Multigram synthesis of 1-(difluoromethyl)imidazoles and -benzimidazoles

Article abstract of DOI:10.1055/s-0030-1258470

An expedient approach to the difluoromethylation of imidazoles and benzimidazoles has been developed. The key feature of the procedure is the gradual generation of the difluoromethylation reagent in the reaction mixture, which is achieved by the simultane

Full text of DOI:10.1055/s-0030-1258470

PAPER
1243
Multigram Synthesis of 1-(Difluoromethyl)imidazoles and -benzimidazoles
1
-(Difluoromethyl
a
)imidazoles
d
a
nd-benzim
y
idazoles m Levterov,a Oleksandr O. Grygorenko,*a,b Pavel K. Mykhailiuk,*a,b Andrey A. Tolmacheva,b
a
Enamine Ltd., Alexandra Matrosova Street 23, 01103 Kiev, Ukraine
Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska Street 64, 01033 Kiev, Ukraine
Fax +380(44)2351273; E-mail: gregor@univ.kiev.ua; E-mail: pavel.mykhailiuk@gmail.com
b
Received 30 November 2010; revised 12 February 2011
N
Abstract: An expedient approach to the difluoromethylation of
imidazoles and benzimidazoles has been developed. The key fea-
ture of the procedure is the gradual generation of the difluorometh-
ylation reagent in the reaction mixture, which is achieved by the
simultaneous addition of chlorodifluoromethane and alkali. The
method is applicable to functionalized substrates and allows the cor-
responding 1-(difluoromethyl)imidazoles and -benzimidazoles to
be prepared in 60–95% yield on a hundred-gram scale.
NH
Cl
X
F
O
N
F
F
O
N
N
R
N
N
F
F
F
5, R = NHSO2Me, X = Cl
6, R = CH2CH(Cl)COOEt, X = F
4
Key words: fluorine compounds, heterocycles, imidazoles, benz-
imidazoles, difluoromethylation
Figure 2
In this work, our results on the N-difluoromethylation of
imidazoles and benzimidazoles are described. Several ap-
proaches to the synthesis of 1-(difluoromethyl)imidazoles
and -benzimidazoles have been reported to date, including
either reduction of the corresponding 1-(bromodifluoro-
methyl)imidazoles and -benzimidazoles,11,12 or N-difluoro-
methylation of the parent heterocycles with
chlorodifluoromethane,13–18 sodium trifluoroacetate,14
methyl chlorodifluoroacetate,15 chlorodifluoromethyl
phenyl sulfone,19 N-tosyl-S-difluoromethyl-S-phenyl-
sulfoximine20 and other reagents.21,22 Of these sources of
the difluoromethyl group, we turned our attention to chlo-
rodifluoromethane which is readily available commercial-
ly. In most of the previous reports, mixed aqueous organic
solvent systems were used for the N-difluoromethylation
of imidazoles and benzimidazoles with chlorodifluo-
romethane, including aqueous potassium hydroxide in
dioxane,13,17 acetone,14 2-propanol16 and N,N-dimethyl-
formamide,17 as well as tetrahydrofuran or dichlo-
romethane in the presence of benzyltriethylammonium
chloride as a phase-transfer catalyst.18,23 Whereas difluo-
romethylation of the parent benzimidazole and 2-alkyl-
benzimidazoles could be performed in moderate to good
yields (57–87%), in the case of imidazoles the yield of the
corresponding products was diminished significantly (37–
44%).13,14,16,18 Moreover, reactions of functionalized ben-
zimidazoles were complicated by over-difluoromethyla-
tion and other side processes.16–18
The introduction of fluorine-containing groups into or-
ganic molecules represents an important structure modifi-
cation owing to the unique properties of the fluorine
atom.1–3 Nearly 20% of pharmaceuticals, including sever-
al of the top drugs, and 30–40% of agrichemicals contain
fluorine.4 Among other organofluorine compounds, those
possessing a difluoromethyl group (CHF2) can be delin-
eated. Several examples of difluoromethyl-substituted
drugs can be found on the market, including Eflornithine
(1),5 Pantoprazole (2)6 and Garenoxacin (3)7 (Figure 1).
Heterocyclic compounds containing a difluoromethyl
substituent at the nitrogen atom are found among potential
drug candidates (e.g., compound 4 which is a neuropep-
tide Y antagonist8) and as agrichemicals [in particular,
Sulfentrazone (5)9 and Carfentrazone-ethyl (6)10]
(Figure 2).
OMe
MeO
F
N
O
NH2
F
F
N
S
COOH
H2N
O
F
N
H
1
2
O
N
HOOC
O
Imidazoles and benzimidazoles 7a–i considerably varied
in their chemical structure were used as model substrates
in this study (Table 1). The main idea behind our ap-
proach to the difluoromethylation of 7a–i was to avoid a
large excess of strong alkali in the reaction mixture, thus
preventing decomposition of chlorodifluoromethane and
some of the products.
F
NH
F
3
Figure 1 Marketed drugs possessing a difluoromethyl group
SYNTHESIS 2011, No. 8, pp 1243–1248
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1258470; Art ID: N50310SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1
Three types of reaction conditions were developed for the
difluoromethylation of imidazoles and benzimidazoles.
The most general procedure involves the gradual addition

1244
V. Levterov et al.
PAPER
of 35% aqueous potassium hydroxide solution to a solu- ported in the literature afforded mixtures of the corre-
tion of the substrate and dibenzo-18-crown-6 (2 mol%) in sponding products.16,18 In fact, the synthesis of pure 9 has
dioxane, together with constant chlorodifluoromethane not been reported previously; moreover, acetyl-substitut-
bubbling at 70 °C. In particular, difluoromethylation of ed benzimidazole 8h was isolated in only 13% yield prior
the functionalized benzimidazoles 7e–h and imidazole 7i to this work.18
was performed using this procedure. The corresponding
products 8e–i were obtained in 65–86% yield (Table 1). In
the case of substrates 7e and 7f, no difluoromethylation at
the hydroxy group was observed. On the contrary, only
bis(difluoromethylation) product 8g was obtained from 2-
mercapto-1H-benzimidazole (7g); the mono(difluoro-
methyl) derivative 9 was obtained by hydrazinolysis of 8g
(Scheme 1). It is interesting to note that the methods re-
F
S
H
N
F
N
N
N2H4⋅H2O
S
N
i-PrOH
F
F
F
F
8g
9, 87%
Scheme 1
Table 1 Difluoromethylation of Imidazoles and Benzimidazoles 7a–i
Substrate
Conditions
Product
Yield (%)
75
N
N
N
CHClF2, dibenzo-18-crown-6 (2 mol%),
35% aq KOH, DME, 70 °C
7a
8a
N
H
F
F
N
N
CHClF2, dibenzo-18-crown-6 (2 mol%),
35% aq KOH, DME, 70 °C
7b
7c
7d
7e
7f
8b
8c
8d
8e
8f
60
89
95
69
65
N
N
H
F
F
N
N
CHClF2, K2CO3, DMF, 90 °C
CHClF2, K2CO3, DMF, 90 °C
N
N
H
F
F
F
F
F
N
N
N
N
H
F
OH
OH
N
OH
OH
N
CHClF2, dibenzo-18-crown-6 (2 mol%),
35% aq KOH, dioxane, 70 °C
N
N
H
F
N
N
N
CHClF2, dibenzo-18-crown-6 (2 mol%),
35% aq KOH, dioxane, 70 °C
N
H
F
F
F
N
N
N
CHClF2, dibenzo-18-crown-6 (2 mol%),
35% aq KOH, dioxane, 70 °C
S
7g
7h
7i
8g
8h
8i
68
70
86
SH
N
H
F
F
O
N
O
N
CHClF2, dibenzo-18-crown-6 (2 mol%),
35% aq KOH, dioxane, 70 °C
N
N
H
F
F
OH
N
N
N
CHClF2, dibenzo-18-crown-6 (2 mol%),
35% aq KOH, dioxane, 70 °C
N
H
N
N
F
OH
F
Synthesis 2011, No. 8, 1243–1248 © Thieme Stuttgart · New York

PAPER
1-(Difluoromethyl)imidazoles and -benzimidazoles
1245
We have studied the effect of the phase-transfer catalyst hydroxide, concentrated hydrochloric acid or hydrazine
on the difluoromethylation reactions of 7e–i described hydrate in 2-propanol. Therefore, compounds 8a–i can be
above (Table 2). It was found that, at similar catalyst load- used in further chemical transformations even under rath-
ings, dibenzo-18-crown-6 gives similar or remarkably er drastic conditions. In particular, imidazole 8a under-
higher yields of the products than tetrabutylammonium went hydroxymethylation with formaldehyde at 125 °C to
chloride (TBACl). Increasing the catalyst loading of afford alcohol 10 in 90% yield. Reaction of alcohol 10
dibenzo-18-crown-6 from 2% to 5% did not improve the with thionyl chloride resulted in almost quantitative for-
yield significantly.
mation of halide 11. Compound 11 was introduced into a
nucleophilic substitution reaction; thus, reaction with po-
tassium cyanide afforded nitrile 12 which was isolated in
77% yield (Scheme 2). Analogously, nitrile 14 was ob-
tained from 2-(hydroxymethyl)benzimidazole 8e in two
steps via formation of the chloride 13 (Scheme 3).
Table 2 Influence of the Phase-Transfer Catalyst on the Difluoro-
methylation of (Benz)imidazoles 7e–i
Substrate Phase-transfer catalyst
Product Yield (%)
7e
7e
7e
7f
dibenzo-18-crown-6 (2 mol%)
8e
8e
8e
8f
69
71
71
65
69
68
57
70
73
86
64
N
N
dibenzo-18-crown-6 (5 mol%)
TBACl (2 mol%)
OH
CH2O, H2O
125 °C, 24 h
N
N
F
F
F
dibenzo-18-crown-6 (2 mol%)
TBACl (2 mol%)
F
8a
10, 90%
7f
8f
SOCl2
C6H6
.HCl
7g
7g
7h
7h
7i
dibenzo-18-crown-6 (2 mol%)
TBACl (2 mol%)
8g
8g
8h
8h
8i
N
N
CN
Cl
KCN
N
N
dibenzo-18-crown-6 (2 mol%)
TBACl (2 mol%)
CH2Cl2
F
F
F
F
12, 77%
11, 99%
dibenzo-18-crown-6 (2 mol%)
TBACl (2 mol%)
Scheme 2
7i
8i
.HCl
N
N
N
In the case of the difluoromethylation of imidazoles 7a
and 7b, the choice of solvent for the reaction was limited
by the relative volatility of 8a,b which were purified by
distillation. Thus, dioxane was replaced by the more ex-
pensive and more volatile 1,2-dimethoxyethane (DME).
The difluoromethylation products 8a and 8b were ob-
tained in 75% and 60% yield, respectively, as colorless
liquids (see Table 1).
KCN
SOCl2
N
N
N
C6H6
OH
DMSO
Cl
CN
F
F
F
F
F
F
8e
13, 99%
14, 57%
Scheme 3
In conclusion, practical procedures for the difluoromethy-
lation of imidazoles and benzimidazoles have been devel-
oped. The method opens an entry to the multigram
synthesis of the corresponding 1-(difluoromethyl)imida-
zoles and -benzimidazoles. The most general procedure
The reaction of 2-methyl-1H-benzimidazole (7c) under
the conditions described above was much slower; in this
case, the product 8c was obtained in 63% yield. We as-
sume that the higher lipophilicity of 7c compared to other
substrates might be related to that fact. An alternative pro- involves the gradual addition of aqueous alkali to a solu-
cedure for the difluoromethylation of 7c was developed, tion of the substrate and the phase-transfer catalyst in di-
oxane, together with constant chlorodifluoromethane
bubbling. A slightly modified procedure (DME instead of
dioxane as the solvent) was used when volatile difluoro-
methylation products were obtained. Finally, a potassium
carbonate–N,N-dimethylformamide system was fruitful in
the case of more lipophilic benzimidazoles containing no
additional functional groups.
which included heating a mixture of the substrate and po-
tassium carbonate in N,N-dimethylformamide at 90 °C for
two hours, together with constant chlorodifluoromethane
bubbling (see Table 1). Difluoromethylation of benzimi-
dazole 7d was performed under similar conditions. This
procedure allowed the corresponding products 8c and 8d
to be obtained in excellent yields (89% and 95%, respec-
tively). Application of these conditions to the functional-
ized benzimidazoles appeared to be fruitless; tar
formation was observed in these cases.
Solvents were purified according to standard procedures. Com-
pounds 7d,24 7h25 and 7i26 were prepared according to the methods
reported in the literature. Starting materials were purchased from
Acros, Merck and Fluka. Analytical TLC was performed using
The N-difluoromethyl group in the molecules of 8a–i
showed remarkable stability: it remained intact upon re-
fluxing these compounds with 40% aqueous potassium
1
Polychrom SI F254 plates. H, 13C and 19F NMR spectra were re-
corded on a Bruker 170 Avance 500 spectrometer (at 499.9 MHz
Synthesis 2011, No. 8, 1243–1248 © Thieme Stuttgart · New York

1246
V. Levterov et al.
PAPER
for 1H, 124.9 MHz for 13C and 470.3 MHz for 19F). Chemical shifts
are reported in ppm downfield from TMS (1H, 13C) or CFCl3 (19F)
as an internal standard. Elemental analyses were performed on an
Elementar vario MICRO cube CHNS/O analyzer. Mass spectra
were recorded on an Agilent 1100 LC/MSD SL instrument [chemi-
cal ionization (CI)]. The ozone depletion potential of chlorodifluo-
romethane is no longer considered acceptable in many countries.
On a large scale, excess of this reagent can be trapped by hot 40%
aq KOH.
19F NMR (DMSO-d6): d = –92.09 (d, J = 60 Hz, CHF2).
MS (APCI): m/z = 259 [M + H]+.
Anal. Calcd for C15H12F2N2: C, 69.76; H, 4.68; N, 10.85. Found: C,
69.93; H, 4.38; N, 11.09.
1-(Difluoromethyl)(benz)imidazoles 8e–i; General Procedure
A (benz)imidazole 7e–i (1 mol), dibenzo-18-crown-6 (7.2 g, 0.02
mol) and dioxane (1 L) were placed into a 2-L flask equipped with
a condenser, a mechanical stirrer, a gas bubble inlet and a dropping
funnel, and heated to 70 °C. CHClF2 was bubbled through and 35%
aq KOH soln was gradually added to the reaction mixture until dis-
appearance of the starting (benz)imidazole by TLC (approx. 3 mol
of the alkali). The consumption of the KOH soln was monitored by
pH control (indicator paper, pH = 9–11). After the reaction was
complete, the mixture was cooled, the aqueous salt layer was sepa-
rated and the organic phase was concentrated under reduced pres-
sure. The residue was dissolved in benzene (600 mL). The resulting
solution was washed with 10% aq KOH (200 mL) and H2O (200
mL), dried over Na2SO4 and concentrated to dryness. The product
was recrystallized [benzene (8e,f,i) or hexanes with charcoal
(8g,h)].
1-(Difluoromethyl)imidazoles 8a,b; General Procedure
Imidazole 7a or 7b (1 mol), dibenzo-18-crown-6 (7.2 g, 0.02 mol)
and DME (1 L) were placed into a 2-L flask equipped with a con-
denser, a mechanical stirrer, a gas bubble inlet and a dropping fun-
nel, and heated to 65–70 °C. CHClF2 was bubbled through and 35%
aq KOH soln was gradually added to the reaction mixture until dis-
appearance of the starting imidazole by TLC (approx. 3 mol of the
alkali). The consumption of the KOH soln was monitored by pH
control (indicator paper, pH = 9–11). After the reaction was com-
plete, the mixture was cooled, the aqueous salt layer was separated
and the organic phase was concentrated under reduced pressure at
r.t. The residue was distilled under reduced pressure.
[1-(Difluoromethyl)-1H-benzimidazol-2-yl]methanol (8e)
Yield: 137 g (69%); yellowish solid; mp 162 °C.
1-(Difluoromethyl)-1H-imidazole (8a)
Yield: 295 g (75%); colorless liquid; bp 79 °C/12 mmHg.
1H NMR (DMSO-d6): d = 8.09 (t, J = 58.1 Hz, 1 H, CHF2), 7.72 (d,
J = 9.0 Hz, 1 H), 7.70 (d, J = 9.0 Hz, 1 H), 7.33–7.40 (m, 2 H), 5.99
(t, J = 5.5 Hz, 1 H, OH), 4.87 (d, J = 5.5 Hz, 2 H, CH2OH).
13C NMR (DMSO-d6): d = 153.2, 142.6, 131.9, 124.7, 124.1, 120.4,
112.5, 110.2 (t, J = 245 Hz, CHF2), 57.2.
19F NMR (DMSO-d6): d = –98.2 (d, J = 58 Hz, CHF2).
MS (APCI): m/z = 199 [M + H]+.
For spectroscopic and physical data, see ref.18
1-(Difluoromethyl)-2-methyl-1H-imidazole (8b)
Yield: 79 g (60%); colorless liquid; bp 70 °C/12 mmHg.
1H NMR (DMSO-d6): d = 7.00 (t, J = 60.3 Hz, 1 H, CHF2), 6.92 (s,
1 H), 6.72 (s, 1 H), 2.28 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 143.92 (s), 128.29 (s), 115.45 (s), 108.35
(t, J = 247.5 Hz, CHF2), 13.08 (s, CH3).
19F NMR (DMSO-d6): d = –93.36 (d, J = 60 Hz, CHF2).
MS (APCI): m/z = 133 [M + H]+.
Anal. Calcd for C9H8F2N2O: C, 54.55; H, 4.07; N, 14.14. Found: C,
54.31; H, 3.84; N, 14.12.
1-[1-(Difluoromethyl)-1H-benzimidazol-2-yl]ethanol (8f)
Yield: 63 g (65%); colorless solid; mp 66 °C.
For spectroscopic and physical data, see ref.18
Anal. Calcd for C5H6F2N2: C, 45.46; H, 4.58; N, 21.20. Found: C,
45.71; H, 4.23; N, 20.97.
1-(Difluoromethyl)benzimidazoles 8c,d; General Procedure
Benzimidazole 7c or 7d (0.1 mol), K2CO3 (60 g, 0.43 mol) and
DMF (300 mL) were placed into a 1-L flask equipped with a con-
denser, a stirrer, a gas bubble inlet and a dropping funnel, and heat-
ed to 90 °C. CHClF2 was bubbled through the reaction mixture until
disappearance of the starting benzimidazole by TLC. After the re-
action was complete, the mixture was cooled and poured into H2O
(1.5 L). The product was collected by filtration and washed with
H2O (3 × 150 mL). If no solid product was formed (e.g., for 8c), the
mixture obtained after pouring into H2O was extracted with hexanes
(3 × 300 mL). The combined extracts were concentrated, and the
crude product was recrystallized (hexanes with charcoal).
1-(Difluoromethyl)-2-[(difluoromethyl)sulfanyl]-1H-benzimi-
dazole (8g)
Yield: 98 g (68%); colorless solid; mp 60 °C.
For spectroscopic and physical data, see ref.16
1-[1-(Difluoromethyl)-1H-benzimidazol-2-yl]ethanone (8h)
Yield: 35 g (70%); colorless solid; mp 65 °C.
For spectroscopic and physical data, see ref.18
2-[1-(Difluoromethyl)-1H-imidazol-2-yl]-1-phenylethanone
Oxime (8i)
Yield: 18 g (86%); white crystals; mp 150 °C.
1-(Difluoromethyl)-2-methyl-1H-benzimidazole (8c)
Yield: 170 g (89%); colorless solid; mp 84 °C.
For spectroscopic and physical data, see ref.18
1H NMR (DMSO-d6): d = 11.72 (s, 1 H), 7.97 (t, J = 59.1 Hz, 1 H,
CHF2), 7.77 (d, J = 6.4 Hz, 2 H), 7.46 (s, 1 H), 7.35–7.40 (m, 3 H),
6.92 (s, 1 H), 4.33 (s, 2 H).
13C NMR (DMSO-d6): d = 152.2, 143.8, 136.2, 129.3, 129.2, 128.7,
126.7, 116.1, 109.1 (t, J = 247 Hz, CHF2), 24.3.
1-(Difluoromethyl)-2-(4-methylphenyl)-1H-benzimidazole (8d)
Yield: 21 g (95%); yellow crystals; mp 116 °C.
19F NMR (DMSO-d6): d = –91.4 (d, J = 59 Hz, CHF2).
MS (APCI): m/z = 252 [M + H]+.
1H NMR (DMSO-d6): d = 7.87–7.88 (m, 1 H), 7.80–7.81 (m, 1 H),
7.65 (d, J = 8.0 Hz, 2 H), 7.41–7.43 (m, 2 H), 7.39 (d, J = 8.0 Hz, 2
H), 7.32 (t, J = 58.8 Hz, 1 H, CHF2), 2.48 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 152.1, 143.2, 141.3, 129.9, 129.8, 129.3,
125.8, 124.4, 124.3, 120.3, 112.6, 110.3 (t, J = 252.5 Hz, CHF2),
21.5 (s, CH3).
Anal. Calcd for C12H11F2N3O: C, 57.37; H, 4.41; N, 16.73. Found:
C, 56.99; H, 4.28; N, 16.70.
Synthesis 2011, No. 8, 1243–1248 © Thieme Stuttgart · New York

PAPER
1-(Difluoromethyl)imidazoles and -benzimidazoles
1247
1-(Difluoromethyl)-1,3-dihydro-2H-benzimidazole-2-thione (9)
A mixture of bis(difluoromethyl) derivative 8g (250 g, 1 mol), hy-
drazine hydrate (156 g, 3 mol) and i-PrOH (700 mL) was refluxed
for 3 h (monitored by TLC), then cooled and concentrated under re-
duced pressure; the residue was poured into H2O (2 L). The result-
ing mixture was acidified to pH 4–5 with concd HCl; the precipitate
was collected by filtration and washed with H2O (3 × 200 mL).
1H NMR (DMSO-d6): d = 14.10 (br s, 1 H), 8.37 (t, J = 56.8 Hz, 1
H, CHF2), 7.69 (m, 2 H), 7.32–7.36 (m, 2 H), 5.30 (s, 2 H, CH2Cl).
13C NMR (DMSO-d6): d = 148.9, 140.9, 131.4, 125.9, 125.0, 120.1,
112.7, 109.8 (t, J = 248 Hz, CHF2), 36.8 (CH2Cl).
19F NMR (DMSO-d6): d = –95.9 (d, J = 57 Hz, CHF2).
MS (APCI): m/z = 217 [M + H]+.
Yield: 174 g (87%); colorless solid; mp 205 °C (i-PrOH–H2O).
1H NMR (DMSO-d6): d = 13.17 (br s, 1 H, NH), 8.08 (t, J = 58.1
Hz, 1 H, CHF2), 7.50 (d, J = 7.6 Hz, 1 H), 7.26–7.33 (m, 3 H).
Anal. Calcd for C9H8Cl2F2N2: C, 42.71; H, 3.19; Cl, 28.02; N,
11.07. Found: C, 42.86; H, 3.14; Cl, 28.33; N, 10.70.
[1-(Difluoromethyl)-1H-imidazol-2-yl]acetonitrile (12)
To a suspension of finely powdered KCN (260 g, 4 mol) in CH2Cl2
(4 L), dibenzo-18-crown-6 (24 g, 0.067 mol) was added, followed
by chloride 11 (203 g, 1 mol) (CAUTION! HCN is evolved). The
mixture was refluxed with vigorous stirring for 8 h. The mixture
was filtered, and the filtrate was dried over Na2SO4 and then filtered
again. HCl was bubbled through the resulting solution until satura-
tion. The precipitate formed was collected by filtration to give 12 as
the hydrochloride; yield: 177 g (90%).
13C NMR (DMSO-d6): d = 168.5 (C=S), 131.0, 128.0, 124.7, 123.4,
110.64, 110.62, 110.59 (t, J = 246 Hz, CHF2).
19F NMR (DMSO-d6): d = –102.0 (d, J = 58 Hz, CHF2).
MS (APCI): m/z = 201 [M + H]+.
Anal. Calcd for C8H6F2N2S: C, 47.99; H, 3.02; N, 13.99; S, 16.02.
Found: C, 48.16; H, 2.81; N, 14.34; S, 16.15.
[1-(Difluoromethyl)-1H-imidazol-2-yl]methanol (10)
Imidazole 8a (295 g, 2.5 mol) and 40% aq formaldehyde (244 g,
3.25 mol) were heated in an autoclave at 125 °C for 24 h. After the
resulting mixture was cooled, the unreacted starting materials were
distilled off with water steam. The residue was concentrated, and
the crude product was collected by filtration, dried and then recrys-
tallized (CHCl3–hexane).
The hydrochloride was carefully dissolved in sat. aq NaHCO3 (1.2
L). The product 12 was extracted with CH2Cl2 (800 mL, then
2 × 300 mL). The combined organic extracts were dried over
Na2SO4, concentrated and distilled under reduced pressure.
Yield: 121 g (77%); colorless solid; mp 34 °C; bp 97 °C/1 mmHg.
1H NMR (DMSO-d6): d = 7.45 (d, J = 1.2 Hz, 1 H), 7.44 (t, J = 60.2
Hz, 1 H, CHF2), 7.29 (s, 1 H), 4.28 (s, 2 H, CH2CN).
Yield: 333 g (90%); colorless solid; mp 106 °C.
1H NMR (DMSO-d6): d = 7.81 (t, J = 59.8 Hz, 1 H, CHF2), 7.37 (s,
1 H), 6.94 (s, 1 H), 5.74 (br s, 1 H, OH), 4.67 (s, 2 H, CH2OH).
13C NMR (DMSO-d6): d = 136.1, 129.5, 118.4, 114.2, 108.4 (t, J =
251.3 Hz, CHF2), 18.2.
13C NMR (DMSO-d6): d = 147.8, 128.7, 115.8, 108.6 (t, J = 248
19F NMR (DMSO-d6): d = –94.97 (d, J = 60 Hz, CHF2).
MS (APCI): m/z = 158 [M + H]+.
Hz, CHF2), 56.6 (CH2OH).
19F NMR (DMSO-d6): d = –91.7 (d, J = 60 Hz, CHF2).
MS (APCI): m/z = 149 [M + H]+.
Anal. Calcd for C6H5F2N3: C, 45.87; H, 3.21; N, 26.74. Found: C,
45.94; H, 2.98; N, 26.55.
Anal. Calcd for C5H6F2N2O: C, 40.55; H, 4.08; N, 18.91. Found: C,
40.82; H, 3.85; N, 19.06.
[1-(Difluoromethyl)-1H-benzimidazol-2-yl]acetonitrile (14)
To a soln of KCN (130 g, 2 mol) in anhyd DMSO (600 mL), chlo-
ride 13 (126 g, 0.5 mol) was added in portions with stirring (CAU-
TION! HCN is evolved). After the addition was complete, the
resulting mixture was heated at 45–50 °C for 2 h, then cooled, dilut-
ed with CHCl3 (2 L) and washed with H2O (4 × 700 mL). The or-
ganic phase was dried over Na2SO4 and concentrated to dryness.
The residue was recrystallized (benzene with charcoal).
2-(Chloromethyl)-1-(difluoromethyl)(benz)imidazoles 11 and
13; General Procedure
2-(Hydroxymethyl)-1-(difluoromethyl)(benz)imidazole 10 or 8e (1
mol) was suspended in benzene (200 mL), and thionyl chloride (238
g, 2 mol) was added slowly over 2 h with vigorous stirring. After the
addition was complete, the mixture was heated at 50 °C for 15 min
(10) or 5 h (8e), then cooled and concentrated to dryness. CAU-
TION! The products (especially 11) are strong irritants and harmful
to the skin.
Yield: 59 g (57%); yellowish crystals; mp 68 °C.
1H NMR (CDCl3): d = 7.75 (d, J = 7.6 Hz, 1 H), 7.34–7.56 (m, 4 H),
4.20 (s, 2 H, CH2CN).
13C NMR (CDCl3): d = 141.9, 141.6, 132.7, 125.3, 124.5, 120.8,
113.8, 110.1, 108.3 (t, J = 249 Hz, CHF2), 19.3.
19F NMR (CDCl3): d = –89.5 (d, J = 58 Hz, CHF2).
MS (APCI): m/z = 208 [M + H]+.
2-(Chloromethyl)-1-(difluoromethyl)-1H-imidazole Hydrochlo-
ride (11)
Yield: 139 g (99%); colorless solid; mp >250 °C (dec) (MeOH).
1H NMR (DMSO-d6): d = 13.13 (br s, 1 H), 8.26 (t, J = 58.0 Hz, 1
H, CHF2), 7.98 (s, 1 H), 7.54 (s, 1 H), 5.21 (s, 2 H, CH2Cl).
13C NMR (DMSO-d6): d = 143.5, 125.3, 119.2, 108.6 (t, J = 253
Hz, CHF2), 34.0.
Anal. Calcd for C10H7F2N3: C, 57.97; H, 3.41; N, 20.28. Found: C,
57.73; H, 3.42; N, 19.93.
19F NMR (DMSO-d6): d = –94.3 (d, J = 58 Hz, CHF2).
MS (APCI): m/z = 167 [M + H]+.
References
(1) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Biomedicinal
Aspects of Fluorine Chemistry; Elsevier: Amsterdam, 1993.
(2) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry: Principles and Commercial Applications;
Plenum: New York, 1994.
(3) For some recent papers and reviews, see: (a) O’Hagan, D.
J. Fluorine Chem. 2010, 131, 1071. (b) Grygorenko, O. O.;
Artamonov, O. S.; Komarov, I. V.; Mykhailiuk, P. K.
Anal. Calcd for C5H6Cl2F2N2: C, 29.58; H, 2.98; Cl, 34.93; N,
13.80. Found: C, 29.31; H, 3.25; Cl, 35.32; N, 13.61.
2-(Chloromethyl)-1-(difluoromethyl)-1H-benzimidazole Hy-
drochloride (13)
Yield: 51 g (99%); colorless solid; mp >250 °C (dec) (MeOH).
Synthesis 2011, No. 8, 1243–1248 © Thieme Stuttgart · New York

1248
V. Levterov et al.
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Synthesis 2011, No. 8, 1243–1248 © Thieme Stuttgart · New York