One-pot synthesis of pyrimido[1,6-a ]indol-1(2 H)-one derivatives by a nucleophilic addition/Cu-catalyzed N-arylation/Pd-catalyzed C-H activation sequential process

Article abstract of DOI:10.1021/ol101041e

A novel and convenient one-pot synthesis of pyrimido[1,6-a]indol-1(2H)-one derivatives through a nucleophilic addition/Cu-catalyzed N-arylation/Pd- catalyzed C-H activation sequential process is described. The reaction of easily prepared ortho-gem-dibromovinyl isocyanates with N-alkyl-anilines gave the desired indole derivatives in moderate to good yields.

Full text of DOI:10.1021/ol101041e

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3034-3037
One-Pot Synthesis of
Pyrimido[1,6-a]indol-1(2H)-one
Derivatives by a Nucleophilic Addition/
Cu-Catalyzed N-Arylation/Pd-Catalyzed
C-H Activation Sequential Process
Zhi-Jing Wang,† Jian-Guo Yang,‡ Fan Yang,† and Weiliang Bao*,†
Department of Chemistry, Zhejiang UniVersity, Xixi Campus, Hangzhou 310028,
P. R. China, and School of Pharmaceutical and Chemical Engineering,
Taizhou UniVersity, Taizhou 317000, P. R. China
wlbao@css.zju.edu.cn
Received May 6, 2010
ABSTRACT
A novel and convenient one-pot synthesis of pyrimido[1,6-a]indol-1(2H)-one derivatives through a nucleophilic addition/Cu-catalyzed N-arylation/
Pd-catalyzed C-H activation sequential process is described. The reaction of easily prepared ortho-gem-dibromovinyl isocyanates with N-alkyl-
anilines gave the desired indole derivatives in moderate to good yields.
The indole framework represents a privileged structural motif
of important value in biologically active natural products and
pharmaceutical compounds.1 The indole-incorporated pyrimi-
do[1,6-a]indol-1(2H)-one derivatives could be applied as fluo-
rescent materials,2 5-HT3 receptor antagonists,3 topoisomerase
II inhibitors,4 etc. (Figure 1, A-C). However, the methods for
the assembly of these molecules were limited.2-5 Therefore,
Figure 1. Several pyrimido[1,6-a]indol-1(2H)-one derivatives reported
as biologically active compounds and pharmaceutical products.
† Zhejiang University.
‡ Taizhou University.
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996; p
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more efficient and facile routes, to synthesize these useful
molecules under mild conditions, are needed.
Cascade, tandem, and domino reactions could offer the
opportunity to access final products with high efficiency from
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10.1021/ol101041e  2010 American Chemical Society
Published on Web 06/07/2010

simple starting materials because they avoid the tedious step
by step separations and purifications of intermediates and
reduce the amount of pollutant waste, compared to traditional
stepwise synthesis. For these reasons, most of the recently
reported methods for the synthesis of indoles were based on
the use of these types of reactions.6
In the past decade, Cu-mediated sp2 C-X (X ) N, O, S,
etc.) bond formation reactions have drawn considerable
attention for their efficiency and low cost.7 Recently, these
Cu-catalyzed reactions have been successfully applied to the
assembly of various heterocyclic compounds via one-pot
strategies.8 Our research group has also reported alternative
protocols for the synthesis of heterocycles based on Cu-
catalyzed coupling reactions.9 Aza-accumulated olefins such
as carbodiimides9c,g and isothiocyanates,8a,9a,d which could
easily undergo nucleophilic addition, were employed as
common substrates in Cu-catalyzed one-pot protocols. How-
ever, the similar protocols using isocyanates as nucleophilic
acceptors were not well documented.
More recently, ortho-gem-dihalovinylanilines13 have been
developed to synthesize 2-substituted indole derivatives via
domino processes.14-16 2-Substituted benzofuran13,14f,17b and
benzothiophenes17 were also obtained from the corresponding
ortho-gem-dihalovinyl phenols and thiophenols. However,
to the best of our knowledge, the substituents on the ortho
position of the gem-dihalostyrene were all nucleophilic
groups, and none of the reactions of gem-dihalostyrene with
electrophilic ones on the ortho position were reported.
Accordingly, we envisioned an addition/N-arylation/C-H
activation sequential process to access pyrimido[1,6-a]indol-
1(2H)-one derivatives in one pot, from easily prepared ortho-
gem-dibromovinylisocyanates and N-alkyl-anilines. Herein,
we would like to report the results (Scheme 1).
Scheme 1. Strategy for the Synthesis of
Pyrimido[1,6-a]indol-1(2H)-one Derivatives
The C-H activation approach, for its sustainable and
environmentally benign features, has received substantial
attention.10 Most notably, direct arylation on the ortho
positions of anilines via C-H activation have become the
focus of many research groups.11 However, there were only
several reports of reactions in which direct arylations were
involved with another coupling process.12,14h
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Asian J. 2009, 4, 1036.
The proposed sequential process was first examined using
ortho-gem-dibromovinylisocyanate 1a and N-methyl aniline 2a
to form the addition product 3a nearly quantitatively.18 As we
expected, the N-arylation of 3a catalyzed by CuI occurred to
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Org. Lett., Vol. 12, No. 13, 2010
3035

provide corresponding 2-bromoindole 4a, and the intramolecular
direct arylation of 4a catalyzed by PdCl2 was successful to
access the desired product 5a. Then we searched for the opti-
mized cyclization conditions of C-N bond formation using 3a
as a model substrate, as shown in Table 1.
To achieve the “one-pot” protocol, toluene was employed
as the solvent for the direct arylation of 4a. Different Pd
sources were tested, and Pd(dppf)Cl2 (Table 2, entry 2) was
Table 2. Optimization of the Second Cyclization: Intramolecular
Direct Arylation Conditionsa
Table 1. Optimization of the C-N Bond Formation Reaction
Conditionsa
entry
Pd catalyst
base
yield (%)
1
2
3
4
5
6
7
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
KOAc
62
81
25
trace
65
Pd(dppf)Cl2
Pd(OAc)2
Pd(dba)2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
52
90
a Reaction conditions: N-methyl-N-phenyl-2-bromo-1H-indole-1-car-
boxamide 4a (0.5 mmol), Pd source (0.05 mmol), and base (1.5 mmol, 3.0
equiv) in toluene (4.0 mL) under N2, for 24 h.
found to be the best catalyst for this second cyclization.
Pd(OAc)2 gave a much lower yield (entry 3), while Pd(dba)2
failed to give any product (entry 4). KOAc was found to be
the best base to promote the intramolecular direct arylation
(entry 7). Then, the one-pot protocol was examined. When
the formation of 4a completed, Pd(dppf)Cl2 and KOAc were
directly added to the reaction mixture without further
purification, to obtain 5a successfully in good yield. How-
ever, using Pd(dppf)Cl2 only without CuI could not provide
5a from 3a successfully. K2CO3 and KOAc also could not
well promote the reaction from 3a to 5a independently.
Under the above optimized reaction conditions, various
substituted ortho-gem-dibromovinyl isocyanates were used
to test the generality of the reaction (Table 3). All the
substituted ortho-gem-dibromovinyl isocyanates tested were
converted smoothly to 5a-5f. The method was proved to
be general and efficient to prepare benzo-functionalized
indole derivatives. Both electron-rich ortho-gem-dibromovi-
nyl isocyanates (4,5-diMeO) (entry 2) and electron-deficient
ones (5-Br, 4-Cl, 4-Br) could afford the corresponding
products 5b-5e (entries 3-5). It was worth mentioning that
3-substituted indoles could be provided from the correspond-
ing isocyanate substrate in moderate yield (entry 6, 67%).
Then, various substituted N-alkyl-anilines were also
investigated under the reaction conditions, as shown in Table
4. N-Methyl-anilines with electron-donating groups (4-Me,
4-MeO, 2-Me, 3,5-diMe, 3-Me) reacted efficiently with
ortho-gem-dibromovinyl isocyanate 1a and gave moderate
to good yields (Table 4, entries 1-5). As we expected, 5k
and its isomer 5k′ were obtained as a mixture when
N-methyl-3-Me aniline was used (3:2) (entry 5).19 The
electron-withdrawing groups (4-Cl, 4-Br, 4-CF3O) on the
phenyl ring of N-methyl-aniline were also tolerated (entries
6-8). N-Benzyl-aniline worked even better than N-methyl-
a Reaction conditions: 3-(2-(2′,2′-dibromovinyl)phenyl)-1-methyl-1-
phenylurea 3a (0.5 mmol), Cu source (0.05 mmol), ligand (0.1 mmol), and
base (1.0 mmol) in solvent (4.0 mL) under N2, for 24 h. b 1,10-Phen )
1,10-phenanthroline. c DMEDA ) N,N′-dimethylethylenediamine. d n.r. )
no reaction.
Initial studies focused on the selection of an efficient
ligand. After screening a range of common ligands, DMEDA
was found to be superior (Table 1, entry 4). Then various
bases and solvents were tested, and K2CO3 and toluene
proved to be the most efficient. Reducing the temperature
caused a diminution in the yield (entries 9 and 10). When
the copper source was switched to CuBr or Cu2O (entries
14 and 15), the yield decreased. So, the conditions described
in entry 4 were selected as optimal.
(15) Viera, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008,
10, 4899.
(16) Arthuis, M.; Pontikis, R.; Florent, J.-C. Org. Lett. 2009, 11, 4608.
(17) (a) Bryan, C. S.; Braunger, J. A.; Lautens, M. Angew. Chem., Int.
Ed. 2009, 48, 7064. (b) Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens,
M. Chem. Commun. 2009, 5236.
3036
Org. Lett., Vol. 12, No. 13, 2010

Table 3. Nucleophilic Addition/Cu-Catalyzed N-Arylation/
Pd-Catalyzed C-H Activation Sequential Reaction of
Substituted ortho-gem-Dibromovinyl Isocyanates with
N-Methyl-anilinea
Table 4. Nucleophilic Addition/Cu-Catalyzed N-Arylation/
Pd-catalyzed C-H Activation Sequential Reaction of
ortho-gem-Dibromovinyl Isocyanate with Various Substituted
N-Alkyl-anilinesa
b
c
entry
R3
R4
4-Me
4-MeO
2-Me
3,5-diMe
3-Me
4-Cl
t1 (h)
t2 (h)
yield (%)
80 (5g)
67 (5h)
62 (5i)
64 (5j)
68 (5k, 5k′)
77 (5l)
71 (5m)
69 (5n)
87 (5o)
69 (5p)
entry
R1
R2
t1 (h)b
t2 (h)c
yield (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Me
24
26
30
26
30
26
24
30
24
16
24
24
24
36
36
24
24
36
24
24
1
2
3
4
5
6
H
H
H
H
H
H
CF3
24
18
24
24
36
24
24
24
24
36
24
24
78 (5a)
65 (5b)
57 (5c)
63 (5d)
61 (5e)
67 (5f)
4,5-diMeO
5-Br
4-Cl
4-Br
H
4-Br
4-CF3O
H
a Reaction conditions: ortho-gem-dibromovinyl isocyanate 1 (0.5 mmol),
N-methyl-aniline 2a (0.55 mmol), CuI (0.05 mmol), DMEDA (0.1 mmol),
and K2CO3 (1.0 mmol, 2.0 equiv) in toluene (4.0 mL), under N2 at 120 °C
for t1, then Pd(dppf)Cl2 (0.05 mmol) and KOAc (1.5 mmol), in toluene
(4.0 mL), under N2 at 120 °C for t2. b Time for Cu-Catalyzed N-arylation.
c Time for Pd-catalyzed C-H activation.
10
1-Naphthyl
a Reaction conditions: ortho-gem-dibromovinyl isocyanate 1a (0.5
mmol), N-alkyl-aromatic amine 2 (0.55 mmol), CuI (0.05 mmol), DMEDA
(0.1 mmol), and K2CO3 (1.0 mmol) in toluene (4.0 mL), under N2 at 120
°C for t1, then Pd(dppf)Cl2 (0.05 mmol) and KOAc (1.5 mmol), in toluene
(4.0 mL), under N2 at 120 °C for t2. b Time for Cu-Catalyzed N-arylation.
c Time for Pd-catalyzed C-H Activation.
aniline (entry 9, 87%). N-Methyl-1-naphthylamine also
participated in the sequential process leading to indole
derivative 5p in moderate yield (entry 10, 69%). As a
limitation of our method, N-methyl-aniline, bearing a strongly
electron-withdrawing group on the phenyl ring, such as
4-NO2 and 4-Ac, which had a detrimental effect on nucleo-
philicity, failed to react with ortho-gem-dibromovinyl iso-
cyanate to obtain the addition product. The addition of
diphenylamine with ortho-gem-dibromovinyl isocyanate was
also unsuccessful, due to its high steric hindrance.
In summary, we have developed a novel and convenient
one-pot protocol to synthesize pyrimido[1,6-a]indol-1(2H)-
one derivatives through a nucleophilic addition/Cu-catalyzed
N-arylation/Pd-catalyzed C-H activation sequential process.
The reaction is applicable to a variety of ortho-gem-
dibromovinyl isocyanates and N-alkyl-anilines, and moderate
to good yields are attained. The products are potentially
useful. Further investigations into synthetic applications are
underway.
Acknowledgment. This work was financially supported
by the Specialized Research Fund for the Doctoral Program
of Higher Education of China (20060335036) and Zhejiang
Provincial Natural Science Foundation of China under Grant
No. Y406049.
Supporting Information Available: Experimental pro-
1
cedure, characterization data, and copies of H NMR and
(18) We also examined unprotected anilines, such as aniline and
4-methyl-aniline. The corresponding urea was obtained, but the Cu-catalyzed
N-arylation was unsuccessful.
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) The regioisomer ratio was based on the 1H NMR spectrum, and
the configuration of the isomers was determined by NOE.
OL101041E
Org. Lett., Vol. 12, No. 13, 2010
3037