Co-Catalyzed Hydroarylation of Unactivated Olefins

Article abstract of DOI:10.1021/acs.orglett.6b01662

A mild, general, scalable, and functional group tolerant intramolecular hydroarylation of unactivated olefins using a Co(salen) complex, a N-fluoropyridinium salt, and a disiloxane reagent was reported. This method, which was carried out at room temperature, afforded six-membered benzocyclic compounds from mono-, 1,1- or trans-1,2-di, and trisubstituted olefins.

Full text of DOI:10.1021/acs.orglett.6b01662

Letter
pubs.acs.org/OrgLett
Co-Catalyzed Hydroarylation of Unactivated Olefins
Hiroki Shigehisa,* Takuya Ano, Hiroshi Honma, Kousuke Ebisawa, and Kou Hiroya
Faculty of Pharmacy, Musashino University, 1-1-20, Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
S
* Supporting Information
ABSTRACT: A mild, general, scalable, and functional group
tolerant intramolecular hydroarylation of unactivated olefins
using a Co(salen) complex, a N-fluoropyridinium salt, and a
disiloxane reagent was reported. This method, which was carried
out at room temperature, afforded six-membered benzocyclic
compounds from mono-, 1,1- or trans-1,2-di, and trisubstituted
olefins.
Scheme 1. Representative Activation Mode of
enzocyclic frameworks are important structural motifs in
Hydroarylation of Olefins and Our Approach
B
biologically active compounds. Among them, α,α-dimethyl
benzocycles are frequently found in the structures of retinoic
acid synthetic analogs, retinoids.1 Whereas all-trans-retinoic
acid (1) shows various biological activities associated with
toxicity and teratogenicity due to its flexible structure,
conformationally restricted retinoids containing an arene ring,
known as arotinoids or heteroarotinoids, have historically been
considered to show improved chemotherapeutic ratios
(efficacy/toxicity) and have the potential to be used as
pharmaceuticals, for example, tamibarotene (2, potential
antineoplastic activity against acute promyelocytic leukemia)2
and tazarotene (3, treatment of acne and psoriasis) (Figure 1).3
Therefore, a robust synthetic tool for the construction of
benzocyclic frameworks is highly desired in medicinal chemistry
and synthetic organic chemistry.
on metal (or Brønsted acid) coordinated olefins, followed by
protonation of the metal−carbon bond, was reported by
Dunach,9 Widenhoefer,10 Sames,11 Tan,12 Weghe,13 and West14
̃
(Scheme 1b). However, there is much room for improvement
in terms of functional group tolerance in these nondirecting
group reactions. Besides, there are good examples of
intermolecular versions of such reactions.15
Figure 1. Benzocyclic compound, retinoid, and heteroarotinoids.
Recently, Shenvi reported radical hydroarylation protocols
using a Co complex (three reactions)16 or a Mn complex (for
the synthesis of arylmenthol)17 in the presence of phenylsilane,
which includes a carbon-radical generated by a hydrogen atom
transfer mechanism (Scheme 1c, above). On the other hand, we
independently reported an olefin activation protocol using a
From a synthetic point of view, intramolecular hydro-
arylation of unactivated olefins is a straightforward method for
constructing benzocyclic frameworks (Scheme 1). Indeed,
many groups have reported this type of reaction using various
catalysts. Attractive chelation-assisted intramolecular hydro-
arylation of olefins was reported by Ellman−Bergman,4 Rovis,5
Cramer,6 Yoshikai,7 and Sahoo,8 which essentially required a
directing group on the substrate (Scheme 1a). An alternative
approach, which involves nucleophilic attack by an arene ring
Received: June 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Co(salen) complex, an N-fluoropyridinium salt, and a
disiloxane reagent to enable intermolecular hydroalkoxylation
and intramolecular hydroamination of unactivated olefins with
a broad substrate scope and excellent functional group
tolerance.18 Mechanistically, a carbocationic intermediate
generated from unactivated olefins via carbon-radical is
speculated. Based on this, we envisioned that cyclization can
be achieved using an alkenyl arene substrate to afford a
benzocyclic framework under identical or modified reaction
conditions via generation of a carbocationic intermediate and
C−C bond formation (Scheme 1c, below). In light of our
previous reports and related examples from other groups,16,17,19
broad functional group tolerance can be expected. Herein, we
report a new method for intramolecular hydroarylation of
unactivated olefins using a Co(salen)complex, an N-fluoropyr-
idinium salt, and a disiloxane reagent. The mild reaction
conditions showed a broad substrate scope, including function-
alized complex molecules.
16% yield, together with trisubstituted olefin isomer 4a′ (53%)
and a hydrated compound (29%) (entry 1). Then, we evaluated
a series of ligands for this reaction (entries 2−4). To our
delight, simply changing the diamine unit increased the yield
dramatically; product 5a was obtained in 83% yield using 1,3-
propanediamine containing Co complex 8, together with a
hydrogenated byproduct (7%). Lower loadings of (Me2SiH)2O
offered no appreciable benefit. Further ligand tuning was
conducted by changing the aromatic substituents. It was found
that only the tert-butyl groups at the 3-position (benzaldehyde
numbering) of the aromatic ring were essential for obtaining a
high yield (entries 5, 6). We evaluated a series of various sized
substituents and identified the tert-butyl group as optimal
(entries 7−10). More results from the catalyst screening are
shown in the Supporting Information. Replacing (Me2SiH)2O
with phenylsilane (PhSiH3) or isopropoxy(phenyl)silane [Ph(i-
PrO)SiH2]19y gave an unsatisfactory result (entries 11, 12). The
reaction in the absence of Me3NFPY·OTf gave the desired
product in low yield (entry 13). Furthermore, the use of 0.1
equiv of (Me2SiH)2O (corresponding to the modified Shenvi’s
radical protocol) also yielded the same result (entry 14), which
clearly indicates the beneficial effect of Me3NFPY·OTf in our
cationic pathway.21
We began our study with the hydroarylation of 4a under the
reaction conditions used for the hydroamination of olefins
previously reported by us (Table 1).18c The reaction of 4a
catalyzed by Co complex 6 (3.0 mol %) in trifluorotoluene in
the presence of N-fluoro-2,4,6-trimethylpyridinium trifluoro-
methanesulfonate (Me3NFPY·OTf, 2.0 equiv)20 and
(Me2SiH)2O (2.0 equiv) afforded the desired chroman 5a in
After establishing the optimal reaction conditions, we
explored the scope of the hydroarylation protocol with various
alkenyl arenes, 4b−4m (Table 2). In most cases, hydrogenated
Table 1. Optimum Reaction Conditions
a
Table 2. Scope of Alkenyl Arene
a
entry
Co cat.
Si−H reagent
yield (%) of 5a (4a′)
1
6
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
(Me2SiH)2O
16 (53)
34 (7)
2
7
b
3
8
83 (9), 76
4
9
0 (0)
5
10
11
12
13
14
15
8
34 (4)
6
82 (0)
7
51 (39)
69 (trace)
43 (20)
32 (15)
31 (29)
34 (10)
28 (14)
32 (21)
8
9
10
11
12
c
PhSiH3
PhSiH2(OiPr)
8
d
13
8
(Me2SiH)2O
d
e
14
8
(Me2SiH)2O
a
Yield was determined by 1H NMR analysis of crude reaction mixture
using 1,4-bis(trifluoromethyl)benzene as an internal standard unless
b
c
d
otherwise noted. Isolated yield. 1.3 equiv was used. Without
Me3NFPY·OTf 0.1 equiv was used.
a
b
e
Isolated yield is shown unless otherwise noted. Yield was
1
determined by H NMR analysis of the crude reaction mixture using
1,4-bis(trifluoromethyl)benzene as an internal standard.
byproducts were observed in small amounts (trace to 10%).
Alkenyl arene 4b lacking an electron donating methoxy group
was hydroarylated to afford volatile chroman 5b in 56% yield.
Surprisingly, this protocol was also effective for electron-
withdrawing groups on the aromatic ring, albeit with a lower
yield than that obtained with electron-donating groups (5c−
5e). This tendency is consistent with the inclusion of a
carbocationic intermediate generated from the olefin moiety.
B
DOI: 10.1021/acs.orglett.6b01662
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Organic Letters
Letter
The desired tetralin (5f) and tetrahydroquinoline (5g) were
also obtained by replacing the oxygen atom with methylene or
tosyl amide on the tether unit. Notably, a wide range of
functional groups was tolerated; for example, sulfide-containing
thiochroman (5h) was successfully isolated in acceptable yield
together with a complex product mixture. Moreover, various
chromans were produced from alkenyl arenes bearing an acid-
sensitive acetal (5i), a fluoroanion-sensitive silyl ether group
(5j), and a benzyl group (5k). Vanillin-derived chromans
bearing an acid-sensitive p-methoxybenzyl group (5l) and base-
sensitive acetyl group (5m) were also isolated in acceptable
yields together with complex product mixtures. At this stage,
the method was found to be extremely effective for six-
membered ring cyclization (see Supporting Information).
Encouraged by these results, we attempted the synthesis of
more complex molecules using this reaction (Scheme 2). As
% of catalyst 8; this attempt also afforded 5p without any
problem. Hydroarylation of estrone-derived 4p was examined,
however, catalyst 8 gave hydroarylated products 5p and 5p′,
together with a complex product mixture. To our delight, we
found that catalyst 12 afforded 5p and its isomer 5p′ with a
minimal amount of byproducts by catalyst rescreening (entries
1−5). Acceptable conversion was achieved by increasing the
catalyst loading to give slightly improved yields of 5p and 5p′
(entry 6). The scalability of this reaction was reexamined using
1 g of 4p, and 5p and 5p′ were successfully obtained in
acceptable yields (entry 7).
Next, the scope of the olefin moiety was investigated using
alkenyl arenes 16a−16c/4a′, and we found that the optimal
catalyst should be selected depending on the olefin substitution
pattern (Table 3). In contrast to 1,1-disubstituted olefins,
Table 3. Scope of Olefin Moiety
Scheme 2. Application to Complex Molecule Synthesis
a
b
c
Isolated yield is shown. Reaction time was 1.0 h. Without
Me3NFPY·OTf.
catalyst 6 was found to be superior to catalyst 8 in the case of
monosubstituted olefin 16a. No 16a was obtained without
using Me3NFPY·OTf; the radical pathway is not involved in the
case of monosubstituted olefin. Less nucleophilic arene 16b
could also be used to give tetralin 17b. The superiority of
catalyst 6 for 1,2-trans-disubstituted olefin 16c was quite
noticeable; catalyst 6 gave desired product 17c in excellent
yield, in contrast with catalyst 8 which produced no desired
product.22 Trisubstituted olefin 4a′ was found to be applicable
to this method using catalyst 8 to obtain compound 5a in 76%
yield, which is comparable to the result shown in Table 1, entry
3. Therefore, there might be two reaction pathways leading to
5a: direct conversion from 4a to 5a and/or via 4a′.
a
b
Isolated yield is shown. Purity of commercially available natural
capsaicin is 60% containing the inseparable dihydro form of the olefin.
As such, 5n is also a mixture of 5n and the dihydro product (1:1).
c
d
Determined by chiral phase HPLC analysis. 6 mol % catalyst 8 was
e
f
used. 4p′ is the trisubstituted olefin isomer of 4p. 0.25 mmol. Yield
1
was determined by H NMR analysis of the crude reaction mixture
g
using 1,4-bis(trifluoromethyl)benzene as an internal standard. 1 g of
In summary, we developed the Co-catalyzed intramolecular
hydroarylation of unactivated olefins using a Co(salen)
complex, Me3NFPY·OTf, and (Me2SiH)2O. Screening of the
salen ligand led to the discovery of effective Co complex 8,
enabling efficient synthesis of α,α-dimethyl benzocycles from
1,1-disubstituted olefins. The mild, general, scalable, and
functional group tolerant reaction could be applied to the
synthesis of various molecules, including unnatural amino acid
and estrone derivatives. Based on the result of the control
4p was used.
expected, capsaicin-derived 5n was obtained from 4n, with both
1,2-disubstituted olefin and amide tolerated. We also
successfully synthesized artificial amino acid derivative 5o
from L-tyrosine-derived compound 4o without significant
racemization, together with a hydrogenated dihydro-product
(13%). The scalability was examined using 1 g of 4p and 6 mol
C
DOI: 10.1021/acs.orglett.6b01662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* 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.6b01662.
Experimental procedures and analytical data (1H and 13
NMR) for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cgehisa@musashino-u.ac.jp.
Notes
́ ́
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Natsumi Koseki, Mayu Fujisawa, and Ryohei Kawai
(Musashino university) for synthesizing some materials. This
work was supported by JSPS KAKENHI (Grant Number
26860017), the Uehara Memorial Foundation, and the Takeda
Science Foundation.
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