Three-component, one-pot sequential synthesis of functionalized cyclazines: 3 H-1,2a1,3-triazaacenaphthylenes

Article abstract of DOI:10.1021/jo3021105

An efficient tandem route to the synthesis of 3H-1,2a¹,3- triazaacenaphthylene derivatives of the cyclazine family has been developed. Target compounds were obtained in moderate to good yields by a Yb(OTf) ₃/Ag₂CO₃-catalyzed, three-component domino reaction. This in turn will set the stage for a wide application of this useful reaction for the synthesis of structurally diverse polyheterocyclic skeletons containing the imidazo[1,2-a]pyridine privileged structure.

Full text of DOI:10.1021/jo3021105

Article
pubs.acs.org/joc
Three-Component, One-Pot Sequential Synthesis of Functionalized
Cyclazines: 3H‑1,2a1,3-Triazaacenaphthylenes
Hongpeng Sun,†,‡ Huayong Zhou,‡ Oleg Khorev,§ Ruwei Jiang,‡ Ting Yu,‡ Xin Wang,‡ Yongli Du,†
Yi Ma,† Tao Meng,*,‡ and Jingkang Shen*,‡
†School of Chemistry and Pharmaceutical Engineering, Shandong Polytechnic University, Jinan 250353, P.R. China
‡State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi
Road, Shanghai 201203, P.R. China
§Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland
S
* Supporting Information
ABSTRACT: An efficient tandem route to the synthesis of
3H-1,2a1,3-triazaacenaphthylene derivatives of the cyclazine
family has been developed. Target compounds were obtained
in moderate to good yields by a Yb(OTf)3/Ag2CO3-catalyzed,
three-component domino reaction. This in turn will set the
stage for a wide application of this useful reaction for the
synthesis of structurally diverse polyheterocyclic skeletons
containing the imidazo[1,2-a]pyridine privileged structure.
Scheme 1. Proposed MCR Approach to New Cyclazines
INTRODUCTION
■
Cyclazines are tricyclic fused N-heterocyclic systems with a
central nitrogen atom and an unsaturated periphery.1
A
representative [3.3.3]cyclazine is shown in Figure 1A. We
molecules for biological screening.3 Furthermore, there has
been a growing interest in combinations of MCRs with
subsequent post-MCR modifications (mainly intramolecular
cyclizations) to produce novel compounds possessing increased
molecular complexity and diversity.4
Nitrogen bridgehead-fused heterocycles containing an
imidazole ring are common structural motifs in pharmacolog-
ically important molecules, with activities spanning a diverse
range of targets.5 Among the numerous N-heterocycles,
imidazo[1,2-a]pyridine moieties (Figure 1C), which may be
regarded as privileged structures, have been shown to possess
diverse therapeutic activities.6 Imidazo[1,2-a]pyridine is also
found in marketed drugs such as alpidem (a nonsedative
anxiolytic),7 zolpidem (a hypnotic drug),8 necopidem (a
nonsedative anxiolytic), and zolimidine (an antiulcer drug)9
(Figure 1C), as well as other therapeutic molecules still in
development.10 To access such medicinally important N-fused
imidazoles, several isocyanide-based multicomponent reaction
(IMCR) approaches have been developed.11 Therefore, it
would be of particular interest to design and synthesize a series
Figure 1. (A) A classic cyclazine. (B) The heterocycle synthesized in
this work (X = N, CH). (C) Therapeutic agents based on imidazo[1,2-
a]pyridine (blue).
herein report a synthesis of a functionalized cyclazine, 3H-
1,2a1,3-triazaacenaphthylene (Figure 1B), via a one-pot multi-
component reaction (Scheme 1). Multicomponent reactions
(MCRs) are of increasing importance in organic and medicinal
chemistry.2 By generating several new covalent bonds with high
efficiency and atom economy in a single-step process from
three or more reactants, MCRs provide an attractive way for
the generation of molecules having diverse structures, especially
unusual heterocyclic scaffolds. The latter are particularly useful
for the creation of diverse chemical libraries of druglike
Received: September 26, 2012
© XXXX American Chemical Society
A
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a
Table 1. Optimization of the Cyclization Conditions
b
b
entry
catalyst 1 (mol %)
catalyst 2 (mol %)
solvent
4, yield (%)
5a, yield (%)
1
2
−
−
−
−
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DCM
DMF
0
0
Yb(OTf)3 (10)
71
0
trace
0
3
AgOTf (10)
4
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
AgOTf (10)
AgNO3 (10)
AuCl3 (10)
AgBF4 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
0
61
62
47
56
81
16
13
5
0
6
trace
0
7
8
0
9
11
trace
10
a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv), 2a (1.05 equiv), 3a (1.20 equiv), catalyst 1 (10 mol %), catalyst 2 (10 mol %), solvent (5 mL), 65
b
°C, 4 h. Tf = triflate. Isolated yields.
of tricyclic fused imidazo[1,2-a]pyridines bridged between the
C(3) and C(5) positions (Scheme 1), which also belong to the
cyclazine family.12 To the best of our knowledge, this series of
compounds has never been reported.
was unambiguously established by X-ray crystallographic
analysis (see Supporting Information).
Encouraged by this result, we continued to optimize reaction
conditions to further improve the chemical yield. Screening of
catalysts indicated that Ag2CO3 displayed the highest catalytic
activity toward the formation of 5a with an 81% yield (Table 1,
entry 8). Furthermore, changing the solvents from EtOH to
CH2Cl2 or DMF dramatically decreased the yields of 4 and 5a
(Table 1, entries 9 and 10).
Recent studies in our group have focused on the develop-
ment of new synthetic pathways for the preparation of fused
imidazo[1,2-a]pyridine scaffolds, which rely on the use of
cascade or one-pot reactions based on the Groebke−Black-
burn−Bienayme
́
reaction.13 As part of this effort, we envisioned
On the basis of the results obtained above, a plausible
mechanism of this reaction is illustrated in Scheme 2. The
that 6-alkynyl-2-aminopyridines would participate with alde-
hydes and isocyanides in a Groebke-like condensation followed
by a transition metal-catalyzed intramolecular cyclization
sequence that would result in the one-pot synthesis of a 3H-
1,2a1,3-triazaacenaphthylene scaffold (Scheme 1). The attrac-
tiveness of the one-pot preparation of these structurally unique
molecules is a fundamental goal in organic synthesis, as it
avoids the tedious purification that follows the step-by-step
synthesis.14
Scheme 2. Proposed Mechanism for the Silver-Catalyzed
Cyclization
RESULTS AND DISCUSSION
■
The investigation was initiated with substituted 6-alkynyl-2-
aminopyridines, which can be readily prepared from the
corresponding alkynes and 2-amino-6-bromopyridine by
Sonogashira coupling with satisfactory yields according to the
literature protocol.15 Subsequently, 6-(p-tolylethynyl)-2-amino-
pyridine, benzaldehyde, and ethyl isocyanoacetate were used as
the model substrates to optimize reaction conditions including
different catalysts and various solvents, and the results are
summarized in Table 1. No reaction occurred in the absence of
catalysts (Table 1, entry 1), and using Yb(OTf)3 alone afforded
the GBB product 4 in 71% yield, as well as a trace amount of
cyclized product 5a (Table 1, entry 2). Because silver(I) forms
a complex with isocyanide,16 therefore inhibiting the initial step
(Table, entry 3), it is crucial that AgOTf is added to the
reaction mixture after the Yb(OTf)3-catalyzed GBB-3CR
transformation has completed. The reaction mixture was then
stirred at 65 °C for 3 h, and the cyclized product 5a was
obtained in 61% yield (Table 1, entry 4). The structure of 5a
reaction is expected to proceed via the in situ formation of A.
The next step involves alkyne activation by the silver carbonate,
followed by intramolecular nucleophilic attack of the amine at
the triple bond via a 6-endo-dig fashion to give the six-
membered intermediate C. Finally, protonation of C affords the
final product D.
With the optimal conditions established, we then investigated
the scope of this method. The simplicity of a one-pot procedure
is perfectly amenable to automation for combinatorial synthesis.
Likewise, all the syntheses were performed on a 15-reaction
setup in a parallel synthesizer (Radleys Discovery Technology,
Carousel 12 Place Reaction Station) to give corresponding
products 5b−r in yields ranging from 28% to 85% (Table 2).
First, we examined the reactions of various aldehydes 2a−d and
B
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a
Table 2. Synthesis of 5b−o under Optimized Conditions
C
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Table 2. continued
a
Reaction conditions: 1a−k (1.0 mmol, 1.0 equiv), 2a−d (1.05 equiv), 3a−d (1.20 equiv), Yb(OTf)3 (10 mol %), Ag2CO3 (10 mol %), EtOH (5
b
mL), 65 °C, 16 h. Tf = triflate. Isolated yields.
a
Scheme 3. Synthesis of Compound 7
a
Reagents and conditions: (a) Yb(OTf)3, 65 °C, 4 h, then AgOTf, 65 °C, 12 h.
isocyanides 3a−e with 6-(p-tolylethynyl)-2-aminopyridine,
which proceeded smoothly and efficiently to produce the
corresponding products (5b−h) in moderate to good yields.
The low yield observed for the aromatic isocyanide (3c, Table
2, entry 2) was probably due to the low nucleophilicity of the
aniline in the cyclization step. Subsequently, to extend the
scope of this transformation, reactions of various 6-alknyl-2-
aminopyridines (1b−h) with benzaldehyde (2a) and ethyl
isocyanoacetate (3a) were investigated (Table 2, entries 8−13).
All reactions worked well to produce the expected products 5i−
o in 40−78% yields. As can be seen, the aromatic groups
attached to the triple bond worked better than aliphatic groups
(Table 2, entries 8−10 vs 11−14). Moreover, we were pleased
to find that the pyridine core could be successfully extended to
pyrazine. For example, 6-alknyl-2-aminopyrazines (1i−k)
smoothly reacted with benzaldehyde and ethyl isocyanoacetate
to give the corresponding products 5p−r in 31−47% yields
(Table 2, entries 15−17).
We have recently described the one-pot synthesis of
substituted pyrido[2′,1′:2,3]imidazo[5,1-a]isoquinoliniums,
catalyzed by ytterbium triflate and silver triflate.17 Herein, we
envisioned that by using 2-alknylbenzaldehyde (6) as the
substrate the reaction may also furnish the polyheterocyclic
compound 7 (Scheme 3). According to our previous study, an
equimolar amount of triflate was required as the counterion for
the quaternary ammonium products formation.17 Thus, using
Yb(OTf)3/AgOTf conditions, this unique polycyclic compound
7 could be obtained in 66% yield.
CONCLUSION
In summary, we have developed an efficient and convenient
method for the one-pot construction of novel functionalized
■
D
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102.9, 55.2, 21.3. HRMS(EI) m/z calcd for C29H23N3O: 429.1841,
found 429.1841.
cyclazines containing imidazo[1,2-a]pyridine and imidazo[1,2-
a]pyrazine. Conversion is achieved by treatment of 6-alknyl-2-
aminopyridines/pyrazines, aldehydes, and isocyanides with
ytterbium triflate and silver carbonate. To the best of our
knowledge, this type of scaffold has never been reported. This
approach could be easily applied to the synthesis of more
privileged structure-based analogues that are of interest in drug
discovery. Meanwhile, biological properties of this rarely
described class of compounds are currently under investigation.
3-(Pentan-2-yl)-2-phenyl-4-(p-tolyl)-3H-1,2a1,3-triazaace-
naphthylene (5d). Dark red amorphous solid (85% yield). HPLC
purity 98%; 1H NMR (400 MHz, CDCl3) δ 7.94−7.88 (m, 2H), 7.52
(d, J = 8.1 Hz, 2H), 7.46−7.35 (m, 3H), 7.24−7.17 (m, 2H), 6.82 (d, J
= 8.7 Hz, 1H), 6.66 (m, 1H), 5.89 (s, 1H), 5.81 (d, J = 6.7 Hz, 1H),
3.05 (dd, J = 14.4, 6.3 Hz, 1H), 2.40 (s, 3H), 1.08−1.02 (m, 2H), 0.96
(d, J = 6.8 Hz, 3H), 0.91−0.83 (m, 2H), 0.58 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 152.0, 140.8, 139.7, 135.6, 135.5, 134.6,
131.1, 129.2 (2 × C), 128.3 (2 × C), 127.0 (2 × C), 126.9, 126.8 (2 ×
C), 126.7, 125.3, 114.9, 110.7, 104.4, 67.0, 37.8, 21.4, 20.2, 19.2, 13.7.
HRMS(EI) m/z calcd for C27H27N3: 393.2205, found 393.2205.
3-(Cyclohexylmethyl)-2-phenyl-4-(p-tolyl)-3H-1,2a1,3-tria-
zaacenaphthylene (5e). Dark red solid (65% yield). HPLC purity
EXPERIMENTAL SECTION
■
General Comments. The 1H NMR (400 MHz) spectra were
recorded using high performance digital FT-NMR with TMS as
internal standard, and the 13C NMR (100 MHz) spectra were
recorded using high performance digital FT-NMR. LR-MS and HR-
MS were obtained by EI on a double-focusing mass analyzer, ESI
(positive ion mode) on TOF mass analyzer. Purity was recorded with
high-performance liquid chromatography (HPLC); conditions were as
follows: ACN/H2O eluent at 2 mL/min flow (containing 0.05% TFA)
at 40 °C, 5 min, gradient 5% ACN to 95% ACN, monitored by UV
absorption at both 214 and 254 nm. TLC was carried out with glass
precoated silica gel plates. TLC spots were visualized under UV light.
All the solvents and reagents were used directly as obtained
commercially unless otherwise noted.
1
98%. mp 92−93 °C; H NMR (400 MHz, CDCl3) δ 7.59−7.56 (m,
2H), 7.39−7.35 (m, 2H), 7.29−7.18 (m, 5H), 6.45−6.38 (m, 1H),
6.34 (dd, J = 9.4, 6.6 Hz, 1H), 5.26 (d, J = 6.4 Hz, 1H), 5.04 (s, 1H),
2.82 (d, J = 6.3 Hz, 2H), 2.39 (s, 3H), 1.64−1.57 (m, 3H), 1.51−1.47
(m, 3H), 1.14−1.03 (m, 2 H), 0.96−0.86 (m, 1H), 0.62−0.52 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 153.6, 141.3, 139.9, 137.7,
134.1, 133.0, 129.5 (2 × C), 128.1 (2 × C), 128.0, 127.1 (2 × C),
126.8 (2 × C), 126.7, 126.6, 125.6, 114.4, 103.9, 101.4, 56.3, 36.5, 30.4
(2 × C), 26.1, 25.7 (2 × C), 21.4. HRMS(EI) m/z calcd for C29H29N3:
419.2361, found 419.2354.
Ethyl 2-[2-(4-Methoxyphenyl)-4-(p-tolyl)-3H-1,2a1,3-triazaa-
cenaphthylen-3-yl]acetate (5f). Dark red solid (83% yield). HPLC
purity 100%. mp 136−138 °C; 1H NMR (400 MHz, CDCl3) δ 7.62−
7.58 (m, 2H), 7.36−7.32 (m, 2H), 7.23−7.19 (m, 2H), 6.98−6.94 (m,
2H), 6.60−6.56 (m, 1H), 6.48 (dd, J = 9.3, 6.7 Hz, 1H), 5.54 (d, J =
6.5 Hz, 1H), 5.43 (s, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.75
(s, 2H), 2.39 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.3, 158.6, 151.1, 140.9, 140.3, 136.2, 132.2, 129.7 (2 ×
C), 127.7 (2 × C), 127.3, 126.6, 126.5, 126.4, 125.3, 115.0, 113.9 (2 ×
C), 106.5, 103.0, 61.1, 55.3, 52.5, 21.4, 13.8. HRMS(EI) m/z calcd for
C27H25N3O3: 439.1896, found 439.1895.
Typical Procedure for the Synthesis of Ethyl 2-[2-Phenyl-4-
(p-tolyl)-3H-1,2a1,3-triazaacenaphthylen-3-yl]acetate (5a). To a
solution of 6-(p-tolylethynyl)pyridin-2-amine (1a, 50 mg, 0.24 mmol)
in EtOH (5 mL) was added benzaldehyde (2a, 26 μL, 0.25 mmol) .
After the mixture was stirred at rt for 10 min, Yb(OTf)3 (15 mg, 0.024
mmol) and ethyl 2-isocyanoacetate (3a, 31 μL, 0.29 mmol) were
added. The mixture was stirred at 65 °C for about 4 h. Then Ag2CO3
(6.6 mg, 0.024 mmol) was added to the reaction mixture, and the
mixture was stirred at 65 °C for 12 h. The reaction mixture was cooled
to room temperature and concentrated in vacuo. The residue was
purified by flash chromatography (SiO2, petroleum ether:ethyl acetate
= 2:1) giving a dark brown oil, which was crystallized from a mixture
of petroleum ether and ethyl acetate to give 80 mg (81% yield) of 5a
Ethyl 2-[2-Butyl-4-(p-tolyl)-3H-1,2a1,3-triazaacenaphthylen-
3-yl]acetate (5g). Dark red amorphous solid (75% yield). HPLC
purity 98%; 1H NMR (400 MHz, CDCl3) δ 7.30−7.26 (m, 2H),
7.19−7.15 (m, 2H), 6.39−6.36 (m, 1H), 6.31 (dd, J = 9.3, 6.5 Hz,
1H), 5.30 (dd, J = 6.5, 0.5 Hz, 1H), 5.07 (s, 1H), 4.18−4.13 (q, J = 7.2
Hz, 2H), 3.77 (s, 2H), 2.42−2.35 (m, 5H), 1.65−1.56 (m, 2H), 1.27−
1.22 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.8, 151.5, 140.4, 140.1, 136.6, 132.2,
129.6 (2 × C), 127.1, 126.7 (2 × C), 126.3, 125.6, 114.4, 104.2, 102.0,
61.2, 53.2, 31.4, 27.4, 22.6, 21.3, 14.0, 13.9. HRMS(EI) m/z calcd for
C24H27N3O2: 389.2103, found 389.2101.
1
as a dark red solid. HPLC purity 100%. mp 152−153 °C; H NMR
(400 MHz, CDCl3) δ 7.69−7.67 (m, 2H), 7.41 (t, J = 7.7 Hz, 2H),
7.37−7.33 (m, 2H), 7.29−7.24 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H), 6.60
(d, J = 9.2 Hz, 1H), 6.52−6.47 (m, 1H), 5.56 (d, J = 6.7 Hz, 1H), 5.46
(s, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 2.39 (s, 3H), 1.08 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 151.1, 141.1,
140.4, 136.3, 133.9, 132.1, 129.8 (2 × C), 128.5 (2 × C), 127.5, 127.0,
126.7 (2 × C), 126.6, 126.5 (2 × C), 126.2, 115.1, 106.6, 103.1, 61.1,
52.8, 21.4, 13.8. HRMS(EI) m/z calcd for C26H23O2N3: 409.1790,
found 409.1796.
Ethyl 2-[2-(Pyridin-2-yl)-4-(p-tolyl)-3H-1,2a1,3-triazaace-
naphthylen-3-yl]acetate (5h). Dark red solid (51% yield). HPLC
3-Cyclohexyl-2-phenyl-4-(p-tolyl)-3H-1,2a1,3-triazaacenaph-
thylene (5b). Orange solid (77% yield). HPLC purity 95%. mp 168−
1
purity 98%. mp 147−150 °C; H NMR (400 MHz, CDCl3) δ 8.59−
1
8.56 (m, 1H), 8.05−8.01 (m, 1H), 7.71−7.65 (m, 1H), 7.40−7.35 (m,
2H), 7.23−7.18 (m, 2H), 7.10−7.06 (m, 1H), 6.53−6.44 (m, 2H),
5.46−5.42 (m, 1H), 5.33 (s, 1H), 4.56 (s, 2H), 4.02 (q, J = 7.2 Hz,
2H), 2.38 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.2, 153.4, 151.9, 148.3, 141.2, 140.2, 137.2, 136.2, 132.1,
129.6 (2 × C), 129.4, 128.4, 126.9 (2 × C), 125.3, 121.5, 120.4, 114.6,
105.5, 102.0, 60.9, 53.1, 21.4, 13.9. HRMS(EI) m/z calcd for
C25H22N4O2: 410.1743, found 410.1746.
169 °C; H NMR (400 MHz, CDCl3) δ 8.02−8.00 (m, 2H), 7.58−
7.56 (m, 2H), 7.44−7.40 (m, 2H), 7.28−7.21 (m, 3H), 6.86 (d, J = 9.0
Hz, 1H), 6.72−6.68 (m, 1H), 6.01 (s, 1H), 5.87 (d, J = 6.8 Hz, 1H),
2.87 (m, 1H), 2.42 (s, 3H), 2.03 −1.95 (m, 2H), 1.52 (d, J = 14.7 Hz,
2H), 1.33 (d, J = 13.5 Hz, 1H), 1.04 (ddd, J = 15.8, 11.9, 3.0 Hz, 2H),
0.94−0.82 (m, 2H), 0.79−0.69 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 151.3, 140.8, 139.8, 135.7, 135.4, 134.6, 131.6, 129.3 (2 ×
C), 128.3 (2 × C), 126.9, 126.7 (2 × C), 126.6, 126.4 (2 × C), 124.9,
114.9, 110.9, 104.8, 71.1, 32.0 (2 × C), 26.1 (2 × C), 25.2, 21.4.
HRMS(EI) m/z calcd for C28H27N3: 405.2205, found 405.2201.
3-(4-Methoxyphenyl)-2-phenyl-4-(p-tolyl)-3H-1,2a1,3-tria-
zaacenaphthylene (5c). Dark red solid (28% yield). HPLC purity
Ethyl 2-[4-(Cyclopentylmethyl)-2-phenyl-3H-1,2a1,3-triazaa-
cenaphthylen-3-yl]acetate (5i). Dark red amorphous solid (40%
1
yield). HPLC purity 98%; H NMR (400 MHz, CDCl3) δ 7.49−7.52
(m, 2H), 7.34−7.43 (m, 2H), 7.23−7.27 (m, 1H), 6.51 (d, J = 9.3 Hz,
1H), 6.40 (dd, J = 9.4, 6.7 Hz, 1H), 5.31 (d, J = 6.6 Hz, 1H), 5.01 (s,
1H), 4.11 (q, J = 7.1 Hz, 2H), 3.82(s, 2H), 2.03−1.87 (m, 4H), 1.68−
1.57 (m, 4H), 1.29−1.20 (m, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.1, 150.6, 140.9, 136.5, 133.6, 128.3 (2 × C),
128.1, 127.2 (2 × C), 127.1, 126.4, 124.4, 114.0, 103.0, 101.1, 61.3,
50.2, 38.0, 36.9, 32.2 (2 × C), 24.9 (2 × C), 13.8. HRMS(EI) m/z
calcd for C25H27O2N3: 401.2103, found 401.2095.
1
100%. mp 71−73 °C; H NMR (400 MHz, CDCl3) δ 7.43−7.40(m,
2H), 7.29−7.25 (m, 2H), 7.18−7.10 (m, 3H), 7.04−7.01 (m, 4H),
6.61 (d, J = 9.2 Hz, 1H), 6.53−6.48 (m, 1H), 6.45−6.41 (m, 2H), 5.56
(d, J = 6.8 Hz, 1H), 5.41 (s, 1H), 3.58 (s, 3H), 2.28 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.4, 151.7, 140.6, 139.3, 138.7, 136.4, 133.6,
133.1, 129.3 (2 × C), 129.0 (2 × C), 128.3, 127.7 (2 × C), 127.6 (2 ×
C), 127.3 (2 × C), 127.2, 127.0, 126.6, 115.1, 113.8 (2 × C), 104.6,
E
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Ethyl 2-(4-Butyl-2-phenyl-3H-1,2a1,3-triazaacenaphthylen-
3-yl)acetate (5j). Dark red amorphous solid (46% yield). HPLC
purity 97%; 1H NMR (400 MHz, CDCl3) δ 7.51−7.48 (m, 2H),
7.44−7.34 (m, 2H), 7.28−7.23 (m, 1H), 6.49 (d, J = 9.3 Hz, 1H), 6.39
(dd, J = 9.4, 6.7 Hz, 1H), 5.29 (d, J = 6.6 Hz, 1H), 4.99 (s, 1H), 4.11
(q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 1.92 (t, J = 7.2 Hz, 2H), 1.49−1.39
(m, 4H), 1.15 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.1, 150.9, 140.9, 136.6, 133.6, 128.3 (2 × C),
128.2, 127.3 (2 × C), 127.1, 126.4, 124.1, 113.9, 102.0, 100.9, 61.3,
49.9, 31.3, 28.7, 22.0, 13.9, 13.8. HRMS(EI) m/z calcd for
C23H25O2N3: 375.1947, found 375.1949.
152.6, 142.3, 135.7, 134.5, 132.8, 130.5, 130.1, 129.2 (2 × C), 128.9,
128.7 (2 × C), 128.0, 127.2, 126.7 (2 × C), 126.6 (2 × C), 119.4,
104.3, 61.3, 52.1, 13.8. HRMS(EI) m/z calcd for C24H20N4O2:
396.1586, found 396.1581.
Ethyl 2-(4-(4-Methoxyphenyl)-2-phenyl-3H-1,2a1,3,7-tetraa-
zaacenaphthylen-3-yl)acetate (5q). Dark red amorphous solid
1
(42% yield). HPLC purity 95%; H NMR (400 MHz, CDCl3) δ 8.07
(s, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.50−7.29 (m, 5H), 6.94 (d, J = 7.2
Hz, 2H), 6.63 (s, 1H), 5.36 (s, 1H), 4.04 (q, J = 6.5 Hz, 2H), 3.85 (s,
3H), 3.77 (s, 2H), 1.09 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 168.5, 160.9, 152.1, 141.5, 135.3, 132.4, 130.0, 128.5, 128.3
(2 × C), 127.7 (2 × C), 127.4, 126.9, 126.3 (2 × C), 125.9, 118.7,
114.2 (2 × C), 102.8, 60.9, 55.0, 51.8, 13.4. HRMS(ESI) m/z calcd for
C25H23N4O3 (M + H): 427.1770, found 427.1749.
Ethyl 2-(4-Isobutyl-2-phenyl-3H-1,2a1,3-triazaacenaphthy-
len-3-yl)acetate (5k). Dark red amorphous solid (43% yield).
1
HPLC purity 97%; H NMR (400 MHz, CDCl3) δ 7.53−7.49 (m,
2H), 7.44−7.35 (m, 2H), 7.27−7.24 (m, 1H), 6.53 (d, J = 9.3 Hz,
1H), 6.41 (dd, J = 9.4, 6.7 Hz, 1H), 5.33 (d, J = 6.7 Hz, 1H), 5.02 (s,
1H), 4.11 (q, J = 6.8 Hz, 2H), 3.81 (s, 2H), 1.84−1.76 (m, 3H), 1.16
(t, J = 7.1 Hz, 3H), 1.04 (d, J = 6.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 169.1, 149.9, 140.9, 136.3, 133.5, 128.3 (2 × C), 128.0,
127.9, 127.1 (2 × C), 126.3, 124.5, 114.1, 103.9, 101.1, 61.3, 50.2, 41.0,
25.8, 22.1 (2 × C), 13.81. HRMS(EI) m/z calcd for C23H25O2N3:
375.1947, found 375.1940.
Ethyl 2-(4-Butyl-2-phenyl-3H-1,2a1,3,7-tetraazaacenaphthy-
len-3-yl)acetate (5r). Dark red amorphous solid (31% yield). HPLC
1
purity 95%; H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.45 (m,
2H), 7.41−7.35 (m, 2H), 7.35−7.29 (m, 2H), 6.31 (s, 1H), 4.11 (q, J
= 7.1 Hz, 2H), 3.78 (s, 2H), 1.89 (t, J = 7.1 Hz, 2H), 1.49−1.39 (m,
4H), 1.16 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 168.8, 152.6, 141.8, 135.4, 133.1, 130.7, 128.4 (2 ×
C), 127.9, 127.7 (2 × C), 127.5, 126.8, 117.1, 98.9, 61.5, 49.2, 31.4,
28.7, 22.0, 13.9, 13.7. HRMS(EI) m/z calcd for C22H24N4O2:
376.1899, found 376.1897.
Ethyl 2-(2,4-Diphenyl-3H-1,2a1,3-triazaacenaphthylen-3-yl)-
acetate (5l). Dark red solid (70% yield). HPLC purity 100%. mp
1
143−144 °C; H NMR (400 MHz, CDCl3) δ 7.70−7.66 (m, 2H),
7.48−7.39 (m, 7H), 7.30−7.24 (m, 1H), 6.64−6.59 (m, 1H), 6.50 (dd,
J = 9.3, 6.7 Hz, 1H), 5.58 (d, J = 6.6 Hz, 1H), 5.49 (s, 1H), 4.03 (q, J =
7.2 Hz, 2H), 3.76 (s, 2H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 169.2, 150.9, 141.1, 136.1, 135.1, 133.8, 130.1, 129.1
(2 × C), 128.5 (2 × C), 127.5, 127.0, 126.7 (2 × C), 126.6, 126.4 (2 ×
C), 126.1, 115.3, 107.2, 103.3, 61.1, 52.7, 13.8. HRMS(EI) m/z calcd
for C25H21N3O2: 395.1634, found 395.1649.
Procedure for the Synthesis of 6-(2-Ethoxy-2-oxoethyl)-12-
phenyl-5-(p-tolyl)-6H-3a1,6,12a-triazabenzo[j]fluoranthen-
12a-ium triflate (7). To a solution of 6-(p-tolylethynyl)pyridin-2-
amine (1a, 50 mg, 0.24 mmol) in EtOH (5 mL) was added 2-
(phenylethynyl)benzaldehyde (6, 52 mg, 0.25 mmol). After the
mixture was stirred at rt for 10 min, Yb(OTf)3 (15 mg, 0.024 mmol)
and ethyl 2-isocyanoacetate (3a, 31 μL, 0.29 mmol) were added. The
mixture was stirred at 65 °C for about 4 h. Then AgOTf (6 mg, 0.024
mmol) was added to the reaction mixture, and the mixture was stirred
at 65 °C for 12 h. The reaction mixture was cooled to room
temperature and concentrated in vacuo. The residue was purified by
flash chromatography (SiO2, petroleum ether:ethyl acetate = 2:1) to
give 7 (81 mg, 66% yield) as a dark brown solid, HPLC purity 95%.
mp 188−190 °C; 1H NMR (400 MHz, CDCl3) δ 8.00−7.98 (m, 1H),
7.88−7.83 (m, 1H), 7.74−7.62 (m, 6H), 7.59−7.52 (m, 4H), 7.36−
7.32 (m, 2H), 7.19(dd, J = 9.46, 7.32 Hz, 1H), 6.89 (s, 1H), 6.82 (d, J
= 7.4 Hz, 1H), 6.30 (s, 1H), 5.69 (d, J = 9.1 Hz, 1H), 4.18 (s, 2H),
4.08 (q, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 168.2, 152.2, 142.5, 137.1, 135.3, 133.9,
131.7, 131.4, 131.3, 130.5 (2 × C), 130.4, 130.1, 130.0 (2 × C), 129.5
(2 × C), 129.4, 128.8, 128.0, 127.0 (2 × C), 124.1, 123.4, 121.0, 118.0,
116.8, 112.1, 109.9, 108.3, 62.1, 53.9, 21.6, 13.8. HRMS(ESI) m/z
Ethyl 2-{2-Phenyl-4-[4-(trifluoromethyl)phenyl]-3H-1,2a1,3-
triazaacenaphthylen-3-yl}acetate (5m). Dark red solid (78%
1
yield). HPLC purity 96%. mp 150−152 °C; H NMR (400 MHz,
CDCl3) δ 7.70−7.66 (m, 4H), 7.62−7.58 (m, 2H), 7.45−7.40 (m,
2H), 7.32−7.26 (m, 1H), 6.66 (d, J = 9.3 Hz, 1H), 6.53 (dd, J = 9.4,
6.7 Hz, 1H), 5.65 (d, J = 6.6 Hz, 1H), 5.57 (s, 1H), 4.04 (q, J = 7.2 Hz,
2H), 3.71 (s, 2H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 141.1, 139.1, 135.4, 133.5, 131.8, 128.6 (2 × C), 128.4,
127.4, 127.3, 127.1 (2 × C), 126.4 (2 × C), 126.2, 126.1, 125.8, 125.7,
125.0, 122.3, 116.0, 109.1, 104.3, 61.3, 52.8, 13.8. HRMS(EI) m/z
calcd for C26H20N3O2F3: 463.1508, found 463.1508.
Ethyl 2-[4-(4-Fluorophenyl)-2-phenyl-3H-1,2a1,3-triazaace-
naphthylen-3-yl]acetate (5n). Dark red solid (75% yield). HPLC
1
purity 96%. mp 146−148 °C; H NMR (400 MHz, CDCl3) δ 7.69−
7.65 (m, 2H), 7.48−7.39 (m, 4H), 7.30−7.25 (m, 1H), 7.14−7.08 (m,
2H), 6.64−6.60 (m, 1H), 6.51 (dd, J = 9.4, 6.7 Hz, 1H), 5.58 (d, J =
6.6 Hz, 1H), 5.45 (s, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.73 (s, 2H), 1.08
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 164.9,
162.4, 149.8, 141.1, 135.9, 133.7, 131.1, 131.0, 128.7, 128.6, 128.5 (2 ×
C), 127.5, 127.1, 126.4 (2 × C), 116.4, 116.1, 115.4, 107.3, 103.5, 61.2,
52.7, 13.8. HRMS(EI) m/z calcd for C25H20N3O2F: 413.1540, found
413.1542.
+
calcd for C34H28N3O2 : 510.2182, found 510.2165.
Ethyl 2-{[2-Phenyl-5-(p-tolylethynyl)imidazo[1,2-a]pyridin-
3-yl]amino}acetate (4). To a solution of 6-(p-tolylethynyl)pyridin-
2-amine (1a, 50 mg, 0.24 mmol) in EtOH (5 mL) was added
benzaldehyde (2a, 26 μL, 0.25 mmol). After the mixture was stirred at
rt for 10 min, Yb(OTf)3 (15 mg, 0.024 mmol) and ethyl 2-
isocyanoacetate (3a, 31 μL, 0.29 mmol) were added. The mixture was
stirred at 65 °C for about 4 h. The reaction mixture was cooled to
room temperature and concentrated in vacuo. The residue was purified
by flash chromatography (SiO2, petroleum ether: ethyl acetate = 2:1)
Ethyl 2-(4-(4-Methoxyphenyl)-2-phenyl-3H-1,2a1,3-triazaa-
cenaphthylen-3-yl)acetate (5o). Dark red solid (70% yield).
HPLC purity 100%. mp 156−159 °C;1H NMR (400 MHz, CDCl3)
δ 7.72−7.66 (m, 2H), 7.45−7.36 (m, 4H), 7.30−7.24 (m, 1H), 6.96−
6.90 (m, 2H), 6.60 (dd, J = 9.3, 0.6 Hz, 1H), 6.50 (dd, J = 9.3, 6.7 Hz,
1H), 5.56 (d, J = 6.6 Hz, 1H), 5.44 (s, 1H), 4.03 (q, J = 7.2 Hz, 2H),
3.84 (s, 3H), 3.78 (s, 2H), 1.08 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 169.3, 161.1, 150.8, 141.2, 136.4, 133.9, 128.6 (2 ×
C), 128.2 (2 × C), 127.6, 127.0, 127.2, 126.2, 126.4 (2 × C), 126.6,
114.9, 114.5 (2 × C), 106.1, 103.0, 61.1, 55.4, 52.9, 13.9. HRMS(EI)
m/z calcd for C26H23N3O3: 425.1739, found 425.1743.
1
to give 4 as a yellow oil (70 mg, 71% yield). HPLC purity 100%; H
NMR (400 MHz, CDCl3) δ 8.21 (d, J = 7.2 Hz, 2H), 7.56 (dd, J = 7.7,
2.4 Hz, 1H), 7.45 (dd, J = 15.1, 7.9 Hz, 4H), 7.31 (t, J = 7.4 Hz, 1H),
7.19 (d, J = 8.0 Hz, 2H), 7.09−7.02 (m, 2H), 4.65 (t, J = 6.2 Hz, 1H),
4.03 (q, J = 7.1 Hz, 2H), 3.87 (d, J = 6.2 Hz, 2H), 2.38 (s, 3H), 1.11 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 141.6, 139.5,
135.1, 133.3, 131.1 (2 × C), 128.9 (2 × C), 128.1 (2 × C), 127.0,
127.1, 126.8 (2 × C), 122.9, 119.9, 118.5, 117.9, 117.7, 97.8, 81.1, 60.6,
50.4, 21.2, 13.5. HRMS(ESI) m/z calcd for C26H24N3O2 (M + H):
410.1869, found 410.1861.
Ethyl 2-(2,4-Diphenyl-3H-1,2a1,3,7-tetraazaacenaphthylen-
3-yl)acetate (5p). Dark red amorphous solid (47% yield). HPLC
1
purity 97%; H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.71−7.24
(m, 10H), 6.61 (s, 1H), 5.40 (s, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.74 (s,
2H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8,
F
dx.doi.org/10.1021/jo3021105 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Steenkamp, P. A.; Hoppe, H. C.; Khan, T.; Nkabinde, L. A. Bioorg.
Med. Chem. 2011, 19, 4227.
ASSOCIATED CONTENT
* Supporting Information
Copies of spectra for all the compounds, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(11) (a) Bienayme, H.; Bouzid, K. Angew Chem., Int Ed. 1998, 37,
2234. (b) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635. (c) Polyakov, A. I.; Eryomina, V. A.;
Medvedeva, L. A.; Tihonova, N. I.; Listratova, A. V.; Voskressensky, L.
G. Tetrahedron Lett. 2009, 50, 4389. (d) DiMauro, E. F.; Kennedy, J.
M. J. Org. Chem. 2007, 72, 1013.
(12) (a) Jessep, M. A.; Leaver, D. J. Chem. Soc., Perkin Trans. 1 1980,
1324. (b) Dick, J. W.; Gibson, W. K.; Leaver, D.; Roff, J. E. J. Chem.
Soc., Perkin Trans. 1 1981, 3150. (c) Ceder, O.; Andreasson, E. Chem.
Scr. 1984, 23, 170. Kawamoto, T.; Tomimatsu, K.; Ikemoto, T.; Abe,
H.; Hamamura, K.; Takatani, M. Tetrahedron Lett. 2000, 41, 3447.
(13) (a) Meng, T.; Zhang, Z.; Hu, D.; Lin, L.; Ding, J.; Wang, X.;
Shen, J. J. Comb. Chem. 2007, 9, 739. (b) Meng, T.; Zhang, Y.; Li, M.;
Wang, X.; Shen, J. J. Comb. Chem. 2010, 12, 222. (c) Meng, T.; Zou,
Y.; Khorev, O.; Jin, Y.; Zhou, H.; Zhang, Y.; Hu, D.; Ma, L.; Wang, X.;
Shen, J. Adv. Synth. Catal. 2011, 353, 918.
AUTHOR INFORMATION
Corresponding Author
*Tel: +86 21 50806600 5407; fax: +86 21 50807088; e-mail:
tmeng@sibs.ac.cn; jkshen@mail.shcnc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science &
Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (no. 2012ZX09103-101-026)
and the National Natural Science Foundation of China (grants
81001355 and 81273367).
(14) Domling, A. Chem. Rev. 2006, 106, 17.
(15) Li, L. S.; Rader, C.; Matsushita, M.; Das, S.; Barbas, C. F.;
Lerner, R. A.; Sinha, S. C. J. Med. Chem. 2004, 47, 5630.
(16) Bell, A.; Edwards, D. A. J. Chem. Soc., Dalton Trans. 1984, 1317.
(17) Zhou, H.; Wang, W.; Khorev, O.; Zhang, Y.; Miao, Z.; Meng, T.;
Shen, J. Eur. J. Org. Chem. 2012, 5585.
REFERENCES
■
(1) Joule, J. A., Mills, K. Heterocyclic Chemistry; John Wiley & Sons:
Hoboken, NJ, 2010; pp 552−555.
(2) For selected reviews, see: (a) Zhu, J.; Bienayme, H.
́
Multicomponent Reactions; Wiley-VCH: Weinheim, Germany, 2005.
(b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169.
(c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(d) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
(3) For selected reviews, see: (a) Nair, V.; Rajesh, C.; Vinod, A. U.;
Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res.
2003, 36, 899. (b) Ugi, I.; Werner, B.; Domling, A. Molecules 2003, 8,
̈
53. (c) Isambert, N.; Lavilla, R. Chem.Eur. J. 2008, 14, 8444.
(d) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (e) Tietze, L.
F.; Modi, A. Med. Res. Rev. 2000, 20, 304. (f) Ruijter, E.; Scheffelaar,
R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234.
(4) For recent selected examples, see: (a) Sunderhaus, J. D.; Martin,
S. E. Chem.Eur. J. 2009, 15, 1300. (b) Banfi, L.; Riva, R.; Basso, A.
Synlett 2010, 23. (c) Ramachary, D. B.; Jain, S. Org. Biomol. Chem.
2011, 9, 1277.
(5) (a) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992, 40,
1170. (b) Lhassani, M.; Chavignon, O.; Chezal, J. M.; Teulade, J. C.;
Chapat, J. P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.;
Gueiffier, A. Eur. J. Med. Chem. 1999, 34, 271. (c) Hayakawa, M.;
Kaizawa, H.; Kawaguchi, K.; Ishikawa, N.; Koizumi, T.; Ohishi, T.;
Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.; Raynaud, F. I.;
Waterfield, M. D.; Parker, P.; Workman, P. Bioorg. Med. Chem. 2007,
15, 403. (d) Scribner, A.; Dennis, R.; Hong, J.; Lee, S.; McIntyre, D.;
Perrey, D.; Feng, D.; Fisher, M.; Wyvratt, M.; Leavitt, P.; Liberator, P.;
Gurnett, A.; Brown, C.; Mathew, J.; Thompson, D.; Schmatz, D.; Biftu,
T. Eur. J. Med. Chem. 2007, 42, 1334.
(6) (a) Katritzky, A. R.; Xu, Y. J.; Tu, H. B. J. Org. Chem. 2003, 68,
4935. (b) Ismail, M. A.; Brun, R.; Wenzler, T.; Tanious, F. A.; Wilson,
W. D.; Boykin, D. W. J. Med. Chem. 2004, 47, 3658. (c) Palmer, A. M.;
Grobbel, B.; Jecke, C.; Brehm, C.; Zimmermann, P. J.; Buhr, W.; Feth,
M. P.; Simon, W. A.; Kromer, W. J. Med. Chem. 2007, 50, 6240.
(7) Schneier, F. R.; Carrasco, J. L.; Hollander, E.; Campeas, R.;
Fallon, B.; Saoud, J. B.; Feerick, J.; Liebowitz, M. R. J. Clin.
Psychopharmacol. 1993, 13, 150.
(8) Harrison, T. S.; Keating, G. M. CNS Drugs 2005, 19, 65.
(9) Almirant., L.; Polo, L.; Mugnaini, A.; Provinci., E.; Rugarli, P.;
Biancott., A.; Gamba, A.; Murmann, W. J. Med. Chem. 1965, 8, 305.
(10) (a) Cai, L.; Cuevas, J.; Temme, S.; Herman, M. M.; Dagostin,
C.; Widdowson, D. A.; Innis, R. B.; Pike, V. W. J. Med. Chem. 2007, 50,
4746. (b) Boggs, S.; Elitzin, V. I.; Gudmundsson, K.; Martin, M. T.;
Sharp, M. J. Org. Process Res. Dev. 2009, 13, 781. (c) Bode, M. L.;
Gravestock, D.; Moleele, S. S.; van der Westhuyzen, C. W.; Pelly, S. C.;
G
dx.doi.org/10.1021/jo3021105 | J. Org. Chem. XXXX, XXX, XXX−XXX