Difluoro-λ3-bromane-induced oxidative carbon-carbon bond-forming reactions: Ethanol as an electrophilic partner and alkynes as nucleophiles

Article abstract of DOI:10.1021/ja801097c

Reported here for the first time are the oxidative couplings of alkynes and primary alcohols yielding conjugated enones. Although the BF₃-catalyzed reaction of terminal alkynes with p-trifluoromethylphenyl(difluoro)-λ³-bromane results in the fluoro-λ³-bromanation of triple bonds to afford (E)-β-fluorovinyl-λ³-bromanes, reaction of an alkyne with the difluoro-λ³-bromane in the presence of an alcohol and BF₃-Et₂O affords directly conjugated enones in good yields. The reaction proceeds in a highly stereo- and regioselective manner under metal-free conditions. Interestingly, no formation of enones was detected, when difluoro-λ3-iodane p-CF₃C₆H₄IF₂ was used instead of the λ³-bromane. A mechanism involving a λ³-bromane-induced oxidation of an alcohol to an aldehyde, [2 + 2] cyclization with alkynes yielding 2H-oxetes, and finally the electrocyclic ring opening is discussed. Copyright

Full text of DOI:10.1021/ja801097c

Published on Web 02/28/2008
Difluoro-λ3-Bromane-Induced Oxidative Carbon-Carbon Bond-Forming
Reactions: Ethanol as an Electrophilic Partner and Alkynes as Nucleophiles
Masahito Ochiai,* Akira Yoshimura, Takeshi Mori, Yoshio Nishi, and Masaya Hirobe
Graduate School of Pharmaceutical Sciences, UniVersity of Tokushima, 1-78 Shomachi, Tokushima 770-8505, Japan
Received December 27, 2007; E-mail: mochiai@ph.tokushima-u.ac.jp
Scheme 1
To increase the complexity of a simple organic molecule using
efficient, selective, and high-yielding methods under metal-free
conditions is one of the paramount challenges in modern organic
synthesis.1 Development of oxidative carbon-carbon bond-forming
reactions of alcohols with alkynes yielding R,â-unsaturated ketones
with defined stereochemistry is an interesting example of achieving
this goal but has never been reported. We report herein the first
Table 1. λ3-Bromane-Induced Oxidative Coupling of Alcohols and
Alkynes 1a
example for one-pot synthesis of conjugated enones 3 via oxidative
coupling of alkynes 1 and primary alcohols using p-trifluorometh-
ylphenyl(difluoro)-λ3-bromane (2)2 under transition-metal-free con-
ditions, in which very high levels of stereo- and regiocontrol were
attained (Scheme 1).
alkyne 1
entry
R1
R2
RCH2OH (R)
3 yield (%)b
1
2
n-C6H13
n-C8H17
n-C8H17
Me2CH(CH2)2
c-C6H11
Ph(CH2)2
Cl(CH2)4
Cl(CH2)9
Br(CH2)4
MeO(CH2)9
AcO(CH2)9
PhCO2(CH2)9
4-CF3C6H4CO2(CH2)9
3,5-(CF3)2C6H3CO2(CH2)9
MeO2C(CH2)8
3,5-(CF3)2C6H3O2C(CH2)8
4-MeOC6H4
4-MeC6H4
Ph
4-CF3C6H4
n-C7H15
Ph
Ph
n-C8H17
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a 76
3b 77
3b 0
3c 60
3d 55
3e 59
3f 50
3g 79
3h 60
3i 34
Recently, we reported the stereoselective synthesis and charac-
terization of (E)-â-fluorovinyl-λ3-bromanes.3 The reaction involves
BF3-catalyzed fluoro-λ3-bromanation of terminal alkynes with
difluoro-λ3-bromane 2 and proceeds in a Markovnikov fashion
yielding (E)-â-fluorovinyl-λ3-bromanes stereoselectively. Use of an
alcohol as an additive in the reaction, however, dramatically
changed the reaction course: for instance, reaction of 1-decyne (1b)
with difluorobromane 2 in the presence of EtOH (2-4 equiv) and
BF3-Et2O in dichloromethane afforded trans-2-dodecen-4-one (3b),
instead of the â-fluoro-1-decenylbromane, in moderate yields (22-
48%). After extensive studies on reaction conditions, we found an
efficient procedure for the oxidative carbon-carbon bond forming
reaction, which involves initial exposure of EtOH (5 equiv) to
difluorobromane 2 (3 equiv) in the presence of BF3-Et2O (2 equiv)
at -30 °C for 30 min, followed by the addition of 1b. The reaction
(at -30 °C for 24 h) afforded a 77% yield of the trans-enone 3b
stereoselectively with no evidence for formation of the Z-isomer
(Table 1, entry 2). Use of chloroform or 1,2-dichloroethane gave
comparable results, while more polar solvents (MeCN, AcOEt,
Et2O, DME, etc.) afforded low yields (less than 15%) of 3b. It
should be noted that no formation of the enone 3b was detected,
when difluoro-λ3-iodane p-CF3C6H4IF2 was used instead of bromane
2, and a large amount of 1b was recovered unchanged (entry 3).
A wide range of terminal alkynes efficiently undergo the λ3-
bromane-mediated oxidative coupling with ethanol under metal-
free conditions and afforded moderate to good yields of trans-
enones 3a-s in a exclusively stereo- and regioselective manner:
no formation of the regioisomeric enals was detected. Yields of
the conjugated enones 3j-m gradually increase with the increasing
electron-withdrawing nature of the terminal acyloxy groups of 10-
undecynyl esters (entries 11-14), while in the reaction with
phenylacetylenes the presence of more electron-donating para
substituents increase the reaction efficiency (entries 17-20). To
our delight, the coupling reactions of internal alkynes such as
2-decyne and 1-phenyl-1-propyne were found to be exclusively
regioselective: thus, an ethylidene group derived from EtOH
combined with the acetylenic carbon atom attached to a methyl
group, while an oxo group attached to the other acetylenic carbon,
yielding (E)-enones 3t and 3u stereoselectively (entries 21, 22).
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Ph
H
H
3c
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3j 48
3k 61
3l 64
3m 67
3n 44
3o 51
3p 78
3q 62
3r 41
3s 23
3t 54
3u 84
3v 65d
3w 39
3x 61e
n-C8H17
4-NO2C6H4
a Conditions: an alcohol (5 equiv)/difluorobromane 2 (3 equiv)/BF3-
Et2O (2 equiv)/Ar. b Isolated yields. c Difluoroiodane (p-CF3C6H4IF2),
instead of 2, was used. d E/Z ratio ) 96:4. e E/Z ratio ) 98:2.
A possible reaction mechanism shown in Scheme 2 involves an
initial λ3-bromane-induced oxidation of EtOH to acetaldehyde,
which probably proceeds via (1) activation of λ3-bromane 2 by the
coordination of BF3 that increases the polarization of the hypervalent
F-Br-F bonding, (2) formation of the tetracoordinated species 4,
(3) generation of the alkoxy-λ3-bromane 5 via ligand exchange on
Br(III), and (4) reductive â-elimination of a λ3-bromanyl group with
a very high leaving group ability, producing acetaldehyde. [2 + 2]
Cyclization of the aldehyde with alkynes, probably accelerated by
HBF4 generated in situ, would result in the regioselective formation
of 2H-oxete 6, because of steric factors, and finally the concerted
electrocyclic conrotatory ring opening will afford the conjugated
enones 3 selectively.
This mechanism expects that the terminal ethylidene group in
3b originates from ethanol, while the R-vinylic hydrogen comes
9
3742
J. AM. CHEM. SOC. 2008, 130, 3742-3743
10.1021/ja801097c CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Scheme 5
Scheme 6
Scheme 3
2-propanol and benzyl alcohol. Although 2-propanol is readily
oxidized to acetone (70% yield) by difluorobromane 2 under the
conditions, the subsequent [2 + 2] cyclization with 1b does not
take place, probably because of the increased steric demands of
acetone. In the reaction of benzyl alcohol with 2, oxidation to
benzaldehyde competes with the more facile oxidative 1,2-phenyl
rearrangement that produces fluoromethyl phenyl ether 7 (Scheme
6).9 Decreased migratory aptitude of the p-nitrophenyl group favors
oxidation of p-nitrobenzyl alcohol to the aldehyde, which, in turn,
results in formation of the coupling product 3x.
In summary, the difluoro-λ3-bromane-induced oxidative coupling
of alcohols with alkynes was shown to directly afford the construc-
tion of conjugated enones. The reaction is highly stereo- and
regioselective and avoids the use of transition metal catalysts.
Scheme 4
Supporting Information Available: Experimental details and
Figures S1. This material is available free of charge via the Internet at
http://pubs.acs.org.
from 1-decyne, which is compatible with the results obtained in
the deuterium labeling experiments shown in Scheme 3.
References
(1) Guillena, G.; Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46,
2358.
Oxidation of EtOH to acetaldehyde with difluorobromane 2 does
take place at -30 °C in the presence of BF3-Et2O, but in moderate
yield (40%), probably because of the competing oxidative dimer-
ization with formation of ethyl acetate (Scheme 4, Figure S1).
Therefore, use of excess amounts of ethanol and bromane 2 is
required for oxidative coupling with alkynes. Interestingly, the
oxidation of EtOH also occurs even without using BF3-Et2O, when
the reaction was carried out at room temperature (Figure S1). In
marked contrast, difluoro-λ3-iodane p-CF3C6H4IF2 showed no
evidence for the formation of acetaldehyde and recovered the
alcohol unchanged under the BF3-catalyzed conditions, which is
in good agreement with the result shown in Table 1, entry 3.4
Lewis acid catalyzed5 or photochemical condensations6 of
carbonyl compounds with alkynes, producing R,â-unsaturated
ketones, are well documented.7 Intermediacy of a highly labile 2H-
oxete has been firmly established by the isolation in a low-
temperature reaction of hexafluoroacetone with ethoxyacetylene.8
We found that the condensation of 1-decyne (1b) with acetaldehyde
in dichloromethane at -30 °C is catalyzed by Brφnsted acid HBF4-
Et2O yielding the enone 3b, probably via the intermediate formation
of 2H-oxete (Scheme 5). In contrast, Lewis acid BF3-Et2O was
found to be less effective for the condensation.
(2) (a) Frohn, H. J.; Giesen, M. J. Fluorine Chem. 1998, 89, 59. (b) Ochiai,
M.; Nishi, Y.; Goto, S.; Shiro, M.; Frohn, H. J. J. Am. Chem. Soc. 2003,
125, 15304.
(3) Ochiai, M.; Nishi, Y.; Mori, T.; Tada, N.; Suefuji, T.; Frohn, H. J. J. Am.
Chem. Soc. 2005, 127, 10460.
(4) This is probably due to a greater oxidizing ability of difluorobromane 2
compared to that of p-CF3C6H4IF2. In fact, the ionization potential of PhBr
(8.98 eV) is larger than that of PhI (8.69 eV). See: CRC Handbook of
Chemistry and Physics; Lide, D. R., Ed.; CRC: Boca Raton, FL, 1992.
(5) (a) Hayashi, A.; Yamaguchi, M.; Hirama, M. Synlett 1995, 195. (b)
Vieregge, H.; Schmidt, H. M.; Renema, J.; Bos, H. J. T.; Arens, J. F.
Recl. TraV. Chim. Pays-Bas 1966, 85, 929. (c) Fuks, R.; Viehe, H. G.
Chem. Ber. 1970, 103, 564. (d) Rhee, J. U.; Krische, M. J. Org. Lett.
2005, 7, 2493. (e) Viswanathan, G. S.; Li, C.-J. Tetrahedron Lett. 2002,
43, 1613.
(6) (a) Buchi, G.; Kofron, J. T.; Koller, E.; Rosenthal, D. J. Am. Chem. Soc.
1956, 78, 876. (b) Miyamoto, T.; Shigemitsu, Y.; Odaira, Y. Chem.
Commun. 1969, 1410.
(7) For intramolecular versions of alkyne-carbonyl coupling to form conju-
gated enones, see: (a) Harding, C. E.; Stanford, G. R. J. Org. Chem.
1989, 54, 3054. (b) Wempe, M. F.; Grunwell, J. R. J. Org. Chem. 1995,
60, 2714. (c) Balf, R. J.; Rao, B.; Weiler, L. Can. J. Chem. 1971, 49,
3135. (d) Sisko, J.; Balog, A.; Curran, D. P. J. Org. Chem. 1992, 57,
4341. (e) Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8,
231.
(8) (a) Middleton, W. J. J. Org. Chem. 1965, 30, 1307. (b) Bosch, G.; Bos,
H. J. T.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1966, 85, 567. (c)
Friedrich, L. E.; Bower, J. D. J. Am. Chem. Soc. 1973, 95, 6869. (d)
Baukov, Yu. I.; Zaitseva, G. S.; Livantsova, L. I.; Bekker, R. A.;
Savostyanova, I. A.; Oleneva, G. I.; Lutsenko, I. F. Zh. Obsh. Khim. 1981,
51, 1304. (e) Martino, P. C.; Shevlin, P. B. J. Am. Chem. Soc. 1980, 102,
5430.
Use of 1-propanol and p-nitrobenzyl alcohol in the oxidative
coupling with 1b afforded selectively the conjugated enones 3w
and 3x in moderate to good yields (entries 24, 25); however, no
formation of enones 3 was observed in the attempted reaction using
(9) For oxidation of benzyl alcohols to fluoromethyl aryl ethers with XeF2,
see: Stavber, S.; Zupan, M. Tetrahedron Lett. 1993, 34, 4355.
JA801097C
9
J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008 3743