One-pot synthesis of pyrazoles through a four-step cascade sequence

Article abstract of DOI:10.1002/chem.201204322

A one-pot synthesis of 3,4,5- and 1,3,5-pyrazoles from tertiary propargylic alcohols and para-tolylsulfonohydrazide has been accomplished. The pyrazoles are formed through a four-step cascade sequence, including FeCl ₃-catalyzed propargylic substitution, aza-Meyer-Schuster rearrangement, base-mediated 6πelectrocyclization, and thermal [1,5] sigmatropic shift. In this reaction, the 3,4,5- and 1,3,5-pyrazoles are produced selectively according to different substituents in the starting alcohols. A one-pot recipe: The synthesis of 3,4,5- and 1,3,5-pyrazoles from tertiary propargylic alcohols and para-tolylsulfonohydrazide has been accomplished. The pyrazoles are formed through a four-step cascade sequence (see figure), and are produced selectively according to different substituents in the starting alcohols.

Full text of DOI:10.1002/chem.201204322

FULL PAPER
DOI: 10.1002/chem.201204322
One-Pot Synthesis of Pyrazoles through a Four-Step Cascade Sequence
Lu Hao, Jun-Jie Hong, Jun Zhu, and Zhuang-Ping Zhan*[a]
Abstract: A one-pot synthesis of 3,4,5- and 1,3,5-pyrazoles from tertiary propargyl-
ic alcohols and para-tolylsulfonohydrazide has been accomplished. The pyrazoles
are formed through a four-step cascade sequence, including FeCl3-catalyzed pro-
pargylic substitution, aza-Meyer–Schuster rearrangement, base-mediated 6p elec-
trocyclization, and thermal [1,5] sigmatropic shift. In this reaction, the 3,4,5- and
1,3,5-pyrazoles are produced selectively according to different substituents in the
starting alcohols.
Keywords: domino
heterocycles · pericyclic reaction ·
pyrazoles · rearrangement
reactions
·
G
E
U
Introduction
acrylonitriles from trimethylsilyl-substituted tertiary propar-
gylic alcohols and para-tolylsulfonohydrazide (Scheme 1).[8d]
In the work reported herein, we utilized the same readily
Pericyclic reactions have proven to be a powerful strategy
for the synthesis of heterocycles due to their high efficiency,
regioselectivity, and enantioselectivity.[1,2] For example, cy-
cloadditions, including the well-known Diels–Alder reaction
and 1,3-dipolar cycloaddition, are rapidly becoming the
method of choice for the construction of heterocycles.[2]
However, although cycloadditions have enjoyed great suc-
cess in this arena, electrocyclization and sigmatropic shift re-
actions are much less utilized.[3] Accordingly, further devel-
opment of pericyclic methods for heterocyclic synthesis, es-
pecially in a domino and selective manner,[4] is still an ex-
tremely attractive yet challenging task.
Pyrazole is an extensively used heterocyclic unit in medic-
inal, agrochemical, and ligand chemistry.[5] Selected pharma-
ceutical examples include the well-known drugs Celebrex,
Mavacoxib, and Acomplia.[6] As a result, substantial atten-
tion has been paid to developing efficient strategies for their
syntheses.[7] Two strategies are commonly used: the func-
tionalization of pre-existing pyrazole-containing precursors
through the introduction of new functional groups, and the
assembly of a new pyrazole ring from acyclic precursors. In
general, the latter route has greater potential for obtaining
diversity rapidly in functionalized pyrazoles. Thus, new ap-
proaches allowing for the efficient assembly of different pyr-
azole skeletons with diverse substitution patterns are in high
demand.
Scheme 1. Cascade pericyclic strategies toward pyrazoles. Ts=tosyl.
available starting materials to provide an efficient access to
pyrazoles. Specifically, we performed a four-step one-pot
cascade process to prepare two different kinds of pyrazoles
substituted at multiple sites, in moderate to excellent yields
with high regioselectivity (Scheme 1).
Results and Discussion
Our research began with solvent and base screening
(Table 1). We treated the propargylic alcohol 1a with 2
using 10 mol% FeCl3 as the catalyst at 608C for 1 h. Then,
the base was added directly and the mixture was heated to
1008C for 3 h. After careful screening, the optimal condi-
tions were determined (Table 1, entry 8). We found that the
basicity of the base plays an important role in the reaction:
the use of weak and medium bases, including NaHCO3 and
NaOAc, gave no or low yields. On the other hand, reactions
employing strong bases, such as EtONa and tBuOK, afford-
ed the product in moderate yields. Notably, K2CO3 displayed
an acceptable efficacy albeit inferior to that of Cs2CO3
(Table 1, entry 3). It was also found that performing the re-
As a part of our studies on propargylic chemistry,[8] we
have reported a novel FeCl3-catalyzed domino synthesis of
[a] L. Hao, J.-J. Hong, J. Zhu, Prof. Z.-P. Zhan
Department of Chemistry and Key Laboratory for Chemical Biology
of Fujian Province, College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005, Fujian (P.R. China)
Fax: (+86)592-2180318
E-mail: zpzhan@xmu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204322.
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Table 1. Screening of conditions for the synthesis of pyrazoles.[a]
propargylic alcohols bearing aryl substituents on the alkyne
position (R3 =aryl) proceeded very well, and led to the ex-
pected products in good to excellent yields (Table 2, 3a–3e
and 3i–3p). By comparison, the reactions of propargylic al-
cohols substituted with alkyl groups (R3 =alkyl) gave rela-
tively low yields (Table 2, 3 f–3h). It was noteworthy that
good regioselectivity of R2 migration was observed in the
above-mentioned cases: the aryl groups migrated exclusively
to the adjacent carbon atom, thereby producing the 3,4,5-
pyrazoles 3 (Table 2, 3a–3p).
Encouraged by these results, we next examined the reac-
tivity of propargylic alcohols substituted with aryl and alkyl
groups (R1 =aryl, R2 =alkyl). Interestingly, 1,3,5-pyrazoles 4
in which the alkyl group (R2) migrated to the adjacent nitro-
gen atom were generated (Table 3, 4q–4t). We also tested
the reactivity of dimethyl-substituted propargylic alcohol
1u. However, it proved to be a uniquely challenging partner
and the expected product 4u was not obtained. The chemi-
cal structure of 4q was determined by single-crystal X-ray
diffraction (Figure 1).
Entry
Catalyst
Solvent[b]
Base (equiv)
Yield [%][c] of 3a
1
2
3
4
5
6
7
8
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
AgOTf
CH3NO2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
toluene
THF
1,4-dioxane
DCE
PhCl
PhCl
PhCl
PhCl
PhCl
NaHCO3 (3.0)
NaOAc (3.0)
K2CO3 (3.0)
EtONa (3.0)
tBuOK (3.0)
Na2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (2.2)
none
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
Cs2CO3 (2.2)
0
35
90
78
85
82
94
95
trace
62
trace
12
27
trace
34
47
0
trace
complex
9
10
11[d]
12
13[d]
14[e]
15
16
17
18[f]
19
CuN
In(OTf)3
A
CeCl3
ZnCl2
AuCl3
PhCl
[a] Conditions: 1a (0.5 mmol), 2 (0.6 mmol), and catalyst (10 mol%) re-
acted in solvent (5 mL) in air at 608C for 1 h, then the base was added di-
rectly to the reaction mixture and the temperature was increased to
1008C for 3 h. [b] THF=tetrahydrofuran; DCE=1,2-dichloroethane.
[c] Yields of isolated products based on 1a. [d] The reactions were per-
formed at reflux after addition of the base. [e] About 60% of the starting
alcohol was recovered. [f] About 50% of the starting alcohol was recov-
ered.
action without using base only gave a trace amount of 3a
(Table 1, entry 9). The solvent screening showed that PhCl
was still the preferred solvent (Table 1, entries 10–13). Nota-
bly, the 1,3,5-pyrazole (4a), in which the phenyl group mi-
grated to the adjacent N position rather than the C position,
was not observed. The screening for the Lewis acid catalysts
showed that FeCl3 was still the preferred catalyst (Table 1,
entries 14–20).
We next sought to evaluate the substrate scope of this re-
action by using a variety of tertiary propargylic alcohols
(Table 2). The tertiary alcohols reacted well offering a facile
access to trisubstituted pyrazoles, and a range of functionali-
ties including chloro, fluoro, nitro, ethyloxycarbonyl, me-
thoxy, and thiophenyl groups
Figure 1. X-ray structure of 4q.
When the reaction of 1w was investigated (Scheme 2), the
result was very interesting. In this reaction, indene 5w
rather than pyrazole 4w was obtained.[9,16] Next, intermedi-
ate 9w was isolated in 75% yield, which could be trans-
formed into 5w under base-mediated conditions in 96%
yield. This result confirmed the participation of TsNHNH2
(2) in the transformation of 1w into 5w.
The synthetic utility of this approach was further high-
lighted by the one-pot cascade synthesis of dibenzo-
could be well tolerated. In the
examples of symmetric diaryl-
substituted alcohols (R1 =R2 =
aryl), the pyrazoles were ob-
tained in moderate to good
yields (Table 2, 3a–3n). On the
other hand, a mixture of two
isomers was generated in the
reactions of asymmetric alco-
hols (Table 2, 3o and 3p). No-
tably, the conversion of the Scheme 2. Reaction of propargylic alcohol 1w.
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Synthesis of Pyrazoles through a Cascade Sequence
Table 2. One-pot cascade synthesis of 3,4,5-pyrazoles.[a]
FULL PAPER
AHCTUNGTRENNUNG
To probe the mechanism, attempts were made to
capture the reaction intermediates (Scheme 4).
First, by subtle control of the reaction conditions,
the propargylic substitution product (5a) and the
aza-Meyer–Schuster rearrangement product (9a)
were isolated [Scheme 4, Eqs. (1) and (2)]. We dis-
covered that both 5a and 9a could be smoothly
converted into 3a under the standard conditions.
Subsequently, the intermediate 11a was isolated in
55% yield [Scheme 4, Eq. (3)]. We found that 3a
could be obtained from 11a in nearly quantitative
yield under thermal conditions without adding any
base [Scheme 4, Eq. (4)]. Moreover, 11a trans-
formed into 3a gradually when at room tempera-
ture for over a month. These results showed that
the [1,5] sigmatropic shift of 11a into 3a was a con-
certed process not affected by any other factors.
We next propose the mechanism of this reaction
3a 95%
3b 98%
3c 80%
3d 90%
R1 =C6H5
R2 =C6H5
R3 =C6H5
R1 =p-Me-C6H4
R2 =p-Me-C6H4
R3 =C6H5
R1 =p-Cl-C6H4
R2 =p-Cl-C6H4
R3 =C6H5
R1 =p-F-C6H4
R2 =p-F-C6H4
R3 =C6H5
3e 98%
3 f 70%
3g 42%
3h 65%
(Scheme 5). First, propargylic alcohol
1 reacts
R1 =p-MeO-C6H4
R2 =p-MeO-C6H4
R3 =C6H5
R1 =C6H5
R2 =C6H5
R3 =n-butyl
R1 =p-F-C6H4
R2 =p-F-C6H4
R3 =n-butyl
R1 =C6H5
R2 =C6H5
under iron catalysis to yield propargylic cation 7,
which is attacked regioselectively by the terminal
R3 =cyclopropyl
À
nitrogen ( NH2) of 2, thus resulting in the substitu-
tion product 5. Next, 5 undergoes an FeCl3-cata-
À
lyzed [1,3] shift of the NHNHTs group through
the transition state 6, which leads to allene 8. Then,
after rapid tautomerization from 8 to 9, the latter
transforms into 11 through a base-mediated 6p-
electrocyclic ring closure.[9a] According to the type
of R2 group, the thermal [1,5] sigmatropic shift pro-
ceeds in two ways: either on the adjacent carbon
atom or on the adjacent nitrogen atom. The former
route produces the 4H-pyrazoles 12, which subse-
quently experience a rapid isomerization to form
3,4,5-pyrazoles 3, whereas the latter affords the
1,3,5-pyrazoles 4 directly.
3i 98%
3j 75%
3k 95%[b]
3l 85%
R1 =C6H5
R2 =C
R1 =C6H5
R1 =C6H5
R1 =C6H5
R2 =C6H5
R3 =o-Me-C6H4
R2 =C6H5
R2 =C6H5
R3 =p-MeO-C6H4
R3 =p-O2N-C6H4
R3 =p-EtOOC-C6H4
To gain insight into the regioselectivity of the
[1,5] sigmatropic shift, we performed density func-
tion theory (DFT) calculations. As shown in
Scheme 6, the reaction involving shift of the phenyl
group is more exothermic than that of the tBu
group, in line with the higher yields of the reaction
of propargylic alcohols with aryl substituents over
alkyl groups observed experimentally. In addition,
the shift of the phenyl group to the adjacent carbon
atom is thermodynamically more favorable than
that to the adjacent nitrogen atom. In sharp con-
trast, the shift of the tBu group to the adjacent ni-
trogen atom is thermodynamically more favorable
than that to the adjacent carbon atom. To further
probe the origin of the relative stability between
3,4,5- and 1,3,5-pyrazoles, we first examined the
steric effect on these pyrazoles. In particular, the
closest H···H distances between the phenyl and tBu
3m 73%
3n 97%
R1 =C6H5, R2 =C6H5, R3 =a-thiophenyl
R1 =C6H5, R2 =C6H5, R3 =p-Br-C6H4
3o 98%[c]
3p 98%[c]
R1 =C6H5, R2 =p-Me-C6H4, R3 =C6H5
R1 =C6H5, R2 =p-MeO-C6H4, R3 =C6H5
[a] Conditions: 1 (0.5 mmol), 2 (0.6 mmol), and FeCl3 (10 mol%) reacted in PhCl
(5 mL) in air at 608C for 1 h, then Cs2CO3 (2.2 equiv) was added directly to the reac-
tion mixture and the temperature was increased to 1008C for 3 h. Yields of isolated
products based on 1. [b] 4 ꢁ molecular sieves were added to prevent hydrolysis of the
COOEt group. [c] The isomer ratios of 3o and 3p were 57:43 and 60:40, respectively.
Chem. Eur. J. 2013, 19, 5715 – 5720
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Z.-P. Zhan et al.
Table 3. One-pot cascade synthesis of 1,3,5-pyrazoles.[a]
Conclusion
We have developed an expeditious one-pot protocol
for the synthesis of 3,4,5- and 1,3,5-pyrazoles from
readily available starting materials. The pyrazoles
are formed through a four-step cascade sequence.
Importantly, a cascade pericyclic strategy is incor-
porated into the synthetic process. Further study on
this topic is in progress in our group.
Experimental Section
4q 53%[b]
4r 52%
General procedure for the syntheses of 3a–3p, 3v, 5w, and
4q–4t: Propargylic alcohol 1 (0.5 mmol, 1.0 equiv), para-tolyl-
sulfonohydrazide 2 (0.6 mmol, 1.2 equiv), and PhCl (5 mL)
were added successively in air to a flame-dried 10 mL flask
equipped with a magnetic bar. The mixture was stirred until 2
fully dissolved. Subsequently, FeCl3 (10 mol%, 0.05 mmol) was
added. The reaction mixture was stirred at room temperature
in air for about 10 min until the reaction system became homo-
geneous. Next, the mixture was heated to 608C and stirred for
1 h. Then, Cs2CO3 (1.1 mmol, 2.2 equiv) was added directly to
the reaction mixture, which was heated to 1008C within 15 min
and maintained at this temperature for 3 h. The residue was
purified by column chromatography on silica gel to afford the
pyrazoles.
R1 =p-MeO-C6H4,
R2 =tBu, R3 =C6H5
R1 =p-MeO-C6H4,
R2 =tBu, R3 =p-Br-C6H4
4s 60%
4t 17%
4u 0%
R1 =p-MeO-C6H4, R2 =tBu
R3 =p-MeO-C6H4
R1 =C6H4, R2 =Me
R3 =C6H5
R1 =Me, R2 =Me
R3 =C6H5
Computational details: All structures were optimized at the
M06-2X level of DFT.[11] In addition, frequency calculations
were performed to confirm the characteristics of the calculated
structures as minima. In the M06-2X optimizations, the stand-
ard 6-31G(d) basis set was used.[12] To assess the degree of aro-
maticity in 3,4,5- and 1,3,5-pyrazoles, NICS values were calcu-
[a] Conditions: 1 (0.5 mmol), 2 (0.6 mmol), and FeCl3 (10 mol%) reacted in PhCl
(5 mL) in air at 608C for 1 h, then the Cs2CO3 (2.2 equiv) was added directly to the re-
action mixture and the temperature was increased to 1008C for 3 h. Yields of isolated
products based on 1. [b] The structure of 4q was determined by single-crystal X-ray
diffraction.
Scheme 3. Synthesis of dibenzo
strategy.
ACHTUNGTRENUN[NG e,g]indazoles through a ring-expansion
groups in 3a’ and 4a’ are 2.237 and 2.375 ꢁ, respectively,
which indicates that the steric effect should play a role in
the stability of 3a’ and 4a’. However, the closest H···H dis-
tances between the phenyl groups in 3a and 4a are as far as
3.064 and 3.241 ꢁ, respectively, thus suggesting the steric
effect should not apply for 3a and 4a. We then examined
the aromaticity of the pyrazole ring in 3a and 4a by com-
puting the nucleus-independent chemical shifts (NICSs).[10]
The NICS(1)zz values in 3a and 4a are À24.0 and
À21.4 ppm, respectively, which indicate better conjugation
of the pyrazole ring in 3a. Thus, the interplay of the steric
effect and aromaticity results in the regioselectivity of the
[1,5] sigmatropic shift observed in our experiment.
Scheme 4. Isolation of reaction intermediates.
lated by using the gauge including atomic orbital (GIAO) method[13] at
the M06-2X level with the 6-311+ +GACHTUNGTRNEUNG
(d,p) basis set.[14] We applied the
NICS(1)zz version, which is readily obtained as the negative of the out-of-
plane tensor component of the magnetic shielding at a position 1.0 ꢁ
above or below the ring plane.[10b] This index has shown promise as a
readily computable and well-performing substitute for NICSzz(0), the
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Synthesis of Pyrazoles through a Cascade Sequence
FULL PAPER
[3] For reviews of electrocyclization,
see: a) R. Huisgen, Angew.
Chem. 1980, 92, 979–1005;
Angew. Chem. Int. Ed. Engl.
1980, 19, 947–973; b) E. C.
Taylor, I. J. Turchi, Chem. Rev.
1979, 79, 181–231.
[4] Recent examples of cascade peri-
cyclic reactions: a) B. O. Ashburn,
R. G. Carter, L. N. Zakharov, J.
Org. Chem. 2008, 73, 7305–7309;
b) M. Alajarꢂn, M.-M. Ortꢂn, P.
Sꢃnchez-Andrada, ꢄ. Vidal, J.
Org. Chem. 2006, 71, 8126–8139.
[5] Selected examples of pyrazoles as
potential therapeutic agents and
bifunctional
ligands:
a) T. S.
Haque, S. Tadesse, J. Marcinkevi-
ciene, M. J. Rogers, C. Sizemore,
L. M. Kopcho, K. Amsler, L. D.
Ecret, D. L. Zhan, F. Hobbs, A.
Slee, G. L. Trainor, A. M. Stern,
R. A. Copeland, A. P. Combs, J.
Scheme 5. Proposed mechanism for the synthesis of pyrazoles.
Med. Chem. 2002, 45, 4669–4678;
b) J. A. Pfefferkorn, C. Choi,
S. D. Larsen, B. Auerbach, R.
Hutchings, W. Park, V. Askew, L. Dillon, J. C. Hanselman, Z. Lin,
G. H. Lu, A. Robertson, C. Sekerke, M. S. Harris, A. Pavlovsky, G.
Bainbridge, N. Caspers, M. Kowala, B. D. Tait, J. Med. Chem. 2008,
51, 31–45; c) Z. K. Sweeney, S. F. Harris, N. Arora, H. Javanbakht,
Y. Li, J. Fretland, J. P. Davidson, J. R. Billedeau, S. K. Gleason, D.
Hirschfeld, J. J. Kennedy-Smith, T. Mirzadegan, R. Roetz, M. Smith,
S. Sperry, J. M. Suh, J. Wu, S. Tsing, A. G. VillaseÇor, A. Paul, G.
Su, G. Heilek, J. Q. Hang, A. S. Zhou, J. A. Jernelius, F.-J. Zhang, K.
Klumpp, J. Med. Chem. 2008, 51, 7449–7458; d) H. Kotsuki, M.
Wakao, H. Hayakawa, T. Shimanouchi, M. Shiro, J. Org. Chem.
1996, 61, 8915–8920; e) A. Togni, U. Burckhardt, V. Gramlich, P. S.
Pregosin, R. Salzmann, J. Am. Chem. Soc. 1996, 118, 1031–1037;
f) H. Willms, W. Frank, C. Ganter, Organometallics 2009, 28, 3049–
3058; g) A. Ficks, C. Sibbald, M. John, S. Dechert, F. Meyer, Orga-
nometallics 2010, 29, 1117–1126.
Scheme 6. Gibbs free energies (G) at 298 K and electronic energies (E)
of the [1,5] sigmatropic shift to the adjacent nitrogen (left) and carbon
(right) obtained by M06-2X calculations.
most advanced and precise NICS version. When the environments at
points 1 ꢁ above and below the ring centers are not equivalent, the aver-
aged values are used for NICS(1)zz. All the optimizations were performed
with the Gaussian 09 software package.[15]
[6] a) W. G. Bensen, Pain 2003, 515–521; b) H. H. Seltzman, Drug Dev.
Res. 2009, 70, 601–615; c) A. Guzman-Perez, R. T. Wester, M. C.
Allen, J. A. Brown, A. R. Buchholz, E. R. Cook, W. W. Day, E. S.
Hamanaka, S. P. Kennedy, D. R. Knight, P. J. Kowalczyk, R. B.
Marala, C. J. Mularski, W. A. Novomisle, R. B. Ruggeri, W. R.
Tracey, R. J. Hill, Bioorg. Med. Chem. Lett. 2001, 11, 803–807.
[7] Recent reviews and examples of the synthesis of pyrazoles: a) S.
Fustero, M. Sꢃnchez-Rosellꢅ, P. Barrio, A. Simꢅn-Fuentes, Chem.
Rev. 2011, 111, 6984–7034; b) Y. L. Janin, Chem. Rev. 2012, 112,
3924–3958; c) J. Joule in Comprehensive Heterocyclic Chemistry,
Vol. 4 (Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven,
R. J. K. Taylor), Elsevier, Amsterdam, 2008, pp. 1–142; d) N. Panda,
A. K. Jena, J. Org. Chem. 2012, 77, 9401–9406; e) H. Kawai, Z.
Yuan, E. Tokunaga, N. Shibata, Org. Lett. 2012, 14, 5330–5333;
f) M. Zora, A. Kivrak, J. Org. Chem. 2011, 76, 9379–9390; g) B.
Willy, T. J. J. Mꢆller, Org. Lett. 2011, 13, 2082–2085; h) Y. Wang, X.
Bi, W.-Q. Li, D. Li, Q. Zhang, Q. Liu, B. S. Ondon, Org. Lett. 2011,
13, 1722–1725; i) D. Verma, S. Mobin, I. N. N. Namboothiri, J. Org.
Chem. 2011, 76, 4764–4770; j) G. Shan, P. Liu, Y. Rao, Org. Lett.
2011, 13, 1746–1749; k) J. Qian, Y. Liu, J. Zhu, B. Jiang, Z. Xu, Org.
Lett. 2011, 13, 4220–4223; l) O. Jackowski, T. Lecourt, L. Micouin,
Org. Lett. 2011, 13, 5664–5667; m) D. J. Babinski, H. R. Aguilar, R.
Still, D. E. Frantz, J. Org. Chem. 2011, 76, 5915–5923; n) T. Okitsu,
K. Sato, A. Wada, Org. Lett. 2010, 12, 3506–3509; o) L. Ackermann,
H. K. Potukuchi, Org. Biomol. Chem. 2010, 8, 4503–4513; p) J. D.
Kirkham, S. J. Edeson, S. Stokes, J. P. A. Harrity, Org. Lett. 2012, 14,
5354–5357; q) M. Yoshimatsu, K. Ohta, N. Takahashi, Chem. Eur. J.
Acknowledgements
This project was financially supported by the National Natural Science
Foundation of China (Nos. 21072159 and 21272190), the Program for
Changjiang Scholars and Innovative Research Team in University, and
the 973 Projects (No. 2011CB935901).
[1] a) F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Part A,
Springer, New York, 2007, pp. 833–964; b) F. A. Carey, R. J. Sund-
berg, Advanced Organic Chemistry, Part B, Springer, New York,
2007, pp. 473–617.
[2] Selected reviews for application of the Diels–Alder reaction and
1,3-dipolar cycloaddition in heterocyclic synthesis: a) Synthetic Ap-
plications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocy-
cles and Natural Products (Eds.: A. Padwa, W. H. Pearson), Wiley,
New York, 2003; b) F. Amblard, J. H. Cho, R. F. Schinazi, Chem.
Rev. 2009, 109, 4207–4220; c) I. Coldham, R. Hufton, Chem. Rev.
2005, 105, 2765–2810.
Chem. Eur. J. 2013, 19, 5715 – 5720
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5719

Z.-P. Zhan et al.
2012, 18, 15602–15606; r) S.-X. Xu, L. Hao, T. Wang, Z.-C. Ding,
Z.-P. Zhan, Org. Biomol. Chem. 2013, 11, 294–298.
[8] a) Z.-P. Zhan, J.-L. Yu, H.-J. Liu, Y.-Y. Cui, R.-F. Yang, W.-Z. Yang,
J.-P. Li, J. Org. Chem. 2006, 71, 8298–8301; b) L. Hao, Y. Pan, T.
Wang, M. Lin, L. Chen, Z.-P. Zhan, Adv. Synth. Catal. 2010, 352,
3215–3222; c) T. Wang, X.-L. Chen, L. Chen, Z.-P. Zhan, Org. Lett.
2011, 13, 3324–3327; d) L. Hao, F. Wu, Z.-C. Ding, S.-X. Xu, Y.-L.
Ma, L. Chen, Z.-P. Zhan, Chem. Eur. J. 2012, 18, 6453–6456.
[9] For the formation of diazo compounds and carbene from N-tosylhy-
drazones, see: a) Q. Xiao, Y. Zhang, J. Wang, Acc. Chem. Res. Arti-
cle ASAP, DOI: 10.1021/ar300101k; b) H. E. Zimmerman, M. C.
Hovey, J. Org. Chem. 1979, 44, 2331–2345; c) G. L. Closs, L. E.
Closs, J. Am. Chem. Soc. 1961, 83, 2015–2016.
[15] Gaussian 09, Revision B.01, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X.
Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Po-
melli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzew-
ski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D.
Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J.
Fox, Gaussian, Inc., Wallingford CT, 2009.
[10] a) P. v. R. Schleyer, C. Maerker, A. Dransfeld, H. Jiao, N. J. R. v. E.
Hommes, J. Am. Chem. Soc. 1996, 118, 6317–6318; b) H. Fallah-
Bagher-Shaidaei, C. S. Wannere, C. Corminboeuf, R. Puchta, P. V. R.
Schleyer, Org. Lett. 2006, 8, 863–866.
[16] We proposed a plausible mechanism for the formation of 5w:
[11] a) Y. Zhao, D. G. Truhlar, Theor.
Chem. Acc. 2008, 120, 215–241;
b) Y. Zhao, D. G. Truhlar, Acc.
Chem. Res. 2008, 41, 157–167.
[12] P. C. Hariharan, J. A. Pople,
Theor. Chim. Acta 1973, 28, 213–
222.
[13] K. Wolinski, J. F. Hilton, P. Pulay,
J. Am. Chem. Soc. 1990, 112,
8251–8260.
Received: December 5, 2013
Revised: January 18, 2013
Published online: February 28, 2013
[14] R. Krishnan, J. S. Binkley, R. Seeger, J. Pople, J. Chem. Phys. 1980,
72, 650–654.
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