Sequential electrophilic trifluoromethanesulfanylation-cyclization of tryptamine derivatives: Synthesis of C(3)-trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles

Article abstract of DOI:10.1021/jo3013385

A practical and efficient synthesis of C(3)-trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles 5 from tryptamine derivatives was described. The features of this synthesis included electrophilic activation of C(3) of tryptamine derivatives with CF₃S⁺ ? and cascade ring cyclization by carbamate nucleophile attacking at C(2). Surprisingly, when Lewis acid (BF₃·OEt₂) was used as activator instead of proton acid (TsOH·H₂O) for the electrophilic trifluoromethanesulfanylation of tryptamine derivatives, the uncyclized product 6 was formed preferentially. This sequential trifluoromethanesulfanylation- cyclization protocol was used to synthesize several pyrrolidinoindolinic alkaloid analogues. The cytotoxicity activities of these trifluoromethanesulfanylated alkaloid analogues were evaluated against three cancer cell lines (K562, HeLa, L929).

Full text of DOI:10.1021/jo3013385

Article
pubs.acs.org/joc
Sequential Electrophilic Trifluoromethanesulfanylation−Cyclization
of Tryptamine Derivatives: Synthesis of C(3)-
Trifluoromethanesulfanylated Hexahydropyrrolo[2,3‑b]indoles
Yi Yang,†,§ Xueliang Jiang,† and Feng-Ling Qing*,†,‡
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling
Lu, Shanghai 200032, China
‡College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620,
China
§School of Chemistry and Pharmaceutical Engineering, Sichuan University of Science & Engineering, 180 Xueyuan Street, Huixing
Lu, Zigong, Sichuan 643000, China
S
* Supporting Information
ABSTRACT: A practical and efficient synthesis of C(3)-
trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles
5 from tryptamine derivatives was described. The features of
this synthesis included electrophilic activation of C(3) of
tryptamine derivatives with “CF3S+” and cascade ring
cyclization by carbamate nucleophile attacking at C(2).
Surprisingly, when Lewis acid (BF3·OEt2) was used as
activator instead of proton acid (TsOH·H2O) for the
electrophilic trifluoromethanesulfanylation of tryptamine derivatives, the uncyclized product 6 was formed preferentially. This
sequential trifluoromethanesulfanylation−cyclization protocol was used to synthesize several pyrrolidinoindolinic alkaloid
analogues. The cytotoxicity activities of these trifluoromethanesulfanylated alkaloid analogues were evaluated against three cancer
cell lines (K562, HeLa, L929).
INTRODUCTION
■
Natural products containing a hexahydropyrrolo[2,3-b]indole
(HPI) unit usually exhibit interesting biological activities, such
as miotic, anticancer, anticholinergic and neuroprotective
properties.1 The C(3) substituted pyrrolidinoindolines, as
exemplified by (−)-physostigmine 1 and (−)-phenserine 2,
have been found to be clinically useful for treating glaucoma
and relieving symptoms of Alzheimer’s disease.2 Besides the
C(3) carbon-centered group substituted pyrrolidinoindolines,
the C(3) nitrogen and oxygen-substituted ones also received a
significant amount of attention from synthetic and medicinal
chemistry communities (Figure 1).3 To gain diverse sub-
stitutions at C(3) position, the thio-substituted pyrrolidinoin-
dolines are appealing targets for drug modification and total
synthesis efforts. However, the rapid and efficient approaches to
construct C(3) thio-substituted pyrrolidinoindolines remain
limited.4 The CF3S moiety possesses an extremely large Hansch
lipophilicity parameter (π = 1.44).5 Consequently compounds
bearing CF3S group are potentially important targets in the
pharmaceutical and agrochemical fields.6 We anticipate that if
the CF3S group can be incorporated into the C(3) site of
hexahydropyrrolo[2,3-b]indole, this novel structural motif
could be attractive and valuable for the development of
biologically active compounds.
Figure 1. Various substitutions at C(3) position of hexahydropyrrolo-
[2,3-b]indole.
Trifluoromethanesulfanylation in an electrophilic fashion has
emerged as powerful synthetic tools in this arena. Recently,
Billard and Langlois report the trifluoromethanesulfanylation of
A variety of processes for the incorporation of the CF3S
Received: June 27, 2012
Published: August 13, 2012
group into diverse organic molecules have been developed.7
© 2012 American Chemical Society
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electron-rich (hetero)arenes like indoles using trifluorometha-
nesulfanylamides as easy-to-handle equivalents of the trifluor-
omethanesulfanyl cation (Scheme 1).8−10 Inspired by this work,
uncyclized compound 6a was probably due to the strong
interaction13 between BF3·OEt2 and the side chain nitrogen.
This interaction resulted in the inhibition of subsequent
cyclization onto the at C(2) position of thiiranium ion
4a′14,15 by the side chain nitrogen. Thereby, the reaction
proceeded in Path II instead of Path I to provide C(2)-
trifluoromethanesulfanylated product 6a preferentially (Scheme
3).
Scheme 1. Electrophilic Trifluoromethanesulfanylation of
Indole
With the optimum reaction conditions determined (Table 1,
entry 2), the scope of this cascade electrophilic activation/
cyclization process was investigated with respect to both the
attached nucleophile and the substitution pattern of the indole
structural core. First, a wide variety of nucleophiles at the side
chain were examined (Table 2). When tryptamine 4b was taken
as substrate for this sequential trifluoromethanesulfanylation−
cyclization, its conversion was less than 10% (entry 1). For
acetyl, tosyl protected tryptamine and side chain prolonged
substrates (4c, 4d and 4e), the uncyclized products 6c, 6d and
6e were formed respectively in priority instead of cyclized
products (entries 2−4). In the cases of substrates (4f and 4g) in
which the center of nucleophile in the side chain was carbon or
oxygen, there was no formation of the cyclized products
(entries 5−6). These results showed that the nucleophile was
very critical in this sequential trifluoromethanesulfanylation−
cyclization process.
we anticipate that the C(3)-trifluoromethanesulfanylated
hexahydropyrrolo[2,3-b]indoles could be formed through
electrophilic activation of the electron-rich C(3) position of
indole with the trifluoromethanesulfanyl cation equivalent
(“CF3S+”) and subsequent cyclization onto the resulting C(2)
iminium ion by the side chain nitrogen (Scheme 2, biomimetic
approach). It was noteworthy that the efficiencies of accesses to
C(3)-substituted hexahydropyrrolo[2,3-b]indoles via biomi-
metic approach11 were limited, as this reaction profile was
highly sensitive to the nature of the electrophiles and the indole
substrates.12 Herein, we describe a practical and efficient
construction of C(3)-trifluoromethanesulfanylated
hexahydropyrrolo[2,3-b]indoles by electrophilic activation of
C(3) of tryptamine derivatives with “CF3S+” and cascade ring
cyclization by carbamate nucleophile attacking at C(2).
With the proper nitrogen nucleophile determined, the
substitution patterns of the indole structural core went into
examination (Table 3). The reaction tolerated various
carbamate functions on the side chain nitrogen (entries 1−3),
but the lower ratio of 5i:6i was observed for Troc-protected
form (entry 2). Substitutions at the 5 or 6 position of the indole
substrate impacted the regioselectivity and/or reactivity. In
comparison with electron-withdrawing substituent (fluorine in
4m), the electron-donating groups (methyl and methoxyl) are
beneficial for the higher ratio of cyclized products formation
(entries 4−6, 10−11). In addition, the R2 groups on the indole
nitrogen atom were also examined. The ratio of 5n:6n was
decreased to 1:1 when the indole Na atom was masked by
methyl group (entry 7). The Na-allyl indole gave the same
result besides keeping the double bond of the ally group intact
(entry 8).9 However, Na-acetyl indole did not afford the
electrophilic trifluoromethanesulfanylation product due to the
attenuated electron-density of C(3) position (entry 9).
To illustrate the synthetic utility of this methodology and
explore the biological properties of the newly found structural
motif, we undertook the synthesis of trifluoromethanesulfany-
lated analogues 7 in which the trifluoromethanesulfanyl group
mimics the acetoxyl function of alkaloid A16 (Scheme 4). The
analogues 7 can be easily obtained from intermediates 5j, 5q
and 5r by Fmoc deprotection (Scheme 4).
RESULTS AND DISCUSSION
■
Chemistry. We began our synthesis of C(3)-trifluorome-
thanesulfanylated hexahydropyrrolo[2,3-b]indoles with trypt-
amine derivative 4a as a model substrate (Table 1).
Trifluoromethanesulfanylamide 3 was chosen for the formation
of “CF3S+” equivalent.8 Initially, treatment of compound 4a
with 3 using p-toluenesulfonic acid (TsOH) as acid activator at
elevated temperature (50 °C) gave nearly 1:1 mixture of the
desired product 5a and uncyclized compound 6a in 95% yield
(Table 1, entry 1). But compounds 5a and 6a could not be
separated by column chromatography. To our delight, the ratio
of 5a:6a was greatly improved to 20:1 when the reaction was
conducted at room temperature (entry 2). It was found that 5a
was converted into 6a completely upon treatment with TsOH
at 50 °C for 12 h. This result indicated that reaction
temperature played key role in the formation of 5a.
(+)-Camphorsulfonic acid (CSA) and methanesulfonic acid
(MsOH) were also proven to be the efficient activator for the
formation of the desired cyclic product 5a preferentially
(entries 3−4). However, carboxylic acids HOAc and
CF3CO2H were poor activators for this reaction. There was
no reaction in the presence of HOAc (entry 5). When
CF3CO2H was used as acid activator, the yield and ratio of
5a:6a were decreased (entry 6). Interestingly, the uncyclized
compound 6a was formed as the single product in the presence
of the Lewis acid BF3·OEt2 (entry 7). The formation of the
Other analogues bearing methyl at Na or Nb atom could also
be synthesized from intermediates 5j and 5r (Scheme 5). The
indole Na atoms in 5j and 5r were methylated through
reductive methylation by using formaldehyde, HOAc, and
Scheme 2. Biomimetic Approach
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a
Table 1. Optimization of the Sequential Trifluoromethanesulfanylation−Cyclization of Tryptamine Derivative 4a
b
entry
acid
temp (°C)
time (h)
ratio (5a:6a)
isolated yield (%)
1
2
3
4
5
6
TsOH
50
rt
rt
rt
rt
rt
rt
12
12
12
12
24
24
48
1:1
95
TsOH
>20:1
>20:1
9:1
96
c
(+)-CSA
MsOH
94
95
HOAc
NR
NR
d
CF3CO2H
BF3·OEt2
5.5:1
33
e
7
nearly only 6a
97
a
b
All the reactions were run on 0.2 mmol scale in CH2Cl2 (2 mL), CF3SNHPh (1.2 equiv), acid (2.5 equiv). The ratio of 5a:6a was determined by
c
d
e
19F NMR of the crude product. Nearly racemic product 5a was afforded (ee < 5%). 1/3 PhNHSCF3 was consumed. 5 equiv of BF3·OEt2 were
added in two portions at 24 h intervals.
Scheme 3. Pathway for Formation of 6a
sodium cyanoborohydride, repectively. Then deprotection of
Fmoc group on Nb atoms in 8j and 8r were conducted under
the treatment of piperidine. Finally, compounds 10j and 10r
were obtained by a second reductive methylation at Nb atom.
Compound 10j could be interpreted as the trifluoromethane-
sulfanylated analogue of alkaloid CPC-1,17 in which the
methoxyl group was replaced by trifluoromethanesulfanyl
(Scheme 5).
cell (entry 4), and 8r exhibited better selectivity than 7r for
inhibition against K562 cancer cell (entry 7). Overall, the
bioassay data indicated that the introduction of trifluorome-
thanesulfanyl group at C(3) position of hexahydropyrrolo[2,3-
b]indoles renders us a novel framework for pursuing new
anticancer agents.
CONCLUSION
■
Biological Evaluation. The antiproliferative activities of
the trifluoromethanesulfanylated analogues were evaluated
against three cancer cell lines: K562 (human myelogenous
leukemia), HeLa, and L929 (mouse fibroblast cell), which were
grown in vitro (cell lines were provided from the American
Type Culture Collection, ATCC, M anassas, VA). Taxol was
used as positive control. The IC50 values (μM) were
summarized in Table 4. Compounds 10j and 10r were not
evaluated against cancer cell lines, as they were unstable.
Compounds 8j, 5a, 5j and 5h showed no or negligible
inhibition toward all three cell lines: K562, HeLa, and L929
(Table 4, entries 8−11). Compound 5i displayed moderate
inhibition to K562, HeLa, L929 with IC50 values of 21.4, 14.5,
and 55.2 μM, respectively (entry 12). Compound 7q presented
higher potency than 7j and alkaloid A for L929 cell line (entries
1−3). Compounds 7r and 8r bearing CH3O group on the fused
aryl group (R3 = OCH3) were found to be the most potent in
inhibiting K562 cancer cell growth than the other compounds
with IC50 values of 4.7 and 6.4, μM respectively (entries 4, 7).
Furthermore, 7r showed good inhibition toward HeLa cancer
In conclusion, we have demonstrated a practical and efficient
approach to synthesize the C(3)-trifluoromethanesulfanylated
hexahydropyrrolo[2,3-b]indoles. This methodology highlights
the electrophilic activation at C(3) site with “CF3S+” and a
carbamate nucleophile attacking the generated iminium ion.
The application of this chemistry for the concise synthesis of
several trifluoromethanesulfanylated alkaloid analogues was also
described. Further investigations of the scope and enantioin-
duction of this sequential trifluoromethanesulfanylation−
cyclization are underway, and the results will be reported in
due course.
EXPERIMENTAL SECTION
■
Chemistry. N-[(Trifluoromethyl)thio]aniline (3). A flame-dried
double-necked vessel was successively charged, under nitrogen, with
diisopropylethylamine (7 mL, 40 mmol) and anhydrous dichloro-
methane (80 mL). The resulting mixture was cooled to −20 °C before
addition of diethylaminosulfurtrifluoride (5.5 mL, 44 mmol), followed
by the addition of trimethylsilyltrifluoromethane (5.9 mL, 40 mmol) in
20 min intervals. After stirring under at −20 °C for 1 h, aniline (1
equiv) was added at 0 °C. The reaction mixture was stirred at room
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a
Table 2. Investigation of the Nucleophiles
a
All reactions were run on 0.2 mmol scale in CH2Cl2 (2 mL), CF3SNHPh (1.2 equiv), TsOH (2.5 equiv).
temperature overnight. The reaction mixture was washed with distilled
water. The organic phase was dried over Na2SO4 and evaporated in
vacuo. The crude residue was purified by distillation under reduced
pressure to afford the corresponding sulfanylamide 3 as yellow oil
3.14 (t, J = 6.6 Hz, 2H), 1.92 (s, 3H); 19F NMR (282 MHz, CDCl3) δ
−43.2 (s, 3F); 13C NMR (100.7 MHz, CDCl3) δ 170.4, 137.7, 128.4
(q, J = 312.7 Hz), 127.2, 124.9, 124.0, 120.4, 119.9, 113.8, 111.5, 39.9,
24.9, 23.2; IR (KBr) υmax 3404, 3266, 2923, 1704, 1654, 1535, 1133,
1109, 745 cm−1; MS (ESI) m/z 303 (M + H)+, 325 (M + Na)+;
HRMS (ESI-TOF) m/z [M + H]+ Calcd for C13H14N2OF3S 303.0779,
found 303.0773.
1
(5.25 g, Yield 68%): bp 46 °C/20 Pa; H NMR (300 MHz, CDCl3)
7.28 (t, J = 7.5 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.97 (t, J = 7.2 Hz,
1H), 5.08 (NH); 19F NMR (282 MHz, CDCl3) −52.5 (s, 3F).
General Procedure for the Protic Acid Catalyzed Eletrophilic
Trifluoromethananesulfanylation of Tryptamine Derivatives with
N-[(Trifluoromethyl)thio]aniline 3. To a solution of compound 3
(0.24 mmol) in dichloromethane (2 mL) were added tryptamine
derivative (0.2 mmol) and then TsOH (0.5 mmol). The reaction
mixture was stirred at room temperature for 12−36 h until the
substrate disappeared by TLC detecting. Then, the organic phase was
washed with saturated NaHCO3 solution and then dried over sodium
sulfate. After removing the solvent in vacuo, the residue was purified
by flash chromatography on silica gel (petroleum ether:ethyl acetate =
5:1) to afford the corresponding product.
4-Methyl-N-(2-(2-(trifluoromethylthio)-1H-indol-3-yl)ethyl)-
1
benzenesulfonamide (6d). White solid: mp 143 °C; H NMR (400
MHz, acetone-d6) δ 10.8 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.60 (d, J =
8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.25 (t,
J = 7.6 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.60 (t, J = 6.0 Hz, 1H),
3.24−3.19 (m, 2H), 3.14−3.10 (m, 2H), 2.37 (s, 3H); 19F NMR (282
MHz, acetone-d6) −39.0 (s, 3F); 13C NMR (100.7 MHz, acetone-d6)
δ 142.8, 138.3, 138.1, 129.5, 128.8 (q, J = 310.5 Hz), 127.0, 126.9,
124.4, 123.1, 119.9, 119.6, 113.2, 111.7, 43.5, 25.4, 20.4; IR (KBr) υmax
3335, 3058, 2924, 1699, 1445, 1323, 1158, 1110, 746, 663 cm−1; MS
(ESI) m/z 415 (M + H)+, 432 (M + NH4)+, 437 (M + Na)+; HRMS
(ESI-TOF) m/z [M + Na]+ Calcd for C18H17N2O2F3S2Na 437.0581,
found 437.0576.
N-(2-(2-(Trifluoromethylthio)-1H-indol-3-yl)ethyl)acetamide (6c).
White solid: mp 133 °C; 1H NMR (300 MHz, CDCl3) δ 9.26 (s, 1H),
7.66 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 6.3 Hz,
1H), 7.12 (t, J = 6.9 Hz, 1H), 5.80 (s, 1H), 3.58 (q, J = 6.3 Hz, 2H),
Methyl 3-(2-(trifluoromethylthio)-1H-indol-3-yl)propylcarbamate
(6e). White solid: mp 100 °C; 1H NMR (300 MHz, CDCl3) δ 8.79 (s,
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rotamers, both reported) δ 7.53 (d, J = 4.5 Hz, 1H), 7.44 (t, J = 7.8
Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.92 (t, J = 8.1 Hz, 1H), 5.90 (s,
0.6H), 5.87 (s, 0.4H), 4.83 (br, 1H), 4.15−4.06 (m, 1H), 4.07 (s,
1.2H), 3.99 (s, 1.8H), 3.37 (q, J = 9.3 Hz, 1H), 2.90−2.80 (m, 2H);
19F NMR (282 MHz, CDCl3) (ca. 3:2 mixture of rotamers, both
Table 3. Exploration of the Substitution Patterns in the
Indole Structural Core
a
reported) −37.0 (s, 1.8F), −37.1 (s, 1.2F); 13C NMR (100.7 MHz,
CDCl3) δ 155.1, 154.3, 149.1, 148.8, 130.6, 129.6 (q, J = 309.0 Hz),
125.6, 124.5, 124.4, 119.9, 119.7, 110.2, 110.1, 81.2, 80.9, 63.6, 62.5,
52.9, 52.6, 45.0, 44.8, 36.8, 36.7; IR (KBr) υmax 3354, 2955, 2884,
1697, 1609, 1452, 1386, 1110, 747 cm−1; MS (ESI) m/z 319 (M +
H)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C13H14N2O2F3S
319.0728, found 319.0723. Anal. Calcd for C13H13F3N2O2S: C, 49.05;
H, 4.12; N, 8.80. Found: C, 49.31; H, 4.34; N, 8.85.
4h−
time
(h)
ratio
isolated
h
b
entry
4r
R1
R2
R3
(5:6)
yield (%)
c
1
2
3
4
5
4h
4i
H
H
H
H
Cbz
30
36
12
12
10
10:1
5.5:1
10:1
24:1
37:1
83
d
H
H
H
H
Troc
Fmoc
Moc
Moc
81
c
e
4j
95 (82 )
(3a,8a)-Benzyl 3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5h). Clear oil:
1H NMR (400 MHz, CDCl3) (ca. 3:2 mixture of rotamers, both
c
4k
5-Me
96
c
4l
5-
94
MeO
4m 6-F
reported) δ 7.41−7.32 (m, 5H), 7.23 (d, J = 7.2 Hz, 1H), 7.18−7.13
(m, 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 0.6H), 6.57 (d, J
= 8.0 Hz, 0.4H), 5.65 (s, 0.6H), 5.63 (s, 0.4H), 5.27−5.17 (m, 0.8H),
5.20−5.08 (m, 1.2H), 4.90 (br, 1H), 3.86 (t, J = 8.8 Hz, 0.4H), 3.80−
3.75 (m, 0.6H), 3.16−3.08 (m, 1H), 2.62−2.55 (m, 2H); 19F NMR
(282 MHz, CDCl3) (ca. 3:2 mixture of ratamers, both reported) δ
−37.7 (s), −37.8 (s); 13C NMR (100.7 MHz, CDCl3) δ 154.5, 153.7,
149.1, 148.8, 136.2, 136.1, 130.6, 129.6 (q, J = 310.5 Hz), 128.8, 128.6,
128.4, 128.2, 128.1, 128.0, 125.7, 125.5, 124.5, 124.4, 120.0, 119.7,
110.3, 110.1, 81.3, 80.9, 67.5, 67.2, 63.5, 62.6, 45.1, 44.9, 36.8, 36.6; IR
(KBr) υmax 3363, 3033, 2952, 2880, 1698, 1417, 1117, 740 cm−1; MS
(ESI) m/z 395 (M + H)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd
for C19H18N2O2F3S 395.1041, found 395.1036.
f
6
H
Moc
Moc
Moc
Moc
Fmoc
Fmoc
24
24
18
24
12
12
4:1
1:1
1:1
92
g
7
4n
4o
4p
4q
4r
H
Me
Allyl
Ac
H
52
d
8
H
81
9
H
NR
c
10
11
5-Me
20:1
18:1
87
c
5-
H
95
MeO
a
All the reactions were run on 0.2 mmol scale in CH2Cl2 (2 mL),
b
CF3SNHPh (1.2 equiv), TsOH (2.5 equiv). The ratio of 5:6 was
c
determined by 19F NMR of the crude product. After flash
chromatgrapy, the ratio of 5:6 became greater than 20:1 (determined
d
by 19F NMR). After flash chromatgrapy, the cyclized product and
(3a,8a)-2,2,2-Trichloroethyl 3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5i). Clear oil:
1H NMR (400 MHz, CDCl3) (ca. 3:2 mixture of rotamers, both
e
uncyclized product can be separated and characterized. After
recrystallization, the ratio of 5j:6j became greater than 100:1
f
(determined by 19F NMR). After flash chromatgrapy, 5m and 6m
reported) δ 7.26 (d, J = 6.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.86−
6.82 (m, 1H), 6.68−6.65 (m, 1H), 5.71 (s, 0.6H), 5.69 (s, 0.4H), 5.32
(br, 0.4H), 5.16 (br, 0.6H), 5.00 (d, J = 12.4 Hz, 0.6H), 4.82 (d, J =
12.0 Hz, 0.4H), 4.70 (s, 0.6H), 4.67 (s, 0.4H), 3.92−3.85 (m, 1H),
3.26−3.14 (m, 1H), 2.67−2.63 (m, 2H); 19F NMR (282 MHz,
CDCl3) (ca. 1.1:1 mixture of rotamers, both reported) δ −36.9 (s),
−37.0 (s); 13C NMR (100.7 MHz, CDCl3) δ 152.8, 151.8, 148.9,
148.6, 130.8, 130.7, 129.6 (q, J = 311.1 Hz), 125.5, 125.2, 124.5, 124.4,
120.1, 119.9, 110.2, 110.1, 95.5, 95.3, 81.5, 81.0, 74.9, 74.9, 63.4, 62.6,
45.4, 45.0, 36.7, 36.2; IR (KBr) υmax 3422, 3381, 2953, 2886, 1716,
1609, 1416, 1110, 747 cm−1; MS (ESI) m/z 437 (M + H)+, 459 (M +
Na)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C14H13N2O2F3SCl3
434.9715, found 434.9710.
2,2,2-Trichloroethyl 2-(2-(trifluoromethylthio)-1H-indol-3-yl)-
ethylcarbamate (6i). White solid: mp 105 °C; 1H NMR (400
MHz, CDCl3) (ca. 9:1 mixture of rotamers, both reported) δ 8.54 (s,
1H), 7.67 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 8.0
Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 5.14 (s, 0.9 H), 4.91 (s, 0.1 H), 4.77
(0.3 H), 4.73 (s, 1.7 H), 3.55 (q, J = 6.8 Hz, 2H), 3.17 (t, J = 7.6 Hz,
2H); 19F NMR (282 MHz, CDCl3) (ca. 9:1 mixture of ratamers, both
reported) δ −42.3 (s), −42.4 (s); 13C NMR (100.7 MHz, CDCl3) δ
154.6, 137.6, 128.4 (q, J = 312.3 Hz), 127.1, 125.0, 123.7, 120.6, 120.0,
114.0, 111.4, 95.5, 74.9, 74.5, 42.1, 41.6, 25.9, 25.3. IR (KBr) υmax
3401, 3323, 2950, 1723, 1519, 1110, 815, 746, 727 cm−1; MS (ESI) m/
z 437 (M + H)+, 459 (M + Na)+; HRMS (ESI-TOF) m/z [M + Na]+
Calcd for C14H12N2O2F3SCl3Na 456.9535, found 456.9529.
g
were obtained as a mixture in the ratio of 4:1. After flash
chromatgrapy, only pure 5n was obtained. Isolated yield of a mixture
of 5 and 6.
h
1H), 7.59 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 6.9
Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 4.87 (s, 1H), 3.68 (s, 3H), 3.24 (d, J
= 5.7 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 1.94−1.84 (m, 2H); 19F NMR
(282 MHz, CDCl3) δ −43.4 (s, 3F); 13C NMR (100.7 MHz, CDCl3) δ
157.3, 137.7, 128.5 (q, J = 312.5 Hz), 127.0, 126.4, 124.6, 120.1, 119.8,
113.0, 111.5, 52.1, 40.8, 30.5, 22.0; IR (KBr) υmax 3403, 3298, 2944,
2860, 1709, 1526, 1262, 1110, 745 cm−1; MS (ESI) m/z 333 (M +
H)+, 355 (M + Na)+; HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
C14H15N2O2F3SNa 355.0704, found 355.0699.
Dimethyl 2-(2-(2-(trifluoromethylthio)-1H-indol-3-yl)ethyl)-
malonate (6f). Light yellow oil: 1H NMR (400 MHz, CDCl3) δ
8.49 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.30 (t,
J = 7.2 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 3.75 (s, 6H), 3.47 (t, J = 7.2
Hz, 1H), 3.00 (t, J = 8.0 Hz, 2H), 2.33 (q, J = 7.6 Hz, 2H); 19F NMR
(282 MHz, CDCl3) δ −42.6 (s, 3F); 13C NMR (100.7 MHz, CDCl3) δ
169.7, 137.6, 128.5 (q, J = 312.3 Hz), 127.0, 125.8, 124.8, 120.3, 120.0,
113.4, 111.4, 52.6, 51.3, 29.4, 22.6; IR (KBr) υmax 3367, 2954, 1731,
1434, 1344, 1132, 1109, 746 cm−1; MS (ESI) m/z 376 (M + H)+, 393
(M + NH4)+, 398 (M + Na)+; HRMS (ESI-TOF) m/z [M + Na]+
Calcd for C16H16F3O4NSNa 398.0650, found 398.0644.
(3a,8a)-Methyl 3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5a). White
solid: mp 112 °C; H NMR (300 MHz, CDCl3) (ca. 3:2 mixture of
(3a,8a)-(9H-Fluoren-9-yl)methyl 3a-(trifluoromethylthio)-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5j).
1
Scheme 4. Synthesis of Trifluoromethanesulfanylated Analogues 7 of Alkaloid A
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Article
Scheme 5. Synthesis of other Analogues Bearing Methyl at Na or Nb
Table 4. Structures of Trifluoromethanesulfanylated Pyrrolidinoindolines and Their in Vitro Inhibition against Cancer Cell
Lines
a
IC50 (μM)
entry
compound
R1
R2
R3
R4
K562
28.9
HeLa
L929
b
b
b
1
A
H
H
H
OAc
66.1
>100
>100
10.0
61.9
87.5
20.9
2
7j
7q
7r
9r
9j
8r
8j
5a
5j
5h
5i
H
H
H
SCF3
SCF3
SCF3
SCF3
SCF3
SCF3
SCF3
SCF3
SCF3
SCF3
SCF3
>100
>100
4.7
3
H
H
Me
OMe
OMe
H
4
H
H
>100
5
Me
Me
Me
Me
H
H
57.9
68.4
6.4
>100
21.6
>100
>100
>100
>100
>100
>100
>100
6
H
7
Fmoc
Fmoc
Moc
Fmoc
Cbz
Troc
OMe
H
>100
>100
>100
>100
>100
14.5
8
>100
9
H
>100
>100
>100
10
11
12
13
H
H
H
H
H
H
21.4
1.7
55.2
c
Taxol
1.1
31.2
a
b
c
IC50 is the concentration of drug that inhibits the cell growth by 50% relative to the control. IC50 values of alkaloid A was reported in ref 16. Taxol
was used as a positive control standard.
1
Yellow solid: mp 143 °C; H NMR (400 MHz, CDCl3) (ca. 55:45
CDCl3) (ca. 4:3 mixture of rotamers, both reported) δ −36.9 (s),
−37.1 (s); 13C NMR (100.7 MHz, CDCl3) δ 155.1, 154.4, 146.9,
146.6, 132.8 (q, J = 305.1 Hz), 131.2, 129.5, 129.2, 128.1, 125.8, 124.8,
124.7, 110.3, 110.1, 81.5, 81.1, 63.7, 62.7, 52.8, 52.5, 45.0, 44.8, 36.6,
20.8; IR (KBr) υmax 3358, 2957, 1704, 1619, 1497, 1452, 1385, 1113,
773 cm−1; MS (ESI) m/z 333 (M + H)+; HRMS (ESI-TOF) m/z [M
+ H]+ Calcd for C14H16N2O2F3S 333.0885, found 333.0879.
mixture of rotamers, both reported) δ 7.87−7.10 (m, 10H), 6.84 (d, J
= 7.2 Hz, 0.45H), 6.76 (t, J = 6.8 Hz, 0.55H), 6.67 (d, J = 7.6 Hz,
0.45H), 6.37 (d, J = 8.0 Hz, 0.55H), 5.65 (s, 0.45H), 5.32 (s, 0.45H),
5.04 (s, 0.55H), 4.77 (dd, J = 6.0 Hz, 4.8 Hz, 0.45H), 4.68 (dd, J = 6.0
Hz, 4.8 Hz, 0.55H), 4.49−4.40 (m, 1H), 4.31 (t, J = 3.6 Hz, 0.45H),
4.23 (t, J = 6.8 Hz, 0.55H), 3.86 (s, 0.55H), 3.77−3.73 (m, 0.45H),
3.68 (t, J = 9.2 Hz, 0.55H), 3.18−3.11 (m, 0.45H), 3.00−2.94 (m,
0.55H), 2.67−2.64 (m, 1H), 2.50−2.37 (m, 1H); 19F NMR (282
MHz, CDCl3) (ca. 1:1.2 mixture of ratamers, both reported) −36.8
(s), −37.1 (s); 13C NMR (100.7 MHz, CDCl3) δ 154.5, 153.5, 149.1,
148.6, 143.9, 143.8, 143.7, 141.7, 141.3, 141.3, 130.6, 130.4, 129.6 (q, J
= 309.7 Hz), 127.9, 127.8, 127.4, 127.3, 127.1, 125.6, 125.3, 125.0,
124.9, 124.6, 124.4, 124.4, 124.3, 110.3, 109.6, 98.7, 81.3, 80.7, 67.4,
66.4, 63.1, 62.5, 47.3, 47.2, 44.9, 44.7, 36.8, 36.5; IR (KBr) υmax 3419,
3364, 3063, 2953, 2892, 1701, 1608, 1420, 1109, 740 cm−1; MS (ESI)
m/z 483 (M + H)+, 505 (M + Na)+, 521 (M + K)+; HRMS (ESI-
TOF) m/z [M + H]+ Calcd for C26H22N2O2F3S 483.1354, found
483.1349.
(3a,8a)-Methyl 5-methoxy-3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5l). Light yellow
1
oil: H NMR (300 MHz, CDCl3) (ca. 3:2 mixture of rotamers, both
reported) δ 6.83 (s, 0.4H), 6.82 (s, 0.6H), 6.77 (d, J = 8.7 Hz, 0.6H),
6.75 (d, J = 8.7 Hz, 0.4H), 6.62 (s, 0.6H), 6.59 (s, 0.4H), 5.62 (s,
0.6H), 5.60 (s, 0.4H), 4.58 (br, 1H), 3.87−3.80 (m, 1H), 3.83 (s,
1.2H), 3.76 (s, 3H), 3.71 (s, 1.8H), 3.15−3.06 (m, 1H), 2.60−2.50 (m,
2H); 19F NMR (282 MHz, CDCl3) (ca. 3:2 mixture of rotamers, both
reported) δ −36.8 (s), −37.0 (s); 13C NMR (100.7 MHz, CDCl3)
δ155.1, 154.4, 154.3, 154.1, 143.0, 142.7, 131.4 (q, J = 310.9 Hz),
131.1, 128.1, 127.1, 116.5, 116.4, 111.4, 111.3, 110.2, 110.1, 82.0, 81.6,
64.0, 62.9, 56.0, 52.8, 52.5, 44.9, 44.8, 36.7, 36.6; IR (KBr) υmax 3356,
2952, 1701, 1495, 1452, 1384, 1201, 1112 cm−1; MS (ESI) m/z 349
(M + H)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C14H16F3N2O3S 349.0834, found 349.0828.
(3a,8a)-Methyl 5-methyl-3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5k). Clear oil:
1H NMR (400 MHz, CDCl3) (ca. 3:2 mixture of rotamers, both
reported) δ 7.04 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 7.6 Hz,
1H), 5.61 (s, 0.6H), 5.58 (s, 0.4H), 4.80 (br, 1H), 3.86−3.80 (m,
0.4H), 3.79 (s, 1.2H), 3.74−3.68 (m, 0.6H), 3.70 (s, 1.8H), 3.08 (q, J
= 7.6 Hz, 1H), 2.60−2.53 (m, 2H), 2.27 (s, 3H); 19F NMR (282 MHz,
(3a,8a)-Methyl 6-fluoro-3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5m) and Methyl
2-(6-fluoro-2-(trifluoromethylthio)-1H-indol-3-yl)ethylcarbamate
(6m). After purification by flash chromatography on silica gel
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(petroleum ether:ethyl acetate = 4:1), compounds 5m and 6m are
obtained as a mixture. Clear oil: 1H NMR (400 MHz, CDCl3) (ca. 4:1
mixture of two compounds, both reported) δ 8.80 (s, 0.2H), 7.63 (t, J
= 6.4 Hz, 0.2H), 7.16 (t, J = 5.6 Hz, 0.8H), 7.05 (d, J = 9.2 Hz, 0.2H),
6.94 (t, J = 6.8 Hz, 0.2H), 6.48 (q, J = 7.6 Hz, 0.8H), 6.33 (d, J = 9.2
Hz, 0.8H), 5.64 (s, 0.5H), 5.63 (s, 0.3H), 5.46 (br, 0.5H), 5.03 (br,
0.3H), 4.86 (s, 0.2H), 3.80 (s, 0.9H), 3.72 (s, 1.5H), 3.68 (s, 0.6H),
3.14−3.07 (q, J = 10.8 Hz, 1.2H), 3.49−3.44 (m, 0.4H), 2.59−2.47
(m, 1.6H); 19F NMR (282 MHz, CDCl3) (ca. 4:1 mixture of two
compounds, both reported) δ −36.7 (s, 1.7F), −36.9 (s, 1.3F), −42.4
(s, 0.72F), −109.9 (m, 0.4F), −110.0 (m, 0.6F), −115.8 (s, 0.24F);
13C NMR (100.7 MHz, CDCl3) (ca. 4:1 mixture of two compounds,
both reported) δ 166.1, 163.6, 162.6, 160.2, 157.1, 155.1, 154.2, 150.7
(d, J = 12.4 Hz), 150.4 (d, J = 12.4 Hz), 137.7, 137.6, 129.5 (q, J =
310.1 Hz), 125.7, 125.5, 125.4, 123.9, 122.7 (q, J = 326.3 Hz), 121.2,
109.9, 109.6, 106.7, 106.5, 106.4, 106.2, 97.8, 97.7, 97.6, 97.4, 81.9,
81.6, 62.9, 61.9, 52.9, 52.6, 52.1, 44.9, 44.7, 41.3, 37.0, 36.8, 29.7, 25.4;
IR (KBr) υmax 3346, 2959, 1697, 1619, 1454, 1393, 1142, 1112, 775
cm−1; MS (ESI) m/z 337 (M + H)+, 359 (M + Na)+; HRMS (ESI-
TOF) m/z [M + H]+ Calcd for C13H13N2O2F4S 337.0634, found
337.0628.
4.46−4.36 (m, 1H), 4.28 (t, J = 4.0 Hz, 0.54H), 4.20 (t, J = 6.8 Hz,
0.46H), 3.79 (br, 0.5H), 3.74−3.65 (m, 1H), 3.16−3.09 (m, 0.46H),
2.99−2.92 (m, 0.54H), 2.60 (q, J = 4.4 Hz, 1H), 2.47−2.39 (m, 1H),
2.28 (s, 1.38H), 2.22 (s, 1.62H); 19F NMR (282 MHz, CDCl3) (ca.
5:6 mixture of rotamers, both reported) δ −37.2 (s), −37.4 (s); 13C
NMR (100.7 MHz, CDCl3) δ 154.5, 153.6, 146.8, 146.4, 143.9, 143.8,
143.7, 141.6, 141.3, 141.2, 131.3, 131.1, 129.3, 129.0, 127.9, 127.8,
127.4, 127.3, 127.1, 125.8, 125.5, 125.0 (q, J = 313.7 Hz), 124.9, 124.7,
124.6, 124.4, 120.3, 120.2, 120.0, 110.4, 109.6, 81.5, 80.9, 67.4, 66.5,
63.3, 62.7, 47.3, 47.2, 44.9, 44.7, 36.6, 36.4, 20.8, 20.7; IR (KBr) υmax
3412, 3355, 2952, 1701, 1497, 1419, 1200, 1114, 757, 740 cm−1; MS
(ESI) m/z 497 (M + H)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd
for C27H24N2O2F3S 497.1511, found 497.1505.
(3a,8a)-(9H-Fluoren-9-yl)methyl 5-methoxy-3a-(trifluorome-
thylthio)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxy-
1
late (5r). Light yellow oil: H NMR (400 MHz, CDCl3) (ca. 45:55
mixture of rotamers, both reported) δ 7.79 (t, J = 8.0 Hz, 1H), 7.72 (d,
J = 7.2 Hz, 1H), 7.61−7.56 (m, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.47−
7.39 (m, 1H), 7.39−7.32 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H), 6.82 (s,
0.45H), 6.72 (s, 0.55H), 6.76−6.68 (m, 1H), 6.58 (d, J = 8.8 Hz,
0.45H), 6.32 (d, J = 8.0 Hz, 0.55H), 5.62 (s, 0.45H), 5.07 (s, 0.55H),
4.70 (dd, J = 4.8 Hz, 4.4 Hz, 0.5H), 4.62 (dd, J = 4.8 Hz, 4.4 Hz,
0.5H), 4.45−4.36 (m, 1H), 4.26 (t, J = 4.4 Hz, 0.55H), 4.19 (t, J = 7.6
Hz, 0.45H), 3.74 (s, 1.35H), 3.70 (s, 1.65H), 3.69−3.65 (m, 1H),
3.15−3.09 (m, 0.45H), 2.96 (dt, J = 10.8 Hz, 6.0 Hz, 0.55H), 2.57 (t, J
= 8.0 Hz, 1H), 2.45−2.32 (m, 1H); 19F NMR (282 MHz, CDCl3) (ca.
1:1 mixture of rotamers, both reported) δ −36.5 (s), −36.8 (s); 13C
NMR (100.7 MHz, CDCl3) δ 154.5, 154.1, 153.9, 153.6, 144.0, 143.9,
143.8, 143.7, 143.0, 142.6, 141.7, 141.3, 141.2, 129.7 (q, J = 310.5 Hz),
129.6 (q, J = 310.3 Hz), 127.9, 127.8, 127.4, 127.3, 127.1, 126.8, 125.0,
124.9, 124.4, 120.2, 120.2, 120.0, 116.5, 116.4, 111.5, 110.8, 110.2,
110.0, 82.1, 81.5, 67.4, 66.5, 63.6, 63.0, 56.0, 47.3, 47.2, 44.8, 44.7,
36.8, 36.5; IR (KBr) υmax 3398, 2952, 2889, 1699, 1494, 1417, 1349,
1112, 740 cm−1; MS (ESI) m/z 513 (M + H)+; HRMS (ESI-TOF) m/
z [M + H]+ Calcd for C27H24N2O3F3S 513.1460, found 513.1454.
General Procedure for Boron Trifluoride Etherate Mediated
Eletrophilic Trifluoromethananesulfanylation of Tryptamine De-
rivatives with N-[(Trifluoromethyl)thio]aniline 3. To a solution of
compound 3 (0.24 mmol) in dichloromethane (2 mL) were added the
indicated indolic substrate (0.2 mmol) and then BF3·OEt2 (0.5 mmol).
The reaction mixture was stirred at room temperature for 24 h.
Additional BF3·OEt2 (0.5 mmol) was added dropwise, and the reaction
was stirred for another 24 h until the indolic substrate disappeared by
TLC monitoring. Then the organic phase was washed with saturated
NaHCO3 solution and then dried over sodium sulfate. After removing
the solvent in vacuo, the residue was purified by flash chromatography
on silica gel (petroleum ether:ethyl acetate = 4:1) to afford the
corresponding uncyclized product.
(3a,8a)-Methyl 8-methyl-3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5n). Clear oil:
1H NMR (300 MHz, CDCl3) (ca. 55:45 mixture of rotamers, both
reported) δ 7.21−7.17 (m, 2H), 6.74 (t, J = 7.5 Hz, 1H), 6.43 (d, J =
8.1 Hz, 1H), 5.79 (s, 0.55H), 5.70 (s, 0.45H), 4.03−3.86 (m, 1H), 3.80
(s, 1.2 H), 3.75 (s, 1.8H), 3.07 (s, 1.8H), 2.98 (s, 1.2H), 3.06−3.00
(m, 1H), 2.43 (m, 2H); 19F NMR (282 MHz, CDCl3) (ca.1:1 mixture
of rotamers, both reported) δ −37.0 (s), −37.1 (s); 13C NMR (100.7
MHz, CDCl3) δ 155.7, 154.9, 150.9, 131.0, 130.6, 129.7 (q, J = 310.4
Hz), 127.9, 124.3, 118.3, 118.1, 106.9, 106.8, 87.9, 87.5, 63.1, 62.0,
52.7, 44.6, 38.7, 38.3, 33.5, 32.9, 31.6, 29.0, 22.6, 18.7, 14.1, 11.4; IR
(KBr) υmax 2954, 2884, 1709, 1607, 1447, 1386, 1113, 745 cm−1; MS
(ESI) m/z 333 (M + H)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd
for C14H16F3N2O2S 333.0885, found 333.0879.
(3a,8a)-Methyl 8-allyl-3a-(trifluoromethylthio)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5o). Light yellow
1
oil: H NMR (300 MHz, CDCl3) (ca. 1:1 mixture of rotamers, both
reported) 7.21−7.13 (m, 2H), 6.73 (t, J = 7.5 Hz, 1H), 6.44 (d, J = 7.8
Hz, 1H), 5.91−5.80 (m, 2H), 5.25 (d, J = 15.6 Hz, 1H), 5.16 (s,
0.5H), 5.13 (s, 0.5H), 4.11 (s, 1H), 4.03−3.97 (m, 1H), 3.90−3.84 (m,
1H), 3.76 (s, 1.5H), 3.74 (s, 1.5H), 3.08 (t, J = 9.3 Hz, 1H), 2.44 (m,
2H); 19F NMR (282 MHz, CDCl3) (ca. 1:1 mixture of rotamers, both
reported) −37.1 (s), −37.4(s); 13C NMR (100.7 MHz, CDCl3) δ
155.4, 154.7, 149.9, 133.8, 130.5, 129.4 (q, J = 309.5 Hz), 126.2, 125.9,
124.5, 124.4, 118.3, 118.1, 116.2, 116.1, 107.2, 107.1, 98.7, 86.6, 63.3,
62.3, 52.7, 49.3, 49.1, 44.2, 39.0, 38.6; IR (KBr) υmax 3080, 3054, 2956,
2886, 1711, 1606, 1448, 1116 cm−1; MS (ESI) m/z 359 (M + H)+,
381 (M + Na)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C16H18F3N2O2S 359.1041, found 359.1036.
Methyl 2-(2-(trifluoromethylthio)-1H-indol-3-yl)ethylcarbamate
1
(6a). White solid: mp 120 °C; H NMR (300 MHz, CDCl3) δ 8.63
Methyl 2-(1-allyl-2-(trifluoromethylthio)-1H-indol-3-yl)-
(s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.30 (t, J =
6.9 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 4.82 (s, 1H), 3.67 (s, 3H), 3.49
(q, J = 6.3 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H); 19FNMR (282 MHz,
CDCl3) −42.2 (s, 3F); 13C NMR (100.7 MHz, CDCl3) δ 157.2, 137.6,
128.4(q, J = 312.2 Hz), 127.1, 124.9, 124.0, 120.4, 119.9, 113.9, 111.4,
52.1, 41.3, 25.4; IR (KBr) υmax 3407, 3299, 2950, 1707, 1527, 1131,
1109, 745 cm−1; MS (ESI) m/z 319 (M + H)+; HRMS (ESI-TOF) m/
z [M + H]+ Calcd for C13H14N2O2F3S 319.0728, found 319.0723.
Benzyl 2-(2-(trifluoromethylthio)-1H-indol-3-yl)ethylcarbamate
1
ethylcarbamate (6o). Light yellow solid: mp 90 °C; H NMR (300
MHz, CDCl3) δ 7.74 (d, J = 8.1 Hz, 1H), 7.37−7.30 (m, 2H), 7.18 (t,
J = 7.8 Hz, 1H), 5.90 (m, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.96 (s, 2H),
4.90 (s, 1H), 4.80 (s, 1H), 3.67 (s, 3H), 3.50 (q, J = 6.3 Hz, 2H), 3.20
(t, J = 7.2 Hz, 2H); 19F NMR (282 MHz, CDCl3) −43.6 (s, 3F); 13
C
NMR (100.7 MHz, CDCl3) δ 156.4, 144.0, 141.3, 136.4, 128.9 (q, J =
310.1 Hz), 127.7, 127.0, 125.1, 122.2, 122.1, 120.0, 119.5, 118.7, 112.9,
111.2, 66.5, 47.3, 41.3, 25.8; IR (KBr) υmax 3340, 2950, 1713, 1525,
1454, 1137, 1102, 744 cm−1; MS (ESI) m/z 359 (M + H)+, 376 (M +
NH4)+, 397 (M + K)+; HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C16H18F3N2O2S 359.1041, found 359.1036.
1
(6h). Light yellow solid: mp 117 °C; H NMR (300 MHz, CDCl3)
δ 8.49 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.37−7.24 (m, 7H), 7.13 (t, J
= 7.5 Hz, 1H), 5.11 (s, 2H), 4.86 (s, 1H), 3.50 (q, J = 6.6 Hz, 2H),
3.14 (t, J = 6.6 Hz, 2H); 19F NMR (282 MHz, CDCl3) −43.3 (s, 3F);
13C NMR (100.7 MHz, CDCl3) δ 156.4, 137.6, 136.5, 128.5, 128.4 (q,
J = 316.2 Hz), 128.1, 127.2, 124.9, 124.0, 120.5, 120.0, 113.9, 111.4,
66.7, 41.4, 25.4. IR (KBr) υmax 3413, 3299, 2950, 1704, 1519, 1131,
1109, 745 cm−1; MS (ESI) m/z 395 (M + H)+, 412 (M + NH4)+, 417
(M + Na)+, 433 (M + K)+; HRMS (ESI-TOF) m/z [M + Na]+ Calcd
for C19H17N2O2F3SNa 417.0861, found 417.0855.
(3a,8a)-(9H-Fluoren-9-yl)methyl 5-methyl-3a-(trifluoromethylth-
io)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate
(5q). Light yellow oil: 1H NMR (400 MHz, CDCl3) (ca. 46:54 mixture
of rotamers, both reported) δ 7.81 (t, J = 8.0 Hz, 1H), 7.74 (d, J = 7.2
Hz, 1H), 7.61−7.34 (m, 5H), 7.27 (t, J = 7.6 Hz, 1H), 7.04 (s, 0.46H),
6.97 (d, J = 8.0 Hz, 0.46H), 6.93 (s, 0.54H), 6.90 (d, J = 8.0 Hz,
0.54H), 6.56 (d, J = 8.0 Hz, 0.46H), 6.28 (d, J = 8.4 Hz, 0.54H), 5.61
(s, 0.46H), 5.16 (br, 0.5H), 5.06 (s, 0.54H), 4.74−4.62 (m, 1H),
7544
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(3a,8a)-3a-(Trifluoromethylthio)-1,2,3,3a,8,8a-hexahydropyrrolo-
[2,3-b]indole (7j). To a solution of compound 5j (825 mg, 1.7 mmol)
in acetomitrile (5 mL) was added piperidine (0.34 mL, 3.4 mmol).
The reaction mixture was stirred at room temperature for 10 h. The
solvent was removed in vacuo, and the residue was purified by column
chromatography on silica gel (DCM:MeOH = 20:1) to give diamine
38.7, 38.6, 33.5, 32.1; IR (KBr) υmax 3065, 2952, 2889, 1708, 1607,
1493, 1115, 739 cm−1; MS (ESI) m/z 497 (M + H)+; HRMS (ESI-
TOF) m/z [M + H]+ Calcd for C27H24N2O2F3S 497.1511, found
497.1505.
(3a,8a)-(9H-Fluoren-9-yl)methyl 5-methoxy-8-methyl-3a-(tri-
fluoromethylthio)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-
carboxylate (8r). Using the same condition as described for
compound 8j, compound 8r (21 mg, Yield 80%) was prepared as
1
7j (415 mg, Yield 94%) as clear oil: H NMR (300 MHz, CDCl3) δ
7.23 (d, J = 5.0 Hz, 1H), 7.08 (t, J = 6.9 Hz, 1H), 6.79−6.74 (m, 1H),
6.57−6.54 (m, 1H), 5.38 (s, 1H), 3.08 (t, J = 6.6 Hz, 1H), 2.79−2.70
(m, 1H), 2.50 (br, 2H), 2.34 (d, J = 12.3 Hz, 1H), 2.18−2.12 (m, 1H);
19F NMR (282 MHz, CDCl3) δ −37.5 (s, 3F); 13C NMR (100.7 MHz,
CDCl3) δ 149.9, 129.8 (q, J = 309.9 Hz), 129.7, 127.8, 125.1, 119.4,
109.4, 85.7, 64.5, 44.9, 42.7; IR (KBr) υmax 3395, 3257, 2967, 1608,
1484, 1312, 1115, 745 cm−1; MS (ESI) m/z 261 (M + H)+; HRMS
(ESI-TOF) m/z [M + H]+ Calcd for C11H12N2F3S 261.0673, found
261.0668.
1
clear oil from compound 5r (25.5 mg, 0.05 mmol): H NMR (400
MHz, CDCl3) (ca. 1:1 mixture of rotamers, both reported) δ 7.72 (d, J
= 6.4 Hz, 2H), 7.60−7.54 (m, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.28 (t, J
= 7.6 Hz, 2H), 6.81 (s, 0.5H), 6.74 (s, 0.5H), 6.75 (d, J = 8.4 Hz,
0.5H), 6.69 (d, J = 8.4 Hz, 0.5H), 6.36 (d, J = 8.4 Hz, 0.5H), 6.22 (d, J
= 8.4 Hz, 0.5H), 5.75 (s, 0.5H), 5.17 (s, 0.5H), 4.81 (dd, J = 10.0 Hz,
3.6 Hz, 0.5H), 4.59 (dd, J = 10.0 Hz, 3.6 Hz, 0.5H), 4.50−4.42 (m,
1H), 4.21 (t, J = 4.8 Hz, 1H), 3.89 (t, J = 10.6 Hz, 0.5H), 3.81−3.74
(m, 0.5H), 3.71 (s, 1.5H), 3.67 (s, 1.5H), 3.10−3.04 (m, 0.5H), 3.00
(s, 1.5H), 2.93−2.86 (m, 0.5H), 2.42−2.38 (m, 0.5H), 2.33 (s, 1.5H),
2.30−2.24 (m, 1H), 2.13 (q, J = 8.8 Hz, 0.5H); 19F NMR (376.4 MHz,
CDCl3) (ca. 1:1 mixture of rotamers, both reported) δ −37.4 (s),
−37.7 (s); 13C NMR (100.7 MHz, CDCl3) δ 155.0, 154.2, 153.2,
145.4, 145.2, 144.0, 143.8, 143.8, 143.5, 141.6, 141.4, 129.5 (q, J =
310.0 Hz), 127.8, 127.5, 127.2, 127.1, 125.0, 124.9, 124.5, 120.1, 120.0,
116.0, 110.5, 108.2, 108.0, 88.8, 88.4, 67.3, 66.7, 63.0, 62.2, 56.0, 47.3,
44.7, 44.4, 38.6, 38.4, 34.7, 33.5; IR (KBr) υmax 3068, 2950, 2892,
2831, 1708, 1500, 1115, 757, 740 cm−1; MS (MALDI) m/z 526 (M+);
HRMS (MALDI-TOF) m/z [M]+ Calcd for C28H25N2O3F3S
526.1538, found 526.1533.
(3a,8a)-8-Methyl-3a-(trifluoromethylthio)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (9j). To a solution of compound 8j
(135 mg, 0.27 mmol) in acetomitrile (3 mL) was added piperidine (54
μL, 0.54 mmol). The reaction mixture was stirred at room temperature
for 10 h. The solvent was removed in vacuo, and the residue was
purified by column chromatography on silica gel (petroleum
ether:ethyl acetate = 1:1) to give compound 9j (70 mg, 96%) as
clear oil: 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.6 Hz, 1H), 7.14
(t, J = 6.8 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.37 (d, J = 7.6 Hz, 1H),
5.14 (s, 1H), 3.12 (dd, J = 11.6 Hz, 7.2 Hz, 1H), 2.89 (s, 3H), 2.69 (dt,
J = 11.2 Hz, 5.6 Hz, 1H), 2.34 (dd, J = 12.4 Hz, 5.2 Hz, 1H), 2.23 (s,
1H), 2.11−2.06 (m, 1H); 19F NMR (376.4 MHz, CDCl3) δ −37.7 (s,
3F); 13C NMR (100.7 MHz, CDCl3) δ 151.1, 129.9, 129.7 (q, J =
309.9 Hz), 127.4, 124.8, 117.3, 105.8, 92.3, 63.1, 45.1, 43.0, 32.0; IR
(KBr) υmax 3331, 2938, 2877, 1607, 1496, 1115, 741 cm−1; MS
(MALDI) m/z 275 (M + H)+; HRMS (MALDI-TOF) m/z [M + H]+
Calcd for C12H14N2F3S 275.0830, found 275.0824.
(3a,8a)-5-Methoxy-8-methyl-3a-(trifluoromethylthio)-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (9r). Using the same
condition as described for compound 9j, compound 9r (1.30 g, 90%
yield) was prepared as clear oil from compound 8r (2.50 g, 4.74
mmol): 1H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 2.8 Hz, 1H), 6.74
(dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 5.09 (s, 1H),
3.75 (s, 3H), 3.12 (ddd, J = 11.6 Hz, 7.2 Hz, 1.6 Hz, 1H), 2.86 (s, 3H),
2.60 (br, 1H), 2.76−2.69 (m, 1H), 2.32 (ddd, J = 12.8 Hz, 5.2 Hz, 1.6
Hz, 1H), 2.12−2.04 (m, 1H); 19F NMR (376.4 MHz, CDCl3) δ −37.7
(s, 3F); 13C NMR (100.7 MHz, CDCl3) δ 152.6, 145.7, 129.5 (q, J =
309.6 Hz), 128.8, 115.4, 111.3, 107.0, 93.2, 63.2, 56.0, 45.1, 42.7, 33.4;
IR (KBr) υmax 3337, 2938, 2877, 2825, 1500, 1278, 1217, 1115 cm−1;
MS (MALDI) m/z 304 (M+); HRMS (MALDI-TOF) m/z [M]+
Calcd for C13H15N2F3SO 304.0857, found 304.0852.
(3a,8a)-1,8-Dimethyl-3a-(trifluoromethylthio)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (10j). To a solution of compound 9j
(40 mg, 0.146 mmol) in methanol (5 mL) was added formalin
(HCHO aq, 37%) (55 μL, 0.729 mmol). The mixture was stirred at 0
°C for 10 min, and then NaBH(OAc)3 (155 mg, 0.729 mmol) was
added in portions, and the reaction mixture was returned to room
temperature by stirring 3 h. The reaction mixture was quenched with
saturated NaHCO3 solution and extracted by EtOAc. The organic
phase was dried over sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by flash chromatog-
raphy (petroleum ether:ethyl acetate = 10:1) on silica gel to give
(3a,8a)-5-Methyl-3a-(trifluoromethylthio)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (7q). Using the same condition as
described for compound 7j, compound 7q (52 mg, Yield 90%) was
prepared as clear oil from compound 5q (108 mg, 0.21 mmol),
1
piperidine (65 μL, 0.65 mmol): H NMR (300 MHz, CDCl3) δ 7.05
(s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 7.5 Hz, 1H), 5.38 (s,
1H), 3.08 (dd, J = 11.4 Hz, 6.9 Hz, 1H), 2.75 (dt, J = 11.4 Hz, 4.8 Hz,
1H), 2.35 (dd, J = 12.3 Hz, 4.2 Hz, 1H), 2.19−2.04 (m, 1H); 19F
NMR (282 MHz, CDCl3) δ −38.1 (s, 3F); 13C NMR (100.7 MHz,
CDCl3) δ 147.7, 130.4, 129.9 (q, J = 309.9 Hz), 129.0, 128.2, 125.5,
109.7, 85.9, 64.8, 44.9, 42.6, 20.8; IR (KBr) υmax 3255, 3054, 2970,
2881, 1608, 1484, 1107, 745 cm−1; MS (EI) m/z 274 (M+); HRMS
(EI-TOF) m/z [M]+ Calcd for C12H13N2F3S 274.0752, found
274.0750.
(3a,8a)-5-Methoxy-3a-(trifluoromethylthio)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (7r). Using the same condition as
described for compound 7j, compound 7r (569 mg, Yield 86%) was
prepared as clear oil from compound 5r (1.17 g, 2.28 mmol),
piperidine (0.45 mL, 4.57 mmol): 1H NMR (300 MHz, CDCl3) δ 6.84
(s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.39 (s,
1H), 3.77 (s, 3H), 3.2 (br, 2H), 3.10 (dd, J = 10.2 Hz, 7.5 Hz, 1H),
2.79 (dt, J = 10.8 Hz, 5.1 Hz, 1H), 2.36 (dd, J = 12.0 Hz, 4.5 Hz, 1H),
2.16 (dt, J = 10.8 Hz, 7.2 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ
−37.4 (s, 3F); 13C NMR (100.7 MHz, CDCl3) δ 154.1, 143.8, 129.8
(q, J = 309.7 Hz), 129.5, 115.9, 111.0, 110.5, 86.3, 65.0, 55.9, 44.7,
42.3; IR (KBr) υmax 3291(br), 2944, 2831, 1495, 1213, 1113, 1032
cm−1; MS (ESI) m/z 291 (M + H)+; HRMS (ESI-TOF) m/z [M +
H]+ Calcd for C12H14F3N2OS 291.0779, found 291.0773.
(3a,8a)-(9H-Fluoren-9-yl)methyl 8-methyl-3a-(trifluoromethylth-
io)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (8j).
To a solution of compound 5j (24 mg, 0.05 mmol) in acetonitrile (1
mL) were added HOAc (14 μL, 0.25 mmol) and formalin (HCHO aq,
37%) (19 μL, 0.25 mmol). The mixture was stirred at room
temperature for 10 min and then cooled to 0 °C. NaBH3CN (13
mg, 0.20 mmol) was added in portions, and the reaction mixture was
returned to room temperature by stirring 1 h. The reaction mixture
was quenched with saturated NaHCO3 solution and extracted by
EtOAc. The organic phase was dried over sodium sulfate. The solvent
was removed under reduced pressure, and the residue was purified by
flash chromatography (petroleum ether:ethyl acetate = 10:1) on silica
1
gel to give compound 8j as clear oil (19 mg) in 75% yield: H NMR
(300 MHz, CDCl3) (ca.1:1 mixture of rotamers, both reported) δ 7.77
(d, J = 6.9 Hz, 2H), 7.63−7.58 (m, 2H), 7.43−7.31 (m, 4H), 7.19 (d, J
= 6.0 Hz, 1H), 7.12 (d, J = 6.6 Hz, 1H), 6.76−6.66 (m, 1H), 6.44 (d, J
= 7.2 Hz, 0.5H), 6.30 (d, J = 7.2 Hz, 0.5H), 5.79 (s, 0.5H), 5.21 (s,
0.5H), 4.84 (d, J = 9.9 Hz, 0.5H), 4.63 (d, J = 9.9 Hz, 0.5H), 4.48 (s,
1H), 4.27 (s, 1H), 3.93 (t, J = 8.4 Hz, 0.5H), 3.81 (t, J = 9.0 Hz, 0.5H),
3.04 (s, 2.0H), 3.14−3.00 (m, 0.5H), 2.48−2.38 (m, 1H), 2.36 (s,
1.5H), 2.35−2.30 (m, 0.5H), 2.24−2.14 (m, 0.5H); 19F NMR (282
MHz, CDCl3) (ca.1:1 mixture of rotamers, both reported) δ −37.1
(s), −37.4 (s); 13C NMR (100.7 MHz, CDCl3) δ 155.1, 154.3, 150.9,
150.7, 144.0, 143.9, 143.6, 141.7, 141.4, 130.6, 130.5, 129.4 (q, J =
317.3 Hz), 127.8, 127.2, 126.2, 126.0, 125.0, 124.9, 124.5, 124.3, 120.1,
118.2, 107.0, 106.7, 87.9, 87.5, 67.4, 66.8, 62.9, 62.1, 47.3, 44.7, 44.4,
7545
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Article
1
compound 10j as a clear oil (40 mg) in 95% yield: H NMR (300
MHz, CDCl3) δ 7.24−7.15 (m, 2H), 6.76 (t, J = 7.2 Hz, 1H), 6.50 (d,
J = 7.8 Hz, 1H), 4.81 (s, 1H), 3.00 (s, 3H), 2.81 (dt, J = 4.8 Hz, 3.6
Hz, 1H), 2.57 (s, 3H), 2.59−2.51 (m, 1H), 2.30−2.25 (m, 2H); 19F
NMR (282 MHz, CDCl3) δ −38.5 (s, 3F); 13C NMR (100.7 MHz,
CDCl3) δ 152.1, 129.9, 129.3 (q, J = 310.0 Hz), 124.5, 118.2, 107.7,
96.7, 62.3, 50.9, 40.2, 37.3, 36.9; IR (KBr) υmax 2964, 2931, 2866,
2796, 1606, 1490, 1111, 741 cm−1; MS (EI) m/z 288 (M+); HRMS
(EI-TOF) m/z [M]+ Calcd for C13H15N2F3S 288.0908, found
288.0903.
(3a,8a)-5-Methoxy-1,8-dimethyl-3a-(trifluoromethylthio)-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (10r). Using the same
condition as described for compound 10j, compound 10r (47 mg, 90%
yield) was prepared as clear oil from compound 9r (50 mg, 0.164
mmol): 1H NMR (300 MHz, CDCl3) δ 6.85 (d, J = 2.8 Hz, 1H), 6.74
(dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 5.09 (s, 1H),
3.75 (s, 3H), 3.12 (ddd, J = 11.6 Hz, 7.2 Hz, 1.6 Hz, 1H), 2.86 (s, 3H),
2.60 (br, 1H), 2.76−2.69 (m, 1H), 2.32 (ddd, J = 12.8 Hz, 5.2 Hz, 1.6
Hz, 1H), 2.12−2.04 (m, 1H); 19F NMR (376.4 MHz, CDCl3) δ −37.3
(s, 3F). The 13C NMR and MS of compound 10r were not given
because of its instability.
Biological Assay. All the cell lines were originally obtained from
the American Type Culture Collection (ATCC, Manassas, VA) and
were cultured in DMEM medium (HeLa) or RIPM1640 (L929, K562)
with 10% FBS and supplemented with 1% P/S (penicillin/
streptomycin). Cell Counting Kit-8 (CK-04) was bought from
Dojindo (Kumamoto, Japan) for the Cytotoxicity Assay. All
compounds tested were dissolved in DMSO to a concentration of
0.5, 5, 50 mM. The DMSO concentration is ≤0.04%. Cytotoxicity of
the above compounds to the three cell lines was determined using the
Cell Counting Kit-8 (CCK-8). In brief, 4 × 103 cells (per well) were
seeded in 96-well plates and were treated for 48 h with the compounds
in Table 4 at concentrations of 0, 0.5, 5, 50 μM (arranged triplicate).
After 48 h of treatment, 10 μL of CCK-8 solution (Dojindo) were
added to each well. Plates were incubated for an additional 2−4 h at 37
°C, after which the absorbance at 450 nm was recorded using a
SpectraMax190 microplate reader (Molecular Devices, USA) to
calculate the inhibition rate.
(2) Sorbera, L, A.; Castaner, J. Drugs Future 2003, 28, 18−25 and
references cited therein.
(3) For reviews, see: (a) Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F.;
́
Alvarez, M. Chem.Eur. J. 2011, 17, 1388−1408. (b) Steven, A.;
Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488−5508 and
references cited therein.
(4) (a) Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem. Soc. 2010,
132, 8282−8284. (b) Villanueva-Margalef, I.; Thurston, D. E.; Zinzalla,
G. Org. Biomol. Chem. 2010, 8, 5294−5303.
(5) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lien,
E. J. J. Med. Chem. 1973, 16, 1207−1216.
(6) (a) Szmuszkovicz, J.; Glenn, E. M.; Heinzelman, R. V.; Hester, J.
B.; Youngdale, G. A. J. Med. Chem. 1966, 9, 527−536. (b) Smart, B. E.;
Tatlow, J. Organofluorine Chemistry: Principles and Commercial
Applications; Plenum: New York, 1994. (c) Becker, A. Inventory of
Industrial Fluoro-Biochemicals; Eyrolles: Paris, 1996. (d) Langlois, B. R.;
Billard, T.; Large, S.; Roques, N. Fluorinated Bioactive Compounds;
Fluorine Technology Ltd.: Cheshire, 1999. (e) Hiyama, T. Organo-
fluorine Compounds: Chemistry and Applications; Springer Verlag:
Berlin, 2000. (f) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev.
2005, 105, 827−856.
(7) For review, see: (a) Boiko, V. N. Beilstein J. Org. Chem. 2010, 6,
880−921. For recent examples through cross-coupling: (b) Tever-
ovskiy, G.; Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011,
50, 7312−7314. (c) Zhang, C.-P.; Vicic, D. A. J. Am. Chem. Soc. 2012,
134, 183−185. (d) Chen, C.; Xie, Y.; Chu, L.; Wang, R.-W.; Zhang, X.;
Qing, F.-L. Angew. Chem., Int. Ed. 2012, 51, 2492−2495. (e) Zhang,
C.-P.; Vicic, D. A. Chem.Asian J. 2012, 7, 1756−1758. (f) Chen, C.;
Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 12454−12457.
(8) Ferry, A. l.; Billard, T.; Langlois, B. R.; Bacque,
́
E. J. Org. Chem.
2008, 73, 9362−9365.
(9) Ferry, A.; Billard, T.; Langlois, B. R.; Bacque,
́
E. Angew. Chem.,
Int. Ed. 2009, 48, 8551−8555.
(10) Ferry, A.; Billard, T.; Bacque, E.; Langlois, B. R. J. Fluorine Chem.
́
2012, 134, 160−163.
(11) (a) Lozano, O.; Blessley, G.; Martinez del Campo, T.;
Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman,
R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105−8109.
(b) Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2009, 324, 238−
241. (c) Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
10886−10887. (d) He, B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem.
2008, 74, 298−304. (e) Movassaghi, M.; Schmidt, M. A. Angew. Chem.,
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data of trypt-
amine derivatives 4, and copies of 1H NMR, 19F NMR, and 13
C
NMR spectra of all the new compounds. These materials are
available free of charge via the Internet at http://pubs.acs.org.
Int. Ed. 2007, 46, 3725−3728. (f) Lop
́
ez-Alvarado, P.; Caballero, E.;
Avendano, C.; Menendez, J. C. Org. Lett. 2006, 8, 4303−4306.
́
̃
(g) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W.
C. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5482−5487. (h) Tan, G.
H.; Zhu, X.; Ganesan, A. Org. Lett. 2003, 5, 1801−1803. (i) Kawahara,
M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675−678. (j) Crich,
D.; Huang, X. J. Org. Chem. 1999, 64, 7218−7223. (k) Bruncko, M.;
Crich, D.; Samy, R. J. Org. Chem. 1994, 59, 5543−5549. (l) Bruncko,
M.; Crich, D.; Samy, R. Heterocycles 1993, 36, 1735. (m) Bourne, G.
T.; Crich, D.; Davies, J. W.; Horwell, D. C. J. Chem. Soc., Perkin Trans.
1 1991, 1693−1699. (n) Taniguchi, M.; Gonsho, A.; Nakagawa, M.;
Hino, T. Chem. Pharm. Bull. 1983, 31, 1856.
AUTHOR INFORMATION
Corresponding Author
*E-mail: flq@mail.sioc.ac.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
National Natural Science Foundation of China (21072028,
20832008) and National Basic Research Program of China
(2012CB21600) are greatly acknowledged for funding this
work.
(12) Lucarini, S.; Bartoccini, F.; Battistoni, F.; Diamantini, G.;
Piersanti, G.; Righi, M.; Spadoni, G. Org. Lett. 2010, 12, 3844−3847.
(13) Del Bene, J. E.; Alkorta, I.; Elguero, J.; Mo,
Chem. A 2010, 114, 12775−12779.
́ ́
O.; Yanez, M. J. Phys.
̃
(14) For a selected example of analogous seleniranium ions in indole
substrates, see: Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski,
A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,
11953−11963.
REFERENCES
■
(1) For selected reviews, see: (a) Giacobini, E. Ann. N. Y. Acad. Sci.
2000, 920, 321−327. (b) Sneader, W. Drug News Perspect. 1999, 12,
433−437. (c) Pelletier, S. W. Alkaloids: Chemical and Biological
Perspectives; Pergamon: New York, 1999. (d) Triggle, D. J.; Mitchell, J.
M.; Filler, R. CNS Drug Rev. 1998, 4, 87−136. (e) Giacobini, E.
Neurochem. Int. 1998, 32, 413−419. (f) Hino, T.; Nakagawa, M. The
Alkaloids: Chemistry and Pharmacology; Academic Press: New York,
1989.
(15) For thiiranium ion involved in double bond functionalization,
see: (a) Rayner, C. M. In Organosulfur Chemistry: Synthetic Aspects;
Page, P., Ed.; Academic Press: London, 1995; Chapter 3. (b) Smit, V.
A.; Zefirov, N. S.; Bodrikov, I. V.; Krimer, M. Z. Acc. Chem. Res. 1979,
12, 282−288.
7546
dx.doi.org/10.1021/jo3013385 | J. Org. Chem. 2012, 77, 7538−7547

The Journal of Organic Chemistry
Article
(16) Li, L.-Y.; Ding, Y.; Groth, I.; Menzel, K.-D.; Peschel, G.; Voigt,
K.; Deng, Z.-W.; Sattler, I.; Lin, W.-H. J. Asian Nat. Prod. Res. 2008, 10,
765−770.
(17) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama, H.
Tetrahedron Lett. 2006, 47, 3199−3202.
7547
dx.doi.org/10.1021/jo3013385 | J. Org. Chem. 2012, 77, 7538−7547