The catalytic enantioselective synthesis of tetrahydroquinolines containing all-carbon quaternary stereocenters via the formation of aza-ortho-xylylene with 1,2-dihydroquinoline as a precursor

Article abstract of DOI:10.1039/c5cc07752d

Tetrahydroquinolines (THQs) with an all-carbon quaternary stereocenter were effectively obtained via the in situ formation of aza-ortho-xylylene (AOX) with easily accessible 1,2-dihydroquinolines as precursors. The reaction was rationalized with chiral phosporic acid to afford chiral THQs with high yield and excellent enantioselectivity.

Full text of DOI:10.1039/c5cc07752d

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: G. Li, H. Liu, Y.
Wang, S. Zhang, S. Nai, L. Tang, J. Zhao and Z. Tang, Chem. Commun., 2015, DOI:
10.1039/C5CC07752D.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C5CC07752D
Tetrahydroquinolines (THQs) with all-carbon quaternary stereocenter were effectively obtained via the in
situ formation of aza-ortho-xylylene (AOX) with easily accessible 1,2- dihydroquinolines as precussors. The
reaction was rationalized with chiral phosporic acid to afford chiral THQs with high yield and excellent
enantioselectivity.

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C5CC07752D
Chemical Communication
COMMUNICATION
Catalytic Enantioselective Synthesis of Tetrahydroquinolines
Containing All-carbon Quaternary Stereocenters via Formation of
Aza-ortho-xylylene with 1,2-Dihydroquinoline as Precursor
Received 00th January 20xx,
Accepted 00th January 20xx
Guangxun Li,a* Hongxin Liu,a Yingwei Wang,b Shiqi Zhang,b Shujun Lai,c Ling Tang, a Jinzhong Zhao,c
Zhuo Tanga*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Tetrahydroquinolines (THQs) with an all-carbon quaternary tremendous efforts made in this field.6 One of the difficulties
stereocenter were effectively obtained via the in situ formation of in constructing all-carbon stereocenter is their congested
aza-ortho-xylylene (AOX) with easily accessible 1,2- nature.7 Inspired by Van Straten’s work8 for constructing
dihydroquinolines as precussors. The reaction was rationalized all-carbon quaternary center at the C-4 of DHQs with AlCl3 as
with chiral phosporic acid to afford chiral THQs with high yield and well as our previous work of forming reactive AOX with
excellent enantioselectivity.
Brønsted acid3, we challenged the Brønsted acid catalyzed
Friedel-Craft reaction with indoles as substrates9, which could
afford DHQs containing all-carbon quaternary centers. To our
knowledge, accesses to THQs containing all-carbon quaternary
chiral centers were rare. Herein we report an efficient strategy
to form THQs with all-carbon quaternary stereocenters based
on DHQs, in which the double bond was functionalized via the
formation of AOX and subsequent nucleophilic substitution
with indoles (Scheme 1b).
Tetrahydroquinolines (THQs) belong to a class of nitrogen
containing heterocycles, which have attracted attention from
medicinal and synthetic chemists because of their abundance
in both natural products and drug molecules.1 Therefore
methods for rapid assembly of chiral THQs were very
demanding despite of the numerous synthetic approaches
available.2 Recently, our group reported an efficient way of
forming the aza-ortho-xylylene (AOX) by dearomatization of
1,2-Dihydroquinolines (DHQs) 1
with catalytic Brønsted acid.3
The resulting intermediate formed in situ could be efficiently
transfer hydrogenated with HEH to afford THQs with high
yields and enantioselectivities (Scheme 1a). The advantages of
this approach including the highly reactive AOX generated
through simple way,4 the easily accessible substrates obtained
from simple aromatic amines and ketones, and the highly
enantioselectivities of the corresponding chiral THQs
,
Scheme 1 Ways of the formation and application of AOX
prompted us to investigate and develop more reaction types
accordingly.
Our previous work demonstrated that the electron
properties of the DHQs played an important role in the
formation of AOX intermediate. Enhancing the electron
density of the alkene by installing electron donating group
on the phenyl ring could make the alkene easily protonated
with Brønsted acid at mild reaction conditions. Therefore,
we initiated this work by screening the DHQs accordingly. As
a result, several DHQs with different substituents on the
phenyl ring were prepared and subjected to indoles with 5
mol% TsOH in CHCl3 (Table 1). The results were quite similar
with the corresponding transfer hydrogenation. Neither 1a
without substituent (Table 1, entry 1), nor 1b or 1c with
electron withdrawing groups such as 6-Cl or 6-CF3 (Table 1,
As we know that the preparation of compounds containing
all-carbon
quaternary
stereocenters
with
catalytic
enantioselective reactions are particularly demanding because
of their wide distribution in natural products and bioactive
substances.5 However, catalytic enantioselective construction
of these centers poses a daunting challenge in spite of the
a.Natural Products Research Center, Chengdu Institution of Biology, Chinese
Academy of Science, Chengdu, Sichuan 610041(China)
E-mail: ligx@cib.ac.cn; E-mail: tangzhuo@cib.ac.cn
b.College of Chemical Engineering, Si Chuan University, Chengdu, Sichuan
610041(China)
c. College of Art and Sciences, Shanxi Agricultural University Taigu, Shanxi
030800(China)
†Electronic Supplementary Information (ESI) available: Complete experimental
procedures and characterization data for the prepared compounds See
DOI: 10.1039/x0xx00000x
entries 2-3) could react to afford the corresponding THQs.
The same results were found for 1d with weak electron
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C5CC07752D
Journal Name
COMMUNICATION
donating group on the phenyl ring (Table 1, entry 4). We
therefore further enhanced the electron density of the
alkene. Interestingly, DHQ 1e with 7-methoxy on the phenyl
ring could be efficiently transformed to the corresponding
THQ 3e (Table 1, entry 5). Nevertheless, 1f and 1g with
6-methoxy or 6,8-dimethoxy could not afford the
corresponding product (Table 1, entries 6-7). 1h with
5,7-dimethoxy afforded THQ 3h quantitatively (Table 1,
entry 8).These results indicated that substitution pattern of
electron donating group on the proper position of DHQs was
crucial for the dearomatization. We then continued to
investigate the reaction with different types of catalysts
including brønsted acid TFA (Table 1, entry 9), strong Lewis
acid Yb(OTf)3 (Table 1, entry 10) and mild Lewis acid MgBr2
(Table 1, entry 11). The results revealed that all of these
catalysts could drive the reaction with excellent yield.
improve the reaction enantioselectivity to 88% (Table 2, entry
15). Further decreasing the reaction temperature to -10
℃
slightly improved enantioselectivity but greatly decreased the
reaction yield (Table 2, entry 16). Finally, we examined the
catalyst loading of the reaction and found the reaction
proceeded smoothly without sacrificing the yield and
enantioselectivity with 3 mol % of 4c (Table 2, entries 17-18).
These preliminary studies revealed that the optimal condition
was equal equiv. of
1 and 2 with 3 mol % of catalyst 4c at 0 °C
in chloroform for 48 h with 4 Å molecular sieves as additive.
Table 2 Optimizing the reaction conditions
Table 1 Screening of appropriate DHQs
entrya
1
4 (mol %)
4a (5)
4b (5)
4c (5)
4d (5)
4e (5)
4f (5)
4g (5)
4h (5)
4i (5)
solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
Toluene
THF
temp (
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
0
℃
)
ee (%)b yield (%)c
H
N
7
82
85
92
78
75
84
87
83
90
<5
<5
62
<5
92
92
77
90
85
5
4
H
2
46
78
30
34
44
65
41
77
-
6
3
N
Cat, (5 mol %)
solvent
2
1
3
7R
+
N
8
4
H
N
H
R
1
3
2a
5
entrya
1, R
1a, R = H
1b, R = 6-Cl
1c, R = 6-CF3
1d, R =6-Me
1e, R = 7-OCH3
1f, R = 6-OCH3
1g, R = 6,8-di-OCH3
1h, R = 5,7-di-OCH3
1h, R = 5,7-di-OCH3
1h, R = 5,7-di-OCH3
1h, R = 5,7-di-OCH3
cat.
3 (%)b
3a (-)
3b (-)
3c (-)
3d (-)
3e (95)
3f (-)
6
1
2
3
4
5
6
7
8
9
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TFA
7
8
9
10
11
12
13
14
15d
16d
17
18
4c (5)
4c (5)
4c (5)
4c (5)
4c (5)
4c (5)
4c (5)
4c (3)
4c (1)
-
3g (-)
15
-
3h (98)
3h (99)
3h (95)
3h (85)
Et2O
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
83
88
89
88
87
10
11
Yb(OTf)3
MgBr2
0
aReaction conditions: 0.2 mmol 1, 0.2 mmol 2, cat. (5 mol %), 2 mL of
CHCl3 at 25 ℃, nitrogen atmosphere. bIsolated yield
-10
0
0
aGeneral conditions: equal equiv of 1 and 2. bEnantioselectivity was
determined by HPLC with chiral OD-H; cThe yield were determined after
purification by flash column; d4 Å molecular sieves were added.
Then we continued to develop an organocatalytic
enantioselective synthesis of THQs with an all-carbon
quaternary center. As we know, using chiral Brønsted acid as
catalyst would allow the formation of an ionic pair between
AOX and an optically active phosphoric anion, which could be
trapped by indoles to provide chiral THQs10. Therefore, we
systematically investigated the Friedel-Craft reaction between
indole 2a and DHQ 1h in presence of BINOL derived chiral
Under the obtained optimal reaction condition, we explored
the scope of the Brønsted acid catalyzed Friedel-Craft reaction
for the formation of various THQs with a chiral quaternary
carbon center (Table 3). On one hand, indoles
donating groups or electron withdrawing groups were
2 with electron
rationally used to react with 1h to get the corresponding THQs
with good yields (85-90%) and moderate
enantioselectivities (83-88%). On the other hand, DHQs with
different groups were systematically examined. THQs with one
methoxy group (3e), two methoxy groups (3l) and three
methoxy groups (3m), THQs with 7-methoxy and different
phosphoric acids 4 (Table 2).
3i
-k
We firstly optimized the reaction by screening catalysts. The
results revealed that 4c was better than other catalysts in
terms of the enantioselectivities (Table 2, entries 1-9). Then
we investigated the reaction solvent and found that
chloroform was astonishingly more efficient than other
solvents in terms of the reaction yields and enantioselectivities
(Table 2, entries 10-13). We guessed that the AOX might be
formed more easily in chloroform than other solvents, which
caused the Friedel-Craft reaction to occur more easily. Next, we
examined the reaction temperature and found that conducting
halogens at C-6 (3n
3q ), were obtained under the optimal reaction condition
with admirable yields (85-93%) and excellent
-p) THQs with different 7-alkoxy goups
(
-s
enantioselectivities (82-97%). Moreover, all these results
revealed that bulky alkoxy at C-7 of the DHQs was vital for high
enantioselectivity. Interestingly, DHQ with a methylthio at C-7
afforded the corresponding THQ with high yield and
enantioselectivity, (3t). While DHQs with a nitogen containing
substituent at C-7 afforded the corresponding THQs with
the reaction at
0
℃ could greatly improve the
enantioselectivity without sacrificing the yield (Table 2, entry
14). Meanwhile, 4 Å molecular sieves as an additive could
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 2
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C5CC07752D
Journal Name
COMMUNICATION
slightly lower ee due to the higher reaction temperature
required, (3u, 3v). Meanwhile, 7,8-benzo-tetrahydroquinoline
3w could be achieved with good yield (93%) and moderate ee
(84%). However, 3X which has a phenyl substituted at
4-position, was not obtained due to the slightly large steric
hindrance. The absolute configuration of the product was
detected by converting 3h to 3y and assigned as (4R) by X-ray
crystallographic analysis (see the Supporting Information).
Notes and references
1
Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Chem. Rev.
2011, 111, 7157.
2
(a) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721; (b)
Masson, G.; Lalli, C.; Benohoud, M.; Dagousset, G. Chem. Soc.
Rev. 2013, 42, 902; (c) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem.
Res. 2011, 44, 1156; (d) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc.
Chem. Res. 2012, 45, 1278; (e) Allen, A. E.; MacMillan, D. W.
C. Chemical Science 2012,
3
, 633;
(f) Akiyama, T.; Morita,
Table 3 Reaction scope with indoles as nucleophiles.a,b
H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070; (g)
Bergonzini, G.; Gramigna, L.; Mazzanti, A.; Fochi, M.;
Bernardi, L.; Ricci, A. Chem. Commun. 2010, 46, 327; (h) Lin,
J.-H.; Zong, G.; Du, R.-B.; Xiao, J.-C.; Liu, S. Chem. Commun.
2012, 48, 7738; (i) Ren, L.; Lei, T.; Ye, J.-X.; Gong, L.-Z. Angew.
Chem., Int. Ed. 2012, 51, 771; (j) Mori, K.; Ehara, K.; Kurihara,
K.; Akiyama, T. J. Am. Chem. Soc. 2011, 133, 6166; (k) Han,
Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc.
2009, 131, 9182; (l) Wang, C.; Han, Z.-Y.; Luo, H.-W.; Gong,
L.-Z. Org. Lett. 2010, 12, 2266; (m) He, L.; Bekkaye, M.;
Retailleau, P.; Masson, G. Org. Lett. 2012, 14, 3158; (n)
Dagousset, G.; Zhu, J.; Masson, G. J. Am. Chem. Soc. 2011,
133, 14804; (o) Liu, H.; Dagousset, G.; Masson, G.; Retailleau,
P.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598
H
N
Ar
4c
(3 mol %) 48 h
Ar
Ar
+
N
Ar
N
CHCl3 4 A MS
H
1
H
2
N
3
H
3
4
Li, G.; Liu, H.; Lv, G.; Wang, Y.; Fu, Q.; Tang, Z. Org. Lett. 2015,
17, 4125.
(a) Ito, Y.; Miyata, S.; Nakatsuka, M.; Saegusa, T. J. Am.
Chem. Soc. 1981, 103, 5250; (b) Fishwick, C. W. G.; Storr, R.
C.; Manley, P. W. J. Chem. Soc., Chem. Commun. 1984, 1304;
(c) X. Dou, W. Yao, B. Zhou, Y. Lu, Chem. Commun. 2013, 49
,
9224-9226; (d) S. Ma, X. Han, S. Krishnan, S. C. Virgil, B. M.
Stoltz, Angew. Chem., Int. Ed. 2009, 48, 8037; (e) Lee, A.;
Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.; Scheidt, K.
A. J. Am. Chem. Soc. 2014, 136, 10589; (f) H.-H. Liao, A.
Chatupheeraphat, C.-C. Hsiao, I. Atodiresei, M. Rueping,
Angew. Chem., Int. Ed. 2015, doi: 10.1002/anie.201505981.
(a) Wang, B.; Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207; (b)
Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem. Res.
2015, 48, 740; (c) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388.
5
6
(a) Liu, S.; Tong, M.; Yu, Y.; Xie, H.; Li, H.; Wang, W. Chem.
Commun. 2015, 51, 11221; (b) Jiang, B.; Si, Y.-G. Angew.
Chem., Int. Ed. 2004, 43, 216.
7
8
Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181.
N. C. R. van Straten, T. H. J. van Berkel, D. R. Demont, W.-J. F.
Karstens, R. Merkx, J. Oosterom, J. Schulz, R. G. van
Someren, C. M. Timmers, P. M. van Zandvoort, J. Med. Chem.
2005, 48, 1697.
a Yields given were isolated yields; ee were analysed with chiral OD-H column;
Reaction condition: 0.2 mmol 1, 0.2 mmol 2, 4c (3 mol %), 2 mL of CHCl3 at 0 ℃,
nitrogen atmosphere, 100 mg 4 Å molecular sieve as additive. b 3u and 3v were
obtained from the optimized reaction conditions at 30 ℃.
9
(a) Mori, K.; Akiyama, T. In Comprehensive Enantioselective
Organocatalysis; Wiley-VCH Verlag GmbH & Co. KGaA: 2013,
p 289; (b) M. Rueping, B. J. Nachtsheim, W. Ieawsuwan, I.
Atodiresei, Angew. Chem., Int. Ed. 2011, 50, 6706; (c) M.
Rueping, B. J. Nachtsheim, S. A. Moreth, M. Bolte, Angew.
Chem., Int. Ed. 2008, 47, 593; (d) Q. Kang, Z.-A. Zhao, S.-L.
You, J. Am. Chem. Soc. 2007, 129, 1484; (e) D. Enders, A. A.
Narine, F. Toulgoat, T. Bisschops, Angew. Chem., Int. Ed.
2008, 47, 5661; (f) M. Rueping, S. Raja, A. Nunez, Adv. Syn.
Catl. 2011, 353, 563; (g) M.-L. Li, D.-F. Chen, S.-W. Luo, X.
Wu, Tetrahedron: Asymmetry 2015, 26, 219.
In summary, we succeeded in developing an interesting
Friedel-Craft reaction between easily accessible DHQs and
indoles. Enhancing the electron density of the phenyl ring of
DHQs could make the alkene group protonated more easily
with simple Brønsted acid. The resulted AOX intermediate was
electrophilically reactive and reacted with indoles to afford
THQs effectively. Moreover, the method was rationalized with
catalytic phosphoric acid to afford THQs containing an
all-carbon quaternary center with high yields and excellent
enantioselectivities. The scopes of the reaction types with this
highly reactive AOX intermediate, the pharmaceutical activity
of the obtained compounds are under investigation in our lab.
This work was supported by the National Sciences Foundation
of China (Grant No. 21402188).
10 (a) Akiyama, T. Chem. Rev. 2007, 107, 5744; (b) Parmar, D.;
Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114
,
9047; (c) Huang, Y.; Yang, X.; Lv, Z.; Cai, C.; Kai, C.; Pei, Y.;
Feng, Y. Angew. Chem., Int. Ed. 2015, 54, 7299; (d) Miles, D.
H.; Guasch, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 7632;
(e) Kanomata, K.; Toda, Y.; Shibata, Y.; Yamanaka, M.;
Tsuzuki, S.; Gridnev, I. D.; Terada, M. Chem. Sci. 2014, 5,
3515; (f) Makiguchi, K.; Yamanaka, T.; Kakuchi, T.; Terada,
M.; Satoh, T. Chem. Commun. 2014, 50, 2883.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins