Organic Letters
Letter
(5) Andrews, S. P.; Ball, M.; Wierschem, F.; Cleator, E.; Oliver, S.;
reagents, those processes could involve six-center (10, 11) or
four-center (12) transition states (Figure 1);16,55−57 the radical
Hogenauer, K.; Simic, O.; Antonello, A.; Hunger, U.; Smith, M. D.; Ley,
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Inoue, M.; Hirama, M. J. Nat. Prod. 2011, 74, 357.
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(9) Plummer, C. W.; Wei, C. S.; Yozwiak, C. E.; Soheili, A.; Smithback,
S. O.; Leighton, J. L. J. Am. Chem. Soc. 2014, 136, 9878.
(10) Bejjani, J.; Chemla, F.; Audouin, M. J. Org. Chem. 2003, 68, 9747.
(11) Kartika, R.; Taylor, R. E. Angew. Chem., Int. Ed. 2007, 46, 6874.
(12) Ding, R.; Fu, J.-G.; Xu, G.-Q.; Sun, B.-F.; Lin, G.-Q. J. Org. Chem.
2014, 79, 240.
Figure 1. Addition of allyl Grignard reagents involving either six-center
or four-center transition states.16,55−57
(13) Moon, N. G.; Harned, A. M. Org. Lett. 2015, 17, 2218.
(14) (a) Gajewski, J. J.; Bocian, W.; Harris, N. J.; Olson, L. P.; Gajewski,
J. P. J. Am. Chem. Soc. 1999, 121, 326. (b) Holm, T. J. Am. Chem. Soc.
1993, 115, 916.
(15) Kinetic isotope effect studies suggest that allyllithium reagents
react with alkyl aldehydes by a polar mechanism (ref 14a).
(16) The carbon−carbon bond-forming step in reactions of Grignard
reagents with aromatic aldehydes and ketones can involve a single-
electron-transfer (SET) process, depending on the substrate:
clock experiments cannot differentiate between these possibil-
ities. We cannot discount a stepwise single-electron mechanism
completely, however. If the addition of a Grignard reagent to an
alkyl aldehyde proceeded by one-electron reduction of the
aldehyde to form a ketyl radical and an alkyl radical and then
recombination of these two radicals (Scheme 1), the rate
constant of the two radicals recombining would need to be faster
than the rate of the particularly fast ring-opening rearrangement
(Scheme 2).24,28 In this situation, because the second step is so
fast, the stepwise reaction becomes effectively concerted.58−60
In summary, studies with an aldehyde substrate bearing a
radical clock provide evidence against a single-electron-transfer
mechanism for the addition of allylmagnesium reagents to
aliphatic aldehydes. A number of other Grignard reagents,
including Ph3CMgCl, which is capable of producing a highly
stabilized alkyl radical,54 also did not provide products consistent
with radical intermediates.
Hoffmann, R. W.; Holzer, B. Chem. Commun. 2001, 491.
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(17) The additions to both alkyl methyl ketones and alkyl
trifluoromethyl ketones have been proposed to involve polar
mechanisms, not single-electron-transfer reactions: Felix, C.; Laurent,
A.; Mison, P. J. Fluorine Chem. 1995, 70, 71.
(18) Nevill, S. M.; Pincock, J. A. Can. J. Chem. 1997, 75, 232.
(19) Newcomb, M., Radical Kinetics and Clocks. In Encyclopedia of
Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer,
A., Eds.; Wiley: Hoboken, 2012.
(20) Tanko, J. M.; Gillmore, J. G.; Friedline, R.; Chahma, M. J. Org.
Chem. 2005, 70, 4170.
(21) Tanko, J. M.; Li, X.; Chahma, M.; Jackson, W. F.; Spencer, J. N. J.
Am. Chem. Soc. 2007, 129, 4181.
(22) Tanko, J. M.; Brammer, L. E. J. Chem. Soc., Chem. Commun. 1994,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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S
1165.
(23) Dixon, C. E.; Hughes, D. W.; Baines, K. M. J. Am. Chem. Soc. 1998,
120, 11049.
(24) Tzirakis, M. D.; Alberti, M. N. ARKIVOC 2015, iii, 83.
(25) Newcomb, M. Tetrahedron 1993, 49, 1151.
Experimental data and NMR spectra (PDF)
(26) Zelechonok, Y.; Silverman, R. B. J. Org. Chem. 1992, 57, 5785.
(27) Milnes, K. K.; Baines, K. M. Organometallics 2007, 26, 2392.
(28) Castellino, A. J.; Bruice, T. C. J. Am. Chem. Soc. 1988, 110, 7512.
(29) Molander, G. A.; McKie, J. A. J. Org. Chem. 1991, 56, 4112.
(30) Timberlake, J. W.; Chen, T. Tetrahedron Lett. 1994, 35, 6043.
AUTHOR INFORMATION
Corresponding Author
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Notes
(31) Aulenta, F.; Holemann, A.; Reißig, H.-U. Eur. J. Org. Chem. 2006,
̈
The authors declare no competing financial interest.
1733.
(32) Tomioka, H.; Miyagawa, H. J. Chem. Soc., Chem. Commun. 1988,
1183.
ACKNOWLEDGMENTS
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(33) Szostak, M.; Spain, M.; Eberhart, A. J.; Procter, D. J. J. Org. Chem.
2014, 79, 11988.
(34) Szostak, M.; Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2014, 136,
This research was supported by the National Institutes of Health,
National Institute of General Medical Sciences (GM-61066).
The Bruker Avance-400 MHz NMR spectrometer was acquired
through support of the National Science Foundation (CHE-
01162222). We thank Dr. Michael Yang (BASF) for preliminary
experiments related to this project. D.A.L.O. gratefully acknowl-
edges the Department of Chemistry, NYU, for a Margaret
Strauss Kramer Fellowship.
8459.
(35) Additions of carbon nucleophiles to aldehydes with radical clocks
have been reported without discussing the mechanism of addition. See,
́
for example: (a) Topolski, M.; Duraisamy, M.; Rachon, J.; Gawronski, J.;
Gawronska, K.; Goedken, V.; Walborsky, H. M. J. Org. Chem. 1993, 58,
546. (b) Nevill, S. M.; Pincock, J. A. Can. J. Chem. 1997, 75, 232. (c) Xu,
L.; Newcomb, M. J. Org. Chem. 2005, 70, 9296.
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