Simple indole synthesis by one-pot sonogashira coupling-NaOH-mediated cyclization

Article abstract of DOI:10.1055/s-0028-1083624

Coupling of o-iodoanilines with terminal alkynes under standard Sonogashira conditions, and further treatment with NaOH under conventional heating or microwave irradiation, afford 2-substituted indoles in usually high yields. Functionalities such as halides, nitro, and cyano groups are tolerated under the reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083624

3006
LETTER
Simple Indole Synthesis by One-Pot Sonogashira Coupling–NaOH-Mediated
Cyclization
Indole Synthesisoberto Sanz,* Verónica Guilarte, M. Pilar Castroviejo
Departamento de Química, Área de Química Orgánica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n,
09001-Burgos, Spain
Fax +34(947)258831; E-mail: rsd@ubu.es
Received 23 June 2008
Dedicated to Prof. Dr. Josep Font on the occasion of his 70th birthday.
mediated cyclization takes place under conventional heat-
Abstract: Coupling of o-iodoanilines with terminal alkynes under
ing, or more conveniently, under microwave irradiation.
standard Sonogashira conditions, and further treatment with NaOH
under conventional heating or microwave irradiation, afford 2-sub-
stituted indoles in usually high yields. Functionalities such as ha-
lides, nitro, and cyano groups are tolerated under the reaction
conditions.
Our studies started with the model reaction of o-hex-1-
ynylaniline (1a) with finely powdered NaOH in DMF as
solvent under different conditions. As shown in Table 1,
the cyclization does not take place at room temperature
using a high excess of NaOH (entry 1), and after some ex-
perimentation we determined that the reaction must be
conducted at 140 °C with 3 equivalents of base to get
complete conversion of the starting aniline 1a to 2-butyl-
indole (2a, Table 1, entry 2). Due to the fact that micro-
wave heating has emerged as a versatile method to speed
up many chemical processes, getting cleaner reactions,
and delivering high yields in a few minutes,12 we decided
to try our reaction under microwave irradiation (Table 1,
entries 3 and 4). Under these conditions N,N-dimethyl-
acetamide (DMA) gave cleaner results than DMF and, in
this way, complete cyclization of 1a under optimized con-
ditions took place in 8 minutes with only 1.5 equivalents
of NaOH at 170 °C, affording 2a in high yield (Table 1,
entry 4).
Key words: indoles, cyclizations, alkynes, microwave irradiation
The indole ring system is a prominent structural unit fre-
quently found in numerous natural products and pharma-
ceutically active compounds.1 The synthesis and
functionalization of indoles has been a major challenge
for synthetic organic chemists, and numerous methods for
their preparation have been developed.2 The implementa-
tion of practical, safe, and scalable methods for the large-
scale preparation of indoles is of interest and so, the devel-
opment of practical methodologies that allow the synthe-
sis of a great variety of substituted indoles is a current
objective in organic synthesis. Among the many methods
for indole-ring synthesis, the cyclization reactions of
2-alkynylaniline derivatives are some of the most useful
procedures for the construction of the indole nucleus.3 In
this field, an interesting access to 2-substituted indoles
makes use of a metal-alkoxide-mediated cyclization of
2-alkynylaniline derivatives. Several examples of this
methodology typically involved the use of NaOEt4 or
KOt-Bu5 with N-substituted anilines, usually carbamates.
In this context, Knochel reported a milder procedure
which relied on the use of N-methyl-2-pyrrolidone (NMP)
as the reaction solvent and KH or KOt-Bu as bases.6 This
strategy has also been employed by other authors for the
preparation of azaindoles,7 2-alkynylindoles,8 as well as
amino and nitroindoles.9 Most of these methods suffer
from drawbacks like high temperatures, long reaction
times, low yields, and the use of moisture-sensitive
bases.10 During the last years we have been interested in
the development of suitable methodologies for the synthe-
sis of functionalized indoles.11 Herein, we report a new
method for the one-pot synthesis of 2-substituted indoles
from o-iodoanilines using a NaOH-mediated 5-endo-dig
cyclization of o-alkynylanilines as the key step. This base-
Having established the best reaction conditions for cy-
clization of 1a, both under conventional heating and mi-
crowave irradiation, we then explored the scope of this
indole synthesis with respect to the substituent at the C2-
Table 1 Sodium hydroxide Mediated Cyclization of o-Hex-1-ynyl-
aniline (1a)a
n-Bu
NaOH (n equiv)
temp, time
n-Bu
DMF (Δ) or DMA (MW)
N
NH2
H
2a
1a
Entry
NaOH Heating Temp
Time
(min)
Ratiob
2a/1a
Yield
(%)c
(equiv)
(°C)
d
1
2
3
4
6
D
20
120
150
10
0:1
1:0
6:1
1:0
–
3
D
140
140
170
85
d
6
MW
MW
–
1.5
8
89
a All reactions were carried out with 1a (0.5 mmol) in anhyd DMF or
DMA (2 mL).
SYNLETT 2008, No. 19, pp 3006–3010
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1083624; Art ID: D22308ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8
b Determined by 1H NMR analysis of the crude product.
c Isolated yield of 2a after column chromatography.
d Not determined.

LETTER
Indole Synthesis
3007
position in the final indole 2. As shown in Table 2, 2-sub-
stituted indoles 2b–f were synthesized in usually high
yields. In general, slightly better yields were obtained un-
der microwave irradiation (Table 2, entries 2, 4, 6, and 8),
although the most important fact was the significant re-
duction in reaction time, from several hours to typically
10–20 minutes.
Table 3 2-Substituted-1H-indoles 2 by One-Pot Sonogashira
Coupling–NaOH-Mediated Cyclization of o-Iodoaniline 3a with
Terminal Alkynesa,17
I
1) PdCl2(PPh3)2 (3 mol%),
CuI (5 mol%), Et2NH (1.5 equiv), solvent,
r.t., 1−2 h or MW (70 °C), 10 min
NH2
3a
+
R
2) NaOH (10 equiv), solvent, 140 °C, time, or
NaOH (4 equiv), DMA, MW (temp), time
R
N
Table 2 2-Substituted-1H-indoles 2b–f by NaOH-Mediated
Cyclization of o-Alkynylanilines 1a
H
2
R
Entry Alkyne
(R)
Solvent Heating
(temp)
Time
Prod. Yield
(%)b
NaOH (3 equiv)
DMF, 140 °C, 2−9 h
R
or NaOH (1.5 equiv)
1
2
3
4
5
6
7
8
9
n-Bu
n-Bu
Ph
DMF
DMA MW (170 °C) 10 min 2a
DMA D (140 °C) 6 h 2b
DMA MW (190 °C) 20 min 2b
DMF D (140 °C) 2 h 2c
D (140 °C)
3.5 h 2a
78
81
76
77
82
88
60
69
68
76
70
40
71
74
N
NH2
DMA, MW (170 °C), 7–40 min
H
1
2
Entry Starting
aniline
R
Heating Time
Product Yield
(%)b
Ph
1
2
3
4
5
6
7
8
9
1b
1b
1c
1c
1d
1d
1e
1e
1f
Ph
D
9 h
2b
74
81
87
91
77
78
72
76
83
c
c
c-C6H9
c-C6H9
3-Thd
Ph
MW
D
20 min 2b
DMA MW (170 °C) 10 min 2c
DMA MW (180 °C) 40 min 2d
c
c
c-C6H9
c-C6H9
3-Thd
3-Thd
2 h
2c
2c
2d
MW
D
7 min
6 h
c-C6H11
n-C5H11
DMA D (140 °C)
6 h
2e
DMF
DMF
D (140 °C)
D (140 °C)
4.5 h 2f
2.5 h 2g
MW
D
40 min 2d
5 h 2e
20 min 2e
2.5 h 2f
10 2-Pye
c-C6H11
c-C6H11
n-C5H11
11 4-MeC6H4
12 2-NH2C6H4
DMA D (140 °C)
4 h
2h
MW
DMA MW (180 °C) 50 min 2i
D
13 4-F-3-MeC6H3 DMA MW (180 °C) 40 min 2j
14 3-ClC6H4 DMA MW (180 °C) 40 min 2k
a Reactions were carried out with 1 (1 mmol) in anhyd DMF (4 mL)
under conventional heating or with 1 (0.5 mmol) in anhyd DMA (2
mL) under microwave irradiation.
a Reactions were carried out with 3a (1 mmol) in anhyd DMF or DMA
(5 mL) under conventional heating or with 3a (0.5 mmol) in anhyd
DMA (2 mL) under microwave irradiation.
b Isolated yield of indoles 2 after column chromatography.
c 1-Cyclohexenyl.
b Isolated yield of indoles 2 after column chromatography.
c 1-Cyclohexenyl.
d 3-Thienyl.
d 3-Thienyl.
Although the starting anilines 1 were easily synthesized
by the Sonogashira cross-coupling of 2-iodoaniline 3a
with 1-alkynes,13 at this point we wondered if 2-substitut-
ed indoles 2 could be prepared by a one-pot, two step pro-
cedure from 3a. To this end, 3a was first treated with 1-
hexyne under standard Sonogashira conditions at room
temperature and then, excess of NaOH (10 equiv) was
added to the mixture and heated to 140 °C for several
hours. Gratifyingly, indole 2a was obtained in 78% over-
all yield without isolation of intermediate 1a (Table 3, en-
try 1).14 In addition, this one-pot procedure for the
synthesis of 2-substituted indoles 2a–k from 2-iodo-
aniline 3a could also be carried out under microwave irra-
diation. In this case, Sonogashira couplings took place in
10 minutes,15 and for the cyclization step the microwave
irradiation allowed the use of a lesser amount of NaOH (4
equiv), as well as the reaction times were reduced from
several hours to 10–40 minutes (Table 3). As shown in
Table 3, different 1-alkynes bearing aliphatic (entries 1, 2,
8, and 9), alkenyl (entries 5 and 6), aryl (entries 3, 4, and
e 2-Pyridyl.
11), heteroaryl (entries 7 and 10), and functionalized aryl
(entries 12–14) substituents were appropriate substrates
for this methodology. In general, satisfactory to high
yields were obtained and, moreover, this one-pot proce-
dure is amenable for the gram-scale synthesis of 2-substi-
tuted indoles 2.16
Once we had established the generality of this one-pot
procedure for the synthesis of 2-substituted indoles 2 with
respect to the alkyne counterpart, we decided to explore
the scope of this synthetic strategy with regard to the
o-iodoaniline moiety (Table 4). Again, reactions could be
performed under conventional heating or under micro-
wave irradiation. First, we observed that N-acetyl-2-io-
doaniline (3b) behaves as a synthetic equivalent of 2-
iodoaniline (3a) since N-deacetylation occurred under the
basic conditions (Table 4, entries 1–3). This methodology
is not restricted to N-unsubstituted starting anilines and
Synlett 2008, No. 19, 3006–3010 © Thieme Stuttgart · New York

3008
R. Sanz et al.
LETTER
Table 4 Functionalized Indoles 2 by One-Pot Sonogashira Coupling–NaOH-Mediated Cyclization of o-Iodoanilines 3a,17
1) PdCl2(PPh3)2 (3 mol%), CuI (5 mol%),
Et2NH (1.5 equiv), DMF or DMA,
R3
R4
I
R3
R4
r.t., 1−2 h or MW (70 °C), 10 min
R2
R2
+
2) NaOH (10 equiv), solvent, 140 °C, time, or
NaOH (4 equiv), DMA, MW (temp), time
N
NH
R1
R1
R5
R5
3
2
Entry Starting R1
aniline
R3
R4
R5
Alkyne
(R2)
Solvent
Heating
(temp)
Time
Product
Yield
(%)b
1
2
3b
3b
3b
3c
3c
3d
3d
3e
3e
3e
3f
COMe
H
H
H
H
H
H
Cl
Cl
F
H
H
H
H
H
H
H
H
H
H
Cl
Cl
F
n-Bu
DMF
DMF
DMA
DMF
DMA
DMF
DMF
DMF
DMA
DMF
DMF
DMF
DMA
DMF
DMA
DMA
D (140 °C)
D (140 °C)
MW (180 °C)
D (140 °C)
MW (170 °C)
D (140 °C)
D (140 °C)
D (140 °C)
MW (180 °C)
D (140 °C)
D (140 °C)
D (140 °C)
D (140 °C)
D (140 °C)
D (140 °C)
MW (180 °C)
2.5 h
3.5 h
20 min
3.5 h
20 min
3 h
2a R1 = H
89
2c R1 = H
75
c
COMe
COMe
Bn
Bn
H
H
c-C6H9
n-C5H11
n-Bu
3
H
2f R1 = H
2l
74
4
H
80
c
5
H
c-C6H9
2m
2n
75
6
H
n-Bu
88
c
7
H
H
c-C6H9
3 h
2o
75
8
H
H
n-Bu
3 h
2p
74
9
H
H
F
Ph
40 min
3 h
2q
66
c
10
11
12
13
14
15
16
H
H
F
c-C6H9
2r
61
c
H
Cl
Cl
Cl
Cl
CN
NO2
H
H
H
H
H
H
c-C6H9
2.5 h
2.5 h
3 h
2s
68 (66)d
78
3f
H
n-C5H11
Ph
2t
3g
3g
3h
3i
H
2u
81
H
F
n-C5H11
Ph
3 h
2v
83
H
H
H
3 h
2w
85
H
n-Bu
20 min
2x
79
a Reactions were carried out with 3 (1 mmol) in anhyd DMF or DMA (5 mL) under conventional heating or with 3 (0.5 mmol) in anhyd DMA
(4 mL) under microwave irradiation.
b Isolated yield of indoles 2 after column chromatography.
c 1-Cyclohexenyl.
d Yield in brackets refers to the reaction carried out under microwave irradiation.
so, N-benzyl-2-iodoaniline (3c) afforded the correspond-
ing N-benzyl indole derivatives 2l and 2m in high yields
I
3a: R1 = H
(Table 4, entries 4 and 5). Furthermore, halo-2-iodoa-
3d: R1 = Cl
R1
NH2
nilines 3d,e and dihalo-2-iodoanilines 3f,g allowed the
synthesis of regioselectively halogenated indole deriva-
tives 2n–v in usually high yields (Table 4, entries 6–14).
Finally, 2-iodoanilines 3h and 3i bearing cyano and nitro
functionalities, respectively, also afforded the corre-
sponding functionalized indoles 2w–x (Table 4, entries 15
and 16), showing that several functional groups are toler-
ated under the reaction conditions.
1) PdCl2(PPh3)2 (3 mol%), CuI (5 mol%),
SPh
R2
Et2NH (1.5 equiv), DMA,
r.t., 1.5 h or MW (70 °C), 10 min
R2
2) NaOH (10 equiv), 140 °C, 4 h, or
NaOH (4 equiv), MW (140 °C), 20 min
3) Ph2S2 (1.2 equiv), 140 °C, 16 h,
or MW (140 °C), 20 min
N
R1
H
4a: R1 = H
R
2 = n-Bu, 68%
4b: R1 = H
R
2 = Ph, 72%
Interestingly, by using this methodology it is also possible
to prepare 3-arylthio-2-substituted indoles 4, due to the
fact that the arylthio group could be selectively introduced
at C-3 under the basic conditions required for the cycliza-
tion step (Scheme 1).18 Again, this one-pot, three-step
procedure could be carried out under conventional ther-
mal heating or under microwave irradiation.19 In the last
4c: R1 = Cl
R
2 = n-C5H11, 81%
Scheme 1 Synthesis of 3-arylthio-2-substituted-1H-indoles 4 from
o-iodoanilines 3
Synlett 2008, No. 19, 3006–3010 © Thieme Stuttgart · New York

LETTER
Indole Synthesis
3009
(9) (a) Dai, W.-M.; Sun, L.-P.; Guo, D.-S. Tetrahedron Lett.
2002, 43, 7699. (b) Sun, L.-P.; Huang, X.-H.; Dai, W.-M.
Tetrahedron 2004, 60, 10983.
(10) Aqueous Bu4NOH has been used for the cyclization of a
2-alkynyl-N-Boc-aniline. See: Sendzik, M.; Hui, H. C.
Tetrahedron Lett. 2003, 44, 8697.
(11) (a) Fañanás, F. J.; Granados, A.; Sanz, R.; Ignacio, J. M.;
Barluenga, J. Chem. Eur. J. 2001, 7, 2896. (b) Barluenga,
J.; Fañanás, F. J.; Sanz, R.; Fernández, Y. Chem. Eur. J.
2002, 8, 2034. (c) Sanz, R.; Escribano, J.; Pedrosa, M. R.;
Aguado, R.; Arnáiz, F. J. Adv. Synth. Catal. 2007, 349, 713.
(d) Sanz, R.; Castroviejo, M. P.; Guilarte, V.; Pérez, A.;
Fañanás, F. J. J. Org. Chem. 2007, 72, 5113.
case, shorter reaction times were required. As shown in
Scheme 1, highly functionalized indole derivatives 4a–c
were obtained in moderate to high yields from commer-
cially available starting materials 3a,d.
In summary, we have developed an efficient route to 2-
substituted indoles using a NaOH-mediated 5-endo-dig
cyclization of o-alkynylanilines as the key step. The reac-
tion can be performed from 2-iodoanilines and alkynes in
a one-pot process that involves an initial Sonogashira cou-
pling followed by the cyclization. This one-pot procedure
is compatible with the presence of several important func-
tional groups onto the benzenoid moiety, and also it does
work with N-unsubstituted anilines as well as with substi-
tuted ones. Moreover, an arylthio group can also be selec-
tively introduced at the C-3 position without isolation of
any intermediate. In addition, all the reactions can be car-
ried out under conventional heating or under microwave
irradiation with considerable reduction of reaction times.
(12) Microwave Assisted Organic Synthesis; Tierney, J. P.;
Lidström, P., Eds.; Blackwell: Oxford, 2005.
(13) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(14) However, when this one-pot procedure was applied to
phenylacetylene, as terminal alkyne counterpart, 2-(2-
phenylethyl)aniline was generated along with the expected
indole derivative 2b. This side reaction due to hydrogenation
of intermediate 2-alkynylaniline 1b was easily avoided
using DMA instead of DMF. Under the reaction conditions
an ammonium formate derivative is probably generated,
which is known to act as a source of hydrogen. See, for
instance: Nacario, R.; Kotakonda, S.; Fouchard, D. M. D.;
Viranga Tillekeratne, L. M.; Hudson, R. A. Org. Lett. 2005,
7, 471.
(15) For some examples of Sonogashira reactions using
microwave heating, see: (a) Erdélyi, M.; Gogoll, A. J. Org.
Chem. 2001, 66, 4165. (b) Schramm, O. G.; Oeser, T.;
Kaiser, M.; Brun, R.; Müller, T. J. J. Synlett 2008, 359.
(16) The amount of 2.31 g of indole 2a (67% isolated yield) were
easily prepared in one batch from 4.38 g (20 mmol) of
2-iodoaniline 3a.
Acknowledgment
We thank Ministerio de Educación y Ciencia and FEDER
(CTQ2007-61436/BQU) and Junta de Castilla y León (BU012A06)
for financial support. V.G. and M.P.C. thank Ministerio de Educa-
ción y Ciencia for MEC-FPU predoctoral fellowships. Many thanks
are due to Dr. F. Rodríguez (Universidad de Oviedo) for helpful
comments.
References and Notes
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Naniwa, T.; Yamamoto, H.; Imagawa, H.; Nishizawa, M.
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J. P.; Li, C. J. Org. Lett. 2007, 9, 627. (d) Trost, B. M.;
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(17) Typical Procedure for the One-Pot Synthesis of 2-
Substituted Indoles 2 from o-Iodoanilines 3 under
Conventional Heating – Synthesis of 2-Cyclohex-1-enyl-
1H-indole (2c; Table 3, Entry 5)
A mixture of 2-iodoaniline (3a, 219 mg, 1 mmol),
1-ethynylcyclohexene (159 mg, 1.5 mmol), PdCl2(PPh3)2
(21 mg, 0.03 mmol), CuI (9.5 mg, 0.05 mmol), and Et2NH
(110 mg, 1.5 mmol) in anhyd DMF (3 mL) was stirred under
N2 at r.t. for 1.5 h (the consumption of the starting material
was monitored by GC-MS). Then, DMF (2 mL) and freshly
powdered NaOH (400 mg, 10 mmol) were added to the
reaction mixture, and it was heated at 140 °C for 2 h (the end
of the cyclization was monitored by GC-MS). The reaction
was cooled to r.t. and then, CH2Cl2 (15 mL) and HCl aq
(20 mL of a 0.5M solution) were added. The separated
aqueous phase was extracted with CH2Cl2 (2 × 15 mL), and
the combined organic layers were washed with H2O
(3 × 50 mL). The organic phase was dried (Na2SO4) and
concentrated under reduced pressure. The crude product was
purified by column chromatography on SiO2 (hexane–
EtOAc, 10:1) to afford 2c (162 mg, 82%) as a white solid;
mp 137–139 °C (lit.20 mp 140–141 °C). 1H NMR (300 MHz,
CDCl3): d = 8.06 (br s, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.35
(dd, J = 7.8, 1.2 Hz, 1 H), 7.29–7.14 (m, 2 H), 6.53 (d,
J = 1.7 Hz, 1 H), 6.15–6.09 (m, 1 H), 2.57–2.48 (m, 2 H),
2.36–2.27 (m, 2 H), 1.92–1.82 (m, 2 H), 1.82–1.72 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 139.6 (C), 136.2 (C),
129.1 (C), 129.0 (C), 122.7 (CH), 122.0 (CH), 120.4 (CH),
119.8 (CH), 110.5 (CH), 98.7 (CH), 26.1 (CH2), 25.6 (CH2),
22.6 (CH2), 22.3 (CH2). LRMS (EI): m/z (%) = 197 (100)
[M+], 182 (13), 168 (58), 130 (33). HRMS: m/z calcd for
C14H15N: 197.1204; found: 197.1199.
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Angew. Chem. Int. Ed. 2000, 39, 2488. (b) Koradin, C.;
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Org. Lett. 2008, 10, 113.
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(8) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.
Tetrahedron 2008, 64, 53.
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3010
R. Sanz et al.
LETTER
to r.t. and then, CH2Cl2 (15 mL) and HCl aq (20 mL of a
(18) For the reaction of indoles with Ar2S2, see: Atkinson, J. G.;
Hamel, P.; Girard, Y. Synthesis 1988, 480.
(19) Typical Procedure for the One-Pot Synthesis of 3-
Arylthio-2-Substituted Indoles 4 from o-Iodoanilines 3
under Microwave Irradiation – Synthesis of 6-Chloro-2-
pentyl-3-phenylsulfanyl-1H-indole (4c)
0.5 M solution) were added. The separated aqueous phase
was extracted with CH2Cl2 (2 × 15 mL), and the combined
organic layers were washed with H2O (3 × 50 mL). The
organic phase was dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by column
chromatography on SiO2 (hexane–EtOAc, 15:1) to afford 4c
(133 mg, 81%) as a light brown oil; Rf = 0.27 (hexane–
EtOAc, 15:1). 1H NMR (300 MHz, CDCl3): d = 8.37 (br s,
1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 1.7 Hz, 1 H),
7.22–7.15 (m, 2 H), 7.15–7.02 (m, 4 H), 2.89 (t, J = 7.5 Hz,
2 H), 1.71–1.60 (m, 2 H), 1.36–1.25 (m, 4 H), 0.86 (t, J = 6.9
Hz, 3 H). 13C NMR (75.4 MHz, CDCl3): d = 146.4 (C), 139.2
(C), 135.9 (C), 128.9 (C), 128.8 (2 × CH), 128.0 (C), 125.5
(2 × CH), 124.7 (CH), 121.4 (CH), 120.0 (CH), 111.0 (CH),
99.2 (C), 31.5 (CH2), 29.2 (CH2), 26.5 (CH2), 22.4 (CH2),
14.0 (CH3). LRMS (EI): m/z (%) = 331 (37) [M+ + 2], 329
(92) [M+], 272 (57), 236 (100), 204 (38), 164 (60). IR (neat):
3411, 2931, 1582, 1454, 808, 740, 690 cm–1. HRMS: m/z
calcd for C19H20ClNS: 329.1005; found: 329.1004.
A mixture of 5-chloro-2-iodoaniline (3d, 127 mg, 0.5
mmol), 1-heptyne (72 mg, 0.75 mmol), PdCl2(PPh3)2 (10.5
mg, 0.015 mmol), CuI (4.8 mg, 0.025 mmol), and Et2NH (55
mg, 0.75 mmol) in DMA (2 mL) was charged under air in a
35 mL thick-walled glass sealed tube and irradiated, under
stirring, at 70 °C in the microwave cavity for 10 min (CEM
Focused Microwave System, Discover S-Class).
Temperature measurements were conducted using an IR
sensor located below the microwave-cavity floor, and
reaction times refer to the total hold time at the indicated
temperature. The maximum wattage supplied was 70–80
W). After cooling, freshly powdered NaOH (80 mg, 2 mmol)
was added to the reaction mixture and it was heated at
180 °C in the microwave cavity for 20 min. The reaction
mixture was cooled to r.t. and then, Ph2S2 (131 mg, 0.6
mmol) was added to the mixture, and it was heated at 140 °C
in the microwave cavity for 20 min. The reaction was cooled
(20) Kano, S.; Sugino, E.; Shibuya, S.; Hibino, S. J. Org. Chem.
1981, 46, 3856.
Synlett 2008, No. 19, 3006–3010 © Thieme Stuttgart · New York