Rh(III)-Catalyzed Redox-Neutral Annulation of Primary Benzamides with Diazo Compounds: Approach to Isoquinolinones

Article abstract of DOI:10.1021/acs.joc.5b02824

Reported herein is a Rh-catalyzed redox-neutral annulation of primary benzamides with diazo compounds, representing an efficient and economic protocol to isoquinolinones. The procedure exhibited good functional group tolerability, scalability, and regioselectivity, obviating the need for oxidants, and only environmentally benign N₂ and H₂O were released. Further utilization of the method provided an alternative route to functionalized isoquinolines.

Full text of DOI:10.1021/acs.joc.5b02824

Note
pubs.acs.org/joc
Rh(III)-Catalyzed Redox-Neutral Annulation of Primary Benzamides
with Diazo Compounds: Approach to Isoquinolinones
Youzhi Wu,† Peng Sun,† Kaifan Zhang, Tie Yang, Hequan Yao,* and Aijun Lin*
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical
University, Nanjing, 210009, P. R. China
S
* Supporting Information
ABSTRACT: Reported herein is a Rh-catalyzed redox-neutral annulation of primary benzamides with diazo compounds,
representing an efficient and economic protocol to isoquinolinones. The procedure exhibited good functional group tolerability,
scalability, and regioselectivity, obviating the need for oxidants, and only environmentally benign N2 and H2O were released.
Further utilization of the method provided an alternative route to functionalized isoquinolines.
oxidants were needed and only environmentally benign N2 and
he development of a new synthetic strategy to enhance
Tthe selectivity and step economy and reduce the H2O were released.
Initially, our investigations focused on the combination of
generation of undesired waste is an important goal of chemists.
During the past two decades, the direct C−H functionalization
has been proved to be one powerful approach to satisfy this
expectation due to its inherent advantages of avoiding
prefunctionalization of substrates1 and achieving highly
regioselective functionalization of one C−H bond over the
others employing directing group assisted transition-metal-
mediated transformations.2
benzamide 1a and ethyl diazoacetoacetate 2a to optimize the
reaction conditions (Table 1). The desired product 3aa was
obtained in 17% yield in the presence of [Cp*RhCl2]2 (2.5 mol
%) and AgSbF6 (10 mol %) in 1,2-dichloroethane (DCE) at
100 °C under an argon atmosphere (Table 1, entry 1). When
a
Table 1. Optimization of the Reaction Conditions
Recently, the readily available diazo compounds as carbene
precursors have been widely employed in C−H activation for
direct C−C bond formation, particularly in the heterocycles
synthesis with N-protected benzamides3a−c or anlines,3d,e
aryloximes,3f,g sulfoximines,3h and others.3i To the best of our
knowledge, primary benzamides as substrate candidates
involved in the transition-metal-mediated C−H activation
processes4 with diazo compounds has not been reported up
to date. To further explore diazo compounds as participant in
C−H activation and also in conjunction with our ongoing
interest in diazo chemistry,5 herein, we will report the first
example of Rh-catalyzed annulation reaction between primary
benzamides and diazo compounds, leading to the direct
synthesis of isoquinolinones. Isoquinolinones are important
heterocycles found in natural products6 and pharmaceuticals,7
and the syntheses have been achieved through transition-metal-
mediated tandem C−H activation/annulation of benzamides
with alkynes,8 while either external or internal oxidants are
necessary to ensure the catalytic cycles.9 Moreover, the
regioselectivity of internal alkynes could not be well controlled
in some cases.10 In our work, the primary benzamides could
serve as good substrates and directing groups for direct C−H
bond activation as well as predisposing the intermediates
toward the intramolecular C−N bond formation. Moreover, no
b
entry
additives (mol %)
temperature (°C)
yield (%)
1
2
3
4
5
6
7
8
AgSbF6 (10)
NaOAc (10)
KOAc (10)
100
100
100
100
100
100
100
80
17
34
28
35
38
66
Cu(OAc)2 (10)
CsOAc (10)
CsOAc (20)
CsOAc (50)
CsOAc (50)
CsOAc (50)
CsOAc (50)
c
98(96)
78
d
9
e
100
100
70
10
N.R.
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), [Cp*RhCl2]2
(2.5 mol %), additives in DCE (2.0 mL) was stirred at 100 °C for 7 h
b
under Ar. Yield was determined by 1H NMR using dibromomethane
c
d
as the internal standard. Isolated yield. 1.5 mol % of [Cp*RhCl2]2.
e
Without [Cp*RhCl2]2.
Received: December 13, 2015
© XXXX American Chemical Society
A
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Note
CsOAc (10 mol %) was employed as the additive, the yield of
3aa was increased to 38% (Table 1, entry 5). Further increasing
the amount of CsOAc to 50 mol %, the yield was significantly
improved to 98% (Table 1, entry 7). An attempt to lower the
reaction temperature resulted in decreased yield (Table 1, entry
8). When 1.5 mol % catalyst was used, the yield was decreased
to 70% (Table 1, entry 9). Omission of [Cp*RhCl2]2
completely shut down the reaction (Table 1, entry 10).
With the optimized conditions in hand, we investigated the
substrate scope of benzamides to test the generality of this
annulation reaction (Table 2). It was found that a variety of
amides could successfully cyclize to give the desired products in
good to excellent yields. An electron-donating group such as a
methyl, a tert-butyl and a methoxy group at the para-position of
the benzene ring offered 3ba, 3ca, and 3da in 97%, 93%, and
86% yield, respectively. Halogen substituents offered 3ea−3ha
in 76−97% yields, which could be subjected to further synthetic
transformations. An electron-withdrawing group such as a CF3
and an ester group afforded 3ia and 3ja in 91% and 90% yields.
3la and 3ma with unsaturated CC double bonds and CC
triple bonds could be obtained in 75% and 61% yields. It was
interesting to note that the reaction could also tolerate an
unprotected OH group and the 3ka was completed in 53%
yield. Owing to the steric effect, ortho-phenzyl-substituted
benzamide provided 3pa in 70% yield, while para- and meta-
phenzyl-substituted benzamides provided 3na and 3oa in 89%
and 91% yields. 3qa with a CF3 group at the ortho-position
could be furnished in 95% yield. 1-Naphthamide gave the
desired product 3ta with three continuous six-membered rings
in 82% yield. In regard to the heteroaromatic amides such as
thiophene, furane and thiazole delivered the desired products
3ua−3xa in 89−98% yields. Both the thiophene-2-carboxamide
and thiophene-3-carboxamide were compatible in our system.
The reaction could also work well with the complex substrate,
benzamide 1y, derived from estrone, which reacted smoothly
under the optimal conditions, affording the corresponding
product 3ya in 63% yield. An alkenyl amide, such as
cinnamamide, could not offer the desired product 3za.
Moreover, the reaction could proceed smoothly on a gram
scale (5 mmol), offering 3aa in 1.13 g (98% yield).
a b
,
Table 2. Substrates of Primary Benzamides
After the examination of benzamides, dizao compounds were
also investigated, and the results are described in Table 3.
a b
,
Table 3. Scope of Diazo Compounds
a
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), [Cp*RhCl2]2
(2.5 mol %), and CsOAc (0.5 equiv) in DCE (2.0 mL) was stirred at
100 °C for 7 h under Ar. Isolated yield.
b
When the ester with a methyl, a tert-butyl, or a benzyl group
was used, the 3ab−3ad were given in 77−81% yields. R1 with
an ethyl or an n-propyl group afforded 3ae and 3af in 98% and
81% yields. When R1 with branched alkyl groups such as an
isopropyl and a tert-butyl group were used, the 3ag and 3ah
were given in 91% and 94% yields. R1 with a phenyl group
could not give the desired product 3ai. When diethyl 2-
diazomalontae 2j was used as the substrate, 3aj was not
observed. R2 with a Ts group gave 3ak in moderate yield. R2
a
Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), [Cp*RhCl2]2
(2.5 mol %), and CsOAc (0.5 equiv) in DCE (2.0 mL) was stirred at
100 °C for 7 h under Ar. Isolated yield.
b
B
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Note
with amides (2l, 2m) were also compatible and offered 3al and
3am in 87% and 88% yields.
Scheme 2. Further Transformation of Generated
Isoquinolinone
To understand the reaction mechanism, we conducted an
isotope-labeling experiment with deuterium-labeled benzamide.
Significant primary kinetic isotope effects were observed (kH/kD
= 3.02), which suggested that the C−H bond cleavage was
likely to be involved in the rate-limiting step. On the basis of
the above-mentioned observation and literature prece-
dents,3b,f,11 a plausible reaction mechanism is proposed in
Scheme 1. After the anion exchange with CsOAc, the active
Scheme 1. Mechanism Study
provided a facile method to the direct synthesis of
isoquinolinones and exhibited good functional group toler-
ability, scalability, and regioselectivity, obviating the need for
oxidants, and only environmentally benign N2 and H2O were
released. Primary mechanistic insights revealed that the C−H
bond cleavage of the benzene ring is the key rate-limiting step.
Initial functionalization reactions illustrated the synthetic
prospect of our method to isoquinolines.
EXPERIMENTAL SECTION
■
General Information. All chemicals and reagents were purchased
from commercial suppliers and used without further purification. The
products were purified by column chromatography on silica gel.
Melting point (mp) was measured on a microscopic melting point
apparatus. 1H NMR spectra were recorded at a 300 MHz NMR
spectrometer. 13C NMR spectra were recorded at 75 and 125 MHz
NMR spectrometers. NMR experiments were reported in δ units, parts
per million (ppm), and were referenced to CDCl3 (δ 7.26 or 77.0
ppm) or DMSO-d6 (δ 2.50 or 40.5 ppm) as the internal standard.
Infrared spectra (IR) were recorded on the FT-IR spectrometer. High-
resolution mass measurement was performed with an electrospray
ionization (ESI) method on a Q-TOF mass spectrometer operating in
positive ion mode.
catalyst A was generated. Then, an arene rhodation occurred
and afforded the intermediate B, which reacted with diazo
compound 2 to give the intermediate C via the Rh carbene
formation pathway.3b,f Migratory insertion of carbenoid gave a
six-membered rhodacylic intermediate D. At this stage, two
pathways were possible. In pathway “a”, protonation of D
delivered the alkylated intermediate E and regenerated A to the
next reaction cycle. The final product 3 was formed via
intramolecular nucleophilic addition of E with the elimination
of water. In pathway “b”,11 protonation of D delivered the
carbonyl intermediate F. The formed Rh−N bond could add
across the carbonyl group, affording the cyclorhodated
intermediate G, which then underwent protonolysis and
elimination of H2O to give the final product 3 and the
recovered A.
General Procedure for the Synthesis of Diazo Compounds.
Diazo substrates were synthesized from the corresponding ketonic
esters or ketonic amides.5a,14
To enlarge the application of our method, isoquinolinone
3aa could be further transformed to isoquinolines (Scheme 2),
which are also one of the most important structural motifs
present in natural products12 with wide range of biological
activities.13 First, treatment of 3aa with POBr3 in DCM gave
bromination product 4, which could be easily functionalized. 5a
and 5b were obtained via Ullmann reaction of 4 in 98% and
93% yield, respectively. 1-Cyano substituted isoquinoline 5c
was obtained in 40% yield. Similarly, 1-alkyl-substituted
isoquinoline 5d could be obtained via nucleophilic substitution
reaction in 88% yield. Alkynyl-substituted product 5e was
obtained in moderate yield through Sonogashira reaction.
In summary, we have developed the first example of Rh-
catalyzed redox-neutral annulation of primary benzamides with
diazo compounds. This tandem C−H activation/annulation
To a solution of 1 (5 mmol) in CH3CN was added 6 mmol of
TsN3. Then, the reaction mixture was cooled to 0 °C and a solution of
DBU (6 mmol) in 10 mL of CH3CN was added dropwise. Next, the
reaction temperature was raised to room temperature. After stirring for
3 h, the residue was extracted with ethyl acetate for 3 times. The
combined organic layers were washed with water and brine
sequentially, dried over Na2SO4, filtered, and concentrated. The
crude product was purified by column chromatography on silica gel to
afford the corresponding products in 70−90% yields.
General Procedure for the Synthesis of 1a−1x. Aryl carboxylic
acid (10 mmol) in SOCl2 (10 mL) was refluxed at 85 °C. After 30
min, the mixture turned clear. The reaction was stopped, and the
reaction solution was concentrated to give the acyl chloride. A solution
of acyl chloride prepared above in anhydrous dichloromethane (10
C
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Note
mL) was injected dropwise to an aqueous ammonia solution (con. 20
mL) in an ice bath. After stirring for 30 min, the precipitate was
collected by suction filtration, washed with water and n-hexane, and
dried under reduced pressure at 50 °C. Recrystallization from ethyl
acetate afforded the desired compounds 1a−1x.
Ethyl 6-tert-Butyl-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
boxylate (3ca). 134 mg, 93% yield; light yellow solid, mp 194−196
°C; 1H NMR (300 MHz, CDCl3) δ 12.37 (s, 1H), 8.36 (d, J = 8.5 Hz,
1H), 7.96 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 4.48 (q, J = 6.9 Hz, 2H),
2.61 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 1.39 (s, 9H) ppm; 13C NMR (75
MHz, CDCl3) δ 167.3, 164.3, 156.5, 141.6, 135.8, 127.0, 124.5, 121.6,
120.5, 109.5, 61.1, 35.5, 31.1, 18.8, 14.4 ppm; IR (KBr) 3174, 3044,
1701, 1655, 1617, 1460, 1291, 1177, 1108 cm−1; HRMS (ESI) calcd
for [C17H21NO3 + H]+ 288.1594, found 288.1593.
General Procedure for the Synthesis of 1y.15
Ethyl 6-Methoxy-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
boxylate (3da).16 112 mg, 86% yield; light yellow solid, mp 182−
185 °C; 1H NMR (300 MHz, CDCl3) δ 12.28 (s, 1H), 8.31 (d, J = 8.9
Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.9, 2.1 Hz, 1H), 4.45
(q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.60 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 167.1, 163.9, 163.4, 142.9, 138.1,
129.2, 117.6, 115.9, 108.6, 105.6, 61.1, 55.4, 19.2, 14.4 ppm; IR (KBr)
3191, 2908, 1693, 1682, 1611, 1366, 1328, 1172, 1072, 840, 641 cm−1;
HRMS (ESI) calcd for [C14H15NO4 + H]+ 262.1074, found 262.1076.
Ethyl 6-Fluoro-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
boxylate (3ea). 117 mg, 94% yield; light yellow solid, mp 233−234
Step 1: Pyridine (10.0 mmol, 2.0 equiv) was added to a stirring
solution of estrone (5.0 mmol, 1.0 equiv) in DCM (25 mL) under Ar.
Then, triflic anhydride (6.0 mmol, 1.2 equiv) was added dropwise to
the mixture in an ice bath. The mixture was warmed to room
temperature and stirred for 5 h. Then, the reaction was quenched by
the addition of water. The layers were separated, and the aqueous
phase was extracted with DCM (30 mL × 3). The combined organic
phase was washed with brine, dried over sodium sulfate, filtered, and
evaporated under reduced pressure to afford the corresponding crude
trifluoromethane-sulfonate substituted compound. The crude com-
pound was used without further purification.
Step 2: Pd(OAc)2 (0.25 mmol, 5 mol %), 1,1′-bis(diphenyl-
phosphino)ferrocene (1 mmol, 20 mol %), and potassium acetate (20
mmol, 4 equiv) were added to the crude compound in DMSO (50
mL). The reaction mixture was stirred at 60 °C under a balloon of CO
overnight. The mixture was then cooled to room temperature,
quenched with 1 M HCl (pH < 3), and extracted with EtOAc (50 mL
× 3). The combined organic phase was washed with brine, dried over
sodium sulfate, filtered, and evaporated under reduced pressure to
afford the corresponding crude carboxylic acid. The crude carboxylic
acid was purified by column chromatography on silica gel to obtain the
corresponding acid.
Step 3: 1y was obtained by the same way as that for 1a−1x.
General Procedure for the Rhodium-Catalyzed Annulations.
A sealed tube was charged with benzamide 1 (0.5 mmol),
[Cp*RhCl2]2 (0.0125 mmol, 2.5 mol %), CsOAc (0.25 mmol), and
dry 1,2-dichloroethane (2.0 mL). After stirring the reaction mixture at
room temperature for 5 min, diazo compound 2 (0.75 mmol) was
added. Under an argon atmosphere, the reaction mixture was stirred at
100 °C for 7 h. Then, the mixture was cooled to room temperature
and diluted with dichloromethane (10 mL), then filtered through a
Celite pad, and washed with dichloromethane (20 mL × 3). The
filtrate was concentrated, and the product was purified by column
chromatography on silica gel with dichloromethane/MeOH as eluent
to afford the corresponding product 3.
Ethyl 3-Methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate
(3aa).16,17 113 mg, 98% yield; white solid, mp 191−193 °C; 1H
NMR (300 MHz, CDCl3) δ 12.26 (s, 1H), 8.42 (d, J = 7.3 Hz, 1H),
7.95 (d, J = 8.3 Hz, 1H), 7.74−7.59 (m, 1H), 7.48 (t, J = 7.5 Hz, 1H),
4.46 (q, J = 7.1 Hz, 2H), 2.61 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 167.0, 164.4, 141.4, 135.9, 133.1, 127.3,
1
°C; H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.26 (s, 1H),
7.63 (d, J = 11.0 Hz, 1H), 7.34 (s, 1H), 4.37 (d, J = 6.5 Hz, 2H), 2.41
(s, 3H), 1.35 (d, J = 6.2 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-
d6) δ 166.4, 165.2 (d, 1JC‑F = 247.2 Hz), 161.3, 145.2, 138.1, 130.7 (d,
2
2
3JC‑F = 10.5), 121.3, 114.9 (d, JC‑F = 23.4), 109.8 (d, JC‑F = 24.5),
106.7, 61.3, 18.9, 14.5 ppm; IR (KBr) 3174, 3038, 2991, 1720, 1682,
1617, 1330, 1283, 870, 777 cm−1; HRMS (ESI) calcd for
[C13H12FNO3 + H]+ 250.0874, found 250.0876.
Ethyl 6-Chloro-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
boxylate (3fa).16 101 mg, 76% yield; light yellow solid, mp 213−
214 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.18 (d, J =
8.5 Hz, 1H), 7.91 (s, 1H), 7.51 (s, 1H), 4.36 (d, J = 7.1 Hz, 2H), 2.39
(s, 3H), 1.33 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6)
δ 166.3, 161.5, 145.2, 137.1, 129.4, 129.4, 127.7, 126.8, 123.2, 106.1,
61.3, 19.0, 14.5 ppm; IR (KBr) 3168, 2973, 2925, 1718, 1684, 1457,
1323, 1283, 874, 671 cm−1; HRMS (ESI) calcd for [C13H12ClNO3 +
H]+ 266.0578, found 266.0576.
Ethyl 6-Bromo-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
boxylate (3ga). 150 mg, 97% yield; light yellow solid, mp 223−225
1
°C; H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.11−8.08 (m,
2H), 7.63 (d, J = 8.4 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H),
1.36 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 166.3,
161.5, 145.2, 137.1, 129.4, 129.4, 127.7, 126.8, 123.2, 106.1, 61.3, 19.0,
14.5 ppm; IR (KBr) 3168, 3032, 2981, 1719, 1685, 1621, 1285, 1198,
870, 771 cm−1; HRMS (ESI) calcd for [C13H12BrNO3 + H]+
310.0073, found 310.0071.
Ethyl 6-Iodo-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxy-
late (3ha). 166 mg, 93% yield; light yellow solid, mp 239−240 °C; 1H
NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.28 (s, 1H), 7.92 (d, J
= 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 4.61−4.13 (m, 2H), 2.40 (s,
3H), 1.36 (t, J = 6.4 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ
166.3, 161.8, 144.7, 136.9, 135.0, 133.0, 128.9, 123.5, 105.9, 102.2,
61.3, 19.0, 14.5 ppm; IR (KBr) 3174, 3032, 2970, 1697, 1648, 1596,
1286, 1245, 784, 634 cm−1; HRMS (ESI) calcd for [C13H12INO3 +
H]+ 357.9935, found 357.9934.
Ethyl 3-Methyl-1-oxo-6-(trifluoromethyl)-1,2-dihydroisoquino-
line-4-carboxylate (3ia). 136 mg, 91% yield; light yellow solid, mp
199−200 °C; 1H NMR (300 MHz, CDCl3) δ 12.67 (s, 1H), 8.14 (d, J
= 8.3 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 4.46
(q, J = 7.0 Hz, 2H), 2.59 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ 166.9, 161.7, 142.8, 138.7, 131.8, 129.7 (q,
126.3, 124.4, 124.0, 109.4, 61.2, 18.8, 14.3 ppm; IR (KBr) 3174, 3049,
2984, 1709, 1682, 1614, 1201, 868, 784 cm−1; HRMS (ESI) calcd for
[C13H13NO3 + H]+ 232.0968, found 232.0967.
3
1
Ethyl 3,6-Dimethyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate
2JC‑F = 32.4 Hz), 128.9, 126.1 (q, JC‑F = 7.5 Hz), 123.8 (q, JC‑F
=
(3ba).16 119 mg, 97% yield; white solid, mp 206−207 °C; H NMR
1
271.4 Hz), 120.9, 109.2, 61.4, 18.2, 14.2 ppm; IR (KBr) 3185, 3097,
2991, 1720, 1678, 1634, 1376, 1273, 824, 674 cm−1; HRMS (ESI)
calcd for [C14H12F3NO3 + H]+ 300.0842, found 300.0844.
(300 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.59
(s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.43 (s,
3H), 2.35 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz,
DMSO-d6) δ 167.0, 162.0, 143.4, 142.1, 135.6, 128.0, 127.3, 124.0,
122.2, 107.6, 61.2, 22.1, 18.4, 14.5 ppm; IR (KBr) 3174, 3056, 2975,
1708, 1683, 1619, 1288, 1176, 897, 792 cm−1; HRMS (ESI) calcd for
[C14H15NO3 + H]+ 246.1125, found 246.1126.
4-Ethyl 6-Methyl 3-Methyl-1-oxo-1,2-dihydroisoquinoline-4,6-
dicarboxylate (3ja). 130 mg, 90% yield; light yellow solid, mp
1
201−204 °C; H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.51
(s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 4.40 (q, J =
6.8 Hz, 2H), 3.92 (s, 3H), 2.41 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H) ppm;
D
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Note
13C NMR (75 MHz, DMSO-d6) δ 166.4, 166.1, 161.5, 144.5, 135.4,
61.5, 19.3, 14.3 ppm; IR (KBr) 3191, 2997, 2809, 1676, 1655, 1317,
1304, 1190, 1176, 1120, 1085, 638 cm−1; HRMS (ESI) calcd for
[C14H12F3NO3 + H]+ 300.0842, found 300.0841.
133.5, 127.9, 127.1, 126.1, 126.0, 107.1, 61.3, 53.0, 18.8, 14.5 ppm; IR
(KBr) 3191, 3056, 2985, 1737, 1723, 1678, 1623, 1279, 1245, 765
cm−1; HRMS (ESI) calcd for [C15H15NO5 + H]+ 290.1023, found
290.1021.
Ethyl 8-Chloro-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
boxylate (3ra). 97 mg, 73% yield; light yellow solid, mp 195−197
1
°C; H NMR (300 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.78−7.59 (m,
Ethyl 6-Hydroxy-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
2H), 7.49 (dd, J = 7.2, 1.6 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.31 (s,
3H), 1.33 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ
166.9, 160.3, 142.7, 138.7, 134.3, 133.4, 129.5, 123.6, 120.6, 107.8,
61.5, 18.1, 14.5 ppm; IR (KBr) 3174, 3079, 2991, 1725, 1672, 1619,
1254, 1139, 806, 641 cm−1; HRMS (ESI) calcd for [C13H12ClNO3 +
H]+ 266.0578, found 266.0577.
boxylate (3ka). 65 mg, 53% yield; light yellow solid, mp 246−247
1
°C; H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.37 (s, 1H),
8.06 (d, J = 8.7 Hz, 1H), 7.15 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.35
(q, J = 6.9 Hz, 2H), 2.33 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H) ppm; 13C
NMR (75 MHz, DMSO-d6) δ 167.1, 161.9, 161.8, 142.6, 137.6, 129.6,
116.9, 116.3, 108.2, 107.2, 61.1, 18.5, 14.6 ppm; IR (KBr) 3303, 3144,
1652, 1599, 1360, 1243, 1173, 794, 647 cm−1; HRMS (ESI) calcd for
[C13H13NO4 + H]+ 248.0917, found 248.0916.
Ethyl 8-Bromo-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-car-
boxylate (3sa). 100 mg, 65% yield; light yellow solid, mp 195−197
1
°C; H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.74 (s, 1H),
(E)-Ethyl 3-Methyl-1-oxo-6-styryl-1,2-dihydroisoquinoline-4-car-
boxylate (3la). 125 mg, 75% yield; light yellow solid, mp 216−218
°C; 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.20 (d, J = 8.4
Hz, 1H), 7.92 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 7.4 Hz,
2H), 7.51−7.24(m, 5H), 4.43 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.39
(t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 166.9,
161.8, 142.8, 141.7, 137.0, 136.1, 131.8, 129.2, 128.7, 128.3, 127.7,
127.4, 123.8, 123.3, 123.0, 107.7, 61.3, 18.5, 14.6 ppm; IR (KBr) 3179,
3020, 2890, 1700, 1663, 1610, 1286, 1068, 688, 638 cm−1; HRMS
(ESI) calcd for [C21H19NO3 + H]+ 334.1438, found 334.1434.
Ethyl 3-Methyl-1-oxo-6-(phenylethynyl)-1,2-dihydroisoquinoline-
4-carboxylate (3ma). 101 mg, 61% yield; light yellow solid, mp 175−
177 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.22 (d, J =
8.2 Hz, 1H), 8.03 (s, 1H), 7.62 (t, J = 6.6 Hz, 3H), 7.50−7.43 (m,
3H), 4.40 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H)
ppm; 13C NMR (75 MHz, DMSO-d6) δ 166.6, 161.6, 144.1, 135.6,
132.1, 129.8, 129.3, 128.9, 127.8, 127.3, 127.1, 123.9, 122.2, 106.8,
92.2, 89.2, 61.4, 18.8, 14.5 ppm; IR (KBr) 3179, 3050, 2979, 1717,
1664, 1654, 1618, 1275, 1196, 751, 689 cm−1; HRMS (ESI) calcd for
[C21H17NO3 + H]+ 332.1281, found 332.1272.
Ethyl 3-Methyl-1-oxo-6-phenyl-1,2-dihydroisoquinoline-4-car-
boxylate (3na). 137 mg, 89% yield; light yellow solid, mp 232−234
°C; 1H NMR (300 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.29 (d, J = 8.3
Hz, 1H), 8.10 (s, 1H), 7.79−7.71 (m, 3H), 7.56−7.43 (m, 3H), 4.41
(q, J = 7.0 Hz, 2H), 2.42 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm; 13C
NMR (75 MHz, DMSO-d6) δ 166.8, 161.9, 144.8, 143.4, 139.9, 136.0,
129.6, 128.8, 128.1, 127.5, 125.3, 123.4, 122.4, 107.6, 61.2, 18.7, 14.6
ppm; IR (KBr) 2997, 2902, 1714, 1683, 1620, 1289, 1187, 647 cm−1;
HRMS (ESI) calcd for [C19H17NO3 + H]+ 308.1281, found 308.1279.
Ethyl 3-Methyl-1-oxo-7-phenyl-1,2-dihydroisoquinoline-4-car-
boxylate (3oa). 140 mg, 91% yield; light yellow solid, mp 241−243
°C; 1H NMR (300 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.45 (d, J = 1.8
Hz, 1H), 8.07 (dd, J = 8.6, 1.9 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.77
(d, J = 7.4 Hz, 2H), 7.54−7.49 (m, 2H), 7.42 (t, J = 7.2 Hz, 1H), 4.40
(q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm; 13C
NMR (75 MHz, DMSO-d6) δ 166.8, 162.1, 142.7, 139.3, 138.1, 134.7,
131.8, 129.6, 128.3, 127.1, 125.4, 124.8, 124.5, 107.4, 61.3, 18.6, 14.6
ppm; IR (KBr) 3168, 2914, 1705, 1658, 1612, 1339, 1211, 833, 694
cm−1; HRMS (ESI) calcd for [C19H17NO3 + H]+ 308.1281, found
308.1283.
7.71 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.32 (s,
3H), 1.33 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ
166.9, 160.3, 142.5, 138.6, 133.5, 133.3, 124.2, 122.1, 121.3, 107.9,
61.5, 18.1, 14.5 ppm; IR (KBr) 3174, 3067, 2991, 1714, 1677, 1620,
1369, 1275, 1201, 1140, 812, 641 cm−1; HRMS (ESI) calcd for
[C13H12BrNO3 + H]+ 310.0073, found 310.0072.
Ethyl 3-Methyl-1-oxo-1,2-dihydrobenzo[h]isoquinoline-4-carbox-
ylate (3ta). 115 mg, 82% yield; light yellow solid, mp 205−208 °C; 1H
NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 10.12 (d, J = 8.5 Hz,
1H), 8.19 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 9.1
Hz, 1H), 7.73 (dd, J = 8.5, 1.4 Hz, 1H), 7.68−7.63 (m, 1H), 4.43 (q, J
= 7.1 Hz, 2H), 2.44 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6) δ 167.3, 162.8, 142.8, 137.4, 134.4, 131.6, 131.6,
128.7, 126.9, 126.8, 122.4, 117.1, 109.3, 61.6, 18.0, 14.5 ppm; IR (KBr)
3073, 3026, 1711, 1652, 1607, 1297, 1225, 1112, 1024, 828, 645 cm−1;
HRMS (ESI) calcd for [C17H15NO3 + H]+ 282.1125, found 282.1127.
Ethyl 5-Methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-4-carbox-
ylate (3ua). 116 mg, 98% yield; light yellow solid, mp 180−182 °C;
1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.08 (d, J = 5.3 Hz,
1H), 7.74 (d, J = 5.3 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H),
1.35 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 165.8,
158.5, 148.1, 144.7, 134.7, 127.6, 126.3, 105.3, 60.9, 19.2, 14.6 ppm; IR
(KBr) 3085, 2867, 1698, 1646, 1590, 1276, 1121, 791, 615 cm−1;
HRMS (ESI) calcd for [C11H11NO3S + H]+ 238.0532, found
238.0533.
Ethyl 6-Methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbox-
ylate (3va). 116 mg, 98% yield; light yellow solid, mp 262−263 °C;
1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.59 (d, J = 5.5 Hz,
1H), 7.45 (d, J = 5.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H),
1.36 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 165.2,
158.9, 148.9, 148.0, 128.4, 127.5, 123.6, 103.7, 61.3, 19.8, 14.6 ppm; IR
(KBr) 3079, 2973, 1701, 1647, 1593, 1304, 1274, 1227, 1104, 727, 628
cm−1; HRMS (ESI) calcd for [C11H11NO3S + H]+ 238.0532, found
238.0531.
Ethyl 6-Methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridine-7-carboxy-
late (3wa). 108 mg, 98% yield; light yellow solid, mp 219−221 °C;
1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.92 (d, J = 2.1 Hz,
1H), 6.94 (d, J = 2.1 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H),
1.33 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 163.8,
159.2, 158.3, 149.2, 144.7, 114.1, 106.8, 99.5, 60.8, 18.7, 14.7 ppm; IR
(KBr) 2979, 2814, 1712, 1677, 1310, 1261, 1104, 644 cm−1; HRMS
(ESI) calcd for [C11H11NO4 + H]+ 222.0761, found 222.0760.
Ethy 2-(4-Fluorophenyl)-6-methyl-4-oxo-4,5-dihydrothiazolo[4,5-
c]pyridine-7-carboxylate (3xa). 148 mg, 89% yield; light yellow solid,
Ethyl 3-Methyl-1-oxo-8-phenyl-1,2-dihydroisoquinoline-4-car-
boxylate (3pa). 107 mg, 70% yield; light yellow solid, mp 260−262
1
°C; H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H), 7.82−7.61 (m,
2H), 7.31−7.16(m, 6H), 4.38 (d, J = 6.7 Hz, 2H), 2.32 (s, 3H), 1.35
(t, J = 6.4 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 166.9,
160.8, 143.5, 142.9, 141.3, 136.5, 131.6, 129.5, 128.4, 127.0, 126.2,
123.4, 120.9, 107.6, 60.8, 17.6, 14.0 ppm; IR (KBr) 3091, 2395, 1715,
1662, 1620, 1472, 1262, 1230, 1131, 756, 697 cm−1; HRMS (ESI)
calcd for [C19H17NO3 + H]+ 308.1281, found 308.1283.
1
mp 296−298 °C; H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H),
8.02 (dd, J = 8.6, 5.4 Hz, 2H), 7.36 (t, J = 8.7 Hz, 2H), 4.30 (q, J = 7.0
Hz, 2H), 2.61 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75
MHz, DMSO-d6) δ 164.6, 164.0 (d, 1JC‑F = 251.6), 157.4, 150.5, 144.8,
3
2
Ethyl 3-Methyl-1-oxo-8-(trifluoromethyl)-1,2-dihydroisoquino-
line-4-carboxylate (3qa). 142 mg, 95% yield; light yellow solid, mp
179−180 °C; 1H NMR (300 MHz, CDCl3) δ 12.42 (s, 1H), 8.40 (d, J
= 8.3 Hz, 1H), 8.25 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 4.47 (q, J = 7.1
Hz, 2H), 2.63 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75
142.0, 129.7, 129.3 (d, JC‑F = 8.7), 116.8 (d, JC‑F = 22.1), 61.7, 19.8,
14.5 ppm; IR (KBr) 3061, 2997, 2902, 2867, 1664, 1479, 1345, 1230,
1103, 838, 645 cm−1; HRMS (ESI) calcd for [C16H13FN2O3S + H]+
333.0704, found 333.0703.
(3aS,3bR,11bS,13aS)-Ethyl 9,13a-Dimethyl-1,7-dioxo-
2,3,3a,3b,4,5,7,8,11b,12,13,13a-dodecahydro-1H-cyclopenta[5,6]-
naphtho[1,2-g]isoquinoline-10-carboxylate (3ya). 128 mg, 63%
2
MHz, CDCl3) δ 166.2, 163.5, 143.7, 135.9, 134.6 (q, JC‑F = 32.1),
1
3
128.3, 125.8, 123.7 (q, JC‑F = 271.4), 122.3 (q, JC‑F = 3.6), 108.9,
E
DOI: 10.1021/acs.joc.5b02824
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
yield; light yellow solid, mp 218−220 °C; 1H NMR (300 MHz,
CDCl3) δ 11.81 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 4.47 (dd, J = 13.7,
6.7 Hz, 2H), 3.07−3.02 (m, 2H), 2.64−2.32 (m, 6H), 2.20−1.94 (m,
4H), 1.67−1.43 (m, 9H), 0.92 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 220.6, 167.2, 163.9, 146.2, 140.5, 135.8, 133.6, 126.7, 121.9,
120.9, 109.1, 61.1, 50.7, 47.9, 44.8, 37.7, 35.8, 31.5, 28.9, 26.3, 25.5,
21.6, 19.0, 14.4, 13.8 ppm; IR (KBr) 3197, 2914, 1739, 1655, 1618,
1189 cm−1; HRMS (ESI) calcd for [C25H29NO4 + H]+ 408.2169,
found 408.2166.
NMR (75 MHz, CDCl3) δ 169.2, 163.0, 145.3, 135.9, 133.1, 127.3,
126.8, 124.1, 123.5, 109.6, 61.8, 36.7, 29.3, 14.0 ppm; IR (KBr) 3185,
1731, 1646, 1613, 1349, 1177, 1042, 779 cm−1; HRMS (ESI) calcd for
[C16H19NO3 + Na]+ 296.1257, found 296.1244.
3-Methyl-4-tosylisoquinolin-1(2H)-one (3ak). 69 mg, 44% yield;
light yellow solid, mp 143−145 °C; 1H NMR (300 MHz, DMSO-d6) δ
11.97 (s, 1H), 8.21−8.14 (m, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.62 (t, J
= 8.0 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.34−7.31 (m, 2H), 2.75 (s,
3H), 2.30 (s, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 165.9,
152.8, 148.1, 144.5, 137.5, 137.5, 134.3, 131.5, 131.0, 130.4, 128.6,
128.4, 115.0, 25.3, 24.1 ppm; IR (KBr) 2910, 2843, 1664, 1596, 1463,
1269, 1257, 1151, 764, 750 cm−1; HRMS (ESI) calcd for
[C17H15NO3S + H]+ 314.0845, found 314.0846.
N,N-Diethyl-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxa-
mide (3al). 112 mg, 87% yield; light yellow solid, mp 145−147 °C; 1H
NMR (300 MHz, CDCl3) δ 12.13 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H),
7.66−7.54 (m, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H),
3.62 (q, J = 7.0 Hz, 2H), 3.16 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.29 (t,
J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 167.4, 164.3, 135.7, 134.8, 133.2, 127.5, 126.4, 124.1, 123.2,
113.0, 43.2, 39.2, 17.1, 14.3, 12.9 ppm; IR (KBr) 2967, 2914, 1676,
1639, 1618, 1472, 1434, 1286, 609 cm−1; HRMS (ESI) calcd for
[C15H18N2O2 + H]+ 259.1441, found 259.1443.
Methyl 3-Methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate
(3ab).17 88 mg, 81% yield; light yellow solid, mp 216−218 °C; H
1
NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.22 (d, J = 7.4 Hz,
1H), 7.81 (d, J = 8.1 Hz, 1H), 7.78−7.67 (m, 1H), 7.50 (t, J = 7.1 Hz,
1H), 3.90 (s, 3H), 2.37 (s, 3H) ppm; 13C NMR (75 MHz, DMSO-d6)
δ 167.4, 162.1, 142.6, 135.5, 133.4, 127.2, 126.6, 124.5, 124.3, 107.5,
52.4, 18.5 ppm; IR (KBr) 2932, 2360, 2336, 1715, 1618, 1297, 1208,
653 cm−1; HRMS (ESI) calcd for [C12H11NO3 + H]+ 218.0812, found
218.0810.
tert-Butyl 3-Methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate
(3ac).16 102 mg, 79% yield; light yellow solid, mp 208−210 °C; H
1
NMR (300 MHz, CDCl3) δ 12.20 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H),
7.90 (d, J = 8.2 Hz, 1H), 7.76−7.61 (m, 1H), 7.46 (t, J = 7.3 Hz, 1H),
2.58 (s, 3H), 1.65 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.4,
164.3, 139.8, 136.0, 133.0, 127.3, 126.1, 124.1, 124.0, 111.1, 82.2, 28.4,
18.5 ppm; IR (KBr) 2908, 1713, 1687, 1635, 1474, 1295, 1151, 1122,
653 cm−1; HRMS (ESI) calcd for [C15H17NO3 + H]+ 260.1281, found
260.1280.
3-Methyl-4-(piperidine-1-carbonyl)isoquinolin-1(2H)-one (3am).
1
119 mg, 88% yield; light yellow solid, mp 214−216 °C; H NMR
(300 MHz, CDCl3) δ 12.01 (s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 7.72−
7.62 (m, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 5.1 Hz, 1H), 3.94−
3.76 (m, 2H), 3.37−3.17 (m, 2H), 2.41 (s, 3H), 1.70 (d, J = 3.1 Hz,
4H), 1.46 (d, J = 3.5 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ
166.3, 164.3, 135.6, 135.0, 133.2, 127.5, 126.4, 124.1, 123.4, 112.6,
47.9, 42.6, 26.9, 25.9, 24.4, 17.2 ppm; IR (KBr) 2926, 2849, 1679,
1630, 1618, 1439, 1213, 614 cm−1; HRMS (ESI) calcd for
[C16H18N2O2 + H]+ 271.1441, found 271.1440.
Benzyl 3-Methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate
(3ad).16 113 mg, 77% yield; light yellow solid, mp 191−192 °C; H
1
NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.22 (dd, J = 8.0, 1.0
Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.71 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H),
7.54−7.46 (m, 3H), 7.46−7.33 (m, 3H), 5.41 (s, 2H), 2.36 (s, 3H)
ppm; 13C NMR (75 MHz, DMSO-d6) δ 166.8, 162.1, 142.7, 136.2,
135.5, 133.3, 129.0, 128.7, 127.3, 126.6, 124.4, 124.4, 107.4, 67.0, 18.6
ppm; IR (KBr) 3044, 2908, 2849, 1715, 1673, 1616, 1281, 1204, 727,
638 cm−1; HRMS (ESI) calcd for [C18H15NO3 + H]+ 294.1125, found
294.1123.
General Procedure for the Mechanism Study. Under an argon
atmosphere, a mixture of 1a (0.25 mmol) and 1a-d5 (0.25 mmol) was
allowed to react with 2a (0.75 mmol) in the presence of [Cp*RhCl2]2
(7.7 mg, 2.5 mol %), CsOAc (0.5 equiv), and DCE (2 mL) at 100 °C
for 10 min. The reaction was cooled down quickly in an ice bath.
Then, the crude mixture was filtered through a Celite pad and washed
with DCM (10 mL × 3). The filtrate was concentrated and
Ethyl 3-Ethyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (3ae).
120 mg, 98% yield; light yellow solid, mp 184−186 °C; 1H NMR (300
MHz, CDCl3) δ 12.18 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 7.88 (d, J =
8.2 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 4.46 (q,
J = 6.9 Hz, 2H), 2.87 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 6.8 Hz, 6H)
ppm; 13C NMR (75 MHz, CDCl3) δ 167.2, 164.6, 146.1, 135.8, 133.1,
127.3, 126.3, 124.4, 124.1, 109.0, 61.3, 26.1, 14.3, 14.0 ppm; IR (KBr)
3032, 2979, 1718, 1670, 1618, 1290, 1204, 786, 638 cm−1; HRMS
(ESI) calcd for [C14H15NO3 + H]+ 246.1125, found 246.1124.
Ethyl 1-Oxo-3-propyl-1,2-dihydroisoquinoline-4-carboxylate
1
determined by H NMR analysis of the reaction mixture (see the
Supporting Information for details).
Ethyl 1-Bromo-3-methylisoquinoline-4-carboxylate (4).18
A
sealed tube was charged with ethyl 3-methyl-1-oxo-1,2-dihydroisoqui-
noline-4-carboxylate 3aa (0.5 mmol), POBr3 (1.5 mmol), and DCM
(4 mL). The reaction mixture was vigorously stirred at 150 °C for half
an hour. The anisole was removed under reduced pressure, and the
residue was diluted with DCM (15 mL), washed with saturated
aqueous Na2CO3 (15 mL), and brine (15 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated. The product was
purified by column chromatography on silica gel to give ethyl 1-
bromo-3-methylisoquinoline-4-carboxylate 4. 144 mg, 98% yield;
(3af).16 105 mg, 81% yield; light yellow solid, mp 146−148 °C; H
1
NMR (300 MHz, CDCl3) δ 12.11 (s, 1H), 8.42 (d, J = 7.4 Hz, 1H),
7.87 (d, J = 8.1 Hz, 1H), 7.75−7.61 (m, 1H), 7.51−7.46 (m, 1H), 4.46
(q, J = 7.1 Hz, 2H), 2.85−2.80 (m, 2H), 1.96−1.76 (m, 2H), 1.44 (t, J
= 7.1 Hz, 3H), 1.08 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 167.2, 164.4, 144.7, 135.8, 133.1, 127.3, 126.4, 124.4, 124.1,
109.4, 61.3, 34.4, 23.0, 14.3, 14.0 ppm; IR (KBr) 3168, 2843, 1719,
1676, 1620, 1284, 1205, 682, 632 cm−1; HRMS (ESI) calcd for
[C15H17NO3 + H]+ 260.1281, found 260.1283.
1
white solid, mp 68−70 °C; H NMR (300 MHz, CDCl3) δ 8.23 (d,
J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.58
(t, J = 7.5 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.43 (t, J =
7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 167.7, 149.2, 145.8,
134.7, 132.0, 128.9, 128.2, 126.7, 124.2, 123.8, 61.9, 22.6, 14.3 ppm; IR
(KBr) 2926, 2849, 1679, 1630, 1618, 1439, 1213, 614 cm−1; HRMS
(ESI) calcd for [C13H12BrNO2 + H]+ 294.0124, found 294.0123.
Ethyl 3-Methyl-1-morpholinoisoquinoline-4-carboxylate (5a). A
sealed tube was charged with ethyl 1-bromo-3-methylisoquinoline-4-
carboxylate 4 (0.5 mmol) and morpholine (5 mL). The reaction
mixture was stirred at 150 °C for 5 h. The mixture was diluted with
DCM and washed with water. The aqueous layer was washed twice
with DCM, and the combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel to give 3-methyl-1-morpholinoi-
Methyl 3-Isopropyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate
1
(3ag). 112 mg, 91% yield; light yellow solid, mp 188−190 °C; H
NMR (300 MHz, CDCl3) δ 11.23 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H),
7.79−7.60 (m, 2H), 7.51−7.47 (m, 1H), 3.99 (s, 3H), 3.31−3.22 (m,
1H), 1.46 (s, 3H), 1.44 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ
168.1, 164.0, 147.8, 135.4, 133.1, 127.5, 126.5, 124.3, 124.2, 108.4,
52.4, 30.9, 20.8 ppm; IR (KBr) 2985, 1719, 1655, 1618, 1331, 1274,
1214, 1042, 654 cm−1; HRMS (ESI) calcd for [C14H15NO3 + Na]+
268.0944, found 268.0939.
Ethyl 3-tert-Butyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate
1
(3ah). 128 mg, 94% yield; white solid, mp 185−187 °C; H NMR
1
(300 MHz, CDCl3) δ 10.20 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 7.67 (t, J
= 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 4.44
(q, J = 7.1 Hz, 2H), 1.51 (s, 9H), 1.43 (t, J = 7.2 Hz, 3H) ppm; 13C
so-quinoline-4-carboxylate 5a. 147 mg, 98% yield; colorless oil; H
NMR (300 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.4
Hz, 1H), 7.61−7.56 (m, 1H), 7.48−7.35 (m, 1H), 4.48 (q, J = 7.1 Hz,
F
DOI: 10.1021/acs.joc.5b02824
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The Journal of Organic Chemistry
Note
2H), 3.96−3.84 (m, 4H), 3.51−3.37 (m, 4H), 2.61 (s, 3H), 1.43 (t, J =
7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 169.1, 161.0, 148.7,
136.0, 130.4, 125.4, 125.4, 124.4, 118.7, 117.7, 66.9, 61.2, 51.6, 23.3,
14.3 ppm; IR (KBr) 2932, 2849, 2377, 2336, 1711, 1275, 1257, 1234,
764, 750 cm−1; HRMS (ESI) calcd for [C17H20N2O3 + H]+ 301.1547,
found 301.1549.
colorless oil; 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J = 8.1 Hz, 1H),
7.88 (d, J = 8.4 Hz, 1H), 7.77−7.67 (m, 3H), 7.67−7.56 (m, 1H),
7.45−7.33 (m, 3H), 4.54 (q, J = 7.1 Hz, 2H), 2.76 (s, 3H), 1.46 (t, J =
7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 149.4, 145.1,
133.4, 132.3, 131.5, 129.5, 128.5, 127.4, 127.2, 124.0, 123.2, 121.9,
95.0, 86.6, 61.8, 23.1, 14.3 ppm; IR (KBr) 2922, 2353, 1721, 1693,
1649, 1351, 1261, 1061, 763 cm−1; HRMS (ESI) calcd for
[C21H17NO2 + H]+ 316.1332, found 316.1330.
Ethyl 3-Methyl-1-phenoxyisoquinoline-4-carboxylate (5b).19
A
sealed tube with a magnetic stirring bar was charged with CuI (4.8 mg,
5 mol %), K2CO3 (0.6 mmol), 4 (0.5 mmol), phenol (0.6 mmol), and
DMF (2 mL) under air. The reaction mixture was stirred for 30 min at
room temperature and then transferred to a preheated oil bath at 110
°C. At the end of the reaction, the mixture was cooled to room
temperature and diluted with EA, and the mixture was filtered through
a Celite pad and washed with EA (10 mL × 3). The filtrate was
concentrated, and the residue was purified by column chromatography
on silica gel to provide the desired product 5b. 143 mg, 93% yield;
colorless oil; 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 8.3 Hz, 1H),
7.93 (d, J = 8.5 Hz, 1H), 7.71−7.65 (m, 1H), 7.54−7.49 (m, 1H),
7.44−7.34 (m, 2H), 7.28−7.16 (m, 3H), 4.48 (q, J = 7.1 Hz, 2H), 2.50
(s, 3H), 1.41 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ
168.7, 159.9, 153.8, 148.7, 136.4, 131.7, 129.4, 126.6, 124.8, 124.3,
123.8, 121.8, 119.1, 117.7, 61.4, 23.1, 14.4 ppm; IR (KBr) 2926, 1720,
1573, 1489, 1380, 1239, 1201, 763, 749 cm−1; HRMS (ESI) calcd for
[C19H17NO3 + H]+ 308.1281, found 308.1284.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02824.
Experimental procedures, and H and 13C NMR spectra
1
for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ajlin@cpu.edu.cn (A.L.).
*E-mail: hyao@cpu.edu.cn (H.Y.).
■
Author Contributions
†Y. Wu and P. Sun contributed equally.
Ethyl 1-Cyano-3-methylisoquinoline-4-carboxylate (5c).20
A
sealed tube was charged with ethyl 1-bromo-3-methylisoquinoline-4-
carboxylate 4 (0.5 mmol), CuCN (1 mmol), and dimethylformamide
(2 mL). The reaction mixture was refluxed at 140 °C for 3 h under
nitrogen. At the end of the reaction, the mixture was poured into water
(15 mL), the precipitate was filtered, and the residue was washed with
EA (15 mL × 3). The water phase was washed with EA (10 mL × 3).
The combined organic phase was washed with water and brine, dried
over Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel to give the desired compound 5c. 48 mg,
40% yield; white solid, mp 128−130 °C; 1H NMR (300 MHz, CDCl3)
δ 8.37−8.28 (m, 1H), 7.94−7.91 (m, 1H), 7.86−7.81 (m, 1H), 7.78−
7.73 (m, 1H), 4.59 (q, J = 7.1 Hz, 2H), 2.76 (s, 3H), 1.49 (t, J = 7.1
Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 167.1, 149.9, 135.0,
133.4, 132.6, 129.2, 127.3 127.0, 125.5, 124.4, 115.4, 62.4, 22.6, 14.3
ppm; IR (KBr) 2360, 2341, 1728, 1654, 1637, 1241, 1218, 765, 669
cm−1; HRMS (ESI) calcd for [C14H12N2O2 + H]+ 241.0972, found
241.0973.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC21572272 and NSFC21502232),
the Natural Science Foundation of Jiangsu Province
(BK20140655), and the Foundation of State Key Laboratory
of Natural Medicines (ZZJQ201306) is gratefully acknowl-
edged.
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5d. 145 mg, 88% yield; white solid, mp 133−135 °C; H NMR (300
MHz, CDCl3) δ 8.00 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H),
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