Palladium-catalyzed three-component arylcyanation of internal alkynes with Aryl bromides and K4[Fe(CN)6]

Article abstract of DOI:10.1021/ol703018t

The one-pot, palladium-catalyzed, three-component coupling of aryl bromides, internal alkynes, and environmentally friendly K₄[Fe(CN) ₆] provides an efficient and direct method for the preparation of β-arylalkenylnitriles.

Full text of DOI:10.1021/ol703018t

ORGANIC
LETTERS
2008
Vol. 10, No. 5
901-904
Palladium-Catalyzed Three-Component
Arylcyanation of Internal Alkynes with
Aryl Bromides and K4[Fe(CN)6]
Yi-nan Cheng, Zheng Duan,* Liujian Yu, Zhongxian Li, Yu Zhu, and Yangjie Wu*
Chemistry Department, the Key Lab of Chemical Biology and Organic Chemistry of
Henan ProVince, the Key and Open Lab of Applied Chemistry of Henan UniVersities,
Zhengzhou UniVersity, Zhengzhou 450052, P.R. China
duanzheng@zzu.edu.cn; wyj@zzu.edu.cn
Received December 15, 2007
ABSTRACT
The one-pot, palladium-catalyzed, three-component coupling of aryl bromides, internal alkynes, and environmentally friendly K4[Fe(CN)6] provides
an efficient and direct method for the preparation of -arylalkenylnitriles.
â
Transition-metal-catalyzed domino coupling of aryl halides,
alkynes, and various functional groups has become a simple
and convenient method in organic synthesis. These reactions
proceed via a key vinylpalladium intermediate, which reacts
with various terminators to give aromatic derivatives or
multisubstituted olefins.1 However, this method has not been
applied to the synthesis of alkenylnitrile (eq 1), as the
resulting products contain important structural motifs of
numerous biologically active compounds.2 In addition, the
cyanide group has broad synthetic applications in organic
and material chemistry.3
to alkynes (eq 2),4 and cyanation of alkenyl halides (eq 3).5
Despite the significant progress made in this area, there is
still a need for new methods that involve readily available
starting material and environmentally friendly cyanation
reagent.
Several transition-metal-catalyzed or -mediated alkenylni-
trile formations from two-component reactions have been
reported, such as additions of cyanide-containing σ bonds
(4) (a) Chatani, N.; Takeyasu, T.; Horiuchi, N.; Hanafusa, T. J. Org.
Chem. 1988, 53, 3539. (b) Nozaki, K.; Sato, N.; Takaya, H. Bull. Chem.
Soc. Jpn. 1996, 69, 1629. (c) Obora, Y.; Baleta, A. S.; Tokunaga, M.; Tsuji,
Y. J. Organomet. Chem. 2002, 660, 173. (d) Taw, F. L.; White, P. S.;
Bergman, R. G.; Brookhart, M. J. Am. Chem. Soc. 2002, 124, 4192. (e)
Garcia, J. J.; Brunkan, N. M.; Jones, W. D. J. Am. Chem. Soc. 2002, 124,
9547. (f) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126,
13904. (g) Suginome, M.; Yamamoto, A.; Murakami, M. Angew. Chem.,
Int. Ed. 2005, 44, 2380. (h) Nishihara, Y.; Inoue, Y.; Itazaki, M.; Takagi,
K. Org. Lett. 2005, 7, 2639. (i) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama,
T. J. Am. Chem. Soc. 2006, 128, 8146. (j) Nakao, Y.; Oda, S.; Yada, A.;
Hiyama, T. Tetrahedron 2006, 62, 7567. (k) Kobayashi, Y.; Kamisaki, H.;
Yanada, R.; Takemoto, Y. Org. Lett. 2006, 8, 2711. (l) Nakao, Y.; Yukawa,
T.; Hirata, Y.; Oda, S.; Satoh, J.; Hiyama, T. J. Am. Chem. Soc. 2006, 128,
7116. (m) Nakao, Y.; Hirata, Y.; Hiyama, T. J. Am. Chem. Soc. 2006, 128,
7420. (n) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc.
2007, 129, 2428 and references therein.
(1) For recent examples, see: (a) Quan, L. G.; Gevorgyan, V.; Yama-
moto, Y. J. Am. Chem. Soc. 1999, 121, 3545. (b) Roesch, K. R.; Zhang, H.
M.; Larock, R. C. J. Org. Chem. 2001, 66, 8042. (c) Roesch, K. R.; Larock,
R. C. J. Org. Chem. 2001, 66, 412. (d) Pletnev, A. A.; Tian, Q. P.; Larock,
R. C. J. Org. Chem. 2002, 67, 9276. (e) Tian, Q. P.; Pletnev, A. A.; Larock,
R. C. J. Org. Chem. 2003, 68, 339. (f) Zhang, D. H.; Yum, E. K.; Liu, Z.
J.; Larock, R. C. Org. Lett. 2005, 7, 4963. (g) Shibata, K.; Satoh, T.; Miura,
M. Org. Lett. 2005, 7, 1781. (h) Zhou, C. X.; Larock, R. C. J. Org. Chem.
2005, 70, 3765. (i) Zhao, J.; Larock, R. C. J. Org. Chem. 2006, 71, 5340
and references therein.
(2) (a) Gilbert, J.; Miquel, J. F.; Pre´cigoux, G.; Hospital, M.; Raynaud,
J. P.; Michel, F.; Paulet, A. C. J. Med. Chem. 1983, 26, 693. (b) Bignon,
E.; Pons, M.; Paulet, A. C.; Dore, J. C.; Gilbert, J.; Abecassis, J.; Miquel,
J. F.; Ojasoo, T.; Raynaud, J. P. J. Med. Chem. 1989, 32, 2092.
(3) (a) Rappoport, Z., Ed. Chemistry of the Cyano Group; John Wiley
& Sons: London, 1970. (b) Larock, R. C. ComprehensiVe Organic
Transformations. A Guide to Functional Group Preparations; VCH: New
York, 1989.
(5) For recent results, see: (a) Li, G.; Watson, K.; Buckheit, R. W.;
Zhang, Y. Org. Lett. 2007, 9, 2043. (b) Boyd, D. R.; Sharma, N. D.; Coen,
G. P.; Gray, P. J.; Malone, J. F.; Gawronski, J. Chem. Eur. J. 2007, 13,
5804. (c) Wang, C. Y.; Wang, C.; Wang, Q. F.; Wang, Z. H.; Sun, H.;
Guo, X. Y.; Xi, Z. F. Chem. Eur. J. 2007, 13, 6484 and references therein.
10.1021/ol703018t CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/25/2008

Herein, we describe the first example of Pd-catalyzed,
sequential three-component arylcyanation of internal alkynes
with aryl bromides and environmentally friendly K4[Fe-
(CN)6],6 which provided an efficient route for the synthesis
of highly substituted â-arylalkenylnitriles from simple start-
ing materials (eq 4).
In an initial research, we found that the reaction of
bromobenzene (1 equiv), diphenylacetylene (1.5 equiv), and
K4[Fe(CN)6] (0.3 equiv) in the presence of Pd(OAc)2 (2 mol
%) and Na2CO3 (1 equiv) in N,N-dimethylacetamide (DMAc)-
at 120 °C for 5 h, provided the desired product 3a in a low
but promising yield (Table 1, entry 1, 41%) along with 38%
Figure 1. Crystal structure of 3f.
Table 1. Pd-Catalyzed Arylcyanation of Diphenylacetylenea
obtained when NEt3 was used (entry 3). No satisfied results
were obtained with K2CO3 and NaOAc (entries 4, 5). Na2-
CO3 was observed to furnish the highest yield (entry 2). The
reaction in DMAc (entry 2) is better than the reaction in
DMF or NMP (entries 7, 8).
entry
base
cat.
solvent yield(%)b
When PdCl2 or Pd(PPh3)4 was used as catalyst, 3a was
isolated in a low yield (entries 9, 10). The side reaction was
found to be enhanced significantly by adding phosphine
ligands, and tetraphenylnaphthalene was isolated in more than
40% yield (entries 11, 12). Although Pd(OAc)2-catalyzed
cyanation of aryl bromides with K4[Fe(CN)6] has been
developed efficiently,6c to our delight, this three-component
reaction proceeded with high selectivity, and only a very
small amount of benzonitrile was observed by GC.
1
2
3
4
5
6
7
8
9
Na2CO3 Pd(OAc)2
Na2CO3 Pd(OAc)2
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
NMP
DMAc
DMAc
41c
76
trace
20
46
68d
53
38
45
40
43
NEt3
K2CO3
NaOAc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NaHCO3 Pd(OAc)2
Na2CO3 Pd(OAc)2
Na2CO3 Pd(OAc)2
Na2CO3 PdCl2
Na2CO3 Pd(PPh3)4
Na2CO3 Pd(OAc)2 + PPh3(4 mol %) DMAc
Na2CO3 Pd(OAc)2 + PCy3(4 mol %) DMAc
10
11
12
As indicated in Table 1, the reaction conditions of entry
2 were used for the further examination of the scope of this
reaction with various aryl bromides and internal alkynes. The
typical results are summarized in Table 2. As shown in Table
2, all of electron-neutral (entries 1, 9, 11, 12, 13), electron-
rich (entries 2, 3), and electron-poor (entries 7, 8) aryl
bromides could afford the fully substituted R,â-unsaturated
nitriles in good yields. Even substrates with stronger electron-
donating groups, such as 4-dimethylaminobromobenzene and
4-bromoanisole, could work well when NaHCO3 was used
as base (entries 5, 6). Dialkyl-substituted alkynes also could
be used in this reaction. For example, 5-decyne and 4-octyne
provided the corresponding alkyl-substituted acrylonitriles
3l and 3m in 66% and 61% yields, respectively (entries 12,
13).
41
a All reactions were carried out with 0.75 mmol of 1a, 0.5 mmol of 2a,
0.15 mmol of K4[Fe(CN)6], 1 equiv of base and 2 mol % of catalyst in 1
mL of DMAc under nitrogen atmosphere at 120 °C for 5 h. b Isolated yield
of 3a. c 0.5 mmol of 1a, 0.75 mmol of 2a. d 2 equiv of NaHCO3 were used.
yield of tetraphenylnaphthalene.7 Further research revealed
that the formation of tetraphenylnaphthalene could be sup-
pressed significantly by changing the molar ratio of 1a:2a
from 1:1.5 to 1.5:1; the isolated yield of 3a was increased
to 76% (entry 2). The base played an important role in this
reaction. Only trace amount of the desired product 3a was
Ortho substituents hampered the reaction and led to the
formation of the product in low yields (entry 4, 39%). The
starting materials were recovered when the reaction was
carried out with 2,6-dimethylbromobenzene. The reaction
with more reactive iodobenzene provided 3a only in 46%
yield, and tetraphenylnaphthalene was isolated in 50% yield.
Unfortunately, under the standard conditions, heteroaryl
(6) For application of K4[Fe(CN)6] as cyanation reagent, see: (a)
Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 12, 1388. (b)
Schareina, T.; Zapf, A.; Beller, M. J. Organomet. Chem. 2004, 689, 4576.
(c) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508.
(d) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett. 2005, 46, 2585.
(e) Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189. (f) Li, L. H.; Pan,
Z. L.; Duan, X. H.; Liang, Y. M. Synlett 2006, 13, 2094. (g) Cheng, Y. N.;
Duan, Z.; Li, T.; Wu, Y. J. Synlett 2007, 4, 543. (h) Cheng, Y. N.; Duan,
Z.; Li, T.; Wu, Y. J. Lett. Org. Chem. 2007, 4, 352. (i) Pinto, A.; Jia, Y.
X.; Neuville, L.; Zhu, J. P. Chem. Eur. J. 2007, 13, 961. (j) Schareina, T.;
Zapf, A.; Ma¨gerlein, W.; Mu¨ller, N.; Beller, M. Chem. Eur. J. 2007, 13,
6249. (k) Mariampillai, B.; Alliot, J.; Li, M. Z.; Lautens, M. J. Am. Chem.
Soc. 2007, 129, 15372.
(7) Wu, G. Z.; Rheingold, A. L.; Geib, S. J.; Heck, R. F. Organometallics
1987, 6, 1941.
902
Org. Lett., Vol. 10, No. 5, 2008

Table 2. Palladium-Catalyzed Arylcyanation of Internal Alkyne with Aryl Bromides and K4[Fe(CN)6]a
a All reactions were carried out with 0.75 mmol of aryl bromide, 0.5 mmol of internal alkyne, 0.15 mmol of K4[Fe(CN)6], 1 equiv of Na2CO3, and 2 mol
% of Pd(OAc)2 in 1 mL of DMAc under N2 atmosphere at 120 °C for 5 h. b Isolated yield. c 2 equiv of NaHCO3 were used.
bromides and aryl chlorides exhibited very low reactivity,
and no desired product was obtained.
Scheme 1. Proposed Reaction Mechanism
It is worth noting that the reaction proceeded with high
stereoselectivity and gave the cis-addition product. The
structure of 3f was confirmed by X-ray analysis (Figure 1).
We proposed the following reaction mechanism (Scheme
1): (1) oxidative addition of the aryl bromide to Pd(0) giving
an arylpalladium(II) intermediate 4; (2) cis-carbopalladation
of the internal alkyne, giving a vinylic palladium intermediate
5; (3) ligand exchange with cyanide ion6b of K4[Fe(CN)6] to
form a new intermediate 6; (4) reductive elimination,
producing acrylonitrile 3 with simultaneous regeneration of
the Pd(0) catalyst.
In summary, we developed an efficient three-component
coupling procedure for stereoselective synthesis of fully
substituted R,â-unsaturated nitriles. The use of readily
accessible internal alkynes, aryl bromides, and an environ-
mentally friendly cyanation reagent made this Pd-catalyzed
arylcyanation attractive. This reaction also provides a simple
Org. Lett., Vol. 10, No. 5, 2008
903

and direct method to â-arylalkenylnitriles, potential inter-
mediates of biologically active compounds as well as organic
materials.4f Efforts for expansion of the scope, especially with
heteroaryl halides, and further utilization of the reaction
products are currently underway in our laboratories.
(No. 0621001100) for financial support. We are grateful to
Pacific ChemSource Inc. for generous donation of Pd
catalyst.
Supporting Information Available: General reaction
1
procedures, copy of H and 13C NMR spectra of products
and crystallographic data of 3f (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (No. 20472074, 20702050), the
Innovation Fund for Outstanding Scholar of Henan Province
OL703018T
904
Org. Lett., Vol. 10, No. 5, 2008