Synthesis of polycyclic benzonitriles via a one-pot aryl alkylation/cyanation reaction

Article abstract of DOI:10.1021/ja064742p

A norbornene-mediated palladium-catalyzed tandem alkylation/cyanation sequence is described in which an alkyl-aryl bond and a nitrile-aryl bond are formed in one pot. A variety of sterically hindered, five-, six-, and seven-membered ring benzonitriles wer

Full text of DOI:10.1021/ja064742p

Published on Web 10/24/2006
Synthesis of Polycyclic Benzonitriles via a One-Pot Aryl Alkylation/Cyanation
Reaction
Brian Mariampillai, Dino Alberico, Vale´rie Bidau, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario, Canada, M5S 3H6
Received July 4, 2006; E-mail: mlautens@chem.utoronto.ca
Table 1. Synthesis of Bicyclic Benzonitriles via
The cyanation of aryl halides and pseudohalides using palladium
has emerged as one of the most reliable and efficient methods for
the synthesis of the aryl-cyanide bond.1 Despite these advances,
the use of this valuable cross-coupling reaction in a tandem process
is largely unknown.2 Recently, we have reported a norbornene-
mediated palladium-catalyzed tandem process for the synthesis of
fused aromatic heterocycles.3,4 Our approach toward developing a
tandem reaction relies on using the inherent reactivity of norbornene
to initiate a competitive C-H functionalization pathway, so that
C-C and C-CN bond formation can occur sequentially. Herein,
we describe the application of this sequence to the rapid synthesis
of complex and sterically hindered bi- and tricyclic benzonitriles.
Initial exploration of the reaction focused on the synthesis of
oxygen-containing ring systems. While preliminary experiments
yielded a mixture of both cyclized and uncyclized benzonitriles,
the formation of the uncyclized benzonitriles could be suppressed
by careful variation of the reaction temperature. Under the optimized
conditions [aryl halide (1 equiv), Pd(OAc)2 (10 mol %), PPh3 (22
mol %), Cs2CO3 (2 equiv), norbornene (3 equiv), and Zn(CN)2 (1
equiv) in DME (0.05 M) under microwave irradiation at 150 °C
for 4000 s], substrate 1 was transformed into the five-membered
ring oxacycle 2 in 91% yield (Table 1, entry 1).5 Lowering the
catalyst loading to 5 mol % palladium gave 2 in 63% yield.
Extension to larger ring systems was also possible under these
conditions affording the desired six- and seven-membered rings in
78% and 62% yields, respectively (entries 2 and 3). Next, the nitro-
(7) and methoxy-(9) containing aryl iodides were subjected to the
reaction conditions to ascertain the effect of different ortho blocking
substituents on the yield of the reaction. Gratifyingly, both substrates
furnished the corresponding benzonitriles in good yields (entries 4
and 5); demonstrating that both electron-withdrawing and electron-
donating ortho blocking substituents are tolerated under the reaction
conditions. All attempts using substrates lacking an ortho substituent
were found to give complex mixtures.
Palladium-Catalyzed Tandem Alkylation/Cyanation Reactiona
The synthesis of nitrogen-containing heterocyclic benzonitriles
also proved to be very efficient. Five- and six-membered ring
products were generated in 78% and 79% yields, respectively
(entries 6-7), while seven-membered ring formation occurred in
a lower 67% yield (entry 8). We also investigated the feasibility of
using aryl bromides under the optimized reaction conditions. To
our delight 11b underwent cyclization to give 12 in 57% yield (entry
9). Similar results were obtained for the transformation of 13b and
15b. Although there was a substantial drop in the yield, these results
demonstrate the potential for using aryl bromides in the reaction.
The successful preparation of bicyclic substrates led us to extend
the reaction scope to include tricyclic benzonitriles through a double
ortho-alkylation/cyanation sequence (Table 2).
a All reactions were run under the following conditions: aryl halide (1
equiv), Pd(OAc)2 (10 mol %), PPh3 (22 mol %), Cs2CO3 (2 equiv),
norbornene (3 equiv), and Zn(CN)2 (1 equiv) in DME (0.05 M) were heated
in a sealed tube at 150 °C for 4000 s under microwave irradiation. b Isolated
yield. c Yield from aryl bromide.
While the 5,6,5-ring system product 18 was prepared in 88%
yield (entry 1), larger 6,6,6- and unsymmetrical 5,6,6-ring systems
were generated in 75% and 56% yields, respectively (entries 2 and
3). In addition, fully substituted tricyclic benzonitrile 24 was
prepared in 74% yield from the corresponding p-methoxy aryl
iodide 23 (entry 4).
9
14436
J. AM. CHEM. SOC. 2006, 128, 14436-14437
10.1021/ja064742p CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of Tricyclic Benzonitriles via
In summary, we have developed an approach toward the
synthesis of highly substituted benzonitriles via a palladium-
catalyzed intramolecular alkylation/intermolecular cyanation reac-
tion. This method has been applied toward the synthesis of a variety
of synthetically useful bicyclic and tricyclic benzonitrile products.
Studies toward the tandem intermolecular alkylation/intermolecular
cyanation reaction are currently underway and will be reported in
due course.
Palladium-Catalyzed Tandem Alkylation/Cyanation Reactiona
Acknowledgment. We gratefully acknowledge the financial
support of the Natural Sciences and Engineering Research Council
(NSERC) of Canada, the Merck Frosst Centre for Therapeutic
Research for an Industrial Research Chair, and the University of
Toronto. We thank Eric Fang, Andrew Martins, Alena Rudolph,
and Mark Scott for helpful discussions.
Supporting Information Available: Experimental procedures and
spectroscopic characterization of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For selected articles on palladium-catalyzed cyanation, see (a) Sundermeier,
M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003, 42, 1661-1664.
(b) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.; Weiss,
S.; Beller, M. Chem.sEur. J. 2003, 9, 1828-1836. (c) Schareina, T.;
Zapf, A.; Beller, M. Chem. Commun. 2004, 1388-1389. (d) Anderson,
B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.; Wepsiec, J. P.
J. Org. Chem. 1998, 63, 8224-8228. (e) Sundermeier, M.; Mutyala, S.;
Zapf, A.; Spannenberg, A.; Beller, M. J. Organomet. Chem. 2003, 684,
50-55. (f) Schareina, T.; Zapf, A.; Beller, M.; J. Organom. Chem. 2004,
689, 4576-4583. (g) Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837-
2840. (h) Marcantonio, K. M.; Frey, L. F.; Liu, Y.; Chen, Y.; Strine, J.;
Phenix, B.; Wallace, D. J.; Chen, C. Org. Lett. 2004, 6, 3723-3725. (i)
Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189-1191. (j) Weissman,
S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508-1510.
(2) For tandem palladium-catalyzed cyanation reactions, see (a) Larock, R.
C.; Takagi, K.; Hershberger, S. S.; Mitchell, M. A. Tetrahedron Lett. 1981,
22, 5231-5234. (b) Larock, R. C.; Hershberger, S. S.; Takagi, K.;
Mitchell, M. A. J. Org. Chem. 1986, 51, 2450-2457. (c) Torii, S.;
Okumoto, H.; Ozaki, S.; Nakayasu, S.; Kotani, T. Tetrahedron Lett. 1990,
31, 5319-5322. (d) Torii, S.; Okumoto, H.; Ozaki, S.; Nakayasu, S.;
Tadokoro, T.; Kotani, T. Tetrahedron Lett. 1992, 33, 3499-3502. (e)
Grigg, R.; Santhakumar, V.; Sridharan, V. Tetrahedron Lett. 1993, 34,
3163-3164. (f) Nakamura, H.; Shibata, H.; Yamamoto, Y. Tetrahedron
Lett. 2000, 41, 2911-2914. (g) Tanaka, M. Bull. Chem. Soc. Jpn. 1981,
54, 637-638. (h) Nozaki, K.; Sato, N.; Takaya, H. J. Org. Chem. 1994,
59, 2679-2681.
a All reactions were run under the following conditions: iodoarene (1
equiv), Pd(OAc)2 (10 mol %), PPh3 (22 mol %), Cs2CO3 (2 equiv),
norbornene (3 equiv), Zn(CN)2 (1 equiv) in DME (0.05 M) were heated in
a sealed tube at 150 °C for 4000 s under microwave irradiation. b Isolated
yield.
Scheme 1. Modification of Benzonitrile Product
(3) For previous work by our group on norbornene-mediated ortho-alkylation
chemistry, see (a) Lautens, M.; Alberico, D.; Bressy, C.; Fang, Y.-Q.;
Mariampillai, B.; Wilhelm, T. Pure Appl. Chem. 2006, 78, 351-361. (b)
Martins, A.; Marquardt, U.; Kasravi, N.; Alberico, D.; Lautens, M. J.
Org. Chem. 2006, 71, 4937-4942. (c) Martins, A.; Alberico, D.; Lautens,
M. Org. Lett. 2006, 8, 4827-4829. (d) Blaszykowski, C.; Aktoudianakis,
E.; Bressy, C.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 2043-2045.
(e) Alberico, D.; Paquin, J.-F.; Lautens, M. Tetrahedron 2005, 61, 6283-
6296. (f) Pache, S.; Lautens, M. Org. Lett. 2003, 5, 4827-4830.
(4) For recent work by Catellani and co-workers on norbornene-mediated
ortho-functionalization chemistry, see (a) Ferraccioli, R.; Carenzi, D.;
Motti, E.; Catellani, M. J. Am. Chem. Soc. 2006, 128, 722-723. (b)
Catellani, M.; Motti, E.; Faccini, F.; Ferraccioli, R. Pure and Appl. Chem.
2005, 77, 1243-1248. (c) Deledda, S.; Motti, E.; Catellani, M. Can. J.
Chem. 2005, 83, 741-747. (d) Faccini, F.; Motti, E.; Catellani, M. J.
Am. Chem. Soc. 2004, 126, 78-79. (e) Catellani, M. Synlett 2003, 298-
313.
(A) LiAlH4 (1 equiv), THF, 0 °C to room temp, 6 h, then HCl in ether;
(B) H2O2 (7.5 equiv), NaOH (0.6 equiv), 95% EtOH, 60 °C, 8 h; (C) NaN3
(12 equiv), NH4Cl (12 equiv), DMF, 220 °C microwave irradiation, 25
min.
To demonstrate the synthetic utility of the resulting benzonitrile
moiety, 18 was converted into three common functional groups,
showing the versatility of our nitrile containing products (Scheme
1). Reduction using lithium aluminum hydride, followed by
formation of the hydrochloride salt resulted in 94% yield of 25.
Conversion of the benzonitrile functionality to the corresponding
amide could be carried out using basic hydrogen peroxide in 77%
yield. Finally, preparation of tetrazole 27 was achieved in modest
yield using sodium azide and ammonium chloride in DMF under
microwave irradiation.6
(5) The reaction could also be carried out in a sealed tube at 150 °C using
conventional heating for 4000 seconds to give 2 in a 77% yield.
(6) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984-7989.
JA064742P
9
J. AM. CHEM. SOC. VOL. 128, NO. 45, 2006 14437