Chiral lithium binaphtholate aqua complex as a highly effective asymmetric catalyst for cyanohydrin synthesis

Article abstract of DOI:10.1021/ja051125c

A highly enantioselective cyanohydrin synthesis with aromatic aldehydes using chiral lithium binaphtholate aqua or alcohol complexes has been developed and is a simple and inexpensive catalyst suitable for process chemistry to give gram-scale cyanohydrins

Full text of DOI:10.1021/ja051125c

Published on Web 07/13/2005
Chiral Lithium Binaphtholate Aqua Complex as a Highly Effective Asymmetric
Catalyst for Cyanohydrin Synthesis
Manabu Hatano, Takumi Ikeno, Takashi Miyamoto, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya, 464-8603, Japan
Received February 22, 2005; E-mail: ishihara@cc.nagoya-u.ac.jp
Table 1. Enantioselective Cyanation Catalyzed by (R)-1 or (R)-2
The catalytic asymmetric cyanation of aldehydes to give cyano-
hydrins is a versatile synthetic method in organic chemistry.1-7
Upon transformation, optically active cyanohydrins give important
intermediates not only in natural product chemistry but also in the
fields of biology and pharmaceuticals.6 However, in contrast to the
development of chiral Lewis acid catalysis,1 examples of asym-
metric cyanation to aldehydes with trimethylsilylcyanide (TMSCN)
catalyzed by a chiral Lewis base3 are still limited to Kagan’s
pioneering work.7 We report here the highly enantioselective
cyanation of aromatic aldehydes by chiral lithium binaphtholates
1 and 2 in the presence of a catalytic amount of water or alcohol
as a co-activator (Chart 1), which is a simple and inexpensive
catalyst suitable for the aim of process chemistry to give gram-
scale cyanohydrins in minimum solvent successfully.
entry
(R)-BINOL (mol %)
n-BuLi (mol %)
H2O (mol %)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
1
10
1
10
1
10
1
10
1
10
2
20
1
10
2
20
-
-
-
-
0.3
3
>99
>99
99
99
>99
95
23 [R]
58 [S]
65 [R]
26 [S]
58 [S]
95 [S]
25 [S]
88 [S]
1
10
>99
>99
Table 2. Effect of Lithium Source upon (R)-1 Catalyzed
Chart 1. Chiral Lithium Binaphtholate Complexes
Enantioselective Cyanationa
entry lithium source yield (%) ee (%) entry lithium source
yield (%)
ee (%)
1
2
3
LiOH
LiOH‚H2O
LiOEt
98
93
94
95
78
97
4
LiOPri
LiOPri
LiOBut
>99 [98]b 97 [90]b
5c
6
97
97
58
96
a 1 mmol scale of 3a. b 1 mol % of (R)-BINOL-LiOPri was used for
First, monolithium catalyst (R)-1 prepared in situ from 1:1 of
(R)-1,1′-bi-2-naphthol ((R)-BINOL) and n-BuLi in toluene was used
to convert 1 mmol of benzaldehyde (3a) into the corresponding
cyanohydrin (4a) with TMSCN (1.0 equiv) at -78 °C for 1 h (Table
1). (S)-4a was obtained quantitatively in 23% ee with 1 mol % of
(R)-1 (entry 1).8 Interestingly, 10 mol % of (R)-1 gave 58% ee of
(R)-4a along with a changeover of enantioselectivity (entry 2). Next,
an attempt with (R)-2 prepared in situ from 1 mol % of (R)-BINOL
and 2 mol % of n-BuLi gave (R)-4a almost quantitatively with 65%
ee (entry 3).8 Here again, 10 mol % of (R)-2 gave 26% ee of 4a in
(S)-form with a changeover in absolute stereochemistry (entry 4).9
For these interesting results, we suspected that the coexistence
of adventitious moisture including the catalyst and/or solvent may
have caused the opposite results regarding the enantiomeric excess.
Thus, we next intended to add a small amount of H2O to confirm
10 mmol of 3a. c 10 mol % of (R)-BINOL and 20 mol % of LiOPri was
used.
2). As expected, the release of H2O after complexation of LiOH
with (R)-BINOL was quite effective and gave (S)-4a with 95% ee
(entry 1). Regarding the effect of H2O in Table 1, LiOH‚H2O had
lower catalytic activity than LiOH and gave (S)-4a with 78% ee
(entry 2), while Li2O or LiOAc12 showed no reactivity. Eventually,
LiOEt, LiOPri, and LiOBut were found to be highly effective, and
the enantioselectivity of (S)-4a was increased up to 97% ee (entries
3-6). LiOPri was such a highly active precursor at promoting
cyanation of 3a (10 mmol) with 1 mol % catalyst loading in
minimum solvent (2 mL) that the gram scale of (S)-4a was obtained
practically with 90% ee almost quantitatively (entry 4). Again,
BINOL-2LiOPri catalyst showed lower catalytic activity than
BINOL-LiOPri catalyst (entry 5).
whether water affects the activity of the well-dried catalyst.5b,10
1
mol % of (R)-1 or (R)-2 with a catalytic amount of water turned
the sense of enantioselectivity of 4a into (S)-form (entries 5 and 7
versus 18 and 38). Higher catalytic activity was observed with 10
mol % of (R)-1‚(H2O)n rather than (R)-2‚(H2O)n: 95% ee (entry
6) versus 88% ee (entry 8). More or less than the optimized amount
of water gradually decreased catalytic activity (see Supporting
Information). We could rule out the possibility of the addition to
aldehyde with HCN, which was generated from TMSCN and H2O,
because low catalytic activity (60% yield, 44% ee (S)) was observed
with (R)-1/HCN.11 Other protic additives such as i-PrOH and
t-BuOH were also effective, but not superior to H2O.
Next, the cyanation of other aldehydes with TMSCN was
examined with LiOPri and (R)-BINOL (i.e., (R)-1‚i-PrOH) (Table
3). Aromatic aldehydes with an electron-withdrawing group or an
electron-donating group gave the corresponding (S)-4 with high
enantioselectivities up to 97% ee almost quantitatively (entries
2-12). R- or â-Naphthaldehydes (3m, 3n) and 3-furylaldehyde (3o)
bearing a heterocycle also gave excellent results up to 98% ee
(entries 13-15). Double cyanation of isophthaldehyde (3p) pro-
ceeded smoothly to give dl-product (S,S)-4p in 85% yield with 98%
ee (entry 16). Notably, even 1-3 mol % of our simple BINOL-
Li catalyst in minimum solvent (2 mL) could afford the various
corresponding cyanohydrins 4 almost quantitatively with high
enantioselectivities in practically useful gram scale (10 mmol). (R)-
1‚i-PrOH showed low enantioselectivity for aliphatic aldehydes.
Encouraged by the effect of catalytic water, we next examined
other lithium sources in place of n-BuLi to generate corresponding
protic compounds in situ by complexation with (R)-BINOL (Table
9
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J. AM. CHEM. SOC. 2005, 127, 10776-10777
10.1021/ja051125c CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Cyanation of Aldehydes Catalyzed by (R)-1‚i-PrOHa
that (R)-1‚i-PrOH may be a mixture of an active monomeric species
and inactive oligomeric species.14 Although a further investigation
of mechanistic aspects is required to acquire a full understanding,
our postulated transition states are shown on the basis of a
monomeric structure or a complex strikingly similar to this species
(Figure 1 and Supporting Information). Taking advantage of the
detailed studies on hypervalent silicon intermediates,15 we found
that transition state assembly 6 is less favorable because of (1) steric
repulsion between the aryl group of aldehyde and ROH coordinating
to the Li center and (2) little overlap of π-π stacking between
aromatic aldehyde and a binaphthyl plane of (R)-BINOL. On the
other hand, 5 avoids this repulsion and shows adequate π-π
interaction and hydrogen bonding, to eventually give (S)-4.
In summary, we have developed a highly enantioselective
cyanation of aromatic aldehydes using a simple and inexpensive
chiral lithium binaphtholate aqua or alcohol complexes. The
cyanation is suitable for process chemistry to ensure the practical
gram-scale cyanohydrin synthesis in minimum solvent. Further
investigations into understanding the role of water and alcohol to
enhance the catalytic activity are in progress.
entry
R (3)
yield (%)
ee (%)
1
2
Ph (3a)
p-FC6H4 (3b)
>99 [98]b
92
97 [90]b
96
3
4
5
6
7
8
9
10
11
12
13
14
15
16
m-FC6H4 (3c)
97
93
p-ClC6H4 (3d)
m-ClC6H4 (3e)
p-BrC6H4 (3f)
98 [99]b
83
92 [91]b
91
98 [95]d
96
97
93 [90]d
87
82
m-BrC6H4 (3g)
p-CF3C6H4 (3h)
m-CF3C6H4 (3i)
m-MeC6H4 (3j)
m-MeOC6H4 (3k)
3,5-(MeO)2C6H3 (3l)
R-naphthyl (3m)
â-naphthyl (3n)
3-furyl (3o)
99
86
96 [97]c
93 [93]d
99 [92]d
95
95 [90]c
97 [95]d
97 [97]d
81
96
95
96 [93]d
85e
98 [93]d
98e
m-CHOC6H4 (3p)
a 10 mol % each of (R)-BINOL and LiOPri for 1 mmol of 3 was used
unless otherwise noted. b 1 mol % each of (R)-BINOL and LiOPri was used
for 10 mmol of aldehyde. c 2 mol % each of (R)-BINOL and LiOPri was
used for 5 mmol of aldehyde. d 3 mol % each of (R)-BINOL and LiOPri
was used for 3.3 mmol of aldehyde. e Isolated yield and enantioselectivitiy
for dl-product. Other 15% yield was meso product.
Acknowledgment. Financial support for this project was
provided by the JSPS, KAKENHI (15205021), and the 21st Century
COE Program of MEXT.
Supporting Information Available: Experimental procedures. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(10) Recently, the enantioselective aldol reaction catalyzed by (R)-2 with excess
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assumed is (R)-1‚(H2O)n < (R)-1‚i-PrOH , dry (R)-1 < dry (R)-2.
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Figure 1. Nonlinear effect (left) and proposed transition states for the
cyanation of ArCHO with (R)-1‚(ROH)n (R ) H or alkyl) (right).
This drawback, however, strongly suggests that the existence of a
weak interaction such as π-π stacking between the aromatic
aldehydes and (R)-BINOL should play a key role in the transition
state of cyanation.
Finally, we turned our attention to the characteristics of the active
BINOL-Li catalyst and the mechanistic aspects. On the basis of
the lack of a nonlinear effect (NLE) between the ee of (S)-4a and
the ee of (R)-1‚(H2O)n (10 mol %) (Figure 1, 9), the active structure
of monolithium binaphtholate aqua complexes in our catalysis is
different from “dry” (R)-1 and (R)-2,13 which have the respective
NLE leading to (R)-4a (Figure 1, b and 2). One possibility is that
the presence of hydroxyl compounds just as water would promote
the dissociation of oligomeric BINOL-Li complexes into highly
active monomeric species. In fact, almost the same reactivities
(>90% yield) with (R)-1‚(H2O)n were exhibited with no relation
to enantiomeric excess of (R)-BINOL (see Supporting Information).
Monolithium binaphtholate alcohol complex (i.e., (R)-1‚i-PrOH)
showed a large positive NLE (Figure 1, [). This can be interpreted
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