Ag-Catalyzed Intramolecular Sequential Vicinal Diamination of Alkynes with Isocyanates: Synthesis of Fused Indole-Cyclic Urea Derivatives

Article abstract of DOI:10.1021/acs.joc.7b00417

A formal intramolecular vicinal 1,2-diamination of alkynes is achieved for the synthesis of indole-cyclic urea fused derivatives through a double cyclization process from readily available aminophenyl propargyl alcohols. This sequential triple C-N bond co

Full text of DOI:10.1021/acs.joc.7b00417

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Article
Ag-Catalyzed Intramolecular Sequential Vicinal Diamination of Alkynes
with Isocyanates: Synthesis of Fused Indole-Cyclic Urea Derivatives
Manda Rajesh, Surendra Puri, Ruchir Kant, and Maddi Sridhar Reddy
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Apr 2017
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Ag-Catalyzed Intramolecular Sequential Vicinal Diamination of Alkynes
with Isocyanates: Synthesis of Fused Indole-Cyclic Urea Derivatives
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Manda Rajesh,a† Surendra Puri,a† Ruchir Kantb and Maddi Sridhar Reddya,c,d
*
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aMedicinal & Process Chemistry Division, bMolecular & Structural Biology Division, CSIRꢀ
Central Drug Research Institute, Lucknow, 226031 (India). cMCB Division, CSIRꢀIndian
Institute of Chemical Technology, Hyderabad, India. dAcademy of Scientific and
Innovative Research, New Delhi 110001, India. † Contributed equally.
Eꢀmail: msreddy@cdri.res.in
ABSTRACT: A formal intramolecular vicinal 1,2ꢀdiamination of alkynes is achieved for the
synthesis of indoleꢀcyclic urea fused derivatives through double cyclization process from
readily available aminophenyl propargyl alcohols. This sequential triple CꢀN bond
construction event was possible using isocyanate as urea precursor and Ag(I) catalyst as
alkyne activating agent.Control experiments reveal that the cyclization followed by 1,3ꢀ
allylic amino dehydroxylation is preceded by urea formation.
INTRODUCTION
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Difunctionalization of alkynes1ꢀ3 is a swift strategy for the rapid construction of a variety of
multifunctional frameworks, mainly olefin bearing scaffolds. In this line, intermolecular 1,2ꢀ
diamination of alkynes2 was well developed as an outstanding strategy for various important
Nꢀheterocycles like imidazoles,2d imidazopyridines,2e quinoxalines,2fꢀh 3ꢀamidoindoles,2i
triazoles (click reaction), cyclic urea derivatives, etc. whereas, intramolecular vicinal
diamination, which would deliver multicyclic Nꢀheterocycles, is less explored perhaps due to
geometric constraints. Nonetheless, few groups (Muñiz et al., Zhu et al., Jin et al., and Duet
al.,)3 successfully achieved this diamination of alkynes through internal double nucleophilic
addition via Pd and/or Cu catalysis. These studies mainly provided the indole based acenes.
On the other hand, the cyclic urea frameworks are privileged structural motifs and are found
in a wide range of biologically active and chemically significant molecules.4ꢀ5 Therefore,
decorations around cyclic ureas have recently attracted much attention of organic chemists.
Chemler et al., Muñiz et al., Fu et al., Youn et al., and others6 reported the intramolecular
cyclization of ureas on to tethered olefins or arenes respectively for the synthesis of
aryl/cycloalkyl fused urea derivatives (Scheme 1, eqs 1ꢀ2). As part of our ongoing program
aiming at the discovery of the novel reactivities of alkyne,7 we herein disclose a
complimentary approach featuring intramolecular sequential vicinal diamination for the
assembly of imidazo[1,5ꢀa]indolꢀ3ꢀone skeletons (Scheme 1, eq 3). Noteworthy, our process
represents the first example of the oneꢀpot urea formation followed by cyclization onto the
triple bond for the synthesis of the indoleꢀfused cyclic urea derivatives.
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Scheme 1. Synthesis of cyclic ureas.
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These indole fused cyclic urea motifs were found to be potent CNS depressant agents,
analgesics, 5ꢀHT3 receptor antagonists, antifungals, antihypertensive agents and TNFꢀα
(Tumor Necrosis Factorꢀα) antagonists.5 The synthesis of these derivatives is thus at a high
demand. It was earlier achieved through hydroamination and annulation process with Pd, Cu,
Au metal catalysis which required harsh reaction conditions and multiple steps.8 Herein we
are disclosing a mild process for these privileged scaffolds through Agꢀ catalyzed sequential
vicinal diamination of alkynes via bis cyclization form readily available starting materials.
RESULTS AND DISCUSSION
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We began our optimization studies using 2ꢀamino phenyl propargylic alcohol 1a and benzyl
isocyanate 2a as test substrates (Tableꢀ1). Initially we used PdCl2 as catalyst and Na2CO3 as
base in CH3CN at room temperature (entry 1) no desired product 3aa was detected. Upon
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heating the reaction contents to 70 C, pleasingly, the product was obtained but in 10% yield
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(entry 2). Changing the catalyst to Pd(OAc)2, Cu(OAc)2 or CuI (entries 3ꢀ5) did not bring any
change in the yield of the desired product (20ꢀ40%) but rather led to the formation of
corresponding quinoline derivative via 6ꢀendo dig cyclization. Next we switched to Ag2CO3
as catalyst where the yield was dramatically improved up to 60% (entry 6). We reasoned that
this silver catalyst gave enough room for urea formation on amino group of 1a before it
underwent 6ꢀendo dig cyclization.
Table 1. Optimization studies.a
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Delightedly, in the absence of the base, the yield was enhanced up to 82% (entry 7). Other Ag
salts were not as productive as Ag2CO3 (entries 8ꢀ10). No desired product was detected in the
absence of the metal catalyst (entry 11). MeCN was found to be best solvent over all the
tested solvents (entries 12ꢀ17).
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With the optimized conditions in hand, we next assessed the generality of this double
cyclization. We first studied the reaction scope of 2ꢀamino phenyl propargylic alcohols. As is
apparent from Table 2, the reaction accommodated substrates with distinct electron
properties. Initially, variation of substitution on alkyne terminus of amino propargylic
alcohols was studied. Substrates with alkylated phenyl substitution on the alkyne terminal
(1bꢀd) led to the desired urea products (3baꢀ3da) with good to excellent yields (80ꢀ82%).
Similarly, substrates with phenyl substitution either on the phenyl group on alkyne terminus
or on core aryl group (1eꢀf) underwent the reaction smoothly to afford the final products 3ea
and 3fa in 74% and 72% yields respectively. The electronic effect on the phenyl substituted
substrates has a perceptible influence on the outcome. Thus the electronꢀrich methoxy
bearing counterpart (1g) gave the corresponding adduct 3ga with high yield (83%) whereas
the halo (F and Br) phenyl substrates (1h-i) showed slightly decreased activity and thus led to
the products with moderate yields (68ꢀ65%).
Likewise, electronically slightly deficient CF3 analogues (1j-k) were transformed to the
desired adducts 3ja-ka in moderate yields (62ꢀ58%) whereas strongly electron deficient NO2
tethered substrate 1l was found to be totally unreactive in this transformation. Here the
intramolecular 6ꢀendo dig cyclization was found to be faster (to yield quinoline byproduct)
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Table 2.Scope of 2-Amino propargylic alcohols.a
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over probable intermolecular urea formation with isocyanate. Proceeding further, the reaction
of the cyclohexenyne 1m under standard conditions smoothly led to the desired cyclohexenyl
substituted indole fused cyclic urea product 3ma in 79% yield. Finally, we aimed to
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synthesize the products with varied substitution at C3 of indole substructure. Thus the
substrates 1n-q having the R3 substitution other than methyl group (nꢀpentyl, nꢀoctyl and
phenyl) was efficiently converted to the final products in 77−65% yields. However, the alkyl
substitution at the alkyne terminus was found to be ineffective for this conversion. In
continuation, we aimed to synthesize 3ꢀunsubstituted derivative 3ra from secondary
propargyl alcohol 1r. Surprisingly, the reaction under standard conditions led to oxy
cyclicoxazine amine derivative 4 in 75% yield probably through urea formation followed by
benzylic/propargyl hydroxyl elimination and urea cyclization (Scheme 2).
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Scheme 2. Benzo-[d][1,3]oxazin-2-amine transformation from 1r.
We reason that the trajectory required for the desired cyclization, i.e. 5ꢀexo dig cyclization, is
developed only in tertiary propargyl alcohols perhaps due to Thorpe Ingold effect. In case of
1r, no intended 5ꢀexo dig cyclization occurred because of the wide angle between the
reaction centres which might have led to the slow elimination of the benzylic/propargylic
group followed by cyclization of urea oxygen on the resultant benzylic/proaprgylic
carbocation.
Moving further, the scope of the double cyclization for indoleꢀurea derivatives was further
investigated with respect to isocyanates (Table 3). A wide range of arylisocyanates including
alkyl and aryl groups with varied substitution were thus employed in the reaction. Initially,
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Table 3. Scope of Isocyantes.a
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Me
Me
OH
Ag2CO3 (30 mol%)
R1NCO (2b-n),
Ph
R1
MeCN, 70 oC
N
Ph
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N
NH2
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O 3ab-3anb
1a
Me
Me
Me
Ph
Ph
Ph
N
O
N
N
N
OMe
OMe
N
N
O
O
3ab, 81%
3ad, 82%
3ac, 80%
OMe
OMe
Me
Me
Ph
Ph
N
N
O
N
N
O
3af
3af, 77%
Cl
F
3ae, 69%
CCDC No.1527102
Me
Me
Me
Ph
Ph
Ph
N
N
N
N
N
N
O
O
O
3ah, 78%
3ag, 74%
CN
Br
3ai
, 72%
NO2
Me
Me
Me
Ph
Ph
Ph
N
N
N
N
N
N
Me
C8H17
Ph
O
O
O
Me
3ak, 69%
3aj, 68%
Me
3al, 65%
Me
Ph
Ph
N
N
O
N
N
Me
O
3am, 69%
Cl
3an, 60%
aReaction conditions: 1a (0.5 mmol), 2 (1.25 mmol), catalyst (0.15 mmol)
in solvent (2.5 mL) at 70 oC under air. bIsolated yield
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the electronically neutral and rich substrates (with single to multiple alkoxy groups) 2b-d
were tested under standard reaction conditions which all pleasingly afforded the desired
products (3abꢀad) in excellent yields (80−82%).
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The halo groups (F, Cl, and Br) as in case of 2e-f survived well in the reaction to deliver the
corresponding adducts 3ae-af in 77ꢀ69% yields. The electron deficient CN and NO2 tethered
aryl isocyanates 2h-i was well tolerated under standard conditions to produce the expected
adducts in 69ꢀ78% yields. The structure of 3af was unambiguously confirmed by Xꢀray
crystallography. Further expanding the scope of the reaction, we aimed to synthesize the
products with alkyl substitution on nitrogen. Thus the aliphatic isocyanates 2j-m, irrespective
of linear, branched or cyclic substitution, were cleanly transformed to the anticipated adducts
3ajꢀ3am in 69ꢀ65% yields. Pleasingly, sensitive chloroethyl group of 2n survived
successfully through the optimized conditions and afforded 3an in 60% yield.
To probe the mechanism, we conducted some control experiments as shown in Scheme 3.
When we conducted a reaction at room temperature in the absence of the catalyst Ag2CO3,
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urea derivative 5 was formed as a sole product. Heating the reaction contents to 70 C,
however, did not lead to the desired product. This urea derivative 5 under the standard
conditions cleanly converted to the final double cyclized product, suggesting that the catalyst
free intermolecular urea formation is the initiating step. Surprisingly, under absence of
isocyanate from the optimized conditions, 1a led to 6ꢀendo dig cyclization to form quinoline
derivative demonstrating that the urea formation prior to the cyclization turned the
atmosphere towards 5ꢀexo dig cyclization.
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Scheme 3. Control experiments.
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On the basis of these observations and previous reports,9 a plausible reaction mechanism was
proposed as shown in Scheme 4. Initially 2ꢀamino phenyl propargylic alcohol 1 was reacted
with isocyanate 2 to give urea intermediate 5 which on Agꢀcatalyzed 5ꢀexo dig cyclization led
to the intermediate A. 1,3ꢀaminative dehydroxylation of A, driven by aromatization, revealed
the end cyclic urea adduct.
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Scheme 4. Proposed reaction mechanism.
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To expand the use of this protocol, we embarked on to derivatize these adducts. We first
attempted to reduce and disengage the cyclic urea to get indoloimidazolidine and indolyl
methyl amine (Scheme 5) respectively. Thus we treated 3ab with 10 equivalents of LiAlH4 in
refluxing THF.10 Surprisingly, this directly produced the demethylative adduct 7 in 65%
yield. This 2ꢀ(aminomethyl)ꢀindole scaffolds represents the key structures that exist in several
indole alkaloids as well as biologically active synthetic compounds.11 Efforts (by varying
temperature of the reaction and equivalents of LiAlH4) on controlled reduction of 3ab
towards indoloimidazolidine were not successful.
Scheme 5.Reductive cleavage of cyclic urea of 3ab.
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CONCLUSIONS
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In summary, we have demonstrated a general and straightforward approach for the synthesis
of indole fused cyclic urea derivatives from readily available 2ꢀamino phenyl propargylic
alcohols. This oneꢀpot triple CꢀN bond construction event was possible using isocyanate as
urea surrogate and Ag(I) catalyst as alkyne activating agent. The proposed reaction
mechanism proceeds likely via urea formation followed by unprecedented sequential vicinal
diamination of alkyne through double cyclization. This new and simple oneꢀpot protocol
features high functional group tolerance along with excellent productivity which makes it an
easy access to the synthesis of highly privileged motifs.
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EXPERIMENTAL SECTION
General Information
All reagents and solvents were purchased from commercial sources and used without
1
purification. NMR spectra were recorded with a 400 or 500 MHz spectrometer for H NMR,
100 or 125 MHz for 13C NMR spectroscopy. Chemical shifts are reported relative to the
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residual signals of tetramethylsilane in CDCl3 or deuterated solvent CDCl3 for H and C
NMR spectroscopy. Multiplicities are reported as follows: singlet (s), doublet (d), doublet of
doublets (dd), doublet of triplets (dt), triplet (t), quartet (q), multiplet (m). HRMS were
recorded by using QTof mass spectrometer. Column chromatography was performed with
silica gel (100–200 mesh) as the stationary phase. All reactions were monitored by using
TLC. The characterization of compounds was further established by using HRMS.
Starting Materials 1 Were Prepared in One Step Following the Literature Procedures. 12,7d
General Procedure A for the Synthesis of 1,2-dihydro-3H-imidazo[1,5-a]indol-3-ones
(3aa-3qa) from (1a-1q) taking Synthesis of 3aa as an example:
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To a stirred solution of 1a (120 mg, 0.5 mmol, 1 eq) in 2.5 mL of CH3CN was added Nꢀ
benzyl isocyanate (2a) (166 mg, 1.25 mmol, 2.5 eq) and Ag2CO3 (41 mg, 0.15 mmol, 0.3 eq)
o
at room temperature. The reaction mixture was stirred at 70 C until complete conversion of
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starting material (12h for 3aa-3da, 10h for 3ea-3fa, 14h for 3ga-3ka, 16h for 3ma-3qa 18h
for 3ab-3nd, 20h for 3ae-3ai 22h for 3aj-3an). The reaction mixture was diluted with EtOAc
and filtered through short celit pad. The filtrate was diluted with water and extracted with
EtOAc. Combined extracts were washed with brine (10 mL) and dried over Na2SO4. After
removal of the solvent under reduced pressure the crude material was purified on silica gel
using 10% EtOAc/hexane to get 3aa (146 mg, 82%) as off white solid.
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2-Benzyl-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3aa):mp 111ꢀ
o
1
1113 C; H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H),
7.41ꢀ7.36 (m, 3H), 7.36ꢀ7.29 (m, 4H), 7.27ꢀ7.19 (m, 5H), 5.33 (s, 1H), 5.15 (d, J = 15.1 Hz,
1H), 3.74 (d, J = 15.1 Hz, 1H), 1.89 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
152.0, 136.4, 135.7, 134.6, 133.9, 130.4, 129.1, 129.0, 128.8, 128.4, 128.1, 127.8, 123.3,
122.1, 118.9,112.6, 107.3, 58.4, 44.5, 7.8; DEPT90 (100 MHz, CDCl3) δ 129.1, 129.0, 128.8,
128.4, 128.1, 127.8, 123.3, 122.1, 118.9, 112.6, 58.4; DEPT135 (100 MHz, CDCl3) δ 129.1,
129.0, 128.8, 128.4, 128.1, 127.8, 123.3, 122.1, 118.9, 112.6, 58.4, 44.5 (ꢀve), 7.8; IR (KBr) ν
3400, 2403, 1567, 1385, 1030, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C24H21N2O [M + H]+
353.1654, found 353.1664.
2-Benzyl-9-methyl-1-(p-tolyl)-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ba): 3ba
(0.147 g) was obtained from 1b (0.126 g, 0.5 mmol) following general procedure A. Yield
o
1
80%; white solid, mp 141ꢀ143 C; Rf = 0.50 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.37ꢀ7.28 (m, 4H), 7.27ꢀ
7.22 (m, 3H), 7.19 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 5.30 (s, 1H), 5.14 (d, J =
15.2 Hz, 1H), 3.73 (d, J = 15.2 Hz, 1H), 2.38 (s, 3H), 1.89 (d, J = 1.4 Hz, 3H); 13C NMR (100
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MHz, CDCl3) δ 152.0,138.9, 136.5, 134.7,133.9, 132.5, 130.4, 129.8, 128.8, 128.4, 128.0,
127.8, 123.2, 122.0, 118.9, 112.5, 107.12, 58.2, 44.4, 21.2, 7.9; IR (KBr) ν 3686, 3401, 1727,
1478, 1456, 1310, 929, 627 cmꢀ1; HRMS (ESIꢀTOF) calcd for C25H23N2O[M + H]+ 367.1810,
found 367.1815.
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2-Benzyl-1-(4-ethylphenyl)-9-methyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ca):
3ca (0.154 g) was obtained from 1c (0.133 g, 0.5 mmol) following general procedure A.
Yield 81%; off white solid, mp 118ꢀ120 oC; Rf = 0.50 (SiO2, 10% EtOAc/Hexanes); 1H NMR
(400 MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.37ꢀ7.30 (m, 4H),
7.29ꢀ7.20 (m, 5H), 7.13 (d, J = 7.9 Hz, 2H), 5.33 (s, 1H), 5.15 (d, J = 15.2 Hz, 1H), 3.77 (d, J
= 15.2 Hz, 1H), 2.70 (q, J = 7.5 Hz, 3H), 1.92 (d, J = 1.4 Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 152.0, 145.2, 136.5, 134.8, 133.9, 132.7, 130.4, 128.8, 128.5,
128.4, 128.0, 127.7, 123.2, 122.0, 118.9, 112.5, 107.1, 58.2, 44.4, 28.5, 15.3, 7.9; IR (KBr) ν
3401, 2400, 1567, 1385, 1029, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C26H25N2O [M + H]+
381.1967, found 381.1970.
2-Benzyl-1-(4-(tert-butyl)phenyl)-9-methyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one
(3da): 3da (0.168 g) was obtained from 1d (0.147 g, 0.5 mmol) following general procedure
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A. Yield 82%; off white solid, mp 117ꢀ119 C; Rf= 0.40 (SiO2, 10% EtOAc/Hexanes); H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.40ꢀ7.36 (m,
4H), 7.28ꢀ7.18 (m, 3H), 7.12 (d, J = 7.2 Hz, 2H), 5.32 (s, 1H), 5.12 (d, J = 15.2 Hz, 1H), 3.79
13
(d, J = 15.2 Hz, 1H), 1.90 (d, J = 1.4 Hz, 3H), 1.33 (s,9H); C NMR (100 MHz, CDCl3) δ
152.1, 152.0, 136.6, 134.7, 134.0, 132.4, 130.4, 128.7, 128.4, 127.7, 125.9, 123.2, 122.0,
118.9, 112.5, 107.1, 58.2, 44.5, 34.7, 31.7, 7.9; IR (KBr) ν 3426, 2401, 1309, 1021, 625 cmꢀ1;
HRMS (ESIꢀTOF) calcd for C28H29N2O [M + H]+ 409.2280, found 409.2285.
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1-([1,1'-Biphenyl]-4-yl)-2-benzyl-9-methyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one
(3ea): 3ea (0.158 g) was obtained from 1e (0.157 g, 0.5 mmol) following general procedure
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A. Yield 74%; pale brown solid, mp 189ꢀ191 C; Rf = 0.45 (SiO2, 20% EtOAc/Hexanes); H
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 1H), 7.66ꢀ7.58 (m, 4H), 7.53ꢀ7.42 (m, 3H),
7.40ꢀ7.29 (m, 5H), 7.28ꢀ7.26 (m, 5H), 5.38 (s, 1H), 5.17 (d, J = 15.2 Hz, 1H), 3.81 (d, J =
15.2 Hz, 1H), 1.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.0, 141.9, 140.2, 136.4, 134.6,
134.5, 134.0, 130.4, 128.9, 128.5, 128.5, 127.8, 127.7, 127.1, 123.4, 122.2, 119.0, 112.6,
107.45, 58.2, 44.6, 8.0; IR (KBr) ν3401, 3019, 2400, 1601, 1524, 1383, 1023, 929, 627 cmꢀ1;
HRMS (ESIꢀTOF) calcd for C30H25N2O [M + H]+429.1967, found 429.1972.
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2-Benzyl-9-methyl-1,7-diphenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3fa): 3fa
(0.154 g) was obtained from 1f (0.157 g, 0.5 mmol) following general procedure A. Yield
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72%; off white solid, mp 140ꢀ142 oC; Rf = 0.55 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.69ꢀ7.62 (m, 3H), 7.59 (dd, J = 8.4 Hz, 1.6 Hz,
1H), 7.48ꢀ7.44 (m, 2H), 7.42ꢀ7.37 (m, 2H), 7.37ꢀ7.30 (m, 4H), 7.26ꢀ7.20 (m, 4H), 5.35 (s,
1H), 5.16 (d, J = 15.2 Hz, 1H), 3.75 (d, J = 15.2 Hz, 1H), 1.92 (d, J = 1.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.0, 142.1, 136.4, 135.9, 135.7, 135.3, 134.6, 129.9, 129.2, 128.9,
128.8, 128.5, 128.2, 128.0, 127.5, 126.8, 123.1, 117.7, 112.8, 107.7, 58.6, 44.7, 8.0; IR (KBr)
ν3401, 3019, 2400, 1730, 1603, 1026, 626 cmꢀ1; HRMS (ESIꢀTOF) calcd for C30H24N2O [M
+ H]+429.1967, found 429.1976.
2-Benzyl-1-(4-methoxyphenyl)-9-methyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one
(3ga): 3ga (0.159 g) was obtained from 1g(0.134 g, 0.5 mmol) following general procedure
A. Yield 83%; white solid, mp 130ꢀ132 oC; Rf = 0.45 (SiO2, 20% EtOAc/Hexanes); 1H NMR
(400 MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.38ꢀ7.28 (m, 4H),
7.26ꢀ7.20 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.29 (s, 1H), 5.12 (d, J
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= 15.1 Hz, 1H), 3.82 (s, 3H), 3.72 (d, J = 15.1 Hz, 1H), 1.88 (s, 3H); C NMR (100 MHz,
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CDCl3) δ 160.1, 151.9, 136.5, 134.8, 134.0, 130.4, 129.4, 128.8, 128.4, 127.8, 127.4, 123.2,
122.1, 118.9, 114.4, 112.6, 107.1, 57.9, 55.3, 44.4, 7.9; IR (KBr) ν 3403, 2401, 1387, 1030,
928, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C25H23N2O2 [M + H]+ 383.1760, found 383.1751.
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2-Benzyl-1-(4-fluorophenyl)-9-methyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ha):
3ha (0.126 g) was obtained from 1h (0.128 g, 0.5 mmol) following general procedure A.
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Yield 68%; pale yellow gum; Rf = 0.50 (SiO2, 20% EtOAc/Hexanes); H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.37ꢀ7.29 (m, 4H), 7.29ꢀ7.20 (m,
3H), 7.20ꢀ7.15 (m, 2H), 7.11ꢀ7.03 (m, 2H), 5.32 (s, 1H), 5.13 (d, J = 15.2 Hz, 1H), 3.74 (d, J
= 15.2 Hz, 1H), 1.89 (d, J = 1.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1 (d, J = 248.8
Hz), 151.9, 136.2, 134.1 (d, J = 40.5 Hz), 131.5 (d, J = 3.2 Hz), 130.4, 129.8 (d, J = 8.4 Hz),
128.8, 128.3, 127.9, 123.5, 122.2, 119.0, 116.2, 116.0, 112.6, 107.4, 57.7, 44.6, 7.9; IR (neat)
ν 3429, 2400, 1606, 1415, 1021, 626 cmꢀ1; HRMS (ESIꢀTOF) calcd for C24H20FN2O [M +
H]+ 371.1560, found 371.1568.
2-Benzyl-7-bromo-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ia):
3ia (0.141 g) was obtained from 1i (0.158 g, 0.5 mmol) following general procedure A. Yield
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65%; yellow solid, mp 148ꢀ150 C; Rf = 0.35 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 8.6 Hz, 1H), 7.62ꢀ7.56 (m, 1H), 7.43ꢀ7.38 (m, 4H), 7.37ꢀ7.30 (m,
4H), 7.25ꢀ7.17 (m, 4H), 5.33 (s, 1H), 5.13 (d, J = 15.2 Hz, 1H), 3.73 (d, J = 15.2 Hz, 1H),
13
1.84 (d, J = 1.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 151.7, 136.2, 135.9, 135.7, 135.3,
129.3, 129.0, 128.9, 128.5, 128.1, 128.0, 126.2, 121.9, 115.5, 113.9, 106.8, 58.6, 44.7 7.8; IR
(KBr) ν3401, 3019, 2399, 1522, 1384, 1023, 627 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C24H20BrN2O [M + H]+431.0759, found 431.0750.
2-Benzyl-9-methyl-1-phenyl-7-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[1,5-
a]indol-3-one (3ja): 3ja (0.169 g) was obtained from 1j (0.190 g, 0.5 mmol) following
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general procedure A. Yield 68%; light yellow solid, mp 152ꢀ154 C; Rf = 0.45 (SiO2, 10%
EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 7.77ꢀ7.73 (m, 2H),
7.72ꢀ7.59 (m, 3H), 7.58 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.42ꢀ7.38 (m, 3H), 7.37ꢀ7.31 (m, 3H),
7.27ꢀ7.19 (m, 4H), 5.36 (d, J = 0.9 Hz, 1H), 5.16 (d, J = 15.1 Hz, 1H), 3.76 (d, J = 15.1 Hz,
1H), 1.92 (d, J = 1.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 51.9, 140.0, 15.9, 133.7 (d, J =
26.9 Hz), 131.3 (d, J = 32.8 Hz), 130.4, 129.3, 128.9, 128.7, 128.4, 128.3, 128.2, 128.0,
127.8, 126.1, 126.1, 125.1, 123.7, 122.3, 119.7, 119.1, 112.6, 107.7, 57.9, 44.8, 7.9; IR (KBr)
ν 3401, 2400, 1385, 929, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C31H24F3N2O [M + H]+
497.1841, found 497.1834.
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2-Benzyl-9-methyl-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[1,5-a]indol-3-
one (3ka): 3ka (0.123 g) was obtained from 1k (0.153 g, 0.5 mmol) following general
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procedure A. Yield 58%; light brown solid; mp 138ꢀ140 C; Rf = 0.55 (SiO2, 20%
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EtOAc/Hexanes); H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0
Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.38ꢀ7.31 (m, 6H), 7.36ꢀ7.26 (m, 1H), 7.23ꢀ7.19 (m, 2H),
5.38 (d, J = 1.0 Hz, 1H), 5.16 (d, J = 15.2 Hz, 1H), 3.65 (d, J = 15.2 Hz, 1H), 1.88 (d, J = 1.4
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Hz, 3H); C NMR (100 MHz, CDCl3) δ 151.8, 145.5, 136.2, 135.5 (d, J = 13.7 Hz), 134.4
(d, J = 37.7 Hz), 130.2, 129.2, 128.8, 128.6, 128.4, 128.1, 127.9, 127.6, 125.6, 125.6, 125.5,
122.9, 117.8, 112.9, 107.6, 58.5, 44.6, 7.9; IR (KBr) ν 3402, 2401, 1730, 1416, 1325, 1020,
928, 626 cmꢀ1; HRMS (ESIꢀTOF) calcd for C25H20F3N2O [M + H]+ 421.1528, found
421.1524.
2-Benzyl-1-(cyclohex-1-en-1-yl)-9-methyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one
(3ma):3ma (0.142 g) was obtained from 1m (0.120 g, 0.5 mmol) following general
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procedure A. Yield 79%; off white solid, mp 132ꢀ134 C; Rf = 0.55 (SiO2, 20%
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EtOAc/Hexanes); H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.9
Hz, 1H), 7.34ꢀ7.31 (m, 4H), 7.31ꢀ7.26 (m, 2H), 7.26ꢀ7.21 (m, 1H), 5.98ꢀ5.91 (m, 1H), 4.96
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(d, J = 15.0 Hz, 1H), 4.84 (s, 1H), 4.08 (d, J = 15.0 Hz, 1H), 2.18ꢀ2.12 (m, 2H), 2.12 (d, J =
1.4 Hz, 3H), 1.66ꢀ1.58 (m, 2H), 1.56ꢀ1.42 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 152.3,
136.9, 133.9, 132.7, 132.4, 130.5, 130.4, 128.6, 128.5, 127.6, 123.0, 121.9, 118.7, 112.4,
107.0, 61.9, 44.7, 25.4, 22.5, 22.3, 22.1, 7.7; IR (KBr) ν 3684, 3020, 2926, 2401, 1725, 1455,
1076, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C24H25N2O [M + H]+ 357.1967 found 357.1973.
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2-Benzyl-9-pentyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3na): 3na (0.157
g) was obtained from 1n (0.147 g, 0.5 mmol) following general procedure A. Yield 77%; off
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white solid, mp 123ꢀ125 C; Rf = 0.40 (SiO2, 10% EtOAc/Hexanes); H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.39ꢀ7.29 (m, 7H), 7.26ꢀ7.21 (m,
3H), 7.21ꢀ7.17 (m, 2H), 5.30 (m, 1H), 5.14 (d, J = 15.2 Hz, 1H), 3.73 (d, J = 15.2 Hz, 1H),
2.40ꢀ2.24 (m, 2H), 1.34ꢀ1.25 (m, 1H), 1.20ꢀ1.04 (m, 3H), 1.02ꢀ0.93 (m, 2H), 0.71 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 152.0, 136.3, 136.2, 134.5, 133.3, 130.4, 129.1,
128.8, 128.4, 128.1, 127.8, 123.2, 122.0, 119.3, 112.6, 112.5, 58.7, 44.5, 31.5, 29.0, 23.6,
22.2, 13.9; IR (KBr) ν3401, 3019, 2399, 1522, 1216, 1070, 928, 669 cmꢀ1; HRMS (ESIꢀTOF)
calcd for C28H29N2O [M + H]+ 409.2280, found 409.2268.
2-Benzyl-9-octyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3oa): 3oa (0.169
g) was obtained from 1o (0.168 g, 0.5 mmol) following general procedure A. Yield 75%; pale
yellow gum; Rf = 0.40 (SiO2, 10% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J
= 8.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.39ꢀ7.36 (m, 3H), 7.35ꢀ7.29 (m, 4H), 7.26ꢀ7.21 (m,
3H), 7.21ꢀ7.17 (m, 2H), 5.30 (m, 1H), 5.15 (d, J = 15.2 Hz, 1H), 3.73 (d, J = 15.2 Hz, 1H),
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2.40ꢀ2.24 (m, 2H), 1.33ꢀ1.19 (m, 3H), 1.19ꢀ0.96 (m, 9H), 0.85 (t, J = 7.1 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 152.0, 136.4, 136.2, 134.5, 133.4, 130.4, 129.1, 128.8, 128.4, 128.1,
127.8, 123.2, 122.0, 119.3, 112.6, 112.5, 58.7, 44.6, 31.8, 29.3, 29.3, 29.2, 29.1, 23.6, 22.6,
14.0; IR (neat) ν 3401, 3019, 2400, 1650, 1385, 1069, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C31H35N2O [M + H]+ 451.2749, found 451.2732.
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2-Benzyl-1,9-diphenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3pa): 3pa (0.140 g)
was obtained from 1p (0.150 g, 0.5 mmol) following general procedure A. Yield 67%; light
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yellow solid, mp 153ꢀ155 C; Rf = 0.50 (SiO2, 20% EtOAc/Hexanes); H NMR (400 MHz,
CDCl3) δ 8.20 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.46ꢀ7.34 (m, 4H), 7.34ꢀ7.28 (m,
4H), 7.27ꢀ7.10 (m, 9H), 5.44 (s, 1H), 5.18 (d, J = 15.2 Hz, 1H), 3.72 (d, J = 15.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 151.8, 136.4, 136.3, 135.1, 132.6, 132.0, 130.9, 129.3, 129.2,
129.0, 128.6, 128.5, 128.4, 128.0, 126.8, 124.0, 123.0, 120.3, 113.9, 113.0, 59.3, 44.7; IR
(KBr) ν 3401, 3019, 2400, 1380, 1023, 929, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C29H23N2O [M + H]+415.1810, found 415.1813.
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2-Benzyl-7-chloro-1,9-diphenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3qa): 3qa
(0.147 g) was obtained from 1q (0.167 g, 0.5 mmol) following general procedure A. Yield
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65%; light brown solid, mp 143ꢀ145 C; Rf = 0.40 (SiO2, 10% EtOAc/Hexanes); H NMR
(400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.39ꢀ7.29 (m, 7H),
7.25ꢀ7.12 (m, 7H), 7.09ꢀ7.00 (m, 2H), 5.42 (s, 1H), 5.15 (d, J = 15.2 Hz, 1H), 3.71 (d, J =
15.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 151.4, 136.2, 136.0, 136.0, 133.1, 131.8, 129.4,
129.2, 129.0, 128.8, 128.6, 128.5, 128.4, 128.4, 128.1, 127.9, 127.1, 124.2, 120.0, 113.8,
113.5, 59.3, 44.7; IR (KBr) ν 3401, 3019, 2399, 1522, 1384, 1023, 627 cmꢀ1; HRMS (ESIꢀ
TOF) calcd for C29H22ClN2O[M + H]+449.1421, found 449.1411.
N-Benzyl-4-(phenylethynyl)-4H-benzo[d][1,3]oxazin-2-amine (4): 4 (0.128 g) was
obtained from 1r (0.112 g, 0.5 mmol) following general procedure A. Yield 75%; light
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yellow solid, mp 105ꢀ107 C; Rf = 0.50 (SiO2, 30% EtOAc/Hexanes); H NMR (400 MHz,
CDCl3) δ 8.85 (bs, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.52ꢀ7.49 (m, 3H), 7.46ꢀ7.41 (m, 1H), 7.40ꢀ
7.31 (m, 7H), 7.30ꢀ7.26 (m, 2H), 6.18 (s, 1H), 4.66ꢀ4.55 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 152.8, 151.8, 137.6, 134.1, 132.1, 129.5, 129.4, 128.7, 128.4, 127.6, 127.6, 125.8,
125.4, 125.4, 124.4, 122.7, 121.0, 90.5, 81.0, 69.3, 44.8; DEPTꢀ135 (100 MHz, CDCl3) δ
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132.1, 129.5, 129.4, 128.7, 128.4, 127.6, 127.6, 125.8, 124.4, 122.7, 69.3, 44.8 (ꢀve); IR
(KBr) ν 3400, 3019, 2401, 1651, 1385, 1069, 929, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C23H19N2O [M + H]+ 339.1497, found 339.1490.
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9-Methyl-1,2-diphenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ab): 3ab (0.138 g)
was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A. Yield 81%; white
solid, mp 156ꢀ158 oC; Rf = 0.40 (SiO2, 10% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ
8.09 (d, J = 8.0 Hz, 1H), 7.52ꢀ7.48 (m, 3H), 7.38ꢀ7.27 (m, 9H), 7.12ꢀ7.07 (m, 1H), 6.14 (d, J
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= 1.3 Hz, 1H), 2.00 (d, J = 1.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 150.4, 137.2, 136.4,
134.2, 133.3, 130.4, 129.1, 128.9, 128.7, 127.3, 124.9, 123.5, 122.5, 122.0, 119.0, 112.8,
107.3, 60.9, 7.9; IR (KBr) ν 3401, 2400, 1567, 1384, 1066, 669 cmꢀ1; HRMS (ESIꢀTOF)
calcd for C23H19N2O [M + H]+ 339.1497, found 339.1499.
2-(4-Methoxyphenyl)-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one
(3ac): 3ac (0.147 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure
A. Yield 80%; light brown solid, mp 140ꢀ142 oC; Rf = 0.45 (SiO2, 10% EtOAc/Hexanes); 1H
NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38ꢀ7.34 (m,
1H), 7.33ꢀ7.25 (m, 8H), 6.82 (d, J = 8.8 Hz, 2H), 6.02 (m, 1H), 3.75 (s, 3H), 1.99 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 157.4, 150.9, 136.6, 134.2, 133.7, 130.6, 130.0, 129.1, 128.9,
127.7, 125.1, 123.6, 122.5, 119.1, 114.4, 112.9, 107.4, 61.9, 55.5, 8.0; IR (KBr) ν 3402,
3021, 2927, 2401, 1733, 1022, 626 cmꢀ1; HRMS (ESIꢀTOF) calcd for C24H21N2O2 [M +
H]+369.1603, found 369.1600.
9-Methyl-1-phenyl-2-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3H-imidazo[1,5-a]indol-3-
one (3ad): 3ad (0.176 g) was obtained from 1a (0.120 g, 0.5 mmol) following general
procedure A. Yield 82%; white solid, mp 169ꢀ171 oC; Rf = 0.35 (SiO2, 10%
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EtOAc/Hexanes); H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.7
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Hz, 1H), 7.35ꢀ7.31 (m, 5H), 7.30ꢀ7.26 (m, 1H), 6.70 (m, 2H), 6.03 (d, J = 1.3 Hz, 1H), 3.78
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(s, 3H), 3.74 (s, 6H), 1.98 (d, J = 1.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 153.1, 150.6,
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136.7, 135.4, 133.2, 133.1, 130.4, 129.1, 128.9, 127.4, 123.6, 122.6, 119.1, 112.7, 107.4,
100.3, 61.7, 60.8, 56.0, 7.9; IR (KBr) ν 3401, 2400, 1514, 1384, 1022, 626 cmꢀ1; HRMS
(ESIꢀTOF) calcd for C26H25N2O4 [M + H]+ 429.1814, found 429.1807.
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2-(4-Fluorophenyl)-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ae):
3ae (0.123 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A.
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Yield 69%; pale yellow solid; mp 130ꢀ132 C; Rf = 0.55 (SiO2, 10% EtOAc/Hexanes); H
NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.43ꢀ7.37 (m,
2H), 7.36ꢀ7.26 (m, 7H), 7.03ꢀ6.94 (m, 2H), 6.07 (s, 1H), 1.99 (d, J = 1.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.0 (d, J = 245.3 Hz), 150.6, 136.4, 134.3, 133.3, 133.2 (d, J = 2.7
Hz), 130.5, 129.2, 129.0, 127.5, 124.5 (d, J = 8.1 Hz), 123.7, 122.7, 119.2, 115.9 (d, J = 23.0
Hz), 112.9, 107.6, 61.5, 8.0; IR (KBr) ν3401, 3019, 2400, 1513, 1024, 669 cmꢀ1; HRMS
(ESIꢀTOF) calcd for C23H18FN2O [M + H]+357.1403, found 357.1404.
2-(4-Chlorophenyl)-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3af):
3af (0.144 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A.
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Yield 77%; light brown solid, mp 189ꢀ191 C; Rf = 0.50 (SiO2, 10% EtOAc/Hexanes); H
NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 1H), 7.51ꢀ7.41 (m, 3H), 7.38ꢀ7.28 (m, 6H),
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7.28ꢀ7.21 (m, 3H), 6.07 (d, J = 0.9 Hz, 1H), 1.98 (d, J = 1.2 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 150.3, 136.1, 136.0, 134.3, 133.0, 130.5, 130.1, 129.3, 129.1, 129.1, 129.0, 127.3,
123.8, 122.9, 122.8, 119.2, 112.9, 107.7, 60.9, 7.9; IR (KBr) ν 3430, 2406, 1506, 1415, 1028,
626 cmꢀ1; HRMS (ESIꢀTOF) calcd for C23H18ClN2O [M + H]+ 373.1108, found 373.1112.
2-(4-Bromophenyl)-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ag):
3ag (0.154 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A.
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Yield 74%; off white solid, mp 219ꢀ221 oC; Rf = 0.55 (SiO2, 10% EtOAc/Hexanes); 1H NMR
(400 MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.42ꢀ7.37 (m, 4H),
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7.36ꢀ7.26 (m, 1H), 6.08 (d, J = 1.0 Hz, 1H), 1.99 (d, J = 1.2 Hz, 3H); C NMR (100 MHz,
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CDCl3) δ 150.2, 136.5, 136.1, 134.3, 133.0, 132.0, 130.5, 129.3, 129.0, 127.3, 123.8, 123.1,
122.8, 119.2, 117.8, 112.9, 107.7, 60.8, 7.9; IR (KBr) ν 3401, 2400, 1650, 1509, 1385, 1083,
909, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C23H18BrN2O [M + H]+ 417.0603, found
417.0608.
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4-(9-Methyl-3-oxo-1-phenyl-1H-imidazo[1,5-a]indol-2(3H)-yl)benzonitrile (3ah): 3ah
(0.142 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A. Yield
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78%; pale yellow solid, mp 213ꢀ215 C; Rf = 0.40 (SiO2, 10% EtOAc/Hexanes); H NMR
(400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H),7.93ꢀ7.89 (m, 1H), 7.81ꢀ7.74 (m, 1H), 7.48 (d,
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J = 7.8 Hz, 1H), 7.40ꢀ7.25 (m, 9H), 6.09 (d, J = 1.4 Hz, 1H), 1.98 (s, 3H); C NMR (100
MHz, CDCl3) δ 149.9, 138.4, 135.6, 134.3, 132.4, 130.3, 129.8, 129.4, 129.2, 127.7, 127.0,
124.9, 123.9, 123.9, 123.0, 119.2, 118.3, 113.1, 112.9, 108.1, 60.5, 7.8; IR (KBr) ν 3401,
2400, 1738, 1579, 1215, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C24H18N3O [M + H]+
364.1450, found 364.1458.
9-Methyl-2-(4-nitrophenyl)-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one
(3ai):
3ai (0.139 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A.
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Yield 72%; yellow solid, mp 205ꢀ207 C; Rf = 0.45 (SiO2, 10% EtOAc/Hexanes); H NMR
(400 MHz, CDCl3) δ 8.16 (d, J = 9.0 Hz, 2H), 8.07 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 9.0 Hz,
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2H), 7.48 (d, J = 7.7 Hz, 1H), 7.41ꢀ7.28 (m, 7H), 6.22 (s, 1H), 2.20 (s, 3H); C NMR (100
MHz, CDCl3) δ 149.7, 143.5, 143.2, 135.6, 134.4, 132.0, 130.3, 129.5, 129.2, 126.7, 124.7,
124.0, 123.2, 119.5, 119.3, 112.9, 108.2, 60.6, 7.8; IR (KBr) ν 3401, 2400, 1335, 1065, 669
cmꢀ1; HRMS (ESIꢀTOF) calcd for C23H18N3O3 [M + H]+ 384.1348, found 384.1342.
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9-Methyl-2-octyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3aj): 3aj (0.127 g)
was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A. Yield 68%
colourless oil; Rf = 0.60 (SiO2, 5% EtOAc/hexanes);1H NMR (400 MHz, CDCl3) δ 8.05ꢀ7.99
(m, 1H), 7.49ꢀ7.45 (m, 1H), 7.40ꢀ7.35 (m, 3H), 7.34ꢀ7.21 (m, 4H), 5.53 (s, 1H), 3.74ꢀ3.59
(m, 1H), 2.96ꢀ2.81 (m, 1H), 1.94 (d, J = 2.4 Hz, 3H), 1.32ꢀ1.19 (m, 12H), 0.89ꢀ0.83 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 152.1, 136.2, 134.8, 133.9, 130.4, 129.1, 129.0, 127.9, 123.2,
122.0, 118.9, 112.5, 106.9, 59.5, 41.1, 31.8, 29.2, 29.1, 27.9, 26.7, 22.6, 14.1, 7.9; IR (neat) ν
3401, 3019, 2399, 1522, 1216, 928, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C25H30N2O [M +
H]+375.2436, found 375.2435.
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9-Methyl-2-phenethyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3ak): 3ak
(0.126 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A. Yield
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69%; yellow solid, mp 139ꢀ141 C; Rf = 0.65 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.40ꢀ7.36 (m, 3H), 7.35ꢀ
7.23 (m, 5H), 7.20ꢀ7.14 (m, 4H), 5.27 (d, J = 1.1 Hz, 1H), 4.00ꢀ3.89 (m, 1H), 3.19ꢀ3.08 (m,
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1H), 3.02ꢀ2.93 (m, 1H), 2.85ꢀ2.74 (m, 1H), 1.90 (d, J = 1.4 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 151.9, 138.6, 135.9, 134.7, 133.9, 130.5, 129.1, 128.8, 128.6, 128.0, 126.6, 123.2,
122.0, 118.9, 112.5, 107.0, 60.0, 42.6, 34.6, 7.9; IR (KBr) ν 3402, 2400, 1646, 1568, 1217,
771, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C25H23N2O [M + H]+ 367.1810, found 367.1806.
2-Isopropyl-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3al): 3al
(0.99 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A. Yield
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65%; light yellow solid, mp 129ꢀ131 C; Rf = 0.60 (SiO2, 20% EtOAc/Hexanes); H NMR
(400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.37ꢀ7.28 (m, 6H),
7.25ꢀ7.20 (m, 1H), 5.56 (s, 1H), 4.14ꢀ4.05 (m, 1H), 1.88 (d, J = 1.2 Hz, 3H), 1.35 (d, J = 6.8
Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 152.0, 138.0, 135.2, 133.9,
130.2, 128.9, 128.8, 127.8, 123.1, 121.9, 118.8, 112.5, 106.5, 58.7, 46.2, 21.2, 20.3, 7.7; IR
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(KBr) ν 3401, 2400, 1455, 1215, 929, 669 cmꢀ1; HRMS (ESIꢀTOF) calcd for C20H21N2O [M
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+ H]+ 305.1654, found 305.1657.
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9-Methyl-2-((1r,4r)-4-methylcyclohexyl)-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-
3-one (3am): 3am (0.124 g) was obtained from 1a (0.120 g, 0.5 mmol) following general
procedure A. Yield 69%; yellow solid, mp 149ꢀ151 oC; Rf = 0.60 (SiO2, 10%
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EtOAc/Hexanes); H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.8
Hz, 1H), 7.36ꢀ7.27 (m, 6H), 7.25ꢀ7.19 (m, 1H), 5.57 (s, 1H), 3.75ꢀ3.62 (m, 1H), 1.87 (d, J =
1.2 Hz, 3H), 1.81ꢀ1.70 (m, 2H), 1.67ꢀ1.53 (m, 3H), 1.29ꢀ1.16 (m, 2H), 1.03ꢀ0.89 (m, 2H),
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0.83 (d, J = 6.5 Hz, 3H); C NMR (100 MHz, CDCl3) δ 152.1, 138.2, 135.3, 133.9, 130.21,
128.8, 128.7, 127.8, 123.1, 121.9, 118.8, 112.5, 106.4, 58.7, 54.1, 34.4, 31.7, 31.2, 30.3, 22.0,
7.7; IR (KBr) ν 3401, 2400, 1384, 1023, 929, 669, 626 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C24H27N2O [M + H]+ 359.2123, found 359.2125.
2-(2-Chloroethyl)-9-methyl-1-phenyl-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (3an):
3an (0.97 g) was obtained from 1a (0.120 g, 0.5 mmol) following general procedure A. Yield
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60%; light yellow solid, mp 129ꢀ131 C; Rf = 0.40 (SiO2, 30% EtOAc/Hexanes); H NMR
(400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.43ꢀ7.37 (m, 3H),
7.36ꢀ7.26 (m, 4H), 5.77 (s, 1H), 4.03ꢀ3.93 (m, 1H), 3.79ꢀ3.69 (m, 1H), 3.59ꢀ3.51 (m, 1H),
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3.31ꢀ3.21 (m, 1H), 1.95 (d, J = 1.3 Hz, 3H); C NMR (100 MHz, CDCl3) δ 151.9, 135.7,
134.4, 134.0, 130.3, 129.3, 129.2, 128.0, 123.4, 122.2, 119.0, 112.5, 107.4, 60.7, 42.9, 42.9,
42.1, 7.9; IR (neat) ν 3686, 3019, 2400, 1413, 1023, 929, 627 cmꢀ1; HRMS (ESIꢀTOF) calcd
for C19H18ClN2O [M + H]+ 325.1108, found 325.1113.
Control experiments
Scheme-A: To a stirred solution of 1a (237 mg, 1 mmol, 1 eq) in 2.5 mL of CH3CN was
added Phenyl isocyanate (332 mg, 2.5 mmol, 2.5 eq) at room temperature. The reaction
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mixture was stirred at RT. until complete conversion of starting material (1h). The reaction
mixture was diluted with water and extracted with EtOAc (2x10 ml). Combined extracts were
washed with brine (10 mL) and dried over Na2SO4. After removal of the solvent under
reduced pressure the crude material was purified on silica gel using 30% EtOAc/hexane to
get 5 (305 mg, 85 %) as off white solid.
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1-(2-(2-Hydroxy-4-phenylbut-3-yn-2-yl)phenyl)-3-phenylurea (5): mp 233ꢀ235 CRf =
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0.40 (SiO2, 30% EtOAc/Hexanes); H NMR (500 MHz, CDCl3) δ 8.51 (bs, 1H), 7.93 (d, J =
7.1 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 6.8 Hz, 2H), 7.35ꢀ7.30 (m, 4H), 7.25ꢀ7.20
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(m, 3H), 7.12ꢀ7.02 (m, 3H), 6.82 (bs, 1H), 3.13 (bs, 1H), 1.93 (s, 3H); C NMR (125 MHz,
CDCl3) δ 153.6, 137.9, 136.7, 132.8, 131.7, 129.1, 128.9, 128.7, 128.3, 126.4, 124.2, 123.5,
123.5, 123.3, 121.6, 120.3, 91.0, 85.9, 71.2, 30.2; IR (KBr) ν 3400, 3019, 1650, 1385, 1069,
669 cmꢀ1 HRMS (ESIꢀTOF) calcd for C23H19N2O [M + ꢀH2O]+ 339.1497, found 339.1487.
Scheme-B: To a stirred solution of 5 (179 mg, 0.5 mmol, 1 eq) in 2.5 mL of CH3CN was
added Ag2CO3 (42 mg, 0.15 mmol, 0.3 eq) at room temperature. The reaction mixture was
o
stirred at 70 C, until complete conversion of starting material (12 h). The reaction mixture
was diluted with water and extracted with EtOAc (2x10 ml). Combined extracts were washed
with brine (10 mL) and dried over Na2SO4. After removal of the solvent under reduced
pressure the crude material was purified on silica gel using 30% EtOAc/hexane to get 3ab
(127 mg, 75 %) as off white solid.
Scheme-C: Starting material 1a was subjected to the general procedure A in absence of
Isocyanate.
The product 6 was compared with reported data.12
Reductive cleavage of cyclic urea
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The 1,2ꢀdihydroꢀ3Hꢀimidazo[1,5ꢀa]indolꢀ3ꢀone 3ab (170 mg, 0.5 mmol, 1 equiv) in THF (10
mL) was added to a suspension of LiAlH4 (189 mg, 5 mmol, 10 equiv) in THF (10 mL). The
mixture was refluxed for 24 h until TLC showed no more starting material. On completion,
the reaction mixture was carefully hydrolysed with aqueous KOH (0.65 mL, 10% solution)
and water (0.8 mL). After complete addition stirring was continued for 2 h. After filtration
the filtrate was diluted with water and extracted with ethyl acetate (20 mL). Combined
extracts were washed with brine (10 mL) and dried over Na2SO4. After removal of the
solvent under reduced pressure the crude material was purified on silica gel using 10%
EtOAc/hexane to get 7 (103 mg, 65%) as off white solid.
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o
N-((3-Methyl-1H-indol-2-yl)(phenyl)methyl)aniline (7): mp 164ꢀ166 CRf = 0.50 (SiO2,
20% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ 8.22 (bs, 1H), 7.57 (d, J = 7.2 Hz, 1H),
7.42ꢀ7.31 (m, 5H), 7.29ꢀ7.26 (m, 1H), 7.19ꢀ7.11 (m, 4H), 6.82ꢀ6.75 (m, 1H), 6.62 (d, J = 7.7
Hz, 2H), 5.74 (d, J = 1.0 Hz, 1H), 4.18 (bs, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
147.5, 141.2, 135.0, 134.6, 129.7, 129.3, 129.0, 127.9, 127.3, 121.6, 119.2, 118.6, 118.4,
113.7, 110.9, 107.4, 56.5, 8.4; IR (KBr) ν 3400, 3019, 2320, 1385, 1069, 669 cmꢀ1 HRMS
(ESIꢀTOF) calcd for C22H21N2 [M + H]+ 313.1705, found 313.1710.
ASSOCIATED CONTENT
Spectroscopic data of all the products is available in Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author* Eꢀmail: msreddy@cdri.res.in
ACKNOWLEDGEMENTS
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This work was supported by MoES (09ꢀDS/03/2014 PCꢀIV), New Delhi. We are thankful to
SAIF, CSIRꢀCDRI, for providing the analytical facilities and Dr.Tejender S. Thakur,
Molecular and Structural Biology Division, CSIRꢀCDRI for supervising the Xꢀray data
collection and structure determination of compounds 3af. M.R. and S.P. thanks CSIR for the
fellowship. CDRI Communication No: 9477.
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