A new lithium alkoxide accelerated diastereoselective cyanation of ketones

Article abstract of DOI:10.1021/ol0069608

(Matrix presented) A remarkably general lithium heteroatom assisted TMSCN or TBSCN addition to aldehydes and ketones has been discovered. The process provides excellent selectivities and high rates. Conformationally constrained ketones such as camphor, fenchone, and nopinone give excellent diastereoselectivities with TMSCN. Reduction of 2 provided diastereopure amino alcohol 3 in good yield. α- and β-Methyl cyclohexanones with TBSCN-LiOR afford high diastereoselectivities and yields.

Full text of DOI:10.1021/ol0069608

ORGANIC
LETTERS
2001
Vol. 3, No. 4
553-556
A New Lithium Alkoxide Accelerated
Diastereoselective Cyanation of Ketones
H. Scott Wilkinson, Paul T. Grover, Charles P. Vandenbossche, Roger P. Bakale,
Nandkumar N. Bhongle, Stephen A. Wald, and Chris H. Senanayake*
Chemical Research and DeVelopment, Sepracor Inc., 111 Locke DriVe,
Marlborough, Massachusetts 01752
csenanay@sepracor.com
Received December 5, 2000
ABSTRACT
A remarkably general lithium heteroatom assisted TMSCN or TBSCN addition to aldehydes and ketones has been discovered. The process
provides excellent selectivities and high rates. Conformationally constrained ketones such as camphor, fenchone, and nopinone give excellent
diastereoselectivities with TMSCN. Reduction of 2 provided diastereopure amino alcohol 3 in good yield. r- and â-Methyl cyclohexanones
with TBSCN−LiOR afford high diastereoselectivities and yields.
The development of practical technology for the preparation
of R-hydroxy-R-substituted acids, ketones, aldehydes, and
â-hydroxy amines from readily available carbonyl com-
pounds is an extremely important area of organic chemistry.
One of the most straightforward entries to the above-
mentioned building blocks is via cyanohydrins.1 Preparation
of cyanohydrins from ketones is well documented, and
limited enantioselective methods are available.2 The most
commonly used method is through the use of the Lewis acid
catalyzed addition of TMSCN to ketones.3 However, general,
mild, high-yielding, and selective processes for cyanation
of hindered carbonyl groups are still lacking.
In our efforts to synthesize conformationally constrained,
enantiomerically pure amino alcohols for use in asymmetric
synthesis, we required a practical procedure for the prepara-
tion of camphor-derived amino alcohol 3. We envisaged that
compound 2, derived from a selective cyanide addition would
provide an easy access to the desired amino alcohols.4 Herein,
we disclose the development of a new and neutral diastereo-
selective cyanation process for the generation of the silyl
ethers of cyanohydrins from ketones using cyanosilanes and
a lithium heteroatom catalyst. The method is applied to the
synthesis of enantiomerically pure amino alcohol 3 in a
convenient, high yielding procedure.
(1) (a) Matthews, B. R.; Gountzos, H.; Jackson, W. R.; Watson, K. G.
Tetrahedron Lett. 1989, 30, 5157. (b) Jackson, W. R.; Jacobs, H. A.;
Jayatilake, G. S.; Matthews, B. R.; Watson, K. G. Aust. J. Chem. 1990, 43,
2045. (c) Jackson, W. R.; Jacobs, H. A.; Matthews, B. R.; Jayatilake, G.
S.; Watson, K. G. Tetrahedron Lett. 1990, 31, 1447. (d) Ziegler, T.; Horsch,
B.; Effenberger, F. Synthesis 1990, 575. (e) Effenberger, F.; Stelzer, U.
Angew. Chem., Int. Ed. Engl. 1991, 30, 873. (f) Zandbergen, P.; Brussee,
J.; Van der Gen, A.; Kruse, C. G. Tetrahedron: Asymmetry 1992, 3, 769.
(g) For a recent review: North, M. Synlett 1993, 807 and references therein.
(f) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649.
(2) (a) Choi, M. C. K.; Chan, S. S.; Matsumoto, K. Tetrahedron Lett.
1997, 38, 6669. (b) Belokon, Y. N.; Green, B.; Ikonnikov, N.; North, M.;
Tararov, V. Tetrahedron Lett. 1999, 40, 6105. (c) Hamashima, Y.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412.
Scheme 1
(3) (a) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J. Chem. Soc.,
Chem. Commun. 1973, 55. (b) Gassman, P. G.; Talley, J. J. Tetrahedron
Lett. 1978, 19, 3773. (c) Noyori, R.; Murato, S.; Suzuki, M. Tetrahedron
1981, 37, 3899. (d) Reetz, M. T.; Drewes, M. W.; Harms, K.; Reif, W.
Tetrahedron Lett. 1988, 29, 3295. (e) Singh, V. K.; Saravanan, P.; Anand,
R. V. Tetrahedron Lett. 1998, 39, 3823 and references therein.
10.1021/ol0069608 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/30/2001

Table 1a
catalyst
(mol%)
temp
(°C)
time
(h)
% yield
dr
Figure 1.
entry
(% conv)
(2a :2b)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
ZnI2 (5)
KCN/18-C-6 (5)
TGMM (5)
22
22
22
22
22
22
22
22
22
60
-10
22
22
22
22
22
24
72
12
4
12
12
12
24
1
1
16
4
4
7
(98)
(35)
(0)
95 (>99)
(0)
72:27
94:6
Initially, we investigated the well-known Evans ZnI2-
catalyzed addition of TMSCN to the hindered ketone
camphor (1).4 This process has been reported to provide 5:3
diastereoselectivity. As a result of the diastereoselectivity
observed with the ZnI2 process, the 18-C-6/KCN catalyzed
addition of TMSCN to camphor was examined.5 The reaction
of 5 mol % of 18-C-6/KCN in THF with 1.2 equiv of
TMSCN at room temperature, followed by the addition of 1
equiv of camphor, provided 2 in a diastereomeric ratio of
94:6 favoring the endo isomer. However, while the dia-
stereoselectivity was high, the rate of the reaction was
extremely slow, requiring 3 days to reach 35% conversion.
Another drawback of the 18-C-6/KCN system is that 18-
C-6 is expensive and toxic. Therefore, our goal was to
develop a selective cyanation system like 18-C-6/KCN with
the emphasis on generality and practicality. First, we explored
the 18-C-6 replacement hoping to find a nontoxic ligand that
can accelerate the cyanation process while maintaining the
diastereoselectivity. We systematically examined several
available bismethylated and monomethylated glymes with
KCN, NaCN, LiCN in DMF, or TMSCN in THF under
various conditions.
Unfortunately, none of these systems mediated the cyanide
addition to camphor. Significantly, deprotonation of inex-
pensive triglyme monomethyl ether (TGMM, 5 mol %) with
LiH (5 mol %) or n-BuLi (5 mol %) in THF at 0 °C provided
a soluble and remarkable lithium alkoxide (LiTGMM, 5 mol
%). The addition of 5 mol % LiTGMM to 1.2 equiv of
TMSCN, followed by the addition of 1.0 equiv of camphor
gave a quantitative conversion of camphor to the desired
silyl-cyanohydrin with 96:4 diastereoselectivity (Table 1,
entry 4).6
LiTGMM (5)
NaTGMM (5)
KTGMM (5)
MgTGMM (5)
TGMM/LiCl (5)
LiTGMM (50)
LiTGMM (5)
LiTGMM (5)
LiOMe (5)
LiOBu (5)
LiNEt2 (5)
LiPPh2 (5)
LiSPh (5)
96:4
(0)
(0)
(0)
96 (>99)
96 (>99)
(40)
95 (>99)
(>99)
(>99)
(>99)
(>99)
96:4
86:14
96:4
96:4
96:4
96:4
96:4
96:4
10
24
a Selectivities were determined by GC%.
(Table 1, entries 5-7).7 It is important to point out that LiCl/
TGMM does not catalyze the reaction; only lithium alkoxide
promotes the cyanation process. We were intrigued to
determine if a polyether-derived lithium alkoxide was
necessary for this catalytic process. Therefore, we examined
other alkoxides, such as LiOMe, LiOEt,8 and LiOBu.
Interestingly, all of the alkoxides promoted the reaction to
the same degree. A study was conducted to understand the
other lithium-heteroatom effects on the TMSCN addition to
camphor. Other lithium anions such as LiNEt2, LiPPh2, and
LiSPh also promoted the reaction with a similar diastereo-
selectivity to alkoxides, but at reduced rates (entries 14-
16).
The salient feature of this catalytic cyanation process is
the high diastereoselectivity, and the excellent rate of the
reaction. The stereochemical outcome of the cyanide addition
to camphor was unambiguously established by the reduction
of cyanohydrin 2 with RED-Al in toluene, followed by
crystallization of the HCl salt in MeOH to give amino alcohol
3 as a single diastereomer in a 72% yield. The amino alcohol
was converted to new oxazolidinone 4, and a single-crystal
X-ray analysis of 4 indicated that the cyanide addition
occurred mainly from the endo-face of the ring system
(Scheme 2).9
Increasing the temperature (up to 60 °C) decreases the
diastereoselectivity and increases the rate of the reaction
(entry 10). On the other hand, decreasing the temperature to
-10 °C did not change the diastereoselectivity but did,
however, decrease the rate of the reaction dramatically (entry
11). Increasing the catalytic loading increases the rate of
reaction while maintaining the diastereoselectivity (entry 9).
Surprisingly, the sodium, potassium, or magnesium salt of
TGMM does not catalyze this important transformation
(4) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J. Org. Chem. 1974,
39, 914.
(5) Greenlee, W. G.; Hangauer, D. G. Tetrahedron Lett. 1983, 24, 4559.
(6) Other solvents such as CH2Cl2, MTBE, and toluene can be use in
this reaction. Preferred solvent is dry THF. It is important to note that
premixing LiOR and TMSCN is critical before addition of ketone or
aldehyde.
(7) Sodium and potassium salt of TGMM were generated upon treatment
of NaH and KH with TGMM, respectively. MgTGMM was produced simply
by treatment of TGMM with EtMgBr.
(8) Available from Aldrich as a 1 M THF solution.
(9) (a) See Supporting Information for X-ray crystallography data of
compound 4. (b) The novel camphor-derived oxazolidinone 4 will be used
as a chiral auxiliary for asymmetric synthesis.
554
Org. Lett., Vol. 3, No. 4, 2001

has been noted in the literature that R-methyl cyclohexanone
cyanate gave an extremely low diastereoselectivity with ZnI2,
KCN/18-C-6, or TMSOTf (2%, 4%, and 16%, respec-
tively).10 Interestingly, R- and â-methyl cycloalkanones
provided good selectivites and excellent yields at -78 °C
with the current procedure (entries 3-5). It is important to
note that R,â-unsaturated ketone carvone undergoes 1,2-
addition only, with high diastereoselectivity (entry 6). The
neutral nature of this cyanation system is exemplified by the
high yielding processes of enolizable ketones, such as ethyl
acetoacetate and ethyl cyclohexyl glyoxlate (entries 7 and
8).
Recently, Jenner reported that 4-amino acetophenone is a
difficult substrate to cyanate with a ZnI2, LiClO4, or LiF4B
protocol.11 It is gratifying to mention the Li-alkoxide
procedure afforded >95% yield (entry 11). Aldehydes and
nonhindered ketones can be cyanated with extremely high
yields. As revealed in Table 2, entry 9, cyclohexyl phenyl
ketone can be converted to the desired cyanohydrin with very
low catalytic loading (0.025 mol % of LiTGMM), while
maintaining a reasonable reaction rate.
Scheme 2
The viability of this lithium heteroatom accelerated cyanide
addition process was examined by applying the procedure
to various ketones and benzaldehyde. As depicted in Table
2, nopinone and fenchone gave high selectivites in excellent
yields with reasonable rates of reaction (entries 1 and 2). It
Table 2. Lithium Alkoxide Mediated TMSCN Addition to
Ketonesa
This important catalytic process is not only applicable for
TMSCN addition to ketones. It can be extended to the
sterically congested TBSCN addition to hindered ketones.
As outlined in Table 3, the isolated yields of the reactions
Table 3. Lithium Alkoxide Mediated TBSCN Addition to
Ketonesa
a All reaction were conducted in THF with 25 mol % of LiTGMM and
1.7 equiv of TBSCN at 22 °C. *50 mol % of LiTGMM was used.
are high. Several interesting observations were noted when
comparing the selectivites obtained from our TMSCN
additions to those reported previously. For instance, Watt
and co-workers reported that cyanation of camphor with
TBSCN in the presence of either ZnI2 or 18-C-6/KCN
provided low diastereoselectivity (67:33 and 62:38, respec-
tively).12 When utilizing Li-alkoxide in the reaction, the
diastereoselectivity is much higher (91:9, entry 1) than with
a All reactions were conducted in THF with LiTGMM and 1.2 equiv of
TMSCN at the specified temperature unless otherwise specified. *Readily
available 1 M THF solution LiOEt was used as the catalyst. **2.2 equiv of
TMSCN was used. The extra 1 equiv of TMSCN is required for silylation
of hydroxyl group. The product is bisilylated.
(10) Matsubara, S.; Takai, T.; Utimoto, K. Chem. Lett. 1991, 1447.
(11) ZnI2 provided a complex product mixture and LiBF4 or LiClO4 gave
<15% yield. See: Jenner, G. Tetrahedron Lett. 1999, 40, 491.
Org. Lett., Vol. 3, No. 4, 2001
555

Watt’s procedure; however, it was a slightly diminished
diastereoselectivity compared to our TMSCN addition proc-
ess (96:4) (Table 1, entry 4). It is gratifying to disclose that
the R- and â-methyl cyclohexanones provided an outstanding
diastereoselectivity and complimentary results to TMSCN
process (Table 2, entries 3 and 4 and Table 3, entries 2 and
3).
The mechanistic details of this lithium alkoxide accelerated
silyl cyanation process are uncertain, but literature prece-
dence13 coupled with our reported data leads to the working
hypothesis illustrated in Scheme 3. We propose that TMSCN
isocyanide delivers to activated ketone to provide lithio-
cyanated adduct 7 and TMSCN. The adduct 7 then reacts
with TMSCN to produce TMS cyanohydrin and regenerate
LiCN for the next catalytic cycle.
In conclusion, we have demonstrated a remarkable lithium
heteroatom accelerated TMSCN or TBSCN addition to
aldehydes and ketones with high yields. This process is
inexpensive and provides good-to-excellent diastereoselec-
tivity. Conformationally constrained structures such as
camphor, fenchone, and nopinone give excellent selectivites.
These adducts could be conveniently converted to their
corresponding amino alcohols and derivatives thereof, which
are currently being evaluated in asymmetric synthesis and
will be forthcoming. The mechanism of this reaction and
the asymmetric version of this important transformation are
currently being investigated. Li-alkoxides are inexpensive
and readily available, and this process does not require any
heavy metals or toxic additives. We believe that this
remarkable, efficient, and general neutral-cyanation method
is a significant addition to synthetic organic chemistry.
Scheme 3
Acknowledgment. The authors thank Professor Stanley
Cameron from Dalhousie University of Halifax in obtaining
the single crystal X-ray. Drs. Alex Jurgens and James Hilborn
from Sepracor Canada Limited are thanked for their support.
Supporting Information Available: Experimental pro-
cedures and analytical data for compounds 2, other silyl
cyanohydrin adducts, and synthetic procedures for 3 and 4
(including X-ray data). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0069608
reacts with LiXR (X ) heteroatom) to generate lithium
cyanide (the catalyst for the reaction sequence). Lithium
cyanide then reacts with TMSCN to form a pentavalent
silicon species 5, which is in equilibrium with isocyanide
intermediate 6. Then as shown in the transition state,
(12) Golinski, M.; Brock, P. C.; Watt, D. S. J. Org. Chem. 1993, 58,
159.
(13) Dixon, D. A.; Hertler, W. R.; Chase, D. B.; Farnham W. B.;
Davidson, F. Inorg. Chem. 1988, 27, 4012. (b) Olah, G. A.; Prakash, G. K.
S.; Sassaman, M. B. J. Org. Chem. 1990, 55, 2016. (c) Denmark, S. E.;
Barsanti, P. A.; Wong, K.; Stavenger, R. A. J. Org. Chem. 1998, 63, 2428.
556
Org. Lett., Vol. 3, No. 4, 2001