Rh2(II)-catalyzed intramolecular aliphatic C-H bond amination reactions using aryl azides as the N-atom source

Article abstract of DOI:10.1021/ja301519q

Rhodium(II) dicarboxylate complexes were discovered to catalyze the intramolecular amination of unactivated primary, secondary, or tertiary aliphatic C-H bonds using aryl azides as the N-atom precursor. While a strong electron-withdrawing group on the nitrogen atom is typically required to achieve this reaction, we found that both electron-rich and electron-poor aryl azides are efficient sources for the metal nitrene reactive intermediate.

Full text of DOI:10.1021/ja301519q

Communication
pubs.acs.org/JACS
Rh2(II)-Catalyzed Intramolecular Aliphatic C−H Bond Amination
Reactions Using Aryl Azides as the N-Atom Source
Quyen Nguyen, Ke Sun, and Tom G. Driver*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S
* Supporting Information
studies suggest that C−N bond formation occurs via a 4π-
electron-5-atom electrocyclization.5b In contrast, aliphatic C−H
ABSTRACT: Rhodium(II) dicarboxylate complexes were
discovered to catalyze the intramolecular amination of
bond amination requires metal-catalyzed C−H insertion or H-
unactivated primary, secondary, or tertiary aliphatic C−H
atom abstraction mechanismsprocesses that have remained
elusive to control using aryl azides as the N-atom source.6
bonds using aryl azides as the N-atom precursor. While a
strong electron-withdrawing group on the nitrogen atom is
typically required to achieve this reaction, we found that
both electron-rich and electron-poor aryl azides are
efficient sources for the metal nitrene reactive intermedi-
ate.
In search of the optimal conditions to achieve intramolecular
aliphatic C−H bond amination using aryl azides, the reactivity
of o-tert-butylaryl azide 1a toward transition metal complexes
was examined (Table 1).7 This aryl azide is relatively thermally
Table 1. Development of Optimal Conditions
he development of transition metal-catalyzed aliphatic C−
T
H bond amination reactions that are stereoselective, use
readily accessible starting materials and catalysts, and are
environmentally benign continues to inspire the efforts of
research groups around the world.1,2 While considerable
progress has been made, the current methods are still limited
by the oxidative conditions to form the nitrene and the
requirement for strong electron-withdrawing groups on the
nitrene (Scheme 1). The use of azides as the N-atom source
a
b
entry
catalyst
additive
conv, %
yield, %
0
1
none
n.a.
0
0
c
2
FeBr2
n.a.
dec
3
CuBr
n.a.
0
0
0
0
0
4
CoTPP
n.a.
0
5
RuCl3·nOH2
[Ir(cod)OMe]2
[Rh(cod)OMe]2
Rh2(O2CC7H15)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
n.a.
0
6
n.a.
0
Scheme 1. Nitrogen Substituent Requirements for Aliphatic
C−H Bond Amination
c
7
n.a.
10
35
99
99
99
99
99
0
8
n.a.
35
75
9
n.a.
10
11
12
13
Boc2O
Ac2O
Bz2O
Tf2O
90
83
aniline
aniline
a
b
As determined using 1H NMR spectroscopy. Isolated after silica gel
c
chromatography. Aniline formed.
robust, with no reaction observed at 120 °C (entry 1).8
Exposure of 1a to commercially available transition metal
complexes known to catalyze N-atom-transfer reactions was
met with limited success. Indoline 3a was not observed in the
presence of iron,9 copper,10 cobalt,2b,4a−c ruthenium,2a,6,11 or
iridium12 complexes (entries 2−6). Partial conversion to
indoline 2 was observed when rhodium octanoate was used
(entry 8). We anticipated that the partial conversions resulted
from catalyst decomposition, and we found that using more
would address these limitations because no oxidant would be
required and the only byproduct of the reaction would the
environmentally benign N2 gas.3 While azides have been used
for a variety of N-atom-transfer reactions,2b,4 these trans-
formations also require electron-withdrawing groups on the
azide. We anticipated that a more general, complementary
solution for aliphatic C−H bond amination might emerge if
conditions were found to use electron-neutral aryl azides as the
N-atom source. While we have reported a number of sp2 C−H
bond amination reactions using aryl azides,5 our mechanism
13
thermally robust Rh2(esp)2 improved both the conversion
and yield of the process (entry 9). Examination of alternative
solvents, concentration, and temperatures, however, did not
Received: February 15, 2012
Published: April 21, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
increase the yield, and control experiments revealed that
oxidative decomposition of the indoline occurred during
purification.
Table 3. Scope and Limitations of Indoline Formation
To improve the isolated yield of the amination reaction, in
situ protection of the nitrogen atom was attempted. In line with
our assumption, we found that the reaction yield was improved
when the indoline was protected with either a Boc or Ac group
(entries 10 and 11). The reaction outcome appeared to
correlate with the pKa of the acid byproduct of the protection
reaction: aniline was produced when the stronger benzoic and
triflic acids were produced (entries 12 and 13).14
Using these optimal conditions, the electronic and steric
constraints of the aliphatic C−H bond amination reaction were
investigated (Table 2). In contrast to existing amination
Table 2. Scope and Limitations of Indoline Formation
a
entry
1
R
yield, %
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
84
63
54
64
70
54
58
73
OMe
Me
CH2CH2Ph
CHCHPh
Ph
1g
1h
3,5-OMe2C6H3
Br
a
Isolated after silica gel chromatography.
processes,2,4 our method does not require an electron-
withdrawing group on the nitrogen: aryl azides bearing para-
electron-releasing, -neutral, or -withdrawing groups were
converted to indolines. Illustrating the chemoselectivity of
our process, olefins were tolerated as substituents (entry 5).
To further examine the scope of the transformation, the
identity of the ortho-alkyl substituent was varied (Table 3).
While replacing one of the methyl groups with an ester group
did not diminish the yield (entry 1), substitution with hydrogen
reduced the reaction efficiency (entry 2). Amination can be
achieved at tertiary and secondary C−H bonds, although
dehydrogenation of 5d occurred to afford indole. Dehydrogen-
ation could be circumvented if an additional substituent was
introduced at the benzylic position on the aryl azide.
Submission of 4e−4k to reaction conditions produced
indolines as single diastereomers (entries 5−11). In contrast,
pyrolysis of aryl azide 4g was reported by Smolinsky to produce
a 1:1 mixture of diastereomers.15 Although reaction with the
methyl C−H bond in azide 4l could produce a six-membered
ring, only amination of the methyl C−H bond was observed to
afford indoline 5l as the sole product. While single
diastereomers were obtained from substrates bearing o-
cyclopentyl or cyclohexyl groups, diminished stereoselectivity
was observed with o-cycloheptyl-substituted aryl azide 4m
(entry 13).
a
b
c
Isolated after silica gel chromatography. 20% aniline observed. 30%
aniline observed.
mediate a reversible one-electron oxidation to generate free
nitrene,19 our current mechanistic hypothesis is that the nitrene
remains metal bound for the C−H bond amination step since
pyrolysis involving free nitrene is not diastereoselective.15 The
mechanism of the amination step could be stepwise or
concerted: hydride20 or H-atom abstraction16a,21 (to form 9
or 10) followed by recombination produces the C−N bond;
alternatively this bond could be formed through the concerted
While indoline formation could occur through several
different mechanisms,10a,16 our reactivity trends suggest that
C−N bond formation occurs through N-atom transfer (Scheme
2). Coordination of the rhodium(II) carboxylate to either the
α- or γ-nitrogen of the aryl azide produces 7.17 Extrusion of N2
then forms the rhodium nitrene 8.18 While rhodium could
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Journal of the American Chemical Society
Communication
stepwise C−H bond amination, two diastereomers of 2-
phenylindoline (dr 50:50) and an intramolecular kinetic isotope
effect (KIE) of 6.7 were observed.23 The magnitude of this
isotope effect is significantly smaller than for reactions involving
an H-atom abstraction by an aryl nitrene21 or an aryl metal
nitrene6c (kH/kD = 12−14), but larger than hydride shift
reactions (kH/kD ≈ 2 for Cannizzaro reaction and Meerwein−
Ponndorf−Verley reduction).24−26 Smaller KIEs were observed
at lower reaction temperatures, revealing that our amination
reaction occurs above the isokinetic temperature and, as a
consequence, is under entropic control.27,28 We found,
however, that the spatial constraints of this reaction override
these isotope effects: cyclopentanone-derived aryl azide 17-d1
reacted preferentially with the syn-C−D bond to form 18
exclusively.29
Scheme 2. Possible Mechanisms for Intramolecular Aliphatic
C−H Bond Amination from Aryl Azides
In conclusion, we have developed an efficient and
diastereoselective rhodium(II)-catalyzed aliphatic C−H bond
amination reaction that uses an aryl azide as the N-atom source.
Our method distinguishes itself from previously reported
aliphatic C−H bond amination reactions by not requiring a
strong electron-withdrawing group on the nitrogen atom. The
reactivity of stereospecific labeled aryl azides revealed that the
amination reaction occurred stepwise with the syn-C−H bond.
Our current aims are to more deeply examine the nature of the
catalytic intermediates in this C−H bond amination reaction
and to extend this newfound reactivity of aryl azides to the
stereoselective synthesis of complex, functionalized N-hetero-
cycles.
insertion16c,22 of the metal nitrene into the proximal C−H
bond via transition state 11. Finally, the indoline is produced
upon dissociation of the rhodium complex from 12.
Insight into the initial steps of the catalytic cycle was
provided by the reactivity of 4-substituted aryl azides toward
reaction conditions (eq 1). Underscoring the difference
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic and analytical data
for the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
between our method for aliphatic C−H bond amination and
others, we found that more electron-rich aryl azides (e.g., 1b)
were more reactive to the reaction conditions. The increased
reactivity of 1b relative to 1a could be due to either preferred
coordination of 1b to Rh2(esp)2 or an accelerated N2 extrusion
from the resulting azide−metal complex 7.
AUTHOR INFORMATION
■
Corresponding Author
tgd@uic.edu
Notes
To examine the nature of the C−H bond cleavage step, two-
labeled aryl azides were examined (Scheme 3). We anticipated
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 3. Isotope Labeling Studies
We are grateful to the National Institutes of Health NIGMS
(R01GM084945) and the University of Illinois at Chicago for
their generous financial support. We thank Mr. Furong Sun
(UIUC) for high-resolution mass spectrometry data.
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