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Synthesis of 5-Amido Analogs of Adenosine (3-5)-Cyclophosphates.

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pectively (e.g. for (2a) in CC14: v,, (CSj) = 1146vw, vs(CS2)
619 cm-1 vs). Spectroscopic and X-ray data indicate pseudooctahedral environment of the metal in (/a)--(2f) with
(pseudo)-Czv symmetry. The IH-NMR spectra indicate in
particular that a n isomeric mixture containing (Ze) and a
tolyldithiocarboxylato derivative is only formed on reaction
of C6HsCH2Re(C0)5 with CS2.
The dithiocarboxylato complexes described above are reactive. For instance, (2b) loses CO on reaction with P(CGHS)~
at 80 “C in benzene to give the stable orange compound cisCGH~C(S)SR~(CO)~P(C
~ H ~pt.
) ~ 190 “C).
Received: May 19, 1970
[Z 229 IE)
German version: Angew. Chem. 8 2 , 6 3 9 (1970)
the fact that a very high spin density is present even on the
aldehyde group as a result of delocalization of the unpaired
electrons of the central metal ion in the ligand. The IH-NMR
spectrum of bis(salicylaldehydato)bis(pyridine)cobalt(II)
shows e . g . the C(O)H signal at-365 ppm relative to TMS 143.
If an excess of morpholine is added to a solution of this
complex and the mixture shaken in presence of air, the signal
of the proton is no longer detectable in the N M R spectrum.
N M R spectroscopy, therefore, can give information about
reactive centers in such complexes. Analogous compounds
having similar N M R parameters ought to show the same
reaction. We have already been able to confirm this in the
case of bis(salicylaldehydato)diaquonickel(~~) (lb).
Received: May 20, 1970
[Z 230 IE]
German version: Angew. Chem. 82, 640 (1970)
[*] Priv.-Doz. Dr. E. Lindner, Dip1.-Chem. R. Grimmer,
and Dr. H. Weber
Institut fur Anorganische Chemie der Universitat
8520 Erlangen, Fahrstrdoe I7 (Germany)
[l] H . Reinheckel and D . Jahnke, Chem. Ber. 99, 23 (1966).
[ 2 ] J . Weidlein, Angew. Chem. 81, 947 (1969); Angew. Chem.
internat. Edit. 8, 927 (1969).
[3] R . Gelius and E . Kirbach, Z. Chem. 10, 117 (1970).
[4] E . Lindner, R . Grimmer, and H . Weber, J. organometallic
Chem. 23, 209 (1970).
Oxidation of the SalicylaldehydeLigand in
Cobalt(I1)- and Nickel(1r) Complexes[**I
[*] Doz. Dr. K . E. Schwarzhans and
Dipl.-Chem. H. G. Biedermann
Anorganisch-chemisches Laboratorium
der Technischen Hochschule
8 Miinchen 2, Arcisstrasse 21 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
[l] H . P . Fritz, W. Gretner, H . J . Keller, and K . E. Schwarzhans, Z . Naturforsch. 23b, 906 (1968).
[2] H . G . Biedermann, Diplomarbeit, Technische Hochschule
Munchen 1969.
[3] D. F. Evans, J. chem. SOC.(London) 1959, 2003.
[4] W. Grefner, Dissertation, Technische Hochschule Miinchen 1969.
By Hans G. Biedermann and Karl E. Schwarzhans[*]
Bis(salicylaldehydato)diaquocobalt(II) ( l a ) reacts with pyridine
and several other unsaturated heterocycles 121 with
substitution of the two trans water molecules in the pseudooctahedral complex.
Synthesis of 5‘-Amido Analogs of Adenosine
By Akira Murayama, Bernd Jastorf, and Hans Hettler[*]
Adenosine (3’-5’)-cyclophosphate plays a key regulatory role
at various levels of organization, e.g. it acts as “chemical
messenger” in the production of blood sugar by the liver, as
aggregation initiator of slime fungi, and as a kind of “second
messenger” for more than a dozen hormones found in mammals, including humans [ *’21. Here we report on the synthesis
of its 5’-amido analogs, 5’-amino- (5a) and 5’-N-methylamino-5’-deoxyadenosine (3’-5’)-cyclophosphoramidate(5b).
In the corresponding reaction with an excess of morpholine
under a n inert gas atmosphere (N2) the neutral ligands are
likewise exchanged and a deep-red 1:2 adduct is formed. If,
however, the reaction is not carried out under inert gas the
color of the reaction solution changes from deep-red to
red-brown; this change of color takes place much more
rapidly when the reaction mixture is heated to about 120 “C
in air, and when only morpholine is present as solvent. An
examination of the susceptibility of such a solution by
Evans’ method [31 shows, however, that n o oxidation of the
central metal ion takes place. The magnetic moment of the
starting complex and of the isolated end product was determined as peE = 4.8 pg. If the reaction of ( l a ) with morpholine is carried out in CHC13 solution at room temperature
in an open vessel 3.4 moles of water are liberated (H20 determination by K. Fischer method) and 0.7-0.8 mole oxygen
is taken up per mole of ( l a ) over a period of 48 hours
(oxygen uptake measured volumetrically). Decomposition of
the oxidation product with 6 N HC1 yields salicylic acid
morpholide; hydrolysis with 6 N KOH followed by cleavage
with 6 N HCl gives salicylic acid in yields of up to 4 0 %
[referred t o ( l a ) ] . The product complex bis(salicylmorpho1idato)bis(morpholine)cobalt(II)
was identified, as was the
secondary product arising from its degradation, by elemental
analysis, determination of melting point or decomposition
point, and by 1H-NMR and I R spectra.
The remarkable ease of oxidation of the aldehyde function
in complex ( l a ) by atmospheric oxygen can be explained by
5 ‘-Amino- ( l a ) [3J and 5‘-N-methylamino-5’-deoxyadenosine
( I b ) [41 are converted into the diester amides (2a) and (Zb),
(a), R = H
( b ) , R = CH3
Angew. Chem. internat. Edit. 1 Vol. 9 (1970) 1 No. 8
respectively, in about 50 yield by reaction with di(p-nitrophenyl) phosphorochloridate 151.
Whereas (56) is obtained directly (55 % yield) on treatment
of (26) with 1 N NaOH/methanol (1:1) in 100 h at room
temperature, (5a) can only be synthesized stepwise. As first
step, one p-nitrophenol group is removed by ammonia/pyridine'water ( 5 : 2: 1); (3) is isolated in 80 % yield by preparative layer chromatography and cyclized according to Borden [61 by treatment with 1 M potassium tert-butoxideltertbutanol in dimethyl sulfoxide (15 min, 10°C) to give the
cyclophosphate analog (5a) which is isolated in 65 % yield
after separation o n a DEAE cellulose column. Ring closure
of (2b) to (5b) proceeds via the unusual cyclic diester amide:
after 1 h it was possible to isolate compound ( 4 ) .
All the compounds gave correct analyses and spectroscopic
data. Compounds (5a) and (5b) are currently being tested in
conjunction with other research teams for biological activity.
Received: May 20, 1970;
supplemented: June 10, 1970
IZ 232 IEI
German version: Angew. Chem. 82,666 (1970)
sulfur (transition state D) 131. A differentiation is possible by
studying the influence of ortho substituents o n the isomerization of the S-aryl substituted compounds ( 2 ) and (3).
The rotation is hinderedr4.51 by large groups R, which must
rotate past X. In contrast the steric hindrance in the transition state of the inversion (D) is less than in the ground
state - hence, the rate of inversion ought to increase with
increasing size of R [3J.
The free enthalpies of activation determined in the case of
isothiouronium perchlorates ( 2 ) and (3) are given in the
following table.
[*I Dr.
A . Murayama, Dr. B. Jastorff, and Dr. H. Hettler
Max-Planck-Institut fur experimentelk Medizin,
Abt. Chemie
34 Gottingen, Hermann-Rein-Strasse 3 (Germany)
[I] J . T . Bonner, Sci. American 221, No. 6, p. 78 (1969).
[2] E. W. Sutherland and T . W . Rnll, Pharmacol. Rev. 12, 265
[3] R. R. Schmidt, H. Schleur, and D . Schwille, Chem. Ber. 101,
590 (1968).
[4] A. Murayama, unpublished.
[5] K . Schimmelschmidt and H. Kappenberger, DAS 1059915
[6] K. F. Borden and M . Smith, J. org. Chemistry 31, 3241
syn-anti-Isomerism at the Carbon-Sulfur Double
Bond in Isothiouronium Salts 111 I**]
By Horst Kessler and Hans-Otto Kalinowski [*I
While the syn-anti isomerism at the C = N double bond in
imines is w d l known, the possibility of syn-anti isomerism
(A, B) at the isoelectronic C=S double bond in thioketoniurn
ions ( I ) has not yet been reported on. In an NMR spectroscopic examination of the isothiouronium salt (1) (X=X' =
N(CH&; Z = aryl, alkyl) at low temperature, we have been
able to detect and "freeze" the equilibrium A + BC21. The
isomerization could be effected by rotation about the partial
CS double bond (transition state C) or by inversion at the
Table. N M R parameters for the syn-anfi isomerization of S-arylisothiouronium perchlorates (2) and (3). Tc = coalescence temperature.
The coalescence of the methyl signal is used for the evaluation 141.
( "C)
TCB [el
9.1 [a]
9.3 [a]
64 10.0 [a]
73 10.2 [a]
- 29 12.0 [hl
89 17.9 [b,dl
c--115 :7.6 Ic]
8.0 [dl
- 80
9.3 [dl
I06 18.5 [dl
[a] The error is f 1 kcal/mole because the simultaneous "freezing-in*'
of the C N rotation interferes with the evaluation; the first results are
w. r. t. the coalescence of the outer singlets, the second to the two inner
Ib] Splitting to a doublet; the C N rotations are only "frozen-in" at
lower temperature. [cl Calculated for an assumed splitting of 40 Hz.
[dl Error If: 0.2 kcallmole.
[el 1,2 4-Trichlorohenzene.
The distinct increase of the AG* values o n going from the
phenyl compounds (2a) and (3a) to the sterically much
hindered tri-tert-butylphenyl compounds (2d) and (3d)
proves that the syn-anti isomerization at the partial CS
double bond is via rotation (transition state C) and not by
inversion, as in the corresponding processin theguanidines [31.
A minimum value of the activation barrier for the inversion
at doubly bonded sulfur is obtained at the same time: it must
be greater than 18.5 kcal/mole [= the value for (3d)I. In
compounds with less strongly electron repelling groups X o n
the thiocarbonyl system, inversion at the sulfur atom oughtaccording to findings in the imine system[3J - to be very
much less probable. The high barrier to inversion should
make a separation of such syn-anti isomers at room temperature possible. This is at present under investigation.
The compounds (2a)-(2c) and (3a)-(3c) can be prepared
from chloroformamidinium chloride and thiophenols (61.
(2d) and (3d) were not prepared via thiophenol but via the
lead or thallium salt.
1,1,3,3-Tetramethyl-2- (2,4,6-tri-tert-butylphenyI)
isothiouronium perchlorate (2d)
Thallium 2,4,6-tri-tert-butylthiophenolate
(4.5 g) was added
with stirring to asolution of tetramethylchloroformamidinium
chloride171 (1.5 g) in anhydrous acetonitrile (50 ml). After
three hours' stirring the reaction mixture was filtered and the
filtrate treated with a solution of NaC104 (1.15 g) in aceto-
Angew. Chem. internat. Edit.
/ Vol. 9 (1970) J NO. 8
64 I
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synthesis, adenosine, amid, analogi, cyclophosphazen
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