4 i 16
SARA GINSBURG A N D IRWINE3
lagen are formed only as the trans diastereoisomers. '!',>(I Nonenzymatic displacements of a hydrogen a t saturated carbon atoms with retention of configuration are relatively rare. One such case is the oxidation of cisdecalin to cis-9-hydroxydecalix1,and of trans-decalin to trans-9-hydroxydecalin b y the action of ozone,51 i\-e may deal here with an internal electrophilic displacement (SE~or "SEi") in which the ozone dipole acts simultaneously as acceptor of the proton and donor of the oxygen function in a concerted front-side displacement. T h e comparable autoxidation, with the diradicaloid oxygen as participant, should proceed by abstraction of a hydrogen radical from trans-decalin only to yield trans-9-decalyl hydroperoxide.5~ The stereoselectivity and retention of configuration is remarkable for a radical reaction. The resonance spectrum of trans-l-hydroxy-L-proline ( 4 K F. Irreveri-e. K
Slorita. .4.
V. Iloberts(,n,
and B Witkop. J
Am.
itkop. and S . Udenfriend, J . Rtol. C'htrn.. 2 3 9 , (.>l)J Iupported b y t h e Diviaion uf Research G i a n t 5 and dl Institutes u f Health. G r a n t B~OOd7:if l t i : r i f t h e 1-nited State.: l ' i , h l t L H r a l t h Service. and l8',ll: (l%3) S . Boyd a n d ICOSHCHk7CH2X Yield, Compd.
Rt
OtSCsHa COOCvHa 02NC6H1 COOCzHs OzKCsHa COOCiHs OnNCsHa COOCzHs OtSCsHa COSHCiHi VI1 COSHCiHi VI11 02NCsH4 COOCHi CsHa XI H XIV C6HsOCHt XVI CsHsOCHz COiTHCiHi x1-11 CeHsOCHz CONHCdHi XX C B H L C H ~ OH CONHCiH7 XXI CsHsCHz0 COXHCIHI XXII CsHaCHtO I Ila IIb IIC
X
Method
%
OH OSOzCeHaCHi OSOICHI
A B B
90 52 80
c1
..
85
A OH B OSOtCsHaCHi B OSOzCsKaCH3 B OSOtCsHCHi A OH B OSOzCsHCHi OSOZC~H&~H~B 4 OH B OSOzC6HKHa
62 45
Y
M p . , --CarbonOC. Calcd. Found
Analyses , To----Hydrogen-Nitrogen--SulfurCalcd. Found Calcd. Fouud Calcd. Found
107 129 121 135 173 113
51.06 52.29 43.33 47.93 52.87 53.44
51.00 52.06 43.35 47.95 52.72 33.04
5.00 4.62 4.48 4.36 5,80 5.16
5.16 4.84 4.35 4.43 5.83 5.30
9.32 14.23 9.35
9.94 6.59 7!89 9.42 14.49 8.89
70 118 118 77 111 91
58.44 59.98 58.05 58.44 59.98
58.11 59.87 58.60 58.17 60 10 5814
5.48 7.19 6.03 5.48 7.19 6.03
5.48 7.19 6.39 5.33 7.08 6.16
4.01 10.00 6.45 4.01 10.00 6.45
3.89 9.75 5.96 3.94 9.99 6.54
9.93 6.42
7.78
Ref.
.. 7.35 8.90
7.40 9.05
b c, d
7.13
6.67
9.18
9.13
.. 60 70 48 71 72 60
58.05
n
.,
e,f 8, h
i c, d, 3
7.38 9.18
7,45 9.25
i,k
..
..
d, j
7.38
7.38
l,m
i
Prepared according t o ref. 5 , Intermediate chlorosulfinate was Prepared by reaction a t room temperature with CHsS02Cl. Recrystallized from H20. very unstable and gave t h e chloro derivative on purification. e I'ield calculated on serine ester HC1. Unstable, rearranges and hydrolyses on standing. 0 Prepared accorde The 0-acyl ester tosic acid salt was formed as a by-product. Unstable; could not be purified. ' Recrystallized from methanol. ] Crude methyl ester treated with 150% excess ing to ref. 16. Reference Reacted a t -25", left a t - 3 " for 15 min. aniine in methanol for 24 h r . , excess amine and methanol distilled off in vacuo. 18. m ;In a t t e m p t to rearrange this tosyl derivative to the oxazoline salt or 0-ester salt by refluxing in aqueous alcohol failed. Treatment with hot 0 . 1 ;V sodium methoxide also failed. I n both cases the starting material was completely recovered. 0
'
TABLE I11 0-ACYLSERINE ESTERS ASD AMIDESSULFONIC ACID SALTS HIN 'CHY CH20COR2X-
Compd.
IIIa IIIb
IX XI11 XV XVIII
Or 02SCsH4 OrSC6H4 CoH5 CnH,OCH? C,H50CH2
COOC2Hb COSHC1H; COOCHB H COT\"C3Hi
X
Method
OSO2C6H4CHa OS02CH3 OSOzCaH4CH3 OS02CBHaCH3 OS02C6H4CH3 OS02C&CH3
C C
C C C C
M p , 'C
--Carbon-Calcd Found
179 162 211
159
50 41 51 54
129 148
55 57 55 74
21 27 38 67
-Analyses, 70--Hydrogen-NitrogenCalcd Found Calcd F o u n d
4 88 5 4 79 4 48 5 39 5 36 5 35 5 53 5 76 5 55 77 6 24 6 50 41 51 54 55
49 21
05 6 17 6 92 7 41 7 41 8 99 8 37 3 54 3 87 3 81 3 31 6 19 6
10 15 61 69 50 30
-SulfurCalcd Found Kef
7 8 6 8 8 7
7 8 86 6 11 8 73 8 05 47
09
14 16
65
Q
05 Q, b 10 7 17 c
Prepared from XI1 by warming in 70% methanol. a Formed also from moist crude tosyl ester on standing a t room temperature. Purified through repeated precipitation with ether from acetone solutions and several recrystallizations from acetone and ethyl a c e t a t e . days. T h e resulting brown sirup was mixed with 50 ml. of methanol and 0 . 1 mole of a methanolic solution ( a b o u t 4 N ) of sodium methylate mas added. Sodium chloride which precipitated was filtered off and the solution distilled in vacuo in order to eliminate the larger part of excess propylamine. T h e residual sirup was dissolved in water and the p H of the solution adjusted to 3 with dilute H C l . This crude solution was used for the next step (Method a). 0-p-Nitrobenzoylserine Ethyl Ester Tosic Acid Salt ( I I I a ) . Method C.-IIa was refluxed for 30 min. in 95'3 ethanol and the solution evaporated to dryness. The yield was practically 1007,. Xfter recrystallization from methanol the salt melted a t 179". 2-p-Nitrophenyl-4-carbethoxyoxazoline(IV) and N-p-Nitrobenzoyldehydroalanine Ethyl Ester (V).-IIa and I I b gave difwhen treated with different bases. ferent proportions of 11- and IT As it is difficult to obtain quantitative separation of the oxazoline base because of its high solubility, it was transformed into its tosic acid salt which in turn hydrolyzed t o the corresponding 0-acyl ester tosic acid salt, I I I a . T h e dehydroalanine was not affected and subsequently recovered. A typical procedure was as follows: the variations in solvent, temperature, and reaction time are indicated in Table I . T o a solution of 0.4 g. 10.004 mole) of potassium acetate in 20 ml. of methanol was added 0.87 g. (0.002 mole) of IIa. ;\fter refluxing the mixture for 30 min. the solvent was evaporated a t low temperature and the residue was washed with water, filtered, and dried a t 75', yielding 0.47 g. (S9$). T h e solid mixture was dissolved in 10 ml. of acetone and 0.34 g . (0.002 mole) of tosic acid was added. h f t e r about 5 min. a heavy precipitate of 0ester tosic acid salt was formed. T o assure complete precipitation, some absolute ether was added and the product was filtered
off, dried, and weighed. The filtrate was evaporated to dryness after addition of sodium bicarbonate solution. T h e solid was washed with water, filtered, dried, and weighed. Melting points confirmed the identity and purity of the products. The results are given in Table I. Compound 11. (free base) was prepared by fractional crystallization of the crude mixture with dehydroalanine (see above ). The oxazoline is the more soluble substance. By discarding the first precipitates from several recrystallizations from aqueous alcohol a pure product was obtained, m.p. 80". This compound is pure as shown by its quantitative conversion to 0-acyl ester tosic acid salt. N-p-Nitrobenzoyldehydroalanine(VI).-Y ( a n d also IIa) was treated a t room temperature for 10 min. with a dilute aqueous methanolic solution of sodium hydroxide in slight excess. Neutralization of the salt with dilute HC1 gave the free dehydroalanine, m.p. 193" (recrystallized twice from acetone). 2-p-Nitrophenyl-4-propylcarbaminooxazoline (XI.-To a methanolic solution of potassium acetate was added \.I11 and the mixture refluxed for 1.5 hr. The solvent was then distilled off under reduced pressure and the residue w a s washed with water, filtered, and dried. T h e yield was practically quanitative, m . p . 163', recrystallized from methanol, m . p . 165". The same results were obtained in a few minutes using sodium methylate or potassium hydroxide instead of potassium acetate. Little reaction occurred with dimethylamine in acetone a t room temperature. However, a t boiling temperature a very good yield of osazoline was obtained. 2-Phenyl-4-carbomethoxyoxazolineTosic Acid Salt (XII).T h e oxazoline was prepared accordiiig to the method of F r y . 5 The oil was dissolved in acetone and a calculated amount of tosic
4720
COMMUXICATIONS TO T H E EDITOR
acid was added followed by a small airiount of absolute e t h e r , 'This compound, n1.p. 138", is relatively stable. 2-Phenoxyacetyl-4-propyIcarbaminooxazoline(XIX~. -A ttempts to prepare the osazoline by the usual illeth!Jd in inethanol ivith potassium acetate or sodium methylate were uusuccessful, possibly because boiling temperature was necessary to diss~)lve the starting material. However, by changing the solvent from methanol to ditnethylformamide, free osazoline was prepared, To a solution of 4.34 g (0.01 mole) of X\.II in 10 nil. of DhIF \viis added 10 Inl. of 1 N sodium niethj-late. ;\iter standing :it rr~oiii temperature for 10 ttiin. water was added and the product was removed by extraction with ether. Evaporati!Jll of the ether left a low melting solid in practically quantitative yield, ti1.p. 52' after two recrystallizations from ether-petroleum ether. i\ddition of t h e calculated ainount of tosic acid to tlie osazt)line in acetone and subsequent recrystallization of tlie salt from acetone and ethyl acetate gave t h e hydroly-sis product itlcnticnl \vith X1.111. Free osazolirie is unaffected by 1 -\-KOH in aqueous methanol a t room temperature, N-Carbobenzoxydehydroalanine n-Propylamide (XXIII) .Reaction of X X I I with a n equivalent m i o u r i t of dilute sodiuiii crystalline methylate gave very guinmp solids in yield. solid, m . p . 68", was obtained after several recrystallizations from ether-petroleum ether. T h e conipountl took up 0.8 equiv. of bromine. ;\nalyses of osazolines and de~ip(lr[J~Llaiiiiies are listed in 'Table
.\
I\.. Bromination.--The possible formation of an unsaturated conipound was tested by uptake of bromine. 'The ineth~itl15-c ti-et1 is a modification of standard inethods. Less than 40 p t n o ~ e sof coin-
34 34 54 ,54 \.I 50 85 S SA 31 S I 1 j7.28 SIX 64 10 11.
1-
4 i '458 54 ti8 1 58 *;o 55 3 41 55 91 j 45 57 27 5 07 6% 90 6 9%
31
LTol SA
-1 74
10.60 10 60 3 42 11 86 3 16 1 5 . 1 6 3 17 3 70 7 0% 1 0 . 6 8 -1 75
10.99 10 46 11 5% 15 27
3.87
8 50
8 '19
10.76
pound \vas dissolved in 1 .O nil. of glacial acetic acid and 1 nil. of 0 . 1 ,V E;BrOj jstaiidardj and 0.1 nil. of 4 N HCI were a d d e d . After $5 inin. 200 ing. of K I \vas added and the iodine was titrated Ivitli 0 . 1 S S;i:SQ with starch :is an indicator. Bromination hclped in tlie identification of the compounds. SC ~ i r b ( i h e i i z o s y d e ~ i y ~ ~ r ( i a ~benzyl a i i i i i e ester took up 0.85 equiv. of broiiiiiie, a n t i coinpound \. 0.97 equiv. Conip~)uiitlS X I I I took u p i).XO equiv. Oxazolines and other coinpourids did not take uli inore than il.!),? equiv. .\I1 pheni~ryacet>-lderivatives used u p 1 .i)equiv. of brolniiie due to substitution in the ring. Ouazolines \\ere further identified by t h e forni:ition of tosic acid salts xnd 'or their hydrolytic products, 0 - i ~ c :imide tosic acid snit\, ;is indic:iteti above.
Acknowledgment.-The authors are pleased to express their indebtedness to Sliss Roberta I i i o for assistance in this work.
COMMUNICATIONS T O THE EDITOR A New Purine Synthesis'
Sir. The condensation of a l-ariiino-j-nitroso-pyrimidine with an active methylene compound has become a classical synthetic route to pteridines in those cases where the intermediate anil is capable of intramolecular cyclization by addition of the o-amino group to an appropriately situated electrophilic center. Thus, condensation of a 4-amino-3-nitrcrso-pyrittiidine with barbituric acid. cyanoacetic acid, or phenylacetontrile* gives pyrimidopteridines, ;-aminopteridirie-(icarboxylic acids, or (i-phenyl-~-aminopteridines, respectively. This reaction has recently been reviewed.' I t appeared to us t h a t this Condensation was potentially capable of giving purines rather than pteridines provided t h a t the ortho-situated amino group could be induced to add intramolecularly to the anil grouping itself rather than to an electrophilic center attached to the anil carbon, -4romatization to the final puriiie would then result from elimination or oxidation. An attractive candidate for the active niethylerie component appeared to be a quatcrnized llannich [ 1) 'l'hi.; work \\as supp(irteti h y a gl-ant i C h ~ 0 2 i i l rti, Princeton VIII iersity f i a m t h e Nationxl Cancel I n s t i t u t e . S a t i u n a l I n i t i t i i t w o f H e a l t h . Public H e a l t h Service ( 2 ) (> h i T i m m i i . . \ ~ c z / M I ' c ~ , 164, 1.10 ( l $ I 4 < l j I G XI l i m m i \ . I- S F;itent 2 i R 1 68il [.Jan 8 , l X i 2 ) C h c m .Ab C i i 'r S Osdene a n d G . XI Tim 4 ) I i G \V Spickett and G T\l t i ' 'C S Osdene in "Pteiidine C h i m n n Pres5 I m n d o n I!M+, pi, fi.i-i,'3
base, since the requisite intramolecular addition cyclization reaction would be facilitated by the positively charged anil nitrogen. Furthermore, the terminal aromatization reaction would involve loss of triniethylaniine and thus parallel the Hoftnann elimination reaction, which proceeds with great facility when leading to an aromatic system \Ye wish to describe a new purine synthesis based upon this principle. Thus, condensation of 1 ,:$dimethyl-4-amino-3-nitrosouracil (1) with benzyltriiiiethylairinioniuiii iodide in refluxing diniethylformaniide solution resulted in the evolution of trimethylamine and the separation in 31c4, yield of S-phenyltheophylline ( 2 , K = CBH5), This reaction appears to be equally applicable to other quaternized llannich bases.G The only notiquaternized 1Iannich base which was successfully employed in this condensation reaction was grainine. Condensation of this latter compound with 1 in refluxing dimethylfortnamide solution resulted in evolution of dimethylamine and the separation of the (2, I< = :j'-iiidolyl). novel S-j:~'-iritlol~-l)tlieoI~hylline =\n attractix-c. mechanism for this facile condensation involves initial elimination of dimethylamine froni gramine. perhaps catalyzed by the riitrosopyriniitline, followed by nucleophilic to ~~-nietli~-leticindoleriine, t f i , ,\ddilic>tial r < , n ~ p o u n~ri-epared ~l~ h y thi. rnethcd were 2 , It :i' methyl 1' ind
