CpCo(III)-Catalyzed C-H/N-N Functionalization of Arylhydrazones for the Synthesis of Isoquinolines

Article abstract of DOI:10.1021/acs.joc.6b02001

Cationic Co(III)-catalyzed C-H/N-N bond functionalization of arylhydrazones with internal alkynes has been developed for the synthesis of isoquinoline derivatives. The arylhydrazones are easy to prepare and require inexpensive and commercially available hydrazine hydrate. The reaction works well with a variety of internal alkynes and arylhydrazones and offers broad scope, good functional group tolerance, and high yields under redox-neutral conditions in the presence of air.

Full text of DOI:10.1021/acs.joc.6b02001

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Note
Cp*Co(III)-Catalyzed C-H/N-N Functionalization of
Arylhydrazones for the Synthesis of Isoquinolines
Amit B. Pawar, Darpan Agarwal, and Dhanaji M Lade
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02001 • Publication Date (Web): 06 Oct 2016
Downloaded from http://pubs.acs.org on October 7, 2016
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Cp*Co(III)-Catalyzed CH/NN Functionalization of Arylhydrazones for
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the Synthesis of Isoquinolines
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Amit B. Pawar†*, Darpan Agarwal‡,⊥ and Dhanaji M. Lade§,⊥
†Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
‡Indian Institute of Science Education and Research, Bhopal, India
§ Academy of Scientific and Innovative Research (AcSIR), CSIR-IICT, Hyderabad 500007, India
Email: amitorgchem@gmail.com, amitorgchem@iict.res.in
ABSTRACT: Cationic Co(III)-catalyzed C−H/N−N bond functionalization of arylhydrazones with
internal alkynes has been developed for the synthesis of isoquinoline derivatives. The arylhydrazones
are easy to prepare and require inexpensive and commercially available hydrazine hydrate. The
reaction works well with a variety of internal alkynes and arylhydrazones and offers broad scope,
good functional group tolerance and high yields under redox-neutral conditions in presence of air.
Isoquinoline represent one of the ubiquitous structural motif found in various natural products and
pharmaceutical compounds.1 In addition, isoquinoline derivatives play an important role in
asymmetric catalysis and photochemistry; where they can be used as ligands.2 Traditional methods to
synthesize isoquinoline such as Bischer-Napieralski, Pictet-Spengler and Pomeranz-Fritsch often
suffers from a few drawbacks such as low yields, narrow substrate scope and harsh reaction
conditions. In recent years, C−H activation reactions3 has provided an alternate route to access
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isoquinoline scaffolds with large diversity in a concise manner.4 Although, these methods provide
straightforward access to isoquinolines; they often require the use of precious transition metals such
as Pd, Rh or Ru. In the recent years, a lot of research has been focused on the utilization of first row
transition metals in the area of C−H functionalization.5 Due to their low toxicity, high natural
abundance and inexpensive nature, first row transition metals are now preferred over precious metals
like Pd, Rh, Ru or Ir. In this context, Kanai and Matsunaga has done pioneering work in the
development of Cp*Co(III) catalysis for C−H activation.6,7 Since then, several other groups across
the globe have extensively put their efforts for further development in this area,8 including our group.9
Recently, several Co(III)-catalyzed isoquinoline synthesis have been reported employing different
directing groups and coupling partners (Scheme 1). In his context, Kanai and Matsunaga, Ackermann,
Sundararaju and Cheng independently reported Co(III)-catalyzed C−H/N−O bond functionalization of
oximes with alkynes for the synthesis of isoquiolines.10 On the other hand, Wang et. al reported
Cp*Co(III)-catalyzed oxidative annulation of N−H imines with alkynes in the presence of external
oxidant to provide isoquinolines.11 Ackermann and Li reported an elegant C−H/N−H bond
functionalization of amidines with diazo compounds to furnish isoquinolines.12 Very recently, Li and
co-workers reported C−H/N−S bond functionalization of N-sulfinyl imines with alkynes to prepare
isoquinolines.13
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Scheme 1. Cp*Co(III)-Catalyzed Synthesis of Isoquinolines
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To the best of our knowledge, Co(III)-catalyzed isoquinoline synthesis via C−H/N−N bond
functionalization of hydrazones using N−N as an internal oxidant has not been realized.14 In
continuation of our interest in Cp*Co(III) catalysis,9 herein, we report Cp*Co(III)-catalyzed
C−H/N−N bond functionalization arylhydrazones with internal alkynes for the synthesis of highly
substituted isoquinolines (Scheme 1). The major advantage of the present protocol is the use of
arylhydrazones as inexpensive starting materials, which are synthesized from benzophenones and
hydrazine hydrate, reagents those are commercially available and cost-effective.
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Table 1. Optimization of Reaction Conditionsa
yield
entry
additive
solvent
temp (C)
(%)b
30
-
1
2
TFE
TFE
120
120
120
120
120
120
120
120
120
120
120
120
80
NaOAc
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50
3
KOAc
CsOAc
AcOH
TFE
4
TFE
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70
5
TFE
PhCO2H
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
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6
TFE
95
7
TFE
77
8
TFE
n.d.
9
MeOH
tAmOH
1,2-DCE
DMSO
TFE
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n.d.
n.d.
n.d.
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aReaction conditions: 1a (0.13 mmol), 2a (0.10 mmol), Cp*Co(CO)I2 (10 mol %), AgSbF6 (20 mol %), additive
b
1
(25 mol %) in solvent (0.8 mL) for 14 h. Yields are based on crude H NMR (internal standard: 1,1,2,2
tetrachloroethane) and calculated with respect to 2a, n.d. = not detected. TFE = 2,2,2-Trifluoroethanol.
We commenced our investigation of Co(III)-catalyzed isoquinoline synthesis using benzophenone
hydrazone 1a as a starting substrate and diphenylacetylene 2a as a coupling partner (Table 1). When
benzophenone hydrazone 1a was treated with diphenylacetylene 2a in the presence of Cp*Co(CO)I2
(10 mol %) and AgSbF6 (20 mol %) in TFE at 120 C for 14 h; it furnished desired isoquinoline 3aa
in low yield (Table 1, entry 1). Gratifyingly, introduction of acetate additives such as NaOAc, KOAc
and CsOAc was found to promote the reaction (Table 1, entries 2-4). More pleasingly, when acid
additives were tested (Table 1, entries 5-7), it was found that addition of pivalic acid furnished the
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required isoquinoline in almost quantitative yield (Table 1, entry 7). When the reaction was performed
under inert atmosphere, the yield of the product dropped to 77% (Table 1, entry 8). Surprisingly, the
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reaction did not work at all in other solvents like MeOH, AmOH, 1,2-DCE and DMSO (Table 1,
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entries 9-12). The lowering of the reaction temperature resulted in the diminished yield of the product
(Table 1, entry 13).
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After having the optimized condition in hand, we investigated the scope and generality of the reaction
using different internal alkynes (Scheme 2). It was found that diarylalkyne having electron donating
functional group on the aromatic ring furnished the corresponding isoquinoline in good yield (3ab).
Intriguingly, disubstituted alkyne also participated in the annulation reaction producing the
corresponding product in moderate yield (3ac).
Scheme 2. Scope of Alkyne
aReaction conditions: 1 (0.26 mmol), 2 (0.20 mmol), Cp*Co(CO)I2 (10 mol %), AgSbF6 (20 mol %), PivOH (25
mol %) in TFE (1.5 mL) for 14 h; isolated yields are given. b Run for 20 h.
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The alkynes bearing electron-withdrawing groups such as Cl, F, CF3 and ester on the aromatic ring
also furnished the corresponding isoquinolines in good to excellent yields (3ad−3ag). When meta-
substituted diarylalkynes were employed, it also delivered the products in high yields (3ah−3aj). The
sterically hindered o-substituted diarylalkyne was also found to be compatible under present reaction
conditions (3ak). The unsymmetrical alkyne, 3-phenylprop-2-yn-1-ol (2l) which possess free
hydroxyl group also tolerated to furnish corresponding product in moderate yield (3al); thus
demonstrating the functional group tolerance. The structure of 3al was confirmed by comparing its 1H
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and C NMR spectrum with the known compound.15 The exact reason for this selectivity is unclear,
however it may be due to intramolecular coordination of phenyl group of 3-phenylprop-2-yn-1-ol (2l)
with cobalt metal in intermediate C (see Scheme 5) in order to stabilize it.16,17 The terminal alkyne
such as phenylacetylene was turned out to be an ineffective coupling partner under the present
reaction conditions.
Scheme 3. Scope of Arylhydrazonesa
aReaction conditions: 1 (0.26 mmol), 2 (0.20 mmol), Cp*Co(CO)I2 (10 mol %), AgSbF6 (20 mol %), PivOH (25
mol %) in TFE (1.5 mL) for 14 h; isolated yields are given.
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After examining the scope of alkynes, scope of arylhydrazones for the synthesis of isoquinoline was
tested (Scheme 3). We were delighted to see that, arylhydrazones having both electron-donating and
electron-withdrawing groups such as Me, OMe, F and Cl reacted smoothly with various
diarylalkynes to furnish the corresponding isoquinoline derivatives in good yields (3bb−3eb). The
hydrazone derived from -tetralone also reacted efficiently with diarylalkynes as well as with
dialkylalkyne (4-octyne, 2n) to generate tricyclic compounds in excellent yields (3fa−3fn).
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To understand and gain insight the mechanism, some preliminary experiments were conducted
(Scheme 4).18 When intermolecular competitive experiment with differently functionalized
hydrazones (1c and 1e) was performed, it was observed that electron rich hydrazone reacts
preferentially. This can be rationalized in terms of intramolecular electrophilic-substitution type CH
activation reaction via carboxylate assistance. Furthermore, intermolecular competitive experiment
with differently functionalized alkynes revealed that electron rich alkyne to be more reactive.
Scheme 4. Control Experiments
Based on the above control experiments and related Rh (III)19 as well as cobalt(III)-catalyzed
annulation reactions;10-14 a plausible mechanism is proposed in as outlined Scheme 5. Initially
Cp*Co(CO)I2 react with AgSbF6 in presence of PivOH to generate catalytically active complex A.
Then complex A undergo cyclometalation with 1a to generate the cobaltacycle B. This is followed by
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migratory insertion of alkyne 2 into B to form seven membered cobaltacyclic intermediate C, which
on pivalic acid-assisted proton transfer,20 generates an intermediate D, which eventually undergo
intramolecular substitution resulting in the formation CN bond and the breakage of NN bond in
order to furnish isoquinoline 3 with concomitant regeneration of catalytically active Co(III) species A.
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Scheme 5. Plausible Mechanism
In summary, we have developed Co(III)-catalyzed [4+2] annulation of arylhydrazones and internal
alkynes via CH/NN bond functionalization. The reaction works with differently functionalized
alkynes and hydrazones in good to excellent yield under redox-neutral conditions. The present
protocol employs simple arylhydrazones as substrates which are easily synthesized from
commercially available benzophenones and hydrazine hydrate thus making this reaction cost-
effective.
EXPERIMENTAL SECTION
General Remarks
Unless otherwise stated, all commercial reagents and solvents were used without additional
purification. Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel 60
F254 plates. Visualization on TLC was achieved by the use of UV light (254 nm). Column
chromatography was undertaken on silica gel (100‒200 mesh) using a proper eluent system. NMR
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spectra were recorded in chloroform-d at 300 or 400 MHz for H NMR spectra and 75 MHz or 100
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MHz for C NMR spectra. Chemical shifts were quoted in parts per million (ppm) referenced to the
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appropriate solvent peak or 0.0 ppm for tetramethylsilane. The following abbreviations were used to
describe peak splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, sept = septet, dd = doublet of doublet, td = triplet of doublet, m = multiplet. Coupling
constants, J, were reported in hertz unit (Hz). For 13C NMR chemical shifts were reported in ppm
referenced to the center of a triplet at 77.0 ppm of chloroform-d. HRMS were recorded using ESI-
TOF techniques. Cp*Co(CO)I2 was synthesized according to the literature.7c The arylhydrazones 1aa
were prepared according to literature procedure.21
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General Procedure for Co-Catalyzed Synthesis of Isoquinolines
To a screw capped vial with a spinvane triangular-shaped Teflon stirbar were added arylhydrazone
(1a, 0.26 mmol), diphenylacetylene (2a, 0.20 mmol), Cp*Co(CO)I2 (9.5 mg, 10 mol %), AgSbF6
(13.8 mg, 20 mol %), PivOH (5.1 mg, 25 mol %), and TFE (1.5 mL) under air atmosphere. The
reaction mixture was stirred at 120 C for 14 h. Afterwards, it was filtered through short pad of celite
and celite pad was washed with CHCl3 (25 mL × 2). The solvent was evaporated under reduced
pressure and the residue was purified by column chromatography on silica gel using n-hexane/EtOAc
(50:1) to give the desired product 3aa as a white solid (62 mg, 87%).
1
1,3,4-Triphenylisoquinoline (3aa).22a White solid (62 mg, 87%); H NMR (300 MHz, CDCl3) δ 8.18
(d, J = 8.1 Hz, 1H), 7.82 (dd, J = 7.9, 1.4 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.63 – 7.46 (m, 5H), 7.46
– 7.33 (m, 5H), 7.33 – 7.25 (m, 2H), 7.24 – 7.09 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 159.8, 149.6,
140.9, 139.8, 137.5, 136.9, 131.3, 130.4, 130.2, 129.9, 129.7, 128.5, 128.3, 127.50, 127.46, 127.2,
126.9, 126.5, 126.0, 125.4 (One carbon is missing due to overlap).
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3,4-Bis(4-methoxyphenyl)-1-phenylisoquinoline (3ab).22b White solid (68.5 mg, 82%); H NMR (300
MHz, CDCl3) δ 8.15 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 7.8, 1.3 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.62
– 7.44 (m, 5H), 7.39 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.74 (d, J
= 8.8 Hz, 2H), 3.86 (s, 3H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.4, 158.7, 158.6, 149.3,
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139.9, 137.4, 133.5, 132.4, 131.7, 130.2, 129.9, 129.7, 128.8, 128.4, 128.2, 127.4, 126.2, 125.9, 125.2,
113.9, 113.1, 55.2, 55.1.
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3,4-Bis(3,4-dimethoxyphenyl)-1-phenylisoquinoline (3ac). White solid (57.0 mg, 60%); m.p. 199– 201
°C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H), 7.86 – 7.75 (m, 3H), 7.64 – 7.44 (m, 5H),
7.16 (dd, J = 8.3, 1.9 Hz, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.90 (dd, J = 8.1, 1.7
Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H),
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3.64 (s, 3H); C NMR (100 MHz, CDCl3) δ 159.5, 149.1, 149.0, 148.2, 148.1, 147.8, 139.8, 137.3,
133.6, 130.3, 130.2, 129.9, 128.9, 128.5, 128.2, 127.4, 126.3, 125.9, 125.3, 123.6, 123.1, 114.5, 113.6,
111.2, 110.5, 55.94, 55.92, 55.8, 55.5; HRMS (ESI) m/z calcd. for C31H27NO4 [M+H]+: 478.2013,
found: 478.2014.
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3,4-Bis(4-chlorophenyl)-1-phenylisoquinoline (3ad).22a White solid (67.0 mg, 79%); H NMR (300
MHz, CDCl3) δ 8.19 (d, J = 8.2 Hz, 1H), 7.79 (dd, J = 7.8, 1.5 Hz, 2H), 7.72 – 7.47 (m, 6H), 7.40 (d,
J = 8.4 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 160.3, 148.5, 139.5, 139.1, 136.7, 135.8, 133.6, 133.3, 132.6, 131.7, 130.3, 130.1,
128.8, 128.7, 128.6, 128.4, 127.9, 127.7, 126.9, 125.6, 125.5.
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3,4-Bis(4-fluorophenyl)-1-phenylisoquinoline (3ae).22a White solid (65.0 mg, 83%); H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H), 7.84 – 7.75 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.63 – 7.57
(m, 1H), 7.57 – 7.46 (m, 4H), 7.42 – 7.33 (m, 2H), 7.28 – 7.20 (m, 2H), 7.10 (t, J = 8.7 Hz, 2H), 6.89
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(t, J = 8.8 Hz, 2H); C NMR (100 MHz, CDCl3) δ 162.1 (d, JC-F = 245.7 Hz), 162.0 (d, JC-F = 245.5
Hz), 160.1, 148.8, 139.6, 136.9, 136.8 (d, JC-F = 2.8 Hz), 133.2 (d, JC-F = 3.1 Hz), 132.9 (d, JC-F = 7.9
Hz), 132.1 (d, JC-F = 8.0 Hz), 130.2, 130.1, 128.6, 128.3, 127.6, 126.8, 125.7, 125.4, 115.6 (d, JC-F
21.3 Hz), 114.6 (d, JC-F = 21.2 Hz) (One carbon is missing due to overlap).
=
1-Phenyl-3,4-bis(4-(trifluoromethyl)phenyl)isoquinoline (3af). White solid (84.0 mg, 85%); m.p. 208–
210 °C; 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J = 8.2 Hz, 1H), 7.85 – 7.74 (m, 2H), 7.75 – 7.63 (m,
13
4H), 7.63 – 7.38 (m, 10H); C NMR (125 MHz, CDCl3) δ 160.8, 148.1, 144.0, 141.0, 139.3, 136.5,
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131.7, 130.7, 130.6, 130.1, 130.0 (q, JC-F = 32.6 Hz), 129.3 (q, JC-F = 32.1 Hz), 128.9, 128.8, 128.4,
127.8, 127.4, 125.7, 125.5, 124.8 (q, JC-F = 3.6 Hz), 124.1 (d, JC-F = 270.5 Hz), 124.0 (d, JC-F = 270.6
Hz) (One carbon is missing due to overlap); HRMS (ESI) m/z calcd. for C29H17NF6 [M+H]+:
494.1338, found: 494.1349.
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Diethyl 4,4'-(1-phenylisoquinoline-3,4-diyl)dibenzoate (3ag). White solid (68.0 mg, 68%); m.p. 73–
75 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.88 (d, J =
8.0 Hz, 2H), 7.82 (d, J = 6.8 Hz, 2H), 7.71 – 7.51 (m, 6H), 7.48 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.0
Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.37 (t, J = 7.1
Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 166.5, 166.3, 160.5, 148.5, 144.9, 142.0, 139.3, 136.5, 131.4,
130.5, 130.4, 130.2, 129.71, 129.69, 129.4, 129.1, 129.0, 128.8, 128.4, 127.8, 127.2, 125.7, 125.6,
61.1, 60.9, 14.34, 14.29; HRMS (ESI) m/z calcd. for C33H27NO4 [M+H]+: 502.2013, found: 502.2019.
1
3,4-Bis(3-methoxyphenyl)-1-phenylisoquinoline (3ah).11 White solid (72.0 mg, 86%); H NMR (300
MHz, CDCl3) δ 8.18 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 6.5 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.64 –
7.45 (m, 5H), 7.32 (t, J = 7.9 Hz, 1H), 7.18 – 7.06 (m, 2H), 7.00 (brs, 1H), 6.97 – 6.87 (m, 2H), 6.85
(brs, 1H), 6.74 (dt, J = 6.9, 2.4 Hz, 1H), 3.72 (s, 3H), 3.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
159.8, 159.6, 158.8, 149.2, 142.1, 139.8, 139.0, 136.9, 130.2, 129.9, 129.6, 129.3, 128.6, 128.5, 128.3,
127.5, 126.6, 126.1, 125.4, 123.8, 123.0, 116.7, 115.3, 113.6, 113.1, 55.3, 55.1.
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1-Phenyl-3,4-di-m-tolylisoquinoline (3ai).22a White solid (61.5 mg, 80%); H NMR (300 MHz,
CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 6.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.63 – 7.42 (m,
13
5H), 7.35 (s, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.19 – 7.10 (m, 3H), 7.10 – 6.90 (m, 3H); C NMR (75
MHz, CDCl3) δ 159.5, 149.6, 140.7, 139.9, 137.7, 137.5, 137.0, 136.9, 131.9, 131.2, 130.2, 129.83,
129.76, 128.42, 128.36, 128.2, 128.1, 127.9, 127.7, 127.5, 127.4, 127.2, 126.4, 126.1, 125.3, 21.4
(One of the methyl carbon attached to aromatic ring is missing due to overlap).
3,4-Bis(3-chlorophenyl)-1-phenylisoquinoline (3aj). White solid (71.8 mg, 84%); m.p. 213– 215 °C;
1H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 6.6 Hz, 2H), 7.72 – 7.62 (m, 2H),
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7.62 – 7.47 (m, 5H), 7.43 – 7.29 (m, 3H), 7.22 – 7.13 (m, 3H), 7.13 – 7.04 (m, 1H); C NMR (125
MHz, CDCl3) δ 160.5, 148.1, 142.2, 139.4, 139.0, 136.6, 134.4, 133.7, 131.1, 130.5, 130.4, 130.1,
129.8, 129.5, 128.8, 128.6, 128.5, 128.4, 127.8, 127.7, 127.4, 127.1, 125.7, 125.6 (One carbon is
missing due to overlap) ; HRMS (ESI) m/z calcd. for C27H17NCl2 [M+H]+: 426.0811, found:
426.0813.
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3,4-Bis(2-methoxyphenyl)-1-phenylisoquinoline (3ak).11 White solid (60.0 mg, 72%); H NMR (300
MHz, CDCl3) δ 8.15 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 6.7 Hz, 2H), 7.68 – 7.42 (m, 6H), 7.37 – 7.23
(m, 2H), 7.22 – 7.06 (m, 2H), 6.94 – 6.79 (m, 3H), 6.68 (d, J = 8.3 Hz, 1H), 3.61 (s, 3H), 3.54 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.4, 157.2, 156.6, 148.6, 139.4, 136.6, 132.2, 131.4, 130.6, 130.3,
129.7, 128.2, 128.8, 128.3, 128.1, 127.6, 126.4, 125.9, 125.6, 119.9, 119.8, 110.3, 55.2, 55.0 (three
carbons are missing due to overlap).
1
(1,3-Diphenylisoquinolin-4-yl)methanol (3al).15 Pale yellow solid (39.0 mg, 63%); H NMR (300
MHz, CDCl3) δ 8.35 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.84 – 7.65 (m, 5H), 7.64 – 7.37
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(m, 7H), 5.10 (s, 2H), 2.16 (s, 1H); C NMR (75 MHz, CDCl3) δ 160.6, 152.1, 140.4, 139.5, 136.7,
130.6, 130.1, 129.9, 128.6, 128.24, 128.16, 128.0, 126.7, 125.9, 124.7, 124.2, 59.5 (one carbon is
missing due to overlap).
3,4-Bis(4-methoxyphenyl)-6-methyl-1-(p-tolyl)isoquinoline (3bb). White solid (65.0 mg, 73%); m.p.
179– 181 °C; 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.47
(s, 1H), 7.42 – 7.26 (m, 5H), 7.19 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 8.8 Hz,
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2H), 3.86 (s, 3H), 3.74 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H); C NMR (75 MHz, CDCl3) δ 159.1, 158.6,
158.5, 149.4, 139.9, 138.2, 137.6, 137.2, 133.8, 132.4, 131.7, 130.1, 128.9, 128.3, 128.1, 127.4, 124.7,
123.6, 113.8, 113.0, 55.20, 55.10, 22.1, 21.3 (one carbon is missing due to overlap); HRMS (ESI) m/z
calcd. for C31H27NO2 [M+H]+: 446.2115, found: 446.2125.
3,4-bis(4-chlorophenyl)-6-methyl-1-(p-tolyl)isoquinoline (3bd).22a White solid (69.0 mg, 76%); H
1
NMR (300 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.49 – 7.29 (m, 8H),
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7.24 – 7.13 (m, 4H), 2.46 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.0, 148.5, 140.7,
139.3, 138.6, 137.0, 136.8, 136.0, 133.4, 133.1, 132.6, 131.7, 130.0, 129.0, 128.8, 127.8, 127.6, 124.4,
123.9, 22.13, 21.36 (two carbons are missing due to overlap).
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6-Methoxy-1-(4-methoxyphenyl)-3,4-diphenylisoquinoline (3ca).11 White solid (67.0 mg, 80%); H
NMR (300 MHz, CDCl3) δ 8.12 (d, J = 9.2 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.46 – 7.32 (m, 5H),
7.32 – 7.26 (m, 2H), 7.21 – 7.10 (m, 4H), 7.07 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 2.3 Hz, 1H), 3.89 (s,
3H), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.5, 160.0, 158.8, 150.1, 141.0, 139.1, 137.9,
132.4, 131.5, 131.2, 130.4, 129.5, 128.7, 128.3, 127.4, 127.2, 126.9, 121.2, 118.7, 113.7, 104.2, 55.4,
55.2.
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6-Methoxy-1-(4-methoxyphenyl)-3,4-di-p-tolylisoquinoline (3cm).22c White solid (66.0 mg, 74%); H
NMR (300 MHz, CDCl3) 8.09 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),
7.25 – 7.14 (m, 4H), 7.11 (dd, J = 9.3, 2.3 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.02 – 6.92 (m, 3H), 3.88
(s, 3H), 3.72 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.4, 159.9, 158.4,
150.0, 139.3, 138.2, 136.6, 136.4, 134.9, 132.5, 131.5, 131.0, 130.3, 129.4, 129.1, 128.4, 128.2, 121.0,
118.5, 113.7, 104.3, 55.3, 55.2, 21.3, 21.1.
3,4-Bis(4-chlorophenyl)-6-methoxy-1-(4-methoxyphenyl)isoquinoline (3cd).22c White solid (76.5 mg,
1
79%); H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.39 (d, J =
8.3 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.25 – 7.13 (m, 5H), 7.07 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 2.4
13
Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H); C NMR (75 MHz, CDCl3) δ 160.8, 160.1, 159.3, 149.1, 139.3,
138.9, 136.2, 133.4, 133.2, 132.5, 132.2, 131.7, 131.4, 129.7, 128.9, 127.8, 127.4, 121.2, 119.0, 113.8,
103.7, 55.4, 55.3.
6-Fluoro-1-(4-fluorophenyl)-3,4-diphenylisoquinoline (3da).22a White solid (61.5 mg, 78%); 1H NMR
(300 MHz, CDCl3) δ 8.15 (dd, J = 9.2, 5.8 Hz, 1H), 7.79 (dd, J = 8.6, 5.5 Hz, 2H), 7.47 – 7.33 (m,
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5H), 7.33 – 7.11 (m, 9H).; C NMR (75 MHz, CDCl3) δ 163.2 (d, JC-F = 246.2 Hz), 163.1 (d, JC-F
=
250.7 Hz), 158.5, 150.6, 140.4, 139.0 (d, JC-F = 9.7 Hz), 137.0, 135.6 (d, JC-F = 3.2 Hz), 131.9 (d, JC-F
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= 8.3 Hz), 131.1, 130.4 (d, JC-F = 9.9 Hz), 130.3, 129.6 (d, JC-F = 5.8 Hz), 128.5, 127.6, 127.3, 122.6,
117.0 (d, JC-F = 25.1 Hz), 115.4 (d, JC-F = 21.5 Hz), 109.7 (d, JC-F = 22.3 Hz) (One carbon is missing
due to overlap).
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6-Chloro-1-(4-chlorophenyl)-3,4-diphenylisoquinoline (3ea).22b White solid (64.0 mg, 75%); 1H NMR
(300 MHz, CDCl3) δ 8.07 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 7.0 Hz, 2H), 7.70 (brs, 1H), 7.59 – 7.50 (m,
2H), 7.47 (d, J = 9.8 Hz, 1H), 7.44 – 7.33 (m, 5H), 7.33 – 7.23 (m, 2H), 7.23 – 7.09 (m, 3H); 13C
NMR (75 MHz, CDCl3) δ 158.4, 150.9, 140.3, 138.1, 137.7, 136.7, 135.1, 131.5, 131.2, 130.4, 129.3,
128.9, 128.7, 128.6, 127.8, 127.7, 127.6, 127.4, 125.0, 123.6 (One carbon is missing due to overlap).
6-Chloro-1-(4-chlorophenyl)-3,4-bis(4-methoxyphenyl)isoquinoline (3eb). Light yellow solid (68.0
mg, 70%); m.p. 169– 171 °C; 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 9.0 Hz, 1H), 7.80 – 7.65 (m,
3H), 7.52 (d, J = 8.2 Hz, 2H), 7.42 (dd, J = 9.0, 1.8 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.5
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Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.76 (s, 3H); C NMR (75
MHz, CDCl3) δ 159.0, 158.9, 158.0, 150.5, 138.5, 137.8, 136.5, 134.9, 132.8, 132.2, 131.6, 131.5,
128.95, 128.86, 128.6, 128.4, 127.4, 124.9, 123.3, 114.2, 113.2, 55.3, 55.1; HRMS (ESI) m/z calcd.
for C29H21Cl2NO2 [M+H]+: 486.1022, found: 486.1024.
2,3-Diphenyl-8,9-dihydro-7H-benzo[de]quinoline (3fa).10c White solid (51.5 mg, 80%); 1H NMR (300
MHz, CDCl3) δ 7.53 – 7.43 (m, 2H), 7.41 – 7.27 (m, 6H), 7.26 – 7.12 (m, 5H), 3.41 (t, J = 6.2 Hz,
2H), 3.19 (t, J = 6.0 Hz, 2H), 2.34 – 2.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 159.2, 149.1, 140.7,
138.5, 137.6, 136.2, 131.3, 130.2, 130.1, 129.1, 128.1, 127.5, 127.0, 126.9, 124.8, 123.8, 123.5, 34.5,
30.6, 23.3.
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2,3-Di-p-tolyl-8,9-dihydro-7H-benzo[de]quinoline (3fm).22b White solid (53.0 mg, 76%); H NMR
(300 MHz, CDCl3) δ 7.50 – 7.38 (m, 2H), 7.33 – 7.22 (m, 3H), 7.14 (d, J = 8.1 Hz, 2H), 7.09 (d, J =
8.1 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 3.35 (t, J = 6.2 Hz, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H),
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2.31 – 2.17 (m, 5H); C NMR (75 MHz, CDCl3) δ 158.9, 149.3, 138.3, 138.2, 136.4, 136.3, 134.8,
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131.1, 130.1, 129.7, 128.8, 128.7, 128.2, 124.4, 123.7, 123.5, 34.6, 30.7, 23.4, 21.2, 21.1 (One carbon
is missing due to overlap).
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2,3-Dipropyl-8,9-dihydro-7H-benzo[de]quinoline (3fn).22d Colourless solid (39.0 mg, 77%); 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.26 (d, J = 7.1 Hz, 1H), 3.28
(t, J = 6.2 Hz, 2H), 3.09 (t, J = 6.0 Hz, 2H), 3.01 – 2.88 (m, 4H), 2.22 – 2.10 (m, 2H), 1.89 – 1.57 (m,
4H), 1.19 – 0.99 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 156.9, 150.6, 139.2, 135.8, 130.0, 126.6,
123.8, 123.6, 120.9, 36.8, 33.7, 30.6, 29.8, 24.0, 23.9, 23.2, 14.5, 14.3.
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ASSOCIATED CONTENT
Supporting Information
13
characterization of new compounds (1H, C NMR spectra). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: amitorgchem@gmail.com, amitorgchem@iict.res.in
Author Contributions
⊥
D.A. and D.M.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
A.B.P thanks DST, New Delhi, India
for the INSPIRE Faculty Award (CH-157, GAP 0520). D. A thanks CSIR-IICT for providing him the
opportunity to work as summer research fellow. D.M.L thanks CSIR for senior research fellowship.
We thank Dr. S. Chandrasekhar (Director, CSIR-IICT) for his support and encouragement.
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(18) See the Supporting Information for details on intermolecular competitive experiments.
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