Counter ion effect in Au/Ag-catalyzed chemoselective 6- endo - Dig N- and O-cyclizations of enyne-urea system: Diversity-oriented synthesis of annulated indoles

Article abstract of DOI:10.1021/jo4013332

A two-step protocol for the diversity-oriented synthesis of annulated indoles following MCR-post MCR modification concept is described. The reaction initially proceeds through the annulation of 2-(2,2-dibromovinyl)aniline, an isocyanate, and a terminal alkyne in a three-component tandem format via Cu/Pd-catalyzed cross coupling to afford N-1 and C-2 functionalized indole. In the subsequent step, the enyne-urea derivative undergoes chemo- and regioselective 6-endo cyclization to afford O-cyclized product in the presence of Au(I)/AgNO₃ and N-cyclized product in the presence of Au(I)/AgOTf under a post-MCR modification step. A mechanistic investigation following a recent pioneering work on the silver effect in gold catalysis (Shi, X. J. Am. Chem. Soc. 2012, 134, 9012) explains the role of counterion on Au/Ag-catalyzed regiodivergent pathways.

Full text of DOI:10.1021/jo4013332

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Article
Counter ion effect in Au/Ag Catalyzed Chemoselective 6-
endo-dig N- and O-Cyclizations of Enyne-Urea system:
Diversity Oriented Synthesis of Annulated Indoles
Sahaj Gupta, Dipankar Koley, Krishnan Ravikumar, and Bijoy Kundu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4013332 • Publication Date (Web): 30 Jul 2013
Downloaded from http://pubs.acs.org on August 11, 2013
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Counter ion effect in Au/Ag Catalyzed Chemoselective 6-endo-dig
N- and O-Cyclizations of Enyne-Urea system: Diversity Oriented
Synthesis of Annulated Indoles
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Sahaj Gupta,† Dipankar Koley,†,‡ Krishnan Ravikumar,§ and Bijoy Kundu*,†,‡
†Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow
‡
226001, India, Academy of Scientific and Innovative Research, New Delhi 110001, India,
§
and X-Ray Crystallography Division, CSIR-Indian Institute of Chemical Technology,
Tarnaka, Hyderabad 500607, India
*Corresponding author. Tel.: +91 522 2612411-18; fax: +91 522 2623405; e-mail:
bijoy_kundu@yahoo.com, b_kundu@cdri.res.in
Abstract
R1
R1
R1
Au(I), AgOTf
Au(I), AgNO3
R3
N-cyclization
O-cyclization
N
N
H
N
N
R3
R3
O
N
O
R2
O
N
R2
R2
Pd/Cu
MCR
R1
Br
12 examples
upto 89% yield
12 examples
upto 88% yield
R3
R2
Br
NH2
O
C N
A two step protocol for the diversity oriented synthesis of annulated indoles following
MCR-post MCR modification concept is described. The reaction initially proceeds through
the annulation of 2-(2,2-Dibromo-vinyl)-aniline, an isocyanate and a terminal alkyne in a
three component tandem format via Cu/Pd-catalyzed cross coupling to afford N-1 and C-2
functionalized indole. In the subsequent step the enyne-urea derivative undergoes chemo- and
regioselective 6-endo cyclization to afford O-cyclized product in the presence of
Au(I)/AgNO3 and N-cyclized product in the presence of Au(I)/AgOTf under post-MCR
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modification step. A mechanistic investigation following a recent pioneering work on the
silver effect in gold catalysis (Shi et al J. Am. Chem. Soc. 2012, 134, 9012) explains the role
of counter ion on Au/Ag catalyzed regiodivergent pathways.
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Introduction
In recent years, transition metal catalyzed consecutive multicomponent reaction (MCR)-post
MCR modification1 concept has become a powerful approach for the diversity oriented
synthesis2,3 (DOS) of drug-like polyheterocyclic chemprobes. Strategically, the concept is
executed by synthesizing MCR product having bifunctionalized handles followed by another
ring formation utilizing those handles under post MCR modification.4 However,
chemoselective activation of MCR products comprising multiple nucleophilic/electrophilic
sites in either of the handles, remains a challenging task.5 Therefore, the development of
complementary set of conditions is required that would lead to the desired chemoselective
transformations from a common starting material.
In continuation to our reports6 for the synthesis of the indole based polyheterocycles,7
we planned for a sequenced MCR-post MCR modification approach that involves the
formation of an indole derived enyne-urea synthon (4) using a three component (3C) strategy
and subsequent chemoselective cyclization of the enyne-urea derivative under the post MCR
modification step (Figure 1). Although there are several reports8 describing intramolecular
nucleophilic attack via either O or N onto alkynes, reports for chemoselective cyclization
using both the nucleophiles are scarce.9 During the course of our manuscript preparation, van
Eycken et al.10 reported chemoselective 5-exo-dig cycloisomerization of propargylic urea to
provide O- and N-cyclized derivatives. Herein, we report a Cu/Pd catalyzed multicomponent
synthesis of bifunctionalized indole synthons and their chemo- and regioselective 6-endo-dig
cyclization to cyclic imidate (5) and pyrimido[1,6-a]indolone (6) derivatives using
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orthogonal set of catalysts, while the former is useful synthetic building block and important
pharmacophore,11 the latter is known to have importance in medicinal chemistry as 5-HT3
receptor antagonist,12 topoisomerase II inhibitor13 and fluorescent material.14
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Figure 1. MCR-post MCR modification concept leading to regio-and chemo-selective O- and
N-cyclized products 5 and 6 from synthon 4.
Results and Discussion
Our initial attempt to derivatize 2-alkynyl indole with the substituted isocyanate to
produce indole derivative 4 was unsuccessful. Therefore a MCR approach was undertaken
using 2-(2,2-Dibromo-vinyl)-aniline (1a), an isocyanate (2a) and a terminal alkyne (3a)
following a modified procedure described earlier by Lautens et al.15 Although the domino
fashion did not furnish the desired bifunctionalized indole 4a, heating 1a and 2a at 100 ºC in
toluene followed by the addition of 3a in the presence of 10% Pd-C/CuI, PPh3 and DIPA
(Diisopropylamine) furnished the desired 4a, albeit in a moderate (51%) yield. Extensive
screening of reaction parameters16 such as varying catalyst, ligand, base and solvent led to an
optimal reaction condition (10% Pd-C/CuI, (2-CH3C6H4)3P, DIPA, toluene, 100 °C) to
produce 4a in 75% isolated yield. The optimized reaction condition allowed annulation of a
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wide range of gem-dibromo-vinyl anilines 1, aryl/alkyl isocyanate derivatives 2 and terminal
aryl/alkyl alkynes 3, giving diverse bifunctionalized indole derivatives 4b-l in good yields
(61-75%, Scheme 1).
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Scheme 1. Three component sequential synthesis of synthon 4a-l in one-pot.
Isolated yields are given in parenthesis.
Given the outstanding performance of gold and silver catalysts17,18 as π-acids, we
examined several gold and silver salts to promote the cycloisomerization using 4a as model
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substrate (Table 1). While Au(I), Au(III), AgOTf completely failed, AgNO3 in toluene at
reflux temperature furnished 5a in moderate yield (Table 1, entries 1–8). Interestingly, while
4a could lead to four possible regiomers (Figure 1) via either 5-exo or 6-endo-dig pathways,19
the process furnished O-cyclized product 5a exclusively. DCE was relatively better than
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Table 1 Optimization of the reaction conditionsa for the synthesis of O- and N-cyclized
products 5a and 6a.
Yield [%]
Entry Catalyst Co-catalyst
Solvent
Time
5a/6ab
–
1
2
AuCl3
AuClPPh3
AuClPPh3
AuClPPh3
AuClPPh3
AgOTf
–
toluene
toluene
24 h
24 h
24 h
16 h
16 h
24 h
16 h
24h
–
–
–
3
toluene, reflux
DCE
–
4
–
–
5
–
DCE, reflux
toluene, reflux
DCE, reflux
toluene, reflux
DCE, reflux
DCE
–
6
–
–
7
AgOTf
–
–
8
AgNO3
–
56c/0
60/0
–
9
AgNO3
–
16 h
16 h
4 h
10
AuCl3
AgNO3
AgNO3
AgNO3
AgNO3
AgI
11 AuClPPh3
DCE
87/0
42d/0
32/0
–
12
13
14
15
16
AuClPPh3
AuClPPh3
AuClPPh3
AuClPPh3
AuClPPh3
THF
16 h
16 h
24 h
24 h
24 h
5 min
30 min
3.5 h
DMF
DCE
AgCl
AgBr
AgOTf
AgOTf
AgNTf2
DCE
–
DCE
–
17 AuClPPh3
DCE
0/85
5/74
0/78
18
AuCl3
DCE
19
AuClPPh3
DCE
aReaction conditions: 4a (0.2 mmol), [Au] catalyst (5 mol%), [Ag] catalyst (20 mol%), solvent (2 mL),
under N2. bIsolated yield. c14% 4a was recovered. d4a was recovered in 34% yield.
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toluene as a solvent (Table 1, entry 9). Various catalytic combinations20 were then employed
to improve the yield (Table 1, entries 10–13). To our delight, AuClPPh3/AgNO3 (catalyst set
A) exclusively afforded 6-endo-dig-O-cyclized 5a in 87% yield at rt in DCE within 4 h.
(Table 1, entry 11). Aiming to promote the chemoselective N-cyclization, several other Ag
salts in combination with Au(Ι) and Au(III) salts were also screened (Table 1, entries 14–18).
Pleasingly, AuClPPh3/AgOTf (catalyst set B) in DCE at rt within 5 min provided 6-endo-dig-
N-cyclized product 6a in 85% yield (entry 16) with no detectable 5a or 5-exo product. Thus, a
novel reaction pathway is obtained on switching the catalyst from AgNO3 to AgOTf.
Although, Shi et al21 demonstrated presence of Tf2N- as coordinating anion with Au catalyst
promoted few reactions which could not be possible by using TfO- and Au catalyst. However,
it promoted only N-cyclization (entry 19) in our system, albeit in a relative slower rate (3.5 h)
with lesser yield (78%).
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We next studied the scope of this reaction. Subjecting substrates 4b-l under the
optimized condition using catalyst set A, O-cyclized derivatives (5b-l) were isolated in 81-
88% yields (Table 2). The reaction was tolerated by both aromatic and aliphatic substituents
Table 2. Scope for chemoselective O- and N-cyclization in 4a-l.
catalyst set A
catalyst set B
substrate
(O-cyclization)a
(N-cyclization)a
4a
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4d
4e
4f
4g
4h
4i
4j
4k
4l
aYield of the isolated product. 5j, 5k, 5l was isolated in 39%, 44%, 42% isolated yield respectively along with
b
the desired product after 8 h of stirring.
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present on either handles (5b-l). Electron-withdrawing or -donating substituents on either of
the aryl rings (R1, R2 and R3) had also no adverse effect on the yield and chemoselectivity
(5a-l). On the contrary, using catalyst set B, the N-cyclized derivatives (6b-i) were isolated in
79-89% yields. Unfortunately, substrates with R3 as aliphatic substituents furnished cyclized
products with very good overall yield in a non-chemoselective fashion. A tentative reason for
the loss of chemoselectivity might be due to the positive inductive effect of the aliphatic
group. The positive inductive effect reduces the electrophilicity of the cationic gold
intermediate. This in turn makes the complex less prone to nucleophilic attack thereby
opening up the probability of the attack by both the O- and N- nucleophiles. However, none
of our substrate led to the formation of 5-exo-dig cyclised product probably to avoid the ring
strain.22 The structures were confirmed unambiguously by X-ray crystallographic analysis of
5e and 6e.23
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A mechanistic study following the recent report of Shi et al21 regarding the “silver
effect in gold catalysis” was conducted to explain the phenomenon for such an excellent
chemoselectivity. We envisaged that the nature of counter ion and/or Ag-catalyst might be
playing a significant role in controlling the O/N cyclization. Therefore, we performed several
control experiments with 4a adding a variety of Ag and K salts as a source for counter ions to
catalyst set B (Table 3). Lowering the concentration of the catalyst set B although did not
affect the chemoselectivity, it took 1 h for the completion (entry 1). AgNO3 with the catalyst
set B promoted the O-cyclization, although in a low yield (entry 2). KNO3 (20 mol%) with
the catalyst set B made the reaction sluggish and furnished 5a in 43% yield, indicating a
possibility of counter anion controlled O-cyclization (entry 3). Addition of KI (20 mol%)
with the catalyst set B resulted only traces of 6a with no detectable 5a thereby ruling out the
involvement of K+ and the result emphasized the exclusive role of nitrate anion in promoting
O-cyclization (entry 4).
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However, to gain further insight, 4a was treated with [Ph3PAu]+TfO− (preformed Ag
free Au-salt derived from the catalyst set B following Shi et al21 protocol). The reaction was
slow and non-chemoselective (entry 5), thereby indicating the necessity of a counter ion
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Table 3. Investigation of the reaction mechanism.a
additiveb
time
entry
1
catalysts (mol %)b
AuClPPh3 (1 ) + AgOTf (4)
(20 mol %)
–
(h)
1
4a:5a:6ac
0:0:100
2
3
AuClPPh3 (1 ) + AgOTf (4)
AuClPPh3 (1 ) + AgOTf (4)
AuClPPh3 (1 ) + AgOTf (4)
[Ph3P–Au]+TfO− (5)
AgNO3
KNO3
KI
1
0:10:90
40:43:17
97:0:3
24
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24
1
4
5
–
3:62:35
81:14:5
93:5:2
6
[Ph3P–Au]+TfO− (5)
AgCl
KI
7
[Ph3P–Au]+TfO− (5)
8
[Ph3P–Au]+TfO− (5)
KNO3
AgNO3
AgOTf
49:41:10
0:92:8
9
[Ph3P–Au]+TfO− (5)
10
[Ph3P–Au]+TfO− (5)
1
0:0:100
b
c
aSee supporting information. For reaction conditions see supporting information. Relative ratio of 4a, 5a and
6a was based on 1H NMR spectra of the crude reaction mixture.
and/or influence of Ag-catalyst for the chemoselective transformation. This is further evident
from the fact that neither AgCl nor KI with [Ph3PAu]+TfO− were able to catalyze the said
transformation (entries 6–7). The addition of KNO3 to [Ph3PAu]+TfO− again made the
reaction sluggish but facilitated the formation of 5a in 41% yield (entry 8). Addition of
AgNO3 to [Ph3PAu]+TfO− favored the exclusive formation of 5a in 92% yield (entry 9). As
anticipated, AgOTf with [Ph3PAu]+TfO− furnished N-cyclized product 6a in quantitative
−
yield (entry 10). It is thus apparent that while using catalyst set A, the NO3 (counter ion)
together with Au complex played a major role in controlling the exclusive formation of the
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O-cyclized product, the use of catalyst set B (Type II gold catalyzed reaction21) involving a
cationic gold complex in association with AgOTf favored the chemoselective N-cyclization.
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8
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Based on these findings, a plausible mechanism is proposed (Figure 2). In the case of
catalyst set B, the intermediate [Ph3P–Au]+TfO−, generated in situ, in the presence of AgOTf
activates the alkyne to form the soft electrophilic intermediate I. Next, the nitrogen of the
urea, being less electronegative than oxygen, favorably attacks as a relatively softer
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Figure 2. A plausible mechanism for the chemoselectivity.
nucleophile onto the electron-deficient alkyne to afford N-cyclized product 6, a phenomenon
that could be well explained following HSAB theory.24 In contrast, O-cyclization promoted
by type III Au catalyst,21 may involve activation of the alkyne by Au catalyst along with
coordination of Ag with the oxygen25 of the urea to furnish the intermediate IV which upon
cyclization and protodeauration delivers the O-cyclized product 5.
Conclusion
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In summary, we have developed a two step protocol using Pd/Cu and Au/Ag catalytic
combinations for the rapid and efficient access of highly functionalized indole based tricyclic
heteroaromatics following MCR-post MCR modification concept. Furthermore, we
implemented chemoselective cycloisomerization processes using orthogonal set of catalysts
leading to the generation of an array of N-[1,3]oxazino[3,4-a]indol-1-ylideneamine and
pyrimido[1,6-a]indolone derivatives from a common intermediate. Our mechanistic
investigation reveal the significance of selecting the correct counter ion for the gold catalyzed
reactions as it can play an important role in identifying new regio-divergence pathway and in
turn lead to diversity oriented synthesis.
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Experimental
I General Information and methods. All reagents and solvents were purchased from
commercial sources and used without purification. NMR spectra were recorded with 200, 300
and 400 MHz spectrometers for 1H NMR, 50, 75 and100 MHz for 13C NMR. Chemical shifts
δ are given in ppm relative to the residual signals of tetramethylsilane in CDCl3 or deuterated
solvent CDCl3/DMSO-d6 for 1H and 13C NMR. Multiplicities are reported as follows: singlet
(s), doublet (d), doublet of doublets (dd), doublet of triplets (dt), triplet (t), quartet (q),
multiplet (m). High resolution mass spectra were taken with a mass spectrometer. Column
chromatography was performed using silica gel (100-200 mesh) as the stationary phase. All
reactions were monitored by thin layer chromatography (TLC). The purity and
characterization of these compounds were further established using HR/EI Mass
spectroscopy. Melting points were measured on a capillary melting point apparatus and are
uncorrected.
General Procedure for the Preparation of 2-(2,2-dibromovinyl)aniline derivatives 1a-c
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To a stirred solution of 2-nitro benzaldehyde derivatives (1.0 equiv) and tetrabromomethane
(1.5 equiv) in dichlomethane (4.5 mL/mmol of 2-nitro benzaldehyde derivatives) at 0 °C was
added triphenyl phosphine (3.0 equiv) slowly in small lots so that internal temperature was at
1-5 °C. After addition, the mixture was stirred for another 0.5 h at 0 °C before warmed to RT
and stirred for another 1h. The reaction mixture was filtered through short plug of silica gel
(60-120 mesh size) and the silica gel was washed with copious amount of dichlomethane
until no product was found. Solvent was removed under vaccum to give a solid mixture of
desired product and tripheny phosphine oxide. To the mixture was added absolute ethanol
(3.0 mL/mmol of 2-nitro benzaldehyde derivatives) under nitrogen followed by the addition
of iron powder (3.0 equiv) and ammonium chloride (3.0 equiv). The resulted suspension was
heated to 90 °C under nitrogen for 1 h. The mixture was cooled to RT and most of the solvent
was removed under vacuum. The residue was dissolved in EtOAc and pass through celite bed
and the bed was washed with EtOAc. To the filtrate was added saturated potassium carbonate
solution and the resulted mixture was extracted with EtOAc. The combined organic layer was
washed with brine and dried over anhydrous sodium sulfate. Solvent was removed under
vacuum. The crude product was purified by silica gel flash chromatography and
concentration of the appropriate fractions in-vacuo afforded the desired compounds (1a-c).
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2-(2,2-dibromovinyl)aniline (1a):
1
Brown liquid; yield 72% (1.320 g); FT-IR (neat) 3105, 3037, 1624, 1490, 1217 cm-1; H
NMR (300 MHz, CDCl3): δ 7.38-7.34 (m, 2H), 7.21-7.18 (m, 1H), 6.86-6.81 (m, 1H), 6.75-
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6.72 (m, 1H), 3.73 (s, 2H) ppm; C NMR (50 MHz, CDCl3): δ 143.6, 134.1, 129.8, 129.3,
121.8, 118.5, 115.9, 92.8 ppm; HRMS (ESI) calcd for C8H8Br2N [M + H] 275.9023 found
275.9005.
6-(2,2-dibromovinyl)-1,3-benzodioxol-5-amine (1b):
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Brown solid; yield 75% (1.235 g); mp 96-97 °C; FT-IR (KBr) 3114, 1613, 1480, 1377, 1174
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cm-1; H NMR (300 MHz, CDCl3): δ 7.24 (s, 1H), 6.88 (s, 1H), 6.27 (s, 1H), 5.88 (s, 2H),
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3.38 (s, 2H) ppm; C NMR (75 MHz, CDCl3): δ 148.7, 140.4, 139.2, 133.5, 113.8, 108.2,
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101.0, 97.9, 91.4 ppm; HRMS (ESI) calcd for C9H8Br2NO2 [M + H] 319.8922 found
319.8904.
4-chloro-2-(2,2-dibromovinyl)aniline (1c):
Brown liquid; yield 73% (1.227 g); FT-IR (neat) 2920, 1631, 1479, 1376 cm-1; 1H NMR (300
MHz, DMSO-d6): δ 7.44 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.07 (dd, J = 7.2, 2.2 Hz, 1H), 6.66
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(d, J = 8.7 Hz, 1H), 5.44 (s, 2H) ppm; C NMR (75 MHz, CDCl3): δ 142.3, 132.9, 129.6,
128.8, 123.1, 123.0, 117.1, 94.3 ppm; HRMS (ESI) calcd for C8H7Br2ClN [M + H] 309.8634
found 309.8624.
II General Procedure for the Preparation of N-and 2-substituted 1H-indole-1-
carboxamide derivatives 4a-l
To a stirred solution of 2-(2,2-dibromovinyl)aniline derivatives 1a-c (1.0 eqiv) in toluene
(15mL/mmol of 1a-c) under N2 was added isocyanate derivatives 2a-e (1.2 equiv) and the
resulted reaction mixture was heated at 100 °C for 2 h. DIPA (2.5 equiv), tri-o-tolylphosphine
(10 mol%) and Pd/C (5 mol%) were added to the reaction mixture under N2 and heated to 100
°C for 5 minutes. It was followed by the addition of alkyne derivatives 3a-f (1.5 equiv) and
CuI (5 mol%) and the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture
was filtered through short celite bed and the bed was washed with EtOAc. The filtrate was
washed with water and brine. The organic layer was dried over anhydrous sodium sulfate
using EtOAc/hexane as eluent and solvent was removed under vacuum. The crude product
was purified by silica gel column chromatography and concentration of the appropriate
fractions in-vacuo afforded the desired compounds (4a-l).
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N-(4-methylphenyl)-2-(2-phenylethynyl)-1H-indole-1-carboxamide (4a):
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Pale yellow solid; yield 75% (0.285 g); mp 140-142 °C; FT-IR (KBr) 3301, 3057, 2254,
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1679, 1606, 1447, 1319 cm-1; H NMR (300 MHz, CDCl3): δ 8.93 (s, 1H), 7.43 (d, J = 8.5
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Hz, 1H), 7.58-7.52 (m, 3H), 7.46 (d, J = 8.4 Hz, 2H), 7.42-7.37 (m, 4H), 7.29-7.24 (m, 1H),
7.16 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 2.34 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
149.3, 137.5, 134.8, 134.4, 131.7, 129.9, 129.7, 128.9, 128.2, 126.2, 123.3, 121.4, 120.8,
120.2, 117.4, 116.6, 116.4, 98.7, 81.2, 20.9 ppm; HRMS (ESI) calcd for C24H19N2O [M + H]
351.1497 found 351.1498.
N-(4-methylphenyl)-2-[2-(4-methylphenyl)ethynyl]-1H-indole-1-carboxamide (4b):
White solid; yield 70% (0.276 g); mp 155-156 °C; FT-IR (KBr) 3299, 2976, 1679, 1521,
1321 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.00 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.56 (d, J =
7.8 Hz, 1H), 7.47-7.36 (m, 5H), 7.28-7.15 (m, 5H), 7.05 (s, 1H), 2.40 (s, 3H), 2.34 (s, 3H)
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ppm; C NMR (50 MHz, CDCl3): δ 149.4, 140.2, 137.4, 134.9, 134.3, 131.6, 129.8, 129.6,
128.2, 126.0, 123.2, 120.8, 120.2, 118.2, 117.6, 116.4, 116.3, 99.0, 80.5, 21.8, 21.0 ppm;
HRMS (ESI) calcd for C25H21N2O [M + H] 365.1654 found 365.1653.
2-{2-[4-(tert-butyl)phenyl]ethynyl}-N-(4-methylphenyl)-1H-indole-1-carboxamide (4c):
White solid; yield 73% (0.321 g); mp 158-159 °C; FT-IR (KBr) 3384, 2956, 1711, 1602,
1530, 1306 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.00 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 7.56
(d, J = 7.8 Hz, 1H), 7.48-7.36 (m, 7H), 7.26 (s, 1H), 7.17 (d, J = 7.6 Hz, 2H), 7.06 (s, 1H),
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2.35 (s, 3H), 1.34 (s, 9H) ppm; C NMR (50 MHz, CDCl3): δ 153.2, 149.5, 137.4, 134.9,
134.3, 131.5, 129.8, 128.2, 126.0, 125.9, 123.2, 120.8, 120.3, 118.3, 117.6, 116.4, 99.1, 80.6,
35.1, 31.2, 21.0 ppm; HRMS (ESI) calcd for C28H27N2O [M + H] 407.2123 found 407.2122.
N-(3-acetylphenyl)- 2-{2-[4-(tert-butyl)phenyl]ethynyl}-1H-indole-1-carboxamide (4d):
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White solid; yield 74% (0.348 g); mp 158-159 °C; FT-IR (KBr) 3358, 2963, 1687, 1606,
1544, 1312 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.30 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.02
(s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.59-7.38 (m, 7H), 7.30-7.26 (m,
1H), 7.08 (s, 1H), 2.48 (s, 3H), 1.34 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3): δ 197.4,
153.5, 149.3, 138.0, 137.9, 137.2, 131.5, 129.6, 128.1, 126.1, 125.9, 124.3, 124.0, 123.4,
120.8, 119.7, 117.9, 117.3, 116.7, 116.3, 99.2, 80.3, 35.0, 31.1, 26.5 ppm; HRMS (ESI) calcd
for C29H27N2O2 [M + H] 435.2073 found 435.2063.
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N-(4-methylphenyl)-6-{2-[4-(tert-butyl)phenyl]ethynyl}-5H-[1,3]dioxolo[4,5-f]indole-5-
carboxamide (4e):
White solid; yield 67% (0.282 g); mp 189-190 °C; FT-IR (KBr) 3379, 2957, 2195, 1705,
1598, 1534, 1322, 1243 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.06 (s, 1H), 7.99 (s, 1H), 7.46-
7.38 (m, 6H), 7.15 (d, J = 8.1 Hz, 2H), 6.92 (s, 1H), 6.89 (s, 1H), 5.99 (s, 2H), 2.34 (s, 3H),
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1.34 (s, 9H) ppm; C NMR (50 MHz, CDCl3): δ 152.9, 149.5, 147.9, 145.1, 134.9. 134.3,
132.8, 131.3, 129.8, 125.9, 122.3, 120.3, 118.5, 116.5, 116.0, 101.4, 98.7, 97.8, 80.8, 35.1,
31.2, 21.0 ppm; HRMS (ESI) calcd for C29H27N2O3 [M + H] 451.2022 found 451.2014.
5-chloro-N-(3-chloro-4-methylphenyl)-2-{2-[4-(tert-butyl)phenyl]ethynyl}-1H-indole-1-
carboxamide (4f):
White solid; yield 71% (0.324 g); mp 149-151 °C; FT-IR (KBr) 3305, 2960, 2138, 1688,
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1598, 1527, 1314, 1197 cm-1; H NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 8.37 (d, J = 8.9
Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.52-7.42 (m, 5H), 7.34-7.31 (m, 2H), 7.18 (d, J = 8.2 Hz,
1H), 6.98 (s, 1H), 2.35 (s, 3H), 1.35 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 153.7,
148.9, 136.0, 135.6, 134.8, 132.3, 131.5, 131.3, 129.2, 129.0, 126.2, 126.0, 120.6, 120.1,
118.7, 118.2, 117.7, 117.4, 115.5, 99.9, 80.0, 35.2, 31.2, 19.6 ppm; HRMS (ESI) calcd for
C28H25Cl2N2O [M + H] 475.1344 found 475.1341.
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2-(2-cyclohex-1-en-1-ylethynyl)-N-(4-methylphenyl)-1H-indole-1-carboxamide (4g):
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White solid; yield 65% (0.249 g); mp 152-153 °C; FT-IR (KBr) 3312, 2927, 2157, 1679,
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1606, 1543, 1317, 1234 cm-1; H NMR (300 MHz, CDCl3): δ 8.99 (s, 1H), 8.43 (d, J = 8.4
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Hz, 1H), 7.54-7.46 (m, 3H), 7.38-7.33 (m, 1H), 7.25-7.18 (m, 3H), 6.94 (s, 1H), 6.34 (s, 1H),
2.35 (s, 3H), 2.23-2.21 (m, 4H), 1.68-1.66 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3): δ
149.6, 138.3, 137.3, 134.9, 134.3, 129.8, 128.2, 125.8, 123.2, 120.6, 120.4, 119.7, 117.8,
116.5, 115.9, 100.7, 78.6, 28.9, 26.0, 22.2, 21.4, 21.0 ppm; HRMS (ESI) calcd for C24H23N2O
[M + H] 355.1810 found 355.1803.
N-octyl-2-(2-phenylethynyl)-1H-indole-1-carboxamide (4h):
White solid; yield 61% (0.246 g); mp 108-109 °C; FT-IR (KBr) 3432, 2925, 1670, 1640,
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1532, 1447, 1316 cm-1; H NMR (300 MHz, CDCl3): δ 8.39 (d, J = 8.5 Hz, 1H), 7.55-7.53
(m, 3H), 7.42-7.34 (m, 4H), 7.26-7.21 (m, 1H), 7.09 (s, 1H), 7.02 (s, 1H), 3.50 (t, J = 6.9 Hz,
2H), 1.68-1.60 (m, 2H), 1.42-1.32 (m, 2H), 1.26-1.23 (m, 8H), 0.86 (t, J = 6.6 Hz, 3H) ppm;
13C NMR (50 MHz, CDCl3): δ 152.1, 137.4, 131.6, 129.6, 128.8, 127.9, 125.9, 122.9, 121.7,
120.6, 117.3, 116.3, 116.2, 97.7, 81.4, 41.2, 31.9, 29.7, 29.4, 29.2, 27.2, 22.7, 14.2 ppm;
HRMS (ESI) calcd for C25H29N2O [M + H] 373.2280 found 373.2272.
N-benzyl-2-(2- cyclohex-1-en-1-ylethynyl)-1H-indole-1-carboxamide (4i):
White solid; yield 69% (0.265 g); mp 138-140 °C; FT-IR (KBr) 3357, 3019, 2930, 1675,
1529, 1325 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.45 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.49
(d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.38-7.29 (m, 4H), 7.24-7.19 (m, 1H), 6.87 (s,
1H), 5.87-5.85 (m, 1H), 4.66 (d, J = 5.2 Hz, 2H), 2.04-2.02 (m, 2H), 1.91-1.90 (m, 2H), 1.59-
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1.52 (m, 4H) ppm; C NMR (75 MHz, CDCl3): δ 152.2, 137.7, 137.6, 137.3, 128.9, 128.3,
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128.1, 127.8, 125.7, 122.9, 120.5, 119.4, 117.9, 116.5, 115.7, 100.0, 78.8, 45.2, 28.3, 25.9,
22.1, 21.3 ppm; HRMS (ESI) calcd for C24H23N2O [M + H] 355.1810 found 355.1804.
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N-(3-chloro-4-methylphenyl)-2-hex-1-ynyl-1H-indole-1-carboxamide (4j):
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White solid; yield 71% (0.281 g); mp 98-99 °C; FT-IR (KBr) 3308, 2934, 1680, 1598, 1533,
1310, 1205 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.12 (s, 1H), 8.41 (d, J = 8.3 Hz, 1H), 7.64
(s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.38-7.34 (m, 2H), 7.25-7.21 (m, 2H), 6.91 (s, 1H), 2.60 (t,
J = 7.0 Hz, 2H), 2.37 (s, 3H), 1.70-1.60 (m, 2H), 1.52-1.42 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H)
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ppm; C NMR (50 MHz, CDCl3): δ 149.4, 136.9, 136.3, 134.8, 132.2, 131.3, 128.1, 125.8,
123.3, 120.7, 120.6, 118.4, 117.7, 116.4, 116.1, 101.0, 73.1, 30.5, 22.3, 19.6, 13.6 ppm;
HRMS (ESI) calcd for C22H22ClN2O [M + H] 365.1421 found 365.1416.
N-(3-chloro-4-methylphenyl)-6-oct-1-ynyl-5H-[1,3]dioxolo[4,5-f]indole-5-carboxamide
(4k):
White solid; yield 72% (0.294 g); mp 104-105 °C; FT-IR (KBr) 3341, 2934, 2869, 2130,
1697, 1604, 1540, 1304 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.16 (s, 1H), 7.96 (s, 1H), 7.61
(s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.26-7.20 (m, 1H), 6.85 (s, 1H), 6.77 (s, 1H), 5.98 (s, 2H),
2.57 (t, J = 7.0 Hz, 2H), 2.36 (s, 3H), 1.69-1.59 (m, 2H), 1.43 (s, 2H), 1.28-1.27 (m, 4H),
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0.87 (s, 3H) ppm; C NMR (75 MHz, CDCl3): δ 149.3, 147.5, 144.9, 136.2, 134.7, 132.1,
132.0, 131.1, 122.0, 120.6, 118.3, 116.1, 116.0, 101.2, 100.5, 98.6, 97.8, 73.1, 31.3, 28.8,
28.5, 22.5, 19.9, 19.4, 14.0 ppm; HRMS (ESI) calcd for C25H26ClN2O3 [M + H] 437.1632
found 437.1633.
5-chloro-N-(3-chloro-4-methylphenyl)-2-oct-1-ynyl-1H-indole-1-carboxamide (4l):
White solid; yield 74% (0.305 g); mp 106-107 °C; FT-IR (KBr) 3300, 2931, 2862, 2225,
1683, 1593, 1534, 1387, 1206 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.09 (s, 1H), 8.35 (d, J =
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ppm; C NMR (50 MHz, CDCl3): δ 149.1, 136.0, 135.2, 134.9, 132.4, 131.3, 129.2, 128.9,
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125.9, 120.8, 119.9, 119.0, 118.4, 117.5, 115.0, 101.9, 72.7, 31.4, 28.9, 28.4, 22.6, 20.0, 19.6,
14.1 ppm; HRMS (ESI) calcd for C24H25Cl2N2O [M + H] 427.1344 found 427.1338.
III General Procedure for the Preparation of oxazino[3,4-a]indol-1-ylidenes 5a-l
To a stirred solution of desired indole-1-carboxamide 4a-l (1.0 equiv) in 1,2-dichloroethane
under N2 (8 mL/mmol of 4) was added AuClPPh3 (5 mol%) and AgNO3 (20 mol%). The
reaction mixture was stirred at RT. After completion, the solvent was removed under vaccum.
The crude product was purified by silica gel column chromatography using EtoAc/ hexane as
eluent and concentration of the appropriate fractions in-vacuo afforded the desired
compounds (5a-l).
(Z)-4-methyl-N-(3-phenyl[1,3]oxazino[3,4-a]indol-1-ylidene)aniline (5a):
White solid; yield 87% (0.087 g); mp 180-181 °C; FT-IR (KBr) 3057, 1680, 1606, 1447,
1400, 1346 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.82 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.4 Hz,
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3H), 7.38-7.30 (m, 5H), 7.24-7.22 (m, 4H), 6.84 (s, 1H), 6.60 (s, 1H), 2.40 (s, 3H) ppm; C
NMR (50 MHz, CDCl3): δ 148.3, 142.4, 137.9, 133.8, 132.9, 131.9, 131.3, 130.8, 129.6,
129.4, 128.8, 124.5, 123.8, 123.6, 123.1, 120.0, 116.5, 101.1, 94.4, 21.1 ppm; HRMS (ESI)
calcd for C24H19N2O [M + H] 351.1497 found 351.1497.
(Z)-4-methyl-N-[3-(4-methylphenyl)[1,3]oxazino[3,4-a]indol-1-ylidene]aniline (5b):
White solid; yield 87% (0.087 g); mp 213-214 °C; FT-IR (KBr) 3023, 2917, 1688, 1403,
1245 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.81 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.1 Hz, 1H),
7.49 (d, J = 8.0 Hz, 2H), 7.39-7.29 (m, 2H), 7.25-7.16 (m, 6H), 6.78 (s, 1H), 6.57 (s, 1H),
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2.39 (s, 3H), 2.35 (s, 3H) ppm; C NMR (50 MHz, CDCl3): δ 148.7, 142.6, 139.9, 138.2,
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133.9, 133.0, 132.2, 130.9, 129.6, 129.5, 128.6, 124.6, 123.8, 123.6, 123.2, 120.0, 116.6,
100.8, 93.7, 21.5, 21.1 ppm; HRMS (ESI) calcd for C25H21N2O [M + H] 365.1654 found
365.1652.
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(Z)-4-methyl- N-{3-[4-(tert-butyl)phenyl][1,3]oxazino[3,4-a]indol-1-ylidene}aniline (5c):
White solid; yield 84% (0.084 g); mp 183-185 °C; FT-IR (KBr) 2959, 1672, 1407, 1078 cm-1;
1H NMR (300 MHz, CDCl3): δ 8.82 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.55 (d, J =
8.4 Hz, 2H), 7.42-7.30 (m, 4H), 7.26-7.23 (m, 4H), 6.82 (s, 1H), 6.59 (s, 1H), 2.41 (s, 3H),
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1.33 (s, 9H) ppm; C NMR (75 MHz, CDCl3): δ 153.0, 148.5, 142.4, 138.1, 133.8, 132.9,
132.1, 130.8, 129.4, 128.5, 125.8, 124.3, 123.7, 123.5, 123.1, 119.9, 116.5, 100.8, 93.7, 34.9,
31.2, 21.1 ppm; HRMS (ESI) calcd for C28H27N2O [M + H] 407.2123 found 407.2127.
(Z)-1-(3-{[3-(4-tert-butyl)phenyl[1,3]oxazino[3,4-a]indol-1-ylidene]amino}phenyl)ethan-
1-one (5d):
White solid; yield 81% (0.081 g); mp 183-184 °C; FT-IR (KBr) 2963, 1677, 1584, 1400,
1353, 1270 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.79 (d, J = 7.7 Hz, 1H), 7.90 (s, 1H), 7.78
(s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.49-7.47 (m, 4H), 7.38-7.31 (m, 4H), 6.83 (s, 1H), 6.61 (s,
1H), 2.64 (s, 3H), 1.31 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 198.3, 153.4, 148.6,
145.9, 139.2, 138.1, 133.8, 132.0, 131.0, 129.1, 128.3, 128.2, 125.9, 124.4, 124.0, 123.9,
123.5, 123.4, 120.2, 116.5, 101.3, 94.1, 34.9, 31.3, 26.9 ppm; HRMS (ESI) calcd for
C29H27N2O2 [M + H] 435.2073 found 435.2069.
(Z)-4-methyl- N-{8-[4-(tert-butyl)phenyl] [1,3]dioxolo[4,5-f][1,3]oxazino[3,4-a]indol-6-
ylidene}aniline (5e):
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White solid; yield 87% (0.087 g); mp 245-246 °C; FT-IR (KBr) 2957, 1693, 1459, 1307,
1212 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.38 (d, J =
8.4 Hz, 2H), 7.24-7.21 (m, 4H), 6.97 (s, 1H), 6.74 (s, 1H), 6.45 (s, 1H), 6.00 (s, 2H), 2.40 (s,
3H), 1.32 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3): δ 152.7, 147.5, 145.7, 145.3, 142.4,
138.2, 132.9, 131.2, 129.5, 128.8, 128.7, 125.9, 125.4, 124.2, 123.3, 101.3, 100.9, 98.7, 98.2,
93.9, 34.9, 31.3, 21.2 ppm; HRMS (ESI) calcd for C29H27N2O3 [M + H] 451.2022 found
451.2021.
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(Z)-N-{3-[4-(tert-butyl)phenyl]-7-chloro[1,3]oxazino[3,4-a]indol-1-ylidene}-3-chloro-4-
methylaniline (5f):
White solid; yield 85% (0.085 g); mp 142-143 °C; FT-IR (KBr) 2956, 1676, 1403, 1273 cm-1;
1H NMR (300 MHz, CDCl3): δ 8.67 (d, J = 8.8 Hz, 1H), 7.55-7.53 (m, 3H), 7.43-7.37 (m,
3H), 7.31-7.24 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.51 (s, 1H), 2.42 (s, 3H), 1.33
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(s, 9H) ppm; C NMR (50 MHz, CDCl3): δ 153.6, 150.0, 149.2, 143.7, 138.4, 134.3, 133.2,
132.1, 131.2, 130.9, 129.5, 128.0, 126.0, 124.5, 124.1, 123.9, 121.9, 119.5, 117.5, 100.2,
93.6, 34.9, 31.3, 19.7 ppm; HRMS (ESI) calcd for C28H25Cl2N2O [M + H] 475.1344 found
475.1333.
(Z)-N-(3-cyclohex-1-en-1-yl[1,3]oxazino[3,4-a]indol-1-ylidene)-4-methylaniline (5g):
White solid; yield 88% (0.088 g); mp 166-168 °C; FT-IR (KBr) 2928, 1671, 1448, 1364 cm-1;
1H NMR (300 MHz, CDCl3): δ 8.77 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.0 Hz, 1H), 7.35-7.29
(m, 2H), 7.17 (s, 4H), 6.49 (s, 1H), 6.33 (s, 1H), 6.24 (s, 1H), 2.37 (s, 3H), 2.21-2.16 (m, 4H),
1.72-1.71 (m, 2H), 1.62-1.60 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3): δ 149.4, 142.6,
138.2, 133.9, 132.8, 132.4, 130.9, 129.4, 129.0, 127.8, 123.6, 123.4, 123.2, 119.9, 116.5,
100.5, 92.9, 25.8, 23.9, 22.3, 21.9, 21.1 ppm; HRMS (ESI) calcd for C24H23N2O [M + H]
355.1810 found 355.1812.
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(Z)-N-octyl-N-(3-phenyl[1,3]oxazino[3,4-a]indol-1-ylidene)amine (5h):
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White solid; yield 84% (0.084 g); mp 72-74 °C; FT-IR (KBr) 2923, 2852, 1639, 1493, 1449,
1351, 1219 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.71 (d, J = 8.1 Hz, 1H), 7.80-7.77 (m, 2H),
7.58 (d, J = 7.5 Hz, 1H), 7.49-7.38 (m, 3H), 7.36-7.25 (m, 2H), 6.78 (s, 1H), 6.53 (s, 1H),
3.72 (t, J = 6.9 Hz, 2H), 1.84-1.74 (m, 2H), 1.60-1.50 (m, 2H), 1.41-1.31(m, 8H), 0.91-0.89
(m, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 153.1, 139.0, 133.8, 132.1, 130.5, 122.9, 122.8,
119.7, 116.1, 98.0, 95.2, 45.6, 32.4, 32.1, 31.4, 29.7, 29.5, 28.8, 27.7, 22.9, 22.2, 14.3, 13.9
ppm; HRMS (ESI) calcd for C25H29N2O [M + H] 373.2280 found 373.2277.
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(Z)-N-benzyl-N-(3-cyclohex-1-en-1-yl[1,3]oxazino[3,4-a]indol-1-ylidene)amine (5i):
White solid; yield 82% (0.082 g); mp 125-127 °C; FT-IR (KBr) 3020, 2932, 1690, 1637,
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1448, 1348, 1215 cm-1; H NMR (300 MHz, CDCl3): δ 8.75 (d, J = 8.0 Hz, 1H), 7.56-7.53
(m, 3H), 7.40-7.33 (m, 2H), 7.31-7.23 (m, 3H), 6.64 (s, 1H), 6.45 (s, 1H), 6.23 (s, 1H), 4.88
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(s, 2H), 2.28-2.26 (m, 4H), 1.79-1.76 (m, 2H), 1.68-1.65 (m, 2H) ppm; C NMR (75 MHz,
CDCl3): δ 149.2, 141.5, 139.7, 134.1, 132.4, 130.7, 128.5, 128.4, 128.3, 127.6, 126.6, 123.6,
123.2, 119.9, 116.4, 100.1, 93.0, 49.5, 25.9, 24.2, 22.5, 22.1 ppm; HRMS (ESI) calcd for
C24H23N2O [M + H] 355.1810 found 355.1800.
(Z)-N-(3-butyl[1,3]oxazino[3,4-a]indol-1-ylidene)-3-chloro-4-methylaniline (5j):
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White solid; yield 86% (0.086 g); mp 87-88 °C; FT-IR (KBr) 2949, 1688, 1400 cm-1; H
NMR (300 MHz, CDCl3): δ 8.74 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 6.7 Hz, 1H), 7.36-7.25 (m,
3H), 7.19 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.42 (s, 1H), 6.15 (s, 1H), 2.42-2.38
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(m, 5H), 1.41-1.26 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H) ppm; C NMR (50 MHz, CDCl3): δ
153.0, 144.1, 139.4, 134.1, 133.5, 131.8, 130.8, 130.7, 124.0, 123.7, 123.5, 121.9, 119.9,
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116.6, 99.3, 96.1, 32.2, 28.6, 22.1, 19.6, 13.9 ppm; HRMS (ESI) calcd for C22H22ClN2O [M +
H] 365.1421 found 365.1410.
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(Z)-N-(8-hexyl[1,3]dioxolo[4,5-f][1,3]oxazino[3,4-a]indol-6-ylidene)-3-chloro-4-
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methylaniline (5k):
White solid; yield 83% (0.083 g); mp 96-97 °C; FT-IR (KBr) 2924, 1678, 1465, 1403, 1302
cm-1; 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 7.26 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.02
(d, J = 7.8 Hz, 1H), 6.95 (s, 1H), 6.30 (s, 1H), 6.09 (s, 1H), 5.99 (s, 2H), 2.40 (s, 3H), 2.37 (s,
2H), 1.59-1.56 (m, 2H), 1.30 (s, 6H), 0.88 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 151.9,
145.4, 145.3, 144.1, 139.5, 134.2, 130.9, 130.8, 130.7, 128.4, 125.2, 124.1, 122.1, 101.3,
99.4, 98.7, 98.3, 96.2, 32.4, 31.6, 28.7, 26.6, 22.6, 19.6, 14.2 ppm; HRMS (ESI) calcd for
C25H26ClN2O3 [M + H] 437.1632 found 437.1630.
(Z)-3-chloro-N-(7-chloro-3-hexyl[1,3]oxazino[3,4-a]indol-1-ylidene)-4-methylaniline (5l):
White solid; yield 82% (0.082 g); mp 115-117 °C; FT-IR (KBr) 2934, 1674, 1595, 1399,
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1154 cm-1; H NMR (300 MHz, CDCl3): δ 8.66 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.28-7.18
(m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.35 (s, 1H), 6.13 (s, 1H), 2.42-2.38 (m, 5H), 1.60-1.56 (m,
2H), 1.30 (s, 6H), 0.89 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 153.8, 143.7, 138.9,
134.2, 133.1, 131.9, 131.8, 131.0, 130.9, 129.3, 123.9, 123.6, 121.9, 119.4, 117.5, 98.5, 95.8,
32.5, 31.6, 28.7, 26.5, 22.6, 19.6, 14.2 ppm; HRMS (ESI) calcd for C24H25Cl2N2O [M + H]
427.1344 found 427.1339.
IV General Procedure for the Preparation of pyrimido[1,6-a]indol-1(2H)-ones 6a-l
To a stirred solution of desired indole-1-carboxamide 4 (1.0 equiv) in 1,2-dichloroethane
under N2 (8 mL/mmol of 4) was added AuClPPh3 (5 mol%) and AgOTf (20 mol%). The
reation mixture was stirred at RT. After completion the solvent was removed under vaccum.
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The crude product was purified by silica gel column chromatography using EtoAc/ hexane as
eluent and concentration of the appropriate fractions in-vacuo afforded the desired
compounds (6).
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2-(4-methylphenyl)-3-phenylpyrimido[1,6-a]indol-1(2H)-one (6a):
White solid; yield 85% (0.085 g); mp 200-201 °C [Lit.14a 199-200 °C]; FT-IR (KBr) 3022,
2995, 1692, 1512, 1366, 1281 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.65 (d, J = 7.2 Hz, 1H),
7.66 (d, J = 7.3 Hz, 1H), 7.39-7.30 (m, 2H), 7.19 (s, 5H), 7.04 (s, 4H), 6.59 (s, 1H), 6.53 (s,
1H), 2.28 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 149.1, 140.7, 137.8, 135.6, 135.4,
134.4, 133.6, 130.9, 129.5, 129.4, 129.0, 128.3, 128.1, 124.0, 122.9, 119.8, 116.4, 101.2,
98.6, 21.2 ppm; HRMS (ESI) calcd for C24H19N2O [M + H] 351.1497 found 351.1497.
2,3-bis(4-methylphenyl)pyrimido[1,6-a]indol-1(2H)-one (6b):
White solid; yield 80% (0.080g); mp 220-222 °C; FT-IR (KBr) 3023, 2930, 1703, 1620, 1385
cm-1; 1H NMR (300 MHz, CDCl3): δ 8.64 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 6.9 Hz, 1H), 7.38-
7.29 (m, 2H), 7.08-6.97 (m, 8H), 6.57 (s, 1H), 6.50 (s, 1H), 2.29 (s, 3H), 2.27 (s, 3H) ppm;
13C NMR (50 MHz, CDCl3): δ 140.8, 138.2, 137.8, 135.6, 134.5, 133.6, 132.5, 131.0, 129.5,
129.4, 128.9, 128.8, 124.0, 122.8, 119.7, 116.4, 100.9, 98.4, 21.3, 21.2 ppm; HRMS (ESI)
calcd for C25H21N2O [M + H] 365.1654 found 365.1652.
3-[4-(tert-butyl)phenyl]-2-(4-methylphenyl)pyrimido[1,6-a]indol-1(2H)-one (6c):
White solid; yield 86% (0.086 g); mp 206-207 °C; FT-IR (KBr) 3025, 2959, 1705, 1631,
1508, 1364, 1270 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.67 (d, J = 7.7 Hz, 1H), 7.68 (d, J =
7.4 Hz, 1H), 7.41-7.32 (m, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.13-7.11 (m, 6H), 6.60 (s, 1H),
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6.55 (s, 1H), 2.32 (s, 3H), 1.27 (s, 9H) ppm; C NMR (75 MHz, CDCl3): δ 151.4, 149.3,
140.8, 137.7, 135.6, 134.6, 133.6, 132.4, 131.0, 129.4, 129.3, 128.7, 124.9, 124.0, 122.8,
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119.7, 116.4, 101.0, 98.4, 34.7, 31.3, 21.2 ppm; HRMS (ESI) calcd for C28H27N2O [M + H]
407.2123 found 407.2123.
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White solid; yield 89% (0.089 g); mp 203-204 °C; FT-IR (KBr) 2963, 1691, 1378, 1279 cm-1;
1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 7.4 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.74 (s,
1H), 7.67 (d, J = 6.8 Hz, 1H), 7.47-7.34 (m, 4H), 7.18 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3
Hz, 2H), 6.63 (s, 1H), 6.58 (s, 1H), 2.48 (s, 3H), 1.22 (s, 9H) ppm; 13C NMR (50 MHz,
CDCl3): δ 197.0, 151.8, 148.9, 140.2, 138.8, 137.6, 134.3, 134.2, 133.6, 132.0, 131.0, 129.8,
129.0, 128.8, 127.5, 125.2, 124.2, 123.1, 119.9, 116.3, 101.5, 99.1, 34.7, 31.2, 26.7 ppm;
HRMS (ESI) calcd for C29H27N2O2 [M + H] 435.2073 found 435.2070.
8-[4-(tert-butyl)phenyl]-7-(4-methylphenyl)[1,3]dioxolo[4,5-f]pyrimido[1,6-a]indol-
6(7H)-one (6e):
White solid; yield 84% (0.084 g); mp 175-176 °C; FT-IR (KBr) 2944, 2891, 1691, 1458,
1396, 1313 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.2 (s, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.09-
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7.07 (m, 6H), 7.01 (s, 1H), 6.47 (s, 2H), 6.00 (s, 2H), 2.29 (s, 3H), 1.24 (s, 9H) ppm; C
NMR (75 MHz, CDCl3): δ 151.3, 149.1, 145.6, 145.0, 139.3, 137.7, 135.7, 133.7, 132.5,
129.4, 129.3, 128.7, 128.3, 125.6, 124.9, 101.2, 101.1, 98.5, 98.3, 97.8, 34.7, 31.3, 31.2 ppm;
HRMS (ESI) calcd for C29H27N2O3 [M + H] 451.2022 found 451.2024.
7-chloro-2-(3-chloro-4-methylphenyl)-3-[4-(tert-butyl)phenyl]pyrimido[1,6-a]indol-
1(2H)-one (6f):
White solid; yield 85% (0.085 g); mp 168-169 °C; FT-IR (KBr) 2956, 1689, 1382, 1284 cm-1;
1H NMR (300 MHz, CDCl3): δ 8.53 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H), 7.29-7.21
(m, 4H), 7.14-7.07 (m, 3H), 6.97 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H), 2.31 (s, 3H), 1.26 (s, 9H)
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ppm; C NMR (50 MHz, CDCl3): δ 152.0, 148.7, 141.2, 136.6, 136.2, 135.5, 134.3, 132.2,
131.9, 131.8, 130.8, 130.2, 129.8, 128.7, 127.9, 125.2, 123.1, 119.3, 117.3, 101.0, 98.1, 34.8,
31.3, 19.9 ppm; HRMS (ESI) calcd for C28H25Cl2N2O [M + H] 475.1344 found 475.1328.
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3-cyclohex-1-en-1-yl-2-(4-methylphenyl)pyrimido[1,6-a]indol-1(2H)-one (6g):
White solid; yield 80% (0.080 g); mp 132-133 °C; FT-IR (KBr) 2932, 1692, 1635, 1369 cm-1;
1H NMR (300 MHz, CDCl3): δ 8.60 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.35-7.18
(m, 6H), 6.50 (s, 1H), 6.35 (s, 1H), 5.94 (s, 1H), 2.40 (s, 3H), 2.02-2.01 (m, 2H), 1.66 (s, 2H),
1.41-1.38 (m, 2H), 1.29-1.26 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3): δ 149.2, 143.9,
138.1, 135.4, 134.9, 134.4, 133.5, 131.2, 131.0, 129.4, 129.3, 123.9, 122.5, 119.6, 116.3,
98.7, 97.7, 28.5, 25.4, 22.3, 21.6, 21.3 ppm; HRMS (ESI) calcd for C24H23N2O [M + H]
355.1810 found 355.1810.
2-octyl-3-phenylpyrimido[1,6-a]indol-1(2H)-one (6h):
Colourless liquid; yield 79% (0.079 g); FT-IR (neat) 2958, 2928, 1638, 1449, 1406, 1360,
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1220 cm-1; H NMR (300 MHz, CDCl3): δ 8.73-8.69 (m, 1H), 7.65-7.62 (m, 1H), 7.48-7.45
(m, 3H), 7.43-7.39 (m, 2H), 7.36-7.33 (m, 2H), 6.49 (s, 1H), 6.32 (s, 1H), 3.86 (t, J = 5.9 Hz,
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2H), 1.59-1.50 (m, 2H), 1.25-1.09 (m, 10H), 0.84 (t, J = 6.8 Hz, 3H) ppm; C NMR (75
MHz, CDCl3): δ 149.2, 140.6, 135.4, 134.4, 133.3, 130.9, 129.2, 129.1, 128.7, 123.9, 122.5,
119.7, 116.4, 101.1, 97.4, 45.7, 31.8, 31.7, 29.1, 29.0, 26.6, 22.7, 14.2 ppm; HRMS (ESI)
calcd for C25H29N2O [M + H] 373.2280 found 373.2276.
2-benzyl-3- cyclohex-1-en-1-ylpyrimido[1,6-a]indol-1(2H)-one (6i):
White solid; yield 85% (0.085 g); mp 103-104 °C; FT-IR (KBr) 3432, 3020, 2932, 1683,
1
1635, 1446, 1355, 1216 cm-1; H NMR (300 MHz, CDCl3): δ 8.65 (d, J = 7.8 Hz, 1H), 7.61
(d, J = 7.8 Hz, 1H), 7.36-7.21 (m, 5H), 7.18 (d, J = 7.1 Hz, 2H), 6.45 (s, 1H), 6.24 (s, 1H),
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5.79 (s, 1H), 5.16 (s, 2H), 2.09-2.04 (m, 4H), 1.68-1.62 (m, 4H) ppm; C NMR (75 MHz,
CDCl3): δ 149.7, 143.3, 138.3, 134.9, 133.4, 133.2, 131.4, 130.9, 128.7, 127.4, 126.9, 123.9,
122.4, 119.6, 116.5, 99.1, 97.3, 48.6, 29.9, 25.4, 22.6, 21.8 ppm; HRMS (ESI) calcd for
C24H23N2O [M + H] 355.1810 found 355.1776.
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3-butyl-2-(3-chloro-4-methylphenyl)pyrimido[1,6-a]indol-1(2H)-one (6j)
White solid; yield 33% (0.033 g); mp 119-120 °C; FT-IR (KBr) 3065, 2972, 1685, 1598,
1396 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.54 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H),
7.40-7.26 (m, 4H), 7.15 (d, J = 8.0 Hz, 1H), 6.47 (s, 1H), 6.33 (s, 1H), 2.46 (s, 3H), 2.18 (t, J
= 7.5 Hz, 2H), 1.52-1.41 (m, 2H), 1.28-1.25 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(50 MHz, CDCl3): δ 149.1, 140.4, 137.4, 136.0, 135.1, 134.6, 133.4, 131.6, 130.9, 130.1,
127.9, 124.0, 122.5, 119.6, 116.2, 97.6, 97.2, 32.6, 29.9, 22.2, 20.0, 13.9 ppm; HRMS (ESI)
calcd for C22H22ClN2O [M + H] 365.1421 found 365.1421.
7-(3-chloro-4-methylphenyl)-8-hexyl[1,3]dioxolo[4,5-f]pyrimido[1,6-a]indol-6(7H)-one
(6k):
White solid; yield 36% (0.036 g); mp 125-126 °C; FT-IR (KBr) 2929, 1697, 1461, 1327 cm-1;
1H NMR (300 MHz, CDCl3): δ 8.06 (s, 1H), 7.39-7.33 (m, 2H), 7.14 (d, J = 7.7 Hz, 1H), 6.99
(s, 1H), 6.36 (s, 1H), 6.27 (s, 1H), 5.99 (s, 2H), 2.46 (s, 3H), 2.15 (t, J = 7.4 Hz, 2H), 1.45-
1.43 (m, 2H), 1.24-1.19 (m, 6H), 0.84 (t, J = 6.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
148.9, 145.6, 144.8, 138.9, 137.3, 136.1, 135.1, 133.8, 131.6, 130.2, 127.9, 127.8, 125.6,
101.1, 98.3, 97.8, 97.7, 97.4, 32.9, 31.5, 28.8, 27.8, 22.5, 20.0, 14.1 ppm; HRMS (ESI) calcd
for C25H26ClN2O3 [M + H] 437.1632 found 437.1631.
7-chloro-2-(3-chloro-4-methylphenyl)-3-hexylpyrimido[1,6-a]indol-1(2H)-one (6l):
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White solid; yield 35% (0.035 g); mp 151-152 °C; FT-IR (KBr) 3435, 1644, 1494, 1435,
1396, 1288 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.45 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 1.4 Hz,
1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.26-7.21 (m, 1H), 7.14 (d, J = 8.0
Hz, 1H), 6.40 (s, 1H), 6.32 (s, 1H), 2.46 (s, 3H), 2.16 (s, 2H), 1.52-1.45 (m, 2H), 1.25-1.20
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(m, 6H), 0.85 (t, J = 5.9 Hz, 3H) ppm; C NMR (75 MHz, CDCl3): δ 148.9, 141.4, 137.6,
135.8, 135.7, 135.2, 132.2, 131.7, 130.0, 129.7, 127.7, 122.6, 119.1, 117.1, 97.4, 96.5, 32.9,
31.5, 28.8, 27.7, 22.5, 20.1, 14.1 ppm; HRMS (ESI) calcd for C24H25Cl2N2O [M + H]
427.1344 found 427.1339.
Acknowledgments:
S. Gupta is thankful to CSIR, New Delhi, India for fellowships. The author would like to
thank SAIF, CDRI, India for providing NMR data. CDRI Communication No. 8498.
Supporting Information available.
Copies of NMR spectra, and information regarding the X-ray crystal structures. This material
is available free of charge via the Internet at http://pubs.acs.org.
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