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Ethyl -Cyano--isocyanoalkanoates from -Metalated Ethyl Isocyano-acetates or -propionates and Acrylonitriles.

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relaxation measurements .requires a knowledge of the
equilibrium constants K , . However, the microscopic constants can be determined by combination of potentiometric
and spectrophotometric titrations"] only under the limiting
assumption that the absorption by the deprotonated thiol
group is independent of the prevailing degree of protonation
of the amino group. This assumption can be tested by
kinetic methods if the reaction volume AV(=V,-V,) is
known and provided that it can be decided upon which
side the equilibrium lies. It is then possible to determine
K = FB/Fc =y/( 1 -y) unambiguously by measuring the
maximal sound absorption amplitude
( A ~ / V ) , , ,=
~ ~const.y(l -y)AV2.
Such a compound (R=C6HlI; R'=CH,, M=Au, n = l )
is formed (as trimer) when methanolic potassium hydroxide
solution (157 mg/l8.9 ml) and then, with stirring, cyclohexyl isocyanide (305 mg) are added to a suspension of
chloro(triphenylphosphane)gold(rfin methanol. After 0.5 h
the suspension is concentrated to half volume in a waterpump vacuum. The white precipitate is recrystallized from
chloroform/methanol (m. p.
190°C with gradual decomposition and violet coloration above 160°C).
However, it can be shown that for the systems studied, the
intramolecular proton exchange between neighboring
groups is faster by two or three orders of:magnitude than
the protolysis (or hydrolysis) reactionsr7](see Table) :
group ( ~ = 5 . 9 9ppm). No N-H, 0-H, or -NECstretching vibration was observed in the W spectrum, but
,
B + H+=A+C+H+
or B $ D + H + e C [ 7 ]
The 'H-NMR spectrum, in CDCl,, measured from T = - 10
to 30 ppm, contains only signals that can be assigned to
the cyclohexyl ( ~ ~ 5 and
. 7 8.3 ppm) and the methoxyl
+
@
I
I
only -C=Nand =C-OCH,
stretching vibrations at
1535 (vs, br.) and 1130 (s) cm-', respectively. The compound is non-conducting in methylene chloride. The molecular weight in chloroform amounted to 1031 and is independent of concentration (0.81 - 3.1 wt.-%).
I
Table. Relaxation times for the intramolecular proton transfers.
Compound
= rs1
Cysteine
Homocysteine
Penicillamine
Glutathione
Cysteamine
2.8
4.4 x
4.9 x
1.6 x
3.3 x
Q
These findings and the position of the -C=Nvibration indicate a formula of type (I).
stretching
10-9
10-8
10-8
lo-'
10-8
Au
zN===C
This means that the direct proton exchange between the
two functional groups with interchange'of hydrogen bonds
can occur appreciably more easily than the corresponding
reactions of the free protons or hydroxide ions.
These results are of particular interest for enzyme reactions
in which mutually reacting groups are brought into close
contact by rapid structural interchanges
s). They
show that the individual steps of intramolecular proton
transfer are as fast as, or faster than, the structural changes.
Received: January 14,1972 [Z 604 IE]
German version: Angew. Chem. 84,430 (1972)
[I] R. E. Benesch and R. Benesch, J. Amer. Chem. Soc. 77,5877 (1955).
[2] K . Waiienfels and Ch. Sfrefer, Biochem. 2. 346, 119 (1966).
131 E. Coates, C. Marsden, and B. Rigg, Trans. Faraday Soc. 65, 863
(1969).
[4] J . I: Edsalland J . Wyman: Biophysical Chemistry. Vol. 1. Academic
Press, New York 1966.
[5] M . Eigen and L. de Maeyer in A . Weissberger: Technique of Organic
Chemistry. Vol. 8/2, Interscience, New York 1963.
[6] F. Peters, Acustica, in press.
[7] M . Eigen, Angew. Chem. 75, 489 (1963); Angew. Chem. internat.
Edit. 3, 1 (1964).
Trimeric 1-(Cyclohexylimino)rnethoxymethylgold( I),
A New Type of Organometallic Compound
CsHL
,Au
'OCH,
(11
If aromatic isocyanides are used instead of cyclohexyl
isocyanide, monomeric (not trimeric) ligand-stabilized
compounds such as
[(C6H,),P]AuC(=N-C6H,-CH,)OCH,
are formed"].
Except for the unstable cyclopentadienylgold(1) and
[C6H,-c~C-Au],,
the compound ( I ) described here
is the only organogold(1)compound['] that does not require
stabilization by ligands such as phosphanes or isocyanides.
Received: December 20,1971 [Z 616 IE]
German version: Angew. Chem. 84, 482 (1972)
[1] G . Minghetti and F. Bonati, Rend. Accad. Naz. Lincei, Classe Sci.
fis. mat. nat. [VIII], 49, 287 (1970).
[2] B. Armer and H . Schmidbauer, Angew. Chem. 82, 120 (1970);
Angew. Chem. internat. Edit. 9, 101 (1970).
Ethyl y -Cyano-a-isocyanoalkanoates from
a-Metalated Ethyl Isocyano-acetates or
-propionates and AcrylonitrilesI']
By Ulrich Schollkopf and Paul-Hermann Porsch"]
No organometallic compound corresponding to the general
formula [R-N=C( OR')-],M
has hitherto been known.
y-Cyano-a-isocyanoalkanoic esters (6) deserve attention
because they have several reactive centers and can react in
many ways, e.g. by hydrolysis of the isocyano group to
yield a-amino-y-cyanoalkanoates. They are obtained by
[*] Dr. G. Minghetti and Prof. Dr. F. Bonati
[*I
By Giovanni Minghetti and Flavio Bonati[*]
Istituto di Chimica Generale dell'Universita
1-20133 Milano, via Venezian 21 (Italy)
Angew. Chem. internat. Edit. / Vol. 11 (1972) 1 No. 5
Prof. Dr. U. Schollkopf and Dip1.-Chem. P.-H. Porsch
Organisch-Chemisches Institut der Universitat
34 Gottingen, Windausweg 2 (Germany)
429
cyanoethylating, for example, ethyl isocyanoacetate (1)
(R' = H) or isocyanopropionate (2) (R' = CH,) in ethanol
with sodium ethoxide as catalyst at ~ 3 0 ° C .Essential
intermediates are the a-metalated isocyanoalkanoic esters
(3) or ( 4 ) which add to the double bond of acrylonitrile
(5). The adducts (6) result by protonation.
The I-pyrrolines (11) can be reduced to 3-cyanoproline
ethyl esters (ethyl 4-cyanopyrrolidine-2-carboxylates)(13)
by catalytic hydrogenation in ethanol ox'er palladium
on activated charcoal.
Ethyl y-cyano-a-isocyano-P-methylbutyrate (6a)
NHCHO
I
(8)
H5Cz0,C-C-CHRZ-CHR3-CN
8'
NHCHO
I
H5C,0zC- C [CHR2-CHR3- CN], (9)
R'
R'
R3
(6a)
H
(6b)
(6c)
(6d)
(de)
H
CH,
C,H,
H
CH,
C,H,
H
H
H
H
H
CH,
H
CH3
H
Cpd.
16f)
CH,
CH,
CH,
CH,
H
(70)
H
(76)
(7Cl
H
CH,
B.p.
("Citorr)
M. p.
("C)
106/0.1
-
103/0.02
991015
100/0.15
-
941005
175/0.1
-
17310.1
Yield (%)
-
IlO[f3
-
44-46 [g]
50-52[h]
-
.a]
b]
-c]
:d]
-el
Molar ratio, ( I ) or ( 2 ) : ( 5 ) = 2: 1.
Molar ratio, (1) or (2) : ( 5 ) = I :2.
Molar ratio, ( I ) or (2) : ( 5 ) = 1 : 1.
Amount of bis adduct = about 30% of the weight of monoadduct.
Amount of monoadduct = about 30% of the weight of bis adduct.
.fl From cyclohexane.
g ] From ethanol/cyclohexane.
-h] From ethanol/water.
Bis adducts of type (7) can be formed from isocyanoacetic
esters ( I ) because the anions from compounds (6) can
react further with acrylonitrile (5) when R'=H. In
experiments to date, acrylonitrile (5) (Rz=R3= H) and
methacrylonitrile ( 5 ) (R2= H, R3= CH,) afford only
the bis adducts-even when an excess of isocyanoacetic
ester is used-whereas, for example, crotononitrile and
cinnamonitrile give monoadducts of type (6) as isolable
products.
Compounds (6) and (7) can be hydrolyzed by 2N hydrochloric acid in ethanol to y-cyano-a-(N-formylamino)
esters (8) and ( 9 ) , respectively, the nitrile group remaining
intact.
If the cyanoethylation of ethyl isocyanopropionate (2)
(R' =CH,) is carried out at 65 "C with an equimolar amount
of sodium ethoxide, the 3-cyanopyrroline-5-carboxylic
esters (11) or, if R3=H, (12) result; they are formed by
way of the anions (10).
430
A solution (1 ml) of sodium ethoxide (prepared from 5 g of
sodium in 100 ml of anhydrous ethanol) was added to one of
ethyl isocyanoacetate"' (11.3 g, 0.1 mol) in anhydrous
ethanol (30 ml). Then a solution of crotononitrile (3.35 g,
50 mmol) in anhydrous ethanol (15 ml) was added dropwise
over 30 min, the temperature not rising above 30°C.
The mixture was kept at room temperature for 15 h,
then neutralized with glacial acetic acid, and the solvent
was removed in a vacuum (bath-temperature max. SOOC).
The residue was dissolved in methylene chloride (50 ml)
and washed three times with water (20 ml portions),
and the organic phase was dried with sodium sulfate
and evaporated. This residue afforded 50% (4.5 g) of a
1 :I diastereoisomeric mixture (6a). IR spectrum (film):
2250 (vcN)>
2140 (vN=,), 1750 cm-' (vco); NMR spectrum
(CDCI,): r=5.46 (d, J a , p n . 4 H ~5.60
) , (d, J,,p=4Hz), 8.58
(d, J x 7 Hz), 7.43 ppm (m). The distillation residue contained ca. 1.5 g of the bis adduct (7c).
4-Ethoxycarbonyl-4-isocyano-3,5-dimethyiheptanedinitrile
(7c):
A mixture of crotononitrile (13.4 g, 0.2 mol) and ethyl isocyanoacetate (11.3 g, 0.1 mol) in anhydrous ethanol
(30 ml) is added to a mixture of anhydrous ethanol (30 ml)
and sodium ethoxide solution (2 ml; from 5 g of sodium
and 100 ml anhydrous ethanol) during ca. 30 min at such
a rate that the temperature does not exceed 30°C. Working
up is as described above. Fractional distillation of the
crude product afforded 3 g of monoadduct (da) and 10 g
(41%) of (7c). IR spectrum (film): 2260 (vCN),2140 (vNc),
1740 cm-' (vco); NMR spectrum (CDCI,): r=8.60 (m),
7.52 (m), 5.64 (q), 8.73 ppm (m).
4-Ethoxycarbonyl-4~ormylamino-3,5-dimethylheptanedinitrile (9), R2=CH,, R 3 = H
A mixture of (7c) (3.5 g), concentrated hydrochloric acid
(1 ml), and 96% ethanol (15 ml) was stirred at room
temperature until (2.5 h) the isocyanide band was no
longer present in the IR spectrum, neutralized with 10%
potassium hydroxide solution, and worked up as usual,
affording 3 g of ( 9 ) , R2= CH,, R3= H, as a colorless oil.
IR spectrum (film): 3360 (vNH), 2250 (v,,), 1730 (vco),
I6go (VamideI), 520 cm- (Vmnide 11).
'
Ethyl 3-cyano-4,5-dimethyl-2-pyrroline-5-carboxylate ( I 2 ) ,
R~ = CH,
A solution of ethyl isocyanopropionate"] (6.35 g, 50 mmol)
and crotononitrile (3.35 g, 50 mmol) in anhydrous ethanol
Angew. Chem. internat. Edit. 1 Vol. 11 (1972) / No. 5
The isomer of type (I) results, however, from o-nitroaniline
and the dichloride ( 4 ) (40 min, 150°C, 54%). The isomeric
amides differ characteristically in their IR spectra", 'I.
(15 ml) was added with stirring and cooling (water-bath)
to a solution of sodium (1.15 g, 50 mmol) in anhydrous
ethanol (40 ml); the mixture was stirred at 65°C until
the isocyanide band was no longer present in the IR
spectrum (1.5-2
h), and was then neutralized with
glacial acetic acid. Working up as described above afforded 54% (5.2 g) of ( I 2 ) , R2=CH3, b. p. 106"C/0.1 torr.
IR spectrum (film): 3370 (vNH),3095 (vH-,=,), 2190 (vcN),
1730 (v,--), 1600 cm-' (v,~,); NMR spectrum (CCl,):
r=3.08(d,J2,,=3 Hz),4.47(~),5.82(q),6.9(rn),8.7ppm(m).
Mainly the ester amide (6) is formed from ( 2 b ) and N methylaniline (1 :2) in ethanol (3 h, reflux). However, ( 3 )
(R'=C,H,, R'=Me) is formed in n-butanol (3 h, reflux,
56%); even in absence of solvent (1 h, reflux, 1 : 13) 70%
of ( 3 ) is obtained. This indicates a direct reaction (2 b) + ( 3 )
since the rearrangement (I) -+ ( 3 ) occurs only under
catalysis by protons['b*'I. The isomeric 1,2-diamide (I)
(R' =C,H,, RZ= CH,) is conveniently obtained by alkylby methyl iodide and
ation of (i) (R'=C,H,, RZ=H)r2a1
K tert-butoxide in DMF (1 h, 20°C, 43%).
Received: December 23, 1971 [Z 605IEl
German version: Angew. Chem. 84,478 (1972)
Publication delayed at authors' request
Considerable importance attaches to the finding that when
the 1,3-diamides ( 3 ) are heated with an excess of an amine
R3R4NH for 3-20 min with or without a solvent at
150-200°C the amino groups are exchanged, giving ( 5 ) .
The reaction is smooth if the entering amine is more strongly
basic (nucleophilic)than the leaving amine. This method is
an advantageous extension of the usual method of heating
a squaric acid salt with the amine"] and makes aliphatic
1,3-diamides, e . g . (Sd) and (Sf), accessible without the
difficulties previously described for the case of (5d)[le1
(Table 1).
[1] Syntheses with a-Metalated Isocyanides, Part 13.-Part 12: D.
Hoppe and U . Schijllkopf, Angew. Chem. 84,435 (1972); Angew. Chem.
internat. Edit. 11,432 (1972).
[2] I . Ugi, U . Fetzer, U . Eholzer, H . Knupfer, and K . Offeermann,
Angew. Chem. 77, 492 (1965); Angew. Chem. internat. Edit. 4, 472
(1965).
New Routes to Squaric 1,3-Diarnides
By Siegjried Hunig and Hermann Putter"]
Squaric acid (2a) reacts with amines, when heated in
alcohols or DMF, to give 1,3-diamides (3)['],but 1,2diamides (I)['] are formed from squaric esters, e.g. ( 2 b ) .
This rule is broken by feebly reactive amines. Only the
1,3-diamide (3) (R' =o-NO,C,H,,
R2 = H)"] can be
isolated (65%)fromo-nitroanilineand ( 2 b ) (4.5h, 180"C)r31.
0 3
(31
(Za), R = H
(Zb), R = CzH,
1
R3R4Nli
The amide (5c) which is important as starting material for
a squaric amidinerS1can only be prepared in this way;
o-phenylenediamine closes the ring with either ( 2 a ) or
(2b), yielding the 1,2-diamide (7). The compound hitherto
described as (5)'6a1has another structure['e.6b! We have
c1
Table 1. Transamidation of t,3-diamides ( 3 ) by heating with R3R4NH, t o yield ( 5 ) [4]
~
~
Yield
(8)
R'
[*I
Ref.
Prof. Dr. S . Hunig and Dip1.-Cbem. H. Putter
Institut fur Organische Chemie der Universitat
87 Wurzburg, Landwehr (Germany)
This work was supported by the Fonds der Chemischen Industrie,
DECHEMA, and the Badische ~ ~ i l&i Soda-Fabrik
~ AG, as well as
by Chemische Werke Huls who supplied squaric acid derivatives.
[**I
Angew. Chem. internat. Edit.
Val. 11 (1972) 1 No. 5
R3
R4
Ref.
P")
confirmed also that it is impossible to reduce the nitro
group of ( 3 ) (R'=o-NO,C,H,,
R 2 = H ) to an amino
group["].
The reduced reactivity of N-methylaniline is evident here
too: even if the leaving amine of ( 3 ) is favorable, only one
431
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isocyan, propionate, cyan, isocyanoalkanoates, acrylonitrile, ethyl, acetate, metalated
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