Selective Synthesis of (E)- and (Z)-Allyl Nitriles via Decarboxylative Reactions of Alkynyl Carboxylic Acids with Azobis(alkylcarbonitriles)

Article abstract of DOI:10.1021/acs.orglett.7b00860

Allyl nitriles were synthesized from the reactions of arylpropiolic acids with azobis(alkylcarbonitriles) (AIBN or ACCN). In the presence of Cu(OAc)₂ as a catalyst and pyridine as the solvent, the (E)-stereoisomer was formed as the major product. This transformation shows good tolerance toward alkoxy, halogen, alcohol, amine, ester, and ketone functional groups. When the reaction was conducted with the sterically bulky amine, ethyldiisopropylamine, in the absence of a copper catalyst, the corresponding (Z)-stereoisomers were formed preferentially.

Full text of DOI:10.1021/acs.orglett.7b00860

Letter
pubs.acs.org/OrgLett
Selective Synthesis of (E)- and (Z)‑Allyl Nitriles via Decarboxylative
Reactions of Alkynyl Carboxylic Acids with Azobis(alkylcarbonitriles)
Francis Mariaraj Irudayanathan and Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
S
* Supporting Information
ABSTRACT: Allyl nitriles were synthesized from the reactions of arylpropiolic
acids with azobis(alkylcarbonitriles) (AIBN or ACCN). In the presence of
Cu(OAc)2 as a catalyst and pyridine as the solvent, the (E)-stereoisomer was
formed as the major product. This transformation shows good tolerance toward
alkoxy, halogen, alcohol, amine, ester, and ketone functional groups. When the
reaction was conducted with the sterically bulky amine, ethyldiisopropylamine,
in the absence of a copper catalyst, the corresponding (Z)-stereoisomers were
formed preferentially.
Scheme 1. Synthesis of Allyl Nitriles
he nitrile group is one of the most important functional
Tgroups in organic synthesis. It is found in natural products
and has been introduced into functional materials, pharma-
ceuticals, and other bioactive compounds. Moreover, it plays a
key role in the synthesis of functional organic compounds
because it is readily converted to other useful functional groups
such as amines,1 amides,2 and carboxylic acids.3 In particular,
the allyl nitrile (or allylcyano) group has been found in
bioactive compounds such as the vitamin D receptor, pesticides,
and antifungal agents, as shown in Figure 1.4
Mao reported the synthesis of isobutyronitrile amides from the
reactions of carboxylic acids with AIBN.13 These results
inspired us to develop decarboxylative coupling reactions of
alkynyl carboxylic acids with AIBN. We have, over many years,
studied decarboxylative reactions with the aim of furnishing
useful building blocks for the synthesis of functional materials.14
In particular, we have widely used arylpropiolic acid derivatives
as starting materials because they are readily prepared through
the one-pot reactions of aryl halides with propiolic acid and
they can be purified by simple acid−base workup procedures.15
Although Mao and Xu reported that they failed to obtain the
desired allyl nitrile from the attempted decarboxylative coupling
reaction of 4-bromophenylpropiolic acid under argon,11 we
found that the corresponding allyl nitrile is formed under
aerobic conditions. Furthermore, we found that (Z)-allyl
nitriles are selectively formed under copper-free conditions.
Herein, we report the efficient and selective synthesis of (E)-
and (Z)-allyl nitriles from arylpropiolic acid derivatives.
Figure 1. Bioactive compounds bearing an allyl nitrile.
A number of synthetic methods for the preparation of allyl
nitriles have been developed (Scheme 1). In the more classical
methods, allyl substrates bearing leaving groups, such as halide,5
acetate,6 alcohol,7 phosphate,8 or carbonate,9 are reacted with a
metal cyanide or trimethylsilyl nitrile. However, these methods
require harsh reaction conditions or expensive catalysts. As an
alternative method, the Huang group reported the decarbox-
ylative coupling reactions of cinnamic acids and 1,1′-azobis-
(cyclohexane-1-carbonitrile) (ACCN) to provide β,γ-unsatu-
rated nitriles in moderate yields.10 Mao and Xu similarly
employed azobis(isobutyronitrile) (AIBN) as a nitrile source
for reactions with terminal alkynes.11 They found that terminal
alkynes were converted into allyl nitriles under argon; however,
alkynyl nitriles were obtained under aerobic conditions.
Azobis(alkylcarbonitriles) such as AIBN (2a) and ACCN
(2b) have mostly been used as radical initiators and have rarely
been employed in organic synthesis as reagents for the
preparation of nitrile-containing compounds.12 Zhang and
Received: March 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00860
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Organic Letters
Letter
To identify the optimum conditions for these trans-
formations, phenylpropiolic acid and AIBN were reacted
under the reaction conditions listed in Table 1. A number of
Scheme 2. Synthesis of (E)-Allyl Nitriles by Copper-
Catalyzed Decarboxylation
a
Table 1. Optimization of Reaction Conditions for the
a
Synthesis of Allyl Nitriles
entry
copper
additive
solvent
yield (%)
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(acac)2
Cu(OTf)2
Cu(NO3)2
Cu(CO3)2
CuF2
toluene
CH3CN
dioxane
DMSO
DMF
1
2
34
20
14
19
15
67
14
1
3
4
5
6
EtOH
7
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
CH3CN
CH3CN
CH3CN
8
9
10
11
12
13
14
15
16
17
2
18
37
24
12
38
37
a
Reaction conditions: 1 (2.0 mmol), AIBN or ACCN (4.0 mmol), and
CuCl2
Cu (0.2 mmol) were reacted in pyridine (5.0 mL) at 80 °C for 12 h,
air.
CuBr2
b
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
pyridine
Et3N
c
DBU
22 (1:1)
afforded a slightly lower yield of (E)-3h. Bromo-, chloro-,
fluoro-, and trifluoromethyl-substituted phenylpropiolic acids
gave the corresponding products, (E)-3i, (E)-3j, (E)-3k, and
(E)-3l in 60%, 57%, 44%, and 41% yield, respectively. 3-(6-
Methoxynaphthalen-2-yl)propiolic acid provided (E)-3m in
61% yield. Alcohol, ester, ketone, and amine substituents on the
benzene ring afforded the corresponding allyl nitriles (E)-3n,
(E)-3o, (E)-3p, and (E)-3q in 47%, 65%, 52%, and 39% yield,
respectively. 3-(Thiophene-2-yl)propiolic acid gave (E)-3r with
60% yield. However, none of the desired product, (E)-3s, was
obtained from the attempted reaction of 4-cyanophenylpro-
piolic acid. Alkyl-substituted alkynyl carboxylic acids, such as 1-
octynoic acid, also provided no product. Except for 3b, 3l, 3o,
and 3p, which were formed as 12.5:1, 11:1, 4.5:1, and 3:1
mixtures of (E)- and (Z)-isomers, respectively, it is noteworthy
that (E)-configured nitriles were exclusively formed in these
reactions. Instead of AIBN, ACCN was also employed as a
nitrile source. Phenylpropiolic acid afforded the desired product
(E)-3t with 50% yield. 4-Methyl-, 4-methoxy-, 4-chloro-, 4-
fluoro-substituted phenylpropiolic acids provided the corre-
sponding allyl nitriles with moderate yields.
Entry 17 in Table 1 reveals that the addition of DBU to the
reaction also resulted in a mixture of (E)-3a and (Z)-3a. This
observation prompted us to develop a stereoselective synthesis
of the corresponding (Z)-isomers. We chose solvents bearing
an amine group and performed the reaction in the absence of
copper. The results of this study are summarized in Table 2.
Trace amounts of the desired allyl nitrile were detected in the
reaction mixture when the reaction was conducted in pyridine
(entry 1). Surprisingly, the desired allyl nitrile was formed
predominantly as the (Z)-isomer when the reaction was carried
out in DBU (entry 2). The use of the more sterically bulky
amine, ethyldiisopropylamine ((i-Pr)2EtN), provided (Z)-3a as
the major product in an 11:1 (Z)/(E) ratio (entry 3). However,
the reaction with the chelating diamine, TMEDA, afforded the
desired product in low yield and with low selectivity (entry 4).
a
Reaction conditions: 1a (0.3 mmol), AIBN (0.6 mmol) and Cu (0.06
b
mmol) were reacted in solvent (1.2 mL) at 80 °C for 12 h, air. 0.9
c
mmol was used. Both (E)-3a and (Z)-3a were formed in a 1:1 ratio.
solvents were tested for the reaction with Cu(OAc)2. Toluene
provided a trace amount of the desired product (E)-3a (entry
1). Reactions in CH3CN, 1,4-dioxane, DMSO, DMF, and
EtOH provided low yields of 3a (entries 2−6); however, when
the reaction carried out in pyridine, the desired product was
formed in 67% yield (entry 7). With pyridine identified as the
solvent of choice, a variety of copper catalysts were tested;
however, all of the Cu(II) catalysts listed in entries 8−14
provided unsatisfactory results. When the reaction was
conducted with 3 equiv of pyridine in CH3CN, the yield of
(E)-3a decreased to 38% (entry 15). Other bases, such as Et3N
and DBU, gave the desired product in 37% and 22% yield,
respectively (entries 16 and 17). It is noteworthy that the (E)-
stereoisomer is formed as the major product in most cases.
However, the reaction in the presence of DBU afforded a 1:1
mixture of (E)-3a and (Z)-3a (entry 17). To obtain the desired
allyl nitrile, (E)-3, from the corresponding alkynyl carboxylic
acid, the optimized conditions were found to involve reacting
the aryl alkynyl carboxylic acid (1.0 equiv), AIBN (2.0 equiv),
and Cu(OAc)2 (20 mol %), in pyridine, at 80 °C for 12 h.
With these optimized conditions in hand, we evaluated the
scope of this reaction for the general synthesis of allyl nitriles
from aryl alkynyl carboxylic acids. The results of this study are
summarized in Scheme 2.
As expected, phenylpropiolic acid acid provided (E)-3a in
67% yield. 2-Methyl-, 4-methyl-, and 4-ethyl-substituted
phenylpropiolic acids were transformed to the corresponding
allyl nitriles (E)-3b, (E)-3c, and (E)-3d in 46%, 65%, and 71%
yield, respectively. Mono-, di-, and trimethoxy-substituted
substrates gave the corresponding desired products in a range
of yields (49−64%); however, 4-ethoxyphenylpropiolic acid
B
DOI: 10.1021/acs.orglett.7b00860
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Organic Letters
Letter
a
Table 2. Copper-Free Reactions in Amine Solvents
Scheme 4. Copper-Free Reaction in a Non-amine Solvent
b
c
entry
1
solvent
yield (%)
ratio of (E)-3a/(Z)-3a
Based on previous reports,11 and our results, we propose the
reaction pathways depicted in Scheme 5 to rationalize our
observations.
1
2
3
4
5
1a
1a
1a
1a
1b
pyridine
DBU
trace
62
56
15
0
1:4
(i-Pr)2EtN
TMEDA
(i-Pr)2EtN
1:11
1:2
Scheme 5. Proposed Reaction Pathways
a
Reaction conditions: 1 (1.0 mmol) and AIBN (2.0 mmol) were
b
reacted in solvent (5 mL) at 80 °C for 12 h, air. Isolated yield.
c
1
Determined by H NMR analysis.
Interesting, no allyl nitrile 3 was formed in the reaction of
phenylacetylene, AIBN, and (i-Pr)2EtN in the absence of
copper catalyst.
With these copper-free conditions identified, a variety of
arylpropiolic acids were employed for the selective syntheses of
(Z)-allyl nitriles. As shown in Scheme 3, (Z)-allyl nitriles were
Scheme 3. Synthesis of (Z)-Allyl Nitriles by Copper-Free
a
Decarboxylation
First, the 2-cyano-2-propyl radical is generated from the
thermal decomposition of AIBN. This radical then reacts with
the arylpropiolic acid salt A, formed through an acid/base
reaction, to provide the intermediate copper complex B,
through path I. Protonation then takes place at both the vinyl
copper and decarboxylation sites to give (E)-3.16 Intermediate
C is formed in the absence of copper, following path II. The
stereochemistry of the vinyl radical center in intermediate C is
most likely determined by steric interactions between the aryl
group, the sterically bulky amine, and the carboxylate. Finally,
vinyl radical C abstracts a hydrogen atom which is delivered
from the bulky amine trans to isobutyronitrile to give (Z)-3. In
the absence of copper in a nonamine solvent, the 2-cyano-2-
propyl radical is converted into intermediate D, which then
reacts with the carboxylic acid, following path III, to give the
isobutyronitrile amide 4. However, in no case was the alkynyl
nitrile observed, which may be formed through path IV, even
though the reaction was conducted in air. Mao and Xu obtained
an alkynyl nitrile from the reaction of a terminal alkyne with
AIBN in air. We believe that our results are different because
the reactivity of an alkynyl carboxylic acid toward the 2-cyano-
2-propyl radical is greater than that of a terminal alkyne.
In summary, we have developed decarboxylative reactions for
the synthesis of allyl nitriles. The reactions of arylpropiolic acids
with AIBN (or ACCN), in the presence of pyridine and a
copper catalyst afford the desired allyl nitriles in moderate to
good yields. This reaction shows tolerance toward alkoxy,
halogen, alcohol, amine, ester, and ketone functional groups.
However, 4-cyanophenylpropiolic acid and 1-octynoic acid
failed to produce the corresponding allyl nitrile. We also
developed a selective synthesis of (Z)-3 and found that a
a
Reaction conditions: 1 (2.0 mmol) and AIBN (or ACCN) (4.0
mmol) were reacted in (i-Pr)2EtN (7.0 mL) at 80 °C for 12 h, air.
formed as the major isomer in all cases. 2-Methyl-, 4-methyl-,
and 4-methoxy-substituted phenylpropiolic acids gave (Z)-3b,
(Z)-3c, and (Z)-3e in 39%, 39%, and 44% yield, respectively,
and each exhibited a 12.5:1 (Z)/(E) ratio. The 4-bromo- and 4-
chloro-substituted analogues provided (Z)-3i and (Z)-3j in
37% and 40% yield, respectively; the (Z)/(E) ratio was 11:1 in
each case. (Z)-3o and (Z)-3p were obtained in 45% and 42%,
yield, respectively, with (Z)/(E) ratios of 14:1. 3-(Thiophene-
2-yl)propiolic acid showed the highest stereoselectivity with a
(Z)/(E) ratio of 33.3:1. The reactions with ACCN also
provided the desired products with 30−46% yields. They all
gave (Z)-allyl nitriles as major. We found that stereoselectivity
seems to be largely unaffected by substituents on the aryl
group.
When these reactions were conducted under copper-free and
amine-free conditions, N-(2-cyanopropan-2-yl)-N-isobutyryl-3-
phenylpropiolamide (4a) was formed instead of the allyl nitriles
(3), as shown in Scheme 4. The propiolamide 4a was formed
from the reaction of phenylpropiolic acid with a rearranged
fragment of AIBN. This type reaction has been reported
previously by Zhang and Mao;13 however, they obtained a
secondary amide because the high-temperature reaction
conditions in ClCH2CH2Cl gave rise to the hydrolysis of 4a.
C
DOI: 10.1021/acs.orglett.7b00860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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sterically bulky amine solvent was the key to achieving
selectivity. Compared with previous methods, this method
has several advantages: arylpropiolic acids are more easily
prepared than terminal arylalkynes; there is no requirement to
use excess amounts of the aryl propiolic acid to obtain the allyl
nitrile; the reaction does not require an argon atmosphere, and
can be performed without the requirement of inert conditions;
and the (E)-3 and (Z)-3 stereoisomers are obtained with high
selectively. Further mechanistic studies are ongoing in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00860.
(12) (a) De Vleeschouwer, F.; Van Speybroeck, V. V.; Waroquier,
M.; Geerlings, P.; De Proft, F. D. Org. Lett. 2007, 9, 2721−2724.
(b) Xie, Y.; Guo, S.; Wu, L.; Xia, C.; Huang, H. Angew. Chem., Int. Ed.
2015, 54, 5900−5904. (c) Gao, B.; Xie, Y.; Shen, Z.; Yang, L.; Huang,
H. Org. Lett. 2015, 17, 4968−4971. (d) Xu, H.; Liu, P.-T.; Li, Y.-H.;
Han, F.-S. Org. Lett. 2013, 15, 3354−3357. (e) Teng, F.; Yu, J.-T.;
Yang, H.; Jiang, Y.; Cheng, J. Chem. Commun. 2014, 50, 12139−12141.
(f) Wei, W.; Wen, J.; Yang, D.; Guo, M.; Tian, L.; You, J.; Wang, H.
RSC Adv. 2014, 4, 48535−48538. (g) Wang, R.; Bao, W. RSC Adv.
2015, 5, 57469−57471. (h) Teng, F.; Yu, J.-T.; Zhou, Z.; Chu, H.;
Cheng, J. J. Org. Chem. 2015, 80, 2822−2826.
Experimental procedures and spectral data for the
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sunwoo@chonnam.ac.kr.
ORCID
(13) Rong, G.; Liu, D.; Yan, H.; Chen, J.; Zheng, Y.; Zhang, G.; Mao,
J. Adv. Synth. Catal. 2015, 357, 71−76.
Sunwoo Lee: 0000-0001-5079-3860
Notes
(14) (a) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.; Jung, H.
M.; Lee, S. Org. Lett. 2008, 10, 945−948. (b) Moon, J.; Jang, M.; Lee,
S. J. Org. Chem. 2009, 74, 1403−1406. (c) Park, K.; Bae, G.; Moon, J.;
Choe, J.; Song, K. H.; Lee, S. J. Org. Chem. 2010, 75, 6244−6251.
(d) Park, K.; Lee, S. RSC Adv. 2013, 3, 14165−14182. (e) Hwang, J.;
Park, K.; Choe, J.; Min, H.; Song, K. H.; Lee, S. J. J. Org. Chem. 2014,
79, 3267−3271. (f) Min, H.; Palani, T.; Park, K.; Hwang, J.; Lee, S. J. J.
Org. Chem. 2014, 79, 6279−6285.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a National Research
Foundation of Korea (NRF) grant funded by the Korean
government (MSIP) (NRF-2015R1A4A1041036, NRF-
2014R1A2A1A11050018). The spectral data were obtained
from the Korea Basic Science Institute, Gwangju branch.
(15) Park, K.; Palani, T.; Pyo, A.; Lee, S. Tetrahedron Lett. 2012, 53,
733−737. (b) Park, K.; You, J.-M.; Jeon, S.; Lee, S. Eur. J. Org. Chem.
2013, 2013, 1973−1978.
(16) When the reaction was carried out in the presence of D2O (5.0
equiv), deuterium incorporation was observed at the vinyl group. See
the Supporting Information for more details.
DEDICATION
■
This paper is dedicated to Professor Jaiwook Park (POST-
ECH) on the occasion of his 60th birthday.
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