Communication
fluoro, ortho-methyl, 3-thienyl, 3-trifluoromethyl, 2-thienyl, 4-
methoxy, 4-methyl, 4-chloro-, 2-furyl, 3,4-difluoro-, 3-methoxy,
and 1,3-dioxolane substituents (3a–o), affording the desired
benzophenone products in good to excellent yields. Interest-
ingly, variation of the electronic nature of the aromatic ring
had little impact on the reaction efficiency, with neutral 3m,
highly electron-withdrawing 3i, and electron-donating sub-
stituents 3o providing the desired ketone products in high
yields. This reactivity compares very favorably with the related
Suzuki coupling by amide NꢀC cleavage,[16c,f] which tends to
be sensitive to the electronics of the electrophile. The reaction
could be further extended to the coupling of functionalized
aryl zinc nucleophiles (3p–ah), affording the desired benzo-
phenones in good to excellent yields. Of particular note are
the cross-couplings of aryl amide electrophiles with indolyl
(3t–w), dimethylamino (3ag,ah), and substituted ortho-me-
thoxy aryl zinc nucleophiles (3x–ac). These reactions furnish
functionalized indolyl, amino- and methoxy-substituted aryl ke-
tones that possess a wide range of biological activities.[1e–g]
Note that these ortho-methoxy-substituted nucleophiles are
not tolerated in Suzuki amide NꢀC couplings.[16c,f] The current
limitation is that 4-ethoxycarbonylphenyl- and 4-cyanophenyl-
zinc reagents, readily prepared by direct halide/magnesium ex-
change,[7] are not tolerated in the reaction; however, the scope
of the reaction surpasses the Suzuki cross-coupling of amides.
Pharmaceutically relevant heterocycles, such as thiophene,
furane, dioxolane, and indole are perfectly accommodated. The
Negishi coupling proceeds under ambient conditions (cf.
Suzuki), which is important for practical applications.[22] Addi-
tional studies to expand the scope of this reaction are under-
way in our laboratories.
Acknowledgements
We acknowledge Rutgers University for financial support. The
Bruker 500 MHz spectrometer used in this study was support-
ed by the NSFMRI grant (CHE-1229030).
Keywords: diaryl ketones · NꢀC activation · Negishi coupling ·
nickel · zinc
[1] a) I. Jabeen, K. Pleban, U. Rinner, P. Chiba, G. F. Ecker, J. Med. Chem.
2012, 55, 3261; b) K. Maeyama, K. Yamashita, H. Saito, S. Aikawa, Y.
Yoshida, Polym. J. 2012, 44, 315; c) W. Sharmoukh, K. C. Kol, C. Noh, J. Y.
Lee, S. U. Son, J. Org. Chem. 2010, 75, 6708; d) S. K. Vooturi, C. M.
Cheung, M. J. Rybak, S. M. Firestine, J. Med. Chem. 2009, 52, 5020;
e) M. P. Lꢁzꢁ, M. Le Borgne, P. Pinson, A. Palusczak, M. Duflos, G. Le Baut,
R. W. Hartmann, Bioorg. Med. Chem. Lett. 2006, 16, 1134; f) M. H. Keylor,
B. S. Matsuura, C. R. J. Stephenson, Chem. Rev. 2015, 115, 8976; g) L.
Brunton, B. Chabner, B. Knollman, Goodman and Gilman’s The Pharma-
cological Basis of Therapeutics, 12th Ed., 2010.
[2] a) B. M. Trost, I. Fleming, Comprehensive Organic Synthesis Pergamon
Press, 1991; b) F. Schmidt, R. T. Stemmler, J. Rudolph, C. Bolm, Chem.
Soc. Rev. 2006, 35, 454; c) S. Mondal, G. Panda, RSC Adv. 2014, 4, 28317;
d) Y. Q. Long, X. H. Jiang, R. Dayam, T. Sanchez, R. Shoemaker, S. Sei, N.
Neamati, J. Med. Chem. 2004, 47, 2561.
[3] a) R. K. Dieter, Tetrahedron 1999, 55, 4177; b) A. Zapf, Angew. Chem. Int.
Ed. 2003, 42, 5394; Angew. Chem. 2003, 115, 5552.
[4] C. Duplais, F. Bures, I. Sapountzis, T. J. Korn, G. Cahiez, P. Knochel,
Angew. Chem. Int. Ed. 2004, 43, 2968; Angew. Chem. 2004, 116, 3028.
[5] a) P. Knochel, Handbook of Functionalized Organometallics Wiley-VCH,
Weinheim, 2005; b) Z. Rappoport, I. Marek, The Chemistry of Organo-
magnesium Compounds, John Wiley & Sons, Chichester, 2008.
[6] a) D. Haas, J. M. Hammann, R. Greiner, P. Knochel, ACS Catal. 2016, 6,
1540; b) A. de Meijere, A. S. Brꢂse, M. Oestreich, Metal-Catalyzed Cross-
Coupling Reactions and More, Wiley, New York, 2014; c) E. Negishi, Q.
Hu, Z. Huang, M. Qian, G. Wang, Aldrichimica Acta 2005, 38, 71; d) E. Ne-
gishi, Handbook of Organopalladium Chemistry for Organic Synthesis
Wiley, New York, 2002.
[7] Reviews: a) A. D. Benischke, M. Ellwart, M. R. Becker, P. Knochel, Synthesis
2016, 1101; b) T. Klatt, J. T. Markiewicz, C. Sꢂmann, P. Knochel, J. Org.
Chem. 2014, 79, 4253; c) B. Haag, M. Mosrin, H. Ila, V. Malakhov, P. Kno-
chel, Angew. Chem. Int. Ed. 2011, 50, 9794; Angew. Chem. 2011, 123,
9968; d) P. Knochel, P. Jones, Organozinc Reagents: A Practical Approach,
Oxford University Press, New York 1999; Selected examples: e) A. Kra-
sovskiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew. Chem. Int. Ed.
2006, 45, 6040; Angew. Chem. 2006, 118, 6186; f) G. Manolikakes, M. A.
Schade, C. M. Hernandez, H. Mayr, P. Knochel, Org. Lett. 2008, 10, 2765;
g) A. Metzger, M. A. Schade, P. Knochel, Org. Lett. 2008, 10, 1107; h) T.
Thaler, B. Haag, A. Gavryushin, K. Schober, E. Hartmann, R. M. Gschwind,
H. Zipse, P. Mayer, P. Knochel, Nat. Chem. 2010, 2, 125; i) T. Bresser, G.
Monzon, M. Mosrin, P. Knochel, Org. Process Res. Dev. 2010, 14, 1299;
j) C. I. Stathakis, S. M. Manolikakes, P. Knochel, Org. Lett. 2013, 15, 1302;
k) J. M. Hammann, D. Haas, P. Knochel, Angew. Chem. Int. Ed. 2015, 54,
4478; Angew. Chem. 2015, 127, 4560.
Importantly, the cross-coupling was carried out on a gram
scale in excellent yield (3s). Given its user-friendly nature
(room temperature, bench-top), economically viable profile of
components (cf. boronic acids, Pd), the method provides an
entry point for the utilization of amide Negishi coupling in in-
dustrial development.[22]
A striking feature of this new Negishi cross-coupling reaction
is the rate of acyl–aryl coupling under exceedingly mild condi-
tions. Monitoring of the reaction profile of 3l indicated that
the reaction is complete in less than 10 min at room tempera-
ture. This marks the fastest NꢀC amide bond cross-coupling
achieved to date,[16,17] which bodes well for the development
of cross-coupling processes with functionalized organozinc re-
agents by amide NꢀC bond activation.
In conclusion, we have demonstrated the first diaryl ketone
synthesis by the Negishi cross-coupling of amides by chemose-
lective NꢀC activation. This versatile method is distinguished
by a broad substrate scope, functional-group tolerance and
mild reaction conditions unattainable by the current state-of-
the-art Suzuki couplings with amide electrophiles. Notably, the
method represents the mildest conditions for amide NꢀC acti-
vation accomplished to date. Given the importance of poly-
functional biaryl motifs and high functional-group tolerance of
organozinc reagents, these studies lay a foundation for a gener-
al application of amide Negishi cross-coupling for the synthesis
of polyfunctionalized ketones.
[8] a) C. Valente, S. Calimsiz, K. H. Hoi, D. Mallik, M. Sayah, M. G. Organ,
Angew. Chem. Int. Ed. 2012, 51, 3314; Angew. Chem. 2012, 124, 3370;
b) M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev, C. J.
O’Brien, C. Valente, Chem. Eur. J. 2006, 12, 4749; c) M. G. Organ, S. Cal-
imsiz, M. Sayah, K. H. Hoi, A. J. Lough, Angew. Chem. Int. Ed. 2009, 48,
2383; Angew. Chem. 2009, 121, 2419; d) N. Hadei, G. T. Achonduh, C.
Valente, C. J. O’Brien, M. G. Organ, Angew. Chem. Int. Ed. 2011, 50, 3896;
Angew. Chem. 2011, 123, 3982.
[9] a) Q. Liu, Y. Lan, J. Liu, G. Li, Y. Wu, A. Lei, J. Am. Chem. Soc. 2009, 131,
10201; b) L. Jin, C. Liu, J. Liu, F. Hu, Y. Lan, A. S. Batsanov, J. A. K.
Howard, T. B. Marder, A. Lei, J. Am. Chem. Soc. 2009, 131, 16656.
[10] a) C. Dai, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 2719; b) J. E. Milne, S. L.
Buchwald, J. Am. Chem. Soc. 2004, 126, 13028; c) B. J. Li, Y. Z. Li, X. Y. Lu,
J. Liu, B. Guan, Z. J. Shi, Angew. Chem. Int. Ed. 2008, 47, 10124; Angew.
&
&
Chem. Eur. J. 2016, 22, 1 – 6
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!