New cyclooxygenase-2/5-lipoxygenase inhibitors. 2. 7-tert-butyl-2,3- dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: Variations of the dihydrobenzofuran ring

Article abstract of DOI:10.1021/jm970680p

A series of 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were found to be nonsteroidal antiinflammatory and analgesic agents. These compounds are inhibitors of 5-1ipoxygenase (5- LOX) and cyclooxygenase (COX) with selectivity for the COX-2 isoform. A series of analogues were prepared to investigate the scope of this lead. Five ketone side chains from active DHDMBFs were used to investigate the effects of changes in the DHDMBF 'core': the size and identity of the heterocycle and the substituent requirements of the heterocycle and phenyl ring. Biological testing showed that a variety of structural changes can be accommodated, but no structure was clearly superior to the DHDMBF structure.

Full text of DOI:10.1021/jm970680p

1124
J . Med. Chem. 1998, 41, 1124-1137
New Cyclooxygen a se-2/5-Lip oxygen a se In h ibitor s. 2.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth ylben zofu r a n Der iva tives a s Ga str oin testin a l
Sa fe An tiin fla m m a tor y a n d An a lgesic Agen ts: Va r ia tion s of th e
Dih yd r oben zofu r a n Rin g
J ohn M. J anusz,*,† Patricia A. Young,† Michael W. Scherz,† Kevin Enzweiler,† Laurence I. Wu,† Lixian Gan,†
Stanislaw Pikul,† Kelly L. McDow-Dunham,† Carl R. J ohnson,‡ C. B. Senanayake,‡ David E. Kellstein,†
Shelley A. Green,† J ulie L. Tulich,† Theresa Rosario-J ansen,† I. J ack Magrisso,† Kenneth R. Wehmeyer,†
Deborah L. Kuhlenbeck,† Thomas H. Eichhold,† and Roy L. M. Dobson†
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, and
Department of Chemistry, Wayne State University, 275 Chemistry, Detroit, Michigan 48202-3489
Received October 7, 1997
A series of 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs)
were found to be nonsteroidal antiinflammatory and analgesic agents. These compounds are
inhibitors of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) with selectivity for the COX-2
isoform. A series of analogues were prepared to investigate the scope of this lead. Five ketone
side chains from active DHDMBFs were used to investigate the effects of changes in the
DHDMBF “core”: the size and identity of the heterocycle and the substituent requirements of
the heterocycle and phenyl ring. Biological testing showed that a variety of structural changes
can be accommodated, but no structure was clearly superior to the DHDMBF structure.
Ch a r t 1
In tr od u ction
Di-tert-butylphenols are well-known antiinflamma-
tory agents which are dual cyclooxygenase (COX) and
5-lipoxygenase (5-LOX) inhibitors in vitro. The combi-
nation of COX/5-LOX inhibition and antioxidant proper-
ties has been proposed to account for the gastrointes-
tinal (GI) safety of some members of this class, as
discussed in the companion paper.1
The evolution of our work in the di-tert-butylphenol
area began with tebufelone (1) (Chart 1) which was
progressed to clinical testing. Among the metabolites
of tebufelone was the 7-tert-butyl-2,3-dihydro-3,3-di-
methylbenzofuran (DHDMBF) 2, a nonphenolic com-
pound. In the companion paper,1 we disclosed that
several 5-keto-substituted DHDMBFs were active an-
tiinflammatory agents as well as COX/5-LOX inhibitors
with selectivity for COX-2. Compound 3 was of par-
ticular interest as it showed excellent gastric safety in
a variety of in vivo tests.
We now report our results on an exploration of the
scope of the nonphenolic lead. Five different 5-keto
substituents which provided active compounds in the
DHDMBF series were appended to heterocyclic ring
variants where ring size, substitution patterns, and
heteroatom identity were changed as depicted in the
generic structure 4 (Chart 1). Biological testing of the
resulting analogues evaluated the effects of these
structural changes on in vivo antiinflammatory and/or
in vitro enzyme inhibition properties.
1-4. The preparation of compounds 8a ,b, in which the
C-3 substituent varied, was accomplished by a route
largely identical to that employed for the synthesis of
the DHDMBF analogues.1 Starting with the appropri-
ate allyl bromides, trans-1-bromo-2-methyl-2-butene (R1
) R2 ) Me) or 1-(bromomethyl)cyclopentene (R1/R2 )
-(CH2)3-), 2,4-dibromo-6-tert-butylphenol (5) was alky-
lated to give the corresponding ethers 6a ,b. These were
cyclized to the dihydrobenzofurans via a hypophospho-
rus acid-induced 5-exo-trig radical ring closure as
described in the companion paper. The cyclization was
generally accompanied by partial dehalogenation at C-5,
to provide a mixture of bromo and desbromo compounds
7 and 8. Complete dehalogenation to either 8a or 8b
was accomplished by lithium-halogen exchange of the
respective mixture followed by an aqueous quench.
The preparation of compounds bearing hydrogen
instead of methyl groups at the C-3 position of the
DHDMBF (or C-4 of the dihydrobenzopyran analogues)
was done using a variant of the Parham cyclialkylation2
wherein the bromo ethers 9a ,b were ring-closed by
lithium-halogen exchange to the dihydrobenzofuran
Ch em istr y
The syntheses of the requisite heterocyclic ring vari-
ants and substitution patterns are shown in Schemes
† Procter & Gamble Pharmaceuticals.
‡ Wayne State University.
S0022-2623(97)00680-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/10/1998

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1125
Sch em e 1
Sch em e 2
(DHBF) 10a and the dihydrobenzopyran (DHBP) 10b
with simultaneous exchange of the remaining aromatic
bromine. The des-tert-butyl DHDMBF 12 was prepared
by a titanium-catalyzed radical cyclization3 of the meth-
allyl ether 11.
Scheme 2 shows the preparation of compounds 15a ,b
where the tert-butyl group has been replaced by other
small alkyl groups. Replacement of the tert-butyl group
with primary or secondary alkyl substituents precluded
the use of the radical cyclization chemistry described
above, possibly due to interference by the benzylic
hydrogens. Instead, a palladium-catalyzed cyclization4
of the methallyl ethers 13a ,b provided the bromo
DHDMBFs 14a ,b which were converted to the respec-
tive desbromo compounds 15a ,b by hydrogenolysis and
lithium-halogen exchange followed by an aqueous

1126 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
Sch em e 3
Sch em e 4
quench, respectively. The dihydrodimethylbenzopyran
19 was prepared by allylation of 5 to 16 followed by
selective lithium-halogen exchange of the o-bromine to
give the 4-bromo ether 17. Oxymercuration/demercu-
ration gave 18 which was cyclized to the dihydroben-
zopyran with aluminum chloride. Lithium-halogen
exchange followed by an aqueous quench gave the
desired compound 19.
The preparations of the sulfur isosteres of the dihy-
drobenzofurans and -pyrans are shown in Scheme 3. In
a modification of a recently described methodology for
ortho lithiation of thiophenols,5,6 2-tert-butylthiophenol
was converted to its dianion which was brominated with
1,2-dibromotetrafluoroethane7 to provide 20. Allylation
with 3-chloro-2-methylpropene provided compound 21
which was subjected to the hypophosphorus acid-
induced 5-exo-trig radical cyclization to provide the
dihyrodimethylbenzothiophene 22. The dihydrothiopy-
ran 24 was prepared from 2-tert-butylthiophenol by
acid-induced ring closure via the 3-methyl-2-butenyl
thioether 23.
The syntheses of the requisite dihydroindole and
tetrahydroquinoline ring systems are shown in Scheme
4. The preparation of the dihydroindole 27 involved,
as a key step, a [2,3] rearrangement-cyclization reac-
tion.8 Reaction of chlorine and ethyl (methylthio)acetate
followed by the addition of 2-tert-butylaniline formed the
azasulfonium salt which, via ylid formation upon treat-
ment with triethylamine, underwent a [2,3] rearrange-
ment which linked the (methylthio)acetate group ortho
to the aniline nitrogen. Acid-catalyzed ring closure and
desulfurization with Raney nickel provided the oxindole
25. Dimethylation of 25 with LDA/CH3I and reduction
with LiAlH4 afforded the dihydroindole 26. Bromina-
tion followed by N-methylation via a reductive amina-
tion gave the bromodihydroindole 27. Synthesis of the
tetrahydroquinoline compound 29b centered around a
6-endo-trig cyclization reaction to provide the interme-
diate 28.9 Reductive amination of 2-tert-butylaniline
with benzaldehyde and amide formation with dimethyl-
acryloyl chloride followed by 6-endo-trig ring closure
with AlCl3 produced the dihydroquinolone 28. In the
absence of the N-benzyl group, cyclization was ac-
companied by loss of the tert-butyl group. A two-step
procedure, reduction of 28 with LiAlH4 followed by
bromination, afforded the bromide 29a (R ) CH2Ph).
The N-Me tetrahydroquinoline 29b was prepared via a
similar procedure with the insertion of debenzylation
and reductive amination steps in the preceding se-
quence.
Methods for the introduction of the keto substituent
are given in Scheme 5. Friedel-Crafts reaction with
trifluoroacetic anhydride activation of the desired car-
boxylic acid (method A) was used for many compounds.10
The reaction was most commonly done in CH2Cl2 but
could also be run in CH3CN or done without solvent. In
the case of the dihydrobenzothiopyran 57, the acyl group
was introduced by a SnCl4-catalyzed Friedel-Crafts
reaction (method B). The â-hydroxy ketone derivatives
(37, 41, 51, 55) were prepared via a Mukaiyama aldol
reaction of the appropriate methyl ketone with acetone
(method C). Introduction of the acyl group in the
dihydroindole and tetrahydroquinoline series involved
lithium-halogen exchange, followed by addition of the

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1127
Sch em e 5
Compounds bearing three types of ketone substitu-
ents, COR3, were selected as targets (see Table 1): alkyl
ketones (butanoyl, pentanoyl, or 4-cyclopropylbutanoyl),
3-hydroxy-3-methylbutanoyl, and hexynoyl. These sub-
stituents provided in vivo activity in the DHDMBF
series (2, 3, 30-32)1 and were used to probe the effect
of changes in the heterocyclic core on biological activity.
Some change of the C-3 geminal dimethyl group was
tolerated. The 3-methyl-3-ethyl compound 33 was ac-
tive, while the spirocyclopentyl analogue 34 was not.
However, geminal dialkyl substitution was not required
as all four compounds lacking the geminal dimethyl
group were active (35-38). In contrast, the tert-butyl
group appeared to be more important for activity: the
butanoyl compound 39 was inactive, the cyclopropyl-
containing analogue 40 was less active than the tert-
butyl analogue 2, and only the hydroxyl-containing 41
retaining activity equivalent to its tert-butyl analogue
32. Compounds 42 and 43 lacking both the geminal
dimethyl and the tert-butyl were inactive. Replacement
of the tert-butyl group by secondary alkyl groups such
as ethyl (44) and cyclopentyl (45) also eliminated
activity.
Attempts at changing the nature of the heterocyclic
ring system met with varied success. In the five-
membered heterocyclic series, the replacement of sulfur
for oxygen produced active derivatives (46, 47), while
the replacement with N-methyl (48) resulted in an
inactive compound. Ring expansion to the 8-tert-butyl-
2,3-dihydro-4,4-methylbenzopyrans 49-52 was a pro-
ductive variation as all four compounds had significant
activity. Variable activity was seen when the geminal
dimethyl group was removed. The pentanoyl and 4-cy-
clopropylbutanoyl derivatives 53 and 54 were inactive,
whereas the 3-hydroxy-3-methylbutanoyl and hexynoyl
compounds 55 and 56 retained activity. Analogously
to the dihydrobenzofuran series, the replacement of
sulfur for oxygen (57) retained activity, whereas of the
four nitrogen-containing analogues 58-61, only the
N-methyltetrahydroquinoline 61 retained some activity.
Most compounds which were active in the CPE assay
were tested in an analgesia model, the phenylquinone
abdominal constriction (PAC) assay. Many showed
significant activity at the screening dose of 70 mg/kg.
Notable exceptions were compounds 50 and 57 which
were inactive at this dose demonstrating that com-
pounds could be good antiinflammatory agents while
having poor activity in the PAC assay. Dose-response
studies with the most promising compounds from the
high-dose screening resulted in a wide range of ED50
values. While ED50 values were generally in the 10-
50 mg/kg range, compound 35 was significantly more
potent with an ED50 of 0.6 mg/kg.
resulting aryllithium to the desired aldehyde. The
resulting alcohol was oxidized without isolation with
tetrapropylammonium perruthenate (TPAP) and 4-meth-
ylmorpholine N-oxide (4-NMMO) (method D).11
Resu lts a n d Discu ssion
In Vivo Activity. The carrageenan paw edema
(CPE) assay was the primary screen used to assess in
vivo antiinflammatory activity. Compounds were tested
for their ability to inhibit paw swelling relative to
tebufelone (positive control) after a single oral screening
dose (50 mg/kg). The CPE data in Table 1 are given in
terms of a CPE index which is the ratio of a compound’s
percent inhibition of paw edema versus control to
tebufelone’s percent inhibition of paw edema versus
control.12 At the 50 mg/kg screening dose, both naprox-
en, a marketed nonsteroidal antiinflammatory agent,
and tebufelone exhibited about the same antiinflam-
matory activity. While uncertainties about bioavail-
ability complicate the interpretation of the CPE results,
the bioavailability of 30 was quite good (62%) in the rat.
In Vitr o Resu lts. Selected compounds were tested
in vitro for inhibition of cyclooxygenase and lipoxyge-
nase (Table 2). Among the eight compounds which were
active in the CPE assay, all were potent inhibitors of
platelet-derived human COX-1 and/or recombinant hu-
man COX-2 with IC50 values < 1 µM except for
compounds 36 and 50. Among the compounds that were
inactive (44, 45, 60) or less active than tebufelone (40)
in the CPE assay, all were weak inhibitors of COX-1
and COX-2 with IC50 values > 1 µM except for com-
pound 60. Among all the compounds, only compound

1128 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Ta ble 1. Structure, Synthetic Methods, and in Vivo Activity
J anusz et al.
o
compd
n
X
R1
R2
R3
method yield
mp, C
formula
CPE indexa PAC assayb
1, tebufelone
1.00c
1.06c
1.16
0.92
0.72
0.49e
0.94
0.68
0.28
0.69
0.50
0.98
0.84
0.31
0.50e
0.39e
0.00
0.13
0.04
0.27
1.04
0.74
0.36
0.69
0.57
0.48e
0.57
0.21
0.05
0.70
1.04
0.86
0.02
0.00
0.42
0.37e
26
1.3
21
38%
11
naproxen
30
31
2
32
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Me
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
H
Pr
Bu
d
d
d
d
d
Me
Me
Me
Me
Me, Et
c-C5H9
H
H
H
H
(CH2)3-c-Pr
CH2C(OH)Me2
(CH2)3CCH
Pr
Pr
Bu
(CH2)3-c-Pr
CH2C(OH)Me2
(CH2)3CCH
Pr
(CH2)3-c-Pr
CH2C(OH)Me2
Bu
NTf
NT
45%
NT
0.6
6
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
A
A
A
A
C
A
A
A
C
A
A
A
A
A
A
D
A
A
C
A
A
A
C
A
B
D
D
D
D
78
22
79
84
74
79
92
65
94
21
22
44
33
22
17
54
79
83
70
83
85
66
72
79
37
45
27
41
64
oil
oil
oil
oil
oil
oil
oil
oil
C
19H28O2
g
C20H28O2
C17H24O2
C19H26O2
C17H24O3
C18H22O2
C14H18O2
C17H22O2
C15H20O3
21
67%
NT
NT
NT
NT
NT
NT
NT
74
Me
Me
Me
H
H
H
H
H
oil
56-57
41-42
oil
oil
oil
oil
44-46
oil
oil
92-93
oil
oil
oil
oil
C13H16O2
H
(CH2)3-c-Pr
(CH2)3-c-Pr
C15H18O2
C19H26O2
C22H30O2
C18H26OS
C21H30OS
C22H33NO
Me
Me
Me
Me
Et
c-C5H9 (CH2)3-c-Pr
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Pr
S
(CH2)3-c-Pr
(CH2)3-c-Pr
Bu
(CH2)3-c-Pr
CH2C(OH)Me2
(CH2)3CCH
Bu
(CH2)3-c-Pr
CH2C(OH)Me2
(CH2)3CCH
Bu
NT
NT
53
NMe Me
O
O
O
O
O
O
O
Me
Me
Me
Me
H
H
H
H
C20H30O2
C22H32O2
C20H30O2
C21H28O2
10%
NT
46%
NT
NT
50%
79%
17%
NT
NT
NT
NT
C18H28O2
C20H28O2
C18H26O3
C19H24O2
C
C
O
S
52-53
oil
109-110
98-99
oil
Me
Me
Me
20H30O S
20H31NO
NH
NH
NMe Me
NMe Me
Bu
(CH2)3-c-Pr
Bu
(CH2)3-c-Pr
C22H33NO
21H33NO
C23H35NO
C
46-47
a
CPE index, carrageenan paw edema index, is defined as the ratio of the reduction in paw volume for test compounds relative to
tebufelone; a value of >1 means more active than tebufelone, <1 means less active; dose ) 50 mg/kg po. Bold faced values are statistically
b
greater than vehicle control and not statistically different from tebufelone. See Experimental Section for complete details. PAC,
phenylquinone-induced abdominal constriction assay. Values are ED50’s in bold or the percent reduction of constrictions at a po dose of
70 mg/kg. Maximal percent reduction is ∼90%. See Experimental Section for complete details. c Percent inhibition of paw swelling for a
d
50 mg/kg po dose was 51.1 ( 10.0 for tebufelone (33-75%, n ) 65) and 54% for naproxen (44-64%, n ) 2). See companion publication.
g
e Activity is statistically greater than vehicle control but less than tebufelone. f NT, not tested. The R1 groups form a spirocyclopentyl
ring.
36 was COX-1-selective, the others being nonselective
(30 and 57) or moderately COX-2-selective with IC50
ratios from 2.5 to 50. The IC50 values for two bench-
mark compounds were determined for comparison. The
marketed NSAID ibuprofen was a modestly selective
COX-1 inhibitor,13 while Searle’s SC-5766614 was a
highly selective (>100-fold) COX-2 inhibitor, results
consistent with literature reports. The inhibition of
5-LOX varies within a narrow range (3-12 µM) for those
compounds tested.
A few trends for changes in in vitro potency and
selectivity with changes in structure are apparent. In
the dihydrobenzofuran series, removal of the C-3 methyl
groups results in a decrease in both COX-1 and COX-2
inhibition potency. The larger effect on COX-2 leads
to a reversal in COX selectivity for 36 vs 2. Likewise,
replacement of the tert-butyl group with H, ethyl, or
cyclopentyl has the greatest effect on COX-2, reducing
inhibition potency and COX-2 selectivity (2 vs 40, 44,
45). The substitution of sulfur for oxygen reduces
COX-1 potency most thereby increasing COX-2 selectiv-
ity (30 vs 46). For the ring-expanded compounds, the
fully substituted dihydrobenzopyrans are less potent
inhibitors of both COX-1 and COX-2 (2 vs 50), although
the dihydrothiopyran 57 is a balanced moderately
potent inhibitor.
Con clu sion s
The antiinflammatory and analgesic activity observed
for the 5-substituted dihydrodimethylbenzofurans1 ex-
tends to a variety of DMDHBF analogues. Changes in
the degree of substitution, ring size, and heteroatom
identity are all tolerated to varying degrees. Thus, the
antiinflammatory/analgesic activity of the DMDHBF is
not unique, and a variety of related nonphenolic struc-
tures are antiinflammatory in vivo and are COX-2-
selective, dual COX/5-LOX inhibitors in vitro. However,

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1129
Ta ble 2. In Vitro Activity of Dihydrodimethylbenzofurans and
Analogues
yl tr a n s-2-Meth yl-2-bu ten yl Eth er (6a ). A solution of 2,4-
dibromo-6-tert-butylphenol1 (5) (13.9 g, 45.3 mmol), acetone
(380 mL), trans-1-bromo-2-methyl-2-butene15 (6.75 g, 45.6
mmol), K2CO3 (7.36 g, 54.4 mmol), and NaI (697 mg, 4.53
mmol) was refluxed for 3 h. The reaction mixture was cooled
to 23 °C, the solids were removed by filtration, and the acetone
was evaporated to give a dark oil. This oil was dissolved in
hexanes (100 mL) and stirred in silica gel (10 g). The silica
was removed by filtration, and the hexanes were evaporated
to give a dark-yellow oil (13.1 g, 77%). 1H NMR analysis
indicated that this oil consisted of a 2:1 mixture of 6a and the
undesired enol ether resulting from double-bond migration.
The mixture was carried forward without further purifica-
tion: 1H NMR δ 7.32 (d, J ) 1.5 Hz, 1 H), 7.56 (d, J ) 1.5 Hz,
1 H), 5.69 (q, J ) 6.8 Hz, 1 H), 4.20 (s, 2 H), 1.82 (s, 3 H), 1.68
(d, J ) 6.8 Hz, 3 H), 1.37 (s, 9 H).
5-Br om o-7-ter t-bu tyl-2,3-d ih yd r o-3-eth yl-3-m eth ylben -
zofu r a n (7a ). A solution of 6a (13.1 g, 35.2 mmol), 80%
aqueous hypophosphorus acid (69 g, 1.06 mol), Et3N (150 mL,
1.06 mol), and dioxane (650 mL) was deoxygenated by bubbling
with nitrogen for 20 min. The reaction mixture was heated
to reflux, and at 0.5-h intervals, 1.0 mL of a similarly
deoxygenated AIBN solution (3.4 g dissolved in 30 mL of
dioxane) was added. The reaction was monitored by TLC (CS2)
and after 4 h was cooled to 23 °C, and 1 N HCl (250 mL) and
saturated brine (100 mL) were added. The H2O/dioxane was
extracted with Et2O (4 × 250 mL), and the Et2O/dioxane layers
were dried (MgSO4) and evaporated to a yellow oil (10.36 g).
This oil was dissolved in EtOAc and shaken with 1 N NaOH
(3 × 20 mL), and the organics were dried and evaporated to a
dark oil (8.59 g). This oil was purified by medium-pressure
chromatography (hexanes) to give the product (3.34 g, 34%)
as a clear oil which was a 20:80 mixture of debrominated (8a )
and brominated (7a ) products: 1H NMR δ 7.15 (d, J ) 1.8 Hz,
1 H), 7.00 (d, J ) 1.8 Hz, 1 H), 4.35 (d, J ) 9.7 Hz, 1 H), 4.11
(d, J ) 9.7 Hz, 1 H), 1.60 (q, J ) 7.7 Hz, 2 H), 1.38 (s, 3 H),
1.30 (s, 9 H), 0.83 (t, J ) 7.7, 3 H).
IC50, µMa
COX-1 COX-2 COX-1/COX-2 IC50, µM
Active in CPE
0.095 0.095
LOXb
compd
30
31
2
1
50
32
4
8.5
12
2
7
0.04
0.22
0.015
8
6
3
0.060
5
36
46
50
57
15
0.33
10
6.6
12
NT
8
1.5
20
∼0.15
3
0.4
0.25
0.4
0.10
1
2.5
NT
3
1, tebufelone
Less Active in CPEc
8
40
25
3.1
4
>5
6.6
NT
Inactive in CPE
44
45
60
20
>100
2
5
20
18
NT
NT
∼0.30
Benchmarks
30
ibuprofen
SC-57666
3
30
0.1
<0.3
>100
a
COX testing was done by testing duplicate samples in dupli-
b
cate. 5-LOX testing was done by testing single samples in
triplicate. c Activity is statistically less than tebufelone but greater
than vehicle.
7-ter t-Bu t yl-2,3-d ih yd r o-3-et h yl-3-m et h ylb en zofu r a n
(8a ). To a -78 °C solution of 7a (2.34 g, 7.9 mmol) in dry
Et2O/hexanes (25 mL of 1:9) was added n-BuLi (1.59 M, 15.8
mmol, 9.9 mL) dropwise over 10 min. The reaction mixture
was stirred at -70 °C for 40 min, and NH4Cl (7.9 mmol, 422
mg) was added. This solution was stirred for 2 h at -10 °C,
H2O (20 mL) was added, and the organics were collected. The
water was extracted with hexanes (3 × 10 mL), and the
combined organics were dried (MgSO4) and evaporated to
provide 8a as a yellow oil (1.63 g, 95%): 1H NMR δ 7.08 (dd,
J ) 7.0, 1.8 Hz, 1 H), 6.90 (dd, J ) 7.0, 1.8 Hz, 1 H), 6.80 (t,
J ) 7.0 Hz, 1 H), 4.32 (d, J ) 9.7 Hz, 1 H), 4.10 (d, J ) 9.7 Hz,
1 H), 1.60 (q, J ) 7.7 Hz, 2 H), 1.36 (s, 9 H), 1.30 (s, 3 H), 0.82
(t, J ) 7.7 Hz, 3 H).
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3-et h yl-3-m et h yl-5-b en zo-
fu r a n yl)bu ta n -1-on e (33). Meth od A. In a three-neck flask
equipped with magnetic stir bar, Ar inlet, and septum inlet
were placed 8a (700 mg, 3.2 mmol), butyric acid (0.29 mL, 3.2
mmol), and CH2Cl2 (5 mL). The solution was cooled to -20
°C, and then trifluoroacetic anhydride (freshly distilled, 0.55
mL, 3.9 mmol) was added. After 2 h at this temperature, the
reaction mixture was allowed to warm to 23 °C and stirred
for 6 h. The reaction was quenched with H2O (15 mL), and
the aqueous layer was extracted with fresh CH2Cl2 (3 × 10
mL) and discarded. The combined organic layers were dried
(MgSO4), filtered, and evaporated to a dark oil (1.08 g) which
was purified by column chromatography using hexanes and
then 1% EtOAc in hexanes as eluent, to provide 547 mg (78%)
of 33 as a light-yellow oil: 1H NMR δ 7.80 (d, J ) 1.8 Hz, 1
H), 7.60 (d, J ) 1.8 Hz, 1 H), 4.43 (d, J ) 8.7 Hz, 1 H), 4.22 (d,
J ) 8.8 Hz, 1 H), 2.89 (t, J ) 7.2 Hz, 2 H), 1.76 (q, J ) 7.4 Hz,
2 H), 1.64 (q, J ) 7.3 Hz, 2 H), 1.38 (s, 9 H), 1.35 (s, 3 H), 1.01
(t, J ) 7.25 Hz, 3 H), 0.81 (t, J ) 7.4 Hz, 3 H); 13C NMR δ
199.3, 162.0, 136.0, 132.6, 130.6, 126.4, 121.1, 82.4, 44.7, 40.1,
34.1, 33.5, 29.1, 25.1, 18.1, 13.9, 8.7; IR 2981, 2874, 1674, 1596,
1453 cm-1; MS 289 (MH+). Anal. (C19H28O2) C, H.
no compounds were found which were more active or
potent than the DHDMBFs.
Exp er im en ta l Section
Gen er a l P r oced u r es. Reagents and solvents were gener-
ally used as received from the commercial supplier. Dry THF
and dry Et2O were obtained by distillation from sodium/
benzophenone ketyl under a N2 atmosphere. Dry hexanes,
CH2Cl2, and DMF were obtained by distillation from CaH2
under a N2 atmosphere. Reactions were routinely performed
under a N2 atmosphere in oven-dried glassware. Melting
points were determined with an electrothermal heating block
and are uncorrected. 1H and 13C NMR spectra were recorded
at 300 or 500 MHz and 75 or 125 MHz, respectively. NMR
spectra were recorded in CDCl3 unless indicated otherwise,
and chemical shifts are reported relative to tetramethylsilane
(δ ) 0.00). Infrared spectra were recorded on a Perkin-Elmer
instrument as a neat thin film on NaCl windows for oils or as
KBr pellets for solids. Routine mass spectra were obtained
using chemical ionization with NH3 or CH4 gas. Elemental
microanalyses were performed by Oneida Laboratories, Inc.
(Whitesboro, NY) or in-house at Procter & Gamble Pharma-
ceuticals in Norwich, NY. High-resolution mass spectral data
were obtained using EI as the ionization method. HPLC was
performed on a Spectra Physics system using a 300-mm C18
reverse-phase column and isocratic elution with 9:1 MeOH-
H2O and a flow rate of 1 mL/min. Low- and medium-pressure
column chromatographies were performed using Merck silica
gel 60 (270-400 mesh). TLC was performed on 250-µm
precoated Merck silica gel 60 F254 glass-backed plates. Pre-
parative TLC was performed using 20- × 20-cm 1500-µm
precoated Analtech silica gel GF plates. Spots were visualized
under 254-nm UV light or by staining with phosphomolybdate
spray reagent.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3-et h yl-3-m et h yl-5-b en zo-
fu r a n yl)bu ta n -1-on e (33). 2,4-Dibr om o-6-ter t-bu tylp h en -

1130 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
1-(7-ter t-Bu tyl-2,3-d ih yd r o-3-sp ir ocyclop en tyl-5-ben zo-
fu r a n yl)bu ta n -1-on e (34). 2,4-Dibr om o-6-ter t-bu tylp h en -
yl 1-Cyclop en t-1-en ylm eth yl Eth er (6b). A solution of 2,4-
dibromo-6-tert-butylphenol (5) (3.63 g, 11.9 mmol), acetone
(100 mL), 1-(bromomethyl)cyclopentene (1.9 g, 11.9 mmol,
prepared from 1-cyclopentenecarboxylic acid by reduction16 and
bromination17), K2CO3 (1.93 g, 14.3 mmol), and NaI (183 mg,
1.19 mmol) was reacted as described for 6a to provide 3.6 g
(78%) of 6b as a dark-yellow oil: 1H NMR δ 7.55 (d, J ) 1.8
Hz, 1 H), 7.40 (d, J ) 1.8 Hz, 1 H), 5.85 (m, 1 H), 4.60 (s, 2 H),
chromatography (hexanes, hexanes/EtOAc, 25/1) to give a
crude oil which was distilled (130-133 °C, 0.4 mmHg): 1H
NMR δ 7.77 (d, J ) 1.5 Hz, 1 H), 7.71 (s, 1 H), 4.64 (t, J ) 9.0
Hz, 2 H), 3.21 (t, J ) 9.0 Hz, 2 H), 2.89 (t, J ) 7.5 Hz, 2 H),
1.71 (m, 2 H), 1.42 (m, 2 H), 1.36 (s, 9 H), 0.95 (t, J ) 7.2 Hz,
3 H); 13C NMR δ 199.5, 162.3, 132.6, 130.2, 127.8, 126.4, 123.3,
71.5, 38.0, 34.1, 29.1, 29.0, 27.0, 22.5, 13.9; IR 2957, 2934, 2871,
1674, 1596, 1414 cm-1; MS 261 (MH+). Anal. (C17H24O2) C,
H.
1-(7-ter t-Bu tyl-2,3-dih yd r o-5-ben zofu r a n yl)-4-cyclop r o-
p ylbu ta n -1-on e (36). Method A was used. Purified by flash
column chromatography on silica (hexanes/EtOAc, 10/1 f
4/1): 1H NMR δ 7.77 (d, J ) 1.5 Hz, 1 H), 7.71 (d, J ) 1.5 Hz,
1 H), 4.65 (t, J ) 8.8 Hz, 2 H), 3.22 (t, J ) 8.5 Hz, 2 H), 2.93
(t, J ) 7.3 Hz, 2 H), 1.83 (quintet, J ) 7.5 Hz, 2 H), 1.29 (q, J
) 7.5 Hz, 2 H), (s, 9 H), 0.70 (m, 1 H), 0.42 (m, 2 H), 0.03 (m,
2 H); 13C NMR δ 199.3, 162.1, 132.5, 130.0, 127.7, 126.2, 123.1,
71.4, 34.9, 34.2, 34.0, 29.0, 28.9, 24.8, 10.6, 4.3; IR 2995, 2956,
2868, 1673, 1596, 1414 cm-1; MS 287 (MH+). Anal. (C19H26O2)
C, H.
2.45 (m, 4 H), 1.95 (quintet, J ) 7.4 Hz, 2 H), 1.40 (s, 9 H); 13
C
NMR δ 154.6, 147.2, 139.8, 134.1, 129.9, 128.0, 119.0, 116.5,
71.9, 33.1, 32.5, 30.7, 29.2, 23.3.
5-Br om o-7-ter t-b u t yl-2,3-d ih yd r o-3-sp ir ocyclop en t yl-
ben zofu r a n (7b). A solution of 6b (3.60 g, 9.33 mmol), 80%
aqueous hypophosphorus acid (18.4 g, 280 mmol), Et3N (40
mL, 280 mmol), and dioxane (175 mL) was reacted as described
for 7a to yield the desired product 7b as a 3:1 mixture with
7-tert-butyl-2,3-dihydro-3-spirocyclopentylbenzofuran (8b) (3.42
g, 119%) of sufficient purity for the next reaction: 1H NMR δ
7.15 (d, J ) 1.8 Hz, 1 H), 7.08 (d, J ) 1.8 Hz, 1 H), 4.28 (s, 2
H), 1.85 (m, 6 H), 1.70 (m, 2 H), 1.34 (s, 9 H).
7-ter t-Bu t yl-2,3-d ih yd r o-3-sp ir ocyclop en t ylb en zofu -
r a n (8b). The 3:1 mixture from above containing primarily
7b (1.62 g, 5.20 mmol) was reacted as described for 8a to
provide 8b as an orange oil (1.37 g, 110%), of sufficient purity
for the next reaction: 1H NMR δ 7.09 (dd, J ) 7.0, 1.8 Hz, 1
H), 7.00 (dd, J ) 7.0, 1.8 Hz, 1 H), 6.84 (t, J ) 7.0 Hz, 1 H),
4.28 (s, 2 H), 1.85 (bs, 6 H), 1.70 (m, 2 H), 1.36 (s, 9 H).
1-(7-ter t-Bu tyl-2,3-d ih yd r o-3-sp ir ocyclop en tyl-5-ben zo-
fu r a n yl)bu ta n -1-on e (34). Prepared by method A. Crude
product was purified by column chromatography using hex-
anes and then 1% EtOAc in hexanes as eluent, to provide 34
(170 mg, 22%) as a clear oil: 1H NMR δ 7.78 (d, J ) 1.8 Hz, 1
H), 7.64 (d, J ) 1.8 Hz, 1 H), 4.36 (s, 2 H), 2.89 (t, J ) 7.2 Hz,
2 H), 1.89-1.73 (m, 10 H), 1.38 (s, 9 H), 1.01 (t, J ) 7.4 Hz, 3
H); 13C NMR δ 199.3, 161.9, 136.4, 132.6, 130.6, 126.4, 120.9,
85.0, 52.0, 40.3, 40.2, 34.2, 29.2, 25.1, 18.2, 14.0; IR 2957, 2871,
1673, 1595 cm-1; MS 301 (MH+). Anal. (C20H28O2) C, H.
1-(7-ter t-Bu tyl-2,3-d ih yd r o-5-ben zofu r a n yl)-3-h yd r oxy-
3-m eth ylbu ta n -1-on e (37). Meth od C. 1-(7-ter t-Bu tyl-2,3-
d ih yd r o-5-ben zofu r a n yl)eth a n on e. To a suspension of
AlCl3 (0.42 g, 3.12 mmol) in CH2Cl2 (20 mL) was added acetyl
chloride (0.24 mL, 3.40 mmol). The resulting suspension was
allowed to stir at -78 °C for 30 min, and a solution of 7-tert-
butyl-2,3-dihydrobenzofuran (0.50 g, 2.84 mmol) in CH2Cl2 (5
mL) was added dropwise using an addition funnel. After the
addition was completed, the reaction mixture (pale-yellow
precipitate) was allowed to warm to room temperature over 4
h. The resulting suspension was cooled to 0 °C, the reaction
was quenched with water, and the layers were separated. The
organic phase was washed with water and brine. The aqueous
layers were extracted with CH2Cl2, and the combined organic
layers were dried (MgSO4), filtered, and concentrated. The
resulting off-white solid was recrystallized using hexanes to
give the title compound (0.54 g, 87%) as white crystals: mp
1
96-97 °C; H NMR δ 7.76 (d, J ) 1.4 Hz, 1 H), 7.70 (d, J )
1.4 Hz, 1 H), 4.65 (t, J ) 8.8 Hz, 2 H), 3.21 (t, J ) 8.8 Hz, 2
H), 2.54 (s, 3 H), 1.36 (s, 9 H); 13C NMR δ 197.1, 162.5, 132.6,
130.3, 127.9, 126.7, 123.5, 71.5, 34.1, 29.0, 28.9, 26.4; IR 3002,
2990, 2952, 2911, 1663, 1580 cm-1; MS (EI) 218 (M+), 204,
203. Anal. (C14H18O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-5-b en zofu r a n yl)p en t a n -1-
on e (35). 2,4-Dibr om o-1-(2-br om oeth oxy)-6-ter t-bu tyl-
ben zen e (9a ). To a pale-brown solution of 2,4-dibromo-6-tert-
butylphenol (5) (5.00 g, 16.24 mmol) in acetone (70 mL) were
added 1,2-dibromoethane (2.80 mL, 32.47 mmol) and K2CO3
(6.70 g, 48.72 mmol), and the mixture was allowed to reflux.
After 14 h, the mixture was filtered and concentrated. The
residue was purified by flash column chromatography on silica
(hexanes) to give an oil which was Kugelrohr distilled (210-
213 °C, 0.1 mmHg) to give 9a (5.97 g, 89%) as a pale-yellow
oil: 1H NMR δ 7.57 (d, J ) 2.3 Hz, 1 H), 7.39 (d, J ) 2.3 Hz,
1 H), 4.33 (t, J ) 6.4 Hz, 2 H), 3.75 (t, J ) 6.3 Hz, 2 H), 1.39
(s, 9 H); 13C NMR δ 153.6, 147.1, 134.2, 130.1, 118.8, 117.1,
1-(7-ter t-Bu tyl-2,3-d ih yd r o-5-ben zofu r a n yl)-3-h yd r oxy-
3-m eth ylbu ta n -1-on e (37). To a cold (-78 °C) solution of
1-(7-tert-butyl-2,3-dihydro-5-benzofuranyl)ethanone (0.45 g,
2.04 mmol) in CH2Cl2 (4.0 mL) were added TMSOTf (0.47 mL,
2.45 mmol) and i-Pr2NEt (0.43 mL, 2.31 mmol) dropwise. The
resulting mixture was stirred at -78 °C for 15 min and then
allowed to warm to room temperature over 1 h. The resulting
colorless solution was recooled to -78 °C, and acetone (0.18
mL, 2.45 mmol) and TiCl4 (0.22 mL, 2.04 mmol) were added
dropwise. The resulting deep-red solution was allowed to
warm to room temperature over 2 h; 1 N HCl was added, and
the mixture was stirred for 30 min. The reaction mixture was
diluted with CH2Cl2 and washed with water and brine. The
aqueous layers were extracted with CH2Cl2. The combined
organic layers were dried (MgSO4), filtered, and concentrated.
The residue was purified by flash column chromatography on
silica (hexanes, hexanes/EtOAc, 10/1, 8/1, 4/1) to give a crude
oil which was distilled (139-142 °C, 0.4 mmHg) to give 37
(0.42, 74%) as a colorless oil: 1H NMR δ 7.76 (s, 1 H), 7.70 (s,
1 H), 4.67 (t, J ) 8.8 Hz, 2 H), 3.22 (t, J ) 8.8 Hz, 2 H), 3.07
(s, 2 H), 1.37 (s, 9 H), 1.33 (s, 6 H); 13C NMR δ 200.6, 163.0,
132.9, 130.3, 128.1, 126.5, 123.4, 71.7, 69.9, 47.9, 34.2, 29.6,
29.2, 28.9; IR 3482, 2969, 2906, 2870, 1654, 1593 cm-1; MS
277 (MH+). Anal. (C17H24O3) C, H; C: calcd, 73.88; found,
73.41.
71.9, 35.8, 30.7, 29.2; IR 2963, 2914, 2873, 1546, 1428 cm-1
;
MS (EI) 418 (M+ + 3), 416 (M+ + 1), 414, 412.
7-ter t-Bu tyl-2,3-d ih yd r oben zofu r a n (10a ). To a cold
(-95 °C, MeOH/Et2O, liquid N2) solution of 9a (5.00 g, 12.05
mmol) in THF/hexanes (100 mL/20 mL) was added n-BuLi
(12.00 mL, 30.12 mmol) dropwise. The reaction mixture was
stirred at -95 °C for 30 min and at -80 °C for 4 h. The
reaction mixture was poured into saturated NH4Cl, extracted
with EtOAc, and washed with water and brine. The aqueous
layers were extracted with EtOAc, and the combined organic
layers were dried (MgSO4), filtered, and concentrated. The
resulting residue was purified by flash column chromatogra-
phy on silica (hexanes) to give an off-white oil which was
Kugelrohr distilled (87-90 °C, 0.25 mmHg) to give 10a (1.52
g, 72%) as a low-melting white solid: 1H NMR δ 7.07 (d, J )
7.5 Hz, 2 H), 6.80 (t, J ) 7.2 Hz, 1 H), 4.56 (t, J ) 8.7 Hz, 2
H), 3.18 (t, J ) 8.7 Hz, 2 H), 1.37 (s, 9 H); 13C NMR δ 158.7,
132.9, 127.3, 124.6, 122.6, 120.1, 70.31, 34.1, 29.7, 29.2; IR
2956, 2912, 2873, 1591, 1482 cm-1; MS (EI) 176 (M+), 161,
133.
1-(7-ter t-Bu tyl-2,3-d ih yd r o-5-ben zofu r a n yl)-5-h exyn -1-
on e (38). Method A was used. Crude product was purified
by flash column chromatography on silica (hexanes, hexanes/
EtOAc, 10/1) to give a yellow oil which was Kugelrohr distilled
(175-177 °C, 0.2 mmHg) to give 38 (0.76 g, 85%): 1H NMR δ
7.78 (s, 1 H), 7.72 (s, 1 H), 4.64 (t, J ) 8.8 Hz, 2 H), 3.20 (t, J
1-(7-ter t-Bu t yl-2,3-d ih yd r o-5-b en zofu r a n yl)p en t a n -1-
on e (35). Method A was used. Purified by flash column

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1131
) 8.7 Hz, 2 H), 3.05 (t, J ) 7.3 Hz, 2 H), 2.33-2.28 (m, 2 H),
1.98-1.92 (m, 3 H), 1.36 (s, 9 H); 13C NMR δ 198.3, 162.4,
132.6, 130.0, 127.8, 126.3, 123.2, 83.9, 71.4, 68.9, 36.6, 34.1,
29.0, 28.9, 23.2, 17.9; IR 3299, 2957, 2906, 2869, 2152, 1672,
1596 cm-1; MS (EI) 270 (M+), 255, 219, 218, 204, 203. Anal.
(C18H22O2) C, H.
2-Br om o-1-(2-m eth yl-2-p r op en oxy)ben zen e (11). To a
solution of 2-bromophenol (5.00 g, 28.90 mmol) in acetone (50
mL) were added 3-chloro-2-methylpropene (3.14 mL, 31.79
mmol), n-Bu4NI (catalytic amount), and K2CO3 (6.00 g, 43.35
mmol). The reaction mixture was stirred at room temperature
in the dark. After 2 h, the mixture was filtered and concen-
trated. The residue was purified by flash column chromatog-
raphy on silica (hexanes) to give 11 (2.89 g, 44%) as a colorless
oil: 1H NMR δ 7.55 (dd, J ) 8.0, 1.5 Hz, 1 H), 7.24 (td, J )
8.0, 1.5 Hz, 1 H), 6.88 (dd, J ) 8.2, 1.3 Hz, 1 H), 6.83 (td, J )
7.7, 1.5 Hz, 1 H), 5.17 (q, J ) 1.0 Hz, 1 H), 5.02 (t, J ) 1.5 Hz,
1 H), 4.50 (s, 2 H), 1.87 (d, J ) 1.0 Hz, 3 H); 13C NMR δ 155.0,
140.2, 133.3, 128.3, 121.9, 113.4, 112.8, 112.3, 72.4, 19.3.
2,3-Dih yd r o-3,3-d im eth ylben zofu r a n (12). To a de-
gassed solution of 11 (2.44 g, 10.75 mmol) in dimethylaceta-
mide (20 mL) was added NaBH4 (2.44 g, 64.52 mmol) followed
by Cp2TiCl2 (1.07 g, 4.30 mmol) over 2 min. The resulting
purple mixture was stirred at ∼75 °C. After 17 h, the mixture
was cooled to room temperature, diluted with hexanes, and
washed with 0.1 N HCl, water, and brine. The aqueous layers
were extracted with hexanes, and the combined organic layer
was dried over (MgSO4), filtered, and concentrated. The
residue was purified by flash column chromatography on silica
(hexanes) to give 12 (0.44 g, 64%) as a colorless oil: 1H NMR
δ 7.12 (t, J ) 7.2 Hz, 2 H), 6.90 (t, J ) 7.2 Hz, 1 H), 6.81 (d,
J ) 8.7 Hz, 1 H), 4.24 (s, 2 H), 1.36 (s, 6 H); 13C NMR δ 159.1,
136.5, 127.9, 122.2, 120.5, 109.6, 84.4, 41.9, 27.5.
(s, 6 H), 1.32 (s, 6 H); 13C NMR δ 200.2, 164.0, 137.6, 130.9,
130.3, 122.8, 109.4, 85.5, 69.9, 48.0, 41.4, 29.6, 27.6; IR 3473,
2967, 2888, 1659, 1603, 1488 cm-1; MS 249 (MH+). Anal.
(C15H20O3) C, H; C: calcd, 72.55; found, 71.84.
1-(2,3-Dih yd r o-5-b en zofu r a n yl)p en t a n -1-on e
(42).
Method A was used. The crude product was purified by flash
chromatography eluting with 10% EtOAc/hexanes and then
crystallized from 10% EtOAc/hexanes: mp 56-57 °C; 1H NMR
δ 7.84 (s, 1 H), 7.83 (d, J ) 8.4 Hz, 1 H), 6.79 (d, J ) 8.4 Hz,
1 H), 4.65 (t, J ) 8.7 Hz, 2 H), 3.25 (t, J ) 8.7 Hz, 2 H), 2.89
(t, J ) 7.2 Hz, 2 H), 1.75 (m, 2 H), 1.39 (m, 2 H), 0.94 (t, J )
7.2 Hz, 3 H); 13C NMR δ 199.1, 164.1, 130.5, 130.0, 127.6,
125.3, 108.9, 72.1, 38.1, 29.0, 26.9, 22.6, 14.0; IR 3020, 2962,
2934, 2873, 1669, 1602, 1492 cm-1; MS 205 (MH+), 233 (M +
C2H5+), 245 (M + C3H5+). Anal. (C13H16O2) C, H.
1-(2,3-Dih yd r o-5-ben zofu r a n yl)-4-cyclop r op ylbu ta n -1-
on e (43). Method A was used. The crude product was
purified by flash chromatography eluting with 10% EtOAc/
hexanes and was then recrystallized from 5% EtOAc/hex-
anes: mp 41-42 °C; 1H NMR δ 7.83 (d, J ) 1.8 Hz, 1 H), 7.78
(dd, J ) 9.0, 1.8 Hz, 1 H), 6.76 (d, J ) 9.1 Hz, 1 H), 4.65 (t, J
) 6.6 Hz, 2 H), 3.25 (t, J ) 6.7 Hz, 2 H), 2.85 (t, J ) 7.0 Hz,
2 H), 1.82 (m, 2 H), 1.23 (q, J ) 7.0 Hz, 2 H), 0.65 (m, 1 H),
0.40 (m, 2 H), 0.12 (m, 2 H); 13C NMR δ 200.1, 164.1, 130.5,
130.0, 127.6, 125.3, 108.9, 72.1, 38.0, 34.3, 29.0, 24.8, 10.7, 4.4;
IR 3020, 1669, 1606 cm-1; MS 231 (MH+), 147. Anal.
(C15H18O2) C, H.
1-(2,3-Dih yd r o-3,3-d im eth yl-7-eth yl-5-ben zofu r a n yl)-4-
cyclop r op ylbu ta n -1-on e (44). 2,4-Dibr om o-6-eth ylp h e-
n ol. To a solution of 2-ethylphenol (50 g, 0.41 mol) in MeOH
(100 mL) at 0 °C was added Br2 (42 mL, 0.86 mol) dropwise
over 45 min. The reaction mixture was allowed to warm to
23 °C and stirred for 3 h. The reaction was quenched with
H2O (50 mL), the MeOH evaporated, and the water extracted
with CH2Cl2 (3 × 50 mL). The organic layers were dried
(MgSO4) and evaporated to a dark oil which was dissolved in
hexanes (100 mL) and stirred with silica gel (70 g). The silica
was removed by filtration, and the hexanes were evaporated
to give the product as an orange oil (113 g, 99%), which was
used without further purification: 1H NMR δ 7.42 (d, J ) 1.5
Hz, 1 H), 7.20 (d, J ) 1.5 Hz, 1 H), 5.60 (s, 1 H), 2.69 (q, J )
8.7 Hz, 2 H), 1.25 (t, J ) 8.7 Hz, 3 H).
2,4-Dibr om o-6-eth ylp h en yl 2-Meth a llyl Eth er (13a ). A
mixture of 2,4-dibromo-6-ethylphenol (25 g, 89 mmol), acetone
(500 mL), 3-chloro-2-methylpropene (13.3 mL, 134 mmol),
K2CO3 (14.8 g, 107 mmol), and NaI (1.33 g, 8.9 mmol) was
refluxed 6 h. The reaction mixture was cooled to 23 °C, the
solids were removed by filtration, and the acetone was
evaporated to give 13a as a yellow oil (28.64 g, 97%) which
was used without further purification: 1H NMR δ 7.57 (d, J
) 1.5 Hz, 1 H), 7.29 (d, j ) 1.5 Hz, 1 H0, 5.21 (s, 1 H), 5.03 (s,
1 H), 4.28 (s, 2 H), 2.70 (q, J ) 8.7 Hz, 2 H), 1.93 (s, 3 H), 1.27
(t, J ) 8.7 Hz, 3H).
5-Br om o-2,3-d ih yd r o-3,3-d im e t h yl-7-e t h ylb e n zofu -
r a n (14a ). A solution of 13a (26 g, 78 mmol), Pd(OAc)2 (875
mg, 3.9 mmol), triphenylphosphine (1.02 g, 3.9 mmol), and
anhydrous DMF (1200 mL) was degassed with N2 for 15 min
and then heated to 70 °C. To this solution was added a
solution of piperidine (30 mL) and 98% formic acid (85 mL) in
anhydrous DMF (800 mL) at a rate of 0.9 mL/min. After 200
mL was added, the addition was stopped and the reaction
mixture stirred at 70 °C overnight. The reaction mixture was
then cooled and the volume doubled with H2O. The DMF/H2O
was extracted extensively with hexanes which were dried
(MgSO4) and evaporated to a dark oil (15.5 g). The oil was
taken up in hexanes and extracted with 1 M NaOH (3 × 50
mL) and then H2O (50 mL). The organic phase was dried
(MgSO4) and evaporated, and the resulting oil was chromato-
graphed over SiO2 by medium-pressure chromatography (1%
EtOAc/hexanes). The desired product, 14a , was obtained as
a yellow oil (1.38 g, 7%). Also isolated were 2,3-dihydro-3,3-
dimethyl-7-ethylbenzofuran (15a ) (275 mg) and 2,4-dibromo-
6-ethylphenyl 2-methyl-1-propenyl ether (3.66 g, 15%): 1H
NMR δ 7.08 (d, J ) 1.8 Hz, 1 H), 7.02 (d, J ) 1.8 Hz, 1 H),
1-(2,3-Dih yd r o-3,3-d im et h yl-5-b en zofu r a n yl)b u t a n -1-
on e (39). Method A was used. The crude product was
purified by flash column chromatography on silica (hexanes,
hexanes/EtOAc, 20/1) to give an oil which was distilled (84-
1
87 °C, 0.5 mmHg) to give a solid: mp 47-48 °C; H NMR δ
7.80 (dd, J ) 8.5, 2.0 Hz, 1 H), 7.78 (d, J ) 2.0 Hz, 1 H), 6.79
(d, J ) 8.5 Hz, 1 H), 4.32 (s, 2 H), 2.89 (t, J ) 7.2 Hz, 2 H),
1.75 (sextet, J ) 7.5 Hz, 2 H), 1.37 (s, 6 H), 1.38 (t, J ) 7.5
Hz, 3 H); 13C NMR δ 199.0, 163.3, 137.3, 130.8, 130.0, 122.8,
109.8, 85.4, 41.5, 40.2, 27.6, 18.1, 14.0; IR 2950, 2873, 1676,
1605, 1488 cm-1; MS 219 (MH+). Anal. (C14H18O2) C, H.
4-Cyclopr opyl-1-(2,3-dih ydr o-3,3-dim eth yl-5-ben zofu r a-
n yl)bu ta n -1-on e (40). Method A was used. The crude
product was purified by flash column chromatography on silica
(hexanes, hexanes/EtOAc, 20/1) to give an oil which was
distilled (95-99 °C, 0.4 mmHg): 1H NMR δ 7.80 (dd, J ) 8.5,
2.0 Hz, 1 H), 7.77 (d, J ) 2.0 Hz, 1 H), 6.79 (d, J ) 8.0 Hz, 1
H), 4.31 (s, 2 H), 2.93 (t, J ) 7.3 Hz, 2 H), 1.83 (quintet, J )
7.5 Hz, 2 H), 1.36 (s, 6 H), 1.29 (q, J ) 7.5 Hz, 2 H), 0.69 (m,
1 H), 0.40 (m, 2 H), 0.03 (m, 2 H); 13C NMR δ 199.0, 163.3,
137.3, 130.8, 130.0, 122.7, 109.1, 85.4, 41.5, 38.0, 34.3, 27.6,
24.7, 10.6, 4.4; IR 3074, 2959, 2929, 1674, 1605, 1487 cm-1
Anal. (C17H22O2) C, H.
.
1-(2,3-Dih ydr o-3,3-dim eth yl-5-ben zofu r an yl)-3-h ydr oxy-
3-m eth ylbu ta n -1-on e (41). 1-(2,3-Dih yd r o-3,3-d im eth yl-
5-ben zofu r a n yl)eth a n on e. Method C was used. The crude
product was purified by flash column chromatography on silica
(hexanes/EtOAc, 20/1) to give an oil which was distilled (72-
74 °C, 0.5 mmHg) to afford a solid: yield 77%, mp 35-37 °C;
1H NMR δ 7.80 (dd, J ) 8.5, 1.5 Hz, 1 H), 7.77 (d, J ) 1.5 Hz,
1 H), 6.79 (d, J ) 8.5 Hz, 1 H), 4.31 (s, 2 H), 2.54 (s, 3 H), 1.36
(s, 6 H); 13C NMR δ 196.7, 163.5, 137.3, 130.9, 130.5, 122.9,
109.2, 85.4, 41.3, 27.6, 26.4; IR 2960, 2884, 1673, 1606, 1487
cm-1
.
1-(2,3-Dih ydr o-3,3-dim eth yl-5-ben zofu r an yl)-3-h ydr oxy-
3-m eth ylbu ta n -1-on e (41). Method C was used. The crude
product was purified by flash column chromatography on silica
(hexanes, hexanes/EtOAc, 10/1, 3/1) to give 41 (0.32 g, 94%,
based on recovered starting material) as a colorless oil: 1H
NMR δ 7.78 (dd, J ) 8.5, 2.0 Hz, 1 H), 7.75 (d, J ) 2.0 Hz, 1
H), 6.79 (d, J ) 8.5 Hz, 1 H), 4.32 (s, 2 H), 3.07 (s, 2 H), 1.36

1132 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
4.21 (s, 2 H), 2.57 (q, J ) 8.7 Hz, 2 H), 1.33 (s, 6 H), 1.19 (t, J
) 8.7 Hz, 3 H).
δ 7.29 (dd, J ) 7.8, 1.8 Hz, 1 H), 7.15 (dd, J ) 7.8, 1.8 Hz, 1
H), 6.75 (t, J ) 7.8 Hz, 1 H), 4.20 (s, 2 H), 3.05 (m, 1 H), 2.05
(m, 2 H), 1.50-1.80 (m, 6 H), 1.30 (s, 6 H).
2,3-Dih yd r o-3,3-d im eth yl-7-eth ylben zofu r a n (15a ). A
solution of 14a (840 mg) and 10% Pd/C (125 mg) in EtOH (10
mL) was shaken under 45 psi H2 atmosphere for 18 h. The
reaction mixture was filtered through a pad of Celite, and the
filtrate was evaporated to a thick orange oil (650 mg). This
was taken up in hexanes, the insolubles were filtered, and the
hexanes were evaporated to give 15a as a light-orange oil (464
mg, 80%) which was used without further purification: 1H
NMR δ 7.08 (d, J ) 7.8 Hz, 1 H), 6.97 (t, J ) 7.8 Hz, 1 H),
6.84 (t, J ) 7.8 Hz, 1 H), 4.22 (s, 2 H), 2.61 (q, J ) 8.7 Hz, 2
H), 1.36 (s, 6 H), 1.24 (t, J ) 8.7 Hz, 3 H).
1-(2,3-Dih yd r o-3,3-d im eth yl-7-eth yl-5-ben zofu r a n yl)-4-
cyclop r op ylbu ta n -1-on e (44). Method A was used. The
crude product was purified by preparative TLC (1500 µm, 2%
EtOAc/hexanes): 1H NMR δ 7.68 (d, J ) 1.5 Hz, 1 H), 7.62 (d,
J ) 1.5 Hz, 1 H), 4.34 (s, 2 H), 2.95 (t, J ) 7.7 Hz, 2 H), 2.65
(q, J ) 8.7 Hz, 2 H), 1.85 (quintet, J ) 7.7 Hz, 2 H), 1.38 (s, 6
H), 1.30 (m, 2 H), 1.26 (t, J ) 8.7 Hz, 3 H), 0.71 (m, 1 H), 0.42
(m, 2 H), 0.02 (m, 2 H); 13C NMR δ 199.3, 162.0, 136.6, 130.9,
129.1, 125.8, 120.4, 85.2, 41.7, 38.0, 34.4, 27.7, 24.8, 22.8, 13.8,
10.7, 4.4; IR 2963, 1672, 1599, 1460 cm-1; MS 287 (MH+). Anal.
(C19H26O2) C, H.
1-(7-Cyclopen tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zofu r a-
n yl)-4-cyclop r op ylb u t a n -1-on e (45). 6-Cyclop en t yl-2,4-
d ibr om op h en ol. To a solution of 2-cyclopentylphenol (24 g,
148.8 mmol) in MeOH (50 mL) at 0 °C was added Br2 (22.87
mL, 446 mmol) dropwise over 1 h. The reaction mixture was
warmed to 23 °C and stirred for 64 h. The reaction mixture
was quenched with H2O (50 mL), the MeOH evaporated, and
the aqueous mixture extracted with CH2Cl2 (3 × 50 mL). The
organic layers were dried (MgSO4) and evaporated to a dark-
red oil which was dissolved in hexanes (30 mL) and stirred in
silica gel (5 g). The silica was removed by filtration, and the
hexanes were evaporated to provide the product as an orange
oil (43.33 g, 92%) which was used without further purifica-
tion: 1H NMR δ 7.41 (d, J ) 1.5 Hz, 1 H), 7.23 (d, J ) 1.5 Hz,
1 H), 5.58 (s, 1 H), 3.25 (quintet, J ) 9.7 Hz, 1 H), 1.98-2.10
(m, 2 H), 1.60-1.90 (m, 4 H), 1.52-1.58 (m, 2 H).
6-Cyclop en tyl-2,4-d ibr om op h en yl 2-Meth a llyl Eth er
(13b). Prepared from 6-cyclopentyl-2,4-dibromophenol as
described for 13a to give a dark oil (28.6 g). This oil was
dissolved in hexanes (100 mL) and stirred with silica gel (40
g). The silica was removed by filtration, and the hexanes were
evaporated to give 13b as a dark-yellow oil (38 g, 75%), suitable
for the next reaction without further purification: 1H NMR δ
7.50 (d, J ) 1.5 Hz, 1 H), 7.31 (d, J ) 1.5 Hz, 1 H), 5.19 (s, 1
H), 5.00 (s, 1 H), 4.28 (s, 2 H), 3.34 (quintet, J ) 10.3 Hz, 1
H), 2.05 (m, 2 H), 1.90 (s, 3H), 1.65-1.90 (m, 4 H), 1.25-1.35
(m, 2 H).
5-Br om o-7-cyclop en t yl-2,3-d ih yd r o-3,3-d im et h ylb en -
zofu r a n (14b). Prepared from 13b as described for 14a to
give a dark oil (21.2 g). This oil was dissolved in hexanes,
washed with 1 M NaOH (3 × 50 mL), and then purified by
medium-pressure chromatography (1% EtOAc/hexanes) to give
14b as a yellow oil (4.21 g, 14%), suitable for the next
reaction: 1H NMR δ 7.10 (d, J ) 1.8 Hz, 1 H), 6.99 (d, J ) 1.8
Hz, 1 H), 4.20 (s, 2 H), 3.05 (quintet, J ) 8.3 Hz, 1 H), 2.05
(m, 2 H), 1.50-1.80 (m, 6 H), 1.33 (s, 6 H); 13C NMR δ 156.1,
138.2, 130.5, 128.4, 122.6, 112.4, 84.3, 42.2, 39.9, 32.8, 27.4,
25.4.
7-Cyclop e n t yl-2,3-d ih yd r o-3,3-d im e t h yl-5-b e n zofu -
r a n (15b). This compound was isolated as a side product in
the following carboxylation reaction. To a solution of 14b (3.95
g, 13.4 mmol) in dry THF (15 mL) at -78 °C was added n-BuLi
(10.7 mL, 26.8 mmol, 2.5 M solution in hexanes) dropwise over
10 min. The reaction mixture was slowly warmed to -20 °C
and then cooled back to -50 °C. A large excess of freshly
crushed dry ice was added and the milky-brown suspension
warmed to 0 °C for 1 h. The THF was then evaporated, and
the reaction mixture was dissolved in Et2O and washed with
1 N NaOH (50 mL). The Et2O was dried (MgSO4) and
evaporated to give 15b (595 mg, 21%) as a yellow oil: 1H NMR
1-(7-Cyclopen tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zofu r a-
n yl)-4-cyclop r op ylbu ta n -1-on e (45). Method A was used.
The crude product was purified by preparative TLC (1500 µm,
hexanes/EtOAc, 99/1): 1H NMR δ 7.73 (d, J ) 1.5 Hz, 1 H),
7.61 (d, J ) 1.5 Hz, 1 H), 4.32 (s, 2 H), 3.14 (m, 1 H), 2.96 (t,
J ) 8.7 Hz, 2 H), 2.05 (m, 2 H), 1.83 (m, 4 H), 1.68 (m, 4 H),
1.38 (s, 6 H), 1.30 (q, J ) 8.7 Hz, 2 H), 0.70 (m, 1 H), 0.42 (m,
2 H), 0.05 (m, 2 H); 13C NMR δ 199.2, 161.4, 136.6, 130.9, 128.1,
127.5, 120.2, 85.0, 41.6, 40.0, 38.0, 34.3, 32.7, 27.6, 25.4, 24.8,
10.7, 4.4; IR 2957, 1673, 1598 cm-1; MS 327 (MH+); HRMS
calcd for C22H30O2 (MH+) 327.2324, found 327.2298; HPLC:
89.6%. Anal. (C22H30O2) C, H; C: calcd, 80.94; found, 81.68.
1-(7-ter t-Bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zoth ien yl)-
bu ta n -1-on e (46). 2-Br om o-6-ter t-bu tylth iop h en ol (20).
To a solution of tetramethylethylenediamine (198.4 mmol, 30
mL) in cyclohexanes (140 mL) was slowly added n-BuLi (99.2
mL, 198.4 mmol, 2 M solution in cyclohexanes) at 23 °C. The
resulting solution was cooled to 0 °C. A solution of 2-tert-
butylthiophenol (15.0 g, 90.2 mmol) in cyclohexanes (40 mL)
was then added at a rate such that the temperature stayed
below 10 °C. The reaction mixture was then stirred at 0 °C
for 5 h and allowed to warm to 23 °C overnight. To the
resulting yellow solution at 23 °C was added sec-BuLi (69.4
mL, 90.2 mmol, 1.3 M solution in cyclohexanes) over 0.5 h.
The resulting solution gradually turned orange. After 1.5 h,
the orange, cloudy reaction mixture was cannulated into a
stirring solution of 1,2-dibromotetrafluoroethane (21.5 mL,
180.4 mmol) in THF (50 mL) over 1 h. After addition was
complete, the resulting reaction was quenched with 1 N HCl
(80 mL) and extracted with hexanes (3 × 100 mL). The
hexanes were dried (MgSO4) and evaporated to a dark oil
(29.48 g). This oil was taken up in 1 N NaOH (100 mL) and
extracted with CH2Cl2 (3 × 50 mL). The organic phase was
discarded, and the aqueous phase was acidified with 12 N HCl
and extracted with CH2Cl2 (3 × 100 mL). The organic phase
was dried (MgSO4) and evaporated to provide 20 as a yellow
oil (12.4 g, 56%): 1H NMR δ 7.46 (dd, J ) 8.7, 1.4 Hz, 1 H),
7.30 (dd, J ) 8.7, 1.4 Hz, 1 H), 6.90 (t, J ) 8.7 Hz, 1 H), 4.85
(s, 1 H), 1.47 (s, 9 H); MS 244, 246 (MH+).
2-Br om o-6-ter t-bu tylph en yl 2-Meth allyl Th ioeth er (21).
A solution of 20 (12.4 g, 50.6 mmol), K2CO3 (8.44 g, 61.1 mmol),
NaI (766 mg, 50.6 mmol), and 3-chloro-2-methylpropene (5.17
mL, 50.6 mmol) in acetone (250 mL) was heated at reflux for
2 h. The reaction mixture was allowed to cool to 23 °C, and
the precipitated solids were filtered off. The filtrate was
evaporated to a dark-yellow oil, which was taken up in hexanes
(100 mL) and stirred with silica gel (10 g) for 20 min. The
silica gel was filtered off and discarded, and the filtrate was
evaporated to yield 21 as a light-yellow oil (9.01 g, 59.4%): 1H
NMR δ 7.58 (dd, J ) 8.0, 0.9 Hz, 1 H), 7.42 (dd, J ) 8.0, 0.9
Hz, 1 H), 7.08 (t, J ) 8.0 Hz, 1 H), 4.98 (s, 1 H), 4.91 (s, 1 H),
3.53 (s, 2 H), 1.94 (s, 3 H), 1.58 (s, 9 H).
7-t er t -B u t y l-2,3-d i h y d r o -3,3-d i m e t h y lb e n z o t h i o -
p h en e (22). A solution of 21 (9.00 g, 30.0 mmol), i-Pr2NEt
(160 mL, 0.90 mol), and 80% aqueous hypophosphorus acid
(58 g, 0.90 mol) in dioxane (450 mL) was reacted as described
for 7a to yield the crude product as a yellow oil (5.61 g). Short-
path vacuum distillation (85 °C, 40 mmHg) of this material
provided 22 as a faint-yellow oil of approximately 80% purity
by GC analysis, which was used without further purification:
1H NMR δ 7.19 (d, J ) 7.0 Hz, 1 H), 7.10 (t, J ) 7.0 Hz, 1 H),
6.92 (d, J ) 7.0 Hz, 1 H), 3.07 (s, 2 H), 1.41 (s, 9 H), 1.33 (s, 6
H); MS 221 (MH+).
1-(7-ter t-Bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zoth ien yl)-
bu ta n -1-on e (46). Method A was used. The crude product
was purified by medium-pressure chromatography (1% EtOAc/
hexanes): 1H NMR δ 7.84 (d, J ) 1.7 Hz, 1 H), 7.54 (d, J )
1.7 Hz, 1 H), 3.19 (s, 2 H), 2.94 (t, J ) 7.1 Hz, 2 H), 1.78 (m,
J ) 7.1 Hz, 2 H), 1.48 (s, 9 H), 1.43 (s, 6 H), 1.02 (t, J ) 7.1
Hz, 3 H); 13C NMR δ 200.1, 150.0, 145.4, 144.7, 134.0, 125.1,
120.1, 47.3, 46.3, 40.6, 36.0, 29.2, 27.8, 18.2, 14.2; IR 2950,

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1133
as a yellowish oil, which solidified upon refrigeration: mp 64-
2928, 2871, 1679 cm-1; HRMS calcd for C18H26OS (MH+)
291.1783, found 291.1776; HPLC 95.2%. Anal. (C18H26OS) C,
H, S; C: calcd, 74.43; found, 73.73.
1
65 °C; H NMR δ 7.13 (d, J ) 1.8 Hz, 1 H), 7.00 (d, J ) 1.8
Hz, 1 H), 3.33 (s, 2 H), 1.31 (s, 9 H), 1.27 (s, 6 H); MS 283
(MH+).
1-(7-ter t-Bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zoth ien yl)-
4-cyclop r op ylbu ta n -1-on e (47). Method A was used. The
crude product was purified by medium-pressure chromatog-
raphy (1% EtOAc/hexanes): 1H NMR δ 7.80 (d, J ) 1.7 Hz, 1
H), 7.70 (d, J ) 1.7 Hz, 1 H), 3.15 (s, 2 H), 2.96 (t, J ) 7.5 Hz,
2 H), 1.84 (m, 2 H), 1.42 (s, 9 H), 1.38 (s, 6 H), 1.30 (m, 2 H),
0.70 (m, 1 H), 0.41 (m, 2 H), 0.10 (m, 2 H); 13C NMR δ 200.0,
149.7, 145.0, 144.4, 133.9, 124.9, 119.8, 47.0, 45.9, 38.1, 35.6,
5-Br om o-7-t er t -b u t yl-2,3-d ih yd r o-1,3,3-t r im e t h ylin -
d ole (27). Formaldehyde (1.64 mL, 21.9 mmol, 37% aqueous
solution) and NaBH3CN (0.50 g, 8.0 mmol) were added to a
solution of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylindole
(2.07 g, 7.3 mmol) in 10 mL of of 1:9 HOAc-CH3CN mixture.
The reaction mixture was stirred for 0.5 h, poured into a 1:1
mixture of H2O and 50% aqueous NaOH, and extracted with
Et2O. The extract was washed with H2O, dried (MgSO4), and
concentrated in vacuo. Purification of the residue by flash
column chromatography on silica gel (1% f 2% EtOAc/
hexanes) yielded 27 (1.52 g, 70%) as a yellowish oil: 1H NMR
δ 7.15 (d, J ) 1.8 Hz, 1 H), 7.02 (d, J ) 1.8 Hz, 1 H), 3.36 (s,
2 H), 3.08 (s, 3 H), 1.34 (s, 9 H), 1.30 (s, 6 H); MS 296 (MH+).
4-Cyclop r op ylbu ta n a l. Pyridinium chlorochromate (12.33
g, 57.2 mmol) was added to a solution of 4-cyclopropylbutanol
(3.78 g, 33.2 mmol) in 82 mL of CH2Cl2. The brown reaction
mixture was vigorously stirred for 1.5 h; Et2O was added to
the mixture, and stirring was continued for 20 min. The
resulting mixture was filtered through a short column of silica
gel and concentrated in vacuo to give 3.17 g of the crude
product. Purification by flash column chromatography on
silica gel (5% Et2O/hexanes) afforded 2.48 g (67%) of 4-cyclo-
propylbutanal as a yellowish oil: 1H NMR δ 9.77 (d, J ) 1.1
Hz, 1 H), 2.46 (dt, J ) 7.4, 1.1 Hz, 2 H), 1.73 (m, 2 H), 1.24 (q,
J ) 7.4 Hz, 2 H), 0.66 (m, 1 H), 0.40 (m, 2 H), 0.03 (m, 2 H).
7-ter t-Bu tyl-5-(4-cyclopr opylbu tan oyl)-2,3-dih ydr o-1,3,3-
tr im eth ylin d ole (48). Meth od D. t-BuLi (1.6 mL, 2.7 mmol,
1.7 M in pentane) was added dropwise to a solution of 27 (0.38
g, 1.3 mmol) in 7 mL of anhydrous Et2O at -78 °C; the
resulting yellow solution was stirred at -78 °C for 10 min,
and 4-cyclopropylbutanal (0.21 g, 1.9 mmol) was introduced.
The reaction mixture was kept at -78 °C for 15 min, warmed
to -20 °C, quenched with H2O, and warmed to room temper-
ature. The ethereal layer was dried (MgSO4) and concentrated
to give a yellowish viscous oil, which was dissolved in 5 mL of
CH2Cl2 and reacted for 3 h with 4-methylmorpholine N-oxide
(0.09 g, 0.8 mmol) and tetrapropylammonium perruthenate
(0.04 g, 0.1 mmol). The reaction mixture was filtered through
34.2, 28.8, 27.4, 24.7, 10.6, 4.3; IR 2961, 1676, 1587 cm-1
;
HRMS calcd for C21H30OS (MH+) 331.2096, found 331.2106;
HPLC 96.4%.
7-ter t-Bu tyl-5-(4-cyclopr opylbu tan oyl)-2,3-dih ydr o-1,3,3-
tr im eth ylin dole (48). 7-ter t-Bu tyl-2-in d olin on e (25). Eth-
yl (methylthio)acetate (13.0 mL, 0.1 mol) was added dropwise
to a solution of chlorine (ca. 9.4 g, 0.13 mol) in 500 mL of CH2-
Cl2 at -78 °C. To the reaction mixture at -78 °C was added
over 10 min 2-tert-butylaniline (15.6 mL, 0.1 mol) followed by
Et3N (25 mL, 0.18 mol) over 25 min. The resulting brown
suspension was warmed to room temperature and the reaction
quenched with 1 N HCl. This mixture was stirred for 1 h,
and the organic layer was washed with H2O, dried over
anhydrous MgSO4, and concentrated to give 30.0 g of a brown
solid. This solid residue was dissolved in 220 mL of EtOAc,
and the resulting solution was hydrogenated for 24 h with
Raney nickel (30 g). The reaction mixture was filtered through
a short column of silica gel; the filtrate was placed at room
temperature for 3 days to allow for slow evaporation of the
solvent, thus affording 6.51 g (34%) of 25 as slightly amber
1
transparent crystals: mp 162-163 °C; H NMR δ 8.56 (bs, 1
H), 7.21 (d, J ) 7.6 Hz, 1 H), 7.10 (d, J ) 7.6 Hz, 1 H), 6.98 (t,
J ) 7.6 Hz, 1 H), 3.52 (s, 2 H), 1.39 (s, 9 H); MS 190 (MH+),
207 (MNH4+).
7-ter t-Bu tyl-3,3-d im eth yl-2-in d olin on e. Lithium diiso-
propylamide (30.0 mL, 60.0 mmol, 2.0 M solution in heptane-
THF-ethylbenzene) was added to a solution of 25 (3.0 g, 15.9
mmol) in 60 mL of anhydrous THF at -78 °C. The reaction
mixture was stirred at -78 °C for 15 min, and CH3I (2.5 mL,
40.1 mmol) was added. The resulting mixture was kept at
-78 °C for 0.5 h, warmed to 0 °C, stirred for 0.5 h, quenched
with H2O, and extracted with EtOAc. The extract was dried
(MgSO4) and concentrated to give a yellow solid residue.
Recrystallization from acetone afforded 2.87 g (83%) of the title
a
short column of silica gel and concentrated in vacuo.
Purification of the residue by flash column chromatography
on silica gel (10% Et2O/hexanes) gave 48 (0.23 g, 54%) as a
light-yellow oil which solidified upon storage in a refrigera-
1
compound as a light-orange solid: mp 167-170 °C; H NMR
1
δ 8.55-8.25 (br, 1 H), 7.18 (d, J ) 8.0 Hz, 1 H), 7.00 (m, 2 H),
1.35 (s, 15 H); 13C NMR δ 183.8, 137.2, 136.9, 132.0, 124.7,
122.3, 120.3, 43.3, 34.0, 29.8, 24.4; IR 3206, 3083, 2965, 1709,
1601 cm-1; MS 218 (MH+).
tor: mp 44-46 °C; H NMR δ 7.89 (d, J ) 1.8 Hz, 1 H), 7.47
(d, J ) 1.8 Hz, 1 H), 3.20 (s, 2 H), 3.05 (s, 3 H), 2.88 (t, J ) 7.4
Hz, 2 H), 1.79 (m, 2 H), 1.43 (s, 9 H), 1.27 (m, 2 H), 1.25 (s, 6
H), 0.66 (m, 1 H), 0.38 (m, 2 H), 0.02 (m, 2 H); 13C NMR δ
199.2, 154.4, 143.2, 143.2, 133.9, 128.6, 119.5, 71.8, 44.4, 39.5,
37.8, 34.6, 34.4, 31.6, 28.6, 25.0, 10.6, 4.30; IR 2957, 2865, 1668,
1600, cm-1; MS 328 (MH+). Anal. (C22H33NO) C, H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth ylin d ole (26). A so-
lution of 7-tert-butyl-3,3-dimethyl-2-indolinone (2.17 g, 10.0
mmol) in 50 mL of THF was added to a suspension of LiAlH4
(2.20 g, 57.9 mmol) in 50 mL of ether. The reaction mixture
was heated at reflux for 17 h, cooled to 0 °C, and quenched
with H2O until white solids precipitated out of solution. The
organic phase was decanted out, and the solid residue was
rinsed with EtOAc. The combined organics were dried (Na2-
SO4) and concentrated to afford 26 (1.86 g, 91%) as an oil: 1H
NMR δ 7.07 (dd, J ) 8.0, 1.8 Hz, 1 H), 6.94 (dd, J ) 8.0, 1.8
Hz, 1 H), 6.74 (t, J ) 8.0 Hz, 1 H), 3.32 (s, 2 H), 1.37 (s, 9 H),
1.28 (s, 6 H); 13C NMR δ 147.5, 139.2, 131.6, 124.1, 119.8,
118.6, 61.3, 40.8, 34.1, 29.4, 27.5; IR 3427, 2957, 2865, 1591
cm-1; MS 204 (MH+).
5-Br om o-7-ter t-b u t yl-2,3-d ih yd r o-3,3-d im et h ylin d ole.
A solution of bromine (1.0 mL, 18.5 mmol) in 5 mL of CH2Cl2
was added to a solution of 26 (3.75 g, 18.5 mmol) in 65 mL of
CH2Cl2. The reaction mixture was stirred for 0.5 h and
concentrated to afford 6.35 g of a solid residue, which was
washed with hexane, suspended in 100 mL of MeOH, and
reacted for 0.5 h with Et3N (1.77 g, 17.5 mmol). This mixture
was concentrated in vacuo, and the residue was partitioned
between Et2O and H2O. The organic layer was dried (MgSO4)
and concentrated to furnish 4.57 g (87%) of the title compound
2,4-Dibr om o-6-ter t-bu tyl-1-((3-m eth yl-2-bu ten yl)oxy)-
ben zen e (16). To a solution of 2,4-dibromo-6-tert-butylphenol
(5) (10.00 g, 32.5 mmol) in EtOH (50 mL) were added K2CO3
(6.73 g, 48.7 mmol), a catalytic amount of n-Bu4NI, and
4-bromo-2-methyl-2-butene (5.80 mL, 39.0 mmol). The result-
ing suspension was stirred at room temperature for 48 h,
filtered, and concentrated. The residue was purified by flash
column chromatography on silica (hexanes) to give 16 (12.40
g, 100%) as an oil: 1H NMR δ 7.57 (d, J ) 2.5 Hz, 1 H), 7.38
(d, J ) 2.0 Hz, 1 H), 5.01 (t, J ) 6.5 Hz, 1 H), 4.57 (d, J ) 6.5
Hz, 2 H), 1.82 (s, 3 H), 1.76 (s, 3 H), 1.38 (s, 9 H); 13C NMR δ
157.7, 147.1, 137.9, 134.0, 129.9, 128.3, 119.7, 116.5, 70.4, 35.9,
30.7, 25.9, 18.5; IR 2963, 2873, 1568 cm-1
.
4-Br om o-2-ter t-bu tyl-1-((3-m eth yl-2-bu ten yl)oxy)ben -
zen e (17). To a cold (-78 °C) solution of 16 (12.47 g, 33.15
mmol) in THF/hexanes (100 mL/25 mL) was added n-BuLi
(13.3 mL, 2.5 M/hexanes, 33.15 mmol) dropwise. The resulting
pale-yellow solution was stirred at -78 °C for 15 min and the
reaction quenched by slow addition of H2O. The mixture was
diluted with hexanes, and the layers were separated. The
organic layer was washed with H2O followed by brine. The

1134 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
aqueous layers were extracted with hexanes; the combined
organic layers were dried (MgSO4), filtered, and concentrated.
The residue was purified by flash column chromatography on
silica (hexanes) to give 17 (9.35 g, 95%) as an oil: 1H NMR δ
7.35 (d, J ) 2.0 Hz, 1 H), 7.25 (dd, J ) 8.7, 2.3 Hz, 1 H), 6.73
(d, J ) 9.0 Hz, 1 H), 5.01 (t, J ) 6.5 Hz, 1 H), 4.51 (d, J ) 6.5
Hz, 2 H), 1.80 (s, 3 H), 1.73 (s, 3 H), 1.36 (s, 9 H); 13C NMR δ
156.8, 140.7, 137.2, 129.7, 129.4, 119.8, 114.0, 112.6, 65.1, 35.0,
IR 2958, 2872, 1674, 1595, 1465 cm-1; MS 303 (MH+). Anal.
(C20H30O2) C, H.
1-(8-ter t-Bu tyl-2,3-d ih yd r o-4,4-d im eth yl-6-ben zop yr a -
n yl)-4-cyclop r op ylbu ta n -1-on e (50). Method A was used.
The crude product was purified by flash column chromatog-
raphy on silica (hexanes, hexanes/EtOAc, 20/1) to give an oil
which was distilled (114-116 °C, 0.5 mmHg): 1H NMR δ 7.85
(d, J ) 2.5 Hz, 1 H), 7.76 (d, J ) 2.5 Hz, 1 H), 4.26 (t, J ) 5.5
Hz, 2 H), 2.95 (t, J ) 7.5 Hz, 2 H), 1.87-1.81 (m, 4 H), 1.39 (s,
9 H), 1.37 (s, 6 H), 1.30 (q, J ) 7.5 Hz, 2 H), 0.71 (m, 1 H),
0.42 (m, 2 H), 0.04 (m, 2 H); 13C NMR δ 199.8, 157.0, 137.6,
131.7, 128.7, 125.9, 124.7, 62.7, 37.8, 37.0, 35.0, 34.4, 31.4, 31.0,
29.5, 25.7, 18.2; IR 2872, 1583 cm-1
.
4-Br om o-2-t er t -b u t yl-1-((3-h yd r oxy-3-m e t h ylb u t yl)-
oxy)ben zen e (18). To a yellow suspension of Hg(OAc)2 (6.36
g, 19.94 mmol) in THF/H2O (25 mL/30 mL) was added 17 (5.93
g, 19.941 mmol) in THF (5 mL) dropwise, and the mixture
stirred at room temperature for 4 h. To the resulting pale-
yellow solution was added NaOH (15 mL, 3 M) followed by
NaBH4 (0.75 g, 19.94 mmol) in NaOH (5 mL, 3 M). The
resulting ash-colored suspension was stirred at room temper-
ature for 30 min, diluted with hexanes, and washed with
water, saturated aqueous NH4Cl, and brine. The aqueous
layers were extracted with hexanes; the combined organic
layers were dried (MgSO4), filtered, and concentrated. The
residue was purified by flash column chromatography on silica
(hexanes/EtOAc, 10/1 f 3/1) to give 18 (4.21 g, 67%) as an oil:
1H NMR δ 7.35 (d, J ) 2.0 Hz, 1 H), 7.26 (dd, J ) 8.5, 2.5 Hz,
1 H), 6.78 (d, J ) 8.5 Hz, 1 H), 4.15 (t, J ) 7.5 Hz, 2 H), 2.07
(t, J ) 7.5 Hz, 2 H), 1.67 (s, 1 H), 1.35 (s, 9 H), 1.34 (s, 6 H);
13C NMR δ 156.8, 140.5, 129.7, 129.5, 114.1, 113.0, 70.1, 65.2,
29.6, 24.9, 10.7, 4.4; IR 3074, 2998, 2959, 1673, 1595 cm-1
MS 329 (MH+). Anal. (C22H32O2) C, H.
;
1-(8-ter t-Bu tyl-2,3-d ih yd r o-4,4-d im eth yl-6-ben zop yr a -
n yl)-3-h yd r oxy-3-m eth ylbu ta n -1-on e (51). 1-(8-ter t-Bu -
tyl-2,3-d ih yd r o-4,4-d im eth yl-6-ben zop yr a n yl)eth a n on e.
Method C was used. AlCl3 (0.32 g, 2.39 mmol, 1.2 equiv),
acetyl chloride (0.15 mL, 2.19 mmol, 1.1 equiv), and 19 were
reacted as described for 37 except that the reaction was kept
at -78 °C for 2 h and was then quenched. The crude product
was purified by flash column chromatography on silica (hex-
anes, hexanes/EtOAc, 20/1) to give a solid which was recrystal-
lized using hexanes to give the title compound (0.40 g, 76%)
1
as a white solid: mp 118-119 °C; H NMR δ 7.84 (d, J ) 2.5
Hz, 1 H), 7.75 (d, J ) 2.0 Hz, 1 H), 4.26 (t, J ) 5.5 Hz, 2 H),
2.55 (s, 3 H), 1.85 (t, J ) 5.5 Hz, 2 H), 1.39 (s, 9 H), 1.37 (s, 6
H); 13C NMR δ 197.4, 157.2, 137.7, 131.8, 128.9, 126.1, 125.0,
42.3, 34.9, 29.8, 29.6; IR 2958, 1583, 1463 cm-1
.
62.7, 37.0, 35.0, 31.3, 31.0, 29.6, 26.2; IR 2959, 1672, 1595 cm-1
.
6-Br om o-8-ter t-bu tyl-2,3-dih ydr o-4,4-dim eth ylben zopy-
r a n . To a cold (0 °C) suspension of AlCl3 (1.67 g, 12.51 mmol)
in CH3NO2 (20 mL) was added a solution of 18 (3.94 g, 12.51
mmol) in CH3NO2 (5 mL). The resulting red solution was
stirred at 0 °C. After 1 h, the reaction was quenched by slow
addition of H2O. The mixture was diluted with hexanes, the
layers were separated, and the organic layer was washed with
H2O and brine. The aqueous layers were extracted with
hexanes; the combined organic layers were dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
column chromatography on silica (hexanes) to give the title
compound (2.87 g, 77%) as a solid which was recrystallized
1-(8-ter t-Bu tyl-2,3-d ih yd r o-4,4-d im eth yl-6-ben zop yr a -
n yl)-3-h yd r oxy-3-m eth ylbu ta n -1-on e (51). Method C was
used. 1-(8-tert-Butyl-2,3-dihydro-4,4-dimethyl-6-benzopyra-
nyl)ethanone was reacted as described for 37. The crude
product was purified by flash column chromatography on silica
(hexanes, hexanes/EtOAc, 10/1) to give 51 (0.30 g, 70%) as a
pale-yellow solid which was recrystallized using pentane: mp
1
92-93 °C; H NMR δ 7.82 (d, J ) 2.0 Hz, 1 H), 7.73 (d, J )
2.0 Hz, 1 H), 4.51 (s, 1 H), 4.28 (t, J ) 5.5 Hz, 2 H), 3.07 (s, 2
H), 1.86 (t, J ) 5.5 Hz, 2 H), 1.38 (s, 9 H), 1.37 (s, 6 H), 1.34
(s, 6 H); 13C NMR δ 201.0, 157.9, 138.0, 132.0, 128.9, 126.1,
122.8, 69.9, 62.8, 47.7, 36.9, 35.1, 31.4, 31.0, 29.7, 29.6; IR 3478,
2963, 1659, 1593 cm-1; MS 319 (MH+), 261 (MH+ - acetone).
Anal. (C20H30O3) C, H.
1
from hexanes to give white crystals: mp 62-63 °C; H NMR
δ 7.23 (d, J ) 2.5 Hz, 1 H), 7.16 (d, J ) 2.0 Hz, 1 H), 4.15 (t,
J ) 5.5 Hz, 2 H), 1.81 (t, J ) 5.5 Hz, 2 H), 1.33 (s, 9 H), 1.31
(s, 6 H); 13C NMR δ 151.8, 140.2, 134.1, 127.7, 127.3, 112.2,
1-(8-ter t-Bu tyl-2,3-d ih yd r o-4,4-d im eth yl-6-ben zop yr a -
n yl)-5-h exyn -1-on e (52). Method A was used. The crude
product was purified by flash column chromatography on silica
(hexanes, hexanes/EtOAc, 20/1) to give an oil which was
distilled (109-111 °C, 0.4 mmHg): 1H NMR δ 7.87 (d, J ) 2.0
Hz, 1 H), 7.77 (d, J ) 2.0 Hz, 1 H), 4.26 (t, J ) 5.5 Hz, 2 H),
3.07 (t, J ) 7.5 Hz, 2 H), 2.33 (td, J ) 7.0, 2.5 Hz, 2 H), 2.00
(s, 1 H), 1.97 (q, J ) 7.0 Hz, 2 H), 1.80 (m, 2 H), 1.39 (s, 9 H),
1.37 (s, 6 H); 13C NMR δ 198.8, 157.2, 137.7, 131.8, 128.76,
125.9, 124.7, 83.9, 68.9, 62.7, 37.0, 36.4, 35.0, 31.4, 31.0, 29.6,
23.3, 18.0; IR 3307, 2959, 1672, 1595 cm-1; MS 313 (MH+).
Anal. (C21H28O2) C, H.
1,5-Dibr om o-2-((3-br om op r op yl)oxy)-3-ter t-b u t ylb en -
zen e (9b). Prepared as described for 9a but with 1,3-
dibromopropane. The crude product was purified by flash
column chromatography on silica (hexanes) to give an off-white
oil which was Kugelrohr distilled (220-222 °C, 0.1 mmHg) to
give 9b (6.13 g, 88%) as a pale-yellow oil: 1H NMR δ 7.57 (s,
1 H), 7.39 (s, 1 H), 4.18 (t, J ) 5.4 Hz, 2 H), 3.67 (t, J ) 6.3
Hz, 2 H), 2.44 (m, 2 H), 1.36 (s, 9 H); 13C NMR δ 154.3, 147.0,
134.1, 130, 119, 116.7, 70.7, 35.8, 33.2, 30.8, 29.6; IR 2964,
2912, 1545 cm-1; MS (EI) 432 (M+ + 3), 430 (M+ + 1), 428,
310, 308, 306.
62.3, 37.3, 35.1, 31.5, 31.2, 29.6; IR 2960, 2872, 1436 cm-1
.
8-ter t-Bu tyl-2,3-d ih yd r o-4,4-d im eth ylben zop yr a n (19).
To a cold (-78 °C) solution of 6-bromo-8-tert-butyl-2,3-dihydro-
4,4-dimethylbenzopyran (2.29 g, 7.72 mmol) in THF/hexanes
(28 mL/7 mL) was added n-BuLi (3.70 mL, 2.5 M/hexanes, 9.26
mmol) dropwise. The resulting pale-yellow solution was
stirred for 30 min at -78 °C and the reaction quenched by
slow addition of H2O. The mixture was diluted with hexanes,
and the layers were separated. The organic layer was washed
with 1 N HCl, H2O, and brine. The aqueous layers were
extracted with hexanes; the combined organic layers were
dried (MgSO4), filtered, and concentrated. The residue was
purified by flash column chromatography on silica (hexanes)
to give 19 (1.60 g, 95%) as a solid which was recrystallized
using hexanes to afford white crystals: mp 34-35 °C; 1H NMR
δ 7.20 (dd, J ) 8.0, 2.0 Hz, 1 H), 7.15 (dd, J ) 7.5, 1.5 Hz, 1
H), 6.87 (t, J ) 7.7 Hz, 1 H), 4.22 (s, 2 H), 1.87 (m, 2 H), 1.42
(s, 9 H), 1.38 (s, 6 H); 13C NMR δ 152.8, 137.7, 132.0, 125.1,
124.2, 119.5, 62.2, 37.8, 34.9, 31.7, 31.0, 29.8; IR 2958, 1583
cm-1
.
1-(8-ter t-Bu tyl-2,3-d ih yd r o-4,4-d im eth yl-6-ben zop yr a -
n yl)p en ta n -1-on e (49). Method A was used. The crude
product was purified by flash column chromatography on silica
(hexanes, hexanes/EtOAc, 20/1) to give an oil which was
distilled (105-109 °C, 0.4 mmHg): 1H NMR δ 7.85 (d, J ) 2.0
Hz, 1 H), 7.75 (d, J ) 2.0 Hz, 1 H), 4.26 (t, J ) 5.5 Hz, 2 H),
2.91 (t, J ) 7.5 Hz, 2 H), 1.86 (t, J ) 5.5 Hz, 2 H), 1.72 (m, 2
H), 1.42 (m, 2 H), 1.39 (s, 9 H), 1.38 (s, 6 H), 0.96 (t, J ) 7.3
Hz, 3 H); 13C NMR δ 199.8, 157.2, 137.7, 131.7, 128.7, 125.9,
124.8, 62.7, 37.8, 37.1, 35.0, 31.4, 31.0, 29.6, 26.9, 22.6, 14.0;
8-ter t-Bu tyl-2,3-d ih yd r oben zop yr a n (10b). Prepared as
described for 10a . The crude product was purified by flash
column chromatography on silica (hexanes) to give an off-white
oil which was Kugelrohr distilled (100-103 °C, 0.3 mmHg) to
give 10b (1.92 g, 87%) as an off-white oil: 1H NMR δ 7.11 (d,
J ) 7.2 Hz, 1 H), 6.92 (d, J ) 7.2 Hz, 1 H), 6.79 (t, J ) 7.3 Hz,
1 H), 4.20 (t, J ) 5.2 Hz, 2 H), 2.83 (t, J ) 6.6 Hz, 2 H), 2.01
(m, 2 H), 1.38 (s, 9 H); 13C NMR δ 154.0, 137.7, 128.0, 124.3,

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1135
122.6, 119.4, 65.6, 34.8, 29.6, 25.4, 22.4; IR 2951, 2870, 1587
cm-1; MS (EI) 190 (M+), 176, 175, 147.
mmol) in 20 mL of anhydrous THF was added. The reaction
mixture was stirred for 30 min at 0 °C and for 15 min at room
temperature. The reaction mixture was diluted with 500 mL
of Et2O and washed with 1 M NaOH. The organics were dried
over Na2SO4 and concentrated under reduced pressure to give
13.5 g (96% yield) of 23 as a tan liquid which was used without
further purification: 1H NMR δ 7.40 (m, 2 H), 7.18 (m, 2 H),
5.38 (m, 1 H), 3.59 (d, J ) 7.8 Hz, 2 H), 1.72 (s, 3 H), 1.63 (s,
3 H), 1.52 (s, 9 H); 13C NMR δ 149.7, 136.6, 136.0, 132.8, 126.3,
126.1, 126.0, 119.0, 36.5, 34.6, 30.4, 25.6, 17.66.
8-t er t -Bu t yl-2,3-d ih yd r o-4,4-d im e t h ylb e n zot h iop y-
r a n (24). Compound 23 (11 g, 47 mmol) and 85% H3PO4 (8.25
g, 71.6 mmol) in 110 mL of benzene were refluxed for 16 h.
Then, over an 8-h period, three 5.5-g (116 mmol) portions of
P2O5 were added to the refluxing mixture. The reaction
mixture was stirred at reflux for 16 h. The mixture was cooled
to room temperature, and the solution was decanted off the
resulting red residue into a separatory funnel containing a 10%
solution of NaCl. The residue was washed with Et2O and 10%
NaCl, and both of these washings were added to the separatory
funnel. The product was extracted into the benzene/Et2O
layer, and this was washed again with salt solution. The
organics were dried over Na2SO4 and concentrated under
reduced pressure to give 24 (6.5 g, 60% yield): 1H NMR δ 7.38
(d, J ) 8.7 Hz, 1 H), 7.27 (d, J ) 8.7 Hz, 1 H), 7.04 (t, J ) 8.7
Hz, 1 H), 2.99 (t, J ) 6.8 Hz, 2 H), 2.00 (t, J ) 6.8 Hz, 2 H),
1.57 (s, 9 H), 1.42 (s, 6 H); 13C NMR δ 146.9, 143.5, 128.3,
124.7, 124.3, 123.4, 37.8, 36.7, 34.4, 31.1, 30.1, 23.98.
1-(8-ter t-Bu t yl-2,3-d ih yd r o-4,4-d im et h yl-6-b en zot h io-
p yr a n yl)p en ta n -1-on e (57). Meth od B. To compound 24
(500 mg, 2.1 mmol) and valeryl chloride (0.29 mL, 2.34 mmol)
in 10 mL of benzene at 0 °C was added SnCl4 (0.27 mL, 2.34
mmol). The reaction mixture was allowed to stir for 1 h at 0
°C and was then diluted with Et2O and washed with H2O and
10% NaCl. The product was purified by flash silica gel
chromatography, eluting with 7/3 hexanes/EtOAc to give 57
(250 mg, 37% yield): 1H NMR δ 7.90 (s, 1 H), 7.82 (s, 1 H),
3.03 (t, J ) 8.0 Hz, 2 H), 2.92 (t, J ) 8.0 Hz, 2 H), 1.98 (t, J )
7.8 Hz, 2 H), 1.73 (m, 2 H), 1.55 (s, 9 H), 1.42 (m, 2 H), 1.40 (s,
6 H), 0.98 (t, J ) 8.2 Hz, 3 H); 13C NMR δ 200.2, 146.0, 143.2,
138.9, 131.6, 124.0, 123.7, 37.7, 36.7, 34.2, 30.6, 29.8, 29.3, 26.6,
23.9, 22.3, 13.8; MS (MH+) 319. Anal. (C20H30OS) C, H.
8-ter t-Bu tyl-4,4-d im eth yl-6-p en ta n oyl-1,2,3,4-tetr a h y-
d r oqu in olin e (58). N-Ben zyl-2-ter t-bu tyla n ilin e. Ben-
zaldehyde (22.1 g, 0.21 mol) was added to a solution of 2-tert-
butylaniline (31.0 g, 0.21 mol) in 500 mL of a 4:1 CH3CN-
HOAc mixture. The resulting yellow solution was stirred for
15 min, and NaBH3CN (13.3 g, 0.21 mol) was added. The
reaction mixture was stirred for 3 h, concentrated to ca. 150
mL in volume, poured into a cold 25% aqueous NaOH solution,
and extracted with Et2O. The extract was washed with 10%
aqueous NaOH solution and H2O, dried (MgSO4), and concen-
trated to afford 48.3 g (96%) of the title compound as a colorless
oil: 1H NMR δ 7.45-6.65 (m, 9 H), 4.42 (s, 2 H), 1.45 (s, 9 H);
MS 240 (MH+).
1-(8-ter t-Bu tyl-2,3-d ih yd r o-6-ben zop yr a n yl)p en ta n -1-
on e (53). Method A was used. The crude product was
purified by flash column chromatography (hexanes, hexanes/
EtOAc, 25/1) to give a crude oil which was distilled (135-139
°C, 0.5 mmHg) to give 53 (0.49 g, 85%) as a colorless oil: 1H
NMR δ 7.77 (d, J ) 2.1 Hz, 1 H), 7.55 (d, J ) 2.0 Hz, 1 H),
4.26 (t, J ) 5.3 Hz, 2 H), 2.88 (t, J ) 7.5 Hz, 2 H), 2.85 (t, J )
6.6 Hz, 2 H), 2.02 (m, 2 H), 1.70 (m, 2 H), 1.42 (m, 2 H), 1.38
(s, 9 H), 0.95 (t, J ) 7.5 Hz, 3 H); 13C NMR δ 199.9, 158.1,
137.7, 128.8, 128.6, 124.9, 122.1, 66.2, 37.8, 34.8, 29.5, 26.9,
25.4, 22.5, 21.9, 13.9; IR 2956, 2933, 2872, 1675, 1582 cm-1
MS 275 (MH+). Anal. (C18H26O2) C, H.
;
1-(8-ter t-Bu t yl-2,3-d ih yd r o-6-b en zop yr a n yl)-4-cyclo-
p r op ylbu ta n -1-on e (54). Method A was used. The crude
product was purified by flash column chromatography on silica
(hexanes/EtOAc, 10/1-4/1): 1H NMR δ 7.77 (d, J ) 2.0 Hz, 1
H), 7.56 (d, J ) 2.0 Hz, 1 H), 4.27 (t, J ) 5.0 Hz, 2 H), 2.92 (t,
J ) 7.5 Hz, 2 H), 2.85 (t, J ) 7.0 Hz, 2 H), 2.02 (m, 2 H), 1.83
(quintet, J ) 7.5 Hz, 2 H), 1.38 (s, 9 H), 1.29 (q, J ) 7.5 Hz, 2
H), 0.70 (m, 1 H), 0.42 (m, 2 H), 0.03 (m, 2 H); 13C NMR δ
199.7, 158.0, 137.6, 128.7, 128.5, 124.8, 122.0, 66.2, 37.8, 34.8,
34.3, 29.5, 25.4, 24.8, 21.9, 10.6, 4.4; IR 2998, 2952, 2870, 1675,
1581 cm-1; MS 261 (MH+). Anal. (C20H28O2) C, H.
1-(8-ter t-Bu tyl-2,3-dih ydr o-6-ben zopyr an yl)-3-h ydr oxy-
3-m eth ylbu ta n -1-on e (55). 1-(8-ter t-Bu tyl-2,3-d ih yd r o-6-
ben zop yr a n yl)eth a n on e. Method C was used. Compound
10b was reacted as described for 37. The resulting off-white
solid was recrystallized using hexanes to give the title com-
pound (0.67 g, 79%) as white crystals: mp 74-75 °C; 1H NMR
δ 7.75 (d, J ) 1.5 Hz, 1 H), 7.75 (d, J ) 1.0 Hz, 1 H), 4.27 (t,
J ) 5.1 Hz, 2 H), 2.85 (t, J ) 6.5 Hz, 2 H), 2.53 (s, 3 H), 2.02
(m, 2 H), 1.42 (s, 9 H); 13C NMR δ 197.4, 158.3, 137.7, 129.2,
128.8, 125.1, 122.1, 66.4, 34.8, 29.5, 26.2, 25.4, 21.8; IR 2977,
2956, 2872, 1671, 1589 cm-1; MS (EI) 232 (M+), 218, 217, 189.
Anal. (C15H20O) C, H.
1-(8-ter t-Bu tyl-2,3-dih ydr o-6-ben zopyr an yl)-3-h ydr oxy-
3-m eth ylbu ta n -1-on e (55). Method C was used. 1-(8-tert-
Butyl-2,3-dihydro-6-benzopyranyl)ethanone was reacted as
described for 37. The crude product was purified by flash
column chromatography on silica (hexanes, hexanes/EtOAc,
10/1, 8/1, 4/1) to give a crude oil which was distilled (138-141
°C, 0.5 mmHg) to give 55 (0.40, 72%) as a colorless oil: 1H
NMR δ 7.75 (d, J ) 2.5 Hz, 1 H), 7.54 (d, J ) 2.0 Hz, 1 H),
4.28 (t, J ) 5.0 Hz, 2 H), 3.06 (s, 2 H), 2.85 (t, J ) 6.5 Hz, 2
H), 2.02 (m, 2 H), 1.33 (s, 9 H), 1.33 (s, 6 H); 13C NMR δ 201.0,
158.9, 138.0, 129.0, 128.8, 124.9, 122.2, 69.9, 66.4, 47.7, 34.9,
29.6, 29.5, 25.4, 21.0; IR 3482, 2987, 2874, 1655, 1579, 1558
cm-1; MS 291 (MH+). Anal. (C18H26O3) C, H; C: calcd, 74.45;
found, 73.94.
1-(8-ter t-Bu tyl-2,3-d ih yd r o-6-ben zop yr a n yl)-5-h exyn -1-
on e (56). Method A was used except that the reaction was
performed in CH3CN at 40 °C. The crude product was purified
by flash column chromatography on silica (hexanes, hexanes/
EtOAc, 10/1) to give a yellow oil (0.75 g, 92%) which was
recrystallized using hexanes to give 56 (0.64 g, 79%) as white
N-Ben zyl-N-(2-ter t-b u t ylp h en yl)-3,3-d im et h yla cr yla -
m id e. A solution of 3,3-dimethylacryloyl chloride (24.5 mL,
0.22 mol) in 210 mL of benzene was added over 30 min to a
solution of N-benzyl-2-tert-butylaniline (50.7 g, 0.21 mol) in
210 mL of benzene. The reaction mixture was stirred for 24
h, quenched with aqueous Na2CO3 solution, and diluted with
Et2O. The organic layer was washed with aqueous Na2CO3
solution and H2O, dried (MgSO4), and concentrated to afford
66.3 g (98%) of the title compound as a yellowish solid: mp
82-83 °C; 1H NMR δ 7.54 (dd, J ) 7.4, 2.2 Hz, 1 H), 7.28 (m,
6 H), 6.96 (dt, J ) 7.4, 2.2 Hz, 1 H), 6.42 (dd, J ) 7.4, 2.2 Hz,
1 H), 5.80 (d, J ) 12.9 Hz, 1 H), 5.37 (bs, 1 H), 3.72 (d, J )
12.9 Hz, 1 H), 2.18 (s, 3 H), 1.64 (s, 3 H), 1.38 (s, 9 H).
1-Ben zyl-8-ter t-b u t yl-3,4-d ih yd r o-4,4-d im et h yl-2(1H)-
qu in olin on e (28). AlCl3 (29.3 g, 0.22 mol) was added in one
portion to a solution of N-benzyl-N-(2-tert-butylphenyl)-3,3-
dimethylacrylamide (66.3 g, 0.21 mol) in 520 mL of 1,2-
dichloroethane. The reaction mixture was stirred for 2 h,
quenched with cold H2O, stirred for 0.5 h, and diluted with
1
crystals: mp 52-53 °C; H NMR δ 7.77 (d, J ) 1.9 Hz, 1 H),
7.55 (d, J ) 1.9 Hz, 1 H), 4.27 (t, J ) 5.1 Hz, 2 H), 3.05 (t, J
) 7.2 Hz, 2 H), 2.85 (t, J ) 6.6 Hz, 2 H), 2.30 (m, 2 H), 2.04-
1.93 (m, 5 H), 1.42 (m, 2 H), 1.38 (s, 9 H); 13C NMR δ 198.8,
158.3, 137.8, 128.8, 128.5, 124.8, 122.1, 83.9, 68.9, 66,3, 37.8,
36.5, 34.9, 29.5, 25.4, 23.2, 21.9, 18.0; IR 3306, 2954, 2873,
2128, 1672, 1581 cm-1; MS (EI) 284 (M+), 269, 233, 232. Anal.
(C19H24O2) C, H.
1-(8-ter t-Bu t yl-2,3-d ih yd r o-4,4-d im et h yl-6-b en zot h i-
op yr a n yl)p en t a n -1-on e (57). 2-ter t-Bu t ylp h en yl 1-(3-
Meth ylbu t-2-en yl) Su lfid e (23). NaH as an 80% dispersion
in mineral oil (2 g, 69 mmol) was washed twice with hexanes
under argon atmosphere. To this was added 20 mL of
anhydrous THF. The mixture was cooled to 0 °C. 2-tert-
Butylthiophenol (10 g, 60 mmol) was dissolved in 60 mL of
THF and added slowly to the NaH mixture. After 40 min at
0 °C, a solution of 4-bromo-2-methyl-2-butene (6.9 mL, 60

1136 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
1
CH2Cl2. The organic layer was washed with H2O, dried
(MgSO4), and concentrated in vacuo. Purification of the
residue by flash column chromatography on silica gel (10% f
25% Et2O/hexanes) gave 54.1 g (80%) of 28 as an off-white
solid: mp 120-121 °C; 1H NMR δ 7.42 (dd, J ) 7.4, 2.2 Hz, 1
H), 7.07 (m, 4 H), 6.96 (dd, J ) 7.4, 2.2 Hz, 1 H), 6.79 (m, 2
H), 5.50 (d, J ) 12.9 Hz, 1 H), 4.32 (d, J ) 12.9 Hz, 1 H), 2.38
(d, J ) 14.2 Hz, 1 H), 2.15 (d, J ) 14.2 Hz, 1 H), 1.47 (s, 9 H),
1.17 (s, 3 H), 0.23 (s, 3 H); MS 322 (MH+).
1-Ben zyl-8-ter t-bu tyl-4,4-d im eth yl-1,2,3,4-tetr a h yd r o-
qu in olin e. To a suspension of LiAlH4 (1.48 g, 39.0 mmol) in
10 mL of Et2O at reflux was added a solution of 28 (10.0 g,
31.2 mmol) in 63 mL of 1:2 THF-Et2O mixture. The reaction
mixture was heated at reflux for 2.5 h and cooled to room
temperature. To it was added 30 mL of H2O followed by 30
mL of 10% aqueous NaOH solution. The organic layer was
separated, and the aqueous layer was extracted with Et2O;
the combined organics were dried over MgSO4 and concen-
trated to yield 9.20 g of a yellowish solid. Purification by flash
column chromatography on silica gel (2% f 5% ether/hexanes)
yielded 6.72 g (70%) of the title compound as a colorless solid:
mp 101-103 °C; 1H NMR δ 7.55 (d, J ) 7.1 Hz, 2 H), 7.43 (d,
J ) 7.4 Hz, 2 H), 7.32 (m, 3 H), 7.12 (t, J ) 7.4 Hz, 1 H), 4.06
(br, 2 H), 3.07 (br, 2 H), 1.61 (m, 2 H), 1.57 (s, 9 H), 1.40 (br,
6 H); MS 308 (MH+).
°C; H NMR δ 7.81 (d, J ) 1.8 Hz, 1 H), 7.77 (d, J ) 1.8 Hz,
1 H), 4.72 (bs, -NH, 1 H), 3.46 (m, 2 H), 2.87 (t, J ) 7.4 Hz,
2 H), 1.73 (m, 4 H), 1.40 (s, 9 H), 1.37 (m, 2 H), 1.31 (s, 6 H),
0.93 (t, J ) 7.3 Hz, 3 H); 13C NMR δ 199.1, 146.1, 130.6, 129.1,
125.3, 125.1, 124.5, 38.2, 37.4, 35.8, 33.9, 32.1, 30.7, 29.8, 27.3,
22.6, 13.9; IR 3468, 2958, 2871, 1657, 1593 cm-1; MS 302
(MH+). Anal. (C20H31NO) C, H, N.
8-ter t-Bu t yl-6-(4-cyclop r op ylb u t a n oyl)-4,4-d im et h yl-
1,2,3,4-tetr a h yd r oqu in olin e (59). Method D was used. The
crude product was purified by flash column chromatography
on silica gel (2% f 5% EtOAc/hexanes) and gave 0.35 g (27%)
of 59 initially as a light-yellow syrup which upon storage and
washing with hexanes became a light-yellow solid: mp 98-
1
99 °C; H NMR δ 7.81 (d, J ) 1.8 Hz, 1 H), 7.78 (d, J ) 1.8
Hz, 1 H), 4.70 (s, 1 H), 3.45 (m, 2 H), 2.87 (t, J ) 7.4 Hz, 2 H),
1.87 (m, 2 H), 1.74 (m, 2 H), 1.41 (s, 9 H), 1.32 (s, 6 H), 1.28
(m, 2 H), 0.71 (m, 1 H), 0.42 (m, 2 H), 0.03 (m, 2 H); 13C NMR
δ 199.5, 146.4, 130.8, 129.4, 125.7, 125.5, 124.8, 38.5, 37.7, 36.0,
34.7, 34.3, 32.4, 31.0, 30.1, 25.5, 11.0, 4.61; IR 3467, 2074, 2959,
1652, 1593 cm-1; MS 328 (MH+). Anal. (C22H33NO) C, H, N.
8-ter t-Bu t yl-6-p en t a n oyl-1,2,3,4-t et r a h yd r o-1,4,4-t r i-
m eth ylqu in olin e (60). 8-ter t-Bu tyl-1,2,3,4-tetr a h yd r o-
1,4,4-tr im eth ylqu in olin e. A solution of 1-benzyl-8-tert-butyl-
4,4-dimethyl-1,2,3,4-tetrahydroquinoline (20.0 g, 65 mmol) in
100 mL of EtOAc was hydrogenated for 24 h with palladium
hydroxide on carbon (1.0 g) as the catalyst. The reaction
mixture was filtered through a short column of silica gel and
concentrated to yield 7.8 g of a yellow oil, which was dissolved
in 63 mL of a 1:20 HOAc-CH3CN mixture; formaldehyde (14.8
mL, 0.18 mol, 37% aqueous solution) and NaBH3CN (3.5 g,
55.7 mmol) were added. The reaction mixture was stirred for
24 h, diluted with ether, washed with 1 N aqueous NaOH
solution, dried (MgSO4), and concentrated in vacuo. Purifica-
tion of the residue by flash column chromatography on silica
gel (2.5% Et2O/hexanes) yielded 7.25 g (48%) of the title
compound as a colorless oil: 1H NMR δ 7.20 (d, J ) 7.4 Hz, 2
H), 6.99 (t, J ) 7.4 Hz, 1 H), 3.04 (m, 2 H), 2.59 (s, 3 H), 1.45
(m, 2 H), 1.45 (s, 9 H), 1.30 (s, 6 H); MS 232 (MH+).
6-Br om o-8-ter t-bu tyl-1,2,3,4-tetr a h yd r o-1,4,4-tr im eth -
ylqu in olin e (29b). A solution of bromine (1.7 mL, 31.2 mmol)
in 50 mL of CH2Cl2 was added dropwise over 0.5 h to a solution
of 8-tert-butyl-1,2,3,4-tetrahydro-1,4,4-trimethylquinoline (7.2
g, 31.2 mmol) in 50 mL of CH2Cl2 at 0 °C. The reaction
mixture was stirred at 0 °C for 0.5 h, diluted with Et2O,
washed with 1 N aqueous NaOH solution and water, dried
(MgSO4), and concentrated in vacuo. Purification of the
residue by flash column chromatography on silica gel (5%
ether/hexanes) provided 9.44 g (97%) of 29b as a yellowish
oil: 1H NMR δ 7.28 (s, 2 H), 3.02 (m, 2 H), 2.55 (s, 3 H), 1.42
(m, 2 H), 1.41 (s, 9 H), 1.25 (s, 6 H); MS 310 (MH+).
8-ter t-Bu t yl-6-p en t a n oyl-1,2,3,4-t et r a h yd r o-1,4,4-t r i-
m eth ylqu in olin e (60). Method D was used. The crude
product was purified by flash column chromatography on silica
gel (5% ether/hexanes) and gave 0.51 g (41%) of 60 as a yellow
oil: 1H NMR δ 7.87 (d, J ) 1.8 Hz, 1 H), 7.81 (d, J ) 1.8 Hz,
1 H), 3.08 (m, 2 H), 2.91 (t, J ) 7.4 Hz, 2 H), 2.66 (s, 3 H), 1.80
(m, 2 H), 1.72 (m, 2 H), 1.48 (s, 9 H), 1.43 (m, 2 H), 1.34 (s, 6
H), 0.97 (t, J ) 7.3 Hz, 3 H); 13C NMR δ 200.5, 153.5, 144.2,
141.8, 131.4, 126.8, 124.6, 47.7, 46.6, 37.9, 36.7, 33.6, 32.5, 32.3,
32.0, 26.9, 22.5, 13.9; IR 2934, 2865, 1677, 1591 cm-1; MS 316
(MH+). Anal. (C21H33NO) C, H, N.
8-ter t-Bu tyl-6-(4-cyclop r op ylbu ta n oyl)-1,2,3,4-tetr a h y-
d r o-1,4,4-tr im eth ylqu in olin e (61). Method D was used. The
crude product was purified by flash column chromatography
on silica gel (5% EtOAc/hexanes) and gave 0.66 g (64%) of 61
initially as a yellowish viscous oil which upon storage in a
refrigerator became a yellowish solid: mp 46-47 °C; 1H NMR
δ 7.83 (d, J ) 1.8 Hz, 1 H), 7.78 (d, J ) 1.8 Hz, 1 H), 3.05 (m,
2 H), 2.91 (t, J ) 7.4 Hz, 2 H), 2.62 (s, 3 H), 1.79 (m, 4 H), 1.42
(s, 9 H), 1.30 (s, 6 H), 1.27 (m, 2 H), 0.68 (m, 1 H), 0.39 (m, 2
H), 0.01 (m, 2 H); 13C NMR δ 200.2, 153.7, 144.1, 141.7, 131.2,
126.7, 124.6, 47.5, 46.6, 37.9, 36.6, 34.3, 33.5, 32.5, 32.2, 31.7,
24.7, 10.6, 4.3; IR 2934, 2865, 1677, 1591 cm-1; MS 342 (MH+).
Anal. (C23H35NO) C, H, N.
1-Ben zyl-6-br om o-8-ter t-bu tyl-4,4-d im eth yl-1,2,3,4-tet-
r a h yd r oqu in olin e (29a ). A solution of bromine (3.04 g, 19.0
mmol) in 30 mL of CH2Cl2 was added dropwise over 0.5 h to
a well-stirred solution of 1-benzyl-8-tert-butyl-4,4-dimethyl-
1,2,3,4-tetrahydroquinoline (5.80 g, 18.9 mmol) in 30 mL of
CH2Cl2 at 0 °C. The reaction mixture was stirred at 0 °C for
0.5 h, warmed to room temperature over 2.5 h, quenched with
Et3N, and concentrated in vacuo. The solid residue thus
obtained was dissolved in Et2O; the resulting solution was
washed with 1 N aqueous NaOH solution and H2O, dried
(MgSO4), and concentrated to produce 10.2 g of a yellow solid.
Recrystallization from hexanes provided 7.12 g (97%) of 29a
1
as a colorless solid: mp 120-121 °C; H NMR δ 7.45 (d, J )
7.1 Hz, 2 H), 7.40-7.25 (m, 5 H), 3.95 (bs, 2 H), 2.98 (m, 2 H),
1.54 (m, 2 H), 1.49 (s, 9 H), 1.32 (br, 6 H); MS 386 (MH+).
1-Ben zyl-8-ter t-bu tyl-4,4-d im eth yl-6-p en ta n oyl-1,2,3,4-
tetr a h yd r oqu in olin e. Meth od D. t-BuLi (9.6 mL, 16.4
mmol, 1.7 M in pentane) was added dropwise to a solution of
29a (3.08 g, 8.0 mmol) in 40 mL of anhydrous THF at -78 °C.
This solution was stirred at -78 °C for 10 min, and valeral-
dehyde (1.1 mL, 10.0 mmol) was introduced. The reaction
mixture was warmed to room temperature, quenched with
H2O, and extracted with Et2O. The extract was dried (MgSO4)
and concentrated to give 4.02 g of a brownish oil. A solution
of this crude oil (1.30 g) in 30 mL of CH2Cl2 was reacted for
1.5 h with 4-methylmorpholine N-oxide (0.72 g, 6.2 mmol) and
tetrapropylammonium perruthenate (0.06 g, 0.2 mmol). The
reaction mixture was washed with aqueous sodium bisulfite
solution and brine, dried (MgSO4), and concentrated in vacuo.
Purification of the residue by flash column chromatography
on silica gel (5% f 10% EtOAc/hexanes) provided 0.86 g (28%)
of the title compound as a yellow oil, which solidified upon
storage in a refrigerator: mp 89-90 °C; 1H NMR δ 7.90 (d, J
) 1.8 Hz, 1 H), 7.88 (d, J ) 1.8 Hz, 1 H), 7.42-7.25 (m, 5 H),
4.01 (s, 2 H), 3.04 (m, 2 H), 2.94 (t, J ) 7.4 Hz, 2 H), 1.71 (m,
4 H), 1.53 (s, 9 H), 1.42 (m, 2 H), 1.33 (s, 6 H), 0.97 (t, J ) 7.3
Hz, 3 H); 13C NMR δ 200.4, 153.8, 144.8, 143.2, 137.8, 132.3,
128.4, 128.1, 126.9, 126.0, 125.3, 60.0, 42.0, 38.0, 36.7, 33.5,
33.1, 31.5, 30.7, 26.7, 22.5, 13.9; IR 3467, 2074, 2959, 1652,
1593 cm-1; MS 392 (MH+).
8-ter t-Bu tyl-4,4-d im eth yl-6-p en ta n oyl-1,2,3,4-tetr a h y-
d r oqu in olin e (58). Meth od D. A mixture of 1-benzyl-8-tert-
butyl-4,4-dimethyl-6-pentanoyl-1,2,3,4-tetrahydroquinoline (0.86
g, 2.2 mmol), palladium hydroxide on carbon (0.17 g), and 20
mL of EtOAc was hydrogenated at 50 psi for 2 h. The mixture
was filtered through a short column of silica gel and concen-
trated in vacuo. Purification of the residue by flash column
chromatography on silica gel (5% f 10% EtOAc/hexanes)
yielded 0.30 g (45%) of 58 as an off-white solid: mp 109-110

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1137
of Lithium Thiophenolate. New Methodology for the Preparation
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Biologica l P r oced u r es. The procedures for the carrag-
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