Iodine-induced regioselective C-C and C-N bonds formation of N -protected indoles

Article abstract of DOI:10.1021/jo1023014

A mild, metal-free, and environmently benign iodine-promoted regioselective C-C and C-N bonds formation of N-protected indole derivatives giving 2,3′-biindoles 2 and 4-(1H-indol-2-yl)morpholines 4 is successfully demonstrated. Various bioactive 2,3′-biindoles and 4-(1H-indol-2-yl) morpholines, bearing electron-rich to moderately electron-poor substituents, can be prepared in moderate to good yields.

Full text of DOI:10.1021/jo1023014

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number of dimeric diketopiperazine alkaloids,6 are all based
on the structure having an indole core (Figure 1). Thus, the
Iodine-Induced Regioselective C-C and C-N Bonds
Formation of N-Protected Indoles
Ying-Xiu Li, Ke-Gong Ji, Hai-Xi Wang, Shaukat Ali, and
Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, and State Key Laboratory of Solid
Lubrication, Lanzhou Institute of Chemical Physics, Chinese
Academy of Science, Lanzhou 730000, People’s Republic of
China
liangym@lzu.edu.cn
Received November 19, 2010
FIGURE 1. Natural products of indole alkaloids.
direct functionalization of the indoles has attracted great
attention in recent years. However, the direct formation of
C-C and C-N bonds of indole derivatives is particularly
challenging because of the poor control of both the chemo-
and regioselectivities. Synthesis of 2,30-biindolyl7a-d and
4-(1H-indol-2-yl)morpholine scaffolds,7e which are useful
structural units that are frequently found in pharmaceuticals
and functional materials, look quite attractive. Both chemi-
cal and enzymatic synthetic methods have been reported for
the construction of biindolyls.8 Recently, a few publications
have been reported by employing transition metal-catalyzed
cross coupling reaction and direct functionalization of the
indole derivatives to afford biindolyls.9 For instance, Zhang
and co-workers first reported the oxidative cross dimeriza-
tion of N-protected indole derivatives to give 2,30-linked
products (Scheme 1a).10 Shi and co-workers reported oxida-
tive dimerization of N-protected and free indole derivatives
affording 3,30-biindoles via Pd-catalyzed direct C-H trans-
formations (Scheme 1b).11Most of these procedures require
A mild, metal-free, and environmently benign iodine-
promoted regioselective C-C and C-N bonds formation
of N-protected indole derivatives giving 2,30-biindoles 2
and 4-(1H-indol-2-yl)morpholines 4 is successfully dem-
onstrated. Various bioactive 2,30-biindoles and 4-(1H-
indol-2-yl)morpholines, bearing electron-rich to moderately
electron-poor substituents, can be prepared in moderate to
good yields.
(6) (a) Springer, J. P.; Buchi, G.; Kobbe, B.; Demain, A. L.; Clardy, J.
Tetrahedron Lett. 1977, 18, 2403. (b) Barrow, C. J.; Cai, P.; Snyder, J. K.;
Sedlock, D. M.; Sun, H. H.; Cooper, R. J. Org. Chem. 1993, 58, 6016.
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Since the first preparation of indole by Baeyer in 1866,1 its
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of its prevalence in the structures of many biologically active
natural products, including some useful drugs.1,2 For in-
stance, biologically active natural products, such as the Glio-
cladins A and B,3 Mollenine A,4 Asperazine,5 and a great
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744 J. Org. Chem. 2011, 76, 744–747
Published on Web 12/23/2010
DOI: 10.1021/jo1023014
r
2010 American Chemical Society

Li et al.
JOCNote
SCHEME 1. Design of Iodine-Mediated Tandem Reaction
TABLE 1. Optimization of the Dimerization a
entry I2 (equiv) additive (equiv) solvent time (h) yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.5
0.75
0.5
0
(CH3)3COK
KOH
Na2CO3
K2CO3
NaOAc
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
toluene
THF
CH3CN
dioxane
DMF
NMP
DCE
DCE
DCE
DCE
DCE
8
10
12
8
12
8
12
8
8
12
12
12
12
12
8
56
41
c
_
60
c
_
83
NaHCO3
N(C2H5)3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
c
_
50
63
c
_
c
_
c
_
expensive metal catalysts and high loading of metal oxidants
and more attention has been payed to the direct C-C
bond formation of indoles. However, examples of the direct
functionalization of indoles with selective C-N bond for-
mation are rarely reported. Therefore, a new and effective
practical reaction system, involving mild, environmently
benign, atom economic, and metal-free conditions, for the
regioselective construction of C-C and C-N bonds of
N-protected indole derivatives is still of high demand in
modern organic synthesis.
In recent years, the electrophile-promoted tandem reac-
tions have proven to be an effective method for the synthesis
of heterocyclic compounds.12 We and others have reported
that the electrophilic cyclization13 can be a very powerful
tool for the preparation of a wide variety of interesting
heterocyclic compounds, due to the efficient, mild, and clean
reactions. Thus, electrophile-promoted tandem reactions con-
tinue to be an area of active research in the field of synthetic
chemistry. In this communication, we report the first suc-
cessful example of iodine-induced regioselective C-C and
C-N bonds formation of N-protected indole derivatives
affording 2,30-biindoles 2 and 4-(1H-indol-2-yl)morpholines
c
_
c
_
74
73
77
28
0
8
8
8
8
aConditions: 0.5 mmol 1a with 1-equiv of I2 in 1,2-dichloroethane
(DCE) (2.0 mL) at room temperature. bIsolated yield. cMixture.
4 (Scheme 1c), in which the key step is the attack of indoles or
morpholine on 3-iodo-3H-indol-1-iums Btriggered by iodonium
at room temperature.
Initially, we started by using 0.5 mmol of N-methylindole
1a, 1.0 equiv of I2, and 2.0 equiv of (CH3)3COK in 1,2-
dichloroethane (DCE) at room temperature; to our delight,
the desired product 1,10-dimethyl-1H,10H-2,30-biindole 2a
was isolated in 56% yield after 8 h (Table 1, entry 1). To
improve the reaction efficiency, the effect of bases was then
investigated (entries 2-7). It was found that the weak base
NaHCO3 gave the best result and an 83% yield was obtained
after 8 h (entry 6), whereas other bases, such as KOH,
Na2CO3, NaOAc, and N(C2H5)3, were less effective or
ineffective. With an attempt to optimize the yield of the
product, we further studied the influence of different reaction
media (entries 10-14). From the results obtained, it can be
seen that the use of CH2Cl2 and toluene gave an almost
identical result, albeit with a lower yield (entries 8 and 9).
THF, CH3CN, 1,4-dioxane, DMF, and NMP proved to be
less effective. Furthermore, the iodine loading was also in-
vestigated in this reaction, and the yield is good with anywhere
from 0.75 to 2 equiv of I2, but at 0.5 equiv it drops significantly
(entries 15-18). We also carried out this reaction in the
absence of I2 but no expected product was observed (entry
19). With a series of detailed investigations mentioned above,
the reaction conditions were eventually optimized as (entry 6)
follows: 0.5 mmolof 1, 1.0 equiv of I2, 2.0 equivofNaHCO3 as
the base, DCE (2.0 mL) as solvent at room temperature.
With the optimized conditions in hand, various represen-
tative N-protected indole derivatives 1a-q were then sub-
jected to the optimized conditions, as depicted in Table 2.
Thus, a tandem carbon-carbon bond formation of N-
protected indoles 1a-q proceeded smoothly to provide corre-
sponding 2,30-biindoles in moderate to good yields, except 1f
and 1 h. The molecular structure of the representative product
(11) Li, Y.; Wang, W.-H.; Yang, S.-D.; Li, B.-J.; Feng, C.; Shi, Z.-J.
Chem. Commun. 2010, 46, 4553.
(12) For early studies on electrophilic cyclization reaction, see: (a) Ren,
X.-F.; Turos, E. Tetrahedron Lett. 1993, 34, 1575. (b) Kitamura, T.; Takachi,
T.; Kawasato, H.; Taniguchi, H. J. Chem. Soc., Perkin Trans. 1 1992, 1969.
(c) Kitamura, T.; Kobayashi, S.; Taniguchi, H.; Hori, K. J. Am. Chem. Soc.
1991, 113, 6240. (d) Ten Hoedt, R. W. M.; Van Koten, G.; Noltes, J. G.
Synth. Commun. 1977, 7, 61. (e) Sonoda, T.; Kawakami, M.; Ikeda, T.;
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Org. Lett. 2004, 6, 1581. (i) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org.
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12230. (k) Tang, B.-X.; Tang, D.-J.; Tang, S.; Yu, Q.-F.; Zhang, Y.-H.;
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1266 and reference cited therein.
(13) (a) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang, S.-H.;
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Org. Chem. 2009, 2283. (f) Ji, K.-G.; Zhu, H.-T.; Yang, F.; Shu, X.-Z.; Zhao,
S.-C.; Shaukat, A.; Liu, X.-Y.; Liang, Y.-M. Chem.;Eur. J. 2010, 16, 1615.
(g) Ji, K.-G.; Zhu, H.-T.; Yang, F.; Shaukat, A.; Xia, X.-F.; Yang, Y.-F.; Liu,
X.-Y.; Liang, Y.-M. J. Org. Chem. 2010, 75, 5670.
J. Org. Chem. Vol. 76, No. 2, 2011 745

Li et al.
JOCNote
TABLE 2. Iodine-Induced Regioselective C-C Bond Formation of N-
SCHEME 2. Synthesis 1,10-Dimethyl-20,30-dihydro-1H,10H-
Protected Indoles toward 2-(1H-indol-3-yl)-1H-indole 2a
2,30-biindole 3a from N-Protected Indole 1a
TABLE 3. Iodine-Induced Regioselective C-N Bond Formation of
N-Protected Indoles toward 4-(1H-Indol-2-yl)morpholines 4a
entry
indole
R1
R2
products4
yieldb (%)
1
2
3
4
5
6
1a
1b
1c
1e
1p
1j
H
Me
Me
Me
Me
Allyl
Bn
4a
4b
4c
4e
4p
4j
74
60
50
55
54
70
4- Me
5- Me
7- Me
5-OCH3
4- Me
aConditions: 0.5 mmol 1a, 1.25 mmol of morpholine with 1.0 mmol of
I2, 1.0 mmol of NaHCO3 in acetonitrile (2.0 mL) at room temperature.
bThe molecular structure of the representative product 4a was deter-
mined by X-ray crystallography.
aConditions: 0.5 mmol 1a with 0.5 mmol of I2, 1.0 mmol of NaHCO3
in 1,2-dichloroethane (DCE, 2.0 mL) at room temperature. bIsolated
yield. cOnly a trace amount of 2g was observed after 24 h.
To our surprise, various 4-(1H-indol-2-yl)morpholines 4
were obtained in good to excellent yield, as depicted in Table 3.
In summary, we have developed an efficient method for
the regioselective C-C and C-N bonds formation of N-
protected indole derivatives to prepare 2,30-biindoles 2 and
4-(1H-indol-2-yl)morpholines 4 by iodine in moderate to
good yield. Further functionalization of indoles and other
heterocycles are the future goals of our research group.
2a was determined by X-ray crystallography. The reaction
can tolerate a variety of functional groups at the 4, 5, and 7
positions of N-protected indoles. Electron-rich groups show-
ed better results than electron-withdrawing groups in this
dimerization (1d vs 1f). Substrate 1g with an electron-with-
drawing R1 group only gave a trace amount of desired
product 2g (entry 7). When 1h was subjected to the optimized
conditions, no desired product was obtained (entry 8).To
explore more the scope of this reaction, different N-protected
R2 groups were also investigated (entries 9-18). It was found
that under the optimized conditions, the substrates 1i-q
were transferred into 2,30-biindoles 2i-q in moderate to
good yield (entries 9-16). Unfortunately, substrates like 1q
gave no reaction (entry 17).
Furthermore, we also investigated the dimerization of 0.5
mmol of 1a, 1.0 equiv of I2, and 2.0 equiv of HCl; fortunately,
1,10-dimethyl-20,30-dihydro-1H,10H-2,30-biindole 3a was ob-
tained in 76% yield (Scheme 2). The molecular structure of
the representative product 3a was determined by X-ray
crystallography. In 1996, Anna Berlin and co-workers re-
ported the same result, which is an acid-catalyzed reaction of
N-protected indole toward 3-(2-indolinyl)indole through
Smith’s mechanism.14
Experimental Section
General Procedure for the Synthesis of 2-(1H-indol-3-yl)-1H-
indole Derivatives 2. A mixture of indole derivative (0.5 mmol),
NaHCO3 (84 mg, 1 mmol), I2 (254 mg, 1 mmol), and 1,2-dichloro-
ethane (2 mL) was stirred at room temperature for 8 h. The
reaction mixture was quenched with a saturated solution of
Na2S2O3 (5 mL) and extracted with ethyl acetate (3ꢀ25 mL).
The combined organic phases were washed with brine (45 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated.
The residue was purified by flash column chromatography,
using a mixture of petrolium ether and ethyl acetate (15:1) as
eluent, to afford the corresponding products 2a as a white solid
(83% yield): mp 110-111 °C; 1H NMR (400 MHz, CDCl3,
TMS) δ 7.71 (d, J=8.0 Hz,1H), 7.64 (d, J = 7.6 Hz, 1H),
7.12-7.41 (m, 7H), 6.62 (s, 1H), 3.89 (s, 3H), 3.76 (s, 3H); 13
C
NMR (100 MHz, CDCl3, TMS) δ 138.0, 137.0, 135.1, 128.4,
127.7, 122.4, 121.0, 120.4, 120.2, 120.1, 119.6, 109.6, 109.4,
107.4, 101.4, 33.0, 31.0; IR (neat, cm-1) 2925, 2854, 1462, 740.
General Procedure for the Synthesis of 1,10-Dimethyl-20,30-
dihydro-1H,10H-2,30-biindole 3a. A mixture of 1-methyl-1H-
indole (0.5 mmol), HCl (3 N, 0.2 mL), I2 (254 mg, 1 mmol), and
dichloroethane (2 mL) was stirred at room temperature for 2 h.
The reaction mixture was quenched with a saturated solution of
Na2S2O3 (5 mL) and extracted with ethyl acetate (3ꢀ25 mL).
The combined organic phases were washed with brine (45 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated.
The residue was purified by flash column chromatography,
using a mixture of petroleum ether and ethyl acetate (15:1) as
As we know, the regioselective C-N bond formation of N-
protected indoles is very important in modern organic
synthesis, especially for the synthesis of alkaloids. So, we
investigated the reaction of a wide range of N-protected
indole derivatives with morpholine in the presence of iodine.
(14) Berlin, A.; Canavesi, A Tetrahedron 1996, 52, 7947.
746 J. Org. Chem. Vol. 76, No. 2, 2011

Li et al.
JOCNote
eluent, to afford the corresponding products 3a as a white solid
(76% yield): mp 112-113 °C; 1H NMR (400 MHz, CDCl3,
TMS) δ 7.73 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H),
7.26-7.30 (m, 1H), 7.10-7.21 (m, 4H), 6.76 (t, J=7.2 Hz, 1H),
6.57 (d, J=7.6 Hz, 1H), 4.66 (dd, J=11.2 Hz, 8.8 Hz, 1H), 3.82
(s, 3H), 3.35 (dd, J=8.8 Hz, 15.6 Hz, 1H), 3.24 (dd, J=11.2 Hz,
15.6 Hz, 1H), 2.69 (s, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ
153.4, 137.5, 129.2, 127.5, 127.3, 126.8, 124.0, 121.8, 120.1,
119.0, 117.7, 115.2, 109.3, 107.1, 64.7, 37.9, 34.1, 32.7; IR
(neat, cm-1) 2925, 1462, 748; HRMS (M þ H) calcd for
C18H18N2 (MP) 263.1543, found 263.1545.
by flash column chromatography, using a mixture of petro-
leum ether and ethyl acetate (10:1) as eluent, to afford the
corresponding products 4a as a white solid (74% yield): H
NMR (400 MHz, CDCl3, TMS) δ 7.47 (d, J=7.6 Hz, 1H),
7.20-7.05 (m, 3H), 5.91 (s, 1H), 3.84 (t, J = 4.8 Hz, 4H),
3.57 (s, 3H), 2.97 (t, J=4.8 Hz, 4H); 13C NMR (100 MHz,
CDCl3, TMS) δ 149.9, 135.2, 127.4, 120.3, 119.5, 119.3, 108.6,
86.9, 66.8, 52.7, 28.9; IR (neat, cm-1) 2838, 1547, 1114, 741;
HRMS (MþH) calcd for C13H16ON2 (MP) 217.1335, found
217.1338.
1
General Procedure for the Synthesis of 4-(1H-indol-2-yl)mor-
pholines 4. A mixture of indole derivative (0.5 mmol), mor-
pholine (128 mg, 1.25 mmol), Cs2CO3 (325 mg, 1 mmol), I2
(254 mg, 1 mmol), and acetonitrile (2 mL) was stirred at room
temperature for 8 h. The reaction mixture was quenched with
a saturated solution of Na2S2O3 (5 mL) and extracted with
ethyl acetate (3ꢀ25 mL). The combined organic phases were
washed with brine (45 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified
Acknowledgment. We thank the NSF (NSF-20732002,
NSF-20872052, NSF-20090443) for financial support.
Supporting Information Available: The detailed experimen-
tal procedure and copies of 1H NMR and 13C NMR spectra of
all compounds and X-ray data of 2a, 3a, and 4a in CIF format.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 747