NBS mediated nitriles synthesis through CC double bond cleavage

Article abstract of DOI:10.1039/c3ob42118j

An NBS mediated nitriles synthesis through CC double bond cleavage has been developed. TMSN₃ was employed as the nitrogen source for this Cu(OAc)₂ promoted nitrogenation reaction. This transformation has a relatively high regio-selectivity to form aromatic nitriles.

Full text of DOI:10.1039/c3ob42118j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
NBS mediated nitriles synthesis through CvC
double bond cleavage†
Xiaolin Zong,a Qing-Zhong Zhenga and Ning Jiao*a,b
Cite this: Org. Biomol. Chem., 2014,
12, 1198
Received 24th October 2013,
Accepted 27th November 2013
DOI: 10.1039/c3ob42118j
www.rsc.org/obc
An NBS mediated nitriles synthesis through CvC double bond
cleavage has been developed. TMSN3 was employed as the nitro-
gen source for this Cu(OAc)2 promoted nitrogenation reaction.
This transformation has a relatively high regio-selectivity to form
aromatic nitriles.
The cyano group is a key intermediate in organic synthesis as
a very useful precursor for the generation of a variety of func-
tional groups, such as amines, amides, aldehydes,1 as well as
heterocyclic compounds.2 Moreover, the cyano group itself is
also an important functional group in many compounds, such
as dyes, medicines, and agrochemicals.3 Considering the
broad application of the cyano group, many methodologies
have been reported to prepare nitriles, including the Sand-
meyer reaction from aryl diazonium salts,4 the dehydration
approach from amines, alcohols or oximes5 and so on. Despite
the significances of these methods, some drawbacks, such as
multiple steps, harsh reaction conditions, bad functional
group tolerance, or expensive and hazardous reagents, are
involved in these processes. In past decades, some novel
approaches to nitriles through C–H or C–C bond cleavage have
been developed.6 Our group has also developed some direct
conversions from methyl and alkynes into nitriles.7 Very
recently, we successfully achieved the transition metal free
TEMPO catalyzed transformation of alkenes to nitriles through
CvC bond cleavage (a, Scheme 1).8,9 Unfortunately, there are
some limitations in the substrates scope. For styrene derivative
substrates, the desired aromatic nitriles could not be afforded
under the standard conditions (b, Scheme 1).
Scheme 1 The TEMPO catalyzed nitriles synthesis from alkenes and
the design of this report.
employing an alkenyl azide intermediate7d generated in situ
(c, Scheme 1). According to this hypothesis, the styrene deriva-
tives could be attacked by an electrophile to generate a three-
membered ring halonium ion,10 which could be attacked by
azido nucleophiles,11 and then underwent the following relay
of elimination and rearrangement to afford the corresponding
aromatic nitriles (c, Scheme 1). Herein, we describe an NBS
mediated aromatic nitriles synthesis through highly regioselec-
tive CvC double bond cleavage of styrenes.
We began our experiments by choosing the trimethylsilyl
azide (TMSN3) as the nucleophile, and 1-methoxy-4-vinyl-
benzene (1a) as the substrate in the presence of N-bromosuccin-
imide (NBS), Cu(OAc)2 and K2CO3. We were excited to obtain
the desired aromatic nitrile 2a under an atmosphere of O2,
although the yield was only 47% (Table 1, entry 1). This initial
system was very complex with the formation of many unknown
byproducts, which made the purification difficult. It is note-
worthy that the yield of the reaction under air was almost the
same as that under O2 (Table 1, entry 2), while the system was
much more simple and easy to purify. Other kinds of azides,
such as diphenylphosphoryl azide (DPPA) and tosyl azide
(TsN3), showed worse results than that of TMSN3 (Table 1,
entries 3 and 4). As for the catalysts, we tried many kinds of
copper salts but no better results were obtained than those
using Cu(OAc)2 (Table 1, entries 5–6, and also see ESI†). After
In order to realize the direct transformation from styrenes
to aromatic nitriles, we proposed a tandem reaction process by
aState Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191,
China. E-mail: jiaoning@bjmu.edu.cn; Fax: (+86)-010-8280-5297;
Tel: (+86)-01082805297
bLaboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen, 518055, China
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ob42118j
1198 | Org. Biomol. Chem., 2014, 12, 1198–1202
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 1 Optimization of the reaction conditionsa
group was at the para position, but with an electron-withdraw-
ing group, the desired nitrile product 2f was obtained in a
53% yield without the diazidation byproduct (Table 2). When
tert-butyl(2-methoxy-5-vinyl-phenoxy) dimethylsilane (1k) was
treated using this method, the corresponding 3-((tert-butyl-
dimethylsilyl)oxy)-4-methoxybenzonitrile was not achieved.
Entry
Cat. (20%)
[N3] (eq.)
Base (eq.)
Yieldb
However, 51% of 3-hydroxy-4-methoxybenzonitrile with
a
naked hydroxyl group was obtained. Notably, 1,2-disubstituted
styrene could also accomplish this transformation smoothly,
leading to the corresponding aromatic nitriles in moderate
yields (Table 2, 1l and 1m). To our delight, 1-ethynyl-
4-methoxy-benzene 1n could also be smoothly transformed
1c
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
TMSN3 (2.0)
TMSN3 (2.7)
DPPA (2.7)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
Na2CO3 (1.0)
t-BuONa (1.0)
K3PO4·7H2O (1.0)
K3PO4·7H2O (2.0)
K3PO4·7H2O (2.0)
K3PO4·7H2O (2.0)
K3PO4·7H2O (2.0)
K3PO4·7H2O (2.0)
K3PO4·7H2O (2.0)
K3PO4·7H2O (2.0)
42%
47%
Trace
Trace
25%
<25%
22%
<10%
49%
61%
77%
64%
65%
59%
55%
49%
TsN3 (2.7)
TMSN3 (2.7)
TMSN3 (2.7)
TMSN3 (2.7)
TMSN3 (2.7)
TMSN3 (2.7)
TMSN3 (2.7)
TMSN3 (2.3)
TMSN3 (2.3)
TMSN3 (2.3)
TMSN3 (2.3)
TMSN3 (2.3)
TMSN3 (2.3)
CuCl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
None
into the corresponding nitrile product in
a 39% yield
(Table 2), which largely expanded the substrate scope of this
transformation.
9
10
11
12d,e
13d, f
14d
15d,g
16h
It is noted that when electron deficient styrenes or styrenes
with weak electron-donating groups were employed as the sub-
strates, the reactions afforded not only the desired aromatic
nitriles but also the diazidation byproducts, which could not
be converted into aromatic nitriles under the standard con-
ditions even with longer reaction time (Table 3). In some
cases, the diazidation of CvC became the main process,
although the nitriles could also be obtained. The yields of the
nitriles suffered from the strength of the electron-withdrawing
of the substituent groups at the benzene ring. The stronger the
groups withdraw electrons, the higher the yield of the diazida-
tion products. The control experiment indicates that the diazi-
dation product 3q could not be further converted into the
desired nitrile under the optimal conditions with 94% recovery
of 3q (eqn (1)). Fortunately, the diazidation products11 of sty-
renes have some special applications,11a,12 such as an inter-
mediate for the synthesis of certain ligands.
To probe the mechanism of this transformation, some
control experiments have been investigated. When 4-methoxy-
benzaldehyde 4 was treated under the standard conditions,
4-methoxybenzonitrile 2a was not obtained, with 80% of the
starting materials recovered (eqn (2)). In the absence of NBS,
4-methoxybenzaldehyde was completely recovered (eqn (3)).
These results may rule out the pathway of going through an
aldehyde intermediate, which has been widely reported.13
Although the preparation of the proposed (1-azido-2-bromo-
ethyl)benzene intermediate C (Scheme 2) failed, we syn-
thesized 1-(1-azidovinyl)-4-methoxybenzene 5, which per-
formed well under the standard conditions in the absence of
NBS and TMSN3, affording 4-methoxybenzonitrile 2a in an
84% yield (eqn (4)).
Cu(OAc)2
Cu(OAc)2
a The reaction was stirred in MeCN (2.5 mL) at 80 °C employing 1a
(0.4 mmol, 1.0 eq.) for 25 h. b Isolated yields. c The reaction was carried
out under O2 and in 2 mL of MeCN. d NMR yield using 1,1,2,2-
tetrachloroethane as an internal standard. e 10 mol% of Cu(OAc)2 was
used. f 5 mol% of Cu(OAc)2 was used. g The reaction was carried out
under Ar. h 72 mg of water (10.0 eq.) was added.
all these attempts, we thought maybe the base was not suit-
able for the elimination step to generate the alkenyl azide
intermediate in situ. Therefore, different types of bases, includ-
ing Na2CO3, t-BuONa, and Et3N, were investigated (Table 1,
entries 7–8, and also see ESI†). However, these bases did not
perform well. Interestingly, when K3PO4·7H2O was chosen as
the base, the desired aromatic nitrile 2a was obtained in a
77% yield (Table 1, entry 11). Considering that the base was
very important for this transformation, we also tried other
kinds of potassium phosphates. However, they did not show
higher efficiency than K3PO4·7H2O (see ESI†). The addition of
10.0 eq. of water decreased the efficiency (entry 16). Further inves-
tigations showed that Argon atmosphere was not required for this
present chemistry (Table 1, entry 15). In addition, a copper-salt is
not essential for this transformation, although the presence of
Cu(II) could enhance the efficiency (Table 1, entry 14).
With the optimized condition in hand (Table 1 entry 11),
we investigated the substrate scope of this transformation
(Table 2). Substrates with an electron-donating or weak elec-
tron-donating group at the para position of vinyl in benzene
rings proceeded well (Table 2). Substrates with a methoxyl- or
an ethoxyl- group at the para position gave good results with
yields up to 77% (Table 2, 1a and 1b). When there was a
phenyl- group at the para position of the vinyl-, the corres-
ponding nitrile product was obtained in a 66% yield with the
formation of a trace amount of (1% yield) the diazidation
byproduct (Table 2, 1c). Unfortunately, substrates with elec-
tron-withdrawing substituent groups at the benzene ring could
not afford the corresponding nitriles (Table 3). If a methoxyl-
ð1Þ
ð2Þ
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1198–1202 | 1199

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 The substrate scope of this transformationa
Substrate
Product
Substrate
Product
1ab
2a, 77%
1h
2h, 54%
1b
2b, 70%
2c, 66%
2d, 26%
1id
1jd
1kd
2i, 59%
2j, 56%
2k′, 51%
1ce
1dc
1e
1f
2e, 52%
2f, 53%
1l
2a, 50%
2d, 52%
1mc
1gd
2g, 53%
1nd,e
2a, 39%
a Reaction conditions: substrate 1 (0.4 mmol, 1.0 eq.), NBS (0.48 mmol, 1.2 eq.), TMSN3 (1.1 mmol, 2.7 eq.), K3PO4·7H2O (0.8 mmol, 2.0 eq.),
Cu(OAc)2 (0.08 mmol, 20 mol%), isolated yields. b 2.5 eq. of TMSN3 were used, and NBS was 1.0 eq. c TMSN3 2.5 eq. and NBS 1.2 eq., GC yield
using n-dodecane as an internal standard. d NMR yield using 1,1,2,2-tetrachloroethane as an internal standard. e 1.0 eq. of NIS was used instead
of NBS, 2.5 eq. of TMSN3 were used.
Table 3 The reaction of substrates with electron-withdrawing groupsa
Substrate
2
3
1o, R = 4-tBu 2o, 50%
3o, 20%
1pb, R = 4-Cl
2p, trace
3p, 87%
3q, 77%
1qb, R = 4-Br 2q, trace
1rc
2r, 59%
3r, 21%
a Reaction conditions: substrate 1 (0.4 mmol, 1.0 eq.), NBS (0.48 mmol,
1.2 eq.), TMSN3 (1.1 mmol, 2.7 eq.), K3PO4·7H2O (0.8 mmol, 2.0 eq.),
Cu(OAc)2 (0.08 mmol, 20 mol%), isolated yields. b 3.0 eq. of TMSN3
were used. c 1.2 eq. of NIS were used instead of NBS.
Scheme 2 Possible mechanism.
1200 | Org. Biomol. Chem., 2014, 12, 1198–1202
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Chem., 2012, 26, 4218; (c) J. Raap, S. Nieuwenhuis,
A. Creemers, S. Hexspoor, U. Krgagl and J. Lugtenburg,
Eur. J. Org. Chem., 1999, 2609.
2 S. Ueda and H. Nagasawa, J. Am. Chem. Soc., 2009, 131,
15080.
3 (a) M. Sundermeier, A. Zapf, M. Beller and S. Sans, Tetra-
hedron Lett., 2001, 42, 6707; (b) J. S. Miller and J. L. Manson,
Acc. Chem. Res., 2001, 34, 563; (c) M. B. Smith and J. March,
March’s Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure, Wiley, Hoboken, NJ, 6th edn, 2007.
ð3Þ
ð4Þ
On the basis of all the results mentioned above, a possible
mechanism is illustrated (Scheme 2). Substrate 1 reacts with
NBS forming a three-membered ring bromonium ion A, which
could equilibrate to a benzylic cation B,14a which is sub-
sequently attacked by azide ions to generate species C. The
intermediate C undergoes elimination assisted by a base to
form the corresponding alkenylazide intermediate D.7d,14 The
following rearrangement of D promoted by the copper catalyst
via intermediate E6i leads to the nitrile products 2 through
carbon–carbon bond cleavage. For the electron deficient
styrene substrates, it is difficult for intermediate A to equili-
brate to a benzylic cation B.14a An azide nucleophile could
attack the three-membered ring bromonium ion A, resulting in
intermediates C and/or F. Due to the effect of the electron-
withdrawing group, the elimination of intermediates F and C
to generate an alkenyl azide intermediate is difficult. They
prefer the substitution reaction with another azide nucleophile
to form diazidation products 3, which could not be further
converted to nitriles 2 under the standard conditions.
4 (a) A. J. Fatiadi, Preparation and synthetic applications of
cyano compounds, Wiley, New York, 1983; (b) R. C. Larock,
Comprehensive Organic Transformations, VCH, New York,
1989.
5 (a) K. Ishihara, Y. Furuya and H. Yamamoto, Angew. Chem.,
Int. Ed., 2002, 41, 2983; (b) C. W. J. Kuo, L. J. Zhu, D. Wu,
C. M. Chu, C. F. Yao and K. S. Shia, Chem. Commun., 2007,
301; (c) E. Choi, C. Lee, Y. Na and S. Chang, Org. Lett.,
2002, 4, 2369; (d) K. Yamaguchi, H. Fujiwara, Y. Ogasawara,
M. Kotani and N. Mizuno, Angew. Chem., Int. Ed., 2007, 46,
3922; (e) S. Iida and H. Togo, Tetrahedron, 2007, 63, 8274;
(f) T. Oischi, K. Yamaguchi and N. Mizuno, Angew. Chem.,
Int. Ed., 2009, 48, 6286.
6 For some recent examples see: (a) T.-J. Gong, B. Xiao,
W.-M. Cheng, W. Su, J. Xu, Z.-J. Liu, L. Liu and Y. Fu, J. Am.
Chem. Soc., 2013, 135, 10630; (b) S. Xu, X. Huang, X. Hong
and B. Xu, Org. Lett., 2012, 14, 4614; (c) J. Kim, H. J. Kim
and S. Chang, Angew. Chem., Int. Ed., 2012, 51, 11948;
(d) J. Kim, J. Choi, K. Shin and S. Chang, J. Am. Chem. Soc.,
2012, 134, 2528; (e) W. Zhou, J. Xu, L. Zhang and N. Jiao,
Synlett, 2011, 887; (f) Y. Yang, Y. Zhang and J. Wang, Org.
Lett., 2011, 13, 5608; (g) X. Ren, J. Chen, F. Chen and
J. Cheng, Chem. Commun., 2011, 47, 6725; (h) S. Ding and
N. Jiao, J. Am. Chem. Soc., 2011, 133, 12374; (i) S. Chiba,
L. Zhang, G. Y. Ang and B. W.-Q. Hui, Org. Lett., 2010, 12,
2052; ( j) W. Zhou, J. Xu, L. Zhang and N. Jiao, Org. Lett.,
2010, 12, 2888; (k) K. Banert, J. R. Fotsinga, M. Hagedorna,
H. P. Reisenauer and G. Maier, Tetrahedron, 2008, 64, 5645.
7 (a) W. Zhou, L. R. Zhang and N. Jiao, Angew. Chem., Int.
Ed., 2009, 48, 7094; (b) F. Chen, X. Huang, Y. Cui and
N. Jiao, Chem.–Eur. J., 2013, 19, 11199; (c) C. Qin and
N. Jiao, J. Am. Chem. Soc., 2010, 132, 15893; (d) T. Shen,
T. Wang, C. Qin and N. Jiao, Angew. Chem., Int. Ed., 2013,
52, 6677.
Conclusions
In conclusion, we have developed a novel NBS mediated highly
selective aromatic nitriles synthesis from styrenes through
CvC double bond cleavage. This kind of nitrogenation trans-
formation has a relatively high position-selectivity. Tandem
substitution, elimination, and rearrangement reactions are
involved in this process. Further investigations on expanding
the reaction scope and the application of this transformation
are ongoing in our laboratory.
Acknowledgements
Financial support from the National Science Foundation of
China (no. 21172006) and the Ph.D. Programs Foundation of
the Ministry of Education of China (no. 20120001110013) are
greatly appreciated. We thank Miancheng Zou in this group for
reproducing the reactions of 1b and 1l.
8 T. Wang and N. Jiao, J. Am. Chem. Soc., 2013, 135, 11692.
9 (a) T. Kitamura, S. Kobayashi and H. Taniguchi, J. Org.
Chem., 1984, 49, 4755; (b) V. Nair, S. B. Panicker,
S. Thomas, V. Santhi and S. Mathai, Tetrahedron, 2002, 58,
3229; (c) I. Shimizu, M. Fujita, T. Nakajima and T. Satoh,
Synlett, 1997, 887.
10 (a) M. J. Raihan, R. R. Rajawinsli, V. Kavala, C. W. Kuo,
T. S. Kuo, C. H. He, H. N. Huang and C. F. Yao, J. Org.
Chem., 2013, 78, 8872; (b) Y. Cai, X. Liu, J. Jiang, W. Chen,
L. Lin and X. Feng, J. Am. Chem. Soc., 2011, 133, 5636;
(c) U. Hennecke, C. H. Müller and R. Fröhlich, Org. Lett.,
2011, 13, 860.
Notes and references
1 (a) O. Domínguez-Quintero, S. Martínez, Y. Henríquez,
L. D’Ornelas, H. Krentzien and J. Osuna, J. Mol. Catal. A:
Chem., 2003, 197, 185; (b) R. García-Álvarez, S. E. García-
Garrido, J. Díez, P. Crochet and V. Cadierno, Eur. J. Inorg.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1198–1202 | 1201

View Article Online
Communication
Organic & Biomolecular Chemistry
11 (a) J. Wang, J. Wang, P. Lu and Y. Wang, J. Org. Chem.,
2013, 78, 8816; (b) X. Fan, L.-A. Fu, N. Li, X.-M. Cui and
Y. Qi, Org. Biomol. Chem., 2013, 11, 2147; (c) J. Wu, X. Sun and
W. Sun, Org. Biomol. Chem., 2006, 4, 4231; (d) M. Baumann,
I. R. Baxendale, S. V. Ley, N. Nikbin, C. D. Smith and
J. P. Tierney, Org. Biomol. Chem., 2008, 6, 1577.
12 (a) M. J. Palmer, J. A. Kenny, T. Walsgrove, A. M. Kawamoto
and M. Wills, J. Chem. Soc., Perkin Trans. 1, 2002, 416;
(b) D. Pini, A. Iuliano, C. Rosini and P. Salvadori, Synthesis,
1990, 1023; (c) F. Orsini, G. Sello and G. Beststti, Tetra-
(f) A. O. Teret’ev, I. B. Krylov, V. A. Kokorekin and
G. I. Nikishin, Synth. Commun., 2008, 38, 3797;
(g) P. Magnus, M. B. Roe and C. Hulme, J. Chem. Soc.,
Chem. Commun., 1995, 263; (h) R. M. Moriarty and
J. S. Khosrowshahi, Tetrahedron Lett., 1986, 27, 2809.
13 (a) G. C. Nandi and K. K. Laali, Tetrahedron Lett., 2013, 54,
2177; (b) L. M. Dornan, Q. Cao, J. C. A. Flanagan,
J. J. Crawford, M. J. Cook and M. J. Muldoon, Chem.
Commun., 2013, 49, 6030; (c) D. D. Patil, G. C. Wadhava and
A. K. Deshmukh, Asian J. Chem., 2012, 24, 1401.
hedron: Asymmetry, 2001, 12, 2961; (d) T. Sasaki, 14 (a) A. Hassner, F. P. Boerwinkle and A. B. Levy, J. Am. Chem.
K. Kanematsu and Y. Yukimoto, J. Org. Chem., 1972, 37,
890; (e) D. A. Kamble, P. U. Karabal, P. V. Chouthaiwale and
A. Sudalai, Tetrahedron Lett., 2012, 53, 4195;
Soc., 1970, 92, 4879; (b) A. Hassner and F. P. Boerwinkle,
J. Am. Chem. Soc., 1968, 90, 216; (c) A. Hassner and
J. S. Teeter, J. Org. Chem., 1971, 36, 2176.
1202 | Org. Biomol. Chem., 2014, 12, 1198–1202
This journal is © The Royal Society of Chemistry 2014