Fe-catalyzed oxidative coupling of heteroarenes and methylamines

Full text of DOI:10.1002/asia.200900157

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DOI: 10.1002/asia.200900157
Fe-Catalyzed Oxidative Coupling of Heteroarenes and Methylamines
Masaki Ohta,[a] Matthias P. Quick,[b] Junichiro Yamaguchi,[a] Bernhard Wꢀnsch,*[b] and
Kenichiro Itami*[a]
À
À
Benzylic amines are ubiquitous structural constituents in
pharmacologically important molecules with many interest-
ing actions (Figure 1).[1] Classically, benzylic amines have
system for the oxidative C H/C H cross-coupling of elec-
tron-rich heteroarenes and methylamines.[4]
We embarked on the goal of developing new methods for
benzylic amine synthesis taking inspiration from the impor-
tant contributions of Murahashi[5] and Li[6], who clearly
À
demonstrated that certain a-C H bonds in amines can be
oxidatively functionalized through the utilization of a transi-
tion metal such as ruthenium or copper.[7] For example,
À
Murahashi has established that tert-butyldioxylation of a-C
H bonds of amines can be accomplished by treatment with
tBuOOH in the presence of catalytic amounts of RuCl2
AHCTUNGTRENNUNG
(PPh3)3.[8] Similarly, a-methoxylation (with MeOH)[9] and a-
cyanation (with NaCN)[10] of tertiary amines can be carried
out with related Ru catalyst/oxidant systems. Li has estab-
lished that the combination of CuBr and a stoichiometric
Figure 1. Representative drugs with benzylic amine structure.
À
oxidant can promote the functionalization of a-C H bonds
of amines by various carbon nucleophiles such as terminal
alkynes, nitroalkanes, and activated methylene com-
pounds.[11] Although the precise mechanisms of these inter-
esting catalytic processes remain unknown, metal-bound
iminium species generated by the interaction of an amine
and a transition metal have been proposed to be involved as
key intermediates. Thus, we surmised that such iminium spe-
cies could be trapped by nucleophilic heteroarenes furnish-
ing the corresponding benzylic amines (Figure 2).[12]
We began our study by applying the catalytic conditions
established by Murahashi, (RuCl3/O2) and Li (CuBr/
tBuOOH) for the reaction of 3-methoxythiophene (1A) and
N,N-dimethylbenzylamine (2a) (Table 1). Unfortunately,
been elaborated by the nucleophilic substitution reaction of
amines with benzylic halides and related processes. With the
advent of high-throughput chemistry, an efficient, straight-
forward, and diversity-oriented synthetic method toward
this class of compounds is in high demand. As part of our
program aimed at accessing privileged organic structures
through direct C H bond functionalization,[2,3] we attempted
À
to develop a new catalyst for the synthesis of benzylic
amines. Herein, we describe a new iron-based catalytic
[a] M. Ohta, Dr. J. Yamaguchi, Prof. Dr. K. Itami
Department of Chemistry
À
À
these conditions did not afford the expected C H/C H cou-
Graduate School of Science
Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
Fax : (+81)52-788-6098
E-mail: itami@chem.nagoya-u.ac.jp
[b] M. P. Quick, Prof. Dr. B. Wꢀnsch
Institut fꢀr Pharmazeutische und Medizinische Chemie
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
48149 Mꢀnster (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900157.
Figure 2. Synthesis of benzylic amines through oxidative cross-coupling
reaction of arenes and methylamines.
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Chem. Asian J. 2009, 4, 1416 – 1419

Table 1. Discovery of oxidative cross-coupling of heteroarenes and methylamines.
that picolylamide 4 is superior
to bipy furnishing 3Aa in 64%
yield (entry 8).
With a new iron-based cata-
lytic system for the oxidative
cross-coupling in hand, we
next examined the cross-cou-
pling using other substrates to
gain a rough grasp of the scope
Conditions
Yield of 3Aa
RuCl3 (5%), O2 (1 atm), MeOH/HOAc, 608C, 12 h (Murahashiꢃs conditions: Ref. [10])
CuBr (5%), tBuOOH (1.3 equiv), neat, 508C, 12 h (Liꢃs conditions: Ref. [12])
RuI3 (5%), pyridine N-oxide (2 equiv), MeCONHMe, 1308C, 24 h
<1%
<1%
59%
FeCl2 (10%), pyridine N-oxide (2 equiv), MeCONMe2, 1308C, 24 h
24%
of
the
current
method
(Figure 3). In this study, the
pling product 3Aa. After extensive screening of conditions,
a new ruthenium-based system was identified. In the pres-
ence of RuI3 (5 mol%) and pyridine N-oxide (2 equiv), 1A
(1 equiv) and 2a (2.5 equiv) underwent cross-coupling in
MeCONHMe at 1308C to yield 3Aa in 59% yield (Table 1).
More interestingly, we also found that the combination of
FeCl2/C5H5N-O/MeCONMe2 also promoted the desired cou-
pling reaction, albeit with lower efficiency (24%).[13] It
should be mentioned that Li and Li have recently reported
À
À
that iron can catalyze the oxidative C H/C H cross-cou-
pling of alkanes and 1,3-dicarbonyl compounds.[14–16]
Considering the obvious advantages of ubiquitous and
cheap iron salts,[17] further optimization was conducted with
the iron-based catalytic system (Table 2). The use of
Table 2. Optimization of Fe-catalyzed coupling of 1A and 2a.[a]
Entry
Fe salt
Additive
Yield [%][b]
1
2
3
4
5
6
7
8
FeCl2
FeCl2·4H2O
FeF2
FeBr2
FeI2
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
–
–
–
–
24
24
9
29
54 (53)
46
60 (60)
64
Figure 3. Substrate scope.[a]
–
optimized FeCl2·4H2O/KI/bipy/C5H5N-O system was em-
ployed. Other than simple tertiary methylamines, N,N-dime-
thylglycine ethyl ester (2b) also reacted with 1A at the
KI (20%)
KI (20%), bipy (10%)
KI (20%), 4 (20%)
À
methyl C H bond giving 3Ab. Interestingly, the coupling
did not take place with trialkylamines such as tri
A
mine (2c). As exemplified in Figure 3, the present coupling
À
[a] Conditions: 1 A (1.0 mmol), 2a (2.5 mmol), pyridine N-oxide
(2.0 mmol), Fe salt (0.1 mmol), DMAc (0.5 mL), 1308C, 24 h. [b] Deter-
mined by GC analysis using n-undecane as an internal standard. Isolated
yield is given in parenthesis.
reaction took place predominantly at N-methyl C H bonds
in the presence of other reactive bonds including the more
À
À
acidic benzylic C H (in 2a) and the C H bond a to the car-
bonyl group (in 2b).[13] The high selectivity for “N-methyl”
substituents is interesting considering that chemoselective
demethylation of N-methyl tertiary amines is catalyzed by
cytochrome P-450.[18]
Although the simple (unsubstituted) thiophene was found
to be a poor heteroarene coupling partner, 2-methoxythio-
phene (1B) reacted with 2a to give the corresponding ben-
zylic amine 3Ba in 47% yield (Figure 3). Similarly, 2,3-di-
methylfuran (1C) cross-coupled with 2a in 40% yield. In all
of these examples, the coupling proceeded selectively at the
a-position of the thiophene or furan ring. Further investiga-
FeCl2·4H2O, which is considerably cheaper than its anhy-
drous form, provided 3Aa in 24% yield (entry 2). Subse-
quent examination of various iron halides led to the finding
that FeI2 is a much better catalyst precursor, producing the
coupling product in 54% yield (entry 5). Along these lines,
we finally identified that the coupling proceeds equally well
with FeCl2·4H2O catalyst when KI and 2,2’-bipyridyl (bipy)
are added as additives (entry 7). Further examination by the
addition of supporting ligands on iron also led to the finding
Chem. Asian J. 2009, 4, 1416 – 1419
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B. Wꢀnsch, K. Itami et al.
COMMUNICATION
tion of alternative heteroarenes uncovered that the coupling
using indoles results in a complex mixture under the influ-
ence of the FeCl2·4H2O/KI/bipy/C5H5N-O system. After re-
investigating the conditions, it was found that the use of
aqueous H2O2 solution (30%) in place of pyridine N-oxide
furnishes the desired cross-coupling product at lower tem-
perature (808C). For example, the coupling of N-methylin-
dole (1D) and 2a afforded 3 Da in 61% isolated yield. Simi-
larly, the reaction using N-methyl-7-azaindole (1E) provided
the corresponding aminomethylated product 3Ea in 56%
yield.
ity of 6 toward s1 receptor is promising as a lead for further
optimization.[20]
In summary, we have developed a new iron-based catalyt-
ic system for the oxidative cross-coupling of electron-rich
heteroarenes and methylamines. The successful identifica-
tion of a new ligand family for the s1 receptor speaks well
for the potential of the present iron catalysis in a range of
applications. Future work will be devoted to mechanistic in-
vestigations and the development of highly active second-
generation catalyst.
Having developed a new protocol for making benzylic
amines from readily available coupling partners (heteroar-
enes and methylamines), we next surmised that a pharma-
ceutical relavant structure can be created by our method.
Given that benzazepines and their bioisosteres are potent li-
gands for s- and NMDA receptors,[19] we examined the in-
Experimental Section
Typical Procedure for Fe-Catalyzed Oxidative Coupling of Heteroarenes
and Methylamines
A 20 mL glass vessel equipped with a J. Young O-ring tap and containing
a magnetic stirring bar was dried with a heatgun under vacuum and filled
with argon after cooling to room temperature. To this vessel were added
FeCl2·4H2O (19.8 mg, 0.10 mmol), KI (33.4 mg, 0.20 mmol), 2,2’-bipyridyl
(15.6 mg, 0.10 mmol), pyridine N-oxide (190.2 mg, 2.0 mmol), 3-methoxy-
thiophene (1A: 114.2 mg, 1.0 mmol), N,N-dimethylbenzylamine (2a:
338.0 mg, 2.5 mmol), and N,N-dimethylacetamide (DMAc: 0.5 mL). The
vessel was sealed with an O-ring tap and then heated at 1308C for 24 h
in an 8-well reaction block with stirring. After cooling the reaction mix-
ture to room temperature, Et2O (2 mL) was added to the mixture, fol-
lowed by filtration through Celite (washed with Et2O). The filtrate was
washed with water (5 mLꢄ3) and brine (5 mLꢄ2). The combined organic
layer was dried over Na2SO4 and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (hexane/
EtOAc=3:1) to afford 3Aa (147.9 mg, 60% yield) as a colorless oil.
À
À
tramolecular C H/C H coupling for the generation of ben-
zazepine-like bicyclic nitrogen heterocycles (Figure 4). Thus
Acknowledgements
This work was supported by a Grant-in-Aid for Priority Areas “Chemis-
try of Concerto Catalysis” from MEXT (Japan). Funding of a doctoral
fellowship to M.P.Q. by the Deutsche Forschungsgemeinschaft within the
International Research Training Group Mꢀnster–Nagoya “Complex
Functional Systems in Chemistry: Design, Synthesis and Applications” is
gratefully acknowledged.
À
À
Figure 4. Intramolecular C H/C H coupling leading to a new s1-receptor
ligand.
À
Keywords: C H functionalization · heterocycles · iron ·
cross-coupling · oxidation
the thiophene 5 having a tethered methylamino group was
prepared and subjected to the Fe-catalyzed reaction. Al-
though the efficiency was not satisfactory under the current
conditions, the target bicyclic product 6 was formed in 27%
GC yield (isolated in 7% yield after extensive purification
suitable for biological testing). The low efficiency might
arise from the general difficulty of cyclizing a seven-mem-
bered ring.
Nevertheless, with the target compound 6 in hand, we in-
vestigated its affinity and selectivity towards s1, s2, and
NMDA receptors. The receptor binding affinities were de-
termined by competition experiments with radioligands;
[3H]-(+)-pentazocine (s1 receptor), [3H]-di-o-tolylguanidine
(s2 receptor), and [3H]-MK-801 (NMDA receptor). Com-
pound 6 showed affinity toward s1 receptors (Ki =320 nm)
and s2 receptors (Ki =657 nm), while there was essentially
no affinity toward the NMDA receptor (the inhibition at
1 mm was 17%). Though not excellent, a good binding affin-
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Chem. Asian J. 2009, 4, 1416 – 1419

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Received: April 29, 2009
Published online: July 20, 2009
Chem. Asian J. 2009, 4, 1416 – 1419
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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