Enantioselective Synthesis of 4-Cyanotetrahydroquinolines via Ni-Catalyzed Hydrocyanation of 1,2-Dihydroquinolines

Article abstract of DOI:10.1021/acs.orglett.0c03171

A Ni-catalyzed asymmetric hydrocyanation that enables the formation of 4-cyanotetrahydroquinolines in good yields with excellent enantioselectivities is presented herein. A variety of functional groups are well-tolerated, and a gram-scale reaction supports the synthetic potential of the transformation. Additionally, several crucial intermediates for pharmaceutically active agents, including a PGD2 receptor antagonist, are now accessible through asymmetric synthesis using this new protocol.

Full text of DOI:10.1021/acs.orglett.0c03171

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Letter
Enantioselective Synthesis of 4‑Cyanotetrahydroquinolines via Ni-
Catalyzed Hydrocyanation of 1,2-Dihydroquinolines
Mingdong Jiao,† Jihui Gao,† and Xianjie Fang*
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ABSTRACT: A Ni-catalyzed asymmetric hydrocyanation that enables the formation of 4-cyanotetrahydroquinolines in good yields
with excellent enantioselectivities is presented herein. A variety of functional groups are well-tolerated, and a gram-scale reaction
supports the synthetic potential of the transformation. Additionally, several crucial intermediates for pharmaceutically active agents,
including a PGD2 receptor antagonist, are now accessible through asymmetric synthesis using this new protocol.
hiral 1,2,3,4-tetrahydroquinolines (THQs) are wide-
Cspread motifs in many natural products, pharmaceuticals,
and biologically active compounds1 (Scheme 1a). Therefore,
their preparation has attracted the attention of both medicinal
and organic chemists. Asymmetric cyclization reactions,1d,f
such as the Povarov reaction2 and Michael addition,3 and
asymmetric dearomatization reactions, namely, hydrogenation4
and Reissert-type reaction,5 have been developed to prepare
highly desirable chiral THQ derivatives over the past few
decades. Despite considerable progress, the site-selective
introduction of substituents onto the quinoline rings to
synthesize enantioenriched THQs is a nontrivial task. Recently,
enantioselective hydrofunctionalization of 1,2-dihydroquino-
lines (DHQs) has become a new strategy to access chiral
THQs,6 and a handful of functional groups (i.e., 4-amino, 4-
allyl, 3-boryl, etc.) could be introduced (Scheme 1b).
Nitriles not only constitute versatile building blocks but also
represent unique and specific intermediates in materials
science.7 They can be easily converted to carboxylic acid
derivatives, ketones, N-heterocycles, amines, aldehydes, and
many others.8 In particular, the most conceptually straightfor-
ward and atom-economical strategy for the synthesis of chiral
nitriles is the catalytic asymmetric hydrocyanation of alkenes.9
In this regard, the incorporation of a cyano group onto THQs
would provide plentiful opportunities to expand the diversity
of THQs, thus enriching the medicinal chemistry library. On
the basis of our longstanding interest in hydrocyanation of
alkenes10 and the ever-increasing importance of nitriles and
THQs, herein we report a highly enantioselective hydro-
cyanation of 1,2-dihydroquinolines that tolerates a wide variety
of quinoline derivatives (Scheme 1c). Moreover, both
hydrocyanated tetrahydronaphthalenes and chromans can
also be obtained using the same hydrocyanation method.
We started our studies by testing the hydrocyanation of 1,2-
dihydroquinoline 1a using Ni(COD)2 supported by chiral
phosphite ligand L1 or L2 as the catalyst system and acetone
cyanohydrin 2 as a HCN surrogate. Ligand L1 was previously
used in the asymmetric hydrocyanation of styrenes by Schmalz
and co-workers.8c When L1 was employed, 3a was obtained in
only 8% yield (Table 1, entry 1). Next, the binaphthol-based
diphosphite ligand series L2a−g were investigated (Table 1,
entries 2−9). With ligand L2a bearing a phenyl substituent, the
yield dramatically increased from 8% to 53%, but the ee value
slightly decreased from 93% to 87% (Table 1, entry 2). In
contrast, only a trace of the desired product was observed
when ligand L2a′ was used, indicating a mismatch in the
chirality (Table 1, entry 3). Further investigations showed that
the m-tert-butyl-substituted ligand L2b enhances the yield of
product 3a (Table 1, entry 4). Then the p-trifluoromethyl-
substituted ligand L2c delivered the hydrocyanation product in
Received: September 21, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03171
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Scheme 1. Background for the Development of the Current
Work
Table 1. Optimization of the Reaction Conditions
b
c
entry
ligand
T (°C)
yield of 3a (%)
ee of 3a (%)
1
2
3
4
5
6
7
8
9
L1
100
100
100
100
100
100
100
100
100
80
8
93
87
−
L2a
L2a’
L2b
L2c
L2d
L2e
L2f
L2g
L2g
L2g
L2g
L2g
53
trace
85
64
72
92
95
97
88
90
87
88
89
91
93
95
91
80
d
10
11
99 (96 )
60
80
80
36
92
29
e
12
f
13
a
Reaction condition: 1a (0.1 mmol), 2 (0.3 mmol), Ni(COD)2 (5
mol %), ligand (5 mol %), and toluene (0.3 mL) at the specified
b
temperature for 12 h. Determined by GC analysis using n-dodecane
c
as the internal standard. Determined by chiral HPLC analysis.
d
e
f
Isolated yield. n-Hexane as the solvent. CH3CN as the solvent.
cyanation reaction (Scheme 2). Various substrates 1 with
electron-donating groups (−Me, −Ph, −SMe, −OTs, and
−OAc) at the 7-position of the DHQ were well-tolerated, and
the corresponding products (3b−3f) were obtained in high
yields (75−92%) with excellent enantioselectivities (90−95%
ee). Substrate 1g with a strong electron-withdrawing group
could also be transformed to the hydrocyanated product 3g
(75% yield, 90% ee). DHQs bearing diverse substituents such
as fluoro (1h) and methyl (1i) provided the corresponding
hydrocyanated THQs 3h and 3i in moderate yields with 63%
ee and 90% ee, respectively. The substrates containing a
heterocyclic substituent at the 7-position could also be
transformed in high yields with excellent enantioselectivities
(3j−l). The substrates with diverse N-protecting groups,
moderate yield with 90% ee (Table 1, entry 5). Furthermore,
para-substituted ligands with electron-donating groups like
MeO (L2d), TMS (L2e), and t-Bu (L2f) were tested and
resulted in yields of 72−95% with 87−89% ee (Table 1, entries
6−8). These results signify that the electron-donating
substituents on the phenyl moiety of the ligand have a
significant effect on the catalysis of this reaction. Thus, with
ligand L2g, which bears the strongest electron-donating group,
the desired product was produced in 97% yield with 91% ee
(Table 1, entry 9). To our delight, lowering the temperature to
80 °C increased the yield to 99% with 93% ee (Table 1, entry
10). When the temperature was further reduced to 60 °C, a
decrease in yield was observed (Table 1, entry 11). None of
the other solvents that were tested, namely, n-hexane and
acetonitrile, were as efficient as toluene under the same
reaction conditions (Table 1, entries 12 and 13; for more
details, see Table S1).
including −COPh, −COtBu, −CO2 Pr, and −Ts, delivered the
n
hydrocyanated products (3m−3p) in good yields (71−84%)
with good enantioselectivities (80−91% ee). It is worth noting
that unprotected 1,2-dihydroquinoline could also be tolerated
in this asymmetric transformation, furnishing the desired
product 3q in 90% yield with 73% ee. To our surprise, 2H-
chromene (1r) and 1,2-dihydronaphthalene (1s) gave rise to
the corresponding hydrocyanated products 3r and 3s in 92%
yield with 82% ee and 92% yield with 80% ee, respectively.
Under the optimized conditions (Table 1, entry 10), we
investigated the substrate scope of this asymmetric hydro-
B
https://dx.doi.org/10.1021/acs.orglett.0c03171
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a
Scheme 2. Substrate Scope
a
Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol, 3.0 equiv), Ni(COD)2 (5 mol %), L2g (5 mol %), and toluene (1.0 mL) at 80 °C for 12 h.
b
Yields of isolated products are shown. The ee and dr values were determined by chiral HPLC. The reaction was conducted at 100 °C for 12 h.
c
d
Ni(COD)2 (10 mol %) and L2g (10 mol %). The reaction was conducted at 80 °C for 24 h.
Moreover, satisfactory conversion was observed when a 2,2-
dimethyl group was introduced at the 2-position (78% yield,
96% ee; 3t). When 3-methyl-1,2-dihydroquinoline 1u was
used, the trans-stereoselective single product 3u was obtained
(56% yield, 96% ee, dr >20:1). Substrate 1v was also well-
tolerated, furnishing trans-only 3v in 42% yield with 90% ee.
According to our previous contribution,10d this transformation
merges allylic cyanation and asymmetric hydrocyanation. Even
the substrates with either a methyl, n-butyl, or phenyl
substituent at the 2-position could provide the corresponding
products as single diastereomers (42% yield, 91% ee, dr >20:1,
3w; 42% yield, 91% ee, dr >20:1, 3x; 34% yield, 85% ee, dr
>20:1, 3y). In addition, the starting materials 1w′, 1x′, and 1y′
were recovered in 45% yield with 63% ee, 53% yield with 55%
ee, and 60% yield with 35% ee, respectively. Finally, this
transformation was also applicable to 1z, which contains an N-
methanonecyclopropyl substituent at the 1-position. The
corresponding product 3z was delivered in 41% yield with
90% ee, and 1z′ was recovered in 47% yield with 27% ee. The
absolute configuration of 3p was unambiguously identified as S
by X-ray crystallographic analysis, and the absolute config-
urations of 3a−v were tentatively assigned by analogy. The
absolute configuration of 3y was confirmed to be (2S,4R) in
the same way.
To showcase the synthetic utility of this asymmetric
transformation, a gram-scale synthesis with 1a was performed.
The desired product 3a was produced in 84% yield with 93%
ee (Scheme 3a). To further demonstrate the utility of this
transformation, 3w was reduced and further converted into
3w-1 in good yield using NiCl2/NaBH4 in MeOH for 4 h
followed by treatment with pyridine/TsCl. MOM protection
of the secondary amine to form 3w-2 followed by TMSOTf-
mediated cyclization through iminium ion formation11
delivered 3w-3 with a similar skeleton as analogues of
C
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supported the synthetic potential of the reaction. Moreover,
it is worth mentioning that the transformation of a hydro-
cyanated product into a chiral PGD2 receptor antagonist
further illustrates the practicability of this methodology.
Scheme 3. Gram-Scale Reaction and Derivatizations of the
Product
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03171.
(Experimental procedures, characterization data, copies
of NMR spectra and HPLC chromatograms for all new
products PDF)
Accession Codes
CCDC 2021652, 2023939, and 2031548 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Xianjie Fang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
People’s Republic of China; orcid.org/0000-0002-3471-
8171; Email: fangxj@sjtu.edu.cn
Authors
Mingdong Jiao − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
People’s Republic of China
Jihui Gao − Shanghai Key Laboratory for Molecular Engineering
of Chiral Drugs, School of Chemistry and Chemical Engineering,
Frontiers Science Center for Transformative Molecules, Shanghai
Jiao Tong University, Shanghai 200240, People’s Republic of
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03171
Author Contributions
dinapsoline12 in 61% yield over two steps (Scheme 3b).
Interestingly, no epimerization of the products was observed in
any of these processes. The absolute configuration of 3w-3 was
unambiguously confirmed as (2S,4S) by X-ray crystallographic
analysis, and stereochemical assignments of the products 3w,
3x, and 3z were tentatively made on this basis. Considering
that THQs constitute a core skeleton element of many
alkaloids, pharmacophores, and bioactive compounds, we
explored a route to synthesize the important chiral PGD2
receptor antagonist13 3z-2 in only two steps through hydrolysis
and condensation of 3z (Scheme 3b).
In summary, a novel method for the enantioselective
synthesis of 4-cyanotetrahydroquinolines via a Ni-catalyzed
asymmetric hydrocyanation reaction has been established. The
protocol provides versatile and optically active nitrile-
containing THQ derivatives. The gram-scale reaction
†M.J. and J.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Recruitment Program of Global
Experts and startup funding from Shanghai Jiao Tong
University is greatly appreciated.
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