Sequential Phosphine-Catalyzed [4 + 2] Annulation of β′-Acetoxy Allenoates: Enantioselective Synthesis of 3-Ethynyl-Substituted Tetrahydroquinolines

Article abstract of DOI:10.1021/acs.orglett.9b00130

The first enantioselective sequential phosphine-catalyzed (SPC as abbreviation) mode for the formation of tetrahydroquinolines with an ethynyl-substituted all-carbon quaternary stereogenic center is reported. In this SPC process, a novel [4 + 2] annulation process was devised employing α-substituted allenoates as C2 synthons (α-β′, 1,2-dipole) for the first time. 3-Ethynyl-substituted tetrahydroquinolines were readily prepared in good yields and high enantioselectivities.

Full text of DOI:10.1021/acs.orglett.9b00130

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sequential Phosphine-Catalyzed [4 + 2] Annulation of β′-Acetoxy
Allenoates: Enantioselective Synthesis of 3‑Ethynyl-Substituted
Tetrahydroquinolines
Qinglong Zhang,† Hongxing Jin,† Jiaxu Feng,† Yannan Zhu,† Penghao Jia,† Chengzhou Wu,†
and You Huang*,†,‡
†State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: The first enantioselective sequential phosphine-catalyzed
(SPC as abbreviation) mode for the formation of tetrahydroquinolines
with an ethynyl-substituted all-carbon quaternary stereogenic center is
reported. In this SPC process, a novel [4 + 2] annulation process was
devised employing α-substituted allenoates as C2 synthons (α−β′, 1,2-
dipole) for the first time. 3-Ethynyl-substituted tetrahydroquinolines were
readily prepared in good yields and high enantioselectivities.
ver the past decades, nucleophilic phosphine catalysis
has been intensely investigated as a powerful tool for
activated alkenes was also completed (Scheme 1, eq 2).5 In
2013, Huang and Marinetti independently reported the
utilization of γ-substituted allenoates in phosphine-catalyzed
[4 + 2] annulation reactions with activated olefins to construct
spirocyclic structures, and allenoates were used as C4 synthons
(α−δ, 1,4-dipole) in those studies (Scheme 1, eq 3).6
Subsequently, cyclization reactions involving substituted
allenoate compounds as diverse dipoles have been reported
(Scheme 1).7 In 2010, Tong8 and co-workers disclosed a novel
[4 + 1] annulation of β′-acetoxy allenoates; it is noteworthy
that allenoates were used as C4 synthons by the 1,4-
biselectrophile intermediates (Scheme 1, eq 2). Next,
enantioselective [4 + 1] annulation of β′-acetoxy allenoates
was also reported by the groups of Lu and Fu.9 To the best of
our knowledge, besides the two reaction mechanisms based on
the (1,n)-zwitterion intermediate and the 1,4-bis-electrophile
intermediates of phosphine-catalyzed reactions, no other
reaction mechanism has been reported. We report herein a
novel sequential phosphine-catalyzed mode for the highly
enantioselective formation of tetrahydroquinolines by [4 + 2]
annulation reaction with α-substituted allenoates (Scheme 1,
eq 4).
O
preparing structurally divergent molecules or chiral molecules.1
From the angle of mechanism, nucleophilic addition of a
nucleophilic phosphine to activated alkenes, allenes, or alkynes
to form a zwitterion intermediate, which is then trapped by an
electrophile, is involved. Since the pioneering report of Lu’s [3
+ 2] cycloaddition,2 the research paradigm of the phosphine-
catalyzed cycloadditions of activated allenes has been well
established in which allenoates were used as C3 synthons
(Scheme 1, eq 1). Subsequently, [3 + 2] annulations have been
a powerful tool to construct five-membered carbocyclic and
heterocyclic compounds.3 In 2003, Kwon4 reported a novel [4
+ 2] annulation of α-substituted allenoates with N-
sulfonylimines, in which allenoates first act as C4 synthons
(β′-γ, 1,4-dipole). Later, [4 + 2] annulation of allenoates with
Scheme 1. Previous Works and This Work
Substituted tetrahydroquinolines are widespread in many
natural products and medically synthetic molecules and exhibit
a wide spectrum of significant biological activities, which have
attracted considerable attention from organic and medicinal
chemists.10 There are some examples of these ring systems
contributing to biological activities (Figure 1a).11 Meanwhile,
terminal alkynyl linking in a quaternary stereogenic center as a
key structural element in numerous natural alkaloids and
Received: January 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00130
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Substrate Scope for the Synthesis of
a
Tetrahydroquinolines 3
b
entry
R1
R2
R3
R4
3
yield (%)
c
1
2
3
4
5
6
7
8
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
4-NO2C6H4
4-PhC6H4
2,4-Cl2C6H3
Ph
H
H
H
H
H
H
H
H
H
H
H
H
5-Cl
5-Br
5-Me
H
H
H
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Mts
Ms
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Et
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3ab
3ac
3pa
3qa
82
59
41
83
79
42
78
76
58
66
NR
81
70
73
66
85
84
88
77
Figure 1. Examples of biologically active compounds.
bioactive molecules has led to a great demand for the efficient
construction of this skeleton (Figure 1b).12
Although numerous methods have thus been developed to
access tetrahydroquinoline ring skeletons, the development of
new effective methods, which tolerate special functional
groups, is still very important. To the best of our knowledge,
there are no reports on the synthesis of chiral alkynyl-
substituted tetrahydroquinoline skeletons via asymmetric
phosphine catalysis. Recently, 2-aminochalcones were used to
construct tetrahydroquinolines and indolines.13 On the basis of
our continuous interest in exploring phosphine-catalyzed
domino reactions and asymmetric phosphine catalysis,14 we
envisioned that α-substituted allenoates containing a leaving
group could be transferred to enyne intermediates to promote
[4 + 2] annulation of 2-aminochalcones with enynes to
construct 3-alkynyl-substituted tetrahydroquinoline skeletons
by a sequential phosphine-catalyzed process (Scheme 1, eq 4).
In this SPC process, α-substituted allenoates, for the first time,
act as C2 synthons of α and β′ sites. Herein, we document a
novel [4 + 2] annulation reaction between 2-aminochalcones
and α-substituted allenoates involving a SPC process, leading
to highly enantioselective construction of 3-alkynyl-substituted
tetrahydroquinoline architectures.
We initiated our investigation by examining the reaction
between 2-aminochalcone 1a and allenoate 2a using PPh3 (20
mol %) in CHCl3 (1.0 mL) at 25 °C (see the Supporting
Information for details). To our delight, the reaction
proceeded smoothly and afforded the desired product 3aa in
70% yield (Table S1, entry 1). For further optimization study,
various solvents such as THF, acetone, hexane, and toluene
were scanned (Table S1, entries 2−6); when THF was used,
3aa was obtained in 75% yield (Table S1, entry 2). No base
could improve the yields (Table S1, entries 7−10). For the
screening of nucleophilic phosphine catalysis (Table S1, entries
11−17), PhPEt2 could improve the reaction and 3aa was
obtained in 82% yield (Table S1, entry 15). If a tosyl group
was used instead of the Mts (mesityl-λ5-sulfanedione) group,
the yield of 3aa decreased.
9
10
11
12
13
14
15
16
17
18
19
Me
2-furyl
4-BrC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
Bn
Bn
H
Ms
a
Unless otherwise specified, all reactions were carried out with 1a(0.1
mmol), 2a (0.15 mmol), PhPEt2 (20 mol %), Cs2CO3 (0.12 mmol),
b
c
and 1.0 mL of THF at 25 °C. Isolated yield. Mts = mesityl-λ5-
sulfanedione.
(R2), namely 5′-Br, 5′-Cl, and 5′-Me, on the aromatic ring of
the aniline moiety were well-tolerated and led to a high
reactivity (Table 1, entries 12−15). For α-substituted
allenoates, when R3 was a variety of ester groups, the reactions
converted into the corresponding 3ab and 3ac in high yields
(Table 1, entries 16 and 17). Use of an Ms group instead of an
Mts group also led to the corresponding tetrahydroquinolines
in high yields (Table1, entries 18 and 19).
After establishing a practical and highly efficient method for
the synthesis of 3-alkynyl-substituted tetrahydroquinoline
adducts, we next focused on the development of an
enantioselective organocatalytic version. For this purpose,
several catalysts, additives, and solvent combinations were
evaluated with 1r and 2d as model substrates (see the
Supporting Information for details, Table S2 and Table S3).
To our delight, the bifunctional catalyst F in toluene delivered
the desired products in high enantiomeric excesses and yields.
The substituent steric effects of α-substituted allenoates were
screened, and the isopropyl group led to the best result (er =
95:5).
All of the 2-tosylaminochalcones generated the respective
products consistently with moderate to high enantioselectiv-
ities and yields (Table 2, entries 1−13). The absolute
stereochemistry of 3rd was determined by X-ray diffraction
analysis. The substituent steric effect of 2-tosylaminochalcones
obviously influenced the enantioselectivities (Table 2, entries
1−3). Unfortunately, alkyl group substituted 2-aminochalcones
could not give the corresponding products because of low
reactivity (Table 2, entry 8).
With the optimized reaction conditions in hand, the
established reaction conditions were applicable to a variety
of substituted 2-aminochalcones and gave the corresponding
products in moderate to high yields (Table 1). Increasing the
steric bulk of the aryl groups led to a lower reactivity (Table 1,
entries 1−3). It was noted that the electron-deficient aryl
groups led to a higher reactivity than the electron-rich aryl
groups (Table 1, entries 4−10). Unfortunately, alkyl group
substituted 2-aminochalcones could not give the correspond-
ing products because of low reactivity (Table 1, entry 11).
Screening revealed that the 2-aminochalcone 1l with a 2-furyl
group could also smoothly convert into the corresponding 3la
in good yield (81%) (Table 1, entry 11). Several substituents
B
DOI: 10.1021/acs.orglett.9b00130
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Scope for the Enantioselective Synthesis
of Tetrahydroquinolines 3
Scheme 2. Gram-Scale Synthesis of 3aa and 3rd and Further
Transformation from 3aa
a
a
b
time
(d)
yield
(%)
c
entry
R1
R2
R3
3
er
1
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-ClC6H4
4-FC6H4
4-PhC6H4
Ph
H
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Bn
Et
4
4
3rd
3sd
3td
67
95:5
2
H
59
74:26
3
H
4
trace
73
4
H
4
3ud
3vd
3wd
3xd
3yd
3zd
3aad
3bbd
3ra
91:9
83:17
93:7
91:9
5
H
5
65
6
H
5
60
7
H
5
43
8
Me
H
10
4
NR
53
9
2-Furyl
H
86:14
91:9
93:7
92:8
93:7
a
Conditions: (a) PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N
10
11
12
13
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
5-Br
5-Me
H
4
42
(2.5 equiv), THF, rt, 2 h, 85% yield; (b) copper(I) thiophene-2-
carboxylate (10 mol %), TsN3 (1.5 equiv), DCM (0.1 M), rt, 99.2%
yield; (c) PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N (2.5
equiv), PhI (2.0 equiv) THF, rt, 2 h, 54% yield.
4
53
4
4
80
72
H
3rc
a
Unless otherwise specified, all reactions were carried out with 1 (0.1
mmol), 2 (0.15 mmol), Cat. F (20 mol %), Cs2CO3 (0.12 mmol), and
Scheme 3. Control Experiments
b
c
1.0 mL of toluene at 25 °C Isolated yield. Determined by chiral-
phase HPLC.
To demonstrate the further synthetic utility of this protocol,
we carried out the reaction on gram scale using 1a with 2a as
the representative substrate to provide 3aa in 81% yield.
Similarly, 3rd was obtained in 78% yield and high
enantioselectivity (er = 90:10). The reduction of the ee
value is probably due to the reaction being too long. It was
noted that 3rd (> 99% ee) could be obtained by
recrystallization. Self-coupling and click reaction of 3aa were
achieved in good yields (Scheme 2). Meanwhile, internal
alkynyl-substituted tetrahydroquinoline (5c) could be pro-
duced by metal-catalyzed cross-coupling of 3-ethynyl-sub-
stituted tetrahydroquinolines that were not directly con-
structed using this SPC process (see the Supporting
Information for details).
Scheme 4. Proposed Reaction Mechanism Involving a
Sequential Phosphine-Catalyzed Process
Control experiments (Scheme 3, eq 1) showed that 4a was
obtained in 50% isolated yield from 2a using PEt2Ph (20 mol
%) and Cs2CO3 (1.2 equiv) in CHCl3. The separation yield of
4a is low due to the instability of the intermediate 4a. Then the
reaction of 4a and 1a under the standard conditions did not
provide the desired product (Scheme 3, eq 2), but 3aa was
obtained in 55% yield without Cs2CO3 (Scheme 3, eq 3). It
proved that the reaction was achieved via the intermediate 4a
by a SPC process. Meanwhile, the base played a role in the first
catalytic cycle, and a negative result for the second catalytic
cycle was found when an excess of base was used.
According to the control experimental results and previous
studies, a possible mechanism, involving a SPC process, was
proposed to account for the formation of 3-ethynyl-substituted
tetrahydroquinoline derivatives (Scheme 4). Initially, the Lee−
Tong intermediate II was produced by a phosphine catalyst
from α-substituted allenoates 2 via an addition and elimination
reaction.8,15 Then the key intermediate 4a was obtained by the
elimination of the phosphine catalyst from Int II under the
base to accomplish the first catalytic cycle (Scheme 3).
Subsequently, in a recatalytic process, nucleophilic attack of
C
DOI: 10.1021/acs.orglett.9b00130
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
PR3 to 4a generated intermediate III. Then, nucleophilic
addition of Int III to 2-aminochalcones 1 generated Int IV.
Sequential proton shift and nucleophilic addition process led
to the desired tetrahydroquinoline 2 after the release of catalyst
PR3, accomplishing the second catalytic cycle. It is worth
mentioning that the results of deuterium-labeling experiments
also supported the proposed mechanism (see the Supporting
Information for details).
The key hydrogen-bonding interactions between the NH
group of the ester are crucial for the stereochemical outcome
of the reaction (see the transition state depicted in Scheme 4,
b).
In summary, we have unraveled a novel enantioselective
SPC mode of asymmetric [4 + 2] annulation reaction between
α-substituted allenes and 2-aminochalcones. In this SPC
process, α-substituted allenoates were used as C2 synthons
(α−β′, 1,2-dipole) for the first time. Notably, it is proven that
this reaction involves a phosphine sequential catalytic process
via the isolation of the intermediate 4a in the mechanistic
study. It provides a new method for construction of 3-ethynyl-
substituted tetrahydroquinolines in moderate to high yields
and high enantioselectivities, and only one isomer was isolated
in all reactions. Further diversity transformations of the
products were also carried out. Further development of new
annulation reactions by the SPC mode is ongoing in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00130.
■
S
Experimental procedures and spectroscopic data (PDF)
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Accession Codes
CCDC 1491301 contains the supplementary crystallographic
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via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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AUTHOR INFORMATION
■
Corresponding Author
*Email:hyou@nankai.edu.cn.
ORCID
Hongxing Jin: 0000-0001-6024-3600
You Huang: 0000-0002-9430-4034
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21672109, 21871148, and
21472097) and the Natural Science Foundation of Tianjin
(15JCYBJC20000).
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DEDICATION
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Dedicated to the 100th anniversary of Nankai University and
the 100th anniversary of the birth of Academician Ruyu Chen.
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DOI: 10.1021/acs.orglett.9b00130
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