Synthesis and structural optimization of multiple H-bonding region of diarylalkyl (thio)amides as novel TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmc.2009.10.043

Structural optimization of multiple H-bonding region and structure-activity relationship of diarylalkyl amides/thioamides as novel TRPV1 antagonists are described. In particular, we identified amide 34o and thioamides 35o and 35r, of which antagonistic activities were highly enhanced by an incorporation of cyano or vinyl-substituent to the multiple H-bonding region. They exhibited potent ⁴⁵Ca²⁺ uptake inhibitions in rat DRG neuron with IC₅₀s of 25, 32 and 28 nM, respectively.

Full text of DOI:10.1016/j.bmc.2009.10.043

Bioorganic & Medicinal Chemistry 17 (2009) 8149–8160
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and structural optimization of multiple H-bonding region
of diarylalkyl (thio)amides as novel TRPV1 antagonists
Fu-Nan Li a, Nam-Jung Kim a, Dong-Jo Chang a, Jaebong Jang a, Hannah Jang a, Jong-Wha Jung 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:
Structural optimization of multiple H-bonding region and structure–activity relationship of diarylalkyl
amides/thioamides as novel TRPV1 antagonists are described. In particular, we identified amide 34o
and thioamides 35o and 35r, of which antagonistic activities were highly enhanced by an incorporation
of cyano or vinyl-substituent to the multiple H-bonding region. They exhibited potent 45Ca2+ uptake inhi-
bitions in rat DRG neuron with IC50s of 25, 32 and 28 nM, respectively.
Received 9 September 2009
Revised 21 October 2009
Accepted 22 October 2009
Available online 27 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
ration of an additional substituent into region A of thiourea
enhances antagonistic activity, and this finding encouraged us to
Neuropathic pain affects 26 million worldwide patients, and in-
curs healthcare costs exceeding three billion dollars per year.1 De-
spite availability of the powerful drugs for effective pain
management the necessity of new non-narcotic analgesics still re-
mains. The nerve damage and analgesic effect of TRPV1 (transient
receptor potential vanilloid subfamily 1) agonist are preceded by
an intense painful hyperanalgesia caused by TRPV1 activation.2
Intensive genetic and pharmacological studies on TRPV1 have been
conducted since it was cloned in 1997 and these studies have im-
plied that TRPV1 could be a key molecular target for pain manage-
ment.3 Thus, much effort has been expended on the excavation of
potent and selective antagonists of TRPV1.4–6
In this context, we previously reported dibenzyl thioureas
(Fig. 1)7,8 as potent TRPV1 antagonists and their structure–activity
relationship (SAR).9 Recently, we also reported new variants of the
lipophilic C-region of diarylalkyl amides.10 However, our previous
studies revealed that amide series exhibited lower antagonistic
activities compared to the corresponding thiourea series in spite
of optimization of the lipophilic C-region. Thus, our recent work
has focused on optimization of the multiple H-bonding part A to
improve potency and metabolic and pharmacokinetic profiles of
the diarylalkyl amide or thioamide series because they seem to
be preferred scaffold in terms of therapeutic application. Fortu-
nately, during our previous studies,10 we observed that an incorpo-
execute an extensive investigation in A-region optimization. We
herein report potency enhancement by structural optimization of
A-region of diarylalkyl amides or thioamides as well as their SAR.
B
C
A
O
OCH3
OH
N
H
Capsaicin
Cl
OH
OH
S
S
Capsazepine
N
H
N
F
N
H
N
H
SC-0030
NHMs
S (O)
R1
R2
N
H
Analogues
NHMs
R3
* Corresponding author.
E-mail address: ygsuh@snu.ac.kr (Y.-G. Suh).
Figure 1. Capsaicin, capsazepine, SC-0030, and potency-enhanced amide analogs.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.10.043

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F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
sequential deprotection and salt formation. Treatment of 13 with
2. Results and discussion
2.1. Chemistry
CuCN afforded cyanide, which was readily converted to 15 under
acidic condition. Stille coupling11 of benzylamine 13 with tributyl-
vinyltin gave the vinylbenzylcarbamate 16, which was treated
with 5 N HCl to afford olefin 18. Pd-catalyzed hydrogenation of
16 followed by Boc-deprotection gave the saturated analogue 19
(Scheme 3). Trisubstituted benzylamines 28–31 were prepared
from commercially available aniline 5a (Scheme 4). Sequential
cyanation and iodination of aniline 5a, reduction of nitrile 21 with
borane and Boc-protection followed by methanesulfonylation
provided the key intermediate 23. Treatment of 23 with Zn(CN)2
afforded cyanide 24, which was readily converted to 28 under
acidic condition. Sonogashira coupling12 of 23 with TMS acetylene
gave 25, which was subjected to the conditions for desilylation and
Boc-deprotection to afford 29 in 60% overall yield. Stille coupling of
23 with tributylvinyltin followed by Boc-deprotection gave
analogue 30. Simmons–Smith cyclopropanation13 of 26 with
diethylzinc and CH2I2 followed by Boc-deprotection provided
cyclopropane 31.
Syntheses of a variety of A-region as benzylamine ammonium
salts (4a–e and 8a–e) are described in Schemes 1 and 2. Borane
reduction of cyanides 1a–e, followed by Boc-protection and
methanesulfonylation of the resulting benzylamines provided
3a–e. The benzylamines 3a–e, were readily converted to the key
intermediates 4a–e via sequential deprotection and salt formation.
The commercially available anilines (5a–f) were mesylated, and
then resulting sulfonamides (6a–e) were treated with CuCN to
afford 7a–e. The ammonium salts (8a–e) were obtained by BH3
reduction of 7a–e followed by treatment with 2 N HCl. The
analogues 14, 15, 18 and 19 were also prepared by the procedure
described in Scheme 3. Aniline 9 was transformed into 13 by
sequential iodination of 9, nitrile reduction, Boc-protection of the
resulting benzylamine followed by methanesulfonylation. The
benzylamine 13 was readily converted to the intermediate 14 via
R1
R1
R1
R1
R2
R2
R2
NC
R2
b, c
BocHN
d
a
H3N
Cl
H3N
Cl
NHMs
NH2
NHMs
NH2
4a-e
2a-e
3a-e
R3
R3
R3
R3
1a:
R1=H, R2=CF3, R3=H
1b: R1=H, R =NO2, R =H
1c: R1=Cl, R22=H,
1d:
1e:
R33=H
R3=H
R1=CF3,R2=H,
R1=H, R2=Cl, R3=CH3
Scheme 1. Reagents and conditions: (a) 1 M BH3ÁTHF, THF, reflux, then 2 N HCl, 99–100%; (b) (Boc)2O, DMAP, Et3N, CH2Cl2, 69–93%; (c) CH3SO2Cl, pyridine, CH2Cl2, 36–95%;
(d) 5 N HCl, EtOAc, reflux, 100%.
X
R1
X
R1
NC
R1
R1
d
b
c
H3N
Cl
NH2
NHMs
NHMs
NHMs
6a-e
7a-e
8a-e
R2
R2
R2
R2
5a: X=I, R1=F,
5b: X=I, R1=Cl,
R2=H
R2=H
R2=H
5c:
5d:
X=I, R1=CH3,
X=I, R1=CO2H, R2=H
a
5e: X=I, R1=CO2Me, R2=H
5f:
X=Br, R1=CH3,
R2=CH3
Scheme 2. Reagents and conditions: (a) TMSCl, MeOH, reflux, 49%; (b) CH3SO2Cl, pyridine, CH2Cl2, 37–93%; (c) CuCN, DMF, 130 °C, 54–98%; (d) 1 M BH3ÁTHF, THF, reflux, then
2 N HCl, 99–100%.
I
NC
NC
I
I
d
c
a
b
BocHN
H3N
Cl
NH2
NH2
NH2
NH2
12
11
10
9
I
g
e
BocHN
H3N
Cl
BocHN
BocHN
NHMs
f, e
NHMs
NHMs
NHMs
13
16
18
e
h
I
CN
e
H3N
Cl
H3N
Cl
H3N
Cl
NHMs
NHMs
NHMs
14
15
17
19
Scheme 3. Reagents and conditions: (a) I2, H2O2, MeOH, 79%; (b) 1 M BH3ÁTHF, THF, reflux, then 2 N HCl, 99%; (c) (Boc)2O, DMAP, Et3N, CH2Cl2, 83%; (d) CH3SO2Cl, pyridine,
CH2Cl2, 93%; (e) 5 N HCl, EtOAc, reflux, 99–100%; (f) CuCN, DMF, 130 °C, 72%; (g) Pd(PPh3)4, CH2CHSnBu3, toluene, reflux, 97%; (h) 10% Pd/C, H2, THF, 84%.

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
8151
I
F
NC
F
NC
F
F
e
BocHN
b
a
c, d
NH2
NH2
NH2
NH2
21
22
20
5a
I
I
F
F
f
H3N
Cl
BocHN
j
NHMs
NHMs
24
28
29
CN
CN
F
F
g
h
H3N
Cl
BocHN
F
k, j
BocHN
NHMs
NHMs
NHMs
25
23
I
TMS
F
F
H3N
Cl
BocHN
j
j
NHMs
NHMs
26
30
31
i
F
F
H3N
Cl
BocHN
NHMs
NHMs
27
Scheme 4. Reagents and conditions: (a) CuCN, DMF, 130 °C, 80%; (b) 1 M ICl, CH2Cl2, 66%; (c) 1 M BH3ÁTHF, 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) trimethylsilyl acetylene, (PPh3)2PdCl2, CuI, Et3N, THF, reflux, 84%; (h) Pd(PPh3)4,
CH2CHSnBu3, toluene, reflux, 69%; (i) Et2Zn, CH2I2, CH2Cl2, 40 °C, 99%; (j) 5 N HCl, EtOAc, reflux, 100%; (k) NaOH, THF/H2O = 2:1, rt, 71%.
Propanoic acid intermediate 33 was prepared by Knoevenagel
condensation14 of aldehyde 32 with malonic acid and hydrogena-
tion of the resulting olefin. Amides 34a–r were prepared by
DMTMM-mediated coupling15 of various benzylamine ammonium
salts (4a–e, 8a–e, 14, 15, 18, 19, 28, 29, 30 and 31) with acid 33.
Treatment of amides 34a–r with Lawesson’s reagent gave thioam-
ides 35a–r (Scheme 5). Hydrolysis of 35l afforded 36 while treat-
ment of 35l with N,O-dimethylhydroxylamine afforded Weinreb
amide 37, which was then reacted with methyl magnesium iodide
to give ketone 38 (Scheme 6).
retained the same antagonistic activity as the parent thiourea SC-
0030, which indicates that thioamide moiety could be a useful bio-
isostere for thiourea scaffold in this series. In addition, the thioam-
ide analogues generally exhibited slightly higher antagonistic
activities than the corresponding amides. However, no analogue
with the disubstituted A-moiety showed higher potency than the
parent thiourea (SC-0030) regardless of substituent or substitution
pattern. Move of chloro substituent from R2 to R1 position of 35b
resulted in a moderate decrease in 45Ca2+ uptake inhibitory activ-
ity. Analogues with electron-withdrawing groups at R2-position,
such as cyano (35j), nitro (35k), fluoro (35a) and chloro (35b)
exhibited good antagonistic activities in the range of 40–100 nM.
However, introduction of trifluoromethyl (35e and 35f) or carbonyl
The in vitro activities of the synthesized analogues are summa-
rized in Table 1. Most of the analogues displayed excellent or con-
siderable TRPV1 antagonistic activities. The thioamide 35a
S
O
O
R1
R1
CHO
R2
R2
OH
N
H
N
H
a, b
c
d
NHMs
NHMs
R3
R3
34a-r
35a-r
32
33
Scheme 5. Reagents and conditions: (a) malonic acid, pyridine, piperidine, reflux, 86%; (b) 10% Pd/C, H2, THF, 84%; (c) 4a–e, 8a–e, 14, 15, 18, 19, 28, 29, 30 and 31, DMTMM,
NMM, Et3N, THF, 35–90%; (d) Lawesson’s reagent, toluene, reflux, 41–97%.
S
S
CO2CH3
NHMs
CO2H
NHMs
a
N
H
N
H
35l
36
b
S
O
S
O
OCH3
N
H
N
H
N
c
CH3
NHMs
NHMs
38
37
Scheme 6. Reagents and conditions: (a) LiOH, THF/H2O = 1:1, rt, 50%; (b) N,O-dimethylhydroxylamine, i-PrMgCl, THF, 0 °C, 72%; (c) CH3MgI, THF, 0 °C, 28%.

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F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
Table 1
45Ca2+ Uptake inhibition by the amide/thioamide analogues
X
R1
R2
Y
N
H
NHMs
R3
Compound
Y
X
R1
R2
R3
Antagonistic activity, IC50 (nM)
SC-0030
35a
35b
35c
35d
35e
35f
35g
35h
35i
35j
35k
36
35l
38
NH
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
O
S
O
S
O
S
O
S
O
S
O
H
H
H
Cl
H
CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
F
Cl
H
I
H
CF3
CH3
Ethyl
Vinyl
CN
NO2
CO2H
CO2CH3
Acetyl
CH3
CH3
Cl
Cl
F
F
F
F
F
F
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
Vinyl
Vinyl
Acetylene
Acetylene
Cyclopropyl
Cyclopropyl
CN
37
40
96
3500
300
2400
940
60
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
240
61
55
72
22,600
3700
1000
2900
620
80
100
32
25
35m
34m
35n
34n
35o
34o
35p
34p
35q
34q
35r
75
170
270
360
28
34r10
F
CN
85
substituent (36, 35l and 38) led to a significant reduction in antag-
onistic activity. Interestingly, the methyl-substituted analogue 35g
exhibited more potent activity than the trifluoromethyl-substi-
tuted analogue 35f.
plated onto Terasaki plates previously coated with 10
lg/mL
poly- -ornithine at a density of 1500–1700 neurons/well. The cells
D
were then cultured for three 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 condi-
tioned by C6 glioma cells (two days on a confluent monolayer) in
a humidified atmosphere at 37 °C containing 5% CO2. Medium
was supplemented with 200 ng/mL nerve growth factor. Cytosine
We were very much interested in the R3-substituent effect on
antagonistic effect because we anticipated a potency enhancement
by an additional substitution at R3-position. The substituent effect
at R3-position was quite interesting. Introduction of methyl group
(35n) at R3-position of 35b was tolerable, whereas methyl incorpo-
ration at R3-position of 35g possessing methyl substituent at R2-
position exhibited a significant decreased antagonistic activity. It
is noticeable that introduction of vinyl or nitrile substituent at
R3-position enhance antagonistic activity. In particular, the vinyl-
substituted thioamide 35o and the cyano-substituted thioamide
arabinoside (100 lM) was added for the first two days to kill divid-
ing nonneuronal cells.
2.2.2. Uptake assays
Terasaki plates containing DRG neurons grown for three days
were equilibrated with four washes of HEPES (10 mM, pH 7.4)–
buffered calcium and magnesium-free Hank’s balanced salt solu-
tion. The solution in each well was removed from the individual
35r exhibited higher potency than the parent SC-0030 with IC50
s
of 32 and 28 nM, respectively. The vinyl-substituted amide 34o
exhibited even better antagonistic activity with IC50 of 25 nM than
the corresponding thioamide 35o. However, amide 34r with a cy-
ano group at R3-position was threefold less potent than the corre-
sponding thioamide 35r.
wells. For antagonistic studies, medium (10
lL) containing
10
l
Ci/mL 45Ca2+ and 0.5 M capsaicin together with the test con-
centration of the compound was added to each well. The neurons
were incubated at room temperature for 10 min, and then the Ter-
asaki plates were washed six times in HEPES (10 mM, pH 7.4)–buf-
fered calcium and magnesium-free Hank’s balanced salt solution
2.2. Biological evaluation
2.2.1. 45Ca2+ Uptake assays. Culture of DRG neurons
and dried in an oven. Sodium dodecyl sulfate (0.3%, 10 lL) was
then added to dissolve the cells and extract the 45Ca2+. The con-
tents of each well were transferred to scintillation vials and
counted in 3 mL of aquasol-2 scintillant. Antagonistic activities of
test compounds were given as IC50 (the concentration of the com-
DRG neurons were prepared from neonatal Sprague-Dawley
rats. DRGs of all spinal levels were dissected aseptically and
collected. Ganglia were incubated sequentially for 30 min at
37 °C in 200 U/mL collagenase and 2.5 mg/mL trypsin. The diges-
tion was halted by an addition of an equal volume of DME/F12
medium supplemented with 10% horse serum. The ganglia were
then triturated through a fire-polished Pasteur pipet, filtered
through nylon membrane, and spun down. Dissociated cells were
pound necessary to 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 inde-
pendent experiments.

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
8153
4.1.6. tert-Butyl 4-(methylsulfonamido)-3-(trifluoromethyl)-
benzylcarbamate (3a)
solution of 4-(aminomethyl)-2-(trifluoromethyl) aniline
ammonium salt 2a (154 mg, 0.87 mmol) and Et3N (363 L,
3. Conclusion
A
Our effort for potency enhancement by structural optimization
of the multiple H-bonding region has been carried out and this en-
abled us to identify novel and highly potent TRPV1 antagonists
with the therapeutically favorable amide or thioamide scaffolds
in B-region. In particular, incorporation of an additional substitu-
ent such as cyano or vinyl group at R3-position of SC-0030 en-
l
2.6 mmol) in CH2Cl2 was put into the flask and then cooled to
0 °C. To the solution were added DMAP (21 mg, 0.17 mmol) and
di-tert-butyl-bicarbonate (571 mg, 2.6 mmol) then stirred for 5 h.
After confirming the completion of the reaction with TLC, the
resulting solution was extracted with CH2Cl2, washed with water
and brine, dried over MgSO4 and concentrated in vacuo. The
obtained liquid was purified by column chromatography (EtOAc/
n-hexane = 1:2) to give tert-butyl 4-amino-3-(trifluoromethyl)ben-
zylcarbamate as a yellow solid (147 mg, 70%). 1H NMR (CDCl3,
300 MHz): d 7.87 (s, 1H), 7.44 (br s, 1H), 7.23 (d, 1H, J = 8.3 Hz),
4.83 (br s, 1H), 4.22 (br s, 2H), 1.49 (s, 9H).
hanced the antagonistic activity. This obviously provided
a
valuable compensation for the inevitable potency decrease by
replacement of thiourea with the therapeutically preferred amide
or thioamide scaffold. Currently, studies on therapeutic application
of the analogues 34o, 35o and 35r are in progress.
4. Experimental
To the solution of tert-butyl 4-amino-3-(trifluoromethyl)ben-
zylcarbamate (73 mg, 0.25 mmol) and pyridine (41
in CH2Cl2 (4 mL) was added methanesulfonyl chloride (33
l
L, 0.51 mmol)
L,
4.1. General methods
l
0.43 mmol) at 0 °C and heated to reflux for overnight. After con-
firming the completion of the reaction with TLC, the reaction solu-
tion was acidified by 10% HCl, extracted with EtOAc, washed with
water and brine, and dried over MgSO4 followed by evaporation.
The obtained solid was purified by column chromatography
(EtOAc/n-hexane = 1:2) to yield a yellow liquid 3a (47 mg, 51%,
two steps). 1H NMR (300 MHz, CDCl3): d 7.75 (d, 1H, J = 8.4 Hz),
7.53 (s, 1H), 7.47 (d, 1H, J = 8.4 Hz), 6.62 (s, 1H), 4.94 (br s, 1H),
4.32 (d, 2H, J = 5.9 Hz), 2.97 (s, 3H), 1.44 (s, 9H).
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.
4.1.7. tert-Butyl 4-(methylsulfonamido)-3-nitrobenzylcarba-
mate (3b)
The compound was prepared from 2b by the procedure for the
synthesis of 3a in 57% yield (two steps) as a white solid. 1H NMR
(CDCl3, 300 MHz): d 9.65 (br s, 1H), 8.48 (d, 1H, J = 2.0 Hz), 7.67
(d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 8.8, 2.0 Hz), 4.97 (br s, 1H),
4.42 (d, 2H, J = 5.9 Hz), 3.10 (s, 3H), 1.46 (s, 9H).
4.1.1. 4-(Aminomethyl)-2-(trifluoromethyl)aniline ammonium
salt (2a)
To a solution of 4-amino-3-(trifluoromethyl)benzo-nitrile 1a
(842 mg, 3.2 mmol) in THF (8 mL) was added BH3ÁTHF (1 M solu-
tion 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-(tri-
fluoromethyl)aniline ammonium salt 2a, which was directly used
for the next step.
4.1.8. tert-Butyl 2-chloro-4-(methylsulfonamido)benzylcar-
bamate (3c)
The compound was prepared from 2c by the procedure for the
synthesis of 3a in 78% yield (two steps) as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.87 (s, 1H), 7.33–7.45 (m, 2H), 5.11 (br s,
1H), 4.43 (d, 2H, J = 5.2 Hz), 3.02 (s, 3H), 1.45 (s, 9H).
4.1.2. 4-(Aminomethyl)-2-nitroaniline ammonium salt (2b)
The compound was prepared from 1b by the procedure for the
synthesis of 2a in 100% yield; white solid, which was directly used
for the next step.
4.1.9. tert-Butyl 4-(methylsulfonamido)-2-(trifluoromethyl)-
benzylcarbamate (3d)
The compound was prepared from 2d by the procedure for the
synthesis of 3a in 63% yield (two steps) as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.94 (s, 1H), 7.37–7.49 (m, 2H), 5.04 (br s,
1H), 4.41 (d, 2H, J = 5.1 Hz), 2.99 (s, 3H), 1.42 (s, 9H).
4.1.3. 4-(Aminomethyl)-3-chloroaniline ammonium salt (2c)
The compound was prepared from 1c by the procedure for the
synthesis of 2a in 100% yield; white solid, which was directly used
for the next step.
4.1.10. tert-Butyl 3-chloro-5-methyl-4-(methylsulfonamido)-
benzylcarbamate (3e)
The compound was prepared from 2e by the procedure for the
synthesis of 3a in 86% yield (two steps) as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.24 (s, 1H), 7.10 (s, 1H), 4.88 (br s, 1H),
4.24 (d, 2H, J = 5.3 Hz), 3.07 (s, 3H), 2.48 (s, 3H), 1.45 (s, 9H).
4.1.4. 4-(Aminomethyl)-3-(trifluoromethyl)aniline ammonium
salt (2d)
The compound was prepared from 1d by the procedure for the
synthesis of 2a in 100% yield; white solid, which was directly used
for the next step.
4.1.11. N-[4-(Aminomethyl)-2-(trifluoromethyl)phenyl]methane-
sulfonamide ammonium salt (4a)
To a solution of 3a (160 mg, 0.47 mmol) in EtOAc (6 mL)
was added 5 N HCl (583 lL) and stirred for 1 h. After confirm-
4.1.5. 4-(Aminomethyl)-2-chloro-6-methylaniline ammonium
salt (2e)
ing the completion of the reaction with TLC, the reaction solu-
tion was concentrated in vacuo to yield a brown crude solid 4a
(100%).
The compound was prepared from 1e by the procedure for the
synthesis of 2a in 99% yield; white solid, which was directly used
for the next step.

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F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
4.1.12. N-[4-(Aminomethyl)-2-nitrophenyl]methanesulfon-
amide ammonium salt (4b)
The compound was prepared from 3b by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
4.1.22. N-(4-Cyano-2-fluorophenyl)methanesulfonamide (7a)
To a solution of N-(2-fluoro-4-iodophenyl)methanesulfonamide
6a (120 mg, 0.38 mmol) in DMF (5 mL) was added CuCN (41 mg,
0.46 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 diluted solution was washed
water (2Â) and brine, and then dried over MgSO4. A residue was
purified with silica gel column chromatography (EtOAc/n-hex-
ane = 1:2) to provide 7a (65 mg, 80%) as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.71 (t, 1H, J = 8.0 Hz), 7.41–7.48 (m, 2H),
6.83 (br s, 1H), 3.11 (s, 3H).
4.1.13. N-[4-(Aminomethyl)-3-chlorophenyl]methanesul-
fonamide ammonium salt (4c)
The compound was prepared from 3c by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
4.1.14. N-[4-(Aminomethyl)-3-(trifluoromethyl)phenyl]methane-
sulfonamide ammonium salt (4d)
The compound was prepared from 3d by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
4.1.23. N-(2-Chloro-4-cyanophenyl)methanesulfonamide (7b)
The compound was prepared from 6b by the procedure for the
synthesis of 7a in 81% yield; white solid. 1H NMR (CDCl3,
300 MHz): d 7.89 (d, 1H, J = 1.8 Hz), 7.78 (d, 1H, J = 8.5 Hz), 7.69
(dd, 1H, J = 8.5, 1.8 Hz), 3.11 (s, 3H).
4.1.15. N-[4-(Aminomethyl)-2-chloro-6-methylphenyl]methane-
sulfonamide ammonium salt (4e)
The compound was prepared from 3e by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
4.1.24. N-(4-Cyano-2-methylphenyl)methanesulfonamide (7c)
The compound was prepared from 6c by the procedure for the
synthesis of 7a in 66% yield; white solid. 1H NMR (CDCl3,
300 MHz): d 7.49–7.61 (m, 3H), 6.53 (br s, 1H), 3.10 (s, 3H), 2.29
(s, 3H).
4.1.16. Methyl 2-amino-5-iodobenzoate (5e)
4.1.25. Methyl 5-cyano-2-(methylsulfonamido)benzoate (7d)
The compound was prepared from 6d by the procedure for the
synthesis of 7a in 54% yield; white solid. 1H NMR (CDCl3,
300 MHz): d 10.8 (br s, 1H), 8.34 (s, 1H), 7.74–7.82 (m, 2H), 3.95
(s, 3H), 3.13 (s, 3H).
To
a solution of 2-amino-5-iodobenzoic acid 5d (2.0 g,
7.6 mmol) in MeOH (8.0 mL) was added TMSCl (4.8 mL, 38.0 mmol)
dropwise. The reaction mixture was refluxed for 24 h and concen-
trated in vacuo. The mixture was quenched by aq NaHCO3 and ex-
tracted with EtOAc, washed with brine and dried over MgSO4.
Purification of the residue by silica gel column chromatography
(EtOAc/n-hexane = 1:20) was conducted to afford 5e (1.0 g, 49%).
1H NMR (CDCl3, 300 MHz): d 8.12 (d, 1H, J = 2.0 Hz), 7.47 (dd, 1H,
J = 8.6, 2.2 Hz), 6.45 (d, 1H, J = 8.6 Hz), 5.74 (br s, 2H), 3.84 (s, 3H).
4.1.26. N-(4-Cyano-2,6-dimethylphenyl)methanesulfonamide
(7e)
The compound was prepared from 6e by the procedure for the
synthesis of 7a in 98% yield; white solid. 1H NMR (CDCl3,
300 MHz): d 7.38 (s, 2H), 3.03 (s, 3H), 2.34 (s, 6H).
4.1.17. N-(2-Fluoro-4-iodophenyl)methanesulfonamide (6a)
The compound was prepared from 5a by the procedure for the
synthesis of 3a in 87% yield as a white solid. 1H NMR (CDCl3,
300 MHz): d 7.48 (d, 2H, J = 8.5 Hz), 7.30 (t, 1H, J = 8.3 Hz), 6.48
(br s, 1H), 3.01 (s, 3H).
4.1.27. N-[4-(Aminomethyl)-2-fluorophenyl]
methanesulfonamide ammonium salt (8a)
The compound was prepared from 7a by the procedure for the
synthesis of 2a in 100% yield; white solid, which was directly used
for the next step.
4.1.18. N-(2-Chloro-4-iodophenyl)methanesulfonamide (6b)
The compound was prepared from 5b by the procedure for the
synthesis of 3a in 93% yield as a white solid. 1H NMR (CDCl3,
300 MHz): d 7.74 (d, 1H, J = 2.0 Hz), 7.60 (dd, 1H, J = 2.0, 8.6 Hz),
7.38 (d, 1H, J = 8.6 Hz), 6.73 (br s, 1H), 3.00 (s, 3H); LRMS (FAB+)
m/z 332 (M+H+).
4.1.28. N-[4-(Aminomethyl)-2-chlorophenyl]methanesulfona-
mide ammonium salt (8b)
The compound was prepared from 7b by the procedure for the
synthesis of 2a in 99% yield; white solid, which was directly used
for the next step.
4.1.19. N-(4-Iodo-2-methylphenyl)methanesulfonamide (6c)
The compound was prepared from 5c by the procedure for the
synthesis of 3a in 55% yield as a white solid. 1H NMR (CDCl3,
300 MHz): d 7.52–7.56 (m, 2H), 7.21 (d, 1H, J = 8.2 Hz), 6.11 (br s,
1H), 3.00 (s, 3H), 2.25 (s, 3H).
4.1.29. N-[4-(Aminomethyl)-2-methylphenyl]methanesulfona-
mide ammonium salt (8c)
The compound was prepared from 7c by the procedure for the
synthesis of 2a in 100% yield; white solid, which was directly used
for the next step.
4.1.20. Methyl 5-iodo-2-(methylsulfonamido)benzoate (6d)
The compound was prepared from 5e by the procedure for the
synthesis of 3a in 37% yield as a white solid. 1H NMR (CDCl3,
300 MHz): d 10.4 (br s, 1H), 8.34 (d, 1H, J = 2.2 Hz), 7.82 (dd, 1H,
J = 9.0, 2.2 Hz), 7.52 (d, 1H, J= 9.0 Hz), 3.93 (s, 3H), 3.04 (s, 3H).
4.1.30. Methyl 5-(aminomethyl)-2-(methylsulfonamido)benzoate
ammonium salt (8d)
The compound was prepared from 7d by the procedure for the
synthesis of 2a in 100% yield; white solid, which was directly used
for the next step.
4.1.21. N-(4-Bromo-2,6-dimethylphenyl)methanesulfonamide
(6e)
4.1.31. N-[4-(Aminomethyl)-2,6-dimethylphenyl] methanesul-
fonamide ammonium salt (8e)
The compound was prepared from 5f by the procedure for the
synthesis of 3a in 66% yield as a white solid. 1H NMR (CD3OD,
300 MHz): d 7.26 (s, 2H), 3.07 (s, 3H), 2.37 (s, 6H).
The compound was prepared from 7e by the procedure for the
synthesis of 2a in 100% yield; white solid, which was directly used
for the next step.

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
8155
4.1.32. 4-Amino-3-iodobenzonitrile (10)
gas, followed by stirring for 8 h at room temperature. The
resulting mixture was diluted with Et2O, filtered through Celite
pad, and then concentrated in vacuo to give 17 (310 mg, 84%).
1H NMR (CDCl3, 300 MHz): d 7.40 (d, 1H, J = 8.1 Hz), 7.11–7.15
(m, 2H), 6.15 (s, 1H), 4.82 (br s, 1H), 4.26 (d, 2H, J = 5.5 Hz),
2.99 (s, 3H), 2.63 (q, 2H, J= 7.5 Hz), 1.44 (s, 9H), 1.22 (t, 3H,
J = 7.5 Hz).
To a solution of 4-aminobenzonitrile 9 (1.0 g, 8.5 mmol) in
MeOH was added I2 (1.3 g, 5.1 mmol). The reaction mixture was
stirred at room temperature for 30 min, then added a solution of
H2O2 (0.83 mL) in THF dropwise over 20 min. The reaction mixture
was stirred at room temperature for three days. After confirming
the completion of the reaction with TLC, the reaction was
quenched by aq Na2S2O3 and stirred for 20 min, extracted with
CH2Cl2, washed with brine and dried over MgSO4. Purification of
the residue by silica gel column chromatography (EtOAc/n-hex-
ane = 1:5) to afford 10 (1.6 g, 79%). 1H NMR (CDCl3, 300 MHz): d
7.88 (d, 1H, J = 1.8 Hz), 7.37 (dd, 1H, J = 1.8, 8.4 Hz), 6.68 (d, 1H,
J= 8.4 Hz), 4.59 (br s, 2H).
4.1.40. N-[4-(Aminomethyl)-2-vinylphenyl]methane
sulfonamide ammonium salt (18)
The compound was prepared from 16 by the procedure for the
synthesis of 4a in 99% yield; white solid, which was directly used
for the next step.
4.1.33. 4-(Aminomethyl)-2-iodoaniline ammonium salt (11)
The compound was prepared from 10 by the procedure for the
synthesis of 2a in 99% yield; white solid, which was directly used
for the next step.
4.1.41. N-[4-(Aminomethyl)-2-ethylphenyl]methane
sulfonamide ammonium salt (19)
The compound was prepared from 17 by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
4.1.34. tert-Butyl 4-amino-3-iodobenzylcarbamate (12)
The compound was prepared from 11 by the procedure for the
synthesis of 3a in 83% yield; white solid. 1H NMR (CDCl3,
300 MHz): d 7.52 (d, 1H, J = 1.7 Hz), 7.04 (d, 1H, J = 8.0 Hz), 6.67
(d, 1H, J= 8.0 Hz), 4.73 (br s, 1H), 4.12 (d, 2H, J = 5.5 Hz), 4.05 (br
s, 2H), 1.43 (s, 9H).
4.1.42. 4-Amino-3-fluorobenzonitrile (20)
The compound was prepared from 5a by the procedure for the
synthesis of 7a in 80% yield as a white solid. 1H NMR (CDCl3,
300 MHz): d 7.21–7.26 (m, 2H), 6.74 (t, 1H, J = 8.3 Hz), 4.20 (br s,
2H).
4.1.35. tert-Butyl 3-iodo-4-(methylsulfonamido)benzylcarbamate
(13)
4.1.43. 4-Amino-3-fluoro-5-iodobenzonitrile (21)
To a solution of benzonitrile 20 (4.1 g, 30.0 mmol) in CH2Cl2
(100 mL) was added ICl (1 M solution in CH2Cl2, 40 mL, 40.0 mmol)
dropwise. The reaction mixture was stirred at room temperature
for 20 h, then quenched by addition of saturated aq Na2S2O3 fol-
lowed by dilution 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 column chromatography (EtOAc/
n-hexane = 1:5) to afford 21 (3.4 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).
The compound was prepared from 12 by the procedure for the
synthesis of 3a in 93% yield; white solid. 1H NMR (CDCl3,
300 MHz): d 7.72 (d, 1H, J = 1.8 Hz), 7.57 (d, 1H, J = 8.3 Hz), 7.26
(dd, 1H, J = 1.8, 8.3 Hz), 6.57 (br s, 1H), 4.88 (br s, 1H), 4.24 (d,
2H, J = 5.9 Hz), 2.97 (s, 3H), 1.44 (s, 9H).
4.1.36. N-[4-(Aminomethyl)-2-iodophenyl]methanesulfonamide
ammonium salt (14)
The compound was prepared from 13 by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
4.1.44. tert-Butyl 4-amino-3-fluoro-5-iodobenzylcarbamate
(22)
The compound was prepared from 21 by the procedure for the
synthesis of 2a and 3a in 80% yield as a white solid. 1H NMR (CDCl3,
300 MHz): d 7.30 (s, 1H), 6.91 (d, 1H, J = 11.0 Hz), 4.76 (br s, 1H),
4.13 (d, 2H, J = 4.6 Hz), 1.44 (s, 9H).
4.1.37. N-[4-(Aminomethyl)-2-cyanophenyl]methanesulfonamide
ammonium salt (15)
The compound was prepared from 13 by the procedure for the
synthesis of 7a and 4a in 72% yield as a white solid, which was di-
rectly used for the next step.
4.1.45. tert-Butyl 3-fluoro-5-iodo-4-(methylsulfonamido)-
benzylcarbamate (23)
4.1.38. tert-Butyl 4-(methylsulfonamido)-3-vinylbenzylcarbamate
(16)
To a solution of 13 (1.0 g, 2.3 mmol) in toluene (20 mL) were
added tributylvinyltin (830 lL, 2.8 mmol) and Pd(PPh3)4 (140 mg,
0.12 mmol). The mixture was refluxed for 4 h followed by dilution
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-hexane = 1:2) was
conducted to afford 16 (740 mg, 97%). 1H NMR (CDCl3, 300 MHz):
d 7.41 (d, 1H, J = 8.2 Hz), 7.38 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H,
J = 1.8, 8.3 Hz), 6.87 (dd, 1H, J = 11.0, 17.0 Hz), 6.32 (br s, 1H),
5.71 (dd, 1H, J = 0.9, 17.0 Hz), 5.46 (dd, 1H, J = 0.9, 11.0 Hz), 4.86
(br s, 1H), 4.29 (d, 2H, J = 5.9 Hz), 2.96 (s, 3H), 1.44 (s, 9H).
The compound was prepared from 22 by the procedure for
the synthesis of 3a in 36% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.56 (s, 1H), 7.08 (d, 1H, J = 10.0 Hz), 6.12
(s, 1H), 4.92 (br s, 1H), 4.24 (d, 2H, J = 5.9 Hz), 3.23 (s, 3H),
1.44 (s, 9H).
4.1.46. tert-Butyl 3-cyano-5-fluoro-4-(methylsulfonamido)-
benzylcarbamate (24)
To a solution of benzylcarbamate 23 (156 mg, 0.35 mmol) in
DMF (3 mL) were 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 diluted
with EtOAc. A diluted solution was washed with water (2Â) and
brine, and then dried over MgSO4. The residue was purified by sil-
ica gel column chromatography (EtOAc/n-hexane = 1:3) to afford
24 as a solid (76 mg, 63%).1H NMR (CDCl3, 300 MHz): 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).
4.1.39. tert-Butyl 3-ethyl-4-(methylsulfonamido)benzylcarbamate
(17)
To
a solution of tert-butyl 4-(methylsulfonamido)-3-vinyl-
benzylcarbamate 16 (350 mg, 1.1 mmol) in THF was added cat-
alytic amount of 10% palladium on activated carbon under H2

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F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
4.1.47. tert-Butyl 3-fluoro-4-(methylsulfonamido)-5-
[(trimethylsilyl)ethynyl]benzylcarbamate (25)
4.1.53. N-[4-(Aminomethyl)-2-cyclopropyl-6-fluorophenyl]met-
hanesulfonamide ammonium salt (31)
To a solution of benzylcarbamate 23 (130 mg, 0.29 mmol) in
THF (10 mL) were added CuI (2.8 mg, 0.01 mmol), (PPh3)2PdCl2
The compound was prepared from 27 by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
(10 mg, 0.01 mmol), trimethylsilyl acetylene (62
lL, 0.44 mmol)
and Et3N (122 L, 0.88 mmol). A reaction mixture was heated to
l
70 °C, stirred for 3 h, cooled to room temperature, and was diluted
with EtOAc. A diluted solution was washed with water and brine,
and then dried over MgSO4. The residue was purified by column
chromatography (EtOAc/n-hexane = 1:2) to afford 25 as a solid
(102 mg, 84%).1H NMR (CDCl3, 300 MHz): d 7.18 (s, 1H), 7.08 (d,
1H, J = 10.8 Hz), 6.40 (s, 1H), 4.90 (br s, 1H), 4.23 (d, 2H,
J = 5.9 Hz), 3.21 (s, 3H), 1.44 (s, 9H), 0.25 (s, 9H).
4.2. General procedure for coupling to amides (34a–35r)
To a solution of 4-tert-butylbenzaldehyde 32 (1.0 mmol) in pyr-
idine (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 completion of the reaction,
the resulting mixture was acidified with 2 N HCl and then ex-
tracted with EtOAc. The combined organic phases were washed
with water and brine, dried over MgSO4, concentrated in vacuo
to give (E)-3-(4-tert-butylphenyl)acrylic acid 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
(s, 9H).
To a solution of (E)-3-(4-tert-butylphenyl)acrylic acid in THF
was added a catalytic amount of 10% palladium on activated car-
bon under H2 gas followed by stirring for 1 h at room temperature.
The resulting mixture was diluted with Et2O, filtered through Cel-
ite pad, and then concentrated in vacuo to give 3-(4-tert-butyl-
phenyl) propanoic acid 33, which was directly used for the next
step. 1H NMR (CDCl3, 300 MHz): d 7.31 (d, 2H, J = 8.3 Hz), 7.14 (d,
2H, J = 8.3 Hz), 2.95 (t, 2H, J = 7.9 Hz), 2.69 (t, 2H, J = 7.9 Hz), 1.29
(s, 9H).
4.1.48. tert-Butyl 3-fluoro-4-(methylsulfonamido)-5-
vinylbenzylcarbamate (26)
The compound was prepared from 23 by the procedure for the
synthesis of 16 in 69% yield as a white solid. 1H NMR (CDCl3,
300 MHz): d 7.29 (s, 1H), 7.13 (dd, 1H, J = 18.0, 11.0 Hz), 6.98 (dd,
1H, J = 1.8, 10.0 Hz), 6.34 (br s, 1H), 5.75 (d, 1H, J = 18.0 Hz), 5.41
(d, 1H, J = 11.0 Hz), 4.99 (br s, 1H), 4.27 (d, 2H, J = 6.1 Hz), 3.03
(d, 3H, J = 1.1 Hz), 1.44 (s, 9H).
4.1.49. tert-Butyl 3-cyclopropyl-5-fluoro-4-(methylsulfonamido)
benzylcarbamate (27)
To a solution of vinylbenzylcarbamate 26 (50 mg, 0.15 mmol) in
CH2Cl2 (2 mL) were added diethylzinc (440
lL, 0.44 mmol) and
diiodomethane (60 L, 0.73 mmol) at 0 °C. The reaction mixture
l
was stirred for 48 h at 40 °C, cooled to room temperature, then
quenched by addition of saturated aqueous NaHCO3 followed by
dilution with EtOAc. A diluted solution was washed with water
and brine, and then dried with MgSO4. The residue was purified
by column chromatography (EtOAc/n-hexane = 1:2) to afford ben-
zylcarbamate 27 (52 mg, 99%).1H NMR (CDCl3, 300 MHz): d 6.89 (d,
1H, J = 13.0 Hz), 6.63 (s, 1H), 6.00 (s, 1H), 4.85 (br s, 1H), 4.22 (d,
2H, J = 6.2 Hz), 3.14 (d, 3H, J = 1.1 Hz), 2.26 (m, 1H), 1.44 (s, 9H),
1.03–1.07 (m, 2H), 0.65–0.69 (m, 2H).
To a solution of acid 33 (1.0 mmol) in the THF were added 4-
(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlo-
ride (DMTMM) (1.5 mmol), NNM (1.0 mmol) and Et3N (2.0 mmol).
The reaction mixture was stirred for 4 h, and then benzylammoni-
um salt (1.2 mmol) was added. The mixture was stirred for 10 h at
room temperature. The reaction mixture was concentrated in va-
cuo. The residue was extracted with CH2Cl2. A combined organic
layer was washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel using CH2Cl2/MeOH as eluent.
To a solution of amide (1.0 mmol) in toluene was added Lawes-
son’s reagent (2.0 mmol). The reaction mixture was refluxed for
5 h. After cooling to ambient temperature followed by dilution
with EtOAc, the organic layer was washed with water and brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel using
EtOAC/n-hexane as eluent.
4.1.50. N-[4-(Aminomethyl)-2-cyano-6-fluorophenyl]methane-
sulfonamide ammonium salt (28)
The compound was prepared from 24 by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
4.1.51. N-[4-(Aminomethyl)-2-ethynyl-6-fluorophenyl]methane-
sulfonamide ammonium salt (29)
To a solution of benzylcarbamate 25 (102 mg, 0.25 mmol) in THF/
H2O (2:1, 10 mL) was added NaOH (49 mg, 1.2 mmol). The reaction
mixture was stirred at room temperature for 2.5 h, then diluted with
EtOAc. 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 = 1:1) to
afford tert-butyl 3-ethynyl-5-fluoro-4-(methylsulfonamido) ben-
zylcarbamate (60 mg, 71%). 1H NMR (CDCl3, 300 MHz): d 7.23 (br s,
1H), 7.10 (d, 1H, J = 10.8 Hz), 6.37 (s, 1H), 4.90 (br s, 1H), 4.24 (d,
2H, J = 6.2 Hz), 3.45 (s, 1H), 3.23 (s, 3H), 1.44 (s, 9H).
4.2.1. 3-(4-tert-Butylphenyl)-N-[3-fluoro-4-(methylsulfonamido)
benzyl]propanamide (34a)
The compound was prepared from 8a by the general procedure
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), 1.29 (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;
LRMS (FAB+): m/z 407 (M+H+); HRMS (FAB+) calcd for
C21H28FN2O3S (M+H+): 407.1805, found 407.1802.
The compound 29 was prepared from tert-butyl 3-ethynyl-5-
fluoro-4-(methylsulfonamido)benzylcarbamate by the procedure
for the synthesis of 4a in 100% yield; white solid, which was
directly used for the next step.
4.2.2. 3-(4-tert-Butylphenyl)-N-[3-chloro-4-(methylsulfonamido)
benzyl]propanamide (34b)
4.1.52. N-[4-(Aminomethyl)-2-fluoro-6-vinylphenyl]methane-
sulfonamide ammonium salt (30)
The compound was prepared from 26 by the procedure for the
synthesis of 4a in 100% yield; white solid, which was directly used
for the next step.
The compound was prepared from 8b by the general procedure
for the synthesis of amides in 90% yield as a white solid. 1H NMR
(CDCl3, 500 MHz): d 7.53 (d, 1H, J = 8.4 Hz), 7.28–7.29 (m, 3H),
7.10 (d, 2H, J = 8.2 Hz), 7.07 (dd, 1H, J = 1.7, 1.7 Hz), 6.74 (br s,
1H), 4.34 (d, 2H, J = 6.0 Hz), 2.97 (s, 3H), 2.94 (t, 2H, J = 7.6 Hz),

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
8157
2.51 (t, 2H, J = 7.6 Hz), 1.28 (s, 9H); 13C NMR (CDCl3, 125 MHz): d
4.2.8. 3-(4-tert-Butylphenyl)-N-[3-ethyl-4-(methylsulfonamido)
benzyl]propanamide (34h)
172.3, 149.2, 137.4, 137.1, 132.6, 128.8, 128.0, 127.4, 125.5,
125.2, 122.6, 42.4, 39.9, 38.3, 34.4, 31.3, 31.0; IR (neat) cmÀ1
:
The compound was prepared from 19 by the general procedure
3264, 2955, 1649, 1515, 1452, 1332, 1154; LRMS (FAB+): m/z 423
(M+H+); HRMS (FAB+) calcd for C21H28ClN2O3S (M+H+): 423.1509,
found 423.1512.
for the synthesis of amides in 51% yield as a white solid. 1H NMR
(CDCl3, 300 MHz):
d 7.36 (d, 1H, J = 8.0 Hz), 7.28 (d, 2H,
J = 7.9 Hz), 7.11 (d, 3H, J = 7.9 Hz), 7.01 (d, 1H, J = 8.1 Hz), 6.34 (s,
1H), 5.71 (br s, 1H), 4.35 (d, 2H, J = 5.7 Hz), 2.98 (s, 3H), 2.94 (t,
2H, J = 8.1 Hz), 2.62 (t, 2H, J = 7.5 Hz), 2.50 (t, 2H, J = 7.8 Hz), 1.28
(s, 9H), 1.20 (t, 3H, J = 7.5 Hz); IR (neat) cmÀ1: 3296, 2962, 1649,
1541, 1489, 1323, 1153; LRMS (FAB+): m/z 417 (M+H+).
4.2.3. 3-(4-tert-Butylphenyl)-N-[2-chloro-4-(methylsulfonamido)
benzyl]propanamide (34c)
The compound was prepared from 4c by the general procedure
for the synthesis of amides in 83% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.20–7.29 (m, 4H), 7.09 (d, 2H, J = 8.2 Hz),
6.98 (dd, 1H, J = 8.2, 2.2 Hz), 6.81 (br s, 1H), 5.82 (br s, 1H),
4.42 (d, 2H, J = 6.0 Hz), 2.99 (s, 3H), 2.92 (t, 2H, J = 7.6 Hz), 2.51
(t, 2H, J = 7.6 Hz), 1.28 (s, 9H); IR (neat) cmÀ1: 3357, 2958,
1667, 1550, 1484, 1314, 1146, 617; LRMS (FAB+): m/z 423
(M+H+).
4.2.9. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfonamido)-3-vin-
ylbenzyl]propanamide (34i)
The compound was prepared from 18 by the general procedure
for the synthesis of amides in 73% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.25–7.41 (m, 4H), 7.09–7.14 (m, 3H), 6.84
(dd, 1H, J = 17.0, 11.0 Hz), 6.23 (br s, 1H), 5.69 (d, 1H, J = 18.0 Hz),
5.62 (br s, 1H), 5.47 (d, 1H, J = 11.0 Hz), 4.38 (d, 2H, J = 5.9 Hz),
2.99 (s, 3H), 2.92–2.97 (m, 2H), 2.51 (t, 2H, J = 7.6 Hz), 1.28 (s,
9H); 13C NMR (CDCl3, 100 MHz): d 172.1, 137.6, 136.8, 132.4,
131.3, 128.3, 128.0, 126.8, 125.8, 125.4, 118.8, 64.0, 43.0, 40.1,
38.4, 34.4, 31.3, 31.1; IR (neat) cmÀ1: 3295, 2960, 1648, 1541,
1324, 1152; LRMS (FAB+): m/z 415 (M+H+); HRMS (FAB+) calcd
for C23H31N2O3S (M+H+): 415.2055, found 415.2048.
4.2.4. 3-(4-tert-Butylphenyl)-N-[3-iodo-4-(methylsulfonamido)
benzyl]propanamide (34d)
The compound was prepared from 14 by the general procedure
for the synthesis of amides in 58% yield as a white solid. 1H NMR
(CDCl3, 300 MHz):
d 7.65 (d, 1H, J = 1.8 Hz), 7.46 (d, 1H,
J = 8.4 Hz), 7.17–7.28 (m, 2H), 7.06–7.12 (m, 3H), 6.63 (s, 1H),
5.98 (br s, 1H), 4.28 (d, 2H, J = 5.9 Hz), 2.92 (s, 3H), 2.90 (t, 2H,
J = 7.9 Hz), 2.48 (t, 2H, J = 7.7 Hz), 1.29 (s, 9H); IR (neat) cmÀ1
:
4.2.10. 3-(4-tert-Butylphenyl)-N-[3-cyano-4-(methylsulfonamido)
benzyl]propanamide (34j)
3300, 2960, 1650, 1542, 1485, 1366, 1155; LRMS (FAB+): m/z 515
(M+H+).
The compound was prepared from 15 by the general procedure
for the synthesis of amides in 80% yield as a white solid. 1H NMR
4.2.5. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfonamido)-2-(tri-
fluoromethyl)benzyl]propanamide (34e)
(CDCl3, 300 MHz): d 7.62 (d, 1H, J = 8.6 Hz), 7.47 (d, 1H,
J = 2.0 Hz), 7.40 (d, 1H, J = 8.6 Hz), 7.30 (d, 2H, J = 8.3 Hz), 7.11 (d,
2H, J = 8.3 Hz), 6.85 (s, 1H), 5.72 (br s, 1H), 4.37 (d, 2H,
J = 6.0 Hz), 3.08 (s, 3H), 2.95 (t, 2H, J = 7.5 Hz), 2.53 (t, 2H,
J = 7.5 Hz), 1.29 (s, 9H); IR (neat) cmÀ1: 3397, 2960, 2222, 1649,
1539, 1334, 1155; LRMS (FAB+): m/z 414 (M+H+).
The compound was prepared from 4d by the general proce-
dure for the synthesis of amides in 80% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.42–7.43 (m, 2H), 7.25–7.32 (m,
3H), 7.18 (d, 2H, J = 8.3 Hz), 6.63 (s, 1H), 5.68 (br s, 1H), 4.51 (d,
2H, J = 5.9 Hz), 3.02 (s, 1H), 2.93 (t, 2H, J = 7.6 Hz), 2.50 (t, 2H,
J = 7.6 Hz), 1.28 (s, 9H); 13C NMR (CDCl3, 75 MHz): d 172.6,
149.3, 137.3, 136.5, 133.1, 132.2, 127.9, 125.5, 123.6, 117.8,
55.9, 39.9, 38.3, 34.4, 31.3, 31.0; IR (neat) cmÀ1: 2961, 1651,
1543, 1473, 1367, 1316, 1156, 1054, 972, 759; LRMS (FAB+): m/
z 457 (M+H+).
4.2.11. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfonamido)-3-
nitrobenzyl]propanamide (34k)
The compound was prepared from 4b by the general procedure
for the synthesis of amides in 38% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 9.65 (br s, 1H), 8.08 (s, 1H), 7.80 (d, 1H,
J = 8.5 Hz), 7.47 (d, 1H, J = 8.5 Hz), 7.28 (d, 2H, J = 8.3 Hz), 7.10 (d,
2H, J = 8.3 Hz), 5.74 (br s, 1H), 4.40 (d, 2H, J = 6.1 Hz), 3.10 (s, 3H),
2.94 (t, 2H, J = 7.6 Hz), 2.53 (t, 2H, J = 7.3 Hz), 1.28 (s, 9H); IR (neat)
cmÀ1: 3288, 2961, 1649, 1536, 1345; LRMS (EI): m/z 433 (M+).
4.2.6. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfonamido)-3-(tri-
fluoromethyl)benzyl]propanamide (34f)
The compound was prepared from 4a by the general proce-
dure for the synthesis of amides in 54% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.73 (m, 1H), 7.53 (m, 1H), 7.35
(m, 1H), 7.26–7.30 (m, 2H), 7.10 (d, 2H, J = 6.6 Hz), 6.65 (br s,
1H), 5.83 (br s, 1H), 4.40 (d, 2H, J = 6.1 Hz), 2.96 (s, 3H), 2.94 (d,
2H, J = 5.9 Hz), 2.54 (t, 2H, J = 3.9 Hz), 1.27 (s, 9H); IR (neat) cm
À1: 2959, 1541, 1471, 1366, 1316, 1133, 753; LRMS (EI): m/z
456 (M).
4.2.12. Methyl 5-{[3-(4-tert-butylphenyl)propanamido]methyl}-
2-(methylsulfonamido)benzoate (34l)
The compound was prepared from 8d by the general procedure
for the synthesis of amides in 43% yield as a white solid. 1H NMR
(CDCl3, 300 MHz):
d 7.93 (d, 1H, J = 2.2 Hz), 7.67 (d, 1H,
J = 8.6 Hz), 7.37 (dd, 1H, J = 8.6, 2.2 Hz), 7.29 (d, 2H, J = 8.4 Hz),
7.37 (d, 2H, J = 8.3 Hz), 5.67 (br s, 1H), 4.37 (d, 2H, J = 5.9 Hz),
3.91 (s, 3H), 3.02 (s, 3H), 2.98 (t, 2H, J = 7.3 Hz), 2.53 (t, 2H,
J = 8.1 Hz), 1.29 (s, 9H); IR (neat) cmÀ1: 2926, 1687, 1264, 1157,
794; LRMS (EI): m/z 446 (M+).
4.2.7. 3-(4-tert-Butylphenyl)-N-[3-methyl-4-(methylsulfonamido)
benzyl]propanamide (34g)
The compound was prepared from 8c by the general procedure
for the synthesis of amides in 44% yield as a white solid. 1H NMR
(CDCl3, 300 MHz):
d
7.36 (d, 1H, J = 8.0 Hz), 7.30 (d, 2H,
4.2.13. 3-(4-tert-Butylphenyl)-N-[3,5-dimethyl-4-(methylsulfona-
mido)benzyl]propanamide (34m)
J = 8.3 Hz), 7.08–7.13 (m, 3H), 7.03 (d, 1H, J = 8.3 Hz), 6.20 (br s,
1H), 5.62 (br s, 1H), 4.35 (d, 2H, J = 5.7 Hz), 2.98 (s, 3H), 2.97 (t,
2H, J = 7.7 Hz), 2.52 (t, 2H, J = 7.7 Hz), 2.27 (s, 3H), 1.28 (s, 9H);
13C NMR (CDCl3, 75 MHz): d 172.1, 149.2, 137.6, 136.3, 133.9,
130.8, 130.7, 128.0, 126.6, 125.4, 123.1, 43.0, 40.0, 38.4, 34.4,
31.4, 31.1; IR (neat) cmÀ1: 2961, 1644, 1322, 1153; LRMS (FAB+):
m/z 403 (M+H+); HRMS (FAB+) calcd for C22H31N2O3S (M+H+):
403.2055, found 403.2056.
The compound was prepared from 8e by the general procedure
for the synthesis of amides in 51% yield as a white solid. 1H NMR
(CDCl3, 300 MHz):
d 7.29 (d, 2H, J = 8.3 Hz), 7.10 (d, 2H,
J = 8.3 Hz), 6.91 (s, 2H), 5.88 (br s, 1H), 5.65 (br s, 1H), 4.28 (d,
2H, J = 5.7 Hz), 3.03 (s, 3H), 2.94 (t, 2H, J = 7.7 Hz), 2.49 (t, 2H,
J = 7.7 Hz), 2.33 (s, 6H), 1.25 (s, 9H); IR (neat) cmÀ1: 3272, 2961,
1648, 1539, 1316, 1145; LRMS (EI): m/z 416 (M+).

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F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
4.2.14. 3-(4-tert-Butylphenyl)-N-[3-chloro-5-methyl-4-
(methylsulfonamido)benzyl]propanamide (34n)
4.2.19. 3-(4-tert-Butylphenyl)-N-[3-fluoro-4-(methyl-
sulfonamido)benzyl]propanethioamide (35a)
The compound was prepared from 4e by the general procedure
for the synthesis of amides in 35% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.28–7.31 (m, 2H), 7.11–7.16 (m, 3H), 7.04
(s, 1H), 6.07 (s, 1H), 5.68 (br s, 1H), 4.33 (d, 2H, J = 6.1 Hz), 3.06
(s, 3H), 2.95 (t, 2H, J = 7.6 Hz), 2.52 (t, 2H, J = 7.6 Hz), 2.46 (s, 3H),
1.28 (s, 9H); 13C NMR (CDCl3, 125 MHz): d 172.2, 149.2, 141.2,
139.5, 137.5, 130.5, 129.6, 128.0, 126.4, 125.5, 41.5, 38.3, 34.4,
31.4, 31.0, 20.0; IR (neat) cmÀ1: 3296, 2960, 1650, 1540, 1472,
1153, 794; LRMS (FAB+): m/z 437 (M+); HRMS (FAB+) calcd for
C22H30ClN2O3S (M+H+): 437.1666, found 437.1662.
The compound was prepared from 34a by the general procedure
for the synthesis of thioamides in 80% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.48 (t, 1H, J = 8.1 Hz), 7.30 (d, 2H, J = 8.2 Hz),
7.13 (d, 2H, J = 8.3 Hz), 6.90–6.97 (m, 2H), 6.57 (br s, 1H), 4.71 (d,
2H, J = 5.3 Hz), 3.11 (t, 2H, J = 7.1 Hz), 2.99 (s, 3H), 2.97 (t, 2H,
J = 7.1 Hz), 1.27 (s, 9H); 13C NMR (CDCl3, 125 MHz): d 205.1, 154.9,
153.0, 149.4, 136.9, 135.3, 135.2, 128.1, 125.4, 123.6, 115.6, 115.4,
48.8, 48.6, 39.9, 34.8, 34.3, 31.3; IR (neat) cmÀ1: 3255, 2961, 1590,
1513, 1445, 1402; LRMS (FAB+): m/z 423 (M+); HRMS (FAB+) calcd
for C21H28FN2O2S2 (M+H+): 423.1576, found 423.1574.
4.2.15. 3-(4-tert-Butylphenyl)-N-[3-fluoro-4-(methyl-
sulfonamido)-5-vinylbenzyl]propanamide (34o)
4.2.20. 3-(4-tert-Butylphenyl)-N-[3-chloro-4-(methyl-
sulfonamido)benzyl]propanethioamide (35b)
The compound was prepared from 30 by the general procedure
for the synthesis of amides in 63% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.22–7.32 (m, 3H), 7.08–7.18 (m, 3H), 6.92
(d, 1H, J = 10.0 Hz), 5.92 (br s, 1H), 5.76 (d, 1H, J = 17.0 Hz), 5.69
(br s, 1H), 5.44 (d, 1H, J = 11.0 Hz), 4.39 (d, 2H, J = 6.0 Hz), 3.05 (s,
3H), 2.96 (t, 2H, J = 7.6 Hz), 2.52 (t, 2H, J = 7.6 Hz), 1.28 (s, 9H);
13C NMR (CDCl3, 100 MHz): d 174.1, 149.2, 139.4, 137.5, 131.6,
128.0, 125.5, 121.0, 118.0, 114.2, 114.0, 42.9, 40.9, 40.8, 38.3,
34.8, 31.3, 31.0; IR (neat) cmÀ1: 3233, 2922, 1646, 1540, 1317,
1151; LRMS (FAB+): m/z 433 (M+); HRMS (FAB+) calcd for
C23H30FN2O3S (M+H+): 433.1961, found 433.1954.
The compound was prepared from 34b by the general proce-
dure for the synthesis of thioamides in 70% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.57 (d, 1H, J = 8.4 Hz), 7.26–7.30
(m, 3H), 7.12 (d, 2H, J = 8.3 Hz), 7.06 (dd, 1H, J = 8.4, 2.0 Hz), 6.75
(br s, 1H), 4.71 (d, 2H, J = 5.3 Hz), 3.11 (t, 2H, J = 6.6 Hz), 2.99 (s,
3H), 2.98 (t, 2H, J = 6.8 Hz), 1.27 (s, 9H); 13C NMR (CDCl3,
100 MHz): d 205.1, 149.5, 136.9, 134.5, 133.2, 129.4, 128.1, 128.0,
125.5, 125.0, 122.3, 48.9, 48.7, 40.0, 34.9, 34.4, 31.4; IR (neat) cm
À1: 3307, 2960, 1499, 1390, 1329, 1158; LRMS (FAB+): m/z 439
(M+H+); HRMS (FAB+) calcd for C21H28ClN2O2S2 (M+H+):
439.1281, found 439.1269.
4.2.16. 3-(4-tert-Butylphenyl)-N-[3-acetylene -5-fluoro-4-
(methylsulfonamido)benzyl]propanamide (34p)
4.2.21. 3-(4-tert-Butylphenyl)-N-[2-chloro-4-(methyl-
sulfonamido)benzyl]propanethioamide (35c)
The compound was prepared from 29 by the general procedure
for the synthesis of amides in 90% yield as a white solid. 1H NMR
(CDCl3, 300 MHz): d 7.31 (d, 1H, J = 8.2 Hz), 7.18 (s, 1H), 7.12 (d,
1H, J = 8.0 Hz), 7.02 (br s, 1H), 6.39 (s, 1H), 5.68 (br s, 1H), 4.34
(d, 2H, J = 6.1 Hz), 3.46 (s, 1H), 3.23 (s, 3H), 2.95 (t, 2H,
J = 7.5 Hz), 2.51 (t, 2H, J = 7.5 Hz), 1.28 (s, 9H); 13C NMR (CDCl3,
125 MHz): d 172.4, 149.2, 138.9, 139.8, 137.4, 128.0, 127.6, 127.5,
125.4, 120.5, 120.4, 117.0, 116.9, 84.9, 42.5, 42.4, 42.3, 38.2, 34.4,
31.3, 31.0; IR (neat) cmÀ1: 3269, 2959, 1581, 1482, 1332, 1154,
762; LRMS (FAB+): m/z 431 (M+); HRMS (FAB+) calcd for
C23H28FN2O3S (M+H+): 431.1805, found 431.1797.
The compound was prepared from 34c by the general procedure
for the synthesis of thioamides in 83% yield as a white solid. 1H
NMR (CDCl3, 300 MHz):
d 7.25–7.29 (m, 4H), 7.10 (d, 2H,
J = 8.2 Hz), 7.01 (dd, 1H, J = 2.4, 8.2 Hz), 6.87 (br s, 1H), 4.80 (d,
2H, J = 5.5 Hz), 3.06 (t, 2H, J = 6.9 Hz), 3.02 (s, 3H), 2.94 (t, 2H,
J = 6.9 Hz), 1.28 (s, 9H); IR (neat) cmÀ1: 3433, 3218, 2957, 1667,
1525, 1318, 1153, 979; LRMS (FAB+): m/z 439 (M+H+).
4.2.22. 3-(4-tert-Butylphenyl)-N-[3-iodo-4-(methyl-
sulfonamido)benzyl]propanethioamide (35d)
The compound was prepared from 34d by the general proce-
dure for the synthesis of thioamides in 71% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.70 (d, 1H, J = 1.8 Hz), 7.52 (d, 1H,
J = 8.4 Hz), 7.28 (d, 2H, J = 8.2 Hz), 7.09–7.20 (m, 4H), 6.60 (s, 1H),
4.68 (d, 2H, J = 5.3 Hz), 3.08 (t, 2H, J = 7.0 Hz), 2.98 (s, 3H), 2.95
(t, 2H, J = 7.0 Hz), 1.28 (s, 9H); IR (neat) cmÀ1: 3322, 2960, 1533,
1488, 1386, 1329; LRMS (FAB+): m/z 531 (M+H+).
4.2.17. 3-(4-tert-Butylphenyl)-N-[3-cyclopropyl-5-fluoro-4-
(methylsulfonamido)benzyl]propanamide (34q)
The compound was prepared from 31 by the general procedure
for the synthesis of amides in 87% yield as a white solid. 1H NMR
(CDCl3, 300 MHz):
d 7.30 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H,
J = 8.4 Hz), 6.80 (d, 1H, J = 10.0 Hz), 6.06 (s, 1H), 6.01 (s, 1H), 5.61
(br s, 1H), 4.32 (d, 2H, J = 5.9 Hz), 3.14 (d, 3H, J = 1.1 Hz), 3.02 (s,
3H), 2.95 (t, 2H, J = 7.7 Hz), 2.50 (t, 2H, J = 7.6 Hz), 2.24 (m, 1H),
1.28 (s, 9H), 1.02–1.08 (m, 2H), 0.62–0.68 (m, 2H); IR (neat)
cmÀ1: 3432, 2961, 1645, 1371, 1318, 1151; LRMS (FAB+): m/z
447 (M+).
4.2.23. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfonamido)-2-
(trifluoromethyl)benzyl]propanethioamide (35e)
The compound was prepared from 34e by the general proce-
dure for the synthesis of thioamides in 80% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.42–7.43 (m, 2H), 7.25–7.32 (m,
3H), 7.18 (d, 2H, J = 8.3 Hz), 6.63 (s, 1H), 5.68 (br s, 1H), 4.51 (d,
2H, J = 5.9 Hz), 3.02 (s, 3H), 2.93 (t, 2H, J = 7.6 Hz), 2.50 (t, 2H,
J = 7.6 Hz), 1.28 (s, 9H); 13C NMR (CDCl3, 75 MHz): d 172.6, 149.3,
137.3, 136.5, 133.1, 132.2, 127.9, 125.5, 123.6, 117.8, 55.9, 39.9,
38.3, 34.4, 31.3, 31.0; IR (neat) cmÀ1: 2961, 1651, 1543, 1473,
1367, 1316, 1156, 1054, 972, 759; LRMS (FAB+): m/z 457 (M+H+).
4.2.18. 3-(4-tert-Butylphenyl)-N-[3-cyano-5-fluoro-4-
(methylsulfonamido)benzyl]propanamide (34r)
The compound was prepared from 28 by the general proce-
dure for the synthesis of amides in 39% yield 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) cmÀ1: 3432, 2960, 2499, 2222, 1641, 1429, 1328, 1278;
LRMS (FAB+): m/z 432 (M+); HRMS (FAB+) calcd for
C22H27FN3O3S (M+H+): 432.1757, found 432.1762.
4.2.24. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfon amido)-3-
(trifluoromethyl)benzyl]propanethioamide (35f)
The compound was prepared from 34f by the general procedure
for the synthesis of thioamides in 54% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.73 (m, 1H), 7.55 (m, 1H), 7.35 (m,
1H), 7.26–7.30 (m, 2H), 7.10 (d, 2H, J = 6.6 Hz), 6.66 (br s, 1H),
5.83 (br s, 1H), 4.40 (d, 2H, J = 6.1 Hz), 2.96 (s, 3H), 2.93 (t, 2H,

F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
8159
J = 5.9 Hz), 2.54 (t, 2H, J = 5.9 Hz), 1.27 (s, 9H); IR (neat) cmÀ1
2959, 1541, 1471, 1366, 1316, 1133, 753; LRMS (EI): m/z 456 (M).
:
3H), 3.11 (t, 2H, J = 7.1 Hz), 2.98 (t, 2H, J = 6.6 Hz), 1.27 (s, 9H);
13C NMR (CDCl3, 75 MHz): d 205.9, 149.6, 136.9, 135.9, 133.7,
132.3, 128.1, 125.8, 125.5, 119.8, 48.7, 47.9, 40.9, 34.9, 34.4, 31.3;
IR (neat) cmÀ1: 3293, 2960, 1623, 1534, 1389, 1344; LRMS
(FAB+): m/z 450 (M+); HRMS (FAB+) calcd for C21H28N3O4S2
(M+H+): 450.1521, found 450.1532.
4.2.25. 3-(4-tert-Butylphenyl)-N-[3-methyl-4-(methyl-
sulfonamido)benzyl]propanethioamide (35g)
The compound was prepared from 34g by the general proce-
dure for the synthesis of thioamides in 77% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.37 (d, 1H, J = 8.3 Hz), 7.30 (d, 2H,
J = 8.3 Hz), 7.09–7.13 (m, 3H), 6.99 (dd, 1H, J = 8.1, 1.9 Hz), 6.23
(br s, 1H), 4.67 (d, 2H, J = 5.1 Hz), 3.10 (t, 2H, J = 7.2 Hz), 3.00 (s,
3H), 2.95 (t, 2H, J = 7.1 Hz), 2.27 (s, 3H), 1.28 (s, 9H); 13C NMR
(CDCl3, 75 MHz): d 204.6, 149.4, 137.1, 134.5, 133.9, 131.2, 130.8,
128.1, 127.1, 125.5, 123.0, 49.6, 48.9, 40.2, 34.9, 34.4, 31.4, 18.0;
IR (neat) cmÀ1: 3293, 2960, 1505, 1396, 1322, 1153; LRMS
(FAB+): m/z 419 (M+H+); HRMS (FAB+) calcd for C22H31N2O2S2
(M+H+): 419.1827, found 419.1830.
4.2.30. Methyl 5-{[3-(4-tert-butylphenyl)propanethioamido]-
methyl}-2-(methylsulfonamido)benzoate (35l)
The compound was prepared from 34l by the general procedure
for the synthesis of thioamides in 91% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.95 (d, 1H, J = 2.0 Hz), 7.67 (d, 1H,
J = 8.4 Hz), 7.33 (dd, 1H, J = 8.6, 2.2 Hz), 7.28 (d, 2H, J = 8.2 Hz),
7.12 (d, 2H, J = 8.2 Hz), 4.73 (d, 2H, J = 5.1 Hz), 3.92 (s, 3H), 3.10
(t, 2H, J = 7.0 Hz), 3.03 (s, 3H), 2.97 (t, 2H, J = 7.5 Hz), 1.27 (s, 9H);
IR (neat) cmÀ1: 3211, 2959, 1689, 1585, 1503, 1398; LRMS
(FAB+): m/z 463 (M+).
4.2.26. 3-(4-tert-Butylphenyl)-N-[3-ethyl-4-(methyl-
sulfonamido)benzyl]propanethioamide (35h)
4.2.31. 3-(4-tert-Butylphenyl)-N-[3,5-dimethyl-4-(methyl-
sulfonamido)benzyl]propanethioamide (35m)
The compound was prepared from 34h by the general proce-
dure for the synthesis of thioamides in 74% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.32 (d, 1H, J = 8.2 Hz), 7.23 (d, 2H,
J = 8.2 Hz), 7.05–7.08 (m, 4H), 6.93 (dd, 1H, J = 2.0, 8.3 Hz), 6.26
(s, 1H), 4.64 (d, 2H, J = 5.0 Hz), 3.03 (t, 2H, J = 7.4 Hz), 2.94 (s,
3H), 2.78 (t, 2H, J = 7.3 Hz), 2.57 (q, 2H, J = 7.5 Hz), 1.23 (s, 9H),
1.16 (t, 3H, J = 7.5 Hz); IR (neat) cmÀ1: 3301, 2962, 1504, 1489,
1397, 1323, 1153; LRMS (FAB+): m/z 433 (M+H+).
The compound was prepared from 34m by the general proce-
dure for the synthesis of thioamides in 75% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.29 (d, 2H, J = 8.2 Hz), 7.13 (d, 2H,
J = 8.4 Hz), 6.96 (s, 2H), 5.75 (br s, 1H), 4.65 (d, 2H, J = 5.1 Hz),
3.10 (t, 2H, J = 7.3 Hz), 3.09 (s, 3H), 2.95 (t, 2H, J = 7.3 Hz), 2.38 (s,
6H), 1.27 (s, 9H); IR (neat) cmÀ1: 3182, 2920, 1646, 1517, 1401,
1306; LRMS (FAB+): m/z 433 (M+).
4.2.27. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfonamido)-3-
vinylbenzyl]propanethioamide (35i)
4.2.32. 3-(4-tert-Butylphenyl)-N-[3-chloro-5-methyl-4-
(methylsulfonamido)benzyl]propanethioamide (35n)
The compound was prepared from 34i by the general procedure
for the synthesis of thioamides in 63% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.38 (d, 1H, J = 8.3 Hz), 7.36 (d, 1H,
J = 2.0 Hz), 7.27 (d, 2H, J = 8.3 Hz), 7.14 (br s, 1H), 7.11 (d, 2H,
J = 8.3 Hz), 7.05 (dd, 1H, J = 2.0, 8.2 Hz), 6.84 (dd, 1H, J = 11.0,
17.4 Hz), 6.36 (s, 1H), 5.70 (d, 1H, J = 18.1 Hz), 5.48 (d, 1H,
J = 11.7 Hz), 4.72 (d, 2H, J = 5.1 Hz), 3.08 (t, 2H, J = 7.2 Hz), 2.98 (s,
3H), 2.94 (t, 2H, J = 7.1 Hz), 1.27 (s, 9H); 13C NMR (CDCl3,
75 MHz): d 204.8, 149.4, 137.0, 134.5, 133.0, 132.4, 131.1, 128.7,
128.1, 127.4, 125.5, 124.4, 119.6, 49.6, 48.9, 40.2, 34.9, 34.4, 31.4,
29.7; IR (neat) cmÀ1: 3299, 3020, 2962, 2920, 1497, 1397, 1326;
LRMS (EI): m/z 430 (M+); HRMS (FAB+) calcd for C23H31N2O2S2
(M+H+): 431.1827, found 431.1820.
The compound was prepared from 34n by the general proce-
dure for the synthesis of thioamides in 56% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.27–7.32 (m, 2H), 7.11–7.16 (m, 3H),
7.05 (br s, 1H), 6.03 (br s, 1H), 4.73 (d, 2H, J = 5.1 Hz), 3.08 (s, 3H),
2.96 (t, 2H, J = 7.3 Hz), 2.49 (t, 2H, J = 7.3 Hz), 2.03 (s, 3H), 1.29 (s,
9H); 13C NMR (CDCl3, 100 MHz): d 205.6, 181.9, 135.7, 134.5,
130.1, 128.1, 128.0, 126.9, 126.4, 125.5, 110.0, 48.6, 41.7, 41.5,
34.9, 34.4, 31.4, 30.9; IR (neat) cmÀ1: 3248, 2960, 1650, 1536,
1323, 1153; LRMS (FAB+): m/z 453 (M+); HRMS (FAB+) calcd for
C22H30ClN2O2S2 (M+H+): 453.1437, found 453.1441.
4.2.33. 3-(4-tert-Butylphenyl)-N-[3-fluoro-4-(methylsulfon-
amido)-5-vinylbenzyl]propanethioamide (35o)
The compound was prepared from 34o by the general proce-
dure for the synthesis of thioamides in 83% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.26–7.28 (m, 4H), 7.07–7.16 (m, 3H),
6.89 (dd, 1H, J = 6.0, 9.9 Hz), 5.99 (s, 1H), 5.76 (d, 1H, J = 17.5 Hz),
5.45 (d, 1H, J = 11.1 Hz), 4.74 (d, 2H, J = 5.4 Hz), 3.09 (t, 2H,
J = 7.4 Hz), 3.06 (s, 3H), 2.95 (t, 2H, J = 7.4 Hz), 1.27 (s, 9H); 13C
NMR (CDCl3, 75 MHz): d 205.3, 149.5, 139.5, 137.0, 131.4, 131.3,
128.1, 125.5, 121.7, 118.5, 114.7, 49.2, 48.8, 48.1, 41.1, 41.0, 34.9,
34.4, 31.3; IR (neat) cmÀ1: 3305, 2961, 1578, 1533, 1445, 1398;
LRMS (FAB+): m/z 449 (M+); HRMS (FAB+) calcd for C23H30FN2O2S2
(M+H+): 449.1733, found 449.1726.
4.2.28. 3-(4-tert-Butylphenyl)-N-[3-cyano-4-(methyl-
sulfonamido)benzyl]propanethioamide (35j)
The compound was prepared from 34j by the general procedure
for the synthesis of thioamides in 65% yield as a white solid. 1H
NMR (CDCl3, 300 MHz): d 7.62 (d, 1H, J = 8.6 Hz), 7.47 (d, 1H,
J = 2.2 Hz), 7.35 (dd, 1H, J = 2.2, 8.6 Hz), 7.29 (d, 2H, J = 8.4 Hz),
7.20 (br s, 1H), 7.11 (d, 2H, J = 8.4 Hz), 6.92 (s, 1H), 4.75 (d, 2H,
J = 5.7 Hz), 3.09 (s, 3H), 3.06–3.11 (m, 2H), 2.94–2.99 (m, 2H),
1.28 (s, 9H); 13C NMR (CDCl3, 75 MHz): d 205.8, 149.6, 138.8,
136.9, 134.1, 132.3, 128.1, 125.6, 121.6, 115.6, 104.4, 64.0, 48.8,
48.1, 40.8, 38.4, 34.8, 34.4, 31.4; IR (neat) cmÀ1: 3311, 2959,
2222, 1534, 1500, 1418, 1336, 1158; LRMS (FAB+): m/z 430
(M+H+); HRMS (FAB+) calcd for C22H28N3O2S2 (M+H+): 430.1623,
found 430.1631.
4.2.34. 3-(4-tert-Butylphenyl)-N-[3-acetylene-5-fluoro-4-
(methylsulfonamido)benzyl]propanethioamide (35p)
The compound was prepared from 34p by the general proce-
dure for the synthesis of thioamides in 41% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.30 (d, 1H, J = 8.2 Hz), 7.18 (s, 1H),
7.12 (d, 1H, J = 8.1 Hz), 7.00 (br s, 1H), 6.41 (s, 1H), 4.71 (d, 2H,
J = 5.3 Hz), 3.48 (s, 1H), 3.24 (s, 3H), 3.08 (t, 2H, J = 7.3 Hz), 2.95
(t, 2H, J = 6.9 Hz), 1.28 (s, 9H); 13C NMR (CDCl3, 75 MHz): d 205.5,
149.4, 136.9, 136.3, 136.2, 126.1, 125.5, 120.3, 117.5, 117.3, 85.4,
48.8, 48.5, 42.6, 42.5, 34.9, 34.4, 31.3; IR (neat) cmÀ1: 3270,
2959, 1581, 1482, 1332, 1154, 763; LRMS (FAB+): m/z 447 (M +);
4.2.29. 3-(4-tert-Butylphenyl)-N-[4-(methylsulfonamido)-3-
nitrobenzyl]propanethioamide (35k)
The compound was prepared from 34k by the general proce-
dure for the synthesis of thioamides in 58% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 9.69 (br s, 1H), 8.11 (d, 1H, J = 2.0 Hz),
7.81 (d, 1H, J = 8.8 Hz), 7.47 (dd, 1H, J = 8.4, 2.0 Hz), 7.29 (d, 2H,
J = 8.4 Hz), 7.12 (d, 2H, J = 8.3 Hz), 4.80 (d, 2H, J = 5.9 Hz), 3.12 (s,

8160
F.-N. Li et al. / Bioorg. Med. Chem. 17 (2009) 8149–8160
HRMS (FAB+) calcd for C23H28FN2O2S2 (M+H+): 447.1576, found
447.1587.
To a solution of benzamide 37 (46 mg, 0.09 mmol) in THF
(4 mL) was added methyl magnesium iodide (1.0 M in ether,
0.12 mL, 0.12 mmol) at 0 °C. The reaction mixture was stirred at
0 °C for 2 h, then diluted with EtOAc. The organic layer was washed
with water and brine, dried over MgSO4, and concentrated in va-
cuo. Purification of the residue by silica gel column chromatogra-
phy (EtOAc/n-hexane = 1:1) was conducted to afford 38 (12 mg,
28%). 1H NMR (CDCl3, 300 MHz): d 7.85 (d, 1H, J = 2.2 Hz), 7.60
(d, 1H, J = 8.6 Hz), 7.24–7.26 (m, 3H), 7.06 (d, 2H, J = 8.3 Hz), 4.71
(d, 2H, J = 5.7 Hz), 3.04 (t, 2H, J = 7.2 Hz), 2.99 (s, 3H), 2.94 (t, 2H,
J = 7.1 Hz), 2.58 (s, 3H), 1.22 (s, 9H); IR (neat) cmÀ1: 3762, 2960,
1651, 1505, 1394, 1335, 1156; LRMS (EI): m/z 446 (M+).
4.2.35. 3-(4-tert-Butylphenyl)-N-[3-cyclopropyl-5-fluoro-4-
(methylsulfonamido)benzyl]propanethioamide (35q)
The compound was prepared from 34q by the general proce-
dure for the synthesis of thioamides in 97% yield as a white solid.
1H NMR (CDCl3, 300 MHz): d 7.28 (d, 2H, J = 8.3 Hz), 7.17 (br s, 1H),
7.11 (d, 2H, J = 8.1 Hz), 6.75 (d, 1H, J = 10.1 Hz), 6.64 (s, 1H), 6.09 (s,
1H), 4.66 (d, 2H, J = 5.3 Hz), 3.15 (s, 3H), 3.08 (t, 2H, J = 7.4 Hz), 2.29
(t, 2H, J = 7.2 Hz), 2.21 (m, 1H), 1.27 (s, 9H), 1.02–1.09 (m, 2H),
0.62–0.67 (m, 2H); IR (neat) cmÀ1: 3302, 2961, 1535, 1446, 1324,
1152; LRMS (FAB+): m/z 463 (M+).
Acknowledgments
4.2.36. 3-(4-tert-Butylphenyl)-N-[3-cyano-5-fluoro-4-
(methylsulfonamido)benzyl]propanethioamide (35r)
The compound was prepared from 34r by the general procedure
for the synthesis of thioamides in 96% yield as a white solid. 1H
This research work was supported by Grant R01-2007-000-
20052-0 from the Basic Research Program of the Korea Science
and Engineering Foundation and by the grant from AmorePacific
Corporation.
NMR (CDCl3, 300 MHz):
d 7.20–7.32 (m, 4H), 7.12 (d, 2H,
J = 8.4 Hz), 6.35 (s, 1H), 4.78 (d, 2H, J = 5.7 Hz), 3.30 (s, 3H), 3.09
(t, 2H, J = 6.6 Hz), 2.99 (t, 2H, J = 6.6 Hz), 1.28 (s, 9H); 13C NMR
(CDCl3, 125 MHz): d 205.6, 149.7, 138.5, 136.8, 134.2, 132.3,
128.1, 125.6, 121.7, 115.5, 48.9, 47.8, 40.8, 38.4, 34.8, 34.3, 31.3;
IR (neat) cmÀ1: 3200, 2954, 2224, 1726, 1531, 1326, 1159; LRMS
(FAB+): m/z 448 (M+); HRMS (FAB+) calcd for C22H27FN3O2S2
(M+H+): 448.1529, found 448.1520.
References and notes
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3769.
4.2.37. 5-{[3-(4-tert-Butylphenyl)propanethioamido]methyl}-
2-(methylsulfonamido)benzoic acid (36)
To a solution of thioamide 35l (100 mg, 0.22 mmol) in THF/
H2O = 1:1 (2 mL) was added LiOH–H2O (27 mg, 0.65 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, con-
centrated in vacuo to give the acid 36 (48 mg, 50%) as a white solid.
1H NMR (CDCl3, 300 MHz): d 8.05 (d, 1H, J = 1.7 Hz), 7.58 (d, 1H,
J = 8.6 Hz), 7.33 (dd, 1H, J = 8.4, 2.2 Hz), 7.27 (d, 2H, J = 8.0 Hz),
7.13 (d, 2H, J = 8.2 Hz), 4.74 (s, 2H), 3.06 (t, 2H, J = 7.3 Hz), 2.98
(s, 3H), 2.91 (t, 2H, J = 7.7 Hz), 1.25 (s, 9H); IR (neat) cmÀ1: 3229,
2958, 1682, 1502, 1393, 1327; LRMS (FAB+): m/z 449 (M+).
4.2.38. N-[3-Acetyl-4-(methylsulfonamido)benzyl]-3-(4-tert-
butylphenyl)propanethioamide (38)
To a solution of thioamide 35l (60 mg, 0.14 mmol) in THF (4 mL)
was added NHMe(OMe) (20 mg, 0.20 mmol). The reaction mixture
was added dropwise of i-PrMgCl (2.0 M in THF, 0.28 mL,
0.56 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for
2 h, then diluted with EtOAc. 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-hexane = 3:2) to afford 37 (46 mg, 72%).
15. Kunishima, M.; Morita, J.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Synlett
1999, 1255.