Catalytic asymmetric three-component reaction of 2-alkynylbenzaldehydes, amines, and dimethylphosphonate

Article abstract of DOI:10.1021/acs.orglett.0c02487

An efficient enantioselective synthesis of cyclic α-aminophosphonates via multicomponent reactions of 2-alkynylbenzaldehydes, amines, and dimethylphosphonate has been developed with the use of a chiral silver spirocyclic phosphate as the catalyst. This protocol provides straightforward access to a series of chiral C1-phosphonylated 1,2-dihydroisoquinoline derivatives with high yields (up to 99%) and high enantioselectivities (up to 94% ee) for a broad substrate scope. The products could be further transformed into densely functionalized compounds and corresponding α-aminophosphonic acids.

Full text of DOI:10.1021/acs.orglett.0c02487

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Letter
Catalytic Asymmetric Three-Component Reaction of
2‑Alkynylbenzaldehydes, Amines, and Dimethylphosphonate
Liangliang Zou, Jiaying Huang, Na Liao, Yan Liu, Qixiang Guo,* and Yungui Peng*
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ABSTRACT: An efficient enantioselective synthesis of cyclic α-aminophosphonates via multicomponent reactions of 2-
alkynylbenzaldehydes, amines, and dimethylphosphonate has been developed with the use of a chiral silver spirocyclic phosphate
as the catalyst. This protocol provides straightforward access to a series of chiral C1-phosphonylated 1,2-dihydroisoquinoline
derivatives with high yields (up to 99%) and high enantioselectivities (up to 94% ee) for a broad substrate scope. The products could
be further transformed into densely functionalized compounds and corresponding α-aminophosphonic acids.
catalytic asymmetric synthesis of 1,2-dihydroisoquinolin-1-
ylphosphonates and their derivatives (Scheme 1b).3g However,
this method suffers from two drawbacks in that a low reaction
temperature is required as well as prior preparation of silyl
phosphite as the nucleophile. When diethyl phosphonate was
used as a nucleophile in the same reaction under otherwise
identical conditions, the desired product was not observed.
This result might be attributed to diethyl phosphonate existing
almost exclusively as the favored unreactive form over the
reactive phosphite via equilibrium. Thus, development of an
efficient method for convenient access to enantiopure 1,2-
dihydroisoquinolin-1-yl phosphonate derivatives with the use
of dialkylphosphonate as a readily available nucleophile under
mild reaction conditions would be highly desirable.
Multicomponent tandem reactions (MCTRs) have emerged
as efficient strategies for synthesizing a wide range of functional
and structural diverse frameworks.4−6 Among MCTRs of 2-
alkynylbenzaldehydes, amines, and various nucleophiles for the
generation of 1,2-dihydroisoquinoline derivatives, dialkyl-
phosphonate has been used in the successive nucleophilic
step to yield racemic 1,2-dihydroisoquinolin-1-ylphosphonate-
s.3a,b As part of our ongoing interest in developing methods for
the synthesis of chiral phosphorus-containing compounds,7 we
α-Aminophosphonic acids are isosteric analogues of corre-
sponding α-amino acids, which have a variety of potentially
useful biological and biochemical properties,1 such as
antibacterial, antifungal, antiviral, antitumor, HIV-protease
inhibitory, and alanine racemase inhibitory activities. Addi-
tionally, 1,2-dihydroisoquinoline is a common substructure
present in many natural products and pharmaceutical
compounds with remarkable biological activities.2 Therefore,
combining the substructure of α-aminophosphonic acids and
1,2-dihydroisoquinoline into a single 1,2-dihydroisoquinolin-1-
ylphosphonate derivative would be of great utility. However,
the development of methodologies for such syntheses has not
been widely reported to date.3 Wu’s group reported a synthesis
of racemic 1,2-dihydroisoquinolin-1-ylphosphonate (Scheme
1a).3a,b For the chiral variant, only one report has described
Scheme 1. Previous Studies and Our Strategy
Received: July 26, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02487
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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hope to develop an asymmetric version of the multicomponent
reaction of 2-alkynylbenzaldehydes, amines, and dialkyl-
phosphonate as the most straightforward approach to enable
acquiring chiral 1,2-dihydroisoquinolin-1-yl phosphonate de-
rivatives (Scheme 1c).8 Herein, we hope to report our results.
The study commenced with the reaction of 2-alkynylben-
zaldehyde 1a, amine 2a, and dibenzylphosphonate 3a. After
initial trials, we were delighted to find that this model reaction
proceeded smoothly and gave the desired 1,2-dihydroisoqui-
nolin-1-ylphosphonate 4aaa in 67% yield with 7% ee through
catalysis of silver phosphonate, formed in situ from Ag2CO3 (5
mol %) and chiral spirocyclic phosphate acid (SPA)9 Ia (10
mol %), in toluene at 0 °C in the presence of 4 Å molecular
sieves (MS) (Table 1, entry 1 and Scheme 2). Encouraged by
this result, a series of chiral SPA bearing different substituents
at the 3,3′-positions were screened (Table 1, entries 2−13).
We found that the electronic effect of the group located at the
para position of the 3,3′-substituent phenyl had little influence
on the enantioselectivity, irrespective of its electron-donating
(MeO, Ib) or -withdrawing nature (CF3, Ic); changes of the
Scheme 2. Screened Chiral Phosphoric Acids
enantioselectivity were noted (Table 1, entries 2 and 3).
Further increases of the steric hindrance of the substituents on
the 3,3′-phenyl caused the enantioselectivity to decrease
(Table 1, entry 4). Gratifyingly, when the SPA had a
substituted biphenyl 4-(4-tBuC6H4)C6H4 at the 3,3′-position
(Ih), the enantioselectivity was markedly improved, and up to
57% ee was achieved. On the basis of these results, we further
introduced a methyl group at the 3-position on the middle
phenyl (Ii), and the enantioselectivity continued to increase up
to 66% ee (Table 1, entry 9). However, when both of the 3-
positions on the middle phenyl had methyl groups (Ij), both
the yield and the enantioselectivity sharply decreased (Table 1,
entry 10). We also changed the methyl into ethyl (Ik) and
isopropyl (Il) groups and moved it from the 3-position to 2-
position (Im); however, no better performance of the SPA was
observed (Table 1, entries 11−13). The silver phosphate from
1,10-binaphthol (BINOL)- and octahydrodinaphthol (H8-
BINOL)-based phosphoric acids was also applied in the
model reaction. These results were inferior to that of Ii (see
the Supporting Information, SI). The reaction parameters,
including the type of additive molecular sieves (Table 1, entries
9 and 14, and see SI), reaction temperature (Table 1, entries
14 and 15 and see SI), and the solvents were optimized. MTBE
was found to be the suitable solvent (Table 1, entries 15 and
18−22). The effect of the counterion of silver salts (see SI),
the influence of the ratio of Ii to Ag2CO3 (see SI), and catalyst
loads on the reaction were also investigated. When the catalyst
loading decreased from 10 mol % to 5 mol %, both the
reactivity and enantioselectivity decreased and only gave 75%
yield with 57% ee (Table 1, entries 16 vs 15). When 20 mol %
of catalyst was employed, the same yield was observed with
75% ee (Table 1, entries 17 vs 15). In order to keep the
reaction system in the catalytic scope, we opted to employ 10
mol % of catalyst to promote the reaction. We further
investigated the influence of dialkylphosphonate on the
reaction, and to our delight, when using dimethylphosphonate
3b to replace dibenzylphosphonate 3a, the enantioselectivity of
the product increased greatly up to 91% ee (Table 1, entries 23
vs 20). Diethylphosphonate 3c only gave 59% yield with
almost the same enantiselectivity (90% ee) (Table 1, entry 24).
Diisopropylphosphonate has shown lower reactivity and led to
16% yield with 71% ee (Table 1, entry 25). When we changed
the aniline into 4-methoxyaniline and 4-isopropoxyaniline, the
enantioselectivity further increased from 91% ee to 92% ee and
94% ee (Table 1, entries 23, 26, and 27). Thus, the best result
Table 1. Optimization of Reaction Conditions
yield of
b
ee
yield of
b
a
c
entry
CPA
R2
sol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
4 (%)
(%)
5 (%)
1
2
3
4
5
6
7
8
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ii
Ij
Ik
Il
Im
Ii
Ii
Ii
Ii
Ii
Ii
Ii
Ii
Ii
Ii
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Et
4aaa, 67
4aaa, 57
4aaa, 63
4aaa, 53
4aaa, 56
4aaa, 57
4aaa, 76
4aaa, 67
4aaa, 73
4aaa, 37
4aaa, 45
4aaa, 46
4aaa, 48
4aaa, 96
4aaa, 90
4aaa, 75
4aaa, 90
4aaa, 94
4aaa, 70
4aaa, 96
4aaa, 68
4aaa, 77
4aab, 87
4aac, 59
4aad, 16
4abb, 92
4acb, 91
7
9
trace
trace
trace
-
trace
-
-
-
-
-
-
-
-
-
-
-
-
-
10
-
-
-
-
-
-
13
7
10
20
5
57
66
7
66
56
57
62
70
57
75
68
80
81
66
72
91
90
71
92
94
9
10
11
12
13
d
14
de
,
15
16
17
18
19
20
21
22
23
24
25
26
27
de f
,
,
de g
,
,
tol
de
,
THF
Et2O
MTBE
DME
EA
MTBE
MTBE
MTBE
MTBE
MTBE
de
,
de
,
de
,
de
,
de
,
de
,
Ii
Ii
de
,
iPr
Me
Me
de h
,
,
Ii
Ii
-
-
de i
,
,
a
Unless otherwise specified, the reaction was performed with 1a (0.12
mmol), 2a (0.11 mmol), 3 (0.1 mmol), 4 Å MS (100 mg), SPA (10
mol %), and Ag2CO3 (5 mol %) in 1.0 mL of solvent at 0 °C for 3
b
c
d
days under argon. Isolated yield. Determined by chiral HPLC. 5 Å
e
f
MS was added. Reaction at −10 °C. Ii (5 mol %)/Ag2CO3 (2.5 mol
%). Ii (20 mol %)/Ag2CO3 (10 mol %). 2b was used. 2c was used.
g
h
i
B
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was achieved when the 4-isopropoxyaniline (2c) and
dimethylphosphite 3b were used as the other two reaction
partners in the catalysis of silver phosphonate formed in situ
from Ag2CO3 (5 mol %) and SPA Ii (10 mol %) in MTBE at
−10 °C in the presence of 5 Å MS.
Having established the optimized reaction conditions, we
proceeded to investigate the scope of the reaction with various
substrates. These results are summarized in Scheme 3 and
Scheme 4. Substrate Scope of the Asymmetric Three-
Component Reaction
Scheme 3. Influence of Substituent (R1) at the Alkyne
Terminus of 2-Alkynylbenzaldehyde
a
All reactions were performed with 1 (0.12 mmol), 2 (0.11 mmol),
3b (0.1 mmol), 5 Å MS (100 mg), Ii (10 mol %), and Ag2CO3 (5 mol
%) in 1.0 mL of MTBE at −10 °C for 3 days under argon. Isolated
yield by flash chromatography. Enantioselectivities were determined
by HPLC analysis.
reaction. The corresponding chiral 1,2-dihydroisoquinolin-1-yl
phosphonate derivatives were obtained in good yields and
enantioselectivities (Scheme 3, 4pcb−4rcb). Styrenyl-substi-
tuted substrates gave moderate yields and enantioselectivities
(Scheme 3, 4scb). Unfortunately, 2-alkynylbenzaldehyde,
having an alkyl (R1) at the alkyne terminus, gave unsatisfactory
results, with good yields but low to moderate enantioselectiv-
ities (Scheme 3, 4tcb−4vcb).
a
We next turned our attention to screening of other amines,
including aniline, 4-benzoxyaniline, 3-methylaniline, and 4-
fluoroaniline, as reaction partners. These amines were
accommodated by this reaction and achieved excellent yields
and enantioselectivities (Scheme 4, 4aab−4afb). The effects of
substituents on the aromatic moiety adjacent to the aldehyde
were also investigated. In general, when a substituent was
located at the 4- or 5-position of the substrate, irrespective of
its electron-donating or -withdrawing properties, good yields
and enantioselectivities were observed (Scheme 4, 4ahb−
4anb). However, when the substituent at the 4-position was
MeO−, a yield of only 52% yield and 63% ee were obtained
(Scheme 4, 4ajb). Notably, even for small substituents at the 3-
position, such as fluorine, the reactivity considerably decreased
to give 28% yield and 84% ee (Scheme 4, 4agb). 2-Alkynyl-3-
pyridinecarboxaldehyde was also used in this reaction and gave
moderate yield (52%) and good enantioselectivity (87% ee)
(Scheme 4, 4aob). The absolute configuration of products
4aab was determined to be (S) by single-crystal X-ray analysis.
We assumed a common reaction pathway; thus, the absolute
All reactions were performed with 1 (0.12 mmol), 2c (0.11 mmol),
3b (0.1 mmol), 5 Å MS (100 mg), Ii (10 mol %), and Ag2CO3 (5 mol
%) in 1.0 mL of MTBE at −10 °C for 3 days under argon. Isolated
yield by flash chromatography. Enantioselectivities were determined
by HPLC analysis.
Scheme 4. First, the influence of substituent R1 connected to
the triple bond of 2-alkynylbenzaldehydes was investigated. In
general, good yields and enantioselectivities were achieved
when R1 was a substituted phenyl with electron-donating or
-withdrawing groups at the para- or meta-positions of the
phenyl ring (Scheme 3, 4acb−4mcb). However, strong
electron-withdrawing groups (−CN) markedly decreased the
yield while maintaining good enantioselectivity (Scheme 3,
4hcb). When the substituent was located at the ortho-position,
both the yield and enantioselectivity markedly decreased
(Scheme 3, 4ncb and 4ocb). This result might be attributed to
the steric hindrance effect of the ortho-substituent. Substrates
bearing a naphthyl or heterocyclic ring, such as thienyl and
furyl, at the terminal alkyne were also compatible with this
C
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configuration of the other products 4 was deduced from this
result.
Scheme 6. Proposed Catalytic Cycle
To gain insight into the mechanism of this multicomponent
reaction, control experiments were performed, as shown in
Scheme 5. In the absence of the central metal Ag(I), the model
Scheme 5. Control Experiments
imine from its Si-face via transition state D to give intermediate
E. The stereocontrol of this process is governed by the chiral
ion pairs. Finally, protonation of the intermediate E delivers
the target product 4aab and regenerates the catalyst AgSPA.
To demonstrate the potential synthetic utility of this
method, the reaction was scaled up to mmol as 1a (1.2
mmol), 2c (1.1 mmol), and 3b (1.0 mmol), and this reaction
performed smoothly and afforded 4acb in 85% yield with 93%
ee. Reduction of 4acb with NaBH3CN in the presence of acetic
acid gave chiral C1-phosphonylated tetrahydroisoquinoline
derivative 6 in 95% yield with almost the same enantiose-
lectivity, 92% ee, and >20:1 dr. The configuration of C-3 was
identified by NOE, HMQC, and HMBC spectra and deduced
from the configuration of C-2. Treatment of 4acb with I2 or
NBS gave the derivatives of 4-iodo-substituted 7 or 4-bromo-
substituted 8, respectively, which suggests the possibility for
further downstream functionalizing transformations (Scheme
7).11
reaction only generated the Kabachnik−Fields reaction8c
product as 5aab (Scheme 5a), which could not be further
transformed into the cyclic target compound under the
identical optimized reaction conditions, even when treated
by a stronger base (Cs2CO3) (Scheme 5b). These results show
that the reaction process does not proceed via an intra-
molecular cyclization by 5aab. Next, we compared the
efficiencies of the catalyst formed in situ and that preformed
from SPA (1k) and Ag2CO3. The in situ formed catalyst gave
slightly better yields and stereocontrol. This result might be
attributed to the synergistic effects of the presence of a slight
excess of SPA (1k) to cocatalyze this transformation (Scheme
5c,d). When only SPA (1k) was used to promote the reaction,
an almost racemic Kabachnik−Fields reaction product 5aaa
was observed. This result indicates that both the central metal
Ag(I) and chiral SPA are indispensable for achieving these
asymmetric multicomponent reactions. For the Kabachnik−
Fields reaction procedure, stereocontrol was not independently
achieved by SPA (1k).
Scheme 7. Derivatization of the Products
On the basis of the above experiments and other reports10
involving 2-alkynylbenzaldehyde as the starting material, we
propose a possible catalytic cycle for the asymmetric
multicomponent reactions (Scheme 6). First, the condensation
of 2-alkynylbenzaldehyde and aniline affords imine A, which is
coordinated and activated by the π-acidity of the silver salt
(AgSPA). This species interacts with the triple bond, followed
by an intramolecular imine-yne 6-endo-dig cyclization to give
isoquinolinium intermediate C. Then, the dimethyl phosphite,
as a tautomer of the dimethyl phosphonate, is activated
through hydrogen-bond interactions with the phosphine oxide
double bond of the chiral spirocyclic phosphate. This species
undergoes asymmetric nucleophilic addition to the positive ion
In summary, an efficient asymmetric three-component
cyclization/Mannich tandem reaction of o-alkynylbenzalde-
hyde, arylamine, and phosphite was realized for the first time in
the catalysis of chiral silver spirocyclic phosphate. Various
chiral C1-phosphonylated 1,2-dihydroisoquinoline derivatives
were provided in excellent yields (up to 99%) and high
enantioselectivities (up to 94% ee). This method features
simple operation, mild reaction conditions, and good atom
economy. The achieved 1,2-dihydroisoquinoline products
could be further used in organic synthesis and transformed
into other function-containing compounds.
D
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02487.
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Experimental procedures and detailed characterization
data of all new compounds (PDF)
Accession Codes
CCDC 1953874 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
Corresponding Authors
■
Qixiang Guo − Key Laboratory of Applied Chemistry of
Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, China;
orcid.org/0000-0002-0405-7958; Email: qxguo@
swu.edu.cn
Yungui Peng − Key Laboratory of Applied Chemistry of
Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, China;
orcid.org/0000-0002-5815-1261; Email: pengyungui@
hotmail.com, pyg@swu.edu.cn
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Authors
Liangliang Zou − Key Laboratory of Applied Chemistry of
Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, China
Jiaying Huang − Key Laboratory of Applied Chemistry of
Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, China
Na Liao − Key Laboratory of Applied Chemistry of Chongqing
Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, China
Yan Liu − Key Laboratory of Applied Chemistry of Chongqing
Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, China;
orcid.org/0000-0002-1597-5762
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(b) Yu, X. X.; Ye, S. Q.; Wu, J. Adv. Synth. Catal. 2010, 352, 2050.
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(d) Li, S. Y.; Wu, J. Org. Lett. 2011, 13, 712. (e) Yu, X. X.; Qiu, G. S.;
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Wang, H. H.; Wu, J. Tetrahedron 2012, 68, 5197.
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was sponsored by the National Science Foundation
of China (21472151), Natural Science Foundation of
Chongqing (cstc2019jcyj-msxmX0414), and Fundamental
Research Funds for the Central Universities
(XDJK2019AA003).
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