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4720 CO MMU X ICA T IO N SO THE EDITOR LTol SA

acid was added followed by a small a i r i o u n t of absolute ether,'This compound, n1.p. 138", is relatively stable.

2-Phenoxyacetyl-4-propyIcarbaminooxazoline XIX~.A t-tempts to prepare the osazoline by the usua l illeth Jd i n inethan olivith potassium acetate or sodium methylate were uusuccessful,possibly because boiling temperature wa s necessary to diss~)lvethe starti ng material. However, by changing the solvent frommethanol to ditnethylformamide, free osazoline was prepared,To a solut ion of 4.34 g ( 0.0 1 mole) of X \ . I I in 10 n i l . of DhIF \vi is

added 10 Inl. of 1 N sodium niethj-late. ;\iter standing :it r r ~o

temperature for 10 ttiin. water was added and th e product was re-

moved by extr actio n with ethe r. Evaporati Jll of the eth er left alow melting solid in practically q uan ti tat ive yield, ti1.p. 52' aftertwo recrystallizations from ether-petroleum ethe r.

i\ddition of th e calculated ainou nt of tosic acid to tlie osazt)linein acetone and subsequent recrystallization of tlie salt from ace-tone an d ethy l acet ate gave t he hydroly-sis prod uct itlcnticnl \vithX1.111. Free osazolirie is unaffected by 1 -\-K O H in aqueousmethanol at room tempera ture,

N-Carbobenzoxydehydroalanine n-Propylamide XXIII)Reaction of XXII with an equivalent m i o u r i t o f d i l u t e sodiuiiimethylate gave very guin mp solids in yield. .\ crystallinesolid, m.p. 68", was obtained after several recrystallizations from

ether-petroleum ether . The conipountl took up 0.8 equiv. ofbromine.

; \ nal yses of osazolines and de~ip(lr[J~Llaiiiiiesre listed in 'TableI\..

Bromination.--The possible forma tion of an unsaturated coni-pound was teste d by upt ake of bromine. 'The ineth~ i t l 5 c ti-et1 isa modification of stan dard inethods. Less than 40 ptno~esf coin-

11. 34 34 31 4 i 458 -1 74 10 . 60 10 . 99

1- 54 ,54 54 ti8 1 5 8 -1 75 10 60 10 46

\ . I 50 85 *;o 55 3 41 3 4 2 11 86 11 5%

SA 31 55 91 45 3 16 15 . 16 15 27

S I 1 j 7 . 2 8 57 27 5 07 3 1 7 3 70 3 87 8 50 8 '19

S X 6410

6% 906 9% 7

0

10 . 68 10 . 76

pound \vas dissolved in 1 O n i l . of glacial acetic acid and 1 nil. of

0.1 V E;BrOj jstaiidardj and 0.1 ni l . of 4 N HCI were a d d e d .A f t e r 5 inin. 200 ing. of K I \vas added and the iodine was titratedIvitli 0 . 1 S;i:SQ with starch :is an indicator.

S

C~irb( ihei izosyde~iy~~r( ia~ai i i i i eenzyl ester took up 0.85 equ iv. ofbroiiiiiie, a n t i coinpound \. 0.97 equiv. Conip~)uiitl X I I I tooku p i).XO equiv. Oxazolines and other coinpourids did not take

uli inore than il. ),? equiv. .\I1 pheni~ryacet>-l erivatives usedu p 1 .i equiv. of brolniiie due to substitution in the ring.

Ouazolines \ \ e r e further identified by the forni:ition of tosicacid salts x n d 'or their hydrolytic products, 0 - i ~ c

:imide tosic acid snit\, ;is indic:iteti above.

Bromination hclped in tlie identification of the compounds.

Acknowledgment.-The aut hor s are pleased to ex-

press their indebtedness to Sl iss Roberta I i i o for as-

sistance in this work.

COMMUNICATIONS T O THE EDITOR

A New Purine Synthesis'

Sir

The condensation of a l-ariiino-j-nitroso-pyrimidine

with a n active methylene compound has become a

classical synt heti c route to pteridines in those cases

where the intermediate anil is capable of int ramolecular

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 phen ylac eton -

trile* gives pyrimidopterid ines, ;-aminopteridirie-(i-

carboxylic acids, or (i-phenyl-~-aminopteridines, re-

spectively. This reaction has recently been reviewed.'

I t appeared to us t ha t this Condensation was poten-

tially capable of giving purines rather than pteridines

provided that the ortho-situated amino group could beinduced to add intramolecularly to the anil grouping

itself rat her tha n to an electrophilic center attached to

the anil carbon, -4romatization to th e final puriiie

would then resul t from elimination or oxidation.

An attractive candidate for the active niethylerie

component appeared to be a quatcrnized llannich

[ 1) l hi.; wo rk \\as supp(irteti h y a gl-ant i C h ~ 0 2 i i l r i, Prince ton V I I I

i e rs i ty f i a m the Na t ionxl Cance l In s t i tu te . Sa t iuna l Ini t i t i i tw o f Heal th .

Public Health Service

2 ) (> h i Timmi 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 Spicke t t and G T\l

t i ' 'C S Osdene in "Pte i id ine Ch

imnn Pres5 I m n d o n I M+, pi, f i . i - i , '3

base, since the requisite intramolecular addition

cyclization reaction would be facilitated by the posi-

tively charged anil nitrogen. Furt herm ore, the ter-minal aromatization reaction would involve loss of

triniethylaniine and thus parallel the Hoftnann elimi-

nation 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 benzyltri-

iiiethylairinioniuiii iodide in refluxing diniethylform-

aniide solution resulted in the evolution of t rimethyl-

amine and the separation in 31c4, yield of S-phenyl-

theophylline 2 , K = CBH5),

This reaction appears to be equally applicable to

other quaternized llannich bases.G

The only notiquaternized 1Iannich base which wassuccessfully employed i n this condensation reaction was

grainine. Condensation of thi s lat ter compound with 1

in refluxing dimethylfortnamide solution resulted in

evolution of dimethylamine a n d the separation of the

novel S - j : ~ - i r i tl o l ~ - l ) t li e o I ~ h y l l i n e2, I< = :j'-iiidolyl).

= n attractix-c. mechanism for this facile condensation

involves initial elimination of dimethylamine froni

gramine. perhaps catalyzed by the riitrosopyriniitline,

to ~ ~ - n i e t l i ~ - l e t i c i n d o l e r i i n e ,ollowed by nucleophilic

t f i , \d di li c> ti al r < , n ~ p o u n ~ l ~ri -epared y thi. rnethcd were 2 It :im e t h y l 1 ' i n d < l l l l . R = i i i m e t h ? l ~ - l ' ~ ~ y : i r ~ i x y p h e n y l ,n d I< = :imethyl 2 ' 11~dz;ixylihenyl

:ill rcmp, ,und. I epm ted

Satli iact, , i y :rnalytic.il d a t a were iilitainrrl for

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N o v . 5, 1964 COMMUNICATIONSO THE EDITOR 4721

0

CH3

1

HJC2

add ition of t he nitroso nitrogen to the methylene group-

ing in a manner analogous to the common Michael

reaction ( skatylation ) observed with gramine.? Th e

product of this condensation would be the nitrone 3),

which should undergo immediate intramolecular addi-

tion of t he ortho-situated amino group t o the polarized

>C=T\i-+O bond .8 Deh ydra tion of this addition prod-

uct leads directly to 2 (R = 3’-indolyl).

I t is interesting to note that the methylene compo-

nent need no t be ac tivated provided th at condensation

with the 5-nitroso group is intramolecular and tha t

sufficiently strenuous conditions are employed. Thus ,

it has recently been reported g tha t 4-amino-5-nitro-

souracil derivatives carrying -CH2- or -CH3 substi-

tue nts on the -&amino group a re cyclized by thermally

induced intramolecular dehydration to 8-substituted

xanthines.

( 7 ) For an exh austive discussion of the se reactions see H Hel lmann and

G. Opi tz , “a -Aminoa ikyi ie rung,” Verlag Chemie G m h.H . , Weinhe im

Bers t r , 1960.

8 ) The fo rm a t ion of a ni t rone by condensa t ion of a qua te rnized pyrrole

Mannich base with p-dimethylaminonitrosobenzene has heen demonst ra ted

[A Triebs and G F r i t z , Ang ew C h ~ m 6 6 , 562 (195411, but the reac t ion

appeared to fa i l wi th gramine i t se l f

(9) H. Goldner , G I l ie tz. an d E Cars tens , .Volurwiss 61 137 (1964)

DEPARTMEST O F CHEMISTRY EDWARD. TAYLOR

PRINCETOSN I V E R S I T Y EDWARD. GARCIA

RE EIVED 4 ~ - ~ ~ - ~ ~, 1964

PRINCETO?;, XE\V JERSEY

~

Synthesis of 8-Substituted Theophyllines. Isolation ofa 7-N-Oxide Intermed iate and a n Unusual Leuckart

Reduction with Dimethylformamidel

Sir:

We wish to describe a new synthesis of 8 -sub stitu ted

theophyllines in which a 7-N-oxide has been charac-

(1) This work was supported b y a re search gran t (CA~023.51) o Prince ton

Univers i ty from the Sa t iona l Cancer Ins t i tu te , Sa t ion a l Ins t i tu tes of

Hea l th , Publ ic Hea l th Service

terized as an intermediate , and an unusual Leuckart-

typ e reduction of t he la tte r effected by dimethylform-

amide.

Treatment of 1,3-dimethyl-4-amino-S-nitrosouracil

1 ) with benzaldehyde in dimethylformamide solution

results in the evolution of dimethylam ine a nd th e sepa-

ration of 8-phenyltheophylline (6). Concentration of

th e filtrate gives a second, lower melting product which

is extremely light sensitive; m.p . dec. above 169’.

Anal. Calcd. for C13H12N403: C, 57.35; H, 4.44;N, 20.58. Found: C, 57.25; H, 4.39; N , 20.71 .Although this compound is isomeric with the simple

anil 2, its solubility in dilute sodium hydroxide solution

and the observation tha t i t gives a positive ferric chlo-

ride test identifies i t as the 7-IV-oxide 3.3 This was

confirmed by methylation in dilute alkaline solution

with dimethyl sulfate to give a white, light-stable

crystalline 0-methyl derivative 4 ; n.m.r. (DCC13)

shar p, unsplit singlets at r 6.65, 6.45, and 3.92.

Anal. Calcd. for C14H14N4O3: C, 58.73; H , 4.93; N,19.57. Found: C, 58.76; H , 4.79; N , 19.95. Cata-

lytic reduction results in cleavage of the 0-methyl

group with th e formation of 8-phenyltheo phylline (6).

Heating the S-oxide 3 in dimethylformamide results

in the evolution of dimethylamine and th e formation

of 6 ; the IV-oxide 3 is clearly an intermediate in the

conversion of 1 to 6. The reduction of 3 by dimethyl-

formamide may be explained by formation of a n inter -

mediate complex 5 ) ,which can undergo an intramolecu-

lar oxidation-reduction sequence either by transfer of a

hydride ion to the 8-position of the purine ring (pa th a)

or by direct collapse to 6, carbon dioxide, an d dimethyl-

amine (path b) . perhaps O ~ U cyclic transition state

involving th e &carbonyl group. In both cases consider-

able driving force would derive from the delocalization

possible in th e initially formed anions. To our knowl-

edge this is the first example of t he participation of

dimethylformamide alone as the reducing agent in a

Leuckart- type reduction.

Since a mi xture of the N-oxide 3 and S-phenyltheo-

phylline (6) was formed in the above reaction of 1,

benzaldehyde, and dimethylformamide, reduction of 3

must take place slowly under these conditions, and it

was reasoned t ha t addition of a more effective reducing

agent to the reaction medium should result in higher

yields of 6. I n accordance with this expectation,

addit ion of formic acid resulted in the formation of 6 in

moder ate yield; no N-oxide was isolat ed. LVe were

able to isolate and characterize 1,3.6,8-tetramethyl-

2,4,5, -( H,HH,GH,SH)pyrirnido [ 5 , 4 jpteridinetetrone

(7) 4 and 1,3-dimethyluric acid5 as by-prod ucts in th is

reaction.

The reaction of 1 with aldehydes in a mixture ofdimethylformamide and formic acid a ppears to be a gen-

eral synthesis of 8-su bsti tuted theophyllines. Indole-

2) This compound has been desc ribed by G P Hager and C. Ka ise r ,

J Am . P h a r m . A s s o ~ 43 148 (1954), i t was prepared b y condensation of

1,3~dimethyl~4,5-diaminouraci lnd benzoic acid in the presence of phospho~

rus oxychloride.

( 3 ) Some years ago Timmis G M . Timmis , I . Cooke , and R . G W

Spicke t t in “The Chemis t ry and Biology of Purines , ” G E. W . W d s t e n

holme and C. M . O’Connor, Ed. , J and A Churchill . I. td. , i .ondon, 19.57.

p 1 3 4 ) reported some pre liminary experiments in which a purine 7~N- axi de

resulted fr om th e reaction of a 4-amino~j-nitrosopyrimidinewith an a ldehyde

anil . Th e reaction failed with aldehy des themselves This work has not

been reported in detail .

(4) E. C . Ta y l o r , C . K C a i n , a nd H hl. .oux, J A m ChPm FOG 6.

874 1954) .

5 ) W. Tra uhe , Bw 53 3035 (1900)