Microwave-enhanced aminocarbonylations in water

Article abstract of DOI:10.1021/ol0512031

(Chemical Equation Presented) Aryl bromides can be rapidly converted to the corresponding secondary and tertiary benzamides in water. By using Mo(CO) ₆ as the source of carbon monoxide, aminocarbonylations were conducted under air after only 10

Full text of DOI:10.1021/ol0512031

ORGANIC
LETTERS
2
005
Vol. 7, No. 15
327-3329
Microwave-Enhanced
Aminocarbonylations in Water
Xiongyu Wu and Mats Larhed*
3
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala
Biomedical Center, Uppsala UniVersity, P.O. Box 574, SE-751 23 Uppsala, Sweden
mats@orgfarm.uu.se
Received May 23, 2005
ABSTRACT
Aryl bromides can be rapidly converted to the corresponding secondary and tertiary benzamides in water. By using Mo(CO)
6
as the source
of carbon monoxide, aminocarbonylations were conducted under air after only 10 min of high-density microwave heating.
The development of metal-catalyzed organic transformations
large amounts of organic solvents are consumed in both lead
generation and lead optimization work. Thus, there is a
definite request for aqueous methods.
1
,2
9
in water has become an important research area just as
microwave-enhanced procedures have proved to possess a
high utility due to great reaction control and high reaction
rates.3 Among the different solvent alternatives in organic
Palladium(0)-catalyzed coupling reactions utilizing aryl
halides as arylmetal precursors are among the most important
-5
6
10
chemistry, water is extremely cheap and nontoxic. In
methods in modern organic synthesis. Such transformations
addition to these two general advantages, several benefits
for the reaction are expected when using water as reaction
medium for microwave-superheated protocols. First, water
is rapidly heated by microwave irradiation to high reaction
temperatures, enabling water to act as a less polar pseudo-
include cross-coupling reactions, Heck reactions, Buchwald-
Hartwig couplings, Sonogashira couplings, carbonylation
1
0
reactions, and many others. Today, most of these reaction
11
types have been carried out both in aqueous media and
1
2
under controlled microwave irradiation.
7
organic solvent. Second, precise control of the reaction
An increasing number of palladium-catalyzed protocols
have also been performed in microwave-heated water.1
Palladium-catalyzed carbonylation of aryl halides affords
3-15
temperature is easily achieved because of the very high heat
capacity of water. Third, the lack of flammable properties
makes the use of water safe also with pressurized exothermic
1
6,17
different benzoic acid derivatives.
Depending on the
7
reactions.
nucleophile employed, aromatic acids, amides, esters, or
In addition, there is a need to implement more sustainable
methods, not only for large-scale production but also for lab-
scale medicinal chemistry research. Although the aim of
(
(
(
8) Strauss, C. R. Aust. J. Chem. 1999, 52, 83-96.
9) Sheldon, R. A. CHEMTECH 1994, 24, 38-47.
8
10) Handbook of Organopalladium Chemistry for Organic Synthesis;
developing novel pharmaceutical drugs is commendable,
Negishi, E.-i., Ed.; Wiley-Interscience: New York, 2002.
11) Shaughnessy, K. H.; DeVasher, R. B. Curr. Org. Chem. 2005, 9,
(
5
85-604.
(
1) Sinou, D. Top. Curr. Chem. 1999, 206, 41-59.
(12) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
(2) Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305-
717-727.
3
17.
(13) Wang, J. X.; Hu, Z.; Wei, B. G.; Bai, L. J. Chem. Res., Synop.
(
3) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-6284.
2000, 484-485.
(4) Lidstr o¨ m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
(14) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 888-892.
(15) Arvela, R. K.; Leadbeater, N. E. J. Org. Chem. 2005, 70, 1786-
1790.
5
7, 9225-9283.
5) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb.
Chem. 2002, 4, 95-105.
6) Andrade, C. K. Z.; Alves, L. M. Curr. Org. Chem. 2005, 9, 195-
18.
7) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665-1692.
(
(16) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W. J.
Mol. Catal. A 1995, 104, 17-85.
(17) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6, 1097-
1119.
(
2
(
1
0.1021/ol0512031 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/24/2005

Scheme 1. Mo(CO)
6
-Mediated Aminocarbonylation in Water
Table 2. Fast Aminocarbonylation of Aryl Bromides with
n-Butylamine or Piperidine in Watera
aldehydes are smoothly obtained. Noteworthy, all disclosed
aqueous carbonylations of aryl halides have up to now
provided only the hydroxycarbonylation product (the benzoic
18-21
acid).
As an effort in the development of complementary
carbonylation reactions in pure water, we examined the
potential of carrying out aminocarbonylations with high
efficiency. We now wish to report the first protocol for
aminocarbonylation of aryl bromides in water. All presented
examples were performed after only 10 min of microwave
2
2,23
6
heating and with Mo(CO) alone as the CO source.
We started our development of an aqueous amidation
protocol by examining the reported conditions for microwave-
promoted aminocarbonylations using Mo(CO)
ladium catalysis. Aiming for a thermostable catalytic system
6
and pal-
24
25
and mild reaction conditions, Herrmann’s palladacycle was
selected as a suitable Pd(0) source and Na CO was chosen
2
3
as a weak base (Scheme 1). The reactions were in all cases
executed on a 1.0-mmol scale and heated in sealed vessels
under an atmosphere of air. As shown in Table 1, 1-naphthyl
bromide (1g) was reacted in different ratios with n-butyl-
amine (2a) at 170 °C, delivering the expected amide product
3g, accompanied by different amounts of the competing
hydroxycarbonylation product 1-naphthoic acid (4g). The
outcome of the reaction depended, as expected, on the varied
1g/2a stoichiometry, and in the complete absence of 2a, the
aromatic acid was the only isolated product (Table 1).
Increasing the amount of 1g afforded higher and higher yields
of 3g (from 62% up to 81%), although competing hydroxy-
carbonylation also profited. To conclude the chemical
optimization, the conditions utilizing a 2:1 ratio of 1g/2a
were selected as our standard protocol despite the fact that
a higher aryl bromide concentration afforded sligthly im-
proved yields of amide 3g.
Table 1. Selective Formation of Aromatic Amide or Acid by
Fast Carbonylation Reactions in Watera
1
-naphthyl
n-butyl-
amine (2a)
isolated yield
of amide (3g)
isolated yield
of acid (4g)
a
bromide (1g)
1.0 mmol 2, 2.0 of equiv 1a-h, 0.5 equiv of Mo(CO)6, 3.0 equiv of
Na2CO3, 5 mol % palladacycle, 2.0 mL of H2O, microwave irradiated under
1
1
1
1
2
5
.0 mmol
.0 mmol
.0 mmol
.2 mmol
.0 mmol
.0 mmol
0
67%
10%
10%
0.12 mmol
0.29 mmol
0.38 mmol
air at 170 °C for 10 min; >95% purity by GC-MS. b 180 °C for 10 min.
2.0 mmol
5.0 mmol
1.0 mmol
1.0 mmol
1.0 mmol
62%
67%
63%
79%
81%
b
b
c
We next decided to investigate the scope of the aqueous
protocol with different aryl bromides, using both a primary
amine and a secondary amine (Table 2). n-Butylamine (2a)
and piperidine (2b) were selected as the model amines. Good
yields were obtained in most cases with 2a and formation
of piperidine products 3i-p demonstrated that secondary
b
c
a
1
g, 2a, 0.5 equiv of Mo(CO)6, 3.0 equiv of Na2CO3, 5 mol %
palladacycle, 2.0 mL of H2O, microwave irradiated at 170 °C for 10 min.
Yield based on 1g. Yield based on 2a. Noncomplete conversion of 1g.
b
c
3328
Org. Lett., Vol. 7, No. 15, 2005

To further investigate the limits of compatibility, various
nucleophilic amines were tested for their respective reactivity
with aryl bromide 1b using the identical water-based
protocol. From Table 3, it can be concluded that the reaction
is general although the noncyclic secondary amine 2i
afforded a reduced yield (53%). In contrast, unhindered
primary amines benzylamine and pyrrolidine provided excel-
lent productivity after only 10 min of irradiation. Even the
sterically congested tert-butylamine competed favorably with
water and the accompanying hydroxycarbonylation, affording
a useful 60% yield of secondary 3t.
Table 3. Fast Aminocarbonylation of p-Tolyl Bromide with
Miscellaneous Amines in Watera
6
To conclude, in the presence of Mo(CO) and a palladium
catalyst, aryl bromides were rapidly transformed into benz-
amides under microwave conditions. Despite the use of water
as solvent, aminocarbonylation strongly dominated over
hydroxycarbonylation, providing good yields of both second-
ary and tertiary model benzamides. This air-tolerant aqueous
aminocarbonylation protocol provides operational conven-
ience and increased safety for small-scale high-speed syn-
thesis.
Acknowledgment. This work was supported by the
Swedish Research Council and the Knut and Alice Wallen-
berg Foundation. We also thank Biotage AB for providing
us with the Smith microwave synthesizer. Finally, we would
like to thank Dr. Kristofer Olofsson for intellectual contribu-
tions to this project.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and purity data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a
1
.0 mmol 2c-l, 2.0 equiv of 1b, 0.5 equiv of Mo(CO)6, 3.0 equiv of
Na2CO3, 5 mol % palladacycle, 2.0 mL of H2O, microwave irradiated under
air at 170 °C for 10 min; >95% purity by GC-MS.
OL0512031
amines also served as productive nucleophiles in water (Table
(
18) Cheprakov, A. V.; Ponomareva, N. V.; Beletskaya, I. P. J.
Organomet. Chem. 1995, 486, 297-300.
19) Miyawaki, T.; Nomura, K.; Hazama, M.; Suzukamo, G. J. Mol.
Catal. A 1997, 120, L9-L11.
20) Lapidus, A. L.; Petrovskii, K. B.; Bruk, L. G.; Beletskaya, I. P. Zh.
2). We were further able to achieve amidation of aryl
bromides carrying electron-donating as well as electron-
withdrawing functionalities. Aminocarbonylations leading to
formation of ortho-substituted benzamides 3c, 3g, 3k, and
(
(
Org. Khim. 1999, 35, 1668-1671.
3o also worked satisfactorily. Disappointingly, the reaction
(21) Uozumi, Y.; Watanabe, T. J. Org. Chem. 1999, 64, 6921-6923.
(
22) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580-
between 3-thienyl bromide (1h) and n-butylamine did not
proceed as smoothly as the corresponding reaction with
piperidine. However, on raising the temperature to 180 °C,
this aminocarbonylation furnished 54% isolated yield of 3h
5
2
588.
(
23) Herrero, M. A.; Wannberg, J.; Larhed, M. Synlett 2004, 2335-
338.
(
24) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750-5753.
(
25) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C.-P. J. Organomet.
(Table 2).
Chem. 1999, 576, 23-41.
Org. Lett., Vol. 7, No. 15, 2005
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