Sulfur-assisted and 1,8-diazabicy clo [5.4.0] undec-7-ene (DBU)catalyzed cyclization of 2-alkynylanilines for the metal-free synthesis of indole derivatives

Article abstract of DOI:10.1002/adsc.201000280

A sulfur-assisted and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed cyclization of 2-alkynylanilines for the metal-free synthesis of indole derivatives is reported. As a result of the metal-free process, the ready availability of the starting materials and the simple and convenient operation, the type of reaction presented here has potential utility in organic synthesis. A 10-gram scale preparation may demonstrate the possibility of its application in the environmentally friendly synthesis of indole derivatives.

Full text of DOI:10.1002/adsc.201000280

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DOI: 10.1002/adsc.201000280
Sulfur-Assisted and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-
U
Catalyzed Cyclization of 2-Alkynylanilines for the Metal-Free
Synthesis of Indole Derivatives
Hongwei Zhou,a,* Da Zhu,a Yanpeng Xing,a and Huafeng Huanga
a
Department of Chemistry, Zhejiang University (Campus Xixi) , Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+ 86)-571-8892-0271; e-mail: zhouhw@zju.edu.cn
Received: April 10, 2010; Revised: July 2, 2010; Published online: August 20, 2010
This paper is dedicated to the memory of Prof. Xian Huang.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000280.
Abstract: A sulfur-assisted and 1,8-diazabicyclo-
ACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU)-catalyzed cyclization of
– for conducting a Prummerer reaction, which might
be prepared via a classic oxidization of 1-butyl-2-
(phenylthiomethyl)indole. However, using N-butyl-2-
[3-(phenylthio)prop-1-ynyl]aniline (1a) as the starting
material,[6] we failed to obtain the expected 1-butyl-2-
(phenylthiomethyl)indole via Lewis acids- or Pd-pro-
moted approaches,[3f,4b] probably because the presence
of the sulfur atom is harmful to the Pd and Lewis
acids. Although the cyclizations of 2-alkynylanilines
in the presence of excesses of strong bases, such as t-
BuOK, EtONa, CsOH or NaOH, were documented,[7]
we only obtained sluggish results, which were unsuita-
ble to the large-scale preparation.
2-alkynylanilines for the metal-free synthesis of
indole derivatives is reported. As a result of the
metal-free process, the ready availability of the
starting materials and the simple and convenient
operation, the type of reaction presented here has
potential utility in organic synthesis. A 10-gram
scale preparation may demonstrate the possibility
of its application in the environmentally friendly
synthesis of indole derivatives.
Keywords: cyclization; DBU-catalyzed reaction;
1,8-diazabicyclo
derivatives; metal-free conditions; sulfur-assisted
recation
[5.4.0]undec-7-ene (DBU); indole
Based on our previous understanding of the sulfur-
assisted propargyl-allenyl isomerization,[8] we pro-
posed an allene intermediate N-butyl-2-[3-(phenyl-
thio)propa-1,2-dienyl]aniline, which could be easily
produced in situ by 1a in the presence of a suitable
base, to reach our expected product. The allene
moiety could be thought of as an “activated olefin”,
Indoles may be one of the most important heterocy- which may enhance the cyclization possibility com-
clic compounds which exhibit a variety of biological pared with that of the thermodynamically more stable
activities.[1] Due to their applications in pharmaceuti- alkyne.
cal fields, investigations on the development of effi-
This proposal stimulated us to investigate the possi-
cient preparative methods for indole derivatives have bility of a base-promoted cyclization of 1a to access 1-
continuously attracted the attention of organic chem- butyl-2-(phenylthiomethyl)indole (2a) without transi-
ists. Many powerful methodologies for the synthesis tion metals or Lewis acids (Figure 1).
of these heterocycles have been developed, including
the Fischer indole synthesis,[2] cyclization of 2-alkyn- ing 1a with various bases and examining the solvent
ACHTUNGTRENNUNG
ylanilines,[3] a metal-catalyzed cascade reaction,[4] and effect. Weak inorganic bases such as K2CO3 or tri-
As a first attempt, we initiated our study by treat-
[5]
À
intramolecular C H amination of azidoacrylates. In
the above methodologies, cyclization of 2-alkynylani- strong bases t-BuOK and EtONa gave low yields.
lines promoted by the transition metals or metal salts DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN
(Lewis acids) is widely used because of the readily (1,5-diazabicyclo[4.3.0]non-5-ene) gave the expected
available starting materials and reagents. 2a in good yields at various reaction temperatures
ACHTUNGTRENeNUNG thylamine could not trigger the reaction whereas
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
During our research, we tried to prepare a particu- (Table 1).
lar substrate – 1-butyl-2-(phenylsulfinylmethyl)indole
Adv. Synth. Catal. 2010, 352, 2127 – 2131
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Hongwei Zhou et al.
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Although we did not detect the allene intermediate
shown in Figure 1, we conducted control experiments
which might be helpful for supporting the pathway
proposed. We firstly prepared N-butyl-2-(3-phenoxy-
prop-1-ynyl)aniline (3) and N-butyl-2-(oct-1-ynyl)ani-
line (4) for replacing the sulfur by oxygen and carbon,
respectively, and conducted the reactions under the
same conditions. Only the starting materials were re-
covered, illustrating that the sulfur atom might play a
role in this reaction (Scheme 1).
Then we synthesized N-butyl-2-[3-methyl-3-(phe-
nylthio)but-1-ynyl]aniline (5) as the substrate to ex-
amine the reaction, in which the propargyl-allenyl iso-
merization was prevented. We recovered 5 in 86%
yield, showing that the allene intermediate is essential
for the cyclization (Scheme 2).
Figure 1. Proposal of the cyclization via an allene intermedi-
ate.
Table 1. Base and solvent effects.[a]
As a simple and efficient route to indole deriva-
tives, the usefulness of this synthetic method should
be demonstrated on a multi-gram scale preparation.
We thus ran the cyclization of 1a on a 10-gram scale
and obtained 2a in a yield of 86%. For the original
purpose of preparation of 1-butyl-2-(phenylsulfinyl-
methyl)indole (6), we oxidized 2a using NaIO4 as the
oxidant and obtained 6 in a satisfactory yield
(Scheme 3).
Entry Base
Solvent Time [h] Temp. [8C] Yield of 2a
(Arylmethyl)ACTHUNTGRNEUNG(phenyl)sulfane derivatives, containing
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
toluene 24
THF 24
MeCN 24
reflux
reflux
reflux
reflux
r.t.
50
r.t.
reflux
60
90
r.t.
60
reflux
60
90
NR
NR
NR
NR
an acidic methylene group and a sulfur atom, could
be used in the transformations such as reduction,[9]
oxidation to sulfone,[10] alkylation[11] and acylation[12]
of the sulfane group. Thus, it may be reasonably envi-
sioned that the 2-(phenylthiomethyl)indoles might
also be useful building blocks in organic synthesis.
In summary, we have developed a facile and effi-
cient cyclization of 2-alkynylanilines for the synthesis
of indole derivatives. As a result of the metal-free
process, the ready availability of the starting materials
K2CO3 MeCN 24
t-BuOK NMP
EtONa NMP
12
12
35%
32%
NR
42%
34%
76%
NR
75%
58%
38%
84%
DBU
DBN
DBN
DBN
DBU
DBU
DBU
DBU
DBU
toluene 24
THF 12
MeCN 12
toluene 12
9
10
11
12
13
14
15
THF
toluene 12
THF 12
24
MeCN 12
toluene 12
[a]
Substrate 1a (0.5 mmol) and base (0.6 mmol) in solvent
(1 mL) under an N2 atmosphere.
Although stoichiometric DBU gave an acceptable
result, a catalytic dosage of DBU would make this re-
action environmentally friendly and useful for large- Scheme 1. The O- and C-analogues.
scale preparation. Thus, we examined the reaction in
the presence of 0.3 equiv., 0.1 equiv. and 0.05 equiv. of
DBU, respectively; 0.3 equiv. of DBU gave a similar
result to 1.2 equiv. and 0.05 equiv. required 70 h for
the completion. Catalyzed by 0.1 equiv. of DBU the
reaction offered 86% yield and went to completion in
30 h.
With this result in hand, we examined the scope of
the reaction and obtained the expected indoles in
good yields under mild conditions (Table 2).
Scheme 2.
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Adv. Synth. Catal. 2010, 352, 2127 – 2131

Sulfur-Assisted and 1,8-DiazabicycloACHTUNGRTEN[NUNG 5.4.0]undec-7-ene (DBU)-Catalyzed Cyclization of 2-Alkynylanilines
Table 2. Synthesis of indole derivatives.[a]
Table 2. (Continued)
Entry
1
2
Yield [%]
Entry
1
1
2
Yield [%]
84
9
83
2
3
4
5
82
88
72
86
10
86
11
12
82
66
13
14
88
54[b,c]
6
7
80
89
15
2b
79[b]
[a]
All reactions were run under the following conditions,
unless otherwise specified: 0.5 mmol of 1 and 0.05 mmol
of DBU in 1 mL of toluene at 908C under an N2 atmos-
phere for 30 h.
0.6 mmol of DBU was added.
36% of 2k was observed.
[b]
[c]
8
85
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Hongwei Zhou et al.
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Scheme 3.
and the simple and convenient operation, the type of
reaction presented here has potential utility in organic
synthesis. A 10-gram scale preparation may demon-
strate the possibility of the application in the environ-
mentally friendly synthesis of indole derivatives.
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[6] The substrates (1a–1o) could be easily prepared via a
Sonogashira reaction. Typical Procedure for the Syn-
thesis of 1a: To a solution of N-butyl-2-iodoaniline
(2.0 mmol) and phenyl(prop-2-ynyl)sulfane (2.2 mmol)
in 10 mL of THF was added CuI (10 mg. 0.05 mmol)
Experimental Section
General Procedure for the Synthesis of 2a
To 0.5 mmol of N-butyl-2-[3-(phenylthio)prop-1-ynyl]aniline
(1a) was added 1 mL of DBU in toluene (0.05M) under an
N2 atmosphere, followed by a heating to 908C for 30 h.
After evaporation, chromatography on silica gel (eluent:
EtOAc/petroleum ether=1:20) of the reaction mixture af-
forded the desired product 2a as an oil; yield: 124 mg
(84%). 1H NMR (400 MHz, CDCl3): d=7.53–7.51 (d, J=
7.6 Hz, 1H), 7.35–7.33 (d, J=7.2 Hz, 2H), 7.31–7.24 (m,
3H), 7.21–7.16 (m, 2H), 7.09–7.06 (t, J=7.4 Hz, 1H), 6.32
(s, 1H), 4.24 (s, 2H), 4.17–4.13 (t, J=7.6 Hz, 2H), 1.83–1.75
(m, 2H), 1.43–1.33 (m, 2H), 0.97–0.93(t, J=7.4 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d=137.2, 135.7, 134.6, 130.7,
129.0, 127.5, 126.9, 121.4, 120.5, 119.4, 109.5, 102.4, 43.4,
32.4, 31.5, 20.5, 13.9; MS: m/z=295 (M, 22), 109 (PhS, 100);
IR (neat): n=1583.8, 1480.9 cmÀ1; HR-MS: m/z=295.1389,
calcd for C19H21NS: 295.1395.
and PdCl2ACTHNUGTRNEUNG(PPh3)2 (35 mg, 0.05 mmol), then 1 mL of
Et3N was added under an N2 atmosphere at room tem-
perature for 2 h. The reaction mixture was quenched
with water, extracted with Et2O, and dried over anhy-
drous Na2SO4. After evaporation of the Et2O, chroma-
tography on silica gel (eluent: EtOAc/petroleum
ether=1:15) of the crude product afforded 1a in a yield
of 92%.
Acknowledgements
Financial support was received from the Natural Science
Foundation of China (Nos. 20702046, 20972134).
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