Access to Diverse Oxygen Heterocycles via Oxidative Rearrangement of Benzylic Tertiary Alcohols

Article abstract of DOI:10.1021/acs.orglett.6b00672

A facile method for the synthesis of challenging medium-sized cyclic ethers has been developed via a novel oxidative rearrangement of benzylic tertiary alcohols. The reaction provides access to cyclic acetals with diverse substitution at both C2 and the a

Full text of DOI:10.1021/acs.orglett.6b00672

Letter
pubs.acs.org/OrgLett
Access to Diverse Oxygen Heterocycles via Oxidative Rearrangement
of Benzylic Tertiary Alcohols
Brandon T. Kelley, Jennifer C. Walters, and Sarah E. Wengryniuk*
Temple University, Department of Chemistry, 1901 North 13th Street, Philadelphia, Pennsylvania 19122, United States
S
* Supporting Information
ABSTRACT: A facile method for the synthesis of challenging medium-sized cyclic ethers has been developed via a novel
oxidative rearrangement of benzylic tertiary alcohols. The reaction provides access to cyclic acetals with diverse substitution at
both C2 and the aromatic ring. The unique reactivity is enabled by poly(cationic) hypervalent iodine reagents and represents the
first synthetic application of this underexplored class of compounds.
currently no methods to directly transform commonly
encountered alcohol substrates into cyclic ethers (Figure 2).
edium-sized cyclic ethers, such as oxepines and
Moxecanes, are commonly encountered structural motifs
in natural products (1−3) (Figure 1). As such, methods for the
synthesis of these diverse scaffolds have prompted a long-
standing pursuit.1−3
Figure 2. Readily available tertiary alcohols would serve as useful
precursors to medium-size oxacycles.
In principle, the ubiquity and relative ease of synthesis make
tertiary alcohols very attractive precursors to much more
challenging medium-sized heterocycles. Such a method could
provide access to an array of structural diversity, including
different ring sizes (by varying n), substitution at C2 (by
varying R′), and remote ring functionality (by varying R).
In developing such a method, we took inspiration from the
Criegee rearrangement of activated alkyl peroxides, wherein the
O−O bond is labilized via reaction with an anhydride,
promoting C-to-O migration (Scheme 1A).12,13 We envisioned
an analogous transformation in the context of simple alcohols
via electrophilic activation with a hypervalent iodine reagent
(Scheme 1B).14−17 Attack of the alcohol on the iodine center
would generate an activated intermediate (4) wherein the
oxygen is now electrophilic. This sets the stage for a carbon-to-
Figure 1. Diverse medium-sized oxacyclic natural products.
Unlike the corresponding furan and pyran derivatives, the
synthesis of medium-sized ethers is problematic due to
unfavorable entropic penalties and transannular interactions
associated with their formation.4,5 Common methods include
ring closing metathesis,6 lactone formation with subsequent
reduction,7 Prins-type cyclizations,8,9 regioselective epoxide
opening,10 and cyclopropane fragmentation.11 While these
approaches have been widely utilized, the discovery of new,
readily available precursors and novel disconnections to access
such valuable ring systems is of continued interest.3 We
approached this problem with the realization that there are
Received: March 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00672
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Organic Letters
Letter
a
Scheme 1. (A) Criegee Rearrangement of Tertiary
Peroxides; (B) Proposed Rearrangement of Tertiary
Alcohols via Activation with Hypervalent Iodine
Table 1. Optimization of Oxidative Rearrangement
entry
conditions
PIDA, CH2Cl2, rt
product (yield)
1
7
2
PIFA, CH2Cl2, rt
12
12
12
12
12
3
PhI(OH)OTs, CH2Cl2, rt
PIFA, K2CO3, EtOAc, rt
4
b
5
PIFA, base, CH2Cl2, rt
6
PhICl2, CH2Cl2, rt
14, CH2Cl2, rt
c
7
13 (33%)
cd
,
8
14, HFIP, 0 °C
11 (55%)
11 (68%)
11 (84%)
oxygen alkyl migration, driven by the loss of iodine in its
normal valency (IAr), and the resultant oxonium ion (5) could
be trapped by a nucleophile to give the functionalized ether
scaffold (6). Hypervalent iodine (HVI) reagents are ideal for
this transformation due to their low cost, low toxicity, ease of
handling, and excellent leaving group ability.18 HVI reagents
have been utilized in numerous electrophilic rearrangements,
including Hoffman rearrangements19,20 and carbocyclic ring
expansions;21 however, there are no reports employing an
alcohol functionality. Their application in the context of
alcohols has primarily been limited to simple oxidations, either
via two- or one-electron processes, to generate the carbonyl or
oxygen-centered radicals, respectively.22,23
Herein, we report the oxidative rearrangement of benzylic
tertiary alcohols, which provides access to a variety of aromatic
fused oxepane and oxecane derivatives, with diverse sub-
stituents at C2 as well as the aromatic ring. The obtained
acetals are readily functionalized using known methods, giving
rise to an array of structural diversity. This unique reactivity is
enabled by (poly)cationic hypervalent iodine reagents and
represents the first systematic report on a synthetic application
of this class of reagents.
e
cd
,
9
14, HFIP, CH2Cl2, −25 °C
e
c
10
14, HFIP, 3 Å MS, CH2Cl2, −25 °C
a
b
Reaction conditions: HVI (1.5 equiv), solvent (0.2 M). Base:
c
d
pyridine, triethylamine, dimethylaminopyridine. Isolated yield. 5−
e
10% ketone 13 observed over several trials. 20 equiv.
an activated peroxide. With this in mind, it was then that we
discovered a report by Weiss from 1994, describing the
electrostatic activation of HVI compounds via the use of
positively charged nitrogen ligands.24 Since this initial report,
these reagents have received very little attention from the
synthetic community.25−27 Recent reports have shown them to
be effective oxidants to access high-valent transition met-
als,28−31 but no attention has been paid to their synthetic utility.
Scheme 2. Screening of Cationic HVI Reagents with Varied
Heterocyclic Nitrogen Ligands
We began our studies with alcohol 7 and screened HVI
reagents with varied electronics about both the aryl iodide and
the ligands (Table 1) (for a full list of reagents screened, see
Supporting Information). We anticipated the formation of the
rearranged acetal wherein the terminal nucleophile (X) would
be derived from the respective iodine ligands or nucleophilic
solvent (8−11) (Table 1). Traditional reagents including
phenyliodine diacetate (PIDA), phenyliodine bis-
(trifluoroacetate) (PIFA), Koser’s reagent, and derivatives
thereof failed to give any of the desired rearranged acetals,
leading instead to elimination (12) or recovered starting
material (Table 1, entires 1−3). In an attempt to suppress
elimination, we then buffered the reaction (Table 1, entries 4−
5); however, this led to only elimination or recovered starting
material.22 Switching from oxygen to chloride ligands with the
use of iodobenzene dichloride (Table 1, entry 6) also failed to
give any desired product, giving only dehydration (12). At this
stage we hypothesized that the alcohol oxygen was not
developing sufficient partial positive charge to promote the
desired alkyl migration. As such we needed to identify HVI
reagents with significantly more electron-deficient iodine
centers, in an effort to more closely mimic the O−O bond of
a
Reactions required warming to rt and 18 h to reach completion.
Starting material decomposition.
b
We began our exploration into these cationic reagents with a
known pyridine derivative24 (14) (Scheme 2), and to our
delight, the desired rearrangement was observed for the first
time, albeit giving the product as open chain ketone 13,
resulting from rearrangement with adventitious water as a
terminal nucleophile and subsequent ring opening (Table 1,
entry 7). It is worth noting that, while formation of 13 is a
result of the desired rearrangement, its formation should be
avoided as the resulting phenol can also undergo competitive
B
DOI: 10.1021/acs.orglett.6b00672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
subsequent oxidation, leading to decreased yields. With this
promising result in hand, a solvent screen revealed that the use
of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at 0 °C gave rise
to the desired cyclic acetal as the HFIP adduct (11) in 55%
yield, through addition of HFIP to the intermediate oxonium
(Table 1, entry 8). The yield of 11 could be improved to 68%
by using 20 equiv of HFIP in CH2Cl2 and lowering the reaction
temperature to −25 °C; however, variable amounts of ketone
were still observed over multiple trials (Table 1, entry 9). The
inclusion of 3 Å MS eliminated any ketone formation, and
finally the addition of 14 in HFIP to a precooled (−25 °C)
solution of substrate in CH2Cl2 gave 11 as the exclusive
product in 84% yield (Table 1, entry 10).
give unsaturated products 23 and 24 are noteworthy as
traditional HVI reagents are known to activate π-bonds via
formation of iodonium intermediates, and in the presence of
tertiary alcohols, electrophilic cyclizations have been re-
ported.33,34 This further highlights the unique reactivity and
chemoselectivity of the (poly)cationic HVI reagents.
We then examined substitution at both the aromatic and
alkyl ring (Scheme 4). In addition to oxepines, the rearrange-
Scheme 4. Substrate Scope with Respect to Substitution at
Both the Alkyl and Aryl Ring
Having established effective conditions for the rearrangement
using pyridine-reagent 14, we wanted to investigate the effect of
altering the nitrogen ligands on the hypervalent iodine (15−
19) (Scheme 2). It was found that tuning of either the
electronic or steric parameters had an effect on the reaction
efficiency; more electron-rich DMAP and N-Me imidazole
reagents 15 and 16 gave comparable yields to 14, but required
prolonged reaction times, whereas o-substituted reagents 18
and 19 led to decreased yields or complete decomposition.
Given these results, we continued with reagent 14 for further
study in this report; however, the ability to modulate the
reactivity of these unique reagents is a key feature that will
likely prove vital to the further development of synthetic
applications.
Scheme 3. Substrate Scope with Varied Substitution at
Tertiary Alcohol
a
Reaction ran at 35 °C for 48 h.
ment was found to be effective for accessing 8-membered
oxecanes, with a benzosuberone-derived substrate reacting
smoothly to give 27. Substitution adjacent to the tertiary
alcohol was well tolerated, giving 28 as exclusively the cis-
diastereomer. Both electron-donating (29 and 30) and
electron-withdrawing (32) aromatic substituents performed
well, although 32 required prolonged heating. Halogens as well
as boronic esters were also compatible (31, 33), providing
valuable functional handles for subsequent derivatization.
Somewhat surprisingly, even an oxidatively labile indole
performed well, giving enol ether 34 in high yield.32
The rearrangement was found to be highly scalable, with a
gram scale reaction producing 11 in 83% yield (Scheme 5A).
Conveniently, the obtained HFIP-derived acetals are amenable
to a variety of subsequent derivatizations (Scheme 5B). Acetal
11 was readily eliminated to give enol ether 35 with exposure to
mild acid and heat, allylated to give 36 with TMS allyl silane
under Bronsted acid catalysis, or substituted upon exposure to
Bronsted acid and various silylated nucleophiles, including
Et3SiH and TMSCN to give 37 and 38, respectively. Notably,
traditional Lewis acid catalysis was not effective for these
transformations, consistently giving selective cleavage of the
endocyclic C−O bond resulting in formation of undesired
ketone 13 with a range of catalysts.
With the optimized conditions in hand, we examined the
scope of the reaction. A variety of substitutions at the tertiary
alcohol were well tolerated, including alkyl (11, 20−22),
unsaturated (23 and 24), and both electron-neutral and
-deficient aryl groups (25 and 26) (Scheme 3). All products
were isolated as their HFIP-acetals, with the exception of 25,
wherein elimination gave the corresponding dihydrooxepin.32
Gratifyingly, benzyl acetal 22 was highly crystalline, allowing us
to confirm the structure of the HFIP-acetal products via X-ray
crystallography (see Supporting Information). The reactions to
In conclusion, we have developed a novel method for the
synthesis of 7- and 8-membered oxygen heterocycles via the
C
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range of substitutions at both the tertiary alcohol and the
aromatic ring, allowing access to products with diverse scaffolds
and functional handles. The resulting acetals are readily
derivatized allowing for further functionalization of the ether
moiety. The reaction is enabled by the unique reactivity of
(poly)cationic hypervalent iodine reagents, and this represents
the first synthetic application of this underexplored class of
reagents. Studies to extend this reaction to other heteroatoms
as well as secondary alcohols are ongoing in our laboratory and
will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00672.
(25) Pirkuliyev, N. S.; Brel', V. K.; Zhdankin, V. V.; Zefirov, N. S.
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Experimental procedures; characterization for all new
compounds (PDF)
Crystallographic data for 18 (CIF)
Crystallographic data for 22 (CIF)
̌
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N.; Battaglia, P.; Togni, A. Tetrahedron 2010, 66, 5753−5761.
(28) Corbo, R.; Pell, T. P.; Stringer, B. D.; Hogan, C. F.; Wilson, D. J.
D.; Barnard, P. J.; Dutton, J. L. J. Am. Chem. Soc. 2014, 136, 12415−
12421.
AUTHOR INFORMATION
Corresponding Author
(29) Corbo, R.; Georgiou, D. C.; Wilson, D. J. D.; Dutton, J. L. Inorg.
Chem. 2014, 53, 1690−1698.
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(30) Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.;
Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T.
Science 2011, 334, 639−642.
*E-mail: sarahw@temple.edu.
Notes
(31) Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 2012, 134,
17456−17458.
The authors declare no competing financial interest.
(32) In the case of products 25 and 34, the preferential formation of
the enol ether can be rationalized by the resulting acetals being much
more prone to ionization to the corresponding oxoniums relative to
the other substrates (benzylic in 25 and more electron-rich in 34),
resulting in subsequent elimination.
ACKNOWLEDGMENTS
■
This research was conducted with the generous financial
support of Temple University. J.C.W. was supported by a
Temple University Future Faculty Fellowship. We would like to
thank Prof. Michael Zdilla and Michael Gau (Temple
University) for their assistance in acquiring X-ray structures.
We would also like to thank Susan Gramlich (Temple
University) for her work on the synthesis of various hypervalent
iodine reagents.
(33) Silva, L. F.; Vasconcelos, R. S.; Nogueira, M. A. Org. Lett. 2008,
10, 1017−1020.
(34) Vasconcelos, R. S.; Silva, L. F.; Giannis, A. J. Org. Chem. 2011,
76, 1499−1502.
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DOI: 10.1021/acs.orglett.6b00672
Org. Lett. XXXX, XXX, XXX−XXX