Direct catalytic anti-markovnikov hydroetherification of alkenols

Article abstract of DOI:10.1021/ja309635w

A direct intramolecular anti-Markovnikov hydroetherification reaction of alkenols is described. By employing catalytic quantities of commercially available 9-mesityl-10-methylacridinium perchlorate and 2-phenylmalononitrile as a redox-cycling source of a

Full text of DOI:10.1021/ja309635w

Communication
pubs.acs.org/JACS
Direct Catalytic Anti-Markovnikov Hydroetherification of Alkenols
David S. Hamilton and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-3290, United States
S
* Supporting Information
Scheme 1. Divergent Regioselectivity in Alkene Addition
Reactions
ABSTRACT: A direct intramolecular anti-Markovnikov
hydroetherification reaction of alkenols is described. By
employing catalytic quantities of commercially available 9-
mesityl-10-methylacridinium perchlorate and 2-phenyl-
malononitrile as a redox-cycling source of a H-atom, we
report the anti-Markovnikov hydroetherification of alkenes
with complete regioselectivity. In addition, we present
results demonstrating that this novel catalytic system can
be applied to the anti-Markovnikov hydrolactonization of
alkenoic acids.
he development of catalytic protocols for the direct
Taddition of heteroatom nucleophiles to alkenes has been
an area of intense study over the past two decades.1 The vast
majority of these methods give rise to primarily Markovnikov-
type addition products. Given the challenges associated with
reversal of innate alkene polarization, there are comparatively
few methods that allow for the direct anti-Markovnikov
addition of nucleophiles to olefins.1,2 Although Hartwig3,4 and
Grubbs5 have demonstrated transition metal catalyst systems
for the anti-Markovnikov addition of amines and water,
respectively, to alkenes, success has been limited to terminal
styrenes. We were drawn to the possibility that single electron
oxidation of olefins to their respective cation radicals could
provide a basis to develop a general catalyst system for a range
of heteroatom nucleophiles with unactivated alkenes.6−9
Herein, we report the direct intramolecular anti-Markovnikov
addition of alcohols to alkenes via a unique two-component
single electron photoredox system. This transformation
provides a reactivity profile that complements traditional
Markovnikov-based Brønsted acid catalyzed reactions (Scheme
1).10,11
Scheme 2. Anti-Markovnikov Reactivity of Cation Radicals
photosensitized anti-Markovnikov alcohol additions are limited
to 1,1-diarylethylenes.17−19
After analysis of this body of literature, we proposed that the
critical step preventing the development of catalytic protocols
was the fate of putative radical intermediate 9. We hypothesized
that using an alternative class of photooxidants might enable a
general approach to this problem. We recognized that good
candidates for a single electron redox catalyst should (i) exhibit
nearly complete redox reversibility, (ii) be capable of oxidizing
alkenes in the range +1.0 to +2.0 V, and (iii) be positively
charged to minimize unproductive back electron transfer to 7
via minimization of Coulombic attraction in the reduced
(neutral) form of the catalyst.
Seminal work from Arnold12 and Gassman13,14 provided the
first evidence for cation radical-mediated anti-Markovnikov
reactivity. Arnold further characterized the initial nucleophile-
cation radical adduct as the three-membered intermediate 8 by
density functional theory calculations.15 It is likely that the
observed anti-Markovnikov selectivity results from the rupture
of the weaker of the two C−X bonds, giving rise to the more
stable radical intermediate 9 (Scheme 2). Additionally,
Gassman and Arnold have each demonstrated that single
electron photooxidants can serve as effective single electron
oxidants to access reactive olefin cation radicals (7). To date,
however, this method remains significantly limited in scope and
requires nearly stoichiometric quantities of the photooxidant
that can often result in oxidant incorporation into the reaction
products as well as undesired side reactivity.16 Truly catalytic
Reports of commercially available 9-mesityl-10-methylacridi-
nium perchlorate (2), first employed by Fukuzumi et al., drew
our attention as a photooxidant for this application.20 Given the
Received: September 28, 2012
Published: October 31, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
acridinium moiety’s strong absorption band in the visible region
(λ = 430 nm), high excited state oxidizing power (E1/2red* =
+2.06 V vs SCE),21 and utility in a number of reported
transformations relying on single electron transfer path-
ways,22,23 we predicted that cation radicals could be
conveniently generated from an electronically diverse range of
ensure exothermic H-atom transfer, we limited our survey of
potential H-atom redox catalysts to moieties possessing R−H
bonds with BDE <90 kcal/mol (Table 1, entries 3−5).25
Though 0.5 equiv of either N-hydroxyphthalimide (BDE = 87
kcal/mol, entry 3) or 9-phenylfluorene (BDE = 74 kcal/mol,
entry 4) gave modest increases in reaction efficiency, we were
pleased to find that 2-phenylmalononitrile (3, BDE = 77 kcal/
mol) furnished anti-Markovnikov adduct 6 in 73% yield (entry
5) with no trace of the undesired Markovnikov regioisomer.
Further control experiments demonstrate that both the
acridinium photocatalyst and light are necessary for reactivity
(entries 6, 7).26 The utility of the acridinium catalyst as a single
alkenes. Additionally, the reduced form of the acridinium
ox
catalyst (11) is a moderate single electron reductant (E1/2
=
−0.57 V vs SCE)21 that we presumed would be capable of
return electron transfer to radical intermediate 12.
As a starting point, we focused on the development of a
catalytic system for the direct intramolecular anti-Markovnikov
hydroetherification of alkenols.2,24 To date, Mizuno has
reported the only known direct anti-Markovnikov hydro-
etherification reaction of alkenols which is believed to proceed
via exciplex formation and is limited to diphenylethylene
alkenes.18 To begin, we subjected alkenol 4 to 5 mol % of
catalyst 2 in degassed 1,2-dichloroethane (DCE) under
irradiation with 450 nm LEDs. The anti-Markovnikov adduct,
tetrahydrofuran 6, was obtained, albeit in low yields (36% yield,
Table 1, entry 1), though significantly higher than when
electron photooxidant is underscored when compared directly
2+
with the frequently employed Ru(bpy)3
,
27 which failed to give
any of the desired product (entry 8). This result demonstrates
the advantage of acridinium catalysts as visible light single
electron photooxidants and should allow for greater latitude in
potential substrates with alkenes possessing oxidation potentials
ranging up to +2.0 V.
Our mechanistic hypothesis outlined in Scheme 3 proposes
that, following H-atom transfer from 3, the resulting radical 13
could serve as an oxidant for radical 11, regenerating the
ground state photooxidation catalyst (2). Following this redox
event, proton transfer would regenerate the H-atom donor (3)
and furnish the desired product.
a
Table 1. Catalyst Optimization Studies
Having identified a viable catalyst system, we investigated the
scope of the intramolecular anti-Markovnikov hydroalkoxyla-
tion of alkenols (Table 2). Electronically distinct styrenes
(entries 1−3) ranging from electron-rich (4-(MeO)C6H4, entry
1; 80% yield) to electron-deficient (4-ClC6H4, entry 2; 60%
yield) provided good yields of the desired 5-exo adducts.
Additionally, Thorpe−Ingold assistance is not required in the
backbone of the molecule, as the substrate in entry 3, which
lacked the geminal dimethyl substituent, gave nearly identical
levels of reaction efficiency (82% yield) as in entry 1 (80%
yield). Furthermore, the mild reaction conditions are high-
lighted in entry 6, where a silyl-protected alcohol remains
unperturbed by the cyclization conditions. A gram-scale
reaction of the alkenol in entry 4 produced the expected
tetrahydrofuran product in 77% isolated yield. Though long
reaction times are required for most substrates, significantly
shorter reaction times are possible by increasing the amount of
3 employed.28
In addition to the formal 5-exo cyclization mode (entries 1−
6), other ring closure types were possible. The alkenol in entry
8 underwent 6-exo cyclization to furnish the anticipated
disubstituted tetrahydropyran adduct in 68% yield and 2.5:1
d.r. Treatment of β-citronellol to the catalyst conditions
resulted in 7-exo cyclization in modest but reproducible yields
(46% yield, 1.2:1 d.r., entry 9). The reactions in entries 8 and 9
required 2.0 equiv of PhCH(CN)2 to avoid longer reaction
times. Given their high oxidation potentials, monosubstituted
alkenes are inaccessible by this catalyst system; however,
expansion of the substrate scope will be a focus of future efforts
through catalyst development.
b
b
b
entry
1
conditions
standard conditions
conversion
yield
6:5
83%
21%
36%
5%
>20:1
>20:1
cd
,
2
3
4
0.2 equiv of 9,10-dicyanoanthracene
instead of 2
ce
,
0.5 equiv of 1-cyanonaphthalene
instead of 2
47%
48%
15%
41%
>20:1
>20:1
with 0.5 equiv of N-
hydroxyphthalimide
5
6
7
8
with 0.5 equiv of 9-phenylfluorene
with 0.5 equiv of PhCH(CN)2 (3)
no photooxidant
78%
89%
<5%
<5%
<5%
51%
73%
<5%
<5%
<5%
>20:1
>20:1
−
f
f
no light
−
−
fg
9 ,
Ru(bpy)3Cl2 instead of 2
a
Reactions irradiated with a 15 W 450 nm LED flood lamp.
Determined by H NMR analysis. Irradiated with 10 × 8 W T5
fluorescent bulbs (output > 290 nm). Benzene as solvent. MeCN as
b
c
1
d
e
f
g
solvent with 0.5 equiv of biphenyl. With 0.5 equiv of 3. With 1.0
equiv of methyl viologen.
employing the cyanoarene photooxidants (entries 2 and 3)
used by Mizuno and Gassman in their pioneering studies. No
trace of the Markovnikov adduct (5) was observed and conversion
of the starting alkenol was relatively high (83%), but yields
were significantly diminished by extensive unidentifiable
byproduct formation that likely arose from competing radical
processes.
After evaluation of a number of known single electron
photooxidants failed to afford synthetically useful yields of the
desired adduct, we felt that a distinctly different approach to
this problem was required. Speculating that the reduction of
radical 9 was still limiting reactivity, we hypothesized that
employing a H-atom donor could facilitate this process while
simultaneously serving as a single electron redox mediator.
Potential H-atom donors were selected on the basis of their
respective homolytic bond dissociation energies (BDE). To
It is particularly noteworthy that all of the reactions in Table
2 furnished the anti-Markovnikov hydroalkoxylation adducts
exclusively. To emphasize the unique regioselectivity of this
process, a direct comparison of alkene reactivity with cation
radicals or Brønsted acids is depicted in eqs 1 and 2. Alkenol 14
is known to undergo Brønsted acid assisted Markovnikov
hydroetherification to furnish tetrahydropyran 15, while
tetrahydrofuran 16 is obtained exclusively using our catalytic
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Journal of the American Chemical Society
Communication
Scheme 3. Proposed Mechanism for the Anti-Markovnikov Hydroetherification of Alkenols
a
Table 2. Scope of the Intramolecular Anti-Markovnikov Hydroetherification Reaction of Alkenols
a
Yields of cyclic ether products averaged from two reactions after 36−196 h. In all cases, the anti-Markovnikov adduct was formed in >20:1
b
−
selectivity. All alkenol oxidation potentials were measured in MeCN with 0.1 M Bu4N+ClO4 and Ag/AgCl as the reference electrode. With 2.0
equiv of PhCH(CN)2. Determined by H NMR analysis of the crude reaction mixture.
c
1
protocol. Perhaps most intriguing was the tetrahydropyran
product obtained in eq 4 from a formal 6-endo cyclization mode
despite the availability of a more kinetically viable 5-exo
pathway. A control experiment where 17 was subjected to triflic
acid furnished Markovnikov adduct 18, further distinguishing
this catalytic protocol from traditional Brønsted acid methods.
Finally, we have preliminary results pertaining to the use of
alcohols and carboxylic acids as nucleophiles (eqs 5and 6).
Intermolecular addition of methanol to anethole (20) provided
anti-Markovnikov adduct 21 exclusively in 81% isolated yield,
further demonstrating the utility of this catalyst system (eq 5).
Finally, treatment of alkenoic acid 22 under the standard
conditions in the presence of 2,6-lutidine resulted in exclusive
anti-Markovnikov hydrolactonization with complete regiose-
lectivity to afford 23 in 72% isolated yield. This reaction
provides a potentially valuable disconnection to access a range
of biologically active γ-butyrolactones.14,29
In summary, we have developed a direct anti-Markovnikov
hydroetherification of alkenols employing a unique two-
component organic photoredox catalyst system. We believe
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) Kotani, H.; Ohkubo, K.; Fukuzumi, S. J. Am. Chem. Soc. 2004,
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AUTHOR INFORMATION
Corresponding Author
nicewicz@unc.edu
Notes
■
(25) Please see the Supporting Information for a more extensive list
The authors declare no competing financial interest.
of the H-atom donors that were evaluated.
(26) The BF4− salt of catalyst 2 can be employed without significant
variation in yields.
ACKNOWLEDGMENTS
■
The authors are grateful to J. Roberts for aid in obtaining the
cyclic voltammograms of the alkenol substrates and C. Price for
the preparation of some of these substrates. The project
described was supported by The University of North Carolina
at Chapel Hill, Award No. R01 GM098340 from the National
Institute of General Medical Sciences and an Eli Lilly New
Faculty Award.
(27) For reviews, see: (a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat.
Chem. 2010, 2, 527. (b) Narayanam, J. M. R.; Stephenson, C. R. J.
Chem. Soc. Rev. 2011, 40, 102.
(28) Please see the Supporting Information for details.
(29) Seitz, M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285.
REFERENCES
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