Synthesis and electron-transfer reactions of some 3-difluoroacetylated imidazo[1,2-a]pyridine derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00388-4

The synthesis of new 3-chlorodifluoroacetylated imidazo[1,2-a]pyridines 1-6 and their difluoroacetyl derivatives is presented. The reductive cleavage of the halogenated ketones was investigated by cyclic voltammetry, and tetrakis(dimethylamino)ethylene (T

Full text of DOI:10.1016/S0040-4039(01)00388-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3077–3080
Synthesis and electron-transfer reactions of some
3-difluoroacetylated imidazo[1,2-a]pyridine derivatives
Conrad Burkholder,a William R. Dolbier, Jr.,a Maurice Me´debielleb,* and Samia Ait-Mohandb
aUniversity of Florida, Department of Chemistry, PO Box 117200, Gainesville, FL 32611-7200, USA
bUniversite´ Denis Diderot-Paris 7, Laboratoire d’Electrochimie Mole´culaire, UMR CNRS 7591, 2 Place Jussieu,
Case courrier 7107, 75251 Paris Cedex 05, France
Received 5 March 2001; accepted 6 March 2001
Abstract—The synthesis of new 3-chlorodifluoroacetylated imidazo[1,2-a]pyridines 1–6 and their difluoroacetyl derivatives is
presented. The reductive cleavage of the halogenated ketones was investigated by cyclic voltammetry, and tetra-
kis(dimethylamino)ethylene (TDAE) was found to be an effective reductant for the generation of the corresponding a,a-
difluoroacetyl anions and for the synthesis of new gem-difluoromethylated imidazo[1,2-a]pyridine derivatives 7–12. © 2001
Elsevier Science Ltd. All rights reserved.
There continues to be an interest in the synthesis of new
gem-difluorinated compounds because of the potential
biological properties of such molecules.1 Electrophilic
carbonyl derivatives, such as a,a-difluoroketones, are
compounds of great interest because they have the
capability to form hydrates and hemiketals.1 It is
believed that this property allows some fluorinated
ketones to mimic the transition states involved in the
hydrolytic action of many enzymes.1 Azaindolizine and
particularly imidazo[1,2-a]pyridine derivatives are
important heterocycles that have received a great deal
of attention because of their significant and potential
biological activities [benzodiazepine receptor ligands
(Zolpidem; Fig. 1),2 antiviral molecules,3 antibacterial
agents4 and anti-ulcer agents5]. Even recently, bicyclic
imidazo derivatives (imidazo[1,2-a]pyridine, imi-
dazo[2,1-b]thiazole) have been screened as new anti-
HIV-1 compounds (Fig. 1) such as non-nucleoside
reverse transcriptase (RT) inhibitors (NNRTIs)6 and
HIV-1 protease inhibitors.7
As part of our ongoing efforts in the search of new
methodologies for the synthesis of fluorinated com-
pounds with potential biological applications,8 we wish
to report the synthesis of new chloro- and
difluoroacetylated imidazo[1,2-a]pyridine derivatives 1–
6 and their single electron-transfer reactions, using the
tetrakis(dimethylamino)ethylene (TDAE) as an electron
donor.8d,8e,9 In such a way novel gem-difluorinated
imidazo[1,2-a]pyridine derivatives 7–12 were obtained
from the corresponding a,a-difluoroacetyl anions and
subsequent in situ nucleophilic addition to aromatic
and heterocyclic aldehydes. Imidazo[1,2-a]pyridine
derivatives 2–6 were synthesized in moderate to good
yields, according to Tschitschibabin, by condensation
of 2-aminopyridine with the appropriate a-bromoke-
N
CH3
N
Y
HIV-1 RT inhibitors
N
N
X=S IC50=13 µM
X=O IC50=18 µM
X
X
ZOLPIDEM X=Y=CH3; R1=R2=CH3
O
O
NR1R2
Figure 1.
Keywords: imidazo[1,2-a]pyridine; cyclic voltammetry; tetrakis(dimethylamino)ethylene; fluorine and compounds.
* Corresponding author. Present address: Universite´ Claude Bernard-Lyon 1, Domaine Scientifique de la Doua, Laboratoire SERCOF (UMR
CNRS 5622), Baˆtiment E. Chevreul (303), 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne Cedex, France. Fax: +33 (0) 4 72 43 13 23; e-mail:
medebiel@univ-lyon1.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00388-4

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C. Burkholder et al. / Tetrahedron Letters 42 (2001) 3077–3080
tone.10 Introduction of the COCF2Cl moiety at the C-3
position was achieved using 2.5 equiv. of chlorodi-
fluoroacetic anhydride in refluxing anhydrous 1,2-
dichloroethane for 24 h. Imidazo[1,2-a]pyridine-3-
COCF2Cl 1, was obtained in a similar manner from
commercially available imidazo[1,2-a]pyridine. The
products can be purified by simple recrystallization
from the crude product or by silica gel chromatogra-
phy. The corresponding difluoroacetyl derivatives 1A–
6A were obtained under mild conditions, by reductive
dechlorination using sodium formaldehyde sulfoxylate
(Rongalite)11 in refluxing absolute ethanol (Scheme 1).
point, our studies on the cyclic voltammetry of
TDAE,8e as well as on the chlorodifluoromethylated
ketones 2–6 (first peak potential varies from −1.15 to
−1.28 V versus SCE in DMF+0.1 M NBu4PF6 at 0.2
V/s), prompted us to try TDAE as a mild and concep-
tually different synthetic electron-transfer reagent (as
compared to the classical Reformatsky reaction1) for
the generation of difluoroacetyl anions, and subsequent
reactions with aromatic and imidazo[1,2-a]pyridine-3-
carbaldehyde derivatives as trapping agents. In a typi-
cal experiment, 1 equiv. of ketone 1 was condensed, in
anhydrous DMF at −20°C, with 1 equiv. of benzalde-
hyde in the presence of TDAE; as we have reported for
the reactions involving aromatic chlorodifluoromethyl-
ated ketones,8d an equimolar amount of TDAE was
necessary for complete reduction of the starting ketone
1, with the reaction being almost complete after 2 h
(TLC). After the usual work-up, fluorine NMR of the
crude product revealed the presence of the desired
alcohol 7 characterized by two doublets of doublets (lF
−110.8 and −121.7 ppm/CFCl3 with JFꢀF=261 Hz and
3JHꢀF=18.12 and 6.82 Hz) and the difluoroacetylated
Cyclic voltammetry of 1, chosen as a model substrate
(in anhydrous DMF+0.1 M NBu4PF6), shows that the
first two-electron reduction wave (as compared with the
one-electron oxidation wave of the ferrocene) located at
−1.25 V versus SCE (first peak potential Epc1 at 0.2 V/s
on a glassy carbon electrode) is irreversible (up to 500
V/s) and corresponds to the cleavage of the CꢀCl bond
and to the formation of the corresponding
difluoroacetyl derivative 1A (Epc2=−1.58 V versus SCE
at 0.2 V/s) as the reduction product, as was shown by
comparison with an authentic sample. The cleavage of
the radical anion is very fast (stepwise mechanism) and,
therefore, the major pathway of the a,a-difluoroacetyl
radical is a further reduction to the hydrogenolysis
product, probably at a close potential to 1. At this
ketone 1A (lF −126.3 ppm/CFCl3; doublet with 2JHꢀF
=
55 Hz) in a 2:1 ratio. The alcohol adduct was isolated
as a white solid in 56% yield after purification by silica
gel chromatography and preparative TLC.12 Similarly,
in the presence of benzaldehyde (1 equiv.) and TDAE
(1 equiv.), ketone 2 gave the desired alcohol 8 in 67%
(ClCF2CO)2O
R
N
R
acetone
+
(2.5 eq)
COCH2Br
2
N
ethanol
reflux
2 hours
N
NH2
ClCH2CH2Cl
reflux
24 hours
3
51-62%
R
Rongalite
(1.5 eq)
N
R
N
2
N
N
2
EtOH
reflux
5 hours
3
3
COCF2Cl
COCF2H
42-61%
R=p-CH3, 2A; p-Cl, 3A;
p-Br, 4A; p-C6H5, 5A;
m-NO2, 6A
R=p-CH3, 2; p-Cl, 3;
p-Br, 4; p-C6H5, 5;
m-NO2, 6
Scheme 1.
8
N
N
7
TDAE (1eq)/ArCHO (1eq)
R
R
2
N
2
6
N
DMF, -20°C to RT
H
3
3
5
Ar=phenyl
3-pyridinyl, p-fluorophenyl
imidazo[1,2-a]pyridine
COCF2Cl
CF2C Ar
OH
1eq
O
R=H, 1;p-CH3-C6H4, 2
R=H, Ar= phenyl, 7 (56%)
R=p-CH3-C6H4, Ar= phenyl, 8 (67%)
R=H, Ar= 3-pyridinyl, 9 (62%)
R=H, Ar=imidazo[1,2-a]pyridine, 10 (38%)
R=p-CH3-C6H4, Ar= imidazo[1,2-a]pyridine, 11 (46%)
R=H, Ar= 3-pyridinyl, 12 (40%)
Scheme 2.

C. Burkholder et al. / Tetrahedron Letters 42 (2001) 3077–3080
3079
yield. Imidazo[1,2-a]pyridine-3-carbaldehyde13 was also
found to be a good electrophile and the corresponding
alcohols were obtained in reasonable yields. Formation
of the products was monitored by TLC and the yields
were moderate (Scheme 2).
5. Kaminsky, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi,
R. K.; Conn, D. J.; Elliott, A. J.; Lovey, R. G.; Guzik,
H.; Chiu, P. J. S.; Long, J. F.; McPhail, A. T. J. Med.
Chem. 1989, 32, 1686–1700.
6. Moog, C.; Wick, A.; Le Ber, P.; Kirn, A.; Aubertin,
A.-M. Antivir. Res. 1994, 24, 275–288.
7. Smith, H. W. The Upjohn Company, PCT/US 95/04444
(Word Patent Application 95/29922), November 1995.
8. (a) Hapiot, P.; Me´debielle, M. J. Fluorine Chem. 2001,
107, 285–300; (b) Burkholder, C.; Dolbier, Jr., W. R.;
Me´debielle, M. J. Fluorine Chem. 2000, 102, 369–376; (c)
Burkholder, C.; Dolbier, Jr., W. R.; Me´debielle, M. J.
Fluorine Chem. 1999, 95, 127–130; (d) Burkholder, C.;
Dolbier, Jr., W. R.; Me´debielle, M.; Ndedi, A. Tetra-
hedron Lett. 1998, 39, 8853–8856; (e) Burkholder, C.;
Dolbier, Jr., W. R.; Me´debielle, M. J. Org. Chem. 1998,
63, 5385–5394.
9. (a) Chambers, R. D.; Nakamura, T. J. Chem. Soc.,
Perkin Trans. 1 2001, 398–406; (b) Kuroboshi, M.;
Tanaka, M.; Kishimoto, S.; Goto, K.; Mochizuki, M.;
Tanaka, H. Tetrahedron Lett. 2000, 41, 81–84; (c) Kuro-
boshi, M.; Goto, K.; Mochizuki, M.; Tanaka, H. Synlett
1999, 1930.
10. Blewitt, H. L. In Special Topics in Heterocyclic Chem-
istry; Weissberger, A.; Taylor, E. C., Eds.; Wiley: New
York, 1977; p. 117.
11. (a) Kumar, V.; McCloskey, P.; Bell, M. R. Tetrahedron
Lett. 1994, 35, 833; (b) Harris, A. R. Synth. Commun.
1987, 17, 1587; (c) Dolbier, Jr., W. R.; Me´debielle, M.;
Ait-Mohand, S. Tetrahedron Lett., submitted.
The only side-products, which represent the remaining
balance material, were the hydrogenolysis compounds
RCOCF2H resulting from protonation of the a,a-
difluoroacetyl anion. None of the yields have been
optimized and room for improvement certainly exists.
In conclusion, to the best of our knowledge, this is the
first report of a facile synthesis of gem-difluorinated
imidazo[1,2-a]pyridine derivatives.14 Based on the cyclic
voltammetric experiments, TDAE has been found (as in
our previous studies) to be effective for the generation
of stable a,a-difluoroacetyl anions. The addition prod-
ucts are good candidates for further chemical elabora-
tion and are potentially useful for biological
applications. Work is in progress to use these
chlorodifluoroacetylated ketones, as well as new
bicyclic imidazo halogenodifluoromethyl ketone deriva-
tives (imidazo[1,2-a]pyrimidine, imidazo[2,1-b]thiazole
and imidazo[2,1-b]oxazole), in various single electron-
transfer (TDAE and SRN115) reactions of synthetic
utility.
Acknowledgements
12. A typical procedure for the reaction between 1, TDAE
and benzaldehyde is as follows: Into a two-necked flask
equipped with a silica gel drying tube and a nitrogen inlet
were added, under nitrogen at −20°C, a 5 ml anhydrous
DMF solution of 1 (0.35 g, 1.52 mmol) and benzaldehyde
(0.16 g, 1.52 mmol; 0.15 ml). The solution was stirred and
maintained at this temperature for 30 min and then the
TDAE (0.30 g, 1.52 mmol, 0.15 ml) was added dropwise
(via a syringe). A red color immediately developed with
the formation of a fine, white precipitate. The solution
was vigorously stirred at −20°C for 1 h and then warmed
up to room temperature for 2 h. After this time, TLC
analysis (EtOAc–hexane, 90:10) clearly showed that the
ketone 1 was totally consumed. The orange-red turbid
solution was filtered (to remove the octamethyloxami-
dinium dichloride) and hydrolyzed with 30 ml of H2O.
The aqueous solution was extracted with CHCl3 (3×30
ml), the combined organic solutions were washed with
brine (3×30 ml), H2O (3×30 ml) and then dried over
MgSO4. Evaporation of the solvent left an orange viscous
liquid as crude product. Purification by silica gel chro-
matography (EtOAc–hexane, 90:10 as eluent) and prepar-
ative TLC (hexane–CH2Cl2, 98:2) gave 0.256 g (0.85
mmol, 56%) of the alcohol 7 as a white solid. 2,2-
Difluoro-3-hydroxy-1-imidazo[1,2-a]pyridin-3-yl-3-phenyl-
The authors would like to thank Marie-Noelle Rager
(ENSCP, Paris) for the fluorine and proton NMR
spectra and David Clainquart (Universite´ Denis
Diderot-Paris 7) for the mass spectra. M.M. and
S.A.-M. would like to thank the Universite´ Denis
Diderot-Paris 7 for a research grant (Appel d’offres
SIDA 1999).
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1
propan-1-one. H NMR (CDCl3): lH 5.37–5.43 (1H, dd,
J=17.5, 6.44 Hz, -CHOH), 7.18–7.22 (1H, m, H-6),
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C. Burkholder et al. / Tetrahedron Letters 42 (2001) 3077–3080
13. Prepared in good yields by formylation (with POCl3 in
DMF at 80°C) of the corresponding imidazo[1,2-
a]pyridine derivatives.
14. The synthesis of imidazo[2,1-b]thiazole-5-COCF3 has
been reported: Hopkinson, C. P.; Meakins, G. D.; Pur-
cell, R. J. J. Chem. Res., S. 1993, 161, 201.
15. Recently SRN1 reactions (nitronate anions as nucle-
ophiles) with bicyclic imidazo derivatives (imidazo[1,2-
a]pyridine and pyrimidine, imidazo[2,1-b]thiazole) have
been published: (a) Roubaud, C.; Vanelle, P.; Maldon-
ado, J.; Crozet, M. P. Tetrahedron 1995, 51, 9643–9656;
(b) Vanelle, P.; Madadi, N.; Roubaud, C.; Maldonado,
J.; Crozet, M. P. Tetrahedron 1991, 47, 5173–5184. We
recently synthesized the 5-chlorodifluoroacetyl imi-
dazo[2,1-b]thiazole and applied the SRN1 reaction with
phenyl thiolate as nucleophile; the desired substituted
product was obtained in 80% yield and subsequent
reduction of the carbonyl with NaBH4 gave the alcohol
product in 76% yield. The compound is regarded as an
analogue of known HIV-1 protease inhibitors (Ref. 7).
Its activity as a potent HIV-1 RT (see Ref. 6) and
protease (see Ref. 7) inhibitors will be checked, as
well as the activity of the imidazo[2,1-b]thiazole-5-
COCF2SPh.
.
.