New cyclooxygenase-2/5-lipoxygenase inhibitors. 3. 7-tert-Butyl-2,3- dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: Variations at the 5 position

Article abstract of DOI:10.1021/jm9802416

We report an expansion of the scope of our initial discovery that 5- keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

Full text of DOI:10.1021/jm9802416

J . Med. Chem. 1998, 41, 3515-3529
3515
New Cyclooxygen a se-2/5-Lip oxygen a se In h ibitor s. 3.
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 a t th e 5 P osition †
J ohn M. J anusz,* Patricia A. Young, J ames M. Ridgeway, Michael W. Scherz, Kevin Enzweiler, Laurence I. Wu,
Lixian Gan, J ulian Chen, David E. Kellstein, Shelley A. Green, J ennifer 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
Received April 21, 1998
We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tert-
butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic
agents. Several other functional groups have been introduced at the 5 position: amides,
amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl
substituents in the 5 position all provide active compounds. These compounds are dual
cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and
COX-2 with up to 33-fold selectivity for COX-2.
In tr od u ction
6 and amides 7-27 and 31-33 (Scheme 1). Compound
5 was prepared by lithium-halogen exchange of the
5-bromo compound I1 with tert-butyllithium followed by
carbonation with CO2. Acid-catalyzed esterification
gave the methyl ester 6. Treatment of 5 with oxalyl
chloride followed by addition of the appropriate amine
gave the amides 7-27 and 31-33 (method A). The
tertiary cyclopropyl amides 28-30 were prepared from
the secondary cyclopropyl amide 13 by phase-transfer
alkylation (method B).3 The amidine 34 was prepared
via the same lithio dihydrobenzofuran mentioned above
by quenching with dimethylcyanamide.4
The nitrile II was an intermediate for the preparation
of two analogues, 35 and 46 (Scheme 2). The amidine
35 was prepared by conversion of II (prepared from I
with chlorosulfonylisocyanate5) to the imidate III fol-
lowed by treatment with excess pyrrolidine. The 1,2,4-
oxadiazole 46 was prepared via the oxime IV by
treatment with acetyl chloride.6
The 5-amino dihydrobenzofuran V was the key start-
ing material for the preparation of several different
types of compounds (Scheme 2). It was prepared by
nitration of 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo-
furan1 with nitric acid in acetic acid followed by
hydrogenation of the nitro compound over palladium.
Acylation of V with acetyl chloride gave the “reversed”
amide 36. Reaction with the appropriate isocyanates
gave the ureas 37 and 38 (method C). Reaction with
imidazoline-2-sulfonic acid7 gave the cyclic guanidine
39, while treatment with diphenyliodonium-2-carboxy-
late and cupric acetate8 gave the anthranilic acid
derivative 40.
The 5-bromoacetyl-substituted dihydrobenzofuran VI1
was the starting material for the preparation of several
other compounds (Scheme 3). Heating with formamide
gave the oxazole 44. Reaction with ethylthiooxamate
followed by hydrolysis and decarboxylation gave the
thiazole 45, while reaction with thiourea gave the
aminothiazole 47. The guanidinothiazole 48 was pre-
pared similarly by reaction with 1-amidinothiourea.
Reaction with 2-aminothiazoline gave the imidazothia-
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 GI safety of
some members of this class, as discussed in a preceding
paper.1
The evolution of our work in the di-tert-butylphenol
area began with the discovery of the antiinflammatory
agent tebufelone (1). Among the metabolites of tebu-
felone was the 7-tert-butyl-2,3-dihydro-3,3-dimethylben-
zofuran (DHDMBF) 2, a nonphenolic compound. In the
first paper in this series,1 we disclosed that several
5-keto-substituted DHDMBFs were active antiinflam-
matory agents as well as COX/5-LOX inhibitors with
selectivity for COX-2. Compound 3 was of particular
interest since it showed excellent gastric safety in a
variety of in vivo tests. We also showed that a variety
of structural changes in the dihydrobenzofuran moiety
led to active compounds.2 In both of these papers, all
of the active compounds described were 5-keto-substi-
tuted compounds.
We now report results on a more extensive variation
of the substituent in the 5 position of 7-tert-butyl-2,3-
dihydro-3,3-dimethylbenzofuran. A variety of com-
pounds (4) containing carboxyl, amido, heterocyclic,
heteroaromatic, and othr substituents at the 5 position
were prepared. Biological testing was done to evaluate
the effects of these structural changes on in vivo
antiinflammatory and analgesic activity and on in vitro
COX/5-LOX inhibitory properties. Many of these new
compounds showed significant in vivo antiinflammatory
activity, thus greatly extending the scope of the substi-
tuted DHDMBF class of antiinflammatory agents.
Ch em istr y
The 5-carboxy-2,3-dihydro-3,3-dimethylbenzofuran 5
was the intermediate used for the preparation of ester
† Dedicated to the memory of our friend and colleague Hoang Do.
S0022-2623(98)00241-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/05/1998

3516 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
J anusz et al.
Sch em e 1
Ch a r t 1
with DMF) provided the starting material for the final
group of compounds (Scheme 5). Wittig reaction of VII
with 2-(triphenylphosphoranylidine)-γ-butyrolactone gave
compound 52. Condensations with psuedothiohydan-
toin or 2-thiopheneacetic acid12 gave 53 and 60, respec-
tively. While 60 was resistant to thermal decarboxy-
lation,13 heating to 250 °C in the presence of copper14
gave an 85/15 E/Z mixture of decarboxylated product
61. A more convenient method for the stereoselective
synthesis of 61 involved a Horner-Emmons15 reaction
with ethyl 2-thiophenemethylphosphonate. The pyridyl
compounds 64 and 65 were also prepared from VII by
Wittig reactions: the 2-picolyl ylide gave exclusively the
E isomer 64, while the 3-picolyl ylide gave a 40/60 E/Z
mixture from which the E isomer 65 was separated by
chromatography. The styrylisoxazole 62 was prepared
by an isoxazolylmethyl carbanion approach. The car-
banion generated by regioselective deprotonation at the
5-methyl position of 3,5-dimethylisoxazole with n-BuLi16
was reacted with aldehyde VII. Dehydration of the
resulting alcohol with toluenesulfonic acid gave 62.
Conversion of 62 to the styrylpyrazole 63 was carried
out following Kobayashi’s hydrogenolysis procedure17
using Mo(CO)6 followed by pyrazole ring formation
using hydrazine.
zoline 49 which could be oxidized to 50 and 51 by
sequential addition of m-chloroperbenzoic acid.9 Scheme
3 also shows the synthesis of the isoxazoline 41 which
was prepared by reaction of the 3-chloro-3-methylbu-
tanoyl-substituted dihydrobenzofuran1 with hydroxyl-
amine.
The 5-bromo compound I was also the source of
additional analogues (Scheme 4). Stille coupling10 of
2-tri-n-butyltin-substituted furan and thiophene with
I gave compounds 42 and 43 (method D). The hetero-
cyclic ketones 54-59 were prepared by addition of
5-lithio dihydrobenzofuran to the desired aldehyde
followed by oxidation of the resulting alcohol with
4-methylmorpholine N-oxide (4-NMO) and a catalytic
amount of tetrapropylammonium perruthenate (method
E).11 Conversion of I to 5-formyl dihydrobenzofuran VII
(by lithium-halogen exchange followed by quenching
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

DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3517
Sch em e 2
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.18 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 cyclopropyl ketone 3 was quite
good (62%) in the rat.
With the goal of defining the scope of the substituents
in the 5 position that provide compounds with antiin-
flammatory activity, our work was guided by the
structure-activity trends observed for the 5-keto dihy-
drobenzofurans1 and by the type of substituents that
led to activity in the di-tert-butylphenol series. We
began with the 5-carboxylic acid 5 which had modest
although significant activity. The corresponding ester
6 and primary amide 7, however, were inactive. We
next prepared a series of secondary amides. For n-alkyl
amides, the ethyl and propyl compounds 8 and 9 were
active, while the higher homologues 10 and 11 were not.
The branched and cyclic C-3 alkyl compounds 12 and
13 were active, while the homologated cyclopropyl
compounds 14 and 15 and the larger cycloalkyl com-
pounds 16 and 17 as well as the aniline amide 18 were
not. Similar trends were observed with the 5-keto
dihydrobenzofurans where modest increases in alkyl
chain length or ring size led to a loss of activity.1 Many
of the larger secondary amides were high melting
compounds with limited solubility which may have
contributed to their lack of in vivo activity.
In an effort to improve the solubility of our secondary
amides, compounds incorporating heteroatoms in the
amide substituent were prepared. While the hydroxy-
ethyl amide 19 was inactive, the methoxyethyl com-
pound 20 had very good activity. The dihydroxypropyl
compound 21 had modest activity while the dimeth-
ylaminoethyl compound 22 was inactive. Incorporating
heteroatoms into a 5-membered ring provided the active
heterocyclic amides 23 and 24. Thus, incorporation of
heteroatoms into otherwise inactive secondary amides
led to active compounds in four out of six cases.
An alternative way to improve solubility was to
prepare tertiary amides which lack the N-H bond.
Intermolecular hydrogen bonding can lead to higher
melting, less soluble compounds. Eight of the nine
tertiary amides 25-33 were active. These included
compounds with up to six carbons in the alkyl substit-
uents (30) and five carbons in a cyclic ring (32) thereby
extending the size of the alkyl substituents which lead
to active compounds compared to secondary amides. The
results for the tertiary amides prompted us to prepare
the isosteric N,N-dialkyl amidines 34 and 35, both of
which were active.
A variety of compounds which bear a nitrogen rather
than a carbon atom linked to C-5 were prepared. The
reversed secondary amide 36 was active as was the

3518 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
J anusz et al.
Sch em e 3
Sch em e 4
shorter of the two alkyl ureas, 37. The guanidino
compound 39 had very good activity. Finally, the
anthranillic acid derived amine 40 was also active.
A series of compounds 41-51 with either a heteroaryl
or heterocyclic groups directly attached to C-5 was
prepared. In general, activity across this series was
good. The active isoxazoline 41 was readily prepared
from the acyclic â-chloroketone precursor which itself
was an active compound.1 Five unsubstituted or alkyl-
substituted heteroaryl compounds 42-46 were pre-
pared, and all except the oxazolyl compound 44 were
active. Five additional substituted or fused-ring het-
erocycles, 47-51, were prepared. While the amino-
substituted thiazole 47 was inactive, the guanidino-
substituted compound 48 was active. In the fused
imidazothiazole series 49-51, the sulfide and sulfoxide
forms were active.
di-tert-butylphenol KME-4,19 was active. In contrast,
the iminothiazolidinone 53, the dihydrobenzofuran ana-
logue of the active di-tert-butylphenol CI-1004,20 was
inactive. The final group of compounds (54-65), all
bear heteroaromatic groups which are linked to the
dihydrobenzofuran via an intervening carbonyl group
(54-59) or carbon-carbon double bond (60-65). The
ketones 54-59 were all active. The olefin-linked het-
eroaromatics 60-65 were generally active with the
exception of the 3-methylisoxazole 62 and the 2-pyridyl
compound 64.
The correlation of antiinflammatory activity in the
CPE assay with analgesic activity in the phenylquinone-
induced abdominal constriction assay (PAC) is quite
good. Of the 32 compounds which were active in the
CPE assay, 27 were likewise active in the PAC assay.
The five outliers fall into different structural categories
and it is difficult to find a common explanation for their
inactivity. Among the compounds active in the PAC
Two compounds with heterocycles fused to a double
bond at the 5 position were prepared. The lactone 52,
which is the dihydrobenzofuran analogue of the active

DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3519
Sch em e 5
assay, the two most active were the anthranillic acid
selective. Tertiary amides (26, 28, 30) were less potent
inhibitors of COX-2 and, therefore, had low selectivities.
Curiously, the amidine and guanidine compounds 35
and 39 failed to inhibit either COX-1 or COX-2. Both
were active in the CPE assay but not in the PAC assay,
suggesting that some unknown pharmacology may be
responsible for their antiinflammatory efficacy. The
anthranillic acid derivative 40 had modest potency and
little selectivity. Among the remaining tested com-
pounds, all of which were heterocycles, COX-2 selectivity
was generally quite low. Several compounds (49, 52,
56, 58, and 61) were quite potent (ED50 < 100 nm)
inhibitors of both COX-1 and COX-2. The most potent
versus COX-2, 52 (3.5 nM), was also the most selective
(13-fold). Compound 52 was also the most potent 5-LOX
inhibitor. 5-LOX ED50 determinations ranged from 4
to >50 µM for those compounds tested. In general, the
selectivity for COX-2 observed for the compounds in
Table 3 was less than for the 5-keto compounds previ-
ously tested.1,2
Except for the two compounds noted above, all of the
compounds inhibited COX-1 and or COX-2 with ED50s
in the low µM range or below. Thus, it was reasonable
to expect that all of the compounds might show in vivo
activity. This prediction was true except for three
compounds, the secondary amides 10 and 11 and the
iminothiazolidinone 53. The poor solubility of the
secondary amides, mentioned above, could result in poor
bioavailability. A lack of bioavailability could also be
the reason for the inactivity of compound 53.
derivative 40 and the furyl ketone 55 both with ED50
10 mg/kg.
<
Finally, it is interesting to compare the antiinflam-
matory activity of the DHDMBFs with the correspond-
ing di-tert-butylphenols (Table 2). It was, in fact, the
correspondence of antiinflammatory activity in the two
series for the hexynoyl side chain that led us to explore
the DHDMBFs. This same correspondence holds for the
thienyl ketone 56.21 However, for the new substituents
at the 5 position, the correspondence is poor. For the
carboxylate derivatives 5, 7, 25, and 36, only one
compound gave consistent results in both series.22 For
heterocyclic groups that are directly attached to the
phenyl ring of DHDMBF or di-tert-butylphenol, the
activity of the oxdiazole 46 does not correlate,6 while
the imidazothiazoles 49, 50, and 51 do correlate.9 For
the remaining heterocycles, either fused to a methylene
group (5219 and 5320) or attached via a carbonyl (56) or
an ethenyl group (61-65),12,17a the correspondence is
again random. Thus, while drawing analogies from the
di-tert-butylphenol literature was a source of several
active DHDMBFs, activity in the di-tert-butylphenol
series was not accurately predictive of activity in the
DHDMBF series.
In Vitr o Resu lts. Selected compounds were tested
in vitro for inhibition of COX and 5-LOX (Table 3). The
COX-2 selectivity that we observed for many of the
5-keto-substituted dihydrobenzofurans1,2 prompted us
to look for similar selectivity for compounds with
different substituents at C-5. Potency and selectivity
were determined using human platelet-derived COX-1
and recombinant human COX-2. In addition, selected
compounds were assayed for inhibition of 5-lipoxygenase
in RBL cells.
Con clu sion s
A large variety of substituents in the 5 position led
to antiinflammatory and analgesic 7-tert-butyl-2,3-di-
hydro-3,3-dimethylbenzofurans. This observation has
greatly expanded the scope of the dihydrobenzofuran
lead. The substituents leading to active compounds
include amides, amidines, ureas, guanidines, amines,
heterocycles, heteroaromatics, heterocyclic ketones, and
heteroaromatic ethenyl compounds. The in vivo activity
For the series of secondary amides (8-20 and 36),
there was a trend for increasing COX-2 selectivity with
increasing chain length as was observed for alkyl
ketones.1 The most selective compound in the series
was the methoxyethyl amide 20 which was 33-fold

3520 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
J anusz et al.
Ta ble 1. Structure, Synthetic Methods, and in Vivo Activity of Dihydrodimethylbenzofurans
compd
R
method
yield, %
mp, °C
formula
CPE indexa
PAC assayb
1, tebufelone
naproxen
5
6
7
1.00c
1.06c
0.47
0.16
0.07
0.88
1.17
0.46
0.16
1.09
0.68
0.44
0.06
0.00
0.00
0.01
0.33
1.47
0.51
0.00
0.49
0.81
0.36
0.86
0.91
1.82
1.14
1.41
0.78
0.52
0.71
0.47
0.80
0.66
0.73
0.41
1.49
0.78
0.56
0.93
0.92
0.19
1.53
0.83
0.26
1.38
0.81
0.96
0.19
0.93
0.07
0.70
0.68
0.58
0.62
1.24
0.75
0.76
0.77
0.00
0.56
0.50
0.78
37
1.3
CO2H
CO2Me
CONH2
CONHEt
CONHPr
CONHBu
CONHPen
CONH-i-Pr
CONH-c-Pr
CONHCH2-c-Pr
CONH(CH2)2-c-Pr
CONH-c-Bu
CONH-c-Pen
CONHC6H5
CONH(CH2)2OH
CONH(CH2)2OMe
CONHCH2CH(OH)CH2OH
CONH(CH2)2NMe2
CONH-2-thiazole
CONH-2-thiazoline
CONMe2
CONMeEt
CONMePr
CONMe-c-Pr
CONEt-c-Pr
CONPr-c-Pr
CON(C4H8)
CON(C5H10
CON(C4H8S)
C(dNH)NMe2
C(dNH)(C4H8N)
NHCOMe
NHCONHEt
NHCONHPr
NH(C3H5N2)
NH-o-(CO2H)C6H4
3-(5,5-di-Me)isoxazolinyl
2-furyl
Scheme 1
Scheme 1
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
A
A
95
79
100
77
42
68
45
55
93
30
32
51
28
35
85
69
69
71
61
35
89
86
73
57
59
49
74
87
91
20
54
22
51
39
32
57
31
43
43
41
36
52
52
35
63
75
64
78
29
84
67
74
80
47
23
34
86
75
42
81
38
197-202
33-34
C15H20O3
C16H22O3
C15H21NO2
C17H25NO2
C18H27NO2
C19H29NO2
C20H31NO2
NTd
NT
NT
56%
63%
NT
NT
43%
20
182-184
204-205
195-197
185-186
165-168
226-227
>200 dec
206-208
185-186
>200 dec
254-256
247-249
168-170
150-152
140-142
160-162
230-232
158-160
91-93
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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
62
63
64
65
C18H27NO2
C18H25NO2
C19H27NO2
C20H29NO2
C19H27NO2
C20H29NO2
C21H25NO2
C17H25NO3
C18H27NO3
C18H27NO4
C19H30N2O2
C18H22N2O2S
NT
NT
NT
NT
NT
NT
84%
NT
NT
NT
65%
NT
19
C18H24N2O2S
C17H25NO2
C18H27NO2
61-62
73-75
C
19H29NO2
36%
10
70-72
C19H27NO2
C20H29NO2
C21H31NO2
81-83
NT
NT
NT
34%
29%
NT
0%e
22%e
36%
NT
8%e
<10
80%
7%e
52%
NT
59%
NT
NT
77%
68%
NT
NT
NT
NT
24
90-92
90-92
C19H27NO2
C20H29NO2
C19H27NO2S
C17H26N2O
C19H28N2O
C16H23NO2
C17H26N2O2
C18H28N2O2
C17H25N3O
C21H25NO3
C19H27NO2
C18H22O2
C18H22OS
C17H21NO2
C17H21NOS
C17H22N2O2
C17H22N2OS
)
105-107
143-145
>160 dec
255-256
154-155
197-198
193-194
>264 dec
204-206
96-98
A
Scheme 1
Scheme 2
Scheme 2
C
C
Scheme 2
Scheme 2
Scheme 3
D
oil
61-63
141-142
100-101
81-82
2-thienyl
4-oxazolyl
4-thiazolyl
D
Scheme 3
Scheme 3
Scheme 2
Scheme 3
Scheme 3
Scheme 3
Scheme 3
Scheme 3
Scheme 5
Scheme 5
E
3-(5-Me)-1,2,4-oxdiazolyl
4-(2-amino)thiazolyl
4-(2-guanidino)thiazolyl
6-imidazo[2.1-b]thiazolyl
6-imidazo[2.1-b]thiazolyl-1-oxide
6-imidazo[2.1-b]thiazolyl-1,1-dioxide
3-methylene-γ-butyrolactonyl
5-methylene-2-imino-4-thiazolidinonyl
CO-2-furyl
CO-3-furyl
CO-2-thienyl
CO-3-thienyl
CO-2-(N-Me)pyrrole
CO-2-thiazolyl
(E)-CHdC(CO2H)-2-thienyl
(E)-CHdCH-2-thienyl
(E)-CHdCH-3-(3-Me)-5-isoxazolyl
(E)-CHdCH-3-(5-Me)-1H-3-pyrazolyl
(E)-CHdCH-2-pyridyl
(E)-CHdCH-3-pyridyl
161-162
237-238
189-190
217-219
275-276
122-123
>213 dec
103-104
120-121
103-105
89-90
C
18H24N4OS
C19H24N2OS
C19H24N2O2S
C
19H24N2O3S
C19H24O3
C18H22N2O2S
C
19H22O3
E
E
E
E
C19H22O3
C19H22O2S
3
34
40%
57
C
19H22O2S
oil
C20H25NO2
C18H21NO2S
C21H24O3S
C20H24OS
E
101-103
183-185
113.5-115
122-123
145-147
122-123
72-74
28
Scheme 5
Scheme 5
Scheme 5
Scheme 5
Scheme 5
Scheme 5
19%e
13
C20H25NO2
NT
35%
NT
45%
C
20H26N2O
C21H25NO
C21H25NO
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 >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 Section1 for complete details. PAC,
phenylquinone-induced abdominal constriction assay. Values are ED50 in bold or the percent reduction of constrictions at a po dose of 70
mg/kg; maximal percent reduction is ∼90%. See Experimental Section1 for complete details. c Percent inhibition of paw swelling for a 50
d
mg/kg po dose was 51.1 ( 10.0 for tebufelone (33-75%, n ) 65) and 54% for naproxen (44-64%, n ) 2). NT, not tested. e Activity is not
statistically different from vehicle control.

DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3521
Ta ble 2. Comparative Activity of Di-tert-butylphenols versus Dihydrodimethylbenzofurans in the CPE Assay
compd
R
a
2
5
7
CO(CH2)3CCH
CO2H
CONH2
CONMe2
NHCOMe
3-(5-Me)-1,2,4-oxdiazolyl
+
-
-
+
-
-
+
+
-
+
+
+
+
+
+
+
+
+
+
-
-
+
+
+
+
-
+
-
+
+
-
+
-
+
b
25
36
46
49
50
51
52
53
56
61
62
63
64
65
6-imidazo[2.1-b]thiazolyl
6-imidazo[2.1-b]thiazolyl-1-oxide
6-imidazo[2.1-b]thiazolyl-1,1-dioxide
3-methylene-γ-butyrolactonyl
5-methylene-2-imino-4-thiazolidinonyl
CO-2-thienyl
c
c
(E)-CHdCH-2-thienyl
(E)-CHdCH-3-(3-Me)-5-isoxazolyl
(E)-CHdCH-3-(5-Me)-1H-3-pyrazolyl
(E)-CHdCH-2-pyridyl
(E)-CHdCH-3-pyridyl
a
A + indicates that the compound is orally active with an ED35 or ED50 e15 mg/kg or with g25% inhibition of paw swelling at a dose
e50 mg/kg. A - indicates an inactive compound. c Test results from an adjuvant arthritis model.
b
) 2.0 Hz, 1 H), 4.35 (s, 2 H), 1.40 (s, 9 H), 1.39 (s, 6 H); 13C
NMR δ 172.8, 162.5, 137.7, 133.1, 128.5, 122.8, 121.5, 84.8,
41.1, 34.2, 29.1, 27.6; MS m/z 249 (MH+), 231; IR 2959, 1676,
1603 cm-1. Anal. (C15H20O3) C, H.
correlated reasonably well with the inhibition of cy-
clooxygenase. Active compounds inhibited both COX-1
and COX-2 with up to 33-fold selectivity for COX-2.
7-ter t-Bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zofu r an Car -
boxylic Acid Meth yl Ester (6). A solution of acid 5 (995
mg, 4.01 mmol), MeOH (20 mL), and concentrated H2SO4 (0.1
mL) was heated at reflux for 14 h. The reaction was quenched
with 10% aqueous NaHCO3 (20 mL). The resulting mixture
was extracted with hexanes, and the combined organic layers
were dried (MgSO4), filtered, and evaporated to give a yellow
oil that was purified by preparative TLC (2% EtOAc/hexanes)
to give 840 mg (79%) of 6 as a colorless oil which solidified on
standing, mp 33-34 °C: 1H NMR δ 1.36 (s, 6 H), 1.38 (s, 9
H), 3.87 (s, 3 H), 4.35 (s, 2 H), 7.65 (d, J ) 1.2 Hz, 1 H), 7.84
(d, J ) 1.2 Hz, 1 H); 13C NMR δ 167.0, 162.0, 137.4, 132.9,
127.5, 122.3, 122.0, 84.5, 51.7, 41.0, 34.1, 29.1, 27.5; MS 263
m/z (MH+). Anal. (C16H22O3) C, H.
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 NMR 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 other-
wise, and chemical shifts are reported relative to tetrameth-
ylsilane (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 Labora-
tories, Inc. (Whitesboro, NY) or in-house at Procter & Gamble
Pharmaceuticals (Norwich NY). 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.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-eth yl-5-ben zo-
fu r a n ca r boxa m id e (8). Meth od A. To a solution of acid 5
(21.5 g, 86.7 mmol), dry THF (300 mL), and DMF (5 mL) at 0
°C was added oxalyl chloride (11.4 mL, 130 mmol, 1.5 equiv)
dropwise over 10 min, and gas evolution was observed. The
reaction was allowed to warm to 23 °C and stirred for 2.5 h,
at which time the solvent was evaporated to provide 27 g
(110%) of crude acid chloride as a dark oil, suitable for use in
subsequent reactions. The oil was stored under N2 in the
refrigerator. The acid chloride could also be prepared for each
individual reaction and used without evaporation of the
solvent: 1H NMR δ 1.37 (s, 15 H), 4.37 (s, 2 H), 7.74 (d, J )
2.0 Hz, 1 H), 7.91 (d, J ) 2.0 Hz, 1 H); IR 2961, 1747, 1683,
1598 cm-1
.
7-ter t-Bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zofu r an Car -
boxylic Acid (5). A solution of 5-bromo-7-tert-butyl-2,3-
dihydro-3,3-dimethylbenzofuran I1 (13.3 g, 48.2 mmol) in dry
Et2O (17 mL) and dry hexanes (150 mL) was cooled to -78
°C, and t-BuLi (59.0 mL, 1.59 M in pentane, 94 mmol, 2.0
equiv) was added dropwise over 10 min. The resulting yellow
solution was allowed to stir at -78 °C for 45 min, and then
CO2 was slowly bubbled through for 30 min. Excess dry ice
was added, and the reaction allowed to warm to 23 °C. The
reaction was partitioned between Et2O (150 mL) and 4 N
NaOH (2 × 100 mL). The aqueous layer was acidified to pH
2 with concentrated HCl and extracted with Et2O. The
extracts were combined, dried (MgSO4), and evaporated to give
11.63 g (95%) of 5 as a light yellow solid, mp 197-202 °C: 1H
NMR δ 12.40 (br s, 1 H), 7.95 (d, J ) 2.0 Hz, 1 H), 7.80 (d, J
To a solution of acid chloride (950 mg, 3.56 mmol) in CH2-
Cl2 (10 mL) was added ethylamine (765 mg, 1.45 mL, 17.8
mmol, 5 equiv. Note: 5-10 equiv of amine were generally
used) over 5 min. The reaction was stirred for 1 h at 23 °C,
and then the solvent was evaporated. The residue was taken
up in 1 N HCl (10 mL), and the insoluble material was
collected by filtration and crystallized from 5:1 i-PrOH/H2O
to yield 754 mg (77%) of 8 as white needles, mp 204-205 °C
(note: reaction time using method A varied from 1 h to
overnight. An alternative workup was often used which
involved quenching the reaction with 1 N HCl followed by
extraction of the product into CH2Cl2, evaporation of the
solvent, and purification): 1H NMR δ 1.23 (t, J ) 7.5 Hz, 3
H), 1.32 (s, 6 H), 1.35 (s, 9 H), 3.49 (dq, J ) 7.5, 7.5 Hz, 2 H),

3522 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
J anusz et al.
Ta ble 3. In Vitro Activity of 5-Substituted Dihydrodimethylbenzofurans
IC50, µMa
compd
COX-1
COX-2
COX-1/COX-2
IC50, µM 5-LOXb
8
9
CONHEt
CONHPr
CONHBu
CONHPen
CONH-c-Pr
CONH(CH2)2OMe
CONMeEt
CONMe-c-Pr
CONPr-c-Pr
20
6
3.33
0.58
11.4
8.00
0.53
33.0
0.55
5.00
1.13
-
NT
>50
NT
NT
>50
∼50
22
12
NT
30
NT
7.5
NT
NT
9
NT
10
4
0.55
2.5
2.0
0.29
1.0
2.5
5
0.95
0.22
0.25
0.55
0.03
4.5
1
10
11
13
20
26
28
30
35
36
39
40
41
43
48
49
52
53
56
58
61
1
4.5
4
C(dNH)(C4H8N)
NHCOMe
NH(C3H5N2)
>100
>100
3.5
3.5
1.00
-
>100
>100
NH-o-(CO2H)C6H4
3-(5,5-di-Me)isoxazolinyl
2-thienyl
4-(2-guanidino)thiazolyl
6-imidazo[2.1-b]thiazolyl
3-methylene-γ-butyrolactonyl
5-methylene-2-imino-4-thiazolidinonyl
CO-2-thienyl
2.5
0.07
0.2
4
0.2
0.63
0.35
2.85
1.67
5.00
12.86
1.60
1.15
0.77
0.57
2.5
0.07
9
0.015
0.0035
3
0.038
0.045
0.035
0.10
15
0.075
0.045
5
0.045
0.035
0.02
0.25
NT
10
NT
6
CO-2-(N-Me)pyrrole
(E)-CHdCH-2-thienyl
tebufelone
3
benchmarks
Ibuprofen
SC-57666
3
30
30
<0.3
0.1
>100
a
b
COX testing was done by testing duplicate samples in duplicate. 5-LOX testing was done by testing single samples in triplicate.
4.25 (s, 2 H), 6.00, (br s, 1 H), 7.40 (d, J ) 1.5 Hz, 1 H), 7.50
(d, J ) 1.5 Hz, 1 H); 13C NMR δ 167.8, 159.9, 137.4, 132.9,
127.2, 124.1, 119.1, 84.3, 41.2, 34.8, 34.1, 29.1, 27.4, 15.0; IR
3256, 3081, 2961, 2870, 1631 cm-1; MS 276 m/z (MH+). Anal.
(C17H25NO2) C, H, N.
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a n -
ca r boxa m id e (7). Method A was used with ammonium
hydroxide, and the resulting compound 7 was recrystallized
from 3:5 EtOAc/hexanes: 1H NMR δ 7.58 (d, J ) 2.1 Hz, 1 H),
7.50 (d, J ) 2.1 Hz, 1 H), 5.95 (br s, 2 H), 4.32 (s, 2 H), 1.39 (s,
9 H), 1.37 (s, 6 H); 13C NMR δ 168.0, 159.1, 137.0, 131.5, 126.6,
124.9, 120.0, 83.9, 40.7, 33.8, 29.0, 27.1; MS m/z 248 (MH+),
232; IR 3346, 3195, 2959, 1656 cm-1. Anal. (C15H21NO2) C,
H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-p r op yl-5-ben -
zofu r a n ca r boxa m id e (9). Method A was used with propyl-
amine, and the resulting compound 9 was recrystallized from
8:1 EtOH/H2O: 1H NMR δ 0.94 (t, J ) 7.7 Hz, 3 H), 1.35 (s, 6
H), 1.39 (s, 9 H), 1.65 (sextet, J ) 7.7 Hz, 2 H), 3.40 (m, 2 H),
4.25 (s, 2 H), 6.10 (br s, 1 H), 7.40, (d, J ) 2.0 Hz, 1 H), 7.50
(d, J ) 2.0 Hz, 1 H); 13C NMR δ 167.8, 159.9, 137.4, 132.9,
127.2, 124.1, 119.1, 84.3, 41.6, 41.2, 34.1, 29.0, 27.4, 23.0, 11.4;
IR 3266, 3085, 2960, 2870, 1630, 1550 cm-1; MS 290 m/z
(MH+). Anal. (C18H27NO2) C, H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-p en tyl-5-ben -
zofu r a n ca r boxa m id e (11). Method A was used with pen-
tylamine, and the resulting compound 11 was triturated with
hot hexanes: 1H NMR δ 0.91 (t, J ) 6.8 Hz, 3 H), 1.35 (s, 6
H), 1.38 (s, 9 H), 1.38-1.45 (m, 4 H), 1.60 (m, 2 H), 3.45 (q, J
) 6.8 Hz, 2 H), 4.28 (s, 2 H), 6.15 (br s, 1 H), 7.40 (d, J ) 1.5
Hz, 1 H), 7.54 (d, J ) 1.5 Hz, 1 H); 13C NMR δ 167.9, 160.0,
137.5, 133.0, 127.3, 124.3, 119.2, 84.4, 41.3, 40.1, 34.2, 29.6,
29.2 (2), 27.5, 22.4, 14.0; IR 3279, 2956, 1628, 1547 cm-1; MS
m/z 318 (MH+). Anal. (C20H31O2N) C, H, N.
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-N-isop r op yl-5-
ben zofu r a n ca r boxa m id e (12). Method A was used with
isopropylamine, and the resulting compound 12 was recrystal-
lized from EtOAc: 1H NMR δ 1.27 (d, J ) 6.4 Hz, 6 H), 1.33
(s, 6 H), 1.37 (s, 9 H), 4.28 (s, 2 H), 4.30 (m, 1 H), 6.03 (d, J )
7.5 Hz, 1 H), 7.40 (d, J ) 2.0 Hz, 1 H), 7.53 (d, J ) 2.0 Hz, 1
H); 13C NMR δ 23.1, 27.7, 29.4, 34.4, 41.5, 42.0, 84.6, 119.3,
124.6, 127.6, 133.2, 137.6, 160.1, 167.3; IR 3250, 2954, 1628
cm-1; MS m/z 290 (MH+). Anal. (C18H27NO2) C, H, N.
7-ter t-Bu tyl-N-cyclop r op yl-2,3-d ih yd r o-3,3-d im eth yl-5-
ben zofu r a n ca r boxa m id e (13). Method A was used with
cyclopropylamine, and the resulting compound 13 was recrys-
tallized from EtOAc: 1H NMR δ 0.62 (m, 2 H), 0.83 (m, 2 H),
1.32 (s, 6 H), 1.38 (s, 9 H), 2.87 (m, 1 H), 4.26 (s, 2 H), 6.39 (br
s, 1 H), 7.38 (d, J ) 1.8 Hz, 1 H), 7.50 (d, J ) 1.8 Hz, 1 H); 13
C
N-Bu tyl-7-ter t-bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-ben zo-
fu r a n ca r boxa m id e (10). Method A was used with butyl-
amine, and the resulting compound 10 was triturated with
hot hexanes: 1H NMR δ 0.95 (t, J ) 6.8 Hz, 3 H), 1.35 (s, 6
H), 1.38 (s, 9 H), 1.38-1.45 (m, 2 H), 1.60 (m, 2 H), 3.43 (q, J
) 6.8 Hz, 2 H), 4.28 (s, 2 H), 6.15 (br s, 1 H), 7.40 (d, J ) 1.5
Hz, 1 H), 7.53 (d, J ) 1.5 Hz, 1 H); 13C NMR δ 167.9, 159.9,
137.4, 133.0, 127.3, 124.3, 119.2, 84.4, 41.3, 39.8, 34.2, 32.0,
NMR δ 6.8, 23.2, 27.5, 29.2, 34.2, 41.3, 84.5, 119.3, 124.4, 126.9,
133.0, 137.5, 160.1, 169.3; IR 3243, 2949, 1630, 1522 cm-1; MS
m/z 288 (MH+). Anal. (C18H25NO2) C, H, N.
7-ter t-Bu t yl-N-cyclop r op ylm et h yl-2,3-d ih yd r o-3,3-d i-
m eth yl-5-ben zofu r a n ca r boxa m id e (14). Method A was
used with aminomethylcyclopropane, and the resulting com-
pound 14 was recrystallized from EtOAc: 1H NMR δ 0.27 (m,
2 H), 0.53 (m, 2 H), 1.05 (m, 1 H), 1.33 (s, 6 H), 1.36 (s, 9 H),
3.30 (dd, J ) 5.7, 5.6 Hz, 2 H), 4.27 (s, 2 H), 6.20 (br s, 1 H),
29.2, 27.5, 20.2, 13.8; IR 3306, 2958, 1633, 1606, 1548 cm-1
;
MS m/z 304 (MH+). Anal. (C19H29O2N) C, H, N.

DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3523
7.42 (d, J ) 1.7 Hz, 1 H), 7.53 (d, J ) 1.7 Hz, 1 H); 13C NMR
δ 3.5, 10.9, 27.5, 29.2, 34.2, 41.3, 44.9, 84.4, 119.3, 124.4, 127.2,
133.0, 137.5, 160.0, 167.9; IR 3267, 2956, 1628 cm-1; MS m/z
302 (MH+). Anal. (C19H27NO2) C, H, N.
with 2-methoxyethylamine, and the resulting compound 20
was chromatographed with 1:6 and then with 2:3 EtOAc/
hexanes: 1H NMR δ 7.54 (d, J ) 1.8 Hz, 1 H), 7.41 (d, J ) 1.8
Hz, 1 H), 6.48 (br, 1 H), 4.28 (s, 2 H), 3.64 (dt, J ) 4.9 Hz, 2
H), 3.56 (t, J ) 4.9 Hz, 2 H), 3.39 (s, 3 H), 1.36 (s, 9 H), 1.33
(s, 6 H); 13C NMR δ 167.9, 160.1, 137.5, 133.0, 126.9, 124.5,
119.3, 84.4, 71.5, 58.8, 41.3, 39.7, 34.2, 29.2, 27.5; IR 3271,
7-ter t-Bu tyl-N-(2-cyclop r op yleth yl)-2,3-d ih yd r o-3,3-d i-
m eth yl-5-ben zofu r a n ca r boxa m id e (15). Step 1. 2-Cy-
clop r op yleth yla m in e. Concentrated sulfuric acid (1.09 mL,
20.0 mmol) was added dropwise to a vigorously stirred solution
of lithium aluminum hydride (1.53 g, 40.0 mmol) in 40 mL of
ether at 0 °C. The reaction mixture was warmed to room
temperature and stirred for 1 h, and a solution of cyclopropyl-
acetonitrile (1.06 g, 13.0 mmol, Lancaster) in 5 mL of ether
was added dropwise. The resulting mixture was heated at
reflux for 2 h, cooled to 0 °C, and slowly quenched with water.
A solution of sodium hydroxide (2 g) in 18 mL of water was
added, and the organic phase was decanted from the resulting
aluminum hydroxide precipitate which was rinsed with three
20-mL portions of ether. All ethereal portions were combined,
and the solvent was distilled off to leave 1.10 g (99%) of
2-cyclopropylethylamine as a colorless liquid: 1H NMR δ 2.77
(t, J ) 6.9 Hz, 2 H), 1.34 (q, J ) 6.9 Hz, 2 H), 0.67 (m, 1 H),
0.42 (m, 2 H), 0.04 (m, 2 H).
2955, 1630, 1548 cm-1; MS m/z 306 (MH+). Anal. (C18H27
-
NO3) C, H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-N-(2,3-d ih yd r oxyp r op yl)-3,3-
d im eth yl-5-ben zofu r a n ca r boxa m id e (21). Method A was
used with 2,3-dihydroxypropylamine, and the resulting com-
pound 21 was chromatographed without workup with EtOAc
and then with 10:1 EtOAc/MeOH, followed by recrystallization
from EtOAc: 1H NMR (CD3OD) δ 7.65 (d, J ) 1.9 Hz, 1 H),
7.54 (d, J ) 1.9 Hz, 1 H), 4.90 (s, 2 H), 4.30 (s, 1 H), 3.83 (m,
1 H), 3.58-3.38 (m, 4 H), 1.36 (s, 9 H), 1.34 (s, 6 H); 13C NMR
(CDCl3/CD3OD) δ 170.1, 160.8, 137.9, 133.4, 126.1, 125.3,
119.8, 84.8, 71.4, 63.8, 42.8, 41.5, 34.5, 29.4, 27.7; IR 3442,
3324, 2959, 1649, 1545 cm-1; MS m/z 322 (MH+), 248. Anal.
(C18H27NO4) C, H, N.
7-t er t -Bu t yl-2,3-d ih yd r o-3,3-d im e t h yl-N -(2-d im e t h -
yla m in oeth yl)-5-ben zofu r a n ca r boxa m id e (22). Method A
was used with N,N-dimethyethylenediamine, and the resulting
compound 22 was chromatographed with 10:1 CH2Cl2/MeOH:
1H NMR δ 7.53 (d, J ) 1.9 Hz, 1 H), 7.41 (d, J ) 1.9 Hz, 1 H),
6.66 (br, 1 H), 4.27 (s, 2 H), 3.54 (q, J ) 5.8 Hz, 2 H), 2.54 (t,
J ) 6.0 Hz, 2 H), 2.28 (s, 6 H), 1.37 (s, 9 H), 1.34 (s, 6 H); 13C
NMR δ 168.0, 160.0, 137.4, 132.9, 127.2, 124.5, 119.3, 84.4,
58.1, 45.3, 41.3, 37.3, 34.2, 29.1, 27.5; IR 3297, 2961, 1630,
1547 cm-1; MS m/z 319 (MH+). Anal. (C19H30N2O2) C, H, N.
N-(2-Am in ot h ia zolyl)-7-ter t-b u t yl-2,3-d ih yd r o-3,3-d i-
m eth yl-5-ben zofu r a n ca r boxa m id e (23). Method A was
used with 2-aminothiazole, and the resulting compound 23 was
chromatographed with 1:7 EtOAc/hexanes and then washed
with hot hexane: 1H NMR δ 12.6 (br, 1 H), 7.81 (d, J ) 1.8
Hz, 1 H), 7.68 (d, J ) 1.8 Hz, 1 H), 7.09 (d, J ) 3.6 Hz, 1 H),
6.91 (d, J ) 3.6 Hz, 1 H), 4.34 (s, 2 H), 1.34 (s, 15 H); 13C NMR
δ 166.1, 161.4, 160.7, 137.9, 137.2, 133.5, 126.2, 124.8, 120.6,
113.2, 84.7, 41.3, 34.3, 29.0, 27.6; IR 3235, 2961, 1640, 1547
cm-1; MS m/z 331 (MH+), 231. Anal. (C18H22N2O2S) C, H, N,
S.
Step 2. 7-ter t-Bu tyl-N-(2-cyclop r op yleth yl)-2,3-d ih y-
d r o-3,3-d im eth yl-5-ben zofu r a n ca r boxa m id e (15). Method
A was used with 2-cyclopropylethylamine, and the resulting
compound 15 was chromatographed with 10 f 20% EtOAc/
hexanes: 1H NMR δ 7.49 (d, J ) 1.8 Hz, 1 H), 7.40 (d, J ) 1.8
Hz, 1 H), 6.16 (br s,1 H), 4.26 (s, 2 H), 3.53 (q, J ) 7.4 Hz, 2
H), 1.52 (q, J ) 7.4 Hz, 2 H), 1.35 (s, 9 H), 1.32 (s, 6 H), 0.74
(m, 1 H), 0.50 (m, 2 H), 0.12 (m, 2 H); 13C NMR δ 167.7, 160.0,
137.4, 132.8, 127.2, 124.0, 119.2, 84.3, 41.2, 40.2, 34.4, 34.1,
29.0, 27.4, 8.63, 4.08; IR 3266, 3079, 2956, 2869, 1630 cm-1
;
MS m/z 316 (MH+). Anal. (C20H29NO2) C, H, N.
7-ter t-Bu tyl-N-cyclobu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-
ben zofu r a n ca r boxa m id e (16). Method A was used with
cyclobutylamine, and the resulting compound 16 was recrys-
tallized from EtOAc: 1H NMR δ 1.33 (s, 6 H), 1.35 (s, 9 H),
1.75 (m, 2 H), 1.96 (m, 2 H), 2.42 (m, 2 H), 4.27 (s, 2 H), 4.59
(m, 1 H), 5.99 (br s, 1 H), 7.39 (d, J ) 1.5 Hz, 1 H), 7.50 (d, J
) 1.5 Hz, 1 H); 13C NMR δ 15.2, 27.5, 29.2, 31.4, 34.2, 41.3,
45.3, 84.5, 119.3, 124.5, 126.9, 133.1, 137.5, 160.1, 167.1; IR
3243, 2955, 1627 cm-1; MS m/z 302 (MH+). Anal. (C19H27
-
NO2) C, H, N.
N-(2-Am in o-2-th ia zolin yl)-7-ter t-bu tyl-2,3-d ih yd r o-3,3-
d im eth yl-5-ben zofu r a n ca r boxa m id e (24). Method A was
used with 2-aminothiazoline, and the resulting compound 24
was chromatographed with 2:3 EtOAc/hexanes and then
triturated with hot ether: 1H NMR δ 7.93 (d, J ) 1.8 Hz, 1
H), 7.77 (d, J ) 1.8 Hz, 1 H), 4.28 (s, 2 H), 3.68 (t, J ) 7.6 Hz,
2 H), 3.22 (t, J ) 7.6 Hz, 2 H), 1.35 (s, 9 H), 1.32 (s, 6 H); 13C
NMR δ 174.1, 173.1, 161.1, 137.3, 132.7, 128.0, 127.2, 121.6,
84.6, 47.4, 41.2, 34.2, 30.0, 29.2, 27.6; IR 3356, 2959, 1620,
1599 cm-1; MS m/z 333 (MH+) 247. Anal. (C18H24N2O2S) C,
H, N, S.
7-ter t-Bu tyl-N-cyclop en tyl-2,3-d ih yd r o-3,3-d im eth yl-5-
ben zofu r a n ca r boxa m id e (17). Method A was used with
cyclopentylamine, and the resulting compound 17 was recrys-
tallized from EtOAc: 1H NMR δ 1.33 (s, 6 H), 1.36 (s, 9 H),
1.50 (m, 2 H), 1.70 (m, 4 H), 2.10 (m, 2 H), 4.27 (s, 2 H), 4.37
(m, 1 H), 5.99 (br s, 1 H), 7.36 (d, J ) 1.8 Hz, 1 H), 7.49 (d, J
) 1.8 Hz, 1 H); 13C NMR δ 23.8, 27.4, 29.0, 33.1, 34.1, 41.2,
51.5, 84.3, 119.0, 124.2, 127.3, 132.9, 137.3, 160.1, 167.3; IR
3265, 2954, 1624 cm-1; MS m/z 316 (MH+). Anal. (C20H29
NO2) C, H, N.,
-
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-p h en yl-5-ben -
zofu r a n ca r boxa m id e (18). Method A was used with aniline,
and the resulting compound 18 was recrystallized from
EtOAc: 1H NMR δ 1.35 (s, 6 H), 1.38 (s, 9 H), 4.30 (s, 2 H),
7.12 (t, J ) 7.4 Hz, 1 H), 7.35 (t, J ) 8.4 Hz, 2 H), 7.66-7.56
(m, 3 H), 7.85 (s, 1 H); 13C NMR δ 27.5, 29.0, 34.2, 41.2, 84.5,
119.4, 120.1, 124.1, 124.6, 127.2, 128.9, 133.2, 137.7, 138.2,
160.1, 166.1; IR 3278, 2959, 1645 cm-1; MS m/z 324 (MH+).
Anal. (C21H25NO2) C, H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-N,N-d im eth yl-3,3-d im eth yl-5-
ben zofu r a n ca r boxa m id e (25). Method A was used with
dimethylamine, and the resulting compound 25 was chromato-
graphed with 1:1 EtOAc/hexanes: 1H NMR (CD3OD) δ 7.17
(d, J ) 1.8 Hz, 1 H), 7.11 (d, J ) 1.8 Hz, 1 H), 4.26 (s, 2 H),
3.04 (s, 6 H), 1.34 (s, 9 H), 1.31 (s, 6 H); 13C NMR (CD3OD) δ
174.5, 160.0, 138.8, 134.1, 129.1, 125.9, 121.0, 85.4, 42.5, 40.5,
30.2, 29.8, 27.9; IR 2957, 1629, 1496 cm-1; MS m/z 276 (MH+),
275, 231. Anal. (C17H25NO2) C, H, N.
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-N-(2-h yd r oxy-
eth yl)-5-ben zofu r a n ca r boxa m id e (19). Method A was used
with ethanolamine, and the resulting compound 19 was
chromatographed with 3:2 EtOAc/hexanes: 1H NMR δ 7.53
(d, J ) 1.8 Hz, 1 H), 7.42 (d, J ) 1.8 Hz, 1 H), 6.58 (s, 1 H),
4.32 (s, 2 H), 3.84 (t, J ) 6.9 Hz, 2 H), 3.65 (q, J ) 6.9 Hz, 2
H), 1.38 (s, 9 H), 1.33 (s, 6 H); 13C NMR δ 169.2, 160.2, 137.5,
132.0, 126.2, 124.5, 119.3, 84.4, 62.6, 43.0, 41.1, 34.1, 29.0, 27.4;
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-eth yl-N-m eth -
yl-5-ben zofu r a n ca r boxa m id e (26). Method A was used
with ethylmethylamine, and the resulting compound 26 was
recrystallized from hexane: 1H NMR δ 7.13 (d, J ) 1.8 Hz, 1
H), 7.03 (d, J ) 1.8 Hz, 1 H), 4.24 (s, 2 H), 3.42 (br s, 2 H),
3.01 (s, 3 H), 1.45 (s, 9 H) 1.41 (s, 6 H), 1.18 (t, J ) 8.6 Hz, 3
H); 13C NMR δ 172.2, 157.9, 136.7, 132.4, 128.4, 123.9, 118.9,
83.8, 45.8, 42.4, 41.1, 33.9, 29.3, 27.3, 13.4; IR 2964, 1620 cm-1
;
MS m/z 292 (MH+), 215, 140; IR 3410, 3275, 2958, 1610 cm-1
.
MS m/z 290 (MH+), 231. Anal. (C18H27NO2) C, H, N.
Anal. (C17H25NO3) C, H, N.,
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-N-(2-m et h oxy-
eth yl)-5-ben zofu r a n ca r boxa m id e (20). Method A was used
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-m eth yl-N-p r o-
p yl-5-ben zofu r a n ca r boxa m id e (27). Method A was used
with methylpropylamine, and the resulting compound 27 was

3524 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
J anusz et al.
chromatographed with 1:1 EtOAc/hexanes: 1H NMR δ 7.12
(d, J ) 1.8 Hz, 1 H), 7.02 (d, J ) 1.8 Hz, 1 H), 4.24 (s, 2 H),
3.37 (br s, 2 H), 3.01 (s, 3 H), 1.65 (m, 2 H), 1.38 (s, 9 H), 1.31
(s, 6 H), 0.88 (br s, 3 H); 13C NMR δ 174.1, 158.0, 136.8, 132.6,
128.5, 124.1, 119.1, 83.9, 51.3, 49.1, 41.2, 34.0, 29.1, 27.4, 21.0,
thiomorpholine, and the resulting compound 33 was chro-
matographed in 1:6 and then in 1:3 EtOAc/hexanes: 1H NMR
δ 7.10 (d, J ) 1.8 Hz, 1 H), 7.02 (d, J ) 1.8 Hz, 1 H), 4.25 (s,
2 H), 3.87 (br m, 4 H), 2.66 (br m, 4 H), 1.33 (s, 9 H), 1.31 (s,
6 H); 13C NMR (CDCl3) δ 170.7, 157.6, 136.4, 132.0, 126.5,
123.4, 118.5, 83.2, 45.3 (br), 40.3, 33.2, 28.2, 26.5, 25.6; IR 2959,
1630 cm-1; MS m/z 334 (MH+), 231. Anal. (C19H27NO2S) C,
H, N, S.
10.9; MS m/z 304 (MH+), 303, 231; IR 2958, 1628, 1465 cm-1
.
Anal. (C19H29NO2) C, H, N.
7-ter t-Bu t yl-N-cyclop r op yl-N-m et h yl-2,3-d ih yd r o-3,3-
d im eth yl-5-ben zofu r a n ca r boxa m id e (28). Meth od B. To
a stirring solution of cyclopropyl amide 13 (2.0 g, 6.97 mmol)
in 25 mL of benzene at room temperature were added
powdered K2CO3 (1.0 g, 7.0 mmol), powdered NaOH (1.1 g,
27.9 mmol), and tetrabutylammonium bisulfate (0.1 g, 0.3
mmol). The resulting mixture was stirred for 1 h at room
temperature. To this stirring solution was added methyl
iodide (0.5 mL, 7.7 mmol), and the reaction was then heated
to reflux. The reaction was monitored by TLC for the absence
of starting material. Upon completion, the reaction was
diluted with 100 mL of ethyl ether and washed with water.
The organic layer was dried over MgSO4 and filtered, and the
solvent was removed in vacuo. Purification by silica gel flash
chromatography with 1:3 EtOAc/hexanes gave 1.2 g (57%) of
28, mp 70-72 °C: 1H NMR δ 7.23 (d, J ) 1.8 Hz, 1 H), 7.09
(d, J ) 1.8 Hz, 1 H), 4.20 (s, 2 H), 2.98 (s, 3 H), 2.79 (m, 1 H),
1.37 (s, 9 H), 1.35 (s, 6 H), 0.58 (d, J ) 8.0 Hz, 2 H), 0.40 (br
s, 2 H); 13C NMR δ 173.0, 158.3, 136.5, 132.2, 129.0, 125.2,
119.9, 84.1, 41.2, 35.5, 34.1, 33.0, 29.6, 29.2, 8.9; MS m/z 302
7-ter t-Bu tyl-2,3-d ih yd r o-N,N-d im eth yl-3,3-d im eth yl-5-
ben zofu r a n ca r boxim id a m id e Hyd r och lor id e (34). To a
solution of the 5-bromo dihydrobenzofuran compound I (500
mg, 1.8 mmol) in Et2O (0.6 mL) and hexanes (5.5 mL) at -78
°C was added t-BuLi (1.5 M in hexanes, 3.3 mL, 5.3 mmol,
2.9 equiv) at such a rate that the reaction temperature did
not exceed -60 °C. This solution was stirred for 1 h and then
was slowly cannulated into a -78 °C solution of dimethylcy-
anamide (0.15 mL, 1.8 mmol, 1.0 equiv) in Et2O (5 mL). The
reaction was kept at -78 °C for 0.5 h and then was allowed to
warm to 0 °C. After 1.5 h, TLC (10% MeOH in CHCl3)
indicated the reaction to be complete. The reaction was
quenched with H2O (10 mL) and 1 N HCl (10 mL) and then
extracted with Et2O. The aqueous layer was brought to pH 9
with 1 N NaOH and extracted with Et2O. The combined Et2O
extracts were dried (MgSO4) and evaporated to a yellow oil
(410 mg). This oil was purified by preparative TLC (15%
MeOH in CHCl3) to give a yellow oil, which was stirred in
EtOH (5 mL) and 1 N HCl (10 mL) for 5 min. The EtOH was
evaporated, and the resulting solution was extracted with
CH2Cl2. The dried organic layers were evaporated to a yellow
oil, which was triturated with Et2O to give 110 mg (20%) of
(MH+), 262, 231; IR 2958, 1623 cm-1
0.5H2O) C, H, N.
. Anal. (C19H27NO2‚
7-ter t-Bu tyl-N-cyclop r op yl-N-eth yl-2,3-d ih yd r o-3,3-d i-
m eth yl-5-ben zofu r a n ca r boxa m id e (29). Method B was
used with ethyl iodide. Additional ethyl iodide was used to
drive the reaction to completion. Compound 29 was chro-
matographed with 1:3 EtOAc/hexanes, followed by recrystal-
lization from hexanes: 1H NMR δ 7.25 (d, J ) 1.7 Hz, 1 H),
7.12 (d, J ) 1.7 Hz, 1 H), 4.25 (s, 2 H), 3.56 (q, J ) 7.2 Hz, 2
H), 2.77 (m, 1 H), 1.34 (s, 9 H), 1.31 (s, 6 H), 1.25 (t, J ) 7.2
Hz, 3 H), 0.67 (m, 2 H), 0.50 (m, 2 H); 13C NMR δ 173.0, 158.3,
136.6, 132.3, 129.4, 125.0, 119.8, 84.1, 42.7, 41.3, 34.2, 30.7,
29.3, 27.6, 13.6, 9.4; IR 3202, 2959, 1618 cm-1; MS m/z 316
(MH+). Anal. (C20H29NO2) C, H, N.
7-ter t-Bu tyl-N-cyclop r op yl-N-n -p r op yl-2,3-d ih yd r o-3,3-
d im eth yl-5-ben zofu r a n ca r boxa m id e (30). Method B was
used with propyl iodide. Additional propyl iodide was used
to drive the reaction to completion. Compound 30 was
recrystallized from hexane, followed by chromatography of the
mother liquors with 1:3 EtOAc/hexanes: 1H NMR δ 7.25 (d, J
) 1.7 Hz, 1 H), 7.12 (d, J ) 1.7 Hz, 1 H), 4.24 (s, 2 H), 3.45 (t,
J ) 7.4 Hz, 2 H), 2.73 (m, 1 H), 1.71 (m, 2 H), 1.34 (s, 9 H),
1.31 (s, 6 H), 0.95 (t, J ) 7.4 Hz, 3 H), 0.65 (m, 2 H), 0.48 (m,
2 H); 13C NMR δ 173.3, 158.3, 136.6, 132.3, 129.4, 125.1, 119.8,
84.1, 49.4, 41.3, 34.1, 31.1, 29.3, 27.6, 21.3, 11.5, 9.6; IR 3204,
2959, 1620 cm-1; MS m/z 330 (MH+). Anal. (C21H31NO2) C,
H, N.
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h ylp yr r olid in yl-5-
ben zofu r a n ca r boxa m id e (31). Method A was used with
pyrrolidine, and the resulting compound 31 was chromato-
graphed in 3:2 EtOAc/hexanes: 1H NMR δ 7.28 (d, J ) 1.8
Hz, 1 H), 7.18 (d, J ) 1.8 Hz, 1 H), 4.24 (s, 2 H), 3.56 (br s, 4
H), 1.90 (br s, 4 H), 1.34 (s, 9 H), 1.31 (s, 6 H); 13C NMR δ
170.3, 159.7, 136.7, 132.3, 129.0, 124.7, 119.6, 84.0, 48.2, 41.2,
34.1, 29.1, 27.4, 26.1; MS m/z 302 (MH+), 301, 231; IR 2956,
2871, 1616 cm-1. Anal. (C19H27NO2) C, H, N.
7-t er t -Bu t yl-2,3-d ih yd r o-3,3-d im e t h ylp ip e r id in yl-5-
ben zofu r a n ca r boxa m id e (32). Method A was used with
piperidine, and the resulting compound 32 was chromato-
graphed in 3:2 EtOAc/hexanes: 1H NMR δ 7.05 (d, J ) 1.8
Hz, 1 H), 6.95 (d, J ) 1.8 Hz, 1 H), 4.15 (s, 2 H), 3.43 (br s, 4
H), 1.58 (br s, 4 H), 1.51 (br s, 2 H), 1.29 (s, 9 H), 1.26 (s, 6 H);
13C NMR δ 171.0, 159.2, 136.9, 132.5, 128.1, 124.3, 119.3, 83.9,
48.1, 41.2, 34.0, 29.1, 27.4, 26.0, 24.5; MS m/z 316 (MH+), 231,
112; IR 2950, 2860, 1627 cm-1. Anal. (C20H29NO2) C, H, N.
1
34 as a white powder, mp >160 °C dec: H NMR δ 1.34 (s, 9
H), 1.33 (s, 6 H), 3.10 (s, 6 H), 4.27 (s, 2 H), 7.05 (d, J ) 1.8
Hz, 1 H), 7.11 (d, J ) 1.8 Hz, 1 H); 13C NMR δ 27.5, 29.2,
34.3, 40.1, 41.4, 84.3, 119.9, 125.0, 126.5, 133.5, 137.7, 158.0,
169.1; IR 2958, 1576 cm-1; MS m/z 275 (MH+). Anal.
(C17H26N2O‚1.75HCl) C, H, N.
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-(im in o-1-p yr -
r olid in ylm eth yl)ben zofu r a n Hyd r och lor id e (35). Step 1.
7-ter t-Bu t yl-5-cya n o-2,3-d ih yd r o-3,3-d im et h ylb en zofu -
r a n (II). A solution of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-
benzofuran (16.75 g, 82 mmol) in CH2Cl2 (175 mL) was heated
to reflux, and chlorosulfonylisocyanate (25.4 mL, 287 mmol,
3.5 equiv) was added in a single portion. The reaction was
judged to be complete by TLC (5% EtOAc/hexanes) after 2 h.
The reaction mixture was then cooled to 0 °C, and DMF (65
mL, 0.82 mol, 10 equiv) was added. The solution was allowed
to stir at ambient temperature for 1.5 h. The solvents were
evaporated, and the resulting oil was partitioned between
hexanes and H2O. The aqueous phase was discarded, and the
hexanes were dried (MgSO4) and evaporated to a yellow oil
which solidified upon sitting (18.2 g). This solid was purified
by medium-pressure chromatography (5% EtOAc/hexanes) to
give 8.58 g (46%) of II as a yellow oil of sufficient purity (∼85%
1
by H NMR) for the next reaction: 1H NMR δ 1.35 (s, 15 H),
4.28 (s, 2 H), 7.25 (d, J ) 1.0 Hz, 1 H), 7.39 (d, J ) 1.0 Hz, 1
H).
St ep 2. E t h yl 7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-
ben zofu r a n -5-ca r boxim id ic Acid Hyd r och lor id e (III).
Into a solution of II (4.90 g, 18.6 mmol) in Et2O (30 mL) and
EtOH (3.2 mL, 55.8 mmol, 3 equiv) was bubbled HCl gas for
10 min. The red solution was stirred at 23 °C for 4 days.
(Using higher reaction temperatures to speed the reaction
reduced the yield.) The solvents were evaporated, and the
resulting red oil was triturated with hexanes (30 mL) to
produce a red solid which was collected by filtration to give
3.55 g (62%) of III as a red powder of sufficient purity for the
next reaction: 1H NMR δ 1.6 (t, J ) 6.8 Hz, 3 H) 1.39 (s, 15
H), 4.41 (s, 2 H), 4.65 (q, J ) 6.8 Hz, 2 H), 4.95 (br s, 2 H),
7.85 (s, 2 H).
Step 3. 7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(im in o-
1-p yr r olid in ylm eth yl)ben zofu r a n Hyd r och lor id e (35). To
a solution of III (400 mg, 1.29 mmol) in dioxane (10 mL) was
added excess pyrrolidine (0.6 mL). A color change from red
to yellow was observed during the addition, and a precipitate
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth ylth iom or p h olin yl-
5-ben zofu r a n ca r boxa m id e (33). Method A was used with

DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3525
formed. The reaction was also monitored by TLC (10% MeOH/
CHCl3). After 3 h, the yellow precipitate was collected by
filtration and purified by preparative TLC (10% MeOH/CHCl3)
to give 210 mg (54%) of 35 as a white powder, mp 255-256
°C: 1H NMR (CD3OD) δ 1.39 (s, 9 H) 1.38 (s, 6 H), 1.95
(quintet, J ) 7.3 Hz, 2 H), 2.15 (quintet, J ) 7.3 Hz, 2 H),
3.55 (t, J ) 7.3 Hz, 2 H), 3.60 (t, J ) 7.3 Hz, 2 H), 4.35 (s, 2
H), 7.25 (s, 2 H); 13C NMR (CD3OD) δ 26.0, 26.7, 27.7, 29.5,
35.4, 42.6, 50.0, 53.5, 85.8, 121.7, 123.3, 126.5, 135.1, 140.0,
161.8, 165.0; IR 3418, 2958, 1656, 1607 cm-1; MS m/z 301
(MH+). Anal. (C19H28N2O‚1.7HCl) C, H, N.
N-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-ben zofu r a -
n yl)eth a n a m id e (36). Step 1. 7-ter t-Bu tyl-2,3-d ih yd r o-
3,3-d im eth yl-5-n itr oben zofu r a n . To a solution of 7-tert-
butyl-2,3-dihydro-3,3-dimethylbenzofuran (10.0 g, 49.0 mmol)
in glacial acetic acid (80 mL) was added dropwise 70% HNO3
(4.0 mL, 5.7 g, 63.7 mmol). The reaction mixture darkened to
a deep green color over the course of the addition. The reaction
was monitored by TLC (2% EtOAc/hexanes) and was allowed
to stir at 22 °C for 4 h. Then the reaction mixture was
partitioned between Et2O and H2O. The ethereal layer was
washed with saturated aqueous Na2CO3, dried (MgSO4),
filtered, and evaporated to a red solid (9.12 g). Crystallization
from hexane provided the title compound as orange prisms
(2.26 g, 18.5%), mp 93-94 °C. A second crop yielded slightly
less pure material (4.93 g, 40.3%) which was used without
further purification: 1H NMR δ 1.38 (s, 15 H), 4.40 (s, 2 H),
7.91 (d, J ) 1.5 Hz, 1 H), 8.12 (d, J ) 1.5 Hz, 1 H); 13C NMR
δ 163.5, 142.2, 138.4, 133.8, 122.4, 116.8, 85.4, 41.2, 34.4, 28.9,
27.6. Anal. (C14H19NO3) C, H, N.
Step 2. 5-Am in o-7-ter t-bu tyl-2,3-d ih yd r o-3,3-d im eth -
ylben zofu r a n (V). A suspension of 7-tert-butyl-2,3-dihydro-
3,3-dimethyl-5-nitrobenzofuran (2.2 g, 8.8 mmol) in absolute
EtOH (60 mL) was hydrogenated over 10% palladium on
charcoal at 40 psi of H2 pressure on a Parr hydrogenation
apparatus for 3 h at 22 °C. The reaction was judged to be
complete by TLC (hexanes/EtOAc, 19:1; visualized with Dragen-
dorff reagent). The reaction mixture was filtered through
Celite and evaporated to yield 1.7 g (88%) of V as a purple
solid which was used without further purification: 1H NMR δ
1.28 (s, 6 H), 1.33 (s, 9 H), 3.32 (br s, 2 H), 4.13 (s, 2 H), 6.32
(d, J ) 1.5 Hz, 1 H), 6.45 (d, J ) 1.5 Hz, 1 H); 13C NMR δ
27.1, 29.3, 34.0, 41.7, 83.5, 107.5, 112.4, 133.3, 137.8, 139.5,
150.5; MS m/z 220 (MH+).
St ep 3. N-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-
ben zofu r a n yl)et h a n a m id e (36). To a solution of V (800
mg, 3.68 mmol) and DMAP (494 mg, 4.05 mmol) in CH2Cl2
(40 mL) was added acetyl chloride (0.26 mL, 3.68 mmol). The
reaction was monitored by TLC and was judged to be complete
after 1 h. The reaction mixture was diluted with Et2O, and
the precipitated solids were filtered and discarded. The filtrate
was evaporated, and the residue was purified by preparative
TLC with 9:1 hexanes/EtOAc to yield 212 mg (22%) of 36 as a
white solid, mp 154-155 °C: 1H NMR δ 1.31 (s, 6 H), 1.35 (s,
9 H), 2.14 (s, 3 H), 4.20 (s, 2 H), 6.92 (d, J ) 1.5 Hz, 1 H), 7.22
(br s, 1 H), 7.33 (d, J ) 1.5 Hz, 1 H); 13C NMR δ 24.2, 27.2,
29.1, 34.0, 41.6, 83.8, 113.3, 117.6, 130.7, 132.5, 136.5, 153.5,
167.5; IR 3313, 2960, 1664, 1619 cm-1; MS m/z 262 (MH+).
Anal. (C16H23NO2) C, H, N.
N-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-ben zofu r a -
n yl)-N′-p r op ylu r ea (38). Method C was followed using
propylisocyanate, and the resulting compound 38 was recrys-
tallized from EtOAc: 1H NMR δ 0.89 (t, J ) 7.9 Hz, 3 H), 1.27
(s, 6 H), 1.33 (s, 9 H), 1.49 (m, J ) 7.8 Hz, 2 H), 3.18 (br s, 2
H), 4.20 (s, 2 H), 5.20 (br s, 1 H), 6.89 (br s, 1 H), 7.00 (br s, 1
H); 13C NMR δ 11.3, 23.4, 27.3, 29.2, 34.1, 41.6, 41.9, 83.9,
115.3, 120.0, 131.0, 133.6, 137.8, 154.0, 156.9; IR 3323, 2960,
2870, 1639, 1562 cm-1; MS m/z 305 (MH+). Anal. (C18H28N2O2)
C, H, N.
2-(N-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zo-
fu r a n yl)a m in o)im id a zolin e (39). To a solution of V (0.3
g, 1.3 mmol) in 10 mL of CH3CN at room temperature was
added of imidazoline-2-sulfonic acid (0.2 g, 1.3 mmol). The
reaction was then refluxed overnight. As the solution cooled
to room temperature, the pure product precipitated out of
solution and was filtered to give 120 mg (32%) of 39, mp
264 °C dec: 1H NMR (CD3OD) δ 6.94 (d, J ) 1.7 Hz, 1 H), 6.92
(d, J ) 1.7 Hz, 1 H), 4.24 (s, 2 H), 3.67 (s, 4 H), 1.24 (s, 9 H),
1.21 (s, 6 H); 13C NMR δ 173.2, 158.3, 137.4, 134.1, 129.7,
125.4, 120.0, 84.9, 41.0, 36.0, 34.5, 29.8, 26.8; MS m/z 288
(MH+), 220, 205, 164; IR 3167, 2959, 1664 cm-1
. Anal.
(C17H25N3O‚0.8H2SO4) C, H, N.
2-[5-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth ylben zofu r a -
n yl)a m in o]ben zoic Acid (40). A mixture of V (1.05 g, 4.8
mmol), diphenyliodonium-2-carboxylate monohydrate (1.3 g,
4.0 mmol), cupric acetate (0.03 g, 0.2 mmol), and 7 mL of
2-propanol was heated at reflux for 4 h. The dark reaction
mixture was cooled to room temperature and concentrated in
vacuo. The residue was dissolved in ether, washed with 1 N
NaOH solution and with 1 N HCl, dried over anhydrous Na2-
SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (5% MeOH/CH2Cl2) afforded
0.90 g (57%) of 40 as a light yellow solid, mp 204-206 °C: 1H
NMR δ 8.03 (dd, J ) 8.0, 1.5 Hz, 1 H), 7.31 (m, 1 H), 6.97 (m,
2 H), 6.88 (d, J ) 1.8 Hz, 1 H), 6.47 (t, J ) 8.0 Hz, 1 H), 4.25
(s, 2 H), 1.37 (s, 9 H), 1.34 (s, 6 H); 13C NMR δ 186.6, 173.7,
154.6, 150.9, 138.1, 135.1, 133.9, 132.4, 122.3, 117.1, 115.8,
113.5, 109.0, 83.9, 41.6, 34.1, 29.2, 27.3; IR 3338, 1660, 1605,
1577 cm-1; MS m/z 340 (MH+). Anal. (C21H25NO3) C, H, N.
3-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-5,5-d im eth ylisoxa zolin e (41). A solution of 1-(7-tert-
butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-3-chloro-3-
methylbutan-1-one (500 mg, 1.56 mmol), hydroxylamine hy-
drochloride (1.87 mmol, 1.2 equiv), EtOH (13 mL), and 2 N
NaOH (0.78 mL, 1.56 mmol, 1 equiv) was heated to 50 °C and
stirred for 36 h at which time TLC (10% EtOAc/hexanes)
showed completion of the reaction. A white precipitate was
removed by filtration and discarded. The filtrate was evapo-
rated to a gummy, yellow solid (547 mg). This solid was
purified by preparative TLC (10% EtOAc/hexanes) to give 145
mg (31%) of 41 as a white solid, mp 96-98 °C: 1H NMR δ
1.33 (s, 6 H), 1.38 (s, 9 H), 1.50 (s, 6 H), 3.13 (s, 2 H), 4.24 (s,
2 H), 7.30 (d, J ) 1.7 Hz, 1 H), 7.36 (d, J ) 1.7 Hz, 1 H); 13C
NMR δ 27.2, 27.4, 29.1, 34.1, 41.3, 47.2, 84.2, 84.2, 118.3, 122.6,
123.8, 133.2, 137.0, 156.6, 158.6; IR 2961, 1605, 1457 cm-1
;
MS m/z 302 (MH+). Anal. (C19H27NO2) C, H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(2-fu r a n yl)ben -
zofu r a n (42). Meth od D. A mixture of I (1.13 g, 4.0 mmol),
2-(tributylstannyl)furan (1.71 g, 4.8 mmol, Aldrich), tetrakis-
(triphenylphosphine)palladium (0.46 g, 0.4 mmol), and 20 mL
of toluene was heated under argon at reflux for 30 min. The
reaction mixture was cooled to room temperature and concen-
trated in vacuo. The residue was diluted with ether, washed
with 10% NH4OH and with brine, dried over anhydrous
MgSO4, and concentrated to give a dark oil. Purification by
flash column chromatography on silica gel (1% EtOAc/hexanes)
yielded 0.47 g (43%) of 42 as a light yellow oil: 1H NMR δ
7.55 (d, J ) 1.8 Hz, 1 H), 7.48 (dd, J ) 1.8, 0.9 Hz, 1 H), 7.37
(d, J ) 1.8 Hz, 1 H), 6.58 (dd, J ) 3.4, 0.9 Hz, 1 H), 6.47 (dd,
J ) 3.4, 1.8 Hz, 1 H), 4.30 (s, 2 H), 1.50 (s, 9 H), 1.41 (s, 6 H);
13C NMR δ 156.9, 155.0, 140.9, 137.6, 133.3, 123.9, 121.1,
116.0, 111.4, 102.8, 84.0, 41.4, 34.2, 29.3, 27.4; IR 2958, 2870,
1454 cm-1; MS m/z 271 (MH+). Anal. (C18H22O2) C, H.
N-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-ben zofu r a -
n yl)-N′-eth ylu r ea (37). Meth od C. Ethylisocyanate (0.18
mL, 2.28 mmol) was added dropwise to a solution of V (500
mg, 2.28 mmol) in Et2O (5 mL). A solid formed after 10 min,
and the reaction was quenched with H2O (10 mL) after 40 min.
The reaction was extracted with Et2O, and the organic layers
were dried (MgSO4) and evaporated to a tan solid (657 mg).
This solid was recrystallized from EtOAc to give 335 mg (51%)
of 37 as white prisms, mp 197-198 °C: 1H NMR δ (1.06 t, J
) 7.9 Hz, 3 H), 1.28 (s, 6 H), 1.33 (s, 9 H), 3.23 (br s, 2 H),
4.20 (br s, 2 H), 5.20 (br s, 1 H), 6.91 (br s, 1 H), 6.95 (br s, 1
H), 7.00 (br s, 1 H); 13C NMR δ 15.4, 27.2, 29.1, 34.0, 34.9,
41.5, 83.8, 114.9, 119.7, 131.0, 133.5, 137.7, 154.0, 157.2; IR
3326, 2960, 2869, 1643, 1571 cm-1; MS m/z 291 (MH+). Anal.
(C17H26N2O2) C, H, N.

3526 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
J anusz et al.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(2-th ien yl)ben -
zofu r a n (43). Method D was followed using 2-(tributylstan-
nyl)thiophene (Aldrich). Purification by flash column chro-
matography on silica gel (0.5% EtOAc/hexanes) yielded 0.98
g (43%) of 43 as a colorless oil, which solidified upon standing,
mp 61-63 °C: 1H NMR δ 7.35 (d, J ) 1.8 Hz, 1 H), 7.19 (m,
3 H), 7.07 (m, 1 H), 4.27 (s, 2 H), 1.43 (s, 9 H), 1.37 (s, 6 H);
13C NMR δ 157.0, 145.5, 137.7, 133.3, 127.7, 127.0, 123.3,
123.3, 121.7, 118.0, 84.0, 41.4, 34.1, 29.2, 27.4; IR 3071, 2958,
2871, 1458 cm-1; MS m/z 287 (MH+). Anal. (C18H22OS) C, H,
S.
27.4; IR 3491, 3386, 2958, 2869, 1641, 1609, 1483 cm-1; MS
m/z 263 (MH+). Anal. (C15H22N2O2) C, H, N.
Step 2. 3-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-ben -
zofu r a n yl)-5-m eth yl-1,2,4-oxa d ia zole (46). To a solution
of IV (1.05 g, 4.0 mmol) in 20 mL of pyridine was added acetyl
chloride (0.43 mL, 6.0 mmol). The reaction mixture was
heated at 95 °C for 22 h and cooled to room temperature. The
pyridine was removed in vacuo at 50 °C, and the residue was
partitioned between water and EtOAc. The organic layer was
washed with water and with brine, dried over MgSO4, filtered,
and concentrated in vacuo to give 1.33 g of the crude product.
Purification by flash column chromatography on silica gel (10%
EtOAc/hexanes) produced 0.60 g (52%) of 46 as a white solid,
mp 81-82 °C: 1H NMR δ 7.81 (d, J ) 1.8 Hz, 1 H), 7.65 (d, J
) 1.8 Hz, 1 H), 4.28 (s, 2 H), 2.62 (s, 3 H), 1.38 (s, 9 H), 1.35
(s, 6 H); 13C NMR δ 175.8, 168.6, 159.7, 137.8, 133.5, 124.6,
119.4, 118.7, 84.2, 41.2, 34.1, 29.0, 27.3, 12.2; IR 2959, 2871,
1585, 1437 cm-1; MS m/z 287 (MH+). Anal. (C17H22N2O2) C,
H, N.
2-Am in o-4-(7-ter t-bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben -
zofu r a n yl)th ia zole (47). A mixture of VI1 (1.03 g, 3.2 mmol),
thiourea (0.42 g, 5.4 mmol), and 17 mL of ethanol was heated
at reflux for 2 h. The reaction mixture was cooled to room
temperature, concentrated in vacuo, and poured into water.
The resulting solution was adjusted to pH 9 with saturated
aqueous K2CO3 and extracted with EtOAc. The extract was
dried over MgSO4 and concentrated in vacuo. Purification of
the residue by flash column chromatography on silica gel (30%
EtOAc/hexanes) gave 0.50 g (52%) of 47 as a white solid,
mp 161-162 °C: 1H NMR δ 7.51 (d, J ) 1.8 Hz, 1 H), 7.39 (d,
J ) 1.8 Hz, 1 H), 6.55 (s, 1 H), 5.20 (br s, 2 H), 4.23 (s, 2 H),
1.39 (s, 9 H), 1.34 (s, 6 H); 13C NMR δ 167.0, 157.1, 152.0,
137.3, 133.0, 127.4, 123.0, 117.9, 100.2, 84.0, 41.4, 34.1, 29.2,
27.4; IR 3465, 3276, 1633, 1520 cm-1; MS m/z 303 (MH+). Anal.
(C17H22N2OS) C, H, N, S.,
4-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-2-gu a n id in oth ia zole (48). A mixture of VI1 (0.66 g, 2.0
mmol), 2-iminothiobiuret (0.24 g, 2.0 mmol), and 10 mL of
acetone was heated at reflux for 24 h. The reaction mixture
was cooled to room temperature and concentrated in vacuo.
The residue was dissolved in 1:1 EtOAc/THF, and this solution
was washed with aqueous K2CO3. The organic layer was dried
over MgSO4 and concentrated in vacuo. Purification of the
residue by flash column chromatography on silica gel (5%
MeOH/CHCl3) afforded 0.24 g (35%) of 48 as a white solid,
mp 237-238 °C: 1H NMR (CD3COCD3) δ 7.60 (d, J ) 1.8 Hz,
1 H), 7.54 (d, J ) 1.8 Hz, 1 H), 6.86 (s, 1 H), 4.25 (s, 2 H), 1.40
(s, 9 H), 1.38 (s, 6 H); 13C NMR (CD3COCD3) δ 175.8, 157.9,
157.6, 152.1, 138.2, 133.2, 129.5, 123.5, 118.5, 101.5, 84.7, 42.1,
34.7, 29.3, 27.6; IR 3446, 3400, 3118, 2960, 2872, 1717, 1663,
1604 cm-1; MS m/z 345 (MH+). Anal. (C18H24N4OS) C, H, N.
6-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)im id a zo[2.1-b]th ia zolin e (49). A mixture of VI1 (0.81
g, 2.5 mmol), 2-aminothiazoline (0.25 g, 2.5 mmol), and 10 mL
of ethanol was heated at reflux for 20 h. The reaction mixture
was cooled to room temperature, concentrated to ca. 5 mL in
volume, and poured into water. This solution was adjusted
to pH 9 with 20% aqueous K2CO3 and extracted with ether.
The extract was washed with brine, dried over MgSO4, and
concentrated in vacuo. Purification of the residue by flash
column chromatography on silica gel (20% ether/hexanes f
ether) gave 0.52 g (63%) of 49 as a white solid, mp 189-
190 °C: 1H NMR δ 7.40 (d, J ) 1.8 Hz, 1 H), 7.37 (s, 1 H),
7.14 (d, J ) 1.8 Hz, 1 H), 4.23 (s, 2 H), 4.16 (t, J ) 7.0 Hz, 2
H), 3.80 (t, J ) 7.0 Hz, 2 H), 1.39 (s, 9 H), 1.37 (s, 6 H);
13C NMR δ 156.4, 149.5, 148.1, 137.3, 132.9, 126.7, 121.3,
116.7, 110.9, 83.9, 46.1, 41.4, 34.5, 34.0, 29.2, 27.4; IR 2956,
1462, 1409 cm-1; MS m/z 329 (MH+). Anal. (C19H24N2OS) C,
H, N, S.
4-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)oxa zole (44). A mixture of the 5-bromoacetyl compound
VI1 (1.30 g, 4.0 mmol) and formamide (2.60 g, 57.8 mmol) was
heated to 160 °C for 2 h. The reaction mixture was cooled to
room temperature, poured into water, and extracted with
ether. The ethereal extract was dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (3% EtOAc/hexanes) to
give 0.45 g (41%) of 44 as a white solid, mp 140.5-141.5
°C: 1H NMR δ 7.90 (s, 1 H), 7.85 (s, 1 H), 7.44 (d, J ) 1.8 Hz,
1 H), 7.35 (d, J ) 1.8 Hz, 1 H), 4.24 (s, 2 H), 1.40 (s, 9 H), 1.33
(s, 6 H); 13C NMR δ 157.3, 150.8, 140.7, 137.6, 133.3, 132.1,
122.9, 122.4, 117.4, 83.9, 41.3, 34.0, 29.1, 27.3; IR 3118, 2956,
1628, 1514 cm-1; MS m/z 272 (MH+). Anal. (C17H21NO2) C,
H, N.
4-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h ylben zo-5-fu r a -
n yl)th ia zole (45). Step 1. 4-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-
d im eth yl-5-ben zofu r a n yl)-2-(eth oxyca r bon yl)th ia zole. A
mixture of VI1 (3.58 g, 11.0 mmol), ethyl thiooxamate (1.60 g,
12.0 mmol), and 60 mL of ethanol was heated at reflux for 2
h. The reaction mixture was cooled to room temperature and
concentrated in vacuo. The solid residue was dissolved in CH2-
Cl2 and was washed with aqueous NaHCO3 solution and with
water, dried over MgSO4, and concentrated in vacuo to yield
4.56 g of the crude product. Purification by flash column
chromatography on silica gel (8% EtOAc/hexanes) gave 3.52 g
(89%) of the title compound as a colorless solid, mp 125-126
°C: 1H NMR δ 7.61 (d, J ) 1.8 Hz, 1 H), 7.58 (m, 2 H), 4.48 (q,
J ) 7.0 Hz, 2 H), 4.24 (s, 2 H), 1.29 (t, J ) 7.0 Hz, 3 H), 1.39
(s, 9 H), 1.35 (s, 6 H); 13C NMR δ 160.4, 159.0, 157.9, 157.3,
137.7, 133.2, 126.2, 123.5, 118.9, 116.5, 84.1, 62.4, 41.4, 34.1,
29.2, 27.4, 14.2; IR 3077, 2956, 1714, 1470 cm-1; MS m/z 360
(MH+).
Step 2. 4-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-ben -
zofu r a n yl)t h ia zole (45). A mixture of 4-(7-tert-butyl-2,3-
dihydro-3,3-dimethyl-5-benzofuranyl)-2-(ethoxycarbonyl)thia-
zole (2.80 g, 7.8 mmol), NaOH (0.6 g, 15.0 mmol), and 30 mL
of ethanol was heated at reflux for 0.5 h. The reaction mixture
was cooled to room temperature and concentrated to give 2.16
g of the crude product. Purification by flash column chroma-
tography on silica gel (10% EtOAc/hexanes) afforded 0.80 g
(36%) of 45 as a light yellow solid, mp 100-101 °C: 1H NMR
δ 8.86 (d, J ) 1.9 Hz, 1 H), 7.64 (d, J ) 1.9 Hz, 1 H), 7.56 (d,
J ) 1.8 Hz, 1 H), 7.38 (d, J ) 1.8 Hz, 1 H), 4.27 (s, 2 H), 1.41
(s, 9 H), 1.37 (s, 6 H); 13C NMR δ 157.5, 157.0, 152.5, 137.7,
133.4, 127.0, 123.5, 118.5, 110.2, 84.1, 41.5, 34.2, 29.3, 27.5;
IR 3449, 3081, 2959, 1610, 1457 cm-1; MS m/z 288 (MH+).
Anal. (C17H21NOS) C, H, N, S.
3-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-5-m eth yl-1,2,4-oxa d ia zole (46). Step 1. 7-ter t-Bu tyl-
2,3-d ih yd r o-3,3-d im eth yl-5-ben zofu r a n ca r boxa m id e Ox-
im e (IV). A mixture of II (6.39 g, 27.9 mmol), K2CO3 (15.80
g, 114.0 mmol), hydroxylamine hydrochloride (7.93 g, 114.0
mmol), and 135 mL of ethanol was heated at reflux for 20 h.
The reaction mixture was cooled to room temperature, filtered,
and concentrated in vacuo to give a solid residue. Purification
by flash column chromatography on silica gel (20% EtOAc/
hexanes f 5% MeOH/CH2Cl2) furnished 3.13 g (43%) of IV as
a colorless, foamy solid, mp 109-110 °C: 1H NMR δ 7.36 (d,
J ) 1.8 Hz, 1 H), 7.26 (d, J ) 1.8 Hz, 1 H), 4.88 (br s, 2 H),
4.25 (s, 2 H), 1.37 (s, 9 H), 1.33 (s, 6 H); 13C NMR δ 158.8,
153.5, 137.5, 133.2, 124.8, 123.1, 118.1, 84.2, 41.4, 34.2, 29.2,
6-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)im id a zo[2.1-b]th ia zolin e 1-Oxid e (50). m-Chloroper-
benzoic acid (0.82 g, ∼2.6 mmol, 50-60% pure) was added to
a solution of 49 (0.87 g, 2.6 mmol) in 10 mL of CHCl3 at 0 °C.
The reaction was complete within 5 min. The reaction mixture

DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3527
was washed with aqueous NaHCO3 and with water, dried over
MgSO4, and concentrated to give a pink solid. Purification
by flash column chromatography on silica gel (35% EtOAc/
hexanes f 5% MeOH/CHCl3) yielded 1.0 g of a pink solid,
which was redissolved in CHCl3. Treatment of this solution
with hexane resulted in the precipitation of 0.67 g (75%) of 50
as a light pink solid, mp 217-219 °C: 1H NMR δ 7.40 (s, 2
H), 7.34 (s, 1 H), 4.77 (m, 1 H), 4.35 (m, 1 H), 4.23 (s, 2 H),
3.70 (m, 2 H), 1.38 (s, 9 H), 1.35 (s, 6 H); 13C NMR δ 157.2,
152.8, 150.8, 137.6, 133.2, 125.7, 122.2, 117.3, 112.6, 84.0, 55.6,
43.1, 41.4, 34.1, 29.2, 27.4; IR 2958, 2869, 1446 cm-1; MS m/z
345 (MH+), 373 (M + C2H5+), 385 (M + C3H5+). Anal.
(C19H24N2O2S‚0.5H2O) C, H, N, S.
6-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)im id a zo[2.1-b]t h ia zolin e 1,1-Dioxid e (51). m-Chlo-
roperbenzoic acid (0.29 g, ∼1.0 mmol, 50-60% pure) was added
to a solution of 50 (0.33 g, 1.0 mmol) in 10 mL of CH2Cl2 at 0
°C. The reaction mixture was stirred at 0 °C for 15 min and
then at room temperature for 16 h and quenched with aqueous
NaHCO3. The organic layer was washed with water, dried
over MgSO4, and concentrated in vacuo. Purification of the
residue by flash column chromatography on silica gel (5% f
10% MeOH/CHCl3) yielded 0.23 g (64%) of 51 as a white
solid, mp 275-276 °C: 1H NMR (CD3COCD3) δ 7.70 (s, 1 H),
7.56 (d, J ) 1.8 Hz, 1 H), 7.52 (d, J ) 1.8 Hz, 1 H), 4.75 (t, J
) 7.5 Hz, 2 H), 4.26 (s, 2 H), 4.10 (t, J ) 7.5 Hz, 2 H), 1.39 (s,
9 H), 1.34 (s, 6 H); 13C NMR (CD3COCD3) δ 157.9, 150.0, 144.2,
138.6, 133.6, 127.1, 122.8, 118.1, 114.5, 84.7, 54.0, 42.1, 41.3,
34.7, 29.3, 27.5; IR 3448, 3150, 2954, 1447 cm-1; MS m/z 361
(MH+). Anal. (C19H24N2O3S) C, H, N, S.
water, and air-dried to give 0.81 g of the crude product, which
was washed with ether to furnish 0.26 g (29%) of 53 as a yellow
1
solid, mp 213-215 °C dec: H NMR (CD3COCD3) δ 7.64 (s, 1
H), 7.36 (d, J ) 1.8 Hz, 1 H), 7.29 (d, J ) 1.8 Hz, 1 H), 4.33 (s,
2 H), 1.39 (s, 9 H), 1.37 (s, 6 H); 13C NMR (CD3SOCD3) δ 182.2,
174.2, 158.2, 138.3, 132.8, 131.3, 126.7, 126.3, 123.2, 122.5,
84.0, 40.7, 33.8, 28.9, 27.0; IR 3150, 2959, 1737, 1672, 1582,
1456 cm-1; MS (ion spray) m/z 331 (MH+), 353 (M + Na+),
369 (M + K+). Anal. (C18H22N2O3S‚0.25H2O) C, H, N, S; S:
calcd, 9.57; found, 9.02.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(2-fu r oyl)ben -
zofu r a n (54). Meth od E. tert-Butyllithium (5.5 mL, 9.4
mmol, 1.7 M in pentane) was added dropwise to a solution of
I (1.13 g, 4.0 mmol) in 16 mL of anhydrous THF at -78 °C.
The resulting yellow solution was stirred at -78 °C for 10 min,
and 2-furaldehyde (0.50 mL, 6.0 mmol) was introduced. The
reaction mixture was warmed to 0 °C, stirred for 30 min,
quenched with water, and extracted with ether. The extract
was dried over MgSO4 and concentrated to give 1.55 g of an
oily residue, which was dissolved in 25 mL of CH2Cl2 and
reacted for 2 h with 4-methylmorpholine N-oxide (0.90 g, 7.7
mmol) and tetrapropylammonium perruthenate (0.16 g, 0.46
mmol). The reaction mixture was filtered through a short
column of silica gel and concentrated to yield 1.57 g of the
crude product. Purification by flash column chromatography
on silica gel (2.5% f 4% EtOAc/hexanes) gave 1.0 g (84%) of
54 as a white solid, mp 103-104 °C: 1H NMR δ 7.83 (d, J )
1.8 Hz, 1 H), 7.66 (d, J ) 1.8 Hz, 2 H), 7.17 (d, J ) 3.4 Hz, 1
H), 6.57 (dd, J ) 3.4, 1.8 Hz, 1 H), 4.29 (s, 2 H), 1.38 (s, 9 H),
1.36 (s, 6 H); 13C NMR δ 181.6, 161.5, 152.7, 146.3, 137.5,
132.8, 130.0, 127.9, 122.0, 119.3, 111.8, 84.6, 41.0, 34.2, 29.1,
27.5; IR 2959, 1640, 1593, 1562, 1507, 1464 cm-1; MS m/z 299
(MH+). Anal. (C19H22O3) C, H.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(3-fu r oyl)ben -
zofu r a n (55). Method E was followed using 3-furaldehyde,
and the resulting compound 55 was purified by flash column
chromatography on silica gel (2.5% EtOAc/hexanes): 1H NMR
δ 7.88 (dd, J ) 1.5, 0.9 Hz, 1 H), 7.70 (d, J ) 1.8 Hz, 1 H),
7.54 (d, J ) 1.8 Hz, 1 H), 7.48 (dd, J ) 1.8, 1.5 Hz, 1 H), 6.87
(dd, J ) 1.8, 0.9 Hz, 1 H), 4.32 (s, 2 H), 1.37 (s, 9 H), 1.35 (s,
6 H); 13C NMR δ 188.3, 161.4, 147.3, 143.5, 137.7, 132.9, 131.5,
127.5, 126.7, 121.6, 110.5, 84.6, 41.0, 34.1, 29.1, 27.5; IR 2959,
2870, 1642, 1595 cm-1; MS m/z 299 (MH+). Anal. (C19H22O3)
C, H.
(Z)-3-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zo-
fu r a n yl)m eth ylen e-γ-bu tyr ola cton e (52). Step 1. 7-ter t-
Bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-for m ylben zofu r an (VII).
To aryl bromide I (20.2 g, 71.4 mmol) in Trapps solvent (4:1:1
THF/ether/hexanes, 180 mL) at -78 °C was added dropwise
t-BuLi (1.7 M in pentane, 88.2 mL, 148 mmol) over 20 min.
The mixture was stirred at -78 °C for 1 h. Anhydrous DMF
(6.1 mL, 78.5 mmol) was added over 10 min. The resulting
yellow solution was stirred at -78 °C for 30 min and warmed
to room temperature over 40 min. The reaction mixture was
quenched with water and extracted with ether. The combined
organic phase was washed with brine, dried over anhydrous
Na2SO4, and filtered. Evaporation of the solvent yielded a
yellow oil (21.9 g) which was filtered through a silica gel pad
with 10% ether in hexane to provide aldehyde VII as a yellow-
brown oil (15.9 g, 96.5%). This product was estimated to be
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(2-th en oyl)ben -
zofu r a n (56). Method E was followed using 2-thiophenecar-
boxaldehyde, and the resulting compound 56 was purified by
flash column chromatography on silica gel (10% EtOAc/
hexanes): 1H NMR δ 7.75 (d, J ) 1.8 Hz, 1 H), 7.66 (m, 2 H),
7.58 (d, J ) 1.8 Hz, 1 H), 7.15 (dd, J ) 4.8, 3.5 Hz, 1 H), 4.33
(s, 2 H), 1.40 (s, 9 H), 1.37 (s, 6 H); 13C NMR δ 186.9, 161.0,
144.0, 137.6, 133.5, 132.9, 132.8, 130.9, 128.0, 127.6, 122.1,
84.7, 41.2, 34.3, 29.2, 27.6; IR 2958, 2869, 1727, 1632, 1594
cm-1; MS m/z 315 (MH+). Anal. (C19H22O2S) C, H, S.
1
1
∼90% pure on the basis of H NMR analysis: H NMR δ 9.83
(s, 1 H), 7.61 (d, J ) 1.5 Hz, 1 H), 7.53 (d, J ) 1.5 Hz, 1 H),
4.33 (s, 2 H), 1.37 (s, 9 H), 1.35 (s, 6 H); 13C NMR δ 191.1,
162.9, 138.4, 133.6, 130.3, 129.4, 121.4, 84.8, 40.8, 34.1, 29.0,
27.5; IR 2960, 2869, 1688, 1593, 1454 cm-1; MS m/z 233 (MH+).
Step 2. (Z)-3-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-
ben zofu r a n yl)m eth ylen e-γ-bu tyr ola cton e (52). A mixture
of VII (0.77 g, 3.3 mmol), 2-(triphenylphosphoranylidene)-γ-
butyrolactone (prepared according to the procedure of Lyga23
et al., 1.19 g, 3.4 mmol), and 30 mL of benzene was heated at
reflux for 2 h. The reaction mixture was cooled to room
temperature and concentrated to afford a brown solid. Puri-
fication by flash column chromatography on silica gel (10% f
75% ether/hexane) gave 0.77 g (78%) of 52 as a white solid,
mp 122-123 °C: 1H NMR δ 7.55 (t, J ) 2.8 Hz, 1 H), 7.28 (d,
J ) 1.8 Hz, 1 H), 7.12 (d, J ) 1.8 Hz, 1 H), 4.45 (t, J ) 7.4 Hz,
2 H), 4.29 (s, 2 H), 3.24 (dt, J ) 2.8, 7.4 Hz, 2 H), 1.36 (s, 9 H),
1.35 (s, 6 H); 13C NMR δ 173.2, 159.1, 138.2, 137.6, 133.7,
128.1, 127.5, 122.1, 119.2, 84.5, 65.3, 41.2, 34.2, 29.1, 27.6, 27.5;
IR 2958, 1748, 1649, 1601, 1455 cm-1; MS m/z 301 (MH+).
Anal. (C19H24O3) C, H.
(Z)-5-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zo-
fu r a n yl)m eth ylen e-2-im in o-4-th ia zolid in on e (53). A mix-
ture of VII (0.62 g, 2.7 mmol), pseudothiohydantoin (0.29 g,
2.5 mmol), sodium acetate (0.51 g, 6.2 mmol), and 12 mL of
acetic acid was heated at reflux for 22 h. The reaction mixture
was cooled to room temperature and poured into cold water.
The resulting orange precipitate was collected, washed with
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(3-th en oyl)ben -
zofu r a n (57). Method E was followed using 3-thiophenecar-
boxaldehyde, and the resulting compound 57 was purified by
flash column chromatography on silica gel (3% EtOAc/hex-
anes): 1H NMR δ 7.88 (dd, J ) 2.8, 1.0 Hz, 1 H), 7.71 (d, J )
1.8 Hz, 1 H), 7.56 (m, 2 H), 7.37 (dd, J ) 4.8, 2.8 Hz, 1 H),
4.33 (s, 2 H), 1.40 (s, 9 H), 1.38 (s, 6 H); 13C NMR δ 189.3,
161.3, 142.0, 137.3, 132.5, 132.0, 131.1, 128.6, 128.1, 125.6,
122.1, 84.5, 41.0, 34.0, 29.0, 27.4; IR 2958, 1642, 1594 cm-1
;
MS m/z 315 (MH+). Anal. (C19H22O2S) C, H, S.
7-ter t-Bu tyl-2,3-dih ydr o-3,3-dim eth yl-5-[2-(N-m eth ylpyr -
r oloyl)]ben zofu r a n (58). Method E was followed using
1-methyl-2-pyrrolecarboxaldehyde except that n-BuLi was
used, and the stoichiometry of n-BuLi/I/aldehyde was 1/1/0.8.
58 was purified by flash column chromatography on silica gel
(5% EtOAc/hexanes): 1H NMR δ 7.68 (d, J ) 1.8 Hz, 1 H),
7.52 (d, J ) 1.8 Hz, 1 H), 6.85 (br s, 1 H), 6.70 (m, 1 H), 6.15
(m, 1 H), 4.30 (s, 2 H), 3.99 (s, 3 H), 1.34 (s, 9 H), 1.32 (s, 6 H);
13C NMR δ 185.5, 160.5, 136.9, 132.4, 132.2, 130.7, 130.3,
127.6, 121.9, 121.2, 107.6, 84.4, 41.0, 36.9, 34.0, 29.0, 27.4; IR

3528 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
J anusz et al.
2958, 2869, 1623, 1592 cm-1; MS m/z 312 (MH+). Anal.
(C20H25NO2‚0.25H2O) C, H, N.
5-[E-2′-(3′′-Met h ylisoxa zol-5′′-yl)et h en yl]-7-ter t-b u t yl-
2,3-d ih yd r o-3,3-d im eth ylben zofu r a n (62). Step 1. 1-(7′-
ter t-Bu t yl-2′,3′-d ih yd r o-3′,3′-d im et h yl-5-b en zofu r a n yl)-
2-(3′′m eth ylisoxa zol-5′′-yl)eth a n ol. To 3,5-dimethylisox-
azole (1.47 mL, 15.0 mmol) in THF (15 mL) at -78 °C was
added n-BuLi (1.47 M in hexanes, 10.0 mL, 14.7 mmol). The
mixture was stirred at -78 °C for 2 h. To the resulting yellow
solution at -78 °C was added dropwise aldehyde VII (3.48 g,
15.0 mmol) in THF (60 mL). The reaction mixture was stirred
at room temperature for 5 h and evaporated. The residue was
partitioned between water and EtOAc. The organic layer was
washed with brine, dried over anhydrous Na2SO4, and con-
centrated to give a brown oil. Silica gel chromatography
afforded the title alcohol as a thick yellow oil (4.36 g, 88.2%)
which solidified, mp 71-72 °C: 1H NMR δ 7.03 (d, J ) 1.5
Hz, 1 H), 6.97 (d, J ) 1.5 Hz, 1 H), 5.88 (s, 1 H), 4.98 (m, 1 H),
4.21 (br s, 2 H), 3.21-3.01 (m, 2 H), 2.24 (s, 3 H), 1.33 (s, 9 H),
1.31 (s, 3 H), 1.29 (s, 3 H); 13C NMR δ 169.8, 159.6, 156.8,
137.3, 134.8, 132.9, 122.4, 117.1, 103.1, 83.8, 72.5, 41.3, 36.6,
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(2-th ia zoloyl)-
ben zofu r a n (59). Method E was followed using 2-thiazole-
carboxaldehyde. 59 was purified by flash column chromatog-
raphy on silica gel (2.5% EtOAc/hexanes): 1H NMR δ 8.45 (d,
J ) 1.8 Hz, 1 H), 8.22 (d, J ) 1.8 Hz, 1 H), 8.05 (d, J ) 3.2 Hz,
1 H), 7.67 (d, J ) 3.2 Hz, 1 H), 4.33 (s, 2 H), 1.40 (s, 9 H), 1.38
(s, 6 H); 13C NMR δ 182.5, 169.0, 162.5, 144.4, 137.6, 133.0,
130.2, 128.0, 125.2, 124.0, 84.8, 41.0, 34.2, 29.1, 27.6; IR 2959,
1634, 1589 cm-1; MS m/z 316 (MH+). Anal. (C18H21NO2S) C,
H, N, S.
E-3-(7′-ter t-Bu tyl-2′,3′-d ih yd r o-3′,3′-d im eth yl-5′-ben zo-
fu r a n yl)-2-(2′′-th iop h en e)p r op en oic Acid (60). To a mix-
ture of aldehyde VII (1.064 g, 4.59 mmol) and 2-thiophene-
acetic acid (978 mg, 6.88 mmol) was added piperidine (1.5 mL).
The mixture was heated at 140 °C (oil bath temperature) for
4 h, cooled to room temperature, quenched with water and
extracted with EtOAc. The organic layer was washed with
brine, dried over anhydrous Na2SO4, and evaporated to give
a brown semisolid. Silica gel chromatography (5% MeOH/
CH2Cl2) provided 543 mg (34.0%) of 60 as a yellow solid, mp
183-185 °C: 1H NMR δ 8.00 (s, 1 H), 7.41 (dd, J ) 5.0, 1.0
Hz, 1 H), 7.08 (dd, J ) 5.0, 3.5 Hz, 1 H), 7.05 (d, J ) 2.0 Hz,
1 H), 6.97 (dd, J ) 3.5, 1.0 Hz, 1 H), 6.70 (d, J ) 2.0 Hz, 1 H),
4.21 (s, 2 H), 1.20 (s, 9 H), 1.19 (s, 6 H); 13C NMR δ 172.4,
159.3, 146.3, 137.4, 136.6, 132.9, 129.5, 127.9, 127.3, 126.8,
126.4, 123.4, 119.8, 84.3, 40.8, 33.9, 28.9, 27.3; IR 2959 (v br),
1678, 1594 cm-1; MS m/z 374 (MNH4+), 357 (MH+). Anal.
(C21H24O3S) C, H, S.
5-[E-2′-(2′′-Th ioph en e)eth en yl]-7-ter t-bu tyl-2,3-dih ydr o-
3,3-d im eth ylben zofu r a n (61). 2-Th iop h en em eth yl Ch lo-
r id e. To 2-thiophenemethanol (9.5 mL, 100 mmol) in CH2Cl2
(100 mL) at 0 °C was added thionyl chloride (14.6 mL, 200
mmol), followed by the addition of pyridine (9.7 mL, 120 mmol).
The mixture was stirred at room temperature for 30 min and
concentrated via rotary evaporation. The resulting brown oil
was filtered through a silica gel pad, washed with 5% ether/
hexanes, and evaporated to give the title compound as an
orange oil (6.50 g, 48.9%) which was stored in the cold and in
the dark, and was used within a week: 1H NMR δ 7.35-6.97
(m, 3 H), 4.85 (s, 2 H).
Dieth yl 2-Th iop h en em eth yl P h osp h on a te. A mixture
of 2-thiophenemethyl chloride (1.1 g, 8.3 mmol) and triethyl
phosphite (2.07 mL, 12.1 mmol) was heated at 130 °C for 4 h.
The resulting mixture was subjected to Kugelrohr distillation
to remove the excess triethyl phosphite (50 °C/0.005 mm)
followed by the title phosphonate as a clear oil (90-130 °C/
0.005 mm, 1.00 g, 51.8%): 1H NMR δ 7.18-6.92 (m, 3 H), 4.05
(dq, J ) 7.5, 7.5 Hz, 4 H), 3.36 (d, J ) 20.5 Hz, 2 H), 1.27 (t,
J ) 7.0 Hz, 6 H); MS m/z 235 (MH+).
5-[E-2′-(2′′-Th ioph en e)eth en yl]-7-ter t-bu tyl-2,3-dih ydr o-
3,3-d im eth ylben zofu r a n (61). A mixture of aldehyde VII
(90%, 8.76 g, 33.95 mmol), diethyl 2-thiophenemethylphos-
phonate (8.04 mL, 40.7 mmol), and NaH (60% in mineral oil
(3.26 g, 81.5 mmol) washed with hexanes three times and dried
in vacuo prior to use) in anhydrous DME (68 mL) was heated
at reflux under nitrogen for 2 h (vigorous evolution of H2
started at ∼5-10 min of heating; therefore, good ventilation
should be ensured). Upon completion of the reaction, the
mixture was quenched carefully with water and extracted with
ether. The organic layer was washed with brine, dried over
anhydrous Na2SO4, and concentrated via rotary evaporation.
The resulting residue was recrystallized from a 1:1 mixture
of CH2Cl2/hexanes to provide 7.05 g (65.9%) of 61 as a white
solid. Silica gel chromatography (5% CH2Cl2/hexanes) of the
mother liquid afforded more 61 (2.04 g, total 86% yield), mp
113.5-115 °C: 1H NMR δ 7.16-7.11 (m, 3 H), 7.03 (d, J )
16.0 Hz, 1 H), 7.02-6.96 (m, 2 H), 6.91 (d, J ) 16.0 Hz, 1 H),
4.24 (s, 2 H), 1.38 (s, 9 H), 1.35 (s, 6 H); 13C NMR δ 152.1,
138.4, 132.5, 128.0, 124.4, 123.9, 122.2, 119.7, 118.8, 118.1,
113.6, 112.2, 78.9, 36.1, 28.9, 24.0, 22.2; IR 2958, 2871, 1600,
1455 cm-1; MS m/z 313 (MH+), 257. Anal. (C20H24OS) C, H,
S.
34.0, 29.1, 27.3, 27.2, 11.2; IR 3378 (br), 2958, 2869, 1606 cm-1
;
MS m/z 330 (MH+). Anal. (C20H27NO3) C, H, N.
Step 2. 5-[E-2′-(3′′-Meth ylisoxa zol-5′′-yl)eth en yl]-7-ter t-
bu tyl-2,3-d ih yd r o-3,3-d im eth ylben zofu r a n (62). To the
above alcohol (3.23 g, 9.80 mmol) in toluene (50 mL) was added
p-toluenesulfonic acid monohydrate (9 mg). The mixture was
heated at reflux for 2 h with removal of water via a Dean-
Stark trap. After concentration, the residue was purified by
silica gel chromatography (65% CH2Cl2 in hexanes), followed
by recrystallization from hexanes/CH2Cl2 (15 mL/1 mL) to
provide a 15:1 mixture, as determined by 1H NMR analysis,
of olefin 62 and the Z-isomer (2.28 g, 74.8%), mp 121.5-123
°C: 1H NMR δ 7.36-7.15 (m, 3 H), 6.77 (d, J ) 16.5 Hz, 1 H),
6.02 (s, 1 H), 4.26 (s, 2 H), 2.30 (s, 3 H), 1.38 (s, 9 H), 1.35 (s,
6 H); 13C NMR δ 168.8, 159.9, 158.4, 137.9, 135.1, 133.4, 128.2,
125.0, 118.2, 109.9, 100.9, 84.2, 41.2, 34.0, 29.1, 27.4, 11.4; IR
2959, 2872, 1640, 1590 cm-1; MS m/z 312 (MH+). Anal.
(C21H25NO2) C, H, N.
5-[E-2′-(5′′-Meth yl-1H-p yr a zol-3′′-yl)eth en yl]-7-ter t-bu -
tyl-2,3-d ih yd r o-3,3-d im eth ylben zofu r a n (63). To a mix-
ture of isoxazole 62 (1.54 g, 4.96 mmol) and molybdenum
hexacarbonyl (982 mg, 3.72 mmol) was added acetonitrile (58
mL) and water (89 µL, 4.96 mmol). The mixture was heated
at reflux for 14 h and then concentrated. To the residue were
added MeOH (30 mL) and 2 N HCl (0.8 mL) until the pH ) 1.
The mixture was stirred for 5 h, concentrated again, and then
treated with water (30 mL) and neutralized with 1 N NaOH.
EtOAc and brine were added. The separated aqueous layer
was extracted with EtOAc. The combined organic layers were
filtered through a silica gel pad with CHCl3 washing. The
organic filtrate was concentrated, and the residue was taken
up with EtOAc and filtered through a silica gel pad with EtOAc
washing. The organic layer was treated with acetic acid (78
mL) and 97% hydrazine (0.779 mL, 24.8 mmol). The mixture
was stirred for 20 h, followed by removal of acetic acid via
vacuum evaporation. The residue was washed with water and
filtered. The resulting brown cake was purified by silica gel
chromatography (1% MeOH/CH2Cl2), followed by recrystalli-
zation from hexanes to provide 645 mg (42%) of 63 as a light
yellow solid, mp 145-147 °C: 1H NMR δ 7.27 (d, J ) 1.5 Hz,
1 H), 7.10 (d, J ) 1.5 Hz, 1 H), 7.01 (d, J ) 16.5 Hz, 1 H), 6.87
(d, J ) 16.5 Hz, 1 H), 6.23 (br s, 1 H), 4.21 (s, 2 H), 2.19 (br s,
3 H), 1.31 (s, 9 H), 1.27 (s, 6 H); 13C NMR (CD3OD) δ 159.0
(br), 139.6, 134.5, 132.5 (br), 131.7 (br), 125.4, 122.3 (br), 119.1,
113.6, 103.3 (br), 102.2 (br), 85.6, 42.8, 35.4, 30.6, 30.2, 28.1;
IR 3190, 3100, 2956, 2869, 1583 cm-1; MS m/z 311 (MH+).
Anal. (C20H26N2O) C, H, N.
5-[E-2′-(2′′-P yr id in yl)eth en yl]-7-ter t-bu tyl-2,3-d ih yd r o-
3,3-d im eth ylben zofu r a n (64). To a mixture of 2-picolyl
triphenylphosphonium chloride (1.29 g, 3.3 mmol, prepared
from 2-picolyl chloride and triphenylphosphine) and sodium
amide (90%, 143 mg, 3.3 mmol) was added THF (8 mL). The
mixture was stirred at room temperature for 1 h and then was
cooled to -78 °C. To this pink slurry at -78 °C was added
aryl aldehyde VII (690 mg, 3.00 mmol) in THF (2 mL). The

DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3529
(6) Unangst, P. C.; Shrum, G. P.; Connor, D. T.; Dyer, R. D.; Schrier,
D. J . Novel 1,2,4-Oxdiazoles and 1,2,4-Thiadiazoles as Dual
5-Lipoxygenase and Cyclooxygenase Inhibitors. J . Med. Chem.
1992, 35, 3691-3698.
(7) (a) Maryanoff, C. A.; Stanzione, R. C.; Plampin, J . N.; Mills, J .
E. A Convenient Synthesis of Guanidines from Thioureas. J . Org.
Chem. 1986, 51, 1882-1884. (b) Kim K.; Lin, Y.-T.; Mosher, H.
S. Monosubstituted Guanidines from Primary Amines and
Aminomethanesulfonic Acid. Tetrahedron Lett. 1988, 29, 3183-
3186.
(8) Scherrer, R. A.; Beatty, H. R. Preparation of Ortho-Substituted
Benzoic Acids by the Copper(II)-Catalyzed Reaction of Di-
phenyliodonium-2-carboxylate with Anilines and Other Nucleo-
philes. J . Org. Chem. 1980, 45, 2127-2131.
mixture was stirred at -78 °C for 10 min and then at room
temperature for 30 min. The solvent was removed via rotary
evaporation. The residue was extracted with ether and
filtered. The extract was concentrated, and the residue was
purified via silica gel chromatography (20% ether/hexanes),
followed by recrystallization from a hexanes/CH2Cl2 mixture
to afford 750 mg (81%) of 64 as a white solid, mp 122-123 °C;
1H NMR δ 8.56 (m, 1 H), 7.63 (m, 1 H), 7.57 (d, J ) 16.0 Hz,
1 H), 7.37 (m, 1 H), 7.29 (d, J ) 1.6 Hz, 1 H), 7.24 (d, J ) 1.5
Hz, 1 H), 7.13 (m, 1 H), 7.03 (d, J ) 16.0 Hz, 1 H), 4.25 (s, 2
H), 1.37 (s, 9 H), 1.35 (s, 6 H); 13C NMR δ 158.1, 156.5, 149.8,
138.0, 136.6, 133.5, 133.4, 129.5, 125.4, 125.1, 121.6, 121.5,
118.4, 84.4, 41.5, 34.3, 29.5, 27.7; IR 2958, 2872, 1634, 1584
cm-1; MS m/z 308 (MH+). Anal. (C21H25NO) C, H, N.
5-[E-2′-(3′′-P yr id in yl)eth en yl]-7-ter t-bu tyl-2,3-d ih yd r o-
3,3-d im eth ylben zofu r a n (65). The procedure described for
the preparation of 64 was followed using 3-picolyl triphen-
ylphosphonium chloride (prepared from 3-picolyl chloride and
triphenylphosphine) except that 0.4 equiv of aldehyde VII was
used. The crude product consisted of a 40:60 mixture of the
E/Z double bond isomers. Separation of the isomers was
performed via silica gel chromatography (20-25% EtOAc/
hexanes) to afford the Z-isomer (788 mg, 51%) and the
E-isomer 65 (580 mg, 38%) both as a white solids. For 65:
mp 72-74 °C; 1H NMR δ 8.70 (br s, 1 H), 8.43 (br s, 1 H), 7.79
(br d, J ) 8.0 Hz, 1 H), 7.25 (m, 1 H), 7.21 (d, J ) 2.0 Hz, 1
H), 7.18 (d, J ) 2.0 Hz, 1 H), 7.13 (d, J ) 16.0 Hz, 1 H), 6.90
(d, J ) 16.0 Hz, 1 H), 4.25 (s, 2 H), 1.38 (s, 9 H), 1.36 (s, 6 H);
13C NMR δ 157.6, 148.1, 147.7, 137.7, 133.4, 133.1, 132.0,
131.2, 129.2, 124.4, 123.3, 121.5, 117.6, 84.0, 41.2, 34.0, 29.1,
27.3; IR 3024, 2957, 2868, 1633, 1603 cm-1; MS m/z 308 (MH+).
Anal. (C21H25NO) C, H, N.
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tion. II. Chem. Pharm. Bull. 1983, 31, 3179-3185.
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of Organotin Reagents with Organic Electrophiles. Angew.
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-,
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P. R. Antiinflammatory 2,6-Di-tert-4-(2-arylethenyl)phenols. J .
Med. Chem. 1989, 32, 100-104.
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â,γ-Unsaturated Malonic Acid Derivatives and the Course of
Decarboxylative Condensation Reactions in Pyridine. J . Am.
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(18) As an example, compound 52 (Table 1) inhibited paw edema by
48%, while tebufelone inhibited paw edema by 52% in the same
experiment, for a CPE index of 0.93.
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T.; Katsumi, I.; Kondo, H.; Yamashita, K.; Watanabe, K.
Pharmacological Properties of a New Anti-Inflammatory Com-
pound, R-(3,5-Di-Tert-Butyl-4-Hydroxybenzylidene)-γ-Butyrolac-
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(20) Unangst, P. C.; Connor, D. T.; Cetenko, W. A.; Sorenson, R. J .;
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Biologica l P r oced u r es. The procedures for the carrag-
eenan-induced paw edema (CPE) assay, the phenylquinone-
induced abdominal constriction (PAC) assay, the human COX-
1/COX-2 isolated enzyme assays, and the RBL-2H3 intact cell
assay for LTB4 inhibition are given in a preceding publication.1
Ack n ow led gm en t. We thank Professor Daniel Tai
of the University of Kentucky for the in vitro COX-1/
COX-2 inhibition data.
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