POCl3-mediated synthesis of hydrolysis-prone 2-trifluoroethylbenzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2008.06.069

Loss of a trifluoromethyl group has been observed as an unproductive side reaction in the formation of 2-trifluoroethylbenzimidazoles. A hydrolytic mechanism for this transformation is proposed that is consistent with evidence for the identity of reaction intermediates. Cyclodehydration with POCl₃ suppresses hydrolysis of the trifluoromethyl group and provides 2-trifluoroethylbenzimidazoles in good yields.

Full text of DOI:10.1016/j.tetlet.2008.06.069

Tetrahedron Letters 49 (2008) 5332–5335
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Tetrahedron Letters
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POCl3-mediated synthesis of hydrolysis-prone 2-trifluoroethylbenzimidazoles
*
Kausik K. Nanda , B. Wesley Trotter
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Loss of a trifluoromethyl group has been observed as an unproductive side reaction in the formation of
2-trifluoroethylbenzimidazoles. A hydrolytic mechanism for this transformation is proposed that is con-
sistent with evidence for the identity of reaction intermediates. Cyclodehydration with POCl3 suppresses
hydrolysis of the trifluoromethyl group and provides 2-trifluoroethylbenzimidazoles in good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 23 April 2008
Revised 5 June 2008
Accepted 16 June 2008
Available online 20 June 2008
Keywords:
2-Trifluoroethylbenzimidazole
Trifluoromethyl hydrolysis
Me
Fluorine containing molecules are found in increasing numbers
in small molecule drug discovery efforts.1 Because of its small size
and high electronegativity, fluorine often imparts unique proper-
ties to a molecule. Investigators at Johnson & Johnson recently re-
ported that trifluoroethyl substitution at the 2-position of
benzimidazole androgen receptor antagonists enhanced activity.2
Our own efforts to incorporate fluorinated functionality in the
course of a recent drug discovery project led us to investigate the
synthesis of 2-trifluoroethylbenzimidazoles from precursor di-
amines 2 (Eq. 1).
NH2
N
H
N
N
CF3CH2CO2H
aq. HCl
ð2Þ
2
3
Diamine 2 could be acylated to provide trifluoromethylacetyl
derivative 4 (Eq. 3). Subjecting 4 to acidic conditions3b,c again affor-
ded 3, this time with complete conversion (Table 1, entries 1 and
2). No evidence for formation of 1 was observed. However, upon
expanding our survey to additional cyclodehydration conditions,
CF3
5
NH2
we were pleased to find that POCl3 effected complete conversion
H
N
N
to 1 with no detectable contamination by 3.
ð1Þ
N
Because 3 is produced from 1 even when acetic acid is not pres-
ent in the reaction mixture (entry 2), formation of 3 appears to pro-
ceed via loss of the trifluoromethyl group of 4. We hypothesized
that desired product 1 might be formed under acid-mediated con-
ditions before decomposing to 3. To test this hypothesis, 1 was
heated in acetic acid or ethanolic HCl, and we observed a clean
conversion to 3 under both conditions (Scheme 1).
While LC/MS monitoring of this reaction did not reveal any
intermediate species, we postulated that carboxylic acid 5 might
be formed under acidic conditions and subsequently undergo
rapid decarboxylation to give 3. Hydrolysis of 1 is consistent with
earlier reports of methanolysis of trifluoromethyl groups under
acidic6 or basic7 conditions. To capture the carboxylic acid inter-
mediate, 1 was treated with 1(N) aqueous NaOH solution. This
indeed effected a clean conversion of 1 to 5 (confirmed by LC/MS
and HRMS). Attempted isolation of 5 from the basic medium
resulted in a mixture of 5 and 3 (2:1); this observation is consis-
tent with rapid decarboxylation of 5 under non-basic conditions.
1
2
Precedent for the preparation of 2-trifluoroethylbenzimidazoles
is limited to a few examples found in the patent literature. In these
cases, the desired benzimidazoles were prepared either by conden-
sation of 1,2-diaminobenzene with 3,3,3-trifluoropropionic acid in
aqueous HCl or by cyclodehydration of N-2-aminophenyl-3,3,3-tri-
fluoropropanamides under acidic conditions.3 However, attempts
to apply these conditions3a to directly transform diamine 2 did
not produce any desired benzimidazole 1 (Eq. 2). Instead, 2-meth-
ylbenzimidazole 34 was observed in small amounts.
* Corresponding author. Tel.: +1 215 652 0371; fax: +1 215 652 7310.
E-mail address: kausik_nanda@merck.com (K. K. Nanda).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.069

K. K. Nanda, B. W. Trotter / Tetrahedron Letters 49 (2008) 5332–5335
5333
Table 1
Cyclization of amide 4
F3C
CF3
Me
O
NH
N
N
H
reaction
medium
ð3Þ
N
N
N
+
temperature
4
1
3
Entry
Reaction medium
Temperature (°C)
Ratio of 1:3a
1
2
3
AcOH
EtOH/HCl (satd)
POCl3
100
80
100
(0:100)b
(0:100)
(100:0)c
a
Observed by LC/MS.
Isolated yield: 99%.
Isolated yield: 97%.
b
c
CF3
Me
AcOH
or
EtOH/HCl
N
N
N
N
3
1
AcOH
100oC
1(N) aq NaOH
CO2H
N
CO2H
N
Me
N
N
N
isolation
N
+
5
3
5
(100% conversion by LC/MS)
(2:1)
Scheme 1.
Heating the isolated mixture in acetic acid at 100 °C resulted in
complete conversion to 3.
functional groups such as ester (entry 3), methoxy (entry 5), and
nitrile (entry 6) were also tolerated. This methodology can also
be used to make trifluoroethyl-aza-benzimidazoles (entry 8) in
good yield.
In summary, we have identified an unusual hydrolytic transfor-
mation of 2-trifluoroethylbenzimidazoles.11 While this transfor-
mation prevents formation of fluorinated heterocycles under
conventional acidic cyclization conditions, use of POCl3 to establish
an anhydrous reaction medium provides access to 1. The condi-
tions established here provide straightforward and reliable access
to this class of fluorinated heterocycles.
The proposed mechanism shown in Scheme 2 for loss of the tri-
fluoromethyl group is consistent with these observations. 2-Trifluo-
roethylbenzimidazole 1 can eliminate HF to give difluoroalkene 6.8
Addition of water to 6 provides 7, which can collapse to acylfluo-
ride 8. Hydrolysis9 and decarboxylation would afford 3.10 This pro-
posal is also consistent with the successful application of POCl3 to
the synthesis of 1. This reaction medium provides essentially anhy-
drous conditions and thus precludes the hydrolysis steps necessary
to remove the trifluoromethyl group.
The scope of this method was explored using a range of di-
amines. In practice, treatment of diamines with 3,3,3-trifluoropro-
pionyl chloride under Schotten-Baumann conditions followed by
cyclization in POCl3 provides 2-trifluoroethylbenzimidazoles in
excellent yields. Table 2 summarizes the results. Steric bulk on
the amino group does not affect the efficiency (entries 1, 2, and
3) of this method. The overall yield obtained from the unsubstitut-
ed diamine (entry 4) was compromised slightly by the formation
of a 1,2-bis(trifluoropropanamide) in the first step. Different
Typical reaction procedure: To a vigorously stirred biphasic mix-
ture of
a solution of N-phenyl-o-phenylenediamine (500 mg,
2.714 mmol) in dichloromethane (40 mL) and saturated aqueous
NaHCO3 solution (25 mL) at 0 °C was added a solution of 3,3,3-tri-
fluoropropionyl chloride (0.711 g, 2.985 mmol) in dichlorometh-
ane (10 mL) dropwise. After stirring the reaction mixture for 1 h,
the aqueous solution was extracted with dichloromethane (3ꢀ).
The combined organic solutions were dried over Na2SO4 and con-
centrated to give N-(2-anilinophenyl)-3,3,3-trifluoropropanamide

5334
K. K. Nanda, B. W. Trotter / Tetrahedron Letters 49 (2008) 5332–5335
Table 2 (continued)
OH2
H
Yielda (%)
66
Ph
F
F
Entry
Diamine
Product
Ph
F
F
N
F
N
NH2
Me
H
N
CF3
N
N
H
O
6
Me
N
OH2
1
6
H
N
NC
NC
H
H
N
NH2
CF3
Ph
Ph
OH
F
F
NH2
Me
F
N
7
80
72
N
N
N
H
N
Me
N
8
7
NH2
N
Ph
H2O
H
N
CF3
N
8
Ph
Ph
O
Ph
O
N
H+
OH
N
OH
N
Isolated yield from diamine. All compounds were >95% pure by 1H NMR and
a
were positively identified by HRMS analysis.
N
N
H
9
5
-CO2
(800 mg, 100%). The crude N-(2-anilinophenyl)-3,3,3-trifluoropro-
panamide (225 mg, 0.765 mmol) was dissolved in POCl3 (15 mL)
and heated at 100 °C for 3.5 h. The reaction mixture was then
cooled to room temperature and concentrated. The resulting vis-
cous residue was dissolved in dichloromethane (30 mL) and cooled
to 0 °C, and a saturated aqueous NaHCO3 solution was added
slowly until the aqueous layer became basic. The aqueous solution
was separated and extracted with dichloromethane (3ꢀ). The com-
bined organic solutions were dried over Na2SO4 and concentrated.
Purification by reversed phase HPLC (30 ꢀ 100 mm Phenomenex
Gemini (5–85% MeCN/water containing 0.05% NH4OH over
20 min at 50 mL/min) afforded 1-phenyl-2-(2,2,2-trifluoroethyl)-
1-H-benzimidazole as a white solid (205 mg, 97%). HRMS calcd
Ph
Ph
-H+
N
N
N
Me
Me
N
H
3
10
Scheme 2.
Table 2
Formation of 2-trifluoroethylbenzimidazoles
CF3
for
C
15H12F3N2 (M+H+): 277.0947; found 277.0948. 1H NMR
NH2
N
(500 MHz, CDCl3) d 7.87 (d, 1H, J = 8.08 Hz), 7.64–7.56 (m, 3H),
7.38–7.31 (m, 3H), 7.28 (dd, 1H, J = 7.75, 1.04 Hz), 7.12 (dd, 1H,
J = 8.10, 1.05 Hz), 3.67 (q, 2H, J = 9.87 Hz).
H
N
R1
N
ð4Þ
1. CF3CH2COCl
2. POCl3
R1
R2
R2
product
diamine
Acknowledgments
Entry Diamine
Product
Yielda
(%)
We thank Charles Ross and Joan Murphy for HRMS data.
NH2
Me
References and notes
H
CF3
N
N
1
94
Me
1. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
N
2. (a) Ng, R. A.; Guan, J.; Alford, V. C., Jr.; Lanter, J. C.; Allan, G. F.; Sbriscia, T.;
Linton, O.; Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem. Lett. 2007, 784; (b) Ng, R. A.;
Guan, J.; Alford, V. C., Jr.; Lanter, J. C.; Allan, G. F.; Sbriscia, T.; Lundeen, S. G.; Sui,
Z. Bioorg. Med. Chem. Lett. 2007, 955; (c) Ng, R. A.; Lanter, J. C.; Alford, V. C., Jr.;
Allan, G. F.; Sbriscia, T.; Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem. Lett. 2007,
1784.
3. (a) Ng, R.; Sui, Z.; Guan, J.; Lanter, J. C.; Alford, V. C., Jr. Novel Benzimidazole
Derivatives Useful As Selective Androgen Receptor Modulators (SARMS). WO
2006/039243 A1, 2006; (b) Liu, Z.; Milburn, C.; Page, D.; Walpole, C.; Yang, H.
Benzimidazole Derivatives, Compositions Containing Them, Preparation
Thereof And Uses Thereof. WO 2005/030762 A1, 2006; (c) Anderskewitz, R.;
Martyres, D.; Dollinger, H.; Pouzet, P.; Birke, F.; Bouyssou, T. Haloalkyl- and
Piperidine-Substituted Benzimidazole-Derivatives. WO 2005/019203 A1, 2005.
4. Brian, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814.
NH2
Ph
H
N
CF3
N
2
97
76
Ph
N
Me
NH2
Me
CF3
H
N
Me
Me
N
N
3
MeO2C
MeO2C
5. While POCl3 has not been previously employed in the synthesis of 2-
trifluoroethylbenzimidazoles, this reagent has been successfully used to
prepare non-fluorinated benzimidazoles by cyclodehydration. For example:
(a) Kurasawa, Y.; Shimabukuro, S.; Okamoto, Y.; Takeda, A. Heterocycles 1985,
23, 65; (b) Walser, A.; Flynn, T.; Mason, C. J. J. Heterocycl. Chem. 1991, 28, 1121;
(c) Stefancich, G.; Artico, M.; Corelli, F.; Massa, S. Synthesis 1983, 757.
6. South, M. S. J. Heterocycl. Chem. 1991, 28, 1013.
7. (a) Ramig, K.; Englander, M.; Kallashi, F.; Livchits, L.; Zhou, J. Tetrahedron Lett.
2002, 43, 7731; (b) Mechoulam, R.; Cohen, S.; Kaluszyner, A. J. Org. Chem. 1956,
21, 801; (c) Haider, N.; Wanko, R. Heterocycles 1994, 38, 1805; (d) Kobayashi, Y.;
Kumadaki, I.; Hirose, Y.; Hanzawa, Y. J. Org. Chem. 1974, 39, 1836; (e) King, J. F.;
Gill, M. S. J. Org. Chem. 1996, 61, 7250; (f) Uneyama, K.; Morimoto, O.
Tetrahedron Lett. 1989, 30, 109.
NH2
H
N
CF3
NH2
NH2
4
70
67
N
Me
H
N
CF3
N
5
Me
N
MeO
MeO

K. K. Nanda, B. W. Trotter / Tetrahedron Letters 49 (2008) 5332–5335
5335
8. Consistent with this is our observation that compound 11, which cannot
eliminate HF, converts cleanly to 12 under acidic conditions. No evidence for
loss of the trifluoromethyl group was observed.
9. Hydrolysis of perfluorinated alkenes has been observed under acidic and basic
conditions. For example: (a) England, D. C. J. Org. Chem. 1981, 46, 147; (b)
Ishikawa, N.; Takaoka, A.; Ibrahim, K. J. Fluorine Chem. 1984, 25, 203.
10. Protonation of the benzimidazole nitrogen is likely under acidic conditions and
may favor the decarboxylation event. Consistent with this, indole-2-acetic
acids are stable and can be prepared by hydrolysis of the corresponding esters.
For example: (a) Weber, D.; Berger, C.; Eickelmann, P.; Antel, J.; Kessler, H. J.
Med. Chem. 2003, 46, 1918; (b) Karrick, G. L.; Peet, N. P. J. Heterocycl. Chem.
1986, 23, 1055.
F3C
F
CF3
F
F
NH
O
F
N
H
N
H+
N
Ar
11. All 2-trifluoroethylbenzimidazoles listed in Table 2 are transformed to the
corresponding 2-methylbenzimidazoles when heated in AcOH at 100 °C
(observed by LC/MS).
Ar
12
11
.