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Ethyl -Formylamino--hydroxy-acid Esters (-Substituted N-Formylserine Esters) from Ethyl 2-Oxazoline-4-carboxylates.

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amino group is replaced, giving (8 a ) (43%), (8b) (74 %),
or (8c) (90%).
Received: January 31, 1972 [Z609a IE]
German version : Angew. Chem. 84,480 (1972).
[I] a) H . E. Sprenger and W Ziegenbein, Angew. Chem. 80,541 (1968);
Angew. Chem. internat. Edit. 7,530(1968); b) J . Gauger and G . Manecke,
Tetrahedron Lett. 1967, 3509; c) Chem. Ber. 103, 2996 (1970); d)
H . J . Roth and H. Sporleder,Arch. Pharmaz. 303,895 (1970);e) J . Gauger
and G . Manecke, Chem. Ber. 103, 3553 (1970); f) G. Manecke and
J . Gauger, Tetrahedron Lett. 1968, 1339.
[2] a) G . Maahs and P . Hegenberg, Angew. Chem. 78, 927 (1966);
Angew. Chem. internat. Edit. 5,888 (1966); b) S . G. Cohen and S . Cohen,
J. Amer. Chem. SOC.88, 1533 (1966).
[3] Dimethylaniline arylates (Zbj, as described in [ I g , also in the
[4] Correct spectra and analytical data are available for all the new
[5] S.Hiinigand H . Piitter,Angew. Chem.84,481(1972);Angew.
internat. Edit. 11,433 (1972).
[6] a) S . Skujins and G . A. Webb, Chem. Commun. 1968,598; b) W Ried
and W Kunstmann, Chem. Ber. 102, 1439 (1969).
[7] Prepared analogously to the method given in [1 c].
Ethyl a -Formylamino-P-hydroxy-acid Esters
@-Substituted N-Formylserine Esters) from
Ethyl 2-Oxazoline-4-carboxylates['1
mild conditions, probably because the negative charge
arising on the nitrogen atom when a hydroxide ion
attacks C-2 is taken over by the carbonyl group at position
4 in the neighboring group effect.
The plane in which the ethoxycarbonyl group lies must
therefore be perpendicular to that of the five-membered
ring, and this is hindered particularly by cis-substituents
on the ring. This consideration explains satisfactorily
the various times required for the hydrolyses (cf. Table).
Water-soluble a-formylamino-P-hydroxy-acid esters (2)
are isolated by removing the excess of water in a vacuum
and distilling the residue or taking it up in carbon tetrachloride or ether and awaiting crystallization ; sparingly
soluble esters (2) are precipitated by water. These esters
can be converted into a-amino-P-hydroxy acids (Psubstituted serines) by heating them with 5 N hydrochloric
By Dieter Hoppe and Ulrich Schollkopf [*I
N-Formylthreonine ethyl ester (2b)
Ethyl 2-okazoline-4-carboxylates ( I ) are obtained conveniently and in good yields from ethyl isocyanoalkanoates
and carbonyl compounds in weakly basic alcoholic
media[21. Their conversion into ethyl a-formylaminoP-hydroxy-acid esters (2) can be accomplished almost
quantitatively by warming 1 mol of ( I ) with 2-3 mol of
water and 0.03 mol of triethylamine (if necessary, with
addition of a little ethanol).
Ethyl trans-5-methyl-2-oxazoline-4-carboxylate[2J
(5.4 g,
34 mmol), water (1.8 g), and triethylamine (0.1 g, 0.1 mmol)
are heated for 30 min at 100°C. The water is then distilled
off at 1 torr and 80°C (bath-temperature), ether (10 ml) is
added, and the solution is left at 0°C for crystallization.
This yields (2 b) (3.9 g, 68 %), m. p. 74 "C (from 2 :1 carbon
tetrachloride/chloroform). NMR spectrum (in CDCl,) :
z=5.4 (m/C-2-H and C-3-H), 5.6 (-OH), 8.75 ppm
(d/J = 7 Hz, -CH,).
Alkaline hydrolysis is unusual for 2-0xazolines[~~;
it can
be achieved with the compounds (1) under relatively
erythro- and threo-N-Formyl-2-methyl-3-phenylserine
ester (2 h) [4*51
1.5 [fl
6 [g
6 rfl
6 rfl
90 [CI
51 [d]
80 re1
Until ( I ) is no longer detectable by IR spectroscopy (1620 cmIsolated product.
Crude product.
Precipitated by water.
Distilled at 0.05 torr.
:fI 0.5 ml of ethanol per g of ( 1 ) added.
:g] After chromatographic separation of the diastereoisomers.
[*] Dr. D. Hoppe and Prof. Dr. U. Schollkopf
Organisch-Chemisches Institut der Universitat
34 Gottingen, Windausweg 2 (Germany)
(2b) was converted by 5 N HCl into threonine. alloThreonine was not detectable either by IR spectroscopy
or by thin-layer chromatography.
Ethyl 4-methyl-5-phenyl-2-oxazoline-4-carboxylate[2~
(cis:trans = 2.5:l) (4.7 g, 20 mmol), water (1.0 ml), ethanol
(2.5 ml) and triethylamine (0.1 g) were heated under reflux
for 6 h at 100°C. The solvent was distilled off at 100°C in
a water-pump vacuum and the residue was chromatographed on silica gel (200 g; 0.05-0.2 mm; column
diameter 3 cm) with ethyl acetate/chloroform (6 :4).
The fractions (each 20 ml) were investigated by thinlayer chromatography (silica gel F 1500 LS 254, Schleicher
and Schiill; above solvent). Removing the solvent at
water-pump vacuum from the fractions containing the
faster migrating substance (RF= 0.26) gave erythro-(2 h)
as a residual viscous oil (2.8 g, 56%) that slowly crystallized
from ether/pentane (2:l) at -10°C (m.p. 74°C). NMR
spectrum (CDCI,): z=4.15 and 4.85 (d/J=8.5 Hz,
8.35 (s/-CH,)['],
5.77 and 8.72 ppm
Concentration of the fractions containing the slower
migrating component (R,=O.19) and of the mixed
fractions afforded an oil (1.5 g) that, when treated with
ether (10 ml), yielded crystals of threo-(2h) (1.0 g, 20%),
m.p. 105°C. NMR spectrum (CDCl,): z= 5.0 (-CHOH),
8.6['] and 8.73 (s/-CH,), 5.75 and 5.90t51,as well as 8.70
and 8.831'1 (-OCH,-CH,).
Since the relative intensities
Angew. Chem. internat. Edit.
Voi. I1 (1972) f No. 5
of the groups of signals change in CD,OD we assume
that the signal splitting is caused by competition between
intra- and inter-molecular hydrogen-bridge formation.
Received: January 27, 1972 [Z 606IEl
German version: Angew. Chem. 84,435 (1972)
[l] Syntheses with a-Metalated Isocyanides, Part 12.-Part
11 :
U. Schollkopf and R . Schroder, Angew. Chem. 84, 289 (1972); Angew.
Chem. internat. Edit. 11, 311 (1972).
121 D. Hoppe and U . Schollkopf,Angew. Chem. 82,290 (1970); Angew.
Chem. internat. Edit. 9, 300 (1970).
[3] Review: J . W Cornforth in R. C. Elderfield: Heterocyclic Compounds. Vol. 5, Wiley, New York 1957, p. 386.
[4] Another access to 2-methyl-3-phenylserines: a) S . H . Pines,
S . Karady, and M . Sletringer, J. Org. Chem. 33, 1758 (1968); b) S . H .
Pines, S . Karady, M . A . Kozfowski, and M. Sletzinger, ibid. 33, 1962
[5] The relative chemical shifts are very similar to those of the N-acetyl
compounds; cf. [4b].
A Squaric Diamidine and an Aza Analog of
By Siegjried Hiinig and Hermann Putter[*]
The replacement of oxygen in squaric acid by nitrogen has
hitherto been extended only to provide 1,2-['] and 1,3diamides"! We here describe the first squaric acid diamidine.
All previous attempts to introduce further amino groups
into the 1,2-diamide (2), e. g., by o-phenylenediamine (3),
failedL3].On the other hand, the 1,3-diamidec4I( I ) has
now been shown to be a useful starting material. When ( I )
is heated in polyphosphoric acid a dark green reaction
mixture is formed from which a green (poly?)phosphate
( 4 0 ) of indefinite composition is precipitated by water.
Thence perchloric acid produces the extremely sparingly
soluble green diperchlorate (4b)"' (dec. from 295 "C;
IRr6]:3150, 1610, 1550, 1460, 1100, 1040, 780 cm-I). ( 4 )
can be regarded as a highly stabilized cyclobutadienyl
When stirred in DMF suspension in absence of air, ( 4 b )
changes without visible alteration into the equally very
sparingly soluble diamidine (S)['l (m. p. from 210°C +(6),
318°C; [IRC6]:3150-2800, 1610, 1580, 1510, 1460, 1420,
1230, 750 cm-'1. Localization of the two H atoms in one
hetero ring is unlikely since in our experience[31structures
of benzocyclobutadiene characterk7]like (7) are avoided.
The structure of the skeleton of ( 4 ) and ( 5 ) follows from
the smooth oxidation to yellow quinoxalino[2',3': 1,2]cyclobuta[3,4-b]quinoxaline (6) [hmax (CH3CN)=443
(61 700), 413 (24200), 280 nm (50000);m. p. 324"C], which
can be reduced back to (5). Structure (6) is indicated by :
a) the mass spectrum (M' =256); b) an IR spectrum (1505,
1360, 1055, 760 cm-') containing few bands and no NH
band but with an intense band at 760 cm-' characteristic
of o-disubstituted benzenesL8];c) NMR signals only in the
aromatic region where they are of AA',BB' type
[(D,-DMSO): 6=7.86, 8.06 ppm; JAB=8.50,J,,.=1.50,
= 6.00 Hz]. (6) can be described in the limiting formula
( 6 ~ as
) a cyclobutadiene annelated to two quinoxaline
systems and is the first example[" of a cyclobutadiene
stabilized by incorporation into pyrazine rings.
Compound (8)['01 described a long time ago has a different
structure'"! Even very recent attempts to synthesize (8)
have failed"'].
Received: January 31,1972 [Z 609b IE]
German version: Angew. Chem 84, 481 (1972)
[I]Literature cited in [4].
[2] S . Skujins and G. A . Webb, Chem. Commun. 1968, 598.
[3] H . Putter, Diploma thesis, Universitat Wurzburg (Germany) 1970.
[4] S . Hiinig and H . Piirrer. Angew. Chem. 84, 480 (1972); Angew.
Chem. internat. Edit. 11, 431 (1972).
[S] Correct elemental analyses are available.
[6] All IR spectra were measured for Nujol suspensions.
[7] M . P. Caua and M . J . Mitchell: Cyclobutadiene and Related
Compounds. Academic Press, New York 1967.
[XI A. J . Bellamy: Ultrarotspektrum und chemische Konstitution.
Steinkopff, Darmstadt 1967.
[9] a) M . P. Catiaand L. Bravo, Chem. Commun. 1968,1538 ;b) R . F. C .
Brown, N . D. Crow, and R. K . Solly, Chem. Ind. (London) 1966, 343;
c) M . P . Caua, M . J . Mitchell, D. C. de Jong, and R. !I tian Vossen,
Tetrahedron Lett. 1966, 2947.
[lo] A . 7:Mason and L. A. Dryfoor, J. Chem. SOC.63, 1293 (1893).
[11] P. England and R . H . McDougall, J. Chem. SOC.C 1971,2685.
[12] P. England and R. H . McDougall, J. Chem. SOC.C 1971,3605.
Cyclodimerization of Heated
By Paul Binger"]
Prof. Dr. S . Hiinig and Dip1.-Chem. H. Putter
Institut fur Organische Chemie der Universitat
87 Wiirzburg, Landwehr (Germany)
[*'] This work was supported by the Fonds der Chemischen Industrie. DECHEMA, and the Badische Anilin- & Soda-Fabrik as well
as by Chemische Werke Hiils who supplied squaric acid derivatives.
Angew. Chem. internat. Edit. 1 Vol. I1 (1972)
No. 5
The now readily available methylenecyclopropane(l)['] dimerizes on a nickel(0) catalyst between -15 and 0°C to
[*I Dr. P. Binger
Max-Planck-Institut fur Kohlenforschung
433 Miilheimpuhr, Kaiser-Wilhelm-Platz 1 (Germany)
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acid, carboxylated, oxazoline, formylamino, esters, formylserine, substituted, ethyl, hydroxy
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