The syntheses of nonnucleoside, HIV-1 reverse transcriptase inhibitors containing a CF2 group: The SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole with the anions derived from heterocyclic thiols and phenolic compounds

Article abstract of DOI:10.1016/S0022-1139(99)00314-0

In an effort to prepare new fluorine-containing compounds which are active against HIV, the S_RN1 reactions of 2-(bromodifluoromethyl)benzoxazole (5) with the anions of heterocyclic thiols and phenolic compounds were carried out. The products (6

Full text of DOI:10.1016/S0022-1139(99)00314-0

Journal of Fluorine Chemistry 102 (2000) 369±376
The syntheses of nonnucleoside, HIV-1 reverse transcriptase
inhibitors containing a CF2 group
The SRN1 reactions of 2-(bromodi¯uoromethyl)benzoxazole with the
anions derived from heterocyclic thiols and phenolic compounds
a a,*
Conrad R. Burkholder , William R. Dolbier Jr. , Maurice Medebielle
b,1
Â
aDepartment of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL 32611-7200, USA
b
 Â
Universite Denis Diderot (Paris 7), Laboratoire d'Electrochimie Moleculaire, UMR CNRS 7591,
Â
2 Place Jussieu, 75251 Paris Cedex 05, France
Received 21 June 1999; accepted 31 October 1999
Dedicated to Professor Paul Tarrant on the occasion of his 85th birthday
Abstract
In an effort to prepare new ¯uorine-containing compounds which are active against HIV, the SRN1 reactions of 2-
(bromodi¯uoromethyl)benzoxazole (5) with the anions of heterocyclic thiols and phenolic compounds were carried out. The products
(6a±j and 7a±f), which all have a CF2 group, were tested for activity against HIV, and several were found to be active, including 6f which
was very active. By comparing the activity of 6e, which contains a CF2 group, to that of 10, where the CF2 is replaced by a CH2 group, it
was demonstrated that ¯uorine atom substitution produces a 10-fold increase in activity against HIV-1. # 2000 Elsevier Science S.A. All
rights reserved.
Keywords: SRN1 reactions; Heterocyclic thiols; Phenolic compounds
1. Introduction
expensive, have some adverse side effects, and the patient
must adhere to a strict drug regimen for the remainder of his
life. Thus, the HIV protease inhibitors are an effective
treatment, but not the ideal cure that is so highly sought after.
The problem then remains to ®nd new drugs which are
effective against AIDS, and especially effective against the
resistant mutant strains of HIV which rapidly arise upon
treatment with active chemical compounds.
Certain simple chemical compounds known as non-
nucleoside reverse transcriptase inhibitors (NNRTIs) [2±
4] have been found to be very active against the HIV virus
in vitro and in clinical trials; however, they suffer from the
drawback of the rapid onset of viral resistance from mutant
strains of HIV. If a way could be found to induce activity
against mutant strains of HIV, then such compounds would
be useful in the treatment of AIDS.
The AIDS disease (acquired immunode®ciency syn-
drome) has been shown to be caused by a virus designated
as HIV-1 (human immunode®ciency virus type 1). There is a
current worldwide AIDS epidemic of major proportions,
especially on the African continent where the rate of infec-
tion by HIV in the population has been estimated to be 25%
or higher in some African nations.
Recent results in the treatment of AIDS with drugs which
work by inhibiting the HIV protease enzyme [1], have lead
to a decrease in the number of AIDS-related deaths in the
United States; however, it has been found that, in order to
prevent the HIV from developing resistance to the drugs, a
strict regimen of frequent doses must be followed, as well as
using a combination therapy popularly referred to in the
press as a drug cocktail. These drugs are exceedingly
Compound 1 is a potent NNRTI [5±8] agent, although to
our knowledge it has not been approved by the FDA for use
in AIDS treatment. The aim of the research reported in this
paper was to selectively incorporate ¯uorine substituents
into structural analogues of compound 1, in order to deter-
mine the impact of such substitution on biological activity.
* Corresponding author. Tel.: ‡1-352-392-0591; fax: ‡1-352-846-1962.
E-mail addresses: wrd@chem.ufl.edu (W.R. Dolbier Jr.),
Â
mauricem@paris7.jussieu.fr (M. Medebielle).
1 Fax: ‡33-1-44-27-76-25.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 3 1 4 - 0

370
C.R. Burkholder et al. / Journal of Fluorine Chemistry 102 (2000) 369±376
Table 1
Dramatic enhancements of potency have been reported in
many cases for partially ¯uorinated analogs of biologically
active compounds [9]. As part of an ongoing project inves-
tigating the synthesis of ¯uorine-containing heterocycles,
synthetic methods were developed whereby various analogs
of 1 could be prepared wherein one CH2 was replaced with a
CF2 and where the other CH2 was replaced with a heteroa-
tom (X). Thus, the plan was to keep the benzoxazole ring of
1 and modify not only the two-atom tether, but the pyridone
ring as well, so that the target compounds would have the
general appearance of 2.
Conditions and isolated yields for the reactions of 5 with the anions of
benzenethiol and mercapto-substituted heterocycles (RSH) to give 6a±j
Entry
RSH
Conditions
Product
% Yield
1
RT, 15 min
6a
86
2
3
4
5
6
RT, 23 h
6b
6c
6d
6e
6f
82
51
76
65
62
RT, 23 h
RT, 23 h
608C, 24 h
608C, 24 h
2. Chemical results and discussion
Analogues of 1 were, in part, chosen as synthetic targets
because of the ready availability of ¯uorinated precursor, 5.
A convenient two-step synthesis of 5 from 2-aminophenol
(3) was recently reported, via bromodi¯uoroacetylation
with CF2BrCO2Et to give amide 4, followed by cyclization
with polyphosphoric acid (PPA) to give 5 [10].
7
8
608C, 24 h
608C, 24 h
6g
6h
74
72
9
608C, 24 h
6i
6j
59
84
10
1008C, 23 h
of 2-mercaptopyridine (entry 2) is much less reactive than
benzenethiolate (Entry 1). Multiple nitrogen substitution in
the heterocyclic ring of the anion results in greatly reduced
reactivity as can be seen for the anion of 5-mercapto-1-
methyltetrazole, which only reacted at 1008C after 24 h
(Entry 10). This is consistent with an electronic effect where
electron-withdrawing substitution of the anion slows down
the reaction.
It was expected that the CF2Br group of 5 would be
reactive with sulfur nucleophiles [11]. Initial experimenta-
tion with 5 and sodium thiolate lead to the observation that
the reaction giving 6a was rapid and exothermic, being
complete in only 15 min. It was soon discovered that a wide
range of anions from mercapto-substituted heterocycles,
RSH, were able to be successfully reacted with 5 to give
6a±j, as can be seen by looking at Table 1. The anions were
conveniently generated using dry NaH, which was weighed
out rapidly in the air and transferred to the reaction appa-
ratus as quickly as possible. The isolated yields of these
reactions vary from 51 to 86%, and no signi®cant optimiza-
tion of the yields was performed other than using a two-fold
excess of the anion and following the reaction by TLC until
the starting material (5) was gone. By looking at Table 1, it
can be seen that substitution of an aromatic CH with a
nitrogen leads to lowered reactivity with 5. Thus, the anion
Several sulfur-based nucleophiles that did not work in this
reaction were discovered: for example, the anions of 5-
methyl-1,3,4-thiadiazole-2-thiol, 2-imidazolidinethione, 2-
mercaptobenzoxazole, 6-mercaptopurine, penta¯uoroben-
zenethiol, 2-thiouracil and 4-(tri¯uoromethyl)-2-pyrimidi-
nethiol gave decomposition from which none of the desired
product could be isolated. Also, the attempted reaction of
sodium thiocyanate lead to decomposition.

C.R. Burkholder et al. / Journal of Fluorine Chemistry 102 (2000) 369±376
371
Scheme 1. Steps of the SRN1 reaction.sc1
The displacement of bromide from the CF2Br group does
not occur by a simple SN2 mechanism due to the presence of
the alpha ¯uorines. Instead, it proceeds by an SRN1 mechan-
ism [12] involving a single electron transfer chain process as
represented in Scheme 1. The observation that the presence
of 1,4-dinitrobenzene strongly inhibits the reaction of 5 with
sodium benzenethiolate is evidence for the SRN1 mechan-
ism. Thus, the reaction of the CF2Br group is limited to
nucleophiles that can react by such an SRN1 mechanism.
It was found that sodium phenolate reacts with the CF2Br
of 5 much more slowly than sodium benzenethiolate; how-
ever, after 24 h at room temperature, the reaction was
complete, and the desired product 7b was isolated in
70% yield. In fact, other substituted phenolates, as well
as related benzenoid derivatives reacted with 5 to give the
expected displacement products 7a±f (Table 2). The only
heterocyclic oxyanion that was tried for this reaction was
the anion of 2-hydroxypyridine, and it gave only decom-
position when heated with 5.
In order to be able to determine whether the ¯uorine
substitution enhances the activity against HIV, it was neces-
sary to prepare at least one analog of an active compound
where the only difference in the chemical structure is the
replacement of the two ¯uorine atoms with two hydrogen
atoms. The active compound that was chosen for this study
was 6e, and the hydrogen-substituted analog 10 was easily
synthesized in three steps. Firstly, 2-aminophenol was
chloroacetylated with chloroacetyl chloride to give amide
8 in moderate yield; secondly, amide 8 was cyclodehydrated
by heating with polyphosphoric acid to give 2-(chlorodi-
¯uoromethyl)benzoxazole 9 in moderate yield; and lastly, 9
was allowed to react with the anion of 2-mercaptopyrimi-
dine to give 10 in excellent yield.
Table 2
Conditions and isolated yields for the reactions of 5 with the anions of
phenol and hydroxybenzenoid compounds to give products 7a±f
3. Biological activity
Entry
ROH
Conditions
Product
% Yield
Compounds 6a±j, 7a±f and 10 were evaluated in the
preliminary screen of the In Vitro Anti-AIDS Drug Dis-
covery Program at the National Cancer Institute.2 The
activity data are reported as effective concentration
(EC50), the concentration of compound for which there is
50% protection in cells infected by HIV-1. The data for the
active compounds are presented in Table 3; those com-
pounds not included in the table were found to be inactive.
The compounds are listed in order of decreasing potency,
and it should be noted that smaller values for the EC50 are an
indication of higher activity.
There are several points that are worth mentioning con-
cerning the structure activity relationships in this series of
compounds. Firstly, all of the active compounds were
derivatives of benzoxazole, this system having been chosen
to test the impact of ¯uorine substitution on activity (a) on
the basis of the activity of prototype molecule 1, and (b)
1
RT, 6 h
7a
44
2
3
4
RT, 24 h
RT, 24 h
RT, 24 h
7b
7c
7d
70
32
47
5
6
RT, 24 h
7d
7f
42
28
1008C, 2 h
2 For a description of the Anti-AIDS testing protocol see [3].

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C.R. Burkholder et al. / Journal of Fluorine Chemistry 102 (2000) 369±376
Table 3
Table 4
Effective concentrations (EC50) of active compounds against HIV-1
Effective concentrations (EC50) for 6e and 6f against drug-resistant mutant
strains of HIV
Entry
1
Number
Structure
EC50Â10 6 M
Entry
HIV variant
strains
EC50Â10 6 M 6e
EC50Â10 6 M 6f
6f
0.0646
1
2
3
4
5
6
7
8
9
HIV-1 (IIIB)
DdI resistanta
4ÂAZT (AZT-R)b
OC/100c
HEPT/236d
Calo resistante
DPSf
3.36
0.067
Inactive
0.373
4.08
0.159
Inactive
0.38
2
3
6g
6e
2.16
3.14
8.64
0.11
3.2
0.43
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
HIV-2 (ROD)
SIV (B670)g
a A ddI-resistant mutant bearing a mutation at amino acid codon 74.
b AZT-resistant mutant bearing four mutations.
c An oxathiin carboxanilide-resistant mutant bearing a mutation at
amino acid codon 100, changing from leucine to isoleucine.
d A HEPT-resistant mutant bearing a mutation at amino acid codon
236.
4
5
6
7d
6b
10
13.0
29.2
35.3
e A Calanolide-resistant mutant bearing a mutation at amino acid
codon 139, changing from threonine to isoleucine.
f A diphenyl sulfone-resistant mutant bearing a mutation at amino acid
codon 181, changing from tyrosine to cysteine.
g Simian immunodeficiency virus.
7
6a
36.0
the adjacent benzoxazole ring, thus increasing it's binding to
the lipophilic pocket of the binding site of the reverse
transcriptase enzyme. If this is the case, then it may well
be that this enhancement of activity by ¯uorine substitution,
could be applicable to many other biologically active com-
pounds where it is possible to replace a CH2 group which is
adjacent to an aromatic ring with a CF2 group.
Compounds 6e and 6f were referred for testing in the
advanced screens, and the results can be seen by looking at
Table 4. Although the activity of 6f against the wild type
HIV-1 (III B) was very good (Entry 1), it was inactive
against a number of mutant strains of HIV (Entries 3, 7, 8
and 9). Compound 6e was similarly inactive in a number of
cases (Entries 2, 7, 8 and 9).
Although the results of these studies have demonstrated
that ¯uorine atom substitution can enhance the activity
against HIV substantially, it must be concluded from the
advanced screening that there is no unusual activity against
drug resistant mutant strains of HIV induced by ¯uorine
atom substitution. Consequently, even the most potent
compound (6f) resulting from this work is unlikely to be
clinically useful in the treatment of AIDS. The discovery
that ¯uorine atom substitution enhances biological activity
is an intriguing result which may well be widely applicable
to other biologically active systems.
because of synthetic convenience (based on availability of
precursor 5). Secondly, only compounds with six-membered
rings such as benzene, pyridine or pyrimidine rings attached
to the sulfur were active, while compounds with ®ve-
membered rings such as 6c, 6d, 6h, 6i, and 6j were inactive.
Of the compounds with six-membered rings, it was found
that those with a pyrimidine ring was most potent, followed
by those with a pyridine ring, and then those with a benzene
ring. This conclusion follows by comparing the activities of
compounds 6e (Entry 3), 6b (Entry 5) and 6a (Entry 7).
Furthermore, the activity of the pyrimidine-substituted
compound is greatly enhanced by the addition of a methyl
group in the 4-positon of the pyrimidine ring as in 6f (Entry
1), which was the most potent compound in this study;
however, having two methyls, as in 6g (Entry 2), did not
further enhance the activity, and, in fact, the addition of a
second methyl produced a decrease in potency. Nearly all of
the active compounds had a sulfur atom in the tether
connecting the two heterocyclic rings, while compounds
with an oxygen in place of the sulfur were all inactive except
for 7d (Entry 4). From comparing the activity of 6a (Entry 7)
to 7b which was inactive, it can be concluded that having a
sulfur in the tether rather than an oxygen, enhances the
activity. Lastly, but most importantly, a comparison of the
activity of the ¯uorine-containing compound 6e (Entry 3),
to the hydrogen-substituted analog 10 (Entry 6), leads to the
conclusion that ¯uorine substitution is responsible for a 10-
fold increase in potency. One can speculate why this is so.
The ¯uorine substituents may enhance the lipophilicity of
4. Experimental section
4.1. General comments
1
Melting points are uncorrected. The H NMR spectra
were measured at 300 MHz and chemical shifts are reported

C.R. Burkholder et al. / Journal of Fluorine Chemistry 102 (2000) 369±376
373
in ppm down®eld of internal SiMe4. The 19F NMR spectra
were measured at 282 MHz, and chemical shifts are
reported in ppm up®eld of internal CFCl3. The 13C NMR
spectra were measured at 75 MHz with all protons
decoupled, and the chemical shifts are reported in ppm
down®eld of SiMe4. The mass spectra were recorded at
70 eV. All of the solvents and reagents were used as received
from the supplier without puri®cation.
After workup by Procedure A, 0.9596 g (86%) of 6a was
obtained as a white solid, mp 59.5±61.88C: 1H NMR
(CDCl3) d 7.82 (dm, 1H, Jˆ7.6 Hz), 7.64 (m, 3H), 7.5±
7.35 (m, 5H); 19F NMR (CDCl3) f 74.9 (s); 13C NMR
(CDCl3) d 156.5 (t, JCFˆ33.5 Hz), 150.6 (s), 139.8 (s),
136.9 (s), 130.7 (s), 129.3 (s), 127.1 (s), 125.5 (s), 124.6 (t,
JCFˆ2.0 Hz), 121.4 (s), 121.0 (t, JCFˆ277.5 Hz), 111.4 (s);
HRMS (70 eV) calcd for C14H9F2NOS 277.0373, found
277.0328. Anal. Calcd for C14H9F2NOS: C, 60.64; H, 3.27;
N, 5.05. Found C, 60.57; H, 3.02; N, 4.90.
4.1.1. 2-(Bromodifluoromethyl)benzoxazole (5)
Compound 5 was prepared according to a previously
reported procedure [10].
4.2.2. 2-[Difluoro-(2-pyridylthio)methyl]benzoxazole
(6b)
4.2. General procedure for SRN1 reactions of compound 5
Following the General Procedure, the reaction of 5 with
2-mercaptopyridine was carried out at room temperature for
23 h. After workup by Procedure A, 0.9172 g (82%) of 6b
A 25 ml, three-necked, round-bottom ¯ask was equipped
with a magnetic stirrer, two rubber septa and a glass stopper.
After ¯ushing with nitrogen, 15 ml of dry DMF (commer-
cial anhydrous) was added by syringe followed by 204 mg
(8.08 mmol) of NaH (dry, 95%).
To the stirred suspension was added 8.08 mmol of the
indicated mercaptoheterocycle or phenolic compound, a
little bit at a time, over a period of 5 min. Hydrogen gas
was evolved and the ¯ask became warm. After stirring for
20 min, a clear solution was obtained.
Then 1.00 g (4.03 mmol) of 2-(bromodi¯uoromethyl)-
benzoxazole (5) was added all at once, and the solution
was allowed to stir at the indicated temperature for the
indicated amount of time. The product was isolated by one
of the three following procedures.
Procedure A: The reaction mixture was poured into a
solution of 0.43 g (8.04 mmol) of NH4Cl in 45 ml of water,
and the mixture was extracted ®ve times with 10 ml portions
of CHCl3. The combined organic layers were dried over
Na2SO4 and concentrated by rotary evaporation at reduced
pressure (water aspirator, 708C). The resulting liquid was
subjected to full vacuum (0.15 mm) for 6 h to remove the
DMF. The resulting oil was puri®ed by ¯ash column
chromatography [13] on silica gel and eluting with ethyl
acetate/hexane.
1
was obtained as a yellow solid, mp 50±548C: H NMR
(CDCl3) d 8.45 (ddd, 1H, Jˆ1.0, 2.0, and 4.8 Hz), 7.81 (dm,
1H, Jˆ7.8 Hz), 7.7±7.6 (m, 3H), 7.48 (dt, 1H, Jdˆ1.5 and
Jtˆ7.3 Hz), 7.42 (dt, 1H, Jdˆ1.3 and Jtˆ7.4 Hz), 7.2 (ddd,
1H, Jˆ1.6, 4.9, and 7.2 Hz); 19F NMR (CDCl3) f 74.3 (s);
13C NMR (CDCl3) d 156.6 (t, JCFˆ33.0 Hz), 150.6 (s),
150.4 (s), 150.2 (t, JCFˆ2.5 Hz), 139.9 (s), 137.4 (s), 128.4
(t, JCFˆ1.8 Hz), 127.2 (s), 125.5 (s), 123.4 (s), 121.4 (s),
121.2 (t, JCFˆ277.2 Hz), 111.5 (s); HRMS (70 eV) calcd for
C13H8F2N2OS 278.0325, found 278.0325. Anal. Calcd for
C13H8F2N2OS: C, 56.11; H, 2.90; N, 10.07. Found C, 55.95;
H, 2.76; N, 9.96.
4.2.3. 2-[Difluoro-[(1H-imidazol-2-yl)thio]methyl]-
benzoxazole (6c)
Following the General Procedure, the reaction of 5 with
2-mercaptoimidazole was carried out at room temperature
for 23 h. After workup by Procedure A, 0.5445 g (51%) of
6c was obtained as an off-white solid, mp 162.5±163.88C:
1H NMR (CDCl3) d 7.79 (m, 1H), 7.57 (m, 1H), 7.44 (m,
2H), 7.28 (s, 2H); 19F NMR (CDCl3) f 74.1 (s); 13C NMR
(DMSO-d6) d 155.3 (t, JCFˆ33.0 Hz), 150.4 (s), 139.4 (s),
127.9 (s), 126.9 (t, JCFˆ3.5 Hz), 126.0 (s), 121.4 (s), 120.4
(t, JCFˆ278.2 Hz), 112.0 (s); HRMS (70 eV) calcd for
C11H7F2N3OS 267.0278, found 267.0265. Anal. Calcd
for C11H7F2N3OS: C, 49.44; H, 2.64; N, 15.72. Found C,
49.90; H, 2.55; N, 15.72.
Procedure B: The reaction mixture was poured into 45 ml
of water, and the mixture was extracted ®ve times with
10 ml portions of CHCl3. The combined organic layers were
washed ®ve times with 50 ml portions of water to remove
the DMF, then dried over Na2SO4 and concentrated by
rotary evaporation at reduced pressure (water aspirator,
708C). The resulting oil was puri®ed by ¯ash column
chromatography [13] on silica gel and eluting with ethyl
acetate/hexane.
4.2.4. 2-[Difluoro-[(1-methyl-1H-imidazol-2-yl)thio]-
methyl]benzoxazole (6d)
Following the General Procedure, the reaction of 5 with
2-mercapto-1-methylimidazole was carried out at room
temperature for 23 h. After workup by Procedure A,
0.8575 g (76%) of 6d was obtained as a pale amber solid,
mp 84.0±86.68C: 1H NMR (CDCl3) d 7.82 (m, 1H), 7.63 (m,
1H), 7.49 (dt, 1H, Jdˆ1.5 and Jtˆ7.6 Hz), 7.43 (dt, 1H,
Jdˆ1.3 and Jtˆ7.4 Hz), 7.16 (br s, 2H), 3.84 (s, 3H); 19F
NMR (CDCl3) f 74.1 (s); 13C NMR (CDCl3) d 155.3 (t,
JCFˆ32.7 Hz), 150.4 (s), 139.4 (s), 131.3 (s), 129.9 (t,
JCFˆ2.8 Hz), 127.1 (s), 125.6 (s), 125.3 (s), 121.1 (s),
Procedure C: The reaction mixture was poured into 45 ml
of water, and the resulting precipitate was collected by
suction ®ltration and puri®ed by recrystallization.
4.2.1. 2-[Difluoro(phenylthio)methyl]benzoxazole (6a)
Following the General Procedure, the reaction of 5 with
thiophenol was carried out at room temperature for 15 min.

374
C.R. Burkholder et al. / Journal of Fluorine Chemistry 102 (2000) 369±376
120.4 (t, JCFˆ280.0 Hz), 111.2 (s), 34.1 (s); HRMS (70 eV)
calcd for C12H9F2N3OS 281.0434, found 281.0433. Anal.
Calcd for C12H9F2N3OS: C, 51.24; H, 3.22; N, 14.94. Found
C, 51.27; H, 3.08; N, 14.75.
4.2.8. 2-[Difluoro-[(1-methyl-1H-1,3,4-triazol-2-
yl)thio]methyl]benzoxazole (6h)
Following the General Procedure, the reaction of 5 with
4-methyl-4H-1,2,4-triazole-3-thiol was carried out at 608C
for 24 h. After workup by Procedure A, 0.814 g (72%) of 6h
was obtained as a pale yellowish solid, mp 143.6±145.58C:
1H NMR (CDCl3) d 8.40 (s, 1H), 7.82 (dm, 1H, Jˆ7.3 Hz),
7.65 (dm, 1H, Jˆ8.0 Hz), 7.52 (dt, 1H, Jdˆ1.5 and
Jtˆ7.4 Hz), 7.45 (dt, 1H, Jdˆ1.3 and Jtˆ7.3 Hz), 3.87 (s,
3H); 19F NMR (CDCl3) f 72.1 (s); 13C NMR (CDCl3) d
154.6 (t, JCFˆ32.2 Hz), 150.5 (s), 147.4 (s), 140.7 (s), 139.3
(s), 127.5 (s), 125.6 (s), 121.3 (s), 120.0 (t, JCFˆ281.5 Hz),
111.4 (s), 32.0 (s); HRMS (70 eV) calcd for C11H8F2N4OS
282.0387, found 282.0382. Anal. Calcd for C11H8F2N4OS:
C, 46.81; H, 2.86; N, 19.85. Found C, 46.70; H, 2.66; N,
19.84.
4.2.5. 2-[Difluoro-(2-pyrimidinylthio)methyl]benzoxazole
(6e)
Following the General Procedure, the reaction of 5 with
2-mercaptopyrimidine was carried out at 608C for 24 h.
After workup by Procedure A, 0.7311 g (65%) of 6e was
1
obtained as an amber solid, mp 64.0±68.58C: H NMR
(CDCl3) d 8.41 (d, 2H, Jˆ4.9 Hz), 7.82 (dm, 1H,
Jˆ7.3 Hz), 7.64 (dm, 1H, Jˆ7.3 Hz), 7.5±7.4 (m, 2H),
7.0 (t, 1H, Jˆ4.9 Hz); 19F NMR (CDCl3) f 77.3 (s);
13C NMR (CDCl3) d 166.7 (t, JCFˆ5.6 Hz), 157.4 (s), 157.1
(t, JCFˆ32.2 Hz), 150.4 (s), 140.1 (s), 126.8 (s), 125.2 (s),
121.2 (s), 120.4 (t, JCFˆ273.7 Hz), 111.3 (s); HRMS (FAB)
calcd for C12H8F2N3OS 280.0356, found 280.0352. Anal.
Calcd for C12H7F2N3OS: C,51.61; H, 2.53; N, 15.05. Found
C, 51.93; H, 2.46; N, 14.86.
4.2.9. 2-[Difluoro-[(1H-benzimidazol-2-yl)thio]methyl]-
benzoxazole (6i)
Following the General Procedure, the reaction of 5 with
2-mercaptobenzimidazole was carried out at 608C for 24 h.
After workup by Procedure C with recrystallization from
THF (2 crops), 0.7599 g (59%) of 6i was obtained as a white
4.2.6. 2-[Difluoro[(4-methyl-2-pyrimidinyl)thio]methyl]-
benzoxazole (6f)
1
solid, mp 2678C (dec): H NMR (DMSO-d6) d 13.5 (br s,
Following the General Procedure, the reaction of 5 with
2-mercapto-4-methylpyrimidine hydrochloride was carried
out at 608C for 24 h with the exception that 408 mg
(16.16 mmol) of NaH was used.. After workup by Proce-
dure B, 0.7294 g (62%) of 6f was obtained as a yellow solid,
mp 69.5±72.68C: 1H NMR (CDCl3) d 8.22 (d, 1H,
Jˆ5.1 Hz), 7.82 (dm, 1H, Jˆ7.3 Hz), 7.64 (dm, 1H,
Jˆ7.6 Hz), 7.49±7.38 (m, 2H), 6.82 (d, 1H, Jˆ4.9 Hz),
2.18 (s, 3H); 19F NMR (CDCl3) f 77.4 (s); 13C NMR
(CDCl3) d 168.1 (s), 166.0 (t, JCFˆ6.0 Hz), 157.6 (t,
JCFˆ32.0 Hz), 156.9 (s), 150.3 (s), 140.2 (s), 126.7 (s),
125.2 (s), 121.1 (s), 120.6 (t, JCFˆ273.0 Hz), 117.9 (s),
111.2 (s), 23.5 (s); HRMS (70 eV) calcd for C13H9F2N3OS
293.0434, found 293.0435. Anal. Calcd for C13H9F2N3OS:
C, 53.24; H, 3.09; N, 14.33. Found C, 53.24; H, 3.03; N,
14.00.
1H), 7.91 (m, 2H), 7.66±7.52 (m, 4H), 7.36±7.22 (m, 2H);
19F NMR (DMSO-d6) f 71.2 (s); 13C NMR (125.7 MHz,
DMSO-d6) d 154.9 (t, JCFˆ32.6 Hz), 150.2 (s), 139.1 (s),
136.2 (s), 127.9 (s), 126.0 (s), 123.2 (br s), 121.3 (s), 120.3
(t, JCFˆ279.2 Hz), 111.9 (s); HRMS (70 eV) calcd for
C15H9F2N3OS 317.0434, found 317.0428. Anal. Calcd
for C15H9F2N3OS: C, 56.78; H, 2.86; N, 13.24. Found C,
56.68; H, 2.74; N, 13.09.
4.2.10. 2-[Difluoro-[(1-methyl-1H-tetrazol-5-yl)-
thio]methyl]benzoxazole (6j)
Following the General Procedure, the reaction of 5 with
5-mercapto-1-methyltetrazole was carried out at 1008C for
23 h. After workup by Procedure B, 0.9642 g (84%) of 6j
was obtained as a yellow solid, mp 79.0±82.08C: 1H NMR
(CDCl3) d 7.83 (dm, 1H, Jˆ7.6 Hz), 7.66 (dm, 1H,
Jˆ7.8 Hz), 7.54 (dt, 1H, Jdˆ1.5 and Jtˆ7.4 Hz), 7.48 (dt,
1H, Jdˆ1.3 and Jtˆ7.5 Hz), 4.25 (s, 3H); 19F NMR (CDCl3)
4.2.7. 2-[Difluoro-[(4,6-dimethyl-2-pyrimidinyl)-
thio]methyl]benzoxazole (6g)
f
70.4 (s); 13C NMR (CDCl3) d 153.9 (t, JCFˆ31.5 Hz),
Following the General Procedure, the reaction of 5 with
4,6-dimethyl-2-mercaptopyrimidine was carried out at 608C
for 24 h. After workup by Procedure B, 0.9172 g (74%) of
6g was obtained as an off-white solid, mp 57.3±62.08C: 1H
NMR (CDCl3) d 7.82 (dm, 1H, Jˆ7.3 Hz), 7.63 (dm, 1H,
Jˆ7.3 Hz), 7.43 (m, 2H), 6.65 (s, 1H), 2.12 (s, 6H); 19F
NMR (CDCl3) f 77.5 (s); 13C NMR (CDCl3) d 167.4 (s),
165.3 (t, JCFˆ6.0 Hz), 157.9 (t, JCFˆ32.2 Hz), 150.2 (s),
140.3 (s), 126.6 (s), 125.1 (s), 121.1 (s), 120.8 (t,
JCFˆ272.5 Hz), 117.3 (s), 111.1 (s), 23.2 (s); HRMS
(70 eV) calcd for C14H11F2N3OS 307.0591, found
307.0591. Anal. Calcd for C14H11F2N3OS: C, 54.72; H,
3.61; N, 13.67. Found C, 54.91; H, 3.56; N, 13.49.
150.4 (s), 144.0 (t, JCFˆ2.5 Hz), 139.1 (s), 127.76 (s), 125.7
(s), 121.3 (s), 119.6 (t, JCFˆ282.8 Hz), 111.4 (s), 34.8 (s);
HRMS (70 eV) calcd for C10H7F2N5OS 283.0339, found
283.0347. Anal. Calcd for C10H7F2N5OS: C, 42.40; H, 2.49;
N, 24.72. Found C, 42.55; H, 2.49; N, 24.44.
4.2.11. 2-(Difluoro-2-benzoxazolylmethoxy)dibenzofuran
(7a)
Following the General Procedure, the reaction of 5 with
2-hydroxydibenzofuran was carried out at room tempera-
ture for 6 h. After workup by Procedure B, 0.620 g (44%) of
1
7a was obtained as a white solid, mp 106.0±108.08C: H
NMR (CDCl3) d 7.96±7.87 (m, 3H), 7.67 (m, 1H), 7.59±

C.R. Burkholder et al. / Journal of Fluorine Chemistry 102 (2000) 369±376
375
7.33 (m, 7H); 19F NMR (CDCl3) f 68.4 (s); 13C NMR
(CDCl3) d 156.9 (s), 154.5 (t, JCFˆ42.8 Hz), 153.9 (s),
150.5 (s), 144.7 (t, JCFˆ2.0 Hz), 139.7 (s), 127.7 (s), 127.1
(s), 125.4 (s), 125.0 (s), 123.6 (s), 122.8 (s), 121.5 (s), 121.3
4.2.15. 2-[Difluoro-(2-naphthalenyloxy)methyl]-
benzoxazole (7e)
Following the General Procedure, the reaction of 5 with
2-naphthol was carried out at room temperature for 24 h.
After workup by Procedure B, 0.5322 g (42%) of 7e was
obtained as a white solid, mp 51.5±53.68C: 1H NMR
(CDCl3) d 7.9±7.78 (m, 5H), 7.66 (dm, 1H, Jˆ7.3 Hz),
7.54±7.42 (m, 5H); 19F NMR (CDCl3) f 68.0 (s); 13C
NMR (CDCl3) d 154.6 (t, JCFˆ42.8 Hz), 150.6 (s), 147.0
(s), 139.7 (s), 133.6 (s), 131.6 (s), 129.7 (s), 127.71 (s),
127.67 (s), 127.2 (s), 126.8 (s), 126.0 (s), 125.5 (s), 121.6
(s), 121.0 (s), 118.9 (s), 115.8 (t, JCFˆ261.1 Hz), 111.4 (s);
HRMS (70 eV) calcd for C18H11F2NO2 311.0758, found
311.0783. Anal. Calcd for C18H11F2NO2: C, 69.45; H, 3.56;
N, 4.50. Found C, 69.41; H, 3.49; N, 4.40.
(s), 120.8 (s), 115.7 (t, JCFˆ260.9 Hz), 114.3 (t, JCF
ˆ
1.0 Hz), 112.1 (s), 111.7 (s), 111.4 (s); HRMS (70 eV)
calcd for C20H11F2NO3 351.0707, found 351.0703. Anal.
Calcd for C20H11F2NO3: C, 68.38; H, 3.16; N, 3.99. Found
C, 68.48; H, 3.12; N, 3.97.
4.2.12. 2-[Difluoro(phenoxy)methyl]benzoxazole (7b)
Following the General Procedure, the reaction of 5 with
phenol was carried out at room temperature for 24 h. After
workup by Procedure B, 0.7347 g (70%) of 7b was obtained
1
as a pale amber liquid: H NMR (CDCl3) d 7.88 (dm, 1H,
Jˆ7.3 Hz), 7.66 (dm, 1H, Jˆ7.3 Hz), 7.54±7.26 (m, 7H);
19F NMR (CDCl3) f 68.3 (s); 13C NMR (CDCl3) d 154.5
(t, JCFˆ42.6 Hz), 150.5 (s), 149.4 (s), 139.6 (s), 129.5 (s),
127.1 (s), 126.4 (s), 125.4 (s), 121.8 (s), 121.5 (s), 115.5 (t,
JCFˆ261.1 Hz), 111.3 (s); HRMS (70 eV) calcd for
C14H9F2NO2 261.0601, found 261.0590. Anal. Calcd for
C14H9F2NO2: C, 64.37; H, 3.47; N, 5.36. Found C, 64.29; H,
3.42; N, 5.29.
4.2.16. 2-[Difluoro-(3-hydroxy-2-naphthalenyloxy)-
methyl]benzoxazole (7f)
Following the General Procedure, the reaction of 5 with
2,3-dihydroxynaphthalene was carried out at 1008C for 2 h.
After workup by Procedure B, 0.3684 g (28%) of 7f was
obtained as a white solid, mp 114±2018C: 1H NMR (CDCl3)
d 7.86 (dm, 1H, Jˆ7.6 Hz), 7.81 (br s, 1H), 7.75 (dm, 1H,
Jˆ8.1 Hz), 7.69 (dm, 1H, Jˆ8.1 Hz), 7.62 (dm, 1H,
Jˆ8.1 Hz), 7.52±7.32 (m, 5H); 19F NMR (CDCl3) f
67.2 (s); 13C NMR (CDCl3) d 154.6 (t, JCFˆ43.6 Hz),
150.5 (s), 147.0 (s), 138.8 (s), 137.9 (s), 132.9 (s), 128.1 (s),
127.6 (s), 127.5 (s), 126.5 (s), 126.4 (s), 125.8 (s), 124.3 (s),
121.4 (s), 120.5 (s), 115.7 (t, JCFˆ261.9 Hz), 112.9 (s),
111.5 (s); HRMS (70 eV) calcd for C18H11F2NO3 327.0707,
found 327.0681. Anal. Calcd for C18H11F2NO3: C, 66.06;
H, 3.39; N, 4.28. Found C, 65.81; H, 3.01; N, 4.21.
4.2.13. 2-[Difluoro-(2,6-dimethylphenoxy)methyl]-
benzoxazole (7c)
Following the General Procedure, the reaction of 5 with
2,6-dimethylphenol was carried out at room temperature for
24 h. After workup by Procedure B, 0.379 g (32%) of 7c
was obtained as a clear, pale yellow oil: 1H NMR (CDCl3) d
7.90 (dm, 1H, Jˆ7.1 Hz), 7.68 (dm, 1H, Jˆ7.3 Hz), 7.54±
7.44 (m, 2H), 7.10 (m, 3H), 2.41 (s, 6H); 19F NMR (CDCl3)
f
66.7 (s); 13C NMR (CDCl3) d 155.0 (t, JCFˆ43.1 Hz),
150.6 (s), 146.6 (t, JCFˆ2.0 Hz), 139.7 (s), 132.7 (s), 129.0
4.2.17. 2-Chloro-N-(2-hydroxyphenyl)acetamide (8)
(s), 127.1 (s), 126.5 (s), 125.4 (s), 121.5 (s), 116.3 (t, JCF
ˆ
To a rapidly stirred solution of 5.00 g (0.0458 mol) of 2-
aminophenol in 50 ml of ethyl acetate was added 5.18 g
(0.0459 mol) of chloroacetyl chloride over a period of
two min. Some gas was evolved, and the ¯ask became
warm. After stirring for 26 min, the mixture was washed
with 20 ml of dilute HCL (9 parts water to 1 part conc. HCl),
and the aqueous layer was extracted three times with 10 ml
portions of ethyl acetate. The combined organic layers were
dried over Na2SO4 and concentrated by rotary evaporation
at reduced pressure (water aspirator, 708C) to give 7.87 g of
a crude, off-white solid. Recrystallization fom 19 ml of
ethylene chloride (one crop) gave 5.00 g (59%) of 8 as a
262.6 Hz), 111.4 (s), 17.1 (t, JCFˆ3.3 Hz); HRMS (70 eV)
calcd for C16H13F2NO2 289.0914, found 289.0895. Anal.
Calcd for C16H13F2NO2: C, 66.43; H, 4.53; N, 4.84. Found
C, 66.34; H, 4.57; N, 4.84.
4.2.14. 2-[Difluoro-(3,4,5-trimethylphenoxy)methyl]-
benzoxazole (7d)
Following the General Procedure, the reaction of 5 with
3,4,5-trimethylphenol was carried out at room temperature
for 24 h. After workup by Procedure B, 0.5699 g (47%) of
7d was obtained as a white solid, mp 40.0±42.68C: 1H NMR
(CDCl3) d 7.87 (dm, 1H, Jˆ7.3 Hz); 7.66 (dm, 1H,
Jˆ7.6 Hz), 7.52±7.42 (m, 2H), 6.98 (s, 2H), 2.29 (s, 6H),
2.14 (s, 3H); 19F NMR (CDCl3) f 68.0 (s); 13C NMR
(CDCl3) d 154.8 (t, JCFˆ43.1 Hz), 150.5 (s), 146.5 (t,
JCFˆ1.8 Hz), 139.7 (s), 137.8 (s), 133.3 (s), 127.0 (s),
125.3 (s), 121.5 (s), 120.6 (s), 115.5 (t, JCFˆ260.1 Hz),
111.3 (s), 20.5 (s), 14.8 (s); HRMS (70 eV) calcd for
C17H15F2NO2 303.1071, found 303.1074. Anal. Calcd for
C17H15F2NO2: C, 67.32; H, 4.98; N, 4.62. Found C, 67.19;
H, 5.07; N, 4.64.
1
white solid, mp 132±135.28C ([14] mp 139±140.58C): H
NMR (DMSO-d6) d 10.0 (br s, 1H), 9.45 (br s, 1H), 7.90 (dd,
1H, Jˆ8.0 and 1.5 Hz), 6.93 (m, 2H), 6.78 (dt, 1H, Jdˆ1.7
and Jtˆ7.6 Hz).
4.2.18. 2-(Chloromethyl)benzoxazole (9)
A 250 ml, single-necked, round-bottom ¯ask was
equipped with an egg-shaped stir bar and a CaSO4 drying
tube. To the ¯ask 19 g of polyphosphoric acid and 4.50 g
(24.2 mmol) of amide 8 was added. The ¯ask was heated in

376
C.R. Burkholder et al. / Journal of Fluorine Chemistry 102 (2000) 369±376
[2] T. Roth, M.L. Morningstar, P.L. Boyer, S.H. Hughes, R.W. Buckheit
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[3] K.A. Parker, A. Dermatakis, J. Org. Chem. 62 (1997) 4164.
an oil bath at 1508C for 30 min. The solid amide slowly
dissolved as it reacted.
After cooling to room temperature, 239 ml of crushed ice
and 44 ml of concentrated aqueous ammonia were added
and the mixture was triturated with a spatula until all of the
PPA had dissolved. The mixture was extracted ®ve times
with 40 ml portions of CHCl3, and the combined organic
layers were dried over Na2SO4, then concentrated by rotary
evaporation at reduced pressure (water aspirator, 708C) to
give a liquid. Puri®cation by simple vacuum distillation
gave 2.31 g (57%) of a clear, colorless distillate, bp 998C at
4.0 mm ([15] bp 65±688C at 0.05 mm), which was pure 9:
1H NMR (CDCl3) d 7.75 (m, 1H), 7.55 (m, 1H), 7.37 (m,
2H), 4.76 (s, 2H).
Â
[4] D.B. Kireev, J.R. Chretien, D.S. Grierson, C. Monneret, J. Med.
Chem. 40 (1997) 4257.
[5] N.B. Mantlo, P.K. Chakravarty, D.L. Ondeyka, P.K.S. Siegl, R.S.
Chang, V.J. Lotti, K.A. Faust, T. Chen, T.W. Schorn, C.S. Sweet, S.E.
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[6] W.S. Saari, J.S. Wai, T.E. Fisher, C.M. Thomas, J.M. Hoffman, C.S.
Rooney, A.M. Smith, J.H. Jones, D.L. Bamberger, M.E. Goldman,
J.A. O'Brien, J.H. Nunberg, J.C. Quintero, W.A. Schleif, E.A. Emini,
P.S. Anderson, J. Med. Chem. 35 (1992) 3792.
[7] 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. Schleif, E.A. Emini, P.S. Anderson, J. Med. Chem.
36 (1993) 953.
[8] J.S. Wai, T.M. Williams, D.L. Bamberger, T.E. Fisher, J.M.
Hoffman, R.J. Hudcosky, S.C. MacTough, C.S. Rooney, W.S. Saari,
C.M. Thomas, M.E. Goldman, J.A. O'Brien, E.A. Emini, J.H.
Nunberg, J.C. Quintero, W.A. Schleif, P.S. Anderson, J. Med. Chem.
36 (1993) 249.
4.2.19. 2-[(2-pyrimidinylthio)methyl]benzoxazole (10)
Following the General Procedure, the reaction of 9 with
2-mercaptopyrimidine was carried out at room temperature
for 10 min. After workup by Procedure B, 0.890 g (91%) of
10 was obtained as a white solid, mp 56.0±57.98C: 1H NMR
(CDCl3) d 8.55 (d, 1H, Jˆ4.9 Hz), 7.70 (m, 1H), 7.50 (m,
1H), 7.30 (m, 2H), 7.01 (t, 1H, Jˆ4.8 Hz), 4.71 (s, 2H); 13C
NMR (CDCl3) d 169.9, 162.7, 157.1, 150.7, 140.9, 124.7,
124.0, 119.7, 116.8, 110.3, 27.4; HRMS (70 eV) calcd for
C12H9N3OS 243.0466, found 243.0464. Anal. Calcd for
C12H9N3OS: C, 59.24; H, 3.73; N, 17.27. Found C,
59.20; H, 3.71; N, 17.31.
[9] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, USA, 1991.
Â
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CT, USA, 1990, pp. 193±252.
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[15] H. Kristinsson, Synthesis (1979) 102.
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