Three-component domino reaction synthesis of highly functionalized bicyclic pyrrole derivatives

Article abstract of DOI:10.1016/j.tet.2013.12.062

An efficient one-pot synthesis of highly functionalized bicyclic pyrrole derivatives by a three-component domino reaction of heterocyclic ketene aminals (HKAs), arylglyoxal monohydrate, and indoles in ethanol medium catalyzed by acetic acid is described. In this procedure, three sigma bonds were formed simultaneously. The present synthesis features excellent regio-selectivity, easy purification as well as simple starting materials.

Full text of DOI:10.1016/j.tet.2013.12.062

Tetrahedron 70 (2014) 1047e1054
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Three-component domino reaction synthesis of highly
functionalized bicyclic pyrrole derivatives
*
*
Xue-Bing Chen, Xiao-Ying Wang, Dan-Dan Zhu, Sheng-Jiao Yan , 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, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 October 2013
Received in revised form 13 December 2013
Accepted 24 December 2013
Available online 31 December 2013
An efficient one-pot synthesis of highly functionalized bicyclic pyrrole derivatives by a three-component
domino reaction of heterocyclic ketene aminals (HKAs), arylglyoxal monohydrate, and indoles in ethanol
medium catalyzed by acetic acid is described. In this procedure, three sigma bonds were formed si-
multaneously. The present synthesis features excellent regio-selectivity, easy purification as well as
simple starting materials.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Bicyclic pyrroles
Heterocyclic ketene aminals
Three-component
Domino reaction
1. Introduction
cholesterol-lowering agent (Atorvastatin, Fig. 1),9a myosin ATPase
inhibitor (Fig. 1),9b and
a human topoisomerase I inhibitor
Multicomponent reactions (MCRs)1 are powerful tools in the
modern drug discovery and development process as they allow rapid
access to structural variation and complexity within single-step con-
versions. The features of such reactions2 include rapidity, diversity,
efficiency, atom-economy, and environmental amiability. Because of
these advantages, developing new MCRs with environmentally be-
nign protocols has been recognized as one of the most important
topics of synthetic chemistry.3 In this article, we provide a novel
multicomponent domino reaction for heterocyclic construction.
The indole skeleton is one of the most abundant and relevant
heterocycles in natural products and it can perhaps be considered
as the most important single class of heterocyclic systems.4 A vast
number of natural and synthetic indoles have found applications as
pharmaceuticals.5 Amongst them, 3-substituted indole is a ‘privi-
leged medicinal scaffold’ found in many natural products and bi-
ologically active compounds.6 Furthermore, they are important
building blocks for the synthesis of various biologically active
molecules.7 Consequently, the development of new synthetic
methodologies for the construction of the 3-substituted indole
scaffold is very important in organic synthesis.8
(Lamellarin D, Fig. 1), etc.9c Substituted bicyclic pyrrole nucleoside
derivatives are reported to have various biological activities, i.e.,
antitumor,10 anti-HIV type 1,11 antiviral,12 antifungal,13 anti-HCV,14
and antibacterial activity;15 they could also include inhibitors of
PI3K,16 Janus kinases,17 glycosidase,18 firefly luciferase,19 gastric acid
pumps,20 dihydrofolate reductase (DHFR),21 and so on.22 The im-
portance of such molecules has stimulated many synthetic chem-
ists to develop novel, efficient synthetic routes for the synthesis of
On the other hand, the pyrrole core is featured in a number of
natural products as well as medicinally relevant compounds;9 as
* Corresponding authors. E-mail addresses: yansj@ynu.edu.cn (S.-J. Yan), linjun@
ynu.edu.cn, linjunyn@yahoo.com.cn (J. Lin).
Fig. 1. Biological activity pyrroles and bicyclic pyrroles.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.062

1048
X.-B. Chen et al. / Tetrahedron 70 (2014) 1047e1054
these kinds of bicyclic pyrroles. Although various approaches23 for
the preparation of bicyclic pyrroles containing a ring-junction ni-
trogen framework have been developed, preparation of these in-
dole ketene-containing bicyclic pyrroles via an environmentally
friendly and highly regioselective domino procedure has rarely
been studied.
No transformation occurred in the presence of a basic catalyst or
without a catalyst, even within 6 h (Table 1, entries 1e5). However,
when 10 mol % acetic acid was added to the ethanol in reflux, the
yield of 4a reached 88% (Table 1, entry 6). Inspired by this result, we
continued to optimize the reaction conditions to further improve
the chemical yield; p-TSA, L-proline, and TFA were used as protic
As a type of versatile synthetic intermediate, HKAs have been
used for the synthesis of a wide variety of heterocyclic and fused
heterocyclic compounds.24 Furthermore, a number of efficient ap-
proaches for bicyclic pyrrole derivatives through HKAs have been
explored.25 Despite so many synthetic approaches for bicyclic
pyrrole derivatives, the development of efficient access to highly
functionalized bicyclic pyrroles via multicomponent domino re-
action is very limited. Arylglyoxal monohydrate,26 as a readily
available 1,2-biacceptor,27 can provide two active sites that can be
attacked by nucleophilic reagents; this molecule has been shown to
be an important synthon in the construction of heterocyclic sys-
tems.26,28 Accordingly, we turned our attention to simultaneously
utilizing these two fascinating synthons to develop a new strategy
for the synthesis of bicyclic pyrroles.
acids to catalyze the domino reaction; however, the reactions car-
ried out using these acids did not give better results than using
acetic acid as the catalyst (Table 1, entries 7e9). Subsequently, we
performed the model reaction in other solvents, such as acetoni-
trile, dioxane, and DMF. The results revealed that those solvents
were completely ineffective for the formation of 4a (Table 1, entries
10e12). Next, the amount of acetic acid was screened, and 0.1 equiv
was found to be the best (Table 1, entries 6, 13 & 14). Briefly, the
optimum results were obtained when the HKAs, arylglyoxal mon-
ohydrate, and indole in ethanol were treated with 10 mmol% of
acetic acid as the catalyst at reflux for 2 h.
Based on the success of the model system, a series of products
4aez were constructed in order to evaluate the applicability of this
reaction sequence (Table 2). A wide variety of HKAs 1aef, indole
2aec, and arylglyoxal monohydrate 3a,b were explored and the
results are summarized in Table 2.
HKAs possess two nucleophilic centers (a-C atom and NH
group). Similarly, indoles contain three nucleophilic centers; C-
nucleophilicity at the C3 position is stronger than that of the C2
position and the NH group. As a readily available 1,2-biacceptor,
arylglyoxal monohydrate can provide two electrophilic centers that
Table 2
Domino reaction synthesis of products 4 from various of 1e3a
can be attacked by the indole C3 atom as well as the HKA b-C and
NH group for the formation of the CeC and CeN bonds.
Herein, we developed a synthetic method to synthesize such
a pyrrolo[1,2-a]pyrimidine ring by simply heating HKA 1, indole 2,
and arylglyoxal monohydrate 3, catalyzed by HOAc in ethanol, to
obtain the target compounds in good to excellent yields (72e95%).
1 n/R1
2/R2
3/R3
4
Yieldb (%)
2. Result and discussion
Entry
1
2
3
4
5
6
7
8
1a (1/p-F)
1a (1/p-F)
1a (1/p-F)
1a (1/p-F)
1a (1/p-F)
1a (1/p-F)
1b (1/o-F)
1b (1/o-F)
1c (1/p-Cl)
1c (1/p-Cl)
1c (1/p-Cl)
1c (1/p-Cl)
1c (1/p-Cl)
1d (1/o-Cl)
1d (1/o-Cl)
1d (1/o-Cl)
1d (1/o-Cl)
1d (1/o-Cl)
1d (1/o-Cl)
1e (1/p-H)
1e (1/p-H)
1e (1/p-H)
1e (1/p-H)
1e (1/p-H)
1f (1/p-CH3)
1g (2/p-Cl)
2a/H
2a/H
3a/F
3b/H
3a/F
3b/H
3a/F
3b/H
3a/F
3b/H
3b/H
3a/F
3b/H
3a/F
3b/H
3a/F
3b/H
3a/F
3b/H
3a/F
3b/H
3b/H
3a/F
3b/H
3a/F
3b/H
3b/H
3a/F
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
88
86
91
91
94
92
93
91
83
89
87
93
91
91
90
93
90
95
92
83
86
84
91
88
72
94
In the preliminary experiments, for the synthesis of pyrrolo-
[1,2-a]pyrimidines 4, the heterocyclic ketene aminals 1a, indole 2a,
and arylglyoxal monohydrate 3a in the green solvent ethanol were
selected as model reactants for the optimization process (Table 1).
2b/CH3
2b/CH3
2c/Ph
2c/Ph
2b/CH3
2b/CH3
2a/H
2b/CH3
2b/CH3
2c/Ph
2c/Ph
2a/H
Table 1
Optimization of the reaction conditionsa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2a/H
2b/CH3
2b/CH3
2c/Ph
2c/Ph
2a/H
2b/CH3
2b/CH3
2c/Ph
2c/Ph
2b/CH3
2c/Ph
Entry
Solvent
Catalyst
t (ꢀC)
Time (h)
Yielde (%)
4s
4t
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
Dioxane
DMF
d
rt
6
6
6
6
6
1
1
2
2
2
2
2
2
2
n.r.
n.r.
n.r
n.r.
n.r.
88
81
n.r.
25
d
Piperidineb
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
110 ꢀC
Reflux
Reflux
4u
4v
4w
4x
4y
4z
Et3Nb
DABCOb
HOAcb
p-TSAb
L
-Prolineb
a
The reaction was performed with 1 (1 mmol), 2 (1.1 mmol), 3 (1.1 mmol), and
HOAc (0.1 mmol) in EtOH (15 mL) under reflux.
9
TFAb
10
11
12
13
14
HOAcb
HOAcb
HOAcb
HOAcc
HOAcd
50
b
Isolated yields based on HKA 1.
Trace
n.r.
83
EtOH
EtOH
81
As shown in Table 2, HKAs bearing different groups (F, Cl, H, CH3)
and indoles with different groups at the C2 position (H, CH3, Ph)
could also smoothly give the corresponding products; the yields
ranged from 72% to 95%. This confirmed that the electronic nature
of the aromatic rings of HKAs has a significant impact on the re-
action yield. It was clearly demonstrated that the electron-
a
The reaction was performed with 1a (1 mmol), 2a (1.1 mmol), 3a (1.1 mmol),
and the solvent (15 mL).
b
Catalyst (0.1 mmol).
Catalyst (0.2 mmol).
Catalyst (0.3 mmol).
Isolated yields based on HKA 1a. n.r.¼no reaction.
c
d
e

X.-B. Chen et al. / Tetrahedron 70 (2014) 1047e1054
1049
withdrawing aromatic rings of HKAs 1 could encourage the yield of
the reaction (Table 2, compare entries 2, 9 & 20). Furthermore, the
HKAs with substituents at ortho-positions afforded higher yields
than those counterparts at the para-position (Table 2, entries 7
vs 3). The indole C2 position with electron-donating groups affor-
ded a much higher yield (Table 2, entries 9, 11 & 13). We speculated
that an electron-donating group can increase the nucleophilicity of
the C3 position, which facilitated nucleophilic addition.
Comparing with the previous results, we next changed the se-
quence of adding initial substrates. For example, we added 2b and
3a first. The expected intermediate (Int 2) was not detected when
the above reaction mixtures were heat, instead the compound 12
was afforded. This phenomenon was also observed even if the
arylglyoxal monohydrate was residual (Scheme 2).
In order to further investigate the scope of HKAs, the seven-
membered HKA (n¼2) 1g also was employed in this process (Table
2, entry 26), and giving the corresponding product with higher
yields than that of six-membered HKAs. Moreover, the bulkiness of
2-phenyl indole 2c did not hamper the reaction process.
It is noteworthy that all of the isolated products needed only
washing with ethanol instead of column chromatography or re-
crystallization for the work-up. The easy purification makes this
protocol facile, environmentally benign, and rapid to execute.
All compounds were fully characterized by IR, 1H NMR, 13C NMR,
and HRMS spectroscopy. The structure of product 4l was further
confirmed by X-ray crystallographic analysis (Fig. 2).
Scheme 2. Verification of reaction mechanism: starting from 2 and 3.
According to the experimental outcomes, a mechanism hy-
pothesis for this domino reaction is proposed as shown in Scheme
3. First, the hydroxyl of arylglyoxal monohydrate 3 accepts one
proton to form 5. With the strong electron-withdrawing keto-car-
bonyl group at the a-position of the HKA and the electron-donating
diamino groups of HKA, HKA 4 serves as a heteroene component to
react with compound 5 accompanying the loss of one molecule of
H2O to obtain the intermediate 6 via an aza-ene reaction. Then,
compound 6 is followed by imineeenamine tautomerisation29 to
produce 7. The keto-carbonyl group acquires one proton to give 8.
The NH group of intermediate 8 attacks the intramolecular carbonyl
Fig. 2. X-ray crystal structures of 4l; ellipsoids are drawn at 30% probability level.
Both HKAs and indoles possesses nucleophilic centers, for ex-
ample, the arylglyoxal monohydrate can provide two electrophilic
centers that can be attacked by the C3 of the indole or the b-C and
NH of the HKA. Thus, the domino reaction might occur in two di-
rections. To propose a plausible reaction mechanism, some addi-
tional experiments were performed. As an initial attempt, we began
our investigation by testing the reaction of 1c and 3a. An in-
termediate (Int 1) (see Supplementary data) was obtained after half
an hour. Then, 2b was added to the resulting mixture, our desired
target molecule 4f was obtained with the consumption of 1c
(Scheme 1). Moreover, Int 1 can be separated and further reacted
with 2b in the same condition. To our delight, the product 4f was
afforded in excellent yield (97%).
Scheme 1. Verification of reaction mechanism: starting from 1 and 3.
Scheme 3. Plausible mechanism for the formation of 4.

1050
X.-B. Chen et al. / Tetrahedron 70 (2014) 1047e1054
group via a cyclization reaction to afford 9, which followed by de-
hydration to give intermediate 10. Next, the intermediate 11 is
formed by intermolecular Michael addition between 10 and 2. Fi-
nally, intermediate 11 loses a molecule of H2O leads to the forma-
tion of bicyclic pyrrolo 4.
109.5, 102.9, 42.0, 38.3, 21.5; HRMS (TOF ESþ): m/z calcd for
C
28H23F2N3O [(MþH)þ], 454.1725; found, 454.1723.
4.2.2. (7-(1H-Indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]
pyrimidin-8-yl)(4-fluorophenyl)methanone 4b. Yellow solid; mp
>300 ꢀC; IR (KBr): 3279, 1602, 1529, 1417, 1219, 1153, 841, 746 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6):
d
¼10.60 (br, 1H, NH), 8.00 (br, 1H,
3. Conclusion
NH), 7.23 (d, J¼7.6 Hz, 2H, ArH), 7.19 (t, J¼7.4 Hz, 2H, ArH), 7.12e7.15
(m, 1H, ArH), 7.07 (d, J¼8.0 Hz, 1H, ArH), 7.01 (t, J¼6.7 Hz, 2H, ArH),
6.92 (d, J¼7.9 Hz,1H, ArH), 6.85 (t, J¼7.4 Hz, 1H, ArH), 6.64e6.70 (m,
2H, ArH), 6.38 (t, J¼8.5 Hz, 2H, ArH), 3.76e3.84 (m, 2H, NCH2),
3.45e3.51 (m, 2H, NCH2), 1.97e2.06 (m, 2H, NCH2); 13C NMR
In summary, we have successfully developed a procedure for the
facile synthesis of a variety of potentially biologically active highly
functionalized bicyclic pyrrole derivatives based on a novel regio-
selective domino reaction. This is the first report of the preparation
of the highly functional title compounds. The features of this
strategy include environmentally friendly conditions, convenient
one-pot operation, excellent regioselectivity, and easy purification.
Moreover, this series of bicyclic pyrroles may provide new classes of
biologically active compounds for biomedical screening. Further
investigations into the in vitro biological activities of compounds 4
are in progress.
(125 MHz, DMSO-d6):
d
¼188.3, 161.6 (d, J¼243.8 Hz), 148.8, 138.5,
136.2,132.4,130.9,130.9,130.1,128.6,128.6,127.3,125.9,121.1,119.8,
118.8, 113.3 (d, J¼21.3 Hz), 113.1 (d, J¼21.3 Hz), 112.3, 111.4, 110.0,
103.4, 42.6, 38.7, 22.0; HRMS (TOF ESþ): m/z calcd for C28H23FN3O
[(MþH)þ], 436.1820; found, 436.1822.
4.2.3. (4-Fluorophenyl)(6-(4-fluorophenyl)-7-(2-methyl-1H-indol-3-
yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4c. Yellow solid; mp 279e281 ꢀC; IR (KBr): 3348, 1601, 1523, 1410,
1221, 1152, 842, 607 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d¼10.40
4. Experimental
(br, 1H, NH), 8.00 (br, 1H, NH), 7.11e7.15 (m, 2H, ArH), 6.97e7.03 (m,
3H, ArH), 6.90e6.96 (m, J¼4.7 Hz, 2H, ArH), 6.87 (d, J¼7.8 Hz, 1H,
ArH), 6.80 (t, J¼7.4 Hz, 1H, ArH), 6.68 (t, J¼7.3 Hz, 1H, ArH), 6.33 (d,
J¼8.8 Hz, 2H, ArH), 3.79e3.86 (m, 2H, NCH2), 3.43e3.49 (m, 2H,
NCH2), 1.97e2.09 (m, 2H, NCH2), 1.74 (s, 3H, CH3); 13C NMR
4.1. General information
All compounds were fully characterized by spectroscopic data.
The NMR spectra were recorded on a Bruker DRX400 & DRX500,
chemical shifts (d) are expressed in parts per million, and J values
(100 MHz, DMSO-d6):
d
¼187.8, 162.2 (d, J¼244.0 Hz), 161.1 (d,
are given in Hertz, and deuterated DMSO-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 thin layer chroma-
tography (TLC) using silica gel GF254. The melting points were de-
termined on XT-4A melting point apparatus and are uncorrected.
HRMS were performed on an Agilent LC/Msd TOF instrument. All
chemicals and solvents were used as received without further pu-
rification unless otherwise stated. Compounds 1 were prepared
according to the literature.30 The materials 2aec and 3a,b were
purchased from Aldrich Corporation Limited.
J¼243.0 Hz),148.5,137.7,135.4,133.1,131.8,131.7,129.6,129.5,129.3,
128.7, 124.7, 120.0, 118.4, 118.3, 115.4 (d, J¼21.0 Hz), 115.2 (d,
J¼21.0 Hz), 112.5 (d, J¼21.0 Hz), 112.3 (d, J¼21.0 Hz), 111.6, 110.1,
106.7, 102.5, 42.0, 38.2, 21.5, 12.2; HRMS (TOF ESþ): m/z calcd for
C
29H24F2N3O [(MþH)þ], 468.1882; found, 468.1885.
4.2.4. (4-Fluorophenyl)(7-(2-methyl-1H-indol-3-yl)-6-phen-yl-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4d. Yellow solid; mp 285e286 ꢀC; IR (KBr): 3332, 1601, 1525, 1413,
1220, 1154, 742, 696 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d¼10.34
(br,1H, NH), 7.97 (br,1H, NH), 7.15(t, J¼7.0 Hz, 2H, ArH), 7.08e7.11(m,
3H, ArH), 6.86e6.97 (m, 4H, ArH), 6.76e6.80 (m,1H, ArH), 6.64e6.68
(m, 1H, ArH), 6.33 (t, J¼8.6 Hz, 2H, ArH), 3.77e3.87 (m, 2H, NCH2),
3.43e3.51 (m, 2H, NCH2), 1.96e2.05 (m, 2H, CH2), 1.73 (s, 3H, CH3);
4.2. General procedure for the synthesis of 1,3-
diazaheterocycle-fused[1,2-a]indoles 4
HKAs 1 (1.0 mmol), indole 2 (1.1 mmol), arylglyoxal mono-
hydrate 3 (1.1 mmol), solvent EtOH (15 mL), and HOAc (0.1 mmol)
were charged into a 25 mL round-bottom flask, and the mixture
was stirred at reflux until HKA 1 was completely consumed. The
mixture was cooled to room temperature. Then, the precipitation
was filtered and recrystallized by ethanol to afford the pure prod-
ucts 4 in good yield (72%e95%). The products were further identi-
fied by FT-IR, NMR, and HRMS, and were in good agreement with
the assigned structures.
13C NMR (100 MHz, DMSO-d6):
d
¼188.0,162.2 (d, J¼244.0 Hz),148.6,
137.8,135.5,133.2,132.3,139.8,129.6,129.5,128.4,126.7,125.8,120.0,
118.4, 112.6 (d, J¼21.0 Hz), 112.3 (d, J¼21.0 Hz), 111.6, 110.2, 107.0,
102.6, 42.3, 38.3, 21.6, 12.2; HRMS (TOF ESþ): m/z calcd for
C
29H25FN3O [(MþH)þ], 450.1976; found, 450.1981.
4.2.5. (4-Fluorophenyl)(6-(4-fluorophenyl)-7-(2-phenyl-1H-indol-3-
yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4e. Yellow solid; mp 281e283 ꢀC; IR (KBr): 3325, 1603, 1525, 1418,
1221, 1153, 840, 748 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d¼10.92
4.2.1. (4-Chlorophenyl)(6-(4-fluorophenyl)-7-(1H-indol-2-yl)-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4a. Yellow solid; mp >300 ꢀC; IR (KBr): 3342, 1602, 1523, 1417,
(br, 1H, NH), 8.11 (br, 1H, NH), 7.39 (d, J¼7.4 Hz, 2H, ArH), 7.29 (t,
J¼7.3 Hz, 2H, ArH), 7.17e7.23 (m, 2H, ArH), 7.11 (d, J¼4.9 Hz, 2H, ArH),
7.03e7.07 (m, 1H, ArH), 6.92e6.99 (m, 3H, ArH), 6.79e6.82 (m, 1H,
ArH), 6.63 (d, J¼5.2 Hz, 2H, ArH), 6.27 (t, J¼8.5 Hz, 2H, ArH),
3.80e3.90 (m, 2H, NCH2), 3.48e3.56 (m, 2H, NCH2), 2.00e2.10 (m,
1219, 1151, 842, 738 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
¼10.59
(br,1H, NH), 7.99 (br,1H, NH), 7.23e7.27 (m, 2H, ArH), 6.06e6.10 (m,
1H, ArH), 6.98e7.08 (m, 4H, ArH), 6.92 (d, J¼7.9 Hz, 1H, ArH),
6.83e6.88 (m, 1H, ArH), 6.60e6.66 (m, 1H, ArH), 6.63 (d, J¼1.8 Hz,
1H, ArH), 6.35e6.41 (m, 2H, ArH), 3.76e3.80 (m, 2H, NCH2),
3.44e3.52 (m, 2H, NCH2), 1.97e2.07 (m, 2H, CH2); 13C NMR
2H, CH2); 13C NMR (125 MHz, DMSO-d6):
d
¼187.8, 161.9 (d,
J¼241.0 Hz), 161.5 (d, J¼242.5 Hz), 148.9, 137.8, 136.1, 134.7, 132.8,
131.5, 130.1, 128.7, 128.5, 128.3, 127.0, 126.4, 124.9, 121.7, 119.3, 119.0,
115.2(d, J¼20.0Hz),115.0 (d, J¼20.0 Hz),112.5 (d, J¼21.3Hz),112.3 (d,
J¼21.3 Hz),111.6,110.9,107.4,101.6, 42.0, 38.1, 21.4; HRMS (TOF ESþ):
m/z calcd for C34H26F2N3O [(MþH)þ], 530.2038; found, 530.2036.
(100 MHz, DMSO-d6):
d
¼187.8, 163.0 (d, J¼89.0 Hz), 160.6 (d,
J¼88.0 Hz), 148.4, 138.0, 135.8, 132.5 (d, J¼8.0 Hz), 132.4 (d,
J¼8.0 Hz), 129.8 (d, J¼8.0 Hz), 129.7 (d, J¼8.0 Hz),128.4,127.9, 125.5,
124.3, 120.8, 119.4, 118.5, 118.3, 115.3 (d, J¼21.0 Hz), 115.1 (d,
J¼21.0 Hz), 112.9 (d, J¼21.0 Hz), 112.7 (d, J¼21.0 Hz), 112.1, 111.1,
4.2.6. (4-Fluorophenyl)(6-phenyl-7-(2-phenyl-1H-indol-3-yl)-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone

X.-B. Chen et al. / Tetrahedron 70 (2014) 1047e1054
1051
4f. Yellow solid; mp 294e297 ꢀC; IR (KBr): 3303, 1603, 1524, 1422,
1221, 909, 744, 697 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
(br, 1H, NH), 8.07 (br, 1H, NH), 7.36 (d, J¼7.7 Hz, 2H, ArH), 7.26 (t,
J¼7.5 Hz, 2H, ArH), 7.01e7.19 (m, 8H, ArH), 6.94 (t, J¼7.5 Hz, 1H,
ArH), 6.78 (t, J¼7.4 Hz, 1H, ArH), 6.55e6.59 (m, 2H, ArH), 6.22 (t,
J¼8.8 Hz, 2H, ArH), 3.78e3.91 (m, 2H, NCH2), 3.45e3.54 (m, 2H,
NCH2), 1.97e2.05 (m, 2H, CH2); 13C NMR (100 MHz, DMSO-d6):
(125 MHz, DMSO-d6):
d
¼187.6, 161.0 (d, J¼243.7 Hz), 148.5, 139.8,
;
d
¼10.84
135.3, 133.0, 131.6, 129.3, 128.8, 128.5, 125.5, 124.7, 119.9, 118.3,
118.2, 115.3 (d, J¼21.2 Hz), 115.1 (d, J¼21.2 Hz), 111.4, 110.0, 106.6,
102.5, 42.0, 38.2, 21.4, 12.1; HRMS (TOF ESþ): m/z calcd for
C
29H25ClFN3O [(MþH)þ], 484.1586; found, 484.1585.
4.2.11. (4-Chlorophenyl)(7-(2-methyl-1H-indol-3-yl)-6-phenyl-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4k. Yellow solid; mp 273e275 ꢀC; IR (KBr): 3291, 1602, 1526, 1412,
d
¼187.9, 161.9 (d, J¼243.0 Hz), 149.1, 138.0, 136.1, 134.9, 132.9, 132.0,
130.4, 129.6, 128.8, 128.7, 128.6, 128.2, 127.0, 126.8, 126.5, 126.1,
121.2, 119.4, 119.1, 112.6 (d, J¼21.0 Hz), 112.4 (d, J¼21.0 Hz), 111.6,
111.0, 107.7, 101.8, 42.3, 38.2, 21.5; HRMS (TOF ESþ): m/z calcd for
1166, 1090, 743, 692 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼10.40
(br,1H, NH), 8.01 (br,1H, NH), 7.17 (t, J¼7.3 Hz, 2H, ArH), 7.11e7.13 (m,
3H, ArH), 6.96 (d, J¼7.9 Hz, 1H, ArH), 6.79e6.92 (m, 4H, ArH),
6.65e6.69 (m, 1H, ArH), 6.58 (d, J¼8.0 Hz, 2H, ArH), 3.79e3.90 (m,
2H, NCH2), 3.44e3.54 (m, 2H, NCH2),1.96e2.08 (m, 2H, CH2),1.75 (s,
C
34H29FN3O [(MþH)þ], 512.2133; found, 512.2131.
4.2.7. (2-Fluorophenyl)(6-(4-fluorophenyl)-7-(2-methyl-1H-indol-3-
yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4g. Yellow solid; mp 288e290 ꢀC; IR (KBr): 3320, 1609, 1526, 1271,
3H, CH3); 13C NMR (125 MHz, DMSO-d6):
d¼188.1,149.0,140.3,135.8,
133.5,132.6,130.1,129.9,129.2,128.7,127.0,126.2,126.0,120.4,118.7,
111.8, 110.5, 107.3, 103.1, 42.6, 38.6, 21.9, 12.6; HRMS (TOF ESþ): m/z
calcd for C29H25ClN3O [(MþH)þ], 466.1681; found, 466.1687.
1157, 1055, 838, 747 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d¼10.25
(br,1H, NH), 8.06 (br,1H, NH), 7.07e7.11 (m, 2H, ArH), 6.88e7.00 (m,
4H, ArH), 6.68e6.79 (m, 4H, ArH), 6.30e6.39 (m, 2H, ArH),
3.87e3.93 (m, 1H, NCH2), 3.72e3.77 (m, 1H, NCH2), 3.34e3.58 (m,
2H, NCH2), 1.94e2.10 (m, 2H, CH2), 1.80 (s, 3H, CH3); 13C NMR
4.2.12. (4-Chlorophenyl)(6-(4-fluorophenyl)-7-(2-phenyl-1H-indol-
3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4l. Yellow solid; mp >300 ꢀC; IR (KBr): 3303, 1603, 1525, 1420,
(100 MHz, DMSO-d6):
d
¼184.2, 161.1 (d, J¼242.0 Hz), 158.2 (d,
J¼243.0 Hz), 148.4, 135.3, 133.3, 131.6 (d, J¼8.0 Hz), 131.5 (d,
J¼8.0 Hz), 129.9, 129.7, 129.3, 129.2, 128.5, 128.3, 125.3, 121.9, 119.8,
118.5, 118.1, 115.4 (d, J¼21.0 Hz), 115.2 (d, J¼21.0 Hz), 113.9 (d,
J¼22.0 Hz), 113.7 (d, J¼22.0 Hz), 111.8, 110.0, 105.6, 103.9, 42.0, 38.2,
21.4, 12.1; HRMS (TOF ESþ): m/z calcd for C29H24F2N3O [(MþH)þ],
468.1882; found, 468.1883.
1216, 1091, 835, 745 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
¼10.92
(br, 1H, NH), 8.10 (br, 1H, NH), 7.37 (d, J¼7.8 Hz, 2H, ArH), 7.37 (d,
J¼7.6 Hz, 2H, ArH), 7.15e7.20 (m, 2H, ArH), 7.08e7.14 (m, 2H, ArH),
7.02 (d, J¼7.9 Hz,1H, ArH), 6.97 (d, J¼7.2 Hz,1H, ArH), 6.89e6.95 (m,
3H, ArH), 6.92 (t, J¼8.9 Hz, 3H, ArH), 6.80 (t, J¼7.4 Hz, 1H, ArH), 6.55
(d, J¼8.3 Hz, 2H, ArH), 3.79e3.88 (m, 2H, NCH2), 3.47e3.56 (m, 2H,
NCH2), 2.00e2.08 (m, 2H, CH2); 13C NMR (100 MHz, DMSO-d6):
4.2.8. (2-Fluorophenyl)(7-(2-methyl-1H-indol-3-yl)-6-phen-yl-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)-methanone
4h. Yellow solid; mp 295e298 ꢀC; IR (KBr): 3329, 1609, 1530, 1415,
d
¼187.7, 161.2 (d, J¼243.0 Hz), 149.1, 140.1, 136.1, 134.8, 132.9, 131.6,
131.6, 130.2, 128.6, 128.3, 128.2, 127.1, 126.5, 125.7, 125.1, 121.8, 119.4,
119.1, 115.3 (d, J¼22.0 Hz), 115.1 (d, J¼22.0 Hz), 111.7, 111.0, 107.3,
101.8, 42.1, 38.2, 21.4; HRMS (TOF ESþ): m/z calcd for C34H26ClFN3O
[(MþH)þ], 546.1743; found, 546.1739.
1259, 744, 546, 439 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d¼10.20
(br, 1H, NH), 8.04 (br, 1H, NH), 7.05e7.16 (m, 5H, ArH), 6.93 (d,
J¼7.7 Hz, 1H, ArH), 6.87 (d, J¼7.9 Hz, 1H, ArH), 6.64e6.78 (m, 4H,
ArH), 6.30e6.36 (m, 2H, ArH), 3.89e3.92 (m, 1H, NCH2), 3.73e3.77
(m, 1H, NCH2), 3.45e3.55 (m, 2H, NCH2), 1.98e2.06 (m, 2H, CH2),
4.2.13. (4-Chlorophenyl)(6-phenyl-7-(2-phenyl-1H-indol-3-yl)-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4m. Yellow solid; mp 174e177 ꢀC; IR (KBr): 3343, 1603, 1524, 1417,
1.77 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6):
d
¼184.2, 158.2 (d,
J¼243.0 Hz), 148.4, 135.3, 133.2, 132.0, 130.1, 129.9, 129.8, 129.5,
129.2, 128.3, 126.6, 126.4, 121.9, 119.7, 118.5, 118.0, 113.9 (d,
J¼21.0 Hz), 113.7 (d, J¼21.0 Hz), 111.7, 109.9, 105.7, 104.0, 42.1, 38.2,
21.4, 12.1; HRMS (TOF ESþ): m/z calcd for C29H25FN3O [(MþH)þ],
450.1976; found, 450.1981.
1219, 1151, 842, 739 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼10.90
(br, 1H, NH), 8.11 (br, 1H, NH), 7.39 (d, J¼7.6 Hz, 2H, ArH), 7.28 (t,
J¼7.7 Hz, 2H, ArH), 7.15e7.20 (m, 2H, ArH), 6.97e7.12 (m, 6H, ArH),
6.96 (t, J¼7.3 Hz,1H, ArH), 6.76e6.82 (m, 1H, ArH), 6.53 (d, J¼8.2 Hz,
2H, ArH), 6.47 (d, J¼8.3 Hz, 2H, ArH), 3.80e3.88 (m, 2H, NCH2),
3.47e3.53 (m, 2H, NCH2), 1.97e2.06 (m, 2H, CH2); 13C NMR
4.2.9. (7-(1H-Indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]
pyrimidin-8-yl)(4-chlorophenyl)methanone 4i. Yellow solid; mp
(125 MHz, DMSO-d6):
d
¼187.6, 149.1, 140.1, 136.0, 134.8, 132.8,
132.6, 131.8, 130.4, 129.5, 128.5, 128.1, 128.0, 127.0, 126.7, 126.5,
126.2, 125.6, 121.6, 119.3, 119.0, 111.5, 110.9, 107.5, 101.9, 42.2, 38.2,
21.4; HRMS (TOF ESþ): m/z calcd for C34H27ClN3O [(MþH)þ],
528.1837; found, 528.1839.
>300 ꢀC; IR (KBr): 3277,1600,1528,1417,1275, 1098, 741, 690 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6):
d
¼10.68 (br, 1H, NH), 8.01 (br, 1H,
NH), 7.22e7.26 (m, 2H, ArH), 7.19 (t, J¼7.4 Hz, 2H, ArH), 7.13 (t,
J¼7.1 Hz, 1H, ArH), 7.06 (d, J¼8.1 Hz, 1H, ArH), 6.94 (d, J¼8.3 Hz, 2H,
ArH), 6.91 (d, J¼7.9 Hz, 1H, ArH), 6.85 (t, J¼7.5 Hz, 1H, ArH), 6.67 (d,
J¼4.4 Hz, 2H, ArH), 6.60 (d, J¼8.3 Hz, 1H, ArH), 3.75e3.85 (m, 2H,
NCH2), 3.42e3.52 (m, 2H, NCH2), 1.98e2.06 (m, 2H, CH2); 13C NMR
4.2.14. (2-Chlorophenyl)(6-(4-fluorophenyl)-7-(1H-indol-3-yl)-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4n. Yellow solid; mp 282e284 ꢀC; IR (KBr): 3365, 1608, 1529, 1413,
(125 MHz, DMSO-d6):
d
¼188.1, 148.9, 140.6, 136.2, 133.5, 132.3,
1156, 743, 653, 548 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6):
d
¼10.42
130.8, 129.5, 128.6, 127.3, 126.4, 126.0, 121.1, 119.8, 118.8, 112.3, 111.4,
(br, 1H, NH), 8.12 (br, 1H, NH), 7.17e7.25 (m, 2H, ArH), 6.93e7.03 (m,
4H, ArH), 6.80e6.88 (m, 2H, ArH), 6.60e6.75 (m, 4H, ArH),
3.76e3.84 (m, 2H, NCH2), 3.47e3.53 (m, 2H, NCH2), 1.98e2.06 (m,
109.9, 103.5, 42.6, 38.7, 21.9; HRMS (TOF ESþ): m/z calcd for
C
28H23ClN3O [(MþH)þ], 452.1542; found, 452.1541.
2H, CH2); 13C NMR (100 MHz, DMSO-d6):
d¼186.1, 161.3 (d,
4.2.10. (4-Chlorophenyl)(6-(4-fluorophenyl)-7-(2-methyl-1H-indol-
3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4j. Yellow solid; mp 282e285 ꢀC; IR (KBr): 3313, 1602, 1526, 1410,
J¼243.0 Hz), 148.5, 140.8, 135.7, 132.1, 130.0, 128.6, 128.4, 128.1,
125.4, 125.3, 125.0, 120.6, 119.5, 118.3, 115.2 (d, J¼21.0 Hz), 115.0 (d,
J¼21.0 Hz), 111.9, 110.9, 108.1, 103.9, 42.0, 38.2, 21.4; HRMS (TOF
ESþ): m/z calcd for C28H22ClFN3O [(MþH)þ], 470.1430; found,
470.1435.
1213, 837, 747, 666 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6):
d
¼10.46
(br, 1H, NH), 8.02 (br, 1H, NH), 7.14 (d, J¼5.1 Hz, 2H, ArH), 6.97e7.07
(m, 3H, ArH), 6.79e6.93 (m, 4H, ArH), 6.69 (d, J¼6.9 Hz, 1H, ArH),
6.59 (d, J¼7.9 Hz, 2H, ArH), 3.80e3.90 (m, 2H, NCH2), 3.44e3.54 (m,
2H, NCH2), 1.96e2.96 (m, 2H, CH2), 1.78 (s, 3H, CH3); 13C NMR
4.2.15. (7-(1H-Indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]
pyrimidin-8-yl)(2-chlorophenyl)methanone 4o. Yellow solid; mp

1052
X.-B. Chen et al. / Tetrahedron 70 (2014) 1047e1054
>300 ꢀC; IR (KBr): 3345, 1606, 1531, 1418, 1279, 1103, 742,
693 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼186.0, 149.3, 140.2, 136.0, 133.2, 131.8, 131.2, 129.7, 129.4, 128.8,
d¼10.41 (br, 1H, NH), 8.13
128.2, 128.2, 127.0, 126.9, 126.7, 126.5, 124.3, 121.6, 119.9, 118.8, 111.7,
(br, 1H, NH), 7.18 (d, J¼7.2 Hz, 2H, ArH), 7.13 (t, J¼7.1 Hz, 2H, ArH),
7.09 (d, J¼6.9 Hz, 1H, ArH), 6.97e7.03 (m, 2H, ArH), 6.82e6.86 (m,
2H, ArH), 6.71 (d, J¼6.3 Hz, 2H, ArH), 6.61e6.67 (m, 2H, ArH),
3.76e3.84 (m, 2H, NCH2), 3.45e3.53 (m, 2H, NCH2), 1.98e2.06 (m,
110.7, 107.0, 102.3, 42.2, 38.3, 21.4; HRMS (TOF ESþ): m/z calcd for
C
34H27ClN3O [(MþH)þ], 528.1837; found, 528.1833.
4.2.20. (7-(1H-Indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]
2H, CH2); 13C NMR (125 MHz, DMSO-d6):
d
¼186.5, 149.0, 141.2,
pyrimidin-8-yl)(phenyl)methanone 4t. Yellow solid; mp >300 ꢀC; IR
136.1, 132.2, 130.4, 129.2, 128.8, 128.6, 128.4, 128.4, 127.2, 126.9,
125.7, 125.3, 121.0, 120.0, 118.6, 112.2, 111.2, 108.7, 104.4, 42.5, 38.7,
21.9; HRMS (TOF ESþ): m/z calcd for C28H23ClN3O [(MþH)þ],
452.1542; found, 452.1533.
(KBr): 3277, 1602, 1526, 1415, 1276, 1105, 742, 696 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6):
d¼10.45 (br, 1H, NH), 8.01 (br, 1H, NH),
7.09e7.22 (m, 5H, ArH), 6.97e7.04 (m, 3H, ArH), 6.94 (d, J¼7.9 Hz,
1H, ArH), 6.80e6.88 (m, 2H, ArH), 6.57e6.68 (m, 4H, ArH),
3.77e3.83 (m, 2H, NCH2), 3.44e3.52 (m, 2H, NCH2), 1.97e2.07 (m,
4.2.16. (2-Chlorophenyl)(6-(4-fluorophenyl)-7-(2-methyl-1H-indol-
3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4p. Yellow solid; mp 271e273 ꢀC; IR (KBr): 3344, 1609, 1525, 1369,
2H, CH2); 13C NMR (100 MHz, DMSO-d6):
d
¼189.3, 148.4, 141.7,
135.8, 132.1, 130.4, 128.6, 128.2, 128.0, 127.5, 126.8, 126.2, 125.5,
125.3, 120.6, 119.5, 118.3, 112.1, 111.0, 109.6, 103.1, 42.2, 38.3, 21.6;
HRMS (TOF ESþ): m/z calcd for C28H25N3O [(MþH)þ], 418.1914;
found, 418.1913.
1269, 1157, 748, 542 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
¼10.23
(br, 1H, NH), 8.12 (br, 1H, NH), 7.06e7.11 (m, 2H, ArH), 6.97 (t,
J¼8.7 Hz, 3H, ArH), 6.88 (d, J¼7.8 Hz, 1H, ArH), 6.79 (t, J¼7.3 Hz, 2H,
ArH), 6.66e6.73 (m, 3H, ArH), 6.54e6.62 (m, 1H, ArH), 3.87e3.91
(m, 1H, NCH2), 3.72e3.76 (m, 1H, NCH2), 3.42e3.59 (m, 2H, NCH2),
1.99e2.06 (m, 2H, CH2), 1.83 (s, 3H, CH3); 13C NMR (100 MHz,
4.2.21. (6-(4-Fluorophenyl)-7-(2-methyl-1H-indol-3-yl)-1,2,3,4-tet-
rahydropyrrolo[1,2-a]pyrimidin-8-yl)(phenyl)methanone 4u. Yellow
solid; mp 246e247 ꢀC; IR (KBr): 3363, 1604, 1526, 1400, 1218, 1158,
DMSO-d6):
d
¼186.0, 161.2 (d, J¼242.0 Hz), 148.8, 140.2, 135.3, 131.6,
837, 740 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
¼10.29 (br, 1H, NH),
131.5, 130.2, 128.4, 127.9, 125.7, 124.4, 119.8, 118.8, 118.1, 115.4 (d,
J¼21.0 Hz), 115.1 (d, J¼21.0 Hz), 111.6, 110.0, 109.9, 103.5, 42.0, 38.2,
21.4, 12.3; HRMS (TOF ESþ): m/z calcd for C29H24ClFN3O [(MþH)þ],
484.1586; found, 484.1593.
8.02 (br,1H, NH), 7.12e7.16 (m, 2H, ArH), 7.00 (d, J¼8.8 Hz, 2H, ArH),
6.79e6.96 (m, 5H, ArH), 6.78 (t, J¼7.4 Hz, 1H, ArH), 6.67 (t, J¼7.4 Hz,
1H, ArH), 6.59 (t, J¼7.6 Hz, 2H, ArH), 3.80e3.86 (m, 2H, NCH2),
3.44e3.52 (m, 2H, NCH2), 1.96e2.96 (m, 2H, CH2), 1.75 (s, 3H, CH3);
13C NMR (100 MHz, DMSO-d6):
d
¼189.2, 161.1 (d, J¼242.0 Hz),
4.2.17. (2-Chlorophenyl)(7-(2-methyl-1H-indol-3-yl)-6-phen-yl-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4q. Yellow solid; mp 289e290 ꢀC; IR (KBr): 3325, 1607, 1528, 1471,
148.5, 141.2, 135.4, 133.2, 131.8 (d, J¼8.0 Hz), 131.7 (d, J¼8.0 Hz),
129.3, 128.8, 128.6, 127.3, 125.8, 124.6, 119.8, 118.3, 115.3 (d,
J¼21.0 Hz), 115.1 (d, J¼21.0 Hz), 111.7, 110.2, 106.8, 102.6, 42.0, 38.2,
21.5, 12.2; HRMS (TOF ESþ): m/z calcd for C29H25FN3O [(MþH)þ],
450.1976; found, 450.1971.
1276, 1166, 742, 696 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼10.20
(br, 1H, NH), 8.13 (br, 1H, NH), 7.12 (d, J¼7.3 Hz, 2H, ArH), 7.04e7.09
(m, 3H, ArH), 6.98 (d, J¼6.9 Hz, 1H, ArH), 6.87 (d, J¼7.7 Hz, 1H, ArH),
6.78 (t, J¼7.3 Hz, 2H, ArH), 6.63e6.75 (m, 3H, ArH), 6.55e6.61 (m,
1H, ArH), 3.89e3.93 (m, 1H, NCH2), 3.73e3.79 (m, 1H, NCH2),
3.50e3.58 (m, 1H, NCH2), 3.43e3.47 (m, 1H, NCH2), 2.05e2.11 (m,
1H, CH2), 1.98e2.02 (m, 1H, CH2), 1.73 (s, 3H, CH3); 13C NMR
4.2.22. (7-(2-Methyl-1H-indol-3-yl)-6-phenyl-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)(phenyl)methanone
4v. Yellow solid; mp >300 ꢀC; IR (KBr): 3311,1601,1525,1406,1273,
1052, 742, 696 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6):
d¼10.29 (br,
(125 MHz, DMSO-d6):
d
¼186.4, 149.3, 140.6, 135.7, 132.4, 130.7,
1H, NH), 8.02 (br, 1H, NH), 7.08e7.16 (m, 5H, ArH), 6.85e6.94 (m,
5H, ArH), 6.73e6.79 (m, 1H, ArH), 6.62e6.68 (m, 1H, ArH), 6.58 (t,
J¼7.3 Hz, 3H, ArH), 3.82e3.88 (m, 2H, NCH2), 3.45e3.53 (m, 2H,
NCH2), 2.17e2.27 (m, 2H, CH2),1.73 (s, 3H, CH3); 13C NMR (100 MHz,
129.9, 128.7, 128.7, 128.3, 127.1, 124.8, 120.2, 119.2, 118.4, 111.9, 110.3,
104.0, 42.5, 38.6, 21.8, 12.8; HRMS (TOF ESþ): m/z calcd for
C
29H25ClN3O [(MþH)þ], 466.1681; found, 466.1679.
DMSO-d6):
d
¼189.2, 148.5, 141.3, 135.4, 133.1, 132.4, 129.8, 129.5,
4.2.18. (2-Chlorophenyl)(6-(4-fluorophenyl)-7-(2-phenyl-1H-indol-
3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4r. Yellow solid; mp >300 ꢀC; IR (KBr): 3325,1611,1527,1420,1222,
128.6, 128.3, 127.4, 126.5, 125.8, 125.6, 119.7, 118.4, 118.2, 111.6, 110.1,
106.9, 102.6, 42.2, 38.2, 21.6, 12.2; HRMS (TOF ESþ): m/z calcd for
C29H26N3O [(MþH)þ], 432.2070; found, 432.2068.
1021, 743, 552 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6):
d¼10.78 (br,
1H, NH), 8.21 (br, 1H, NH), 7.46 (d, J¼7.7 Hz, 2H, ArH), 7.28e7.33 (m,
2H, ArH), 7.17e7.22 (m, 1H, ArH), 7.12 (d, J¼7.8 Hz, 1H, ArH),
7.01e7.09 (m, 3H, ArH), 6.85e6.95 (m, 4H, ArH), 6.78e6.82 (m, 1H,
ArH), 6.69e6.74 (m, 1H, ArH), 6.32e6.36 (m, 2H, ArH), 3.78e3.88
(m, 2H, NCH2), 3.50e3.58 (m, 2H, NCH2), 2.00e2.08 (m, 2H, CH2);
4.2.23. (6-(4-Fluorophenyl)-7-(2-phenyl-1H-indol-3-yl)-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)(phenyl)methanone
4w. Yellow solid; mp 286e287 ꢀC; IR (KBr): 3353, 1602, 1525, 1410,
1219, 1021, 751, 696 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼10.79
(br, 1H, NH), 8.11 (br, 1H, NH), 7.35 (d, J¼7.4 Hz, 2H, ArH), 7.27 (t,
J¼7.3 Hz, 2H, ArH), 7.16e7.20 (m, 1H, ArH), 7.07e7.14 (m, 3H, ArH),
7.05 (d, J¼7.8 Hz, 1H, ArH), 6.89e6.95 (m, 3H, ArH), 6.85 (t, J¼7.1 Hz,
1H, ArH), 6.79 (t, J¼7.2 Hz,1H, ArH), 6.61 (d, J¼7.3 Hz, 2H, ArH), 6.49
(t, J¼7.3 Hz, 2H, ArH), 3.79e3.88 (m, 2H, NCH2), 3.46e3.56 (m, 2H,
NCH2), 2.00e2.08 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
13C NMR (100 MHz, DMSO-d6):
d¼186.0, 161.2 (d, J¼242.0 Hz),
149.3, 140.1, 136.0, 133.1, 131.3, 131.0, 129.7, 128.7, 128.3, 128.1, 127.0,
126.5, 125.6, 124.3, 121.6, 119.8, 118.8, 115.3 (d, J¼21.0 Hz), 115.1 (d,
J¼21.0 Hz), 111.8, 110.7, 106.7, 102.8, 42.1, 38.3, 21.4; HRMS (TOF
ESþ): m/z calcd for C34H26ClFN3O [(MþH)þ], 546.1743; found,
546.1741.
d
¼189.2,161.0 (d, J¼242.5 Hz),148.9, 141.4, 136.0,134.8,132.9,131.6,
130.2,128.4,128.1,126.9,126.6,126.5,125.7,124.7,121.5,119.3,118.9,
115.2 (d, J¼21.3 Hz), 115.0 (d, J¼21.3 Hz), 111.9, 110.9, 107.4, 101.8,
42.0, 38.1, 21.4; HRMS (TOF ESþ): m/z calcd for C34H27FN3O
[(MþH)þ], 512.2133; found, 512.2128.
4.2.19. (2-Chlorophenyl)(6-phenyl-7-(2-phenyl-1H-indol-3-yl)-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone
4s. Yellow solid; mp >300 ꢀC; IR (KBr): 3307,1607,1525,1323,1215,
1104, 745, 694 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6):
d
¼10.76 (br,
1H, NH), 8.22 (br, 1H, NH), 7.44e7.52 (m, 2H, ArH), 7.26e7.34 (m,
2H, ArH), 6.90e7.23 (m, 10H, ArH), 6.71e6.81 (m, 3H, ArH),
6.31e6.35 (m, 1H, ArH), 3.80e3.89 (m, 2H, NCH2), 3.49e3.58 (m,
2H, NCH2), 2.00e2.06 (m, 2H, CH2); 13C NMR (100 MHz, DMSO-d6):
4.2.24. Phenyl(6-phenyl-7-(2-phenyl-1H-indol-3-yl)-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)methanone 4x. Yellow solid;
mp >300; IR (KBr): 3306, 1603, 1522, 1413, 1215, 1173, 744,
692 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d¼10.76 (br, 1H, NH), 8.12

X.-B. Chen et al. / Tetrahedron 70 (2014) 1047e1054
1053
2010, 12, 875e878; (d) Barry, B. T.; Dennis, G. H. Chem. Rev. 2009, 109,
4439e4486; (e) Kumaravel, K.; Vasuki, G. Green Chem. 2009, 11, 1945e1947; (f)
Candeias, N. R.; Veiros, L. F.; Afonso, C. A. M.; Gois, P. M. P. Eur. J. Org. Chem.
2009, 12, 1859e1863; (g) Ma, N.; Jiang, B.; Zhang, G.; Tu, S.-J.; Wever, W.; Li, G.-
G. Green Chem. 2010, 12, 1357e1361; (h) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.;
Li, G.-G. J. Am. Chem. Soc. 2009, 131, 11660e11661.
4. (a) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559e590; (b) Toyota, M.; Ihara, N. Nat.
Prod. Rep. 1998, 15, 327e340; (c) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J.
C. Chem. Rev. 2009, 109, 3080e3098; (d) Ishikura, M.; Yamada, K. Nat. Prod. Rep.
2009, 26, 803e852; (e) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24,
843e868; (f) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761e765; (g)
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875e2911.
(br, 1H, NH), 7.36 (d, J¼7.7 Hz, 2H, ArH), 7.27 (t, J¼7.5 Hz, 2H, ArH),
7.15e7.19 (m, 1H, ArH), 7.01e7.12 (m, 7H, ArH), 6.93 (t, J¼7.4 Hz, 1H,
ArH), 6.84 (t, J¼7.2 Hz, 1H, ArH), 6.78 (t, J¼7.4 Hz, 1H, ArH), 6.58 (d,
J¼7.6 Hz, 1H, ArH), 6.48 (t, J¼7.4 Hz, 2H, ArH), 6.32e6.36 (m, 2H,
ArH), 3.89 (q, J¼5.8 Hz, 1H, NCH2), 3.80e3.92 (m, 2H, NCH2),
3.46e3.56 (m, 2H, NCH2), 2.00e2.07 (m, 2H, CH2); 13C NMR
(125 MHz, DMSO-d6):
d
¼189.2, 149.0, 141.4, 136.0, 134.8, 133.0,
132.0, 130.1, 129.6, 128.4, 128.1, 126.8, 126.8, 126.5, 125.9, 125.7,
121.4, 119.4, 118.9, 111.8, 110.9, 107.6, 101.9, 42.2, 38.2, 21.5; HRMS
(TOF ESþ): m/z calcd for C34H28N3O [(MþH)þ], 494.2227; found,
494.2226.
5. (a) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110,
4489e4497; (b) Shiri, M. Chem. Rev. 2012, 112, 3508e3549; (c) Yamashita, T.;
Kawai, N.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2005, 127,
15038e15039; (d) Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci, L. S.; Jones,
J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J. L.; DiCioccio, A. T.; Petrova, T.; Mitschler, A.;
4.2.25. (7-(2-Methyl-1H-indol-3-yl)-6-phenyl-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)(p-tolyl)methanone
4y. Yellow solid; mp >300; IR (KBr): 3288, 1602, 1526, 1410, 1272,
~
Podjarny, A. D. J. Med. Chem. 2005, 48, 3141e3152; (e) Estevao, M. S.; Carvalho,
L. C. R.; Freitas, M.; Gomes, A.; Viegas, A.; Manso, J.; Erhardt, S.; Fernandes, E.;
Cabrita, E. J.; Marques, M. M. B. Eur. J. Med. Chem. 2012, 54, 823e833.
6. (a) Wu, Y.-S.; Coumar, M. S.; Chang, J.-Y.; Sun, H.-Y.; Kuo, F.-M.; Kuo, C.-C.; Chen,
Y.-J.; Chang, C.-Y.; Hsiao, C. L.; Liou, J.-P.; Chen, C.-P.; Yao, H. T.; Chiang, Y. K.; Tan,
U. K.; Chen, C.-T.; Chu, C.-Y.; Wu, S.-Y.; Yeh, T. K.; Lin, C.-Y.; Hsieh, H. P. J. Med.
Chem. 2009, 52, 4941e4945; (b) Thirumurugan, P.; Nandakumar, A.; Mur-
alidharan, D.; Perumal, P. T. J. Comb. Chem. 2010, 12, 161e167; (c) Zhu, S.; Ji, S.;
Su, X.; Sun, C.; Liu, Y. Tetrahedron Lett. 2008, 49, 1777e1781; (d) Liu, W.-G.; Liu,
K.; Wood, H. B.; McCann, M. E.; Doebber, T. W.; Chang, C.-H.; Akiyama, T. E.;
Einstein, M.; Berger, J. P.; Meinke, P. T. J. Med. Chem. 2009, 52, 4443e4453.
7. (a) Yadav, J. S.; Subba- Reddy, B. V.; Praneeth, K. Tetrahedron Lett. 2008, 49,
2815e2819; (b) Amat, M.; Llor, N.; Checa, B.; Molins, E.; Bosch, J. J. Org. Chem.
2010, 75, 178e189; (c) Mason, J. J.; Bergman, J.; Janosik, T. J. Nat. Prod. 2008, 71,
1447e1450; (d) Garr, A. N.; Luo, D.-H.; Brown, N.; Cramer, C. J.; Buszek, K. R.;
Velde, D. V. Org. Lett. 2010, 12, 96e99.
1168, 744, 695 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6):
d
¼10.29 (br,
1H, NH), 7.96 (br, 1H, NH), 7.13 (d, J¼7.2 Hz, 2H, ArH), 7.07e7.11 (m,
3H, ArH), 6.94 (d, J¼8.0 Hz, 1H, ArH), 6.86 (d, J¼7.8 Hz, 1H, ArH),
6.74e6.81 (m, 3H, ArH), 6.62e6.66 (m, 1H, ArH), 6.36 (d, J¼7.8 Hz,
2H, ArH), 3.86 (t, J¼5.7 Hz, 2H, NCH2), 3.44e3.50 (m, 2H, NCH2),
2.01 (t, J¼5.0 Hz, 2H, CH2), 1.98 (s, 3H, CH3), 1.72 (s, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6):
d¼189.2,148.3, 138.5, 137.9, 135.4, 133.1,
132.4, 130.0, 129.5, 128.3, 127.5, 126.5, 126.3, 125.5, 119.7, 118.4,
118.2, 111.7, 109.9, 107.1, 102.7, 42.2, 38.2, 21.6, 21.3, 12.2; HRMS (TOF
ESþ): m/z calcd for C30H28N3O [(MþH)þ], 446.2227; found,
446.2229.
8. (a) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469e6480; (b) Regina, G. L.; Coluccia,
A.; Brancale, A.; Piscitelli, F.; Gatti, V.; Maga, G.; Samuele, A.; Pannecouque, C.;
Schols, D.; Balzarini, J.; Novellino, E.; Silvestri, R. J. Med. Chem. 2011, 54,
1587e1589.
4.2.26. (4-Chlorophenyl)(7-(4-fluorophenyl)-8-(2-methyl-1H-indol-
3-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepin-9-yl)meth-
anone 4z. Yellow solid; mp >300; IR (KBr): 3348, 1542, 1412, 1225,
ꢀ
ꢀ
9. (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39,
€
4402e4421; (b) Preller, M.; Chinthalapudi, K.; Martin, R.; Knolker, H.-J.; Man-
strin, D. J. J. Med. Chem. 2011, 54, 3675e3685; (c) Marco, E.; Laine, W.; Tardy, C.;
Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly, C.; Gago, F. J. Med. Chem. 2005, 48,
3796e3807.
1086, 836, 738, 671 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
¼10.44
(br, 1H, NH), 7.91 (br, 1H, NH), 7.06 (d, J¼7.2 Hz, 4H, ArH), 6.90e6.96
(m, 3H, ArH), 6.79e6.83 (m, 2H, ArH), 6.62e6.69 (m, 3H, ArH),
3.73e3.79 (m, 1H, NCH2), 3.57e3.63 (m, 1H, NCH2), 3.33e3.37 (m,
1H, NCH2), 3.17e3.23 (m, 1H, NCH2), 1.79e1.94 (m, 4H, CH2), 1.74 (s,
10. (a) Wang, L.; Cherian, C.; Desmoulin, S. K.; Mitchell-Ryan, S.; Hou, Z.-J.;
Matherly, L. H.; Gangjee, A. J. Med. Chem. 2012, 55, 1758e1770; (b) Gangjee, A.;
Jain, H. D.; Queener, S. F.; Kisliuk, R. L. J. Med. Chem. 2008, 51, 4589e4600; (c)
Deng, Y.-J.; Wang, Y.-Q.; Cherian, C.; Hou, Z.-J.; Buck, S. A.; Matherly, L. H.;
Gangjee, A. J. Med. Chem. 2008, 51, 5052e5063; (d) Soares, M. L.; Brito, A. F.;
3H, CH3); 13C NMR (100 MHz, DMSO-d6):
d
¼190.2, 161.1 (d,
~
Laranjo, M.; Paixao, J. A.; Botelho, M. F.; Melo, T. M. V. D. P. Eur. J. Med. Chem.
J¼243.0 Hz),155.1, 138.7, 135.4,134.1,132.9,131.8 (d, J¼8.0 Hz),131.7
(d, J¼8.0 Hz), 129.4, 129.1, 127.0, 125.8, 118.4, 118.2, 115.8 (d,
J¼21.0 Hz), 115.6 (d, J¼21.0 Hz), 113.1, 110.2, 106.5, 106.2, 47.9, 46.5,
30.1, 27.3, 12.1; HRMS (TOF ESþ): m/z calcd for C30H26ClFN3O
[(MþH)þ], 498.1743; found, 498.1742.
2013, 60, 254e262; (e) Wang, L.; Desmoulin, S.; Cherian, K. C.; Polin, L.; White,
K.; Kushner, J.; Fulterer, A.; Chang, M.-H.; Mitchell-Ryan, S. M.; Romero, M. F.;
Hou, Z.-J.; Matherly, L. H.; Gangjee, A. J. Med. Chem. 2011, 54, 7150e7164; (f)
Tangeda, S. J.; Garlapati, A. Eur. J. Med. Chem. 2010, 45, 1453e1458.
11. Regueiro-Ren, A.; Xue, Q.-M.; Swidorski, J. J.; Gong, Y.-F.; Mathew, M.; Parker, D.
D.; Yang, Z.; Eggers, B.; D’Arienzo, C.; Sun, Y.-N.; Malinowski, J.; Gao, Q.; Wu, D.-
D.; Langley, D. R.; Colonno, R. J.; Chien, C.; Grasela, D. M.; Zheng, M.; Lin, P.-F.;
Meanwell, N. A.; Kadow, J. F. J. Med. Chem. 2013, 56, 1656e1669.
12. (a) Pudio, J. S.; Saxena, N. K.; Nassiri, M. R.; Turk, S. R.; Drach, J. C.; Townsend, L.
B. J. Med. Chem. 1988, 31, 2086e2092; (b) Saxena, N. K.; Hagenow, B. M.;
Genzlinger, G.; Turk, S. R.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1988, 31,
1501e1506.
Acknowledgements
We gratefully acknowledge the financial support of Natural
Science Foundation of China (Nos. 81160384, 21162037, 21262042,
U1202221 and 21362042), Yunnan Province Department of Edu-
cation Fund (2013J074), and the Talent Found in Yunnan Province
(2012HB001).
13. E1-Gaby, M. S. A. A.; Gaber, M.; Atalla, A. A.; Abd Al-Wahab, K. A. IL Farmaco
2002, 57, 613e617.
14. Varaprasad, C. V. N. S. S.; Ramasamy, K.; Girardet, J. L.; Gunic, E.; Lai, V.; Zhong,
Z.; An, H.; Hong, Z. Bioorg. Chem. 2007, 35, 25e34.
15. Trzoss, M.; Bensen, D. C.; Lia, X.-M.; Chen, Z.-Y.; Lam, T.; Zhang, J.-Z.; Creighton,
C. J.; Cunningham, M. L.; Kwan, B.; Stidham, M.; Nelson, K.; Brown-Driver, V.;
Castellano, A.; Shaw, K. J.; Lightstone, F. C.; Wong, S.-E.; Nguyen, T. B.; Finn, J.;
Tari, L. W. Bioorg. Med. Chem. Lett. 2013, 23, 1537e1543.
Supplementary data
16. Chen, Z.-C.; Venkatesan, A. M.; Dehnhardt, C. M.; Ayral-Kaloustian, S.; Brooij-
mans, N.; Mallon, R.; Feldberg, L.; Hollander, I.; Lucas, J.; Yu, K.; Kong, F.-M.;
Mansour, T. S. J. Med. Chem. 2010, 53, 3169e3682.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.12.062.
17. (a) Clark, M. P.; George, K. M.; Bookland, R. G.; Chen, J.; Laughlin, S. K.; Thakur,
K. D.; Lee, W.; Davis, J. R.; Cabrera, E. J.; Brugel, T. A.; VanRens, J. C.; Lau-
fersweiler, M. J.; Maier, J. A.; Sabat, M. P.; Golebiowski, A.; Easwaran, V.; Web-
ster, M. E.; Dea, B.; Zhang, G. Bioorg. Med. Chem. Lett. 2007, 17, 1250e1253; (b)
Weinberg, L. R.; Albom, M. S.; Angeles, T. S.; Breslin, H. J.; Gingrich, D. E.; Huang,
Z.-Q.; Lisko, J. G.; Mason, J. L.; Milkiewicz, K. L.; Thieu, T. V.; Underiner, T. L.;
Wells, G. J.; Wells-Knecht, K. J.; Dorsey, B. D. Bioorg. Med. Chem. Lett. 2011, 21,
7325e7330.
References and notes
€
1. (a) Domling, A. Chem. Rev. 2006, 106, 17e89; (b) Hulme, C.; Gore, V. V. Curr. Med.
Chem. 2003, 10, 51e80; (c) Lieby-Muller, F.; Constantieux, T.; Rodriguez Jean, J. J.
Am. Chem. Soc. 2005, 127, 17176e17177.
2. (a) Pando, O.; Stark, S.; Dnkert, A.; Porzel, A.; Preusentanz, R.; Wessjohann, L. A.
J. Am. Chem. Soc. 2011, 133, 7692e7695; (b) Singh, M. S.; Chowdhury, S. RSC Adv.
2012, 2, 4547e4592; (c) Shaabani, A.; Rezayan, A. H.; Keshipour, S.; Sarvary, A.;
Ng, S. W. Org. Lett. 2009, 11, 3342e3345; (d) Nair, V.; Rajesh, C.; Vinod, A.;
Bindu, U. S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003,
36, 899e907.
18. Lindsay, K. B.; Pyne, S. G. Tetrahedron 2004, 60, 4173e4176.
19. Liu, Y.; Fang, J.-P.; Cai, H.-Y.; Xiao, F.; Ding, K.; Hua, Y.-H. Bioorg. Med. Chem.
2012, 20, 5473e5482.
€
20. Palmer, A. M.; Munch, G.; Brehm, C.; Zimmermann, P. J.; Buhr, W.; Feth, M. P.;
Simon, W. A. Bioorg. Med. Chem. 2008, 16, 1511e1530.
21. Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey, G. B.; Barredo, J.; Jan-
3. (a) Cheng, C.; Jiang, B.; Tu, S.-J.; Li, G.-G. Green Chem. 2011, 13, 2107e2115; (b)
Ganem, B. Acc. Chem. Res. 2009, 42, 463e472; (c) Aditya, K.; Bela, T. Green Chem.
ꢀ
natipour, M.; Moran, G. R. J. Med. Chem. 1992, 35, 4450e4454.

1054
X.-B. Chen et al. / Tetrahedron 70 (2014) 1047e1054
22. (a) Kaspersen, S. J.; Sundby, E.; Charnock, C.; Hoff, B. H. Bioorg. Chem. 2012, 44,
35e41; (b) Bernotas, R. C.; Lenicek, S.; Antane, S.; Cole, D. C.; Harrison, B. L.;
Robichaud, A. J.; Zhang, G.-M.; Smith, D.; Platt, B.; Lin, Q.; Li, P.; Coupet, J.;
Rosenzweig-Lipson, S.; Beyer, C. E.; Schechter, L. E. Bioorg. Med. Chem. 2009, 17,
5153e5183; (c) Oguro, Y.; Miyamoto, N.; Okada, K.; Takagi, T.; Iwata, H.; Awazu,
Y.; Miki, H.; Hori, A.; Kamiyama, K.; Imamura, S. Bioorg. Med. Chem. 2010, 18,
Tetrahedron Lett. 2011, 52, 465e467; (e) Chen, X.-B.; Liu, X.-M.; Huang, R.; Yan,
S.-J.; Lin, J. Eur. J. Org. Chem. 2013, 69, 4607e4613; (f) Yan, S.-J.; Niu, Y.-F.; Huang,
R.; Lin, J. Synlett 2009, 2821e2824.
25. (a) Wang, L.-B.; Yu, C.-Y.; Huang, Z.-T. Synthesis 1994, 1441e1444; (b) Nie, X.-P.;
Wang, M.-X.; Huang, Z. T. Synthesis 2000, 17, 1439e1448; (c) Alizadeh, A.; Re-
zvanian, A.; Deng, Y. Tetrahedron 2010, 66, 9933e9937.
26. Eftekhari-Sis, B.; Zirak, M.; Akbari, A. Chem. Rev. 2013, 113, 2958e3034.
27. Khalili, B.; Jajarmi, P.; Eftekhari-Sis, B.; Hashemi, M. M. J. Org. Chem. 2008, 73,
2090e2095.
ꢁ
7260e7263; (d) Pittala, V.; Siracusa, M. A.; Modica, M. N.; Salerno, L.; Pedretti,
A.; Vistoli, G.; Cagnotto, A.; Mennini, T.; Romeo, G. Bioorg. Med. Chem. 2011, 19,
5260e5276.
23. (a) Taylor, E.; Patel, H.; Jun, J.-G. J. Org. Chem. 1995, 60, 6684e6687; (b) Cobo, J.;
Nogueras, M. Tetrahedron 1998, 54, 5753e5762; (c) Hopkins, C. R.; Collar, N.
Tetrahedron Lett. 2005, 46, 1845e1848; (d) Chen, W.-T.; Hu, M.; Wu, J.-W.; Zou,
H.-B.; Yu, Y.-P. Org. Lett. 2010, 12, 3863e3865; (e) Chen, Y.-H.; Xiang, H.-Y.; Tan,
C.; Xie, Y.-Y.; Yang, C.-H. Tetrahedron 2013, 69, 2714e2719.
24. (a) Yu, F.-C.; Yan, S.-J.; Hu, L.; Wang, Y.-C.; Lin, J. Org. Lett. 2011, 13, 4782e4785;
(b) Yan, S.-J.; Chen, Y.-L.; Liu, L.; He, N.-Q.; Lin, J. Green Chem. 2010, 12,
2043e2045; (c) Chen, X.-B.; Zhu, D.-D.; Wang, X.-Y.; Yan, S.-J.; Lin, J. Tetrahedron
2013, 69, 9224e9236; (d) Yan, S.-J.; Chen, Y.-L.; Liu, L.; Tang, Y.-J.; Lin, J.
28. (a) Quiroga, J.; Acosta, P. A.; Cruz, S.; Abonía, R.; Insuasty, B.; Nogueras, M.;
Cobo, J. Tetrahedron Lett. 2010, 51, 5443e5447; (b) Fu, L.-P.; Shi, Q.-Q.; Shi, Y.;
Jiang, B.; Tu, S.-J. ACS Comb. Sci. 2013, 15, 135e140; (c) Jiang, B.; Li, Q.-Y.; Zhang,
H.; Tu, S.-J.; Pindi, S.; Li, G.-G. Org. Lett. 2012, 14, 700e703; (d) Li, Y.; Li, Q.-Y.; Xu,
H.-W.; Fan, W.; Jiang, B.; Wang, S.-L.; Tu, S.-J. Tetrahedron 2013, 69, 2941e2964.
29. Yu, C.-Y.; Yang, P.-H.; Zhao, M.-X.; Huang, Z.-T. Synlett 2006, 1835e1840.
30. (a) Huang, Z.-T.; Wang, M.-X. Synthesis 1992, 12, 1273e1275; (b) Li, Z.-J.;
Charles, D. Synth. Commun. 2001, 31, 527e533; (c) Huang, Z.-T.; Liu, Z.-R. Synth.
Commun. 1989, 19, 943e958.