A transition metal-free Minisci reaction: Acylation of isoquinolines, quinolines, and quinoxaline

Article abstract of DOI:10.1021/jo500294z

Transition metal-free acylation of isoquinoline, quinoline, and quinoxaline derivatives has been developed employing a cross dehydrogenative coupling (CDC) reaction with aldehydes using substoichiometric amount of TBAB (tetrabutylammonium bromide, 30 mol %) and K₂S₂O ₈ as an oxidant. This intermolecular acylation of electron-deficient heteroarenes provides an easy access and a novel acylation method of heterocyclic compounds. The application of this CDC strategy for acylation strategy has been illustrated in synthesizing isoquinoline-derived natural products.

Full text of DOI:10.1021/jo500294z

Article
pubs.acs.org/joc
A Transition Metal-Free Minisci Reaction: Acylation of Isoquinolines,
Quinolines, and Quinoxaline
Yogesh Siddaraju, Manjunath Lamani, and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
S
* Supporting Information
ABSTRACT: Transition metal-free acylation of isoquinoline,
quinoline, and quinoxaline derivatives has been developed
employing a cross dehydrogenative coupling (CDC) reaction
with aldehydes using substoichiometric amount of TBAB
(tetrabutylammonium bromide, 30 mol %) and K2S2O8 as an
oxidant. This intermolecular acylation of electron-deficient
heteroarenes provides an easy access and a novel acylation
method of heterocyclic compounds. The application of this
CDC strategy for acylation strategy has been illustrated in
synthesizing isoquinoline-derived natural products.
(2a) as model substrates. The solvent screening studies indicated
that the solvents such as dioxane, CH3CN, DMF, toluene, or
DMSO are not suited for the reaction (entries 1−5, Table 1),
whereas DCE is the most suitable solvent, as the reaction of 1a
with 2a in the presence of TBAB (30 mol %) and K2S2O8 (2
equiv) in DCE furnished 3a in 81% yield (entry 6, Table 1).
Under the similar reaction conditions, TBAI (30 mol %) failed to
promote the reaction (entry 7, Table 1). Although the reaction
proceeded in the presence of NBS or NCS, the formation of 3a
was not observed with NIS or molecular iodine (entries
8−11, Table 1). The reaction did not proceed with oxidants
such as aq TBHP, (NH4)2S2O8, oxone, NaBO3,
m-CPBA (entries 11−16, Table 1). Decreasing the amount of
aldehyde, or TBAB, or oxidant led to lower yield of 3a (entries
17−21, Table 1). In the absence of TBAB, the reaction yielded 3a
in 20% yield (entry 22, Table 1), whereas the reaction did not
proceed in the absence of K2S2O8 (entry 23, Table 1). With these
screening studies, the optimal condition was established using
aldehyde (4 equiv), TBAB (30 mol %), and K2S2O8 (2 equiv) in
DCE (entry 6, Table 1).7
Under optimized reaction conditions, using aldehyde (4 equiv),
TBAB (30 mol %), and K2S2O8 (2 equiv) in DCE, a variety of
isoquinolines were acylated with aromatic or aliphatic aldehydes
(Table 2). 4-Phenylisoquinoline (1a) underwent a smooth
coupling reaction with 4-methoxy benzaldehyde (2b),
3,4-dimethoxybenzaldehyde (2c), and 4-(benzyloxy)-
benzaldehyde (2d) to afford the corresponding coupled acylated
products 3b, 3c, 3d in good yields (entries 1−3, Table 2).
Similarly, aliphatic aldehydes such as 3-methylbutanal (2e),
butanal (2f), and hexanal (2g) underwent a smooth reaction with
4-phenylisoquinoline (1a) to furnish the coupled products, 3e,
3f, and 3g in good to moderate yields (entries 4−6, Table 2).
INTRODUCTION
■
Cross dehydrogenative coupling reactions (CDC) for functionaliza-
tion of organic compounds is a rapidly expanding field as it offers
atom economical shorter routes for the synthesis of
a variety of useful natural products.1−3 Metal-free reaction
for functionalization of C−H bonds to access C−C and
C−heteroatom bonds is a fast emerging area.2 The acyl derivatives
of heterocyclic compounds are present in a variety of drugs that are
important in pharmacological studies.1,2a Acylation of electron-
deficient heteroarenes is a challenging task,2a−c whereas acylation of
electron-rich arenes is facile.2d−j Therefore, synthesis of electron-
deficient heteroarenes using atom economical shorter routes is well
sought. The Minisci reaction, which provides a facile route to
generate radical, offers an alternate method of acylation of
heteroarenes.1a,4 Although the Minisci reaction is useful in coupling
nitrogen-containing heterocyclic compounds with aldehydes, it is
associated with a few limitations.5 Recently, Matcha and Antonchick
reported a metal-free CDC (cross- dehydrogenative coupling)
reaction of heterocycles with aldehydes using PhI(OCOCF3)2 and
TMSN3.2a Besides this report, the acylation of electron-deficient
heterocyclic compounds was carried out using FeSO4, in the
presence of H2O2 or TBHP.2b,c Shi and Glorius reported
intramolecular dehydrogenative arylation of 2-aryl benzaldehydes
to obtain fluorenones using quaternary ammonium salts and
oxidants.2j However, this method2j has not been applied to
intermolecular version of acylation of heteroarenes, which would
provide a novel acylation method of heterocyclic compounds. In this
perspective and in continuation of our quest for developing CDC
reactions,6 herein we report a Minisci reaction of coupling aldehydes
with heterocycles such as isoquinolines, quinolines, and quinoxaline
using TBAB and K2S2O8 (Scheme 1).
RESULTS AND DISCUSSION
■
Optimization Studies. Optimization studies (Table 1) were
carried out using 4-phenylisoquinoline (1a) and 4-methylbenzaldehyde
Received: February 7, 2014
Published: March 28, 2014
© 2014 American Chemical Society
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Scheme 1
a
Table 1. Optimization Studies
(2i), and 4-benzyloxybenzaldehyde (2d), the corresponding
CDC products 3j, 3k, 3l, and 3m were obtained in moderate to
poor yields (entries 9−12, Table 2). Similarly, the reaction of
isoquinoline (1b) with 4-bromobenzladehyde (2j) furnished the
coupled product 3n in 40% yield (entry 12, Table 2), whereas
isoquinoline (1b) in a reaction with aliphatic aldehydes such as
butanal (2f) and 3-methylbutanal (2e) furnished the coupled
products 3o and 3p in 52 and 61% yields, respectively (entries
14−15, Table 2). This coupling reaction was found to proceed
well with electron rich and sterically unhindered alde-
hydes such as aliphatic aldehydes. This limitation of obtaining
moderate to poor yields could be attributed to decomposition of
quinoline and isoquinoline under the reaction conditions.7
To expand the scope of this coupling reaction, a variety of
isoquinoline derivatives were coupled with a number of alde-
hydes (Table 3). As can be seen, 4-(4-methoxyphenyl)-
isoquinoline (1c) underwent coupling under optimal reaction
conditions with 4-methylbenzaldehyde (2a), 4-methoxybenzal-
dehyde (2b), 3,4-dimethoxybenzaldehyde (2c), 3,4,5-trimethox-
ybenzaldehyde (2i), and 4-benzyloxybenzaldehyde (2d) to
afford the coupled products 3q, 3r, 3s, 3t, and 3u in good
to moderate yields (entries 1−5, Table 3). Under the optimal
conditions, thiophene-2-carbaldehyde (2k) also underwent a
facile coupling to afford the product 3v in 41% yield (entry 6,
Table 3). To find the generality of this coupling reaction, 4-(4-
methoxyphenyl)isoquinoline (1c) was further subjected to
coupling with aliphatic aldehydes. As can be seen, the coupling
of 3-methylbutanal (2e) proceeded well to furnish 3w in 68%
yield (entry 7, Table 3). However, the reaction of aldehydes such
as butanal (2f), hexanal (2g), and heptanal (2l) with 4-(4-
methoxyphenyl)isoquinoline (1c) furnished the coupled prod-
ucts 3x, 3y, and 3z in moderate yields (entries 8−10, Table 3).
Further, the scope of the strategy has been studied with 5,6,7-
trimethoxyisoquinoline (1d) as it is an integral part of several
bioactive natural products.1b,c,2a Therefore, 5,6,7-trimethoxyiso-
quinoline (1d) was reacted with 4-methyl benzaldehyde (2a)
and 3-methylbutanal (2e) to obtain the coupled products 3aa
and 3ab in moderate yields (46 and 52%, respectively, entries
11−12, Table 3). 4-Bromoisoquinoline (1e) was found to
react well with 3-methylbutanal (2e) to furnish the coupled pro-
duct 3ac in good yield (77%, Table 3, entry 13). Under the
optimum conditions, quinoxaline (1f) found to react with
4-methoxybenzaldehyde (2b) and 4-methylbenzaldehyde (2a)
to furnish the acylated products 4a and 4b in 66 and 44% yield,
respectively (entries 14−15, Table 3).
b
entry
initiator (mol %)
oxidant (equiv)
solvent
yield (%)
1
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAI (30)
NCS (30)
NBS (30)
NIS (30)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
aq TBHP (4)
aq TBHP (4)
NH4S2O8 (2)
Oxone (2)
NaBO3 (2)
m-CPBA (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 ()
dioxane
CH3CN
DMF
toluene
DMSO
DCE
DCE
DCE
DCE
DCE
DCE
H2O
NR
NR
NR
NR
NR
81
2
3
4
5
6
7
NR
63
8
9
70
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NR
NR
NR
NR
NR
NR
NR
I2 (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (20)
TBAB (10)
TBAB (30)
none
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
c
76
d
55
74
58
65
20
NR
K2S2O8 (2)
none
TBAB (30)
a
Reaction conditions: 1a (0.24 mmol), 2a (0.97 mmol), oxidant (0.49 mmol),
initiator (0.073 mmol) in solvent (2.0 mL). Isolated yield. 3 equiv of
2a. 2 equiv of 2a. NR = no reaction, TBAB = tetra-n-butylammonium
b
c
d
bromide, TBAI
N-iodosuccinimide, NBS
N-chlorosuccinimide.
= tetra-n-butylammonium iodide, NIS =
= N-bromosuccinimide, NCS =
Further, it was found that the reaction of isoquinoline (1b) with
4-methylbenzaldehyde (2a) and 4-methoxybenzaldehyde (2b)
resulted in the formation of coupled products 3h and 3i in 55 and
64% yields, respectively (entries 7−8, Table 2). Although
isoquinoline (1b) reacted well with 3,4-dimethoxybenzaldehyde
(2c), 2,3,4-trimethoxybenzaldehyde (2h), 3,4,5-trimethoxybenzaldehyde
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a b
,
Table 2. Substrate Scope
a
b
Reaction conditions: isoquinoline (0.24 mmol), aldehyde (0.97 mmol), K2S2O8 (0.49 mmol), TBAB (0.073 mmol) in DCE (2.0 mL). Isolated yield.
The acylation strategy of electron-deficient heterocyclic
compounds was further evaluated by reaction of 4-phenyl-
isoquinoline (1a) with the secondary and tertiary aldehydes such
as cyclohexyl carbaldehyde (2k) and pivalaldehyde (2l). The
reaction of cyclohexyl carbaldehyde (2k) with 1a under the
optimal conditions furnished the mixture of alkylated (6a) and
acylated (6b) isoquinoline compounds as an inseparable mixture
in a ratio of 23:77 (Scheme 2), whereas the similar reaction of 1a
with pivalaldehyde (2l) resulted in the formation of correspond-
ing alkylated derivative of isoquinoline 7, and the corresponding
acylated product was not observed. These two experiments
suggest that the stability of acyl radical and alkyl radical is crucial
in the formation of prodcuts.8a
The application of this CDC strategy for acylation of
isoquinoline is illustrated in synthesizing isoquinoline-derived
natural products (Scheme 2).1b−d,2a As can be seen, 5,6,7-
trimethoxyisoquinoline (1d) reacted well with 4-methoxyben-
zaldehyde (2b) under optimal reaction conditions to furnish the
corresponding acylated product 3ad in 50% isolated yield. The
compound 3ad (thalimicrinone)1d,2a is a natural alkaloid isolated
from a thalictrum species. Traditionally, thalimicrinone (3ad) is
synthesized using multistep reaction sequence.9 Similarly, 6,7-
dimethoxyisoquinoline (1g) in a CDC reaction with 4-
methoxybenzaldehyde (2b) furnished the coupled product 3ae
in 29%. Compound 3ae can be easily reduced to O,O-dimethyl-
annocherin,1d,2a which is another biologically active isoquinoline
alkaloid (Scheme 3).
acylayion of isoquinole (1b) with 4-methoxybenzaldehyde (2b).
As can be seen from Scheme 4, the scaling-up reaction proceeded
well to form the corresponding acylated product (3i) in 67% yield.
As the coupling reaction of aldehydes was working well with
isoquinoline, we thought that it would be relevant to subject
quinoline to similar reaction conditions. As can be seen in
Scheme 5, quinoline (1h) was subjected to the similar coupling
reaction with 4-methylbenzaldehyde (2a) to find the mixture of
2-acylated as well as 2,4-diacylated products 5a and 5b in 69%
isolated yields in a ratio of 1.2:1 (Scheme 4). Similarly,
4-benzyloxybenzaldehyde (2d) furnished diacylated product 5c
in poor yield (24%). The reaction of quinoline with butanal (2f)
furnished the mixture of 1-(quinolin-2-yl)butan-1-one 5d and
1,1′-(quinoline-2,4-diyl)bis(butan-1-one) 5e in 40% yield in a
ratio of 1.2:1 (Scheme 5).
Mechanistic Considerations. On the basis of the literature
precedence,2d,j,10 we believe that the reaction is proceeding
through a radical mechanism as shown in Scheme 6. Potassium
persulfate (K2S2O8) is known to form the sulfate radical I. Radical
I thus generated then undergoes H-abstraction from the
aldehyde to form the acyl radical (II). Further addition of acyl
radical to the heteroarene provides the corresponding amidyl
radical III. As the α-proton in this amidyl radical is extremely
acidic because of the neighboring carbonyl group, deprotonation
with the sulfate anion will lead to a radical anion (IV), which in turn
transfers a single electron (SET) to the persulfate giving the product
and radical I along with the sulfate anion to sustain the chain.2d,8b,10b
In further demonstration of the utility and applicability of the
acylation method, we performed a scaling-up experiment of
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a b
,
Table 3. Acylation of Isoquinoline Derivatives
a
Reaction conditions: isoquinoline or quinoxaline (0.24 mmol), aldehyde (0.97 mmol), K2S2O8 (0.49 mmol), TBAB (0.073 mmol) in DCE (2.0 mL).
Isolated yield.
b
product. Further study is underway in our laboratory to explore the
further utility and application of this methodology.
CONCLUSION
■
In summary, intermolecular acylation of isoquinolines and
quinolines to synthesize useful heterocyclic molecules under
transition metal-free conditions has been presented. This Minisci
reaction of acylation of electron-deficient aromatic compounds
using a substoichiometric amount of TBAB with K2S2O8 has been
shown to be useful in synthesizing isoquinoline-derived natural
EXPERIMENTAL SECTION
■
Typical Experimental Procedure for Minisci Reaction of
Quinoline, Isoquinoline, and Quinoxaline with Aldehyde. Quino-
line or isoquinoline or quinoxaline (50 mg, 0.24 mmol), aldehyde (0.97 mmol,
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Scheme 2. Reaction of 4-Phenylisoquinoline with the Secondary and Tertiary Aldehydes
Scheme 3. Synthesis of Isoquinoline-Derived Natural Products
Scheme 4. Scaling-Up Experiment
4 equiv), TBAB (0.073, 0.3 equiv), and K2S2O8 (0.49 mmol, 2 equiv) in DCE
(2 mL) were stirred at 110 °C (12−24 h for aromatic aldehydes) and 100 °C
(2−5 h, for aliphatic aldehydes). After the completion of the reaction
(monitored by TLC), the solvent was removed under a vacuum, saturated
bicarbonate solution (10 mL) was added, and solvent was extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified on a
silica gel column using hexane/EtOAc to get the pure product.
a b
,
Scheme 5. Acylation of Quinoline
a
b
Isolated yields. Reaction conditions: quinoline (0.24 mmol), aldehyde (0.97 mmol), K2S2O8 (0.49 mmol), TBAB (0.073 mmol) in DCE (2.0 mL),
100−110 °C, 2−12 h.
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Scheme 6. Tentative Reaction Mechanism
Characterization Data. (4-Phenylisoquinolin-1-yl)(p-tolyl)-
methanone (3a). White soild; Yield 81%; mp 126 °C; Rf
(10% EtOAc/Hexane) 0.3. Prepared as shown in general experimental
procedure (Reaction completion time 12 h at 110 °C): IR (Neat, cm−1)
3031, 2924, 2855, 1971, 1664, 1605, 1407, 1268, 1251; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.55 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.00
(d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.71−7.67 (m, 1H),
7.62−7.51 (m, 1H), 7.56−7.53 (m, 4H), 7.52−7.48 (m, 1H), 7.29 (d,
J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
194.6, 156.1, 144.7, 141.0, 136.6, 135.1, 135.1, 134.2, 130.9, 130.7, 130.1,
129.2, 128.7, 128.2, 128.0, 126.4, 126.2, 125.3, 21.8; HRESI-MS (m/z)
Calculated for C23H17NO (M+ + Na) 346.1208, found (M+ + Na)
346.1209.
(4-Methoxyphenyl)(4-phenylisoquinolin-1-yl)methanone (3b).
White solid; Yield 78%; mp 145 °C; Rf (10% EtOAc/Hexane) 0.3.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 2925, 2853, 1600,
1426, 1259, 1156; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.54 (s, 1H),
8.24 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 7.6 Hz, 3H), 7.69 (t, J = 8.4 Hz, 1H),
7.61 (t, J = 8.0 Hz, 1H), 7.56−7.55 (m, 4H), 7.53−7.51 (m, 1H), 6.97
(d, J = 8.0 Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
193.4, 164.1, 156.4, 141.0, 136.7, 135.1, 134.9, 133.2, 130.7, 130.1, 129.6,
128.7, 128.2, 127.9, 126.5, 126.1, 125.3, 113.8, 55.5; HRESI-MS (m/z)
Calculated for C23H17NO2 (M+ + H) 340.1338, found (M+ + H)
340.1339.
(3,4-Dimethoxyphenyl)(4-phenylisoquinolin-1-yl)methanone
(3c). Pale yellow oily liquid; Yield 70%; Rf (10% EtOAc/Hexane) 0.1.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 2930, 2846, 1654,
1593, 1511, 1420, 1268; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.55 (s,
1H), 8.23 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H),
7.70 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.57−7.56 (m, 4H),
7.53−7.50 (m, 1H), 7.46- 7.43 (dd, J1 = 8.4, J2 = 2.0 Hz, 1H), 6.87 (d,
J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 193.6, 156.4, 154.1, 149.2, 141.0, 136.6, 135.1, 135.0,
130.7, 130.1, 129.7, 128.7, 128.3, 128.0, 127.1, 126.5, 126.2, 125.3, 111.6,
110.0, 56.2, 56.1; HRESI-MS (m/z) Calculated for C24H19NO3 (M+ +
H) 370.1443, found (M+ + H) 370.1443.
(4-(Benzyloxy)phenyl)(4-phenylisoquinolin-1-yl)methanone (3d).
Pale yellow oily liquid; Yield 72%; Rf (10% EtOAc/Hexane) 0.3.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 2926, 1716, 1523,
1
1398, 1248, 1052, 1027; H NMR (400 MHz, CDCl3) δ (ppm) 8.53
(s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.01−7.97 (m, 3H), 7.67 (t, J = 7.2 Hz,
1H), 7.61−7.47 (m, 6H), 7.42−7.24 (m, 5H), 7.03 (d, J = 8.8 Hz, 2H),
5.14 (s, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.4, 163.3, 156.4,
141.0, 136.7, 136.1, 135.1, 135.0, 133.2, 130.7, 130.1, 129.8, 128.7, 128.2,
127.9, 127.4, 126.5, 126.1, 125.3, 114.7, 70.2; HRESI-MS (m/z)
Calculated for C29H21NO2 (M+ + Na) 438.1470, found (M+ + Na)
438.1469.
3-Methyl-1-(4-phenylisoquinolin-1-yl)butan-1-one (3e). Pale yel-
low oily liquid; Yield 78%; Rf (10% EtOAc/Hexane) 0.7. Prepared as
shown in general experimental procedure (Reaction completion time
2 h at 100 °C): IR (Neat, cm−1) 3058, 3033, 2956, 2929, 2870, 1954,
1693, 1567, 1546; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.92−8.90 (m,
1H), 8.52 (s, 1H), 7.94−7.92 (m, 1H), 7.69−7.63 (m, 2H), 7.56−7.49
(m, 5H), 3.24 (d, J = 6.8 Hz, 2H), 2.42−2.32 (m, 1H), 1.05 (d, J =
6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 204.6, 153.1, 140.9,
136.7, 135.3, 130.3, 130.0, 128.6, 128.6, 128.3, 126.8, 125.5, 125.2, 49.2,
25.0, 22.8; HRESI-MS (m/z) Calculated for C20H19NO (M+ + Na)
312.1364, found (M+ + Na) 312.1361.
1-(4-Phenylisoquinolin-1-yl)butan-1-one (3f). Pale yellow oily
liquid; Yield 60%; Rf (5% EtOAc/Hexane) 0.7. Prepared as shown in
general experimental procedure (Reaction completion time 2 h at 100 °C):
IR (Neat, cm−1) 3030, 2959, 2918, 2850, 2872, 2088, 1695, 1540, 1017,
758; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.93−8.91 (m, 1H), 8.52 (s,
1H), 7.94−7.92 (m, 1H), 7.68−7.63 (m, 2H), 7.56−7.49 (m, 5H), 3.34
(t, J = 7.6 Hz, 2H), 1.89−1.80 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 204.8, 152.8, 140.9, 136.7, 136.7,
135.3, 130.3, 130.0, 128.6, 128.6, 128.3, 126.8, 125.5, 125.2, 42.3, 17.7,
13.9; HRESI-MS (m/z) Calculated for C19H17NO (M+ + Na) 298.1208,
found (M+ + Na) 298.1207.
1-(4-Phenylisoquinolin-1-yl)hexan-1-one (3g). Pale yellow oily
liquid; Yield 54%; Rf (5% EtOAc/Hexane) 0.7. Prepared as shown in
general experimental procedure (Reaction completion time 2 h at 100 °C):
IR (Neat, cm−1) 3030, 2956, 2920, 2851, 2089, 1696, 1540, 1216, 1017,
757; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.93−8.90 (m, 1H), 8.52
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(s, 1H), 7.95−7.92 (m, 1H), 7.69−7.64 (m, 2H), 7.56−7.48
(m, 5H), 3.35 (t, J = 7.6 Hz, 2H), 1.85−1.77 (quintet, 2H), 1.47−
1.35 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 204.9, 152.9, 141.0, 136.7, 136.7, 135.3, 130.3, 130.0, 128.6,
128.6, 128.3, 126.8, 125.5, 125.2, 40.4, 31.5, 24.0, 22.6, 14.0; HRESI-MS
(m/z) Calculated for C21H21NO (M+ + Na) 326.1521, found (M+ + Na)
326.1520.
(d, J = 5.6 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.94−7.87 (m, 3H), 7.76 (d,
J = 5.2 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H),
7.41−7.33 (m, 5H), 7.0 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 193.3, 163.3, 157.0, 141.1, 136.6, 136.1,
133.2, 130.7, 129.7, 128.7, 128.2, 128.2, 127.4, 127.0, 126.3, 122.3, 114.7,
70.2; HRESI-MS (m/z) Calculated for C23H17NO2 (M+ + Na)
362.1157, found (M+ + Na) 362.1151.
Isoquinolin-1-yl(p-tolyl)methanone (3h).2a Pale yellow oily liquid;
Yield 55%; Rf (10% EtOAc/Hexane) 0.5. Prepared as shown in general
experimental procedure (Reaction completion time 12 h at 110 °C): IR
(Neat, cm−1) 3903, 3054, 2918, 2850, 1661, 1604, 1583, 1249; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.58 (d, J = 5.6 Hz, 1H), 8.18 (d, J = 8.8 Hz,
1H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.78 (d, J =
5.6 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.26 (d, J =
8.0 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.5,
156.8, 144.7, 141.2, 136.6, 134.1, 130.8, 130.6, 129.2, 128.2, 127.0, 126.3,
126.2, 122.3, 21.8; HRESI-MS (m/z) Calculated for C17H13NO (M+ +
Na) 270.0895, found (M+ + Na) 270.0895.
(4-Bromophenyl)(isoquinolin-1-yl)methanone (3n).13 White solid;
Yield 40%; mp 88−90 °C (reported 95−98 °C); Rf (10% EtOAc/Hexane)
0.3. Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 3053, 2959, 2931,
2102, 1735, 1653, 1437, 1265; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.59 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.0 Hz,
1H), 7.84−7.81 (m, 3H), 7.75 (t, J = 7.6 Hz, 1H), 7.66−7.60 (m, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 193.5, 155.5, 141.1, 136.8, 135.4,
132.2, 131.7, 130.8, 129.0, 128.5, 127.1, 126.4, 126.0, 123.0; HRESI-MS
(m/z) Calculated for C16H10NOBr(M+ + Na) 333.9843, found (M+ +
Na) 333.9844.
Isoquinolin-1-yl(4-methoxyphenyl)methanone (3i).2a,11 Pale yel-
low oily liquid; Yield 64%; Rf (20% EtOAc/Hexane) 0.4. Prepared as
shown in general experimental procedure (Reaction completion time
12 h at 110 °C): IR (Neat, cm−1) 3055, 2931, 2840, 1663, 1597, 1251,
1152; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.59 (d, J = 5.6 Hz, 1H),
8.17 (d, J = 8.4 Hz, 1H), 7.96−7.89 (m, 3H), 7.78 (d, J = 5.6 Hz, 1H),
7.75−7.70 (m, 1H), 7.61−7.57 (m, 1H), 6.94 (d, J = 8.8 Hz, 2H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.4, 164.1, 157.1,
141.2, 136.6, 133.1, 130.6, 129.5, 128.1, 127.0, 126.3, 126.3, 122.2, 113.8,
55.5; HRESI-MS (m/z) Calculated for C17H13NO2 (M+ + Na)
286.0844, found (M+ + Na) 286.0843.
1-(Isoquinolin-1-yl)butan-1-one (3o).14 Pale yellow oily liquid;
Yield 52%; Rf (10% EtOAc/Hexane) 0.7. Prepared as shown in general
experimental procedure (Reaction completion time 2 h at 100 °C): IR
(Neat, cm−1) 2960, 2931, 2874, 1734, 1435, 1261, 1164, 1018; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.83 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 5.6 Hz,
1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.72−7.64 (m,
2H), 3.30 (t, J = 7.6 Hz, 2H), 1.86−1.77 (m, 2H), 1.05 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 204.80, 153.54, 140.98,
136.95, 130.26, 128.86, 126.91, 126.66, 125.65, 124.14, 42.22, 17.58,
13.84; HRESI-MS (m/z) Calculated for C13H13NO(M+ + H) 200.1075,
found (M+ + H) 200.1074.
(3,4-Dimethoxyphenyl)(isoquinolin-1-yl)methanone (3j).2a,12 Yel-
low solid; Yield 40%; mp 140−142 °C (reported 145−146); Rf (30%
EtOAc/Hexane) 0.2. Prepared as shown in general experimental
procedure (Reaction completion time 12 h at 110 °C): IR (Neat, cm−1)
3056, 3007, 2935, 2839, 1660, 1583, 1513, 1463, 1420, 1263; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.59 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 8.4 Hz,
1H), 7.91 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.75−7.71
(m, 2H), 7.604 (t, J = 7.6 Hz, 1H), 7.37−7.35 (dd, J1 = 8.40, J2 = 1.6 Hz,
1H), 6.83 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 193.4, 156.9, 153.9, 149.1, 141.1, 136.5,
130.6, 129.5, 128.0, 127.0, 126.9, 126.2, 126.1, 122.2, 111.4, 109.9, 56.0,
55.9; HRESI-MS (m/z) Calculated for C18H15NO3 (M+ + Na)
316.0950, found (M+ + Na) 316.0952.
1-(Isoquinolin-1-yl)-3-methylbutan-1-one (3p). Pale yellow oily
liquid; Yield 61%; Rf (10% EtOAc/Hexane) 0.7. Prepared as shown
in general experimental procedure (Reaction completion time 2 h at
100 °C): IR (Neat, cm−1) 3055, 2957, 2928, 2871, 1697, 1581, 1456,
1363,1288; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.82 (d, J = 8.0 Hz,
1H), 8.56 (d, J = 5.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.78 (d, J =
5.6 Hz, 1H), 7.72−7.64 (m, 2H), 3.20 (d, J = 6.8 Hz, 2H), 2.38−2.28 (m,
1H), 1.03 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
204.63, 153.83, 140.99, 136.98, 130.28, 128.87, 126.96, 126.63, 125.64,
124.10, 49.12, 24.96, 22.75; HRESI-MS (m/z) Calculated for
C14H15NO(M+ + Na) 236.1051, found (M+ + Na) 236.1047.
(4-(4-Methoxyphenyl)isoquinolin-1-yl)(p-tolyl)methanone (3q).
Pale yellow solid; Yield 67%; mp 92−94 °C; Rf (10% EtOAc/Hexane)
0.3. Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 2924, 2836, 1655,
1605, 1516, 1268, 1246, 1178; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.53 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.90 (d,
J = 8.0 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.48 (d,
J = 8.4 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 3.90 (s,
3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.6, 159.7,
155.7, 144.7, 141.0, 135.2, 134.9, 134.2, 131.3, 130.9, 130.6, 129.2, 128.8,
127.9, 126.4, 126.2, 125.4, 114.2, 55.4, 21.8; HRESI-MS (m/z)
Calculated for C24H19NO2 (M+ + Na) 376.1313, found (M+ + Na)
376.1317.
Isoquinolin-1-yl(2,3,4-trimethoxyphenyl)methanone (3k).2a
Brown viscous liquid; Yield 32%; Rf (30% EtOAc/Hexane) 0.2.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 2956, 2928, 2874,
1736, 1595, 1435, 1251; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.50 (d,
J = 5.6 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H),
7.75−7.71 (m, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H),
6.81 (d, J = 8.8 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 3.28 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 194.8, 158.9, 158.3, 154.3, 141.7,
141.0, 136.6, 130.4, 128.0, 126.9, 126.6, 126.3, 125.7, 125.4, 122.0, 107.2,
60.8, 60.6, 56.2; HRESI-MS (m/z) Calculated for C19H17NO4 (M+ +
Na) 346.1055, found (M+ + Na) 346.1057.
(4-Methoxyphenyl)(4-(4-methoxyphenyl)isoquinolin-1-yl)-
methanone (3r). Yellow solid; Yield 68%; mp 118−120 °C; Rf (10%
EtOAc/Hexane) 0.2. Prepared as shown in general experimental
procedure (Reaction completion time 12 h at 110 °C): IR (Neat, cm−1)
2931, 1716, 2553, 1716, 1522, 1418, 1248, 1054; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.52 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.99−8.02 (m,
3H), 7.67 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 8.8 Hz,
2H), 7.09 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.5, 164.1, 159.7,
156.0, 141.0, 135.2, 134.7, 133.2, 131.3, 130.6, 129.7, 128.9, 127.8, 126.5,
126.2, 125.4, 114.2, 113.8, 55.5, 55.4; HRESI-MS (m/z) Calculated for
C24H19NO3 (M+ + Na) 392.1263, found (M+ + Na) 392.1263.
(3,4-Dimethoxyphenyl)(4-(4-methoxyphenyl)isoquinolin-1-yl)-
methanone (3s). Yellow solid; Yield 59%; mp 104−107 °C; Rf (20%
EtOAc/Hexane) 0.2. Prepared as shown in general experimental
procedure (Reaction completion time 12 h at 110 °C): IR (Neat, cm−1)
3078, 2930, 2838, 1659, 1592, 1515, 1463, 1421, 1269, 1247; 1H NMR
Isoquinolin-1-yl(3,4,5-trimethoxyphenyl)methanone (3l).2a White
solid; Yield 41%; mp 115−117 °C; Rf (30% EtOAc/Hexane) 0.2.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 2926, 2856, 1637,
1460, 1312, 1226; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.60 (d, J =
5.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.81 (d,
J = 5.6 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.23 (s,
2H), 3.83 (s, 3H), 3.93 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
193.5, 156.4, 152.9, 143.3, 141.0, 136.7, 131.6, 130.7, 128.3, 127.1, 126.4,
126.1, 122.6, 108.3, 60.9, 56.2; HRESI-MS (m/z) Calculated for
C19H17NO4 (M+ + Na) 346.1055, found (M+ + Na) 346.1055.
(4-(Benzyloxy)phenyl)(isoquinolin-1-yl)methanone (3m).2a White
solid; Yield 41%; mp 124−127 °C; Rf (20% EtOAc/Hexane) 0.7.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 3049, 2924, 2854,
1
1645, 1602, 1281, 1259; H NMR (400 MHz, CDCl3) δ (ppm) 8.57
3862
dx.doi.org/10.1021/jo500294z | J. Org. Chem. 2014, 79, 3856−3865

The Journal of Organic Chemistry
Article
(400 MHz, CDCl3) δ (ppm) 8.53 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.03
(d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.6Hz,
1H), 7.49 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz,
2H), 6.86 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 193.6, 159.7, 155.9, 154.0, 149.2,
140.9, 135.2, 134.7, 131.3, 130.6, 129.7, 128.8, 127.9, 127.1, 126.4, 126.2,
125.4, 114.2, 111.6, 109.9, 56.1, 56.1, 55.4; HRESI-MS (m/z)
Calculated for C25H21NO4 (M+ + Na) 422.1368, found (M+ + Na)
422.1365.
HRESI-MS (m/z) Calculated for C20H19NO2 (M+ + Na) 328.1313,
found (M+ + Na) 328.1313.
1-(4-(4-Methoxyphenyl)isoquinolin-1-yl)hexan-1-one (3y). Pale
yellow oily liquid; Yield 46%; Rf (5% EtOAc/Hexane) 0.4. Prepared
as shown in general experimental procedure (Reaction completion time
2 h at 100 °C): IR (Neat, cm−1) 2955, 2929, 2852, 1683, 1696, 1609,
1516, 1248, 1017; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.93−8.90 (m,
1H), 8.504 (s, 1H), 7.98- 7.95 (m, 1H), 7.68−7.65 (m, 2H), 7.44 (d,
J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 3.910 (s, 3H), 3.346 (t, J = 7.2
Hz, 2H), 1.84−1.77 (m, 2H), 1.44−1.37 (m, 4H), 0.92 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 204.9, 159.8, 152.5, 141.0,
136.5, 135.4, 131.2, 130.2, 128.9, 128.5, 126.8, 125.6, 125.3, 114.2, 55.4,
40.3, 31.5, 23.9, 22.5, 14.0; HRESI-MS (m/z) Calculated for
C22H23NO2 (M+ + Na) 356.1626, found (M+ + Na) 356.1625.
1-(4-(4-Methoxyphenyl)isoquinolin-1-yl)heptan-1-one (3z). Pale
yellow oily liquid; Yield 42%; Rf (5% EtOAc/Hexane) 0.4. Prepared as
shown in general experimental procedure (Reaction completion time
2 h at 100 °C): IR (Neat, cm−1)2955, 2928, 2853, 2065, 1668, 1609,
1496, 1247, 1177; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.93−8.90 (m,
1H), 8.50 (s, 1H), 7.98−7.95 (m, 1H), 7.67−7.65 (m, 2H), 7.44 (d,
J = 8.4 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.34 (t, J = 7.6 Hz,
2H), 1.83−1.76 (m, 2H), 1.46−1.41 (m, 2H), 1.36−1.33 (m, 4H), 0.89
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 204.9, 159.8,
152.5, 141.0, 136.5, 135.4, 131.2, 130.2, 128.9, 128.5, 126.8, 125.6, 125.3,
114.2, 55.4, 40.4, 31.7, 29.0, 24.2, 22.5, 14.0; HRESI-MS (m/z)
Calculated for C23H25NO2 (M+ + H) 348.1964, found (M+ + H)
348.1966.
(4-(4-Methoxyphenyl)isoquinolin-1-yl)(3,4,5-trimethoxyphenyl)-
methanone (3t). Pale yellow solid; Yield 51%; mp 130−132 °C; Rf
(20% EtOAc/Hexane) 0.2. Prepared as shown in general experimental
procedure (Reaction completion time 12 h at 110 °C): IR (Neat, cm−1)
2935, 2836, 1663, 1579, 1498, 1413, 1323, 1229, 1127; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.54 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.05
(d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.50
(d, J = 8.4 Hz, 2H), 7.29 (s, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.94 (s, 3H),
3.92 (s, 3H), 3.86 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.6,
159.8, 155.2, 153.0, 143.3, 140.8, 135.3, 135.1, 131.8, 131.3, 130.7, 128.7,
128.0, 126.4, 125.5, 114.2, 108.5, 60.9, 56.3, 55.4; HRESI-MS (m/z)
Calculated for C26H23NO5 (M+ + Na) 452.1474, found (M+ + Na)
452.1478.
(4-(Benzyloxy)phenyl)(4-(4-methoxyphenyl)isoquinolin-1-yl)-
methanone (3u). Pale yellow solid; Yield 55%; mp 108−110 °C; Rf
(20% EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction completion time 12 h at 110 °C): IR (Neat, cm−1)
3403, 3035, 2927, 1654, 1597, 1247, 1171, 1152; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.51 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.0−7.98 (m,
3H), 7.68 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.4 Hz,
2H), 7.42−7.34 (m, 4H), 7.33−7.31 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H),
7.03(d, J = 8.8 Hz, 2H), 5.14 (s, 2H), 3.90 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 193.5, 163.3, 159.7, 155.9, 141.0, 136.1, 135.2, 134.7, 133.2,
131.3, 130.6,129.8, 128.9, 128.7, 128.2, 127.9, 127.4, 126.5, 126.2, 125.4,
70.2, 55.4; HRESI-MS (m/z) Calculated for C30H23NO3 (M+ + Na)
468.1576, found (M + Na) 468.1578.
(4-(4-Methoxyphenyl)isoquinolin-1-yl)(thiophen-2-yl)methanone
(3v). Pale yellow oily liquid; Yield 41%; Rf (10% EtOAc/Hexane) 0.3.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 2927,2852, 1638,
1609, 1508, 1410, 1351, 1247; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.63 (d, J = 8.4 Hz, 1H), 8.56 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.96 (d,
J = 3.6 Hz, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.72−7.64 (m, 2H), 7.48 (d, J =
8.8 Hz, 2H), 7.17 (t, J = 4.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.91 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 186.1, 159.8, 153.5, 142.7,
140.7, 136.6, 136.0, 135.9, 135.4, 131.3, 130.6, 128.7, 128.3, 128.1, 126.6,
126.2, 125.4, 114.2, 55.4; HRESI-MS (m/z) Calculated for C21H15NO2S
(M+ + Na) 368.0721, found (M+ + Na) 368.0720.
p-Tolyl(5,6,7-trimethoxyisoquinolin-1-yl)methanone (3aa). Pale
yellow solid; Yield 46%; mp 102−105 °C; Rf (20% EtOAc/Hexane) 0.5.
Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (KBr, cm−1) 2942, 2851, 2837,
1
1654, 1607, 1489, 1406, 1275, 1124; H NMR (400 MHz, CDCl3)
δ (ppm) 8.48 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.85 (d, J =
8.0 Hz, 2H), 7.40 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 4.07 (s, 3H), 4.02 (s,
3H), 3.93 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
194.9, 154.6, 153.7, 146.7, 144.5, 144.2, 139.6, 134.4, 130.9, 129.2, 129.1,
123.8, 116.7, 100.3, 61.6, 61.2, 56.0, 21.7; HRESI-MS (m/z) Calculated
for C20H19NO4 (M+ + Na) 360.1212, found (M+ + H) 360.1212.
3-Methyl-1-(5,6,7-trimethoxyisoquinolin-1-yl)butan-1-one (3ab).
Yellow solid; Yield 52%; mp 65 °C; Rf (5% EtOAc/Hexane) 0.3.
Prepared as shown in general experimental procedure (Reaction
completion time 4h at 100 °C): IR (Neat, cm−1) 2953, 2918, 2850,
2121, 1687, 1608, 1579, 1473, 1427, 1403; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.47 (d, J = 5.6 Hz, 1H), 8.23 (s, 1H), 8.03 (d, J = 5.6 Hz, 1H),
4.04- 4.02 (m, 9H), 3.22 (d, J = 6.8 Hz, 2H), 2.38−2.28 (m, 1H), 1.03 (d,
J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 205.2, 155.3,
150.4, 146.4, 143.8, 139.6, 129.7, 123.3, 118.4, 100.9, 61.6, 61.1, 56.1,
48.9, 25.0, 22.8; HRESI-MS (m/z) Calculated for C17H21NO4 (M+ + H)
304.1549, found (M+ + H) 304.1549.
1-(4-Bromoisoquinolin-1-yl)-3-methylbutan-1-one (3ac). Pale yel-
low oily liquid; Yield 77%; Rf (5% EtOAc/Hexane) 0.7. Prepared as
shown in general experimental procedure (Reaction completion time
2 h at 100 °C): IR (Neat, cm−1) 2955, 2926, 2870, 1695, 1652, 1558,
1488, 1398; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.83 (d, J = 8.4 Hz,
1H), 8.74 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.71
(t, J = 7.6 Hz, 1H), 3.16 (d, J = 7.2 Hz, 2H), 2.35−2.24 (m, 1H), 1.01 (d,
J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 204.0, 152.8,
142.9, 135.6, 131.5, 129.8, 127.1, 126.8, 126.2, 123.4, 49.1, 25.0, 22.7;
HRESI-MS (m/z) Calculated for C14H14BrNO (M+ + Na) 314.0156,
found (M+ + Na) 314.0158.
1-(4-(4-Methoxyphenyl)isoquinolin-1-yl)-3-methylbutan-1-one
(3w). Pale yellow oily liquid; Yield 68%; Rf (5% EtOAc/Hexane) 0.7.
Prepared as shown in general experimental procedure (Reaction
completion time 2 h at 100 °C): IR (Neat, cm−1) 2956, 2919, 2851,
1
1605, 1262, 1017; H NMR (400 MHz, CDCl3) δ (ppm) 8.92−8.90
(m, 1H), 8.50 (s, 1H), 7.98−7.96 (m, 1H), 7.67−7.65 (m, 2H), 7.44 (d,
J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 3.906 (s, 3H), 3.24 (d, J = 6.8
Hz, 2H), 2.42−2.31 (m, 1H), 1.05 (d, J = 6.8 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ (ppm) 204.6, 159.8, 152.7, 141.0, 136.4, 135.4, 131.2,
130.2, 128.9, 128.5, 126.8, 125.6, 125.3, 114.2, 55.4, 49.1, 25.1, 22.8;
HRESI-MS (m/z) Calculated for C21H21NO2 (M+ + Na) 342.1470,
found (M+ + Na) 342.1470.
1-(4-(4-Methoxyphenyl)isoquinolin-1-yl)butan-1-one (3x). Pale
yellow oily liquid; Yield 38%; Rf (5% EtOAc/Hexane) 0.7. Prepared
as shown in general experimental procedure (Reaction completion time
2 h at 100 °C): IR (Neat, cm−1) 2960, 2920, 2851, 1683, 1608, 1516,
1248, 1018; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.93−8.91 (m, 1H),
8.50 (s, 1H), 7.98−7.95 (m, 1H), 7.67−7.65 (m, 2H), 7.44 (d, J = 8.4
Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 3.33 (t, J = 7.2 Hz, 2H),
1.88−1.79 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 204.8, 159.8, 152.4, 141.0, 136.5, 135.4, 131.2,
130.2, 128.9, 128.6, 126.8, 125.6, 125.3, 114.2, 55.4, 42.3, 17.7, 13.9;
(4-Methoxyphenyl)(5,6,7-trimethoxyisoquinolin-1-yl)methanone
(3ad).2a,9 White solid; Yield 50%; mp 142−145 °C (reported 146−148 °C)
(lit.2a,8 mp 146−148); Rf (50% EtOAc/Hexane) 0.75. Prepared as
shown in general experimental procedure (Reaction completion time
12 h at 110 °C): IR (Neat, cm−1) 2944, 2838, 1651, 1601, 1585, 1478,
1280, 1255; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.47 (d, J = 6.0 Hz,
1H), 7.99−7.94 (m, 3H), 7.36 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 4.07
(s, 3H), 4.02 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 193.8, 164.0, 154.5, 154.0, 146.7, 144.2, 139.5, 133.2,
129.7, 129.1, 123.7, 116.5, 113.7, 100.3, 61.6, 61.2, 56.1, 55.5; HRESI-MS
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(m/z) Calculated for C20H19NO5 (M+ + H) 354.1341, found (M+ + H)
354.1341.
114.5, 70.3, 70.2; HRESI-MS (m/z) Calculated for C37H27NO4 (M+ +
Na) 572.1838, found (M+ + Na) 572.1836.
(6,7-Dimethoxyisoquinolin-1-yl)(4-methoxyphenyl)methanone
(3ae).2a,9,15 Yellow solid; Yield 29%; mp 145−148 °C (lit.2a,8 mp
150−152); Rf (50% EtOAc/Hexane) 0.4. Prepared as shown in general
experimental procedure (Reaction completion time 12 h at 110 °C): IR
(Neat, cm−1) 2940, 2837, 1648, 1607, 1509, 1442, 1338, 1264; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.46 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 8.8 Hz,
2H), 7.64 (d, J = 5.6 Hz, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 6.95 (d, J =
8.8 Hz, 2H), 4.0 (s, 3H), 3.95 (s, 3H), 3.87 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 193.9, 163.9, 153.7, 153.2, 151.0, 140.0,
134.0, 133.3, 129.8, 122.8, 121.2, 113.7, 104.8, 104.1, 56.1, 56.0, 55.5;
HRESI-MS (m/z) Calculated for C19H17NO4 (M+ + H) 324.1236,
found (M+ + H) 324.1235.
1-(Quinolin-2-yl)butan-1-one (5d). Pale yellow oily liquid; Yield
22%; Rf (5% EtOAc/Hexane) 0.3. Prepared as shown in general
experimental procedure (Reaction completion time 2 h at 100 °C): IR
(Neat, cm−1) 3063, 2962, 2933, 2874, 1697, 1594, 1505, 1458, 1374; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.25 (d, J = 8.4 Hz, 1H), 8.19 (d, J =
8.4 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79−7.75
(m, 1H), 7.637 (t, J = 7.2 Hz, 1H), 3.39−3.36 (t, J = 7.6 Hz, 2H),
1.87−1.78 (sex, 2H), 1.07−1.04 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 202.6, 153.2, 147.2, 136.8, 130.5, 129.9, 129.5,
128.4, 127.6, 118.1, 39.4, 17.6, 13.9; HRESI-MS (m/z) Calculated for
C13H13NO (M+ + Na) 222.0895, found (M+ + Na) 222.0899.
1,1′-(Quinoline-2,4-diyl)bis(butan-1-one) (5e). Pale yellow oily
liquid; Yield 18%; Rf (2% EtOAc/Hexane) 0.2. Prepared as shown
in general experimental procedure (Reaction completion time 2 h at
100 °C): IR (Neat, cm−1) 3069, 2962, 2933, 2875, 1697, 1654, 1506,
1458, 1361; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.38 (d, J = 8.4 Hz,
1H), 8.29 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.83−7.80 (m, 1H),
7.73−7.69 (m, 1H), 3.387 (t, J = 7.2 Hz, 2H), 3.069 (t, J = 7.2 Hz, 2H),
1.89−1.77 (m, 4H), 1.08−1.02 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 204.0, 202.1, 152.5, 148.2, 144.2, 131.0, 130.2, 130.0, 125.4,
125.2, 116.2, 44.2, 39.3, 17.6, 17.5, 13.9, 13.7; HRESI-MS (m/z)
(4-Methoxyphenyl)(quinoxalin-2-yl)methanone (4a).16 Yellow
solid; Yield 66%; mp 112−114 °C (reported 112−114 °C) ; Rf (20%
EtOAc/Hexane) 0.3. Prepared as shown in general experimental
procedure(Reaction completion time 8 h at 110 °C): IR (KBR, cm−1)
3448, 3055, 3007, 2937, 2842, 1642, 1598, 1510, 1466, 1343, 1329; 1H
NMR (400 MHz, CDCl3) δ (ppm) 9.46 (s, 1H), 8.29 (d, J = 8.8 Hz,
2H), 8.21 (d, J = 7.9 Hz, 2H), 7.94−7.77 (m, 2H), 7.02 (d, J = 8.8 Hz,
2H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 190.56,
164.10, 149.23, 145.39, 142.95, 140.29, 133.73, 131.75, 130.70, 130.29,
129.33, 128.28, 113.72, 55.53; HRESI-MS (m/z) Calculated for
C16H12N2O2Na (M+ + Na) 287.0796, found (M+ + Na) 287.0796.
Quinoxalin-2-yl(p-tolyl)methanone (4b).2a,16 Yellow solid;
Yield − 44%; mp 100−102 °C (reported 100−102 °C); Rf (10%
EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction completion time 8 h at 110 °C): IR (KBR, cm−1)
3435, 2925, 2852, 1654, 1604, 1323, 1307, 1229; 1H NMR (400 MHz,
CDCl3) δ (ppm) 9.47 (s, 1H), 8.20 (d, J = 8.2 Hz, 2H), 8.15 (d, J =
7.9 Hz, 2H), 7.94−7.78 (m, 2H), 7.34 (d, J = 7.8 Hz, 2H), 2.47 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 192.0, 148.9, 145.3, 144.8, 143.1,
Calculated for C17H19NO2 (M+ + Na) 292.1313, found (M+
Na)292.1313.
+
Reaction of 4-Phenylisoquinoline (1a) with Cyclohexylcarbox-
aladehyde (2l). 4-Phenyl isoquinoline (1a, 50 mg, 0.24 mmol),
cyclohexylcarboxaladehyde (2l, 0.97 mmol, 4 equiv), TBAB (0.073,
0.3 equiv), and K2S2O8 (0.49 mmol, 2 equiv) in DCE (2 mL) were
stirred at 100 °C (2 h). After the completion of the reaction (monitored
by TLC), the solvent was removed under a vacuum, saturated
bicarbonate solution (10 mL) was added, and the solvent was extracted
with EtOAc (3 × 10 mL). The combined organic layer was dried over
Na2SO4 and concentrated under reduced pressure to get the crude
product, which was purified on a silica gel column using hexane/EtOAc
to furnish an inseparable mixure (68 mg) of 1-cyclohexyl-4-phenyl-
isoquinoline (6a) and cyclohexyl(4-phenylisoquinolin-1-yl)methanone
6b. This mixture was subjected to GC−MS analysis (see Supporting
Information).
Reaction of 4-Phenylisoquinoline (1a) with Pivaladehyde (2l).
4-Phenyl isoquinoline (1a, 50 mg, 0.24 mmol), pivaladehyde (2k,
0.97 mmol, 4 equiv), TBAB (0.073, 0.3 equiv), and K2S2O8
(0.49 mmol, 2 equiv) in DCE (2 mL) were stirred at 100 °C (2 h).
After the completion of the reaction (monitored by TLC), the solvent
was removed under a vacuum, saturated bicarbonate solution (10 mL)
was added, and the solvent was extracted with EtOAc (3 × 10 mL). The
combined organic layer was dried over anhy. Na2SO4 and concentrated
under reduced pressure. The crude product was purified on a silica gel
column using hexane/EtOAc to get the pure 1-(tert-butyl)-4-
phenylisoquinoline(7a).
140.4, 132.9, 131.9, 131.4, 130.7, 130.4, 129.4, 129.2, 21.9; HRESI-MS
(m/z) Calculated for C16H12N2O (M+ + Na) 271.0847, found (M+ +
Na) 271.0847.
Quinolin-2-yl(p-tolyl)methanone (5a). White solid; Yield 37%; mp
63−65 °C; Rf (5% EtOAc/Hexane) 0.4. Prepared as shown in general
experimental procedure (Reaction completion time 8 h at 110 °C):
1
IR (Neat, cm−1) 3061, 2921, 1656, 1606, 1560, 1501, 1461, 1318; H
NMR (400 MHz, CDCl3) δ (ppm) 8.31 (d, J = 8.4 Hz, 1H), 8.19 (d, J =
8.8 Hz, 1H), 8.14 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.88 (d,
J = 8.0 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.3 (d,
J = 7.6 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
193.5, 155.0, 146.7, 144.0, 137.0, 133.5, 131.6, 130.5, 130.0, 128.9, 128.8,
128.3, 127.6, 120.8, 21.8; HRESI-MS (m/z) Calculated for C17H13NO
(M+ + Na) 270.0895, found (M+ + Na) 270.0892.
Quinoline-2,4-diylbis(p-tolylmethanone) (5b). Pale yellow oily
liquid; Yield 32%; Rf (5% EtOAc/Hexane) 0.2. Prepared as shown in
general experimental procedure (Reaction completion time 8 h at 110 °C):
1
IR (Neat, cm−1) 3065, 1661, 1605, 1505, 1458, 1353, 1260; H NMR
Pale yellow liquid: Yield 25%; Rf (5% EtOAc/Hexane) 0.6; IR (Neat,
1
cm−1) 3416, 3032, 2966, 2929, 2871, 2645, 2108, 1834; H NMR
(400 MHz, CDCl3) δ (ppm) 8.28 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.0 Hz,
2H), 8.0 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.83−7.78 (m, 3H), 7.62 (t, J =
7.6 Hz, 1H), 7.30 (d, J = 8 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 2.45 (s,
3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 195.3, 192.7,
154.2, 147.2, 145.7, 145.6, 144.3, 133.9, 133.2, 131.6, 131.0, 130.5, 130.5,
129.6, 129.3, 129.0, 125.7, 125.4, 119.3, 21.83, 21.80; HRESI-MS (m/z)
Calculated for C25H19NO2 (M+ + Na) 388.1313, found (M+ +Na)
388.1319.
Quinoline-2,4-diylbis((4-(benzyloxy)phenyl)methanone) (5c).
White solid; Yield 24%; mp 147−149 °C; Rf (20% EtOAc/Hexane)
0.45. Prepared as shown in general experimental procedure (Reaction
completion time 12 h at 110 °C): IR (Neat, cm−1) 3063, 2921, 2623,
2113, 1651, 1597, 1574, 1252; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.29 (t, J = 8.8 Hz, 3H), 8.05 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.86 (d, J =
8.8 Hz, 2H), 7.81 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.45−7.33
(m, 10H), 7.08 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.17 (s, 2H),
5.14 (s, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.1, 191.5, 163.7,
163.0, 154.5, 147.1, 146.0, 136.2, 135.8, 134.0, 132.9, 130.9, 130.5, 129.5,
129.2, 128.8, 128.7, 128.7, 128.4, 128.2, 127.5, 125.6, 125.4, 119.2, 115.0,
(400 MHz, CDCl3) δ (ppm) 8.63- 8.60 (m, 1H), 8.39 (s, 1H),
7.93−7.90 (m, 1H), 7.59−7.56 (m, 2H), 7.51−7.45 (m, 5H), 1.72 (s,
9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 166.74, 140.43, 137.60,
135.70, 131.90, 130.23, 128.85, 128.45, 127.61, 127.35, 126.32, 125.75,
125.46, 39.84, 31.33; HRESI-MS (m/z) Calculated for C19H19NH
(M+ + H) 262.1596, found (M+ + H) 262.1596.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C spectra and spectral data are available for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: prabhu@orgchem.iisc.ernet.in. Tel: +91-80-22932887.
Fax: +91-80-23600529.
■
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14411. (b) Leifert, D.; Daniliuc, C. G.; Studer, A. Org. Lett. 2013, 15,
6286.
(11) Reux, B.; Nevalainen, T.; Raitio, K. H.; Koskinen, A. M. P. Bioorg.
Notes
The authors declare no competing financial interest.
Med. Chem. 2009, 17, 4441.
ACKNOWLEDGMENTS
(12) Neumeyer, J. L.; Boyce, C. B. J. Org. Chem. 1973, 38, 2291−2231.
(13) Popp, F. D.; Wefer, J. M. J. Heterocycl. Chem. 1967, 4, 183.
(14) Correia, C. A.; Yang, L.; Li, C.-J. Org. Lett. 2011, 13, 4581.
(15) Weisbach, J.; Kirkpatrick, J.; Macko, E.; Douglas, B. J. Med. Chem.
1968, 11, 760.
(16) Higashino, T.; Goi, M.; Hayashi, E. Chem. Pharm. Bull. 1976, 24,
238−252.
■
The authors thank IISc, CSIR (01(2415)/10/EMR-II), and RL
Fine Chem for financial support and Dr. A. R. Ramesha (RL Fine
Chem) for useful discussion. Y.S. and M.L. thank CSIR for
fellowships.
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