α,β-Unsaturated acyl cyanide synthesis via triethylamine catalyzed redox cyanation

Article abstract of DOI:10.1016/j.tetlet.2011.02.063

Stereoselective redox cyanation of alkynyl aldehydes was explored, furnishing (E)-α,β-unsaturated acyl cyanides. This reaction was catalyzed by mild TEA base, as a dual role of Lewis base and Bro?nsted base. TMSCN treated with TEA was an effective reagent for generating umpolung intermediates from alkynyl aldehydes, and this nucleophilic intermediate can be protonated by equimolar amount of EtOH, promoting the efficient conversion into α,β-unsaturated acyl cyanides. The synthesized acyl cyanides were successfully applied as the synthetic precursors in the iron-catalyzed arylation reactions.

Full text of DOI:10.1016/j.tetlet.2011.02.063

Tetrahedron Letters 52 (2011) 2312–2315
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
a,b-Unsaturated acyl cyanide synthesis via triethylamine catalyzed
redox cyanation
⇑
Hyung Ho Choi, Young Hoon Son, Min Seok Jung, Eun Joo Kang
Department of Applied Chemistry, Kyung Hee University, Youngin, Gyeonggi, 446-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective redox cyanation of alkynyl aldehydes was explored, furnishing (E)-a,b-unsaturated acyl
Received 18 January 2011
Revised 11 February 2011
Accepted 16 February 2011
Available online 23 February 2011
cyanides. This reaction was catalyzed by mild TEA base, as a dual role of Lewis base and Brönsted base.
TMSCN treated with TEA was an effective reagent for generating umpolung intermediates from alkynyl
aldehydes, and this nucleophilic intermediate can be protonated by equimolar amount of EtOH, promot-
ing the efficient conversion into
cessfully applied as the synthetic precursors in the iron-catalyzed arylation reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
a,b-unsaturated acyl cyanides. The synthesized acyl cyanides were suc-
Keywords:
Redox reaction
Umpolung
Acyl cyanide
Triethylamine
The discovery of new reaction manifolds via reversal of normal
reactivity of organic functional groups, known as umpolung, has
become the focus of increased attention, thereby expanding the
opportunities of new bond formation and functional group trans-
formation.1 N-Heterocyclic carbenes (NHCs), typically researched
for their role of nucleophilic organocatalysts2 and ligands, have
been shown to catalytically convert aldehydes into acyl anion
equivalents under mild conditions during transformations such
as traditional benzoin and Stetter reactions. Rovis, Zeitler, Scheidt,
highly toxic mercury) at a high reaction temperature while alterna-
tive approaches mostly involve several steps, including cyanosily-
lation, cyanohydrin formation, and oxidation. Moreover, there have
been few cases of the synthetic methods for
a,b-unsaturated acyl
cyanides,10 only with chemical data of cinnamoyl cyanide. In this
context, atom economical, catalytic methods for the direct synthe-
sis of acyl cyanides are presented as a way to achieve sustainable,
environmentally benign redox processes as well as stereoselective
preparation of
a,b-unsaturated acyl cyanides using propargylic
and Bode demonstrated that
a
-reducible aldehyde leads to a novel
aldehydes as synthetic precursors.
redox reaction pathway under NHC catalysis in the presence of
alcohols as nucleophiles, resulting in either halide elimination,3
cyclopropane, epoxide and aziridine opening,4 or homoenolate
and homoynolate protonation.5,6 Although the development of
these carbonyl or vinylogous carbonyl anion reactions has received
significant attention, a related strategy featuring catalytic acety-
lenic carbonyl anions has received considerably less attention.
Regarding the initiation of benzoin condensation,7 cyanide ion
from KCN or NaCN acts as a very specific catalyst that generates
acyl anion equivalent. During the key step of this process, deproto-
nation of the aldehyde proton occurs due to increased acidity of the
C-H bond caused by the electron-withdrawing effect of the CN
group. As part of an ongoing study aimed at developing umpolung
reactions, this study examined the reaction mode of CN reagent in
an efficient redox process with mild base catalyst (Scheme 1).8
The classical methods for synthesis of acyl cyanides9 from acyl
halides usually require metal cyanides (potassium, copper, silver or
Based on our hypothesis regarding the formation of a,b-unsat-
urated acyl cyanides, we began our investigation by examining a
suitable base catalyst. Under the reaction conditions described in
Table 1, cyanide nucleophile was generated from trimethylsilyl
cyanide, and the alcohol additive presumably served as the electro-
phile (proton) source. Whereas morpholine, a relatively weak base
proved to be insufficient to complete the reaction, (dimethyl-
amino)pyridine, triethylamine and diisopropylethylamine gave
⇑
Corresponding author. Tel.: +82 31 201 2255; fax: +82 31 202 7337.
E-mail address: ejkang24@khu.ac.kr (E.J. Kang).
Scheme 1. General umpolung strategy.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.063

H. H. Choi et al. / Tetrahedron Letters 52 (2011) 2312–2315
2313
Table 1
Table 2
Optimization of conditions for redox cyanationa
Catalytic redox cyanation of alkynals: substrate scopea
Entry
R
Product
Yieldb (%)
Entry
Base
Additive
Yieldb (%)
Notec
1
2
3
4
5
6
7
8
Ph
2
6
7
8
76 (70)
77 (68)
57
61 (59)
54
67
61
76
19
1-Naphthyl
2-Naphthyl
2-Thienyl
4-MeC6H4
4-MeOC6H4
4-FC6H4
1
2
3
4
5
6
7
8
9
10
Morpholine
DABCO
DMAP
TEA
DIPEA
KOtBu
TEA
TEA
TEA
TEA
EtOH
EtOH
EtOH
EtOH
––
11
40
76
25
<10
––
13
––
10
3 (28)
9
10
11
12
13
14
15
EtOH
EtOH
EtOHd
tBuOH
H2O
4 (17)
5 (10)
4-BrC6H4
9
10
11
4-(CN)C6H4
4-(CH3CO)C6H4
4-NO2C6H4
35
36
di-tBu cresol
a
a
Reactions and conditions: aldehyde (0.4 mmol), TMSCN (0.48 mmol), base
Reactions and conditions: aldehyde (1; 0.4 mmol), TMSCN (0.48 mmol), base
catalyst (0.12 mmol), additive (0.4 mmol), THF (0.4 M), room temperature, under
N2.
catalyst (0.12 mmol), additive (0.4 mmol), THF (0.4 M), room temperature, under
N2.
b
Determined by 1H NMR spectra using internal standard after silica pad filtra-
b
Determined by 1H NMR spectra using internal standard after silica pad
tion. Isolated yields are given in parenthesis.
filtration.
C
Byproducts obtained with yields in parenthesis as follows:
of deprotonated acetylene derivatives. Phenyl, naphthyl, and het-
eroaryl propargylic aldehydes were good substrates for the reac-
tion, and electron-rich aryl propargylic aldehydes also readily
underwent the transformation to give the desired products. Elec-
tron-poor aldehydes showed lower yields, which is identical to
the results of the redox reactions catalyzed by N-heterocyclic carb-
enes.5c The alkynals having sterically-hindered alkyl or silyl sub-
stituents only afforded the trimethylsilyl ethers of the
corresponding cyanohydrins.
As for the mechanistic view of this redox cyanation, the reaction
was initiated by trimethysilylcyanation of aldehydes catalyzed by
triethylamine as a Lewis base,11 affording trimethylsilyl ether of
cyanohydrins I (Fig. 1). Triethylamine as a Brönsted base deproto-
nated the acidic aldehyde protons, which subsequently underwent
d
10 equiv of EtOH used
the desired product with moderate to good yields. The use of a
strong base KOtBu proved not to be productive in terms of the yield
of the reaction. We assume that the strong base completely and
irreversibly deprotonated the aldehyde protons and prevented
the process of proton shuttling. Remarkably, this reaction resulted
in the exclusive formation of the (E)-configured isomer, and 1H
NMR experiments did not show any trace of the (Z)-isomer. While
all of the reactions showed full conversion of propargylic alde-
hydes by TLC analysis, 1H NMR using 1,3,5-trimethoxybenzene as
an internal standard after short silica pad filtration indicated lower
yields, suggesting the possible loss of material according to the
highly reactive acyl cyanide functional group. Additionally, high
purities of acyl cyanides were obtained after flash column chroma-
tography or recrystallization of crude product mixture, with 5ꢀ10%
lower than the 1H NMR yield.
Encouraged by these interesting results, we proceeded to exam-
ine the ability of other alcohols to act as a proton source. An excess
amount of alcohol provided unsaturated ester 4 via attack of sub-
sequent alkoxide nucleophile. Not surprisingly, the use of less
acidic tert-butyl alcohol only showed the lower yield, indicating
that tBuOH was an ineffective proton source. When water was
used, acyl cyanide was transformed further into the corresponding
acid followed by TMS-ester formation. Di-tBu cresol, which was
proven to be a good proton source having nonnucleophilic phenox-
ide, provided acyl cyanide 2 with low yield. The use of diethyl ether
and dioxane as solvents produced 2 with similar yields (70 and
69%), but other solvents such as acetonitrile, dichloromethane,
and toluene gave 2 with lower yields (<5%).
H-migration to provide
These allene intermediates were hydrolyzed and tautomerized to
,b-unsaturated acyl cyanides with the aid of triethylamine. To
a-trimethylsiloxy allenyl cyanides III.
a
gain some insight into the reaction mechanism, redox reaction
was carried out with EtOD, providing deuterio-2 with 14% and
50% content of deuterated vinyl group (Scheme 2). Deuterated
b-protons indicate that the b-protonation did not occur by a
concerted hydride shift, and the deuterated ratio of less than
100% implies that the formation of intermediate II was relatively
rapid to release protons but all the intermediate II cannot afford
the complete conversion to the desired product 2.
A diverse range of substrates was evaluated by employing a
suitable set of reaction conditions using TMSCN (1.2 equiv), TEA
(0.3 equiv), and EtOH (1.0 equiv) in THF solvent (Table 2). Prepara-
tion of the required propargylic aldehydes was straightforward.
They were conveniently prepared either by oxidation of propargy-
lic alcohols, easily accessed through Sonogashira coupling with
unprotected propargylic alcohol, or alternatively via formylation
Figure 1. Plausible catalytic cycles.

2314
H. H. Choi et al. / Tetrahedron Letters 52 (2011) 2312–2315
used as a cyanide nucleophile and proton electrophile source,
respectively. Various types of acyl cyanides were prepared with
moderate to good yields after filtration through a plunge of silica
or recrystallization, although these compounds were relatively
reactive. Based on the plausible mechanism, TEA catalyzed this re-
dox reaction as a Lewis base in the cyanosilylation step and a Brön-
sted base in the umpolung generation step. The synthesized
a,b-
unsaturated acyl cyanide was successfully applied as a synthetic
precursor in the transformation reactions, especially in the iron
catalyzed arylation reactions. The knowledge gained from the
TEA-catalyzed redox reactions is expected to contribute to the de-
sign and development of various electrophiles for use in new bond
formation.
Scheme 2. Deuterium experiment.
Acknowledgments
This study was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, Basic Research
Promotion Fund) (KRF-2008-331-1-C00158) and the National Re-
search Foundation Grant funded by the Ministry of Education, Sci-
ence and Technology (2009-0069496).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.063.
Scheme 3.
a,b-Unsaturated acyl cyanides as synthetic precursors.
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