Highly Regioselective Amination of
Unactivated Alkanes by Hypervalent
Masahito Ochiai,1 Kazunori Miyamoto,1 Takao Kaneaki,1 Satoko Hayashi,2 Waro Nakanishi2*
Amination of alkanes has generally required metal catalysts and/or high temperatures. Here we
report that simple exposure of a broad range of alkanes to N-triflylimino-l3-bromane 1 at ambient
temperature results in C–H insertion of the nitrogen functionality to afford triflyl-substituted
amines in moderate to high yields. Marked selectivity for tertiary over secondary C–H bonds was
observed; primary (methyl) C–H bonds were inert. Addition of hexafluoroisopropanol to inhibit
decomposition of 1 dramatically improved the C–H amination efficiencies. Second-order kinetics,
activation parameters (negative activation entropy), deuterium isotope effects, and theoretical
calculations suggest a concerted asynchronous bimolecular transition state for the metal-free
C–H amination event.
Direct and selective functionalization of alkane C–H bonds constitutes a long- standing goal in synthetic organic chemistry (1–5). Alkanes are major constituents of
petroleum and natural gas, but they are relatively
inert and tend to be functionalized on a commercial scale through an inefficient sequence of
overoxidation followed by reduction. Over the
past several decades, however, substantial progress has been reported, primarily through the
use of transition metal–catalyzed processes.
We focus here on the selective transformation
of ubiquitous but unactivated aliphatic (sp3) C–H
bonds to amines and amides. Both free-nitrene
insertions and metal-nitrenoid aminations have
been reported (Fig. 1A); in general, however, free-nitrene processes are unselective and uncontrollable and, as a result, are of little synthetic value.
Therefore, the discovery by Breslow and Gellman
of the capacity of Mn and Fe tetraphenylporphyrin
complexes to catalyze the tosylamination of cyclohexane (2b) using N-tosylimino-l3-iodane was
a promising development (6). Recently, Fiori et al.
and some other groups greatly extended this methodology and have found an efficient method for
Rh-catalyzed high-yield amination of 2b using
in situ–generated imino-l3-iodane, indicating the
powerful nature of the transition metal–catalyzed
amination of aliphatic C–H bonds (7–10).
Hypervalent aryl-l3-bromanes exhibit higher
reactivity compared with aryl-l3-iodanes (the l3
notation indicates that the bromine and iodine
centers exceed their standard valence by two) (11).
This is probably due to the greater electroneg-
ativity as well as the larger ionization potential of
bromine relative to iodine (12–14). Recently, we
reported synthesis of hypervalent N-(trifluoromethyl-
sulfonyl)imino-l3-bromane 1 (15); the iminobromane
1 serves as an active organo nitrenoid species and
directly undergoes stereospecific aziridination
of olefins with retention of stereochemistry and
transylidation to iodobenzenes, pyridines, and sul-
fides (16). In marked contrast to the reactions of
imino-l3-iodanes, all of these reactions do not
require the use of any transition-metal catalysts
and proceed smoothly, even at room temperature.
These results suggest that 1 might be a more ac-
tive aminating agent of aliphatic C–H bonds,
perhaps even obviating the need for a catalyst.
(Y: leaving group)
1Graduate School of Pharmaceutical Sciences, University of
Tokushima, 1-78 Shomachi, Tokushima 770-8505, Japan. 2De-
partment of Material Science and Chemistry, Faculty of Systems
Engineering, Wakayama University, 930 Sakaedani, Wakayama
*To whom correspondence should be addressed. E-mail:
+ 25 °C
Ar ( )n
n = 1 yield: (92%)
Fig. 1. (A) Strategy for
unactivated C–H amination.
R, arenesulfonyl, alkanesul-fonyl, alkoxysulfonyl, alk-oxycarbonyl, etc. (B) C–H
1 under metal-free conditions at room temperature.
Yields shown in parentheses
were determined by GC;
otherwise, isolated yields
are reported. Tf = CF3SO2.
1 (0.01 M)