A facile route to 1,3-diazaheterocycle-fused [1,2-a ]indole derivatives via acetic acid catalyzed cyclocondensation reactions

Article abstract of DOI:10.1055/s-0030-1258195

A concise and efficient route for the synthesis of 1,3-diazaheterocycle- fused [1,2-a]indoles by simply refluxing a reaction mixture of different types of heterocyclic ketene aminals and 1,4-benzoquinones catalyzed by acetic acid was developed. This protocol provides an alternative method for application in combinatorial and parallel synthesis in drug discovery. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258195

3536
PAPER
A Facile Route to 1,3-Diazaheterocycle-Fused [1,2-a]Indole Derivatives via
Acetic Acid Catalyzed Cyclocondensation Reactions
S
ynthesis of 1,3
i
-Diaza
-
heterocy
J
cle-Fused
u
[1,2-
a
]Indol
a
es n Yang,1 Sheng-Jiao Yan,1 Wen Chen, Jun Lin*
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education,
School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. of China
Fax +86(871)5033215; E-mail: linjun@ynu.edu.cn
Received 7 June 2010; revised 1 July 2010
play important roles in drug discovery and are also used
Abstract: A concise and efficient route for the synthesis of 1,3-di-
azaheterocycle-fused [1,2-a]indoles by simply refluxing a reaction
mixture of different types of heterocyclic ketene aminals and 1,4-
benzoquinones catalyzed by acetic acid was developed. This proto-
col provides an alternative method for application in combinatorial
and parallel synthesis in drug discovery.
as herbicides, pesticides,11 antianxiety agents,12 antileish-
manial agents13 and antibacterial drugs.14
R2
R1
Key words: 1,3-diazaheterocycle-fused [1,2-a]indoles, heterocy-
clic ketene aminals, 1,4-benzoquinones, catalyst, acetic acid
NH
N
n
4 n = 1
5 n = 2
6 n = 3
1,3-Diazaheterocycle-fused [1,2-a]indole and related
compounds, such as 2,3-dihydro-1H-imidazo[1,2-a]in-
dole (4), 1,2,3,4-tetrahydropyrimido[1,2-a]indole (5), and
Figure 1 Chemical structures of 1,3-diazaheterocycle-fused [1,2-
a]indoles
2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indole
(6)
(Figure 1) are commonly found in nature and many alka-
loids exist holding this kind of scaffold.2 For instance, im-
idazoindoles are present as the key structural motif in the
core structures of novel marine natural products and bio-
logically active molecules, including the potent cholecys-
tokinin antagonist asperlicin (7)3 and the antifungal and
moderately cytotoxic fumiquinazolines A (8) and B
(9)2a,b,4 (Figure 2). In addition, such 2-amino-substituted
indoles are versatile building blocks for the total synthesis
of natural products.5 Because of their broad range of bio-
logical activities and their value as synthetic precursors
for pharmaceutical compounds, 2-amino-substituted in-
dole derivatives have received increasing interest over
many years.6 Mild and efficient methods to synthesize 2-
amino-substituted indoles, such as transition metal-cata-
lyzed procedures,7 have been developed. However, such
2-amino-substituted indole moieties are difficult to access
through traditional synthetic methods such as Fischer in-
dole synthesis.5,7–9 The introduction of multiple substitu-
ents into the indole ring often requires multistep reactions
and complex experimental processes. Procedures to pre-
pare highly functional and diverse 2-amino-substituted in-
doles are limited, hence a general and concise approach to
this class of heterocycles that tolerates a wide variety of
functional groups is highly desirable.
R
O
N
N
NH
N
O
N
O
HN
HO
OH
NH
N
NH
N
O
O
8 R = α-Me
9 R = β-Me
7
Figure 2 Structures of natural products containing imidazoindole
structural motif
Recently, we reported novel methods for the construction
of a 1,3-diazaheterocycle-fused [1,2-b]isoquinolin-1(2H)-
one library15a and a bicyclic pyridone library.15b Subse-
quent biological assays revealed that these kinds of com-
pounds possess excellent cytotoxic activities against
cancer cell lines.15 This result prompted us to develop a
methodology for the construction of a structurally similar
and novel 1,3-diazaheterocycle-fused [1,2-a]indole li-
brary, with the expectation of finding better leading com-
pounds in the biological assays. In this paper, we report a
convenient approach for the synthesis of a library of 1,3-
diazaheterocycle-fused [1,2-a]indoles based upon 1,4-
Michael addition and cyclocondensation reaction of
HKAs with 1,4-benzoquinones in good yields.
Heterocyclic ketene aminals (HKAs) are versatile inter-
mediates for the synthesis of a wide variety of fused het-
erocyclic compounds.10 These fused heterocyclic
structures are frequently found in pharmacophores and
To examine the practicality of the projected synthetic
route, we first evaluated the cyclocondensation reaction of
highly functionalized 1,4-benzoquinone 1a and ethyl 2-
(imidazolidin-2-ylidene)acetate (2a). In earlier literature,
SYNTHESIS 2010, No. 20, pp 3536–3544
Advanced online publication: 04.08.2010
DOI: 10.1055/s-0030-1258195; Art ID: F10210SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

PAPER
Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles
Table 1 Optimizing the Reaction Conditions for 3a
3537
only one example of the reaction of 1,4-benzoquinone and
heterocyclic ketene aminal has been examined; however,
an exclusive tricyclic indole was obtained at a very low
yield (9%).16 The mixture in the present study was com-
posed of a 1:1.1 ratio of 2a to 1a and was treated at reflux
in various conditions (Scheme 1, Table 1, entries 1–10).
Evaluation of the catalysts and solvents showed that the
acid catalysts were better than the base catalysts, and that
solvent reactions were superior to solvent-free conditions.
Further screening of the solvents led to the identification
of 1,4-dioxane as the most effective solvent for the trans-
formation to the required product in a high isolated yield
of 90%. Structural identification revealed that the com-
pound obtained was the ethyl 2,3-dihydro-7-hydroxy-5,6-
dimethoxy-8-methyl-1H-imidazo[1,2-a]indole-9-carbox-
ylate (3a). Thus, we found that the optimum reaction con-
dition for the formation of product 3a was AcOH as the
catalyst and 1,4-dioxane as the solvent (90%, Table 1, en-
try 8).
Entry
Catalyst (10%) Solvent
Time (h)
Yield (%)a
1
2
AcOH
Et3N
–
8
8
8
8
8
8
8
8
8
8
15
5
–
3
DBU
–
trace
28
19
40
44
90
48
64
4
AcOH
Et3N
CH2Cl2
CH2Cl2
THF
5
6
AcOH
AcOH
AcOH
Et3N
7
MeCN
1,4-dioxane
1,4-dioxane
toluene
8
9
10
AcOH
a Isolated yields based on HKAs 2a.
O
substituents on the aromatic backbone) and different ring-
sizes 2a–l were all good substrates for the reaction. The
reactions were straightforward and gave very good to ex-
cellent overall yields. Notably, the structures of the HKAs
2 have an obvious influence on the reactivity and product
yield. For example, the reactivity of 2 was increased by
the electron-rich properties of the group on the aromatic
ring (Table 2, entries 2–4, 7–10, 11–14, 15–18). Under the
experimental conditions, the reactivity order of the six-
membered HKAs was 2e > 2f > 2g > 2h. The reactivity or-
der of the seven-membered HKAs also showed the same
tendency, that is, 2i = 2j > 2k > 2l. Additionally, in terms
of the ring-sizes of the HKAs 2, the reactivity of five- and
six-membered HKAs were superior to that of seven-mem-
bered HKAs. It is worth mentioning that the structure of
the 1,4-benzoquinone 1 also had a noticeable influence on
the reaction. The reactivity of 1 varied with the electron-
rich properties of the groups R1 to R3, and the reactivity of
1,4-benzoquinone under the typical conditions was found
to be 1a > 1b (Table 2, entries 1–18).
MeO
MeO
COOEt
NH
O
1a
HO
AcOH (10%)
+
1,4-dioxane, reflux
N
MeO
NH
OMe
3a
COOEt
N
H
2a
Scheme 1 Reaction of 1,4-benzoquinone 1a with HKA 2a in diffe-
rent conditions
Using the AcOH-catalyzed condition (10% AcOH, 1,4-
dioxane), two 1,4-benzoquinones 1 reacted with various
heterocyclic ketene aminals 2 to generate a number of 1,3-
diazaheterocycle-fused [1,2-a]indoles 3, as shown in
Scheme 2 and Table 2 (entries 1–18). As a result, this
methodology was found to be applicable to a diverse
range of HKAs with various substituents and rings 2a–l
and 1,4-benzoquinones 1a,b, producing the correspond-
ing cyclocondensation products. The reactions usually
took 6–8 hours at refluxing temperature in 1,4-dioxane
under AcOH-catalyzed conditions for completion, and the
yields were generally good.
To verify the structure of the 1,3-diazaheterocycle-fused
[1,2-a]indole product, 3a was selected as a representative
compound and characterized by X-ray crystallography, as
shown in Figure 3.17
A proposed mechanism of the acetic acid catalyzed cyclo-
condensation reaction is depicted in Scheme 3. The HKAs
2 react with 1,4-benzoquinone 1 possibly via an aza-ene
The results in Table 2 demonstrate that HKAs, with vari-
ous substituents (electron-withdrawing and -donating
O
R3
R4
O
R2
R1
R3
HO
R2
NH
O
AcOH (10%)
+
n
NH
1,4-dioxane, reflux
R4
N
N
H
n
R1
O
1
2
3
n = 1–3;
R1 = H, MeO; R2 = H, MeO;
R3 = H, Me; R4 = OEt, Ar
Scheme 2 Acetic acid catalyzed synthesis of 1,3-diazaheterocycle-fused [1,2-a]indoles 3
Synthesis 2010, No. 20, 3536–3544 © Thieme Stuttgart · New York

3538
L.-J. Yang et al.
PAPER
addition mechanism10a to give the adduct 10 followed by
imine–enamine tautomerization to form compound 11,
and subsequent condensation and elimination of H2O re-
sulted in the target product 3.
In conclusion, this study offers a novel procedure for the
facile synthesis of 1,3-diazaheterocycle-fused [1,2-a]in-
dole derivatives. By simply refluxing a reaction mixture
of different types of HKAs and 1,4-benzoquinones cata-
lyzed by acetic acid, we obtained a novel library of 1,3-di-
azaheterocycle-fused [1,2-a]indoles. This protocol
provides an alternative method for application in combi-
natorial and parallel syntheses in drug discovery.
Figure 3 X-ray crystal structure of 3a
Table 2 Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles 3
Entry
1
2
Product 3
Yield (%)a
90
O
COOEt
HO
MeO
MeO
NH
O
1
1a
2a
3a
NH
N
H
OEt
N
MeO
OMe
O
O
HN
NH
O
MeO
MeO
O
HO
2
3
1a
1a
2b
3b
93
NH
N
MeO
O
O
OMe
O
HN
NH
MeO
MeO
HO
O
2c
3c
92
NH
N
MeO
O
O
OMe
HN
NH
O
Cl
O
MeO
MeO
HO
4
5
1a
1b
2d
2a
3d
3e
91
78
NH
N
MeO
O
OMe
Cl
O
O
COOEt
NH
NH
O
HO
N
H
OEt
N
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PAPER
Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles
3539
Table 2 Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles 3 (continued)
Entry
1
2
Product 3
Yield (%)a
HN
NH
O
O
O
O
HO
6
1b
2b
3f
86
NH
N
Me
HN
NH
O
O
O
OMe
MeO
MeO
O
HO
7
1a
2e
3g
92
NH
N
MeO
OMe
OMe
HN
NH
O
O
O
MeO
MeO
HO
8
1a
2f
3h
90
NH
N
MeO
O
O
OMe
O
HN
NH
O
MeO
MeO
HO
9
1a
2g
3i
88
NH
N
MeO
O
O
OMe
HN
NH
O
O
Cl
MeO
MeO
HO
10
1a
2h
3j
87
NH
N
MeO
O
OMe
Cl
HN
NH
O
O
O
O
OMe
HO
11
1b
2e
3k
89
NH
N
OMe
Synthesis 2010, No. 20, 3536–3544 © Thieme Stuttgart · New York

3540
L.-J. Yang et al.
PAPER
Table 2 Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles 3 (continued)
Entry
12
1
2
Product 3
Yield (%)a
HN
NH
O
O
O
HO
1b
2f
3l
88
NH
N
O
O
O
HN
NH
HO
13
1b
2g
3m
85
O
NH
N
O
O
HN
NH
O
Cl
O
HO
14
1b
2h
3n
84
NH
N
O
Cl
O
HN
NH
O
O
OMe
O
HO
15
1b
2i
3o
86
NH
N
OMe
O
HN
NH
O
O
HO
16
1b
2j
3p
86
NH
N
O
O
O
HN
NH
O
HO
17
1b
2k
3q
80
NH
N
O
Synthesis 2010, No. 20, 3536–3544 © Thieme Stuttgart · New York

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Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles
3541
Table 2 Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles 3 (continued)
Entry
1
2
Product 3
Yield (%)a
O
HN
NH
O
O
Cl
O
HO
18
1b
2l
3r
76
NH
N
Cl
a Yield of isolated product from the reaction on a 1 mmol scale (based on HKAs 2).
The organic layer was washed with brine (20 mL), dried (Na2SO4),
concentrated, and the residue purified by flash column chromato-
graphy to afford the required product.
O
H
R4
O
N
R3
R3
aza-ene
addition
HO+
R2
O
N
H
n
H
Ethyl 2,3-Dihydro-7-hydroxy-5,6-dimethoxy-8-methyl-1H-imi-
dazo[1,2-a]indole-9-carboxylate (3a)
Starting from 2,3-dimethoxy-5-methylcyclohexa-2,5-diene-1,4-di-
one (1a; 0.20 g, 1.1 mmol), ethyl 2-(imidazolidin-2-ylidene)acetate
(2a; 0.16 g, 1.0 mmol), and AcOH (0.06 g, 0.1 mmol), 3a was ob-
tained as yellow crystals; yield: 0.29 g (90%); mp 180–182 °C.
R2
O
2
R1
R1
1
R4
H
R4
O
O
R3
R3
H
N
H
N
imine–enamine
tautomerization
HO
R2
HO
R2
IR (KBr): 3412, 2979, 2934, 2890, 1686, 1581, 1491, 1455, 1328,
1273, 1098, 1038, 852 cm–1.
1H NMR (500 MHz, acetone-d6): d = 6.96 (br s, 1 H, NH), 6.10 (br
s, 1 H, OH), 4.30–4.26 (m, 2 H, NCH2), 4.18 (q, J = 7.1 Hz, 2 H,
OCH2), 4.07–4.03 (m, 2 H, NCH2), 3.92 (s, 3 H, OCH3), 3.85 (s, 3
H, OCH3), 2.65 (s, 3 H, ArCH3), 1.31 (t, J = 7.1 Hz, 3 H, CH3).
N
N
n
O
n
O
R1
R1
H
11
10
O
R3
R4
HO
R2
13C NMR (125 MHz, acetone-d6): d = 165.2, 160.5, 144.6, 136.8,
136.2, 128.1, 119.8, 112.5, 84.4, 62.4, 61.7, 59.3, 49.8, 46.3, 15.6,
14.3.
HRMS (TOF ES+): m/z calcd for C16H21N2O5 [M + H+]: 321.1445;
found: 321.1445.
condensation
– H2O
NH
N
R1
n
3
Scheme 3 Proposed mechanism for the acetic acid catalyzed cyclo-
condensation reaction of 1,4-benzoquinone 1 and HKAs 2
(2,3-Dihydro-7-hydroxy-5,6-dimethoxy-8-methyl-1H-imida-
zo[1,2-a]indol-9-yl)(p-tolyl)methanone (3b)
Starting from 1a (0.20 g, 1.1 mmol), 2-(imidazolidin-2-ylidene)-1-
p-tolylethanone (2b; 0.20 g, 1.0 mmol), and AcOH (0.06 g, 0.1
mmol), 3b was isolated as a yellow solid (0.34 g, 93%); mp 271–
272 °C.
All new compounds were fully characterized by spectroscopic data.
The NMR spectra were recorded on a Bruker DRX500 (1H: 500
MHz, 13C: 125 MHz), chemical shifts (d) are expressed in ppm, and
J values are given in Hz, and deuterated DMSO-d6 or acetone-d6
was used as solvent. IR spectra were recorded on a FT-IR Thermo
Nicolet Avatar 360 using KBr pellet. The reactions were monitored
by TLC using silica gel GF254. The melting points were determined
on XT-4A melting point apparatus and are uncorrected. HRMS
were performed on an Agilent LC/MSD TOF instrument.
IR (KBr): 3333, 2934, 1601, 1522, 1455, 1407, 1279, 1212, 1091,
1058 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.99 (s, 1 H, NH), 7.49 (d,
J = 7.9 Hz, 2 H, ArH), 7.24 (d, J = 7.9 Hz, 2 H, ArH), 6.34 (br s, 1
H, OH), 4.21 (t, J = 16.4 Hz, 2 H, NCH2), 3.88 (t, J = 16.4 Hz, 2 H,
NCH2), 3.87 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 2.37 (s, 3 H,
ArCH3), 1.75 (s, 3H, ArCH3).
13C NMR (125 MHz, DMSO-d6): d = 187.1, 159.3, 143.8, 140.7,
139.8, 136.2, 135.9, 129.1, 128.8, 127.2, 118.5, 111.7, 94.8, 62.1,
61.1, 49.0, 44.8, 21.4, 15.1.
All chemicals and solvents were used as received without further
purification unless otherwise stated. Column chromatography was
performed on silica gel (200–300 mesh).
The material 2a was synthesized according to the litera-
ture.18Compounds 2b–l were prepared according to the literature.19
Compounds 1a and 1b were purchased from Aldrich.
HRMS (TOF ES+): m/z calcd for C21H23N2O4 [M + H+]: 367.1652;
found: 367.1654.
1,3-Diazaheterocycle-Fused [1,2-a]Indoles 3; General Proce-
dure
In a 50 mL round-bottomed flask, 1,4-benzoquinone 1 (1.1 mmol)
and HKA 2 (1.0 mmol) were mixed with 1,4-dioxane (10 mL) and
AcOH (0.1 mmol) and the mixture was refluxed for 6–8 h until the
HKA 2 was completely consumed (TLC monitoring). The mixture
was diluted with EtOAc (20 mL) and quenched with H2O (20 mL).
(2,3-Dihydro-7-hydroxy-5,6-dimethoxy-8-methyl-1H-imida-
zo[1,2-a]indol-9-yl)(phenyl)methanone (3c)
Starting from 1a (0.20 g, 1.1 mmol), 2-(imidazolidin-2-ylidene)-1-
phenylethanone (2c; 0.19 g, 1.0 mmol), and AcOH (0.06 g, 0.1
mmol), 3c was isolated as a brown liquid (0.32 g, 92%).
Synthesis 2010, No. 20, 3536–3544 © Thieme Stuttgart · New York

3542
L.-J. Yang et al.
PAPER
IR (KBr): 3323, 2932, 1601, 1521, 1459, 1401, 1281, 1210, 1091,
1056, 738 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 187.1, 159.5, 152.5, 139.9,
139.7, 132.1, 129.2, 127.6, 125.7, 108.9, 108.3, 106.2, 93.5, 49.4,
42.5, 21.5.
HRMS (TOF ES+): m/z calcd for C18H17N2O2 [M + H+]: 293.1285;
found: 293.1285.
1H NMR (500 MHz, DMSO-d6): d = 8.01 (br s, 1 H, NH), 7.57 (d,
J = 7.4 Hz, 2 H, ArH), 7.50 (d, J = 7.4 Hz, 1 H, ArH), 7.43 (dd,
J = 7.4, 7.4 Hz, 2 H, ArH), 6.42 (br s, 1 H, OH), 4.22 (t, J = 16.5 Hz,
2 H, NCH2), 3.90 (t, J = 16.5 Hz, 2 H, NCH2), 3.87 (s, 3 H, OCH3),
3.76 (s, 3 H, OCH3), 1.71 (s, 3 H, ArCH3).
13C NMR (125 MHz, DMSO-d6): d = 187.3, 159.5, 143.9, 142.6,
136.2, 135.9, 130.9, 128.6, 128.6, 127.0, 118.5, 111.8, 94.8, 62.1,
61.1, 49.1, 44.8, 15.1.
(1,2,3,4-Tetrahydro-8-hydroxy-6,7-dimethoxy-9-methylpyrim-
ido[1,2-a]indol-10-yl)(4-methoxyphenyl)methanone (3g)
Starting from 1a (0.20 g, 1.1 mmol), 2-[tetrahydropyrimidin-2(1H)-
ylidene]-1-(4-methoxyphenyl)ethanone (2e; 0.23 g, 1.0 mmol), and
AcOH (0.06 g, 0.1 mmol), 3g was isolated as a yellow solid (0.36 g,
92%); mp 237–238 °C.
HRMS (TOF ES+): m/z calcd for C20H21N2O4 [M + H+]: 353.1496;
found: 353.1498.
IR (KBr): 3309, 2936, 1609, 1513, 1423, 1287, 1253, 1158, 1076,
1026, 836 cm–1.
(4-Chlorophenyl)(2,3-dihydro-7-hydroxy-5,6-dimethoxy-8-
methyl-1H-imidazo[1,2-a]indol-9-yl)methanone (3d)
Starting from 1a (0.20 g, 1.1 mmol), 1-(4-chlorophenyl)-2-(imida-
zolidin-2-ylidene)ethanone (2d; 0.22 g, 1.0 mmol) and AcOH (0.06
g, 0.1 mmol), 3d was isolated as a yellow solid (0.35 g, 91%); mp
212–214 °C.
1H NMR (500 MHz, DMSO-d6): d = 8.09 (br s, 1 H, NH), 8.01 (br
s, 1 H, OH), 7.41 (d, J = 8.4 Hz, 2 H, ArH), 6.92 (d, J = 8.4 Hz, 2
H, ArH), 4.29 (t, J = 11.2 Hz, 2 H, NCH2), 3.97 (s, 3 H, OCH3), 3.80
(s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 3.40 (t, J = 11.2 Hz, 2 H,
NCH2), 2.07–2.11 (m, 2 H, CH2), 1.35 (s, 3 H, ArCH3).
IR (KBr): 3325, 2975, 1599, 1519, 1455, 1399, 1279, 1213, 1091,
1017, 849 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 186.8, 161.1, 152.4, 144.0,
137.0, 136.5, 136.1, 130.3, 123.2, 119.9, 113.5, 109.9, 96.1, 62.0,
61.0, 55.6, 42.2, 38.0, 21.4, 15.7.
HRMS (TOF ES+): m/z calcd for C22H25N2O5 [M + H+]: 397.1758;
found: 397.1755.
1H NMR (500 MHz, DMSO-d6): d = 8.04 (br s, 1 H, NH), 7.59 (d,
J = 8.3 Hz, 2 H, ArH), 7.49 (d, J = 8.3 Hz, 2 H, ArH), 6.49 (br s, 1
H, OH), 4.21 (t, J = 16.7 Hz, 2 H, NCH2), 3.89 (t, J = 16.7 Hz, 2 H,
NCH2), 3.87 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 1.80 (s, 3 H,
ArCH3).
13C NMR (125 MHz, DMSO-d6): d = 185.6, 159.6, 144.0, 141.1,
136.4, 135.9, 135.6, 130.6, 128.7, 126.9, 118.6, 111.8, 94.6, 62.1,
61.1, 49.1, 44.8, 15.2.
(1,2,3,4-Tetrahydro-8-hydroxy-6,7-dimethoxy-9-methylpyrim-
ido[1,2-a]indol-10-yl)(p-tolyl)methanone (3h)
Starting from 1a (0.20 g, 1.1 mmol), 2-[tetrahydropyrimidin-2(1H)-
ylidene]-1-p-tolylethanone (2f; 0.22 g, 1.0 mmol), and AcOH (0.06
g, 0.1 mmol), 3h was isolated as a yellow solid (0.34 g, 90%); mp
211–212 °C.
HRMS (TOF ES+): m/z calcd for C20H20ClN2O4 [M + H+]:
387.1106; found: 387.1108.
IR (KBr): 3311, 2933, 1613, 1522, 1452, 1367, 1286, 1157, 1069,
843 cm–1.
Ethyl 7-Hydroxy-2,3-dihydro-1H-imidazo[1,2-a]indole-9-car-
boxylate (3e)
Starting from cyclohexa-2,5-diene-1,4-dione (1b; 0.12 g, 1.1
mmol), 2a (0.16 g, 1.0 mmol), and AcOH (0.06 g, 0.1 mmol), 3e
was isolated as a yellow solid (0.19 g, 78%); mp 214–216 °C.
1H NMR (500 MHz, DMSO-d6): d = 8.20 (br s, 1 H, NH), 8.01 (br
s, 1 H, OH), 7.34 (d, J = 7.8 Hz, 2 H, ArH), 7.18 (d, J = 7.8 Hz, 2
H, ArH), 4.29 (t, J = 11.5 Hz, 2 H, NCH2), 3.87 (s, 3 H, OCH3), 3.75
(s, 3 H, OCH3), 3.41 (t, J = 11.5 Hz, 2 H, NCH2), 2.34 (s, 3 H,
ArCH3), 2.10–2.06 (m, 2 H, CH2), 1.28 (s, 3 H, ArCH3).
13C NMR (125 MHz, DMSO-d6): d = 187.9, 153.1, 144.5, 141.8,
140.4, 137.5, 136.7, 129.3, 129.0, 123.6, 120.5, 110.5, 96.8, 62.5,
61.5, 42.7, 38.5, 21.9, 21.8, 16.2.
IR (KBr): 3415, 3246, 2981, 2353, 1626, 1591, 1512, 1468, 1341,
1243, 1213, 1147, 1041, 870 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.63 (br s, 1 H, NH), 7.11 (s,
1 H, ArH), 6.91 (br s, 1 H, OH), 6.85 (d, J = 8.3 Hz, 1 H, ArH), 6.39
(dd, J = 8.3, 2.3 Hz, 1 H, ArH), 4.17 (q, J = 7.1 Hz, 2 H, OCH2),
4.06–3.98 (m, 4 H, NCH2CH2N), 1.30 (t, J = 7.1 Hz, 3 H, CH3).
HRMS (TOF ES+): m/z calcd for C22H25N2O4 [M + H+]: 381.1809;
found: 381.1806.
13C NMR (125 MHz, DMSO-d6): d = 164.4, 158.4, 152.5, 150.1,
(1,2,3,4-Tetrahydro-8-hydroxy-6,7-dimethoxy-9-methylpyrim-
ido[1,2-a]indol-10-yl)(phenyl)methanone (3i)
Starting from 1a (0.20 g, 1.1 mmol), 2-[tetrahydropyrimidin-2(1H)-
ylidene]-1-phenylethanone (2g; 0.20 g, 1.0 mmol), and AcOH (0.06
g, 0.1 mmol), 3i was isolated as a yellow solid (0.32 g, 88%); mp
229–230 °C.
132.5, 125.4, 108.8, 107.7, 105.7, 58.2, 49.3, 42.7, 15.2.
HRMS (TOF ES+): m/z calcd for C13H15N2O3 [M + H+]: 247.1077;
found: 247.1081.
(2,3-Dihydro-7-hydroxy-1H-imidazo[1,2-a]indol-9-yl)(p-tol-
yl)methanone (3f)
Starting from 1b (0.12 g, 1.1 mmol), 2b (0.20 g, 1.0 mmol), and
AcOH (0.06 g, 0.1 mmol), 3f was isolated as a yellow solid (0.25 g,
86%); mp 271–272 °C.
IR (KBr): 3315, 2934, 1609, 1522, 1459, 1393, 1283, 1153, 1075,
807 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.29 (br s, 1 H, NH), 8.02 (br
s, 1 H, OH), 7.45–7.36 (m, 5 H, ArH), 4.29 (t, J = 11.7 Hz, 2 H,
NCH2), 3.88 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 3.41–3.45 (m, 2
H, NCH2), 2.07–2.11 (m, 2 H, CH2), 1.24 (s, 3 H, ArCH3).
13C NMR (125 MHz, DMSO-d6): d = 187.9, 153.3, 144.6, 144.6,
137.5, 136.8, 130.7, 128.9, 128.8, 123.5, 120.6, 110.6, 96.9, 62.5,
61.5, 42.7, 38.5, 21.8, 16.1.
IR (KBr): 3364, 3121, 2240, 1773, 1593, 1407, 1274, 1164, 1025,
806 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.64 (br s, 1 H, NH), 7.49 (d,
J = 7.6 Hz, 2 H, ArH), 7.30 (d, J = 7.6 Hz, 2 H, ArH), 6.91 (s, 1 H,
ArH), 6.88 (d, J = 8.4 Hz, 1 H, ArH), 6.73 (br s, 1 H, OH), 6.41 (d,
J = 8.4 Hz, 1 H, ArH), 4.07 (t, J = 15.9 Hz, 2 H, NCH2), 3.98 (t,
J = 15.9 Hz, 2 H, NCH2), 2.40 (s, 3 H, ArCH3).
HRMS (TOF ES+): m/z calcd for C21H23N2O4 [M + H+]: 367.1652;
found: 367.1651.
Synthesis 2010, No. 20, 3536–3544 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,3-Diazaheterocycle-Fused [1,2-a]Indoles
3543
(4-Chlorophenyl)(1,2,3,4-tetrahydro-8-hydroxy-6,7-dimeth-
oxy-9-methylpyrimido[1,2-a]indol-10-yl)methanone (3j)
Starting from 1a (0.20 g, 1.1 mmol), 1-(4-chlorophenyl)-2-[tetrahy-
dropyrimidin-2(1H)-ylidene]ethanone (2h; 0.24 g, 1.0 mmol), and
AcOH (0.06 g, 0.1 mmol), 3j was isolated as yellow crystals (0.35
g, 87%); mp 217–218 °C.
1H NMR (500 MHz, DMSO-d6): d = 8.62 (br s, 1 H, NH), 8.50 (br
s, 1 H, OH), 7.48–7.51 (m, 5 H, ArH), 6.89 (d, J = 8.3 Hz, 1 H,
ArH), 6.39 (d, J = 8.3 Hz, 1 H, ArH), 6.03 (s, 1 H, ArH), 3.87–3.91
(m, 2 H, NCH2), 3.43–3.47 (m, 2 H, NCH2), 2.06–2.10 (m, 2 H,
CH2).
13C NMR (125 MHz, DMSO-d6): d = 187.9, 153.4, 153.0, 143.7,
130.2, 129.1, 129.1, 127.7, 127.3, 108.9, 108.5, 105.2, 95.6, 40.0,
38.5, 21.0.
IR (KBr): 3307, 2964, 2349, 1613, 1522, 1392, 1284, 1157, 1078,
842 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.29 (br s, 1 H, NH), 8.06 (br
s, 1 H, OH), 7.44–7.42 (m, 4 H, ArH), 4.29 (t, J = 11.5 Hz, 2 H,
NCH2), 3.88 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 3.41–3.45 (m, 2
H, NCH2), 2.07–2.11 (m, 2 H, CH2), 1.30 (s, 3 H, ArCH3).
13C NMR (125 MHz, DMSO-d6): d = 185.6, 153.0, 144.3, 142.7,
137.2, 136.4, 134.8, 130.3, 128.5, 122.7, 120.2, 109.9, 96.3, 62.0,
61.0, 42.2, 38.0, 21.2, 16.0.
HRMS (TOF ES+): m/z calcd for C18H17N2O2 [M + H+]: 293.1285;
found: 293.1285.
(4-Chlorophenyl)(1,2,3,4-tetrahydro-8-hydroxypyrimido[1,2-
a]indol-10-yl)methanone (3n)
Starting from 1b (0.12 g, 1.1 mmol), 2h (0.24 g, 1.0 mmol), and
AcOH (0.06 g, 0.1 mmol), 3n was isolated as a yellow solid (0.27
g, 84%); mp 262–264 °C.
HRMS (TOF ES+): m/z calcd for C21H22ClN2O4 [M + H+]:
401.1263; found: 401.1257.
IR (KBr): 3319, 3085, 2868, 1616, 1528, 1468, 1313, 1256, 1170,
1083, 847 cm–1.
(1,2,3,4-Tetrahydro-8-hydroxypyrimido[1,2-a]indol-10-yl)(4-
methoxyphenyl)methanone (3k)
Starting from 1b (0.12 g, 1.1 mmol), 2e (0.23 g, 1.0 mmol), and
AcOH (0.06 g, 0.1 mmol), 3k was isolated as a yellow solid (0.29
g, 89%); mp 214–216 °C.
1H NMR (500 MHz, DMSO-d6): d = 8.64 (br s, 1 H, NH), 8.47 (br
s, 1 H, OH), 7.56 (d, J = 8.2 Hz, 2 H, ArH), 7.49 (d, J = 8.2 Hz, 2
H, ArH), 6.92 (d, J = 8.3 Hz, 1 H, ArH), 6.38 (dd, J = 8.3, 1.8 Hz,
1 H, ArH), 6.02 (d, J = 1.8 Hz, 1 H, ArH), 3.91 (t, J = 11.4 Hz, 2 H,
NCH2), 3.45–3.49 (m, 2 H, NCH2), 2.07–2.11 (m, 2 H, CH2).
IR (KBr): 3178, 2957, 2866, 1607, 1531, 1468, 1408, 1309, 1255,
1170, 1018, 843 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 186.3, 153.4, 153.1, 142.3,
134.8, 129.7, 129.3, 129.1, 127.0, 109.1, 108.6, 105.0, 95.5, 40.2,
40.0, 20.9.
HRMS (TOF ES+): m/z calcd for C18H16ClN2O2 [M + H+]:
327.0895; found: 327.0893.
1H NMR (500 MHz, DMSO-d6): d = 8.56 (br s, 1 H, NH), 8.42 (br
s, 1 H, OH), 7.49 (d, J = 8.2 Hz, 2 H, ArH), 7.00 (d, J = 8.1 Hz, 2
H, ArH), 6.92 (d, J = 8.3 Hz, 1 H, ArH), 6.38 (d, J = 8.3 Hz, 1 H,
ArH), 6.21 (s, 1 H, ArH), 3.92 (t, J = 11.0 Hz, 2 H, NCH2), 3.84 (s,
3 H, OCH3), 3.44–3.47 (m, 2 H, NCH2), 2.07–2.10 (m, 2 H, CH2).
13C NMR (125 MHz, DMSO-d6): d = 187.0, 160.7, 152.9, 152.5,
135.4, 129.3, 128.5, 126.9, 113.8, 108.3, 107.8, 104.7, 94.9, 55.6,
39.7, 39.6, 20.5.
(9-Hydroxy-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-
11-yl)(4-methoxyphenyl)methanone (3o)
Starting from 1b (0.12 g, 1.1 mmol), 2-(1,3-diazepan-2-ylidene)-1-
(4-methoxyphenyl)ethanone (2i; 0.25 g, 1.0 mmol), and AcOH
(0.06 g, 0.1 mmol), 3o was isolated as a yellow solid (0.29 g, 86%);
mp 259–261 °C.
HRMS (TOF ES+): m/z calcd for C19H19N2O3 [M + H+]: 323.1390;
found: 323.1392.
IR (KBr): 3166, 2927, 2845, 1754, 1587, 1542, 1457, 1311, 1247,
1170, 1036, 847 cm–1.
(1,2,3,4-Tetrahydro-8-hydroxypyrimido[1,2-a]indol-10-yl)(p-
tolyl)methanone (3l)
Starting from 1b (0.12 g, 1.1 mmol), 2f (0.22 g, 1.0 mmol), and
AcOH (0.06 g, 0.1 mmol), 3l was isolated as a yellow solid (0.27 g,
88%); mp >300 °C.
1H NMR (500 MHz, acetone-d6): d = 8.99 (br s, 1 H, NH), 7.72 (br
s, 1 H, OH), 7.60 (d, J = 8.5 Hz, 2 H, ArH), 7.10 (d, J = 8.5 Hz, 1
H, ArH), 7.02 (d, J = 8.5 Hz, 2 H, ArH), 6.54 (dd, J = 8.5, 2.3 Hz, 1
H, ArH), 6.39 (d, J = 2.3 Hz, 1 H, ArH), 4.09 (t, J = 10.5 Hz, 2 H,
NCH2), 3.90 (s, 3 H, OCH3), 3.46–3.43 (m, 2 H, NCH2), 2.08–1.99
(m, 4 H, CH2CH2).
13C NMR (125 MHz, acetone-d6): d = 190.1, 162.6, 161.4, 153.7,
136.4, 131.1, 130.9, 128.9, 114.5, 110.7, 109.8, 106.2, 99.2, 56.3,
46.8, 46.5, 31.2, 28.4.
IR (KBr): 3324, 3091, 2868, 1615, 1531, 1467, 1311, 1258, 1179,
1076, 839 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.57 (br s, 1 H, NH), 8.46 (br
s, 1 H, OH), 7.41 (d, J = 7.8 Hz, 2 H, ArH), 7.29 (d, J = 7.8 Hz, 2
H, ArH), 6.91 (d, J = 8.4 Hz, 1 H, ArH), 6.38 (dd, J = 8.4, 1.8 Hz,
1 H, ArH), 6.12 (d, J = 1.8 Hz, 1 H, ArH), 3.91 (t, J = 11.1 Hz, 2 H,
NCH2), 3.45–3.48 (m, 2 H, NCH2), 2.41 (s, 3 H, ArCH3), 2.07–2.11
(m, 2 H, CH2).
HRMS (TOF ES+): m/z calcd for C20H21N2O3 [M + H+]: 337.1547;
found: 337.1549.
(9-Hydroxy-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-
11-yl)(p-tolyl)methanone (3p)
Starting from 1b (0.12 g, 1.1 mmol), 2-(1,3-diazepan-2-ylidene)-1-
p-tolylethanone (2j; 0.23 g, 1.0 mmol), and AcOH (0.06 g, 0.1
mmol), 3p was isolated as a yellow solid (0.28 g, 86%); mp 243–
245 °C.
13C NMR (125 MHz, DMSO-d6): d = 187.9, 153.4, 153.0, 140.9,
139.8, 129.6, 129.1, 127.9, 127.3, 108.8, 108.4, 105.3, 95.5, 40.2,
40.1, 22.0, 21.0.
HRMS (TOF ES+): m/z calcd for C19H19N2O2 [M + H+]: 307.1441;
found: 307.1440.
IR (KBr): 3165, 2842, 1583, 1539, 1462, 1421, 1369, 1312, 1261,
1204, 1168, 1043, 837 cm–1.
(1,2,3,4-Tetrahydro-8-hydroxypyrimido[1,2-a]indol-10-
yl)(phenyl)methanone (3m)
Starting from 1b (0.12 g, 1.1 mmol), 2g (0.20 g, 1.0 mmol), and
AcOH (0.06 g, 0.1 mmol), 3m was isolated as a yellow solid (0.25
g, 85%); mp 274–276 °C.
1H NMR (500 MHz, DMSO-d6): d = 8.95 (br s, 1 H, NH), 8.72 (br
s, 1 H, OH), 7.39 (d, J = 7.9 Hz, 2 H, ArH), 7.30 (d, J = 7.9 Hz, 2
H, ArH), 7.09 (d, J = 8.7 Hz, 1 H, ArH), 6.42 (dd, J = 8.7, 2.1 Hz,
1 H, ArH), 6.03 (d, J = 2.1 Hz, 1 H, ArH), 4.02 (t, J = 9.8 Hz, 2 H,
NCH2), 3.40–3.43 (m, 2 H, NCH2), 2.40 (s, 3 H, ArCH3), 1.95–1.88
(m, 4 H, CH2CH2).
IR (KBr): 3320, 3074, 2869, 1617, 1536, 1480, 1312, 1172, 1078,
850 cm–1.
Synthesis 2010, No. 20, 3536–3544 © Thieme Stuttgart · New York

3544
L.-J. Yang et al.
PAPER
Trans. 1 1995, 2345. (c) Barrow, C. J.; Sun, H. H. J. Nat.
Prod. 1994, 57, 471. (d) de la Mora, M. A.; Cuevas, E.;
Muchowski, J. M.; Cruz-Almanza, R. Tetrahedron Lett.
2001, 42, 5351.
13C NMR (125 MHz, DMSO-d6): d = 189.0, 159.8, 152.5, 139.8,
139.8, 129.5, 129.2, 127.5, 127.2, 110.1, 108.9, 104.8, 97.7, 45.5,
44.9, 29.1, 26.9, 21.5.
HRMS (TOF ES+): m/z calcd for C20H21N2O2 [M + H+]: 321.1598;
(3) (a) Goetz, M. A.; Lopez, M.; Monaghan, R. L.; Chang, R. S.
L.; Lotti, V. J.; Chen, T. B. J. Antibiot. 1985, 36, 1633.
(b) Liesch, J. M.; Hensens, O. D.; Springer, J. P.; Chang, R.
S. L.; Lotti, V. J. J. Antibiot. 1985, 36, 1638. (c) Sun, H. H.;
Byard, S. J.; Cooper, R. J. Antibiot. 1994, 47, 599.
(4) Wong, S. M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.;
Gillum, A. M.; Cooper, R. J. Antibiot. 1993, 46, 545.
(5) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545.
(6) (a) Kost, A. N.; Golubeva, G. A.; Portnov, Y. N. Dokl. Akad.
Nauk USSR 1971, 200, 342; Chem. Abstr. 1972, 76, 34047.
(b) Portnov, Y. N.; Golubeva, G. A.; Kost, A. N. Khim.
Geterotsikl. Soedin. 1972, 61; Chem. Abstr. 1972, 77,
448377. (c) Portnov, Y. N.; Golubeva, G. A.; Kost, A. N.;
Volkov, V. S. Khim. Geterotsikl. Soedin. 1973, 647; Chem.
Abstr. 1973, 79, 453269. (d) Coppola, E. M.; Hardtmann, G.
E. J. Heterocycl. Chem. 1979, 16, 769. (e) Sutherland, J. K.
Chem. Commun. 1997, 325.
found: 321.1601.
(9-Hydroxy-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-
11-yl)(phenyl)methanone (3q)
Starting from 1b (0.12 g, 1.1 mmol), 2-(1,3-diazepan-2-ylidene)-1-
phenylethanone (2k; 0.22 g, 1.0 mmol), and AcOH (0.06 g, 0.1
mmol), 3q was isolated as a yellow crystal (0.25 g, 80%); mp 267–
269 °C.
IR (KBr): 3242, 2932, 2868, 1650, 1559, 1471, 1375, 1268, 1174,
1088, 842 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 9.02 (br s, 1 H, NH), 8.67 (br
s, 1 H, OH), 7.54–7.47 (m, 5 H, ArH), 7.10 (d, J = 8.6 Hz, 1 H,
ArH), 6.43 (dd, J = 8.6, 2.1 Hz, 1 H, ArH), 5.94 (d, J = 2.1 Hz, 1 H,
ArH), 4.03 (t, J = 10.7 Hz, 2 H, NCH2), 3.40–3.44 (m, 2 H, NCH2),
1.96–1.89 (m, 4 H, CH2CH2).
13C NMR (125 MHz, DMSO-d6): d = 188.9, 159.9, 152.6, 142.8,
130.0, 129.5, 128.7, 127.3, 127.2, 110.1, 108.9, 104.7, 97.6, 45.5,
44.9, 29.1, 26.9.
(7) Yuen, J.; Fang, Y. Q.; Lautens, M. Org. Lett. 2006, 8, 653.
(8) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc.
1998, 120, 6417.
HRMS (TOF ES+): m/z calcd for C19H19N2O2 [M + H+]: 307.1441;
found: 307.1450.
(9) (a) Snider, B. B.; Zeng, H. Org. Lett. 2002, 4, 1087.
(b) Snider, B. B.; Zeng, H. Org. Lett. 2000, 2, 4103.
(10) (a) Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc.,
Perkin Trans. 1 1999, 321. (b) Yu, C.-Y.; Yang, P.-H.;
Zhao, M.-X.; Huang, Z.-T. Synlett 2006, 1835. (c) Liao, J.-
P.; Zhang, T.; Yu, C.-Y.; Huang, Z.-T. Synlett 2007, 761.
For previous reviews, see: (d) Huang, Z.-T.; Wang, M.-X.
Heterocycles 1994, 37, 1233. (e) Huang, Z.-T.; Wang, M.-
X. Prog. Nat. Sci. 1999, 11, 971.
(4-Chlorophenyl)(2,3,4,5-tetrahydro-9-hydroxy-1H-[1,3]diaze-
pino[1,2-a]indol-11-yl)methanone (3r)
Starting from 1b (0.12 g, 1.1 mmol), 1-(4-chlorophenyl)-2-(1,3-di-
azepan-2-ylidene)ethanone (2l; 0.25 g, 1.0 mmol), and AcOH (0.06
g, 0.1 mmol), 3r was isolated as a yellow solid (0.26 g, 76%); mp
289–291 °C.
(11) (a) Tieman, C. H.; Kollmeyer, W. D.; Roman, S. A. German
Patent 2445421, 1975; Chem. Abstr. 1975, 83, 97297h.
(b) Tieman, C. H.; Kollmeyer, W. D. US Patent 3948934,
1976; Chem. Abstr. 1976, 85, 46680e. (c) Porter, P. E.;
Kollmeyer, W. D. US Patent 4053623, 1977; Chem. Abstr.
1977, 87, 37796g.
(12) (a) Maryanoff, B. E.; Nortey, S. O.; McNally, J. J.;
Sanfilippo, P. J.; McComsey, D. F.; Dubinsky, B.; Shank, R.
P.; Reitz, A. B. Biomed. Chem. Lett. 1999, 9, 1547.
(b) Kondo, H.; Taguchi, M.; Inoue, Y.; Sakamoto, F.;
Tsukamoto, G. J. Med. Chem. 1990, 33, 2012.
IR (KBr): 3254, 2931, 1641, 1583, 1529, 1469, 1357, 1176, 1089,
842 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 9.15 (br s, 1 H, NH), 9.05 (br
s, 1 H, OH), 7.59 (d, J = 7.5 Hz, 2 H, ArH), 7.56 (d, J = 7.5 Hz, 2
H, ArH), 7.12 (dd, J = 8.5, 1.8 Hz, 1 H, ArH), 6.38 (d, J = 8.5 Hz,
1 H, ArH), 6.09 (s, 1 H, ArH), 3.57–3.60 (m, 2 H, NCH2), 3.35–3.40
(m, 2 H, NCH2), 2.07–2.11 (m, 2 H, CH2), 1.74–1.78 (m, 2 H, CH2).
13C NMR (125 MHz, DMSO-d6): d = 186.9, 166.8, 154.4, 142.9,
140.2, 135.3, 129.3, 128.9, 127.2, 110.7, 108.9, 104.7, 93.1, 41.6,
41.6, 27.1, 27.1.
(13) Suryawanshi, S. N.; Pandey, S.; Rashmirathi Bhatt, B. A.;
Gupta, S. Eur. J. Med. Chem. 2007, 42, 511.
(14) Abdelhalim, M. M.; El-Saidi, M. M. T.; Rabie, S. T.;
HRMS (TOF ES–): m/z calcd for C19H17ClN2O2 [M]: 340.0979;
found: 340.0970.
Elmegeed, G. A. Steroids 2007, 72, 459.
(15) (a) Yan, S.-J.; Huang, C.; Su, C.-X.; Ni, Y.-F.; Lin, J.
J. Comb. Chem. 2010, 12, 91. (b) Yan, S.-J.; Niu, Y.-F.;
Huang, R.; Lin, J. Synlett 2009, 2821.
(16) Aggarwal, V.; Kumar, A.; Ila, H.; Junjappa, H. Synthesis
1981, 157.
Acknowledgment
The authors wish to acknowledge financial support in the form of
grants from NSFCs (Nos. 30860342 and 20762013) and NSFYNs
(Nos. 2009cc017, 2008cd063).
(17) CCDC 777124 contains the supplementary crystallographic
data for compound 3a. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(18) Zhao, M.-X.; Wang, M.-X.; Huang, Z.-T. Tetrahedron 2002,
58, 1309.
References
(1) These authors contributed equally to this paper.
(2) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto,
T.; Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi,
H.; Shingu, T. Tetrahedron Lett. 1992, 33, 1621.
(19) (a) Huang, Z.-T.; Wang, M.-X. Synthesis 1992, 1273.
(b) Li, Z.-J.; Charles, D. Synth. Commun. 2001, 31, 527.
(b) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.;
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Synthesis 2010, No. 20, 3536–3544 © Thieme Stuttgart · New York