2-And 3-phenylsulfonylindoles-synthetic equivalents of unsubstituted indole in n-alkylation reactions

Article abstract of DOI:10.1007/s10593-010-0504-3

The N-alkylation of 2- and 3-phenylsulfonylindoles under various conditions and the subsequent removal of the activating phenylsulfonyl group by reductive desulfonylation using Raney nickel leads to N-alkylindoles in high yield. 2-Phenylsulfonylindole readily undergoes the Mitsunobu reaction, while isomeric 3-phenylsulfonylindole is relatively inert under these conditions.

Full text of DOI:10.1007/s10593-010-0504-3

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
2- AND 3-PHENYLSULFONYLINDOLES –
SYNTHETIC EQUIVALENTS OF UNSUBSTITUTED
INDOLE IN N-ALKYLATION REACTIONS*
A. V. Karchava1**, I. S. Shuleva1, A. A. Ovcharenko1, and M. A. Yurovskaya1
The N-alkylation of 2- and 3-phenylsulfonylindoles under various conditions and the subsequent
removal of the activating phenylsulfonyl group by reductive desulfonylation using Raney nickel leads to
N-alkylindoles in high yield. 2-Phenylsulfonylindole readily undergoes the Mitsunobu reaction, while
isomeric 3-phenylsulfonylindole is relatively inert under these conditions.
Keywords: indoles, N-alkylation, reduction desulfonylation, Mitsunobu reaction.
In medicinal chemistry, indole derivatives form one of the most important classes of heterocyclic
compounds [1]. This importance is due to the wide distribution of the indole fragment in the structures of natural
and synthetic biologically active compounds with a broad range of activities. An enormous variety of efficient
synthetic methods for construction of the bicyclic indole system and its modifications is already known [2, 3].
Nevertheless, the search for new, reliable, and simple synthetic transformations for indole derivatives remains a
subject of current research.
The direct N-alkylation of indole is clearly the most attractive method for obtaining N-alkyl derivatives.
The initial generation of the indolyl anion is usually required for the success of this reaction. However, the
ambident properties of the indolyl anion facilitate formation of N-alkylation, C-alkylation, and N,C-dialkylation
products [2, 4, 5]. The selectivity of the reaction of the indolyl anion and the alkylating agent depends
significantly on the nature of the cation, solvent, and structure of the alkylating agent. Although high selectivity
for this reaction may be achieved by varying these factors, the problem of selective preparation of an indole
N-alkylation product requires a specific solution in each concrete case [2, 6-8]. Special synthetic methods based
on the use of phase-transfer catalysis [9-11], ionic liquids as the solvent [12, 13], other special solvents [14, 15],
bases [16], and alkylating agents [17], as well as microwave irradiation have been proposed to resolve this
problem. Furthermore, generation of the indolyl anion from an N-unsubstituted indole and indole derivatives
lacking electron-withdrawing substituents requires the use of a stoichiometric amount of strong bases, which
significantly limits the range of functional group tolerating the reaction conditions. It is also important to note
_______
* Dedicated to Professor V. I. Minkin on the occasion of his seventieth birthday.
** To whom correspondence should be addressed, e-mail: karchava@org.chem.msu.ru.
1Chemistry Faculty, M. V. Lomonosov Moscow State University, Moscow 119991, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 373-385, March, 2010. Original
article submitted January 25, 2010.
0009-3122/10/4603-0291©2010 Springer Science+Business Media, Inc.
291

that elimination competes significantly with alkylation when secondary alkylating agents, especially halides, are
used. This behavior is related to the high basicity of indolyl anions lacking electron-withdrawing substituents [2].
Indolyl anions with electron-withdrawing substituents at C-2 or C-3 undergo direct N-alkylation much more
readily. Firstly, the use of weak inorganic or organic bases is usually sufficient for the generation of such indolyl
anions. Secondly, electron-withdrawing substituents significantly reduce their basicity permitting the use of
secondary alkylating agents. And thirdly, competing C-alkylation is not observed in reactions of indolyl anions
with electron-withdrawing substituents [2]. These circumstances permitted us to propose a new general approach to
the selective preparation of various N-substituted indoles based on the initial N-alkylation of indole derivatives
containing an activating electron-withdrawing substituent at C-2 or C-3 with subsequent removal of this substituent
to give the desired N-alkylation product. We proposed that the phenylsulfonyl group, which can be subsequently
removed with ease by reductive desulfonylation, may be used as the activating electron-withdrawing group [19].
O
O
O
O
SPh
S
Ph
RX or ROTs
S
Ph
[O]
–
B
N
N
H
N
H
R
1a,b
2a,b
3–7
1 a 2-SO2Ph, b 3-SO2Ph; 2 a 2-SPh, b 3-SPh
TABLE 1. Direct N-Alkylation of Indolylphenylsulfones 1a and 1b
Reaction
time, h
Alkylation
product
Substrate
RX
Conditions*
Yield, %*2
1a
MeI
A
A
B
4
8
8
3a
(12)
(34)
(45)
Me2CHI
А
B
C
12
12
18
4a
(<10)
(35)
(27)
Phth(CH2)3Br*3
Me2CHI
B
C
12
12
5a
4b
5b
(23)
(<10)
1b
D
E
12
12
90
94
Phth(CH2)3Br
A
C
E
12
12
12
45
60
76
NCCH2Br
A
E
8
10
6b
7b
65
81
PhOCH2CH2Ts
A
B
E
F
18
12
8
72
50
80
71
12
_______
*A: K2CO3 (2 eq.), RX (2 eq.), acetone, reflux; B: NaH (1.1 eq.), RX
(1.3 eq.), DMF, 25°C; C: K2CO3 (2 eq.), RX (2 eq.), DMF, 60°C; D: NaH
(1.1 eq.), RX (1.3 eq.), DMF, 60°C; E: 1,8-diazabicyclo-[5.4.0]undec-
7-ene (1.1 eq.), RX (1.1 eq.), DMF, 25°C; F: t-BuOH (1.1 eq.), RX
(1.1 eq.), DMF, 25°C.
*2The yields determined by 1H NMR spectroscopy are given in
parentheses. The yields of the isolated reaction products are given by the
numbers without parentheses.
*3 Phth = phthalimido.
292

2-Phenylsulfonylindole (1a) and 3-phenylsulfonylindole (1b), which we propose for use as the synthetic
equivalents of unsubstituted indole in N-alkylation reactions, may be obtained readily by oxidation of the
corresponding sulfides 2a [20] and 2b [21] As described by Broggini et al. [22], the oxidation of indol-3-yl
phenyl sulfide (2b) by 3-chloroperbenzoic acid leads to the corresponding sulfone 1b in high yield. The use of
the same reagent for oxidation of isomeric sulfide 2a yielded corresponding sulfone 1a in only 52% yield.
OXONE® (2KHSO5·KHSO4·K2SO4) [23] proved the most efficient oxidizing agent for this reaction and the
yield of sulfone 1b was 94% in this case.
Our results in a study of the direct N-alkylation of sulfones 1a and 1b using alkyl halides and sulfonates
are given in Table 1. We varied the bases used for generating the indolyl anions and used primary and secondary
alkylating agents. The corresponding N-alkylation products were obtained in high yield in virtually all cases of
using indol-3-yl phenyl sulfone (1b) as the substrate. Under the same conditions, alkylation of the anion of
indol-2-yl phenyl sulfone (1a) was more difficult to achieve. Complete conversion of the substrate was not
observed for any of the proposed conditions, even upon significantly extending the reaction time.
N-Alkyl derivatives of indole may be obtained not only by direct alkylation but also by conjugate
addition to Michael acceptors. We also studied the feasibility of using phenylsulfonylindoles 1a and 1b as
substrates in such reactions.
The reactions of sulfones 1a and 1b with ethyl ether and acrylonitrile gave the corresponding
N-alkylation products but the yields in the case of 2-phenylsulfonylindole 1a were markedly lower (Table 2).
The moderate reactivity of the anion of sulfone 1a in direct alkylation reactions and conjugate addition is related
to steric hindrance due to the phenylsulfonyl group near the nucleophilic site.
Another possible variant for the preparation of N-alkylated indole derivatives is based on the use of the
Mitsunobu reaction [24]. When using the standard oxidation-reduction system containing diethyl
azodicarboxylate and Ph3P, indole derivatives containing electron-withdrawing groups such as C≡N [25], COR
[26], CO2R [26], and SO2Ph [27] in the pyrrole fragment usually serve as the substrate. Bombur and Casi [28]
have also reported the feasibility of alkylating 5-bromoindole under conditions of the Mitsunobu reaction by
primary and secondary alcohols using cyanomethylenetrimethylphosphorane (CMMP) but the use of this
oxidation-reduction system involves a number of experimental difficulties. We studied the possibility of
N-alkylation of model indolyl sulfones 1a and 1b by primary and secondary alcohols using conditions of the
O
O
X
S
Ph
1a,b
N
8, 9
X
TABLE 2. N-Alkylation of Phenylsulfonylindoles 1a and 1b under Conjugate Addition
Conditions
Reaction
time, h
Alkylation
products
Substrate
X
Temperature, оС*
Yield, %
1a
1b
CN
25
25
25
69
8
8
8a
8b
9b
65
82
80
92
CN
CO2Ме
12
10
_______
* Reaction conditions: Triton B (8 mol%), CH2=CHX (2.5 equiv.), THF.
293

Mitsunobu reaction and a standard oxidation-reduction system containing diisopropyl azodicarboxylate (DIAD)
and Ph3P (Table 3). Under these conditions, we discovered inverse reactivity of indolyl sulfones 1a and 1b.
Indol-2-yl phenyl sulfone (1a) is readily alkylated both by primary and secondary alcohols. We should note that
the alkylation of sulfone 1a by 1-phenyl-2-butanol is accompanied by the formation of 18% 1-phenylbut-1-ene,
which is the product of dehydration of the alcohol. On the other hand, the reaction of sulfone 1b with 1-hexanol,
a
primary alcohol, gave the alkylation product in only 30% yield, while secondary
alcohols proved unreactive relative to this substrate with yields of the alkylation products not exceeding 10%.
The use of the oxidation-reduction system containing azodicarboxylic acid dipiperidide (ADDP) and
tributylphosphine [29], which is usually more efficient for substrates with low NH-acidity, did not improve the
yield. Such a significant difference in the behavior of isomeric indolyl sulfones in the Mitsunobu reaction is
related, in our opinion, to the higher NH-acidity of indol-2-yl sulfone 1a than for indol-3-yl sulfone 1b.
An important feature of the Mitsunobu reaction is its stereospecificity [24]. This reaction proceeds with
inversion of the configuration of the chiral alcohol used. This behavior makes the Mitsunobu reaction a reliable
method for the preparation of nonracemic compounds using optically active secondary alcohols. Thus, we
obtained the ethyl ester of (R)-1-(2-phenylsulfonylindol-1-yl)propionic acid as a pure enantiomer upon the
alkylation of substrate 1a by the ethyl ester of (S)-lactic acid.
In order to carry out the reductive desulfonylation of the resultant N-alkylated indolyl sulfones, we
studied the feasibility of using various reducing systems. One such system containing magnesium and methanol,
commonly used for this conversion [30, 31], proved unsuitable for the present problem. No significant
O
O
ROH
Mitsunobu reaction
S
Ph
1a,b
N
R
10–14
TABLE 3. N-Alkylation of Phenylsulfonylindoles 1a and 1b under
Conditions of the Mitsunobu Reaction
Yield, %*2
Alkylation product
Substrate
ROH
Conditions*
1a
PhOCH2CH2OH
n-C6H13OH
10a
A
A
A
A
A
A
A
B
55
90
11a
Ph(CH3)CHOH
12a
68
PhCH2CH(CH2Me)OH
(R,S)-HOCH(Me)CO2Et
(S)-HOCH(Me)CO2Et
n-C6H13OH
13a
70*3
68
(R,S)-14a
(R)-14a
11b
68
1b
25
30
Ph(CH3)CHOH
12b
A
B
(<10)
PhCH2(CH2Me)CHOH
13b
B
B
(<10)
(<10)
(S)-HOCH(Me)CO2Et
(R)-14b
_______
* A: DIAD (1.5 eq.), Ph3P (1.5 eq.), THF, 25°C, 24 h; B: ADDP (1.5 eq.),
Bu3P (1.5 eq.), THF, 48°C, 24 h.
*2 The yields determined by GC/MS are given in parentheses. The yields of
the isolated products in all the other cases are given without parentheses.
*3 PhCH=CHCH2Me was also isolated in 18% yield.
294

conversion of the starting sulfones was noted even when using a large excess of magnesium (20 mol Mg per mol
sulfone), carrying out the reaction at reflux, using ultrasonic radiation, replacing methanol by ethanol, and
adding Hg2+ salts to the reaction mixture [19]. N-Alkylindole sulfones proved stable to the action of a
commercial sample of Raney nickel [32]. On the other hand, the use of 3.5 g fresh-prepared Raney nickel
catalyst per mmole substrate gave the reductive desulfonylation of N-alkylindole sulfones and the corresponding
N-substituted indoles in high yield (Table 4) in virtually all cases. The reaction was carried out in ethanol or
THF (depending on the solubility of the substrate) at reflux. The substrates with cyano (6b, 8a, 8b) and
phthalimide groups (5b) undergo extensive reduction involving these groups.
Table 4 gives the yields of the N-alkylindoles calculated over the two steps involving N-alkylation of
the sulfones and the subsequent reductive desulfonylation of these intermediates. Earlier studies on the synthesis
of optically active -amino acids using reductive desulfonylation by Raney nickel in one of the steps showed the
lack of racemization of the chiral site on the nitrogen atom [33, 34]. Determination of the enantiomeric purity of
the resultant indole 24 (>98% ee) using HPLC with a chiral stationary phase confirmed the lack of racemization
during reductive desulfonylation.
This procedure for the preparation of 1-alkylindoles based on the N-alkylation of indolyl phenyl
sulfones and subsequent reductive desulfonylation may be used for the synthesis of some 1-alkylindoles, which
have previously been difficult to obtain, such as indole derivatives containing a chiral substituent at the nitrogen
atom. Indeed, this simple and reliable procedure augments other methods for the synthesis of such compounds
developed in our laboratory [25, 35, 36].
Ni–Ra
4–13
EtOH (THF)
N
 , 5 h
R
15–24
TABLE 4. Reductive Desulfonylation of N-Alkyl-2- and N-Alkyl-
3-phenylsulfonylindoles
Reaction
product
Yield over
two steps, %
Substrate
4b
R
Solvent
Yield, %
15
Me2CH
EtOH
THF
92
86
68
72
63
71
74
77
26
86
28
69
57
50
49
5b
16
Phth(CH2)3
NCCH2
89*
86*2
88
93*2
90*2
84
6b
17
THF
7b
18
PhOCH2CH2
NCCH2CH2
NCCH2CH2
MeO2CCH2CH2
PhOCH2CH2
n-C6H13
EtOH
THF
8a
19
8b
19
THF
9b
20
THF
10a
11a
11b
12a
13a
(R,S)-14a
(R)-14a
18
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
85
21
96
21
n-C6H13
93
22
PhCHMe
77
23
(R,S)-24
(R)-24
PhCH2CHEt
(R,S)-MeCHCO2Et
(R)-MeCHCO2Et
81
74
74
_______
* Yield of hexahydrophthalimide derivative.
*2 Yield of the product of reduction of the nitrile group.
295

EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer for neat liquid compounds and for suspensions of
1
13
solid compounds in vaseline. The H and C NMR spectra were taken on a Bruker AMX-400 spectrometer at
400 and 100 MHz, respectively, in DMSO-d6. The chemical shifts are given relative to the residual signals of the
solvent at 2.49 ppm. Chromato-mass-spectroscopic investigations were carried out using a gas chromatograph
Carto Erba/Kratos Series (Ultra-1 column, 25 m, 0.25 mm HP), mass spectral detector ITD-700 (Finnigan
MAT). The electron impact ionization voltage was 70 eV. The specific rotation values were measured on a Jasco
DIP-360 polarimeter. The elemental analysis was carried out on a Carlo Erba EA1108 CHNS-O automatic
CHN-microanalyzer. The reaction course was monitored by thin-layer chromatography on Sorbfil-UV plates
using 6:1 hexane–ethyl acetate as the eluent and UV light for development. The chromatographic separation of
the reaction mixtures was carried out by flash chromatography on a column packed with 0.040-0.063-mm Merck
silica gel with elution by 10:1 hexane–ethyl acetate. The melting points were determined in open capillaries
without correction. All the commercial reagents were used without prior purification.
Indol-2-yl Phenyl Sulfide (2a) [20] and Indol-3-yl Phenyl Sulfide (2b) [21] were prepared according
to previously described by Hamel et al.
Indol-2-yl Phenyl Sulfone (1a). Aqueous OXONE® (40 ml 49.5%) was added dropwise to a solution
of sulfide 2a (2.24 g, 10 mmol) in methanol (40 ml) with stirring and cooling to 0°C. The suspension obtained
was stirred at room temperature for 8 h, then, poured into ice water (50 ml) and the reaction mixture was
extracted with four 75-ml portions of ethyl acetate. The combined extracts were washed with saturated aq. NaCl
and dried over Na2SO4. The solvent was removed in vacuum. The residue was recrystallized from ethyl acetate
to give 2.42 g (94%) 1a; mp 149-152°C. 1H NMR spectrum, , ppm (J, Hz): 7.13 (1H, t, J = 7.5, H-5); 7.23 (1H,
s, H-3); 7.31 (1H, t, J = 8.3, H-6); 7.45 (1H, d, J = 8.1, H-7); 7.61-7.73 (4H, m, H-4, m-, p-H{C6H5SO2}); 8.02
13
(2H, d, J = 7.4, o-H{C6H5SO2}); 12.41 (1H, s, NH). C NMR spectrum, , ppm: 116.2, 120.2, 122.0, 123.6,
127.9, 128.8, 132.2 (2C), 129.9, 133.1 (2C), 135.4, 144.1, 147.2. Mass spectrum, m/z (Irel, %): 257 [M]+ (75),
193 (15), 132 (100), 104 (19), 89 (31), 77 (25). Found, %: C 65.49; H 4.28; N 5.50. C14H11NO2S. Calculated, %:
C 65.35; H 4.31; N 5.44.
Indol-3-yl Phenyl Sulfone (1b) was obtained in 87% yield by the oxidation of sulfide 2b by
3-chloroperbenzoic acid analogously to the procedure of Broggini [22], mp 147-149°C (ethanol) (mp 147°C
1
(pentane–benzene) [22]). The H NMR spectral data for this compound were identical to the results given by
Broggini [22].
Alkylation of Sulfones 1a and 1b by Alkyl Halides and Sulfonates (General Method). A. K2CO3
(0.552 g, 4 mmol) was added to a solution of sulfone 1a or 1b (0.51 g, 2 mmol) in dry acetone (10 ml) and
stirred for 30 min at 25°C. Then, alkylating agent (4 mmol) was added and the mixture was stirred at reflux
(here and hereafter, the reaction time is indicated in Table 1) and cooled. The precipitate was filtered off and
washed with 60 ml ethyl acetate. The combined organic extracts were washed with two 50-ml water portions
and dried over Na2SO4. The solvent was removed in vacuum.
B. Suspension of NaH (60%, 88 mg, 2.2 mmol) in mineral oil was added in portions to a solution of
sulfone 1a or 1b (0.51 g, 2 mmol) in dry DMF (15 ml) and stirred for 30 min at 25°C. Then, alkylating agent
(2.6 mmol) was added and stirred at room temperature. The solvent was removed in vacuum. The precipitate
was dissolved in ethyl acetate (50 ml), washed with two 50-ml water portions, and dried over Na2SO4. The
solvent was removed in vacuum.
C. K2CO3 (0.552 g, 4 mmol) was added to a solution of sulfone 1a or 1b (0.51 g, 2 mmol) in dry DMF
(15 ml) and stirred for 30 min at 25°C. Then, alkylating agent (4 mmol) was added and stirred at 60°C. After
cooling, the solvent was removed in vacuum. The precipitate was dissolved in ethyl acetate (50 ml), washed
with two 50-ml water portions, and dried over Na2SO4. The solvent was removed in vacuum.
D. Analogously to procedure B, the reaction mixture was stirred at 60°C.
296

E. A solution of sulfone 1a or 1b (0.51 g, 2 mmol) in DMF (5 ml) was added with stirring to a solution
of diazabicycloundecene (0.32 g, 2.2 mmol) or diisopropylethylamine (0.19 g, 2 mmol) in DMF (10 ml) and
stirred at room temperature for 1 h. Then, a solution of alkylating agent (2.2 mmol) in DMF (10 ml) was added
dropwise. Stirring was continued at room temperature. The mixture was then poured into ice water (50 ml). The
precipitate formed was filtered off, washed several times with ice water, and recrystallized from ethanol.
F. t-BuOK (0.49 g, 4.3 mmol) and alkylating agent (4.29 mmol) in DMF (5 ml) were added in portions
to a solution of sulfone 1a or 1b (1 g, 3.9 mmol) in DMF (25 ml) and stirred at 25°C. The solvent was removed
in vacuum. The residue was treated with 100 ml ice water. The precipitate formed was filtered off, washed with
water, and recrystallized from ethanol.
1-Isopropyl-3-phenylsulfonylindole (4b), mp 148-151°C (ethanol). IR spectrum, , cm-1: 1100-1300
(SO2). 1H NMR spectrum, , ppm (J, Hz): 1.50 (6H, d, J = 6.0, CH3); 4.84 (1H, sept, J = 6.0, CH); 7.17-7.35 (2H,
m); 7.52-7.63 (3H, m); 7.69 (1H, d, J = 7.8, H-4); 7.99 (1H, d, J = 7.0, H-7); 8.35 (1H, s, H-2). Mass spectrum, m/z
(Irel, %): 299 [M]+ (100), 284 [M+ - CH3] (68), 257 [M+ - CH3CH=CH2] (13), 193 (17), 143 (20), 132 (32), 116
(16), 77 (20). Found, %: C 68.25; H 5.71; N 4.71. C17H17NO2S. Calculated, %: C 68.20; H 5.72; N 4.68.
3-Phenylsulfonyl-1-(3-phthalimidopropyl)indole (5b), mp 200-202°C (ethanol). IR spectrum, , cm-1:
1
1100-1300 (SO2). H NMR spectrum, , ppm (J, Hz): 2.13 (2H, m, CH2); 3.63 (2H, m, CH2); 4.35 (2H, m, CH2);
7.27 (2H, m); 7.59 (3H, m); 7.68 (1H, d, J = 7.9, H-4); 7.77 (1H, d, J = 7.9, H-7); 7.81-7.91 (4H, m); 7.97 (2H, d,
J = 6.6, Phth); 8.36 (1H, s, H-2). Mass spectrum, m/z (Irel, %): 444 [M]+ (100), 284 (12), 270 (29), 160 (39), 143
(76), 130 (76), 77 (32). Found, %: C 67.57; H 4.49; N 6.34. C25H20N2O4S. Calculated, %: C 67.55; H 4.54; N 6.30.
1-Cyanomethyl-3-phenylsulfonylindole (6b), mp 148-151°C (ethanol). IR spectrum, , cm-1: 1100-1300
1
(SO2). H NMR spectrum, , ppm (J, Hz): 5.63 (2H, s, CH2); 7.29-7.45 (2H, m); 7.54-7.66 (2H, m); 7.72 (1H, d,
J = 8.4, H-4); 7.84 (1H, t, J = 7.8, H-6); 7.98 (2H, d, J = 8.1, o-C6H5SO2); 8.00 (1H, d, J = 6.8, H-7); 8.34 (1H, s,
H-2). Mass spectrum, m/z (Irel, %): 296 [M]+ (100), 257 [M+ - CHCN] (6), 203 (17), 192 (32), 171 (61), 103 (13),
77 (20). Found, %: C 64.87; H 4.04; N 9.43. C16H12N2O2S. Calculated, %: C 64.85; H 4.08; N 9.45.
1-Phenyloxyethyl-3-phenylsulfonylindole (7b), mp 164-166C (ethanol). IR spectrum, , cm-1:
1
1100-1300 (SO2). H NMR spectrum, , ppm (J, Hz): 4.32 (2H, t, J = 5.0); 4.69 (2H, t, J = 5.0); 6.83 (2H, d,
J = 7.8, o-C6H5O); 6.91 (1H, t, J = 7.8, p-C6H5O); 7.20-7.35 (4H, m); 7.51-7.63 (3H, m); 7.70-7.82 (2H, m);
7.96 (2H, d, J = o-C6H5SO2); 8.31 (1H, s, H-2). Mass spectrum, m/z, (Irel, %): 377 [M]+ (90), 284 [M+ - OPh] (9),
270 [M+ - CH2OPh] (100), 236 (15), 206 (13), 143 (47), 129 (23), 77 (65). Found, %: C 69.99; H 5.04; N 3.73.
C22H19NO3S. Calculated, %: C 70.00; H 5.07; N 3.71.
Alkylation of Sulfones 1a and 1b Under Conjugate Addition Reaction Conditions (General
Method). Two drops of Triton B® (40% in methanol) were added to a solution of sulfone 1a or 1b (0.51 g,
2 mmol) in dry THF (20 ml). Then, a solution of methyl acrylate (or acrylonitrile) (5 mmol) in THF (5 ml) was
added dropwise with stirring. The solution was stirred at either 25 or 69°C (reaction time indicated in Table 2).
Then, 10 ml 10% aq. acetic acid was added and the product was concentrated in vacuum. The residue was
treated with water. The liquid was decanted and the product was recrystallized from ethanol.
1-(2-Cyanoethyl)-3-phenylsulfonylindole (8a), mp 146-148°C (ethanol). IR spectrum, , cm-1:
1100-1300 (SO2). 1H NMR spectrum, , ppm (J, Hz): 2.86 (2H, t, J = 6.7, CH2); 4.66 (2H, t, J = 6.9, CH2); 7.22
(1H, t, J = 7.3, H-5); 7.42 (1H, t, J = 7.8, H-6); 7.46 (1H, s, H-3); 7.67 (2H, t, J = 7.7, m-C6H5SO2); 7.72-7.89
(3H, m); 8.01 (2H, t, J = 7.2, o-C6H5SO2). Mass spectrum, m/z (Irel, %): 310 [M]+ (100), 270 [M+ - CO2CN] (62),
222 (32), 204 (38), 178 (20), 91 (51), 77 (26). Found, %: C 65.77; H 4.54; N 8.98. C17H14N2O2S. Calculated, %:
C 65.79; H 4.55; N 9.03.
1-(2-Cyanoethyl)-3-phenylsulfonylindole (8b), mp 179-181°C (ethanol). IR spectrum, , cm-1:
1100-1300 (SO2). 1H NMR spectrum, , ppm (J, Hz): 3.14 (2H, t, J = 6.7, CH2); 4.62 (2H, t, J = 6.7, CH2); 7.29
(2H, m); 7.53-7.65 (3H, m); 7.72-7.82 (2H, m); 7.97 (2H, d, J = 6.7, o-C6H5SO2); 8.38 (1H, s, H-2). Mass
spectrum, m/z (Irel, %): 310 [M]+ (84), 270 [M+ - CO2CN] (100), 206 (14), 185 (10), 129 [M+ - SO2Ph – CH2CN]
(16), 77 [Ph] (23). Found, %: C 65.84; H 4.49; N 9.05. C17H14N2O3S. Calculated, %: C 65.81; H 4.52; N 9.01.
297

Methyl Ester of 3-(3-Phenylsulfonylindol-1-yl)propionic Acid (9b), mp 159-161°C (ethanol). IR
spectrum, , cm-1: 1100-1300 (SO2). 1H NMR spectrum, , ppm (J, Hz): 2.93 (2H, t, J = 7.7, CH2); 3.55 (3H, s,
CH3); 4.56 (2H, t, J = 7.7, CH2); 7.19-7.34 (2H, m); 7.53-7.63 (2H, m); 7.66 (1H, d, J = 8.5, H-4); 7.77 (1H, d,
J = 7.8, H-7); 7.96 (2H, d, J = 7.4, o-C6H5SO2); 8.25 (1H, s, H-2). Mass spectrum, m/z (Irel, %): 343 [M]+ (100),
270 [M+ - CO2Me] (66), 206 (20), 143 (13), 128 (12), 77 (19). Found, %: C 63.00; H 4.90; N 4.06. C18H17NO4S.
Calculated, %: C 62.96; H 4.99; N 4.08.
Alkylation of Sulfones 1a and 1b Under Conditions of the Mitsunobu Reaction (General Method).
Triphenylphosphine (0.76 g, 3 mmol) and ethanol (3 mmol) were added consecutively in an argon atmosphere
to a solution of sulfone 1a or 1b (0.51 g, 2 mmol) in dry THF (50 ml). Then, a solution of diisopropyl ester of
azodicarboxylic acid (0.6 g, 3 mmol) in THF (20 ml) was added dropwise with stirring and cooling to 0°C and
stirred for 24 h at 25°C. The solvent was removed in vacuum and the residue was subjected to chromatography.
1-(2-Phenyloxyethyl)-2-phenylsulfonylindole (10a), mp 155-157°C (ethanol). IR spectrum,  cm-1:
1100-1300 (SO2). 1H NMR spectrum, , ppm (J, Hz): 4.02 (2H, t, J = 5.2, CH2); 4.75 (2H, t, J = 5.4, CH2); 6.64
(2H, d, J = 7.8, o-C6H5O); 6.88 (1H, t, J = 7.4, m-C6H5O); 7.19 (1H, t, J = 7.5, H-5); 7.34-7.50 (2H, m);
7.61-7.78 (7H, m); 8.00 (2H, d, J = 7.8, o-C6H5SO2). Mass spectrum, m/z (Irel, %): 377 [M]+ (81), 284
[M+ - OPh] (79), [270 [M+ - CH2OPh] (67), 236 (47), 204 (43), 143 (100), 91 (52), 77 (8). Found, %: C 69.99; H
5.09; N 3.69. C22H19NO3S. Calculated, %: C 70.00; H 5.07; N 3.71.
1-Hexyl-2-phenylsulfonylindole (11a), mp 58-60°C (hexane). IR spectrum, , cm-1: 1100-1300 (SO2).
1H NMR spectrum, , ppm (J, Hz): 0.81 (3H, t, J = 6.9, CH3); 1.34-1.38 (8H, m, (CH2)4); 4.28 (2H, t, J = 7.4,
CH2); 7.18 (1H, t, J = 7.5, H-5); 7.37 (1H, t, J = 7.8, H-6); 7.42 (1H, s, H-3); 7.56 (2H, d, J = 8.6, o-C6H5SO2);
7.66-7.96 (5H, m). Mass spectrum, m/z (Irel, %): 341 [M]+ (30), 270 (13), 200 [M+ - SO2Ph] (100), 130 (48), 91
(20), 77 (13). Found, %: C 70.40; H 6.71; N 4.14. C20H21NO2S. Calculated, %: C 70.35; H 6.79; N 4.10.
1-Hexyl-3-phenylsulfonylindole (11b), mp 72-74°C (hexane). IR spectrum, , cm-1: 1100-1300 (SO2).
1H NMR spectrum, , ppm (J, Hz): 0.80 (3H, t, J = 5.7, CH3); 1.21-1.79 (8H, m, (CH2)4); 4.26 (2H, t, J = 6.8,
CH2); 7.20-7.32 (4H, m); 7.52-7.65 (4H, m); 7.89 (1H, d, J = 7.8, H-4); 8.30 (1H, s, H-2). Mass spectrum, m/z
(Irel, %): 341 [M]+ (100), 270 (25), 200 (19), 130 (50), 77 (31). Found, %: C 0.36; H 6.76; N 4.16. C20H23NO2S.
Calculated, %: C 70.35; H 6.79; N 4.10.
1-(1-Phenylet-2-yl)-2-phenylsulfonyl)indole (12a), amorphous compound. IR spectrum, , cm-1:
1
1100-1300 (SO2). H NMR spectrum, , ppm (J, Hz): 1.57 (3H, d, J = 7.1, CH3); 6.17 (1H, q, J = 7.1, CH);
6.88-7.01 (2H, m); 7.06-7.11 (2H, m); 7.19-7.27 (3H, m); 7.51 (1H, s, H-3); 7.64 (2H, t, J = 7.8, C6H5SO2);
7.71-7.79 (3H, m); 8.01 (2H, d, J = 8.1, C6H5SO2). Mass spectrum, m/z (Irel, %): 361 [M]+ (21), 257
[M+ - PhCH=CH2] (90), 219 (23), 132 (45), 105 (PhCH=CH2] (100), 77 (23). Found, %: C 73.10; H 5.26;
N 3.90. C22H19NO2S. Calculated, %: C 73.10; H 5.30; N 3.88.
1-(1-Phenylbut-2-yl)-3-phenylsulfonylindole (13a) was obtained as an amorphous compound. IR
1
spectrum, , cm-1: 1100-1300 (SO2). H NMR spectrum, , ppm (J, Hz): 0.10 (3H, t, J = 7.4, CH3); 1.56 (1H, m);
2.11 (1H, m); 2.95 (1H, m); 3.25 (1H, m); 4.85 (1H, m); 7.06 (2H, d, J = 6.8, o-C6H5); 7.15-7.27 (4H, m); 7.38 (1H,
t, J = 7.8, H-5); 7.43 (1H, s, H-2); 7.62-7.68 (2H, m); 7.74 (1H, m); 7.81 (1H, d, J = 7.8, H-7); 7.86-7.95 (3H, m).
Mass spectrum, m/z (Irel, %): 389 [M]+ (15), 298 [M+ - PhCH2] (85), 157 [M+ - PhCH2 – SO2Ph] (100), 92 (32), 77
(8). Found, %: C 74.00; H 5.88; N 3.59. C24H23NO2S. Calculated, %: C 74.00; H 5.95; N 3.60.
Ethyl Ester of (R,S)-2-(3-Phenylsulfonylindol-1-yl)propionic Acid ((R,S)-14a)) was obtained as an
1
amorphous compound. IR spectrum, , cm-1: 1100-1300 (SO2), 1740 (C=O). H NMR spectrum, , ppm (J, Hz):
0.9 (3H, t, J = 7.1, CH2CH3); 1.48 (3H, d, J = CHCH3); 3.93-3.99 (2H, m, OCH2); 5.65 (1H, m, CH); 7.20 (1H, t,
J = 7.8, H-5); 7.27 (1H, d, J = 7.7, H-4); 7.36 (1H, t, J = 7.5, H-6); 7.50 (1H, s, H-3); 7.64 (2H, t, J = 7.1,
m-C6H5SO4); 7.73 (3H, m); 7.79 (1H, d, J = 7.8, H-7). Mass spectrum, m/z (Irel, %): 357 [M]+ (30), 284
(M+ - CO2Et] (84), 216 (12), 143 [M+ - SO2Ph+ - CO2Et] (100), 115 [M+ - SO2Ph+ - MeCHCO2Et] (12), 77 (12).
Found, %: C 63.89; H 5.29; N 3.89. C19H19NO4S. Calculated, %: C 63.85; H 5.36; N 3.92.
298

Ethyl Ester of (R)-2-(3-Phenylsulfonylindol-1-yl)propionic Acid ((R)-14a) was obtained as an
amorphous compound from the ethyl ester of (S)-lactic acid, []D25 -17° (neat), >98% ee. []D25 -2.5° (c = 1.2,
ethanol). Found, %: C 63.91; H 5.33; N 3.94. C19H19NO4S. Calculated, %: 63.85; H 5.36; N 3.92.
Reductive Desulfonylation of N-Alkyl-2- and N-Alkyl-3-phenylsulfonylindoles (General Method).
Fresh-prepared raney nickel [37] (3.5 g) was added to a solution of N-alkyl-2- or N-alkyl-3-phenyl-
sulfonylindole (1 mmol) in ethanol or THF (25 ml) (see Table 4). The resultant mixture was stirred at reflux
until the starting sulfone was completely consumed. The catalyst was filtered off and the solvent was removed in
vacuum. The residue was dissolved in 20 ml ethyl acetate, washed with two 30-ml water portions, dried over
Na2SO4, concentrated, and subjected to chromatography.
1-Isopropylindole (15) was obtained in 92% yield (0.146 g) as a light-yellow viscous liquid. The
1H NMR spectral parameters of this product were in accord with the data of Botta [38].
2-[3-(1H-Indol-1-yl)propyl]hexahydro-1H-isoindole-1,3(2H)-dione (16) was obtained in 89% yield
(0.27 g) as an amorphous compound. 1H NMR spectrum, , ppm (J, Hz): 1.25-1.43 (4H, m); 1.50-1.79 (4H, m);
1.87-1.91 (2H, m); 2.87-2.94 (2H, m); 3.66-3.42 (2H, m); 4.15-4.12 (2H, m); 6.43 (1H, d, J = 3.1, H-3); 7.04
(1H, t, J = 8.4, H-5); 7.12 (1H, t, J = 8.4, H-6); 7.40 (1H, d, J = 3.1, H-2); 7.44 (1H, d, J = 8.1, H-7); 7.54 (1H,
d, J = 7.8, H-4). Mass spectrum, m/z (Irel, %): 310 [M]+ (76), 194 (15), 157 [M+ - RH] (17), 144 [M+ - RCH2]
(22), 130 [M+ - RCH2CH2] (100), 117 [M+ - RCH2CH2CH2] (15), 103 [R=N(CO2)2C6H10] (6). Found, %:
C 73.58; H 7.09; N 9.01. C19H22N2O2. Calculated, %: C 73.52; H 7.14; N 9.03.
1-(2-Aminoethyl)indole (17) was obtained in 86% yield (0.140 g) as a light-yellow viscous liquid. The
1H NMR spectral parameters of this product were in accord with the data of Cuardo [39].
1-(2-Phenyloxylethyl)indole (18) was obtained in 88% yield (0.21 g) as a colorless viscous liquid.
1H NMR spectrum, , ppm (J, Hz): 4.29 (2H, t, J = 5.3, CH2); 4.58 (2H, t, J = 5.3, CH2); 6.86-6.95 (4H, m); 7.03
(1H, t, J = 7.5, H-5); 7.12-7.18 (2H, m); 7.43 (1H, d, J = 3.2, H-2); 7.55 (2H, t, J = 7.7, m-C6H5O); 7.60 (1H, t,
J = 7.6, H-6). Mass spectrum, m/z (Irel, %): 237 [M]+ (47), 144 [M+ - PhO] (10), 130 [M+ - CH2OPh] (100), 103
(8), 89 (9), 77 (15). Found, %: C 81.01; H 6.33; N 5.91. C16H15NO. Calculated, %: C 80.98; H 6.37; N 5.90.
1-(3-Aminopropyl)indole (19) was obtained in 93% yield (0.25 g) as a colorless viscous liquid.
1H NMR spectrum, , ppm (J, Hz): 1.14 (2H, t, J = 7.1, CH2); 1.99-2.15 (2H, m, CH2); 4.28 (2H, t, J = 6.8,
CH2); 6.45 (1H, m, H-3); 7.03 (1H, t, J = 7.2, H-5); 7.13 (1H, m, H-4); 7.39 (1H, d, J = 2.8, H-2); 7.47-7.58
(2H, m, H-6, H-7). Mass spectrum, m/z (Irel, %): 172 [M+ - H2] (2), 158 [M+ - NH2] (3), 131 (100), 117 (15), 58
(23), 44 (17). Found, %: C 75.85; H 8.13; N 16.11. C11H14N2. Calculated, %: C 75.82; H 8.10; N 16.08.
Methyl Ester of 3-(Indol-1-yl)propionic Acid (20) was obtained in 86% yield (0.17 g) as a light-
yellow viscous liquid. The 1H NMR spectral parameters of this product were in accord with the data of Bennasar
[40].
1
1-Hexylindole (21) was obtained in 96% yield (0.20 g) as a light-yellow viscous liquid. H NMR
spectrum, , ppm (J, Hz): 0.85-1.24 (9H, m); 1.74 (2H, m); 4.13 (2H, m); 6.41 (1H, d, J = 2.8, H-3); 7.00 (1H, t,
J = 7.8, H-5); 7.11 (1H, t, J = 7.2, H_6); 7.35 (1H, d, J = 3.2, H-2); 7.45 (1H, d, J = 7.1, H-7); 7.53 (1H, d,
J = 7.15, H-4). Mass spectrum, m/z (Irel, %): 201 [M]+ (38), 130 [M+ - C5H11] (100), 117 [M+ - C6H12] (10).
Found, %: C 83.57; H 9.48; N 6.91. C14H19N. Calculated, %: C 83.53; H 9.51; N 6.96.
1-(1-Phenylethyl)indole (22) was obtained in 77% yield (0.17 g) as a light-yellow viscous liquid.
1H NMR spectrum, , ppm (J, Hz): 1.95 (3H, d, J = 7.1, CH3); 5.70 (1H, q, J = 7.1, CH); 6.59 (1H, d, J = 3.2,
H-3); 7.08-7.18 (4H, m); 7.22-7.34 (5H, m); 7.66 (1H, d, J =7.1, H-7). Mass spectrum, m/z (Irel, %): 221 [M]+
(79), 117 [M+ - PhCH=CH2] (100), 105 [CH2=CHPh] (96), 89 (35). Found, %: C 86.80; H 6.88; N 6.35.
C16H15N. Calculated, %: C 86.84; H 6.83; N 6.33.
1-(1-Phenylbut-2-yl)indole (23) was obtained in 81% yield (0.20 g) as a light-yellow viscous liquid.
1H NMR spectrum, , ppm (J, Hz): 0.79 (3H, t, J = 7.1, CH3); 1.97 (2H, m); 3.16 (2H, m); 4.45 (1H, m, CH);
6.53 (1H, d, J = 3.2, H-3); 7.00 (2H, d, J = 6.3, H-7); 7.06-7.35 (7H, m); 7.63 (1H, d, J = 7.8, H-4). Mass
299

spectrum, m/z (Irel, %): 249 [M]+ (12), 158 [M+ - PhCH2] (100), 117 [M+ - MeCH2CH-CHPh] (17), 91 [PhCH2]
(12). Found, %: C 86.71; H 7.57; N 5.68. C18H19N. Calculated, %: C 86.75; H 7.63; N 5.62.
Ethyl Ester of (R,S)-2-(Indol-2-yl)propionic Acid ((R,S)-24) was obtained in 74% yield (0.16 g). IR
spectrum, , cm-1: 1740 (CO). 1H NMR spectrum, , ppm (J, Hz): 1.15 (3H, t, J = 7.7, OCH2CH3); 1.73 (3H, d,
J = 7.9, CHCH3); 4.12 (2H, m, OCH2CH3); 5.76 (1H, m, CHCH3); 6.49 (1H, d, J = 3.1, H-3); 7.08 (2H, m); 7.42
(2H, m); 7.55 (1H, d, J = 7.8, H-4). Mass spectrum, m/z (Irel, %): 217 [M]+ (18), 144 [M+ - CO2Et] (100), 117
(10), 89 (10), 43 (58). Found, %: C 71.93: H 6.88; N 6.48. C13H15NO2. Calculated, %: C 71.87; H 6.96; N 6.45.
Ethyl Ester of (R)-2-(Indol-1-yl)propionic Acid ((R)-24) was obtained in 74% yield (0.16 g) as a
light-yellow, viscous liquid, []D25 -13.5° (ethanol, 3.2). Found, %: C 71.91; H 6.93; N 6.42. C13H15NO2.
Calculated, %: C 71.87; H 6.96; N 6.45.
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