Preparation and utility of trihaloethyl imidates: Useful reagents for the synthesis of amidines

Article abstract of DOI:10.1021/jo902159z

(Chemical Equation Presented) 2,2,2-Trifluoro- and trichloroethyl imidates, which are easily prepared by reaction of a nitrile and a trihaloethanol in the presence of HCl, have proven to be excellent reagents for the preparation of amidines under mild reaction conditions. Depending on the nature of the amine nucleophile, the imidates can react either as the free-base or the hydrochloride salt in a telescoped process. In several cases, the p-bromobenzoate salt of the desired product was directly isolated from the reaction mixture.

Full text of DOI:10.1021/jo902159z

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of an amidine was necessary as an intermediate (2) to a
Preparation and Utility of Trihaloethyl Imidates:
Useful Reagents for the Synthesis of Amidines
pyrazolotriazinone.8 We were surprised to find that while the
formation of the amidine from the monosubstituted amino-
pyrazole 1a proceeded in near quantitative yield with the
ethoxyimidate, only 10% of the desired product was ob-
tained from the corresponding disubstituted derivative 1b.
Gratifyingly, the analogous thioimidate9 gave the desired
product in 63% yield showing the importance in the selection
of the leaving group based on the nature of the nucleophile
(Table 1).
ꢀ
Stephane Caron,* Lulin Wei, Jasmin Douville, and
Arun Ghosh
Chemical R&D, Pfizer Global R&D, MS-8118D/4002,
Eastern Point Road, Groton, Connecticut 06340
stephane.caron@pfizer.com
Received October 14, 2009
TABLE 1. Preparation of Amidines from Aminopyrazoles
entry
SM
R1
X
% yield
2,2,2-Trifluoro- and trichloroethyl imidates, which are
easily prepared by reaction of a nitrile and a trihaloetha-
nol in the presence of HCl, have proven to be excellent
reagents for the preparation of amidines under mild
reaction conditions. Depending on the nature of the
amine nucleophile, the imidates can react either as the
free-base or the hydrochloride salt in a telescoped pro-
cess. In several cases, the p-bromobenzoate salt of the
desired product was directly isolated from the reaction
mixture.
1
2
3
4
1a
1b
1b
1b
H
OEt
OEt
95
10
63
50
4-ClPh
4-ClPh
4-ClPh
SCH2Napth
OCH2CF3
While this method proved effective, we sought a superior
and more cost-effective reagent for this transformation.
Herein, we report that 2,2,2-trifluoroethyl and 2,2,2-trichloro-
ethyl imidates are effective reagents for the preparation of
amidines. Indeed, the preparation of 2 with 2,2,2-trifluoro-
ethyl acetimidate provided a 50% yield without optimization
(entry 4, Table 1).
We believed that a more general class of reagents for the
formation of amidines would require a leaving group super-
ior to the nitrogen nucleophile, leading to a productive
collapse of the tetrahedral intermediate. More importantly,
the inductive effect of the leaving group should provide
increased reactivity at the electrophilic carbon, especially in
the case of hindered substrates. On the basis of our initial
results outlined above, we estimated that trifluoroethanol
(pKa = 23.1)10 and trichloroethanol (pKa = 19.5) could
provide this advantage (EtOH pKa = 29.5).11
Amidines are an important class of compounds that have
demonstrated utility in the fields of catalyst design,1 material
science,2 and medicinal chemistry.3,4 Recent studies have
demonstrated their capacity to fix carbon dioxide.5,6
The preparation of amidines has been reviewed7 and
generally originates from either nitrile or amide starting
materials. As part of the development of a cannabinoid-1
(CB1) receptor antagonist clinical candidate, the preparation
(1) Coles, M. P. Dalton Trans. 2006, 985–1001.
(2) Ikeda, M.; Tanaka, Y.; Hasegawa, T.; Furusho, Y.; Yashima, E.
J. Am. Chem. Soc. 2006, 128, 6806–6807.
(3) Edwards, P. D.; Albert, J. S.; Sylvester, M.; Aharony, D.; Andisik, D.;
Callaghan, O.; Campbell, J. B.; Carr, R. A.; Chessari, G.; Congreve, M.;
Frederickson, M.; Folmer, R. H. A.; Geschwindner, S.; Koether, G.; Kolmodin,
K.; Krumrine, J.; Mauger, R. C.; Murray, C. W.; Olsson, L.-L.; Patel, S.; Spear,
N.; Tian, G. J. Med. Chem. 2007, 50, 5912–5925.
Both 2,2,2-trifluoroethyl acetimidate and 2,2,2,-trichloro-
ethyl acetimidate have previously been prepared and
their stability evaluated.12-14 The rate of aminolysis of
(4) Peterlin-Masic, L.; Kikelj, D. Tetrahedron 2001, 57, 7073–7105.
(5) Desset, S. L.; Cole-Hamilton, D. J. Angew. Chem., Int. Ed. 2009, 48,
1472–1474.
(6) Phan, L.; Chiu, D.; Heldebrant, D. J.; Huttenhower, H.; John, E.; Li,
X.; Pollet, P.; Wang, R.; Eckert, C. A.; Liotta, C. L.; Jessop, P. G. Ind. Eng.
Chem. Res. 2008, 47, 539–545.
(9) Shearer, B. G.; Oplinger, J. A.; Lee, S. Tetrahedron Lett. 1997, 38,
179–182.
(10) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(11) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980,
45, 3295–3299.
(12) Shvekhgeimer, G. A.; Shul’man, M. L. Dokl. Akad. Nauk SSSR
(7) Dunn, P. J. In Comprehensive Organic Functional Group Transform-
mations II; Elsevier: Oxford, UK, 2005; Vol. 5, pp 655-699.
(8) Brandt, T. A.; Caron, S.; Damon, D. B.; Di Brino, J.; Ghosh, A.;
Griffith, D. A.; Kedia, S.; Ragan, J. A.; Rose, P. R.; Vanderplas, B. C.; Wei,
L. Tetrahedron 2009, 65, 3292–3304.
1967, 173, 378–380.
(13) Shul’man, M. L.; Shvekhgeimer, G. A. Zh. Org. Khim. 1969, 5,
229–234.
(14) Shvekhgeimer, G. A.; Shul’man, M. L. Zh. Org. Khim. 1968, 4, 1734–
1737.
DOI: 10.1021/jo902159z
r
Published on Web 01/12/2010
J. Org. Chem. 2010, 75, 945–947 945
2010 American Chemical Society

Caron et al.
JOCNote
TABLE 2. Preparation of Imidate Hydrochlorides
TABLE 3. Preparation of Amidines As p-Bromobenzoate Salts
entry
compd
R
X
methoda
% yield
1
2
3
4
5
3a
3b
3c
3d
3e
Me
Me
Et
i-Pr
Ph
F
Cl
F
F
F
A
A
B
B
A
65
75
46
40
64
aMethod A: HCl gas. Method B: 4 N HCl/dioxane.
2,2,2-trifluoroethyl benyzimidate has also been studied.15,16
However, the potential utility of these reagents for the
formation of amidines has not been reported.
The desired reagents were prepared through a Pinner
reaction with use of either HCl gas (Method A) or 4 N HCl
in dioxane (Method B). The resulting imidate salts were
directly isolated in good to moderate yields and were not
individually optimized (Table 2). In general, Method A pro-
vided higher yields than Method B, although the latter has
the advantage of being operationally simpler. All of these
compounds are crystalline solids that proved to be stable at
room temperature on the benchtop for a few months pro-
vided that they were kept away from moisture. The methyl
derivatives 3a and 3b proved to be more prone to hydrolysis
then the ethyl (3c) and isopropyl (3d) reagents while the
benzimidate (3e) was the fastest to undergo hydrolysis.
Efforts to prepare the tert-butyl derivative proved to be
unsuccessful. In the case of the acetimidates, the trichloro
reagent was preferred due to the higher yield obtained in its
preparation (Table 2, entries 1 and 2).
aPrepared and isolated directly as the HCl salt without free basing.
TABLE 4. Preparation of N-Phenylamidine p-Bromobenzoate Salts
entry
product
reagent
R
% yield
1
2
3
4
4a
4i
4j
4k
3a
3c
3d
3e
Me
Et
i-Pr
Ph
92
91
88
71a
aPrepared in EtOH without neutralization of 3e and isolated as the
free base after extractive workup.
The reactivity of acetimidate 3a was first evaluated with
use of aniline as a nucleophile. It was determined that it was
preferable to first neutralize the hydrochloride salt to the
free base to increase reactivity. 2-Methyltetrahydrofuran
(2-MeTHF) proved to be an acceptable solvent for perform-
ing both the salt break (aqueous K2CO3) as well as the
subsequent amidine formation. While the reaction pro-
ceeded rapidly, the resulting amidine proved to be an oil
that was difficult to isolate and purify. Several salts were
prepared (HCl, HBr, AcOH, PhCO2H) and it was discovered
that the p-bromobenzoate provided a crystalline solid of high
purity. Furthermore, the amidine formation proceeded in
the presence of the acid to afford the desired salt directly in a
single operation.
Acetimidates 3a and 3b reacted in a similar fashion (entries
1 and 2, Table 3) and the reaction was performed with use of
the trichloro derivative with several amines. The reaction
proceeded in high yield with a variety of anilines (entries
2-6) and only in the case of the more sterically demanding
2,4-xylidine (entry 6) was the yield below 90%. Condensa-
tion with more nucleophilic primary amines also proved to
be high yielding (entries 7 and 8). In the case of 4-phenyl-
piperidine, the amine was sufficiently reactive that the de-
sired product (4h) could be accessed directly in 92% yield
from the HCl salt of the amidine, thereby avoiding the need
to generate the free base of the reagent (entry 9).
Substitution on the imidate reagent was also evaluated
by using aniline as the nucleophile, and the trifluoroethyl
derivatives were used for comparison. In the first three cases,
using the protocol leading to isolation of the p-bromobenzo-
ate, the overall yield obtained was high and consistent (Table 4,
entries 1-3). Because of concerns about hydrolysis of the
benzimidate reagent (3e), it was reacted with aniline in
ethanol followed by an extractive workup to provide the
desired N-phenyl imidate (4k) in 71% yield (entry 4). As a
comparison, preparation of 4k from the nitrile proceeds in
17
80% yield but requires the use of the pyrophoric AlMe3
and has not been previously reported with use of either the
methyl or ethyl imidate reagents.
In summary, the versatility and utility of trifluoroethyl
and trichloroethyl imidates has been demonstrated for the
preparation of amidines. Formation of the p-bromobenzoate
salts is a convenient method for isolation and purification of
the products when the HCl salt of the starting imidate cannot
be used directly. These reagents offer the advantage of being
readily prepared in a single step from inexpensive starting
materials, display reasonale stability, and react under mild
process-friendly conditions. Reports on our evaluation of
(17) Asproni, B.; Pau, A.; Bitti, M.; Melosu, M.; Cerri, R.; Dazzi, L.; Seu,
E.; Maciocco, E.; Sanna, E.; Busonero, F.; Talani, G.; Pusceddu, L.;
Altomare, C.; Trapani, G.; Biggio, G. J. Med. Chem. 2002, 45, 4655–4668.
(15) Gilbert, H. F.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104, 6769–6779.
(16) Gilbert, H. F.; Jencks, W. P. J. Am. Chem. Soc. 1979, 101, 5774–5779.
946 J. Org. Chem. Vol. 75, No. 3, 2010

Caron et al.
JOCNote
the addition of other nucleophiles on this class of imidates
will be reported in due course.
(t, 2, J = 7.47 Hz), 7.51 (d, 2, J = 8.30 Hz), 7.79 (d, 2, J =
8.30 Hz), 8.59 (br s, 1), 11.14 (br s, 2). 13C NMR (DMSO) δ
124.4, 125.5, 127.3, 130.1, 131.2, 131.9, 137.7, 138.5, 170.9. Anal.
Calcd for C15H15BrN2O2: C, 53.75; H, 4.51; N, 8.36. Found: C,
53.76; H, 4.27; N, 8.27. HREIMS m/z 135.0917 (calcd m/z
135.0917 for C18H10N2 þ H). The free base is known and has
been characterized.18,19
Experimental Section
Representative Examples of Reagent 3 Preparation. Method
A: 2,2,2-Trichloroethyl Acetimidate Hydrochloride (3b). To a
mixture of trichloroethanol (200 mL, 2.08 mol) and acetonitrile
(130 mL, 2.48 mol) at 0 °C was bubbled HCl gas for 7 h. The
mixture was sealed and stored in a freezer for 72 h. The product
was isolated by filtration, washed with cold acetonitrile (3 ꢀ
150 mL), and dried to provide 2,2,2-trichloroethyl acetimidate
1-(4-Phenylpiperidin-1-yl)ethanimine Hydrochloride (4h).
2,2,2-Trichloroethyl acetimidate hydrochloride (3b) (2.67 g,
11.8 mmol) and 4-phenylpiperidine (1.58 mL, 9.98 mmol) were
added to EtOH (20 mL). The solution was stirred at rt over-
night and concentrated under reduced pressure, then the crude
solid was triturated with MTBE. The solids were filtered to
afford 1-(4-phenylpiperidin-1-yl)ethanimine hydrochloride (4h)
(2.20 g, 92%) as a white solid. Mp 223-225 °C. 1H NMR
(DMSO) δ 1.68 (dq, 1, J = 12.89, 3.90 Hz), 1.75 (dq, 1, J =
12.89, 3.90 Hz), 1.95-2.05 (m, 2), 2.45 (s, 3), 2.79 (dt, 1, J = 12.11,
3.51 Hz), 3.10-3.20 (m, 1), 3.26 (dt, 1, J = 12.89, 2.34 Hz), 3.94
(d, 1, J = 13.67 Hz), 4.85 (d, 1, J = 13.67 Hz), 7.13-7.28 (m, 5),
9.47 (br s, 1), 9.95 (br s, 1). 13C NMR (DMSO) δ 20.0, 32.1, 33.3,
41.5, 47.7, 48.7, 126.7, 126.8, 128.7, 143.7, 162.4. HREIMS m/z
203.1544 (calcd m/z 203.1543 for C13H18N2 þ H).
1
hydrochloride (3b) (354 g, 75%). Mp 201-203 °C. H NMR
(DMSO) δ 2.54 (s, 3), 5.36 (s, 2), 12.38 (br s, 2). 13C NMR δ 19.3,
80.1, 93.6, 177.8.
Method B: 2,2,2-Trifluoroethyl Propionimidate Hydrochloride
(3c). To a mixture of trifluoroethanol (69.0 g, 0.689 mol) and
propionitrile (32.0 g, 0.574 mol) at 0 °C was added 4 N HCl in
dioxane (215 mL, 0.860 mol). The mixture was allowed to warm
to rt and was stirred for 48 h. The volatiles were removed under
reduced pressure and the crude product was triturated with
MTBE (200 mL). The product was isolated by filtration and
dried to provide 2,2,2-trifluoroethyl propionimidate hydro-
N-Phenylbenzamidine (4k). To 2,2,2-Trifluoroethyl benzimi-
date hydrochloride (3e) (0.48 g, 2.0 mmol) and aniline (0.55 g,
5.91 mmol) was added EtOH (10 mL). The mixture was stirred
at 40 °C for 48 h. The mixture was concentrated and partitioned
between MTBE (15 mL) and aq K2CO3 (10 mL). The MTBE
layer was concentrated and the crude residue was triturated
with heptanes to afford N-phenylpropionimidamide (4k) (0.28 g,
71%). HREIMS m/z 197.1074 (calcd m/z 197.1073 for C13H12-
1
chloride (3c) (50.0 g, 46%). Mp 148-150 °C. H NMR δ 1.28
(t, 3, J = 7.42 Hz), 2.80 (q, 2, J = 7.42 Hz), 5.10 (q, 2, J =
7.42 Hz). 13C NMR δ 9.5, 26.8, 69.0 (q, J = 38 Hz), 121.3 (q, J =
278 Hz), 180.0.
RepresentativeExamples of Amidine Preparation. N1-Phenyl-
acetamidine 4-Bromobenzoate (4a). 2,2,2-Trifluororoethyl acet-
imidate hydrochloride (3a) (2.873 g, 16.18 mmol) was dissolved
in H2O (10 mL) and 2-MeTHF (5 mL) followed by addition of
K2CO3 (4.14 g, 30.0 mmol). The layers were separated and the
crude organic layer was added to aniline (0.940 g, 10.1 mmol)
and p-bromobenzoic acid (2.02 g, 10.1 mmol) in 2-MeTHF
(40 mL). The reaction mixture was stirred at rt overnight. The
solids were filtered and washed with 2-MeTHF (3 ꢀ 10 mL) to
afford N-phenylacetimidamide 4-bromobenzoate (4a) (3.10 g,
1
N2 þ H). The H NMR data were identical with the previously
reported data.17,20
Acknowledgment. The authors would like to thank Brian
P. Jones for his assistance and helpful discussions.
Supporting Information Available: Complete experimental
procedures and characterization data of the compounds pre-
pared and 1H and 13C NMR spectra of compounds 3c, 3d, 4e, 4g,
and 4h. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
92%) as a white solid. Mp 178-179 °C. H NMR (DMSO) δ
2.17 (s, 3), 7.15 (d, 2, J = 7.47 Hz), 7.24 (t, 1, J = 7.47 Hz), 7.39
(18) Daoust, B.; Lessard, J. Can. J. Chem. 1995, 73, 362–374.
(19) Ferreira, S. B.; Costa, M. S.; Boechat, N.; Bezerra, R. J. S.; Genestra,
M. S.; Canto-Cavalheiro, M. M.; Kover, W. B.; Ferreira, V. F. Eur. J. Med.
Chem. 2007, 42, 1388–1395.
(20) Zhou, L.; Zhang, Y. Synth. Commun. 1998, 28, 3249–3262.
J. Org. Chem. Vol. 75, No. 3, 2010 947