Synthesis and Structure-Activity Relationship of Novel, Highly Potent Metharyl and Methcycloalkyl Cyclooxygenase-2 (COX-2) Selective Inhibitors

5484

J . Med. Chem. 2003, 46, 5484-5504

Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip of Novel, High ly P oten t

Meth a r yl a n d Meth cycloa lk yl Cyclooxygen a se-2 (COX-2) Selective In h ibitor s

Subhash P. Khanapure,* David S. Garvey, Delano V. Young, Maiko Ezawa, Richard A. Earl, Rick D. Gaston,

Xinqin Fang, Madhavi Murty, Allison Martino, Matthew Shumway, Mark Trocha, Przemyslaw Marek,

S. William Tam, David R. J anero, and L. Gordon Letts

NitroMed, Inc., 12 Oak Park Drive, Bedford, Massachusetts 01730

Received J une 3, 2003

A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for

cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood

(HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues

were investigated. The spacer group and substitutions in the spacer group were found to be

quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a -c),

carbonyl group (12a -c), or methylidene group (7a -c) connected cycloalkyl groups to the central

benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-

substituted compounds linked to the central ring by either a methylene or a carbonyl spacer

resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo-

[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that

substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas

substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at

meta position(s), as in 22c and 22h , was advantageous for both in vitro COX-2 potency and

selectivity (e.g., COX-2 IC₅₀for 22c ) 1 µM and COX-1 IC₅₀for 22c ) 20 µM in HWB assay).

Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene

series, as shown in structures 7c, 8a , 12a , 21c, 22c, 22e, and 22h , selectively inhibited COX-2

activity by 40-50% at a test concentration of 1 µM in an in vitro HWB assay.

In tr od u ction

ability. In addition, one of the mediators produced by

this pathway, LTB₄, is a potent chemotactic agent⁴that

exerts its biological activity via BLT-1 and recently

identified BLT-2 receptors.^5,6At the site of inflamma-

tion, increased LTB₄production also leads to activation

of proinflammatory cytokines, e.g., tissue necrosis fac-

tor-R (TNF-R) and interleukin-1â (IL-1â). After the

discovery of COX-2, it has been confirmed that IL-1â-

stimulated chondrocytes from normal as well as osteo-

arthritic human cartilage induced COX-2 expression,⁷

whereas, COX-1 was not detected in either normal or

osteoarthritic chondrocytes.⁸Since there is no COX-1

in chondrocytes, traditional nonselective nonsteroidal

antiinflammatory drugs (NSAIDs) are effective in re-

ducing pain in arthritis by inhibiting COX-2.

NSAIDs are widely used for reducing pain and

inflammation. However, chronic NSAID use may cause

serious GI side effects, such as ulceration. NSAIDs

induce GI damage by multiple mechanisms and vary

in ulcerogenic activity in different regions of the GI

tract. Both PG-dependent and -independent factors are

responsible for the NSAID gastric toxicity. PG-depend-

ent factors include the influences of PGs on mucus-

bicarbonate secretion, regulation of acid secretion, and

blood flow. Since the discovery of inducible COX-2, it

has been possible to separate the roles of constitutive

COX-1 and inducible COX-2 isozymes. Selective inhibi-

tion of COX-2 has proved to be a useful therapeutic

target.⁹As a result, pharmaceutical companies have

developed and tested extensive libraries of COX-2-

selective inhibitors^1,10with the hypothesis that selective

Cyclooxygenases (COXs) and lipoxygenases (LOXs)

are key enzymes in arachidonic acid (AA) metabolism.

Eicosanoid mediators derived from COX and LOX

pathways profoundly influence the development and

progression of several inflammatory diseases. Prosta-

glandins (PGs) produced by COXs play physiological and

pathophysiological roles in inflammation and in noci-

ceptive transmission. COX exists in two isoforms: COX-1

and COX-2. Both COX isoforms metabolize AA to PGH₂,

the common substrate for thromboxane-A₂(TXA₂), pros-

tacyclin (PGI₂), and prostaglandin-E₂(PGE₂) synthesis.

TXA₂, PGI₂, and PGE₂play important roles in the

maintenance of cardiovascular homeostasis. TXA₂is

primarily synthesized by COX-1 in platelets. COX-1-

derived constitutive PGs are cytoprotective in the gas-

trointestinal (GI) tract. Inducible COX-2 is expressed

at sites of inflammation by monocytes and macrophages

and plays a key role in mediating the inflammatory

process.¹PGE₂and leukotriene-B₄(LTB₄) are the

predominant eicosanoid inflammatory mediators.

Under basal physiological conditions, LOX-derived

leukotrienes (LTs) are not produced by the GI mucosa

in appreciable quantities. However, LTs are generated

under inflammatory conditions²in the GI tract.³LT

production during COX-1 inhibition due to diversion of

the substrate AA to 5-LOX may contribute to GI

mucosal injury by increasing microvascular perme-

* To whom correspondence should be addressed. Tel: 781-685-9711.

Fax: 781-275-1127. Email: skhanapure@nitromed.com.

Published on Web 11/07/2003

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5485

Ch a r t 1

by various substitutions on the other aryl ring. By

utilizing a variety of five-member ring templates to give

o-diaryl-substituted compounds with rigid conformation,

many COX-2 selective inhibitors have been identified.

Several interesting five-member ring templates include

pyrazoles,^11,30furanones,¹²cyclopentenes,^31,32cyclopen-

tenones,³³imidazoles,^34,35isoxazoles,¹⁷pyrroles,³⁶oxa-

zoles,³⁷oxazolones,³⁸and spiroheptenes.³⁹The three

FDA approved drugs, e.g., celecoxib, rofecoxib, and

valdecoxib, are representative examples of the diaryl-

substituted pyrazole, diaryl-substituted furanone, and

diaryl-substituted isoxazole series, respectively. The

five-member rings have also been replaced by six-

member aryl⁴⁰and heteroaryl rings.⁴¹Etoricoxib is an

example of a diaryl-substituted pyridine COX-2 selective

inhibitor.^41,42A few bicyclic systems have been explored

as central templates for the development of COX-2-

selective inhibitors. Among the bicyclic systems, diaryl-

substituted indanones⁴³and pyrazolopyrimidines⁴⁴have

been reported. Classical NSAID templates have also

been used to convert a COX-1-selective compound into

a COX-2 selective inhibitor by slight modification. For

example, conversion of indomethacin into various amide

derivatives has generated COX-2 selective inhibitors.⁴⁵

On the basis of the COX-1 and COX-2 crystal structures,

rationally designed COX-2 selectivity was achieved in

flurbiprofen analogues.⁴⁶Molecular modeling experi-

ments also provide a better understanding of COX-2

enzyme-inhibitor interactions and possible guidelines

to predict structure-activity relationships for novel

COX-2 inhibitor design.^47-49

As a part of our ongoing program to explore novel

classes of COX-2 inhibitors, we report a new series of

metharyl COX-2 selective inhibitors. In a novel ap-

proach to ortho-substituted aryl or cycloalkyl COX-2-

selective inhibitors, we determined the effect of incor-

porating a spacer group between the cycloalkyl, aryl,

or heteroaryl ring and central ring. Primarily, we have

used a one-carbon spacer between the central benzo-

1,3-dioxolane ring (template) and the aryl, heteroaryl,

or cycloalkyl rings; therefore, as a generic name we refer

to these compounds as the metharyl and the methcy-

cloalkyl series compounds. In the present study, benzo-

1,3-dioxolane was selected as the central ring for the

SAR study in view of the easier access to substituent

variation. Herein, we report that analogues of the

vicinal-substituted benzo-1,3-dioxolanes are potent COX-2

inhibitors and a spacer group between the central ring

and the cycloalkyl-, aryl- or heteroaryl group plays an

important role in COX-2 inhibitory potency. Details of

the synthetic studies and structure-activity relation-

ships among these compounds are presented.

COX-2 inhibiton should block the prostaglandin produc-

tion in inflammatory cells, while not interfering with

the production of gastroprotective PGs in the GI tract

by COX-1.

A number of pharmaceutical companies directed their

research efforts and resources for the development of

potent and selective COX-2 inhibitors. The clinical

efficacy and impressive GI safety of COX-2 inhibitors

resulted in the United States Food and Drug Adminis-

tration (FDA) approval of two COXIBs, celecoxib and

rofecoxib (Chart 1), as the first-generation, selective

COX-2 inhibitors marketed for the treatment of inflam-

matory diseases. Specifically, for the treatment of acute

pain, osteoarthritis, and rheumatoid arthritis,^11-14they

seem to be as effective as classical NSAIDs with reduced

deleterious GI side effects.¹⁵Recently, valdecoxib re-

ceived FDA approval as a COX-2 selective antiinflam-

matory drug,^16,17and another COX-2 selective inhibitor,

J TE-522,¹⁸is in a phase II clinical trial while COX-189¹⁹

and etoricoxib are completing phase III clinical studies.

Prior to the proposal and confirmation of the COX-2

hypothesis, compounds such as NS-398 and DuP-697

demonstrated antiinflammatory activity with GI-spar-

ing profiles in animal models.^20-22Later, it was con-

firmed that DuP-697 and NS-398 preferentially inhib-

ited COX-2 over COX-1.^23,24These two compounds were

the early lead candidates of COX-2-selective inhibitors,

and especially, the central thiophene ring of DuP-697

provided a five-member ring template for the develop-

ment of COX-2 inhibitors.

Structural biology^25,26and X-ray crystallography^27,28

provided more useful information for the development

of COX-2 inhibitors. Generally, for good COX-2 inhibi-

tory activity and selectivity, compounds require a key

pharmacophore,²⁹the 4-methylsulfonylphenyl group,

attached to a five-membered ring in which additional

vicinal aryl ring substitution is present. The methyl

sulfone group may be replaced by a sulfonamide,

whereas the COX-2 inhibitory potency can be tuned-up

Ch em istr y

Our initial strategy was to investigate 1-(6-(cyclo-

alkylmethyl)(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-4-(meth-

ylsulfonyl)benzene analogues such as 8a and 8b in an

effort to determine if incorporating a methylene spacer

group between the central benzo-1,3-dioxolane ring and

the cycloalkyl ring might improve in vitro COX-2

inhibitory potency. Synthesis of a series of (cycloalkyl-

methyl)benzo-1,3-dioxolanes 8a and 8b was conve-

niently accomplished as shown in Scheme 1. The known

bromopiperonal 2 was prepared by bromination of

5486 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

Sch em e 1

Sch em e 2

Sch em e 3

piperonal 1 using bromine in acetic acid.⁵⁰The resulting

bromoaldehyde 2 was converted to the key synthon 6-(4-

methylthiophenyl)-2H-benzo[d]1,3-dioxolane-5-carbal-

dehyde 4 in high yield by Suzuki cross-coupling with

4-(methylthio)phenyl boronic acid 3 using standard

conditions.⁵¹The Wittig coupling of carbaldehyde 4 with

the ylides generated from 5a or 5b afforded the desired

tricyclic compounds 6a or 6b in good yields. Oxidation

of methylthio compounds 6a and 6b with Oxone gave

the corresponding methyl sulfones 7a and 7b in excel-

lent yields. Hydrogenation of 7a and 7b using Pd/C

catalyst at 25-40 psi pressure provided 8a and 8b in

nearly quantitative yields.

Sch em e 4

COX in vitro screening and SAR studies. One such

example is illustrated in Scheme 4. Wittig condensation

of methylsulfonyl aldehyde 15 with the ylide derived

from phosphonium 5c gave 7c in one step.

The synthetic method for the preparation of 12a -c

is outlined in Scheme 2. Reaction of aldehyde 4 with

appropriately substituted Grignard reagents gave tri-

cyclic compounds 10a -c. These compounds 10a -c were

then oxidized with Oxone to give the corresponding

methyl sulfones 11a -c. The benzylic hydroxyl groups

in 11a -c were either deoxygenated by hydrogenolysis

to give 8a -c or oxidized to give the corresponding

carbonyl compounds 12a -c.

As shown in Scheme 3, an initial focus of our strategy

was to prepare appropriately substituted key synthons,

e.g., (6-(4-methylsulfonyl)phenyl)-2H-benzo[d]1,3-dioxo-

lane-5-carbaldehyde) 15, 1-(6-(chloromethyl) (2H-benzo-

[3,4-d]1,3-dioxolan-5-yl))-4-(methylsulfonyl)phenyl)-2H-

benzene 16, and use these intermediates in a convergent

manner to prepare the planned target compounds for

As will be discussed below, our attention was next

focused toward alternative core structures related to 21

and 22. The syntheses of these compounds were ac-

complished as shown in Scheme 5. Aldehyde 4 (Scheme

1) was prepared in large quantities (200-300 g) in two

steps from commercially available piperonal in 62%

overall yield. Lithio derivatives 18a -j were conveniently

prepared by metal halogen exchange of the correspond-

ing haloarenes with n-BuLi or t-BuLi at -78 °C and

subsequently quenched by addition of aldehyde 4 in

THF to provide alcohols 19a -j. Alternatively, Grignard

reagents 17a -j were prepared from the corresponding

haloarenes and then treated with aldehyde 4 to give

19a -j. These compounds 19a -j were then oxidized with

Oxone to form the corresponding sulfones 20a -j. The

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5487

Sch em e 5

Oxidation of 26 using PCC gave the compound 28, with

a carbonyl spacer group.

Using a similar reaction sequence as that shown in

Scheme 6, the methyl-substituted 2-pyridyl analogue 31,

with a carbonyl spacer group was prepared as shown

in Scheme 7. However, the same methodology when

used to prepare 6-(4-(methylsulfonyl)phenyl)(2H-benzo-

[d]1,3-dioxolan-5-yl) 3-pyridyl ketone 36, unexpectedly

gave two products, 35 and 36 (Scheme 8). Initial

metalation of 4-bromopyridine 32 gave a mixture of two

lithiated species, 4-bromo-3-lithio- and 4-lithiopyridine,

which upon quenching with 4 resulted in a mixture of

33 and 34. The mixture was separated by flash column

chromatography to give pure compounds 33 and 34,

each one was independently converted to the corre-

sponding methyl sulfone, and subsequently the alcohol

was oxidized to give compounds 35 and 36, respectively.

A number of other alternative piperidinyl-substituted

structures were pursued as well. The preparations of

38a -f are illustrated in Scheme 9. Chloro compound

16 was reacted with various substituted piperidine

derivatives 37 using potassium carbonate as base,

giving the corresponding diaryl sulfones 38a -f in good

yields.

To decrease the basicity of the nitrogen in 38a , the

heterocyclic pattern of 38a was modified. Compound 42

was synthesized by a straightforward transformation

of the methylthio compound 4 as shown in Scheme 10.

doubly benzylic hydroxyl groups in 20a -j were con-

verted to the ketones by treatment with pyridinium

chlorochromate (PCC) in dichloromethane to give the

desired compounds 22a -j. Alternatively, the hydroxyl

groups in 20a -j were deoxygenated by hydrogenolysis

to give 21a -j.

Attention was also focused on preparing (pyridyl-

methyl)benzo-1,3-dioxolane derivatives. Benzo-1,3-di-

oxolane-2-, 3-, and 4-(pyridylmethyl) derivatives were

synthesized from 4 utilizing the same methodology, as

depicted in Scheme 4. In Scheme 6, details of the

preparation of the 3-(pyridylmethyl)-substituted ana-

logue 27 are illustrated. 3-Lithiated-pyridine 24 was

prepared by metal halogen exchange of 3-bromopyridine

23 with t-BuLi at -78 °C, followed by quenching the

3-lithiopyridine 24 by the aldehyde 4 to give the sulfide

25. Oxidation of sulfide 25, with Oxone proceeded

smoothly to yield methyl sulfone 26. Deoxygenation of

26 was carried out at room temperature by treating 26

with triethylsilane in dichloromethane/TFA to give 27.⁵²

An alternative approach to decrease the basicity of

nitrogen in 38a was achieved by preparing compounds

as 45a ,b and 46a ,b. Carboxylic acid 43a was prepared

in two steps. It was then converted to the corresponding

acid chloride 43b and coupled with heterocycles 44a ,b

to give the heterocycloalkyl-substituted benzo-1,3-dioxa-

lane analogues 46a , 46b, and 45b in which a carbonyl

group spacer is introduced between the heterocyclic ring

and the central benzo-1,3-dioxolane ring, as shown in

Scheme 11.

To examine the effect of sulfonamide pharmacophore

on the COX-2 potency and selectivity, the methyl sulfone

in 21a was transformed into a sulfonamide to give 47

as shown in Scheme 12.

To study the effects of fluoro substitution on the

phenylmethyl sulfone pharmacophore, the correspond-

ing (fluoromethyl)phenyl sulfone 50 was prepared as

Sch em e 6

5488 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

Sch em e 7

Sch em e 11

Sch em e 8

Sch em e 12

Sch em e 13

Sch em e 9

Sch em e 10

obtained in nearly quantitative yield. The formation of

48 can be rationalized on the basis of stable doubly

benzylic carbocation formation followed by ring closure.

Fluorination of thiomethyl group in 49a was performed

by treating 49a with [bis(2-methoxyethyl)amino] sulfur

trifluoride in the presence of a catalytic amount of SbCl₃

to furnish 49b, which was subsequently oxidized with

m-chloroperbenzoic acid to give 50.

For studying the SAR of the dioxolane ring, com-

pounds not containing this ring, such as 56 and 60, were

prepared. The details are outlined in Schemes 14 and

15. Compounds containing no spacer group between the

central ring and the aryl ring, such as 65, were prepared

as shown in Scheme 16.⁴⁰To study the effect of

lengthening the spacer (linker) between the aryl and

central ring, as in 21a , compound 67 with a three-

shown in Scheme 13.⁵³Hydroxyl compound 19a was

hydrogenated overnight at 40 psi pressure to give the

deoxygenated product 49a . Interestingly, when com-

pound 19a was treated with sodium borohydride in the

presence of trifluoroacetic acid, the desired product 49a

was not obtained. Instead, tricyclic compound 48 was

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5489

Sch em e 14

Resu lts a n d Discu ssion

As an initial screen to determine the in vitro COX-1

and COX-2 inhibitory activity, we evaluated compounds

for their ability to inhibit recombinant human or ovine

COX-1 at a 100 µM test concentration and COX-2 at

both 10 and 1 µM test concentrations (Tables 1 and 2).

Compounds that showed good COX-2 inhibition at 1 µM

were also evaluated at various concentrations as COX-2

and COX-1 inhibitors to assess COX-2 selectivity (Table

3). Once initial lead compounds were so identified, they

were evaluated in a human whole blood (HWB) assay,

which takes into account the interactions of inhibitors

with blood proteins and the ability of test compounds

to traverse cellular membranes in a physiological set-

ting. Eventually, all newly synthesized compounds were

evaluated only in the HWB assay.

Recently, it has been reported that the bulky cyclo-

hexyl group, as compared to the aryl group, enhances

the COX-2 selectivity of J TE-522, an oxazole series

COX-2 inhibitor.¹⁸In our initial SAR studies, we used

4-(methylsulfonylphenyl)benzo-1,3-dioxolane as a tem-

plate and explored the effects of cycloalkyl groups of

various sizes at the vicinal position as well as the

linkage between the central ring and the cycloalkyl ring.

We were gratified to find that several of the initial

compounds screened in the recombinant enzyme assay

were very potent, highly selective COX-2 inhibitors.

Compounds 7a , 7b, and 8a did not inhibit COX-1, even

at 100 µM in the enzyme assay. Our studies demon-

strated that, by connecting the cycloalkyl substituent

to the central benzo-1,3-dioxolane template by a one-

carbon spacer group, it was possible to prepare potent,

selective COX-2 inhibitors. Evaluation of compounds

7a -c and 8a -c in the HWB assay confirmed that these

compounds are potent COX-2 inhibitors; however, under

these conditions some COX-1 inhibition was also de-

tected (Table 1). Introduction of a double bond between

the cycloalkyl substituent and the central ring improved

the COX-2 inhibitor profile. When connected by a rigid

double bond, the corresponding compounds such as

7a -c were found to be slightly more potent COX-2

inhibitors than 8a -c having a methylene group in the

linkage. At a 10 µM concentration, 7a -c and 8a -c

exerted substantial (75-90%) COX-2 inhibition in HWB.

Sch em e 15

Sch em e 16

SAR of Ar yl-Su bstitu ted An a logu es. Aryl group

substitution is commonly incorporated into o-diaryl

substituted COX-2 inhibitor design. It is well-estab-

lished that p-methyl sulfone or sulfonamide on one of

the phenyl rings is required for good COX-2 potency and

selectivity. A variety of substituents could be added to

the other phenyl ring to secure or enhance the COX-2

inhibitory potency. To investigate the SAR of the aryl-

substituted analogues, we next focused attention on the

preparation of aryl-substituted analogues of 8a . In most

of the known diaryl-substituted COX-2 inhibitors, the

two rings are periplanar to the central ring. We expected

that in the metharyl-substituted compound 21a the

methylene linkage that acts as a spacer between the

aryl ring and the central benzo-1,3-dioxolane ring

should give the molecule more flexibility to adopt a

conformation suitable for the interaction at the enzyme’s

active site. Unsubstituted-aryl-ring compound 21a ex-

hibited modest COX-2 inhibitory potency (IC₅₀) 10 µM),

as well as a 6-fold COX-2/COX-1 selectivity (IC₅₀for

Sch em e 17

carbon spacer group was prepared, as shown in

Scheme 17. In addition, the dimethoxy compound 72

and benzo[e]1,4-dioxin-2-yl compound 74 were also

prepared (Scheme 18).

5490 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

Sch em e 18

Ta ble 1. Percent Inhibition of Recombinant COX-1 (Human or Ovine), COX-2 (Human) Enzyme Activity and Human COX-1 and

COX-2 Enzyme Activity in HWB

recombinant^a

HWB^d

COX-1

COX-2

COX-1

COX-2

compd

7a

7b

7c

8a

substituent

(100 µM)^b

(10 µM)^b

(1 µM)^b

(100 µM)^b

(10 µM)^b

(1 µM)^b

n ) 1

n ) 2

n ) 0

n ) 1

n ) 2

n ) 0

n ) 1

0

0^c

90

100

90

100

70

90

100

65

100

90

50

35

70

50

40

90

75

80

40

25

55

20

25

80^c

0

8b

8c

10^c

20^c

40

12a

20a

21a

21b

21c

21d

21e

21f

55

85

40

0

85

0

85

R ) H

65

75

25

50

40

90

10

5

40

R ) 2-F

R ) 3-F

R ) 4-F

10^c

0

10

R ) 3-Me

R ) 3-MeO

R) 2-F, 5-Me

R ) 3,5-di-F

R ) 3-Cl

R ) 4-Me

R ) H

10

35

40

70

65

45

75

70

50

95

90

50

90

60

NT

75

40

10

50

40

100

10

65

95

5

85

75

90

95

100

10

100

10

0

25

15

40

0

25

30

50

0

40

10

25

50

15

0

21g

21h

21i

15^c

90

21j

25^c

0

80

90

50

10

22a

22b

22c

22d

22e

22f

22g

22h

22i

R ) 2-F

R ) 3-F

R ) 4-F

R ) 3-Me

R ) 3-MeO

R ) 2-F, 5-Me

R ) 3,5-di-F

R ) 3-Cl

R ) 4-Me

0^c

40

10

22j

celecoxib

rofecoxib

80

0

100

90

40

50

75

a

b

Unless indicated otherwise, percent inhibition of recombinant human COX-1. Concentration of test inhibitor. ^cInhibition of

d

recombinant ovine COX-1. Average percent inhibition of two donors.

COX-1 ) 60 µM) in HWB (Table 4). The length of the

spacer between the central ring and the aryl group is

also critical for COX-2 inhibition. Lengthening the

spacer to three carbons, as in 67 (Table 2), resulted in

the loss of COX-2 inhibitory potency.

Next we explored the effects of aryl substitution at

ortho-, meta-, and para-positions on the phenyl ring of

compound 21a on COX inhibitor potency and selectivity

in the HWB assay. As shown in Table 1, differences in

COX-2 inhibitory potencies were observed when the aryl

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5491

Ta ble 2. Percent Inhibition of Recombinant COX-1 (Human or Ovine), COX-2 (Human) Enzyme Activity and Human COX-1 and

COX-2 Enzyme Activity in HWB

5492 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Ta ble 2. (Continued)

Khanapure et al.

a

b

Unless indicated otherwise, percent inhibition of recombinant human COX-1. Concentration of test inhibitor. ^cPercent inhibition of

d

recombinant ovine COX-1. Average percent inhibition of two donors.

Ta ble 3. IC₅₀Values of Various Compounds in Recombinant

pound 21d abrogated the COX-2 inhibitory activity. In

COX-1 (Human), COX-2 (Human) Enzyme Assay

general, 4-fluoro substitution on the aryl ring increases

IC₅₀(µM)

COX-1

COX-2 potency. The active site of COX-2 offers more

accessible space than that of COX-1, due to substitution

of the amino acid valine for isoleucine at position

523.^25,26The valine substitution opens up additional

space that has proven to be important for the binding

of selective COX-2 inhibitors, as thoroughly explored in

the development of COX-2-selective inhibitors. None-

theless, the steric requirement by the enzyme for the

inhibitor is also critical. In the benzo-1,3-dioxolane

system, the spacer group combined with 4-substitution

on the aryl ring presumably exceeded the steric require-

ment for significant COX-2 affinity. We have also

observed a similar difference in COX-2 potency for

4-fluoro-substituted compounds 22a and 22d . In con-

trast, compounds substituted at the meta-positions were

potent COX-2 inhibitors. Among the meta-substituents,

compounds substituted with electron-withdrawing groups

such as 21e, 21h , and 21i were moderately potent,

whereas an electron-donating substituent, as in 21f,

decreased the COX-2 inhibitory potency. COX-2 inhibi-

tory potency and selectivity are extremely sensitive to

minor changes in chemical structure within the same

chemical series. In this series, 3-fluoro substitution on

the aryl ring as in 21c resulted in a potent COX-2

inhibitor, whereas fluorine substitution at the 2-position

decreased the COX-2 potency.

COX-2/COX-1

selectivity

compd

7a

7b

47

celecoxib

rofecoxib

COX-2

>100 (nd^a)

>100 (nd)

25

<100

>100

0.07

0.2

0.05

0.054

1.0

>1400

>500

500

nd

>100

a

nd ) not determined.

Ta ble 4. IC₅₀Values of Various Compounds and Standard

COX-2 Inhibitors for COX-1 and COX-2 Enzymes in Human

Blood

IC₅₀(µM)

COX-2/COX-1

selectivity

compd

21a

22c

47

celecoxib

rofecoxib

COX-1

COX-2

60

20

60

14

40

10

20

nd

11

133

1.0

nd^a

1.2

0.3

a

nd ) not determined.

ring was substituted at position 2-, 3-, or 4 with, for

instance, halogen, methoxy, or methyl groups. In this

bicyclic system, incorporation of substituent at the para-

position of the phenyl ring had a deleterious effect on

COX-2 inhibitory potency. Compounds 21j and 22j, with

a 4-Me substituent, were not COX-2 inhibitors at a 1

µM test concentration in HWB. It is important to note

the differences in COX-2 potency of 21j in the enzyme

assay and in HWB. In the enzyme assay 21j exhibited

50% inhibition at 1 µM test concentration, whereas at

this concentration it did not exhibit COX-2 inhibition

in HWB. Surprisingly, 4-fluoro substitution in com-

SAR of Ar yl An a logu es w ith Su bstitu ted Sp a c-

er s. We found significant differences in COX-2 inhibitor

potencies when the spacer group was substituted.

Hydroxyl substitution as in 20a resulted in the loss of

COX-2 inhibitory potency (0% inhibition at 10 µM con-

centration in recombinant enzyme assay), but carbonyl

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5493

substitution in the spacer (e.g., compound 22a ) retained

the COX-2 inhibitory potency (Table 1). It is noteworthy

that compounds 22a and 22e, with a carbonyl spacer,

exhibited significantly less (10%) COX-2 inhibition at 1

µM concentration in the enzyme assay, whereas the

inhibition observed for the same concentration (1 µM)

in HWB was considerably higher (25% and 40%, respec-

tively). The carbonyl spacer can increase the polarity

of the molecule and/or may have some effect on the

hydrophobicity of the compounds. The theoretical C log

P values for the compounds with carbonyl spacer are

approximately 1 unit less than the corresponding com-

pounds with methylene spacer (C log P values: 21a ,

4.41; 22a , 3.53; 21e, 4.96; 22e, 4.09). The 3-aryl-

substituted compounds 22c, 22e, and 22h with carbonyl

spacer exhibited good COX-2 inhibition (40-50%) at 1

µM concentration in HWB and modest COX-1 inhibition

(50-65%) at a very high (100 µM) concentration. In

contrast, 4-aryl-substituted compounds 22d and 22j did

not exhibit any significant COX-2 inhibition (5-10%),

even at a high 10 µM concentration in HWB. The COX

inhibition by compounds with a carbonyl spacer, 22a -j,

is given in Table 1.

These data also show that interchangeability of the

methyl sulfone group and the sulfonamide group for

COX-2 inhibition is dependent upon other structural

components, including the central ring system present

within a particular inhibitor.

We also studied the effect of fluorine substitution on

the methyl sulfone moiety. In this benzo-1,3-dioxolane

bicyclic series, when the methyl sulfone was changed

to a (fluoromethyl)sulfone as in compound 50, an

approximately 10-fold decrease of COX-2 inhibitory

potency was observed in the enzyme assay.

SAR of P yr id yl An a logu es. The pyridyl moiety

imparts more hydrophilicity to a molecule. It can form

a salt in the acidic pH of the GI tract, increasing

aqueous solubility and helping to improve the absorp-

tion and bioavailability of a molecule, giving rise to

enhanced in vivo potency.⁵⁵We evaluated substituted

2- and 3-(pyridylmethyl) analogues for their COX-2 and

COX-1 inhibition in the HWB assay. In this series, only

the 3-(pyridylmethyl) analogue 27 (Table 2) was active

in the enzyme assay: 65% COX-2 inhibition at 10 µM

test concentration. The COX-2 inhibitory potency ob-

served for 27 in the enzyme assay was much higher

than that observed in the HWB assay. In the HWB

assay, 27 showed only 15% COX-2 inhibition at a

concentration of 10 µM. The 3-(pyridylmethyl) analogue

28 with a carbonyl spacer was also found to be inactive.

The substituted 3-(pyridylmethyl) analogue 35 and the

2-(pyridylmethyl) analogue 31 were not COX-2 inhibi-

tors.

SAR of Meth yl Su lfon e COX-2 P h a r m a cop h or e.

Replacement of the methyl sulfone group by a sulfona-

mide moiety usually decreases COX-2 selectivity but

enhances oral bioavailability.^32,54For the SAR study of

this pharmacophore in the bicyclic system, we screened

only one sulfonamide (47, Scheme 12) analogue of

methyl sulfone 21a . Its COX-2 and COX-1 inhibitory

potencies were first determined in the enzyme assay and

then in the HWB assay. Sulfonamide substitution, as

in 47, increased the COX-2 inhibitory potency in the

enzyme assay. In this series, both the methyl sulfone

21a and the sulfonamide 47 exhibited excellent COX-2

inhibition in the enzyme assay (Table 3). Sulfonamide

47 was found to be even more potent in the enzyme

assay than the corresponding methyl sulfone 21a with

an IC₅₀of 0.05 µM against COX-2 and an IC₅₀of 25 µM

against COX-1 (a 500-fold COX-2 selectivity). In the

HWB assay, in contrast to methyl sulfone 21a , the

sulfonamide group in 47 abrogated the COX-2 inhibitory

activity completely, yet 47 exhibited weak COX-1 in-

hibitory activity. To confirm this unexpected finding, we

repeated the experiment using a known reference

sample as a control and obtained the same results.

Methyl sulfone and sulfonamide are the two well-known

pharmacophores used in the development of COX-2

inhibitors. Even before the HWB assay was developed

for the evaluation of COX-2 inhibitors, based on the

potency in the enzyme assay, it has been reported and

subsequently always presumed that sulfonamide in

general increases the oral bioavailability and decreases

COX-2 selectivity, which does not seem to be the general

case. The sulfonamide 47 did not inhibit COX-2 even

at high concentration (100 µM) in HWB, yet inhibited

the COX-1 at higher concentrations. We even attempted

to determine its IC_50sfor COX-2 and COX-1 in HWB.

For concentrations up to 100 µM, no COX-2 inhibition

was observed. The COX-1 IC₅₀for sulfonamide 47 in

HWB was 60 µM (Table 4). This divergence in results

depending upon assay conditions underscores the im-

portance of screening the compounds in an assay that

more accurately reflects the physiological conditions.

SAR of Nitr ogen -Con ta in in g An a logu es. Since

earlier SAR studies demonstrated that cyclohexyl sub-

stitution (as in 8a ) resulted in a potent and selective

COX-2 inhibitor, another variation was introduced with

the aim of retaining COX-2 potency and improving

bioavailability. The cyclohexyl ring in 8a was replaced

by piperidine, as in 38a (Table 2). Introduction of the

amine nitrogen into 38a was detrimental to COX-2

potency. While cyclohexyl analogue 8a (Table 1) showed

100% COX-2 inhibition at 1 µM in the enzyme assay,

its N-containing analogue 38a was inactive. Substituted

analogues 38b-f exhibited low COX-2 potency in the

recombinant enzyme assay; 25-40% inhibitions at 10

µM were observed. The loss in COX-2 inhibitory potency

of 38a -f was postulated to reflect the basicity of the

nitrogen. If COX-2 inhibitory potency were compromised

to be due to basicity of nitrogen in 38a -f, then addition

of a carbonyl into either the six-member ring as in 42

or into the spacer as in 45b to give the corresponding

amides should be beneficial for COX-2 inhibition. This

modification was also guided by the good COX-2 inhibi-

tory potency of 12a and 22a , which contain a carbonyl

spacer (12a : 40% inhibition at 1 µM and 90% inhibition

at 10 µM in HWB assay). Unlike compound 12a , the

nitrogen-containing analogue 45b was a weak COX-2

inhibitor. Interestingly, the lactam 42 showed reason-

ably potent COX-2 inhibition in the enzymatic assay.

However, once again this inhibition profile was not

reproduced in the HWB assay (Table 2).

SAR of Sp a cer a n d 1,3-Dioxola n e Rin g. To deter-

mine the contribution of the spacer and the dioxolane

ring, compounds 65 with no spacer (Scheme 16) and 56,

59a , and 60a with no dioxolane ring (Scheme 15) were

screened in the HWB assay, and their potencies were

5494 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

visualized under 254 nm UV light or by staining with phos-

phomolybdate (10% solution in ethanol) spray reagent.

compared to the corresponding compounds containing

those groups. Compounds 21h and 22h with methylene

and carbonyl spacer groups, respectively, showed excel-

lent COX-2 inhibition in HWB. In contrast, compound

65, without a spacer group, did not show any COX-2

inhibition at a 10 µM concentration in the HWB assay.

Similarly, we also found that the 1,3-dioxolane ring

contributed to COX-2 inhibitory potency. Compounds

with no dioxolane rings, such as 56, 59a , and 60a , were

less potent than the corresponding compounds 7a , 21c,

and 22c. Compound 60a showed weak COX-2 inhibition

at a 1 µM concentration in the HWB assay compared

to 22c, which showed 50% inhibition at a 1 µM concen-

tration in WHB. When dimethoxy groups, as in 72,

replaced the 1,3-dioxolane ring in 21h , the COX-2

inhibitory potency was considerably decreased. Replace-

ment of the 1,3-dioxolane ring in 22c by 1,4-dioxinyl ring

as in 74 also reduced COX-2 inhibitory potency consid-

erably.

In Vivo Activity. To assess the oral activity of benzo-

1,3-dioxolane COX-2 inhibitors, selected methyl sulfones

7c and 21c were evaluated in an acute inflammation

model (the air pouch assay) and were found to be

inactive (0% inhibition at 16 mg/kg). The reason for the

lack of oral in vivo activity for 7c and 21c may reflect

limited oral bioavailability. For the purpose of quick

evaluation, we decided to directly administer the com-

pound into the air pouch and determine the activity.

The potent 3-fluorophenyl-substituted analogue 22c

inhibited 80% of the PGE₂production in the air pouch

(80% inhibition at 2 mg/kg) when administered directly

into the air pouch.

Assa y for In h ibition of Recom bin a n t COX-1 (Hu m a n

or Ovin e) a n d COX-2 (Hu m a n ) En zym e Activity. Inhibi-

tion of recombinant human or ovine COX-1 and human COX-2

enzyme activities was measured using either the COX (human)

inhibitor screening assay or the COX (ovine) inhibitor screen-

ing assay (Cayman Chemical, Ann Arbor, MI, cat. no. 560121

or 560101, respectively), which also contained the prostaglan-

din screening EIA used for quantification of the prostaglandin

product. These commercial assays supplied the COX enzymes.

The instructions provided with the assay were followed with

some modification. Glass test tubes placed in a 25 °C water

bath received 950 µL of reaction buffer (0.1 M Tris-HCl, pH

8.0, containing 5 mM EDTA and 2 mM phenol), 10 µL of a

100 µM heme solution, and 10 µL (5 units) of either human or

ovine COX-1 or human COX-2 enzyme, and the resulting

mixture was incubated for 2 min. Twenty microliters of test

compound or solvent (e.g., DMSO) was added. Each tube was

mixed vigorously immediately after this addition. The enzyme

was incubated with the inhibitor for 20 min at 25 °C. The

enzymatic reaction was then initiated by the addition of 10

µL of freshly prepared 10 mM arachidonic acid (neutralized

with KOH) and mixing. After 2 min at 37 °C, the reaction was

terminated by addition of 50 µL of 1 M HCl, mixing, and

cooling to room temperature. One hundred microliters of a

saturated stannous chloride solution (50 mg/mL of 0.1 M HCl)

was added and the reaction mixture was allowed to stand at

room temperature for at least 5 min. PGs produced in the

COX-mediated reactions were quantified by EIA. Activity is

expressed as percent inhibition relative to the control reaction

containing solvent only (i.e., without test compound).

Assa y for In h ibition of COX-1 a n d COX-2 En zym e

Activity in Hu m a n Wh ole Blood . The assay for COX-1 and

COX-2 enzyme activity in human whole blood was performed

essentially as described by Young et al.⁵⁶Briefly, human blood

from nonfasted, male or female donors who had not taken any

aspirin or NSAIDs for 14 days was collected in sodium heparin

(20 units per mL blood) and distributed in 1 mL aliquots per

well of a 24-well tissue culture plate. The plate was placed on

a gently rotating platform shaker in a 5% CO₂incubator at

37° C for 15 min. Test compounds were dissolved and diluted

in DMSO and 1 µL of each dilution of the test compound was

added per well in duplicate wells.

To induce COX-2, lipopolysaccharide (LPS) from Escherichia

coli (LPS, serotype 026:B6 or serotype 0127:B8, Sigma Chemi-

cal Co., St. Louis, MO, cat. no. L3755 or L3129, respectively)

was added at 10 µg/mL (2 µL of 5 mg/mL LPS in DMSO) to

appropriate wells 15 min after the addition of the test

compounds. For the stimulation of COX-1, the calcium iono-

phore A23187 (Sigma Chemical Co., St. Louis, MO, cat. no.

C7522) was added to a final concentration of 25 µM (1 µL of

25 mM stock in DMSO) to separate wells 4.5 h after the

addition of the test compounds. (All control wells not receiving

test compounds, LPS, or A23187 received equal volumes of

DMSO) At 30 min after A23187 addition or 5 h after LPS

addition, all incubations were terminated by cooling on ice and

adding EGTA to a final concentration of 2 mM. The blood

samples were then transferred by polyethylene transfer pipets

to 15 mL polypropylene centrifuge tubes and centrifuged at

1200g for 10 min at 4 °C. One hundred microliters of plasma

was removed from each blood sample and added to 1 mL of

methanol in a 15 mL polypropylene centrifuge tube, mixed

vigorously, and stored overnight at -20 °C. The next day, the

samples were centrifuged at 2000g for 10 min at 4 °C, and

the supernatants were transferred to glass tubes and evapo-

rated to dryness. After reconstitution with EIA buffer and

appropriate dilution (2000-fold for COX-1 and 500-fold for

COX-2), the samples were assayed for TXB₂using EIA kits

supplied by Cayman Chemical Co. (Ann Arbor, MI, cat. no.

519031) in duplicate wells.

Con clu sion s

We have designed and synthesized a series of novel

disubstituted metharyl benzo-1,3-dioxolane compounds,

many of which are highly potent and selective COX-2

inhibitors. Our SAR studies demonstrate for the first

time that incorporation of a one-carbon spacer group

between the central benzo-1,3-dioxolane ring and the

cycloalkyl or aryl substituent provides more flexibility

and leads to more potent COX-2 inhibitors. In this

series, fluorine substitution at meta-position(s) of a

phenyl ring, e.g., 21c, 22c, and 22h generated potent

and selective COX-2 inhibitors.

Exp er im en ta l Section

Gen er a l Com m en ts. Reagents and solvents were generally

used as obtained from commercial suppliers. Dry tetrahydro-

furan (THF), ethyl ether, hexanes, dichloromethane, dimeth-

ylformamide (DMF), and methylsulfoxide (DMSO) were ob-

tained from VWR or Fisher Scientific. Reactions were routinely

performed under a nitrogen atmosphere in oven-dried glass-

ware. Melting points were determined with an electrothermal

1

heating block and are uncorrected. H and ¹³C NMR spectra

were determined at 300 and 75.45 MHz, respectively. NMR

spectra were recorded in CDCl₃unless otherwise indicated,

and chemical shifts are reported relative to tetramethylsilane

(δ ) 0.00). Routine mass spectra were obtained on a PE

SCIEX, API 150 EX instrument with Turbo ion spray injector

coupled with a Perkin-Elmer autosampler HPLC unit and

785A UV/vis detector, using an atmospheric pressure ioniza-

tion method. Elemental microanalyses were performed by

Robertson Microlit Laboratories (Madison, NJ ). Flash column

chromatography was performed using Merck silica gel 60

(270-400 mesh). TLC was performed on a 250 µm precoated

Merck silica gel 60 F254 glass-backed plates. Spots were

Air P ou ch Mod el of In fla m m a tion .⁵⁷Male SD rats (175-

200 g, Charles River Laboratories) were used, and the rats

were fasted with free access to water at 24 h prior to

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5495

experiment. On day zero, animals received subcutaneous

injections of 20 mL of sterile air into the intrascapular area

of the back. An additional 10 mL of air was injected into the

pouch on day -3 to keep the pouch open, allowing the interior

membrane to be developed. On day six, vehicle or the test

compound in 0.5% methyl cellulose was administered by oral

gavage. One hour later inflammation was induced by injecting

1 mL of 1% carrageenan into the air pouch. Three hours after

carrageenan injection, rats were sacrificed. Pouch exudates

were collected, washed, and the number of leukocytes in the

exudate were determined by cell counting with a Coulter

counter. The total white blood cells (WBC) counts and percent

inhibition of the cell infiltration were calculated. The exudate

samples were also assayed for PGE₂by specific ELISAs

(Cayman Chemical Co.).

extracts were washed with water (2 × 50 mL) and brine (1 ×

25 mL), dried over sodium sulfate, and filtered. The filtrate

was evaporated under reduced pressure, and the product was

either purified by trituration with ethyl acetate/hexane or by

chromatography on silica gel and elution with hexanes:EtOAc

(19:1) to give the desired (methylsulfonyl) compound as a white

solid in excellent yield.

Gr ign a r d Rea ction : Meth od D. The desired Grignard

reagent (4 mmol), if not commercially available, was freshly

prepared by refluxing the equimolar amounts of haloarene and

magnesium in the presence of a catalytic amount of iodine in

THF (20 mL). The solution of the corresponding magnesium

bromide (4 mmol) in THF (20 mL) was then added to a

precooled (0 °C) solution of carbaldehyde (4 mmol) in anhy-

drous THF (40 mL) under nitrogen atmosphere. The reaction

mixture was stirred at 0 °C for 10 min and then at room

temperature for 2 h. It was quenched with saturated aqueous

ammonium chloride, acidified with 1 N HCl, and then ex-

tracted with ethyl acetate (2 × 50 mL). The combined organic

extracts were washed with water (1 × 25 mL) and brine (1 ×

25 mL), dried over sodium sulfate, and filtered, and the filtrate

was evaporated under reduced pressure to give the crude

product. Purification by silica gel column chromatography

using 20% ethyl acetate in hexane gave the desired compound

as a white solid.

Hyd r ogen a tion Rea ction : Meth od E. The product to be

hydrogenated (1 mmol) was dissolved in a mixture of EtOAc

(5 mL) and EtOH (25 mL). The catalyst, 10% palladium on

carbon (250 mg), was added under a stream of nitrogen. The

hydrogenation was performed at 20 psi of hydrogen for 3 h.

The solution was filtered to remove the catalyst, and the

filtrate was evaporated under reduced pressure to give the

crude product that was triturated with hexanes:EtOAc (5:1)

to give the title compound in good yield.

Deoxygen a tion Rea ction Usin g Na BH₄/TF A: Meth od

F . The hydroxyl compound (8 mmol) was dissolved in a

minimal amount of CH₂Cl₂and under argon atmosphere was

added to trifluoroacetic acid at 0 °C. The reaction mixture was

stirred at 0 °C for 15 min. To the resulting solution was then

added, in small portions, sodium borohydride (1.39 g, 36.72

mmol). The reaction mixture was stirred at 0 °C for an

additional 30 min. The solvent and trifluoroacetic acid were

evaporated under reduced pressure to give a gray foam. Ice-

cold water (20 mL) was added to the foam, and the aqueous

layer was made basic (pH 8-9) by addition of NaOH (50%).

The aqueous layer was extracted with CH₂Cl₂(2 × 50 mL),

and the combined organic layers were dried over sodium

sulfate and filtered. The filtrate was evaporated under reduced

pressure to give the crude product that was either purified by

recrystallization from CH₂Cl₂:hexanes or by silica gel column

chromatography using 20% ethyl acetate in hexane to give the

desired compound as a white solid.

P CC Oxid a tion Rea ction : Meth od G. A suspension of

the hydroxyl compound (1 mmol) and alumina (2 g) in

anhydrous CH₂Cl₂(50 mL) was stirred at room temperature.

While stirring, pyridinium chlorochromate (3 mmol) was

added, and the reaction mixture was stirred at room temper-

ature for 1 h. The mixture was diluted with CH₂Cl₂, and the

alumina was removed by filtration. The filtrate was washed

with water (1 × 50 mL), saturated aqueous sodium bicarbonate

(2 × 50 mL), and brine (1 × 50 mL), dried over anhydrous

sodium sulfate, and filtered. The filtrate was evaporated under

reduced pressure. Purification by flash column chromatogra-

phy on silica gel and elution with hexanes:EtOAc (19:1) gave

the desired compound as a white solid.

For determining the activity of COX-2 inhibitor in the air

pouch directly, on day six, vehicle or the test compounds in

0.5% methylcellulose were administered by an injection into

the air pouch, 1 h prior to the carrageenan injection.

6-Br om o-2H -b en zo[d ]1,3-d ioxolen e-5-ca r b a ld eh yd e-

(m eth ylsu lfon yl)ben zen e (2). The title compound was syn-

thesized as described.⁵⁰Treatment of piperonal 1 (60 g) with

bromine (60 mL) in acetic acid (750 mL) and carbon disulfide

(75 mL) containing a catalytic amount of iodine at room

temperature, overnight, gave the title compound (69 g, 70%

yield): mp 128-130 °C; ¹H NMR (CDCl₃) δ 10.17 (s, 1H, 7.33

(s, 1H), 7.03 (s, 1H), 6.06 (s, 2H); ¹³C NMR (CDCl₃) δ 190.3,

153.3, 148.1, 128.0, 121.5, 113.2, 108.1, 102.7; LRMS (APIMS)

m/z 229 (Br 79) and 231 (Br 81) (M + H)⁺LRMS (APIMS) m/z

229 (M + H)⁺and 231 ((M + H) + 2)⁺.

Gen er a l P r oced u r es. Su zu k i Cou p lin g R ea ct ion :

Meth od A. The bromo compound (50 mmol) and 4-(methyl-

thio)benzeneboronic acid 3 (8.4 g, 50 mmol) were dissolved

in toluene (500 mL), and sodium carbonate (2 M, 50 mL,

100 mmol) was added. To this reaction mixture was added

ethanol (20 mL) followed by tetrakis(triphenylphosphine)-

palladium (3.4 g, 2.5 mmol). The reaction mixture was refluxed

overnight under a nitrogen atmosphere and then diluted with

water (250 mL), the organic layer was separated, and the

aqueous layer was extracted with EtOAc (2 × 150 mL). The

combined organic extracts were washed with water (4 × 250

mL) and brine (1 × 250 mL), dried over sodium sulfate, and

filtered. The filtrate was evaporated under reduced pressure

to give the crude product. The product was either purified by

trituration with ethyl acetate/hexane or by chromatography

on silica gel and elution with hexanes:EtOAc (19:1) to give the

title compound as a white solid.

Wittig Rea ction : Meth od B. A suspension of cycloalkyl-

(triphenyl)phosphonium bromide (20 mmol) in anhydrous THF

(125 mL) was stirred at -78 °C. n-BuLi (7 mL of 2.5 M in

hexane, 17.5 mmol) was added dropwise to the stirred suspen-

sion under nitrogen atmosphere. The reaction mixture was

stirred at -78 to -60 °C for over a period of 1 h. The

suspension of ylide was then cooled to -78 °C, and the

aldehyde (5 mmol) in THF (25 mL) was added dropwise to the

ylide solution. The reaction mixture was gently stirred for 1.5

h at -78 °C, slowly allowed to warm to room temperature,

and stirred at room temperature overnight. The reaction

mixture was then quenched with saturated aqueous am-

monium chloride and extracted with EtOAc (2 × 50 mL). The

combined organic extracts were washed with water (1 × 50

mL) and brine (1 × 50 mL), dried over sodium sulfate, and

filtered. The filtrate was evaporated and the residue was

purified by chromatography on silica gel and elution with

hexanes:EtOAc (9:1). This gave the desired product as a white

powder in yields varying from 57% to 75%.

Oxon e Oxid a tion Rea ction : Meth od C. The thiomethyl

compound (4 mmol) was dissolved in methanol (60 mL) with

stirring at room temperature. A solution of Oxone (8 mmol)

in water (20 mL) was added. The reaction mixture was stirred

at room temperature for 2 h. The solvent methanol was

evaporated at reduced pressure and the remainder was diluted

with water (25 mL), neutralized with ammonium hydroxide,

and extracted with EtOAc (2 × 50 mL). The combined organic

N-Alk yla tion Rea ction : Meth od H. The appropriately

substituted halo compound (1.2 mmol) and substituted pip-

eridinyl compound (138 mg, 1.2 mmol) were dissolved in

anhydrous DMF (5 mL). Potassium carbonate (830 mg, 6

mmol) was added, and reaction mixture was stirred at room

temperature overnight. The reaction mixture was then treated

with ice-cold water and extracted with ethyl acetate (2 × 75

mL). The combined organic extracts were washed with water

(1 × 50 mL) and brine (1 × 50 mL), dried over sodium sulfate,

5496 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

and filtered. The filtrate was evaporated under reduced

pressure to give the crude product that was purified by flash

column chromatography using methanol:dichloromethane (5:

95) to give the desired compound as a white solid in high yield.

Na BH₄Red u ction : Meth od I. The carbaldehyde (4 mmol)

was dissolved in ethanol (50 mL), and to this solution was

added sodium borohydride (12 mmol). The reaction mixture

was stirred at room temperature for 2 h. The solvent was

evaporated under reduced pressure and the residue was

treated with water (25 mL), neutralized with 1 N HCl, and

extracted with ethyl acetate (2 × 50 mL). The combined

organic extracts were washed with water and brine, dried over

sodium sulfate, and filtered. The filtrate was evaporated under

reduced pressure to give the crude product. Trituration with

10% ethyl acetate in hexane gave the pure desired compound

as a white solid.

combined organic layers were dried over anhydrous sodium

sulfate and filtered. The filtrate was concentrated under

reduced pressure. Purification by flash column chromatogra-

phy using 20% ethyl acetate in hexanes as the eluant gave

the title compound 7c as a white solid (280 mg, 72% yield):

mp 145-147 °C; ¹H NMR (CDCl₃) δ 7.94-7.91 (m, 2H), 7.51-

7.48 (m, 2H), 6.97 (s, 1H), 6.75 (s, 1H), 6.00-5.97 (m, 3H), 3.11

(s, 3H), 2.41 (t, J ) 6.8 Hz, 2H), 2.31 (t, J ) 7.0 Hz, 2H), 1.77-

1.54 (m, 4H); ¹³C NMR (CDCl₃) δ 147.4, 147.3, 146.9, 146.0,

138.5, 132.3, 131.1, 130.7, 126.9, 111.0, 109.6, 108.8, 101.2,

44.5, 34.8, 30.9, 26.8, 25.4; LRMS (APIMS) m/z 374 (M +

NH₄)⁺. Anal. (C₂₀H₂₀SO₄) C, H.

1-(6-(Cycloh exylm eth yl)(2H-ben zo[3,4-d ]1,3-d ioxolen -

5-yl))-4-(m eth ylsu lfon yl)ben zen e (8a ). The product 7a was

converted to 8a using method E to give the title compound 8a

in 54% yield: mp 112-116 °C; ¹H NMR (CDCl₃) δ 7.94 (d, J )

8.2 Hz, 2H), 7.43 (d, J ) 8.2 Hz, 2H), 6.75 (s, 1H), 6.61 (s,

1H), 5.97 (s, 2H), 3.10 (s, 3H), 2.34 (d, J ) 5.1 Hz, 2H), 1.6-

0.80 (m, 11H); ¹³C NMR (CDCl₃) δ 148.1, 147.4, 145.5, 138.7,

133.3, 132.5, 130.7, 127.1, 109.8, 109.5, 101.1, 44.5, 40.2, 39.8,

32.9 (2 × C), 26.3, 26.2 (2 × C); LRMS (APIMS) m/z 390 (M +

NH₄). Anal. (C₂₁H₂₄SO₄) C, H.

6-(4-Met h ylt h iop h en yl)-2H -b en zo[d ]1,3-d ioxola n e-5-

car baldeh yde (4). This compound was prepared using method

A. It was obtained as a white solid in 88% yield: mp 111-112

°C; ¹H NMR (CDCl₃) δ 9.74 (s, 1H), 7.41 (s, 1H), 7.29 (m, 4H),

6.80 (s, 1H), 6.07 (s, 2H), 2.52 (s, 3H); ¹³C NMR (CDCl₃) δ

190.3, 152.3, 148.5, 143.3, 140.8, 140.2, 130.9, 128.8, 127.4,

110.1, 106.7; 102.4, 44.4; LRMS (APIMS) m/z 273 (M + H)⁺.

1-(6-(Cycloh exylid en em et h yl)(2H -b en zo[3,4-d ]1,3-d i-

oxola n -5-yl))-4-m eth ylth ioben zen e (6a ). Using method B,

compound 6a was obtained as a white powder in 67% yield:

4-(6-(Cycloh eptylsm eth yl)(2H-ben zo[3,4-d]1,3-dioxolan -

5-yl))-1-(m eth ylsu lfon yl)ben zen e (8b). As described above,

the product 8a was similarly converted to 8b using method E

to give the title compound 8b in 80% yield: mp 89-92 °C; ¹H

NMR (CDCl₃) δ 7.91 (d, J ) 8.3 Hz, 2H), 7.39 (d, J ) 8.3 Hz,

2H), 6.72 (s, 1H), 6.57 (s, 1H), 5.92 (s, 2H), 3.07 (s, 3H), 2.33

(d, J ) 7.1 Hz, 2H), 1.53-1.14 (m, 11H), 0.90 (q, J ) 10.2 Hz,

2H); ¹³C NMR (CDCl₃) δ 147.9, 147.4, 145.4, 138.6, 133.3,

132.8, 130.6, 127.0, 109.6, 109.4, 101.0, 44.4, 41.1, 40.4, 33.9,

1

mp 83-84 °C; H NMR (CDCl₃) δ 7.31 (m, 4H), 6.79 (s, 1H),

6.72 (s, 1H), 5.92 (s, 2H), 5.88 (s, 1H), 2.51 (s, 3H), 2.23 (t, J

) 5.6 Hz, 2H), 2.11 (m, 2H), 1.45-1.55 (m, 6H).

4-(6-(Cycloh ep tylid en em eth yl)(2H-ben zo[3,4-d ]1,3-d i-

oxola n -5-yl))-1-m eth ylth ioben zen e (6b). Using (cyclohep-

tyl)triphenyl phosphine bromide and following method B, the

title compound 6b was obtained as oil in 57% yield: ¹H NMR

(CDCl₃) δ 7.22 (s, 4H), 6.77 (d, J ) 3.1 Hz, 2H), 5.94 (s, 3H),

2.48 (s, 3H), 2.40-2.36 (m, 2H), 2.25-2.20 (m, 2H), 1.63-1.32

(m, 8H); ¹³C NMR (CDCl₃) δ 146.2, 146.0, 143.4, 138.2, 136.6,

134.0, 130.4, 130.2, 125.9, 125.4, 109.9, 109.5, 100.9, 37.4, 31.1,

29.9, 28.9, 28.9, 27.0, 15.8.

1-(6-(Cycloh exylid en em et h yl)(2H -b en zo[3,4-d ]1,3-d i-

oxola n -5-yl))-4-(m eth ylsu lfon yl)ben zen e (7a ). The com-

pound 7a was prepared from 6a by using method C in 56%

yield. It was obtained as crystalline solid: mp 147-151 °C;

¹H NMR (CDCl₃) δ 7.89 (d, J ) 8.3 Hz, 2H), 7.84 (d, J ) 8.3

Hz, 2H), 6.77 (s, 1H), 6.72 (s, 1H), 5.98 (s, 2H), 5.84 (s, 1H),

3.07 (s, 3H), 2.14 (t, J ) 5.6 Hz, 2H), 2.08 (m, 2H), 1.51-1.30

(m, 6H); ¹³C NMR (CDCl₃) δ 147.2, 147.1, 146.4, 143.2, 138.3,

135.5, 130.6, 130.5, 126.8, 120.9, 110.5, 109.4, 101.2, 44.5, 36.9,

29.5, 28.2. 27.3, 26.4; LRMS (APIMS) m/z 371 (M + H)⁺. Anal.

(C₂₁H₂₂SO₄) C, H.

28.1, 26.0; LRMS (APIMS) m/z 404 (M + NH₄)⁺. Anal. (C₂₂H₂₆

SO₄) C, H.

-

4-(6-(Cyclopen th ylm eth yl)(2H-ben zo[3,4-d]1,3-dioxolan -

5-yl))-1-(m eth ylsu lfon yl)ben zen e (8c). Compound 8c was

prepared by method E. The pure compound was obtained a

1

white solid, in 83% yield: mp 103-105 °C; H NMR (CDCl₃)

δ 7.98-7.94 (m, 2H), 7.48-7.44 (m, 2H), 6.80 (s, 1H), 6.64-

6.61 (m, 1H), 5.98 (s, 2H), 3.10 (s, 3H), 2.49-2.43 (m, 2H),

1.98-1.83 (m, 1H), 1.59-1.40 (m, 6H), 0.98-0.78 (m, 2H); ¹³

C

NMR (CDCl₃) δ 148.0, 147.5, 145.5, 138.7, 133.5, 133.0, 130.7,

127.1, 109.7, 109.6, 101.1, 44.6, 41.9, 38.3, 32.3, 24.6; LRMS

(APIMS) m/z 376 (M + NH₄)⁺. Anal. (C₂₀H₂₂SO₄) C, H.

Cycloh exyl(6-(4-m eth ylth iop h en yl)(2H-ben zo[d ]1,3-d i-

oxola n -5-yl))m eth a n -1-ol (10a ). The compound 10a was

prepared by using method D. The product was obtained as a

white solid in 93% yield: mp 110-112 °C; ¹H NMR (CDCl₃) δ

7.26 (d, J ) 8.4 Hz, 2H), 7.18 (d, J ) 8.4 Hz, 2H), 7.01 (s, 1H),

6.64 (s, 1H), 5.97 (dd, J ) 4.1 and 1.3 Hz, 2H), 4.4 (dd, J ) 8.7

and 3.2 Hz, 1H), 2.52 (s, 3H), 2.0 (m, 1H, OH), 1.80-1.50 (m,

5H), 1.20-0.5 (m, 6H); ¹³C NMR (CDCl₃) δ 147.3, 146.4, 137.9,

137.0, 135.0, 134.8, 130.0 (2 × C), 126.2 (2 × C), 109.7, 106.2,

101.1, 74.9, 44.9, 29.3, 29.2, 26.2, 26.0, 28.9, 15.7; LRMS

(APIMS) m/z 730 (2 M + NH₄)⁺, 339 (M - OH)⁺.

1-(6-(Cycloh exylh yd r oxym et h yl)(2H -b en zo[3,4-d ]1,3-

d ioxola n -5-yl))-4-(m eth ylsu lfon yl)ben zen e (11a ). The thio-

methyl compound 10a was converted to 11a using method C.

The product 11a was obtained in 92% yield: mp 140-142 °C;

¹H NMR (CDCl₃) δ 7.93 (d, J ) 8.3 Hz, 2H), 7.46 (d, J ) 8.4

Hz, 2H), 7.03 (s, 1H), 6.60 (s, 1H), 5.98 (s, 2H), 4.21 (d, J )

6.8 Hz, 1H), 3.1 (s, 3H), 2.85 (br s, 1H, OH), 2.0 (m, 1H), 1.7-

0.5 (m, 10H); ¹³C NMR (CDCl₃) δ 148.1, 147.1, 146.7, 139.0,

134.8, 133.4, 130.7 (2 × C), 127.3 (2 × C), 109.2, 106.6, 101.4,

74.8, 45.0, 44.5, 29.3, 29.1, 26.1, 25.9, 25.8; LRMS (APIMS)

m/z 406 (M + NH₄)⁺.

4-(6-(Cycloh ep tylid en em eth yl)(2H-ben zo[3,4-d ]1,3-d i-

oxola n -5-yl))-1-(m eth ylsu lfon yl)ben zen e (7b). The com-

pound 7b was prepared from 6b using method C in 75% yield.

1

It was obtained as a white solid: mp 168-169 °C; H NMR

(CDCl₃) δ 7.91 (d, J ) 8.3 Hz, 2H), 7.51 (d, J ) 8.2 Hz, 2H),

6.79 (d, J ) 2.1 Hz, 2H), 6.00 (s, 2H), 5.92 (s, 1H), 3.09 (s,

3H), 2.32 (t, J ) 14.4 Hz, 2H), 2.23-2.17 (m, 2H), 1.61-1.51

(m, 8H); ¹³C NMR (CDCl₃) δ 147.3, 146.4, 145.0, 138.4, 132.5,

131.0, 130.7, 126.8, 124.5, 110.3, 109.5, 101.3, 44.6, 37.5, 31.2,

29.9, 29.0, 28.9, 26.9; LRMS (APIMS) m/z 402 (M + NH₄)⁺.

Anal. (C₂₂H₂₄SO₄) C, H.

4-(6-(Cyclop en tylid en em eth yl)(2H-ben zo[3,4-d ]1,3-d i-

oxola n -5-yl))-1-(m eth ylsu lfon yl)ben zen e (7c). A suspen-

sion of cyclopentyltriphenylphosphine bromide 5c (1.24 g, 3

mmol) in anhydrous THF (15 mL) was stirred at 0 °C under

nitrogen atmosphere. A solution of t-BuOK (2.5 mL of 1M in

THF, 2.5 mmol) was added dropwise and stirred for 15 min.

To the resulting dark orange colored mixture was added the

carbaldehyde 15 (3.04 g, 3 mmol) in anhydrous THF (10 mL)

and DMF (10 µL) dropwise. The reaction mixture was stirred

at 0 °C for 30 min and then slowly allowed to warm to room

temperature and stirred for 3 h at room temperature. The

reaction was quenched with saturated aqueous ammonium

chloride, and the organic layer was separated. The aqueous

layer was diluted and extracted with ethyl acetate. The

Cycloh exyl 6-(4-(Met h ylsu lfon yl)p h en yl)(2H -b en zo-

[d ]1,3-d ioxola n -5-yl) Keton e (12a ). Oxidation of 11a using

1

method G gave 12a in 82% yield: mp 172-174 °C; H NMR

(CDCl₃) δ 7.93 (d, J ) 8.3 Hz, 2H), 7.45 (d, J ) 8.4 Hz, 2H),

7.03 (s, 1H), 6.80 (s, 1H), 6.05 (s, 2H), 3.06 (s, 3H), 2.25 (m,

1H), 1.7-1.5 (m, 5H), 1.30-0.80 (m, 5H); ¹³C NMR (CDCl₃) δ

149.4, 147.7, 139.3, 134.0, 133.8, 129.6 (2 × C), 127.4 (2 × C),

110.2, 108.6, 102.0, 49.7, 44.5 (2 × C), 29.1 (2 × C), 25.6 (2 ×

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5497

C); LRMS (APIMS) m/z 404 (M + NH₄), 387 (M + H)⁺. Anal.

(C₂₁H₂₂SO₅) C, H.

(4-F lu or op h en yl)(6-(4-m et h ylt h iop h en yl)(2H -b en zo-

[d ]1,3-d ioxola n -5-yl))m eth a n -1-ol (19d ): colorless thick oil;

¹H NMR (CDCl₃) δ 7.25 (d, J ) 8.3 Hz, 2H), 7.15-7.00 (m,

3H), 7.00-6.84 (m, 4H), 6.8 (s, 1H), 5.96 (s, 2H), 5.79 (s, 1H),

2.50 (s, 3H), 2.11 (br s, 1H, OH); LRMS (APIMS) m/z 351 (M

- OH)⁺, 754 (2M + NH₄)⁺.

(6-(4-Meth ylth iop h en yl)-2H-ben zo[d ]1,3-d ioxolen -5-yl-

)m eth a n -1-ol (13). The carbaldehyde 4 was reduced to 13 by

method I. The title compound 13 was obtained as a white solid

in 66% yield: mp 95-97 °C; ¹H NMR (CDCl₃) δ 7.25 (m, 4H),

6.99 (s, 1H), 6.72 (s, 1H), 5.96 (s, 2H), 4.41 (s, 2H), 2.50 (s,

3H), 1.95 (br s, 1H, OH); ¹³C NMR (CDCl₃) δ 147.0, 146.8,

137.3, 137.1, 134.6, 131.7, 129.6 (2 × C), 126.2 (2 × C), 109.9,

108.7, 101.1, 62.7, 15.7; LRMS (APIMS) m/z 292 (M + NH₄)⁺.

1-(6-(Hyd r oxym et h yl)(2H -b en zo[3,4-d ]1,3-d ioxolen -5-

yl)-4-(m eth ylsu lfon yl)ben zen e (14). The compound 13 was

converted to 14 by method C. The pure product 14 was

obtained as a white crystalline solid, in 97% yield: mp 163

(3-Met h ylp h en yl)(6-(4-m et h ylt h iop h en yl)(2H -b en zo-

[d ]1,3-d ioxola n -5-yl))m eth a n -1-ol (19e): colorless thick oil;

¹H NMR (CDCl₃) δ 7.26-7.12 (m, 5H), 7.02-6.95 (m, 4H) 6.68

(s, 1H), 5.94 (d, J ) 1.2 Hz, 2H), 5.77 (d, J ) 3.3 Hz, 1H), 2.50

(s, 3H), 2.29 (s, 3H), 2.16-2.13 (br s, 1H); ¹³C NMR (CDCl₃) δ

147.3, 146.7, 143.8, 137.8, 137.4, 135.1, 134.6, 130.0, 128.1,

127.9, 127.0, 126.2, 123.4, 109.8, 107.5, 101.2, 72.1, 21.4, 15.8;

LRMS (APIMS) m/z 746 (2M + NH₄)⁺, 347 (M - OH)⁺.

(3-Meth oxyp h en yl)(6-(4-m eth ylth iop h en yl)(2H-ben zo-

[d ]1,3-d ioxola n -5-yl))m eth a n -1-ol (19f): white solid; mp 95

1

°C; H NMR (CDCl₃) δ 7.95 (d, J ) 8.1 Hz, 2H), 7.55 (d, J )

8.2 Hz, 2H), 7.03 (s, 1H), 6.72 (s, 1H), 6.00 (s, 2H), 4.43 (s,

2H), 3.09 (s, 3H), 2.1 (br s, 1H, OH); ¹³C NMR (CDCl₃) δ 147.9,

147.3, 146.3, 139.1, 133.3, 131.8, 130.3, 127.3, 109.7, 109.3,

101.4, 62.6, 44.5; LRMS (APIMS) m/z 324 (M + NH₄)⁺.

6-(4-(Meth ylsu lfon yl)ph en yl)-2H-ben zo[d]1,3-dioxolan e-

5-ca r ba ld eh yd e (15). Compound 14 was oxidized using

method G to give the title compound as a white solid, in 68%

1

°C; H NMR (CDCl₃) δ 7.28-7.25 (m, 2H), 7.21 (s, 2H), 6.95

(d, J ) 0.5 Hz, 1H), 6.82-6.77 (m, 2H), 6.75 (s, 2H), 6.69 (d, J

) 0.9 Hz, 1H), 5.97-5.95 (m, 2H), 5.80 (d, J ) 3.8 Hz, 1H),

3.76 (d, J ) 0.9 Hz, 3H), 2.51 (d, J ) 0.9 Hz, 3H), 2.04-2.01

(m, 1H); ¹³C NMR (CDCl₃) δ 159.6, 147.4, 146.8, 145.6, 137.5,

137.4, 134.9, 134.7, 130.0, 129.3, 126.3, 118.7, 112.6, 112.1,

109.8, 107.5, 101.2, 72.0, 55.2, 15.8; LRMS (APIMS) m/z 778

(2M + NH₄)⁺, 363 (M - OH)⁺.

1

yield: mp 152-153 °C; H NMR (CDCl₃) δ 9.74 (s, 1H), 8.06

(d, J ) 8.2 Hz, 2H), 7.59 (d, J ) 8.2 Hz, 2H), 7.51 (s, 1H), 6.86

(s, 1H), 6.16 (s, 2H), 3.16 (s, 3H); ¹³C NMR (CDCl₃) δ 189.3,

152.3, 148.5, 143.3, 140.9, 130.9 (2 × C), 128.8, 127.4 (2 × C),

110.0, 106.7, 102.4, 49.7, 44.4; LRMS (APIMS) m/z 322 (M +

NH₄)⁺, 305 (M + H)⁺. Anal. (C₁₄H₁₂SO₃) C, H.

(2-Flu or o-5-m eth ylph en yl)(6-(4-m eth ylth ioph en yl)(2H-

ben zo[d ]1,3-d ioxolen -5-yl))m eth a n -1-ol (19g): white solid;

1

mp 110 °C; H NMR (CDCl₃) δ 7.26-7.18 (m, 5H), 7.01-6.98

(m, 1H), 6.87 (s, 1H), 6.82-6.76 (m, 1H), 6.69 (s, 1H), 5.97 (s,

1H), 5.95 (s, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 2.10 (s, 1H); ¹³C

NMR (CDCl₃) δ 147.1, 146.8, 137.4, 137.3, 135.0, 133.4, 133.4,

130.2, 129.8, 129.3, 129.2, 128.0, 127.9, 126.2, 115.0, 114.8,

110.0, 107.5, 101.2, 67.2, 20.8, 15.8; LRMS (APIMS) m/z 782

(2M + NH₄)⁺, 365 (M - OH)⁺.

1-(6-(Ch lor om eth yl)(2H-ben zo[3,4-d]1,3-dioxolan -5-yl))-

4-(m eth ylsu lfon yl)ben zen e (16). To a solution of methyl

sulfone 14 (1.53 g, 5 mmol) in anhydrous benzene (35 mL) was

added thionyl chloride (0.8 mL) followed by a catalytic amount

of pyridine (3 or 4 drops). The reaction mixture was stirred at

room-temperature overnight. The solvent was evaporated

under reduced pressure, and the residue on addition of hexane

gave a white solid. The product was used without further

purification. The sample was characterized after purification

by silica gel column chromatography using ethyl acetate

hexane (1:1): mp 146-148 °C; ¹H NMR (CDCl₃) δ 8.00 (d, J )

8.3 Hz, 2H), 7.6 (d, J ) 8.3 Hz, 2H), 6.99 (s, 1H), 6.71 (s, 1H),

6.02 (s, 2H), 4.38 (s, 2H), 3.11 (s, 3H); ¹³C NMR (CDCl₃) δ

148.1, 145.7, 139.6, 134.1, 130.2, (2 × C), 128.5, 127.4 (2 × C),

110.3, 109.7, 101.7, 44.4; LRMS (APIMS) m/z 342 (M + NH₄)⁺.

Anal. (C₁₄H₁₄SO₃) C, H.

1-(6-(Hyd r oxyp h en ylm eth yl)(2H-ben zo[3,4-d ]1,3-d iox-

ola n -5-yl))-4-(m eth ylsu lfon yl)ben zen e (20a ): white solid;

1

mp 144-148 °C; H NMR (CDCl₃) δ 7.89 (d, J ) 8.0 Hz, 2H),

7.44 (d, J ) 8.0 Hz, 2H), 7.23 (m, 3H), 7.12 (m, 2H), 7.0 (s,

1H), 6.65 (s, 1H), 5.97 (s, 2H), 5.69 (s, 1H), 3.06 (s, 3H), 2.44

(br s, 1H, OH); ¹³C NMR (CDCl₃) δ 148.1, 146.9, 146.5, 143.4,

139.2, 134.9, 133.0, 130.5, 128.3, 127.4, 127.1, 126.3, 109.4,

107.8, 101.4, 72.1, 44.5; LRMS (APIMS) m/z 400 (M + NH₄)⁺.

1-(6-((2-F lu or op h en yl)h yd r oxym et h yl)(2H-b en zo[3,4-

d ]1,3-d ioxola n -5-yl))-4-(m et h ylsu lfon yl)b en zen e (20b ):

1

white solid; mp 163-169 °C; H NMR (CDCl₃) δ 7.85 (d, J )

Using methods D, C, E, G, and I and carbaldehyde 4 as a

starting material, compounds 21a -j and compounds 22a -j

were prepared good yields. Spectral data for the few repre-

sentative examples are given below.

(6-(4-Met h ylt h iop h en yl)(2H -b en zo[d ]1,3-d ioxola n -5-

yl))p h en ylm eth a n -1-ol (19a ): white solid; mp 96-99 °C; ¹H

NMR (CDCl₃) δ 7.21 (m, 9H), 6.95 (s, 1H), 6.69 (s, 1H), 5.94

(s, 2H), 5.82 (s, 1H), 2.50 (s, 3H), 2.24 (br s, 1H, OH); ¹³C NMR

(CDCl₃) δ 147.2, 146.7, 143.9, 137.4, 137.3, 134.9, 134.5, 129.9,

128.2, 127.1, 126.3, 126.2, 109.7, 107.5, 101.1, 72.0, 15.7; LRMS

(APIMS) m/z 333 (M - OH)⁺, 718 (2M + NH₄)⁺.

(2-F lu or op h en yl)(6-(4-m et h ylt h iop h en yl)(2H -b en zo-

[d ]1,3-d ioxola n -5-yl))m eth a n -1-ol (19b): white solid; mp

130-135 °C; ¹H NMR (CDCl₃) δ 7.51 (t, J ) 8.3 Hz, 1H), 7.32

(d, J ) 8.4 Hz, 1H), 7.30-7.20 (m, 5H), 6.91 (m, 1H), 6.85 (s,

1H), 6.71 (s, 1H), 6.02 (s, 1H), 5.94 (s, 2H), 2.50 (s, 3H), 2.31

(br s, 1H, OH); ¹³C NMR (CDCl₃) δ 161.3, 158.0, 146.8, 137.3,

134.9, 133.4, 130.8, 129.8, 128.8, 127.5, 127.1, 126.2, 123.9,

115.2, 110.0, 107.4, 101.2, 67.0, 15.8; LRMS (APIMS) m/z 351

(M - OH)⁺, 754 (2M + NH₄)⁺.

(3-F lu or op h en yl)(6-(4-m et h ylt h iop h en yl)(2H -b en zo-

[d ]1,3-d ioxola n -5-yl))m eth a n -1-ol (19c): white solid; mp

97-99 °C; ¹H NMR (CDCl₃) δ 7.28-7.18 (m, 5H), 6.92 (m, 3H),

6.87 (s, 1H), 6.70 (s, 1H), 5.96 (d, J ) 1.8 Hz, 2H), 5.79 (d, J

) 3.6 Hz, 1H), 2.51 (s, 3H), 2.18 (d, J ) 3.8 Hz, 1H, OH); ¹³C

NMR (CDCl₃) δ 164.4, 161.1, 147.4 (d, J ) 34 Hz), 146.6 (d, J

) 6.6 Hz), 137.7, 137.2, 134.7, 134.4, 129.8 (2 × C), 126.9 (d,

J ) 8.2 Hz), 126.3 (2 × C), 121.9, 114.0 (d, J ) 21 Hz), 113.3

(d, J ) 22 Hz), 109.8, 107.4, 101.3, 71.5, 15.7; LRMS (APIMS)

m/z 386 (M + NH₄)⁺, 754 (2M + NH₄)⁺.

6.4 Hz, 2H), 7.46 (d, J ) 6.5 Hz, 2H), 7.4-7.1 (m, 3H), 6.85 (s,

1H), 6.80 (m, 1H), 6.61 (s, 1H), 5.99 (s, 2H), 5.91 (d, J ) 3.8

Hz, 1H), 3.07 (s, 3H), 2.44 (d, J ) 4.1 Hz, 1H, OH); LRMS

(APIMS) m/z 418 (M + NH₄)⁺. Anal. (C₂₁H₁₇SFO₅) C, H.

1-(6-((3-F lu or op h en yl)h yd r oxym et h yl)(2H-b en zo[3,4-

d ]1,3-d ioxola n -5-yl))-4-(m et h ylsu lfon yl)b en zen e (20c):

1

white solid; mp 163-169 °C; H NMR (CDCl₃) δ 7.92 (d, J )

8.4 Hz, 2H), 7.47 (d, J ) 8.4 Hz, 2H), 7.4 (m, 1H), 6.93 (s, 1H),

6.88 (m, 3H), 6.67 (s, 1H), 5.99 (d, J ) 1.8 Hz, 2H), 5.68 (d, J

) 3.2 Hz, 1H), 3.08 (s, 3H), 2.50 (d, J ) 3.8 Hz, 1H, OH); ¹³C

NMR (CDCl₃) δ 164.4, 161.1, 148.2, 147.2, 146.4, 139.4, 134.5,

133.2, 130.5 (2 × C), 129.9 (d, J ) 8 Hz), 127.3 (2 × C), 121.9,

114.2 (d, J ) 21 Hz), 113.3 (d, J ) 22 Hz), 109.5, 107.8, 101.6,

71.5, 44.5; LRMS (APIMS) m/z 418 (M + NH₄)⁺.

1-(6-((4-F lu or op h en yl)h yd r oxym et h yl)(2H-b en zo[3,4-

d ]1,3-d ioxola n -5-yl))-4-(m et h ylsu lfon yl)b en zen e (20d ):

white solid; mp 85-95 °C; ¹H NMR (CDCl₃) δ 7.90 (d, J ) 8.2

Hz, 2H), 7.37 (d, J ) 8.2 Hz, 2H), 6.89 (d, J ) 7.1 Hz, 4H),

6.69 (s, 1H), 6.68 (s, 1H), 5.98 (s, 2H), 3.77 (s, 2H), 3.07 (s,

3H); ¹³C NMR (CDCl₃) δ 162.8, 159.6, 147.7, 147.1, 146.8,

139.0, 136.5, 133.3, 131.5 (2 × C), 130.3, 129.8 (2 × C), 129.7,

127.2, 115.0, 110.4, 109.7, 101.3, 44.5, 37.9; LRMS (APIMS)

m/z 418 (M + NH₄)⁺.

4-(6-(Hyd r oxy(3-m eth ylp h en yl)m eth yl)(2H-ben zo[3,4-

d ]1,3-d ioxola n -5-yl))-1-(m et h ylsu lfon yl)b en zen e (20e):

1

white solid; mp 154 °C; H NMR (CDCl₃) δ 7.93, (d, J ) 8.5

Hz, 2H), 7.46 (d, J ) 8.4 Hz, 2H), 7.16 (t, J ) 7.6 Hz, 1H),

7.05-7.04 (m, 2H), 6.95-6.90 (m, 2H), 6.68 (s, 1H), 6.01-6.00

(m, 2H), 5.68 (d, J ) 3.5 Hz, 1H), 3.09 (s, 3H), 2.29 (s, 3H),

2.04 (s, 1H); ¹³C NMR (CDCl₃) δ 148.0, 147.0, 146.6, 143.4,

5498 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

139.2, 138.1, 135.0, 133.0, 130.6, 128.3, 128.3, 127.2, 127.0,

123.4, 109.4, 107.8, 101.5, 72.2, 44.5, 21.4; LRMS (APIMS) m/z

414 (M + NH₄)⁺, 379 (M - OH)⁺.

120.9, 114.7, 111.0, 110.6, 109.7, 101.3, 55.1, 44.5, 38.7; LRMS

(APIMS) m/z 810 (2M + NH₄

SO₅) C, H.

)⁺, 397 (M + H)⁺. Anal. (C₂₂H₂₀

-

4-{6-[(2-F lu or o-5-m eth ylp h en yl)m eth yl](2H-ben zo[3,4-

d ]1,3-d ioxola n -5-yl)}-1-(m et h ylsu lfon yl)b en zen e (21g):

1-(6-(H yd r oxy(3-m et h oxyp h en yl)m et h yl)(2H -b en zo-

[3,4-d ]1,3-d ioxola n -5yl))-4-(m eth ylsu lfon yl)ben zen e (20f):

white solid (1.00 g, 93% yield); mp 154 °C; ¹H NMR (CDCl₃) δ

7.92 (d, J ) 8.1 Hz, 2H), 7.47 (d, J ) 8.0 Hz, 2H), 7.23-7.1

(m, 1H), 7.01 (s, 1H), 6.77-6.67 (m, 4H), 5.99 (d, J ) 2.6 Hz,

1

white solid; mp 98-100 °C; H NMR (CDCl₃) δ 7.93 (d, J )

8.2 Hz, 2H), 7.43 (d, J ) 8.2 Hz, 2H), 7.00-6.90 (m, 1H), 6.82

(t, J ) 9.1 Hz, 1H), 6.69 (s, 2H), 6.64 (d, J ) 7.2 Hz, 1H), 5.99

(s, 2H), 3.98 (s, 2H), 3.09 (s, 3H), 2.21 (s, 3H); ¹³C NMR (CDCl₃)

δ 157.3, 147.8, 147.3, 146.2, 139.0, 133.4, 131.0, 130.7, 130.4,

128.4, 127.2, 115.0, 114.7, 110.2, 109.7, 101.3, 44.6, 31.9, 20.7;

LRMS (APIMS) m/z 416 (M + NH₄)⁺.

2H), 5.67 (s, 1H), 3.75 (s, 3H), 3.08 (s, 3H), 2.32 (br s, 1H); ¹³

C

NMR (CDCl₃) δ 159.6, 148.0, 147.0, 146.5, 145.2, 139.2, 134.8,

133.0, 130.6, 129.4, 127.2, 118.7, 112.5, 112.3, 109.4, 107.7,

101.5, 72.0, 55.2, 44.5; LRMS (APIMS) m/z 430 (M + NH₄)⁺.

4-(1-(3′,5′-Diflu or op h en yl)-1-h yd r oxym eth yl)-1,2-m eth -

ylen ed ioxy-5-(4-m eth ylth iop h en yl)ben zen e. (3,5-Diflu o-

r op h en yl)(6-(4-m eth ylth iop h en yl)(2H-ben zo[d ]1,3-d iox-

ola n -5-yl))m eth a n -1-ol (19h ). The resulting product was

used for the next reaction without further purification.

4-(1-(3′,5′-Diflu or op h en yl)-1-h yd r oxym eth yl)-1,2-m eth -

ylen edioxy-5-(4-m eth ylsu lfon ylph en yl)ben zen e (20h ). The

product was used without purification.

5-(1-(3′,5′-Diflu or op h en yl)m eth yl)-1,2-m eth ylen ed ioxy-

4-(4-m eth ylsu lfon ylp h en yl)ben zen e (21h ). Compound 21h

was prepared by method F to give a light brown solid in 63%

overall yield for three steps from 19h ): mp 140-141°C; ¹H

NMR (CDCl₃) δ 7.91 (m, 2H), 7.36 (m, 2H), 6.71 (s, 1H), 6.70

(s, 1H), 6.59 (m, 1H), 6.42 (m, 2H), 6.02 (s, 2H), 3.80 (s, 2H),

3.09 (s, 3H); LRMS (APIMS) m/z 420 (M + NH₄)⁺.

4-(6-((2-F lu or o-5-m et h ylp h en yl)h yd r oxym et h yl)(2H -

b en zo[3,4-d ]1,3-d ioxola n -5-yl))-1-(m et h ylsu lfon yl)b en -

1

zen e (20g): white solid; mp 169-171 °C; H NMR (CDCl₃) δ

7.92 (d, J ) 8.4 Hz, 2H), 7.49 (d, J ) 8.4 Hz, 2H), 7.26-7.22

(m, 1H), 7.00-6.98 (m, 1H), 6.94 (s, 1H), 6.80-6.74 (m, 1H),

6.67 (s, 1H), 6.00-5.99 (m, 2H), 5.88 (s, 1H), 3.10 (s, 3H), 2.31

(s, 3H), 2.25 (s, 1H); ¹³C NMR (CDCl₃) δ 147.9, 147.1, 146.4,

139.2, 133.7, 133.3, 130.5, 130.1, 129.6, 129.5, 127.7, 127.2,

115.0, 114.8, 109.6, 107.7, 101.5, 66.8, 44.5, 20.8; LRMS

(APIMS) m/z 846 (2M + NH₄)⁺, 432 (M + NH₄)⁺.

4-(Met h ylsu lfon yl)-1-(6-b en zyl(2H -b en zo[3,4-d ]1,3-d i-

oxola n -5-yl))ben zen e (21a ): white solid; mp 111-114 °C; ¹H

NMR (CDCl₃) δ 8.1 (d, J ) 8.4 Hz, 2H), 7.90 (d, J ) 8.4 Hz,

2H), 7.40 (d, J ) 8.3 Hz, 2H), 7.25-7.10 (m, 3H), 6.94 (d, J )

7.0 Hz, 2H), 6.71 (s, 1H), 6.70 (s, 1H), 5.99 (s, 2H), 3.81 (s,

2H), 3.08 (s, 3H); ¹³C NMR (CDCl₃) δ 147.8, 147.3, 146.2, 140.9,

138.9, 133.8, 133.4, 131.7, 130.4, 130.2, 128.52, 128.48, 127.2,

126.1, 110.6, 109.7, 101.3, 44.6, 38.8; LRMS (APIMS) m/z 384

(M + H)⁺. Anal. (C₂₁H₁₈SO₄) C, H.

4-{6-[(3-Ch lor op h en yl)m eth yl](2H-ben zo[3,4-d ]1,3-d i-

oxola n -5-yl)}-1-(m eth ylsu lfon yl)ben zen e (21i): white solid;

1

mp 112-113 °C; H NMR (CDCl₃) δ 7.91 (d, J ) 8.4 Hz, 2H),

7.37 (d, J ) 8.3 Hz, 2H), 7.13-7.12 (m, 2H), 6.87 (s, 1H), 6.82-

6.80 (m, 1H), 6.70 (s, 2H), 6.00 (s, 2H), 3.79 (s, 2H), 3.09 (s,

3H); ¹³C NMR (CDCl₃) δ 147.8, 147.1, 146.4, 142.9, 139.1,

134.1, 133.6, 130.8, 130.3, 129.6, 128.5, 127.2, 126.7, 126.3,

110.5, 109.8, 101.4, 44.5, 38.5; LRMS (APIMS) m/z 418 (M +

NH₄)⁺. Anal. (C₂₁H₁₇ClO₄) C, H.

1-(6-((2-F lu or op h en yl)m et h yl)(2H -b en zo[3,4-d ]1,3-d i-

oxolan -5-yl))-4-(m eth ylsu lfon yl)ben zen e (21b): white solid;

mp 98-99 °C; ¹H NMR (CDCl₃) δ 7.92 (d, J ) 6.8 Hz, 2H),

7.42 (d, J ) 7.6 Hz, 2H), 7.20 (m, 1H), 7.05-6.80 (m, 3H), 6.69

(s, 1H), 6.68 (s, 1H), 5.97 (s, 2H), 3.81 (s, 2H), 3.08 (s, 3H); ¹³

C

4-{6-[(4-Meth ylp h en yl)m eth yl](2H-ben zo[3,4-d ]1,3-d i-

oxola n -5-yl)}-1-(m eth ylsu lfon yl)ben zen e (21j): white solid;

NMR (CDCl₃) δ 162.3, 159.05, 147.7, 147.2, 146.2, 139.0, 133.4,

130.5, 130.3 (2 × C), 127.9, 127.2 (2 × C), 115.3, 115.0, 110.2,

109.7, 101.3, 44.55, 31.8; LRMS (APIMS) m/z 402 (M + NH₄)⁺.

Anal. (C₂₁H₁₇FSO₄) C, H.

1

mp 153-154 °C; H NMR (CDCl₃) δ 7.93 (d, J ) 7.3 Hz, 2H),

7.43 (d, J ) 7.4 Hz, 2H), 7.05 (d, J ) 6.9 Hz, 2H), 6.86 (d, J )

7.0 Hz, 2H), 6.72 (s, 2H), 5.99 (s, 2H), 3.79 (s, 2H), 3.10 (s,

3H), 2.31 (s, 3H); ¹³C NMR (CDCl₃) δ 147.7, 147.3, 146.1, 138.9,

137.8, 135.5, 133.3, 132.0, 130.4, 129.1, 128.3, 127.1, 110.5,

109.6, 101.2, 44.5, 38.3, 20.9; LRMS (APIMS) m/z 398 (M +

NH₄)⁺. Anal. (C₂₂H₂₀SO₆) C, H.

1-(6-((3-F lu or op h en yl)m et h yl)(2H -b en zo[3,4-d ]1,3-d i-

oxola n -5-yl))-4-(m eth ylsu lfon yl)ben zen e (21c): white solid;

1

mp 110-111 °C; H NMR (CDCl₃) δ 7.89 (d, J ) 8.4 Hz, 2H),

7.37 (d, J ) 8.3 Hz, 2H), 7.15 (m, 1H), 6.83 (dt, J ) 5.2 and

2.3 Hz, 1H), 6.70 (m, 3H), 6.60 (d, J ) 9.9 Hz, 1H), 5.99 (s,

2H), 3.81 (s, 2H), 3.08 (s, 3H); ¹³C NMR (CDCl₃) δ 164.5, 161.2,

147.9, 146.4, 143.5, 139.1, 133.6, 130.9, 130.4 (2 × C), 129.9

(d, J ) 8.2 Hz), 127.2 (2 × C), 124.2, 115.3 (d, J ) 21.5 Hz),

113.9 (d, J ) 21 Hz), 110.6, 109.8, 101.4, 44.5, 38.6; LRMS

(APIMS) m/z 402 (M + NH₄)⁺. Anal. (C₂₁H₁₇SFO₄) C, H.

6-(4-(Meth ylsu lfon yl)ph en yl)(2H-ben zo[d]1,3-d ioxola n -

1

5-yl) p h en yl k eton e (22a ): white solid; mp 180-184 °C; H

NMR (CDCl₃) δ 7.72 (d, J ) 8.0 Hz, 2H), 7.61 (d, J ) 7.5 Hz,

2H), 7.41 (m, 3H), 7.27 (m, 2H), 7.03 (s, 1H), 6.89 (s, 1H), 6.10

(s, 2H), 2.93 (s, 3H); ¹³C NMR (CDCl₃) δ 196.8, 149.4, 147.5,

145.9, 139.0, 137.5, 134.9, 132.9, 132.8, 129.9, 129.8, 128.2,

127.2, 110.1, 109.8, 102.1, 44.4; LRMS (APIMS) m/z 381 (M +

H)⁺. Anal. (C₂₁H₁₆SO₅) C, H.

1-(6-((4-F lu or op h en yl)m et h yl)(2H -b en zo[3,4-d ]1,3-d i-

oxolan -5-yl))-4-(m eth ylsu lfon yl)ben zen e (21d): white solid;

2-F lu or op h en yl 6-(4-(m eth ylsu lfon yl)p h en yl)(2H-ben -

zo[d ]1,3-d ioxola n -5-yl) k eton e (22b): white solid; mp 212-

215 °C; ¹H NMR (CDCl₃) δ 7.74 (d, J ) 6.4 Hz, 2H), 7.42-7.3

(m, 4H), 7.13 (s, 1H), 7.02 (t, J ) 7.6 Hz, 1H), 6.86 (d, J ) 9.3

Hz, 1H), 6.82 (s, 1H), 6.11 (s, 2H), 2.95 (s, 3H); LRMS (APIMS)

m/z 399 (M + H)⁺. Anal. (C₂₁H₁₅FSO₅) C, H.

1

mp 130-132 °C; H NMR (CDCl₃) δ 7.9 (d, J ) 8.4 Hz, 2H),

7.3 (d, J ) 8.4 Hz, 2H), 6.9 (d, J ) 8.3 Hz, 4H), 6.9 (s, 1H), 6.8

(s, 1H), 5.97 (s, 2H), 3.80 (s, 2H), 3.1 (s, 3H); LRMS (APIMS)

m/z 402 (M + NH₄)⁺. Anal. (C₂₁H₁₇SFO₄) C, H.

4-{6-[(3-Meth ylp h en yl)m eth yl](2H-ben zo[3,4-d ]1,3-d i-

oxolan -5-yl)}-1-(m eth ylsu lfon yl)ben zen e (21e): white solid;

mp 84-86 °C; ¹H NMR (CDCl₃) δ 7.91 (d, J ) 8.3 Hz, 2H),

7.42 (d, J ) 8.3 Hz, 2H), 7.11 (t, J ) 7.8 Hz, 1H), 6.98 (d, J )

7.6 Hz, 1H), 6.76-6.71 (m, 4H), 5.99 (s, 2H), 3.78 (s, 2H), 3.09

(s, 3H), 2.27 (s, 3H); ¹³C NMR (CDCl₃) δ 147.7, 147.4, 146.1,

140.8, 138.9, 138.0, 133.4, 131.9, 130.4, 129.3, 128.3, 127.2,

126.8, 125.6, 110.6, 109.6, 101.3, 44.5, 38.7, 21.4; LRMS

(APIMS) m/z 398 (M + NH₄)⁺. Anal. (C₂₂H₂₀SO₄) C, H.

3-F lu or op h en yl 6-(4-(m eth ylsu lfon yl)p h en yl)(2H-ben -

zo[d ]1,3-d ioxola n -5-yl) k eton e (22c): white solid; mp 205-

209 °C; ¹H NMR (CDCl₃) δ 7.75 (d, J ) 8.3 Hz, 2H), 7.38-

7.30 (m, 5H), 7.24 (t, J ) 5.2 Hz, 1H), 7.04 (s, 1H), 6.89 (s,

1H), 6.12 (s, 2H), 2.95 (s, 3H); ¹³C NMR (CDCl₃) δ 195.5, 163.9,

160.7, 150.0, 147.7, 145.7, 139.7, 139.2, 135.1, 132.2, 130.0,

129.9 (2 × C), 127.3 (2 × C), 125.6, 119.9 (d, J ) 21 Hz), 116.4

(d, J ) 22 Hz), 110.0 (d, J ) 35 Hz), 102.3, 44.4; LRMS

4-(6-(3-Meth oxyp h en yl)m eth yl)(2H-ben zo[3,4-d ]1,3-d i-

oxola n -5-yl))-1-(m eth ylsu lfon yl)ben zen e (21f): white solid;

(APIMS) m/ z 399 (M + H)⁺, 416 (M + NH₄)⁺. Anal. (C₂₁H₁₅

-

SFO₅) C, H.

4-F lu or op h en yl 6-(4-(m eth ylsu lfon yl)p h en yl)(2H-ben -

zo[d ]1,3-d ioxola n -5-yl) k eton e (22d ): white solid; mp 189-

190 °C; ¹H NMR (CDCl₃) δ 7.73 (d, J ) 8.4 Hz, 2H), 7.63 (dd,

J ) 8.8 and 5.3 Hz, 2H), 7.36 (d, J ) 8.4 Hz, 2H), 7.0 (m, 4H),

6.1 (s, 2H), 2.94 (s, 3H); ¹³C NMR (CDCl₃) δ 195.5, 167.1, 163.8,

1

mp 125-126 °C; H NMR (CDCl₃) δ 7.90 (d, J ) 8.4 Hz, 2H),

7.41 (d, J ) 8.4 Hz, 2H), 7.14 (t, J ) 7.9 Hz, 1H), 6.73-6.70

(m, 3H), 6.56-6.53 (m, 1H), 6.47 (s, 1H), 5.98 (s, 2H), 3.79 (s,

2H), 3.73 (s, 3H), 3.08 (s, 3H); ¹³C NMR (CDCl₃) δ 159.6, 147.7,

147.3, 146.2, 142.6, 138.9, 133.4, 131.5, 130.4, 129.3, 127.2,

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5499

149.8, 147.6, 145.7, 139.7, 139.1, 134.7, 133.8, 132.5 (2 × C),

129.9 (2 × C), 127.3, 115.5, 115.2, 110.2, 109.6, 102.2, 44.4;

LRMS (APIMS) m/z 399 (M + H)⁺, 416 (M + NH₄)⁺. Anal.

(C₂₁H₁₅SFO₅) C, H.

NMR (CDCl₃) δ 8.23 (d, J ) 4.3, Hz, 1H), 8.17 (s, 1H), 7.51 (d,

J ) 7.8 Hz, 1H), 7.18 (d, J ) 8.1 Hz, 2H), 7.13 (m, 1H), 7.08

(d, J ) 8.1 Hz, 2H), 6.89 (s, 1H), 6.64 (s, 1H), 5.81 (d, J ) 3.0

Hz, 2H), 5.80 (s, 1H), 4.5 (br s, 1H, OH), 2.45 (s, 3H); ¹³C NMR

(CDCl₃) δ 147.8, 147.7, 147.4, 146.8, 140.0, 137.6, 137.1, 134.5,

134.4, 134.2, 129.7, 126.2, 123.1, 109.8, 107.3, 101.2, 60.3, 15.6;

LRMS (APIMS) m/z 352 (M + H)⁺.

3-Meth ylp h en yl 6-(4-(m eth ylsu lfon yl)p h en yl)(2H-ben -

zo[d ]1,3-d ioxola n -5-yl)k eton e (22e): white solid; mp 168-

170 °C; ¹H NMR (CDCl₃) δ 7.75 (d, J ) 8.3 Hz, 2H), 7.44-

7.37 (m, 4H), 7.26-7.18 (m, 2H), 7.18 (s, 1H), 7.04 (s, 1H), 6.12

(s, 2H), 3.00 (s, 3H), 2.36 (s, 3H); ¹³C NMR (CDCl₃) δ 196.9,

149.7, 147.5, 146.0, 139.0, 138.6, 137.5, 134.9, 133.8, 133.0,

130.3, 129.9, 128.2, 127.3, 127.2, 110.2, 109.8, 102.1, 44.4, 21.2;

LRMS (APIMS) m/z 412 (M + NH₄)⁺, 395 (M + H)⁺.

3-Met h oxyp h en yl 6-(4-(m et h ylsu lfon yl)p h en yl)(2H -

ben zo[d ]1,3-d ioxola n -5-yl) k eton e (22f): white solid; mp

158 °C; ¹H NMR (CDCl₃) δ 7.75 (d, J ) 8.3 Hz, 2H), 7.39 (d, J

) 8.3 Hz, 2H), 7.20-7.16 (m, 3H), 7.03 (s, 1H), 7.00-6.96 (m,

1H), 6.90 (s, 1H), 6.11 (s, 2H), 3.77 (s, 3H). 2.96 (s, 3H); ¹³C

NMR (CDCl₃) δ 196.5, 159.4, 149.7, 147.4, 145.9, 139.0, 138.8,

134.9, 132.8, 129.9, 129.2, 127.2, 122.8, 119.3, 114.0, 110.1,

109.7, 102.1, 55.4, 44.4; LRMS (APIMS) m/z 411 (M + H)⁺.

Anal. (C₂₂H₁₈SO₆) C, H.

1-(6-(Hyd r oxy-3-p yr id ylm eth yl)(2H-ben zo[3,4-d ]1,3-d i-

oxola n -5-yl))-4-(m eth ylsu lfon yl)ben zen e (26). The product

of the above example, 25 (501 mg, 1.45 mmol), was dissolved

in MeOH (35 mL). To this solution was added Oxone (1.9 g,

2.9 mmol) in water (12 mL) dropwise. The reaction mixture

was stirred at room temperature for 2 h and diluted with

water, and ammonium hydroxide was added until the solution

was basic. The solvent was evaporated under reduced pressure.

The resulting product was extracted with ethyl acetate (3 ×

50 mL), washed with brine (1 × 50 mL), dried over anhydrous

sodium sulfate, and filtered. The filtrate was evaporated under

reduced pressure to give the title compound 26 that was used

without further purification (550 mg, 99% yield): mp 165-

1

185 °C; H NMR (CDCl₃) δ 8.32 (br s, 1H), 8.19 (s, 1H), 7.88

(d, J ) 8.0 Hz, 2H), 7.50 (d, J ) 7.7 Hz, 1H), 7.41 (d, J ) 8.0

Hz, 2H), 7.18 (m, 1H), 6.91 (s, 1H), 6.65 (s, 1H), 5.99 (d, J )

2-Flu or o-5-m eth ylp h en yl6-[4-(m eth ylsu lfon yl)p h en yl]-

(2H-ben zo[d ]1,3-d ioxola n -5-yl) k eton e (22g): white solid;

mp 153-154 °C; ¹H NMR (CDCl₃) δ 7.77 (s, 1H), 7.74 (s, 1H),

7.40 (s, 1H), 7.38 (s, 1H), 7.20-7.17 (m, 1H), 7.15-7.10 (m,

2H), 6.83 (s, 1H), 6.78-6.72 (m, 1H), 6.12 (s, 2H), 2.97 (s, 3H),

2.24 (s, 3H); ¹³C NMR (CDCl₃) δ 193.4, 150.2, 147.7, 146.0,

139.1, 135.6, 134.5, 134.4, 133.8, 133.7, 131.2, 130.1, 127.0,

116.04, 115.8, 110.2, 109.8, 102.2, 44.4, 20.3; LRMS (APIMS)

m/z 842.4 (2M + NH₄), 413 (M + H)⁺. Anal. (C₂₁H₁₅ClO₅S)

C, H.

4-(1-(3′,5′-Diflu or oph en yl)-1-oxom eth yl)-1,2-m eth ylen e-

d ioxy-5-(4-m eth ylsu lfon ylp h en yl)ben zen e (22h ). The com-

pound 22h was prepared from 20h by method G as a white

crystalline solid in 43.2% yield overall for three steps: ¹H NMR

(CDCl₃) δ 7.80 (m, 2H), 7.37 (m, 2H), 7.10 (m, 2H), 7.05 (s,

1H), 6.91 (s, 1H), 6.87 (m, 1H), 6.14 (s, 2H), 2.98 (s, 3H); LRMS

(APIMS) m/z 434 (M + NH₄)⁺. Anal. (C₂₁H₁₄SF₂O₅) C, H.

3-Ch lor op h en yl 6-[4-(m eth ylsu lfon yl)p h en yl](2H-ben -

zo[d ]1,3-d ioxola n -5-yl) k eton e (22i): white solid; mp 182-

183 °C; ¹H NMR (CDCl₃) δ 7.76 (d, J ) 7.7 Hz, 2H), 7.52-

7.48 (m, 2H), 7.36 (d, J ) 7.5 Hz, 3H), 7.28-7.20 (m, 1H), 7.06

(s, 1H), 6.91 (s, 1H), 6.13 (s, 2H), 2.96 (s, 3H); ¹³C NMR (CDCl₃)

δ 195.3, 150.1, 147.7, 145.6, 139.2, 135.2, 134.3, 132.6, 132.0,

129.9 (2 × C), 129.7, 129.5, 127.7, 127.2 (2 × C), 110.1, 109.8,

102.2, 44.3; LRMS (APIMS) m/z 846 (2M + NH₄)⁺, 415 (M +

H)⁺. Anal. (C₂₁H₁₅ClO₅S) C, H.

3.0 Hz, 2H), 5.71 (s, 1H), 3.95 (br s, 1H, OH), 3.07 (s, 3H); ¹³

C

NMR (CDCl₃) δ 148.3, 148.2, 147.8, 147.3, 146.3, 139.5, 134.3,

134.1, 133.0, 130.5 (2 × C), 127.4 (2 × C), 123.3, 109.5, 107.8,

101.6, 69.9, 44.5; LRMS (APIMS) m/z 384 (M + H)⁺.

4-(Met h ylsu lfon yl)-1-(6-(3-p yr id ylm et h yl)(2H -b en zo-

[3,4-d ]1,3-d ioxola n -5-yl))ben zen e (27). The hydroxyl com-

pound 26 (540 mg, 1.41 mmol) was dissolved in anhydrous

dichloromethane (5 mL), and under nitrogen atmosphere

trifluoroacetic acid (10 mL) was added followed by triethyl-

silane (5 mL). The reaction mixture was stirred at room

temperature overnight. The solvent and trifluoroacetic acid

were evaporated under reduced pressure, and the residue was

extracted with dichloromethane. The combined organic ex-

tracts were washed with water and brine, dried over sodium

sulfate, and filtered. The filtrate was evaporated under

reduced pressure to give the crude product that was purified

by silica gel column chromatography using 5% methanol in

dichloromethane as the eluant to give the title compound as a

white solid 27 (255 mg, 41% yield): mp 121-137 °C; ¹H NMR

(CDCl₃) δ 8.38 (d, J ) 4.0 Hz, 1H), 8.17 (s, 1H), 7.90 (d, J )

8.2 Hz, 2H), 7.37 (d, J ) 8.2 Hz, 2H), 7.21 (d, J ) 7.9 Hz, 1H),

7.12 (dd, J ) 7.8 and 4.5 Hz, 1H), 6.7 (s, 1H), 6.68 (s, 1H),

5.99 (s, 2H), 3.81 (s, 2H), 3.08 (s, 3H); LRMS (APIMS) m/z

368 (M + H)⁺. Anal. (C₂₀H₁₇SNO₄) C, H.

6-(4-(Meth ylsu lfon yl)ph en yl)(2H-ben zo[d]1,3-d ioxola n -

5-yl) 3-P yr id yl Keton e (28). A suspension of the hydroxyl

compound 26 (80 mg, 0.209 mmol) and alumina (1 g) in

anhydrous CH₂Cl₂(10 mL) was stirred at room temperature.

To this mixture was added pyridinium chlorochromate (48 mg,

0.21 mmol), and the mixture was stirred at room temperature

for 15 min. The reaction mixture was diluted with CH₂Cl₂, and

the alumina was removed by filtration. The filtrate was

washed with water (3 × 25 mL), saturated aqueous sodium

bicarbonate (2 × 25 mL), and brine (1 × 25 mL) and then dried

over anhydrous sodium sulfate and filtered. The filtrate was

evaporated under reduced pressure. Purification by flash

column chromatography using ethyl acetate as the eluant gave

the title compound 28 as a white solid (110 mg, 96.5% yield):

mp 186-190 °C; ¹H NMR (CDCl₃) δ 8.70 (br s, 1H), 8.59 (br s,

1H), 7.91 (d, J ) 7.5 Hz, 1H), 7.75 (d, J ) 8.0 Hz, 2H), 7.40 (d,

J ) 8.0 Hz, 2H), 7.25 (br s, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.14

(s, 2H), 2.94 (s, 3H); LRMS (APIMS) m/z 382 (M + H)⁺.

4-Meth yl-3-p yr id yl 6-[4-(m eth ylsu lfon yl)p h en yl](2H-

ben zo[d ]1,3-d ioxola n -5-yl) k eton e (31): white solid; mp

192-194 °C; ¹H NMR (CDCl₃) δ 8.23 (d, J ) 3.9 Hz, 1H), 7.70

(d, J ) 7.9 Hz, 2H), 7.35 (d, J ) 7.8 Hz, 2H), 7.16 (s, 1H), 7.07

(m, 1H), 6.78 (s, 1H), 6.08 (s, 2H), 2.95 (s, 3H). 2.37 (s, 3H);

¹³C NMR (CDCl₃) δ 196.6, 154.0, 150.3, 147.8, 146.7, 145.8,

138.9, 136.3, 134.2, 133.3, 129.7 (2 × C), 128.2, 126.7 (2 × C),

125.1, 110.4, 110.0, 102.2, 44.4, 19.0; LRMS (APIMS) m/z 396

(M + H)⁺. Anal. (C₂₁H₁₇SNO₅) C, H.

4-Meth ylp h en yl 6-[4-(m eth ylsu lfon yl)p h en yl](2H-ben -

zo[d ]1,3-d ioxola n -5-yl) k eton e (22j): white solid; mp 150-

151 °C; ¹H NMR (CDCl₃) δ 7.75 (d, J ) 8.0 Hz, 2H), 7.55 (d, J

) 7.7 Hz, 2H), 7.40 (d, J ) 7.9 Hz, 2H), 7.10 (d, J ) 7.6 Hz,

2H), 6.90 (s, 1H), 6.82 (s, 1H), 6.10 (s, 2H), 2.96 (s, 3H), 2.33

(s, 3H); ¹³C NMR (CDCl₃) δ 196.4, 149.5, 147.4, 145.9, 144.0,

138.8, 134.8, 134.5, 133.1, 130.0, 129.8, 128.9, 127.2, 110.1,

109.6, 102.0, 44.4, 21.5; LRMS (APIMS) m/z 412 (M + NH₄),

395 (M + H)⁺. Anal. (C₂₂H₁₈O₅S) C, H.

(6-(4-Met h ylt h iop h en yl)(2H -b en zo[d ]1,3-d ioxola n -5-

yl))-3-p yr id ylm eth a n -1-ol (25). To a -78 °C precooled solu-

tion of 3-bromopyridine 23 (632 mg, 4 mmol) in anhydrous

THF (20 mL) was added t-BuLi (1.7 M, 4.64 mL, 8 mmol). The

resulting dark blue solution of 3-lithiopyridine 24 was stirred

at -78 °C for 10 min, and then carbaldehyde 4 (820 mg, 3

mmol) in THF (15 mL) was added dropwise. The reaction

mixture was then stirred at -78 °C for 30 min, slowly allowed

to warm to room temperature, and stirred for an additional

30 min at room temperature. The reaction was quenched with

saturated aqueous ammoniun chloride solution, and the THF

layer was separated. The aqueous layer was extracted with

ethyl acetate. The combined organic layers were dried over

sodium sulfate and filtered, and the filtrate was evaporated

under reduced pressure to give the crude product. Purification

by silica gel flash column chromatography using ethyl acetate/

hexane (1:1) and then ethyl acetate as the eluants gave the

1

title compound 25 (320 mg, 23% yield): mp 130-135 °C; H

5500 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

4-Br om o-3-p yr id yl 6-[4-(m et h ylsu lfon yl)p h en yl](2H -

ben zo[d ]1,3-d ioxola n -5-yl) k eton e (35): white solid; mp

180-190 °C; ¹H NMR (CDCl₃) δ 8.10 (m, 2H), 7.76 (d, J ) 7.8

Hz, 2H), 7.36 (d, J ) 7.8 Hz, 2H), 7.3-7.2 (m, 1H), 7.2 (s, 1H),

6.81 (s, 1H), 6.15 (s, 2H), 3.10 (s, 3H); LRMS (APIMS) m/z

460 (M + H)⁺, 462 (M + 2 + H)⁺. Anal. (C₂₀H₁₄BrSNO₅) C, H.

4-(Met h ylsu lfon yl)-1-[6-(p ip er id ylm et h yl)(2H -b en zo-

[3,4-d ]1,3-d ioxola n -5-yl)]ben zen e (38a ). Compound 38a was

prepared by alkylation of piperidine 37a with chloromethyl

compound 16 using method H. Pure product 38a was obtained

as white solid in 69% yield: mp 138-141 °C; ¹H NMR (CDCl₃)

δ 7.93 (d, J ) 8.3 Hz, 2H), 7.58 (d, J ) 8.4 Hz, 2H), 7.25 (s,

1H), 7.03 (s, 1H), 5.98 (s, 2H), 3.17 (s, 2H). 3.10 (s, 3H), 2.23

(m, 4H), 1.47 (m, 6H); ¹³C NMR (CDCl₃) δ 147.4, 147.3, 146.4,

138.7, 133.9, 130.6, 130.5, 130.5, 126.8, 110.3, 109.6, 101.2,

60.4, 54.0, 45.5, 26.0, 24.3; LRMS (APIMS) m/z 374 (M + H)⁺.

Anal. (C₂₀H₂₃SNO₄) C, H.

in anhydrous DMF (5 mL). Potassium carbonate (830 mg, 6

mmol) was added, and reaction mixture was stirred at room

temperature overnight. The reaction mixture was then treated

with ice-cold water and extracted with ethyl acetate (2 × 75

mL). The combined organic extracts were washed with water

(1 × 50 mL) and brine (1 × 50 mL), dried over sodium sulfate,

and filtered. The filtrate was evaporated under reduced

pressure to give the crude product that was purified by flash

column chromatography using methanol:dichloromethane (5:

95) as an eluent to give the title compound 38f as a white solid

(410 mg, 80% yield): mp 127-137 °C; ¹H NMR (CDCl₃) δ 7.92

(d, J ) 6.4 Hz, 2H), 7.56 (d, J ) 6.4 Hz, 2H), 7.26 (s, 1H), 6.67

(s, 1H), 5.98 (s, 2H), 3.45 (m, 2H), 3.21 (s, 2H). 3.10 (s, 3H),

2.63 (m, 1H), 2.42 (m, 1H), 1.90-1.07 (m, 8H); ¹³C NMR

(CDCl₃) δ 147.5, 147.4, 146.6, 138.8, 134.0, 130.5, 130.2, (2 ×

C), 127.0 (2 × C), 110.2, 109.7, 101.3, 66.7, 60.4, 56.9, 53.8,

44.6, 38.2, 27.3, 24.6; LRMS (APIMS) m/z 404 (M + H)⁺. Anal.

(C₂₁H₂₅SNO₅) C, H.

(6-(4-Meth ylth ioph en yl)-2H-ben zo[d]1,3-dioxolan -5-yl)-

m eth yla m in e (39). To a stirred mixture of carbaldehyde 4

(2.72 g, 10 mmol), 4 A molecular sieves (6 g), and NH₄OAc

(11.6 g, 150 mmol) in MeOH (80 mL) was added sodium

cyanoborohydride (0.95 g, 15 mmol). The reaction mixture was

stirred at room temperature for 4 days and filtered, and the

filtrate was evaporated under reduced pressure. The resulting

residue was dissolved in EtOAc (200 mL), washed with 2 M

aqueous sodium carbonate, dried over sodium sulfate, and

filtered. The filtrate was evaporated under reduced pressure.

The crude product obtained was purified by flash chromatog-

raphy using MeOH:CH₂Cl₂(1:9) with a trace amount of NH₄-

OH as the eluant to give the title compound 39 as a viscous

oil which solidified on standing (1.70 g, 62% yield): mp 42 °C;

¹H NMR (CDCl₃) δ 7.28 (dd, J ) 6.5, 1.8 Hz, 2H), 7.20 (dd, J

) 6.5, 1.8 Hz, 2H), 6.94 (s, 1H), 6.69 (s, 1H), 5.96 (s, 2H), 3.67

(s, 2H), 2.51 (s, 3H), 1.53 (br, 2H); LRMS (APIMS) m/z 274

(M + H)⁺.

Eth yl 1-({6-[4-(Meth ylsu lfon yl)p h en yl]-2H-ben zo[d ]1,3-

dioxolan -5-yl}m eth yl)piper idin e-3-car boxylate (38b). Com-

pound 38b was prepared by alkylation of 3-(carboxyethyl)-

piperidine 37b with chloromethyl compound 16 using method

H. Pure product 38b was obtained as white solid in 93%

yield: mp 144-145 °C; ¹H NMR (CDCl₃) δ 7.93 (d, J ) 8.3

Hz, 2H), 7.54 (d, J ) 8.3 Hz, 2H), 7.01 (s, 1H), 6.67 (s, 1H),

5.98 (s, 2H), 4.05 (q, J ) 7.2 Hz, 2H), 3.22 (s, 2H), 3.09 (s,

3H), 2.74 (m, 1H), 2.53 (m, 2H), 2.2 (m, 1H), 1.95 (m, 2H), 1.80

(m, 1H), 1.65 (m, 2H), 1.18 (t, J ) 7.2 Hz, 3H); ¹³C NMR

(CDCl₃) δ 174.1, 147.5, 147.2, 146.5, 138.8, 133.8, 130.5, 129.9,

126.9, 110.1, 109.6, 101.2, 60.2, 59.9, 54.8, 53.3, 45.5, 41.8, 26.8,

24.5. 14.1; LRMS (APIMS) m/z 446 (M + H)⁺. Anal. (C₂₃H₂₇

SNO₆) C, H.

-

Eth yl 1-({6-[4-(Meth ylsu lfon yl)p h en yl]-2H-ben zo[d ]1,3-

dioxolan -5-yl}m eth yl)piper idin e-4-car boxylate (38c). Com-

pound 38c was prepared by alkylation of 4-(carboxyethyl)-

piperidine 37c with chloromethyl compound 16 using method

H. Pure product 38c was obtained as white solid in 94%

yield: mp 121-122 °C; ¹H NMR (CDCl₃) δ 7.92 (d, J ) 8.3

Hz, 2H), 7.55 (d, J ) 8.3 Hz, 2H), 7.0 (s, 1H), 6.67 (s, 1H),

5.98 (s, 2H), 4.09 (q, J ) 7.1 Hz, 2H), 3.19 (s, 2H), 3.09 (s,

3H), 2.69 (m, 2H), 2.1 (m, 1H), 1.8-1.5 (m, 6H), 1.21 (t, J )

7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 175.1, 147.5, 147.2, 146.5,

138.8, 133.9, 130.5 (2 × C), 130.1, 126.9 (2 × C), 110.2, 109.6,

101.2, 60.2, 58.9, 52.4 (2 × C), 44.5, 41.0, 28.3 (2 × C), 14.2;

LRMS (APIMS) m/z 446 (M + H)⁺. Anal. (C₂₃H₂₇SNO₆) C, H.

1-((6-(4-Meth ylsu lfon yl)p h en yl)-2H-ben zo[d ]1,3-d ioxo-

la n -5-yl)m eth yl)p ip er id in -2-on e (42). Lactam 41 was pre-

pared by alkylation of 39 with bromo ester 40, and subse-

quently 41 was oxidized to give 42 using method C. Pure

product 42 was obtained as white prisms (108 mg, 70% yield):

1

mp 156-157 °C; H NMR (CDCl₃) δ 7.97 (d, J ) 8.4 Hz, 2H),

7.46 (d, J ) 8.4 Hz, 2H), 6.81 (s, 1H), 6.68 (s, 1H), 6.01 (s,

2H), 4.47 (s, 2H), 3.11 (s, 3H), 2.95 (t, J ) 6.0 Hz, 2H), 2.38 (t,

J ) 6 0 Hz, 2H), 1.75-1.71 (m, 4H); ¹³C NMR (CDCl₃) δ 169.9,

148.2, 146.8, 146.4, 139.3, 133.4, 130.4, 128.4, 127.4, 109.6,

107.9, 101.4, 47.1, 44.5, 32.3, 23.1, 21.3; LRMS (APIMS) m/z

388 (M + H)⁺. Anal. (C₂₀H₂₁SNO₅) C, H, N, S.

1-{6-[(4-Hyd r oxyp ip er id yl)m eth yl](2H-ben zo[3,4-d ]1,3-

d ioxola n -5-yl)}-4-(m eth ylsu lfon yl)ben zen e (38d ). Com-

pound 38d was prepared by alkylation of 4-hydroxypiperidine

37d with chloromethyl compound 16 using method H. Pure

product 38d was obtained as white solid in 90% yield: mp 76-

6-[4-(Meth ylsu lfon yl)ph en yl](2H-ben zo[d]1,3-d ioxolen -

5-yl) P yr r olid in yl Keton e (45a ). Acid chloride 43b was

prepared from 6-[4-(methylsulfonyl)phenyl]-2H-benzo[d]1,3-

dioxolene-5-carboxylic acid 43a and it was reacted with

pyrrolidine using method H to yield pure product 45a in 57%

yield as a white solid: mp 189-192 °C; ¹H NMR (CDCl₃) δ

7.94 (d, J ) 8.5 Hz, 2H), 7.65 (d, J ) 8.5 Hz, 2H), 6.91 (s, 1H),

6.87 (s, 1H), 6.06 (s, 2H), 3.37 (t, J ) 7.0 Hz, 2H), 3.08 (s, 3H),

2.79 (t, J ) 7.0 Hz, 2H), 1.67 (quin., J ) 7.0 Hz, 2H), 1.54

(quin., J ) 7.0 Hz, 2H); LRMS (APIMS) m/z 374 (M + H)⁺.

Anal. (C₁₉H₁₉SNO₅) C, H.

1

82 °C; H NMR (CDCl₃) δ 7.92 (d, J ) 7.0 Hz, 2H), 7.55 (d, J

) 7.1 Hz, 2H), 7.01 (s, 1H), 6.67 (s, 1H), 5.98 (s, 2H), 3.62 (m,

1H), 3.20 (s, 2H). 3.09 (s, 3H), 2.59 (m, 2H), 1.99 (m, 2H), 1.8-

1.4 (m, 5H); ¹³C NMR (CDCl₃) δ 147.5, 147.3, 146.5, 138.8,

133.9, 130.6, 130.2, 126.9, 110.2, 109.7, 101.3, 67.9, 59.5, 50.5,

44.5, 34.5; LRMS (APIMS) m/z 390 (M + H)⁺. Anal. (C₂₀H₂₃

SNO₅) C, H.

-

1-(6-{[2-(Hyd r oxym eth yl)p ip er id yl]m eth yl}(2H-ben zo-

[3,4-d]1,3-dioxolan -5-yl))-4-(m eth ylsu lfon yl)ben zen e (38e).

Compound 38e was prepared by alkylation of 2-(hydroxy-

methyl)piperidine 37e with chloromethyl compound 16 using

method H. Pure product 38e was obtained as white solid in

6-[4-(Meth ylsu lfon yl)ph en yl](2H-ben zo[d]1,3-d ioxolen -

5-yl) P ip er id yl Keton e (45b). Acid chloride 43b was pre-

pared from 6-[4-(methylsulfonyl)phenyl]-2H-benzo[d]1,3-diox-

olene-5-carboxylic acid 43a and it was reacted with piperidine

using method H to yield pure product 45b in 55% yield as a

1

81% yield: mp 127-137 °C; H NMR (CDCl₃) δ 7.93 (d, J )

6.5 Hz, 2H), 7.53 (d, J ) 6.5 Hz, 2H), 7.00 (s, 1H), 6.67 (s,

1H), 5.98 (s, 2H), 3.85 (d, J ) 13.6 Hz, 1H), 3.57 (dd, J ) 11

and 4.1 Hz, 1H), 3.37 (dd, J ) 11 and 4.1 Hz, 1H), 3.18 (d, J

) 13.6 Hz, 1H), 3.1 (s, 3H), 2.63 (m, 1H), 2.42 (m, 1H), 2.00-

1.20 (m, 7H); ¹³C NMR (CDCl₃) δ 147.6, 147.4, 146.5, 138.8,

133.9, 130.5, 130.1, 126.9, 110.2, 109.7, 101.3, 66.6, 60.4, 56.9,

53.8, 44.5, 38.2, 27.2, 24.6; LRMS (APIMS) m/z 404 (M + H)⁺.

Anal. (C₂₁H₂₅SNO₅) C, H.

1

white solid: mp 152-154 °C; H NMR (CDCl₃) δ 7.95 (d, J )

8.5 Hz, 2H), 7.64 (d, J ) 8.5 Hz, 2H), 6.87 (s, 1H), 6.86 (s,

1H), 6.06 (d, J ) 3.9 Hz, 2H), 3.56 (m, 1H), 3.36 (m, 1H), 3.07

(s, 3H), 3.03 (m, 1H), 2.71 (m, 1H), 1.48-1.23 (m, 5H), 0.77

(m, 1H); LRMS (APIMS) m/z 388 (M + H)⁺. Anal. (C₂₀H₂₁SNO₅)

C, H.

1-(6-((3-(Hyd r oxym eth yl)p ip er id yl)m eth yl)(2H-ben zo-

[3,4-d]1,3-dioxolan -5-yl))-4-(m eth ylsu lfon yl)ben zen e (38f).

The chloromethyl compound 16 (410 mg, 1.2 mmol) and

2-piperidine methanol 37f (138 mg, 1.2 mmol) were dissolved

4-Meth ylp ip er a zin yl 6-[4-(Meth ylsu lfon yl)p h en yl](2H-

ben zo[d ]1,3-d ioxolen -5-yl) Keton e (46a ). Acid chloride 43b

was prepared from 6-[4-(methylsulfonyl)phenyl]-2H-benzo[d]-

1,3-dioxolene-5-carboxylic acid 43a and it was reacted with

Metharyl and Methcycloalkyl COX-2 Inhibitors

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5501

N-methylpiperazine using method H to yield pure product 46a

in 80% yield as a white solid: mp 204-206 °C.; ¹H NMR

(CDCl₃) δ 7.96 (d, J ) 8.3 Hz, 2H), 7.63 (d, J ) 8.3 Hz, 2H),

6.88 (s, 1H), 6.86 (s, 1H), 6.06 (s, 2H), 3.55 (t, J ) 5.0 Hz, 2H),

3.09 (s, 3H), 3.04 (m, 1H), 2.82 (m, 1H), 2.32 (m, 1H), 2.11 (s,

3H), 2.04 (m, 1H), 1.97 (m, 1H), 1.41 (m, 1H); LRMS (APIMS)

m/z 403 (M + H)⁺.

6-[4-(Meth ylsu lfon yl)p h en yl](2H-ben zo[d ]1,3-d ioxolen -

5-yl) Mor p h olin -4-yl Keton e (46b). Acid chloride 43b was

prepared from 6-[4-(methylsulfonyl)phenyl]-2H-benzo[d]1,3-

dioxolene-5-carboxylic acid 43a and it was reacted with

morpholine using method H to yield pure product 46b in 92%

yield as a white solid: mp 203-205 °C; ¹H NMR (CDCl₃) δ

7.98 (d, J ) 8.5 Hz, 2H), 7.63 (d, J ) 8.5 Hz, 2H), 6.89 (s, 1H),

6.86 (s, 1H), 6.07 (s, 2H), 3.59 (m, 2H), 3.45 (m, 1H), 3.32 (m,

2H), 3.09 (s, 3H), 3.04 (m, 1H), 2.76 (m, 2H); LRMS (APIMS)

m/z 390 (M + H)⁺. Anal. (C₁₉H₁₉SNO₆) C, H.

Flu or o({4-[6-ben zyl(2H-ben zo[3,4-d ]1,3-d ioxola n -5-yl)]-

p h en yl}su lfon yl)m eth a n e (50). (Fluoromethyl) sulfone 50

was prepared in a two-step procedure. In a 25 mL two-neck

round-bottom flask, to a solution of [bis(2-methoxyethyl)amino]

sulfur trifluoride (130 µL) in anhydrous dichloromethane (2

mL) was added solution of 49a (134 mg, 0.4 mmol) in

dichloromethane (1 mL), followed by catalytic amount of SbCl₃

(5 mg). The reaction mixture was stirred at room temperature

overnight. It was then diluted with dichloromethane and

washed with saturated aqueous sodium bicarbonate. The

organic layer was separated and concentrated to approxi-

mately 10 mL, to this solution was added 98% m-chloroper-

benzoic acid (178 mg) (1 mmol), and the mixture stirred at

room temperature for 2 h. The resulting mixture was diluted

with CH₂Cl₂(50 mL), washed with 2 M aqueous sodium

bicarbonate, dried over sodium sulfate, and filtered. The

filtrate was evaporated under reduced pressure. The crude

product obtained was purified by flash chromatography using

EtOAc:hexanes (1:1) as the eluant to give the title compound

5-[4-(Am in osu lfon yl)p h en yl]-4-b en zyl-1,2-m et h ylen e-

d ioxyben zen e (47). 4-Benzyl-1,2-methylenedioxy-5-(4-meth-

ylsulfonylphenyl)benzene 21a (152 mg, 0.419 mmol) was

dissolved in dry THF (0.7 mL) in an oven-dried 25 mL single

necked round-bottom flask which had been cooled to ambient

temperature under argon. The flask was placed in a water bath

and n-BuLi (1.2 equiv, 0.503 mmol, 0.3 mL of a 1.6 M solution

in hexanes) was added, generating a dark yellow solution. The

reaction mixture was stirred at ambient temperature for 0.5

h and then to the solution was added chloromethyltrimethyl-

silane (78 mg, 1.5 equiv, 0.635 mmol, 0.09 mL) in one portion.

The orange reaction mixture was stirred at ambient temper-

ature for 4 h, at which point TLC (3:7 EtOAc:hexanes)

indicated the reaction to be complete. Tetrabutylammonium

fluoride (5.4 equiv, 2.27 mmol, 2.27 mL of a 1 M solution in

THF) was then added, generating a clear dark solution. The

reaction flask was fitted with a reflux condenser and heated

to the reflux temperature for 0.5 h. The reaction was cooled

to ambient temperature and to the reaction mixture was added

sequentially NaOAc (189 mg, 5.5 equiv, 2.31 mmol), H₂O (7

mL), and hydroxylamine-O-sulfonic acid (269 mg, 5.7 equiv,

2.38 mmol). The reaction mixture was stirred at ambient

temperature overnight at which point TLC (3:7 EtOAc:hex-

anes) showed the reaction to be complete. The reaction mixture

was poured into a separatory funnel and diluted with 15 mL

of EtOAc, and the aqueous layer was removed. The organic

layer was sequentially washed with saturated aqueous NaH-

CO₃(2 × 7 mL), water (1 × 7 mL), and brine (1 × 7 mL). The

organic layer was dried over Na₂SO₄, the reaction mixture

filtered, and the solvent removed in vacuo, affording a brown

oil. The oil was chromatographed on two 20 × 20 cm, 1 mm

thick Alltech silica gel plates eluting once with methylene

chloride and then once with 3:97 EtOAc:CH₂Cl₂. The desired

band was scraped from the plates and extracted into CH₂Cl₂,

affording 65 mg (43% yield) of the sulfonamide 47 as a white

1

50 as a white solid (52 mg, 36% yield): mp 142-143 °C; H

NMR (CDCl₃) δ 7.64 (d, J ) 8.1 Hz, 2H), 7.40 (d, J ) 8.1 Hz,

2H), 7.20 (m, 2H), 6.94 (d, J ) 7.0 Hz, 2H), 6.71 (s, 2H), 5.98

(s, 2H), 5.2 (dd, J ) 9.0 and 4.0 Hz, 1H), 5.0 (dd, J ) 9.0 and

4.0 Hz, 1H), 3.82 (s, 2H); LRMS (APIMS) m/z 385 (M + H)⁺.

2-(4-Meth ylth iop h en yl)ben za ld eh yd e (52). Compound

52 was prepared using 51 and 3 by method A. The title

compound 52 was obtained as colorless thick oil in 96% yield:

¹H NMR (CDCl₃) δ 9.98 (s, 1H), 8.01 (dd, J ) 7.8 and 1.2 Hz,

1H), 7.60 (dt, J ) 7.5 and 1.4 Hz, 2H), 7.62-7.40 (m, 2H),

7.30-7.25 (m, 3H), 2.53 (s, 3H); LRMS (APIMS) m/z 229 (M

+ H)⁺.

(2-(4-Meth ylth iop h en yl)p h en yl)m eth a n -1-ol (53). The

product of the above example was converted to 53 by method

I. The title compound was obtained as a white solid in 97%

1

yield: mp 81-85 °C; H NMR (CDCl₃) δ 7.55 (m, 1H), 7.40-

7.20 (m, 7H), 4.61 (s, 2H), 2.50 (s, 3H), 1.63 (br s, 1H, OH);

LRMS (APIMS) m/z 248 (M + NH₄)⁺.

1-(2-(Hyd r oxym eth yl)p h en yl)-4-(m eth ylsu lfon yl)ben -

zen e (54). Compound 54 was prepared by method C in 89%

yield: mp 123-124 °C; ¹H NMR (CDCl₃) δ 8.02 (d, J ) 8.2

Hz, 2H), 7.65 (d, J ) 8.2 Hz, 2H), 7.62 (s, 1H), 7.52-7.41 (m,

2H), 7.31 (d, J ) 8.2 Hz, 1H), 4.60 (s, 2H), 3.15 (s, 3H), 2.10

(br s, 1H, OH); ¹³C NMR (CDCl₃) δ 146.5, 139.4, 139.2, 137.8,

130.2 (2 × C), 129.8, 129.0, 128.7, 127.9, 127.2 (2 × C), 62.7,

44.5; LRMS (APIMS) m/z 280 (M + NH₄)⁺.

2-(4-(Meth ylsu lfon yl)p h en yl)ben za ld eh yd e (55). The

product of the above example 54 was oxidized to 55 by method

G. The title compound 55 was obtained as a white solid in 64%

1

yield: mp 115-116 °C; H NMR (CDCl₃) δ 9.99 (s, 1H), 8.09

(m, 3H), 7.73 (t, J ) 7.3 Hz, 1H), 7.63 (m, 3H), 7.46 (d, J ) 7.4

Hz, 1H), 3.17 (s, 3H); ¹³C NMR (CDCl₃) δ 191.1, 143.7, 143.3,

140.2, 133.8, 133.6, 130.8 (2 × C), 130,6, 129.8, 128.5, 127.4

(2 × C) 44.5; LRMS (APIMS) m/z 278 (M + NH₄)⁺.

1

solid: mp 165-167 °C; H NMR (CDCl₃) δ 7.89 (m, 2H), 7.36

(m, 2H), 7.20 (m, 3H), 6.95 (m, 2H), 6.70 (m, 2H), 5.98 (s, 2H),

4.79 (br s, 2H), 3.82 (s, 2H); LRMS (APIMS) m/ z 385 (M +

NH₄)⁺. Anal. (C₂₀H₁₇SNO₄) C, H.

1-(2-(Cycloh exylid en em eth yl)p h en yl)-4-(m eth ylsu lfo-

n yl)ben zen e (56). Compound 56 was prepared by method B

using cyclohexyltriphenylphosphonium bromide 5b and 55.

The title compound was obtained as a white powder 35%

yield: mp 83 °C; ¹H NMR (CDCl₃) δ 8.00 (d, J ) 7.9 Hz, 2H),

7.63 (d, J ) 7.9 Hz, 2H), 7.33 (m, 4H), 6.01 (s, 1H), 3.15 (s,

3H), 2.21 (m, 4H), 1.60-1.46 (m, 6H); LRMS (APIMS) m/z 344

(M + NH₄)⁺. Anal. (C₂₀H₂₂SO₂) C, H.

7-Me t h ylt h io-5-p h e n yl-2H -flu or e n o[2,3-d ]1,3-d ioxo-

la n e (48). Treatment of compound 19a under the conditions

described in method F resulted in the formation of 48 in nearly

quantitative yield: white solid; mp 173-175 °C; ¹H NMR

(CDCl₃) δ 7.50 (d, J ) 8.0 Hz, 2H), 7.30-7.00 (m, 7H), 6.70 (s,

1H), 5.96 (s, 2H), 4.80 (s, 1H), 2.44 (s, 3H); ¹³C NMR (CDCl₃)

δ 148.8, 147.7, 147.5, 141.7, 141.2, 138.8, 136.0, 134.4, 128.8

(2 × C), 128.3 (2 × C), 127.0, 126.3, 123.9, 119.2, 106.1, 101.3,

100.3, 54.1, 16.6.

4-Meth ylth io-1-[6-ben zyl(2H-ben zo[3,4-d ]1,3-d ioxola n -

5-yl)]ben zen e (49a ). Compound 19a was hydrogenated over-

night at 40 psi using method E to furnish 49a as a white solid

in 71% yield: mp 86-87 °C; ¹H NMR (CDCl₃) δ 7.25 (m, 7H),

7.00 (d, J ) 8.5 Hz, 2H), 6.73 (s, 1H), 6.67 (s, 1H), 5.95 (s,

2H), 3.85 (s, 2H), 2.53 (s, 3H); ¹³C NMR (CDCl₃) δ 147.1, 145.9,

141.7, 138.4, 137.1, 135.0, 131.8, 130.0 (2 × C), 128.8 (2 × C),

128.4 (2 × C) 126.4 (2 × C), 126.3, 125.9, 110.3, 101.1, 38.9,

16.0.

(3-F lu or op h e n yl)(2-(4-m e t h ylt h io p h e n y l)p h e n y l)-

m eth a n -1-ol (57). The Grignard reagent was prepared by

refluxing 1-bromo-3-fluorobenzene and was reacted with car-

baldehyde 4 by method D to give the title compound 57 as

colorless thick oil in 98% yield: ¹H NMR (CDCl₃) δ 7.47 (d, J

) 7.1 Hz, 1H), 7.40-7.18 (m, 8H), 6.90 (m, 3H), 5.91 (d, J )

3.6 Hz, 1H), 2.52 (s, 3H), 2.25 (br s, 1H, OH); ¹³C NMR (CDCl₃)

δ 164.4, 161.1, 146.4, 140.7, 140.6, 137.7, 137.3, 130.1, 129.7

(2 × C), 129.6, 128.0, 127.7, 127.3, 126.3 (2 × C), 122.1, 114.0

(d, J ) 21 Hz), 113.5 (d, J ) 22 Hz), 71.8, 15.8; LRMS (APIMS)

m/z 342 (M + NH₄)⁺.

1-(2-((3-F lu o r o p h e n y l)h y d r o x y m e t h y l)p h e n y l)-4-

(m eth ylsu lfon yl)ben zen e (58). The (methylthio) compound

5502 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25

Khanapure et al.

57 (220 mg, 0.679 mmol) was dissolved in dichloromethane

(20 mL). Saturated aqueous sodium bicarbonate (5 mL) was

added, followed by recrystallized m-chlorobenzoic acid (302 mg,

1.69 mmol, 98% yield), and the reaction mixture was stirred

at room temperature for 2 h. The organic layer was separated.

The aqueous layer was extracted with dichloromethane, and

the combined organic layers were washed with 10% sodium

bicarbonate (3 × 25 mL), water (1 × 25 mL), and brine (1 ×

25 mL), dried over sodium sulfate, and filtered. The filtrate

was evaporated under reduced pressure to give the crude

product. Trituration with 10% ethyl acetate in hexane gave

the title compound as a white solid that was recrystallized from

hexane (190 mg, 79% yield): mp 117-119 °C; ¹H NMR (CDCl₃)

δ 7.99 (d, J ) 8.2 Hz, 2H), 7.62 (d, J ) 7.6 Hz, 1H), 7.51 (d, J

) 8.2 Hz, 2H), 7.44 (m, 2H), 7.31-7.20 (m, 2H), 7.00-6.70 (m,

3H), 5.86 (s, 2H), 3.15 (s, 3H), 2.35 (br s, 1H, OH); LRMS

(APIMS) m/z 374 (M + NH₄)⁺.

with ethyl acetate:hexane to give the title compound as a white

solid (21.3 g, 85% yield): mp 114-115 °C; ¹H NMR (CDCl₃) δ

9.83 (s, 1H), 7.64 (s, 1H), 7.43-7.23 (m, 4H), 6.83 (s, 1H), 3.98

(d, J ) 2.4 Hz, 6H), 2.55 (s, 3H); ¹³C NMR (CDCl₃) δ 190.9,

153.4, 148.7, 140.8, 138.9, 134.1, 130.5, 126.9, 126.1, 112.5,

108.7, 56.2, 56.1, 15.6; LRMS (APIMS) m/z 289 (M + H)⁺.

4-(1-(3′,5′-Diflu or op h en yl)-1-h yd r oxym et h yl)-1,2-d i-

m eth oxy-5-(4-m eth ylth iop h en yl)ben zen e (70). Grignard

reagent 17h was prepared by refluxing magnesium metal (2.21

g, 91.06 mmol), dry THF (200 mL), and 3,5-difluorobromoben-

zene (11.04 mL, 95.85 mmol) and reacted with carbaldehyde

69 (91 mmol) using method D. The crude product obtained was

oxidized using method C to afford the desired product 70 that

was used without further purification.

5-(1-(3′,5′-Diflu or op h en yl)m eth yl)-1,2-d im eth oxy-4-(4-

m eth ylsu lfon ylp h en yl)ben zen e (72). Product 70 was oxi-

dized using Oxone by method C to give methyl sulfone 71, and

the crude product 71 obtained was subsequently deoxygenated

using method F to yield the title compound 72 as a white solid

(18.74 g, 93.4% overall yield for the three steps from 70): mp

157-159°C; ¹H NMR (CDCl₃) δ 7.92 (m, 2H), 7.40 (m, 2H),

6.75 (s, 1H), 6.73 (s, 1H), 6.59 (m, 1H), 6.44 (m, 2H), 3.89 (s,

6H), 3.86 (s, 2H), 3.09 (s, 3H); LRMS (APIMS) m/z 436 (M +

NH₄)⁺. Anal. (C₂₂H₂₀SF₂O₄) C, H.

5-(1-(3′,5′-Diflu or op h en yl)m eth yl)-1,2-d ih yd r oxy-4-(4-

m eth ylsu lfon ylp h en yl)ben zen e (73). Dimethoxy compound

72 (18.74 g, 44.78 mmol) was dissolved in dry CH₂Cl₂(500 mL)

and cooled to 0 °C, and boron tribromide (0.112 mol, 10.6 mL)

was added over a period of 2-3 min. The resulting solution

was stirred at 0 °C for 45 min. The reaction was quenched at

0 °C by the addition of MeOH (70 mL) followed a minute later

by the addition of water (70 mL). The reaction mixture was

warmed to room temperature. The solvent (CH₂Cl₂and MeOH)

was evaporated under reduced pressure to give a solid. The

solid was removed by filtration, washed with water, and then

dried under high vacuum overnight to give the title compound

73 as a pale yellow solid (17.0 g, 97.2% yield): mp 214°C

(dec): ¹H NMR (DMSO-d₆) δ 9.15 (s, 1H), 9.13 (s, 1H), 7.90

(m, 2H), 7.47 (m, 2H), 6.99 (m, 1H), 6.64 (s, 1H), 6.62 (s, 1H),

6.60 (m, 2H), 3.81 (s, 2H), 3.24 (s, 3H); LRMS (APIMS) m/z

408 (M + NH₄)⁺.

1-(7-((3,5-Diflu or oph en yl)m eth yl)(2H,3H-ben zo[3,4-e]1,4-

d ioxin -6-yl))-4-(m eth ylsu lfon yl)ben zen e (74). To a stirred

mixture of 73 (0.400 g, 1.02 mmol) and 1,2-dibromoethane

(0.21 g, 0.140 mL, 1.13 mmol) in dry acetone (50 mL) was

added powdered potassium carbonate (2.96 mmol, 0.409 g).

The mixture was heated at reflux for 4 h, then additional 1,2-

dibromoethane (0.105 g, 0.070 mL) and potassium carbonate

(0.205 g) were added, and the mixture refluxed overnight. The

reaction mixture was cooled, filtered through Celite, and

washed with acetone. The filtrate was evaporated under

reduced pressure, and the resulting residue was partitioned

between ethyl acetate and water. The organic layer was

separated, washed with brine, dried over magnesium sulfate,

and filtered, and the filtrate was evaporated to near dryness.

Addition of ether resulted in the formation of off-white crystals

of the title compound 74 (0.308 g, 73% yield): mp 160-162

°C; ¹H NMR (CDCl₃) δ 7.93 (td, J ) 1.9, 8.4 Hz, 2H), 7.39 (td,

J ) 1.9, 8.4 Hz, 2H), 6.80 (s, 1H), 6.78 (s, 1H), 6.61 (tt, J )

2.3, 9.0 Hz, 1H), 6.45 (m, 2H), 4.34 (s, 4H), 3.82 (s, 2H), 3.12

(s, 3H); MS (APIMS) m/e 434 (M + NH₄)⁺. Anal. (C₂₂H₁₈SF₂O₄)

C, H.

1-(2-((3-F lu or op h en yl)m eth yl)p h en yl)-4-(m eth ylsu lfo-

n yl)ben zen e (59a ). Compound 59a was prepared from 58 by

method F. The title compound 59a was obtained as a white

1

solid in 83% yield: mp 97-98 °C; H NMR (CDCl₃) δ 7.97 (d,

J ) 8.3 Hz, 2H), 7.45 (d, J ) 8.3 Hz, 2H), 7.45-7.15 (m, 5H),

6.98 (dt, J ) 8.4 and 2.2 Hz, 1H), 6.75 (d, J ) 7.6 Hz, 1H),

6.63 (d, J ) 10 Hz, 1H), 3.97 (s, 2H), 3.15 (s, 3H); ¹³C NMR

(CDCl₃) δ 164.4, 161.2, 147.2, 143.3 (d, J ) 7 Hz), 140.3, 139.2,

137.2, 130.7, 130.1 (2 × C), 129.9, 129.7 (d, J ) 2.5 Hz), 128.6,

127.1 (2 × C), 126.9, 124.3 (d, J ) 2.5 Hz), 115.4 (d, J ) 21

Hz), 112.9 (d, J ) 21 Hz), 44.5, 38.9; LRMS (APIMS) m/z 358

(M + NH₄)⁺. Anal. (C₂₀H₁₇SFO₂) C, H.

3-Flu or oph en yl 2-(4-(Meth ylsu lfon yl)ph en yl)ph en yl Ke-

ton e (60a ). Compound 58 was converted to 60a by method G

to give the title compound 60a as a white crystalline solid in

1

79% yield: mp 105-106 °C; H NMR (CDCl₃) δ 7.79 (d, J )

8.1 Hz, 2H), 7.35-7.15 (m, 10H), 2.83 (s, 3H); ¹³C NMR (CDCl₃)

δ 196.4, 164.0, 160.7, 145.7, 139.3, 138.2, 131.0, 130.2, 130.1,

130.0, 129.8 (2 × C), 129.1, 128.2, 127.7 (2 × C), 125.7 (d, J )

12 Hz), 120.1 (d, J ) 22 Hz), 116.3 (d, J ) 22 Hz), 44.4; LRMS

(APIMS) m/z 372 (M + NH₄)⁺. Anal. (C₂₀H₁₅SFO₃) C, H.

1-[6-(3,5-Diflu or op h en yl)(2H-ben zo[3,4-d ]1,3-d ioxola n -

5-yl)]-4-(m eth ylsu lfon yl)ben zen e (65). Compound 65 was

prepared from carbaldehyde 61 in three steps. Suzuki coupling

reaction of 61 with 4-(methylthio)phenylboronic acid 3 using

standard conditions as described in method A gave the product

62 after purification by column chromatography. Another

Suzuki coupling reaction of 62 with 3,5-difluoro-4-(methylthio)-

phenylboronic acid 63 using method A gave the methylthio

compound 64, which was oxidized with Oxone using method

C to afford the desired product 65 as a white solid (three steps

1

overall 26% yield): mp 195-198 °C; H NMR (CDCl₃) δ 7.79

(d, J ) 8.3 Hz, 2H), 7.24 (d, J ) 8.4 Hz, 2H), 6.86 (m, 2H),

6.7-6.5 (m, 3H), 6.02 (s, 2H), 3.05 (s, 3H); ¹³C NMR (CDCl₃)

δ 164.2, 160.9, 148.0, 146.5, 143.9, 138.7, 132.4, 130.6, 127.2,

113.0 (d, J ) 8 Hz), 112.8, 110.4, 102.4 (t, J ) 25.2 Hz), 101.8,

44.5; LRMS (APIMS) m/z 406 (M + NH₄)⁺. Anal. (C₂₀H₂₃SNO₄)

C, H.

4-(Meth ylsu lfon yl)-1-[6-(3-ph en ylpr opyl)(2H-ben zo[3,4-

d ]1,3-d ioxola n -5-yl)]ben zen e (67). Compound 67 was pre-

pared from carbaldehyde 4 in three steps. First, carbaldehyde

4 was treated with (phenethyl)magnesium chloride according

to method D, the product obtained was oxidized with Oxone

using method C, and then deoxygenation was performed using

method E to give the desired product as a white solid: mp

1

110-114 °C; H NMR (CDCl₃) δ 7.9 (d, J ) 8.1 Hz, 2H), 7.40

Refer en ces

(d, J ) 8.1 Hz, 2H), 7.25 (m, 3H), 7.00 (d, J ) 6.8 Hz, 2H),

6.80 (s, 1H), 6.63 (s, 1H), 5.97, (s, 2H), 3.1 (s, 3H), 2.47 (m,

4H), 1.76 (m, 2H); LRMS (APIMS) m/z 412 (M + NH₄)⁺. Anal.

(C₂₃H₂₂SO₄) C, H.

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J M030268B

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Synthesis and Structure-Activity Relationship of Novel, Highly Potent Metharyl and Methcycloalkyl Cyclooxygenase-2 (COX-2) Selective Inhibitors

DOI: 10.1021/jm030268b

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