New one-pot, efficient, and regioselective method for the synthesis of 3-Trifluoromethyl-1H-1-phenylpyrazoles and alkyl 3-carboxylate analogs

Article abstract of DOI:10.1016/j.tetlet.2012.07.119

An efficient and regioselective procedure for the synthesis of a series of alkyl(aryl/heteroaryl) substituted 3-trifluoromethyl-1H-1-phenylpyrazoles and alkyl 3-carboxylate analogs, from the cyclocondensation reactions of 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones [CX₃C(O)CR²=CR ¹(OMe/OEt), where R¹ = H, Me, Ph, 2-Furyl; R² = H; R¹-R² = -C₄H₈- and X = F, Cl] and 1-phenylsemicarbazide in an acidified alcoholic medium (R ³OH/H₂SO₄), where R³ = Me, Et, Prⁱ was successfully applied and is described here in detail. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.07.119

Tetrahedron Letters 53 (2012) 5488–5491
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Tetrahedron Letters
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New one-pot, efficient, and regioselective method for the synthesis of
3-Trifluoromethyl-1H-1-phenylpyrazoles and alkyl 3-carboxylate analogs
⇑
Helio G. Bonacorso , Michele S. Correa, Liliane M. F. Porte, Everton P. Pittaluga, Nilo Zanatta,
Marcos A. P. Martins
Núcleo de Química de Heterociclos–NUQUIMHE, Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and regioselective procedure for the synthesis of a series of alkyl(aryl/heteroaryl) substituted
3-trifluoromethyl-1H-1-phenylpyrazoles and alkyl 3-carboxylate analogs, from the cyclocondensation
reactions of 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones [CX3C(O)CR2=CR1(OMe/OEt), where R1 = H, Me, Ph,
2-Furyl; R2 = H; R1-R2 = -C4H8- and X = F, Cl] and 1-phenylsemicarbazide in an acidified alcoholic medium
(R3OH/H2SO4), where R3 = Me, Et, Pri was successfully applied and is described here in detail.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 5 July 2012
Revised 24 July 2012
Accepted 26 July 2012
Available online 3 August 2012
Keywords:
Phenylpyrazoles
3-Trifluoromethylpyrazoles
Esterification reactions
Cyclization reactions
Phenylsemicarbazides
The synthesis of pyrazole derivatives has been extensively ex-
plored by our research group through the cyclocondensation reac-
tion of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones and different
hydrazines contemplating their biological activities as analgesic
and anti-inflammatory,1 antimycobacterial,2 antimicrobial,3 antin-
ociceptive,4 and antioxidant agents.5 The method to introduce a
trihalomethyl group into heterocycles based on the above cited tri-
halomethylated building block approach, in most cases regioselec-
tively leads to the C-5 trihalomethyl-substituted pyrazoles or to
mixtures of 1,3- and 1,5-isomers.6
Variously substituted pyrazoles and their derivatives bearing a
diversity of functional groups are important biological agents and
a significant amount of research activity has been directed toward
this class. Special interest has been devoted to developing efficient
approaches to introduce a CF3 group at a pyrazole ring in a regio-
selective manner, mostly because trifluoromethyl-substituted pyr-
azoles at the C-3 position often show pharmacological activities
such as the anti-inflammatory7 CelecoxibÒ and the anticoagulant
RazaxabanÒ.8 Moreover, the phenylpyrazole structure is the scaf-
fold of common worldwide over-the-counter drugs as a potent
antipyretic and analgesic9a,b DipyroneÒ and the insecticide
FipronilÒ.9c
tion usually implement one or more steps from b-diketones, hydra-
zines, and derivatives thereof,10 high-cost solvents11 or present a
limited scope of substituents in the pyrazole ring.12
Therefore, because of the above mentioned importance and our
ongoing research interest in introducing CX3 groups in heterocy-
cles, we have decided to investigate the regioselectivity in the
cyclocondensation reaction of 4-alkoxy-1,1,1-trihaloalk-3-en-2-
ones [CX3C(O) CR2=CR1 (OMe/OEt), where R1 = H, Me, Ph, 2-Furyl;
R2 = H; R1-R2 = -C4H8- and X = F, Cl] and 1-phenylsemicarbazide in
order to regioselectively obtain 3-trihalomethyl-substituted 1-
phenylpyrazoles as the main isomer.
So, in this Letter, we report first a new, simple, and efficient
method for the regio insertion of CF3 group in 1-phenylpyrazoles.
By this new method, the C-3 position of pyrazoles can be selec-
tively trifluormethylated with a good yield under a mild and sim-
ple reaction step, employing facile solvent and catalyst access. In
addition, we also describe the indirect carboxyalkylation reaction
from 3-trichloromethyl-substituted pyrazole analogs under similar
conditions.
The optimized synthesis of 3-trifluoromethyl pyrazoles (4a–e)
from the cyclocondensation reaction of 4-alkoxy-1,1,1-trifluoro-
3-alken-2-ones (1a–e) and 1-phenylsemicarbazide (3) was done
in the presence of sulfuric acid, methanol as the reaction solvent
in a 1:1.5 molar ratio.13,14 In comparison to other polar solvents,
methanol was shown to be more suitable to solubilize the 1-phe-
nylsemicarbazide at room temperature, as well as contributing
more to achieve the desired regioisomer product. The reactions
were performed by stirring the mixtures at 60 °C for 24 h
A literature survey revealed that mixtures of 1,3- and 1,5-regioi-
somers are frequently obtained by various synthetic procedures.10–
12 Studies which increase the regioselectivity in the product forma-
⇑
Corresponding author. Tel.: +55 55 3220 8867; fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.119

H. G. Bonacorso et al. / Tetrahedron Letters 53 (2012) 5488–5491
5489
Table 1
(Scheme 1). Compounds 4a–e were obtained as dark-yellow col-
ored oils with 50–85% yields.15,16
Yield and isomer relationship for compounds 4a–e
Product
Yielda (%)/(Lit.)b
Isomer 1,3:1,5c/(Lit.)b
This methodology resulted in a series of 5-alkyl(aryl/hetero-
aryl)-3-trifluoromethyl-1H-1-phenylpyrazoles (4a–e) in a one-step
reaction without the isolation of 3-hydroxy-pyrazoline ring inter-
mediate. It is probable that the drops of concentrated sulfuric acid
used as catalyst promoted the in situ dehydration of the interme-
diate and lead to the aromatic pyrazoles (4). Besides, it is widely
known that similar acidic condition promotes the hydrolysis of
C(O)-N function with the respective elimination of the carbamoyl
group.17
4a
4b
4c
4d
4e
50/(16)23, (94)24a
77/(70)24c, (80)24b
54
50:50/(100:0)23,24a
100:0/(50:50)24b,c
97:3
d
65/(À )24c, (65)25
100:0/(82:18)24c, (100:0)25
100:0/(100:0)24c
d
85/(À )24c
a
b
c
Yields of isolated products.
Literature data.
GC–MS data analysis.
d
Uninformed yields from literature data.
The structures of all compounds 4a–e were confirmed by 1H
and 13C {1H} NMR, mass spectrometry (GC–MS) data analysis
where the mixture of synthesized regioisomers of this work and
the 5-trifluormethyl-1H-pyrazoles previously acquired were com-
pared.18 The GC chromatograms showed unequivocal specific
retention times for each regioisomer. This comparison permitted
to identify the desired product and proved that the 3-CF3-substi-
tuted pyrazole regioisomers were fully isolated by employing this
new methodology (Table 1).14–16
Consequently, the first attack to the b-olefinic carbon of the vi-
nyl ketone is conducted by N1 with subsequent elimination of an
alcohol molecule (ROH). Hereafter, a second attack promoted by
N2 to the vinyl ketone carbonyl group closes the five membered
ring with subsequent aromatization of the system by the dehydra-
tion and the elimination of the carbamoyl group in a one-step reac-
tion (Scheme 2).
All the results are in agreement to the literature where it is
well-known that the amino group linked to the phenyl ring of 1-
phenylsemicarbazide (N1) is the best nucleophile of the precursor,
while the second amino group (N2) has its nucleophilicity de-
creased due the resonance with the strong electron withdrawing
of the carbamoyl group.19
Following the successful demonstration of the regioselective
trifluoromethylation at C-3 position of pyrazoles 4, we proceeded
to extend the generality of the reaction conditions to trichlorome-
thylated precursors (2a–e). Thus, we employed the 4-alkoxy-1,1,1-
trichloro-3-alken-2-ones (2a–e) aiming to obtain the 3-trichloro-
O
OR
1a-e (X = F)
X3C
R1
2a-e (X = Cl)
R2
X = Cl
ii
X = F
X = Cl
R2
CF3
R2
CO2Me
CO2R3
N
N
N
R1
R1
Me
N
N
N
Ph
Ph
Ph
4a-e
6b-c
5a-e
(75 - 77%)
(51 - 89%)
(50 - 85%)
1-2, 4-6
a
b
c
d
e
Me
R
Et Me Me Me
H
H
R1
R2
R3
Me
H
Et
Ph 2-Furyl
H
-C4H8-
H
i-Pr
Scheme 1. Reagents and conditions: (i) Ph(NH)2CONH2(3),MeOH, H2SO4conc., 60 °C, 24 h; (ii) Ph(NH) CONH2(3), R3OH, H2SO4conc., 60 °C, 24 h.

5490
H. G. Bonacorso et al. / Tetrahedron Letters 53 (2012) 5488–5491
H
O
OR
O
O
OR
R1
R3OH
H
H
N
N
NH2
X3C
R1
Ph
N
H
NH2
X3C
N
R2
R2
Ph
O
- ROH
R2
CF3
X3C
R2
R1
OH2
O
- CO2, -NH3
X=F
H2SO4
NH2
H
N
N
NH2
N
R1
R1
X3C
N
N
N
R2
Ph
O
O
Ph
4
Ph
Scheme 2. Proposed mechanism for the formation of the 3-trifluoromethyl-substituted pyrazoles.
R2
CO2R3
R2
CO2H
R2
CCl3
R3OH
H3O
N
N
N
R1
R1
R1
N
N
N
Ph
Ph
Ph
5, 6
Scheme 3. Proposed convention of the trichloromethyl group to the respective ester.
Table 2
zole-3-carboxylates (6b–c) using other alcohols as the reaction sol-
vents. As a result, we found that the larger the alcohol structure,
the lower the regioselectivity for the resultant ester and conse-
quently also lower yields. Compounds 6b–c were obtained as dark
yellow colored oils in 75–77% yields.14,15,22
The structures of all compounds 5a–e and 6b–c were compared
with the literature data and confirmed by 1H, 13C {1H} NMR, and by
the mass spectrometry (GC-MS) (Table 2).21,22
In conclusion, we have developed a mild, convenient, and im-
proved protocol for the regioselective synthesis of 3-trifluoro-
methyl- and 3-carboxyalkyl-1H-1-phenylpyrazoles in alcoholic
reaction solvents and sulfuric acid as catalyst. The present proce-
dure is carried out in easier work-up and good yields. The method
reported here is not only simple to operate but also efficient for the
achievement of regioselective products.
Yield and isomer relationship of compounds 5a–e and 6b–c
Product
Yielda (%)/(Lit.)b
Isomer 1,3:1,5c
5a
5b
5c
5d
5e
6b
6c
51/(15)26
88
73
70
74:26/(100:0)26
100:0
100:0
100:0
100:0
89
75/(62)27a, (60)27b
77
98:2/(100:0)27a, (À )27b
d
96:4
a
b
c
Yields for isolated products.
Literature data.
GC–MS data analysis.
d
Uninformed yields from literature data.
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. 1H and 13C NMR spectra were acquired on a Bruker
DPX 200 spectrometer (1H at 200.13 MHz and 13C at 50.32 MHz)
or Bruker DPX 400 spectrometer (1H at 400.13 MHz and 13C at
100.61 MHz), 5 mm sample tubes, 298 K, digital resolution
0.01 ppm, in CDCl3, using TMS as internal reference. Mass spectra
were registered in a HP 5973 MSD connected to a HP 6890 GC and
interfaced by a Pentium PC. The GC was equipped with a split–
splitless injector, autosampler, cross-linked HP-5 capillary column
(30 m, 0.32 mm of internal diameter), and He was used as the car-
rier gas.
methyl-substituted pyrazoles under similar conditions. However,
we observed that water present in methanol (reaction solvent)
due to the dehydration reaction and the acid catalyst was respon-
sible for converting the trichloromethyl group to ester similarly as
described previously by us (Scheme 3).20 By this synthetic proce-
dure, a series of methyl-5-alkyl(aryl/heteroaryl)-1H-1-phenylpyra-
zole-3-carboxylates (5a–e) were obtained as dark yellow colored
oils in 51–89% yields (Scheme 1).14,15,21
By taking the compound 5b as standard to propose evaluating
the solvent influence in the isomeric relationship between the
products acquired and to show the versatility of the methodology,
we promoted the synthesis of alkyl-5-methyl-1H-1-phenylpyra-

H. G. Bonacorso et al. / Tetrahedron Letters 53 (2012) 5488–5491
5491
12. Hamper, B. C.; Kurtzweil, M. L.; Beck, J. P. J. Org. Chem. 1992, 57, 5680.
13. (a) Bonacorso, H. G.; Correa, M. S.; Porte, L. M. F.; Martins, M. A. P.; Zanatta, N.
BR Patent deposited on National Institute for Industrial Property INPI
Acknowledgments
-
The authors thank the financial support from Conselho Nacional
de Desenvolvimento Científico e Tecnológico–CNPq (Proc. nr.
303.013/2011-7 and 470.788/2010-0 - Universal). Fellowships
from CAPES and CNPq are also acknowledged.
(PI1105807-2) in agreement to Federal University of Santa Maria, 2011.; (b)
Correa, M. S. Master Dissertation, Federal University of Santa Maria, Brazil,
2011.
14. Synthesis
of
5-alkyl(aryl/heteroaryl)-3-carboxyalkyl/trifluoromethyl)-1H-1-
phenylpyrazoles (4a–e, 5a–e, 6b–c). General procedure: To a stirred solution of
1a–e, 2a–e (1 mmol) and 1-phenylsemicarbazide (3) (1.5 mmol) in (methyl,
ethyl or i-propyl) alcohol (20 mL) was added four drops of concentrated
sulfuric acid. After addition, the reaction mixture was stirred at 60 °C for 24 h,
then water was added (10 mL) and the mixture was neutralized with NaOH
0.1 M. The resulting solution was extracted with dichloromethane (3 Â 30 mL)
and distilled water (2 Â 20 mL). The dichloromethane layer was separated,
dried over anhydrous Na2CO3 and filtered. The solvent was evaporated under
reduced pressure, obtaining the corresponding compounds 4a–e, 5a–e, 6b–c
which were purified following the next procedures.
References and notes
1. (a) Martins, M. A. P.; Sauzem, P. D.; Machado, P.; Rubin, M. A.; Sant’anna, G. S.;
Faber, H. B.; Souza, A. H.; Mello, C. F.; Beck, P.; Burrow, R. A.; Bonacorso, H. G.;
Zanatta, N. Eur. J. Med. Chem. 2008, 43, 1237; (b) Martins, M. A. P.; Machado, P.;
Rosa, F. A.; Rossatto, M.; Sauzem, P. D.; Silva, R. M. S.; Rubin, M. A.; Ferreira, J.;
Bonacorso, H. G.; Zanatta, N. ARKIVOC 2007, xvi, 281.
2. Silva, P. E. A.; Ramosa, D. F.; Bonacorso, H. G.; Iglesia, A. I.; Oliveira, M. R.;
Coelho, T.; Navarini, J.; Morbidoni, H. R.; Zanatta, N.; Martins, M. A. P. Int. J. of
Antimicrob. Ag. 2008, 32, 139.
3. (a) Bonacorso, H. G.; Pittaluga, E. P.; Alves, S. H.; Schaffer, L. F.; Cavinatto, S.;
Porte, L. M. F.; Paim, G. R.; Martins, M. A. P.; Zanatta, N. ARKIVOC 2012, viii, 62.;
(b) Zanatta, N.; Alves, S. H.; Coelho, H. S.; Borchhardt, D. M.; Machado, P.;
Flores, K. M.; Silva, F. M.; Spader, T. B.; Santurio, J. M.; Bonacorso, H. G.; Martins,
M. A. P. Bioorg. Med. Chem. 2007, 15, 1947.
4. Milano, J.; Oliveira, S. M.; Rossato, M. F.; Sauzem, P. D.; Machado, P.; Beck, P.;
Zanatta, N.; Martins, M. A. P.; Mello, C. F.; Rubin, M. A.; Ferreira, J.; Bonacorso,
H. G. Eur. J. Pharmacol. 2008, 581, 86.
15. Compounds 4a–e, 5a–e, 6b–c were obtained as oils and purified by flash
chromatography on silica gel (eluent hexane/ethyl acetate 4:1). Compounds
4a–e, 5a–e, 6b–c were characterized by 1H and 13C NMR and GC–MS.
16. Data of 3-trifluoromethyl-1-phenyl-4,5,6,7-tetrahydro-1H- indazole (4c): Yield
54%, oil. 1H NMR (200.13 MHz, CDCl3): d 7.48–7.47 (m, 5H, Ph), 2.70–2.68 (m,
4H, H-1; H-4), 1.84–1.78 (m, 4H, H-2; H-3). 13C NMR (100.61 MHz, CDCl3): d
2
142.5 (q, JC-F = 38, C-3), 140.0 (Ph), 138.8 (Ph), 129.1 (Ph), 128.6 (Ph), 125.2
1
(Ph), 121.3 (q, JC-F = 268, CF3), 104.7 (C-4), 99.9 (C-5), 12.1 (Me). GC/MS (EI,
70 eV): m/z (%) 266 (M+, 100), 238 (98), 197 (21), 77 (37). Melting points and
yields of compounds 4. Compd. [Physical property, Yield (%)]: 4a [oil, 50]; 4b
[oil, 77]; 4d [oil, 65]; 4e [oil, 85].
5. Bonacorso, H. G.; Cavinatto, S.; Campos, P. T.; Porte, L. M. F.; Navarini, J.; Paim,
G. R.; Martins, M. A. P.; Zanatta, N.; Stuker, C. Z. J. Fluorine Chem. 2012, 135, 303.
6. (a) Cunico, W.; Cechinel, C. A.; Bonacorso, H. G.; Martins, M. A. P.; Zanatta, N.;
de Souza, M. V. N.; Freitas, I. O.; Soares, R. P. P.; Krettli, A. U. Bioorg. Med. Chem.
Lett. 2006, 16, 649; (b) Martins, M. A. P.; Cunico, W.; Brondani, S.; Peres, R. L.;
Zimmermann, N. E. K.; Rosa, A.; Fiss, G. F.; Zanatta, N.; Bonacorso, H. G.
Synthesis 2006, 1485; (c) Bonacorso, H. G.; Wentz, A. P.; Lourega, R. V.; Cechinel,
C. A.; Moraes, T. S.; Coelho, H. S.; Zanatta, N.; Martins, M. A. P.; Höerner, M.;
Alves, S. H. J. Fluorine Chem. 2006, 127, 1066; (d) Bonacorso, H. G.; Porte, L. M.
F.; Cechinel, C. A.; Paim, G. R.; Deon, E. D.; Zanatta, N.; Martins, M. A. P.
Tetrahedron Lett. 2009, 50, 1392.
7. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter,
S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
17. (a) Bonacorso, H. G.; Wastowski, A. D.; Zanatta, N.; Martins, M. A. P.; Naue, J. A.
J. Fluorine Chem. 1998, 92, 23; (b) Bonacorso, H. G.; Wastowski, A. D.; Zanatta,
N.; Martins, M. A. P. Synth. Commun. 2000, 30(8), 1457.
18. Braibante, M. E. F.; Clar, G.; Martins, M. A. P. J. Heterocycl. Chem. 1993, 30, 1159.
19. Shaban, M. E. J. Chem. Soc. Pak. 1988, 10, 235.
20. (a) Martins, M. A. P.; Freitag, R.; Flores, A. F. C.; Zanatta, N. Synthesis 1995, 1491;
(b) Martins, M. A. P.; Flores, A. F. C.; Bastos, G. P.; Sinhorin, A.; Bonacorso, H. G.;
Zanatta, N. Tetrahedron Lett. 2000, 41, 293; (c) Martins, M. A. P.; Cunico, W.;
Pereira, C. M. P.; Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H. G.; Zanatta, N. Cur.
Org. Chem. 2004, 1, 391. and references cited therein.
21. Data of methyl-5-methyl-1H-1-phenylpyrazole-3-carboxylate (5b): Yield 88%, oil.
1H NMR (200.13 MHz, CDCl3): 7.49–7.43 (m, 5H, Ph); 6.75 (s, 1H, H-4); 3.93 (s,
3H, Me); 2.34 (s, 3H, CH3). 13C NMR (100.61 MHz, CDCl3): 162.9 (CO); 143.3 (C-
3); 140.5 (C-5); 139.0 (Ph); 129.0 (Ph); 128.5 (Ph); 125.3 (Ph), 109.1 (C-4); 51.8
(Me); 12.2 (CH3). GC–MS (EI, 70 eV): m/z (%) 218 (M+, 80), 187 (100), 159 (53),
77 (96). Melting points and yields of compounds 5. Compd. [Physical property,
Yield (%)]: 5a [oil, 51]; 5c [oil, 73]; 5d [oil, 70]; 5e [oil, 89].
22. Data of isopropyl 5-methyl-1H-1-phenylpyrazole-3-carboxylate (6c): Yield 77%,
oil. 1H NMR (200.13 MHz, CDCl3): d 7.46 (s, 5H, Ph), 6.72 (s, 1H, H-4), 4.95–4.83
(m, 1H, H), 2.33 (s, 3H, Me), 1.24 (d, J = 6, 6H, Me). 13C NMR (50.32 MHz,
CDCl3): d 162.0 (CO), 156.8 (C-3), 140.2 (C-5), 138.9 (Ph), 128.9 (Ph), 128.3 (Ph),
125.3 (Ph), 112.9 (C-4), 68.2 (CH), 21.8 (Me), 12.1 (Me). GC/MS (EI, 70 eV): m/z
(%) 244 (M+, 24), 185 (79), 158 (100), 77 (21). Melting point and yield of
compound 6b: oil, 75%.
23. Tanaka, K.; Maeno, S.; Mitsuhashi, K. Bull. Chem. Jpn. 1985, 58, 1841.
24. (a) Cristau, H.; Cellier, P. P.; Spindler, J.; Taillefer, M. Eur. J. Org. Chem. 2004,
695; (b) Martins, M. A. P.; Pereira, C. M. P.; Moura, S.; Frizzo, C. P.; Beck, P.;
Zanatta, N.; Bonacorso, H. G.; Flores, A. F. C. J. Heterocycl. Chem. 2007, 44, 1195;
(c) Sloop, J. C.; Bumgardner, C. L.; Loehle, W. D. J. Fluorine Chem. 2002, 118, 135.
25. Diab, J.; Laurent, A.; Le Dréan, I. J. Fluorine Chem. 1997, 84, 145.
26. Molteni, G.; Pont, A.; Orlani, M. New J. Chem. 2002, 26, 1340.
8. Varnes, J. D.; Wacker, D. A.; Pinto, D. J. P.; Orwat, M. J.; Theroff, J. P.; Wells, B.;
Galemo, R. A.; Luettgen, J. M.; Knabb, R. M.; Bai, S.; He, K.; Lam, P. Y. S.; Wexler,
R. R. Bioorg. Med. Chem. Lett. 2008, 18, 749.
9. (a) Levy, M.; Zylber-Katz, E.; Rosenkranz, B. Clin. Pharmacokinet. 1995, 28, 216;
(b) Lorenzetti, B. B.; Ferreira, S. H. Eur. J. Pharmacol. 1985, 114, 375; (c) Stevens,
M. M.; Helliwell, S.; Warren, G. N. Field Crops Res. 1998, 57, 195.
10. (a) Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1998, 39, 489; (b)
Sing, S. P.; Kumar, D.; Batra, H.; Naithani, R.; Rozas, I.; Elguero, J. Can. J. Chem.
2000, 78, 1109; (c) Song, L. P.; Chu, Q. L.; Zhu, S. Z. J. Fluorine Chem. 2001, 107,
107; (d) Zhu, S. Z.; Wang, Y. L.; Peng, W. M.; Song, L. P.; Jin, G. F. Curr. Org. Chem.
2002, 6, 1057; (e) Hojo, M.; Okada, E.; Masuda, R. Heterocycles 1992, 34, 791; (f)
Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753;
(g) Singh, S. P.; Kumar, V.; Aggarwal, R.; Elguero, J. J. Heterocycl. Chem. 2006, 43,
1003.
11. (a) Fustero, S.; Román, R.; Sanz-Cervera, J. F.; Simón-Fuentes, A.; Cuñat, A. C.;
Villanova, S.; Murguía, M. J. Org. Chem. 2008, 73, 3523; (b) Raghupathi, R. A.;
Goverdhan, G.; Sampath, A.; Thirupathi, R. A.; Yakambram, B. US Patent 2008/
0234491 A1, 2008.
27. (a) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990, 55, 13; (b) Schmidt,
A.; Habeck, T.; Kindermann, M. K.; Nieger, M. J. Org. Chem. 2003, 68, 5977.