Synthesis of indoles via diethylzinc-mediated intramolecular hydroamination reactions of alkynyl sulfonamides

Article abstract of DOI:10.1055/s-0028-1083236

A series of indole derivatives were synthesized through the intramolecular hydroamination of alkynyl sulfonamides using 20 mol% of diethylzinc as the catalyst. A tandem cyclization-nucleophilic addition reaction was also possible to afford C2,C3-disubstit

Full text of DOI:10.1055/s-0028-1083236

4036
PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Indoles via Diethylzinc-Mediated Intramolecular
Hydroamination Reactions of Alkynyl Sulfonamides
D
iethylzinc-Media
a
ted Hydroa
n
mination of Alkyny
Y
l
Sulfonamides in, Zhuo Chai, Wen-Ying Ma, Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhaog@mail.sioc.ac.cn
PSP
Received 17 April 2008; revised 16 August 2008
No142
Abstract: A series of indole derivatives were synthesized through the intramolecular hydroamination of alkynyl sulfonamides using 20
mol% of diethylzinc as the catalyst. A tandem cyclization–nucleophilic addition reaction was also possible to afford C2,C3-disubstituted
indoles using 120 mol% of diethylzinc.
Key words: diethylzinc, intramolecular hydroamination, alkynyl sulfonamides, cyclizations, tandem reactions
R1
E
''Zn''
R1
Et2Zn
electrophile
R2
R2
R1
R2
N
Ts
N
NHTs
Ts
1
2, 5
Scheme 1
Introduction
salt intermediate could undergo reactions with acid chlo-
ride or halides to form C2,C3-disubstituted indoles. Nota-
The synthesis of nitrogen-containing heterocycles such as bly, the choice of sulfonyl groups as the protecting group
indoles has been one of the most active areas in organic was crucial to effect such a cyclization process and the use
chemistry due to their extensive existence in a great num- of unprotected primary amine or acyl-protected substrates
ber of biologically active compounds.1 Among the numer- all failed in this transformation.5
ous methods for the preparation of these azaheterocycles,2
the intramolecular hydroamination reaction represents a
highly atom-economic way and many kinds of catalysts
Scope and Limitations
have been developed for this transformation.3 Recently, as
a continuation of their pioneering work in zinc-mediated Firstly, a series of 4-substituted 2-ethynyl-N-tosylanilines
cyclization of 2-ynylphenol or -aniline, Nakamura and co- were prepared and studied in the cyclization reaction with
workers have developed a novel tandem cyclization/ 20 mol% of diethylzinc in toluene (Scheme 1, Table 1). In
nucleophilic addition procedure of N-benzyl-protected general, both the substrates with electron-withdrawing or
alkynylanilines with electrophiles to form indole deriva- electron-donating groups could provide the desired indole
tives mediated by one equivalent of n-BuLi, ZnCl2, derivative products in excellent yields, while a shorter re-
[Pd2(dba)3] (cat.) or n-BuLi, ZnCl2, CuCN·2LiCl.4
action time was observed for the electron-withdrawing
ones (Table 1, entries 3–7). It was found that both halogen
and nitro group were well tolerated in the reaction. In ad-
dition, compounds with alkyl and functionalized alkyl
substituents on the acetylene terminal (R1) were also test-
ed under similar reaction conditions and the correspond-
ing indole products could also be obtained in high yields
(Table 1, entries 8–11). Unfortunately, when the substitu-
ent was TMS, the cyclization was inhibited completely,
affording only the deprotected aniline 1i after 24 hours
(1l/1i = 6:1) (Table 1, entry 12). 6
Our group has demonstrated that the use of alkynyl sul-
fonamides bearing a more acidic NH permits the use of di-
ethylzinc instead of the more basic n-butyllithium.5 The
use of this weaker base allows for the generation of a suf-
ficiently nucleophilic nitrogen anion for cyclization,
while conceding for a broader functional group tolerance.
Moreover, a catalytic amount of diethylzinc was found to
be able to catalyze the cyclization reaction and when an
excess of diethylzinc was used, the resulting indole zinc
SYNTHESIS 2008, No. 24, pp 4036–4040
x
x.
x
x
.
2
0
0
8
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083236; Art ID: M10308SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Hydroamination of Alkynyl Sulfonamides
4037
Table 1 Cyclization of a Series of 2-Ethynyl-N-Sulfonylanilinesa
R1
R2
R2
Et2Zn (20 mol%)
toluene, reflux
R1
N
NHTs
Ts
Entry
1
Substrate
Product
Time (h) Yield (%)b
Ph
Ph
1a
1b
1c
1d
1e
1f
2a
3
98
90
93
92
92
94
N
Ts
NHTs
Ph
Me
F
Me
F
2
3
4
5
6
2b
2c
2d
2e
2f
4
Ph
N
Ts
NHTs
Ph
2.5
2.5
2.5
2
Ph
N
Ts
NHTs
Ph
Ph
Cl
Cl
Ph
Ph
N
Ts
NHTs
NHTs
Br
Br
N
Ts
Ph
Ph
O2N
O2N
Ph
N
Ts
NHTs
NHTs
Cl
Cl
7
8
1g
1h
2g
2h
2
3
93
95
Ph
N
Ts
O2N
O2N
N
Ts
NHTs
NHTs
9
1i
1j
2i
2j
3
3
97
98
N
Ts
OH
OH
10
N
Ts
NHTs
O
O
11
12
1k
1l
2k
3
3
82
–
N
Ts
NHTs
NHTs
c
–
TMS
1l + 1i (6:1)d
24
a Reaction conditions: amines (0.3 mmol), Et2Zn (0.06 mmol), toluene (6 mL).
b Yields of isolated products after flash chromatography.
c Unreacted 1l was recovered.
d The ratio of 1l to 1i was determined by 1H NMR spectroscopic analysis.
Synthesis 2008, No. 24, 4036–4040 © Thieme Stuttgart · New York

4038
Y. Yin et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Cyclization of Aliphatic Alkynyl Aminesa
Entry
Substrate
Catalyst loading
(mol%)
Product
Time (h)
Yield (%)b
NHTs
c
c
1
2
3a n = 1
3b n = 2
120
120
–
12
12
–
Ph
n
63d
93
N
Ph
Ts
NHTs
3
4
5
3c n = 1
3d n = 2
3e
20
120
20
3
12
3
N
Ts
n
e
e
–
–
O
NHTs
95
O
O
N
O
Ts
a Reaction conditions: amines (0.3 mmol), Et2Zn (as indicated in Table 2), toluene (6 mL).
b Yield of isolated products after flash chromatography.
c Compound 3a was recovered.
d Recovered 3b = 33%.
e Recovered 3d = 89%.
Next, a series of N-tosyl-protected aliphatic aminoalkynes ence of 1.2 equivalents of diethylzinc (Table 2, entries 1
were also investigated under similar reaction conditions to and 4).
further evaluate the substrate scope (Table 2). It was
found that the results were highly susceptible to the struc-
tural variations of the substrates. Although the d-alkynyl-
amine 3b and 2-propynyl N-tosylcarbamate (3e)
underwent the 5-exo-dig cyclization smoothly to give the
corresponding cyclized products (Table 2, entries 2 and
5), alkyne 3c was transformed to 2,3-dihydropyrrole in
high yields through a 5-endo-dig cyclization favored by
Baldwin rules (Table 2, entry 3).7 Disappointingly, sub-
strates 3a and 3d with different alkyl chain length failed
to cyclize even under prolonged reaction time in the pres-
Subsequently, it was found that when substrate 1a was
treated with 120 mol% of diethylzinc and the reaction was
quenched with D2O, 96.8% deuterium incorporation at the
C3 position of indole was observed, which was in support
of the existence of a reactive zinc salt intermediate that
could serve as a useful intermediate to synthesize poly-
functional indoles.8 After completion of the cyclization
step, several acid chlorides were introduced into the reac-
tion system to give the desired 3-acylindoles in good
yields (Scheme 1, Table 3, entries 1–6). In addition, 3-
Table 3 Tandem Cyclization–Nucleophilic Additiona
Ph
E
1. Et2Zn (1.2 equiv)
Ph
2. electrophile
NHTs
N
Ts
1a
5
Entry
Electrophile
acryloyl chloride
PhCOCl
Product
5a
Time (h)b
Yield (%)c
1
2
3
4
5
6
7
2
2
2
2
2
2
1
85
90
86
89
88
90
65
5b
2-furoyl chloride
EtCOCl
5c
5d
cyclopropanecarboxylic acid chloride
5e
pivaloyl chloride
NBS
5f
5g
a All reactions were performed in refluxing toluene for 3 h with amines (0.3 mmol) and Et2Zn (0.36 mmol), then the reaction systems were
cooled to r.t. and the corresponding acid chloride (0.36 mmol) was added.
b Reaction time of sequent nucleophilic addition reaction.
c Isolated yield after flash chromatography.
Synthesis 2008, No. 24, 4036–4040 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Hydroamination of Alkynyl Sulfonamides
4039
column chromatography (10% EtOAc in PE) afforded 5b as a white
solid; yield: 122 mg (90%); mp 194–195 °C; Rf = 0.44 (EtOAc–PE,
10:90).
bromo-2-phenylindole derivative 5g could also be ob-
tained with NBS as the electrophile in moderate yield
(Table 3, entry 7). Control experiments demonstrated that
2a, the isolated cyclized product of 1a, failed to react with
benzoyl chloride to give the acylated product 5b in the ab-
sence or presence of diethylzinc at room temperature.
Thus these acylation transformations may only be ex-
plained by a tandem cyclization–nucleophilic process.
The method thus provides a new entry into the present
methods9 of introducing substitution at the C3-position of
indoles.
IR (KBr): 3074, 2919, 1701, 1442, 1361, 1254, 1172, 1084, 751,
710, 581 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.98–7.95 (m, 2 H), 7.78–7.75 (m,
1 H), 7.42–7.40 (m, 3 H), 7.32–7.26 (m, 6 H), 7.13–7.07 (m, 6 H),
2.09 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 169.7, 144.8, 138.7, 136.2, 134.3,
132.8, 132.6, 131.5, 131.3, 130.1, 129.2, 129.1, 129.0, 128.8, 128.7,
128.1, 127.6, 123.7, 122.1, 95.1, 85.4, 21.4.
MS (ESI): m/z = 452.2 [M + H]+.
In summary, we have developed a novel and efficient pro-
cedure for the intramolecular hydroamination of alkynyl
sulfonamides to form nitrogen-containing heterocycles
and a tandem cyclization–nucleophilic addition reaction
of 2-phenylethynyl sulfonamide with electrophiles to give
the corresponding C2,C3-disubstituted indoles in high
yields mediated by diethylzinc.
Anal. Calcd for C28H21NO3S: C, 74.48; H, 4.69; N, 3.10. Found: C,
74.57; H, 4.88; N, 2.95.
Acknowledgment
The generous financial support from the National Natural Science
Foundation of China, QT Program, Shanghai Natural Science
Council, and Excellent Young Scholars Foundation of NNSF is
gratefully acknowledged.
Procedures
1H and 13C NMR spectra were recorded at 300 and 75 MHz, respec-
tively) with TMS as an internal standard. Chemical shifts (d) are
given in ppm relative to TMS, coupling constants (J) in Hz. IR spec-
tra (KBr) were recorded on a PerkinElmer PE 1759 FT-IR spec-
trometer in the range of 400–4000 cm–1. MS spectra were measured
using the EI (70 eV) or ESI method of ionization. Melting points are
uncorrected. Petroleum ether (PE) used had bp range 60–90 °C.
References
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5-Chloro-6-nitro-2-phenyl-1-(toluene-4-sulfonyl)indole (2h);
Typical Procedure
Et2Zn (0.06 mmol, 1.0 M in hexanes) was added to a solution of sul-
fonamide 1h (128 mg, 0.3 mmol) in anhyd toluene (6 mL). The mix-
ture was stirred at reflux for 2 h, cooled to r.t., and quenched with
aq sat. NH4Cl (2 mL). The mixture was extracted with Et2O (3 × 25
mL), and the combined Et2O layers were washed with brine (50
mL), dried (Na2SO4), and concentrated. Purification of the crude
product by silica gel column chromatography (8% EtOAc in PE) af-
forded 2h (119 mg, 93%) as a yellow solid; mp 174–175 °C;
Rf = 0.52 (EtOAc–PE, 10:90).
IR (KBr): 2925, 1738, 1527, 1448, 1380, 1177, 1089, 661, 582
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.92 (s, 1 H), 7.60–7.44 (m, 6 H),
7.26–7.09 (m, 4 H), 6.54 (s, 1 H), 2.33 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.8, 137.5, 137.0, 135.9, 134.4,
129.7, 129.1, 127.3, 126.9, 126.4, 124.6, 123.4, 120.9, 117.4, 114.4,
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C, 59.24; H, 3.59; N, 6.40.
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Phenyl[2-phenyl-1-(toluene-4-sulfonyl)indol-3-yl]methanone
(5b); Typical Procedure
Et2Zn (0.36 mmol) was added to a solution of 1a (104 mg, 0.3
mmol) in anhyd toluene (6 mL). The mixture was stirred at reflux
for 3 h. At the end of the reaction, the mixture was cooled to r.t. and
anhyd benzoyl chloride (51 mg, 0.36 mmol) was added. At the end
of the nucleophilic addition reaction, the mixture was quenched
with aq sat. NH4Cl (2 mL). The mixture was extracted with Et2O
(3 × 25 mL), the combined Et2O layers were dried (Na2SO4), and
concentrated in vacuo. Purification of the crude product by silica gel
Synthesis 2008, No. 24, 4036–4040 © Thieme Stuttgart · New York

4040
Y. Yin et al.
PRACTICAL SYNTHETIC PROCEDURES
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Synthesis 2008, No. 24, 4036–4040 © Thieme Stuttgart · New York