Phosphine-catalyzed [3+2] cycloaddition reactions of azomethine imines with electron-deficient alkenes: A facile access to dinitrogen-fused heterocycles

Article abstract of DOI:10.1002/chem.201303625

An efficient method for the phosphine-catalyzed [3+2] cycloaddition reaction of azomethine imines with diphenylsulfonyl alkenes to give dinitrogen-fused bi- or tricyclic heterocyclic compounds in high yields has been described. Moreover, two phenylsulfony

Full text of DOI:10.1002/chem.201303625

DOI: 10.1002/chem.201303625
Full Paper
&
Organic Synthesis
Phosphine-Catalyzed [3+2] Cycloaddition Reactions of
Azomethine Imines with Electron-Deficient Alkenes: A Facile
Access to Dinitrogen-Fused Heterocycles
Zhen Li, Hao Yu, Honglei Liu, Lei Zhang, Hui Jiang, Bo Wang, and Hongchao Guo*[a]
Abstract: An efficient method for the phosphine-catalyzed
[3+2] cycloaddition reaction of azomethine imines with di-
phenylsulfonyl alkenes to give dinitrogen-fused bi- or tricy-
clic heterocyclic compounds in high yields has been de-
scribed. Moreover, two phenylsulfonyl groups installed on
the heterocyclic products could be conveniently removed or
transformed to other functional groups, making the reaction
more useful.
Introduction
dene-d-valerolactones
gave
tetrahydropyrazolodiaze-pi-
nones.[15] Au-catalyzed [3+3] annulation of azomethine imines
with propargyl esters[16] and N-heterocyclic carbene-catalyzed
stereoselective formal [3+3] cycloaddition reactions of azome-
thine imines with enals[17] provided tetrahydropyrazolopyridazi-
nones. Rh-catalyzed [3+3] annulation of azomethine imines
with enoldiazoacetate led to pyrazolidinone derivatives.[18] Ti-
or Brønsted acid-catalyzed [3+2] cycloaddition reactions of
azomethine imines with alkenes delivered tricyclic tetrahydro-
isoquinoline derivatives.[19] Ni-catalyzed [3+3] cycloaddition re-
actions of aromatic azomethine imines with 1,1-cyclopropane
diesters gave unique tricyclic dihydroquinoline derivatives.[20]
Multifunctional primary-amine-catalyzed [3+2] cycloaddition
reactions of azomethine imines and cyclic enones[21] furnished
tetrahydropyrazolone-fused tricyclic heterocycles. All these re-
actions demonstrate that the cycloaddition reactions based on
azomethine imines are very useful for the synthesis of hetero-
cyclic compounds with interesting structures.
Dinitrogen-fused heterocycles are present in many pharma-
ceuticals, agrochemicals, biologically active compounds, and
other useful chemicals. Among these compounds (Figure 1),
pyrazolone derivatives are important dyes in the food, textile,
photography, and cosmetics industries.[1] Phenazone is an old
analgesic and antipyretic drug,[2] phenylbutazone displays anti-
inflammatory activity,[2] phenidone can inhibit lipoxygenase,[3]
BW357U has anorectic activity.[4] Tetrahydropyrazolopyrazo-
lones have been studied as antibacterial agents,[2] antitumor
agents,[5] calcitonin agonists,[6] anti-Alzheimer agents,[7] and
herbicides and pesticides.[8] Therefore, new synthetic method-
ologies for the synthesis of dinitrogen-fused heterocycles have
attracted much attention. Among various methods, the cyclo-
addition reactions based on azomethine imines are practical
and efficient methods, and have been extensively investigat-
ed.[9]
Numerous metal-catalyzed and organocatalytic cycloaddi-
tions of azomethine imines could be employed for the synthe-
sis of diverse dinitrogen-fused heterocycles.[10] Cu, Ni, or di-
arylprolinol salt-catalyzed [3+2] cycloaddition reactions of azo-
methine imines with alkenes[11] and gold(I)-catalyzed [3+2] cy-
cloaddition reactions of azomethine imines with N-allenyl
amides[12] afforded tetrahydropyrazolopyrazolones. Cu-cata-
lyzed [3+2] cycloadditions of azomethine imines with alkynes
provided an efficient protocol for the synthesis of dihydropyra-
zolopyrazolone.[13] Pd-catalyzed [3+3] cycloadditions of azome-
thine imines with trimethylenemethane produced hexahydro-
pyridazine derivatives under mild conditions.[14] Pd-catalyzed
[4+3] cycloadditions of azomethine imines with g-methyli-
Most recently, we developed phosphine-catalyzed [3+2],
[3+3], [4+3], and [3+2+3] annulation reactions of N,N’ or C,N-
cyclic azomethine imines with allenoates, affording biologically
important dinitrogen-fused heterocycles, such as tetrahydro-
pyrazolopyrazolone, tetrahydropyrazolopyridazinone, tetrahy-
dropyrazolodiazepinone, tetrahydropyrazolodiazocinone, tricy-
clic dihydroisoquinoline, and tetrahydroisoquinoline deriva-
[a] Z. Li, H. Yu, H. Liu, L. Zhang, H. Jiang, B. Wang, Prof. Dr. H. Guo
Department of Applied Chemistry, China Agricultural University
2 West Yuanmingyuan Road, Beijing 100193 (P.R. China)
Fax: (+86)10-6281-5579
E-mail: hchguo@cau.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303625.
Figure 1. Selected examples of biologically active dinitrogen-fused heterocy-
cles.
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tives.[22] Inspired by this work, we conceived the possibility of
introducing electron-deficient olefins to react with azomethine
imines to furnish [3+2] cycloaddition reactions under phos-
phine catalysis conditions. Nucleophilic phosphine catalysis has
emerged as an efficient tool to prepare carbo- and heterocy-
cles.[23] Generally, in most of the phosphine-catalyzed cycload-
ditions, activated allenes, alkynes, Morita–Baylis–Hillman (MBH)
carbonates and acetates acted as electrophiles to be attacked
by phosphine to give active zwitterions, which then react with
electrophilic coupling partners, leading to various annulation
reactions.[23] The electron-deficient alkenes had often been
used as electrophilic coupling reagents to accomplish the cy-
cloaddition reactions,[23] and seldom employed as an electro-
phile to react with phosphine to form active zwitterions for
conducting further annulation reactions. Herein, we report the
first example of phosphine-catalyzed [3+2] cycloaddition reac-
tions of various azomethine imines with electron-deficient phe-
nylsulfonyl alkenes.
nucleophilicity were screened (entries 2–9). Using 20 mol% of
PPh3, the azomethine imine 1a was treated with 1.5 equiva-
lents of 2a for 48 h; delightfully, the [3+2] product 3a could
be obtained in 76% yield (entry 2). Unfortunately, the product
is a mixture of several diastereomers, which could not be sepa-
rated by flash column and could also not completely be sepa-
rated on several commercially available chiral columns by
HPLC analysis. Moreover, the NMR spectrum of the product 3a
looks like the data of a pure compound. Therefore, the diaste-
reomeric ratio of the cycloaddition reactions could not be de-
termined. In Table 1, only the isolated yields of the product 3a
as a diastereomeric mixture were reported. Next, screening re-
vealed that several other phosphines could also catalyze the
cycloaddition reaction, giving the corresponding product in
moderate to good yields (entries 3–9). Among these phos-
phines, MePPh2 gave the best yield of 84% (entry 5). Some ter-
tiary amines, such as Et3N, 1,4-diazobicyclo[2.2.2]octane
(DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 4-di-
methylaminopyridine (DMAP), have also been examined for im-
proving yields (entries 10–13). These amine catalysts could also
enable the reaction to give the corresponding products, albeit
in moderate yields. To achieve asymmetric cycloaddition, sever-
al commercially available chiral phosphines, such as 2,2’-bis-
(diphenylphosphino)-1,1’-binaphthyl (BINAP) and (+)-1,2-
bis[(2R,5R)-2,5-diethylphospholano]ethane (BPE), have been
tried in the reaction of azomethine imine 1a with 2a, but the
racemic product was obtained. These results have been includ-
ed in the Supporting Information.
Results and Discussion
Initial optimization experiments were conducted with N,N’-
cyclic azomethine imine 1a and commercially available (Z)-1,2-
bis(phenylsulfonyl)ethylene (2a) as the model substrates. Since
numerous cycloadditions of azomethine imines with electron-
deficient alkenes in the absence of metal catalyst or organoca-
talyst are known,[24] the potential background reaction from
direct cycloaddition of 1a with 2a was first investigated. The
reaction of 1a and 2a was carried out in 1,2-dichloroethane at
808C in the absence of catalyst for 48 h. TLC monitoring re-
vealed no new spot was generated and the substrate 1a was
almost not consumed (Table 1, entry 1), therefore the back-
ground reaction at room temperature could be excluded.
Then, several commercially available phosphines with different
With the optimized conditions established (1 (1 equiv), 2a
(1.5 equiv), MePPh2 (20 mol% in CH2Cl2)), the scope of the sub-
strate 1 was examined (Table 2). Various N,N’-cyclic azomethine
imines bearing different substituents on the benzene rings car-
ried out the [3+2] cycloaddition, giving the tetrahydro-1H,5H-
pyrazolo[1,2-a]pyrazol-1-one derivatives in 69–93% yields
(Table 2, entries 1–21). Azomethine imines bearing electron-do-
nating groups on the benzene ring afforded excellent yields of
the cycloadducts (entries 2–4). Azomethine imines bearing
electron-withdrawing groups on the benzene ring also worked
smoothly to provide the corresponding products in high yields
(entries 5–18), but those azomethine imines with strong elec-
tron-withdrawing groups (NO2, CN, CF3) on the benzene ring
resulted in slightly lower yields (entries 14–18) relative to other
azomethine imines. Interestingly, for those azomethine imines
with halo substituents on the benzene ring, azomethine
imines containing meta-substituted benzene rings provided
the corresponding cycloadducts in a somewhat lower yield
than those azomethine imines bearing ortho- or para-substitut-
ed benzene rings (entries 5–13). The azomethine imines bear-
ing 1-naphthyl, 2-naphthyl, and 2-furyl groups, were also suita-
ble substrates, readily giving the corresponding cycloadducts
in 70–84% yields (entries 19–21). Very satisfactorily, when alkyl
imine was employed, the yield of the cycloadduct reached an
excellent 90% (entry 22). Disappointingly, in most cases, the
diastereomeric mixture of the products could not be separated
by chiral HPLC analysis. The diastereomeric mixtures of only
3e, 3 f, 3p, 3s, and 3t were barely separated. In these cases,
without exception, all diastereomeric ratios were unanimously
Table 1. Optimization of reaction conditions for [3+2] cycloaddition reac-
tions of N,N’-cyclic azomethine imines with diphenylsulfonyl alkenes.[a]
Entry
Catalyst
T [8C]
Yield [%][b]
1[c]
2
3
4
5
6
7
8
–
PPh3
Bu3P
80
25
25
25
25
25
25
25
25
25
25
25
25
0
76
72
80
84
72
74
50
67
61
72
63
35
Me2PPh
MePPh2
n-PrPPh2
iPrPPh2
tBuPPh2
CyPPh2
Et3N
DABCO
DBU
DMAP
9
10
11
12
13
[a] 1.5 equiv of 2a was used. [b] Isolated yield. [c] Without catalyst and
with 1,2-dichloroethane as the solvent.
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Table 2. MePPh2-catalyzed [3+2] cycloaddition reactions of azomethine
imines 1 with the alkene 2a.[a]
Table 3. Optimization of reaction conditions for [3+2] cycloaddition reac-
tions of C,N-cyclic azomethine imine 4a with (Z)-1,2-bis(phenylsulfonyl)-
ethylene (2a).[a]
Entry
R
Product
Yield [%][b]
d.r.[c]
[d]
Entry
Catalyst
Yield [%][b]
1
2
3
4
5
6
7
8
Ph (1a)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
84
87
93
88
82
76
86
85
76
82
85
80
86
71
73
76
69
72
84
82
70
90
–
–
–
–
1[c]
2
3
4
5
6
7
8
–
0
80
88
75
87
85
87
87
4-MeC6H4 (1b)
4-OMeC6H4 (1c)
4-iPrC6H4 (1d)
2-FC6H4 (1e)
Me2PPh
MePPh2
PPh3
Et3N
DABCO
DBU
(>99:1)
(98:2)
3-FC6H4 (1 f)
4-FC6H4 (1g)
2-ClC6H4 (1h)
3-ClC6H4 (1i)
–
–
–
–
–
–
–
–
9
DMAP
10
11
12
13
14
15
16
17
18
19
20
21
22
4-ClC6H4 (1j)
2-BrC6H4 (1k)
3-BrC6H4 (1l)
4-BrC6H4 (1m)
2-NO2C6H4 (1n)
3-NO2C6H4 (1o)
4-NO2C6H4 (1p)
4-CNC6H4 (1q)
4-CF3C6H4(1r)
1-naphthyl (1s)
2-naphthyl (1t)
2-furanyl (1u)
cyclohexyl (1v)
[a] 1.2 equiv of 2a was used. [b] Isolated yields. [c] Without catalyst and
using 1,2-dichloroethane as the solvent.
–
(>99:1)
–
dure (Table 3, entry 1). Then, several commercially available
Lewis base catalysts were evaluated. The screening results indi-
cated that at room temperature and with dichloromethane as
the solvent, all these catalysts could efficiently catalyze the cy-
cloaddition reaction, providing the corresponding [3+2] cyclo-
adduct in 75–88% yield (entries 2–8). MePPh2 afforded the
highest yield of 88% (entry 3). Although the product 5a was
observed as a spot on TLC, it is a diastereomeric mixture. Un-
fortunately, the mixture could not be separated on several
commercially available chiral columns by HPLC analysis. When
using MePPh2 as the catalyst, the scope of the C,N-cyclic azo-
methine imines was investigated (Table 4). The reaction is tol-
erant to a range of azomethine imines (4b–f), providing
a series of the corresponding cycloadducts in 82–93% yields.
Electron-donating alkyl-substituted azomethine imines provid-
ed slightly higher yields than those with electron-withdrawing
groups (entries 2, 3 vs. 4, 5, 6). The X-ray crystallographic struc-
ture of the major diastereomer of 5a is shown in Figure 3.[25]
Any two adjacent groups among the two phenylsulfonyl
groups and benzoyl group are oriented in opposing directions.
–
3s
3t
3u
3v
(98:2)
93:7
–
–
[a] 1.5 equiv of 2a was used. [b] Isolated yield. [c] By HPLC analysis on
chiral column. [d] The diastereomeric mixtures of these products
a
couldn’t be separated by a chiral column.
excellent (entries 5, 6, 16, 19, 20). The relative stereochemistry
of the major diastereomer was assigned by X-ray crystallogra-
phy of tetrahydropyrazolopyrazolone 3h (Figure 2).[25] The crys-
tals of 3h were obtained in >70% yield, which indicated that
the crystals were from the major diastereomer. In the crystallo-
graphic structure of 3h, 5-aryl and 6-phenylsulfonyl are orient-
ed homolateral in the plane; moreover, there is a strong p–p
stacking between them, which allows the configuration to be
more favorable. The 7-phenylsulfonyl group is oriented in the
opposing direction of 5-aryl and 6-phenylsulfonyl.
Next, we explored the [3+2] cycloaddition of C,N-cyclic azo-
methine imines 4 with (Z)-1,2-bis(phenylsulfonyl)ethylene (2a).
As shown in Table 3, the reaction conditions were first opti-
mized with azomethine imines 4a as the model substrate. The
background reaction was first excluded by the above proce-
Table 4. MePPh2-catalyzed [3+2] cycloaddition of C,N-cyclic azomethine
imines 4 with (Z)-1,2-bis(phenylsulfonyl)ethylene (2a).[a]
Entry
R
Product
Yield [%][b]
1
2
3
4
5
6
H (4a)
5a
5b
5c
5d
5e
5 f
88
88
93
87
82
84
5-Me (4b)
7-Me (4c)
6-Br (4d)
7-Br (4e)
7-Cl (4 f)
[a] 1.2 equiv of 2a was used. [b] Isolated yield.
Figure 2. The X-ray crystallographic structure of 3h.
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Figure 3. The X-ray crystallographic structure of 5a.
We also examined the reaction of azomethine imines 1a or
4a with (E)-1,2-bis(phenylsulfonyl)ethylene (2b) (Scheme 1). As
expected the reactions worked efficiently to give the same
products as the products from (Z)-1,2-bis(phenylsulfonyl)ethy-
lene (2a), namely 3a and 5a, respectively. This indicated that
the configuration of the double bond in 2a or 2b has no influ-
ence on the reaction activity and stereoselectivity.
Scheme 2. MePPh2-catalyzed [3+2] cycloadditions of aromatic azomethine
imines with (Z)-diphenylsulfonylethylene (2a).
Scheme 1. MePPh2-catalyzed [3+2] cycloadditions of azomethine imines
with (E)-1,2-bis(phenylsulfonyl)ethylene (2b).
Figure 4. The X-ray crystallographic structure of 7.
Besides N,N’-cyclic azomethine imines 1 and C,N-cyclic azo-
methine imines 4, several aromatic azomethine imines (6, 8,
10, and 12) had also been studied (Scheme 2a–d). All these
azomethine imines were suitable substrates, and carried out
[3+2] cycloaddition reactions to give the corresponding prod-
ucts (7, 9, 11, and 13) in 79–94% yields. The X-ray crystallo-
graphic structure of the major diastereomer of 7 is shown in
Figure 4.[25] Its configuration is similar to that of 5a. Any two
adjacent groups among two phenylsulfonyl groups and benzo-
yl group are oriented in opposing directions.
cycloadduct. Satisfactorily, the MePPh2-catalyzed cycloaddition
reaction of 2d with C,N-cyclic imine 4a proceeded well, giving
the corresponding product 16 in 70% yield and the thermal
cycloaddition product was obtained in <5% yield. Very disap-
pointedly, under the standard phosphine catalysis conditions,
the thermal cycloaddition reaction of dimethyl fumatate 2e
with either 1a or 4a dominated the reaction process, forming
Next, we examined the activity of methyl (E)-3-(phenylsulfo-
nyl)acrylate (2c), diethyl maleate (2d), and dimethyl fumatate
(2e) in the [3+2] cycloaddition with azomethine imine
(Scheme 3). The background reaction from direct [3+2] cyclo-
addition of 1a with 2c at room temperature was excluded ac-
cording to the above-mentioned procedure. Employing
20 mol% of MePPh2 as the catalyst, the reaction proceeded at
room temperature for 48 h to give the target [3+2] cycload-
duct 14 in 66% yield. In contrast, using diethyl maleate (2d) as
the substrate, its thermal cycloaddition reaction with azome-
thine imine 1a could not be avoided at room temperature,
leading to the corresponding product in 20% yield, and its
phosphine-catalyzed cycloaddition reaction with azomethine
imine 1a worked inefficiently, affording the cycloaddition prod-
uct 15 in 36% yield, which is the diastereomer of the thermal
Scheme 3. MePPh2-catalyzed [3+2] cycloadditions of azomethine imines
with (E)-3-(phenylsufonyl)acrylate (2c) and diethyl maleate (2d).
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the thermal cycloadduct, and a little phosphine-catalyzed cy-
cloadduct was observed on the TLC analysis. This indicated
that the configuration of the double bond in 2d and 2e has
a remarkable influence on the reaction activity, and (E)-alkene
2e was more likely to undergo the thermal cycloaddition.
The proposed mechanism for phosphine-catalyzed [3+2] cy-
cloaddition of the azomethine imine and electron-deficient
alkene is presented in Scheme 4. The zwitterion A from conju-
gate addition of phosphine to the alkene 2 attacks azomethine
imine to give the intermediate B. Next intramolecular nucleo-
philic attack accomplishes the [3+2] cyclization and regener-
ates the catalyst forming the final [3+2] cycloaddition product.
product 3n also underwent alcoholysis to give the derivative
20 in 89% yield, the structure of which was unambiguously
determined by the X-ray crystallographic structure (Figure 5).[25]
Figure 5. The X-ray crystallographic structure of 18.
The phenylsulfonyl groups could be removed by reduction.
First, the dry methanol and cleaned magnesium turnings were
mixed and stirred, then 3a was added and stirring was contin-
ued until reduction was completed, leading to reductive desul-
fonylation product 18 in 75% yield. The modified Barton–Zard
reaction of 3a with ethyl isocyanoacetate in the presence of
potassium tert-butoxide gave an interesting tricyclic heterocy-
cle 19 in 70% yield, which has never been reported before
and might find potential application in bioactivity exploration.
When the product 5a was treated with magnesium in metha-
nol at 508C, 5,6-dihydropyrazolo[5,1-a]isoquinoline (21), which
was synthesized by an intramolecular palladium-catalyzed CÀH
bond activation by Heo in 2010, was obtained in 78% yield.[26]
Compared with Heo’s method, this procedure is more concise.
In summary, we have developed an efficient phosphine-cata-
lyzed [3+2] cycloaddition of azomethine imines with diphenyl-
sulfonyl alkenes with broad substrate variables, providing dini-
trogen-fused heterocyclic compounds in high yields. The reac-
tion provided a practical synthetic method for bicyclic or tricy-
clic heterocycles, which would be interesting in the study of
bioactivities. Moreover, two phenylsulfonyl groups installed on
the heterocyclic products could be conveniently removed or
transformed to other functional groups, making the reaction
more useful.
Scheme 4. Putative mechanism of phosphine-catalyzed [3+2] cycloaddition.
The next synthetic transformations demonstrated that these
products are versatile synthons (Scheme 5). Since the sulfonyl
group always acts as an activating group in many synthetic
methodologies, further elaboration was very easily. When the
phenylsufonyl-substituted dinitrogen-fused heterocycle 3a was
treated in methanol at room temperature, the phenylsufonyl
group at the 7-position of 3a was smoothly substituted by
methoxy to give the alcoholysis product 17 in 86% yield. The
Experimental Section
General procedure for the phosphine-catalyzed [3+2] cyclo-
addition reaction
An oven-dried Schlenk tube (15 mL) was charged with azomethine
imine (0.125 mmol), CH2Cl2 (5 mL), and 1,2-bis(phenylsulfonyl)ethy-
lene (0.15 mmol or 0.19 mmol) at room temperature. Then, catalyst
(0.025 mmol) was added to the above solution. The reaction mix-
ture was stirred at room temperature for 48 h, and was then con-
centrated. The residue was purified by flash column (ethyl acetate/
petroleum ether) to afford the corresponding product.
Acknowledgements
This study was supported by the National Natural Science
Foundation of China (no. 21172253, 21372256), the Program
Scheme 5. Synthetic transformations of the cycloadducts.
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Keywords: alkenes
cycloaddition reactions · phosphine
·
azomethine imine
·
catalysis
·
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Received: September 13, 2013
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Published online on January 8, 2014
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