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CuF2-Assisted Synthesis of Heterocyclotetraaromatics by Nucleophilic Aromatic Substitution.

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give only small amounts of the 5'-cyanides beside cyclization and degradation products, regardless of whether a crown
ether is present or
The new compounds, whose structures are confirmed by
mass spectra, UV spectra [ ( Z a ) : im,,=259nm; ( 2 b ) : 258nm
in H 2 0 , pH 71, and a characteristic IR absorption band at
2250cm-', can be divested of the ketalic 2',3' protective function by acid treatment. The water-soluble 5'-deoxy-5'cyanonucleosides ( 3 a ) and ( 3 b ) provide an entry to the
nucleosides of 5'-deoxy-~-~-ribohexafuranuronic
acid which
were formerly inaccessible by a simple pathway. Thus hydrolysis of ( 3 a ) in alkaline hydrogen peroxide gave both the
amide ( 4 a ) and the 5'-deoxyadenosine-5'-carboxylicacid
( 5 a ) . Hitherto only analogous carboxylic acid derivatives
stemming from adenosine itself were known which are formed
as C5'-OH epimer mixtures (cf. ref. [,I). ( 5 a ) closes the gap
between adenosine-5'-uronic acid and 5'-deoxyadenosine-5'acetic acid"] and like the latter carboxylic acid is also a
model compound for adenosine-5'-phosphate (AMP); for
instance, ( 5 a ) is deaminated to the inosine derivative by the
enzyme AMP aminohydrolase (EC 3.5.4.6).
Like the natural nucleosides, ( 3 a ) , ( 3 b ) , and ( 5 a ) in
aqueous solution prefer the anti conformation of the base
relative to the C-N glycosidic bond. This is deduced from
the typical downfield shift of the ring proton signals in the
'H-NMR spectrum by the adjacent polar 5'-sub~tituent~'~1.
( 5 a ) exhibits the same long-wave CD spectrum as AMP
-4800 deg cm2 dmol-I). However, the CD spectrum of ( 3 a ) displays an exceptionally low ellipticity and
- 1300,
in the short-wave region a high ellipticity ([0]260=
[0]210=
+7000 deg cm2 dmol-I); this behavior confirms
the relation deduced between structure, conformation, and
circular dichroism for other adenosine derivatives with
strongly polar 5'-substituents['ol.
5'-Deoxy-5'-cyanoadenosine( 3 a )
Compound (1 a ) (0.92g, 2mmol) and [18]crown-6 (0.20g)
are stirred vigorously in anhydrous dioxane (1 5 ml) with dried
KCN (0.65g, 10mmol)at room temperature for 20 h. Removal
of the solid salts and preparative layer chromatography of
the concentrated solution on silica gel with chloroform/methanol(6: 1 ) (Rf=0.74) afford ( Z a ) (0.35g, 55 %) which crystallizes as needles (m. p. 202-204°C) from methanol.-In order
to remove the protecting group, ( 2 a ) (0.32 g) is suspended
in 50% formic acid (5ml) and left to stand for 5 d at room
temperature. Concentration in uacuo and freeze drying of the
residue from water give a quantitative yield (0.27g) of pure
(3a).
[2] P. Howgateand A. Hampron,Carbohyd. Res. 21,309 (1972); A. Hampron,
P. Howgate, P. J. Harper, F. Perini, F. Kappler, and R. K. Preston,
Biochemistry 12, 3328 (1973); A. Hampron and R. R . Chawla, J .
Carbohyd., Nucleosid. Nucleotid. 2, 281 (1975).
[j] J. J. Baker, A. M. Mian, and J . R. 'Firtensor, Tetrahedron 30, 2939
(1974); J. J. Baker, P. Mellish, C . Riddlr, A. R. Someruille, and J.
R. Tirrensor, J. Med. Chem. 17, 764 (1974).
[4] R. Kuhn and W Jahn, Chem. Ber. 98, 1699 (1965); W Jahn, ibid.
98, I705 ( 1 965).
[5] F. W Lichrerirhaler and H. J. Muller, Synthesis 1974. 199.
[6] J. A. Montgomery, A. G. Laseter, and K . Hen'.mn, J. Heterocycl. Chem.
1 1 , 211 (1974).
[7] J . W Zubrick, E . I. Dunbar. and H. D . Durst, Tetrahedron Lett. 1975,
71.
[8] H. Follmann, Tetrahedron Lett. 1973, 397.
[9] This reaction has formerly only been accomplished wiih thymidine:
G . Etzold, G . Kollowik, and P . Langen, Chem. Commun. 1968, 422.
[lo] H. Follmcmn and G. Gremels, Eur. J. Biochem. 47, 187 (1974); H. Follmanii, I . Kuntz, and W Zacharias, ibid. 58, 31 (1975).
CuF,-Assisted Synthesis of Heterocyclotetraaromatics
by Nucleophilic Aromatic Substitution[**]
By Thomas Kauffmann and Rolf Otterp]
Ten heterocyclopo1yaromatics~'lwere recently prepared in
low yield (<26%)[*' as the first representatives of a new class
of substances.
The apparently obvious idea of cyclizing a monolithiated
diheteroaromatic like ( I ) containing a strongly nucleophilic
and a strongly electrophilic center by double nucleophilic
aromatic substitution has not yet been realized. Thus the
lithium compound (1 ), obtained almost quantitatively from
the metal-free compound by the action of lithium diisopropylamide, does not yield ( 3 ) on warming to 34°C in ether131
but instead gives the open-chain oligomers ( 2 ) ( n = 1-5, m. p.
170, 183, 196-198, 227, 242--244"C, yields 10, 12, 13, 9,
5%)r41. This could be a consequence of the chelate bridge
in (1 ) which fixes the two reactive centers in the trans position
unfavorable for cyc1ization.-The desired cyclization to give
(3) (rn.p.372-374°C; yield 9 %) only occurred on treatment
of the solution of ( 1 ) in THF at -20°C with anhydrous
CuF, in the molar ratio 1 :2.
5'-Deoxyadenosine-5'-carboxamide ( 4 a ) and -5'-carboxylic
acid ( 5 a )
Compound ( 3 a ) (0.27g, 1 mmol) is warmed to 30°C for
1 h in 5 % H 2 0 2 (5ml) (PH 10). The solution is then applied
to an anion exchange column (formate form) and eluted
with a water/formic acid gradient (pH 5 to pH 2) to give
the amide ( 4 a ) (0.16 g, 55 %), a little adenine, and the carboxylic acid ( 5 a ) (O.O7g, 26%). Direct hydrolysis of ( 4 a ) in more
strongly alkaline solution led mainly to elimination of adenine.
Received: May 17, 1976 [Z 479 IE]
German version: Angew. Chem. 88, 512 (1976)
CAS Registry numbers:
( I a), 5605-63-0; ( I 6 ) . 7354-93-0; (2aj, 59696-80-9; ( Z b ) , 59696-81-0; ( 3 a ) .
59696.82-1 ; ( 3 b ) , 59696-83-2; ( 4 a ) , 59696-84-3; ( J U ) , 59696-85-4
____
[I]
500
H. Follmann, Angew. Chem. 86, 41 (1974); Angew. Chem. Int. Ed.
Engl. 13,77 11974); 7.E. Walker, H. Foilmann, and H. P. C . Hogenkamp,
Carbohyd. Res. 27, 225 (1973).
Unlike (1 ), the benzo-homologs ( 4 ) also cyclize without
addition of CuF2. Addition of anhydrous CuF, or NiF, in
the molar ratio 1 :2 did however enhance the yield of (6)
(m. p. 41 9-420°C) from 11 to 63 (experiment 3 in Table
1). Thus a heterocyclopolyaromatic has now become available
for the first time in preparatively useful yield.-Comparison
of the experiments 1, 2, and 4 in Table 1 reveals that CuFz
also promotes formation of the open-chain dimer (5), n= 1
(m. p. 231 "C) and the open-chain trimer ( 5 ) , a = 2 (m. p. 348349 "C).
p]
Prof. Dr. Th. Kauffmann and Dip].-Chem. R. Otter
Organisch-Chemisches Institut der Universitat
Orleans-Ring 23,4400 Miinster (Germany)
[**I Heterocyclopolyaromatics, Pat. 4. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
Refs. C2a-2~1 are to be regarded as Parts I to 3.
A n g m , . Chem. lnr. Ed. Engi.
1 Vol. 15 (1976) No. 8
\
I
Preliminary model studies['] showed that CuF2 and NiF2
also favor formation of 2-(2-thienyl)pyridine from 2-lithiothiophene and 2-fluoropyridine: under the reaction conditions
employed [30min -4O"C, 4 h O'C, 30min 20°C in ether/THF
(cu. 1 : i)] the thienylpyridine was formed in 8 % yield without
addition of metal fluoride, and in 24 and 12 % yield respectively
on addition of NiFz and CuFz in the molar ratio 1 : 2.-The
.\
mode of action of the two transition metal fluorides is still
a matter of conjecture.
logenation of a tetramethylphosphonium salt (1) with sodamide in boiling tetrahydrofuran[']. On carrying out this reaction in our laboratory, however, it has been established that
this procedure is not free of side reactions and that, with
suitable adjustment of the reaction conditions, the methylenedi-h5-phosphazene ( 4 ) is obtained in high yields. In addition
to ammonia there is also methane evolved, which could be
identified by gas chromatography.
We suspect that the imide['] (3) is formed as a precursor,
since cleavage of hydrocarbons from phosphonium salts with
alkali metal amide has been observed previously in at least
two cases13].As a strong nucleophile, the anion ofthis precursor
can then attack a second phosphonium center with cleavage
of methane and formation of ( 4 ) . If the reaction is allowed
to proceed at room temperature, instead of reflux temperature,
the secondary reactions are (presumably for solubility reasons)
more rapid than the primary formation of ( 2 ) , so the latter
is continually being used up.
Table I Effect of CuF, on the cyclization of ( 4 1 in T H F [3, 41.
-
~
Run
I
1:o
1
I :2.0
3
I :2.0
4
5
__
( 4 ) : CuF,
1 : 1.0
I :0.5
-~~
Recovery o r yield [ %]
Reaction
temp. time
rC]
[h]
(5)
(5)
(5)
II=O
r1=1
n=2
- 55
I '2
5
I,'2
5
50
._
14
-
112
11
-
17
+ 30
- 30
+ 20
-55
- 20
- 55
I12
38
20
I12
20
61
- 20
4.5
+/I/
- NaBr
- CH4
-.--
I
11
23
18
~
63
13
21
1
I2
20
- 20
- 55
(6)
Received: May 19, 1976 [Z 480 I€]
German version: Angew. Chem. 88, 513 (1976)
CAS Registry numbers:
1 1 ) . 59710-54-2; ( 2 ) . I I =I. 59696-70-7; (2). 11=2, 59696-71-8: ( 2 ) , If=.?,
59696-72-9: 1 2 ) , n=4. 59696-73-0; ( 2 ) ? 1 1 ~ 5 59696-74-1
,
; (J), 59696-75-2:
1 4 ) . 59710-53-1; 1 5 ) . u=O, 59696-76-3: ( 5 ) . I T = I . 59696-77-4; (5). n = 2 ,
59696-78-5: ( 6 ) . 59696-79-6: CuF,, 7789-19-7
(c H , ), P=N -P=CH~
I
141
CH,
( 4 ) is a pale yellow, highly reactive liquid which readily
crystallizes on cooling. It follows from the 'H-, I3C-, and
'P-spectra that this ylide is a fluctional compound; at elevated
temperature the 17H, the 6C and the 2P atoms each are
spectroscopically equivalent ! The different positions of the
atoms in the molecule can be differentiated only on strong
cooling. This phenomenon can be interpreted only as the
result of a rapid proton transferI41,which in ( 4 ) proceeds both
by an intramolecular and by an intermolecular me~hanism[~l.
The proton transfer in (2) is somewhat slower.
-
"I
The term "heterocyclopolyaromatics" includes compounds which, like
4,6,4",6"'-tetraaza-m-hexaphenylene [2c], contain not only heterocyclic
units but also carbocyclic nuclei as ring members, and is therefore
more convenient than "cyclopolyheteroaromatics" as a collective designation.
PI a ) B. Grecing. A. Woltermnffn,and TIf. Kauffmantl, Angew. Chem. 86,
475 ( I 974): Angew. Chem. Int. Ed. Engl. 13,467 (1974): b) 7%. Karrfrmami,
B. Grrrirfy, J . Kiinig, A. Mitschker, and A . Wolrermonri, ibkl. 87, 745
(1975) and 14, 713 (1975) respectively; c) Th. Kaufmann. B. Muke. R .
Orrer, and D. Tigler, ibid. H7. 746 (1975) and 14, 714 (1975), respectively.
of n-hexane introduced with n-butylr31 All solvents listed contained ca. 10 2,
lithium.
r41 Since the elimination step of the substitution reaction is only incomplete,
if it occurs at all, rearomatization required oxidation with KMnO,
in acetone after hydrolysis.
PI Experiments by H. Lexy, Dissertation, Universitat Munster, planned
for 1977. Other experiments by R. Otter. Dissertation, Universitat
Munster, planned for 1976.
Reaction of acids or their ammonium saltsi61with ( 4 ) leads
to the bis(trimethylphosphorany1idene)ammoniumsalts ( 5 ) ,
which were previously only accessible with difficulty via
another router'].
X = C1, B r . I , e t c .
Like other ylides['', ( 4 ) is an excellent complexing agent
A Methylene-di-h'-phosphazene by Amide Cleavage of
Tetramethylphosphonium Salts
By Hubert Schmidbaur and Hans-Joachim Fuller"]
It has been reported that the salt-free trimethyl(methy1ene)phosphorane (2) can be conveniently prepared by dehydroha-~
['I
Prof. Dr. H. Schmidbaur and Dipl.-Chem. H.-J. Fuller
Anorganisch-chemisches Laboratorium der Technischen Universitat
Arcisstrasse 21, 8000 Miinchen 2 (Germany)
for numerous metal centers with which o-bonded organomet a l k compounds can be synthesized. Thus, e. g., reaction with
trimethylgallium, like the corresponding reaction with (2)['],
leads initially to a 1 : 1 adduct ( 6 ) , m.p. 25--27"C[']. In
contrast to (CH3)3P-CH2-Ga(CH3)3r which can be distilled
without decompositi~n[~],
( 6 ) loses methane on heating and
yields the chelate ( 7 j , m. p. 68--69"C['~.
No corresponding precursor is detectable in the reaction
of ( 4 ) with diethylzinc or dimethylcadmium-immediate formation of the chelates (8) and ( 9 ) , respectively, takes place
(m. p. 75-77 and 86-88 "C, resp.1'1).
501
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