Catalytic Synthesis of Saturated Oxygen Heterocycles by Hydrofunctionalization of Unactivated Olefins: Unprotected and Protected Strategies

Article abstract of DOI:10.1021/jacs.6b05720

A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent is described. This reaction was carried out at ro

Full text of DOI:10.1021/jacs.6b05720

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Article
Catalytic Synthesis of Saturated Oxygen Heterocycles
by Hydrofunctionalization of Unactivated Olefins:
“Unprotected” and “Protected” Strategies
Hiroki Shigehisa, Miki Hayashi, Haruna Ohkawa, Tsuyoshi Suzuki, Hiroki Okayasu, Mayumi Mukai,
Ayaka Yamazaki, Ryohei Kawai, Harue Kikuchi, Yui Satoh, Akane Fukuyama, and Kou Hiroya
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b05720 • Publication Date (Web): 27 Jul 2016
Downloaded from http://pubs.acs.org on July 27, 2016
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Journal of the American Chemical Society
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Catalytic Synthesis of Saturated Oxygen Heterocycles by Hy-
drofunctionalization of Unactivated Olefins: “Unprotected”
and “Protected” Strategies
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Hiroki Shigehisa*, Miki Hayashi, Haruna Ohkawa, Tsuyoshi Suzuki, Hiroki Okayasu, Mayumi Mukai,
Ayaka Yamazaki, Ryohei Kawai, Harue Kikuchi, Yui Satoh, Akane Fukuyama, and Kou Hiroya
Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi Nishitokyo-shi, Tokyo 202-8585, Japan
ABSTRACT: A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unacti-
vated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent is described. This reaction was car-
ried out at room temperature and afforded five- and six-membered oxygen heterocyclic compounds, such as cyclic ethers and lac-
tones. The Co-complex was optimized for previously rare medium-ring formation by hydrofunctionalization of unactivated olefins.
The powerful Co-catalyst system also enables the deprotective hydroalkoxylation of O-protected alkenyl alcohol and hydroacyloxy-
lation of alkenyl ester to afford cyclic ethers and lactones directly. The substrate scope and mechanistic proof of deprotection were
investigated. The experimental evidence supports the concerted transition state of the bond-forming step involving a cationic Co
complex.
1. Introduction
fenbacher reported intramolecular hydroalkoxylation catalyzed
by a self-assembled hexameric capsule affording seven-
membered products; however, the substrate scope is funda-
mentally limited by the encapsulation.4aa Nicewicz reported an
exclusive anti-Markovnikov selective hydroalkoxylation and
an example of oxepane formation.6 Meanwhile, to the best of
our knowledge, the formation of rings of more than seven
members in the hydroacyloxylation of olefins has not been
reported. In contrast, haloetherification7 and halolactoniza-
tion7b,8 have been thoroughly investigated. Although these
approaches have the merit of enabling further manipulation on
the halogen atom, removal of the terminal halogen, if unneces-
sary, entails an additional step.
Saturated oxygen heterocycles, such as cyclic ethers and
lactones, are found in the structures of many biologically ac-
tive natural products.1 Beyond the common five- and six-
membered rings, rings of seven or more members, also called
medium rings, have also been discovered; examples include
polycyclic marine toxins (e.g., ciguatoxin), lauroxanes (e.g.,
laurencin), heliannuols (e.g., helianane), sodwanone S, zoapa-
tanol, aphanamixoids (e.g., aphanamixoid A), and octalactins
(e.g., octalactin A).2 From a drug discovery perspective, there
is still much room for the development of a chemical space
derived from a medium-ring framework.3
In the field of organic synthesis, straightforward methods
for accessing the motif of saturated oxygen heterocycles in-
clude catalytic regioselective intramolecular hydroalkoxyla-
tion and hydroacyloxylation, which refer to the direct coupling
of olefins with hydroxyl groups and carboxyl groups, respec-
tively. Consequently, many research groups have reported
various examples of attractive Markovnikov-selective intra-
molecular hydroalkoxylation4 and hydroacyloxylation4b,4d,4e,5
over the past decade (Scheme 1). For example, some reactions
are based on nucleophilic attack by OH-groups on the metal-
coordinated olefins and protonation of the metal–carbon bond,
as presented by Widenhoefer,4a He,4b and others.4c-f Non-
metallic systems also enable the hydrofunctionalization of
olefins.4g,4i-k Catalytic hydrofunctionalizations starting from O-
nucleophile activation by a metal complex were also reported
by Marks,4l,4m Duñach,4n,4o Hartung,4p and others.4q,4r Despite
the development of these elegant approaches, the examples of
medium-ring formation by hydroalkoxylation are quite limited,
and these scant examples are further limited to the formation
of rings of no more than seven members.4d,4v,4aa Recently, Tie-
Medium-ring formation is often fundamentally troublesome
because of entropic factors (the approach frequency of two
reactive sites), strain of the medium ring, and transannular
interactions in the substrate. Therefore, a powerful and selec-
tive activation of the olefin in the reaction is highly desired for
the development of a general and robust approach based on
both hydroalkoxylation and hydroacyloxylation for medium-
ring formation with good functional group tolerance.
We recently reported an intermolecular hydroalkoxyla-
tion,9 an intramolecular hydroamination,10 and a intramolecu-
lar hydroarylation11 using Co(salen) complex 1, an N-fluoro-
2,4,6-trimethylpyridinium
salt,
and
a
1,1,3,3-
tetramethyldisiloxane [(Me2SiH)2O]. In these reactions, it is
thought that a cationic intermediate enables bond formation
between the olefins and nucleophile (Scheme 1a, b, c). The
reaction demonstrated a broad substrate scope as a result of its
high reactivity and functional group tolerance. In light of these
previous observations and recent relevant examples,12 we en-
visioned that intramolecular C-O bond formation may
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Scheme 1. Our previous reports and this work
Scheme 2. Preliminary result of hydroalkoxylation of ole-
fins and deprotective cyclization9a
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supported the concerted transition state of the bond forming
step involving a cationic Co complx.
2. RESULTS AND DISCUSSION
Synthesis of five- and six-membered cyclic ethers and lac-
tones
First, the scope of alkenyl alcohol was investigated under
the reaction conditions of the intramolecular hydroamination
we previously reported: namely, Co complex 1 (3.0 mol%) in
toluene and in the presence of N-fluoro-2,4,6-
trimethylpyridinium
trifluoromethanesulfonate
(Me3NFPY·OTf, 2.0 equiv.)14 and (Me2SiH)2O (2.0 equiv.)
(Table 1). We found that various five- to six-membered cyclic
ethers were obtained in good-to-excellent yields. Alkenyl al-
cohol 2a was smoothly cyclized to afford tetrahydrofuran 3a
in toluene. Substrates 2b and 2c (containing a bulky hydroxyl
group) and 2d (1,1-disubstituted olefin) were also subjected to
cyclization to afford the desired products 3b, 3c (0% yield in
ref 4i), and 3d, respectively, in excellent yield. 3e and 3f were
obtained from alkenyl alcohol containing the acid-sensitive
acetal group 2e and diol 2f. A steroidal compound 3g was also
synthesized in good yield. Unfortunately, the phenolic hy-
droxyl group was found to be unsuitable for the cyclization,
resulting in a complex product mixture (2h). Concerning the
six-membered rings, tetrahydropyran 3i and isochroman 3j, 3k
could be synthesized. The investigation of the functional
group tolerance of this method revealed that isochromans 3l-
3n were obtained from allyl-benzylalcohol-bearing, fluoro-
anion-sensitive silyl ether (2l), acid-sensitive acetal (2m), and
benzyl ether (2n). Unfortunately, the synthesis of three- or
four-ring compounds was found to be ineffective in our condi-
tions (see Supporting Information).
occur under the identified or modified reaction conditions to
yield both cyclic ethers and lactones with excellent functional
group tolerance (Scheme 1d). Previously, we reported a pre-
liminary result in which cyclization-biased alkenyl alcohol 2a
was used to obtain cyclic ether 3a in excellent yield (Scheme
2).9a Furthermore, TBS-protected alkenyl alcohol 2aa was
directly cyclized to afford the same product 3a. In the multi-
step synthesis of complex molecules, the use of protective
group is often unavoidable because of the functional group
reactivity, solubility, and high polarity of the compound. This
deprotective cyclization approach has the advantage of being
step-economical, allowing the deprotection step to be omitted.
Nevertheless, there are few examples of deprotective cycliza-
tion for simple substrates under harsh conditions; Niggemann
reported only one reaction of benzyl-deprotective hydroalkox-
ylation (dichloromethane, 80°C),4f and Duñach reported the
hydroacyloxylation of alkenyl ester (dichloroethane or nitro-
methane, reflux).13
Herein, we developed a catalytic, mild, and functional
group tolerant intramolecular hydroalkoxylation and hy-
droacyloxylation of unactivated olefins using a Co(salen)
complex 1, an N-fluoro-2,4,6-trimethylpyridinium salt, and
(Me2SiH)2O to produce a various five- and six-membered ring
products. Next, the structure-reactivity relationship of the
salen ligand was studied, identifying the optimum Co(salen)
complex for medium-ring formation (seven- to nine-
membered). It was then found that various cyclic ethers or
lactones were directly obtained from O-protected alkenyl al-
cohol or alkenyl ester, respectively, by the Co-catalyst system
at room temperature. The ultimate co-products of the protec-
tive group were also investigated to clarify the mechanism of
the deprotection step. Finally, the experimental evidences
Encouraged by this result, we also investigated the hy-
droacyloxylation of olefins using a series of alkenyl carboxyl-
icacids under the same reaction conditions (Table 2). To our
delight, five-membered lactones were obtained from the sub-
strate, including cyclization-biased 4a and 1,1-disubstituted
olefins 4b and 4c in excellent yield. Isobenzofuranone 5d was
obtained from benzoic acid derivative 4d. Six-membered
products, such as lactones 5e, 5f; 3-isochromanone 5g; and 1-
isochromanone 5h, were obtained in good yield.
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Table 1. Scope of alkenyl alcohol for hydroalkoxylation of
unactivated olefinsa
30% yield along with considerable amounts of olefin isomers
1
2
3
4
5
6
7
8
and recovered 6a (entry 1), we conducted a systematic screen-
ing of the salen ligand in the Co-complex. We found that de-
creasing the bulkiness of diamine moiety improved the yield
and that the ethylenediamine-containing salen ligand was ef-
fective (entry 2-4). Longer diamines gave worse results (entry
5, 6). Next, we examined the effect of substituents on the aro-
matic rings. It was found that using Co complexes possessing
smaller methyl groups in either the 3 or 5 position (benzalde-
hyde numbering) dramatically decreased the yield of the de-
sired product 7a (entry 7, 8). Given the importance of both of
the substituents on the aromatic ring, a kit of Co complexes
containing substituents of different sizes was investigated (en-
try 9-12). Although further screening of Co complexes was
investigated, we ultimately identified 17 as being optimal (see
Supporting Information). Dilute conditions gave almost the
same result (entry 13).
9
10
11
12
13
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16
17
18
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58
59
60
Table 3. Optimization of reaction condition for medium
ring formation by hydroalkoxylation of unactivated olefins
entry
1
Co cat
1
yield (%)a
30
20
2
8
b
aIsolation yield (0.25 mmol scale, 0.1 M). NMR yield using
3
9
40
4
10
11
12
13
14
15
16
17
18
17
43, (41)b
1,4-bis(trifluoromethyl)benzene as the internal standard.
5
25
Table 2. Scope of alkenyl carboxylic acid for hy-
droacyloxylation of unactivated olefinsa
6
<5
7
<5
8
22
9
8
10
11
12
13d
57
60, (50)c
57
60
aNMR yield using 1,4-bis(trifluoromethyl)benzene as internal
standard (0.25 mmol scale, 0.1 M). bCF3Ph was used cIsolation
yield. dconc = 0.03 M.
aIsolation yield (0.25 mmol scale, 0.1 M).
Synthesis of medium-ring products
We explored the possibility of achieving unprecedented
medium-ring formation by hydrofunctionalization under a Co-
catalyst system. First, we investigated the hydroalkoxylation
of alkenyl alcohol 6a containing monosubstituted olefins (Ta-
ble 3). Because the reaction condition for the synthesis of
common ring sizes using complex 1 gave oxepane 7a in only
Having demonstrated the catalytic activity of complex 17,
we next examined the scope of other substrates (Table 4). In
the case of synthesizing seven-membered rings by hydroal-
koxylation, oxepane 7b and 1,4-dioxepane 7c, 7d were ob-
tained from alkenyl alcohol containing mono- and disubstitut-
ed olefin. Nitrogen-containing 1,4-oxazepine 7e was also syn-
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thesized by this method. In the case of eight-membered ring substrates 2fa-2fe, the yield of the desired product was highest
1
2
3
4
5
6
7
8
formation affording 7f, we reconfirmed the superiority of
complex 17 in terms of yield. Furthermore, this method was
applicable for nine-membered ring formation affording 7g.
Compared to hydroalkoxylation, hydroacyloxylation gave
slightly higher yields of oxepanone 7h (vs 7a), benzodioxo-
canone 7i (vs 7f), and benzodioxonanone 7j (vs 7g). At this
stage, some substrates were identified as being unsuitable even
when using the optimum catalyst 17 because the isomerization
of olefin was unavoidably faster than the cyclization (see Sup-
porting Information). Although the yield of the medium-ring
product was inferior to that of the small-ring product, various
medium-ring products that had not been achieved previously
were obtained by the hydrofunctionalization of olefins.
for the MOM-protected 2fb. Although the phenolic hydroxyl
group was unsuitable for substrate 2h (Table 1), to our delight,
the yield of benzofuran 3h was excellent for any protective
group (2ha-2he). More electron rich substrate 2hb’ was appli-
cable. In the case of six-membered ring formation, the yield of
tetrahydropyran 3i was also quite high when using the MOM
group (2ib) and exceptionally high when using the benzyl
group (2ie). However, isochroman 3j was only obtained in
good yield from the MOM-group-containing substrate 2jb.
Considering the result of 3d as well, it was concluded that the
MOM group is required when using styrene-type substrates.
Indeed, each protective group was effective for the synthesis
of other types of isochroman 3k. We next examined the func-
tional group tolerance using the substrate, and various iso-
chromans were obtained from substrate bearing TBS (2lb),
MOM (2mb), and benzyl groups (2nb). Unfortunately, the
synthesis of medium-ring compounds by deprotective hy-
droalkoxylation was found to be ineffective, even when using
MOM groups. After continued investigation, only the eight-
membered cyclic ether 7f was obtained in 26% yield using
MOM-protected 6fb.
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10
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12
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Table 4. Scope of alkenyl alcohol and alkenyl carboxylic
acid affording medium ring productsa
Table 5. Scope of protective group for hydroalkoxylation
of unactivated olefins
entry
PG
time (h)
0.5
yield (%)a
1
2
3
4
5
6
7
TBS (2aa)
MOM (2ab)
MEM (2ac)
BOM (2ad)
Bn (2ae)
99
99
97
99
93
87
27
0.5
0.5
0.5
1.5
Me (2af)
1.5
Ac (2ag)
6.5
aIsolation yield (0.25 mmol scale, 0.1 M).
Deprotective intramolecular hydroacyloxylation of unacti-
vated olefins
aIsolation yield (0.25 mmol scale, 0.1 M). bCatalyst 1 (3
Furthermore, the method of deprotective cyclization was
found to be applicable to alkenyl esters. The results of the
hydroacyloxylation of alkenyl esters 4aa-4ae are presented
(Table 7). This method was applicable to all protective groups
examined. In particular, the methyl group, being sterically
smallest, gave the highest reactivity. We next investigated the
substrate scope for various methyl esters (Table 8). The five-
membered lactones 5b and 5d were obtained in good yield.
However, 5c was not obtained at all, and instread, the olefin
isomer (tri-substituted olefin) was formed. C−O bond cleavage
of the oxonium cation to afford a stable carbocation interme-
diate might be faster than the deprotection step in the case of
1,1-disubstituted styrene-type substrate. Indeed replacing the
methyl group on olefin moiety of 4ba to phenyl group did not
afford the desired product 5b at all. Six-membered lactones,
such as 5e-5h, were obtained in good to excellent yield. The
desired product was obtained from styrene-type substrates 4ga
(mono-substituted olefin). The functional group tolerance was
also investigated for hydroacyloxylation using alkenyl-ester-
bearing TBS (19aa), MOM (19ba), acetyl (19ca), and hy-
droxyl groups (19da). The eight-membered ring lactone 7i
mol %) was used.
Deprotective intramolecular hydroalkoxylation of unacti-
vated olefins
We next investigated the scope of the protective group us-
ing cyclization-biased alkenyl alcohol 2aa to 2ag by the Co
catalyst system (Table 5). In addition to the TBS group previ-
ously shown to be effective (Scheme 2), acetal (methoxyme-
thyl acetal (MOM), methoxyethoxymethyl acetal (MEM),
benzyloxymethyl acetal (BOM), and benzyl and methyl
groups were found to be applicable. In contrast, the cyclization
of 2ag containing an acetyl group did not occur smoothly.
Encouraged by this result, we next investigated the substrate
scope for three protective groups per substrate (Table 6).
Overall, it was found that MOM was much more effective for
the deprotective cyclization than either TBS or benzyl
groups.15 For example, in the case of five-membered ring for-
mation, tetrahydrofuran 3b and 3d were obtained in acceptable
yield from MOM-protected 2bb16 and 2db, respectively,
whereas the other two protective groups provided the desired
products in low yields, if at all. Among the bis-protected diol
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Table 6. Substrate scope of deprotective hydroalkoxylation of unactivated olefinsa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
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53
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55
56
57
58
59
60
c
d
a0.25 mmol scale, 0.1 M. bNMR yield using 1,4-bis(trifluoromethyl)benzene as the internal standard. Isolation yield. Catalyst 17
(3 mol %) was used.
was also obtained from alkenyl ester 6ia.
Table 7. Scope of protective group for hydroacyloxylation
of unactivated olefins
Reaction mechanism
The mechanistic implications of this deprotective cycliza-
tion merit discussion. First, in the case of the phenolic sub-
strate (2h in Table 1 vs 2ha-2he in Table 6), the yield of de-
sired product 3h was dramatically improved by using a protec-
tive group. Second, the investigation of the functional group
tolerance using substrates 2lb-2nb (Table 6) and 19aa-19ba
(Table 7) shows that the protective groups irrelevant to the
cyclization remained intact under the reaction condition.
Therefore, cyclization should begin with the formation of an
oxonium intermediate, followed by deprotection. The experi-
mental results show that the protective group was trapped by
2,4,6-trimethylpyridine (collidine) to generate the alkylpyri-
dinium salt in the cases of MOM, benzyl, and methyl groups,
entry
PG
time (h)
0.5
1.0
19
yield (%)a
1
2
3
4
5
Me (4aa)
Et (4ab)
Bn (4ac)
PMB (4ad)
tBu (4ae)
99
99
97
99
93
3
19
aIsolation yield (0.25 mmol scale, 0.1 M).
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Table 8. Scope of alkenyl methylester for hydroacyloxylation of unactivated olefinsa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
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36
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40
41
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43
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52
53
54
55
56
57
58
59
60
aIsolation yield (0.25 mmol scale, 0.1 M). bConc = 0.03 M cCatalyst 17 (3 mol %) was used.
Scheme 3. Plausible reaction mechanism
aNMR yield using dimethylsulfone as the internal standard (0.25 mmol scale). bIsolation yield (0.25 mmol scale, 0.1 M).
although the final product for the TBS group is still unclear
(Scheme 3a).
The ligand optimization affected the yield of the desired
product, as shown in Table 3, which sheds additional light on
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(2) Cossy, J. Synthesis of Saturated Oxygenated Heterocycles II:
7-to 16-Membered Rings, Springer, Paris, 2014
(3) Bauer, R. A.; Wenderski, T. A.; Tan, D. S. Nat. Chem. Biol.
2013, 9, 21.
the reaction mechanism. Furthermore, the measurable enanti-
oselectivity was observed when using a chiral Co catalyst 2417
(Scheme 3b, not fully optimized). We propose that the Co
complex could significantly interfere with the transition state
of the C−O bond-forming step.
1
2
3
4
5
6
7
8
9
(4) olefin activation with a metal catalyst: (a) Qian, H.; Han, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536. (b) Yang,
C. G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553. (c)
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Organomet. Chem. 2007, 692, 671. (e) Adrio, L. A.; Quek, L. S.;
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Diba, A.; Begouin, J.-M.; Niggemann, M. Tetrahedron Lett. 2012,
53, 6629. olefin activation with a non-metal catalyst: (g)
Coulombel, L.; Dunach, E. Green Chem. 2004, 6, 499. (h)
Coulombel, L.; Favier, I.; Dunach, E. Chem. Commun. 2005,
2286. (i) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.;
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3822. (k) Sultana, S.; Devi, N. R.; Saikia, A. K. Asian J. Org.
Chem. 2015, 4, 1281. O-nucleophile activation(l) Dzudza, A.;
Marks, T. J. Chem. Eur. J. 2010, 16, 3403. (m) Dzudza, A.; Marks,
T. J. Org. Lett. 2009, 11, 1523. (n) Coulombel, L.; Rajzmann, M.;
Pons, J.-M.; Olivero, S.; Duñach, E. Chem. Eur. J. 2006, 12, 6356.
(o) Coulombel, L.; Weïwer, M.; Duñach, E. Eur. J. Org. Chem.
2009, 2009, 5788. (p) Schuch, D.; Fries, P.; Dönges, M.; Pérez, B.
M.; Hartung, J. J. Am. Chem. Soc. 2009, 131, 12918. (q) Kamiya,
I.; Tsunoyama, H.; Tsukuda, T.; Sakurai, H. Chem. Lett. 2007, 36,
646. (r) Murayama, H.; Nagao, K.; Ohmiya, H.; Sawamura, M.
Org. Lett. 2015, 17, 2039. only one reaction of hydroalkoxylation:
(s) Miller, Y.; Miao, L.; Hosseini, A. S.; Chemler, S. R. J. Am.
Chem. Soc. 2012, 134, 12149. others: (t) Marotta, E.; Foresti, E.;
Marcelli, T.; Peri, F.; Righi, P.; Scardovi, N.; Rosini, G. Org. Lett.
2002, 4, 4451. (u) Komeyama, K.; Morimoto, T.; Nakayama, Y.;
Takaki, K. Tetrahedron Lett. 2007, 48, 3259. (v) Singh, S. A.;
Kabiraj, S.; Khandare, R. P.; Nalawade, S. P.; Upar, K. B.; Bhat,
S. V. Synth. Commun. 2009, 40, 74. (w) Jeong, Y.; Kim, D.-Y.;
Choi, Y.; Ryu, J.-S. Org. Biomol. Chem. 2011, 9, 374. (x)
Schlüter, J.; Blazejak, M.; Hintermann, L. ChemCatChem 2013, 5,
3309. (y) Deka, M. J.; Indukuri, K.; Sultana, S.; Borah, M.; Saikia,
A. K. J. Org. Chem. 2015, 80, 4349. (z) Notar Francesco, I.;
Cacciuttolo, B.; Pucheault, M.; Antoniotti, S. Green Chem. 2015,
17, 837. (aa) Catti, L.; Tiefenbacher, K. Chem. Commun. 2015, 51,
892. (ab) Schlüter, J.; Blazejak, M.; Boeck, F.; Hintermann, L.
Angew. Chem. Int. Ed. 2015, 54, 4014.
A proposed mechanism that is consistent with the experi-
mental data is provided in Scheme 3c. In this mechanism, hy-
drogen atom transfer18 to generate the carbon radical interme-
diate A19 along with the recovery of the Co complex, is plausi-
ble according to Shenvi and Herzon’s insightful
discussions.12f,12g Notably in our mechanism, both single-
electron oxidation of the carbon radical by the cationic Co
species and intramolecular nucleophilic trapping by the oxy-
gen atom could occur simultaneously to generate oxonium
intermediate B via a concerted transition state.20 Finally, the
protective group (or proton in the case of an unprotected sub-
10
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strate) was transferred from intermediate
B to 2,4,6-
trimethylpyridine, with the formation of the desired product
and co-product.
3. Conclusion
We developed Co-catalyzed intramolecular hydroalkoxyla-
tion and hydroacyloxylation to afford five- and six-membered
saturated oxygen heterocycles. The mild reaction condition
realized a broad substrate scope and excellent functional group
tolerance. The use of the optimum catalyst 17 paved the way
for the synthesis of medium rings by the hydrofunctionaliza-
tion of unactivated olefins. It was found that the high reactivi-
ty of this Co catalyst system enabled the deprotective cycliza-
tion of protected alkenyl alcohol and alkenyl ester to directly
afford oxygen heterocycles. The experimental evidence sup-
ported the concerted transition state of the bond-forming step
involving a cationic Co complex. Based on the results of this
study, improving the enantioselectivity is ongoing.
Associated Content
Supporting Information. Experimental procedures and analyti-
cal data (1H and 13C NMR) for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(5) (a) Chaminade, X.; Coulombel, L.; Olivero, S.; Dunach, E.
Eur. J. Org. Chem. 2006, 2006, 3554. (b) Komeyama, K.; Mieno,
Y.; Yukawa, S.; Morimoto, T.; Takaki, K. Chem. Lett. 2007, 36,
752. (c) Goo; Ohlmann, D. M.; Dierker, M. Green Chem. 2010,
12, 197. (d) Sakuma, M.; Sakakura, A.; Ishihara, K. Org. Lett.
2013, 15, 2838. (e) Nagamoto, M.; Nishimura, T. Chem. Commun.
2015, 51, 13466.
(6) (a) Hamilton, D. S.; Nicewicz, D. A. J. Am. Chem. Soc. 2012,
134, 18577. (b) Nicewicz, D.; Hamilton, D. Synlett 2014, 25,
1191.
(7) (a) Brunel, Y.; Rousseau, G. J. Org. Chem. 1996, 61, 5793. (b)
Verma, A.; Jana, S.; Durga Prasad, C.; Yadav, A.; Kumar, S.
Chem. Commun. 2016, 52, 4179.
(8) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y.
J. Am. Chem. Soc. 2012, 134, 16492.
Corresponding Author
*cgehisa@musashino-u.ac.jp.
Funding Sources
This work was supported by JSPS KAKENHI Grant number
26860017, the Uehara memorial Foundation, Takeda Science
Foundation.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Kazuaki Katakawa (Musashino University) for Micro-
wave apparatus. We also thank Nao Shimizu, Natsumi Koseki
(Musashino University) for synthesizing some materials.
(9) (a) Shigehisa, H.; Aoki, T.; Yamaguchi, S.; Shimizu, N.;
Hiroya, K. J. Am. Chem. Soc. 2013, 135, 10306. (b) Shigehisa, H.;
Kikuchi, H.; Hiroya, K. Chem. Pharm. Bull. 2016, 64, 371.
(10) Shigehisa, H.; Koseki, N.; Shimizu, N.; Fujisawa, M.; Niitsu,
M.; Hiroya, K. J. Am. Chem. Soc. 2014, 136, 13534.
REFERENCES
(1) Cossy, J. Synthesis of Saturated Oxygenated Heterocycles I: 5-
and 6-Membered Rings, Springer, Paris, 2014
(11) Shigehisa, H.; Ano, T.; Honma, H.; Ebisawa, K.; Hiroya, K.
Org. Lett. 2016.
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(12) hydration: (a) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989,
1
2
3
4
5
6
7
8
18, 1071. mechanism: (b) Tokuyasu, T.; Kunikawa, S.;
Masuyama, A.; Nojima, M. Org. Lett. 2002, 4, 3595. recent
examples: (c) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J.
Am. Chem. Soc. 2006, 128, 11693. (d) Ishikawa, H.; Colby, D. A.;
Seto, S.; Va, P.; Tam, A.; Kakei, H.; Rayl, T. J.; Hwang, I.; Boger,
D. L. J. Am. Chem. Soc. 2009, 131, 4904. (e) Crossley, S. W. M.;
Barabé, F.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 16788. (f)
Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.;
Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300. (g) King, S. M.;
Ma, X.; Herzon, S. B. J. Am. Chem. Soc. 2014, 136, 6884. (h) Lo,
J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304.
(i) Obradors, C.; Martinez, R. M.; Shenvi, R. A. J. Am. Chem. Soc.
2016, 138, 4962. (j) Shigehisa, H.; Nishi, E.; Fujisawa, M.;
Hiroya, K. Org. Lett. 2013, 15, 5158. (k) Shigehisa, H. Synlett
2015, 26, 2479.
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(13) Cacciuttolo, B.; Poulain-Martini, S.; Duñach, E. Eur. J. Org.
Chem. 2011, 2011, 3710.
(14)
N-fluoro-2,4,6-trimethylpyridinium
trifluoromethanesulfonate was used instead of tetrafluoroborate to
avoid hydrofluorination. See ref 12j.
(15) The desired bond cleavage is hypothesized to not occur from
the posturated oxonium intermediate in the case of TBS and
benzyl groups, whereas C−O bond cleavage is assisted by lone
pair of electrons on the oxygen atom of the MOM group.
(16) Use of NFPY·OTf instead of Me3NFPY·OTf did not improve
the yield of the desired product (45% yield with NFPY·OTf).
(17) Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew.
Chem. Int. Ed. 1995, 34, 2145.
(18) A deuterium experiment was conducted to determine the
source of terminal hydrogen. See ref 9a.
(19) The existence of a carbon radical intermediate was supported
by radical clock and O2 uptake experiments. See ref 9a.
(20) Zhu, R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52,
12655.
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Graphical abstract
159x73mm (300 x 300 DPI)
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Scheme 1
103x156mm (300 x 300 DPI)
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Scheme 2
105x89mm (300 x 300 DPI)
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Table 1
119x154mm (300 x 300 DPI)
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Table 2
121x88mm (300 x 300 DPI)
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Table 3
112x26mm (300 x 300 DPI)
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Table 3
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Table 4
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Table 5
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Table 6
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Table 7
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Table 8
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Scheme 3
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