A convenient one-pot synthesis of 7-trifluoromethyl-substituted imidazo [4,5-b] pyridines

Article abstract of DOI:10.1055/s-2008-1077794

This communication describes a practical and facile one-pot approach for the Synthesis of 7-trifluoromethyl-substituted imi-dazo[4,5-6]pyridines by the reaction of in situ generated 5-ami-noimidazole and a 1,3-CCC-biselectrophile.

Full text of DOI:10.1055/s-2008-1077794

LETTER
1459
A Convenient One-Pot Synthesis of 7-Trifluoromethyl-Substituted Imida-
zo[4,5-b]pyridines
O
ne-Pot Synthe
h
sis of 7-Trif
l
o
uoromethyl-
m
S
ubstituted Imidazo
a
[4,5-
b
]pyri
s
dines Wesch, Viktor O. Iaroshenko, Ulrich Groth*
Department of Chemistry, University of Konstanz, Universitätsstraße 10, 78457 Konstanz, Germany
Fax +49(7531)884155; E-mail: ulrich.groth@uni-konstanz.de
Received 19 February 2008
CF3
CF3
Abstract: This communication describes a practical and facile one-
pot approach for the synthesis of 7-trifluoromethyl-substituted imi-
dazo[4,5-b]pyridines by the reaction of in situ generated 5-ami-
noimidazole and a 1,3-CCC-biselectrophile.
N
N
N
O
+
NH2
N
R2
N
R1
R1
O
R2
5
4
3
Key words: cyclizations, fluorine, heterocycles, imidazopyridines,
aminoimidazoles
N
CN
NH2
+
R1
O
2
1
Imidazo[4,5-b]pyridines are an important class of biolog-
ically active compounds showing anticancer,1 antiviral,2
antimitotic,3 and tuberculostatic4 properties depending on
the nature and position of substituents within the hetero-
cycle. These compounds are typically prepared by con-
densation of an appropriate o-diaminopyridine and an
electrophilic carbon unit.5
Scheme 1 Retrosynthetic approach
N
CN
N
EtO
1
i
NH2
R1
N
R1
NH2
2
To avoid the synthesis of highly substituted o-diamino-
pyridines, which are not easy accessible, we developed an
alternative access to imidazo[4,5-b]pyridine starting from
ethyl N-(cyanomethyl)-formimidate (1) by a two-step cy-
clocondensation with any amine of type 2a–i to obtain in
a one-pot procedure the corresponding 5-aminoimidazole
3. There was no need for reduction6 or decarboxylation.7
Hence, after the in situ synthesis of 5-aminoimidazole an-
other cyclocondensation with a trifluormethyl-containing
building block 4a–e follows to obtain selectively the 7-tri-
fluoromethyl-substituted imidazo[4,5-b]pyridines 5. The
convergent manner of this approach allows the synthesis
of versatile substituted imidazo[4,5-b]pyridines depend-
ing on amine and 1,3-electrophilic reagents (Scheme 1).
3
O
O
CF3
F3C
R2
ii
4
N
N
N
R2
R1
5
Scheme 2 Reagents and conditions: (i) amine, CH2Cl2, reflux, for-
mimidate 1, reflux, 3 h; (ii) 1,3-diketone (1 equiv), reflux, 8 h.
following 1,3-electrophilic reagents: 4-trifluoromethyl-
1,3-diones,10 alkoxyvinyl trifluoromethyl ketones,11 b-tri-
fluoroacetylvinylsulfones,12 and trifluoroacetimidoyl ha-
lides.13
Since it is known that the insertion of perfluoroalkyl sub-
stituents in bioactive molecules leads to an increase of lip-
id solubility, and thereby enhances the adsorption rate and
the transportation in vivo,8 heterocyclic compounds bear-
ing a trifluoromethyl group are the subject of continuous
interest due to their potent pharmacological properties.
Basically, there are two important ways to insert a trifluo-
romethyl group in a heterocylic system. One is the orga-
nometallic mediated exchange form bromine or iodine
substituent with a trifluoromethyl group.9 However, the
most widespread method to produce heterocycles with a
trifluoromethyl group is assembly from trifluoromethyl-
containing building blocks. Recently, the most popular
trifluoromethyl-containing building blocks have been the
To evaluate the feasibility of our concept, we first opti-
mized the cyclization conditions. The starting material
ethyl N-(cyanomethyl)formimidate, which was accessible
in three steps beginning from formaldehyde and KCN,14–
16 is highly sensitive to moisture. The cyclization was car-
ried out under an inert-gas atmosphere using dried re-
agents. Use of the solvents such as ethanol, acetonitrile,
and DMF resulted in poor yields and many byproducts.
The solvent resulting in the best yields and only little
byproduct was dichloromethane (Scheme 2). Hence, all
following reactions were carried out in dried CH2Cl2.17
The method was applicable for a number of amines
(Table 1).
Now, the method should be extended to other 1,3-biselec-
trophiles such as 4a–e to obtain a variation in the decora-
tion of the imidazo[4,5-b]pyridine scaffold. We used the
SYNLETT 2008, No. 10, pp 1459–1462
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1077794; Art ID: G03408ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1460
T. Wesch et al.
LETTER
Table 1 Variation of N3 Substitution Depending on Initial Amine 2
Compound
Amine
Product
Yield (%)a
70
5a
Benzylamine
R1 = Bn
R2 = Ph
5b
5c
5d
5e
5f
Benzylamine
R1 = Bn
R2 = Me
88
55
68
41
56
50
85
89
50
(4-Metoxyphenyl)methyl amine
(2,4-Dimethoxyphenyl)methyl amine
1,1-Diphenylmethyl amine
(R)-1-Phenylethyl amine
R1 = PMB
R2 = Me
R1 = 4,2-Dimetoxybenzyl
R2 = Me
R1 = 1,1-Diphenylmethyl
R2 = Me
R1 = (R)-1-(1-Phenylethyl)
R2 = Me
5g
5h
5i
2,2-Dimethoxyethyl amine
(R)-1-Cyclohexylethyl amine
(S)-1-Cyclohexylethyl amine
2-(4-Methoxyphenyl)ethyl amine
R1 = 2,2-Dimethoxyethyl
R2 = Me
R1 = (R)-1-(1-Cyclohexylethyl)
R2 = Me
R1 = (S)-1-(1-Cyclohexylethyl)
R2 = Me
5j
R1 = 2-(4-Methoxyphenyl)ethyl
R2 = Me
a Yields refer to isolated products.
same reaction procedure described above, varying the spin coupling of fluorine and carbon was a useful tool.
biselectrophile. The yields decreased with the number of The neighbor carbon atom to the CF3 group is split up to
fluorine substituents in the 1,3-biselectrophiles (Table 2). a quartet with a spin–spin coupling constant of about
2JCF = 34 Hz. The observed chemical shift of the carbon
During the reaction with 4,4,4-trifluoro-3-oxybutyrate it
atom situated para to the pyridine nitrogen is about d =
was possible to isolate the intermediate 6 (Scheme 3).
130 ppm (100 MHz, CDCl3). The C2 carbon atom in the
This result is consistent with the work by Volochnyuk et
pyridine has a chemical shift of about d = 150 ppm (100
MHz, CDCl3). In our experiments we could only isolate
trifluoromethyl-substituted compounds where the C4 car-
bon atom shows a chemical shift about d =130 ppm and a
quartet with the coupling constant about J = 30 Hz. This
is a clear evidence for the desired regiochemistry. In addi-
tion, we confirmed the substitution pattern by a X-ray
structure analysis of compound 5a.19
al.18 The chemical shift of the neighbor carbon of CF3 is
d = 74 ppm [13C NMR (100 MHz, CDCl3)] and d = –82
ppm [19F NMR (376 MHz, CDCl3)], indicating that the
condensation was not complete. This kind of intermediate
can only be isolated with the 3-oxybutyrate derivative.
With the 1,3-diketones, these intermediates were not ob-
served, because of the higher reactivity.
During the experiments a considerable regioselectivity
could be observed. With asymmetric trifluoromethyl-con-
taining 1,3-diketones only the g-CF3 substituted imida-
zopyridines were isolated. The structure determination
was carried out by 13C NMR, 1H NMR, and X-ray crystal-
lography. In the case of the 13C NMR analyses, the spin–
The regioselectivity could be explained with the known
characteristics of of 5-aminoimidazole and asymmetric
trifluoromethyl-containing 1,3-diketones. The aminoimi-
dazoles are N,C-ambident nucleophiles. Ramsden et al.20
studied the chemical behavior of aminoimidazoles. Ac-
cording to them, the side of reaction was confirmed by
AM1 calculations on the aminoimidazole structure and by
synthetical experiments. Thus, the C4 carbon atom favors
addition of soft electrophiles (low-energy LUMO) at this
position, whereas the exocyclic amino function prefers the
addition of hard electrophiles.
O
O
O
HO CF3
N
N
F3C
OEt
N
N
OEt
CH2Cl2, 40 °C, 8 h
60%
NH2
NH2
R
R
The trifluoromethyl ketones are known as highly reactive
electrophilic carbonyl compounds. Studies by Linderman
and Jamois21 show that the acceptor orbital (LUMO) en-
ergy level for fluoroketones are about 21.2–28.4 kcal/mol
3
6
Scheme 3 In situ generated 5-aminoimidazoles react with ethyl
4,4,4-trifluoro-3-oxibutyrate without ring closing to intermediate 6
Synlett 2008, No. 10, 1459–1462 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 7-Trifluoromethyl-Substituted Imidazo[4,5-b]pyridines
1461
Table 2 Variation of Scaffold Substitution Pattern Depending on Initial 1,3-Biselectrophile
O
O
RF
N
R
RF
PMB amine
N
N
N
N
CN
2b
4a–e
NH2
O
1
R
PMB
3
PMB
5
Compound
R
RF
Yield (%)a
5k
5l
Me
Ph
CF3
CF3
55
60
23
48
25
5m
5n
5o
Me
Me
CF3
C2F5
CHF2
CF3
a Yields refer to isolated products.
Westerhout, J.; Spangenberg, T.; Brussee, J.; Ijzerman, A. P.
J. Med. Chem. 2007, 50, 828. (d) Mladenova, G.; Lee-Ruff,
E. Tetrahedron Lett. 2007, 48, 2787.
lower than the LUMO energy level of the nonfluorinated
analogues. These properties and our experimental results
in mind we suppose, that the regiochemistry could be ex-
plained by the hard–soft acid–base (HSAB) principle.22
We could not yet observe other effects which control the
regioselectivity.
(6) (a) Lawhorn, B. G.; Mehl, R. A.; Begley, T. P. Org. Biomol.
Chem. 2004, 2, 2538. (b) Clayton, R.; Davis, M. L.; Fraser,
W.; Li, W.; Ramsden, C. A. Synlett 2002, 1483.
(c) Humphries, M. J.; Ramsden, C. A. Synthesis 1999, 985.
(7) Bhat, B.; Groziak, M. P.; Leonard, N. J. J. Am. Chem. Soc.
1990, 112, 4891.
(8) (a) Bégué, J.-P.; Bonnet-Delpon, D. In Chimie Bioorganique
et Médicinale du Fluor; CNRS Édition: Paris, 2005.
(b) Hiyama, T. In Organofluorine Compounds, Chemistry
and Applications; Springer: Berlin, Heidelberg, 2000.
(9) (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992,
48, 6555. (b) Nowak, I.; Robins, M. J. J. Org. Chem. 2007,
72, 2678.
In summary, we have developed a useful tool to synthe-
size 5,7-disubstituted imidazo[4,5-b]pyridines in a one-
pot reaction. With this approach it was possible to intro-
duce a CF3 group selectively in para position to the pyri-
dine nitrogen.
Acknowledgment
(10) Ohkura, H.; Berbarasov, D. O.; Soloshonok, V. A.
Tetrahedron Lett. 2003, 44, 2417.
V. I. thanks the DAAD, Euler program, for a fellowship and the
partnership program between the University of Konstanz and the
NTSU Kiew for having the opportunity to perform his doctoral stu-
dies in Konstanz. We are grateful to the Bayer AG, the Merck
KGaA and the Wacker AG for generous gifts of reagents.
(11) (a) Zanatta, N.; Amaral, S. S.; Esteves-Souza, A.;
Echevarria, A.; Brondani, P. B.; Flores, D. C.; Bonacorso, H.
G.; Flores, A. F. C.; Martins, M. A. P. Synthesis 2006, 2305.
(b) Marins, M. A. P.; Pereira, C. M. P.; Zimmermann, N. E.
K.; Cunico, W.; Moura, S.; Beck, P.; Zanatta, N.; Bonacorso,
H. G. J. Fluorine Chem. 2003, 123, 261; and references cited
therein. (c) Narsaiah, B.; Sivaprasad, A.; Venkataratnam, R.
V. J. Fluorine Chem. 1994, 66, 47. (d)Schlosser, M.;Volle,
J.-N.; Leroux, F.; Schenk, K. Eur. J. Org. Chem. 2002,
2913. (e) Druzhinin, S. D.; Balenkova, E. S.; Nenajdenko,
V. G. Tetrahedron 2007, 63, 7753.
(12) (a) Krasovsky, A. L.; Hartulyari, A. S.; Nenajdenko, V. G.;
Balenkova, E. S. Synthesis 2002, 133. (b) Krasovsky, A. L.;
Moiseev, A. M.; Nenajdenko, V. G.; Balenkova, E. S.
Synthesis 2002, 901.
(13) (a) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32. (b) Uneyama, K.
J. Fluorine Chem. 1999, 97, 11.
References and Notes
(1) (a) Temple, C.; Rose, J. D.; Comber, R. N.; Rener, G. A.
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Camaioni, E.; Lupidi, G.; Mohmoud, N.; Belvilaqua, F.;
Palu, G. J. Med. Chem. 1995, 38, 4019. (b) Cundy, D. J.;
Holan, G.; Otaegui, M.; Simpson, G. W. Bioorg. Med.
Chem. Lett. 1997, 7, 669.
(3) Temple, C. J. Med. Chem. 1990, 33, 656.
(4) Bukoski, L.; Janowiec, M. Pharmazie 1989, 44, 267.
(5) (a) Mantlo, N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegl,
P. K. S.; Chang, R. S.; Lotti, V. J.; Faust, K. A.; Chen, T.-B.;
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(b) Bavetsias, V.; Sun, C.; Bouloc, N.; Reynisson, J.;
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(17) General Procedure
A solution of amine 2a–i (5 mmol) in dried CH2Cl2 (2,5 mL)
was heated until reflux. After a period of 15 min ethyl N-
(cyanomethyl)formimidate 1 (5 mmol, 560 mg) was added
under N2 counterflow. The mixture was allowed to stir
Synlett 2008, No. 10, 1459–1462 © Thieme Stuttgart · New York

1462
T. Wesch et al.
LETTER
under reflux for 2 h. To the hot reaction mixture the 1,3-
biselectrophile of type 4a–e (5 mmol) was added. The
mixture was stirred for 8 h. Then it was cooled down to
ambient temperature. The crude product was worked up
through flash column chromatography to obtain the product
as white needles.
(18) Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531.
(19) CCDC 683462 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Selected Data for 5o
1H NMR (400 MHz, CDCl3): d = 3.79 (s, 3 H, OCH3), 5.47
(s, 2 H, CH2), 6.89 (m, 2 H, Ph), 7.33 (m, 2 H, Ph), 7.87 (s,
1 H, H-6), 8.31 (s, 1 H, H-2). 13C NMR (100 MHz, CDCl3):
d = 47.5 (OCH3), 55.3 (CH2), 111.5 (m, C-6), 122.3 (q,
1JCF = 278 Hz, CF3), 121.6 (q, 1JCF = 278 Hz, CF3), 114.4
(Ph), 126.6 (Ph), 130.1 (Ph), 160.4 (Ph), 129.7 (q, 2JCF = 36
Hz, C-7), 133.6 (C-7a), 143.1 (q, 2JCF = 35 Hz, C-5), 148.4
(C-3a), 148.6 (C-2). 19F NMR (376 MHz, CDCl3): d =
–62.59, –66.55.
(20) (a) Al-Shaar, A. H. M.; Gilmour, D. W.; Lythgoe, D. J.;
McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Perkin
Trans. 1 1992, 2779. (b) Al-Shaar, A. H. M.; Chambers, R.
K.; Gilmour, D. W.; Lythgoe, D. J.; McClenaghan, I.;
Ramsden, C. A. J. Chem. Soc., Perkin Trans. 1 1992, 2789.
(c) Humphries, M. J.; Ramsden, C. A. Synlett 1995, 203.
(21) Linderman, R. J.; Jamois, E. A. J. Fluorine Chem. 1991, 53,
79.
(22) (a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533.
(b) Pearson, R. G.; Parr, R. G. J. Am. Chem. Soc. 1983, 105,
7512. (c) Ayers, P. W. Faraday Discuss. 2007, 135, 161.
Synlett 2008, No. 10, 1459–1462 © Thieme Stuttgart · New York

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