Divergent Reactivity of Nitrocyclopropanes with Huisgen Zwitterions and Facile Syntheses of 3-Alkoxy Pyrazolines and Pyrazoles

Article abstract of DOI:10.1021/acs.orglett.6b02415

A novel annulation reaction of trans-2-substituted-3-nitrocyclopropane-1,1-carboxylates with in situ generated Huisgen zwitterions is reported, providing facile synthesis of 3-alkoxy pyrazolines in good yields and high diastereoselectivities. This reactio

Full text of DOI:10.1021/acs.orglett.6b02415

Letter
pubs.acs.org/OrgLett
Divergent Reactivity of Nitrocyclopropanes with Huisgen Zwitterions
and Facile Syntheses of 3‑Alkoxy Pyrazolines and Pyrazoles
Changjiang Yang, Wei Liu, Zijian He, and Zhengjie He*
The State Key Laboratory of Elemento-Organic Chemistry and Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: A novel annulation reaction of trans-2-substituted-
3-nitrocyclopropane-1,1-carboxylates with in situ generated
Huisgen zwitterions is reported, providing facile synthesis of 3-
alkoxy pyrazolines in good yields and high diastereoselectivities.
This reaction unveils the divergent reactivity of the nitro-
cyclopropanes as a kind of versatile donor−acceptor cyclo-
propanes. It is also demonstrated that the prepared 3-alkoxy pyrazolines from di-tert-butyl azodicarboxylate can be readily
transformed into the corresponding 3-alkoxy 1H-pyrazoles in moderate yields.
yrazoline and pyrazole are both privileged structural motifs
frequently present in a large number of agrochemicals,
functionality.10,11 Prior studies have shown that both the nature
of substituents and substitution pattern significantly affect the
reactivity of nitrocyclopropanes. Most of the studied nitro-
cyclopropanes have a common substitution pattern: adjacent to
an electron-donor substituent, the nitro and another electron-
acceptor group (usually an ester or carbonyl group) are geminally
positioned at the cyclopropane backbone. This kind of
nitrocyclopropanes exhibit typical reactivity of D−A cyclo-
propanes, engaging in ring-opening reactions, formal cyclo-
additions, and rearrangements through a key 1,3-dipolar
intermediate (Scheme 1a).11a−g Other nitrocyclopropanes with
P
pharmaceuticals, and other bioactive molecules.1 Polysubstituted
pyrazoles are also utilized as functional units in material science,2
and as effective ligands in transition metal-catalyzed reactions.3
Among numerous bioactive pyrazolines and pyrazoles, it is
noteworthy that a group of 3-oxy(oxo) analogues possess
important and diverse properties including antipyretic, analgesic,
fungicidal, and anti-inflammatory activities (Figure 1).4,5 Under
Scheme 1. Reactivity of Nitrocyclopropanes as D−A
Cyclopropanes
Figure 1. Bioactive 3-oxy(oxo) pyrazolines and pyrazoles.
this circumstance, the development of effective synthetic
methods for pyrazolines and pyrazoles has therefore stimulated
much interest from chemists.6−8 Traditional approaches such as
the condensation of 1,3-dicarbonyl compounds with hydrazines
and the [3 + 2] cycloaddition of 1,3-dipoles have proven to be
effective;6 however, alternative and efficient synthetic strategies
for structurally diverse pyrazolines and pyrazoles remain highly
desirable. Over the past decade, great progress in this aspect has
been witnessed.7,8
Donor−acceptor (D−A) cyclopropanes have emerged as
popular building blocks in the synthesis of a variety of
carbocycles and heterocycles.9 Their versatility in organic
synthesis may be attributed to the unique and diverse reactivity
that is synergistically rendered by vicinal electron-donor and
-acceptor substituents and inherent ring strain of the cyclo-
propane backbone as well. As a typical class of D−A
cyclopropanes, nitrocyclopropanes have drawn considerable
attention due to rich chemical transformations of nitro
different substitution patterns usually exhibit divergent and often
unexpected reactivity.11h−m For example, Srinivasan et al. found
that, upon treatment of Lewis acids, trans-2-aryl-3-nitro-
cyclopropane-1,1-dicarboxylates undergo ring-opening rear-
rangement and the Nef reaction to give aroylmethylidene
malonates.11i On the basis of this unique chemistry of
nitrocyclopropanes, the same group has recently developed a
couple of elegant synthetic methods for heterocycles (Scheme
Received: August 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02415
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1b).11i−l It is thus anticipated that exploring the diverse reactivity
of nitrocyclopropanes with different substitutions will further
strengthen their utility in organic synthesis.
azodicarboxylate 2a and Ph3P resulted in a substantial increase in
the yield of 3a (Table 1, entries 7−9), and the substrate molar
ratio of 1:2.5:2.5 was preferred (Table 1, entry 8). Different
azodicarboxylates 2 were then tested in the reactions with 1a.
Diethyl azodicarboxylate 2b gave normal product 3b in 43% yield
while bulky di-tert-butyl azodicarboxylate 2c delivered its
corresponding product 3c in 70% yield in a shortened reaction
time (Table 1, entries 10 and 11). Nitrocyclopropanes 1 bearing
different ester groups were further surveyed with azodicarbox-
ylate 2c used as a reactant. Dimethyl trans-2-nitro-3-phenylcyclo-
propane-1,1-dicarboxylate 1b delivered product 3d in 88% yield
in 2 h (Table 1, entry 12). In contrast, nitrocyclopropanes 1c and
1d bearing bulky ester groups gave inferior results (Table 1,
entries 13 and 14).
The Huisgen zwitterions are a class of classical and famous 1,3-
dipolar intermediates, generally in situ formed from Ph3P and
dialkyl azodicarboxylates.12 Recent renewed interest from
chemists has disclosed that Huisgen zwitterions could readily
undergo a series of annulation reactions with various electro-
philes, affording unique and efficient approaches to aza-
heterocycles.13 We are also interested in exploring new
annulations of Huisgen zwitterions and have achieved some
recent successes in the synthesis of complex aza-heterocy-
cles.4b,14 As part of our continuous efforts, recently we
investigated the possible reactions of nitrocyclopropanes with
Huisgen zwitterions and found an unprecedented annulation
reaction leading to facile syntheses of 3-alkoxy pyrazolines and
pyrazoles. Herein we wish to communicate the relevant results.
Our investigation was commenced with the substrates trans-2-
nitro-3-phenylcyclopropane-1,1-dicarboxylate 1a and diisoprop-
yl azodicarboxylate 2a (Table 1). Under a N2 atmosphere, a
The scope of nitrocyclopropanes 1 was further explored
(Table 2). A variety of 2-substituted-3-nitrocyclopropane-1,1-
a
Table 2. Scope of Nitrocyclopropanes 1
Table 1. A Brief Survey on the Annulation Reaction between
a
Nitrocyclopropanes 1 and Huisgen Zwitterions
b
c
entry
1, R2
time (h)
3
(%)
E/Z
1
1b, Ph
2
1
1
1
1
1
1
1
1
2
2
2
2
2
2
1
1
1
1
1
1
2
2
24
1
3d (88)
3f (82)
3g (82)
3h (89)
3i (83)
3j (81)
3k (91)
3l (95)
3m (93)
3n (84)
3o (85)
3p (91)
3q (93)
3r (92)
3s (86)
3t (78)
3u (80)
3v (83)
3w (78)
3x (65)
3y (62)
3z (89)
3A (84)
−
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
5:1
2
1e, 4-FC6H4
1f, 2-ClC6H4
1g, 3-ClC6H4
1h, 4-ClC6H4
1i, 2,4-Cl2C6H3
1j, 2-BrC6H4
1k, 3-BrC6H4
1l, 4-BrC6H4
1m, 2-MeC6H4
1n, 3-MeC6H4
1o, 4-MeC6H4
1p, 2-OMeC6H4
1q, 3-OMeC6H4
1r, 3,4,5-(OMe)3C6H2
1s, 3-NO2C6H4
1t, 4-NO2C6H4
1u, 4-CF3C6H4
1v, 1-naphthyl
1w, 2-furyl
3
4
5
molar ratio
1/2/Ph3P
time
(h)
6
bc
,
entry
1
2
solvent
3
(%)
7
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
2c
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:2.0:2.0
1:2.5:2.5
1:3.0:3.0
1:2.5:2.5
1:2.5:2.5
1:2.5:2.5
1:2.5:2.5
1:2.5:2.5
THF
48
48
48
48
48
48
48
48
48
48
12
2
3a (40)
3a (45)
3a (44)
−
−
−
3a (58)
3a (68)
3a (67)
3b (43)
3c (70)
3d (88)
3e (56)
−
8
2
CH2Cl2
CHCl3
CH3CN
toluene
DMF
9
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
9
10
11
12
13
14
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
−
24
24
1x, 2-thienyl
a
Typical conditions: under a N2 atmosphere, to a mixture of 1 (0.3
1y, 3-pyridyl
1z, E-styryl
mmol) and 2 (0.45−0.9 mmol) in a solvent (2.0 mL) was added PPh3
(0.45−0.9 mmol); the mixture was then stirred at rt for a specified
1A, n-hexyl
b
c
time. Isolated yields. In all cases, the E/Z ratio > 20:1 as determined
d
25
1j
3k (87)
>20:1
1
by H NMR assay of the isolated products.
a
Typical conditions: Under a N2 atmosphere, to a mixture of 1 (0.3
mmol) and 2c (173 mg, 0.75 mmol) in CH2Cl2 (2.0 mL) was added
PPh3 (197 mg, 0.75 mmol), and the resulting mixture was then stirred
at rt for a specified time. For details, see Supporting Information.
mixture of 1a (0.3 mmol), 2a (0.45 mmol), and PPh3 (0.45
mmol) in THF (2.0 mL) was stirred at rt for 48 h. To our delight,
a pyrazoline product 3a was collected in 40% yield and high
diastereoselectivity after column chromatographic isolation
(Table 1, entry 1). This result unveiled a novel route to highly
functionalized pyrazolines. To further improve the reaction
efficiency, a brief survey of reaction conditions was conducted.
Solvent screening indicated that CH2Cl2 and CHCl3 provided
better yields than THF (Table 1, entries 2 and 3); other common
solvents such as CH3CN, toluene, and DMF were found to be
inappropriate for the reaction (Table 1, entries 4−6). With
CH2Cl2 chosen as the solvent, increasing the loadings of both
b
c
Isolated yields. Determined by 1H NMR assay of the isolated
d
product. Run on a 3.0 mmol scale.
dicarboxylates 1 were evaluated in the reactions with
azodicarboxylate 2c. Under very mild conditions, a series of
different aryl- or heteroaryl-substituted nitrocyclopropanes 1
smoothly gave their corresponding annulation products 3d,f−z
in moderate to excellent yields (Table 2, entries 1−22). A broad
range of aryl substituents having different electronic and steric
properties were well tolerated in the reaction. It is noteworthy
B
DOI: 10.1021/acs.orglett.6b02415
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Letter
that all pyrazolines 3 were obtained as virtually single
diastereomers with an E-configuration exocyclic alkene moiety
except product 3u in a modest 5:1 E/Z ratio (Table 2, entry 17).
E-Styryl substituted nitrocyclopropane 1z was also effective,
furnishing product 3A in 84% yield and high diastereoselectivity
(Table 2, entry 23). However, aliphatic n-hexyl-substituted 1A
failed to yield the normal annulation product even though it was
reacted for 24 h (Table 2, entry 24). A gram-scale synthesis of 3k
was also illustrated in 87% yield with 3.0 mmol of 1j used (Table
2, entry 25).
Scheme 3. A Proposed Mechanism
To glean some mechanistic insights into this annulation
reaction, we deliberately conducted the following experiments.
Three control experiments were first run (for a schematic
presentation, see Supporting Information). Under similar
reaction conditions, nitrocyclopropane 1b (0.3 mmol) was
treated with Ph3P (0.75 mmol) in the absence of azodicarbox-
ylate 2c for 24 h and no reaction was observed. This result clearly
indicated that Ph3P alone was not able to trigger any reactions of
nitrocyclopropane 1b. Also, two cyclopropanes dimethyl 2-
phenylcyclopropane-1,1-dicarboxylate 1B and dimethyl 2-
methyl-2-nitro-3-phenylcyclopropane-1,1-dicarboxylate 1C
were found to be ineffective in the reactions with azodicarbox-
ylate 2c under the standard conditions (see Supporting
Information). Two deuterium-labeling experiments were further
performed (Scheme 2). Under the standard conditions,
pyrazoles 4 has been realized by taking full advantage of the
vulnerability of the tert-butoxycarbonyl group to acids such as
trifluoroacetic acid (TFA) (Scheme 4). In a typical procedure,
Scheme 4. Synthesis of Functionalized 1H-Pyrazoles 4
Scheme 2. Deuterium-Labeling Experiments
deuterated nitrocyclopropane 1h-d1 (purity >99%) was reacted
with azodicarboxylate 2c and PPh3, affording a 78% yield of 3i-d1
with 40% deuterium incorporation at the olefinic carbon. Under
the same conditions, another deuterated nitrocyclopropane 1l-d1
(purity 82%) also provided 3m-d1 in 86% yield with 45%
deuterium incorporation at the olefinic carbon (Scheme 2).
These results implicated that proton exchanges occurred
between 2- and 3-carbons of nitrocyclopropanes 1 in the
annulation reaction.
Although a precise mechanism of this annulation reaction
remains elusive, on the basis of the above mechanistic studies and
previous reports,5c,15 a proposed mechanism for formation of
pyrazolines 3 is exemplified in Scheme 3. Presumably the
reaction sequence starts with the formation of Huisgen
zwitterion A. Acting as a nucleophile, A engages in a substitution
of nitrocyclopropane 1b to give intermediate B.15 Upon
deprotonation by the released nitrous anion,16 B yields
interconvertible zwitterionic intermediates C and D, which
undergo a ring-opening rearrangement to form intermediate
E.17,18 Subsequently E undergoes a migration of the ester group
from a N to C atom followed by an intramolecular aza-Wittig
reaction to furnish the annulation product 3d and byproduct
Ph3PO.19
pyrazoline 3 (0.2 mmol) from azodicarboxylate 2c was treated
with trifluoroacetic acid (0.2 mL) in CH2Cl2 (2.0 mL) at rt for 20
min, and the solvent and volatile components were removed on a
rotary evaporator. The residue was then dissolved in DMF (2.0
mL) and heated at reflux for 1 h, readily giving the corresponding
functionalized 1H-pyrazole 4 in moderate yield after workup and
isolation (Scheme 4). In pyrazolines 3, ester groups other than
tert-butoxycarbonyl remained intact in the reaction (Scheme 4,
4a−c). Other aryl-substituted pyrazolines 3 readily delivered
their corresponding 1H-pyrazoles 4d−w in acceptable yields
except 3z (R2 = 3-pyridyl) only yielded 1H-pyrazole 4x in a trace
amount. E-Styryl-substituted 3A also smoothly delivered its
product 4y in 51% yield. Thus, the annulation reaction also
provides a facile access to the functionalized 3-alkoxy 1H-
pyrazoles.
In summary, we have successfully developed a novel
annulation reaction of nitrocyclopropanes with in situ generated
Huisgen zwitterions, leading to efficient synthesis of 3-alkoxy
pyrazolines in good yields and high diastereoselectivities. This
reaction represents a rare annulation reaction and accordingly
reveals the new and divergent reactivity of nitrocyclopropanes as
a kind of popular D−A cyclopropanes. Upon exposure toward
the acid TFA, one-pot transformations of the prepared
To expand its synthetic application of the annulation reaction,
one-pot transformation of pyrazolines 3 into functionalized 1H-
C
DOI: 10.1021/acs.orglett.6b02415
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Organic Letters
Letter
Sun, H.-Y.; Wang, M.; Wu, A.-X. Org. Lett. 2015, 17, 1914. (f) Li, F.; Nie,
J.; Sun, L.; Zheng, Y.; Ma, J.-A. Angew. Chem., Int. Ed. 2013, 52, 6255.
(g) Decuypere, E.; Specklin, S.; Gabillet, S.; Audisio, D.; Liu, H.;
Plougastel, L.; Kolodych, S.; Taran, F. Org. Lett. 2015, 17, 362.
(h) Schmitt, D. C.; Taylor, A. P.; Flick, A. C.; Kyne, R. E., Jr. Org. Lett.
2015, 17, 1405. (i) Chen, B.; Zhu, C.; Tang, Y.; Ma, S. Chem. Commun.
2014, 50, 7677. (j) Zhang, G.; Zhao, Y.; Ge, H. Angew. Chem., Int. Ed.
2013, 52, 2559.
(9) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(b) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (c) Cavitt,
M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43, 804.
(d) Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew. Chem., Int. Ed. 2014,
53, 5504. (e) Grover, H. K.; Emmett, M. R.; Kerr, M. A. Org. Biomol.
Chem. 2015, 13, 655.
pyrazolines from di-tert-butyl azodicarboxylate into correspond-
ing 1H-pyrazoles have also been realized, providing a facile access
to biologically important 3-alkoxy 1H-pyrazoles. Further
expansion of the scope and applications in organic synthesis of
this annulation reaction is currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02415.
Experimental details, characterization data, NMR spectra
for new compounds (PDF)
Crystallographic data for 3a (CIF)
(10) (a) Ballini, R.; Palmieri, A.; Fiorini, D. ARKIVOC 2007, vii, 172.
(b) Averina, E. B.; Yashin, N. V.; Kuznetsova, T. S.; Zefirov, N. S. Russ.
Chem. Rev. 2009, 78, 887.
Crystallographic data for 4h (CIF)
(11) For typical reports, see: (a) O’Bannon, P. E.; Dailey, W. P.
Tetrahedron 1990, 46, 7341. (b) Wurz, R. P.; Charette, A. B. Org. Lett.
2005, 7, 2313. (c) Lifchits, O.; Charette, A. B. Org. Lett. 2008, 10, 2809.
(d) Lifchits, O.; Alberico, D.; Zakharian, I.; Charette, A. B. J. Org. Chem.
2008, 73, 6838. (e) So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. Org.
Lett. 2012, 14, 444. (f) Hardman, A. M.; So, S. S.; Mattson, A. E. Org.
Biomol. Chem. 2013, 11, 5793. (g) Schmidt, C. D.; Kaschel, J.; Schneider,
T. F.; Kratzert, D.; Stalke, D.; Werz, D. B. Org. Lett. 2013, 15, 6098.
(h) Cai, S.; Zhang, S.; Zhao, Y.; Wang, D. Z. Org. Lett. 2013, 15, 2660.
(i) Selvi, T.; Srinivasan, K. J. Org. Chem. 2014, 79, 3653. (j) Selvi, T.;
Srinivasan, K. Chem. Commun. 2014, 50, 10845. (k) Selvi, T.; Srinivasan,
K. Adv. Synth. Catal. 2015, 357, 2111. (l) Selvi, T.; Vanmathi, G.;
Srinivasan, K. RSC Adv. 2015, 5, 49326. (m) Wang, C.; Ren, X.; Xie, H.;
Lu, Z. Chem. - Eur. J. 2015, 21, 9676.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhengjiehe@nankai.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Foundation
of China (Grant Nos. 21272119, 21472096, J1103306) is
gratefully acknowledged.
(12) (a) Cookson, R. C.; Locke, J. M. J. Chem. Soc. 1963, 6062.
(b) Huisgen, R.; Blaschke, H.; Brunn, E. Tetrahedron Lett. 1966, 7, 405.
(d) Brunn, E.; Huisgen, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 513.
(13) For reviews, see: (a) Nair, V.; Biju, A. T.; Mathew, S. C.; Babu, B.
P. Chem. - Asian J. 2008, 3, 810. (b) Xu, S.; He, Z. RSC Adv. 2013, 3,
16885. For typical examples, see: (c) Otte, R. D.; Sakata, T.; Guzei, I. A.;
Lee, D. Org. Lett. 2005, 7, 495. (d) Nair, V.; Biju, A. T.; Vinod, A. U.;
Suresh, E. Org. Lett. 2005, 7, 5139. (e) Nair, V.; Mathew, S. C.; Biju, A.
T.; Suresh, E. Angew. Chem., Int. Ed. 2007, 46, 2070. (f) Cui, S.-L.; Wang,
J.; Wang, Y.-G. Org. Lett. 2008, 10, 13. (g) Lian, Z.; Guan, X.-Y.; Shi, M.
Tetrahedron 2011, 67, 2018. (h) Sankar, M. G.; Garcia-Castro, M.;
Wang, Y.; Kumar, K. Asian J. Org. Chem. 2013, 2, 646.
(14) Yang, C.; Chen, X.; Tang, T.; He, Z. Org. Lett. 2016, 18, 1486.
(15) The nitro group of aliphatic nitro compounds could be readily
replaced by various anions. Kornblum, N.; Boyd, S. D.; Stuchal, F. W. J.
Am. Chem. Soc. 1970, 92, 5783.
(16) The excessive Huisgen zwitterion in the reaction mixture may also
act as a base in the deprotonation.
(17) Early results from the reactions of similar nitrocyclopropanes with
nucleophiles such as sodium methoxide and sodiomalonate could also
be rationalized by this substitution−ring opening rearrangement
mechanism. Kohler, E. P.; Darling, S. F. J. Am. Chem. Soc. 1930, 52, 424.
(18) Another possible pathway to intermediate E is provided in the
Supporting Information, which circumvents the substitution of the nitro
group.
(19) Similar mechanisms involving ester group migration and aza-
Wittig reaction steps are also proposed for the reactions of allenoates
and Huisgen zwitterions. See ref 5c.
REFERENCES
■
(1) For selected reviews, see: (a) Marella, A.; Rahmat Ali, M.; Tauquir
Alam, M.; Saha, R.; Tanwar, O.; Akhter, M.; Shaquiquzzaman, M.;
Mumtaz Alam, M. Mini-Rev. Med. Chem. 2013, 13, 921. (b) Kucu̧ kguzel,
̈
̈
̈
Ş
. G.; S
(2) (a) Rurack, K.; Resch-Genger, U. Chem. Soc. Rev. 2002, 31, 116.
(b) Pettinari, C.; Tabacaru, A.; Galli, S. Coord. Chem. Rev. 2016, 307, 1.
(3) (a) Singer, R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do, N. M.
Synthesis 2003, 2003, 1727. (b) Singer, R. A.; Dore, M.; Sieser, J. E.;
Berliner, M. A. Tetrahedron Lett. 2006, 47, 3727. (c) Bellarosa, L.; Díez,
J.; Gimeno, J.; Lledos, A.; Suarez, F. J.; Ujaque, G.; Vicent, C. Chem. -
̧enkardes,̧ S. Eur. J. Med. Chem. 2015, 97, 786.
̌
̌
́
́
́
Eur. J. 2012, 18, 7749. (d) Tian, C.; Gong, L.; Meggers, E. Chem.
Commun. 2016, 52, 4207.
(4) (a) Brogden, R. N. Drugs 1986, 32 (suppl.4), 60. (b) Yang, C.; Li, J.;
Zhou, R.; Chen, X.; Gao, Y.; He, Z. Org. Biomol. Chem. 2015, 13, 4869.
(c) Kuo, S.-C.; Huang, L.-J.; Nakamura, H. J. Med. Chem. 1984, 27, 539.
(d) Stegelmeier, H.; Brandes, W. DE 3243714, 1984.
(5) For syntheses of 3-alkoxy pyrazolines and pyrazoles, see:
(a) Guillou, S.; Janin, Y. L. Chem. - Eur. J. 2010, 16, 4669. (b) Karad,
S. C.; Purohit, V. B.; Raval, D. K. Eur. J. Med. Chem. 2014, 84, 51.
(c) Nair, V.; Biju, A. T.; Mohanan, K.; Suresh, E. Org. Lett. 2006, 8, 2213.
(d) Chakravarty, M.; Kumar, N. N. B.; Sajna, K. V.; Swamy, K. C. K. Eur.
J. Org. Chem. 2008, 2008, 4500. (e) Yamazaki, S.; Maenaka, Y.; Fujinami,
K.; Mikata, Y. RSC Adv. 2012, 2, 8095.
(6) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, U.K., 1984; Vol. 5, p
167. (b) Yet, L. In Comprehensive Heterocyclic Chemistry III; Katritzky, A.
R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Oxford, U.K., 2008; Vol. 4, p 1.
́ ́ ́
(7) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
Chem. Rev. 2011, 111, 6984. (b) Yet, L. Prog. Heterocycl. Chem. 2011, 23,
231.
(8) For selected recent examples: (a) Zhang, G.; Ni, H.; Chen, W.;
Shao, J.; Liu, H.; Chen, B.; Yu, Y. Org. Lett. 2013, 15, 5967. (b) Wen, J.-J.;
Tang, H.-T.; Xiong, K.; Ding, Z.-C.; Zhan, Z.-P. Org. Lett. 2014, 16,
5940. (c) Vanjari, R.; Guntreddi, T.; Kumar, S.; Singh, K. N. Chem.
Commun. 2015, 51, 366. (d) Zhang, F.-G.; Wei, Y.; Yi, Y.-P.; Nie, J.; Ma,
J.-A. Org. Lett. 2014, 16, 3122. (e) Shu, W.-M.; Zheng, K.-L.; Ma, J.-R.;
D
DOI: 10.1021/acs.orglett.6b02415
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