Synthesis of 2-dimethylaminobenzazoles via a guanidine intermediate: Reaction of 2-substituted aniline derivatives with 2-chloro-1,1,3,3-tetramethyl-formamidinium chloride

Article abstract of DOI:10.3987/COM-02-S39

Reactions of 2-aminophenols, 2-aminothiophenol and ophenylenediamines with 2-chloro-1,1,3,3-tetramethylformamidinium chloride proceeded easily via cyclization of guanidine intermediates to give the corresponding benzazoles having a dimethylamino group at

Full text of DOI:10.3987/COM-02-S39

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 317 - 322, Received, 31st July, 2002
SYNTHESIS
OF
2-DIMETHYLAMINOBENZAZOLES
VIA
A
GUANIDINE INTERMEDIATE: REACTION OF 2-SUBSTITUTED
ANILINE DERIVATIVES WITH 2-CHLORO-1,1,3,3-TETRAMETHYL-
FORMAMIDINIUM CHLORIDE
Kosei Ohno,* Wakako Ishida (nee Kusakari), Kazuyuki Kamata, Kazuaki Oda,
and Minoru Machida
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan
cpohno@hoku-iryo-u.ac.jp
Abstract – Reactions of 2-aminophenols, 2-aminothiophenol and o-
phenylenediamines with 2-chloro-1,1,3,3-tetramethylformamidinium chloride
proceeded easily via cyclization of guanidine intermediates to give the
corresponding benzazoles having a dimethylamino group at 2-position.
Benzazoles have attracted considerable interest because of their potential biological activities including
an antimicrobial activity,1 and served as one of the pharmacophore in clinical medicines. For example,
benzazole derivatives with a basic moiety at 2-position, such as 2-piperazinyl- and 2-
piperidinylbenzazoles, have been synthesized in relation to the structure-activity relationships (SAR)
studies on the antagonists or agonists for 5-HT receptors 2 and antiallergic agents.3
During the course of our study on the chemistry of guanidino group, we found that 2-guanidinophenol
cyclized readily to give 2-dimethylaminobenzoxazole. This finding led us to an exploitation of a useful

synthetic method of 2-aminobenzazole derivatives. The general synthetic methods need multi-steps via
2, 3
2-chloro-4, 5, 6 or 2-methylsulfone-benzazoles
as an intermediate. In this paper we wish to report a
facile synthesis of 2-dimethylaminobenzazole by a one-pot reation via guanidino intermediates.
N(CH3)2
Cl
N(CH3)2
N(CH3)2
Cl C
R
Z H
N C
R
Z H
NH2
N
R
2
N(CH3)2
N(CH3)2
N(CH3)2
Z H
CHCl3 / (C2H5)3N
3
1
6
-30 ～ -20 ˚C → r t
R
R
Z
CH3
CH3
Z
N(CH3)2
N(CH3)2
N
N
N
H
5
4
Compd R
Z
Products
Compd R
Z
Products
H
O
O
5a
5b
1a
1b
H
NH
NH
5d
5e
1d
1e
NO2
NO2
H
S
5c
1c
Scheme 1
First, in order to obtain a guanidino derivative, reation of o-aminophenol (1a) with 2-chloro-1,1,3,3-
tetramethylformamidinium chloride (2) in the presence of triethylamine in chloroform was carried out at
-30 - -20 °C, and subsequently the reaction mixture was allowed to stand at an ambient temperature for 3
1
h. A usual basic workup furnished a crude product, the H NMR spectrum of which indicated it
consisted of three compounds (3a, 4a, and 5a) in a ratio of 57 : 31 : 12. Since the cyclized product (5a)
had formed along with the intermediates (3a, 4a), we anticipated that an acid would catalyze the
cyclization of these intermediates to yield the corresponding benzazole. Thus, when a chloroform
solution of the mixture was stirred in the presence of silica gel for 1.5 h at room temperature, 5a was
obtained in 76% yield. In the similar reaction of 2-aminothiophenol (1c) with 2, the cyclization
occurred more readily to give a mixture of an intermediate (3c) and the benzothiazole (5c), the ratio

being 3 to 97, which on standing at room temperature for 4.5 h without silica gel afforded 5c in 84%
yield. In the case of o-phenylenediamine (1d), we presumed that the cyclization of an intermediate
(3d) would be less facile than the oxygen counterpart since an intramolecular acid-base catalysis by a
proximate effect as depicted in Scheme 1 should decrease. Therefore, the isolated crude product (3d)
was heated under reflux in xylene in the presence of catalytic acetic acid for 4 h to give the
benzimidazole (5d) in 84% yield.
Thus, it was indicated that the C-N double bond in guanidino group was electrophilic enough to allow
the nucleophilic attack of a lone pair of hetero atoms at ortho-position, and a dimethylamino group
served as a leaving group as shown in Scheme 1.
Next, one pot reaction of 1a with 2 was examined to yield the benzazole (5a) without isolation of
intermediates (3a and 4a). After reacting at -30 ~ -20°C for 3 h, the reaction mixture was allowed to stir
overnight in the presence of silica gel at room temperature. Filtration of the silica gel followed by
workup as described above afforded 5a in 78% yield.
Finally, in order to investigate the effect of a nitro group on the formation of azole rings, the reaction of
2-amino-5-nitrophenol (1b) with 2 was examined. After standing for 3.5 h at room temperature, 5b
was obtained in 91% yield. Similar reaction of 4-nitrophenylenediamine (1e) gave 5e in 85% yield.
In this case, however, it seems likely that the cyclization did not take place via 3e (2-amino-4-
nitrophenylguanidine intermediate), but via 6e (2-amino-5-nitrophenylguanidine intermediate). It was
shown that the introduction of a nitro group on benzene ring accelerated the formation of azole ring.
Thus, 2-chloro-1,1,3,3-tetramethylformamidinium chloride (2) was applied in the heterocyclic synthesis
for the first time. The present reaction may serve as a convenient and useful method for the synthesis
of 2-dimethylaminobenzazoles.
EXPERIMENTAL
All melting points were determined on a Yamato melting point apparatus (Yanaco MP-J3) and are
uncorrected. NMR spectra were recorded on JEOL JNM-FX 90Q spectrometer. MS spectra were

determined with a Shimadzu GC MS-9100-MS gas chromatograph-mass spectrometer with a direct inlet
system.
2-Chloro-1,1,3,3-tetramethylformamidinium chloride (2) 7
A mixture of N,N,N’,N’-tetramethylurea (22.6 g, 0.195 mol) and oxalyl chloride (37.0 g, 0.92 mol) in
anhydrous chloroform (100 mL) was refluxed over night. After evaporating chloroform, the residual
solids were washed with dry ether (3 x 100 mL) to give formamidinium chloride (2) (32.6 g, 98% yield),
mp 111-113℃ (lit.,7 mp 110-112℃), light gray needles. The chloride was used in the next step without
further purification.
Preparation of 2-dimethylaminobenzazoles (1a-e): General Procedure
A solution of 2-substituted aniline derivatives (1a-e) (30 mmol), 2-chloro-1,1,3,3-tetramethyl-
formamidinium chloride (31.5 mmol), and triethylamine (60 mmol) in chloroform (30 mL) was stirred at
-30 ~ -20 °C for 3.5 ~ 5 h. The reaction mixture was poured into 10% Na2CO3 solution, and extracted
with CHCl3. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness
to give the crude mixture. Then silica gel (ca. equivalent weight to the reation mixture; Kieselgel 60,
Merck) was added to the mixture dissolved in chloroform, and the resulting mixture was stirred at rt for
2 ~ 3 h. Filtration of the silica gel followed by evaporation of the solvent in vacuo gave the benzazoles
(5a-e). In the one-pot reaction of 1a and 2, the reaction mixture was treated directly with silica gel
without isolation of intermediates (3a) and (4a) to afford benzoxazole (5a). In the case of o-
phenylenediamine (1d), after workup, a mixture of products was chromatographed on aluminum oxide
90 using CHCl3-MeOH (97:3, v/v) as an eluent to give the amino-guanidine (3d) (85%). A solution of
3d in xylene was refluxed in the presence of acetic acid for 4 h to give benzimidazole (5d).
2-Dimethylaminobenzoxazole (5a): Yield, 76%, mp 90-91°C (hexane) (lit.,4 mp 88-89 °C), reddish
1
orange needles. IR (Nujol): 1650, 1580 cm-1. H NMR (CDCl3) δ: 3.19 (s, 6H, N(CH3)2), 6.85-7.45 (m,

4H, Ar-H). 13C NMR (CDCl3) δ: 37.65, 108.60, 116.08, 120.18, 123.88, 143.72, 149.18, 163.10. MS:
m/z 162 (M+). Anal. Calcd for C9H10N2O: C, 66.65 H, 6.22; N, 17.27. Found: C, 66.57; H, 6.30; N,
17.30.
2-Dimethylamino-6-nitrobenzoxazole (5b): Yield, 91%, mp 174.5-176 °C (CHCl3/MeOH), yellowish
orange needles. IR (Nujol): 1665, 1620, 1590, 1380 cm-1. 1H NMR (DMSO-d6) δ: 3.27 (s, 6H, N(CH3)2),
7.29 (dd, J=2.5, 8.8 Hz, 1H, C4-H), 8.11 (d, J=2.5 Hz, 1H, C7-H), 8.15 (dd, J=2.5, 8.8 Hz, 1H, C5-H).
13C NMR (CDCl3) δ: 37.69, 104.80, 114.49, 121.32, 141.09, 148.11, 150.46, 165.61. MS: m/z 207 (M+).
Anal. Calcd for C9H9N3O3: C, 52.17; H, 4.38; N, 20.28. Found: C, 52.16; H, 4.48; N, 20.32.
2-Dimethylaminobenzthiazole (5c): Yield, 84%, mp 89-91 °C (hexane/ether) (lit.,4 mp 86-88 °C), pale
yellow needles. IR (Nujol): 1600, 1560, 1550 cm-1. 1H NMR (CDCl3) δ: 3.18 (s, 6H, N(CH3)2), 6.90-7.70
13
(m, 4H, Ar-H). C NMR (CDCl3) δ: 40.12, 118.81, 120.57, 120.83, 125.90, 131.17, 153.34, 168.69.
MS: m/z 178 (M+). Anal. Calcd for C9H10N2S: C, 60.66; H, 5.66; N, 15.72; S, 17.96. Found: C, 60.59; H,
5.71; N, 15.58; S, 17.92.
2-Dimethylaminobenzimidazole (5d): Yield, 84%, mp > 300 °C (CHCl3) (lit.,5 mp 312-314 °C), pale
yellow needles. IR (Nujol): 1630, 1600, 1575 cm-1. 1H NMR (DMSO-d6) δ: 3.03 (s, 6H, N(CH3)2), 6.75-
13
7.25 (m, 4H, Ar-H). C NMR (CDCl3) δ: 38.00, 108.50, 114.90, 119.25, 156.85. MS: m/z 161 (M+).
Anal. Calcd for C9H11N3: C, 67.05; H, 6.88; N, 26.07. Found: C, 66.90; H, 6.94; N, 26.08.
2-Dimethylamino-5 (or 6)-nitrobenzimidazole (5e): Yield, 85%, mp 244.5-246 °C (EtOH) (lit.,6 mp
1
242-243 °C), yellowish orange needles. IR (Nujol): 1640, 1610, 1590, 1380 cm-1. H NMR (DMSO-d6)
δ: 3.16 (s, 6H, N(CH3)2), 7.20 (dd, J=1.3, 8.8 Hz, 1H, C4-H), 7.89 (dd, J=2.5, 8.8 Hz, 1H, C5-H), 7.94
13
(d, J=2.5 Hz, 1H, C7-H). C NMR (CDCl3) δ: 37.7, 106.0, 111.3, 116.6, 137.3, 139.8, 147.1. MS: m/z
206 (M+). Anal. Calcd for C9H10N4O2•1/2H2O: C, 50.23; H, 5.12; N, 26.04. Found: C, 50.49; H, 5.14; N,

26.33.
Compound 3d: Yield, 84%, mp 50-51°C (hexane), light gray fine needles. IR (Nujol): 3450, 3350, 1610,
1585, 1560 cm-1. 1H NMR (CDCl3) δ: 2.68 (s, 12H, 2 x N(CH3)2), 3.85 (br. s, 2H, NH2), 6.25-6.85(m,4H,
Ar-H). MS: m/z 206 (M+).
ACKNOWLEDGMENTS
This work was supported in part by a Grant-in-Aid for the High Technology Research Programs from
Ministry of Education, Culture, Sports, Science and Technology in Japan. We are grateful to the
Instrumental Analytical Center of Hokkaido University for elemental analyses.
REFERENCES
1. a) E. Çetinkaya, B. Alici. Y. Gök, R. Durmaz, and S. Günal, J. Chemother., 1999, 11, 83 and
references cited therein. b) Í. Ören, Ö. Temiz, Í. Yalçin, E. Sener, and N. Altanlar, Eur. J. Pharm.
Sci., 1998, 7, 153 and references cited therein.
2. a) A. Monge, M. d-C. Pena, J. A. Palop, J. M. Caldero, J. Roca, E. Garcia, G. Romero, J. Del Rio,
and B. Lasheras, J. Med. Chem., 1994, 37, 1320. b) M. Yamada, Y. Sato, K. Kobayashi, F. Konno,
T. Soneda, and T. Watanabe, Chem. Pharm. Bull., 1998, 46, 445.
3. A. Orjales, M. Bordell, and V. Rubio, J. Heterocycl. Chem., 1995, 32, 707.
4. R. Benassi, R. Grandi, U. M. Pagnoni, F. Taddei, G. Bocelli, and P. Sgarabotto, J. Chem. Soc.,
Perkin Trans. II, 1985, 1513.
5. L. Joseph and A. H. Albert, J. Hetrocycl. Chem., 1966, 3, 107.
6. J. Sam and S. B. Advani, J. Hetrocycl. Chem., 1967, 4, 141.
7. H. Eilingsfeld, G. Neubauer, M. Seefelder, and H. Weidinger, Chem. Ber., 1963, 97, 1232.
In this paper, 2-chloro-1,1,3,3-tetramethylformamidinium chloride (2) was prepared from
tetramethylurea with phosgene (COCl2) in dry THF at reflux in 96 % yield, mp 110-112℃.