Dimethylformamide as a carbon monoxide source in fast palladium-catalyzed aminocarbonylations of aryl bromides

Article abstract of DOI:10.1021/jo025965a

Dimethylformamide (DMF) acts as an efficient source of carbon monoxide and dimethylamine in the palladium-catalyzed aminocarbonylation (Heck carbonylation) of p-tolyl bromide to provide the dimethylamide. Addition of amines to the reaction mixture in excess delivers the corresponding aryl amides in good yields. The amines employed, benzylamine, morpholine, and aniline, all constitute good reaction partners. The reaction proceeds smoothly with bromobenzene and more electron-rich aryl bromides, but electron-deficient aryl bromides fail to undergo aminocarbonylation. The reactions are conducted at 180-190°C for 15-20 min with microwave heating in a reaction mixture containing imidazole and potassium tert-butoxide: the latter is required to promote decomposition of the DMF solvent at a suitable rate. The beneficial effects of controlled microwave irradiation as an energy source for the rapid heating of the carbonylation reaction mixture are demonstrated. The carbonylation procedure reported herein, which relies on the in situ generation of carbon monoxide, serves as a convenient alternative to other carbonylation methods and is particularly applicable to small-scale reactions where short reaction times are desired and the direct use of carbon monoxide gas is impractical.

Full text of DOI:10.1021/jo025965a

SCHEME 1
Dim eth ylfor m a m id e a s a Ca r bon Mon oxid e
Sou r ce in F a st P a lla d iu m -Ca ta lyzed
Am in oca r bon yla tion s of Ar yl Br om id es
Yiqian Wan, Mathias Alterman,* Mats Larhed, and
Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, BMC,
Uppsala University, P.O. Box 574,
carbon monoxide limit the use of carbonylation reactions
for the small-scale synthesis of compound libraries.2
More than three decades ago, Corey and Hegedus
reported the use of several equivalents of the hazardous
Ni(CO)4 as a combined C-X activator and liquid carbon
monoxide source3 for efficient aminocarbonylation reac-
tions with vinyl bromides. Recently, our laboratory
reported that the less harmful Mo(CO)6 acts as a solid
carbon monoxide releasing reagent4 in microwave-as-
sisted palladium-catalyzed5 carbonylation reactions. This
technique of in situ delivery of carbon monoxide is very
suitable for high-throughput organic synthesis. However,
it is obvious that the concept of in situ liberation would
be even more appealing if inexpensive organic materials,
preferably the solvent itself, could serve as the source of
carbon monoxide. In fact, the common solvent dimeth-
ylformamide (DMF) has previously been utilized as a
liquid carbon monoxide source but only for preparation
of inorganic metal-carbonyl complexes.6
SE-751 23 Uppsala, Sweden
mathias.alterman@orgfarm.uu.se;
anders.hallberg@orgfarm.uu.se
Received May 24, 2002
Abstr a ct: Dimethylformamide (DMF) acts as an efficient
source of carbon monoxide and dimethylamine in the pal-
ladium-catalyzed aminocarbonylation (Heck carbonylation)
of p-tolyl bromide to provide the dimethylamide. Addition
of amines to the reaction mixture in excess delivers the
corresponding aryl amides in good yields. The amines
employed, benzylamine, morpholine, and aniline, all consti-
tute good reaction partners. The reaction proceeds smoothly
with bromobenzene and more electron-rich aryl bromides,
but electron-deficient aryl bromides fail to undergo ami-
nocarbonylation. The reactions are conducted at 180-190
°C for 15-20 min with microwave heating in a reaction
mixture containing imidazole and potassium tert-butoxide:
the latter is required to promote decomposition of the DMF
solvent at a suitable rate. The beneficial effects of controlled
microwave irradiation as an energy source for the rapid
heating of the carbonylation reaction mixture are demon-
strated. The carbonylation procedure reported herein, which
relies on the in situ generation of carbon monoxide, serves
as a convenient alternative to other carbonylation methods
and is particularly applicable to small-scale reactions where
short reaction times are desired and the direct use of carbon
monoxide gas is impractical.
We herein report that dimethylformamide is an excel-
lent carbon monoxide precursor in fast palladium-
catalyzed aminocarbonylations of aryl bromides. In the
presence of potassium tert-butoxide (KOt-Bu), imidazole,
and various amines, the corresponding aryl amides were
isolated in moderate to high yields after reaction times
of 15-20 min at 180-190 °C.
In an ongoing medicinal chemistry program,7 we
wished to synthesize N-arylated imidazoles, which we
planned to prepare by Buchwald-Hartwig aminations
using a strong base.8 In a model reaction, we employed
imidazole and 4-bromotoluene as reactants with DMF as
solvent but were surprised to find that the dimethylamide
1, rather than the aryl imidazole, was the predominant
product, formed in good yield by controlled microwave
heating at 180 °C for 15 min (Scheme 1). This finding
encouraged us to study the scope and limitations of DMF
as a potential carbon monoxide precursor for carbonyla-
tion reactions in more detail.
Palladium-catalyzed aminocarbonylation (Heck carbo-
nylation) is a selective and useful method for the direct
synthesis of aryl amides from aryl halides.1 Carbon
monoxide gas is the most commonly employed source of
the carbonyl group in these transformations.1c-e The
recent interest in new high-throughput chemistry tech-
niques has redirected focus toward the automated han-
dling of liquids and solids rather than the development
of special gas delivery systems that, in theory, also could
make the direct use of reactive gases feasible for provid-
ing reactants in fast reactions. Today, the somewhat
troublesome gas handling procedure and the toxicity of
(2) (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J .
Comb. Chem. 2002, 4, 95-105. (b) Larhed, M.; Hallberg, A. Drug
Discovery Today 2001, 6, 406-416. (c) Strauss, C. R.; Trainor, R. W.
Aust. J . Chem. 1995, 48, 1665-1692.
(3) Corey, E. J .; Hegedus, L. S. J . Am. Chem. Soc. 1969, 91, 1233-
1234.
(4) Kaiser, N.-F. K.; Hallberg, A.; Larhed, M. J . Comb. Chem. 2002,
4, 109-111.
(5) (a) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582-9584.
(b) Alterman, M.; Hallberg, A. J . Org. Chem. 2000, 65, 7984-7989.
(6) (a) Rusina, A.; Vlcek, A. A. Nature 1965, 206, 295-296. (b) Serp,
P.; Hernandez, M.; Richard, B.; Kalck, P. Eur. J . Inorg. Chem. 2001,
2327-2336.
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Samuelsson, B.; Hallberg, A. J . Med. Chem. 1999, 42, 3835-3844.
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1999, 576, 125-146.
(1) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318-3326. (b) Schoenberg, A.; Heck, R. F. J . Org. Chem. 1974,
39, 3327-3331. (c) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaint-
ner, C. W. J . Mol. Catal. A: Chem. 1995, 104, 17-85. (d) Soderberg,
B. C. In Comprehensive Organometallic Chemistry II; Hegedus, L. S.,
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10.1021/jo025965a CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002
6232
J . Org. Chem. 2002, 67, 6232-6235

SCHEME 2
180 °C. By increasing the amount of base to 1.5 equiv,
the yield of 2 was improved to 73%, while 2.0 equiv
resulted in somewhat lower isolated yields. A consider-
able amount of starting material was recovered after
shortening the reaction time to 10 min (53% yield) or
after performing the reaction at 150 °C for 15 min (3%
yield), but a minor improvement was achieved (76% yield)
by performing the reaction at 190 °C for 15 min.9
The preparative results obtained with various aryl
bromides and different amines are shown in Table 2. As
apparent from Table 2, benzylamine, aniline, and the
secondary amine morpholine were all suitable amines for
the aminocarbonylation reaction with 4-bromotoluene,
producing isolated yields of the amides 2-4, ranging from
76% to 78% with high selectivities (<5% of 1). The yield
of 1, which relies on the liberation of dimethylamine from
the solvent, was slightly lower (59%, entry 1). In addition,
electron-rich and sterically hindered aryl bromides also
afforded high yields of 5-7 (70-94%), while no trace of
the desired aryl amide was observed in reactions with
electron-deficient 4-bromobenzonitrile or 4-bromobenzo-
trifluoride. Instead, 4-benzylaminobenzonitrile and 4-ben-
zylaminobenzotrifluoride, derived from competing Buch-
wald-Hartwig aminations,8 were isolated as the major
products. In the absence of any aryl bromide, transami-
dation occurred and N-formylbenzylamine was isolated
in 67% yield.
We postulate that the aminocarbonylation reactions
proceed as outlined in Scheme 3. It is well established
that DMF decarbonylates under heating to yield carbon
monoxide and dimethylamine in the presence of base.10
However, the present methodology is, to the best of our
knowledge, the first example where the carbon monoxide
is both liberated from the solvent and thereafter utilized
in an efficient organic carbonylation procedure.6b
As apparent from the pressure graphs, that we antici-
pate to reflect the liberation of these gases, KOt-Bu, not
imidazole or the palladium catalyst,6b,11 seems to promote
this decomposition upon heating to 180 °C (Figure 1A).
Both of the two components formed by the DMF decar-
bonylation reaction participate in the aminocarbonylation
reaction to give 1, and the pressure in the reaction vessel
during the aminocarbonylation is found to be relatively
low (Figure 1B).
TABLE 1. P a lla d iu m -Ca ta lyzed Am in oca r bon yla tion of
4-Br om otolu en e u n d er Differ en t Rea ction Con d ition s
isolated
yield
entrya solvent precatalyst ligand
additive
imidazole
imidazole
imidazole
imidazole
base of 2 (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Pd(OAc)2 dppf
Pd(OAc)2 dppp
Pd(OAc)2 binap
Pd(OAc)2 PPh3
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
63
37
49
0
Pd(OAc)2 P(o-Tol)3 imidazole
0
Pd(OAc)2
imidazole
N-Me-imidazole KOt-Bu
DMAP
b
Pd(OAc)2 dppf
Pd(OAc)2 dppf
Pd(OAc)2 dppf
dppf
0c
KOt-Bu
KOt-Bu
KOt-Bu
K2CO3
0c
0c
0d
0d
0c
10
11
12
imidazole
imidazole
imidazole
Pd(OAc)2 dppf
DMAc Pd(OAc)2 dppf
KOt-Bu
a
Reaction conditions: 4-bromotoluene (0.75 mmol), benzyl-
amine (3.0 mmol), additive (0.75 mmol), KOt-Bu (0.75 mmol),
palladium acetate/ligand (0.038 mmol/0.038 mmol), solvent (1 mL),
and microwave heating (180 °C, 15 min). bVial eruption. cN-Benzyl-
4-methylaniline was the major product. dN-Benzylformamide was
the major product.
First, we decided to employ benzylamine as an external
amine to assess whether aryl amides other than aryl
dimethylamides were accessible. Thus, 4-bromotoluene
(0.75 mmol), benzylamine (3.0 mmol), imidazole (0.75
mmol), KOt-Bu (0.75 mmol), and palladium acetate/dppf
(0.038 mmol/0.038 mmol) were warmed with a microwave
synthesizer in sealed Pyrex vessels to 180 °C in DMF.
The aryl benzylamide 2 could be isolated in 63% yield
after a reaction time of 15 min (Scheme 2).
A series of combinations of reagents were screened, and
the results are presented in Table 1. Only bidentate
ligands delivered products, while monodentate ligands
resulted in no desired product 2 (cf. entries 1-5).
Attempts to conduct the reaction with palladium
acetate in the absence of ligand caused an uncontrollably
high pressure in the reaction vessel and in some cases
also an eruption of the contents from the reaction vessel
(entry 6). The cause of the high pressure may be at-
tributed to deposition of metallic palladium on the Pyrex
wall and subsequent failure of the temperature-micro-
wave feedback control. Furthermore, neither employing
N-methylimidazole or DMAP (4-(dimethylamino)pyri-
dine) instead of imidazole nor the absence of imidazole
provided 2 (<1% by GC/MS, entries 7-9).
The lower pressure monitored is accounted for by the
consumption of carbon monoxide and dimethylamine in
the reaction process. The arylpalladium oxidative addi-
tion complex (8), initially created from palladium(0) and
the aryl bromide, coordinates the carbon monoxide, and
subsequently, an aroylpalladium compound (9) is gene-
rated.1c-e The nucleophilic catalyst imidazole reacts with
the aroylpalladium species, delivering a reactive aroylim-
idazole (10), anticipated to be attacked smoothly by the
amine to provide the amide 1.12 Since substitution of
imidazole for N-methylimidazole is deleterious to the
reaction, it seems that the formation of the aroylimida-
zole species is crucial for the reaction to occur.
Omitting the palladium catalyst or employing potas-
sium carbonate as base resulted in the predominant
formylation of the benzylamine and recovery of the
starting material (entries 10, 11). It also became clear
that a reaction conducted in dimethyl acetamide (DMAc)
did not render 2 with the Buchwald-Hartwig amination
as the predominant reaction (entry 12). The reactions in
Table 1 were conducted with 1.0 equiv of KOt-Bu at
(9) Corresponding experiment with classical oil-bath heating of 130
°C for 10 h furnished a 25% yield of compound 2.
(10) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
(11) Coalter, J . N.; Huffman, J . C.; Caulton, K. G. Organometallics
2000, 19, 3569-3578.
(12) Schnyder, A.; Beller, M.; Mehltretter, G.; Nsenda, T.; Studer,
M.; Indolese, A. F. J . Org. Chem. 2001, 66, 4311-4315.
J . Org. Chem, Vol. 67, No. 17, 2002 6233

TABLE 2. P a lla d iu m -Ca ta lyzed Am in oca r bon yla tion of Ar yl Br om id es w ith DMF a s Ca r bon Mon oxid e Sou r ce
a
Reaction conditions: aryl bromide (0.75 mmol), amine (3.0 mmol), imidazole (0.75 mmol), KOt-Bu (1.13 mmol), palladium acetate/
dppf (0.038 mmol/0.038 mmol), DMF (1 mL), microwave heating. Less than 5% of 1 was formed in entries 2-7.
SCHEME 3
F IGURE 1. Pressure curves recorded from microwave heating
of sealed vessels at 180 °C (15 min): (A) DMF, KOt-Bu; (B)
The activation of carboxylic acids by conversion to the
corresponding carbonylimidazoles is a common strategy
in peptide synthesis.13 In entries 2-7 in Table 2, large
excesses (4 equiv) of benzylamine, aniline, or morpholine
were added to the reaction mixture to enable favorable
competition with dimethylamine. The KOt-Bu, which is
consumed in the regeneration of the palladium, is added
in excess to ensure the continuous liberation of carbon
monoxide and the dimethylamine. The use of dppf and
binap effected efficient generation of product 2, while
reactions with the monodentate ligands failed (Table 1).
This corroborates well with the fact that bidentate
ligands are known to inhibit the agglomeration of Pd
atoms and the formation of less-active palladium-
carbonyl complexes.14
DMF, imidazole, 4-bromotoluene, Pd(OAc)2, dppf, KOt-Bu
(Table 2, entry 1).
The fact that the electron-deficient aryl bromides do
not deliver aryl amides is accounted for, at least in part,
by a nonfavored insertion of carbon monoxide to afford
the aroylpalladium complex from the arylpalladium-
carbonyl complex. This assumption is supported by the
previous observation that electron-poor aroylpalladium
halides are considerably more prone to undergoing de-
carbonylation than their electron-rich counterparts.15
Hence, with the electron-deficient aryl bromides, the
competing Buchwald-Hartwig amination was strongly
favored.
Recently, Schnyder et al. reported on formamide as an
ammonia synthon and efficiently synthesized, under
carbon monoxide pressure, a series of primary aromatic
(13) Sauve, G.; Le Berre, N.; Zacharie, B. J . Org. Chem. 1990, 55,
3002-3004.
6234 J . Org. Chem., Vol. 67, No. 17, 2002

gies for the aminocarbonylation of aromatics: in particu-
lar for small-scale reactions where short reaction times
are desired.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. 1H and 13C NMR spectra were
recorded at 270.2 and 67.9 MHz, respectively. Chemical shifts
are given as δ values (ppm) downfield from tetramethylsilane.
Flash column chromatography was performed on silica gel 60
(0.04-0.063 mm). Thin-layer chromatography was performed on
precoated silica gel F-254 plates (0.25 mm) and was visualized
with UV light or ninhydrin in ethanol. All chemicals were
purchased from commercial suppliers and used directly without
further purification.
All microwave reactions were carried out in 2-mL vials. The
microwave heating was performed in a single mode cavity,
producing controlled irradiation at 2450 MHz. It is r ecom -
m en d ed to p er for m th ese p r essu r ized h igh -tem p er a tu r e
r ea ction s in a d ed ica ted a n d sa fe m icr ow a ve r ea ctor . GC-
MS was performed with an electron impact (70 eV) mass
selective detector and a capillary column using a 70-305 °C
temperature gradient. The isolated compounds 1,17 2,18 3,19
5,18a,20 6,21 7,22 and N-formylbenzylamine23 have previously been
characterized and corresponded satisfactorily with NMR litera-
ture data. The isolated compound 424 has previously been
characterized and corresponded satisfactorily with boiling point
data; NMR data are provided in the Supporting Information.
Gen er a l P r oced u r e for Syn th esis of Am id es 2-7. A vial
was charged with aryl bromide (0.75 mmol), amine (3 mmol),
Pd(OAc)2 (0.038 mmol), dppf (0.038 mmol), imidazole (0.75
mmol), potassium tert-butoxide (1.13 mmol), and DMF (1 mL).
The reaction mixture was flushed with nitrogen, and the cap
was tightened thoroughly. The vessel was exposed to microwave
irradiation for 15-20 min. The reaction tube was thereafter
cooled to room temperature, and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and
brine and dried over potassium carbonate, and the solvent was
removed under reduced pressure. The products were purified
on silica gel.
F IGURE 2. Temperature curve recorded from microwave
synthesizer heating of a typical reaction mixture (Table 2,
entry 2).
amides in high yields by aminocarbonylation of aryl
halides.12 These reactions required a palladium catalyst
in combination with a nucleophilic Lewis base such as
imidazole or DMAP. In one example given, an aryl
dimethylamide was prepared in 89% yield. Imidazole was
utilized here as the base and DMF as both the solvent
and the dimethylamine source. The reaction proceeded
for 18 h at a carbon monoxide pressure of 5 bar.
Importantly, the inlet of carbon monoxide gas into the
reaction flask was a prerequisite for amide formation.
This is sharply different from our observations under the
more basic conditions depicted in Scheme 1 and Table 2.
The fast heating of the reaction mixture achieved by
controlled microwave irradiation is demonstrated in
Figure 2. A temperature of 190 °C is reached after only
2 min by the high power and specific internal heating of
the polar reaction mixture, and the temperature drops
rapidly, by active air-cooling, after the switch off of the
microwave power. Wall effects and seed formation are
suppressed by this methodology, and superheating can
be achieved both conveniently and rapidly.16
In summary, the solvent DMF has been shown to be
an excellent source of carbon monoxide and dimethy-
lamine, with both gases serving as building blocks in the
palladium-catalyzed aryl amide synthesis, provided that
a strong base, such as KOt-Bu and imidazole, is used as
a coreactant. An excess of amine in the reaction medium
affords the corresponding aryl amide in good isolated
yield. The in situ carbon monoxide generation methodol-
ogy works efficiently with bromobenzene and more
electron-rich aryl bromides, but aminocarbonylation of
electron-deficient aromatic systems fails. Although only
a limited number of examples are presented herein, we
believe the method will attract attention due to the
experimental simplicity and the fact that no external
carbon monoxide gas needs to be added. It should serve
as a convenient alternative to other existing methodolo-
Ack n ow led gm en t. We gratefully acknowledge Dr.
Kristofer Olofsson for creative discussions. We also
acknowledge the financial support from the Swedish
Research Council and from the Knut and Alice Wallen-
bergs Foundation. We thank Personal Chemistry for
providing the microwave synthesizers.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data and purification details for all the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O025965A
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