Dimethyl sulfide induced [3 + 2] annulation strategy: An efficient synthesis of functionalized dihydropyrazole derivatives using the Baylis-Hillman bromides

Article abstract of DOI:10.1021/ol800424v

Baylis-Hlllman bromides have been successfully employed as a valuable source of 1,3-dipoles for cycloaddition onto dialkyl azodicarboxylates (dipolarophiles) under the influence of dimethyl sulfide and potassium carbonate to provide functionalized dihydropyrazole derivatives in a simple one-pot [3 + 2] annulation strategy.

Full text of DOI:10.1021/ol800424v

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1819-1822
Dimethyl Sulfide Induced [3 + 2]
Annulation Strategy: An Efficient
Synthesis of Functionalized
Dihydropyrazole Derivatives Using the
Baylis-Hillman Bromides
Deevi Basavaiah* and Suparna Roy
School of Chemistry, UniVersity of Hyderabad, Hyderabad-500 046, India
dbsc@uohyd.ernet.in
Received February 24, 2008
ABSTRACT
Baylis-Hillman bromides have been successfully employed as a valuable source of 1,3-dipoles for cycloaddition onto dialkyl azodicarboxylates
(dipolarophiles) under the influence of dimethyl sulfide and potassium carbonate to provide functionalized dihydropyrazole derivatives in a
simple one-pot [3 + 2] annulation strategy.
The pyrazole framework belongs to an important class of
heterocyclic compounds possessing pharmacological proper-
ties such as antiviral, antitumor, anti-inflammatory, and
antimicrobial activities.1 Certain 1H-pyrazole-4-carboxylic
esters are known to exhibit antimicrobial activity and are
also found to act as intermediates for agrochemical micro-
bicides and herbicides.2 Because of the remarkable medicinal
and pharmacological potential of pyrazole derivatives,
development of simple and efficient methodologies for
synthesis of these compounds with different substitution
profiles has been and continues to be a challenging and
attractive endeavor in organic and medicinal chemistry.1b–d,3
Recently, some interesting publications appeared from the
research groups of Wang3a and Nair3b,c on the application
of Huisgen zwitterions for the synthesis of pyrazole deriva-
tives. Fascinated by these reports and also in continuation
of our interest in the heterocyclic compounds4 we report
herein a simple, facile, and one-pot synthesis of function-
alized dihydropyrazole derivatives via [3 + 2] annulation
strategy using the Baylis-Hillman bromides as a source of
(1) (a) Goodell, J. R.; Puig-Basagoiti, F.; Forshey, B. M.; Shi, P.-Y.;
Ferguson, D. M. J. Med. Chem. 2006, 49, 2127–2137. (b) Manna, F.;
Chimenti, F.; Fioravanti, R.; Bolasco, A.; Secci, D.; Chimenti, P.; Ferlini,
C.; Scambia, G. Bioorg. Med. Chem. Lett. 2005, 15, 4632–4635. (c) Bekhit,
A. A; Abdel-Aziem, T. Bioorg. Med. Chem. 2004, 12, 1935–1945. (d) Bhat,
B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel, M.; Qazi,
G. N. Bioorg. Med. Chem. Lett. 2005, 15, 3177–3180.
(2) (a) Tsutomu, I.; Hideo, Y.; Toshiaki, K.; Hitoshi, S.; Yoshinori, T.;
Katsutoshi, I. JP 01,113,371 [89,113,371] Chem. Abstr. 1989, 111214479x.
(b) Tsutomu, I.; Toshiaki, K.; Hitoshi, S.; Yoshinori, T.; Katsutoshi, I. JP
01,106,866 [89,106,866] Chem. Abstr. 1989, 111194759h. (c) Sridhar, R.;
Perumal, P. T.; Etti, S.; Shanmugam, G.; Ponnuswamy, M. N.; Prabavathy,
V. R.; Mathivanan, N. Bioorg. Med. Chem. Lett. 2004, 14, 6035–6040.
(3) (a) Cui, S.-L.; Wang, J.; Wang, Y.-G. Org. Lett. 2008, 10, 13–16.
(b) Nair, V.; Mathew, S. C.; Biju, A. T.; Suresh, E. Angew. Chem., Int. Ed.
2007, 46, 2070–2073. (c) Nair, V.; Biju, A. T.; Mohanan, K.; Suresh, E.
Org. Lett. 2006, 8, 2213–2216. (d) Adib, M.; Sayahi, Md. H.; Rahbari, S.
Tetrahedron Lett. 2005, 46, 6545–6547. (e) Lee, K. Y.; Kim, J. M.; Kim,
J. N. Tetrahedron Lett. 2003, 44, 6737–6740.
(4) (a) Basavaiah, D.; Aravindu, K. Org. Lett. 2007, 9, 2453–2456. (b)
Basavaiah, D.; Reddy, K. R. Org. Lett. 2007, 9, 57–60. (c) Basavaiah, D.;
Srivardhana Rao, J.; Reddy, R. J.; Jaganmohan Rao, A. Chem. Commun.
2005, 2621–2623. (d) Basavaiah, D.; Satyanarayana, T. Chem. Commun.
2004, 32–33. (e) Basavaiah, D.; Srivardhana Rao, J. Tetrahedron Lett. 2004,
45, 1621–1625. (f) Basavaiah, D.; Jaganmohan Rao, A. Chem. Commun.
2003, 604–605. (g) Basavaiah, D.; Satyanarayana, T. Org. Lett. 2001, 3,
3619–3622.
10.1021/ol800424v CCC: $40.75
Published on Web 04/10/2008
2008 American Chemical Society

Table 1. Standardization: Reaction of Methyl (2Z)-2-Bromomethyl-3-phenylprop-2-enoate (1a) (1 mmol) with Diethyl Azodicarboxylate
(3a) (1 mmol) under the Influence of Me2S and a Base at Room Temperature To Provide the Dihydropyrazole Derivative (4a)
entry
Me2S (mmol)
base (1 mmol)
solvent system
time (h)
yielda (%)
1
2
3
4
5
6
1.5
1.5
1.2
1.2
1.5
1.5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
THF (1 mL)
72
72
36
7
7
12
30
29
57
74
72
36
THF (1 mL)/H2O (0.01 mL)
CH3CN (1 mL)/H2O (0.01 mL)
CH3CN (1 mL)/H2O (0.1 mL)
CH3CN (1 mL)/H2O (0.2 mL)
CH3CN (1 mL)/H2O (0.1 mL)
a Isolated yields of product 4a.
1,3-dipoles under the influence of dimethyl sulfide and
potassium carbonate, in reaction with dialkyl azodicarboxy-
lates as dipolarophiles.
which can easily add to azodicarboxylates to provide the
desired dihydropyrazole derivatives (retrosynthetic strategy
is given in Scheme 1).
In recent years the Baylis-Hillman reaction has become
a popular atom-economy carbon-carbon bond forming
reaction in organic chemistry because it provides useful
classes of densely functionalized molecules in an operation-
ally simple procedure.5,6 Recently, the Baylis-Hillman
bromides/acetates have been conveniently transformed into
carbocyclic derivatives via the phosphine catalyzed (phos-
phorus ylides based) [3 + 6] and [3 + 2] annulation strategy.7
Also sulfur ylides8 derived from the Baylis-Hillman bro-
mides have been employed for the synthesis of cyclopropane
and aziridine derivatives.9 The Baylis-Hillman adducts have
been successfully used for synthesis of pyrazoles via Michael
reaction with hydrazine derivatives followed by cyclization
strategy.3e,10 But to the best of our knowledge, the sulfur
ylides derived from the Baylis-Hillman bromides have not
been employed for [3 + 2] annulation reaction with ap-
propriate dipolarophiles. It therefore occurred to us that sulfur
ylides, derived from the Baylis-Hillman bromides (BH
bromides), might in principle serve as a source of 1,3-dipoles
Scheme 1
.
Retrosynthetic Strategy for the Synthesis of
Dihydropyrazole Derivatives 4
Accordingly, we have first selected methyl (2Z)-2-bromom-
ethyl-3-phenylprop-2-enoate (1a) as a source of 1,3-dipole for
addition onto diethyl azodicarboxylate (DEAD) under the
influence of Me2S. In this direction the best results were
obtained when we treated Baylis-Hillman bromide 1a (1
mmol) with DEAD (3a) (1 mmol) in the presence of Me2S
(1.2 mmol) and K2CO3 (1 mmol) in acetonitrile/water (1 mL:
0.1 mL) solvent system at room temperature for 7 h to provide
the expected dihydropyrazole derivative 4a in 74% isolated
yield. It is interesting to note that use of 0.1 mL of water is
necessary (Table 1, entry 4) probably, to dissolve the in situ
generated salt, thus making the reaction medium homogeneous
leading to faster reaction rate with higher yields. To determine
the generality of this methodology we have successfully
transformed the various Baylis–Hillman bromides (1a-i) into
dihydropyrazole derivatives (4a-r)11 in 64-79% isolated yields
via the simple one-pot reaction with diethyl and diisopropyl
azodicarboxylates (Table 2, entries 1-18).
(5) For leading reviews on the Baylis-Hillman reaction, see: (a)
Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. ReV. 2007, 36, 1581–
1588. (b) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 4614–4628. (c) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana,
T. Chem. ReV. 2003, 103, 811–891. (d) Ciganek, E. Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1997: Vol. 51, p 201–350. (e)
Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R. Tetrahedron 1996, 52,
8001–8062. (f) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653–
4670.
(6) (a) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III Angew.
Chem., Int. Ed. 2007, 46, 1878–1880. (b) Shafiq, Z.; Liu, L.; Liu, Z.; Wang,
D.; Chen, Y.-J. Org. Lett. 2007, 9, 2525–2528. (c) Srivardhana Rao, J.;
Briere, J.-F.; Metzner, P.; Basavaiah, D. Tetrahedron Lett. 2006, 47, 3553–
3556. (d) Deb, I.; Dadwal, M.; Mobin, S. M.; Namboothiri, I. N. N. Org.
Lett. 2006, 8, 1201–1204. (e) Krafft, M. E.; Wright, J. A. Chem. Commun.
2006, 2977–2979. (f) Aroyan, C. E.; Vasbinder, M. M.; Miller, S. J. Org.
Lett. 2005, 7, 3849–3851. (g) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem.
Soc. 2005, 127, 3790–3800. (h) Kataoka, T.; Kinoshita, H. Eur. J. Org.
Chem. 2005, 45–58. (i) Turki, T.; Villieras, J.; Amri, H. Tetrahedron Lett.
2005, 46, 3071–3072. (j) Santos, L. S.; Pavam, C. H.; Almeida, W. P.;
Coelho, F.; Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 43, 4330–4333.
(k) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett. 2004, 6, 1337–1339.
(l) Luo, S.; Mi, X.; Xu, H.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004,
69, 8413–8422. (m) Basavaiah, D.; Sreenivasulu, B.; Jaganmohan Rao, A.
J. Org. Chem. 2003, 68, 5983–5991. (n) Yang, K.-S.; Lee, W.-D.; Pan,
J.-F.; Chen, K. J. Org. Chem. 2003, 68, 915–919. (o) Li, G.; Gao, J.; Wei,
X., II; Enright, M. Org. Lett. 2000, 2, 617–620. (p) Frank, S. A.; Mergott,
D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404–2405. (q) Basavaiah,
D.; Muthukumaran, K.; Sreenivasulu, B. Synthesis 2000, 545–548. (r)
Basavaiah, D.; Suguna Hyma, R.; Padmaja, K.; Krishnamacharyulu, M.
Tetrahedron 1999, 55, 6971–6976.
(7) (a) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987–1989. (b) Du,
Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42, 1035–1037.
(8) For recent references on S-ylides, see: (a) Aggarwal, V. K.; Winn,
C. L. Acc. Chem. Res. 2004, 37, 611–620. (b) Li, A.-H.; Dai, L.-X.;
Aggarwal, V. K. Chem. ReV. 1997, 97, 2341–2372.
(9) (a) Lee, K. Y.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48,
2007–2011. (b) Lee, K. Y.; Kim, S. C.; Kim, J. N. Tetrahedron Lett. 2006,
47, 977–980. (c) Lee, K. Y.; Kim, S. C.; Kim, J. N. Bull. Korean Chem.
Soc. 2006, 27, 319–321.
(10) Pyrazole aldehydes have been employed as electrophiles in the
Baylis-Hillman reaction with activated alkenes. Nag, S.; Singh, V.; Batra,
S. ArkiVoc 2007, 14, 185–203.
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Org. Lett., Vol. 10, No. 9, 2008

Table 2. Synthesis of Dihydropyrazole Derivatives 4a-r via the
Reaction of 1a-i with DEAD (3a) and DIAD (3b)a
Scheme 3. Plausible Mechanism
entry
Ar
C6H5
C6H5
C6H5
4-MeC6H4 Me
4-BrC6H4 Me
4-BrC6H4 Bu
4-ClC6H4 But
4-BrC6H4 But
3-ClC6H4 Me
R
bromides R′ t (h) productb yieldc (%)
1
2
3
4
5
6
7
8
9
Me
Et
But
1a
1b
1c
1d
1e
1f
Et
Et
Et
Et
Et 10
Et 12
7
8
9
8
4a
4b
4c
4d
4e
4f
74
69
68
74
75
66
67
64
69
75
67
69
79
75
71
67
74
70
1g
1h
1i
1a
1b
1c
1d
1e
1f
Et
Et
Et
Pri
Pri
Pri
Pri 10
Pri
Pri 12
Pri
Pri
Pri
9
9
7
8
8
9
4g
4h
4i
4j
4k
4l
4m
4n
4o
4pd
4q
4r
10 C6H5
11 C6H5
12 C6H5
13 4-MeC6H4 Me
14 4-BrC6H4 Me
15 4-BrC6H4 Bu
16 4-ClC6H4 But
17 4-BrC6H4 But
18 3-ClC6H4 Me
Me
Et
But
salt, via the reaction of Baylis-Hillman bromide (1) with
dimethyl sulfide. This salt would become a ylide (2) in the
presence of a base (K2CO3) and then serve as a 1,3-dipole
(or an equivalent) for [3 + 2] annulation reaction with dialkyl
azodicarboxylate (3) to provide the desired functionalized
dihydropyrazole derivative 4.
9
1g
1h
1i
9
9
7
In conclusion, we have developed a novel [3 + 2]
annulation strategy for the synthesis of an interesting class
of pyrazole derivatives, with different substitution profiles,
employing the Baylis-Hillman bromides as a valuable
source of 1,3 dipoles in reaction with dialkyl azodicarboxy-
lates in an operationally simple one-pot procedure.
a All of the reactions were carried out on a 1 mmol scale of BH bromides
(1a-i) with 1 mmol of dialkyl azodicarboxylates (3a, 3b) in the presence
of Me2S (1.2 mmol) and K2CO3 (1 mmol) in CH3CN (1 mL):H2O (0.1
mL) at room temperature. b All of the compounds were isolated as colorless
viscous liquids and fully characterized (see the Supporting Information).
c Isolated yields were based on the BH bromides (1a-i). d On standing
(for about 20-25 days), this compound became solid (mp 110 °C).
Acknowledgment. We thank DST (New Delhi) for
funding this project. S.R. thanks CSIR (New Delhi) for her
research fellowship. We thank UGC (New Delhi) for support
and for providing some instrumental facilities. We thank the
National Single Crystal X-ray Facility funded by DST. We
also thank Professor S. Pal, School of Chemistry, University
of Hyderabad, for helpful discussions regarding X-ray data
analysis.
Scheme 2
.
Synthesis of Dihydropyrazole-4-Carboxylic Acids
5-7a
Supporting Information Available: Experimental pro-
cedures (with all spectral data, crystal data and ORTEP
diagrams), 1H and 13C NMR spectra of all compounds 4a-r,
5, 6, and 7; DEPT 135, NMR spectra for compounds 4d
and 4e, CIF files. This material is available free of charge
via the Internet at http://pubs.acs.org.
a All reactions were carried out on a 0.5 mmol scale of 4l, 4p, and 4q
in the presence of CH3SO3H (1.5 mmol) in dichloromethane (1 mL).
To confirm further the structures of dihydropyrazole
derivatives (4a-r) we have treated three representative esters
4l, 4p, and 4q with CH3SO3H to obtain the corresponding
acids 5-7 respectively as crystalline solids (Scheme 2).
Single crystal X-ray data12 of these acids (5, 6, and 7) are
in complete agreement with the structures (see the Supporting
Information for the ORTEP diagrams of 5, 6, and 7).
A plausible mechanism for this interesting [3 + 2]
annulation strategy is provided in Scheme 3. The reaction is
believed to proceed first through the formation of sulfonium
OL800424V
(11) One of the reviewers has asked the following question: Why does
the double bond favor the spot out of conjugation between the aryl and the
ester? We feel that this is probably due to the fact that the removal of proton
(R to the aryl group) by base followed by double bond shift is not favorable
due to electrionic factors or this might be due to the fact that such kind of
conjugation might result in steric crowding rendering the compound less
stable.
(12) Detailed X-ray crystallographic data is available from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, for compounds 5 (CCDC No.
678381), 6 (CCDC No. 678382), and 7 (CCDC No. 678383).
Org. Lett., Vol. 10, No. 9, 2008
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