Zinc-promoted cyclization of tosylhydrazones and 2-(dimethylamino)malononitrile: An efficient strategy for the synthesis of substituted 1-tosyl-1: H -pyrazoles

Article abstract of DOI:10.1039/c7cc04610c

A Zn(OTf)₂-promoted cyclization reaction of tosylhydrazones with 2-(dimethylamino)malononitrile has been successfully developed providing an efficient strategy for the synthesis of substituted 1-tosyl-1H-pyrazoles.

Full text of DOI:10.1039/c7cc04610c

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DOI: 10.1039/C7CC04610C
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Zinc-Promoted Cyclization of Tosylhydrazones and 2-
(Dimethylamino)malononitrile: an Efficient Strategy for the
Synthesis of Substituted 1-Tosyl-1H-pyrazoles†
Received 00th January 20xx,
Accepted 00th January 20xx
Bang-Hong Zhang,a Lin-Sheng Lei,a Si-Zhan Liu,a Xue-Qing Mou,a Wei-Ting Liu,a Shao-Hua
DOI: 10.1039/x0xx00000x
Wang,a,b,c,* Jie Wang,a Wen Bao,a Kun Zhangb
www.rsc.org/
A Zn(OTf)2-promoted cyclization reaction of tosylhydrazones and heterocycle has also attracted the long-standing interests of
2-(dimethylamino)malononitrile has been successfully developed synthetic chemists.11 Within the strategies developed,
providing an efficient strategy for the synthesis of substituted 1- substituted hydrazones, a versatile synthetic intermediate,12
tosyl-1H-pyrazoles.
have been commonly used as the starting materials for the
preparation of pyrazole compounds,13-20 as the pre-existing
key atoms like the two nitrogen atoms could simplify the
synthesis process and thus increase the synthetic efficiency.
Selected examples include the cyclization of β,γ–unsaturated
hydrazones by Xiao,14 Chen15 and Huang,16 the [4+1]
cyclization of hydrazones by Glorius,17 Ji,18 and Wang,19 as well
as the cyclization of α,β-alkynictosylhydrazones by Tsui.20
Although several approaches for the preparation of pyrazole
derivatives from hydrazones are available, it is still highly
desirable to further explore under this topic for the pursuing of
transformation efficiency and molecular diversity.
Nitrogen-containing heterocycles play a pivotal role in modern
organic chemistry, for example, as important and basic
structural moieties, they exist broadly in a large number of
natural products, pharmaceuticals and functional materials.1
Because of such a fact, the development of efficient methods
for the synthesis of nitrogen-containing heterocycles is always
a hot topic in organic chemistry community.2 Among these
molecules, those with a pyrazole skeleton have shown broad
biological activities, such as analgesic,3 antipyretic,4
antibacterial,5 antihyperglycemic,6 and anti-inflammatory
activities,7and a variety of them have been used as marketed
medicines, selected examples like celecoxib,8 mavacoxib,9 and
razaxaban10 (Figure 1). Therefore, the construction of this
Scheme 1. The design of the cyclization reaction
Previously, we have developed
a
copper-catalyzed
dicyanation of N,N-disubstituted formamide with trimethylsilyl
cyanide for the synthesis of 2-dialkylamino-malononitriles.21
Under the inspiration of the structural feature of the obtained
2-dialkylamino-malononitriles, i.e., the existence of amine and
cyano groups as well as their special connection pattern, a
tandem strategy toward the construction of multi-substituted
pyrroles has been successfully realized (Scheme 1, eq 1),22
which prompted us to further systematically explore the
synthetic utility of such type of compound. Toward the above
research goal and in connection with our interest in the
synthesis of nitrogen-containing heterocycles, we envisioned
that 2-(dimethylamino)malononitrile, which could be readily
obtained by our method, might be used as a C1 synthon to
react with different hydrazones affording the multi-substituted
Figure 1. Selected bioactive molecules with a pyrazole moiety
a.School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. China. E-mail:
wangshh@lzu.edu.cn
b.School of Chemical and Environmental Engineering, Wuyi University, Jiangmen
529020, P. R. China.
c. Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of
Education, Sichuan University, Chengdu, P. R. China.
† Patent pending, Chinese patent application (No. 201710417604.6)
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1. Reaction condition optimizationa
pyrazoles (Scheme 1, eq 2). In this paper, a zinc-promoted
cyclization of tosylhydrazones and 2-
View Article Online
DOI: 10.1039/C7CC04610C
(dimethylamino)malononitrile is presented, and it features
broad substrate cope and good transformation efficiency.
Following the original assumption, we started our
investigation
with
hydrazone
1a
and
2-
entry
catalyst
(equiv)
solvent
temp (oC) time yieldb
(dimethylamino)malononitrile 2a as the model substrates.
Initial test with our previously used conditions,22 i.e., Cu(OTf)2
as the catalyst in n-heptane at 80 ºC to activate substrate 2a
(h)
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
36
36
36
36
(%)
10
trace
15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Cu(OTf)2 (0.2)
AgOTf (0.2)
Zn(OTf)2 (0.2)
Zn(OTf)2 (0.2)
Zn(OTf)2 (0.2)
Zn(OTf)2 (0.2)
Zn(OTf)2 (0.2)
Cu(OTf)2 (0.2)
AlCl3 (0.2)
Yb(OTf)3 (0.2)
Y(OTf)3 (0.2)
TsOH (0.2)
TFA (0.2)
HOTf (0.2)
Zn(OTf)2 (0.3)
Zn(OTf)2 (0.5)
Zn(OTf)2 (1.0)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.2)
Zn(OTf)2 (0.3)
Zn(OTf)2 (1.0)
n-heptane
n-heptane
n-heptane
1,4-dioxane
THF
80
80
80
80
reflux
80
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60
,
successfully afforded the expected product 3a in 10% yield
(Table 1, entry 1). Although most of the starting material was
left unreacted, the result supported the feasibility of such a
transformation. Additional test with Zn(OTf)2 further increased
the yield of 3a to 15% (Table 1, entry 3). Considering that n-
heptane might not be a good choice for such a reaction, we
decided to test the solvent effect with Zn(OTf)2 as the catalyst.
Among the solvents screened, the employment of 1,2-
dichloroethane led to the best yield of 41% (Table 1, entries 4
to 7). Next, some other Lewis acids and Brønsted acids were
also examined, and none of them gave better yield than that
of Zn(OTf)2 (Table 1, entries 8 to 14). Based on these results,
the reaction was further carried out with different amount of
Zn(OTf)2. It was found that the use of 0.5 equiv of Zn(OTf)2
produced the compound 3a with the highest yield of 68%
(Table 1, entries 15 to 17). Meanwhile, lowering the reaction
temperature resulted in the decrease of the yield of 3a (Table
1, entry 18). Finally, elongation of the reaction time to 36 h in
the presence of different amount of Zn(OTf)2 revealed that the
yield could be enhanced to 92% with 0.5 equiv of Zn(OTf)2
(Table 1, entries 19 to 22). Therefore, using 0.5 equiv of
Zn(OTf)2 as the promoter in DCE at reflux was selected as the
optimal reaction conditions (Table 1, entry19).
With the optimal reaction conditions in hand (Table 1, entry
19), the substrate scope was further investigated. As shown in
Table 2, a variety of hydrazones prepared from different
aromatic ketones, aliphatic ketones and hydrazides were
applicable for this cyclization reaction, and most of the
substrates tested could afford the expected products in good
yields. For the hydrazones derived from different substituted
acetophenones, no clear steric effect was observed. For
example, when the substituent was a methyl or chloro group,
all the substrates tested were converted to the desired
products in good yields despite the position of the substituents.
Similarly, there was no clear electronic effect associated with
this reaction based on current results. For the substrates with
a substituent at the para-position of the phenyl ring, the
majority of them could produce the corresponding pyrazoles in
high yield regardless of the electronic property of the
substituent. Among them, only the substrate 1k with a cyano
group, which might not be stable enough in this acidic
conditions, gave the corresponding product 3k in a moderate
yield of 55%. The presence of these substituents, in particular
the halogen atoms, would provide additional reaction site for
further derivatizations. Besides, another two substrates 1m
and 1n with two electron withdrawing or donating groups on
the phenyl ring were also amenable to this reaction, and both
23
n,dc
n.dc
41
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
21
8
13
7
n.dc
trace
trace
66
68
66
60
92
45
61
75
reflux
reflux
reflux
reflux
DCE
aReaction conditions: 1a (0.18 mmol, 50 mg), 2a (0.27 mmol, 28 mg), solvent
(2.0 mL). bIsolated yield. cn.d. = not detected.
of them could be transformed to the desired products in good
yields. Additionally, we also carried out the reaction with three
typical benzocyclicketone derived hydrazones, and they all
went through the reactions smoothly to deliver the products
3o-3q in moderate to good yields. We also tried the hydrazone
1r prepared from propiophenone, which could also give the
product 3r, albeit in a low yield of 32%. Next, a series of
hydrazones made from aliphatic ketones, which are less
reactive than the aromatic ketones derived ones, were
evaluated with this transformation, and all gave the desired
products. Among them, substrates 1s and 1t, which were
synthesized from the corresponding acyclic aliphatic ketones,
led to the products 3s and 3t in low yield. While, for the
substrates related to the cyclic aliphatic ketones with different
ring size, they underwent the cyclization reaction efficiently to
afford the pyrazole-fused bicyclic products in moderate to
good yields. Moreover, except the tosylhydrazones, another
two hydrazones obtained from benzenesulfonohydrazide and
2,4,6-trimethylbenzenesulfonohydrazide with acetophenone
were also applicable for this reaction giving the products 3z
and 3aa in 84% and 76% yields, respectively.
According to the results of the substrate scope investigation,
the potential utility of this reaction was exhibited by a
synthesis of the key intermediate of B-Raf kinase inhibitors
(Scheme 2). 23 The hydrazone
and 4-methylbenzenesulfonohydrazide 5 in a yield of 90%, and
6 was synthesized from ketone 4
Table 2. Substrate scope investigationa
2 | J. Name., 2012, 00, 1-3
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group of the product 3a could be readily removed in the
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DOI: 10.1039/C7CC04610C
presence of NaOH in MeOH to produce compound 8, which
would also benefit subsequent derivatization process (Scheme
2).
To better understand the mechanism of this cyclization
reaction, some control experiments were performed. Firstly,
no product 3a was observed when compound 2a was absent
from the reaction system, which indicated the C1 synthon was
not from other components of the reaction mixture (Scheme 3,
eq 1). Secondly, replacing compound 2a with another
dialkylamino-malononitrile 2b also could afford the expected
product 3a in 28% yield (Scheme 3, eq 2). This confirmed that
the dialkylamino-malononitrile 2a (2b) should act as the C1
synthon during the cyclization reaction.
Scheme 3. Control experiments for reaction mechanism
investigation
Based on the experimental results above, the reaction
mechanism is proposed using the transformation between
substrates 1a and 2a as an example. As shown in Scheme 4,
under the promotion of Zn(OTf)2 in elevated temperature, the
decyanation of 2a will give the intermediate I, which could
react with compound 1a to afford intermediate II after
releasing a proton. Next, the intermediate III will be generated
from intermediate II through dehydrocyanation, and produce
intermediate IV by an intramolecular cyclization. Finally,
deamination of intermediate IV will lead to the product 3a 24
.
aReaction conditions:
1 (50 mg), 2a (1.5 equiv) in DCE (2.0 mL) at reflux
for 36 h, the yields are isolated yields.
applied in the newly developed cyclization reaction with compound
2 to give the known intermediate 7 in 54% yield completing the
formal synthesis of the B-Raf inhibitors. Compared with the
reported method,23 the use of our strategy could improve the
overall yield of the intermediate 7 from 14% to 49%, and might
facilitate the related biological studies. Furthermore, the Ts
Scheme 4. Proposed reaction mechanism
In conclusion, we have successfully developed a Zn(OTf)2-
promoted cyclization reaction of tosylhydrazones and 2-
(dimethylamino)malononitrile providing an efficient strategy
for the synthesis of substituted 1-tosyl-1H-pyrazoles.25 As a
beneficial complement for the construction of pyrazole ring,
this method features broad substrate scope and good yield,
which is higher than the known strategy using DMF-DMA in
the synthesis of the B-Raf kinase inhibitors. Therefore, the
method might facilitate related biological studies. Currently,
further investigation of the potential utility of this method and
2-dialkylamino-malononitriles is on-going in the same group.
Scheme 2. Synthetic applications of the reaction
Acknowledgement
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Knabb, G. L. Skiles and K. He, Drug Metab. DispVoiesw.,A2rt0ic0le8O,n3lin6e
,
This work was supported by the NSFC (21202073 and
21472077), the Fundamental Research Funds for the Central
Universities (lzujbky-2015-k12, lzujbky-2016-145), and the
Opening Project of Key Laboratory of Drug Targeting and Drug
Delivery System, Ministry of Education (Sichuan University).
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25 Caution: The reaction should be handled with care in a fume
hood as HCN will be released from the reaction mixture.
10 D. Zhang, N. Raghavan, S.-Y. Chen, H. Zhang, M. Quan, L.
Lecureux, L. M. Patrone, P. Y. S. Lam, S. J. Bonacorsi, R. M.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7CC04610C
Graphic Abstract
Zinc-Promoted Cyclization of Tosylhydrazones and 2-(Dimethylamino)malononitrile:
an Efficient Strategy for the Synthesis of Substituted 1-Tosyl-1H-pyrazoles
An efficient strategy for the synthesis of substituted 1-tosyl-1H-pyrazoles has been developed
through a cyclization reaction of tosylhydrazones and 2-(dimethylamino)malononitrile.