimal solvent due to the marginally better
chemical yield obtained. THF, however, was found to be
inappropriate as solvent for this reaction (Table 1, entry
10). Interestingly, the use of lower or higher temperatures
did not induce a dramatic change in the enantioselectivity
of the process, but only a substantial modification in the
reaction rate. On the stereochemical side-walk we found
that, in all cases, working with the (R)-configured
aluminium complex 3 as catalyst, the absolute configura-
tion of carbonate 4a was S. Absolute configurations were
unambiguously determined by comparison with pure
Initially we examined the cyanoformylation reaction
(
Scheme 1) of benzaldehyde and benzyl cyanoformate (1.5
equiv.) at room temperature in dry toluene as solvent,
without and with metal-containing co-catalysts (Table 1,
entries 1–6). The addition reaction completely failed in
the presence of (R)-BINOLAM as the only catalyst. Next,
titaniumandaluminiumco-catalysts(Table1, entries2–6)
were tested, best enantiomeric ratios (er) being found
when in situ preparing catalyst 3 by mixing (R)-BINO-
LAM with dimethylaluminium chloride (entry 6). Initial
results were encouraging though we recognised two major
problems to overcome: The appearance of secondary
products (mainly benzyl alcohol) presumably derived
from competing reactions and the long reaction times
examples by reaction of enantiomerically pure
6
cyanohydrins
with
methyl
chloroformate
in
dichloromethane. As expected, enantiomerically enriched
carbonates (R)-4 were prepared in identical chemical yield
and enantiomeric purity starting from (S)-BINOLAM
aluminium complex 3.
(
probably caused by a poor turnover step). The first of
them was solved using methyl cyanoformate, in which
case the crude reaction product could be obtained in high
purity (Table 1, entry 7). The long reaction times required
We next explored the scope of this reaction under the
optimised conditions shown in entry 8 (Table 1). Alde-
hydes reacted smoothly with methyl cyanoformate (1.5–4
equiv.) in the presence of (R)-BINOLAM–AlCl (10
were somewhat reduced by employing 4 A molecular
,
sieves (50 mg/0.25 mmol of aldehyde containing a 7.5%
of water) (Table 1, entry 8). The beneficial effect of using
molecular sieves in organic reactions is, in most cases,
obscure, but in the literature, these effects have been
mol%) and 4 A molecular sieves in dry toluene at room
,
temperature obtaining O-methoxycarbonylcyanohydrins
4 in high yields and good enantiomeric ratios (Scheme 2
Scheme 1.
Table 1. Optimisation of the reaction conditions for the synthesis of O-formylated cyanohydrins 4a and 4a%
Entry
R
Co-catalyst
Additive
Solvent
T (°C)
Time (h)
Yield (%)a
erb
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
–
–
–
–
–
–
–
–
4 A
4 A
4 A
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH Cl
25
25
25
25
25
25
25
25
25
25
96
24
48
3
48
5
72
28
28
44
–
91
–
\95
53
\95
94
94
87
80
–
i
Ti(OPr )
Ti(OPr ) Cl
Me Al
Me AlCl
Et AlCN
Me AlCl
Me AlCl
Me AlCl
63:37
–
4
i
2
2
50:50
88:12
56:44
89:11
89:11
89:11
76:24
3
2
2
2
,
MS
MS
MS
2
,
2
2
2
1
0
Me AlCl
,
THF
2
a
Isolated yield of pure crude compounds determined by 1H NMR.
Determined by chiral HPLC (Daicel Chiralcel OD-H).
b
Scheme 2.

J. Casas et al. / Tetrahedron: Asymmetry 14 (2003) 197–200
199
1
0
and Table 2). Aromatic aldehydes reacted in almost
quantitative yields to give the protected cyanohydrins
with up to 78% e.e. However, the reaction of heteroaro-
matic aldehydes such as 2-pyridinecarboxaldehyde took
place in high chemical yield but, unfortunately, with no
enantioselection, (Table 2, entry 5), probably because in
this case the racemic cycle, where the pyridine nitrogen
atom act as a base in activating methyl cyanoformate,
predominates. Conjugated and aliphatic aldehydes
report of Deng et al., is however an indirect evidence
for the dual mechanistic role our catalyst must play (see
below). As described previously, ligand 2 could be
recovered by extractive work-up and subsequently
reused without any loss of activity.
The dual LA-LB mechanism (Scheme 3) we assign to
the catalyst in this reaction is supported by some exper-
imental studies. Thus, on the one hand, as reported by
Deng et al., chiral tertiary amines working as Lewis
bases catalyse the cyanoformylation of ketones only.
On the other hand, the use of a tertiary amine-depleted
catalyst such as (S)-BINOL–AlCl led to no reaction
after 2 days at room temperature, thus showing that a
Lewis acid alone does not promote the reaction. In our
catalyst, the role of the diethylamino group, acting as a
10
(
Table 2, entries 6–10) also gave good enantiomeric
ratios, 3-methylbut-2-enal being a suitable substrate for
this reaction (82% e.e.). Surprisingly, no reaction was
observed with ketones using the bifunctional catalyst 3
or the chiral basic ligand 2, under the typical reaction
conditions or even when working at higher tempera-
tures. This a priori unexpected result, in light of the
14
Table 2. Synthesis of cyanoformates 4
Entry
R
NCCO Me (equiv.)
Time (h)
4
Yield (%)a
erb
2
1
2
3
4
5
6
7
8
9
Ph
4-Cl-C H
4-MeO-C H
2-Naphthyl
2-Pyridyl
(E)-PhCHꢀCH
Me CꢀCH
(E)-MeCHꢀCH
PhCH CH
3
4
4
4
4
4
4
1.5
4
28
24
20
48
20
24
12
20
20
20
4a
4b
4c
4d
4e
4f
4g
4h
4i
\98
\98
\98
\98
96
89:11c,d
90:10
89:11
85:15
50:50
83:17
91:9
77:23
79:21f
84:16f
6
4
6
4
e
95
\98
\98
\98
\98
2
2
2
1
0
CH (CH )
3
4j
3
2 5
a
b
c
d
e
f
Isolated yield of pure crude compounds determined by 1H NMR.
Determined by chiral HPLC (Daicel Chiralcel OD-H and Chiralpak AD and AS).
The opposite absolute configuration of compound 4 was obtained employing (S)-3.
Identical results were observed with recovered ligand 2.
5
00 mg of 4 A
,
molecular sieves were employed for 0.25 mmol of cinnamaldehyde.
Determined by chiral GC (g-cyclodextrin).
Scheme 3.

2
00
J. Casas et al. / Tetrahedron: Asymmetry 14 (2003) 197–200
Lewis base and the Al–Cl moiety acting as Lewis acid,
is supported by the following facts: (1) only carbonyl
compounds capable of coordinating to the Lewis acid
centre, i.e. aldehydes but not ketones, do in fact react;
2. (a) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem.
Commun. 2002, 1989–1999; (b) Matsunaga, S.; Ohshima,
T.; Shibasaki, M. Adv. Synth. Catal. 2002, 344, 3–9; (c)
Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49,
511–524; (d) Rowlands, G. J. Tetrahedron 2001, 57, 1865–
1882; (e) Gr o¨ ger, H. Chem. Eur. J. 2001, 7, 5246–5251.
3. (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 1999, 121, 2641–2642; (b) Hamashima,
Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M.
Tetrahedron 2001, 57, 805–814.
(
2) the addition of a competing external base such as
triethylamine (20 mol%) lowered the er down to 65:35,
while simultaneously increased the reaction rate (3 h,
>
99% yield). Accordingly we propose a catalytic cycle
where the central aluminium atom might reach
1
5,16
pentacoordination
by amino and carbonyl group
ligation to give species II–III, where, the aldehyde is
fixed by a two point interaction: a strong one involving
aluminium and one of the electron pairs on the oxygen
carbonyl and a weaker one involving the aldehydic
4
. Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.;
Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650–1652.
. (a) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 6327–6328; (b) Takamura,
M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 6801–6808.
5
1
7
proton and the chlorine atom. The activation of
8,10
methyl cyanoformate by the tertiary amine,
followed
by transfer of the cyanide to the carbonyl group by the
re face, affords intermediate IV allowing final carbony-
lation of the cyanohydrin to occur. At this point in our
studies we have not assigned a clear-cut role to the
water-containing molecular sieves other than facilitat-
ing the turnover of the catalyst, possibly at the final
step of the cycle.
6
. Casas, J.; N a´ jera, C.; Sansano, J. M.; Sa a´ , J. M. Org. Lett.
2
002, 4, 2589–2592.
. (a) Scholl, M.; Lim, C.-K.; Fu, G. C. J. Org. Chem. 1995,
0, 6229–6231; (b) Shin, D.-S.; Jung, Y. S.; Kim, J.-J.; Ahn,
7
6
C. Bull. Korean Chem. Soc. 1998, 19, 119–120.
. (a) Berthiaume, D.; Poirier, D. Tetrahedron 2000, 56,
8
9
5995–6003; (b) Deardorff, D. R.; Taniguchi, C. M.; Tafti,
S. A.; Kim, H. Y.; Choi, S. Y.; Downey, K. J.; Nguyen,
T. V. J. Org. Chem. 2001, 66, 7191–7194.
This work reports for the first time the enantioselective
cyanation–methoxycarbonylation of aldehydes with a
monometallic, bifunctional catalyst using mild reaction
conditions. The reactions occur in good chemical yields
and high enantioselectivities, the chiral ligand BINO-
LAM 2 being easily recovered. The thus obtained enan-
tioenriched cyanohydrin carbonates can be exploited in
the synthesis of important building blocks for the syn-
thesis of enantiopure 1,2-bifunctional compounds such
. Okimoto, M.; Chiba, T. Synthesis 1996, 1188–1190.
1
1
1
0. Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123,
6195–6196.
1. Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2002, 41, 3636–3638.
2. The role of molecular sieves as an H O donor has been
2
demonstrated in the case of binaphthol-derived titanium
complexes: Terada, M.; Matsumoto, Y.; Nakamura, Y.;
Mikami, K. Chem. Commun. 1997, 281–282.
10
as b-amino alcohols by reduction with LiAlH4 and
also in palladium(0)-catalysed allylic substitution in the
13. The influence of Ph PO to prevent oligomerisation of the
18
3
case of a,b-unsaturated aldehyde derivatives. An
exploration of the scope of these applications and
mechanistic studies are currently underway.
catalyst and to activate trimethylsilyl cyanide has been
pointed out by: Vogl, E. M.; Gr o¨ ger, H.; Shibasaki, M.
Angew. Chem., Int. Ed. 1999, 38, 1570–1577.
14. Typical experimental procedure: To a suspension of enan-
tiopure (R)-BINOLAM 2 (0.025 mmol, 11.4 mg) and 4 A
,
Acknowledgements
molecular sieves (previously dried at 120°C for 4 h) in dry
toluene (1 mL), under an inert atmosphere (nitrogen), was
added dimethylaluminium chloride (1 M solution in hex-
anes, 0.025 mmol, 25 mL) and the resulting suspension was
stirred at room temperature for 1 h. To this mixture freshly
distilled aldehyde (0.25 mmol) and methyl cyanoformate
This work has been supported by the Direcci o´ n Gen-
eral de Investigaci o´ n of the Spanish Ministerio de Cien-
cia y Tecnolog ´ı a (MCyT) (BQU2001-0724) and the
Generalitat Valenciana (CTIDIB2002/320). A.B. thanks
the Generalitat Valenciana for a predoctoral fellowship.
(
see Table 2) were added in one portion. The reaction was
1
monitored by H NMR spectroscopy and GC and when
it was judged complete 1 M aqueous solution of hydrochlo-
ric acid (2 mL) and ethyl acetate (2 mL) were added and
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