An efficient synthesis of aryloxyphenyl cyclopropyl methanones: A new class of anti-mycobacterial agents

Article abstract of DOI:10.1016/j.bmcl.2005.07.007

An efficient, high yield and one-pot synthesis of phenyl cyclopropyl methanones by reaction of different aryl alcohols with 4′-fluoro-4-chloro- butyrophenone in THF/DMF in the presence of NaH/TBAB is reported. Most of the methanones were further reduced t

Full text of DOI:10.1016/j.bmcl.2005.07.007

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4526–4530
An efficient synthesis of aryloxyphenyl cyclopropyl methanones:
a new class of anti-mycobacterial agentsq
Namrata Dwivedi,a Neetu Tewari,a V. K. Tiwari,a Vinita Chaturvedi,b Y. K. Manju,b
A. Srivastava,b A. Giakwad,c S. Sinhac and R. P. Tripathia,*
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow-226001, India
bDivision of Microbiology, Central Drug Research Institute, Lucknow-226001, India
cDivision of New Drug Target Discovery, Central Drug Research Institute, Lucknow-226001, India
Received 25 May 2005; revised 28 June 2005; accepted 4 July 2005
Available online 8 August 2005
Abstract—An efficient, high yield and one-pot synthesis of phenyl cyclopropyl methanones by reaction of different aryl alcohols with
40-fluoro-4-chloro-butyrophenone in THF/DMF in the presence of NaH/TBAB is reported. Most of the methanones were further
reduced to respective alcohols or methylenes. All the compounds were evaluated for their anti-tubercular activities against M. tuber-
culosis H37Rv in vitro displaying MICs ranging from 25 to 3.125 lg/mL. The most active compounds showed activity against MDR
strains and two of them (14 and 16) showed marginal enhancement of MST in mice.
ꢀ 2005 Elsevier Ltd. All rights reserved.
An increase in the global burden of tuberculosis with the
worldwide mortality rate of 23% is a major cause of con-
cern in the socioeconomic and health sectors.1,2 The syn-
ergy of this disease with HIV infection and the emergence
of MDR tuberculosis (TB) poses a threatening global
challenge particularly in the developing countries.3
Although a number of lead molecules exist today to devel-
op new drugs, no new chemical entity has emerged for
clinical use over the last 40 years for the treatment of this
disease.4,5 Therefore, there is an urgent need to develop
new drugs, acting through a novel mechanism of action
for the chemotherapy of TB. The incredible thickness of
mycobacterial cell wall, absent in human cells, is respon-
sible for longer period of treatment and the emergence
of resistance against the known first line anti-TB
drugs.6–8 Therefore, it is a selective target and many cru-
cial enzymes involved in the biosynthesis of cell wall mac-
romolecules and their inhibitors are being looked at as
future hope to develop new drugs against this disease.
One such enzyme system is FAS-II required in the initial
steps of mycolic acid biosynthesis.9 Many inhibitors of
FAS-II system are known and among them phenethyl
alcohol10 and triclosan10 are important for lead optimiza-
tion (Fig. 1). Recently, anti-mycobacterial activities
have been reported in simple acetophenones,11a benzylid-
eneacetophenones11b and p-nitro-a-acetylamino-b-
hydroxypropiophenones.11c,11d We have also identified
a glycosylated phenyl cyclopropyl methanone (Fig. 2)
as a very good anti-tubercular agent active even
against MDR strains of M. tuberculosis and in vivo
OH
OH
O
Cl
Cl
Cl
Phenethyl alcohol
Triclosan
Figure 1. FAS-II inhibitors.
O
O
O
O
O
O
Keywords: Tuberculosis; Tetrabutylammonium bromide; Phenyl cyclo-
propyl methanones; Wolf–Kishner reduction.
q
CDRI Communication No. 6759.
Corresponding author. Tel.: +91 522 2622412x4462; fax: +91 522
26224305; e-mail: rpt_56@yahoo.com
O
*
Figure 2. Glycosyl phenylcyclopropylmethanone.
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.007

N. Dwivedi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4526–4530
4527
too.12 Cyclopropyl ring is a common structural element of
the mycobacterial cell wall13 and its chemotherapeutic14
importance is also well known. Further, aryl cyclopropyl
ketones play a prominent role as intermediates in the syn-
thesis of many other biologically active compounds.15
Keeping in view the above, we were prompted to synthe-
size aryl cyclopropyl methanones and evaluate them for
anti-mycobacterial activity.
while the most active compounds 14 and 16 were also
evaluated in mice model.24
As evident from Table 1, except compounds 9, 10, 12,
15, 17–19 and 28 all other compounds displayed activity
with MIC ranging from 25 to 3.25 lg/mL against the
virulent strain M. tuberculosis H37Rv. However, none
of the compounds except compound 16 was active
against avirulent strain H37Ra indicating that these
compounds are specific for virulent strain. Further,
compound 16, having fluoro substituent, completely
inhibited the growth of clinical isolates of MDR strains
of M. tuberculosis H37Rv at 6.25 lg/mL while the stan-
dard first line anti-TB drugs were ineffective at their crit-
ical concentrations for MDR strains (Table 2).
A number of methods for the synthesis of cyclopropyl
ring formation exist in the literature16 and very recently,
we have reported a rapid one-pot procedure for the syn-
thesis of combinatorial library of phenyl cyclopropyl
methanones on solid phase.17 Requirements for larger
quantity of material for biological evaluation led us to
explore a new conventional approach for their synthesis.
A closer look into the structure–activity relationship in
these compounds shows that cyclopropyl phenyl metha-
nones 6, 9, 10 and 12 are inactive as their MICs are
Phenyl cyclopropylmethanones 1–12 were prepared by
reaction of 4-chloro-40-fluoro butyrophenone with
furylmethyl-, phenylmethyl-, 4-methoxy phenylmethyl-,
3,4-dimethoxy phenylmethyl-, 2-chloro phenylmethyl-,
4- fluoro phenylmethyl-, 3-pyridylmethyl-, 4-pyridylm-
ethyl-, 4-chlorophenylmethyl-, 3,4-dichloro phenylmeth-
yl-, cyclohexyl and cyclopentyl alcohols in THF/DMF
(1:1) in the presence of NaH and tetrabutylammonium
bromide (TBAB) as phase transfer catalysts at 0–
100 ꢁC in very good yields (Scheme 1). The structures
of all the compounds were determined on the basis of
their spectroscopic data and microanalysis.18
Table 1. In vitro antimycobacterial activities of compounds 1–29
Comp-
ound
X
MABA MIC Agar microdilution
(lg/ml) MIC (lg/ml)
against against
M. tuberculosis M. tuberculosis
H37Ra
H37Rv
1
2
Phenyl
25
>50
25
6.25
12.5
12.5
12.5
25
4-Methoxy phenyl
3,4-Methoxy phenyl
4-Fluoro phenyl
Furfuyl
3
4
>25
25
The keto group in most of the active methanones has
been partially or completely reduced to alcohol and
methylene groups with sodium borohydride and Wolf–
Kishner reduction, respectively, to see its effect on
anti-tubercular activity profile. Thus, reduction of phen-
yl cyclopropyl ketones 1–8 and 11 with NaBH4 in etha-
nol gave compounds 13–21, respectively, in good
yields.19 However, reduction of compounds 1–6 and 8
with hydrazine hydrochloride followed by heating in
the presence of KOH led to the respective phenyl cyclo-
propyl methanes 22–28 in moderate yields.20
5
6
3-Pyridyl
4- Pyridyl
>25
>25
>25
>25
25
7
12.5
12.5
25
8
2-Chloro phenyl
4-Chloro phenyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
3,4-Dichloro phenyl >25
25
25
Cyclopentyl
Cyclohexyl
Phenyl
>25
>25
>50
>50
>25
25
4-Methoxy phenyl
3,4-Methoxy phenyl
4-Fluoro phenyl
Furyl
3.12
>50
6.25
>25
>25
>25
-
3.12
25
>25
>25
>25
>25
25
In one of the most active compounds, 16, the hydroxyl
group was further derivatized as O-(epoxy-n-propyl)
derivative 29 by its reaction with epichlorohydrin in
THF in the presence of catalytic amount of tetrabutyl
ammonium bromide following our earlier reported
method21 (Scheme 2).
3-Pyridyl
4- Pyridyl
2-Chloro phenyl
Cyclopentyl
Phenyl
3.12
12.5
25
>50
>25
4-Methoxy phenyl
3,4-Methoxy phenyl
4-Fluoro phenyl
Furfuryl
12.5
25
nd
25
12.5
25
All the compounds synthesized were evaluated for their
anti-tubercular activity against M. tuberculosis H37Ra
by MABA method22 while Agar Microdilution meth-
od23 was used against M. tuberculosis H37Rv. Com-
pound 16 was also screened against MDR strains,
3-Pyridyl
2-Chloro phenyl
4-Fluoro phenyl
>25
>25
nd
25
>50
3.12
O
O
NaH/ THF/ TBAB
0 0C/ 30 0C/ Reflux
O
Cl
+
XCH2OH
F
XH2C
1-12
Scheme 1.

4528
N. Dwivedi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4526–4530
>25 lg/mL. However, compounds 1–4, 7–8 have MICs
A
120
100
80
60
40
20
0
in the range of 12.5–6.25 lg/mL. It is interesting to note
that the partially reduced alcohols 14 (3.12 lg/mL), 16
(6.25 lg/mL) and 21 (3.12 lg/mL) of the corresponding
phenyl cyclopropyl methanones 2 (12.5 lg/mL), 4
(12.5 lg/mL) and 11 (25 lg/mL) did offer better protec-
tion. Among the completely reduced cyclopropyl phenyl
methanes, none of the compounds offer better inhibition
than the parent ketones as the MICs were either retained
or enhanced. Further, replacement of aryloxy moiety in
these compounds with heteroaryloxy group did not im-
prove the anti-tubercular efficacy. Replacement of aryl-
oxy group with cyclopentyloxy moiety in the alcohols
did offer a better result. However, in general, replacing
the aryloxy group with cycloalkyloxy group gave com-
pounds with comparable activities. Two of the cyclopro-
pyl phenyl methanols, compounds 14 and 16 with 4-
methoxybenzyloxy and 4-fluorobenzyloxy substituents
offer very good protection (MICs 3.125 and 6.25 lg/
mL, respectively). Since it is known that fluoro group
plays a very important role in the biological activity pro-
file of many biologically active molecules in vivo, there-
fore, compound 16 was further functionalized to the
respective O-(n-epoxypropyl) derivative 29, which has
MIC of 3.12 lg/mL.
Compound 14
untreated con
0
15
30
days after infection
B 120
100
80
Compound 16
untreated cont
60
40
20
0
0 5 10 15 20 25 30 35
Days after infection
Cytotoxicity of the two compounds 14 and 16 in VERO
cell line at different concentrations beginning from
10 · MIC of the compounds was assayed and is ex-
pressed as inhibitory concentration (IC50). On the basis
Figure 3. (A) Chemotherapeutic efficacy of compound 14 against M.
tuberculosis H37Rv in mice. (B) Chemotherapeutic efficacy of Com-
pound 16 against M. tuberculosis H37Rv in mice.
OH
NaBH , Methanol
O
4
1-6, 8
XH2C
1-8, 11
0-25oC
13-21
NH NH 2HCl
2.
2.
KOH/Diethylene glycol
0
F
F
190
C
Epichlorohydrin
NaH/THF/TBAB
0-25oC
O
O
OH
O
XH2C
O
O
22-28
29
16
Scheme 2.
Table 2. In vitro activity of compound 16 and standard drugs against MDR strains of M. tuberculosis H37Rv
Compd. or drug
Growth of MDR strains after six weeks
BC-248(1)
BC-283 (1)
VA-101 (2)
BC-426 (3)
BC-437 (3)
Compound 16 (6.25 lg/ml)
INH (1 lg/ml)
Rifampicin (64 lg/ml)
Ethambutol (6 lg/ml)
No drug control
--
--
--
--
--
++
++
++
++
++
++
++
++
++
++
++
++
++
++
--
++
++
--
++
++
--, no growth; +, 1–20 growth (resistance), ++, heavy growth; (1) Strains resistant to rifampicin, isoniazid and ethambutol. (2) Strains resistant to
rifampicin, isoniazid and ethambutol. (3) Strains resistant to rifampicin and isoniazid.

N. Dwivedi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4526–4530
4529
10. Richard, J. H.; Stephen, W. W.; Charles, O. R. Progr.
Lipid Res. 2001, 40, 467.
of IC50 values, selectivity index (SI) of these compounds
was found to be 16 and 10, respectively, indicating that
these compounds are suitable for in vivo evaluation.
11. (a) Rajabi, L.; Courreges, C.; Montoya, J.; Aguilera, R. J.;
Primm, T. P. Lett. Appl. Microbiol. 2005, 40, 212; (b) Lin,
Y. M.; Zhou, Y.; Flavin, M. T.; Zhou, L. M.; Nie, W.;
Chen, F. C. Bioorg. Med. Chem. 2002, 10, 2795; (c)
Morgan, M. A.; Doerr, K. A.; Hampel, H. O.; Goodman,
N. L.; Roberts, G. D. J. Clin. Microbiol. 1985, 21, 634; (d)
Rastogi, N.; Goh, K. S.; David, H. L. Res. Microbiol.
1989, 140, 419.
12. Novel phenyl cyclopropyl methanones useful as antituber-
cular agents. Grover, R. K.; Mishra, R. C.; Verma, S.
S.;Tripathi, R. P.; Roy, R.; Srivastava, R.; Srivastava, A.
Chaturvedi, V.; Krishana, M.Y.; Srivasatava, B. S.; Lal, J.;
Gupta, R.C 036DEL2004 Filing Date 31/3/04 New Delhi.
13. Barry, C. E., III; Lee, R. E.; Mdluli, K. Progr. Lipid Res.
1998, 37, 143.
The efficacy of compounds 14 and 16 against challenge
of M. tuberculosis H37Rv was also seen at 100 mg/kg
in vivo in the mouse model. As evident from Figures
3A and B, there were 27% and 17% enhancements in
MST of the mice as compared to control by compounds
14 and 16, respectively.
In conclusion, we have developed a novel one-pot syn-
thesis of aryloxyphenyl cyclopropyl methanones and
their derivatives, which have shown very good activity
against M. tuberculosis. It will be interesting to prepare
an analogue of the active compound, which may be non-
toxic to eukaryotes but strongly anti-tubercular.
14. (a) Hansch, C.; Sammes, P. G.; Taylor, J. B.; Dryton, C. J.
In Comprehensive Medicinal Chemistry; Pergamon:
Oxford, UK, 1990; Vol. 6; (b) Koshikenen, A. M. P.;
Hassila, H. Acta Chem. Scan. 1996, 50, 323.
15. Shi, M.; Yang, Y. H.; Xu, B. Tetrahedron 2005, 61, 1893,
and references cited therein.
Acknowledgments
16. (a) Davies, H. M. L. Tetrahedron 1993, 49, 5203; (b)
Mann, J. Tetrahedron 1986, 42, 4611; (c) Peirs, E. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 5, pp 899–971; (d) Hud-
licky, T.; Fan, R.; Reed, J.; Gadasetty, K. G. Org. React.
1992, 41, 1; (e) Taylor, R. E.; Engelhardt, F. C.; Schmitt,
M. J. Tetrahedron 2003, 59, 5623.
17. Grover, R. K.; Mishra, R. C.; Kundu, B.; Tripathi, R. P.;
Roy, R. Tetrahedron Lett. 2004, 43, 7331.
18. General procedure for the synthesis of phenyl cyclopropyl
The authors thank Mr. R. Grover and Mr. R. C. Mishra
for their partial contribution during this work. N. D.
and N. T. are thankful to CSIR, New Delhi, for fellow-
ships. We also thank Dr. B. S. Srivastava and Dr. R. Sri-
vastava, Microbiology Division, CDRI, for their
constructive suggestions.
References and notes
methanones: To
a stirring slurry of NaH (2.8 g,
118.8 mmol) in anhydrous THF (20 mL), 4-fluorobenzyl
alcohol (5 mL, 39.6 mmol) was added at 0 ꢁC. 4-Chloro-
40-fluorobutyrophenone (7.9 mL, 39.6 mmol) was added
to this stirring reaction mixture followed by the addition
of TBAB (0.8 g) and stirring continued for further 18 h
at ambient temperature. The excess of NaH was
quenched with aq NH4Cl solution and filtered on Cellite
and the filtrate was evaporated and the crude product,
thus obtained, was extracted with ethyl acetate and
washed with water. The organic layer was dried
(Na2SO4) and evaporated to give a crude mass, which
was purified over SiO2 column using hexane/ethyl acetate
(5:1) as eluent to give compound 4. Colourless granules,
mp 116–118 ꢁC. Yield 90%, FAB MS m/z = 271 [M+H]+,
IR mmax cmꢀ1 2945 (C–H stretching), 1600 (C–O); 1H
NMR (200 MHz, CDCl3) d = 8.03 and 7.90 (each d,
J = 8.80 Hz, each 2H, Ar-H), 7.34 and 7.01 (each m, each
2H, ArH), 5.04 (s, 2H, OCH2Ar), 2.60 (m, 1H, cyclo-
propyl CH), 1.21 and 0.98 (each m, each 2H, cyclopropyl
CH2s); 13C NMR (50 MHz, CDCl3) d = 199.2 (C@O),
165.4, 162.6, 132.5, 132.4, (ArC), 130.6, 129.8, 129.6,
116.2, 115.7, 114.9 (Ar-CH), 69.8 (OCH2Ar), 17.0
(cyclopropyl CH), 11.5 (cyclopropyl CH2s). Anal. Calcd
for C17H15O2F (270): C, 75.55; H, 5.55; Found: C, 75.31;
H, 5.64.
1. (a) Stokstad, E. Science 2000, 287, 2391(b) WHO Global
tuberculosis programme—Tuberculosis Fact Sheet, 2002.
World Health Organisation. Global Tuberculosis Control,
WHO Report 2001.; (c) World Health Organisation,
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www.who.int/mediacentre/factsheets/who104/en/index.html.
2. (a) Mooran, N. Nat. Med. 1996, 2, 377; (b) Dye, C.;
Scheele, S.; Dolin, P.; Pathania, V.; Raviglione, M. C. J.
Am. Med. Assoc. 1999, 282, 677.
3. (a) Dooley, S. W.; Jarvis, W. R.; Martone, W. J.; Snyder,
D. E., Jr. Ann. Int. Med. 1992, 117, 257; (b) Raviglione, M.
C., Jr.; Snider, D. E., Jr.; Kochi, A. JAMA 1995, 273, 220;
(c) Farmer, P.; Bayona, J.; Beccera, M.; Henry, J.; Furin,
C.; Hiarr, H. ;.; Kim, J. Y.; Mimic, C.; Nardell, E.; Shin,
S. Int. J. Tuberc. Lung. Dis. 1998, 2, 869.
4. Hudson, A.; Imamura, T.; Gutteridge, W.; Kanyok, T.;
Nunn, P. The current anti-TB drug research and devel-
opment pipeline WHO TDR/PRD/03.1W Geneva, 2003.
5. Tripathi, R. P.; Tewari, N.; Dwivedi, N.; Tiwari, V. K.
Med. Res. Rev. 2005, 25, 93.
6. Chopra, I.; Brennan, P. Tubercle Lung Dis. 1988, 78(2), 89.
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9. Cole, S. T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher,
C.; Harris, D.; Gordon, S. V.; Eiglmeier, K.; Gas, S.;
Barry, C. E.; Tekaia, F.; Badcock, K.; Basham, D.;
Brown, D.; Chillingworth, T.; Conner, R.; Davies, R.;
Devlin, K.; Feltwell, T.; Gentless, S.; Hamlin, N.; Holrod,
S.; Hornsby, T.; Jagels, K.; Krogh, A.; Mclean, J.; Moule,
S.; Murphy, L.; Oliver, K.; Osborne, S. J.; Quail, M. A.;
Rajandream, M. A.; Rogers, J.; Rutter, S.; Seeger, K.;
Skeleton, J.; Squares, R.; Squares, S.; Sulston, J. E.;
Taylor, K.; Whitehead, S.; Barrel, B. G. Nature 1998, 393,
537, and references cited therein.
19. General procedure for the partial reduction of ketones
with NaBH4: To the stirring solution of cyclopropyl
methanone 4 (4.0 g, 14.81 mmol) in methanol (20 mL) at
0 ꢁC, NaBH4 (0.56 g, 14.81 mmol) was added and the
stirring was continued for next 3 h at an ambient
temperature. The reaction was quenched with aq NH4Cl
at 0 ꢁC and the solvent was evaporated under reduced
pressure. The residue obtained was extracted with ethyl
acetate (50 mL) and washed with water. The organic layer
was dried (anhydr. Na2SO4) and concentrated to give a

4530
N. Dwivedi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4526–4530
crude mass, which was chromatographed over SiO2
temperature. After disappearance of the starting material,
excess of NaH was quenched with aq NH4Cl solution and
filtered on Cellite and the filtrate was concentrated. The
residue, thus obtained, was extracted with ethyl acetate
(50 mL) and washed with water. The organic layer was
dried (anhydr. Na2SO4) and concentrated to give a crude
mass, which was purified over SiO2 column using hexane/
ethyl acetate (4:1) as eluent to give compound 29.
Colourless flakes. Yield 85%, mp 90–92 ꢁC FAB MS m/
z = 328 [M+H]+, IR mmax cmꢀ1 3338.7 (OH stretching),
2930.4 (C–H stretching), 1608.7 (C–O); 1H NMR
(200 MHz, CDCl3) d = 7.42 and 7.38 (each d,
J = 8.60 Hz, each 2H, Ar-H), 7.28 (m, 4H, ArH), 7.10
and 6.96 (each d, J = 8.60 each 2H, ArH), 5.01 (s, 2H,
HA
column using hexane/ethyl acetate (3:1) as eluent to afford
the compound 16 as colourless powder. Yield 85%, mp
82–83 ꢁC. FAB MS m/z = 273 [M+H]+, IR mmax cmꢀ1
3339.7 (OH stretching), 2933.4 (C–H stretching), 1609.7
(C–O); 1H NMR (200 MHz, CDCl3) d = 8.07 and 7.98 (d,
8.80 Hz, 2H, Ar-H), 7.41 and 7.47 (m, 2H, ArH), 7.25 and
7.07 (m, 4H, ArH), 5.08 (s, 2H, OCH2Ar), 3.80 (s, 3H,
OCH3) 2.60 (m, 1H, cyclopropyl CH), 1.73 (s, 1H, OH
exchangeable with D20) 1.20and 0.98 (each m, each 2H,
cyclopropyl CH2s); 13C NMR (50 MHz, CDCl3) d 158.4,
136.9, 135.8, 135.1, (ArC), 129.8, 129.6, 127.7, 116.1,
115.6, 115.0, (Ar-CH), 82.5 (CHOH ), 69.7 (OCH2Ar),
19.5 (cyclopropyl CH), 3.1, 2.0 (cyclopropyl CH2s). Anal.
Calcd for C17H17O2F (272): C, 75.00; H, 6.25; Found: C,
74.89; H, 6.50.
OCH2Ar), 3.72 (m, 1H,
) 3.54 (m, 1H,
O
O
20. General procedure for the complete reduction of ketones:
Compound 4 (2 g, 7.35 mmol), NH2NH2Æ2HCl (0.27 g,
7.35 mmol) and KOH (0.5 g) in diethylene glycol (15 mL)
were refluxed at 200 ꢁC for 4 h. The reaction was quenched
and extracted with CHCl3 and washed with water. The
organic layer was evaporated and the residue obtained
purified over SiO2 using hexane/ethyl acetate (60:40) as
eluent to give compound 25 as colourless solid, mp 46–
48 ꢁC . FAB MS m/z = 256 [M+H]+, IR mmax cmꢀ1 2916.6
(C–H stretching), 1607.3 (C–O); 1H NMR (200 MHz,
CDCl3) d = 7.25 and 7.21 (d, J = 8.2, 2H, Ar-H), 7.15 and
7.05 (m, 2H, ArH), 6.95 and 6.92 (m, 2H, ArH), 6.74 and
6.70 (d, J = 8.5, 2H, ArH), 4.80 (s, 2H, OCH2Ar), 2.32 (d,
2H, –CH2) 1.22 (m, 1H, cyclopropyl CH), 0.78, .02 (m,
each 2H, cyclopropyl CH2s); 13C NMR (50 MHz, CDCl3)
d 165.3, 160.4, 157.3, 135.1, (ArC), 129.8, 129.7 128.6,
116.1, 115.6,115.0 (Ar-CH), 69.8 (OCH2Ar), 39.8 (CH2),
12.5 cyclopropyl (CH), 5.03 (both cyclopropyl CH2s).
Anal. Calcd for C17H17OF (256): C, 79.68; H, 6.64;
Found: C, 79.80; H, 6.89.
HB
O
O
O
), 3.39 (m, 1H,
), 2.74 (m, 2H,
O
H
H2
C
O
), 1.25 (m, 1H, cyclopropyl-CH), 0.48, 0.44 and
O
0.42 (m, 4H, cyclopropyl CH2s); 13C NMR (50 MHz,
CDCl3) d 165.3, 158.6, 134.6, 133.2 (ArC), 127.4, 127.3,
126.2, 126.1, 113.7, 113.3, 112.7 (Ar-CH), 83.8 (CHOH),
H2
O
67.4 (OCH2Ar), 66.9 (
), 49.1 (
),
C
O
HC
O
O
H2
42.7 (
), 15.5 (cyclopropyl CH), 2.3, 0.1
C
O
O
(cyclopropyl CH2s). Anal. Calcd for C20H20O3F (327):
C, 73.39; H, 6.11; Found: C, 73.50; H, 6.31.
22. Gerhard, U.; Mackay, J. P.; Maplestone, R. A.; Williams,
D. H. J. Am. Chem. Soc. 1993, 115, 232.
23. (a) Caughey, G. H.; Raymond, W. W.; Bucci, E.;
Lamberdy, R. J.; Tidwell, R. R. J. Pharmacol. Exp. Ther.
1993, 264, 676; (b) Garcia, M.; Rio, X. del.; Silvestre, S.;
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21. General procedure for the epoxy derivative of compound
16: To a stirring slurry of NaH (0.39 g, 16.53 mmol) in
anhydr. THF (5 mL) at 0 ꢁC compound 16 (1.5 g,
5.51 mmol) was added slowly and after 15 min epichloro-
hydrin (0.35 mL, 5.51 mmol) in anhydr. THF (10 mL) was
added slowly followed by the addition of TBAB (0.20 g).
The stirring was continued for next 10 h at an ambient
24. Tiwari, V. K.; Tewari, N.; Katiyar, D.; Tripathi, R. P.;
Arora, K.; Gupta, S.; Srivastava, A. K.; Khan, M. A.;
Murthy, P. K. Bioorg. Med. Chem. 2003, 11, 1789.