P(RNCH2CH2)N: Efficient catalysts for the cyanosilylation of aldehydes and ketones

Article abstract of DOI:10.1016/j.tetlet.2005.09.032

The 1,2-addition of trialkylsilylcyanides to aldehydes and ketones produces the corresponding protected cyanohydrins in good to excellent yields when carried out at 0°C to room temperature in the presence of catalytic amounts of the nonionic strong base P(RNCH₂CH₂)N (R = Me, i-Pr) in THF. These catalysts are easily removed from the product by hydrolysis or column filtration through silica gel.

Full text of DOI:10.1016/j.tetlet.2005.09.032

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8061–8066
P(RNCH2CH2)N: efficient catalysts for the cyanosilylation
of aldehydes and ketones
Brandon M. Fetterly and John G. Verkade*
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 3 August 2005; revised 7 September 2005; accepted 7 September 2005
Available online 30 September 2005
Abstract—The 1,2-addition of trialkylsilylcyanides to aldehydes and ketones produces the corresponding protected cyanohydrins in
good to excellent yields when carried out at 0 ꢀC to room temperature in the presence of catalytic amounts of the nonionic strong
base P(RNCH2CH2)N (R = Me, i-Pr) in THF. These catalysts are easily removed from the product by hydrolysis or column filtra-
tion through silica gel.
ꢁ 2005 Published by Elsevier Ltd.
1. Introduction
of this type have been shown to catalyze a variety of
organic reactions.8 Here, we report improvements to a
procedure previously published by our group.9 The pre-
vious procedure involved the use of 10 mol % of 1a to
afford products in moderate to excellent yields at room
temperature. We now show that the use of 1b gives
yields that are not only better in most cases than those
previously published, but also require lower catalyst
loading.
Cyanohydrins and cyanohydrin trialkylsilylethers are
versatile intermediates in organic synthesis.1 It is there-
fore no surprise that many catalysts have been devel-
oped for the reaction of trimethylsilylcyanide
(TMSCN) with aldehydes and ketones.2 Because tri-
methylsilyl groups are easily removed under a variety of
reaction conditions,3 bulkier trialkylsilylcyanides such
as tert-butyldimethylsilyl cyanide (TBSCN) or tert-butyl-
diphenylsilyl cyanide (TBDPSCN) are advantageous.
TBS or TBDPS-protected alcohols possess two of the
most popular silyl protecting groups currently used
and are approximately 104 times more resistant to
hydrolysis than the corresponding TMS-protected alco-
hol.3 Such protected alcohols are also stable to a variety
of organic transformations carried out on other func-
tional groups in the molecule, and these bulkier silyl
groups are also easily removed by a variety of methods.3
Despite the usefulness of TBS and TBDPS-protected
cyanohydrins, a one step conversion to this functionality
from aldehydes and ketones is still rare.4
R
R
R
P
N
N
N
N
1a R = Me
1b R = i-Pr
1c R = i-Bu
After testing a series of trisaminophosphines (Table 1),
we concluded that base 1b is the optimal catalyst for
reactions of the type shown in this table, providing an
appropriate balance of basicity and steric bulk. As in
our previous work with 1a, we still observed desilylation
after work-up when the reactions were performed with
aldehydes in the presence of 1b (Table 2). However, this
table also shows that the low yields previously associ-
ated with the use of aromatic aldehydes bearing electron
withdrawing groups were greatly improved using cata-
lyst 1b instead of 1a (entries 3 and 4). In our previous
work, it was suggested on the basis of analogy with a
mechanism proposed in the previous literature that
We have previously reported the synthesis of exceed-
ingly strong nonionic bases 1a5 and 1b6 whose conjugate
acids have pKaÕs of 32.90 and 33.63, respectively.7 Bases
Keywords: Proazaphosphatrane; Aldehyde; Ketone; Trimethylsilyl-
cyanide; Cyanohydrin.
*
Corresponding author. Tel.: +1 515 2945023; fax: +1 515 2940105;
e-mail: jverkade@iastate.edu
0040-4039/$ - see front matter ꢁ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.09.032

8062
B. M. Fetterly, J. G. Verkade / Tetrahedron Letters 46 (2005) 8061–8066
Table 1. Screening of trisaminophosphines
EWG on the phenyl ring results in a more electroposi-
tive carbonyl oxygen which requires a more electron rich
silicon for the formation of a higher concentration of a
more robust activated species.10 Such a species would be
provided by the more basic 1b, even though this catalyst
is more bulky than 1a. In this regard, too much bulk
may be the reason that 1c gives rise to a poor yield in
the screening reaction in Table 1. Other aldehydes, such
as furfural, hydrocinnamaldehyde, and heptaldehyde,
gave the corresponding cyanohydrins in very good to
excellent yields (89–99%). As shown in Table 2, yields
in the reactions catalyzed by 1b meet or exceed those ob-
tained when 1a is used as a catalyst and are better than
those found in the literature in seven out of the nine
reactions studied in the present work.
OH
CN
1.2 equiv. TMSCN
10 mol % catalyst
CHO
Cl
THF, rt, 30 min
Cl
Catalyst
Yield (%)
(Me2N)3P
(i-Bu2N)3P
EtC(CH2N-i-Bu)3Pa
1b
1c
0
50
25
99
15
a Ref. 13.
trimethylsilylation proceeds via Lewis base activation of
The results of the trimethylsilylcyanation of ketones
in the presence of 1b are shown in Table 3. Ketones of
silicon by the phosphorus of 1a.9 It may be that the
Table 2. The reaction of aldehydes with TMSCN using 1b as a catalysta
Entry
Aldehyde
Reaction condition
T (ꢀC)/t (h)/catalyst (mol %)
Product
Yield
(%)
Yield w/1a
(%)
Lit. yield
(%)
CHO
CH(CN)OH
1
2
0/1/1
0/1/3
97b
98
92
94
62–99d,e,f
CHO
CH(CN)OH
CH(CN)OH
CH(CN)OH
60–92g,h,i j,k,l
MeO
Cl
MeO
Cl
CHO
3
4
5
6
7
rt/0.5/5
rt/0.5/3
rt/0.5/3
0/1/3
99c
97
99
89
99
68
59
83
84
90
60–85d,g
CHO
CHO
60j,k
CN
CN
CH(CN)OH
76–88g,i,j,k
79–86d,f,h
70–86d,j,k,l
O
O
CHO
CH(CN)OH
CHO
CH(CN)OH
CH(CN)OH
0/2/3
85–97f,j,k
62–99f,i
CHO
8
9
0/1/3
98
95
92
95
Ph
Ph
CH3(CH2)5CHO
rt/0.5/3
CH3(CH2)5CH(CN)OH
a 3 mol % catalyst was used unless stated otherwise.
b 1 mol % catalyst was used.
c 5 mol % catalyst was used.
d Ref. 14.
e Ref. 15.
f Ref. 16.
g Ref. 17.
h Ref. 18.
i Ref. 19.
j Ref. 20.
k Ref. 21.
l Ref. 22.

B. M. Fetterly, J. G. Verkade / Tetrahedron Letters 46 (2005) 8061–8066
Table 3. The reaction of ketones with TMSCN using 1b as a catalysta
8063
Entry
Ketone
Product
OTMS
CN
Yield (%)
Yield w/1a (%)
Lit. yield (%)
O
1
90
94
50–99g,h,i,j,k,l,m
Ph
Ph
TMSO
Ph
O
CN
Ph
2
3
87e
99
91
86
61–98h,i,j,n
Ph
Ph
Ph
O
OTMS
CN
97j,o
Ph
O
TMSO CN
4b
99
99
54
88
O
OTMS
CN
5
O
O
O
O
CN
OTMS
O
6c
85 (79:21)d
99 (53:47)d
89
94
86–99l,p
O
TMSO CN
7
8b
26f
99
33
90
68–95j,l
OTMS
O
CN
OTMS
CN
O
9c
a All reactions were conducted for 1 h with 3 mol % catalyst unless stated otherwise.
b Reaction time was 5 h.
c Reaction time was 0.5 h.
d The diastereomeric ratio was determined by 13C NMR spectroscopic integration.
e 5 mol % catalyst was used.
f 10 mol % catalyst was used.
g Ref. 23.
h Ref. 2a.
i Ref. 24.
j Ref. 25.
k Ref. 26.
l Ref. 2b.
m Ref. 27.
n Ref. 28.
o Ref. 29.
p Ref. 30.
various types react smoothly with TMSCN to afford the
corresponding products in good to excellent yields. a,b-
Unsaturated ketones (entries 3 and 4) react solely in the
1,2 mode, and no Michael addition products were de-
tected. Interestingly, (À)-menthone affords an excellent
yield of product, but with no diastereoselectivity (entry
7). (1R)-(+)-Camphor, on the other hand (entry 8),
was found to afford only the diastereomeric product
shown,11 but the overall yield for this reaction was only
26% at a 10 mol % catalyst loading. Our yields in the
reactions catalyzed by 1b (Table 3) were improved in five
of the nine cases studied compared with the yields ob-
tained when 1a was used as a catalyst. A comparison
of literature yields found for five reactions in Table 3 re-
veals that our yields obtained with 1b exceed those in the
literature in only one case, with camphor again showing
very disappointing results for reasons that may be steric
in origin.

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B. M. Fetterly, J. G. Verkade / Tetrahedron Letters 46 (2005) 8061–8066
Table 4. The reaction of aldehydes with TBSCN using 1b as a catalysta
Entry
1
Aldehyde
Reaction condition T (ꢀC)/t (h)
Product
CH(CN)OTBS
Yield (%)
99
Lit. yield (%)
984c
CHO
0/1
CHO
CH(CN)OTBS
CH(CN)OTBS
CH(CN)OTBS
2
3
4
0/1
99
99
99
MeO
Cl
MeO
Cl
CHO
rt/0.5
rt/0.5
CHO
CHO
CN
CN
CH(CN)OTBS
5
6
7
rt/0.5
0/1
99
99
99
O
O
954c
CHO
CH(CN)OTBS
CHO
CH(CN)OTBS
CH(CN)OTBS
0/2
CHO
8
9
0/1
99
99
Ph
Ph
CH3(CH2)5CHO
rt/0.5
CH3(CH2)5CH(CN)OTBS
a 3 mol % catalyst was used.
Because products obtained from the reaction of alde-
hydes and ketones with TMSCN are easily hydrolyzed
by adventitious water, we decided to use TBSCN, which
affords a product that is less sensitive to hydrolysis.3
Although we found earlier12 that both 1a and 1b cata-
lyze the hydrolysis of TBS ethers, those reactions em-
ploy longer times and higher temperatures than those
required herein. Under our conditions, no desilylation
products were found in the reactions of TBSCN with
aldehydes (Table 4). Furthermore, the reactions pro-
ceeded much more cleanly than those in which TMSCN
was used. Our yields shown in this table are uniformly
nearly quantitative and exceed those reported for the
two cases found in the literature.
realized, which is significantly below the range
reported.
In summary, although other methods are known for
cyanosilylating aldehydes and ketones, they either in-
volve lengthy reaction times or the use of a Lewis acid
or crown ether/KCN as a catalyst.9 Herein, a wide range
of aldehydes and ketones have been shown to undergo
trialkylsilylcyanation in generally excellent yield, with
the use of the proazaphosphatrane 1b. Aryl aldehydes
and ketones react cleanly under mild conditions, tolerat-
ing many different types of functional groups. The cata-
lyst is easily removed by filtration through a pad of silica
gel, affording NMR-pure products in a substantial num-
ber of cases. Catalyst 1b is also a generally superior cat-
alyst for the t-butyldimethylsilylcyanation of aldehydes
and ketones.
The results of the reactions of TBSCN with ketones are
shown in Table 5. Acetophenone (entry 1) requires
7 mol % of catalyst 1b to obtain the near-quantitative
product yield realized with 3 mol % of catalyst for seven
other ketones. Also noteworthy is the nearly twofold in-
crease in yield in the reaction of (1R)-(+)-camphor with
TBSCN compared with TMSCN, again with no loss of
diastereoselectivity. Using TBSCN instead of TMSCN
in the reaction of (À)-menthone, on the other hand, pro-
vided no significant increase in diastereoselectivity. Our
yields in the reactions catalyzed by 1b, as shown in Table
5, exceed those found in the literature in two cases, but
with camphor as a substrate (entry 8) a yield was
2. Typical procedure for reaction of aldehydes with
TMSCN
In this and subsequent typical procedures, all reactions
were carried out in an argon atmosphere, and THF
˚
was freshly distilled from Na and stored over 4 A molec-
ular sieves. To a solution of TMSCN (1.8 mmol) and an
aldehyde (1.5 mmol) in THF (2.0 mL) was added (com-
mercially available from Aldrich and Strem) 1b (1–

B. M. Fetterly, J. G. Verkade / Tetrahedron Letters 46 (2005) 8061–8066
Table 5. The reaction of ketones with TBSCN using 1b as a catalysta
8065
Entry
Ketone
Product
OTBS
CN
Yield (%)
Lit. yield (%)
864b
O
1
99e
Ph
Ph
TBSO
Ph
O
CN
Ph
2
3
99
98
Ph
Ph
O
OTBS
CN
834b
Ph
Ph
O
TBSO CN
4b
99
99
O
OTBS
CN
5
O
O
O
O
CN
OTBS
O
6c
99 (63:37)d
99 (61:39)d
O
TBSO CN
7
8b
42f
99
91–944a,b
OTBS
O
CN
OTBS
CN
O
9c
a All reactions were conducted for 1 h with 3 mol % catalyst unless stated otherwise.
b Reaction time was 5 h.
c Reaction time was 0.5 h.
d The diastereomeric ratio was determined by 13C NMR spectroscopic integration.
e 7 mol % catalyst was used.
f 10 mol % catalyst was used.
5 mol % of aldehyde, as specified in Table 2) at 0 ꢀC.
After the reaction conditions stated in Table 2 had been
met, an aqueous solution of HCl (1 M, 5 mL) and ether
(20 mL) was added and the mixture was stirred at room
temperature for another hour. The phases were sepa-
rated and the water layer was washed with brine
(2 · 20 mL) and dried over MgSO4. The solvent was re-
moved with a rotary evaporator to give the crude prod-
uct, which was purified by flash chromatography
(hexane–ethyl acetate = 10:1) to give cyanohydrin.
10 mol % as specified in Table 3) at room temperature.
After the reaction conditions stated in Table 3 had been
met, the reaction mixture was loaded onto a small silica
gel column for elution (ether–methanol = 20:1). Re-
moval of the solvent from the eluate under reduced pres-
sure afforded the crude product which was purified by
flash chromatography (hexane–ethyl acetate = 100:1)
to give the cyanohydrin silyl ether.
4. Typical procedure for the reaction of aldehydes and
ketones with TBSCN
3. Typical procedure for the reaction of ketones with
TMSCN
To a solution of TBSCN (1.8 mmol) and an aldehyde or
ketone (1.5 mmol) in THF (2.0 mL) was added 1b (3–
10 mol % of aldehyde or ketone, as specified in Tables
4 and 5) at 0 ꢀC. After the reaction conditions in Tables
To a solution of TMSCN (1.8 mmol) and a ketone
(1.5 mmol) in THF (2.0 mL) was added 1b (3–

8066
B. M. Fetterly, J. G. Verkade / Tetrahedron Letters 46 (2005) 8061–8066
9. Wang, Z.; Fetterly, B. M.; Verkade, J. G. J. Organomet.
Chem. 2002, 646, 161.
4 and 5 had been met, the reaction mixture was loaded
onto a small silica gel column for elution (ether–metha-
nol = 20:1). Removal of the solvent from the eluate
under reduced pressure afforded the crude product
which was purified when necessary by flash chromato-
graphy (hexane–ethyl acetate = 100:1) to give the cyano-
hydrin silyl ether.
10. Although a 31-P chemical shift was reported in Ref. 9 for
an adduct of TMSCN and 1a, we have more recently been
unable to observe a shift for that species or a correspond-
ing one for the analogous adduct with 1b.
11. The diastereomer shown for the product is the same as
that obtained in the corresponding literature references
shown in Tables 3 and 5.
12. Yu, Z.; Verkade, J. G. J. Org. Chem. 2000, 65, 2065.
13. Urgaonkar, S.; Xu, J. H.; Verkade, J. G. J. Org. Chem.
2003, 68, 8416.
14. Aspinall, H. C.; Greeves, N.; Smith, P. M. Tetrahedron
Lett. 1999, 40, 1763.
Acknowledgements
The authors are grateful to the Petroleum Research
Fund administered by the American Chemical Society,
for Grant support of this research.
15. Zhou, X.; Huang, J.; Ko, P.; Cheung, K.; Che, C. J. Chem.
Soc., Dalton Trans. 1999, 3303.
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