Convenient synthesis of highly functionalized pyrazolines via mild, photoactivated 1,3-dipolar cycloaddition

Article abstract of DOI:10.1021/ol7017328

A mild, photoactivated 1,3-dipolar cycloaddition procedure was successfully developed for the synthesis of polysubstituted pyrazolines. This procedure involved the in situ generation of the reactive nitrile imine dipoles using a hand-held UV lamp at 302 n

Full text of DOI:10.1021/ol7017328

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4155-4158
Convenient Synthesis of Highly
Functionalized Pyrazolines via Mild,
Photoactivated 1,3-Dipolar Cycloaddition
Yizhong Wang, Claudia I. Rivera Vera, and Qing Lin*
Department of Chemistry, UniVersity at Buffalo, the State UniVersity of New York,
Buffalo, New York 14260
qinglin@buffalo.edu
Received July 20, 2007
ABSTRACT
A mild, photoactivated 1,3-dipolar cycloaddition procedure was successfully developed for the synthesis of polysubstituted pyrazolines. This
procedure involved the in situ generation of the reactive nitrile imine dipoles using a hand-held UV lamp at 302 nm, followed by spontaneous
cycloaddition with a broad range of 1,3-dipolarophiles with excellent solvent compatibility, functional group tolerance, regioselectivity, and
yield.
Pyrazolines are an important class of heterocycles with
myriad biological activities, including anticancer activity by
inhibiting kinesin spindle proteins, antibacterial activity
against Helicobacter pylori, antiviral activity against the West
Nile virus, anti-obesity agents by antagonizing CB1 recep-
tors, and therapeutic candidates for Parkinson’s disease.1
Among various synthetic methods to prepare pyrazolines,
1,3-dipolar cycloaddition between nitrile imine dipoles and
alkene dipolarophiles is particularly attractive because of the
high regioselectivity and broad functional group tolerance.2
The nitrile imine dipole can be generated either by treating
R-halohydrazones with base3 or by subjecting tetrazole
precursors to heating4 or photolysis5 (Scheme 1). We are
Scheme 1. Synthesis of Functionalized Pyrazolines via
1,3-Dipolar Cycloaddition
(1) (a) Lange, J. H. M.; Coolen, H. K. A. C.; vanStuivenberg, H. H.;
Dijksman, J. A. R.; Herremans, A. H. J.; Ronken, E.; Keizer, H. G.; Tipker,
K.; McCreary, A. C.; Veerman, W.; Wals, H. C.; Stork, B.; Verveer, P. C.;
denHartog, A. P.; deJong, N. M. J.; Adolfs, T. J. P.; Hoogendoorn, J.; Kruse,
C. G. J. Med. Chem. 2004, 47, 627-643. (b) Chimenti, F.; Bolasco, A.;
Manna, F.; Secci, D.; Chimenti, P.; Befani, O.; Turini, P.; Giovannini, V.;
Mondovi, B.; Cirilli, R.; La Torre, F. J. Med. Chem. 2004, 47, 2071-
2074. (c) Camacho, M. E.; Leon, J.; Entrena, A.; Velasco, G.; Carrion, M.
D.; Escames, G.; Vivo, A.; Acuna-Castroviejo, D.; Gallo, M. A.; Espinosa,
A. J. Med. Chem. 2004, 47, 5641-5650. (d) Chimenti, F.; Bizzarri, B.;
Manna, F.; Bolasco, A.; Secci, D.; Chimenti, P.; Granese, A.; Rivanera,
D.; Lilli, D.; Scaltrito, M. M.; Brenciaglia, M. I. Bioorg. Med. Chem. Lett.
2005, 15, 603-607. (e) Rajendra Prasad, Y.; Lakshmana Rao, A.; Prasoona,
L.; Murali, K.; Ravi Kumar, P. Bioorg. Med. Chem. Lett. 2005, 15, 5030-
5034. (f) Cox, C. D.; Torrent, M.; Breslin, M. J.; Mariano, B. J.; Whitman,
D. B.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber,
M. D.; Lobell, R. B.; Tao, W.; South, V. J.; Kohl, N. E.; Yan, Y.; Kuo, L.
C.; Prueksaritanont, T.; Slaughter, D. E.; Li, C.; Mahan, E.; Lu, B.; Hartman,
G. D. Bioorg. Med. Chem. Lett. 2006, 16, 3175-3179. (g) Goodell, J. R.;
Puig-Basagoiti, F.; Forshey, B. M.; Shi, P. Y.; Ferguson, D. M. J. Med.
Chem. 2006, 49, 2127-2137.
particularly interested in the photoactivation approach be-
cause of the potential of the use of tetrazoles as photoacti-
vatable building blocks in the protein target-guided in situ
synthesis of small-molecule inhibitors.6
(2) (a) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565-598. (b)
Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 633-645. (c) Bianchi, G.;
Gandolfi, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; pp 470-477.
10.1021/ol7017328 CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/15/2007

The photoactivated 1,3-dipolar cycloaddition reaction was
first reported by Huisgen and co-workers between 2,5-
diphenyltetrazole and methyl crotonate in benzene.5a The
presence of the short-lived nitrile imine intermediate was
Table 1. Photoactivated 1,3-Dipolar Cycloaddition of 1a and
2a in Various Solventsa
established by the 15N-labeled fragmentation study.7
A
remarkable rate acceleration was observed when the reaction
was performed in aqueous medium,8 consistent with a
concerted reaction mechanism. However, in all the photo-
activation approaches, an intense 450-W Hanovia immersion
lamp with broad emission spectrum was used, severely
limiting the range of applications suitable for the reaction.
As a result, there were only a few reports in the literature in
the past 40 years that utilized this photoactivation approach
for the synthesis of pyrazoline compounds.5b,c Herein, we
report an extremely mild photoactivation procedure that
allows for rapid synthesis of highly functionalized pyrazo-
lines from easily accessible diaryl-tetrazole building blocks.9
Because of high quantum yield of the photolysis (0.5-
0.9) in generating the reactive nitrile imine intermediate,10
we found that a hand-held benchtop UV lamp (UVP, 302
nm, 0.16 AMPS, typically used in the lab for TLC monitor-
ing) was sufficiently robust to initiate the reactions. In our
initial study, a reaction mixture containing 1 equiv of
tetrazole (1a) and 20 equiv of methyl methacrylate (2a) in
common organic solvents, as well as an EtOH/H2O solvent
mixture, was irradiated for 2 h at room temperature. In almost
all cases, pure product (3aa) was obtained in quantative
yields after evaporation of solvents and excess reagents
(Table 1), based on the 1H NMR and mass spectrometry data.
The cycloaddition was found to be insensitive to solvent
polarity (entries 1-10) and tolerant of protic solvents
including H2O (entries 2-4, 11). The reaction was highly
regioselective as the opposite regioisomer 3aa′ was not
observed in all conditions we tested. Further experiments
indicated that the amount of dipolarophile 2a can be reduced
to 1 equiv without detectable decrease in yield and regio-
selectivity.
yield (%)b
entry
solvent
3aa
3aa′
1
2
3
4
5
6
7
8
PhH
iPrOH
EtOH
MeOH
EtOAc
CH2Cl2
THF
hexane
MeCN
DMF
99.2
96.3
97.7
85.0
100
100
100
100
9
10
11
92.1
100
7:3 EtOH/H2O
100
a Reactions were conducted by irradiating 5.5 mg of 1a and 20 equiv of
2a in 2 mL of solvent in quartz test tubes. b Crude yields after evaporation
of solvent and excess 2a.
activation procedure, and the results are summarized in Table
2. The regiochemistry was determined by NMR signals of
the pyrazoline ring protons. All electron-deficient alkenes
gave excellent yields and exclusive regioselectivity with the
electron-withdrawing group residing at the C5-position, for
example, monosubstituted ethylenes (entries 2, 3) and gem-
disubstituted ethylenes (entries 7-9). It is noteworthy that
the in situ generated reactive nitrile imine reacted selectively
with alkenes over the nitrile and aldehyde groups (entries 2,
9). Simple alkenes such as 1-decene afforded the pyrazoline
product with a moderate yield after 2 h irradiation (entry
10). Conjugate alkenes such as styrene derivatives were also
efficient dipolarophiles (entries 11-19). Yields were gener-
ally higher when styrene rings carry electron-withdrawing
groups such as halogens and the cyano group (entries 14-
18). Interestingly, a cyclic styrene analog, indene, also
participated in this photoactivated cycloaddition, giving the
fused ring product with 87% isolated yield (entry 19). A
small amount of oxidized pyrazole products was isolated for
methyl acrylate and styrene dipolarophiles (entries 1, 11);
however, it appears the occurrence is structure-dependent
because it was not observed for other dipolarophiles we
tested. For electron-rich alkenes such as n-butyl vinyl ether,
tetrazine (dimer of nitrile imine) was isolated instead of the
pyrazoline adduct, presumably due to MO mismatch between
the nitrile imine dipole and the electron-rich dipolarophiles.11
Next, we examined the reactivity of a range of 1,3-
dipolarophiles toward tetrazole 1a using this mild photo-
(3) (a) Wang, Y. G.; Zhang, J.; Lin, X. F. Syn. Lett. 2003, 10, 1467-
1468. (b) Sibi, M. P.; Stanley, L. M.; Jasperse, C. P. J. Am. Chem. Soc.
2005, 127, 8276-8277. (c) Manyem, S.; Sibi, M. P.; Lushington, G. H.;
Neuenswander, B.; Schoenen, F.; Aube, J. J. Comb. Chem. 2007, 9, 20-
28.
(4) (a) Huisgen, R.; Seidel, M.; Sauer, J.; McFarland, J. W.; Wallbillich,
G. J. Org. Chem. 1959, 24, 892-893. (b) Huisgen, M.; Seidel, M.;
Wallbillich, G.; Knupfer, H. Tetrahedron 1962, 17, 3-29. (c) Atir, R.;
Mallouk, S.; Bougrin, K.; Soufiaoui, M. Synth. Commun. 2006, 36, 111-
120.
(5) (a) Clovis, J. S.; Eckell, A.; Huisgen, R.; Sustmann, R. Chem. Ber.
1967, 100, 60-70. (b) Angadiyavar, C. S.; George, M. V. J. Org. Chem.
1971, 36, 1589-1594. (c) Padwa, A.; Nahm, S.; Sato, E. J. Org. Chem.
1978, 43, 1664-1671.
(6) For a recent example, see: Manetsch, R.; Krasinski, A.; Radic, Z.;
Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J. Am. Chem. Soc.
2004, 126, 12809-12818.
(7) Toubro, N. H.; Holm, A. J. Am. Chem. Soc. 1980, 102, 2093-2094.
(8) (a) Molteni, G.; Orlandi, M.; Broggini, G. J. Chem. Soc., Perkin
Trans. 1 2000, 3742-3745. (b) Molteni, G.; Ponti, A.; Orlandi, M. New J.
Chem. 2002, 26, 1340-1345.
(9) (a) Ito, S.; Tanaka, Y.; Kakehi, A.; Kondo, K. Bull. Chem. Soc. Jpn.
1976, 49, 1920-1923. (b) Ito, S.; Tanaka, Y.; Kakehi, A. Bull. Chem. Soc.
Jpn. 1976, 49, 762-766.
(10) Lohse, V.; Leihkauf, P.; Csongar, C.; Tomaschewski, G. J. Prakt.
Chem. 1988, 330, 406-414.
(11) (a) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem.
Soc. 1973, 95, 7301-7315. (b) Houk, K. N. Acc. Chem. Res. 1975, 8, 361-
369.
4156
Org. Lett., Vol. 9, No. 21, 2007

Table 2. Photoactivated 1,3-Dipolar Cycloaddition of 1a with Diverse Dipolarophilesa
a Reactions were conducted by irradiating 5.5 mg of 1a and 2.0 equiv of 2 in 2 mL of benzene in quartz test tubes for 2 h using a hand-held 302 nm UV
lamp unless otherwise specified. Yields were isolated yields. b The yield of the oxidized side product was given in the parenthesis. c Reactions were conducted
by irradiating 13.0 mg of 1a and 2.0 equiv of 2 in 2 mL of benzene for 2 h. d EtOH was used as the solvent. e EtOAc was used as the solvent.
We further examined the reactivity of various 2,5-
disubstituted tetrazoles, and the results are summarized in
Table 3. Both electron-rich and electron-neutral diaryl-
tetrazoles reacted with 2a regioselectively and afforded the
pyrazoline products in excellent yields (entries 1-6, 8, 9).
However, when a nitro group was introduced into either the
N2- or C5-phenyl ring, the photolysis of tetrazoles slowed
down significantly such that an estimated 80-90% of starting
materials remained after 2 h photoirradiation (entries 7, 13).
It is noteworthy that carboxylic acid can be tolerated during
the reaction (entry 10). In addition, a tetrazole directly
substituted with a carboxylate group at the C5-position gave
Org. Lett., Vol. 9, No. 21, 2007
4157

Scheme 2. Synthesis of Nutlin-3 Analog via Photoactivated
Table 3. Photoactivated 1,3-Dipolar Cycloaddition of 2a with
Various Tetrazolesa
1,3-Dipolar Cycloaddition
tetrazole
yield (%)b
entry
no.
R1
R2
(recovered 1 (%))
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
p-MeOPh
p-MeOPh
p-MeOPh
p-MeOPh
p-MePh
Ph
100
100
100
100
89
99
20 (80)c
95
100
93d
82
88
10 (90)c
98
p-MePh
p-ClPh
p-BrPh
Ph
p-MePh
p-O2NPh
p-BrPh
p-ClPh
Ph
p-NMe2Ph
Ph
p-MePh
p-ClPh
p-MePh
p-MePh
2,4-(MeO)2Ph
2,4-(MeO)2Ph
p-(HOOC)Ph
p-EtOOCPh
2-Pyridyl
p-O2NPh
EtOOC
a Reactions were conducted by irradiating 6 µL of 2a and 1 equiv of 1
in 2 mL of benzene, unless otherwise indicated, in quartz test tubes for 2
h. b Crude yields after solvent romoval. c Yields were determined by 1H
NMR. d Reaction was performed in EtOH.
the methyl group followed by alkylation with 2 equiv of
2-iodopropane at 50 °C under the basic condition. Irradiating
5 with a 302 nm hand-held UV lamp in the presence of 1.25
equiv of 4-chlorostyrene for 4.5 h afforded the pyrazoline
analog 6 with an isolated yield of 54%.
In summary, we have shown a mild, photoactivated 1,3-
dipolar cycloaddition procedure for the synthesis of polysub-
stituted pyrazolines. The employment of this procedure for
protein target-guided in situ synthesis of pyrazoline analogs
is currently underway.
an excellent yield during the cycloaddition (entry 14),
suggesting that the tetrazole structure can be significantly
expanded beyond the diaryl system.
To illustrate the utility of this mild photoactivation
procedure in synthesizing highly functionalized pyrazolines,
we prepared a water-soluble pyrazoline analog 6, which
contains an isomeric core while retaining three key hydro-
phobic appendages of Nutlin-3,12 a potent MDM2 inihibitor
(Scheme 2). An appropriately functionalized 2,5-disubstituted
tetrazole 4 was prepared from 4-hydroxy-2-methoxybenzal-
dehyde in three steps with an overall yield of 42%. The
isopropyl-containing tetrazole 5 was subsequently obtained
by treating 4 with 0.6 equiv of BBr3 to selectively remove
Acknowledgment. We gratefully acknowledge the Pe-
troleum Research Fund (Grant No. PRF 45503-G4), SUNY
Buffalo, and New York State Center of Excellence in
Bioinformatics and Life Sciences for financial support.
Supporting Information Available: Experimental details
and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.;
Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.;
Liu, E. A. Science 2004, 303, 844-848.
OL7017328
4158
Org. Lett., Vol. 9, No. 21, 2007