TBHP-mediated oxidative thiolation of an sp3 C-H bond adjacent to a nitrogen atom in an amide

Article abstract of DOI:10.1039/c1cc15397h

The first example of molecular sieve-promoted TBHP-mediated direct oxidative thiolation of an sp³ C-H bond adjacent to a nitrogen atom with disulfides under metal-free conditions, which allows for preparation of numerous S,N-containing compounds, is presented. Moreover, diverse benzothiazoles and a fipronil analog can be synthesized through this strategy.

Full text of DOI:10.1039/c1cc15397h

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TBHP-mediated oxidative thiolation of an sp3 C–H bond adjacent to a
nitrogen atom in an amidew
Ri-Yuan Tang,ab Ye-Xiang Xie,a Yi-Li Xie,b Jian-Nan Xiang*a and Jin-Heng Li*a
Received 30th August 2011, Accepted 14th October 2011
DOI: 10.1039/c1cc15397h
The first example of molecular sieve-promoted TBHP-mediated
direct oxidative thiolation of an sp3 C–H bond adjacent to a
nitrogen atom with disulfides under metal-free conditions, which
allows for preparation of numerous S,N-containing compounds,
is presented. Moreover, diverse benzothiazoles and a fipronil
analog can be synthesized through this strategy.
by TBHP (tert-butyl hydroperoxide)-mediated oxidative thiolation
of an sp3 C–H bond adjacent to a nitrogen atom in an amide
without the aid of metals (eqn (1)).
ð1Þ
The development of catalytic reactions using an sp3 C–H bond
cleavage (activation) strategy is a challenging and powerful
technology for preparing diverse compounds from simpler
starting materials.1–9 Recently, considerable efforts were
devoted to this field; particularly to the construction of
numerous C–C bonds via metal-catalyzed oxidative functio-
nalization of an sp3 C–H bond adjacent to a heteroatom (often
nitrogen or oxygen).1–4 This strategy allows introduction of
diverse functional groups, including indole, benzofuran, alkyne,
alkene, cyano, enol ether and pre-functionalized sp3 carbon, to
the carbon adjacent to a nitrogen atom3,5 or an oxygen
atom.4,6 Despite a significant achievement in the C–C bond
formation by the sp3 C–H bond oxidative functionalization
process, the carbon–heteroatom bond formation using a similar
strategy8 receives less attention.6c,9 Moreover, in these trans-
formations many required one or two metal catalysts,1–8 and
rare focused on metal-free oxidative functionalization of an
sp3 C–H bond.4b,9 To the best of our knowledge, there is no
example on metal-free functionalization of an sp3 C–H bond
adjacent to a heteroatom for the carbon–heteroatom bond
construction.
Our study begins with the reaction of diphenyldisulfide (1a)
with DMA (N,N-dimethylacetamide) (2a) and oxidant under
heating conditions (Table 1).12 While no reaction was
observed using a DDQ oxidizing reagent (entry 1), the reaction
in the presence of TBHP afforded the target product 3 in 77%
yield (entry 2). Screening revealed that the reaction temperature
affected the reaction: 78% yield at 150 1C (entry 3) and 41% yield
at 100 1C (entry 4). We found that 1.2 mmol TBHP gave
identical results to those of 0.8 mmol TBHP (entry 5), but
0.4 mmol TBHP lowered the yield slightly (entry 6). Gratifyingly,
molecular sieves could improve the reaction: the yield of 3 was
enhanced to 86% in 100 mg molecular sieves (entry 7). Among
the different amounts of DMF examined, it turned out that good
Table 1 Screening optimal conditionsa
Sulfur-containing compounds are valuable synthetic inter-
mediates as well as important structural units in many naturally
occurring and bioactive compounds.10 In recent years, formation
of metal-catalyzed intermolecular or intramolecular C–S bonds
through an sp2 C–H activation has become an alternative and
intriguing strategy to sulfides.11 However, the cleavage of an
sp3 C–H bond leading to the C–S bond formation is unexplored.
We report here on the first realization of the C–S bond-formation
Entry Oxidant (mmol) Additive (mg) T/1C Isolated yield (%)
1
2
3
4
5
6
7
DDQ (0.8)
TBHP (0.8)
TBHP (0.8)
TBHP (0.8)
TBHP (1.2)
TBHP (0.4)
TBHP (0.8)
TBHP (0.8)
TBHP (0.8)
TBHP (0.8)
TBHP (0.8)
TBHP (0.8)
—
—
—
—
—
—
120
120
150
100
120
120
0
77
78
41
78
72
86
71
87
87
51
85
4 A MS (100) 120
4 A MS (100) 120
4 A MS (100) 120
4 A MS (100) 120
4 A MS (100) 120
8b
9c
10d
11e
12f
a State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China. E-mail: jhli@hnu.edu.cn, jnxiang@hnu.cn;
Fax: 0086731 8887 2531; Tel: 0086731 8887 2576
b College of Chemistry and Materials engineering,
Wenzhou University, Wenzhou, 325035, China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc15397h
—
120
a
Reaction conditions: 1a (0.2 mmol), 2a (2 mL, 21.5 mmol), and oxidant
for 12 h. TBHP (70% in water solution). 4 A MS = 4 A molecular sieve.
b
c
2a (1 mL, 10.8 mmol). 2a (3 mL, 31.3 mmol). In the dark. K2CO3
d
e
f
(0.8 mmol) was added. K2CO3 (0.1 mmol) was added.
c
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Chem. Commun., 2011, 47, 12867–12869 12867

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results were obtained in 2 mL or 3 mL DMF (entries 7–9). The
reaction was not affected in the dark (entry 10). While 0.8 mmol
of K2CO3 reduced the yield to 51% (entry 11), satisfactory
results were obtained using 0.1 mmol K2CO3 without molecular
sieves (entry 12). It is noteworthy that no reaction is observed
when 5 mol% CuBr or FeCl3 was added.12 Thus, we deduce that
molecular sieves may play the role of a weak base to promote the
reaction by adjusting the pH value of reaction solution.
Table 3 TBHP-mediated synthesis of benzothiazolesa
With the optimal reaction conditions in hand, the scope of
both disulfides and amides was explored (Table 2). The results
demonstrated that diaryl disulfides 1, bearing either electron-
withdrawing or electron-donating groups on the aromatic
ring, were perfectly tolerated (products 4–10). For example,
bromo-substituted disulfide smoothly underwent the reaction
with DMA (2a), TBHP and molecular sieves to afford the
corresponding product 7 in 84% yield. Disulfide with an ester
group was also suitable, providing product 10 in 61% yield.
To our delight, a heteroaryl disulfide displayed high reactivity
leading to the target product 11 in 75% yield. We found that
product 12 was isolated from an aliphatic disulfide in moderate
yield after prolonging the reaction time. To our surprise, DMF
(N,N-dimethylformamide) reacted with diphenyldisulfide (1a)
to selectively give two products, N-methyl-N-(phenylthio-
methyl)formamide (13) and S-phenyl dimethylcarbamothioate
(14), in 45% and 48% yields, respectively. It is noteworthy
that the selectivity toward the CH2 group adjacent to a
nitrogen atom in the ring is superior to that toward the N-Me
group for 1-methylpyrrolidin-2-one (products 15–18).3a For
instance, treatment of 1-methylpyrrolidin-2-one with disulfide
1a and TBHP afforded products 15 and 16 in 75% total yield
with the 1 : 6.7 ratio. However, 1-methylpyrrolidine was unsuitable
for the reaction.
a
Reaction conditions: 1 (0.2 mmol), 2 (2 mL), TBHP (0.8 mmol, 70%
in water solution) and 4 A molecular sieve (100 mg) at 120 1C for 12 h.
As shown in Table 3, applications of this thiolation reaction
in benzothiazoles synthesis were investigated because benzo-
thiazoles are very important compounds for pharmaceuticals
and materials industries.13 The results demonstrated that this
thiolation reaction could be used for the synthesis of benzo-
thiazoles through the formation of two bonds: a C–S bond and
a C–N bond. We found that three amides 2a–2c were treated
with 2,20-disulfanediyldianiline, TBHP and molecular sieves
smoothly leading to the corresponding 2-substituted benzo-
thiazoles 19–21 in moderate yields. To our delight, the standard
conditions were consistent with numerous 2,20-disulfanediyl-
dianilines with MeO, Me, F, or Cl groups on the aryl ring
(products 22–26).
Significantly, a new fipronil analog 27 was readily prepared
by this sp3 C–H functionalization strategy in good yields
(eqn (2)).14,15 This successful S–S bond cleavage of pyrazole
disulfide followed by the sp3 C–S bond formation would be
significant for pesticide and drug design.16
Table 2 Thiolation of an sp3 C–H bond adjacent to a nitrogen atoma
ð2Þ
Notably, the reaction of disulfide 1a with amide 2a could
not take place in the presence of the radical inhibitors,
1,1-diphenylethylene or TEMPO, suggesting that the present
reaction proceeds via a free radical process.7 Therefore, a
possible mechanism as outlined in Scheme 1 was proposed.1–9
Initially, the reaction of TBHP with substrate 2 affords inter-
mediate A, followed by reaction with R2SSR2 1, which gives
the target product and the R2Sꢀ free radical intermediate. The
R2Sꢀ free radical intermediate undergoes the reaction with
substrate 2 resulting in the target product and RSH. RSH is
readily converted to R2SSR2 in the presence of TBHP. In
the synthesis of benzothiazoles, intermediate A reacts with
a
Reaction conditions: 1 (0.2 mmol), 2 (2 mL), TBHP (0.8 mmol, 70%
in water solution) and 4 A molecular sieve (100 mg) at 120 1C for 12 h.
For 20 h. The ratio given in parentheses was determined by
b
c
1H NMR spectra.
c
12868 Chem. Commun., 2011, 47, 12867–12869
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Eur. J. Org. Chem., 2010, 1235–1238; (b) Y. Li and W.-L. Bao,
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Scheme 1 Possible mechanism.
2,20-disulfanediyldianilines to give intermediate B, followed by
oxidation to afford the iminium ion C. Subsequently, inter-
mediate C undergoes a nucleophilic attack process to yield
intermediate D. Finally, cleavage of the C–N bond in inter-
mediate D gives the corresponding benzothiazoles.
In summary, we have described the first example of direct
oxidative thiolation of an sp3 C–H bond adjacent to a nitrogen
atom under metal-free conditions. This thiolation method is
valuable for preparing numerous S,N-containing compounds.
It is noteworthy that these S,N-containing compounds with
sweet-scented smell will be a good guideline for the new spices
discovery.17 Moreover, diverse benzothiazoles and a fipronil
analog can be synthesized through the present TBHP-oxidative
thiolation of an sp3 C–H bond process.13,14
This research was supported by the NSFC (No. 21172060),
DSTF of Hunan (No. 2009WK4005), and DSTF of Changsha
(No. K0802152-31).
Notes and references
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c
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Chem. Commun., 2011, 47, 12867–12869 12869