C1-Benzyl and benzoyl isoquinoline synthesis through direct oxidative cross-dehydrogenative coupling with methyl arenes

Article abstract of DOI:10.1039/c5cc04791a

An oxidative cross-dehydrogenative coupling (CDC) of isoquinolines with methyl arenes has been developed, allowing for the facile synthesis of a broad range of structurally diverse C₁-benzyl and -benzoyl isoquinolines. The direct use of readily available methyl arenes as coupling partners avoids unproductive steps for preactivating the functional group installation, and is therefore attractive. The method exhibits excellent chemoselectivity, affording exclusive benzylated products in the presence of DTBP and a catalytic amount of Y(OTf)₃, and yielding benzoylated ones with TBHP and a catalytic amount of MnO₂.

Full text of DOI:10.1039/c5cc04791a

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COMMUNICATION
C1-Benzyl and Benzoyl Isoquinoline Synthesis through Direct
Oxidative Cross-Dehydrogenative Coupling with Methyl Arenes†
Miao Wan,a Hongxiang Loua and Lei Liu*a,b
Zaikanba Received 00th January
20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
other types of alkaloids (Scheme 1).2 The direct C–H
An oxidative cross-dehydrogenative coupling (CDC) of isoquinolines with
methyl arenes has been developed, allowing for facile synthesis of a broad
range of structurally diverse C1-benzyl and -benzoyl isoquinolines. The
direct use of readily available methyl arenes as coupling partners avoids
unproductive steps for preactivating functional group installation, and is
thereby attractive. The method exhibits excellent chemoselectivity,
affording exclusive benzylated products in the presence of DTBP and
catalytic amount of Y(OTf)3, and yielding benzoylated ones with TBHP and
catalytic amount of MnO2.
functionalization of nitrogen-containing heterocycles has
emerged as efficient and robust alternatives to traditional
synthetic
PhI(OCOCF3)2/TMSN3
strategies.3
Antonchick
mediated benzoylation
developed
a
system,
allowing the oxidative CDC of isoquinolines with diverse aryl
aldehydes in good to excellent yields (Scheme 2, eq 1).4a Our
group reported a trityl ion-mediated metal-free oxidative C–H
benzylation of THIQs with a number of benzyl boronates
(Scheme 2, eq 2).5a Albeit high efficiency, preactivating factors
in coupling partners were prerequisite for the reactions, with the
carbonyl moiety for the former, and the boronate for the latter.
C1-Substituted isoquinolines and tetrahydroisoquinolines
(THIQs) represent ubiquitous structural motifs in numerous
biologically
active
natural
products
and
synthetic
Oxidative C-H benzoylation of isoquinolines with aldehydes (Antonchick, Prabhu)
pharmaceuticals.1 Among them, C1-benzyl and benzoyl
substituted moieties are the most commonly encountered and
serve as key intermediates in the synthesis and biosynthesis of
O
PhI(OCOCF3)2
TMSN3
N
eq 1
+
N
H
Ar
H
O
Ar
O
MeO
MeO
N
H
Oxidative C-H benzylation of THIQs with organoboranes (our group)
N
N
O
Me
MeO
MeO
H
H
MeO
OMe
OMe
O
Ph3CClO4
eq 2
NCbz
Ar
+
Ar
BRn
NCbz
MeO
O
MeO
OMe
OMe
H
Tetrahydropalmatine
(anxiolytic and sedative drugs)
Papaverine
(antispasmodic drug)
Noscapine
(antitussive effect)
Oxidative C-H benzylation/benzoylation of isoquinolines with methyl arenes (this work)
COOH
MnO2
TBHP
TFA
H
Y(OTf)3
DTBP
HO
HO
COOH
MeO
N
N
eq 3
+
N
Ar
N
O
N
O
N
O
MeO
MeO
benzoylation
15 examples
benzylation
22 examples
H
Ar
O
Ar
HO
MeO
RHN
Scheme 2 C1-Benzyl and Benzoyl Isoquinoline Synthesis through Oxidative C–H
Cleavage.
OH
R = C(O)3,4-Cl2C6H3
(acetylcholinesterase
inhibitor)
(Inhibitor of IGF-binding
proteins)
(potent CRTH2 antagonist)
Scheme 1 Representative C1-Benzyl and Benzoyl Isoquinolines.
The direct oxidative C–H functionalization of methyl arenes
has recently emerged as an efficient and economic approach to
deliver increases in molecular complexity and functional group
content.6,7 We envisioned that utilizing readily available and
inexpensive methyl arenes as surrogates for the benzylation and
benzoylation of isoquinolines would not require traditional
reagents like benzyl boronates and aryl aldehydes with
preactivating functional groups, and thus avoid unproductive
steps for the installation of these factors. Herein, we disclosed a
facile synthesis of C1-benzyl and benzoyl substituted
a Key Lab of Chemical Biology of Education Ministry, School of Pharmaceutical
Sciences, Jinan 250012, China.
E-Mail: leiliu@sdu.edu.cn
b Key Lab for Colloid and Interface Chemistry of Education Ministry, School of
Chemistry and Chemical Engineering, Shandong University, Jinan 250100, People’s
Republic of China.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1 Reaction condition optimizationa
prompted us to further explore the optimized condition for the
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DOI: 10.1039/C5CC04791A
benzoylation of isoquinoline with toluene. The coupling in the
presence of TFA and TBHP afforded 4a in 52% yield (Table 1,
entry 15). An extensive exploration of the additive revealed that
catalytic amount of manganese-based candidates were
beneficial for improving the reaction efficiency, with 66% yield
for MnO2, and 68% yield for Mn(OAc)3·2H2O (Table 1, entries
16-18). Increasing the loading of the additive delivered a
compromised yield (Table 1, entry 19). While Mn(OAc)3
excelled MnO2 in terms of the yield, the use of the latter for
further study would be more attractive based on economical
and environmental issues.
H
H
N
N
oxidant, acid
+
H
+
N
additive, 120 °C
O
2a
1a
H
3a
4a
Entry
Oxidant
Acid
Yieldb (%,
3a)
< 5
22
Yieldb (%,
4a)
< 5
18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17d
18e
19f
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
H2O2
―
TFA
Cu(OTf)2
La(OTf)3
Sc(OTf)3
Yb(OTf)3
In(OTf)3
Bi(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
―
―
TFA
TFA
TFA
TFA
TFA
31
50
46
54
45
63
75
11
< 5
70
< 5
< 5
10
< 5
< 5
n.d.
n.d.
< 5
< 5
< 5
< 5
< 5
< 5
< 5
41
< 5
< 5
< 5
< 5
50
R1
H
DTBP (3 equiv)
Y(OTf)3 (5 mol %)
N
R1
+
N
120 °C
R2
R2
H
3
2
1
N
N
N
DCP
K2S2O8/TBAB
PIFA/TMSN3
TBHP
3b, 75%
3c, 80%
3a
, 73%
TBHP
TBHP
TBHP
TBHP
66
68
42
45
N
N
N
N
N
Cl
3f, 61%
3e
, 72%
3d, 55%
3g, 70%
3j, 72%
aGeneral conditions: 1a (0.2 mmol), 2a (1.8 mmol), oxidant (0.6 mmol for DTBP;
1.0 mmol for TBHP), acid (0.01 mmol for Y(OTf)3; 0.2 mmol for TFA), and additive
(0.02 mmol) at 120 °C for 12-24 h, unless stated otherwise. bIsolated yield. cMnO2
as the additive. dMn(OAc)3·2H2O as the additive. eMn(OAc)2·4H2O as the additive.
fMnO2 (30 mol %). DTBP = di-tert-butyl peroxide. TBHP = tert-butyl hydroperoxide.
DCP = dicumyl peroxide. TBAB = tert-n-butylammonium bromide. n.d. = not
determined.
OMe
N
N
N
S
3h
3i
, 35%
, 49%
Cl
Br
N
isoquinolines through a direct oxidative C–H functionalization
using methyl arenes as the coupling partners (Scheme 2, eq 3).
Initially, the oxidative CDC of isoquinoline 1a with toluene
2a was selected as the model reaction for optimization (Table
1). No reaction was observed when DTBP was employed as the
oxidant without any acid (Table 1, entry 1). According to our
3k
3l
, 70%
, 41%
N
N
N
Br
previous observations in the C–H benzylation of
N-acyl THIQs
(Scheme 2, eq 2),5a we envisioned that an acid additive might
be beneficial for enhancing the electrophilicity of isoquinolines.
To our delight, acidic additives proved to be crucial to the
efficiency and selectivity of the coupling. The reaction with 1
equiv of TFA afforded an equivalent of benzylated 3a and
benzoylated 4a in a total yield of 40% (Table 1, entry 2).
Employing catalytic amount of Lewis acids (5 mol %) was
beneficial to suppressing the benzoylation process with a
considerable amount of 1a recovered when Cu(OTf)2, La(OTf)3,
Sc(OTf)3, Yb(OTf)3, or In(OTf)3 was used (Table 1, entries 3-7).
Finally, Y(OTf)3 was found to be the optimal choice for the
benzylation reaction in terms of the reaction efficiency (Table 1,
entries 3-9). Extensive examination of other types of peroxides
identified DTBP to be optimal (Table 1, entries 9-12).
Previously reported oxidation systems for CDC of
isoquinolines with aryl aldehydes were uneffective for the
reaction (Table 1, entries 13 and 14).4
3o
, 82%
R1
3m, 72%
3n, 75%
iPr
Et
MeO
N
N
N
Et
MeO
Et
R1 = H, 3r, 50%
3q, 62%
3p
, 60%
R1 = OMe, , 41%
3s
Ph
Br
MeO
N
N
N
MeO
papaverine (3v)
3t, 65%
3u
, 42%
40%
Scheme 3 C1-Benzyl Isoquinoline Synthesis. Reaction conditions:
(1.8 mmol), DTBP (0.6 mmol), and Y(OTf)3 (0.01 mmol) at 120 °C for 12-24 h.
1 (0.2 mmol), 2
The scope of the benzylation of isoquinolines with methyl
arenes was explored (Scheme 3). Mono-substituted toluene
derivatives bearing electron-donating and -withdrawing
functional groups like methyl, methoxy, chloride, and bromide,
were well compatible with the oxidation system for further
When either TFA or TBHP was employed as the
component, a considerable amount of benzoylated isoquinoline
4a was isolated (Table 1, entries 2 and 10). The observation
diversifications (3b-3h). Notably, the reaction efficiency was
2 | J. Name., 2012, 00, 1-3
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not sensitive to the substituent pattern of the methyl arenes.
Methyl heteroarene (2i) and methyl naphthalenes (2j and 2k
were suitable components. Di-substituted toluene moieties
proved to be effective coupling partners (2l and 2m). With
respect to the methyl arenes containing more than one benzyl
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H
benzylation
condition
N
)
+
N
H
3a
77%
2a
1a
1.3 g/10 mmol
methyl groups (2b, 2c, 2e, 2l, and 2m), the exclusive formation
H
benzoylation
condition
N
of mono-arylated product was observed, with the other methyl
group intact. The reaction exhibited overwhelming
regioselectivity at the less sterically hindered methyl group
when two types of benzylic C–H bonds were present in methyl
arenes, as demonstrated by the substrates bearing an ethyl or
+
N
O
H
4a
61%
2a
1a
1.3 g/10 mmol
Scheme 5 Gram Scale Reaction Exploration.
isopropyl substituent at the 2-, 3-, or 4-position of toluene (3n
3q). The substituent effect on isoquinolines was also
investigated, with electron-rich and -deficient substrates
-
benzylation
KH/KD = 4.4
benzoylation
1a + 2a + D8-2a
N
eq 1
N
KH/KD = 6.8
O
tolerated in moderate efficiency (3r
-
3u). The direct benzylation
Ph(D5-Ph)
Ph(D5-Ph)
of isoquinolines with methyl arenes allowed for the facile
preparation of papaverine
antispasmodic drug.
(
3v), an opium alkaloid
benzoylation
condition
N
N
N
eq 2
+
1a 2a 2dd
+
+
+
Ph
O
Ph
4a, < 5%
O
(4-Me)Ph
4d, 80%
R1
H
3a
, < 5%
TBHP (5 equiv)
MnO2 (10 mol %)
N
R1
+
D
D
D
N
TFA (1 equiv)
120 °C
CH3
O
R2
benzoylation
condition
N
R2
CD3
H
D
2
4
1
2a
eq 3
1a
4a
72%
3a
O
D
CH3
D8-2a
N
N
N
H
R2
2dd
O
O
O
Scheme 6 Mechanistic Studies.
R2
R2 = H, 4a, 65%
R2 = Me, 4f, 64%
4g
4h
, 60%
R2 = Me, 4b, 60%
R2 = OMe, , 50%
R2 = Cl,
, 38%
Intermolecular kinetic isotope effects (KH
/KD = 4.4 for
4c
R3 R4
R2 = Br, 4d, 49%
benzylation; KH KD = 6.8 for benzoylation) were observed for
/
R1
R1
R2 = Cl, , 40%
4e
the reaction of 1a with an equivalent of toluene and deuterated
toluene, indicating the involvement of the cleavage of the
benzylic C–H bond in the rate-determining step (Scheme 6, eq
1). According to the above analysis, a plausible mechanism for
the benzylation reaction was proposed in Scheme 7. Toluene
N
N
O
Ph
N
R1 = OMe, R3 = R4 = H, 4k, 45%
R1 = R3 = OMe, R4 = H, 4l, 55%
4m
O
O
R1 = R3 = H, R4 = Ph,
, 66%
4i
, 51%
4j, 49%
(
2a) is converted to benzyl radical 5a in the presence of DTBP
R1 = R3 = H, R4 = Br, 4n, 43%
at 120 ºC. Isoquinoline (1a) can be activated by Y(OTf)3 to
facilitate the addition of 5a onto 1a giving radical 6a, which
Scheme 4 C1-Benzoyl Isoquinoline Synthesis. Reaction conditions:
(1.8 mmol), TBHP (1.0 mmol), TFA (0.2 mmol), and MnO2 (0.02 mmol) at 120 °C
for 12-24 h.
1 (0.2 mmol),
2
then reacts with tert-butoxyl radical to yield 3a
.
tBuOOtBu
The scope of benzoylation of isoquinolines was next
examined in the presence of TBHP and catalytic amount of
MnO2 (Scheme 4). Similarly to the benzylation process, a broad
range of toluene derivatives bearing both electron-donating and
-withdrawing functional groups with different substitution were
120 °C
N
Yb(OTf)3
tBuO
1a
tBuO
H
N
N
Ph CH3
Ph CH2
H
2a
5a
tBuOH
tBuOH
Ph
Ph
3a
6a
tolerated (4a
latter ones (4d
variety of functional groups participated in the benzoylation
reaction in moderate yields (4k 4n).
Under the standard CDC conditions, benzylation and
benzoylation reactions with 1a on a 1.3 g (10 mmol) scale
proceeded smoothly affording comparable yields (75% for 3a
and 61% for 4a) to the smaller scale reactions (73% for 3a and
65% for 4a), demonstrating the capacity to apply the protocol
to scaled up reactions (Scheme 5).
-
4j), though decreased yields were observed for the
Scheme 7 Proposed Mechanism for the Benzylation Process.
,
4e, and 4g). Substituted isoquinolines bearing a
In the course of the benzoylation reaction, the formation of
-
a considerable amount of benzaldehyde and benzylated 3a was
detected by 1H NMR together with the benzoylated 4a
.
Therefore, two possible sequences could be envisaged for the
benzoylation process (Scheme 8). The first one involves an
initial benzylation reaction, followed by an overoxidation of 3a
affording 4a. Alternatively, toluene (2a) might be oxidized to
benzaldehyde (7a) that undergoes a radical coupling with 1aa
giving 4a. Several control experiments were conducted to
elucidate the nature of the mechanism. A crossover experiment
involving a mixture of toluene (2a) and 4-methylbenzaldehyde
The reaction mechanism was next studied. The addition of
2,2,6,6-tetramethylpiperidine 1-oxyl free radical (1 equiv)
completely quenched the reaction of isoquinoline (1a) with
toluene (2a), suggesting the radical nature of the mechanism.
(
2dd) with 1a gave exclusive benzoylated 4d, suggesting the
feasibility of the second pathway given the generation of 7a in
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indicating the first pathway might be viable (Scheme 6, eq 3).
,
5D, 1O1I:21;0(.1o039/C5CC04791A
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Pathway 1
NH
b
TFA
1aa H
TBHP
N
Ph CH2
Ph CH3
2a
(
a
or tBuOO
tBuO
then
5a
tBuOH or
tBuOOH
b
Ph
3a
c
[O]
d
Pathway 2
tBuO
tBuOO
or
e
O
O
1aa
[O]
f
N
O
Ph
C
Ph CH3
2a
Ph CH
then tBuO
8a
7a
g
)
,
or t
BuOO
Ph
4a
Scheme 8 Proposed Mechanism for the Benzyolation Process.
h
i
In conclusion, an oxidative CDC of isoquinolines with
methyl arenes has been disclosed, allowing for facile synthesis
of a broad range of structurally diverse C1-benzyl and -benzoyl
substituted isoquinolines, respectively. The direct use of readily
available methyl arenes as coupling partners avoids
unproductive steps for preactivating functional group
installation, and is thereby attractive. The scaled-up reactions
provided comparable efficiency to smaller scale reactions,
demonstrating the capacity in real alkaloid synthesis.
We gratefully acknowledge the National Science
Foundation of China (21202093, 21472112), the Program for
New Century Excellent Talents in University (NCET-13-0346),
and the Shandong Science Fund for Distinguished Young
Scholars (JQ201404), Young Scientist Foundation Grant of
Shandong Province (BS2013YY001), and the Fundamental
Research Funds of Shandong University (2014JC005,
2015JC035) for financial support.
6
(a
,
b
,
c
d
e
f
,
g
,
(
h
,
7
(
(
a
b
,
414; (
c
,
d)
e
5
f
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) S.-L. Zhou, L.-N. Guo, S. Wang, X.-H. Duan, Chem.
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heterocycles, see: ( ) C.-J. Li, Acc. Chem. Res. 2009, 42, 335;
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