Rhodium(III)-catalyzed arylation of Boc-imines via C-H bond functionalization

Article abstract of DOI:10.1021/ja109562x

The first rhodium-catalyzed arylation of imines proceeding via C-H bond functionalization is reported. Use of a non-coordinating halide abstractor is important to obtain reactivity. Aryl-branched N-Boc-amines are formed, and a wide range of functionality is compatible with the reaction.

Full text of DOI:10.1021/ja109562x

COMMUNICATION
pubs.acs.org/JACS
Rhodium(III)-Catalyzed Arylation of Boc-Imines via C-H Bond
Functionalization
Andy S. Tsai,† Michael E. Tauchert,‡ Robert G. Bergman,*,§ and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Department of Chemistry, University of California, Berkeley, California 94720, United States
§Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
S Supporting Information
b
Table 1. Screening of Reaction Conditionsa
ABSTRACT: The first rhodium-catalyzed arylation of
imines proceeding via C-H bond functionalization is
reported. Use of a non-coordinating halide abstractor is
important to obtain reactivity. Aryl-branched N-Boc-amines
are formed, and a wide range of functionality is compatible
with the reaction.
entry
catalyst
additive
solvent
% yieldb
1
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*IrCl2]2
[Cp*RuCl2]n
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
none
CH2Cl2
CH2Cl2
THF
0
55
30
0
n the area of C-H bond functionalization, arylations of
I
alkenes and alkynes have been well explored.1 In contrast,
2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOAc
AgOTs
AgBF4
analogous additions across C-O2 or C-N3-5 multiple bonds
are rare. Due to the prevalence of R-branched amines in drugs
and natural products,6 we sought a method for the arylation of
imines via C-H bond functionalization. The most closely related
transformations are Pd-catalyzed additions to N-tosyl imines that
rely on the functionalization of acidic C-H bonds.5 Herein, we
report the high-yielding 2-pyridyl-directed arylation of a wide
range of aromatic N-Boc-imines with a Rh(III) catalyst.
Our investigations focused on additions to N-Boc-imines due
to the convenience and ease of removal of the exceedingly popu-
lar Boc protecting group. As the test substrate for arylation, we
chose 2-phenylpyridine (1a) because of the pyridyl directing
group's high chemical stability and rich history in C-H function-
alization with a variety of transition metals.1d,1e,7
We began our reaction exploration with Rh(III) catalysts. This
type of catalyst has been proposed to activate C-H bonds via an
electrophilic deprotonation mechanism to generate an aryl-Rh-
(III) species.8 However, upon heating 10 mol % [Cp*RhCl2]2
(Cp* = pentamethyl cyclopentadienyl) with 2-phenylpyridine
and N-Boc-benzaldimine in CH2Cl2, no product was observed
(entry 1, Table 1). Theorizing that the lack of reactivity may be
due to the chloride ligands on the metal, which could prevent
coordination of the N-Boc-imine, AgSbF6 was added as a halide
abstractor and provided the desired product 3a in 55% yield
(entry 2).9 Utilizing coordinating solvents such as THF (entry 3)
and DMF (entry 4) resulted in lower activity, while solvents such
as benzene failed due to insolubility of the catalyst system (entry
5). Analogous iridium- (entry 6) and ruthenium-based (entry 7)
complexes were found to be inactive for this transformation.
Variable substrate stoichiometries were also explored (entries 8
and 9), with the highest yield being achieved by employing
2 equiv of the least expensive component, 2-phenylpyridine
(entry 9). Under these conditions, the excess 2-phenylpyridine
was recovered. Unreacted N-Boc-imine was not observed, and
3
4
DMF
5
C6H6
0
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
7
8c
0
60
87
trace
30
77
69
0
9d
10d
11d
12d
13d
14d
AgClO4
NaBPh4
a All reactions were performed by employing 0.05 mmol of 2-phenyl-
pyridine and 0.05 mmol of imine in 0.5 mL of solvent with 10 mol %
catalyst and 40 mol % additive. b Yields are based on NMR using 2,
6-dimethoxytoluene as an internal standard. c 0.1 mmol of imine. d 0.1 mmol
of 2-phenylpyridine.
only small amounts of the hydrolyzed aldehyde product were
detected. Other halide abstractors were also explored (entries
10-14), but AgSbF6 proved to be optimal (entry 9).
Evaluation of substituted 2-arylpyridines established that both
electron-poor and -rich derivatives are effective arylation sub-
strates and that the reaction is compatible with chloro, keto, and
acetanilido functional groups (Scheme 1). For 2-(3-methyl-
phenyl)pyridine, functionalization occurred solely para to the
methyl group to provide 3f. Multicyclic pyridine derivatives also
serve as effective directing groups, with the bicyclic quinoline and
tricyclic benzo[h]quinoline both providing the expected prod-
ucts 3g and 3h, respectively, in good yields. Notably, for all of
Received: October 24, 2010
Published: January 4, 2011
r
2011 American Chemical Society
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Journal of the American Chemical Society
COMMUNICATION
Scheme 1. Arylpyridine Substrate Scopea
Table 2. Substrate Scope of Substituted Iminesa
entry
R
protecting group
product
% yieldb
1
C6H5
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
P(O)Ph2
Ts
3a
3i
82 (70)c
77 (64)c
2
4-ClC6H4
4-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-MeC6H4
4-MeOC6H4
4-CO2MeC6H4
2-ClC6H4
2-MeC6H4
3-CHOC6H4
2-thiophene
4-MeC6H4
nBu
3
3j
77
a All reactions were performed by heating 2-phenylpyridine (2 equiv),
imine (1 equiv), [Cp*RhCl2]2 (10 mol %), AgSbF6 (40 mol %), and
CH2Cl2 (0.1 M) in a sealed tube for 20 h at 75 °C. Isolated yields are
reported.
4
3k
3l
50
95 (81)c
5
6
7d
3m
3n
3o
3p
3q
3r
70
70 (51)c
70
8
9d
10d
11
12d
13e
14f
15f
16
17
76
the 2-arylpyridine substrates, products resulting from bis-arylation
were not detected.
92
The substrate scope was further extended to a broad variety of
substituted aromatic N-Boc-imines (Table 2, entries 1-12).
Both electron-poor (entries 3, 5, 8, and 11) and electron-rich
(entry 7) aromatic imines provided branched amine products in
high yields. Substitutions at the ortho (entries 9 and 10), meta
(entry 11), and para (entries 2-8) positions were all well toler-
ated. Moreover, the reaction showed excellent functional group
compatibility, with N-Boc-imines substituted with chloro (entries 2
and 9), nitro (entry 3), methoxy (entry 7), ester (entry 8), and
even the electrophilic carboxaldehyde (entry 11) functionality all
providing branched amine products in high yields. In addition,
the 2-thienyl-substituted branched amine product 3s was ob-
tained by addition to a heteroaromatic imine substrate (entry
12). Of the functionalities evaluated, only the nitrile group (entry
4) gave a low yield, likely due to competitive coordination of the
CN group to the Rh(III) center. In support of this explanation, a
dramatic reduction in yield was observed upon addition of ben-
zonitrile to a previously successful substrate combination (see
entry 13 versus 6). While a 1:4 ratio of [Cp*RhCl2]2 to AgSbF6
gave consistently good results, we found that ratio could be de-
creased to 1:2 for most substrates with no effect on rates or yields
(see entries 7, 9, 10, and 12). However, the reaction failed to
work when the ratio was below 1:2. For more reactive imines,
good yields may be obtained with 5 mol % [Cp*RhCl2]2 (entry 5).
This lower catalyst loading provided a moderate reduction in
yields when applied to less reactive substrates as a result of
competitive imine decomposition pathways (entries 1, 2, and 7).
Further decreasing the catalyst loading to 2.5 mol % [Cp*RhCl2]2
resulted in low yields.
Alkyl N-Boc-imines were not effective substrates for this transfor-
mation as a result of self-condensation via imine-to-enamine tau-
tomerization. We therefore explored other protecting groups for
alkyl imine substrates. While N-diphenylphosphinoyl-pentaldimine
proved to be unreactive (entry 14), addition to the corresponding
N-tosyl-imine proceeded in good yield (entry 15). This result
prompted us to also evaluate the reactivity of an aromatic N-tosyl-
imine substrate, but N-tosyl-benzaldimine reacted with poor con-
version to give the branched amine 3v in only 40% yield (entry 16).
We considered that the moderate yield observed might possibly be
attributed to the reversibility of arylation of 3v. This reversibility was
demonstrated by subjecting purified 3v to the reaction conditions,
81
3s
71
3m
3t
27
0
nBu
3u
3v
3w
72
C6H5
Ts
40
C6H5
Ns
51
a All reactions were performed by heating 2-phenylpyridine (2 equiv),
imine (1 equiv), [Cp*RhCl2]2 (10 mol %), AgSbF6 (40 mol %), and
CH2Cl2 (0.1 M) in a sealed tube for 20 h at 75 °C. b Isolated yield.
c Values in parentheses correspond to isolated yields after 40 h at 75 °C
using [Cp*RhCl2]2 (5 mol %) AgSbF6 (20 mol %). d AgSbF6 (20 mol %).
e PhCN (1 equiv) added. f 2-Phenylpyridine (1 equiv).
which resulted in an equilibrium mixture of 3v, 2-phenylpyridine,
and N-tosyl-benzaldimine (eq 1),
consistent with the distribution observed in the arylation reaction
(Table 2, entry 16). Significantly, while β-aryl elimination from
aryl carbinols has been reported,10 to our knowledge, the corres-
ponding transformation for branched amines has not previously
been described. The mechanisms of β-aryl elimination for both
the previously reported carbinols and 3v are likely to be similar,
but further studies are needed. The reversibility of the reaction
could be slightly shifted toward product by replacing the N-
tosyl with the more electronegative N-nosyl11 group (entry 17).
Reversibility was not observed for the arylation products of
aromatic N-Boc-imines or aliphatic N-tosyl-pentanaldimine.
A mechanism for the arylation reaction could involve initial
electrophilic deprotonation of the o-phenyl C-H bond of 2-phenyl-
pyridine to form an Ar-Rh(III) intermediate (Scheme 2).8
Coordination of the N-Boc-imine would then activate the imine
for addition, followed by protonolysis to regenerate the catalyst.
Alternatively, rhodium could serve as a Lewis acid to activate the
imine for electrophilic aromatic substitution (EAS).12 However,
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Journal of the American Chemical Society
COMMUNICATION
Scheme 2. Proposed Catalytic Cycle
(2) Leading references on the arylation of C-O multiple bonds: (a)
Kuninobu, Y.; Nishina, Y.; Takeuchi, T.; Takai, K. Angew. Chem., Int. Ed.
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Huang, H. J. Am. Chem. Soc. 2010, 132, 3650–3651. (b) Aydin, J.; Szabꢀo,
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(6) The importance of this compound class has led to intensive
development of transition metal catalyzed additions, including enantio-
selective catalytic additions, of aryl organometallic reagents to imines.
(a) For a review on transition-metal catalyzed additions of organoboron
reagents, see: Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1535–1553. (b)
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O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.; Russell, D. R. Dalton Trans.
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in combination with [Cp*RhCl2]2: (a) Patureau, F. W.; Glorius, F. J. Am.
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this latter pathway is unlikely, given that only the electronically
deactivated ortho position is functionalized on the electron-
deficient 2-phenylpyridine. Furthermore, the observation that
the reaction is more efficient for electron-poor 2-arylpyridines
(see Scheme 1, 3b vs 3c) is inconsistent with an EAS pathway but
supports an electrophilic deprotonation mechanism.
In summary, [Cp*RhCl2]2/AgSbF6 catalyzes the addition of
2-arylpyridines to N-Boc- and N-sulfonyl-imines via C-H bond
functionalization to give branched amine products. Many com-
monly encountered functional groups, such as ketone, aldehyde,
ester, halide, trifluoromethyl, amide, and nitro groups, are com-
patible with the method. Mechanistic studies and the investigation
of alternative directing groups will be reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental details
b
and spectral data for all compounds described. This material is
available free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
rbergman@berkeley.edu; jonathan.ellman@yale.edu
’ ACKNOWLEDGMENT
This work was supported by the NIH grant GM069559 (to
J.A.E.) and by the Director, Office of Energy Research, Office of
Basic Energy Sciences, Chemical Sciences Division, U.S. Depart-
ment of Energy under contract DE-AC02-05CH11231 (to
R.G.B.). A.S.T. is grateful for an Eli Lilly Fellowship, and
M.E.T. thanks the Deutsche Forschungsgemeinschaft (DFG)
for a research fellowship (Ta 733/1-1).
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