Visible-Light-Mediated Direct Decarboxylative Acylation of Electron-Deficient Heteroarenes Using α-Ketoacids

Article abstract of DOI:10.1021/acs.joc.9b00004

Acylation of electron-deficient heteroaromatic compounds has been developed using visible light. α-Ketoacids have been used as an efficient source of acyl radicals under photoredox conditions. The in situ generated acyl radicals from α-ketoacids have been coupled to a wide variety of electron-deficient heteroaromatic compounds in a Minisci type reaction. This method would be attractive to access biologically attractive molecules.

Full text of DOI:10.1021/acs.joc.9b00004

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Article
Visible light-mediated Direct Decarboxylative Acylation
of Electron Deficient Heteroarenes using #-Ketoacids
Sabyasachi Manna, and Kandikere Ramaiah Prabhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00004 • Publication Date (Web): 01 Apr 2019
Downloaded from http://pubs.acs.org on April 1, 2019
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Page 1 of 33
The Journal of Organic Chemistry
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Visible light-mediated Direct Decarboxylative Acylation of Electron
9
Deficient Heteroarenes using α-Ketoacids
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Sabyasachi Manna, and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India.
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Ir-PC1 (2 mol %)
O
het
Na2S2O8 (2 equiv)
OH
het
+
Ph
CH3CN:H2O, rt, CFL
12-24h
O
O
Ph
ABSTRACT: Acylation of electron deficient heteroaromatic compounds has been developed using
visible light. α-Ketoacids have been used as an efficient source of acyl radicals under photoredox
conditions. The in situ generated acyl radicals from α-ketoacids have been coupled to a wide variety of
electron deficient heteroaromatic compounds in a Minisci type reaction. This method would be
attractive to access biologically attractive molecules.
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Page 2 of 33
INTRODUCTION
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Advances in photoredox catalysis are opening new avenues in organic synthesis as these methods offer
excellent sustainability in functionalization of C-H bonds.1 Formation of C-C bonds is facile in the light-
mediated radical decarboxylation of carboxylic acids, which involves radical decarboxylative
functionalization and extrusion of CO2.2 This method offers the advantage of using readily available
acids. The initial and simultaneous efforts from MacMillan, Yoon and Stephenson groups’ has made an
emphatic emergence of the visible light mediated reactions in the field of synthetic organic chemistry.3
Acylation of heteroarenes has attracted chemists due to the occurrence of the acylated
heterocyclic scaffold in various natural products and drugs (Fig 1).4 While the acylation of electron-rich
aryl system is facile and well established using metal catalysts,5 acylation of heteroaromatic compounds
is a challenging task.6 Nevertheless, the acylation of heterocyclic compounds has been accomplished
using acyl radicals employing Minisci reaction conditions.7 The classical Minisci reaction involves the
acylation of heteroarenes using α-keto acid under harsh reaction conditions, which limits its scope.7
Therefore, several variations of Minisci reactions can be seen in the literature5a, 8-10 for the acylation of
heteroarenes. However, most of these reactions also involve harsh reaction conditions. There are many
approaches to overcome these constraints with a varied degree of success (Scheme 1). Recently,
Antonchick reported a metal-free CDC (cross dehydrogenative coupling) reaction of heteroarenes using
PhI(OCOCF3)2 and TMSN3.5a Soon after this report, our group has demonstrated acylation of
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H
CO2
HO
HO
CO2H
O
N
N
O
N
O
O
O
O
HN
HO
O
Cl
Cl
OH
O
Acetylcholinesterase
inhibitor
Potent CRTH2 antagonist
Inhibitor of IGF binding proteins
Figure 1. Bio-active Benzoyl Isoquinolines
2
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The Journal of Organic Chemistry
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electron- deficient heterocycles using TBAB/K2S2O8 combination with aldehydes.8 Subsequently there
were a few more reports on acylation of electron deficient heteroarenes using aldehydes.9 Liu and co-
workers, as well as other groups, employed methyl arenes to acylate electron-deficient heteroarenes10. In
order to achieve milder conditions, light-mediated reactions were designed which led to a variety of
reactions such as the alkylation of heterocyclic compounds, C-C bond forming reactions, etc.11 The
transition-metal-catalyzed decarboxylative coupling strategies are attractive and useful reactions for the
formation of C-C and C-hetero bonds. The Minisci reaction, generally, employs acyl radical,12 but there
are a few reports, which employed ketoacids as mild reactants for achieving the acylation of
heterocyclic compounds.12,13,14 We envisioned the utility of ketoacids as an effective source of the acyl
radical under visible light conditions.
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Scheme 1. Minisci C-H Acylation of N-Heteroarenes
(i) Antonchick et al.
O
R1
PhI(OCOCF3)2
TMSN3
R1
+
N
O
N
R2
H
R1
CH3
R1
(ii) Liu et al.
R1
MnO2, TBHP
TFA
N
+
R2
N
O
R2
(iii) Previous report from our lab
R1
TBAB, K2S2O8
°C
R1
O
N
O
+
R2
N
110
H
R2
O
This work
(iv)
via COR
het
OH
+
het
C
R
R
O
O
3
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RESULTS AND DISCUSSION
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To verify this hypothesis, we subjected isoquinoline 1 to phenylglyoxalic acid 2 as an acylating reagent
using 2 mol % of [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (Ir-PC1, dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)pyridine, dtbbpy = 4,4´-di-tert-butyl-2,2´-bipyridine) as a photocatalyst and sodium
persulfate as an oxidant under 5W blue LED irradiation using CH3CN as a solvent (entry 1, Table 1). To
our delight, the acylated isoquinoline 3 was obtained in 20% yield (1H NMR yield). Further, solvent
screening studies showed that a mixture of degassed CH3CN and H2O (1:1) is a better solvent system as
it furnished the acylated product 3 in 65% yield (entries 2-6). The reaction of 1 with 2.4 equiv. of keto
acid 2 furnished the product 3 in 66% yield (entry 7). The similar reaction of 1a with 2 using K2S2O8
for 24h furnished the product 3 in 64% yield (entry 8). The use of [Ir(dF(CF3)ppy)2(bpy)]PF6 (Ir-PC2)
furnished the product 3 in 62% yield (entry 9). The reaction of 1 with 2 in the presence of Ir-PC1 using
K2S2O8 for 12h furnished the product 3 in 55% yield (entry 10). The similar reaction for 24h with low
catalyst loading (1 mol%) resulted in the formation of the product 3 in 60% (entry 11), whereas
increasing the catalyst loading to 3% was not of great use as this reaction rendered the product in 65%
(entry 12). Ru(III)-Catalyst under the similar conditions furnished the product 3 in a low yield of 16%
(entry 13). Oxidant screening studies showed that Na2S2O8 is a better-suited oxidant whereas other
oxidants such as NH4S2O8, TBHP, benzoquinone, benzylperoxide, and NaClO2 gave either diminished
yields or furnished no product (entries 14). The reaction mixture, when irradiated under CFL, instead of
blue LED, gave almost the same yield (65%, entry 15). Further control studies revealed that there was
no reaction in the absence of light irradiation, or the oxidant, or the photocatalyst (entries 16-18).
Table 1. Optimization of the Decarboxylative Acylation of Isoquinolinea
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photocatalyst
O
oxidant (2 equiv)
N
OH
+
Ph
N
solvent, rt, CFL
24 h
3
2
O
1
O
Ph
photocatalyst
(mol %)
oxidant
(2 equiv)
solvent
yield
(%)b
entry
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The Journal of Organic Chemistry
(2 mL)
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1
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7d
8
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC2 (2)
Ir-PC1(2)
Ir-PC1(1)
Ir-PC1(3)
Na2S2O8
CH3CN
DMSO
Toluene
DCM
20
12
5
15
65 (56)c
54
66
64
62
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65
16
traceg
65
4
0
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
K2S2O8
K2S2O8
Na2S2O8
K2S2O8
K2S2O8
CH3CN:H2O (1:1)
CH3CH2CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
9
10 e
11
12 f
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14
15h
16i,j
17
18
Ru(bpy)3(PF6)2 (2) K2S2O8
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
Ir-PC1 (2)
none
other oxidants
Na2S2O8
Na2S2O8
none
Na2S2O8
trace
a General conditions: 1 (0.2 mmol, 1 equiv.), 2 (0.4 mmol, 2 equiv), Ir-PC1 (0.004 mmol, 0.004 equiv.), oxidant (0.4 mmol, 2 equiv.) and
CH3CN:H2O (2 mL, 1:1 v/v). b Yields determined by 1H NMR spectroscopy using terephthaldehyde as internal standard. c Isolated yield in
the parentheses. d Ketoacid 2.5 equiv . eNa2S2O8 2.5 equiv. f Reaction time 12h. g NH4S2O8, TBHP, BQ, BPO, and NaClO2 furnished less
than 15 % yields. h.CFL light was used instead of LED. i Time: 6 h. j Reaction performed in the absence of light. (Ir-PC1, dF(CF3)ppy = 2-
(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine, bpy = 2,2´-bipyridine). Ir-PC2 = [Ir(dF(CF3)ppy)2(bpy)]PF6
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Having the optimized reaction conditions at hand (entry 2, Table 1), we explored the scope of
the C-H acylation reaction with a variety of heteroarenes. As can be seen, electron-deficient
heteroarenes were acylated at the most electrophilic position with phenylglyoxalic acid (Scheme 2).
Isoquinoline with no substituent at the C4-position gave the desired product 3 in 56% isolated yield
(entry 1), whereas 4-bromoisoquinoline and 5-bromoisoquinoline furnished the corresponding acylated
products 4 and 5 in 70 and 76% yields, respectively. The reaction of 4-arylated isoquinolines with
glyoxalic acid 2 was facile, and corresponding acylated products were obtained in good to excellent
yields. Thus, 4-phenylisoquinoline furnished the acylated product 6 in 77% yield. The reaction of 4-(4-
chlorophenyl)isoquinoline, 4-(4- ethylphenyl)isoquinoline, 4-(4-bromophenyl)isoquinoline, and 4-(4-
(tert-butyl)phenyl)isoquinoline with glyoxalic acid was facile furnishing the corresponding acylated
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products 7, 8, 9, and 10 in 76, 61, 54, , and 73% yields, respectively. The reaction of 4-(4-
(phenylethynyl)phenyl)isoquinoline with 2 furnished the product 11 in 26% yield and the low yield may
be attributed to the decomposition of the isoquinoline under the oxidative photoredox conditions. The
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reaction of 4-(2,4-difluorophenyl)isoquinoline, 4-(4-phenethylphenyl)isoquinoline, and
1-(4-
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(isoquinolin-4-yl)phenyl)ethan-1-one under the optimal reaction conditions furnished the corresponding
acylated products 12, 13, and 14 in 89, 73, and 77% yields, respectively. Interestingly, the reaction of
phenanthridine with glyoxalic acid was facile furnishing the corresponding acylated product 15 in 88%
yield. The reaction was also successful with 4-(naphthalen-1-yl)isoquinoline furnishing the expected
acylated product 16 in 79% yield. The acylation of the 4-cyanopyridine using the present strategy
afforded the corresponding acylated product 17 48% yield. Quiniloine derivatives underwent the
acylation successfully. Thus, the acylation of 4,7-dichloroquinoline gave the corresponding acylated
product 18 in 72% yield. 8-Methylisoquinoline was acylated successfully but furnished a mixture of
mono- and diacylated products 19 and 20 in 46 and 35% yields, respectively. The acylation of
quinoxaline is a difficult task. However, the acylation of quinoxaline under the optimal reaction
conditions was facile furnishing the desired acylated product 21 in 47% yield. In most of the reactions
wherein the yields are modest, it was observed that the starting materials were decomposed and no other
side products were detected under the reaction conditions.
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Scheme 2. Scope of Heteroarenesa
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The Journal of Organic Chemistry
Ir-PC1 (2 mol %)
Na2S2O8 (2 equiv)
O
O
1
2
3
4
OH
het
+
Ph
Ph
CH3CN:H2O, rt, CFL
het
2
O
3-21
1
12-24h
5
6
Br
Br
Ph
7
8
N
N
N
N
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O
Ph
O
Ph
O
Ph
O
Ph
b
3
4
5
6
, (56%)
Cl
, (70%, 67% )
, (76%)
, (77%)
tBu
Et
Br
N
N
N
N
O
Ph
O
Ph
O
9
Ph
, (54%)
O Ph
10
, (73%)
8
, (61%)
7
, (76%)
Ph
Ph
O
F
F
N
Ph
N
N
N
O
O
Ph
O
13
Ph
O
11
Ph
, (26%)
12
14
Cl
N
, (89%)
, (77%)
, (73%)
CN
N
N
O
N
O
Ph
Cl
O
Ph
15
Ph
O
16
17
18
, (72%)
, (88%)
, (79%)
, (48%)
O
Ph
N
N
Ph
N
Ph
N
O
O
19
20
21
, (47%)
, (46%)
, (35%)
O
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a
Reaction conditions: Heteroarene (0.2 mmol), phenylglyoxalic acid (0.4 mmol), Na2S2O8 (2 mmol), Ir-PC1 (0.004 mmol) in 2 mL
1
2
3
4
5
6
CH3CN:H2O (1:1) under CFL for 24 h. b 5 mmol scale.
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9
After exploring the scope for heteroarenes, we turned our attention to exploring the scope of the
reaction with α-ketoacids for this decarboxylation reaction (Scheme 3). Thus, the reaction of 2-oxo-2-
(p-tolyl)acetic acid and 2-(4-methoxyphenyl)-2-oxoacetic acid with isoquinoline under optimal reaction
conditions gave the corresponding acylated products 22 and 23 in 59 and 64% yields, respectively. The
reaction of aliphatic glyoxalic acids such as pyruvic acid, 2-oxobutyric acid ,and 4-methyl-2-oxovaleric
acid with 4-bromoisoquinoline gave the corresponding acylated product 24, 25, 26 in 36, 41 and 71%
yield respectively. The scaled up reaction of 4-bromoisoquinoline (5 mmol, 1.04 g) with
phenylglyoxalic acid 2 (10 mmol, 1.50 g) under optimal reaction conditions afforded the acylated
product 4 in 67% yield, which compares to the yield obtained on smaller scale (see Scheme 2).
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Scheme 3. Scope of Glyoxalic acida
O
Ir-PC1 (2 mol %)
Na2S2O8 (2 equiv)
het
OH
R
R
het
+
CH3CN:H2O, rt, CFL,8-24 h
O
O
Br
Br
Br
N
O
N
O
N
O
N
N
O
O
O
23
24
25
26
27 (
71%)
(59%)
(64%)
(36%)
(41%)
a
Reaction conditions: Heteroarene (0.2 mmol), phenylglyoxalic acid (0.4 mmol), Na2S2O8 (2 mmol), Ir-PC1 (0.004 mmol) in 2 mL
CH3CN:H2O (1:1) under CFL for 24 h
To showcase the applicatioin of the methodology, we employed the present strategy to synthesize (6,7-
dimethoxyisoquinolin-1-yl)(3,4-dimethoxyphenyl)methanone, which is a acetylcholinesterase inhibitor
(Fig 1). Thus 6,7-dimethoxyisoquinoline (22a) was reacted with the keto acid 2-(3,4-dimethoxyphenyl)-
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The Journal of Organic Chemistry
2-oxoacetic acid (22bb) under optimal conditions to obtain the acylated product 22 in 52% yield
1
2
3
(Scheme 4).
4
5
6
7
Scheme 4. Synthesis of acetylcholinesterase inhibitor a
8
9
O
HO
O
O
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12
13
14
15
16
17
18
19
20
21
22
23
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60
O
O
N
O
Ir-PC1 (2 mol %)
Na2S2O8 (2 equiv)
O
O
O
N
O
CH3CN:H2O, rt, CFL,28 h
O
22a
)
22b
)
22
(52%)
(1 equiv
(2 equiv
a Reaction conditions: 22a (37.8 mg, 0.2 mmol), 22b (84 mg, 0.4 mmol), Na2S2O8 (95.6 mg, 2 mmol), Ir-PC1 (4.48 mg, 0.004 mmol) in 2
mL CH3CN:H2O (1:1) under CFL for 24 h
Once the scope of the reaction was explored, we attempted to understand the mechanism of this
direct acylation reaction. A reaction of 4-bromoisoquinoline with phenylglyoxalic acid 2 in the
presence of TEMPO (2 equiv) under optimal failed to furnish the expected product suggesting the
possible involvement of acyl radical intermediate in the reaction. Based on the literature reports,15 we
present a tentative mechanism of the reaction here in Scheme 5. Photo-irradiation of photocatalyst
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (PC1) under visible light from household light bulb (CFL) produces a
long-lived photoexcited state *[Ir(dF(CF3)ppy)2(dtbbpy)]PF6. The produced *IrIII is a strong reductant
(E1/2IV/*III = -0.88 vs SCE in MeCN/H2O = 2:1)16 and, it is capable of reducing the persulfate anion (E1/2
= 1.75 V vs SCE)17 to afford the oxidized iridium species (IrIV), sulfate dianion and sulfate radical
anion. The acyl radical A is then generated through hydrogen-atom transfer (HAT) between the ketoacid
2 and the sulfate radical anion, followed by decarboxylation.18 It was expected that the resulting acyl
radical A would be sufficiently nucleophilic to add to the protonated (from the proton transfer between
bisulfate anion and the heteroarene) electron deficient heteroarenes to produce the amine radical cation
B. This cation B upon deprotonation would give α-amino radical C, which can take part in another
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single electron transfer (SET) event with the oxidized iridium species IrIV (IrIV/III = + 1.70V vs SCE in
MeCN/H2O = 2:1)11 to regenerate the ground state photocatalyst and the desired acylated heteroarene.
1
2
3
4
5
6
7
8
9
Scheme 5. Proposed catalytic cycle
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O
O
OH
NH
O
A
2
acyl radical
Keto acid
2
2
H
+
+
SO4
SO4
sulfate
radical
SO4
NH
O
2
S2O8
persulfate
B
IrIV
oxidant
NH
H
Irlll
reductant
O
C
NH
O
IrIII
[Ir(dtbbpy)(ppy)2][PF6]
household light bulb
CONCLUSION
In summary, we have developed a photoredox catalytic approach to the direct acylation of electron
deficient heteroarenes. This mild and efficient protocol can be applied to acylate a variety of
isoquinoline, quinolone, phenanthridine, and pyridine derivatives. We anticipate this visible light
mediated C-H functionalization protocol will find broad application in academic and pharmaceutical
chemistry.
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The Journal of Organic Chemistry
1
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3
EXPERIMENTAL SECTION
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8
9
General Information: All chemicals were purchased from commercial suppliers and used as delivered.
Pd(OAc)2 (product number: 10516) has been obtained from Alfa Aesar. Tricyclohexylphosphine
(product number: 261971) was procured from Sigma Aldrich. THF (Finar AR dry grade) was used
directly for all the procedures. 1H NMR and 13C NMR spectra were recorded at 400 MHz and 100 MHz,
respectively. Chemical shifts are reported in parts per million (ppm) and coupling constants in Hertz
(Hz). Tetramethylsilane (TMS) (δ = 0.00 ppm) or residual CHCl3 in CDCl3 (δ = 7.26 ppm) served as
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1
internal standard for recording. H NMR and the residual non-deuterated solvent signal of CDCl3 (δ =
77.16 ppm) was used as internal standard for 13C NMR (proton decoupled).1,2 IR spectra were recorded
using Perkin Elmer FT-IR instrument; Mass spectra (EI) were recorded using Shimadzu; and High-
resolution mass spectra (HRMS) were recorded on Q-TOF (Micromass) spectrometer. Melting points of
the product were determined on Buchi melting point apparatus. Flash column chromatography was
carried out using commercially obtained silica gel and thin-layer chromatography (TLC) was performed
using Merck silica gel 60 F254 TLC plates.
Preparation of starting isoquinolines
The isoquinoline (3a),19a and its derivatives 4-bromoisoquinoline (4a),19b 5-bromoisoquinoline (5a),19c
phenanthridine (15a),20a isonicotinonitrile (17a),20b 8-methylquinoline (19a),21 and quinoxaline (21a)22
were procured from commercial sources and used as is. 4-Phenylisoquinoline (6a),23a 4-(4-
chlorophenyl)isoquinoline (7a),23b 4-(4-ethylphenyl)isoquinoline (8a), 4-(4-bromophenyl)isoquinoline
(9a),23c 4-(4-(tert-butyl)phenyl)isoquinoline (10a),23a 4-(phenylethynyl)isoquinoline (11a),23d 4-(2,4-
difluorophenyl)isoquinoline
(12a),
4-phenethylisoquinoline
(13a),23d
1-(4-(isoquinolin-4-
yl)phenyl)ethan-1-one
(14a),23e
4-(naphthalen-1-yl)isoquinoline
(16a),23f
and
6,7-
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dimethoxyisoquinoline (22a)8b were prepared according to the modified reported methods, 23d,,23g and
1
2
3
the data were matched with reported values.
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5
6
7
8
General procedure for preparation for 4-phenylisoquinolines
9
In an oven dried round bottom flask, 4-bromoisoquinoline (250 mg, 1.2 mmol, 1 equiv) was taken in a
mixture of 1.5 mL of EtOH, 3 mL water and 6 mL toluene and degassed for 15 min. To the resulting
mixture, phenylboronic acid (1.5 equiv), K2CO3 (4.8 mmol, 4 equiv) and Pd(PPh3)4 (0.06 mmol, 0.025
equiv) were added at r.t. The resulting mixture was stirred at 95 °C (oil bath) under argon atmosphere
for 36h. The reaction mixture was cooled to r.t., quenched with saturated aq. NH4Cl solution, extracted
with CH2Cl2. The combined organic layer was collected, dried over Na2SO4, concentrated in vacuo to
give crude product which was purified by flash column chromatography over silica using 20-30%
EtOAc in petrolium ether as eluent to obtain 4-phenylisoquinolines as pure product.
Characterisation data for unknown 4-phenylisoquinolines:
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15
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4-(4-Ethylphenyl)isoquinoline (8a).
Et
N
8a
Purified by silica gel (230-400 mesh) column chromatography using 20% EtOAc in petroleum ether.
Reddish oil; Yield 83% (233.3 mg); Rf (20% EtOAc/Hexane) 0.4; IR (Neat, cm-1) 2965, 1619, 1495,
1390; 1H NMR (400 MHz, CDCl3): δ 9.24 (s, 1 H), 8.48 (s, 1 H), 8.02 (d, J = 8.2 Hz, 1 H), 7.94 (d, J =
8.4 Hz, 1 H), 7.43 (d, J = 8 Hz, 2 H), 7.35 (d, J = 8 Hz, 2 H), 2.76 (q, J = 7.6 Hz, 2 H), 1.33 (t, J = 7.6
Hz, 3 H); 13C NMR {1H} (100 MHz, CDCl3): δ 151.7, 144.0, 142.8, 134.3, 134.2, 133.3, 130.4, 130.0,
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The Journal of Organic Chemistry
129.4, 128.4, 128.1, 127.8, 127.0, 124.8, 28.6, 15.5; HRESI-MS (m/z) Calculated for C17H15NH (M+H)
1
2
3
234.1283 found (M+H) 234.1285.
4
5
6
7
8
9
4-(2,4-Difluorophenyl)isoquinoline (12a).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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59
60
F
F
N
12a
Purified by silica gel (230-400 mesh) column chromatography using 30% EtOAc in petroleum ether.
Yellowish oil; Yield 89% (257.6 mg); Rf (20% EtOAc/Hexane) 0.3; IR (Neat, cm-1) 3050, 1621, 1509;
1H NMR (400 MHz, CDCl3): δ 9.30 (s, 1 H), 8.47 (s, 1 H), 8.06-8.03 (m, 1 H), 7.71-7.62 (m, 3 H),
7.42-7.36 (m, 1 H), 7.07-6.98 (m, 2 H); 13C NMR {1H} (100 MHz, CDCl3): δ 163.1 (dd, J= 11.34, 248.7
Hz), 160.4 (dd, J=11.34, 248.7 Hz), 152.8, 143.5, 134.3, 133.0 (dd, J=4.9, 9.5 Hz), 130.8, 128.2, 127.9,
127.4, 126.6, 124.4, 120.5 (dd, J=4.1, 16.7 Hz), 111.7 (dd, J=3.8, 21.2 Hz) , 104.3 (dd, J=25.6, 25.6 Hz);
19F NMR (376 MHz,CDCl3):δ 108.9 (d, J = 8.3 Hz), 109.2 (d, J = 8.3 Hz ); HRESI-MS (m/z)
Calculated for C15H9F2NH (M+H) 242.0781 found (M+H) 242.0785.
Typical general experimental procedure
General procedure for visible light mediated acylation of heteroarenes: To an oven dried 8 mL vial
containing a magnetic stirring bar, heteroarene (0.2 mmol, 1 equiv), arylglyoxalic acid (0.4 mmol, 2
equiv), sodium persulfate (0.4 mmol, 2 equiv) and [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.004 mmol, 2 mol%)
were added. The vial was flushed with argon and closed with a PTFE cap followed by addition of 2 mL
of CH3CN:H2O (1:1) to it via syringe. The resulted mixture was then degassed with argon for 15 min
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and was kept stirring for 12 h under the irradiation of 2×27W Philips Tornado CFL bulb (at a distance
of 5 cm from the bulb) with a fan above it. The mixture was then transferred in a round bottom flask
with washing with EtOAc. CH3CN were then removed under reduced pressure. To the residue, saturated
NaHCO3 was added and the aqueous phase was extracted 3 times with EtOAc. The combined organic
layer was washed with brine followed by drying over sodium sulfate. The solvent was then removed
under reduced pressure and the product was purified by flash column chromatography.
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Experimental procedure for Scaling up reaction: To a oven dried 100 mL round bottom flask
containing an oval shaped magnetic stirring bar, 4-bromoisoquinoline (5 mmol, 1 equiv),
Phenylglyoxalic acid (10 mmol, 2 equiv), sodium persulfate (10 mmol, 2 equiv) and
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.1 mmol, 2 mol%) were added. The flask was flushed with argon and
closed with a rubber septum followed by addition of 50 mL of CH3CN:H2O (1:1) to it via syringe. The
resulted mixture was then degassed with argon for 20 min and was kept stirring for 24 h under the
irradiation of 2×27W Philips Tornado CFL bulb with a fan above it. The mixture was then transferred in
a round bottom flask with washing with EtOAc. CH3CN were then removed under reduced pressure. To
the residue, saturated NaHCO3 was added and the aqueous phase was extracted 3 times with EtOAc.
The combined organic layer was washed with brine followed by drying over sodium sulfate. The solvent
was then removed under reduced pressure and the product was purified by flash column
chromatography.
Characterization data for the products
Isoquinolin-1-yl(phenyl)methanone (3).24,25
N
O
3
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The Journal of Organic Chemistry
Prepared as described in the general experimental procedure. White solid; Yield 56% (26.1 mg); mp:
1
2
3
1
74-76 °C (lit.24 74-75 °C); Rf (20%EtOAc/Hexane) 0.6; IR (KBr, cm-1) 2923, 1670; H NMR (400
4
5
6
MHz, CDCl3): δ 8.61 (d, J = 5.3 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 1 H), 7.96-7.92 (m, 3 H), 7.81 (d, J =
13
5.81 Hz, 1 H), 7.76-7.73 (m, 1 H), 7.64-7.59 (m, 2 H), 7.49-7.46 (m, 2 H); C NMR{1H} (100 MHz,
7
8
9
CDCl3): δ 194.7, 156.4, 141.1, 136.7, 136.6, 133.7, 130.7, 130.4, 128.5, 128.3, 127.1, 126.4, 126.2,
122.6; HRESI-MS (m/z) Calculated for C16H11NONa (M+Na) 256.0738 found (M+Na) 256.0742.
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11
12
13
14
15
16
17
18
19
20
21
22
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(4-Bromoisoquinolin-1-yl)(phenyl)methanone (4).
Br
N
O
4
Prepared as described in the general experimental procedure. White solid; Yield 70% (43.6 mg); mp:
1
131 °C (lit.25 129-130 °C) ; Rf (20%EtOAc/Hexane) 0.6; IR (KBr, cm-1) 2962, 1666; H NMR (400
MHz, CDCl3): δ 8.80 (s, 1 H), 8.29 (d, J = 8.46 Hz, 1 H), 8.23 (d, J = 8.46 Hz, 1 H), 7.95-7.93 (m, 2 H),
13
7.88-7.84 (m, 1 H), 7.71-7.66 (m, 1 H), 7.64-7.60 (m, 1 H), 7.50-7.46 (m, 1 H); C NMR{1H} (100
MHz, CDCl3): δ193.9, 155.7, 142.9, 136.3, 135.5, 133.9, 132.0, 130.7, 129.2, 128.5, 127.5, 126.6,
126.4, 121.7; HRESI-MS (m/z) Calculated for C16H10BrNONa (M+Na) 333.9843 found (M+Na)
333.9845.
(5-Bromoisoquinolin-1-yl)(phenyl)methanone (5).
Br
N
O
5
Prepared as described in the general experimental procedure. Colorless liquid; Yield 76% (47.5 mg);
1
Rf (20%EtOAc/Hexane) 0.7; IR (KBr, cm-1) 2922, 1671; H NMR (400 MHz, CDCl3): δ 8.71 (d, J =
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5.69 Hz, 1 H), 8.20-8.17 (m, 2 H), 8.03 (d, J = 7.4 Hz, 1 H), 7.94-7.92 (m, 2 H), 7.64-7.60 (m, 1 H),
7.50-7.45 (m, 3 H); 13C NMR{1H} (100 MHz, CDCl3): δ 194.3, 156.8, 142.5, 136.3, 135.7, 134.4,
133.9, 130.7, 128.6, 128.5, 127.4, 125.9, 122.0, 121.4; HRESI-MS (m/z) Calculated for C16H10BrNONa
(M+Na) 333.9843 found (M+na) 333.9840.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
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59
60
Phenyl(4-phenylisoquinolin-1-yl)methanone (6).8
N
O
6
Prepared as described in the general experimental procedure. Yellow liquid; Yield 77% (47.6 mg);
Rf (20%EtOAc/Hexane) 0.6; IR (Neat, cm-1) 2922, 1663; H NMR (400 MHz, CDCl3):δ 8.56 (s, 1 H),
1
8.30 (d, J = 8.32 Hz, 1 H), 8.03-7.99 (m, 3 H), 7.72-7.68 (m, 1 H), 7.64-7.60 (m, 2 H), 7.57-7.56 (m, 4
13
H), 7.53-7.48 (m, 3 H); C NMR{1H} (100 MHz, CDCl3):δ 194.8, 140.9, 136.6, 136.5, 135.3, 135.1,
133.7, 130.8, 130.1, 128.7, 128.5, 128.3, 128.1, 126.3, 126.2, 125.4; HRESI-MS (m/z) Calculated for
C22H15NONa (M+Na) 332.1051 found (M+Na) 332.1053.
(4-(4-Chlorophenyl)isoquinolin-1-yl)(phenyl)methanone (7).
Cl
N
7
O
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The Journal of Organic Chemistry
Prepared as described in the general experimental procedure. White solid; Yield 76% (52.3 mg); mp:
1
2
3
4
5
6
7
8
9
1
148 °C; Rf (10%EtOAc/Hexane) 0.5; IR (Neat, cm-1) 2924, 1656; H NMR (400 MHz, CDCl3):δ 8.52
(s, 1 H), 8.29 (d, J = 8.43, 1 H), 8.02-8.0 (m, 2 H), 7.96-7.94 (m, 1 H), 7.75-7.71 (m, 1 H), 7.67-7.61 (m,
2 H), 7.56-7.49 (m, 6 H); 13C NMR{1H} (100 MHz, CDCl3):δ 194.7, 156.1 , 140.9, 136.6, 135.0, 134.9,
134.6, 134.1, 133.8, 131.4, 131.0, 130.8, 129.0, 128.5, 128.2, 126.5, 126.2, 125.0; HRESI-MS (m/z)
Calculated for C15H12FNOH (M+H) 242.0981 found (M+H) 242.0981.
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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34
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59
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(4-(4-Ethylphenyl)isoquinolin-1-yl)(phenyl)methanone (8).
Et
N
8
O
Prepared as described in the general experimental procedure. Yellow liquid; Yield 61% (41.2 mg);
Rf (20%EtOAc/Hexane) 0.6; IR (KBr, cm-1) 2964, 1668; 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1 H),
8.29 (d, J = 8.35 Hz, 1 H), 8.05-8.01 (m, 3 H), 7.71-7.68 (m, 1 H), 7.64-7.60 (m, 2 H), 7.54-7.47 (m, 4
H), 7.41-7.35 (m, 2 H), 2.78 (q, J = 7.52 Hz), 1.34 (t, J = 7.53 Hz); 13C NMR{1H} (100 MHz, CDCl3): δ
194.9, 144.5, 141.0, 136.7, 135.4, 135.2, 133.8, 133.6, 130.8, 130.6, 130.1, 128.5, 128.2, 128.0, 126.3,
126.3, 125.5, 28.6, 15.5; HRESI-MS (m/z) Calculated for C24H19NONa (M+Na) 360.1364 found (M +
Na) 360.1366.
(4-(4-Bromophenyl)isoquinolin-1-yl)(phenyl)methanone (9).
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Br
1
2
3
4
5
6
N
7
8
9
9
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
37
38
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41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Prepared as described in the general experimental procedure. Yellowish solid; Yield 54% (41.9 mg);
1
mp: 157 °C; Rf (20%EtOAc/Hexane) 0.7; IR (Neat, cm-1) 3059, 1669; H NMR (400 MHz, CDCl3):δ
8.43 (s, 1 H), 8.20 (d, J = 8.33 Hz, 1H), 7.92-7.86 (m, 2 H), 7.85 (d, J = 8.47 Hz, 1H), 7.61-7.53 (m, 3
13
H), 7.42-7.40 (m, 2 H), 7.38-7.35 (m, 2 H), 7.33-7.16 (m, 2 H);; C NMR{1H} (100 MHz, CDCl3):δ
194.6, 156.1, 140.8, 136.5, 135.4, 134.8, 134.0, 133.7, 131.9, 131.6, 131.0, 130.7, 128.5, 128.2, 126.4,
126.1, 124.9, 122.7; HRESI-MS (m/z) Calculated for C16H15NOH (M+ H) 238.1232 found (M+H)
238.1232.
(4-(4-(tert-Butyl)phenyl)isoquinolin-1-yl)(phenyl)methanone (10).
tBu
N
10
O
Prepared as described in the general experimental procedure. White sticky liquid; Yield 73% (53.4
mg); Rf (20%EtOAc/Hexane) 0.7; IR (Neat, cm-1) 2962, 1670; 1H NMR (400 MHz, CDCl3):δ 8.56 (s, 1
H), 8.29 (d, J = 8.44 Hz, 1 H), 8.06 (d, J = 8.41 Hz, 1 H), 8.03-8.01 (m, 2 H), 7.71-7.67 (m, 1 H), 7.63-
13
7.57 (m, 4 H), 7.51-7.47 (m, 4 H), 1.42 (s, 9 H); C NMR{1H} (100 MHz, CDCl3):δ 194.8, 155.4,
151.3, 141.0, 136.7, 135.3, 135.1, 133.6, 130.8, 130.6, 129.8, 128.4, 128.0, 126.3, 125.6 125.5, 34.7,
31.3; HRESI-MS (m/z) Calculated for C26H23NONa (M+Na) 388.1677 found (M+Na) 388.1674.
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The Journal of Organic Chemistry
Phenyl(4-(phenylethynyl)isoquinolin-1-yl)methanone (11).
1
2
3
4
5
6
7
8
9
N
10
11
12
13
14
15
16
17
11
O
Prepared as described in the general experimental procedure. Yellow liquid; Yield 26% (17.3 mg);
1
Rf (10%EtOAc/Hexane) 0.5; IR (Neat, cm-1) 2922, 1666; H NMR (400 MHz, CDCl3):δ 8.83 (s, 1 H),
8.47 (d, J = 8.45 Hz, 1 H), 8.28 (d, J = 8.41 Hz, 1 H), 7.98-7.96 (m, 2 H), 7.88-7.84 (m, 1 H), 3.71-7.67
(m, 3 H), 7.61-7.61 (m, 1 H), 7.51-7.48 (m, 2 H), 7.46-7.43 (m, 3 H); 13C NMR{1H} (100 MHz,
CDCl3):δ 194.3, 155.3 , 144.4, 136.5, 136.4 , 133.8 , 131.9 , 131.4, 129.2 , 128.8, 128.6, 128.5 , 126.5,
125.7 , 125.6 122.5, 118.1, 98.3, 84.3; HRESI-MS (m/z) Calculated for C24H15NONa (M+Na) 356.1051
found (M+Na) 356.1054.
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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(4-(2,4-Difluorophenyl)isoquinolin-1-yl)(phenyl)methanone (12).
F
F
N
12
O
Prepared as described in the general experimental procedure. Brown liquid; Yield 89% (61.5 mg); Rf
(20%EtOAc/Hexane) 0.6; IR (KBr, cm-1) 3065, 1669; 1H NMR (400 MHz, CDCl3):δ 8.53 (s, 1 H), 8.28
(d, J = 8.50 Hz, 1 H), 8.02-8.00 (m, 2 H), 7.74-7.73 (m, 2 H), 7.66-7.61 (m, 2 H), 7.52-7.48 (m, 2 H),
7.46-7.42 (m, 1 H), 7.12-7.03 (m, 2 H); C NMR{1H} (100 MHz, CDCl3):δ 194.5, 163.3 (dd, J=12.0,
13
250.7 Hz), 160.3 (dd, J=12.7, 250.9 Hz), 156.6, 141.7, 136.4, 135.2, 133.7, 132.9 (dd, J = 5.1, 9.3 Hz),
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131.0, 130.7, 128.5, 128.4, 128.2, 126.4, 126.0, 124.9 (d, J=1.05 Hz), 120.1 (dd, J=5.7, 14.7 Hz), 111.8
1
2
3
19
(dd, J=4.3, 20.9 Hz), 104.4 (dd, J=25.6 Hz); F NMR (376 MHz,DMSO-d6):δ 108.62 (d, J = 8.2 Hz),
4
5
6
108.8 (dd, J = 8.2 Hz ) HRESI-MS (m/z) Calculated for C22H13F2NONa (M+Na) 368.0863 found
7
8
(M+Na) 368.0866.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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60
(4-Phenethylisoquinolin-1-yl)(phenyl)methanone (13).
Ph
N
O
13
Prepared as described in the general experimental procedure. Colorless liquid; Yield 73% (49.3 mg);
1
Rf (10%EtOAc/Hexane) 0.6; IR (Neat, cm-1) 2931, 1664; H NMR (400 MHz, CDCl3):δ 8.38 (s, 1 H),
8.28 (d, J = 8.56 Hz, 1 H), 8.13 (d, J = 8.52 Hz, 1 H), 7.94 (d, J = 7.54, 2 H), 7.80-7.76 (m, 1 H), 7.64-
7.58 (m, 2 H), 7.48-7.44 (m, 2 H), 7.33-7.29 (m, 2 H), 7.24-7.21 (m, 3 H), 3.41 (t, J = 7.45 Hz, 2 H),
3.09 (t, J = 8.54 Hz, 2 H); 13C NMR{1H} (100 MHz, CDCl3):δ 194.8, 155.0, 140.9, 136.8, 135.3, 133.5,
133.0, 130.7, 130.6, 128.5, 128.4, 128.3, 127.8, 126.9, 126.3, 126.2, 123.1, 36.7, 32.3; HRESI-MS
(m/z) Calculated for C24H19NONa (M+Na) 360.1364 found (M+Na) 360.1365.
1-(1-Benzoylisoquinolin-4-yl)ethan-1-one (14).
O
N
O
14
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Prepared as described in the general experimental procedure. Yellowish liquid; Yield 77% (54.1
1
2
3
4
5
mg); Rf (40%EtOAc/Hexane) 0.6; IR (KBr, cm-1) 2962, 1670; 1H NMR (400 MHz, CDCl3):δ 8.56 (s, 1
H), 8.30 (d, J = 8.39 Hz, 1 H), 8.16 (d, J = 8.05 Hz, 2 H), 8.02-8.00 (m, 2 H), 7.95 (d, J = 8.42 Hz, 1 H),
6
13
7.76-7.72 (m, 1 H), 7.69-7.62 (m, 4 H), 7.51 (t, J = 7.81 Hz, 2 H), 2.71 (s, 3 H); C NMR{1H} (100
7
8
9
MHz, CDCl3):δ 197.6, 194.6, 156.4, 141.4, 140.8, 136.8, 136.5, 134.7, 134.1, 133.8, 131.1, 130.7,
110.4, 128.7, 128.5, 128.3, 126.5, 126.1, 124.9, 26.7; HRESI-MS (m/z) Calculated for C24H17NO2Na
(M+Na) 374.1157 found (M+Na) 374.1156.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenanthridin-6-yl(phenyl)methanone (15).
N
O
15
Prepared as described in the general experimental procedure. Colorless liquid; Yield 88% (49.9 mg);
1
Rf (10%EtOAc/Hexane) 0.6; IR (Neat, cm-1) 2927, 1673; H NMR (400 MHz, CDCl3):δ 8.69 (d, J =
8.47 Hz, 1 H), 8.63 (d, J = 8.08 Hz, 1 H), 8.21 (d, J = 7.40 Hz, 1 H), 8.13 (d, J = 8.18 Hz, 1 H), 8.03 (d,
J = 8.05 Hz, 2 H), 7.89-7.85 (m, 1 H), 7.70-7.73 (m, 2 H), 7.66-7.59 (m, 2 H), 7.48-7.45 (m, 2 H); 13C
NMR{1H} (100 MHz, CDCl3):δ 194.7, 157.4, 142.6, 136.1, 134.0, 133.2, 131.2, 126.5, 130.8, 130.6,
129.1, 128.8, 128.5, 128.1, 127.8, 127.3, 124.4, 123.7, 122.3, 122.1; HRESI-MS (m/z) Calculated for
C20H13NONa (M+Na) 306.0895 found (M + Na) 306.0895.
(4-(Naphthalen-1-yl)isoquinolin-1-yl)(phenyl)methanone (16).
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1
2
3
4
5
N
6
7
O
8
9
16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Prepared as described in the general experimental procedure. Yellow liquid; Yield 79% (56.8 mg);
Rf (20%EtOAc/Hexane) 0.8; IR ( KBr, cm-1 ) 2927, 1669; 1H NMR (400 MHz, CDCl3):δ 8.63 (s, 1 H),
8.33 (d, J = 8.25 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 8.03-7.96 (m, 2 H), 7.65-7.59 (m, 3 H), 7.56-7.49
13
(m, 6 H), 7.44-7.42 (m, 1 H), 7.38-7.34 (m, 1 H); C NMR{1H} (100 MHz, CDCl3):δ 194.8, 156.1,
141.9, 136.6, 136.4, 134.1, 133.9, 133.7, 133.5, 132.6, 130.8, 130.7, 128.9, 128.5, 128.4, 128.3, 128.2,
126.5, 126.3, 126.2, 126.0, 125.4; HRESI-MS (m/z) Calculated for C26H17NOH (M+H) 360.1388 found
(M+H) 360.1385.
2-Benzoylisonicotinonitrile (17).12
CN
N
O
17
Prepared as described in the general experimental procedure. Yellow liquid; Yield 48% (19.9 mg);
1
Rf (30%EtOAc/Hexane) 0.4; IR (Neat, cm-1) 2927, 1669; H NMR (400 MHz, CDCl3):δ 8.91 (d, J =
4.89 Hz, 1 H), 8.28 (s, 1 H), 8.09-8.06 (m, 2 H), 7.73 (dd, J1 = 4.94 Hz, J2 = 1.45 Hz, 1 H), 7.65 (t, J =
13
7.46 Hz, 1 H), 7.54-7.50 (m, 2 H); C {1H} NMR (100 MHz, CDCl3):δ 191.6, 156.1, 149.4, 135.1,
133.6, 131.0, 128.4, 127.2, 126.4, 121.9, 115.8; HRESI-MS (m/z) Calculated for C13H8N2ONa (M+Na)
231.0534 found (M+Na) 231.0543.
(4,7-Dichloroquinolin-2-yl)(phenyl)methanone (18).
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Cl
1
2
3
4
5
6
7
8
9
10
Cl
N
O
18
Prepared as described in the general experimental procedure. White solid; Yield 72% (43.5 mg); mp:
148-149 °C; Rf (10%EtOAc/Hexane) 0.7; IR ( KBr, cm-1) 3071, 1656; H NMR (400 MHz, CDCl3):δ
8.24-8.18 (m, 5 H), 7.70-7.62 (m, 2 H), 7.54-7.50 (m, 2H); 13C NMR{1H} (100 MHz, CDCl3):δ 192.0,
155.3, 147.8, 143.9, 137.1, 135.4, 133.4, 131.3, 130.3, 129.6, 128.2, 125.5, 125.4, 121.1; HRESI-MS
(m/z) Calculated for C16H9Cl2NOH (M+H) 302.0139 found (M+H) 302.0138.
1
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8-Methylquinolin-2-yl)(phenyl)methanone (19).25
N
O
19
Prepared as described in the general experimental procedure. Colorless liquid; Yield 46% (22.7 mg);
mp: 71 °C (lit.25 63-64 °C) ; Rf (20%EtOAc/Hexane) 0.5; IR ( KBr, cm-1) 2921, 1659; H NMR (400
1
MHz, CDCl3):δ 8.36 (d, J = 7.35 Hz, 2 H), 8.31 (d, J = 8.44 Hz, 1 H), 8.18 (d, J = 8.45 Hz, 1H), 7.75-
7.70 (m, 1 H), 7.64-7.60 (m, 2 H), 7.57-7.50 (m, 3 H), 2.78 (s, 3H); 13C NMR{1H} (100 MHz, CDCl3):δ
193.5, 153.0, 145.8, 138.8, 137.2, 136.5, 132.7, 132.4, 131.7, 130.9, 130.1, 129.0, 128.8, 128.3, 127.8,
125.5, 120.4, 17.9; HRESI-MS (m/z) Calculated for C17H13NONa (M+Na) 270.0895 found (M+Na)
270.0889.
(8-Methylquinoline-2,4-diyl)bis(phenylmethanone) (20).
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1
2
O
3
4
5
6
N
O
7
20
8
9
Prepared as described in the general experimental procedure. Yellow liquid; Yield 35% (24.6 mg);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
mp: 138 °C; IR (KBr, cm-1) 2922, 1664; Rf (40% EtOAc/Hexane) 0.6; H NMR (400 MHz, CDCl3):δ
8.37 (d, J = 7.38 Hz, 2 H), 8.19 (s, 1 H), 7.88 (d, J = 7.53 Hz, 2 H), 7.78 (d, J = 8.25 Hz, 1 H), 7.69-7.63
(m, 3 H), 7.55-7.47 (m, 5 H), 2.83 (s, 3 H); C NMR{1H} (100 MHz, CDCl3):δ 196.0, 192.7, 152.1,
13
146.2, 145.7, 139.4, 136.4, 136.1, 134.3, 132.9, 131.6, 130.6, 130.3, 129.4, 128.8, 127.9, 125.7, 123.1,
118.9, 18.3; HRESI-MS (m/z) Calculated for C24H17NO2Na (M+Na) 374.1157 found (M+Na)
374.1161.
Phenyl(quinoxalin-2-yl)methanone (21).25
N
N
O
21
Prepared as described in the general experimental procedure. Colorless liquid; Yield 47% (22 mg);
IR (KBr, cm-1) 2928, 1726; Rf (40% EtOAc/Hexane) 0.6; 1H NMR (400 MHz, CDCl3):δ 9.50 (s, 1 H),
8.26-8.23 (m, 3 H) 8.21-8.20 (m, 1 H), 7.94-7.87 (d, 2 H), 7.70-7.66 (m, 1 H), 7.57-7.53 (m, 2 H); 13C
NMR{1H} (100 MHz, CDCl3):δ 192.3, 148.7, 145.3, 143.1, 140.4, 135.5, 133.6, 132.0, 131.2, 130.8,
130.4, 129.4, 128.4; HRESI-MS (m/z) Calculated for C15H10N2ONa (M+Na) 257.0691 found (M+Na)
257.0692.
(4,7-Dichloroquinolin-2-yl)(phenyl)methanone (22).8a
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O
1
2
3
4
5
6
7
8
9
10
N
O
O
O
O
22
Prepared as described in the general experimental procedure. White solid; Yield 52% (36.7 mg); mp:
1
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
204-206 °C (lit.8a 205-207 °C); Rf (50% EtOAc/Hexane) 0.3; IR ( KBr, cm-1) 2938, 1680; H NMR
(400 MHz, CDCl3):δ 8.46 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 2 Hz, 1 H), 7.65 (d, J = 5.2 Hz, 1 H), 7.55 (s,
1 H), 7.44 (d, J = 2 Hz, 1 H), 7.41 (d, J = 2 Hz, 1 H), 7.15 (s, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 4.06 (s, 3
H), 3.96 (s, 6 H), 3.95 (s, 3 H); C NMR{1H} (100 MHz, CDCl3):δ 193.9, 153.8, 153.7, 153.2, 150.9,
13
149.0, 140.0, 133.9, 129.9, 126.8, 122.8, 121.2, 111.8, 109.9, 104.8, 104.0, 56.1, 56.0, 55.9; HRESI-
MS (m/z) Calculated for C20H19NO5H (M+H) 354.1341 found (M+H) 354.1342.
Isoquinolin-1-yl(p-tolyl)methanone (23).25
N
O
23
Prepared as described in the general experimental procedure. Yellowish liquid; Yield 59% (29.2
mg); IR (Neat, cm-1) 2926, 1718; Rf (20% EtOAc/Hexane) 0.6; 1H NMR (400 MHz, CDCl3):δ 8.59 (d, J
= 5.61 Hz, 1 H), 8.19 (d, J = 8.54 Hz, 1 H), 7.91 (d, J = 8.21, 2.4 Hz, 1 H), 7.85 (d, J = 8.06 Hz, 2 H),
7.79 (d, J = 5.64 Hz, 1 H), 7.74-7.71 (m, 1 H), 7.62=7.58 (m, 1 H), 7.27 (d, J = 7.54 Hz, 2 H), 2.42 (s, 3
H); C NMR{1H} (100 MHz, CDCl3):δ 194.5, 156.8, 144.7, 141.1, 136.6, 134.0, 130.8, 130.6, 129.2,
13
128.2, 127.0, 126.3, 126.2, 122.4, 21.8; HRESI-MS (m/z) Calculated for C17H13NONa (M+Na)
270.0895 found (M+Na) 270.0893.
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Isoquinolin-1-yl(4-methoxyphenyl)methanone (24).25
1
2
3
4
5
6
N
O
7
8
O
24
9
Prepared as described in the general experimental procedure. Yellowish liquid; Yield 64% (33.5
mg); Rf (20% EtOAc/Hexane) 0.4; IR (Neat, cm-1) 1687, 2964; 1H NMR (400 MHz, CDCl3):δ 8.59 (d,
J = 5.57 Hz, 1 H), 8.15 (d, J = 8.35 Hz, 1 H), 8.05 (d, J = 7.79 Hz, 1 H), 7.83-7.78 (m, 4 H), 6.99-6.97
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(d, J = 8.68 Hz, 2 H), 3.86 (s, 3 H); C NMR{1H} (100 MHz, CDCl3):δ 193.3, 157.0, 141.0, 136.6,
133.1, 130.7, 129.8, 129.4, 128.1, 127.0, 126.2, 122.3, 113.5, 55.3; HRESI-MS (m/z) Calculated for
C17H13NO2Na (M+Na) 286.0844 found (M+H) 286.0846.
(1-(4-Bromoisoquinolin-1-yl)ethan-1-one (25).
Br
N
O
25
Prepared as described in the general experimental procedure. Yellow liquid; Yield 36% (18 mg); Rf
(10%EtOAc/Hexane) 0.7; IR (Neat, cm-1) 1621;1H NMR (400 MHz, CDCl3): δ 8.99 (d, J = 8.58 Hz, 1
H), 8.78 (s, 1 H), 8.25 (d, J = 8.29 Hz, 1 H), 7.86-7.82 (m, 1 H), 7.77-7.73 (m, 1 H), 2.84 (s, 3 H); 13C
NMR{1H} (100 MHz, CDCl3): δ197.6, 151.8, 142.9, 135.6, 131.6, 130.0, 127.3, 126.3, 124.0, 28.6;
HRESI-MS (m/z) Calculated for C11H8BrONNa (M+Na) 271.9687 found (M+Na) 271.9685.
(1-(4-Bromoisoquinolin-1-yl)ethan-1-one (26).
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Br
1
2
3
N
4
5
O
6
7
26
8
9
Prepared as described in the general experimental procedure. Yellow solid; Yield 41% (21.6 mg);
10
11
mp: 82-84 °C Rf (10%EtOAc/Hexane) 0.7; IR (Neat, cm-1) 2975, 1693; 1H NMR (400 MHz, CDCl3): δ
8.88 (d, J = 8.8 Hz, 1 H), 8.76 (s, 1 H), 8.24 (d, J = 8.4 Hz, 1H), 7.85-7.81 (m, 1 H), 7.75-7.71 (m, 1 H),
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
3.32 (q, J = 7.2 Hz, 2 H), 1.26 (t, J = 7.6 Hz, 1 H); C NMR{1H} (100 MHz, CDCl3): δ204.6, 152.4,
142.9, 135.6, 131.5, 129.7, 127.2, 126.8, 126.2, 123.5; HRESI-MS (m/z) Calculated for C12H10BrNOH
(M+H) 264.0024 found (M+H) 264.0023.
(1-(4-Bromoisoquinolin-1-yl)ethan-1-one (27).
Br
N
O
27
Prepared as described in the general experimental procedure. Yellow liquid; Yield 71% (41.4 mg);
1
Rf (10%EtOAc/Hexane) 0.8; IR (Neat, cm-1) 2958, 2924, 2869, 1695; H NMR (400 MHz, CDCl3): δ
8.85 (d, J = 8.4 Hz, 1 H), 8.75 (s, 1 H), 8.23 (d, J = 8.4 Hz, 1H), 7.84-7.80 (m, 1 H), 7.74-7.70 (m, 1 H),
13
3.17 (t, J = 7.2 Hz, 2 H), 2.37-2.27 (m, 1 H), 1.02 (d, J = 6.8 Hz, 6 H) ; C NMR{1H} (100 MHz,
CDCl3): δ203.9, 152.8, 142.9, 135.6, 131.5, 129.7, 127.1, 126.8, 126.3, 123.4, 49.1, 25.0, 22.7; HRESI-
MS (m/z) Calculated for C14H14BrNOH (M+H) 292.0337 found (M+H) 292.0336.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
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Photoreactor set-up, 1H NMR and 13C spectra for all compounds (PDF).
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AUTHOR INFORMATION
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Corresponding Author
8
9
* E-mail: prabhu@iisc.ac.in
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ORCID
Kandikere Ramaiah Prabhu: 0000-0002-8342-1534
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This work was supported by SERB (EMR/2016/006358), New-Delhi, CSIR (No. 02(0226)15/EMR-
II), New-Delhi, Indian Institute of Science, and R. L. Fine Chem. We thank Dr. A. R. Ramesha (R. L.
Fine Chem) for useful discussion.
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A.; Tlahuext-Aca, A.; Tavakoli,G.; Glorius, F. ACS Catal. 2017, 7, 4057−4061
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(3) Selected reviews on visible light photoredox catalysis: (a) Visible light photocatalysis as a greener
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2
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Org. Lett., 2009, 11, 3120-3123. (c) Wang, S.; Yang, Z.; Liu, J.; Xie, K.; Wang, A.; Chen, X.; Tan,
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secondary benzamides with aldehydes and intramolecular cyclization: The direct synthesis of 3-
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