and 5). Borinamide 24, whose structure was unambiguously
confirmed by X-ray crystallographic analysis, indicates an
intermediacy of amidyl radical ii that is captured by Et3B
(Figure 1).10-12 The reason why borinamide 24 was produced
the previously reported hydroxyalkylation reaction in which
only one R-hydrogen was selectively substituted with a
carbon atom,3a the present reaction gave not only expected
monoanilide but also biscarbamoylated products such as 21.
This may be rationalized by the intramolecular 1,5-hydrogen
transfer of amidyl or oxyradical intermediate (Scheme 2).14
Scheme 2. Plausible Mechanism of Double R-C-H
Carbamoylation of N-Methylpyrrolidine (7)
Figure 1. ORTEP diagram of borinamide 24.
in this particular case is unclear, although it is likely that
the stability against hydrolysis owing to its structural rigidity
enabled the successful isolation.13 Interestingly, contrary to
(2) For recent exmaples of C-C bond formations via R-amino sp3C-H
functionalization, see: (a) Hartwig, J. F.; Seth, B. H. J. Am. Chem. Soc.
2007, 129, 6690-6690. (b) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad.
Sci. U.S.A. 2006, 103, 8928. (c) Campos, K. R.; Klapars, A.; Waldman, J.
H.; Dormer, P. G.; Chen, C.-y. J. Am. Chem. Soc. 2006, 128, 3538-3539.
(d) Pastine, S. J.; Gribkov, D. V.; Sames, D. Am. Chem. Soc. 2006, 128,
14220-14221. (e) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M.
P. J. Am. Chem. Soc. 2006, 128, 5648-5649. (f) Matsuo, J.; Tanaki, Y.;
Ishibashi, H. Org. Lett. 2006, 8, 4371-4374. (g) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 3672-3673. (h) Li, Z.; Li, C.-J. Eur. J. Org. Chem.
2005, 15, 3173-3176. (i) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126,
11810-11811. (j) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997-4999. (k)
DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556-
6557. (l) Murahashi, S.-i.; Komiya, N.; Terai, H.; Nakase, T. J. Am. Chem.
Soc. 2003, 125, 15312-15313. (m) Davies, H. M. L.; Venkataramani, C.;
Hansen, T.; Hopper, D. W. J. Am. Chem. Soc. 2003, 125, 6462-6468. (n)
Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002, 41,
2197-2199. (o) Suga, S.; Suzuki, S.; Yoshida, J. J. Am. Chem. Soc. 2002,
124, 30-31. (p) Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto,
A.; Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546-9549. (q) Chatani,
N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am.
Chem. Soc. 2001, 123, 10935-10941. (r) Chatani, N.; Fukuyama, T.;
Tatamidani, H.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65, 4039-
4047. (s) Marinkovic, S.; Hoffmann, N. Chem. Commun. 2001, 1576-
1578.
(3) (a) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Am. Chem. Soc. 2005,
127, 11610-11611. (b) Yoshimitsu, T.; Nagaoka, H.; Tanaka, T. J. Synth.
Org. Chem., Jpn. 2007, 65, 665-675. (c) Yoshimitsu, T. Farumashia 2007,
43, 219-223.
(4) Reviews of Et3B as radical source: (a) Ollivier, C.; Renaud, P. Chem.
ReV. 2001, 101, 3415-3434. (b) Yorimitsu, H.; Oshima, K. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
Germany, 2001; Vol. 1, pp 11-27. (c) O’Mahony, G. Synlett 2004, 572-
573. Also see: (d) Yoshimitsu, T. Et3B+O2 (first update). In Handbook of
Reagents for Organic Synthesis: Reagents for Direct Functionalization of
C-H Bonds; Fuchs, P. L., Ed.; Wiley-VCH: Weinheim, Germany, 2006;
pp 351-356.
A similar rationale may be applicable to the formation of
bisanilides 22, 26, 27, and 29;15 the 1,5-radical transposition
took place between the heteroradical center generated on the
carbamoyl substituent and the hydrogens located at the
δ-position from the radical center.16 N,N-Dimethylcyclo-
hexylamine (9) was also moderately converted into anilides
(8) Nakakoshi, M.; Ueda, M.; Sakurai, S.; Miyata, O.; Sugiura, M.; Naito,
T. Magn. Reson. Chem. 2006, 44, 807-812.
(9) Intermediacy of ethoxyl radical in Et3B/air system: (a) Sonnenschein,
M. F.; Webb, S. P.; Kastl, P. E.; Arriola, D. J.; Wendt, B. L.; Harrington,
D. R. Macromolecules 2004, 37, 7974-7978. (b) Sato, T.; Hibino, K.; Otsu,
T. Nippon Kagakukai Shi 1975, 1080-1084. We have also found that
PhNCO reacts slowly with (EtO)3B, an oxidation product of Et3B possibly
generated in situ, giving ethyl carbamate 12.
(10) Borinamide 24 was not produced by reacting isolated anilide 23
with Et3B, suggesting that 24 was directly generated by capturing radical
intermediate ii. For details, see Supporting Information.
(11) Isomerization of O-borinate that was possibly produced by capturing
the oxyradical intermediate with Et3B into borinamide 24 may also be
assumed.
(12) Et3B and amines probably form Lewis acid/base adducts (ate
complexes), and there may be a small amount of the free Et3B present at
equilibrium that is responsible for the successful radical processes. Similar
observations have been made in the Pd/Et3B-catalyzed allylic amination
reactions reported by Kimura and Tamaru et al.; see: Kimura, M.; Futamata,
M.; Shibata, K.; Tamaru, Y. Chem. Commun. 2003, 234.
(13) As shown in Table 1, entry 4, borinamide 20 was obtained from
N-methylpyrrolidine (7) by either method A or B, albeit in low yield (4-
5%). The structure was elucidated by NMR, IR, and HRMS analysis.
(14) If amidyl radicals ii abstract hydrogens from amines intermolecularly
to generate R-aminoalkyl radicals via radical chain processes, then a
relatively small or even a catalytic amount of Et3B/air (O2) would be
sufficient enough to promote the carbamoylation reactions. However, we
have not yet succeeded in such catalytic chain transformations under the
Et3B/air conditions, indicating that the above-hypothesized chain process
may not be involved in the present transformations.
(5) Alkyl radical addition reaction with isocyanates has met with limited
success: (a) Minin, P. L.; Walton, J. C. J. Org. Chem. 2003, 68, 2960-
2963. (b) Heinrich, M. R.; Pe´rez-Martin, I.; Zard, S. Z. Chem. Commun.
2005, 5928-5930. Also see: (c) Tlumak, R. L.; Day, J. C.; Slanga, J. P.;
Skell, P. S. J. Am. Chem. Soc. 1982, 104, 7257-7267.
(6) Another approach to radical carbamoylation: Cannella, R.; Clerici,
A.; Panzeri, W.; Pastori, N.; Punta, C.; Porta, O. J. Am. Chem. Soc. 2006,
128, 5358-5359.
(15) Stereochemistry of 27 was established by both X-ray analysis and
chemical correlations (see Supporting Information). Bisanilide 22 is a single
isomer, and its stereochemistry has yet to be determined.
(7) Reviews of R-aminoalkyl radical chemistry: (a) Aurrecoechea, J. M.;
Suero, R. ARKIVOC 2004, 10-35. (b) Hart, D. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany,
2001; Vol. 2, pp 279-302. (c) Renaud, P.; Giraud, L. Synthesis 1996, 913-
926.
(16) It is unlikely that the direct C-H carbamoylation of borinamide
intermediate 20 (or 24) takes place to give bisanilides 21 and 22 (or 26 and
27) because, under the present conditions, monoanilide 20 (or 24) is present
in a much smaller amount than its C-H substrate 7 (or 8) that is susceptible
to hydrogen abstraction.
Org. Lett., Vol. 9, No. 24, 2007
5117