1, 3-Dipolar cycloaddition reactions of vinylidenecyclopropane-diesters with aromatic diazomethanes generated in situ

Article abstract of DOI:10.1021/jo100105k

(Figure Presented) 1, 3-Dipolar cycloaddition reactions of VDCP-diesters with aromatic diazomethanes generated in situ from the corresponding aromatic aldehydes and tosylhydrazine mediated by base produce pyrazole derivatives in good yields under mild conditions. A plausible reaction mechanism has been proposed on the basis of control experiments along with the discussion on the regioselectivity.

Full text of DOI:10.1021/jo100105k

pubs.acs.org/joc
1,3-Dipolar Cycloaddition Reactions of Vinylidenecyclopropane-Diesters
with Aromatic Diazomethanes Generated in Situ
Lei Wu and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
Received January 22, 2010
1,3-Dipolar cycloaddition reactions of VDCP-diesters with aromatic diazomethanes generated in
situ from the corresponding aromatic aldehydes and tosylhydrazine mediated by base produce
pyrazole derivatives in good yields under mild conditions. A plausible reaction mechanism has been
proposed on the basis of control experiments along with the discussion on the regioselectivity.
Introduction
and safe alternative to handling aryldiazomethanes and has
been employed in the sulfur ylide-mediated synthesis of
epoxides from carbonyl compounds, aziridination of imines,
cyclopropanation of alkenes, homologation of aldehydes,
Wittig reactions, and preparation of pyrazoles via [3þ2]
cycloadditions with alkenes and alkynes.4 Vinylidenecyclo-
propanes (VDCPs) as highly strained small rings have an
allene moiety connected by a cyclopropane. Thus far, the
chemistry of vinylidenecyclopropanes (VDCPs) has been
extensively explored in our laboratory and other groups during
the last several years. Many novel intramolecular rearrange-
ments and intermolecular cycloaddition reactions with carbon-
carbon or carbon-heteroatom multiple bonds such as imines,
aldehydes, nitriles as well as R,β-unsaturated ketones could
take place smoothly either upon heating and photoirradiation5
Diazo compounds are remarkably versatile building
blocks in organic synthesis, which are known to take part
in 1,3-dipolar cycloaddition reactions with a wide range of
dipolarophiles,1 although they are also known to be toxic
and potentially explosive. Recently a new method based on
the Bamford-Stevens reaction2 has been reported for gene-
rating aromatic diazomethanes from stable tosylhydrazone
derivatives in situ,3 which has proven to be a highly effective
*To whom correspondence should be addressed. Fax: 86-21-64166128.
(1) (a) Regitz, M.; Heydt, H. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; pp 393-558. (b) Maas, G. In The
Chemistry of Heterocyclic Compounds, Vol. 59: Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry toward Heterocycles and Natural Products;
Padwa, A., Pearson, W., Eds.; Wiley: New York, 2002; pp 539-621.
(2) For related work of the Bamford-Stevens reaction, see: (a) Bamford,
W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735-4740. For Other methods for the
generation of diazo compounds from their corresponding tosylhydrazone salts, by
photolysis see: (b) Lemal, D. M.; Fry, A. J. J. Org. Chem. 1964, 29, 1673-1676.
By vacuum pyrolysis: (c) Creary, X. Org. Synth. 1986, 64, 207. By thermolysis of
a suspension in a suitable solvent: (d) Farnum, D. G. J. Org. Chem. 1963, 28, 870–
872. (e) Jonczyk, A.; Wlostowska, J. Synth. Commun. 1978, 8, 569–572. (f)
Jonczyk, A.; Wlostowska, J.; Makosza, M. Bull. Chem. Soc. Belg. 1977, 86, 739–
740. (g) Kaufman, G. M.; Smith, J. A.; Vander-Stouw, G. G.; Shechter, H. J. Am.
Chem. Soc. 1965, 87, 935–937. (h) Powell, J. W.; Whiting, M. C. Tetrahedron
1959, 7, 305–310. (i) Bayless, J. H.; Friedman, L.; Cook, F. B.; Shechter, H. J. Am.
Chem. Soc. 1968, 90, 531–533. (j) Friedman, L.; Shechter, H. J. Am. Chem. Soc.
1959, 81, 5512–5513. (k) Maas, G. Angew. Chem., Int. Ed. 2009, 48, 2–12.
(3) For other examples of generating and using diazo compounds in situ,
see: (a) Barrett, A. G. M.; Braddock, D. C.; Lenoir, I.; Tone, H. J. Org.
Chem. 2001, 66, 8260–8263. (b) Wurz, R. P.; Charette, A. B. Org. Lett. 2002,
4, 4531–4533. (c) May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124,
12426–12427.
(4) (a) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer,
M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430–
1433. (b) Aggarwal, V. K.; Alonso, E.; Fang, G.-Y.; Ferrara, M.; Hynd, G.;
Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433–1436. (c) Aggarwal, V.
K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001, 3, 2785–2788. (d)
Aggarwal, V. K.; de Vicente, J.; Pelotier, B.; Holmes, I. P.; Bonnert, R. V.
Tetrahedron Lett. 2000, 41, 10327–10331. (e) Aggarwal, V. K.; de Vicente, J.;
Bonnert, R. V. J. Org. Chem. 2003, 68, 5381–5383. (f) Aggarwal, V. K.;
Fulton, J. R.; Sheldon, C. G.; de Vicente, J. J. Am. Chem. Soc. 2003, 125,
6034–6035. (g) Velikorodov, A. V.; Kovalev, V. B.; Krivosheev, O. O. Russ.
J. Org. Chem. 2009, 45, 1208–1209.
(5) (a) Mizuno, K.; Sugita, H.; Hirai, T.; Maeda, H.; Otsuji, Y.; Yasuda,
M.; Hashiguchi, M.; Shima, K. Tetrahedron Lett. 2001, 42, 3363–3366. (b)
Mizuno, K.; Nire, K.; Sugita, H.; Otsuji, Y. Tetrahedron Lett. 1993, 34, 6563–
6566. (c) Sasaki, T.; Eguchi, S.; Ogawa, T. J. Am. Chem. Soc. 1975, 97, 4413–
4414.
2296 J. Org. Chem. 2010, 75, 2296–2301
Published on Web 03/05/2010
DOI: 10.1021/jo100105k
r
2010 American Chemical Society

Wu and Shi
JOCArticle
TABLE 1. Optimization of the [3þ2] Cycloaddition Reaction Conditionsa
total yield of the product (%)b
entry
X equiv
solvent
base (y equiv)
3aa
4aa
1
2
3
1.0
2.0
4.0
0.8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
5.0 M NaOH (1.0)
5.0 M NaOH (2.0)
5.0 M NaOH (4.0)
5.0 M NaOH (0.8)
5.0 M NaOH (2.0)
5.0 M NaOH (2.0)
NaH (2.0)
16
25
20
9
18
30
25
16
4
5c
6d
7
trace
complex
10
8
9
NaOEt (2.0)
KOtBu (2.0)
13
45
trace
26
complex
17
28
10
11
12
13
14
10.0 M NaOH (2.0)
20.0 M NaOH (2.0)
10.0 M NaOH (2.0)
10.0 M NaOH (2.0)
10.0 M NaOH (2.0)
30
56
30
THF
toluene
22
aAll the reactions were carried out by stirring benzaldehyde 1a and TsNHNH2 in the solvent (2.0 mL) for 4 h at room temperature followd by adding
the base with stirring for an additional 1 h. Then VDCP-diester 2a (0.2 mmol) in the same solvent (4.0 mL) was added and the reaction mixture was stirred
at 50 °C for 2 d unless otherwise specified. bIsolated yields. cThe phase transfer catalyst (PTC) BnEt3NCl (10 mol %) was added. dLewis acid BF3 OEt2
(10 mol %) was added.
3
or catalyzed/mediated by Lewis acids and Brønsted acids, giving
the corresponding rearranged products as well as the cycload-
ducts in moderate to good yields under mild conditions.6-8
In our recent work, we have found that VDCPs with gemi-
nal installation of two EWGs at the cyclopropane ring
could undergo formal [3þ3] cycloaddition reaction with
1,3-dipolar nitrones catalyzed by Yb(OTf)3.9 We anticipated
that cycloaddition reactions of VDCP-diesters10 with 1,3-dipolar
diazo compounds could also take place smoothly under
mild conditions. To our delight, it was found that such a
cycloaddition takes place with the triple bond tautome-
rized from the allene moiety rather than the original allene
moiety or the cyclopropane of VDCP-diesters, affording a
one-pot procedure for the preparation of pyrazole deriva-
tives. In this paper, we wish to report this cycloaddition
reaction of VDCP-diesters with aromatic diazomethanes
generated in situ under mild conditions.
(6) (a) Li, W.; Shi, M. J. Org. Chem. 2008, 73, 4151–4154. (b) Lu, J.-M.;
Shi, M. Tetrahedron 2006, 62, 9115–9122. (c) Fall, Y.; Doucet, H.; Santelli,
M. Tetrahedron Lett. 2007, 48, 3579–3581. (d) Lu, J.-M.; Shi, M. Tetrahedron
2007, 63, 7545–7549. (e) Zhang, Y.-P.; Lu, J.-M.; Xu, G.-X.; Shi, M. J. Org.
Chem. 2007, 72, 509–516. (f) Shao, L.-X.; Zhang, Y.-P.; Qi, M.-H.; Shi, M.
Org. Lett. 2007, 9, 117–120. (g) Xu, G.-C.; Liu, L.-P.; Lu, J.-M.; Shi, M.
J. Am. Chem. Soc. 2005, 127, 14552–14553. (h) Xu, G.-C.; Ma, M.; Liu, L.-P.;
Shi, M. Synlett 2005, 1869–1872. (i) Lu, J.-M.; Shi, M. Org. Lett. 2006, 8,
5317–5320. (j) Lu, J.-M.; Shi, M. Org. Lett. 2007, 9, 1805–1808. (k) Stepakov,
A. V.; Larina, A. G.; Molchanov, A. P.; Stepakova, L. V.; Starova, G. L.;
Kostikov, R. R. Russ. J. Org. Chem. 2007, 43, 41–49. (l) Zhu, Z.-B.; Shao,
L.-X.; Shi, M. Eur. J. Org. Chem. 2009, 2576–2580. (m) Yu, F.-F.; Yang,
W.-G.; Shi, M. Chem. Commun. 2009, 1392–1394. (n) Su, C.-L.; Huang, X.;
Liu, Q.-Y.; Huang, X. J. Org. Chem. 2009, 74, 8272–8279. (o) Li, W.; Yuan,
W.; Shi, M.; Hernandez, E.; Li, G.-G. Org. Lett. 2010, 12, 64–67. (p) Lu,
J.-M.; Shi, M. Org. Lett. 2008, 10, 1943–1946. (q) Lu, J.-M.; Shi, M. Chem.;
Eur. J. 2009, 15, 6065–6073. (r) Lu, B.-L.; Lu, J.-M.; Shi, M. Tetrahedron
Lett. 2010, 51, 321–324. (s) Lu, B.-L.; Lu, J.-M.; Shi, M. Tetrahedron 2009,
65, 9328–9335.
(7) Stepakov, A. V.; Larina, A. G.; Molchanov, A. P.; Stepakova, L. V.;
Starova, G. L.; Kostikov, R. R. Russ. J. Org. Chem. 2007, 43, 40–45.
(8) (a) Lu, J.-M.; Shi, M. J. Org. Chem. 2008, 73, 2206–2210. (b) Lu,
J.-M.; Shi, M. Chem.;Eur. J. 2009, 15, 6065–6073. (c) Shi, M.; Yao, L.-F.
Chem.;Eur. J. 2008, 14, 8725–8731. (d) Lu, J.-M.; Zhu, Z.-B.; Shi, M.
Chem.;Eur. J. 2009, 15, 963–971. (e) Zhu, Z.-B.; Shi, M. Chem.;Eur. J.
2008, 14, 10219–10222. (f) Shi, M.; Li, W. Tetrahedron 2007, 63, 6654–6660.
(g) Li, W.; Shi, M. Tetrahedron 2007, 63, 11016–11020. (h) Li, W.; Shi, M.
J. Org. Chem. 2008, 73, 6698–6705. (i) Li, W.; Shi, M. Eur. J. Org. Chem.
2009, 270–274. (j) Li, W.; Shi, M. J. Org. Chem. 2009, 74, 856–860. (k) Yao,
L.-F.; Shi, M. Chem.;Eur. J. 2009, 15, 3875–3881. (l) Wu, L.; Lu, J.-M.; Shi,
M. J. Org. Chem. 2008, 73, 8344–8347. (m) Wu, L.; Lu, J.-M.; Shi, M.
Tetrahedron 2008, 64, 3315–3321. (n) Li, W.; Shi, M.; Li, Y.-X. Chem.;Eur.
J. 2009, 15, 8852–8860. (o) Yao, L.-F.; Shi, M. Eur. J. Org. Chem. 2009,
4971–4982.
Results and Discussion
To determine the best cycloaddition conditions, initial
examinations were carried out with VDCP-diester 2a and
benzaldehyde 1a as the substrates and the results are sum-
marized in Table 1. We found that the corresponding
cycloadducts 3aa and 4aa were obtained in the total yield
of 34% from the cycloaddition of VDCP-diester 2a (0.2
mmol) with phenyl diazomethane generated in situ from
benzaldehyde 1a (0.2 mmol, 1.0 equiv) and tosylhydrazine
(0.2 mmol, 1.0 equiv) mediated by the base of 5.0 M aqueous
NaOH solution (40 μL, 1.0 equiv) in CH3CN (6.0 mL)
(Table 1, entry 1). Changing the employed amount of
benzaldehyde 1a from 4.0 equiv to 0.8 equiv, we found that
the highest yield was obtained using 2.0 equiv of benzalde-
hyde 1a (Table 1, entries 2-4). We also examined some
additives such as phase transfer catalyst (BnEt3NCl) (Bn =
C6H5CH2) (10 mol %) and Lewis acid BF3 OEt2 (10 mol %)
3
in this reaction, but no improvements were observed in both
(10) For the preparation of VDCP-diesters, see: Campbell, M. J.;
Pohlhaus, P. D.; Min, G.; Ohmatsu, K.; Johnson, J. S. J. Am. Chem. Soc.
2008, 130, 9180–9181.
(9) Wu, L.; Shi, M. Chem. Eur. 2010, 16, 1149–1152.
J. Org. Chem. Vol. 75, No. 7, 2010 2297

Wu and Shi
JOCArticle
TABLE 2. Scope of the [3þ2] Cycloaddition Reaction of VDCP-Diesters 2 with Aromatic Diazomethanes Generated in Situ from Corresponding
Aromatic Aldehydes 1a
aAll the reactions were carried out by stirring aromatic aldehydes 1 (0.4 mmol, 2.0 equiv) and TsNHNH2 (0.4 mmol, 2.0 equiv) in THF (or CH3CN)
(2.0 mL) for 4 h at room temperature followd by adding 10.0 M NaOH (40 μL, 2.0 equiv) with stirring for an additional 1 h. Then VDCP-diesters 2 (0.2
mmol, 1.0 equiv) in THF (or CH3CN) (4.0 mL) were added and the reaction mixture was stirred at 50 °C for 2 d unless otherwise specified. bIsolated
yields. cIn THF, a trace amount of 3ab and 4ab was formed.
SCHEME 1. Transformations of Pyrazole Derivatives 3ca and 4ad with TsCl
cases (Table 1, entries 5 and 6).11 Other bases were also tested
and it was found that aqueous NaOH solution afforded
a better result than those of NaH, NaOEt, or KOtBu
(Table 1, entries 7 to 9). Moreover, we also examined the
effect of the concentration of NaOH aqueous solution on
the reaction outcome. Products 3aa and 4aa were obtained
in a higher total yield (71%) in the presence of 10.0 M of
NaOH aqueous solution, while raising the concentration
further to 20.0 M resulted in complex product mixtures
(Table 1, entries 10 and 11). The examination of solvent
effect in CH3CN, 1,2-dichloroethane (DCE), toluene, and
tetrahydrofuran (THF) revealed that THF was the solvent
of choice, affording 3aa and 4aa in 84% total yield (Table 1,
entries 12-14).
(11) With the addition of BF3 OEt2, we mainly obtained the cyclopropane
ring-opening product C in 70% yield of VDCP-diester attacked by H2O.
3
2298 J. Org. Chem. Vol. 75, No. 7, 2010

Wu and Shi
JOCArticle
FIGURE 1. ORTEP drawing of 5ca.
With the optimal reaction conditions in hand, we next
examined the scope and limitations of the cycloaddition
reaction of VDCP-diesters 2 with various aromatic diazo-
methanes generated in situ from the corresponding aromatic
aldehydes 1 and tosylhydrazine and the results of these
experiments are summarized in Table 2. In the reactions of
VDCP-diester 2a with aromatic diazomethanes generated in
situ from aromatic aldehyde 1b bearing a Me group or
aromatic aldehyde 1c having a chloro substituent at the
para-position of the benzene ring, a pair of the desired
products 3ba and 4ba as well as 3ca and 4ca were obtained
in good total yields of 80% and 83%, respectively, under the
standard conditions (Table 2, entries 1 and 2). As for VDCP-
diester 2b, in which R is a methyl group, a trace of the desired
products 3ab and 4ab was obtained in THF, but they could
be obtained in 25% and 47% yield, respectively, in CH3CN
(Table 2, entry 3). The change of the employed solvent also
should be made for VDCP-diesters 2c, 2d, and 2e with an
aromatic ring connected to the allene moiety because higher
yield of the desired product 4ac was obtained when the
reaction of VDCP-diester 2c with the diazomethane gene-
rated from 1a was carried out in CH3CN than that in THF
(Table 2, entries 4 and 5). It should be emphasized here that
in this case, the cycloadduct 4ac was obtained in 80% yield as
the sole product presumably due to the steric effect of the
phenyl group (R0) and the aromatic group (Ar) which may
impair the formation of cycloadduct 3. The regioselective
[3þ2] cycloaddition reactions of VDCP-diesters 2c, 2d, and
2e with aromatic diazomethanes generated in situ from
aromatic aldehydes 1 proceeded smoothly under the stan-
dard conditions and showed a broad substrate scope with
respect to a variety of electronically and structurally diverse
aromatic aldehydes 1. Irrespective of the electron-poor and
electron-rich substituents on the aromatic rings of the alde-
hydes 1 or at the ortho- or meta-positions, the corresponding
[3þ2] cycloadducts were obtained in good yields (Table 2,
entries 6-12). As for the heteroaromatic aldehyde 1h, a
similar result was obtained (Table 2, entry 13). However,
FIGURE 2. ORTEP drawing of 6ad.14
applying VDCP-diester 2f with an aliphatic substituent
(Bn = C6H5CH2) on the allene moiety to this reaction
provided the desired product 4af in 10% yield under the
standard reaction conditions (Table 2, entry 14).
The structures of the cycloadducts 3ca and 4ad were
unambiguously determined by the X-ray diffraction of the
corresponding products 5ca and 6ad through further trans-
formation by treatment with p-toluenesulfonyl chloride
(TsCl) under basic conditions (Scheme 1). Their ORTEP
drawings are shown in Figures 1 and 2, respectively, and their
CIF data are presented in the Supporting Information.12,13
In the case of 4ad, the pyrazole ring possesses two nitrogen
atoms which are adjacent to two aromatic rings respectively,
favoring an anionic equilibrium between these two nitrogen
atoms in the presence of a base. Therefore, they can react
with TsCl to give the corresponding product mixtures,
respectively. As for 3ca, there is only one aromatic ring
(12) The crystal data of 5ca have been deposited with the Cambridge Crystal-
lographic Data Centre; deposition no. 755464. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre, 12 Union Rd.,
Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/retrieving.html.
(13) The crystal data of 6ad have been deposited with the Cambridge Crystal-
lographic Data Centre; deposition no. 752526. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre, 12 Union Rd.,
Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/retrieving.html.
J. Org. Chem. Vol. 75, No. 7, 2010 2299

Wu and Shi
JOCArticle
SCHEME 2. A Plausible Reaction Mechanism
adjacent to the nitrogen atom, disfavoring such an anionic
equilibrium, thus only one product is formed (Scheme 1, see
the Supporting Information for the details).
HRMS spectra were recorded by EI and ESI method. Organic
solvents used were dried by standard methods when necessary.
Satisfactory CHN microanalyses were obtained with an analy-
zer. Commercially obtained reagents were used without further
purification. All these reactions were monitored by TLC with
silica gel coated plates. Flash column chromatography was
carried out with use of silica gel at increased pressure.
On the basis of the above results, a plausible mechanism
for this [3þ2] cycloaddition reaction of VDCP-diesters 2
with aromatic diazomethanes generated in situ from the
corresponding aromatic aldehydes 1 with tosylhydrazine
mediated by base is tentatively outlined in Scheme 2 by using
VDCP-diester 2c and benzaldehyde 1a as an example. First,
condensation of tosylhydrazine with benzaldehyde 1a fol-
lowed by treatment with an aqueous solution of NaOH leads
to a solution of benzaldehyde tosylhydrazone sodium salt,
which upon heating to 50 °C gives a reddish solution of
phenyl diazomethane A. Meanwhile, under the basic condi-
tion, VDCP-diester 2c tautomerizes to its alkyne isomer
2c0,15 which furnishes intermediate B through [3þ2] cycload-
dition with phenyl diazomethane A. The proton transfer in
intermediate B affords the final product 4ac. The high
regioselectivity observed in these 1,3-dipolar cycloadditions
of VDCP-diesters 2c, 2d, and 2e can be explained from two
points of view: one is the steric interaction of the substituents
on the reactants and the other is the atomic orbital coefficients
of the HOMO (diazo compound)-LUMO (alkyne) favor the
interaction expected for this type of cycloaddition, which is in
keeping with previous literature reports involving cycloaddi-
tions onto arylacetylenes.16 As for VDCP-diesters 2a and 2b,
probably because of the absence of the aromatic ring con-
nected to the allene moiety, the regioselectivity is poor in the
cycloaddition process, resulting in two regioisomers.
In conclusion, we have disclosed a one-pot method for the
preparation of pyrazole derivatives by 1,3-dipolar cycload-
ditions of VDCP-diesters with aromatic diazomethanes gen-
erated in situ from the corresponding aromatic aldehydes
and tosylhydrazine. VDCP-diesters with an allene moiety
connecting to an aromatic group can undergo [3þ2] cycload-
dition reactions with diazomethanes via tautomerization,
affording a series of pyrazole derivatives in good yields
with high regioselectivities under mild reaction conditions.
Efforts are underway to further elucidate the reaction
mechanism and to understand the scope and limitations of
this process.
General Procedure for the Cycloaddition Reaction of VDCP-
Diesters with Aromatic Diazomethanes. The aromatic aldehyde 1
(0.4 mmol, 2.0 equiv) and tosylhydrazine (0.4 mmol, 2.0 equiv)
were dissolved in THF or CH3CN (2.0 mL) and the mixture was
stirred at room temperature for 4 h. The 10 M aqueous NaOH
solution (40 μL, 2.0 equiv) was added into the reaction mixtures
and stirring was continued for an additional hour. Then, VDCP-
diester 2 (0.2 mmol) in THF or CH3CN (4.0 mL) was added and
the above reaction mixture was warmed to 50 °C and stirred
continuously for 2 days. After the reaction was finished
(monitored by TLC plates), the solvent was removed under
reduced pressure and the residue was purified by silica gel flash
chromatography to afford the desired products 3 and/or 4.
General Procedure for the Reaction of Pyrazole Derivatives
with TsCl. To a solution of pyrazole derivative 3 or 4 (0.20
mmol) and tetrabutylammonium hydrogen sulfate (0.02 mmol,
10 mol %) in CH2Cl2 (5.0 mL) was added 50% NaOH aqueous
solution (120 μL). After the mixture was stirred for a few
minutes, TsCl (0.30 mmol, 1.5 equiv) was added to the reaction
mixture and the solution was then stirred vigorously at room
temperature (20 °C). When the reaction was completed
(monitored by TLC plates), the solution was poured into water
and extracted with dichloromethane. The combined organic
layers were dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by silica gel
flash chromatography to afford the desired products 5 or 6.
Compound 3aa: light yellow oil; 1H NMR (CDCl3, 400 MHz,
TMS) δ 1.84 (dd, J = 9.6, 5.2 Hz, 1H, CH), 2.22 (dd, J = 9.6,
5.2 Hz, 1H, CH), 3.20 (dd, J = 9.2, 8.0 Hz, 1H, CH), 4.89 (d, J =
12.0 Hz, 1H, CH2), 4.94 (d, J = 12.0 Hz, 1H, CH2), 5.14 (d, J =
12.4 Hz, 1H, CH2), 5.23 (d, J = 12.4 Hz, 1H, CH2), 6.36 (s, 1H,
CH), 7.02 (d, J = 6.8 Hz, 2H, Ar), 7.09-7.15 (m, 3H, Ar),
7.28-7.42 (m, 8H, Ar), 7.58 (d, J = 6.8 Hz, 2H, Ar); 13C NMR
(CDCl3, 100 MHz, TMS) δ 19.7, 24.9, 37.0, 67.4, 67.5, 102.0,
125.5, 127.96, 128.04, 128.20, 128.25, 128.5, 128.8, 130.5, 135.0,
135.2, 144.3, 147.1, 166.6, 169.1; IR (CH2Cl2) ν 3033, 2925,
1727, 1498, 1455, 1380, 1322, 1273, 1193, 1128, 959, 764, 695
cm-1; MS (%) m/z 452 (Mþ, 3), 361 (17), 318 (18), 263 (9), 108
(14), 91 (100), 79 (11), 65 (7); HRMS (EI) calcd for C28H24N2O4
452.1736, found 452.1738.
Experimental Section
Compound 4aa: light yellow oil; 1H NMR (CDCl3, 400 MHz,
TMS) δ 1.80 (dd, J = 9.6, 5.2 Hz, 1H, CH), 2.06 (dd, J = 9.6, 5.2
Hz, 1H, CH), 3.13 (t, J = 9.6 Hz, 1H, CH), 4.83 (d, J = 12.0 Hz,
1H, CH2), 4.89 (d, J = 12.0 Hz, 1H, CH2), 5.16 (d, J = 12.8 Hz,
1H, CH2), 5.29 (d, J = 12.8 Hz, 1H, CH2), 6.95-6.97 (m, 2H,
Ar), 7.11-7.17 (m, 3H, Ar), 7.25-7.33 (m, 9H, Ar), 7.57-7.58
(m, 2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS) δ 20.4, 24.6,
37.5, 67.2, 67.3, 127.4, 127.7, 127.9, 128.0, 128.1, 128.16, 128.21,
128.3, 128.49, 128.50, 128.6, 129.5, 135.1, 135.5, 166.5, 169.2;
IR (CH2Cl2) ν 3341, 3033, 2929, 1728, 1497, 1455, 1382, 1319,
1130, 737, 697 cm-1; MS (%) m/z 452 (Mþ, 2), 361 (9), 318 (10),
General Remarks. 1H and 13C NMR spectra were recorded at
400 (or 300) and 100 (or 75) MHz, respectively. Mass and
(14) The ORTEP drawing of 6ad is the mixture of two isomers which
cannot be separated by silica gel chromatography.
(15) During our preparation of the VDCP-diesters under the basic
conditions, we observed the formation of the corresponding alkyne isomers
and the NMR spectroscopic data of 2c0 are presented in the Supporting
Information.
(16) (a) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John Wiley &
Sons: New York, 1984; Vol. I. (b) Bastide, J.; Henri-Rousseau, O. Bull. Soc.
Chim. Fr. 1973, 2294–2296.
2300 J. Org. Chem. Vol. 75, No. 7, 2010

Wu and Shi
JOCArticle
263 (5), 108 (8), 91 (100), 79 (8), 65 (5); HRMS (EI) calcd for
C28H24N2O4 452.1736, found 452.1731.
37.8, 67.4, 67.7, 105.5, 127.5, 127.8, 127.9, 128.0, 128.2, 128.4,
128.6, 128.7, 129.7, 134.6, 134.9, 135.0, 135.2, 143.1, 145.5,
152.8, 165.8, 168.3; IR (CH2Cl2) ν 2941, 2911, 1729, 1597,
1381, 1193, 1134, 1091, 813, 698, 667, 583 cm-1; MS-ESI (%)
m/z 641.3 (M þ Hþ); HRMS (ESI) calcd for C35H29ClN2NaO6S
663.1327, found 663.1336.
Compound 4ac: light yellow oil; 1H NMR (CDCl3, 400 MHz,
TMS) δ 1.49 (dd, J = 8.8, 4.8 Hz, 1H, CH), 1.57 (dd, J = 8.8, 4.8
Hz, 1H, CH), 3.08 (s, 3H, OCH3), 3.36 (t, J = 8.8 Hz, 1H, CH),
3.72 (s, 3H, OCH3), 7.34-7.40 (m, 6H, Ar), 7.60-7.62 (m, 4H,
Ar); 13C NMR (CDCl3, 100 MHz, TMS) δ 22.4, 24.0, 36.5, 52.0,
52.6, 108.8, 127.8, 128.1, 128.4, 131.1, 167.0, 170.2; IR (CH2Cl2)
ν 3328, 2952, 1731, 1604, 1493, 1437, 1370, 1328, 1290, 1132,
775, 732, 698 cm-1; MS (%) m/z 376 (Mþ, 34), 344 (26), 301 (25),
257 (100), 244 (91), 228 (16), 128 (17), 104 (12), 77 (34), 57 (17);
HRMS (EI) calcd for C22H20N2O4 376.1423, found 376.1422.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (06XD14005,
08dj1400100-2), National Basic Research Program of China
(973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (20872162,
20672127, 20821002, 20732008, and 20702059), as well as
Mr. Sun Jie for performing X-ray diffraction.
1
Compound 5ca: colorless solid; mp 127-130 °C; H NMR
(CDCl3, 400 MHz, TMS) δ 1.98 (dd, J = 9.6, 5.6 Hz, 1H, CH),
2.04 (dd, J = 8.0, 6.8 Hz, 1H, CH), 2.31 (s, 3H, CH3), 3.74 (t,
J = 9.2 Hz, 1H, CH), 4.73 (d, J = 12.0 Hz, 1H, CH2), 4.77 (d,
J = 12.0 Hz, 1H, CH2), 5.24 (d, J = 12.0 Hz, 1H, CH2), 5.34 (d,
J = 12.0 Hz, 1H, CH2), 6.17 (s, 1H, CH), 6.88-6.91 (m, 2H, Ar),
7.04-7.08 (m, 3H, Ar), 7.11 (d, J = 8.8 Hz, 2H, Ar), 7.32-7.39
(m, 7H, Ar), 7.62 (d, J = 8.4 Hz, 2H, Ar), 7.89 (d, J = 8.8 Hz,
2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS) δ 20.1, 21.6, 24.1,
Supporting Information Available: Spectroscopic data of
all the new compounds and detailed descriptions of experi-
mental procedures as well as CIF data of 5ca and 6ad. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 7, 2010 2301