Hypervalent iodine(III)-promoted metal-free S-H activation: An approach for the construction of S-S, S-N, and S-C bonds

Article abstract of DOI:10.1002/ejoc.201402180

The activation of the sulfur atom of thiols with (diacetoxyiodo)benzene (DIB) has been explored in the preparation of symmetrical disulfides and sulfenamides. Disulfides can be produced in excellent yields (75-95%) upon treatment of thiols with DIB. The reaction was complete in less than five minutes at room temperature. Aliphatic, aromatic, and heteroaromatic thiols are compatible with this transformation. Moreover, heteroaromatic disulfides obtained from heteroaromatic thiols further reacted with a nucleophilic amine in the presence of a base to provide the corresponding sulfenamides in fair to good yields (43-90%) in a one-pot fashion. The methodology was successfully extended to indole as a representative electron-rich aromatic compound, which allowed successful construction of a S-C bond in one pot. The key benefits of this reaction include lower toxicity, low cost of DIB reagent, and mild reaction conditions (room temperature, undried solvents and open flask).

Full text of DOI:10.1002/ejoc.201402180

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DOI: 10.1002/ejoc.201402180
Hypervalent Iodine(III)-Promoted Metal-Free S–H Activation: An Approach
for the Construction of S–S, S–N, and S–C Bonds
Eakkaphon Rattanangkool,[a] Watanya Krailat,[b] Tirayut Vilaivan,[c]
Preecha Phuwapraisirisan,[c] Mongkol Sukwattanasinitt,[a] and Sumrit Wacharasindhu*[a]
Keywords: Hypervalent compounds / Oxidation / Iodine / Sulfur / Heterocycles / Disulfides
The activation of the sulfur atom of thiols with (diacetoxy-
iodo)benzene (DIB) has been explored in the preparation of
symmetrical disulfides and sulfenamides. Disulfides can be
produced in excellent yields (75–95%) upon treatment of thi-
ols with DIB. The reaction was complete in less than five min-
utes at room temperature. Aliphatic, aromatic, and heteroaro-
matic thiols are compatible with this transformation. More-
over, heteroaromatic disulfides obtained from heteroaromatic
thiols further reacted with a nucleophilic amine in the pres-
ence of a base to provide the corresponding sulfenamides in
fair to good yields (43–90%) in a one-pot fashion. The meth-
odology was successfully extended to indole as a representa-
tive electron-rich aromatic compound, which allowed suc-
cessful construction of a S–C bond in one pot. The key bene-
fits of this reaction include lower toxicity, low cost of DIB rea-
gent, and mild reaction conditions (room temperature, un-
dried solvents and open flask).
disulfide formation from the thiol catalyzed by laccase, un-
der air shows an example of a green transformation.[9] To
obtain sulfenamides, disulfides have to be converted into
sulfenyl chlorides with chlorine or NCS followed by amin-
ation.[10] This method not only requires three synthetic
steps but it also involves sulfenyl chlorides, which are very
unstable and undergo rapid hydrolysis. Recently, a direct
synthesis of sulfenamides from either thiols or disulfides
was developed by Taniguchi by using a copper-catalyzed
amination reaction.[11] Although this reaction is highly ef-
ficient and compatible with many functional groups, metal
and elevated temperature are still required in the transfor-
mation. Therefore, the development of a metal-free method
Introduction
Organosulfur compounds containing disulfide or sulfur–
nitrogen bonds are important building blocks for a broad
range of applications in biological, pharmaceutical, and
material sciences. Disulfides (S–S) are vital for the stabiliza-
tion of peptide structures in proteins,[1] chemical protection
group,[2] and vulcanization.[3] Organosulfur compounds
having an S–N bond, on the other hand, are used as biolo-
gically active compounds[4] and as intermediates in organic
synthesis[5] and material chemistry.[6] The conventional
method for preparing disulfides involves oxidation of thiols
by using metal-containing oxidants or catalysts such as Fe,
Pb, Ce, Mn, Co, Cr, Cu, or Al.[7] Metal-free oxidation
methods using halogen (I2, Br2), hydrogen peroxide, azo
reagents, graphite, sodium nitrite, or Burgess reagent have
also been applied (Scheme 1, a).[8] However, the high toxic-
ity and cost of the reagents, combined with the harsh reac-
tion conditions such as elevated temperature, long reaction
time, and risk of over-oxidation represent significant disad-
vantages. The recent discovery by Beifuss of heterocyclic
[a] Nanotec-CU Center of Excellence on Food and Agriculture,
Department of Chemistry, Faculty of Science, Chulalongkorn
University,
Bangkok 10330, Thailand
E-mail: sumrit.w@chula.ac.th
http://www.chula.ac.th/en/
[b] Program of Petrochemistry and Polymer Science,
Chulalongkorn University,
Bangkok, Thailand
[c] Department of Chemistry, Faculty of Science, Chulalongkorn
University,
Scheme 1. (a) Conventional method for the preparation of di-
sulfides and sulfenamides. (b) Utilization of hypervalent iodine rea-
gents for the preparation of disulfides and sulfenamides.
Bangkok 10330, Thailand
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402180.
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that can be conducted under mild conditions for the synthe- Table 1. Oxidation of 4-chlorothiophenol with hypervalent
iodine(III) reagents.[a]
sis of dithiols and sulfenamides remains a challenge.
In the past few decades, hypervalent iodine compounds
have been developed as selective reagents for oxidative
transformation and construction of carbon–heteroatom
and carbon–carbon bonds.[12] Importantly, the environmen-
tally friendly character and commercial availability at rea-
Entry
Hypervalent iodine(III)
Time
Yield [%][b]
sonable cost make these compounds suitable for synthetic
organic reactions. Due to the thiophilic nature of hyperva-
lent iodine reagents, such compounds have recently been
shown to activate sulfur atoms such as thioethers, thioam-
ides, and thioureas.[13] Recently, Patel demonstrated a syn-
thesis of benzimidazoles by using hypervalent iodine(III)
reagents such as (diacetoxyiodo)benzene (DIB) to perform
intramolecular C–N bond formation between isothio-
cyanates and amines.[14] To the best of our knowledge, how-
ever, no full investigations on the activation of simple thiols
by hypervalent iodine reagents have been reported.[15]
Therefore, taking clues from this and other works, we
sought to exploit the thiophilic properties of hypervalent
iodine(III) compounds for the preparation of disulfides and
construction of S–N as well as S–C bonds from the disulf-
ides in a one-pot fashion using thiols as starting materials
(Scheme 1, b). This reaction was expected to provide a
metal-free approach for the direct synthesis of disulfide,
sulfonamides, and aromatic sulfides.
1
2
3
4
PhI(OH)(OTs)
PhI(OCOCF3)2
PhI(OCOtBu)2
PhI(OCOCH3)2
10 min
3 h
45 min
1 min
54
55
72
87
[a] Reaction conditions: 4-chlorothiophenol (1.0 equiv.), hyperva-
lent iodine (1.0 equiv.), iPrOH, r.t., open air. [b] Isolated yield after
silica gel chromatography.
HPLC after 5 min and the results show complete conver-
sion into 2a in every case. These results suggested a broad
solvent compatibility and robustness of DIB for thiol oxi-
dation. The effects of the stoichiometry of DIB were investi-
gated as shown in Table 2 (entry 9–11). Only 0.5 equiv. of
DIB was found to be sufficient to drive the oxidation com-
pletely. At this stage we hypothesized that aerobic oxidation
of thiols by the oxygen in air may also be involved. To en-
sure complete conversion, we decided to use DIB (1 equiv.)
in the less toxic solvent, 2-propanol, as the optimized condi-
tions for further studies (entry 4).
Table 2. Optimization of oxidation of 4-chlorothiophenol with
PhI(OAc)2.[a]
Results and Discussion
Synthesis of Disulfides from Thiols
Initially, various commercially available hypervalent
iodine(III) reagents were screened with 4-chlorothiophenol
(1a) as substrate to establish the most effective oxidant/acti-
vator (Table 1). It was our goal to develop a mild and con-
venient reaction, therefore, all tested reactions were con-
ducted in undried 2-propanol, and in open air conditions
at room temperature. The use of [hydroxy(tosyloxy)iodo]-
benzene [PhI(OH)OTs], also known as Koser’s reagent, gave
the corresponding symmetrical disulfide 2a in 54% yield
in 10 min (Table 1, entry 1). Moreover, organic iodine(III)
reagents carrying an ester group such as trifluoroacetoxy,
tert-butoxy, and acetoxy gave better results; converting thiol
1a into disulfide 2a in 55, 72, and 87% yield, respectively.
Specifically, (diacetoxyiodo)benzene (DIB) not only gave
the best yield among the tested hypervalent iodine reagents,
but the starting material 1a was completely consumed
within less than one minute under the conditions examined.
Considering the high reactivity, combined with benign envi-
Entry
DIB [equiv.]
Solvent
Conversion [%][b]
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.3
0.5
0.7
EtOAc
toluene
xylene
100
100
100
100
100
100
100
100
84
iPrOH
nBuOH
CH2Cl2
hexane
DMSO
iPrOH
iPrOH
iPrOH
9
10
11
100
100
[a] Reaction conditions: 4-chlorothiophenol (1.0 equiv.), DIB
(1.0 equiv.), solvent, r.t., under air, 5 min. [b] Determined by HPLC
analysis.
With the optimized conditions in hand, we explored the
ronmental characteristics, low cost, and wide availability of generality and scope of this reaction by using a variety of
DIB, this reagent was selected as the oxidizing agent for thiols including aliphatic, cyclic aromatic, and heterocyclic
further investigation.
substrates. Twelve thiols were subjected to the optimized
With the results of the hypervalent iodine reagent screen- oxidation conditions and the results are presented in
ing process in hand, we next studied the effects of solvent Table 3. The oxidation of aliphatic and cyclic thiols pro-
and stoichiometry of the oxidation of 4-chlorothiophenol ceeded smoothly and the desired disulfides 2b–d were iso-
(1a) with DIB. Eight solvents (all undried) were tested for lated in 90, 86 and 80% yield, respectively, after column
the oxidation of 1a with DIB (1 equiv.) at room temperature chromatography. Importantly, DIB reacted specifically with
(Table 2, entry 1–8). The reactions were monitored by only the thiol group, leaving the primary alcohol in 1e un-
2
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Hypervalent Iodine(III)-Promoted S–H Activation
Table 3. Synthesis of symmetrical disulfides from thiols.[a]
[a] Isolated yield after silica gel chromatography.
touched. Aromatic thiols having electron-donating groups ducting the reaction with cyclohexane thiol and 4-methyl-
such as amino, and methyl moieties gave the corresponding thiophenol at room temperature overnight. On the other
disulfides 2f and 2g in excellent yields. The nitrogen-con- hand, 2-mercaptopyridine (1h) generated a mixture of di-
taining heteroaromatic thiols were also tested with DIB. sulfide 2h and the expected sulfenamide 3a in 33 and 47%
Monocyclic ring derivatives such as 2- and 4-mercapto-pyr- yield, respectively. These encouraging results not only show
idines and pyrimidinethiol 1h–k smoothly oxidized to pro- that the reaction could be used to produce heterocyclic
vide disulfides 2h–k in good to excellent yields. Moreover, sulfenamides in a one-pot synthesis, but they also provide
bicyclic substrates including 2-mercaptobenzothiazole (1l) some clues for the reaction mechanism. The disulfide is
and quinoline-2-thiol (1m) were also transformed into di- most likely an intermediate in this transformation.
sulfides 2l and 2m in decent yields. TLC monitoring sug-
gested that, in all cases, the starting thiols were completely
consumed within five minutes at room temperature in an
open flask setup. These results suggested that this method
is highly efficient and convenient, making it applicable for
modern organic synthesis.
One-Pot Synthesis of Sulfenamides from Thiols
With successful results from the oxidation of thiols using
DIB, we next explored the use of this hypervalent iodine
reagent to synthesize various sulfenamides in a one-pot pro-
cess. Based on recent reports of using hypervalent iod-
ine(III) reagent to activate the sulfur atom,[14b] we hypoth-
esized that the reagent could also be used to further activate
the disulfide bond. Subsequent nucleophilic attack by a nu-
cleophile such as an amine should generate a sulfenamide.
Therefore, we selected three different classes of substrates
including cyclohexane (1d), chlorobenzene (1a), and pyr-
Scheme 2. Amination reaction of thiols with DIB reagent.
Although the reaction is only suitable for the amination
idine (1h) thiols for reaction screening using DIB as the of heterocyclic thiols into sulfenamide derivatives, such
oxidant/activator and used butylamine as a nucleophile in compounds are valuable building blocks in medicinal chem-
the presence of DIPEA as a base for the neutralization of istry and pharmaceuticals. Sulfenamides containing hetero-
the acid produced from the reaction (Scheme 2). Disap- cyclic moieties were reported to show acetylcholine inhibi-
pointingly, only disulfides 2a and 2d were isolated as the tion, insecticidal activities, and antitumor activities among
sole products in 87 and 80% yields, respectively, by con- others.[4f,16] We therefore optimized the reaction using 2-
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mecaptopyridine (1h) with DIB and butylamine (Table 4). reaction efficiency was similar to that obtained when the
Substituting the base DIPEA with 1,8-diazabicyclo[5.4.0]- reaction was conducted with 0.5 equiv. DIB. We suspected
undec-7-ene (DBU) resulted in the exclusive formation of that the amine may have lost its nucleophilicity by coordi-
N-butylsulfenamide 3a in 82% yield after 4 h without re- nation with the excess DIB reagent. Based on these results,
maining disulfide 2h (entry 1). A short survey of hyperva- we used DIB (1.1 equiv.) as the oxidant/activator and DBU
lent iodine(III) reagents showed that DIB is by far the most as the base in 2-propanol at room temperature in an open
effective reagent (entries 2–4). Unlike the method used for flask as the optimized conditions for further studies (en-
the preparation of disulfide, this reaction is solvent depend- try 1).
ent (entries 5–7). Using MeCN and N,N-dimethylform-
In development of a new methodology, it is important to
amide (DMF) as solvent gave the desired sulfenamide 3a in demonstrate the compatibility of the method with various
53 and 45%yield, respectively. In addition, disulfide 2h was substrates. Thus, a panel of amine nucleophiles were sub-
also isolated in 26 and 16% yield, respectively. An attempt jected to the optimized sulfenylation conditions employing
to drive the reaction to completion by raising the tempera- two heteroaromatic thiols 2- and 4-mercaptopyridines 1h
ture to 125 °C was made, but lower yields of both the sulf- and 1i (Table 5). Without external nucleophile, disulfide 2h
enamide and disulfide products were observed (entry 7). In was isolated as the sole product in 90% yield in the case of
the absence of DBU, the disulfide was isolated as the major 1h. In the presence of simple primary amines such as benzyl
product in 56% yield along with the desired sulfenamide 3a and cyclohexylamines, sulfenamides 3b and 3c were ob-
in just 26% yield (entry 8). Changing the base from DBU tained in 65 and 54% yield, respectively, along with disulf-
to DIPEA or K2CO3 gave lower yields of the desired sulfen- ide 2h in ca. 23% yield. Secondary amines including pyr-
amide 3a (entries 9 and 10). The amount of DIB reagent rolidine, piperidine, and morpholine were acceptable sub-
was crucial in this reaction (entries 11 and 12). When the strates and the corresponding N,N-dialkyl sulfenamides 3d–
reaction was performed without DIB, only a small amount f were isolated 58–60% yields along with small amounts of
of disulfide 2h was obtained (25% yield) with no detectable 2h. Amine nucleophiles carrying other functional groups
sulfenamide product. When 0.5 equiv. DIB was used, the such as hydroxy or acetal were also compatible with the
sulfenamide was produced in only 25% yield along with the reaction conditions, generating the corresponding sulfen-
disulfide in 51% yield (entry 12). These results suggested amides 3g and 3h, respectively, in 43 and 57% yields.
that DIB also facilitated the amination reaction after the Attempts to improve the formation of sulfenamide 3 by in-
oxidation step. However, when an excess amount of DIB creasing the temperature, nucleophile amount, or reaction
(2 equiv.) was added to the reaction mixture (entry 13), the time, resulted in insignificant improvements. Unfortunately,
the sterically hindered tert-butylamine and the less nucleo-
philic aniline did not act as a nucleophile and only disulfide
2h could be isolated. Similarly, 4-mercaptopyridine (2i) gave
the corresponding sulfenamides 3k–r in slightly better
yields compared with 2-mercaptopyridine (2h).
Table 4. Optimization of one-pot synthesis of sulfenamide from 2-
mercaptopyridine.[a]
Although, this reaction generally gave only moderate
yields when compared with traditional multistep synthesis
involving oxidation chlorination and amination, this
method can provide a complementary way to prepare sulf-
enamide derivatives under benign and convenient condi-
tions. With these encouraging results in hand, a panel of
commercially available heteroaromatic thiols 1j–m was then
examined to demonstrate the generality of this DIB-medi-
ated direct amination reaction (Scheme 3); the results are
summarized in Table 6. It was shown that this new S–N
bond-forming reaction is suitable for generating heteroaro-
matic sulfenamides ranging from monocyclic to bicyclic
with good efficiency. The reaction of benzylamine in the
presence of DIB and DBU gave the desired N-benzylsulfen-
amides 3u–x in good yields of 64–73%. We would like to
Entry Oxidant (equiv.)
Base
Sol-
vent
Yield 3a/2h [%][b]
1
2
3
4
5
6
PhI(OCOCH3)2 (1.1)
PhI(OCOCF3)2 (1.1)
PhI(OCOtBu)2 (1.1)
PhI(OH)(OTs) (1.1)
PhI(OCOCH3)2 (1.1)
PhI(OCOCH3)2 (1.1)
PhI(OCOCH3)2 (1.1)
PhI(OCOCH3)2 (1.1)
DBU iPrOH
DBU iPrOH
DBU iPrOH
DBU iPrOH
DBU MeCN
DBU
DBU
–
82:0
26:67
13:81
36:50
53:19
45:26
5:16
25:56
64:25
9:79
DMF
DMF
iPrOH
7[c]
8
9
PhI(OCOCH3)2 (1.1) DIPEA iPrOH
10
11
12
13
PhI(OCOCH3)2 (1.1)
–
PhI(OCOCH3 (0.5))
PhI(OCOCH3) (2.0)
K2CO3 iPrOH
DBU iPrOH
DBU iPrOH
DBU iPrOH
0:24
25:51
27:57
[a] Reaction conditions: 2-mercaptopyridine (1.0 equiv.), hypervalent
iodine(III) (1.1 equiv.), iPrOH, 0 °C, 1 min, then base (2.0 equiv.), n-
butylamine (2.0 equiv.), 0 °C to r.t., 4 h. [b] Isolated yield after silica
gel chromatography. [c] Reaction heated to reflux.
Scheme 3. Synthesis of 3-(4-chlorophenylthio)-1H-indole.
4
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Hypervalent Iodine(III)-Promoted S–H Activation
Table 5. The scope of the reaction with respect to amine nucleophiles in the DIB-mediated direct amination of 2- or 4-mercaptopyr-
idine.[a], [b]
.
[a] Reaction conditions: 2- or 4-mercaptopyridine (1.0 equiv.), DIB (1.1 equiv.), iPrOH, 0 °C, 1 min, then DBU (2.0 equiv.), amine
(2.0 equiv.), 0 °C to r.t., under air, 4 h. [b] Isolated yield after silica gel chromatography. [c] Amine and DBU were not added.
Table 6. One-pot synthesis of sulfenamide from heterocyclic thiols.[a]
note that, in comparison with pyridinethiols 1h–i, heterocy-
cles 1j–m underwent complete amination reaction without
any disulfide remaining in the reaction. The higher reactiv-
ity of these heterocyclic thiols in comparison with pyridine
is governed by increases in the electrophilicity of the sulfur
atom, which facilitates nucleophilic substitution by the
amines.
Applications in S–C Bond Formation: Direct Sulfenylation
of Indole
In addition to the preparation of sulfenamides, we ex-
panded our discovered methodology to the synthesis of sul-
fenylindoles. Such compounds represent pharmaceutically
and biologically important structures, with their therapeutic
[a] Reaction conditions: heteroaromatic thiol (1.0 equiv.), DIB
value in the treatment of heart disease, allergies, cancer,
(1.1 equiv.), iPrOH, 0 °C, 1 min, then DBU (2.0 equiv.), benzyl-
HIV, and obesity.[17] Traditional approaches for synthesi-
amine (2.0 equiv.), 0 °C to r.t., 4 h. [b] Isolated yield after silica gel
chromatography. [c] DMF was used as solvent.
zing this class of compound include sulfenylation of the
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indole ring by various sulfenylating agents such as sulfenyl formation of S–S, S–N and S–C bonds from thiols. The
halides, N-thioimides, and disulfides.[18] These approaches reaction proceeds smoothly under mild conditions without
require multiple-step transformations because the starting exclusion of air or moisture. The corresponding disulfides
sulfenating agents are derived from the thiols. We herein and sulfenamides were obtained in fair to good yields.
report the applicability of the present DIB-mediated sulf- Moreover, the reaction can be used to prepare a representa-
enylation reaction for a direct synthesis of sulfenylindole tive 3-sulfenylindole directly from indole and thiol. This
from thiols (Scheme 3). In a slight modification of the pre- novel method provides an environment friendly, low cost,
vious conditions for sulfenamide formation, 4-chlorophen- and easy to operate alternative synthetic route to disulfides,
ylthiol (1a) was treated with DIB followed by DBU and 1H- sulfenamides, and sulfenylindoles directly from thiols.
indole at 120 °C under open atmosphere for 12 h. To our
delight, thioether 4 was obtained in 43% yield along with
disulfide 2a in 31% yield.
Experimental Section
General Remarks: All reagents were purchased from Sigma–Ald-
rich, Fluka (Switzerland) or Merck (Germany) and used without
further purification. All reactions were carried out under air atmo-
sphere. All solvents were used without distillation. MS (ESI) and
Proposed Mechanism for DIB-Mediated Disulfide and
Sulfenamide Formation
A plausible mechanism of the DIB-mediated formation HRMS (ESI) were obtained with a micrOTOF Bruker mass spec-
trometer. 1H and 13C NMR spectra were recorded (CDCl3,
of the disulfides and sulfenamides is shown in Scheme 4.
CD3OD, and [D6]DMSO as solvent) at 400 and 100 MHz, respec-
Based on previous work on the activation of sulfur by
tively, with a Varian Mercury+ 400 NMR or a Bruker (Avance 400)
hypervalent iodine reagents,[14b] we hypothesize that the re-
NMR spectrometer using tetramethylsilane (TMS) as internal stan-
action involves ligand exchange between DIB and thiol,
dard. Chemical shifts are reported in ppm downfield from TMS.
leading to the formation of sulfenyl iodide intermediate 5.
Analytical thin-layer chromatography (TLC) was performed on
A second molecule of thiol then undergoes ligand exchange
with 5 to produce the disulfide product. This process is fa-
precoated Merck silica gel 60 F254 plates (thick layer, 0.25 mm) and
visualized by 254 nm ultraviolet lamp and potassium permanganate
cilitated by the reductive elimination to leave iodobenzene
6, which is a well-known reaction for hypervalent iodine
compounds.[19] From the formation of sulfenamide, there
are two possible pathways (A and B). In the presence of a
strong nucleophile such as amine, a sulfur atom on the di-
sulfide is attacked and expels a sulfide anion, which un-
as the detecting agent. Column chromatography was performed by
using Merck silica gel 60 (70–230 mesh).
General Procedure for Synthesis of Thiols 2a–m (Procedure A): To
a solution of thiol 2 (1.0 equiv.) in iPrOH was added DIB
(1.0 equiv.) and the solution was stirred at ambient temperature for
5 min. The solvent was removed by rotary evaporation and the
dergoes further ligand exchange with DIB reagent to again crude product was purified by silica gel chromatography.
form the reactive key intermediate 5 (pathway A). This pro-
cess makes the leaving group sulfide anion form the starting
key intermediate 5 and drive the reaction forward. To verify
the proposed mechanism, disulfide 2h was treated with n-
butylamine in the absence of DIB. Under these conditions,
sulfenamide 3a was isolated in 27% yield, supporting the
conclusion that disulfide is an intermediate in this reaction.
However, the possibility of direct nucleophilic substitution
by the nitrogen amine on the sulfur atom of intermediate 5
could not be ruled out (pathway B).
1,2-Bis(4-chlorophenyl)disulfane (2a):[20] [CAS: 1142-19-4]: Synthe-
sized according to procedure A using 4-chlorothiophenol (100 mg,
0.691 mmol), DIB (222 mg, 0.691 mmol) in iPrOH (4 mL) to afford
1a (86.6 mg, 0.346 mmol, 87%) as a yellow solid. 1H NMR
(CDCl3, 400 MHz): δ = 7.40 (d, J = 8.7 Hz, 4 H), 7.27 (d, J =
8.7 Hz, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 135.2, 133.7,
129.4, 129.3 ppm. IR (neat): ν = 3079, 2925, 1470, 1385 cm–1.
˜
1,2-Dioctyldisulfane (2b):[21] [CAS: 822-27-5]: Synthesized accord-
ing to procedure A using 1-octanethiol (118 μL, 0.684 mmol), DIB
(220 mg, 0.684 mmol) in iPrOH (4 mL) to afford 2b (89.0 mg,
1
0.342 mmol, 90%) as a colorless oil. H NMR (CDCl3, 400 MHz):
δ = 3.30 (m, 4 H), 2.70 (m, 4 H), 1.69 (t, J = 7.5 Hz, 4 H), 1.30 (d,
J = 2.7 Hz, 16 H), 0.9 (s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 39.2, 31.8, 29.2, 28.6, 22.6, 14.1 ppm. IR (neat): ν = 3056, 2928,
˜
2859, 1268, 1131 cm–1.
1,2-Dibenzyldisulfane (2c):[8g] [CAS: 150-60-7]: Synthesized accord-
ing to procedure A using benzyl mercaptan (94.0 μL, 0.804 mmol),
DIB (277 mg, 0.804 mmol) in iPrOH (4 mL) to afford 2c (85.7 mg,
1
0.402 mmol, 86%) as pink crystals. H NMR (CDCl3, 400 MHz):
δ = 7.37–7.29 (m, 10 H), 3.65 (s, 4 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 137.4, 129.4, 128.5, 127.4, 43.4 ppm. IR (neat): ν =
˜
Scheme 4. A plausible mechanism of disulfide and sulfenamide for-
mation.
3052, 3029, 2914, 2857, 1497, 1456, 1405 cm–1.
1,2-Dicyclohexyldisulfane (2d):[8g] [CAS: 2550-40-5]: Synthesized
according to procedure
A using cyclohexanethiol (101 μL,
0.860 mmol), DIB (277 mg, 0.860 mmol) in iPrOH (4 mL) to afford
2d (79.7 mg, 0.430 mmol, 80%) as white crystals. 1H NMR (CDCl3,
400 MHz): δ = 2.65 (m, 2 H), 2.01 (s, 4 H), 1.77 (s, 4 H), 1.60 (t,
Conclusions
We have demonstrated an operationally simple and ef-
ficient DIB-mediated one-pot direct methodology for the J = 6 Hz, 2 H), 1.25 (m, 10 H) ppm. 13C NMR (CHCl3, 100 MHz):
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42180
/KAP1
Date: 23-06-14 19:41:23
Pages: 11
Hypervalent Iodine(III)-Promoted S–H Activation
δ = 50.0, 32.9, 26.1, 25.7 ppm. IR (neat): ν = 2931, 2853, 1450,
(100 mg, 0.599 mmol), DIB (192 mg, 0.599 mmol) in iPrOH (4 mL)
to afford 2l (85.9 mg, 0.299 mmol, 89%) as a white solid. 1H NMR
(CDCl3, 400 MHz): δ = 7.87 (d, J = 8.1 Hz, 2 H), 7.70 (d, J =
8.1 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.29 (t, J = 7.2 Hz, 2
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 167.8, 154.5, 136.2,
˜
1340, 1262 cm–1.
6,6Ј-Disulfanediyldihexan-1-ol (2e):[22] [CAS: 80901-86-6]: Synthe-
sized according to procedure
A using 6-mercapto-1-hexanol
(101 μL, 0.745 mmol), DIB (240 mg, 0.745 mmol) in iPrOH (4 mL)
to afford 2e (87.0 mg, 0.373 mmol, 87%) as a yellow solid. 1H
NMR (CDCl3, 400 MHz): δ = 3.66 (t, J = 6.6 Hz, 4 H), 2.77–2.62
(m, 4 H), 1.71 (m, 4 H), 1.59 (m, 4 H), 1.51–1.34 (m, 8 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 62.8, 39.1, 32.6, 29.1, 28.2,
126.6, 125.3, 122.7, 121.3 ppm. IR (neat): ν = 3058, 2978, 2928,
˜
2869, 1464, 1423, 1317, 1237 cm–1.
1,2-Di(quinolin-2-yl)disulfane (2m):[26] [CAS: 2889-13-6]: Synthe-
sized according to procedure A using quinoline-2-thiol (100 mg,
0.620 mmol), DIB (199 mg, 0.620 mmol) in iPrOH (4 mL) to afford
2m (90.4 mg, 0.310 mmol, 91%) as a yellow solid. 1H NMR
(CDCl3, 400 MHz): δ = 7.95 (m, 4 H), 7.74 (d, J = 8.0 Hz, 2 H),
7.65 (m, 4 H), 7.42 (t, J = 8.0 Hz, 2 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 158.3, 146.9, 136.5, 129.4, 127.3, 126.7, 125.4, 124.4,
25.4 ppm. IR (neat): ν = 3346, 2934, 2859, 1465, 1053 cm–1.
˜
1,2-Di-p-tolyldisulfane (2f):[8g] [CAS: 103-19-5]: Synthesized accord-
ing to procedure
A
using 4-methyl thiophenol (100 mg,
0.804 mmol), DIB (259 mg, 0.804 mmol) in iPrOH (4 mL) to afford
2f (94.4, 0.402 mmol, 95%) as a yellow oil. 1H NMR (CDCl3,
400 MHz): δ = 7.30 (d, J = 8.4 Hz, 4 H), 7.03 (d, J = 8.4 Hz, 4 H),
2.24 (s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 137.5, 133.9,
116.3 ppm. IR (neat): ν = 3058, 2922, 2849, 1612, 1585, 1556, 1491,
˜
1447, 1423 cm–1.
General Procedure for Synthesis of 3a–x (Procedure B): A solution
of N-heterocyclic thiol (1.0 equiv.) in iPrOH and DIB (1.1 equiv.)
was stirred at 0 °C for 1 min, then DBU (2.0 equiv.) and amine
(2.0 equiv.) were added and the mixture was stirred at 0 °C to room
temperature for 4 h. The crude product was purified by silica gel
column chromatography.
129.8, 128.6, 21.0 ppm. IR (neat): ν = 3020, 2914, 2852, 1488,
˜
1397 cm–1.
2,2Ј-Disulfanediyldianiline (2g):[8c] [CAS: 1141-88-4]: Synthesized
according to procedure A using 2-aminothiophenol (85.0 μL,
0.799 mmol), DIB (257 mg, 0.799 mmol) in iPrOH (4 mL) to afford
2g (74.6 mg, 0.399 mmol, 75%) as a yellow solid. 1H NMR
(CDCl3, 400 MHz): δ = 7.18 (t, J = 11.0 Hz, 4 H), 6.74 (m, 2 H),
6.62 (m, 2 H), 4.19 (s, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
N-Butyl-2-pyridinesulfenamide (3a): Synthesized according to pro-
cedure B using 2-mercaptopyridine (50.0 mg, 0.450 mmol), DIB
(159 mg, 0.495 mmol), DBU (134 μL, 0.900 mmol), n-butylamine
(88.9 μL, 0.900 mmol) in iPrOH (4 mL) to afford 3a (73.7 mg,
0.405 mmol, 90%) as a colorless oil. 1H NMR (CDCl3, 400 MHz):
δ = 8.36 (d, J = 4.0 Hz, 1 H), 7.51 (td, J = 8.0, 4.0 Hz, 1 H), 7.26
(d, J = 8.0 Hz, 1 H), 6.89 (dd, J = 8.0, 4.0 Hz, 1 H), 3.07 (br. s, 1
H), 2.92 (m, 2 H), 1.50 (m, 2 H), 1.30 (m, 2 H), 0.85 (t, J = 7.3 Hz,
3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 164.9, 148.1, 135.2,
= 148.6, 136.8, 131.6, 118.8, 115.3 ppm. IR (neat): ν = 3377, 3294,
˜
3067, 2925, 2852, 1606, 1580, 1470, 1441 cm–1.
1,2-Di(pyridine-2-yl)disulfane (2h):[8g] [CAS: 2127-03-9]: Synthe-
sized according to procedure A using 2-mercaptopyridine (50.0 mg,
0.450 mmol), DIB (159 mg, 0.495 mmol) in iPrOH (4 mL) to afford
2h (44.4 mg, 0.202 mmol, 90%) as a white solid. 1H NMR (CDCl3,
400 MHz): δ = 8.40 (d, J = 8.1 Hz, 2 H), 7.60–7.49 (m, 4 H), 7.04
(m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.0, 149.6,
118.1, 116.8, 52.5, 32.6, 20.0, 13.9 ppm. IR (neat): ν = 3366, 3017,
˜
2957, 2927, 2396, 1708, 1649, 1627, 1578, 1557, 1439, 1422, 1359,
1326 cm–1. HRMS (ESI): m/z calcd. for [C9H14N2S + H]+ 183.0956;
found 183.0950.
137.4, 121.1, 119.7 ppm. IR (neat): ν = 3168, 3098, 1604, 1570,
˜
1487, 1438 cm–1. IR (neat): ν = 3046, 2987, 1574, 1556, 1444,
˜
1414 cm–1.
N-Benzyl-2-pyridinesulfenamide (3b): Synthesized according to pro-
cedure B using 2-mercaptopyridine (50.0 mg, 0.450 mmol), DIB
(159 mg, 0.495 mmol), DBU (134 μL, 0.900 mmol), benzylamine
(98.3 μL, 0.90 mmol) in iPrOH (4 mL) to afford 3b (63.2 mg,
1,2-Di(pyridin-4-yl)disulfane (2i):[23] [CAS: 2645-22-9]: Synthesized
according to procedure A using 4-mercaptopyridine (50.0 mg,
0.450 mmol), DIB [159 mg, 0.495 mmol in iPrOH (4 mL)] to afford
2i (42.6 mg, 0.194 mmol, 86%) as a white solid. 1H NMR (CDCl3,
400 MHz): δ = 8.42 (d, J = 5.5 Hz, 4 H), 7.29 (d, J = 5.5 Hz, 4
1
0.293 mmol, 65%) as a yellow oil. H NMR (CDCl3, 400 MHz): δ
= 8.48 (d, J = 4.8 Hz, 1 H), 7.57 (td, J = 8.0, 4.8 Hz, 1 H), 7.44–
7.27 (m, 6 H), 6.89 (dd, J = 8.0, 4.8 Hz, 1 H), 4.15 (d, J = 8.0 Hz,
2 H), 3.55 (br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
164.0, 149.5, 139.3, 136.3, 128.5, 128.4, 127.6, 119.6, 118.3,
H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 148.9, 145.3,
119.0 ppm. IR (neat): ν = 3032, 3002, 2922, 1568, 1544, 1479,
˜
1405 cm–1.
1,2-Bis(5-bromopyridin-2-yl)disulfane (2j):[24] [CAS: 872273-36-4]:
Synthesized according to procedure A using 5-bromopyridine-2-
thiol (100 mg, 0.526 mmol), DIB (169 mg, 0.526 mmol) in iPrOH
(4 mL) to afford 2j (81.5 mg, 0.263 mmol, 82%) as yellow crystals.
1H NMR (CDCl3, 400 MHz): δ = 8.45 (d, J = 2.4 Hz, 2 H), 7.66
(dd, J = 8.5, 2.4 Hz, 2 H), 7.43 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 157.2, 150.6, 139.9, 121.1, 118.3 ppm. IR
56.7 ppm. IR (neat): ν = 3323, 3059, 3028, 2987, 1599, 1577, 1556,
˜
1500, 1495, 1456, 1416, 1280, 1220 cm–1. HRMS (ESI): m/z calcd.
for [C12H12N2S-H]– 215.0643; found 215.0637.
N-Cyclohexyl-2-pyridinesulfenamide (3c): [CAS: 178735-21-2]: Syn-
thesized according to procedure
B using 2-mercaptopyridine
(50.0 mg, 0.450 mmol), DIB (159 mg, 0.495 mmol), DBU (134 μL,
0.900 mmol), cyclohexylamine (103 μL, 0.900 mmol) in iPrOH
(4 mL) to afford 3c (50.5 mg, 0.243 mmol, 54%) as a colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 8.33 (d, J = 4.0 Hz, 1 H), 7.50
(m, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.88 (m, 1 H), 2.98 (br. s, 1
H), 2.67 (m, 1 H), 1.95 (m, 2 H), 1.66 (m, 2 H), 1.52 (m, 1 H),
1.25–0.99 (m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 164.9,
(neat): ν = 3099, 3058, 2922, 1550, 1438, 1343 cm–1.
˜
1,2-Di(pyrimidin-2-yl)disulfane (2k):[25] [CAS: 15718-46-4]: Synthe-
sized according to procedure
A using 2-mercaptopyrimidine
(100.00 mg, 0.89 mmol), DIB (287.31 mg, 0.89 mmol) in iPrOH
(4.0 mL) to afford 2k (74.00 mg, 0.45 mmol, 75%) as yellow crys-
1
tals. H NMR (CDCl3, 400 MHz): δ = 8.52 (d, J = 4.8 Hz, 4 H),
148.1, 135.2, 118.1, 116.8, 58.5, 32.6, 24.8, 23.8 ppm. IR (neat): ν
˜
7.02 (t, J = 4.8 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
= 3342, 3040, 3013, 2937, 2847, 1572, 1552, 1449, 1413, 1367, 1343,
1272, 1258 cm–1. MS (ESI): m/z calcd. for [C11H16N2S + H]+
209.11; found 209.11.
169.8, 157.9, 118.1, 29.7 ppm. IR (neat): ν = 3114, 3067, 2919,
˜
2846, 1550, 1426, 1364, 1264 cm–1.
1,2-Bis(benzo[d]thiazol-2-yl)disulfane (2l):[8g] [CAS: 120-78-5]: Syn-
N-Piperidinyl-2-pyridinesulfenamide (3d): [CAS: 178735-24-5]: Syn-
thesized according to procedure A using 2-mercaptobenzothiazole
thesized according to procedure B using 2-mercaptopyridine
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42180
/KAP1
Date: 23-06-14 19:41:23
Pages: 11
S. Wacharasindhu et al.
FULL PAPER
(35.0 mg, 0.450 mmol), DIB (111 mg, 0.346 mmol), DBU (94 μL,
0.630 mmol), piperidine (62 μL, 0.630 mmol) iPrOH (3 mL) to af-
(88.9 μL, 0.900 mmol) in iPrOH (4 mL) to afford 3k (63.1 mg,
1
0.47 mmol, 77%) as a colorless oil. H NMR (CDCl3, 400 MHz):
ford 3d (37.3 mg, 0.192 mmol, 61%) as a colorless oil. 1H NMR δ = 8.33 (d, J = 6.1 Hz, 2 H), 7.10 (d, J = 6.1 Hz, 2 H), 2.92 (m, 1
(CDCl3, 400 MHz): δ = 8.40 (d, J = 4.3 Hz, 1 H), 7.58 (td, J = 8.1,
1.7 Hz, 1 H), 7.48 (d, J = 8.1 Hz, 1 H), 6.93 (dd, J = 6.8, 5.4 Hz,
1 H), 3.21–3.10 (m, 4 H), 1.68 (dt, J = 11.2, 5.8 Hz, 4 H), 1.50 (dd,
H), 2.66 (br. s, 1 H), 1.49 (m, 2 H),1.31 (m, 2 H), 0.86 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 154.0, 148.1,
115.6, 51.1, 31.6, 19.0, 12.8 ppm. IR (neat): ν = 3209, 3063, 3026,
˜
J = 11.6, 6.0 Hz, 2 H), 1.66 (m, 2 H), 1.52 (m, 1 H), 1.25–0.99 (m, 3000, 2953, 2920, 2870, 2867, 2442, 2392, 1665, 1575, 1542, 1476,
5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 165.8, 149.3, 136.4,
1436, 1406, 1376, 1366, 1313, 1296, 1213 cm–1. HRMS (ESI): m/z
119.1, 118.0, 57.6, 27.4, 23.3 ppm. IR (neat): ν = 3016, 2937, 2857,
calcd. for [C9H14N2S + H]+ 183.0956; found 183.0950.
˜
2827, 1575, 1555, 1442, 1419, 1363, 1213 cm–1. MS (ESI): m/z
N-Benzyl-4-pyridinesulfenamide (3l): Synthesized according to pro-
cedure B using 4-mercaptopyridine (50.0 mg, 0.450 mmol), DIB
(159 mg, 0.495 mmol), DBU (134 μL, 0.900 mmol), benzylamine
(98.3 μL, 0.900 mmol) in iPrOH (4 mL) to afford 3l (49.6 mg,
0.230 mmol, 51%) as a pale-yellow solid. 1H NMR (CDCl3,
calcd. for [C10H14N2S + H]+ 195.10; found 195.10.
N-Morpholinyl-2-pyridinesulfenamide (3e): [CAS: 2244-48-6]: Syn-
thesized according to procedure
B using 2-mercaptopyridine
(50.0 mg, 0.450 mmol), DIB (159 mg, 0.495 mmol), DBU (134 μL,
0.900 mmol), morpholine (77.9 μL, 0.900 mmol) in iPrOH (4 mL) 400 MHz): δ = 8.35 (d, J = 5.9 Hz, 2 H), 7.32–7.23 (m, 5 H), 7.13
1
to afford 3e (52.1 mg, 0.266 mmol, 59%) as a yellow oil. H NMR
(CDCl3, 400 MHz): δ = 8.36 (d, J = 4.4 Hz, 1 H), 7.53 (td, J = 8.0,
0.8 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 6.91 (m, 1 H), 3.71 (m, 4
H), 3.17 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 164.2,
(d, J = 5.9 Hz, 2 H), 4.06 (d, J = 5.7 Hz, 2 H), 3.00 (br. s, 1 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 154.3, 149.2, 138.8, 128.7, 128.2,
127.9, 116.7, 56.4 ppm. IR (neat): ν = 3335, 3086, 3063, 3033, 2960,
˜
2445, 2395, 1668, 1572, 1545, 1495, 1479, 1452, 1409, 1353, 1316,
149.4, 136.5, 119.6, 118.1, 67.9, 56.2 ppm. IR (neat): ν = 3040,
1216 cm–1. HRMS (ESI): m/z calcd. for [C12H12N2S + H]+
˜
2953, 2914, 2844, 1569, 1555, 1452, 1412, 1280, 1246 cm–1. MS 217.0799; found 217.0793.
(ESI): m/z calcd. for [C9H12N2OS + H]+ 197.07; found 197.07.
N-Cyclohexyl-4-pyridinesulfenamide (3m): [CAS: 178735-22-3]:
N-Pyrrolidinyl-2-pyridinesulfenamide (3f): Synthesized according to
procedure B using 2-mercaptopyridine (50.0 mg, 0.450 mmol), DIB
(159 mg, 0.495 mmol), DBU (134 μL, 0.900 mmol), pyrrolidine
(73.9 μL, 0.900 mmol) in iPrOH (4 mL) to afford 3f (48.6 mg,
0.270 mmol, 60%) as a colorless oil. 1H NMR ([D4]MeOH,
400 MHz): δ = 8.21 (d, J = 4.4 Hz, 1 H), 7.61 (td, J = 8.0, 2.0 Hz,
Synthesized according to procedure B using 4-mercaptopyridine
(50.0 mg, 0.450 mmol), DIB (159 mg, 0.495 mmol), DBU (134 μL,
0.900 mmol), cyclohexylamine (103 μL, 0.900 mmol) in iPrOH
(4 mL) to afford 3m (62.7 mg, 0.302 mmol, 67%) as a white solid.
1H NMR (CDCl3, 400 MHz): δ = 8.31 (d, J = 6.1 Hz, 2 H), 7.14
(d, J = 6.1 Hz, 2 H), 2.64 (br. m, 2 H), 1.93 (d, J = 11.4 Hz, 2 H),
1 H), 7.30 (d, J = 8.0 Hz, 1 H), 6.96 (m, 1 H), 3.14 (t, J = 6.6 Hz, 1.67 (d, J = 12.4 Hz, 2 H), 1.53 (d, J = 11.5 Hz, 1 H), 1.26–1.00
4 H), 1.86 (m, 4 H) ppm. 13C NMR ([D4]MeOH, 100 MHz): δ = (m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 155.7, 149.0,
167.2, 149.9, 138.4, 120.6, 119.1, 56.5, 27.2 ppm. IR (neat): ν =
116.7, 59.6, 33.7, 25.7, 24.8 ppm. IR (neat): ν = 3345, 3066, 3013,
˜
˜
3016, 2967, 2860, 1572, 1555, 1452, 1412, 1210 cm–1. HRMS (ESI):
2930, 2860, 2449, 2395, 1715, 1668, 1582, 1542, 1469, 1442, 1409,
1366, 1349, 1316, 1250, 1210 cm–1. MS (ESI): m/z calcd. for
[C11H16N2S + H]+ 209.11; found 209.11.
m/z calcd. for [C9H12N2S + H]+ 181.0799; found 181.0786.
N-(2-Hydroxyethyl)-2-pyridinesulfenamide (3g): Synthesized ac-
cording to procedure
B
using 2-mercaptopyridine (35.0 mg,
N-Piperidinyl-4-pyridinesulfenamide (3n): Synthesized according to
procedure B using 4-mercaptopyridine (50.0 mg, 0.450 mmol), DIB
(159 mg, 0.495 mmol), DBU (134 μL, 0.900 mmol), piperidine
0.315 mmol), DIB (111 mg, 0.346 mmol), DBU (94.0 μL,
0.630 mmol), ethanolamine (38.0 μL, 0.630 mmol) in iPrOH
(3 mL) to afford 3g (23.0 mg, 0.135 mmol, 43%) as a yellow oil. 1H (88.9 μL, 0.900 mmol) in iPrOH (4 mL) to afford 3n (55.0 mg,
1
NMR ([D4]MeOH, 400 MHz): δ = 8.35 (d, J = 4.6 Hz, 1 H), 7.74
(td, J = 8.1, 1.7 Hz, 1 H), 7.57 (d, J = 8.1 Hz, 1 H), 7.10 (dd, J =
0.284 mmol, 63%) as a colorless oil. H NMR (CDCl3, 400 MHz):
δ = 8.33 (m, 2 H), 7.13 (d, J = 6.0 Hz, 2 H), 2.99 (t, J = 6.0 Hz, 4
6.8, 5.4 Hz, 1 H), 3.68 (t, J = 5.6 Hz, 2 H), 3.11 (t, J = 5.6 Hz, 1 H), 1.63 (m, 4 H), 1.44 (m, 2 H) ppm. 13C NMR (CDCl3,
H), 3.10 ppm. 13C NMR ([D4]MeOH, 100 MHz): δ = 167.5, 149.8, 100 MHz): δ = 152.5, 148.2, 116.0, 56.6, 26.2, 22.2 ppm. IR (neat):
138.4, 120.8, 119.2, 62.2, 55.4 ppm. IR (neat): ν = 3336, 3020, 2947,
ν = 3070, 3013, 2940, 2850, 2824, 2442, 2389, 1569, 1535, 1476,
˜
˜
2923, 2864, 1575, 1552, 1442, 1412, 1280, 1213 cm–1. HRMS (ESI):
1452, 1439, 1402, 1366, 1353, 1309, 1216 cm–1. MS (ESI): m/z
m/z calcd. for [C7H10N2OS + H]+ 171.0595; found 171.0592.
calcd. for [C10H14N2S + H]+ 195.0956; found 195.0950.
N-(2,2-Diethoxyethyl)-2-pyridinesulfenamide (3h): Synthesized ac-
N-Morpholinyl-4-pyridinylsufenamide (3o): Synthesized according
to procedure B using 4-mercaptopyridine (50.0 mg, 0.450 mmol),
DIB (159.0 mg, 0.495 mmol), DBU (134 μL, 0.900 mmol), morph-
cording to procedure
0.450 mmol), DIB (159 mg, 0.495 mmol), DBU (134 μL,
0.900 mmol), aminoacetaldehyde diethylacetal (131 μL,
B using 2-mercaptopyridine (50.0 mg,
oline (77.9 μL, 0.900 mmol) in iPrOH (4 mL) to afford 3o (56.5 mg,
1
0.900 mmol) in iPrOH (4 mL) to afford 3h (62.1 mg, 0.257 mmol, 0.288 mmol, 64%) as a yellow oil. H NMR (CDCl3, 400 MHz): δ
1
57%) as a yellow oil. H NMR ([D4]MeOH, 400 MHz): δ = 8.22
(d, J = 4.4 Hz, 1 H), 7.64 (td, J = 8.0, 1.6 Hz, 1 H), 7.49 (d, J =
= 8.36 (d, J = 6.1 Hz, 2 H), 7.15 (d, J = 6.1 Hz, 2 H), 3.72 (t, J =
4.0 Hz, 4 H), 3.02 (t, J = 4.0 Hz, 4 H) ppm. 13C NMR (CDCl3,
8.0 Hz, 1 H), 6.97 (m, 1 H), 4.52 (t, J = 5.3 Hz, 1 H), 3.62 (m, 2 100 MHz): δ = 151.1, 148.4, 116.1, 66.7, 55.2 ppm. IR (neat): ν =
˜
H), 3.46 (m, 2 H), 2.97 (d, J = 5.4 Hz, 2 H), 1.10 (t, J = 5.4 Hz, 6 3070, 3020, 2970, 2890, 2429, 2392, 1569, 1542, 1519, 1476, 1449,
H) ppm. 13C NMR ([D4]MeOH, 100 MHz): δ = 167.6, 149.8, 138.4,
1406, 1363, 1313, 1256, 1223 cm–1. HRMS (ESI): m/z calcd. for
120.8, 119.2, 103.5, 63.7, 56.0, 15.7 ppm. IR (neat): ν = 3345, 3040, [C9H12N2OS + H]+ 197.0749; found 197.0742.
˜
2970, 2920, 1569, 1552, 1449, 1416, 1373, 1296, 1276, 1236,
N-Pyrrolidinyl-4-pyridinesulfenamide (3p): Synthesized according to
1213 cm–1. HRMS (ESI): m/z calcd. for [C11H18N2O2S + Na]+
procedure B using 4-mercaptopyridine (100 mg, 0.900 mmol), DIB
(318.0 mg, 0.990 mmol), DBU (269 μL, 1.80 mmol), pyrrolidine
(148 μL, 1.80 mmol) in iPrOH (5 mL) to afford 3p (111 mg,
0.612 mmol, 68%) as a colorless oil. 1H NMR ([D4]MeOH,
400 MHz): δ = 8.31 (d, J = 6.3 Hz, 2 H), 7.24 (d, J = 6.3 Hz, 2 H),
265.1009; found 265.0987.
N-Butyl-4-pyridinesulfenamide (3k): Synthesized according to pro-
cedure B using 4-mercaptopyridine (50.0 mg, 0.450 mmol), DIB
(159 mg, 0.495 mmol), DBU (134 μL, 0.900 mmol), n-butylamine
8
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Hypervalent Iodine(III)-Promoted S–H Activation
3.20 (t, J = 6.5 Hz, 4 H), 1.97 (m, 4 H) ppm. 13C NMR ([D4]
MeOH, 100 MHz): δ = 158.1, 149.4, 118.1, 56.5, 27.2 ppm. IR
57.1 ppm. IR (neat): ν = 3345, 3176, 3063, 3016, 2973, 2392, 1492,
˜
1456, 1429, 1353, 1309, 1273, 1220 cm–1. MS (ESI): m/z calcd. for
(neat): ν = 3063, 2967, 2857, 2445, 2395, 1665, 1575, 1539, 1482, [C14H12N2S + H]+ 273.00; found 273.05.
˜
1456, 1452, 1406, 1339, 1319, 1286, 1216 cm–1. HRMS (ESI): m/z
N-Benzyl-2-quinolinesulfenamide (3x): Synthesized according to
calcd. for [C9H12N2S + H]+ 181.0799; found 181.0800.
procedure B using 2-quinolinethiol (60.0 mg, 0.372 mmol), DIB
(132.0 mg, 0.409 mmol) in iPrOH (4 mL) to afford 3x (63.4 mg,
0.238 mmol, 64%) as a yellow solid. 1H NMR (CDCl3, 400 MHz):
δ = 7.91 (d, J = 8.6 Hz, 2 H), 7.67 (d, J = 8.6 Hz, 1 H), 7.60 (t, J
= 7.6 Hz, 1 H), 7.41–7.16 (m, 7 H), 4.15 (d, J = 5.2 Hz, 2 H), 3.68
(br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 163.9, 148.3,
136.0, 129.9, 128.6, 128.5, 128.1, 127.8, 127.6, 125.4, 117.0,
N-(2-Hydroxyethyl)-4-pyridinesulfenamide (3q): Synthesized ac-
cording to procedure
B using 4-mercaptopyridine (50.0 mg,
0.450 mmol), DIB (159.0 mg, 0.495 mmol), DBU (134 μL,
0.900 mmol), ethanolamine (54.3 μL, 0.900 mmol) in iPrOH
(4 mL) to afford 3q (43.7 mg, 0.257 mmol, 57%) as a yellow oil. 1H
NMR ([D4]MeOH, 400 MHz): δ = 8.19 (d, J = 6.4 Hz, 2 H), 7.25
(d, J = 6.4 Hz, 2 H), 3.55 (t, J = 5.6 Hz, 2 H), 2.96 (t, J = 5.6 Hz,
2 H) ppm. 13C NMR ([D4]MeOH, 100 MHz): δ = 158.8, 149.2,
56.8 ppm. IR (neat): ν = 3276, 3060, 3023, 2920, 1612, 1588, 1555,
˜
1489, 1456, 1419, 1293 cm–1. HRMS (ESI): m/z calcd. for
˜
[C16H14N2S + H]+ 267.0956; found 267.0954.
118.3, 67.3, 55.0 ppm. IR (neat): ν = 3458, 3405, 3020, 2970, 2927,
2442, 2399, 1751, 1711, 1618, 1575, 1539, 1519, 1479, 1412, 1363,
1220 cm–1. HRMS (ESI): m/z calcd. for [C7H10N2OS + H]+
171.0622; found 171.0592.
3-(4-Chlorophenylthio)-1H-indole (4):
A solution of 4-chloro-
thiophenol (50.0 mg, 0.346 mmol, 1.00 equiv.) and DIB (123 mg,
0.381 mmol, 1.10 equiv.) in DMF (3.50 mL) was stirred at ambient
temperature for 5 min. DBU (103 μL, 0.692 mmol, 2.00 equiv.) and
1H-indole (81.3 mg, 0.692 mmol, 2.00 equiv.) were added and the
mixture was stirred at 120 °C for 12 h. The crude product was puri-
fied by silica gel chromatography to afford 4 (33.5 mg, 0.149 mmol,
43%) as a colorless oil and 2a (8.41 mg, 0.0294 mmol, 17%). 1H
NMR (400 MHz, [D6]DMSO): δ = 11.74 (s, 1 H), 7.79 (d, J =
2.7 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 1 H),
7.30–7.23 (m, 2 H), 7.20 (t, J = 7.1 Hz, 1 H), 7.08 (t, J = 7.5 Hz,
1 H), 7.04–6.97 (m, 2 H) ppm. 13C NMR ([D6]DMSO, 100 MHz):
δ = 138.4, 136.7, 132.6, 129.3, 128.7, 128.4, 126.8, 122.2, 120.2,
118.1, 112.4, 98.6 ppm. HRMS (ESI): m/z calcd. for C14H10ClNS
259.0222; found 259.0228.
N-(2,2-Diethoxyethyl)-4-pyridinesulfenamide (3r): Synthesized ac-
cording to procedure
B using 4-mercaptopyridine (100 mg,
0.900 mmol), DIB (318.0 mg, 0.990 mmol), DBU (269 μL,
1.80 mmol), aminoacetaldehyde diethylacetal (262 μL, 1.80 mmol)
in iPrOH (5 mL) to afford 3r (136 mg, 0.558 mmol, 62%) as a col-
orless oil. 1H NMR ([D4]MeOH, 400 MHz): δ = 8.32 (d, J =
6.4 Hz, 2 H), 7.35 (d, J = 6.4 Hz, 2 H), 4.61 (t, J = 5.3 Hz, 1 H),
3.72 (m, 2 H), 3.57 (m, 2 H), 3.07 (d, J = 5.3 Hz, 2 H), 1.22 (t, J
= 7.1 Hz, 6 H) ppm. 13C NMR ([D4]MeOH, 100 MHz): δ = 158.8,
149.2, 118.2, 103.5, 63.8, 55.7, 15.7 ppm. IR (neat): ν = 3355, 3013,
˜
2973, 2923, 2485, 2452, 2402, 1661, 1572, 1542, 1479, 1439, 1409,
1376, 1346, 1316, 1300, 1210 cm–1. HRMS (ESI): m/z calcd. for
[C11H18N2O2S + H]+ 243.1167; found 243.1167.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all products.
N-Benzyl-5-bromo-2-pyridinesulfenamide (3u): Synthesized accord-
ing to procedure
B using 5-bromopyridine-2-thiol (50.0 mg,
0.262 mmol), DIB (92.8 mg, 0.288 mmol), DBU (78.4 μL,
0.524 mmol), benzylamine (57.2 μL, 0.524 mmol) in iPrOH (3 mL)
to afford 3u (51.6 mg, 0.176 mmol, 67%) as a white solid. 1H NMR
([D4]MeOH, 400 MHz): δ = 8.32 (s, 1 H), 7.72 (dd, J = 4.0, 8.0 Hz,
1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.23–7.12 (m, 5 H), 4.00 (s, 2
H) ppm. 13C NMR ([D4]MeOH, 100 MHz): δ = 166.2, 150.8, 140.9,
Acknowledgments
This study was financially supported by the Thailand Research
Fund (TRF-RSA5480004), the National Nanotechnology Center
(NANOTEC), NSTDA, Thailand, and the Ministry of Science and
Technology, Thailand, through a program of the Center of Excel-
lence Network. This work was also financially supported by the
Thai Government as part of the Project for Establishment of a
Comprehensive Center for Innovative Food, Health Products and
Agriculture, Stimulus Package 2 (TKK2555, SP2) and by Chula-
longkorn University (Higher Education Research Promotion and
Ratchadaphiseksomphot Endowment Fund; grant number
RES560530126-AM). E. R. is a PhD candidate supported by a
Chulalongkorn University Dutsadi Phiphat Scholarship.
140.5, 129.5, 129.4, 128.4, 120.9, 116.6, 57.1 ppm. IR (neat): ν =
˜
3261, 3066, 3023, 2918, 1700, 1601, 1555, 1533, 1499, 1444,
1342 cm–1. HRMS (ESI): m/z calcd. for [C12H11BrN2S + H]+
294.9921; found 294.9905.
N-Benzyl-2-pyrimidinesulfenamide (3v): Synthesized according to
procedure B using 2-pyrimidinethiol (50.0 mg, 0.446 mmol), DIB
(158 mg, 0.490 mmol), DBU (133 μL, 0.892 mmol), benzylamine
(97.4 μL, 0.892 mmol) in iPrOH (4 mL) to afford 3v (69.7 mg,
0.321 mmol, 72%) as a yellow solid. 1H NMR (CDCl3, 400 MHz):
δ = 8.52 (d, J = 4.8 Hz, 2 H), 7.37–7.17 (m, 5 H), 6.92 (t, J =
4.6 Hz, 1 H), 4.14 (s, 2 H), 3.56 (br. s, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 175.9, 157.4, 139.2, 128.5, 128.4, 127.5, 116.8,
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Synthesized according to procedure B using 2-Mercaptobenzothi-
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1
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154.8, 138.5, 135.1, 128.7, 128.4, 128.0, 126.0, 123.8, 121.7, 121.1,
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Wacharasindhu et al.
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Received: March 3, 2014
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42180
/KAP1
Date: 23-06-14 19:41:23
Pages: 11
Hypervalent Iodine(III)-Promoted S–H Activation
Synthetic Methods
Disulfides and sulfenamides can be easily
prepared from the corresponding thiols by
using (diacetoxyiodo)benzene as activator
at room temperature under open-flask con-
ditions.
E. Rattanangkool, W. Krailat, T. Vilaivan,
P. Phuwapraisirisan, M. Sukwattanasinitt,
S. Wacharasindhu* .......................... 1–11
Hypervalent Iodine(III)-Promoted Metal-
Free S–H Activation: An Approach for the
Construction of S–S, S–N, and S–C Bonds
Keywords: Hypervalent compounds
/
Oxidation / Iodine / Sulfur / Heterocycles /
Disulfides
Eur. J. Org. Chem. 0000, 0–0
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11