Unusual difluoromethylation of 2-mercaptoazoles

Article abstract of DOI:10.1016/S0022-1139(01)00350-5

The conditions for difluoromethylation of 2-mercaptobenzimidazoles with difluorocarbene (CHClF₂ in alkaline medium) at the sulfur atom or at two reaction centres - sulfur and nitrogen or two nitrogen atoms - were found. In the similar reaction,

Full text of DOI:10.1016/S0022-1139(01)00350-5

Journal of Fluorine Chemistry 108 .2001) 211±214
Unusual di¯uoromethylation of 2-mercaptoazoles
K.I. Petko, L.M. Yagupolskii*
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya Street, Kiev 02094, Ukraine
Received 29 November 2000; accepted 25 January 2001
Abstract
The conditions for di¯uoromethylation of 2-mercaptobenzimidazoles with di¯uorocarbene .CHClF2 in alkaline medium) at the sulfur
atom or at two reaction centres Ð sulfur and nitrogen or two nitrogen atoms Ð were found. In the similar reaction, 2-mercapto-4.5)-.4-
nitrophenyl)imidazole gives the product of bis.di¯uoromethylation) at the sulfur and nitrogen atoms. Benzimidazoles with two ¯uorinated
alkyl substituents at the two nitrogen atoms were prepared for the ®rst time. The N-di¯uoromethyl derivative of benzothiazole-2-thione was
obtained by this procedure. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: 2-Mercaptoazoles; Di¯uorocarbene; 1,3-Bis.di¯uoromethyl)benzimidazole-2-thione
1. Introduction
SCHF2 group. The bis.di¯uoromethylation) product 6 was
isolated from the reaction mixture in a low yield of 5%
.Scheme 2).
An electron-donor ethoxy substituent in the aromatic ring
enhances the nucleophilicity of the nitrogen atom and makes
possible the di¯uoromethylation of 5.6)-ethoxy-2-mer-
capto-benzimidazole .7) at the two reaction centres. The
reaction furnishes a dif®cult-to-separate 1:1 mixture of
isomers 8 and 9 together with the product of di¯uoromethy-
lation at the sulfur atom 10 .Scheme 3).
In order to effect di¯uoromethylation of 2-mercaptoben-
zimidazole simultaneously at the two reaction centres we
used more severe reaction conditions, i.e. solid potassium
hydroxide in anhydrous dimethylformamide. The reaction
proceeded with strongevolution of heat to give the products
of di¯uoromethylation at the sulfur and nitrogen atoms
simultaneously .6) and at the sulfur atom only .5) together
with unexpected product, 1,3-bis-.di¯uoromethyl)benzimi-
dazole-2-thione 11 .Scheme 4).
Di¯uoromethylation reactions of phenols and thiophenols
with chlorodi¯uoromethane in an alkaline medium are well-
studied [1]. Similar di¯uoromethylation at nitrogen atom is
also known for some heterocyclic bases [2,3] and dithio-
carbamates, the ambident systems containingreactive nitro-
gen and sulfur atoms [4].
In the present work, we investigated the interaction of
di¯uorocarbene, formed from CHClF2 in alkaline medium,
with 2-mercaptoazoles havingtwo reaction centres, the thiol
and the less nucleophilic heterocyclic nitrogen atom.
2. Results and discussion
It was found that the di¯uoromethylation of 2-mercapto-
4.5)-.4-nitrophenyl)imidazole 1 occurred simultaneously at
the two reaction centres. Only one of the two heterocyclic
nitrogen atoms was involved in the reaction with the for-
mation of compound 2. The alternative isomer 3 was not
formed presumably due to steric and electron-withdrawing
effects of the 4-nitrophenyl substituent .Scheme 1).
2-Mercaptobenzimidazole 4 is di¯uoromethylated under
the conditions indicated above, mainly at the sulfur atom to
afford compound 5. Di¯uorocarbene very slowly reacts with
the secondary nitrogen atom of the benzimidazole ring as its
nucleophilicity is decreased by the electron-withdrawing
Benzimidazole derivatives with ¯uorinated alkyl substi-
tuents at the two nitrogen atoms of the heterocycle were
previously unknown.
It is likely that in a strongly alkaline medium 2-mercap-
tobenzimidazole 4 gives the dianion 12 which is attacked by
di¯uorocarbenes on the two reaction centres and is trans-
formed into the dianion 13. The presence of two negative
charges in the latter increases the electron density at the
second nitrogen atom. This makes possible the interaction of
the electrophilic di¯uorocarbene with this atom and the
formation of the intermediate 14 which is stabilised by
elimination of the: CF2 group either from the nitrogen or
* Correspondingauthor. Fax: ‡380-44-573-26-43.
E-mail address: lev@fluor-ukr.kiev.ua .L.M. Yagupolskii).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 . 0 1 ) 0 0 3 5 0 - 5

212
K.I. Petko, L.M. Yagupolskii / Journal of Fluorine Chemistry 108 12001) 211±214
Scheme 1.
Scheme 2.
Scheme 4.
from the sulfur atom to give bis.di¯uoromethylated) pro-
ducts 6 and 11 .Scheme 5).
It was shown that, on heatingcompound 6 with solid KOH
in DMF in the absence of CHClF2, there occurred the
abstraction of the di¯uoromethyl group from the nitrogen
atom and the formation of 2-di¯uoromethylthiobenzimida-
Scheme 3.
Scheme 5.

K.I. Petko, L.M. Yagupolskii / Journal of Fluorine Chemistry 108 12001) 211±214
213
.30 ml) and KOH .16.8 g, 0.3 mol) CHClF2 gas was bubbled
for 3 h at a temperature of 70±758C. After keepingthe
reaction mixture at 08C for 12 h, the precipitate formed
was ®ltered off, washed with water .3 Â 50 ml), dried at
508C, and crystallised from 2-propanol. Yield 5.30 g.72%),
mp 126±1278C 1H NMR .DMSO-d6): d ˆ 7:58 .t,
JHÀF ˆ 55 Hz, 1H); 7.89 .t, JHÀF ˆ 59 Hz, 1H); 8.13±
8.17, 8.27±8.31 .m, 4H); 8.75 .s, 1H). 19F NMR .CDCl3):
d ˆ À93:66 .d, JFÀH ˆ 59 Hz, 2F); À91.65 .d,
JFÀH ˆ 55 Hz, 2F). Found: C 40.95; H 2.24; N 12.94,
calculated for C11H7F4N3O2S: C 41.12; H 2.20; N 13.08%.
Scheme 6.
zole 5. This ®ndingindicates that the rearrangement via
migration of the: CF2 group from the sulfur to nitrogen atom
in the formation of 11 is unlikely.
5.6)-Ethoxy-2-mercapto-benzimidazole 7 reacts with
CHClF2 and solid KOH in DMF in much the same fashion
as 2-mercaptobenzimidazole 4 to give 1,3-bis.di¯uoro-
methyl)-5-ethoxybenzimidazole-2-thione .15) in about
25% yield and the products of di¯uoromethylation at the
nitrogen and sulfur atoms 8±10 .Scheme 6).
On di¯uoromethylation of 2-mercaptobenzothiazole 16
under the same conditions as above, besides the previously
described di¯uoromethylthio derivative 17 [5,6], there was
isolated the N-di¯uoromethylated product 18 in 16% yield.
The low yield of 18 is probably accounted for by lower
electron density on the nitrogen atom of the anion derived
from 2-mercaptobenzothiazole compared to the dianion 12
.Scheme 7).
3.1.2. 2-Difluoromethylthiobenzimidazole 15)
Through a stirred solution of 4 .2 g, 0.013 mol) in a
mixture of 2-propanol .10 ml), water .10 ml) and KOH
.7.8 g, 0.14 mol) CHClF2 gas was bubbled for 4 h at 70±
758C. Absorption of the gas was observed only during the
®rst 20 min. The reaction mixture was ®ltered, the organic
layer was separated and the aqueous layer was extracted
with diethyl ether .3 Â 20 ml). The combined organic solu-
tions were washed with water .3 Â 30 ml) and dried
.MgSO4, 12 h). The combined aqueous solutions were
neutralised to pH 8 with 10% aq. HCl and the white
precipitate .crude 5) was ®ltered and dried.
The organic extracts were evaporated. Hexane .10 ml)
was added to the residue and the mixture was stirred for
5 min. The undissolved residue was ®ltered off and com-
bined with the crude 5, which was crystallised from 2-
propanol to give pure 5. Yield 1.50 g.56%), mp 206±
2088C. 1H NMR .acetone-D6): d ˆ 7:30±7.35 .m, 2H);
7.36 .t, JHÀF ˆ 55 Hz, 1H); 7.40±7.46 .m, 2H); 9.60
.br.s, 1H). 19F NMR .acetone-D6): d ˆ À92:05 .d,
JFÀH ˆ 55 Hz, 2F). IR: 3480 cmÀ1 .NH). Found: N
14.18; S 16.17, calculated for C8H6F2N2S: N 13.99; S
16.02%.
Thus, we have found the reaction conditions for prepara-
tion of bis.di¯uoromethylated) benzimidazoles with CHF2
groups at the sulfur and one nitrogen atom or at two nitrogen
atoms and the N-di¯uoromethyl derivative of benzothiazole-
2-thione.
3. Experimental
3.1. General
The hexane extract was evaporated to leave crude 6
.>80% purity shown by 19F NMR spectra). Yield 0.17 g
.5%).
Boilingand meltingpoints are uncorrected. 1H NMR:
Varian VXR-300 .300 MHz, TMS as internal standard). 19
F
NMR: Varian VXR-300 .288 MHz, CCl3F as internal stan-
dard). IR spectra were measured on an UR-20 spectro-
photometer in CCl4 solutions.
3.1.3. 1-Difluoromethyl-2-difluoromethylthio-5
and 6-ethoxybenzimidazoles 18 and 9) and
2-difluoromethylthio-516)-ethoxybenzimidazole 110)
The reaction was carried out as above by using 7 .0.97 g,
0.005 mol), KOH .2.8 g, 0.05 mol), water .5 ml) and 2-
propanol .5 ml).
3.1.1. 1-Difluoromethyl-2-difluoromethylthio-4-14-
nitrophenyl)imidazole 12)
Through a vigorously stirred suspension of 1 .5 g,
0.0225 mol) in a mixture of 2-propanol .30 ml), water
The products 8 and 9 were isolated as a semisolid mass
by vacuum distillation. Yield 0.6 g.41%), bp 146±150 8C
Scheme 7.

214
K.I. Petko, L.M. Yagupolskii / Journal of Fluorine Chemistry 108 12001) 211±214
.0.02 Torr). 1H NMR .CD3CN): d ˆ 1:34 .t, 3H); 1.35
.t, 3H); 3.98 .q, 2H); 4.01 .q, 2H); 7.00±7.15 .m, 2H);
7.20±7.27 .m, 2H); 7.34 .t, JHÀF ˆ 55 Hz, 1H); 7.41
.t, JHÀF ˆ 55 Hz, 1H); 7.60±7.67 .m, 2H); 7.68
.t, JHÀF ˆ 59 Hz, 1H); 7.71 .t, JHÀF ˆ 59 Hz, 1H). 19F
NMR .CDCl3): d ˆ À96:73 .d, JFÀH ˆ 59 Hz, 2F);
À96.06 .d, JFÀH ˆ 59 Hz, 2F); À91.60 .d, JFÀH ˆ 55 Hz,
4F). Found: N 9.93; S 10.77, calculated for C11H10F4N2 OS:
N 9.52; S 10.89%.
®ltered off, dried, and crystallised from 2-propanol. Yield
0.53 g.8%).
3.1.5. 1,3-Bis1difluoromethyl)-5-ethoxy-
benzimidazole-2-thione 115)
The reaction was carried out as above by using 7 .0.97 g,
0.005 mol), KOH .2 g, 0.035 mol) and DMF .4 ml). After
pouringinto water, the mixture of products was extracted
with diethyl ether, dried .MgSO4, 12 h), and chromato-
graphed on a silica gel .MN-Kieselgel-60, eluent CCl4) to
give 0.36 g .24%) of 15 as white crystals, Rf ˆ 0:7, mp 117±
1188C .from hexane). 1H NMR .CDCl3): d ˆ 1:35 .t, 3H);
4.00 .q, 2H); 7.00±7.30 .m, 3H); 7.86 .t, JHÀF ˆ 58 Hz, 1H);
7.90 .t, JHÀF ˆ 58 Hz, 1H). 19F NMR .CDCl3):
d ˆ À104:48 .d, JFÀH ˆ 58 Hz, 2F); À103.59 .d,
JFÀH ˆ 59 Hz, 2F). Found: N 9.73; S 10.51, calculated
for C11H10F4N2OS: N 9.52; S 10.89%.
Product 10 was crystallised from 2-propanol. Yield 0.29 g
1
.24%), mp 136±1378C. H NMR .DMSO-d6): d ˆ 1:34 .t,
3H); 4.01 .q, 2H); 7.10±7.40 .m, 3H); 7.74 .t, JHÀF ˆ 55 Hz,
1H); 12.95 .br.s, 1H). 19F NMR .DMSO-d6): d ˆ À91:40 .d,
JFÀH ˆ 55 Hz, 2F). IR: 3480 cmÀ1 .NH). Found: N 11.25; S
13.32, calculated for C10H10F2N2 OS: N 11.47; S 13.13%.
3.1.4. 1,3-Bis1difluoromethyl)benzimidazole-
2-thione 111) and 1-difluoromethyl-2-difluoromethyl-
thiobenzimidazole 16)
The mixture of 8 and 9 was also separated by chromato-
graphy .MN-Kieselgel-60, eluent CCl4). Yield 0.33 g
.22%). Compound 10 was isolated from aqueous solution.
Yield 0.085 g.7%).
To a vigorously stirred solution of 4 .4.5 g, 0.03 mol) in
anhydrous DMF .20 ml) was added ®nely crushed KOH
.3.8 g, 0.067 mol) in one portion and an intense stream of
CHClF2 was bubbled through the suspension until the rate of
absorption decreased .3±4 min). The temperature rose there-
with to 50±608C. Then, with stirringand intense bubbling, a
second portion of KOH .9.3 g, 0.165 mol) was added. The
reaction mixture turned greenish-blue and the temperature
rose to 110±1208C in 1±2 min. After 5 min the absorption of
the gas stopped and the colour disappeared. The reaction
mixture was cooled and poured into water .150 ml). The
precipitated solid was ®ltered to separate it from the oil,
washed with cold hexane .10 ml), dried at 308C, and crystal-
lised from hexane with a silica gel additive to give pure 11 as
longcolourless needles. Yield 2.15 g.28%), mp 121±122 8C.
1H NMR .CD3CN): d ˆ 7:40±7.50 .m, 2H); 7.58±7.68 .m,
2H); 8.02 .t, JHÀF ˆ 58 Hz, 2H). 19F NMR .CD3CN):
d ˆ À104:32 .d, JFÀH ˆ 58 Hz, 4F). Found: N 11.34; S
12.62, calculated for C9H6F4N2S: N 11.20; S 12.81%.
The oil separated from crude 11 was extracted with
hexane .3 Â 40 ml). The extract was dried .MgSO4, 12 h)
and combined with the mother liquor from crystallisation of
11. The solvent was evaporated and the residue was chro-
matographed on a silica gel column .MN-Kieselgel-60,
eluent CCl4) to give an additional portion of 11 .0.75 g,
11%, Rf ˆ 0:8; overall yield 39%) and 6 .Rf ˆ 0:3) as a
yellow oil which solidi®ed into colourless crystals after
vacuum distillation. Yield 2.58 g.34%), bp 80±81 8C
3.1.6. 2-Difluoromethylthiobenzothiazole 117) and 1-
difluoromethylbenzothiazole-2-thione 118)
To a vigorously stirred solution of 16 .8.3 g, 0.05 mol) in
DMF .25 ml) ®nely crushed KOH .14.2 g, 0.25 mol) was
added in one portion and an intense stream of CHClF2 was
bubbled through the suspension. The temperature rose to
608C in 1±2 min. The reaction mixture was heated to 1108C
and, after stirringwith bubblingfor 10 min, it was cooled
and poured into water. The oil formed was extracted with
diethyl ether .3 Â 50 ml). The extract was dried .MgSO4)
and, after evaporation of the solvent, 17 and 18 were
separated by column chromatography .MN-Kieselgel-60,
eluent CCl4).
17: Yellow oil, solidi®ed after vacuum distillation, Rf ˆ
0:55, yield 5.34 g.50%), bp 78±80 8C .0.5 Torr); lit.: 708C
.0.2 Torr) [5], mp 358C .from hexane); lit.: 34±358C [6].
18: Colourless crystals, Rf ˆ 0:8, yield 1.76 g.16%), mp
1
51±528C .from hexane). H NMR .CDCl3): d ˆ 7:32±7.48
.m, 3H); 7.64±7.68 .m, 1H); 8.15 .t, JHÀF ˆ 58 Hz, 1H). 19
F
NMR .CDCl3): d ˆ À107:17 .d, JFÀH ˆ 58 Hz, 2F). Found:
N 6.60; S 30.18, calculated for C8H5F2NS2: N 6.45; S
29.52%.
References
1
.0.07 Torr), mp 55±578C .from hexane). H NMR .acet-
[1] L.M. Yagupolskii, Aromatic and Heterocyclic Compounds with
Fluorine-containingSubstituents, Naukova Dumka, Kiev, 1988 .in
Russian).
one-D6): d ˆ 7:15±7.25 .m, 1H); 7.40±7.50 .m, 2H); 7.51 .t,
JHÀF ˆ 55 Hz, 1H); 7.76 .t, JHÀF ˆ 59 Hz, 1H); 7.80±7.85
.m, 1H). 19F NMR .acetone-D6): d ˆ À96:03 .d,
JFÀH ˆ 59 Hz, 2F); À92.42 .d, JFÀH ˆ 55 Hz, 2F). Found:
N 11.24; S 12.87, calculated for C9H6F4N2S: N 11.20; S
12.81%.
[2] V.G. Poludnenko, O.B. Didinskaya, A.F. Pozharskii, Khim. Geter-
otsikl. Soedin. .1984) 520.
[3] J.W. Lyga, R.M. Patera, J. Fluor. Chem. 92 .1998) 141.
[4] K.I. Petko, L.M. Yagupolskii, Z. Org. Khim. 34 .1998) 712.
[5] M.S. Raash, US Patent 3,153,653 .1963), CA 62,1666b .1965).
[6] L.M. Yagupolskii, N.A. Malichenko, Z. Obshch. Khim. 36 .1966)
1983.
The water solution left after extraction with hexane was
neutralised to pH 8 with 10% aq. HCl and precipitated 5 was