Formation of acrylanilides, acrylamides, and amides directly from carboxylic acids using thionyl chloride in dimethylacetamide in the absence of bases

Article abstract of DOI:10.1021/op060125+

A general one-pot procedure is described that rapidly converts acrylic acid to anilides upon sequential treatment of the acid in dimethylacetamide (DMAC) with thionyl chloride and stoichiometric amounts of anilines in 88-98% yields, with DMAC offering rate and stability advantages over the use of DMF. The use of DMAC was extended to other organic acids in forming anilides. Benzylamine amides can also be formed using stoichiometric amounts of benzylamine and brought to completion by warming in the absence of additional base. In addition, it was shown that tert-butylamides can be easily formed with the addition of excess tert-butylamine at 20 °C.

Full text of DOI:10.1021/op060125+

Organic Process Research & Development 2006, 10, 944−946
Communications to the Editor
Formation of Acrylanilides, Acrylamides, and Amides Directly from Carboxylic
Acids Using Thionyl Chloride in Dimethylacetamide in the Absence of Bases
Raymond J. Cvetovich* and Lisa DiMichele
Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey, U.S.A.
Scheme 1. Synthesis of acrylanilides 3a-g from acryloyl
Abstract:
chloride
A general one-pot procedure is described that rapidly converts
acrylic acid to anilides upon sequential treatment of the acid
in dimethylacetamide (DMAC) with thionyl chloride and
stoichiometric amounts of anilines in 88-98% yields, with
DMAC offering rate and stability advantages over the use of
DMF. The use of DMAC was extended to other organic acids
in forming anilides. Benzylamine amides can also be formed
using stoichiometric amounts of benzylamine and brought to
completion by warming in the absence of additional base. In
addition, it was shown that tert-butylamides can be easily
formed with the addition of excess tert-butylamine at 20 °C.
(<$6/kg) and thionyl chloride (<$3/kg) led us to directly
convert acrylic acid to acrylanilide 3g in a one-pot reaction
in DMAC with thionyl chloride and aniline 1g.3 Indeed, when
acrylic acid was dissolved in DMAC at -5 °C and treated
sequentially with thionyl chloride [Note: thionyl chloride
reacts with DMAC at 20 °C; therefore, thionyl chloride
should be added neat.] and 2,6-dichloroaniline and warmed
to 20 °C and then crystallized with water, a 95% yield of
acrylanilide 3g was isolated.4
A solvent comparison between DMAC, DMF, and NMP5
using anilines 1a and 1g was conducted. In DMF, coupling
with aniline 1g required warming and was prone to polym-
erization, as stated above, while aniline 1a gave anilide 3a
rapidly at 0-20 °C but in only 37% yield. In NMP, aniline
1g gave anilide 3g in 92% yield, similar to DMAC in reaction
rate and yield, but aniline 1a gave anilide 3a in only 63%
yield.
The need to prepare a variety of acrylanilides from ani-
lines 1 and acryloyl chloride 2, in particular 2,6-dichloro-
acrylanilide 3g, in support of a large-scale synthesis project
was initially satisfied by the addition of aniline 1g to acryloyl
chloride in Et2O or CH2Cl2 with amine bases, providing
isolated yields of only 40%,1 even in the presence of excess
base or acryloyl chloride. This was due to the insolubility
of 2,6-dichloroaniline HCl salt that formed in the reaction.
Requiring kilogram quantities of acrylanilide 3g, the low
yield of this procedure necessitated the exploration of
alternative procedures. It was found that when acryloyl
chloride in DMF at 0-5 °C was treated with 1 equiv of
aniline 1g in the absence of base, a slow reaction ensued at
20 °C that required warming to 60 °C to achieve complete
reaction. This procedure gave a 90% yield of acrylanilide
3g. It was observed, however, that at 60-70 °C polymeri-
zation of product can occur under these highly acidic
conditions. When dimethylacetamide (DMAC) was used in
place of DMF, a slightly exothermic reaction occurred at 5
°C, which when warmed to 15-20 °C resulted in the
complete formation of acrylanilide 3g. Product was isolated
by crystallization in 90% yield with the simple addition of
water to the reaction. The series of anilines 1a-g were all
successfully converted to acrylanilides 3a-g and isolated
in 88-98% isolated yields as crystalline solids (Scheme 1).
Although excellent yields of anilides were recently
reported by Chen et al.2 using acryloyl chloride in acetone/
water/base, the cost of acryloyl chloride (∼$300/kg for
multikilogram orders) relative to the cost of acrylic acid
The generality of anilide formation in DMAC with this
simple procedure with other acids (4-9) was tested and is
(2) Chen, I.-L.; Wang, T.-C.; Chen, Y.-L.; Tzeng, C.-C. J. Chin. Chem. Soc.
2000, 47, 155. (b) Wang, E.-C.; Huang, K.-S.; Lin, G.-W.; Lin, J.-R. J.
Chin. Chem. Soc. 2001, 48, 83.
(3) (a) For a comprehensive listing of methods for conversion of carboxylic
acids to amides up to 1999, see: Larock, R. C. ComprehensiVe Organic
Transformations, 2nd ed.; Wiley-VCH: New York, 1999; pp 1932-1941.
More recently: (b) Shiina, I.; Kawakita, Y.-i. Tetrahedron 2004, 60, 4729
used benzoic anhydrides. (c) Kunishima, M.; Kawachi, C.; Morita, J.; Terao,
K.; Iwasaki, F.; Tani, S. Tetrahedron 1999, 55, 13159 used 2-chloro-4,
6-dimethoxy-1, 3, 5-triazine (CDMT). (d) Sheng, S.-R.; Wang, X.-C.; Liu,
X.-L.; Song, C.-S. Synth. Commun. 2003, 33, 2867 used solid-phase
synthesis. (e) Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani, S.
Tetrahedron 2001, 57, 1551 used 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-
methylmorpholinium chloride (DMT-MM). (f) Srinivas, K. V. N. S.; Das,
B. J. Org. Chem. 2003, 68, 1165 used Fe3+-K-10 Montmorillonite clay.
(4) Carboxylic acid conversion to aniline-amides in DMAC: see Morris, J. J.;
Hughes, L. R.; Glen, A. T.; Taylor, P. J. J. Med. Chem. 1991, 34, 447.
(5) NMP in methylene chloride was used in making N-phenylbenzamide:
Higashi, F.; Nishi, T. J. Polym. Sci., Part A: Polym. Chem. 1986, 24, 701.
* To
raymond_cvetovich@merck.com.
(1) (a) Falbe, J.; Korte, F. Chem. Ber. 1962, 95, 2680.
whom
correspondence
should
be
addressed.
E-mail:
944
•
Vol. 10, No. 5, 2006 / Organic Process Research & Development
10.1021/op060125+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/10/2006

a
Scheme 2. Anilides from carboxylic acids using DMAC
and SOCl2
Scheme 4. Hindered amides using DMAC and SOCl2
a
a Reagents and conditions: i, DMAC, SOCl2; ii, (R)-methyl benzylamine;
iii, t-butylamine.
the reaction achieved 100% conversion and resulted in a 90%
isolated yield of amide 18. In this way, acrylic acid and acids
4, 5, 6, 8, and 9 were readily converted to benzylamides
16-21, each in >80% yield, except for acrylic acid, which
produced a mixture (80:20) of acrylamide 16 and chloro-
propylamide 22 (Scheme 3).
The most rapid conversion to amide occurred with
nicotinic acid 8. When pyridine was added to acrylic acid
after the addition of benzylamine, the conversion proceeded
rapidly at 20 °C to produce a mixture of amide 16 and
pyridine adduct 23 (observed and analyzed by HPLC and
LC/MS). When the reaction was quenched with water and
adjusted to pH 10, this species converted to amide 16, which
was isolated in 75% yield.
a Reagents and conditions: i, DMAC, -5 °C, SOCl2; ii, aniline, 0-20 °C.
Scheme 3. Benzyl amides from acids using DMAC and
a
SOCl2
When acid 7 was treated with thionylchloride and (R)-
methylbenzylamine, similar to benzyl amine, the reaction
proceeded to 50% conversion to amide 243b at -5 to 0 °C
and then was completed when heated to 55 °C (Scheme 4).
The preparation of tert-butylamides was also accom-
plished but required the use of excess tert-butylamine. After
warming to 20 °C, amide 253c was obtained in an 80% yield
from acid 6 (see Scheme 4). The need for excess tert-
butylamine, in this case, is due to tert-butylamine HCl salt
insolubility in DMAC.
Summary
Acrylic acid and a variety of other carboxylic acids were
smoothly converted to anilides, benzyl amides, and tert-butyl
amides in high isolated yields by the action of thionyl
chloride and the aniline/amine in dimethylacetamide. Com-
plete reactions can be achieved using stoichiometric quanti-
ties of acid and amine in the absence of bases (i.e., neither
excess aniline/amine nor other bases such as TEA, pyridine),
with the exception of tert-butylamine.
Experimental
Formation of Acrylanilides, General Procedure from
Acryloylchloride. Aniline (0.25 mol) was dissolved in N,N-
dimethylacetamide (80 mL) and cooled to -5 °C in a
mechanically stirred round-bottom flask equipped with a
nitogen inlet and an aqueous NaOH scrubber. Acryloyl
chloride (22 mL, 0.27 mol) was added dropwise over 45
min while maintaining the reaction temperature at <0 °C.
[Note: the atmosphere above the reaction contains HCl,
and the reaction should be vented to a scrubber.] After
stirring for 15 min, the near homogeneous mixture was
warmed to 20 °C and stirred for 1 h. Water (300 mL) was
added dropwise over 1 h while stirring with a mechanical
a Reagents and conditions: i, DMAC, -5 °C, SOCl2; ii, benzylamine,
0-60 °C.
shown in Scheme 2. In each case, reactions were complete
within 1 h and gave >90% isolated yields of anilides
10-15.
It was anticipated that the use of stoichiometric amounts
of primary amines such as benzylamine, which are stronger
bases than aniline, would lead to only 50% conversion to
amides. Indeed, after addition of benzylamine to a mixture
of acid 5, DMAC, and SOCl2 at -5 °C a 1:1 mixture of
acid:amide was observed. However, after warming to 50 °C,
Vol. 10, No. 5, 2006 / Organic Process Research & Development
•
945

stirrer. The reaction mixture initially became homogeneous
then produced a thick crystalline slurry. After stirring for 1
h at 20 °C the product was recovered by filtration, washed
with water (3 × 20 mL), and then dried in vacuo at 50 °C.
Formation of Amides from Acid, General Procedure.
A solution of dimethylacetamide (80 mL) and the chosen
acid (0.25 mol) was cooled to -5 °C in a mechanically
stirred round-bottom flask equipped with a nitogen inlet and
an aqueous NaOH scrubber. Thionyl chloride (0.27 mol) was
added dropwise (by addition funnel or syringe) over 15 min.
[Note: thionyl chloride reacts with DMAC, so it is added
neat.7] After stirring for 10 min, the amine or aniline (0.25
mol) (or 1.0 mol as in the case of tert-butylamine), either
neat or as a solution in DMAC, was added over 15-30 min.
Upon complete addition, the mixture was warmed to 20 °C
[Note: the atmosphere above the reaction contains HCl,
and the reaction should be vented to a scrubber.] and
stirred for up to 1 h (or warmed to 50 °C when necessary).
With the reaction mixture at 20 °C, water (300 mL) was
added dropwise over 1 h while stirring with a mechanical
stirrer. After stirring for 1 h at 20 °C the product was
recovered by filtration, washed with water (3 × 20 mL),
and then dried in vacuo at 50 °C. For amides 11 and 16,
product was precipitated by the addition of 1 N NaOH to
bring the pH to 7. In cases where an oil was formed (i.e.,
12), product was extracted with MTBE.
The following compounds are known in the literature:
(3a, c, d, f),3d 3b,2b 3g,1 10,6a 11,3b 12,3f 13,3b 14,6b 15,6c 16,3d
17,6d 18,3b 19,3f 20,6e 21,6f 24,3b 25.3c
N-(2,6-Difluorophenyl)acrylamide (3e): 1H NMR (400.25
MHz) d6-DMSO: δ 9.90 (s, 1H), 7.36 (om, 1H), 7.18 (om,
2H), 6.47 (dd, J ) 17.1, 10.2 Hz, 1H), 6.27 (dd, J ) 17.2,
1.9 Hz, 1H), 5.80 (dd, J ) 10.2, 1.9 Hz, 1H). 13C NMR
(100.65 MHz) CDCl3: δ 163.4, 157.7 (dd, J ) 248.8, 5.4
Hz, 2C), 130.4, 128.0 (t, J ) 9.9 Hz), 127.7, 114.3 (t, J )
16.9 Hz), 111.8 (dd, J ) 17.9, 5.1 Hz, 2C). HRMS (ES+)
calcd for C9H7F2NO (M + 1) 184.0568, found 184.0575.
Supporting Information Available
(6) (a) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006. (b) Schoenberg,
A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327. (c) Tani, K.; Suwa, K.;
Tanigawa, E.; Ise, T.; Yamagata, T. J. Organomet. Chem. 1989, 370, 203.
(d) Greico, P. A.; Clark, D. S.; Withers, G. P. J. Org. Chem. 1979, 44,
2945. (e) Pop, I. E.; Deprez, B. P.; Tartar, A. L. J. Org. Chem. 1997, 62,
2594. (f) Steglich, W.; Schmidt, H.; Hollitzer, O. Synthesis 1978, 78, 622.
(7) When thionyl chloride (2 ml) is added to DMAC (10 ml) at 20 °C, an
exothermic reaction ensues, and the temperature rises to 65 °C over 20 min
with the mixture turning dark brown. At -5 °C, no exotherm was observed,
but it is preferred to add the thionyl chloride neat.
1H NMR and 13C NMR spectra for compounds 3a-3g,
10-21, 24, and 25. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review June 21, 2006.
OP060125+
946
•
Vol. 10, No. 5, 2006 / Organic Process Research & Development