Palladium-Catalyzed Oxidative Cyclization for the Synthesis of 2-Alkylimidazo[5,1,2-cd]indolizines

Article abstract of DOI:10.1002/ejoc.201601019

An effective palladium-catalyzed direct arylation of 2-alkyl-imidazo[1,2-a]pyridine with alkynes towards imidazo[5,1,2-cd]indolizines through double C–H functionalization was developed. The catalyst system is an ionic palladium(II) complex bearing amido-functionalized N-heterocyclic carbene and triphenylphosphine ligands. A mere 2.5 mol-% loading of palladium was sufficient for catalyzing the reactions. Copper acetate and n-tetrabutylammonium bromide were employed as oxidant and phase-transfer catalyst, respectively. Beside imidazo[1,2-a]pyridine, desirably, less electron-rich derivatives could be employed as coupling partners. Also a wide range of diarylalkynes was used. The structure of one 2-alkyl-imidazo[5,1,2-cd]indolizine was established by single-crystal X-ray diffraction analysis. UV and PL spectra of the compounds confirmed that some are highly fluorescent. The method provides an easy synthetic route for the preparation of these new fluorescent materials.

Full text of DOI:10.1002/ejoc.201601019

A Journal of
Accepted Article
Title: Palladium-Catalyzed Oxidative Cyclization for the Synthesis of 2-Alkyl-
Imidazo[5,1,2-cd]indolizines
Authors: Sanjay Kumar Ghosh; Debalina Ghosh; Ratnava Maitra; Ya-Ting Kuo; Hon
Man Lee
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601019
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European Journal of Organic Chemistry
10.1002/ejoc.201601019
Palladium-Catalyzed Oxidative Cyclization for the Synthesis of 2-Alkyl-Imidazo[5,1,2-cd]indolizines
Sanjay Kumar Ghosh, Debalina Ghosh, Ratnava Maitra, Ya-Ting Kuo and Hon Man Lee*
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan, R.O.C.
*E-mail: leehm@cc.ncue.edu.tw
An effective palladium-catalyzed direct arylation of 2-alkyl-imidazo[1,2-a]pyridine with alkyne via
double C–H functionalization to yield 2-alkyl-imidazo[5,1,2-cd]indolizines was successfully developed. The
catalyst precursor used was an ionic palladium(II) complex bearing amido-functionalized N-heterocyclic
carbene and triphenylphosphine ligands.
Key Topic: Organometallic Chemistry
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European Journal of Organic Chemistry
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Palladium-Catalyzed Oxidative Cyclization for the Synthesis of 2-Alkyl-Imidazo[5,1,2-cd]indolizines
Sanjay Kumar Ghosh, Debalina Ghosh, Ratnava Maitra, Ya-Ting Kuo and Hon Man Lee*
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan, R.O.C.
*E-mail: leehm@cc.ncue.edu.tw
Abstract
An effective palladium-catalyzed direct arylation of 2-alkyl-imidazo[1,2-a]pyridine with alkyne via
double C–H functionalization to yield imidazo[5,1,2-cd]indolizines was successfully developed. The
catalyst system comprised of an ionic palladium(II) complex bearing amido-functionalized N-heterocyclic
carbene and triphenylphosphine ligands. A mere 2.5 mol% of palladium loading was sufficient for
catalyzing the reactions. Copper acetate and n-tetrabutylammonium bromide were employed as oxidant and
phase transfer catalyst, respectively. Beside imidazo[1,2-a]pyridine, desirably, less electron-rich
imidazo[1,2-a]pyrimidine substrates could also be employed as coupling partners. Also a wide range of
diaryl alkynes could also be used. One of the 2-alkyl-imidazo[5,1,2-cd]indolizines has been successfully
established by single-crystal X-ray diffraction analysis. UV and PL spectra of these compounds confirmed
that some of these new compounds were highly fluorescent. The methodology developed provides an easy
synthetic route for the preparation of these new fluorescent materials.
Keywords: C–H Functionalization; Imidazo[5,1,2-cd]indolizines; N-heterocyclic Carbene; Homogeneous
Catalysis
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Introduction
Transition-metal-catalyzed C–H bond functionalization for the construction of fused polycyclic
heteroaromatic compounds have been receiving considerable attention.[1],[2],[3] This process provides a green
route to π-conjugated heteroaromatic molecules, which exhibit diversified biological and pharmacological
activities.[4] This class of compounds can have a wide range of applicability to organic electronics and
luminescent materials as well.[5] Previously, we have reported the use of an ionic palladium complex of N-
heterocyclic carbene (NHC), [PdL(PPh3)(H2O)2](SO3CF3)2 (1a) to catalyze the double C–H
functionalization of various nitrogen- and sulfur-containing heteroarenes to form fused polycyclic
heteroaromatic compounds with alkynes (Chart 1).[6] Interestingly, for the coupling reaction employing C2-
aryl imidazo[1,2-a]pyridine as substrate, beside the major linearly fused tetracyclic compounds,
imidazo[5,1,2-cd]indolizine featuring a fused tricyclic core was also obtained as minor product. The
formation of these two kinds of products can be explained by the possible formation of two different
palladacycle intermediates via two possible sites of C–H activation. Imidazo[5,1,2-cd]indolizines belonging
to a rare class of heterocycle were previously prepared by the tandem [8+2] cycloaddition-
[2+6+2]dehydrogenation reactions.[7] Only a few examples of palladium-catalyzed oxidative coupling
reactions yielding high yields of imidazo[5,1,2-cd]indolizines were known.[8] To avoid the formation of the
aforementioned teteracyclic compounds, C2-phenyl group on the imidazo[1,2-a]pyridine can be replaced by
alkyl substituents, such that 2-alkyl-imidazo[5,1,2-cd]indolizines can be formed exclusively. A direct route
for the formation of this rare type of π-conjugated heterocyclic scaffold should be of significant interest
since earlier work by Gryko et al. had demonstrated that related benzo[a]imidazo[5,1,2-cd]indolizines
exhibited interesting photophysical properties.[7b] Herein, we report our results on the palladium-catalyzed
double C–H functionalization for the formation of 2-alkyl-imidazo[5,1,2-cd]indolizines and their
photophysical properties.
Chart 1. Palladium-Catalyzed Oxidative Cyclization
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European Journal of Organic Chemistry
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Results and Discussion
Catalytic Investigation.
An initial investigation was carried out to confirm the effectiveness of the ionic complex 1a in the
oxidative coupling reactions (Table 1). The coupling reaction between 2-tert-butylimidazo[1,2-a]pyridine
and diphenylacetylene was carried out as the benchmark reaction and our previous conditions of using 2.5
mol% of palladium complex as precatalyst, a reaction temperature of 90 C, Cu(OAc)2 as base, a reaction
time of 16 h, DMF as solvent, and n-tetrabutylammonium bromide (TBAB) as phase transfer catalyst were
employed for the reaction.[6] Entry 1 clearly showed that the ionic NHC complex 1a was the most effective
complex, affording a good 74 % yield of coupled product. The neutral dichloropalladium(II) complex 1b
bearing the same NHC ligand and tricyclohexylphosphine,[9] reported by us earlier, was much less effective
(entry 2). Palladium(II) NHC complex with IMes ligand (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-
ylidene) has been proven to be highly effective in various cross-coupling reactions.[10] However, the in situ
catalyst system of PdCl2/2IMes·HCl with 10 mol% of Pd loading delivered only an inferior product yield of
45 % (entry 3). The catalytic reaction did not work well neither when the imidazolium ligand precursor was
replaced by PPh3 (entry 4). Ligand-free palladium acetate was also less effective than complex 1a in
catalyzing the coupling reaction as the former complex afforded only a 40 % yield of coupled product with
10 mol% of catalyst loading (entries 5 vs. 1).
Table 1. Catalysts Screeninga
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Entry
Cat.
Yield (%)
1
2
74
28
3
4
PdCl2/2IMesHCl
PdCl2/2PPh3
Pd(OAc)2
45b
32b
40c
5
aConditions
(unless
otherwise
specified):
2-tert-
butylimidazo[1,2-a]pyridine (0.5 mmol), diphenylacetylene (0.6
mmol), Pd(II) complex (2.5 mol%), Cu(OAc)2 (1.25 mmol),
TBAB (1.0 mmol), DMF (1.5 mL), 16 h, 90 °C, isolated yield.
b10 mol% PdCl2, 20 mol% ligand additive. c10 mol% Pd(OAc)2.
Next, the solvent system for catalyzing the coupling reaction was screened (Table 2). As shown in
entries 1 and 2, both high polar DMA and DMF were good solvents for the reaction, affording good product
yields of 70 and 74 %, respectively. DMSO which is also a high polar solvent, however, delivered an
inferior product yield of 53 % (entry 3). Protic and nonpolar solvents were proven to be unsuitable for the
catalytic reactions (entries 4 and 5).
Table 2. Solvent Screeninga
Entry
Cat.
Yield (%)
1
2
3
4
5
DMA
DMF
DMSO
toluene
AcOH
70
74
53
5
0
aConditions: 2-tert-butylimidazo[1,2-a]pyridine (0.5 mmol),
diphenylacetylene (0.6 mmol), complex 1a (2.5 mol%),
Cu(OAc)2 (1.25 mmol), TBAB (1.0 mmol), solvent (1.5 mL),
16 h, 90 °C, isolated yield.
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With the best conditions in hand, the substrate scope of the catalyst system was then explored. Initially,
we evaluated the coupling reaction of 2-methylimidazo[1,2-a]pyridine (2a) with different acetylenes (Table
3). Using diphenylacetylene (3a) as substrate, a decent 67 % yield of coupled product 4aa was obtained. The
reaction between di-p-tolylacetylene (3b) with 2a also went smoothly to afford the product 4ab in 71 %
yield. Sterically demanding di-o-tolylacetylene substrate could be successfully applied as substrate as well
albeit with a slightly lower 60 % yield of product 4ab'. Bis(4-methoxyphenyl)acetylene (3c) coupled with
2a leading to a 63 % yield of product 4ac. Compounds 4ad–f were obtained in 63–68% yield in reactions
with 2a and bis(4-halophenyl)acetylenes. Noteworthy, the halide groups on the products allowed these
compounds amenable to further functionalization via C─C coupling reactions. We then replaced the methyl
group on 2a with the sterically hindered tert-butyl group and investigated the coupling activities of this 2-
tert-butylimidazo[1,2-a]pyridine (2b) with different acetylenes. In general, slightly better yields of
imidazo[5,1,2-cd]indolizine products were obtained. For example, using 2b as substrate, the coupling
reaction led to the coupled product 4ba in 78 % yield which is better than that of 67 % yield of 4aa using 2a
as substrate. The coupling reaction between 2b and bis(4-chlorophenyl)acetylene went well affording the
coupled product 4be in a good 80 % yield.
Table 3. Pd-Catalyzed Oxidative Coupling of Imidazo[1,2-
a]pyridine Substrates with Alkynesa
aConditions: heteroarene (0.16 mmol), alkyne (0.20 mmol), 1 (2.5
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mol%), Cu(OAc)2 (0.4 mmol), TBAB (0.32 mmol), DMA (1 mL),
16 h, 90 °C, isolated yield.
Instead of imidazo[1,2-a]pyridine, we then investigated the possible utilization of the less electron-rich
imidazo[1,2-a]pyrimidine as substrate. Fused pyrimidines were found to possess remarkable
pharmacological properties and they are essential components of important naturally occurring substances
such as nucleic acids.[11] As shown in Table 4, a decent 61 % yield for 6ba was obtained using 2-tert-
butylimidazo[1,2-a]pyrimidine (5b) and diphenylacetylene as coupling partners. This yield was lower than
that of 78 % for 4ba using 2-tert-butylimidazo[1,2-a]pyridine and diphenylacetylene as substrates. Similarly,
the 68 % yield of 6be from 5b was also lower than the 80 % yield of 4be obtained from 2b. Substitution on
the pyridine ring in 2a also affect the yields of coupling reactions. In the reaction of 2c bearing a methyl
group on the C7 position, the coupled product 4ca was obtained in 63 % yield, which was slightly inferior to
that of 67 % yield of 4aa produced from the unsubstituted 2a as substrate. The coupling reaction between 2c
and bis(4-fluorophenyl)acetylene afforded a 59 % yield of coupled product 4cd which was also slightly
inferior to the 68 % yield of 4ad obtained from the unsubstituted 2a. Noteworthy, the coupling reaction did
not work when dialkylacetylene was used as substrate. Thus no coupling product was obtained when di-n-
hexylacetylene was reacted with 2-tert-butylimidazo[1,2-a]pyridine. The desired tricyclic product was not
formed neither in the reaction between 2-tert-butylimidazo[1,2-a]pyridine and an unsymmetrically aryl/alkyl
substituted alkyne, 1-phenyl-1-propyne. Our results on the failure of using such internal alkynes was in line
with similar observations published in the work by Hajra et. al.[8a]
Table 4. Pd-Catalyzed Oxidative Coupling of Imidazo[1,2-a]pyridine
Substrates with Alkynesa
aConditions: heteroarene (0.16 mmol), alkyne (0.20 mmol), 1 (2.5
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mol%), Cu(OAc)2 (0.4 mmol), TBAB (0.32 mmol), DMA (1 mL), 16 h,
90 °C, isolated yield.
Previously, we have shown that for C2-aryl imidazo[1,2-a]pyridine bearing ortho-phenyl protons,
deprotonation at these sites were possible leading to the fused tetracyclic compounds. Therefore, blocking of
these ortho-phenyl protons with methyl groups should avoid the tetracyclic product but favor the formation
of imidazo[5,1,2-cd]indolizine. Pleasingly, the reaction between 2-mesityl-H-imidazo[1,2-a]pyridine (2d)
and diphenylacetylene successfully allowed the construction of imidazo[5,1,2-cd]indolizine product 4da in
66 % yield (eq. 1). Similar strategy has been employed by Fan et al. in obtaining similar imidazo[5,1,2-
cd]indolizine product.[8c] Ethyl imidazo[1,2-a]pyridine-2-carboxylate was attempted as coupling partner in
reactions with diphenylacetylene. However, no desired imidazo[5,1,2-cd]indolizine product was obtained.
Noteworthy, free imidazo[1,2-a]pyridine without C2-substituition did not yield the desired coupling product
with diphenylacetylene neither using our new protocol. This result was in contrast to that published by Mira
et. al. who observed a 49 % of the desired tricyclic product using free Pd(OAc)2 as catalyst precursor.[8b]
A
higher reaction temperature of 120 C (instead of 90 C in our case) in a mixed pivalic acid/DMA solvent
system was used in their conditions.
To further understand the coupling efficiency of substrates with different electronic properties,
competition experiments were performed (Scheme 1). Consistent with our aforementioned findings, 2-tert-
butylimidazo[1,2-a]pyridine (2b) reacted more favorably compared with the electron-poor 2-tert-
butylimidazo[1,2-a]pyrimidine (5b) giving the coupled products 4ba and 6ba in a ratio of 66:34. The
competition experiment involving a mixture of 2b, di-p-tolyacetylene, and bis(4-fluorophenyl)acetylene led
to coupled products 4bb and 4bd in a ratio of 35:65, indicating that the electronic-poor alkynes reacted
preferentially.
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Scheme 1. Competitive Experiments.
Finally, to prove the practicability of the catalyst system based on complex 1a in organic synthesis, an
upscaling reaction between 2a and di-p-4-chlorophenylacetylene was performed (eq. 2). Desirably, the
coupled product 4ae was obtained in 0.27 g (72 % yield) using a 2.5 mmol of starting material.
Structural Description
The structure of 4bd was successfully established by single-crystal X-ray diffraction analysis (Figure 1).
The summation of bond angles around the central nitrogen atom N1 is 360, reflecting the planarity nature
of the fused tricyclic ring. The three peripheral bond angles of ∠C14─C13─C21, ∠C7─C8─C9, and ∠
C11─C12─N2 defining the shape of the fused ring system are 153.52(17), 142.69(18) and 137.48(16),
respectively. Noteworthy, the bond angle of 153.52(17)  around C13 atom is exceptionally large for a sp2
carbon on a cyclic ring. One of the aryl rings forms a large 72.96(4) interplanar angle with the central
tricyclic core, whereas the corresponding interplanar angle of 39.25(4) with the other aryl ring was much
smaller.
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Figure 1. Molecular structure of 4bd with 50 % probability ellipsoids for non-H atoms. H-atoms were
omitted for clarity. Selected bond distances (Å) and angles (deg) around N1 in 4bd: C13─N1, 1.358(2);
C12─N1, 1.360(2); C8─N1, 1.636(2); C13─N1─C8, 115.87(15); C13─N1─C12, 112.34(15); C12─N1
─C8, 131.78(15).
Proposed Mechanism
A catalytic cycle for the annulation reaction between 2-alkyl-imidazo[1,2-a]pyridine and alkyne is
proposed in Scheme 2. The catalytic reaction should be initiated by the palladium(II) complex A and an
initial C–H activation of the heteroaromatic substrate and its coordination via the C3 atom led to the
formation of the palladium(II) complex B. The insertion of the alkyne substrate into the Pd–C bond
produced the intermediate C. Further C–H activation generated the palladacycle intermediate D with the
release of HX. An subsequent reductive elimination afforded the imidazo[5,1,2-cd]indolizine product and
the palladium(0) complex E which was oxidized and transformed back to palladium complex A by copper(II)
acetate.
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Scheme 2. Mechanistic Proposal for the Oxidative Annulation Reaction of 2-Alkyl-imidazo[1,2-a]pyridine
with Alkyne.
Optical Properties.
The UV and PL spectra of selected compounds in THF (10-5 M) are summarized in Table 5. The new
imidazo[5,1,2-cd]indolizine 4 exhibited absorption maxima in the range of 388–396 nm. Their PL spectra
except that of 4ac exhibit single broad emission in the range of 518–532 nm. Interestingly, compound 4ac
with 4-methoxy groups on the phenyl rings exhibits the strongest fluorescence among the new compounds
(ФF = 0.445) with dual emission maxima at 427 nm and 536 nm (Figure 2). This anomalous emission
should be related to the methoxy groups. Noteworthy, Gryko et al. also observed dual emission but in the
solid-state for a benzo[a]imidazo[5,1,2-cd]indolizine bearing an OMe group.[7b] In their case, the methoxy
group acts as an additional hydrogen-bond acceptor, altering crystal packing and thus the formation of
polymorphs. The emission of compound 4af bearing 4-bromophenyl rings at 520 nm was slightly blue-
shifted compared with those of other imidazo[5,1,2-cd]indolizine 4a bearing C2-methyl groups at ca. 530
nm or above (see Figure 2). The emission maxima of compound 4b with C2-t-butyl groups were blue shifted
at ca. 520 nm compared with those of 4a. (Figure 3). The absorption maxima of compound 6ba and 6be
with nitrogen atoms replacing carbon atoms on the tricyclic ring cores are bathochromatically shifted by 23
nm in comparison to those of parent imidazo[5,1,2-cd]indolizines 4ba and 4be (Figure 4). Their emission
maxima were also red shifted by 46 and 36 nm, respectively. These red shift of emission maximum
wavelength for 6ba and 6be suggests the intramolecular charge transfer involving the extra pyrimidine
nitrogen lone pairs at the excited state.
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Table 5. Photophysical Properties of New Compoundsa
Absorption
Emission
b
ФF 
Compound
R1
R2
X
log 

max (nm)
393
396
392
394
395
389
389
389
393
388
412
412

max (nm)
531
0.164
0.445
0.141
0.160
0.146
0.136
0.159
0.117
0.142
0.149
0.119
0.139
Me
Me
Me
Me
Me
t-Bu
t-Bu
t-Bu
t-Bu
Me
H
OMe
F
Cl
Br
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CMe
N
3.82
3.54
3.89
3.84
3.90
3.90
3.86
3.97
3.90
3.89
3.94
3.87
4aa
4ac
4ad
4ae
4af
4ba
4bd
4be
4bf
4ca
6ba
6be
427, 536
532
531
520
519
518
525
520
526
565
F
Cl
Br
H
H
Cl
t-Bu
t-Bu
N
561
aMeasured in THF. Determined with reference to anthracene in ethanol (ФF =
b
0.27)
Figure 2. UV and PL spectra of 4aa, 4ac, 4ad, 4ae, and 4af in THF
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Figure 3. UV and PL spectra of 4ba, 4bd, 4be, and 4bf in THF
Figure 4. UV and PL spectra of 6ba and 6be vs. those of 4ba and 4be in THF
Figure 5. Charge transfer in compounds 6ba (R = H) and 6be (R = Cl)
Conclusion
In summary, the catalyst system based on 1a was highly effective in catalyzing the oxidative coupling
reactions between diarylacetylenes and imidazo[1,2-a] pyridines leading to imidazo[5,1,2-cd]indolizines
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product. Less electron-rich imidazo[1,2-a]pyrimidines could also be applied as substrate leading to similar
coupled products albeit with slightly inferior yields. Importantly, the methodology was based on C2
substituted imidazo[1,2-a] pyridines and imidazo[1,2-a]pyrimidine without C2 phenyl protons, which were
crucial in avoiding the formation of previously reported fused tetracyclic product. This simple palladium-
catalyzed direct arylation protocol allows an easy access of fluorescent imidazo[5,1,2-cd]indolizines and
related compounds. Further studies on introducing different functionality on the tricyclic skeleton and fine
tuning of their photophysical properties are underway.
Experimental Section
All manipulations were performed under a dry nitrogen atmosphere using standard Schlenk techniques.
Unless otherwise noted, all the catalytic reactions were carried out in thick walled sealable tubes. All the
solvents were directly used as received without any further purification unless otherwise specified. Common
1
13
starting chemicals were purchased from commercial source and used as received. H, and C{1H} NMR
spectra were recorded at 300.13 and 75.48 MHz, respectively. CDCl3 as solvent and tetramethylsilane (TMS)
as the internal standard were employed. Chemical shifts were reported in units (ppm) by assigning TMS
1
1
resonance in the H NMR spectrum as 0.00 ppm. The data of H NMR was reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet and br = broad), coupling constant (J
13
values) in Hz and integration. Chemical shifts for C NMR spectra were recorded in ppm from TMS using
the central peak of CDCl3 (77.0 ppm) as the internal standard. Flash chromatography was performed using
230‐400 mesh silica gel. EI-MS was carried out on a sector field mass spectrometer. UV-vis spectra were
recorded on a HP-8453 spectrophotometer with a diode array detector, and the resolution was set at 1 nm.
Photoluminescence spectra were recorded on a Cary Eclipse Fluorescence spectrophotometer. Compound
2a,[12] 2b,[13] and 2c[14] were prepared following a literature procedure of similar compounds.[15]
2-Mesity-lH-imidazo[1,2-a]pyridine (2d). To a stirred solution of 2-bromo-1-mesitylethanone (1.2 g,
5.0 mmol) in ethanol (30 mL) was added 2-aminoypyridine (470 mg, 5.0 mmol) in portions, followed by
addition of NaHCO3 (1.2 g, 15 mmol). The mixture was refluxed for 4 h. The reaction mixture was then
cooled to room temperature, filtered and concentrated under reduced pressure. The crude material was
purified by flash chromatography using ethyl acetate/hexane (4:6) as eluent. A brown oil was obtained (80
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European Journal of Organic Chemistry
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mg, 68% yield). 1H NMR (CDCl3, 300 MHz): δ 8.12 (dd, J = 6.9, 1.8 Hz, 1H), 7.60 (dd, J = 6.9, 1.8 Hz, 1H),
13
7.42 (s, 1H), 7.17-7.12 (m, 1H), 6.92 (s, 2H), 6.77 (td, J = 6.9, 1.8 Hz, 1H), 2.30 (s, 3H), 2.12 (s, 6H). C
NMR (CDCl3, 75 MHz): δ 145.1, 144.8, 137.7, 137.5, 131.0, 128.1, 125.5, 124.0, 117.6, 112.1, 110.9, 21.2,
20.7. HRMS (EI) calcd. for C16H16N2 [M+]: 236.1313. Found: 236.1310.
2-tert-Butylimidazo[1,2-a]pyrimidine (5b). To a stirred solution of 2-aminopyrimidine (0.5 g, 5.25
mmol) in ethanol (25.0 mL) was added 1-bromo-3,3-dimethylbutan-2-one (1.41 g, 7.9 mmol). The mixture
was stirred at reflux for overnight. After the reaction was completed, the mixture was evaporated, diluted
with ethyl acetate (50.0 mL) and washed with 1N NaOH solution (50.0 mL). The organic layer was dried
over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column
chromatography. An off-white solid was obtained (0.59 g, 64 % yield). mp = 185.8.–186.6 ºC; 1H NMR
(CDCl3, 300 MHz): δ 8.39 (s, 1H), 8.30 (dd, J = 6.6, 1.8 Hz, 1H), 7.20 (s, 1H), 6.74-6.70 (m, 1H), 1.34 (s,
9H). 13C NMR (CDCl3, 75 MHz): δ 159.2, 149.0, 148.2, 132.8, 108.1, 104.9, 32.7, 29.9. HRMS (EI) calcd.
for C10H13N3 [M+]: 175.1109. Found: 175.1102.
Typical Procedure for Pd(II)-Catalyzed Double C-H Functionalization. To a 15 mL oven-dried
sealed tube containing stir bar were added heteroarene (0.16 mmol), Pd catalyst (2.5 mol%), Cu(OAc)2 (72
mg, 0.40 mmol), alkyne (0.20 mmol), TBAB (103 mg, 0.32 mmol) in DMF or DMA (1－1.5 mL). The
o
reaction mixture was stirred at 90 C for 16 h. Upon completion, EtOAc was added to dilute the mixture
which was then washed with water (2 x 20 mL) and saturated NaCl (aq). The organic layer was dried over
MgSO4, evaporated, and purified by flash column chromatography on silica gel with a gradient eluent of
hexane and ethyl acetate (25:1 v/v) to afford the corresponding cyclized product.
2-Methyl-3,4-diphenylH-imidazo[5,1,2-cd]indolizine (4aa). Off-white solid (33 mg, 67% yield), mp
= 135.0–135.8 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.90-7.85 (m, 3H), 7.54 (d, J = 6.0 Hz, 2H), 7.47 (d, J =
13
6.0 Hz, 2H), 7.42-7.28 (m, 6H), 2.90 (s, 3H). C NMR (CDCl3, 75 MHz): δ 150.1, 139.6, 134.1, 133.7,
131.4, 130.9, 130.5, 130.2, 128.8, 128.7, 128.0, 127.1, 126.3, 125.5, 112,1, 110.0, 16.8. HRMS (EI) calcd.
for C22H16N2 [M+]: 308.1313. Found: 308.1310.
2-Methyl-3,4-dip-tolylH-imidazo[5,1,2-cd]indolizine (4ab). Off-white solid (38 mg, 71% yield), mp
= 135.4-136.3 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.88 (s, 3H), 7.44 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 7.8 Hz,
2H), 7.24-7.19 (m, 4H), 2.90 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 149.6, 137.8,
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European Journal of Organic Chemistry
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136.8, 131.7, 131.2, 130.9, 130.8, 130.3, 129.9, 129.5, 129.4, 129.3, 129.1, 126.3, 125.4, 112.0, 109.9, 21.4,
21.3, 16.7. HRMS (EI) calcd. for C24H20N2 [M+]: 336.1626. Found: 336.1617.
2-Methyl-3,4-dio-tolylH-imidazo[5,1,2-cd]indolizine (4ab'). Off-white solid (32 mg, 60% yield), mp.
1H NMR (CDCl3, 300 MHz): δ 7.92-7.84 (m, 2H), 7.69 (d, J = 6.9 Hz, 1H), 7.28-7.18 (m, 8H), 2.74 (s, 3H),
13
2.12 (s, 3H), 2.04 (s, 3H). C NMR (CDCl3, 75 MHz): δ 149.9, 138.8, 131.7, 131.6, 130.5, 130.4, 130.3,
128.1, 127.7, 126.8, 125.9, 125.7, 125.6, 112.1, 109.9, 20.4, 16.1. HRMS (EI) calcd. for C24H20N2 [M+]:
336.1626. Found: 336.1632.
3,4-Bis(4-methoxyphenyl)-2-methylH-imidazo[5,1,2-cd]indolizine (4ac). Off-white solid (37 mg,
1
63% yield), mp = 172.9-173.6 ºC; H NMR (CDCl3, 300 MHz): δ 7.83 (s, 3H), 7.46 (d, J = 8.7 Hz, 2H),
13
7.40 (d, J = 8.7 Hz, 2H), 6.95-6.91 (m, 4H), 3.84 (s, 3H), 3.83 (s, 3H), 2.89 (s, 3H). C NMR (CDCl3, 75
MHz): δ 159.4, 158.7, 148.2, 145.7, 131.7, 131.6, 131.2, 130.4, 126.5, 126.1, 126.0, 124.8, 119.8, 114.3,
114.2, 111.8, 109.7, 55.3, 16.8. HRMS (EI) calcd. for C24H20N2O2 [M+]: 368.1525. Found: 368.1528.
3,4-Bis(4-flurophenyl)-2-methylH-imidazo[5,1,2-cd]indolizine (4ad). Yellow solid (35 mg, 68%
1
yield), mp = 167.0-167.9 ºC; H NMR (CDCl3, 300 MHz): δ 7.89-7.82 (m, 3H), 7.53 (dd, J = 8.7, 5.4 Hz,
2H), 7.40 (dd, J = 8.7, 5.7 Hz, 2H), 7.14-7.06 (m, 4H), 2.87 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 162.8 (d,
J = 247 Hz), 162.1 (d, J = 247 Hz), 150.2, 139.7, 132.0 (d, J = 8.3 Hz), 131.7 (d, J = 7.5 Hz), 131.3, 129.9 (d,
J = 3.0 Hz), 129.7, 129.6 (d, J = 3.0 Hz), 126.4, 125.1, 124.4, 115.9 (d, J = 21.8 Hz), 111.9, 110.3, 16.7.
HRMS (EI) calcd. for C22H14N2F2 [M+]: 344.1125. Found: 344.1120.
3,4-Bis(4-chlorophenyl)-2-methylH-imidazo[5,1,2-cd]indolizine (4ae). Off-white solid (54 mg, 68%
yield), mp = 160.3-161.2 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.91-7.89 (m, 3H), 7.47-7.38 (m, 8H), 2.88 (s,
13
3H). C NMR (CDCl3, 75 MHz): δ 150.4, 139.7, 134.3, 133.3, 132.3, 131.9, 131.6, 131.3, 131.1, 129.6,
129.2, 129.1, 126.7, 125.0, 124.3, 112.2 110.5, 16.8. HRMS (EI) calcd. for C22H14Cl2N2 [M+]: 376.0534.
Found: 376.0531.
3,4-Bis(4-bromophenyl)-2-methylH-imidazo[5,1,2-cd]indolizine (4af). Light yellow solid (47 mg,
1
63% yield), mp = 164.6-165.8 ºC; H NMR (CDCl3, 300 MHz): δ 7.89-7.83 (m, 3H), 7.56-7.49 (m, 4H),
7.37 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 2.86 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 150.5, 139.8,
132.8, 132.4, 132.1, 132.0, 131.9, 131.6, 131.0, 129.5, 126.6, 124.9, 124.1, 122.6, 121.5, 112.1, 110.5, 16.8.
HRMS (EI) calcd. for C22H14Br2N2 [M+]: 463.9524. Found: 463.9532.
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European Journal of Organic Chemistry
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2-tert-Butyl-3,4-diphenylH-imidazo[5,1,2-cd]indolizine (4ba). Off-white solid (44 mg, 78% yield),
1
mp = 207.3-208.2 ºC; H NMR (CDCl3, 300 MHz): δ 8.00-7.88 (m, 3H), 7.46-7.38 (m, 7H), 7.32-7.22 (m,
13
3H), 1.38 (s, 9H). C NMR (CDCl3, 75 MHz): δ 164.7, 138.8, 135.8, 134.2, 131.6, 131.0, 130.6, 130.0,
128.4, 128.2, 128.0, 127.0, 126.7, 125.9, 124.7, 112.2, 110.3, 35.0, 30.9. HRMS (EI) calcd. for C25H22N2
[M+]: 350.1783. Found: 350.1787.
2-tert-Butyl-3,4-di-p-tolylH-imidazo[5,1,2-cd]indolizine (4bb). Off-white solid (45 mg, 75% yield),
1
mp = 250.7–251.8 ºC; H NMR (CDCl3, 300 MHz): δ 7.92-7.81 (m, 3H), 7.27-7.22 (m, 4H), 7.19-7.14 (m,
2H), 7.05 (d, J = 7.8 Hz, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 1.33 (s, 9H). 13C NMR (CDCl3, 75 MHz): δ 164.4,
138.7, 137.6, 136.3, 132.8, 131.5, 131.3, 130.8, 130.7, 129.8, 129.2, 128.9, 127.0, 125.8, 124.8, 112.1, 110.1,
34.9, 30.9, 21.5. HRMS (EI) calcd. for C27H26N2 [M+]: 378.2096. Found: 378.2092.
2-tert-Butyl-3,4-bis(4-fluorophenyl)H-imidazo[5,1,2-cd]indolizine (4bd). Off-white solid (46 mg,
1
74% yield), mp = 201.2-202.0 ºC; H NMR (CDCl3, 300 MHz): δ 8.00-7.96 (m, 1H), 7.91 (d, J = 4.8 Hz,
2H), 7.41-7.37 (m, 2H), 7.34-7.29 (m, 2H), 7.12 (t, J = 8.7 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 1.38 (s, 9H).
13C NMR (CDCl3, 75 MHz): δ 164.3, 162.9 (d, J = 282.8 Hz), 161.8 (d, J = 247 Hz), 138.8, 132.6 (d, J = 4.7
Hz), 131.5 (d, J = 4.7 Hz), 131.4, 130.3, 129.9 (J = 3.0 Hz), 126.2, 126.1, 124.5, 115.6 (d, J = 21 Hz), 115.4
(d, J = 20 Hz), 112.1, 110.5, 35.0, 30.9. HRMS (EI) calcd. for C25H20F2N2 [M+]: 386.1595. Found: 386.1587.
2-tert-Butyl-3,4-bis(4-chlorophenyl)H-imidazo[5,1,2-cd]indolizine (4be). Off-white solid (46 mg,
1
80% yield), mp = 212.9-213.7 ºC; H NMR (CDCl3, 300 MHz): δ 8.00-7.96 (m, 1H), 7.91 (d, J = 4.8 Hz,
2H), 7.41-7.36 (m, 4H), 7.28 (s, 4H), 1.38 (s, 9H). 13C NMR (CDCl3, 75 MHz): δ 165.0, 138.8, 134.3, 134.0,
132.9, 132.3, 132.2, 131.1, 130.2, 130.1, 128.9, 128.7, 126.3, 125.8, 124.4, 112.2, 110.7, 35.0, 31.0. HRMS
(EI) calcd. for C24H20Cl2N2 [M+]: 418.1004. Found: 418.1003.
3,4-Bis(4-bromophenyl)-2-tert-butylH-imidazo[5,1,2-cd]indolizine (4bf). Light yellow solid (53 mg,
1
66% yield), mp = 210.7-211.5 ºC; H NMR (CDCl3, 300 MHz): δ 7.95-7.87 (m, 3H), 7.50 (d, J = 8.4 Hz,
13
2H), 7.39 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 1.33 (s, 9H). C NMR
(CDCl3, 75 MHz): δ 156.0, 138.8, 134.5, 132.8, 132.5, 131.8, 131.6, 131.4, 130.9, 130.1, 126.4, 125.8,
124.4, 122.6, 121.1, 112.2, 110.7, 35.0, 31.0. HRMS (EI) calcd. for C25H20Br2N2 [M+]: 505.9993. Found:
505.9991.
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European Journal of Organic Chemistry
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2,7-Dimethyl-3,4-diphenylH-imidazo[5,1,2-cd]indolizine (4ca). Off-white solid (32 mg, 61% yield),
1
mp = 125.1–125.9 ºC; H NMR (CDCl3, 300 MHz): δ 7.77 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H),
7.53 (dd, J = 7.5, 1.5 Hz, 2H), 7.46 (dd, J = 8.4, 1.5 Hz, 2H), 7.42-7.29 (m, 6H), 2.94 (s, 3H), 2.88 (s, 3H).
13C NMR (CDCl3, 75 MHz): δ 148.3, 138.9, 134.3, 133.9, 130.4, 130.1, 130.0, 129.8, 128.7, 128.6, 127.8,
127.7, 127.0, 125.5, 125.4, 121.3, 112.2, 16.7, 15.9. HRMS (EI) calcd. for C23H18N2 [M+]: 322.1470. Found:
322.1477.
3,4-Bis(4-fluorophenyl)-2,7-dimethylH-imidazo[5,1,2-cd]indolizine (4cd). Light yellow solid (34 mg,
59% yield), mp = 106.1-107.3 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.71 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.1
13
Hz, 1H), 7.46-7.34 (m, 4H), 7.10-7.02 (m, 4H), 2.91 (s, 3H), 2.83 (s, 3H). C NMR (CDCl3, 75 MHz): δ.
162.5 (d, J = 246.8 Hz), 162.1 (d, J = 245.3 Hz), 148.2, 138.9, 132.0 (d, J = 8.3 Hz), 131.6 (d, J = 8.3 Hz),
130.0 (d, J =3.8 Hz), 129.7 (d, J = 3.0 Hz), 129.6, 128.7, 127.7, 126.1, 124.4, 121.6, 115.9 (d, J = 22 Hz),
115.8 (d, J = 22 Hz), 112.1, 16.6, 15.9. HRMS (EI) calcd. for C23H16F2N2 [M+]: 358.1282. Found: 358.1276.
2-Mesityl-3,4-diphenylH-imidazo[5,1,2-cd]indolizine (4da). Light yellow solid (44 mg, 66% yield),
1
mp = 136.7–137.8 ºC; H NMR (CDCl3, 300 MHz): δ 7.99-7.89 (m, 3H), 7.51 (dd, J = 6.9, 1.8 Hz, 2H),
7.40-7.30 (m, 3H), 7.12-7.08 (m, 3H), 7.00-6.94 (m, 2H), 6.82 (s, 2H), 2.27 (s, 3H), 1.91 (s, 9H). 13C NMR
(CDCl3, 75 MHz): δ 138.9, 138.0, 137.1, 134.3, 133.0, 132.2, 131.1, 130.9, 130.2, 129.9, 128.9, 128.2,
128.1, 127.8, 127.3, 126.5, 125.7, 112.5, 111.3, 21.3, 20.4. HRMS (EI) calcd. for C30H24N2 [M+]: 412.1939.
Found: 412.1943.
2-(tert-Butyl)-3,4-diphenyl-1,2a1,7-triazacyclopenta[cd]indene (6ba). Light yellow solid (35 mg,
63% yield), mp = 235.8–236.7 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.93 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 5.4
13
Hz, 1H), 7.39 (s, 5H), 7.31-7.20 (m, 5H), 1.34 (s, 9H). C NMR (CDCl3, 75 MHz): δ 172.0, 146.6, 145.8,
135.9, 134.7, 133.7, 133.1, 130.5, 129.6, 128.7, 128.5, 128.4, 127.2, 127.1, 123.3, 107.9, 35.7, 30.6. HRMS
(EI) calcd. for C24H21N3 [M+]: 351.1735. Found: 351.1741.
2-(tert-Butyl)-3,4-bis(4-chlorophenyl)-1,2a1,7-triazacyclopenta[cd]indene (6be). Light yellow solid
(46 mg, 68% yield), mp = 217.2-218.0 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.92 (d, J = 5.4 Hz, 1H), 7.78 (d,
13
J = 5.4 Hz, 1H), 7.38 (d, J = 6.6 Hz, 2H), 7.31-7.16 (m, 6H), 1.33 (s, 9H). C NMR (CDCl3, 75 MHz): δ
172.4, 146.7, 146.1, 135.0, 134.3, 133.4, 133.3, 132.9, 131.8, 131.3, 130.8, 129.1, 129.0, 126.0, 123.1, 107.8,
35.8, 30.7. HRMS (EI) calcd. for C24H19Cl2N3 [M+]: 419.0956. Found: 419.0951.
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European Journal of Organic Chemistry
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X-ray Crystallography. Samples were collected at 150(2) K on a X-ray diffractometer equipped with a
CCD area detector and a graphite monochromater utilizing MoKradiation (λ = 0.71073 Å). The unit cell
parameters were obtained by least-squares refinement. Data collection and reduction were performed using
the APEX2 and SAINT software.[16] Absorption corrections were performed using the SADABS program.[17]
All the structures were solved by direct methods and refined by full-matrix least squares methods against F2
with the SHELXTL software package.[18] All non-H atoms were refined anisotropically. All H-atoms were
fixed at calculated positions and refined with the use of a riding model. Crystallographic data are listed in
Table S1 of the Supporting Information. CCDC files 1487706 (4bd) contain 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.
Acknowledgements. We are grateful to the Ministry of Science and Technology of Taiwan for
financial support of this work.
Supporting Information Available. NMR spectra for all products and crystallographic data of 4bd.
This material is available free of cost via the Internet at http://pubs.acs.org. We also thank the National
Center for High-performance Computing of Taiwan for computing time and financial support of the
Conquest software.
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