Journal of the American Chemical Society
Article
Tan, Y.; Munoz-Molina, J. M.; Fu, G. C.; Peters, J. C. Chem. Sci. 2014,
5, 2831−2835. (e) For a related study, see: Yoo, W.-J.; Tsukamoto,
T.; Kobayashi, S. Org. Lett. 2015, 17, 3640−3642.
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CONCLUSION
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We have expanded the scope of photoinduced, copper-
catalyzed cross-couplings of alkyl electrophiles: with respect
to the nucleophile, we have shown for the first time that a
carbon nucleophile can be employed; with respect to the
electrophile, we have provided the first examples of the use of
secondary alkyl chlorides as electrophiles. More specifically, we
have established that, with a combination of light and a copper
catalyst, the cyanation of a variety of unactivated secondary
alkyl chlorides, including very sterically demanding substrates,
proceeds in good yield under unusually mild conditions (room
temperature) to generate nitriles, a useful class of organic
molecules. An inexpensive precatalyst (CuI) and light source
are used, no added ligand is necessary, the method is versatile
(e.g., secondary alkyl bromides, a very hindered primary alkyl
chloride, and an unactivated tertiary alkyl chloride serve as
suitable electrophiles under the same conditions), and the
cyanation can even be achieved at 0 °C. Initial mechanistic
observations are consistent with possible roles for [Cu-
(CN)2]−*, alkyl iodides, and alkyl radicals as intermediates.
Further efforts are underway to exploit the unusual reactivity
provided by copper and light to accomplish new families of
bond constructions for organic synthesis.
(4) For independent work by Hwang (C−C), see: Sagadevan, A.;
Hwang, K. C. Adv. Synth. Catal. 2012, 354, 3421−3427.
(5) (a) Carbazoles as nucleophiles: Bissember, A. C.; Lundgren, R.
J.; Creutz, S. E.; Peters, J. C.; Fu, G. C. Angew. Chem., Int. Ed. 2013, 52,
5129−5133. (b) Amides as nucleophiles: Do, H.-Q.; Bachman, S.;
Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2014, 136,
2162−2167.
(6) For recent overviews of photoinduced, copper-catalyzed
reactions, see: (a) Majek, M.; von Wangelin, A. J. Angew. Chem., Int.
Ed. 2013, 52, 5919−5921. (b) Paria, S.; Reiser, O. ChemCatChem
2014, 6, 2477−2483.
(7) For leading references, see: (a) Science of Synthesis; Murahashi,
S.-I., Ed.; Georg Thieme Verlag: Stuttgart, Germany, 2004; Vol. 19.
(b) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J.
Med. Chem. 2010, 53, 7902−7917.
(8) Vildagliptin and verapamil are two examples of alkyl nitriles that
serve as pharmaceutical drugs.
(9) For example, see: (a) Smiley, R. A.; Arnold, C. J. Org. Chem.
1960, 25, 257−258.
(189 °C; DMSO). 2-Chlorobutane and 2-
chlorooctane were cyanated in 69% and 70% yield, respectively.
(b) Cook, F. L.; Bowers, C. W.; Liotta, C. L. J. Org. Chem. 1974, 39,
3416−3418.
(83 °C; CH3CN/18-crown-6). 2-Chlorooctane was
cyanated in 78% yield (based on recovered starting material; 10 days),
whereas cyclohexyl chloride did not furnish any of the desired product.
(c) Shaw, J. E.; Hsia, D. Y.; Parries, G. S.; Sawyer, T. K. J. Org. Chem.
1978, 43, 1017−1018. (80 °C; HMPA). 2-Chlorooctane was cyanated
in 87% yield. (d) Reddy, M. S.; Rajan, S. T.; Eswaraiah, S.;
Satyanarayana, R. Improved Process for Manufacture of Pregabalin.
Patent WO 2009/001372 A2, Dec 31, 2008. A secondary alkyl
chloride was cyanated in ∼70% yield.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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S
Experimental procedures and compound characterization
(10) For example, see: (a) Nickel catalyst/60 °C: Satoh, Y.; Obora,
Y. RSC Adv. 2014, 4, 15736−15739. (b) Copper catalyst/180 °C:
Ren, Y.; Dong, C.; Zhao, S.; Sun, Y.; Wang, J.; Ma, J.; Hou, C.
Tetrahedron Lett. 2012, 53, 2825−2827. (c) Palladium catalyst/140
°C: Ren, Y.; Yan, M.; Zhao, S.; Sun, Y.; Wang, J.; Yin, W.; Liu, Z.
Tetrahedron Lett. 2011, 52, 5107−5109. (d) Titanium catalyst/0 °C
(benzhydryl chloride): Zieger, H. E.; Wo, S. J. Org. Chem. 1994, 59,
3838−3840.
(11) The UVC bulbs can be purchased from a retailer such as
amazon.com ($15).
(12) Notes: (a) The temperature of the reaction mixture during the
course of the cross-coupling has been determined to be ≤25 °C. (b) A
very small amount (∼2%) of reduction of the alkyl chloride (Cl → H)
is observed.
AUTHOR INFORMATION
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Corresponding Authors
Author Contributions
†T.S.R. and S.B. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(13) An aryl halide (iodide) can also undergo cyanation, albeit in
modest yield.
We thank Dr. Junwon Choi, Nathaniel T. Kadunce, Dr. Wesley
Sattler, Dr. David VanderVelde, Dr. Scott C. Virgil, Paul
Walton, and Dr. Daniel T. Ziegler for experimental assistance
and for helpful discussions, and we thank the Gordon and Betty
Moore Foundation, the National Science Foundation (graduate
research fellowship to T.S.R.), and the NIH (NIGMS: R01
GM109194) for funding.
(14) Notes: (a) In the absence of light and/or CuI, no cyanation was
observed. (b) This method is not yet general: under the current
conditions, more hindered tertiary alkyl chlorides react more slowly.
We have not yet pursued optimization of this process.
(15) The cyanation of a tertiary alkyl chloride under SN1 conditions
has been described. For example, see: Reetz, M. T.; Chatziiosifidis, I.
Angew. Chem., Int. Ed. Engl. 1981, 20, 1017−1018.
(16) In preliminary studies under our standard conditions, an
unactivated secondary alkyl fluoride and an unactivated secondary
alkyl tosylate did not serve as suitable coupling partners.
(17) Note: We are also considering mechanisms that incorporate
features such as out-of-cage chemistry of the alkyl radical, including
carbon−carbon bond formation via reaction of the alkyl radical with a
Cu(I)−CN complex.
(18) Cyclohexyl chloride can be a challenging substrate for cyanation,
including under “naked nucleophile” conditions (ref 9b).
(19) During the course of a catalyzed cyanation, we have observed
the accumulation of only a trace (<1%) of the alkyl iodide.
(20) Photolysis (254 nm) of cyclohexyl iodide in CH3CN leads to its
gradual disappearance over 24 h. In contrast, under the same
REFERENCES
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