Synthesis of 5,6-Dihydropyrazolo[5,1-a]isoquinoline and Ethyl (Z)-3-Acetoxy-3-tosylpent-4-enoate through Tertiary-Amine-Catalyzed [3+2] Annulation

Article abstract of DOI:10.1002/ejoc.201600577

The 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed divergent [3+2] annulation of C,N-cyclic azomethine imines with δ-acetoxyallenoates was developed; 5,6-dihydropyrazolo[5,1-a]isoquinolines and ethyl (Z)-3-acetoxy-3-tosylpent-4-enoates were afforded in moderate to good yields in a one-pot manner under mild conditions. This annulation reaction provides a highly efficient method to construct dinitrogen-fused heterocycles and ethyl (Z)-3-acetoxy-3-tosylpent-4-enoates at the same time.

Full text of DOI:10.1002/ejoc.201600577

DOI: 10.1002/ejoc.201600577
Communication
Heterocycles
Synthesis of 5,6-Dihydropyrazolo[5,1-a]isoquinoline and Ethyl
(Z)-3-Acetoxy-3-tosylpent-4-enoate through Tertiary-Amine-
Catalyzed [3+2] Annulation
Yu Lei,[a] Jiao-Jiao Xing,[a] Qin Xu,[a] and Min Shi*[a,b]
Abstract: The 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed manner under mild conditions. This annulation reaction pro-
divergent [3+2] annulation of C,N-cyclic azomethine imines
with δ-acetoxyallenoates was developed; 5,6-dihydropyraz-
olo[5,1-a]isoquinolines and ethyl (Z)-3-acetoxy-3-tosylpent-4-
enoates were afforded in moderate to good yields in a one-pot
vides a highly efficient method to construct dinitrogen-fused
heterocycles and ethyl (Z)-3-acetoxy-3-tosylpent-4-enoates at
the same time.
Introduction
development of efficient and simple methods for the synthesis
of dinitrogen-fused heterocycles has recently attracted much
attention. Among the various methods, azomethine imines, as
a class of 1,3-dipoles, have been widely used in [3+n] annula-
tions.[7]
Dinitrogen-fused heterocycles are present in many pharmaceu-
ticals, agrochemicals, biologically active compounds, and other
useful chemicals. Among these compounds (Figure 1), pyrazole
derivatives are well acknowledged to possess a wide range of
bioactivities.[1] For example, Celecoxib is an effective antiphlo-
gistic drug,[2] Rimonabant acts as a diet pill,[3] Sidenafil is gener-
ally used as a phosphodiesterase inhibitor,[4] and Chloantranili-
prole displays insecticidal activity.[5] Various isoquinoline deriva-
tives have been studied as antibacterial agents.[6] Therefore, the
Metal catalysts such as Cu,[8] Ni,[9] Au,[10] Pd,[11] and Rh,[12]
have been widely used to construct dinitrogen-fused heterocy-
cles through the annulation of azomethine imines with other
π-fragments. Apart from metal catalysts, organocatalytic annu-
lations of azomethine imines have also been widely explored
and have been established as an effective method for the con-
struction of a wide range of dinitrogen-fused heterocycles.[13]
In 2007, Scheidt reported N-heterocyclic carbene catalyzed ster-
eoselective formal [3+3] annulation reactions of azomethine
imines with enals[13b] to provide tetrahydropyrazolopyridazino-
nes in good yields. In 2011, Kwon and Guo reported phosphine-
catalyzed [3+2], [3+3], [3+4], and [3+2+3] annulations of N,N-
cyclic azomethine imines with different allenoates to give the
cycloadducts in high yields.[13f] Later, they also developed phos-
phine-catalyzed [3+2] and [3+4] annulations of C,N-cyclic azo-
methine imines and allenoates.[13g] More recently, Guo and co-
workers disclosed phosphine-catalyzed highly enantioselective
[3+3] annulations of Morita–Baylis–Hillman carbonates with
C,N-cyclic azomethine imines[13l] to afford the corresponding
cycloadducts in high yields with good to excellent diastereose-
lectivities and extremely excellent enantioselectivities. As part
of our ongoing investigation on the annulations of azo-
methine,[14] we attempted to synthesize dinitrogen-fused het-
erocycles through tertiary-amine-catalyzed [3+2] annulation of
δ-acetoxyallenoates with C,N-cyclic azomethine imines. Coinci-
dentally, Tong and co-workers developed thermally induced
1,3-dipolar cycloadditions of δ-acetoxyallenoates with C,N-cy-
clic azomethine imines[15] to give 2,3-dihydropyrazole deriva-
tives in good yields (Scheme 1). To our delight, we found that
the annulation of azomethine imines 1 with δ-acetoxyalleno-
ates 2 gave distinct pyrazole derivatives and other ethyl (Z)-3-
acetoxy-3-tosylpent-4-enoates at the same time in a one-pot
Figure 1. Selected examples of biologically active dinitrogen-fused heterocy-
cles.
[a] State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
E-mail: Mshi@mail.sioc.ac.cn
http://www.sioc.ac.cn/
[b] Key Laboratory for Advanced Materials and Institute of Fine Chemicals,
School of Chemistry & Molecular Engineering, East China University of
Science and Technology,
130 Mei Long Road, Shanghai 200237, China
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600577.
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Communication
manner in the presence of a tertiary amine. Herein, we wish to (DABCO), 4-(dimethylamino)pyridine (DMAP), 1,8-diazabicyclo-
report this new finding.
[5.4.0]undec-7-ene (DBU), imidazole, and Et3N, were screened
in this reaction. All of these amines smoothly catalyzed this
annulation reaction to give the corresponding products 3a and
4a in moderate to good yields (Table 1, Entries 4–8). It was
found that DABCO was the best catalyst, as it afforded 3a in
88 % yield and 4a in 72 % yield (Table 1, Entry 4). We next
examined the solvent effects of this reaction in THF, CH2Cl2, and
MeCN. We identified that toluene was the best solvent for this
reaction (Table 1, Entries 4 and 9–11). By reducing the catalyst
loading to 10 mol-%, the yields of 3a and 4a decreased to 50
and 48 %, respectively (Table 1, Entry 12).
Scheme 1. Annulations of C,N-cyclic azomethine imines with δ-acetoxyalleno-
ates.
With the optimized reaction conditions [1 (1.0 equiv.), 2
(2.0 equiv.), DABCO (20 mol-%) in toluene at room temperature]
in hand, we next turned our attention to the scope and limita-
tions of this interesting annulation reaction by using a variety
of C,N-cyclic azomethine imines 1 with δ-acetoxyallenoates 2,
Results and Discussion
Initial optimization experiments were conducted with C,N-cyclic and the results are summarized in Table 2. We examined the
azomethine imine 1a and δ-acetoxyallenoate 2a as model sub- reaction of C,N-cyclic azomethine imine 1a as the substrate
strates. Given the large number of annulations of azomethine with substituted δ-acetoxyallenoates 2b–h and found that sub-
imines with electron-deficient alkenes and electron-deficient strates 2b–f with electron-donating or electron-withdrawing
allenoates in the absence of an organocatalyst or metal catalyst substituents on the aromatic ring gave the corresponding prod-
that are known,[14a,15,16] the potential background reaction for ucts 3b–f in good yields (up to 86 % yield) and 4b–f in moder-
the direct annulation of 1a with 2a was first examined in tolu- ate yields (53–68 % yields) (Table 2, Entries 1–5). If R3 was a
ene at room temperature for 6 h, and we found that unex- hydrogen atom (R3 = H), this annulation reaction only afforded
pected cycloadduct 3a was obtained in 39 % yield (Table 1, the corresponding product 3g in 37 % yield along with 4g in a
Entry 1). Raising the reaction temperature to 50 °C afforded the trace amount (Table 2, Entry 6). The configuration of 3g was
corresponding product 3a in 46 % yield within 3 h (Table 1, assigned by X-ray diffraction. Its ORTEP drawing is shown in
Entry 2). To improve the yield of 3a, azomethine imine 1a was Figure 2, and the corresponding crystallographic data are pre-
treated with 2a (2.0 equiv.) in the presence of PPh3 (20 mol-%) sented in the Supporting Information.[17] If R3 was a methyl
at room temperature for 6 h. Delightfully, the corresponding group (R3 = Me), the reaction afforded the desired product 3h
[3+2] product 3a was afforded in 93 % yield along with ethyl in 86 % yield and 4h in 74 % yield (Table 2, Entry 7). Using δ-
(Z)-3-acetoxy-5-phenyl-3-tosylpent-4-enoate (4a) in 38 % yield acetoxyallenoate 2a or 2h as the substrate, we next examined
(Table 1, Entry 3). To further improve the yield of 4a, some the substrate scope of the C,N-cyclic azomethine imines. As for
tertiary amines, including 1,4-diazobicyclo[2.2.2]octane azomethine imines, irrespective of a 7-methyl or 5-methyl sub-
Table 1. Optimization of the reaction conditions for the [3+2] annulation of 1a and 2a.
Entry
Catalyst
Solvent
Time [h]
Yield [%][a]
3a
4a
1
2[b]
3
4
5
6
7
8
9
–
–
PPh3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
6
3
6
6
6
6
6
6
6
6
6
6
39
46
93
88
73
86
72
79
78
47
64
50
–
–
38
72
86
66
76
89
68
56
55
48
DABCO
DMAP
DBU
imidazole
Et3N
DABCO
DABCO
DABCO
DABCO
10
11
12[c]
CH2Cl2
MeCN
toluene
[a] Yield of isolated product. [b] The reaction mixture was stirred at 50 °C. [c] The catalyst loading was reduced to 10 mol-%.
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Table 2. Substrate scope of the [3+2] annulation of C,N-cyclic azomethine imine 1 with δ-acetoxyallenoate 2.
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), and DABCO (0.04 mmol) were stirred in toluene (2.0 mL) at r.t. for 6 h. [b] Yield of isolated product.
stituent on the aromatic ring, the reaction with 2a or 2h pro-
ceeded very well to produce the corresponding products 3 and
4 in good yields (Table 2, Entries 8, 9, 11, and 12). Azomethine
imine 1d having a condensed ring structure was also compati-
ble with the reaction conditions, and it afforded tetracyclic
products 3k or 3n in 71 % yields and 4h or 4a in 72 or 63 %
yield, respectively (Table 2, Entries 10 and 13). If R2 was a steri-
cally more bulky 2,4,6-trimethylphenyl moiety, the correspond-
ing cycloadduct 3a was obtained in high yield (92 %) but was
formed along with 4i in a trace amount, perhaps as a result
of steric effects (Table 2, Entry 14). Notably, these N,N-cyclic
azomethine imines were also used by Tong and co-workers in
the reaction with the same δ-acetoxyallenoates, which led to
2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one derivatives in
moderate yields.[15]
A plausible mechanism for this tertiary-amine-catalyzed
[3+2] cycloaddition along with the production of ethyl (Z)-3-
acetoxy-3-tosylpent-4-enoate at the same time is proposed in
Figure 2. X-ray crystal structure of product 3g.
Scheme 2 on the basis of our experimental results and previous product 3a. The release of Ts– along with the production of
literature.[13l,15,18] The addition of DABCO to allenoate 2a gener- stable product 3a provides the thermodynamic driving force
ates intermediate A through 1,2-elimination of the acetate an- for this cyclization. As for the formation of 4a, Ts– attacks the
ionic group, which undergoes subsequent addition with 1a to ꢀ-position of allenoate 2a and removes an acetate anion to
yield intermediate B. Intermediate B undergoes intramolecular afford intermediate G, which undergoes Michael addition with
Michael addition to form intermediate C, which is converted the acetate anion and an intermolecular proton-transfer process
into intermediate D through an intermolecular proton-transfer to give product 4a along with the formation of the acetate
process. Then, 1,2-elimination of the DABCO catalyst leads to anion again. The two reaction processes assist each other
intermediate E. Moreover, intermediate E likely undergoes an- through the generation of the acetate anion and Ts– for inter-
other intermolecular proton-transfer process to form intermedi- molecular proton transfer and intermolecular nucleophilic at-
ate F, and the final elimination of Ts– from intermediate F gives tack, respectively, to produce compounds 3 and 4 smoothly.
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Keywords: Amines · Annulation · Azo compounds ·
Nitrogen heterocycles · Synthetic methods
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We established DABCO-catalyzed divergent [3+2] annulations
of C,N-cyclic azomethine imines with δ-acetoxyallenoates to af-
ford 5,6-dihydropyrazolo[5,1-a]isoquinolines and ethyl (Z)-3-
acetoxy-3-tosylpent-4-enoates in moderate to good yields in a
one-pot manner under mild conditions. A plausible reaction
mechanism was proposed on the basis of previous literature
and our own results. The two reactions assist each other to give
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Experimental Section
General Procedure: Under argon, δ-acetoxyallenoate 2 (0.4 mmol)
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1
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Acknowledgments
This work was supported by the Joint NSFC-ISF Research Pro-
gram, funded by the National Natural Science Foundation of
China and the Israel Science Foundation. We are also grateful
for financial support from the National Basic Research Program
of China [(973)-2015CB856603] and the National Natural Sci-
ence Foundation of China (20472096, 21372241, 21361140350,
20672127, 21421091, 21372250, 21121062, 21302203,
20732008, and 21572052).
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Received: May 11, 2016
Published Online: July 4, 2016
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