An efficient transformation from benzyl or allyl halides to aryl and alkenyl nitriles

Article abstract of DOI:10.1021/ol101094u

(Figure presented) A novel approach to aryl or alkenyl nitriles from benzyl and allyl halides has been developed. A tandem TBAB-catalyzed substitution and the subsequent novel oxidative rearrangement are involved in this transformation. To the best of our knowledge, this is the first transformation from allyl halides to alkenyl nitriles. The broad reaction scope and the mild conditions may make these methods of use in organic synthesis.

Full text of DOI:10.1021/ol101094u

ORGANIC
LETTERS
2
010
Vol. 12, No. 12
888-2891
An Efficient Transformation from Benzyl
or Allyl Halides to Aryl and Alkenyl
Nitriles
2
†
Wang Zhou, Jiaojiao Xu, Liangren Zhang, and Ning Jiao*
†
†
,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, Xue Yuan Road 38, Beijing 100191, China, and
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
jiaoning@bjmu.edu.cn
Received May 13, 2010
ABSTRACT
A novel approach to aryl or alkenyl nitriles from benzyl and allyl halides has been developed. A tandem TBAB-catalyzed substitution and the
subsequent novel oxidative rearrangement are involved in this transformation. To the best of our knowledge, this is the first transformation
from allyl halides to alkenyl nitriles. The broad reaction scope and the mild conditions may make these methods of use in organic synthesis.
The value of aryl and alkenyl nitriles in chemistry and
biology as unique structural units and versatile building
blocks in organic synthesis for natural products, pharma-
ceuticals, agricultural chemicals, and dyes has inspired the
Recently, we reported a direct transformation of methyl
arenes to aryl nitriles at room temperature (a, Scheme 1).
However, there still are some flaws in our method: (1) a
p-heteroatom on the aromatic ring is required for the
transformation, which extremely limited the substrate scope;
(2) excess amounts of NaN (4.0 equiv) and the oxidant
3
(phenyliodonium diacetate, PIDA, 3.2 equiv) were employed
to realize the transformation; (3) alkenyl methanes cannot
8
1
invention of numerous methods for their preparation. To
2
–6
date, many elegant methods have been developed. How-
ever, the transformation from simple and readily available
organic halides is still limited. To the best of our knowledge,
only a few approaches from benzyl halides to aryl nitriles
7
have been reported. The conversion from allyl halides to
(2) Synthesis of nitriles by Sandmeyer and transition-metal-mediated
cyanation. For reviews, see: (a) Ellis, G. A.; Romney-Alexander, T. M.
Chem. ReV. 1987, 87, 779. (b) Grushin, V. V.; Alper, H. Chem. ReV. 1994,
alkenyl nitriles has not been disclosed.
9
4, 1047. (c) Galli, C. Chem. ReV. 1988, 88, 765. For some recent examples,
†
Peking University.
Chinese Academy of Sciences.
see: (d) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388.
(e) Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837. (f) Chen, G.; Weng,
J.; Zheng, Z.; Zhu, X.; Cai, Y.; Cai, J.; Wan, Y. Eur. J. Org. Chem. 2008,
3524. (g) Schareina, T.; Zapf, A.; Maegerlein, W.; M u¨ eller, N.; Beller, M.
Chem.sEur. J. 2007, 13, 6249. (h) Zhu, Y.-Z.; Cai, C. Eur. J. Org. Chem.
2007, 2401. (i) Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189. (j)
Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.;
Beller, M. Chem.sEur. J. 2003, 9, 1828. (k) Ren, Y.; Wang, W.; Zhao, S.;
Tian, X.; Wang, J.; Yin, W.; Cheng, L. Tetrahedron Lett. 2009, 50, 4595.
(l) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984. (m) Zanon,
J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890. (n)
Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M. Chem.sEur. J. 2005,
11, 2483. (o) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int.
Ed. 2003, 42, 1661.
‡
(1) (a) Fatiadi, A. J. In Preparation and Synthetic Applications of Cyano
Compounds; Patai, S., Rappaport, Z., Ed.; Wiley: New York, 1983. (b)
Larock, R. C. ComprehensiVe Organic Transformations; VCH: New York,
1
989. (c) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substance: Synthesis, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, 2001. (d) Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34,
5
63. (e) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed.; Wiley: Hoboken, NJ, 2007.
(
f) Fleming, F. F.; Wang, Q. Chem. ReV. 2003, 103, 2035. (g) Magnus, P.;
Scott, D. A.; Fielding, M. R. Tetrahedron Lett. 2001, 42, 4127. (h) Murdoch,
D.; Keam, S. J. Drugs 2005, 65, 2379. (i) Njar, V. C. O.; Brodie, A. M. H.
Drugs 1999, 58, 233.
10.1021/ol101094u  2010 American Chemical Society
Published on Web 05/26/2010

Scheme 1
.
Strategies for Preparation of Aryl and Alkenyl
Nitriles
Table 1. The Direct Approach to Alkenyl Nitrile 2a from Allyl
Bromide 1a
a
oxidant
(equiv)
time
(h)
yield of
2a (%)
b
entry
solvent
c
1
DDQ (2.0)
PIDA (2.0)
CAN (2.0)
DDQ (1.3)
BQ (2.0)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
CH
CH
CH
CH
CH
CH
CH
CH
2
3
3
3
2
2
2
2
ClCH
CN
CN
2
Cl
12
6
6
2
2
0.5
2
2
2
2
3
8
0
70
0
84 (81)
80
0
65
42
37
22
16
2
3
4
5
6
CN
ClCH
ClCH
ClCH
ClCH
2
2
2
2
Cl
C
Cl
Cl
d
7
e
8
be transformed to alkenyl nitriles under those conditions. Our
continued efforts in the development of efficient nitriles
synthesis promoted us to explore a broad-spectrum approach
to nitriles. In our reported method, it was demonstrated that
benzyl azide is the key intermediate, which undergoes a novel
f
9
dioxane
CH NO
f
1
1
1
1
0
1
2
3
3
2
ethyl acetate
DMSO
DMF
2
2
2
8
f
f
a
Reaction conditions: 1a (0.5 mmol), NaN
3
(0.6 mmol), TBAB (0.025
for 24 h; oxidant
(
3) Recent examples for synthesis of nitriles from amides or oximes:
a) Ishihara, K.; Furuya, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2002,
1, 2983. (b) Kuo, C.-W.; Zhu, J.-L.; Wu, J.-D.; Chu, C.-M.; Yao, C.-F.;
Shia, K.-S. Chem. Commun. 2007, 301. (c) Choi, E.; Lee, C.; Na, Y.; Chang,
S. Org. Lett. 2002, 4, 2369. (d) Yamaguchi, K.; Fujiwara, H.; Ogasawara,
Y.; Kotani, M.; Mizuno, N. Angew. Chem., Int. Ed. 2007, 46, 3922. (e)
Zhou, S.; Addis, D.; Das, S.; Junge, K.; Beller, M. Chem. Commun. 2009,
mmol) in dry solvent (2 mL), stirred at 25 °C under N
was then added, and the mixture was heated to reflux. GC yield using
2
(
b
4
n-dodecane as internal standard; the number in the parentheses is the isolated
c
yield. The oxidant was added together with the other reagents at the first
d
step and then refluxed for 12 h. 18-Crown-6 (0.05 equiv) was used instead
e
f
of TBAB. The reaction was carried out in the absence of TBAB. The
nd step was carried out at 100 °C.
2
4
2
7
6
2
883. (f) Yadav, L. D. S.; Srivastava, V. P.; Patel, R. Tetrahedron Lett.
009, 50, 5532. (g) Singh, M. K.; Lakshman, M. K. J. Org. Chem. 2009,
4, 3079. (h) Saha, D.; Saha, A.; Ranu, B. C. Tetrahedron Lett. 2009, 50,
088. (i) Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M. Org. Lett.
009, 11, 2461.
oxidative rearrangement to afford aryl nitrile. We envisioned
that benzyl and allyl azides, which could be easily prepared
from simple and readily available organic halides, could be
the potential precursors for the corresponding aryl and
alkenyl nitriles through a proper oxidation (b, Scheme 1).
Herein, we demonstrate a novel TBAB (tetra-n-butylammo-
nium bromide)-catalyzed tandem substitution and the sub-
sequent oxidative rearrangement approach to aryl and alkenyl
nitriles from benzyl and allyl halides, respectively (b, Scheme
(
4) Recent examples for synthesis of nitriles from amines or alcohols:
(
a) Iida, S.; Togo, H. Tetrahedron 2007, 63, 8274. (b) Oischi, T.;
Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2009, 48, 6286. (c)
Chen, F.-E.; Kuang, Y.-Y.; Dai, H.-F.; Lu, L.; Huo, M. Synthesis 2003,
1
7, 2629. (d) Reddy, K. R.; Maheswari, C. U.; Venkateshwar, M.;
Prashanthi, S.; Kantam, M. L. Tetrahedron Lett. 2009, 50, 2050. (e) Chen,
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G. D.; Wilfred, C. D.; Taylor, R. J. K. Synlett 2002, 8, 1291.
(
5) Recent examples for direct cyanation through C-H bond function-
alization: (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (b) Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M.
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Y.; Tohma, H.; Kita, Y. Org. Lett. 2005, 7, 537. (d) Yan, G.; Kuang, C.;
Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 1052. (e) Jia, X.; Yang, D.; Zhang,
S.; Cheng, J. Org. Lett. 2009, 11, 4716. (f) Dohi, T.; Morimoto, K.;
Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y.
J. Org. Chem. 2007, 72, 109. (g) Jia, X.; Yang, D.; Wang, W.; Luo, F.;
Cheng, J. J. Org. Chem. 2009, 74, 9470. (h) Lu, Z.; Hu, C.; Guo, J.; Li, J.;
Cui, Y.; Jia, Y. Org. Lett. 2010, 12, 480. (i) Do, H.-Q.; Daugulis, O. Org.
Lett. 2010, 12, 2517.
1
).
Our approach was initiated using cinnamyl bromide 1a
as the electrophile (Table 1). As we expected, (E)-3-phenyl-
-propenenitrile (2a) was detected in 3% yield when 1a was
2
treated with sodium azide in the presence of DDQ (2,3-
dichloro-5,6-dicyanobenzoquinone) and a catalytic amount
of TBAB refluxed in DCE (1,2-dichloroethane) for 12 h
(6) Other methods: (a) L u¨ cke, B.; Narayana, K. V.; Martin, A.; J a¨ hnisch,
K. AdV. Synth. Catal. 2004, 346, 1407. (b) Telvekar, V. N.; Patel, K. N.;
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Arote, N. D.; Bhalerao, D. S.; Akamanchi, K. G. Tetrahedron Lett. 2007,
(entry 1, Table 1). Considering that the presence of an
oxidant would probably affect the substitution step forming
the allyl azide intermediate, we tried to add the oxidant
subsequently. Gratifyingly, when DDQ was simply added
after the reaction mixture had stirred at room temperature
4
8, 3651. (d) Sasson, R.; Rozen, S. Org. Lett. 2005, 7, 2177. (e) Rudler,
H.; Denis, B. Chem. Commun. 1998, 2145. (f) Altamura, A.; Daccolti, L.;
Detomaso, A.; Dinoi, A.; Fiorentino, M.; Fusco, C.; Curci, R. Tetrahedron
Lett. 1998, 39, 2009. (g) Fernandez, R.; Gasch, C.; Lassaletta, J. M.; Llera,
J. M.; Vazquez, J. Tetrahedron Lett. 1993, 34, 141. (h) Nakao, Y.; Oda,
S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 13904. (i) Nakao, Y.; Yukawa,
T.; Hirata, Y.; Oda, S.; Satoh, J.; Hiyama, T. J. Am. Chem. Soc. 2006, 128,
(7) (a) Iida, S.; Ohmura, R.; Togo, H. Tetrahedron 2009, 65, 6257. (b)
Iida, S.; Togo, H. Synlett 2008, 11, 1639. (c) McCleverty, J. A.; Ninnes,
C. W.; Wolochowicz, I. J. Chem. Soc., Dalton Trans. 1986, 743. (d) Sato,
R.; Ityoh, K.; Itoh, K.; Nishina, H.; Goto, T.; Saito, M. Chem. Lett. 1984,
1913.
7
2
116. (j) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc.
007, 129, 2428. (k) Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y.
Org. Lett. 2004, 6, 3917. (l) Peppe, C.; Mello, P. A.; dasChagas, R. P. J.
Organomet. Chem. 2006, 691, 2335. (m) Tomioka, T.; Takahashi, Y.;
Vaughan, T. G.; Yanase, T. Org. Lett. 2010, 12, 2171. (n) Chiba, S.; Zhang,
L.; Ang, G. Y.; Hui, B. W.-Q. Org. Lett. 2010, 12, 2052.
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7094.
Org. Lett., Vol. 12, No. 12, 2010
2889

a
a, b
Table 2. Synthesis of Alkenyl Nitrile from Allyl Halides
Table 3. Synthesis of Aryl Nitrile from Benzyl Halides
a
Reaction conditions: 1 (0.5 mmol), NaN
3
(0.6 mmol), TBAB (0.025
for 24 h; then the
mmol) in dry solvent (2 mL), stirred at 25 °C under N
oxidant was added and the mixture was heated to reflux. Isolated yield;
2
b
the number in parentheses is the ratio of the E- to Z-isomers of the product
1
determined by H NMR or GC (see the Supporting Information).
for 24 h, followed by refluxing for 0.5 h, 2a was isolated in
8
1% yield (entry 6). Other oxidants, such as PIDA, CAN
a
Reaction conditions: 3 (0.5 mmol), NaN
3
(0.6 mmol), TBAB (0.025
for 24 h; DDQ
(
ceric ammonium nitrate), or BQ (benzoquinone), exhibited
mmol) in dry solvent (2 mL), stirred at 25 °C under N
(0.75 mmol) was then added, and the mixture was heated to reflux. Isolated
yield. GC yield using n-dodecane as internal standard. DDQ (1.8 equiv)
was used. DDQ (1.5 equiv) was used.
2
b
lower efficiency than DDQ (cf. entries 2-5). In some cases,
a trace of cinnamaldehyde was detected as byproduct.
However, no product 2a was obtained in the absence of
TBAB (entry 8). Notably, 18-crown-6 worked equally well
as phase-transfer catalyst (entry 7). Other solvents, such as
c
d
e
the results in Table 2 demonstrate that the reaction has a
high degree of functional-group tolerance. Aryl or alkenyl
substitutents are well-tolerated (entries 1-10). Even alkyl-
substituted allyl chlorides such as 1k underwent this
conversion to generate 2k, but in lower yield (35%, entry
11). In addition, when allyl halides containing trisubsti-
tuted carbon-carbon double bond were employed as the
substrates, such as (E)-1c, (E)-1g, and (E)-1h, the corre-
sponding alkenenitriles were preferentially formed the
E-isomers (entries 3, 7, and 8).
1
3 2
,4-dioxane, acetonitrile, CH NO , ethyl acetate, DMF, or
DMSO, gave 2a in lower yield (entries 9-13, Table 1).
After confirming the optimum reaction conditions, we
then probed the scope of this novel transformation (Table
2
). A range of allyl chlorides and bromides proceeded
efficiently to give the corresponding alkenyl nitriles in
moderate to excellent yields. There is no significant effect
on yield between allyl bromides and chlorides as the
starting materials (cf. entries 1 and 2, 7 and 8). Moreover,
2890
Org. Lett., Vol. 12, No. 12, 2010

As shown in Table 3, this procedure worked well with a
wide range of aryl halides 3 and gave the corresponding aryl
nitriles in moderate to excellent yields. High yields were
achieved with substrates containing methyl (4g, 4o), tert-
butyl (4m), phenyl (4c), and iodo (4e) functional groups.
and allyl halides produce benzyl and allyl azides, which are
oxidized by DDQ to form benzyl and allyl cations A,
9
respectively. Then the cations A undergo Schmidt-type
1
0
rearrangement to afford the product aryl and alkenyl
nitriles. During this procedure, the intermediates A could
1
1
2-Bromomethylnaphthalene and 10-chloromethylanthracene
be attacked by water, leading to aldehydes, which were
observed in some cases by GC.
gave the corresponding nitriles in 77% and 96% yields,
respectively (4d, 4i). Moreover, heteroaryl bromomethanes
such as 3f and 3h performed well, producing corresponding
nitriles 4f and 4h in 94% and 92% yields, respectively (Table
In summary, we have developed a novel TBAB catalyzed
tandem approach to aryl and alkenyl nitriles. To the best of
our knowledge, this is the first transformation from allyl
halides to allkenenitriles. This opens the door not only for
other types of transformations for the synthesis of aryl and
alkenyl nitriles with these simple and readily available
substrates but also for the novel DDQ-oxidized rearrange-
ment mechanism. The broad reaction scope, the readily
available substrates, and the mild conditions may make these
methods of significance in organic synthesis. Further studies
on the mechanism and synthetic applications are ongoing in
our group.
3). Notably, 4-methylthiobenzyl chloride (3l) was converted
to nitrile 4l in good yield (87%) without further oxidation.
Moderate yields were observed for the substrates with
electron-withdrawing groups (4b, 4n).
Acknowledgment. Financial support from Peking Uni-
versity, National Science Foundation of China (Nos. 20702002,
To investigate the practical application of this transforma-
tion in organic synthesis, gram-scale reaction of 1a was
conducted (eq 1). Interestingly, 2a was produced in 85%
yield without any decrease compared to the small-scale
reaction (cf. eq 1 and entry 1, Table 2).
20872003), National Basic Research Program of China (973
Program 2009CB825300), and Program for “NCET” is
greatly appreciated. We thank Chong Qin of this group for
reproducing the results of 2g (entry 7, Table 2).
The plausible mechanism of this transformation is pro-
posed in Scheme 2. The initial substitution reaction of benzyl
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 2
.
Proposed Mechanism for the Cascade
Transformation
OL101094U
(
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