Phosphorus oxychloride in organic synthesis. Part 2. Synthesis of cinnamic acid arylamides

Full text of DOI:10.1023/A:1010429106521

Pharmaceutical Chemistry Journal
Vol. 35, No. 2, 2001
PHOSPHORUS OXYCHLORIDE IN ORGANIC SYNTHESIS.
1
PART 2. SYNTHESIS OF CINNAMIC ACID ARYLAMIDES
A. A. Avanesyan2 and A. V. Simonyan2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 2, pp. 37 – 38, February, 2001.
Original article submitted April 3, 2000.
The study of new pathways in the synthesis of cinnamic
acid derivatives is of interest from the standpoint of the tar-
geted search for new biologically active compounds. Previ-
ously [1], we reported on the use of phosphorus oxychloride
in the synthesis of cinnamic acids substituted at the aromatic
fragment. Below we describe a simple method for the syn-
thesis of cinnamic acid arylamides possessing pronounced
antioxidant, antihypoxant, bile-expelling, and fungicidal
properties [2 – 5].
However, we suggested that enamines (III) would never-
theless appear to interact as nucleophiles with carbocation
(IV) formed from the aromatic aldehyde under the action of
POCl3 [1], which would eventually lead to cinnamic acid
acetanilides:
+
C
+
Ar CH · Cl
–
–
H2C
O
POCl2
+
HN Ar
III
O
POCl2
IV
Traditional pathways for the synthesis of acid arylamides
(including those of cinnamic acid) represent multistage pro-
cesses. Typically, the following principal stages are involved
[6, 7]: (i) synthesis of cinnamic acid; (ii) obtaining halo-
gen-containing acid anhydride; (iii) condensation of the
halogen-containing anhydride with amines. In the case of
cinnamic acid arylamides, all these process stages are rather
laborious, while usually providing a low yield of the target
products.
Kira and Gadalla [8] described the reaction of condensa-
tion of DMF with dimethylacetamide in the presence of
POCl3, which leads to the formation of the corresponding
b-dimethylacrylamides. However, acetanilides were never
used in these transformations because it was believed that
stabilization of a carbocation (I) formed under the action of
POCl3 would proceed with the formation of an imido ester
(II) as a result of proton detachment from the amide group. It
was therefore implied that deprotonation of the methyl group
with the formation of enamine (III) is unlikely.
+ O(POCl2)2 + HCl
O
Ar CH CH
C
NHAr
V – XVI
Indeed, heating a mixture of equimolar amounts of an ar-
omatic aldehyde and acetanilide in an excess of POCl3 for
60 – 90 min led to a high yield of the corresponding
cinnamamides. Table 1 presents comparative data on the
yields of the target compounds synthesized by the proposed
method (B) and by the known pathways (A). For method B,
the yield is calculated for acetanilide and for method A, for
TABLE 1. Yields of Cinnamic Acid Arylamides (V – XVI)
Yield, %
Compound
R1
R2
R3
Method A Method B
V
H
H
H
H
H
H
H
H
63.2
63.7
63.2
63.5
63.6
55.5
55.4
55.4
55.6
55.6
62.4
63.5
71.0
79.0
70.0
75.2
75.0
76.4
71.0
76.0
79.0
73.0
81.0
83.0
VI
OC(O)C2H5
H
H3C
C
O
VII
VIII
IX
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
Br
HN
Ar
OC(O)CH3
OC(O)C2H5
OC(O)CH3
H
POCl3
+
O
X
OCH3
OCH3
OCH3
H
H2C
C
O
POCl2
H3C
C
POCl2
H3C
C
O
POCl2
–H+
+H+
–H+
+H+
XI
–
HN
Ar
HN Ar
I
N
Ar
Cl
XII
XIII
XIV
XV
XVI
OC(O)C2H5
H
II
III
Br
H
OC(O)C2H5
H
NO2
H
1
2
For part 1, see [1].
State Medical Academy, Volgograd, Russia.
NO2
H
OC(O)C2H5
99
0091-150X/01/3502-0099$25.00 © 2001 Plenum Publishing Corporation

100
A. A. Avanesyan and A. V. Simonyan
TABLE 2. Physicochemical Characteristics of Cinnamic Acid Arylamides (V – XVI)
Spectral characteristics
IR: nmax, cm – 1
Empirical
formula
Compound
M.p., °C
UV: lmax, nm
C=O
C=C
N–H
E–HC=CH
V
149 – 150
172 – 174
127 – 128
184 – 185
156 – 157
163 – 165
96 – 98
C15H13NO
296, 222
330, 220
276
1680
1680
1680
1680
1680
1680
1680
1680
1685
1685
1690
1690
1630
1634
1630
1630
1640
1630
1635
1630
1630
1625
1625
1625
1525, 1260
1530, 1260
1530, 1270
1530, 1265
1520, 1260
1525, 1265
1520, 1260
1525, 1265
1530, 1270
1525, 1260
1530, 1265
1530, 1270
975
975
970
970
970
975
970
975
970
970
975
970
VI
C18H17NO3
C16H15NO2
C18H17NO4
C19H19NO4
C19H19NO5
C17H17NO3
C20H21NO5
C15H12BrNO
C18H16BrNO3
C15H12N2O3
C18H16N2O5
VII
VIII
IX
325, 230
328, 230
330, 213
327, 234
336, 230
310, 220
300, 222
329, 259
327, 270
X
XI
XII
XIII
187 – 188
187 – 188
115 – 116
228 – 229
224 – 225
XIV
XV
XVI
the initial aromatic aldehyde. Some physicochemical charac-
teristics of the synthesized compounds are summarized in
Table 2.
Thus, the new method proposed for the synthesis of
cinnamic acid arylamides offers a number of significant ad-
vantages over the traditional pathways: the target products
are obtained in a single-stage process, the time of synthesis is
markedly shorter, while the product yields increase from
55 – 63% to 70 – 80%.
of the corresponding amine in the same solvent. The precipi-
tating cinnamamides were separated by filtration, washed
with a small amount of ethanol and then with water, dried,
and recrystallized from ethanol or 2-propanol.
Method B. To a solution of acetanilide (0.01 mole) in
6 – 10 ml of POCl3 was added aromatic aldehyde
(0.01 mole) and the mixture was heated for 60 – 90 min at
80 – 90°C. Upon cooling, the reaction mixture was poured
into 50 – 100 ml of an ice – water mixture. The precipitate
was separated by filtration, washed with water until neutral
reaction, dried, and recrystallized as above.
EXPERIMENTAL PART
Method A. Cinnamic acid arylamides are obtained by a
patented method as described in [6]. A mixture of 3 ml of
freshly distilled acetic acid, 0.01 mole of the corresponding
aromatic aldehyde, and 1.5 g of anhydrous sodium acetate
was boiled for 8 – 16 h. Upon cooling, the reaction mixture
was poured into 50 – 100 ml of an ice – water mixture acidi-
fied with hydrochloric acid. The precipitate was separated by
filtration, washed with water until neutral reaction, and dried.
Finally, the product was recrystallized from water, aqueous
ethanol, or anhydrous ethanol.
REFERENCES
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Khim.-Farm. Zh., 25(12), 33 – 35 (1991).
3. A. V. Simonyan, E. N. Kupko, and V. K. Vereshchagin, Khim.-
Farm. Zh., 26(12), 48 – 50 (1992).
4. A. V. Simonyan and A. S. Saraf, Khim.-Farm. Zh., 26(7), 45 – 48
(1992).
5. A. V. Simonyan,
S. P. Vlasenko,
and
A. S. Dimoglo,
Khim.-Farm. Zh., 27(7), 29 – 32 (1993).
To a toluene solution of the obtained acid was added an
excess amount of thionyl chloride and the mixture was
heated on a water bath for 30 – 60 min. To the resulting solu-
tion of cinnamic acid chloroanhydride was added a solution
6. USSR Patent No. 728712; Byull. Izobret., No. 14, 263.
7. Jpn. Patent No. 60 – 41649 (1985).
8. M. A. Mira and K. Z. Gadalla, Egypt. J. Chem., 21(2), 153 – 155
(1978).