Enantioselective synthesis of isoquinoline-1,3(2: H,4 H)-dione derivatives via a chiral phosphoric acid catalyzed aza-Friedel-Crafts reaction

Article abstract of DOI:10.1039/c9cc04057a

A highly enantioselective aza-Friedel-Crafts reaction of structurally new ketimines with indoles and pyrrole is developed by using a chiral phosphoric acid as the catalyst. This protocol enables the first enantioselective synthesis of isoquinoline-1,3(2H,

Full text of DOI:10.1039/c9cc04057a

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DOI: 10.1039/C9CC04057A
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Enantioselective Synthesis of Isoquinoline-1,3(2H,4H)-dione
Derivatives via Chiral Phosphoric Acid Catalyzed aza-
Friedel−Crafts Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Yong You,*a Wen-Ya Lu,b Ke-Xin Xie,c Jian-Qiang Zhao,a Zhen-Hua Wang,a and Wei-Cheng Yuan*a,b
A
highly enantioselective aza-Friedel−Crafts reaction of
structurally new ketimines with indoles and pyrrole is developed
by using a chiral phosphoric acid as the catalyst. This protocol
enables first enantioselective synthesis of isoquinoline-1,3(2H,4H)-
dione derivatives in good to excellent yields (up to 99% yield) and
excellent enantioselectivities (up to >99% ee).
Isoquinoline-1,3(2H,4H)-dione framework is
a
class of
privileged structural motif because of its prevalence in
pharmaceutical and biologically active molecules (Figure 1).1
For example, compound
I is an excellent aldose reductase
inhibitors and has been proved to be effective for the control
of certain diabetic complications; importantly, studies
suggested that the (R)-enantiomer shows higher
enantioselectivity for the aldose reductase binding site than
the (S)-enantiomer.1c As a result, increasing efforts have been
devoted to the synthesis of structurally diverse isoquinoline-
1,3(2H,4H)-dione derivatives (Figure 2).2-6 Noteworthily, in the
lighting of literature research, existing reports are all non-
asymmetric synthesis. As is well-known, the pharmacological
activity, metabolic process and toxicity of the enantiomers of
chemical drugs containing chiral factors are significantly
different in body. Accordingly, enantioselective synthesis
delivering the single enantiomer is significant for
pharmaceutical sciences. Given the importance of
Figure 2. Strategies for synthesis of isoquinoline-1,3(2H,4H)-
dione derivatives.
Imines are an important class of synthon in asymmetric
synthesis because of the characters including high-activity,
easy to control stereoselectivity and convenience for
synthesizing chiral amines and so on. To date, various types of
imines such as aldimines, isatin-derived ketimines, cyclic
imines are synthesized and used for the asymmetric
conversion to construct chiral amines.7 Among them,
especially, asymmetric aza-Friedel−Crafts reaction of imines
with indoles is an important reaction8 because the products of
this reaction provide easy access to the synthesis of
enantiopure 3-indolyl methanamine derivatives.9 Based on the
importance of imines in synthetic chemistry and isoquinoline-
1,3(2H,4H)-dione skeleton in pharmaceutical chemistry, we
intended to prepare new-type isoquinoline-1,3,4(2H)-trione
ketimines and expected them could engage in asymmetric
transformations to access chiral isoquinoline-1,3(2H,4H)-dione
derivatives. Fortunately, the target ketimines were successfully
prepared.10 Therewith, we envisioned that the asymmetric
aza-Friedel−Crafts reaction of this ketimines with arenes such
as indoles11 could be achieved with suitable catalytic system
(Figure 2). If so, the resulting chiral products combining two
privileged structure motifs, isoquinoline-1,3(2H,4H)-dione and
3-indolyl methanamine, would show great potential in
diversity-oriented synthesis and drug discovery. Herein, we
isoquinoline-1,3(2H,4H)-dione
skeleton
and
the
enantioselective synthesis of these compounds remaining to
date elusive, the development of effective method for
enantioselective synthesis of which is in high demand.
Figure 1. Bioactive isoquinoline-1,3(2H,4H)-dione-containing
molecules.
a.Institute for Advanced Study, Chengdu University, Chengdu 610106, China.
b.National Engineering Research Center of Chiral Drugs, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China.
c. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041,
China.
E-mail: yuanwc@cioc.ac.cn, youyong@cdu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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9V7iew Article>O9n9line
wish to report our research on this subject. Notably, this
methodology represents the first example of catalytic
asymmetric reaction for the construction of chiral
isoquinoline-1,3(2H,4H)-dione derivatives.
4
5
D
E
F
DCM
DCM
DCM
DCM
DCM
25
25
25
25
25
25
25
25
25
25
40
40
60
80
2
48
48
3
15
15
15
15
15
10
5
85
86
98
93
86
DOI: 10.1039/C9CC0470357A
6
67
>99
>99
99
7d
D
D
D
D
D
D
D
D
D
D
D
Based on the successful synthesis of ketimines
1
, we started to
8e
investigate the aza-Friedel−Crafts reaction of the ketimines
with indoles. As shown in Table 1, optimization of the process
commenced with using ketimine 1a, indole 2a, 10 mol % chiral
9e
CHCl3
10e
11e
12e
toluene
CH3CN
THF
toluene
toluene
toluene
toluene
toluene
98
99
trace
NR
97
ND
/
98
phosphoric acid (CPA)
A
in DCM at 25 oC. The reaction
performed smoothly and the corresponding product 3aa was 13e,f
obtained with good yield (91 %) but low enantioselectivity
14e
98
99
(only 4 % ee) after 48 h (entry 1). Magnifying the hindrance of 15e,g
9
7
7
97
97
86
>99
>99
>99
16e,g
R substituents at the 3,3′-positions of catalyst such as 2-
17e,g
naphthyl and 2,4,6-(i-Pr)3C6H2 significantly promoted the
enantioselectivity (96% and 93% ee respectively), but shown aUnless otherwise noted, the reactions were conducted with
1a (0.05 mmol), 2a (0.10 mmol) and 10 mol % catalyst in 1.0
mL of solvent at 25 oC for indicated time. bIsolated yields.
cDetermined by chiral HPLC analysis. d5 mol % catalyst was
used. 2 mol % catalyst was used. 0.5 mL toluene was used.
g1.1 equivalents of 2a was used. ND = No Detection. NR = No
Reaction. DCM = dichloromethane. THF = tetrahydrofuran.
inconducive for reactivity (entries 2-3). Pleasingly, by
employing spirocyclic CPA (R = 9-anthryl) as the catalyst, the
reactivity and enantioselectivity could be improved
D
e
f
concurrently, obtaining the almost optically pure product 3aa
in excellent yield (entry 4). Furthermore, catalysts
delivered inferior results on reactivity as well as
enantioselectivity (entries 5-6). Having identified CPA as the
E and F
D
With the optimized conditions in hand, the substrate scope of
the reaction was evaluated. We first performed experiments
optimal catalyst, the influence of catalyst loading, solvent,
substrate concentration, temperature, and the molar ratio of
substrates was investigated. Halving the catalyst loading, no
differences were observed on reactivity and enantioselectivity
(entry 7). Further decreasing to 2 mol %, 3aa also could be
obtained in excellent results, albeit a prolonged reaction time
was needed (entry 8). Solvent screening revealed that toluene
is the best candidate (entry 10 vs entries 8-9 and 11-12).
Increasing the concentration of 1a to 0.1 M could promote the
reactivity but slightly corroded the enantioselectivity (entry 13
to assess the use of ketimines
1 possessing different
substituents on N1 atom or benzene ring in the aza-
Friedel−Crafts reaction. As shown in Scheme 1, when
substituent on N1 atom was changed from aromatic phenyl to
alkyl such as Bn, n-Pr, the enantioselectivity was persistent
under the optimal conditions but a prolonged reaction time
was needed for satisfying yield (3aa vs 3ba and 3ca). When R1
was H, the stereoselectivity was not affected and the adduct
3da could be obtained in 99% yield with >99% ee. In addition,
the ketimines with either electron-rich or electron-poor
substituents on the phenyl ring were also viable, furnishing the
o
vs entry 10). To our delight, raising the temperature to 40 C
could facilitate the reactivity without any erosion on
enantioselectivity (entry 14 vs entry 10). Decreasing the molar
ratio of 2a:1a from 2:1 to 1.1:1, there were no effects on the
desired products in 96-99% yields with >99% ee values (3ea
-
3ga). Understandably, the reactivity of electron-poor ketimines
is higher than electron-rich ketimine, which corresponds to the
nature of the aza-Friedel−Crafts reaction.
results but a longer reaction time was needed (entry 15 vs
entry 14), which could be improved by raising the temperature
o
o
to 60 C (entry 16). Further rising to 80 C, no effects were
observed on reactivity and enantioselectivity, but the yield was
decreased (entry 17). Hence, the optimal reaction conditions
were established as shown in table 1, entry 16.
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Substrates scope of ketimines
1. Reaction condition:
the reactions were conducted with (0.05 mmol), 2a (0.055
1
temp.
(oC)
25
25
25
time
(h)
48
48
48
yield
(%)b
91
97
98
ee
(%)c
4
96
93
D
in 1.0 mL of toluene at 60 oC for
entry Cat. solvent
mmol) and 2 mol % catalyst
indicated time. aIsolated yields. bDetermined by chiral HPLC
analysis.
1
2
3
A
B
C
DCM
DCM
DCM
2 | J. Name., 2012, 00, 1-3
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Next, we examined the effect of substituents on the indole
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2
enabled the ketimines
1
incorporating various substituents to
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DOI: 10.1039/C9CC04057A
reacting with ketimine 1a (Scheme 2). It was found that the engage in the aza-Friedel−Crafts reaction smoothly and deliver
electronic effect of substituents on the benzene ring of indole the corresponding products in moderate to excellent yields
2
obviously affects the reactivity. Generally, the reactivity of with good ee values (65-99% yields, 86-97% ee). Combining
electron-rich indoles was significantly higher than that of alkyl substituents into N1 atom of ketimines showed better
electron-deficient indoles. For example, reaction of ketimine reactivity than aryl (5b and 5c vs 5a). In addition, experimental
1a with electron-donating groups such as Me, OMe, OBn, OH results suggested that the enantioselectivity of ketimines with
substituted indoles regardless of the position on the benzene electron-withdrawing substituents on benzene ring are liable
ring could proceed smoothly and finished within shorter time to be controlled with the established catalytic system (5d and
under the optimal conditions, giving the desire products in 94- 5e vs 5f). The absolute (S)-configuration of 5c was determined
99% yields with ≥99% ee (3ac- 5
3aj and 3aq). However, when by X-ray analysis.12 The configurations of the other products
substituent at 4-position was methyl, the reactivity decreased, in Scheme 3 were assigned on the assumption of a uniform
which might attribute to the steric hindrance (3ab). Replacing mechanistic pathway.
electron-donating substituents with electron-withdrawing
substituents including Cl, Br, F, regardless of the position, the
aza-Friedel−Crafts reaction performed very slowly (data not
shown). Nevertheless, by increasing concentration of 1a to 0.1
M and molar ratio of
accelerated, delivering the target products 3ak
2
:
1a to 2:1, the reaction could be
3ap in 37-99%
-
yields with excellent enantioselectivities within acceptable
reaction time. Moreover, disubstituted 6-bromo-5-methyl-1H-
indole was also suitable for the adjusted reaction conditions
and gave the almost optically pure product 3ar in 83% yield.
Particularly, installing methyl, an electron-donating substituent,
on 2-position of indole, the reaction still needed to carry out
under the adjusted reaction conditions, which might due to
the increase of steric hindrance (3as).
Scheme 3. Aza-Friedel−Crafts reaction of pyrrole and ketimines
. Reaction condition: the reactions were conducted with
1
1
(0.05 mmol), 4 (0.10 mmol) and 2 mol % catalyst D in 0.5 mL of
toluene at 60 oC for indicated time. aIsolated yields.
bDetermined by chiral HPLC analysis.
Scheme 4. Gram-scale experiment and transformation of the
product 3aa
.
In addition to providing high-value products in near-perfect
enantioselectivity, this reaction can be easily performed on
Scheme 2. Substrates scope of indoles
the reactions were conducted with 1a (0.05 mmol),
mmol) and 2 mol % catalyst
in 1.0 mL of toluene at 60 oC for reacted with 3.08 mmol of 2a, which is 56 times larger than
indicated time. aIsolated yields. bDetermined by chiral HPLC the scale of the original reaction shown in Table 1, entry 16, to
analysis. cThe reactions were conducted with 1a (0.05 mmol),
afford 3aa in 94% yield and >99% ee. The absolute (S)-
in 0.5 mL of toluene at 60 configuration of 3aa was determined by X-ray analysis.12 The
configurations of the other products were assigned on the
assumption of a uniform mechanistic pathway. Next, the Boc
Following these promising results, we attempted to further group of 3aa could be removed easily under acidic conditions
extend the methodology to the pyrrole for construction of to give the primary amine in 87% yield with 99% ee.
pyrrole-containing isoquinoline-1,3(2H,4H)-dione derivatives. Furthermore, treatment of 3aa with KOH in MeOH/DMSO (v/v
2
. Reaction condition: gram scale at decreased catalyst loading without impacting
2
(0.055 yield or selectivity. Using 1 mol % CPA , 2.80 mmol of 1a
D
D
2
(0.10 mmol) and 2 mol % catalyst
oC for indicated time.
D
3
6
As shown in Scheme 3, the adjusted reaction conditions = 1:1) afforded the compound
7
containing isoindolinone
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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framework12, a class of important motif frequently found in
pharmaceuticals and bioactive natural products,13 without the
loss of enantioselectivity, which provided an effective way to
access the isoindolinone derivatives.
2. For selected representative examples, see: (a)VWiew.AKrtoicnlegO,nMline.
Casimiro, N. Fuentes, E. Merino, and C. Nevado, Angew.
Chem., Int. Ed. 2013, 52, 13086. (bD)OLI.: 1L0i.,10M39./CD9eCnCg0,4S0.5-7CA.
Zheng, Y.-P. Xiong, B. Tan, and X.-Y. Liu, Org. Lett. 2014, 16
,
504. (c) M. Zhang, P. Xie, W. Zhao, B. Niu, W. Wu, Z. Bian, C.
U. Pittman Jr, and A. Zhou, J. Org. Chem. 2015, 80, 4176. (d)
W. Yu, P. Hu, Y. Fan, C. Yu, X. Yan, X. Li, and X. Xu, Org.
Biomol. Chem. 2015, 13, 3308. (e) X.-F. Xia, S.-L. Zhu, J.-B.
Liu, D. Wang, and Y.-M. Liang, J. Org. Chem. 2016, 81, 12482.
3. L. Li, Y.-L. Zhao, H. Wang, Y.-J. Li, X. Xu, and Q. Liu, Chem.
Commun. 2014, 50, 6458.
A control experiment was conducted to verify the catalytic
process. Employing N-methyl indole 2t to react with 1a under
the standard conditions, the reaction failed to response, which
suggests the free N–H of the indole is crucial to ensure
reactivity (Scheme 5). Therefore, based on the result, the
absolute configuration of 3aa and previous reports8d, 8e, a
potential transition state can be proposed to account for the
observed stereochemical outcome of the aza-Friedel−Crafts
reaction. The chiral phosphoric acid simultaneously activates
both indole and ketimine through the hydrogen bonding
interaction, which create a chiral environment wherein the 3-
position of indole preferentially attacks the Si-face of the C=N
group and gives the specific product.
4. (a) Y. Yang, Y. Li, C. Cheng, G. Yang, J. Zhang, Y. Zhang, Y.
Zhao, L. Zhang, C. Li, and L. Tang, J. Org. Chem. 2018, 83
,
3348. (b) Y. Yang, Y. Li, C. Cheng, G. Yang, S. Wan, J. Zhang, Y.
Mao, Y. Zhao, L. Zhang, C. Li, and L. Tang, J. Org. Chem. 2019,
84, 2316.
5. N. Jegham, A. Bahi, N. E. Guesmi, Y. Kacem, and B. B. Hassine,
Arab. J. Chem. 2017, 10, S3889.
6. (a) A. Srivastava, A. Yadav, and S. Samanta, Tetrahedron Lett.
2015, 56, 6003. (b) N. I. Guranova, D. Daŕin, G. Kantin, A. S.
Novikov, O. Bakulina, and M. Krasavin, J. Org. Chem. 2019,
84, 4534.
7. For selected reviews, see: D.-J. Cheng, and Y.-D. Shao, Adv.
Synth. Catal. 2018, 360, 3614. For selected representative
examples of asymmetric conversion of imines, see: (a) S.
Fioravanti, Tetrahedron 2016, 72, 4449. (b) W. Yan, D. Wang,
J. Feng, P. Li, D. Zhao and R. Wang, Org Lett. 2012, 14, 2512.
(c) K. Zhao, T. Shu, J. Jia, G. Raabe and D. Enders, Chem. Eur.
J. 2015, 21, 3933. (d) H. Lv, B. Tiwari, J. Mo, C. Xing and Y.
Robin Chi, Org. Lett. 2012, 14, 5412. (e) Q. Chen, L. Xie, Z. Li,
Y. Tang, P. Zhao, L. Lin, X. Feng and X. Liu, Chem. Commun.
2018, 54, 678.
Scheme 5. Control experiments and the proposed transition
state for the aza-Friedel–Crafts reaction of indole with
ketimine.
8. For selected representative examples of asymmetric aza-
Friedel−Crafts reaction of indoles with imines, see: (a) Q.
Kang, Z.-A. Zhao, and S.-L. You, J. Am. Chem. Soc. 2007, 129
,
1484. (b) D. Enders, A. A. Narine, F. Toulgoat, and T.
Bisschops, Angew. Chem., Int. Ed. 2008, 47, 5661. (c) J. Feng,
W. Yan, D. Wang, P. Li, Q. Sun, and R. Wang, Chem.
Commun. 2012, 48, 8003. (d) K.-F. Zhang, J. Nie, R. Guo, Y.
Zheng, and J.-A. Ma, Adv. Synth. Catal. 2013, 355, 3497. (e)
In summary, we have prepared a new class of ketimines and
developed an enantioselective aza-Friedel−Crafts reaction
using this ketimines with indoles for first enantioselective
synthesis of isoquinoline-1,3(2H,4H)-dione derivatives in
E. Xie, A. Rahman, and X. Lin, Org. Chem. Front. 2017, 4,
moderate
to
quantitative
yields
with
excellent
1407. (f) S. Nakamura, T. Furukawa, T. Hatanaka, and Y.
Funahashi, Chem. Commun. 2018, 54, 3811.
enantioselectivities. And this reaction was also applicable to
pyrrole, yielding the pyrrole-containing products in high yields
and enantioselectivities. Moreover, the synthetic utility of this
methodology has been demonstrated by gram-scale
preparation and converting the product into another
important isoindolinone derivative. Further investigations
employing this ketimines in catalytic asymmetric reaction are
currently being pursued in our laboratories.
9. (a) P. M. Dewick, Medicinal Natural Products: A Biosynthetic
Approach; Wiley: Chichester, U.K., 2009. (b) P. S. Sidhu, N.
Nassif, M. M. McCallum, K. Teske, B. Feleke, N. Y. Yuan, P.
Nandhikonda, J. M. Cook, R. K. Singh, D. D. Bikle, and L. A.
Arnold, ACS Med. Chem. Lett. 2014, 5, 199. (c) J. Zhu, H.
Chen, X. E. Guo, X.-L. Qiu, C.-M. Hu, A. R. Chamberlin, and
W.-H. Lee, Eur. J. Med. Chem. 2015, 96, 196.
10. For details see SI.
11. For selected recent examples of indoles on asymmetric
Friedel−Crafts Reactions, see: (a) F. A. Cruz, Y. Zhu, Q. D.
Tercenio, Z. Shen and V. M. Dong, J. Am. Chem. Soc. 2017,
139, 10641. (b) M. A. Saputra, B. Nepal, N. S. Dange, P. Du, F.
R. Froncɀek, R. Kumar and R. Kartika, Angew. Chem., Int. Ed.
2018, 57, 15558. (c) J. Mansot, S. Aubert, N. Duchemin, J.-J.
Vasseur, S. Arseniyadis and M. Smietana, Chem. Sci. 2019,
10, 2875.
We are grateful for financial support from the NSFC (No.
21801024, 21572223, 21871252 and 21801026) and the Start-
up Fund of Chengdu University (2081917041).
Conflicts of interest
There are no conflicts to declare.
Notes and references
12. CCDC-1917780 (3aa), 1917782 (5c), 1917781 (7) contains the
1. For selected representative examples, see: (a) J. L. Archibald,
J. T. Arnott Boyle, and J. C. Saunders, US 3870721A, 1975. (b)
E. Kutter, G. Griss, W. Grell, M. Kleemann, and B. Riss, US
3708486A, 1973. (c) M. S. Malanias, T. C. Hohman, J. Millen,
J. Med. Chem. 1994, 37, 2043. (d) S. K. V. Vernekar, Z. Liu, E.
Nagy, L. Miller, K. A. Kirby, D. J. Wilson, J. Kankanala, S. G.
Sarafianos, M. A. Parniak, and Z. Wang, J. Med. Chem. 2015,
58, 651.
supplementary crystallo-graphic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
13. (a) K. Speck, and T. Magauer, Beilstein J. Org. Chem. 2013, 9,
2048. (b) K. Wang, L. Bao, Q. Qi, F. Zhao, K. Ma, Y. Pei, and H.
Liu, J. Nat. Prod. 2015, 78, 146.
4 | J. Name., 2012, 00, 1-3
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