Selective Synthesis of N-Unsubstituted and N-Arylindoles by the Reaction of Arynes with Azirines

Article abstract of DOI:10.1021/acs.joc.6b01472

The transition-metal-free and temperature-dependent highly selective reaction of arynes with 2H-azirines allowing the synthesis of either N-unsubstituted or N-arylindoles has been developed. At 60 °C, arynes generated from 2-(trimethylsilyl)aryl triflates smoothly insert into 2H-azirines to form 2,3-diarylindoles with high selectivity. Interestingly, when the reaction was performed at -10 °C, the selectivity was switched to the formation of 1,2,3-triarylindoles in good yields.

Full text of DOI:10.1021/acs.joc.6b01472

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Note
Selective Synthesis of N-Unsubstituted and N-
Aryl Indoles by the Reaction of Arynes with Azirines
Manikandan Thangaraj, Sachin Suresh Bhojgude, Shailja Jain, Rajesh G. Gonnade, and Akkattu T. Biju
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01472 • Publication Date (Web): 17 Aug 2016
Downloaded from http://pubs.acs.org on August 17, 2016
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Selective Synthesis of N-Unsubstituted and N-Aryl Indoles by the
Reaction of Arynes with Azirines
Manikandan Thangaraj,†,‡ Sachin Suresh Bhojgude,†,‡ Shailja Jain,Ł Rajesh G.
Gonnade§ and Akkattu T. Biju*,†,‡
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Ł
§
†Organic Chemistry Division, Physical/Materials Chemistry Division, Centre for Materials
Characterization, CSIRꢀNational Chemical Laboratory (CSIRꢀNCL), Dr. Homi Bhabha Road,
Pune ꢀ 411008, India.
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India
Eꢀmail: at.biju@ncl.res.in
ABSTRACT: The transitionꢀmetalꢀfree and temperature dependent highly selective reaction of
arynes with 2Hꢀazirines allowing the synthesis of either Nꢀunsubstituted or Nꢀaryl indoles has
been developed. At 60 °C, arynes generated from 2ꢀ(trimethylsilyl)aryl triflates smoothly insert
into 2Hꢀazirines to form 2,3ꢀdiaryl indoles with high selectivity. Interestingly, when the reaction
was performed at ꢀ10 °C, the selectivity was switched to the formation of 1,2,3ꢀtriaryl indoles in
good yields.
The indole nucleus is a structural motif present in numerous biologically active natural
products, pharmaceutical compounds and agrochemicals.1 Consequently, development of
straightforward and flexible synthetic routes for the construction of functionalized indoles is of
great importance.2 Among the various routes to indoles, the Fischer indole synthesis stands as
one of the most widely used procedure.3 Additionally, the annulation of 2ꢀalkynyl anilines under
metalꢀcatalysis,4 cyclization of 2ꢀhalogenated anilines with alkynes,5 reductive annulation of 2ꢀ
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nitro aromatics6 etc. offers convenient route to achieve indoles. Methods employing transitionꢀ
metalꢀcatalyzed CꢀH bond functionalization reactions has emerged as one of the convenient and
efficient protocols for the synthesis of indoles.7 Furthermore, transitionꢀmetalꢀfree
transformations are also uncovered recently for the synthesis of indole derivatives.8
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The transitionꢀmetalꢀfree synthesis of indoles employing arynes9 as the aryl source has
been a convenient method, which obviates the use of hydrazines/amines as the starting materials.
The use of 2ꢀ(trimethylsilyl)aryl triflate precursor in the presence of fluoride source allows the
mild method for aryne generation.10 In 2010, Wang and coꢀworkers demonstrated the synthesis
of 2,3ꢀdisubstituted indoles from arynes and 2ꢀazidoacrylates (Scheme 1, eq 1).11 In addition,
Greaney and coꢀworkers used Nꢀtosyl hydrazones as the coupling partner for arynes resulting in
the synthesis of Nꢀtosyl indoles via the benzyne Fischer indole reaction (eq 2).12 Recently, Zhu
and coꢀworkers engaged arynes in the BischlerꢀMöhlau synthesis of indoles, where arynes
undergo an insertionꢀcyclization sequence with Nꢀaryl αꢀaminoketones (eq 3).13 Notably, a
common method for the highly selective synthesis of both Nꢀunsubstituted as well as Nꢀaryl
indoles using aryne chemistry has not been reported. Herein, we report the transitionꢀmetalꢀfree
and highly selective synthesis of both Nꢀunsubstituted and Nꢀaryl indoles by the reaction of
arynes with 2Hꢀazirines, and importantly, the product selectivity depends on the temperature
used. When the reaction was carried out at ꢀ10 °C, Nꢀaryl indoles are formed in high yields.
Gratifyingly, when the reaction was performed at 60 °C, 2,3ꢀdiaryl Nꢀunprotected indoles are
formed in moderate to good yields and excellent selectivity. It may be noted in this context that
the reaction of 2,3ꢀdiphenylꢀ1ꢀazirine with aryne generated by the thermal decomposition of
benzene diazonium 2ꢀcarboxylate leading to the mixture of 2,3ꢀdiphenyl indole and 1,2,3ꢀ
triphenyl indole was reported by the Nair group as early as 1975.14 This seminal work also
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demonstrates the mechanism for the formation of Nꢀunsubstituted and Nꢀaryl indoles by the
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reaction of arynes with azirines.
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Scheme 1. Synthesis of Indoles via Arynes
Against the literature backdrop and given the importance of functionalized indoles in
organic synthesis, the present study was initiated by treating 2,3ꢀdiphenylꢀ1ꢀazirine 1a with the
benzyne generated from the 2ꢀ(trimethylsilyl)aryl triflate precursor 2a using KF in presence of
18ꢀcrownꢀ6 as additive in THF at 30 °C. Under these conditions, the 2,3ꢀdiaryl indole 3a was
formed in 40% yield and 1,2,3ꢀtriaryl indole 4a was formed in 21% yield in 54:46 ratio (Table 1,
entry 1). Interestingly, when the reaction was performed at 60 °C, 3a was isolated in 65% yield
and 97:3 selectivity (entry 2). Under this condition, only traces of 4a was formed. The use of
other fluoride sources such as CsF and tetrabutyl ammonium fluoride (TBAF) did not improve
the yield of 3a and 4a (entries 3,4). When the reaction was carried out at ꢀ10 °C and warmed to
30 °C, a complete switching in selectivity from 3a to 4a was observed (98:2) and 4a was isolated
in 76% yield. Finally, the yield of 4a was improved to 83% when the reaction was done at ꢀ10 °C
(entry 6).15
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Table 1. Optimization of the reaction conditionsa
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temp
(°C)
yield of yield of 3a:4ac
3a (%)b 4a (%)b
entry fluoride source
1
KF/18ꢀcrownꢀ6 30
KF/18-crown-6 60
40
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57
<5
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<5
<5
<5
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83
54:46
97:3
83:17
ND
2:98
1:99
2d
3e
4
CsF
TBAF.3H2O
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60
5f
6f
KF/18ꢀcrownꢀ6 ꢀ10 to 30 <5
KF/18-crown-6 -10 <5
a General conditions: 1a (0.25 mmol), 2a (0.30 mmol), KF (2.4 equiv), 18ꢀ crownꢀ6 (2.4 equiv), THF (1.0
b
c
mL), for the indicated temperature and 12 h. Yield of the isolated products are given. Selectivity was
d
determined using GC analysis of the crude reaction mixture. Reaction performed using 1.8 equiv of 2a
and 3.6 equiv of KF/18ꢀcrownꢀ6 and 6.0 mL THF.
Reaction carried out using 3.0 equiv of 2a and 6.0 equiv of KF/18ꢀcrownꢀ6 and 1.0 mL THF.
e
f
Reaction performed using 1.0 mL CH3CN.
After optimizing the reaction conditions for the selective synthesis of Nꢀunsubstituted and
Nꢀaryl indoles, we then examined the substrate scope of both transformations. First, we evaluated
the scope of the synthesis of NꢀH indoles (Scheme 2). A series of symmetrical 2Hꢀazirines
bearing electronꢀreleasing and ꢀwithdrawing groups at the 4ꢀposition of the aryl moiety of 1 are
well tolerated at 60 °C leading to the selective synthesis of 2,3ꢀdiaryl indoles in moderate to
good yield and good selectivity (3a-3f). Notably, in the case of 4ꢀCF3 substituted 2Hꢀazirine, the
selectivity was moderate only. The structure of 3f was further confirmed by singleꢀcrystal Xꢀray
analysis.16 Moreover, the substitution at the 2ꢀposition, 1ꢀposition as well as disubstitution on the
2,3ꢀdiaryl moiety of 1 did not affect the aryne reactivity and furnished the desired products in
moderate yield and high selectivity (3g-3j). As expected, the unsymmetrical 2Hꢀazirines afforded
the inseparable mixture of regioisomers in moderate to good yield (3k-3m). Interestingly,
unsymmetrical 2ꢀmethylꢀ3ꢀphenylꢀ2Hꢀazirine afforded the single regioisomer 3n in 61% yield
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and 97:3 selectivity. Additionally, symmetrical arynes generated from the corresponding
precursors readily underwent smooth reaction with 2Hꢀazirine 1a to furnish the NꢀH indoles in
moderate to good yields and high selectivity (3o-3q).
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a
General conditions: 1 (0.50 mmol), 2 (0.90 mmol), KF (1.80 mmol), 18ꢀcrownꢀ6 (1.80 mmol), THF
(12.0 mL), 60 °C, 12 h. Yields of the isolated products are given. Selectivity determined by GC analysis
of crude reaction mixture is given in parentheses. b Reaction run on 0.25 mmol scale. c Regioisomer ratio
determined by GC analysis.
Scheme 2. Substrate Scope for the Synthesis of NꢀUnsubstituted Indoles
With this result in hand, we then focused our attention on the synthesis of 1,2,3ꢀ
trisubstituted indoles (Scheme 3). As in the case of reactions performed at 60 °C for the selective
synthesis of NꢀH indoles, the experiments carried out at ꢀ10 °C also showed good functional
group compatibility and high selectivity towards the synthesis of trisubstituted indoles. A wide
variety of symmetrical 2Hꢀazirines with different substitution pattern readily underwent efficient
aryne reactions leading to the synthesis of 1,2,3ꢀtriaryl indoles in good yields (>71% in all cases)
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and excellent selectivity (>92:8 in all cases) (4a-4j). In the case of 4h, the structure was
confirmed by singleꢀcrystal Xꢀray analysis.16 Moreover, the reaction of arynes with
unsymmetrical 2Hꢀazirines at ꢀ10 °C furnished the regioisomeric mixture of 1,2,3ꢀtriaryl indoles,
where the selectivity over the NꢀH indoles are excellent in all cases (4k-4m). In contrast to the
reaction of 2ꢀmethylꢀ3ꢀphenylꢀ2Hꢀazirine with aryne at 60 °C, the reaction at ꢀ10 °C afforded
regioisomeric mixture of products (1.5:1) 4n and 4n' in 88% yield. Furthermore, the variation of
aryne moiety was also feasible, leading to the formation of the corresponding trisubstituted
indoles in moderate to good yield and high selectivity thus further expanding the scope of this
aryne reaction (4o-4q).
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a
General conditions: 1 (0.25 mmol), 2 (0.75 mmol), KF (1.5 mmol), 18ꢀcrownꢀ6 (1.5 mmol), THF (1.0
4
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mL), ꢀ10 °C, 12 h. Yields of the isolated products are given. Selectivity was determined by GC analysis
of crude reaction mixture is given in parentheses. b Regioisomer ratio determined by GC analysis.
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Scheme 3. Substrate Scope for Synthesis of Nꢀaryl Indolesa
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Considering the mixture of regioisomers obtained in the reaction of arynes with
unsymmetrical 2Hꢀazirines, a tentative mechanism of this reaction is showed in Scheme 4. The
nucleophilic addition of 2Hꢀazirines onto arynes generate the 1,4 zwitterionic intermediate A.17,18
The zwitterion A could cyclize in two pathways. In path a, the aryl anion adds to the C=N bond
(1,2ꢀaddition) to generate the intermediate B. A 1,2ꢀhydrogen shift to nitrogen can result in the
formation of 3. Alternatively, a 1,2ꢀhydrogen shift to carbon can generate the intermediate C,
which can undergo another 1,3 hydrogen shift to afford 3.19 An ene reaction of C with another
molecule of aryne can furnish 4. In path b, the aryl anion adds to carbon attached to R2 (breaking
of CꢀN bond) to generate the intermediate D. A 1,3ꢀhydrogen shift on D can afford the
regioisomer 3'. Moreover, the ene reaction of D with another molecule of aryne can result in the
formation of Nꢀaryl indole 4'.
Scheme 4. Proposed Mechanism of the Reaction
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Treatment of the NꢀH indole 3a with excess aryne at ꢀ10 °C did not afford the Nꢀaryl
indole 4a (Scheme 5). This experiment rules out the possibility of initial formation of 3a in the
reaction of 1a and 2a for the synthesis of 4a. This also sheds light on the mechanism proposed in
Scheme 4.
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Scheme 5. Attempted Reaction of 3a with Arynes
To demonstrate the synthetic utility of the reaction, a scaleꢀup experiment was performed.
Carrying out the reaction in a 5.0 mmol scale of 1a afforded 3a in 63% yield and 97:3 selectivity
indicating the practical nature of the reaction (Scheme 6, eq 5). Reaction of 3a with alkyne 5
under Rh(III)ꢀcatalysis following the procedure of Miura, Satoh and coꢀworkers20 with a minor
modification afforded the indolo[2,1ꢀa]isoquinoline derivative 6a in 93% yield (eq 6). Moreover,
3a could easily be transformed to the dibenzocarbazole derivative 7a via dehydrogenative
coupling reaction (eq 7).21 Compounds 6a and 7a are nitrogenꢀdoped conjugated systems (πꢀ
expanded) having potential organic semiconductor applications.
Scheme 6. Synthetic Utility of the Method
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In conclusion, we have demonstrated the highly selective and transitionꢀmetalꢀfree
reaction of arynes with 2Hꢀazirines leading to the synthesis of either Nꢀunsubstituted or Nꢀaryl
indoles. The reaction of arynes with 2Hꢀazirines at 60 °C afforded 2,3ꢀdiaryl indoles.
Interestingly, the selectivity was switched to the formation of 1,2,3ꢀtriaryl indoles when the
reaction was performed at ꢀ10 °C. Both reactions took place with high selectivity and broad
substrate scope.
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Experimental Section
General Information: Unless otherwise specified, all reactions were carried out under an
atmosphere of argon in flameꢀdried reaction vessels with Teflon screw caps. Reaction
temperatures are reported as the temperature of the bath surrounding the reaction vessel. 30 °C
corresponds to the room temperature of the lab, when the experiments were carried out. THF was
freshly purified by distillation over Naꢀbenzophenone and was transferred under argon. 18ꢀ
Crownꢀ6 was recrystallized from dry CH3CN and KF was dried by heating at 110 °C for 12 h
and left to cool under argon and stored in glove box. The 2(trimethylsilyl)phenyl
trifluoromethane sulfonate 2a and the other symmetric and unsymmetric aryne precursors were
synthesized following literature procedure.22 The azirines used in this work were prepared from
the corresponding diaryl 1,2ꢀdiones following the literature procedure.23 Melting points were
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determined with a melting apparatus. H and 13C NMR spectra were recorded in CDCl3 as
solvent. Chemical shifts (δ) are given in ppm. The residual solvent signals were used as
references and the chemical shifts converted to the TMS scale (CDCl3: δH = 7.26 ppm, δC =
77.16 ppm). HRMS measurements were carried out using ESI method and ionꢀtrap mass
analyzer. Infrared (IR) spectra were recorded on a FTꢀIR spectrometer as thin films using NaCl
plates.
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General Procedure for the synthesis of N-Unsubstituted indoles
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To a flameꢀdried screwꢀcapped test tube equipped with a magnetic stir bar was added 18ꢀcrownꢀ
6 (0.475 g, 1.8 mmol), KF (0.105 g, 1.8 mmol) inside the glove box. Then the corresponding 2Hꢀ
azirine 1 (0.5 mmol) was added outside the glovebox. Then the mixture was dissolved in 12.0
mL of THF and the resultant reaction mixture was kept stirring at 30 °C for 5 min. To the stirring
solution was added aryne precursor 2 (0.90 mmol). Then the reaction mixture was immediately
placed in a preheated oil bath at 60 °C. When TLC control showed the completion of the reaction
(typically after 12 h), the solvent was evaporated and subsequently the crude residue was
purified by flash column chromatography on silica gel (using Pet. etherꢀEtOAc) to afford the
corresponding Nꢀunsubstituted indoles 3 in moderate to good yields. Selectivity ratio was
determined by GC analysis of crude reaction mixture.
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2,3-Diphenyl-1H-indole (3a)24: (yellow solid, 0.087 g, 65%, 97:3). Rf (Pet. ether /EtOAc =
95/05): 0.35; Melting point: 109ꢀ111 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (bs, 1H), 7.22 (d, J
= 7.6 Hz, 1H), 7.48 ꢀ7.39 (m, 6H), 7.35 ꢀ7.26 (m, 5H), 7.23ꢀ7.13 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 136.0, 135.2, 134.2, 132.8, 130.3, 128.9, 128.8, 128.6, 128.3, 127.8, 126.3, 122.8,
+
120.5, 119.8, 115.1, 111.1. HRMS (ESI) calculated [M+H] for C20H16N: 270.1277, found:
270.1278. FTIR (cm-1): 3679, 3458, 3415, 3060, 3018, 1722, 1670, 1598, 1496, 1449, 1319,
1217, 1031, 764, 702.
2,3-Di-p-tolyl-1H-indole (3b)25: (pale sticky yellow liquid, 0.034 g, 46%, 96:4, reaction
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performed on a 0.25 mmol scale of 1b). Rf (Pet. ether /EtOAc = 95/05): 0.35; H NMR (400
MHz, CDCl3) δ 8.19 (bs, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.45ꢀ7.37 (m, 5H), 7.30 ꢀ7.17 (m, 6H),
2.46 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 137.6, 135.9, 135.8, 134.2, 132.3,
130.1, 130.0, 129.5, 129.4, 129.1, 128.1, 122.6, 120.4, 119.8, 114.7, 110.9, 21.4. HRMS (ESI)
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calculated [M+H] + for C22H20N: 298.1590, found: 298.1585. FTIR (cm-1): 3463, 3018, 1605,
1582, 1453, 1326, 1248, 1115, 1043, 930, 821, 772.
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2,3-Bis(4-bromophenyl)-1H-indole (3c)24: (yellow solid, 0.122 g, 57%, 96:4). Rf (Pet. ether
/EtOAc = 95/05): 0.24; Melting point: 151ꢀ153 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (bs,
1H), 7.65 (d, J = 7.9 Hz, 1H), 7.55ꢀ7.44 (m, 5H), 7.32ꢀ7.28 (m, 5H), 7.20 (t, J = 7.4 Hz, 1H).
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13C NMR (100 MHz, CDCl3) δ 136.1, 133.8, 133.2, 132.2, 132.0, 131.8, 131.4, 129.8, 128.5,
+
123.4, 122.2, 121.0, 120.6, 119.6, 114.4, 111.2. HRMS (ESI) calculated [M+H]
for
C20H14NBr2: 425.9488, found: 425.9484. FTIR (cm-1): 3458, 3018, 1587, 1544, 1499, 1453,
1392, 1312, 1215, 1070, 996, 772.
2,3-Bis(4-chlorophenyl)-1H-indole (3d)25: (pale yellow solid, 0.114 g, 67%, 96:4). Rf (Pet.
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ether /EtOAc = 95/05): 0.25; Melting point: 129ꢀ131 °C; H NMR (400 MHz, CDCl3) δ 8.24
(bs, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.41 ꢀ7.29 (m, 9H), 7.23 ꢀ7.20 (m,
1H). 13C NMR (100 MHz, CDCl3) δ 136.1, 134.0, 133.4, 133.2, 132.4, 131.4, 131.0, 129.5,
+
129.2, 129.0, 128.5, 123.3, 120.9, 119.6, 114.3, 111.2. HRMS (ESI) calculated [M+H] for
C20H14NCl2: 338.0498, found: 338.0500. FTIR (cm-1): 3450, 3058, 1546, 1482, 1432, 1328,
1296, 1215, 1014, 966, 831, 769.
2,3-Bis(4-fluorophenyl)-1H-indole (3e)24: (pale yellow solid, 0.098 g, 64%, 97:3). Rf (Pet. ether
1
/EtOAc = 95/05): 0.28; Melting point: 130ꢀ132 °C; H NMR (400 MHz, CDCl3) δ 8.21 (bs,
1H), 7.66 (d, J = 7.8 Hz, 1H), 7.47ꢀ7.38 (m, 5H), 7.31 ꢀ7.27 (m, 1H), 7.21 ꢀ7.18 (m, 1H), 7.13ꢀ
7.04 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 162.5 (d, J = 248.2 Hz), 161.8 (d, J = 246.0 Hz),
135.9, 133.4, 131.7 (d, J = 7.8 Hz), 130.9 (d, J = 3.4 Hz), 130.1 (d, J = 8.5 Hz), 128.8, 123.1,
120.8, 119.6, 116.0 (d, J = 21.9 Hz), 115.7 (d, J = 21.5 Hz), 114.2, 111.1. HRMS (ESI)
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calculated [M+H] + for C20H14NF2: 306.1089, found: 306.1083. FTIR (cm-1): 3460, 3018, 1651,
1560, 1494, 1436, 1328, 1218, 1096, 838, 772.
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2,3-Bis(4-(trifluoromethyl)phenyl)-1H-indole (3f): (yellow solid, 0.099 g, 49%, 75:25,
reaction performed on a 0.25 mmol scale of 1f). Rf (Pet. ether /EtOAc = 95/05): 0.27; Melting
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point: 130ꢀ132 °C; H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.68ꢀ7.66 (m, 3H), 7.63 (d, J =
7.7 Hz, 2H), 7.55ꢀ7.49 (m, 5H), 7.34 (t, J = 7.2 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 138.6, 136.3, 135.9, 133.2, 130.4, 128.5, 128.4, 126.1 (q, J = 3.7 Hz), 125.9 (q,
J = 3.5 Hz), 123.9, 121.3, 121.1, 119.8, 118.7, 115.2, 111.4. HRMS (ESI) calculated [M+H] +
for C22H14NF6: 406.1025, found: 406.1024. FTIR (cm-1): 3457, 1674, 1494, 1323, 1216, 1125,
1066, 966, 845, 768.
2,3-Bis(3-methoxyphenyl)-1H-indole (3g)26: (yellow viscous liquid, 0.069 g, 42%, 97:3). Rf
(Pet. ether /EtOAc = 95/05): 0.14; 1H NMR (400 MHz, CDCl3) δ 8.32 (bs, 1H), 7.74 (d, J = 7.9
Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.29ꢀ7.24 (m, 2H), 7.19 (t, J = 7.4
Hz, 1H), 7.08ꢀ7.05 (m, 3H), 7.00 (s, 1H), 6.90ꢀ6.85 (m, 2H), 3.78 (s, 3H), 3.69 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 159.8, 159.7, 136.6, 135.9, 134.1, 134.0, 129.8, 129.6, 128.8, 122.9,
122.9, 120.6, 120.5, 119.8, 115.6, 115.2, 113.8, 113.6, 112.3, 111.1, 55.3, 55.2. HRMS (ESI)
calculated [M+H] + for C22H20O2N: 330.1489, found: 330.1486. FTIR (cm-1): 3459, 3017, 1603,
1583, 1482, 1430, 1284, 1216, 1046, 771, 668.
2,3-Bis(3-chlorophenyl)-1H-indole (3h)26: (pale sticky yellow liquid, 0.097 g, 57%, 93:7). Rf
(Pet. ether /EtOAc = 95/05): 0.28; 1H NMR (400 MHz, CDCl3) δ 8.27 (bs, 1H), 7.70 (d, J = 8.1
13
Hz, 1H), 7.49ꢀ7.44 (m, 3H), 7.33 ꢀ7.21 (m, 8H). C NMR (100 MHz, CDCl3) δ 136.7, 136.1,
134.8, 134.5, 134.2, 133.0, 130.2, 130.1, 130.0, 128.5, 128.4, 128.1, 127.9, 126.8, 126.7, 123.5,
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121.0, 119.7, 114.6, 111.2. HRMS (ESI) calculated [M+H] + for C20H14NCl2: 338.0498, found:
338.0503. FTIR (cm-1): 3457, 3019, 1597, 1487, 1328, 1217, 1077, 928, 771, 699.
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2,3-Bis(2-chlorophenyl)-1H-indole (3i): (yellow solid, 0.101 g, 60%, 97:3). Rf (Pet. ether
/EtOAc = 95/05): 0.34; Melting point: 129ꢀ131 °C; 1H NMR (400 MHz, CDCl3) δ 8.55 (bs,
1H), 7.52ꢀ7.45 (m, 4H), 7.34ꢀ7.11 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 135.5, 134.8, 133.9,
133.3, 133.1, 132.8, 132.7, 131.5, 130.3, 129.9, 129.6, 128.4, 127.8, 126.9, 126.7, 123.0, 120.4,
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+
120.3, 114.7, 111.2. HRMS (ESI) calculated [M+H] for C20H14NCl2: 338.0498, found:
338.0496. FTIR (cm-1): 3457, 3060, 3010, 1596, 1489, 1330, 1244, 1122, 1063, 1033, 969, 754.
2,3-Bis(3,4-dichlorophenyl)-1H-indole (3j)27: (sticky yellow liquid, 0.081 g, 40%, 70:30). Rf
(Pet. ether /EtOAc = 95/05): 0.28; 1H NMR (400 MHz, CDCl3) δ 8.33 (bs, 1H), 7.66 (d, J = 8.0
Hz, 1H), 7.59 (s, 2H), 7.50ꢀ7.43 (m, 3H), 7.36 ꢀ7.30 (m, 2H), 7.23ꢀ7.21 (m, 2H). 13C NMR (100
MHz, CDCl3) δ 136.1, 134.7, 133.3, 132.9, 132.4, 132.2, 131.7, 131.0, 130.9, 130.8, 129.5,
+
128.2, 127.8, 123.9, 121.4, 119.5, 114.6, 113.9, 111.4. HRMS (ESI) calculated [M+H] for
C20H12NCl4: 405.9718, found: 405.9723. FTIR (cm-1): 3453, 3019, 1648, 1595, 1469, 1377,
1215, 1134, 1030, 928, 883, 757.
3-Phenyl-2-(p-tolyl)-1H-indole (3k) and 2-Phenyl-3-(p-tolyl)-1H-indole (3k’)28: (yellow
viscous oil, 0.095 g, 67%, regioisomer ratio: 4:1, selectivity: 97:3). Rf (Pet. ether /EtOAc =
1
95/05): 0.29; H NMR (400 MHz, CDCl3) δ 8.20 (bs, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.47ꢀ7.14
(m, 12H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.0, 135.9, 134.0, 133.0, 132.1, 130.1,
129.4, 128.8, 128.3, 127.7, 126.3, 122.8, 120.5, 119.9, 111.0, 21.4. Representative peaks of
Minor Isomer: 1H NMR (400 MHz, CDCl3) δ 2.38 (s). 13C NMR (100 MHz, CDCl3) δ 130.3,
129.5, 129.0, 128.6, 128.2, 122.7, 119.7, 115.1. HRMS (ESI) calculated [M+H] + for C21H18N:
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284.1434, found: 284.1436. FTIR (cm-1): 3460, 3018, 1602, 1514, 1452, 1327, 1043, 929, 771,
697.
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2-(4-Nitrophenyl)-3-phenyl-1H-indole (3l) and 3-(4-Nitrophenyl)-2-phenyl-1H-indole
(3l’)25: (orange solid, 0.080 g, 51%, regioisomer ratio: 1:1, selectivity: 95:5). Rf (Pet. ether
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/EtOAc = 95/05): 0.14; H NMR (400 MHz, CDCl3) δ 8.42ꢀ8.38 (m, 1H), 8.22 (d, J = 8.6 Hz,
1H), 8.16 (d, J = 8.6 Hz, 1H), 7.73ꢀ7.65 (m, 1H), 7.60ꢀ7.55 (m, 2H), 7.48 (d, J = 8.1 Hz, 1H),
7.43ꢀ7.29 (m, 6H), 7.25ꢀ7.17 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 146.7, 146.0, 142.9,
139.3, 136.7, 136.1, 134.3, 132.0, 131.4, 130.4, 130.3, 129.2, 129.1, 128.9, 128.7, 128.6, 128.4,
127.9, 127.2, 124.2, 124.1, 123.4, 121.4, 121.2, 120.4, 119.2, 118.4, 113.0, 111.5, 111.4. HRMS
(ESI) calculated [M+Na] + for C20H14O2N2Na: 337.0974, found: 337.0945. FTIR (cm-1): 3455,
3020, 1596, 1552, 1451, 1343, 1250, 1150, 1072, 855, 756.
3-(4-Bromophenyl)-2-(4-nitrophenyl)-1H-indole (3m) and
2-(4-Bromophenyl)-3-(4-
nitrophenyl)-1H-indole (3m’): (red solid, 0.042 g, 43%, regioisomer ratio: 1.3:1, selectivity:
71:29, reaction performed on a 0.25 mmol scale of 1m). Rf (Pet. ether /EtOAc = 95/05): 0.14; 1H
NMR (400 MHz, CDCl3) δ 8.53ꢀ8.51 (m, 1H), 8.26ꢀ8.18 (m, 2H), 7.64ꢀ7.48 (m, 6H), 7.39ꢀ7.24
(m, 4H). 13C NMR (100 MHz, CDCl3) δ 146.8, 146.1, 138.9, 136.7, 134.7, 133.3, 132.4, 132.3,
130.5, 130.1, 128.5, 124.4, 124.3, 123.7, 122.9, 121.4, 120.0, 119.3, 116.9, 111.5.
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Representative peaks of Minor Isomer: H NMR (400 MHz, CDCl3) δ 8.51 (bs). C NMR
(100 MHz, CDCl3) δ 142.5, 136.2, 131.8, 121.5, 111.5. HRMS (ESI) calculated [M+H] + for
C20H14O2N2Br: 393.02332, found: 393.02335. FTIR (cm-1): 3393, 3061, 1658, 1513, 1451,
1343, 1247, 1109, 855, 754.
2-Methyl-3-phenyl-1H-indole (3n)24: (pale sticky yellow liquid, 0.104 g, 61%, 97:3). Rf (Pet.
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ether /EtOAc = 95/05): 0.25; H NMR (400 MHz, CDCl3) δ 7.86 (bs, 1H), 7.79 (d, J = 7.3 Hz,
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1H), 7.62ꢀ7.54 (m, 4H), 7.42 ꢀ7.34 (m, 2H), 7.27ꢀ7.20 (m, 2H), 2.52 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 135.5, 135.3, 131.6, 129.5, 128.6, 127.9, 125.9, 121.6, 120.1, 118.9, 114.5,
110.5, 12.6. HRMS (ESI) calculated [M+H] + for C15H14N: 208.1121, found: 208.1118. FTIR
(cm-1): 3464, 3058, 1618, 1562, 1495, 1330, 1255, 1188, 1019, 771.
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4,7-Dimethyl-2,3-diphenyl-1H-indole (3o): (pale sticky yellow liquid, 0.124 g, 83%, 96:4). Rf
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(Pet. ether /EtOAc = 95/05): 0.38; H NMR (400 MHz, CDCl3) δ 8.23 (bs, 1H), 7.50ꢀ7.41 (m,
7H), 7.36ꢀ7.27 (m, 3H), 7.04 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 7.1 Hz, 1H), 2.62 (s, 3H), 2.19 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 137.2, 135.2, 133.9, 133.0, 131.9, 129.6, 129.3, 128.8,
128.6, 127.9, 127.8, 127.3, 127.1, 126.8, 123.1, 122.1, 117.8, 117.1, 20.2, 16.5. HRMS (ESI)
calculated [M+H] + for C22H20N: 298.1590, found: 298.1587. FTIR (cm-1): 3316, 3058, 1659,
1599, 1477, 1317, 1217, 1072, 801, 766.
2,3-Diphenyl-1H-benzo[f]indole (3p): (pale yellow viscous liquid, 0.041 g, 51%, 96:4, reaction
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performed on a 0.25 mmol scale of 1p). Rf (Pet. ether /EtOAc = 95/05): 0.23; H NMR (400
MHz, CDCl3) δ 8.55 (bs, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.67ꢀ7.59 (m,
2H), 7.55ꢀ7.47 (m, 5H), 7.38ꢀ7.21 (m, 7H). 13C NMR (100 MHz, CDCl3) δ 137.3, 132.9, 132.8,
132.4, 131.6, 130.2, 128.9, 128.7, 127.6, 127.3, 127.2, 125.6, 124.2, 123.4, 122.1, 118.1, 112.6.
HRMS (ESI) calculated [M+H] + for C24H18N: 320.1434, found: 320.1432. FTIR (cm-1): 3459,
3018, 1602, 1494, 1370, 1320, 1216, 1067, 926, 765, 669.
6,7-Diphenyl-5H-[1,3]dioxolo[4,5-f]indole (3q): (brown solid, 0.102 g, 65%, 94:6). Rf (Pet.
ether /EtOAc = 95/05): 0.1; Melting point: 135ꢀ137 °C; 1H NMR (400 MHz, CDCl3) δ 8.13
(bs, 1H), 7.50ꢀ7.39 (m, 5H), 7.37 ꢀ7.28 (m, 5H), 7.08 (s, 1H), 6.91 (s, 1H), 5.97 (s, 2H). 13C
NMR (100 MHz, CDCl3) δ 145.5, 143.7, 135.3, 132.9, 131.0, 130.7, 130.2, 128.8, 128.7, 128.1,
127.8, 127.3, 126.4, 123.1, 115.5, 105.2, 102.8, 100.8, 98.4, 91.9. HRMS (ESI) calculated
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[M+H] for C21H16O2N: 314.1176, found: 314.1170. FTIR (cm-1): 3460, 3018, 1602, 1502,
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1485, 1437, 1284, 1216, 1064, 949, 770.
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General Procedure for the synthesis of N-Aryl Indoles
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To a flameꢀdried screwꢀcapped test tube equipped with a magnetic stir bar was added 18ꢀcrownꢀ
6 (0.396 g, 1.5 mmol), KF (0.087 g, 1.5 mmol) inside the glove box. Then the corresponding 2Hꢀ
azirine 1 (0.25 mmol) was added outside the glovebox. Then the mixture was dissolved in 1.0
mL of solvent. The resultant reaction mixture was cooled to ꢀ10 °C and kept stirring for 5 min.
To the stirring solution was added aryne precursor 2 (0.75 mmol) and kept stirring at ꢀ10 °C for
12h. When TLC control showed the completion of the reaction (typically after 12 h), the
reaction was quenched and the solvent was evaporated and subsequently the crude residue was
purified by flash column chromatography on silica gel (using Pet. etherꢀEtOAc) to afford the
corresponding Nꢀaryl indole derivatives 4 in moderate to good yields. Selectivity ratio was
determined by GC analysis of crude reaction mixture.
1,2,3-Triphenyl-1H-indole (4a)29: (white solid, 0.072 g, 83%, 99:1). Rf (Pet. ether /EtOAc =
95/05): 0.75; Melting point: 184ꢀ186 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 ꢀ7.87 (m, 1H),
7.46 ꢀ7.35 (m, 8H), 7.33 ꢀ7.26 (m, 5H), 7.22 ꢀ7.16 (m, 5H). 13C NMR (100 MHz, CDCl3) δ
138.3, 138.1, 137.2, 135.1, 131.7, 131.3, 130.4, 129.2, 128.4, 128.0, 127.7, 127.5, 127.3, 126.1,
+
122.9, 121.0, 119.7, 116.9, 110.8. HRMS (ESI) calculated [M+H] for C26H20N: 346.1590,
found: 346.1589. FTIR (cm-1): 3018, 2925, 1598, 1547, 1495, 1450, 1371, 1219, 1073, 1025,
763.
1-Phenyl-2,3-di-p-tolyl-1H-indole (4b)29: (yellow solid, 0.066 g, 71%, 99:1). Rf (Pet. ether
/EtOAc = 95/05): 0.58; Melting point: 175ꢀ177 °C; 1H NMR (400 MHz, CDCl3) δ 7.88ꢀ7.85
(m, 1H), 7.45 ꢀ7.35 (m, 6H), 7.31ꢀ7.25 (m, 4H), 7.23 (d, J = 7.8 Hz, 2H), 7.07ꢀ6.96 (m, 4H), 2.44
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(s, 3H), 2.33(s, 3H). C NMR (100 MHz, CDCl3) δ 138.5, 138.0, 137.1, 135.5, 132.2, 131.1,
130.2, 129.6, 129.2, 128.9, 128.8, 128.5, 127.9, 127.1, 122.6, 120.9, 119.7, 116.5, 114.6, 110.7,
21.4. HRMS (ESI) calculated [M+H] + for C28H24N: 374.1903, found: 374.1901. FTIR (cm-1):
3017, 1596, 1499, 1369, 1217, 1103, 832, 771, 668.
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2,3-Bis(4-bromophenyl)-1-phenyl-1H-indole (4c)29: (yellow solid, 0.103 g, 82%, 99:1). Rf (Pet.
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ether /EtOAc = 95/05): 0.69; Melting point: 223ꢀ225 °C; H NMR (400 MHz, CDCl3) δ 7.76
(d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.44ꢀ7.40 (m, 2H), 7.38ꢀ7.29 (m, 4H), 7.27ꢀ7.22
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(m, 6H), 6.95 (d, J = 8.3 Hz, 2H). C NMR (100 MHz, CDCl3) δ 138.2, 137.8, 135.9, 133.8,
132.7, 131.9, 131.8, 131.5, 130.4, 129.5, 128.4, 127.7, 127.3, 123.4, 122.1, 121.4, 120.3, 119.5,
+
116.0, 111.0. HRMS (ESI) calculated [M+H] for C26H18NBr2: 501.9801, found: 501.9791.
FTIR (cm-1): 3045, 1592, 1545, 1452, 1370, 1243, 1167, 1068, 822, 771, 746.
2,3-Bis(4-chlorophenyl)-1-phenyl-1H-indole (4d)29: (white solid, 0.092 g, 89%, 98:2). Rf (Pet.
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ether /EtOAc = 95/05): 0.73; Melting point: 200ꢀ202 °C; H NMR (400 MHz, CDCl3) δ 7.79 ꢀ
7.77 (m, 1H), 7.46 ꢀ7.24 (m, 12H), 7.18 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 138.2, 137.9, 135.9, 133.8, 133.4, 132.4, 132.1, 131.5, 129.9, 129.4, 128.8,
128.6, 128.4, 127.7, 127.4, 123.33, 121.4, 119.5, 116.0, 110.9. HRMS (ESI) calculated [M+H] +
for C26H18NCl2: 414.0811, found: 414.0810. FTIR (cm-1): 3019, 1650, 1571, 1498, 1406, 1369,
1216, 1106, 1016, 837, 772.
2,3-Bis(4-fluorophenyl)-1-phenyl-1H-indole (4e): (yellow solid, 0.077 g, 81%, 92:8). Rf (Pet.
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ether /EtOAc = 95/05): 0.55; Melting point: 148ꢀ150 °C; H NMR (400 MHz, CDCl3) δ 7.81 ꢀ
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7.79 (m, 1H), 7.46 ꢀ7.36 (m, 6H), 7.32ꢀ7.26 (m, 4H), 7.12ꢀ7.07 (m, 4H), 6.93ꢀ6.88 (m, 2H). C
NMR (100 MHz, CDCl3) δ 162.2, (d, J = 248.3 Hz), 161.6 (d, J = 245.5 Hz), 138.0 (d, J = 5.4
Hz), 136.2, 132.9 (d, J = 8.9 Hz), 131.8 (d, J = 7.7 Hz), 130.8 (d, J = 3.2 Hz), 129.4, 128.4,
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127.5, 123.1, 121.2, 119.5, 116.0, 115.5 (d, J = 21.3 Hz), 115.3 (d, J = 21.53 Hz), 110.9. HRMS
(ESI) calculated [M+H] + for C26H18NF2: 382.1402, found: 382.1400. FTIR (cm-1): 3048, 1597,
1497, 1369, 1216, 1157, 1093, 841, 801, 772.
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1-Phenyl-2,3-bis(4-(trifluoromethyl)phenyl)-1H-indole (4f)30: (pale yellow solid, 0.098 g,
82%, 99:1). Rf (Pet. ether /EtOAc = 95/05): 0.69; Melting point: 168ꢀ170 °C; 1H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 6.8 Hz, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.50ꢀ7.37 (m, 8H), 7.34ꢀ7.29
(m, 2H), 7.26ꢀ7.22 (m, 4H). 13C NMR (100 MHz, CDCl3) 138.5, 138.4, 137.6, 136.0, 135.0,
131.4, 130.5, 129.9, 129.6, 128.6, 128.4, 128.0, 127.2, 125.6 (q, J = 3.6 Hz), 125.3 (q, J = 3.4
+
Hz), 123.8, 123.2, 122.8, 121.7, 119.6, 116.6, 111.2. HRMS (ESI) calculated [M+H] for
C28H18NF6: 482.1338, found: 482.1337. FTIR (cm-1): 3020, 1610, 1495, 1365, 1219, 1119,
1019, 929, 850, 745, 668.
2,3-Bis(3-methoxyphenyl)-1-phenyl-1H-indole (4g): (yellow solid, 0.088 g, 87%, 99:1). Rf
1
(Pet. ether /EtOAc = 95/05): 0.37; Melting point: 123ꢀ125 °C; H NMR (400 MHz, CDCl3) δ
7.86ꢀ7.83 (m, 1H), 7.42ꢀ7.39 (m, 2H), 7.35ꢀ7.32 (m, 2H), 7.28ꢀ7.22 (m, 5H), 7.07 (t, J = 7.9 Hz,
1H), 7.01 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.82 (dd, J1 = 8.2 Hz, J2 = 1.9 Hz, 1H), 6.75ꢀ6.71 (m,
2H), 6.64 (s, 1H), 3.71 (s, 3H), 3.53 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.6, 159.1, 138.3,
138.0, 137.0, 136.4, 132.9, 129.4, 129.3, 129.0, 128.4, 127.6, 127.3, 123.9, 122.9, 122.8, 121.1,
119.8, 116.8, 116.2, 115.5, 113.9, 112.2, 110.8, 55.2, 55.1. HRMS (ESI) calculated [M+H] + for
C28H24O2N: 406.1802, found: 406.1800. FTIR (cm-1): 3011, 2835, 1598, 1498, 1429, 1368,
1284, 1217, 1154, 1046, 756, 667.
2,3-Bis(3-chlorophenyl)-1-phenyl-1H-indole (4h): (white solid, 0.094 g, 91%, 99:1). Rf (Pet.
1
ether /EtOAc = 95/05): 0.63; Melting point: 159ꢀ161 °C; H NMR (400 MHz, CDCl3) δ 7.83ꢀ
7.81 (m, 1H), 7.48 ꢀ7.36 (m, 5H), 7.33ꢀ7.26 (m, 6H), 7.22ꢀ7.20 (m, 2H), 7.15ꢀ7.11 (m, 2H), 7.03
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(d, J = 7.8 Hz, 1H). C NMR (100 MHz, CDCl3) δ 138.1, 137.7, 136.6, 135.8, 134.3, 134.0,
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133.2, 131.0, 130.1, 129.8, 129.4, 128.5, 128.3, 128.0, 127.8, 127.3, 126.5, 123.5, 121.5, 119.6,
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116.1, 111.0. HRMS (ESI) calculated [M+H] for C26H18NCl2: 414.0811, found: 414.0812.
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FTIR (cm-1): 3064, 1596, 1487, 1425, 1319, 1239, 1078, 997, 888, 758.
2,3-Bis(2-chlorophenyl)-1-phenyl-1H-indole (4i): (yellow solid, 0.091 g, 88%, 95:5). Rf (Pet.
ether /EtOAc = 95/05): 0.57; Melting point: 147ꢀ149 °C; 1H NMR (400 MHz, CDCl3) 7.61ꢀ
7.53 (m, 1H), 7.48ꢀ7.43 (m, 2H), 7.40ꢀ7.28 (m, 7H), 7.27ꢀ7.22 (m, 4H), 7.20ꢀ7.14 (m, 2H), 7.13ꢀ
13
7.09 (m, 1H). C NMR (100 MHz, CDCl3) δ 137.8, 137.3, 135.6, 135.4, 134.9, 133.7, 133.3,
131.4, 131.1, 129.9, 129.8, 129.4, 129.0, 128.5, 127.8, 127.3, 126.6, 126.1, 122.9, 120.8, 120.5,
+
116.1, 114.6, 110.8. HRMS (ESI) calculated [M+H] for C26H18NCl2: 414.0811, found:
414.0809. FTIR (cm-1): 3059, 1596, 1499, 1435, 1320, 1216, 1121, 1062, 1032, 749.
2,3-Bis(3,4-dichlorophenyl)-1-phenyl-1H-indole (4j): (yellow solid, 0.097 g, 80%, 99:1). Rf
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(Pet. ether /EtOAc = 95/05): 0.65; Melting point: 164ꢀ166 °C; H NMR (400 MHz, CDCl3) δ
7.77 (d, J = 7.4 Hz, 1H), 7.59 (s, 1H), 7.49ꢀ7.42 (m, 4H), 7.35ꢀ7.24 (m, 6H), 7.18 (s, 1H), 7.12
(d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 138.2, 137.4,
134.9, 134.7, 132.7, 132.6, 132.5, 132.3, 131.7, 131.2, 130.7, 130.5, 130.4, 130.3, 129.7, 129.6,
128.3, 128.1, 126.9, 123.8, 121.7, 119.4, 117.5, 115.4, 111.1. HRMS (ESI) calculated [M+H] +
for C26H16NCl4: 482.0031, found: 482.0035. FTIR (cm-1): 3061, 1594, 1498, 1451, 1375, 1258,
1215, 1110, 888, 757.
1,2-Diphenyl-3-(p-tolyl)-1H-indole (4k) and 1,3-Diphenyl-2-(p-tolyl)-1H-indole (4k’): (white
solid, 0.082 g, 91%, regioisomer ratio: 1:1, selectivity: 98:2). Rf (Pet. ether /EtOAc = 95/05):
0.64; 1H NMR (400 MHz, CDCl3) δ 7.83ꢀ7.81 (m, 2H), 7.41ꢀ7.11 (m, 30H), 6.99 (d, J = 7.8 Hz,
2H), 6.95 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 138.4,
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138.3, 138.0, 137.3, 137.2, 137.0, 135.6, 135.2, 132.0, 131.9, 131.3, 131.1, 130.4, 130.2, 129.2,
128.8, 128.7, 128.5, 128.4, 128.0, 127.8, 127.4, 127.2, 126.0, 122.8, 122.7, 120.9, 119.8, 119.6,
110.7, 21.4, 21.3. HRMS (ESI) calculated [M+H] + for C27H22N: 360.17468, found: 360.17465.
FTIR (cm-1): 3011, 1597, 1500, 1454, 1369, 1320, 1216, 1168, 1074, 1025, 827, 766, 699.
2-(4-Nitrophenyl)-1,3-diphenyl-1H-indole (4l) and 3-(4-Nitrophenyl)-1,2-diphenyl-1H-
indole (4l’): (yellow viscous liquid, 0.093 g, 95%, regioisomer ratio: 1.4:1, selectivity: 99:1). Rf
(Pet. ether /EtOAc = 95/05): 0.46; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz, 1H), 8.00
(d, J = 8.7 Hz, 1H), 7.86ꢀ7.80 (m, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.47ꢀ7.20 (m, 13H), 7.12ꢀ7.10
(m, 1H). 13C NMR (100 MHz, CDCl3) δ 146.6, 142.8, 138.8, 137.8, 137.6, 134.3, 134.1, 131.7,
130.9, 130.4, 129.7, 128.8, 128.4, 128.3, 127.8, 127.6, 126.9, 124.0, 123.3, 121.8, 120.6, 119.3,
114.6, 111.3, 111.0. Representative peaks of Minor Isomer: 13C NMR (100 MHz, CDCl3) δ
145.8, 138.2, 131.2, 138.6, 129.4, 128.5, 127.9, 126.9, 123.8, 123.5, 121.6, 120.2, 119.1. HRMS
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(ESI) calculated [M+H] for C26H19O2N2: 391.1441, found: 391.1438. FTIR (cm-1): 3064,
1596, 1548, 1454, 1369, 1288, 1215, 1105, 910, 859, 777.
3-(4-Bromophenyl)-2-(4-nitrophenyl)-1-phenyl-1H-indole (4m) and 2-(4-Bromophenyl)-3-
(4-nitrophenyl)-1-phenyl-1H-indole (4m’): (yellow solid, 0.087 g, 74%, regioisomer ratio:
1
1.2:1, selectivity: 97:3). Rf (Pet. ether /EtOAc = 95/05): 0.46; H NMR (400 MHz, CDCl3) δ
8.24 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.84ꢀ7.76 (m, 1H), 7.54 (d, J = 8.6 Hz, 2H),
7.48ꢀ7.39 (m, 3H), 7.37ꢀ7.31 (m, 4H), 7.28ꢀ7.25 (m, 4H), 7.0 (d, J = 7.1 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 146.7, 145.9, 138.3, 138.2, 137.5, 134.4, 133.1, 132.7, 131.8, 131.7, 130.5,
130.4, 129.9, 129.7, 127.2, 124.0, 123.7, 123.4, 122.7, 121.9, 121.7, 120.9, 119.2, 117.8, 111.3,
111.1. Representative peaks of Minor Isomer: 13C NMR (100 MHz, CDCl3) δ 142.3, 138.6,
137.3, 137.2, 132.0, 131.9, 129.6, 128.3, 128.2, 128.0, 126.7, 124.2, 120.6, 119.8, 115.0, 114.6.
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HRMS (ESI) calculated [M+H] + for C26H18O2N2Br: 469.0546, found: 469.0544. FTIR (cm-1):
1595, 1514, 1497, 1411, 1395, 1344, 1289, 1174, 1071, 860, 753.
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2-Methyl-1,3-diphenyl-1H-indole (4n)31 and 3-Methyl-1,2-diphenyl-1H-indole (4n’)32
(yellow solid, 0.062 g, 88%, regioisomer ratio: 1.5:1, selectivity: 98:2). Rf (Pet. ether /EtOAc =
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95/05): 0.50; H NMR (400 MHz, CDCl3) δ 7.70 ꢀ7.68 (m, 1H), 7.53 ꢀ7.49 (m, 2H), 7.37ꢀ7.33
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(m, 4H), 7.24ꢀ7.20 (m, 6H), 7.18 (m, 1H), 2.44 (s, 3H). C NMR (100 MHz, CDCl3) δ 138.8,
137.7, 135.6, 132.2, 129.8, 129.1, 128.3, 128.0, 127.4, 126.7, 122.6, 120.5, 119.0, 110.8, 110.2,
12.2. 1H NMR (400 MHz, CDCl3) for minor isomer δ: 7.75ꢀ7.73 (m), 7.61ꢀ7.56 (m), 7.47ꢀ7.43
13
(m), 7.32ꢀ7.27 (m), 7.18ꢀ7.16 (m), 2.37 (s). C NMR (100 MHz, CDCl3) for minor isomer δ
138.0, 137.0, 133.7, 130.7, 129.7, 128.7, 128.1, 127.2, 126.1, 120.8, 120.2, 118.8, 110.5, 9.7.
HRMS (ESI) calculated [M+H] + for C21H18N: 284.1434, found: 284.1433. FTIR (cm-1): 3057,
1597, 1499, 1397, 1247, 1177, 1074, 915, 794, 700.
1-(2,5-Dimethylphenyl)-4,7-dimethyl-2,3-diphenyl-1H-indole (4o): (yellow viscous liquid,
1
0.041 g, 41%, selectivity: 94:6). Rf (Pet. ether /EtOAc = 95/05): 0.38; H NMR (400 MHz,
CDCl3) δ 7.53ꢀ7.43 (m, 1H), 7.33ꢀ7.24 (m, 5H), 7.08ꢀ7.0 (m, 7H), 6.90ꢀ6.84 (m, 2H), 2.34 (s,
3H), 2.20 (s, 3H), 1.90 (s, 3H), 1.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 139.1, 138.7, 137.3,
135.3, 135.0, 132.5, 132.0, 131.8, 131.2, 129.7, 129.3, 129.0, 127.3, 127.1, 126.6, 126.3, 125.0,
+
122.0, 119.6, 117.8, 20.9, 20.8, 18.8, 17.3. HRMS (ESI) calculated [M+H] for C30H28N:
402.2216, found: 402.2213. FTIR (cm-1): 3006, 1647, 1507, 1414, 1352, 1285, 1113, 1033, 989,
842, 753.
1,2,3-Triphenyl-1H-benzo[f]indole (4p)29: (yellow viscous liquid, 0.054 g, 55%, selectivity:
1
99:1). Rf (Pet. ether /EtOAc = 95/05): 0.49; H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.0ꢀ
7.83 (m, 7H), 7.59 ꢀ7.52 (m, 4H), 7.44 (t, J = 7.6 Hz, 2H), 7.39 ꢀ7.33 (m, 3H), 7.25ꢀ7.16 (m,
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4H). 13C NMR (100 MHz, CDCl3) δ 147.1, 140.7, 139.0, 136.2, 134.9, 133.7, 132.2, 131.5,
131.2, 131.0, 130.5, 129.7, 129.6, 129.2, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.6, 126.8,
126.7, 126.5, 126.3, 124.2, 123.1, 117.3, 116.3, 106.1. FTIR (cm-1): 3020, 1660, 1596, 1502,
1443, 1383, 1216, 1110, 1061, 925, 862, 763.
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5-(Benzo[d][1,3]dioxol-4-yl)-6,7-diphenyl-5H-[1,3]dioxolo[4,5-f]indole (4q)29: (brown solid,
0.069 g, 64%, selectivity: 99:1). Rf (Pet. ether /EtOAc = 95/05): 0.27; Melting point: 184ꢀ186 °C;
1H NMR (400 MHz, CDCl3) δ 7.32ꢀ7.28 (m, 4H), 7.25ꢀ7.21 (m, 1H), 7.16ꢀ7.13 (m, 4H), 7.09ꢀ
7.06 (m, 2H), 6.78ꢀ6.67 (m, 4H), 5.99 (s, 2H), 5.93 (s, 2H). 13C NMR (100 MHz, CDCl3) δ
148.1, 146.9, 145.5, 143.9, 136.1, 135.2, 133.7, 132.2, 131.8, 131.1, 130.2, 128.4, 128.0, 127.2,
126.0, 122.0, 121.4, 116.8, 109.4, 108.3, 101.8, 100.9, 98.2, 91.8. HRMS (ESI) calculated
+
[M+H] for C28H20O4N: 434.1387, found: 434.1380. FTIR (cm-1): 3019, 1602, 1489, 1464,
1334, 1291, 1180, 946, 879, 770, 700.
5,6,12-Triphenylindolo[2,1-a]isoquinoline (6a)33: To a 5 mL screwꢀcapped test tube equipped
with a magnetic stir bar, 2,3ꢀdiphenylꢀ1Hꢀindole (3a, 30 mg, 0.1 mmol), 1,2ꢀdiphenylacetylene
(5, 24 mg, 0.13 mmol, 1.2 equiv), [(Cp*RhCl2)2] (1.0 mg, 0.02 mmol, 2 mol%), Cu(OAc)2·H2O
(1.0 mg, 0.1 mmol, 10 mol%), and 1 mL oꢀxylene were added sequentially. The tube (not sealed)
was immersed in an oil bath (100 °C) and stirred vigorously under air. When TLC control
showed the completion of the reaction (after 6 h), the solvent was evaporated and subsequently
the crude residue was purified by flash column chromatography on silica gel (using Pet. etherꢀ
EtOAc) to afford the corresponding indolo[2,1ꢀa]isoquinoline derivative 6a as a yellow solid
1
(0.046 g, 93% yield). Rf (Pet. ether /EtOAc = 95/05): 0.54; Melting point: 193ꢀ195 °C; H NMR
(400 MHz, CDCl3) δ 8.01 (d, J = 7.9 Hz, 1H), 7.71 ꢀ7.63 (m, 4H), 7.57 (d, J = 7.5 Hz, 2H), 7.41
13
(s, 5H), 7.31ꢀ7.17 (m, 9H), 6.90 (t, J = 7.8 Hz, 1H), 6.08 (d, J = 8.9 Hz, 1H). C NMR (100
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MHz, CDCl3) δ 137.0, 136.6, 136.1, 135.7, 132.0, 131.7, 131.3, 131.2, 131.0, 130.8, 130.7,
129.2, 128.8, 128.0, 127.4, 127.1, 126.9, 126.6, 126.2, 126.0, 124.6, 121.8, 120.9, 119.1, 114.6,
112.2. HRMS (ESI) calculated [M+H] + for C34H24N: 446.1903, found: 446.1900. FTIR (cm-1):
3063, 1603, 1549, 1483, 1379, 1332, 1216, 1109, 1030, 924, 766, 670.
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Supporting Information
Crystallographic data of compounds 3f and 4j, Details on computational studies, and
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copies of H and C NMR spectra of all products, This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgement
Generous financial support from CSIRꢀNew Delhi (as part of 12th FiveꢀYear plan program under
ORIGINꢀCSC0108) is kindly acknowledged. A.T.B. thanks the AvH Foundation for an
equipment grant. M.T and S.S.B. thank CSIR for the senior research fellowship. We thank Mr.
Dnyaneshwar R. Baviskar for experimental support, Dr Kumar Vanka for the computational
studies, Dr. P. R. Rajamohanan for the NMR spectra, Dr. B. Santhakumari for the HRMS data.
References
1. (a) KochanowskaꢀKaramyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. (b) Somei,
M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73. (c) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep.
2005, 22, 761. (d) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996.
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K. Tetrahedron Lett. 2015, 56, 296. (b) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29. (c)
Shiri, M. Chem. Rev. 2012, 112, 3508. (d) Shi, Z.; Glorius, F. Angew. Chem., Int. Ed. 2012,
51, 9220. (e) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (f) Humphrey, G. R.;
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Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (g) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873. (h) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163.
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3. (a) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: New York, 1982. (b)
Robinson, B. Chem. Rev. 1963, 63, 373. (c) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges.
1883, 16, 2241.
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