Radical-mediated hydroxytrifluoromethylation of α,β-unsaturated esters

Article abstract of DOI:10.1016/S0040-4039(03)01783-0

Treatment of α,β-unsaturated esters with trifluoromethyl iodide and triethylborane in the presence of KF and H₂O gave the corresponding hydroxytrifluoromethylated esters.

Full text of DOI:10.1016/S0040-4039(03)01783-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7027–7029
Radical-mediated hydroxytrifluoromethylation of
a,b-unsaturated esters
Tomoko Yajima, Hajime Nagano* and Chiaki Saito
Department of Chemistry, Faculty of Science, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
Received 18 June 2003; revised 18 July 2003; accepted 18 July 2003
Abstract—Treatment of a,b-unsaturated esters with trifluoromethyl iodide and triethylborane in the presence of KF and H2O gave
the corresponding hydroxytrifluoromethylated esters.
© 2003 Elsevier Ltd. All rights reserved.
The addition reactions of perfluoroalkyl radical to car-
bon–carbon double bonds are very efficient and ver-
satile for the direct introductions of perfluoroalkyl
group to organic molecules,1 but the reactions are
mainly limited to electron rich alkenes.2 With electron
deficient alkenes, the formation of undesired dimeric,
telomeric and polymeric products is often observed.3
Recently we reported the chelation-controlled
diastereoselective alkyl radical additions to a-methyl-
ene-g-oxycarboxylic acid esters and the origin of
stereoselectivity.4 As an extension of the radical reac-
tions, we report herein the radical-mediated hydroxy-
trifluoromethylation of a,b-unsaturated esters 1a–f
using CF3I and Et3B in the presence of KF and H2O.
contamination of water during the bubbling of CF3 gas
at −30°C. We next performed the reaction in the pres-
ence of H2O (4 equiv.) and KF (30 equiv.), but without
the tin reagent. The reaction gave 2a in 50% isolated
and 90% conversion yields (entry 3). No reaction took
place in the absence of the radical initiator Et3B. The
reaction performed without KF gave lower yield (entry
Scheme 1.
Table 1. Hydroxytrifluoromethylation of 1a with CF3Ia
Initially, we examined the radical reaction of ethyl
2-phenethylpropenoate 1a with CF3I (Scheme 1). Table
1 summarizes the representative results of the radical
reaction under selected conditions. Following the pro-
cedure for the alkyl radical addition,4 the reaction of 1a
with CF3I (gaseous, ca. 6 equiv.) was performed in the
presence of Et3B (1 equiv.) and Bu3SnH (3 equiv.) in
anhydrous CH2Cl2 at −30°C for 6 h. Work-up with KF
and H2O5 gave hydroxytrifluoromethylated ester 2a in
61% isolated yield (Table 1, entry 1). Neither tri-
fluoromethylated ester 3 nor iodotrifluoromethylated
ester 42b formed. As it was found that Bu3SnH did not
act as a hydrogen donor, the reaction was performed
without the additives (entry 2). But the reaction gave a
complex mixture and 2a was isolated only in 20% yield.
The formation of alcohol 2a is probably due to the
Entry
Additive
(equiv.)
Solvent
Temp. (°C)
Yield of 2a
(%)b
1
2
3
Bu3SnH (3)
–
CH2Cl2
CH2Cl2
CH2Cl2
−30
rt
rt
61
20
50 (90)
H2O (4),
KF (30)
H2O (4)
H2O (4),
KF (30)
H2O (4),
K2CO3 (10)
4
5
CH2Cl2
THF
rt
rt
25
75 (95)
6
THF
rt
46 (53)
a For entry 1: 1a was treated with CF3I (ca. 6 equiv.), Et3B (1 equiv.)
and Bu3SnH at −30°C and after completion of reaction, the mixture
was stirred with KF and H2O at rt for an additional 3 h. For entry
2: the reaction was performed with CF3I (ca. 6 equiv.) and Et3B (1
equiv.). For entries 3, 4 and 6: the reaction was performed similarly
to the typical procedure (Ref. 7). For entry 5: see Ref. 7.
b Isolated yield. Conversion yield in parenthesis.
Keywords: hydroxytrifluoromethylation; a,b-unsaturated esters; radi-
cal reaction.
* Corresponding author. Fax: +81-3-5978-5715.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01783-0

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T. Yajima et al. / Tetrahedron Letters 44 (2003) 7027–7029
Table 2. Hydroxytrifluoromethylation of electron deficient
alkenes 1b–f with CF3I
The addition of trifluoromethyl radical to g-methoxy-a-
methylenecaboxylic acid ester 1e4b,d gave the hydroxy-
trifluoromethylated esters 2e10 in 76% yield with a poor
diastereoselectivity,
(2R*,2%R*)-2e:(2S*,2%R*)-2e=
60:40 (entry 4). The success in the chelation-controlled
1,3-asymmetric induction in the alkyl radical addition
to a-methylene-g-oxycaboxylic acid esters4 prompted us
to apply the chelation control to the hydroxytri-
fluoromethylation reaction. However, Lewis acid
La(OTf)3, which is known to coordinate with carbonyl
oxygens even in water,11 did not improve the
diastereoselectivity (entry 5).12 The reaction of g-benzyl-
oxy-a-methylenecarboxylic acid ester 1f4b,d also gave
hydroxytrifluoromethylated esters 2f10 in good yield,
but with a poor diastereoselectivity (entry 6).
These results mentioned above show that the hydroxy-
trifluoromethylation reaction proceeded in a radical
manner and the hydroxyl group in 2a arose from water.
In fact the reaction of 1a using H218O gave 18O labeled
2a (HRMS: calcd for C14H17F316O218O (M+) 292.1240,
found 292.1215). The alcohol 2a was not transformed
into 18O labeled 2a under radical reaction conditions in
the presence of H218O. These results suggest the hydroly-
sis of iodide 4 into the alcohol 2a. A possible reaction
pathway for the formation of hydrotrifluoromethyla-
tion products is shown in Scheme 2. The addition of
trifluoromethyl radical to electron deficient alkenes A
give the radical intermediate B. The subsequent iodine-
atom transfer reaction may give trifluoromethylated
iodide C, which is unstable and easily hydrolyzed with
water to give hydroxytrifluoromethylated product D.
The reaction of 1a with the electron deficient radical
derived from ethyl iodoacetate gave alcohol 5 in 71%
isolated and 83% conversion yields, but the reaction
with ethyl bromoacetate did not give the alcohol
because the bromine-atom transfer reaction is slower
compared to the iodine-atom transfer reaction.13 The
result suggests the reaction proceeded through the a-
iodoester, although the intermediate was not detected
in the reaction mixture because of rapid hydrolysis with
water. In order to verify the rapid hydrolysis, diethyl
2-iodo-2,4-dimethylpentanedioate (7)14 and ethyl 2-
iodo-2-methylpentanoate (8)15 were allowed to react
with KF and water in THF under the conditions simi-
lar to those shown in Ref. 7 (Scheme 3). The hydrolysis
of iodide 7 bearing an electron-withdrawing ethoxycar-
bonyl group b to the quaternary carbon atom was
completed within 6 h and the corresponding tert-alco-
4). The use of THF as solvent enhanced the yield of 2a
(75% isolated and 95% conversion yields, entry 5).
6
K2CO3 was less effective than KF (entry 6).
We applied subsequently the best reaction conditions7
(Table 1, entry 5) to various electron deficient alkenes
1b–f (Table 2). The reaction of ethyl 2-hexylpropenoate
1b afforded the corresponding hydroxytrifluoromethyl-
ated product 2b in 70% yield (entry 1). Nonterminal
alkene 1c was also reacted with trifluoromethyl radical
to give 2c despite the radical addition reaction of
nonterminal alkenes is in general sluggish (entry 2).8
a-Methylene-g-lactone 1d9 also gave the corresponding
hydroxytrifluoromethylated lactone 2d, although the
yield was lower (entry 3). However, the addition
of electron deficient trifluoromethyl radical was not
suitable for the highly electron deficient 2-
phenethylacrylonitrile8 and the starting material was
recovered.
Scheme 2. Possible reaction pathway.

T. Yajima et al. / Tetrahedron Letters 44 (2003) 7027–7029
7029
oxyperfluoroalkylation reaction of simple alkenes using
molecular oxygen, see: (e) Yoshida, M.; Ohkoshi, M.;
Aoki, N.; Ohnuma, Y.; Iyoda, M. Tetrahedron Lett.
1999, 40, 5731–5734.
3. For radical-mediated perfluoroalkylation reactions of a-
methylene esters, see: (a) Kamigata, N.; Fukushima, T.;
Terakawa, Y.; Yoshida, M.; Iyoda, M. J. Chem. Soc.,
Perkin Trans. 1 1991, 627–633; (b) Qui, Z.-M.; Burton,
D. J. J. Org. Chem. 1995, 60, 3465–3472 and references
cited therein.
4. (a) Nagano, H.; Toi, S.; Yajima, T. Synlett 1999, 53–54;
(b) Nagano, H.; Hirasawa, T.; Yajima, T. Synlett 2000,
1073–1075; (c) Nagano, H.; Matsuda, M.; Yajima, T. J.
Chem. Soc., Perkin Trans. 1 2001, 174–182; (d) Nagano,
H.; Toi, S.; Hirasawa, T.; Matsuda, M.; Hirasawa, S.;
Yajima, T. J. Chem. Soc., Perkin Trans. 1 2002, 2525–
2538; (e) Nagano, H.; Ohkouchi, H.; Yajima, T. Tetra-
hedron 2003, 59, 3649–3663.
Scheme 3.
hol 9, analogous to compound 5, was yielded quantita-
tively. However, the hydrolysis of iodide 8 was slower
and only 70% of 8 was converted into the correspond-
ing alcohol 10. The role of KF was found to be the
acceleratation of hydrolysis, because without KF the
hydrolysis was sluggish.
The conversion of halides to alcohols, via peroxyl radi-
cal intermediates, with oxygen and Et3B has been
reported.2e,16 In our case, however, the reaction of 1a
with CF3I performed in the presence of Et3B and 2
equiv. of molecular oxygen in CH2Cl2 gave hydroper-
oxide 6 in 45% yield together with 2a (30% yield; see,
entry 2 in Table 1). The hydroperoxide 6 was easily
reduced to the corresponding alcohol 2a under H2-Pd/C
conditions. The radical intermediate formed by the
addition of trifluoromethyl radical may react with
molecular oxygen to give the hydroperoxide 6 (see, E in
Scheme 2).
5. Leibner, J. E.; Jacobus, J. J. Org. Chem. 1979, 44,
449–550.
6. Transformation of alkyl halides to alcohols using
aqueous carbonate has been reported: (a) Smith, J. G.;
Dibble, P. W.; Sandborn, R. E. J. Org. Chem. 1986, 51,
3762–3768; (b) Ji, J.; Zhang, C.; Lu, X. J. Org. Chem.
1995, 60, 1160–1169.
7. Typical procedure: To a flask containing alkene (0.15
mmol, 1 equiv.) and THF (1.5 mL), equipped with a N2
balloon, were added H2O (11 mL, 4 equiv.), KF (200 mg),
Et3B (1 mol/L solution in hexane, 0.15 mL, 1 equiv.) and
CF3I (gaseous, ca. 6 equiv.) at −30°C. Then the reaction
mixture was stirred at rt for 6 h, and filtered through a
pad of Celite. The filtrate was concentrated and the
residue was chromatographed on silica gel to afford the
product.
In summary, we have reported the first example of the
radical-mediated hydroxytrifluoromethylation of a,b-
unsaturated esters using trifluoromethyl iodide and tri-
ethylborane in the presence of KF and H2O. The new
method would be useful for the synthesis of tri-
fluoromethyl-containing organic compounds.
8. Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753–764.
9. Urabe, H.; Kobayashi, K.; Sato, F. J. Chem. Soc., Chem.
Commun. 1995, 1043–1044.
10. The relative configuration of (2R*,2%R*)-2e was deter-
mined by X-ray analysis Crystal data for (2R*,2%R*)-2e:
C15H19F3O4, M=320.30, monoclinic, space group P21/n,
Acknowledgements
This work was supported by a Grant-in-Aid from the
Ministry of Education, Science, Sports, and Culture,
Japan (No. 12740397). We are also grateful to F-Tech,
Inc., for a generous supply of tirfluoromethyl iodide.
,
a=18.265(7), b=6.7669(15), c=12.870(3) A, i=
3
99.15(2)°, V=1570.5(8) A , Z=4, v=1.037 mm−1, T=
,
293 K, Rint=0.1937, 4693 reflections were collected and
2839 independent reflections were used. R1=0.0946,
wR2=0.2362 (I>2|(I) observed data); R1=0.1264, wR2=
0.3036 (all data). CCDC reference number 195916. The
relative configurations of 2f were determined by compar-
ing the chemical shift values in 1H and 13C NMR with
those of 2e.
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