Oxidative Coupling of Enamines and Disulfides via Tetrabutylammonium Iodide/tert-Butyl Hydroperoxide-Mediated Intermolecular Oxidative C(sp2) S Bond Formation Under Transition Metal-Free Conditions

Article abstract of DOI:10.1002/adsc.201501099

The reaction of enamine compounds with disulfides in the presence of tert-butyl hydroperoxide and a catalytic amount of tetrabutylammonium iodide conveniently afforded a variety of α-thioenamine compounds through the intermolecular oxidative C(sp²) S coupling. Incorporating both of the sulfide moieties in the disulfides into the final products under oxidative conditions, this novel approach exhibits the feature of atom efficiency. A radical mechanistic pathway for the reaction process has been proposed. (Figure presented.) .

Full text of DOI:10.1002/adsc.201501099

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DOI: 10.1002/adsc.201501099
Oxidative Coupling of Enamines and Disulfides via Tetrabutylam-
monium Iodide/tert-Butyl Hydroperoxide-Mediated Intermolecu-
2
À
lar Oxidative C(sp ) S Bond Formation Under Transition Metal-
Free Conditions
Jiyun Sun,a Daisy Zhang-Negrerie,a and Yunfei Dua,b,*
a
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, Peopleꢀs Republic of China
Fax : (+86)-22-2740-4031; phone: (+86)-22-2740-4031; e-mail: duyunfeier@tju.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, Peopleꢀs Republic of
b
China
Received: December 1, 2015; Revised: April 5, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501099.
Abstract: The reaction of enamine compounds with
disulfides in the presence of tert-butyl hydroperox-
ide and a catalytic amount of tetrabutylammonium
iodide conveniently afforded a variety of a-thioena-
indole and disulfides in the presence of metal or non-
metal catalysts.[7] In these studies,[7a–h,8] disulfides were
recognized as a less toxic and easier-to-handle sulfur
source in comparison to thiophenol derivatives. In
2
À
mine compounds through the intermolecular oxida-
this regard, developing convenient C(sp ) S bond
2
À
tive C(sp ) S coupling. Incorporating both of the
coupling methods that would allow both of the sulfur
moieties in the disulfides to be introduced into the
products is undoubtedly highly desirable for the
reason of atom efficiency.
sulfide moieties in the disulfides into the final prod-
ucts under oxidative conditions, this novel approach
exhibits the feature of atom efficiency. A radical
mechanistic pathway for the reaction process has
been proposed.
a-Thioenamines are a class of sulfur-containing
compounds that are potentially related to certain bio-
logical and pharmaceutical activities. For example,
both compound A, a dual specificity protein phospha-
tase inhibitor, and compound B, a cyclic thioenamine
peptide, possess the a-thioenamine motif in their re-
spective scaffolds (Figure 1).[9] However, only a few
synthetic methods have been reported for the con-
Keywords: tert-butyl hydroperoxide/tetrabutylam-
2
À
monium iodide; C(sp ) S bond formation; oxida-
tive coupling; radical mechanism
struction of such a-thioenamine compounds.
A
common approach is via nucleophilic attack of a thiol
2
[1]
À
The formation of the C(sp ) S bond is potentially on an enol-tosylate, affording the a-thioenamine
a useful approach for the assemblage of sulfur-con- structure in good yields (Scheme 1, a).[10a] Such a-
taining compounds. However, while a vast number of thio
ACHTUNGTRENeNUNG namine compounds can also be achieved through
established methods concern the construction of an oxidative coupling reaction between enamines and
2
[2]
2
[3]
À
À
C(sp ) O bonds and C(sp ) N bonds, methods for
2
[4]
À
forming C(sp ) S bonds remain relatively limited.
Among the existing approaches, using coupling reac-
tions of thiols with alkenyl/aryl halides in the pres-
ence of transition metals[5] is the most commonly ap-
2
À
plied strategy for building C(sp ) S bonds. Besides
that there are the coupling reactions of various alkyl
halides and lithium arylthiolates, generated by direct
halogen-lithium exchange to afford alkyl aryl sul-
fides.[6] Construction of 3-sulfenylindoles, a class of
pharmaceutically and biologically important com-
Figure 1. Pharmaceutically active a-thioenamine com-
pounds, could also be realized from the coupling of pounds.
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Table 1. Optimization of the reaction conditions.
Entry Oxidant Solvent Temp.
Time
[h]
Yield
[%][c]
[oC]
1
2
3
4
5
6
7
8
TBHP[a,b] DCE
r.t.
r.t.
6
6
6
4
4
4
4
4
4
4
4
47
37
54
68
87
56
91
75
TBHP
TBHP
TBHP
TBHP
TBHP
DMF
Scheme 1. Existing synthetic routes to form a-thioenamine
compounds.
CH3CN r.t.
CH3CN 40
CH3CN 60
CH3CN reflux
disulfides using a silver salt as oxidant (Scheme 1,
b).[10b] However, 2.0 equivalent of the disulfide are
necessary in the latter case since another equivalent
of the arylthiol radical generated during the reaction
is captured by the metal silver. To the best of our
TBHP[e] CH3CN 60
TBHP[f] CH3CN 60
TBHP[g] CH3CN 60
PIDA[h] CH3CN r.t.
9
10
11
78
N.D.[d]
N.D.[d]
PhIO[h]
CH3CN r.t.
knowledge, no intermolecular metal-free oxidative
C(sp ) S coupling reaction between enamines and di-
sulfides has been reported so far.
The metal-free oxidative system of TBAI/TBHP
has drawn considerable attention due to its low cost,
low toxicity, easy-to-handle benefits, environmentally
2
[a]
À
TBHP (70% in water) was extracted with petroleum
ether and evaporated before use.
Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol),
TBHP (5.0 mmol), TBAI (0.1 mmol) in solvent (10 mL)
unless otherwise stated.
Isolated yield.
No desired product detected.
3.0 mmol TBHP were used.
1.5 mmol TBHP were used.
[b]
[c]
[d]
[e]
[f]
benign nature, as well as its applications in facilitating
[11]
À
À
oxidative C O and C N bond formations.
In our
previous work, we realized the cross-coupling of en-
[g]
amines and electron-deficient amines through oxida-
This reaction was performed by using 1.5 mmol of TBHP
under an oxygen atmosphere. 13% of substrate was re-
covered.
2
À
tive C(sp ) N bond formation by using TBAI as cata-
lyst and TBHP as oxidant.[12] As a continuation of our
[h]
1.2 mmol of PhIO were used.
work, we investigated the possibility of forming
2
À
C(sp ) S bonds under similar conditions. We herein
report the results of such a case study, where a series
of a-thioenamine compounds were conveniently syn- slightly, to 91% (Table 1, entry 7). Other commonly
thesized in satisfactory to excellent yields via cross- employed oxidants such as phenyliodine diacetate
coupling of enamines with disulfides mediated by (PIDA) and iodosobenzene (PhIO) were shown to be
TBAI/TBHP (Scheme 1, c).
completely ineffective, with no desired product being
Initially, enamine 1a and bis(benzothiazol-2-yl) di- detected.
sulfide 2a were subjected to the “standard conditions”
Under the optimized reaction conditions, the scope
previously developed for the coupling of enamines of this newly developed method was studied using
with electron-deficient amines, namely, 5.0 equiv. of various enamines and diaryl disulfides. As shown in
TBHP as the oxidant and TBAI as the catalyst in 1,2- Table 2, a wide range of enamines could be well toler-
dichloroethane (DCE) as solvent at room tempera- ated under the conditions stated in this methodology
ture. The reaction afforded the desired product 3a in (Table 2, 3a–n). Results show that the electronic ef-
a modest 47% yield (Table 1, entry 1). Solvent screen- fects of both R1 and R4 are insignificant, as the yield
ing identified acetonitrile as the most appropriate sol- values of substrates bearing different R1 ranging be-
vent for this transformation (Table 1, entries 1–3). tween aryl, pyridyl, furyl, and alkyl stay between 79–
Searching for the most ideal temperature revealed 90% (Table 2, 3b–e), and yields of those bearing vari-
that the yield peaked (87%) at 608C (Table 1, en- ous R4 from slightly electron-donating (Ph) to highly
tries 3–6). Reducing the amount of oxidant (TBHP) electron-withdrawing (NO2) groups remain practically
to 3.0 equiv. further improved the yield, although only the same (Table 2, 3e–h). On the other hand, the
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Table 2. Synthesis of a-thioenamines mediated by TBHP/TBAI.[a]
[a]
General conditions: substrate 1 (1.0 mmol), disulfide 2 (0.5–0.6 mmol), TBHP (3.0 mmol), and TBAI (0.1 mmol) in
CH3CN (10 mL) at 608C unless otherwise stated.
Isolated yield.
AlCl3 (0.3 mmol) was added, and substrates 1o–q (2.0 mmol) and DCE (10 mL) were used in the cases of 3o–q.
[b]
[c]
steric effect at the R1 position was noticeable. The promote the conversion. Including 0.3 mmol of AlCl3
yield values between 3h and 3i, with the phenyl group as additive, the reaction proceeded under the opti-
of R1 in the former replaced by the bulky tert-butyl mized conditions and formed the expected products
group in the latter, decreased from 84% to 60%.
in satisfactory yields (Table 2, 3o–q). Results from
The method was found to also apply to enamines these three case studies suggested that electron-donat-
bearing various R2 and R3 groups (Table 2, 3j–n). ing substituents on the diaryl disulfide would favor
Among all the substrates, 3j, where R2 =Ph was the reaction while electron-withdrawing substituents
formed in the highest yield of 90% within relatively disfavor the reaction. We tentatively ascribe the
short reaction time. In contrast, the yield of 3k, with reason for this observation to the instability of the
R2 being a benzyl group was only 45% due to side re- ArS radical bearing an electron-withdrawing substitu-
actions forming unidentified by-products. A ring R2– ent, which caused the formation of undesired by-
R3 group (3m) and a cyclic enamine (3n) also success- products.
fully afforded the corresponding products in satisfac-
tory yields.
The method was found to be also applicable to
other N-containing heterocyclic compounds including
Several diaryl disulfides were also examined to fur- indole and pyrrole. The S-containing moiety of
ther probe the scope of the method. Initially, no reac- bis(benzothiazol-2-yl) disulfide was successfully intro-
tion was observed with 1,2-diphenyl disulfide under duced to the 3-position of indole and pyrrole in satis-
the standard conditions. After many trials using vari- factory yields (Scheme 2, 3r and 3s).[14]
ous additives, including different Brønsted bases,
Lewis acids and NaN3 (see the optimization Table we also investigated the applicability of the method
in the Supporting Information), we found that Lewis to forming C Se bonds. As shown in Table 3, various
acids in general, notably aluminium trichloride, could enamine substrates afforded the desired a-selenylated
As both selenium and sulfur belong to group VIA,
[13]
À
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hamper the reaction, suggesting a radical pathway in
this conversion. As illustrated in Scheme 3, the radical
process is initiated by the tert-butoxyl radical, which is
formed from TBHP with the assistance of the catalyt-
ic iodide anion.[15] Next, this radical reacts with disul-
fides to form the intermediate aromatic thiol radical
(ArSC) 4 and aromatic tert-butoxysulfane or tert-butyl-
peroxysulfane. Then, the reaction of enamine 1a with
ArSC affords the carbon-centered radical 5a. An elec-
tron transfer process enables the conversion of inter-
mediate 5a to the iminium 6a, along with the conver-
sion of tert-butoxysulfane or tert-butylperoxysulfane
to tert-butoxyl or tert-butylperoxyl anion, respectively,
as well as a simultaneous generation of the aromatic
thiol radical 4. Finally, assisted by the tert-butoxyl or
tert-butylperoxyl anion, b-proton abstraction takes
place in 6a to afford the title product 3a.
Scheme 2. TBAI/TBHP-mediated 3-sulfenylation of indole
and pyrrole.
Table 3. Synthesis of a-selenoenamine compounds mediated
by TBHP/TBAI.[a]
In summary, we have developed a novel method for
the synthesis of a variety of a-thioenamine and a-se-
Entry R1
R2
3
Time [h] Yield [%][b]
lenoenamine compounds through an intermolecular
oxidative C(sp ) X (S, Se) coupling reaction between
1
2
3
4
Me
Ph
CO2Me 3t
CO2Me 3u
2
2
2
3
36
33
42
28
2
À
enamines and disulfides/diselenides mediated by the
TBHP/TBAI oxidative system. Other than the desira-
ble feature of being transition metal-free, this method
also boasts other advantages such as mild reaction
conditions and high atom efficiency.
p-Br-C6H4 CO2Me 3v
Ph CN 3w
[a]
General conditions: substrate 1 (2.0 mmol), diselenide 2e
(0.5 mmol), TBHP (2.0 mmol), TBAI (0.1 mmol) and
AlCl3 (0.3 mmol) in DCE (10 mL) at 408C.
Isolated yield.
[b]
Experimental Section
products. However, the yields were in general signifi-
cantly lower than the sulfide counterparts due to the
formation of additional unidentified by-products even
under various modified conditions adjusted for ach-
ieving higher yields.
General Procedure for the Oxidative Cross-Coupling
Reaction
Procedure I: To a suspension of enamine 1 (1.0 mmol), di-
sulfide 2 (0.5–0.6 mmol) and TBAI (0.1 mmol) in dried
Control experiments were carried out for a mecha-
nistic study. Addition of TEMPO was found to CH3CN (10 mL) in a sealed tube was added, dropwise,
Scheme 3. Proposed reaction mechanism.
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TBHP (3.0 mmol) at room temperature. The resulting mix-
ture was heated at 608C until TLC indicated the total con-
sumption of enamine 1. The residue was treated with satu-
rated aqueous Na2S2O3 solution (50 mL) and then extracted
with etrhyl acetate (30 mLꢂ3). The organic phase was
washed with brine (50 mLꢂ1) and dried over anhydrous
Na2SO4. The solvent was removed and the residue was puri-
fied by flash column chromatography on silica gel (EA/PE)
to afford the desired compound 3.
Procedure II: To a suspension of enamine 1 (2.0 mmol),
disulfide/diselenide 2 (0.5 mmol) and TBAI (0.1 mmol) in
dried DCE (10 mL) in a sealed tube was added, dropwise,
TBHP (3.0 or 2.0 mmol) at room temperature. Anhydrous
AlCl3 (0.15 mmol) was then added to the reaction mixture
at the same temperature. The resulting mixture was heated
at 408C until TLC indicated the total consumption of disul-
fides/diselenide 2. The residue was treated with saturated
aqueous Na2S2O3 solution (50 mL) and then extracted with
ethyl acetate (30 mLꢂ3). The organic phase was washed
with brine (50 mLꢂ1) and dried over anhydrous Na2SO4.
The solvent was removed and the residue was purified by
flash column chromatography on silica gel (EA/PE) to
afford the desired compound 3.
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We acknowledge the National Natural Science Foundation of
China (#21472136), Tianjin Research Program of Applica-
tion
Foundation
and
Advanced
Technology
(#15JCZDJC32900) and the National Basic Research Proj-
ects (2015CB856500) for their financial support.
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Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!

COMMUNICATIONS
Oxidative Coupling of Enamines and Disulfides via
7
Tetrabutylammonium Iodide/tert-Butyl Hydroperoxide-
2
À
Mediated Intermolecular Oxidative C(sp ) S Bond
Formation Under Transition Metal-Free Conditions
Adv. Synth. Catal. 2016, 358, 1 – 7
Jiyun Sun, Daisy Zhang-Negrerie, Yunfei Du*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!