Convergent domino synthesis of 1,2,3-triaroylindolizines from methyl ketones and pyridines via self-division of labor strategy

Article abstract of DOI:10.1016/j.tet.2012.06.091

A highly efficient method for the synthesis of 1,2,3-triaroylindolizines has been established from readily available methyl ketones and pyridines in the presence of iodine. This reaction also examplified the self-division of labor strategy in convergent domino synthesis.

Full text of DOI:10.1016/j.tet.2012.06.091

Tetrahedron 68 (2012) 7338e7344
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convergent domino synthesis of 1,2,3-triaroylindolizines from methyl ketones
and pyridines via self-division of labor strategy
*
Yan Yang, Meng Gao, Dong-Xue Zhang, Liu-Ming Wu, Wen-Ming Shu, An-Xin Wu
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2012
Received in revised form 7 June 2012
Accepted 21 June 2012
Available online 28 June 2012
A highly efficient method for the synthesis of 1,2,3-triaroylindolizines has been established from readily
available methyl ketones and pyridines in the presence of iodine. This reaction also examplified the
self-division of labor strategy in convergent domino synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indolizine
Convergent domino
Pyridine
Methyl ketone
Self-division of labor
1. Introduction
envision that a substrate could simultaneously involve in two or
more different domino sequences and generate suitably function-
The development of efficient synthetic strategies that enable
direct construction of complex molecules from simple substrates is
an ongoing interest in organic chemistry. To date, great success has
been achieved with domino reactions by combining a series of
chemical transformations in a single operation (Fig. 1a).1 Based on
our interests in developing novel domino reactions, we have suc-
cessfully developed self-sorting and focusing domino strategies
(Fig. 1b).2 To further establish more efficient domino strategies, we
alized intermediates to converge on the product (Fig. 1c). In this
designed strategy, the substrate could simultaneously play multiple
roles and this self-division of labor behavior could efficiently in-
crease the complexity of products. Herein, we would like to
examplify this strategy through the efficient synthesis of pharma-
cologically important indolizines.3
Giving the importance of indolizines in natural products and
medicinal chemistry,3 many efforts have been focused on their effi-
cient synthesis.4 However, their substrates are usually not easily
available and need to be prepared via multi-step synthesis. To dem-
onstratethepowerand potentialofourproposed strategy, wepresent
herein a very convenient and efficient method for the synthesis of
1,2,3-triaroylindolizines directly from methyl ketones and pyridines.
On the basis of ourprevious studies,2 we supposedthat themethyl
ketones could be self-sorting in two parts: one part of them would
generate a-ketoaldehydes B via domino iodinationeKornblum oxi-
dation, and the other two parts would generate pyridinium ylides D
via domino iodinationenucleophilic substitution (Scheme 1). The
condensation of a-ketoaldehydes B with pyridinium ylides D in an
equivalent ratio would generate intermediate E, which further par-
ticipated in a formal [3þ2] cycloaddition reaction with pyridinium
ylides D to converge on the dihydroindolizine intermediate F, fol-
lowed by dehydroaromatization reaction to afford the 1,2,3-
triaroylindolizine products. It should be noted that the same pyr-
idiniumylides D also played different roles in this reactionwith a self-
division of labor behavior. Moreover, the possible excess N-acylme-
thylpyridinium iodides C may be oxidized toward the corresponding
Fig. 1. Domino reaction strategies.
* Corresponding author. E-mail address: chwuax@mail.ccnu.edu.cn (A.-X. Wu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.091

Y. Yang et al. / Tetrahedron 68 (2012) 7338e7344
7339
Pleasingly, all methyl ketones, regardless of their electronic or steric
properties, proceeded efficiently to afford their corresponding prod-
ucts in moderate to excellent yields (59e93%; Table 2). For example,
electron-neutral (entries 1e3), electron-rich (entries 4e8), electron-
deficient (entry 9) and sterically hindered (entries 10e11) methyl
ketones all reacted efficiently, giving moderate to high yields
(59e85%). To our delight, good yields were also obtained with halo-
genated substrates (78e81%;entries 12e14). Much to oursatisfaction,
the heteroaryl methyl ketones could also give their corresponding
products in good to excellent yields (64e93%; entries 15e17). The
structureof 3qawas also confirmed byX-ray diffraction.5 However, no
desired products were obtained with the use of
a,b-unsaturated
methyl ketones (entry 18), which may be due to the high reactivity of
the activated vinyl group with pyridinium ylide intermediates.6
Table 2
Scope of methyl ketonesa
Scheme 1. Proposed reaction pathway.
a
-ketoaldehydes,4d,7 which would guarantee the convergent effi-
ciency in a thermodynamic manner.
2. Results and discussion
Entry
Methyl ketones 1 (R1)
3
Yield (%)b
1
2
3
4
5
6
7
8
1a (C6H5)
1b (4-MeC6H4)
1c (4-PhC6H4)
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
85
82
72
59
62
70
73
62
65
76
83
81
80
78
93
64
80
ec
To test our hypothesis, we first screened the reaction conditions
using acetophenone 1a and pyridine 2a as model substrates in the
presence of iodine with DMSO as the solvent (Table 1). On the basis
of our previous experience with iodination of methyl ketones,2 the
reaction was first carried out with 1.0 equiv of CuO at 70 ꢀC; for-
tunately, the desired product 3aa was obtained in 31% yield (Table
1, entry 1). When the temperature was elevated to 100 ꢀC, the yield
increased to 52% (Table 1, entry 2). To our delight, the yield was
significantly increased to 85% by increasing 2a to 2.0 equiv and CuO
was not necessary for this transformation (Table 1, entry 4). How-
ever, a further elevation of temperature resulted in a significant
decrease in the yield (entries 5 and 6). With the aim of accelerating
the reaction rate, we also screened various bases, but none of them
gave better results (Table 1, entries 7e14).
1d (2-MeOC6H4)
1e (3-MeOC6H4)
1f (4-MeOC6H4)
1g (2,3-Dihydrobenzo[b]-[1,4]dioxin-6-yl)
1h (4-Morpholinophenyl)
1i (4-NO2C6H4)
1j (1-Naphthyl)
1k (2-Naphthyl)
1l (4-ClC6H4)
1m (4-BrC6H4)
1n (4-FC6H4)
1o (2-Furyl)
1p (2-Benzofuryl)
1q (2-Thienyl)
9
10
11
12
13
14
15
16
17
18
1r ((E)-PheCH]CHe)
By using the optimized reaction conditions (entry 4 of Table 1), the
reaction scope was first studied with various methyl ketones.
a
Reaction was performed with methyl ketone 1 (1.0 mmol), pyridine (2.0 mmol),
and I2 (1.0 mmol) in DMSO (5 mL) at 100 ꢀC for 36 h.
b
Isolated yield.
No desired product was obtained.
Table 1
c
Optimization of the reaction conditionsa
Next, thegeneralityof thisprocesswasexpanded by the utilization
of a variety of symmetrically substituted pyridines (Scheme 2). The
electron-withdrawing methoxycarbonyl and cyano groups
substituted at C4 of pyridine afforded indolizines 3ab and 3ac in 85%
and 88% yield, respectively. On the contrary, the reaction was rather
ineffective in the case of electron-donor-substituted pyridines, as il-
lustrated for 4-methoxypyridine, which gave only 8% yield of com-
pound 3ad. Thereactionalsoprovedtobeamenableforsymmetrically
3,5-disubstituted pyridines. Treatment of 3,5-dimethylpyridine
afforded product 3ae in moderate yield (57%), but lower yields were
obtained with 3,5-dichloropyridine and 3,5-dibromopyridine, 3af
(21%) and 3ag (17%). To our delight, quinoline (2h) and isoquinoline
(2i) could also react with acetophenone 1a to afford 1,2,3-
tribenzoylpyrrolo[1,2-a]quinoline 3ah and 1,2,3-tribenzoylpyrrolo
[2,1-a]isoquinoline 3ai in yields of 15% and 58%, respectively.
As presented in Table 3, the regioselectivity of 3-substituted
pyridines was addressed and the ratio of the corresponding indo-
lizine isomers is highly dependent on the substituent nature.
Although the electron-withdrawing group (CO2CH3) led to
product 4aj in preference over 5aj (Table 3, entry 1), the regiose-
lectivity was reversed for 3-methylpyridine, 3-chloropyridine, and
3-bromopyridine, which yielded indolizines 5 as the major isomers
Entry
Pyridine
(equiv)
I2 (equiv)
Base (equiv)
Temp (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
CuO (1.0)
CuO (1.0)
CuO (1.0)
d
70
100
100
100
120
140
100
100
100
100
100
100
100
100
31
52
83
85
67
12
ec
ec
ec
10
71
54
64
39
d
d
K2CO3 (1.0)
Cs2CO3 (1.0)
NaOH (1.0)
NaHCO3 (1.0)
Al2O3 (1.0)
Et3N (1.0)
DABCO (1.0)
DBU (1.0)
9
10
11
12
13
14
a
Reaction conditions: acetophenone 1a (1.0 mmol), pyridine 2a (x equiv), iodine
(1.0 mmol), and base (1.0 equiv) in 5 mL of DMSO for 36 h.
b
Isolated yields.
No desired product was obtained.
c

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Y. Yang et al. / Tetrahedron 68 (2012) 7338e7344
O
O
Me
O
MeO
I2
1b
1f
O
I
I
MeO
Me
I-A
I-B
N
N
DMSO DMSO
O
O
O
O
N+
I-
N+
I-
CHO
MeO
CHO
MeO
Me
Me
I-D
I-E
I-F
I-C
H3C
H3C
H3CO
H3C
CH3
CH3
CH3
OCH3
CH3
O
O
O
O
N
N
O
N
N
O
O
O
O
O
O
O
CH3
OCH3
OCH3
CH3
M-1
M-2
M-3
M-4
H3CO
H3C
H3CO
H3CO
OCH3
OCH3
CH3
O
O
O
O
O
Scheme 2. Reaction was performed with acetophenone 1a (1.0 mmol), pyridine 2
(2.0 mmol), and I2 (1.0 mmol) in DMSO (5 mL) at 100 ꢀC for 36 h. Yields of the isolated
product shown.
N
O
N
N
N
O
O
O
O
O
O
OCH3
CH3
OCH3
OCH3
M-8
M-7
M-5
M-6
Table 3
Scope of 3-substituted pyridinesa
Entry
Pyridines 2 (R2)
4
5
4/5b
Yield (%)c
1
2
3
4
5
2j (CO2CH3)
2k (CH3)
2l (Cl)
2m (Br)
2n (OH)
4aj
4ak
4al
4am
4an
5aj
5ak
5al
5am
5an
1.2:1
1:3.3
1:4.8
1:3.9
77
72
58
54
43
Only 5an
a
Reaction was performed standard conditions.7
b
c
Estimated by 1H NMR spectroscopy of the crude reaction mixture.
Isolated yield.
(entries 2e4). To our delight, the active hydroxyl group was not
only compatible under this condition but also exclusively led to the
regioisomer 5an (entry 5).
To provide insight into the proposed mechanism, control exper-
iments were performed (Scheme 3).7 When 2.0 equiv of pyridinium
iodide 6a8 was treated with 1.0 equiv of phenylglyoxal 7a in DMSO at
100 ꢀC for 36 h, the desired product 3aa was obtained in 92% yield
(Scheme 3a). To extend our method for the preparation of un-
symmetrical indolizines, pyridinium iodide 6b was treated with p-
methoxyphenylglyoxal 7b, the desired 1,2,3-heteroaroylindolizine 8
was obtained in 90% yield (Scheme 3b). The high yield and high
regioselectivity of this reaction not only confirmed our proposed
mechanism but also made this method promising for the prepara-
tion of 1,2,3-heteroaroylindolizines.
Fig. 2. Control experiments. LC-(TIC/EIC)-MS analysis of the cross-coupling reaction
between 40-methylacetophenone 1b and 40-methoxyacetophenone 1f: (A) TIC
chromatogram of crude reaction extract; (BeE) corresponding EIC chromatogram
(target molecular weight is shown between brackets).
Scheme 3. Control experiments.

Y. Yang et al. / Tetrahedron 68 (2012) 7338e7344
7341
In order to further confirm our proposed mechanism, we in-
and argon filled Schlenk tube. After addition of anhydrous DMSO
(5 mL), the mixture was stirred at 100 ꢀC for 36 h. After the reaction
completed, the mixture was diluted with water and treated with
Na2S2O3 (5% w/w, aq) until the color turned to pale yellow. The
mixture was then extracted with CH2Cl2 (3ꢂ20 mL), the combined
organic extracts were dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (eluent: CH2Cl2/EtOAc¼200:1) to af-
ford a yellow solid 3aa (397 mg, 92%).
vestigated the cross-coupling reaction between two representative
substrates
40-methylacetophenone
1b
and
40-methox-
yacetophenone 1f under standard conditions. According to our
proposed reaction mechanism, the reaction of equimolar 1b and 1f
would give eight indolizine products. Fortunately, all the eight
products were successfully identified by LC-(TIC/EIC)-MS analysis
of the crude reaction extract, which clearly confirmed our proposed
mechanism (Fig. 2).7
3. Conclusion
4.3.2. Experimental procedure for Scheme 3b. 1-(2-Oxo-2-(p-tolyl)
ethyl)pyridin-1-ium iodide 6b (678 mg, 2.0 mmol) and 2-(4-
methoxyphenyl)-2-oxoacetaldehyde 7b (164 mg, 1.0 mmol) were
placed in an oven-dried and argon filled Schlenk tube. After addi-
tion of anhydrous DMSO (5 mL), the mixture was stirred at 100 ꢀC
for 36 h. After the reaction completed, the mixture was diluted with
water and treated with Na2S2O3 (5% w/w, aq) until the color turned
to pale yellow. The mixture was then extracted with CH2Cl2
(3ꢂ20 mL), the combined organic extracts were dried over Na2SO4
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (eluent: CH2Cl2/
EtOAc¼150:1) to afford a yellow solid 8 (438 mg, 90%).
In summary, we have developed a direct metal-free protocol for
the efficient construction of 1,2,3-triaroylindolizines from simple
methyl ketones and pyridines. This reaction is the first example of
convergent integration of three domino sequences for the synthesis
of complex molecules from one substrate via self-division of labor
strategy. Further studies on the applications of this strategy will be
reported in due course.
4. Experimental section
4.1. General methods
All reagents were purchased from commercial suppliers and
used without further purification. 6a, 6b, 7a, 7b were synthesized
according to the literature method.1 Dimethyl sulfoxide was freshly
distilled at reduced pressure from calcium hydride. Reactions were
carried out under an argon atmosphere unless indicated otherwise.
IR spectra were recorded on an infrared spectrometer as KBr pellets
4.4. Spectroscopic data
4.4.1. Indolizine-1,2,3-triyltris(phenylmethanone)
solid; mp 201e203 ꢀC; 1H NMR (CDCl3, 400 MHz):
(3aa).4e Yellow
9.65 (d,
d
J¼6.8 Hz,1H), 8.05 (d, J¼9.2 Hz,1H), 7.46e7.41 (m, 3H), 7.38e7.33 (m,
4H), 7.29e7.25 (m, 3H), 7.17e7.13 (m, 5H), 7.03 (t, J¼7.2 Hz, 2H); 13C
with absorption in cmꢁ1
.
1H spectra were recorded in CDCl3 or
NMR (CDCl3,100 MHz): d 191.8,191.2,187.5,139.8,139.7,138.2,138.0,
DMSO-d6 on 400/600 MHz NMR spectrometers and resonances (
d
)
136.9, 132.6, 131.9, 131.8, 128.7, 128.64, 128.55, 127.94, 127.87, 127.8,
127.6, 122.1, 119.6, 116.1, 115.0; IR (KBr): 1667, 1628 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C29H20NO3: 430.1438; found: 430.1433.
are given in parts per million relative to tetramethylsilane. 13C
spectra were recorded in CDCl3 on 100/150 MHz spectrometers and
resonances (d) are given in ppm relative to the center line of a triplet
at 77.0 ppm of chloroform-d. MS was carried out on a Finnigan Trace
MS spectrometer (EI, 70 eV). HRMS were obtained on a FT-ICR MS
equipped with an electrospray source. The X-ray crystal-structure
determination of 3qa was obtained on a Bruker SMART APEX CCD
system. LCeMS analysis was performed on an Agilent 1200 Series
liquid chromatography, interfaced to an Agilent 6130 Quadruple
Mass Spectrometer. Column Used: Agilent ZORBAX SB-C18,
4.4.2. Indolizine-1,2,3-triyltris(p-tolylmethanone)
solid; mp 206e208 ꢀC; 1H NMR (CDCl3, 400 MHz):
(3ba).4e Yellow
9.56 (d,
d
J¼7.2 Hz,1H), 7.96 (d, J¼9.2 Hz,1H), 7.40e7.34 (m, 3H), 7.29e7.18 (m,
4H), 7.09 (t, J¼6.8 Hz, 1H), 6.99e6.94 (m, 4H), 6.85 (d, J¼8.0 Hz, 2H),
2.33 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
191.4, 190.6, 187.0, 143.1, 142.4, 142.3, 137.4, 137.0, 136.9, 136.5,
135.9, 128.8, 128.6, 128.5, 128.4, 128.3, 128.2, 127.5, 126.9, 122.0,
119.3, 115.6, 115.0, 21.4, 21.3, 21.2; IR (KBr): 1668, 1607 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C32H26NO3: 472.1907; found: 472.1904.
4.6ꢂ250 mm, 5
mm. The following mobile phase was applied: (A)
aqueous ammonium formate buffer (pH 3.5); (B) acetonitrile. Col-
umn chromatography was performed on silica gel (200e300 mesh).
4.4.3. Indolizine-1,2,3-triyltris([1,10-biphenyl]-4-ylmethanone) (3ca).4d
4.2. General experimental procedure for the preparation of
1,2,3-triaroylindolizines (3aa as an example)
Yellow solid; mp 143e145 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.68 (d,
J¼6.8 Hz, 1H), 8.09 (d, J¼9.2 Hz, 1H), 7.61e7.34 (m, 26H), 7.28e7.26
(m, 2H), 7.17 (t, J¼6.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d 191.5,
Acetophenone 1a (120 mg, 1.0 mmol), pyridine 2a (158 mg,
2.0 mmol), and iodine (254 mg, 1.0 mmol) were placed in an oven-
dried and argon filled Schlenk tube. After addition of anhydrous
DMSO (5 mL), the mixture was stirred at 100 ꢀC for 36 h. After the
reaction completed, the mixture was diluted with water and
treated with Na2S2O3 (5% w/w, aq) until the color turned to pale
yellow. The mixture was then extracted with CH2Cl2 (3ꢂ20 mL), the
combined organic extracts were dried over Na2SO4 and concen-
trated under reduced pressure. The crude product was purified by
column chromatography on silica gel (eluent: CH2Cl2/
EtOAc¼200:1) to afford a yellow solid 3aa (122 mg, 85%).
190.7, 187.1, 145.1, 144.6, 144.5, 139.71, 139.69, 139.5, 138.6, 138.4,
137.9, 137.2, 137.1, 129.4, 129.3, 129.2, 128.8, 128.7, 128.2, 127.9, 127.6,
127.04, 127.01, 126.98, 126.6, 126.44, 126.35, 122.2, 119.6, 116.1,
115.3; IR (KBr): 1628, 1601 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C47H32NO3: 658.2377; found: 658.2351.
4.4.4. Indolizine-1,2,3-triyltris((2-methoxyphenyl)methanone) (3da).
Light yellow solid; mp 195e196 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
10.08 (d, J¼7.2 Hz, 1H), 8.26 (d, J¼8.8 Hz, 1H), 7.50e7.45 (m, 1H),
7.32e7.28 (m, 1H), 7.17e6.99 (m, 6H), 6.66 (d, J¼8.0 Hz, 1H),
6.63e6.59 (m, 2H), 6.54 (d, J¼8.4 Hz, 1H), 6.49 (t, J¼7.2 Hz, 1H), 6.42
(d, J¼8.4 Hz, 1H), 3.55 (s, 3H), 3.53 (s, 3H), 3.52 (s, 3H); 13C NMR
4.3. Control experiment
(CDCl3, 100 MHz): d 189.8, 188.6, 185.9, 159.0, 156.5, 156.3, 143.3,
138.8,133.9,131.1,131.0,130.9,130.0,129.3, 129.1,128.9,128.8,128.7,
125.6, 121.1, 119.7, 119.5, 119.3, 119.1, 116.0, 114.3, 110.8, 110.3, 110.0,
55.2, 55.1, 55.0; IR (KBr): 1640,1610 cmꢁ1; HRMS (ESI): m/z [MþH]þ
calcd for C32H26NO6: 520.1755; found: 520.1748.
4.3.1. Experimental procedure for Scheme 3a. 1-(2-Oxo-2-
phenylethyl)pyridine-1-ium iodide 6a (650 mg, 2.0 mmol) and
phenylglyoxal 7a (134 mg, 1.0 mmol) were placed in an oven-dried

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Y. Yang et al. / Tetrahedron 68 (2012) 7338e7344
4.4.5. Indolizine-1,2,3-triyltris((3-methoxyphenyl)methanone) (3ea).
Yellow solid; mp 121e122 ꢀC; 1H NMR (CDCl3, 400 MHz):
9.59 (d,
J¼7.2 Hz, 1H), 8.21 (d, J¼9.0 Hz, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.66 (d,
J¼8.4 Hz, 1H), 7.63 (d, J¼7.8 Hz,1H), 7.56 (d, J¼7.8 Hz,1H), 7.53e7.46
(m, 6H), 7.42e7.36 (m, 6H), 7.29 (d, J¼8.4 Hz,1H), 7.23e7.18 (m, 3H),
7.12 (t, J¼7.2 Hz, 1H), 6.96 (d, J¼7.2 Hz, 1H); 13C NMR (CDCl3,
d
J¼7.2 Hz, 1H), 8.09 (d, J¼8.8 Hz, 1H), 7.41 (t, J¼8.0 Hz, 1H), 7.14e7.10
(m, 2H), 7.07e7.01 (m, 3H), 6.95e6.82 (m, 7H), 6.67 (s, 1H), 3.65 (s,
3H), 3.64 (s, 3H), 3.58 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
191.3,
100 MHz): d 191.6, 191.1, 187.3, 138.3, 137.5, 137.1, 137.0, 135.5, 134.8,
190.9, 187.1, 159.1, 158.9, 141.17, 141.16, 139.8, 137.9, 136.7, 128.9,
128.7, 127.8, 127.6, 122.3, 122.1, 121.54, 121.53, 119.7, 119.6, 118.79,
118.78, 116.1, 115.0, 112.3, 111.3, 55.05, 55.03, 54.9; IR (KBr): 1661,
1635, 1583 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C32H26NO6:
520.1755; found: 520.1750.
134.6, 134.4, 131.8, 131.6, 131.3, 130.5, 130.4, 130.3, 129.2, 128.7,
128.4, 128.3, 128.12, 128.07, 127.9, 127.7, 127.5, 127.32, 127.28, 127.2,
126.30, 126.26,124.3, 124.0, 123.4, 122.5, 119.7, 116.2,115.4; IR (KBr):
1659, 1621 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C41H26NO3:
580.1907; found: 580.1899.
4.4.6. Indolizine-1,2,3-triyltris((4-methoxyphenyl)methanone) (3fa).4e
4.4.12. Indolizine-1,2,3-triyltris((4-chlorophenyl)methanone) (3la).4e
Yellow solid; mp 131e132 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.47
Yellow solid; mp 183e184 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.63 (d,
(d, J¼7.2 Hz, 1H), 7.98 (d, J¼9.2 Hz, 1H), 7.51 (d, J¼8.8 Hz, 2H),
7.40 (d, J¼8.4 Hz, 2H), 7.37e7.32 (m, 3H), 7.06 (t, J¼6.8 Hz, 1H),
6.69e6.64 (m, 4H), 6.57 (d, J¼8.4 Hz, 2H), 3.81 (s, 3H), 3.77 (s,
J¼7.2 Hz, 1H), 7.97 (d, J¼8.8 Hz, 1H), 7.49e7.43 (m, 3H), 7.30e7.25
(m, 4H), 7.21e7.17 (m, 5H), 7.07 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3,
150 MHz):
d 190.7, 189.5, 185.9, 139.6, 138.6, 138.4, 138.03, 137.97,
3H), 3.73 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
190.6, 190.1, 186.4,
137.8, 136.49, 136.46, 130.2, 130.0, 129.8, 128.43, 128.41, 128.21,
128.15, 128.1, 121.8, 119.5, 116.5, 114.9; IR (KBr): 1669, 1614,
1587 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C29H17Cl3NO3:
532.0269; found: 532.0261.
163.1, 162.7, 137.5, 136.2, 132.8, 132.6, 132.1, 131.2, 131.0, 130.9,
127.68, 126.70, 122.2, 119.6, 115.5, 115.1, 113.2, 55.4, 55.3; IR (KBr):
1657, 1596 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C32H26NO6:
520.1755; found: 520.1747.
4.4.13. Indolizine-1,2,3-triyltris((4-bromophenyl)methanone) (3ma).4d
4.4.7. Indolizine-1,2,3-triyltris((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)
Yellow solid; mp 188e190 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.25 (d,
J¼7.2 Hz, 1H), 7.95 (d, J¼9.2 Hz, 1H), 7.48e7.44 (m, 1H), 7.39e7.37
(m, 6H), 7.24e7.16 (m, 7H); 13C NMR (CDCl3, 100 MHz):
190.9,
methanone) (3ga). Brown-yellow solid; mp 211e213 ꢀC; 1H NMR
(CDCl3, 400 MHz):
d
9.47 (d, J¼7.2 Hz, 1H), 7.99 (d, J¼8.8 Hz, 1H),
d
7.37e7.33 (m, 1H), 7.08e7.02 (m, 3H), 6.97e6.91 (m, 3H), 6.81 (d,
J¼2.0 Hz,1H), 6.69e6.64 (m, 2H), 6.56 (d, J¼8.8 Hz,1H), 4.28e4.12 (m,
189.6, 186.0, 138.3, 138.2, 138.0, 136.8, 136.5, 131.41, 131.37, 131.2,
130.3, 130.1, 129.9, 128.5, 128.3, 128.2, 127.2, 127.0, 121.7, 119.5, 116.5,
114.8; IR (KBr): 1671, 1615, 1583 cmꢁ1; HRMS (ESI): m/z [MþH]þ
calcd for C29H17Br3NO3: 665.8734; found: 665.8719.
12H); 13C NMR (CDCl3, 100 MHz):
d 190.2, 189.7, 186.0, 147.5, 147.12,
147.09,143.0,142.9,142.7,137.4,136.4,133.5,133.4,132.8,127.6,126.8,
123.4, 123.2, 122.1, 119.5, 117.9, 117.7, 117.2, 116.5, 116.4, 115.6, 115.1,
64.5, 64.4, 64.3, 63.8; IR (KBr): 1656,1623,1600 cmꢁ1; HRMS (ESI): m/
z [MþH]þ calcd for C35H26NO9: 604.1602; found: 604.1600.
4.4.14. Indolizine-1,2,3-triyltris((4-fluorophenyl)methanone) (3na).
Yellow solid; mp 185e187 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.59 (d,
J¼7.2 Hz, 1H), 7.99 (d, J¼9.2 Hz, 1H), 7.54e7.50 (m, 2H), 7.47e7.43
4.4.8. Indolizine-1,2,3-triyltris((4-morpholinophenyl)methanone)
(m, 1H), 7.40e7.35 (m, 4H), 7.19e7.15 (m, 1H), 6.91e6.87 (m, 4H),
(3ha). Yellow solid; mp 170e171 ꢀC; 1H NMR (CDCl3, 600 MHz):
6.77 (t, J¼8.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
d 190.3, 189.4,
d
9.38 (d, J¼6.6 Hz, 1H), 7.91 (d, J¼9.0 Hz, 1H), 7.52 (d, J¼8.4 Hz, 2H),
185.8, 166.7, 166.3, 166.1, 164.1, 163.7, 163.6, 138.0, 136.3, 136.05,
136.02, 135.88, 135.86, 134.73, 134.71, 131.3, 131.24, 131.16, 131.1,
128.0, 121.8, 119.5, 116.3, 115.4, 115.3, 115.2, 115.1, 115.0, 114.8; IR
(KBr): 1675, 1618, 1596 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C29H17F3NO3: 484.1155; found: 484.1146.
7.41 (d, J¼8.4 Hz, 2H), 7.32 (d, J¼8.4 Hz, 2H), 7.29e7.27 (m, 1H), 7.00
(t, J¼7.2 Hz, 1H), 6.64 (d, J¼8.4 Hz, 2H), 6.58 (d, J¼8.4 Hz, 2H), 6.53
(d, J¼8.4 Hz, 2H), 3.85e3.79 (m, 12H), 3.23e3.15 (m, 12H); 13C NMR
(CDCl3, 100 MHz):
d 190.0, 189.4, 185.8, 153.5, 153.4, 136.8, 135.5,
130.9, 130.7, 130.5, 130.3, 130.2, 130.0, 127.2, 125.7, 122.2, 119.3,
115.0, 114.8, 112.9, 112.8, 112.6, 66.22, 66.18, 47.4, 47.3; IR (KBr):
1595 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C41H41N4O6:
685.3021; found: 685.3008.
4.4.15. Indolizine-1,2,3-triyltris(furan-2-ylmethanone) (3oa). Yellow
solid; mp 177e178 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.37 (d,
J¼7.2 Hz, 1H), 8.19 (d, J¼8.8 Hz, 1H), 7.48 (s, 1H), 7.43e7.39 (m, 1H),
7.29e7.24 (m, 2H), 7.11e7.04 (m, 3H), 6.97 (d, J¼3.2 Hz, 1H),
4.4.9. Indolizine-1,2,3-triyltris((4-nitrophenyl)methanone) (3ia).4d
6.42e6.40 (m, 3H); 13C NMR (CDCl3, 100 MHz):
d 178.6, 177.4, 173.3,
Yellow solid; mp 276e277 ꢀC; 1H NMR (DMSO-d6, 400 MHz):
d
9.59
153.5, 153.0, 152.6, 146.7, 146.0, 145.7, 137.6, 133.2, 127.22, 127.17,
127.1, 121.2, 119.7, 118.6, 117.9, 116.1, 113.5, 112.6, 112.4, 112.3; IR
(KBr): 1651, 1630, 1607 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C23H14NO6: 400.0816; found: 400.0808.
(d, J¼7.2 Hz, 1H), 8.17 (d, J¼8.0 Hz, 2H), 8.09 (d, J¼8.0 Hz, 2H), 7.93
(d, J¼8.0 Hz, 2H), 7.76 (d, J¼8.4 Hz, 2H), 7.72e7.68 (m, 2H),
7.66e7.58 (m, 4H), 7.47e7.44 (m, 1H); 13C NMR spectrum could not
be obtained due to the poor solubility; IR (KBr): 1676, 1616,
1598 cmꢁ1; MS (EI): m/z (%): 564.33 (100).
4.4.16. Indolizine-1,2,3-triyltris(benzofuran-2-ylmethanone) (3pa).
Brown-yellow solid; mp 207e209 ꢀC; 1H NMR (CDCl3, 400 MHz):
4.4.10. Indolizine-1,2,3-triyltris(naphthalen-1-ylmethanone) (3ja). -
Brown-yellow solid; mp 132e133 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.60 (d, J¼7.2 Hz, 1H), 8.40 (d, J¼9.2 Hz, 1H), 7.56e7.49 (m, 4H),
7.43e7.34 (m, 4H), 7.28e7.14 (m, 6H), 6.96 (br s, 1H), 6.82 (d,
J¼8.0 Hz, 1H), 6.89e6.66 (m, 1H); 13C NMR (CDCl3, 100 MHz):
d
10.00 (d, J¼7.2 Hz,1H), 8.07e7.86 (m, 4H), 7.53e7.16 (m, 16H), 7.08
(t, J¼7.6 Hz, 1H), 7.01 (t, J¼7.6 Hz, 1H), 6.91e6.82 (m, 2H); 13C NMR
d 180.3, 178.7, 174.4, 155.2, 154.7, 153.1, 152.9, 152.5, 138.2, 134.3,
(CDCl3, 150 MHz):
d
192.4, 191.7, 187.8, 140.6, 138.6, 137.5, 136.7,
128.3, 127.7, 127.6, 127.5, 127.4, 126.8, 126.7, 126.4, 123.81, 123.76,
123.6, 123.0, 122.8, 121.5, 119.8, 116.7, 113.8, 113.1, 112.1, 111.6, 111.5;
IR (KBr): 1650, 1610 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C35H20NO6: 550.1285; found: 550.1278.
133.8,133.7,133.0,132.7,132.6,132.4,131.1,131.0,129.9,129.8,129.4,
128.6, 128.5, 128.0, 127.70, 127.65, 127.4, 127.3, 127.2, 126.8, 126.7,
125.9, 125.8, 125.7, 125.6, 125.0, 124.7, 123.8, 123.4, 123.1, 122.9,
119.6, 116.4; IR (KBr): 1652, 1631, 1609 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C41H26NO3: 580.1907; found: 580.1897.
4.4.17. Indolizine-1,2,3-triyltris(thiophen-2-ylmethanone) (3qa).
Yellow solid; mp 214e215 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.30 (d,
4.4.11. Indolizine-1,2,3-triyltris(naphthalen-2-ylmethanone) (3ka).4d
J¼7.2 Hz, 1H), 8.07 (d, J¼9.2 Hz, 1H), 7.54e7.51 (m, 3H), 7.43e7.33
Yellow solid; mp 119e121 ꢀC; 1H NMR (CDCl3, 600 MHz):
d 9.76 (d,
(m, 4H), 7.11e7.07 (m, 1H), 6.99e6.97 (m, 1H), 6.91e6.89 (m, 1H),

Y. Yang et al. / Tetrahedron 68 (2012) 7338e7344
7343
6.85e6.82 (m, 1H); 13C NMR (CDCl3, 100 MHz):
d
183.6, 182.6, 178.8,
d
7.90e7.84 (m, 3H), 7.80 (d, J¼7.6 Hz, 1H), 7.72 (d, J¼8.0 Hz, 1H),
7.55 (d, J¼9.6 Hz, 1H), 7.50e7.41 (m, 5H), 7.37e7.29 (m, 6H),
7.19e7.11 (m, 4H); 13C NMR (CDCl3, 100 MHz):
191.8, 191.3, 189.4,
146.4, 145.3, 144.9, 137.1, 135.1, 134.11, 134.06, 133.9, 133.7, 133.6,
128.0, 127.41, 127.35, 127.32, 127.28, 126.9, 122.0, 119.6, 115.9, 114.7;
IR (KBr): 1647, 1603 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C23H14NO3S3: 448.0130; found: 448.0124.
d
140.1, 138.5, 137.6, 135.9, 133.8, 132.4, 132.2, 131.9, 129.5, 129.2,
128.9, 128.7, 128.5, 128.0, 127.9,127.3, 125.7,125.4, 118.5, 117.7,115.8;
IR (KBr): 1656, 1601 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C33H22NO3: 480.1594; found: 480.1587.
4.4.18. Methyl 1,2,3-tribenzoylindolizine-7-carboxylate (3ab).4d
Light yellow solid; mp 137e138 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.51 (d, J¼7.2 Hz, 1H), 8.74 (s, 1H), 7.66e7.64 (m, 1H), 7.46e7.25
4.4.25. Pyrrolo[1,2-b]isoquinoline-1,2,3-triyltris(phenylmethanone)
(m, 9H), 7.17e7.13 (m, 4H), 7.06 (t, J¼7.6 Hz, 2H), 3.97 (s, 3H); 13C
(3ai).4e Light yellow solid; mp 212e213 ꢀC; 1H NMR (CDCl3,
NMR (CDCl3, 100 MHz):
d
191.2, 191.1, 187.7, 164.9, 139.4, 139.3,
400 MHz):
J¼7.6 Hz, 2H), 7.74 (d, J¼8.0 Hz, 1H), 7.54 (t, J¼7.6 Hz, 1H), 7.45e7.21
(m, 11H), 7.12e7.06 (m, 4H); 13C NMR (CDCl3, 100 MHz):
194.5,
d
9.10 (d, J¼7.6 Hz, 1H), 8.08 (d, J¼8.0 Hz, 1H), 7.80 (d,
138.2, 136.5, 136.3, 132.8, 132.4, 132.3, 128.8, 128.7, 128.6, 128.1,
128.04, 127.95, 127.2, 123.3, 122.2, 117.7, 114.9, 52.7; IR (KBr): 1728,
1649, 1620, 1597 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C31H22NO5: 488.1493; found: 488.1485.
d
191.6, 187.4, 140.2, 138.9, 138.3, 133.6, 133.4, 132.4, 132.2, 131.8,
129.51, 129.0, 128.7, 128.6, 128.4, 128.2, 128.0, 127.9, 127.3, 125.1,
124.1, 123.8, 123.5, 118.6, 115.9; IR (KBr): 1659, 1616, 1597 cmꢁ1
;
4.4.19. 1,2,3-Tribenzoylindolizine-7-carbonitrile (3ac). Yellow solid;
HRMS (ESI): m/z [MþH]þ calcd for C33H22NO3: 480.1594; found:
mp 210e211 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.49 (d, J¼7.6 Hz,
480.1589.
1H), 8.43 (s, 1H), 7.43e7.23 (m, 9H), 7.18e7.14 (m, 5H), 7.06 (t,
J¼7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
d
190.7, 187.5, 138.9,
4.4.26. Methyl 1,2,3-tribenzoylindolizine-6-carboxylate (4aj).4d
Light yellow solid; mp 204e205 ꢀC; 1H NMR (CDCl3, 600 MHz):
137.9, 136.4, 134.9, 133.0, 132.6, 128.7, 128.5, 128.14, 128.07, 126.0,
123.8, 117.5, 116.9, 115.3, 109.4; IR (KBr): 2227, 1672, 1622,
1597 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C30H19N2O3:
455.1390; found: 455.1381.
d
10.23 (s, 1H), 8.00 (d, J¼9.0 Hz, 1H), 7.91 (d, J¼9.0 Hz, 1H), 7.48 (d,
J¼7.2 Hz, 2H), 7.39e7.36 (m, 4H), 7.31e7.27 (m, 3H), 7.19e7.14 (m,
4H), 7.06 (t, J¼7.8 Hz, 2H), 3.99 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
191.3, 190.9, 187.5, 164.8, 139.4, 138.2, 138.1, 137.9, 132.9, 132.3,
4.4.20. (7-Methoxyindolizine-1,2,3-triyl)tris(phenylmethanone) (3ad).
131.71, 131.68, 128.83, 128.79, 128.6, 128.2, 128.1, 128.0, 126.6, 123.0,
119.6, 119.2, 115.7, 52.7; IR (KBr): 1722, 1677, 1626 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C31H22NO5: 488.1493; found: 488.1484.
Yellow solid; mp 191e192 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.55
(d, J¼7.6 Hz, 1H), 7.55 (s, 1H), 7.36e7.22 (m, 9H), 7.15e7.06 (m,
4H), 7.00 (t, J¼7.2 Hz, 2H), 6.85e6.84 (m, 1H), 3.91 (s, 3H); 13C
NMR (CDCl3, 100 MHz):
d
191.8, 187.2, 160.1, 141.2, 140.3, 140.1,
4.4.27. Methyl 1,2,3-tribenzoylindolizine-8-carboxylate (5aj).4d
Light yellow solid; mp 215e216 ꢀC; 1H NMR (CDCl3, 600 MHz):
138.4, 137.7, 132.6, 131.6, 131.5, 129.5, 128.6, 128.5, 127.88, 127.85,
127.82, 121.6, 113.3, 110.5, 97.4, 55.8; IR (KBr): 1678, 1647, 1620,
1599 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C30H22NO4:
460.1543; found: 460.1535.
d
9.76 (d, J¼7.2 Hz, 1H), 7.84 (d, J¼7.2 Hz, 1H), 7.67 (d, J¼7.2 Hz, 2H),
7.39 (t, J¼7.2 Hz, 1H), 7.34 (t, J¼7.2 Hz, 1H), 7.31e7.21 (m, 7H),
7.15e7.10 (m, 3H), 7.05 (t, J¼7.2 Hz, 2H), 3.45 (s, 3H); 13C NMR
(CDCl3, 100 MHz):
d 191.8, 191.6, 187.1, 165.3, 139.9, 138.4, 138.3,
4.4.21. (6,8-Dimethylindolizine-1,2,3-triyl)tris(phenylmethanone) (3ae).
136.4, 132.7, 132.4, 132.0, 130.6, 129.4, 129.0, 128.8, 128.7, 128.2,
128.0, 127.9, 123.7, 121.5, 117.3, 114.4, 51.9; IR (KBr): 1725, 1664,
Yellow solid; mp 82e83 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.40 (s,
1H), 7.64 (d, J¼7.6 Hz, 2H), 7.37e7.17 (m, 9H), 7.08 (t, J¼7.6 Hz, 2H),
1622 cmꢁ1
;
HRMS (ESI): m/z [MþH]þ calcd for C31H22NO5:
7.03e6.98 (m, 3H), 2.38 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3,
488.1493; found: 488.1477.
100 MHz):
d 193.0, 191.8, 186.9, 140.6, 139.0, 138.6, 134.9, 134.2,
132.8, 132.2, 131.4, 129.9, 129.3, 128.6, 128.5, 128.0, 127.7, 127.6,
4.4.28. (6-Methylindolizine-1,2,3-triyl)tris(phenylmethanone) (4ak),
(8-methylindolizine-1,2,3-triyl)tris(phenylmethanone)
(5ak). Chromatographic purification of the crude reaction afforded
a mixture of indolizines 4ak and 5ak (1:3.3). Yellow solid; 1H NMR
125.5, 123.0, 120.7, 116.8, 20.3, 18.3; IR (KBr): 1658, 1619,1598 cmꢁ1
;
HRMS (ESI): m/z [MþH]þ calcd for C31H24NO3: 458.1751; found:
458.1740.
(CDCl3, 400 MHz):
J¼9.2 Hz, 1H), 7.65 (d, J¼7.8 Hz, 2H), 7.44e7.00 (m, 31H), 2.44 (s,
3H), 2.31 (s, 3H); 13C NMR (CDCl3, 100 MHz):
193.2, 191.9, 191.2,
d
9.56 (d, J¼7.8 Hz, 1H), 9.46 (s, 1H), 7.65 (d,
4.4.22. (6,8-Dichloroindolizine-1,2,3-triyl)tris(phenylmethanone)
(3af). Yellow solid; mp 171e172 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
d
9.64 (s, 1H), 7.76 (d, J¼7.8 Hz, 2H), 7.48 (t, J¼7.2 Hz, 1H), 7.35e7.26
187.5,187.1,140.6,140.0,139.9,139.1,138.6,138.4,136.8,136.6,135.5,
135.3, 132.9, 132.5, 132.4, 131.8, 131.7, 131.6, 130.7, 129.6, 129.5,
128.8, 128.65, 128.60, 128.1, 127.9, 127.84, 127.76, 126.7, 126.2, 125.8,
125.4, 121.9, 121.1, 119.0, 117.1, 115.6, 114.9, 20.6, 18.6; IR (KBr): 1656,
1613 cmꢁ1; HRMS (ESI) (mixture of 4ai and 5ai): m/z [MþH]þ calcd
for C30H22NO3: 444.1594; found: 444.1589.
(m, 7H), 7.18e7.07 (m, 6H); 13C NMR (CDCl3, 100 MHz):
d
191.6,
191.0, 186.9, 139.8, 138.8, 138.4, 135.2, 133.3, 132.8, 132.3, 130.1,
129.5, 128.8, 128.7, 128.3, 128.1, 127.9, 126.2, 125.6, 123.9, 122.8,
122.0, 118.2; IR (KBr): 1672, 1659, 1618 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C29H18Cl2NO3: 498.0658; found: 498.0646.
4.4.23. (6,8-Dibromoindolizine-1,2,3-triyl)tris(phenylmethanone) (3ag).
4.4.29. (6-Chloroindolizine-1,2,3-triyl)tris(phenylmethanone) (4al).
Light yellow solid; mp 161e162 ꢀC; 1H NMR (CDCl3, 400 MHz):
Yellow solid; mp 206e208 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.77
(s, 1H), 7.77 (d, J¼7.6 Hz, 2H), 7.59 (s, 1H), 7.48 (t, J¼7.6 Hz, 1H),
d
9.70 (s, 1H), 8.00 (d, J¼9.6 Hz, 1H), 7.44e7.24 (m, 10H), 7.17e7.12
7.36e7.26 (m, 6H), 7.17e7.06 (m, 6H); 13C NMR (CDCl3,
(m, 4H), 7.04 (t, J¼8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
d 191.3,
100 MHz):
d
191.9, 191.1, 186.9, 139.8, 139.1, 138.4, 135.0, 133.4,
191.0, 187.5, 139.51, 139.48, 138.2, 136.6, 135.9, 132.8, 132.2, 132.1,
128.72, 128.67, 128.6, 128.03, 127.97, 127.93, 125.7, 124.5, 122.1,
120.0, 115.6; IR (KBr): IR (KBr): 1667, 1627, 1597 cmꢁ1; HRMS (ESI):
m/z [MþH]þ calcd for C29H19ClNO3: 464.1048; found: 464.1042.
132.8, 132.3, 131.6, 130.9, 129.6, 128.8, 128.7, 128.4, 128.2, 127.9,
126.4, 121.7, 119.1, 112.9, 109.3; IR (KBr): 1672, 1659, 1615 cmꢁ1
;
HRMS (ESI): m/z [MþH]þ calcd for C29H18Br2NO3: 587.9630;
found: 587.9623.
4.4.30. (8-Chloroindolizine-1,2,3-triyl)tris(phenylmethanone) (5al).
4.4.24. Pyrrolo[1,2-a]quinoline-1,2,3-triyltris(phenylmethanone) (3ah).4e
Yellow solid; mp 172e173 ꢀC; 1H NMR (CDCl3, 400 MHz):
Yellow solid; mp 168e169 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.56 (d,
J¼7.2 Hz, 1H), 7.77 (d, J¼8.4 Hz, 2H), 7.46 (t, J¼7.2 Hz, 1H), 7.34e7.18

7344
Y. Yang et al. / Tetrahedron 68 (2012) 7338e7344
(m, 9H), 7.11e7.05 (m, 4H), 6.98 (t, J¼7.2 Hz, 1H); 13C NMR (CDCl3,
Supplementary data
100 MHz): d 192.1, 191.4, 186.9, 140.1, 139.0, 138.5, 135.2, 133.1, 132.6,
132.0,131.9,129.5,128.8,128.6,128.2,128.0,127.8,126.0,125.4,125.2,
121.8, 117.5, 114.8; IR (KBr): 1659, 1633, 1596 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C29H19ClNO3: 464.1048; found: 464.1043.
The general experimental methods and the characterizing data
including 1H NMR, 13C NMR, IR, and HRMS for compound 4 are
available in Supplementary data. Supplementary data associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tet.2012.06.091.
4.4.31. (6-Bromoindolizine-1,2,3-triyl)tris(phenylmethanone) (4am).
Light yellow solid; mp 160e162 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
9.79 (s, 1H), 7.94 (d, J¼9.6 Hz, 1H), 7.47 (d, J¼9.6 Hz, 1H), 7.43 (d,
J¼7.8 Hz, 2H), 7.38e7.34 (m, 4H), 7.29e7.24 (m, 3H), 7.16e7.13 (m,
References and notes
4H), 7.04 (t, J¼7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
d 191.3, 191.0,
1. For reviews on domino reactions, see: (a) Tietze, L. F.; Brasche, G.; Gericke, K.
187.5,139.5,138.2,136.5,136.1,132.8,132.2,132.1,130.7,128.8,128.7,
128.6, 128.1, 128.00, 127.97, 127.9, 122.1, 120.2, 115.7, 111.2; IR (KBr):
1667, 1627, 1597 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C29H19BrNO3: 508.0543; found: 508.0536.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006;
ꢀ
(b) Zhu, J. P.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
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4.4.32. (8-Bromoindolizine-1,2,3-triyl)tris(phenylmethanone) (5am).
Yellow solid; mp 177e178 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.62 (d,
J¼7.2 Hz, 1H), 7.79 (d, J¼7.6 Hz, 2H), 7.49e7.44 (m, 2H), 7.35e7.17 (m,
8H), 7.11e7.04 (m, 4H), 6.91 (t, J¼7.2 Hz, 1H); 13C NMR (CDCl3,
150 MHz): d 192.4, 191.5, 186.9, 140.2, 139.3, 138.5, 135.2, 133.1, 132.6,
132.5, 132.0, 129.6, 129.1, 128.8, 128.6, 128.2, 128.0, 127.8, 126.5, 121.6,
118.3, 115.1, 112.6; IR (KBr): 1661, 1620, 1597 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C29H19BrNO3: 508.0543; found: 508.0536.
3. For reviews, see: (a) Flitsch, W. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996;
Vol. 8; (b) Behnisch, A.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T. In In-
dolizine; Houben-Weyl, Ed.; 1994; Vol. E6b/1(2a), pp 323e450; (c) Michael, J. P.
Alkaloids 2001, 55, 91e258; (d) Shipman, M. Sci. Synth. 2001, 10, 745e787; (e)
Micheal, J. P. Nat. Prod. Rep. 2008, 25, 139e165.
4.4.33. (6-Hydroxyindolizine-1,2,3-triyl)tris(phenylmethanone) (5an).
Yellow solid; mp 149e150 ꢀC; 1H NMR (CDCl3, 600 MHz):
d 11.83 (s,
1H), 9.02 (d, J¼7.2 Hz, 1H), 7.37 (t, J¼7.2 Hz, 1H), 7.32 (d, J¼7.8 Hz,
2H), 7.25e7.20 (m, 4H), 7.18e7.12 (m, 5H), 7.02e6.99 (m, 3H),
6.97e6.94 (m, 2H); 13C NMR (CDCl3, 100 MHz):
d 195.0, 190.9, 188.0,
4. For reviews and selected recent examples: (a) Uchida, T.; Matsumoto, K.
Synthesis 1976, 209e236; (b) Katritzky, A. R.; Qiu, G.; Yang, B.; He, H.-Y. J. Org.
150.6, 139.9, 139.3, 138.3, 136.7, 132.9, 132.3, 131.8, 128.72, 128.69,
128.5, 127.94, 127.89, 127.7, 124.3, 119.6, 118.2, 113.6, 112.2; IR (KBr):
3445, 3424, 1662, 1629, 1595, 1573 cmꢁ1; HRMS (ESI): m/z [MþH]þ
calcd for C29H20NO4: 446.1387; found: 446.1377.
€
Chem. 1999, 64, 7618e7621 and references cited therein; (c) Schutze, D.-I.;
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Krohnke, F. Liebigs Ann. 1973, 765, 20e28; (d) Wei, X.; Hu, Y.; Li, T.; Hu, H.
Synth. Commun. 1992, 22, 2103e2109; (e) Mao, Z.; Li, X.; Lin, X.; Lu, P.; Wang, Y.
Tetrahedron 2012, 68, 85e91; (f) Zhang, L.; Liang, F.; Sun, L.; Hu, Y.; Hu, H.
Synthesis 2000, 1733e1737; (g) Kaloko, J.; Hayford, A. Org. Lett. 2005, 7,
4305e4308; (h) Yavari, I.; Hossaini, Z.; Sabbaghan, M. Tetrahedron Lett. 2006,
47, 6037e6040; (i) Wasnaire, P.; de Merode, T.; Marko, I. E. Chem. Commun.
2007, 4755e4757; (j) Barluenga, J.; Lonzi, G.; Riesgo, L.; Lopez, L. A.; Tomas, M.
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4.4.34. (2-(4-Methoxybenzoyl)indolizine-1,3-diyl)bis(p-tolylmetha-
none) (8). Yellow solid; mp 189e190 ꢀC; 1H NMR (CDCl3,
400 MHz):
d
9.57 (d, J¼6.8 Hz, 1H), 7.98 (d, J¼9.2 Hz, 1H), 7.41e7.27
(m, 7H), 7.08 (t, J¼6.8 Hz, 1H), 6.98 (d, J¼7.2 Hz, 2H), 6.86 (d,
J¼7.2 Hz, 2H), 6.63 (d, J¼8.4 Hz, 2H), 3.82 (s, 3H), 2.29 (s, 3H), 2.34
(s, 3H); 13C NMR (CDCl3, 100 MHz):
d 191.0, 190.4, 187.4, 163.1, 142.6,
142.4,137.8,137.3,137.2,136.8,132.1,131.0,129.0,128.8,128.6,128.5,
127.9, 127.0, 122.2, 119.6, 115.7, 115.1, 113.0, 55.4, 21.5, 21.4; IR (KBr):
1656, 1600 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C32H26NO4:
488.1856; found: 488.1848.
5. CCDC 827627 (3qa) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
6. Liu, Y.; Zhang, Y.; Shen, Y.-M.; Hu, H.-W.; Xu, J.-H. Org. Biomol. Chem. 2010, 8,
2449e2456.
7. For more details, see Supplementary data.
Acknowledgements
8. (a) For the preparation of 6a, 6b, see: King, L. C.; McWhirter, M.; Rowland, R. L. J.
Am. Chem. Soc. 1948, 70, 239e242; (b) For the preparation of 7a, 7b, see: Riley,
H. A.; Gray, A. R. Organic Syntheses; Wiley & Sons: New York, NY, 1943; Collect.
Vol. No. II; p 509.
We thank the National Natural Science Foundation of China
(Grant 20872042 and 21032001).
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