close

Вход

Забыли?

вход по аккаунту

?

One-Step Syntheses of Fused Pyrimidinethiones.

код для вставкиСкачать
COMMUNICATIONS
R-CH=P(C,%),
Reaction of Alkylidenephosphoranes with
Halogenoacetic Esters
+
X-CO,C,H,
By Prof. Dr. H. J. Bestmann, Dr. K. Rostock, and
cand. chem. H. Dornauer
Institut fur Organische Chemie der Universitat
Erlangen-Niirnberg (Germany)
The halogen atom is decisive for the mode of reaction of
alkylidenephosphoranes ( I ) with halogenoacetic esters.
B.p. of ( 8 )
or (9)
['C/mm Hgl
R
1. On treating compounds ( I ) (salt-free solutions in boiling
tetrahydrofuran or benzene [I]) with iodo- or bronio-acetic
esters (2), one obtains a$-unsaturated carboxylic esters ( 3 ) ,
triphenylphosphine (4), and a phosphonium salt (5).
78/0.4
88/0.4
50/13
84/13
111/13
+
36/13
(Br)I-CH,-COOR2
(IJ
I
R'
(2)
Halogen
in ( 2 )
Acid in ( 3 )
Br
Br
Br
I
I
Br
Cinnamic
4-Chlorocinnamic
2-Hexenoic
5-Phen yl-2-pentenoic
3-Cyclohexylacrylic
8- Methylcinnamic
B.p. of (3)
I W m m Hgl
Yield of
13)
1x1
1 15j0.3
I ;:
32/0.2
150/0.4
75/0.3
127/10
50
71
60
59
95/0.3
Other cz-halogenocarboxylic esters can be used in place of
bromo- or iodo-acetic esters. Thus ( I ) , R = CsH5, RI = H,
and ethyl a-bromopropionate afford the a-methylcinnamic
ester in 59 % yield.
2. Trimethyl trans-cyclopropanetricarboxylate(6) and the
corresponding phosphonium chloride are obtained in 5 5 "/,
yield from alkylidenephosphoranes ( I ) and methyl chloroacetate in n-pentane at room temperature.
The reaction does not involve a carbene intermediate. Presence of cyclohexene does not lead to formation of a norcaranecarboxylic ester. If the reaction mixture is treated with
dimethyl fumarate fully deuterated at the double bond, deuterium is found in the product ( 6 ) .
3. Ethyl fluoroacetate and alkylidenephosphoranes (salt-free
in boiling benzene[ll) undergo a Wittig reaction at the carbonyl group [21. Enol ethers (8) of fluoroketones are obtained.
Enol ethers (9) of trifluoroketones result analogously from
ethyl trifluoroacetate and alkylidenephosphoranes.
308
1x1
65
45
50
82
71
59
76
[Z 146/974 IE]
Received: September 27th, 1965
German version: Angew. Chem. 78, 335 (1966)
Publication delayed at the authors' request
(4)
(3)
R
+
Yield
of ( 8 ) or
(91
[l] H. J. Bestmann, Angew. Chem. 77,609 (1965); Angew. Chem.
internat. Edit. 4, 583 (1965).
[2] At the IUPAC Symposium on Organophosphorus Compounds in Heidelberg in 1964, H . Muchleidt and W. Grellreported
ester-alkenylation of diethyl oxalate with ethoxycarbonylidenetriphenylphosphoranes and ester-alkenylation with derivatives
of ethyl diethoxyphosphinylacetate. H . Muchleidt and W. Grell,
Liebigs Ann. Chem. 609, 79 (1965).
One-Step Syntheses of Fused Pyrimidinethiones"l
By Prof. Dr. E. C. Taylor, Dr. S. Vromen,
Dr. R. V. Ravindranathan, and Dr. A. McKillop
Department of Chemistry, Princeton University,
Princeton, New Jersey (U.S.A.)
Previously available methods for the preparation of fused
pyrimidinethiones involve either laborious and inefficient
multistage syntheses, or drastic conditions. We have now
found that fused pyrimidinethiones may be prepared from oaminonitriles, ethyl orthoformate, and NaHS in a one-step
reaction which proceeds in high yield and under mild conditions. 3.0 g of a n o-aminonitrile is refluxed either with a mixture of 30 ml of ethyl orthoformate and 30 ml of acetic anhydride, or with 30 ml of ethyl orthoformate alone[21, for
1-3 hours. Evaporation of the reaction mixture under reduced pressure gives the intermediate, crude ethoxymethyleneamino derivative which, without further purification, is
treated with 100 ml of a 1.5 N solution of sodium hydrosulfide in anhydrous ethanol. The reaction mixture is refluxed
for 10-12 hours, evaporated to dryness and the residual solid
taken up in hot water, treated with charcoal, filtered and
acidified with glacial acetic acid. The fused pyrimidinethione
precipitates in an extremely high state of purity and in yields
often in excess of 90 % (see Table).
The effectiveness of this method may be illustrated by the
synthesis of 4(5H)-pyrazolo[3,4-d]pyrimidinethione. This
compound has previously been prepared 131 from 3-amino-4cyanopyrazole by a 4-step sequence involving initial hydrolysis of the nitrile with concentrated sulfuric acid to the amide,
cyclization with formamide to 4 (SH)-pyrazolo[3,4-d]pyrimidinone, then to the 4-chloro derivative with phosphorus oxychloride, and finally conversion to the thione with thiourea.
Direct conversion of the pyrimidinone to the thione with
phosphorus pentasulfide proved even less satisfactory [31. By
Arigew. Cheni. interticit. Edit.
I
Vol. 5 (1966) 1 No. 3
0-Aminonitrite
Pyrimidinethione
4-Amino- I benzyl-3c;,anopiperidine
3-Amino-4cyanopyrazoli
5-Amino-4cyano- I methylpyrazole
5 - Amino4-cyanoI-phenylpyrazole
4-Amino5-cyanopyriniidine
2-Aniinobenzonitrile
I -Amino2-cyanocyclopent-I-ene
I-Amino2-cyanocyclohex-l -en,
2-Benzyl- I ,2,3,4-tetrahydro-S(7H)-pyridinol4,3-rl]pyrimidinethione
4(5 H)-Pyrazolo[3,4-d]pyriniidinethione
I-Methyl-4(5H)pyrazolo [3,4-d]pyrimidinethione
Time
Ihrs.1
Yield
1n.p.
l%1
[
-c1
By Prof. Dr. E. C. Taylor, Dr. R. N. Warrener, and
Dr. A. McKillop
220-225
(decomp.)
3
97
2
91
I -Phen yl-4(5 H ) pyrazolo[3,4-d]pyri midinethione
2
94
4(3H)-Pyrimido[4,5-dlpyrimidinethione
4(3 H)-Quinazolinethione
7(6H)-Cyclopenteno[dlpyrimidinethione
8(7 H)-C yclohexeno[dlpyrimidinet hione
2
69
73
70
0.75
68
354&356
(decomp.)
309-311
(decomp.)
280--282
(decomp.)
-. 360
326-330
(decomp.)
275-277
(decomp.)
268-274
(decomp.)
contrast, 4 (5H)-pyrazolo[3,4-d]pyrimidinethionemay be prepared from 3-amino-4-cyanopyrazole by our procedure in a
single step in 97 % yield; the product is analytically pure as
isolated directly from the reaction mixture.
A second one-step synthesis of fused pyrimidinethiones, although less advantageous and involving more strenuous conditions, consists of the reaction of o-aminonitriles with phenyl
isothiocyanate in acidic medium. Heating 1.2 g of 2-aminobenzonitrile and 1.4 g of phenylisothiocyanate in 15 ml of dimethylformamide (saturated at 0 "C with dry HCl) at 85 "C
for 15 hrs. results in gradual dissolution followed by separation of a yellow solid. Evaporation under reduced pressure,
trituration of the residue with water, filtration and recrystallization from methanol gives 1.3 g (79 %) of 4(3H)-quinazolinethione, m.p. 326-330 "C (decomp.). Similarly, 5amino-4-cyano-1-niethylpyrazole
is converted into l-methyl4(5H)-pyrazolo[3,4-d]pyrimidinethione in 67 % yield, and
5-amino-4-cyano-1-phenylpyrazoleto l-phenyl-4(5H)-pyrazolo[3,4-d]pyrimidinethionein 48 % yield.
With the use of 14C-labelled dimethylformamide it was shown
that the C-2 atom of 4(3H)-quinazolinethione originated from
the dimethylformamide and not from the phenyl isothiocyanate. The reaction sequence probably involves nucleophilic attack of phenyl isothiocyanate upon the protonated
o-aminonitrile to give thioanthranilamide, which then undergoes formylation by the dimethylformamide/hydrogen chloride mixture and subsequent cyclization. Strong support for
this interpretation was found in the reaction of 4-amino-5cyanopyrimidine with phenyl isothiocyanate and dimethylformamide/hydrogen chloride to give a 57 % yield of 4aminopyrimidine-5-thiocarboxamide,which did not undergo subsequent formylation and cyclization, apparently because of decreased nucleophilicity of the 4-amino group.
Received: November 23rd, 1965
[ Z 138/972 IE]
German version: Angew. Chem. 78, 332 (1966)
[l] This work was supported by grants from the Smith Kline and
French Laboratories and the National Cancer Institute, National
Institutes of Health, Public Health Service (Grant CA-02551).
[2] A mixture of equal volumes of ethyl orthoformate and acetic
anhydride is the reagent of choice for the formation of ethoxymethyleneamino derivatives. However, in some cases (3-amino4-cyanopyrazole, 2-aminobenzonitrile, I-amino-2-cyanocyclopent-1-ene) acetylation of the amino group may take precedence
over formation of the latter derivative and resort must be made
to the use of ethyl orthoformate alone.
[3] C. C. Cheng and R . K . Robins, J. org. Chemistry 21, 1240
(1956).
Angew. Chem. internat. Edit.
A One-Step Synthesis of Fused
Pyrimidinedithiones'l*
/ VoI. 5 (1966) / N o . 3
Department of Chemistry, Princeton University,
Princeton, New Jersey (U.S.A.)
The reaction of aromatic and heterocyclic o-aminonitriles
with CS2 in pyridine gives fused pyrimidinedithiones (dimercaptopyrimidines). 3.0 g of 2-aminobenzonitrile, 10 ml of CS2,
and 10 ml of pyridine were heated for 2 hrs. under reflux. On
dilution of the reaction mixture with methanol, 4.82 g (97 :$)
of quinazoline-2,4(1 H,3H)-dithione separated out. The other
compounds listed in the Table were prepared in analogous
fashion.
In order to investigate the course of this conversion, 5.00 g
of 3-amino-4-cyanopyrazole ( I ) , 50 ml of CS2, and 50 ml of
pyridine were heated under reflux for 1 hr., whereupon 10.25 g
of a yellow, crystalline pyridinium salt separated. Treatment
of this salt with cold, dilute HCI gave 4(5H)-imino-6(7H)pyrazolo[4,3-d]-thiazinethione
(2). The structure of this intermediate was established by microanalysis, by the absence of
-CN absorption and the presence of a strong imine N-H
band at 3510 cm-1 in its infrared spectrum, by its ultraviolet
= 237, 262, 311, and 382 m p (E = 11,160,
spectrum
12,270, 11,340, and 2,950)] and by its rearrangement in quantitative yield by 1 N sodium hydroxide to 4,6(5H,7H)-pyrazolo[3,4-d]pyrimidinedithione( 3 ) .
-
qCN
"N
NHZ
H
L
J
(1)
I
V
(31
o-Aminonitrile
2-Aminobenzonitrile
2-Amino5-methoxybenzonitrile
2-Amino5-piperidinobenzonitrile
2-Amino5-bromobenzonitrile
4-Amino5-cyanopyrimidine
5-Amino4-cyanol-methylpyrazole
5-Amino4-cyanoI-phenylpyrizole
3-Amino4-cyanopyrazole
Pyrimidinedithione
Time
[hrs.]
Quinazoline-7,4( I H , 3H)-dithione
6- Methoxyquinazoline2,4(IH, 3H)dithione
6-Piperidinoquinazoline-2,4( 1 H , 3H)dithione
6-Bromoquinazoline2,4-(IH, 3H)dithione
2,4(1 H, 3H)-Pyrimido[4,5-dlpyrimidinedithione
I-Methyl-4,6(5H, 7H)pyrazolo[3,4-d]pyrimidinedithione
2
Yiek
r %I
M.p.
[ "CI
I
99
I
95
335-338
(decomp.)
350-352
(decomp.)
282-285
(decomp.)
68
92
-,360
10
68
I. 360
52
87
321 323
(decomp.)
I-Phenyl-4,6(5H, 7H)pyrazoIo[3,4-d]pyri midinedithione
115
97
248-260
(decomp.)
4,6(5H, 7H)Pyrazolo[3,4-d]pyrimidinedithione
1
81
97
-- 360
Received: Novemter 23rd, 1965 [Z 139/973 I E ]
German version: Angew. Chem. 78, 333 (1966)
[ I ] This work was supported by grants from the Smith Kline and
French Laboratories and the National Cancer Institute, National
Institutes of Health, Public Health Service (Grant CA-02551).
309
Документ
Категория
Без категории
Просмотров
0
Размер файла
214 Кб
Теги
step, one, fused, pyrimidinethiones, synthese
1/--страниц
Пожаловаться на содержимое документа