Transition metal-free Minisci reaction promoted by NCS, and TBHP: Acylation of heteroarenes

Article abstract of DOI:10.1016/j.tet.2015.12.065

A method for acylation for heteroarenes under metal-free conditions has been described using NCS as an additive and TBHP as an oxidant. This method has been successfully employed in acylation of a variety of aldehyde with heteroarenes. The application of the method has been illustrated in synthesizing isoquinoline derived natural products. This strategy provides an efficient, mild and inexpensive method for acylation of heteroarenes.

Full text of DOI:10.1016/j.tet.2015.12.065

Accepted Manuscript
Transition Metal-Free Minisci Reaction Promoted by NCS, and TBHP: Acylation of
Heteroarenes
Yogesh Siddaraju, Kandikere Ramaiah Prabhu
PII:
S0040-4020(15)30313-6
10.1016/j.tet.2015.12.065
TET 27391
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 October 2015
Revised Date: 10 December 2015
Accepted Date: 24 December 2015
Please cite this article as: Siddaraju Y, Prabhu KR, Transition Metal-Free Minisci Reaction Promoted by
NCS, and TBHP: Acylation of Heteroarenes, Tetrahedron (2016), doi: 10.1016/j.tet.2015.12.065.
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Transition metal-free Minisci reaction promoted by
NCS, TBHP: Acylation of heteroarenes
Yogesh Siddaraju and Kandikere Ramaiah Prabhu*
Leave this area blank for abstract info.
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.

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1
Tetrahedron
journal homepage: www.elsevier.com
Transition Metal-Free Minisci Reaction Promoted by NCS, and TBHP: Acylation of
Heteroarenes
Yogesh Siddaraju and Kandikere Ramaiah Prabhu
a Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method for acylation for heteroarenes under metal-free conditions has been described using
NCS as an additive and TBHP as an oxidant. This method has been successfully employed in
acylation of a variety of aldehyde with heteroarenes. The application of the method has been
illustrated in synthesizing isoquinoline derived natural products. This strategy provides an
efficient, mild and inexpensive method for acylation of heteroarenes.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
isoquinoline
Minisci reaction
C-H functionalization
Acylation
Metal-free reactions
———
*e-mail: prabhu@orgchem.iisc.ernet.in Fax: (+)91-80-23600529

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2
Tetrahedron
1. Introduction
observed using iodine sources such as TBAI, KI, or I2 (entries
10-12, Table 1). It was also found that aq TBHP is useful in
promoting the reaction (58%, entries 13, Table 1).10 Further
screening studies with a variety of oxidants revealed that TBHP
in decane 5.5M, is better suited for the reaction, whereas oxidants
such as aq hydrogen peroxide, di tert butyl peroxide, and cumune
hydroperoxide failed to promote the reaction (entries 14-16).
Under the similar reaction conditions, NCS and K2S2O8 furnished
3a in low yield (21%, entries 17, Table 1). Further screening
studies indicated that decreasing the amount of aldehyde resulted
in formation of 3a in low yields (entries 18-19, Table
1).Increasing the amount of NCS (50 mol %) led to the formation
of 3a in 62% (entry 20, Table 1). Decreasing the amount of NCS
also has resulted in the formation of 3a in low yields (entries 21-
22, Table 1). Increasing the amount of TBHP to 3equiv or 4
equiv led to increase in yields of 3ato 70% and 68% (entries 23-
24, Table 1). Decreasing the amount of TBHP to 1equiv resulted
in lowering the yield of 3a (entry 25, Table 1). In the absence of
NCS, the reaction yielded 3a in 21% yield (entry 26), whereas
the reaction did not proceed in the absence of TBHP (entry 27).
With these screening studies, the optimal condition was
established using aldehyde (4 equiv), NCS (30 mol %), and
TBHP in decane (5.5M, 3 equiv) in DCE (entry 23, Table 1).
The C-C bond forming reaction is a fundamental reaction in
synthetic organic chemistry and C−H functionalization strategy
for constructing C−C bonds has gained considerable attention in
recent years.1 In this direction, cross-dehydrogenative coupling
(CDC) reactions have emerged as an important tool in C-C bond
forming reactions.2Aldehyde is an important precursor which can
be easily employed as a substrate in CDC reactions. The cleavage
and functionalization of C-H bonds of aldehyde for the formation
of C-C bonds offers atom economical routes for synthesizing a
variety of useful compounds.3 There are several reports that
employ aldehydes for the acylation of arenes4 and heteroarenes5
using C-H functionalization strategy. Acylation of heterocyclic
compounds is a challenging task but it provides an easy access
for a variety of pharmaceutically active compounds and natural
products.5a,5b,6 Although there are several synthetic strategies
which employ radical intermediates to accomplish acylation of
heterocyles using Minisci reaction,6a,7 there are few limitations
associated with these approaches.6a,8 Matcha and Antonchick
have reported a metal-free CDC reaction of heterocylces with
aldehydes using PhI(OCOCF3) and TMSN3.5a Recently, we have
reported an intermolecular acylation of heteroarenes using TBAB
and K2S2O8.5b
Recently, acylation of isoquinoline using
Table 1 Optimization studies.
methylarenes with AlCl3 and TBHP has been reported by Patel
and coworker,5f whereas Liu and coworker reported the acylation
of isoquinoline using MnO2 and TBHP.5g However, our attempts
for acylation of isoquinoline using TBAB and K2S2O8 for
synthesizing isoquinoline derived natural products were
unsuccessful5b and the acylation of a few aldehydes including
aliphatic aldehydes led to the expected products in low yields. In
persuit of our search in metal-free CDC reactions,9 herein we
Entry Additive
(mol %)
Oxidant
Solvent
DCE
Yield
(%)b
60
(equiv)
describe
a successful Minisci reaction for acylation of
NCS (30 )
TBHP in decane (2)
1
heterocyclic compounds promoted by NCS, and TBHP (Scheme
1).
2
3
NCS (30 )
NCS (30 )
NCS (30 )
NCS (30 )
NCS (30 )
BTAC (30)
NBS(30)
TBAB (30)
TBAI (30)
KI (30)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane(2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
aq TBHP (2)
DMSO
DMF
10
11
48
43
Scheme 1.Acylation of heterocyclic compounds
4
Toluene
CH3CN
5
6
chlorobenzene 52
7
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
31
8
9
42
22
10
11
12
13
14
15
16
17
18c
19d
20
21
22
23
24
25
26
27
NR
NR
NR
58
I2 (30)
NCS (30 )
NCS (30 )
NCS (30 )
NCS (30 )
NCS (30 )
NCS (30 )
NCS (30)
NCS (50)
NCS (20)
NCS (10)
NCS (30)
NCS (30)
NCS (30)
none
aq H2O2 (2)
DTBP (2)
NR
NR
NR
21
CHP (2)
K2S2O8 (2)
2. Results & Discussion
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (2)
TBHP in decane (3)
TBHP in decane(4)
TBHP in decane (1)
TBHP in decane (3)
none
56
50
The optimization studies were performed using isoquinoline
(1a) and 2,3,4,-trimethoxybenzaldehyde (2a) as model substrates
under a variety of reaction conditions(Table 1). The initial
screening reaction began by treating 1 with TBHP (in decane,
5.5M, 2 equiv) as an oxidant and NCS (30 mol %) as an additive.
As can be seen in Table 1, the solvent screening studies revealed
that the DCE is the most suitable solvent, which furnished the
product 3a in 60% yield (entry 1, Table 1). Whereas, other
solvents such as DMSO, DMF, toluene, CH3CN, or
chlorobenzene furnished the product 3a in low yields (10, 11, 48,
43, and 52% respectively, entries 2-6, Table 1). The screening of
additives suggested that NCS is ideal, whereas other additives
such as benzyltriethylammonium chloride, NBS, and TBAB
furnished the product 3a in low yields (31, 42, and 22%
respectively, entries 7-9, Table 1). The formation of 3a was not
62
55
50
70
68
40
21
NCS (30)
NR
aReaction conditions: 1 (0.77 mmol), 2 (3.0 mmol), oxidant (2.24 mmol),
additive (0.23mmol) in DCE (2 mL) at 105 °C. bIsolated yield. c3 Equiv of 2.
d2 Equiv of 2. TBAI = tetra-n-Butylammonium iodide, TBAB = tetra-n-Butyl
ammonium bromide, NBS
=
N- bromosuccinimide, BTAC
=
Benzyltriethylammonium Chloride, NCS = N-chlorosuccinimide, TBPB=
tert-Butyl peroxy benzoate, CHP = Cumene hydro peroxide, NR = no
reaction.

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3
(0.23 mmol), tbhp in decane (5.5M) (2.31 mmol) in DCE (2.0 mL). 100-
105 °C, 4-16h. bIsolated yield.
Having found the optimal reaction conditions, the scope
of the coupling reaction was explored using a variety of
aldehydes with isoquinoline ( ). Isoquinoline ( ) underwent
smooth coupling reaction with 3,4,5-
trimethoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, 4-
(benzyloxy)benzaldehyde, 3-phenoxybenzaldehyde, 4-
methoxy benzaldehyde and 4-methyl benzaldehyde to
afford the corresponding acylated products 3b 3c 3d, 3e, 3f
and 3g in good yields (69, 68, 68, 56, 80, and 76%,
respectively, Scheme 2). Similarly, the reaction proceeded
well with aliphatic aldehydes such as decanal, octanal,
heptanal, and 3-methylbutanal which furnished theiracylated
1
1
In view of expanding the scope of this coupling
reaction, we attempted coupling of 4-phenylisoquinoline
with a variety of aldehydes (Scheme 3). As can be seen, 4-
phenylisoquinoline underwent a smooth coupling with
benzaldehyde under optimal reaction conditions to furnish
4a in 73% yield. Further, alkoxy substituted aldehydes such
as, 2,4-dimethoxybenzaldehyde, benzo[d][1,3]dioxole-5-
carbaldehyde, and 3-methoxybenzaldehyde underwent a
a
,
,
smooth reaction to afforded the coupled products 4b, 4c, and
4d in good to moderate yields (61, 44, and 67%,
respectively, Scheme 3). The alkyl substituted aldehydes
products 3h
81%, respectively, Scheme 2). As can be seen from the
Scheme 2, the reaction of isoquinoline ( ) was studied with
secondary and tertiary aldehydes such as
, 3i, 3j, and 3k in good yields (69, 76, 75, and
such
as,
4-isopropylbenzaldehyde
and
2-
1
methylbenzaldehyde furnished the coupled products 4e and
4f in good to moderate yields (52% and 88%, respectively,
Scheme 3). The scope of the strategy has been studied with
halogen containing aldehydes such as 4-fluorobenzaldehyde
and 4-chlorobenzaldehyde, which furnished their
corresponding acylated products 4g and 4h in 75% and 45%
cyclohexanecarbaldehyde and pivalaldehyde. The reaction
of cyclohexanecarbaldehyde with isoquinoline under the
optimal conditions furnished the mixture of acylated (3la
)
and alkylated 3lb isoquinoline compounds as an
(
)
inseparable mixture in a ratio of 1:0.92 (Schem 2). However,
the similar reaction with pivalaldehyde, the expected
product was not formed. Similarly under the reaction condition
crotanaldehyde and cinnamaldehyde failed to furnish
corresponding acylated products (Scheme 2).
yields,
respectively
(Scheme
3).
Similarly,
2-
naphthaldehyde furnished the acylated product 4i in 51%
yield. Under the optimal reaction conditions, thiophene
containing aldehyde derivatives such as thiophene-2-
carbaldehyde and thiophene-3-carbaldehyde underwent a
facile coupling to afford the products 4j and 4k in 51% and
53% yields (Scheme 3). To find the generality of this
coupling reaction, a reaction of aliphatic aldehyde, 3-
methylbutanal, was performed with 4-phenylisoquiniline,
which yielded the acylated product 4l in 83% yield (Scheme
3).
Scheme 2. Substrate Scopea, b
NCS (30 mol %),
O
N
TBHP in decane (3equiv)
+
R
H
N
100 -105 oC, 4 -16 h, DCE
R O
3
1a (0.77 mmol)
2
N
N
N
Scheme 3. Substrate Scopea, b
OMe
OMe
O
OMe
O
O
OMe
OBn
OMe
3b, 69%
3c, 68%
3d, 68%
N
N
N
OPh
O
O
O
OMe
3e, 56%
3f, 80%
3g, 76%
N
N
N
N
O
O
O
O
3h, 69%
3i, 76%
3j, 75%
3k, 81%
N
N
N
N
+
O
O
3la
3lb
or
3ma
3mb
not formed
3la:3lb (1:0.92), 74% (40:34)
N
N
O
O
3n, NR
3o, NR
aReaction conditions: isoquinoline (0.48 mmol), aldehyde (1.92mmol), NCS
(0.14mmol), TBHP in decane (5.5M) (1.4mmol) in DCE (1 mL), 100-105 °C,
4-16h. bIsolated yield.
aReaction conditions: isoquinoline (0.77 mmol), aldehyde (3.0 mmol), NCS

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4
Tetrahedron
The application of this methodology was further
Scheme 5. Acylation of various heterocyclic compounds
extended in synthesizing isoquinoline derived natural
products (Scheme 4). As can be seen, under optimal reaction
condition 5,6,7-trimethoxyisoquinoline reacted well with 4-
methoxybenzaldehyde to furnish the 5a in 61% isolated
yield. The compound 5a (thalimicrinone) is a natural
alkaloid isolated from a thalictrumspecies.5a,5b,6 Similarly,
6,7-dimethoxyisoquinoline in a CDC reaction with 3,4-
dimethoxybenzaldehyde,
and
4-methoxybenzaldehyde
furnished the coupled product 5b and 5c in 59% and 64%
(Scheme 4). It is noteworthy that the compound 5b is an
acetylcholinesterase inhibitor.5g Compound 5c can be easily
reduced to O,O-dimethyl-annocherin
6 in 68% yield, which
is a biologically active isoquinoline alkaloid. Compound 5b
can be easily reduced to paverine
7, which is another
biologically active isoquinoline alkaloid.5a Similarly,
[1,3]dioxolo[4,5-g]isoquinoline in a CDC reaction with 3,4-
dimethoxybenzaldehyde,
and
4-methoxybenzaldehyde
furnished the coupled products 5d and 5e in 48% and 47%
(Scheme 4). Interestingly, 5d and 5e are also biologically
active isoquinoline alkaloids.5a Traditionally, these
derivatives are synthesized using multistep reaction
sequence,11 whereas the present strategy offers a unique
single-step synthesis.
aReaction conditions: Heteroarenes (0.77 mmol), aldehyde (3.0 mmol), NCS
(0.23 mmol), TBHP in decane (5.5M) (2.31 mmol) in DCE (2.0 mL), 105 °C.
bIsolated yield, cchlorobenzene used as a solvent.
The scope of this versatile coupling reaction was further
studied with other few heterocyles such as quinoline, acridine,
quinaxaline and phenanthridine. Quinoline under the optimal
reaction conditions coupled with 4-methyl benzaldehyde to
furnish a mixture of mono- and diacylated products 8a and 8b in
67% yields in a ratio of 42:25 (Scheme 5). Similarly, acridine
coupled with 4-methoxybenzaldehyde to afford the acylated
Scheme 4. Synthesis of isoquinoline-derived natural
products.
product
9 in 59% yield. Under the optimal conditions,
quinoxaline found to react with 4-methylbenzaldehyde to furnish
a mixture of mono- and diacylated products 10a and 10b in 53%
yield in a ratio of 42:11. When phenanthridine was subjected to
the similar coupling reaction with 4-methylbenzaldehyde, the
corresponding acylated product 11 was obtained in excellent
yield 90% (Scheme 5).
To understand the mechanism of this reaction, a reaction
of isoquinoline with benzaldehyde under the optimized
reaction conditions was carried out in the presence of
TEMPO or BHT. In these reactions, the corresponding
acylated product was not observed. However, in the reaction
of TEMPO the corresponding coupled product 12 was
obtained in 67% yield. This observation suggests that the
reaction is proceeding through a radical reaction (Scheme 6).
Scheme 6. Control experiments for mechanistic studies.
aReaction conditions: isoquinoline (0.5 mmol), aldehyde (2.0 mmol), NCS
b
(0.15 mmol), tbhp in decane (5.5M) (1.5 mmol) in DCE (2.0 mL). Isolated
c
yield. Reaction performed in reaction vial at 80°C for 15 h with acetonotrile
as a solvent. d reduced from 5c using 1.1eqv of NaBH4 in methanol.
Based on these experiments, and the literature
precedence,4a,12 we believe that TBHP forms tert-butyloxy
radical (I) and hydroxyl radical in the presence of NCS,
which abstracts the proton from the aldehyde to form an acyl

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5
radical (II). Further, the addition of acyl radical to
heteroarene forms amidyl radical (III). Finally, tert-butyloxy
radical or ydroxyl radical abstracts hydrogen radical III to
furnish the acylated product (Scheme 6). Alternatively, the
reaction may proceed by transfering an electron from III to
TBHP to produce cation IV, which upon further
deprotonation affords the acylated product (Scheme 6).
4.3 Characterization data
4.3.1 Isoquinolin-1-yl(2,3,4-trimethoxyphenyl)methanone (3a):5b
Brown oily; Yield 70% (174 mg); Rf (30% EtOAc/Hexane) 0.2.
Prepared as shown in general experimental procedure (Reaction
time 15 h at 105°C): IR (Neat, cm–1): 3053, 2930, 2847, 2690,
h
1
1745, 1659, 1586,1494; H NMR (400 MHz, CDCl3) δ (ppm)
8.50 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0
Hz, 1H), 7.73 – 7.66 (m, 3H), 7.61 (t, J = 7.6 Hz, 1H), 6.81 (d, J
= 8.8 Hz, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 3.29 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 194.6, 158.7, 158.2, 154.2, 141.6,
140.9, 136.4, 130.3, 127.9, 126.8, 126.5, 126.2, 125.5, 125.2,
121.9, 107.1, 60.6, 60.5, 56.0; (1913C peaks) HRESI-MS (m/z):
Scheme 7. A Tentative reaction mechanism
Calculated for C19H17NO4 (M+ + Na): 346.1055, found (M+
Na): 346.1057.
+
4.3.2
Isoquinolin-1-yl(3,4,5-trimethoxyphenyl)methanone
(3b):5a,5b Yellow solid; Yield 69% (173 mg); mp 126–128 °C; Rf
(30% EtOAc/Hexane) 0.2. Prepared as shown in general
experimental procedure (Reaction time 15 h at 105°C): IR (KBr,
cm–1): 3053, 2925, 2834, 2289, 1743, 1663, 1581, 1501, 1458; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.61 (d, J = 5.6 Hz, 1H), 8.21
(d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 5.6 Hz,
1H), 7.75 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.24 (s,
2H), 3.94 (s, 3H), 3.83 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 193.4, 156.3, 152.9, 143.1, 140.9, 136.6, 131.5, 130.7,
128.2, 127.0, 126.3, 126.1, 122.5, 108.2, 60.8, 56.1; (16 13C
peaks) HRESI-MS (m/z): Calculated for C19H17NO4 (M+ + Na):
346.1055, found (M+ + Na): 346.1055.
3. Conclusion
In summary, intermolecular acylation of heterocycles has
been described using NCS and TBHP. This method is easily
adopted for acylation of a variety of aldehydes with
heterocycles. The application of this methodology has been
demonstrated in synthesizing a variety of natural products in
one step.
4.3.3
(3,4-dimethoxyphenyl)(isoquinolin-1-yl)methanone
(3c):5a,5b Pale yellow solid; Yield 68% (154 mg); mp 140–142
°C; Rf (30% EtOAc/Hexane) 0.2. Prepared as shown in general
experimental procedure (Reaction time 16 h at 105°C): IR (KBr,
cm–1): 3065, 3000, 2941, 2841, 2287, 1657, 1621, 1581; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.58 (d, J = 5.6 Hz, 1H), 8.15 (d, J =
8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.78 – 7.68 (m, 3H), 7.58
(t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz,
1H), 3.95 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 193.2, 156.8, 153.8, 148.9, 140.9, 136.4, 130.5, 129.4,
127.9, 126.8, 126.8, 126.1, 126.0, 122.0, 111.3, 109.8, 55.9, 55.8;
(18 13C peaks) HRESI-MS (m/z): Calculated for C18H15NO3 (M+
+ Na): 316.0950, found (M+ + Na): 316.0952.
4. General experimental
NMR spectra were recorded on
spectrometers in CDCl3, tetramethylsilane (TMS; δ = 0.00 ppm)
served as an internal standard for H NMR. The corresponding
residual non-deuterated solvent signal (CDCl3; δ = 77.00 ppm)
was used as internal standard for 13C NMR. IR spectra were
measured using FT/IR spectrometers. Mass spectra were
measured uisng Q-Tof (ESI-HRMS). Column chromatography
was carried out on Silica gel 100-200 mesh (commercial
suppliers) and thin-layer chromatography was carried out using
SILICA GEL GF-254.
a 400 MHz NMR
1
4.3.4
(4-(benzyloxy)phenyl)(isoquinolin-1-yl)methanone
(3d):5a,5b White solid; Yield 68% (178 mg); mp 123–125 °C; Rf
(5% EtOAc/Hexane) 0.2. Prepared as shown in general
experimental procedure (Reaction time 16 h at 105°C): IR (KBr,
cm–1): 3048, 2919, 2857, 1737, 1644, 1599, 1572, 1499; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.57 (d, J = 5.6 Hz, 1H), 8.16 (d, J =
8.4 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H),
7.75 (d, J = 5.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6
Hz, 1H), 7.41 – 7.30 (m, 5H), 7.00 (d, J = 8.4 Hz, 2H), 5.11 (s,
2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.2, 163.1, 156.9,
141.0, 136.5, 136.0, 133.1, 130.6, 129.6, 128.6, 128.1, 128.1,
127.3, 126.9, 126.2, 126.1, 122.2, 114.6, 70.04; (19 13C peaks)
4.2 Typical Experimental Procedure for Minisci reaction of
Isoquinoline with aldehyde
Isoquinoline (100 mg, 0.77mmol), aldehyde (3.0 mmol, 4
equiv), NCS (0.23, 0.3 equiv) and TBHP in decane (5.5M,
2.3mmol, 3equiv) in ClCH2CH2Cl (2 mL) were stirred at 105 °C
(12- 16h for aromatic aldehyde) and 100 °C (4h for aliphatic
aldehyde). After the completion of the reaction (monitored by
TLC), the solvent was removed under vacuum, added aq
bicarbonate solution (10 mL, 5% solution) and extracted with
EtOAc or DCM (3x10mL). 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.
HRESI-MS (m/z): Calculated for C23H17NO2 (M+
362.1157, found (M+ + Na): 362.1160.
+
Na):
4.3.5
Isoquinolin-1-yl(3-phenoxyphenyl)methanone
(3e):
Yellow oily; Yield 56% (141 mg); Rf (10% EtOAc/Hexane) 0.4.
Prepared as shown in general experimental procedure (Reaction
time 15 h at 105°C): IR (Neat, cm–1): 3058, 2921, 2850, 2731,
2376, 1775, 1670, 1580, 1485, 1435; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.58 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 8.4 Hz,
1H), 7.90 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.72 (t, J
= 7.2 Hz, 1H), 7.66 (s, 1H). 7.63 – 7.59 (m, 2H), 7.41 (t, J = 7.6
Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.11

ACCEPTED MANUSCRIPT
6
Tetrahedron
(t, J = 7.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H); 13C NMR (100
CDCl3) δ (ppm) 8.83 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 5.6 Hz,
1H), 7.853(d, J = 8.0 Hz, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.71 –
7.63 (m, 2H), 3.32 (t, J = 7.2 Hz, 2H), 1.81 – 1.74 (m, 2H), 1.43
– 1.41 (m, 2H), 1.33 – 1.27 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 204.9, 153.5, 141.0, 136.9,
130.2, 128.8, 126.9, 126.6, 125.6, 124.1, 40.3, 31.6, 29.0, 24.1,
22.5, 14.0; (16 13C peaks) HRESI-MS (m/z): Calculated for
C16H19NO (M+ + Na): 264.1364, found (M+ + Na): 264.1369.
MHz, CDCl3) δ (ppm) 193.9, 157.5, 156.4, 155.9, 141.0, 138.3,
136.6, 130.7, 129.8, 129.7, 128.3, 127.0, 126.3, 126.0, 125.8,
123.8, 122.7, 120.2, 119.1; (19 13C peaks) HRESI-MS (m/z):
Calculated for C22H15NO2 (M+ + Na): 348.1000, found (M+
Na): 348.1004.
+
4.3.6
Isoquinolin-1-yl(4-methoxyphenyl)methanone (3f):5a,5b
Pale yellow oily; Yield 80% (162 mg); Rf (10% EtOAc/Hexane)
0.2. Prepared as shown in general experimental procedure
(Reaction time 16 h at 105°C): IR (Neat, cm–1): 3055, 3008,
4.3.11 1-(isoquinolin-1-yl)-3-methylbutan-1-one (3k):5b Pale
yellow oily; Yield 81% (135 mg); Rf (5% EtOAc/Hexane) 0.4.
Prepared as shown in general experimental procedure (Reaction
time 4 h at 100°C): IR (Neat, cm–1): 3366, 3054, 2957, 2869,
1
2928, 2842, 2577, 1775, 1659, 1597, 1508; H NMR (400 MHz,
CDCl3) δ (ppm) 8.58 (d, J = 6.0 Hz, 1H), 8.16 (d, J = 8.4 Hz,
1H), 7.95 – 7.89 (m, 3H), 7.77 (d, J = 5.6 Hz, 1H), 7.72 (t, J =
7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H),
3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.3, 164.0,
156.08, 141.0, 136.5, 133.0, 130.5, 129.3, 128.0, 126.9, 126.13,
126.1, 122.1, 113.7, 55.4; (15 13C peaks) HRESI-MS (m/z):
1
2723, 2376, 2313, 1923, 1836, 1694, 1620, 1581; H NMR (400
MHz, CDCl3) δ (ppm) 8.82 (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), 3.21 (d, J = 6.8 Hz, 2H), 2.39 – 2.29 (m, 1H), 1.03
(d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 204.6,
153.8, 141.0, 137.0, 130.3, 128.9, 127.0, 126.6, 125.6, 124.1,
49.1, 24.9, 22.7; (13 13C peaks) HRESI-MS (m/z): Calculated for
C14H15NO (M+ + Na): 236.1051, found (M+ + Na): 236.1050.
Calculated for C17H13NO2 (M+ + Na): 286.0844, found (M+
Na): 386.0843
+
4.3.7
Isoquinolin-1-yl(p-tolyl)methanone
(3g):5a,5b
Pale
yellow oily; Yield 76% (145 mg); Rf (10% EtOAc/Hexane) 0.5.
Prepared as shown in general experimental procedure (Reaction
time 16 h at 105°C): IR (Neat, cm–1): 3386, 3053, 2921, 2852,
4.3.12 Cyclohexyl(isoquinolin-1-yl)methanone,
and
1-
Cyclohexylisoquinoline (3la+ 3lb): Pale yellow oily; Yield (74%;
40:34) (131mg); Rf (5% EtOAc/Hexane) 0.2. Prepared as shown
in general experimental procedure (Reaction time 4 h at 100°C):
IR (Neat, cm–1): 3850, 3583, 3361, 3051, 2928, 2852, 2662,
1
2611, 1738, 1664, 1604; H NMR (400 MHz, CDCl3) δ (ppm)
8.59 (d, J = 5.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4
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) 194.3,
156.6, 144.5, 141.0, 136.4, 133.9, 130.7, 130.5, 129.0, 128.0,
126.9, 126.1, 126.0, 122.2, 21.6; (15 13C peaks) HRESI-MS
(m/z): Calculated for C17H13NO (M+ + Na): 270.0895, found (M+
+ Na): 270.0895.
1
2231, 1917, 1845, 1770, 1692, 1621, 1559; H NMR (400 MHz,
CDCl3) δ (ppm) 8.59 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 5.6 Hz,
1H), 8.47 (d, J = 5.6 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.83 (d, J
= 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 5.6 Hz, 1H),
7.69 (t, J = 7.6 Hz, 1H), 7.64 – 7.61 (m, 2H), 7.56 (t, J = 7.6 Hz,
1H), 7.46 (d, J = 5.6 Hz, 1H), 3.88 – 3.82 (m, 1H), 3.58 – 3.52
(m, 1H), 2.02 – 1.88 (m, 6H), 1.87 – 1.79 (m, 5H), 1.73 – 1.71
(m, 1H), 1.58 – 1.48 (m, 4H), 1.45 – 1.37 (m, 4H), 1.31 – 1.21
(m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 207.3, 165.7,
154.6, 141.8, 141.1, 136.9, 136.4, 130.3, 129.5, 128.6, 127.5,
126.9, 126.8, 126.6, 126.3, 126.0, 124.7, 123.6, 118.9, 46.8, 41.5,
32.6, 28.4, 26.9, 26.2, 26.1, 25.7; (27 13C peaks) HRESI-MS
(m/z): Calculated for C16H17NO (M+ + Na): 262.1208, found (M+
+ Na): 262.1209; Calculated for C15H17NO (M+ + H): 212.1439,
found (M+ + H): 212.1439.
4.3.8
1-(isoquinolin-1-yl)decan-1-one (3h): Pale yellow
Oily; Yield 69% (152 mg); Rf (5% EtOAc/Hexane) 0.4. Prepared
as shown in general experimental procedure (Reaction time 4 h at
100°C): IR (Neat, cm–1): 3053, 2925, 2855, 1779, 1695, 1619,
1
1581; H NMR (400 MHz, CDCl3) δ (ppm) 8.83 (d, J = 8.4 Hz,
1H), 8.57 (d, J = 5.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.80 (d, J
= 5.6 Hz, 1H), 7.73 – 7.64 (m, 2H), 3.31 (t, J = 7.2 Hz, 2H), 1.81
– 1.73 (m, 2H), 1.45 – 1.40 (m, 2H), 1.38 – 1.26 (m, 10H), 0.87
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 205.0,
153.6, 141.0, 137.0, 130.3, 128.9, 126.9, 126.7, 125.7, 124.2,
40.4, 31.9, 29.5, 29.5, 29.3, 29.3, 24.1, 22.6, 14.1; (19 13C peaks)
4.3.13 Phenyl(4-phenylisoquinolin-1-yl)methanone
(4a):
Colourless oily; Yield 73% (110 mg); Rf (5% EtOAc/Hexane)
0.2. Prepared as shown in general experimental procedure
(Reaction time 12 h at 105°C): IR (Neat, cm–1): 3747, 3581,
HRESI-MS (m/z): Calculated for C19H25NO (M+
306.1834, found (M+ + Na): 306.1834.
+ Na):
1
3403, 3057, 2925, 1965, 1666, 1593, 1549; H NMR (400 MHz,
CDCl3) δ (ppm) 8.56 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.03 – 8.0
(m, 3H), 7.72 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 8.0 Hz, 2H), 7.57 –
7.49 (m, 7H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.7, 155.7,
140.9, 136.6, 136.5, 135.2, 135.0, 133.6, 130.7, 130.0, 128.6,
128.4, 128.2, 128.0, 126.3, 126.2, 125.3; (17 13C peaks) HRESI-
MS (m/z): Calculated for C22H15NO (M+ + Na): 332.1051, found
(M+ + Na): 332.1055.
4.3.9
1-(isoquinolin-1-yl)octan-1-one (3i): Pale yellow oily;
Yield 76% (150 mg); Rf (5% EtOAc/Hexane) 0.4. Prepared as
shown in general experimental procedure (Reaction time 4 h at
100°C): IR (Neat, cm–1): 3053, 2926, 2857, 1776, 1695, 1619,
1
1581, 1553, 1498, 1458; H NMR (400 MHz, CDCl3) δ (ppm)
8.83 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 8.0
Hz, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.72 – 7.64 (m, 2H), 3.31 (t, J
= 7.6 Hz, 2H), 1.81 – 1.71 (m, 2H), 1.44 – 1.38 (m, 4H), 1.37 –
1.29 (m, 4H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 205.0, 153.6, 141.0, 137.0, 130.3, 128.9, 126.9,
126.7, 125.7, 124.1, 40.4, 31.7, 29.3, 29.1, 24.1, 22.6, 14.1; (17
4.3.14 (2,4-dimethoxyphenyl)(4-phenylisoquinolin-1-
yl)methanone (4b): Pale yellow oily; Yield 61% (110 mg); Rf
(20% EtOAc/Hexane) 0.3. Prepared as shown in general
experimental procedure (Reaction time 16 h at 105°C): IR (Neat,
cm–1): 3348, 3188, 2995, 2928, 2842, 1767, 1713, 1587, 1482; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.45 (s, 1H), 8.30 (d, J = 8.4
Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.67
(t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.54 – 7.48 (m, 5H),
6.62 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 3.86 (s, 3H), 3.45 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 194.0, 165.3, 161.7, 158.5,
141.0, 136.9, 134.8, 134.3, 133.9, 130.3, 130.1, 128.6, 128.0,
13C peaks) HRESI-MS(m/z): Calculated for C17H21NO (M+
Na): 278.1521, found (M+ + Na): 278.1526.
+
4.3.10
1-(isoquinolin-1-yl)heptan-1-one (3j): Pale yellow oily;
Yield 75% (140 mg); Rf (5% EtOAc/Hexane) 0.4. Prepared as
shown in general experimental procedure (Reaction time 4 h at
100°C): IR (Neat, cm–1): 3369, 3053, 2956, 2926, 2856, 2377,
2350, 2313, 1784, 1695, 1620, 1581; 1H NMR (400 MHz,
127.5, 126.5, 125.2, 125.0, 120.7, 105.7, 98.8, 55.7, 55.5; (22 13
C

ACCEPTED MANUSCRIPT
7
peaks) HRESI-MS (m/z): Calculated for C24H19NO3 (M+ + Na):
392.1263, found (M+ + Na): 392.1262.
7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.59 – 7.50 (m, 5H), 7.17
(t, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.1,
167.4, 164.8, 155.2, 140.9, 136.5, 135.5, 135.2, 133.6, 133.5,
133.1, 133.1, 130.8, 130.1, 128.7, 128.3, 128.2, 126.3, 125.4,
115.8, 115.6; (21 13C peaks) HRESI-MS (m/z): Calculated for
C22H14FNO (M+ + Na): 350.0957, found (M+ + Na): 350.0956.
4.3.15 Benzo[d][1,3]dioxol-5-yl(4-phenylisoquinolin-1-
yl)methanone (4c): White solid; Yield 44% (77 mg); mp 138–
140 °C; Rf (10% EtOAc/Hexane) 0.2. Prepared as shown in
general experimental procedure (Reaction time 14 h at 105°C):
IR (KBr, cm–1): 3104, 3055, 2895, 2780, 2610, 2309, 1651, 1604,
4.3.20 (4-chlorophenyl)(4-phenylisoquinolin-1-yl)methanone
(4h): Yellow oily; Yield 45% (76 mg); Rf (2% EtOAc/Hexane)
0.3. Prepared as shown in general experimental procedure
(Reaction time 15 h at 105°C): IR (Neat, cm–1): 3195, 3028,
1
1493, 1435; H NMR (400 MHz, CDCl3) δ (ppm) 8.54 (s, 1H),
8.22 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.6
Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.57 – 7.53 (m, 7H), 6.87 (d, J
= 8.0 Hz, 1H), 6.08 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 193.0, 156.2, 152.5, 148.1, 140.9, 136.5, 135.0, 131.3,
130.7, 130.1, 128.6, 128.2, 128.2, 127.9, 126.3, 126.1, 125.3,
109.8, 108.0, 101.9; (20 13C peaks) HRESI-MS (m/z): Calculated
for C23H15NO3 (M+ + Na): 376.0950, found (M+ + Na): 376.0952.
1
2921, 2850, 1774, 1712, 1661, 1580, 1486, 1446; H NMR (400
MHz, CDCl3) δ (ppm) 8.55 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.02
– 7.97 (m, 3H), 7.72 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H),
7.56 – 7.52 (m, 5H), 7.48 (d, J = 8.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ (ppm) 193.5, 154.9, 140.9, 140.2, 136.5, 135.7,
135.2, 135.1, 132.2, 130.9, 130.1, 128.8, 128.7, 128.4, 128.3,
126.3, 126.2, 125.5; (18 13C peaks) HRESI-MS (m/z): Calculated
for C22H14ClNO (M+ + Na): 366.0662, found (M+ + Na):
366.0664.
4.3.16
(3-methoxyphenyl)(4-phenylisoquinolin-1-
yl)methanone (4d): White solid; Yield 67% (111 mg); mp 106–
108 °C; Rf (10% EtOAc/Hexane) 0.3. Prepared as shown in
general experimental procedure (Reaction time 16 h at 105°C):
IR (KBr, cm–1): 3200, 3034, 2998, 2921, 2847, 1850, 1710, 1656,
4.3.21
Naphthalen-2-yl(4-phenylisoquinolin-1-yl)methanone
1
1584, 1458, 1424; H NMR (400 MHz, CDCl3) δ (ppm) 8.55 (s,
(4i): Yellow solid; Yield 51% (90 mg); mp 94–96 °C; Rf (10%
EtOAc/Hexane) 0.5. Prepared as shown in general experimental
procedure (Reaction time 12 h at 105°C): IR (KBr, cm–1): 3290,
3055, 2980, 2923, 2856, 2720, 1776, 1704, 1652, 1495; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.60 (s, 1H), 8.43 (s, 1H), 8.33 (d, J
= 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H),
7.97 (d, J = 8.8 Hz, 1H), 7.90 (t, J = 6.8 Hz, 2H),7.73 (t, J = 7.6
Hz, 1H), 7.66 – 7.48 (m, 8H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 194.8, 156.0, 141.0, 136.6, 135.9, 135.3, 135.1, 134.0,
133.7, 132.3, 130.8, 130.1, 129.8, 128.8, 128.7, 128.4, 128.3,
128.1, 127.8, 126.7, 126.4, 126.3, 125.4, 125.3; (24 13C peaks)
1H), 8.27 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.71 (t, J
= 7.6 Hz, 1H), 7.66 – 7.48 (m, 8H), 7.38 (t, J = 7.6 Hz, 1H), 7.18
(d, J = 7.6 Hz, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 194.6, 159.7, 155.8, 141.0, 138.0, 136.5, 135.2, 135.0,
130.7, 130.1, 129.4, 128.7, 128.3, 128.0, 126.3, 126.1, 125.3,
124.0, 120.4, 114.3, 55.5; (21 13C peaks) HRESI-MS (m/z):
Calculated for C23H17NO2 (M+ + Na): 362.1157, found (M+
Na): 362.1158.
+
4.3.17 (4-isopropylphenyl)(4-phenylisoquinolin-1-
yl)methanone (4e): Colorless oily; Yield 52% (90 mg); Rf (5%
EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction time 12 h at 105°C): IR (Neat, cm–1): 3375,
HRESI-MS (m/z): Calculated for C26H17NO (M+
382.1028, found (M+ + Na): 382.1209.
+ Na):
1
3055, 2961, 2868, 1665, 1603, 1563, 1498; H NMR (400 MHz,
4.3.22
(4-phenylisoquinolin-1-yl)(thiophen-2-yl)methanone
CDCl3) δ (ppm) 8.55 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.00 (d, J
= 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H),
7.61 (t, J = 7.6 Hz, 1H), 7.56 – 7.49 (m, 5H), 7.35 (d, J = 8.0 Hz,
2H), 3.02 – 2.84 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 194.5, 156.1, 155.4, 140.9, 136.6,
135.1, 135.0, 134.5, 131.0, 130.7, 130.1, 128.6, 128.2, 128.0,
126.6, 126.4, 126.2, 125.3, 34.4, 23.6; (20 13C peaks) HRESI-MS
(m/z): Calculated for C25H21NO (M+ + Na): 374.1521, found (M+
+ Na): 374.1526.
(4j): Pale yellow oily; Yield 51% (78 mg); Rf (5%
EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction time 15 h at 105°C): IR (Neat, cm–1): 3378,
3062, 2923, 2850, 2792, 2375, 2093, 1823, 1642, 1575; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.63 (d, J = 8.0 Hz, 1H), 8.58 (s,
1H), 7.99 – 7.95 (m, 2H), 7.78 (d, J = 4.8 Hz, 1H), 7.71 – 7.64
(m, 2H), 7.59 – 7.49 (m, 5H), 7.18 (t, J = 4.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 186.1, 153.9, 142.7, 140.7, 136.6,
136.5, 136.1, 136.0, 135.3, 130.7, 130.1, 128.7, 128.3, 128.0,
126.5, 126.1, 125.3; (17 13C peaks) HRESI-MS (m/z): Calculated
for C20H13NOS (M+ + Na): 338.0616, found (M+ + Na):
338.0614.
4.3.18
(4-phenylisoquinolin-1-yl)(o-tolyl)methanone
(4f):
Colorless oily; Yield 88% (139 mg); Rf (5% EtOAc/Hexane) 0.3.
Prepared as shown in general experimental procedure (Reaction
time 15 h at 105°C): IR (Neat, cm–1): 3058, 2968, 2924, 2855,
4.3.23
(4-phenylisoquinolin-1-yl)(thiophen-3-yl)methanone
1
2734, 2400, 1914, 1778, 1669, 1603, 1561; H NMR (400 MHz,
(4k): Pale yellow oily; Yield 53% (82 mg); Rf (5%
EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction time 15 h at 105°C): IR (Neat, cm–1): 3389,
CDCl3) δ (ppm) 8.51 – 8.48 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H),
7.72 – 7.64 (m, 2H), 7.53 – 7.41 (m, 7H), 7.33 (d, J = 7.2 Hz,
1H), 7.22 (t, J = 7.6 Hz, 1H), 2.59 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 197.7, 156.2, 141.1, 139.7, 137.3, 136.5, 135.5,
135.1, 132.0, 131.9, 131.8, 130.7, 130.1, 128.6, 128.3, 126.4,
126.2, 125.4, 125.4, 21.3; (20 13C peaks) HRESI-MS (m/z):
Calculated for C23H17NO (M+ + Na): 346.1208, found (M+ + Na):
346.1209.
1
3106, 3058, 2924, 2855, 1654, 1546, 1505, 1412; H NMR (400
MHz, CDCl3) δ (ppm) 8.56 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.24
(d, J = 1.6 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 4.8 Hz,
1H), 7.71– 7.61 (m, 2H), 7.57 – 7.48 (m, 5H), 7.38 – 7.36 (m,
1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 187.9, 155.4, 141.3,
140.8, 136.8, 136.5, 135.6, 135.2, 130.7, 130.0, 128.7, 128.4,
128.3, 128.1, 126.4, 126.0, 125.9, 125.3; (18 13C peaks) HRESI-
MS (m/z): Calculated for C20H13NOS (M+ + Na): 338.0616,
found (M+ + Na): 338.0614.
4.3.24 3-Methyl-1-(4-phenylisoquinolin-1-yl)butan-1-one (4l):5b
Colourless oily; Yield 83% (117 mg); Rf (5% EtOAc/Hexane) 0.
5. Prepared as shown in general experimental procedure
(Reaction time 4 h at 100°C): IR (Neat, cm–1): 3367, 3049, 2956,
4.3.19
(4-fluorophenyl)(4-phenylisoquinolin-1-yl)methanone
(4g): Yellow oily; Yield 75% (120 mg); Rf (2% EtOAc/Hexane)
0.5. Prepared as shown in general experimental procedure
(Reaction time 16 h at 105°C): IR (Neat, cm–1): 3061, 2924,
2740, 2604, 2264, 1960, 1780, 1780, 1668, 1594, 1548; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.55 (s, 1H), 8.31 (d, J = 8.4 Hz,
1H), 8.09 – 8.05 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.71 (t, J =

ACCEPTED MANUSCRIPT
8
Tetrahedron
1
2870, 1692, 1550, 1498, 1452; H NMR (400 MHz, CDCl3) δ
13C peaks) HRESI-MS (m/z): Calculated for C19H15NO5 (M+ +
Na): 360.0848, found (M+ + Na): 360.0848.
(ppm) 8.93 – 8.90 (m, 1H), 8.52 (s, 1H), 7.95 – 7.92 (m, 1H),
7.69 – 7.64 (m, 2H), 7.56 – 7.49 (m, 5H), 3.25 (d, J = 6.8 Hz,
2H), 2.43 – 2.32 (m, 1H), 1.06 (d, J = 6.4 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, 126.7, 125.5, 125.2, 49.2, 25.0,
22.8; (16 13C peaks) HRESI-MS (m/z): Calculated for
C20H19NO (M+ + Na): 312.1364, found (M+ + Na): 312.1365.
4.3.29 [1,3]dioxolo[4,5-g]isoquinolin-5-yl(4-
methoxyphenyl)methanone (5e):5a White solid; Yield 47% (73
mg); mp 150–152 °C; Rf (30% EtOAc/Hexane) 0.3. Prepared as
shown in general experimental procedure (Reaction time 12 h at
105°C and reaction performed in a screw capped reaction vial
with acetonitonitrile as asolvent): IR (KBr, cm–1): 3060, 3008,
2973, 2913, 2834, 2569, 1993, 1695, 1647, 1499, 1459; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.41 (d, J = 5.2 Hz, 1H), 7.93 (d, J =
8.4 Hz, 2H), 7.59 (d, J = 5.2 Hz, 1H), 7.47 (s, 1H), 7.12 (s, 1H),
6.93 (d, J = 8.4 Hz, 2H), 6.08 (s, 2H), 3.86 (s, 3H);13C NMR (100
MHz, CDCl3) δ (ppm) 193.6, 163.9, 154.7, 151.0, 149.2, 140.3,
135.4, 133.1, 129.5, 123.8, 121.7, 113.6, 102.7, 102.1, 101.8,
55.5; (16 13C peaks) HRESI-MS (m/z): Calculated for C18H13NO4
(M+ + H): 308.0923, found (M+ + H): 308.0926.
4.3.25
(4-methoxyphenyl)(5,6,7-trimethoxyisoquinolin-1-
yl)methanone (5a):5a,5b White solid; Yield 61% (108 mg); mp
146–148 °C; Rf (30% EtOAc/Hexane) 0.5. Prepared as shown in
general experimental procedure (Reaction time 16 h at 105°C):
IR (KBr, cm–1): 3119, 3079, 3011, 2942, 2837, 2569, 2144, 1743,
1
1648, 1576, 1474; H NMR (400 MHz, CDCl3) δ (ppm) 8.48 (d,
J = 5.6 Hz, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 8.8 Hz,
2H), 7.37 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 4.08 (s, 3H), 4.03 (s,
3H), 3.93 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 193.7, 163.9, 154.4, 154.0, 146.6, 144.1, 139.5, 133.2,
129.6, 129.1, 123.7, 116.5, 113.6, 100.2, 61.5, 61.1, 56.0, 55.5;
(18 13C peaks) HRESI-MS (m/z): Calculated for C20H19NO5 (M+
+ Na): 376.1161, found (M+ + Na): 376.1160.
4.3.30 (6,7-dimethoxyisoquinolin-1-yl)(4-
methoxyphenyl)methanol (6):5a White solid; Yield 68% (114 mg);
mp 140–142 °C; Rf (50% EtOAc/Hexane) 0.2. Prepared by
reducti on with 1.1eqv of NaBH4 in methanol (Reaction time 30
min at RT): IR (KBr, cm–1): 3354, 3283, 3012, 2916, 2839, 2286,
2238, 2055, 2000, 1894, 1737, 1608, 1571, 1508, 1468; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.38 (d, J = 5.6 Hz, 1H), 7.48 (d, J =
5.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.06 – 7.04(m, 2H), 6.81
(d, J = 8.4 Hz, 2H), 6.15 (s, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 3.72
(s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 159.0, 156.6,
152.5, 149.6, 138.7, 135.7, 133.4, 128.8, 120.7, 119.6, 114.0,
105.1, 103.1, 72.2, 55.9, 55.7, 55.1; (17 13C peaks) HRESI-MS
(m/z): Calculated for C19H19NO4 (M+ + H): 326.1392, found (M+
+ H): 326.1395.
4.3.26 (6,7-dimethoxyisoquinolin-1-yl)(3,4-
dimethoxyphenyl)methanone (5b):5a Yellow solid; Yield 59%
(105 mg); mp 205–207 °C; Rf (50% EtOAc/Hexane) 0.4.
Prepared as shown in general experimental procedure (Reaction
time 18 h at 105°C)(DCM is necessary for workup, partially
soluble in ethylacetate): IR (KBr, cm–1): 3066, 3006, 2971, 2933,
1
2836, 2608, 2481, 1882, 1716, 1655, 1619, 1583, 1504, 1455; H
NMR (400 MHz, CDCl3) δ (ppm) 8.46 (d, J = 5.2 Hz, 1H), 7.72
(s, 1H), 7.65 (d, J = 5.2 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J = 8.4,
1H), 7.14 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.05 (s, 3H), 3.96 (s,
6H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.9,
153.7, 153.6, 153.1, 150.9, 148.9, 139.9, 133.8, 129.8, 126.8,
4.3.31 Quinolin-2-yl(p-tolyl)methanone (8a).5a,5b White solid;
Yield 42% (80 mg); mp 63–65 °C; Rf (5% EtOAc/Hexane) 0.4.
Prepared as shown in general experimental procedure (Reaction
time 12 h at 105°C): IR (Neat, cm–1): 3583, 3295, 3060, 2921,
122.7, 121.2, 111.8, 109.8, 104.7, 103.9, 56.0, 56.0, 55.9; (19 13
C
peaks) HRESI-MS (m/z): Calculated for C20H19NO5 (M+ + Na):
376.1161, found (M+ + Na): 376.1163.
1
2855, 2304, 1657, 1605, 1562; H NMR (400 MHz, CDCl3) δ
(ppm) 8.28 (d, J = 8.4 Hz, 1H), 8.19 – 8.13 (m, 3H), 8.05 (d, J =
8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H),
7.60 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 193.3, 154.9, 146.5, 143.8,
136.9, 133.4, 131.5, 130.3, 129.9, 128.8, 128.7, 128.1, 127.5,
120.7, 21.6; (15 13C peaks) HRESI-MS(m/z): Calculated for
C17H13NO (M+ + Na): 270.0895, found (M+ + Na): 270.0894
4.3.27 (6,7-dimethoxyisoquinolin-1-yl)(4-
methoxyphenyl)methanone (5c):5a,5b White solid; Yield 64% (104
mg); mp 145–147 °C; Rf (50% EtOAc/Hexane) 0.5. Prepared as
shown in general experimental procedure (Reaction time 16 h at
105°C): IR (KBr, cm–1): 3383, 3048, 3005, 2921, 2835, 2642,
1
2506, 1737, 1648, 1603, 1575, 1507, 1439; H NMR (400 MHz,
4.3.32 Quinoline-2,4-diylbis(p-tolylmethanone) (8b).5b Pale
yellow oily liquid; Yield 25% (72 mg); Rf (5% EtOAc/Hexane)
0.2. Prepared as shown in general experimental procedure
(Reaction time 12 h at 105°C):IR (Neat, cm–1): 3061, 2921, 2856,
2591, 2380, 1928, 1661, 1604, 1569; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.28 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.0 Hz,
2H), 8.08 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.83 – 7.78 (m, 3H),
7.63 (t, J = 7.6 Hz, 1H), 7.34 – 7.25 (m, 4H), 2.45 (s, 3H), 2.43
(s, 3H);13C NMR (100 MHz, CDCl3) δ (ppm) 195.3, 192.6,
154.1, 147.1, 145.7, 145.5, 144.2, 133.9, 133.1, 131.5, 130.9,
130.5, 129.5, 129.2, 128.9, 125.6, 125.3, 119.3, 21.8, 21.7; (20
CDCl3) δ (ppm) 8.45 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 8.8 Hz,
2H), 7.63 (d, J = 5.2 Hz, 1H), 7.56 (s, 1H), 7.13 (s, 1H), 6.95 (d,
J = 8.4 Hz, 2H), 4.03 (s, 3H), 3.95 (s, 3H), 3.86 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 193.8, 163.8, 153.6, 153.0,
150.9, 139.9, 133.8, 133.1, 129.7, 122.7, 121.1, 113.6, 104.7,
103.9, 56.0, 55.9, 55.4; (17 13C peaks) HRESI-MS (m/z):
Calculated for C19H17NO4 (M+ + H): 324.1236, found (M+ + H):
324.1232.
4.3.28 [1,3]dioxolo[4,5-g]isoquinolin-5-yl(3,4-
dimethoxyphenyl)methanone (5d):5a White solid; Yield 48% (81
mg); mp 202–204 °C; Rf (30% EtOAc/Hexane) 0.2. Prepared as
shown in general experimental procedure (Reaction time 12 h at
105°Cand reaction performed in a screw capped reaction vial
with acetonitonitrile as a solvent): IR (KBr, cm–1): 3077, 3003,
2920, 2848, 2691, 2600, 1744, 1651, 1579, 1515, 1458; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.43 (d, J = 5.6 Hz, 1H), 7.70 (s,
1H), 7.60 (d, J = 5.6 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J = 8.4 Hz,
1H), 7.13 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.09 (s, 2H), 3.96 (s,
3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.6,
154.6, 153.8, 151.0, 149.2, 149., 140.3, 135.4, 129.6, 126.8,
123.8, 121.8, 111.6, 109.8, 102.7, 102.1, 101.8, 56.0, 56.0; (19
13C peaks) HRESI-MS(m/z): Calculated for C25H19NO2 (M+
+
Na): 388.1313, found (M+ + Na): 388.1313.
4.3.33 Acridin-9-yl(4-methoxyphenyl)methanone (9). Yellow
solid; Yield 59% (142 mg); mp 215–217 °C; Rf (20%
EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction time 12 h at 105°C and Chlorobenzene used
as solvent): IR (KBr, cm-1): 3157, 3064, 3009, 2983, 2843, 2588,
1
1649, 1594, 1564, 1509; H NMR (400 MHz, CDCl3) δ (ppm)
8.31 (d, J = 8.8 Hz, 2H), 7.81 – 7.74 (m, 6H), 7.47 (t, J = 7.6 Hz,
2H), 6.90 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (100 MHz,

ACCEPTED MANUSCRIPT
9
CDCl3) δ (ppm) 195.9, 164.7, 148.5, 144.0, 132.5, 130.4, 129.8,
Supplementary data
126.6, 125.5, 122.9, 114.3, 55.6; (12 13C peaks) HRESI-MS(m/z):
Calculated for C21H15NO2 (M+ + H): 314.1181, found (M+
H):314.1181.
+
Supplementary data contains 1H and 13C NMR spectra for all
compounds which can be obtained in the online version.
4.3.34 Quinoxalin-2-yl(p-tolyl)methanone (10a).5a,5b Yellow
solid; Yield 42% (80 mg); mp 100–102 °C; Rf (10%
EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction time 12 h at 105°C and chlorobenzene used
as a solvent): IR (KBr, cm-1): 3299, 3051, 2916, 2849, 2667,
References and notes
1. Reviews on C-H activations, see: a) Guo, X.-X.; Gu, D.-W.; Wu,
Z.; Zhang, W. Chem. Rev. 2015, 115, 1622-1651. b) Li, B.;
Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744-5767. C) Song, G.;
Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651-3678. d)
Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879-5918. e) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem.
Rev. 2011, 111, 1780-1824. f) Le Bras, J.; Muzart, J. Chem. Rev.
2011, 111, 1170-1214.
1
1652, 1600, 1565, 1486; H NMR (400 MHz, CDCl3) δ (ppm)
9.46 (s, 1H), 8.21 – 8.14 (m, 4H), 7.91 – 7.83 (m, 2H), 7.34 (d, J
= 8.0 Hz, 2H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 191.9, 148.9, 145.3, 144.7, 143.0, 140.4, 132.9, 131.8,
131.3, 130.7, 130.4, 129.3, 129.1, 21.8; (14 13C peaks) HRESI-
MS(m/z): Calculated for C16H12N2O (M+ + Na): 271.0847, found
(M+ + Na): 271.0848.
2. Reviews on cross-dehydrogenative coupling (CDC) reactions, see:
a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215-1292.
b) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068-5083. c) Bugaut, X.; Glorius, F. Angew. Chem.,
Int. Ed. 2011, 50, 7479-7481. d) Li, C.-J. Acc. Chem. Res. 2009,
42, 335-344.
3. a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett.
2009, 11, 3120-3123. b) Chan, C.-W.; Zhou, Z.; Chan, A. S. C.;
Yu, W.-Y. Org. Lett. 2010, 12, 3926-3929. c) Li, C.; Wang, L.; Li,
P.; Zhou, W. Chem. –Eur. J. 2011, 17, 10208-10212. d) Wu, Y.;
Li, B.; Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011, 13, 3258-
3261. e) Wang, J.; Liu, C.; Yuan, J.; Lei, A. Angew. Chem., Int.
Ed. 2013, 52, 2256-2259. f) Yang, W.-C.; Weng, S.-S.;
Ramasamy, A.; Rajeshwaren, G.; Liao, Y.-Y.; Chen, C.-T. Org.
Biomol. Chem. 2015, 13, 2385-2392.
4. a) Wertz, S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928-931.
b) Shi, Z.; Glorius, F. Chem. Sci. 2013, 4, 829-833. c) Rao, H.;
Ma, X.; Liu, Q.; Li, Z.; Cao, S.; Li, C.-J. Adv. Synth. Catal. 2013,
355, 2191-2196. d) Wang, P.; Rao, H.; Hua, R.; Li, C.-J. Org.
Lett. 2012, 14, 902-905. e) Tang, B.-X.; Song, R.-J.; Wu, C.-Y.;
Liu, Y.; Zhou, M.-B.; Wei, W.-T.; Deng, G.-B.; Yin, D.-L.; Li, J.-
H. J. Am. Chem. Soc. 2010, 132, 8900-8902.
4.3.35 Quinoxaline-2,3-diylbis(p-tolylmethanone) (10b). Pale
red solid; Yield 11% (30 mg); mp 168–170 °C; Rf (10%
EtOAc/Hexane) 0.2. Prepared as shown in general experimental
procedure (Reaction time 12 h at 105°C and chlorobenzene used
as a solvent): IR (KBr, cm-1): 3059, 2920, 2852, 2591, 1659,
1600, 1563; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.21 – 8.19 (m,
2H), 8.00 (d, J= 7.6 Hz, 4H), 7.92 – 7.89 (m, 2H), 7.31 (d, J =
8.0 Hz, 4H), 2.44 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
192.2, 152.1, 145.0, 140.1, 132.6, 131.9, 131.0, 129.8, 129.2,
21.8; (10 13C peaks) HRESI-MS(m/z): Calculated for C24H18N2O2
(M+ + Na): 389.1266, found (M+ + Na): 389.1262.
4.3.36 Phenanthridin-6-yl(p-tolyl)methanone(11).5c
White
5. a) Matcha, K.; Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52,
2082-2086. b) Siddaraju, Y.; Lamani, M.; Prabhu, K. R. J. Org.
Chem. 2014, 79, 3856-3865. c) Cheng, P.; Qing, Z.; Liu, S.; Liu,
W.; Xie, H.; Zeng, J. Tetrahedron Lett. 2014, 55, 6647-6651. d)
Pruet, J. M.; Robertus, J. D.; Anslyn, E. V. Tetrahedron Lett.
2010, 51, 2539-2540. e) Caronna, T.; Galli, R.; Malatesta, V.;
Minisci, F. J. Chem. Soc. C. 1971, 1747-1750. f) Ali, W.; Behera,
A.; Guin, S.; Patel, B. K. J. Org. Chem. 2015, 80, 5625. g) Wan,
M.; Lou, H.; Liu, L. Chem. Commun. 2015, 51, 13953. h) While
preparing this manuscript a report on acylation of heterocycles
using TFA and TBHP appeared on Org. Biomol. Chem: Chen, J.;
Wan, M.; Hua, J.; Sun, Y.; Lv, Z.; Li, W.; Liu, L. Org. Biomol.
Chem., 2015, 13, 11561-11566.
solid; Yield 90% (207 mg); mp 155–157 °C; Rf (10%
EtOAc/Hexane) 0.4. Prepared as shown in general experimental
procedure (Reaction time 12 h at 105°C): IR(KBr, cm–1): 3741,
3608, 3290, 3029, 2910, 2853, 2301, 2058, 1952, 1726, 1654,
1602, 1567;1H NMR (400 MHz, CDCl3) δ (ppm) 8.72 (d, J = 8.4
Hz, 1H), 8.67 – 8.65 (m, 1H), 8.23 – 8.21 (m, 1H), 8.12 (d, J =
8.4 Hz, 1H), 7.94 – 7.87 (m, 3H), 7.81 – 7.74 (m, 2H), 7.66 (t, J
= 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 2.43 (s, 3H);13C NMR
(100 MHz, CDCl3) δ (ppm) 194.4, 157.7, 145.0, 142.5, 133.6,
133.0, 131.1, 130.8, 130.4, 129.2, 128.9, 127.9, 127.6, 127.2,
124.3, 123.6, 122.2, 122.0, 21.7; (19 13C peaks) HRESI-MS(m/z):
Calculated for C21H15NO (M+ + Na): 230.1051, found (M+ + Na):
320.1056.
6. a) Duncton, M. A. J., Minisci reactions: Med. Chem. Commun.
2011, 2, 1135-1161. b) Slavík, J.; Slavíková, L. Collec. Czech.
Chem. Commun. 1996, 61, 1047-1052.
7. a) Correia, C. A.; Yang, L.; Li, C.-J. Org. Lett. 2011, 13, 4581-
4583. b) Minisci, F.; Citterio, A.; Giordano, C. Acc. Chem. Res.
1983, 16, 27-32. b) Minisci, F.; Fontana, F.; Vismara, E. J.
Heterocycl. Chem. 1990, 27, 79-96. c) Minisci, F. Synthesis, 1973,
1973, 1-24. d) Molander, G. A.; Colombel, V.; Braz, V. A. Org.
Lett. 2011, 13, 1852-1855.
8. a) Duncton, M. A. J.; Estiarte, M. A.; Johnson, R. J.; Cox, M.;
O’Mahony, D. J. R.; Edwards, W. T.; Kelly, M. G. J. Org. Chem.
2009, 74, 6354-6357. b) Minisci, F.; Recupero, F.; Cecchetto, A.;
Punta, C.; Gambarotti, C.; Fontana, F.; Pedulli, G. F. J.
Heterocycl. Chem. 2003, 40, 325-328. c) Désaubry, L.;
Bourguignon, J.-J. Tetrahedron Lett. 1995, 36, 7875-7876. d)
Baur, R.; Sugimoto, T.; Pfleiderer, W., Pteridines. Helv.
Chim.,Acta. 1988, 71, 531-543.
4.3.36 2,2,6,6-tetramethylpiperidin-1-yl benzoate (12).13 White
solid; Yield 67% (75 mg); mp 87–89 °C; Rf (2% EtOAc/Hexane)
0.2. IR (KBr, cm–1): 3067, 2979, 2927, 2859, 1737, 1594, 1448;
1H NMR (400 MHz, CDCl3) δ (ppm) 8.08 (d, J = 8.0 Hz, 2H),
7.56 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 1.82 – 1.70 (m,
3H), 1.60 – 1.567 (m, 2H), 1.47 – 1.42 (m, 1H), 1.28 (s, 6H),
1.12 (s, 6H). 13C NMR (100 MHz, CDCl3) δ (ppm) 166.3, 132.8,
129.7, 129.5, 128.4, 60.3, 39.0, 31.9, 20.8, 17.0. (10 13C peaks)
HRESI-MS(m/z): Calculated for C16H23NO2 (M+
284.1626, found (M+ + Na): 284.1625.
+ Na):
Acknowledgments
9. a) Dhineshkumar, J.; Lamani, M.; Alagiri, K.; Prabhu, K. R. Org.
Lett. 2013, 15, 1092-1095. b) Dhineshkumar, J.; Prabhu, K. R.
Org. Lett. 2013, 15, 6062-6065. c) Lamani, M.; Prabhu, K. R.
Chem. –Eur. J. 2012, 18, 14638-14642. d) Lamani, M.; Prabhu, K.
R. J. Org. Chem. 2011, 76, 7938-7944. e) Ojha, D. P.; Prabhu, K.
R. Org. Lett. 2015, 17, 18-21. f) Alagiri, K.; Devadig, P.; Prabhu,
K. R. Chem. –Eur. J. 2012, 18, 5160-5164. g) Siddaraju, Y.;
Prabhu, K. R. Org. Biomol. Chem., 2015, 13, 6749-6753.
The authors thank IISc, DST (NO. SB/S1/OC-56/2013), New-
Delhi, and RL Fine Chem for financial support and Dr. A. R.
Ramesha (RL Fine Chem) for useful discussion. YS thanks CSIR
for a fellowship.

ACCEPTED MANUSCRIPT
10
Tetrahedron
h)Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem., 2015, 13,
11651-11656.
10. Although the reaction with aq TBHP has furnished 58% yield, the
reactions with aliphatic aldehydes and other aldehydes the yield
were low. Threfore, TBHP in decane was used in rest of the
reactions.
11. Shankar, R.; More, S. S.; Madhubabu, M. V.; Vembu, N.; Syam
Kumar, U. K. Synlett 2012, 23, 1013-1020.
12. a) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su,
S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 14411-14415. b) Tang, R.-J.; Kang, L.; Yang, L. Adv.
Synth. Catal. 2015, 357, 2055-2060.
13. Pilo, M.; Porcheddu, A.; De Luca, L. Org. Biomol. Chem, 2013,
11, 8241-8246
.