Tandem reaction of propargyl alcohol and N-sulfonylhydrazone: Synthesis of dihydropyrazole and its utility in the preparation of 3,3-diarylacrylonitrile

Article abstract of DOI:10.1021/ol201203g

An efficient and straightforward strategy for the synthesis of 4-methylene-1-(phenylsulfonyl)-4,5-dihydro-1H-pyrazole from propargyl alcohol and N-sulfonylhydrazone is described. N-Sulfonyl allenamide is postulated to be the key intermediate for this tandem transformation.

Full text of DOI:10.1021/ol201203g

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3553–3555
Tandem Reaction of Propargyl Alcohol
and N-Sulfonylhydrazone: Synthesis of
Dihydropyrazole and Its Utility in the
Preparation of 3,3-Diarylacrylonitrile
Yuanxun Zhu, Shan Wen, Guangwei Yin, Deng Hong, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
pinglu@zju.edu.cn; orgwyg@zju.edu.cn
Received May 6, 2011
ABSTRACT
An efficient and straightforward strategy for the synthesis of 4-methylene-1-(phenylsulfonyl)-4,5-dihydro-1H-pyrazole from propargyl alcohol and
N-sulfonylhydrazone is described. N-Sulfonyl allenamide is postulated to be the key intermediate for this tandem transformation.
Allenamides, as a subclass of allenes, have shown impres-
sive synthetic potentials in organic chemistry.1 Many reac-
tions based on allenamides were well established in the past
decades, such as [4 þ 2] cycloadditions,2 [2 þ 2] cyclo-
additions,3 and radical cyclization.4 The attendance of an
allenamide motif enhances the diversity of reaction possibi-
lities. In the formation of cyclic compounds, the allenamide
serves as a nucleophilic reagent to undergo catalyzed cycli-
zation with another electrophilic center such as organ-
ohalides.5 More importantly, due to the electron-rich
central carbon which can be easily activated in the presence
of an electrophile and the unique geometry of allenamide,
these reactions often proceed efficiently in highly stereo-
selective control, thus providing an attractive tool for the
stereoselective synthesis of cyclic molecules.
As a part of our continuing research on the development
of a tandem reaction of allenamide intermediates,6 we herein
report an efficient and general approach to the formation of
4-methylene-1-(phenylsulfonyl)-4,5-dihydro-1H-pyrazoles
(3) through a BF3 Et2O catalyzed tandem reaction between
3
propargyl alcohols (1) and N-sulfonylhydrazones (2). Struc-
tures of 3a and 3f were established by X-ray analysis.
Exhausive studies of the reaction conditions for the
synthesis of 3a from 1a and 2a were conducted (Table 1).
These results showed that BF3 OEt2 was the most efficient
3
catalyst for the transformation among others, such as HOTf,
Yb(OTf)3, Cu(OTf)2, and AgOTf (Table 1, entries 1ꢀ5),
whereas dichloromethane (DCM) was the most suitable
solvent in comparison with others, such as tetrahydrofuran,
acetonitrile, and toluene (Table 1, entries 6ꢀ8). In addition
to these two key factors, further screening of the catalytic reac-
tion conditions revealed that formation of 3a largely
depended on the reaction time and reaction temperature.
Prolonging the reaction time would slightly influence
the yield (Table 1, entry 9), while shortening the time made
the reaction incomplete (Table 1, entry 10). A similar
situation was observed for the reaction temperature survey
(Table 1, entries 11 and 12). Thus, the most suitable reaction
(1) Wei, L. L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773.
(2) (a) Hayashi, R.; Feltenberger, J. B.; Hsung, R. P. Org. Lett. 2010,
12, 1152. (b) Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430. (c)
Song, Z.; Hsung, R. P.; Lu, T.; Lohse, A. G. J. Org. Chem. 2007, 72,
9722. (d) Kimura, M.; Wakamiya, Y.; Horino, Y.; Tamaru, Y. Tetra-
hedron Lett. 1997, 38, 3963.
(3) Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru,
Y. J. Am. Chem. Soc. 1997, 119, 10869.
(4) Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775.
(5) (a) Grigg, R.; Sansano, J.; Santhakumar, V.; Sridharan, V.;
Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D. Tetrahedron
1997, 53, 11803. (b) Grigg, R.; Sridharan, V.; Xu, L.-H. J. Chem. Soc.,
Chem. Commun. 1995, 1903.
(6) (a) Yin, G. W.; Zhu, Y. X.; Zhang, L.; Lu, P.; Wang, Y. G. Org.
Lett. 2011, 13, 940. (b) Zhu, Y. X.; Yin, G. W.; Hong, D.; Lu, P.; Wang,
Y. G. Org. Lett. 2011, 13, 1024.
r
10.1021/ol201203g
2011 American Chemical Society
Published on Web 06/10/2011

Table 1. Screening for the Reaction Conditionsa
Table 2. Tandem Synthesis of 3a
product/
yieldb
(%)
temp
time
(h)
yieldb
(%)
entry
catalyst
(°C)
solvent
entry
1 (R1/R2/R3)
2 (R4)
1
BF3 Et2Oc
0
0
2
4
DCM
DCM
DCE
65
55
41
25
36
nre
42
0
3
1
1a (H/C6H5/C6H5)
2a (C6H5)
2a
3a/65
3b/72
3c/55
3d/41
3e/37
3f/50
2
HOTfd
d
2
1b (H/4-ClC6H4/4-ClC6H4)
3
Yb(OTf)3
80
80
80
0
4
d
3
1c (H/4-MeC6H4/ 4-MeC6H4) 2a
4
Cu(OTf)2
2
DCE
4
1d (H/C6H5/Me)
2a
2a
2a
5
AgOTfd
1
DCE
5
1e (n-Bu/C6H5/C6H5)
6
BF3 Et2Oc
2
THF
3
3
3
3
3
3
3
6
1f (C6H5/C6H5/C6H5)
7
BF3 Et2Oc
0
2
MeCN
Toluene
DCM
DCM
DCM
DCM
7
1a
1a
1a
1a
1a
2b (3,4-Me2C6H3) 3g/73
8
BF3 Et2Oc
0
2
8
2c (4-MeC6H4)
2d (4-BrC6H4)
2e (3-BrC6H4)
2f (2-BrC6H4)
2g (4-NO2C6H4)
2h (1-naphthyl)
2i (CH2C6H5)
3h/74
3i/63
3j/62
3k/60
3l/43
3m/74
3n/33
3o/30
3p/78
3q/78
3r/60
3s/40
9
BF3 Et2Oc
0
3
64
52
59
53
9c
10
11
10
11
12
BF3 Et2Oc
0
1
BF3 Et2Oc
ꢀ20
20
12
1
BF3 Et2Oc
12c 1a
a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), solvent (5 mL).
b Isolated yield referred to 2. c Equivalent molar to 1. d Catalyst (0.1 mmol)
used. e nr = no reaction.
13
14
15
16
17
18c 1d
19c 1d
1a
1a
1a
1d
1d
2j (n-C5H11
)
2b
2c
2d
2g
conditions for the formation of 3a were established (Table 1,
entry 1).
With the optimized reaction conditions in hand, we
tested the substrate diversity for the transformation, and
the results are presented in Table 2. Various propargyl
alcohols (1aꢀ1f) and N-sulfonylhydrazones (2aꢀ2j) read-
ily underwent this cascade process to afford 3aꢀ3s in
moderate to good yields (30ꢀ78%), accordingly. With
different aryl groups (R2, R3) occupied on the propargyl
alcohol (1aꢀ1c), reactions proceeded smoothly (Table 2,
entries 1ꢀ3). When acetophenone derived propargylic
alcohol (1d) was used as the substrate, Z-3d was obtained
diastereoselectively (Table 2, entry 4). A Z-configuration
was confirmed by the nuclear overhouser effect (NOE)7
between methyl and hydrogen as we indicated in Figure 1.
E-3d was not detected due to the steric hindrance of two
phenylringsinE-3dand its anticipated higherenergyofthe
transition state of the formation of E-3d. In cases of 1e and
1f, with the internal triple bond, lower yields were observed
(Table 2, entries 5 and 6). A substituent effect on the aryl of
N-sulfonylhydrazones (2bꢀ2h) was not apparent (Table 2,
entries 7ꢀ13 and 16ꢀ19). However, when N-sulfonylhy-
drazones derived from aliphatic aldehydes (2i, 2j) were
used as substrates, reactions were not so effective (Table 2,
entries 14 and 15).
a Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), BF3 Et2O (0.6
3
mmol), DCM (5 mL), reaction time (2 h). b Isolated yields refer to 2.
c 20 mL of solvent used.
nitrogen, the internal carbon of allene was electron-rich
and could nucleophilically attack the electron-deficient
carbon of the hydrazone. Thus, a cyclized intermediate C
was constructed. Finally, intramolecular migration9 of the
sulfonyl group led to the formation of 3a.
A possible mechanism for the reaction is depicted in
Scheme 1. Assisted by a Lewis acid, 1a was converted to
allenic carbocation A via MeyerꢀSchuster rearrangement.8
It could be trapped in situ by 2a to form N-sulfonylallena-
mide B. Because of the electron-donating nature of the
Figure 1. Diastereoselective formation of Z-3d.
(9) A controlled experiment was conducted to evidence the intramo-
lecular migration of sulfonyl group. Sodium p-toluene sulfinate was
added in the reaction between 1a and 2a. After workup, only 3a was
isolated (see Supporting Information for details). For one example for
the intramolecular migration of sulfonyl group, see: Groszek, G.; Blazej,
S.; Brud, A.; Swierczynski, D.; Lemek, T. Tetrahedron 2006, 62, 2622.
(7) For NOE experiments of 3d, see Supporting Information.
(8) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429.
3554
Org. Lett., Vol. 13, No. 14, 2011

obtained via NꢀN bond cleavage in a yield of 93%. The
structure of 4a was established by X-ray analysis. By
similar treatment, 4bꢀ4e were prepared in yields between
86 and 96% (Table 3). Compounds 4aꢀ4e possessed a
substructure of 3,3-diarylacrylonitrile, which might have
potential utility in bioactivity.
Scheme 1. Proposed Mechanism for the Tandem Trans-
formation
Table 3. Synthesis of 4a
Acrylonitriles have proven to be versatile building
blocks in organic synthesis for nitrile-containing natural
products, pharmaceuticals, and dyes.10 For example, 3,3-
diarylacrylonitriles could be served as tubulin polymeriza-
tion inhibitors for potential utility in cancer chemotherapy
(Figure 2).11
entry
3 (R1/R2)
3a (H/H)
product
yield (%) b
1
2
3
4
5
4a
4b
4c
4d
4e
93
96
96
95
86
3b (Cl/H)
3c (Me/H)
3f (H/3,4-Me2)
3h (H/4-Br)
a Reaction conditions: 3 (0.25 mmol), DCM (5 mL). b Isolated yields
refer to 3.
In summary, we have developed an efficient method
to synthesize 4-methylene-1-(phenylsulfonyl)-4,5-dihydro-1
H-pyrazole via a Lewis acid catalyzed tandem reaction of
propargyl alcohol and N-sulfonylhydrazone. A possible
mechanism for this reaction was proposed, which involves
the formation of a N-sulfonyl allenamide intermediate and
the 1,2-sulfonyl group migration. More significantly, 3,3-
diarylacrylonitriles could be efficiently obtained from the
synthesized pyrazoles via NꢀN bond cleavage in excellent
yields. Further research on the chemistry of N-sulfonyl
allenamide is ongoing in our laboratory.
Figure 2. A potential inhibitor of tubulin polymerization.
Inorder toexplorethe reactivity of 3, wefirst examined3
in the presenceof anacid. Itwas foundthat3awas stable to
either a Lewis acid (Cu(OTf)212) or Bronsted acid (HOTf).
However, compound 3a was unstable under the basic con-
ditions. When 3a was treated with sodium tert-butoxide, a
3,3-diarylacrylonitrile derivative (4a) was unexpectedly
Acknowledgment. We thank the National Nature Science
Foundation of China (21032005, J0830413, and 20872128).
(10) (a) Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34, 563. (b)
Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.
(11) (a) Fang, Z.; Song, Y.; Sarkar, T.; Hamel, E.; Fogler, W. E.;
Agoston, G. E.; Fanwick, P. E.; Cushman, M. J. Org. Chem. 2008, 73,
4241. (b) Zhang, L.-H.; Wu, L.; Raymon, H. K.; Chen, R. S.; Corral, L.;
Shirley, M. A.; Krishna Narla, R.; Gamez, J.; Muller, G. W.; Stirling,
D. I.; Bartlett, J. B.; Schafer, P. H.; Payvandi, F. Cancer Res. 2006,
66, 951.
Supporting Information Available. Detailed experimen-
1
tal procedures, characterizaton data, copies of H, 13C
NMR spectra, and crystallographic information files (CIF)
for compounds 3a, 3f, and 4a. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) For an example of NꢀN cleavage, see: Nakamura, I.; Shiraiwa,
N.; Kanazawa, R.; Terada, M. Org. Lett. 2010, 12, 4198.
Org. Lett., Vol. 13, No. 14, 2011
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