Rh(III)-catalyzed C-H activation/cyclization of indoles and pyrroles: Divergent synthesis of heterocycles

Article abstract of DOI:10.1021/jo500902n

We report herein a new strategy of the Rh(III)-catalyzed C-H activation/cyclization of indoles and pyrroles, for the divergent synthesis of privileged heterocycles. A simple derivation of indoles and pyrroles to N-carboxamides with oxidative bidentate dir

Full text of DOI:10.1021/jo500902n

Article
pubs.acs.org/joc
Rh(III)-Catalyzed C−H Activation/Cyclization of Indoles and Pyrroles:
Divergent Synthesis of Heterocycles
Yan Zhang, Jing Zheng, and Sunliang Cui*
Institute of Materia Medica and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
S
* Supporting Information
ABSTRACT: We report herein a new strategy of the Rh(III)-
catalyzed C−H activation/cyclization of indoles and pyrroles,
for the divergent synthesis of privileged heterocycles. A simple
derivation of indoles and pyrroles to N-carboxamides with
oxidative bidentate directing group could enable rhodacycle
formation and late-stage redox-neutral cyclization with alkynes,
alkenes and diazo compounds, for access to five- and six-
membered fused heterocycles, such as pyrimido[1,6-a]indol-
1(2H)-one, 3,4-dihydropyrimido[1,6-a]indol-1(2H)-one, and
1H-imidazo[1,5-a]indol-3(2H)-ones. Kinetic isotope effect
study was conducted, and a plausible mechanism was
proposed. Furthermore, this protocol was applied to concise synthesis of 5-HT3 receptor antagonist in gram-scale.
INTRODUCTION
■
Indoles and pyrroles are probably the most ubiquitous
heterocycles in nature and have been referred as privileged
structures in drug discovery,1 and consequently, there are many
powerful methodologies for the synthesis of these scaffolds.2
Polycyclic indole-fused and pyrrole-fused heterocycles, such as
pyrimido[1,6-a]indol-1(2H)-one, 3,4-dihydropyrimido[1,6-a]-
indol-1(2H)-one, 1H-imidazo[1,5-a]indol-3(2H)-one and the
pyrrole-containing analogues, are an integral part of many
biologically active natural molecules and synthetic compounds,
drugs (Figure 1), acting as fluorescent material, antihyperten-
sive agent, 5-HT3 receptor antagonist, CNS depressant, etc.3
Construction of these polycyclic heterocycles either requires
multistep synthesis or suffers from narrow substrate scope.4
Therefore, the development of new approaches that allow rapid
establishment of these scaffolds in simple operation from
readily available precursors remains challenge and importance.
Recently, the Rh(III)-catalyzed functionalization of aryl C−
H bond has enjoyed tremendous advance owing to their wide
applications to the rapid assembly of various complex molecular
structures, particular in the fields of medicinal chemistry.5,6 The
pioneering works on Rh(III)-catalyzed C−H/O−H and C−H/
N−H cyclizations were reported by Miura and Satoh, Fagnou
and Jones.7 Particularly, Rh(III)-catalyzed cyclization of
benzamides has been well developed by Fagnou, Glorius,
Indoles and pyrroles have been popular molecules in
transition-metal catalyzed C−H functionalization owing to
their numerous biological activities,10−13 despite this fact,
unique C−H functionalization for these compounds toward
new heterocycle skeletal construction still remains rare. In
Rovis and so on, to access various nitrogen-containing
heterocycles with the fashion of external oxidant free (eq 1).8
These protocols involve a sequence of C−H activation of
benzamides to generate rhodacycles and subsequent annulation
reaction with alkenes, alkynes and allenes, etc. More recently,
Rovis established a coupling of benzamides and donor/acceptor
diazo compounds to form γ-lactams via Rh(III)-catalyzed C−H
activation (eq 2).9
Received: April 23, 2014
Published: June 20, 2014
© 2014 American Chemical Society
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Figure 1. Selected examples of natural products and pharmaceuticals containing polycyclic indole-fused and pyrrole-fused heterocycles.
continuation of our interest in Rh(III)-catalyzed C−H
functionalization toward biologically interesting small molecule
synthesis,14 we proposed that a simple derivation of indoles and
pyrroles to their N-carboxamide derivatives as oxidative
bidentate directing group could enable a Rh(III)-catalyzed
C−H activation of indoles and pyrroles at 2-position, and a
further coupling with various alkynes, alkenes and diazo
compounds would deliver interesting heterocycles. Herein, we
wish to report a divergent synthesis of heterocycles via Rh(III)-
catalyzed C−H activation/cyclization of indoles and pyrroles
(eq 3).
further optimize the reaction condition. Variation of additives
showed that KOAc led to the formation of product in a slightly
lower yield (Table 1, entry 3), while CsOAc was superior to
afford the product in 93% yield (Table 1, entry 4). Replacing
CsOAc with CsOPiv gave a comparable yield (Table 1, entry
5). Further screening of solvents revealed that EtOH, TFE and
CH3CN were inferior to MeOH (Table 1, entries 6−8).
With the optimized reaction condition in hand, we next
investigated the generality of this scope for pyrimido[1,6-
a]indol-1(2H)-one synthesis. As shown in Table 2, both
symmetrical and unsymmetrical alkynes with valuable func-
tional groups such as hydroxyl, ester, could proceed smoothly
in this transformation to provide the corresponding pyrimido-
[1,6-a]indol-1(2H)-one products in good to excellent yields
(3a−3h, 50−95%). Moreover, the insertion of an aryl-alkyl
disubstituted alkyne occurred regioselectively with the sp2
center being installed at the 3-position (3d and 3e). The
reaction was also compatible with terminal alkynes with
terminal end being located at the 4-position (3f−3h), except
for that n-hexyne was used to afford a mixture of regioisomers
(3i and 3j). A variety of N-carboxamides of indoles were also
well applicable to access diverse pyrimido[1,6-a]indol-1(2H)-
ones. For example, the N-carboxamides derived from 5-
methylindole, 5-methoxyindole, 4-benzyloxyindole and 3-
methylindole could proceed efficiently to generate polysub-
stituted privileged pyrimido[1,6-a]indol-1(2H)-ones in good to
excellent yields (3k−3q, 68−97%). The N-(pivaloyloxy)-1H-
pyrrole-1-carboxamide 1g was also employed in this Rh(III)-
catalyzed C−H activation/cyclization process to construct
pyrrolo[1,2-c]pyrimidin-1(2H)-ones in good to excellent yields
(3r−3v, 64−98%), which usually required multistep synthesis
in traditional methods. Moreover, the structure of 3f was
unambiguously confirmed by single X-ray analysis (see
Supporting Information), identical to characterization. Consid-
ering the wealth of these pyrimido[1,6-a]indol-1(2H)-ones in
pharmaceuticals, this process represents a simple and
straightforward entry to these compounds with ample structural
diversity.
RESULTS AND DISCUSSION
■
We initially commenced our study by investigating N-
(pivaloyloxy)-1H-indole-1-carboxamide 1a and 4-octyne 2a,
with [Cp*RhCl2]2 as catalyst and MeOH as solvent. However,
no new products were observed, and the starting materials were
recovered (Table 1, entry 1). To our delight, the addition of
equivalent amount of NaOAc resulted in a formation of cyclic
pyrimido[1,6-a]indol-1(2H)-one product 3a in 87% yield
(Table 1, entry 2), and this was attributed to a C−H
activation/cyclization of 1a. The result encouraged us to
a
Table 1. Optimization of Reaction Conditions
b
entry
solvent
additive
yield (%)
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
none
0
NaOAc (1 equiv)
KOAc (1 equiv)
CsOAc (1 equiv)
CsOPiv (1 equiv)
CsOAc (1 equiv)
CsOAc (1 equiv)
CsOAc (1 equiv)
87
83
93
90
80
51
37
c
TFE
Since alkenes were another ideal coupling partners in
Rh(III)-catalyzed C−H activation/cyclization, this scope was
extended by investigating the use of alkenes under the standard
reaction condition (Table 3). Gratifyingly, alkenes performed
well in this reaction to deliver the partially saturated 3,4-
CH3CN
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (1
b
c
mol %), additive, solvent (2 mL), at rt for 8 h. Isolated yield. TFE =
trifluoroethanol.
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captured by diazo compounds for insertion.9,14b By slightly
changing the reaction condition using CH3CN as solvent, the
reaction performed smoothly at room temperature to furnish
the polycyclic 1H-imidazo[1,5-a]indol-3(2H)-ones in moderate
to excellent yields (Table 4, 49−93%). As shown in Table 4,
donor/acceptor diazo compounds were broadly tolerated with
reasonable scope. Differential substitution on the ester gave the
corresponding products in high yields (7a−7d), and a wide
range of substituents on the aromatic ring were tolerated (7e−
7h), with valuable functional group, such as chloro, bromo,
ester, nitro. When alkyl substituted diazo was used, the reaction
condition should be slightly elevated by increasing the
temperature to 50 °C (7i). Interestingly, the cyclic diazo
substrate delivered the spiro oxindole-fused products in good
yields (7j). Differentially substituted indole and pyrrole derived
N-carboxamides were well applicable to furnish the polysub-
stituted products in good yields (7k−7u) with extraordinary
structural diversities, and definitely would facilitate the process
in drug discovery. Moreover, the structure of 7a was confirmed
by X-ray analysis (see Supporting Information).
Table 2. Rh(III)-Catalyzed Synthesis of Pyrimido[1,6-
a]indol-1(2H)-one
a
A practical synthesis of 5-HT3 receptor antagonist was also
carried out to demonstrate the synthetic utility of this protocol
(Scheme 1). Under the standard reaction condition, 3,4-
dihydro pyrimido[1,6-a]indol-1(2H)-one 5k was obtained in
simple operation. 5k was then converted to 8 and a subsequent
deprotection of 8 soon led to the formation of 5-HT3 receptor
antagonist 9 in gram-scale. Obviously, this strategy opens a new
avenue to this pharmaceuticals synthesis with readily available
starting materials and high efficiency, and therefore could be
applied to divergent synthesis of 5-HT3 receptor antagonist.
Considering this Rh(III)-catalyzed divergent synthesis
includes a C−H activation step, kinetic isotope effect (KIE)
study was conducted to probe the mechanism. As shown in
Scheme 2, a deuterium labeled [D]-1a was synthesized with
83% D incorporation and was subject to the parallel
experiments. A primary KIE value (1.44) was obtained,
suggesting that C−H bond cleavage occurs during the rate-
determining step.15
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (1
mol %), CsOAc (0.2 mmol), MeOH (2 mL), at rt for 2−5 h, isolated
yields.
On the basis of these experiments and literature
precedents,8,16 a plausible mechanism for this divergent
synthesis was proposed in Scheme 3. The initial rhodium
dicarboxylate was generated from [Cp*RhCl2]2 and CsOAc,
and a carboxylate-assisted C−H activation of N-carboxamides
of indoles and pyrroles 1 occurred via a concerted metalation/
dihydropyrimido[1,6-a]indol-1(2H)-ones, contrary to related
systems where β-hydride elimination occurred giving rise to
Heck-type adducts.10b Interestingly, the unsubstituted 3,4-
dihydropyrimido[1,6-a]indol-1(2H)-ones can be synthesized at
ambient pressure using a balloon of ethylene gas (5a, 5f, 5h, 5j,
5k, 5n, 5o). The reaction tolerated with valuable functional
groups, such as ester, cyano, hydroxyl, thus offering ample
opportunities for further derivation. When the unsymmetrical
alkenes participated, the products formed with regioselectivity
ranging from 5.9:1 (5p) to >20:1 (5l and 5m). Moreover, the
structure of 5k was unambiguously confirmed by single X-ray
analysis (see Supporting Information), in addition to standard
characterization. It should be noted that 3,4-dihydropyrimido-
[1,6-a]indol-1(2H)-one represents core structure of various
biologically interesting scaffolds, and this synthetic method
makes a direct access toward the construction of these
compounds.
deprotonation (CMD) pathway to form rhodacycle A.17
A
shows divergent reactivity: (1) In the presence of alkynes and
alkenes, A is coordinated with alkynes 2 or alkenes 4 to give
complex B. The subsequent insertion delivers rhodium species
C. Then a C−N bond formation takes place to afford D along
with N−O bond cleavage. The final step is protonation of D to
furnish pyrimido[1,6-a]indol-1(2H)-one 3 or 3,4-
dihydropyrimido[1,6-a]indol-1(2H)-one 5 with concomitant
Rh(III) catalysis regeneration; (2) In the presence of diazo
compounds 6, a diazo insertion occurs with extrusion of N2 to
form Rh-carbene E, which would undergo a 1,1-migratory
insertion to generate rhodium species F.9,14b Then a C−N
bond formation takes place to afford G along with N−O bond
cleavage. Finally, G is protonated to furnish the 1H-imidazo-
[1,5-a]indol-3(2H)-one product 7 with regeneration of Rh(III)
catalysis.
With these results in hand, we next tried to extend the
divergent synthesis scope of this transformation using diazo
compounds to deliver interesting heterocycles. Considering
that this Rh(III)-catalyzed transformation of N-carboxamides of
indoles and pyrroles includes the formation of rhodacycles
intermediate, we postulated that the rhodium species could be
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a
Table 3. Rh(III)-Catalyzed Synthesis of 3,4-Dihydropyrimido[1,6-a]indol-1(2H)-one
a
Reaction conditions: 1 (0.2 mmol), 4 (0.4 mmol), [Cp*RhCl2]2 (1 mol %), CsOAc (0.2 mmol), MeOH (2 mL), at rt for 2−5 h, isolated yield,
b
c
1
regioselectivity determined by H NMR of isolated products. Balloon of ethylene gas was used. Run at 50 °C for 14 h.
column chromatography on silica gel using ethyl acetate/petroleum
ether (v/v, 1:6) as eluent to give pyrimido[1,6-a]indol-1(2H)-one
product 3a as a yellow solid (49.8 mg, 93% yield).
CONCLUSION
■
In summary, we have established divergent synthesis of
heterocycles, via Rh(III)-catalyzed C−H activation/cyclization
of indoles and pyrroles to couple with various alkynes, alkenes
and diazo compounds. This protocol makes a feature of readily
available starting materials, mild reaction condition, broad
substrate scope and external oxidant free. KIE study was
conducted and a plausible mechanism was proposed.
Furthermore, this protocol was applied to a concise synthesis
of 5-HT3 receptor antagonist in gram-scale.
Typical Procedure for Synthesis of 5. [Cp*RhCl2]2 (1.3 mg, 1
mol %), N-(pivaloyloxy)-1H-indole-1-carboxamide 1a (52 mg, 0.2
mmol), CsOAc (38.4 mg, 0.2 mmol) were added to a vial. MeOH (2
mL) was added, followed by addition of t-butyl acrylate 2b (58 μL, 0.4
mmol). The mixture was kept at room temperature under air. After
completion within 5 h, it was diluted with CH2Cl2 and transferred to a
round-bottom flask. Silica was added to the flask and volatiles were
evaporated under a vacuum. The purification was performed by flash
column chromatography on silica gel using ethyl acetate/petroleum
ether (v/v, 1:2) as eluent to give 5b as a yellow solid (42.9 mg, 75%
yield).
Typical Procedure for Synthesis of 7. [Cp*RhCl2]2 (1.3 mg, 1
mol %), N-(pivaloyloxy)-1H-indole-1-carboxamide 1a (52 mg, 0.2
mmol), CsOAc (38.4 mg, 0.2 mmol) were added to a vial. CH3CN (2
mL) was added, followed by addition of diazo compound 6a (70.4 mg,
0.4 mmol). The mixture was kept at room temperature under air. After
completion within 5 h, it was diluted with CH2Cl2 and transferred to a
round-bottom flask. Silica was added to the flask, and volatiles were
evaporated under a vacuum. The purification was performed by flash
column chromatography on silica gel using ethyl acetate/petroleum
ether (v/v, 1:5) as eluent to give 7a as a yellow solid (55.7 mg, 91%
yield).
EXPERIMENTAL SECTION
■
Infrared spectra were obtained on a FTIR spectrometer. 1H NMR and
13C NMR spectra were recorded on 500 or 400 NMR machine. HRMS
were performed on TOF LC−MS apparatus (ESI). Melting points
were measured with micro melting point apparatus.
Typical Procedure for Synthesis of 3. [Cp*RhCl2]2 (1.3 mg, 1
mol %), N-(pivaloyloxy)-1H-indole-1-carboxamide 1a (52 mg, 0.2
mmol), CsOAc (38.4 mg, 0.2 mmol) were added to a vial. MeOH (2
mL) was added, followed by addition of 4-octyne 2a (58.5 μL, 0.4
mmol). The mixture was kept at room temperature under air. After
completion within 5 h, it was diluted with CH2Cl2 and transferred to a
round-bottom flask. Silica was added to the flask, and volatiles were
evaporated under a vacuum. The purification was performed by flash
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a
Table 4. Rh(III)-Catalyzed Synthesis of 1H-imidazo[1,5-a]indol-3(2H)-one
a
Reaction conditions: 1 (0.2 mmol), 6 (0.4 mmol), [Cp*RhCl2]2 (1 mol %), CsOAc (0.2 mmol), CH3CN (2 mL), at rt for 3−5 h, isolated yield.
Run at 50 °C for 8 h.
b
Scheme 1. Practical Synthesis of 5-HT3 Receptor Antagonist
Scheme 2. Kinetic Isotope Effect Study
was charged with NaH (0.32 g, 8 mmol), which was then evacuated
and backfilled with Argon for three times. Anhydrous DMF (30 mL)
was added, and the solution was cooled to 0 °C. Then DMF solution
(5 mL) of 5k (0.8 g, 4 mmol) was added dropwise to the reaction
solution over 30 min and kept at that temperature for another 30 min.
Afterward, it was warmed to 50 °C and kept for 2 h. The reaction
solution was cooled to 0 °C, and DMF solution (5 mL) of 4-
(chloromethyl)-5-methyl-1-trityl-1H-imidazole (1.488 g, 4 mmol) was
added. Afterward, the solution was warmed to 50 °C and kept for 1 h.
The reaction mixture was then diluted with H2O (100 mL) to give a
precipitate. The precipitate collected was dissolved in CH2Cl2. The
organic layer was washed with H2O and brine, dried over MgSO4, and
evaporated in vacuo. The residue was subject to column chromatog-
raphy on silica gel (2% MeOH−CH2Cl2) to get 8 (1.93 g, 90%) as
white solid. A solution of 8 (1.93 g, 3.6 mmol) in AcOH−H2O (4:1,
50 mL) was heated at 65 °C for 8 h. After evaporation of the solvent,
the residue was neutralized with aqueous NaHCO3 solution and
extracted with CH2Cl2. The organic layer was washed with H2O and
Synthesis of 5-HT3 Receptor Antagonist 9. [Cp*RhCl2]2 (31
mg, 1 mol %), 3-methyl-N-(pivaloyloxy)-1H-indole-1-carbox-amide 1e
(1.37 g, 5 mmol) and CsOAc (0.96 g, 5 mmol) were added to two
necked flask, which was then evacuated and backfilled with balloon of
ethylene gas. MeOH (30 mL) was added, and the solution was kept at
rt to be completed within 3 h. The solution was concentrated and
subject to flash column chromatography on silica gel using ethyl
acetate/petroleum ether (v/v, 1:2) as eluent to give 5k as a yellow
solid (0.8 g, 80% yield). A 100 mL three-necked flask with a stir-bar
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Scheme 3. Proposed Mechanism
brine, dried over MgSO4, and concentrated. The residue was purified
by column chromatography on silica gel (5% MeOH−CH2Cl2) to give
the product 9 as white solid (1.04 g, 98% yield).
115.4, 102.7, 96.7, 13.0; IR (KBr) v 3205, 3112, 1694, 1654, 1630,
1601, 1450, 1406, 1367, 768, 732, 700 cm−1; HRMS (ESI) (m/z)
calcd for C18H14N2O ([M + H]+), 275.1179, found 275.1178.
4-(Hydroxymethyl)-3-phenylpyrimido[1,6-a]indol-1(2H)-one (3e).
White solid (50% yield, 29 mg): mp 235−237 °C; 1H NMR (DMSO-
d6, 400 MHz) δ 10.98 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 7.72−7.51 (m,
6H), 7.37−7.28 (m, 2H), 6.84 (s, 1H), 5.18 (t, J = 5.2 Hz, 1H), 4.36
(d, J = 5.2 Hz, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 147.6, 137.1,
136.2, 132.4, 132.2, 130.4, 129.3, 128.2, 123.5, 121.8, 119.7, 115.3,
107.6, 97.1, 56.9; IR (KBr) v 3345, 3187, 1690, 1630, 1602, 1575,
1452, 1408, 1210, 770, 758, 745 cm−1; HRMS (ESI) (m/z) calcd for
C18H14N2O2 ([M + H]+), 291.1128, found 291.1129.
3,4-Dipropylpyrimido[1,6-a]indol-1(2H)-one (3a). Yellow solid
(93% yield, 50 mg): mp 182−184 °C; 1H NMR (CDCl3, 400
MHz) δ 10.42 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.2 Hz,
1H), 7.39−7.26 (m, 2H), 6.50 (s, 1H), 2.64−2.59 (m, 4H), 1.87−1.81
(m, 2H), 1.73−1.67 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H), 1.05 (t, J = 7.6
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 150.1, 138.1, 134.2, 133.0,
130.9, 123.8, 121.9, 119.6, 116.1, 108.0, 96.1, 31.7, 29.2, 22.9, 22.2,
14.4, 14.1; IR (KBr) v 3214, 3111, 2962, 2871, 1686, 1643, 1616,
1605, 1578, 1554, 1451, 1407, 1379, 1200, 782, 737 cm−1; HRMS
(ESI) (m/z) calcd for C17H20N2O ([M + H]+), 269.1649, found
269.1647.
3-(tert-Butyl)pyrimido[1,6-a]indol-1(2H)-one (3f). Gray solid (91%
1
yield, 43.7 mg): mp 240−242 °C; H NMR (CDCl3, 400 MHz) δ
3,4-Diethylpyrimido[1,6-a]indol-1(2H)-one (3b). Yellow solid
(95% yield, 45.6 mg): mp 217−219 °C; 1H NMR (CDCl3, 400
MHz) δ 9.91 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz,
1H), 7.38−7.30 (m, 2H), 6.51 (s, 1H), 2.64 (q, J = 7.6 Hz, 4H), 1.38
(t, J = 7.6 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 149.9, 137.7, 134.9, 133.2, 131.0, 123.8, 122.1, 119.6, 116.1,
109.0, 96.0, 23.0, 20.3, 14.4, 13.5; IR (KBr) v 3215, 3112, 2963, 1698,
1643, 1602, 1578, 1555, 1450, 1380, 1206, 825, 783, 756, 745 cm−1;
HRMS (ESI) (m/z) calcd for C15H16N2O ([M + H]+), 241.1336,
found 241.1337.
10.23 (s, 1H), 8.85 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.34−
7.38 (m, 2H), 6.49 (s, 1H), 6.29 (d, J = 1.6 Hz, 1H), 1.47 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ 150.3, 146.5, 136.2, 132.7, 131.2, 123.9,
122.1, 119.7, 116.0, 97.2, 93.7, 34.5, 28.6; IR (KBr) v 3213, 3118,
2965, 1693, 1645, 1605, 1578, 1557, 1398, 1081, 820, 770 cm−1;
HRMS (ESI) (m/z) calcd for C15H16N2O ([M + H]+), 241.1336,
found 241.1335.
3-(2-Hydroxypropan-2-yl)pyrimido[1,6-a]indol-1(2H)-one (3g).
Gray solid (90% yield, 43.6 mg): mp 176−178 °C; 1H NMR
(CDCl3, 400 MHz) δ 9.03 (s, 1H), 8.60−8.58 (m, 1H), 7.62−7.60 (m,
1H), 7.38−7.31 (m, 2H), 6.35 (s, 1H), 6.18 (d, J = 1.6 Hz, 1H), 2.88
(s, 1H), 1.65 (s, 6H); 13C NMR (CDCl3, 400 MHz) δ 149.3, 143.1,
135.3, 132.8, 131.0, 124.0, 122.5, 119.8, 116.0, 98.3, 93.8, 70.5, 29.3; IR
(KBr) v 3555, 3211, 3111, 2963, 1691, 1646, 1606, 1579, 1560, 1449,
1397, 1352, 1192, 834, 779, 756 cm−1; HRMS (ESI) (m/z) calcd for
C14H14N2O2 ([M + H]+), 243.1128, found 243.1128.
3,4-Bis(hydroxymethyl)pyrimido[1,6-a]indol-1(2H)-one (3c). Gray
1
solid (92% yield, 44.9 mg): mp 143−145 °C; H NMR (DMSO-d6,
400 MHz) δ 10.59 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.2
Hz, 1H), 7.34−7.24 (m, 2H), 6.74 (s, 1H), 5.26 (t, J = 6.0 Hz, 1H),
4.96 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.2 Hz, 2H), 4.43 (d, J = 5.6 Hz,
2H); 13C NMR (DMSO-d6, 100 MHz), δ 147.7, 137.1, 136.1, 132.2,
130.3, 123.4, 121.7, 119.6, 115.3, 107.7, 96.5, 56.6, 55.4; IR (KBr) v
2962, 2926, 2855, 1694, 1652, 1449, 1377, 1261, 1094, 1026. 803
cm−1; HRMS (ESI) (m/z) calcd for C13H12N2O3 ([M + H]+),
245.0921, found 245.0921.
(1-Oxo-1,2-dihydropyrimido[1,6-a]indol-3-yl)methyl benzoate
1
(3h). White solid (57% yield, 36.2 mg): mp 209−211 °C; H NMR
(DMSO-d6, 400 MHz) δ 11.17 (s, 1H), 8.52 (d, J = 8.8 Hz, 1H),
8.06−8.04 (m, 2H), 7.71−7.67 (m, 2H), 7.58−7.54 (m, 2H), 7.33−
7.29 (m, 2H), 6.73 (s, 1H), 6.68 (s, 1H), 5.14 (s, 2H); 13C NMR
(DMSO-d6, 100 MHz) δ 165.3, 148.0, 135.3, 133.6, 133.4, 132.3,
130.2, 129.5, 129.3, 128.8, 123.6, 122.1, 119.8, 115.3, 98.0, 97.9, 62.5;
IR (KBr) v 3210, 3104, 2966, 1701, 1652, 1561, 1449, 1389, 1269,
1096, 781, 719, 707 cm−1; HRMS (ESI) (m/z) calcd for C19H14N2O3
([M + H]+), 319.1077, found 319.1078.
4-Methyl-3-phenylpyrimido[1,6-a]indol-1(2H)-one (3d). Pale
green solid (62% yield, 34 mg): mp 255−257 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 10.91 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H),
7.69 (d, J = 7.2 Hz, 1H), 7.52−7.46 (m, 5H), 7.36−7.28 (m, 2H), 6.68
(s, 1H), 2.09 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 147.7, 138.1,
134.0, 133.1, 132.5, 130.2, 129.5, 128.9, 128.3, 123.5, 121.9, 119.7,
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3-Butylpyrimido[1,6-a]indol-1(2H)-one (3i). Brown solid (70%
yield, 33.6 mg): mp 170−172 °C; H NMR (CDCl3, 400 MHz) δ
1097, 1030, 802, 751 cm−1; HRMS (ESI) (m/z) calcd for C16H18N2O
([M + Na]+), 277.1311, found 277.1306.
1
3,4-Bis(hydroxymethyl)-5-methylpyrimido[1,6-a]indol-1(2H)-one
10.33 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.37−
7.32 (m, 2H), 6.44 (s, 1H), 6.19 (s, 1H), 2.58 (t, J = 7.6 Hz, 2H),
1.83−1.74 (m, 2H), 1.54−1.48 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 150.4, 138.9, 136.2, 132.8, 131.1, 123.9,
122.0, 119.6, 116.0, 96.6, 96.5, 32.7, 29.9, 22.4, 13.9; IR (KBr) v 3206,
2956, 1701, 1651, 1618, 1606, 1577, 1451, 1402, 817, 777, 755 cm−1;
HRMS (ESI) (m/z) calcd for C15H16N2O ([M + H]+), 241.1336,
found 241.1333.
1
(3p). Yellow solid (71% yield, 36.6 mg): mp 230−232 °C; H NMR
(DMSO-d6, 400 MHz) δ 10.42 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 7.65
(d, J = 7.6 Hz, 1H), 7.36−7.25 (m, 2H), 5.26 (t, J = 5.6 Hz, 1H), 4.97
(t, J = 5.2 Hz, 1H), 4.59 (d, J = 5.2 Hz, 2H), 4.42 (d, J = 5.6 Hz, 2H),
2.56 (s, 3H); 13C NMR (DMSO-d6, 400 MHz) δ 147.8, 135.8, 131.9,
131.6, 131.4, 123.0, 121.9, 117.6, 115.2, 108.3, 105.2, 56.6, 54.4, 8.9; IR
(KBr) v 3358, 2962, 1684, 1654, 1635, 1617, 1547, 1458, 1383, 1263,
1004, 804 cm−1; HRMS (ESI) (m/z) calcd for C14H14N2O3 ([M +
H]+), 259.1077, found 259.1074.
4-Butylpyrimido[1,6-a]indol-1(2H)-one (3j). Brown solid (22%
yield, 10.6 mg): mp 150−152 °C; 1H NMR (CDCl3, 400 MHz) δ 9.94
(d, J = 3.6 Hz, 1H), 8.71−8.69 (m, 1H), 7.69−7.67 (m, 1H), 7.40−
7.36 (m, 2H), 6.59 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 1.72−1.64 (m,
2H), 1.48−1.39 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 149.8, 137.0, 133.2, 130.4, 123.9, 122.6, 120.6, 119.9,
116.2, 112.5, 97.2, 30.4, 28.7, 22.6, 14.0; IR (KBr) v 3211, 3103, 2955,
1696, 1651, 1561, 1451, 1400, 1206, 796, 772 cm−1; HRMS (ESI) (m/
z) calcd for C15H16N2O ([M + H]+), 241.1336, found 241.1337.
7-Methyl-3,4-dipropylpyrimido[1,6-a]indol-1(2H)-one (3k). Yel-
low solid (97% yield, 54.7 mg): mp 202−204 °C; 1H NMR
(CDCl3, 400 MHz) δ 10.08 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 7.42
(s, 1H), 7.14 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 6.41 (s, 1H), 2.59 (t, J
= 7.2 Hz, 4H), 2.51 (s, 3H), 1.84−1.78 (m, 2H), 1.71−1.65 (m, 2H),
1.10 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 149.9, 138.1, 133.9, 133.3, 131.3, 131.2, 123.5, 119.3,
115.7, 108.0, 95.8, 31.7, 29.2, 22.9, 22.2, 21.8, 14.4, 14.1; IR (KBr) v
3215, 3104, 2961, 2871, 1703, 1638, 1617, 1578, 1554, 1371, 1262,
1096, 1031, 798 cm−1; HRMS (ESI) (m/z) calcd for C18H22N2O ([M
+ H]+), 283.1805, found 283.1805.
3-(tert-Butyl)-5-methylpyrimido[1,6-a]indol-1(2H)-one (3q).
White solid (74% yield, 37.6 mg): mp 226−228 °C; 1H NMR
(CDCl3, 400 MHz) δ 9.44 (s, 1H), 8.61−8.59 (m, 1H), 7.60−7.58 (m,
1H), 7.41−7.31 (m, 2H), 6.21 (d, J = 2.0 Hz, 1H), 2.38 (s, 3H), 1.44
(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 150.0, 145.1, 132.3, 132.1,
131.9, 123.5, 122.2, 117.7, 115.8, 104.9, 91.9, 34.4, 28.7, 8.4; IR (KBr)
v 3223, 3123, 2967, 1781, 1693, 1651, 1605, 1482, 1455, 1378, 1262,
1081, 813, 749 cm−1; HRMS (ESI) (m/z) calcd for C16H18N2O ([M +
Na]+), 277.1311, found 277.1311.
3,4-Dipropylpyrrolo[1,2-c]pyrimidin-1(2H)-one (3r). Yellow solid
(98% yield, 42.7 mg): mp 120−122 °C; 1H NMR (CDCl3, 400 MHz)
δ 9.89 (s, 1H), 7.55−7.54 (m, 1H), 6.63 (t, J = 3.6 Hz, 1H), 6.25−6.24
(m, 1H), 2.54−2.49 (m, 4H), 1.74−1.58 (m, 4H), 1.03−0.97(m, 6H);
13C NMR (CDCl3, 100 MHz) δ 148.3, 133.9, 130.1, 114.5, 113.5,
109.1, 102.0, 31.3, 29.2, 23.0, 22.4, 14.4, 13.9; IR (KBr) v 3212, 3110,
2960, 1708, 1640, 1617, 1554, 1404, 1353, 831, 776, 711 cm−1; HRMS
(ESI) (m/z) calcd for C13H18N2O ([M + H]+), 219.1492, found
219.1491.
3,4-Diethylpyrrolo[1,2-c]pyrimidin-1(2H)-one (3s). White solid
(95% yield, 36.1 mg): mp 175−177 °C; 1H NMR (CDCl3, 400
MHz) δ 9.97 (s, 1H), 7.57−7.56 (m, 1H), 6.63 (t, J = 3.6 Hz, 1H),
6.27−6.26 (m, 1H), 2.59−2.55 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H), 1.21
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 148.3, 133.6,
131.1, 114.6, 113.6, 110.1, 101.8, 22.6, 20.3, 14.6, 13.8; IR (KBr) v
3210, 3113, 2963, 1693, 1654, 1640, 1406, 1349, 1261, 1093, 1031,
802, 707 cm−1; HRMS (ESI) (m/z) calcd for C11H14N2O ([M +
H]+),191.1179, found 191.1180.
3,4-Bis(hydroxymethyl)-7-methylpyrimido[1,6-a]indol-1(2H)-one
1
(3l). Yellow solid (79% yield, 41 mg): mp 185−187 °C; H NMR
(DMSO-d6, 400 MHz) δ 10.52 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.44
(s, 1H), 7.10−7.07 (m, 1H), 6.65 (s, 1H), 5.27 (s, 1H), 4.95 (s, 1H),
4.53 (s, 2H), 4.42 (s, 2H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 100
MHz) δ 147.6, 137.1, 135.9, 132.4, 130.5, 123.2, 119.3, 114.9, 107.7,
96.1, 56.5, 55.4, 21.3; IR (KBr) v 3320, 2958, 1686, 1644, 1617, 1575,
1400, 1045, 1008, 802 cm−1; HRMS (ESI) (m/z) calcd for
C14H14N2O3 ([M + H]+), 259.1077, found 259.1080.
3,4-Diphenylpyrrolo[1,2-c]pyrimidin-1(2H)-one (3t). Pale green
7-Methoxy-3,4-dipropylpyrimido[1,6-a]indol-1(2H)-one (3m).
Brown solid (90% yield, 53.6 mg): mp 195−196 °C; 1H NMR
(CDCl3, 400 MHz) δ 10.51 (br, s, 1H), 8.52 (d, J = 8.8 Hz, 1H), 7.09
(d, J = 2.4 Hz, 1H), 6.94 (dd, J1 = 9.2 Hz, J2 = 2.0 Hz, 1H), 6.42 (s,
1H), 3.90 (s, 3H), 2.59 (m, 4H), 1.85−1.79 (m, 2H), 1.71−1.65 (m,
2H), 1.11 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 156.7, 149.9, 138.8, 134.3, 131.9, 127.8, 116.8,
111.2, 107.9, 101.6, 95.8, 55.7, 31.7, 29.2, 22.9, 22.2, 14.4, 14.1; IR
(KBr) v 3209, 3104, 2956, 2871, 1687, 1640, 1614, 1585, 1548, 1479,
1439, 1376, 1262, 1093, 1033, 804 cm−1; HRMS (ESI) (m/z) calcd for
C18H22N2O2 ([M + H]+), 299.1754, found 299.1754.
1
solid (64% yield, 36.6 mg): mp 205−206 °C; H NMR (CDCl3, 400
MHz) δ 9.00 (s, 1H), 7.62 (q, J = 1.6 Hz, 1H), 7.28−7.23 (m, 10H),
6.63 (t, J = 3.2 Hz, 1H), 6.19 (q, J = 1.6 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 147.2, 135.0, 133.8, 133.4, 130.7, 129.4, 129.3, 128.7,
128.6, 128.5, 127.7, 115.2, 114.7, 112.3, 106.0; IR (KBr) v 3214, 3066,
2958, 1717, 1654, 1616, 1597, 1405, 1349, 1262, 1032, 800, 700 cm−1;
HRMS (ESI) (m/z) calcd for C19H14N2O ([M + H]+), 287.1179,
found 287.1180.
3-(tert-Butyl)pyrrolo[1,2-c]pyrimidin-1(2H)-one (3u). Green solid
(94% yield, 35.7 mg): mp 155−157 °C; 1H NMR (CDCl3, 400 MHz)
δ 9.86 (br, s, 1H), 7.55 (m, 1H), 6.62 (t, J = 3.2 Hz, 1H), 6.26−6.24
(m, 2H), 1.36 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 148.5, 142.4,
131.9, 114.8, 113.3, 103.1, 94.3, 34.1, 28.8; IR (KBr) v 3214, 2970,
1781, 1694, 1663, 1641, 1495, 1402, 1082, 1026, 822, 804, 717 cm−1;
HRMS (ESI) (m/z) calcd for C11H14N2O ([M + H]+), 191.1179,
found 191.1179.
3-(2-Hydroxypropan-2-yl)pyrrolo[1,2-c]pyrimidin-1(2H)-one (3v).
Pale yellow oil (91% yield, 34.9 mg): 1H NMR (DMSO-d6, 400 MHz)
δ 10.40 (br, s, 1H), 7.45−7.42 (m, 1H), 6.59 (t, J = 3.2 Hz, 1H), 6.42
(d, J = 1.6 Hz, 1H), 6.26−6.24 (m, 1H), 5.28 (s, 1H), 1.43 (s, 6H);
13C NMR (DMSO-d6, 100 MHz) δ 146.7, 142.1, 131.3, 114.4, 112.7,
103.0, 92.8, 68.9, 28.9; IR (KBr) v 3379, 2978, 1694, 1641, 1560, 1402,
1333, 1159, 824, 717 cm−1; HRMS (ESI) (m/z) calcd for C10H12N2O2
([M + H]+), 193.0972, found 193.0972.
6-(Benzyloxy)-3,4-dipropylpyrimido[1,6-a]indol-1(2H)-one (3n).
1
Yellow solid (68% yield, 51 mg): mp 248−249 °C; H NMR (400
MHz, DMSO-d6), δ 10.62 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.54−7.35
(m, 5H), 7.15 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.54 (s,
1H), 5.27 (s, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H),
1.59 (sext, J = 7.2 Hz, 4H), 0.96 (quint, J = 7.2 Hz, 6H); 13C NMR
(100 MHz, DMSO-d6), δ 150.6, 147.9, 137.2, 136.6, 134.8, 133.4,
128.4, 127.8, 127.7, 122.2, 121.0, 108.6, 106.3, 105.0, 92.0, 69.3, 30.3,
28.1, 22.5, 21.9, 13.9, 13.5; IR (KBr) v 3435, 3215, 3113, 2961, 1700,
1641, 1498, 1364, 1266, 1044, 768, 693 cm−1; HRMS (ESI) (m/z)
calcd for C24H26N2O2 ([M + Na]+), 397.1896, found 397.1892.
3,4-Diethyl-5-methylpyrimido[1,6-a]indol-1(2H)-one (3o). White
1
solid (70% yield, 35.6 mg): mp 222−224 °C; H NMR (CDCl3, 400
MHz) δ 9.15 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.2 Hz,
1H), 7.40−7.31 (m, 2H), 2.78 (q, J = 7.6 Hz, 2H), 2.60 (q, J = 7.6 Hz,
2H), 2.57 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 149.7, 134.0, 132.4, 132.3, 123.4,
122.5, 117.5, 116.1, 109.9, 105.0, 100.1, 22.9, 19.7, 13.6, 10.0; IR
(KBr) v 3223, 3128, 2963, 1695, 1654, 1631, 1452, 1420, 1371, 1261,
3,4-Dihydropyrimido[1,6-a]indol-1(2H)-one (5a). Yellow solid
(83% yield, 31.2 mg): mp 126−128 °C; 1H NMR (CDCl3, 400
MHz) δ 8.35 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.31−7.20 (m, 2H),
6.74 (s, 1H), 6.34 (s, 1H), 3.55−3.52 (m, 2H), 3.10 (t, J = 6.0 Hz,
2H); 13C NMR (CDCl3, 100 MHz) δ 152.7, 135.4, 134.8, 129.3,
123.6, 122.8, 120.0, 115.3, 103.3, 39.4, 23.2; IR (KBr) v 3231, 3118,
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1694, 1654, 1596, 1473, 1420, 1333, 1300, 1194, 791, 758 cm−1;
HRMS (ESI) (m/z) calcd for C11H10N2O ([M + H]+), 187.0866,
found 187.0867.
tert-Butyl 1-oxo-1,2,3,4-tetrahydropyrimido[1,6-a]indole-3-car-
boxylate (5b). Yellow solid (75% yield, 42.9 mg): mp 143−145 °C;
1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J = 8.0 Hz, 1H), 7.48 (d, J =
1322, 1245, 1200, 1167, 1130, 815, 778 cm−1; HRMS (ESI) (m/z)
calcd for C12H12N2O2 ([M + H]+), 217.0972, found 217.0973.
7-Methoxy-1-oxo-1,2,3,4-tetrahydropyrimido[1,6-a]indole-3-car-
bonitrile (5i). White solid (66% yield, 31.8 mg): mp 208−209 °C; 1H
NMR (DMSO-d6, 400 MHz) δ 8.63 (d, J = 4.0 Hz, 1H), 8.05 (d, J =
8.8 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 9.2 Hz, J2= 2.8
1
Hz, 1H), 6.54(s, 1H), 4.99 (q, J = 4.0 Hz, 1H), 3.78 (s, 3H), 3.42 (d, J
= 4.4 Hz, 2H); 13C NMR (DMSO-d6, 400 MHz) δ 155.6, 149.4, 132.8,
129.8, 129.2, 119.3, 115.1, 112.2, 104.5, 103.1, 55.3, 40.8, 26.2; IR
(KBr) v 3194, 3118, 2962, 2200, 1716, 1599, 1479, 1439, 1333, 1205,
1169, 1036, 861, 806, 746 cm−1; HRMS (ESI) (m/z) calcd for
C13H11N3O2 ([M + H]+), 242.0924, found 242.0927.
6-(Benzyloxy)-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (5j).
White solid (78% yield, 45.5 mg): mp 185−187 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.96 (d, J = 8.0 Hz, 1H), 7.48 (m, 2H), 7.42−
7.33 (m, 3H), 7.18 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.53
(s, 1H), 5.82 (s, 1H), 5.21 (s, 2H), 3.56−3.52 (m, 2H), 3.10 (t, J = 6.0
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 151.2, 150.5, 136.3, 135.6,
132.0, 127.5, 126.8, 126.3, 123.4, 118.7, 107.8, 103.7, 99.5, 69.0, 38.6,
22.1; IR (KBr) v 3223, 3118, 1688, 1577, 1493, 1435, 1242, 1043, 771,
748 cm−1; HRMS (ESI) (m/z) calcd for C18H16N2O2 ([M + H]+),
293.1285, found 293.1287.
7.6 Hz, 1H), 7.29−7.19 (m, 2H), 6.36 (s, 1H), 6.04−6.01 (m, 1H),
4.24−4.21 (m, 1H), 3.44−3.39 (m, 1H), 3.20−3.13 (m,1H), 1.46(s,
9H); 13C NMR (CDCl3, 400 MHz) δ 168.7, 150.8, 135.4, 132.4,
129.3, 124.0, 123.0, 120.1, 115.4, 104.2, 83.6, 53.1, 28.0, 26.6; IR
(KBr) v 3384, 3235, 3131, 2982, 1728, 1706, 1676, 1596, 1454, 1414,
1370, 1156, 802, 747 cm−1; HRMS (ESI) (m/z) calcd for C16H18N2O3
([M + H]+), 287.1390, found 287.1389.
1-Oxo-1,2,3,4-tetrahydropyrimido[1,6-a]indole-3-carbonitrile
1
(5c). White solid (80% yield, 33.7 mg): mp 181−182 °C; H NMR
(DMSO-d6, 400 MHz) δ 8.71 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 8.4 Hz,
1H), 7.59−7.57 (m, 1H), 7.29−7.20 (m, 2H), 6.62 (s, 1H), 5.03−5.00
(m, 1H), 3.45−3.44 (m, 2H); 13C NMR (DMSO-d6, 400 MHz) δ
149.5, 134.6, 132.2, 128.8, 123.7, 122.8, 120.4, 119.2, 114.5, 104.6,
40.7, 26.2; IR (KBr) v 3224, 3119, 2925, 1713, 1677, 1600, 1456,
1415, 1329, 1220, 814, 755 cm−1; HRMS (ESI) (m/z) calcd for
C12H9N3O ([M + H]+), 212.0819, found 212.0828.
3-(Hydroxymethyl)-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one
5-Methyl-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (5k). White
solid (78% yield, 31.2 mg): mp 185−186 °C; H NMR (CDCl3, 400
1
1
(5d). Gray solid (81% yield, 35 mg): mp 141−143 °C; H NMR
(DMSO-d6, 400 MHz) δ 8.20 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.51
(d, J = 7.6 Hz, 1H), 7.19−7.15 (m, 2H), 6.47 (s, 1H), 5.06 (m, 1H),
3.81−3.76 (m, 1H), 3.62−3.56 (m, 1H), 3.51−3.46 (m, 1H), 3.37−
3.29 (m, 1H), 3.25−3.19 (m, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
150.9, 137.2, 134.6, 128.9, 122.9, 122.1, 120.0, 114.6, 102.0, 60.9, 40.4,
35.9; IR (KBr) v 3269, 2881, 1694, 1593, 1572, 1479, 1455, 1325,
1211, 1048, 802, 759 cm−1; HRMS (ESI) (m/z) calcd for
C12H12N2O2([M + H]+), 217.0972, found 217.0972.
MHz) δ 8.32 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.31−7.22
(m, 2H), 6.26 (s, 1H), 3.57−3.53 (m, 2H), 3.03 (t, J = 6.4 Hz, 2H),
2.21 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 152.71, 135.0, 130.5,
130.2, 123.8, 122.5, 118.1, 115.2, 110.8, 39.4, 21.3, 8.5; IR (KBr) v
3230, 3118, 2918, 1694, 1653, 1625, 1479, 1423, 1335, 1198, 1081,
781, 755, 740 cm−1; HRMS (ESI) (m/z) calcd for C12H12N2O ([M +
H]+), 201.1023, found 201.1022.
tert-Butyl 5-methyl-1-oxo-1,2,3,4-tetrahydropyrimido[1,6-a]-
indole-3-carboxylate (5l). White solid (58% yield, 34.8 mg): mp
157−159 °C; 1H NMR (CDCl3, 400 MHz) δ 7.28 (d, J = 6.8 Hz, 1H),
6.57 (d, J = 6.0 Hz, 1H), 6.45−6.37 (m, 2H), 5.26 (s, 1H), 3.92−3.89
(m, 1H), 3.23−3.18 (m, 1H), 2.99−2.93 (m, 1H), 2.26 (s, 3H), 1.65
(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 168.9, 150.9, 135.0, 130.5,
127.9, 124.2, 122.7, 118.2, 115.3, 111.9, 83.6, 53.1, 28.1, 24.8, 8.5; IR
(KBr) v 3239, 3125, 2977, 2920, 1735, 1695, 1629, 1459, 1226, 1158,
756 cm−1; HRMS (ESI) (m/z) calcd for C17H20N2O3 ([M + Na]+),
323.1366, found 323.1369.
Ethyl 5-methyl-1-oxo-1,2,3,4-tetrahydropyrimido[1,6-a]indole-3-
carboxylate (5m). Yellow solid (74% yield, 40.2 mg): mp 116−118
°C; 1H NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 7.46−7.44 (m, 1H),
7.32−7.22 (m, 2H), 6.09 (s, 1H), 4.35−4.24 (m, 3H), 3.44−3.39 (m,
1H), 3.16−3.10(m, 1H), 2.22 (s, 3H), 1.30(t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 169.8, 150.9, 135.0, 130.5, 127.7, 124.2,
122.7, 118.3, 115.3, 112.1, 62.4, 52.5, 24.5, 14.2, 8.5; IR (KBr) v 3246,
3125, 2965, 1752, 1735, 1710, 1691, 1459, 1426, 1343, 1191, 1025,
805, 756 cm−1; HRMS (ESI) (m/z) calcd for C15H16N2O3 ([M +
H]+), 273.1234, found 273.1236.
1,3,4,4a,5,12b-Hexahydro-1,4-methanoindolo[1,2-c]quinazolin-
6(2H)-one (5e). White solid (89% yield, 44.9 mg): mp 212−213 °C;
1H NMR (CDCl3, 400 MHz) δ 8.40 (d, J = 8.0 Hz, 1H), 7.49 (d, J =
7.6 Hz,1H), 7.28−7.18 (m, 2H), 6.35 (s, 1H), 6.20−5.92 (m, 1H),
3.72 (d, J = 8.8 Hz, 1H), 3.25 (d, J = 8.8 Hz, 1H), 2.47 (s, 1H), 2.31
(s, 1H), 1.66−1.61 (m, 3H), 1.50−1.47 (m, 1H), 1.29−1.21 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 150.4, 137.6, 135.2, 129.8, 123.5,
122.8, 119.8, 116.1, 104.1, 58.0, 47.3, 45.8, 39.6, 33.5, 28.9, 25.4; IR
(KBr) v 3221, 3105, 2960, 2873, 1710, 1584, 1563, 1453, 1439, 1330,
1309, 1082, 1034, 787, 749 cm−1; HRMS (ESI) (m/z) calcd for
C16H16N2O ([M + H]+), 253.1336, found 253.1332.
7-Methyl-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (5f). Yellow
1
solid (92% yield, 36.8 mg): mp 170−171 °C; H NMR (CDCl3, 400
MHz) δ 8.20 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.10 (dd, J 1= 8.4 Hz,
J2= 1.2 Hz, 1H), 6.48−6.40 (m, 1H), 6.26 (d, J = 0.8 Hz, 1H), 3.55−
3.51 (m, 2H), 3.08 (t, J = 6.4 Hz, 2H), 2.44 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 152.6, 134.8, 133.6, 132.2, 129.5, 125.0, 120.0,
114.9, 103.1, 39.5, 23.2, 21.5; IR (KBr) v 3235, 3122, 2917, 1702,
1598, 1476, 1421, 1324, 1196, 1045, 798, 751, 701 cm−1; HRMS (ESI)
(m/z) calcd for C12H12N2O ([M + H]+), 201.1023, found 201.1023.
7-Methyl-1-oxo-1,2,3,4-tetrahydropyrimido[1,6-a]indole-3-car-
2-(1-Oxo-1,2,3,4-tetrahydropyrimido[1,6-a]indol-5-yl)ethyl ace-
tate (5n). Pale yellow solid (70% yield, 38 mg): mp 137−139 °C;
1H NMR (CDCl3, 400 MHz) δ 8.34 (d, J = 7.6 Hz, 1H), 7.51 (d, J =
7.2 Hz, 1H), 7.31−7.22 (m, 2H), 6.28 (s, 1H), 4.26 (t, J = 7.2 Hz,
2H), 3.58−3.54 (m, 2H), 3.08 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 7.2 Hz,
2H), 2.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 171.1, 152.4,
135.2, 131.8, 129.5, 124.0, 122.7, 118.1, 115.5, 111.1, 63.8, 39.5, 23.7,
21.5, 21.1; IR (KBr) v 3247, 3122, 2917, 1732, 1690, 1618, 1458,
1233, 1041, 802, 760 cm−1; HRMS (ESI) (m/z) calcd for C15H16N2O3
([M + H]+), 273.1235, found 273.1234.
1
bonitrile (5g). Yellow solid (71% yield, 32 mg): mp 205−207 °C; H
NMR (DMSO-d6, 400 MHz) δ 8.65 (d, J = 4.0 Hz, 1H), 8.05 (d, J =
8.0 Hz, 1H), 7.35 (s, 1H), 7.08 (dd, J = 8.4 Hz, J2= 1.2 Hz, 1H),
1
6.53(s, 1H), 4.99 (q, J = 4.4 Hz, 1H), 3.42 (d, J = 4.0 Hz, 2H), 2.38 (s,
3H); 13C NMR (DMSO-d6, 100 MHz) δ 149.5, 132.9, 132.2, 131.7,
129.1, 124.9, 120.2, 119.2, 114.2, 104.3, 40.8, 26.2, 21.0; IR (KBr) v
3239, 3138, 2986, 2200, 1719, 1653, 1597, 1409, 1334, 1287, 1195,
1057, 811, 753 cm−1; HRMS (ESI) (m/z) calcd for C13H11N3O ([M +
H]+), 226.0975, found 226.0977.
7-Methoxy-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (5h). Pale
yellow solid (87% yield, 37.6 mg): mp 164−165 °C; 1H NMR
(CDCl3, 400 MHz) δ 8.20 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.8 Hz,
1H), 6.89 (q, J = 2.4 Hz, 1H), 6.45 (s, 1H), 6.26 (s, 1H), 3.85 (s, 3H),
3.55−3.51 (m, 2H), 3.07 (t, J = 6.0 Hz, 2H); 13C NMR (CDCl3, 400
MHz) δ 156.0, 152.5, 135.5 130.1, 115.9, 112.1, 103.2, 102.9, 55.8,
39.5, 23.2; IR (KBr) v 3235, 3116, 1691, 1598, 1480, 1421, 1333,
3,4-Dihydropyrrolo[1,2-c]pyrimidin-1(2H)-one (5o). White solid
1
(88% yield, 24 mg): mp 79−81 °C; H NMR (CDCl3, 400 MHz) δ
7.29 (dd, J1 = 3.2 Hz, J2 = 1.2 Hz, 1H), 6.69 (br, s, 1H), 6.18 (t, J = 3.2
Hz, 1H), 5.99−5.98 (m, 1H), 3.52−3.48 (m, 2H), 2.94 (t, J = 6.4 Hz,
2H); 13C NMR (CDCl3, 100 MHz) δ 151.6, 128.8, 117.4, 110.9,
107.9, 39.9, 22.2; IR (KBr) v 3222, 2968, 1760, 1702, 1572, 1436,
1322, 1261, 1106, 801, 733, 698 cm−1; HRMS (ESI) (m/z) calcd for
C7H8N2O ([M + H]+), 137.0710, found 137.0709.
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Ethyl 1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-c]pyrimidine-3-carbox-
ylate (5p). Pale yellow oil (72% yield, 30 mg): 1H NMR (CDCl3, 400
MHz) δ 7.30−7.29 (m, 1H), 6.30−6.26 (m, 1H), 6.17 (t, J = 3.2 Hz,
1H), 6.02−6.01 (m, 1H), 4.33−4.20 (m, 3H), 3.34−3.29 (m, 1H),
3.11−3.05 (m, 1H), 1.28(t, J = 7.2 Hz, 3H) ; 13C NMR (CDCl3, 100
MHz) δ 169.8, 149.8, 126.2, 117.9, 111.3, 108.9, 62.4, 53.0, 25.5, 14.2;
IR (KBr) v 3143, 2963, 2926, 1747, 1732, 1714, 1698, 1575, 1417,
1261, 1095, 1027, 801, 727 cm−1; HRMS (ESI) (m/z) calcd for
C10H12N2O3 ([M + H]+), 209.0921, found 209.0920.
Methyl 3-oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,5-a]indole-1-
carboxylate (7a). Pale brown solid (91% yield, 55.7 mg): mp 204−
205 °C; 1H NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 8.0 Hz, 1H), 7.61
(d, J = 8.0 Hz, 1H), 7.57−7.54 (m, 2H), 7.42−7.31 (m, 4H), 7.26 (m,
1H), 6.99 (s, 1H), 6.74 (s, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 169.6, 151.5, 137.7, 137.5, 133.3, 130.6, 129.3, 125.6, 124.3,
123.2, 121.5, 112.9, 101.8, 67.3, 53.9; IR (KBr) v 3325, 1759, 1584,
1479, 1450, 1260, 743, 701 cm−1; HRMS (ESI) (m/z) calcd for
C18H14N2O3 ([M + H]+), 307.1077, found 307.1071.
Ethyl 3-oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,5-a]indole-1-
carboxylate (7b). Pale yellow solid (93% yield, 59.5 mg): mp 205−
206 °C; 1H NMR (CDCl3, 400 MHz) δ 8.0 (d, J = 8.0 Hz, 1H), 7.62
(d, J = 8.0 Hz, 1H), 7.56−7.54 (m, 2H), 7.42−7.36 (m, 3H), 7.34−
7.32 (m, 1H), 7.28−7.25 (m, 1H), 4.31−4.25 (m, 2H), 1.30−1.26 (t,
3H); 13C NMR (CDCl3, 100 MHz) δ 169.0, 151.5, 137.9, 133.3,
130.6, 129.3, 125.6, 124.2, 123.2, 121.5, 112.9, 101.7, 67.2, 63.3, 14.1;
IR (KBr) v 3320, 2847, 1755, 1729, 1486, 1394, 800, 747, 696 cm−1;
HRMS (ESI) (m/z) calcd for C19H16N2O3 ([M + H]+), 321.1234,
found 321.1235.
Benzyl 3-oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,5-a]indole-1-
carboxylate (7c). Pale yellow solid (86% yield, 65.7 mg): mp 152−
154 °C; 1H NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 8.0 Hz, 1H), 7.60
(d, J = 8.0 Hz, 1H), 7.50−7.49 (m, 2H), 7.36−7.33 (m, 4H), 7.31−
7.28 (m, 3H), 7.26−7.23 (m, 3H), 6.72−6.70 (m, 2H), 5.23−5.22 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ 168.8, 151.4, 137.6, 137.5,
134.6, 133.3, 129.28, 128.83, 128.79, 128.4, 125.6, 124.3, 123.2, 121.6,
68.8, 67.3; IR (KBr) v 3232, 3123, 1732, 1478, 1451, 1384, 1211, 751,
696 cm−1; HRMS (ESI) (m/z) calcd for C24H18N2O3 ([M + H]+),
383.1390, found 383.1380.
Allyl 3-oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,5-a]indole-1-car-
boxylate (7d). Pale yellow solid (63% yield, 41.8 mg): mp 171−173
°C; 1H NMR (CDCl3, 400 MHz) δ 7.99 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz,
1H), 7.63−7.55 (m, 3H), 7.41−7.23 (m, 5H), 6.93 (s, 1H), 6.75 (s,
1H), 5.91−5.81(m, 1H), 5.28−5.21 (m, 2H), 4.71−4.69 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 168.7, 151.4, 137.6, 137.55, 133.3, 130.8,
130.6, 129.32, 129.29, 125.6, 124.3, 123.2, 121.6, 119.8, 113.0, 101.9,
67.5, 67.2; IR (KBr) v 3341, 2962, 1744, 1454, 1400, 1265, 1092, 726,
702, 662, 519 cm−1; HRMS (ESI) (m/z) calcd for C20H16N2O3 ([M +
H]+), 333.1234, found 333.1246.
Methyl 3-oxo-1-(p-tolyl)-2,3-dihydro-1H-imidazo[1,5-a]indole-1-
carboxylate (7e). Pale yellow solid (78% yield, 49.9 mg): mp 155−
157 °C; 1H NMR (CDCl3, 400 MHz) δ 7.99 (d, J = 7.6 Hz, 1H), 7.61
(d, J = 8.0 Hz, 1H), 7.44−7.42 (m, 2H), 7.35−7.31 (m, 1H), 7.28−
7.24 (m, 1H), 7.19 (s, 1H), 7.17 (s, 1H), 7.13 (s, 1H), 6.72 (s, 1H),
3.81 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3, 400 MHz) δ 169.7,
151.5, 139.3, 137.8, 134.6, 133.3, 130.6, 129.9, 125.5, 124.2, 123.2,
121.5, 112.9, 101.7, 67.1, 53.9, 21.2; IR (KBr) v 3270, 2956, 2850,
1731, 1454, 1356, 1258, 1093, 820, 777, 749 cm−1; HRMS (ESI) (m/
z) calcd for C19H16N2O3 ([M + H]+), 321.1234, found 321.1232.
Methyl 1-(4-chlorophenyl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]-
indole-1-carboxylate (7f). Pale yellow solid (88% yield, 59.8 mg): mp
116−118 °C; 1H NMR (CDCl3, 500 MHz) δ 7.99 (dd, J1 = 8.0 Hz, J2
= 0.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52−7.50 (m, 2H), 7.39−
7.36 (m, 2H), 7.35−7.34 (m, 1H), 7.30−7.26 (m, 1H), 7.02 (s, 1H),
6.73 (d, J = 0.5 Hz, 1H), 3.84 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
169.3, 151.5, 137.3, 136.1, 135.4, 133.3, 130.6, 129.5, 127.1, 121.5,
123.4, 121.6, 113.0, 101.9, 66.7, 54.1; IR (KBr) v 3301, 1740, 1493,
1455, 1407, 1249, 780, 749 cm−1; HRMS (ESI) (m/z) calcd for
C18H13ClN2O3 ([M + H]+), 341.0687, found 341.0685.
Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52−7.50 (m, 2H), 7.54−7.51 (m,
2H), 7.48−7.45 (m, 1H), 7.37−7.33 (m, 1H), 7.30−7.26 (m, 2H),
6.74 (s, 1H), 3.83 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.2,
151.6, 137.2, 136.6, 133.2, 132.4, 130.6, 127.4, 124.5, 123.6, 123.4,
121.6, 113.0, 101.9, 66.8, 54.1; IR (KBr) v 3228, 3131, 1741, 1480,
1452, 1436, 1407, 1245, 778, 755 cm−1; HRMS (ESI) (m/z) calcd for
C18H13BrN2O3 ([M + H]+), 385.0182, found 385.0183.
Methyl 1-(4-nitrophenyl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]-
indole-1-carboxylate (7h). Brown solid (68% yield, 47.7 mg): mp
1
185−186 °C; H NMR (CDCl3, 400 MHz) δ 8.23−8.20 (m, 2H),
7.95 (d, J = 8.0 Hz, 1H), 7.81−7.78 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H),
7.47(s, 1H), 7.35−7.31 (m, 1H), 7.28−7.22(m, 1H), 6.76 (s, 1H),
3.84 (s, 3H); 13C NMR (CDCl3, 400 MHz) δ 168.7, 151.7, 148.3,
144.1, 136.25, 133.2, 130.6, 127.0, 124.8, 124.4, 123.6, 121.8, 113.0,
102.3, 66.8, 54.4; IR (KBr) v 3230, 3127, 1747, 1527, 1449, 1401,
1354, 1261, 1217, 1096, 787, 745 cm−1; HRMS (ESI) (m/z) calcd for
C18H13N3O5 ([M + H]+), 352.0928, found 352.0935.
Methyl 1-benzyl-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indole-1-
carboxylate (7i). Pale yellow oil (70% yield, 44.8 mg): 1H NMR
(CDCl3, 400 MHz) δ 7.93 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz,
1H), 7.34−7.24 (m, 5H), 7.19−7.18 (m, 2H), 6.63 (s, 1H), 5.88 (s,
1H), 3.78 (s, 3H), 3.67 (d, J = 13.6 Hz, 1H), 3.20 (d, J = 13.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 169.7, 151.6, 138.3, 133.8,
133.2, 130.5, 129.9, 128.9, 128.1, 124.1, 123.1, 121.5, 112.9, 99.9, 65.6,
53.5, 45.5; IR (KBr) v 3328, 1740, 1480, 1452, 1403, 1355, 1305,
1261, 748, 702 cm−1; HRMS (ESI) (m/z) calcd for C19H16N2O3 ([M
+ H]+), 321.1234, found 321.1235.
1′-Methylspiro[imidazo[1,5-a]indole-1,3′-indoline]-2′,3(2H)-
1
dione (7j). Pink solid (70% yield, 42.4 mg): mp 212−214 °C; H
NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 7.6 Hz, 1H), 7.63−7.50 (m,
3H), 7.37−7.26 (m, 4H), 7.08 (s, 1H), 6.73 (s, 1H), 3.83 (s, 3H); 13C
NMR (CDCl3, 400 MHz) δ 169.3, 151.5, 137.3, 136.1, 135.4, 133.2,
130.6, 129.4, 127.1, 124.5, 123.4, 121.6, 113.0, 101.9, 66.7, 54.1; IR
(KBr) v 3239, 1736, 1613, 1492, 1450, 1406, 750, 721 cm−1; HRMS
(ESI) (m/z) calcd for C18H13N3O2 ([M + Na]+), 326.0900, found
326.0902.
Methyl 7-methyl-3-oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,5-a]-
indole-1-carboxylate (7k). White solid (84% yield, 53.8 mg): mp
202−204 °C; 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J = 8.0 Hz, 1H),
7.55−7.52 (m, 2H), 7.40−7.38 (m, 4H), 7.17 (dd, J1 = 8.4 Hz, J2 = 1.2
Hz, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 3.83 (s, 3H), 2.46 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 169.7, 151.5, 137.81, 137.75, 133.7, 132.9,
129.4, 128.9, 125.8, 125.7, 121.4, 112.6, 101.7, 67.3, 54.0, 21.8; IR
(KBr) v 3225, 3120, 1732, 1449, 1251, 1226, 1098, 794, 698, 665
cm−1; HRMS (ESI) (m/z) calcd for C19H16N2O3 ([M + H]+),
321.1234, found 321.1246.
Methyl 7-methoxy-3-oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,5-
a]indole-1-carboxylate (7l). Pale yellow solid (74% yield, 49.7 mg):
mp 202−204 °C; 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, J = 8.8 Hz,
1H), 7.57−7.54 (m, 2H), 7.42−7.34 (m, 3H), 7.09−7.08 (m, 2H),
6.97 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 6.68 (s, 1H), 3.86 (s, 3H), 3.82
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.6, 156.3, 151.5, 138.5,
137.5, 134.1, 129.2, 125.6, 125.4, 113.53, 113.46, 104.0, 101.6, 67.2,
55.9, 53.9; IR (KBr) v 3226, 3124, 1736, 1584, 1478, 1410, 1249,
1135, 817, 698 cm−1; HRMS (ESI) (m/z) calcd for C19H16N2O4 ([M
+ H]+), 337.1183, found 337.1185.
Methyl 1-(4-chlorophenyl)-7-methoxy-3-oxo-2,3-dihydro-1H-
imidazo[1,5-a]-indole-1-carboxylate (7m). Yellow solid (81% yield,
59.9 mg): mp 160−162 °C; 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J
= 8.8 Hz, 1H), 7.53−7.51 (m, 2H), 7.38−7.36 (m, 2H), 7.07 (d, J =
2.4 Hz, 1H), 6.98 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 6.64 (s, 1H), 6.53
(s, 3H), 3.86 (s, 3H), 3.84 (s, 3H); 13C NMR (CDCl3, 400 MHz) δ
169.3, 156.5, 151.2, 138.0, 136.2, 135.5, 134.1, 129.5, 127.1, 125.5,
113.7, 113.6, 104.1, 101.8, 66.6, 55.9, 54.1; IR (KBr) v 3252, 1731,
1479, 1441, 1417, 1262, 1204, 1130, 1094, 1014, 905, 850 cm−1;
HRMS (ESI) (m/z) calcd for C19H16ClN2O4 ([M + H]+), 371.0793,
found 371.0783.
Methyl 8-(benzyloxy)-3-oxo-1-phenyl-2,3-dihydro-1H-imidazo-
[1,5-a]indole-1-carboxylate (7n). Pale yellow solid (93% yield, 76.6
mg): mp 168−170 °C; 1H NMR (CDCl3, 400 MHz) δ 7.62 (d, J = 8.0
Methyl 1-(4-bromophenyl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-
a]indole-1-carboxylate (7g). Pale yellow solid (71% yield, 54.5
mg): mp 157−158 °C; 1H NMR (CDCl3, 400 MHz) δ 7.99 (d, J = 7.6
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Hz, 1H), 7.57−7.54 (m, 2H), 7.53−7.51 (m, 2H), 7.45−7.34 (m, 6H),
7.26 (t, 1H), 6.92 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 5.22
(s, 2H), 3.83 (s, 3H) ; 13C NMR (CDCl3, 400 MHz) δ 169.6, 152.5,
151.5, 137.5, 137.1, 136.0, 129.3, 128.7, 128.1, 127.7, 125.6, 125.3,
123.9, 106.3, 104.7, 99.4, 70.3, 67.2, 54.0; IR (KBr) v 3416, 1736,
1450, 1436, 1401, 1241, 806, 750, 705 cm−1; HRMS (ESI) (m/z)
calcd for C25H20N2O4 ([M + H]+), 413.1496, found 413.1499.
Methyl 9-methyl-3-oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,5-a]-
indole-1-carboxylate (7o). White solid (78% yield, 49.9 mg): mp
176−178 °C; 1H NMR (CDCl3, 400 MHz) δ 7.87 (d, J = 8.0 Hz, 1H),
7.45 (d, J = 8.0 Hz, 1H), 7.28−7.24 (m, 4H), 7.24−7.21 (m, 2H),
7.19−7.15 (t, 1H), 6.73−6.66 (m, 1H), 3.73 (s, 1H), 2.16 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 170.1, 151.4, 137.0, 134.4, 132.4, 130.2,
129.30, 129.26, 126.0, 124.3, 122.7, 119.5, 112.8, 111.1, 67.8, 53.5, 9.0;
IR (KBr) v 3249, 1732, 1629, 1454, 1406, 1350, 1308, 1253, 756, 740,
695 cm−1; HRMS (ESI) (m/z) calcd for C19H16N2O3 ([M + H]+),
321.1234, found 321.1239.
Methyl 1-(4-bromophenyl)-9-methyl-3-oxo-2,3-dihydro-1H-
imidazo[1,5-a]indole-1-carboxylate (7p). White solid (75% yield,
59.7 mg): mp 182−183 °C; 1H NMR (CDCl3, 400 MHz) δ 7.96 (d, J
= 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.28−7.24 (m, 4H), 7.52−
7.50 (m, 2H), 7.38−7.34 (m, 1H), 7.31−7.29 (m, 1H), 7.27−7.24 (t,
1H), 6.56 (s, 1H), 3.86 (s, 3H), 2.25 (s, 3H); 13C NMR (CDCl3, 400
MHz) δ 169.8, 151.2, 136.1, 134.4, 132.5, 131.9, 130.2, 127.9, 124.6,
123.6, 122.9, 119.6, 112.8, 111.4, 67.3, 53.7, 9.0; IR (KBr) v 3232,
3131, 1755, 1738, 1453, 1402, 1351, 1255, 1236, 1009, 756, 746 cm−1;
HRMS (ESI) (m/z) calcd for C19H15BrN2O3 ([M + H]+), 399.0339,
found 399.0325.
Methyl 9-(2-acetoxyethyl)-3-oxo-1-phenyl-2,3-dihydro-1H-
imidazo[1,5-a]indole-1-carboxylate (7q). Yellow solid (54% yield,
42.3 mg): mp 143−144 °C; 1H NMR (CDCl3, 400 MHz) δ 8.00 (d, J
= 8.0 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.40−7.33 (m, 6H), 7.31−7.26
(m, 1H), 6.65 (s, 1H), 4.14−4.10 (m, 2H), 3.92 (s, 3H), 3.13−3.06
(m, 1H), 3.02−2.94 (m, 1H), 1.99 (s, 3H) ; 13C NMR (CDCl3, 100
MHz) δ 171.0, 169.6, 151.1, 137.1, 133.7, 129.54, 129.45, 126.0, 124.6,
123.0, 120.2, 112.9, 111.0, 67.9, 63.3, 53.9, 24.0, 21.1; IR (KBr) v 3338,
2955, 1755, 1734, 1457, 1399, 1246, 1023, 744, 694 cm−1; HRMS
(ESI) (m/z) calcd for C22H20N2O5 ([M + Na]+), 415.1264, found
415.1255.
2-(1′-Methyl-2′,3-dioxo-2,3-dihydrospiro[imidazo[1,5-a]indole-
1,3′-indolin]-9-yl)ethyl acetate (7r). Pink solid (49% yield, 38.1 mg):
mp 142−144 °C; 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J = 8.0 Hz,
1H), 7.44(d, J = 8.0 Hz, 1H), 7.36−7.24 (m, 2H), 7.20−7.16 (m, 2H),
7.01 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 3.86−
3.73 (m, 1H), 3.72−3.67 (m, 1H), 3.25 (s, 3H), 2.51−2.44 (m, 1H),
2.39−2.31 (m, 1H), 1.85 (s, 3H) ; 13C NMR (CDCl3, 100 MHz) δ
172.7, 170.9, 152.6, 143.9, 135.0, 133.4, 131.4, 130.8, 125.9, 125.0,
124.4, 124.2, 123.0, 119.6, 113.1, 109.4, 108.1, 62.9, 27.3, 23.3, 21.1; IR
(KBr) v 3238, 2946, 1732, 1693, 1613, 1471, 1454, 1237, 1034, 752
cm−1; HRMS (ESI) (m/z) calcd for C22H19N3O4 ([M + Na]+),
412.1268, found 412.1257.
781, 762, 697 cm−1; HRMS (ESI) (m/z) calcd for C15H14N2O3 ([M +
H]+), 271.1077, found 271.1084.
Methyl spiro[indoline-3,1′-pyrrolo[1,2-c]imidazole]-2,3′(2′H)-
1
dione (7u). Gray solid (60% yield, 30.3 mg): mp 213-215 °C; H
NMR (CDCl3, 400 MHz) δ 7.43−7.39 (m, 1H), 7.19 (d, J = 7.6 Hz,
1H), 7.12−7.08 (m, 2H), 6.94 (d, J = 7.6 Hz, 1H), 6.36 (t, 1H), 6.20−
6.17 (m, 1H), 5.80 (dd, J1 = 3.6 Hz, J2 = 0.8 Hz, 1H), 3.27 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 173.1, 152.7, 144.0, 133.3, 131.0,
126.5, 125.0, 124.0, 116.6, 112.9, 109.2, 103.2, 63.1, 27.2; IR (KBr) v
3318, 3117, 1736, 1614, 1493, 1471, 1412, 1366, 1309, 1218, 1108,
790, 760, 688 cm−1; HRMS (ESI) (m/z) calcd for C14H11N3O2 ([M +
Na]+), 276.0743, found 276.0749.
ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization data, including CIF files for compounds 3f, 5k
and 7a. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: slcui@zju.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the NNSFC (21202143) and Zhejiang
University for financial support.
■
REFERENCES
■
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