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Simple New Synthesis of N6-Substituted Adenosines and 2-Aminoadenosines.

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viscosity the ESR spectrum of ( I ) shows a poorly resolved
hyperfine structure (six lines), which we ascribe to a
diradical whose exchange energy J is Large compared with the N coupling constant uN["' ( J $ u N ;
4 2 = 5.5 & 1G); in addition there is the interaction energy
of the electrons with the ortho-proton (aHO=
3.5+_ 1 G); cf.
1,2-dihydro-2,2-dimethyl-4H-benz[~]-[l,3]-0xazine~~~~
:
uN= 10.8, ~,o,n=3.1,~,m=0.95 G.
In ethanol glass, ( I ) shows the characteristic spectrum of a
non-cylindrically symmetrical triplet. The half-field resonance shows the (Am=2) transition. In the ( A m = l )
spectrum (Fig. 1) there are three pairs of bands from whose
centers in the point-dipole approximation amounts to
about 5.8 A ; Dreiding models give the following N-N
and 0-0 separations: doubIe h2lf-chair form, 4.9-5.1 A ;
double half-boat form, 5.0-5.8 A.
That the midpoints of the pairs of bands do not coincide
arises from the anisotropic g factor; in agreement with
results for m o n ~ n i t r o x i d e s '~
~ find for the diagonal
I ' ~we
elements: g,,>gyy>grz (Fig. 1).
Hyperfine structure due to aniosotropic coupling with the
N nuclei can be recognized only for the z components:
five equidistant bands with intensity relations 1:2:3 :2:1.
This corresponds to the spectrum of a diradical with
J >> D[161and AJ2 = 12 G. That the hyperfine structure
of the other pairs of bands is not resolved agrees with
the fact that the xx and yy diagonal elements of a coupling
tensor (assumed to be cylindrically symmetrical) are
expected to have appreciably lower values than those
observed for the zz element"'* 16].
Studies of biological systems by means of ( I ) as spin
label are in progress.
9YY
Y II H , c
z ll H,
c
gxx
X I1 H,
f
Received: November 8,1971 [Z 584 IE]
German version : Angew. Chem. 84, 353 (1972)
20
.2
qzz
0+3E
D
-
3E
Fig. 1. ESR spectrum of (1) in ethanol glass at -130OC (in definition
of the axes the molecular skeleton is assumed to be planar to a first
approximation).
separations the zero-field parameters of the dipolar electron-electron interaction can be obtained" - 'l: D= 140 G
and E = 18 G. From the value of D it can be concluded
that for the triplet ( I ) the distance between the radical
[I]A . Rassat, Int. Symp. Conformational Analysis, Brussels 1969 ;
Pure Appl. Chem. 25,623 (1971).
[2] A . Calder, A. R . Forrester, P . G . James, and G . R . Luckhurst,
J. Amer. Chem. SOC.91, 3724 (1969).
[3] a) J . F. W Keana and R . J . Dinerstein, J. Amer. Chem. SOC.93,
2808 (1971); b) J . Michon and A . Rassat: French Pat. 7115999 (May 4,
1971).
[4] A. R. Forrester and R. Ramasseul, J. Chem. SOC.B 1971, 1645.
[5] R . M . Dupeyre, G. Gagnaire, J . .Michon, P . Michon, C . Morat,
A . Rassat, and J . Ronraud? unpublished.
[6] J . P . C . Smith in J . R. Bolton, D. Borg, and H . Schwarz: Biological
Applications of Electron Spin Resonance Spectroscopy. InterscienceWiley, New York 1971 and literature cited therein.
[7] C. Kothe, K H . Denkel, and W Summermann, Angew. Chem. 82,
935 (1970); Angew. Chem. internat. Edit. 9,906 (1970).
[a] A. R . Forrester, R. H . Thomson, and G . R . luckhursr, J Chem. Soc.
Simple New Synthesis of N6-Substituted
Adenosines and Z-Aminoaden~sines[**~
By Helmut Vorbriigged''
Since their isolation from tRNA['] the N6-substituted
adenosines have become increasingly important as
cytokinins"] and experimental drugsr3].
Up to now, inosine and guanosine were converted in
several steps into the free or protected 6-chloro, 6-bromo or
6-alkylthiopurine n u ~ l e o s i d e dwhich
~ ~ , gave with amines
the N6-substituted adenosines and 2-aminoadenosines
respectively. To simplify this reaction sequence in analogy
to our new cytidine synthesis[51,we converted the nucleosides into their persilylated derivatives ( I ) in order
to protect the alcoholic hydroxy groups and activate the
6-position of the purine moiety. But even on heating with
amines for days up to 180°C the persilylated derivatives
( I ) gave only traces of the N6-substituted adenosines or
2-amino-adenosines (2).
B 1968. 1311.
[91 A . Cufdrr and A . R . Forresrer. J. Chem. SOC. c' 1969. 1459.
[lo] M . T. Bogerr and A. H . Krop/J J.Amer. Chem. SOC.31.841 (190Y).
1111 F. W froily and A . C. Cope, J Amer. Chem. Soc 66. 1875 (1944).
R. M . Dupe!re, H . Lemuire, C. Morat. 1. Russrrt. and
P. Rey, Bull SOC.Chim. Fr. 1965,3290.
[I31 E . G . Rozantsec: Free Nitroxyl Radicals. Plenum Press, New
York--London 1970. p. 139.
[14] 0.H . Grflith, D. W Cornell, and H. .M.bJcConnell, J Chem.
Phys. 43, 2909 (1965)
[15] H . Lrmaire. These, Grenoble 1967; Rapport C.E.A. n' R 3119.
[ 161 J . Ronzaud, unpublished work ; see also K Ifoh. H. Huyashi. and
S . Nagakura, ~Mol.Phys. 17, 561 (1969).
.
304
(Cl13)3Si6
110
OSi(CH3),
R = H. NH-Sl(CH,),
R
= H,
OH
NK,
[*] Dr. H. Vorbruggen
Forschungslaboratorien der Schenng A. G.
1 Berlin 65, Miillerstrasse 170-172 (Germany)
[**J Synthesis of Nucleosides, Part 6.-Part 5: [5].
Anyew. Chem. internat. Edit. 1 Voi. I 1 (1972) 1 N o . 4
As a typical addition-elimination reaction to the iminotrimethylsilyl ether partial structureI6] of the purine
moiety the reaction of ( 1 ) with amines should be accelerated
by attack of a proton or a Lewis acid on the basic N'nitrogen. We therefore treated ( 1 ) with amines in the
presence of 0.1-0.2 equivalents of amine salts or Lewis
acids and obtained in this "one-step reaction" the N 6 substituted adenosines and 2-aminoadenosines (2), often
in very good yields. Most effective were stannic chloride,
mercuric chloride and mercuric acetate, although the
mercuric salts led to considerable oxidation of the amines,
which were used in a threefold molar excess and served
as solvents.
This reaction can be applied to the corresponding
persilylated purines ( 3 )['I, which on treatment with
amines in the presence of HgCl, afford the corresponding
N6-substituted purines ( 4 ) in good yields.
R = H, NH-Si(CH,),
R =
6.67 g (90%) of N6-(P-phenethy1)adenosine was obtained
in two crops, m.p. 166--167°C.
Received: December 27,1971 [ Z 581 a IE]
German version: Angew. Chem. 84,347 (1972)
[I] K . Biemann ef al., Angew. Chem. 78, 600 (1966); Angew. Chem.
internat. Edit. 5, 590 (1966); R. H. Hall, Progr. Nucl. Acid Mol. Biol.
10,57 (1970).
[2] F. Skoog and D. J . Armstrong, Annu. Rev. Plant Physiol. 21, 359
(1970).
[3] K . Dietmann, H . Birkenheier, and W. Schaumann, ArzneimForsch. 20,1749 (1970).
[4] J . 3. Fox, I . Wempen, A. Hampton, and I . L. Doerr, J. Amer. Chem.
SOC.80, 1669 (1958); J . F. Gerster, 3. W Jones, and R . K . Robins,
J. Org. Chem. 28,945 (1963).
[ 5 ] H . Vorbriiggen and U . Niedballa, Angew. Chem. 83, 729 (1971);
Angew. Chem. internat. Edit. 10,657 (1971).
161 C. K . Banks, J. Amer. Chem. SOC.66, 1127 (1944); G. Illuminati,
Advan. Heterocycl. Chem. 3, 285 (1964); R. Roger and D. G. Nelson,
Chem. Rev. 61,193 (1961).
171 I: Nishimura and 1. Iwai, Chem. Pharm. Bull. 12, 352 (1964).
[S] E. P. Gracheua et al., Izvest. Akad. Nauk SSSR, Ser. Khim. 1970,
420.
[9] M . Thief, K. Stach, K . Dietmann, W Kampe, and W. Schaumann,
DOS 1670077 (1970), Boehringer Mannheim GmbH.
Simple Amination of Aromatic
Hydroxy-Nitrogen Heterocycles
H. NH,
By Helmut Vorbriiggen['l
A similar activation by Lewis acids, especially by mercuric
chloride, was recently described by E. P. Gracheua et ~ 1 . ' ' ~
in the reaction of 6-methylthiopurines with amines.
Several examples of this reaction are listed in the following
table.
Aromatic hydroxy-nitrogen heterocycles are usually
aminated via their chloro derivatives''], which are obtained
by treatment with phosphorus oxychloride or phosphorus
pentachloride. In some cases, e.g. with 4-hydroxyquinoline['l, an amination with higher boiling amines can be
Table. Synthesis of compounds (2) and ( 4 ) .
a
b
c
d
e
f
g
h
H
H
H
H
H
H
N H 2 [a]
NH, [a]
hornoveratrylamine
8-phenylethylamine
P-phenylethylamine
a-phenylethylarnine
P-phenylethylarnine
pyrrolidine
pyrrolidine
p-anisidine
HgCl,
SnC1,
(NH,),SO,
BF,-ether
Hg(OAc),
HgCIz
SnCI,
HgCIz
145
145
145
145
145
120
120
145
20
22
21
20
22
72
22
96
68
70
50
41
90
54
41
35
122
166-167
166-167
166-161
166-167
142-144
208-210
225-232
a
b
c
H
H
NH, [a]
b-phenylethylarnine
pyrrolidine
pyrrolidine
HgCl,
HBCI,
HgCL
140
120
120
60
24
26
62
83
50
241-244
297-300
263-266
[9]
[9]
[9]
[9]
[a] Is present in ( I ) and ( 3 ) in the silylated form as (CH,), SiNH-group
N6-( P-Phenethyl)aden~sine[~~
(Exampfe ( 2 e ) )
Inosine (5.36 g, 20 mmol) was dissolved by 16 hours'
refluxing at 155°C (bath temperature) in 100 ml hexamethyldisilazane and 0.5 ml trimethylchlorosilane. The
reagents were then removed under reduced pressure
and with exclusion of moisture and the residue stirred with
7.6 ml (60 mmol) P-phenethylamine and 0.638 g (2 mmol)
mercuric acetate for 22 h at 145°C under nitrogen. The
dark solution was evaporated in vacuum and the residue
thus obtained was refluxed for 3 h in 250 ml methanol,
decolorized with charcoal, and filtered. On cooling
Angew. Chem. internat. Edit. / Vol. I 1 (1972) 1 No. 4
achieved directly by acid catalyzed dehydration. However,
the reaction of hydroxy-nitrogen heterocycles with tetrakis(dimethylamin~)titanium[~~
or with amines and equimolar
amounts of titanium tetrachlorideC4lgives only low yields
of the aromatic amino derivatives.
We have found that our method for the aminationL5'of
purines and purine nucleosides can be applied to the
mono- and poly(trimethylsily1) ethersr6] of aromatic
p] Dr. H. Vorbriiggen
Forschungslaboratorien der Schering A. G.
1 Berlin 65, Mullerstrasse 170-172 (Germany).
305
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