Z-selective or stereospecific alkenylation reaction: A novel synthetic method for α-fluoro-α,β-unsaturated esters

Article abstract of DOI:10.1246/cl.2005.998

The Z-selective formation of α-fluoro-α,β-unsaturated esters was achieved using the deselenenic acid of the syn-and/or anti-3-aryl-2-fluoro-3-hydroxy-2-organoselanylacetates 3 and 4 with trifluoromethanesulfonic acid. In contrast, the 3-alkyl-substituted propanoates 3f and 4b stereospecifically underwent alkenylation to give the (E)- or (Z)-α-fluoro-α,β-unstaurated esters 5f. We were also successful in the one-pot alkenylation reactions. Copyright

Full text of DOI:10.1246/cl.2005.998

998
Chemistry Letters Vol.34, No.7 (2005)
Z-Selective or Stereospecific Alkenylation Reaction:
A Novel Synthetic Method for ꢀ-Fluoro-ꢀ,ꢁ-unsaturated Esters
Mitsuhiro Yoshimatsu,ꢀ Yoshinori Murase, Akinori Itoh, Genzoh Tanabe,y and Osamu Muraokay
Department of Chemistry, Faculty of Education, Gifu University, Yanagido 1-1, Gifu 501-1193
ySchool of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502
(Received March 24, 2005; CL-050394)
The Z-selective formation of ꢀ-fluoro-ꢀ,ꢁ-unsaturated
um 2,2,6,6-tetramethylpiperidide (LTMP). The corresponding
esters was achieved using the deselenenic acid of the syn-
and/or anti-3-aryl-2-fluoro-3-hydroxy-2-organoselanylacetates
3 and 4 with trifluoromethanesulfonic acid. In contrast, the 3-
alkyl-substituted propanoates 3f and 4b stereospecifically under-
went alkenylation to give the (E)- or (Z)-ꢀ-fluoro-ꢀ,ꢁ-unstau-
rated esters 5f. We were also successful in the one-pot alkenyla-
tion reactions.
alcohol 3a was obtained in almost the same yields as both the
syn and anti diastereomers (syn:anti = 64:36).12 The relative
configuration of each isomer was determined by X-ray analysis
(Figure 1).13 The reactions with some aldehydes and ketones
provided the alcohols 3b–3j and 4a and 4b as shown in Table 1.
The treatment of 3a with trifluoromethanesulfonic acid in
1,2-dichloroethane gave the ꢀ,ꢁ-unsaturated ester 5a, accompa-
nied by diphenyl diselenide. The stereochemistry of the ethyl
(Z)-2-fluorocinnamate (5a) was confirmed on the basis of the
coupling constant of the product.14 When p-toluenesulfonic acid
was used as the acid, the product was obtained in 53% yield as a
mixture of the diastereomers (E:Z = 47:53). We reexamined the
formation of the double bond in each isomer; however, the same
product 5a was obtained from the syn- or anti-alcohols 3a. The
dehydration reactions of some alcohols were examined using
almost the same procedure, and these results are shown in
Table 2. The reactions of the 3-aryl-3b–3d and 3-styryl-3-
hydroxyacetates 3e exclusively provided the (Z)-ꢀ-fluoro-ꢀ,ꢁ-
unsaturated esters 5b–5e (Entries 3–8). The reaction of 3c with
ꢀ-Fluoro-ꢀ,ꢁ-unsaturated esters are novel building blocks
for biologically active compounds, agrochemicals, and poly-
mers.1 The main synthetic routes for the ꢀ-fluoro-ꢀ,ꢁ-unsaturat-
ed esters are the Wittig and Horner–Wadsworth–Emmons
(HWE) reactions. However, the Z-selective HWE reactions are
quite limited.2 Nagao et al. reported a modified method for the
ꢀ-fluoro-ꢀ,ꢁ-unsaturated esters as an alternative route.3
While the ꢀ-organosulfanyl, sulfinyl, and sulfonyl ꢀ-fluoro-
acetic acid esters are widely used for the synthesis of ꢀ-fluoro-
ꢀ,ꢁ-unsaturated esters,4 ꢀ-fluoroalkenes,5 ꢀ,ꢀ-difluoroacetic
acid esters,6 and 2-fluoroallylic alcohols,7 in contrast, the ꢀ-
organoselanylacetic esters are quite limited.8,9 Previously, we
have explored a new field in synthetic organic chemistry using
ꢁ-alkoxyalkenyl lithiums.10 The addition reactions of alkenyl
lithiums with aldehydes and ketones, and the successive hydrol-
ysis afford the corresponding types of alkenes. This two-step
procedure using the carbanion of the ꢀ-fluoro-ꢀ-organoselanyl-
acetic acid esters would be expected to give the ꢀ-fluoro-ꢀ,ꢁ-
unsaturated esters because the treatment of the ꢁ-hydroxy-ꢀ-
organoselanylalkanes with acids is well-known to afford the
alkenes by removal of the organoselenenic acid (RSeOH).11
We have investigated the synthetic utilization using ꢀ-fluoro-
ꢀ-organoselanylacetic acid esters, and the transformation of
the ꢀ-fluoro-ꢁ-hydroxy-ꢀ-organoselanylalkanes was found to
form the corresponding ꢀ-fluoroalkenes. Herein, we report the
Z-selective synthetic methods of the ꢀ-fluoro-ꢀ,ꢁ-unsaturated
esters (Scheme 1).
Table 1. Synthesis of ethyl 2-fluoro-3-hydroxy-2-(organosel-
anyl)alkanoates 3–4
F
SeR1
R2
R3
1) LTMP(2equiv.)/-78 o
2) R2COR3
C
R1Se
F
CO2Et
1-2
CO2Et
OH
3-4
Entry
R1
R2
R3
Yield (syn:anti)
1
2
Ph
Ph
Ph
H
H
H
H
H
H
3a (69; 64:36)
3b (60; 72:16)
3c (66; 58:42)
3d (63; 41:59)
3e (53; 55:45)
3f (36; 58:42)
3g (68)
2,4,6-Me3C6H2
4-MeOC6H4
4-ClC6H4
3
Ph
4
Ph
5
Ph
(E)-PhCH=CH
PhCH2CH2
(CH2)5
6
Ph
7
Ph
8
Ph
(CH2)4
3h (61)
9
Ph
(CH2)2CHPh(CH2)2
CH=CH(CH2)3
4-MeOC6H4
PhCH2CH2
3i (99)
We first prepared the ꢀ-fluoro-ꢀ-phenylselanyl and ꢀ-butyl-
selanylacetic acid ethyl esters 1 (82%) and 2 (54%) by the usual
method from the commercially available chlorofluoroacetic acid
ethyl ester and the corresponding diorganyl diselenides/NaBH4
in EtOH. Next, we performed the lithiation and reaction with
benzaldehyde with the normal amide bases such as LDA or lithi-
10
11
12
Ph
3j (50; 68:32)
4a (51; 57:43)
4b (72; 64:36)
n-Bu
n-Bu
H
H
R1Se
SeR1
CO2Et
R2
R3
H+
R2
R3
R2
R3
F
F
F
O
CO2Et
-R1SeOH
CO2Et
OH
Scheme 1. ꢀ-Fluoroalkenylation using ꢀ-fluoro-ꢀ-organosel-
anylacetates.
Figure 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
999
Table 2. Synthesis of ethyl 2-fluoroalkanoates with acids
R
SeR
Se
F
Ar
F
+
(Z)-3
(E)-3
SeR1
Ar
H
F
F
R2
R3
R2
condition
H
+ (R1Se)2
CO2Et
H
CO2Et
CO2Et
CO2Et
3-4
6
cis-7
R3
OH
5
R
SeR
Se+
Condition
Yield/%
Yield/%
H
+
Entry
Alcohol
F
F
a
(R1Se)2
Ar
Method/temp and time
5 (Z:E)
Ar
CO2Et
CO2Et
1
2
s-3a
a-3a
A/rt/10 min
A/rt/10 min
A/rt/10 min
B
5a (74)(99:1)
5a (85)(99:1)
5b (99)(99:1)
5c (75)(99:1)
5d (63)(99:1)
5d (84)(99:1)
5d (70)(99:1)
5e (35)(99:1)
5f (71)(1:99)
5f (99)(99:1)
5g (77)
(71)
(71)
(31)
(46)
(49)
(54)
(17)
(50)
(93)
(13)
(—)
(70)
(45)
(32)
(—)
(—)
(—)
trans-7
Figure 2.
3
s- and a-3b
s- and a-3c
s-3d
the reaction mixture was treated with some acids. Excellent
yields and stereoselectivities were obtained using methanesul-
fonyl chloride at ꢂ78 ꢁC. Especially, the 2,4,6-trimethylphenyl
derivative was obtained in excellent yield. The excellent Z-
selectivity of the reactions would be considered as shown in
Figure 2. The dehydration of the 3-aryl-3-hydroxypropanoate
with acid gives the cationic intermediate 6, which is stabilized
by the organoselanyl group through a bridged intermediate 7.
The 3-aryl intermediate 6 should be further stabilized by the aryl
group, therefore, the extrusion of the selanyl moiety would be
very slow and proceed via the preferred cis-7, which minimizes
the steric interactions. On the other hand, the stereospecificity
during the formation of the double bond in the reactions of the
3-alkyl derivatives 3f and 4b would proceed with retention of
its stereochemistry without the equilibrium like 6 because the
corresponding cationic intermediates would be less stable than
the aromatic 6.
4
5
A/rt/10 min
A/rt/10 min
C
6
a-3d
7
s-3d
8
3e
A/0 ꢁC/10 min
A/83 ꢁC/10 min
A/83 ꢁC/10 min
A/0 ꢁC/50 min
A/0 ꢁC/10 min
A/rt/10 min
A/0 ꢁC/10 min
A/0 ꢁC/10 min
A/83 ꢁC/10 min
A/83 ꢁC/10 min
9
s-3f
10
11
12
13
14
15
16
17
a-3f
3g
3h
5h (59)
3i
5i (47)
3j
5j (18)
s- and a-4a
s-4b
5c (51)
5f (42)(1:99)
5f (42)(99:1)
a-4b
Method A: CF3SO3H(2.0 equiv.)/Cl(CH2)2Cl; Method B: CF3SO3Me(2
equiv.)/NEt3(3 equiv.)/DMF/rt/10 min; Method C: Sc(OTf)3/(0.05
equiv.)/Cl(CH2)2Cl/rt/5 min; aThe yield of diphenyl diselenide was
confirmed by the starting alcohol 3 or 4.
References and Notes
1
J. T. Welch, Tetrahedron, 43, 3123 (1987); ‘‘Fluorine in Bioorganic
Chemistry,’’ ed. by J. T. Welch and S. Eswarakrishnan, Wiley, New York
(1991); R. Filler and Y. Kobayashi, ‘‘Biomedicinal Aspect of Fluorine
Chemistry,’’ Kodansha/Elsevier, Tokyo/New York (1993).
S. Sano, R. Teranishi, and Y. Nagao, Tetrahedron Lett., 43, 9183 (2002);
Y. Suzuki amd M. Sato, Tetrahedron Lett., 45, 1679 (2004); T. Ishihara
and M. Kuroboshi, Chem. Lett., 1987, 1145; J. F. Normant, J. P. Foulon,
D. Masure, R. Sauvetre, and J. Villiera, Synthesis, 1975, 122.
S. Sano, K. Yokoyama, R. Teranishi, M. Shiro, and Y. Nagao, Tetrahe-
dron Lett., 43, 281 (2002); S. Sano, K. Saito, and Y. Nagao, Tetrahedron
Lett., 44, 3987 (2003).
D. Chevrie, T. Lequeux, and J.-C. Pommelet, Tetrahedron, 58, 4759
(2002); A. Wong, C. J. Welch, J. T. Kuethe, E. Vazquez, M. Shaimi, D.
Henderson, I. W. Davies, and D. L. Hughes, Org. Biomol. Chem., 2,
168 (2004).
T. Satoh, N. Itoh, K. Onda, Y. Kitoh, and K. Yamakawa, Tetrahedron
Lett., 33, 1483 (1992).
methyl trifluoromethanesulfonate/triethylamine (Method B)
also afforded the alkene 5c in good yield (Entry 4). The yield
of diphenyl diselenide was found to be lower than that of the
ꢀ,ꢁ-unsaturated esters; however, we could not understand the
reasons for it. The reaction of the alkyl (R2 = CH2CH2Ph;
R3 = H) substituted alcohol 3f did not proceed at room temper-
ature; however, the reaction at 83 ꢁC stereospecifically proceed-
ed to give the (E)- or (Z)-alkene 5f in high yields (Entries 9 and
10). The alkenylation of the butylselanyl derivative 4b also
succeeded (Entries 16 and 17). We also examined the Lewis
acid-catalyzed alkenylation of the 3-hydroxy-2-phenylselanyl-
propanoate 3d which succeeded under the following conditions:
scandium triflate (0.05 mol) in ClCH2CH2Cl at room tempera-
ture (Method C, Entry 7). Overall, the stereoselectivities of the
ꢀ,ꢁ-unsaturated esters were excellent; however, the yields of
the products were not satisfactory because the alkenylation
process consisted of stepwise procedures. We then examined
the one-pot reaction as a modified method of the alkenylation
step including the addition reaction of the carbanion with
aldehydes or ketones and the removal of the benzeneselenenic
acid (Scheme 2).
2
3
4
5
6
S. Bildstein, J.-B. Ducep, and D. Jacobi, Tetrahedron Lett., 37, 8759
(1996).
A. Fujii, Y. Usuki, H. Iio, and T. Tokoroyama, Synlett, 1994, 725.
T. Fuchigami, T. Hayashi, and A. Konno, Tetrahedron Lett., 33, 3161
(1992).
7
8
9
10 M. Yoshimatsu, J. Synth. Org. Chem. Jpn., 60, 847 (2002).
S. Murakami, S. Kim, H. Ishii, and T. Fuchigami, Synlett, 2004, 815.
11 J. Remion, J. R. Dumont, and A. Krief, Tetrahedron Lett., 17, 1385 (1976);
D. Labar and A. Krief, J. Chem. Soc., Chem. Commun., 1982, 564.
12 Each diastereomer was easily purified by preparative TLC or column
chromatography on silica gel. In all cases, the 2,3-syn derivatives are less
polar compounds similar to the corresponding sulfur analogs.
After the addition of the corresponding aldehyde or ketone,
13 Crystal data for syn-3d. Orthorombic, space group P21=a, a ¼ 6:203ð7Þ,
ꢁ
ꢀ
ꢀ 3
b ¼ 22:74ð3Þ, c ¼ 12:29ð2Þ A, ꢁ ¼ 98:21ð5Þ , V ¼ 1715ð3Þ A , Z ¼ 4,
Dc ¼ 1:556 g/cm3, crystal dimensions: 0:10 ꢃ 0:12 ꢃ 0:20 mm3. Total re-
flections (Mo Kꢀ radiation, !-2ꢂ scan technique, 2ꢂmax ¼ 55:0ꢁ): 16189.
Unique reflections with I > 0ꢃðIÞ: 15942 (Rint ¼ 0:055). Final R and Rw
values, based on F2, were 0.108 and 0.155, respectively. Deposition
number at Cambridge Crystallog. Data Centre: CCDC 270027.
PhSe
i
R1
F
CO2Et
F
H
CO2Et
Reagent: i, LTMP/THF/R1CHO/
− 78oC/MeSO2Cl
5a (R1 = Ph)(68%)(Z:E = 99:1)
5b (R1 = 2,4,6-Me3C6H2)(99%)(Z:E = 99:1)
14 The coupling constant of (Z)-5a was obtained from the reference 8: ꢄH:
6.92 (d, JH{F ¼ 35 Hz, olefinic H), ꢄF: ꢂ47:6 ppm (J ¼ 35 Hz). Z-5a:
ꢄH: 6.91 ppm (d, JH{F ¼ 22 Hz, olefinic H), ꢄF: ꢂ39:5 ppm (J ¼ 22 Hz).
Scheme 2. One pot synthesis of ꢀ-fluoro-ꢁ-hydroxy-ꢀ-organo-
selenanylalkanoates.
Published on the web (Advance View) June 11, 2005; DOI 10.1246/cl.2005.998