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Ethyl 3-Acyl-2-thioxo-1 3-oxazolidine-4-carboxylates and Their Conversion into Ethyl -(N-Acylamino)acrylates.

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crystallizes. The filtrate is taken up in ethanol and a further
crop of crystalline (2) is obtained in the cold. Recrystallizing twice from ethanol affords 56.1 mg (3.7%)of analytically
pure ( 2 ) of m.p. 182--183.C.
Received: May 7, 1973 [Z 835 IE]
German version: Angew. Chem. XS, 657 (1973)
[ I ] Reactions of Sterically Hindered Nitro Compounds. Part 3 -Part
2 : A . Brrndr, Tetrahedron Lett. 1970, 173.-This work was supported
by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie, as well as by Chemische Werke Huls and Deutsche Shell
AG.
[2] A. Berndr. Tetrahedron 25, 37 (1969).
[3] C. Egg. Zahlentafeln zur Massenspektrometrie und Elementaranalyse. Verlag Chemie, Weinheim 1970.
[4] H . H . Perkampiis, 1. Sandmann, and C . J . Emmons: UV-Atlas
organischer Verbindungen. Butterworths, London, und Verlag Chemie,
Weinheim, Vol. 11, C 7/5.
[ 5 ] J . S(,huntl. Monatsh. Chemie 103. 1705 11972)
Fig. I . a ) ESR spectrum of the radical anion of ( 2 ) in acetonitrile
at 25 C: b) computer simulated spectrum with ov=5.1 G (2 N) and
a"=2.0 G (2 H), line width 0.75 G.
for the radical anion of azobenzene. Assuming a direct proportionality between uNand the spin density at the nitrogen
pN,which is justifiable in numerous cases, a proportionality
constant QN of 16.5 G is obtained from aN=8.25G for the
radical anion of 2,2'-azoisobutane[' ' I and pN= 0.5. Hence
a value of pN=0.31 follows for the radical anion of (2).
The spin density at C, is calculated as ipFI=O.O85 with
the aid of the McConnell equation and the value of
Q,"-,,
= - 23.7 G generally valid for radical anions. The
normalization condition
p, = 1 thus yields a spin
density of 0.28 at cg, p: beink given a theoretically justified
negative sign. H M O spin density calculations by the
McLachlan method['21 with the parameters used for
the azobenzene radical anion give pN=0.30, p:= -0.10,
and p;=O.30 if the effect of the terr-butyl substituents
is neglected.
In the mass spectrum of ( 2 ) which contains relatively
few fragment ions the signal at m/q = 153 is particularly
striking since it represents the base peak at electron impact
above 20 eV and still has 80% of the intensity of the
molecular ion at 16 eV whereas only the fragments
M - 56 and M - 57 then have intensities above 5 % (loss
of tert-butyl radicals and of isobutylene respectively). The
absence of a half integral signal at m/q=153.5 proves
that the peak at 153 (exact mass 153.1515) is not due
to a doubly charged molecular ion but to an ion ofcomposition C,,H,,N+. In contrast to azobenzene, which preferentially fragments with cleavage of the C-N bond['31, (2)
very readily cleaves at the N=N bond.
Attempts to convert nitroalkenes subject to less steric hindrance into the corresponding divinylazo compounds have
so far been unsuccessful
1
[6] H . Rarr, Angew. Chem. 85, 248 (1973): Angew. Chem. internat. Edit.
12, 224 ( 1973).
[7] J . Buckingham and R. D. Gufhriu. J.C.S. Chern. Comm. 1967, 1241.
[ 8 ] J . Griffirhs, Chem. SOC.Rev. 1 , 481 (1972).
[9] A. J . Futiudi, J. Res. Nat. Bur. Stand. A 71, 277 (1967).
[lo] A. G. Evans, J . C . Ecans, P . J . Emes, C . L James, and P . J .
Pomery, J. Chem. SOC.B1971, 1484, and further literature cited therein.
[ I I] U . Krynirz, F. Curson, N. Wihery, and M . Vrith, Angew. Chem.
81, 745 (1969): Angew. Chem. internat. Edit. 8, 755 (1969).
[12] A . D. McLurhlan. Mol. Phys. 3. 233 11960).
[13] J . H . Bowie, G. E Lewis, and R G. Cooks, J Chern. SOC.B1967.621
Ethyl 3-Acyl-Zthioxo-l,3-oxazoIidinekarboxylates and Their Conversion into
Ethyl a-(N-Acylamino)acrylates[**3
By Dieter Hoppe"]
Ethyl 2-thioxo- 1,3-oxazolidine-4-carboxylates (3) are
formed in good yields by basic condensation of ethyl 3isothiocyanatoacetates with carbonyl compounds' 'I. Their
acylation with acyl halides in benzene/triethylamine at
room temperature leads to ethyl 3-acyl-2-thioxo- 1,3-oxazoIidine-4-carboxylates (2)[4 (procedure A, see Table 1).
The acyl compounds (2) are more conveniently obtained
$
\
C02C,H5
3,8-Di-tert-butyl-2,2~~-tetramethyl-5,6-diuzudecu-3,5,7-triene ( 2 ):
A Grignard solution obtained from magnesium (1.46 g,
60 mmol) and terr-butyl chloride (5.56 g, 60 mmol) is
slowly added dropwise to a solution of ( I ) (1.85 g, 10
mmol) in dry ether (4 ml) at - 15-C (ice/salt) under an
inert gas. After 10 minutes' stirring of the cooled mixture
it is hydrolyzed with aqueous ammonium chloride solution.
The aqueous phase is extracted into ether; the combined
ether extracts are twice washed neutral with water. After
drying of the ethereal solution over magnesium sulfate
and evaporation of the ether, part of the product (2)
656
directly from alkali metal salts (1) formed as primary
products in the synthesis of (3)"' by addition of acyl
halides to the reaction mixture (procedure B).
[*I Dr. D. Hoppe
Organisch-Chemisches lnstitut der Universitat
34 Gottingen, Windausweg 2 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
Angew. Chem. internat. Edit. / Vol. 12 (1973) / N o . X
The structural assignment of ( 2 ) as N-acylation product
follows from the IR spectrum: an intense absorption at
1770cm-' shows the compounds (2u)-(29) to be urethanes ;aC=N frequency at about 1600cm- characteristic
of the alternative oxazoline structure is not observed.
The acyl compounds ( 2 ) are converted into the ethyl
%-( N-acy1amino)acrylates (6) by treatment with potassium
terr-butoxide (50% excess) in tetrahydrofuran at - 60 'C
and subsequent neutralization with glacial acetic acid
(Table 1). ( 6 6 ) and ( 6f ) were obtained by heating ( 2 6 )
and ( 2 f ) to 160-180°C for 2 h with 5 mol-x of triethylammonium chloride.
'
All compounds (6) gave satisfactory CH analyses and
were characterized by their IR and NMR spectra. Stereochemical assignments were based on the NMR spectra.
Isomeric oxazolidinethiones ( 2 ) and aminoacrylates ( 6 )
can be separated by chromatography on silica gel with
ether/light petroleum.
rx-Acylaminoacrylic esters (6) are of significance for the
preparation of unsubstituted@]and p-functional a-aminoacids[']; since not only R ' and R2 but also R3 can be
varied within wide limits, the amino protecting group can
be adapted to subsequent synthetic steps from the very
beginning of a reaction sequence.
bamic acid ( 5 ) on acidification and thence into the
aminoacrylates (6) by loss of carbon oxide sulfide. ( 4 )
can be trapped, e.y. with benzyl bromide, as N-acyl-Nvinylthiourethane ( 8 ) .
Available evidence indicates a concerted ring cleavage131.
Thus truns-(2y) gives exclusively 2-(69), while cis-(2g)
affords predominantly E - ( 6 g ) ( E / Z z 3: 1). A two-step process uiu the anion (7)-analogous to base-induced ring
cleavage of o ~ a z o l i n e - [and
~ ] 2-alkylthiooxazoline-4-carboxylic e~ters[~~-wouldgive roughly equal product
ratios starting from both isomers. Moreover, base-catalyzed H/D exchange could not be detected in oxazolidinethione. Isomerization of the thiocarbamic anion E - ( 4 y ) ,
as has been detected for E - ( 4 u ) , probably accounts for
the incomplete stereospecificity of the reaction of ci.7429).
Diethyl 5,5-diinrth~~l-2-thi~x~-l,3-oxazolidine-3,4-dicurboxylate ( 2 6 ) :
Route A: Ethyl chloroformate (2.17 g, 20mmol) was added
without cooling to a solution ofethyl 5,5-dimethyl-2-thioxooxazolidine-4-carboxylate1'1( 3 6 ) (4.06 g, 20 mmol) and
triethylamine (2.15g, 21 mmol) in benzene (50ml) initially
cooled to 0 - C . The mixture was then stirred for 30min
at room temperatureand allowed tostand for 1 h at &5"C
before the triethylammonium chloride was filtered off and
the solvent evaporated off in a water pump vacuum. The
residue was recrystallized from tetrachloromethane and
afforded 4.5g of ( 2 6 ) . IR (KBr): 1740, 1770cm-' (CO).'H-NMR (CDCI3):r=5.35 (s, 4-H), 8.37 and 8.53 (both
S, CH3).
0
II
R:
C-SH
I
/N-COR3
/c=c
R2
'COzCzH5
S
Ethyl cis- and truns-3-benz~Ioxy~urb~~n~~l-5-phen~1-2-rhioxo1,3-oxuzolidine-4-carbox~~Iure
( 2g ) :
J
f 51
(4)
Route B: A mixture of ethyl isothiocyanatoacetate (5.8 g,
40 mmol) and benzaldehyde (4.3 g) in tetrahydrofuran
( 10 ml) was added dropwise to a vigorously stirred solution
of potassium tert-butoxide (4.5g, 40 mmol) in dry tetrahydrofuran (50ml) under nitrogen at -60°C. Stirring was
continued for 30min at -60 ,C and the mixture was then
allowed to warm up to -20 C whereupon benzyl chloroformate (6.9g, 40mmol) in a little tetrahydrofuran was
run in. After 30min the solvent was removed under waterpump vacuum in a rotary evaporator and the residue
taken up in dichloromethane (100ml) and ice-water (30ml).
Washing twice with water (2 x 30ml), drying the solution
over sodium sulfate, and evaporation of the solvent in
a vacuum furnished 14.8 g of crude ( 2 g ) as a bright yellow
COR~
The first detectable intermediate formed is N-acyl-N-vinylthiocarbamate ( 4 ) which is converted into the free thiocar-
Table 1. Ethyl 3-acyl-2-thioxo-1,3-oxazolidinecarboxylates
(2) and ethyl a-(N-acylamino)acr41ates 16) synthesized
R'
R*
R'
(2)
Yield
[%]
161
M.p. ["C]
(cispuns)
12.5: I )
86-87
103-104
(I:[)
(I:[)
(1:2.0)
( 1 :2.5)
(<S:lOO)
(100: < S )
144-146
Yield
[".I
8 5 Eel
71 [f, g]
80 [el
76[e]
80 1.3
60 [e, g]
79 [el
98[c]
98 [c]
89 [d]
(E!Z)
I :4
_.
M.p. ["C]
( B . p . [ C'torr])
Z : 71 72
( I2511 .O)
37
~
I :4
I:?
I :4
l:3.3
<:5:100
3. I
-
~
Z . 107
~
z
5x
~
141
:a]
.b]
:c]
Id]
-e]
Route A.
Route B.
Crude product.
After purification by recrystallization.
After chromatographic purification or separation of isomers
.fl Alter purification by distillation.
.g] Prepared by therrnolysis of (I),see text.
Angew. Chum. internut. Edit.
J Vul. 12 ( 1 9 7 3 )
No. 8
657
oil. Crystallization with diethyl ether (100ml) at 0°C
afforded 9.5 g of ( 2 9 ) having m.p. 85-95°C
(cis/trans=l :2.5), 'H-NMR (CDCI,): cis-(2g) r=4.12 (d) and
4.84 (d) (J=9.5 Hz, 5-H and 4-H), 6.44 and 9.32 (AA'X3
part, OC2H5); trans-(2g) r=4.40 (d) and 5.13 (d)
(J=4.5Hz, 5-H and 4-H), 5.83 (9) and 8.83 (t) (OC2H5).
Ethyl E- and Z-a-(~-benzyloxycarbonylamino)c~nna~ate
pounds are treated with potassium tert-butoxide or sodium
(69):
hydride in tetrahydrofuran['] and the resulting salts ( 1 )
( 2 g ) (cis/trans= 1 : 2.5; 7.7 g, 20 mmol) in tetrahydrofuran
are allowed to react with alkyl halides. The oxazoline
(30ml) was added dropwise to a vigorously stirred solution
structure follows from the strong IR band at 1600cm-'
of potassium tert-butoxide (30 mmol) in dry tetrahydro(C=N).
furan at - 60"C. After 30 min acetic anhydride was squirted
The 2-alkylthiooxazolines ( 2 ) are anionized cc to the carinto the mixture which was then permitted to warm to
bony1 group by strong bases such as potassium tert-butoxroom temperature. The product was worked up as deide in tetrahydrofuran at -60°C. The anions (3) undergo
scribed for ( 2 9 ) but with diethyl ether as solvent to give
ring
yielding the S-alkyl-N-vinylthiourethane
6.5g(l00%)ofcrude ( 6 g ) ( E / Z = 1 :3.3). Chromatography
anion ( 4 ) . After acidification with acetic anhydride the
on an 80-fold amount (w/w) of silica gel (neutral) with
ethyl a-(N-alky1thiocarbonylamino)acrylates( 5 ) can be
light petroleum (4&60 .'C)/ether (1 : 1) afforded 1.3 g (20 YO)
isolated by chromatography or crystallization (Table I).
of E - ( 6 g ) (Rf=0.59, TLC silica gel commercial films) as
a colorless oil and 4.5g (69%) of Z - ( 6 g ) (Rf=0.44) of
m.p. 58T-IR
(film): 3300 (NH), 168&1730 (C=O),
1640 (C=C), 1490 and 1520 cm-' (amide II).-'H-NMR
(CDCI3), E - ( 6 g ) : r=2.45 (s, vinyl H), 2.90 (s, NH), 5.95
-B C1 - S R 3
SR3
(q), and 9.05 (t) (OC2Hs); 2 4 6 9 ) : r=2.55 (s, vinyl H),
3.5 (s, NH), 5.80 (q), and 8.77 (t) (OCzH5).
Received: May 7, 1973 [Z 837a IE]
German version: Angew. Chem. 8.7. 659 (1973)
[ I ] D. Hoppr, Angew. Chem. 84, 956 (1972); Angew. Chem. internat.
Edit i / , 933 (1972).
[ 2 ] I f attack at the nitrogen is sterically hindered, as r . 9 . in the case
of ethyl ~is-4-methyl-5-phenyl-2-thioxo-1,3-oxazolidine-4-carboxylate
[R'=CoHs, R 2 = H , CHJ in place of H in (3)] then S-alkylation is
observed under the experimental conditions given. Above 1OO'C 2-acylthio- I,3-oxazoline isomerizes to the N-acyl compound (2).
[3] Concerning the problem of the mechanism, see: F . G. Bordwrll,
Accounts Chem. Res. 5 , 374 (1972); J . Sirhrr, Angew. Chem. 84, 177
(1972): Angew. Chem. internat. Edit. / I , 200 (1972).
[4] U . Schiiflkopf, F. Grrhart, R. Schriider, and D. Hoppr, Liebigs Ann.
Chem 766, 116 (1972); L'. Srhollkupf, F. Crrhurt, and R. Schroder, Angew.
Chem. 81, 701 (1969). Angew. Chem. internat. Edit. 8, 672 (1969).
[5] D Hoppu. Angew. Chem. 85, 660 (1973): Angew. Chem. internat.
Edit. / 2 . 658 (1973).
[6] For the asymmetric hydrogenation of aminoacrylic esters see H .
B. K a y u n and T - P . Dung, 1. Amer. Chem. SOC.94,6429 (1972).
[7] For the synthesis of cysteine derivatives see: U . S<,hof/kopfand D.
Hoppr, Angew. Chem. 82, 253 (1970): Angew. Chem. internat. Edit. 9,
236 (1970).
2-Alkylthio-2-oxazoline-4-carboxylic
Esters and Their Conversion into
a-(N-Alkylthiocarbony1amino)acrylic
Esters[* *I
By Dieter Hoppep]
Whereas acylation of ethyl 2-thioxo- 1,3-oxazolidine-4-carboxylates"] or their ambidentate anions ( I ) leads to 3-acyl1,3-0xazolidine-2-thiones[~~,
alkyl halides attack the sulfur
atom to yield ethyl 2-alkylthio-2-oxazoline-4-carboxylates
f 2).
The oxazolines ( 2 ) are obtained without intermediate isolation when ethyl isothiocyanatoacetate and carbonyl com[*] Dr. D. Hoppe
Organisch-Chemisches lnstitut der Universitat
34 Gottingen, Windausweg 2 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
658
Diastereomeric oxazolines [R' +RZ in ( 2 ) ] yield E / Z mixtures of aminoacrylates (5) that are readily separated
by chromatography on silica gel with ethernight petroleum.
Expectedly, ring cleavage is not stereospecific: thus trans(2e) gives the acrylic ester ( 5 e ) in an E/Z ratio of 1 :3.3.
Compounds (5) are of potential interest as reactants for
amino acid synthesis, particularly since the alkylthio group
can be removed ~electively["~.
The aminoacrylic esters gave satisfactory CH analyses.
They were characterized by their NMR and IR spectra
[3300 (NH),
171&1720 (C02R),1640 and 1500 (NCOSR)
and 1600--1650cm-' (C=C)].
Ethyl 2-benzy/thio-5,5-dim~thyl-2-oxazolinP-4-c~~boxy/at~.~
(2h):
A mixture of ethyl isothiocyanatoacetate (5.8 g, 40 mmol)
and acetone (2.4 g, 40mmol) in tetrahydrofuran (20 ml)[']
was added dropwise over 30min to a stirred suspension
of finely divided sodium hydride (0.98 g, 40mmol) in anhydrous tetrahydrofuran at 20--30°C under nitrogen. Stirring
was continued at this temperature until evolution of hydrogen had ceased (1 h), the mixture cooled to -2O"C,
and after removal of the cooling bath benzyl bromide
was added (6.8g, 40mmol). After 30 minutes' stirring at
room temperature the solvent was evaporated off in a
water pump vacuum and the residue taken up in chloroform (100ml) and ice-water (30ml). Washing was repeated
twice with water (2 x 30ml), the chloroform solution dried
over sodium sulfate and concentrated in a rotary evaporator. Distillation afforded 9.0g of (2b).--IR (film): 1735
(C=O), 1590cm-' (C=N).-'H-NMR
(CCL):r=5.82 (s,
4-H), 8.54 (s), and 8.74 (s) (gem. CH3).
Angew. Chem. internat. Edit.
1 Vul. 12 (1973) 1 No. 8
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