Design, synthesis, and biological evaluation of novel diarylalkyl amides as TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmc.2009.04.010

We have developed a new class of diarylalkyl amides as novel TRPV1 antagonists. They exhibited potent ⁴⁵Ca²⁺ uptake inhibitions in rat DRG neuron. In particular, the amide 59 was identified as a potent antagonist with IC₅₀ of 57 nM. The synthesis and structure-activity relationship of the diarylalkyl amides are also described.

Full text of DOI:10.1016/j.bmc.2009.04.010

Bioorganic & Medicinal Chemistry 17 (2009) 3557–3567
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis, and biological evaluation of novel diarylalkyl amides
as TRPV1 antagonists
Fu-Nan Li a, Nam-Jung Kim a, Seung-Mann Paek a, Do-Yeon Kwon a, Kyung Hoon Min b, Yeon-Su Jeong c,
Sun-Young Kim c, Young-Ho Park c, Hee-Doo Kim d, Hyeung-Geun Park a, Young-Ger Suh a,
*
a College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
b College of Pharmacy, Chung-Ang University, Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea
c Amorepacific R&D Center 314-1, Bora-dong, Giheung-gu, Yongin-si, Gyeonggi-do 446-729, Republic of Korea
d College of Pharmacy, Sookmyung Women’s University, 52 Hyochangwon-Gil, Yongsan-gu, Seoul 140-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 February 2009
Revised 7 April 2009
Accepted 8 April 2009
Available online 11 April 2009
We have developed a new class of diarylalkyl amides as novel TRPV1 antagonists. They exhibited potent
45Ca2+ uptake inhibitions in rat DRG neuron. In particular, the amide 59 was identified as a potent antag-
onist with IC50 of 57 nM. The synthesis and structure–activity relationship of the diarylalkyl amides are
also described.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diarylalkyl amides
TRPV1 antagonists
1. Introduction
2. Results and discussion
TRPV1 (transient receptor potential vanilloid subfamily 1),1 as a
ligand-gated non-selective cation channel with high 45Ca2+ perme-
ability, is predominantly expressed on primary sensory neurons.
TRPV1 has evoked great interest since it was clearly demonstrated
as a new target for treatment of various pain states, by molecular
cloning and various in vivo pain models.2–5 In particular, recent
extensive findings have implied that direct blockade of TRPV1 by
its antagonists could be a promising way for the discovery of novel
analgesics.6
2.1. Chemistry
Our work commenced with an introduction of amide moiety in
the B region of 1, known as a dipolar interaction part8,9 for the
exclusion of thiourea moiety because sulfur atom is known to be
easily oxidized by the endogenous metabolic enzymes.10 We ini-
tially attempted to replace the thiourea moiety with other pharma-
cologically useful isosteric moieties such as urea and amide (Fig. 1).
Over the recent years, a number of new TRPV1 antagonists have
been reported.7 We have also reported the dibenzyl thiourea ana-
logs including SC-0030 (1),8 which exhibit highly potent competi-
tive TRPV1 antagonistic effects, as well as their structure–activity
relationship (SAR).9 More recently, we have extended our work
for structural optimization of our thiourea series via incorporation
of new scaffolds, which are expected to improve metabolic and
pharmacokinetic profiles of the thiourea series. We herein report
novel diarylalkyl amides as a new class of TRPV1 antagonists with
excellent 45Ca2+ uptake inhibitions in rat DRG neuron as well as
their structure–activity relationship.
S
F
NHMs
N
H
N
H
1
O
F
X
N
H
R1
NHMs
R2
C
B
A
R1, R2: alkyl groups
X: C, N
* Corresponding author. Tel.: +82 2 880 7875; fax: +82 2 888 0649.
E-mail address: ygsuh@snu.ac.kr (Y.-G. Suh).
Figure 1. Amide and urea analogs based on thiourea 1.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.04.010

3558
F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
O
The urea analog 4 (Scheme 1) was synthesized by an assembly of
the benzylamines 39 and 2.11 The corresponding amides 7 and
26b were also prepared to simplify the urea moiety by eliminating
one of the nitrogen of urea moiety.
R1
R2
CHO
R1
R2
a or a,b
OH
22a-b from 12-13 (a, and b)
22c-d from 14-15 (a only)
22e-j from 15-20 (a, and b)
22k from 21 (a only)
R3
R3
The amide 7 (Scheme 2) was synthesized by coupling of 4-tert-
butylbenzylamine 2 with the ester 6, which was prepared by
methanesulfonylation of 5 and Heck reaction of the resulting sul-
fonamide with methylacrylate12 followed by olefin reduction.
For further optimization of C region of the amide series, the ana-
logs 23–34b with a variety of C regions were prepared by a unified
synthetic procedure (Scheme 4). The acids 10 and 11 (Scheme 3)
instead of the corresponding aldehydes bearing methylcyclopropyl
or iso-butyl substituents were separately synthesized for the amide
analogs 27 and 28 (Scheme 4). Wittig olefination of 8 followed by
cyclopropanation of the resulting olefin and then Heck reaction
12 R1=H, R2=H, R3=H
13 R1=H, R2=Br, R3=H
14 R1=H, R2=I, R3=H
15 R1=H, R2=t-Bu, R3=H
16 R1=H, R2=CF3, R3=H
c
22l from 21 (a, and b)
O
17 R1=H, R2=Oi-Pr, R3=H
18 R1=H, R2=Ot-Bu, R3=H
19 R1=t-Bu, R3=H, R3=t-Bu
20 R1=CF3, R3=H, R3=CF3
R1
R2
F
N
H
NHMs
CHO
R3
21
23 R1=H, R2=H, R3=H
24 R1=H, R2=Br, R3=H
25 R1=H, R2=I, R3=H (cinnamoyl)
26a R1=H, R2=t-Bu, R3=H (cinnamoyl)
26b R1=H, R2=t-Bu, R3=H
27 R1=H, R2=i-Bu, R3=H
28a R1=H, R2=methylcyclopropyl, R3=H (cinnamoyl)
28b R1=H, R2=methylcyclopropyl, R3=H
29 R1=H, R2=CF3, R3=H
with methylacrylate afforded the
a,b-unsaturated ester 9, which
were readily converted to the acids 10 and 11 by sequential hydro-
genation and ester hydrolysis.
30 R1=H, R2=Oi-Pr, R3=H
31 R1=H, R2=Ot-Bu, R3=H
32 R1=t-Bu, R2=H, R3=t-Bu
Other acids 22 of Scheme 4 were prepared by Knoevenagel con-
densation of the corresponding benzaldehydes 12–21 with malon-
ic acid, followed by hydrogenation of the resulting olefin. All
amides 23–34b were prepared by DMTMM-mediated coupling of
3 with the corresponding acids. The di-tert-butyl analog 32 and
the tetrahydronaphthalene analog 34b have been prepared for an
investigation of steric effect of the substituted aromatic moiety.
33 R1=CF3, R2=H, R3=CF3
34a
34b
Scheme 4. Reagents and conditions: (a) malonic acid, pyridine, piperidine, reflux,
82–99%; (b) 10% Pd/C, H2, THF, 72–96%; (c) 3, DMTMM, NMM, Et3N, THF, 62–88%.
The selected cinnamoyl analogs were prepared to examine the
rigidity effect of the linker between the B and C regions.
NH2
O
F
a
N
H
N
H
The dihydrobenzofuranyl and the dihydrochromanyl amide
analogs 39–42 were synthesized as described in Scheme 5. The
key intermediates 38a and 38b were prepared by bromination
and O-alkylation of 35, followed by sequential cyclization13 and
formylation. The amide coupling of 38a–b with 3 provided the cin-
namoyl amide 39 and 41 while coupling of the saturated acid of
38a–b with 3 afforded the dihydrocinnamoyl analogs 40 and 42.
The cinnamoyl amide 47 was prepared by coupling of the acid
46 with the amine 3 in the presence of DMTMM. The cinnamoic
acid intermediate 46 was prepared by sequential O-alkylation of
43, Claisen rearrangement of the resulting allyl ether, intramolec-
ular etherification and then formylation, followed by condensation
of the resulting aldehyde with malonic acid (Scheme 6). The dihy-
2
+
NHMs
F
H3N
Cl
4
NHMs
3
Scheme 1. Reagents and conditions: (a) (Boc)2O, DMAP, Et3N, CH2Cl2, 53%.
O
I
F
F
a-c
MeO
NH2
NHMs
6
5
O
F
N
H
d
NHMs
7
n
n
Br
OH
O
O
CHO
Br
Br
Scheme 2. Reagents and conditions: (a) CH3SO2Cl, pyridine, CH2Cl2, 95%; (b)
Pd(OAc)2, DPPF, methylacrylate, Et3N, DMF, 80 °C, 91%; (c) 10% Pd/C, H2, MeOH,
86%; (d) 2, toluene, reflux, 63%.
a, b
c, d
n=1,2
35
37
36
O
I
a, b, c
OMe
OH
n
n
O
O
O
O
F
O
e
OH
g, or f, g
9
8
N
H
e, f
f or d, f
NHMs
O
O
OH
38a n=1
38b n=2
39 n=1, cinnamoyl
40 n=1
10
11a cinnamoyl
11b dihydrocinnamoyl
41 n=2, cinnamoyl
42 n=2
Scheme 3. Reagents and conditions: (a) CH3PPh3Br, n-BuLi, THF, 73%; (b) CH2I2,
Et2Zn, toluene, 99%; (c) methylacrylate, Pd(OAc)2, DPPF, Et3N, DMF, 80 °C, 84%; (d)
10% Pd/C, H2, THF, 2 h, 94%; (e) 10% Pd/C, H2, THF, 8 h, 77%; (f) LiOH, THF/H2O, 91–
100%.
Scheme 5. Reagents and conditions: (a) BTMABr3, CH2Cl2/MeOH = 5:2, 96%; (b)
BrCH2CH2CH2Br or BrCH2CH2Br, NaOH, H2O, reflux, 48–77%; (c) n-BuLi, THF, ꢀ78 °C,
59–69%; (d) t-BuLi, DMF, THF, 56–93%; (e) malonic acid, pyridine, piperidine, reflux,
86–90%; (f) 10% Pd/C, H2, THF, 92–99%; (g) 3, DMTMM, NMM, Et3N, THF, 49–81%.

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
3559
Br
Br
iodobenzonitrile 53 was prepared from the commercially available
2-fluoro-4-iodoaniline 5 via sequential cyanation and iodination.
Reduction of the nitrile 53 with borane and protection of the
resulting benzylamine provided 54. Methanesulfonylation of the
aniline 54 and subsequent Zn(CN)2 treatment afforded the cyanide
55, which was readily converted to the key intermediate 56. Finally
amide coupling of 56 with the corresponding arylpropanoic acids
afforded the desired amide analogs.
The in vitro activities of the synthesized analogs are summa-
rized in Table 1. The urea analog 4 exhibited lower antagonistic
activity than the thiourea 1 as reported in our previous papers.9
As we anticipated, the amide 7 exhibited threefold lower antago-
nistic activities than the parent urea 4 in 45Ca2+ uptake inhibition.
In contrast, the amide 26b is more active than the urea, which im-
plies that the amide possessing the nitrogen at the A region site
could be an alternative scaffold for the thiourea.
We also examined the antagonistic activity of the C region mod-
ified amide analogs. Our previous work revealed that the thiourea
analogs consisting of the 4-tert-butylbenzyl groups in the C region
are more active than any other C region modified analogs. The
amide series also exhibited the similar trend as shown in Table
1. The analogs 24 and 25 possessing para-halogen substituent
showed a significant loss of antagonistic activity. The analogs 28,
which possess methylcyclopropyl substituent known as an isostere
of tert-butyl group, exhibited slightly lower potency than the 4-
tert-butyl analog 26b. However, the 4-trifluoromethyl analog 29
exhibited moderate activity. Replacement of 4-tert-butyl group
by iso-propoxy (30) or tert-butoxy (31) led to a complete loss of
antagonistic activity.
CHO
a, b
c, d
O
HO
e
HO
OH
44
45
43
O
O
F
g,o r f, g
N
H
O
O
NHMs
46
47 cinnamoyl
48 dihydrocinnamoyl
Scheme 6. Reagents and conditions: (a) 3-bromo-2-methylpropene, K2CO3, ace-
tone, reflux, 99%; (b) DMF, 190 °C, 87%; (c) I2, CH2Cl2, 80%; (d) t-BuLi, DMF, THF,
86%; (e) malonic acid, pyridine, piperidine, reflux, 72%; (f) 10% Pd/C, H2, THF, 72%;
(g) 3, DMTMM, NMM, Et3N, THF, 91%.
drocinnamoyl analog 48 was prepared by Pd-catalyzed hydrogena-
tion of 46, followed by amidation of the resulting acid with the
amine 3.
The 2,2-dimethylchromanyl analogs 51 and 52 were also pre-
pared from the acid 50 by the same procedure described in Scheme
6. The acid 50 was derived from 49 via benzopyran ring forma-
tion14 and Knoevenagel condensation (Scheme 7).
Finally, the A region optimized analogs 57–59, which possess
the C regions of the representative potent amides 26b, 28b and
34b, were synthesized by coupling the ammonium salt 56 with
the corresponding phenylpropanoic acid (Scheme 8). The
O
On the basis of our previous studies,15 the substituent effect of
the C region were also confirmed. Interestingly, the analog 32,
which possesses 2,4-di-tert-butylphenyl group was almost equipo-
tent to the amide 26b having 4-tert-butylphenyl group. The similar
trend was observed in the trifluoromethyl series of 29 and 33
although they exhibited much lower antagonistic activities com-
pared to those of the 4-tert-butyl series. The bulkier tetramethyl–
tetrahydronaphthyl analogs exhibited good or excellent antagonis-
tic activities. Thus, the electronic and steric effects of the C region
on antagonistic activity were further examined by introduction of a
variety of heterobicyclic systems. The dihydrobenzofuranyl ana-
logs 39, 40, 47 and 48 exhibited weak activity. However, the ana-
logs consisting of benzopyranyl moieties 41, 42, 51 and 52
exhibited higher activities compared to those of the corresponding
benzofuranyl analogs although their potencies were still not satis-
CHO
OH
a, b
HO
O
50
d, or c, d
49
O
F
N
H
O
NHMs
51 cinnamoyl
52 dihydrocinnamoyl
Scheme 7. Reagents and conditions : (a) 1-bromo-3-methyl-2-butene, K10, CCl4,
8.4%; (b) malonic acid, pyridine, piperidine, reflux, 86%; (c) 10% Pd/C, H2, THF, 93%;
(d) 3, DMTMM, NMM, Et3N, THF, 77–92%.
NC
F
F
F
I
F
BocHN
e, f
BocHN
a, b
c, d
NH2
NH2
NHMs
NH2
I
I
CN
5
53
54
55
O
F
g
F
H3N
Cl
h
N
H
NHMs
NHMs
CN
56
CN
CN
57
j
i
O
O
F
F
N
H
N
H
NHMs
NHMs
CN
58
59
Scheme 8. Reagents and conditions: (a) CuCN, DMF, 130 °C, 80%; (b) 1 M ICl, CH2Cl2, 66%; (c) 1 M BH3ꢁTHF, THF, reflux, then 2 N HCl, 99%; (d) (Boc)2O, DMAP, Et3N, CH2Cl2,
81%; (e) CH3SO2Cl, pyridine, CH2Cl2, 36%; (f) Zn(CN)2, Pd(PPh3)4, DMF, 130 °C, 63%; (g) 5 N HCl, EtOAc, reflux, 100%; (h) 22e, DMTMM, NMM, Et3N, THF, 39%; (i) 11b, DMTMM,
NMM, Et3N, THF, 69%; (j) 22l, DMTMM, NMM, Et3N, THF, 59%.

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F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
Table 1
45Ca2+ Uptake inhibition by the amide analogs
Y
F
Ar
X
Z
NHMs
R
Compound
Ar=
X
Y
Z
R
Antagonistic activity, IC50 (nM)
1
4
7
4-tert-Butylphenyl
4-tert-Butylphenyl
4-tert-Butylphenyl
Phenyl
4-Bromophenyl
4-Iodophenyl
4-tert-Butylphenyl
4-tert-Butylphenyl
NH
NH
NH
CH2
CH2
CH
S
NH
NH
CH2
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN
CN
CN
37
710
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2800
>10,000
>10,000
>10,000
490
170
640
390
360
4600
>10,000
>10,000
200
2500
340
23
24
25
26a
26b
27
28a
28b
29
30
31
32
33
34a
34b
39
40
41
42
47
48
51
52
57
58
59
CH
CH2
CH2
CH
CH2
CH2
CH2
CH2
CH2
CH2
CH
CH2
CH
CH2
CH
CH2
CH
CH2
CH
4-iso-Butylphenyl
4-Methylcyclopropylphenyl
4-Methylcyclopropylphenyl
4-Trifluoromethylphenyl
4-iso-Propoxyphenyl
4-tert-Butoxyphenyl
3,5-Di-tert-butylphenyl
3,5-Ditrifluoromethylphenyl
5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthyl
5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthyl
5-tert-Butyl-2,3-dihydrobenzofuranyl
5-tert-Butyl-2,3-dihydrobenzofuranyl
6-tert-Butylchroman
180
1500
5000
920
6-tert-Butylchroman
280
2,2-Dimethyl-2,3-dihydrobenzofuranyl
2,2-Dimethyl-2,3-dihydrobenzofuranyl
2,2-Dimethylchroman
2,2-Dimethylchroman
4-tert-Butylphenyl
4300
>10,000
1400
7200
85
CH2
CH2
CH2
CH2
4-Methylcyclopropylphenyl
5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthyl
210
57
factory. It is noticeable that the analog 42 was 17-fold potent com-
pared to the analog 40. Olefin effect in the B region seems not con-
sistent because the cinnamoyl analogs (25, 26a, 28a, 34a, 39, 41, 47
and 51) exhibited a variety of potencies compared to those of the
corresponding arylpropanoyl analogs.
Finally, the antagonistic activities of 57–59, obtained via further
A region-optimization of 26b, 28b and 34b on the basis of our pre-
liminary studies,16 were examined. These analogs possessing cya-
nide at the R2 position of the A region exhibited two to fourfold
increases in TRPV1 antagonistic activity.
2.2.2. Uptake assays
Terasaki plates containing DRG neurons grown for 3 days were
equilibrated with four washes of HEPES (10 mM, pH 7.4)-buffered
calcium- and magnesium-free Hank’s balanced salt solution. The
solution in each well was removed from the individual wells. For
antagonistic studies, medium (10 lL) containing 10 l
Ci/mL 45Ca2+
and 0.5 M capsaicin together with the test concentration of the
compound was added to each well. The neurons were incubated
at room temperature for 10 min, and then the Terasaki plates were
washed six times in HEPES (10 mM, pH 7.4)-buffered calcium and
magnesium-free Hank’s balanced salt solution and dried in an
2.2. Biological evaluation
oven. Sodium dodecyl sulfate (0.3%, 10 lL) was then added to dis-
solve the cells and extract the 45Ca2+. The contents of each well
were transferred to scintillation vials and counted in 3 mL of aqua-
sol-2 scintillant. Antagonistic activities of test compounds were gi-
ven as IC50 (the concentration of the compound necessary to
2.2.1. 45Ca2+ Uptake assays. Culture of DRG neurons
DRG neurons were prepared from neonatal Sprague-Dawley
rats. DRGs of all spinal levels were dissected aseptically and col-
lected. Ganglia were incubated sequentially for 30 min at 37 °C in
200 U/mL collagenase and 2.5 mg/mL trypsin. The digestion was
halted by an addition of an equal volume of DME/F12 medium sup-
plemented with 10% horse serum. The ganglia were then triturated
through a fire-polished pasteur pipet, filtered through nylon mem-
brane, and spun down. Dissociated cells were plated onto Terasaki
reduce the response to 0.5 lM capsaicin by 50%). The IC50 values
were estimated at least three replicates at each concentrated. Each
compound was tested at least in two independent experiments.
3. Conclusion
plates previously coated with 10 lg/mL poly-D-ornithine at a den-
We have developed a number of novel amide series of TRPV1
antagonists with a variety of lipophilic moieties, which enable
the replacement of the representative tert-butylbenzyl moiety.
Moreover, we have identified new and potent TRPV1 antagonists
of diarylalkyl amide via further optimization of A, B regions. Com-
bination of cyano, fluoro and sulfonamido groups in A-region with
sity of 1500–1700 neurons/well. The cells were then cultured for
3 days in DME/F12 medium containing 1.2 g/L sodium bicarbonate,
15 mM HEPES, 50 mg/L gentamycin, and 10% horse serum, diluted
1:1 with identical medium conditioned by C6 glioma cells (2 days
on a confluent monolayer) in a humidified atmosphere at 37 °C
containing 5% CO2. Medium was supplemented with 200 ng/mL
4-tert-butylbenzyl,
4-methylcyclopropylphenyl
or
tetra-
nerve growth factor. Cytosine arabinoside (100
lM) was added
hydronaphthylmethyl groups in C-region provided the best activi-
for the first 2 days to kill dividing nonneuronal cells.

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
3561
ties. In particular, the amides 57 and 59 were identified as the
highly potent TRPV1 antagonists with IC50s of 85 and 57 nM,
respectively. They are 12-fold potent than the parent amide 26b,
which was a variant of the urea 4. We have also established the
structure–activity relationship of the synthesized amide analogs
through the structural optimization. Currently, systematic studies
on the therapeutic application including pharmacokinetic profiles
of the potent amide analogs are in progress.
A solution of (E)-methyl 3-[3-fluoro-4-(methylsulfonami-
do)phenyl]acrylate (78 mg, 0.29 mmol) and 10% palladium on car-
bon (10 mg) in MeOH (10 mL) were hydrogenated under a balloon
of hydrogen for 3 h (TLC check). The reaction mixture was filtered
through a pad of Celite, then rinsed with Et2O. The filtrate was con-
centrated and dried under vacuum to give 6 (68 mg, 86%). 1H NMR
(CDCl3, 300 MHz) d 7.45 (t, 1H, J = 8.2 Hz), 6.98 (d, 1H, J = 8.3 Hz),
6.46 (s, 1H), 3.66 (s, 3H), 3.00 (s, 3H), 2.91 (t, 2H, J = 7.6 Hz), 2.60
(t, 2H, J = 7.6 Hz).
4. Experimental
4.1.3. N-(4-tert-Butylbenzyl)-3-[3-fluoro-4-(methyl-
sulfonamido)phenyl]propanamide (7)
4.1. General methods
To a solution of 6 (30 mg, 0.11 mmol) in toluene (4 mL) was
added 4-tert-butylbenzylamine 2 (150 lL, 0.92 mmol). The mix-
All reagents including starting materials and solvents were pur-
chased from Aldrich Chemical Co. or TCI and used without further
purification. Silica gel column chromatography was performed on
Silica Gel 60, 230–400 mesh, Merck. NMR spectra were recorded
on a JEOL LNM-LA 300 (300 MHz), Bruker, FT NMR AVANCE 400
(400 MHz), Bruker, FT-NMR AVANCE 500 (500 MHz) and TMS (tet-
ramethylsilane) was used as an internal standard. Chemical shifts
(d) were recorded in ppm and coupling constants (J) in hertz
(Hz). IR (infrared) spectra were recorded on a Jasco FT/IR-4200
and Perkin–Elmer 1710 FT spectrometer. Low resolution mass
spectra were obtained on a VG Trio-2 GC–MS. High resolution mass
spectra were obtained on a JEOL JMS-AX 505wA and JEOL JMS-HX/
HX 110A spectrometer.
ture was refluxed for 3 h and diluted with water, and extracted
with CH2Cl2 several times. The combined organic layers were
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by silica gel column chroma-
tography (EtOAc/n-hexane = 1:1) to afford 7 (28 mg, 63%) as a
white solid. 1H NMR (CDCl3, 300 MHz) d 7.39 (t, 1H, J = 8.2 Hz),
7.29 (d, 2H, J = 8.3 Hz), 7.07 (d, 2H, J = 8.3 Hz), 6.92–6.95 (m, 2H),
6.33 (s, 1H), 5.54 (s, 1H), 4.31 (d, 2H, J = 5.6 Hz), 2.93 (s, 3H), 2.92
(t, 2H, J = 7.4 Hz), 2.41 (t, 2H, J = 7.6 Hz), 1.24 (s, 9H); IR (neat)
cmꢀ1: 3234, 2960, 1639, 1513, 1401, 1325, 1155; 13C NMR (CDCl3,
100 MHz) d 171.1, 155.4, 153.0, 150.7, 140.5, 134.9, 127.6, 125.6,
125.0, 124.9, 124.0, 122.5, 122.4, 115.9, 115.7, 43.4, 39.7, 37.7,
34.5, 31.3, 30.8; HR-MS (FAB+) calcd for C21H28FN2O3S (M+H+):
407.1805, found 407.1808.
4.1.1. N-(4-[({4-tert-Butylbenzyl}aminocarboyl)-
amino]methyl-2-fluorophenyl)methanesulfonamide (4)
4.1.4. (E)-Methyl 3-(4-(1-methylcyclopropyl) phenyl)acrylate
(9)
A mixture of amine 2 (100
lL, 0.57 mmol), DMAP (21 mg,
0.17 mmol), (Boc)2O (149 mg, 0.68 mmol) and Et3N (236
lL,
To a solution of CH3PPh3Br (2.2 g, 6.1 mmol) in THF were
added n-BuLi (1.6 M solution in THF, 3.3 mL, 5.3 mmol) at 0 °C.
The reaction mixture was stirred at same temperature for 2 h,
then a solution of 1-(4-iodophenyl)ethanone 8 (1.0 g, 4.1 mmol)
in THF was added. The reaction mixture was warmed to room
temperature. After confirming the completion of the reaction with
TLC, the reaction was quenched by aq NH4Cl and stirred for
20 min. The resulting solution was concentrated, extracted with
EtOAc, washed with brine and dried over MgSO4. Purification of
the residue by silica gel column chromatography (EtOAc/n-hex-
ane = 1:5) to yield colorless oil 724 mg (73%) of 1-iodo-4-(prop-
1-en-2-yl)benzene.
1.70 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for
4 h. 3-Fluoro-4-methylsulfonamidobenzylamine salt 3 (159 mg,
0.62 mmol) was added into the reaction mixture. The mixture
was then stirred at room temperature for 10 h and extracted with
CH2Cl2. The combined organic phases were washed with water
and brine, dried over MgSO4, and concentrated in vacuo. Purifica-
tion of the residue by silica gel column chromatography (EtOAc/
n-hexane = 2:1) to give 4 as a white solid (123 mg, 53%). 1H NMR
(CDCl3+CD3OD, 300 MHz) d 7.35 (t, 1H, J = 8.1 Hz), 7.29 (d, 2H,
J = 8.4 Hz), 7.15 (d, 2H, J = 8.6 Hz), 7.00–6.93 (m, 2H), 4.24 (s, 2H);
4.22 (s, 2H), 2.91 (s, 3H), 1.24 (s, 9H); LRMS (FAB+): m/z 408 (M+H+).
To a solution of 1-iodo-4-(prop-1-en-2-yl)benzene (500 mg,
2.0 mmol) in toluene at 0 °C were added CH2I2 (825 lL, 10 mmol)
4.1.2. Methyl 3-3-fluoro-4-[(methanesulfony)-
amino]phenylpropanoate (6)
and Et2Zn (1.0 M solution in THF, 10 mL, 10 mmol.). The tempera-
ture of reaction mixture was raised to room temperature. After
confirming the completion of the reaction with TLC, the solution
mixture was quenched by aq NH4Cl and stirred for 20 min. The
resulting solution was concentrated, extracted with EtOAc, washed
with brine and dried over MgSO4. The obtained liquid was concen-
trated under reduced pressure to yield a pale yellow oil 523 mg
(99%) of 1-iodo-4-(1-methylcyclopropyl)benzene.
To a solution of 2-fluoro-4-iodoaniline 5 (1.50 g, 6.33 mmol) in
CH2Cl2 (40 mL) were added pyridine (1.02 mL) and methanesulfo-
nyl chloride (700 lL, 9.50 mmol). The mixture was stirred at room
temperature for 1.5 h and then diluted with water, and extracted
with CH2Cl2 several times. The combined organic layers were
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by silica gel column chroma-
tography (EtOAc/n-hexane = 1:3) afforded 1.89 g (95%) of N-(2-flu-
oro-4-iodophenyl)methanesulfonamide.
To
(285 mg, 1.1 mmol) in DMF (5 mL) were added Pd(OAc)2 (12 mg,
0.06 mmol), DPPF (37 mg, 0.07 mmol), Et3N (306 L, 2.2 mmol)
and methylacrylate (300 L, 3.3 mmol). The reaction mixture was
a solution of 1-iodo-4-(1-methylcyclopropyl) benzene
To a solution of N-(2-fluoro-4-iodophenyl)methane- sulfon-
amide (100 mg, 0.32 mmol) in DMF (10 mL) were added Pd(OAc)2
l
(3.6 mg,
0.016 mmol),
1,10-bis(diphenylphosphino)ferrocene
l
stirred at 80 °C for 12 h, cooled to room temperature and then di-
luted with Et2O. The organic layer was washed with water and
brine, dried over MgSO4, and concentrated in vacuo. Purification
of the residue by silica gel column chromatography (EtOAc/n-hex-
ane = 1:5) to afford 9 (201 mg, 84%). 1H NMR (CDCl3, 300 MHz) d
7.69 (d, 1H, J = 15.9 Hz), 7.44 (d, 2H, J = 8.3 Hz), 7.24 (d, 2H,
J = 8.3 Hz), 6.41 (d, 1H, J = 15.9 Hz), 3.79 (s, 3H), 1.40 (s, 3H), 0.84
(m, 2H, J = 5.2 Hz), 0.76–0.82 (m, 2H).
(10 mg, 0.018 mmol), Et3N (90
l
L, 0.64 mmol) and methylacrylate
(276 mg, 3.20 mmol). The mixture was stirred at 60 °C for 24 h, and
was then diluted with water, and extracted with CH2Cl2 several
times. The combined organic layers were washed with water and
brine, dried over MgSO4, and concentrated in vacuo. Purification
of the residue by silica gel column chromatography (EtOAc/n-hex-
ane = 1:1) to afford 78 mg (91%) of (E)-methyl 3-[3-fluoro-4-
(methylsulfonamido)phenyl]acrylate.

3562
F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
4.1.5. 3-(4-sec-Butylphenyl)propanoic acid (10)
NMR (CDCl3, 300 MHz) d 7.29 (t, 2H, J = 7.6 Hz), 7.18–7.22 (m, 3H),
2.97 (t, 2H, J = 7.6 Hz), 2.66 (t, 2H, J = 7.6 Hz).
To a solution of (E)-methyl 3-(4-(1-methylcyclopropyl) phenyl)
acrylate 9 (100 mg, 0.46 mmol) was dissolved in anhydrous THF
(10 mL), and added a catalytic amount of 10% palladium on acti-
vated carbon to carry out hydrogenation, followed by stirring at
room temperature for 8 h. The resulting mixture was diluted with
Et2O, filtered through Celite pad, and then concentrated under re-
duced pressure to yield 78 mg (77%) of methyl 3-(4-sec-
butylphenyl)propanoate.
4.2.2. 3-(4-Bromophenyl)propanoic acid (22b)
The compound was prepared from 13 by the general procedure
for the synthesis of acids in 83% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.25 (d, 2H, J = 8.4 Hz), 7.13 (d, 2H,
J = 8.4 Hz), 2.92 (t, 2H, J = 7.5 Hz), 2.65 (t, 2H, J = 7.5 Hz).
To a solution of methyl 3-(4-sec-butylphenyl)- propanoate
(78 mg, 0.35 mmol) in THF/H2O = 1:1 (2 mL) was added LiOH–
H2O (19 mg, 0.46 mmol). The reaction mixture was stirred at room
temperature for 1 h, acidified with 1 N HCl and then extracted with
EtOAc. The combined organic phases were washed with water and
brine, dried over MgSO4, concentrated and dried on a vacuum to
give the acid 10 (73 mg, 100%) as a white solid. 1H NMR (CDCl3,
300 MHz) d 7.11 (d, 4H, J = 1.5 Hz), 2.93 (t, 2H, J = 7.9 Hz), 2.67 (t,
2H, J = 7.9 Hz), 2.55 (m, 1H); 1.51–1.61 (m, 2H), 1.22 (d, 3H,
J = 7.0 Hz), 0.80 (t, 3H, J = 7.4 Hz).
4.2.3. (E)-3-(4-Iodophenyl)acrylic acid (22c)
The compound was prepared from 14 by the general procedure
for the synthesis of acids in 90% yield as a white solid. 1H NMR
(CDCl3, 300 MHz)
d 7.76 (d, 2H, J = 8.3 Hz), 7.58 (d, 1H,
J = 16.1 Hz), 7.36 (d, 2H, J = 8.3 Hz), 6.51 (d, 1H, J = 16.1 Hz).
4.2.4. (E)-3-(4-tert-Butylphenyl)acrylic acid (22d)
The compound was prepared from 15 by the general procedure
for the synthesis of acids in 88% yield as a white solid. 1H NMR
(CDCl3, 300 MHz)
d 7.78 (d, 1H, J = 16.0 Hz), 7.50 (d, 2H,
J = 8.4 Hz), 7.42 (d, 2H, J = 8.6 Hz), 6.43 (d, 1H, J = 16.0 Hz), 1.32
4.1.6. (E)-3-(4-(1-Methylcyclopropyl)phenyl) acrylic acid (11a)
The compound was prepared from 9 by the procedure for the
synthesis of 10 in 91% yield; white solid. 1H NMR (CDCl3,
300 MHz) d 7.72 (d, 1H, J = 15.9 Hz), 7.41 (d, 2H, J = 8.4 Hz), 7.19
(d, 2H, J = 8.2 Hz), 6.36 (d, 1H, J = 15.9 Hz), 1.35 (s, 3H), 0.83 (t,
2H, J = 5.2 Hz), 0.71–0.77 (m, 2H).
(s, 9H).
4.2.5. 3-[4-(tert-Butyl)phenyl]propanoic acid (22e)
The compound was prepared from 15 by the general procedure
for the synthesis of acids in 74% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.31 (d, 2H, J = 8.4 Hz), 7.14 (d, 2H,
J = 8.2 Hz), 2.95 (t, 2H, J = 7.9 Hz), 2.69 (t, 2H, J = 7.9 Hz), 1.29 (s,
9H).
4.1.7. 3-(4-(1-Methylcyclopropyl)phenyl)propanoic acid (11b)
The compound was prepared from 9 by the procedure for the
synthesis of 10 in 86% (2 steps) yield; white solid. 1H NMR (CDCl3,
300 MHz) d 7.11 (d, 2H, J = 8.3 Hz), 7.04 (d, 2H, J = 8.3 Hz), 2.84 (t,
2H, J = 7.9 Hz), 2.56 (t, 2H, J = 7.9 Hz), 1.31 (s, 3H), 0.75 (t, 2H,
J = 5.2 Hz), 0.61–0.64 (m, 2H).
4.2.6. 3-(4-(Trifluoromethyl)phenyl)propanoic acid (22f)
The compound was prepared from 16 by the general procedure
for the synthesis of acids in 93% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.53 (d, 2H, J = 8.1 Hz), 7.31 (d, 2H,
J = 8.1 Hz), 3.00 (t, 2H, J = 7.6 Hz), 2.68 (t, 2H, J = 7.6 Hz).
4.2. General procedure for coupling to amides (23–34b)
4.2.7. 3-(4-Isopropoxyphenyl)propanoic acid (22g)
The compound was prepared from 17 by the general procedure
for the synthesis of acids in 90% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.08 (d, 2H, J = 8.4 Hz), 6.80 (d, 2H,
J = 8.4 Hz), 4.49 (m, 1H), 2.87 (t, 2H, J = 7.8 Hz), 2.63 (t, 2H,
J = 7.7 Hz), 1.26–1.30 (m, 6H).
To
a solution of substituted benzaldehyde (1.0 mmol) in
pyridine (5 mL) were added malonic acid (1.5 mmol) and
piperidine (dropwise 0.3 mmol). The reaction mixture was
refluxed for 2 h as confirming CO2 generation. After the com-
pletion of the reaction, the resultant mixture was acidified
with 2 N HCl and then extracted with EtOAc. The combined
organic phases were washed with water and brine, dried over
MgSO4, concentrated and dried on a vacuum to give the acid
as a white solid.
To a solution of acid in THF was added a catalytic amount of 10%
palladium on activated carbon to carry out hydrogenation, fol-
lowed by stirring for 0.5–2 h at room temperature. The resulting
mixture was diluted with Et2O, filtered through Celite pad, and
then concentrated in vacuo to give the crude acid, which was di-
rectly used for the next step.
To a solution of acid (1.0 mmol) in the THF were added 4-(4,6-
dimethoxy-1,3,5-triazin-2-yl)-4-methyl- morpholinium chloride
(DMTMM) (1.5 mmol), NNM (1.0 mmol) and Et3N (2.0 mmol).
The reaction mixture was stirred for 4 h, and then methanesulfon-
amide HCl salt (1.2 mmol) was added into the reaction mixture.
The mixture was stirred for 10 h at room temperature. The reaction
mixture was concentrated in vacuo. The residue was extracted
with CH2Cl2. A combined organic layer was washed with water
and brine, dried over MgSO4, and concentrated in vacuo. The resi-
due was purified by flash column chromatography on silica gel
using CH2Cl2/MeOH as eluant.
4.2.8. 3-(4-tert-Butoxyphenyl)propanoic acid (22h)
The compound was prepared from 18 by the general procedure
for the synthesis of acids in 96% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.52 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H,
J = 8.6 Hz), 2.98 (t, 2H, J = 7.6 Hz), 2.71 (t, 2H, J = 7.6 Hz), 1.37 (s,
9H).
4.2.9. 3-(3,5-Di-tert-butylphenyl)propanoic acid (22i)
The compound was prepared from 19 by the general procedure
for the synthesis of acids in 82% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.21 (t, 1H, J = 1.7 Hz), 6.98 (d, 2H,
J = 1.6 Hz), 2.92 (t, 2H, J = 7.3 Hz), 2.65 (t, 2H, J = 7.3 Hz), 1.27 (s,
18H).
4.2.10. 3-(3,5-Bis(trifluoromethyl)phenyl)propanoic acid (22j)
The compound was prepared from 20 by the general procedure
for the synthesis of acids in 83% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.71 (s, 1H), 7.62 (s, 2H), 3.02 (t, 2H,
J = 6.8 Hz), 2.66 (t, 2H, J = 6.8 Hz).
4.2.11. (E)-3-(5,5,8,8-Tetramethyl-5,6,7,8-
4.2.1. 3-Phenylpropanoic acid (22a)
tetrahydronaphthalen-2-yl)acrylic acid (22k)
The compound was prepared from 12 by the general procedure
The compound was prepared from 21 by the general procedure
for the synthesis of acids in 95% yield (2 steps) as a white solid. 1H
for the synthesis of acids in 94% yield as a yellow solid. 1H NMR

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
3563
(CDCl3, 300 MHz): d 7.78 (d, 1H, J = 15.9 Hz), 7.45 (s, 1H), 7.33 (d,
4.2.18. 3-(4-sec-Butylphenyl)-N-(3-fluoro-4-
2H, J = 0.9 Hz), 6.41 (d, 1H, J = 15.9 Hz), 1.68 (s, 4H), 1.28 (s, 6H),
(methylsulfonamido)benzyl)propanamide (27)
1.27 (s, 6H).
The compound was prepared from 10 by the general procedure
for the synthesis of amides in 62% yield as a white solid. 1H NMR
(CDCl3, 300 MHz) d 7.45 (t, 1H, J = 8.2 Hz), 7.06–7.12 (m, 4H),
6.94 (t, 2H, J = 9.2 Hz), 6.51 (s, 1H), 5.69 (s, 1H), 4.34 (d, 2H,
J = 6.0 Hz), 2.98 (s, 3H), 2.94 (t, 2H, J = 7.5 Hz), 2.51 (t, 2H,
J = 7.5 Hz), 2.53–2.56 (m, 1H); 1.55 (t, 2H, J = 7.2 Hz), 1.19 (d, 3H,
J = 7.0 Hz), 0.78 (t, 3H, J = 7.3 Hz); IR (neat) cmꢀ1: 3289, 2960,
2925, 1650, 1514, 1335, 1158, 1112, 973, 823; LRMS (FAB+): m/z
407 (M+H+).
4.2.12. 3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)propanoic acid (22l)
The compound was prepared from 21 by the general procedure
for the synthesis of acids in 83% yield (2 steps) as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.23 (d, 1H, J = 8.1 Hz), 7.12 (d, 1H,
J = 2.0 Hz), 6.97 (dd, 1H, J = 2.0, 2.0 Hz), 2.90 (t, 2H, J = 7.9 Hz),
2.65 (t, 2H, J = 7.8 Hz), 1.65 (s, 4H), 1.25 (s, 12H).
4.2.13. N-(3-Fluoro-4-(methylsulfonamido)benzyl)-3-
phenylpropanamide (23)
4.2.19. (E)-N-(3-Fluoro-4-(methylsulfonamido)benzyl)-3-(4-(1-
methylcyclopropyl)phenyl)acrylamide (28a)
The compound was prepared from 22a by the general proce-
dure for the synthesis of amides in 83% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.45 (t, 1H, J = 8.4 Hz), 7.17–7.27 (m,
5H), 6.89–6.92 (m, 2H), 6.41 (br s, 1H), 5.62 (br s, 1H), 4.35 (d,
2H, J = 6.2 Hz), 2.99 (s, 3H), 2.96 (t, 2H, J = 7.5 Hz), 2.52 (t, 2H,
J = 7.5 Hz); IR (neat) cmꢀ1: 2925, 1649, 1515, 1452, 1332, 1156,
972, 758; LRMS (FAB+): m/z 351 (M+H+).
The compound was prepared from 11a by the general proce-
dure for the synthesis of amides in 87% yield as a white solid.
1H NMR (CDCl3, 300 MHz) d 7.66 (d, 1H, J = 15.6 Hz), 7.51 (t,
1H, J = 8.2 Hz), 7.40 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz),
7.07–7.14 (m, 2H), 6.59 (s, 1H), 6.39 (d, 1H, J = 15.6 Hz), 6.08
(br s, 1H), 4.52 (d, 1H, J = 6.0 Hz), 2.99 (s, 3H), 1.39 (s, 3H),
0.84 (t, 2H, J = 5.2 Hz), 0.74–0.80 (m, 2H); IR (neat) cmꢀ1
:
3270, 1655, 1617, 1514, 1330, 1155, 1111, 977, 757; HR-MS
(FAB+) calcd for C21H24FN2O3S (M+H+): 403.1492, found
403.1494.
4.2.14. 3-(4-Bromophenyl)-N-(3-fluoro-4-(methyl-
sulfonamido)benzyl)propanamide (24)
The compound was prepared from 22b by the general proce-
dure for the synthesis of amides in 64% yield as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.47 (t, 1H, J = 8.3 Hz), 7.38 (d, 2H,
J = 8.1 Hz), 7.06 (d, 2H, J = 8.1 Hz), 6.90–6.93 (m, 2H), 6.43 (br s,
1H), 5.63 (br s, 1H), 4.34 (d, 2H, J = 6.0 Hz), 3.00 (s, 3H), 2.94 (t,
2H, J = 7.3 Hz), 2.49 (t, 2H, J = 7.3 Hz); IR (neat) cmꢀ1: 2925, 1650,
1515, 1452, 1332, 1155, 1111, 973, 816; LRMS (FAB+): m/z 429
(M+H+).
4.2.20. N-(3-Fluoro-4-(methylsulfonamido)benzyl)-3-(4-(1-
methylcyclopropyl)phenyl)propanamide (28b)
The compound was prepared from 11b by the general proce-
dure for the synthesis of amides in 67% yield as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.47 (m, 1H), 7.07–7.16 (m, 4H), 6.93 (t,
2H, J = 9.3 Hz), 6.45 (s, 1H), 5.63 (s, 1H), 4.36 (d, 2H, J = 6.0 Hz),
2.99 (s, 3H), 2.94 (t, 2H, J = 7.5 Hz), 2.50 (t, 2H, J = 7.5 Hz), 1.37 (s,
3H), 0.79 (t, 2H, J = 5.9 Hz), 0.68–0.72 (m, 2H); IR (neat) cmꢀ1
:
4.2.15. (E)-N-(3-Fluoro-4-(methylsulfonamido) benzyl)-3-(4-
iodophenyl)acrylmide (25)
3269, 1651, 1585, 1514, 1334, 1157, 1111, 757; HR-MS (FAB+)
calcd for C21H26FN2O3S (M+H+): 405.1648, found 405.1654.
The compound was prepared from 22c by the general procedure
for the synthesis of amides in 87% yield as a white solid. 1H NMR
4.2.21. N-(3-Fluoro-4-(methylsulfonamido)benzyl)-3-(4-
(trifluoromethyl)phenyl)propanamide (29)
(CDCl3, 300 MHz)
d 7.75 (d, 2H, J = 8.3 Hz), 7.58 (d, 1H,
J = 15.9 Hz), 7.46 (m, 1H), 7.33 (d, 2H, J = 8.3 Hz), 7.14 (t, 2H,
J = 8.1 Hz), 6.66 (d, 1H, J = 15.9 Hz), 4.46 (s, 2H), 2.96 (s, 3H); IR
(neat) cmꢀ1: 2921, 2397, 1647, 1611, 1512, 1324, 1146, 1111,
971, 814; LRMS (EI+): m/z 474 (M).
The compound was prepared from 22f by the general procedure
for the synthesis of amides in 75% yield as a white solid. 1H NMR
(CDCl3, 300 MHz) d 7.51 (d, 2H, J = 7.9 Hz), 7.45 (t, 1H, J = 8.2 Hz),
7.29 (d, 2H, J = 7.9 Hz), 6.90–6.93 (m, 2H), 6.45 (s, 1H), 5.68 (br s,
1H), 4.35 (d, 2H, J = 6.1 Hz), 3.05 (t, 2H, J = 7.5 Hz), 2.99 (s, 3H),
2.53 (t, 2H, J = 7.5 Hz); IR (neat) cmꢀ1: 3226, 2921, 1643, 1540,
1324, 1154, 1110, 827; LRMS (FAB+): m/z 419 (M+H+).
4.2.16. (E)-3-(4-tert-Butylphenyl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)acrylamide (26a)
The compound was prepared from 22d by the general proce-
dure for the synthesis of amides in 88% yield as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.66 (d, 1H, J = 15.6 Hz), 7.50 (t, 1H,
J = 8.3 Hz), 7.35–7.44 (q, 4H, J = 16.8 Hz), 7.08–7.14 (t, 2H,
J = 8.3 Hz), 6.47 (s, 1H); 6.36 (d, 1H, J = 15.6 Hz), 5.96 (br s, 1H),
4.52 (d, 2H, J = 6.1 Hz), 2.99 (s, 3H), 1.30 (s, 9H); HR-MS (FAB+)
calcd for C21H26FN2O3S (M+H+): 405.1648, found 405.1637.
4.2.22. N-(3-Fluoro-4-(methylsulfonamido)benzyl)-3-(4-
isopropoxyphenyl)propanamide (30)
The compound was prepared from 22g by the general proce-
dure for the synthesis of amides in 66% yield as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.46 (t, 1H, J = 8.2 Hz), 7.07 (d, 2H,
J = 8.4 Hz), 6.92 (t, 2H, J = 9.9 Hz), 6.78 (d, 2H, J = 8.6 Hz), 6.44 (br
s, 1H), 5.59 (br s, 1H), 4.48 (m, 1H), 4.34 (d, 2H, J = 6.2 Hz), 2.99
(s, 3H), 2.91 (t, 2H, J = 6.9 Hz), 2.49 (t, 2H, J = 6.9 Hz), 1.30 (d, 6H,
J = 6.0 Hz); IR (neat) cmꢀ1: 3273, 2976, 1651, 1586, 1512, 1366,
1333, 1240, 1157, 1115, 766; LRMS (FAB+): m/z 409 (M+H+).
4.2.17. 3-(4-tert-Butylphenyl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)propanamide (26b)
The compound was prepared from 22e by the general proce-
dure for the synthesis of amides in 71% yield as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.40 (t, 1H, J = 8.2 Hz), 7.23 (d, 2H,
J = 8.3 Hz), 7.06 (d, 2H, J = 8.3 Hz), 6.88–6.91 (m, 2H), 6.49 (s, 1H),
5.68 (br s, 1H), 4.30 (d, 2H, J = 5.6 Hz), 2.93 (s, 3H), 2.89 (t, 2H,
J = 7.6 Hz), 2.54 (t, 2H, J = 7.4 Hz), 1.19 (s, 9H); 13C NMR (CDCl3,
100 MHz) d 172.3, 155.2, 152.8, 149.2, 137.7, 137.6, 137.4, 127.9,
125.4, 124.0, 123.6, 115.0, 114.8, 42.5, 39.7, 38.3, 34.3, 31.3, 31.0;
HR-MS (FAB+) calcd for C21H28FN2O3S (M+H+): 407.1805, found
407.1802.
4.2.23. 3-(4-tert-Butoxyphenyl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)propanamide (31)
The compound was prepared from 22h by the general proce-
dure for the synthesis of amides in 71% yield as a white solid. 1H
NMR (CDCl3, 300 MHz) d 7.43 (t, 1H, J = 8.2 Hz), 7.05 (d, 2H,
J = 8.6 Hz), 6.86 (d, 2H, J = 8.4 Hz), 6.82–6.84 (m, 2H), 5.77 (br s,
1H), 4.32 (d, 2H, J = 5.9 Hz), 2.98 (s, 3H), 2.92 (t, 2H, J = 7.4 Hz),
2.49 (t, 2H, J = 7.4 Hz), 1.29 (s, 9H); IR (neat) cmꢀ1: 3289, 2977,
1651, 1510, 1334, 1159, 1111, 763; LRMS (FAB+): m/z 423 (M+H+).

3564
F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
4.2.24. 3-(3,5-Di-tert-butylphenyl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)propanamide (32)
tography (EtOAc/n-hexane = 1:3) to afford 36 (333 mg, 48%) as a
colorless oil. 1H NMR (CDCl3, 300 MHz): d 7.47 (s, 2H), 4.27 (t,
2H, J = 6.9 Hz), 3.71 (t, 2H, J = 6.9 Hz), 1.26 (s, 9H).
The compound was prepared from 22i by the general procedure
for the synthesis of amides in 88% yield as a white solid. 1H NMR
(CDCl3, 300 MHz) d 7.34 (t, 1H, J = 5.4 Hz), 7.28 (s, 1H), 7.06 (s,
2H), 6.82–6.85 (m, 2H), 6.42 (br s, 1H), 5.66 (br s, 1H), 4.36 (d,
2H, J = 5.9 Hz), 2.98 (s, 3H), 2.95 (t, 2H, J = 7.3 Hz), 2.55 (t, 2H,
J = 7.3 Hz), 1.28 (s, 18H); IR (neat) cmꢀ1: 2960, 1650, 1597, 1543,
1366, 1311, 1157, 758; HR-MS (FAB+) calcd for C25H36FN2O3S
(M+H+): 463.2431, found 463.2426.
4.3.2. 1,3-Dibromo-2-(3-bromopropoxy)-5-tert-butylbenzene
(36b)
The reaction was performed by same preparation method of
36a, then the crude product was purified by silica gel chromatog-
raphy (EtOAc/n-hexane = 1:10) to provide 36b (77%) as a yellow
oil. 1H NMR (CDCl3, 300 MHz): d 7.47 (s, 2H), 4.09 (t, 2H,
J = 5.7 Hz), 3.71 (t, 2H, J = 6.6 Hz), 2.30–2.40 (m, 2H), 1.26 (s, 9H).
4.2.25. 3-(3,5-Bis(trifluoromethyl)phenyl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)propanamide (33)
4.3.3. 5-tert-Butyl-2,3-dihydrobenzofuran-7-carbaldehyde
(37a)
The compound was prepared from 22j by the general procedure
for the synthesis of amides in 82% yield as a white solid. 1H NMR
n-BuLi (1.0 mL, 1.6 M in hexanes, 1.6 mmol) was added to a
solution of 1,3-dibromo-2-(2-bromoethoxy)-5-tert-butylbenzene
36a (647 mg, 1.6 mmol) in THF (6 mL) at ꢀ78 °C under argon.
The mixture was stirred at this temperature for 30 min, allowed
to warm to 0 °C, and poured into water (20 mL). The layers were
separated and the aqueous layer was extracted with Et2O
(2 ꢂ 20 mL). The combined extracts were dried over MgSO4 and
concentrated in vacuo to give a residue which was purified by flash
chromatography over silica using (EtOAc/n-hexane = 1:10) as the
eluant to give 7-bromo-5-tert-butyl-2,3-dihydrobenzofuran
(235 mg, 59%) as a white solid. 1H NMR (CDCl3, 300 MHz): d 7.23
(br s, 1H), 7.13 (br s, 1H), 4.62 (t, 2H, J = 8.7 Hz), 3.28 (t, 2H,
J = 8.7 Hz), 1.27 (s, 9H).
(CDCl3, 300 MHz)
d 7.72 (s, 1H), 7.66 (s, 2H), 7.47 (t, 1H,
J = 8.6 Hz), 6.94 (t, 2H, J = 9.7 Hz), 6.43 (br s, 1H), 5.63 (br s, 1H),
4.37 (d, 2H, J = 6.0 Hz), 3.13 (t, 2H, J = 7.1 Hz), 2.99 (s, 3H), 2.56
(t, 2H, J = 7.4 Hz); IR (neat) cmꢀ1: 3296, 1654, 1589, 1544, 1371,
1313, 1281, 1133, 974, 683; LRMS (FAB+): m/z 487 (M+H+).
4.2.26. (E)-N-(3-Fluoro-4-(methylsulfonamido) benzyl)-3-
(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- naphthalen-2-
yl)acrylamide (34a)
The compound was prepared from 22k by the general proce-
dure for the synthesis of amides in 68% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.59 (d, 1H, J = 15.5 Hz), 7.44 (d, 1H,
J = 8.3 Hz), 7.39 (d, 1H, J = 4.8 Hz), 7.24 (d, 2H, J = 1.1 Hz), 7.02–
7.09 (m, 2H), 6.40 (d, 1H, J = 15.5 Hz), 4.45 (s, 2H), 2.94 (s, 3H),
1.63 (s, 4H), 1.23 (s, 6H),1.22 (s, 6H); IR (neat) cmꢀ1: 2925, 1658,
1619, 1514, 1333, 1156, 977; HR-MS (FAB+) calcd for
C25H32FN2O3S (M+H+): 459.2118, found 459.2115.
To a solution of 7-bromo-5-tert-butyl-2,3-dihydrobenzofuran
(235 mg, 0.92 mmol) in THF (5 mL) was added dropwise of t-BuLi
(1.7 M in hexanes, 1.1 mL, 1.9 mmol) at ꢀ78 °C, then warmed to
0 °C. To the reaction mixture was added DMF (78 lL, 1.0 mmol),
then stirred at 0 °C for 30 min followed by dilution with Et2O.
The organic layer was washed with water and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by sil-
ica gel column chromatography (EtOAc/n-hexane = 1:10) to afford
37a (176 mg, 93%). 1H NMR (CDCl3, 300 MHz): d 10.16 (s, 1H), 7.55
(br s, 1H), 7.46 (br s, 1H), 4.70 (t, 2H, J = 8.7 Hz), 3.21 (t, 2H,
J = 8.7 Hz), 1.29 (s, 9H).
4.2.27. N-(3-Fluoro-4-(methylsulfonamido)benzyl)-3-(5,5,8,8-
tetramethyl-5,6,7,8-tetrahydronaphtha-alene-2-
yl)propanamide (34b)
The compound was prepared from 22l by the general procedure
for the synthesis of amides in 80% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.47 (m, 1H), 7.22 (d, 1H, J = 7.9 Hz), 6.92–
7.12 (m, 4H), 6.56 (s, 1H), 5.74 (br s, 1H), 4.37 (d, 2H, J = 5.9 Hz),
2.99 (s, 3H), 2.92 (t, 2H, J = 7.8 Hz), 2.52 (t, 2H, J = 7.8 Hz), 1.64 (s,
4H), 1.24 (s, 6H), 1.23 (s, 6H); IR (neat) cmꢀ1: 3271, 2959, 1650;
1586, 1514, 1335, 1157, 974, 758; HR-MS (FAB+) calcd for
C25H34FN2O3S (M+H+): 461.2274, found 461.2258.
4.3.4. 6-tert-Butylchroman-8-carbaldehyde (37b)
The compound was prepared from 36b by the procedure for the
synthesis of 37a in 39% yield (2 steps) as a white solid. 1H NMR
(CDCl3, 300 MHz): d 10.38 (s, 1H), 7.64 (d, 1H, J = 2.6 Hz), 7.27 (t,
1H, J = 1.3 Hz), 4.26 (t, 2H, J = 5.2 Hz), 2.81 (t, 2H, J = 6.5 Hz),
2.00–2.07 (m, 2H), 1.27 (s, 9H).
4.3. 5-tert-Butyl-2,3-dihydrobenzofuranyl/6-tert-
Butylchroman analogues are prepared by below methods
4.3.5. (E)-3-(5-tert-Butyl-2,3-dihydrobenzofuran-7-yl)acrylic
acid (38a)
4.3.1. 1,3-Dibromo-2-(2-bromoethoxy)-5-tert-butylbenzene
(36a)
The compound was prepared from 37a by the general proce-
dure for the synthesis of acids in 90% yield as a yellow solid. 1H
NMR (CDCl3, 300 MHz): d 7.79 (d, 1H, J = 15.9 Hz), 7.26 (br s, 1H),
7.20 (br s, 1H), 6.75 (d, 1H, J = 15.9 Hz), 4.65 (t, 2H, J = 8.7 Hz),
3.20 (t, 2H, J = 8.6 Hz), 1.28 (s, 9H).
To a solution of 4-tert-butyl- phenol 35 (1.2 g, 8.2 mmol) in
CH2Cl2/MeOH = 5:2 (35 mL) were added benzyltrimethylammoni-
um tribromide (6.4 g, 16 mmol). The reaction mixture was stirred
at room temperature for 1 h and diluted with CH2Cl2. The organic
layer was washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography (EtOAc/n-hexane = 1:3) to afford 2,6-dibro-
mo-4-tert-butylphenol (2.5 g, 96%) as a colorless oil. 1H NMR
(CDCl3, 300 MHz): d 7.42 (s, 2H), 5.71 (s, 1H), 1.26 (s, 9H).
4.3.6. (E)-3-(6-tert-Butylchroman-8-yl)acrylic acid (38b)
The compound was prepared from 37b by the general proce-
dure for the synthesis of acids in 86% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 8.05 (d, 1H, J = 16.3 Hz), 7.33 (d, 1H,
J = 2.4 Hz), 7.09 (d, 1H, J = 2.4 Hz), 6.58 (d, 1H, J = 15.9 Hz), 4.24
(t, 2H, J = 5.1 Hz), 2.78 (t, 2H, J = 6.5 Hz), 1.93–2.01 (m, 2H), 1.28
(s, 9H).
1,2-Dibromoethane (420 lL, 4.9 mmol) was added to a stirred
solution of sodium hydroxide (156 mg, 3.9 mmol) and 2,6-dibro-
mo-4-tert-butylphenol (1.0 g, 3.3 mmol) in water (15 mL). The stir-
red mixture was refluxed 12 h, cooled and the product was
extracted into Et2O (2 ꢂ 100 mL). The combined extracts were
washed with 2 N HCl and brine (100 mL), dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash chroma-
4.3.7. (E)-3-(5-tert-Butyl-2,3-dihydrobenzofuran-7-yl)-N-(3-
fluoro-4-(methylsulfonamido)benzyl)acrylamide (39)
The compound was prepared from 38a by the general proce-
dure for the synthesis of amides in 63% yield as a white solid. 1H

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
3565
NMR (CDCl3, 300 MHz): d 7.62 (d, 1H, J = 15.5 Hz), 7.49 (t, 2H,
4.4.2. 2,2-Dimethyl-2,3-dihydrobenzofuran-5-carbaldehyde
(45)
J = 8.0 Hz), 7.07–7.21 (m, 3H), 6.78 (d, 1H, J = 15.5 Hz), 6.53 (br s,
1H), 5.98 (br s, 1H), 4.62 (t, 2H, J = 8.7 Hz), 4.53 (d, 2H,
J = 6.1 Hz), 3.19 (t, 2H, J = 8.7 Hz), 2.99 (s, 3H), 1.27 (s, 9H); IR (neat)
cmꢀ1: 2960, 1653, 1592, 1513, 1451, 1333, 1280, 1157, 977, 821,
733; LRMS (FAB+): m/z 447 (M+H+).
To a solution of phenol 44 (120 mg, 0.53 mmol) in CH2Cl2 (5 mL)
was added I2 (27 mg, 0.11 mmol). The reaction mixture was stirred
at room temperature for 12 h, then quenched by addition of satu-
rated aqueous Na2S2O3 and diluted with CH2Cl2. The organic layer
was washed with water and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by silica gel column chro-
mate-graphy (EtOAc/n-hexane = 1:3) to afford 5-bromo-2,2-
dimethyl-2,3-dihydrobenzofuran (96 mg, 80%). 1H NMR (CDCl3,
300 MHz) d 7.18–7.27 (m, 2H), 6.63 (d, 1H, J = 8.4 Hz), 3.00 (s,
2H), 1.48 (s, 6H).
4.3.8. 3-(5-tert-Butyl-2,3-dihydrobenzofuran-7-yl)-N-(3-fluoro-
4-(methylsulfonamido)benzyl)propanamide (40)
The compound was prepared from 38a by the general proce-
dure for the synthesis of amides in 75% yield (2 steps) as a white
solid. 1H NMR (CDCl3, 300 MHz): d 7.46 (m, 1H), 7.10 (m, 1H),
6.89–6.96 (m, 2H), 6.58 (d, 1H, J = 6.4 Hz), 6.11 (br s, 1H), 5.96
(br s, 1H), 4.56 (t, 2H, J = 8.7 Hz), 4.37 (d, 2H, J = 5.9 Hz), 3.13 (t,
2H, J = 8.6 Hz), 2.99 (s, 3H), 2.90 (t, 2H, J = 7.6 Hz), 2.58 (t, 2H,
J = 7.7 Hz), 1.25 (s, 9H); IR (neat) cmꢀ1: 3267, 2959, 1585, 1514,
1480, 1335, 1281, 1157, 975, 819, 757; LRMS (FAB+): m/z 449
(M+H+).
To a solution of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran
(171 mg, 0.75 mmol) in THF (4 mL) was added dropwise of t-BuLi
(1.7 M in hexanes, 885
the reaction mixture was added DMF (64
l
L) at ꢀ78 °C, then warmed to 0 °C. To
l
L, 0.83 mmol), then
reaction mixture were stirred at 0 °C for 30 min followed by dilu-
tion with Et2O. The organic layer was washed with water and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (EtOAc/n-hex-
ane = 1:3) to afford 45 (114 mg, 86%). 1H NMR (CDCl3, 300 MHz)
d 9.77 (s, 1H), 7.67 (s, 1H), 7.64 (d, 1H, J = 8.3 Hz), 6.80 (d, 1H,
J = 8.3 Hz), 3.02 (s, 2H), 1.48 (s, 6H).
4.3.9. (E)-3-(6-tert-Butylchroman-8-yl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)acrylamide (41)
The compound was prepared from 38b by the general proce-
dure for the synthesis of amides in 60% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.83 (d, 1H, J = 15.8 Hz), 7.47 (t, 2H,
J = 8.1 Hz), 7.27 (d, 1H, J = 2.4 Hz), 7.03–7.14 (m, 2H), 6.61 (d, 1H,
J = 15.8 Hz), 6.09 (br s, 1H), 4.52 (d, 2H, J = 6.0 Hz), 4.20 (t, 2H,
J = 5.1 Hz), 2.98 (s, 3H), 2.77 (t, 2H, J = 6.4 Hz), 1.94–2.02 (m, 2H),
1.25 (s, 9H); IR (neat) cmꢀ1: 3269, 2958, 1655, 1615, 1515, 1451,
1333, 1223, 1157, 977; 757; LRMS (FAB+): m/z 461 (M+H+).
4.4.3. (E)-3-(2,2-Dimethyl-2,3-dihydrobenzofuran-5-yl)acrylic
acid (46)
The compound was prepared from 45 by the general procedure
for the synthesis of acids in 72% yield as a yellow solid. 1H NMR
(CDCl3, 300 MHz): d 7.74 (d, 1H, J = 15.7 Hz), 7.36 (s, 1H), 7.32 (d,
1H, J = 8.3 Hz), 6.73 (d, 1H, J = 8.3 Hz), 6.28 (d, 1H, J = 15.7 Hz),
3.01 (s, 2H), 1.47 (s, 6H).
4.3.10. 3-(6-tert-Butylchroman-8-yl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)propanamide (42)
The compound was prepared from 38b by the general proce-
dure for the synthesis of amides in 49% yield (2 steps) as a white
solid. 1H NMR (CDCl3, 300 MHz): d 7.44 (t, 1H, J = 8.3 Hz), 6.91–
6.99 (m, 4H), 6.65 (s, 1H), 6.03 (br s, 1H), 4.37 (d, 2H, J = 5.9 Hz),
4.10 (t, 2H, J = 5.1 Hz), 2.99 (s, 3H), 2.89 (t, 2H, J = 7.7 Hz), 2.74 (t,
2H, J = 6.5 Hz), 2.55 (t, 2H, J = 7.7 Hz), 1.87–1.95 (m, 2H), 1.26 (s,
9H); IR (neat) cmꢀ1: 2957, 1648, 1516, 1480, 1333, 1157, 974,
757; HR-MS (FAB+) calcd for C24H31FN2O4S (M+H+): 462.1989,
found 462.1985.
4.4.4. (E)-3-(2,2-Dimethyl-2,3-dihydrobenzofuran-5-yl)-N-(3-
fluoro-4-(methylsulfonamido)benzyl) acrylamide (47)
The compound was prepared from 46 by the general procedure
for the synthesis of amides in 91% yield as a white solid. 1H NMR
(CDCl3, 300 MHz) d 7.62 (d, 1H, J = 15.4 Hz), 7.50 (m, 1H), 7.29 (s,
1H), 7.09–7.15 (m, 2H), 6.70 (d, 1H, J = 8.1 Hz), 6.51 (m, 1H), 6.25
(d, 1H, J = 15.4 Hz), 5.91 (br s, 1H), 4.53 (d, 2H, J = 6.1 Hz), 2.99 (s,
3H), 2.98 (s, 2H), 1.46 (s, 6H); IR (neat) cmꢀ1: 3269, 1655, 1588,
1514, 1484, 1335, 1156, 1111, 974, 820, 757; LRMS (FAB+): m/z
419 (M+H+).
4.4. 2,2-dimethyl-2,3-dihydrobenzofuran analogues are
prepared by below methods
4.4.5. 3-(2,2-Dimethyl-2,3-dihydrobenzofuran-5-yl)-N-(3-
fluoro-4-(methylsulfonamido)benzyl)propanamide (48)
The compound was prepared from 46 by the general procedure
for the synthesis of amides in 91% yield (2 steps) as a white solid.
1H NMR (CDCl3, 300 MHz) d 7.46 (m, 1H), 7.10 (m, 1H), 6.88–6.95
(m, 2H), 6.69 (s, 1H), 6.61 (d, 1H, J = 8.0 Hz), 6.31 (br s, 1H), 5.77 (br
s, 1H), 4.35 (d, 2H, J = 5.9 Hz), 2.99 (s, 3H), 2.98 (s, 2H), 2.88 (t, 2H,
4.4.1. 4-Bromo-2-(2-methylallyl) phenol (44)
To a solution of 4-bromophenol 43 (300 mg, 1.73 mmol) in ace-
tone (7 mL) was added K2CO3 (1.2 g, 8.67 mmol) and 3-bromo-2-
methypropene (192 lL, 1.91 mmol). The reaction mixture was re-
fluxed for overnight. The resulting mixture was cooled to ambient
temperature and then diluted with CH2Cl2. The organic layer was
washed with water and brine, dried over MgSO4, and concentrated
in vacuo to give 1-bromo-4-(2-methyl- allyloxy)benzene (392 mg,
99%) which was directly used for the next step. 1H NMR (CDCl3,
300 MHz) d 7.36 (t, 1H, J = 2.7 Hz), 7.33 (t, 1H, J = 2.8 Hz), 6.80 (t,
1H, J = 2.8 Hz), 6.77 (t, 1H, J = 2.7 Hz), 5.06 (br s, 1H), 4.98 (br s,
1H), 4.38 (s, 2H), 1.80 (s, 3H).
J = 7.5 Hz), 2.48 (t, 2H, J = 7.4 Hz), 1.43 (s, 6H); IR (neat) cmꢀ1
:
3273, 2928, 1651, 1584, 1514, 1486, 1335, 1156, 1112, 973, 818,
757; LRMS (FAB+): m/z 421 (M+H+).
4.5. 2,2-dimethyl-chromane analogues are prepared by below
methods
To
a
solution of 1-bromo-4-(2-methylallyloxy) benzene
4.5.1. (E)-3-(2,2-Dimethylchroman-6-yl)acrylic acid (50)
To a solution of 4-hydroxybenzaldehyde 49 (300 mg, 2.5 mmol)
in anhydrous CCl4 (15 mL) was added montmorillonite K10 Clay
(259 mg, 1.1 mmol) in DMF (7 mL) was refluxed for overnight.
After cooling to ambient temperature and dilution with Et2O, the
organic layer was washed with water and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (EtOAc/n-hexane = 1:3) to afford 44
(221 mg, 87%). 1H NMR (CDCl3, 300 MHz) d 7.08–7.18 (m, 2H),
6.63(d, 1H, J = 9.2 Hz), 5.79 (s, 1H), 4.82 (s, 1H), 4.72 (s, 1H),
3.23(s, 2H), 1.64 (s, 3H).
(1313 mg, 20 equiv) and 1-bromo-3-methyl-2-butene (317 lL,
2.7 mmol). The reaction mixture was stirred at room temperature
for 16 h. The solid was removed by filtering over Celite and washed
with CH2Cl2. The combined filtrate and washes were concentrated
in vacuo to give a colorless oil. Purification of the residue by silica
gel chromatography (EtOAc/n-hexane = 1:3) provided 2,2-di-

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F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
methyl chroman-6-carbaldehyde (39 mg, 8.4%). 1H NMR (CDCl3,
300 MHz): 9.80 (s, 1H), 7.58–7.61(m, 2H), 6.85 (d, 1H,
ylaminopyridine (78 mg, 0.64 mmol) and di-tert-butyldicarbonate
(2.1 g, 9.6 mmol) then stirred for 12 h. After confirming the com-
pletion of the reaction with TLC, the resulting solution was ex-
tracted with CH2Cl2, washed with water and brine, dried over
MgSO4 and concentrated under reduced pressure. The obtained li-
quid was purified by column chromatography (EtOAc/n-hex-
ane = 1:2) to give 54 as a yellow solid (940 mg, 80%, 2 steps). 1H
NMR (CDCl3, 300 MHz) d 7.29 (s, 1H), 6.91 (dd, 1H, J = 1.3,
1.5 Hz), 4.85 (s, 1H), 4.12 (d, 2H, J = 7.0 Hz), 1.42 (s, 9H).
d
J = 9.0 Hz), 2.82 (t, 2H, J = 6.7 Hz), 1.81–1.85 (m, 2H), 1.35 (s, 6H).
The reaction was performed by same general preparation proce-
dure, then purification of the crude product by silica gel chroma-
tography (CH2Cl2/MeOH = 20:1) provided 50 (55 mg, 86%) as a
white solid. 1H NMR (CDCl3, 300 MHz): d 7.71 (d, 1H, J = 15.9 Hz),
7.26–7.31 (m, 2H), 6.78 (d, 1H, J = 8.4 Hz), 6.29 (d, 1H,
J = 15.9 Hz), 2.78 (t, 2H, J = 6.8 Hz), 1.81 (t, 2H, J = 6.8 Hz), 1.33 (s,
6H).
4.6.3. tert-Butyl 3-cyano-5-fluoro-4-(methylsulfon-
amido)benzylcarbamate (55)
4.5.2. (E)-3-(2,2-Dimethylchroman-6-yl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)acrylamide (51)
To a solution of tert-butyl 4-amino-3-fluoro-5-iodobenzylcarba-
The compound was prepared from 50 by the general procedure
for the synthesis of amides in 77% yield as a white solid. 1H NMR
(CDCl3, 300 MHz) d 7.61 (d, 1H, J = 15.4 Hz), 7.50 (m, 1H), 7.19
(br s, 1H), 7.07–7.14 (m, 2H), 7.75 (d, 1H, J = 8.4 Hz), 6.51 (s, 1H),
6.27 (d, 1H, J = 15.4 Hz), 5.93 (br s, 1H), 4.53 (d, 2H, J = 6.1 Hz),
2.99 (s, 3H), 2.75 (t, 2H, J = 6.8 Hz), 1.79 (t, 2H, J = 6.8 Hz), 1.32 (s,
6H); IR (neat) cmꢀ1: 3269, 1582, 1514, 1336, 1271, 1156, 975,
819, 757; LRMS (FAB+): m/z 433 (M +H+).
mate 54 (300 mg, 0.82 mmol) and pyridine (200
CH2Cl2 (20 mL) was put into the flask and then cooled to 0 °C. To
the solution was added methanesulfonyl chloride (76 L,
lL, 2.5 mmol) in
l
0.98 mmol) and heated to reflux for overnight. After confirming
the completion of the reaction with TLC, the reaction solution
was acidified by 10% HCl, extracted with EtOAc, washed with water
and brine, dried over MgSO4 and evaporated. The obtained solid
was purified by column chromatography (EtOAc/n-hexane = 1:2)
to yield a yellow liquid tert-butyl 3-fluoro-5-iodo-4-(methylsulfo-
namido)benzylcarbamate (130 mg, 36%). 1H NMR (300 MHz,
CDCl3): d 7.56 (s, 1H), 7.09 (dd, 1H, J = 1.8, 1.7 Hz), 6.32 (s, 1H),
4.99 (br s, 1H), 4.24 (d, 2H, J = 5.7 Hz), 3.22 (s, 3H), 1.44 (s, 9H).
To a solution of tert-butyl 3-fluoro-5-iodo-4-(methylsulfonami-
do)benzylcarbamate (156 mg, 0.35 mmol) in DMF (3 mL) was
added Zn(CN)2 (82 mg, 0.70 mmol) and Pd(PPh3)4 (81 mg,
0.07 mmol). A reaction mixture was heated to 130 °C, stirred for
3 h, cooled to room temperature, and was diluted with EtOAc. A di-
luted solution was washed water (2ꢂ) and brine, and then dried
with MgSO4. The residue was purified by column chromatography
(EtOAc/n-hexane = 1:3) to yield solid 55 (76 mg, 63%). 1H NMR
(300 MHz, CDCl3) d 7.34–7.40 (m, 2H), 6.48 (s, 1H), 5.01 (br s,
1H), 4.31 (d, 2H, J = 6.4 Hz), 3.28 (s, 3H), 1.44 (s, 9H).
4.5.3. 3-(2,2-Dimethylchroman-6-yl)-N-(3-fluoro-4-
(methylsulfonamido)benzyl)propanamide (52)
The compound was prepared from 50 by the general procedure
for the synthesis of amides in 92% yield (2 steps) as a white solid.
1H NMR (CDCl3, 300 MHz) d 7.45 (m, 1H), 7.09 (m, 1H), 6.86–6.96
(m, 2H), 6.71 (s, 1H), 6.66 (d, 1H, J = 9.0 Hz), 6.28 (br s, 1H), 5.79 (br
s, 1H), 4.33 (d, 2H, J = 5.9 Hz), 2.99 (s, 3H), 2.86 (t, 2H, J = 7.5 Hz),
2.69 (t, 2H, J = 6.8 Hz), 2.48 (t, 2H, J = 7.5 Hz), 1.75 (t, 2H,
J = 6.8 Hz), 1.29 (s, 6H); IR (neat) cmꢀ1: 3271, 2931, 1650, 1584,
1512, 1336, 1157, 974, 819, 758; LRMS (FAB+): m/z 435 (M+H+).
4.6. A part-modified analogues are prepared by below methods
4.6.1. 4-Amino-3-fluoro-5-iodobenzonitrile (53)
To a solution 2-fluoro-4-iodoaniline 5 (2.0 g, 8.4 mmol) in DMF
(30 mL) was added CuCN (982 mg, 11 mmol). The reaction mixture
was stirred at 130 °C for 8 h. After cooling to room temperature,
the mixture was poured into water and extracted with EtOAc. A di-
luted solution was washed water (2ꢂ) and brine, and then dried
with MgSO4. A residue was purified with column chromatography
(EtOAc/n-hexane = 1:2) to provide 4-amino-3-fluorobenzonitrile
(914 mg, 80%) as a white solid. 1H NMR (CDCl3, 300 MHz): d
7.21–7.26 (m, 2H), 6.74 (t, 1H, J = 8.4 Hz), 4.20 (br s, 2H).
4.6.4. N-(4-Aminomethyl-2-cyano-6-fluorophenyl)
methanesulfonamide (56)
To a solution 55 (160 mg, 0.47 mmol) in EtOAc (6 mL) was
added 5 N HCl (583 lL) and stirred for 1 h. After confirming the
completion of the reaction with TLC, the reaction solution was con-
centrated under reduced pressure to yield a brown crude solid 56
(crude 100%).
4.6.5. 3-(4-tert-Butylphenyl)-N-(3-cyano-5-fluoro-4-
To a solution of 4-amino-3-fluorobenzonitrile (2.6 g, 19 mmol)
in CH2Cl2 (20 mL) was added ICl (1.0 M CH2Cl2, 38 mL, 38 mmol).
The reaction mixture was stirred for 20 h, then quenched by add-
ing Na2S2O3 solution. The aqueous solution was extracted with
CH2Cl2 then the combined organic solution was washed with water
and brine, dried with MgSO4, concentrated in vacuo. The residue
was purified with column chromatography (EtOAc/n-hexane = 1:2)
to give 53 as a white solid (3.3 g, 66%). 1H NMR (CDCl3, 300 MHz), d
7.69 (t, 1H, J = 1.5 Hz), 7.23 (dd, 1H, J = 1.7, 10.0 Hz), 4.68 (br s, 2H).
(methylsulfonamido)benzyl)propanamide (57)
The reaction was performed by same general preparation proce-
dure, then purification of the crude product by silica gel chroma-
tography (CH2Cl2/MeOH = 20:1) to afford 57 (39%) as a white
solid. 1H NMR (CD3OD, 500 MHz) d 7.46 (s, 1H), 7.33 (d, 1H,
J = 10.4 Hz), 7.31 (d, 2H, J = 8.2 Hz), 7.11 (d, 2H, J = 8.2 Hz), 4.34
(s, 2H), 3.12 (s, 3H), 2.90 (t, 2H, J = 7.4 Hz), 2.54 (t, 2H, J = 7.4 Hz),
1.28 (s, 9H); 13C NMR (CD3OD, 125 MHz) d 176.4, 161.5, 159.5,
151.1, 144.1, 139.7, 130.1, 130.0, 129.8, 127.2, 122.1, 121.9,
117.8, 117.0, 43.6, 43.0, 39.6, 36.0, 33.0, 32.6; IR (neat) cmꢀ1
:
4.6.2. tert-Butyl 4-amino-3-fluoro-5-iodobenzylcarbamate (54)
To a solution of 53 (842 mg, 3.2 mmol) in THF (8 mL) was added
BH3–THF (1 M solution in THF, 9.6 mL, 9.6 mmol) dropwise. The
reaction mixture was refluxed for 3 h and 2 N HCl (1.0 mL) was
added. The resulting mixture was refluxed for an additional 1 h
and then concentrated in vacuo to give 971 mg (99%) of the crude
4-(aminomethyl)-2-fluoro-6-iodoaniline HCl salt, which was di-
rectly used for the next step.
3432, 2960, 2499, 2222, 1641, 1429, 1328, 1278; HR-MS (FAB+)
calcd for C22H27FN3O3S (M+H+): 432.1757, found 432.1762.
4.6.6. N-(3-Cyano-5-fluoro-4-(methylsulfonamido)benzyl)-3-
(4-(1-methylcyclopropyl)phenyl)propanamide (58)
The reaction was performed by the general preparation proce-
dure, then purification of the crude product by silica gel chroma-
tography (CH2Cl2/MeOH = 20:1) to afford 58 (69%) as a white
solid. 1H NMR (CD3OD, 300 MHz) d 7.35 (s, 1H), 7.20 (dd, 1H,
J = 1.8, 2.0 Hz), 7.04 (m, 1H), 6.96–6.99 (m, 3H), 4.23 (s, 2H), 3.19
(s, 3H), 2.79 (t, 2H, J = 7.4 Hz), 2.43 (t, 2H, J = 7.4 Hz), 1.26 (s, 3H),
A solution of 4-(aminomethyl)-2-fluoro-6-iodoaniline (971 mg,
3.2 mmol,) and Et3N (1.3 mL, 9.6 mmol) in CH2Cl2 was put into the
flask and then cooled to 0 °C. To the solution were added 4-dimeth-

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 3557–3567
3567
0.65–0.71 (m, 2H), 0.57–0.60 (m, 2H); 13C NMR (CD3OD, 125 MHz)
d 176.3, 161.5, 159.5, 147.1, 144.2, 140.1, 139.8, 130.1, 130.0,
129.0, 128.6, 122.1, 121.9, 117.7, 117.1, 43.6, 43.0, 39.6, 33.0,
26.9, 21.0, 16.9; IR (neat) cmꢀ1: 3363, 2959, 2222, 1644, 1546,
1424, 1323, 1148, 980, 770; HR-MS (FAB+) calcd for C22H25FN3O3S
(M+H+): 430.1601, found 430.1602.
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4.6.7. N-(3-Cyano-5-fluoro-4-(methylsulfonamido)benzyl)-3-
(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-
yl)propanamide (59)
7. (a) Doherty, E. M.; Fotsch, C.; Bo, Y.; Chakrabarti, P. P.; Chen, N.; Gavva, N.; Han,
N.; Kelly, M. G.; Kincaid, J.; Klionsky, L.; Liu, Q.; Ognyanov, V. I.; Tamir, R.;
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Bioorg. Med. Chem. Lett. 2003, 13, 4389.
The reaction was performed by the general preparation proce-
dure, then purification of the crude product by silica gel chroma-
tography (CH2Cl2/MeOH = 20:1) to afford 59 (59%) as a white
solid. 1H NMR (CD3OD, 300 MHz): d 7.49(s, 1H), 7.37 (dd, 1H,
J = 1.8, 2.0 Hz), 7.20 (d, 1H, J = 8.0 Hz), 7.14 (d, 1H, J = 1.8 Hz),
6.91 (dd, 1H, J = 2.0, 2.0 Hz), 4.36 (s, 2H), 3.12 (s, 3H), 2.87 (t, 2H,
J = 7.5 Hz), 2.52 (t, 2H, J = 7.5 Hz), 1.67 (s, 4H), 1.23 (s, 12H); 13C
NMR (CD3OD, 125 MHz) d 176.5, 146.7, 144.6, 139.7, 130.1,
130.0, 128.5, 128.1, 127.8, 127.4, 122.1, 122.0, 117.1, 43.7, 43.0,
39.6, 37.1, 37.0, 35.9, 35.7, 33.2, 33.1, 33.0; IR (neat) cmꢀ1: 2959,
2224, 1707, 1654, 1585, 1540, 1492, 1337, 1157, 974, 771; HR-
MS (FAB+) calcd for C26H33FN3O3S (M+H+): 486.2227, found
486.2218.
9. Suh, Y.-G.; Lee, Y.-S.; Min, K.-H.; Park, O.-H.; Kim, J.-K.; Seung, H.-S.; Seo, S.-Y.;
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Acknowledgment
12. (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771; (b) Stille, J. K. Angew. Chem., Int.
Ed. Engl 1986, 25, 508; (c) Mitchell, T. N. Synthesis 1992, 803.
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Med. Chem. Lett. 2004, 14, 1693.
This research work was supported by the grant from AmorePa-
cific Corporation and by Grant R01-2007-000-20052-0 from the
Basic Research Program of the Korea Science and Engineering
Foundation.
References and notes
16. Unpublished results.
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