Coupled Flavin-Iodine Redox Organocatalysts: Aerobic Oxidative Transformation from N-Tosylhydrazones to 1,2,3-Thiadiazoles

Article abstract of DOI:10.1021/acscatal.7b01535

A bioinspired two-component redox organocatalyst system using 1,10-bridged flavinium and NH₄I was developed to perform environmentally friendly aerobic oxidative ring formation of 1,2,3-thiadiazoles from N-tosylhydrazones and sulfur. The redox

Full text of DOI:10.1021/acscatal.7b01535

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Letter
Coupled Flavin-Iodine Redox Organocatalysts: Aerobic Oxidative
Transformation from N-Tosylhydrazones to 1,2,3-Thiadiazoles
Tatsuro Ishikawa, Maasa Kimura, Takuma Kumoi, and Hiroki Iida
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01535 • Publication Date (Web): 29 Jun 2017
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Coupled Flavin-Iodine Redox Organocatalysts: Aerobic Oxidative
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Transformation from N-Tosylhydrazones to 1,2,3-Thiadiazoles
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Tatsuro Ishikawa, Maasa Kimura, Takuma Kumoi, and Hiroki Iida*
Department of Chemistry, Interdisciplinary Graduate School of Science and Engineering, Shimane University, 1060 Nishiꢀ
kawatsu, Matsue 690ꢀ8504, Japan
ABSTRACT: A bioinspired twoꢀcomponent redox organocatalyst system using 1,10ꢀbridged flavinium and NH I was developed to
4
perform environmentally friendly aerobic oxidative ring formation of 1,2,3ꢀthiadiazoles from Nꢀtosylhydrazones and sulfur. The
redox organocatalysis of the flavinium promoted the iodineꢀcatalyzed system without the use of any sacrificial reagents, except for
environmentally benign molecular oxygen.
KEYWORDS: redox organocatalyst, flavin, iodine, aerobic oxidation, thiadiazole
The development of aerobic oxidative transformations is a
major, but highly rewarding, challenge in modern chemistry
because such reactions utilize ambient molecular oxygen as an
easily available, inexpensive, and minimally polluting oxiꢀ
1
dant. For providing environmentally friendly aerobic oxidaꢀ
tions that fulfill the requirement of green chemistry, construcꢀ
tion of biomimetic dual or multiple catalytic systems is recogꢀ
nized as one of the most promising approaches despite the
2
difficulty. Flavin catalysts, which have been developed by
mimicking the functions of flavinꢀdependent monooxygenasꢀ
es, have received increasing attention as unique biomimetic
redox organocatalysts that promote metalꢀfree catalytic oxyꢀ
2ꢀ4
genations through the activation of molecular oxygen. Thus,
the use of flavinꢀcatalyzed systems is an attractive strategy for
designing green and sustainable oxidative transformations
using molecular oxygen as the terminal oxidant. However,
examples of such strategies remain limited in spite of the poꢀ
tential applications evidenced by the versatile functions of
Scheme 1. Flavin-Catalyzed (A) Aerobic Oxygenation of
Substrate Using Reductant and (B) Aerobic Oxidative
–
Transformation of I to I2
8c
4ꢀ6
presence of K S O gave 1,2,3ꢀthiadiazoles (3), which are not
flavoproteins. Moreover, biomimetic aerobic oxygenation of
various substrates generally requires sacrificial reductants
2
2
8
only key structural moieties with bioactive and pharmacologiꢀ
9
4
a,4c,4h
4b,4d
4f
cal properties, but also a great source of reactive intermediꢀ
(
e.g., hydrazine,
zinc,
ascorbic acid, Hantzsch’s
4e
4g
ates for the synthesis of diverse sulfurꢀcontaining comꢀ
ester, and formic acid ) to convert the flavin catalyst (Fl) to
reduced flavin (Flred), which then generates the oxidatively
9
a,10
pounds.
transformations of 1 to 2, this catalytic system requires an
excess amount of oxidants, such as TBHP, TBPB, and K S O ,
Because I is employed to mediate the oxidative
2
active flavin hydroperoxide (FlOOH) via O activation (Scheme
2
1
A), and a novel approach without sacrificial reductants reꢀ
2
2
8
–
to reoxidize in situ generated I to I , which is a relatively exꢀ
mains a challenge.
2
pensive process and/or generates copious amounts of waste
Iodine catalysts have recently drawn considerable attention
as nontoxic and readily available redox organocatalysts for
8
(Scheme 2). The development of a novel strategy is required
7
to provide ecoꢀfriendly iodineꢀcatalyzed reactions that use
molecular oxygen as the terminal oxidant. We anticipated that
the flavinꢀcatalyzed aerobic oxygenation system could be apꢀ
plied to these iodineꢀcatalyzed reactions to replace the stoichiꢀ
ometric oxidants with molecular oxygen, thus providing novel
bioinspired dual catalytic system for environmentally friendly
diverse oxidative transformations. Among a series of iodineꢀ
catalyzed reactions, metalꢀfree oxidative transformations of Nꢀ
tosylhydrazones (1) with nucleophiles through azoalkene inꢀ
termediates (2) have been demonstrated as a useful tool for the
synthesis of pharmacologically important nitrogenꢀcontaining
8
heterocyclic compounds (3–5, Scheme 2). For example, the
aerobic oxidative transformations (Scheme 2). As a result,
TBAIꢀcatalyzed oxidative cyclization of 1 with sulfur in the
–
green catalytic conversion from I to I would occur without
2
the use of any sacrificial reagents, except for molecular oxyꢀ
gen, by the flavinꢀcatalyzed aerobic transformation. In this
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case, flavin catalysis would provide I efficiently in both the
We initially investigated the catalytic activity of various flaꢀ
vins for the reaction of acetophenone tosylhydrazone (1a) with
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oxidation and oxygenation steps (Scheme 1B). In other words,
–
I plays the dual role of reductant in the oxidation step and
sulfur in the presence of NH I in DMAc under molecular oxyꢀ
4
substrate in the oxygenation step.
gen (1 atm) at 100 ˚C for 8 h. Novel 1,10ꢀbridged alloxaꢀ
zinium chloride and triflate (8•Cl and 8•TfO) were readily
synthesized through the reaction of SOCl and 6b, which can
2
be prepared from commercially available riboflavin (6a) via
4g
two steps (Chart 1, Supporting Information). All of the flaꢀ
vins (6–8) were tolerated under these reaction conditions and
successfully promoted aerobic oxidative ring formation to give
the desired 1,2,3ꢀthiadiazole (3a) in 42–63% yields (Table 1,
entries 1–4). Among them, we chose the 1,10ꢀbridged alloxaꢀ
zinium salt (8•Cl) as the best from the viewpoint of catalytic
efficiency. An examination of 10 solvents (Supporting Inforꢀ
mation, Table S1) revealed the best efficiency in DMAcꢀ
pyridine (49:1, v/v). Attempts using various iodine sources
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Scheme 2. Previous and Present Approaches to Iodine-
Catalyzed Oxidative Transformations of 1
revealed that NH I gave the highest yield, whereas no reaction
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occurred without an iodine source (Table S1). Further optimiꢀ
zation of the reaction conditions revealed that the present flaꢀ
vinꢀiodineꢀcatalyzed system was successful with only 1.2
equiv of sulfur in the presence of 5 mol% of 8•Cl and 10
a
Table 1. Screening of Flavin Catalysts
mol% of NH I in DMAcꢀpyridine (19:1, v/v, entry 5). Preꢀ
4
sumably, the slow generation of the oxidatively active peroxꢀ
ide (FlOOH) results in an atomꢀeconomical process because it
circumvents the problems of sulfur consumption and/or easily
oxidizable reaction intermediates, which occur in conventional
processes using a stoichiometric amount of oxidant. Control
experiments were performed to gain additional insight into the
b
entry
flavin
sulfur (equiv)
yield (%)
1
2
3
4
5
6a
6b
10
10
46
42
48
63
37
82
18
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mechanism. Reactions under a N atmosphere or in the abꢀ
2
sence of the flavin catalyst gave poor yields (entries 6 and 7,
7•TfO
8•Cl
8•TfO
10
respectively), indicating that flavinꢀcatalyzed O
plays an essential role in the reaction.
2
activation
10
10
Given these results, we next explored the substrate scope of
tosylhydrazones using the optimized reaction conditions (Taꢀ
ble 2). A variety of tosylhydrazones were found to display
comparable reactivity and afforded good yields of 1,2,3ꢀ
thiadiazoles. The oxidative ring formation was applicable for
substrates bearing both electronꢀdonating and electronꢀ
withdrawing groups on the phenyl ring (3c–3f), and ring forꢀ
mation under air (1 atm) also proceeded smoothly. The reacꢀ
tion tolerated a range of functional groups such as ester, hyꢀ
droxy, iodo, bromo, and chloro groups to produce 3g–3k. The
reaction of tosylhydrazone bearing an alkene functionality also
occurred without transformation of the alkene, giving the corꢀ
responding product 3l in 60% yield. Interestingly, the thio
functionality was wellꢀtolerated; that is, 3m was produced in
c
d
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8•Cl
1.2
1.2
1.2
c,e
d
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8•Cl
c
8
None
a
Reactions of 1a were carried out in DMAcꢀpyridine (0.2 M,
9:1, v/v) in the presence of flavin (10 mol%), NH I (20
4
4
b
mol%), and sulfur at 100 ˚C for 8 h under O (1 atm). Yields
were determined by H NMR spectroscopy using 1,1,2,2ꢀ
tetrachloroethane as an internal standard. DMAcꢀpyridine (0.5
2
1
c
M, 19:1, v/v) and NH I (10 mol%) were used as the solvent and
4
d
e
iodine source, respectively. 5 mol%. Under N .
2
8
8% yield even though sulfides are known to be easily conꢀ
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verted to sulfoxides under oxidative conditions. Apparently,
–
oxygenation of I occurs preferentially to that of the thio funcꢀ
12
tionality, leading to intriguing chemoselectivity. 1,2,3ꢀ
Thiadiazoles bearing thienyl and furanyl groups (3n and 3o)
were isolated in 67 and 60% yields, respectively, whereas the
stoichiometric reaction of 1n with I (1.2 equiv) gave 3n in a
2
relatively lower 37% yield.
–
The flavinꢀcatalyzed aerobic oxidation of I was then invesꢀ
tigated by following the absorption spectral changes of HI in
DMAc at 80 ˚C under air (Supporting information, Figure S1).
In the presence of 8•TfO, which has better solubility than
8•Cl, the absorption signals centered at approximately 296 and
Chart 1. Structures of Flavin Catalysts
–
366 nm increased with time. We assign these signals to I3
species generated from I through the dynamic equilibrium
2
–
13
between I and I3 (Figure S1 (a, b, and d–h)). A similar
2
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spectral change was observed during the stoichiometric oxidaꢀ
tion of I with
, which is mediated by the flavinꢀcatalyzed system through the
use of molecular oxygen as the terminal oxidant.
–
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Table 2. Substrate Scope of the Flavin-Iodine-Catalyzed
In one final example, we show that the present flavinꢀ
iodineꢀcatalyzed system is capable of realizing crossꢀcoupling
of 1a and isocyanide to yield 5ꢀaminopyrazole 4a (Scheme
a
System.
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4), which was previously achieved using a stoichiometric
8
b
amount of TBHP as a terminal oxidant (Scheme 2). Altꢀ
hough the reaction efficiency was moderate, this preliminary
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Scheme 3. Proposed Mechanism for the Flavin-Iodine-
Catalyzed Aerobic 1,2,3-Thiadiazole Ring Formation
a
Reactions of 1 were performed in DMAcꢀpyridine (0.5 M,
Scheme 4. Flavin-Iodine-Catalyzed Aerobic Cross-
Coupling of 1a and Isocyanide
1
9:1, v/v) in the presence of 8•Cl (5 mol%), NH I (10 mol%),
4
b
and sulfur (1.2 equiv) at 100 ˚C for 8 h under O (1 atm). Unꢀ
der air (1 atm). Reaction was performed in DMAcꢀpyridine
2
c
(0.5 M, 19:1, v/v) in the presence of I (1.2 equiv) and sulfur
2
result clearly suggests the potential versatility of the present
flavinꢀiodineꢀcatalyzed system.
(1.2 equiv) at 100 ˚C for 8 h under N2.
In conclusion, we have developed a unique flavinꢀiodineꢀ
catalyzed system for chemoselective, metalꢀfree aerobic oxiꢀ
dative ring formation of 1,2,3ꢀthiadiazoles bearing various
functionalities from Nꢀtosylhydrazones and sulfur. The present
aerobic twoꢀcomponent organocatalyst system is applicable
not only to diverse iodideꢀcatalyzed transformations that have
conventionally required stoichiometric oxidants, but also for
the development of unprecedented green transformations utiꢀ
lizing molecular oxygen. Further studies using this strategy are
currently underway in our laboratory.
TBHP (Figure S2). In contrast, hardly any spectral changes
occurred in the absence of 8•TfO (Figure S1 (b and c)).
8
Based on these experimental results and previous reports, a
plausible mechanism for flavinꢀiodineꢀcatalyzed aerobic oxiꢀ
dative ring formation of 1,2,3ꢀthiadiazoles from tosylhydraꢀ
zones is proposed in Scheme 3. In the presence of I , tosylhyꢀ
2
drazone 1 is oxidatively converted to give corresponding azoꢀ
+
–
alkene 2, H , and I through αꢀiodation of 1 and subsequent HI
elimination of αꢀiodo hydrazine. After the addition of S8,
which is a main allotrope of molecular sulfur, to 2, cyclization
of zwitterionic 9 and subsequent elimination of S and TsH
7
AUTHOR INFORMATION
8c
give the desired product, 1,2,3ꢀthiadiazole 3 product. Flavin
–
Corresponding Author
catalyst 8 facilitates the oxidation of I to give I and reduced
2
flavin 8red, which activates molecular oxygen to give hydropꢀ
iida@riko.shimaneꢀu.ac.jp
eroxyflavin 8OOH. Then, catalytically generated 8OOH particiꢀ
–
pates in the oxygenation of I to give I , 8, and environmentalꢀ
ASSOCIATED CONTENT
Supporting Information
2
–
14,15
ly benign H O via the generation of IO .
efficiently regenerated by both oxidation and oxygenation of I
Thus, I can be
2
–
2
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The Supporting Information is available free of charge on
the ACS Publications website.
(6) For examples of the cooperative catalysis of flavins, see: (a)
Yano, Y.; Hoshino, Y.; Tagaki, W. Chem. Lett. 1980, 9, 749ꢀ752. (b)
Shinkai, S.; Yamashita, T.; Kusano, Y.; Manabe, O. J. Org. Chem.
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980, 45, 4947ꢀ4952. (c) Bergstad, K.; Jonsson, S. Y.; Bäckvall, J.ꢀE.
Experimental procedures and NMR spectra of novel comꢀ
pounds and products
J. Am. Chem. Soc. 1999, 121, 10424ꢀ10425. (d) Marz, M.; Chudoba,
J.; Kohout, M.; Cibulka, R. Org. Biomol. Chem. 2017, 15, 1970ꢀ1975
and refs 5d and 5k.
ACKNOWLEDGMENT
(7) For selected recent reviews, see: (a) Jereb, M.; Vražič, D.;
Zupan, M. Tetrahedron 2011, 67, 1355ꢀ1387. (b) Merritt, E. A.; Olꢀ
ofsson, B. Synthesis 2011, 517ꢀ538. (c) Parvatkar, P. T.; Parameswaꢀ
ran, P. S.; Tilve, S. G. Chem. Eur. J. 2012, 18, 5460ꢀ5489. (d) Ren, Y.
M.; Cai, C.; Yang, R. C. Rsc Adv. 2013, 3, 7182ꢀ7204. (e) Samanta,
R.; Matcha, K.; Antonchick, A. P. Eur. J. Org. Chem. 2013, 2013,
5769ꢀ5804. (f) Dong, D.ꢀQ.; Hao, S.ꢀH.; Wang, Z.ꢀL.; Chen, C. Org.
Biomol. Chem. 2014, 12, 4278ꢀ4289. (g) Wu, X.ꢀF.; Gong, J.ꢀL.; Qi,
X. Org. Biomol. Chem. 2014, 12, 5807ꢀ5817. (h) Liu, D.; Lei, A.
Chem. Asian J. 2015, 10, 806ꢀ823.
This work was supported in part by JSPS/MEXT
KAKENHI (GrantꢀinꢀAid for Scientific Research (C), no.
16K05797 and GrantꢀinꢀAid for Scientific Research on
Innovative Areas ”Advanced Molecular Transformations by
Organocatalysts”, no. 26105724) and the Sumitomo Founꢀ
dation. This work was performed in part under the Cooperꢀ
ative Research Program of the Institute for Protein Reꢀ
search, Osaka University, CRꢀ16ꢀ05. The authors thank Dr.
Michiko Egawa of Shimane University for her help with
elemental analysis.
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(
11) The flavinꢀcatalyzed system is also known to promote the oxiꢀ
3
dation of sulfides to sulfoxides, see refs. 3.
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reaction of 1a in the presence of methylphenylsulfide (1 equiv) gave
(
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(
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9
2
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(
–
stage of the reaction (<10% yield) where an excess amount of I exꢀ
ists, the generated I
through the dynamic equilibrium between I
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–
2 3
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–
2
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and I . (a) Awtrey, A.
1
Angew. Chem., Int. Ed. 2005, 44, 1704ꢀ1706. (c) Imada, Y.; Iida, H.;
Ono, S.; Masui, Y.; Murahashi, S.ꢀI. Chem. Asian. J. 2006, 1, 136ꢀ
1
2
47. (d) Chen, S.; Hossain, M. S.; Foss, F. W. Org. Lett. 2012, 14,
806ꢀ2809. (e) Chen, S.; Foss, F. W. Org. Lett. 2012, 14, 5150ꢀ5153.
–
–
–
(14) The stoichiometric oxygenation of I to I
3
via IO with the
(
f) Imada, Y.; Kitagawa, T.; Wang, H.ꢀK.; Komiya, N.; Naota, T.
analogous hydroperoxyflavin has been reported. Bruice, T. C.; Noar,
J. B.; Ball, S. S.; Venkataram, U. V. J. Am. Chem. Soc. 1983, 105,
Tetrahedron Lett. 2013, 54, 621ꢀ624. (g) Murahashi, S.ꢀI.; Zhang, D.;
Iida, H.; Miyawaki, T.; Uenaka, M.; Murano, K.; Meguro, K. Chem.
Commun. 2014, 50, 10295ꢀ10298. (h) Kotoučová, H.; Strnadová, I.;
Kovandová, M.; Chudoba, J.; Dvořáková, H.; Cibulka, R. Org. Bio-
mol. Chem. 2014, 12, 2137ꢀ2142.
2
452ꢀ2463.
15) There may be another possibility; Through the dynamic equiꢀ
librium, 8OOH forms 8 and H which may also participate in the
. The contribution of the inꢀsitu generated
could not be thoroughly ruled out, although the oxidation ability
(
2
O
2
–
oxygenation of I to give I
H O
2 2
2
(
5) For recent examples of other flavinꢀcatalyzed oxidative transꢀ
formations with molecular oxygen: (a) Imada, Y.; Iida, H.; Naota, T.
J. Am. Chem. Soc. 2005, 127, 14544ꢀ14545. (b) Imada, Y.; Kitagawa,
T.; Ohno, T.; Iida, H.; Naota, T. Org. Lett. 2010, 12, 32ꢀ35. (c)
Teichert, J. F.; den Hartog, T.; Hanstein, M.; Smit, C.; ter Horst, B.;
HernandezꢀOlmos, V.; Feringa, B. L.; Minnaard, A. J. ACS Catal.
4
of flavin hydroperoxide is 10 times stronger than H
fact, H promoted the present ring formation in the absence of the
2 2
O (ref. 14). In
2
O
2
flavin catalyst although the yield was moderate (Scheme S3, Supportꢀ
ing Information).
(16) 5ꢀAminopyrazoles have been widely utilized in synthetic inꢀ
termediates and pharmaceutical agents. For reviews, see: (a) Abu
Elmaati, T. M.; ElꢀTaweel, F. M. J. Heterocyclic Chem. 2004, 41,
2
011, 1, 309ꢀ315. (d) Iwahana, S.; Iida, H.; Yashima, E. Chem. Eur.
J. 2011, 17, 8009ꢀ8013. (e) Chen, S.; Hossain, M. S.; Foss, F. W. ACS
Sus. Chem. Eng. 2013, 1, 1045ꢀ1051. (f) Murray, A. T.; Dowley, M.
J. H.; PradauxꢀCaggiano, F.; Baldansuren, A.; Fielding, A. J.; Tuna,
F.; Hendon, C. H.; Walsh, A.; LloydꢀJones, G. C.; John, M. P.; Carꢀ
bery, D. R. Angew. Chem., Int. Ed. 2015, 54, 8997ꢀ9000. (g)
Muhldorf, B.; Wolf, R. Angew. Chem., Int. Ed. 2016, 55, 427ꢀ430. (h)
Neveselý, T.; Svobodová, E.; Chudoba, J.; Sikorski, M.; Cibulka, R.
Adv. Synth. Catal. 2016, 358, 1654ꢀ1663. (i) Hartman, T.; Cibulka, R.
Org. Lett. 2016, 18, 3710ꢀ3713. (j) Zhu, C. J.; Li, Q.; Pu, L. L.; Tan,
Z. T.; Guo, K.; Ying, H. J.; Ouyang, P. K. Acs Catal. 2016, 6, 4989ꢀ
1
09ꢀ134; (b) Aggarwal, R.; Kumar, V.; Kumar, R.; Singh, S. P.
Beilstein J. Org. Chem. 2011, 7, 179ꢀ197.
4
994. (k) Hering, T.; Mühldorf, B.; Wolf, R.; König, B. Angew.
Chem., Int. Ed. 2016, 55, 5342ꢀ5345.
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