One-pot, three-component synthesis of chiral 4-alkylidene-2-oxazolidinones

Article abstract of DOI:10.1055/s-0029-1218353

A one-pot convenient access to chiral 2-oxazolidinones is described. Diethylzinc-mediated asymmetric alkynylation of aldehydes with propiolates in the presence of β-sulfonamide alcohol as the chiral ligand, followed by treatment with isocyanates, yielded

Full text of DOI:10.1055/s-0029-1218353

LETTER
3171
One-Pot, Three-Component Synthesis of Chiral 4-Alkylidene-2-oxazoli-
dinones
O
ne-Pot, Three-Co
a
mponent
S
o
ynthesis of
C
t
hiral
2
o
-Oxazolidinone
s
Kojima,* Shogo Nishijima, Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0879, Japan
Fax +81(6)68798214; E-mail: t-tanaka@phs.osaka-u.ac.jp
Received 1 September 2009
isocyanates. Initial screening of the reaction conditions
demonstrated that the conditions developed by Wang’s
group9 gave the best results for our purpose.
Abstract: A one-pot convenient access to chiral 2-oxazolidinones
is described. Diethylzinc-mediated asymmetric alkynylation of al-
dehydes with propiolates in the presence of b-sulfonamide alcohol
as the chiral ligand, followed by treatment with isocyanates, yielded
chiral 4-alkylidene-2-oxazolidinones.
Diethylzinc-mediated (3.0 equiv) asymmetric alkynyla-
tion of cyclohexanecarbaldehyde (1.0 equiv) with ethyl
propiolate (3.0 equiv) in the presence of Ti(Oi-Pr)4 (30
mol%) and 1,2-dimethoxyethane (DME, 1.0 equiv) using
b-sulfonamide alcohol (30 mol%) as the chiral ligand in
toluene at room temperature, followed by treatment with
tosyl isocyanate (3.2 equiv), afforded (R,E)-4-alkylidene-
3-tosyloxazolidin-2-one 1a in 77% yield with good
enantioselectivity10 and complete E-stereoselectivity11
(Table 1, entry 1).12,13
Key words: oxazolidinone, heterocycle, multicomponent reaction,
asymmetric synthesis, alkyne
Avid interest in modern organic chemistry has been di-
rected toward the development of simple and convenient
ways to access useful heterocyclic compounds under mild
and environmentally friendly conditions. Multicompo-
nent reactions (MCR) have recently emerged as a valuable
tool for the preparation of chemical libraries of druglike
heterocyclic compounds.1
To demonstrate the generality of this method, we exam-
ined the scope and limitations of the present one-pot syn-
thesis (Table 1). The reaction with methyl or tert-butyl
propiolates in place of ethyl propiolate also proceeded un-
der the same conditions and corresponding products 1b,c
were obtained with similar isolated yields and selectivities
(entries 2 and 3). Use of aryl isocyanates in place of tosyl
isocyanate gave 2-oxazolidinones in low yields (entries 4
and 5); however, the reaction with ethyl isocyanate was
sluggish (entry 6). The reaction was extended to different
aldehydes, and most of them, with the exception of 4-
nitrobenzaldehyde (entry 11), gave the corresponding
products with high enantioselectivities (entries 7–10, 12).
For instance, the one-pot reaction with 2-bromobenzalde-
hyde, ethyl propiolate, and tosyl isocyanate afforded
product 1h in 73% yield and 95% ee (>99% ee after re-
crystallization, entry 11).
2-Oxazolidinones play prominent roles in daily life. They
are widely used in pharmaceutical manufacturing,2 agri-
culture, and industry, and as chiral auxiliaries in organic
synthesis.3 Among the many methods for the syntheses of
2-oxazolidinones,4 the 5-exo cyclization of O-propargyl
or O-allyl carbamates is one of the most attractive meth-
ods because it enables easy access to various substituted
2-oxazolidinones. The base-promoted cyclization of O-
propargyl carbamates has long been established.5 The in-
termolecular hydroamination of O-propargyl carbamates
in the presence of a transition metal, such as Cu2+ or Au+
salt, has also been reported.6 Baba and co-workers report-
ed that the addition of allyltin reagents to a,b-unsaturated
aldehyde, followed by treatment with isocyanates, gave 2-
oxazolidinones in one-pot reactions.7 Herein, we report
the one-pot, three-component synthesis of chiral 4-alky-
lidene-2-oxazolidinones with aldehydes, propiolates, and
isocyanates.
As mentioned above, this one-pot reaction gave 2-oxazo-
lidinones with complete E-stereoselectivity for any com-
binations of substrates. However, Z-isomer 1b existed in
the early stage of the reaction, indicating that Z-isomer 1b
isomerizes to E-isomer 1a under the reaction conditions
(Table 2).
Although the asymmetric alkynylation of carbonyl com-
pounds by zinc acetylides is a well-known method for the
synthesis of chiral propargyl alcohol derivatives,8 the re-
sulting zinc alkoxides have been scarcely used for further
transformation as most zinc–oxygen bonds are hydro-
lyzed to propargyl alcohols despite their sufficient nucleo-
philicity. We devised a one-pot synthesis of chiral 2-
oxazolidinones, which involved asymmetric alkynylation
of aldehydes with propiolates, followed by treatment with
A plausible mechanism of the isomerization is shown in
Scheme 1. (E)-Alkenylzinc 3b can isomerize into (Z)-al-
kenylzinc 3a via zinc allenolate 414 or enol 5, giving (E)-
oxazolidin-2-one 1a as the sole isomer. The more reason-
able intermediate is the former, not the latter,15 because no
decrease in optical purity was observed throughout the
one-pot reaction.
Conformational analysis using Gaussian 03 program16
SYNLETT 2009, No. 19, pp 3171–3174
Advanced online publication: 11.11.2009
DOI: 10.1055/s-0029-1218353; Art ID: U08709ST
x
x
.x
x
.2
0
0
9
[B3LYP/6-31+G(d)]
supported
this
speculation
(Figure 1). The heat of formation of 3a (R1 = R2 = X = Et,
© Georg Thieme Verlag Stuttgart · New York

3172
N. Kojima et al.
LETTER
Table 1 One-Pot Synthesis of Chiral 2-Oxazolidionesa
O
Et Et
R3
Bn
OH
NHTs
R1CHO
+
O
N
R3-NCO
time 2
(30 mol%)
Et2Zn, Ti(Oi-Pr)4
DME, toluene
time 1
R1
R2O2C
CO2R2
1a–k
Entry
R1
R2
Et
R3
Ts
Ts
Ts
Time 1 (h)
Time 2 (h)
Yield (%)b
1a 77
1b 72
1c 74
1d 37
1e 31
n.d.
ee (%)c
1
2
c-Hex
2
2
2
2
2
2
2
4
2
5
4
5
18
18
18
18
18
18
6
80
c-Hex
Me
t-Bu
Et
82
3
c-Hex
81
4
c-Hex
4-FC6H4
Ph
86
5
c-Hex
Et
75
6
c-Hex
Et
Et
n.d.
90
7
Et
Et
Ts
1f 51
8
Ph
Et
Ts
2
1g 57
1h 73
1i 45
93 (98)d
95 (>99)d
87
9
2-BrC6H4
4-MeC6H4
4-O2NC6H4
2-naphthyl
Et
Ts
6
10
11
12
Et
Ts
2
Et
Ts
2
1j 18
62
Et
Ts
2
1k 31
87
a The reactions were performed with aldehyde (1.0 equiv), propiolate (3.0 equiv), Et2Zn (3.0 equiv), Ti(Oi-Pr)4 (30 mol%), DME (1.0 equiv),
b-sulfonamide alcohol (30 mol%), and isocyanate (3.2 equiv) in toluene at r.t.
b Isolated yield.
c Determined by chiral HPLC analysis.
d The ee after recrystallization.
Table 2 Time Dependence of Yields of Productsa
O
O
R3
c-Hex CHO
+
OH
O
N
Et2Zn, Ti(Oi-Pr)4
DME, toluene
Ts
O
N
+
CO2Et
+
R1
•
c-Hex
Et Et
R2
c-Hex
CO2Et
O
O
Bn
OH
R1
TsNCO
OZnX
R2O
4
R3
R3
2
O
N
NHTs
O
N
1a R1 = CO2Et, R2 = H
1b R1 = H, R2 = CO2Et
CO2R2
R1
R2O2C
R1
ZnX
O
Entry
Time
Yield (%)
XZn
3b
R3
O
N
3a
1a
28
53
67
77
1b
24
17
0
2
R1
HO
ZnX
OR2
1
2
3
4
10 min
1 h
34
30
27
20
5
6 h
Scheme 1 Plausible mechanism of isomerization
18 h
0
a The reactions were performed with cyclohexanecarbaldehyde (1.0
equiv), ethyl propiolate (3.0 equiv), Et2Zn (3.0 equiv), Ti(Oi-Pr)4 (30
mol%), DME (1.0 equiv), b-sulfonamide alcohol (30 mol%), and
tosyl isocyanate (3.2 equiv) in toluene at r.t.
trostatic repulsion between the carbonyl oxygen atom on
the ester moiety and the sulfonyl oxygen atom.
In conclusion, we have developed a novel one-pot, three-
component synthesis of chiral 4-alkylidene-2-oxazolidin-
ones using aldehydes, propiolates, and isocyanates. This
one-pot reaction makes it possible to prepare easily chiral
R3 = Ts) is approximately 36 kJ/mol more stable than that
of 3b. This energy difference can be explained by the elec- substituted 2-oxazolidinones. The applications of this
Synlett 2009, No. 19, 3171–3174 © Thieme Stuttgart · New York

LETTER
One-Pot, Three-Component Synthesis of Chiral 2-Oxazolidinones
3173
(10) The absolute configuration of 2-oxazolidinone 1a was
assumed based on propargyl alcohol 2 whose absolute
configuration was determined by the modified Mosher
method.
(11) The stereochemistry of the alkene moiety was assigned by
nuclear Overhauser effect (NOE) experiment. Irradiation of
the alkenyl proton caused an increment of the area intensity
of the aromatic proton at the meta position of the tosyl group.
(12) General Procedure for One-Pot, Three-Component
Synthesis of Chiral 2-Oxazolidinones (Table 1, Entry 1)
Ethyl propiolate (0.304 mL, 3.00 mmol) was added to a
stirred mixture of (S)-2-(methanesulfonylamino)-1,1-
diethyl-3-phenyl-1-propanol (108 mg, 0.300 mmol), DME
(0.105 mL, 1.00 mmol), and Et2Zn (1.0 M in n-hexane,
3.00 mL, 3.00 mmol) in toluene (6 mL) at r.t. under Ar
atmosphere. After 12 h at the same temperature, Ti(Oi-Pr)4
(0.089 mL, 0.300 mmol) was added and the reaction mixture
stirred for 0.5 h. To the resulting solution was added
cyclohexanecarbaldehyde (0.121 mL, 1.00 mmol) in one
portion. After 2 h, tosyl isocyanate (0.490 mL, 3.20 mmol)
was added to the mixture. After 12 h, the reaction was
quenched with sat. NH4Cl, and the mixture was extracted
with EtOAc. The combined organic layers were washed with
sat. NH4Cl, H2O, and brine, dried, and the solvent was
evaporated. Purification by column chromatography over
silica gel with n-hexane–Et2O (19:1) as eluent yielded
(R,E)-ethyl 2-(5-cyclohexyl-2-oxo-3-tosyloxazolidin-4-
ylidene)acetate (1a, 316 mg, 77%, 80% ee) as a colorless
amorphous solid.
Figure 1 Optimized geometry of alkenylzinc intermediates 3a and
3b (R1 = R2 = X = Et, R3 = Ts) calculated at the B3LYP/6-31+G(d)
level
method to the synthesis of biologically active compounds
are under way.
Acknowledgment
This work was supported by a Grant-in-Aid for Young Scientists
(Start-up) [No. 18890096] from Japan Society for the Promotion of
Science (JSPS).
(13) Characterization Data of Selected Compounds
(R,E)-Ethyl 2-(5-Cyclohexyl-2-oxo-3-tosyloxazolidin-4-
ylidene)acetate (1a)
References and Notes
Colorless amorphous solid; [a]D26 +148.9 (c 1.00, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.83–0.91 (m, 1 H), 1.01–
1.16 (m, 2 H), 1.22–1.39 (m, 4 H), 1.32 (t, J = 7.3 Hz, 3 H),
1.53–1.61 (m, 1 H), 1.73–1.75 (m, 2 H), 2.01–2.11 (m, 1 H),
2.47 (s, 3 H), 4.19 (q, J = 7.3 Hz, 2H), 5.54 (s, 1 H), 6.45 (s,
(1) For a recent review of multicomponent reactions, see:
Ganem, B. Acc Chem. Res. 2009, 42, 463.
(2) For a recent review of the biological activities of 2-oxa-
zolidinones, see: Zappia, G.; Menendez, P.; Monache, G. D.;
Misiti, D.; Nevola, L.; Botta, B. Mini Rev. Med. Chem. 2007,
7, 389.
(3) For a recent review of 2-oxazolidinones in synthetic organic
chemistry, see: Zappia, G.; Cancelliere, G.; Gacs-Baitz, E.;
Monache, G. D.; Misiti, D.; Nevola, L.; Botta, B. Curr. Org.
Synth. 2007, 4, 238.
(4) For a recent review of the synthesis of 2-oxazolidinones, see:
Zappia, G.; Gacs-Baitz, E.; Monache, G. D.; Misiti, D.;
Nevola, L.; Botta, B. Curr. Org. Synth. 2007, 4, 81.
(5) Ramesh, R.; Chandrasekaran, Y.; Megha, R.;
Chandrasekaran, S. Tetrahedron 2007, 63, 9153; and
references therein.
1 H), 7.39 (d, J = 7.9 Hz, 2 H), 7.98 (d, J = 7.9 Hz, 2 H). 13
NMR (75 MHz, CDCl3): d = 14.2, 21.8, 23.8, 25.5, 25.6,
C
26.0, 29.2, 41.7, 60.6, 83.2, 98.3, 128.4 (2 C), 129.9 (2 C),
133.7, 146.8, 149.9, 150.6, 165.7. IR (KBr): 1805, 1709,
1647 cm–1. MS (EI): m/z (%) = 407 (1.1) [M]+, 362 (10.6)
[M – OEt]+, 325 (100) [M + H – C6H11]+, 252 (17.2) [M –
Ts]+. HRMS (EI): m/z [M]+ calcd for C20H25O6NS:
407.1403; found: 407.1405. HPLC column: DAICEL
CHIRALPAK® IC (250 × 4.6 mm), n-hexane–i-PrOH
(91:9), 5 mL/min, tR = 35.2 min for 1a and tR = 33.1 min for
enantio-1a.
(R,E)-Ethyl 2-[5-Cyclohexyl-3-(4-fluorophenyl)-2-
(6) (a) Ritter, S.; Hackeliier, K.; Schmalz, H.-G. Heterocycles
2007, 74, 731. (b) Ritter, S.; Horino, Y.; Lex, J.; Schmalz,
H.-G. Synlett 2006, 3309. (c) Tamaru, Y.; Kimura, M.;
Tanaka, S.; Kure, S.; Yoshida, Z. Bull. Chem. Soc. Jpn.
1994, 67, 2383. (d) Ohe, K.; Matsuda, H.; Ishihara, T.;
Chatani, N.; Kawasaki, Y.; Murai, S. J. Org. Chem. 1991,
56, 2267. (e) Kimura, M.; Kure, S.; Yoshida, Z.; Tanaka, S.;
Fugami, K.; Tamaru, Y. Tetrahedron Lett. 1990, 31, 4887.
(f) For a related Pd-catalyzed transformation, see: Lei, A.;
Lu, X. Org. Lett. 2000, 2, 2699; and references therein.
(7) (a) Kato, H.; Shibata, I.; Kanazawa, N.; Yasuda, M.; Baba,
A. Eur. J. Org. Chem. 2006, 1117. (b) Shibata, I.; Kato, H.;
Kanazawa, N.; Yasuda, M.; Baba, A. J. Am. Chem. Soc.
2004, 126, 466.
oxooxazolidin-4-ylidene]acetate (1d)
Colorless needles; [a]D25 +139.8 (c 1.00, CHCl3); mp 160–
161 °C (n-hexane–EtOAc). 1H NMR (500 MHz, CDCl3):
d = 1.14–1.39 (m, 4 H), 1.25 (t, J = 7.3 Hz, 3 H), 1.52–1.60
(m, 2 H), 1.67–1.70 (m, 1 H), 1.82–1.93 (m, 3 H), 2.26–2.34
(m, 1 H), 4.11 (dq, J = 11.0, 7.3 Hz, 1 H), 4.16 (dq, J = 11.0,
7.3 Hz, 1 H), 4.99 (d, J = 1.8 Hz, 1 H), 5.70 (t, J = 1.8 Hz, 1
H), 7.17–7.29 (m, 4 H). 13C NMR (75 MHz, CDCl3):
d = 14.1, 24.0, 25.65, 25.71, 26.1, 29.6, 41.1, 60.1, 84.0,
91.0, 117.1 [d, 2J(C,F) = 23.0 Hz, 2 C], 128.6 [d,
4J(C,F) = 3.1 Hz], 129.2 [d, 3J(C,F) = 8.7 Hz, 2 C], 155.0,
157.0, 162.6 [d, 1J(C,F) = 249.7 Hz], 166.1. IR (KBr): 1792,
1701, 1645 cm–1. MS (EI): m/z (%) = 347 (17.6) [M]+, 302
(4.3) [M – OEt]+, 265 (100.0) [M + H – C6H11]+. HRMS (EI):
m/z [M]+ calcd for C19H22NO4F: 347.1533; found: 347.1556.
HPLC column: DAICEL CHIRALPAK® IC (250 × 4.6
mm), n-hexane–i-PrOH (91:9), 5 mL/min, tR = 22.0 min for
1d and tR = 24.1 min for enantio-1d.
(8) For a recent review of asymmetric alkynylations of carbonyl
compounds, see: Trost, B. M.; Weiss, A. H. Adv. Synth.
Catal. 2009, 351, 963.
(9) Lin, L.; Jiang, X.; Liu, W.; Qiu, L.; Xu, Z.; Xu, J.; Chan,
A. S. C.; Wang, R. Org. Lett. 2007, 9, 2329.
Synlett 2009, No. 19, 3171–3174 © Thieme Stuttgart · New York

3174
N. Kojima et al.
LETTER
(R,E)-Ethyl 2-[5-(2-Bromophenyl)-2-oxo-3-
tosyloxazolidin-4-ylidene]acetate (1h)
the one-pot reaction, indicating isomerization of
(E)-alkenylzinc 3b into alkenylzinc 3a via enol 5.
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox,
D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
23
Colorless plates; mp 175–176 °C (n-hexane–EtOAc); [a]D
+204.8 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 1.12 (t, J = 7.3 Hz, 3 H), 2.50 (s, 3 H), 3.98 (dq, J = 11.0,
7.3 Hz, 1 H), 4.02 (dq, J = 11.0, 7.3 Hz, 1 H), 6.67 (d, J = 2.4
Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 7.08–7.11 (m, 1 H), 7.22–
7.25 (m, 2 H), 7.43 (d, J = 8.5 Hz, 2 H), 7.60–7.63 (m, 1 H),
8.05 (d, J = 8.5 Hz, 2 H). 13C NMR (75 MHz, CDCl3):
d = 13.9, 21.8, 60.7, 80.1, 100.2, 124.8, 127.6, 127.9, 128.5
(2 C), 130.1 (2 C), 131.1, 133.4 (2 C), 134.6, 147.08, 147.13,
149.7, 164.7. IR (KBr): 1809, 1714, 1655 cm–1. MS (EI):
m/z (%) = 479 (3.6) [M]+, 400 (19.8) [M – Br]+, 371 (6.2)
[M – Br – Et]+, 324 (18.4) [M + H – Br – C6H5]+, 278 (26.7)
[M – Br – C6H5 – OEt]+, 91 (100). HRMS (FAB): m/z [M +
H]+ calcd for C20H19BrNO6S: 480.0116; found: 480.0103.
HPLC column: DAICEL CHIRALPAK® IC (250 × 4.6
mm), n-hexane–CH2Cl2 (30:70), 1 mL/min, tR = 41.7 min
for 1h and tR = 44.8 min for enantio-1h.
(14) A similar mechanism of the isomerization was reported. See:
Naito, H.; Hata, T.; Urabe, H. Tetrahedron Lett. 2008, 49,
2298.
(15) In the case of the use of phenyl isocyanate (Table 1, entry 5),
the slight decrease in optical purity was observed throughout
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision E.01; Gaussian, Inc.: Wallingford /
CT, 2004.
Synlett 2009, No. 19, 3171–3174 © Thieme Stuttgart · New York