I2-TBHP-catalyzed oxidative cross-coupling of N -sulfonyl hydrazones and isocyanides to 5-aminopyrazoles

Article abstract of DOI:10.1021/acs.orglett.5b00398

I₂-TBHP-catalyzed oxidative cross coupling of N-sulfonyl hydrazones with isocyanides has been realized for the synthesis of 5-aminopyrazoles through formal [4 + 1] annulation via in situ azoalkene formation. Notable features are the metal/alkyn

Full text of DOI:10.1021/acs.orglett.5b00398

Letter
pubs.acs.org/OrgLett
I2−TBHP-Catalyzed Oxidative Cross-Coupling of N‑Sulfonyl
Hydrazones and Isocyanides to 5‑Aminopyrazoles
Gopal Chandru Senadi,† Wan-Ping Hu,‡ Ting-Yi Lu,† Amol Milind Garkhedkar,† Jaya Kishore Vandavasi,†
and Jeh-Jeng Wang*,†
†Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan First Rd, Sanmin District,
Kaohsiung City, 807, Taiwan
‡Department of Biotechnology, Kaohsiung Medical University, No. 100, Shih-Chuan First Rd, Sanmin District, Kaohsiung City, 807,
Taiwan
S
* Supporting Information
ABSTRACT: I2−TBHP-catalyzed oxidative cross coupling of
N-sulfonyl hydrazones with isocyanides has been realized for
the synthesis of 5-aminopyrazoles through formal [4 + 1]
annulation via in situ azoalkene formation. Notable features are
the metal/alkyne-free strategy, C−C and C−N bond
formation, atom economy, catalytic I2, broad functional
group tolerance, good reaction yields, shorter time, and also applicability to one-pot methodology.
ydrazones are important precursors in synthetic chemistry
owing to their high reactivity.1 In particular, the formation
which was then trapped with anilines for the synthesis of 1,2,3-
H
triazoles (Scheme 2A).4 On the other hand, oxidative C−H
of 1,2-diaza-1,3-dienes (azo-alkenes) from dehydrohalogenation
of hydrazones has emerged as a powerful tool for the synthesis of
nitrogen-containing heterocycles.2 In this context, El Kaim et al.
developed an elegant approach to construct aminopyrazoles
from α-halo ketohydrazones and isocyanides in the presence of
base via an azo-alkene intermediate (Scheme 1a),3a but the lack
Scheme 2. Previous Approaches and Present Study
Scheme 1. Previous Approaches to 5-Aminopyrazoles
functionalization by metal-free versions has become very popular
for avoiding expensive metals and environmental hazards.5 In
this view, the I2/oxidant combination has become an efficient
method for the construction of various C−C6 or C−N7 bonds.
These metal-free advancements prompted Wang and Ji to
establish a practical and simple I2−TBPB-mediated azo-alkene
generation through an α-halo ketohydrazone intermediate from
hydrazones, which was also trapped with anilines to afford 1,2,3-
triazoles (Scheme 2B).8 Based on the above study and to the best
of our knowledge, there is no literature precedence to afford 5-
aminopyrazoles by direct oxidative α-CSP3−H functionaliza-
tion5d of hydrazones with isonitriles. As part of our continuing
interest in iodine9a−c and isocyanide9d chemistry, we herein
of readily available starting material and utilization of activated
hydrazones are drawbacks of this method. Later, the same group
developed an improved protocol for starting material synthesis
from the Mannich reaction of hydrazones with aldehydes and
amines to afford the azo-alkene precursor A (Scheme 1b).3b−d
Despite their remarkable advances, they also suffer from certain
limitations such as prefunctionalized hydrazones, limited
substrate scope, and the need for a stoichiometric base. To
overcome these issues, Zhang et al. disclosed a facile oxidative
C−H functionalization approach to beget azo-alkenes from
hydrazones for the first time mediated by Cu(OAc)2/PivOH,
Received: February 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
report an environmentally benign I2−TBHP-catalyzed oxidative
cross-coupling of N-sulfonyl hydrazones with isocyanides
through conjugate (C−C bond) and zwitterionic (C−N bond)
bond formation via in situ generated azoalkenes (Scheme 2C).
5-Aminopyrazoles are one of the privileged classes of nitrogen
heterocycles, and they find extensive application in pharmaceut-
ical chemistry10 and possess versatile biological properties
(Figure 1), for example, as positive allosteric modulators
Table 1. Optimization of the Reaction Conditions
g
b
entry
catalyst
oxidant
solvent
yield (%)
c
1
I2
I2
I2
I2
I2
I2
I2
I2
I2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
0
trace
trace
0
d
2
Oxone
K2S2O8
H2O2
d
3
e
4
l
5
BPO
71
d
6
Tempo
DTBP
TBHP
TBHP
TBHP
<10
trace
80
d
7
f
8
9
85
0
d
10
d
11
I2
trace
70
Figure 1. Examples of 5-aminopyrazoles.
12
13
14
15
16
17
18
19
20
21
22
KI
NaI
NIS
TBAI
PIDA
NBS
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
72
(CDPPB),11a insecticides (fipronil),11b sulfonamide antibacte-
rials (sulfaphenazole),11c,d etc. They also represent a potential
building block for the synthesis of various fused N-heterocyles.12
Therefore, the development of non-prefunctionalized, green,
efficient, and especially catalytic metal/base-free synthetic routes
toward pyrazoles is highly desirable for the synthetic community.
We began our investigation reaction between 4-methyl-N′-(1-
phenylethylidene)benzenesulfonylhydrazide 3a and cyclohexyl
isocyanide 4a as the model substrate with a stoichiometric
amount of I2 (2.0 equiv) in 1,4-dioxane at 90 °C for 16 h, but the
desired compound 5a was unsuccessful (Table 1, entry 1). Next,
the feasibility of reaction was tested with various oxidants (Table
1, entries 2−9) and catalytic I2 (20 mol %). To our surprise, the
desired compound 5a was achieved in 85% in 1 h using TBHP
(5−6 M) in decane (Table 1, entry 9). The reaction failed to
proceed in the absence of I2 or TBHP (Table 1, entries 10 and
11), suggesting that both I2 and TBHP are very crucial for the
formation of compound 5a. Several other iodide sources such as
KI, NaI, NIS, TBAI, and PIDA in the presence of TBHP (Table
1, entries 12−16) as an oxidant revealed NIS as the best choice
among them by affording 84% of 5-aminopyrazoles 5a (entry
14). Replacing NIS with NBS as the “Br” source failed to proceed
with the remaining starting material (Table 1, entry 17). We have
selected I2 as compared with NIS for further optimization by
considering the benefits like the environmentally benign nature
of I2 and cost-effectiveness.13 The solvent study revealed 1,4-
dioxane (Table 1, entry 9) as the best solvent (Table 1, entries
18−22). Furthermore, the lower loading of I2 (10 mol %)
showed a decreased reaction yield for 5a (74%) and no
significant change on higher loading of I2 (Table 1, entries 23
and 24). Finally, the effect of time and temperature was
examined, and it was found that longer time (Table 1, entry 27)
and lower temperature (Table 1, entry 25) reduced the yield of
compound 5a and led to no substantial change at 100 °C (Table
1, entry 26). Thus, the reaction parameters given in Table 1,
entry 9, were the optimal reaction conditions.
84
17
0
0
24
I2
1,2-DCE
0
I2
toluene
59
I2
DMSO
<10
42
I2
DMF
h
23
I2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
74
i
24
I2
87
j
25
I2
78
k
26
I2
84
d
27
I2
70
a
Reaction conditions: 3a (0.175 mmol), 4a (0.190 mmol), catalyst (20
mol %), oxidant (0.346 mmol), solvent (0.7 mL), time (1 h), temp (90
°C). Isolated yields. I2 (2.0 equiv) and stirred for 16 h. For 16 h.
H2O2 (30% in water). TBHP (70% aqueous). TBHP (5−6 M in
decane). I2 (10 mol %). I2 (30 mol %). At 70 °C. At 100 °C. BPO
b
c
d
e
f
g
h
i
j
k
l
(benzoyl peroxide).
CF3, 3,4-dichloro, p-CN, and p-COOMe were well tolerated to
give the corresponding target compounds 5b,c,e−l,k in 72−80%
yields. In the case of the p-F substituent (5d), NIS was used as a
catalyst due to the low yield and complex mixture with iodine.
The reaction was also successful with heterocyclic and
cycloalkanones derivatives such as furyl and α-tetralone by
affording the desired final compounds 5m and 5n in 63−68%
yields, respectively, except for the 6-MeO-α-tetralone, which
resulted in the inseparable mixture after purification.14a
However, hydrazones such as p-CONH2, p-COOH, and α-
substituted and aliphatic N-sulfonyl hydrazones did not create
the required pyrazole compounds 5j,l,p,q.14b
To further explore the synthetic potential of this methodology,
several isocyanides as well as hydrazone groups were investigated
as substrates under the optimized reaction conditions (Scheme
4). Tertiary and benzyl isocyanides were converted to the
corresponding products 6a,c,d in high yields (70−88%), except
the compound 6b (60%), which may attribute to the steric
hindrance of the methoxy group at the ortho position. Aryl
isocyanide substrates bearing an electron-donating group on the
benzene ring gave a higher yield (6e and 6f) than the electron-
withdrawing group (6h and 6i). In the case of p-fluoro isocyanide
substituent (6g), I2 was replaced by NIS because of the complex
With the optimal reaction conditions, we decided to examine
the scope of this conversion with a diverse set of N-sulfonyl
hydrazones and isocyanides (Schemes 3 and 4). As shown in
Scheme 3, a variety of N-tosyl hydrazones 3a−q reacting with
cyclohexyl isocyanide 4a were first investigated for the formation
of 5-aminopyrazoles. If the R-position of N-sulfonyl hydrazones
is attached to a phenyl ring, both electron-donating groups and
electron-withdrawing groups such as p-Me, p-MeO, m-Br, m-I, p-
B
DOI: 10.1021/acs.orglett.5b00398
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Organic Letters
Letter
a
Scheme 3. Scope of I2−TBHP-Catalyzed Synthesis of 5-
Aminopyrazoles with Various N-Tosyl Hydrazones and
Cyclohexyl Isocyanide
Scheme 4. Scope of Isocyanides and Hydrazones
a
a
Reaction conditions: compound 3a,o−s (0.5 mmol), cyclohexyl
isocyanide 4a (0.55 mmol), I2 (20 mol %), TBHP (1.0 mmol), 1,4-
b
c
dioxane (2.0 mL), 90 °C, 1 h. NIS was used instead of I2. Bs
a
(brosyl).
Reaction conditions: compound 3a-q (0.5 mmol), cyclohexyl
isocyanide 4a (0.55 mmol), I2 (20 mol %), TBHP (1.0 mmol), 1,4-
b
c
dioxane (2.0 mL), 90 °C, 1 h. NIS was used instead of I2. The exact
yield of the compound could not be determined due to the inseparable
mixture along with desired compound.
Scheme 5. One-Pot Reaction of Aryl Methyl Ketones,
Tosylhydrazines, and Isocyanides
a
mixture and low reaction yield. In addition, the scope of reaction
worked well with simple benzenesulfonyl and 4-bromobenzene-
sulfonyl by obtaining the respective aminopyrazoles derivatives
6l−n in 72−81% yields. On the other hand, replacing N-sulfonyl
hydrazones with tertiary butyl carbazate and benzoyl hydrazides
did not produce the desired final compounds 6o and 6p. The
structures of compound 6c and 6g were confirmed by X-ray
analysis.
To check the feasibility of the reaction in a one-pot strategy, we
initially examined tosyl hydrazine 2, acetophenone 1a, and
cyclohexyl isocyanide 4a in a 1/1.1/1.1 ratio under the optimized
conditions for 1 h (Scheme 5), and to our surprise, the desired
compound 5a was obtained in 40% yield. The reason for the low
yield could be the shorter reaction time and the presence of
unreacted hydrazone intermediate 3. On the basis of this result,
when the reaction was heated for longer time (12 h), the yield
decreased with the complex mixture.15 To further explore the
scope of the one-pot reaction, some of the representative ketones
and isocyanides were tested, and all of them resulted in the
desired products 5f,6a,k,l albeit in low to average reaction yields.
a
Reaction conditions: compound 2a,b (0.53 mmol), compound 1a,f
(0.59 mmol), isocyanide 4 (0.59 mmol), I2 (20 mol %), TBHP (1.06
mmol), 1,4-dioxane (2.0 mL), 90 °C, 1 h. Isolated yields of N-
sulfonyl hydrazones 3.
b
was regenerated.8 Then the reaction of isocyanide 4 with highly
electrophilic C-4 carbon2a of azo-alkene B gave zwitterion
intermediate C through the conjugate addition (C−C bond).3
Finally, the desired aminopyrazoles were obtained by zwitter-
ionic 5-exo-dig cyclization (C−N bond) of intermediate C
followed by [1,3]-H shift.9d
From the obtained results and previous literature reports,3,4,8
a
plausible mechanism was proposed as shown in Scheme 6. The
N-sulfonyl hydrazones 3 were converted to α-iodo hydrazones A
in the presence of catalytic iodine, and subsequently, the
intermediate A was transformed to the azoalkene B by the
elimination of HI. The probable reason for this elimination may
be attributed to weak nucleophilicity of isocyanides to displace
the aliphatic iodide of intermediate A. The eliminated HI was
oxidized to I2 in the presence of TBHP, and the catalytic cycle
In summary, we have developed the first example of I2−
TBHP-catalyzed formal [4 + 1]-annulation of N-sulfonyl
hydrazones with isocyanides for the synthesis of 5-amino-
pyrazole via in situ generation of azo-alkene. This metal-free
approach is realized through conjugate addition (C−C bond
formation) and zwitterionic cyclization (C−N bond formation).
The key features of this work include environmentally benign
catalytic I2, applicable to one-pot methodology, atom-econom-
C
DOI: 10.1021/acs.orglett.5b00398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 6. Plausible Reaction Mechanism
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization, and spectral data of
the starting materials and final products. X-ray structures of
compound 6c (CCDC No. 1038285) and 6g (CCDC No.
1048006). This material is available free of charge via the Internet
at http://pubs.acs.org.
(10) For reviews on 5-aminopyrazoles, see: (a) Aggarwal, R.; Kumar,
V.; Kumar, R.; Singh, S. P. Beilstein J. Org. Chem. 2011, 7, 179.
(b) Elmaati, T. M. A.; El-Taweel, F. M. J. Heterocycl. Chem. 2004, 41,
109. (c) Anwara, H. F.; Elnagdi, M. H. ARKIVOC 2009, (i), 198.
(11) (a) Paulis, T. D.; Hemstapat, K.; Chen, Y.; Zhang, Y.; Saleh, S.;
Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.; Conn, P. J. J. Med. Chem.
2006, 49, 3332. (b) Ratra, G. S.; Casida, J. E. Toxicol. Lett. 2001, 122,
215. (c) Aggarwal, R.; Kumar, V.; Tyagi, P.; Singha, S. P. Bioorg. Med.
Chem. 2006, 14, 1785. (d) Browne, S. G. Int. J. Lepr. 1961, 29, 502.
(12) Marinozzi, M.; Marcelli, G.; Carotti, A.; Natalini, B. RSC Adv.
2014, 4, 7019 and references therein.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jjwang@kmu.edu.tw.
Notes
The authors declare no competing financial interest.
(13) The price of I2 was comparatively 5 times lesser than NIS. For
example, I2 (25 g, 99.8% purity) is $20 USD and NIS (25 g, 99.8%
purity) is $95 USD.
(14) (a) The reaction worked to afford the desired compound, but
after the column purification NMR spectra showed an inseparable
mixture (see the Supporting Information, 5o). (b) The starting material
was analyzed by TLC to isolate other unidentified compounds instead of
the desired pyrazoles.
ACKNOWLEDGMENTS
We gratefully acknowledge funding from the Ministry of Science
and Technology (MOST), Taiwan.
■
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D
DOI: 10.1021/acs.orglett.5b00398
Org. Lett. XXXX, XXX, XXX−XXX