Metal-Free Direct Hydrosulfonylation of Azodicarboxylates with Sulfinic Acids Leading to Sulfonylhydrazine Derivatives

Article abstract of DOI:10.1080/00397911.2015.1034871

(Chemical Equation Presented). A metal-free direct hydrosulfonylation protocol of azodicarboxylates with sulfinic acids has been developed for the construction of sulfonylhydrazine-1,2-dicarboxylates at room temperature. This methodology provides an effic

Full text of DOI:10.1080/00397911.2015.1034871

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Metal-Free Direct Hydrosulfonylation of
Azodicarboxylates with Sulfinic Acids
Leading to Sulfonylhydrazine Derivatives
Jiangwei Wena, Wei Weia, Daoshan Yanga, Yufeng Fana, Lulu Fua &
Hua Wanga
a Key Laboratory of Life Organic Analysis and Key Laboratory of
Pharmaceutical Intermediates and Analysis of Natural Medicine,
School of Chemistry and Chemical Engineering, Qufu Normal
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University, Qufu, Shandong, China
Accepted author version posted online: 05 May 2015.Published
online: 05 May 2015.
To cite this article: Jiangwei Wen, Wei Wei, Daoshan Yang, Yufeng Fan, Lulu Fu & Hua
Wang (2015) Metal-Free Direct Hydrosulfonylation of Azodicarboxylates with Sulfinic Acids
Leading to Sulfonylhydrazine Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 45:13, 1574-1584, DOI:
10.1080/00397911.2015.1034871
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Synthetic Communications1, 45: 1574–1584, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1034871
METAL-FREE DIRECT HYDROSULFONYLATION OF
AZODICARBOXYLATES WITH SULFINIC ACIDS
LEADING TO SULFONYLHYDRAZINE DERIVATIVES
Jiangwei Wen, Wei Wei, Daoshan Yang, Yufeng Fan, Lulu Fu,
and Hua Wang
Key Laboratory of Life Organic Analysis and Key Laboratory of
Pharmaceutical Intermediates and Analysis of Natural Medicine, School of
Chemistry and Chemical Engineering, Qufu Normal University, Qufu,
Shandong, China
GRAPHICAL ABSTRACT
Abstract A metal-free direct hydrosulfonylation protocol of azodicarboxylates with sulfinic
acids has been developed for the construction of sulfonylhydrazine-1,2-dicarboxylates at
room temperature. This methodology provides an efficient and practical approach to
prepare various sulfonylhydrazine-1,2-dicarboxylates in good to excellent yields, which
has the advantages of operation simplicity, environmental friendliness, high atom
economy, and mild reaction conditions.
Keywords Hydrosulfonylation; metal-free; sulfinic acids; sulfonylhydrazine-1,2-
dicarboxylates
INTRODUCTION
As extremely valuable organic compounds, sulfonylhydrazines and their
derivatives have attracted considerable attention both from synthetic and medicinal
chemists, because they not only serve as useful synthetic precursors for a varity of
Received September 15, 2014.
Address correspondence to Wei Wei or Hua Wang, Key Laboratory of Life Organic Analysis and
Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry
and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China. E-mail:
weiweiqfnu@163.com; huawang_qfnu@126.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1574

SYNTHESIS OF SULFONYLHYDRAZINES
1575
organic transformations[1] but also are an important class of pharmaceutical
melecules with a broad spectrum of biological activities.[2–6] For example, as shown
in Scheme 1, compound I (VNP40101 M or laromustine)[3] is a sulfonylhydrazine
alkylating agent that has been demonstrated to have antitumor activity in preclinical
studies; compound II (KS900)[4] is a alkylating agent that targets the O-6 position of
guanine in DNA; compound III[5] exhibits potent inhibitory activity of HCV RNA
polymerase (NS5b); and compound IV[6] can be used as a selective inhibitor of c-Jun
N-terminal kinases (JNK). In addition, sulfonylhydrazines derivatives can also be
used in the production of azo dyestuffs[7] or as blowing agents in cellular rubber
and plastics.[8] Generally, sulfonylhydrazine compounds are prepared by the amina-
tion of sulfonyl chlorides with the corresponding hydrazines, which usually suffer
from poor tolerance of functional groups and the generation of large amounts of
unwanted by-products. Recently, palladium-catalyzed or palladium-free aminosulfo-
nylation reactions of aryl halides, boronic acids, and diazonium salts leading to sul-
fonylhydrazines have been proposed by Nguyen et al.[9] and Ye and Wu,[10] in which
the use of DABCO · (SO2)2 or K2S2O5 as the sulfonylation reagent was thought to be
a breakthrough [Scheme 2, Eq. (1)]. In 2014, Wang et al. also reported a copper-
catalyzed, three-component reaction of triethoxysilanes, sulfur dioxide, and hydra-
zines for the construction of sulfonylhydrazines [Scheme 2, Eq. (2)].[11] Despite some
advantages of these reactions, they might in a way encounter low atom-economy or
the use of transition-metal catalyst.[9,10a,b,11] Thus, the development of more simple,
convenient, atom-economical, and green methods for the construction of
sulfonylhydrazine compounds is still highly desirable.
Very recently, sulfinic acids as a simple and readily available sulfonylating
source have been emerged for constructing sulfone-containing compounds with high
atom efficiency.[12,13] Here, we report a simple, highly efficient, and catalyst-free
direct hydrosulfonylation of azodicarboxylates with sulfinic acids leading to
sulfonylhydrazine-1,2-dicarboxylates via S-N bond formation at room temperature
with 100% atom efficiency [Scheme 2, Eq. (3)].
Scheme 1. Examples of bioactive sulfonylhydrazine compounds.

1576
J. WEN ET AL.
Scheme 2. Methods for synthesis of sulfonylhydrazine compounds.
RESULTS AND DISCUSSION
Initially, the reaction of benzenesulfinic acid 1a with diisopropyl azodicarboxylate
2a catalyzed by Cu(OAc)2 was investigated. To our delight, the desired product was
obtained in 81% yield in tetrahydrofuran (THF) at room temperature (Table 1, entry
1). Further optimization of catalysts showed that the similar yields were achieved in
the presence of Pd(OAc)2 and AgNO3 (Table 1, entries 2 and 3). Based on the findings,
we envisioned that the efficiency of this reaction might not be affected by the metal salts.
As expected, the desired product was obtained in 86% yield when the reaction was
performed in the absence of catalyst (Table 1, entry 4). Moreover, the increase of tem-
perature did not improve the efficiency of the reaction (Table 1, entries 5 and 6). The rela-
tively lower yields were obtained when bases such as Et3N, pyridine, and 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU) were employed as the additives (Table 1, entries 7–9). The
experimental results indicate that the reaction efficiency could be significantly influenced
by the employed solvents (Table 1, entries 4 and 10–16). Among the various solvents
tested, protic solvent CH3OH was proven to be the optimal reaction medium compared
to the others (Table 1, entry 12). Notably, the desired product could also be obtained in
good yield (92%) when CH3OH=H2O was used as cosolvent (Table 1, entry 18).
Under the optimized reaction conditions, the scope of this hydrosulfonylation
reaction was investigated with a variety of sulfinic acids and azodicarboxylates, with
the results shown in Table 2. In general, arylsulfinic acids which have electron-
donating or electron-withdrawing groups on the aryl rings were suitable for this
transformation, and the products were obtained in good to excellent yields (Table
2, entries 1–11). Various functionalities including halogen, nitro, acetyl, and aceta-
mino groups were compatible with this reaction leading to the corresponding pro-
ducts 3a–3 k, which could be employed for the synthesis of more complicated
derivatives via various organic transformations (Table 2, entries 4–7). In addition,
naphthalene-1-sulfinic acid was also be used in this reaction system to give the corre-
sponding product 3 l in 60% yield (Table 2, entry 12). Notably, alkylsulfinic acid such

SYNTHESIS OF SULFONYLHYDRAZINES
1577
Table 1. Optimization of the reaction conditionsa
Entry
Catalyst
Additive (1 equiv)
T (oC)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Cu(OAc)2
Pd(OAc)2
AgNO3
—
—
—
25
25
25
25
50
Reflux
25
25
25
25
25
25
25
25
25
25
25
25
THF
THF
THF
THF
THF
THF
THF
THF
THF
81
72
72
86
85
85
69
73
71
58
95
98
90
81
85
28
54
92
—
—
—
—
—
—
—
Et3N
Pyridine
DBU
—
—
—
—
CH3CN
EtOAc
CH3OH
EtOH
Toluene
1,4-Dioxane
DMSO
H2O
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CH3OH=H2O (1:1)
aReaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), catalyst (5mol %), solvent (2mL), 25 °C, air, 12h.
bIsolated yields based on 2a.
as trifluoromethanesulfinic acid was also preferred for this reaction to give the
expected 3 m in 87% yield (Table 2, entry 13). Furthermore, to broaden the scope
of the reaction, a series of azodicarboxylates including diethyl, di-tert-butyl, and
dibenzyl azodicarboxylates were also used in the reaction with various sulfinic acids
to give the corresponding products (3n–3w) in good yields (Table 2, entries 14–23).
In addition, the synthetic applicability of this method was investigated on a
gram scale by using the model reaction between 1a and 2a. As shown in Scheme
3, the reaction could afford 3a in 87% yield (3.0 g), confirming that the present
procedure could serve as a practical and efficient protocol to synthesize sulfonylhy-
drazine-1,2-dicarboxylates.
It is well known that the addition of sulfinic acids to alkynes or alkenes may
proceed via a radical process under air.[12,13] To elucidate whether the reaction
involves a radical pathway, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and
butylated hydroxytoluene (BHT), the commonly used radical-capturing species, were
added in the present reaction system (Scheme 4). Nevertheless, the reaction efficiency
was not significant affected by TEMPO or BHT, because the desired products 3a
were still obtained in good yields (84% and 85%, respectively). Accordingly, it is
thought that this reaction might not involve a radical process.
To obtain further insights into this reaction, several control experiments were
carried out as shown in Schemes 5 and 6. When azodicarboxylate 2a reacted with

1578
J. WEN ET AL.
Table 2. Results for the reaction of the hydrosulfonylation of azodicarboxylates with sulfinic acidsa,b
Entry
1
Sulfinic acid
Azodicarboxylate
Product
Yield (%)
3a (98%)
2
3
3b (97%)
3c (86%)
4
5
6
7
3d (98%)
3e (81%)
3f (87%)
3 g (86%)
8
9
3 h (87%)
3i (93%)
(Continued)

SYNTHESIS OF SULFONYLHYDRAZINES
1579
Table 2. Continued
Entry
10
Sulfinic acid
Azodicarboxylate
Product
Yield (%)
3 j (88%)
11
12
3 k (97%)
3 l (60%)
13
14
3 m (87%)
3n (95%)
15
16
17
3o (76%)
3p (73%)
3q (98%)
18
19
3r (84%)
3 s (84%)
(Continued)

1580
J. WEN ET AL.
Table 2. Continued
Entry
20
Sulfinic acid
Azodicarboxylate
Product
Yield (%)
3t (83%)
21
22
23
3u (80%)
3v (83%)
3w (76%)
aReaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), CH3OH (2 mL), 12–24 h, 25 °C, under air.
bIsolated yields based on 2.
benzenesulfonic acid under the optimal conditions, no desired product was
obtained (Scheme 5). Only a trace amount of product 3a was detected when sodium
benzenesulfinate was performed in the present reaction system (Scheme 6). Fur-
thermore, the product 3a was obtained in 95% yield when 1 equiv of CF3COOH
was added to the reaction system containing sodium benzenesulfinate and
Scheme 3. Gram scale reaction.
Scheme 4. Radical-capturing experiments.

SYNTHESIS OF SULFONYLHYDRAZINES
1581
Scheme 5. The reaction of benzenesulfonic acid with azodicarboxylate 2a.
Scheme 6. The reaction of sodium benzenesulfinate with azodicarboxylate 2a.
Scheme 7. Possible reaction pathway.
azodicarboxylate 2a (Scheme 6). These results indicated that benzenesulfonic acid
might not be an intermediate in this reaction, and the hydrogen ion played a key
role in the formation of product 3a.
Based on this information and previous reports,[12–14] a postulated reaction
pathway was proposed as shown in Scheme 7. First, sulfinic acid 2 gave the sulfinyl
anion 4 resonating with more nucleophilic sulfonyl anion 5 by the loss of hydrogen
proton. Subsequently, the nucleophilic addition of sulfonyl anion 5 to azodicarbox-
ylate 2 would lead to the formation of intermediate 6. Finally, the protonation of 6
produced the desired product 3.
CONCLUSION
In conclusion, a novel and practical protocol of metal-free direct hydrosulfony-
lation of azodicarboxylates with sulfinic acids has been developed under mild con-
ditions via direct S-N bond formation. The reaction is tolerant of a wide variety
of functional groups. Taking into account the combination of desirable features,
such as cheap and readily available materials, operation simplicity, high atom
economy, and metal-free conditions, the proposed protocol is expected to offer a

1582
J. WEN ET AL.
highly efficient and attractive access to versatile sulfonylhydrazine compounds.
Further applications of this new transformation in organic synthesis are underway
in our group.
EXPERIMENTAL
All commercially available reagent-grade chemicals were purchased from
Aldrich, Acros, Alfa Aesar, and Beijing Ouhe Chemical Company and used as
received without further purification unless otherwise stated. All solvents were dried
according to standard procedures.1H NMR and13C NMR were recorded in CDCl3
on a Bruker Avance III 400 spectrometer with tetramethylsilane (TMS) as internal
standard (400 MHz1H, 100 MHz13C) at room temperature, the chemical shifts (d)
were expressed in parts per million (ppm), and J values were given in hertz (Hz).
The following abbreviations are used to indicate the multiplicity: singlet (s), doublet
(d), triplet (t), quartet (q), doublet of doublets (dd), doublet of triplets (dt), and
multiplet (m). All first-order splitting patterns were assigned on the basis of the
appearance of the multiplet. Splitting patterns that could not be easily interpreted
were designated as multiplet (m). Mass analyses and high-resolution mass spec-
trometry (HRMS) were obtained on a Finnigan-LCQDECA mass spectrometer
and a Bruker Daltonics Bio-TOF-Q mass spectrometer by the electrospray ioniza-
tion (ESI) method, respectively. Column chromatography was performed on silica
gel (200–300 mesh).
Typical Procedure for Metal-Free Direct Hydrosulfonylation of
Azodicarboxylates with Sulfinic Acids
CH3OH (2 mL) was added to a mixture of benzenesulfinic acid 1a
(0.6 mmol) and diisopropyl azodicarboxylate 2a (0.5 mmol) in a 25-mL round-
bottomed flack at room temperature. The reaction vessel was allowed to stir at
room temperature for 12 h. After the reaction, the solvent was then removed
under vacuum. The residue was purified by flash column chromatography using
a mixture of petroleum ether and ethyl acetate as eluent to give the desired
product 3a.
Product 3a
Compound 3a was obtained in 98% yield according to the typical procedure
(12 h).
1H NMR (CDCl3, 400 MHz, ppm): d 8.15 (d, J ¼ 7.6 Hz, 2 H), 7.65 (t, J ¼ 7.3
Hz, 1 H), 7.54 (t, J ¼ 8.0 Hz, 2 H), 7.17 (brs, 1 H), 5.01–4.91 (m, 2 H), 1.33–1.11

SYNTHESIS OF SULFONYLHYDRAZINES
1583
(m, 12 H);13C NMR (CDCl3, 100 MHz, ppm): 154.6, 150.9, 138.3, 134.0, 129.4,
128.6, 73.0, 71.0, 21.9, 21.5. HRMS (ESI) calcd. for C14H20N2O6NaS (M þ Na)þ
367.0940; found 367.0945.
FUNDING
This work was supported by the National Natural Science Foundation of
China (Nos. 21302109, 21302110, and 21375075), the Taishan Scholar Foundation
of Shandong Province, the Excellent Middle-Aged and Young Scientist Award
Foundation of Shandong Province (BS2013YY019), and the Scientific Research
Foundation of Qufu Normal University (BSQD 2012020).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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