One-pot synthesis of conjugated alkynenitriles from aldehydes

Article abstract of DOI:10.1016/j.tetlet.2007.01.157

A method of preparing conjugated alkynenitriles was developed from various aldehydes with CCl₃CN and PPh₃ in the presence of ^tBuLi. The reaction proceeded via α-chlorovinyl nitrile as an intermediate without any side react

Full text of DOI:10.1016/j.tetlet.2007.01.157

Tetrahedron Letters 48 (2007) 2299–2301
One-pot synthesis of conjugated alkynenitriles from aldehydes
Joong-Gon Kim,c Eun Hwa Leea and Doo Ok Janga,b,
*
aDepartment of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
bCenter for Bioactive Molecular Hybrids, Yonsei University, Seoul 120-749, Republic of Korea
cBiotechnology Division, Hanwha Chemical R&D Center, Daejeon 305-345, Republic of Korea
Received 15 December 2006; revised 24 January 2007; accepted 30 January 2007
Available online 2 February 2007
Abstract—A method of preparing conjugated alkynenitriles was developed from various aldehydes with CCl3CN and PPh3 in the
t
presence of BuLi. The reaction proceeded via a-chlorovinyl nitrile as an intermediate without any side reactions such as chlorina-
tion of starting aldehydes.
Ó 2007 Elsevier Ltd. All rights reserved.
Conjugated alkynenitriles have been utilized for synthe-
sizing various carbocyclic and heterocyclic compounds
under nucleophilic addition and cycloaddition reaction
conditions.1 Many methods have been reported for pre-
paring the conjugated alkynenitriles including the reac-
tion of metallated acetylides with halocyanides,2 and
the dehydration of acetylenic carboxamates with de-
hydrating agents.3 It has been reported that acetylenic
halides or acetylene derivatives were transformed into
the conjugated alkynenitriles by using cyanating
reagents such as cuprous cyanide,4 1-cyanoimidazole,5
or 1-cyanobenotriazole.6 Recently, the intramolecular
Wittig reaction of b-oxo-alkylidenetriphenylphosphor-
anes for the synthesis of the conjugated alkynenitriles
was described by Rao.7 However, these methods limit
their applicability because of their drawbacks. The pre-
cursors had to be prepared or toxic reagents had to be
used under difficult reaction conditions. Here we report
an efficient one-pot procedure for converting aldehydes
into the corresponding conjugated alkynenitriles with
Ph3P and CCl3CN.
simple process furnished the product, 3-(4-nitro-
phenyl)propynenitrile, in 87% isolated yield (Table 1,
entry 1).
We optimized the reaction by varying the bases and tem-
peratures. Using an excess of the reagents did not affect
the yields of the product (entries 2–4). The reaction did
n
not proceed at À78 °C at the second step with BuLi or
tBuOK (entries 5 and 7). However, when the tempera-
ture of the second step was increased to room tempera-
ture, the reaction proceeded smoothly giving high yields
of the product (entries 6 and 8). These experiments
showed that low temperature was not necessary for the
second step. The whole procedure could be carried out
at room temperature.
The reaction proceeded via a-chlorovinyl nitrile, 5
(R = 4-NO2C6H4), as an intermediate, which was iso-
lated and characterized showing the Z-isomer exclu-
sively. It has been reported that a-chlorovinyl nitrile
was produced when 1 was treated with PPh3 and an
excess of aldehydes (Scheme 1).8 However, the yield of
the a-chlorovinyl nitrile was very poor (based on the
amount of aldehydes), and an extra Ph3PCl2 was gener-
ated giving chlorinated products such as (dichloro-
When reagent 1 which was prepared from Ph3P and
t
CCl3CN in situ was treated with BuLi at À78 °C,
a brown color was immediately observed, indicating
the formation of an ylide. After adding 4-nitrobenz-
methyl)benzene as
a
by-product. Therefore, the
t
aldehyde, the mixture was treated with BuLi. This
method is not suitable for the generation of a-chlorovinyl
nitriles.
The present method was applied to the conversion
of various aldehydes into the conjugated alkyne-
nitriles to examine the generality of the reaction. The
results are presented in Table 2. Benzaldehyde gave
Keywords: Alkynenitrile; Aldehyde; Trichloroacetonitrile; Ylide;
a-Chlorovinyl nitrile.
Corresponding author. Tel.: +82 337602261; fax: +82 337602208;
*
e-mail: dojang@yonsei.ac.kr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.157

2300
J.-G. Kim et al. / Tetrahedron Letters 48 (2007) 2299–2301
Table 1. Reaction of 4-nitrobenzaldehyde with 1 under various reaction conditions
1) Base (1 equiv)
Base (1.5 equiv)
Temp, 1 h
Ph3P + CCl3CN
4-NO2C6H4
CN
2) 4-NO2C6H4CHO
(1 equiv)
Entry
Ph3P
CCl3CN
Base
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
1
1
2
2
1
1
1
1
1
1
2
2
1
1
1
1
tBuLi
tBuLi
tBuLi
tBuLi
nBuLi
nBuLi
tBuOK
tBuOK
À78
À78
À78
À78
À78
rt
87
89a
88
90a
0
85
0
73
À78
rt
a 2 equiv of the base was used at the second step.
Cl
3-phenylpropynenitrile in 85% yield (entry 1). Benzalde-
hyde derivatives with an electron-donating group gave
the corresponding alkynenitriles in somewhat lower
yields (entries 2–6) than those with an electron-with-
drawing group (entries 7–13). These results imply that
the rate-determining step for the reaction is the addition
step of ylide into aldehyde, which is very sensitive to the
electronic effect. The a,b-unsaturated aldehydes were
transformed into the corresponding alkynenitriles with-
out isomerization of the double bonds (entries 15 and
16). The reaction with an aliphatic aldehyde such as oct-
anal also proceeded smoothly (entry 17). When a steri-
cally hindered aliphatic aldehyde such as pivalaldehyde
was brought in to react under conditions, the corre-
sponding product was obtained in low yield (entry 18).
In the case of ketones such as acetophenone and isopro-
pylacetone, the reaction did not afford the desired prod-
Ph3P C CN
Cl-
Cl
1
Cl
RCHO
Ph3P
C
+
Ph3PCl2
1
+ Ph3P
RCHCl2
CN
2
3
4
RCHO
CN
Cl
R
5
Scheme 1.
Table 2. Synthesis of conjugated alkynenitriles
1) tBuLi (1 equiv)
2) RCHO (1 equiv)
tBuLi (1.5 equiv)
Ph3P + CCl3CN
R
CN
-78 oC, 1 h
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5
C6H5
CN
84
72
78
75
67
62
79
80
85
84
87
83
85b
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,4,5-(MeO)3C6H2
4-Me2NC6H4
3-ClC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,4,5-(MeO)3C6H2
4-Me2NC6H4
3-ClC6H4
4-ClC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-NCC6H4
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
4-ClC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-NCC6H4
4-CHO-C6H4
CN
NC
C6H4
CN
CN
CN
14
15
2-Thiophenyl
Cinnamyl
70
91
S
Ph
CN
16
(E)-Oct-1-enyl
81
CH3(CH2)5
CH3(CH2)6
17
18
CH3(CH2)6
tBu
CN
77
47
tBu
CN
a Spectroscopic data of 1H NMR, 13C NMR, and IR were in complete agreement with the assigned structures.
t
b The reaction was carried out with 2 equiv of PPh3, 2 equiv of CCl3CN, and 3 equiv of BuLi.

J.-G. Kim et al. / Tetrahedron Letters 48 (2007) 2299–2301
2301
ucts under the reaction conditions. The reactions are
clean, and there are no side reactions such as chlorina-
tion of the starting aldehydes. The experimental proce-
dure is quite simple, and the products are obtained in
high isolated yields. The results show that the present
procedure could be used as a general method of convert-
ing aldehydes in one-pot into the corresponding conju-
gated alkynenitriles.
J = 7.9 Hz, 2H), 7.94 (d, J = 9.0 Hz, 2H); 13C NMR
(CDCl3) d 66.6, 80.1, 104.9, 124.1, 124.2, 134.6, 149.3.
Acknowledgment
This work was supported by Center for Bioactive
Molecular Hybrids at Yonsei University.
In conclusion, we developed an efficient method of
preparing conjugated alkynenitriles in one-pot manner
directly from aldehydes with readily available CCl3CN
and PPh3 in the presence of tBuLi. It is noteworthy that
no side reaction such as chlorination of starting alde-
hydes was observed under the reaction conditions. The
present process is clean and easy to perform, and it
can be applied to the conversion of aldehydes into cor-
responding conjugated alkynenitriles.
References and notes
1. (a) Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. I.;
Elokhina, V. N.; Mal’kina, A. G.; Tarasova, O. A.;
Ushakov, I. A.; Trofimov, B. A. Synthesis 2001, 293; (b)
Heard, N. E.; Turner, J. J. Org. Chem. 1995, 60, 4302; (c)
Bloxham, J.; Dell, C. P. Tetrahedron Lett. 1991, 32, 4051;
(d) Tanee Fomum, Z.; Forsche Asobo, P.; Landor, S. R.;
Landor, P. D. J. Chem. Soc., Perkin Trans. 1 1984, 1078; (e)
Merah, B.; Texier, F. Bull. Soc. Chim. Fr. 1980, 552.
2. (a) Murray, R. E.; Zweifel, G. Synthesis 1980, 150; (b)
Compagnon, P. L.; Grosjean, B. Synthesis 1976, 448.
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Liso, G.; Trapani, G.; Reho, A.; Latrofa, A.; Loiodice, F.
J. Chem. Soc., Perkin Trans. 1 1983, 567.
t
A typical experimental procedure is as follows: BuLi
(2.94 mL, 1.7 M, 5 mmol) was added under argon at
room temperature to a solution of reagent 1 which
was prepared in situ by a reaction of PPh3 (1.31 g,
5 mmol) with CCl3CN (0.5 mL, 5 mmol) in THF
t
(6 mL). The mixture was cooled to À78 °C, and BuLi
4. (a) Luo, F.-T.; Wang, R.-T. Tetrahedron Lett. 1993, 34,
5911; (b) Casarini, A.; Dembech, P.; Reginato, G.; Ricci,
A.; Seconi, G. Tetrahedron Lett. 1991, 32, 2169.
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G. S. Org. Lett. 2000, 2, 795.
(4.41 mL, 1.7 M, 7.5 mmol) was added. 4-Nitrobenz-
aldehyde (760 mg, 5 mmol) in THF (4 mL) was added to
the above mixture and the resulting mixture was stirred
at À78 °C for 1 h. The mixture was then quenched with
saturated aqueous NaCl (6 mL) and diluted with ether,
washed with water, and dried over anhydrous MgSO4.
After evaporation, the residue was purified by column
chromatography on silica gel eluting with hexane–
EtOAc (8:2) to give 3-(4-nitrophenyl)propynenitrile
(748 mg, 87%): mp 142–143 °C (lit.7b 139–141 °C); IR
(Nujol) 2359 (C„N), 2340 (C„C), 1602, 1522 (N@O)
6. Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64,
313.
7. (a) Rao, V. V. V. N. S. R.; Ravikanth, S.; Reddy, G. V.;
Maitraie, D.; Yadla, R.; Rao, P. S. Synth. Commun. 2003,
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Chem. Soc. 1962, 2333.
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1535.
1
1463, 1346 (N@O) cmÀ1; H NMR (CDCl3) d 7.44 (d,