Thermal retro-aldol reaction using fluorous ether F-626 as a reaction medium

Article abstract of DOI:10.1055/s-0030-1258501

A high-boiling, fluorous-organic hybrid ether, F-626, was tested for use in thermal retro-aldol reactions and found to be an excellent reaction medium in view of the ease of separation from the product by fluorous/organic biphasic treatment. The recovered F-626 can be readily reused for subsequent runs.

Full text of DOI:10.1055/s-0030-1258501

LETTER
2193
Thermal Retro-Aldol Reaction Using Fluorous Ether F-626 as a Reaction
Medium
R
etro-Aldol Re
a
action Usin
k
g
F-626 ahide Fukuyama, Takuji Kawamoto, Takahiro Okamura, Aurelien Denichoux, Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549695; E-mail: ryu@c.s.osakafu-u.ac.jp
Received 24 May 2010
Abstract: A high-boiling, fluorous–organic hybrid ether, F-626,
was tested for use in thermal retro-aldol reactions and found to be
C6F13
O
an excellent reaction medium in view of the ease of separation from
the product by fluorous/organic biphasic treatment. The recovered
F-626 can be readily reused for subsequent runs.
bp 214 °C, d 1.354
Figure 1 F-626 (1H,1H,2H,2H-perfluorooctyl 1,3-dimethylbutyl
ether)
Key words: retro-aldol reaction, fluorous ether, F-626, biphasic
system
a by-product through dehydration, in 47% total yield (en-
try 1). The use of the ionic liquid [bmim]NTf2 as a solvent
under similar conditions gave an even worse result: a
50:50 mixture of 2a and 3a (entry 2). We found that F-626
worked quite well for the thermal retro-aldol reaction.
Whereas the fluorous ether solvent, F-626, does not dis-
solve 1a at room temperature, upon heating, one layer re-
sulted (Figure 2). After cooling, biphasic workup using
acetonitrile and FC-72 (perfluorohexanes), followed by
purification using silica gel chromatography, gave a 98%
combined yield of 2a and 3a in a ratio of 95:5 (entry 3).
For this retro-aldol reaction, heating to 200 °C is critical,
since lowering the temperature to 180 °C resulted in a
sluggish reaction (entry 4).
The emergence of new solvents in synthesis has stimulat-
ed renewed interest in traditional organic synthesis nor-
mally based on conventional organic solvents.1,2 We are
interested in the use of F-626 (Figure 1), which is a fluo-
rous–organic hybrid ether that was originally developed
by Kao Corporation,3 as a solvent for green organic syn-
thesis.4 The unique characteristics of F-626 include its
good potential use as a substitute for organic solvents, and
its thermomorphic nature when treated with organic sub-
strates and reagents.5 Despite its relatively high boiling
point (214 °C/760 mmHg), F-626 is nevertheless easily
recoverable by fluorous/organic biphasic treatment. We
previously reported on the use of F-626 as a solvent in a
variety of synthetic reactions, such as the Vilsmeyer
formylation reaction,4a the Wolff–Kishner reduction,4a the
Diels–Alder reaction,4a fluorous tin hydride based radical
reactions,4a and the Mizoroki–Heck reaction.4b
The thermal retro-aldol reaction is a well-known reaction
that is thought to proceed through a concerted mecha-
nism.6,7 The retro-aldol products can be used as useful
synthetic intermediates to prepare analogues of natural
products or for structure confirmation.7 Typically, the re-
action is carried out in a sealed tube because the use of
high-boiling organic solvents often requires cumbersome
procedures to separate them from the products. In this
work, we report that F-626 is an excellent reaction medi-
um for thermal retro-aldol reactions that is easily separa-
ble from the products.
Figure 2 Pictures of the retro-aldol reaction using F-626. (A) Befo-
re heating. 1a is floating on F-626; (B) One layer upon heating at
200 °C for 10 min; (C) After the reaction.
We then examined the thermal retro-aldol reaction of sev-
eral aldol compounds using F-626 as reaction medium.
The results are summarized in Table 2. With the exception
of p-hydroxyl-substituted phenone derivative 1d, retro-
aldol products were obtained with high selectivity in pref-
erence to the dehydration products. In the case of 1d, the
acidic proton arising from the phenol portion, may cata-
lyze the dehydration reaction (entry 5); consistent with
this rationale, the corresponding p-methoxy substrate 1e
gave the retro-aldol product 2e with high selectivity (entry
6). Aldol substrate 1f, having a secondary alcohol moiety,
underwent the retro-aldol reaction in a shorter reaction
time (entry 7). Aliphatic a-hydroxymethyl ketone also
worked well to give a good yield of ketone 2g (entry 8).
We examined the thermally induced retro-aldol reaction
using 2-hydroxymethyl-1-phenyl-1-hexanone (1a) as a
model compound. The results are summarized in Table 1.
Heating 1a at 200 °C for four hours without solvent gave
a 75:25 mixture of the desired product 1-phenyl-1-hex-
anone (2a) and 2-methylene ketone 3a, which is formed as
SYNLETT 2010, No. 14, pp 2193–2196
x
x
.x
x
.2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258501; Art ID: U04110ST
© Georg Thieme Verlag Stuttgart · New York

2194
T. Fukuyama et al.
LETTER
Table 1 Thermal Retro-Aldol Reaction and Reaction Mediaa
O
O
O
∆
OH
+
1a
2a
3a
Temp (°C)
200
Entry
Solvent
neat
Yield (%)b
2a/3a ratioc
75:25
1
2
3
4
47
[bmim]NTf2 (0.5 mL)
F-626 (4 mL)
200
65d
98
50:50
200
95:5
F-626 (4 mL)
180
36d
89:11
a Reaction was carried out on 0.5 mmol scale for 4 h.
b Isolated yields after silica gel chromatography.
c Determined by 1H NMR analysis of the crude reaction mixture.
d NMR yield.
The workup procedure4a is outlined in Scheme 1.8 Thus,
treatment of 1a with F-626 at room temperature gave two
layers that became homogeneous upon heating. After
cooling, the product 2a was extracted into acetonitrile (4
mL) and the resulting acetonitrile layer was separated and
washed with FC-72 (2 mL) to extract the remaining F-
626. The FC-72 solution was combined with the separated
F-626. After evaporation, 98% of F-626 was recovered
that was essentially clean as judged by NMR analysis; re-
covered F-626 could be used for subsequent experiments
without reducing the yield of 2a (Table 2, entry 2).
O
RuHCl(CO)(PPh3)3
OH
(5 mol%)
OH
C6H6, 80 °C, 10 h
O
O
1) evaporation
+
2) F-626
200 °C, 4 h
2g
3g
59% (96:4)
1a
O
O
OH
+
RuHCl(CO)(PPh3)3
(5 mol%)
F-626
(4 mL)
OH
H
PhCHO (10 mol%)
C6H6, 80 °C, 4 h
200 °C
O
O
1) evaporation
FC-72
(2 mL)
MeCN
(4 mL)
+
2a
MeCN
2a
MeCN
SiO2
2) F-626
200 °C, 4 h
2a
F-626
FC-72
2a
3a
F-626
54% (91:9)
homogeneous
F-626
Scheme 2 One-pot protocol for the synthesis of ketones by RuH-
catalyzed coupling reaction and subsequent retro-aldol reaction using
F-626
98% recovery
Scheme 1 Separation and solvent recycling
In summary, thermal retro-aldol reactions can be success-
fully carried out using the high-boiling fluorous–organic
hybrid solvent, F-626, as a reaction medium in which both
separation of the product and recycling of the solvent are
easy to carry out. The procedure was successfully com-
bined with RuH-catalyzed coupling reactions to give al-
dol-type products in a one-pot procedure that can be used
for the synthesis of ketones.
We previously reported on a ruthenium hydride-catalyzed
reaction that gave a-hydroxymethyl ketones as principal
products.9,10,11 The combined procedures – the ruthenium
hydride-catalyzed reaction and the thermal retro-aldol
reaction – would give a new protocol for the synthesis of
ketones. As outlined in Scheme 2, one-pot synthesis of
6-undecanone (2g) and 1-phenyl-1-hexanone (2a) was
attained starting from 2-hexene-1-ol12 or benzyl alcohol,
respectively, upon reaction with 2-hexenal.
Synlett 2010, No. 14, 2193–2196 © Thieme Stuttgart · New York

LETTER
Retro-Aldol Reaction Using F-626
2195
Table 2 F-626-Mediated Retro-Aldol Reactiona
Entry
Substrate
Time (h)
Product
Yield (%)b
(ratio 2/3)c
O
O
O
1
4
4
98 (95:5)
97 (94:6)
OH
2d
1a
1b
2a
2b
3a
3b
O
O
O
3
4
5
6
OH
4
4
4
5
70 (86:14)
75 (93:7)
60 (50:50)
84 (94:6)
O
O
O
O
O
OH
Br
Br
Br
1c
2c
3c
O
OH
HO
HO
HO
1d
2d
3d
O
O
O
OH
MeO
MeO
MeO
1e
2e
3e
O
7
8
OH
2
4
2a
–
84 (>99:1)
79 (98:2)
1f
O
O
O
OH
1g
2g
3g
a The reaction was performed with 1 (0.5 mmol) and F-626 (4 mL) at 200 °C
b Isolated yield after silica gel column chromatography.
c Determined by 1H NMR analysis.
d Recovered F-626 was used.
(2) For reviews on fluorous chemistry, see: (a) Handbook of
Fluorous Chemistry; Gladysz, J. A.; Curran, D. P.; Horváth,
I. T., Eds.; Wiley-VCH: Weinheim, 2004. (b) For a
thematic issue on fluorous chemistry, see: Gladysz, J. A.;
Curran, D. P. Tetrahedron; 2002, 58, 3823. (c) Ryu, I.;
Matsubara, H.; Emnet, C.; Gladysz, J. A.; Takeuchi, S.;
Nakamura, Y.; Curran, D. P. In Green Reaction Media in
Organic Synthesis; Mikami, K., Ed.; Blackwell Publishing:
Oxford, 2005, 59. (d) Matsubara, H.; Ryu, I. In Green
Separation Processes: Fundamentals and Applications;
Afonso, C. A. M.; Crespo, J. G., Eds.; Wiley-VCH:
Weinheim, 2005, 219.
Acknowledgment
T.F. and I.R. acknowledge JSPS and MEXT Japan for funding. We
appreciate the generous gift of F-626 from the Kao Corporation.
References and Notes
(1) (a) Green Reaction Media in Organic Synthesis; Mikami, K.,
Ed.; Blackwell Publishing: Oxford, 2005. (b) Green
Separation Processes: Fundamentals and Applications;
Afonso, C. A. M.; Crespo, J. G., Eds.; Wiley-VCH:
Weinheim, 2005.
(3) (a) Fujii, Y.; Tamura, E.; Yano, S.; Furugaki, H. US Patent
6,060,626, 2000. (b) Fujii, Y.; Furugaki, H.; Yano, S.; Kita,
K. Chem. Lett. 2000, 926. (c) Fujii, Y.; Furugaki, H.;
Tamura, E.; Yano, S.; Kita, K. Bull. Chem. Soc. Jpn. 2005,
78, 456.
Synlett 2010, No. 14, 2193–2196 © Thieme Stuttgart · New York

2196
T. Fukuyama et al.
LETTER
(4) (a) Matsubara, H.; Yasuda, S.; Sugiyama, H.; Ryu, I.; Fujii,
Y.; Kita, K. Tetrahedron 2002, 58, 4071. (b) Fukuyama, T.;
Arai, M.; Matsubara, H.; Ryu, I. J. Org. Chem. 2004, 69,
8105.
(5) Chu, Q.; Yu, M. S.; Curran, D. P. Tetrahedron 2007, 63,
9890.
(6) (a) Smith, G. G.; Yates, B. L. J. Org. Chem. 1965, 30, 2067.
(b) Yates, B. L.; Quijano, J. J. Org. Chem. 1969, 34, 2506.
(c) Westley, J. W.; Evans, R. H. Jr.; Pruess, D. L.; Stempel,
A. Chem. Soc. D. 1970, 1467. (d) Yates, B. L.; Ramirez, A.;
Velasquez, O. J. Org. Chem. 1971, 36, 3579. (e) Ireland, R.
E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.;
McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am.
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Nishizawa, K.; Hasegawa, T. J. Chem. Soc., Chem.
Commun. 1990, 374.
(8) General procedure for retro-aldol reactions using F-626: a-
Hydroxymethyl ketone 1a (0.5 mmol, 104.7 mg) and F-626
(4 mL, 5.64 g) were placed in a 5 mL two-necked round-
bottom flask, and heated at 200 °C for 4 h under nitrogen.
After cooling to room temperature, the reaction mixture was
poured into a separation funnel, and MeCN (4 mL) was
added. The MeCN layer was separated, and extracted with
FC-72 (6 × 0.33 mL). The combined fluorous layers were
evaporated to give F-626 (5.53 g, 98%). The crude reaction
mixture obtained from the MeCN layer was purified by silica
gel chromatography (hexane–EtOAc, 98:2) to give a mixture
of 2a and 3a (87.6 mg; 2a/3a = 95:5)
(9) Doi, T.; Fukuyama, T.; Minamino, S.; Husson, G.; Ryu, I.
Chem. Commun. 2006, 1875.
(10) Doi, T.; Fukuyama, T.; Minamino, S.; Ryu, I. Synlett 2006,
3013.
(7) (a) Granberg, K. L.; Edvinsson, K. M.; Nilsson, K.
Tetrahedron Lett. 1999, 40, 755. (b) Oikawa, H.; Oikawa,
M.; Ichihara, A.; Ubukata, M.; Isono, K. Biosci.,
Biotechnol., Biochem. 1994, 58, 1933. (c) Oikawa, M.;
Ueno, T.; Oikawa, H.; Ichihara, A. J. Org. Chem. 1995, 60,
5048. (d) Kocienski, P. J.; Brown, R. C. D.; Pommier, A.;
Procter, M.; Schmidt, B. J. Chem. Soc., Perkin Trans. 1
1998, 9. (e) Horita, K.; Nagato, S.; Oikawa, Y.; Yonemitsu,
O. Chem. Pharm. Bull. 1989, 37, 1726. (f) Wells, J. L.;
Bordner, J.; Bowles, P.; McFarland, J. W. J. Med. Chem.
1988, 31, 274.
(11) Denichoux, A.; Fukuyama, T.; Doi, T.; Horiguchi, J.; Ryu, I.
Org. Lett. 2010, 12, 1.
(12) To a 5 mL two-necked flask, RuHCl(CO)(PPh3)3 (0.05
mmol, 48.1 mg), benzene (3 mL) and 2-hexene-1-ol (1
mmol, 101.1 mg) were added, and the resulting mixture was
heated at 80 °C for 10 h under nitrogen. After cooling to
room temperature, the solvent was removed under reduced
pressure, F-626 (4 mL) was added and the mixture was
heated at 200 °C for 4 h. Biphasic workup using MeCN and
FC-72, followed by purification using silica gel chroma-
tography (hexane–EtOAc, 98:2) gave a mixture of 2g and 3g
(51 mg; 2g/3g = 96:4)
Synlett 2010, No. 14, 2193–2196 © Thieme Stuttgart · New York