- Email: [email protected]
Investigations in heterocycles. VIII. Quinazolines and pyrimidines
ARCHIVES
OF
BIOCHEMISTRY
AND
BIOPHYSICS
141-151
83,
(1959)
Investigations in Heterocycles. VIII. Quinazolines and Pyrimidines George deStevens, Angelina Halamandaris, R. A. Mull and E. Schlittler Research
Department,
Ciba
Pharmaceutical Received
Products
January
Patricia Inc.,
Summit,
Wenk, New
Jersey
30, 1959
INTRODUCTION In the past decade considerable effort has been directed toward the preparation and biological evaluation of organic nitrogen compounds as antimetabolites. Of particular interest in this study has been the development of several antitumor agents, Sazaguanine (l), 6-mercaptopurine (2), 6-chloropurine (3), 6-thioguanine (4) and, most recently, 5-fluorouracil (5). The work of Robins and co-workers (6, 7) in the field of pyrazolo[3,4-d] pyrimidine has also been channeled along lines leading to potential carcinstats. Our investigations Q-14) in the field of heterocyclic nuclei fused to cycloalkeno rings has induced a study of a class of compounds (II) which bears resemblance to 5,6-disubstituted pyrimidines (I) and to quinazolines m * 5
(1)
4
IIn=O,
1
III
A survey of the literature showed that type II compounds have been explored only to a limited degree. That is, Todd and his group (15) in 1946 and McCasland and Bryce (16) in 1952 reported the preparation of a few of these compounds. The following reaction sequence was employed. 1 For
Part
VII
of this
series,
see destevens, 141
G., J. Org.
Chem.
23, 1572 (1958).
142
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
These investigators assigned these compounds associated with the lactim (enol) form.
AND
SCHLITTLER
the tautomeric
structure
0 HzN
t COOC2H5 n=O,
R
‘C -RR---~ HNP R= -NH2,
1
CH3
Finally, in a most recent communication (17), 2-carbethoxycyclopentanone has been condensed with thiourea giving rise to cyclopentapyrimidines with mercapto substituents at position 2 in the heterocycle. Two other direct routes to the synthesis of these substances involve as intermediates ethyl - 2 - aminocyclohexene (or cyclopentene) carboxylate (18) and 2-aminocyclopentenecarbonitrile (19). RESULTS
AND
DISCUSSION
In Chart I are outlined some of the transformations we have carried out in this serieswhen using both a /3-keto ester and a B-amino ester as intermediates. The interaction of 2-carbethoxycyclopentanone (VII) with urea in ethyl alcohol containing 1 equiv. sodium ethoxide resulted in good yields of 6,7-dihydro-5-cyclopentapyrimidin-2,4-dione (V). This compound was also prepared by reacting ethyl 2-aminocyclopentene carboxylate (VI) with potassium isocyanate. Treatment of V with dimethyl sulfate in potassium hydroxide solution gave rise to the corresponding 1,3-disubstituted derivatives (IX). Zeisel determination on IX was nil indicating that only the N-methyl derivative was formed. Intermediate VI also condensed with phenyl isocyanate leading to IV which was converted through methylation to the 1-methyl-3-phenyl-6,7-dihydrodcyclopentapyrimidin-2,4-dione (VIII). The transformation of VI to 6,7-dihydro-3-methyl-2-thiocyclopentapyrimidin-4-one (X) was accomplished with methyl isothiocyanate. Methylation of X with dimethyl sulfate yielded the 3-methylthio derivative XII which was also prepared by two other separate routes. That is, fusion of 2-carbethoxycyclopentanone with thiourea yielded 6,7-dihydro-2-thio-5cyclopentapyrimidin-4-one (XI), which under the influence of dimethyl sulfate and potassium hydroxide was transformed to XII. When XI was treated with 1 equiv. methyl iodide in sodium hydroxide solution, 6,7dihydro-2-methylthio-5-cyclopentapyrimidin-4-one (XIII) was obtained. That the N-methyl derivative was not formed was clearly demonstrated by comparing XIII with X whose structure is unequivocal from the mode of
HETEROCYCLES.
143
VIII Chart
I
NH2CONH2 \
H
NaOMe MeI CH I 3
XIII XII NH2NH2
NH~NH~ I
I
synthesis. The fully methylated heterocycle XII was again obtained through methylation of XIII. Finally, compound XII was converted to 2-hydrazino-
6,7-dihydro-3-methyl-5-cyclopentapyrimidin-4-one (XIV) under the influence of hydrazine. However, it was observed that yields of XIV were repeatedly low. For comparative purposes, XIII wasrefluxed with hydrasine. Indeed, methyl mercaptan was evolved, but after workup a crystalline material, m.p. 285-286”, whose elemental analysis corresponded to CeHsN20, was isolated in 70% yield. The substance absorbed strongly at 248 rnp in the ultraviolet. These factors suggested two fused five-membered rings, one of which would be heterocyclic. The infrared data showed moderate -N-H absorption (3250 cm.+), a quaternary salt or zwitterion (very strong 2700-2400 cm.+) and medium amide absorption (1614 cm.-1).
144
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
AND
SCHLITTLER
A formulation which incorporates these data is 5,6-dihydro-4-cyclopentaindazalone (XV). We attributed the strong 2700-2400 cm.-l absorption bands in the infrared to the following zwitterion influence:
XIII
a
1 H
XIII XIII
b
c
Confirmatory evidence for this structure will be presented in a forthcoming publication. An authentic sample of XV was synthesized directly from 2-carbethoxycyclopentanone and hydrazine. The two substances were found to give virtually superimposable infrared and ultraviolet absorption spectra, and the mixed melting point was not depressed. We have also found that the cyclohexeneanalog of XIII undergoes this change. To our knowledge, this type of rearrangement has not been heretofore
HETEROCYCLES.
146
VIII
reported. A plausible mechanism for this reaction is outlined in the following sequence. The hydrazine engages in nucleophilic backside attack on the ethylenic carbon of the conjugated amide system leading to an intermediate such as XIIIa which can undergo ring opening and proton shift to XIIIb. The latter intermediate is then electronically and sterically disposed to undergo cyclization to XV in much the same manner as would be expected of the hydrazone of 2-carbethoxycyclopentanone. Another phase of this investigation led to the use of 2-aminocyclopentene carbonitrile as a versatile intermediate in the synthesis of some pyrimidines and quinazolines. In Chart II are outlined some of these reactions. Chart
II
, N]sCH I J cc ac tiH,
NH2
XVII
XVIII
c
CH3I
HCONH2 I
KOH
NH2’!-NH2
I
I
ArCOCl
CH3I
“-‘;” .HI
CH-
Ar
= 3,4,
ki(CH,O),C6H2XXIIIa
Ar
= 4KH30)C6H4 XXIIIb
146
DESTEVENS,
HALSMANDARIS,
WENK,
MULL
AND
SCHLITTLER
Fusion of XVI with formamide according to the method outlined by Robins (20) resulted in a 30 % yield of 4-amino-6,7-dihydro-5-cyclopentapyrimidine (XVII). Thiourea and urea condensation with XVI gave 4-amino6,7-dihydro-2-thio-5-cyclopentapyrimidine (XX) and 4-amino-6,7-dihydro2-hydroxy-5-cyclopentapyrimidine (XIX), respectively, although the yield of the latter compound was quite low. Treatment of XX with only methyl iodide gave what very likely seems to be the hydroiodide salt of the corresponding 4-monomethylamino derivative (XXII). However, condensation of XX dissolved in alkali with methyl iodide yielded 4-amino-2-methylthio6,7-dihydro-5-cyclopentapyrimidine (XVIII).
The 2-aminocyclopentenecarbonitrile (XVI) was also reacted with acid chlorides, and the resulting amides were cycliaed under alkaline conditions to the 2-aryl-6,7-dihydro-5-cyclopentapyrimidine-4-ones, XXIIIa and XXIIIb. Finally, a number of 5,6,7,8-tetrahydroquinaaolines were prepared along the same lines already described for 6,7-dihydro-5-cyclopentapyrimidines. Pertinent data concerning their preparation and physical properties are described under Experimental.
6,7-Dihydro-5-cyclopentapyrimidines J-Pheny1-6,7-dihydro-6-cyclopentapyr~midin-~,~-dione (IV). Five grams (0.035 mole) of ethyl 2-aminocyclopentenecarboxylate was dissolved in 35 ml. xylene containing 1 g. pyridine. Six grams (0.051 mole) of phenyl isocyanate was added, and the solution was refluxed for 2 hr. After chilling the solution overnight, the chunky crystals were collected and found to be N,N’-diphenylurea. The mother liquor was concentrated in 2racuo until a thick residual oil remained. This oil was added to 35 ml. potassium hydroxide solution and heated to boiling. A clear solution resulted which was cooled to room temperature and acidified with dilute hydrochloric acid. The fine white powder was collected and recrystallized from ethyl alcohol to give a 35% yield of pure product, m.p. 319-321”. Anal. Calcd. for Ci3H12NZ02 : C, 68.41; H, 5.30. Found: C, 68.40; H, 5.34. 6,7-Dihydro-1 -methyl-3-phenyl-6-cyclopentapyrimidin-2, .&dione (VIII). Five grams (0.02 mole) of IV was dissolved in 50 ml. methyl alcohol containing 0.48 g. (0.02 g. atom) of sodium, and the solution was refluxed for 30 min. The solution was then chilled to 45”, and 5.0 g. methyl iodide was added slowly with stirring. After refluxing the mixture for 4 hr., it was filtered and the filtrate was evaporated to dryness 2 All
melting
points
are uncorrected.
HETEROCYCLES.
147
VIII
leaving a residue consisting of a mixture of oil and crystals. This mixture was triturated with ethyl alcohol and filtered. From the filtrate there was obtained 1.8 g. of product which was recrystallized from ethyl alcohol-water (3: I), m.p. 162-163’. Anal. Calcd. for CldHr,N~02 : N, 11.58. Found: N, 11.51. 6,7-Dihydro-6-cyclopentapyrimidin-2,4-dione (V).3 To a solution of ethyl alcohol (25 ml.) containing 1.48 g. (0.065 g. atom) of sodium there was added 10 g. (0.065 mole) of carbethoxycyclopentanone and 3.92 g. (0.065 mole) of urea. The mixture was heated under pressure for 8 hr. at 100”. The resulting crystals (2.5 g.) were collected and recrystallized three times from ethyl alcohol to yield pure product, m.p. 305-307”. Anal. Calcd. for C ‘IH 8N 20 2 : C, 55.24; H, 5.30; N, 18.41. Found: C, 55.02; H, 5.22; N, 18.62. 6,7-Dihydro-1 ,b-dimethyl-~Lcyclopentapyrimidin-B,&dione (IX). Three grams of V was dissolved in 20 ml. of 10% potassium hydroxide solution and treated dropwise with two molar equivalents of dimethyl sulfate at 20”. The mixture was allowed to stir for 1 hr. after the addition of the dimethyl sulfate and then extracted with chloroform. The chloroform extract was washed with water and dried over anhydrous sodium sulfate. Removal of the chloroform and recrystallization of the residue from ethyl alcohol yielded 1.3 g. product, m.p. 102-103”. Anal. Calcd. for C&H~~NZOZ : N, 15.58. Found: N, 15.52. 6,7-Dihydro-5-methyl-B-thio-6-cyclopentapyrimidin-4-one (X). A mixture of 3.0 g. VI, 25 ml. xylene 0.7 ml. pyridine, and 2.2 g. methyl isothiocyanate was refluxed for 2 hr. At the end of this reflux period, the solution was chilled whereupon a precipitate of the thiourea intermediate was obtained, m.p. 323”. This crude intermediate was added to boiling 25 ml. of 50/, aqueous potassium hydroxide solution, and heating was continued for 30 min. Chilling followed by acidification with dilute hydrochloric acid led to a light tan precipitate which was recrystallized from ethyl alcohol to yield 1.0 g. of pure product, m.p. 309”. Anal. Calcd. for C8Hn,N20S: C, 52.72; H, 5.53; N, 15.37. Found: C, 52.80; H, 5.49; N, 15.26. 6,7-Dihydro-d-thio-5-cyclopentapyrimidin-a-one (XI). This compound has previously been described (19). It was prepared in the same manner in this investigation in order to serve as a relay to other derivatives. 6,7-Dihydro-S-methyl-~-methylthio-6-cyclopentapyrimid~n-4-~e (XII). This compound was prepared by three different routes as described below. (a) To 10 ml. of 2 N potassium hydroxide solution there was added with stirring 1.50 g. compound X. When complete solution was obtained, 1.05 g. dimethyl sulfate was added dropwise under cooling. When the reaction was complete, the reaction mixture was chilled for several hours. The white precipitate was then collected on a filter and recrystallized from a hexane-ether mixture, yielding pure product, m.p. 82-84”. Anal. Calcd. for CQH~ZNZOS: C, 55.07; H, 6.16; N, 14.27. Found: C, 55.22; H, 6.02; N, 14.23. (5) Ten grams (0.087 mole) of XI was dissolved in 75 ml. of aqueous 2 N potassium hydroxide solution. To this clear solution there was added dropwise with efficient stirring 22.5 g. (0.18 mole) of dimethyl sulfate. The temperature of the reaction mixture was maintained between 5 and 10” during this addition. After stirring for an additional 2 hr., the clear solution was chilled overnight. The crystalline product was 3 This compound was previously b-ethylthio-6,7-dihydro-6-cyclopentapyrimidin-Q-one. mann, D., Bull. sot. chim. France
prepared 1947,
1073.
indirectly through See Polonouski,
the M.,
hydrolysis of and Liber-
148
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
AND
SCHLITTLER
collected at the pump and dried in uucuo. Two recrystallizations from hexane-ethyl ether mixture gave analytically pure material, m.p. 82-W’. Anal. Calcd. for CgH12N20S: C, 55.07; H, 6.16. Found: C, 55.43; H, 6.18. (c) One-hundredth mole (1.82 g.) of 6,7-dihydro-2-methylthio-5-cyclopentapyrimidin-4-one (XIII) (see below for preparation) was dissolved in 25 ml. methyl alcohol containing 0.23 g. (0.01 g. atom) of sodium. A 10% excess of methyl iodide (1.5 g.) was added, and the solution was refluxed gently for 4 hr., after which time the solution was evaporated down to dryness in vaeuo. The crystalline residue was extracted thoroughly with hexane-ethyl ether mixture. This extract was also evaporated to dryness leaving a brown residual powder which was recrystallized twice from hexaneethyl ether mixture. The yield of product melting at 82-84” was 43% of theory. Samples of (a) and (b) when mixed with (c) showed no depression on mixed melting point, and the infrared spectra of all three samples were identical. 6,7-Dihydro-a-methyZthio-6-cycZopentapyrimidin-4-one (XIII). Ten grams (0.088 mole) of 6,7-dihydro-2-thio-5-cyclopentapyrimidin-4-one was dissolved in 200 ml. water containing 9.0 g. sodium hydroxide. The solution was cooled to 5”. Stirring of the solution was then commenced followed by the dropwise addition of 8.5 g. (0.088 mole) of methyl iodide. The addition was complete in 10 min., and the clear solution was stirred for an additional 15 min. Acidification with glacial acetic acid resulted in the formation of a copious white precipitate (9.0 g.) which was purified for analysis by dissolving the material in dilute sodium hydroxide solution and then precipitating the product by the addition of glacial acetic acid. This process was repeated three times to give colorless needles, m.p. 268-270”. Anal. Calcd. for C8H10N20S: C, 52.75; H, 5.54; N, 15.38. Found: C, 52.83; H, 5.52; N, 15.18. 6,6-Dihydro-.J-cyclopentaindazalone (XV). Six grams of XIII was heated at 100” for 24 hr. with 20 ml. hydrazine hydrate. The solution gave no crystals on chilling. Consequently, it was made acidic with glacial acetic acid, and the resulting precipitate was collected, washed with water, and then recrystallized twice from ethyl alcohol to give the product, m.p. 285-286”. Anal. Calcd. for CeH7N20: C, 58.04; H, 6.49; N, 22.56. Found: C, 58.40; H, 6.39; N, 22.70. This substance was also prepared by condensing carbethoxycyclopentanone with hydraeine hydrate under reflux conditions. Recrystallization from ethyl alcohol also gave the product, m.p. 287-288’. Mixed melting point with the substance prepared from XIII gave no depression, and their ultraviolet and infrared absorption spectra were superimposable. Anal. Calcd. for CcH7NzO: C, 58.04; H, 6.49; N, 22.56. Found: C, 58.21; H, 6.80; N, 22.67. d-Amino-B, 7-dihydro-b-cyclopentapyrimidine (XVIII). An intimate mixture of 10.8 g. (0.1 mole) of 2-aminocyclopentenecarbonitrile (XVI) and of 15 ml. formamide was heated under vigorous reflux for 3 hr. The dark-brown solution was cooled to room temperature and diluted with excess acetone. Several triturations of the resulting brown powder with acetone gave 5.5 g. of tan powder, m.p. 21&214”, which was recrystallized from 75 ml. ethyl alcohol containing Norit. Two more similar recrystallizations gave 3.89 g. white needles, m.p. 23%239”. Anal. Calcd. for CrHoN, : C, 62.20; H, 6.71; N, 31.08. Found: C, 61.97; H, 6.61; N, 31.38. 4-Amino-Z-hydroxy-6,7-dihydro-6-cycZopentapyrimidine (XIX). 2-Aminocyclopentane carbonitrile (10.8 g.) was intimately mixed with 18 g. urea, and the mixture was
HETEROCYCLES.
149
VIII
heated at 209-205” for 26 min. After 15 min. a mushy solid WRS obtained. The cooled solid was then dissolved in 2 N sodium hydroxide, and the solution was boiled gentIy for 10 min. with Norit. The boiling filtrate was acidified carefully with glacial acetic acid, and the solution was filtered hot to yield 8.2 g. of a yellow powder. This treatment was repested to give an analytically pure sample, m.p. 288-290”. Anal. Calcd. for C,HgN30: C, 55.27; H, 5.96; N, 27.62. Found: C, 55.20; H, 5.72; N, 27.31. Q-Amino-6,7-dihydro-~-thio-6-cyclopentapyrimidine (XX). Twenty grams of thiourea was mixed well with 10.8 g. of XVI and heated for 30 min. at 190-200”. Upon cooling to room temperature, the resulting solid material was washed well with ethyl alcohol and collected on a filter. This material was purified by precipitation with acetic acid from a boiling dilute basic solution; yield 8.8 g., m.p. 300-303” with dec. Anal. Calcd. for C7H8N3S: C, 50.28; H, 5.43. Found: C, 49.91; H, 5.61. 4-AminoG, 7-dihydro-Smethylthio-6-cyclopentapyrimidine (XVIII). Four grams (0.024 mole) of 4-amino-6,7-dihydro-2-thio-5-cyclopentapyrimidine (XX) was dissolved in 50 ml. water containing 4 g. potassium hydroxide. To this solution there was added 8.0 g. methyl iodide and 50 ml. methyl alcohol. A reaction commenced immediately. After refluxing the mixture for 6 hr., Norit was added and reflux was maintained for another hour. Chilling overnight gave white needles which were collected and washed well with water. The melting point of the dried material was 159-160”. Anal. Calcd. for CsHnNaS: C, 53.00; H, 6.12; N, 23.20. Found: C, 53.23; H, 6.31; N, 23.25. 6,7-Dihydro
-4-methylamino-l -thio-6-cyclopentapyrimidine Hydroiodide (XXII). Four grams (0.024 mole) of compound XX was added to 50 ml. methyl alcohol and heated to reflux. The substance was insoluble in methyl alcohol. Upon the addition of 10 g. methyl iodide, complete solution was obtained immediately. The solution was refluxed for 8 hr. and chilled, and the cubic crystals were collected and recrystallized from ethyl alcohol to give 4.9 g. product, m.p. 283-285”. Anal. Calcd. for C8H121NaS: C, 31.18; H, 3.91; N, 13.61. Found: C, 31.50; H, 4.08; N, 13.47. ,f?-(3,4,&Trimethoxybenzamido)cycZopentane CarbonitriZe (XXIa). To a solution of 4.2 g. (0.034 mole) of XVI dissolved in 20 ml. pyridine there was added slowly with stirring 9.2 g. (0.034 mole) of 3,4,5-trimethoxybeneoyl chloride. After addition was completed, the solution was heated at 100” for 3 hr. The chilled mixture was poured with stirring into a cold solution of 100 ml. water containing 2 g. sodium hydroxide. Eight grams of precipitate was collected and recrystallized from ethyl alcohol. Total yield of pure product, m.p. 160-161°, was 7.05 g. Anal. C&d. for C16HlsN204 : C, 63.56; H, 6.00; N, 9.27. Found: C, 63.25; H, 5.96; N, 9.28. 6,7-Dihydro-S-
(.9,4,6-trimethoxyphenyl)
-b-cycZopentapyrimidin-a-one
(xxIIa).
Compound XXIa (4.4 g.) dissolved in 10 ml. dioxane, was treated slowly with 17 g. sodium hydroxide dissolved in 100 ml. water. Fifty milliliters of 30% hydrogen peroxide was added, and the reaction mixture was refluxed for 1 hr. An additional 20 ml. of 30% hydrogen peroxide was added, and refluxing was continued for 30 min. longer. The solution was cooled to room temperature and diluted with 409 ml. water. The pH of the solution was adjusted to neutral, whereupon B precipitate was obtained which was collected on a filter, washed with water, and dried in ~(ccuo. This crude product was recrystallized from ethyl alcohol to yield 1.2 g. of white crystals, m.p. 288”. Anal. Calcd. for ClbHi8N~04 : C, 63.56; H, 6.00. Found: C, 63.00; H, 5.88.
150
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
AND
SCHLITTLER
2-(p-Methoxybenzamido)-cyclopentane Carbonitrile (XXIb). This 109-llO”, was prepared in the same manner as described above for Anal. Calcd. for C~HilN202 : C, 69.49; H, 5.82; N, 11.57. Found: N, 11.59. 2-(p-Anisyl)-6,7-dihydro-6-cycZopentapyrimidin-4-one (XXIIb). was prepared by the method described above; m.p. 245-247”. Anal. Calcd. for ClaHlaNzOz : N, 11.57. Found: N, 11.63.
compound, m.p. XXIa. C, 69.47; H, 5.76; This
compound
5,6,7,8-Tetrahydroquinazolines J-(o-Chlorophenyl)-6,6,7,8-tetrahydroquinazolin-2,4-dione. Five grams of ethyl 2-aminocyclohexenecarboxylate was added to 50 ml. xylene containing 1 ml. pyridine. To this solution there was added 6.0 g. o-chlorophenylisocyanate, and the resulting solution was refluxed for 2 hr. The solution was then evaporated to dryness in 2racuo. The resulting semicrystalline residue was added to a boiling 5% potassium hydroxide solution, and boiling was continued for 1 hr. Some material did not dissolve in the alkaline solution, and this was removed by filtration. The chilled filtrate was acid. ified with cont. hydrochloric acid, and the resulting precipitate was collected on a Btichner funnel, washed with water, dried in air, and recrystallized from ethyl alcohol to give 4.6 g. of pure product, m.p. 254-255”. Anal. Calcd. for CIIH~~NZO~C~: C, 60.54; H, 4.73; N, 10.12. Found: C, 60.45; H, 4.72; N, 10.24. S-Pheny1-2-thio-6,6,7,8-tetrahydroquinazolin-Q-one. This compound was prepared by the same procedure outlined in the previous example. The yield of pure product, m.p. 310-313”, was 72y0. Anal. Calcd. for CirHlaNzOS: C, 65.08; H, 5.46; N, 10.85. Found: C, 64.87; H, 5.38; N, 11.13. d-MethyZthio-S-phenyZ-5,6,7,8-tetrahydroquinazoZin-4-one. Dimethylsulfate (6.35 g.) was added dropwise to 25 ml. of a 2 N sodium hydroxide solution containing 13.0 g. (0.05 mole) of 3-phenyl-2-thio-5,6,7,8-tetrahydroquinazolin-4-one, maintaining the reaction temperature between 25 and 30”. Chilling the solution overnight gave a white powder, m.p. 200-205”, which was recrystallized from ethyl alcohol. The melting point of the pure product was 204-205”. Anal. Calcd. for C~~H~GNZOS: C, 66.14; H, 5.92; N, 10.29. Found: C, 66.13; H, 5.81; N, 10.41. 2-Hydrazino-9-phenyl-6,6,7,8-tetrahydroquinazolin-Q-one. Three grams of 2-methylthio-3-phenyl-5,6,7,8-tetrahydroquinazolin-4-one, was added to 25 ml. ethyl alcohol containing 5 ml. of 99% hydrazine hydrate, and the solution was refluxed for 4 hr. Chilling the reaction mixture yielded 1.8 g. product, m.p. 209-210”, which was recrystallized from ethyl alcohol. Anal. Calcd. for CUH~ZNZO: C, 65.60; H, 6.29. Found: C, 65.62; H, 5.93. When this reaction was run in the absence of ethyl alcohol or in a sealed tube, the major portion of the material obtained was 4,5,6,7-tetrahydroindazolone, m.p. 298299”. The same substance could be isolated on treatment of 2-thio-5,6,7,8-tetrahydroquinazolin-4-one or its methyl thio derivative (25) with hydrazine hydrate. An authentic sample of 4,5,6,7-tetrahydroindazalone was synthesized by condensing carbethoxycyclohexanone with hydrazine. This substance and those isolated from the rearrangement reactions gave no depression on mixed melting point and their ultraviolet and infrared spectra were identical in all respects.
HETEROCYCLES.
VIII
151
ACKNOWLEDGMENTS
We wish to take this opportunity
to thank Professor Ernest Wenkert for stimulating discussions concerning some theoretical aspects of this paper and Mr. Louis Dorfman and his associates for the microanalytical data. SUMMARY
Various cycloalkenopyrimidines and quinazolines have been prepared from P-amino esters, /3-keto esters and &cyanoamines. Each of these intermediates has led to parent heterocyclic compounds which were easily correlated by alkylation reactions. The effect of hydrazine hydrate on 6,7-dihydro-2-methylthio-5H-cyclopentapyrimidine-4-one (XIII) and on 5,6,7,8-tetrahydro-2-methylthio-4-quinazolinone has led to an unusual rearrangement. The nature of the rearranged product has been established by chemical and physical means, and a mechanism has been postulated to account for this transformation. REFERENCES
G. W., DEWEY, V. C., PARKS, R. E., JR., AND WOODSIDE, G. T., Science 109, 511 (1949). 2. HITCHINGS, G. H., AND RHOADS, C. P., Ann. N. Y. Acad. Sci. 60,183 (1954). 3. BENDICH, A., RUSSELL, P. J., JR., AND Fox, J. J., J. Am. Chem. Sot. 76, 6073 (1954). 4. ELION, G. B., AND HITCHINGS, G. H., J. Am. Chem. Sot. 77, 1676 (1955). 5. HEIDELBEROER, C., AND DUSCHINSKY, R., U. S. Pat. 2,802,005, Aug. 6, 1957. 6. ROBINS, R. K., J. Am. Chem. Sot. 78, 784 (1956). 7. ROBINS, R. K., FURCHT, F. W., GRAUER, A. D., AND JONES, J. W., J. Am. Chem. Sot. 78, 2418 (1956). 8. DESTEVENS, G., LUTS, H. A., AND SCHNEIDER, J. A., J. Am. Chem. Sot. 79, 1516 (1957). 9. DESTEVENS, G., FRUTCHEY, A., HALAMANDARIS, A., AND LUTS, H. A., J. Am. Chem. Sot. 79, 5263 (1957). 10. DESTEVENS, G., AND HALAMANDARIS, A., J. Am. Chem. Sot. 79,571O (1957). 11. DESTEVENS, G., LUTS, H. A., AND HALAMANDARIS, A., J. Org. Chem. 23,114 (1958). 12. DESTEVENS, G., HOPKINSON, A., CONNOLLY, M. A., OKE, P., AND SCHROEDER, D. C., J. Am. Chem. Sot. 80, 220 (1958). 13. DESTEVENS, G., HALAMANDARIS, A., AND HOPKINSON, A. F., J. Am. Chem. Sot. 80, 5196 (1958). 14. DESTEVENS, G., HALAMANDARIS, A., AND DORFMAN, L., J. Am. Chem. Sot. 80, 5198 (1958). 15. HULL, R., TOVELL, B. J., OPENSHAW, H. T., PAYMAN, J., AND TODD, A. R., J. Ch.em. Sot. 1946, 357. 16. MCCASLAND, G., AND BRYCE, J. R. G., J. Am. Chem. Sot. 74, 842 (1952). 17. BIGLINO, C., Farmaco (P&a) Ed. sci. 12, 72 (1957). 18. PRELOG, V., AND SZPILFOGEL, S., Helv. Chim. Acta 28, 1684 (1945). 19. SCHROEDER, H. E., AND RIGBY, C. W., J. Am. Chem. Sot. 71, 2206 (1949). 20. ROBINS, R. K., J. Am. Chem. Sot. 78, 784 (1956). 1. KIDI)ER,
OF
BIOCHEMISTRY
AND
BIOPHYSICS
141-151
83,
(1959)
Investigations in Heterocycles. VIII. Quinazolines and Pyrimidines George deStevens, Angelina Halamandaris, R. A. Mull and E. Schlittler Research
Department,
Ciba
Pharmaceutical Received
Products
January
Patricia Inc.,
Summit,
Wenk, New
Jersey
30, 1959
INTRODUCTION In the past decade considerable effort has been directed toward the preparation and biological evaluation of organic nitrogen compounds as antimetabolites. Of particular interest in this study has been the development of several antitumor agents, Sazaguanine (l), 6-mercaptopurine (2), 6-chloropurine (3), 6-thioguanine (4) and, most recently, 5-fluorouracil (5). The work of Robins and co-workers (6, 7) in the field of pyrazolo[3,4-d] pyrimidine has also been channeled along lines leading to potential carcinstats. Our investigations Q-14) in the field of heterocyclic nuclei fused to cycloalkeno rings has induced a study of a class of compounds (II) which bears resemblance to 5,6-disubstituted pyrimidines (I) and to quinazolines m * 5
(1)
4
IIn=O,
1
III
A survey of the literature showed that type II compounds have been explored only to a limited degree. That is, Todd and his group (15) in 1946 and McCasland and Bryce (16) in 1952 reported the preparation of a few of these compounds. The following reaction sequence was employed. 1 For
Part
VII
of this
series,
see destevens, 141
G., J. Org.
Chem.
23, 1572 (1958).
142
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
These investigators assigned these compounds associated with the lactim (enol) form.
AND
SCHLITTLER
the tautomeric
structure
0 HzN
t COOC2H5 n=O,
R
‘C -RR---~ HNP R= -NH2,
1
CH3
Finally, in a most recent communication (17), 2-carbethoxycyclopentanone has been condensed with thiourea giving rise to cyclopentapyrimidines with mercapto substituents at position 2 in the heterocycle. Two other direct routes to the synthesis of these substances involve as intermediates ethyl - 2 - aminocyclohexene (or cyclopentene) carboxylate (18) and 2-aminocyclopentenecarbonitrile (19). RESULTS
AND
DISCUSSION
In Chart I are outlined some of the transformations we have carried out in this serieswhen using both a /3-keto ester and a B-amino ester as intermediates. The interaction of 2-carbethoxycyclopentanone (VII) with urea in ethyl alcohol containing 1 equiv. sodium ethoxide resulted in good yields of 6,7-dihydro-5-cyclopentapyrimidin-2,4-dione (V). This compound was also prepared by reacting ethyl 2-aminocyclopentene carboxylate (VI) with potassium isocyanate. Treatment of V with dimethyl sulfate in potassium hydroxide solution gave rise to the corresponding 1,3-disubstituted derivatives (IX). Zeisel determination on IX was nil indicating that only the N-methyl derivative was formed. Intermediate VI also condensed with phenyl isocyanate leading to IV which was converted through methylation to the 1-methyl-3-phenyl-6,7-dihydrodcyclopentapyrimidin-2,4-dione (VIII). The transformation of VI to 6,7-dihydro-3-methyl-2-thiocyclopentapyrimidin-4-one (X) was accomplished with methyl isothiocyanate. Methylation of X with dimethyl sulfate yielded the 3-methylthio derivative XII which was also prepared by two other separate routes. That is, fusion of 2-carbethoxycyclopentanone with thiourea yielded 6,7-dihydro-2-thio-5cyclopentapyrimidin-4-one (XI), which under the influence of dimethyl sulfate and potassium hydroxide was transformed to XII. When XI was treated with 1 equiv. methyl iodide in sodium hydroxide solution, 6,7dihydro-2-methylthio-5-cyclopentapyrimidin-4-one (XIII) was obtained. That the N-methyl derivative was not formed was clearly demonstrated by comparing XIII with X whose structure is unequivocal from the mode of
HETEROCYCLES.
143
VIII Chart
I
NH2CONH2 \
H
NaOMe MeI CH I 3
XIII XII NH2NH2
NH~NH~ I
I
synthesis. The fully methylated heterocycle XII was again obtained through methylation of XIII. Finally, compound XII was converted to 2-hydrazino-
6,7-dihydro-3-methyl-5-cyclopentapyrimidin-4-one (XIV) under the influence of hydrazine. However, it was observed that yields of XIV were repeatedly low. For comparative purposes, XIII wasrefluxed with hydrasine. Indeed, methyl mercaptan was evolved, but after workup a crystalline material, m.p. 285-286”, whose elemental analysis corresponded to CeHsN20, was isolated in 70% yield. The substance absorbed strongly at 248 rnp in the ultraviolet. These factors suggested two fused five-membered rings, one of which would be heterocyclic. The infrared data showed moderate -N-H absorption (3250 cm.+), a quaternary salt or zwitterion (very strong 2700-2400 cm.+) and medium amide absorption (1614 cm.-1).
144
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
AND
SCHLITTLER
A formulation which incorporates these data is 5,6-dihydro-4-cyclopentaindazalone (XV). We attributed the strong 2700-2400 cm.-l absorption bands in the infrared to the following zwitterion influence:
XIII
a
1 H
XIII XIII
b
c
Confirmatory evidence for this structure will be presented in a forthcoming publication. An authentic sample of XV was synthesized directly from 2-carbethoxycyclopentanone and hydrazine. The two substances were found to give virtually superimposable infrared and ultraviolet absorption spectra, and the mixed melting point was not depressed. We have also found that the cyclohexeneanalog of XIII undergoes this change. To our knowledge, this type of rearrangement has not been heretofore
HETEROCYCLES.
146
VIII
reported. A plausible mechanism for this reaction is outlined in the following sequence. The hydrazine engages in nucleophilic backside attack on the ethylenic carbon of the conjugated amide system leading to an intermediate such as XIIIa which can undergo ring opening and proton shift to XIIIb. The latter intermediate is then electronically and sterically disposed to undergo cyclization to XV in much the same manner as would be expected of the hydrazone of 2-carbethoxycyclopentanone. Another phase of this investigation led to the use of 2-aminocyclopentene carbonitrile as a versatile intermediate in the synthesis of some pyrimidines and quinazolines. In Chart II are outlined some of these reactions. Chart
II
, N]sCH I J cc ac tiH,
NH2
XVII
XVIII
c
CH3I
HCONH2 I
KOH
NH2’!-NH2
I
I
ArCOCl
CH3I
“-‘;” .HI
CH-
Ar
= 3,4,
ki(CH,O),C6H2XXIIIa
Ar
= 4KH30)C6H4 XXIIIb
146
DESTEVENS,
HALSMANDARIS,
WENK,
MULL
AND
SCHLITTLER
Fusion of XVI with formamide according to the method outlined by Robins (20) resulted in a 30 % yield of 4-amino-6,7-dihydro-5-cyclopentapyrimidine (XVII). Thiourea and urea condensation with XVI gave 4-amino6,7-dihydro-2-thio-5-cyclopentapyrimidine (XX) and 4-amino-6,7-dihydro2-hydroxy-5-cyclopentapyrimidine (XIX), respectively, although the yield of the latter compound was quite low. Treatment of XX with only methyl iodide gave what very likely seems to be the hydroiodide salt of the corresponding 4-monomethylamino derivative (XXII). However, condensation of XX dissolved in alkali with methyl iodide yielded 4-amino-2-methylthio6,7-dihydro-5-cyclopentapyrimidine (XVIII).
The 2-aminocyclopentenecarbonitrile (XVI) was also reacted with acid chlorides, and the resulting amides were cycliaed under alkaline conditions to the 2-aryl-6,7-dihydro-5-cyclopentapyrimidine-4-ones, XXIIIa and XXIIIb. Finally, a number of 5,6,7,8-tetrahydroquinaaolines were prepared along the same lines already described for 6,7-dihydro-5-cyclopentapyrimidines. Pertinent data concerning their preparation and physical properties are described under Experimental.
6,7-Dihydro-5-cyclopentapyrimidines J-Pheny1-6,7-dihydro-6-cyclopentapyr~midin-~,~-dione (IV). Five grams (0.035 mole) of ethyl 2-aminocyclopentenecarboxylate was dissolved in 35 ml. xylene containing 1 g. pyridine. Six grams (0.051 mole) of phenyl isocyanate was added, and the solution was refluxed for 2 hr. After chilling the solution overnight, the chunky crystals were collected and found to be N,N’-diphenylurea. The mother liquor was concentrated in 2racuo until a thick residual oil remained. This oil was added to 35 ml. potassium hydroxide solution and heated to boiling. A clear solution resulted which was cooled to room temperature and acidified with dilute hydrochloric acid. The fine white powder was collected and recrystallized from ethyl alcohol to give a 35% yield of pure product, m.p. 319-321”. Anal. Calcd. for Ci3H12NZ02 : C, 68.41; H, 5.30. Found: C, 68.40; H, 5.34. 6,7-Dihydro-1 -methyl-3-phenyl-6-cyclopentapyrimidin-2, .&dione (VIII). Five grams (0.02 mole) of IV was dissolved in 50 ml. methyl alcohol containing 0.48 g. (0.02 g. atom) of sodium, and the solution was refluxed for 30 min. The solution was then chilled to 45”, and 5.0 g. methyl iodide was added slowly with stirring. After refluxing the mixture for 4 hr., it was filtered and the filtrate was evaporated to dryness 2 All
melting
points
are uncorrected.
HETEROCYCLES.
147
VIII
leaving a residue consisting of a mixture of oil and crystals. This mixture was triturated with ethyl alcohol and filtered. From the filtrate there was obtained 1.8 g. of product which was recrystallized from ethyl alcohol-water (3: I), m.p. 162-163’. Anal. Calcd. for CldHr,N~02 : N, 11.58. Found: N, 11.51. 6,7-Dihydro-6-cyclopentapyrimidin-2,4-dione (V).3 To a solution of ethyl alcohol (25 ml.) containing 1.48 g. (0.065 g. atom) of sodium there was added 10 g. (0.065 mole) of carbethoxycyclopentanone and 3.92 g. (0.065 mole) of urea. The mixture was heated under pressure for 8 hr. at 100”. The resulting crystals (2.5 g.) were collected and recrystallized three times from ethyl alcohol to yield pure product, m.p. 305-307”. Anal. Calcd. for C ‘IH 8N 20 2 : C, 55.24; H, 5.30; N, 18.41. Found: C, 55.02; H, 5.22; N, 18.62. 6,7-Dihydro-1 ,b-dimethyl-~Lcyclopentapyrimidin-B,&dione (IX). Three grams of V was dissolved in 20 ml. of 10% potassium hydroxide solution and treated dropwise with two molar equivalents of dimethyl sulfate at 20”. The mixture was allowed to stir for 1 hr. after the addition of the dimethyl sulfate and then extracted with chloroform. The chloroform extract was washed with water and dried over anhydrous sodium sulfate. Removal of the chloroform and recrystallization of the residue from ethyl alcohol yielded 1.3 g. product, m.p. 102-103”. Anal. Calcd. for C&H~~NZOZ : N, 15.58. Found: N, 15.52. 6,7-Dihydro-5-methyl-B-thio-6-cyclopentapyrimidin-4-one (X). A mixture of 3.0 g. VI, 25 ml. xylene 0.7 ml. pyridine, and 2.2 g. methyl isothiocyanate was refluxed for 2 hr. At the end of this reflux period, the solution was chilled whereupon a precipitate of the thiourea intermediate was obtained, m.p. 323”. This crude intermediate was added to boiling 25 ml. of 50/, aqueous potassium hydroxide solution, and heating was continued for 30 min. Chilling followed by acidification with dilute hydrochloric acid led to a light tan precipitate which was recrystallized from ethyl alcohol to yield 1.0 g. of pure product, m.p. 309”. Anal. Calcd. for C8Hn,N20S: C, 52.72; H, 5.53; N, 15.37. Found: C, 52.80; H, 5.49; N, 15.26. 6,7-Dihydro-d-thio-5-cyclopentapyrimidin-a-one (XI). This compound has previously been described (19). It was prepared in the same manner in this investigation in order to serve as a relay to other derivatives. 6,7-Dihydro-S-methyl-~-methylthio-6-cyclopentapyrimid~n-4-~e (XII). This compound was prepared by three different routes as described below. (a) To 10 ml. of 2 N potassium hydroxide solution there was added with stirring 1.50 g. compound X. When complete solution was obtained, 1.05 g. dimethyl sulfate was added dropwise under cooling. When the reaction was complete, the reaction mixture was chilled for several hours. The white precipitate was then collected on a filter and recrystallized from a hexane-ether mixture, yielding pure product, m.p. 82-84”. Anal. Calcd. for CQH~ZNZOS: C, 55.07; H, 6.16; N, 14.27. Found: C, 55.22; H, 6.02; N, 14.23. (5) Ten grams (0.087 mole) of XI was dissolved in 75 ml. of aqueous 2 N potassium hydroxide solution. To this clear solution there was added dropwise with efficient stirring 22.5 g. (0.18 mole) of dimethyl sulfate. The temperature of the reaction mixture was maintained between 5 and 10” during this addition. After stirring for an additional 2 hr., the clear solution was chilled overnight. The crystalline product was 3 This compound was previously b-ethylthio-6,7-dihydro-6-cyclopentapyrimidin-Q-one. mann, D., Bull. sot. chim. France
prepared 1947,
1073.
indirectly through See Polonouski,
the M.,
hydrolysis of and Liber-
148
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
AND
SCHLITTLER
collected at the pump and dried in uucuo. Two recrystallizations from hexane-ethyl ether mixture gave analytically pure material, m.p. 82-W’. Anal. Calcd. for CgH12N20S: C, 55.07; H, 6.16. Found: C, 55.43; H, 6.18. (c) One-hundredth mole (1.82 g.) of 6,7-dihydro-2-methylthio-5-cyclopentapyrimidin-4-one (XIII) (see below for preparation) was dissolved in 25 ml. methyl alcohol containing 0.23 g. (0.01 g. atom) of sodium. A 10% excess of methyl iodide (1.5 g.) was added, and the solution was refluxed gently for 4 hr., after which time the solution was evaporated down to dryness in vaeuo. The crystalline residue was extracted thoroughly with hexane-ethyl ether mixture. This extract was also evaporated to dryness leaving a brown residual powder which was recrystallized twice from hexaneethyl ether mixture. The yield of product melting at 82-84” was 43% of theory. Samples of (a) and (b) when mixed with (c) showed no depression on mixed melting point, and the infrared spectra of all three samples were identical. 6,7-Dihydro-a-methyZthio-6-cycZopentapyrimidin-4-one (XIII). Ten grams (0.088 mole) of 6,7-dihydro-2-thio-5-cyclopentapyrimidin-4-one was dissolved in 200 ml. water containing 9.0 g. sodium hydroxide. The solution was cooled to 5”. Stirring of the solution was then commenced followed by the dropwise addition of 8.5 g. (0.088 mole) of methyl iodide. The addition was complete in 10 min., and the clear solution was stirred for an additional 15 min. Acidification with glacial acetic acid resulted in the formation of a copious white precipitate (9.0 g.) which was purified for analysis by dissolving the material in dilute sodium hydroxide solution and then precipitating the product by the addition of glacial acetic acid. This process was repeated three times to give colorless needles, m.p. 268-270”. Anal. Calcd. for C8H10N20S: C, 52.75; H, 5.54; N, 15.38. Found: C, 52.83; H, 5.52; N, 15.18. 6,6-Dihydro-.J-cyclopentaindazalone (XV). Six grams of XIII was heated at 100” for 24 hr. with 20 ml. hydrazine hydrate. The solution gave no crystals on chilling. Consequently, it was made acidic with glacial acetic acid, and the resulting precipitate was collected, washed with water, and then recrystallized twice from ethyl alcohol to give the product, m.p. 285-286”. Anal. Calcd. for CeH7N20: C, 58.04; H, 6.49; N, 22.56. Found: C, 58.40; H, 6.39; N, 22.70. This substance was also prepared by condensing carbethoxycyclopentanone with hydraeine hydrate under reflux conditions. Recrystallization from ethyl alcohol also gave the product, m.p. 287-288’. Mixed melting point with the substance prepared from XIII gave no depression, and their ultraviolet and infrared absorption spectra were superimposable. Anal. Calcd. for CcH7NzO: C, 58.04; H, 6.49; N, 22.56. Found: C, 58.21; H, 6.80; N, 22.67. d-Amino-B, 7-dihydro-b-cyclopentapyrimidine (XVIII). An intimate mixture of 10.8 g. (0.1 mole) of 2-aminocyclopentenecarbonitrile (XVI) and of 15 ml. formamide was heated under vigorous reflux for 3 hr. The dark-brown solution was cooled to room temperature and diluted with excess acetone. Several triturations of the resulting brown powder with acetone gave 5.5 g. of tan powder, m.p. 21&214”, which was recrystallized from 75 ml. ethyl alcohol containing Norit. Two more similar recrystallizations gave 3.89 g. white needles, m.p. 23%239”. Anal. Calcd. for CrHoN, : C, 62.20; H, 6.71; N, 31.08. Found: C, 61.97; H, 6.61; N, 31.38. 4-Amino-Z-hydroxy-6,7-dihydro-6-cycZopentapyrimidine (XIX). 2-Aminocyclopentane carbonitrile (10.8 g.) was intimately mixed with 18 g. urea, and the mixture was
HETEROCYCLES.
149
VIII
heated at 209-205” for 26 min. After 15 min. a mushy solid WRS obtained. The cooled solid was then dissolved in 2 N sodium hydroxide, and the solution was boiled gentIy for 10 min. with Norit. The boiling filtrate was acidified carefully with glacial acetic acid, and the solution was filtered hot to yield 8.2 g. of a yellow powder. This treatment was repested to give an analytically pure sample, m.p. 288-290”. Anal. Calcd. for C,HgN30: C, 55.27; H, 5.96; N, 27.62. Found: C, 55.20; H, 5.72; N, 27.31. Q-Amino-6,7-dihydro-~-thio-6-cyclopentapyrimidine (XX). Twenty grams of thiourea was mixed well with 10.8 g. of XVI and heated for 30 min. at 190-200”. Upon cooling to room temperature, the resulting solid material was washed well with ethyl alcohol and collected on a filter. This material was purified by precipitation with acetic acid from a boiling dilute basic solution; yield 8.8 g., m.p. 300-303” with dec. Anal. Calcd. for C7H8N3S: C, 50.28; H, 5.43. Found: C, 49.91; H, 5.61. 4-AminoG, 7-dihydro-Smethylthio-6-cyclopentapyrimidine (XVIII). Four grams (0.024 mole) of 4-amino-6,7-dihydro-2-thio-5-cyclopentapyrimidine (XX) was dissolved in 50 ml. water containing 4 g. potassium hydroxide. To this solution there was added 8.0 g. methyl iodide and 50 ml. methyl alcohol. A reaction commenced immediately. After refluxing the mixture for 6 hr., Norit was added and reflux was maintained for another hour. Chilling overnight gave white needles which were collected and washed well with water. The melting point of the dried material was 159-160”. Anal. Calcd. for CsHnNaS: C, 53.00; H, 6.12; N, 23.20. Found: C, 53.23; H, 6.31; N, 23.25. 6,7-Dihydro
-4-methylamino-l -thio-6-cyclopentapyrimidine Hydroiodide (XXII). Four grams (0.024 mole) of compound XX was added to 50 ml. methyl alcohol and heated to reflux. The substance was insoluble in methyl alcohol. Upon the addition of 10 g. methyl iodide, complete solution was obtained immediately. The solution was refluxed for 8 hr. and chilled, and the cubic crystals were collected and recrystallized from ethyl alcohol to give 4.9 g. product, m.p. 283-285”. Anal. Calcd. for C8H121NaS: C, 31.18; H, 3.91; N, 13.61. Found: C, 31.50; H, 4.08; N, 13.47. ,f?-(3,4,&Trimethoxybenzamido)cycZopentane CarbonitriZe (XXIa). To a solution of 4.2 g. (0.034 mole) of XVI dissolved in 20 ml. pyridine there was added slowly with stirring 9.2 g. (0.034 mole) of 3,4,5-trimethoxybeneoyl chloride. After addition was completed, the solution was heated at 100” for 3 hr. The chilled mixture was poured with stirring into a cold solution of 100 ml. water containing 2 g. sodium hydroxide. Eight grams of precipitate was collected and recrystallized from ethyl alcohol. Total yield of pure product, m.p. 160-161°, was 7.05 g. Anal. C&d. for C16HlsN204 : C, 63.56; H, 6.00; N, 9.27. Found: C, 63.25; H, 5.96; N, 9.28. 6,7-Dihydro-S-
(.9,4,6-trimethoxyphenyl)
-b-cycZopentapyrimidin-a-one
(xxIIa).
Compound XXIa (4.4 g.) dissolved in 10 ml. dioxane, was treated slowly with 17 g. sodium hydroxide dissolved in 100 ml. water. Fifty milliliters of 30% hydrogen peroxide was added, and the reaction mixture was refluxed for 1 hr. An additional 20 ml. of 30% hydrogen peroxide was added, and refluxing was continued for 30 min. longer. The solution was cooled to room temperature and diluted with 409 ml. water. The pH of the solution was adjusted to neutral, whereupon B precipitate was obtained which was collected on a filter, washed with water, and dried in ~(ccuo. This crude product was recrystallized from ethyl alcohol to yield 1.2 g. of white crystals, m.p. 288”. Anal. Calcd. for ClbHi8N~04 : C, 63.56; H, 6.00. Found: C, 63.00; H, 5.88.
150
DESTEVENS,
HALAMANDARIS,
WENK,
MULL
AND
SCHLITTLER
2-(p-Methoxybenzamido)-cyclopentane Carbonitrile (XXIb). This 109-llO”, was prepared in the same manner as described above for Anal. Calcd. for C~HilN202 : C, 69.49; H, 5.82; N, 11.57. Found: N, 11.59. 2-(p-Anisyl)-6,7-dihydro-6-cycZopentapyrimidin-4-one (XXIIb). was prepared by the method described above; m.p. 245-247”. Anal. Calcd. for ClaHlaNzOz : N, 11.57. Found: N, 11.63.
compound, m.p. XXIa. C, 69.47; H, 5.76; This
compound
5,6,7,8-Tetrahydroquinazolines J-(o-Chlorophenyl)-6,6,7,8-tetrahydroquinazolin-2,4-dione. Five grams of ethyl 2-aminocyclohexenecarboxylate was added to 50 ml. xylene containing 1 ml. pyridine. To this solution there was added 6.0 g. o-chlorophenylisocyanate, and the resulting solution was refluxed for 2 hr. The solution was then evaporated to dryness in 2racuo. The resulting semicrystalline residue was added to a boiling 5% potassium hydroxide solution, and boiling was continued for 1 hr. Some material did not dissolve in the alkaline solution, and this was removed by filtration. The chilled filtrate was acid. ified with cont. hydrochloric acid, and the resulting precipitate was collected on a Btichner funnel, washed with water, dried in air, and recrystallized from ethyl alcohol to give 4.6 g. of pure product, m.p. 254-255”. Anal. Calcd. for CIIH~~NZO~C~: C, 60.54; H, 4.73; N, 10.12. Found: C, 60.45; H, 4.72; N, 10.24. S-Pheny1-2-thio-6,6,7,8-tetrahydroquinazolin-Q-one. This compound was prepared by the same procedure outlined in the previous example. The yield of pure product, m.p. 310-313”, was 72y0. Anal. Calcd. for CirHlaNzOS: C, 65.08; H, 5.46; N, 10.85. Found: C, 64.87; H, 5.38; N, 11.13. d-MethyZthio-S-phenyZ-5,6,7,8-tetrahydroquinazoZin-4-one. Dimethylsulfate (6.35 g.) was added dropwise to 25 ml. of a 2 N sodium hydroxide solution containing 13.0 g. (0.05 mole) of 3-phenyl-2-thio-5,6,7,8-tetrahydroquinazolin-4-one, maintaining the reaction temperature between 25 and 30”. Chilling the solution overnight gave a white powder, m.p. 200-205”, which was recrystallized from ethyl alcohol. The melting point of the pure product was 204-205”. Anal. Calcd. for C~~H~GNZOS: C, 66.14; H, 5.92; N, 10.29. Found: C, 66.13; H, 5.81; N, 10.41. 2-Hydrazino-9-phenyl-6,6,7,8-tetrahydroquinazolin-Q-one. Three grams of 2-methylthio-3-phenyl-5,6,7,8-tetrahydroquinazolin-4-one, was added to 25 ml. ethyl alcohol containing 5 ml. of 99% hydrazine hydrate, and the solution was refluxed for 4 hr. Chilling the reaction mixture yielded 1.8 g. product, m.p. 209-210”, which was recrystallized from ethyl alcohol. Anal. Calcd. for CUH~ZNZO: C, 65.60; H, 6.29. Found: C, 65.62; H, 5.93. When this reaction was run in the absence of ethyl alcohol or in a sealed tube, the major portion of the material obtained was 4,5,6,7-tetrahydroindazolone, m.p. 298299”. The same substance could be isolated on treatment of 2-thio-5,6,7,8-tetrahydroquinazolin-4-one or its methyl thio derivative (25) with hydrazine hydrate. An authentic sample of 4,5,6,7-tetrahydroindazalone was synthesized by condensing carbethoxycyclohexanone with hydrazine. This substance and those isolated from the rearrangement reactions gave no depression on mixed melting point and their ultraviolet and infrared spectra were identical in all respects.
HETEROCYCLES.
VIII
151
ACKNOWLEDGMENTS
We wish to take this opportunity
to thank Professor Ernest Wenkert for stimulating discussions concerning some theoretical aspects of this paper and Mr. Louis Dorfman and his associates for the microanalytical data. SUMMARY
Various cycloalkenopyrimidines and quinazolines have been prepared from P-amino esters, /3-keto esters and &cyanoamines. Each of these intermediates has led to parent heterocyclic compounds which were easily correlated by alkylation reactions. The effect of hydrazine hydrate on 6,7-dihydro-2-methylthio-5H-cyclopentapyrimidine-4-one (XIII) and on 5,6,7,8-tetrahydro-2-methylthio-4-quinazolinone has led to an unusual rearrangement. The nature of the rearranged product has been established by chemical and physical means, and a mechanism has been postulated to account for this transformation. REFERENCES
G. W., DEWEY, V. C., PARKS, R. E., JR., AND WOODSIDE, G. T., Science 109, 511 (1949). 2. HITCHINGS, G. H., AND RHOADS, C. P., Ann. N. Y. Acad. Sci. 60,183 (1954). 3. BENDICH, A., RUSSELL, P. J., JR., AND Fox, J. J., J. Am. Chem. Sot. 76, 6073 (1954). 4. ELION, G. B., AND HITCHINGS, G. H., J. Am. Chem. Sot. 77, 1676 (1955). 5. HEIDELBEROER, C., AND DUSCHINSKY, R., U. S. Pat. 2,802,005, Aug. 6, 1957. 6. ROBINS, R. K., J. Am. Chem. Sot. 78, 784 (1956). 7. ROBINS, R. K., FURCHT, F. W., GRAUER, A. D., AND JONES, J. W., J. Am. Chem. Sot. 78, 2418 (1956). 8. DESTEVENS, G., LUTS, H. A., AND SCHNEIDER, J. A., J. Am. Chem. Sot. 79, 1516 (1957). 9. DESTEVENS, G., FRUTCHEY, A., HALAMANDARIS, A., AND LUTS, H. A., J. Am. Chem. Sot. 79, 5263 (1957). 10. DESTEVENS, G., AND HALAMANDARIS, A., J. Am. Chem. Sot. 79,571O (1957). 11. DESTEVENS, G., LUTS, H. A., AND HALAMANDARIS, A., J. Org. Chem. 23,114 (1958). 12. DESTEVENS, G., HOPKINSON, A., CONNOLLY, M. A., OKE, P., AND SCHROEDER, D. C., J. Am. Chem. Sot. 80, 220 (1958). 13. DESTEVENS, G., HALAMANDARIS, A., AND HOPKINSON, A. F., J. Am. Chem. Sot. 80, 5196 (1958). 14. DESTEVENS, G., HALAMANDARIS, A., AND DORFMAN, L., J. Am. Chem. Sot. 80, 5198 (1958). 15. HULL, R., TOVELL, B. J., OPENSHAW, H. T., PAYMAN, J., AND TODD, A. R., J. Ch.em. Sot. 1946, 357. 16. MCCASLAND, G., AND BRYCE, J. R. G., J. Am. Chem. Sot. 74, 842 (1952). 17. BIGLINO, C., Farmaco (P&a) Ed. sci. 12, 72 (1957). 18. PRELOG, V., AND SZPILFOGEL, S., Helv. Chim. Acta 28, 1684 (1945). 19. SCHROEDER, H. E., AND RIGBY, C. W., J. Am. Chem. Sot. 71, 2206 (1949). 20. ROBINS, R. K., J. Am. Chem. Sot. 78, 784 (1956). 1. KIDI)ER,