A facile synthesis of 4-methylene-1,3-oxazolidines from γ-hydroxybutynoate and N-tosylimines

Article abstract of DOI:10.1016/j.tetlet.2009.06.009

Both nucleophilic and basic catalysts have been used to promote the cyclization reactions between γ-hydroxybutynoate and N-tosylimines to afford 4-methylene-1,3-oxazolidines in good yields. E- and Z-isomers of the final products have been isolated and cha

Full text of DOI:10.1016/j.tetlet.2009.06.009

Tetrahedron Letters 50 (2009) 4700–4702
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Tetrahedron Letters
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A facile synthesis of 4-methylene-1,3-oxazolidines from
c-hydroxybutynoate
and N-tosylimines
*
Nicolas Fleury-Brégeot, Arnaud Voituriez, Pascal Retailleau, Angela Marinetti
Institut de Chimie des Substances Naturelles, CNRS UPR 2301 – 1, av. de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Both nucleophilic and basic catalysts have been used to promote the cyclization reactions between
-hydroxybutynoate and N-tosylimines to afford 4-methylene-1,3-oxazolidines in good yields. E- and Z-
isomers of the final products have been isolated and characterized by NMR spectroscopy and X-ray data.
Received 6 May 2009
Revised 28 May 2009
Accepted 2 June 2009
Available online 6 June 2009
c
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Phosphine catalyzed
Activated propargylic alcohol
Methyleneoxazolidine
A number of literature reports highlight the catalytic generation
of strong bases by addition of nucleophilic phosphines to electron-
deficient unsaturated substrates.1 The thus formed zwitterionic
phosphonium salts are basic enough to deprotonate a variety of
carbon based2 and heteroatomic3 pronucleophiles including alco-
hols,4 and therefore initiate simple or multicomponent additions
as well as cyclization processes (Fig. 1).
R
Z
R
Z
NuH
Nu(-)
R
Z
(-)
(+)
R'3P
(+)
R'3P
electrophiles
PR'3
products
Among others, bifunctional substrates such as activated alkynes
bearing alcohol groups, have been used in organocatalytic pro-
cesses of this class in which the alcohol function behaves as the
pronucleophilic group.5 A recent relevant example from William-
son, typifies this strategy (Scheme 1).6 In this case, an alcoholate
function is generated by addition of a nucleophilic phosphine to
Figure 1. Organocatalytic generation of strong bases by addition of nucleophilic
phosphines to unsaturated substrates (umpolung process).
O
HO
CO2Me
R1
PBu3
CO2Et
+
EtO2C
MeO2C
R1
CO2Me
CO2Me
ethyl
c-hydroxy-2-butynoate and subsequent proton exchange
reaction. The alcoholate adds then to highly activated electrophilic
olefins to afford methylenetetrahydrofurans, via formal [3+2]
annulations.7
Scheme 1. Phosphine-promoted synthesis of methylenetetrahydrofurans.6
As a complement to this recent Letter we report herein on the
ture, in the presence of a 10 mol % amount of phosphine, the
reaction of the activated propargylic alcohol 1 with N-tosyl-benz-
aldimine 2a afforded indeed 4-methylene-1,3-oxazolidine 3a as
the unique reaction product (Scheme 2).9
analogous reaction of methyl
c-hydroxy-2-butynoate 1 with N-
tosylimines 2 promoted by phosphine catalysts. We also show that
the same cyclizations can be alternatively performed in the pres-
ence of inorganic bases.
During investigations into enantioselective phosphine-pro-
moted [3+2] cyclizations between alkynyl or allenic esters and imi-
nes,8 we noticed that PBu3 induces a clean reaction between
methyl 4-hydroxybutynoate 1 and N-tosylbenzaldimine, however
none of the expected 3-pyrroline was obtained. At room tempera-
O
Ts
HO
Ph
10 mol% PBu3
CH2Cl2, 24h
60%
N
+
MeO2C
CO2Me
N
Ts
Ph
1
2a
(E)-3a + (Z)-3a
Scheme 2. Phosphine-promoted cyclization between
tosylbenzaldimine.
c
-hydroxybutynoate and N-
* Corresponding author. Tel.: +33 1 6982 3036; fax: +33 1 6907 72 47.
E-mail address: angela.marinetti@icsn.cnrs-gif.fr (A. Marinetti).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.009

N. Fleury-Brégeot et al. / Tetrahedron Letters 50 (2009) 4700–4702
4701
Table 1
Synthesis of 4-methylene-1,3-oxazolidines from
c
-hydroxy-butynoate and N-
tosylimines
O
Ts
HO
PBu3 or K2CO3
r.t., 24 h
Ar
N
+
CO2Me
MeO2C
N
Ts
Ar
1
2a-g
3a-g
K2CO3
Yieldb (%)
PBu3
Ar
Ph
Yielda (%)
E:Z
E:Z
1
2
3
4
5
6
7
3a
60
60
78
95
55
60
<5
54:46c
57:43
56:44
60:40
66:34
60:40
—
91
98
94
91
64
88
86
62:38
60:40
72:28
66:34
65:35
70:30
67:33
1-Naphthyl
CH@CH–Ph
p-NO2–C6H4
p-CF3–C6H4
o-Me–C6H4
p-MeO–C6H4
3b
3c
3d
3e
3f
O
MeO
O
N
Ph
3g
Ts
a
b
c
Reactions performed in CH2Cl2 with a 10% amount of PBu3.
Reactions performed in ether at rt with a 20% amount of K2CO3.
A 65:35 E/Z ratio was obtained when the reaction was performed in ether.
Figure 2. ORTEP drawing of the 4-methylene-1,3-oxazoline (E)-3a.
by a proton exchange between the carbanionic moiety of A and
an hydroxyl function in either an intramolecular (path a) or an
intermolecular process (path b). The alcoholate B (or B0) adds then
to the imine and, finally, an intramolecular Michael reaction gives
oxazolidine 3, while regenerating the phosphine catalyst (or the
key intermediate A).
Since the postulated role of the phosphine is primarily to gener-
ate a strong base, it is expected that the same cyclization reaction A
might take place in the presence of other organic or inorganic
bases. Oxazolidines 3a have been obtained indeed in good yields
by reacting 1 and 2 in the presence of either catalytic amounts of
DMAP (64% yield under the reaction conditions of Scheme 2) or
K2CO3 (in ether at room temperature, 91% yield). In the absence
of bases, no reaction is observed under the conditions mentioned
above. Phosphines such as PPh3 or P(iBu)3 are inactive, which likely
relates to their lower nucleophilic character, compared to PBu3.
The scope of the reaction has been demonstrated by variations
of the imine substituent, as shown in Table 1.
The cyclization product was obtained in 60% isolated yield, as a
mixture of E- and Z-isomers in a 54/46 ratio. The isomers were eas-
ily separated by column chromatography on silica gel and fully
characterized.10 The structural assignment and the stereochemis-
try of the double bond were unambiguously proved by X-ray dif-
fraction study of the E-isomer of 3a. The ORTEP drawing is
shown in Figure 2.
As far as we know, 4-methylene-1,3-oxazolidines have been
barely mentioned in the literature.11 2-Aryl-substituted oxazoli-
dines of this class have been reported only by Lhommet et al.11a
They have been obtained by reacting methyl hydroxybutynoate
with N-(1-phenylethyl)imines in refluxing toluene, in the presence
of hydroquinone. Thus, reaction shown in Scheme 2 affords an
alternative protocol in which phosphine-organocatalysis is applied
to promote these cyclizations under very mild conditions.
Two possible mechanisms for the cyclization reaction are
shown in Scheme 3. As the first step, both pathways involve addi-
tion of PBu3 to 1 to give the phosphonium salt A. This is followed
Starting from several N-tosylimines, the use of K2CO3 as the
base gives oxazolidines in uniformly high yields. For phosphine-
promoted reactions, conversion rates are somewhat lower and
higher substrate dependence is observed, with isolated yields of
between 55% and 95%. The electron-rich p-MeO-benzaldimine
failed to react in the presence of phosphine. Oxazolidines 3a–f
were formed as mixtures of the (E)- and (Z)-isomers in about
60:40 ratios, with only small differences being observed between
the two catalytic systems. Both isomers can be obtained separately
by chromatography on silica gel and 1H NMR data allow reliable
assignments of their respective E/Z stereochemistry. For instance,
the CH2 moieties display typical chemical shifts at d = 4.8–4.9
and 4.1–4.2 ppm for the E- and Z-isomers, respectively.
HO
1
CO2Me
PBu3
HO
(-)
path b
path a
HO
Bu3P(+) CO2Me
CO2Me
(-) O
Bu3P(+)
A
O(-)
P(+)
CO2Me
MeO2C
B'
B
Ts
Ts
N
A few attempts have been made using chiral phosphines as
nucleophilic catalysts with the aim of setting enantioselective pro-
cesses. Electron-rich phosphines such as (S)-t-Bu-Binepine12 and
(S,S)-Cy-FerroPHANE13 displayed good conversion rates, but the
enantiomeric excesses were lower than 10%.14
N
Ar
Ar
2
2
Ar
Ar
N(-)
O
P(+)
(-) N-Ts
Ts
O
In summary, the synthetic protocol reported here represents a
rapid and efficient access to 4-methylene-1,3-oxazolines, a rarely
described heterocyclic platform. The methyleneoxazolines 3 dis-
play interesting chemical features and functionalities and might
serve as suitable precursors to a variety of nitrogen-containing
compounds including b-substituted-b-aminoalcohols and the cor-
responding acids. The use of inorganic bases as catalysts is likely
to represent the easiest and most convenient approach to oxazoli-
dines 3 in racemic form, while the use of suitable chiral nucleo-
philes might open the way to enantiomerically enriched species.
CO2Me
C'
Bu3P(+)
CO2Me
- PBu3
C
Ar
Ts
A
-
N
O
CO2Me
3
CO2Me
HO
P(+)
=
Bu3P (+)
Scheme 3. Proposed key steps for the formation of 3.

4702
N. Fleury-Brégeot et al. / Tetrahedron Letters 50 (2009) 4700–4702
Gouverneur, V. Org. Lett. 2006, 8, 5417–5419; (d) Chung, Y. K.; Fu, G. C. Angew.
Supplementary data
Chem., Int. Ed. 2009, 48, 2225–2227.
6. Pedduri, Y.; Williamson, J. S. Tetrahedron Lett. 2008, 49, 6009–6012.
Experimental procedures and spectral data for compounds 3a–
g. X-ray crystal structure determination for (E)-3a. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.06.009.
7. For
a review on the synthesis of methylenetetrahydrofurans by [3+2]
annulations see: Yamazaki, S. Chem. Eur. J. 2008, 14, 6026–6036.
8. (a) Fleury-Brégeot, N.; Jean, L.; Retailleau, P.; Marinetti, A. Tetrahedron 2007, 63,
11920–11927; (b) Panossian, A.; Fleury-Brégeot, N.; Marinetti, A. Eur. J. Org.
Chem. 2008, 3826–3833.
9. A 10 mol % amount of tributylphosphine (50
lL, 1 M solution in toluene) was
added to a solution of methyl 4-hydroxybut-2-ynoate (57 mg, 0.5 mmol) and N-
tosylimine 2a (0.5 mmol) in anhydrous CH2Cl2 (2 mL) under argon atmosphere.
The resulting mixture was stirred at room temperature for 24 h and the solvents
were removed. The crude product was purified by TLC on silica gel plates
(heptane/ethyl acetate, 7/3 mixture) to give the pure Z- and E-isomers of the final
oxazolidine 3a. No defined by-products have been isolated from these reactions.
10. Compounds (E)-3a and (Z)-3a were separated by TLC on silica gel with a heptane/
ethyl acetate 7/3 mixture as the eluent. (E)-3a: Rf = 0.33; white solid (mp = 117–
120 °C); 1H NMR (300 MHz, CDCl3) d 2.45 (s, 3H), 3.69 (s, 3H), 4.94 (dd,
J = 15.6 Hz, J = 1.8 Hz, 1H), 4.99 (dd, J = 15.6 Hz, J = 1.8 Hz, 1H), 6.11 (t,
J = 1.8 Hz, 1H), 6.53 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.35–7.42 (m, 3H), 7.43–
7.50 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 21.8, 51.5,
70.9, 94.2, 95.9, 127.0, 127.7, 128.8, 129.6, 130.1, 134.7, 137.3, 145.5, 151.5,
167.5 ppm. Anal. Calcd for C19H19NO5S: C, 61.11; H, 5.13; N, 3.75. Found: C,
61.17; H, 5.07; N, 3.51. (Z)-3a. Rf = 0.22; colorless oil; 1H NMR (300 MHz,
CDCl3) d 2.47 (s, 3H), 3.87 (s, 3H), 4.15 (d, J = 13.5 Hz, 1H), 4.19 (d, J = 13.5 Hz,
1H), 5.58 (s, 1H), 6.52 (s, 1H), 7.30–7.40 (m, 5H), 7.53 (d, J = 8 Hz, 2H), 7.79 (d,
J = 8 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 21.8, 52.1, 68.2, 94.1, 106.6, 126.7,
128.1, 128.8, 129.3, 130.0, 135.1, 136.8, 144.1, 145.1, 166.0 ppm.
11. (a) David, O.; Vanucci-Bacqué, C.; Fargeau-Bellassoued, M.-C.; Lhommet, G.
Heterocycles 2004, 62, 839–846; (b) Tejedor, D.; González-Cruz, D.; García-
Tellado, F.; Marrero-Tellado, J. J.; Lopez Rodríguez, M. J. Am. Chem. Soc. 2004,
126, 8390–8391; (c) Tejedor, D.; Santos-Expósito, A.; González-Cruz, D.;
Marrero-Tellado, J. J.; García-Tellado, F. J. Org. Chem. 2005, 70, 1042–1045.
12. (a) Junge, K.; Hagemann, B.; Enthaler, S.; Spannenberg, A.; Michalik, M.;
Oehme, G.; Monsees, A.; Riermeier, T.; Beller, M. Tetrahedron: Asymmetry 2004,
15, 2621–2631; For uses of t-Bu-Binepine as chiral organocatalyst, see: (b)
Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426–1429; (c) Wurz, R.
P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234–12235.
References and notes
1. (a) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035–1050; (b)
Tejedor, D.; González-Cruz, D.; Santos-Expósito, A.; Marrero-Tellado, J. J.; de
Armas, P.; García-Tellado, F. Chem. Eur. J. 2005, 11, 3502–3510; (c) Ye, L.-W.;
Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140–1152; (d) Denmark, S. E.;
Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638; (e) Lu, X.; Zhang, C.;
Xu, Z. Acc. Chem. Res. 2001, 34, 535–544.
2. (a) White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 3597–3600; (b) Yoshida,
T.; Saito, S. Chem. Lett. 1982, 1587–1590; (c) Zhang, C.; Lu, X. Synlett 1995, 645–
646; (d) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127,
9260–9266; (e) Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Mañas, M.;
Sebastian, R. M.; Vallribera, A. Tetrahedron 2005, 61, 8598–8605; (f) Tejedor, D.;
García-Tellado, F.; Marrero-Tellado, J. J.; De Armas, P. Chem. Eur. J. 2003, 9,
3122–3131; (g) Hanédanian, M.; Loreau, O.; Sawicki, M.; Taran, F. Tetrahedron
2005, 61, 2287–2294.
3. (a) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595–7596; (b) Liu, B.;
Davis, R.; Joshi, B.; Reynolds, D. W. J. Org. Chem. 2002, 67, 4595–4598; (c) Lu, C.;
Lu, X. Org. Lett. 2002, 4, 4677–4679; (d) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-
J. Tetrahedron 2006, 62, 3710–3720; (e) Gimbert, C.; Moreno-Manas, M.; Pérez,
E.; Vallribera, A. Tetrahedron 2007, 63, 8305–8310; (f) Gabillet, S.; Lecerclé, D.;
Loreau, O.; Carboni, M.; Dézard, S.; Gomis, J.-M.; Taran, F. Org. Lett. 2007, 9,
3925–3927; (g) Chan, J. W.; Hoyle, C. E.; Lowe, A. B. J. Am. Chem. Soc. 2009, 131,
5751–5753.
4. (a) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241–244; (b) Stewart, I.
C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696–8697; (c)
Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928–
12929; (d) Gabillet, S.; Leclercé, D.; Loreau, O.; Dézard, S.; Gomis, J-M.; Taran, F.
Synthesis 2007, 515–522; (e) Tejedor, D.; Santos-Expósito, A.; Méndez-Abt, G.;
Ruiz-Pérez, C.; García-Tellado, F. Synlett 2009, 1223–1226.
13. Voituriez, A.; Panossian, A.; Fleury-Brégeot, N.; Retailleau, P.; Marinetti, A. J.
Am. Chem. Soc. 2008, 130, 14030–14031.
5. (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819–10820; (b) Kuroda,
H.; Tomita, I.; Endo, T. Org. Lett. 2003, 5, 129–131; (c) Silva, F.; Sawicki, M.;
14. Racemization of the stereogenic carbon of 3a due to the basic reaction
conditions cannot be ruled out.