N-(b,b-Difluorovinyl)oxazolidin-2-ones: First synthesis and application in [3+2]- and [4+2]-cycloaddition-type reactions

Article abstract of DOI:10.1055/s-0029-1217744

N-(,-Difluorovinyl)oxazolidin-2-ones were conveniently prepared in good yields in two steps from the parent oxazolidin-2-ones. The [3+2]- and [4+2]-cycloaddition-type reactions with electron-deficient partners were investigated as first application of the

Full text of DOI:10.1055/s-0029-1217744

2492
LETTER
N-(b,b-Difluorovinyl)oxazolidin-2-ones: First Synthesis and Application in
[3+2]- and [4+2]-Cycloaddition-Type Reactions
N
-(
b
,
b
-Difluoro
h
vinyl)oxazo
a
lidin-2-one
s
nh Binh Nguyen, Arnaud Martel, Robert Dhal, Gilles Dujardin*
UCO2M UMR 6011 CNRS, Université du Maine, 72085 Le Mans, France
Fax +33(243)833344; E-mail: gilles.dujardin@univ-lemans.fr
Received 8 June 2009
O
F
Abstract: N-(b,b-Difluorovinyl)oxazolidin-2-ones were conve-
niently prepared in good yields in two steps from the parent oxazo-
O
F
F
F
OTs
O
NEt2
lidin-2-ones. The [3+2]- and [4+2]-cycloaddition-type reactions
N
O
F
F
with electron-deficient partners were investigated as first applica-
tion of these new enamides. TMSOTf was efficient in promoting
these two reactions, and the corresponding heterocyclic difluoro ad-
ducts were obtained in high yields.
R
1
2
Percy et al.
Ichikawa et al.
3
Key words: N-(b,b-difluorovinyl)oxazolidin-2-ones, trimethylsilyl
trifluoromethanesulfonate, 1,3-dipolar cycloaddition, Diels–Alder
reaction, dipolarophile, nitrone, heterodiene
Figure 1
We now report the first synthesis of N-(b,b-difluoro-
vinyl)oxazolidin-2-ones 3 by a practical method and their
application in [3+2]- and [4+2]-heterocycloaddition-type
reactions with electron-deficient partners.
The incorporation of at least one fluorine atom into organ-
ic molecules often enhances or modifies biological and
therapeutic activities. Consequently, 20% of drugs now
commercialized are fluorinated compounds.1 A myriad of
procedures allows the selective introduction of fluorine
atom and fluoroalkyl groups into organic molecules.2 An
important subset of fluorinated compounds contains a di-
fluoromethylene (CF2) group. This group could be ob-
tained by direct fluorination3 using fluorinating agents
[diethylaminosulfur trifluoride (DAST), SF4, CF3OF, HF,
etc.] which are in general toxic, hazardous and often ag-
gressive towards the substrate. The second strategy using
appropriate fluorinated synthons provides a convenient
approach to such compounds as more and more new fluo-
rinated building blocks are developed and easily avail-
able.4 1,1-Difluoro-2-oxygenated ethylenes such as 1,1-
difluoro-2-(N,N-diethylcarbamato)ethylene (1)5 and 2,2-
difluorovinyl tosylate (2;6 Figure 1) were shown to be
highly valuable synthons. However, the preparation and
the chemistry of their 1-nitrogenated homologues have
been poorly described.7
Our initial attempts to access 3a in one step from 4a start-
ed by using the modified Buchwald’s procedure,8c which
gave excellent yields of N-vinyloxazolidin-2-ones starting
from the corresponding oxazolidin-2-ones and vinyl bro-
mides (Scheme 1). When 4a was treated with 1-bromo-
2,2-difluoroethene under these conditions, the desired
product 3a was formed but rapidly transformed into 5 in
moderate yield (50%). In order to validate the difluoro-
enamide as a transient intermediate of 5, 3a obtained by
another method (described later) was heated with KBr and
K2CO3 in wet toluene and gave rise to 511 in a comparable
yield (45%).
F
F
(2 equiv)
Br
O
F
F
Br
O
F
O
F
CuI (5 mol%)
O
NH
O
N
O
N
(CH2NHMe)2 (10 mol%)
K2CO3
toluene, 110 °C
sealed tube
4a
3a
5
Our group had previously demonstrated the use of N-al-
kenyl oxazolidin-2-ones as dipolarophile in the [3+2] cy-
cloaddition of nitrones8 and as dienophile in the [4+2]
cycloaddition of oxadienes.9 We next attempted to extend
this study to unknown b,b-difluorinated N-vinyloxazoli-
din-2-ones 3 in which the chirality could be introduced via
an alkyl group at the 4-position of the oxazolidinone moi-
ety. Interestingly, no example of such heterocycloaddi-
tions involving heterosubstituted gem-difluoroalkenes as
2p component has been reported to date in the literature.
trace
45–50% yield
F
O
F
KBr (1equiv)
O
N
H2O (1 equiv)
K2CO3, toluene
110 °C
3a
Scheme 1
The same phenomenon has also been reported for related
compounds such as chlorotrifluoroethylene10 or tosylate
2;6b the presence of two fluorine atoms at the b-position of
the double bond in 3a could enhance the reactivity of this
SYNLETT 2009, No. 15, pp 2492–2496
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217744; Art ID: D15409ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-(b,b-Difluorovinyl)oxazolidin-2-ones
2493
O
O
F
F
F
OTs
N
O
O
NEt2
F
F
F
1
2
3a
H2O
O
H2O
O
Li
Li
O
Li
O
F
F
S
stabilized as
or
F
O
NEt2
O
p-tolyl
N
O
F
F
F
LDA
(2 equiv)
n-BuLi
(2 equiv)
lithiated base
(2 equiv)
O
O
O
N
F3C
OTs
F3C
O
NEt2
F3C
7a
6'
6
Scheme 2
carbon center toward a weak nucleophile such as a bro-
mide ion.
Table 1 Preparation of 7a via N-2,2,2-Trifluoroethylation of 4a
CF3
O
O
O
F3C
(1 equiv)
solvent
OR
A simple structural comparison between 1, 2 and 3a re-
vealed that their corresponding lithiated anions at the car-
bon atom are all stabilized by the neighboring Lewis bases
such as lone-pair oxygen of CO or SO2 groups and by a
strong electron-withdrawing effect of the CF2 moiety
(Scheme 2). The product 3a could therefore be prepared
in the same manner as that employed for 15f or 26c starting
from the corresponding N-(b,b,b-trifluoroethyl)oxazoli-
din-2-one 7a via b-elimination of an HF molecule pro-
moted by a lithiated base.
NaH, solvent
r.t., 30 min
HN
NaN
N
O
O
O
4a
7a
Entry
R
Conditionsa
Conversionb (%)
1
2
3
4
5
6
7
Ts
Ts
Ts
Ts
Ts
Tf
Tf
THF, r.t., 24 h
THF, 65 °C, 24 h
0
0
DMF, 60 °C, 24 h
DMF, 150 °C, 24 h
DMF, 150 °C, 72 h
THF, 65 °C, 24 h
DMF, r.t., 0.5 h
5
Thus, we attempted a new indirect approach to 3a starting
via the intermediate 7a that would be reached through
N-2,2,2-trifluoroethylation of 4a (Table 1).
60
90c
0
Initially, we considered that product 7a could be obtained
by treatment of the corresponding sodium salt of 4a, pro-
duced via exposure of 4a to NaH, with CF3CH2OTs in
THF at room temperature (Table 1, entry 1). However, no
desired product formation was observed, even at higher
temperature (65 °C, Table 1, entry 2). A better solvent for
the alkylation such as DMF was next used. At 65 °C, the
reaction proceeded, but slowly (5% of conversion after 24
h, entry 3). By increasing the reaction temperature up to
150 °C, the conversion could be notably enhanced
(Table 1, entries 4 and 5). Nevertheless, at this tempera-
ture, other side reactions occurred with DMF and ren-
dered the purification more difficult, thus lowering the
yield. The sluggish reaction with CF3CH2OTs was attrib-
uted to the fact that a strong electron-withdrawing trifluo-
romethyl group (CF3) could effectively stabilize the
neighboring CO bond, which rendered the tosylate group
hard to remove. On this basis, we envisioned that trifluo-
romethanesulfonate as leaving group should certainly
provide the desired product 7a. This reaction was ineffi-
cient when conducted in THF (Table 1, entry 6) but to our
delight, this reaction carried out in DMF smoothly afford-
100d
a Concentration = 1 M (1 mmol of 4a, 1 mL of solvent).
b Based on 1H NMR signals of CH2N protons of 4a and 7a.
c Yield of isolated product: 40%.
d Yield of isolated product: 75%.
ed the product 7a at room temperature. The white slurry
of the sodium salt of 4a disappeared rapidly at the end of
the addition of CF3CH2OTf 11 (Table 1, entry 7). The op-
timized conditions were next applied to give 7b,c11 in ex-
cellent yields (Scheme 3).
O
CF3
O
F3C OTf
(1 equiv)
O
NaH, DMF
r.t., 30 min
NaN
R1
NH
R2
N
O
O
O
R1
DMF
R1
R2
r.t., 30 min
R2
7a
R1 = R2 = H
1 = H, R2 = Ph
1 = i-Pr, R2 = H
4a
4b
4c
75%
90%
80%
7b
7c
R
R
Scheme 3
Synlett 2009, No. 15, 2492–2496 © Thieme Stuttgart · New York

2494
T. B. Nguyen et al.
LETTER
With 7a–c in hand, we then focused on the elimination
reaction of HF to prepare 3a–c. We were pleased to find
that n-BuLi could be used effectively and the products
3a,c were obtained in high yields (Scheme 4).11
O
H5
N
N
COOEt
Bn
F
F
COOEt
F
F
O
O
O
N
N
Bn
H5
O
H3
H3
O
F
F
CF3
cis-9a
O
O
trans-9a
1) n-BuLi (2.1 equiv)
THF, –78 °C, 30 min
N
N
Figure 2
2) THF–H2O, –20 °C
O
O
R1
R1
R2
R2
F
F
F
CO2Et
Ph
F
EtO2C
Bn
R1 = R2 = H
1 = H, R2 = Ph
1 = i-Pr, R2 = H
81%
83%
81%
O
3a
3b
3c
1) TMSOTf
(1 equiv)
CHCl3
7a
7b
7c
Bn
R
R
N
O
N
N
N
O
O
O
r.t., 7 d
2) aq NaHCO3
Ph
O
Scheme 4
8
9b
3b
1 equiv
dr = 50:30:20:0
82%
Our first attempts to carry out a [3+2]-dipolar cycloaddi-
tion reaction involving the difluoroenamide 3a as the di-
polarophile were conducted under thermal solvent-free
conditions8c and resulted in the degradation of nitrone 8
and in the recovery of 3a (Scheme 5). At this time, we
turned to a specific activation of nitrone 8 with TMSOTf12
which was found to promote efficiently the addition–
cyclization reaction between 8 and b,b-di-C-substituted
N-vinyloxazolidin-2-ones.8b Treatment of an equimolar
mixture of 8 and 3a with a stoichiometric amount of
TMSOTf at room temperature and in CHCl3 led to the
clean formation of the adduct 9a. However, completion of
the reaction (monitored by NMR) required one week.11
Scheme 6
heterocycloaddition of a gem-difluorinated Danishefsky’s
diene with aldehydes and imines to give difluorinated het-
eroadducts was described by Uneyama’s group.14 In con-
trast, to the best of our knowledge, no report concerned
hetero-Diels–Alder reactions involving gem-difluoro-
alkenes as dienophiles toward oxadienes.
Our study on the reactivity of the difluoroenamides 3 was
thus expanded to the [4+2]-cycloaddition with the repre-
sentative oxadiene 10 (Table 2) under various conditions.
Initial investigations began with uncatalyzed solvent-free
thermal conditions which proved to promote the cycload-
dition, albeit with a low cis selectivity (Table 2, entry 1).
Application of previously reported conditions using
Lewis acids,9 such as Eu(fod)3-catalyzed or SnCl4-pro-
moted reactions, proved ineffective when applied to the
difluoroenamide 3a, with either recovery of starting mate-
rials (entry 2) or low conversion (entry 3). Interestingly,
once again TMSOTf was shown to be highly efficient and
led to the clean formation of the desired adduct 11a in
good yield and moderate selectivity (entry 4).11 We next
thought to improve the selectivity of the cycloaddition
process by lowering the reaction temperature to –20 °C. In
order to ensure an appropriate reaction time, the concen-
tration must be as high as possible (entry 5). Under these
conditions, a total conversion was observed after 72 hours
with a slight enhancement of yield and selectivity
(cis:trans up to 88:12).
CO2Et
F
CO2Et
F
F
Bn
Bn
F
EtO2C
Bn
N
TMSOTf
(1 equiv)
N
O
F
F
O
+
O
+
N
N
CHCl3
r.t., 7 d
N
O
N
O
O
O
O
O
8
3a (1 equiv)
cis-9a
48%
trans-9a
43%
Scheme 5
After basic workup (aq NaHCO3) the adduct 9a was ob-
tained as a nearly equimolar mixture of cis and trans iso-
mers which could be easily separated by column
chromatography (48% cis-9a, 43% trans-9a). The relative
configuration of these isolated adducts was determined by
1H NMR NOESY experiments as shown for compounds
cis-9a and trans-9a (Figure 2); the presence of a correla-
tion peak between H-3 and H-5 allowing to deduce the cis
relationship between the ester and oxazolidinone moi-
eties.
The geometry of both adducts could be conveniently de-
duced from the NOESY experiments as demonstrated in
Figure 3 for cis-11a with intense correlation peak between
H-6 and H-4, absent for trans-11a.
The same conditions applied to the reaction between
chiral enamide 3b and 8 led to the formation of a
50:30:20:0 mixture of the corresponding adduct 9b in
83% global yield (Scheme 6).11,13
Finally, the same conditions were applied to the reaction
between chiral enamide 3b and 10 and led to the forma-
tion of the four possible adducts in good yield and poor se-
lectivity (Scheme 7).11,15
In the literature, examples of heterosubstituted gem-difluo-
roalkenes acting as dienophiles was restricted to homo-
Diels–Alder reactions with electron-rich dienes.5a,f The
In this study, N-(b,b-difluorovinyl)oxazolidin-2-ones 3a–
c were synthesized in good yields by a two-step sequence
Synlett 2009, No. 15, 2492–2496 © Thieme Stuttgart · New York

LETTER
N-(b,b-Difluorovinyl)oxazolidin-2-ones
2495
Table 2 [4+2]-Cycloaddition of Oxadiene 10 with Difluoroenamide 3a
Ph
Ph
F
Ph
F
F
F
O
F
F
conditions
O
O
N
MeO2C
O
MeO2C
O
N
O
N
MeO2C
O
O
O
3a (1 equiv)
cis-11a
10
trans-11a
Entry
Conditions
Ratioa
Yieldb (%)
cis/trans
1
2
130 °C, 16 h
Eu(fod)3c (5 mol%), 80 °C, 72 h
67:33
–
74
0
c = 0.2 M (0.2 mmol 10 in 1 mL cyclohexane)
3
4
5
SnCl4 (1 equiv), r.t., 24 h
c = 0.2 M (0.2 mmol 10 in 1 mL CH2Cl2)
83:17
84:16
88:12
<20d
89
TMSOTf (1 equiv.), r.t., 72 h
c = 0.2 M (0.2 mmol 10 in 1 mL CHCl3)
TMSOTf (1 equiv), –20 °C, 72 h
96
c = 2 M (2 mmol 10 in 1 mL CHCl3)
a Based on 1H NMR of crude mixture.
b Yield of of isolated product
c fod: 6,6,7,7,8,8,8-heptafluoropropyl-2,2-dimethyl-3,5-octanedianato.
d Conversion: 20%.
F
H
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
MeO2C
F
O
N
H3
O
H
Acknowledgment
H4
O
H6
cis-11a
We thank the French Ministry of Research for Nguyen Thanh
Binh’s PhD grant.
Figure 3
References and Notes
(1) (a) Thayer, A. M. Chem. Eng. News 2006, 84 (23), 15.
(b) Thayer, A. M. Chem. Eng. News 2006, 84 (23), 27.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (b) Kirk, K. L. Org. Process
Res. Dev. 2008, 12, 305. (c) O’Hagan, D. Chem. Soc. Rev.
2008, 37, 308. (d) Müller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (e) Sun, S.; Adejare, A. Curr. Top.
Med. Chem. 2006, 6, 1457. (f) Iseki, K. Tetrahedron 1998,
54, 13887. (g) Welch, J. T.; Eswarakrishnan, S. Fluorine in
Bioorganic Chemistry; Wiley: New York, 1991. (h) Tozer,
M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8219. (i) Welch,
J. T. Tetrahedron 1987, 43, 3123.
Ph
O
F
Ph
O
F
F
1) TMSOTf
(1 equiv)
CHCl3
O
F
O
N
–20 °C ,7 d
MeO2C
N
O
O
MeO2C
2) NaHCO3
Ph
Ph
11b
10
3b
(1 equiv)
dr = 52:22:18:8
88%
Scheme 7
(3) Singh, R. P.; Schreeve, J. M. Synthesis 2002, 2561.
(4) Percy, J. M. Top. Curr. Chem. 1997, 193, 131.
(5) (a) Arany, A.; Crowley, P. J.; Fawcett, J.; Hursthouse, M. B.;
Kariuki, B. M.; Light, M. E.; Moralee, A. C.; Percy, J. M.;
Salafia, V. Org. Biomol. Chem. 2004, 2, 455. (b) Okano, T.;
Nakajima, A.; Eguchi, S. Synlett 2001, 1449.
from oxazolidin-2-ones. Their reaction with ester nitrone
8 and with heterodiene 10 under TMSOTf-promoted con-
ditions afforded in high yields a set of original adducts
containing a CF2 moiety with a total regioselectivity. This
unprecedented use of azadifluoroalkenes as cycloreac-
tants opens a way to a new family of cycloadducts hardly
accessible by conventional strategies and of potent bio-
logical interest. Further application of difluoroenamides 3
and of the corresponding heterocycloadducts 9 and 11 are
currently under investigation.
(c) Purrington, S. Z.; Thomas, H. N. J. Fluorine Chem. 1998,
90, 47. (d) Howarth, J. A.; Owton, W. M.; Percy, J. M.
Tetrahedron 1995, 51, 10289. (e) Bennette, A. J.; Percy,
J. M. Synlett 1992, 483. (f) Percy, J. M.; Rock, M. H.
Tetrahedron Lett. 1992, 33, 6177.
Synlett 2009, No. 15, 2492–2496 © Thieme Stuttgart · New York

2496
T. B. Nguyen et al.
LETTER
(6) (a) Gogsig, T. M.; Sobjerg, L. S.; Lindhardt, A. T.; Jensen,
K. L.; Skrydstrup, T. J. Org. Chem. 2008, 73, 3404.
(b) Fang, X.; Wu, Y. M.; Deng, J.; Wang, S. W. Tetrahedron
2004, 60, 5487. (c) Ichikawa, J.; Wada, Y.; Fujiwara, M.;
Sakoda, K. Synthesis 2002, 1917. (d) Ichikawa, J.
J. Fluorine Chem. 2000, 105, 257. (e) Ichikawa, J.;
Fujiwara, M.; Nawata, H.; Okauchi, T.; Manami, T.
Tetrahedron Lett. 1996, 37, 8799. (f) Ichikawa, J.; Ikeura,
C.; Minami, T. Synlett 1992, 739. (g) Ichikawa, J.; Hamada,
S.; Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1992, 33,
337. (h) Ichikawa, J.; Moriya, T.; Sonoda, T.; Kobayashi, H.
Chem. Lett. 1991, 20, 961. (i) Ichikawa, J.; Sonoda, T.;
Kobayashi, H. Tetrahedron Lett. 1989, 30, 1641.
(8) (a) Nguyen, T. B.; Vuong, T. M. H.; Martel, A.; Dhal, R.;
Dujardin, G. Tetrahedron: Asymmetry 2008, 19, 2084.
(b) Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Synlett
2008, 2041. (c) Nguyen, T. B.; Martel, A.; Dhal, R.;
Dujardin, G. J. Org. Chem. 2008, 73, 2621. (d) Nguyen,
T. B.; Gaulon, C.; Chapin, T.; Tardy, S.; Tatibouet, A.;
Rollin, P.; Dhal, R.; Martel, A.; Dujardin, G. Synlett 2006,
3255.
(9) (a) Gohier, F.; Bouhadjera, K.; Faye, D.; Gaulon, C.;
Maisonneuve, V.; Dujardin, G.; Dhal, R. Org. Lett. 2007, 9,
211. (b) Gaulon, C.; Dhal, R.; Chapin, T.; Maisonneuve, V.;
Dujardin, G. J. Org. Chem. 2004, 69, 4192. (c) Gaulon, C.;
Gizecki, P.; Dhal, R.; Dujardin, G. Synthesis 2003, 2269.
(d) Gaulon, C.; Gizecki, P.; Dhal, R.; Dujardin, G. Synlett
2002, 952.
(j) Ichikawa, J.; Sonoda, T.; Kobayashi, H. Tetrahedron Lett.
1989, 30, 5437. (k) Ichikawa, J.; Sonoda, T.; Kobayashi, H.
Tetrahedron Lett. 1989, 30, 6379. (l) Tanaka, K.; Nakai, T.;
Ishikawa, N. Tetrahedron Lett. 1978, 4809. (m) Percy, J. M.
Tetrahedron Lett. 1990, 31, 3931.
(10) (a) Feiring, A. E.; Wonchoba, E. R. J. Org. Chem. 1992, 57,
7014. (b) Dlouba, I.; Kvicala, J.; Paleta, O. J. Fluorine
Chem. 2002, 117, 149.
(7) (a) Fustero, S.; Sanz-Cervera, J. F.; Aceña, J. L.; Sánchez-
Roselló, M. Synlett 2009, 525. (b) Zhi, L.; Van Oeveren,
C. A.; Chen, J.-H.; Higuchi, R. I. PCT Int. Appl.,
WO 2002066475, A220020829, 2002. (c) Kudo, Y.;
Katsumata, A.; Maeda, K.; Akiyama, S.; Yaosaka, M.;
Morimoto, K.; Nakahira, K.; Ohki, T.; Hamada, N.;
Yano, T.; Noguchi, J.; Watanabe, S. PCT Int. Appl.,
WO 2001068613, A120010920, 2001. (d) Okamoto, H.;
Kato, S. Jpn. Kokai Tokkyo Koho, JP 02178259,
(11) Procedures and compounds are described in the
Supplementary Information.
(12) Dhavale, D. D.; Trombini, C. J. Chem. Soc., Chem.
Commun. 1992, 1268.
(13) Only minor adduct 9b, of cis configuration, could be
separated from the adduct mixture by column chroma-
tography.
(14) Amiii, H.; Kobayashi, T.; Terasawa, H.; Uneyama, K.
Org. Lett. 2001, 3, 3103.
A19900711, 1990. (e) Haszeldine, R. N.; Tipping, A. E.
J. Chem. Soc. C 1968, 4, 398.
(15) From the NMR study on adduct 11b, the cis/trans
distribution (cis I/cis II/trans I/trans II = 52:22:18:8) was
deduced.
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