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Diketopiperazines from Leuchs Anhydrides.

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rom other even-electron ions has been observed in electronrnpact experiments with dialkyl derivatives ( I ) , R = alkyl[5l.
One factor that apparently renders the overall energy balance
of fragmentation (2d) 4 6 ) favorable, despite the low stability of the neutral particle expelled, is the resonance-stabilization of the ion (6d).
I t is important to note that the ejection of dehydrobenzene a neutral particle - is still a process of lower energy requirement than ejection of a second phenyl radical [(Zd)+(7)].
It has been pointed out 161 that even-electron to odd-electron
decompositions, if not forbidden, are at least rare in organic
mass spectrometry. Ion (7) is absent in the spectra of all
compounds discussed in this paper.
I t should be noted that the major decomposition path (as
judged by relative peak intensities) of the molecular ion of the
dichloro compound ( l e ) is expulsion of neutral SnClz rather
than CI., to give metal- and chlorine-free ion (8),m/e 168
(the base peak a t 12 eV). This observation is consistent with
the known r781 bond strength differences: the Sn-R bond
strength increases in the order Sn-alkyl < Sn-phenyl < Sn-CI.
Diketopiperadnes from Leuchs Anhydrides111[**I
P. Rosenmund and K . Kaiser[*]
Leuchs anhydrides (1,3-oxazolidine-2,5-diones)( I ) prepared
from DL-amino acids react instantaneously with aziridines
with liberation of COz at room temperature to give pure diketopiperazines @iperazine-2,5-diones) ( 4 ) in high yield.
THF and anhydrous and 95% ethanol are suitable solvents.
Highest yields of ( 4 ) are obtained when the Leuchs anhydride
is added in small portions to an excess of aziridine. Diketopiperazines are not formed if amines other than aziridine, e.g.
triethylamine or diethylamine, are used.
In view of the facts that the reaction is independent of solvent
and that aziridines obviously act catalytically we consider
that reaction probably proceeds as follows:
Received: December 2, 1969
[ Z 130 IEl
German version: Angew. Chem. 82, 182 (1970)
[*I Prof. I. Lengyel, Ph.D. and M. J. Aaronson, M.S.,
Department of Chemistry, St. John's University,
Jamaica, New York 11432 (USA)
[l] Presented in part at the 17. Annual Conference on Mass
Spectrometry and Allied Topics, May 18-23,1969, Dallas, Texas,
paper No. 140; cf. Abstracts, p. 403.
[2] E . J . Kupchik, J . A . Ursino, and P . R . BouGouk, J. organometallic Chem. 10, 269 (1967). We thank Professor Kupchik for
kindly providing the samples used in this investigation.
[3] The mass spectra were recorded on both a CEC 21-103C and
a Hitachi RMU-6D instrument, at 70 and 12 eV, 50pA. The
samples were introduced using the direct probe.
[4] The ion-clusters due to the different isotopes of tin, which act
as a natural chemical label, greatly facilitate unambiguous identification of tin-containing ions. The existence of these ionclusters in the mass spectra of organotin compounds largely
obviates the necessity of high-resolution mass spectrometry in
this class of compounds.
[5] I . Lengyel and M . J . Aaronson, unpublished.
[6] F. W. McLafierty: Interpretation of Mass Spectra. Benjamin,
New York 1966, p. 140.
[ 7 ] M . Gielen and J . Nasielski, Bull. SOC.chim. beiges 1968, 77.
[8] D . B . Chambers, F. Glockling, and J . R . C. Light, Quart. Rev.
(chem. SOC.,London) 22, 317 (1968).
Because of the relatively low nucleophilicity of aziridine, reaction (1) is slow and consequently the concentration of ( 2 )
always remains small. Reaction of (2) with ( I ) yields the di-
Angew. Chem. internat. Edit.
1 Vol. 9 (1970) 1 No. 2
peptide aziridide (3) which undergoes rapid cyclization to
give ( 4 ) with simultaneous liberation of aziridine, which thus
becomes available for further reaction. This cyclization
greatly hinders polymerization which otherwise would
readily occur - particularly in the presence of small amounts
of base. That reaction (3) proceeds rapidly can be ascribed
t o the fact that compound (3) has the character of a n activated carboxylic acid derivative.
We have been able t o support this view by the following observations: If N-trifluoroacetylphenylalaninaziridide (prepared in 72% yield, m.p. 107-108°C, by reaction of trifluoroacetylphenylalanine and aziridine by the anhydride
method) is treated with 0.2 N N a O H at room temperature in
order t o remove the trifluoroacetyl residue 121, phenylalanine
is formed exclusively; the aziridino residue, therefore, is just
as labile as the trifluoroacetyl group. Hydrolysis with semiconcentrated aqueous ammonia affords phenylalaninamide
(87 %,). Moreover, sodium ethoxide in ethanol liberates
aziridine from N-trifluoroacetylphenylalaninaziridide.
General method of preparation:
The Leuchs anhydride ( 1 ) is added in small portions (10 nig)
with vigorous stirring at room temperature to a solution of
aziridine (0.3 ml) in ethanol (or T H F ) (3 ml). The mixture is
allowed t o stand after each addition until evolution of COz
is complete and all anhydride has dissolved t o give a clear
solution; addition of anhydride is discontinued as soon as
the solution becomes turbid. After 1--5 min almost analytically pure diketopiperazine ( 4 ) crystallizes out in 70-80%,
yield. The mother liquor contains a further 1CblSX of ( 4 ) .
[Z 132 IE]
Received: September 15, 1969
German version: Angew. Chem. 82, 137 (1970)
Publication delayed a t authors' request
[*I Priv.-Doz. Dr. P. Rosenmund and Dipl.-Chem. K. Kaiser
Institut fur Organische Chemie der Universitat
6 Frankfurt/Main, Robert-Mayer-Strasse 7/9 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
[I] Part of Dissertation by K . Kaiser, Universitat Frankfurtl969.
[2] F. Wqvgand and R . Geiger, Chem. Ber. 89, 647 (1956).
Ionization and Rearrangement of Diphenylphenoxymethylmagnesium Chloride[**I
By H . F. Ebel, V. Dorr, and B. 0 . Wagner[*]
In earlier investigations[ll of metalated ethers and their rearrangement (Wittig rearrangement) the change of properties when going from the magnesium and zinc derivatives of
diphenylphenoxymethane, ( l a ) and ( I b ) respectively, to the
alkali metal derivatives ( I c ) was emphasized. Whereas ( l a )
and ( I b ) are colorless and do not rearrange to the triphenylmethoxides (2a) and (Zb), the alkali metal compounds ( I c )
are deep red and undergo slow conversion into (2c).
We have now found that hexamethylphosphoric acid triamide (HMPT), which has repeatedly been shown t o have
superior solvation properties for organomagnesium [2,31 and
other organometallic compounds 131 and which recently has
been called a "super-solvent" in carbanion chemistry [41,
changes the properties of ( l a ) profoundly.
On adding a solution o f isopropylmagnesium chloride [at
least 2 equiv., relative t o ( I d ) ] in T H F to diphenylphenoxymethane ( I d ) at 65 O C , a colorless solution results. If HMPT
(30 equiv.) is now added, the mixture starts boiling and gradually assumes a deep red color. After 96 hours there is no
(Id)present in the hydrolysis product (gas chromatography:
10m SE-30 column, 5 % o n Chromosorb W, 24 ml N?/min,
250 "C), and after one crystallization the melting point is that
of triphenylmethanol (2d) (m.p. 161-161.4 "C). Using only
H M P T as solvent, the rearrangement is complete after 30 min
at 110 "C (see Experimental).
A 0.13 N solution of ( I d ) in ether was refluxed with an excess
of isopropylmagnesium chloride in presence of H M P T for
several hours, and then diluted with T H F in a closed apparatus, the ratio of dilution varying from 1 : 1000 t o 1 : 125.
The resulting solutions exhibited a well developed absorption
band, hmax = 461 nm, which obeyed the Beer-Lambert law.
The band differs from the absorption measured earlier "1 for
( I c ) only in a shift t o longer wavelengths by 1 2 n m . We
suggest that ( l a ) , Hal = CI, forms solvent-separated ion
pairs in presence o f HMPT. Our measurements on magnesium derivatives of diphenylmethane, triphenylmethane, and
fluorene led to similar results [51.
Thus we have demonstrated by chemical and spectroscopic
means, and using a simple model, that organomagnesium
compounds may assume pronounced carbanionoid[6]
HMPT (0.60mole) is added dropwise under argon t o an
ethereal solution (100 ml) of isopropylmagnesium chloride
(0.097 mole). The ether is then removed by distillation and
( I d ) (0.04 mole) is added at 110 O C to the pale yellow, viscous
solution. A clear red solution is formed with evolution of
gas (propane). After 30 min the mixture is cooled in an ice
bath and treated with twice its volume of 5 N HCI. The
colorless crystals of (2d) (yield 95 % after filtration, washing
with water, and drying) are recrystallized from ethanol
(yield 83%; m.p. 161-161.5 "C).
Received: December 17, 1969
[ Z 131 IE]
German version: Angew. Chem. 82. 136 (1970)
[*I Priv.-Doz. Dr. Hans F. Ebel, Dipl.-Chem. V. Dorr, and
Dr. B. 0. Wagner
Organisch-Chemisches Institut der Universitat
69 Heidelberg, Tiergartenstrasse (Germany)
I**]This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Wirtschaftsministerium/LandesgewerbeamtBaden-Wiirttemberg.
[I] G. Wirtig and E. Stahnecker, Liebigs Ann. Chem. 605, 69
[2] H. F. Ebel and R . Schneider, Angew. Chem. 77, 914 (1965);
Angew. Chem. internat. Edit. 4 , 878 (1965).
[3] H . Normanr, Angew Chem. 79, 1029 (1967); Angew. Chem.
internat. Edit. 6, 1046 (1967).
141 S . J . Rhoads and R . W. Hoider, Tetrahedron 25, 5443 (1969).
[5] H . F. Ebel (lecturer), B. 0.Wagner, and V . Dorr, paper read
at the Chemiedozententagung, Karlsruhe 1969.
[ 6 ] H . F. Ebel, Fortschr. chem. Forsch. 12, 387 (1969).
Nucleophilic Imino- and Aminomethylation
of Ketonest11 [**I
Spectral properties and the tendency to rearrange depend o n
the nature (not specified in the formulas) of the bonds involving the metal atoms; only derivatives ( I ) , in which
the C-R bond is ionic, are deeply colored and capable of
Angew. Chern. internat. Edit. / Vol. 9 (1970)
No. 2
By Thomas Kauffmann, Edgar Koppelmann, and Heike Berg [*I
Electrophilic aminomethylation (Mannich reaction) is a well
known important reaction step in organic synthesis. We have
now found that an aminomethyl group can be introduced
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anhydride, leucht, diketopiperazine
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