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VILSMEIER-HAACK SYNTHESIS OF
AROMATIC ALDEHYDES USING bis-
(TRICHLOROMETHYL) CARBONATE AND
DIMETHYLFORMAMIDE
W. G. Shan a , X. J. Shi a & W. K. Su a
a College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou, 310014, P R CHINA
Published online: 21 Feb 2009.
To cite this article: W. G. Shan , X. J. Shi & W. K. Su (2004): VILSMEIER-HAACK SYNTHESIS OF
AROMATIC ALDEHYDES USING bis-(TRICHLOROMETHYL) CARBONATE AND DIMETHYLFORMAMIDE, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 36:4, 337-340
To link to this article: http://dx.doi.org/10.1080/00304940409458675
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ORGANIC PREPARATIONS AM) PROCEDURES INT., 36 (4), 337-340 (2M4)
VILSMEIER-HAACK SYNTHESIS OF AROMATIC ALDEHYDES USING
bis-(TRICHLOROMETHYL) CARBONATE AND DIMETHYLFORMAMIDE
W. G. Shan, X. J. Shi and W. K. Su*
College of Pharmaceutical Sciences, Zhejiang University of Technology
Hangzhou, 310014, P. R. CHINA
The classical Vilsmeier-Haack reaction is a type of Friedel-Crafts reaction involving
electrophilic substitution of suitable carbon nucleophiles with halomethylene-iminium salts.’
Several substituted aldehydes have been synthesized by the Vilsmeier-Haack rea~tion.~” The
traditional reagents involve a combination of phosphorus oxychloride and N-methylformanilide
(MFA) or di-methylformamide (DMF). In recent years, the use of dimethylformamide and phos-
gene as a formylating reagent has found many applications in the preparation of aromatic alde-
hydes.6 This paper extends the scope and versatility of the Vilsmeier-Haack reaction through the
use of bis-(h-ichloro-methyl) carbonate (BTC) instead of phosphorus oxychloride and phosgene.
ArH * – ASH0 (CH3)2NCHO NaOH
1 cIco~occ13 H20 2
0
a) Ar =p-(CH3)2NCbH4; b) Ar = 2-CH30-l-CloH6; c) Ar = 2-CdH3S; d) Ar = 5-Br-2-C4HzS;
e) Ar = 2-C4H3O; 9 Ar = 2-C4H4N; g) Ar = N-CH3-2-QH3N
BTC is a useful auxiliary to prepare intermediates for the synthesis of several organic
compounds.’ It may be used instead of phosgene, phosphorus oxychloride and thionyl chloride in
reactions with many nucleophiles. Reactions with BTC usually proceed under mild conditions
and often afford good to excellent yields. Moreover, BTC is safer to handle and convenient to
store and transport because it is a stable solid.
+ 113BTC – + HCI
I
COCl H
+ – EN-CO-NZ + HCI
I
COCl H
@ 2004 by Organic Preparations and Procedures Inc.
e ““
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SHAN, SHI AND SU
Our experiments show that the formylation of various electron-rich aromatic and
heteroaromatic substrates is conveniently carried out by using BTC and DMF as the reagent in
carbon tetrachloride. In this system, the formylation of N,N-dimethyl-aniline, 2-methoxynaphtha-
lene, thiophene, 2-bromothiophene, furan, pyrrole, N-methylpyrrole proceeded under mild condi-
tions to give the corresponding aldehydes in good yields (Table 1). In comparison to reported
methods for the synthesis of aldehydes using other Vilsmeier-Haack reagents, the major advan-
tages of our procedure are its simplicity, the low cost, and the environmentally compatible
reagents employed. Although theoretically, 1/3 mole of BTC and one mole of DMF should be
sufficient to react with one mole of substrate, it was found that it was necessary to use a 5%
excess of the reagent for the total conversion of substrates to aldehydes except for 2-bromothio-
phene.
Table 1 Preparation of Aldehydes using BTC and DMF in CCl,"
Cmpd Yieldb mp lit.
–
2a
2b
2c
2d
2e
2f
2g 90
84
87
61
89
82
91 72.8-73.2 74
83.1-83.7 842
oil oil'
oil oil'
oil oil4 IR(C=O)
(cm-')
1605
1665
1674
1668
1674
44-46 44-455 1653
oil oil5 1663 'H NMR
(6) MS(E1)
m/Z(%)
9.740 (lH, s, CHO), 7.726 (2H, d,
J= 8.8, ArH), 6.689 (2H, d, J= 9.2,
ArH), 3.086 (6H, s, CH,)
J = 8.4, ArH), 8.064 (lH, d, J = 9.2,
ArH), 7.774 (lH, d, J= 7.6, ArH), 7.608
(lH, m, ArH), 7.406 (lH, m, ArH), 7.298
(lH, d, J= 9.2, ArH), 4.064 (3H, s, OCH,)
9.958 (lH, s, CHO), 8.154 (lH, m, ArH),
8.047 (IH, m, ArH), 7.339 (IH, m, ArH)
9.787 (lH, S, CHO), 7.527 (lH, d, J=4.0,
ArH ), 7.197 (lH, d, J = 4.0, ArH) ____
10.905 (lH, s, CHO), 9.276 (1H, d, ____
–-
192(60)
191 (100)
190(58)
l89(9 1)
9.670 (lH, S, CHO), 7.731 (lH, t, ArH),
7.299 (lH, d, J= 4.0, ArH), 6.631 (lH,
m, ArH 1
9.720 (lH, s, NH), 9.533 (lH, s, CHO),
7.141 (lH, m, ArH), 6.991 (lH, m, ArH),
6.354 (lH, m, ArH )
9.528 (lH, s, CHO), 6.899 (lH, m, ArH ),
6.882(1H,m, ArH),6.193 (lH, m, AH),
3.939 (3H. s. NCH,) –-
____
–-
a) Substrate (2 mmol), DMF (2.1 mmol), BTC (0.7 mmol) and CC1, (7 mL) were used.
b) Yields based on substrates.
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VILSMEIER-HAACK SYNTHESIS OF AROMATIC ALDEHYDES
King and Nord' had reported that replacement of the bromine atom occurs when 2-
bromothiophene reacts with N-methylformanilide and phosphorus oxychloride, to yield mainly
5-chloro-2-thiophenecarboxaldehyde. However, in our experiment it was found that replacement
of the bromine atom did not take place when 2-bromothiophene reacted with BTC and DMF, to
yield only 5-bromo-2-thenaldehyde (2d), along with unconverted 2-bromothiophene, even when
a 5% excess of the reagent was employed. A possible reason is that the electron-withdrawing
effect of the bromine atom of 2-bromothiophene deactivates the ring thus leading to a decreased
yield. The structure of 5-bromo-2-thenaldehyde was confirmed by MS, 'H NMR and IR.
As shown in Table 1, the yield of pyrrole-2-carboxaldehyde (20 is lower than the 89%5
obtained using phosphorus oxychloride and DMF as reagent because pyrrole reacts with BTC as
shown below.7
Our experiments show that the reaction temperature is very important. While the formy-
lation of aromatic amines and naphthyl ether could be carried out under reflux, the reaction of
heteroaromatic compounds had to be performed at 40-55"C, otherwise the reaction mixture
became black and difficult to process.
In summary, formylation of various electron-rich aromatic and heteroaromatic
substrates using DMF and in carbon tetrachloride BTC (instead of phosphorus oxychloride or
phosgene), is a viable process which avoids the formation of phosphorous salts and thus will be
advantageous in industrial applications from the standpoint of safety and environmental accept-
ability
EXPERIMENTAL SECTION
Melting points were obtained with a capillary melting point apparatus and were uncorrected.
Infrared spectra were recorded on a Thermo Nicolet Avatar 370 spectrophotometer, H' NMR
spectra (CDC1, or DMSO-d,) on a Varian Mercur plus-400 spectrometer using TMS as internal
standard and mass spectra on a Saturn-2000 MS spectrometer. Organic solvents were obtained
from commercial sources. Preparative TCL separations were carried out with silica gel GF-245
coated glass plates. BTC is sold as triphosgene by Aldrich and is listed as a lachrymator.
General Procedure.- In a flask fitted with a thermometer, dropping funnel, condenser, and
stirrer was placed pyrrole (2 mmol) and DMF (2.1 mmol). The flask was immersed in an ice-
bath, the stirrer was started, and BTC (0.7 mmol) dissolved in carbon tetrachloride (7 d), was
added over a period of fifteen minutes. The mixture was allowed to stir for 15-30 minutes after
addition. The ice bath was removed and the mixture was heated to 40-50°C for 2 hr., then cooled
and poured into ice water. The solution was made basic with sodium hydroxide. The layers were
separated. The aqueous phase was extracted three times with a total of about 30 mL, of ether. (If
the starting material was furan, the aqueous phase must be saturated with potassium carbonate
prior to use because of the solubility of furfural in water.) The ethereal and carbon tetrachloride
solutions were combined and dried over sodium sulfate and the solvents were removed under
339
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SHAN, SHI AND SU
reduced pressure. The residue obtained was subjected to chromatographic purification on TLC
silica gel to give pyrrole-2-carboxaldehyde in 82% yield.
Acknowledgement.- We are grateful to the Natural Science Foundation of China (No. 2027602)
and the Natural Science Foundation of Zhejiang Province (No. 2001062 and No. 2002095) for
financial help.
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(Received May 24,2004; in final form July 1,2004)
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