Iodine-catalyzed oxidative multiple C-H bond functionalization of isoquinolines with methylarenes: An efficient synthesis of isoquinoline-1,3,4(2: H)-triones

Article abstract of DOI:10.1039/c7ob01539a

An iodine-catalyzed multiple C-H bond functionalization of isoquinolines with methylarenes via a successive benzylic sp³ C-H iodination/N-benzylation/amidation/double sp² C-H oxidation sequence is developed. This reaction utilizes un

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Iodine-catalyzed oxidative multiple C-H bonds functionalization of
isoquinolines with methylarenes: an efficient synthesis of
isoquinoline-1,3,4(2H)-triones
Received 00th January 20xx,
Accepted 00th January 20xx
Di Zhu, a Wen-Kun Luo, a Luo Yang, a* and Da-You Ma b*
DOI: 10.1039/x0xx00000x
www.rsc.org/
1a
An iodine-catalyzed multiple C-H bonds functionalization of by
SeO2
or
2c
tetraphenylporphin
(Scheme 1a), the oxidation of C5-
iodination/N-benzylation/amidation/double sp2 C-H oxidation substituted isoquinolin-1-one by K2Cr2O7,1a and oxidative
sequence is developed. This reaction utilizes un-functionalized deacylation of
3-acetyl-4-hydroxyisoquinolin-1(2H)-one1c
sensitized
isoquinolines with methylarenes via successively benzylic sp3 C-H photooxygenation2b,
isoquinolines and readily available methylarenes as starting (Scheme 1b). Besides the above reactions involving the
materials, proceeds under metal-free conditions, and avoids muti- oxidation of de-aromatized isoquinolines, isoquinoline-1,3,4-
step experimental operation, to make it an efficent and practical trione can also be prepared by the Beckmann rearrangement
method for the synthesis of N-benzyl isoquinoline-1,3,4-triones.
or Azido-Schmidt reaction of ninhydrin, using hydroxylamine
hydrochloride2d or trimethylsilyl azide, 2e respectively (Scheme
1c). These synthetic methods have the shortcomings of using
functionalized starting materials which are not readily
available thus require multistep experimental operations, toxic
metal oxidants, and being difficult for diversity-oriented
synthesis. Thus, more convenient method to prepare
isoquinoline-triones with varied structures from readily
available sources would be highly desirable, especially under
metal-free conditions.
Isoquinoline-1,3,4(2H)-trione and its derivatives are identified
as novel caspase inhibitors and nerve protectors to treat
various neurodegenerative diseases, especially Alzheimer’s
disease, apoplexy and ischemic brain injuries. 1 For example,
isoquinoline-1,3,4-trione (
I) was used as a lead like hit to
caspase-3, with an IC50 of 0.15
ꢀ
an acyl amino group to C5 (II) greatly improves its activity and
M, while the introduction of
shows low nanomolar potency (40 nM). 1a
O
O
Ph
O
O
NH
O
O
RuO4, NaIO4
SeO2, or
(a)
OAc
O
O
NH
NH
NH
NH
photooxygenation
NH
NH
O
O
O
O
OH
O
R
R
O
O
O
I
II
O
HNO3/H2SO4
or DMSO, 100 o
K2Cr2O7
IC50 ( ꢀM ): 0.15
0.04
(b)
(c)
NH
NH
C
Figure 1 Isoquinolineꢀ1,3,4(2H)ꢀtriones as caspase inhibitors.
O
O
O
O
FeCl3⋅6H2O
NH2OH⋅HCl
In contrast to their fascinating biological profiles, the
synthetic methods for these compounds were rather limited.
As far as we know, the first preparation was realized by the
O
OH
OH
or
NH
FeCl3, TMSN3
O
O
oxidation of 3,4-dihydroisoquinolin-1(2H)-one with RuO4 as
2a
catalyst and NaIO4 as the sacrificed oxidant.
Scheme 1 Various synthetic routes for isoquinolineꢀ1,3,4ꢀtriones.
Later
modifications included the oxidation of isoquinoline-1,3-dione
On the other hand, the use of molecular iodine or iodide
anion as a catalyst is a promising strategy for C-H bond
transformations and has attracted increasing attention, 3 which
has been incorporated into our ongoing interests on the
benzylic C(sp3)-H bonds transformation4a-c for the
functionalization of heterocycles. 4d-h Recently, we disclosed an
oxidative coupling of isoquinoline with methylarenes to
produce isoquinolin-1(2H)-ones with molecular iodine as
catalyst and TBHP (tert-butyl hydroperoxide) as the oxidant,4a
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which identified as a practical method for the synthesis of iodosuccinimide) as catalyst resulted in a much lower yield of
isoquinolin-1(2H)-ones compared with the precedent stepwise 17% (entry 6), which was rather different from our previous
procedure (Scheme 2a). 2a This study and the aforementioned results. 4a Next, addition of excessed TBHP was critical for the
oxidation of substituted isoquinolin-1-one by K2Cr2O7 to success of this multiple C-H bonds transformations, and the
prepare isoquinoline-1,3,4-trione (Scheme 1b), enlightened us yield of 3a was raised gradually from 38% to 65% by increasing
to envision the direct synthesis of isoquinoline-1,3,4-triones the dosage of TBHP from 5 to 10 equivalences, respectively
from un-functionalized isoquinoline and readily available (entries 3, 7-10). Later, the reaction temperature and time
methylarenes via multiple C-H bonds transformations (Scheme were carefully balanced to provide a highest yield of 74%, by
o
2b).
reacting at 110 C for 24 h. It’s worth noting that this reaction
can also be conducted in other solvent such as chlorobenzene,
with 2 equivalents of toluene added as reactant, but leading to
a much lower yield of 21% (entry 12). A control reaction using
10 mol% iodine and 10 equiv TBHP was conducted to give a
yield of 54%, which revealed that addition of 25 mol% iodine
was necessary for this multiple C-H bonds transformations (see
the SI for the detailed optimization).
Table 2 Substrate scope for methylarenes.
Scheme
2 Preparation of isoquinolineꢀ1,3,4ꢀtriones via multiple CꢀH bonds
functionalization.
Table 1 Optimization for the reaction of isoquinoline and toluene a
entry
[I] (mol %)
I2 (10)
I2 (20)
I2 (25)
I2 (30)
KI (50)
NIS(50)
I2 (25)
I2 (25)
I2 (25)
I2 (25)
I2 (25)
I2 (25)
I2 (10)
[O] (equiv)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (6)
TBHP (8)
TBHP (10)
TBHP (12)
TBHP (10)
TBHP (10)
TBHP (10)
yield (%) b
12
1
2
17
3
38
4
23
5
n.d.
17
6
7
45
8
54
9
65
10
11 c
12 c, d
13
35
74
21
54
a
Conditions: 1a (0.4 mmol), [I] catalyst (mol%), oxidant (equiv) and toluene (3a, 3.2
mmol, 8 equiv) were reacted at 120 oC for 12 h under air atmosphere unless otherwise
noted. Isolated yields. Reacted at 110 oC for 24 h. d Toluene (2 equiv) as reactant
b
c
and chlorobenzene (1.0 mL) as solvent were added.
a Conditions: 1a (0.4 mmol), I2 (25 mol%), oxidant (10 equiv) and 2a-2j (3.2 mmol, 8 equiv)
were reacted at 110 oC for 24 h under air atmosphere unless otherwise noted; isolated yields.
b 2k-2n (0.8 mmol, 2 equiv) as reactant and chlorobenzene (0.5 mL) as solvent were added.
With the above considerations in mind, we first examined
the reaction of isoquinoline (1a) with toluene (2a, both as
reactant and solvent). When molecular iodine as catalyst (10
mol%) and TBHP (70% aq., 5 equiv) as the oxidant were added,
the targeted N-benzyl isoquinoline-1,3,4-trione (3a) was
isolated in 12% yield (Table 1, entry 1). The subsequent
optimization revealed that the loading of molecular iodine
catalyst had obvious influence on this multiple C-H bonds
functioanlization, and addition of 25 mol% iodine increased
the yield of isoquinoline-1,3,4-trione to 38% (entries 2-4).
Instead of molecular iodine, when the reaction was promoted
by other iodine sources such as KI, no desired 3a can be
detected (entry 5); while a cationic iodine such as NIS (N-
With the optimized reaction conditions in hand (Table 1,
entry 11), we proceeded to investigate the generality of this
multiple C-H bonds functionalization of isoquinolines with
methylarenes. The substrate scope for the methylarene
moiety is listed in Table 2. Methylarenes bearing electron-
withdrawing or donating substituents were successfully
tolerated to afford the corresponding N-substituted
isoquinoline-1,3,4-triones (3a-3j) in moderate yields, such as
fluoro (2b), chloro (2c), bromo (2d-2f), nitro (2g), cyano (2h),
methoxycarbonyl (2i) and methoxy (2j) groups. Among them,
when substituent group was located at ortho position of arene
2 | J. Name., 2012, 00, 1-3
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such as ortho-bromotoluene, which provided a similar yield to would increase the electron density of the C=C bond due to
the para-, meta-substituted counterparts, so no obvious steric the p-π conjunction of nitrogen with C=C bond.5 In contrast, N-
hindrance effect for this reaction could be found. However, benzylquinolin-2(1H)-one (5) obtained from the reaction of
when the optimized reaction conditions were applied to the quinoline (1f, Table 3) with toluene, was unreactive under the
arenes with more than one methyl groups, such as para- same conditions, because the α,β-unsaturated amide motif in
xylene (2k), meta-xylene (2l), ortho-xylene (2n) and mesitylene N-benzylquinolin-2(1H)-one (5) was much more electron
(
2g), these reactions resulted in much lower yields, might deficient than the enamide motif, thus was reluctant under the
because the introduction of another methyl group to the same oxidative conditions.
methylarene substrates would consume more oxidant and
generate unwanted byproducts. Gratifyingly, by decreasing the
amount of methylarenes (2k-2g) from 8 to 2 equivlance and
adding cholobenzene as solvent, the reaction yields of these
substrates with isoquinoline were improved significantly.
Table 3 Substrate scope for isoquinoline counterpart.
Scheme 3 Mechanistic investigation on the multiple C-H bonds transformation.
To gain more information on the reaction mechanism,
several control experiments were conducted. First, N-
benzylisoquinoline-1,3(2H,4H)-dione (7, prepared according to
the literature, see SI) can be readily oxidized into the N-benzyl
isoquinoline-1,3,4-trione (3a) in 73% yield (Scheme 3a), by
molecular iodine/TBHP combination, which implied that N-
benzylisoquinoline- 1,3(2H,4H)-dione
(
7)
might be an
intermediate during this multiple C-H bonds functionalization.
By running the reaction using TBHP in decane and adding 10
equivalence of H2O18, the isotope labelling experiment was
conducted to reveal that 80% of the oxygen on C4 may come
from TBHP (as the O16 source). A similar control reaction of N-
a Conditions: 1b-1f (0.4 mmol), I2 (25 mol%), oxidant (10 equiv) and toluene (2a, 3.2 mmol 8
equiv) were reacted at 110 oC for 24 h under air atmosphere unless otherwise noted; isolated
yields.
Encouraged by the exciting results obtained from the iodine-
catalyzed multiple C-H bonds functionalization of isoquinoline
benzylisoquinolin-1(2H)-one (6) afforded the 3a product in
69% total yield (Scheme 3b), and the ratio of the product 3a
containing two O18 (labelled by 3a-O218, in Scheme 3b), one O18
and no O18 were determined as 10 : 40 : 50. These isotope
labelling results supported that the oxygen on C3 may
originate from both TBHP and H2O.
(
1a) with various methylarenes, we then focused our attention
on the scope of isoquinoline anologs (Table 3). As expected, 6-
methyl (1b), 6-tert-butyl (1c), 6-chloro (1d) and 6-bromo (1e
)
substituted isoquinolines turned out to be suitable substrates
for this transformation, which all reacted with toluene
smoothly to yield substituted N-benzyl isoquinoline-1,3,4-
triones (4b-4e). Besides isoquinolines, the optimized reaction
conditions was further applied to the reaction of quinoline (1f
)
with toluene, but the corresponding quinoline-2,3,4(1H)-trione
cannot be detected, with N-benzylation/amidation product (1-
benzylquinolin-2(1H)-one, 5 ) in around 5% yield.
During our previous studies on iodine-catalyzed N-
benzylation/amidation cascade to synthesize isoquinolin-
Scheme 4 Plausible mechanism.
1(2H)-one (6), the mechanistic experiments supported a
pathway including: iodination of the benzylic sp3 C-H bond of
toluene to provide benzylic iodide, quaternary ammonium salt
formation and nucleophilic addition of TBHP. 4a We speculated
On the basis of the mechanistic experiments described
4
above and our previous studies, a plausible mechanism for
this iodine-catalyzed multiple C-H bonds functionalization is
proposed in Scheme 4, with the reaction of isoquinoline (1a
)
isoquinolin-1(2H)-one (
multiple C-H bonds functionalization, since isoquinolin-1(2H)-
one ( ) could be further oxidized by the excessed TBHP in the
presence of iodine catalyst, considering that the existence of
6) was the intermediate during this
and toluene (2a) shown as an example. First, the benzylic sp3
C-H bond iodination of toluene with iodine in the presence of
TBHP produces benzyl iodide, through a homolytic radical
pathway. Benzyl iodide reacts with isoquinoline readily to
6
an enamide motif in N-benzylisoquinolin-1(2H)-one (6), which
generate quaternary ammonium salt intermediate
A.
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Compounds, Ed: A. Dandia, S. L. Gupta, and S. Maheshwari,
Green Chemistry: Synthesis of Bioactive Heterocycles, Ed: K.
L. Ameta, and A. Dandia, Springer India, 2014. (b) D. Liu, and
A.-W. Lei, Chem. Asian J., 2015, 10, 806; (c) P. Finkbeiner and
B. J. Nachtsheim, Synthesis, 2013, 45, 979; (d) Q. Gao, X. Wu,
S. Liu and A. Wu, Org. Lett., 2014, 16, 1732; (e) S. Liu, Q. Gao,
Subsequently, the nucleophilic addition of TBHP provides
4a
hemiaminal-type peroxide
B
,
which undergoes O-O bond
). Then,
due to the nucleophilic reactivity of the enamide motif,
protonation of the C4 generates iminium , and the
nucleophilic addition of TBHP or H2O to this iminium yields
hemiaminal-type intermediate or , respectively. The
intermediate or both can be transformed into N-
benzylisoquinoline-1,3(2H,4H)-dione ( ), which explains the
cleavage to afford N-benzylisoquinolin-1(2H)-one (
6
C
X. Wu, J. Zhang, K. Ding and A Wu, Org. Biomol. Chem., 2015
,
13, 2239; (f) V. Rajeshkumar, S. Chandrasekar and G. Sekar,
Org. Biomol. Chem., 2014, 12, 8512.
D
E
D
E
4
For our recent works on iodine-catalyzed C-H
transformation, see: (a) W.-K. Luo, X. Shi, W. Zhou and L.
Yang, Org. Lett., 2016, 18, 2036; (b) X. Shi, F. Zhang, W.-K.
Luo and L. Yang, Synlett, 2017, 28, 494; (c) L. Yang, X. Shi, B.-
Q. Hu and L.-X. Wang, Asian J. Org. Chem., 2016, 5, 494. For
our recent works on C-H functionalization of heterocycles,
see: (d) R.-J. Tang, L. Kang and L. Yang, Adv. Synth. Catal.,
2015, 357, 2055; (e) X. Gao, F. Zhang, G.-J Deng and L. Yang,
Org. Lett., 2014, 16, 3664. (f) F.-F. Wang, C.-P. Luo, G.-J Deng
and L. Yang, Green Chem., 2014, 16, 2428. (g) F.-F. Wang, C.-
P. Luo, Y. Wang, G.-J. Deng and L. Yang, Org. Biomol. Chem.,
2012, 10, 8605; (h) H.-H. Liu, Y. Wang, G. Deng and L. Yang,
Adv. Synth. Catal., 2013, 355, 3369.
7
oxygen on C3 originates from both TBHP and H2O. At last, the
iodination of the acidic C-H bond on C4, subsequent
nucleophilic substitution by TBHP or H2O, and further
transformations afford the product 3a. 6 The molecular iodine
as the catalyst can be regenerated by the oxidation of
hydrogen iodide with TBHP. 3b
Conclusions
We have developed an convenient iodine-catalyzed multiple
C-H bonds functionalization of isoquinolines with
methylarenes, to produce N-benzyl isoquinoline-1,3,4-triones.
The mechanism studies revealed that the reaction was realized
through successively benzylic sp3 C-H iodination/N-
benzylation/amidation/double sp2 C-H oxidation sequence.
This method utilizes un-functionalized isoquinolines and
readily available methylarenes as starting materials, proceeds
under metal-free conditions, and avoids muti-step
experimental operation, to make it a practical method for the
construction of isoquinoline-1,3,4-triones.
5
For nucleophilic reactivity of enamides, see: (a) T. Courant, G.
Dagousset and G. Masson, Synthesis, 2015, 47, 1799; (b) H.-
M. Liu, W. Lu, C.-P. Luo and L. Yang, Tetrahedron Lett., 2016
,
57, 4243; (c) X.-M. Xu, L. Zhao, J. Zhu and M.-X. Wang,
Angew. Chem., Int. Ed., 2016, 55, 3799; (d) L. Yang, Q. Wen, F.
Xiao and G. Deng, Org. Biomol. Chem., 2014, 12, 9519.
(a) Y. Zi, Z.-J. Cai, S.-Y. Wang and S.-J. Ji, Org. Lett., 2014, 16,
3094; (b) G.-F. Li, L.-W. Huang, J.-C. Xu, W.-S. Sun, J.-Q. Xie, L.
Hong and R. Wang, Adv. Synth. Catal., 2016, 358, 2873.
6
.
Acknowledgments
This work was supported by the Opening Fund of Beijing
National Laboratory for Molecular Sciences, Xiangtan
University “Academic Leader Program” (11QDZ20), Hunan
Provincial Natural Science Foundation (2016JJ2122), Key
Foundation of Education Bureau of Hunan Province (17A208)
and Hunan 2011 Collaborative Innovation Centre of Chemical
Engineering & Technology with Environmental Benignity and
Effective Resource Utilization.
The authors declare no competing financial interest.
Notes and references
1
2
(a) Y.-H. Chen, Y.-H. Zhang, H.-J. Zhang, D.-Z. Liu, M. Gu, J.-Y.
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Sharma and K. K. Kapoor, Tetrahedron Lett., 2015, 56, 1915;
(e) J. S. Yadav, B. V. S. Reddy, U. V. S. Reddy and K. Praneeth,
Tetrahedron Lett., 2008, 49, 4742.
,
3
(a) Chapter 10, Molecular Iodine: Mild, Green, and Nontoxic
Lewis Acid Catalyst for the Synthesis of Heterocyclic
4 | J. Name., 2012, 00, 1-3
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Abstract for the Contents Pages
Iodine-catalyzed oxidative multiple C-H bonds
functionalization of isoquinolines with
methylarenes: an efficient synthesis of
isoquinoline-1,3,4(2H)-triones
Graphic:
Di Zhu, Wen-Kun Luo, Luo Yang, * and Da-You
Ma *
Text:
A
n iodine-catalyzed multiple C-H bonds functionalization of
isoquinolines with methylarenes via successively benzylic sp3
C-H iodination/N-benzylation/amidation/double sp2 C-H
oxidation sequence to yield isoquinoline-1,3,4(2H)-triones is
developed for the first time.