Di-tert-Butyl Peroxide-Mediated Atom-Transfer Radical Addition of 2-Chlorodithiane to Aryl Alkynes under Mild Conditions

Article abstract of DOI:10.1002/chem.201502581

Atom transfer radical addition (ATRA) of 2-chlorodithiane onto aryl alkynes through the use of di-tert-butyl peroxide as an oxidant at room temperature directly affords a variety of synthetically valuable β-chloro-(Z)-vinyl dithianes in good yields with high regioselectivities and without the assistance of any transition metals. It provides an operationally simple pathway to access vinyl dithianes with controlled formation of a new C(sp²) - C bond and a C(sp²) - Cl bond.

Full text of DOI:10.1002/chem.201502581

DOI: 10.1002/chem.201502581
Communication
&
Synthetic Methods
Di-tert-Butyl Peroxide-Mediated Atom-Transfer Radical Addition of
2-Chlorodithiane to Aryl Alkynes under Mild Conditions
Junshan Lai,[a] Lixia Tian,[a] Yongping Liang,[a] Yuan Zhang,[b] Xingang Xie,[b] Bowen Fang,[c]
and Shouchu Tang*[a, b]
Abstract: Atom transfer radical addition (ATRA) of 2-chlor-
odithiane onto aryl alkynes through the use of di-tert-
butyl peroxide as an oxidant at room temperature directly
affords a variety of synthetically valuable b-chloro-(Z)-vinyl
dithianes in good yields with high regioselectivities and
without the assistance of any transition metals. It provides
an operationally simple pathway to access vinyl dithianes
with controlled formation of a new C(sp2)ÀC bond and
a C(sp2)ÀCl bond.
Vinyl halides are important organic compounds and intermedi-
ates that can participate in a variety of essential transforma-
tions in organic synthesis.[1,2] The development of efficient and
selective methods allowing rapid construction of these motifs
has attracted immense interest. Among various strategies for
vinyl halide synthesis, atom-transfer radical addition (ATRA)
onto alkynes has emerged as a powerful tool in synthetic or-
ganic chemistry as an atom-economical method of simultane-
Scheme 1. ATRA strategies to give alkenyl halides.
ously forming C(sp2)ÀC and C(sp2)ÀX bonds.[3] During the past
decade, several groups have demonstrated the versatility of
metal-based protocols toward novel ATRA transformations
(Scheme 1). In particular, interest in ATRA reactions using cata-
lysts based on multiple Ru or Ir sources has grown from stud-
ies by the groups of Tsuji [Scheme 1, Eq. (1)][4] and Stephenson
[Scheme 1, Eq. (2)].[5] These works demonstrated the ability of
aroyl, aliphatic acid, and activated halides with alkynes to form
vinyl halides in a step and atom-economical fashion. More re-
cently, there has been remarkable progress in the development
of Cu-catalyzed method to generate vinyl halides under rela-
tively mild conditions, as demonstrated by Hu and co-workers
[Scheme 1, Eq. (3)].[6] However, most of these elegant ap-
proaches require transition metal catalysts, hazardous reagents,
and harsh conditions, and generally proceeded at high temper-
ature (60–1208C). Therefore, the discovery of versatile and
readily available starting materials for ATRA methods under
mild conditions with high regiospecificity and operational sim-
plicity would be particularly worthwhile.
Given the frequent occurrence of dithiane-derived functional
groups in natural product synthesis,[7] a fast and general access
to dithiane derivatives would be highly desirable. Direct cross-
coupling of dithianes with double/triple bonds represents
a seemingly straightforward and convergent tool to access
complex dithiane molecules. In 2014, we reported that 2-chlor-
odithiane can actively participate in the oxidative coupling for
the efficient construction of carbon–carbon bonds.[8] The re-
sulting pathway differed from known dithiane anion relay ap-
proaches in that 2-chlorodithiane served to generate the radi-
cal and induce the formation of the cross-coupling products.
Therefore, there is an incentive to broaden the methodology
for the ATRA of alkynes with 2-chlorodithiane. Herein we de-
scribe a direct ATRA reaction for alkyne difunctionalization to
efficiently produce a series of b-chloroalkenyl dithiane deriva-
tives. The key feature of this method is the combination of
vinyl functionalization and CÀC bond-forming processes that
proceed at room temperature, which provides ready access to
synthetically useful vinyl halides regioselectively [Scheme 1,
Eq. (4)].
[a] J. Lai, L. Tian, Y. Liang, Prof. Dr. S. Tang
School of Pharmacy
Lanzhou University, Lanzhou 730000 (P. R. China)
E-mail: tangshch@lzu.edu.cn
[b] Dr. Y. Zhang, Dr. X. Xie, Prof. Dr. S. Tang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (P. R. China)
[c] Dr. B. Fang
Chemical Engineering Institute, Northwest University for Nationalities
Lanzhou, 730030 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502581.
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In our recent work on radical oxidative coupling, we report-
ed a general method for the proposed ATRA of 2-chlorodi-
thiane and arylalkenes in the presence of an iron catalyst sys-
tem;[8a] toward the further study, we discovered that O2 is also
a highly effective oxidant for dithiane radical oxidative cou-
plings.[8b] Based on these findings, we attempted to apply
a similar oxidation system or metal catalyst to the coupling of
phenylacetylene 1a and 2-chlorodithiane 2. However, the use
of air or O2 led to an extremely slow reaction and resulted in
only trace product at room temperature (Table 1, entry 1). Fur-
Table 2. Scope of ATRA reaction.[a]
Entry
1 (R1, R2)
t [h]
Yield [%][b]
Z/E[c]
94:6
95:5
96:4
20:1
95:5
95:5
96:4
95:5
20:1
94:6
>25:1
>25:1
96:4
1
1a (Ph, H)
12
8
8
3a, 69
3b, 76
3c, 83
3d, 74
3e, 65
3f, 64
3g, 60
3h, 68
3i, 78
3j, 72
3k, 73
3l, 61
3m, 66
2
3
4
5
1b (p-MeC6H4, H)
1c (p-iPrC6H4, H)
1d (p-MeOC6H4, H)
1e (p-FC6H4, H)
8
12
18
24
8
8
8
8
12
12
6
7
8
9
10
11
12
13
1 f (p-ClC6H4, H)
1g (p-BrC6H4, H)
1h (p-BnOC6H4, H)
1i (m-MeOC6H4, H)
1j (m-MeC6H4, H)
1k (o-MeOC6H4, H)
1l (o-BnOC6H4, H)
1m (3,4-Me2C6H3, H)
Table 1. Reaction conditions for the ATRA of phenylacetylene.[a]
Entry
Additive/oxidant (x)
3a [%][b]
T [oC]
t [h]
14
15
4
8
3n, 80
3o, 78
>25:1
>25:1
1
2
3
4
5
6
7
8
9
air
air
trace
30
13
32
67
69
0
trace
0
RT
70
70
70
70
RT
RT
RT
RT
48
24
12
12
12
12
12
24
24
1o (p-MeOC6H4, CH3)
FeCl3 (0.15)
Cu(OAc)2 (0.15)
DTBP (2.0)
DTBP (2.0)
TBHP (2.0)
DDQ (2.0)
H2O2 (2.0)
[a] Reaction conditions: Alkyne (1a–o, 0.23 mmol), 2-chloro-1,3-dithiane
(2, 0.25 mmol), DTBP (2 equiv), DCE (2 mL), RT, 4–24 h. [b] Yields of isolat-
ed product. [c] Determined by D NOESY and H NMR spectroscopy.
1
1
[a] Reaction conditions: Phenylacetylene (1a, 0.23 mmol), 2-chloro-1,3-di-
thiane (2, 0.25 mmol), additive/oxidant (x equiv), 1,2-dichloroethane (DCE;
2 mL), 12–48 h. [b] Yields of isolated product.
tronic properties of the aryl halide (1e–g) did not dramatically
alter the yields or selectivities. Furthermore, a substrate with
a heteroaromatic group (1n) also underwent reaction efficient-
ly to afford the corresponding product 3n in approximately
80% yield (Table 2, entry 14). In every case studied to date, the
ATRA protocol developed displayed complete regioselectivity
for the terminal position, and the vinyl dithiane derivative has
been isolated as a single regioisomer with excellent (Z)-selec-
tivity. For example, 3k was obtained with almost 100% selec-
tivity, and we could not detect any other stereo- or regioisom-
ers by 1H NMR spectroscopy (Table 2, entry 11). These results
suggest that the ATRA reaction may be controlled by an appar-
ent steric effect of the dithiane moiety. Importantly, nontermi-
nal alkynes were also tolerated. For example, the reaction of
the more sterically encumbered 1o also took place at room
temperature to give 3o in 78% yield (Table 2, entry 15). This
transformation allows direct construction of a fully substituted
alkene bearing a dithiane moiety, which remains a challenge in
organic synthesis.
ther experimentation using air revealed that an improved yield
could be obtained by employing a higher reaction tempera-
ture (Table 1, entry 2). However, full conversion of 1a was not
achieved even after 24 h. Surprisingly, the addition of FeCl3 or
the use of Cu(OAc)2 did not significantly improve the coupling
process (Table 1, entries 3 and 4). Di-tert-butyl peroxide (DTBP)
is commonly used as a radical initiator in radical oxidative cou-
pling reactions.[9] We were pleased to discover that a DTBP
system, without use of any metal catalyst, facilitated the ATRA
reaction to give 3a in 69% yield with excellent regioselectivity
at room temperature (Table 1, entry 6). Interestingly, after mon-
itoring the reaction mixture by GC-MS, we were able to deter-
mine that the ATRA product 3a was formed exclusively and
the b-ketodithiane resulting from a competitive reaction path-
way was not detected.[8d] Additionally, other oxidants, such as
tert-butyl hydroperoxide (TBHP),[10] hydrogen peroxide,[11] and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),[12] performed
poorly and gave no desired product (Table 1, entries 7–9).
We next examined the scope of this ATRA process with re-
spect to aryl alkynes (Table 2). We were delighted to find that
a wide array of aromatic alkynes with electron-rich, electron-
neutral, and moderately electron-poor substituents led to the
corresponding b-chloro-a,b-unsaturated dithiane products 3a–
o in good yields and high selectivities. Moreover, a variety of
versatile functional groups were well tolerated and the elec-
Importantly, the novel ATRA-coupled products involving the
vinyl halide and dithiane functionalities enable them to be ver-
satile synthetic intermediates, which can be further derivatized
for synthetic utility. Vinyl chlorides 3a–g were reacted in situ
with carbon nucleophiles such as acetylacetone 4 to deliver
CÀC coupling products 5a–g in good to excellent yields with
tBuOK as the base (Table 3). Excellent regio- and stereoselectiv-
ities were observed regardless of the electronic variation in the
aryl ring. Chloro (5 f) and bromo (5g) groups were also tolerat-
ed. The metal- and ligand-free intermolecular cross-coupling of
vinyl chlorides with nucleophiles is not well documented.[2,13]
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method allowed for the rapid synthesis of the corresponding
b-chloro-a,b-unsaturated imide derivatives 7 by aminolysis
with phenylhydrazine.[15] Alternatively, the alkenyl dithiane 3a
Table 3. Reactions of 3a–g with acetylacetone.[a,b]
could be oxidatively transformed into b-ketodithiane
8
through exposure to aqueous H2SO4.[16] Particularly interesting
is the example that led to the methoxy-substituted dithiane
derivative 9; the reaction sequence was completed by addition
of MeONa in MeOH. Finally, the activated 10, containing
a useful aziridine dithiane motif, was obtained in 81% overall
yield.
To aid our interpretation of the mechanism, a series of ex-
periments were performed. Initially, the ATRA transformations
were found to be inhibited by addition of 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT).
Importantly, if a vinyl cation mechanism is operative, then it is
possible to form the novel ATRA product by nucleophilic trap-
ping experiments. However, we found that adding NaI or NaBr
to a reaction mixture of 1a and 2 under the standard condi-
tions still gave 3a in 67% and 70% yield, respectively. These
experiments indicate that the propagation is a much more
likely reaction pathway than the oxidation of a vinyl radical to
a vinyl cation. Furthermore, inspired by a recent report of
a trans-selective carbohalogenation of terminal alkynes with
steric alkylhalides,[17] we observed that the addition of
10 mol% of CuBr and 30 mol% of 1,10-phenanthroline in the
reaction of 1a and 2 still led to (Z)-3a in 62% yield and the re-
versed ATRA did not take place (Scheme 3).
[a] Reaction conditions: 3a–g (0.25 mmol), acetylacetone (4, 0.50 mmol),
tBuOK (0.63 mmol, 2.5 equiv), DMSO (2 mL), RT, 6–8 h. [b] Yields of isolat-
ed product.
Scheme 3. Mechanistic investigations.
On the basis of the above experimental results, we propose
an ATRA reaction pathway (Scheme 4). In presence of DTBP as
an initiator, pre-association of the dithiane moiety of 2 facili-
tates the release of an electrophilic dithiane radical I. Subse-
quent radical addition with aryl alkyne leads the formation of
a new CÀC bond with concomitant formation of the more
stable vinyl radical intermediate II. Then, propagation of II with
2 affords (Z)-3 and regenerates the dithiane radical I, thus com-
pleting the subsequent radical addition cycle. Moreover, the
stereochemical outcome of the ATRA reaction is most likely de-
pendent on the nature of the dithiane moiety and the less
sterically hindered carbon of the alkyne.
Scheme 2. Synthetic utility of ATRA products. Reaction conditions: a) 1a
(1.01 g, 10 mmol), 2 (1.72 g, 11 mmol), DTBP (2 equiv), DCE (100 mL), RT,
24 h; b) 3a (0.25 mmol), H2O2 (3 equiv), SOCl2 (1.5 equiv), DCE (4 mL), RT,
16 h; c) 3a (0.25 mmol), FeCl3 (10 mol%), PhNHNH2 (1.2 equiv), DMF (4 mL),
RT, 16 h; d) 3a (0.25 mmol), FeCl3 (10 mol%), H2SO4 (2 equiv, 70%), MeOH
(2 mL), 508C, 24 h; e) 3a (0.25 mmol), MeONa (3 equiv), MeOH (2 mL), RT,
1 h; f) 3a (0.25 mmol), NaN3 (1.2 equiv), tBuOK (2 equiv), DMSO (4 mL), RT,
6 h.
To our knowledge, this is the first examples of a straightforward
cross-coupling of vinyl chlorides induced by a dithiane moiety.
Furthermore, this ATRA process could also be performed
well on gram scale (Scheme 2). Subsequently, the dithiane
group could be removed without loss of the chloro moiety,
providing b-chloroalkenyl formyl compound 6.[14] The ATRA
In summary, we have described a direct ATRA protocol for
the efficient conversion of aryl alkynes and 2-chlorodithiane to
complex vinyl dithianes with high regio- and stereoselectivity.
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Scheme 4. Proposed mechanism.
We have demonstrated that this operationally simple method
tolerates a wide range of functional groups. More importantly,
the ATRA transformations can be efficiently scaled up and the
synthetic utility of those ATRA products has been elegantly
demonstrated. Further investigations into the extensions of
the substrate scope as well as the application of these meth-
ods toward the synthesis of natural products are ongoing in
our laboratory.
Acknowledgements
We are grateful for grants from the National Natural Science
Foundation of China for financial support of this project (Nos.
21102064, 21102066, 21402153).
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Keywords: alkynes
· atom transfer · radical addition ·
regioselectivity · sulfur heterocycles
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Received: July 2, 2015
Published online on August 21, 2015
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