Organic Letters
Letter
plex can undergo reinsertion followed by reductive elimination
to effect remote C−H cyanation at the γ position as was
previously observed by Hiyama (Figure 2).35
Examples 2v and 2w demonstrate that heteroarylcyanations
were also possible. To the best of our knowledge, these are the
first examples under nickel catalysis. However, the 2-thiophene
moiety in 1x provided low yields of 2x.
To demonstrate the value of the nitrile functional group, we
set out to diversify 2a. The anticipated versatility of the
cyanomethyl functional handle was fully displayed in a series of
successful derivatization experiments (Scheme 3).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science and Engineering Research
Council (NSERC), the University of Toronto (U of T), and
Alphora Research Inc. for financial support. A.Y. thanks the
Ontario Graduate Scholarship (OGS) for financial support. A.Y.
thanks H. Yoon (U of T) for helpful discussions in the initial
stages of this project. A.Y thanks Y. J. Jang (U of T) and E. Larin
(U of T) for providing substrates 1a−1x, H. Yoon for providing
1a-I, and A. H. Pham (U of T) for the synthesis of 1a-OTf. A.Y.
thanks Dr. I. Franzoni (U of T) and Y. J. Jang for proofreading
the manuscript. Dr. Alan Lough (U of T) is thanked for single-
crystal X-ray structural analysis of 2a, 3a, and 3e.42
An excess of the Reformatsky enolate36 derived from methyl
bromoacetate (5.0 equiv) was used in the Blaise reaction37 to
synthesize β-enamino ester 3a in moderate yield. Notably, the
possibility of further C−C bond construction starting from 3a is
appealing. A modified Ritter reaction38 led to the formation of
N-tert-butylated acetamide 3b in essentially quantitative yield.
Reductive cyclization by treating 2a with LiAlH418b,23b followed
by a brief period of reflux afforded tricyclic pyrroloindoline 3c,
presumably through the cyclization of a transient metal-
loimine.39 A [3 + 2] azide-nitrile cycloaddition furnished
tetrazole 3d in quantitative yield.40 An interesting fusion of
heterocycles was realized through a modification of the Witte-
Seeliger oxazoline synthesis,41 affording 3e in 60% yield. The
straightforward synthesis of 3a−3e from easily accessible 2a thus
demonstrates the ease with which diverse oxindole derivatives
can be accessed.
In conclusion, a nickel-catalyzed arylcyanation for the
synthesis of 3,3-disubstituted oxindoles has been developed.
Operational simplicity is achieved by employing a low-cost, air-
stable precatalyst and bench-stable reagents with accessible
starting materials. In addition, an assortment of novel hetero-
cycles can be readily synthesized from the cyanomethyl
functional handle, thereby demonstrating its exceptional
synthetic versatility. Further studies to identify an appropriate
chiral ligand to render this transformation asymmetric are
underway in our laboratories.
REFERENCES
■
(1) For recent reviews, see: (a) Tasker, S. Z.; Standley, E. A.; Jamison,
T. F. Nature 2014, 509, 299−309. (b) Rosen, B. M.; Quasdorf, K. W.;
Wilson, D. A.; Zhang, N.; Resmerita, A. M.; Garg, N. K.; Percec, V.
Chem. Rev. 2011, 111, 1346−1416.
(2) For leading references, see: (a) Shibasaki, M.; Vogl, E. M.;
Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533−1552. (b) Dounay, A.
B.; Overman, L. E. Chem. Rev. 2003, 103, 2945−2963. (c) Beletskaya, I.
P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009−3066.
(3) (a) Wang, S.-S.; Yang, G.-Y. Catal. Sci. Technol. 2016, 6, 2862−
2876. (b) Lin, B. L.; Liu, L.; Fu, Y.; Luo, S. W.; Chen, Q.; Guo, Q. X.
Organometallics 2004, 23, 2114−2123.
(4) For a recent review, see: Giri, R.; KC, S. J. Org. Chem. 2018, 83,
3013−3022.
(5) (a) Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65−87.
Also see: (b) Grigg, R.; Santhakumar, V.; Sridharan, V. Tetrahedron
Lett. 1993, 34, 3163−3164.
(6) We have recently developed alkene arylcyanation reactions for the
synthesis of heterocycles: (a) Petrone, D. A.; Yen, A.; Zeidan, N.;
Lautens, M. Org. Lett. 2015, 17, 4838−4841. (b) Yoon, H.; Petrone, D.
A.; Lautens, M. Org. Lett. 2014, 16, 6420−6423.
(7) (a) Desrosiers, J. N.; Wen, J.; Tcyrulnikov, S.; Biswas, S.; Qu, B.;
Hie, L.; Kurouski, D.; Wu, L.; Grinberg, N.; Haddad, N.; Busacca, C. A.;
Yee, N. K.; Song, J. J.; Garg, N. K.; Zhang, X.; Kozlowski, M. C.;
Senanayake, C. H. Org. Lett. 2017, 19, 3338−3341. (b) Desrosiers, J.
N.; Hie, L.; Biswas, S.; Zatolochnaya, O. V.; Rodriguez, S.; Lee, H.;
Grinberg, N.; Haddad, N.; Yee, N. K.; Garg, N. K.; Senanayake, C. H.
Angew. Chem., Int. Ed. 2016, 55, 11921−11924.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Optimization tables, experimental procedures, analytical
data, copies of the 1H, 13C, and 19F NMR spectra for all
new compounds (1o, 1p, 1q, 1s−1u, 1a-Cl, 2a−2x, and
3a−3e), and X-ray crystallographic data for 2a, 3a, and 3e
(8) Li, Y.; Wang, K.; Ping, Y.; Wang, Y.; Kong, W. Org. Lett. 2018, 20,
921−924.
(9) Qin, X.; Lee, M. W. Y.; Zhou, J. S. Angew. Chem., Int. Ed. 2017, 56,
12723−12726.
(10) For selected examples, see: (a) Tasker, S. Z.; Gutierrez, A. C.;
Jamison, T. F. Angew. Chem., Int. Ed. 2014, 53, 1858−1861. (b) Gøgsig,
T. M.; Kleimark, J.; Nilsson Lill, S. O.; Korsager, S.; Lindhardt, A. T.;
Norrby, P. O.; Skrydstrup, T. J. Am. Chem. Soc. 2012, 134, 443−452.
(11) Work had previously been done in this area employing catalytic
Ni(cod)2. See: (a) Hinojosa, S.; Delgado, A.; Llebaria, A. Tetrahedron
Lett. 1999, 40, 1057−1060. With stoichiometric Ni(cod)2: (b) Cancho,
Accession Codes
graphic data for this paper. These data can be obtained free of
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
́
Y.; Martín, J. M.; Martínez, M.; Llebaria, A.; Moreto, J. M.; Delgado, A.
́
Tetrahedron 1998, 54, 1221−1232. (c) Sole, D.; Cancho, Y.; Llebaria,
́
A.; Moreto, J. M.; Delgado, A. J. Org. Chem. 1996, 61, 5895−5904.
AUTHOR INFORMATION
■
́
́
(d) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J. Am.
Chem. Soc. 1994, 116, 12133−12134.
Corresponding Author
ORCID
(12) For examples, see: (a) Cao, Z.; Zhou, F.; Zhou, J. Acc. Chem. Res.
2018, 51, 1443−1454. (b) Dalpozzo, R. Adv. Synth. Catal. 2017, 359,
1772−1810. (c) Trost, B. M.; Brennan, M. K. Synthesis 2009, 2009,
3003−3025.
D
Org. Lett. XXXX, XXX, XXX−XXX