Synthesis of primary aromatic amides by aminocarbonylation of aryl halides using formamide as an ammonia synthon

Article abstract of DOI:10.1021/jo015577t

Primary aromatic amides were prepared by a palladium-catalyzed aminocarbonylation reaction of aryl halides in high yields (70-90%) using formamide as the amine source. The reactions require a palladium catalyst in combination with a nucleophilic Lewis base such as imidazole or 4-(dimethylamino)pyridine (DMAP). Aryl, heteroaryl, and vinyl bromides and chlorides were converted to the primary amides under mild conditions (5 bar, 120 °C) using 1 mol % of a palladium-phosphine complex. Best results were obtained in dioxane using triphenylphosphine as the ligand and DMAP as the base. For activated aryl bromides, a phosphine-to-palladium ratio of 2:1 was sufficient, but less reactive aryl bromides or aryl chlorides required ligand-to-palladium ratios up to 8:1 in order to stabilize the catalyst and achieve full conversion. The influence of catalyst, base, solvent, pressure, and temperature was studied in detail. The mechanism of the. reaction could be clarified by isolating and identifying the reaction intermediates. In addition, methylamides and dimethylamides were prepared by the same method using N-methylformamide and N,N-dimethylformamide as the amine source.

Full text of DOI:10.1021/jo015577t

J . Org. Chem. 2001, 66, 4311-4315
4311
Syn th esis of P r im a r y Ar om a tic Am id es by Am in oca r bon yla tion of
Ar yl Ha lid es Usin g F or m a m id e a s a n Am m on ia Syn th on
Anita Schnyder,† Matthias Beller,‡ Gerald Mehltretter,‡ Thomas Nsenda,†
Martin Studer,† and Adriano F. Indolese*,†
Solvias AG, Klybeckstrasse 191, CH-4002 Basel, Switzerland
adriano.indolese@solvias.com
Received February 16, 2001
Primary aromatic amides were prepared by a palladium-catalyzed aminocarbonylation reaction of
aryl halides in high yields (70-90%) using formamide as the amine source. The reactions require
a palladium catalyst in combination with a nucleophilic Lewis base such as imidazole or
4-(dimethylamino)pyridine (DMAP). Aryl, heteroaryl, and vinyl bromides and chlorides were
converted to the primary amides under mild conditions (5 bar, 120 °C) using 1 mol % of a palladium-
phosphine complex. Best results were obtained in dioxane using triphenylphosphine as the ligand
and DMAP as the base. For activated aryl bromides, a phosphine-to-palladium ratio of 2:1 was
sufficient, but less reactive aryl bromides or aryl chlorides required ligand-to-palladium ratios up
to 8:1 in order to stabilize the catalyst and achieve full conversion. The influence of catalyst, base,
solvent, pressure, and temperature was studied in detail. The mechanism of the reaction could be
clarified by isolating and identifying the reaction intermediates. In addition, methylamides and
dimethylamides were prepared by the same method using N-methylformamide and N,N-dimeth-
ylformamide as the amine source.
In tr od u ction
Drawbacks of the method are the price of HMDS and the
low atom efficiency: less than 10 wt % of HMDS ended
up in the product. Ueda et al.4 used a titanium-nitrogen
compound as an ammonia source, giving the primary
amide in modest yields. Interestingly, the titanium-
nitrogen complex was prepared by fixation of elementary
N2 with in situ prepared activated titanium species (Li/
Ti(OiPr)4/TMSCl). As stated in both publications, the
direct use of ammonia in the aminocarbonylation of aryl
halides did not give satisfactory results, and it was
speculated that ammonia is not sufficiently nucleophilic.
On the other hand, Martinelli and Vries5 reported the
aminocarbonylation of an aryl iodide with ammonia in
excellent yield but no details were given. A drawback is
the handling of gaseous ammonia, which is inconvenient
on a small scale. In all three procedures the major
difficulties are connected with the source of the ammonia.
A simple and general procedure for the aminocarbonyl-
ation to primary amides using a cheap and easy to handle
ammonia source would obviously be of great interest to
synthetic chemists.
The palladium-catalyzed aminocarbonylation is an
important method for the selective and direct synthesis
of aromatic amides starting from aryl halides, and the
reactions of primary and secondary amines to the corre-
sponding secondary and tertiary amides are well docu-
mented (eq 1).1,2
In contrast to this, only a few publications describe the
direct synthesis of primary amides by carbonylation of
aryl halides (R1, R2 ) H). Morera and Ortar3 reacted aryl
and vinyl iodides and triflates with hexadimethylsilazane
(HMDS) as an ammonia synthon. The silyl-protected
amides initially formed in the carbonylation reaction
were hydrolyzed during the acidic workup, and the
primary amides were obtained in good to excellent yields.
† Solvias AG, Klybeckstrasse 191, CH-4002 Basel, Switzerland.
‡ Institut fu¨r Organische Katalyseforschung (IfOK) an der Univer-
sita¨t Rostock e.V., Buchbinderstrasse 5-6, D-18055 Rostock, Germany.
(1) (a) Malleron, J .-L.; Fiaud, J .-C.; Legros, J .-Y. In Handbook of
Palladium-Catalyzed Organic Reactions; Academic Press: San Diego,
1997; p 250. (b) Colquhoun, H. M.; Thompson, D. J .; Twigg, M. V. In
Carbonylation. Direct Synthesis of Carbonyl Compounds; Plenum
Press: New York, 1991; p 146. (c) Beller, M.; Cornils, B.; Frohning, C.
D.; Kohlpaintner, C. W. J . Mol. Catal. 1995, 104, 17. (d) Tsuji, J .
In Palladium Reagents and Catalysts; J ohn Wiley and Sons Ltd:
Chichester, 1995; p 188. (e) Heck, R. F. In Palladium Reagents in
Organic Syntheses; Academic Press: London, 1985; p 352.
The starting point of our investigation was the obser-
vation of dimethylamide 3 as a side product in the
(2) (a) Schoenberg, A.; Heck, R. F. J . Org. Chem. 1974, 39, 3327.
(b) Perry, R. J .; Wilson, B. D. J . Org. Chem. 1996, 61, 7482. (c) Ozawa,
F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa, K.;
Yamamoto, T.; Yamamoto, A. J . Am. Chem. Soc. 1985, 107, 3235.
(3) Morera, E.; Ortar, G. Tetrahedron Lett. 1998, 39, 2835.
(4) Ueda, K.; Sato, Y.; Mori, M. J . Am. Chem. Soc. 2000, 122, 10722.
(5) Martinelli, M. J .; Vries, D. L. In Process Chemistry in the
Pharmaceutical Industry; Gadamasetti, K. G., Eds.; Marcel Dekker:
New York, 1999; p 153.
10.1021/jo015577t CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/12/2001

4312 J . Org. Chem., Vol. 66, No. 12, 2001
Schnyder et al.
Ta ble 1. Effect of Liga n d Typ es, Tem p er a tu r e, a n d
P r essu r e on th e Ca r bon yla tion of 1 in F or m a m id ea
Ta ble 2. Ca r bon yla tion of 1 w ith F or m a m id e in th e
P r esen ce of Differ en t Ba sesa
temp CO pressure conv of 1 yield of 4
entry
ligandb
(°C)
(bar)c
(%)
(%)d
1
2
3
4
5
6
7
8
9
dppf
dpephos
dppb
binap
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
120
120
120
120
120
120
25
5
5
5
5
5
5
5
5
5
100
100
100
100
100
100
0
100
100
100
100
100
38
56
79
85
96
82
0
97
74
90
92
93
entry
baseb
conv of 1 (%)
yield of 4 (%)d
e
1
2
3
4
5
6
7
8
9
10
11
12
13
DMAP
PPYc
PPYd
100
99
99
100
97
62
96
87
83
78
78
75
69
64
54
26
90
150
120
120
120
10
11
12
1
8
50
imidazole
100
100
95
100
100
100
100
100
54
1-methylimidazole
1,3,5-triazine
quinoline
pyrazole
2,4-lutidine
pyridine
2-picoline
pyrrole
pyrimidine
a
Reaction conditions: 1 (35.6 mmol), imidazole (38 mmol),
PdCl2 (0.36 mmol), and ligand (Pd/P ) 1:4) in 25 mL of formamide,
in a 250 mL glass autoclave at the indicated temperature for 18
b
h. dppf: 1,1′-bis(diphenylphosphino)ferrocene, dpephos: 2,2′-bis-
(diphenylphosphino)diphenyl ether, dppb: 1,4-bis(diphenylphos-
phino)butane, binap: (R)-2,2′-bis(diphenylphosphino)-1,1′-binaph-
thyl, PPh3: triphenylphosphine. c Initial pressure at room tem-
62
d
perature. GC yields. e Pd/P ) 1:2.
a
Reaction conditions: 1 (35.6 mmol), base (38 mmol), Pd(OAc)2
(0.36 mmol), and ligand (Pd/P ) 1:4) in 25 mL of formamide, in a
250 mL glass autoclave at 120 °C and 5 bar CO (initial pressure
reductive carbonylation of 3-bromobenzotrifluoride (1) in
DMF (eq 2). Similar observations were reported by other
groups, and the formation of the dimethylamide was
ascribed to the reaction of an aroyl palladium species
with the solvent.3,6 We recognized this reaction as a
valuable method for the preparation of various amides,
since formamides would be cheap and easy to handle
amine sources, and of special interest was the synthesis
of primary amides using formamide. Herein we report
the development of this novel amidocarbonylation reac-
tion for the efficient preparation of primary amides. The
critical reaction parameters and the scope of the meth-
odology were evaluated.
b
at room temperature) for 18 h. GC yields. c PPY: 4-pyrroli-
d
dinopyridine. With 10 mol % PPY and 1.1 equiv of NEt3.
yields (entry 5). With binap, dppb, dpephos, or dppf
(entries 1-4), the yields were significantly lower. In situ
formed palladium-phosphine complexes as commonly
used for carbonylation reactions were well suited as
catalysts, and similar results were obtained with differ-
ent precursors such as PdCl2, Pd(OAc)2, or PdCl2(PPh3)2
if the Pd/P ratio was the same (GC yield 95%). The CO
pressure only influenced marginally the yields between
1 and 50 bar (entries 5, 10, 11, and 12). However, without
CO the amide 4 was not formed (<2%), and the main
product was the dehalogenated arene.
Resu lts
Among the different bases tested, the highest yields
and the fastest reactions as judged from the pressure
curves were obtained with DMAP and PPY (4-pyrroli-
dinopyridine) (Table 2). DMAP, PPY, and imidazole are
known to be powerful Lewis bases and acylating cata-
lysts,7 indicating that the base has probably an additional
role besides scavenging the formed acid. In the presence
of 1 equiv of an ordinary base such as triethylamine, the
amount of PPY could be reduced to 10 mol %, although
the yields dropped from 97% to 62% (entries 2 and 3).
While good conversions were obtained in formamide
as the solvent, the quantitative isolation of the products
from the reaction mixture was difficult, and the isolated
yields were generally lower than the GC yields. Advan-
tageously, a variety of solvents, both polar and nonpolar,
gave high yields using 2, 5, or 10 equiv of formamide,
respectively. With only 1.1 equiv of formamide the yields
were significantly lower (about 40% lower). Among the
different solvents, N-methylpyrrolidinone (86% GC-yield)
and dioxane (100% GC-yield) gave the best results.
The scope of the methodology was demonstrated using
1 mol % PdCl2(PPh3)2, DMAP as base, 2 equiv of form-
amide and dioxane as the solvent. A variety of aryl and
vinyl bromides were converted to the desired primary
amides in good yields (Table 3). Aryl bromides with
electron-withdrawing substituents (entries 1-3), 2-bro-
The aryl bromide 1 was used as a weakly activated
substrate to investigate the carbonylation reaction with
DMF (eq 2). With bases such as tributylamine, DBU, or
DABCO, the dimethylamide 3 was formed in very low
yields (<4%). However, with imidazole as the base, amide
3 was isolated in 78% yield. Performing the same reaction
in formamide instead of DMF afforded the primary amide
4 in similar yield (75%) (eq 3).
The influence of critical reaction parameters (temper-
ature, CO pressure, ligand type) was investigated for the
reaction of 1 with formamide (Table 1). In all experi-
ments, full conversion of the starting material 1 was
observed, except when the reaction was carried out at
room temperature (entry 7). The highest yields of 4 were
obtained at temperatures between 90 and 120 °C (entries
5 and 8). At higher temperature (150 °C) nonidentified
side products were formed (entry 9). Among the various
ligands tested, triphenylphosphine gave the highest
(7) (a) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int.
Ed. Engl. 1978, 17, 569. (b) Scriven, E. F. V. Chem. Soc. Rev. 1983,
12, 129.
(6) Perry, R. J .; Wilson, B. D. J . Org. Chem. 1993, 58, 7061.

Aminocarbonylation to Primary Amides
J . Org. Chem., Vol. 66, No. 12, 2001 4313
Ta ble 3. Ca r bon yla tion of Ar yl Ha lid es to P r im a r y
Am id esa
F igu r e 1. Schematic pressure curve of the reaction of 1 with
formamide in dioxane with DMAP as base in the presence of
1 mol % catalyst.
Sch em e 1
formamide. Because of the low solubility of urea in
dioxane, DMAc (N,N-dimethylacetamide) had to be used
as the solvent. Dimethylamides and methyl amides can
also be prepared using DMF and N-methylformamide,
respectively (entries 12 and 13). DMAc was tested as an
alternative source of dimethylamine (entry 14) but gave
lower yields than DMF.
a
Reaction conditions: aryl halide (35.6 mmol), DMAP (38
During our investigations, we noticed an unusual run
of the pressure curve (Figure 1). After the reaction
temperature was reached, the pressure decreased rapidly
in the first few hours until about 50% of the theoretical
amount of CO was consumed. Then, the pressure in-
creased again, until it became almost constant after
20 h.
If the reaction was stopped when the pressure mini-
mum was reached, the aryl bromide was already con-
sumed completely, but only 49% of the primary amide
was formed. In addition, formylimide 5 (8%), diben-
zoylimide 6 (2%) and the side products 7, 8, and 9 were
identified (Scheme 1). Obviously 5 resulted from the
reaction of formamide with an acyl-palladium complex,
while 7, 8, and 9 were formed in subsequent reactions of
imide 5 with formamide and amide 4, respectively. We
assume that these intermediates react to the primary
mmol), PdCl2(PPh3)2 (0.36 mmol), formamide (70 mmol) in 25 mL
of dioxane, in a 250 mL glass autoclave at 120 °C and 5 bar CO
b
(initial pressure at room temperature) for 18 h. Isolated yields.
d
c DMAc as the solvent and with PPY. DMF as the solvent and
with imidazole. e DMAc as the solvent and with imidazole.
mopyridine (entry 4) and â-bromostyrene (entry 9) (all
activated substrates) reacted rapidly, and generally the
isolated yields were above 70%. The very low yields of
the highly reactive 4-bromoacetophenone might be a
consequence of side reactions with the acetyl group (entry
3). Less reactive substrates such as 2-chloropyridine
(entry 5) and aryl bromides bearing electron-donating
substituents (entries 7, 8, and 10) needed higher Pd/P
ratios (up to 1:8) in order to stabilize the catalyst against
decomposition to inactive palladium black.
Urea was also applied as an ammonia equivalent
(entry 11), but the yield was significantly lower than with

4314 J . Org. Chem., Vol. 66, No. 12, 2001
Schnyder et al.
Sch em e 2
amide 4 in the further course of the reaction, since they
were not found at the end of the reaction.
lecular formation of cyclic imides are known in the
literature.12
The imide 5 decomposes slowly under the reaction
conditions, but also undergoes side reactions with the
excess of formamide as indicated by the formation of 7-9.
The formation and decomposition of the imide 5 nicely
explains the observed run of the pressure curve (see
Figure 1). In the first part of the reaction, the consumed
CO is stored in the imide 5, which upon decomposition
to amide 4 releases CO in the further course of the
reaction.
Discu ssion
The simple procedure described here allows the prepa-
ration of a broad variety of primary amides, methyl-
amides, and dimethylamides in one step starting from
the corresponding aryl halides. The reaction conditions
are reasonably mild to tolerate a variety of functional
groups, although nucleophilic groups such as amines,
alcohols, or thiols will probably interfere with the reac-
tion. The protocol is very general for aryl bromides, and
the only parameter to be adjusted is the Pd/P ratio. The
main advantage of the method is the use of inexpensive
and convenient to handle formamides as source of the
amine moiety.
The reaction displayed some interesting features that
raised the question about the mechanism and the role of
the base. On the basis of our observations, we suggest
that the aminocarbonylation proceeds as shown in Scheme
2. The first steps are in analogy to the accepted mecha-
nism of the palladium-catalyzed carbonylation of aryl
halides,8,9 i.e., the aryl halide adds oxidatively to a
palladium(0) complex,10 followed by CO insertion to give
an aroyl palladium species 10. The presence of CO is a
prerequisite for the formation of the aroyl species,
explaining why the reaction does not proceed without a
CO atmosphere (see above).
In the classical carbonylation reactions of aryl halides
with amines or alcohols, the nucleophile reacts directly
with the aroyl moiety 10.9 However, formamide is a very
weak nucleophile, and an acylating catalyst such as
DMAP, PPY, or imidazole is necessary for the transfer
of the aroyl moiety to the formamide. GC analysis of the
reaction mixture indicated that the imidazolide 11 was
indeed formed (comparison with 11 synthesized by the
reaction of 3-trifluoromethylbenzoyl chloride with imid-
azole), but too labile to be isolated. The proposed mech-
anism is supported by recent findings of Yoneyama et
al.,11 who described the formation of dibenzoylimide in
the carbonylation of bromobenzene in the presence of
benzamide. In addition, several examples of the intramo-
Con clu sion s
Formamide is a convenient ammonia source for the
preparation of primary amides by carbonylation of aryl
halides. The new procedure is simple and efficient and
avoids the use of expensive or difficult to handle reagents
such as HMDS or ammonia, and the reactions can be
carried out under mild conditions. For these reasons, the
methodology is not only suitable for laboratory prepara-
tion, but has also the potential for large scale processes.
The new protocol also allows the efficient synthesis of
methylamides and dimethylamides with the correspond-
ing formamides as amine sources.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. For the carbonylation experi-
ments, a 250 mL glass autoclave equipped with a magnet-
driven hollow shaft stirrer was used. The reactions were
carried out under nonisobaric conditions, and the progress of
reaction was followed by measuring the pressure in the
autoclave. CO gas (purity 99.97%) was purchased from Car-
bagas Chemical Co.
Commercially obtained materials were used as received
without further purification. Aryl halides, ligands, reagents
and solvents were purchased from Fluka Chemical Co. with
the exception of 4-bromobenzotrifluoride (Aldrich Chemicals
Co.) and 3-bromobenzotrifluoride (Novartis AG). Anhydrous
dioxane (stored over molecular sieves) was used. Pd(OAc)2 was
purchased from Fluka Chemical Co., PdCl2 (20% Pd in
hydrochloric acid) from Degussa AG, and PdCl2(PPh3)2 from
Avocado Chemical Co. Dpephos was prepared according to a
literature procedure.13
1H and 13C{1H} NMR spectra were recorded on a Bruker
dpx 300 spectrometer. Chemical shifts (δ) are given in ppm
and refer to TMS as internal standard. IR spectra were
(8) (a) Heck, R. F. Adv. Catal. 1977, 26, 323. (b) Garrou, P. E.; Heck,
R. F. J . Am. Chem. Soc. 1976, 98, 4115. (c) Yamamoto, A.; Ozawa, F.;
Osakada, K.; Huang, L.; Son, T.; Kawasaki, N.; Doh, M. Pure Appl.
Chem. 1991, 63, 687.
(9) Moser, W. R.; Wang, A. W.; Kildahl, N. K. J . Am. Chem. Soc.
1988, 110, 2816.
(10) (a) Fitton, P.; Rick, E. A. J . Organomet. Chem. 1971, 28, 287.
(b) Fitton, P.; J ohnson, M. P.; McKeon, J . E. J . Chem. Soc., Chem.
Commun. 1968, 6. (c) Coulson, D. R. J . Chem. Soc., Chem. Commun.
1968, 1530.
(12) (a) Mori, M.; Chiba, K.; Ohta, N.; Ban, Y. Heterocycles 1979,
13, 329. (b) Perry, R. J .; Turner, S. R. J . Org. Chem. 1991, 56, 6573.
(c) Perry, R. J .; Turner, S. R. Makromol. Chem., Macromol. Symp. 1992,
54/ 55, 159. (d) Fuchikami, T.; Ojima, I. Tetrahedron Lett. 1982, 23,
4099.
(13) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120,
3694.
(11) Yoneyama, M.; Nasa, T.; Arai, K. Polym. J . 1998, 30, 697.

Aminocarbonylation to Primary Amides
J . Org. Chem., Vol. 66, No. 12, 2001 4315
recorded on a Perkin-Elmer 1710 spectrometer. Melting points
were measured with a Bu¨chi 520 apparatus and are uncor-
rected. Gas chromatography was performed on a Fisons GC
8000 with a DB-17 column and helium as the carrier gas using
di(ethylene glycol) di-n-butyl ether as internal standard. The
combustion analyses were carried out by Solvias AG, Swit-
zerland.
Hz, 1H), 8.34 (s, 1H), 8.30 (d, J ) 7.9 Hz, 1H), 8.03 (dd, J )
7.8 Hz, 0.7 Hz, 1H), 7.79 (t, J ) 7.8 Hz, 1H); 13C{1H} NMR
(75.5 MHz, DMSO-d6, 297 K) δ 167.2, 165.2, 133.6, 133.3,
130.8, 130.6 (q, J (C-F) ) 4 Hz), 130.3 (q, J (C-F) ) 32 Hz),
125.9 (q, J (C-F) ) 4 Hz), 124.6 (q, J (C-F) ) 272 Hz); IR (KBr,
cm-1) 3246, 1740, 1678, 1469. Anal. Calcd for C9H6F3NO2: C,
49.78; H, 2.79; N, 6.45; F, 26.25; O, 14.74. Found: C, 49.89;
H, 2.83; N, 6.27; F, 26.08; O, 14.75.
Typical Procedure for the Preparative Carbonylation Ex-
periments
Bis-(3-tr iflu or om eth ylben zoyl)im id e (6) was obtained as
colorless crystals (210 mg, 0.6 mmol, 3%). Rf ) 0.50 (EtOAc:
3-Tr iflu or om eth ylben za m id e (4) (Ta ble 3, En tr y 1).
The autoclave was charged with 3-bromobenzotrifluoride (1)
(8.01 g, 35.6 mmol), 4-(dimethylamino)pyridine (4.74 g, 38.0
mmol), formamide (3.12 g, 69.1 mmol), PdCl2(PPh3)2 (243 mg,
0.35 mmol, 1 mol %), and 1,4-dioxane (25 mL). The autoclave
was purged three times with nitrogen (6 bar) and charged with
5 bar CO. The reaction mixture was heated to 120 °C. After
20 h and cooling to room temperature, the solvent was
evaporated in vacuo. The residue was partitioned between
dichloromethane and water. The aqueous layer was extracted
twice with additional dichloromethane. The organic phases
were combined, dried (Na2SO4), and concentrated under
reduced pressure. The crude material was purified by column
chromatography (silica gel, EtOAc/hexane as eluent). An
amount of 4.8 g (25 mmol, 71%) of 4 was obtained as colorless
crystals. Rf ) 0.24 (EtOAc:hexane 1:1); mp: 121.5-122.0 °C
(lit.:14 122-123 °C); 1H NMR (300.1 MHz, DMSO-d6, 297 K) δ
8.25 (s (br), 1H), 8.22-8.17 (m, 2H), 7.89 (dd, J ) 7.8 Hz, 0.7
Hz, 1H), 7.71 (t, J ) 7.8 Hz, 1H), 7.64 (s (br), 1H); 13C{1H}
NMR (75.5 MHz, DMSO-d6, 297 K) δ 167.2, 136.0, 132.3, 130.3,
130.0 (q, J (C-F) ) 32 Hz), 128.6 (q, J (C-F) ) 4 Hz), 124.9 (q,
1
hexane 1:1); mp: 177-178 °C; H NMR (300.1 MHz, DMSO-
d6, 297 K) δ 11.72 (s, 1H), 8.27 (s, 2H), 8.21 (d, J ) 7.9 Hz,
2H), 8.01 (d, J ) 7.8 Hz, 2H), 7.78 (t, J ) 7.8 Hz, 2H); 13C{1H}
NMR (75.5 MHz, DMSO-d6, 297 K) δ 167.4, 135.7, 133.6, 130.6,
129.5 (q, J (C-F) ) 26 Hz), 129.8, 126.1 (q, J (C-F) ) 4 Hz),
124.7 (q, J (C-F) ) 272 Hz); IR (KBr, cm-1) 3267, 1719, 1528,
1336. Anal. Calcd for C16H9F6NO2: C, 53.20; H, 2.51; N, 3.88.
Found: C, 53.13; H, 2.58; N, 3.87.
7 was obtained as colorless crystals (120 mg, 0.21 mmol,
2%). Rf ) 0.48 (EtOAc:hexane 1:2); 1H NMR (300.1 MHz,
DMSO-d6, 297 K) δ 9.46 (d, J ) 6.1 Hz, 3H), 8.28 (s, 3H), 8.23
(d, J ) 7.8 Hz, 3H), 7.96 (dd, J ) 7.8 Hz, 0.6 Hz, 3H), 7.77 (t,
J ) 7.8 Hz, 3H), 7.38 (q, J ) 6.1 Hz, 1H); 13C{1H} NMR (75.5
MHz, DMSO-d6, 297 K) δ 165.2 (3C), 135.4 (3C), 132.7 (3C),
130.6 (3C), 129.9 (q, J (C-F) ) 32 Hz, 3C), 129.1 (q, J (C-F) )
4 Hz, 3C), 125.8 (q, J (C-F) ) 272 Hz, 3C), 125.1 (q, J (C-F) )
4 Hz, 3C), 64.4.
8 and 9 were obtained as a mixture consisting of 80% of 8
(520 mg, 1.2 mmol, 8%) and 20% of 9 (130 mg, 0.5 mmol, 1%).
8: 1H NMR (300.1 MHz, DMSO-d6, 297 K) δ 9.50 (d, J ) 6.2
Hz, 2H), 8.94 (dd, J ) 7.0 Hz, 1.3 Hz, 1H), 8.26 (s, 2H), 8.20
(d, J ) 7.8 Hz, 2H), 8.09 (dd, J ) 1.3 Hz, 0.8 Hz, 1H), 7.95
(dd, J ) 7.8 Hz, 0.7 Hz, 2H), 7.75 (t, J ) 7.8 Hz, 2H), 7.38 (q,
J ) 6.2 Hz, 1H). Additional signals for 9: δ 9.50 (d, J ) 6.2
Hz, 1H), 8.43-8.41 (m, 2H), 6.97-6.90 (m, 1H).
J (C-F) ) 4 Hz), 124.8 (q, J (C-F) ) 272 Hz); IR (KBr, cm-1
)
3333, 3152, 1667, 1628, 1588, 1400. Anal. Calcd for C8H6F3-
NO: C, 50.80; H, 3.20; N, 7.41. Found: C, 50.83; H, 3.21;
N, 7.19.
For experiments under different conditions of temperature
or CO pressure, or with other ligands and bases, the conditions
given in the respective tables were used.
Ack n ow led gm en t. We gratefully acknowledge the
Technical Advisory Board of Novartis for financial
support of this work. We thank Thomas Aemmer,
Andrea Marti, and Marcel Uebelhart for their careful
experimental work, our colleagues Hans-Ulrich Blaser,
Benoit Pugin, Frederic Naud (all Solvias), and Wolfgang
Ma¨gerlein (Scripps Institute) for general discussions,
and Raylene Dyson for helpful comments on the manu-
script.
Isola tion of th e Rea ction In ter m ed ia tes 5-9 (Sch em e
1). The experiment was carried out as described above. After
2 h at 120 °C, the reaction was stopped and the mixture was
cooled to room temperature. The reaction mixture was worked
up as described, and the products were purified by column
chromatography (silica gel, EtOAc/hexane 1:2 as eluent).
3-Tr iflu or om eth ylben za m id e (4) was obtained as color-
less crystals (3.3 g, 17.5 mmol, 49%).
N-F or m yl-3-tr iflu or om eth ylben zoylim id e (5) was ob-
tained as colorless crystals (650 mg, 3.0 mmol, 8%). Rf ) 0.54
(EtOAc:hexane 1:2); mp: 130-130.5 °C; 1H NMR (300.1 MHz,
DMSO-d6, 297 K) δ 11.96 (d, J ) 8.6 Hz, 1H), 9.28 (d, J ) 8.4
Su p p or t in g In for m a t ion Ava ila b le: Spectral data
(1H and 13C NMR, IR, MS), elemental analysis and melting
points of all primary amides. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) Lancaster Catalogue, 93/94.
J O015577T