Synthesis of hexa(methyl/phenyl) substituted pyrazolines and thermolysis to hexasubstituted cyclopropanes

Article abstract of DOI:10.1002/jhet.266

(Chemical Equation Presented) Addition of methyllithium to the 3-position of 4,5-dihydro-3,4,4,5,5-pentasubstituted-N-tosyl-1H-pyrazoles [1a 4,4,5,5-tetramethyl-3-phenyl; 1b 4,4,5-trimethyl-3,5-diphenyl; 1c 4,4-dimethyl-3,5,5-triphenyl] produced the corre

Full text of DOI:10.1002/jhet.266

September 2010
Synthesis of Hexa(methyl/phenyl) Substituted Pyrazolines and
Thermolysis to Hexasubstituted Cyclopropanes
1255
Alfons L. Baumstark,* G. Davon Kennedy,* P. C. Vasquez,
N. Desalegn, and Phong Truong
Department of Chemistry, Center for Biotechnology and Drug Design Georgia State University,
Atlanta, Georgia 30302-4098
*E-mail: chealb@langate.gsu.edu or davon@gsu.edu
Received May 22, 2009
DOI 10.1002/jhet.266
Published online 18 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Addition of methyllithium to the 3-position of 4,5-dihydro-3,4,4,5,5-pentasubstituted-N-tosyl-1H-pyra-
zoles [1a 4,4,5,5-tetramethyl-3-phenyl; 1b 4,4,5-trimethyl-3,5-diphenyl; 1c 4,4-dimethyl-3,5,5-triphenyl]
produced the corresponding hexasubstituted pyrazolines, 2a-c, as the only isolable products. For 2b, the
3,5-phenyl groups were found to be exclusively cis, indicative of facial specificity for the addition reac-
tion. The reaction of phenyllithium with 1b yielded 2c as the minor product. For phenyllithium addition,
direct attack on sulfur of the tosyl group with subsequent loss of phenyl p-tolylsulfone was the major
pathway vs. the SN2i attack at carbon-3. Thermolysis of pyrazolines 2a-c, at 200ꢀC, smoothly produced
the hexasubstituted cyclopropanes [3a 1,1,2,2,3-pentamethyl-3-phenylcyclopropane; 3b cis-1,1,2,3-tetra-
methyl-2,3-diphenylcyclopropane; 3c 1,1,2-trimethyl-2,3,3-triphenylcyclopropane] in excellent yield.
J. Heterocyclic Chem., 47, 1255 (2010).
INTRODUCTION
gon (rxn 1) yielded the hexasubstituted pyrazolines, 2a-
c, respectively, as the only isolated products, in variable
yields. Recovered (unreacted) starting materials
accounted for the remaining product balance. The 3,5-
phenyl groups in
We have an ongoing interest in the development of gen-
eral methods for the synthesis of highly substituted cyclo-
propanes, particularly hexasubstituted systems. Historically,
preferred methods for cyclopropane synthesis include pyra-
zoline thermolysis [For a review and recent articles see ref
1] and carbene/carbenoid addition [2] to alkenes. However,
the latter method generally does not work well for the
preparation of hexasubstituted compounds. Our approach
has focused on synthesis and subsequent thermolysis of
highly substituted pyrazolines. We have developed a meth-
odology for the efficient synthesis of a series of 1-alkoxy
and 1-acetoxy-1,2,2,3,3-pentasubstituted cyclopropanes [3].
However, routes to hexa(alkyl/aryl) substituted cyclopro-
panes are scarce and often highly specialized. [For cyclo-
propanation with dimethylcarbene, From photolysis of
hexaalkylcyclohexane-1,3,5-trione, From reduction of a,c-
dibromides see ref. 4]. We report here a route to hexa(m-
ethyl/phenyl) substituted cyclopropanes via the synthesis
and subsequent thermolysis of hexasubstituted pyrazolines.
2b were found to be exclusively cis based on NMR
data, indicating preferential reaction of the methyl-
lithium with only one face of 1b. Compounds 2a-c were
characterized by spectra and physical data.
The synthesis of 2c was also accomplished in 25%
yield by the reaction of phenyllithium with 1b.
The remaining products were indicative of the formation
of 4,5-dihydro-4,4,5,5-tetramethyl-3-phenyl-1H-pyrazole
[with subsequent air oxidation and decomposition] and
phenyl tolylsulfone. Unlike the reaction with methyl-
lithium, that with phenyllithium yielded products
RESULTS AND DISCUSSION
Addition of methylithium to 4,5-dihydro-3,4,4,5,5-
pentasubstituted-N-tosyl-1H-pyrazoles, 1a-c, under ar-
C
V
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A. L. Baumstark, G. Davon Kennedy, P. C. Vasquez, N. Desalegn, and P. Truong
Vol 47
Scheme 2. Proposed mechanism for the thermolysis of 2b.
tuted pyrazoline (4H-pyrazole) had been documented,
but there appear to be no additional reports since that
early work [5]. This is likely due to the inherent proper-
ties (air sensitivity, etc.) of selected 4,5-dihydro-1H-pyr-
azoles [6]. In addition, attempted N-tosylation of 4,5-
dihydro-1H-pyrazoles with tosyl chloride, surprisingly,
can yield unexpected products, 3-chloro pyrazolines [7]
rather than the expected N-tosylated compounds. Recent
development of synthetic methodology for the synthesis
of 4,5-dihydro, N-tosyl-1H-pyrazoles was the key for
the preparation of the required starting materials [8].
The addition of methyllithium to the N-tosyl 4,5-dihy-
dro-1H-pyrazoles proceeded smoothly to generate the
highly substituted pyrazolines. Interestingly, the results
for conversion of 1b to 2b indicate a facial specificity
of the attack of the methyllithium by an SN2i mecha-
nism as shown in Scheme 1 below.
Figure 1. X-ray structure of 3b.
indicative of preferential attack of phenyllithium on the
tosyl group.
Thermolysis of pyrazolines 2a-c, neat, at 200ꢀC, pro-
duced the hexasubstituted cyclopropanes in excellent
yield (rxn 2). The thermolysis of cis 2b yielded cis 3b
in
For methyllithium, this route appears to be the
favored mode of attack. Results with phenyllithium
showed this route to be the minor pathway with direct
reaction of phenyllithium with the sulfur of the tosyl
group being the major pathway that appears to limit the
scope of reaction 1.
Thermolysis of pyrazolines to cyclopropanes, in high
yield, is a well established route [1]. Thermal decompo-
sition of pyrazolines to cyclopropanes generally is
thought to occur via a diradical mechanism that favors
retention of configuration [1,9]. The present results are
consistent with the diradical mechanism shown below in
Scheme 2 for thermolysis of 2b.
In conclusion, the addition of methyllithium to N-
tosyl-4,5-dihydro-1H-pyrazoles and subsequent thermo-
lysis of the pyrazolines is a useful method for the syn-
thesis of highly substituted cyclopropanes. The method
has obvious limitations in that the substituents must be
stable to organolithium reagents but appears to provide
a more general route to this type of highly substituted
strained ring compound. Work is in progress to explore
the scope of this route.
84% isolated yield. Analysis of the reaction mixture
indicated that the product was a 95%/5% mixture of the
cis/trans cyclopropane. Retention of configuration
occurred with 95% efficiency. The cyclopropanes were
characterized by spectra and physical data. The structure
of 3b, the major product, was confirmed by X-ray crys-
tallography (Fig. 1) to have the cis-2,3-diphenyl
configuration.
The addition of methyllithium to the 3-position of N-
tosylated 4,5-dihydro-1H-pyrazoles to yield a tetrasubsti-
Scheme 1. Proposed pathway for methyl addition to position-3 for 1b.
EXPERIMENTAL
The N-tosylated-4,5-dihydro-1H-pyrazoles, 1a-c, were pre-
pared according to published results [8]. Methyllithium (1.6M)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Hexa(methyl/phenyl) Substituted Pyrazolines and
Thermolysis to Hexasubstituted Cyclopropanes
1257
in diethyl ether and phenyl lithium (1.8M) in cyclohexane-
ether were purchased from Sigma–Aldrich Company and used
without further purification. All solvents were commercially
available. Anhydrous toluene, anhydrous ether, and methanol
were purchased from Aldrich Company and used without fur-
ther purification. Tetrahydrofuran (Aldrich) was distilled from
sodium and benzophenone before use. Acetone, ethanol, and
hexane were purchased from Fisher Scientific Company. All
1H and 13C NMR spectra were obtained from a Varian Unity
Plus 300 MHz instrument. Mass spectra were obtained from a
Shimadzu GP-5000 Mass Spectrometer. Elemental analyses
were performed at the Department of Chemistry at Georgia
State University and at Atlantic Microlab, Atlanta, Georgia.
Melting points were recorded in a calibrated Thomas Hoover
Unimelt apparatus. Exact mass analyses were performed at the
Georgia Institute of Technology. X-ray crystallography was
performed at Emory University.
Synthesis of 3,3,4,4,5-pentamethyl-5-phenyl-4,5-dihydro-
3H-pyrazole (2a). 4,4,5,5-Tetramethyl-3-phenyl-1-(toluene-4-
sulfonyl)-4,5-dihydro-1H-pyrazole (1a) (0.30 g, 0.8415 mmol)
was dissolved in anhydrous toluene (25 mL) under argon
atmosphere. The solution was cooled to 0ꢀC with an ice bath.
Then, methyllithium (2 mL, 3.2 mmol, 3.8 mole equiv) was
added to the solution using a dried glass syringe. The solu-
tion was stirred for 30 min at 0ꢀC and 24 h at room tempera-
ture. Then, the reaction was quenched with 10 mL of satu-
rated, degassed ammonium chloride solution. Diethyl ether
(20 mL) was added to the mixture before washing with satu-
rated sodium bicarbonate (2 ꢁ 20 mL) solution and deion-
ized water (30 mL). The organic layer was dried over mag-
nesium sulfate. The solvent was removed under reduced
pressure. The crude product was purified by flash chromatog-
raphy (hexane/ethyl acetate [95:5]) to give 2a in an isolated
yield of 87% (0.158 g, 0.732 mmol) as a clear and viscous
liquid; 1H NMR (CDCl3) 300 MHz: d 0.34 (s, 3H), d 1.07
(s, 3H), d 1.30 (s, 3H), d 1.35 (s, 3H), d 1.60 (s, 3H), d
7.25–7.36 (m, 5H); 13C NMR (CDCl3) 300 MHz: 20.5, 23.9,
23.9, 24.1, 25.1, 41.8, 91.7, 96.0, 125.5, 126.8, 128.0, 143.8;
Exact Mass Anal. Calcd. for C14H21N2 ¼ 217.17047. Found:
217.17060.
cmꢂ1, 703 cmꢂ1; Anal. Calcd. for C19H22N2 ¼ C, 81.97, H,
7.97, N, 10.06% Found: C, 81.79, H, 8.19, N, 9.66%.
Synthesis of 3,4,4-trimethyl-3,5,5-triphenyl-4,5-dihydro-
3H-pyrazole (2c). 4,4-Dimethyl-3,5,5-triphenyl-1-(toluene-4-
sulfonyl)-4,5-dihydro-1H-pyrazole (1c) (0.5 g, 1.040 mmol)
was dissolved in anhydrous THF (50 mL) under argon atmos-
phere. The solution was cooled to 0ꢀC with an ice bath. Then,
methyllithium (2.6 mL, 4.16 mmol, 4 Eq.) was added to the
solution using a dried glass syringe. The solution was stirred
for 30 min at 0ꢀC and 36 additional hours at room tempera-
ture. The mixture was quenched with 10 mL of saturated,
degassed ammonium chloride solution. Diethyl ether (20 mL)
was added to the reaction before washing with saturated so-
dium bicarbonate (2 ꢁ 40 mL) solution and deionized water
(40 mL). The organic layer was dried over magnesium sulfate.
The solvent was removed under reduced pressure. The crude
product was purified by chromatatron (hexane/ethyl acetate) to
give 2c in an isolated yield of 55% (0.19 g, 0.558 mmol) mp
¼ 117–118ꢀC; 1H NMR CDCl3) 300 MHz: d 0.15 (s, 3H), d
1.16 (s, 3H), d 1.56 (s, 3H), d 7.16–7.97 (m, 15H); 13C NMR
(CDCl3) 300 MHz: 20.7, 21.8, 27.3, 46.6, 96.6, 97.6, 125.7,
126.5, 126.7, 127.0, 127.2, 128.0, 128.1, 142.6, 143.5, 143.9;
Anal. Calcd. for C24H24N2: C, 84.67, H, 7.11, N, 8.23%
Found: C, 84.73, H, 7.19, N, 8.26%.
Synthesis of 1,1,2,2,3-pentamethyl-3-phenylcyclopropane
(3a). 3,3,4,4,5-Pentamethyl-5-phenyl-4,5-dihydro-3H-pyrazole
(2a) (0.100 g, 0.462 mmol) was placed in an NMR tube and
purged with argon gas. The tube was then heated in a silicon
oil bath at 200ꢀC 6 2 for 4 h. When the viscous liquid was
heated, evolution of gas (nitrogen) was observed. The NMR
tube was removed from the oil bath after 4 h of heating and
hexane was added to dissolve the products. The crude product
was purified by chromatatron (hexanes) to yield 93% of 3a
(0.081 g, 0.429 mmol) as a clear viscous liquid. 1H NMR
(CDCl3) 300 MHz: d 0.92 (s, 6H), d 1.16 (s, 6H), d 1.23 (s,
1
3H), d 7.1–7.3 (m, 5H); lit. H NMR d 0.91 (s, 6H), d 1.15 (s,
6H), d 1.23 (s, 3H), d 7.12 (m, 5H) (Gloss et al., 1966; 13C
NMR (CDCl3) 300 MHz: 18.5, 21.70, 21.74, 23.9, 29.7, 33.6,
125.0, 127.9, 130.7, 146.0.
Synthesis of cis-1,1,2,3-tetramethyl-2,3-diphenylcyclopro-
pane (3b). 3,4,4,5-Tetramethyl-3,5-diphenyl-3H-pyrazole (2b)
(0.1 g, 0.359 mmol) was placed in an NMR tube and purged
with argon gas. The tube was then heated in a silicon oil bath
at 200ꢀC 6 2 for 4 h. When heated, the crystals melted and
evolution of nitrogen gas was observed. The NMR tube was
removed from the oil bath after 4 h of heating and hexane was
added to dissolve the product. The crude product was purified
by chromatatron (hexanes) and recrystallized from methanol to
give 2b in 84% yield (0.075 g, 0.301 mmol) as colorless crys-
tals, mp ¼ 79–81ꢀC. 1H NMR (CDCl3) 300 MHz: d 1.12 (s,
3H), d 1.37 (s, 3H), d 1.47 (s, 6H), d 7–7.4 (m, 10H); 13C
NMR (CDCl3) 300 MHz: 18.7, 23.2, 25.4, 27.0, 35.5, 125.3,
127.4, 131.1, 145.6; X-ray structure was obtained at Emory
University; IR peaks: 3083–2927 cmꢂ1, 1599 cmꢂ1, 1577
cmꢂ1, 699 cmꢂ1. Anal. Calcd. for C19H22: C, 91.14, H, 8.86;
found: C, 90.93, H, 9.04%.
Synthesis of cis-3,4,4,5-tetramethyl-3,5-diphenyl-4,5-dihy-
dro-3H-pyrazole (2b). 4,4,5-Trimethyl-3,5-diphenyl-1(tolu-
ene-4-sulfonyl)-4,5-dihydro-1H-pyrazole (1b) (1.0 g, 2.389
mmol) was dissolved in 50 mL of anhydrous THF under ar-
gon atmosphere. The solution was cooled to 0ꢀC with an ice
bath. Then, methyllithium (4.48 mL, 7.17 mmol, 3 equiv)
was added to the solution using a dried glass syringe. The
solution was stirred for 30 min at 0ꢀC and 24 additional
hours at room temperature. The mixture was quenched with
10 mL of saturated, degassed ammonium chloride solution.
Diethyl ether (20 mL) was added to the mixture before
washing with saturated sodium bicarbonate (2 ꢁ 20 mL) so-
lution and deionized water (40 mL). The organic layer was
dried over magnesium sulfate. The solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography (hexane/ethyl acetate [97:3]) to give
2b in an isolated yield of 59% (0.391 g, 1.409 mmol) mp ¼
144–145ꢀC; 1H NMR (CDCl3) 300 MHz: d 0.26 (s, 3H), d
1.34 (s, 3H), d 1.68 (s, 6H), d 7.25–7.36 (m, 10H); 13C
NMR (CDCl3) 300 MHz: 20.2, 23.9, 28.5, 42.9, 96.7, 125.3,
126.9, 128.1, 143.6; IR peaks: 3064 cmꢂ1, 2990 cmꢂ1, 1599
Synthesis of 1,1,2-trimethyl-2,2,3-triphenylcyclopropane
(3c). 3,4,4-Trimethyl-3,5,5-triphenyl-4,5-dihydro-3H-pyrazole
(2c) (0.1 g, 0.2937 mmol) was placed in an NMR tube and
purged with argon gas. The tube was then heated in a silicon
oil bath at 200ꢀC 6 2 for 4 h. When heated, the crystals
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. L. Baumstark, G. Davon Kennedy, P. C. Vasquez, N. Desalegn, and P. Truong
Vol 47
mun 2006, 12, 337; (c) Garcia Ruano, J. L.; Alonso de Diego, S. A.;
Martin, M. R.; Torrenta, E.; Martin Castro, A. M. Org Lett 2004, 6,
4945; (d) Anisimova, N. A.; Berkova, G. A.; Ya, P. T.; Deiko, L. I.
Russ J Gen Chem 2002, 72, 460.
melted and evolution of nitrogen gas was observed. The
NMR tube was removed from the oil bath after 4 h of heat-
ing, and hexane was added to dissolve the products. The
crude product was purified by chromatatron (hexanes) to give
2c in 91% yield (0.83 g, 0.267 mmol) as a colorless viscous
[2] Maas, G. Top Curr Chem 1987, 137, 75.
1
[3] [a] Kennedy, G. D.; Baumstark, A. L.; Dotrong, M.;
Thomas, T.; Narayanan, N. J Heterocycl Chem 1991, 238, 1773; [b]
Vasquez, P. C.; Bennett, D. C.; Towns, K. K.; Kennedy, G. D.; Baum-
stark, A. L. Heteroatom Chem 2000, 11, 299.
liquid. H NMR (CDCl3) 300 MHz: d 1.32 (s, 3H), d 1.33 (s,
3H), d 1.38 (s, 3H), d 6.9–7.6 (m, 15H); 13C NMR (CDCl3)
300 MHz: 22.2, 26.8, 27.2, 28.1, 37.9, 46.2, 125.0, 125.3,
125.5, 127.5, 127.9, 128.1, 131.0, 131.3, 143.9, 144.3, 144.4.
MS Molecular Ion – 312. Anal. Calcd. for C24H24: C, 92.24,
H, 7.74%; Found: C, 92.39, H, 7.60%.
[4] (a) Fischer, P.; Schaefer, G. Angew Chem 1981, 93, 895;
(b) Hostettler, H. U. Tetrahedron Lett 1965, 1941; (c) Kelso, R. G.;
Greenlee, K. W.; Derfer, J. M.; Boord, C. E. J Am Chem Soc 1955,
77, 1751.
Acknowledgments. The authors acknowledge the Georgia State
University Research Foundation for partial support of this
research.
[5] Pirkle, W. H.; Hoover, D. J. J Org Chem 1980, 45, 3407.
[6] Vasquez, P. C.; Baumstark, A. L. In Advances in Oxygen-
ated Processes, Vol. 4; Baumstark, A. L., Ed.; JAI Press, Greenwich,
CN, 1995; p 107.
[7] Szwec, J.; Vasquez, P. C.; Franklin, P. J.; Kennedy, G. D.;
Baumstark, A. L. Heterocycl Commun 2004, 10, 133.
[8] Truong, P.; Kennedy, G. D.; Vasquez, P. C.; Baumstark, A.
L. Heterocycl Commun 2008, 14, 449.
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[9] Dreibelbis, R. L.; Khatri, H. N.; Walborsky, H. M. J Org
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet