Addition of ethyl bromodifluoroacetate to lactones: Reactivity and stereoselectivity

Article abstract of DOI:10.1055/s-2005-917113

Reformatsky-type additions, under various metal-mediated activation, of ethyl bromodifluoroacetate toward a series of unactivated lactones and various sugar lactones proceeded with medium to good yields and in a completely diastereoselective manner. Georg

Full text of DOI:10.1055/s-2005-917113

LETTER
2627
Addition of Ethyl Bromodifluoroacetate to Lactones: Reactivity and
Stereoselectivity
A
dditionof Ethyl
B
romodifluo
a
roacetate toLacto
B
nes . Cuenca, François D’Hooge, Vanessa Gouge, Géraldine Castelot-Deliencourt, Hassan Oulyadi, Eric Leclerc,
Philippe Jubault, Xavier Pannecoucke,* Jean-Charles Quirion*
IRCOF, LHO, UMR CNRS 6014, Université et INSA de Rouen, Rue Lucien Tesnière, 76131 Mont-Saint-Aignan, France
E-mail: xavier.pannecoucke@insa-rouen.fr; E-mail: jean-charles.quirion@insa-rouen.fr
Received 23 August 2005
We wanted to report herein a study on the reactivity of a
series of unactivated lactones towards the classical
Reformatsky reaction and three metal-promoted
Reformatsky-type additions of ethyl bromodifluoroace-
tate under ‘one-pot’, mild and easy conditions. We have
extended this study to the addition of various sugar
lactones. These substrates could be an entry to fluorinated
CF2-glycosides that are of considerable interest in carbo-
hydrate chemistry, as well as in organic synthesis, because
of the stability of the C-glycosidic linkage toward glyco-
sidases. A study of the stereoselectivity outcome of the
reaction when the non-racemic lactones were used as
substrates was also reported.
Abstract: Reformatsky-type additions, under various metal-
mediated activation, of ethyl bromodifluoroacetate toward a series
of unactivated lactones and various sugar lactones proceeded with
medium to good yields and in a completely diastereoselective
manner.
Key words: addition reactions, fluorine, lactones, carbohydrates,
stereoselectivity
Organofluorine compounds have received considerable
interest in recent years due to their growing importance in
life sciences, especially for drug development and crop
protection.1 Modification of the physiological activity of
bioactive compounds by introducing fluorine into the
molecules frequently leads to the discovery of novel and
potent biochemical tools and medicinal agents.
Addition to the Non-Sugar Lactones
Among them, gem-difluoromethylene group has a singu-
lar importance and techniques to meet the particular
demands of its deployment have proliferated.2 However,
the use of special fluorinating agents (DAST, SF4, CF3OF,
HF, Selectfluor and others)3 is limited to specific
compounds because of the high reactivity of these re-
agents. In addition, many of these reagents are expensive,
toxic and hazardous. Consequently, with the increasing
accessibility of fluorinated building blocks, the CF2-syn-
thon approach has blossomed. Reformatsky reaction of
halodifluoroacetates4 and halodifluoroketones is by far
the most common of all these approaches.
Zn(0)-mediated classical Reformatsky8,9 addition of ethyl
bromodifluoroacetate10 to the simple g-lactone 1 and di-
hydrocoumarin (3, Scheme 1) occurs giving the addition
products in moderate yield (Table 1, entries 1 and 7). In
contrast, when the same conditions were used for the
addition to the d-valerolactone (2), only degradation of the
starting material was observed.
In order to circumvent this problem, we tried modified
Reformatsky-type reaction that have been reported in the
literature.11 Indeed, Zn/Cp2TiCl2-promoted12 ‘one-pot’
addition of ethyl bromodifluoroacetate to lactones 1–3
was found to occur under mild conditions at room temper-
ature (Table 1, entries 2, 5 and 8). The number of equiva-
lents of Zn and any additive was optimized in each case,
and only selected results are presented (see Table 1).
In our laboratory, we have focused our attention to ex-
plore the preparation of this kind of ‘flustrate’5 via
Reformatsky-type addition of ethyldifluoroacetate. In this
way, we have reported previously the preparation of dif-
luoroderivatives of chiral 1,3-oxazolidines.6 As continua-
tion of our work in this topic, we have considered the
addition reaction of ethyldifluoroacetate to unactivated
carbonyl lactones. The preparation of such type of
compounds, to our knowledge, has not been previously
reported. In contrast, the applications of different metal-
promoted Reformatsky reactions using non-fluorinated
reagents, with unactivated lactones as well as the sugar
lactones, were reported by various authors.7
R1
R1
O
O
Zn, BrCF2CO2Et
OH
O
CF2CO2Et
metal promoter, THF
R2
n
R2
n
1: R1, R2 = H; n = 1
2: R1, R2 = H; n = 2
4: R1, R2 = H; n = 1
5: R1, R2 = H; n = 2
3: R1, R2 = –C4H4–; n = 2
6: R1, R2 = –C4H4–; n = 2
Scheme 1 Addition of ethyl bromodifluoroacetate on lactone
We also decided to try organocerium derivatives. Indeed,
recent years have seen the development of synthetic pro-
cedures involving lanthanide metals, especially cerium, in
organometallic reactions. One of the most important
examples is the conversion of organolithium compounds
SYNLETT 2005, No. 17, pp 2627–2630
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917113; Art ID: G26505ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
5

2628
A. B. Cuenca et al.
LETTER
Table 1 Reformatsky-Type Reaction between Simple Lactones and
CeCl3·7H2O. The addition occurs in all cases but the
yields of the expected fluorinated lactols were only
slightly improved (Table 1, entries 3, 6 and 9).
Ethyl Bromodifluoroacetate13
Entry Lactone Reaction
BrCF2CO2Et Product Yield (%)
conditionsa (equiv)
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
3
A
3
4
4
4
5
5
5
6
6
6
16
34
40
–
Addition to the Sugar Lactones
B
2
To attain one of our objectives and continue to explore the
reactivity of the lactones towards ethyl bromodifluoro-
acetate, we decided to extend our studies to sugar lactone
derivatives. For this purpose, we have selected three
pyranoid aldonolactones 7, 8 and 9 (Scheme 2).
C
A
B
C
A
B
C
1.5
3
1.1
1.5
3
60
40
42
45
50
6
6
O
CF2CO2Et
OH
Zn/ metal promoter
or SmI2
O
O
BnO
BnO
1
2
5
BnO
BnO
1
2
5
4
3
4
3
OBn
BrCF2CO2Et,
THF
5
OBn
OBn
OBn
1.5
7: glucono lactone (2R,4R)
8: galacto lactone (2R,4S)
9: mannoso lactone(2S,4R)
10 (2R,4R)
11 (2R,4S)
12 (2S,4R)
a Method A: Zn (7 equiv), THF reflux. Method B: Zn (7 equiv)/
Cp2TiCl2 (0.05 equiv), THF, r.t.. Method C: Zn (3.5 equiv)/CeCl3
(0.04 equiv), THF, r.t.
Scheme 2 Addition of ethyl bromodifluoroacetate on sugar lactone
When additions were carried out using the 2,3,4,6-tetra-
O-benzyl-D-glucono-1,5-lactone (7) under classical
Reformatsky conditions, we observed nearly a quantita-
tive conversion, although compound 10 can only be
isolated in 73% yield. Nevertheless, the addition was
completely stereoselective giving a single diastereoiso-
mer (Table 2, entry 1). With titanium or cerium reagents
at room temperature, the additions to the glucono lactone
were also completely stereoselective (Table 2, entries 2
and 3).
to organocerium derivatives by CeCl3. It is well-known
that this salt exerts a strong activation of carbonyl com-
pounds toward addition of organometallics,14 giving in
this way higher conversion of addition products.
Inspired by Shen and Qi’s use of cerium methodology for
the fluoro-Reformatsky reaction,10b,15 we carried out the
addition of ethyl bromodifluoroacetate with the carbonyl
derivatives 1, 2 and 3 in the presence of 0.04 equivalent of
Table 2 Reformatsky-Type Reaction between Sugar Lactones and Ethyl Bromodifluoroacetate13
Entry
Sugar lactone
Reaction
BrCF2CO2Et
(equiv)
Product
Yield
dr
conditionsa
1
2
7
7
7
7
8
8
8
8
9
9
9
9
A
B
C
D
A
B
C
D
A
B
C
D
3
10
10
10
10
11
11
11
11
12
12
12
12
73
65
70
71
72
70
65
71
70
72
55
71
99:1
99:1
99:1
98:2
88:12
99:1
99:1
92:8
99:1
99:1
95:5
99:1
5
3
1.5
3
4
5
3
6
5
7
1.5
3
8
9
3
10
11
12
5
1.5
3
a Method A: Zn (7 equiv), THF, reflux. Method B: Zn (7 equiv)/Cp2TiCl2 (0.05 equiv), THF, r.t. Method C: Zn (3.5 equiv)/CeCl3 (0.04 equiv),
THF, r.t. Method D: SmI2 (8.4 equiv), THF, r.t.
Synlett 2005, No. 17, 2627–2630 © Thieme Stuttgart · New York

LETTER
Addition of Ethyl Bromodifluoroacetate to Lactones
2629
As a new activator, we then decided to try organosamari- In conclusion, we have developed Reformatsky-type
um intermediates. Indeed, both non-asymmetric and additions of ethyl bromodifluoroacetate to a series of
asymmetric versions of SmI2-mediated Reformatsky-type lactones under mild and experimentally single ‘one-pot’
reaction with aldehydes and ketones have been de- conditions. Different reaction conditions were investigat-
scribed.16 On our substrate 7, the mild and rapid SmI2-pro- ed: Zn at THF reflux, Zn with catalytic amount of
moted addition occurred, yielding the fluorinated lactol 10 Cp2TiCl2 or CeCl3 at room temperature, and SmI2 at room
in 71% yield and with excellent stereoselectivity (Table 2, temperature. On our substrates, the three last conditions
entry 4).
gave good results, with the titanocene-promoted reactions
being slightly advantageous. The additions proceeded
with medium to good yields and in a completely dia-
stereoselective manner. The major isomers always had the
ethyldifluoroacetate group in an equatorial position, irre-
spective of the starting sugar lactone, even with an axial
protected hydroxyl group at C-2 position (compound 12).
The sugar adducts could provide an entry to fluorinated
CF2-glycosides that are of considerable interest in carbo-
hydrate chemistry.
Systematically, we applied the same four methodologies
to the 2,3,4,6-tetra-O-benzyl-D-mannoso-1,5-lactone (8).
In this case, the addition of the bromodifluoro compound
required only the presence of Zn(0) to achieve a 72% yield
of expected product, but we also observed a slight loss of
stereoselectivity, 88:12. When titanium, cerium or samar-
ium were used as reaction promoters, the yields were
equivalent, but with better diastereoselectivities (Table 2,
entries 6–8).
With the 2,3,4,6-tetra-O-benzyl-D-galacto-1,5-lactone
(9), the addition proceeded with good yield and complete
diastereoselectivity when the reaction was performed us-
ing Zn(0) alone, or in combination with Ti or Sm promot-
ers (Table 2, entries 9, 10 and 12). However, when cerium
promotion was tested with the lactone derived from galac-
tose 9, both yield and diastereoselectivity slightly de-
creased (Table 2, entry 11). The assignment of the relative
configuration at C-1 of compound 10, 11, 12 was carried
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2
CO2Et
BnO
OH
Figure 1 Correlation observed on the 600 MHz H–19F HOESY
1
spectrum of compound 10 recorded with a mixing time of 200 ms at
17
288 K in CDCl3
We were able to verify that the 1R diastereoisomer was
obtained in all cases, even the mannose derivative one. As
the most stable conformation is the C1, placing the C-2,
4
C-3, C-4 and C-5 groups in equatorial positions (con-
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due to the anomeric effect which stabilizes the axial OH
by orbital interaction.18 Thus, the predominant diastereo-
mer obtained is the more stable stereoisomer according to
the calculations. Unfortunately, we could not determine if
the mechanism proceeded through a kinetically controlled
attack of the organozinc species onto the less hindered
face of the lactone, followed by a rapid anomerization
leading to the thermodynamically more stable R isomer or
a thermodynamically controlled attack of the organozinc
species.
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Synlett 2005, No. 17, 2627–2630 © Thieme Stuttgart · New York

2630
A. B. Cuenca et al.
LETTER
equiv, 1.8 mmol) was added. The reaction mixture was
stirred at the same temperature under inert atmosphere for 2–
3 h. The resulting mixture was then diluted with 1 N aq HCl
and stirred for 10 min before extraction with CH2Cl2. The
extracts were dried over anhyd MgSO4. After removal of the
solvent under reduced pressure, the crude material thus
obtained was subjected to flash silica gel chromatography.
Method D.
To a solution of the required lactone (0.22 mmol, 1 equiv) in
anhyd and degassed THF (20 mL) was added, at r.t. and
under argon, ethyl bromodifluoroacetate (0.66 mmol, 3
equiv). At this moment, a 0.037 M solution of SmI2 (50 mL,
8.40 equiv) was added, at r.t., until the blue color persisted.
The reaction was stirred at the same temperature until the
blue color disappeared and the mixture turned yellow. The
resulting mixture was poured into a solution of NaHCO3 (30
mL) and stirred for 10 min before extraction with CH2Cl2.
The extracts were dried over anhyd MgSO4. After removal
of the solvent under reduced pressure, the crude material
thus obtained was subjected to flash silica gel
(7) For nucleophilic addition of simple lactones, see:
(a) Hanessian, S.; Girard, C. Synlett 1994, 865. (b) For a
review on b-lactone chemistry, see: Pommier, A.; Pons, J.
M. Synthesis 1993, 441. For addition to the sugar lactones
derivatives: (c) Csuk, R.; Franke, U.; Hu, Z.; Krieger, C.
Tetrahedron 2003, 59, 7887. (d) Orsini, F.; di Teodoro, E.
Tetrahedron: Asymmetry 2003, 14, 2521. (e) Hanessian, S.;
Girard, C. Synlett 1994, 865. (f) Grabberger, V.; Berger, A.;
Dax, K.; Fechter, M.; Gradnig, G.; Stütz, A. Liebigs Ann.
Chem. 1993, 379. (g) Csuk, R.; Glänzer, B. I. J. Carbohydr.
Chem. 1990, 9, 797. (h) Srivastava, V. K.; Lerner, L. M. J.
Org. Chem. 1979, 44, 3368; and references cited therein.
(8) (a) Fürstner, A. Synthesis 1989, 571. (b) Fürstner, A.
Organic Reagents, In The Reformatsky Reaction; Knochel,
P.; Jones, P., Eds.; Oxford University Press: Oxford UK,
1999, 287–305.
(9) Cintas, P. Activated Metals in Organic Synthesis; CRC
Press: Boca Raton, 1993, 172–183.
(10) (a) Burton, D. J.; Yang, Z. Y. In Chemistry of Organic
Fluorine Compounds II: A Critical Review; Hudlicky, M.;
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Y.; Q’I, M. J. Fluorine Chem. 1994, 67, 229.
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(15) See also: (a) Ocampo, R.; Dolbier, W. R.; Abboud, K. A.;
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Wessendorf, R. Justus Liebigs Ann. Chem. 1964, 674, 1.
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(13) Method A.
To a suspension of zinc19 (7 equiv, 15.7 mmol) in anhyd
THF (31 mL) warmed to reflux temperature were added
ethyl bromodifluoroacetate (3 equiv, 6.7 mmol) and the
desired lactone (1 equiv, 2.24 mmol) in anhyd THF (31 mL).
The reaction was stirred at the same temperature under inert
atmosphere during a variable period between 2.30–4 h
depending of the substrate. The resulting mixture was then
diluted with 1 N aq HCl and stirred for 10 min before
extraction with CH2Cl2. The extracts were dried over anhyd
MgSO4. After removal of the solvent under reduced
pressure, the crude mixture thus obtained was subjected to
flash silica gel chromatography.
intramolecular processes, see: (j) Tabuchi, T.; Kawamura,
K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
3889. (k) Molander, G. A.; Etter, J. B. J. Am. Chem. Soc.
1987, 109, 6556. (l) Moriya, T.; Handa, Y.; Inanaga, J.;
Yamaguchi, M. Tetrahedron Lett. 1988, 29, 6947.
(17) Ethyl 2-{(2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
[(benzyloxy)methyl]-tetrahydro-2-hydroxy-2H-pyran-2-
yl}-2,2-difluoroacetate (10).
Method B.
To a suspension of zinc (7 equiv, 7 mmol) in anhyd THF (12
mL) was added Cp2TiCl2 (0.05 equiv, 0.05 mmol) at r.t. The
initial reddish color was turned to easily identifiable green
color after 2–3 min, the corresponding lactone (1 equiv, 1
mmol) was then added in anhyd THF (12 mL). Finally ethyl
bromodifluoroacetate (5 equiv, 5 mmol) in anhyd THF (6
mL) was added. The reaction was stirred at the same
temperature under inert atmosphere for 12 h. The resulting
mixture was then diluted with 1 N aq HCl and stirred for 10
min before extraction with CH2Cl2. The extracts were dried
over anhyd MgSO4. After removal of the solvent under
reduced pressure, the crude material thus obtained was
subjected to flash silica gel chromatography.
Procedure A: column chromatography (cyclohexane–
EtOAc = 25:1) of the crude product gave a colorless syrup
(73%); [a]D20 +49.8 (c 0.616, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 7.23–7.17 (m, 18 H), 7.12–7.09 (m, 2 H), 4.80
(s, 1 H), 4.73 (m, 4 H), 4.55–4.37 (m, 3 H), 4.15 (q, 2 H,
J = 7.17 Hz), 4.10 (m, 1 H), 3.95–3.90 (m, 3 H), 3.68–3.51
(m, 3 H), 1.16 (t, 3 H, J = 7.17 Hz). 13C NMR (75 MHz,
CDCl3): d = 162.82 (t, 2JCF = 30.8 Hz), 138.26, 138.16,
137.90, 137.45, 128.29, 127.82, 127.60, 127.52, 112.30 (dd,
JCF = 263.6 Hz, JCF = 259.6 Hz), 96.08 (dd, JCF = 28.17 Hz,
JCF = 26.4 Hz), 83.28, 78.12, 77.33, 75.88, 75.17, 74.97,
73.31, 72.54, 68.16, 63.21, 13.78. 19F NMR (282 MHz,
CDCl3): d = –119.94 (d, 1 F, JFF = 256.5 Hz), –117.63 (d, 1
F, JFF = 256.5 Hz). MS (EI): 685.3 [M + Na]. Anal. Calcd
for C38H40F2O8: C, 68.87; H, 6.08. Found: C, 68.56; H, 5.79.
(18) Collins, P.; Ferrier, R. Monosaccharides; John Wiley and
Sons: New York, 1995.
Method C.
To a mixture of (3.5 equiv, 1.33 mmol) of Zn and CeCl3
(0.06 equiv, 0.023 mmol) in anhyd THF (3 mL) was added a
solution of the required lactone (1 equiv, 0.38 mmol) in
anhyd THF (6 mL) at r.t. Ethyl bromodifluoroacetate (3
(19) Tsuda, K.; Ohki, E.; Nogoe, S. J. Org. Chem. 1963, 28, 783.
Synlett 2005, No. 17, 2627–2630 © Thieme Stuttgart · New York