Mild synthesis of N′-aryl-N,N-dimethylformamidinium chloride by Vilsmeier-Haack reagent

Article abstract of DOI:10.1016/j.cclet.2011.03.009

Formamidine derivatives could be used as the building blocks for substituted heterocyclic compounds with various biological activities. N′-Aryl-N,N-dimethylformamidinium chlorides have been synthesized in high yields by reaction of aromatic primary amines with Vilsmeier-Haack reagent at room temperature. The structures of all the new compounds were identified by ESI-MS, IR and NMR spectra. The steric structures of some of these compounds were clarified by X-ray single crystal analysis.

Full text of DOI:10.1016/j.cclet.2011.03.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1043–1046
www.elsevier.com/locate/cclet
Mild synthesis of N0-aryl-N,N-dimethylformamidinium
chloride by Vilsmeier–Haack reagent
b
b
Ge Meng a, Yao Wu Sha b, , Rui Zhang , Nan Bai
*
a Faculty of Pharmacy, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China
b The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry,
Tsinghua University, Beijing 100084, China
Received 6 December 2010
Abstract
Formamidine derivatives could be used as the building blocks for substituted heterocyclic compounds with various biological
activities. N0-Aryl-N,N-dimethylformamidinium chlorides have been synthesized in high yields by reaction of aromatic primary
amines with Vilsmeier–Haack reagent at room temperature. The structures of all the new compounds were identified by ESI-MS, IR
and NMR spectra. The steric structures of some of these compounds were clarified by X-ray single crystal analysis.
# 2011 Yao Wu Sha. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Vilsmeier–Haack reagent; Formamidinium; X-ray single crystal
Vilsmeier–Haack reaction is a very useful method of synthesizing aromatic aldehydes [1]. In an effort to
synthesize 4-methyl-5-formyl-1,3-thiazole (2), an intermediate for the preparation of cephalosporins used for
treating bacteria infections, we found that no formylation reaction happened upon treatment of 4-methyl-1,3-
thiazole (1) with Vilsmeier–Haack reagent. Considering that the higher p-electron density of thiazole ring may
facilitate the Vilsmeier–Haack reaction, 2-amino-4-methyl-1,3-thiazole (3) was therefore chosen as an alternative
starting material. Much to our surprise, a solid product was obtained and identified to be N0-(4-methylthiazol-2-
yl)-N,N-dimethyl-formamidinium hydroxide salt (4a), instead of the expected formylation products 5 or 6
(Scheme 1).
N0-Aryl-N,N-dimethylformamidine has been widely used in the synthesis of heterocycles such as
benzoimidazole [2], quinoline [3] and indole [4]. In recent years, the total synthesis of various quinazolines
[5], as inhibitors of tyrosine kinase, has been a focus for medicinal chemists. Synthesis of N0-aryl-N,N-
dimethylformamidine was the key step of heterocycle formation. The common method of the synthesis was
through the condensation of aromatic amines and N,N-dimethylformamide dimethylacetal at relative high
temperature. Therefore, development of a mild synthetic strategy is very important and will have broad application
in the synthesis of heterocyclic compounds [6].
* Corresponding author.
E-mail address: shayw@tsinghua.edu.cn (Y.W. Sha).
1001-8417/$ – see front matter # 2011 Yao Wu Sha. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.03.009

[(Scheme_1)TD$FIG]
1044
G. Meng et al. / Chinese Chemical Letters 22 (2011) 1043–1046
S
S
POCl3, DMF
not happened
CHO
N
N
1
2
H H
N C
S
S
H2N
CHO
CHO
N
OH
Cl
N
N
S
H2N
4a
POCl3, DMF
not happened
POCl3, DMF
happened
5
N
OHC
HN
S
H H
3
S
N
N
C
N
N
4b
6
Scheme 1. Identified reactions of VH reagent.
1. Results and discussion
Upon further investigation of this reaction, we found that a white solid product precipitated from the solution
gradually when the reaction was carried out at room temperature. After filtration and washing with solvents, the solid
was characterized as N0-(4-methylthiazol-2-yl)-N,N-dimethylformamidinium chloride (4b). The 1H NMR spectra of
4a and 4b were almost the same except some slightly differences in chemical shift values. However, their melting
points were greatly different (Table 1). The structure was also confirmed by ESI-MS and IR spectra analyses.
Since few practical syntheses of N0-aryl-N,N-dimethylformamidinium have been reported so far [7], we decided to
further investigate the versatility of such transformation. As shown in Table 2, a series of aromatic primary amines 7
were tested with this protocol. In all situations, solid products precipitated gradually from the solution after starting the
materials were mixed at room temperature. All products were characterized by 1H NMR, 13C NMR, 31P NMR, ESI-
MS and IR spectra, respectively, which revealed the formation of formamidinium salts (8). From 31P NMR spectra of
8, no phosphorus peak was observed. Qualitative analysis by silver nitrate demonstrated chloride is the counterpart
anion. As shown in Table 2, most aromatic primary amines were compatible with this reaction protocol and the pure
formamidinium products were obtained in over 50% yield upon simple reaction and filtration.
Furthermore, single crystals of N0-(2-methylphenyl)-N,N-dimethylformamidinium chloride 8b and N0-(4-hydroxy
carbonylphenyl)-N, N-dimethylformamidinium chloride 8p were prepared. The X-ray analysis results were shown in
Fig. 1 [8]. As expected, the two carbon atoms and nitrogen atom of dimethyl amino group were in one plane. The
double bond existed between the groups of –N(CH3)2 and –CH, but the bond was very weak. Distinct hydrogen bonds
existed between chloride anion and hydrogen on NH of anilines. In the crystal structure of 8p, two water molecules
were observed and formed other two hydrogen bonds with chloride anion.
2. Experimental
1
Melting points were taken on a WRS-1 digital melting point apparatus and were uncorrected. H NMR and 13C
NMR spectra were recorded in CDCl3 on a JEOL JNM-ECA300 spectrometer operating at 300 and 75 MHz,
Table 1
Contrast of 1H NMR and 13C NMR data of 4a and 4b.
4aa d (ppm)
4bb d (ppm)
1H NMR
13C NMR
1H NMR
13C NMR
N
CH-N
8.17
3.05
3.09
2.30
6.33
155.1
34.6
40.4
17.4
9.24
3.09
3.27
2.37
6.30
159.4
41.9
35.6
14.2
N-Me-1
N-Me-2
4-Me
5-H
2-C
173.9
149.0
106.4
175.4
139.5
105.3
4-C
5-C
a
mp 62–64 8C.
mp 198–199 8C.
b

G. Meng et al. / Chinese Chemical Letters 22 (2011) 1043–1046
1045
Table 2
Condensation between aromatic amine and VH reagent.
[DT$INLE]
H
N
NH2
N
POCl3, DMF
R
R
Cl
7
8
.
7
8
mp (8C)
Yielda (%)
Aniline
8a
8b
8c
8d
8e
8f
255–260
237–240
233–235
250–255
218–220
248–252
190–192
247–249
270–275
225–227
226–228
225–228
248–252
165–168
230–233
240 dec
198–202
275–280
83.8
52.0
73.9
83.6
26.7
36.5
24.9
45.6
58.4
58.4
38.5
65.4
75.0
35.3
60.8
100
2-Methylanaline
3-Methylanaline
4-Methylanaline
2,6-Dimethylaniline
2-Fluroaniline
3-Fluroaniline
8g
8h
8i
4-Fluroaniline
2,4-Difluroaniline
2,5-Difluroaniline
2-Chloroaniline
3-Chloroaniline
4-Chloroaniline
8j
8k
8l
8m
8n
8o
8p
8q
8r
2-Aminobenzoic acid
3-Aminobenzoic acid
4-Aminobenzoic acid
4-Aminophenol
100
4-Aminosulfonic acid
91.4
a
Isolated yield.
respectively. Chemical shifts (d) are reported in ppm relative to tetramethylsilane (TMS) as an internal standard, and
coupling constants (J) are given in hertz (Hz). IR spectra were recorded on Nicolet AVATAR 360 FT-IR E.S.P. All
reagents were purchased and used without further purification.
2.1. General protocol for the synthesis of 8
A normal Vilsmeier–Haack reagent (15.6 mL) was cooled down with an ice-water bath, to this yellow solution
was added a solution of primary aromatic amine (2.4–4.5 g, 26 mmol) in DMF (15 mL). Since the reaction was
exothermic, the reaction mixture was cooled with an ice-bath to keep bellow room temperature (r.t.). After
addition, the solution was allowed to warm up and was kept stirring at r.t. until the product fully precipitated. The
product was collected by filtration and washed with DMF, acetone, Et2O respectively. Evaporation of the solvent
[(Fig._1)TD$FIG]
Fig. 1. ORTEP view of crystal structures of 8b and 8p with 35% probability ellipsoids.

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G. Meng et al. / Chinese Chemical Letters 22 (2011) 1043–1046
under vacuo could provide another part of product as white or slightly yellow powder. IR (cmꢀ1) 3009 (m), 2854
(st, w), 1693 (s), 1595 (s), 1339 (s), 1H NMR (300 MHz, D2O): d 8.26 (s, 1H, N CHN), 7.39–7.19 (m, 5H, PhH),
3.29 (s, 3H, NCH3), 3.15 (s, 3H, NCH3), 13C NMR (300 MHz, D2O): d 153.30 (1 C, N CHN), 136.65 (1C, 1-
PhCNMe2), 129.96 (2C, 3,5-PhC), 126.85 (1C, 4-PhC), 119.57 (2C, 2,6-PhC), 43.60 (1C, NCH3), 36.68 (1C,
NCH3), EI-MS (m/z), (MꢀCl) 149.
3. Conclusions
Although Vilsmeier–Haack reaction has been used for the direct synthesis of foramidines, most reported methods
have drawbacks such as harsh reaction conditions and difficulties in work up. Our method offers a very easy, mild and
efficient way for the preparation of N0-aryl-N,N-dimethylformamidinium salts for the synthesis of various heterocyclic
compounds, which might have various biological activities. The structures of the final products were verified by X-ray
single crystal determination.
Acknowledgment
The authors are grateful to the Chinese Postdoctoral Science Foundation for financial support (No. 2004036602).
References
[1] (a) J. Quiroga, Y. Diaz, B. Insuasty, et al. Tetrahedron Lett. 51 (2010) 2928;
(b) B. Eftekhari-Sis, M. Zirak, A. Akbari, et al. J. Heterocycl. Chem. 47 (2010) 463;
(c) L. Jiao, C. Yu, J. Li, et al. J. Org. Chem. 74 (2009) 7525.
[2] W. Dohle, A. Staubitz, P. Knochel, Chem. Eur. J. 9 (2003) 5323.
[3] (a) D.S. Yoon, Y. Han, T.M. Stark, et al. Org. Lett. 6 (2004) 4775;
(b) J.A. Heath, M.M. Mehrotra, S. Chi, et al. Bioorg. Med. Chem. Lett. 14 (2004) 4867;
(c) A. Staubitz, W. Dohle, P. Knochel, Synthesis 2 (2003) 233.
[4] D.M. Lindsay, W. Dohle, A.E. Jensen, et al. Org. Lett. 4 (2002) 1819.
[5] (a) J. Domarkas, F. Dudouit, C. Williams, et al. J. Med. Chem. 49 (2006) 3544;
(b) A. Wissner, M.B. Floyd, B.D. Johnson, et al. J. Med. Chem. 48 (2005) 7560.
[6] A. Mekhalfia, R. Mutter, W. Heal, et al. Tetrahedron 62 (2006) 5617.
[7] S. Cicchi, F.M. Cordero, Sci. Synth. 22 (2005) 221.
[8] X-ray single crystal analysis system, Bruker, 1997, XSCANS. Version 2.2, Bruker AXS Inc., 6300 Enterprise Lane, Madison, WI 53719-1173.