Selective synthesis of 4-(sulfonyl)-methyl-1H-pyrazoles and (E)-4,5-dihydro-1H-pyrazoles from N-allenic sulfonylhydrazones

Article abstract of DOI:10.1039/c4ob00550c

Selective synthesis of 4-(sulfonyl)-methyl-1H-pyrazoles and (E)-4,5-dihydro-1H-pyrazoles from N-allenic sulfonylhydrazones with sulfonyl group migrations has been developed. A key feature of these reactions is that the migrations of the sulfonyl groups to different positions can be controlled by changing the Lewis acids. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00550c

Organic &
Biomolecular Chemistry
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Selective synthesis of 4-(sulfonyl)-methyl-1H-
pyrazoles and (E)-4,5-dihydro-1H-pyrazoles from
N-allenic sulfonylhydrazones†
Cite this: Org. Biomol. Chem., 2014,
12, 3797
Received 12th March 2014,
Accepted 10th April 2014
Yu Zhu, Jun-Jie Hong, Yun-Bin Zhou, Yu-Wei Xiao, Min Lin and Zhuang-Ping Zhan*
DOI: 10.1039/c4ob00550c
www.rsc.org/obc
Selective synthesis of 4-(sulfonyl)-methyl-1H-pyrazoles and
(E)-4,5-dihydro-1H-pyrazoles from N-allenic sulfonylhydrazones
with sulfonyl group migrations has been developed. A key feature
of these reactions is that the migrations of the sulfonyl groups to
different positions can be controlled by changing the Lewis acids.
Pyrazoles are found in a variety of biologically active com-
pounds,1 such as celebrex, zoniporide, and fluzaolate. Owing
to their wide applications in pharmaceutical and agrochemical
sciences, substantial attention has been paid to development
of efficient strategies for pyrazoles synthesis.2 Although con-
ventional approaches for the synthesis of pyrazole skeletons
involving either modification of pre-existing pyrazole precur-
sors3 or assembly of new pyrazole rings4 have been well
studied, development of efficient methods to synthesize pyra-
zole derivatives which could lead to the discovery of new bio-
active compounds is still a challenge in organic synthesis.
Allenic sulfonamides as a subclass of allenamides5 have
shown impressive synthetic potential in organic chemistry. A
variety of transformations from allenic sulfonamides have
been demonstrated which offer versatile access to a range of
fascinating structures.6
Recently, our group has reported that a Lewis base catalyzed
the synthesis of multisubstituted 4-sulfonyl-1H-pyrazoles from
N-propargylic sulfonylhydrazones (Scheme 1, eqn (1)).7 As a
part of our continuing research, we conducted the reactions of
N-allenic sulfonylhydrazones 1 as a subclass of allenic sulfona-
mides with Lewis acids. Interestingly, 4-(sulfonyl)-methyl-1H-
pyrazoles 2 and (E)-4,5-dihydro-1H-pyrazoles 3 were obtained
respectively involving regioselective migrations of sulfonyl
groups8 to different positions promoted by different Lewis
acids (Scheme 1, eqn (2)).
Scheme 1 Cyclization of N-allenic sulfonylhydrazone and N-pro-
pargylic sulfonylhydrazone.
In the initial study, the activity of Lewis acids was screened
with N-allenic sulfonylhydrazone 1a as a substrate (Table 1).
The reaction of 1a in the presence of 20 mol% FeCl3 in DCM at
room temperature gave 3a in 83% yield. The single product 3a
was isolated in 44% and 34% yields using Lewis acids
BF3·Et2O and AgOTf, respectively (Table 1, entries 2 and 3).
The rate of the reaction decreased dramatically catalyzed by
10 mol% FeCl3, and a lower yield of 3a was achieved (Table 1,
entry 4). In the presence of 110 mol% FeCl3, the reaction pro-
duced a 34 : 28 mixture of 2a and 3a (Table 1, entry 5). Prolong-
ing the reaction time would not change the ratio of 2a and 3a.
Subsequently, the reactions of 1a were investigated with zinc
salts. Interestingly, 20 mol% Lewis acid of ZnCl2 and ZnBr2
failed to promote those transformations (Table 1, entries
6 and 15). Nevertheless, the unique product 2a was observed
in 75% yield promoted by 1.1 equiv. of ZnCl2 (Table 1, entry 7).
To our delight, ZnBr2 performed better in the formation of 2a
(Table 1, entry 8). Other metal Lewis acids, such as AlCl3, BiCl3
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen, Fujian 361005, People’s Republic of China.
E-mail: zpzhan@xmu.edu.cn
†Electronic supplementary information (ESI) available. CCDC 960118. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4ob00550c
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Table 1 Screening for the reaction conditionsa
Entry
Catalyst (mol%)
Time
Temp.
Yieldb (2a/3a)
1
2
3
4
5
6
7
8
FeCl3 (20)
BF3·Et2O (110)
AgOTf (20)
FeCl3 (10)
FeCl3 (110)
ZnCl2 (20)
ZnCl2 (110)
ZnBr2 (110)
AlCl3 (20)
AlCl3 (110)
BiCl3 (20)
BiCl3 (110)
InCl3 (20)
5 min
5 min
24 h
10 h
5 min
12 h
4 h
4 h
12 h
2 h
12 h
2 h
r.t.c
0 °C
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0/83%
0/44%
0/34%
Trace/24%
34%/28%
0/0d
75%/0
87%/0
9
0/traced
Trace/36%
0/traced
5%/30%
0/0d
10
11
12
13
14
15
12 h
2 h
12 h
InCl3 (110)
ZnBr2 (20)
10%/65%
0/0d
a Reaction conditions: 1a (232 mg, 0.5 mmol), DCM (5 mL). b Isolated
yield. c r.t. = room temperature. d Recovery of substrate 1a.
and InCl3, were also screened. No reaction happened when
20 mol% catalysts were used, while increasing the amount of
Lewis acids to 1.1 equiv. led to 3a in comparatively low yields
(Table 1, entries 9–14). The reaction took place in a less
effective manner when solvents such as CH3CN, THF and DCE
were used. Thus, the most suitable conditions for the synthesis
of 2a and 3a were established (Table 1, entries 1 and 8).
Scheme 2 Synthesis of 4-(sulfonyl)-methyl-(1H)-pyazole. Reaction
conditions: substrate
1 (0.5 mmol), DCM (5 mL), ZnBr2 (123 mg,
0.55 mmol), room temperature. n.r. = no reaction.
With the optimized reaction conditions in hand, the scope
and generality of this zinc-promoted reaction was studied and
the results are summarized in Scheme 2. The substrates 1a
(R1 = 4-MeC6H4) and 1b (R1 = Ph) gave 2a and 2b in 87% and duced (E)-4,5-dihydro-1H-pyrazoles 3f–j and 3m in moderate to
71% yields, respectively. 1c (R1 = 4-MeOC6H4) and 1d (R1
4-BrC6H4) reacted smoothly affording the desired products 2c containing
=
good yields (63–83%). The reactions of substrates 1k and 1l
2-thiophenyl or 1-naphthyl group afforded
a
and 2d in 67% and 85% yields, respectively. 1e was also suc- desired products 3k and 3l in excellent yields (90% and 95%),
cessfully employed in the reaction to give the corresponding respectively. Internal alkyne 1n (R4 = t-C4H9) failed in this
product 2e in excellent yield (96%). Electron-neutral, electron- transformation. No reaction of substrates 1q (R4 = H) and 1r
deficient, and electron-rich aromatic groups (R2 and R3) on the (R4 = TMS) occurred under optimized conditions. The struc-
substrates 1 (1f–j and 1m) were all well tolerated, and the ture of 3l was unambiguously demonstrated by X-ray diffrac-
desired products (2f–j and 2m) were obtained in moderate to tion analysis (see the ESI†).9
excellent yields (83–97%). The substrates 1k and 1l bearing a
We performed a crossover experiment between equimolar
thiophene ring or a fused ring were also well suited for those amounts of N-allenic sulfonylhydrazones 1b and 1j in the pres-
transformations (2k and 2l, 94% and 73% yields). Additionally, ence of 1.1 equiv. of ZnBr2 which yielded the corresponding
internal alkyne substrates 1n–p (R4 = t-C4H9, n-C4H9 and pyrazoles 2b and 2j in 39% and 47% yields, respectively, and
1-cyclohexenyl) readily underwent those reactions to afford 2n–p the crossover products 2a and 2m in 39% and 45% yields,
in moderate to good yields (50%–82%). The results suggested respectively (Scheme 4 eqn (1), determined by HPLC). Further-
that 1q (R4 = H) and 1r (R4 = TMS) failed to form 2q and 2r.
more, the FeCl3-catalyzed reaction of a 1 : 1 mixture of 1b and
Next, we investigated the reactions of N-allenic sulfonyl- 1j afforded the corresponding pyrazoles 3b and 3j in 33% and
hydrazones 1a–r using 20 mol% FeCl3 as a catalyst. The results 45% yields, respectively, and the crossover products 3a and 3m
are summarized in Scheme 3. 1a–d were converted into 3a–d in 39% and 44% yields, respectively (Scheme 4 eqn (2), deter-
in moderate to good yields (63–83%), while the reaction of 1e mined by HPLC). These results clearly indicated that both
led to a mixture. N-Allenic sulfonylhydrazones 1f–j and 1m migrations of the sulfonyl group proceeded in an intermolecu-
bearing electron-deficient or electron-rich aromatic rings pro- lar manner.
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Scheme 5 Interconversion reactions between 2a and 3a.
small sterically hindered effect avails formation of (E)-con-
figuration intermediate 5. The halide ion promotes the N–S
bond of 5 cleavage to give intermediate 6 or 7. For zinc-pro-
moted (MXn = ZnBr2) reaction of the substrates 1, along with
the departure of ZnBr2 from 6, electrons transfer to the exo-
cyclic double bond to render sulfonylation reaction and inter-
mediate 8 is formed. Finally, 8 rearranges to pyrazole 2 via 1,5-
H shift and tautomerization. In iron-catalyzed (MXn = FeCl3)
reaction, elimination of FeCl3 on intermediate 7 and the new
N–S bond formed give (E)-4,5-dihydro-1H-pyrazole 3. The
strength of the M–N bond might play a crucial role in selec-
tively producing 2 and 3. With such simple substrates, the real
role of each catalyst for the different selectivity remains a
puzzle (Scheme 6).
The ready availability of pyrazoles 2 bearing a sulfonyl
moiety opens a new synthetic opportunity for a suitable trans-
formation. Pyrazole derivative 4aa was prepared from 2a and
dimethyl malonate in 75% yield. Malononitrile reacted with 2a
leading to the corresponding product 4ab in 78% yield. Ethyl
acetoacetate and 2a reacted under basic conditions leading to
the mixture 4ac of two corresponding diastereoisomers in 82%
yield. According to the above results, we presumed that under
basic conditions pyrazole 2a underwent elimination of arene-
sulfinic acid, leading to an intermediate vinylogous imine 4a
which when added with nucleophile reagents afforded 4-sub-
stituted pyrazole derivatives (Scheme 7).10
Scheme 3 Synthesis of (E)-4,5-dihydro-(1H)-pyrazole. Reaction con-
ditions: substrates 1 (0.5 mmol, 232 mg), DCM (5 mL), FeCl3 (16 mg,
0.1 mmol), room temperature. 50 mol% FeCl3 was used. n.r. = no
reaction.
Scheme 4 Crossover reactions of 1b and 1j.
The product 2a or 3a remained unchanged in the presence
of ZnBr2 or FeCl3 in DCM at room temperature for 12 hours,
thereby suggesting that interconversion between 2 and 3 does
not take place under the optimized reaction conditions
(Scheme 5).
The above experimental results led us to propose a mechan-
ism for the cyclization of 1. The Lewis-acidic transition metal
coordinates with the nitrogen atom of 1 to form complex 4.
The nitrogen atom donates its lone pair of electrons to the
allenic moiety, followed by the addition of the central sp
carbon to the azomethine carbon atom. The spatial arrange-
ments of R3 and R4 are coplanar in intermediates 5 and 5′. The Scheme 6 Proposed mechanism.
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Scheme 7 KF on basic alumina-promoted additions of active methy-
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Conclusions
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In summary, selective synthesis of 4-(sulfonyl)-methyl-1H-pyra-
zoles and (E)-4,5-dihydro-1H-pyrazoles from N-allenic sulfonyl-
hydrazones has been developed. A key feature of those
reactions is that the migration of the sulfonyl groups to
different positions can be controlled. Employing inexpensive
zinc or iron salt, operational simplicity, mild reaction con-
ditions and absence of byproduct generation would be bene-
ficial for their large-scale use. Studies aiming at exploring
mechanistic aspects of these reactions and developing further
transformations of N-allenic sulfonylhydrazones are ongoing.
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