Diastereoselective Intramolecular Hydride Transfer Triggered by Electrophilic Halogenation of Aryl Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b03548

Diastereoselective hydride transfer could be triggered by electrophilic halogenation (bromination or fluorination) of homoallylic alcohol O-Bn ethers. The resulting diastereomerically enriched haloalkyl alcohols underwent subsequent intramolecular nucleop

Full text of DOI:10.1021/acs.orglett.9b03548

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Intramolecular Hydride Transfer Triggered by
Electrophilic Halogenation of Aryl Alkenes
‡
,‡
Bin Wang,†,§ Dhika Aditya Gandamana,†,§ David Fabian Leon Rayo, Fabien Gagosz,*
́
and Shunsuke Chiba*,†
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
‡Department of Chemistry and Biomolecular Sciences, University of Ottawa, K1N 6N5, Ottawa, Canada
S
* Supporting Information
ABSTRACT: Diastereoselective hydride transfer could be triggered by
electrophilic halogenation (bromination or fluorination) of homoallylic alcohol
O-Bn ethers. The resulting diastereomerically enriched haloalkyl alcohols
underwent subsequent intramolecular nucleophilic substitution to afford the
corresponding tetrahydrofurans.
Scheme 1. Halofunctionalization of Alkenes and 1,5-
Hydride Transfer
lectrophilic halo-functionalization of alkenes via halonium
ion intermediates allows for facile installation of various
E
functional groups onto alkenes.1 In the presence of an
appropriate internal or external nucleophile, the halonium ion
intermediates can undergo ring opening at the carbon best
able to stabilize the positive charge, thus enabling
regioselective halo-functionalization of alkenes. In this regard,
a variety of carbon and heteroatom-based nucleophiles have
been utilized, whereas hydrides (H−), which potentially enable
anti-Markovnikov hydrohalogenation of alkenes, have rarely
been employed for this purpose.
Our group2 recently demonstrated that intramolecular 1,5-
hydride transfer3,4 from alkyl ethers to a carbocation
generated from alcohols (via a protonation-elimination
process) or alkenes (via a protonation event) could proceed
through a six-membered ring chair-like transition state to
construct stereogenic centers with a high level of diaster-
eocontrol.4,5 In this context, we hypothesized that 1,5-hydride
transfer to halonium ions generated from homoallylic alcohol
O-Bn ethers in the presence of an electrophilic halogen source
might enable anti-Markovnikov hydrohalogenation (Scheme
1C). Herein, we demonstrate the execution of this concept
with the development of diastereoselective electrophilic
hydrobromination and fluorination of aryl alkenes. The
resulting diastereomerically enriched haloalkyl alcohols under-
go subsequent intramolecular nucleophilic substitution to
afford substituted tetrahydrofurans under the optimized
reaction conditions.
Treatment of 1a with 1.1 equiv of N-bromosuccinimide
(NBS) in trifluoroethanol at 50 °C afforded 3,4-cis-
disubstituted tetrahydrofuran 2a in 74% yield with a
diastereoselectivity of 91:9 (conditions A). 1-Chloromethyl-
At the outset of the project, we examined the reactivity of
homoallylic alcohol O-benzyl ether 1a having a benzyl group
at the allylic position (Scheme 2A). Extensive screening of
various reaction parameters (see the SI for details) led to the
two complementary optimized reaction conditions A and B.
Received: October 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03548
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
regarded as anti-Markovnikov hydroetherification of aryl
alkenes.
Scheme 2. Stereoselective Formation of 3,4-cis-
Disubstituted Tetrahydrofuran 2a
We then investigated the substituent effect on the synthesis
of 3,4-cis-disubstituted tetrahydrofurans (Scheme 3). As for
Scheme 3. Synthesis of 3,4-cis-Disubstituted
a
Tetrahydrofurans
a
Reaction conditions A: 1a (0.3 mmol), NBS (1.1 equiv),
b
CF3CH2OH (6 mL, 0.05 M), rt, 10 min, then 50 °C, 4 h. Reaction
conditions B: 1a (0.5 mmol), Selectfluor (1.2 equiv), MeNO2−
CF3CH2OH (1:1, 5 mL, 0.1 M), 50 °C, 2 h, then TsOH (10 mol %),
c
50 °C, 48 h. The chemical yields from the reactions in 1 g scale (use
d
of 3 mmol of 1a). The diastereomeric ratio was determined on the
1
basis of H NMR analysis.
a
Reaction conditions: 1 (0.5 mmol) under conditions A or B (see
Scheme 2). Isolated yields and diastereomeric ratio of 2 are given.
4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
borate) (Selectfluor) was found to be an alternative reagent,
allowing the formation of 2a in 76% yield with higher
diastereoselectivity of 96:4. In this case, p-toluenesulfonic acid
(TsOH) (10 mol %) was required to assist the furan ring
closing step, and a longer reaction time was needed to
complete the process (conditions B). The transformation is
initiated by the formation of a halonium ion I, which is under
equilibrium with the tertiary benzylic carbocation II probably
via trifluoroethyl ethers III.5 Subsequent 1,5-hydride shift
from the benzylic position to the carbocation in II proceeds
via a six-membered chairlike transition state IV in which the
bulkier phenyl and benzyl groups adopt pseudo equatorial
positions. Solvolysis of the resulting oxocarbenium ion V
produces the diastereomerically enriched 4-halobutanol VI,
which cyclizes by intramolecular nucleophilic substitution to
form tetrahydrofuran 2a.6,7 The reaction of deuterated 1a-
[D2] resulted in deuterium incorporation at the C3 position of
2a-[D], thus unambiguously proving the 1,5-hydride shift
(Scheme 2C). This multistep conversion of homoallylic
alcohol derivative 1a into tetrahydrofuran 2a could be
the substituent on the alkene, both electron-rich and -deficient
aryl groups could be installed (for 2b−2d), whereas the use of
a sterically hindered ortho-tolyl group rendered the process
sluggish, providing the corresponding tetrahydrofuran 2c in
moderate yields under both reaction conditions A and B.
Introduction of a methyl group at the allylic position of the
substrate did not influence the diastereoselectivity (for 2e).
The method tolerated the presence of various functional
groups such as methyl ether, chloride, cyanide, and
phthalimide (for 2f−2i). Construction of tetrahydrofuran 2j
having an N-tosylpiperidine moiety was successful under the
reaction conditions A with NBS, while the use of Selectfluor
(conditions B) gave a complex mixture of unidentified
compounds probably due to the oxidation of the piperidine
moiety by Selectfluor.
The present strategy allowed for the construction of 2,4-
trans-disubstituted tetrahydrofuran 2k, for which both reaction
conditions A and B led to high diastereoselectivities (Scheme
4). Similarly, 2,3,4-trisubstituted bicyclic tetrahydrofurans 2l
B
DOI: 10.1021/acs.orglett.9b03548
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
and 2m could be synthesized, albeit with moderate efficiency
in the case of 2m.
Scheme 5. Interrupt of 1,5-Hydride Shift
Scheme 4. Synthesis of 2,4-Disubstituted and 2,3,4-
a
Trisubstituted Bicyclic Tetrahydrofurans
a
Reaction conditions: 1 (0.5 mmol) under conditions A or B (see
Scheme 2). Isolated yields and diastereomeric ratio of 2 are given.
During the course of the substrate scope study, we observed
in several cases that the desired 1,5-hydride shift is
interrupted. For example, the reactions of adamantyl
derivative 1n produced the intriguing polycyclic tetrahydro-
furans 3n-Br and 3n-F having a halomethyl tether at the C3
position as a single diastereomer (Scheme 5A). In this case, a
Wagner−Meerwein type 1,2-carbon shift to the halonium ion
intermediates I8 and concomitant cyclization of the OBn
tether could account for the formation of 3n. In this
mechanistic scenario, conformation II would be energetically
favored over conformation III. Substrate 1o having a
benzyloxyethyl tether at the allylic position gave the C2-
halomethyl tetrahydrofurans 4o-Br and 4o-F as a single
diastereomer (Scheme 5B). In this case, the nucleophilic
attack of the ethereal oxygen to the halonium ion IV was
more favorable than the 1,5-hydride shift.9 The observed
diastereoselectivity could be explained by the involvement of
V, a conformer that would be more favorable than VI due to
the presence of the phenyl group at a pseudo equatorial
position.
a
Reaction conditions: 1 (0.5 mmol) under conditions A or B (see
Scheme 2). Isolated yields and diastereomeric ratio of the products
are given.
Scheme 6. Synthesis of Fluoroalcohols 5
Formation of tetrahydrofuran 2 from fluoroalcohol
intermediates VI (Scheme 2) was unexpected, as such
nucleophilic substitution at a nonactivated C(sp3)-F position
has rarely been reported in the literature.10,11 Further
modification of the reaction conditions B led to the
development of an alternative stepwise protocol for the
synthesis of fluoroalcohols as the major products (Scheme 6).
A fluorohydroxylation step was first implemented by treating
alkenes 1 with Selectfluor in the presence of water (5 equiv)
in MeNO2. The solvent system was then switched to 1,2-
dichloroethane (DCE)−trifluoroethanol (4:1), and the
resulting crude mixture was treated with trifluoromethane-
sulfonic acid (TfOH) (10 mol %) at 50 °C for a short period
of time in order to prevent the substitution step. Under these
conditions, fluoroalcohol 5a could be obtained in good yield
with high diastereoselectivity.
a
Reaction conditions: 1a or 1l (0.55 mmol), Selectfluor (0.5 mmol).
b
Isolated yields were measured based on Selectfluor. Reaction
conditions: 1b (0.5 mmol), Selectfluor (0.6 mmol). Isolated yield
was measured based on 1b.
involving a diastereoselective 1,5-hydride shift to a halonium
ion intermediate as the key step. Overall, this transformation
can be regarded as a formal intramolecular anti-Markovnikov
hydroetherification of an aryl alkene, a reactivity scheme that
has been rarely reported in the literature. Further application
In summary, this work demonstrates synthesis of stereo-
chemically defined tetrahydrofurans by a cascade process
C
DOI: 10.1021/acs.orglett.9b03548
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03548.
Experimental procedures, spectral data (PDF)
Accession Codes
CCDC 1956712 and 1956716 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_-
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
(5) Trifluoroethyl ethers III could be isolated under both of the
reaction conditions. See the Supporting Information for details.
(6) For reviews on synthesis of tetrahydrofurans, see: (a) Jalce, G.;
̀
Franck, X.; Figadere, B. Tetrahedron: Asymmetry 2009, 20, 2537.
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AUTHOR INFORMATION
Corresponding Authors
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■
*E-mail: shunsuke@ntu.edu.sg (for S.C.).
*E-mail: fgagosz@uottawa.ca (for F.G.).
ORCID
Fabien Gagosz: 0000-0002-0261-4925
Shunsuke Chiba: 0000-0003-2039-023X
Author Contributions
§B.W. and D.A.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from Nanyang
Technological University (for S.C.), the Singapore Ministry
of Education (Academic Research Fund Tier 1: RG2/18 for
S.C.), the University of Ottawa (for F.G.), and the Natural
Sciences and Engineering Research Council (for F.G.).
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D
DOI: 10.1021/acs.orglett.9b03548
Org. Lett. XXXX, XXX, XXX−XXX