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Base-Catalyzed Addition of Oxazol-5-ones to Activated Multiple Bonds.

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overlapping multiplets from H-2-vinylic and aromatic
protons in the vicinity of 7 ppm. In order to prove unequivocally the structure of the dehydration product, the
tribenzoate ( 4 ) was converted by standard procedures
into ( - )-methyl 5-0-acetyl-3,4-0-isopropylidene-shikimate (7).
We have now found that tris(chloromethy1)amineis readily
accessible by reaction of phosphorus pentachloride with
hexamethylenetetramine, N,(CH,),.
The reactants are
mixed in a molar ratio of 3 : l and refluxed in benzene or
methylene chloride or heated to 100°C without solvent.
Formation of ( I ) according to eq. (1)
Treatment of ( -)-methyl 3,4,5-tri-O-benzoyl-shikimate
(4)
with catalytic amounts of anhydrous methanolic-sodium
methoxide yielded (-)-methyl shikimate (31, m.p. 112 to
114"C, [.ID- 130" (c= 1.88; ethanol), [Ref. [7] : m. p.
115"C, [.ID- 139" (c=2; ethanol)]. The latter readily
condensed with acetone in the presence of anhydrous
copper sulfate to yield the syrupy (-)-methyl 3,4-0-isopropylidene-shikimate (6).Acetylation of (6) using acetic
anhydride/pyridine furnished theester (7), m. p. 72-74"C,
[ ~ ~ ] ~ - (c=1.15;
69~
chloroform), [Ref. [S]: m.p. 75 to
76 "C].
proceeds quantitatively ; product (2) cannot, however, be
isolated. The mechanism of formation of ( I ) , its chemical
properties, and the nature of the other products [formed
from / 2 ) ] will be reported later[']. ( 1 ) is a colorless,
crystalline solid, m. p. 93°C; NMR (CH,Cl,): r=4.9 ;
M. W.: 162 (calc.), 156 (cryoscopic, benzene); correct
elemental analysis.
The 100-MHz NMR spectrum of the ester (7) in CDCl,,
obtained with the aid of spin decoupling, is compatible
only with the structure given. The partial spectrum of (7)
showed : signals at 6 =6.79 (H-2/quintet), 5.10 (H-S/br. m),
4.65 (H-3/br. m), 4.15 ppm (1H/t). Irradiation of the vinylic
proton H-2 caused the broad multiplet centered at 4.65
ppm to collapse to a form of doublet, .T3*.+ = 6 Hz. The fact
that the one-proton multiplet H-5 at 5.10 ppm was absolutely unchanged, excludes unequivocally the presence of
the isomer ( 5 ) in the dehydration procedure. Since trihydroxycyclohexanone (8) can be readily converted via
the triacetyl-['] or 3,4-isopropylidene derivative"'] into
labeled (-)-quinic acid, this method provides a simple
route to the specifically labeled shikimic acid.
Received: May 7, 1971 [Z 449 IE]
German version: Angew. Chem. 83,722 (1971)
[l] J . F . Eykan, Recl. Trav. Chim. Pays-Bas. 4, 32 (1885).
[2] B. A. Bohm, Chem. Rev. 65,435 (1965).
[3] R. McCrindle, K . H . Overton, and R. A. Raphael, J. Chem. SOC.
1960, 1560; E. E. Smissman, J . 'I: Suh, M . Oxman, and R. Daniels, J.
Amer. Chem. SOC.81, 2909 (1959); R. Grewe and S. Kersten, Chem.
Ber. 100, 2546 (1967); H . J . Bestmann and H . A. Heid, Angew. Chem.
83, 329 (1971); Angew. Chem. internat. Edit. 10, 336 (1971).
[4] P. R. Sriniuasan, M . Katagiri, and D. B. Sprinson, J. Amer. Chem.
SOC.77,4943 (1955).
[5] G. Dangschat and H . 0. L. Fischer, Biochem. Biophys. Acta 4, 199
(1950); R. Grewe, H . Biittner, and G . Burmeister, Angew. Chem. 69, 61
(1957).
[6] D. Mercier, J . Cleophax, J . Hildesheim, and A. M . Sepulchre,
Tetrahedron Lett. 1969, 2497.
[7] R. Grewe, H . Jansen, and M . Schnoor, Chem. Ber. 89, 898 (1956).
181 H . 0. L. Fischer and G. Dangschat, Helv. Chim. Acta 20,705 (1937).
[9] R. Grewe and E . Vangermain, Chem. Ber. 98,104 (1965).
[lo] J . Corse and R. E. Lundin, J. Org. Chem. 35, 1904 (1970).
Preparationof Tris(chloromethyl)amine,N(CH,CI)
By Ekkehard Fluck and Peter Meiser[*I
Tris(chloromethyl)amine, N(CH,Cl),, ( I ) , was first described by Moeller and Westlake[" in 1967. They obtained
the compound by reaction of aminomethanesulfonic acid,
H,NCH,SO,H, or the sodium salt of nitrilotrimethanesulfonic acid, N(CH,SO,Na),, with phosphorus pentachloride. In the former case the compound is formed in
only very small amounts, in the latter the yield is 23%.
Procedure :
A mixture of finely ground hexamethylenetetramine (7.0 g,
0.05 mol), PCl, (41.8 g, 0.2 mol), and dry CH,Cl, (150 ml)
is refluxed with gentle stirring for 20 h in a 250-ml roundbottom flask fitted with a reflux condenser and drying tube.
The solvent is then distilled off; the final solvent residues
are removed in uacuo, whereupon small amounts of unreacted phosphorus pentachloride may also sublime over.
Compound ( 1 ) is sublimed from the crystalline residue
at 7O-8O0C/1.5 torr and trapped on a cold-finger; yield
8.0 g (100%). The product can be purified by resublimation
or by recrystallization from CH,CI,.
Received: June 3,1971 [Z 454 IE]
German version: Angew. Chem. 83, 721 (1971)
[I] 'I: Moeller and A. H . Westlake, J. Inorg. Nucl. Chem. 29,957 (1967).
[2] E . Fluck and P. Meiser, to be published.
Base-Catalyzed Addition of Oxazol-9ones to
Activated Multiple Bonds'']
By Wolfgang Steglich, Peter Gruber, Gerhard Hojle, and
Wolfgang Konig"'
The use of oxazol-5-ones as nucleophilic reactants in
Michael additions has hitherto hardly been studied['*'I.
Since oxazolone anions are ambif~nctional[~.
they should,
in principle, react with activated multiple bonds at C-2,
at C-4, and at the exocyclic oxygen. We have found that
the site of reaction is determined primarily by the kind of
activated multiple bond.
Thus benzoylacetylene (1) adds exclusively to position 4
of 4-isopropyl-2-phenyloxazol-5-one( 2 a ) . With triethylamine as a catalyst, (1) reacts in methylene chloride at as
low a temperature as - 10°C within a few minutes to give
the cis-olefin (3a), which is converted into the trans isomer
( 4 a ) on brief warming to 100°C.
The proclivity of ( 1 ) to add at position 4 is so pronounced
that it is influenced but little by steric and electronic effects
in the oxazolone anion. Thus 4-tert-butyl-2-phenyloxazol5-one (2 b ) and 4-isopropyl-2-(p-nitrophenyl)oxazol-5-one
[*] Prof. Dr. W. Steglich, DipLChem. P. Gruber, Dr. G. Hofle, and
[*] Prof. Dr. E. Fluck and DipLChem. P. Meiser
Institut fur Anorganische Chemie der Universitat
7 Stuttgart, Schellingstrasse 26 (Germany)
Dr. W. Konig["'
Organisch-Chemisches Institut der Technischen Universitat
8 Miinchen 2, Arcisstrasse 21 (Germany)
["I Present address: Farbwerke Hoechst AG, 623 FrankfurtlMain 80
(Germany)
Angew. Chem. internat. Edit. / Vol. I0 (1971) / No. 9
653
smoothly form the 4-adducts (3) which rearrange to ( 4 b )
and ( 4 c ) on heating (Table 1). No less than a 2-trifluoromethyl group is required to modify the electron distribution in the anion sufficiently to direct (1) to position 21'1.
Dimethyl acetylenedicarboxylate, acrolein, and methyl
vinyl ketone (7) add to both position 2 and position 4,
giving mixtures of ( 6 ) and 4,4-disubstituted oxazolones
(8)[91.The reaction of ( 2 a ) with (7) is shown as an example.
Under analogous conditions dimethyl acetylenedicarboxylate and acrolein afford the 2-adducts (6) in 34 and 64%
yield, respectively. The product ratio ( 6 h ) / ( 8 h ) can be
varied within limits by modification of the reaction conditions. If triethylamine is replaced by ethyldiisopropylamine,
for example. the proportion of 16 / I falls to 30'4,; on refluxing with triethylaminein carbon tetrachloride it rises to 70%.
All the 4-isopropyl-2-phenyl derivatives ( 6 ) and ( 8 )
studied can readily be distinguished on the basis of their
-H
(2a) + CH2=CH-COCH,
(7)
R2
R2
(3)
(4)
CH,CI,N(C2HS)3
20%
Table 1. 4,4-Disubstituted oxazol-5-ones [a].
NMR spectra (in CDCI,). In (8) the methyl protons give
two adjacent doublets (620.93 and 1.05 ppm, 5 = 7 Hz)
which overlap extensively (1.28 and 1.32 ppm) in the case
of (6). The methine signal of (6) appears considerably
farther downfield (3.0ppm) than that of ( 8 ) (2.1 ppm).
Finally, the phenyl protons of (6) give a broad signal at
6 ~ 7 . ppm
5
which is resolved into two separate multiplets
at 7.5 and 8.0 ppm (3 and 2 protons, respectively) in ( 8 ) .
General procedure :
Reaction of 2-trifluoromethyl-4-isopropyl-2H-oxazol-5one with ( I ) proceeds quantitatively, once again Dia trans
addition, to give the pseudooxazolone ( 5 ) .
Table 2. 2,2-Disubstituted pseudooxazol-5-ones [a].
Cpd. R1
R2
R3
R4
Yield M.p.("C)
(%)
(6d)
(6e)
(6f)
1691
CWCH,),
CH(CH,),
CH(CH,),
CH(CH3)2
C,H5
n-C,H,,
C6H,
C6H5
H
H
CO,CH,
CN
CN
CN
C02CH3
CN
98
95
92
86
oil [b]
oil [b]
71
121
[a] All compounds gave correct elemental analyses
[b] Loses C 0 2 on distillation [8].
The group of reagents that add exclusively to position 2 of
2,4-disubstituted oxazolone anions includes acrylonitrile,
fumaric and maleic esters, and the corresponding dinitriles.
Reaction furnished 2,2-disubstituted pseudooxazolones (6)
(Table 2). They can be used for 3C-homologization of
carboxylic acids"].
654
Triethylamine (3-10 mmol) diluted with methylene
chloride is added dropwise to a stirred solution of oxazol5-one (10 mmol) and an activated alkene (alkyne) (10 mmol)
in methylene chloride (30 ml). With highly reactive electrophiles ( e .q. benzoylacetylene or fumaronitrile) only 3 mmol
of triethylamine are used, with less reactive ones (e.9.
fumaric ester) up to 10 mmol. In the former case the reaction
time is just a few minutes, in the latter the reaction mixture
is allowed to stand for 2-6 h at room temperature. The
triethylamine is extracted with ice-cold 0.1 N HCI and the
organic phase is dried and evaporated down in uacuo. The
adducts are obtained very pure and if required can be
recrystallized from chloroform/light petroleum.
Received. June 14,1971 [Z 458a IE]
German version: Angew. Chem. 83, 725 (1971)
[l] Reactions of oxazol-5-one anions, Part. 6.-Part 5: W Sreglich and
G . H @ / e , Chem. Ber. 102, 1129 (1969).
[2] A . Dzugay, 1. Z . Siemion, and Z . Ojrzynski, Roczniki Chem. 40,
1329 (1966).
[3] 7: Hiraoka and Z Kishrda, Chem. Pharm. Bull. (Tokyo) 16, 1576
(1968).
[4] W Stegtich and G. H$/e, Chem. Ber. 102, 883 (1969).
[5] W. Steglich and C . Hoffe, Chem. Ber. 102,1129 (1969).
[6] W Steglich and G. Hofle, Chem. Ber. 102,899 (1969).
[7] W Steglich and P. Gruber, Angew. Chem. 83, 727 (1971); Angew.
Chem. internat. Edit. 10, 655 (1971).
[S] P. Gruber, Dissertation, in preparation.
[9] Exclusive addition to position 2 occurs with 2-trifluoromethyl2 H-oxazol-5-ones.
Angew. Chem. internat. Edit. J Vol. 10 (1971) J No. 9
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