Synthesis of isoquinolines and heterocycle-fused pyridines via three-component cascade reaction of aryl ketones, hydroxylamine, and alkynes

Article abstract of DOI:10.1021/jo3010414

An efficient one-pot synthesis of isoquinolines and heterocycle-fused pyridines by three-component reaction of aryl ketones, hydroxylamine, and alkynes is developed. The reaction involves condensation of aryl ketones and hydroxylamine, rhodium(III)-cataly

Full text of DOI:10.1021/jo3010414

Article
pubs.acs.org/joc
Synthesis of Isoquinolines and Heterocycle-Fused Pyridines via
Three-Component Cascade Reaction of Aryl Ketones,
Hydroxylamine, and Alkynes
Liyao Zheng, Jia Ju, Yunhui Bin, and Ruimao Hua*
Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of
Education, Beijing 100084, China
S
* Supporting Information
ABSTRACT: An efficient one-pot synthesis of isoquinolines
and heterocycle-fused pyridines by three-component reaction
of aryl ketones, hydroxylamine, and alkynes is developed. The
reaction involves condensation of aryl ketones and hydroxyl-
amine, rhodium(III)-catalyzed C−H bond activation of the in
situ generated aryl ketone oximes, and cyclization with internal alkynes. This protocol enables rapid assembly of multisubstituted
isoquinolines as well as γ-carbolines, furo[2,3-c]pyridines, thieno[2,3-c]pyridines, and benzofuro[2,3-c]pyridines from readily
available substrates.
needed. In 2009, Miura7a and Fagnou7b have independently
reported the Cp*Rh(III)-catalyzed isoquinoline synthesis by
INTRODUCTION
Nitrogen-containing heterocyclic compounds are ubiquitous in
■
oxidative coupling between alkynes and imines using
numerous natural and synthetic bioactive molecules. Among
stoichiometric Cu(OAc)2 as external oxidant. In 2010,
them, isoquinolines and relative fused pyridines are important
Guimond and Fagnou8b reported an elegant isoquinolone
heterocycles that serve as privileged components in medical
chemistry and pharmaceutical industry.1 Furthermore, some
isoquinolines are useful ligands2 for catalytic asymmetric
syntheses2a and electrophosphorescent complexes.2c Motivated
by the need of high throughput screening in modern drug
discovery, rapid building high capacity libraries of drug
candidates from readily available building blocks is particularly
attractive. Therefore, chemists continue to devise novel
synthetic methodologies with minimization of substrate
preactivation and maximization of product diversity.
The development of synthetic chemistry of isoquinolines
gives a good illustration for this concept. Traditional routes,
which are demonstrated well by several name reactions such as
Bischler−Napieralski reaction, Pomeranz−Fritsch reaction, and
Pictet−Gams reaction, typically need highly active substrates
and harsh reaction conditions.3 To address these issues, various
metal-catalyzed cyclizations4 were developed over the past two
decades. For intramolecular approaches, highly prefunctional-
ized substrates, such as imine and oxime derivatives of ortho-
alkynylaryl aldehyde were employed, thus narrowing the
product diversity inherently.4c−g For intermolecular cyclization,
Larock’s group4h,i developed a palladium-catalyzed coupling of
o-haloaldimines and alkynes to construct the isoquinoline
skeleton, while Cheng’s group4j reported a similar strategy
using nickel-catalyzed systems. However, the use of preacti-
vated o-haloaldimines as substrates still leads narrow substrate
broad scope and low atom economy.
synthesis using N−O bond as an internal oxidant for C−N
bond formation and catalyst turnover. Shortly afterward, this
“external-oxidant-free” strategy8 was expanded by Chiba8c and
Li8d for isoquinoline synthesis, where O-acetyl oximes and
oximes are employed as oxidizing directing groups (DGox) for
Rh(III)-catalyzed C−H bond activation, respectively.
In the above examples involving C−H activation for
isoquinoline synthesis, directing groups with nitrogen atoms
are installed in the substrates beforehand; thus, additional steps
for the synthesis of the substrates are needed. For example, in
Chiba’s isoquinoline synthesis,8c the O-acetyl oximes need a
two-step synthesis from corresponding aryl ketones, and a large
amount of pyridine is used as base in both steps. With our
continuing interests in alkyne involved multicomponent
reactions and cascade heterocycle syntheses,9,10 we embarked
on devising cascade reactions by combination of Rh(III)
catalyzed C−H activation with other reactions. We were
specifically interested in generating directing groups (DGs) via
in situ transformation of a preparatory functional group,
namely, pro-directing groups (DGpro) (Scheme 1),11 as inspired
by the concept of “prodrug”. Very recently, Cheng12 reported a
one-pot three-component reaction of aryl aldehydes, methyl-
amines, and alkynes to afford isoquinolinium salts though
Cp*Rh(III)-catalyzed C−H bond activation, where stoichio-
metric Cu(OAc)2 is used as external oxidant. Herein, we
disclose a one-pot synthesis of isoquinolines by three-
component reaction of aryl ketones, hydroxylamine, and
Recently, rhodium-catalyzed C−H activation has emerged as
a versatile tool in heterocycle syntheses.5 Jun6a and Cheng6b
have developed Rh(I)-catalyzed systems for isoquinoline
synthesis, but high temperature (130 °C or higher) was
Received: May 23, 2012
Published: June 18, 2012
© 2012 American Chemical Society
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high yield (entry 2). Replacing base to KOAc displayed nearly
the same efficiency (entry 3), while other acetates such as
NaOAc (entry 4) and other potassium salts such as K2CO3
(entry 5) displayed lower efficiency. No desired product was
detected by using organic base such as Et3N (entry 6).
Considering price and convenience in handling,13 KOAc was
chosen for further optimization. Reducing the dose of KOAc
from 2.1 to 1.5 equiv gave declined activity (entry 7), while 1.1
equiv of KOAc (which is neutralized completely by 1.1 equiv of
acid in H2NOH·HCl to form HOAc) gave no desired product
(entry 8). Prolonging the reaction to 18 h proved to be optimal
(93% GC yield and 85% isolated yield in 2.0 mmol scale).
Hydroxylamine aqueous solution (50 wt %) was also
employed as N-source for further optimization of reaction
conditions, as we wished to reduce the dose of base. However,
no satisfactory results were obtained in several attempts
(entries 10−12). We speculated that the in situ generated
HOAc favors the condensation of aryl ketones and hydroxyl-
amine, as oxygen atom of the carbonyl group can be partly
protonated by weak acid, thus increasing the electropositivity of
the carbon atom of the carbonyl group to favor nucleophilic
attack of H2NOH. Additionally, increased concentration of
OAc− may favor generation of the active Cp*Rh(OAc)n
species.
Scheme 1. Strategy for Nitrogen-Containing Heterocycle
Synthesis via Directed C−H Activation
alkynes. The reaction proceeds under mild conditions in the
external-oxidant-free fashion and can be expanded to synthesis
of various heterocycle-fused pyridines.
RESULTS AND DISCUSSION
■
As a model reaction, acetophenone and 1,2-diphenylacetylene
were employed as substrates, while a variety of nitrogen sources
(N-sources) and bases were examined to optimize the reaction
conditions (Table 1).
By using the optimized reaction condition, the generality for
the synthesis of isoquinolines was next examined (Table 2).
With acetophenone as ketone substrate, a survey of the scope
of alkynes revealed that both aryl and alkyl-substituted
symmetric internal alkynes reacted well to afford isoquinolines
4aa and 4ab, respectively. Notably, asymmetric alkyne 3c and
3d was also applicable with good yield and high regioselectivity.
Alkyne 3e with a hydroxyl group gave corresponding
isoquinoline 4ae with high regioselectivity but low yield
(44%, ca. 40% acetophenone oxime and 3e were recovered)
under the standard conditions. We speculated that the hydroxyl
group could coordinate to Rh, thus reducing the activity of the
catalyst. Fortunately, a much higher yield (72%) was obtained
by simply increasing the catalyst loading and reaction
temperature. Insertion of diarylacetylenes with electron-
donating group (EDG) OMe (3f) or electron-withdrawing
group (EWG) Cl (3g) as para substituent also proceeded
smoothly. Substrates of ketones with various para substituents
were also examined. Generally, ketones with EDGs (1b, 1c)
had higher reactivity than that those with EWGs (1d−1f). As
the first condensation step of aryl ketones and hydroxylamine is
relatively faster than subsequent steps, it is expectable that the
electronic effects of the two coupling partners are matched with
Li’s isoquinoline synthesis,8d which uses ketone oximes and
alkynes as coupling partners.
Table 1. Optimization of Reaction Conditions for
Isoquinoline Synthesis
a
b
entry
N-source
base (equiv)
time (h)
yield (%)
1
H2NOMe·HCl
H2NOH·HCl
H2NOH·HCl
H2NOH·HCl
H2NOH·HCl
H2NOH·HCl
H2NOH·HCl
H2NOH·HCl
H2NOH·HCl
CsOAc (2.1)
CsOAc (2.1)
KOAc (2.1)
NaOAc (2.1)
K2CO3 (2.1)
Et3N (2.1)
12
12
12
12
12
12
12
12
18
18
18
18
27
92
86
53
79
0
2
3
4
5
6
7
KOAc (1.5)
KOAc (1.1)
KOAc (2.1)
KOAc (0.3)
KOAc (1.0)
CsOAc (0.3)
73
0
8
c
9
93 (85 )
d
10
11
12
aq H2NOH
18
45
64
d
aq H2NOH
d
aq H2NOH
a
Unless otherwise noted, reactions were carried out using 1a (0.50
mmol), 2 (1.1 equiv), and 3a (1.1 equiv) with [Cp*RhCl2]2 (1.0 mol
b
%) and base in 1.0 mL of MeOH at 60 °C. Yields of 4a are based on
c
GC by using n-C28H58 as internal standard. Isolated yields in 2.0
d
We next investigated the scope of R2 group in ketone
substrates 1. By using various alkyl groups as the R2 group, we
found that yield of isoquinolines 4 was declined as increase of
steric hindrance of R2. For ethyl phenyl ketone 1g, the
efficiency was as high as that of acetophenone. However, for the
ketones with isopropyl (1h), cyclohexyl (1i), or cyclopropyl
(1j) as the R2 group, the yield of corresponding isoquinolines 4
were unsatisfactory. This substituent effect was owing to the
inactive isomer of oxime formation in the condensation step.14
As demonstrated by Chiba et al.,8c the isomer of oxime with the
hydroxyl group and the aryl group in the same side cannot
proceed the C−H bond activation process, for the nitrogen
atom can hardly direct Rh to the ortho site. Recent work of
Chiba15a reveals that both of anti- and syn-isomers of oxime can
mmol scale. 50 wt % aqueous solution, containing 1.2 equiv of
H2NOH.
Inspired by Guimond’s isoquinolone synthesis8b using N-
methoxyhydroxamic acids as starting materials, we first choose
N-methoxyhydroxylamine hydrochloride as N-source.
[Cp*RhCl2]2 was used as precursor of catalysis, while an
excess equivalent of CsOAc was added to neutralize hydro-
chloride and provide OAc− to generate Cp*Rh(OAc)n species
as active catalysis. Though the condensation step proceeded
smoothly to form acetophenone N-methoxyoximes, only trace
amount of the desired isoquinoline derivative was obtained
(entry 1). To our delight, simply replacing N-source to
hydroxylamine hydrochloride gave the desired product with
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a
Table 2. Substrate Scope of Isoquinoline Synthesis
Table 3. Substrate Scope of Heterocycle Fused Pyridine
a
Synthesis
a
Unless otherwise noted, reactions were carried out using 1 (2.0
mmol), 3 (1.1 equiv), and H2NOH·HCl (1.1 equiv) with
[Cp*RhCl2]2 (1.0 mol %) and KOAc (2.1 equiv) in 10 mL of
MeOH at 60 °C for 18 h.
carboxaldehydes and alkynes as coupling partners. However,
this approach needs additional steps for substrate synthesis and
stoichiometric external oxidant for annulation. The present
one-pot approach affords a rapid avenue to multisubstituted γ-
carbolines from readily available building blocks. Similar to the
above isoquinoline synthesis, symmetric internal alkynes with
aryl or alkyl groups reacted well to afford desired γ-carbolines
and unsymmetrical alkyne 1c proceeded regioselectiviely to
give 4kc in good yield. The other isomer, though detected in
thin layer chromatography and GC−MS, was too little to be
isolated. The structure of 4kc was unambiguously identified by
HMBC and X-ray analysis (see the Supporting Information).
Notably, the N−H bond of indole, which needs protection in
Jiao’s γ-carbolines system17c and is reactive in some Cp*Rh(III)
catalyzed systems,18 did not hinder the C−H activation process
in our work. For ketones with oxygen- or sulfur-containing
heterocycles, cyclization also proceeded smoothly to afford
furo[2,3-c]pyridine 4la, thieno[2,3-c]pyridine 4ma, and
benzofuro[2,3-c]pyridine 4na.
a
Unless otherwise noted, reactions were carried out using 1 (2.0
mmol), 3 (1.1 equiv), and H2NOH·HCI (1.1 equiv) with
[Cp*RhCl2]2 (1.0 mol %) and KOAc (2.1 equiv) in 10 mL of
b
MeOH at 60 °C for 18 h. 3 (2.0 mmol), 1 (1.2 equiv), H2NOH·HCl
(1.2 equiv), KOAc (2.2 equiv). 80 °C, 2.5 mol % [Cp*RhCl2]2.
(2.0 mmol), 1 (2.0 equiv), H2NOH·HCl (2.0 equiv), KOAc (3.0
equiv).
c
d
3
react well under Cu(OAc)2/[Cp*RhCl2]2 bimetallic catalytic
system15 via iminyl copper and then iminyl rhodium species.
However, in our [Cp*RhCl2]2/KOAc catalytic system, only
when these two groups were in the opposite side, the oxime
group can serve as a directing group for C−H bond activation.
With increase of steric hindrance of R2, the ratio of inactive
oxime isomer increased, thus resulting in declined yields. To
address this issue, we changed the reactant ratio to ensure that
there was enough active isomer of oxime relative to 1 equiv of
alkyne. As expected, yields of 4ha, 4ia, and 4ja were increased
to about twice over that in the standard condition (alkyne was
excess) when 2 equiv of ketones were used. It is worth noting
that no rearrangement products were detected by using 1j as
substrates, while both E and Z isomers of ring-opening
products were obtained in Chiba’s bimetallic catalytic
system.15a The ketone excess condition was also applied
successfully to synthesize isoquinolines 4aa−4ag, when
expensive alkyne substrates 3a−3g were used as ketone
substrates to couple with much cheaper acetophenone.
With a general catalytic system for fused pyridines in hand,
we wonder if this one-pot strategy could be expanded to
pyridine synthesis.19 (E)-4-Phenylbut-3-en-2-one (1o) was
employed as ketone substrate to react with H2NOH·HCl and
alkyne 3a under our standard [Cp*RhCl2]2/KOAc catalytic
system. However, corresponding pyridine 4oa was obtained in
very low yield (<10%). Neither elevating the reaction
temperature to 80 °C nor replacing the base with CsOAc
gave much favor to improve the yield. Fortunately, we found
that the reaction proceed smoothly with an acceptable yield
(71%) by using K2CO3 as the base under 80 °C, with higher
catalyst loading and prolonged reaction time (Scheme 2).
Although the yield was lower than that of Chiba and Li’s
pyridine synthesis19c from the oxime of 1o (86% for 4oa), a
higher step economic procedure was achieved.
We then extended this three-component reaction to various
ketone substrates with heterocycles to afford heterocycle fused
pyridine skeletons (Table 3).16 By utilization of 3-acetyl indole
as substrate, γ-carbolines17 were obtained in high yield.
Recently, Jiao et al.17c reported a Pd(II)-catalyzed γ-carboline
synthesis by using tert-butylimines of N-substituted indole-3-
As discussed above, ketones with bulky R2 groups carried out
the annulation with lower efficiency than that of aryl methyl
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was prepared following a literature procedure.21 Alkynes 1f and 1g
were prepared by reported procedures with slight modification.22
Typical Experimental Procedure for Synthesis of 4. To a 25
mL tube equipped with a magnetic stirrer, 1,2-diphenylacetylene
(392.1 mg, 2.2 mmol), hydroxylamine hydrochloride (152.8 mg, 2.2
mmol), [Cp*RhCl2]2 (12.4 mg, 0.02 mmol), KOAc (412.2 mg, 4.2
mmol), acetophenone (240.4 mg, 2.0 mmol), and MeOH (10 mL)
were added sequentially. The tube was sealed and stirred at 60 °C in
an oil bath for 18 h. After removal of the solvent under reduced
pressure, purification was performed by flash column chromatography
on silica gel with petroleum ether/ethyl acetate (gradient mixture ratio
from 100:0 to 75:25) as eluant to afford isoquinoline 4aa (500.8 mg,
85%).
Scheme 2. One-Pot Synthesis of Pyridine
ketones. We therefore sought routes to derivatize the 1-methyl
isoquinolines to more complex structures. Recently, Wang et
al.20 revealed that 2-methyl quinolines can conduct addition to
N-sulfonyl aldimines and subsequent elimination to form
corresponding trans-alkenylazaarene under catalyst-free con-
ditions. They also revealed that the addition−elimination
processes can carry out in a one-pot procedure. Considering
the similar reactivity of methyl group in 2-position of quinoline
and 1-position of isoquinoline, we suggested the similar
derivatization can take place for 1-methyl isoquinolines. Thus,
we applied this method to some 1-methyl isoquinolines
synthesized above. As expected, isoquinoline substrates 4aa,
4ba, and 4ac all reacted well to obtain corresponding trans-
alkenyl isoquinolines with highly stereoselectivity (Scheme 3).
1-Methyl-3,4-diphenylisoquinoline (4aa).6b White solid: 1H NMR
(300 MHz, CDCl3) δ 8.14−8.11 (1H, m), 7.65−7.62 (1H, m), 7.52−
7.49 (2H, m), 7.39−7.36 (2H, m), 7.31−7.28 (3H, m), 7.21−7.10
(5H, m), 3.04 (3H, s); 13C NMR (75 MHz, CDCl3) δ 157.7, 149.4,
141.0, 137.6, 136.0, 131.4, 130.2, 129.9, 129.1, 128.2, 127.6, 127.1,
126.9, 126.5, 126.2, 126.1, 125.5, 22.8; GC−MS m/z (% rel. inten.)
295 (M+, 53), 294 (100), 252 (19), 146 (14), 139 (10).
1-Methyl-3,4-dipropylisoquinoline (4ab).6b White solid: H NMR
1
(300 MHz, CDCl3) δ 8.03 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 8.6
Hz), 7.63−7.58 (1H, m), 7.47−7.42 (1H, m), 2.99−2.88 (7H, m),
1.86−1.60 (4H, m), 1.10−1.02 (6H, m); 13C NMR (75 MHz, CDCl3)
δ 155.6, 151.7, 135.4, 129.4, 126.2, 126.1, 126.0, 125.2, 123.6, 37.5,
29.8, 24.2, 23.8, 22.4, 14.6, 14.4; GC−MS m/z (% rel. inten.) 227 (M+,
49), 226 (43), 212 (79), 199 (42), 198 (100), 184 (50), 182 (35),
171(61), 157 (14), 128 (23), 115 (17).
Scheme 3. Derivatization of 1-Methyl Isoquinolines
1,4-Dimethyl-3-phenylisoquinoline (4ac).6b White solid: 1H NMR
(600 MHz, CDCl3) δ 8.09 (1H, d, J = 8.2 Hz), 7.98 (1H, d, J = 8.2
Hz), 7.69−7.66 (1H, m), 7.57−7.52 (3H, m), 7.46−7.43 (2H, m),
7.37−7.35 (1H, m), 2.95 (3H, s), 2.56 (3H, s); 13C NMR (150 MHz,
CDCl3) δ 155.9, 150.7, 141.7, 136.2, 129.9, 129.8, 128.1, 127.4, 126.2,
126.2, 126.0, 124.1, 122.1, 22.5, 15.4; GC−MS m/z (% rel. inten.) 233
(M+, 47), 232 (100), 217 (9), 189 (5), 115 (14), 109 (8).
4-Ethyl-1-methyl-3-phenylisoquinoline (4ad).6b White solid: 1H
NMR (300 MHz, CDCl3) δ 8.12 (1H, d, J = 8.2 Hz), 8.04 (1H, d, J =
8.6 Hz), 7.70−7.65 (1H, m), 7.56−7.34 (6H, m), 3.01−2.95 (5H, m),
1.24 (3H, t, J = 7.6 Hz); 13C NMR (75 MHz, CDCl3) δ 155.8, 150.8,
141.9, 135.2, 129.8, 129.2, 128.5, 128.2, 127.4, 126.7, 126.3, 126.2,
124.1, 22.5, 21.7, 15.7; GC−MS m/z (% rel. inten.) 247 (M+, 54), 246
(100), 232 (20), 231 (23), 230 (15), 217 (9), 189 (5), 115 (18).
(1-Methyl-3-phenylisoquinolin-4-yl)methanol (4ae).8c White
Notably, methyl group substituted at 6-position (4ba) or 4-
position (4ac) of the isoquinoline was inactive in this reaction.
The highly regioselectivity was due to the nitrogen-assisted
concerted process as indicated by Wang.20 Also, stronger
acidity of methyl group in the 1-position made contribution to
the regioselectivity.
In summary, we have developed a versatile and straightfor-
ward route to construct multisubstituted isoquinolines and
relative fused pyridine heterocycles by using readily available
ketones and alkynes. The reaction proceeds efficiently via
cascade reaction involving ketone−hydroxylamine condensa-
tion, C−H activation, and intermolecular cyclization in a “one-
pot” and “external-oxidant-free” approach under mild con-
ditions.
1
solid: H NMR (300 MHz, DMSO-d6) δ 8.36 (1H, d, J = 8.3 Hz),
8.23 (1H, d, J = 7.9 Hz), 7.86−7.65 (4H, m), 7.50−7.45 (3H, m), 5.36
(1H, br s), 4.84 (2H, d, J = 3.8 Hz), 2.92 (3H, s); 13C NMR (75 MHz,
DMSO-d6) δ 158.3, 151.2, 141.4, 136.6, 131.1, 130.7, 128.7, 128.6,
127.7, 126.8, 126.8, 126.0, 125.9, 58.6, 23.3; GC−MS m/z (% rel.
inten.) 249 (M+, 91), 248 (100), 230 (20), 220 (31), 172 (16), 143
(10), 115 (27), 102 (10), 77 (12).
3,4-Bis(4-methoxyphenyl)-1-methylisoquinoline (4af).15b Pale
1
yellow solid: H NMR (300 MHz, CDCl3) δ 8.10−8.06 (1H, m),
7.67−7.64 (1H, m), 7.51−7.43 (2H, m), 7.34 (2H, d, J = 8.9 Hz), 7.11
(2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 6.73 (2H, d, J = 8.9 Hz),
3.75 (3H, s), 3.68 (3H, s), 3.01 (3H, s); 13C NMR (75 MHz, CDCl3)
δ 158.5, 158.5, 157.2, 149.0, 136.3, 133.6, 132.3, 131.5, 129.8, 129.7,
128.1, 126.1, 126.0, 125.9, 125.4, 113.7, 113.1, 55.1, 55.0, 22.7; GC−
MS m/z (% rel. inten.) 355 (M+, 81), 354 (100), 311 (19), 268 (12),
170 (9), 156 (10), 124 (11).
EXPERIMENTAL SECTION
■
General Methods. All organic starting materials are analytically
pure and used without further purification. All reactions were carried
out without any particular precautions to extrude moisture or oxygen.
Nuclear magnetic resonance (NMR) spectra were recorded using
CDCl3 or DMSO-d6 as solvent at 298 K. 1H NMR (300 or 600 MHz)
chemical shifts (δ) were referenced to internal standard TMS (for 1H,
δ = 0.00 ppm). 13C NMR (75 or 150 MHz) chemical shifts were
referenced to internal solvent CDCl3 (for 13C, δ = 77.16 ppm) or
DMSO-d6 (for 13C, δ = 40.45 ppm). Gas chromatography (GC)
analyses were performed on a GC instrument (capillary 25 m column).
Mass spectra (MS) were obtained on a low-resolution GC−MS
spectrometer with a PEG-25M column, and HRMS (ESI) experiments
were performed on a high resolution magnetic sector mass
spectrometer. The melting points were uncorrected. [Cp*RhCl2]2
3,4-Bis(4-chlorophenyl)-1-methylisoquinoline (4ag).15b Pale yel-
1
low solid: H NMR (300 MHz, CDCl3) δ 8.18−8.14 (1H, m), 7.58−
7.55 (3H, m), 7.33−7.27 (4H, m), 7.18−7.10 (4H, m), 3.03 (3H, s);
13C NMR (75 MHz, CDCl3) δ 158.3, 148.2, 139.3, 135.9, 135.8, 133.5,
133.3, 132.7, 131.6, 130.3, 128.8, 128.0 (overlapped), 127.0, 126.3,
125.9, 125.7, 22.8; GC−MS m/z (% rel. inten.) 365 (M+, 40), 364
(76), 363 (57), 362 (100), 327 (20), 164 (15), 146 (45), 125 (15).
1,6-Dimethyl-3,4-diphenylisoquinoline (4ba).6b White solid: 1H
NMR (300 MHz, CDCl3) δ 8.00 (1H, d, J = 8.6 Hz), 7.40−7.25 (7H,
m), 7.20−7.08 (5H, m), 3.00 (3H, s), 2.35 (3H, s); 13C NMR (75
MHz, CDCl3) δ 157.3, 149.5, 141.2, 140.1, 137.7, 136.2, 131.4, 130.2,
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128.7, 128.6, 128.1, 127.5, 127.0, 126.8, 125.4, 125.0, 124.5, 22.7, 22.1;
GC−MS m/z (% rel. inten.) 309 (M+, 54), 308 (100), 252 (15), 146
(17), 139 (9).
(3H, s); 13C NMR (75 MHz, CDCl3) δ 151.9, 151.5, 143.9, 140.5,
139.7, 136.2, 130.4, 130.3, 128.9, 127.6 (overlapped), 127.4, 127.1,
126.0, 122.6, 122.3, 120.7, 117.0, 111.0, 23.7; GC−MS m/z (% rel.
inten.) 334 (M+, 58), 333 (100), 318 (8), 291 (8), 167 (20), 166 (14),
159 (11); HRMS (ESI) calcd for C24H19N2 [M + H]+ 335.1543, found
335.1541.
1-Methyl-3,4-dipropyl-5H-pyrido[4,3-b]indole (4kb). White solid:
mp 206−208 °C; 1H NMR (300 MHz, CDCl3) δ 9.23 (1H, br s), 8.08
(1H, d, J = 7.9 Hz), 7.48−7.38 (2H, m), 7.31−7.25 (1H, m), 2.99
(3H, s), 2.93−2.83 (4H, m), 1.85−1.63 (4H, m), 1.02−0.97 (6H, m);
13C NMR (75 MHz, CDCl3) δ 154.3, 150.2, 144.6, 139.7, 125.7, 123.2,
122.2, 120.6, 116.4, 115.2, 111.0, 36.8, 29.5, 24.4, 23.4, 23.3, 14.5
(overlapped); GC−MS m/z (% rel. inten.) 266 (M+, 39), 251 (64),
238 (22), 223 (40), 221 (29), 210 (100), 196 (12), 167 (11), 105
(23); HRMS (ESI) calcd for C18H23N2 [M + H]+ 267.1856, found
267.1863.
1-Methyl-6-methoxy-3,4-diphenylisoquinoline (4ca).6b White
solid: 1H NMR (300 MHz, CDCl3) δ 8.06 (1H, d, J = 9.3 Hz),
7.36−7.27 (5H, m), 7.22−7.12 (6H, m), 6.90 (1H, d, J = 2.7 Hz), 3.68
(s, 3 H), 3.00 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 160.6, 157.0,
150.2, 141.3, 138.1, 138.0, 131.4, 130.3, 128.6, 128.3, 127.6, 127.5,
127.1, 126.9, 121.9, 118.7, 104.5, 55.2, 22.7; GC−MS m/z (% rel.
inten.) 325 (M+, 54), 324 (100), 281 (29), 155 (11), 146 (8), 139
(11).
6-Chloro-1-methyl-3,4-diphenylisoquinoline (4da).6b White solid:
1H NMR (300 MHz, CDCl3) δ 8.04 (1H, d, J = 8.9 Hz), 7.62 (1H, d, J
= 1.7 Hz), 7.44 (1H, dd, J = 8.6, 1.7 Hz), 7.37−7.30 (5H, m), 7.19−
7.15 (5H, m), 3.00 (3H, s); 13C NMR (75 MHz, CDCl3) δ 157.6,
150.6, 140.6, 137.1, 136.9, 136.3, 131.3, 130.2, 128.4 (overlapped),
127.6, 127.4, 127.4, 127.3, 127.2, 125.0, 124.4, 22.7; GC−MS m/z (%
rel. inten.) 331 (M+, 16), 330 (39), 329 (50), 328 (100), 293 (10),
252 (20), 146 (30), 139 (13).
1,4-Dimethyl-3-phenyl-5H-pyrido[4,3-b]indole (4kc). White solid:
1
mp 315−316 °C; H NMR (300 MHz, DMSO-d6) δ 11.73 (1H, s),
8.14 (1H, d, J = 7.9 Hz), 7.66−7.61 (3H, m), 7.52−7.38 (4H, m), 7.30
(1H, t, J = 7.6 Hz), 2.95 (3H, s), 2.54 (3H, s); 13C NMR (150 MHz,
CDCl3) δ 152.5, 150.1, 145.7, 142.0, 141.1, 130.6, 128.6, 128.0, 126.6,
122.8, 122.7, 120.9, 116.6, 112.2, 111.5, 24.2, 15.0; GC−MS m/z (%
rel. inten.) 272 (M+, 51), 271 (100), 255 (8), 135 (16), 128 (10);
HRMS (ESI) calcd for C19H17N2 [M + H]+ 273.1386, found 273.1385.
6-Bromo-1-methyl-3,4-diphenylisoquinoline (4ea).15b White
solid: 1H NMR (300 MHz, CDCl3) δ 7.98 (1H, d, J = 8.8 Hz),
7.80 (1H, d, J = 2.0 Hz), 7.59 (1H, dd, J = 8.8, 2.0 Hz), 7.36−7.29
(5H, m), 7.19−7.14 (5H, m), 3.01 (3H, s). 13C NMR (75 MHz,
CDCl3) δ157.8, 150.6, 140.6, 137.4, 136.8, 131.3, 130.3, 130.0, 128.5,
128.4, 128.3, 127.7, 127.5, 127.3, 127.2, 125.1, 124.6, 22.7; GC−MS
m/z (% rel. inten.) 375 (M+, 47), 374 (100), 373 (52), 372 (96), 293
(25), 292 (25), 252 (21), 146 (46), 139 (22).
7-Methyl-4,5-diphenylfuro[2,3-c]pyridine (4la).6b White solid: H
1
NMR (300 MHz, CDCl3) δ 7.68 (1H, d, J = 2.4), 7.37−7.17 (10H,
m), 6.68 (1H, d, J = 2.4), 2.84 (3H, s); 13C NMR (75 MHz, CDCl3) δ
150.0, 149.7, 147.9, 141.4, 140.6, 137.7, 134.3, 130.4, 130.2, 128.4,
127.8, 127.1, 127.1, 126.8, 106.5, 18.8; GC−MS m/z (% rel. inten.)
285 (M+, 48), 284 (100), 241 (9), 215 (10), 213 (10), 142 (12), 127
(9).
1-Methyl-6-nitro-3,4-diphenylisoquinoline (4fa).6b Yellow solid:
1H NMR (300 MHz, CDCl3) δ 8.56 (1H, d, J = 1.7 Hz), 8.30−8.22
(2H, m), 7.41−7.35 (5H, m), 7.24−7.16 (5H, m), 3.09 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 158.0, 151.5, 148.1, 139.9, 136.0, 135.7,
131.2, 130.3, 130.2, 128.7, 128.0, 127.7, 127.7, 127.6, 127.5, 122.5,
119.8, 22.9; GC−MS m/z (% rel. inten.) 340 (M+, 69), 339 (100), 293
(53), 292 (41), 281 (14), 189 (13), 146 (25), 139 (24).
7-Methyl-4,5-diphenylthieno[2,3-c]pyridine (4ma).6b White solid:
1H NMR (300 MHz, CDCl3) δ 7.58 (1H, dd, J = 5.5, 0.7), 7.37−7.17
(11H, m), 2.90 (3H, s); 13C NMR (75 MHz, CDCl3) δ 151.5, 151.1,
145.8, 140.6, 138.4, 134.3, 131.0, 130.7, 130.4, 128.4 (overlapped),
127.8, 127.2, 127.2, 124.4, 23.8; GC−MS m/z (% rel. inten.) 301 (M+,
54), 300 (100), 285 (4), 258 (16), 150 (11), 149 (9).
1-Ethyl-3,4-diphenylisoquinoline (4ga).15b White solid: H NMR
1
(300 MHz, CDCl3) δ 8.18−8.15 (1H, m), 7.65−7.61 (1H, m), 7.49−
7.39 (4H, m), 7.28−7.11 (8H, m), 3.41 (2H, q, J = 7.6 Hz), 1.51 (3H,
t, J = 7.6 Hz); 13C NMR (75 MHz, CDCl3) δ 162.1, 149.3, 141.2,
137.8, 136.3, 131.4, 130.4, 129.7, 128.9, 128.2, 127.6, 127.1, 126.9,
126.4, 126.4, 125.3, 125.1, 28.8, 13.9; GC−MS m/z (% rel. inten.) 309
(M+, 55), 308 (100), 293 (13), 280 (10), 146 (10), 139 (10).
1-Isopropyl-3,4-diphenylisoquinoline (4ha).15a White solid: 1H
NMR (300 MHz, CDCl3) δ 8.27−8.22 (1H, m), 7.67−7.62 (1H, m),
7.49−7.45 (4H, m), 7.34−7.09 (8H, m), 4.00 (1H, septet, J = 6.5 Hz),
1.53 (6H, d, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ165.0, 148.7,
141.4, 138.2, 136.6, 131.5, 130.7, 129.5, 128.5, 128.4, 127.5, 127.2,
127.0, 126.6, 126.4, 124.9, 124.6, 31.4, 22.4; GC−MS m/z (% rel.
inten.) 323 (M+, 75), 322 (86), 308 (64), 306 (23), 296 (23), 295
(100), 280 (27), 252 (13), 202 (16), 153 (16), 146 (17), 139 (18).
1-Cyclohexyl-3,4-diphenylisoquinoline (4ia). White solid: mp
1-Methyl-3,4-diphenylbenzofuro[2,3-c]pyridine (4na).15b White
solid: 1H NMR (300 MHz, CDCl3) δ 7.60 (1H, d, J = 8.3 Hz),
7.50−7.44 (1H, m), 7.39−7.29 (7H, m), 7.23−7.18 (3H, m), 7.13−
7.09 (2H, m), 2.93 (3H, s); 13C NMR (75 MHz, CDCl3) δ 157.0,
150.6, 150.3, 141.9, 140.4, 137.3, 130.3, 130.3, 129.8, 129.3, 128.7
(overlapped), 128.3, 127.8, 127.1, 123.5, 123.2, 122.9, 112.3, 19.0;
GC−MS m/z (% rel. inten.) 335 (M+, 56), 334 (100), 263 (11), 167
(10), 152 (12).
6-Methyl-2,3,4-triphenylpyridine (4oa).19c White solid: H NMR
1
(300 MHz, CDCl3) δ 7.27−7.14 (9H, m), 7.08−6.97 (5H, m), 6.87−
6.83 (2H, m), 2.68 (3H, s); 13C NMR (75 MHz, CDCl3) δ 158.0,
157.0, 150.0, 141.1, 139.8, 138.0, 131.7, 131.6, 130.0, 129.4, 127.9,
127.7 (overlapped), 127.3, 127.3, 126.5, 123.3, 24.6; GC−MS m/z (%
rel. inten.) 321 (M+, 47), 320 (100), 304 (5), 215 (5), 159 (8), 152
(18), 146 (4), 139 (4).
Typical Experimental Procedure for Synthesis of 5. To a 25
mL tube equipped with a magnetic stirrer, 4aa (295.4 mg, 1.0 mmol),
p-toluenesulfonamide (188.3 mg, 1.1 mmol), benzaldehyde (116.7 mg,
1.1 mmol), and toluene (2 mL) were added sequentially. The tube was
charged with N2, sealed, and stirred at 120 °C in an oil bath for 24 h.
After removal of the solvent under reduced pressure, purification was
performed by flash column chromatography on silica gel with
petroleum as eluant to afford 5a (317.0 mg, 83%).
1
158−160 °C; H NMR (300 MHz, CDCl3) δ 8.26−8.23 (1H, m),
7.65−7.62 (1H, m), 7.50−7.43 (4H, m), 7.35−7.10 (8H, m), 3.67−
3.57 (1H, m), 2.10−1.78 (7H, m), 1.63−1.32 (3H, m); 13C NMR (75
MHz, CDCl3) δ 164.5, 148.8, 141.4, 138.2, 136.6, 131.5, 130.7, 129.4,
128.4 (overlapped), 127.5, 127.2, 126.9, 126.6, 126.3, 124.9, 124.6,
41.9, 32.7, 27.0, 26.4; GC−MS m/z (% rel. inten.) 363 (M+, 45), 362
(44), 334 (11), 309 (28), 308 (100), 296 (17), 295 (76), 280 (10),
152 (12), 146 (11), 139 (8) ; HRMS (ESI) calcd for C27H26N [M +
H]+ 364.2060, found 364.2065.
1-Cyclopropyl-3,4-diphenylisoquinoline (4ja).15a White solid: H
1
NMR (300 MHz, CDCl3) δ 8.43−8.40 (1H, m), 7.65−7.60 (1H, m),
7.52−7.45 (2H, m), 7.40−7.36 (2H, m), 7.32−7.10 (8H, m), 2.82−
2.73 (1H, m), 1.42−1.37 (2H, m), 1.12−1.06 (2H, m); 13C NMR (75
MHz, CDCl3) δ 160.7, 148.8, 141.3, 138.1, 136.2, 131.5, 130.5, 129.7,
128.4, 128.1, 127.4, 127.2, 126.9, 126.4, 126.3 (overlapped), 124.9,
13.7, 9.6; GC−MS m/z (% rel. inten.) 321 (M+, 75), 320 (100), 243
(12), 152 (13), 146 (11), 139 (8).
(E)-3,4-Diphenyl-1-styrylisoquinoline (5a).8c Yellow solid: 1H
NMR (300 MHz, CDCl3) δ 8.42−8.39 (1H, m), 8.17−8.03 (2H,
m), 7.70−7.64 (3H, m), 7.57−7.45 (4H, m), 7.40−7.15 (11H, m); 13C
NMR (75 MHz, CDCl3) δ 153.5, 149.9, 141.2, 137.9, 137.2, 136.9,
136.2, 131.5, 130.6, 129.9, 129.9, 128.8, 128.6, 128.4, 127.6, 127.6,
127.3, 127.2, 126.7, 126.4, 125.5, 124.4, 123.0; GC−MS m/z (% rel.
inten.) 383 (M+, 100), 382 (63), 306 (17), 304 (13), 277 (7), 183
(10), 182 (9), 176 (8).
1-Methyl-3,4-diphenyl-5H-pyrido[4,3-b]indole (4ka). White solid:
1
mp 185−187 °C; H NMR (300 MHz, CDCl3) δ 8.81 (1H, s), 8.12
(E)-6-Methyl-3,4-diphenyl-1-styrylisoquinoline (5b). Yellow solid:
(1H, d, J = 7.6 Hz), 7.40−7.18 (10H, m), 7.12−7.10 (3H, m), 3.07
mp 186−188 °C; 1H NMR (300 MHz, CDCl3) δ 8.33 (1H, d, J = 8.6
5798
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Article
Hz), 8.11 (1H, d, J = 15.5 Hz), 8.05 (1H, d, J = 15.5 Hz), 7.72−7.69
(2H, m), 7.46−7.18 (15H, m), 2.42 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 153.2, 150.1, 141.4, 140.2, 138.1, 137.3, 137.2, 136.0, 131.6,
130.7, 129.5, 129.0, 128.8, 128.5, 128.4, 127.6 (overlapped), 127.3,
127.1, 125.2, 124.3, 124.0, 123.3, 22.3; GC−MS m/z (% rel. inten.)
397 (M+, 100), 396 (52), 382 (24), 320 (13), 277 (8), 190 (9), 189
(8), 183 (10), 176 (7); HRMS (ESI) calcd for C30H24N [M + H]+
398.1903, found 398.1905.
(E)-4-Methyl-3-phenyl-1-styrylisoquinoline (5c). Yellow solid: mp
102−104 °C; 1H NMR (300 MHz, CDCl3) δ 8.31 (1H, d, J = 8.3 Hz),
8.02−7.91 (3H, m), 7.68−7.59 (5H, m), 7.53−7.44 (3H, m), 7.41−
7.30 (3H, m), 7.27−7.22 (1H, m), 2.58 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 151.8, 151.2, 141.7, 137.2, 136.9, 135.4, 130.3, 129.7, 128.7,
128.3, 128.0, 127.7, 127.6, 127.4, 126.4, 125.3, 124.8, 124.2, 123.2,
123.1, 15.9; GC−MS m/z (% rel. inten.) 321 (M+, 100), 320 (74), 244
(25), 152 (14), 146 (10), 139 (8); HRMS (ESI) calcd for C24H20N
[M + H]+ 322.1590, found 322.1592.
M. J. Org. Chem. 2009, 74, 2893. (f) Yu, X.; Wu, J. J. Comb. Chem.
2009, 11, 895. (g) Gao, H.; Zhang, J. Adv. Synth. Catal. 2009, 351, 85.
For intermolecular cyclization examples, see: (h) Roesch, K. R.;
Larock, R. C. J. Org. Chem. 1998, 63, 5306. (i) Roesch, K. R.; Zhang,
H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042. (j) Korivi, R. P.;
Cheng, C.-H. Org. Lett. 2005, 7, 5179.
(5) For reviews, see: (a) Thansandote, P.; Lautens, M. Chem.Eur. J.
2009, 15, 5874. (b) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16,
11212. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624. (d) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F.
Chem. Soc. Rev. 2011, 40, 4740. (e) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651. (f) Colby, D. A.; Tsai, A. S.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2012, 45, 814.
(6) (a) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, J.-B.; Jun, C.-H.
Org. Lett. 2003, 5, 2759. (b) Parthasarathy, K.; Cheng, C.-H. J. Org.
Chem. 2009, 74, 9359.
(7) For Rh(III)-catalyzed isoquinoline syntheses using Cu(OAc)2 as
external oxidants, see: (a) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh,
T.; Miura, M. Chem. Commun. 2009, 5141. (b) Guimond, N.; Fagnou,
K. J. Am. Chem. Soc. 2009, 131, 12050.
(8) For a highlight, see: (a) Patureau, F. W.; Glorius, F. Angew.
Chem., Int. Ed. 2011, 50, 1977. For selected examples, see:
(b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010,
132, 6908. (c) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett. 2010, 12,
5688. (d) Zhang, X.; Chen, D.; Zhao, M.; Zhao, J.; Jia, A.; Li, X. Adv.
Synth. Catal. 2011, 353, 719. (e) Rakshit, S.; Grohmann, C.; Besset, T.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (f) Wang, H.; Glorius, F.
Angew. Chem., Int. Ed. 2012, DOI: 10.1002/anie.201201273.
(9) For a monograph, see: (a) Multicomponent Reactions; Zhu, J.,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all products, HMBC
spectrum and X-ray structural details of 4kc. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ruimao@mail.tsinghua.edu.cn.
■
Notes
́
Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. For
reviews, see: (b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
(c) D’Souza, D. M.; Mueller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(d) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
̈
■
(10) (a) Huang, Q.; Hua, R. Adv. Synth. Catal. 2007, 349, 849.
(b) Qi, C.; Zheng, Q.; Hua, R. Tetrahedron 2009, 65, 1316. (c) Wu, B.;
Hua, R. Tetrahedron Lett. 2010, 51, 6433. (d) Su, J.; Ju, J.; Hua, R.
Curr. Org. Synth. 2012, 9, 273.
(11) Acyl group itself can also serve as a directing group for Rh(III)-
catalyzed C−H activation; see: (a) Patureau, F. W.; Besset, T.; Glorius,
F. Angew. Chem., Int. Ed. 2011, 50, 1064. (b) Muralirajan, K.;
Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50, 4169.
(c) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc.
This project was supported by the National Natural Science
Foundation of China (21032004, 20972084) and the Bilateral
Scientific Cooperation between Tsinghua University & K. U.
Leuven. The authors thank Miss Yuan Chen, from Liaoning
Normal University, for her kind English proofreading.
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iodobenzenes) in MeCN, with reduced dose of catalyst and base (1
mol % PdCl2(PPh3)2, 2 mol % CuI, and 3.0 equiv of DBU).
5800
dx.doi.org/10.1021/jo3010414 | J. Org. Chem. 2012, 77, 5794−5800