Catalyst-Free S–S Bond Insertion Reaction of a Donor/Acceptor-Free Carbene by a Radical Process: A Combined Experimental and Computational Study

Article abstract of DOI:10.1002/ejoc.201600664

Herein, a donor/acceptor-free carbene insertion reaction of an S–S bond through a radical process is presented. This catalyst-free reaction was thermally induced and provided the dithioketal products in moderate to high yields. A mechanism involving radical intermediates was proposed according to the computational study, and these intermediates were verified experimentally and intercepted for the first time by using a cross-coupling reaction.

Full text of DOI:10.1002/ejoc.201600664

DOI: 10.1002/ejoc.201600664
Full Paper
Radical Reactions
Catalyst-Free S–S Bond Insertion Reaction of a Donor/Acceptor-
Free Carbene by a Radical Process: A Combined Experimental
and Computational Study
Yang Zheng,[a] Rongjian Bian,[a] Xiaolu Zhang,[a] Ruwei Yao,[a] Lihua Qiu,[a]
Xiaoguang Bao,*[a] and Xinfang Xu*[a]
Abstract: Herein, a donor/acceptor-free carbene insertion reac- involving radical intermediates was proposed according to the
tion of an S–S bond through a radical process is presented. This computational study, and these intermediates were verified ex-
catalyst-free reaction was thermally induced and provided the perimentally and intercepted for the first time by using a cross-
dithioketal products in moderate to high yields. A mechanism coupling reaction.
Introduction
displacement mechanism;[11] however, no sufficient experimen-
tal or intermediate-capturing studies were carried out to verify
this mechanism during the 30 years. Here, we describe an S–S
bond-insertion reaction of a donor/acceptor (D/A) free carbene
that proceeds through a process involving radical intermediates
(Scheme 1C, Path II), and the proposed radical intermediates
were intercepted for the first time by using a cross-coupling
reaction.
Diazo compounds are very versatile and powerful reagents that
have been extensively applied in modern synthetic organic
chemistry.[1,2] The direct introduction of two functional groups
to the carbon center of the diazo compound, namely gem-di-
functionalization, has attracted much attention recently.[2–13]
Among these reactions, three major patterns of the dinitrogen
extrusion processes that involve different reactive intermediates
are widely acknowledged: (1) transformations via metal–carb-
ene species (Scheme 1A), which are catalyzed by metal cata-
lysts, and corresponding reactions including three-membered-
ring formations (cyclopropanation, epoxidation),[3] multicompo-
nent reactions (MCRs),[4] σ-bond insertion reactions[5] and oth-
ers;[6] (2) reactions that proceed via a procarbonium ion inter-
mediate (Scheme 1B),[7] which occur through attack of the
nucleophilic carbon center of the diazo group successively by
electrophiles and nucleophiles with concomitant N2 expulsion;
(3) thermolysis- or photolysis-induced free carbene processes
(Scheme 1C),[8] which are far from well developed compared
with the other two versions; especially with respect to studies
on the mechanism, the controversy remains. For example, in the
S–S bond-insertion reaction of a free carbene, ylide formation
followed by a Stevens rearrangement process was a widely ac-
cepted reaction mechanism according to the pioneering works
(Scheme 1C, Path I).[9,10] On the other hand, only Alberti dem-
onstrated that the diphenylcarbene, which was a donor/donor
(D/D) free carbene, reacted with disulfide through a radical-like
[a] Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University,Suzhou 215123, P. R. of China
Scheme 1. Patterns for the difunctionalization of diazo compounds.
E-mail: xinfangxu@suda.edu.cn
It is known that carbenes, carbocations, and radicals are
three reactive intermediates in organic reactions, while proc-
esses involving both carbene and radical intermediates are rare,
and in most cases, transition-metal catalysts are inescapable.[12]
Inspired by those works, together with our continuing interest
xgbao@suda.edu.cn
http://chemistry.suda.edu.cn/index.aspx?lanmuid=69&sublanmuid=604&id=
376
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600664.
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in metal–carbene[13] and radical[14] studies, it could be envi- spect to diazo compounds, which is illustrated in Scheme 2.
sioned that the S–S bond-insertion reaction of a free carbene Generally, all the tested diazoacetates reacted with diphenyl
is an ideal template to study these active species. In addition, disulfide (2a) smoothly and gave the products in high to excel-
the reaction provided dithioketal derivatives, which have drawn lent yields. Diazoacetates with various ester groups (R1) were
much attention because of their unique motifs,[9,10,15] and this reliably accommodated, providing the corresponding products
framework is embodied in many drug candidates,[16–18] includ- in >70 % yields (3a–c). Due to the inseparability of the insertion
ing those used in cancer chemotherapy[17] or as a nontoxic oral products with the byproducts generated from the decomposi-
hypocholesterolemic agents.[18]
tion of the corresponding diazoacetate, an excess amount of
2a was used in some cases, and the unreacted 2a was recov-
ered (see Scheme 2, footnote [b]). Subsequently, diazoacetates
carrying para substituents on the aryl group with different elec-
tronic behaviors provided the corresponding products in high
yields; although in the case of substrates with a strong electron-
withdrawing group such as CF3, the substrate showed a lower
reactivity under the optimized conditions, and an increased
temperature to 120 °C using PhCF3 as solvent was applied,
which gave the corresponding product 3l in 64 % yield. Incor-
poration of ortho- or disubstituted aryl groups gave the inser-
tion products in >95 % yields (3l, 3m). Interestingly, the yield
of 3k with a meta-bromo substituent decreased to 55 %. 2-
Naphthyl α-diazoacetate provided the insertion product in
97 % yield (3n). However, alkyldiazoacetate or acetoacetate did
not give any insertion product under the current conditions. In
addition, the reaction proceeded smoothly on a gram scale, and
3d was obtained in 70 % yield when the reaction was carried
out on a 5.0 mmol scale.
Results and Discussion
Initially, we evaluated this reaction by inducing the thermal de-
composition of diazoacetate 1a in the presence of diphenyl di-
sulfide (2a), and the solution of diazoacetate was added slowly
to the reaction mixture (Table 1). Gratifyingly, the reaction pro-
vided the dithioketal product 3a in 30 % yield when performed
in toluene at 110 °C for 12 h (Entry 1). Besides the reported
studies on S–S bond-insertion reactions with D/D-free carb-
enes,[9–11] this is the only example of D/A-free carbene insertion
into an S–S bond under catalyst-free conditions. Encouraged by
these results, further screening of solvents revealed that
benzotrifluoride (PhCF3) and fluorobenzene (PhF) were superior
to the other solvents and gave the desired product in 60 and
70 % isolated yields, respectively (Entries 4–8). After other reac-
tion parameters, including substrate ratios (Entries 2–4) and re-
action temperature (Entries 8–11), were explored, optimal re-
sults were achieved with a 4:1 ratio of diazoacetate/disulfide in
fluorobenzene at 95 °C, and, under these conditions, a pure
sample of 3a was obtained in 85 % isolated yield (Entry 11). In
addition, the reaction could be performed on a gram scale with
a 2:1 ratio of 1a/2a to give product 3a in 67 % yield (Entry 12).
Table 1. Optimization of the reaction conditions.[a]
Entry
1a/2a
Solvent
T [°C]
Yield [%][b]
1[c]
2[c]
3[c]
4
5
6
7
8
9
1:1.3
1:1.3
1:4
4:1
4:1
4:1
4:1
4:1
4:1
toluene
PhCF3
PhCF3
PhCF3
DCE
dioxane
PhCl
PhF
PhF
PhF
PhF
PhF
110
105
105
105
105
105
105
105
60
30
41
38
60
56
trace[d]
55
Scheme 2. S–S Bond insertion reaction of aryl diazoacatates with 2a. [a] Reac-
tion conditions: 2a (0.1 mmol) with diazo compound (0.4 mmol) in 2.0 mL of
PhF under argon for 12 h. [b] 1 (0.1 mmol) and 2a (0.6 mmol) were used,
and most of 2a was recovered after the reaction. [c] 2.0 equiv. of diazoacetate
was used. [d] The reaction was carried out on a 5.0 mmol scale. [e] In PhCF3
at 120 °C.
70
trace[e]
40
10
11
12
4:1
4:1
2:1
80
95
95
85
67[f]
[a] All reactions were carried out under argon in a sealed tube on a 0.1 mmol
scale in 2.0 mL of solvent at the indicated temperature for 12 h; DCE = 1,2-
dichloroethane. [b] Isolated yields after chromatography. [c] Most of the unre-
acted diphenyl disulfide (2a) was recovered. [d] All of the diazo compound
1a decomposed. [e] Most of the diazo compound 1a was recovered. [f] The
reaction was carried out on a 5.0 mmol scale.
To further explore the potential of this methodology, a vari-
ety of disulfides were investigated. The reaction of substrates
with either electron-withdrawing or electron-donating groups
proceeded well under the reaction conditions (Table 2), and
lower yields were obtained with substrates that possess a
Having established the effective conditions for the thermally strong electron-withdrawing group (3p; 60 %). Aliphatic disulf-
induced S–S bond-insertion reaction of a D/A-free carbene, we ide 2h was also tolerated under these conditions, albeit giving
proceeded to explore the generality of the reaction with re- the corresponding product in low yield (Entry 7).
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Table 2. Substrate generality of disulfides.[a]
[a] All reactions were carried out on a 0.1 mmol scale with 4.0 equiv of diazo
compounds in PhCF3 (2.0 mL) under argon at 105 °C for 12 h. [b] Isolated
yield after chromatography. [c] Compounds 1 (0.1 mmol) and 2 (0.6 mmol)
were used, and most of the disulfide was recovered after the reaction.
Computational studies at the ωB97XD/6-311+G(d,p) level of
theory were carried out to gain a mechanistic insight into this
reaction (see the Supporting Information for computational de-
tails). The thermal dissociation of N2 from 1a to yield a singlet
carbene intermediate 1INT1 via TS1 was found to have an acti-
vation energy barrier of 31.3 kcal/mol (Figure 1). The resulting
singlet carbene intermediate might combine with 2a to afford
the ylide intermediate 1INT2. Subsequently, 1INT2 might un-
dergo S–S bond cleavage to produce the dithioketal product
3a via transition state 1TS2. A three-membered ring structure
Figure 1. Energy profile [kcal/mol] for the generation of the carbene inter-
mediate and the subsequent reaction pathways with 2a to yield 3a.
1
is located in TS2, in which the S1···S2 bond length is length-
ened to 2.38 Å while the C1···S1 distance is shortened to 2.30 A
1
(Figure 2). It should be noted that the conversion from INT2
into the desired product 3a proceeds in a concerted manner
via a singlet carbene intermediate. The predicted free-energy
barrier for this concerted pathway is 17.6 kcal/mol relative to
Figure 2. Optimized structures of 1TS2 and 3TS2 (bond lengths are shown in
Å, and H atoms are omitted for clarity).
1
the energy of separated INT1 and 2a.
It should be noted that the triplet state for the carbene inter-
mediate 3INT1 is stabilized by 4.8 kcal/mol relative to the corre-
sponding singlet state. Thus, singlet-to-triplet carbene inter-
system crossing (ISC) might occur, and the possible reaction
mechanism via the triplet carbene was computationally ex-
plored next. The triplet carbene might electrophilically attack
the S–S bond of 2a via 3TS2, in which the C1···S1 distance is
shortened to 2.44 Å, while the S1···S2 distance is lengthened to
2.16 Å. Unlike 1TS2, a three-membered ring structure is not
found in 3TS2. Instead, the approximately linear transition-state
structure of 3TS2 could lead to the complex of a carbon radical
5.4 kcal/mol lower in energy than that of the singlet-carbene-
involved concerted pathway (1INT1 to TS2 via INT2), which
is therefore kinetically more favorable. In addition, the triplet
state of the carbene intermediate 3INT1 is more stable than
the corresponding singlet-state 1INT1 by 4.8 kcal/mol. Thus, the
catalyst-free S–S bond insertion is more likely to proceed via a
triplet-carbene-intermediate-involved stepwise radical mecha-
nism.
1
1
To verify the computational results, control reactions were
and a PhS· radical (3INT3). After a radical-coupling step be- carried out; the results are summarized in Scheme 3. Firstly, the
tween these two radical intermediates, the desired product unsymmetric disulfide 2i, which has two different aryl groups
could be obtained. Therefore, computational studies indicate with similar electronic properties, was employed, and three dif-
that the formation of 3a via a triplet carbene proceeds in a ferent dithioketal products 3a, 3ab, and 3o, in a 15:60:25 ratio
stepwise manner, which is in a sharp contrast to the concerted were observed [Equation (1)]. Furthermore, when diphenyl di-
manner performed by the singlet carbene. The predicted free- sulfide (2a) and 1,2-di-p-tolyldisulfane (2b) were added to the
energy barrier for this triplet-carbene-involved path is 12.2 kcal/ reaction mixture in a 1:1 ratio, the above three cross-coupling
3
mol relative to the energy of separated INT1 and 2a. The re- products were also obtained in a 26:36:38 ratio [Equation (2)].
3
sulting INT3 intermediate is exothermic by 22.3 kcal/mol rela- These products, including their ratios, were confirmed by 1H
3
tive to INT1. For the triplet-carbene-involved stepwise radical NMR (Figure 3) and HPLC-HRMS analyses (Figures S1–S3).[19]
pathway (3INT1 to 3TS2), the calculated energy barrier is Based on these observations, an S–S bond cleavage process
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Scheme 3. Control experiments.
Figure 3. 1H NMR spectroscopic analysis of cross-coupling products.
could be induced before the second S–C bond was formed,
which is consistent with our computational study prediction
(Figure 1, red path).
Based on the above study and on other reported work,[8a,11]
a plausible reaction mechanism is proposed (Scheme 4). Ini-
tially, diazoacetate 1 decomposed to generate D/A-free carbene
A under thermal conditions.[8] Subsequent addition with disulf-
ide 2 followed by homolytic cleavage of the S–S bond gener-
ated radical species B and C. Final radical coupling provided
the formal S–S bond-insertion product 3. When an asymmetric
disulfide was introduced, four kinds of radical intermediates B,
C, D, and E could be expected and three different cross radical
coupling products were observed (Scheme 4, bottom part).
To confirm the S–S bond cleavage, we examined in more
detail the homolysis process by conducting further experiments
in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
(Scheme 5). First, TEMPO was added to the reaction mixture at
the same time with 1a and 2a, and the formation of 3a was
suppressed, which suggested that free radical species were
probably involved in this transformation. However, compound
5 was not detected, and byproduct 4 was isolated in 80 % yield,
which indicated that the free carbene tended to react with
TEMPO over the disulfide to give the oxidized product 4 [Equa-
tion (3)]. We then performed the above reaction by adding
TEMPO after the reaction of 1a and 2a had been conducted for
Scheme 4. Proposed reaction mechanism.
sulfur radical (PhS·) in this transformation [Equation (4)].[19] To
verify that the sulfur radical (PhS·) was not generated by homo-
lytic cleavage of 2a, a control reaction was conducted in the
absence of diazo compound 1a; as expected, 5 was not de-
tected, and most of the staring material 2a was recovered
[Equation (5)], which confirmed that the reaction was initiated
by thermally induced free-carbene formation from the diazo
compound.
In addition, we found that the optimized reaction conditions
1.0 h, and the reaction mixture was stirred for another 0.5 h were also compatible with the S–H bond insertion reaction of
after the addition. To our delight, 5 was indentified spectro- a D/A-free carbene and gave the sulfur ethers in excellent yields
scopically (Figure S5), which suggested the formation of the [Equation (6)]. Metal-catalyzed S–H insertion with phenyl di-
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tions; start-up funding from Soochow University; the National
Natural Science Foundation of China and Jiangsu province
(SBK20150315 and 15KJD150004). X. B. was supported by the
National Natural Science Foundation of China (NSFC 21302133).
Keywords: Radical reactions · Donor/aceptor systems ·
Carbenes · Insertion · Density functional calculations
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Conclusions
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Experimental Section
To a 10 mL oven-dried vial containing a magnetic stirring bar and
diaryl disulfide (2) (indicated scale) in solvent (1.0 mL, PhF or PhCF3),
was added diazoacetate 1 (indicated scale) in the same solvent
(1.0 mL) by using a syringe pump at the indicated temperature over
60 min. The reaction mixture was then stirred for 12 h. When the
reaction was complete, the reaction mixture was directly purified
by column chromatography on silica gel (hexanes/EtOAc, 50:1 to
30:1) without any additional treatment to give the pure dithioketal
product 3 in moderate to high yield.
Acknowledgments
We are grateful for grants from the Priority Academic Program
Development (PAPD) of the Jiangsu Higher Education Institu-
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Received: May 30, 2016
Published Online: ■
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Radical Reactions
A donor/acceptor-free carbene inser-
tion reaction of an S–S bond through
a radical process is presented. This cat-
alyst-free reaction was thermally in-
duced and provided the dithioketal
products in moderate to high yields. A
mechanism involving radical interme-
diates was proposed according to the
computational study, and these inter-
mediates were identified in a cross-
coupling reaction.
Y. Zheng, R. Bian, X. Zhang,
R. Yao, L. Qiu, X. Bao,* X. Xu* ......... 1–7
Catalyst-Free S–S Bond Insertion Re-
action of
a Donor/Acceptor-Free
Carbene by a Radical Process: A
Combined Experimental and Com-
putational Study
DOI: 10.1002/ejoc.201600664
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim