Selective and facile synthesis of α,β-unsaturated nitriles and amides with N-hydroxyphthalimide as the nitrogen source

Article abstract of DOI:10.1016/j.tetlet.2018.06.011

The direct conversion of α,β-unsaturated aldehydes to corresponding nitriles promoted by Pd(OAc)₂ and phthalic acid which was hydrolyzed from N-hydroxyphthalimide (NHPI) has been disclosed. Additionally, it was found that when water was used as the solvent, α,β-unsaturated amides was obtained as the main products in good to excellent yields. It was first reported that NHPI was utilized as the nitrogen source to synthesize α,β-unsaturated nitriles and amides from aldehydes. Control experiment demonstrated that aldehydes undergo a process of oximation and dehydration to form nitriles and amides.

Full text of DOI:10.1016/j.tetlet.2018.06.011

Accepted Manuscript
Selective and facile synthesis of α,β-unsaturated nitriles and amides with N-
hydroxyphthalimide as the nitrogen source
Yiyan Yan, Xiaohe Xu, Xiaokang Jie, Jingya Cheng, Renren Bai, Qi Shuai,
Yuanyuan Xie
PII:
S0040-4039(18)30740-8
https://doi.org/10.1016/j.tetlet.2018.06.011
TETL 50049
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 April 2018
31 May 2018
4 June 2018
Please cite this article as: Yan, Y., Xu, X., Jie, X., Cheng, J., Bai, R., Shuai, Q., Xie, Y., Selective and facile synthesis
of α,β-unsaturated nitriles and amides with N-hydroxyphthalimide as the nitrogen source, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

X
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Selective and facile synthesis of α,β-unsaturated nitriles and
amides with N-hydroxyphthalimide as the nitrogen source
Leave this area blank for abstract info.
Yiyan Yana, Xiaohe Xua, Xiaokang Jiea, Jingya Chenga, Renren Baia, Qi Shuaib and Yuanyuan Xiea,b*

1
Tetrahedron Letters
Selective and facile synthesis of α,β-unsaturated nitriles and amides with N-
hydroxyphthalimide as the nitrogen source
Yiyan Yana, Xiaohe Xua, Xiaokang Jiea, Jingya Chenga, Renren Baia, Qi Shuaib and Yuanyuan Xiea,b*
a College of Pharmaceutical sciences, Zhejiang University of Technology, Hangzhou, P.R. China.
b Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R. China
ARTICLE INFO
ABSTRACT
The direct conversion of α,β-unsaturated aldehydes to corresponding nitriles promoted by
Pd(OAc)2 and phthalic acid which was hydrolyzed from N-hydroxyphthalimide (NHPI) has been
disclosed. Additionally, it was found that when water was used as the solvent, α,β-unsaturated
amides was obtained as the main products in good to excellent yields. It was first reported that
NHPI was utilized as the nitrogen source to synthesize α,β-unsaturated nitriles and amides from
aldehydes. Control experiment demonstrated that aldehydes undergo a process of oximation and
dehydration to form nitriles and amides.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2018 Elsevier Ltd. All rights reserved.
α,β-Unsaturated nitriles
α,β-Unsaturated amides
Selective synthesis
N-Hydroxyphthalimide
Introduction
The nitrile moiety is one of the most important building
blocks and can be readily converted into various valuable
heterocycles and functional groups such as amines, amides,
carboxylic acids, and esters.1 Especially as one class of nitriles,
α,β-unsaturated nitriles are ubiquitous structural units in
pharmaceuticals, agrochemicals, dyes and functional materials.2
For example, the representative pharmaceutical agents containing
α,β-unsaturated nitrile group include KW-5092, a novel indicator
used to treat acute or chronic heart failure; Entacapone, a drug for
Parkinson’s disease; Rilpivirine,
a
potent anti-HIV
mononucleoside reverse transcriptase inhibitor; and CC-5079, an
anticancer agent (Figure 1).3
Traditional methods4 for preparing nitriles include the
substitution of alkyl halides or aryl diazonium salts with a
stoichiometric amount of inorganic or organic cyanides;
ammoxidation of aldehydes or alcohols; hydrocyanation of
alkenes; and dehydration of amides or oximes. However, these
approaches generally require complicated operations, toxic
reagents (e.g., KCN or CuCN), or harsh reaction conditions.
Thus, it is still in high demand for the development of new
strategy getting access to α,β-unsaturated nitriles. One of the
most traditional ways5 to synthesize α,β-unsaturated nitriles is
using corresponding aldehydes and hydroxylamine as substrates.
However, the commercially available hydroxylamine derivatives
such as hydroxylamine hydrochloride (NH2OH·HCl), hydroxyl
amine-O-sulfonic acid (NH2OSO3H) and MSH reagent (O-
(methylsulfonyl) hydroxylamine) are explosive and unstable6,
prompting us to propose a stable hydroxylamine derivative to
perform such transformation.
Figure 1 Representative examples of pharmaceuticals containing the α,β-
unsaturated nitrile group.
N-hydroxyphthalimide (NHPI) has been wildly used as an
efficient catalyst through a radical pathway for the activation of
C-H bond7 and a stoichiometric reactant for the construction of
8
C-O bond. In the meantime, its commercial availability and
stability make it to be a good starting material. According to our
previous work, the reaction of aldehydes and NHPI in water
afford oximes in great yields. In 2016, Hyodo and Kitagawa et al.
found that CH3CN was a good receptor for the oxime hydroxyl
group to generate nitrile.9 Thus, we envisaged that nitrile could
be obtained in the co-solvent by exposing NHPI to aldehydes.
Herein, we report for the first time using NHPI as the nitrogen
source for the direct synthesis of α,β-unsaturated nitriles from the
aldehydes.

2
Tetrahedron Letter
Results and discussion
aReaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), catalyst (5
In this regard, cinnamaldehyde was chosen as the model
substrate to ascertain the feasibility of its reactivity with NHPI.
At the beginning, we started the investigation using H2O and
CH3CN (5:1, v/v) as the co-solvent in the presence of a catalytic
amount of Pd(OAc)2. The cinnamonitrile 3a was obtained in a
yield of 65%, while the hydrolyzed product cinnamide 4a was
isolated in 26% yield. Applying other Pd catalysts didn’t improve
the yield of 3a or 4a (Table 1, entries 1-4). Other solvents such as
DMSO, DMF, and ethanol (in supporting information) were
failed in the transformation and the best ratio of H2O and CH3CN
was 5:1 (v/v) (entries 4-10). It was worth noting that when the
ratio of H2O and CH3CN was 1:1 (v/v) (entry 5), 3a was not
observed in the reaction. In addition, the transformation didn’t
occur in pure CH3CN (entry 11). The effect of temperature on the
reaction was also investigated, 3a was obtained in 65% yield at
120 oC, further adjustment of the temperature was useless (entries
12-14). More importantly, when using H2O as the solvent, 3a was
completely hydrolyzed to 4a in a promising yield of 89% (entry
15). And it seemed that other metal salts didn’t work in the
reaction (in supporting information). We could only obtain
cinnamaldehyde oxime in the system which could still exist when
no catalyst was applied to reaction (the blank experiment was in
Scheme 1).
mol%), and solvent (3 mL) in 15 mL sealed tube for 4.5 h.
c
bIsolated yield based on 1a. N.D. = Substrate consumed but no
desired product. dN.R. = No reaction.
After obtaining the best conditions, the substrate scope was
investigated and the results were summarized in Table 2. All the
substituted α,β-unsaturated aldehydes gave the nitrile products in
moderate to good yields (45-81%). The electronic and steric
effects had little influence on the transformation, such as 4-Me,
4-OMe, 3-OMe, 2-OMe, 4-F, 4-Cl and 4-Br, substrates.
However, substrates with strong electron-withdrawing group NO2
were exceptional. The yield of 2-NO2 (3k) was 81% while 4-NO2
(3i) and 3-NO2 (3j) products were obtained in a yield of 74% and
55% respectively. The heterocyclic (3l) and polycyclic (3m)
substrates could also be effectively transformed to desired
products. When the method was applied to aliphatic substrates10,
miscellaneous systems were observed and the desired products
(3n and 3o) were obtained in very low yields.
Table 2 Pd(OAc)2 Catalyzed synthesis of α,β-unsaturated
nitriles[a,b]
Table 1 Optimization of the reaction conditionsa
Yield Yield
T
Entry
Catalyst
Solvent(v/v)
of 3a of 4a
(oC)
120
120
120
120
120
120
120
120
120
120
120
130
110
80
(%)b
(%)b
H2O:CH3CN
(5:1)
H2O:CH3CN
(5:1)
H2O:CH3CN
(5:1)
H2O:CH3CN
(5:1)
H2O:CH3CN
(1:1)
H2O:CH3CN
(3:1)
H2O:CH3CN
(9:1)
H2O:DMSO
(5:1)
1
2
Pd(OAc)2
PdCl2
65
26
47
52
23
24
25
20
20
31
75
67
40
N.R.
28
25
25
89
3
Pd(TFA)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4
55
aReactions were carried out with 1 (0.5 mmol), 2 (0.6 mmol),
Pd(OAc)2 (5 mol%), and solvent (3.0 mL) at 120 °C in 15 mL
sealed tubes for 5 h. bIsolated yield based on 1.
5
N.D.c
43
6
As mentioned above, when solvent was switched to pure H2O,
a series of amides could be prepared selectively (Table 3) under
modified conditions, in which the molar ratio of α,β-unsaturated
aldehydes and NHPI was changed into 1.2:1.0 due to the
sensitivity of α,β-unsaturated aldehydes towards oxidation. This
method was proved to be versatile and a variety of α,β-
unsaturated aldehydes with electron-withdrawing or electron-
donating substituents on the phenyl ring could be converted to
corresponding amides (4a-4j) in excellent yields. However, 2-
NO2 substrate only transformed into the amide (4k) in 22% yield.
Additionally, 3-(2-furanyl)-2-propenal and 2-naphthalenepropena
could be converted into the desired products in a yield of 54%
and 90%, respectively. In the section, the reactivity of aliphatic
substrates was poor as well, and only trace product (4n, 4o) was
obtained in the reaction.
7
39
8
N.D.
N.D.
N.D.
N.R.d
60
H2O:DMF
(5:1)
H2O:Ethanol
(5:1)
9
10
11
12
13
14
15
CH3CN
H2O:CH3CN
(5:1)
H2O:CH3CN
(5:1)
H2O:CH3CN
(5:1)
47
46
Table 3 Pd(OAc)2 Catalyzed synthesis of α,β-unsaturated
amides[a, b]
H2O
120
trace

3
Scheme 1. Control experiments.
aReactions were carried out with 1 (0.6 mmol), 2 (0.5 mmol),
o
Pd(OAc)2 (5 mol %), and solvent (3.0 mL) at 120 C in 15 mL
sealed tubes for 9 h. bIsolated yield based on 2. cDMSO (0.2 mL)
was added.11
Control experiments were conducted to study the mechanism
of this reaction. Without the Pd(OAc)2, 1a was fully converted
into cinnamaldehyde oxime, and phthalic acid was also found in
the mixture according to the HRMS (ESI), which was obtained
by the decomposition of NHPI. It suggested that the desired
nitrile was generated from the oximation of oxime. Nevertheless,
when benzaldehyde was applied under the standard conditions,
there was only benzaldoxime obtained due to the matched
activity (Scheme 1). In addition, cinnamaldehyde oxime was
chosen as the starting material, and the results were shown in
Scheme 1. When cinnamaldehyde oxime, catalyst and water were
Scheme 2 Possible reaction pathway.
Conclusions
o
added to the system at 120 C, the cinnamamide was obtained in
In conclusion, we reported a novel and efficient method
for the concise synthesis of α,β-unsaturated nitriles and
amides promoted by Pd(OAc)2, using NHPI as the nitrogen
source. It was found that α,β-unsaturated aldehydes could be
easily converted into nitriles or amides selectively by
controlling the ratio of acetonitrile and water. Moreover, the
transformation could be accelerated by phthalic acid derived
from NHPI. The proposed mechanism was depicted on the
basis of our insight. Further work to explore the scope of
55% yields after 38 h. However, the transformation was
accelerated upon the addition of phthalic acid derived from
NHPI, and the yield of cinnamamide was increased to 88%. The
reaction was ceased when Pd(OAc)2 was removed from the
system. Thus, it was proved that Pd(OAc)2 is crucial to the
transformation and phthalic acid could accelerate the process..
With experimental data and literature12 in hand, a plausible
mechanism for the reaction was depicted in Scheme 2. Initially,
NHPI is hydrolyzed to give A, the nucleophilic addition of which
to aldehyde affords an intermediate B. And then, B is further
hydrolyzed to affords cinnamaldehyde oxime C, releasing
this reaction is underway in our laboratory
.
Acknowledgments
phthalic acid and water. In the presence of Pd(OAc)2,
C is
dehydrated to afford 3a13, which is further hydrolyzed to
amide 4a in water.
We are grateful to the National Natural Science Foundation
of China (No. 21576239) for financial support. We thank Dr.
Bin Mao at Zhejiang University of Technology for
discussions.
References
1 (a) D. T. Mowry, Chem. Rev., 1948, 42, 189-283; (b) R. C. Larock,
Comprehensive Organic Transformations, VCH, New York, 1989; (c) J. S.
Miller, J. L. Manson, Acc. Chem. Res., 2001, 34, 563-570; (d) Z. Rappoport,
The Chemistry of the Cyano Group, Wiley, London, 1970.
2 (a) A. J. Fatiadi, Preparation and Synthetic Applications of Cyano
Compounds, S. Patai and Z. Rappaport, Wiley, New York, 1983; (b) P.
Magnus, D. A. Scott and M. R. Fielding, Tetrahedron Lett., 2001, 42, 4127-
4129.
3 F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk and B. C. Shook, J. Med.
Chem., 2010, 53, 7902-7917.
4 (a) T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17, 2650-2653; (b) H. H.
Hodgson. Chem. Rev., 1947, 40, 251-277; (c) J. K. Kochi, J. Am. Chem. Soc.,
1957, 79, 2942-2948; (d) Y. Nakao, A. Yada, S. Ebata and T. J. Hiyama, J.
Am. Chem. Soc., 2007, 129, 2428-2429; (e) L. S. Stuhl, J. Org. Chem., 1985,

4
Tetrahedron Letter
50, 3934-3936; (f) L. M. Dornan, Q. Cao, J. C. A. Flanagan, Chem.
Commun., 2013, 49, 6030-6032; (g) T. Oishi, K. Yamaguchi, N. Mizuno,
Angew. Chem. Int. Ed., 2009, 48, 6286-6288; (h) L. Bini, C. Muller, J.
Wilting, L. Chrzanowski, A. L. Spek, D. Vogt, J. Am. Chem. Soc., 2007, 129,
12622-12623; (i) S. Enthaler, M. Weidauer, F. Schröder, Tetrahedron Lett.,
2012, 53, 882-885; (j) Y. Y. Xie, J. L. Liu, P. Yang, X. J. Shi, J. J. Li,
Tetrahedron, 2011, 67, 5369-5374; (k)A. Leggio, E. L. Belsito, S. Gallo, A.
Liguori, Tetrahedron Lett., 2017, 58, 1512-1514; (l) E. C. Wang, G. J. Lin,
Tetrahedron Lett., 1998, 39, 4047-4050; (m) A. K. Chakraborti, G. Kaur,
Tetrahedron, 1999, 55, 13265-13268.
5 (a) S. Enthaler, M. Weidauer, F. Schröder, Tetrahedron Lett, 2012, 53, 882-
885; (b) P. Ghosh, R. Subba, Tetrahedron Lett, 2013, 54, 4885-4887; (c) D.
J. Quinn, G. J. Haun, G. Moura-Letts, Tetrahedron Lett, 2016, 57, 3844-
3847; (d) A. Leggio, E. L. Belsito, S. Gallo, A. Liguori, Tetrahedron Letters,
2017, 58 , 1512-1514; (e) L. M. Rodríguez, E. T. Mendivil, J. Francos, C.
Nájera, P. Crochet, V. Cadierno, Catal. Sci. Technol., 2015, 5, 3754-3761;
(f) D. L. Zhang, Y. P. Huang, E. L. Zhang, R. Yi, C. Chen, L. Yu, Q. Xu,
Adv. Synth. Catal. 2018, 360, 784-790.
6 (a) C. R. Johnson, R. A. Kirchhoff, H. G. Corkins, J. Org. Chem., 1974, 39,
2458-2459; (b) E. J. Grayson, G. J. L. Bernardes, J. M. Chalker, O.
Boutureira, J. R. Koeppe, B. G. Davis, Angew. Chem., Int. Ed. 2011, 50,
4127-4132.
7 (a) K. X. Chen, P. F. Zhang, Y. Wang, H. R. Li, Green Chem., 2014, 16,
2344-2374; (b) M. Masui, S. Hara, T. Ueshima, T. Kawaguchi, S. Ozaki,
Chem. Pharm. Bull., 1983, 31, 4209-4211; (c) C. X. Miao, H. Q. Zhao, Q. Y.
Zhao, C. G. Xia, W. Sun, Catal. Sci. Technol., 2016, 6, 1378-1383; (d) Y. Y.
Xie, D. Y. Guo, X. Y. Jiang, H. X. Pan, W. H. Wang, T. T. Jin, Z. S. Mi,
Tetrahedron Letters, 2015, 56, 2533-2536; (e) F. Recupero, C. Punta, Chem.
Rev., 2007, 107, 3800-3842.
8 (a) B. Tan, N. Toda, C. F. Barbas III, Angew. Chem. Int. Ed., 2012, 51,
12538-12541; (b) J. M. Lee, E. J. Park, S. H. Cho, S. Chang, J. Am. Chem.
Soc., 2008, 130, 7824-7825; (c) R. Bag, D. Sar, T. Punniyamurthy, Org. Lett.,
2015, 17, 2010-2013; (d) X. H. Xu, J. Sun, Y. Y. Lin, J. Y, Cheng, P. P. Li,
X. Y. Jiang, R. R. Bai, Y. Y . Xie, Eur. J. Org. Chem. 2017, 47, 7160-7166;
(e) X. H. Xu, J. Sun, Y. Y. Lin, J. Y, Cheng, P. P. Li, Y. Y. Yan, Q. Shuai, Y.
Y. Xie, Org. Biomol. Chem., 2017, 15, 9875-9879; (f) Y. Y. Xie, J. W. Liu,
Y. Y. Huang, L. X. Yao, Tetrahedron Letters, 2015, 56, 3793-3795. (g) X. H.
Xu, P. P. Li, Y. Y. Huang, C. Tong, Y. Y. Yan, Y. Y. Xie, Tetrahedron
Letters, 2017, 58, 1742-1746.
9 K. Hyodo, S. Kitagawa, M. Yamazaki, K. Uchida, Chem. Asian J., 2016,
11, 1348-1352.
10 (a) M. Mosrin, P. Knochel, Org. Lett., 2009, 11, 1837-1840; (b) X. Yang,
F. F. Fleming, Acc. Chem. Res., 2017, 50, 2556-2568.
11 M. A. Alia, T. Punniyamurthy, Adv. Synth. Catal., 2010, 352, 288-292.
12 (a) H. S. Kim, S. H. Kim, J. N. Kim, Tetrahedron Lett. 2009, 50, 1717; (b)
Z. B. Shu, Y. X. Ye, Y. F. Deng, Y. Zhang, J. B. Wang, Angew. Chem. Int.
Ed. 2013, 52, 10573 –10576; (c) M. Sridhar, M. K. K. Reddy, V. V. Sairam,
J. Raveendra, K. R. Godala, C. Narsaiah, B. C. Ramanaiah, C. S. Reddy,
Tetrahedron Letters, 2012, 53, 3421-3424; (d) Y. J. Zhuang, J. Liu, Y. B.
Kang, Tetrahedron Letters, 2016, 57, 5700-5702; (e) C. L. Allen, R.
Lawrence, L. Emmett, J. M. J. Williams, Adv. Synth. Catal. 2011, 353, 3262-
3268;
13 (a) Z. Ren, F. Y. Mo, G. B. Dong, J. Am. Chem. Soc., 2012, 134, 16991-
16994; (b) Z. Ren, G. B. Dong, Organometallics, 2016, 35, 1057-1059.

5
Highlights
An efficient synthetic method of α,β-unsaturated
nitriles and amides was developed;
NHPI was first used as the nitrogen source to
prepare nitriles and amides;
Nitriles or amides were optionally obtained by
adjusting the ratio of the solvents;
The NHPI hydrolyzed product significantly
promoted this reaction.