Synthesis of 3,4-diarylsubstituted hexahydro-1H-indoles

Article abstract of DOI:10.1016/j.tetlet.2018.04.008

Efficient syntheses of 3,4-diarylsubstituted hexahydro-1H-indoles in good yields with excellent diastereoselectivities were achieved with a two-step protocol comprising an allylic cation mediated nucleophilic addition and an intramolecular cyclization rea

Full text of DOI:10.1016/j.tetlet.2018.04.008

Accepted Manuscript
Synthesis of 3,4-diarylsubstituted hexahydro-1H-indoles
Feilong Zhou, Erbao Zhao, Ziqin Yan, Deheng Chen, Yujun Zhao
PII:
S0040-4039(18)30439-8
https://doi.org/10.1016/j.tetlet.2018.04.008
TETL 49871
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Reference:
Tetrahedron Letters
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3 April 2018
Please cite this article as: Zhou, F., Zhao, E., Yan, Z., Chen, D., Zhao, Y., Synthesis of 3,4-diarylsubstituted
hexahydro-1H-indoles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.008
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Tetrahedron Letters
Synthesis of 3,4-diarylsubstituted hexahydro-1H-indoles
Feilong Zhoua,b , Erbao Zhaoa,b, Ziqin Yanb, Deheng Chenb,c and Yujun Zhaob,
a.Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, Jiangsu, 215123, China
b.State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd. Shanghai, 201203, China.
c. University of Chinese Academy of Sciences, Beijing,100049, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Efficient syntheses of 3,4-diarylsubstituted hexahydro-1H-indoles in good yields with excellent
diastereoselectivities were achieved with a two-step protocol comprising an allylic cation
mediated nucleophilic addition and an intramolecular cyclization reaction. The N-aryl sulfonyl
protecting groups of cyclization products were readily removed to furnish free amines with
retention of halogen substitutions and C-C double bonds.
Available online
Keywords:
Aziridine
2009 Elsevier Ltd. All rights reserved.
Hypersaturated indole
Cation
Allylic Cation
Cyclization
Hypersaturated indoles, such as octahydroindole, are unique
bicyclic structures that exist in several classes of bioactive
synthetic compounds and natural products (Figure 1).
Oscillarin (V) are potent inhibitors of thrombin protease activity
with IC50 values in a range of 20-50 nM.11 Moreover, substituted
hypersaturated indoles are also key intermediates 12-17 for the total
syntheses of bioactive Montanine-type alkaloids.4, 5, 18
Comparing with aromatic indole and analogues,
hypersaturated indoles have more sp3 carbon atoms. Although
these sp2- and sp3-enriched compounds share the same backbones,
the sp3 carbon-enriched compounds potentially have certain
biophysical and/or pharmacokinetic advantages such as optimal
aqueous solubility, better cell permeability, higher systemic
exposure, and increased oral bioavailability.19, 20
Figure 1. Nature products and bioactive synthetic compounds that featuring
hypersaturated indole structures
Many of these hypersaturated indole-containing compounds
exhibit interesting bioactivities. For example, compound I
(Figure 1) is an amine-uptake inhibitor has antidepressant activity
in vitro and in vivo.1 Compound II is an inhibitor of three
glycosidases with moderate activities.2 In addition,
hypersaturated indole is also a key structure feature of several
classes of natural alkaloids such as Mesembrines3-5 and
Aeruginosins.6-9 (-)-Mesembrine (III) is a very potent inhibitor of
5-HT transporter with Ki = 1.4 nM,10 while Dysinosin A (IV) and
Scheme 1. Proposed synthesis of hexahydroindole IX (a) in comparison with
previously reported method (b)
In view of the interesting bioactivities and more drug-like
properties of hypersaturated indole-containing nature products
and synthetic compounds, we set out to develop an efficient
———
 Corresponding author. Tel.: +86-21-50800608; e-mail: yjzhao@simm.ac.cn

2
Tetrahedron
method to synthesize 3,4-diaryl-substituted hexahydroindoles.
in the reaction. 1k bearing p-methyl substitution on the phenyl
ring also furnished 3k in moderate yield (60%, dr: 45:55).
We hypothesized that allylic cation generated from VI could be
trapped by the nitrogen atom of VII, which will provide an
allylic amine VIII (Scheme 1, a). Subsequent intramolecular
cyclization of VIII could furnish anticipated hypersaturated
indole IX. Although this transformation looks very straight
forwards, the underlying reaction mechanism is distinct from
previously reported aziridine-olefin addition (Scheme 1, b),
whereas the olefin X acted as a π nucleophile and the aziridine
XI acted as the corresponding electrophile.21-28
Table 2. Substrate scope of aryl aziridinesa
Our investigation started with reaction of 2-aryl substituted
aziridines 1a-1e and 1-phenyl cyclohexenol 2a in the presence of
stoichiometrical amount of SnCl4 at -78 oC in CH2Cl2 (Table 1).
Table 1. Optimization of N-protecting groupsa
Yield
Entry
R
Substrate Product
drc
(%)b
82
1
2
3
4
5
6
7
NO2
CO2Me
F
Br
H
1f
1g
1h
1i
3f
3g
3h
3i
48:52
45:55
37:63
48:52
48:52
45:55
na
53
77
95
89
60
79d
1j
3j
Me
OMe
1k
1l
3k
3ld
[a] The same as Table 1, footnote a. [b] Isolated yield. [c]
Determined by 1H NMR. [d]The product was obtained as 2-
Aminboacetophenone type compound instead of benzylic chloride
type compound (Figure 2, b).
Yield
Entry
R
Substrate Product
drc
(%)b
<5
19
35
95
0
1
2
3
4
5
Me
I
Br
OMe
NO2
1a
1b
1c
1d
1e
3a
3b
3c
3d
3e
na
48:52
45:55
40:60
na
[a] Reaction Conditions: Aziridine (1.0 equiv.) was dissolved in dry
CH2Cl2 and cooled to -78 oC for 15 min. SnCl4 (1.0 equiv.) was
added dropwise via a syringe and the reaction was stirred for 20 min
before addition of allylic alcohol (2.0 equiv.)-CH2Cl2 solution via a
o
syringe. The reaction was allowed to stir at -78 C for 12 h before
quenching with NaHCO3 sat. aqueous solution. [b] Isolated yield. [c]
Determined by 1H NMR.
The allylic amine 3d was obtained in high yield (95%) when the
R group was an OMe group (Entry 4). Interestingly, when p-
iodophenylsulfonyl and p-bromphenylsulfonyl groups were used
to protect the nitrogen atom of the aziridines, the desired product
3b and 3c were obtained in decreased yield as 19% and 35%,
respectively. When a Ts group was used as the N protection
group of the aziridine moiety, the desired product 3a was
obtained less than 5% (Entry 1). In contrast, no desired product
was obtained when R was an electron withdrawing group NO2.
The likely mechanism for this transformation is that the N atom
of the aziridine 1a-1e underwent nucleophilic addition to the
Figure 2. (a) X-ray crystal structure of one isomer of 3i, (b) Chemical
structure of 3l
Interestingly, 3l was obtained in 79% yield as
a 2-
aminoacetophenone type compound instead of a benzylic
chloride type compound, probably because of overoxidation of
benzylic intermediates in the presence of Sn(IV) species (Figure
2, b). In summary, the aryl aziridines could tolerate diverse
substitution groups on the phenyl ring for this reaction.
allylic cation, which was generated from the allylic alcohol 2a
Next, we explored the substrate scope of 2-substituted
cyclohexenols and the results are summarized in Scheme 2. Since
Cl substituted phenyl rings containing compounds often have
improved in vitro and in vivo potency than unsubstituted phenyl
rings,32 we chose 1d as the reaction substrate with the aim to
obtain Cl-phenyl containing hexahydroindoles. As shown in
Table 3, when the R’ groups were a halogen or a methyl group,
the desired products (4b-4e) were all obtained in >80% yield.
Interestingly, a nitrogen substitution on the allylic alcohol 2g was
well tolerated as the desired product 4g was obtained in 80%
yield. Electro-withdrawing substitution as the R’ group was
detrimental for the reaction yield as CF3 substituted product 4f
was obtained in decreased yield (61%). In addition,
cyclohexenols 2h-2j with aliphatic substitutions at 1 position are
also suitable substrates for this reaction. Good yields were
obtained for 4h (91%) and 4j (86%) when the R is a methyl or a
phenylethyl group. When the R is an ethyl group, the reaction
yield is moderate with 4i obtained in 61% yield (Scheme 2).
30
upon treatment of SnCl4.29,
The observed high yield of 3d
correlated with more nucleophilic nitrogen atom of 1d as a result
of electron-donating OMe group on the phenyl ring. Overall, the
p-OMe phenylsulfonyl group is the optimal directing group for
good reaction yield and it was therefore chosen for further
reaction optimization.
Upon identification of the optimal N protecting group, we
turned our attention to examine substrate scope of aryl aziridines
with different substitutions on the phenyl rings (1f-1l, Table 2).
Generally, the aziridines with both electron-withdrawing groups
and electron-donating substitutions were suitable substrates in
this reaction as 3f and 3h-3j were obtained in >75% yield. All the
products were obtained as a mixture of two diastereomers with
ratio around 45:55. We also obtained the X-ray crystal structure
of one isomer of 3i31 to confirm its structure (Figure 2, a). The
CO2Me-containing substrate 1g gave the desired product 3g in
moderate yield (53%) as the ester group was partially hydrolyzed

Finally, we carried out cyclization reaction using the addition
products 3d and 4b-4h in order to construct the 3,4-diaryl-
substituted hexahydro-1H-indoles, and the results are
summarized in Scheme 3. Generally, the cyclization products 5a-
5h were all obtained as single isomers in moderate to good yield
(50-80%) upon treatment of AgSbF6. Different silver salts also
play a role in affecting the reaction yields and AgSbF6 provided
higher yield than AgBF4 in cases of 5c and 5d. Therefore,
AgSbF6 was chosen as the optimal Lewis acid for this
transformation. We also obtained the X-ray crystal structure of
5d31 and it revealed that the hexahydroindole fused ring adopted
cis-conformation, and the p-Cl phenyl group adopted anti
configuration to the two bridge protons (Figure 3).
Figure 3. X-ray crystal structure of 5d
We further examine the diastereoselectivity of this two-step
transformation using
a
chiral aziridine
6
(Scheme 4).
Unfortunately, compound 7 was obtained as a mixture of racemic
compounds without retention of optical purity. This is apparently
because the stereogenic center of 6 racemized when it was
opened up by the Cl anion. The absolute stereochemistry of 7
was confirmed by single crystal X-ray crystallography31 (see
ESI).
Scheme 2. Substrate scope of 2-sbstituted cyclohexenols
In general, the transformation has poor diastereoselectivity as
observed isomer ratio is around 25:75 to 50:50, and the low
diastereoselectivities could be partially explained by low steric
bias when N atom approaches the allylic cationic intermediate. In
summary, the cyclohexenol substrates with a wide range of
aromatic and aliphatic substitutions were well compatible in this
reaction.
Scheme 4. Evaluation of diastereoselective profile of SnCl4 promoted
transformation
Scheme 3. Synthesis of 3,4-diaryl-substituted hexhydroindoles

4
Tetrahedron
10. A. L. Harvey, L. C. Young, A. M. Viljoen and N. P. Gericke, J
Scheme 5. Synthesis of 3,4-diaryl-substituted hexhydroindoles
Ethnopharmacol, 2011, 137, 1124-1129.
11. S. Hanessian, K. Ersmark, X. T. Wang, J. R. Del Valle, N.
Blomberg, Y. F. Xue and O. Fjellstrom, Bioorg Med Chem Lett,
2007, 17, 3480-3485.
12. A. Cordero-Vargas, X. Urbaneja and J. Bonjoch, Synlett, 2007,
2379-2382.
13. S. V. Pansare, R. Lingampally and R. L. Kirby, Org Lett, 2010,
12, 556-559.
14. G. Pandey, R. Kumar, P. Banerjee and V. G. Puranik, Eur J Org
Chem, 2011, 4571-4587.
15. Y. F. Guan, H. B. Zhang, C. X. Pan, J. Wang, R. Huang and Q.
L. Li, Org Biomol Chem, 2012, 10, 3812-3814.
16. G. Pandey and S. R. Gadre, Pure Appl Chem, 2012, 84, 1597-
1619.
17. S. B. Bhorkade and K. B. Gavhane, Tetrahedron Lett, 2016, 57,
2575-2578.
18. Z. Jin, Nat Prod Rep, 2009, 26, 363-381.
19. F. Lovering, J. Bikker and C. Humblet, J Med Chem, 2009, 52,
6752-6756.
20. F. Lovering, Medchemcomm, 2013, 4, 515-519.
21. I. Ungureanu, P. Klotz and A. Mann, Angew Chem Int Edit,
2000, 39, 4615-4617.
In order to remove the arylsulfonyl group that was tethered to
the nitrogen of the 3,4-diaryl-substituted hexahydro-1H-indoles,
we treated 5a, 5e, 7, and 8 with sodium/naphthalene in anhydrous
1,2-dimethoxyethane (Scheme 5)15 and compounds 9-12 were
obtained in moderate yields (22-57%) as single isomers except
12. The Cl and F atoms were well tolerated in the reductive
reaction condition but Br and CF3 groups were not. Overall, this
transformation allows efficient synthesis of 3,4-diaryl-substituted
hexahydro-1H-indoles in the form of free amine.
In conclusion, we reported a two-step protocol that enables
efficient syntheses of 3,4-diaryl-substituted hexahydroindoles in
good to high yields with excellent diastereoselectivities. Firstly,
SnCl4 promoted formation of allylic cations from cyclohexanols,
which underwent nucleophilic addition by aziridines and yielded
allylic amine-containing compounds in good to high yields. In
addition, cyclization of the allylic amine-containing compounds
further furnished 3,4-diaryl-substituted hexahydroindoles in good
yields as single isomers in the presence of silver salts.
Subsequent removal of the N protecting groups of cyclization
products provided 4-diaryl-substituted hexahydroindoles as free
amines. The Cl, F, and aniline groups are compatible in our
methods, while they are also important for fine tuning of
bioactivity. Therefore, this two-step protocol could allow
efficient access to valuable bicyclic building blocks.
22. E. Martinand-Lurin, R. Gruber, P. Retailleau, P. Fleurat-Lessard
and P. Dauban, J Org Chem, 2015, 80, 1414-1426.
23. S. H. Krake and S. C. Bergmeier, Tetrahedron, 2010, 66, 7337-
7360.
24. A. L. Cardoso and T. M. V. D. P. E. Melo, Eur J Org Chem,
2012, 6479-6501.
Acknowledgments
25. P. Dauban and G. Malik, Angew Chem Int Edit, 2009, 48, 9026-
9029.
We thank the National Natural Science Foundation of China
grant 81673295 and "Personalized medicines-molecular
signature-based drug discovery and development", strategic
priority research program of the Chinese Academy of Sciences,
grant No. XDA12020322 for financial support. We also thank
Shanghai Institute of Materia Medica startup-grant and
Recruitment Program of Global Youth Experts (The 1000 Youth
Talents Program) for financial support.
26. Y. J. Zhao, L. J. S. Tan, B. Li, S. M. Li and T. P. Loh, Chem
Commun, 2009, 3738-3740.
27. Z. Chai, Y. M. Zhu, P. J. Yang, S. Y. Wang, S. W. Wang, Z. Liu
and G. S. Yang, J Am Chem Soc, 2015, 137, 10088-10091.
28. T. Y. Lin, H. H. Wu, J. J. Feng and J. L. Zhang, Acs Catal, 2017,
7, 4047-4052.
29. W. S. Johnson, T.-T. Li, C. A. Harbert, W. R. Bartlett, T. R.
Herrin, B. Staskun and D. H. Rich, J Am Chem Soc, 1970, 92,
4461-4463.
30. R. L. Markezich, W. E. Willy, B. E. McCarry and W. S.
Johnson, J Am Chem Soc, 1973, 95, 4414-4416.
31. The CCDC numbers 1811176, 1811174, and 1811175 contains
the supplementary crystallographic data for 3i, 5d, and 7,
respectively. These data can be obtained free of charge from The
References and notes
1. M. Bos, W. P. Burkard, J. L. Moreau and P. Schonholzer, Helv
Chim Acta, 1990, 73, 932-939.
2. C. Gravier-Pelletier, W. Maton, G. Bertho and Y. Le Merrer,
Tetrahedron, 2003, 59, 8721-8730.
3. M. Hayashi, T. Unno, M. Takahashi and K. Ogasawara,
Tetrahedron Lett, 2002, 43, 1461-1464.
4. J. R. Lewis, Nat Prod Rep, 2002, 19, 223-258.
5. J. R. Lewis, Nat Prod Rep, 2001, 18, 95-128.
6. S. Hanessian, M. Tremblay and J. F. W. Petersen, J Am Chem
Soc, 2004, 126, 6064-6071.
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
32. Y. J. Zhao, L. Liu, W. Sun, J. F. Lu, D. McEachern, X. Q. Li, S.
H. Yu, D. Bernard, P. Ochsenbein, V. Ferey, J. C. Carry, J. R.
Deschamps, D. X. Sun and S. M. Wang, J Am Chem Soc, 2013,
135, 7223-7234.
Supplementary Material
7. S. Hanessian, X. T. Wang, K. Ersmark, J. R. DelValle and E.
Klegraf, Org Lett, 2009, 11, 5566-5566.
8. K. Ersmark, J. R. Del Valle and S. Hanessian, Angew Chem Int
Edit, 2008, 47, 1202-1223.
Supplementary data associated with this article can be found,
in the online version, at
9. H. J. Shin, H. Matsuda, M. Murakami and K. Yamaguchi, J Org
Chem, 1997, 62, 1810-1813.

5
Graphical Abstract
Synthesis of 3,4-Diarylsubstituted
Leave this area blank for abstract info.
Hexahydro-1H-indoles
Feilong Zhou, Erbao Zhao, Ziqin Yan, Deheng Chen, and Yujun Zhao*

6
Tetrahedron
Research Highlight
1. First
synthesis
of
3,4-diarylsubstituted
hexahydroindoles in good yields.
2. Mechanism involves nucleophilic addition of an
aziridine into an allylic cation.
3. Intramolecular cyclization for construction of
pyrolidine rings in high yields.