halides, has been recently highlighted as a highly atom
economical transformation that generates hydrogen as the
sole byproduct.9,10 Our group hasbeeninvolvedin the area
by developing N-heterocyclic carbene (NHC) based Ru
catalytic systems.11,12 While investigating the scope of the
reaction, we found that sp3 CÀO cleavage in alkyl ethers
occurred in the reactions of 3-alkoxy-1-propanol deriva-
tives and an amine with concurrent formation of CÀN
bonds (Scheme 1). To the best of our knowledge, this is the
first catalytic CÀN bond formation via sp3 CÀO bond
cleavage. Interestingly, the cleavage occurred selectively in
the C3ÀO position in 3-alkoxy-1-propanols even with
3-benzyloxy-1-propanol.
Scheme 2. Selective CÀO Bond Cleavage in 3-Alkoxy-1-pro-
panola
When 3-benzyloxy-1-propanol (1a) was reacted with ben-
zyl amine (2a) using an (NHC)Ru-based catalytic system for
the oxidative amide synthesis from alcohols and amines,11a to
our surprise, N-benzylbenzamide (3a) and N-benzylpropio-
namide (4a) were isolated in 40% and 50% yields, respec-
tively, instead of the expected amide (Scheme 2). Noticeably,
the C3ÀO bond was selectively cleaved with concurrent
CÀN bond formation instead of the more activated benzylic
CÀO bond. Inspired by the result, we focused on identifying
the key structure for this unique CÀO bond cleavage.
2-Benzyloxy-1-ethanol (5), 4-benzyloxy-1-butanol (6), and
5-benzyloxy-1-pentanol (7) were also tested under the same
conditions, but only uncleaved corresponding amides 8À10
were obtained in excellent yields (Scheme 2). In the cases of
benzyl methyl ether (11) and benzyl propyl ether (12), no
reaction happened (Scheme 2). These results indicated that a
3-alkoxy-1-propanol skeleton is necessary to result in the
CÀO bond cleavage.
a 1.0 equiv of alcohol or ether and 1.1 equiv of amine were used.
[Ru] = 2.5 mol % [RuCl2(p-cymene)]2, 5 mol % N,N-diisopropylimi-
dazolium bromide (13), 5 mol % pyridine, and 15 mol % NaH.
This catalytic CÀO bond cleavage and amidation reac-
tion of 3-benzyloxy-1-propanol (1a) with benzyl amine (2a)
was further optimized (Table S1, Supporting Information).
After extensive screening, an optimized catalytic system
was identified as 5 mol % [RuCl2(benzene)]2, 5 mol % 13,
5 mol % acetonitrile, and 45 mol % NaH and used for the
following study. With the optimized conditions in hand, the
substrate scope of the reaction was studied (Table 1).
3-Benzyloxy-1-propanol (1a) reacted smoothly with 2a to
give 3a and 4a in 88% and 78% isolated yields, respectively
(entry 1). 3-Methoxy-1-propanol (1b) gave 4a in 71% yield,
and the other possible product, N-benzylformamide, was
not observed (entry 2). (NHC)Ru-catalyzed formamide
formation with methanol and amines has not been success-
ful until now.11 3-Ethoxy-1-propanol (1c) yielded 51% of
3cand 70% of 4a under open reaction conditions and an Ar
flow (entry 3). The Ru catalyzed direct amide syntheses
have been reported to perform under open conditions and
an Ar flow to facilitate removal of H2.11,12 As the boiling
point of in situ generated ethanol, a likely CÀO bond
cleavage product, is low, the reaction was run in a sealed
tube. Considerable improvement was achieved for 3c (75%
in a closed system vs 51% in an open system), and a
comparable result was obtained for 4a (70% in a closed
system vs 71% in an open system) (entry 3). These results
suggested that either an open or a closed system does not
considerably affect the efficiency of the CÀO bond clea-
vage. Substrates 1dÀh were selected to evaluate the effect of
substituents on the C1ÀC3 positions. A comparable yield
of 3a with 1a was obtained if 3-benzyloxy-2-methyl-1-
propanol (1d) was used (entry 4), while a slightly lower
yield was observed in the case of 3-benzyloxy-2-phenyl-1-
propanol (1e) (entry 5). However, C2-disubstituted 3-
benzyloxy-2,2-dimethyl-1-propanol (1f) was not reactive
fortheCÀO cleavage (entry6). Only 5% of the correspond-
ing amide N-benzyl 3-benzyloxy-2,2-dimethyl-1-propiona-
mide was isolated. These results demonstrated that at least
a hydrogen should exist at the C2 carbon of 3-alkoxy-1-
propanol. A methyl substituent on the C3 position (1g) was
effective for the CÀO bond cleavage (entry 7). Substrate 1h
with a methyl group on the C1 position worked well to
Scheme 1
(9) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681.
(10) Chen, C.; Hong, S. H. Org. Biomol. Chem. 2011, 9, 20.
(11) (a) Ghosh, S. C.; Muthaiah, S.; Zhang, Y.; Xu, X. Y.; Hong,
S. H. Adv. Synth. Catal. 2009, 351, 2643. (b) Muthaiah, S.; Ghosh, S. C.;
Jee, J. E.; Chen, C.; Zhang, J.; Hong, S. H. J. Org. Chem. 2010, 75, 3002.
(c) Zhang, Y.; Chen, C.; Ghosh, S. C.; Li, Y. X.; Hong, S. H. Organo-
metallics 2010, 29, 1374. (d) Ghosh, S. C.; Hong, S. H. Eur. J. Org. Chem.
2010, 4266. (e) Chen, C.; Zhang, Y.; Hong, S. H. J. Org. Chem. 2011, 76,
10005. (f) Zhang, J.; Muthaiah, S.; Ghosh, S. C.; Hong, S. H. Angew.
Chem., Int. Ed. 2010, 49, 6391.
(12) For other Ru catalyzed oxidative amidations directly from
alcohols and amines: (a) Naota, T.; Murahashi, S.-I. Synlett 1991,
693. (b) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790. (c) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008,
130, 17672. (d) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. Org.
Lett. 2009, 11, 2667. (e) Nova, A.; Balcells, D.; Schley, N. D.;
Dobereiner, G. E.; Crabtree, R. H.; Eisenstein, O. Organometallics
2010, 29, 6548. (f) Schley, N. D.; Dobereiner, G. E.; Crabtree, R. H.
Organometallics 2011, 30, 4174.
Org. Lett., Vol. 14, No. 12, 2012
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