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M. A. Letavic, K. S. Ly / Tetrahedron Letters 48 (2007) 2339–2343
O
R1
R1
[Pd], Mo(CO)6, DBU, solvent,
R3
R3
X
+
HN
N
R2
R2
15 min, air, 100-175 oC, microwave
Scheme 1. Aminocarbonylation reactions of aryl halides.
semi-automated conditions desirable for medicinal
chemistry.9 These studies have also demonstrated that
the reactions can be done in THF or water,10 providing
an alternative to organic solvents. The reaction condi-
tions appear to be quite general, allowing for the prepa-
ration of a variety of benzamides.
yl-piperazine (Table 1, entry 3) was also conducted at
100 °C, with or without added DBU (Scheme 3). Not
surprisingly, the reaction did not proceed in the absence
of DBU. Under the standard conditions at 100 °C, 58%
of the coupling product was obtained and at higher tem-
perature (150 °C) the yield was 76%, indicating that
125 °C is near optimal for this reaction.
Benzamide intermediates are quite useful for a variety of
applications, however, many medicinal chemistry appli-
cations also require the preparation of heteroaromatic
amide intermediates. We were particularly interested in
heterocycle amides related to the potent histamine H3
antagonists 1 and 2.11 Notably, very few heteroaromatic
amides have been prepared using this type of amino-
carbonylation methodology. There are a few examples
of bromothiophenes7,8,10 participating in these reactions
and there are examples of heteroaromatic halides parti-
cipating in aminocarbonylation reactions using carbon
monoxide as a CO source,12,13 however, we have not
found other examples of microwave assisted aminocarb-
onylations of heteroaromatic halides using the more
convenient Mo(CO)6 as a CO source.
Table 1 shows the aryl bromides and amines used to
prepare entries 1–16. Yields ranged from 34% to 97%.
The reaction 1-isopropylpiperazine worked well with
2- and 5-bromopyridines (entries 1, 3 and 5), and
5-bromopyrimidines (entries 2, 4 and 6). It is interesting
to note that in contrast to the reaction of 2-bromo-
pyridine (entry 1) which gave the amide, 2-bromopyrimi-
dine reacted with 1-isopropylpiperazine to give the
aminopyrimidine (52%, entry 10) indicating that the
2-bromopyrimidine reacts with the amine prior to palla-
dium insertion. No products of carbonyl insertion were
isolated from this reaction.
Other heterocycles that gave moderate yields of hetero-
cyclic amides include 3-bromoisoquinoline (entry 11)
and 4-bromoindole (entry 13). The yield for the latter
reaction was low, however, palladium catalyzed cou-
pling reactions of unprotected indoles are not widely
reported, likely due to unwanted side reactions under
normal coupling conditions.
O
O
N
N
N
N
N
N
N
N
N
1
2
histamine H3 Ki=1 nM
histamine H3 Ki=4 nM
Advances in this area include a recent report on the
aminocarbonylation of unprotected indoles in the pres-
ence of palladium, a bidentate ligand and carbon mon-
For our purposes, we required a quick, simple, and gen-
eral method for the conversion of heteroaromatic bro-
mides to amides. Preliminary studies in our group
indicated that aminocarbonylations using microwave
irradiation might provide a viable alternative to either
the two step process of preparing the heteroaromatic
acids and coupling with amines or the alternative
aminocarbonylation using carbon monoxide. We now
report the aminocarbonylation of a variety of commer-
cially available heteroaromatic bromides in order to
demonstrate the utility of this reaction.
O
R
(a)
R
Br
HN
R
Het
N
R
+
Het
HN
HN
HN
N
N
O
H2N
N
O
O
The general reaction is shown in Scheme 2. The reactions
were typically done at 125 °C with microwave heating for
6 min. The palladium source for these reactions was
trans-di-l-acetatobis[2-(di-o-tolylphosphino)benzyl]di-
palladium(II) (3). In all cases tri-tert-butylphosphonium
tetrafluoroborate was used as a preligand and DBU as a
base. Typically, the reactions were concentrated and
chromatographed on silica gel without further work-
up.14
A
B
C
D
Ar
O
Pd
Ar
O
Pd
O
Ar
P
P
O
Ar
Ar= o-tolyl
3
Scheme 2. Aminocarbonylation reactions. Reagents and conditions:
(a) 3, t-Bu3PHBF4, DBU, A–D, Mo(CO)6, THF, microwave, 125 °C,
6 min.
During the course of optimization of this procedure, the
reaction of 5-bromo-2-methoxypyridine with 1-isoprop-