Hydroalkoxylation of unactivated olefins with carbon radicals and carbocation species as key intermediates

Article abstract of DOI:10.1021/ja405219f

A unique Markovnikov hydroalkoxylation of unactivated olefins with a cobalt complex, silane, and N-fluoropyridinium salt is reported. Further optimization of reaction conditions yielded high functional group tolerance and versatility of alcoholic solvent employed, including methanol, i-propanol, and t-butanol. Use of trifluorotoluene as a solvent made the use of alcohol in stoichiometric amount possible. Mechanistic insight into this novel catalytic system is also discussed. Experimental results suggest that catalysis involves both carbon radical and carbocation intermediates.

Full text of DOI:10.1021/ja405219f

Communication
pubs.acs.org/JACS
Hydroalkoxylation of Unactivated Olefins with Carbon Radicals and
Carbocation Species as Key Intermediates
Hiroki Shigehisa,* Tatsuya Aoki, Sumiko Yamaguchi, Nao Shimizu, and Kou Hiroya*
Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi Nishitokyo-shi, Tokyo 202-8585, Japan
S
* Supporting Information
Scheme 1. Co-Catalyzed Hydroalkoxylation: Mukaiyama,
Carreira, and this work
ABSTRACT: A unique Markovnikov hydroalkoxylation
of unactivated olefins with a cobalt complex, silane, and N-
fluoropyridinium salt is reported. Further optimization of
reaction conditions yielded high functional group tolerance
and versatility of alcoholic solvent employed, including
methanol, i-propanol, and t-butanol. Use of trifluoroto-
luene as a solvent made the use of alcohol in
stoichiometric amount possible. Mechanistic insight into
this novel catalytic system is also discussed. Experimental
results suggest that catalysis involves both carbon radical
and carbocation intermediates.
hydrochlorination,16 and hydrooximation17 using a cobalt salen
catalyst (eq 2, Scheme 1). Inspired by this versatile cobalt
catalyst system, we aimed to develop a hydrofluorination
reaction to afford fluorinated compounds, which are being
intensely investigated because of their high demand in
pharmaceutical and agricultural industries.18 Surprisingly,
when subjecting 4-allyl-1,2-dimethoxybenzene (3a) to a
catalytic amount of catalyst 1 in ethanol in the presence of
phenylsilane and N-fluorobenzenesulfonimide (NFSI, F1)
(Table 1, entry 1), the unexpected hydroalkoxylated product
4ab was obtained in 93% yield. This led us to explore functional
group tolerance of the reaction after condition optimization and
mechanistic studies. Initial examinations of catalyst effects
revealed that the presence of catalyst 1 is required for the
hydroalkoxylation to take place (Table 1, entries 1−4). In the
absence of phenylsilane, desired products were not obtained.
Next, we evaluated a series of various F sources (F2−F6) and
found that, while all of them facilitated the hydroalkoxylation of
3a, reactions conducted with N-fluoro-2,4,6-trimethylpyridi-
nium tetrafluoroborate (F6) provided higher yields than those
conducted with F1, F2 (Selectfluor), F3 (N-fluoropyridinium
triflate), F4 (N-fluoropyridinium tetrafluorobrate), and F5 (N-
fluoro-2,4,6-trimethylpyridinium triflate) (Table 1, entries 1, 5−
10).
arkovnikov hydroalkoxylation of olefinsthe coupling
Mof olefins with alcoholsis a pivotal C−O bond-
forming reaction in organic chemistry.1,2 The conventional
oxymercuration−reduction process is well-known; however, the
stepwise nature of the reaction as well as the need for
stoichiometric amounts of toxic reagents are notable drawbacks
associated with the method.3 Because of this, catalytic
processes, particularly those involving a metal catalyst, have
been sought after for decades.4,5 Previously reported
approaches have relied on nucleophilic attack on a metal-
coordinated olefin and protonation of the metal−carbon bond.6
Recently, aerobic hydroalkoxylations have also been reported
by Sigman,7 Sakurai,8 and Hartung.9 Although various reports
of inter- and intramolecular Markovnikov hydroalkoxylations
exist, there remains considerable room for improvement in
terms of functional group tolerance, which could enable a
methodology ideal for use in the field of complex molecule
synthesis.10 Herein, we report a unique intermolecular
Markovnikov hydroalkoxylation of unactivated olefins using a
cobalt catalyst, a hydrogen source, an electrophilic fluorine
reagent, and an alcoholic solvent. It is important to note that
the cobalt catalytic systems described here show exceptional
functional group tolerance and high reactivities at low
temperatures, encompassing a remarkably wide substrate
scope, including sterically demanding nucleophilic alcohols. In
addition, our hydroalkoxylation method is distinguished from
earlier reports in terms of the proposed reaction mechanism.
In 1989, Mukaiyama and Isayama reported the hydration of
olefins using Co(acac)2, PhSiH3, and molecular oxygen (eq 1,
Scheme 1).11 Since then, this powerful reaction and its
modifications have been applied to complex natural product
synthesis.12 Independent to this, Carreira et al. developed
various functional group tolerant transformations, such as
hydrohydrazination,13,14b hydroazidation,14 hydrocyanation,15
Encouraged by this result, we evaluated a series of different
alcohol solvents, including methanol, i-propanol, and t-butanol
(Scheme 2). This hydroalkoxylation of olefins was amenable to
all solvents examined. Of particular note is the high reactivity of
t-butanol; among the hydroalkoxylations reported in literature,
few examples of t-butanol addition to olefins exist.19,20
Experiments probing the substrate scope of monosubstituted
olefins are summarized in Scheme 3. We found that the
Received: May 24, 2013
Published: July 2, 2013
© 2013 American Chemical Society
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Communication
a
Table 1. Optimization of Reaction Parameters
Scheme 3. Scope and Limitation for Monosubstituted
a
Olefins
entry
Co cat
F source
time (h)
yield (%)
1
2
1
F1
F1
F1
F1
−
F2
F3
F4
F5
F6
0.5
22
22
22
22
22
22
22
22
0.5
93
<5
2
3
Co(acac)2
4
−
1
1
1
1
1
1
0
5
<5
21
45
56
78
96
6
7
8
9
10
a
Procedure (A): 3a (0.56 mmol), Co cat. (1.0 mol %), PhSiH3 (1.0
equiv), F source (1.1 equiv), EtOH (0.17 M), 0 °C, under air, 0.5−22
h.
a
Scheme 2. Solvent Scope
a
Procedure (A): 3a (0.56 mmol), 1 (1.0 mol %), PhSiH3 (1.0 equiv),
b
F6 (1.1 equiv), ROH (0.17 M), 0 °C, under air, 0.5−17 h. Mixed
solvent (t-BuOH:CF3Ph = 3:2) was used.
optimum reaction conditions for 3a were not always ideal for
other substrates owing to differing reactivities and formation of
hydration products (OH instead of OR). Generally, electron-
donating group substituted phenylpropanoids (3a−3e) gave
better results than the other substrates (3f−3bb). Accordingly,
a more versatile reaction protocol using complex 1, F5, or F6
and 1,1,3,3-tetramethyldisiloxane [(Me2SiH)2O] under argon
with subsequent degassing was identified, which was able to
tolerate a wide range of functional groups, and applicable to
substrates including sp2 and sp3 substituted olefins. Notably, F5
was superior to F6 in the addition of t-butanol to long-chain
substrates in particular. However, undesired olefin isomer-
ization resulted in lower yields for most cases of t-butanol
addition. 1-Allyl-4-chlorobenzene gave α-hydroalkoxylated
product in both methanol and t-butanol, which should be
generated via isomerization and hydroalkoxylation. Substrates
3d, 3e, and 3q, which possess a potentially reactive hydroxyl
group under typical hydroalkoxylation conditions, remained
intact in this transformation. No cyclized product was detected
in the formation of 4ea and 4ed. Various hydroalkoxylated
products were obtained in useful yields from terminal olefins
featuring fluoroanion-sensitive silyl ethers (TBS), acid-sensitive
groups (PMB, acetal), esters, amides, bromo, nitro, tosylates,
heterocycles, including sulfur atoms, and amino surrogates.
a
(a) Procedure (A): olefin 3, 1 (1.0 mol %), PhSiH3 (1.0 equiv), F6
(1.1 equiv), MeOH, or mixed solvent (t-BuOH:CF3Ph = 3:2) (0.17
M), 0 °C, under air, 1.5 h for 4da or 4.5 h for 4dd. (b) Procedure (B):
olefin 3, 1 (3.0 mol %), (Me2SiH)2O (2.0 equiv), F6 (2.0 equiv, 4aa−
4ea, 4ad−4ed, 4ga−4ga, or F5 (2.0 equiv, 4hd−4ld), MeOH, or
mixed solvent (t-BuOH:CF3Ph = 3:2) (0.10 M), 0 °C, under Ar, 17 h.
(c) Procedure (C): olefin 3, 1 (5.0 mol %), (Me2SiH)2O (4.0 equiv),
F6 (2.0 equiv, 4fa, 4la−4bba), or F5 (2.0 equiv, 4fd, 4ld−4bbd),
MeOH (0.10 M), 0 °C, under Ar, 17 h. (d) Calculated yield after
purification and Boc protection. (e) 3 equiv of F6
Note that the amino group (3x), which has strongly
coordinative and nucleophilic features, was also tolerated.
The shorter carbon chain substrates with tosyl group were also
examined and show that there is no significant difference
among C6−C11. Geminally disubstituted and trisubstituted
olefins also gave corresponding hydroalkoxylated products
(Scheme 4). Although yield can be further improved, the
sterically challenging t-butanol addition to a trisubstituted sp2
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a
Scheme 4. Hydroalkoxylation of Di- and Trisubstituted
Olefins
Scheme 5. Mechanistic Study
a
a
(a) Procedure (B): olefin, 1 (3.0 mol %), (Me2SiH)2O (2.0 equiv),
F6 (2.0 equiv), MeOH (0.17 M), 0 °C, under Ar, 17 h. (b) Procedure
(C): olefin, 1 (5.0 mol %), (Me2SiH)2O (4.0 equiv), F5 (2.0 equiv),
mixed solvent (t-BuOH:CF3Ph = 3:2) (0.10 M), 0 °C, under Ar, 17 h.
carbon, which leads to bis tert-alkyl ether, was achieved. At this
stage, this method was found to be ineffective for reactions of
alkynes.
We extended to use of stoichiometric amount of alcohol in
an inert solvent. We found that use of trifluorotoluene as a
solvent was essential for obtaining a reasonable yield (Table 2).
Moreover, the conditions using less alcohol 9 than olefin 3a
afforded desired product in high yield (entry 3).
a
(1) Deuterium labeling experiment: Procedure (A): olefin 3a, 1 (1.0
mol %), PhSiH3 or PhSiD3 (1.0 equiv), F6 (1.1 equiv), CH3OH or
CD3OD (0.10 M), 0 °C, under air, 30 min. (2) Radical clock
experiment: Procedure (C): olefin 11, 1 (5.0 mol %), (Me2SiH)2O
(4.0 equiv), F6 (2.0 equiv), MeOH (0.10 M), 0 °C, under Ar, 17 h.
(3) Intramolecular hydroalkoxylation of olefins: Procedure (A): olefin
(13 or 14), 1 (1.0 mol %), PhSiH3 (1.0 equiv), F6 (1.1 equiv), MeOH
(0.10 M), 0 °C, under air, 20 min.
a
Table 2. Stoichiometric Amount of Alcohol
carbocation intermediate were as follows: the hydroxyl group in
compound 13 and TBS ether in compound 14 trapped the
resultant cationic carbons to form the identical cyclic ether 15
(Scheme Scheme 5(2)). Because of the inertness of TBS ethers
in the reaction of 3l (Scheme 3), the driving force for Si−O
bond cleavage was thought to be provided by the proximally
generated carbocation. Thus, the mechanism can be presum-
ably distinguished from previously reported conventional and
aerobic hydroalkoxylation.
A proposed mechanism that is consistent with the
experimental data and literature is provided (Scheme 6).
Initially, the catalytic cycle begins with formation of a Co−
fluoride complex together with a cationic Co complex in the
presence of a pyridinium salt (2,4,6-collidine in the optimized
entry
x
y
10 (%)
b
1
2
3
1
1
2
2
1
1
79
67
c
80
a
Procedure (B): 3a (1 or 2 equiv), 9 (1 or 2 equiv), 1 (3.0 mol %),
(Me2SiH)2O (2.0 equiv), F6 (2.0 equiv), CF3Ph (0.17 M), 0 °C,
under Ar, 17 h. Yield was calculated based on 3a. Yield was
calculated based on 9.
b
c
The mechanistic implications of this olefin hydroalkoxylation
merit discussion. Deuterium-labeling experiments, as shown in
Scheme 5(1), resulted in complete deuterium incorporation at
the terminal position from PhSiD3 and not from CD3OD. This
suggested that protonation of the metal−carbon bond involved
in conventional hydroalkoxylation4,5 is not likely and that there
is similarity with Carreira’s methodology involving the presence
of Co-hydrides and carbon radical intermediates. Furthermore,
given the results of C−O bond formation using alcohol
solvents, this hydroalkoxylation implicated not only a carbon
radical but also a carbocation intermediate. First, to probe
whether a carbon radical intermediate was involved in the
reaction, hydroalkoxylation of 11, a radical clock,21 was
conducted under optimized conditions; product 12 was
obtained in which the cyclopropane ring was cleaved (Scheme
5(2)). Furthermore, it should be noted that hydration products
were obtained without degassing, particularly in the case of
long-chain substrates (e.g., 3l), which would be due to the
incorporation of molecular oxygen into a carbon radical
intermediate, followed by reduction to hydroxyl. These two
observations provided further evidence for a carbon radical
intermediate. Second, experimental observations supporting a
Scheme 6. Proposed Mechanism
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
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S
* Supporting Information
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
cgehisa@musashino-u.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by Musashino
university.
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