1434
PAUL
E. FANTA A N D EDWARD A. H E D M A N
was developed wit11 hexane f 5 % acetone (45 X 8 cm.). T h e top-to-bottom sequence was (besides minor
VOl. 78
Anal. (111). Calcd. for C40Ha2: C , , 90.16; H, 9.84. Found: C, 90.54; H , 9 3 1 (after correction for 0.8% ash).
[CONTRIBUTION FROM THE D E P A R T M E N T O F C H E M I S T R Y , I L L I N O I S I N S T I T U T E O F T E C H S O I , O G Y ]
2-Substituted-5-nitropyrimidines by the Condensation of Sodium Nitromalonaldehyde with Amidines' BY P.\uL E. FANTA AND EDWARD H E D M A N ~ RECEIVED JUSB 30, 1955 I n an aqueous solution of Triton B, sodium nitromalonaldehyde condcnses n ith a wide variety of aryl and aryl-alkyl aniidiiies to form the corresponding 2-substituted-S-nitropyri17iidilies. With alkyl and lipdrosynlkyl amidincs, no pyrimidines are formed. The reduction of some 5-nitropyrimidines \vas studied and the diazotization of j-amino-2-plienylpyrimidine i-ias attempted.
As part of a program3 concerned with the investigation of new applications of sorliuni nitronialonaldehyde ( I ) to the synthesis of nitro-substituted heterocyclic conipounds, we have studied the scope of the reaction ~ t I' with amidines. Previously reported reactions of I with conipc)uiids containing
and sodium nitrorrialonaltlehytle is a nitropyrimidine, isolation cll' the product denionstrated t h a t i t is a simple salt, which is unstable at room temperature and decomposes on standing t o form a black resin. 'The crj-stallhe precipitate obtained irnrrieof p-toluaniidiately on inising aqueous s~.~lutions dine hydrochloride ant1 sodiuiii nitromalonaltler cIr=oid hytle is n niore stable salt which gives an elemental analysis corrcspiintling to formula Y. Heating aqueous solutions ril either of these salts with a small aiiiount o f Triton I3 results i t i the €orination of the espcctcrl pyriiiiicliiics. T h e cffect of various reaction inct1i:i on the the guanyl group as illustrated in equation 1 led to the formation of 2-hydroxr.-j-nitropyrimidine iron: condensntion of sotiiiuri nitrc,i;i:ili)n:iltleliy(le with urea ( K = OH)," "amino-j-nitropyrimidine in be~iza:nidine w:is stutlii.(l i n or(1cr t u (:stablisIi a "almost yuaiititative yield" from guanidine (R = procedure resulting in an upti!iiuiii ).icltl of the pyNH2),4-6 S-nitro-2-phenylpyrilnidine from benz- riiiiitlirie. I n x1iieous sciI:iticin, heating :it i'Oc ainidine (I< = CsH5) and 2-niethylthio-5-nitropy-with Triton n for foxr hiiurs w:is significantly sup r i o r t i i thc other cciiitIi~icii!s trictl, arid was rimidine from S-methylthiourea (R = SCH3). j Compounds containing a guariyl group which xloptccl ;IS the stmd:irtl c o t i r l i t i o i i q ior a study of were reported not to react with sodium nitronialon- the coiitlcnscitiori o f other atnitlines. Of the \-:rricius , aiihytlritlt.-pyrialdehyde to form a pyrimidine according t o equa- noii-aclticotis i n u ! i : i ~ t u c ~ i c r l ck,tic i high yicltl of tion l are thiourea, which formed 2-imino-5-nitro- dine at 90' ~ J V C nii c ~ c e ~!!11;111y inetathiazine (IVj4 , 7 and forniamidine,6which gave clean product i i i :Isliort r!:actioii tiiiic. In order to tlett~r~iiiiic~ tlic eil'cct oi v:iri:itioiis i t i i i ( i isolrtble contlensntion product. group R on the ioriiixtiini or lij-riiriicliiies :iccortling /.S€I? 2, CH=O 3 to eqiiatic~nI , ;i \-arict?- of a i i i i c l i n c . hy(!r~!clilc)ritlc.s A?---ITS--," \--so? CTI CdT4C,' [cm, in :iqueous soltitinn xc're tr:.:itctl i v i t l i so(1iiiiii iiitroS - - J \srr2 CII=O ( ~Triton i Tritoii i i i ~ i l c ~ i i : ~ ~ ~ ili ci lthe i ~ - presciiw ~le Y IV I{ is :L -LO';;, aqiivotis solution oi benz!.l triiiietliyl.llthough it has pre\*iously been inferret14,Yth:it aiiiirioniuiii ii>-~lrosi:l[~ tc,chnic:il gr;it!c,. ' t h e rcthe precipitate obtained iliinietliately on niixing :ic~~~eiiu solutions s of benznmitline hydrochloricle t 1 : i t a i t is c\.iLleiitt1i:it re:ic.tioii contliul for the cc~iit1cns:itioiiI I l-ario1is ~ aryl ( I j T h i s \bark was aided l i y g r a n t s from t h e Office of Ordnance Research a n d t h e U n i t e d S t a t e s Public H e a l t h Service and was p r e i e n t e i l and aryl-alI;!.l :itriiclincs mith scitliuiri nitroiiialonalin p a r t a t t h e S a t i o n a l h l e e t i n g of t h e A . C . S . , C h i c a g o , Ill., Septemrlehytle caiiiiiit be esteiicIe,~ito d l i y l :inti li>-(lrosyb e r , 1953 This p a p e r was n b l t r n c t e d from t h e Ph.D. thesis of E. A . alkyl aini(1incs. .l wide \-:iricty of media a i i t l temEiedman, June, peratures were tried for the cond(ms:;tioii of acet(2) Armour Research Foundation Industrial Research Fellorv, 1932-19.55. amidine hydrochloride ant1 sotliuiii nitroinnlunal(3) For t h e preceding paper in t h i s series, see P. E. F n n t a a n d R. A . dehr.de, arid a v c n poor yield of ~-1iic.thy1-3-IiitroStein, THIS J O U R N A L , T I , 10-16 (1936). pyrimidine w n s ol~txiiied when the reactioii was (4) W. J . I I a l e and H .C. Brill, ibid., 3 4 , 82, 296 (1912). run with sotliuin hyclrositle iii cthanol a t 25' or with (5) P. E . Fatita, O r e . S y n t h e s e s , 3 2 , 93 ( 1 9 5 2 ) . (i;)R . 0 . R o h l i n , P. S . LYinnek x n d J P. Ilnglisll, Tnis J O U R S A L , piperidine in the ahscricc of s d v e n t a t 90". lJnder 6 4 , 507 (1912). other conditions either a11 iiitrnctable tar was ( 7 ) & I . P.V. Boarlam1 an11 J . 17. W .McOmie, J . C h e m . Soc., 1218 forined or u n r e x t e d sotliiiiii iiitromnlonnltl~~liy~le ( 19,5 1) . ivss rccovwcri 18) c' A C Ilaley- and P. 3T:iitlnnd ibi.1, RIT).5 ( l 9 . i l ) . \\
[
]
]
~-SUIISTITUTED-~-NITROPYRIMIDINES
April 5 , 195G
14;:7,
TABLE I 2-SUBSTITUTED-5-NITROPYRIMIDINES OBTAINED BY THE CONDENSATION OF S O D I U M NITROMALONALDEHYDE WITH AMIDINES IN
Hydrochloride of amidine, I 1 h1.p.. o c . Obsd. Lit.
70-73 215-210 2 10-2 18 2G1-203 240-234 209-21 1 294-295 207-209 245-249 238-242 234 100-194
AQUEOUS TRITON B
Yield,
Ref.
72 213
(I
d
264-265 241-242
/ 0
h
294-296 203 238-239 2a0 237 180-190
i k h e
I
151-153 153-155 68-70
0 0
n
M.P., 'C.
c/o
Nitropyrimidine, 111 Analyses, Calcd.
C
H
79 87 30 89 81 71 48 41 85 79 G7 36
222-223, 5b 249-2EiO 2 16-2 18 225-227 170-171.5 154-155 235-237 268-270 253-254 133-134 182-183 202-203
G1.40 57.14 42.88 50.95 54,80 48.78 42.8G 09.30 48.78 55.19 53.46
4.22 3.92
77 38 81 77
170 235 219-220 210-211
61.37 56.72 G3.43 59.25
4.22 4.7G 3.09 3.73
2.1G 2.57 2.76 2.46 2.85 4.00 2.48 4.25 2.99
N
19.53 18.18 15.00 17.84
19.99 15.15 22.75 16.09 27.70 19.53 15.27 18.50
%
C
Found
H
02.05 57.52 43.35 51.23 55.07 49.17 43.04 69.47 48.83 55.09 53.G7
4.33 3.87 2.30 2.80 2.89 2.53 3.20 4.05 2.30 4.20 3.14
61.87 5G.21 G3.22 59.43
4.28 4.78 4.08 3.98
N
19.11 18.40 14.75 17.02
19.58 15.00 22.73 16.00 27.53 10.39 15.50 18.08
" 1G4-1GG 0 0 Oil 0 P 125-127 128-129 0 q 1G2-160 171 0 r 81-82 84-85.5 0 A. R . Ronzio and J. B. Ekeley, "Organic Syntheses," Coll. Vol. I, 2nd Ed., John Wiley and Sons, Inc., Yew York, 9. Y.. G. Glock, Ber., 21, 26;iO (1888). The a m i d h e mas characterized as tlie 1941, p. 6. * Reference 4 reports m.p. 219". picrate, observed m.p. 210-21"; reported 213' by P . Oxley and W. F. Short, J . Chew. Soc., 147 (1946). e C. H . Andrews, H King and J. N'nlker, Proc. Roy. soc. ( L o ) z d o u ) , 133B, 20 (19.10); c. A . , 41, 727 (1947); see also refereiice 1;. J . B. Ekeley, D. V. Tieszen arid A . Ronzio, THISJ O U R N A L , 57, 381 (1935). S o literature value reported. A . P. T. Eassoii Obtained and used in the form of the free base, ohserved m.p. 207-209" and F. L. Pyman, J . Chew. Soc., 2991 (1931). reported 203" by R. C. Iris, R. D. Leyva a n d C. R. Ramirez, C. A , , 41, 4117 (1047) and 228' in footnote e of this table. i L. Bauer and J. Cymerman, J . CheuL. Soc., 2078 (19.50). J. Tafel and C. Enoch, Ber., 23, 1550 (1890) S o literature value reported for the hydrochloride. The aniidiiie was characterized as tlie picrate, observed m.p. 228-2.70°, reported 22i228' by W.F. Short and A?. \V.Partridge, U. S. Patent 2,450,386 in C. A . , 43,3456 (1949). Obtaiiied and used in the form of the free base, observed 1n.p. 1Y3-1Xi0, reported 188-189" by 13. Roth and J. M. Smith, THISJ O ~ U R N A L ,71, 016 (1949). A. K', Dox, footnote n of this table, p. 3. Characterized as the picrate, observed m.p. 193-1'33 , reported 195-196' i n footnote h of this table. p P. Eitt1c.r aiid H.Wetz, Ber., 26, 2840 (1893). * A. Pinner, ibid.,23, 2942 (1800). C. C. Price and J. Zoinlefcr, J . Org. Cheni., 14, 2111 (1949). O
I n order to rationalize this observed difference in the behavior of l~enzaniidirie arid acetamidine, othcr properties of arnitlinrs were examined. T h e base strengtlis of the arnidiiics cannot be correlated with the yield of pyrimidine, since two arnidines wliicli give escellciit yieltls nf pyrimidine are guani(line, /iTC4 13.71,9 :mil beii:~aiiiirline, pT-tlrositle solution :it 70" :it i i i tervtils of one-half, one :itid three hours, 1.(!5 iiiinolez of iieriznn~iriiiieevolved 11, :31 anti 817;of the nitrogcn :I\ x n i rrionin, xvliile 1.22 inillinioles of ncet:iiiiitIitie e\ olvccl fi.3, V ~>.II(I91 4; of tlie iiitrogeii as ~ I I I I I I ~ I I ~ : ~ . Reaction of Nitromalonaldehyde with Anirnonia.-In x n n y of the u t t ~ u c i . e . ~ f ~re:tctions il of ~otliuriinitronI:ilou:iltleh~-dexvitli aniiciines :I broivn or lil~ickre-in \\-,is fornictl. A sirnikir product vas ol)t,iiiietl 11 lieii iotli~iiii~ i i t r o ~ i i : i I ~ ~ ~ i (32) I< Aiidrisnno a n d G . ?iIrxlma C A , 4 7 , 1737 f 1 9 2 3 ) . ( 2 3 ) TVe \ \ i s h t o t h a n k n r s . I
