Gold(I)-Catalyzed Oriented Assembly of Dihydropyridines

Article abstract of DOI:10.1055/s-0034-1380123

A novel method for the assembly of multisubstitued dihydropyridines has been developed starting from methyl propiolate and propargylamines. The reactions were efficiently catalyzed by AuPPh₃Cl to get high regioselectivity and high yields. And alternatively, since propargylamines could be easily derived by the CuCl-mediated addition of methyl propiolate to imines, the reactions could be carried out as a sequential three-component model.

Full text of DOI:10.1055/s-0034-1380123

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 834–838
letter
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Y. Li et al.
Letter
Synlett
Gold(I)-Catalyzed Oriented Assembly of Dihydropyridines
Yufeng Li*a
Zhengguang Wub
Yi Panb
Hao Huanga
Jie Shia
Hongzhong Bua
Hongfei Maa
Yingying Lianga
Binbin Huanga
Ar2
Ar2
Ar1
N
Ar1
AuPPh3Cl
N
+
COOMe
H
COOMe
DCE
Et3N
80 °C
COOMe
COOMe
a College of Sciences, Nanjing Tech University, Nanjing, 211816, P. R. of China
yufengli@njtech.edu.cn
b School of Chemistry & Chemical Engineering, Nanjing University, Nanjing,
210093, P. R. of China
Received: 17.11.2014
Accepted after revision: 27.12.2014
Published online: 09.02.2015
compounds but also attractive in synthetic chemistry.2
Therefore, efficient methods in line with the requirement of
green chemistry for constructing this skeleton are a per-
sistent goal pursued by synthetic chemists.
DOI: 10.1055/s-0034-1380123; Art ID: st-2014-w0950-l
Abstract A novel method for the assembly of multisubstitued dihy-
dropyridines has been developed starting from methyl propiolate and
propargylamines. The reactions were efficiently catalyzed by AuPPh3Cl
to get high regioselectivity and high yields. And alternatively, since
propargylamines could be easily derived by the CuCl-mediated addition
of methyl propiolate to imines, the reactions could be carried out as a
sequential three-component model.
We have a long-standing interest in the field of multi-
component reactions (MCR) for heterocycles building.3
During our work, we become fascinated by the reactivity
variation of methyl propiolate, from which numerous het-
erocyclic skeletons could be constructed.3,4 Recently, we
have reported a FeCl3-catalyzed three-component reaction
involving methyl propiolate (2) for the directed construc-
tion of pyrroles (Scheme 1, eq. 1).3a Essentially, it is a cy-
clization of 2 with propargylamines 1, which could be easi-
ly derived from 2 and an imine. As a continuing work, anhy-
drous ZnCl2 was tested by us for the cyclization of 1a with 2
to improve the conversion and selectivity. And besides 3a,
dihydropyridine 4a was surprisingly obtained with 59%
yield (Scheme 1, eq. 2). To enhance the selectivity of 4a, we
checked various solvents such as dioxane, toluene, or N, N-
dimethylformide (DMF) for the cyclization but no desirable
results were given (Table 1, entries 2–5).
Key words triphenylphosphine gold chloride, methyl propiolate,
propargylamines, dihydropyridines
Nitrogen-containing heterocycles are important sub-
structures prevalent in a wide variety of biologically com-
pounds. Nevertheless, they are also attractive in synthetic
chemistry because of their wide uses for the access to bio-
active compounds or materials.1 Dihydropyridine is one of
the important heterocyclic cores not only prevalent in a
wide variety of biologically and medicinally important
COOMe
Ph
(2)
Ph
N
FeCl3
(1)
COOMe
DCE
COOMe
3a
Ph
Ph
N
Ph
H
Ph
COOMe
Ph
Ph
N
(2)
N
1a
+
COOMe
COOMe
COOMe
3a, 30%
COOMe
COOMe
4a, 59%
ZnCl2
DCE
Scheme 1 Simultaneous construction of 3a and 4a starting from methyl propiolate and propargylamines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 834–838

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Y. Li et al.
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R2
COOMe
R1
R2
R1
2
2/AuPPh3Cl
N
R1
N
DCE, Et3N
80 °C, 24 h
CuCl
DCE, 50 °C, 5 h
N
R2
H
COOMe
COOMe
1
COOMe
4
4a, 81%
4b, 87%
4g, 80%
one-pot sequential reaction without
separation of the intermediate 1
Scheme 2 One-pot sequential mode for the synthesis of dihydropyridines
Table 1 Optimization of Reaction Conditions for the Cyclization of 1a and 2a
Ph
Ph
Ph
Ph
Ph
N
N
catalyst
COOMe
Ph
N
+
H
COOMe
COOMe
COOMe
COOMe
COOMe
2
1a
4a
3a
Entry
Catalyst
Solvent
Time (h)
Temp (°C)
4a (%)b
3a (%)b
1
2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
CuCl2
ZrCl4
DCE
10
24
24
24
24
24
24
24
24
24
24
24
80
80
27
59
29
26
25
27
27
0
17
30
11
17
15
21
21
0
DCE
3
DMF
toluene
dioxane
DCE
140
110
100
80
4
5
6
7
DCE
80
8
Pd(OAc)2
PdCl2
DCE
80
9
DCE
80
0
0
10
11
12c
Ag2CO3
AgNO3
DCE
80
0
0
DCE
80
0
0
AuPPh3Cl
DCE
80
83
0
a The reactions were carried out with 1a (10.0 mmol), 2 (11.0 mmol), catalyst (1.0 mmol), Et3N (1.0 mmol), solvent (10.0 mL).
b Isolated yield was calculated from 1a after silica column chromatography purifying.
c The reaction was conducted in the presence of 0.01 mmol catalyst along with 0.01 mmol Et3N.
Next, our attention was turned to other metals for cata-
lyst screening. When CuCl2 was used for the cyclization,
both the yield and selectivity of 4a were lowered (Table 1,
entry 6). While anhydrous ZrCl4 was adopted, no cycliza-
tion product was detected apart from some tarlike products
according to flash thin-layer chromatography (TLC) (Table
1, entry 7). Pd(OAc)2, PdCl2, Ag2CO3, and AgNO3 displayed no
activation on the conversion (Table 1, entries 8–11). Fortu-
nately, when a catalytic amount of AuPPh3Cl was used along
with triethylamine to treat the mixture of 1a and 2 in di-
chloroethane solution, 4a was smoothly generated without
3a detected. With column chromatography purification, 4a
was easily isolated in high yield (83%, Table 1, entry 12).5
Then, a variety of propargylamines were prepared by
the addition of 2 to imines,3a and subsequently examined
for the cyclization. All propargylamines bearing H, alkyl, al-
kyloxyl, and halogen substituents on the benzene ring re-
acted smoothly with 2 to give the the corresponding dihy-
dropyridines with high selectivity and yields (Table 2, en-
tries 1–9), whereas strong electron-withdrawing groups
(CF3 or NO2) inhibited the cyclization completely.
Given that DCE was also a suitable solvent for synthesiz-
ing propargylamines, a sequential model for the reaction
was then explored.6 After the completion of the addition
between N-benzylideneaniline with 2 in the presence of
CuCl, AuPPh3Cl, triethylamine, and 2 were added directly to
the mixture. The cyclization was performed under the opti-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 834–838

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COOMe
mized conditions to give 4a (81% yield), 4b (87% yield), and
4g (80% yield), respectively (Scheme 2). Without separation
of the intermediate, this sequential model was beneficial to
the operation simplicity.
Ar2
Ar2
Ar1
1
NH
N
Ar1
Ar2
[Au]
Cl
COOMe
As shown in Scheme 3, a plausible pathway was pro-
posed by us, which starts with the amination of gold(I) cat-
alyst with propargylamines 1 leading to gold amide 5 with
liberation of HCl.7 As an acid-binding reagent, triethylamine
is helpful to improve the conversion rate of 1. Along with
Ph3P released, 6 is generated by the coordination of 1 with
5. Insertion of the C≡C bond into the Au–N bond of 6 gives
gold-alkenyl species 7. A subsequent intramolecular inser-
tion of coordinated alkyne into the Au–C bond in 7 affords
the gold complex 8. Second amination of 8 with 2 produces
dihydropyridines 4 with regeneration of the gold-amino
species 5.
4
COOMe
COOMe
N
Ph3P
Ar1
[Au]
2
5
2
Ar2
COOMe
Ar1
Ar1
N
N
Ar2
[Au]
[Au]
COOMe
COOMe
COOMe
6
8
Ar1
N
Ar2
COOMe
+ Ph3P
COOMe
[Au]
COOMe
7
Scheme 3 Plausible mechanism of the gold(I)-catalyzed cyclization
Table 2 Cyclization of Propargylamines 1 with 2
Entry
Propargylamine 1
Product
Yield (%)a
1
4a
83
N
N
H
COOMe
COOMe
COOMe
2
3
4
4b
4c
4d
87
89
87
N
N
H
COOMe
COOMe
COOMe
MeO
MeO
N
N
H
COOMe
COOMe
COOMe
N
N
H
COOMe
COOMe
COOMe
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 834–838

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Y. Li et al.
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Yield (%)a
85
Synlett
Table 2 (continued)
Entry
Propargylamine 1
Product
5
4e
t-Bu
N
t-Bu
N
H
COOMe
COOMe
COOMe
6
4f
90
N
N
H
COOMe
COOMe
COOMe
7
4g
82
N
N
N
N
H
COOMe
COOMe
COOMe
OMe
OMe
8
4h
85
N
H
COOMe
COOMe
COOMe
Cl
Cl
9
4i
75
N
H
COOMe
COOMe
COOMe
a Isolated yield.
In summary, we have established an oriented method
for the construction of structurally unique dihydropyri-
dines with AuPPh3Cl as catalyst. The reaction could be alter-
natively performed in a sequential model starting from eas-
ily accessible imines and methyl propiolate. Further re-
searches into the asymmetric aspect of the reaction are
under way in our laboratory.
References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 834–838

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(5) Typical Procedure for the Synthesis of Dihydropyridines
from Propargylamines
In a round-bottomed flask equipped with a magnetic stirring
bar, a mixture of 1a (10.0 mmol) and 2 (11.0 mmol), AuPPh3Cl
(0.01 mmol), and Et3N (0.01 mmol) in DCE (10.0 mL) was heated
at 80 °C under inert nitrogen atmosphere until the consump-
tion of 1 was detected by TLC. The mixture was filtered, and the
filtration was concentrated to give a residue, which was purified
by silica column chromatography to provide 4a as pale yellow
solid, 83% yield; mp 51.7–56.5 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.97 (d, J = 0.8 Hz, 1 H), 7.33–7.27 (m, 7 H), 7.14 (t, J = 7.4 Hz, 1
H), 7.06 (d, J = 7.9 Hz, 2 H), 5.91 (d, J = 6.3 Hz, 1 H), 5.63 (d, J =
5.6 Hz, 1 H), 3.79 (s, 3 H), 3.74 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.40, 165.57, 144.27, 142.22, 140.77, 129.47,
129.22, 128.32, 127.51, 125.38, 125.14, 119.86, 119.80, 102.55,
61.84, 52.26, 51.30 ppm. HRMS (ES): m/z calcd for C21H19NO4:
349.1315; found: 349.1314.
(6) Typical Sequential Synthesis of Dihydropyridines from
Imines
A mixture of N-benzylideneaniline (10.0 mmol), methyl propio-
late (10.0 mmol), and CuCl (1.0 mmol) was heated at 80 °C in
DCE solution for about 5 h. After cooling, AuPPh3Cl (0.01 mmol)
and Et3N (0.01 mmol) were added to the reaction system. The
mixture was further stirred at 80 °C under inert nitrogen atmo-
sphere. The reaction was completed within 5 h according to
TLC. Conventional processing and purification gave 4a as pale
yellow solid in 81% yield.
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