TMAF-catalyzed conjugate addition of oxazolidinone and thiols

Article abstract of DOI:10.1055/s-2004-836057

TMAF (Me₄NF) is a useful catalyst for the conjugate addition of oxazolidinone and thiols to a range of Michael acceptors including esters, ketones, nitroolefins and cinnamaldehyde.

Full text of DOI:10.1055/s-2004-836057

LETTER
95
TMAF-Catalyzed Conjugate Addition of Oxazolidinone and Thiols
T
MAF-Catalyzed Con
i
c
ddition of
k
O
xazolidino
a
ne and Thio
ë
ls l Ménand,a Vincent Dalla*b
a
Structure et Fonction de Molécules Bioactives – UMR CNRS 7613 – Équipe ‘Chimie des Glucides’, Université Pierre et Marie Curie,
4 place Jussieu, 75252 Paris CEDEX 05, France
Unité de Recherche en Chimie Organique et Macromoléculaire, Faculté des Sciences et Techniques de l'Université du Havre,
25 rue Philippe Lebon, BP 540, 76058 Le Havre CEDEX, France
b
Fax +33(2)32744391; E-mail: vincent.dalla@univ-lehavre.fr
Received 8 October 2004
efficient catalyst for the conjugate addition of simple eno-
lates derived from a-trialkylsilyl esters.9 The conjugate
addition of thiols under guidance of TBAF has also been
established, but the study remained limited to a restricted
range of activated olefins.10 We communicate herein an
extension of the useful potential of ammonium fluorides
in organic synthesis, by demonstrating their effectiveness
as catalysts for the quite rare5 conjugate addition of oxazo-
lidinone to various electrophilic olefins. We also present
some results that broaden the scope of the usable thiol/ac-
ceptor combinations. In the first part of this work, we
evaluated the conjugate addition of oxazolidinone 1a to
various enoates (Table 1). We initially chose TMAF as a
source of anhydrous catalyst. A first series of experiments
using methyl crotonate 2b as a model substrate allowed us
to select acetonitrile as the more convenient solvent.
These preliminary attempts also revealed that the reaction
did not go to completion below 20 mol% of catalyst load-
ing. Unfortunately, this reaction considerably lacks gener-
ality with respect to the ester structure. Of the enoates
tested, only the most reactive tert-butyl acrylate 2a and
methyl crotonate 2b gave complete conversion affording
after three days the b-amino adducts 3a,b in high yields
(runs 1, 2). There was no reaction in the absence of the
catalyst, indicating that this was indeed a fluoride-mediat-
ed reaction. Small variations in the electronic nature of the
ester structure dramatically affected the reaction profile.
For instance, a slight growth of the electron-donating
properties of the alkoxy group in the crotonate series in-
duced a gradual decrease of the yield of adducts 3b–d
(runs 2–5).
Abstract: TMAF (Me4NF) is a useful catalyst for the conjugate
addition of oxazolidinone and thiols to a range of Michael acceptors
including esters, ketones, nitroolefins and cinnamaldehyde.
Key words: ammonium fluoride, catalysis, Michael addition, ox-
azolidinone, thiols
In 1947, Knunyants and coworkers reported the first ex-
amples of organic reactions promoted by a fluoride ion.1
This initial report has since been followed by many others,
installing the fluoride-mediated generation of anions (ei-
ther via fluorodesilylation of organosilicon substrates or
through fluorodeprotonation) for selective bond-forming
reactions to an important place in modern organic synthe-
sis.2 While metal fluorides (e.g. KF and CsF) were used
extensively in former times,2a,b reports concerning with
the use of tetraalkylammonium fluorides (R4NF) are in-
creasingly widespread and are testament to the increasing
value of these reagents in organic synthesis.3 Applications
have culminated in the development of chiral non-racemic
ammonium fluoride ions and their use in some impressive
catalytic asymmetric C-C bond forming processes.4
Otherwise, the conjugate addition of carbamates to unsat-
urated carboxylic acid derivatives provides the most di-
rect access to the synthetically useful b-amino acid core.
The weakly nucleophilic properties of carbamates have
precluded the development of such methodologies which,
in turn, have only been recently the subject of investiga-
tions.5 In this context, the 1,4-alkylation of oxazolidinone
is an interesting process in its own right, regarding the oc-
currence of pharmaceuticals incorporating an oxazolidi-
none moiety,6 and in conjunction with the fact that
oxazolidinone constitutes a ‘naked’ ethanolamine frag-
ment. Within a general program aimed at developing new
applications in aza Michael reactions,7,8 we have been in-
terested in evaluating the potential of ammonium fluo-
rides keeping in mind that this approach could further
readily open to an enantioselective variant.4 The popular-
ity of ammonium fluorides as catalysts for the Michael
addition of nitroalkanes and active methylene pronucleo-
philes to a variety of acceptors has long been recog-
nized.2b Recently, TMAF has been demonstrated as an
Other methyl enoates like those bearing R1 = C9H19 (2e),
i-Pr (2f) or Ph (2g) as a substituent on the b-carbon failed
to give the desired adducts in good yield.
Next, we shifted towards studying the merit of enones as
conjugate acceptor components, starting with chalcones
4a–e – a typical class of unreactive enones – towards car-
bamates (Table 2).5g An initial experiment with 4a using
the standard procedure, gave a poor conversion in con-
junction with formation of unidentified side-products.
Closer inspection of the reaction conditions revealed that
the use of four equivalents of 1a provided a good compro-
mise between conversion, yield of 5a and diminution of
side-products (run 1).11 These modified conditions could
be applied to the other chalcones 4b–e, affording the ex-
pected adducts 5b–e in comparable yields (runs 2–5).
SYNLETT 2005, No. 1, pp 0095–0098
0
5.
0
1.
2
0
0
5
Advanced online publication: 02.12.2004
DOI: 10.1055/s-2004-836057; Art ID: G40304ST
© Georg Thieme Verlag Stuttgart · New York

96
M. Ménand, V. Dalla
LETTER
Table 1 Aza-Michael Reactions of 1a with Enoates 2a–g
Other enones 6 and 7 were also evaluated and provided
the expected adducts 8 and 9 in good to excellent yields
with better reaction profiles (runs 7 and 8). The complete
conversion exhibited by cyclohexenone 7 with reduced
amount of catalyst emphasized its higher reactivity in this
reaction (run 8). On the other hand, cyclopentenone
remained almost unreactive under standard conditions.
O
O
O
O
Me4NF
N
O
O
NH
R
X
+
MeCN, r.t.
R
X
1a
2a–h
3a–h
Runa
Acceptor
R
Adduct
Yield (%)b,c
On the basis of these results, we were interested in exam-
ining further the generality of our TMAF version in the
context of thiol 1,4-additions. The only reports dealing
with TBAF-catalyzed conjugate alkylation of thiophenol
has been limited to acrylates and simple aliphatic enone
acceptors.10 Experiments that probe the scope of the
usable thiol/acceptor combinations are summarized in
Table 3.
X
1
H
Ot-Bu
OMe
OEt
2a
2b
2c
2c
2d
3a
3b
3c
3c
3d
90
2
Me
Me
Me
Me
86
3
N.d. (50)
N.d. (50)
No reaction
4d
5d
OEt
Ot-Bu
In contrast to the case of oxazolidinone additions, there
appears to be significant latitude in the structure of accep-
tors to enable access to a broad variety of thio-adducts.
Reactions of thiophenol 10a with esters 2c, 2f and 2g – a
range of poor acceptors towards oxazolidinone additions
– (Table 1 and comments thereof), are using the standard
procedure showed promising reaction profiles.
a Unless otherwise indicated, the reactions were carried out with an
oxazolidinone:conjugate acceptor ratio of 1.2:1 at a concentration of
0.5 mol L–1 for 3 d.
b Isolated yields are given.
c The conversion is indicated in brackets and was established by 1H
NMR spectroscopy on the crude product.
d The reaction was carried out at a concentration of 2 mol L–1.
Maximum reactivity could be achieved upon increasing
the concentration by a 4 (runs 1, 2) or a 8 (run 3) fold fac-
tor, giving the desired adducts 13–15 in good yields.
When the reaction was carried out with the ortho-substi-
tuted enones 4d,e, formation of side-products was sup-
pressed, however, at the expense of conversion (runs 4, 5).
Although the use of 10 equivalents of oxazolidinone in the
reaction of 4b afforded the adduct 5b in a slightly aug-
mented yield of 78%, the formation of impurities was not
suppressed (run 6).
The purification of the cinnamyl adduct 15 was precluded
by co-elution with the recovered (ca. 25%) cinnamic acid
methyl ester 2g (run 3). Chalcone 4b, cyclohexenone (7),
nitrostyrene 11 and cinnamaldehyde 12 turned out to be
extremely reactive towards thiophenol, affording after
Table 2 Aza-Michael Reactions of 1a with Various Enones
Run
1c
Enone
Me4NF (equiv)
0.2
Time (h)
96
Adduct
Yield (%)a,b
55 (88)
O
4a
5a
Ph
Ph-p-F
2c
3c
4c
5c
6d
7c
8e
4b
4c
4d
4e
4b
6
0.2
0.2
0.2
0.2
0.2
0.2
0.1
96
96
96
96
96
96
72
5b
5c
5d
5e
5b
8
70 (93)
65 (92)
70 (75)
65 (74)
78 (95)
82 (85)
82 (100)
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph-o-OMe
O
O
O
Ph
Ph
Ph
Ph-o-Cl
Ph
Me
7
9
O
a Isolated yields are given.
b Conversion is indicated between brackets.
c Reaction carried out with 4 equiv of 1a.
d Reaction carried out with 10 equiv of 1a.
e Reaction carried out with 1 equiv of 1a.
Synlett 2005, No. 1, 95–98 © Thieme Stuttgart · New York

LETTER
TMAF-Catalyzed Conjugate Addition of Oxazolidinone and Thiols
97
Table 3 Michael Additions of Thiols 1 with Various Conjugate Acceptors
SR
Me4NF
EWG
R1
EWG
R1
RSH
+
MeCN, r.t.
Run
Thiol
R
Acceptor
R1
Me4NF (equiv)
Time (h)
Adduct
Yield (%)a
EWG
CO2Et
CO2Me
CO2Me
COPh
NO2
1b
2b
3c
4e
5e
6e
7e
8e
9e
Ph
10a
10a
10a
10a
10a
10a
10a
10b
10c
Me
i-Pr
Ph
2c
2f
0.2
96
96
96
1
13
14
15
16
17
18
19
20
21
76
Ph
0.2
77
Ph
2g
4b
11
12
7
0.2
75d
Ph
Ph
0.02
0.02
0.02
0.02
0.02
0.02
100f
100f
60g
Ph
Ph
1
Ph
Ph
CHO
1
Ph
cyclohexenone
1
100f
100f
100f
Ph(CH2)2
CH2CO2Me
Ph
Ph
COPh
COPh
4b
4b
1
30
a Isolated yields are given.
b Reaction carried out at a concentration of 2 mol L–1 with a thiol-conjugate acceptor ratio of 1.2:1.
c Reaction carried out at a concentration of 4 mol L–1 with a thiol-conjugate acceptor ratio of 1.2:1.
d Yield estimated by 1H NMR spectroscopy on the crude product.
e Reaction carried out with 1 equiv of thiol.
f Crude yield.
g Isolated yield given after immediate NaBH4 reduction of the solution of the aldehyde adduct.
2003, 1693. (d) Aldol reaction: Ando, A.; Miura, T.;
Tamematsu, T.; Shioiri, T. Tetrahedron Lett. 1993, 34,
one hour (time not optimized) the b-thio adducts 16–19 in
high yields with very low amounts of catalyst (runs 4–7).
This TMAF-catalyzed process also promoted the addition
of aliphatic thiols with high efficiency (runs 8, 9).
1507. (e) Ando, A.; Bohsako, A.; Shioiri, T. Heterocycles
1996, 42, 93. (f) Horikawa, M.; Busch-Petersen, J.; Corey,
E. J. Tetrahedron Lett. 1999, 40, 3843. (g) Ooi, T.; Doda,
K.; Maruoka, K. Org. Lett. 2001, 3, 1273. (h) Nitroaldol
reaction: Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc.
2003, 125, 2054. (i) Corey, E. J.; Zhang, F. Y. Angew.
Chem. Int. Ed. 1999, 38, 1931. (j) Conjugate addition of
nitroalkanes: Colonna, S.; Hiemstra, H.; Wynberg, H. J.
Chem. Soc., Chem. Commun. 1978, 238. (k) Corey, E. J.;
Zhang, F. Y. Org. Lett. 2000, 2, 4257. (l) Ooi, T.; Doda, K.;
Maruoka, K. J. Am. Chem. Soc. 2003, 125, 9022.
In summary, we have reported new aspects of ammonium
fluoride chemistry, by demonstrating for the first time the
efficiency of TMAF as a catalyst for the conjugate addi-
tion of oxazolidinone to enones and highly reactive
enoates. The present catalytic system also exhibited a
large spectrum of thiol/Michael acceptor combinations.
(5) For Lewis acid-catalyzed (5a–c, 5f–g and 5j–l) and Brønsted
acid-catalyzed (5d,e and 5i) conjugate additions of
carbamates to enones: (a) Gaunt, M. J.; Spencer, J. B. Org.
Lett. 2001, 3, 25. (b) Kakumoto, K.; Sugiura, M.;
References
(1) Knunyants, I. L.; Kildisheva, O. A.; Bykhovskaya, E. G.
Dokl. Akad. Nauk 1947, 67, 49.
Kobayashi, S. Org. Lett. 2002, 4, 1319. (c) Wabnitz, T. C.;
Spencer, J. B. Tetrahedron Lett. 2002, 43, 3891.
(2) For reviews, see: (a) Yakobson, G. G.; Akhmetova, N. E.
Synthesis 1983, 169. (b) Clark, J. H. Chem. Rev. 1980, 80,
429. (c) Surya Prakash, G. K.; Yudin, A. K. Chem. Rev.
1997, 97, 757. (d) Blass, B. E. Tetrahedron 2002, 58, 9301.
(3) For some recent selected references: (a) DeShong, P.;
Pilcher, A. S. J. Org. Chem. 1996, 61, 6901. (b) Konno, H.;
Toshiro, E.; Hinoda, N. Synthesis 2003, 2161. (c) Satoh, T.;
Shimura, T.; Sakai, K. Heterocycles 2003, 59, 137.
(d) Amishiro, N.; Denmark, S. E. J. Org. Chem. 2003, 68,
6997.
(4) (a) For a recent review, see: Ooi, T.; Maruoka, K. Acc.
Chem. Res. 2004, 37, 526. (b) For leading references, see:
Trifluoromethylation of aldehydes: Iseki, K.; Nagai, T.;
Kobayashi, Y. Tetrahedron Lett. 1994, 35, 3137. (c) See
also: Caron, S.; Do, N. M.; Arpin, P.; Larivée, A. Synthesis
(d) Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Synlett 2003,
1070. (e) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5,
2141. (f) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003,
68, 2109. (g) Xu, L.-W.; Xia, C.-G.; Hu, X.-X. Chem.
Commun. 2003, 2570. (h) Xu, L.-W.; Li, L.; Xia, C.-G.;
Zhou, S.-L.; Li, J.-W.; Hu, X.-X. Synlett 2003, 2337.
(i) Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Chem.–Eur. J.
2004, 10, 484. (j) Takasu, K.; Nishida, N.; Ihara, M. Synlett
2004, 1844. (k) Palomo, C.; Oiarbide, M.; Halder, R.; Kelso,
M.; Gomez-Bengoa, E.; Garcia, J. M. J. Am. Chem. Soc.
2004, 126, 9188. (l) Xu, L.-W.; Xia, C.-G. Synthesis 2004,
2191.
Synlett 2005, No. 1, 95–98 © Thieme Stuttgart · New York

98
M. Ménand, V. Dalla
LETTER
(6) See for example: (a) Madhusudhan, G.; Reddy, G. O.;
Ramanathan, J.; Dubey, P. K. Tetrahedron Lett. 2003, 44,
6323. (b) Mallesham, B.; Rajesh, B. M.; Rajamohan Reddy,
P.; Srinivas, D.; Trehan, S. Org. Lett. 2003, 5, 963.
(7) Tranchant, M. J.; Dalla, V.; Jabin, I.; Decroix, B.
Tetrahedron 2002, 58, 8425.
(8) Tranchant, M. J.; Dalla, V. Org. Lett. accepted, under
revision.
(9) Brulé, C.; Bouillon, J. P.; Portella, C. Tetrahedron 2004, 60,
9849.
(10) (a) Kuwajima, I.; Murofushi, T.; Nakamura, E. Synthesis
1976, 602. (b) Miller, J. M.; Carter, S. R.; So, K. H.; Clark,
J. H. Can. J. Chem. 1979, 57, 2629.
(11) General Procedure and Representative Data for the
Reaction of Oxazolidinone with Acyclic Enones.
To a solution of type 4 chalcone (1 mmol) and oxazolidinone
1a (378 mg, 4 mmol) in anhyd MeCN (2 mL) was added dry
Me4NF (19 mg, 0.2 mmol) in one portion. After stirring of
the resulting pale yellow solution for 3 d, H2O and Et2O (3
mL each) were added, followed by the addition of few drops
of aq HCl 1 mol L–1 and a spatula of NaCl. After stirring the
biphasic system for 5 min, the two phases were separated,
the aqueous layer was extracted two times with Et2O. The
organic layer was dried over MgSO4, concentrated and
purified by flash chromatography, eluting with
cyclohexane–EtOAc (1:1).
3-N-Oxazolidinyl-1-(p-F-phenyl)-3-phenylpropan-1-one
(5a): white solid; yield 173 mg, 55%; mp 135 °C. IR
(CHCl3): n = 1747, 1685 cm–1. 1H NMR (200 MHz, CDCl3,
25 °C): d = 3.47 (quint, J = 8.6 Hz, 1 H), 3.51 (dd, J = 6.3,
16.4 Hz, 1 H), 3.55 (quint, J = 8.6 Hz, 1 H), 4.05 (dd, J = 8.6,
16.4 Hz, 1 H), 4.24 (quint, J = 8.6 Hz, 2 H), 5.29 (dd, J = 6.3,
8.6 Hz, 1 H), 7.03–7.18 (m, 2 H), 7.25–7.44 (m, 5 H), 7.91–
8.05 (m, 2 H). 13C NMR (50 MHz, CDCl3, 25 °C): d = 40.4,
43.4, 54.6, 62.0, 115.6, 116.1, 127.3, 128.3, 128.9, 130.8,
131.0, 132.7, 132.8, 138.4, 157.7, 163.4, 168.4, 195.5.
LRMS: m/z (%) = 313 (2) [M+], 225 (66), 131 (29), 123
(base), 103 (53), 95 (85), 77 (30). Anal. Calcd for
C18H16FNO3 (313.33): C, 69.00; H, 5.15; N, 4.47; Found C,
69.05; H, 5.21; N, 4.48.
Synlett 2005, No. 1, 95–98 © Thieme Stuttgart · New York