Syntheses of 2-(bromodifluoromethyl)benzoxazole and 5-(bromodifluoromethyl)-1,2,4-oxadiazoles

Article abstract of DOI:10.1016/S0022-1139(99)00007-X

Facile syntheses of CF₂Br-substituted heterocycles are reported. Preparation of 2-(bromodifluoromethyl)benzoxazole (2) was achieved in two steps by reaction of 2-aminophenol (3) with CF₂BrCO₂Et to give amide (4), followed by cyclization of 4 with PPA to give 2. The 5-(bromodifluoromethyl)-1,2,4-oxadiazoles (6a-c) were prepared by one step reaction of amidoximes (5a-c) with CF₂BrCO₂Et. These CF₂Br-substituted heterocycles are intermediates in an ongoing investigation of the synthesis of inhibitors of HIV reverse transcriptase having a CF₂ substitution.

Full text of DOI:10.1016/S0022-1139(99)00007-X

Journal of Fluorine Chemistry 95 (1999) 127±130
Syntheses of 2-(bromodi¯uoromethyl)benzoxazole and
5-(bromodi¯uoromethyl)-1,2,4-oxadiazoles
a a,*
William R. Dolbier Jr. , Conrad R. Burkholder , Maurice Medebielle
1,b
Â
aUniversity of Florida, Department of Chemistry, P.O. Box 117200, Gainesville, Florida 32611-7200, USA
 Â
Universite Denis Diderot (Paris 7), Laboratoire d'Electrochimie Moleculaire, UMR CNRS 7591, 2 Place Jussieu, 75251 Paris Cedex 05, France
b
Â
Received 18 November 1998; accepted 4 January 1999
Abstract
Facile syntheses of CF2Br-substituted heterocycles are reported. Preparation of 2-(bromodi¯uoromethyl)benzoxazole (2) was achieved in
two steps by reaction of 2-aminophenol (3) with CF2BrCO2Et to give amide (4), followed by cyclization of 4 with PPA to give 2. The 5-
(bromodi¯uoromethyl)-1,2,4-oxadiazoles (6a±c) were prepared by one step reaction of amidoximes (5a±c) with CF2BrCO2Et. These
CF2Br-substituted heterocycles are intermediates in an ongoing investigation of the synthesis of inhibitors of HIV reverse transcriptase
having a CF2 substitution. # 1999 Elsevier Science S.A. All rights reserved.
1. Introduction
mediate. Since there is very little precedent in the literature
for the synthesis of CF2Br-substituted heterocycles, to ®nd a
facile synthesis of 2 as well as other CF2Br-heterocycles
became the immediate goal.
The AIDS epidemic has become a global problem
with millions of people currently infected by HIV. Recent
efforts to ®nd a cure have centered on the development of
non-nucleoside reverse transcriptase inhibitors (NNRTIs)
such as 1 [1]. Although they are very active against HIV-
1 in clinical trials, NNRTIs are not clinically useful for
treating AIDS due to the rapid emergence of resistant HIV
strains.
2. Results and discussion
Initial attempts at brominating the CF2H group of 5-
(di¯uoromethyl)-2-nitrofuran by photolysis with NBS (N-
bromosuccinimide) showed that despite working ®ne for
benzene CF2H groups [3], this synthetic route is not viable
for preparing CF2Br-heterocycles. The reaction gave a
multitude of products having an unreacted CF2H group
and no product with the desired CF2Br. For this reason,
attention was turned to utilizing commercially available
CF2BrCO2Et as the source of the CF2Br group. It is now
reported that 2 can be prepared in two easy steps from 2-
aminophenol (3).
Heating a solution of 3 in ethyl acetate with equimolar
amounts of CF2BrCO2Et and NEt3 gave a good yield of
amide 4. Three aspects of this reaction are worth mention-
ing. Firstly, the ¯uorine atoms of CF2BrCO2Et facilitate
immensely the reactivity of the ester by their strong electron
withdrawing effect [4], and it is worth noting that the EtOAc
solvent does not react at all with 3. Secondly, since no
reaction occurs without NEt3, it must serve as a catalyst for
the reaction. Thirdly, the OH group of 3 is necessary for the
success of the reaction since 2-aminobiphenyl (where the
OH of 3 has been replaced by a phenyl) does not give a clean
Dramatic enhancements of activity have been reported in
many cases for partially ¯uorinated analogs of biologically
active compounds [2]. As part of an ongoing project inves-
tigating the synthesis of ¯uorine-containing heterocycles, a
decision was taken to develop a synthetic method by which
various analogs of 1 could be prepared where one CH2 is
replaced with CF2. It is hoped that activity against resistant
strains of HIV might be induced upon ¯uorine substitution.
A retrosynthetic analysis revealed that 2-(bromodi¯uoro-
methyl)benzoxazole (2) would be a useful synthetic inter-
*Corresponding author. Tel.: +1-352-392-3580; fax: +1-352-846-0296;
e-mail: conrad@chem.ufl.edu
1Fax: +33 (0) 1-44-27-76-25; e-mail: mauricem@paris7.jussieu.fr
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 0 7 - X

128
W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 95 (1999) 127±130
reaction with CF2BrCO2Et.
3. Experimental section
3.1. General comments
Amide 4 undergoes facile cyclization upon heating with
PPA (polyphosphoric acid) to give a good yield of 2. For this
cyclization, only PPA was effective, and other acids did not
give any of the desired 2. An important feature of this
procedure is the work-up with ice and aqueous NH3, which
prevents the conversion of 2 back to 4 by acid-catalyzed
hydrolysis.
Syntheses of CF2Br-oxadiazoles (6a±c) were achieved in
one step by condensation of CF2BrCO2Et with amidoximes
(5a±c). The amidoximes are readily available by reaction of
the appropriate nitriles with hydroxylamine [5±7]. Although
the isolated yields of 6a±c are low, the one-step procedures
are extremely convenient and can be carried out easily on a
large scale. In the case of 6a, the low yield was due to the
formation of PhCN as a side-product as well as a substantial
amount of non-volatile, polymeric material. Analysis by 19F
NMR of the reaction mixture before work-up, using internal
standard bearing ¯uorine, revealed that all of CF2BrCO2Et
took part in the reaction and that the yield of 6a varied from
34% to 40%, thus demonstrating that the low yield was not
due to a loss of 6a during the work-up procedure. Further
attempts to increase the yield using a two-fold excess of
CF2BrCO2Et resulted in no improvement.
1
Melting points were uncorrected. The H NMR spectra
were measured at 300 MHz, and chemical shifts reported in
ppm down®eld of internal SiMe4. The 19F NMR spectra
were measured at 282 MHz, and chemical shifts reported in
ppm up®eld of internal CFCl3. The 13C NMR spectra were
measured at 75 MHz with all the protons decoupled, and the
chemical shifts reported in ppm down®eld of SiMe4. The
mass spectra were recorded at 70 eV. The IR spectra were
recorded using a Fourier transform spectrometer.
All of the solvents and reagents were used as received
from the supplier without puri®cation.
3.2. 2-Bromo-2,2-difluoro-N-(2-hydroxyphenyl)acetamide
(4)
A solution of 30.00 g (0.275 mol) of 2-aminophenol (3),
60.00 g (0.296 mol) of ethyl bromodi¯uoroacetate, and
30.00 g (0.296 mol) of triethylamine in 300 ml of ethyl
acetate was heated at re¯ux for 1 h. After cooling to room
temperature, 300 ml of ethyl acetate was added and the
solution was washed once with 1200 ml of dilute HCl (one
part concentrated HCl to nine parts water). The aqueous
layer was extracted three times with 300 ml portions of
EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated by rotary evaporation at reduced
pressure to give 74.77 g of a crude tan solid which was
recrystallized from 635 ml of CHCl3 (ice bath cooling for
1.5 h) to give 60.0 g (82%) of straw-colored crystals (mp
138.5±140.28C), which was 4: 1H NMR (DMSO-d6): ꢀ
10.20 (br s, 1H), 9.92 (br s, 1H), 7.32 (dd, 1H, J ˆ 1.5
and 7.8 Hz), 7.13 (dt, 1H, Jd ˆ 1.7 and Jt ˆ 7.8 Hz), 6.93
(dd, J ˆ 1.2 and 8.1 Hz), 6.83 (dt, Jd ˆ 1.2 and
Jt ˆ 7.6 Hz); 19F NMR (DMSO-d6): ꢁ 59.4 (s); 13C
NMR (DMSO-d6): ꢀ 158.0 (t, JCF ˆ 27.2 Hz), 151.0 (s),
127.6 (s), 125.7 (s), 122.6 (s), 118.9 (s), 116.0 (s), 111.8 (t,
JCF ˆ 315.2 Hz); IR (KBr) 1686 (C=O) cm 1; HRMS
(70 eV) calcd. for C8H6BrF2NO2, 264.9550; found,
264.9583. Anal. Calcd. for C8H6BrF2NO2: C, 36.12; H,
2.27; N, 5.26. Found: C, 35.93; H, 1.93; N, 5.03.
The CF2Br groups of compounds 2 and 6a display useful
reactivity. In recent published results from this laboratory
[8], it has been reported that 2 and 6a react with aldehydes
when treated with tetrakis(dimethylamino)ethylene
(TDAE) to give b,b-di¯uoroalcohols such as 8. Addition
to aldehyde proceeds by generation of the anion of 2 or 6a
by a two-electron reduction.
Benzene derivatives with a CF2Br group have also been
reported by Haas and coworkers [3] to react with nucleo-
philes such as phenolate, thiolate, and azide anions. Since
the ¯uorine atoms of the CF2Br group prevent attack of
nucleophiles by an SN2 mechanism, only nucleophiles that
can react by an SRN1 mechanism [9] will displace bromide.
Work is currently in progress to determine the scope and
synthetic utility of the reactions of 2 (as well as 6a±c) with
selected nucleophiles, and to prepare some novel CF2-
substituted structures as potential NNRTIs for structure-
activity studies.
3.3. 2-(Bromodifluoromethyl)benzoxazole (2)
To
a 1000 ml, single-necked, round-bottom ¯ask
equipped with a drying tube and an egg-shaped stir bar
was added 89 g of polyphosphoric acid and 30.00 g
(0.113 mol) of 4. The ¯ask was submerged in an oil bath

W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 95 (1999) 127±130
129
which was heated rapidly to 1508C. After 30 min at 1508C,
all of the solid amide was dissolved, and the solution was
allowed to cool to room temperature. To the ¯ask was added
1120 ml of crushed ice, followed by 207.5 ml of concen-
trated ammonia (30% NH3), and the mixture was triturated
using a spatula until all of the polyphosphoric acid was
dissolved. The dissolving of polyphosphoric acid can be
facilitated by not stirring the mixture thoroughly so that the
bottom of the ¯ask becomes slightly warm. The aqueous
solution was extracted ®ve times with 200 ml portions of
CHCl3. The combined organic layers were dried over
Na2SO4 and concentrated by rotary evaporation at reduced
pressure to give an amber liquid which was puri®ed by
simple vacuum distillation to give 20.6 g (73%) of a clear,
colorless liquid which was pure 2 (bp 628C at 1.5 mm): 1H
NMR (CDCl3): ꢀ 7.87 (m, 1H), 7.66 (m, 1H), 7.50 (m, 2H);
19F NMR (CDCl3): ꢁ 51.9 (s); 13C NMR (CDCl3): ꢀ 155.7
(t, JCF ˆ 32.7 Hz), 150.6 (s), 139.6 (s), 127.7 (s), 125.9 (s),
121.9 (s), 111.6 (s), 108.9 (t, JCF ˆ 301.9 Hz); HRMS
(70 eV) calcd. for C8H4BrF2NO, 246.9444; found,
246.9455. Anal. Calcd. for C8H4BrF2NO: C, 38.74; H,
1.63; N, 5.65. Found: C, 38.66; H, 1.36; N, 5.76.
from 100 ml of 2-propanol (ice cooling for 1 h) gave 34.06 g
(79%) of a white solid, mp 130±134.58C ([5±7] mp 134±
1368C), which was 5b: H NMR (DMSO-d6): ꢀ 8.7 (br s,
1H), 5.3 (br s, 2H), 1.6 (s, 3H).
1
3.6. Butyramidoxime (5c)
A solution of 50.5 ml (40.1 g, 0.580 mol) of butyronitrile,
26.07 g (0.652 mol) of NaOH, and 43.41 g (0.625 mol) of
hydroxylamine hydrochloride in 870 ml of 95% ethanol and
216 ml of water was heated at re¯ux for 24 h. Concentration
by rotary evaporation at reduced pressure (water aspirator,
808C) gave a mixture of an oil and a white solid. The oil was
dissolved in 600 ml of CHCl3 and ®ltered to remove the
insoluble NaCl. The ®ltrate was concentrated by rotary
evaporation to give a clear, colorless oil. Puri®cation by
fractional distillation at reduced pressure using a 15 cm
Vigreux column gave 38.31 g (64%) of a clear, colorless oil,
bp 908C at 0.3 mm ([5±7] bp 88±908C at 0.5 mm), which
was 5c: 1H NMR (CDCl3): ꢀ 9.1 (br s, 1H), 4.6 (br s, 2H),
2.12 (t, 2H, J ˆ 7.7 Hz), 1.58 (hextet, 2H, J ˆ 7.6 Hz), 0.95
(t, 3H, J ˆ 7.3 Hz).
3.4. Benzamidoxime (5a)
3.7. 5-(Bromodifluoromethyl)-3-phenyl-1,2,4-oxadiazole
(6a)
A solution of 20.00 g (0.194 mol) of benzonitrile, 14.47 g
(0.210 mol) of hydroxylamine hydrochloride and 8.69 g
(0.217 mol) of NaOH in 290 ml of 95% ethanol and
72 ml of water was heated a re¯ux for 25 h. Concentration
by rotary evaporation at reduced pressure (water aspirator,
heating at 708C) gave a mixture of a colorless oil and a white
solid which was dissolved in 200 ml of CHCl3 and ®ltered to
remove the insoluble NaCl. The CHCl3 ®ltrate was dried
over Na2SO4 and concentrated by rotary evaporation at
reduced pressure to give a clear, colorless oil which was
subjected to full vacuum (0.3 mm) for 1 h. Cooling and
scratching produced very slow crystallization. After stand-
ing overnight, 22.20 g of a crude, white solid was obtained,
which was recrystallized from 124 ml of CHCl3 and 111 ml
of hexanes (scratching done to prevent oil formation; cool-
ing in an ice bath for 40 min) to give 16.80 g (64%) of 5a as
short white needles, mp 63.5±76.08C ([5±7] mp 76±788C):
1H NMR (CDCl3): ꢀ 9.0 (br s, 1H), 7.63 (m, 2H), 7.40 (m,
3H), 4.9 (br s, 2H).
A solution of 61.8 g (0.454 mol) of benzamidoxime (5a),
63 ml (99.7 g, 0.491 mol) of CF2BrCO2Et and 70 ml
(50.8 g, 0.502 mol) of NEt3 in 250 ml of toluene was heated
at re¯ux for 3 h. After cooling in an ice bath for 1.5 h,
suction ®ltration gave 34.53 g of an insoluble solid which
was discarded. The toluene ®ltrate was washed once with
500 ml of dilute aqueous HCl (nine parts water to one part
concentrated HCl) and the aqueous layer was extracted three
times with 250 ml portions of CHCl3. The combined
organic layers were dried over Na2SO4 and concentrated
by rotary evaporation at reduced pressure (water aspirator,
heating at 658C) to give a crude, brown liquid. Puri®cation
by fractional vacuum distillation using a 36 cm Vigreux
column wrapped with glass wool and aluminum foil gave
about 10 ml of a fore-run consisting of benzonitrile and
NEt3 (bp 28±308C at 0.6 mm) followed by distillation of
44.25 g (35%) of 6a as a clear, colorless liquid (bp 708C at
1
1 mm): H NMR (CDCl3): ꢀ 8.12 (m, 2H), 7.5±7.58 (m,
3H); 19F NMR (CDCl3): ꢁ 52.4 (s); 13C NMR (CDCl3): ꢀ
169.6 (t, JCF ˆ 33.5 Hz), 169.0 (s), 132.1 (s), 129.0 (s),
127.6 (s), 125.1 (s), 107.2 (t, JCF ˆ 303.9 Hz); HRMS
(70 eV) calcd. for C9H5BrF2N2O, 273.9553; found,
273.9532. Anal. Calcd. for C9H5BrF2N2O: C, 39.30; H,
1.83; N, 10.18. Found: C, 39.39; H, 1.93; N, 10.15.
3.5. Acetamidoxime (5b)
A solution of 30.3 ml (23.82 g, 0.580 mol) of CH3CN,
26.07 g (0.652 mol) of NaOH, and 43.41 g (0.625 mol) of
hydroxylamine hydrochloride in 870 ml of 95% ethanol and
216 ml of water was heated at re¯ux for 24 h. Concentration
by rotary evaporation at reduced pressure (water aspirator,
758C) gave a white solid which was dissolved in 900 ml of
absolute ethanol and ®ltered to remove the insoluble NaCl.
Concentration of the ®ltrate by rotary evaporation gave
37.85 g of a crude white solid. Recrystallization of the solid
3.8. 5-(Bromodifluoromethyl)-3-methyl-1,2,4-oxadiazole
(6b)
A mixture of 20.00 g (0.270 mol) of acetamidoxime (5b),
60.3 g (0.297 mol) of CF2BrCO2Et, and 30.00 g

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W.R. Dolbier Jr. et al. / Journal of Fluorine Chemistry 95 (1999) 127±130
(0.297 mol) of NEt3 was heated at re¯ux for 3 h. After
cooling to ambient temperature, 150 ml of water was added
and the layers were separated. The aqueous layer was
extracted ®ve times with 50 ml portions of ether. The
combined organic layers were dried over Na2SO4 and then
concentrated by fractional distillation at ambient pressure
using a 23 cm Vigreux column. The distillate (bp 35±
77.58C) was discarded. A total of 29 g of a crude, amber
liquid remained undistilled. The crude product was sub-
jected to vacuum fractional distillation using a 15 cm Vig-
reux column. After the ®rst fraction (bp 50±758C at
214 mm, 3.19 g) was collected, the product distilled as an
azeotrope with water (bp 89±938C at 214 mm). The aqueous
layer was separated and the cloudy liquid product was dried
over activated molecular sieves to give 13.68 g (24%) of a
clear, colorless liquid, which was 6b: 1H NMR (CDCl3): ꢀ
2.51 (s); 19F NMR (CDCl3): ꢁ 52.43 (s); 13C NMR
(CDCl3): ꢀ 169.3 (t, JCF ˆ 33.5 Hz), 168.0 (s), 107.1 (t,
JCF ˆ 303.4 Hz), 11.3 (s); HRMS (70 eV) calcd. for
C4H3BrF2N2O, 211.9397; found, 211.9377. Anal. Calcd.
for C4H3BrF2N2O: C, 22.56; H, 1.42; N, 13.15. Found: C,
23.71; H, 1.64; N, 13.10.
was removed by fractional distillation at ambient pressure
using a 23 cm Vigreux column (bp 35±828C). The residue
was puri®ed by fractional distillation at reduced pressure
using a 15 cm Vigreux column. After a small fore-run, the
product distilled as a clear, colorless liquid (bp 68±708C at
1
20 mm). A total of 19.39 g (41%) of 6c was obtained: H
NMR (CDCl3): ꢀ 2.81 (t, 2H, J ˆ 7.5 Hz), 1.83 (hextet, 2H,
J ˆ 7.5 Hz), 1.01 (t, 3H, J ˆ 7.4 Hz); 19F NMR (CDCl3): ꢁ
52.3 (s); 13C NMR (CDCl3): ꢀ 171.3 (s), 169.3 (t,
JCF ˆ 33.0 Hz), 107.2 (t, JCF ˆ 303.7 Hz), 27.7 (s), 20.0
(s), 13.4 (s); HRMS (POS CI/methane) calcd. for
C6H8BrF2N2O, 240.9788; found, 240.9735.
Analysis by GC indicated that the purity of 6c was 72%.
A second fractional distillation gave 14.93 g of distillate
with a GC purity of 79%. The impurities present in 6c did
not interfere with subsequent SRN1 reactions.
References
[1] J.M. Hoffman, A.M. Smith, C.S. Rooney, T.E. Fisher, J.S. Wai, C.M.
Thomas, D.L. Bamberger, J.L. Barnes, T.M. Williams, J.H. Jones,
B.D. Olson, J.A. O'Brien, M.E. Goldman, J.H. Nunberg, J.C.
Quintero, W.A. Schlief, E.A. Emini, P.S. Anderson, J. Med. Chem.
36 (1993) 953.
Analysis by GC indicated that the product had a purity of
91.5%. A second fractional distillation did not improve the
purity signi®cantly. The impurities present in 6b did not
interfere with subsequent SRN1 reactions.
[2] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, USA, 1991.
[3] A. Haas, M. Spitzer, M. Lieb, Chem. Ber. 121 (1988) 1329.
[4] M. Hudlicky, A.E. Pavlath, Chemistry of Organic Fluorine
Compounds II, ACS Monograph 187, American Chemical Society,
Washington. DC, USA, 1995, p. 840.
3.9. 5-(Bromodifluoromethyl)-3-propyl-1,2,4-oxadiazole
(6c)
[5] S. Chiou, H.J. Shine, J. Heterocycl. Chem. 26 (1989) 125.
[6] F. Eloy, R. Lenaers, Chem. Rev. 62 (1962) 155.
A mixture of 20.00 g (0.196 mol) of butyramidoxime
(5c), 43.7 g (0.215 mol) of CF2BrCO2Et, and 21.7 g
(0.214 mol) of NEt3 was heated at re¯ux for 3 h. After
cooling to ambient temperature, 110 ml of water was added
and the layers were separated. The aqueous layer was
extracted ®ve times with 35 ml portions of ether. The
combined organic layers were dried over Na2SO4 and ether
[7] K.P. Flora, B. Reit, G.L. Wampler, Cancer Res. 38 (1978) 1291.
Â
[8] C. Burkholder, W.R. Dolbier Jr., M. Medebielle, J. Org. Chem. 63
(1998) 5385.
[9] R.A. Rossi, A.B. Pierini, S.M. Palacios, Nucleophilic substitution by
the SRN1 mechanism on alkyl halides, in: D.D. Tanner (Ed.),
Advances in Free Radical Chemistry, vol. 1, JAI Press, Greenwich,
CT, USA, 1990, pp. 193±252.