Intramolecular Hydroalkoxylation of Unactivated Alkenes Using Silane-Iodine Catalytic System

Article abstract of DOI:10.1021/acs.orglett.5b01797

A novel catalytic system using I₂ and PhSiH₃ for the intramolecular hydroalkoxylation of unactivated alkenes is described. NMR study indicated that in situ generated PhSiH₂I is a possible active catalytic species. This catalytic system allows an efficient intramolecular hydroalkoxylation of phenyl-, trialkyl-, and 1,1-dialkyl-substituted alkenes as well as a variety of unactivated monoalkyl- and 1,2-dialkyl-substituted alkenes at room temperature. Mechanistic consideration based on significant experimental observations is also discussed.

Full text of DOI:10.1021/acs.orglett.5b01797

Letter
pubs.acs.org/OrgLett
Intramolecular Hydroalkoxylation of Unactivated Alkenes Using
Silane−Iodine Catalytic System
Shoji Fujita, Masanori Abe, Masatoshi Shibuya,* and Yoshihiko Yamamoto
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya
464-8601, Japan
S
* Supporting Information
ABSTRACT: A novel catalytic system using I2 and PhSiH3 for the
intramolecular hydroalkoxylation of unactivated alkenes is described.
NMR study indicated that in situ generated PhSiH2I is a possible active
catalytic species. This catalytic system allows an efficient intramolecular
hydroalkoxylation of phenyl-, trialkyl-, and 1,1-dialkyl-substituted alkenes as well as a variety of unactivated monoalkyl- and 1,2-
dialkyl-substituted alkenes at room temperature. Mechanistic consideration based on significant experimental observations is also
discussed.
he intramolecular hydroalkoxylation of unactivated
alkenes is an attractive strategy for constructing oxygen-
Table 1. Optimization of Intramolecular Hydroalkoxylation
T
containing heterocycles, because it enables the construction of
cyclic ethers from the corresponding acyclic hydroxy alkenes
with 100% atom efficiency.1 Cyclic ethers are important
structural motifs of biologically active natural products such
as marine natural products,2 acetogenins,3 and sphingosines.4
Despite the potential utilities, the intramolecular hydro-
alkoxylation of monoalkyl- and 1,2-dialkyl-substituted alkenes
is a formidable challenge owing to the difficulty of the
electrophilic activation compared with phenyl-, trialkyl-, and
1,1-dialkyl-substituted alkenes. In 2004, Widenhoefer and co-
workers developed the first catalytic intramolecular hydro-
alkoxylation of the unactivated alkenes using the platinum(II)
halogenation reagent
(mol %)
time
(h)
yield
a
entry
silane (mol %)
solvent
(%)
1
l2 (10)
PhSiH3 (150) toluene
PhSiH3 (150) CH2Cl2
30
1
89
87
95
95
91
2
l2 (10)
3
4
5
l2 (10)
PhSiH3 (10)
PhSiH3 (20)
PhSiH3 (10)
PhSiH3 (10)
PhSiH3 (10)
Ph2SiH2 (20)
Ph3SiH (20)
TMSI (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
l2 (10)
1
NIS (10)
NBS (10)
NCS (10)
l2 (10)
1.5
24
24
2
b
6
77
7
0
complexes.5 In the same year, Coulombel and Dunach also
̃
8
84
reported the TfOH-catalyzed intramolecular hydroalkoxyla-
tion.6 After these two seminal reports, several catalytic
intramolecular hydroalkoxylation methods have been devel-
oped.7 However, even expensive transition-metal-catalyzed
methods mostly require heat and a long reaction time, and
most of the reported monoalkyl- and 1,2-dialkyl-substituted
alkenes have a quarternary carbon to assist the cyclization by
the gem-dialkyl effect.8 The reports on the substrates not having
a quarternary carbon are quite limited. In this context, we
turned to develop a new catalytic system for an intramolecular
hydroalkoxylation. Herein, we report on a unique silicon-based
system for the intramolecular hydroalkoxylation of alkenes.9
This novel catalytic system efficiently causes the desired
reaction of monoalkyl- and 1,2-dialkyl-substituted alkenes
without an elevated temperature.
c
9
l2 (10)
24
1
71
10

95
a
b
c
Isolated yield. 16% recovered starting material 1a. 14% iodoether
3a and 5% tetrahydropyran 4a were obtained.
the reported intramolecular hydroalkoxylations of 1,2-disub-
stituted alkenes afford the products as a mixture of five- and six-
membered cyclic ethers, five-membered cyclic ether 2a was
afforded with high selectivity (>100:1) (see Table S1 in the
Supporting Information).5−7 As a result of solvent screening
(Table S2), it was found that the reaction proceeded with
significantly higher efficiency in CH2Cl2 than in toluene and
was completed within 1 h (entry 2). To our delight, a catalytic
amount of PhSiH3 sufficiently promoted the desired reaction
(entries 3 and 4). These results indicated that a new
We initially paid attention to the high affinity of iodine to
alkenes10 and attempted to develop an iodine-based catalytic
system in the presence of a hydrogen source (Table 1). During
the investigation using silanes as a hydrogen source, we found
that the desired intramolecular hydroalkoxylation reaction of
the γ-hydroxy alkene 1a was caused by 10 mol % I2 and 150
mol % PhSiH3 in toluene at room temperature, although a long
reaction time was required (entry 1). Note that while most of
Received: June 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
catalytically active species in situ generated from I2 and PhSiH3
promoted the desired reaction. 10 mol % of NIS and 10 mol %
of PhSiH3 also caused the desired reaction with similar
efficiency (entry 5), which indicates the generation of active
species identical to that from I2 and PhSiH3. The use of NBS
instead of NIS prolonged the reaction time, and the use of NCS
resulted in no reaction (entries 6 and 7). In the subsequent
evaluation of the substituents on the silanes, several silanes
efficiently catalyzed the reaction in the presence of I2 similarly
to PhSiH3 (Table S3). Triaryl- and trialkyl-substituted silanes
also promoted the desired hydroalkoxylation reaction, although
the bulkier silanes showed lower reaction rates (entries 8−10).
When Ph3SiH was used, a small amount of the tetrahydropyran
4a was produced along with the tetrahydrofuran 2a and the
iodoether 3a (entry 9).
Table 2. Substrate Scope
To identify the active species, 1H NMR of the 1:2 mixture of
I2 and PhSiH3 in CD2Cl2 was recorded (Figure 1a). The new
Figure 1. 1H NMR spectra of the 1:2 mixture of I2 and PhSiH3 (a) and
the 1:1 mixture of NIS and PhSiH3 (b).
peaks were assigned to PhSiH2I (δH = 4.76 ppm), ISiH3 (δH =
3.55 ppm), and benzene (δH = 7.38 ppm), which are consistent
with Keinan’s report.11 PhSiH2I was also observed from the
NMR analysis of the mixture of NIS and PhSiH3, while ISiH3
and benzene were not detected (Figure 1b). These
observations indicate that PhSiH2I is the possible active species
of this reaction. Although the preparation of PhSiH2I is known,
there are no reports on its reactivity to the best of our
knowledge.11,12 The optimization studies in Table 1 indicate
that the silyl iodide (Si−I) moiety of PhSiH2I is important for
its catalytic activity (entries 5−7), although the Si−H moiety is
not necessary (entries 9 and 10). Because the reaction of 1
equiv each of I2 and PhSiH3 generates 1 equiv of HI together
with PhSiH2I, and an additional 1 equiv of PhSiH3 reacts with
HI to provide ISiH3 and PhH, 10 mol % of I2 and 20 mol % of
PhSiH3 in CH2Cl2 (entry 4) were selected as the optimal
conditions, which includes 10 mol % of PhSiH3 to quench in
situ generated HI from the reaction of I2 and PhSiH3.11
a
b
Reaction condition: x mol % I2, 2x mol % PhSiH3, CH2Cl2, rt. Yields
c
are those of isolated products. The reaction mixture was treated with
1.0 equiv of TBAF after 12 h and stirred for additional 30 min at rt.
Under the optimal reaction conditions, the substrate scope
was investigated (Table 2).13 The intramolecular hydro-
alkoxylations of the phenyl-substituted alkenes 1b and 1c
were smoothly completed to give the corresponding cyclic
ethers 2b and 2c in high yields. The mono-, 1,1-di-, 1,2-cis-di-,
1,2-trans-di-, and trisubstituted alkenes 1d−u afforded the
corresponding products 2d−u in high yields. As with the case
of 1a, the 1,2-disubstituted alkenes 1f−h, 1k, 1o, and 1q
B
DOI: 10.1021/acs.orglett.5b01797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
provided the corresponding five-membered cyclic ethers 2f−h,
2k, 2o, and 2q with almost complete selectivity (>100:1). The
secondary alcohols 1f, 1h, and 1n−p also smoothly underwent
the hydroalkoxylation. The dihydroxydiene 1m was converted
to the spirocyclic ether 2m via double hydroalkoxylation. In the
case of 1r, although a small amount of 5-iodo-3-phenylpentan-
2-ol was produced as a byproduct, the treatment with TBAF
after the disappearance of 1r promoted the recyclization of 5-
iodo-3-phenylpentan-2-ol to give 2r in high yield. Notably, the
formations of the tetrahydrofuran 2o−r, which were not
enhanced by the gem-dialkyl effect, efficiently occurred at room
temperature.8 PhSiH2I-catalyzed hydroalkoxylations of the silyl
and benzyl ethers 1s−u provided the desired products 2s−u in
high yields along with less than 10% yield of the desilylation
and the debenzylation products, which exhibit good compati-
bilities with acid-labile protecting groups, although the MOM
ether 1v did not afford 2v. The reaction of the δ-hydroxy alkene
1w provided the tetrahydropyran 4a in 46% yield, together with
the 15% tetrahydrofuran 2a. The reaction of 6-methylhept-5-
en-2-ol (1x) gave small amounts of the desired product 4x and
the HI adduct 5. The formations of six-membered rings are
relatively slow compared with those of five-membered rings and
cause the side reactions such as isomerization and HI addition.
Intramolecular hydroamination of 6a also efficiently proceeded
to give 7a in high yield.
Table 3. Mechanistic Experiments
yield (%)
entry
conditions
time
2a
3a
1a
a
b
10 mol % I2, 20 mol % PhSiH3
10 mol % 57% HI
1 h
95
31
91
75
0
10
<1
10
0
57
<1
5
c
1
24 h
24 h
c
2
10 mol % 57% HI, degass, dark
c
d
e
3
10 mol % I2, 20 mol % AcSH, degass, 24 h
dark
c
4
10 mol %TfOH
24 h
24 h
5
0
0
95
24
c
5
10 mol %TMSOTf
43
a
b
c
Standard conditions. Isolated yield. Determined by NMR using n-
d
octyl ether as an internal standard. 3% tetrahydropyran 4a was
obtained. 7% tetrahydropyran 4a was obtained.
e
conditions after 24 h, together with 95% of the starting material
1a whereas cyclic ethers were obtained in 50% yield (43% 2a +
7% 4a) under TMSOTf-catalyzed conditions.16,18 These results
support the notion that the silyl group of PhSiH2I not only
suppresses the aerobic oxidation of iodide ion but also
contributes to the acceleration of the reaction.19 Very recently,
Sarpong and co-workers have reported a TMSI/H2O method
for hydroamination.9 In striking contrast to the PhSiH2I-
catalyzed reaction, they concluded that anhydrous HI is an
active species in their catalytic system, and they did not observe
any acceleration by the silyl group. To rule out the effect of
adventitious water, we examined the hydroalkoxylation of 1a on
gram scale under strictly anhydrous conditions [in glovebox,
dry CH2Cl2 (water <10 ppm)]. The reaction completed within
1 h to provide 2a in high yield.
To evaluate the stereoselectivity of O−H addition toward
alkenes, the deuterium-labeled γ-hydroxy alkene 1i-d2 was
subjected to the PhSiH2I-catalyzed intramolecular hydro-
alkoxylation (Scheme 1).14 The 1H NMR spectroscopic analysis
Scheme 1. Intramolecular Hydroalkoxylation of Deuterium
Labelled γ-Hydroxy Alkene 1i-d2
On the basis of the above experimental observations, we
propose a plausible mechanism in Scheme 2. In situ generated
Scheme 2. Proposed Reaction Pathway
revealed that the obtained product is the 3ax and 7eq deuterated
2i-d2, which indicates that the O−H addition to alkenes
selectively proceeds in an anti-fashion similar to the TfOH-
catalyzed hydroalkoxylation14 instead of the syn-fashion
proposed for the Al(OTf)3-catalyzed hydroalkoxylation.15
To investigate the reaction mechanism, several control
experiments were carried out (Table 3). To evaluate the
possibility of an in situ generated Brønsted acid, 1a was treated
with 10 mol % of hydroiodic acid (57% HI).16 The reaction was
stopped at a moderate conversion along with the production of
the iodoether 3a (entry 1). The iodoether 3a was presumably
formed via the iodoetherification of 1a, which indicates the
generation of iodine by aerobic oxidation of an iodide ion. Note
that iodoethers were not observed under PhSiH2I-catalyzed
conditions. To suppress the oxidation, 1a was treated with
hydroiodic acid under degassed and dark conditions, and 2a
was produced in good yield, although an obviously longer
reaction time was required than that for the PhSiH2I-catalyzed
method (entry 2). Although 1a was treated with anhydrous HI
prepared by Koreeda’s procedure to exclude the effect of H2O,
the result was similar to the reaction with hydroiodic acid
(entry 3).17 We also examined the catalytic activities of TfOH
and TMSOTf to estimate the effect of the silyl group. As the
result, 2a was obtained in only 5% yield under TfOH-catalyzed
PhSiH2I from I2 and PhSiH3 reacts with the hydroxy group of a
γ-hydroxy alkene to generate HI and the γ-silyloxy alkene. The
electrophilic activation of the double bond of the γ-silyloxy
alkene by HI causes the intramolecular hydroalkoxylation to
provide a cyclic ether. Although γ-hydroxy alkenes can be
activated by HI to afford the corresponding cyclic ethers, the
hydroalkoxylation of γ-silyloxy alkenes is presumably predom-
inant, which is suggested by the fact that a PhSiH2I-catalyzed
hydroalkoxylation is substantially superior to a HI-catalyzed
hydroalkoxylation.
In conclusion, we have developed a novel catalytic system
using I2 and PhSiH3 for intramolecular hydroalkoxylation.
PhSiH2I was observed as the possible active catalytic species by
NMR spectroscopic analysis. Phenyl-, trialkyl-, and 1,1-dialkyl-
substituted alkenes as well as a variety of monoalkyl- and 1,2-
dialkyl-substituted alkenes smoothly afforded the correspond-
C
DOI: 10.1021/acs.orglett.5b01797
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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examples of hydroalkoxylation of olefins. They concluded that
anhydrous HI is an active species of the hydroamination under their
conditions and also reported the similar hydroamination under silicon-
free conditions (NaI and TfOH). On the other hand, we observed that
the combination of TfOH and NaI required a long reaction time
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The reaction was carried out in a glass flask with a plastic cap. The
details are provided in the Supporting Information.
ing cyclic ethers without a need for elevated temperature.
Mechanistic experiments indicate that a cooperative effect of
electrophilic activation of the double bonds by HI and the
acceleration by the silyl groups enables the efficient hydro-
alkoxylation. We expect that the present work will expand the
potential of hydrofunctionalization of C−C unsaturated bonds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data. The Support-
ing Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01797.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: m-shibu@ps.nagoya-u.ac.jp.
Notes
The authors declare no competing financial interest.
(14) Brooner, R. E. M.; Widenhoefer, R. A. Chem. - Eur. J. 2011, 17,
6170−6178.
ACKNOWLEDGMENTS
■
(15) Coulombel, L.; Rajzmann, M.; Pons, J. M.; Olivero, S.; Dunach,
̃
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT, and the
Platform Project for Supporting in Drug Discovery and Life
Science Research from MEXT and AMED.
E. Chem. - Eur. J. 2006, 12, 6356−6365.
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(18) The treatment of 1a with 1 mol % TfOH resulted in the almost
quantitative recovery of 1a, together with a trace amount of 2a.
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penten-1-ol and the corresponding TMS ether by treatment with 1
equiv of TfOH. It was observed that the cyclization of the TMS ether
proceeded substantially faster than that of 4-penten-1-ol. The details
are provided in the Supporting Information.
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