Oxidative Radical Addition-Cyclization of Sulfonyl Hydrazones with Simple Olefins by Binary Acid Catalysis

Article abstract of DOI:10.1021/acs.orglett.6b01360

An unprecedented binary acid accelerated oxidative radical annulation of sulfonyl hydrazones with simple olefins is described. Notably, this method provides a novel oxidative radical cycloaddition for the construction of six-member heterocycles. It offers a rapid and efficient approach to tetrahydropyridazines which are key structural motifs in pharmaceutically active compounds.

Full text of DOI:10.1021/acs.orglett.6b01360

Letter
pubs.acs.org/OrgLett
Oxidative Radical Addition−Cyclization of Sulfonyl Hydrazones with
Simple Olefins by Binary Acid Catalysis
Xingren Zhong,†,‡ Jian Lv,*,†,‡,§ and Sanzhong Luo*,†,‡,§
†Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
‡University of Chinese Academy of Sciences, Beijing, 100049, China
§Collaborative Innovation Center of Chemical and Engineering (Tianjin), Tianjin, 300071, China
S
* Supporting Information
ABSTRACT: An unprecedented binary acid accelerated oxidative
radical annulation of sulfonyl hydrazones with simple olefins is
described. Notably, this method provides a novel oxidative radical
cycloaddition for the construction of six-member heterocycles. It
offers a rapid and efficient approach to tetrahydropyridazines which
are key structural motifs in pharmaceutically active compounds.
s a member of the most important class of transformations
in organic synthesis, cycloaddition reactions, such as Diels−
workers found that iodine could catalyze radical oxidative β-keto
esters with alkenes and alkynes to give five-member annulations
of dihydrofurans and furans (Scheme 1b).10 However, such
radical addition−cyclization leading to six-membered rings has
not been achieved so far, as usually encountered in radical-type
cyclizations. Tetrahydropyridazines are versatile structural motifs
in a number of pharmaceutically active compounds, and few
general methods are applied in their synthesis.11−13 Recently, we
have pursued an oxidative radical coupling between ketone
hydrazone and simple alkenes, providing arguably the most
straightforward and atom economic pathway toward tetrahydro-
pyridazines. This radical [4 + 2] cycloaddition approach is
conceivably challenging when considering that hydrazones, such
as N-tosylhydrazones, tend to form N-radicals, which were
known to undergo five-membered cyclization reactions.14−17 In
addition, the stability of alkenes under the oxidative conditions
would also be of concern, particularly in an intermolecular
context. Herein, we report a distinctive Lewis acid/I2 cocatalytic
strategy for the oxidative radical addition−cyclization reaction of
sulfonyl hydrazones and alkenes. A binary acid catalyst involving
a copper Lewis acid and phosphoric acid18,19 was identified to
facilitate the crucial radical addition and cyclization step and
meanwhile suppress the possible degradation and polymerization
of alkenes (Scheme 1c).
A
Alder reactions, provide a convenient way to construct versatile
heterocyclic compounds.1 Over the past several years, radical
cycloaddition reactions have attracted considerable attention.
The radical cations generated by photocatalysts through single
electron transfer were recently employed in these [4 + 2]
cycloaddition processes (Scheme 1a).2 On the other hand, atom
Scheme 1. Radical Cycloaddition Reaction
Oxidative [4 + 2] cycloaddition of N-tosylhydrazone 2a with
styrene 3a was chosen as a model reaction. The use of typical
oxidative conditions led to no desired product (e.g., Table 1,
entry 2). Unexpectedly, we found that the use of our binary acid
conditions could promote effective production of the desired
adduct 4a. Eventually, we were able to identify a viable complex
composed of Cu(CH3CN)4BF4 and diphenyl phosphate 1. In the
presence of Cu/1 (5 mol %), the desired [4 + 2] cycloadduct 4a
can be obtained in 76% yield (Table 1, entry 1 vs 2). In the
transfer radical cyclization reactions, which involve the transfer of
a halogen atom (X = I, Br, or Cl) from one carbon center to
olefins, tend to form five cyclic compounds or polymerize.3
However, very few examples of a [4 + 2] radical addition−
cyclization reaction were reported.4 Hence, achieving a catalytic
oxidative [4 + 2] radical addition−cyclization reaction with
simple olefins remains elusive, despite the notable advances in [4
+ 2] oxidative cycloaddition through C−H activation.5−7
In the past decade, I2 as a high efficiency catalyst has achieved a
number of direct oxidative C(sp3)−H functionalizations to form
C−X (X = O, N) bond compounds via in situ generated α-
C(sp3)−I intermediates.8,9 In elegant recent studies, Lei and co-
Received: May 10, 2016
© XXXX American Chemical Society
A
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methylstyrene 3i and heteroaromatic 2-vinylthiophene 3k were
also tolerated. Moreover, cyclopentadiene 3j worked well to give
the desired adducts 4j with excellent yield and diastereoselec-
tivity. In addition, an aliphatic alkene, propene 3l, also worked
leading to a 63% yield.
Table 1. Influence of Reaction Parameters on the Catalytic
Oxidative [4 + 2] Cycloaddition of N-Tosylhydrazones 2a and
Styrene 3a
a
Following the success of the formation of tetrahydro-
pyridazines from alkenes 3 and N-tosylhydrazones 2a, we
explored the possibility of performing a one-pot three-
component transformation of styrene 3a, sulfonyl hydrazines 5,
and arylethanones 6a−f. In this process, the hydrazones would
be generated in situ. As can be seen, electron-rich and -deficient
acetophenones gave similar results (4m−q). Unfortunately, the
reaction did not work with heteroarylethanones and alkyletha-
nones such as acetone, or methyl acetoacetate. Finally, different
sulfonyl hydrazines 5b−d were tested, demonstrating similar
performance (4r−s). It was worth mentioning that alkyl sulfonyl
hydrazide 5d could afford the desired product 4t in moderate
46% yield (Scheme 3).
b
entry
catalyst
solvent
yield (%)
1
2
3
4
5
Cu(CH3CN)4BF4/1
none
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
76
trace
33
Cu(CH3CN)4BF4
1
trace
NR
75
HBF4
c
6
d
Cu(CH3CN)4BF4/1
Cu(CH3CN)4BF4/1
7
87
a
General conditions: Cu(CH3CN)4BF4 (5 mol %), 1 (5 mol %), I2 (5
mol %), TBHP (0.8 mmol), 2a (0.2 mmol), and 3a (1.0 mmol) at
b
room temperature. Determined by 1H NMR analysis with an internal
c
standard, 1,3,5-trimethyloxylbenzene. Reaction was carried out in the
d
Scheme 3. Substrate Scopes for Sulfonyl Hydrazines under
One-Pot Reaction Conditions
dark. t = 24 h. NR = No reaction.
presence of diphenyl phosphate 1, other metal cocatalysts (such
as CuII, InIII, MgII, ZnII, FeIII, FeII, and so on) were less effective
under these conditions (<20% yield, Table S1). In control
experiments, the use of either Cu(CH3CN)4BF4 (33% yield,
Table 1, entry 3) or 1 alone (Table 1, entry 4) was ineffective,
highlighting the critical role of the binary acid. The possible effect
of a strong Brønsted acid could also be excluded, as the reaction
in the presence of HBF4 only did not work at all (Table 1, entry
5). The reaction was also applied in the dark to give a similar
yield, excluding the possible photocatalysis (Table 1, entry 1 vs
6). The yield could be slightly improved by extending the
reaction time (Table 1, entry 7 vs 1).
With optimized conditions established, we next explored the
substrate scope. As shown in Scheme 2, an array of simple alkenes
3a−l was tested, resulting in the expected tetrahydropyridazines
4a−l in moderate to excellent yields. Various styrenes 3a−h
could be well applied in the reaction, and 1,1-disubstituted α-
To probe the mechanism of this oxidative annulation process,
different kinds of iodine sources were examined in the model
reaction (Table S2). In the absence of an iodine source, no
reaction was observed. When the widely used iodide source such
as KI and n-Bu4NI was used, no desired product was observed.
However, N-iodosuccinimide (NIS) displayed reactivity similar
to that of I2. Stoichiometric experiments were then carried out to
look into the nature of the iodine catalysis (Scheme 4 and
Supporting Information (SI)). Iodine was found to react with
hydrazine 2a quickly to afford iodinated adduct C-2a/N-2a in the
absence of tert-butyl hydroperoxide (TBHP). The C-iodide and
N-iodide ratio was determined to be 1:2 (Scheme 4A). The
addition of TBHP could transform the mixture containing both
N-2a and C-2a to a single C-iodinated product C-2a along with a
tosyl shifted product 7 (C-2a/7 = 5:1). Separate experiments
between 2a and iodine in the presence of TBHP further affirmed
the sole formation of C-2a (Scheme 4B), and the conversion was
completed in 3 h with a significant amount of 7 being also
detected. When the thus formed C-2a mixture was treated with
styrene 3a in the presence of Cu/1, smooth conversion to the
desired cycloadduct was observed and the desired product was
isolated in 41% yield. In sharp contrast, no reaction was observed
in the absence of a binary acid (Scheme 4C). Taken together,
these experimental observations indicated C-iodinated adduct C-
Scheme 2. Substrate Scopes for Simple Alkenes
B
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(Figure 1C). There seemed also an induction time for the
formation of the desired product 4a, corresponding to the period
of C-2a formation. After the induction period, the steady
formation of 4a along with the decrease of C-2a could be clearly
noted by 1H NMR. These observations verified that C-2a was the
key reactive intermediate for the reaction. A control experiment
in the presence of TEMPO, a typical radical quencher, showed
no reaction under otherwise identical conditions, suggesting the
coupling of C-2a and styrene would be of a free radical nature.
Moreover, a radical clock vinyl-cyclopropane was tested under
the reaction conditions. Though the desired product was not
obtained, ring opening of the cyclopropyl moiety was observed
to form allyl sulfone (see SI), verifying the radical nature of the
reaction.
Scheme 4. Study of Stoichiometric Reaction between N-
Tosylhydrazone 2a and I2
Based on the experimental observations, we proposed a radical
addition/cyclization mechanism (Scheme 5). The co-action of
Scheme 5. Proposed Catalytic Cycle of Oxidative [4 + 2]
Cycloaddition
2a is likely a key intermediate in the reaction and the binary acid
plays a critical role in promoting the coupling of C-2a and
styrene. As also revealed in Scheme 4B, the binary acid showed
no effect in the iodination step.
To define the roles of binary acid Cu(CH3CN)4BF4/1, kinetic
studies were carried out by monitoring the reactions by using in
situ IR. N-Sulfonylhydrazone 2a could be easily oxidized through
I2/TBHP to form C-2a in 10 min even in the absence of a binary
acid (Figure 1A), suggesting that the binary acid CuI/1 did not
participate in this step. In comparison, the promoting effect of
binary acid CuI/1 in the reaction was clearly noted with the
formation of 4a dramatically accelerated in the presence of CuI/1
(Figure 1B). In situ monitoring of the reaction by 1H NMR also
revealed the quick formation of C-iodinated adducts C-2a
iodine and TBHP first generates the C-iodinated C-2a, likely via
an N-iodinated intermediate N-2a. The always isolated side
product 7 adds support to this pathway. It also possible that N-2a
and C-2a are competing products with the first being readily
transferred to C-2a as experimentally verified. Under the acidic
conditions, C-2a undergoes homolysis with the assistance of the
binary acid Cu(I)/1 complex, to give the key radical intermediate
A. With the presence of the Cu(I) complex, a competing single
electron transfer (SET) may also facilitate the generation of
radical A and an iodide anion as known in atom transfer radical
addition (ATRA) processes.3 However, the inefficiency observed
with the Cu(I) halide catalyst (Table S1, entry 2) disfavors the
SET pathway. In addition, the generally applied mild reaction
conditions are also in line with a facile C−I homolysis process,
since ATRA with a copper complex normally require high
temperature.3c That said, we were unable to completely rule out
the SET process at this moment. Subsequently, irreversible
radical addition of A to styrene and cyclization via intermediate B
and C afford the final adduct 4a. In this cycle, the critical roles of
binary acid Cu(CH3CN)4BF4/1 lie in its complexation with the
hydrazine moiety, as verified by NMR (SI, Figure S2), thus
facilitating the homolysis as well as the following radical addition
and cyclization. A Hammett plot was constructed to probe the
electronic effects of the substrate alkene on the reaction rate
(Figure 1D). The plot in Figure 1D revealed a negative, yet small
ρ value (−0.456), which is consistent with the polar effect
Figure 1. (A) Kinetics of the stoichiometric reactions of N-
tosylhydrazone 2a and I2 in the presence of TBHP and acid catalysts
in CH3CN monitored by in situ IR at 1269 cm−1 (C-2a-I) at room
temperature (see SI). (B) Kinetics of the oxidative cycloaddition
reactions monitored by in situ IR at 895 cm−1 (adduct 4a) at room
temperature. (C) In situ monitoring oxidative cycloaddition reaction by
1H NMR at 4.13 ppm (adduct C-2a) and 5.60 ppm (adduct 4a) at room
temperature. (D) Hammett plot of oxidative [4 + 2] cycloaddition of N-
tosylhydrazone 2a and substituted styrenes 3.
C
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The developed oxidative annulation could be performed on a
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sulfonyl group of 4a could be easily removed by reduction to
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In summary, we have developed a distinctive oxidative radical
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oxidative radical cyclization. Further extension of the method-
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ASSOCIATED CONTENT
* Supporting Information
■
S
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01360.
General experimental procedures, characterization details,
and 1H and 13C NMR spectra, IR spectra and HRMS for
new products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
* E-mail: luosz@iccas.ac.cn.
*E-mail: lvjian@iccas.ac.cn.
Notes
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Beauchemin, A. M.; Xiao, W.-J. Angew. Chem., Int. Ed. 2014, 53, 12163−
12167. For one example of preparation of six-membered compounds,
see: (b) Hu, X.-Q.; Qi, X.; Chen, J.-R.; Zhao, Q.-Q.; Wei, Q.; Lan, Y.;
Xiao, W. Nat. Commun. 2016, 7, 11188.
(16) (a) Duan, X.-Y.; Zhou, N.-N.; Fang, R.; Yang, X.-L.; Yu, W.; Han,
B. Angew. Chem., Int. Ed. 2014, 53, 3158−3162. (b) Duan, X.-Y.; Yang,
X.-L.; Fang, R.; Peng, X.-X.; Yu, W.; Han, B. J. Org. Chem. 2013, 78,
10692−10704.
(17) Zhu, X.; Wang, Y.-F.; Ren, W.; Zhang, F.-L.; Chiba, S. Org. Lett.
2013, 15, 3214−3217.
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(19) (a) Lv, J.; Zhong, X.; Luo, S. Chem. - Eur. J. 2014, 20, 8293−8296.
(b) Lv, J.; Zhang, L.; Luo, S.; Cheng, J.-P. Angew. Chem., Int. Ed. 2013,
52, 9786−9790.
(20) (a) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 8069−
8077. (b) Jiang, X.-K. Acc. Chem. Res. 1988, 21, 362−367.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (21390400,
21472193 and 21521002) and the National Basic Research
Program of China (2012CB821600) for financial support. S.L. is
supported by the National Program of Top-notch Young
Professionals and CAS One-hundred Talents Program.
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