Multicomponent domino reactions of acetylenedicarboxylates: Divergent synthesis of multi-functionalized pyrazolones and C-tethered bispyrazol-5-ols

Article abstract of DOI:10.1016/j.tetlet.2012.04.051

An efficient and practical methodology of selectively divergent synthesis of arylidene pyrazolones and C-tethered bispyrazol-5-ols via multicomponent domino reactions of acetylenedicarboxylates, phenylhydrazine and aromatic aldehydes has been developed. T

Full text of DOI:10.1016/j.tetlet.2012.04.051

Tetrahedron Letters 53 (2012) 3169–3172
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Tetrahedron Letters
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Multicomponent domino reactions of acetylenedicarboxylates: divergent
synthesis of multi-functionalized pyrazolones and C-tethered bispyrazol-5-ols
⇑
⇑
Xing-Chao Tu, Hui Feng, Man-Su Tu, Bo Jiang , Shu-Liang Wang, Shu-Jiang Tu
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Xuzhou Normal University,
Xuzhou 211116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 February 2012
Revised 2 April 2012
Accepted 12 April 2012
Available online 21 April 2012
An efficient and practical methodology of selectively divergent synthesis of arylidene pyrazolones and
C-tethered bispyrazol-5-ols via multicomponent domino reactions of acetylenedicarboxylates, phen-
ylhydrazine and aromatic aldehydes has been developed. The electron-donating aryl groups (EDAG)-
attached aldehydes resulted in the pyrazolone skeleton, whereas the electron-withdrawing aryl groups
(EWAG) led to the C-tethered bispyrazol-5-ols with simultaneous formation of two new pyrazole rings.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Divergent synthesis
Arylidene pyrazolones
C-tethered bispyrazol-5-ols
Multicomponent domino reactions
RO2C
N
The development of new methodologies aimed at improving
synthetic efficiency is an important goal in contemporary organic
synthesis. Multicomponent domino reactions (MDRs), which in-
volve several bond-forming reactions in a one-pot manipulation,
represent an attractive strategy in the facile assembly of molecular
architecture.1,2 Such reactions are able to create combinatorial li-
braries of complex and diverse structures in efficient fashion by
virtue of their convergent nature. Several new designed multicom-
ponent reactions have been reported recently,3,4 including pro-
cesses that take advantage of Huisgen 1,4-dipoles formed from
the addition of nitrogen heterocycles or amines to electron-defi-
cient alkynes.5–10 Thus, domino reactions involving primary
amines, acetylenedicarboxylates and a third component have been
provided elegant procedures for the synthesis of various N- and
N,O-heterocycles.11–14 Still, the continuous development of new
multicomponent domino reactions for the synthesis of multi-func-
tionalized heterocycles from activated acetylenes is of great value.
Very recently, we have developed a series of multicomponent
domino reactions (MDRs) that provided easy access to multiple
functionalized ring structures of chemical and pharmaceutical
interest.15,16 During our continuous efforts on the development
of useful multi-component domino reactions, herein, we would
like to report another new divergent approach to regioselective
synthesis of multi-functionalized pyrazolones and C-tethered bis-
pyrazol-5-ols through the control of electronic effect of aryl
CO2R
NH2 Ar
+
Three-component
Ar = EDAG
Ar
+
HN
Ar1
O
N
O
Ar1
CO2R
1
3
2
4
Ar
RO2C
N
CO2R
Five-component
Ar = EWAG
N
N
Ar1
HO
OH
N
Ar1
5
Scheme 1. The divergent synthesis of multi-functionalized pyrazolones and
C-tethered bispyrazol-5-ols.
Ar
RO2C
N
CO2R
CO2R
Ar
NH2
+
2 HN
Ar1
2
+
N
N
O
HO
OH
N
CO2R
1
Ar1
Ar1
3
2
Ar = EWAG
5
Scheme 2. The synthesis of C-tethered bispyrazol-5-ols.
aldehydes (Scheme 1). This reaction was achieved from the same
starting materials such as aromatic aldehyde, aryl hydrazine and
acetylenedicarboxylates in HOAc under microwave irradiation.
The great aspect of the present domino reaction is shown by the
fact that the selective construction of pyrazolone or C-tethered
⇑
Corresponding authors. Tel./fax: +86 516 83500065.
E-mail addresses: jiangchem@xznu.edu.cn (B. Jiang), laotu@xznu.edu.cn
(S.-J. Tu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.051

3170
X.-C. Tu et al. / Tetrahedron Letters 53 (2012) 3169–3172
Table 1
employed in this system were replaced by their electron-with-
Solvent optimization for the synthesis of 4a
drawing counterparts, the reaction occurred to another direction
to form multi-functionalized C-tethered bispyrazol-5-ols 5 that be-
long to another family of important scaffolds for organic synthesis
and drug design in pharmaceutical sciences such as fungicides,
pesticides, insecticides and dyestuffs, and as the chelating and
extracting reagents for different metal ions as well.17 Thus, it is
clear that the divergent pathways were controlled by the electronic
effects of various groups on phenyl ring.
Entry
Solvent
Time (min)
Yielda (%)
1
2
3
4
THF
EtOH
HOCH2CH2OH
AcOH
10
10
10
10
8
39
53
81
a
Isolated yield.
Next, with the aim to improve the yields of 5a in Scheme 2, we
increased the amount of acetylenedicarboxylates and phenylhydr-
azine simultaneously to the feed ratio of 1a–2–3 in 2:2:1 (Scheme
2). After several trials, we found that the reaction in acidic condi-
tion resulted in product 5a in 89% chemical yield at room temper-
ature. Under the optimized conditions mentioned above, the scope
of this new MCR process was next examined using various readily
available starting materials. As revealed in Table 2, a range of
invaluable C-tethered bispyrazol-5-ols 5 can be synthesized in
good to excellent yields. The results indicated that aromatic alde-
hydes bearing diverse electron-withdrawing functional groups
such as nitro, fluoro, chloro or bromo were suitable for the synthe-
sis of compounds 5.
Moreover, the different heterocyclic aldehydes were further
examined. The electron-donating heterocyclic aldehydes such as
thiophene-2-carbaldehyde 3f, indole-3-carbaldehyde 3g resulted
in the corresponding arylidene pyrazolones 4h–4k (Table 2, entries
8–11), whereas C-tethered bispyrazol-5-ol derivatives 5h , 5i were
generated when electron-withdrawing heterocyclic counterpart 3l
was employed (Table 2, entries 19 and 20). Thus, it may be found
that the nature of substituent on formyl group played a crucial role
in controlling the chemoselectivity. To further examine the scope
of the methodology, other aryl hydrazines were employed, such
as electron-donating component 2b and electron-withdrawing
group 2c. Pleasantly, the corresponding arylidene pyrazolones 4l
(Table 2, entry 12) and C-tethered bispyrazol-5-ol derivatives 5j,
5k (Table 2, entries 22 and 23) were generated, respectively.
As shown in Figures 1 and 2, X-ray diffraction of single crystals
of pyrazolones 4b and C-tethered bispyrazol-5-ols 5d has been
bispyrazol-5-ols skeleton was readily achieved via HOAc promoted
divergent reaction in a one-pot operation. The electron-donating
aryl groups (EDAG)-attached aldehydes resulted in the pyrazolone
skeleton, whereas the electron-withdrawing aryl groups (EWAG)
led to the C-tethered bispyrazol-5-ols with simultaneous forma-
tion of two new pyrazole rings.
We devoted our efforts to the study of the reaction of dimethyl
acetylenedicarboxylate (DMAD, 1a) and phenylhydrazine 2 with 4-
methylbenzaldehyde 3a as a model reaction. Experiments were
carried out in various solvents such as ethylene glycol, THF, etha-
nol and HOAc. Unfortunately, the reaction scarcely proceeded in
THF at room temperature. The incomplete reaction was observed
in ethylene glycol or ethanol.
When HOAc was used as the solvent, the reaction proceeded
(Table 1) smoothly and the product 4a was successfully isolated
in 81% yield after 10 min at the room temperature.
With this result in hand, we went on to study the scope of the
methodology. Using the optimized reaction conditions, a variety
of structurally diverse aromatic aldehydes were investigated, and
a series of new multi-functionalized pyrazolones were afforded
in good yields. As shown in Table 2, at the beginning, we made a
search for the aldehyde substrate scope, acetylenedicarboxylates
1 (dimethyl acetylenedicarboxylate, 1a; diethyl acetylenedicarbox-
ylate, 1b) and phenylhydrazine 2a were used as model substrates
(Table 2), and the results indicated that aromatic aldehydes bear-
ing electron donating groups such as methyl, dimethylamino, or
methoxyl were able to affect the synthesis of compound 4. Inter-
estingly, when aromatic aldehydes with electron-donating groups
Table 2
Syntheses of arylidene pyrazolones 4 and bispyrazoles 518,19
Entry
4 or 5a
Ar
Ar1
R
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-Tolyl (3a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
4-Methoxyphenyl (2b)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Methyl (1a)
Ethyl (1b)
Methyl (1a)
Ethyl (1b)
Methyl (1a)
Ethyl (1b)
Ethyl (1b)
Methyl (1a)
Ethyl (1b)
Methyl (1a)
Ethyl (1b)
Methyl (1a)
Methyl (1a)
Methyl (1a)
Ethyl (1b)
Methyl (1a)
Ethyl (1b)
10
10
12
12
15
15
13
15
15
18
18
17
18
15
20
18
19
15
18
20
22
25
25
81
79
85
86
91
90
83
89
88
92
91
89
89
86
89
91
89
82
79
78
75
84
79
4-Methoxyphenyl (3b)
3,4-Dimethoxyphenyl (3c)
3,4-Dimethoxyphenyl (3c)
3,4,5-Trimethoxyphenyl (3d)
3,4,5-Trimethoxyphenyl (3d)
4-Dimethylaminophenyl (3e)
Thiophen-2-yl (3f)
Thiophen-2-yl (3f)
1-H-indol-3-yl (3g)
1-H-indol-3-yl (3g)
3,4,5-Trimethoxyphenyl (3d)
4-Chlorophenyl (3i)
4-Fluorophenyl (3h)
4-Chlorophenyl (3i)
4-Bromophenyl (3j)
4-Bromophenyl (3j)
4-Nitrophenyl (3k)
4-Nitrophenyl (3k)
Pyridin-3-yl (3l)
Pyridin-3-yl (3l)
4-Chlorophenyl (3i)
4-Bromophenyl (3j)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4j
4k
4l
5a
5b
5c
5d
5e
5f
5g
5h
5i
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
Phenyl (2a)
4-Bromophenyl (2c)
4-Bromophenyl (2c)
Methyl (1a)
Ethyl (1b)
Methyl (1a)
Ethyl (1b)
Methyl (1a)
Methyl (1a)
5j
5k
a
Solvents: HOAc (1.5 mL).
Isolated yield.
b

X.-C. Tu et al. / Tetrahedron Letters 53 (2012) 3169–3172
3171
O
O
R
O
O
R
R
O
O
CO2R
Ph NH
NH2
CO2R
HN
Ph
N
HN
Ph
N
H
B
H2
CO2R
1
2
A
H
H
O
OH
H
O
R
Ar
O
OH
Ph
Ar
O
N
RO2C
RO2C
Ph
N
H
N
N
CO2R
N
N
H
C
Ph
-H2O
OH
N
Ar2
RO2C
CO2R
RO2C
Ar
O
RO2C
N
Ph
N
N
Ph
N
N
Ph
N
N
aromatization
OHHO
Ph
4
Ar = electron-donating
aryl groups
5
Ar = electron-with drawing
aryl groups
Scheme 3. Proposed mechanisms for formation of products 4 or 5.
aromatic aldehydes) as an alternative method for divergent syn-
thesis of multi-functionalized pyrazolones and C-tethered bis-
pyrazol-5-ols by controlling the nature of substituent on formyl
group. The three-component reaction proceeds by domino [3+2]
heterocyclization obtaining arylidenepyrazolones 4 in good yields,
showing that the synthetic route allows us to build blocks of pyr-
azolone derivatives with a wide diversity of substituents. The five-
component assembly gave the structurally different C-tethered
bispyrazol-5-ol framework 5. The ready accessibility of the starting
materials, the broad compatibility of aldehyde substrates, and the
generality of this process make the reaction highly valuable in view
of the synthetic and medicinal importance of heterocycles of this
type. Features of this strategy include the mild condition, conve-
nient one-pot operation, short reaction periods of 10–25 min and
excellent regio- and chemoselectivities.
Figure 1. X-ray structure of 4b.
unambiguously determined.20 The structural elucidation and attri-
bution of relative stereochemistry of the products have been char-
acterized by 1H and 13C NMR and other analyses.
The mechanism of these domino reactions is proposed in
Scheme 3. An initial condensation of acetylenedicarboxylate 1
and phenylhydrazine 2 generated 1,3-dipole intermediate A, which
successively underwent proton transfer (A to B) and aminolysis of
the ester group (B to C) generating the pyrazolone derivative C
in situ. The pyrazolone derivative C was subjected with aromatic
aldehydes leading to arylidene pyrazolones 4. The polarity be-
tween C@C bonds in the benzyl position was induced by the elec-
tron-donating groups on phenyl ring, making its reactivity
improve. So the arylidene pyrazolones with electron-withdrawing
groups 4 were further reacted with pyrazolones generated in situ
to give final C-tethered bispyrazol-5-ol derivatives 5.
Acknowledgments
We are grateful for financial support from the National Science
Foundation of China (21072163 and 21102124), PAPD of Jiangsu
Higher Education Institutions, Science Foundation in Interdisci-
plinary Major Research Project of Xuzhou Normal University (No.
09XKXK01), the NSF of Jiangsu Education Committee (11KJB15
0016), Jiangsu Science and Technology Support Program (No.
BE2011045), and Doctoral Research Foundation of Xuzhou Normal
Univ. (XZNU, No. 10XLR20).
In conclusion, we have developed multi-component heterocyc-
lization reactions (acetylenedicarboxylates, phenylhydrazine and
Supplementary data
Supplementary data associated (experimental details and spec-
troscopic characterization of all compounds along with 1H, 13C
NMR, IR and mass spectra) with this article can be found, in the on-
line version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.051.
References and notes
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18. General procedure for the synthesis of compounds 4: In a 10-mL reaction vial,
acetylenedicarboxylate 1(1 mmol, 1.0 equiv), phenylhydrazine
2 (1 mmol,
1.0 equiv) and acetic acid (2 ml) were mixed and then stirred at room
temperature for 1 min. Then the aromatic aldehyde 3a–3g (1 mmol, 1.0 equiv)
was added into the mixture. The new mixture was stirred at room temperature
for 10–18 min. Upon completion as shown by TLC monitoring, the reaction
mixture diluted with cold water. The solid product was filtered, and
subsequently recrystallized from 50% EtOH to give the pure product. (4Z)-
Methyl 4-(3,4,5-trimethoxybenzylidene)-4,5-dihydro-5-oxo-1-phenyl-1H-pyrazole-
3-carboxylate (4e) Orange solid, mp: 173 °C; IR (KBr, m
, cmÀ1): 1715, 1618,
1590, 1517, 1325, 1267, 1198, 1173, 1107, 1020, 990, 743. 1H NMR (400 MHz,
CDCl3) d: 8.69 (s, 1H, CH), 8.07 (s, 2H, Ar-H), 7.90 (d, J = 8.0 Hz, 2H, Ar-H), 7.45
(t, J = 8.0 Hz, 2H, Ar-H), 7.29 (d, J = 7.2 Hz, 1H, Ar-H), 4.01 (s, 2H, OCH3), 4.01 (s,
2H, OCH3), 3.97 (s, 6H).13C NMR (100 MHz, CDCl3) (d, ppm): 207.0, 162.1,
161.7, 153.4, 152.7, 144.0, 139.8, 137.7, 129.0, 128.7, 126.5, 122.1, 121.0, 112.7,
61.2, 56.4, 52.5, 30.9. HRMS (ESI) m/z: calcd for C21H20N2O6: 395.1242 [MÀH]À;
found 395.1239.
19. General procedure for the synthesis of compounds 5: In a 10-mL reaction vial,
acetylenedicarboxylate
1 (2 mmol, 2.0 equiv), phenylhydrazine 2 (2 mmol,
2.0 equiv) and acetic acid (2 ml) were mixed and then stirred at room
temperature for 1 min. Then the aromatic aldehyde 3h–3l (1 mmol, 1.0 equiv)
was added into the mixture. The new mixture was stirred at 40 °C for 15–
22 min. Upon completion as shown by TLC monitoring, the reaction mixture
diluted with cold water. The solid product was filtered, and subsequently
recrystallized from 80% EtOH to give the pure product. Ethyl 4-((3-
(ethoxycarbonyl)-5-hydroxy-1-phenyl-1H-pyrazol-4-yl)(4-chlorophenyl)methyl)-
5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylate (5c) White solid, mp: 194 °C; IR
(KBr, m
, cmÀ1): 1728, 1714, 1598, 1579, 1490, 1443, 1220, 1175, 1049, 1035,
824, 747, 671. 1H NMR (400 MHz, DMSO-d6) d: 7.80 (d, J = 7.5 Hz, 4H, Ar-H),
7.46 (t, J = 6.9 Hz, 4H, Ar-H), 7.40–7.24 (m, 6H, Ar-H), 6.76 (s, 1H, CH), 4.31 (q,
J = 6.9 Hz, 4H, OCH2), 1.31 (t, J = 7.0 Hz, 6H, CH3). 13C NMR (100 MHz, CDCl3) (d,
ppm): 137.8, 137.2, 132.3, 129.0, 128.5, 128.2, 127.8, 123.2, 63.0, 32.5, 14.1.
HRMS (ESI) m/z: calcd for C31H27ClN4O6: 585.1541 [MÀH]À; found 585.1518.
20. The single-crystal growth was carried out in co-solvent of EtOH and CH3COCH3
at room temperature. X-ray crystallographic analysis was performed with a
Siemens SMART CCD and a Siemens P4 diffractometer. Crystal data for 4b:
C
20H18N2O4, crystal dimension 0.43 Â 0.41 Â 0.14 mm, Monoclinic, space
group P2(1)/c, a = 12.9240(11) Å, b = 18.8682(16) Å, c = 7.3157(6) Å,
a
l
=
c
= 90°, b = 101.272(2)°, V = 1749.5(3) Å3, Mr = 350.36, Z = 4, k = 0.71073 Å,
(Mo K
) = 0.094 mmÀ1, F(000) = 736, R1 = 0.0375, wR2 = 0.0645. Crystal data
a
for 5d: C29H23BrN4O6, crystal dimension 0.30 Â 0.24 Â 0.13 mm, Monoclinic,
space group P2(1)/c, a = 10.5957(11) Å, b = 12.1892(12) Å, c = 41.397(3) Å,
a
=
c
= 90°,
b = 96.3800(10)°,
(Mo ,
) = 1.599 mmÀ1
V = 5313.5(9) Å3,
Mr = 603.42,
Z = 8,
k = 0.71073 Å,
wR2 = 0.0714.
l
K
a
F(000) = 2464, R1 = 0.0505,
16. (a) Jiang, B.; Zhang, G.; Ma, N.; Shi, F.; Tu, S.-J.; Kaur, P.; Li, G. Org. Biomol. Chem.
2011, 9, 3834; (b) Jiang, B.; Wang, X.; Shi, F.; Tu, S.-J.; Li, G. Org. Biomol. Chem.