Difunctionalization of alkenes with iodine and tert-butyl hydroperoxide (TBHP) at room temperature for the synthesis of 1-(tert-butylperoxy)-2-iodoethanes

Article abstract of DOI:10.3762/bjoc.13.200

We developed a direct vicinal difunctionalization of alkenes with iodine and TBHP at room temperature. This iodination and peroxidation in a one-pot synthesis produces 1-(tert-butylperoxy)-2-iodoethanes, which are inaccessible through conventional synthetic methods. This method generates multiple radical intermediates in situ and has excellent regioselectivity, a broad substrate scope and mild conditions. The iodine and peroxide groups of 1-(tert-butylperoxy)-2-iodoethanes have several potential applications and allow further chemical modifications, enabling the preparation of synthetically valuable molecules.

Full text of DOI:10.3762/bjoc.13.200

Difunctionalization of alkenes with iodine and tert-butyl
hydroperoxide (TBHP) at room temperature for the
synthesis of 1-(tert-butylperoxy)-2-iodoethanes
Hao Wang1, Cui Chen2, Weibing Liu*2 and Zhibo Zhu*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2023–2027.
1Integrated Hospital of Traditional Chinese Medicine, Southern
Medical University, Guangzhou, 510315, P. R. China. Fax: +86- 20-
6164 8538; Tel: +86- 20 -62789464 and 2College of Chemical
Engineering, Guangdong University of Petrochemical Technology, 2
Guandu Road, Maoming 525000, P. R. China. Fax:
+86-668-2923575; Tel: +86-668-2923956
doi:10.3762/bjoc.13.200
Received: 01 July 2017
Accepted: 08 September 2017
Published: 28 September 2017
Associate Editor: L. Vaccaro
Email:
Weibing Liu* - lwb409@gdupt.edu.cn.; Zhibo Zhu* -
zhuzb676@smu.edu.cn
© 2017 Wang et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
difunctionalization of alkenesiodine; iodination–peroxidation reaction;
TBHP
Abstract
We developed a direct vicinal difunctionalization of alkenes with iodine and TBHP at room temperature. This iodination and perox-
idation in a one-pot synthesis produces 1-(tert-butylperoxy)-2-iodoethanes, which are inaccessible through conventional synthetic
methods. This method generates multiple radical intermediates in situ and has excellent regioselectivity, a broad substrate scope and
mild conditions. The iodine and peroxide groups of 1-(tert-butylperoxy)-2-iodoethanes have several potential applications and
allow further chemical modifications, enabling the preparation of synthetically valuable molecules.
Introduction
Alkenes have attracted considerable interest in recent years as alyzed direct vicinal difunctionalization of alkenes by installing
abundant, simple chemical feedstocks and organic molecules, two substituents across the C=C double bond to form two new
owing to their potential for extensive application in organic syn- bonds or two new functional groups [7-9], such as dioxygena-
theses. Approaches for the efficient, regio- and chemoselective tion [10,11], dihydroxylation [10,12], bisperoxidation [13],
difunctionalization of alkenes have been developed that are oxyamidation [14], aminohydroxylation [15], oxyphosphoryla-
attractive for rapidly building complex difunctionalized mole- tion [16], deamination [17] and carbonylation–peroxidation
cules from simple starting materials in a single operation [1-6]. [18]. Several very recent reports have pertained to metal-free
Traditional studies have mainly focused on transition-metal-cat- catalysts for difunctionalization of alkenes such as UV light
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Beilstein J. Org. Chem. 2017, 13, 2023–2027.
[19,20], hypervalent iodine reagents [21,22], acids [23], vent, furnishing 2a in 72% yield (Table 1, entry 8). Further
organoammonium iodides [24] and iodine [25]. These catalysts screening studies were conducted by altering the amounts of I2
are often employed in combination with a peroxide and general- and TBHP to find the optimum reaction conditions. Notably,
ly produce an organoperoxide. Organic peroxides are important decreasing the amount of I2 to 0.5 equiv decreased the yield to
and useful compounds because of their unique chemical and bi- 51% (Table 1, entry 9). An excess of 3.0 equiv of TBHP or
ological properties [26,27]. Organoperoxides have wide appli- more gave the highest product yields (Table 1, entries 8, 10 and
cations in the field of organic synthesis, as radical initiators, 11).
oxidants that replace transition metal oxidants, and key reactive
intermediates in diverse organic synthesis reactions [28-30], as
Table 1: Optimization studiesa.
well as in medicinal chemistry and pharmacology as medicines
and therapeutic drugs [31,32]. Although many methods have
been developed to synthesize peroxides [33-35], they have a
tendency to decompose because the peroxy (–OO–) bond is
easily cleaved and peroxides are highly sensitivity to reducing
agents. New and general methods to construct peroxides are still
highly desirable and valuable, and highly regioselective and
Entry
Solvent
Time (h)
Yield (%)b
efficient syntheses of peroxides with structural control are
still difficult to achieve. Herein, we report a metal-free iodina-
tion–peroxidation reaction for the direct vicinal difunctionaliza-
tion of alkenes with iodine and tert-butyl hydroperoxide
(TBHP) at room temperature to synthesize 1-(tert-butylper-
oxy)-2-iodoethanes that are inaccessible via conventional
synthetic routes (Scheme 1). To the best of our knowledge,
β-iodoalkyl tert-butyl peroxides are important organic
compounds due to their unique structural features, which
make them available to serve as starting materials for a wide
range of organic oxidations to access other oxygenated products
[36].
1
2
CH3CN
CH3CN
CH3CN
DCE
12
24
36
24
24
24
24
24
24
24
24
45
59
3
59
4
31
5
dioxane
DMF
57
6
trace
trace
72
7
DMSO
toluene
toluene
toluene
toluene
8
9c
10d
11e
51
86
86
aUnless otherwise specified, all reactions were carried out on 1a
0.5 mmol scale, iodine 1.0 equiv, tert-butyl hydroperoxide (TBHP)
2.0 equiv, solvent 2.0 mL; byield calculated by GC; cI2: 0.5 equiv;
dTBHP: 3.0 equiv; eTBHP: 4.0 equiv.
A variety of substituted alkenes were then tested under the
optimal reaction conditions identified above. Styrenes (R = Ar;
R1 = R2 = H) 1a–i bearing functional groups with different elec-
tronic properties on the phenyl ring were all tolerated and did
not substantially alter the reaction efficiency (Scheme 2). Sub-
strates bearing electron-withdrawing substituents (i.e., fluoro-
and chloro-) performed slightly more effectively in this reac-
tion than those bearing electron-donating substituents (i.e.,
Scheme 1: Synthesis of 1-(tert-butylperoxy)-2-iodoethanes.
Results and Discussion
A pilot reaction setup comprised of styrene (1a, 208 mg, methyl-, phenyl-, chloromethyl-, tert-butyl- and methoxy-), and
2.0 mmol) in the presence of I2 (1.0 equiv), TBHP (2.0 equiv), afforded the corresponding products in relatively high yields.
and CH3CN (2.0 mL) was investigated to determine the optimal
reaction conditions. Stirring this mixture at room temperature Notably, the yield of this iodination–peroxidation reaction
for 12 h afforded the desired product (2-iodo-1-(tert- appeared to be unaffected by the position of the same substitu-
butylperoxy)ethyl)benzene (2a) in 45% yield, which was further ent on the phenyl ring. For example, all pairs of 1-methyl-4-
improved to 59% by extending the reaction time to 24 h vinylbenzene and 1,4-dimethyl-2-vinylbenzene, 1-chloro-4-
(Table 1, entries 1–3). The reaction was quite sensitive to the vinylbenzene and 1-chloro-3-vinylbenzene, 1-fluoro-4-vinyl-
solvent medium (Table 1, entries 2, 4–8). Among the various benzene and 1-fluoro-3-vinylbenzene gave almost identical
solvents examined, toluene proved to be the most suitable sol- yields of the corresponding products. In addition, the inclusion
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Beilstein J. Org. Chem. 2017, 13, 2023–2027.
Scheme 2: Direct vicinal difunctionalization of alkenes. All reactions were carried out on a 2.0 mmol scale using toluene (2.0 mL) as the solvent and
all the listed yields are isolated yields.
of different R1 and R2 groups on styrenes, such as 1,1-disubsti- We investigated the addition of the radical inhibitor TEMPO
tuted/1,2-disubstituted/1,1,2-trisubstituted alkenes (1-(prop-1- (2,2,6,6-tetramethylpiperididine-N-oxyl) to gain an insight into
en-2-yl)benzene, 1-methyl-4-(prop-1-en-2-yl)benzene and 1,1- the mechanism of this reaction. The reaction was completely in-
diphenylethene), had no discernible impact on the outcome of hibited in the presence of TEMPO, suggesting that a radical
this iodination–peroxidation reaction. The scope of this reac- pathway may be operating in this reaction. Therefore, we
tion was further extended to a series of chain alkenes, such as propose a possible mechanism for the reaction in Scheme 3,
1-(but-3-enyl)benzene), 1-allylbenzene, oct-1-ene and 3-ethyl- exemplified by the formation of 2a, based on the aforemen-
pent-2-ene, which all reacted as anticipated to give the corre- tioned results and previous literature [36-39]. The process
sponding products in moderate to excellent isolated yields commences with the formation of t-BuOI and HOI from the
(70−81%). It is noteworthy that monosubstituted and 1,1-disub- initial reaction of TBHP with I2 [40]. The subsequent iodina-
stituted terminal alkenes 1j-l, as well 1,2,2-trisubstituted tion reaction could proceed via a homolytic attack involving
internal alkenes 3-ethylpent-2-ene (1n) and 1-methylcyclopent- t-BuOI and HOI to generate intermediate 3, tert-butoxyl radi-
1-ene (1t) under the developed conditions, all result the antici- cals and hydroxyl radicals[41]. In the presence of TBHP, a fast
pated products with excellent yields. Especially, according to reaction between tert-butoxyl radicals and TBHP take place,
the detection of NMR and NOE analysis, the substrate leading to the formation of tert-butylperoxyl radicals and
1-methylcyclopent-1-ene (1t) affords (1R,2R)-1-(tert- tertiary butanol [41,42]. Subsequently, the radical 3 can be
butylperoxy)-2-iodo-1-methylcyclopentane (2t) as the only further oxidized into cation 4 with I2 [24,43,44]. The iodide ion
product. And even more exciting this reaction was easily scaled is then reoxidized with TBHP to regenerate I2 and tert-butoxyl
up to 10 mmol with no obvious loss in product formation effi- radicals [24,45]. Finally, cation 4 can be attacked by TBHP to
ciency.
give the final product 2a.
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Beilstein J. Org. Chem. 2017, 13, 2023–2027.
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In summary, we have established a metal-free process at room
temperature for the direct vicinal difunctionalization of alkenes
with iodine and TBHP to synthesize 1-(tert-butylperoxy)-2-
iodoethanes. This procedure is a simple and high-yielding
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