Sulfuric acid-catalyzed regioselective alkylation of indoles and β-naphthols with ketene dithioacetal-based allylic alcohols

Article abstract of DOI:10.1002/ejoc.201001487

A novel catalytic alkylation of indoles with allylic alcohols has been developed. Catalyzed by sulfuric acid (10 mol-%), the reaction between indoles 2 and allylic alcohols 1 based on ketene dithioacetal affords polyfunctionalized indoles 3 in good to exc

Full text of DOI:10.1002/ejoc.201001487

FULL PAPER
DOI: 10.1002/ejoc.201001487
Sulfuric Acid-Catalyzed Regioselective Alkylation of Indoles and β-Naphthols
with Ketene Dithioacetal-Based Allylic Alcohols
Mang Wang,*[a,b] Shaoguang Sun,[a] Deqiang Liang,[a] Bangyu Liu,[a] Ying Dong,[a] and
Qun Liu*[a]
Keywords: Homogeneous catalysis / C-C coupling / Allylation / Regioselectivity / Indoles
A novel catalytic alkylation of indoles with allylic alcohols
has been developed. Catalyzed by sulfuric acid (10 mol-%),
the reaction between indoles 2 and allylic alcohols 1 based
on ketene dithioacetal affords polyfunctionalized indoles 3 in
good to excellent yields with high regioselectivities under
mild conditions. The catalytic carbon–carbon coupling reac-
tion provides a facile method for the environmentally benign
functionalization of indoles with the advantages of good regi-
ochemistry, atom efficiency, easily available catalyst, good
yields and the synthetic potential of the polyfunctionalized
indole products. Thus, further transformation of the resulting
indoles 3 into pyridoindolone derivatives 4 was investigated.
The efficiency of this carbon–carbon coupling reaction of 1
with 2 under the catalysis of sulfuric acid is due to the ef-
ficient formation of the reactive intermediate I, which is a
carbocation that is strongly stabilized by two alkylthio groups
at the terminal of the carbon–carbon double bond. The ex-
tension of this catalytic strategy to the synthesis of β-naphth-
ols 5 was also achieved.
Introduction
for the promotion of direct coupling between alcohols and
nucleophiles have been developed, and some of these ap-
proaches have been successfully applied to the allylation of
indoles.[6e,6g,6h] Brønsted acids are typically economical, be-
nign, and easily available catalysts for organic reactions,[8]
however, the coupling of alcohols with arenes in the pres-
ence of sub-stoichiometric loadings of Brønsted acids has
been limited to the investigation of the allylation of in-
doles.[9]
During our ongoing research on ketene dithioacetal
chemistry,[10,11] α-hydroxy ketene dithioacetals 1 were rec-
ognized as a type of reactive, functionalized allylic alcohol
that could be used in the synthesis of useful com-
pounds.[11,12] Taking into consideration the versatile reactiv-
ities of 1 as efficient electrophiles and the electron-rich in-
doles 2 as nucleohphiles, together with the importance of
the functionalization of indoles, we decided to investigate
the possibility of coupling 1 and 2 under the action of a
range of available Brønsted acids as catalysts. To our de-
light, the reaction proceeded smoothly to afford the cou-
pling products 3 in good to excellent yields with high regio-
selectivities in the presence of 10 mol-% of H2SO4 in aceto-
nitrile at room temperature. The coupling products 3 were
polyfunctionalized indoles that were successfully applied in
the synthesis of pyridoindolone derivatives 4. Additionally,
the extension of this catalytic strategy to the synthesis of β-
naphthols 5 was also achieved. In this paper, we wish to
report this efficient, regioselective, and environmentally be-
nign method for the allylation of indoles and β-naphthols
using α-hydroxy ketene dithioacetals 1 as allylating agents
under the catalysis of H2SO4.
The functionalization of indoles, especially through low
cost, selective, and economically and environmentally
friendly strategies, is of great synthetic importance for the
preparation of pharmaceuticals, agrochemicals, and fine
chemicals.[1] Among them, Lewis acid promoted Friedel–
Crafts reactions have proved to be remarkably effective in
the C3-alkylation of indoles under homogeneous, as well
as heterogeneous, conditions.[2,3] In this field, although the
alkylation of indoles with allyl halides, allyl acetates or allyl
carbonates provides a valuable method for the direct al-
lylation of indoles, these procedures generally suffer from
problems associated with the regiochemistry of alkylation
at the N1, C2 or C3 positions of the indole nucleus.[3]
Recently, the C–C coupling of alcohols as electrophiles
with reactive carbon-centered nucleophiles has attracted the
interest of many synthetic chemists due to the ready avail-
ability of starting materials, the atom efficiency, and the be-
nign environmental nature.[4] However, the major limitation
of these procedures is that either an excess of a protonic
acid or a stoichiometric amount of a Lewis acid is re-
quired.[5] In the last years, a number of elegant methods
involving metal complexes,[6] or metal salts[4a,7] as catalysts
[a] Department of Chemistry, Northeast Normal University,
Changchun 130024, P. R. of China
Fax: +86-431-85099759
E-mail: wangm452@nenu.edu.cn
liuqun@nenu.edu.cn
[b] State Key Laboratory of Fine Chemicals, Dalian University of
Technology,
Dalian 116012, P. R. of China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001487.
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Regioselective Alkylation of Indoles and β-Naphthols
79 and 90% yield, respectively, and required longer reaction
times (Table 1, entries 3 and 4). Use of acetic acid afforded
the product in only trace amounts, even after an extended
reaction time (Table 1, entry 5). By comparison, coupling
product 3a was not be obtained in the absence of catalyst
(Table 1, entry 6). Additionally, among the solvents tested
(CH3CN, tetrahydrofuran (THF), CH2Cl2, EtOH, and
H2O), acetonitrile proved to be the most efficient with re-
spect to both the yield and reaction time (Table 1, entry 2
vs. entries 7–10).
Results and Discussion
Preparation of Starting Materials
According to the procedure reported previously, α-hy-
droxy ketene dithioacetals 1a–g, 1i, and 1j were conve-
niently prepared in excellent yields through a two-step pro-
cess involving the preparation of α-acetyl ketene dithioacet-
als (containing RЈ = electron-withdrawing group or RЈ = 4-
MeOC6H4) starting from the corresponding active methyl-
ene compounds, carbon disulfide and alkyl halides in the
presence of K2CO3, and sequential reduction of the corre-
sponding α-acetyl ketene dithioacetals with NaBH4.[11] For
the preparation of substrate 1h (RЈ = H), an additional
acid-promoted deacylation[13] was required before reduction
of the α-acetyl ketene dithioacetal. The results are listed in
Scheme 1.
Table 1. Optimization of conditions for the coupling between 1a
and 2a.
Entry Cat.
Solvent
Time [min] Yield [%][a,b]
1
2
3
4
5
6
7
8
9
HCl
H2SO4
TFA
PTSA
AcOH
–
H2SO4
H2SO4
H2SO4
H2SO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
CH2Cl2
EtOH
H2O
120
5
240
30
720
720
60
30
720
720
65
98
79
90
trace[c]
[d]
–
90
94
[d]
–
–
[d]
10
[a] Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst
(0.1 mmol), solvent (3 mL), r.t. [b] Isolated yield. [c] Substrates 1a
and 2a were recovered in 95 and 97%, respectively. [d] No reaction.
Sulfuric Acid-Catalyzed Coupling of α-Hydroxy Ketene
Dithioacetals 1 with Indoles 2
Scheme 1. Preparation of α-hydroxy ketene dithioacetals 1a–j.
Under the optimized conditions (Table 1, entry 2), the
scope of the reaction was investigated. As described in
Table 2, all α-hydroxy ketene diethyl thioacetals 1a–g with
a wide range of functional groups at the α-position, includ-
ing N-aryl/alkyl carbonyl, cyano, and ethoxycarbonyl, re-
acted readily with indole 2a to afford the coupling products
Optimization of Reaction Conditions for the Acid-Catalyzed
Coupling of α-Hydroxy Ketene Dithioacetal 1a with Indole
2a
As an initial attempt, the reaction of 2-[bis(ethylthio)- 3 in excellent yields (Table 2, entries 1–7). In the case of 1h
methylene]-3-hydroxy-N-phenylbutanamide (1a; 1 mmol) (R = Et, RЈ = H) as substrate, the reaction usually led to the
with indole 2a (1 mmol) catalyzed by 10 mol-% concen- formation of an unidentified mixture at room temperature.
trated aqueous HCl, was carried out in acetonitrile (3 mL) When the reaction of 1h and 2a was carried out at –40 °C,
at room temperature for 120 min (Table 1, entry 1). The re- the desired product 3i could be isolated in 78% yield
action furnished a white solid in 65% yield after work-up (Table 2, entry 8). Similarly, α-hydroxy cyclic ketene di-
and column chromatography of the resulting mixture. The thioacetals 1i (with an α-N-aryl carbonyl substituent) and
product was characterized as 2-[bis(ethylthio)methylene]-3- 1j (with an α-aryl substituent) also furnished the corre-
(1H-indol-3-yl)-N-phenylbutanamide (3a) on the basis of its sponding coupling product 3i and 3j, respectively, in high
spectra and analytical data. The model reaction between 1a yield (Table 2, entries 9 and 10). The versatility of the above
and 2a was then further examined to optimize the reaction reaction was then demonstrated with the successful prepa-
conditions. As shown in Table 1, 10 mol-% concentrated ration of the corresponding coupling products 3 by treat-
aqueous H2SO4 could dramatically increase the yield of 3a ment of various indoles 2 (1 mmol) with 1a (1 mmol) under
to 98% within 5 min (Table 1, entry 2). When organic acids the catalysis of H2SO4. It was found that all the tested in-
were selected as catalyst, trifluoroacetic (TFA) and p-tolu- doles 2 with substitutes at the 1-, 2-, 4-, and 5-positions
enesulfonic acid (PTSA) both gave the desired product in were suitable substrates for the reaction, affording 3k–o in
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M. Wang, Q. Liu et al.
FULL PAPER
92–97% yields (Table 2, entries 11–15). It is noteworthy that
these reactions were completed within 15 min to afford ki-
netically stable C3-allylated products, and no products al-
lylated at either the C2 or N1 positions were detected in
any of the cases. It is clear that the above results show a
novel catalytic coupling with respect to a range of ketene
dithioacetal-based allylic alcoholes 1 and indoles 2. Thus,
an efficient, environmental benign, and regioselective
method for the allylation of indoles under very mild condi-
tions has been developed.
Table 2. H2SO4-catalyzed coupling of α-hydroxy ketene dithioacet-
als 1 with indoles 2.
Scheme 2. Synthesis of pyridoindolone derivatives 4 through the
cyclization of 3 in the presence of NCS.
R
RЈ
2
RЈЈ RЈЈЈ
Time Yield
[min] [%][a,b]
1
2
3
4
5
6
7
8
9
1a Et
1b Et
1c Et
1d Et
1e Et
1f Et
1g Et
1h Et
PhNHCO
2,4-Me2C6H3NHCO 2a
2-MeOC6H4NHCO 2a
4-ClC6H4NHCO
MeNHCO
CN
2a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d 10
3e 15
3f
3g
3h
3i
5
5
5
98
98
99
95
93
94
95
78[c]
98
85[c]
97
95
92
93
95
2a
2a
2a
2a
2a
2a
2a
5
5
5
5
5
5
5
CO2Et
H
1i (CH2)2 2-MeC6H4NHCO
10 1j (CH2)2 4-MeOC6H4
3j
3k
3l
11 1c Et
12 1a Et
13 1a Et
14 1a Et
15 1a Et
2-MeOC6H4NHCO 2b Et
PhNHCO
PhNHCO
PhNHCO
PhNHCO
2c Et 2-Ph
2d
2e
2f
H
H
H
4-MeO 3m 15
5-MeO 3n 15
5-Br
3o 12
Figure 1. Molecular structure of 4a.
[a] Reaction conditions: 1 (1 mmol), 2 (1 mmol), conc. H2SO4
(0.1 mmol), CH3CN (3 mL), r.t. [b] Isolated yields. [c] The reaction
was performed at –40 °C.
Mechanism for the Sulfuric Acid-Catalyzed Coupling
Reaction of α-Hydroxy Ketene Dithioacetals 1 with Indoles
2
The H2SO4-catalyzed allylation of indoles described
above represents a green and inexpensive catalytic process
for the C–C coupling of alcohols as electrophiles with nu-
Application of the Resulting Polyfunctionalized Indoles 3
As presented above, the H2SO4-catalyzed coupling reac- cleophiles. It is widely known that the generation of a stable
tion of 1 with 2 gives facile access to polyfunctionalized carbocation from a protonated alcohol is the most impor-
indoles. These functional groups can provide opportunities tant issue in proton-catalyzed nucleophilic substitution of
for further elaboration of these indoles. Thus, a simple cycli- alcohols. Generally, an excess of a protonic acid is required
zation of indoles 3 was examined in the presence of N-chlo- for efficient activation of alcohols due to the poor leaving
rosuccinimide (NCS) under basic conditions[14] for the syn- ability of the hydroxyl group.[5] In fact, the range of possible
thesis of pyridoindolone derivatives 4.[15] As summarized Brønsted acids as catalyst in sub-stoichiometric loadings for
in Scheme 2, all the tested cyclizations of 3 furnished 3- this procedure is rather limited.[4,9] Based on the nature of
[bis(ethylthio)methylene]-4a-chloro-4-methyl-1-aryl-4,4a-di- the functionalized ketene dithioacetals and on our previous
hydro-1H-pyrido[2,3-b]indol-2(3H)-ones 4 in good to high work,[10,11] the efficient production of highly delocalized
yield. No dehydrochlorination product of 4 was isolated in allylic carbocation I, which is stabilized by two alkythiol
any of the cases. Further attempts at the dehydrochlorina- groups, plays an important role in the H2SO4-catalyzed C–
tion of 4 under basic conditions led to complex mixtures. C coupling reaction of α-hydroxy ketene dithioacetals 1
Products 4 were well-characterized by their spectra and an- with indoles 2 in our experiments. As shown in Scheme 3,
alytical data, and their structure was further established by the coupling reaction starts with the formation of carbo-
X-ray diffraction studies of 4a (Figure 1).[16]
cation intermediate I by protonation and sequential dehy-
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Regioselective Alkylation of Indoles and β-Naphthols
dration of 1 in the presence of H2SO4. Then, nucleophilic
attack of indoles 2 on carbocation I leads to the coupling
product 3.
Scheme 5. H2SO4-catalyzed coupling of α-hydroxy ketene di-
thioacetals 1 with β-naphthols 5.
Conclusions
This paper demonstrates an environmentally benign and
regioselective H2SO4-catalyzed allylation of indoles and β-
naphthols with ketene dithioacetal-based allylic alcohols.
The reactions provide densely functionalized indoles and β-
naphthols 3 and 6, which are interesting building blocks in
organic synthesis, from readily available starting materials
1 in good to excellent yields and in high regioselectivities
under very mild reaction conditions. The preparation of py-
ridoindolone derivatives 4 was achieved by the cyclization
of functionalized indoles 3 in the presence of NCS under
the action of base. Future studies will focus on extending
the scope of this catalytic C–C coupling reaction and on its
synthetic applications in organic chemistry.
Scheme 3. Stable carbocation I as an intermediate in the H2SO4-
catalyzed coupling of 1 with 2.
To discover the key role of the ketene dithioacetal func-
tionality for these procedures, the reaction of 1-phenyl-
ethanol and indole was investigated (Scheme 4). In contrast
to the H2SO4-catalyzed coupling reactions of α-hydroxy
ketene dithioacetals 1 with indoles 2, which were completed
within 15 min (Table 2), no reaction was detected when 1-
phenylethanol and indole were submitted to identical reac-
tion conditions for 60 min; prolonging the reaction time to
240 min, led to only trace amounts of an unidentified com-
pound (TLC analysis).
Experimental Section
General: All reagents were purchased from commercial sources and
used without treatment, unless otherwise indicated. The products
were purified by column chromatography over silica gel (300–
400 mesh). All reactions were monitored by TLC, which was per-
formed on precoated aluminum sheets of silica gel 60 (F254). 1H
and 13C NMR spectra were determined at ambient temperature
with a Varian 500 MHz and 125/100 MHz spectrometer, respec-
tively, using TMS as internal standard. All shifts are given in ppm.
IR spectra (KBr) were recorded with a Magna-560 FTIR spectro-
photometer in the range of 400–4000 cm–1. Mass spectra were mea-
sured with an Agilient 1100 LCMsD spectrometer. Elemental
analyses were obtained with a VarioEL analyzer. For X-ray analy-
sis, compound 4a (crystal dimension 0.22ϫ0.18ϫ0.15 mm) was
glued onto a glass fiber. Data were collected with a Bruker Smart
Apex2 CCD diffractometer at 293 K using graphite-monochro-
mated Mo-Kα radiation (λ = 0.71073 Å) and IP technique in the
range 1.60°ϽθϽ26.07°.
Scheme 4. H2SO4-catalyzed reaction of 1-phenylethanol and indole.
Sulfuric Acid-Catalyzed Coupling of α-Hydroxy Ketene
Dithioacetals 1 with β-Naphthols 5
Recently, an AlCl3 (1 equiv.) mediated C–C coupling re-
action between α-hydroxy ketene dithioacetals 1 and β-
naphthols 5 was realized in our laboratory, and an efficient
synthesis of 3,4-disubstituted dihydrocoumarins was thus
developed based on this synthetic strategy.[11c] To pursue a
more efficient coupling between 1 and 5 and also to explore
the scope of the catalytic coupling reaction of ketene di-
thioacetal-based allylic alcohols with nucleophiles, the
H2SO4-catalyzed coupling of 1 with 5 was investigated. As
expected, when the selected α-hydroxy ketene dithioacetals
1a (or 1c, 1f, 1g; 1 mmol) were reacted with β-naphthol 5a
(or 5b; 1 mmol) in acetonitrile (3 mL) at room temperature
in the presence of H2SO4 (10 mol-%), the coupling products
6a–e were obtained in 65–82% isolated yields, respectively,
within 4.5 h (Scheme 5).
Typical Procedure for the Coupling Reaction of 1 with 2. Compound
2a: To a solution of 2-[bis(ethylthio)methylene]-3-hydroxy-N-phen-
ylbutanamide (1a; 311 mg, 1 mmol) and indole 2a (117 mg,
1 mmol) in CH3CN (3 mL) was added concentrated H2SO4 in
CH3CN (0.1 mL, 1 molL–1, 0.1 mmol) at room temperature. The
reaction was allowed to proceed at room temperature and was com-
plete within 5 min. The reaction was quenched with saturated aque-
ous NaHCO3, and 3a (402 mg, 98%) was collected as a white solid
by filtration and dried in air.
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M. Wang, Q. Liu et al.
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Typical Procedure for the Synthesis of 4. Compound 4a: To a solu-
tion of 3a (205 mg, 0.5 mmol) and tBuOK (224 mg, 2 mmol) in
CH2Cl2 (5 mL) was added NCS (160 mg, 1.2 mmol). The reaction
was allowed to proceed at room temperature and was complete
within 5 min. The reaction mixture was poured into saturated
aqueous NaCl (10 mL) and extracted with CH2Cl2 (3ϫ, 10 mL).
The combined organic extracts were washed with water, dried with
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether/
diethyl ether, 12:1) to give 4a (203 mg, 92%) as a yellow solid.
= 8.0 Hz, 1 H, ArH), 7.64 (d, J = 8.0 Hz, 1 H, ArH), 8.09 (s, 1 H,
NH), 8.28 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR (125 MHz,
CDCl3): δ = 166.5, 152.7, 147.8, 136.8, 129.8, 127.8, 127.1, 123.4,
122.2, 122.0, 121.0, 119.7, 119.4, 119.0, 117.5, 111.5, 109.9, 55.5,
35.1, 27.6, 27.5, 18.7, 15.7, 14.8 ppm. IR (KBr): ν = 3377, 3308,
˜
3059, 2970, 2867, 1645, 1285 cm–1. C24H28N2O2S2 (440.16): calcd.
C 65.42, H 6.41, N 6.36; found C 65.69, H 6.55, N 6.36.
2-[Bis(ethylthio)methylene]-N-(4-chlorophenyl)-3-(1H-indol-3-yl)-
butanamide (3d): White solid; m.p. 208–210 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz, 3 H, CH3), 1.42 (t, J
= 7.0 Hz, 3 H, CH3), 1.64 (d, J = 7.0 Hz, 3 H, CH3), 2.71–2.74 (m,
1 H, SCH), 2.83–2.86 (m, 1 H, SCH), 2.98–3.00 (m, 2 H, SCH2),
5.02 (q, J = 7.0 Hz, 1 H, CH), 6.16 (s, 1 H, NH), 6.50 (d, J =
8.5 Hz, 2 H, 2ϫ ArH), 6.94 (s, 1 H, ArH), 7.04 (d, J = 8.5 Hz, 2
H, 2ϫ ArH), 7.19 (t, J = 8.0 Hz, 1 H, ArH), 7.26 (t, J = 8.0 Hz,
1 H, ArH), 7.39 (d, J = 8.0 Hz, 1 H, ArH), 7.60 (d, J = 8.0 Hz, 1
H, ArH), 8.06 (s, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl3): δ
= 166.5, 152.0, 136.7, 136.0, 130.3, 129.1 (2 C), 128.9, 127.2, 122.8,
122.1, 120.9 (2 C), 120.4, 118.4, 117.7, 112.0, 35.1, 27.9, 27.5, 18.9,
Typical Procedure for the Coupling Reaction of 1 with 5. Compound
5a: To a solution of 2-[bis(ethylthio)methylene]-3-hydroxy-N-phen-
ylbutanamide (1a; 311 mg, 1 mmol) and β-naphthol 5a (144 mg,
1 mmol) in CH3CN (3 mL) was added concentrated H2SO4 in
CH3CN (0.1 mL, 1 molL–1, 0.1 mmol) at room temperature. The
reaction was allowed to proceed at room temperature and was com-
plete in 1 h. The reaction was quenched with saturated aqueous
NaHCO3 (pH 6), extracted with CH2Cl2 (3ϫ, 8 mL) and the com-
bined organic extracts were washed with water, dried with anhy-
drous Na2SO4, filtered, and concentrated. The residue was purified
by flash chromatography on silica gel (petroleum ether/diethyl
ether, 80:1 then 40:1) to give 6a (332 mg, 76%) as a white solid.
15.9, 15.0 ppm. IR (KBr): ν = 3386, 3301, 3057, 2973, 1656, 1507,
˜
1102 cm–1. C23H25ClN2OS2 (444.11): calcd. C 62.07, H 5.66, N
6.29; found C 61.91, H 5.59, N 6.31.
2-[Bis(ethylthio)methylene]-3-(1H-indol-3-yl)-N-phenylbutanamide
(3a): White solid; m.p. 186–188 °C. H NMR (500 MHz, CDCl3):
2-[Bis(ethylthio)methylene]-3-(1H-indol-3-yl)-N-methylbutanamide
(3e): White solid; m.p. 148–150 °C. H NMR (500 MHz, CDCl3):
1
1
δ = 1.23 (t, J = 7.0 Hz, 3 H, CH3), 1.42 (t, J = 7.0 Hz, 3 H, CH3),
1.61 (d, J = 7.0 Hz, 3 H, CH3), 2.70–2.75 (m, 1 H, SCH), 2.83–
2.89 (m, 1 H, SCH), 2.95–2.97 (m, 2 H, SCH2), 5.01 (q, J = 7.0 Hz,
1 H, CH), 6.22 (d, J = 3.0 Hz, 1 H, NH), 6.70 (d, J = 7.5 Hz, 3 H,
3ϫ ArH), 6.94 (t, J = 7.5 Hz, 1 H, ArH), 7.09 (q, J = 7.5 Hz, 2
H, 2ϫ ArH), 7.18 (t, J = 7.5 Hz, 1 H, ArH), 7.26 (t, J = 7.5 Hz,
1 H, ArH), 7.40 (d, J = 8.0 Hz, 1 H, ArH), 7.60 (d, J = 8.0 Hz, 1
H, ArH), 8.25 (s, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl3): δ
= 166.7, 152.3, 137.3, 136.7, 130.0, 128.9 (2 C), 127.2, 124.3, 122.6,
122.3, 120.2, 120.0 (2 C), 118.4, 117.4, 112.0, 35.2, 27.8, 27.5, 18.7,
δ = 1.20 (t, J = 7.0 Hz, 3 H, CH3), 1.37 (t, J = 7.0 Hz, 3 H, CH3),
1.63 (d, J = 7.0 Hz, 3 H, CH3), 2.43 (d, J = 4.5 Hz, 3 H, CH3),
2.67–2.73 (m, 1 H, SCH), 2.80–2.84 (m, 1 H, SCH), 2.88–2.98 (m,
2 H, SCH2), 4.59 (d, J = 4.5 Hz, 1 H, NH), 4.98 (q, J = 7.0 Hz, 1
H, CH), 7.06 (s, 1 H, ArH), 7.11 (t, J = 7.0 Hz, 1 H, ArH), 7.19
(t, J = 7.0 Hz, 1 H, ArH), 7.38 (d, J = 8.0 Hz, 1 H, ArH), 7.57 (d, J
= 8.0 Hz, 1 H, ArH), 8.49 (s, 1 H, NH) ppm. 13C NMR (125 MHz,
CDCl3): δ = 169.3, 152.7, 136.5, 128.9, 127.1, 122.3, 122.1, 119.7,
118.9, 118.0, 111.7, 35.0, 27.7, 27.4, 26.2, 19.3, 15.8, 15.0 ppm. IR
(KBr): ν = 3415, 3217, 3049, 2967, 2922, 2868, 1645, 1255 cm–1.
˜
15.9, 15.0 ppm. IR (KBr): ν = 3396, 3298, 3057, 2976, 2361, 1659,
˜
C18H24N2OS2 (348.13): calcd. C 62.03, H 6.94, N 8.04; found C
62.31, H 6.99, N 8.06.
1512 cm–1. C23H26N2OS2 (410.15): calcd. C 67.28, H 6.38, N 6.82;
found C 67.10, H 6.26, N 6.80.
2-[Bis(ethylthio)methylene]-3-(1H-indol-3-yl)butanenitrile (3f):
White solid; m.p. 111–112 °C. 1H NMR (500 MHz, CDCl3): δ =
1.25 (t, J = 7.0 Hz, 3 H, CH3), 1.35 (t, J = 7.0 Hz, 3 H, CH3), 1.62
(d, J = 7.0 Hz, 3 H, CH3), 2.85–2.89 (m, 2 H, SCH2), 3.00–3.05
(m, 2 H, SCH2), 4.83 (q, J = 7.0 Hz, 1 H, CH), 7.11 (t, J = 7.5 Hz,
1 H, ArH), 7.20 (t, J = 7.5 Hz, 2 H, 2ϫ ArH), 7.37 (d, J = 8.0 Hz,
1 H, ArH), 7.60 (d, J = 8.0 Hz, 1 H, ArH), 8.13 (s, 1 H, NH) ppm.
13C NMR (125 MHz, CDCl3): δ = 149.0, 136.1, 126.5, 126.0, 122.1,
121.6, 119.4, 118.8, 117.3, 117.0, 111.4, 34.1, 29.3, 28.6, 19.1, 15.5,
2-[Bis(ethylthio)methylene]-N-(2,4-dimethylphenyl)-3-(1H-indol-3-
yl)butanamide (3b): Yellow solid; m.p. 114–116 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.21 (t, J = 7.0 Hz, 3 H, CH3), 1.22 (s, 3
H, CH3), 1.41 (t, J = 7.0 Hz, 3 H, CH3), 1.65 (d, J = 7.0 Hz, 3 H,
CH3), 2.16 (s, 3 H, CH3), 2.67–2.71 (m, 1 H, SCH), 2.88–2.95 (m,
2 H, SCH2), 3.00–3.03 (m, 1 H, SCH), 5.04 (q, J = 7.0 Hz, 1 H,
CH), 6.07 (s, 1 H, NH), 6.72 (s, 1 H, ArH), 6.84 (t, J = 8.0 Hz, 1
H, ArH), 6.86 (s, 1 H, ArH), 7.12 (t, J = 7.5 Hz, 1 H, ArH), 7.18
(t, J = 7.5 Hz, 1 H, ArH), 7.30 (d, J = 8.0 Hz, 1 H, ArH), 7.34 (d,
J = 8.0 Hz, 1 H, ArH), 7.57 (d, J = 8.0 Hz, 1 H, ArH), 8.20 (s, 1
H, NH) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.7, 152.6,
136.9, 134.5, 133.0, 131.0, 129.9, 129.3, 127.2, 127.1, 122.4 (2 C),
122.2, 120.1, 118.5, 117.3, 112.0, 35.3, 27.8, 27.5, 21.0, 18.7, 16.6,
14.6 ppm. IR (KBr): ν = 3389, 3050, 2969, 2207, 1454, 1226 cm–1.
˜
C17H20N2S2 (316.11): calcd. C 64.52, H 6.37, N 8.85; found C
64.79, H 6.53, N 8.81.
Ethyl 2-[Bis(ethylthio)methylene]-3-(1H-indol-3-yl)butanoate (3g):
15.8, 15.1 ppm. IR (KBr): ν = 3416, 3277, 3060, 2971, 1647,
˜
1
White solid; m.p. 125 °C (dec.). H NMR (500 MHz, CDCl3): δ =
1513 cm–1. C25H30N2OS2 (438.18): calcd. C 68.45, H 6.89, N 6.39;
found C 68.30, H 6.82, N 6.41.
0.87 (t, J = 7.0 Hz, 3 H, CH3), 1.20 (t, J = 7.0 Hz, 3 H, CH3), 1.32
(t, J = 7.0 Hz, 3 H, CH3), 1.60 (d, J = 7.0 Hz, 3 H, CH3), 2.72 (q,
2-[Bis(ethylthio)methylene]-3-(1H-indol-3-yl)-N-(2-methoxyphenyl)- J = 7.0 Hz, 2 H, SCH2), 2.88 (q, J = 7.0 Hz, 2 H, SCH2), 3.92 (q,
butanamide (3c): Yellowish solid; m.p. 162–164 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.20 (t, J = 7.5 Hz, 3 H, CH3), 1.40 (t, J
J = 7.0 Hz, 2 H, OCH2), 4.86 (q, J = 7.0 Hz, 1 H, CH), 7.05 (s, 1
H, NH), 7.09 (t, J = 7.5 Hz, 1 H, ArH), 7.16 (t, J = 7.5 Hz, 1 H,
= 7.5 Hz, 3 H, CH3), 1.64 (d, J = 7.0 Hz, 3 H, CH3), 2.63–2.68 (m, ArH), 7.32 (d, J = 8.0 Hz, 1 H, ArH), 7.60 (d, J = 8.0 Hz, 1 H,
1 H, SCH), 2.85–2.95 (m, 2 H, SCH2), 3.00–3.05 (m, 1 H, SCH), ArH), 7.95 (s, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl3): δ =
3.28 (s, 3 H, CH3), 5.06 (q, J = 7.0 Hz, 1 H, CH), 6.59 (d, J =
7.5 Hz, 1 H, ArH), 6.83 (t, J = 7.5 Hz, 1 H, ArH), 6.88 (t, J =
7.5 Hz, 1 H, ArH), 6.90 (s, 1 H, NH), 6.98 (s, 1 H, ArH), 7.15 (t,
167.8, 149.6, 136.1, 129.9, 127.2, 121.8, 121.3, 119.4, 119.2, 118.1,
110.8, 60.2, 34.5, 27.6, 26.9, 19.5, 15.5, 14.5, 13.6 ppm. IR (KBr): ν
˜
= 3344, 3051, 2970, 2925, 1697, 1297 cm–1. C19H25NO2S2 (363.13):
J = 7.5 Hz, 1 H, ArH), 7.21 (t, J = 7.5 Hz, 1 H, ArH), 7.32 (d, J calcd. C 62.77, H 6.93, N 3.85; found C 62.58, H 6.86, N 3.83.
2470 Eur. J. Org. Chem. 2011, 2466–2473
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Regioselective Alkylation of Indoles and β-Naphthols
3-[4,4-Bis(ethylthio)but-3-en-2-yl]-1H-indole (3h): Red oil. 1H NMR
(500 MHz, CDCl3): δ = 1.21 (t, J = 7.5 Hz, 3 H, CH3), 1.29 (t, J
3 H, 3ϫ ArH), 7.76 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.5, 152.4, 138.3, 137.4, 135.8, 132.3,
= 7.5 Hz, 3 H, CH3), 1.46 (d, J = 7.0 Hz, 3 H, CH3), 2.68–2.75 (m, 131.1, 128.9, 128.4 (2 C), 128.2 (2 C), 128.0, 127.1, 123.8, 121.7,
2 H, SCH2), 2.81–2.90 (m, 2 H, SCH2), 4.52 (q, J = 7.0 Hz, 1 H, 119.9, 119.8 (2 C), 119.6 (2 C), 113.0, 109.2, 36.3, 30.2, 27.5, 26.9,
CH), 6.30 (d, J = 9.5 Hz, 1 H, =CH), 7.00 (s, 1 H, NH), 7.12 (t, J
= 7.5 Hz, 1 H, ArH), 7.20 (t, J = 7.5 Hz, 1 H, ArH), 7.37 (d, J =
8.0 Hz, 1 H, ArH), 7.68 (d, J = 8.0 Hz, 1 H, ArH), 7.96 (s, 1 H,
NH) ppm. 13C NMR (125 MHz, CDCl3): δ = 145.0, 136.4, 127.4,
126.7, 122.0, 120.4, 120.1, 119.7, 119.2, 111.2, 32.7, 27.0, 26.8, 20.8,
19.4, 15.1, 14.5 ppm. IR (KBr): ν = 3407, 3053, 3019, 2962, 2923,
˜
2864, 1672, 1594, 1502, 1465, 1433 cm–1. C30H32N2OS2 (500.20):
calcd. C 71.96, H 6.44, N 5.59; found C 72.05, H 6.36, N 5.56.
2-[Bis(ethylthio)methylene]-3-(4-methoxy-1H-indol-3-yl)-N-phenyl-
butanamide (3m): White solid; m.p. 216–218 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.20 (t, J = 7.0 Hz, 3 H, CH3), 1.37 (t, J
= 7.5 Hz, 3 H, CH3), 1.57 (d, J = 7.0 Hz, 3 H, CH3), 2.58–2.62 (m,
1 H, SCH), 2.77–2.81 (m, 1 H, SCH), 2.88–2.93 (m, 1 H, SCH),
15.4, 14.3 ppm. IR (KBr): ν = 3415, 3055, 2963, 2867, 1455,
˜
1261 cm–1. C16H21NS2 (291.11): calcd. C 65.93, H 7.26, N 4.81;
found C 65.74, H 7.12, N 4.88.
2-(1,3-Dithiolan-2-ylidene)-3-(1H-indol-3-yl)-N-o-tolylbutanamide 3.02–3.07 (m, 1 H, SCH), 3.97 (s, 3 H, OCH3), 5.08 (q, J = 6.5 Hz,
(3i): Yellowish solid; m.p. 200–201 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.24 (s, J = 7.0 Hz, 3 H, CH3), 1.75 (d, J = 7.0 Hz, 3
H, CH3), 3.44–3.51 (m, 4 H, SCH2 CH2S), 4.65 (q, J = 7.0 Hz, 1
H, CH), 6.89 (m, 2 H, 2ϫ ArH), 7.06–7.12 (m, 2 H, 2ϫ ArH),
1 H, CH), 6.51–6.56 (m, 3 H, 3ϫ ArH), 6.62 (d, J = 8.0 Hz, 2 H,
2ϫ ArH), 6.90 (t, J = 7.5 Hz, 1 H, ArH), 6.97 (d, J = 8.0 Hz, 1
H, ArH), 7.05 (t, J = 8.0 Hz, 2 H, 2ϫ ArH), 7.11 (t, J = 8.0 Hz,
1 H, ArH), 8.22 (s, 1 H, NH) ppm. 13C NMR (100 MHz, DMSO):
7.17 (s, 1 H, ArH), 7.21–7.24 (t, J = 8.0 Hz, 1 H, ArH), 7.37 (d, J δ = 166.6, 154.1, 152.7, 138.8, 137.5, 128.4 (2 C), 127.8, 123.2,
= 8.0 Hz, 1 H, ArH), 7.44 (s, 1 H, NH), 7.62 (d, J = 8.0 Hz, 1 H, 121.5, 121.4, 119.8 (2 C), 118.2, 116.4, 104.8, 98.9, 55.1, 35.2, 27.1,
ArH), 7.68 (d, J = 8.0 Hz, 1 H, ArH), 8.24 (s, 1 H, NH) ppm. 13C 26.1, 21.7, 15.5, 14.6 ppm. IR (KBr): ν = 3401, 3285, 3054, 2970,
˜
NMR (125 MHz, [D6-]DMSO): δ = 164.8, 137.6, 136.8, 130.8, 2924, 1658, 1591, 1505, 1434 cm–1. C24H28N2O2S2 (440.16): calcd.
129.6, 127.1, 126.6, 124.8, 123.7, 123.6 (2 C), 122.4, 119.7 (2 C), C 65.42, H 6.41, N 6.36; found C 65.61, H 6.37, N 6.22.
119.6, 116.8, 112.3, 39.0, 38.0, 36.9, 18.8, 17.1 ppm. IR (KBr): ν =
˜
2-[Bis(ethylthio)methylene]-3-(5-methoxy-1H-indol-3-yl)-N-phenyl-
butanamide (3n): White solid; m.p. 168–170 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.22 (t, J = 7.5 Hz, 3 H, CH3), 1.42 (t, J
= 7.5 Hz, 3 H, CH3), 1.60 (d, J = 7.0 Hz, 3 H, CH3), 2.71–2.73 (m,
3284, 3203, 3047, 2965, 2919, 1618, 1515, 1245 cm–1. C22H22N2OS2
(394.12): calcd. C 66.97, H 5.62, N 7.10; found C 67.12, H 5.72, N
7.09.
3-[1-(1,3-Dithiolan-2-ylidene)-1-(4-methoxyphenyl)propan-2-yl]- 1 H, SCH), 2.85–2.88 (m, 1 H, SCH), 2.94–2.96 (m, 1 H, SCH),
1H-indole (3j): Yellowish solid; m.p. 158–160 °C. 1H NMR 3.00–3.02 (m, 1 H, SCH), 3.87 (s, 3 H, OCH3), 4.98 (q, J = 7.0 Hz,
(500 MHz, CDCl3): δ = 1.43 (d, J = 7.0 Hz, 3 H, CH3), 3.25–3.28
(m, 2 H, SCH2), 3.48–3.53 (m, 2 H, SCH2), 3.71 (s, 3 H, CH3),
4.43 (q, J = 7.0 Hz, 1 H, CH), 6.59–6.66 (m, 5 H, 4ϫ ArH, NH),
7.11–7.15 (m, 1 H, ArH), 7.17–7.21 (m, 1 H, ArH), 7.32 (d, J =
7.5 Hz, 1 H, ArH), 7.83 (d, J = 7.5 Hz, 2 H, 2ϫ ArH) ppm. 13C
NMR (125 MHz, CDCl3): δ = 158.3, 136.2, 133.2, 132.9, 131.9,
1 H, CH), 6.24 (s, 1 H, NH), 6.69 (s, 1 H, ArH), 6.75 (d, J =
7.5 Hz, 2 H, 2ϫ ArH), 6.91–6.98 (m, 2 H, 2ϫ ArH), 7.06–7.13 (m,
3 H, 3 ϫ ArH), 7.31 (d, J = 7.5 Hz, 1 H, ArH), 8.20 (s, 1 H,
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.5, 154.3, 151.9,
136.9, 131.5, 129.7, 128.6 (2 C), 126.9, 124.1, 122.9, 119.9 (2 C),
116.3, 112.6, 112.3, 99.7, 55.8, 34.9, 27.5, 27.2, 18.3, 15.5,
130.7 (2 C), 127.4, 121.9, 121.2, 120.1, 119.4, 119.2, 112.9 (2 C), 14.8 ppm. IR (KBr): ν = 3380, 3311, 3052, 3019, 2964, 2927, 2869,
˜
110.8, 55.0, 39.6, 38.2, 37.2, 18.2 ppm. IR (KBr): ν = 3420, 3061,
2829, 1658, 1588, 1515, 1486, 1436 cm–1. C24H28N2O2S2 (440.16):
˜
2954, 2859, 1644, 1242 cm–1. C21H21NOS2 (367.11): calcd. C 68.63, calcd. C 65.42, H 6.41, N 6.36; found C 65.64, H 6.56, N 6.28.
H 5.76, N 3.81; found C 66.76, H 5.70, N 3.85.
2-[Bis(ethylthio)methylene]-3-(5-bromo-1H-indol-3-yl)-N-phenyl-
2-[Bis(ethylthio)methylene]-3-(1-ethyl-1H-indol-3-yl)-N-(2-meth- butanamide (3o): Yellow solid; m.p. 170–172 °C. 1H NMR
oxyphenyl)butanamide (3k): Yellowish solid; m.p. 146–148 °C. 1H
(500 MHz, CDCl3): δ = 1.25 (t, J = 7.5 Hz, 3 H, CH3), 1.43 (t, J
NMR (500 MHz, CDCl3): δ = 1.11 (t, J = 7.0 Hz, 3 H, CH3), 1.18 = 7.5 Hz, 3 H, CH3), 1.63 (d, J = 7.5 Hz, 3 H, CH3), 2.70–2.74 (m,
(t, J = 7.0 Hz, 3 H, CH3), 1.39 (t, J = 7.0 Hz, 3 H, CH3), 1.66 (d, 1 H, SCH), 2.84–2.88 (m, 1 H, SCH), 2.97–3.01 (m, 2 H, SCH2),
J = 7.0 Hz, 3 H, CH3), 2.60–2.64 (m, 1 H, SCH), 2.84–2.92 (m, 2
4.97 (q, J = 6.5 Hz, 1 H, CH), 6.19 (s, 1 H, NH), 6.86 (d, J =
H, SCH2), 2.99–3.04 (m, 1 H, SCH), 3.24 (s, 3 H, OCH3), 3.95– 8.0 Hz, 2 H, 2ϫ ArH), 6.94–6.99 (m, 2 H, 2ϫ ArH), 7.14 (t, J =
4.00 (m, 2 H, NCH2), 5.06 (q, J = 7.0 Hz, 1 H, CH), 6.56 (d, J =
7.5 Hz, 1 H, ArH), 6.82–6.87 (m, 3 H, 3ϫ ArH), 6.93 (s, 1 H, NH),
7.13 (t, J = 7.5 Hz, 1 H, ArH), 7.22 (t, J = 7.5 Hz, 1 H, ArH),
7.26–7.28 (m, 1 H, ArH), 7.62 (d, J = 7.5 Hz, 1 H, ArH), 8.29 (d,
7.5 Hz, 2 H, 2ϫ ArH), 7.26 (t, J = 8.5 Hz, 1 H, ArH), 7.32–7.34
(m, 1 H, ArH), 7.76 (s, 1 H, ArH), 8.13 (s, 1 H, NH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.5, 151.2, 136.8, 134.9, 130.4,
128.8 (2 C), 128.6, 124.9, 124.4, 123.3, 120.8, 120.0 (2 C), 116.6,
J = 7.5 Hz, 1 H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 113.2, 112.9, 34.7, 27.7, 27.2, 18.4, 15.7, 14.8 ppm. IR (KBr): ν =
˜
166.1, 152.8, 147.3, 136.2, 128.6, 127.5, 127.4, 124.6, 122.9, 121.5,
120.6, 119.0 (2 C), 118.8, 116.0, 109.3, 109.2, 55.1, 40.8, 34.8, 27.2
3391, 3257, 2968, 2921, 1653, 1596, 1560, 1522, 1437 cm–1
.
C23H25BrN2OS2 (488.06): calcd. C 56.44, H 5.15, N 5.72; found C
56.62, H 5.24, N 5.68.
(2 C), 18.6, 15.5, 15.0, 14.5 ppm. IR (KBr): ν = 3420, 3063, 2971,
˜
2924, 2362, 1676, 1516 cm–1. C26H32N2O2S2 (468.19): calcd. C
66.63, H 6.88, N 5.98; found C 66.39, H 6.72, N 5.93.
3-[Bis(ethylthio)methylene]-4a-chloro-4-methyl-1-phenyl-4,4a-di-
hydro-1H-pyrido[2,3-b]indol-2(3H)-one (4a): White solid; m.p. 182–
2-[Bis(ethylthio)methylene]-3-(1-methyl-2-phenyl-1H-indol-3-yl)- 184 °C. 1H NMR (500 MHz, CDCl3): δ = 0.94 (d, J = 7.0 Hz, 3
1
N-phenylbutanamide (3l): White solid; m.p. 128–130 °C. H NMR
(500 MHz, CDCl3): δ = 1.17 (t, J = 7.5 Hz, 3 H, CH3), 1.22 (t, J
H, CH3), 1.30 (t, J = 7.5 Hz, 3 H, CH3), 1.42 (t, J = 7.0 Hz, 3 H,
CH3), 2.97–3.10 (m, 4 H, 2ϫ SCH2), 4.60 (q, J = 7.0 Hz, 1 H,
= 7.5 Hz, 3 H, CH3), 1.47 (d, J = 7.5 Hz, 3 H, CH3), 2.64–2.85 (m, CH), 7.17–7.21 (m, 1 H, ArH), 7.31–7.37 (m, 4 H, 4ϫ ArH), 7.42–
4 H, 2ϫ SCH2), 3.37 (s, 3 H, NCH3), 4.96 (q, J = 7.0 Hz, 1 H, 7.46 (m, 2 H, 2ϫ ArH), 7.48–7.54 (m, 2 H, 2ϫ ArH) ppm. 13C
CH), 6.27 (s, 1 H, NH), 6.87 (d, J = 8.0 Hz, 2 H, ArH), 6.98 (t, J NMR (125 MHz, CDCl3): δ = 169.0, 161.9, 157.1, 153.5, 135.8,
= 7.5 Hz, 1 H, ArH), 7.08 (t, J = 7.5 Hz, 1 H, ArH), 7.15 (t, J = 134.7, 130.6, 129.7, 129.3 (2 C), 128.6, 128.2 (2 C), 125.0, 122.2,
7.5 Hz, 2 H, 2ϫ ArH), 7.21–7.31 (m, 4 H, 4ϫ ArH), 7.40–7.42 (m,
120.3, 68.5, 43.0, 31.6, 29.6, 16.4, 15.1, 14.2 ppm. IR (KBr): ν =
˜
Eur. J. Org. Chem. 2011, 2466–2473
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2471

M. Wang, Q. Liu et al.
FULL PAPER
3060, 2958, 2925, 2856, 1672, 1576, 1492, 1257 cm– 1
C23H23ClN2OS2 (442.09): calcd. C 62.35, H 5.23, N 6.32; found C
62.29, H 5.29, N 6.25.
.
7.5 Hz, 3 H, CH3), 2.97–3.10 (m, 4 H, 2ϫ SCH2), 4.59 (q, J =
7.0 Hz, 1 H, CH), 7.22 (d, J = 8.0 Hz, 1 H, ArH), 7.32 (d, J =
7.5 Hz, 2 H, 2ϫ ArH), 7.44 (t, J = 7.0 Hz, 2 H, 2ϫ ArH), 7.52 (t,
J = 7.5 Hz, 2 H, 2ϫ ArH), 7.59 (s, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.1, 161.6, 157.8, 152.6, 136.8, 135.7,
133.5, 129.3 (2 C), 129.0, 128.7, 128.1 (2 C), 125.5, 121.6, 117.9,
3-[Bis(ethylthio)methylene]-4a-chloro-1-(2-methoxyphenyl)-4-
methyl-4,4a-dihydro-1H-pyrido[2,3-b]indol-2(3H)-one (4b): Yellow
solid; m.p. 156 °C (dec.). 1H NMR (500 MHz, CDCl3): δ = 0.98
(d, J = 7.0 Hz, 3 H, CH3), 1.30 (t, J = 7.0 Hz, 3 H, CH3), 1.42 (t,
J = 7.5 Hz, 3 H, CH3), 2.97–3.11 (m, 4 H, 2ϫ SCH2), 3.77 (s, 3
H, OCH3), 4.61 (q, J = 7.0 Hz, 1 H, CH), 7.03 (d, J = 7.0 Hz, 1
H, ArH), 7.08–7.11 (m, 1 H, ArH), 7.14–7.17 (m, 1 H, ArH), 7.29–
7.35 (m, 3 H, 3ϫ ArH), 7.40–7.46 (m, 2 H, 2ϫ ArH) ppm. 13C
NMR (125 MHz, CDCl3): δ = 168.9, 161.7, 155.5, 154.6, 153.9,
135.1, 130.5 (2 C), 130.4, 129.6, 124.9, 124.7, 122.2, 121.3, 120.2,
112.0, 68.6, 55.7, 43.5, 31.3, 29.6, 15.5, 15.3, 14.3 ppm. IR (KBr):
68.1, 42.8, 31.7, 29.7, 16.4, 15.1, 14.2 ppm. IR (KBr): ν = 3434,
˜
3082, 2962, 2922, 1672, 1613, 1570, 1491, 1449 cm– 1
.
C23H22BrClN2OS2 (520.00): calcd. C 52.93, H 4.25, N 5.37; found
C 52.86, H 4.32, N 5.35.
2-[Bis(ethylthio)methylene]-3-(2-hydroxynaphthalen-1-yl)-N-phen-
ylbutanamide (6a): White solid; m.p. 147–149 °C. 1H NMR
(500 MHz, CDCl3): δ = 0.80 (t, J = 7.5 Hz, 3 H, CH3), 1.27 (t, J
= 7.5 Hz, 3 H, CH3), 1.59 (d, J = 7.5 Hz, 3 H, CH3), 2.46–2.50 (m,
1 H, SCH), 2.58–2.52 (m, 1 H, SCH), 2.72–2.75 (m, 2 H, SCH2),
5.09 (q, J = 7.5 Hz, 1 H, CH), 7.12 (d, J = 9.0 Hz, 1 H, ArH), 7.24
(t, J = 8.0 Hz, 1 H, ArH), 7.32 (d, J = 7.5 Hz, 1 H, ArH), 7.43 (t,
J = 7.5 Hz, 2 H, 2ϫ ArH), 7.51 (t, J = 7.5 Hz, 2 H, 2ϫ ArH),
7.62–7.65 (m, 3 H, 2ϫ ArH, OH), 7.77 (d, J = 8.0 Hz, 1 H, ArH),
8.04 (d, J = 8.0 Hz, 1 H, ArH), 10.15 (s, 1 H, NH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 169.6, 152.5, 147.3, 136.8, 136.7, 133.0,
129.3 (2 C), 128.3, 128.8, 128.6, 126.3, 125.5, 122.2, 121.9, 121.2,
120.6, 120.5 (2 C), 35.0, 29.1, 27.5, 17.6, 15.0, 14.9 ppm. IR (KBr):
ν = 3062, 2958, 2919, 2863, 1680, 1572, 1499, 1281 cm–1
.
˜
C24H25ClN2O2S2 (472.10): calcd. C 60.94, H 5.33, N 5.92; found C
60.86, H 5.26, N 5.90.
3-[Bis(ethylthio)methylene]-4a-chloro-1-(4-chlorophenyl)-4-methyl-
4,4a-dihydro-1H-pyrido[2,3-b]indol-2(3H)-one (4c): Yellow solid;
1
m.p. 124 °C (dec.). H NMR (500 MHz, CDCl3): δ = 0.90 (d, J =
7.0 Hz, 3 H, CH3), 1.30 (d, J = 7.5 Hz, 3 H, CH3), 1.40 (t, J =
7.5 Hz, 3 H, CH3), 2.94–3.10 (m, 4 H, 2ϫ SCH2), 4.61 (q, J =
7.5 Hz, 1 H, CH), 7.18 (t, J = 7.5 Hz, 1 H, ArH), 7.28–7.37 (m, 4
H, 4 ϫ ArH), 7.46–7.48 (m, 3 H, 3 ϫ ArH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 168.7, 161.7, 157.8, 153.3, 134.6, 134.4,
134.3, 130.7, 129.6 (2 C), 129.5 (2 C), 129.3, 125.1, 122.3, 120.2,
ν = 3264, 3059, 2966, 2866, 1618, 1541 cm–1. C25H27NO2S2
˜
(437.15): calcd. C 68.61, H 6.22, N 3.20; found C 68.43, H 6.18, N
3.17.
68.4, 42.8, 31.7, 29.7, 16.4, 15.1, 14.2 ppm. IR (KBr): ν = 3061,
˜
2-[Bis(ethylthio)methylene]-3-(2-hydroxynaphthalen-1-yl)-N-(2-meth-
oxyphenyl)butanamide (6b): White solid; m.p. 134–135 °C. 1H
NMR (500 MHz, CDCl3): δ = 0.70 (t, J = 7.5 Hz, 3 H, CH3), 1.27
(t, J = 7.5 Hz, 3 H, CH3), 1.56 (t, J = 7.5 Hz, 3 H, CH3), 2.41–
2.45 (m, 1 H, SCH), 2.50–2.54 (m, 1 H, SCH), 2.64–2.69 (m, 1 H,
SCH), 2.74–2.78 (m, 1 H, SCH), 3.93 (s, 3 H, OCH3), 5.11 (q, J =
7.5 Hz, 1 H, CH), 6.96 (d, J = 8.0 Hz, 1 H, ArH), 7.06 (t, J =
8.0 Hz, 1 H, ArH), 7.13 (d, J = 8.5 Hz, 1 H, ArH), 7.16 (t, J =
8.0 Hz, 1 H, ArH), 7.31 (t, J = 7.5 Hz, 1 H, ArH), 7.51 (t, J =
7.5 Hz, 1 H, ArH), 7.62 (d, J = 8.5 Hz, 1 H, ArH), 7.76 (d, J =
8.0 Hz, 1 H, ArH), 8.05 (d, J = 8.5 Hz, 1 H, ArH), 8.16 (s, 1 H,
OH), 8.50 (d, J = 7.5 Hz, 1 H, ArH), 10.34 (s, 1 H, NH) ppm. 13C
NMR (125 MHz, CDCl3): δ = 169.7, 152.8, 148.5, 148.1, 136.9,
133.4, 129.1, 129.0, 128.8, 126.9, 126.5, 125.1, 122.4, 122.2, 121.6,
121.5, 121.1, 120.6, 110.5, 56.1, 35.2, 28.9, 27.7, 17.7, 14.9,
2958, 2923, 2864, 1660, 1573, 1487, 1273 cm–1. C23H22Cl2N2OS2
(476.06): calcd. C 57.86, H 4.64, N 5.87; found C 57.78, H 4.58, N
5.86.
3-[Bis(ethylthio)methylene]-4a-chloro-5-methoxy-4-methyl-1-phenyl-
4,4a-dihydro-1H-pyrido[2,3-b]indol-2(3H)-one (4d): White solid;
m.p. 164–166 °C. 1H NMR (500 MHz, CDCl3): δ = 0.95 (d, J =
7.0 Hz, 3 H, CH3), 1.30 (t, J = 7.5 Hz, 3 H, CH3), 1.43 (t, J =
7.5 Hz, 3 H, CH3), 3.00–3.08 (m, 4 H, 2ϫ SCH2), 3.97 (s, 3 H,
OCH3), 4.81 (q, J = 7.0 Hz, 1 H, CH), 6.71 (d, J = 8.5 Hz, 1 H,
ArH), 6.99 (d, J = 7.5 Hz, 1 H, ArH), 7.28–7.34 (m, 3 H, 3ϫ
ArH), 7.44 (d, J = 7.0 Hz, 1 H, ArH), 7.51 (t, J = 8.0 Hz, 2 H, 2ϫ
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.5, 162.0, 157.0,
155.3, 154.9, 135.9, 132.2, 129.9, 129.3 (2 C), 128.5, 128.2 (2 C),
120.3, 113.2, 107.9, 69.2, 55.8, 41.8, 31.7, 29.6, 16.4, 15.1,
14.8 ppm. IR (KBr): ν = 3363, 3064, 2967, 1641. 1527 cm–1
.
14.2 ppm. IR (KBr): ν = 2967, 2922, 1675, 1567, 1523, 1488 cm–1.
˜
˜
C26H29NO3S2 (467.16): calcd. C 66.78, H 6.25, N 3.00; found C
66.95, H 6.44, N 2.97.
C24H25ClN2O2S2 (472.10): calcd. C 60.94, H 5.33, N 5.92; found C
61.06, H 5.28, N 5.88.
2-[Bis(ethylthio)methylene]-3-(2-hydroxynaphthalen-1-yl)butane-
nitrile (6c): White solid; m.p. 171–172 °C. 1H NMR (500 MHz,
CDCl3): δ = 0.94 (t, J = 7.0 Hz, 3 H, CH3), 1.23 (t, J = 7.0 Hz, 3
H, CH3), 1.68 (d, J = 7.0 Hz, 3 H, CH3), 2.56–2.61 (m, 1 H, SCH),
2.75–2.81 (m, 3 H, SCH, SCH2), 4.88 (q, J = 7.0 Hz, 1 H, CH),
5.80 (s, 1 H, OH), 7.02 (d, J = 8.0 Hz, 1 H, ArH), 7.33 (t, J =
7.5 Hz, 1 H, ArH), 7.51 (t, J = 7.5 Hz, 1 H, ArH), 7.64 (d, J =
8.5 Hz, 1 H, ArH), 7.77 (d, J = 8.0 Hz, 1 H, ArH), 8.09 (d, J =
8.5 Hz, 1 H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.0,
150.4, 132.6, 129.2, 129.1, 128.9, 126.7, 126.5, 122.8, 122.6, 121.7,
3-[Bis(ethylthio)methylene]-4a-chloro-6-methoxy-4-methyl-1-phenyl-
4,4a-dihydro-1H-pyrido[2,3-b]indol-2(3H)-one (4e): Yellow solid;
m.p. 148–150 °C. 1H NMR (500 MHz, CDCl3): δ = 0.95 (d, J =
7.0 Hz, 3 H, CH3), 1.30 (t, J = 7.5 Hz, 3 H, CH3), 1.42 (t, J =
7.5 Hz, 3 H, CH3), 2.98–3.08 (m, 4 H, 2ϫ SCH2), 3.84 (s, 3 H,
OCH3), 4.57 (d, J = 7.0 Hz, 1 H, CH), 6.82–6.83 (m, 1 H, ArH),
7.03 (d, J = 2.5 Hz, 1 H, ArH), 7.28 (d, J = 7.5 Hz, 1 H, ArH),
7.34 (d, J = 7.5 Hz, 2 H, 2ϫ ArH), 7.43 (d, J = 7.5 Hz, 1 H, ArH),
7.51 (t, J = 7.5 Hz, 2 H, 2ϫ ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.4, 161.7, 157.6, 156.5, 146.6, 136.0, 135.9, 129.8,
129.2 (2 C), 128.4, 128.1 (2 C), 120.6, 114.7, 109.1, 68.5, 55.6, 42.9,
119.1, 118.7, 34.9, 29.8, 28.7, 19.0, 15.4, 15.1 ppm. IR (KBr): ν =
˜
3295, 3068, 2963, 2930, 2215, 1625, 1514, 1302 cm–1. C19H21NOS2
(343.11): calcd. C 66.43, H 6.16, N 4.08; found C 66.65, H 6.21, N
4.15.
31.5, 29.5, 16.3, 15.0, 14.1 ppm. IR (KBr): ν = 3662, 2966, 2926,
˜
1671, 1577, 1476, 1409 cm–1. C24H25ClN2O2S2 (472.10): calcd. C
60.94, H 5.33, N 5.92; found C 60.81, H 5.36, N 5.91.
3-[Bis(ethylthio)methylene]-6-bromo-4a-chloro-4-methyl-1-phenyl-
Ethyl 2-[Bis(ethylthio)methylene]-3-(2-hydroxynaphthalen-1-yl)-
4,4a-dihydro-1H-pyrido[2,3-b]indol-2(3H)-one (4f): White solid; butanoate (6d): Colorless oil. 1H NMR (500 MHz, CDCl3): δ =
m.p. 178–180 °C. 1H NMR (500 MHz, CDCl3): δ = 0.96 (d, J =
7.0 Hz, 3 H, CH3), 1.30 (t, J = 7.5 Hz, 3 H, CH3), 1.42 (t, J =
0.87 (t, J = 7.0 Hz, 3 H, CH3), 1.24 (t, J = 7.0 Hz, 3 H, CH3), 1.44
(t, J = 7.0 Hz, 3 H, CH3), 1.48 (d, J = 7.5 Hz, 3 H, CH3), 2.44–
2472
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2466–2473

Regioselective Alkylation of Indoles and β-Naphthols
Synlett 2002, 1823–1826; c) S. J. Coote, S. G. Davies, D. Mid-
dlemiss, A. Naylor, Tetrahedron Lett. 1989, 30, 3581–3584; d)
A. A. Khalaf, R. M. Roberts, J. Org. Chem. 1972, 37, 4227–
4235.
2.49 (m, 1 H, SCH), 2.58–2.69 (m, 3 H, SCH, SCH2), 4.44 (q, J =
7.0 Hz, 2 H, OCH2), 5.06 (q, J = 7.5 Hz, 1 H, CH), 7.11 (d, J =
8.0 Hz, 1 H, ArH), 7.34 (t, J = 7.5 Hz, 1 H, ArH), 7.53 (t, J =
7.5 Hz, 1 H, ArH), 7.65 (d, J = 8.5 Hz, 1 H, ArH), 7.78 (d, J =
8.0 Hz, 1 H, ArH), 8.06 (d, J = 8.5 Hz, 1 H, ArH), 8.66 (s, 1 H,
OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.8, 152.0, 144.5,
136.9, 132.8, 129.0, 128.7, 128.6, 126.3, 122.4, 122.1, 120.8, 120.6,
[6]
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M. Hidai, S. Uemura, J. Am. Chem. Soc. 2002, 124, 11846–
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Angew. Chem. Int. Ed. 2004, 43, 1414–1416; b) I. Iovel, K. Mer-
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62.4, 34.2, 28.3, 27.2, 17.4, 15.0, 14.7, 14.1 ppm. IR (KBr): ν =
˜
3307, 3057, 2975, 2871, 1684, 1317 cm–1. C21H26O3S2 (390.13):
calcd. C 64.58, H 6.71; found C 64.33, H 6.61.
2-[Bis(ethylthio)methylene]-3-(6-bromo-2-hydroxynaphthalen-1-yl)-
N-(2-methoxyphenyl)butanamide (6e): White solid; m.p. 117–
119 °C. 1H NMR (500 MHz, CDCl3): δ = 0.67 (t, J = 7.0 Hz, 3 H,
CH3), 1.25 (t, J = 7.0 Hz, 3 H, CH3), 1.51 (d, J = 7.5 Hz, 3 H,
CH3), 2.42–2.52 (m, 2 H, SCH2), 2.62–2.66 (m, 1 H, SCH), 2.72–
2.76 (m, 1 H, SCH), 3.92 (s, 3 H, OCH3), 5.00 (q, J = 7.5 Hz, 1 H,
CH), 6.95 (d, J = 8.5 Hz, 1 H, ArH), 7.05 (t, J = 8.0 Hz, 1 H,
ArH), 7.11–7.17 (m, 2 H, 2ϫ ArH), 7.53 (t, J = 8.5 Hz, 2 H, 2ϫ
ArH), 7.90 (t, J = 8.5 Hz, 2 H, 2ϫ ArH), 8.15 (s, 1 H, OH), 8.48
(d, J = 8.0 Hz, 1 H, ArH), 10.53 (s, 1 H, NH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 169.3, 152.9, 148.2, 147.1, 137.0, 131.7,
130.4, 129.9, 129.2, 127.6, 126.5, 124.9, 123.9, 122.5, 121.2, 121.1,
120.3, 115.6, 110.1, 55.7, 34.8, 31.0, 28.5, 27.5, 17.3, 14.6 ppm. IR
[7]
[8]
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a) R. Sanz, D. Miguel, A. Martínez, J. M. Álvarez-Gutiérrez, F.
Rodríguez, Org. Lett. 2007, 9, 2027–2030 and references cited
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(KBr):
ν
˜
=
3310, 2970, 2928, 1640, 1528, 1294 cm–1.
C26H28BrNO3S2 (545.07): calcd. C 57.14, H 5.16, N 2.56; found C
57.36, H 5.29, N 2.50.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectroscopic data of all compounds.
[10]
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Acknowledgments
Financial support of this research by the National Natural Sciences
Foundation of China (20972029/21072027), the Fundamental Re-
search Funds for the Central Universities (NENU-STC08007) and
the State Key Laboratory of Fine Chemicals (KF1003) is gratefully
acknowledged.
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V = 2257.8 Å3; α = 90.00, β = 90.00, γ = 90.00; Z = 4; T =
293 K; F(000) = 928, R1 = 0.0441, wR2 = 0.1010. CCDC-
793925 contains the supplementary crystallographic data
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Received: November 3, 2010
Published Online: March 14, 2011
Eur. J. Org. Chem. 2011, 2466–2473
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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