Modular Synthesis of Carbon-Substituted Furoxans via Radical Addition Pathway. Useful Tool for Transformation of Aliphatic Carboxylic Acids Based on "build-and-Scrap" Strategy

Article abstract of DOI:10.1021/acs.orglett.0c00062

Utilizing radical chemistry, a new general C-C bond formation on the furoxan ring was developed. By taking advantage of the lability of furoxans, a wide variety of transformation of the synthesized furoxans have been demonstrated. Thus, this developed methodology enabled not only the modular synthesis of furoxans but also short-step transformations of carboxylic acids to a broad range of functional groups.

Full text of DOI:10.1021/acs.orglett.0c00062

pubs.acs.org/OrgLett
Letter
Modular Synthesis of Carbon-Substituted Furoxans via Radical
Addition Pathway. Useful Tool for Transformation of Aliphatic
Carboxylic Acids Based on “Build-and-Scrap” Strategy
Ryosuke Matsubara,* Hojin Kim, Takaya Sakaguchi, Weibin Xie, Xufeng Zhao, Yuto Nagoshi,
Chaoyu Wang, Masahiro Tateiwa, Akihiro Ando, Masahiko Hayashi, Masahiro Yamanaka,
and Takao Tsuneda
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ABSTRACT: Utilizing radical chemistry, a new general C−C
bond formation on the furoxan ring was developed. By taking
advantage of the lability of furoxans, a wide variety of trans-
formation of the synthesized furoxans have been demonstrated.
Thus, this developed methodology enabled not only the modular
synthesis of furoxans but also short-step transformations of
carboxylic acids to a broad range of functional groups.
eterocyclic compounds arguably play a central role in the
Hresearch and development of functional molecules, such
as pharmaceuticals and device materials.1 One of these
heterocyclic compounds is furoxan (1,2,5-oxadiazole-2-
oxide),2−8 which has a long history of more than 150 years
9,10
́
since its first synthesis by Kekule.
Furoxan has a unique
heteroatom-rich structure, consisting of a five-membered ring
with the exocyclic oxygen connected to the 2-position nitrogen
atom. The 3- and 4-positions of the furoxan ring are open to
arbitrary substituents, which brings forth the diversity of
furoxan-based molecules. At the research level, furoxan-
containing molecules have been reported to show several
biological activities typical to heterocyclic compounds.6,8
Furthermore, certain classes of furoxans exhibit nitric oxide-
releasing ability under physiological conditions,11−14 which
makes furoxan distinct from other heterocyclic compounds.
Despite its druglike structure, as well as its potential biological
activities, furoxan has been connected with very limited
practical applications so far.15 This phenomenon could
partially be attributed to the scarcity of general and facile
synthesis methods for furoxans with diverse carbon sub-
stituents. With regard to organic reactions of furoxans, they
often suffer ring opening, especially in the presence of strong
nucleophiles or reductive conditions,7 due to their highly
oxidized, thereby electron-deficient nature; therefore, conven-
tionally, carbon substituents had to be installed prior to the
furoxan ring formation (Figure 1A).5 However, this method is
not divergent and therefore inappropriate for establishing a
furoxan-based chemical library. Very recently, our group
reported the first general C−C bond-forming reactions on
the furoxan ring, which allowed the divergent synthesis of
Figure 1. Comparison of synthetic strategies of carbon-substituted
furoxan (A−C) and “build-and scrap” strategy developed in this work
(D).
Received: January 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00062
© XXXX American Chemical Society
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A

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Figure 2. Scope and limitation for radical addition reaction of sulfonyl furoxans. Experimental details are provided in the Supporting Information:
b
c
aAgNO3 (0.4 equiv); K2CO3 (1.5 equiv) was added; AgNO3 (0.4 equiv), K2S2O8 (3.0 equiv).
a
Scheme 1. Modular Synthesis of Carbon-Substituted Furoxans by Utilizing a Radical Reaction
a
Reaction conditions: (a) Figure 2; (b) 3a, toluene, 140 °C, 33%; (c) 3e, BuLi (1.1 equiv), oct-1-yne (1.3 equiv), THF, 0 °C, 44%; (d) 3e, CsF
(2.5 equiv), Me3SiCF3 (2.0 equiv), THF, − 20 °C, 53%. (e) refs 34 and 35; (f) for 5a and 6: 3f, NaOH (2.3 equiv), EtXH (2.0 equiv), THF, rt,
84% (5a), 49% (6); for 5b: 3e, NaOH (6.0 equiv), PhOH (6.0 equiv), DMF, 38 °C, 30%.
carbon-substituted furoxans from a common precursor (Figure
1B).16,17 The key for success was the application of soft carbon
nucleophiles in order to avoid the furoxan ring decomposition.
However, even with this method, the introduced carbon
substituents were limited to alkynyl and cyanide groups. The
sequential installation of both substituents in a modular
fashion has not yet been realized.
We recently developed carbon radical addition to sulfonyl
furoxans using carboxylic acids as a radical source; the details
of this research are presented in this article. The developed
method is a rare example of successful and elusive C−C bond
B
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2).29−33 The distinctive feature of this reaction is its
unconventional regioselectivity; C−C bond formation oc-
curred exclusively at the 3-position, which is in sharp contrast
to the ionic reactions, where reversed selectivity in favor of the
more electrophilic 4-position is generally observed.2,5,34
Various ArSO2 groups are tolerated; products 3b−e were
obtained in good yields. Similar yield could also be obtained in
a gram-scale reaction (3a). A wide range of carboxylic acids
have proven to perform well as a radical donor (3f−z).
Unfortunately, α-ketocarboxylic acid and aryl carboxylic acid
performed poorly (3aa,b). Late-stage furoxan introduction to
natural products and medicinal agents was also successful
(3ac−e).
Figure 3. Proposed reaction mechanism.
To our delight, the sulfonyl group at the 4-position proved
not to be a necessity for the radical addition reaction. Not only
3,4-disulfonyl furoxans, but also 3-sulfonyl furoxans having 4-
position substituents other than a sulfonyl group performed
well as a radical acceptor (Figure 2, bottom).
formation on the furoxan ring.18 The sequential introduction
of two different substituents to the preformed furoxan ring was
feasible, which represents the first example of a fully divergent
furoxan synthesis (Figure 1C). In addition, the synthesized
furoxans (“build” step) were subjected to ring-opening (“scrap”
step) and could be transformed to a variety of other functional
groups. As a result, our work could offer a unique strategy for
late-stage transformation of carboxylic acids to other functional
groups via “build-and-scrap” processing of furoxan (Figure
1D).
Initial investigation for divergent furoxan synthesis began
with disulfonyl furoxan 2, which is readily synthesized from α-
arylsulfonyl acetic acids in one step19,20 and is not of
potentially explosive nature.21 Inspired by reports of carbon
radical addition reactions with a sulfonyl moiety serving as a
radical leaving group,22−28 we investigated C−C bond forming
reactions of disulfonyl furoxans 2 with carbon radicals (Table
S1). To our delight, desired adduct 3a was obtained in high
yield using a combination of AgNO3 and K2S2O8 (Figure
The developed reactions of sulfonyl furoxans with alkyl
radicals enabled the sequential installation of the two
substituents to furoxans in a modular fashion,21 which is
summarized in Scheme 1. 3-Alkyl-4-sulfonyl furoxan 3,
synthesized from disulfonyl furoxan using the developed
radical reaction pathway, was isomerized thermally to 7,
which served as the substrate for the second radical addition
reaction to give 3,4-dialkyl furoxan 4b as a single regioisomer
(path A). The alkynylation of 3 was performed using the
previously developed conditions to afford 8 in good yield (path
B).16 Unprecedented trifluoromethylation of sulfonyl furoxan
using Me3SiCF3 and CsF granted 9 in good yield (path C). 3-
Alkyl furoxan with oxygen or sulfur substituents at the 4-
position were synthesized through alkoxylation or alkylth-
ionylation of disulfonyl furoxan,34,35 followed by radical-
mediated alkylation (path D). The same products can also
Figure 4. (a) Computed potential energy surface and relative Gibbs free energies in radical addition reaction to furoxan at the (u)LC-BLYP/6-
31G(d) level with the polarizable continuum solvation model of SMD and DMSO. All energies are indicated in kcal mol−1, and interatomic
distances are shown in angstroms. (b) Spin density analysis of transition states (3-TS1 and 4-TS1) and intermediates (3-INT and 4-INT) revealed
the distribution of α (blue) and β (green) spin. The hydrogen atoms are omitted for clarity.
C
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Letter
the developed reaction is the exclusive site-selectivity in favor
of the addition at the 3-position of disulfonyl furoxan. To
clarify the origin of this selectivity, we performed long-range
corrected (LC) density functional theory (DFT) calcula-
tions36−38 for the radical addition and elimination steps, using
the simplified substrates (RT1) (Figure 4a). The free-energy
barriers of the alkyl radical addition step for the 3- and 4-
position attacks are calculated to be 13.3 and 18.6 kcal mol−1,
respectively. These results could account for the observed site-
selectivity in favor of 3-position attack. The origin of the
energy difference between 3-TS1 and 4-TS1 can be explained
by considering the stabilization effect derived from spin
delocalization (Figure 4b). The spin density analysis revealed
that the α spin (blue color) on the furoxan ring of 3-TS1 is
delocalized over N2 and O1′ atoms, while that of 4-TS1 is
localized on the N5 atom. This energy difference between the
3- and 4-position attacks becomes more prominent at the stage
of intermediates, 3-INT and 4-INT (ΔG = 15.1 kcal mol−1).
The stabilized nature of 3-INT is readily understandable by the
fact that the resonance form of 3-INT is a nitroxyl radical 16, a
well-known stable radical, as exemplified by 2,2,6,6-tetrame-
thylpiperidine 1-oxyl (TEMPO).39
In recent years, the transformation of common functional
groups under mild conditions has proven effective for the late-
stage molecule functionalization.40 A carboxylic acid group,
which is prevalent in natural products and non-natural
pharmaceuticals, is one of the targets for late-stage
modification. Based on the expectation that furoxans are
prone to a variety of ring-degradation, due to their weak
aromaticity and electron-deficient nature, we propose that
furoxans could serve as synthetically versatile intermediates for
late-stage transformation of carboxylic acids. This so-called
“build-and-scrap” strategy was found to be feasible (Figure 5).
Sulfonylfurazan 17 could be generated from 3e in one step.41
The sulfonyl group of 17 can be a useful synthetic tool to
introduce other substituents to the furazan.42,43 (E,E)-
Dioximes 18 and 19 were stereospecifically obtained by
hydrogenation of the starting furoxans.44 Dioxime 20 with a
CF3 substituent was obtained, although as a regioisomeric
mixture. (Z,Z)-Dioxime 21, a regioisomer of 18, could also be
synthesized in a pure form from the regioisomer of 3e,
generated by photochemical isomerization of 3e. The
reduction of 3e by excess amount of LiAlH4 provided
monoamine 22.45 In contrast, 1,2-diamine 23 could be
obtained by a sequential reduction protocol, i.e., hydro-
genation using Pd/C catalyst followed by LiAlH4. Interestingly,
the reduction of 3e using 2 equiv of tributyltin hydride was
found to afford nitroalkane 24, the mechanism of which
remains a question to be explored. Meanwhile, oxime 25 was
obtained selectively by using increased amount of tributyltin
hydride. Simple treatment of 3e with KOH induced an
unprecedented transformation to afford nitrile 26. Under the
same conditions with a slight modification, α-hydroxyimino
carboxylic acid 27 could be generated as the main product. In
contrast to the reaction using KOH, the use of Bu4NOH
provided the corresponding hydroxide furoxan Bu4N salt.46
The following trifluoromethylsulfonylation gave the 4-
(triflyloxy)furoxan, which was converted to α-nitrocyano
compound 28 upon treatment with Pd(PPh3)4. Although
multiple steps are required, the mild reaction parameters
enable access to a nitrocyanomethyl group, a relatively rare
functional group in literatures.47,48 Compounds 29−31, a
molecule class of isoxazole and isoxazoline with an adjacent
Figure 5. “Build-and-scrap” of furoxans leading to a variety of
functional groups: (a) P(OEt)3 (3 equiv), 100 °C, 54 h, 74%; (b) Pd/
C (10 mol %), H2 (1 atm), MeOH, rt, 100% (18, 2 h), 82% (19, 3 h),
81% (20, 19 h, dr = 3:1); (c) (1) hν (λ = 300−400 nm), C6D6, rt, 2.5
h, 55%, (2) Pd/C (10 mol %), H2 (1 atm), MeOH, rt, 0.5 h, 100%;
(d) LiAlH4 (5 equiv), THF, 0 °C, 7 h, 39%; (e) (1) procedure (b),
(2) LiAlH4 (5 equiv), THF, 0 °C, 3.5 h, 57%; (f) Bu3SnH (2 equiv),
benzene, 40 °C, 5 d, 41%; (g) Bu3SnH (5 equiv), benzene, 40 °C, 5 d,
43%; (h) KOH (2.3 equiv), THF, rt, 3 d, 46%; (i) KOH (5.0 equiv),
THF, rt, 16 h, 18%; (j) (1) Bu4NOH (2 equiv), THF, rt, 1 h, (2)
Tf2O (1.1 equiv), CH2Cl2, 0 °C, 15 min, 21% (2 step), (3) Pd(PPh3)4
(1 equiv), benzene, rt, 10 min, 52%; (k) 1,3-dipolarophile (3 equiv),
DMF, 130−150 °C, 33% (29, using phenylacetylene), 12% (30, using
styrene), 18% (31, using oct-1-yne); (l) phenylacetylene (3 equiv),
toluene, 130 °C, 89 h, 8%.
be synthesized in reverse reaction order: thus, disulfonyl
furoxan 2 was subjected to radical reaction to give 3-alkyl-4-
sulfonyl furoxan 3, which then was subjected to addition−
elimination reaction to give the adducts bearing heteroatom
substituents (5a, 5b, and 6) (path E). Although both routes
provide the same product in comparable yields, one or the
other is preferred under certain conditions, when it comes to
creating a furoxan-based chemical library. When diversity in
the alkyl group is required, the radical addition should follow
the addition−elimination reaction. However, when diversity in
the heteroatom is desired, the addition−elimination reaction
should follow the radical addition.
On the basis of literature precedents,24,33 a plausible
mechanism is depicted in Figure 3. A noteworthy feature of
D
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oxime moiety, could be synthesized by heating a mixture of 3e
and 1,3-dipolarophile, alkyne, and alkene according to the
relevant literature.49 Isoxazole 32, lacking the oxime group
versus 29, could be generated from the same starting furoxan
3e by changing the solvent.50 Thus, functional groups with a
diverse range of size, electronic nature, and hydrogen bonding
ability are easily installed using a carboxylic acid as a synthetic
handle.
In conclusion, we have developed radical addition reactions
to furoxans in which the carbon radical is generated from
carboxylic acids in the presence of a silver catalyst and
persulfate salt. The present strategy enables a rare C−C bond
formation on the furoxan ring. Furthermore, we demonstrated
that the generated furoxans can be transformed to a variety of
functional groups by taking advantage of the lability of the
furoxan ring. Hence, furoxan “build-and-scrap” strategy
provides a powerful method to convert carboxylic acids to a
variety of functional groups in short steps. The expansion of
this strategy to other common functional groups and the
development of other “scrap” methods of furoxans are in
progress in our laboratory.
Masahiko Hayashi − Department of Chemistry, Graduate
School of Science, Kobe University, Kobe 657-8501, Japan;
orcid.org/0000-0002-1716-6686
Masahiro Yamanaka − Department of Chemistry and Research
Center for Smart Molecules, Rikkyo University, Tokyo 171-
8501, Japan; orcid.org/0000-0001-7978-620X
Takao Tsuneda − Graduate School of Science, Technology and
Innovation, Kobe University, Kobe 657-8501, Japan;
orcid.org/0000-0002-0249-5276
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00062
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
Nos. JP16K18844 and JP17J00025, Futaba Electronics
Memorial Foundation, Suzuken Memorial Foundation, In-
amori Foundation, and Daiichi Sankyo Foundation of Life
Science.
ASSOCIATED CONTENT
* Supporting Information
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REFERENCES
■
The Supporting Information is available free of charge at
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Takaya Sakaguchi − Department of Chemistry, Graduate
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Weibin Xie − Department of Chemistry, Graduate School of
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Xufeng Zhao − Department of Chemistry, Graduate School of
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Yuto Nagoshi − Department of Chemistry, Graduate School of
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Chaoyu Wang − Department of Chemistry, Graduate School of
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Masahiro Tateiwa − Department of Chemistry, Graduate
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