A Simplified Method to Prepare 2-Amino-5-bromopyrimidine A Laboratory Experiment Richard Fichter' and Guido E. Bonvicino2 Long Island University1C.W. Post Center, Greenvale, NY 11548 Various 2-substituted-5-cyanopyrimidines were required as intermediates for the syntheses of amino acids containine the pyrimidine ring system as possible antiviral agents. An 111 from interesting synthesis of 2-amino-5-c~~anonvrimidine urea and 3-ethoxy-2-methoxymethyl~nepkpionitrilehas been reported ( I ). I t has also been prepared ( 2 )in 40% yield from 2-amino-5-bromopyrimidine (11) and cuprous cyanide in quinoline, while the preparation of (11) in 41% yield from 2aminopyrimidine (111) and hromine in aqueous medium a t 70-80°C has also been reported (3).
Ha A& I: Y
=
CN
11: Y = Br
Although the synthesis of I, reported by Takamizawa, et al. (I), is interesting, several steps are required to prepare 3ethoxy-2-methoxymethylenepropionitrile (4),and then a t least four additional steps are needed to prepare I. We decided to consider first the route reported by English, et al. (111 I1 1) ( Z 3 ) . Submined in partial fulfillment of the requirements for credit in Chemistry 98, 99 (Independent Study) in the Chemistry Department. Long Island University1C.W. Post Center. Author to whom correspondence should be addressed. 3 The use of an efficientfume hood is stressed due to the hazardous nature of chlorine. "Threshold odor detection: 0.2-0.4 ppm." cf. Stckinger, H. E., in "Patty's Industrial Hygiene and Toxicology"; Editors: Clayton, G. D. and Clayton. F. E.). 3rd ed., Wiley-Interscience, New Yo*. 1981, Vol. 2B, Chapter 40, pp. 2954-2965.
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The rlassical brominations of aromatic compounds are usually carried out with sn excess of hnmune in acid medium (,5I.~The of elemental bromine and acid media can be -~~~ , hazards ~ eliminated and the reaction time considerably shortened if brominations are carried out with hromine chloride in aqueous medium. Examples of this type of halogenations are in the literature ( 6 4 ) . We have modified this procedure to brominate 2-aminopyrimidine and the method reported here is a distinct im~rovementover the Drocedure nreviouslv described (3).The use o f a fume hood in which tocilrry out h e redction is C O ~ D U ~ O nevertheless, ~\::' the renctiun is permitted to tnke place vejsimple equipment. This procedure can he safely nerformed bv undergraduate orcanic chemistry students and can he completed in one lat,ori;ory period. 1t totally eliminates the use of liquid bromine, ncidiesolvents, and elevated temperatures (3): This experiment illustrates several imnortant chemical nrincinles that add interest to laboratory kxercises and better comprehension of the study of organic chemistw. For example: (1) presumahly hromine chloride (8) is generated (eqn. (1))in the procedure when chlorine gas is bubbled into an aqueous solution of bromide ions a t room temperature. Due to the difference in electronegativity between chlorine and bromine, the preparation of hromine chloride from elemental chlorine and bromide ions is an example of an oxidation-reduction reaction, and (2) hromine chloride is an example of an unsymmetrical reagent; the less electronegative partner, the bromine nucleus, is the positive end of a dipole and the chlorine nucleus, the more electronegative partner, is the negative end. Conceivably, therefore, bromonium ions from the dissociation of bromine chloride molecules in the aqueous medium may take part in electrophilic aromatic brominations (eqn. (2)). The insoluble 2-amino-5-bromopyrimidine (II), began to separate almost immediately upon addition of gaseous chlorine to an aqueous solution of 2-aminopyrimidine and one molar equivalent of sodium bromide at room temperature. The rate of chlorine addition had to be controlled since the reaction is exothermic and the yield of I1 was greatly reduced if the temperature was permitted to rise above 50°C. ~~~~
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Employing this technique a t 70-80°C, t h e temperature reported ( 3 )for t h e hromination of I11 with bromine in aqueous medium, resulted in t h e formation of a clear solution from which n o product (11) could be easily isolated. On the other hand, at about 20°C, a n d employing the procedure reported here, an 80%yield of I1 was easily isolated. In one experiment t h e temperature of t h e reaction mixture was permitted t o rise t o 41°C. T h e product (11) dissolved and remained in solution even after t h e solution was cooled a n d was allowed t o stand overnight at room temperature. Addition of dilute ( 3 N ) sodium hydroxide t o p H 10 caused the product t o separate. Presumably, t h e hydrochloride was formed a t t h e higher temperature from which t h e free base was liberated on addition of alkali. T h e product was collected as a pale yellow solid in 68% yield. 2-Amino-5-cyanopyrimidine (I) was prepared from I1 by a literature orocedure (2). Cornoarable vields were ohtained when I1 a n d cuprous cyanide were allowed t o react in dimethylsulfoxide (DMSO), instead of auinoline. under reflux. T h e workup of t h e reaction mixture in DMSO was much simpler and gave a cleaner product t h a n t h e quinoline procedure (2).Another more recent and more complex synthesis of I has been reported (9). T h e preparaiion ut. hromine chloride from N-chlorosuccinimide (NCSI and o d i u m bromide in alcohol a n d its use a s a hrominaring agent 01 suhstitutrd phenols has recently Ijrrn reported (101.'l'hir pnx.edure also gave 2-amino-S-bromopyrimidine (11) in 75'7 yield from 2-aminopyrimidine (1111.
Anal. Caled. for C4H4BrN3 (174.01): C, 27.6; H, 2.32: Br, 45.9; N, 24.2. Found: C, 27.7; H, 2.37; Br, 46.1; N, 24.4. NMR Spectrs-determined in CDCI8, and the chemical shifts (6) are downfield from TMS (Me&-the internal standard; C-2NH2, 6 8.40; C-4H and C-6H. 6 8.75. These values are identical to those recentlv reoortedfor 11, prepared under more drastic conditions (11).
2-Amino-5-bromopyrimidine (10: NCS a n d NaBrIalcohol Method From 2.38g of 2-aminopyrimidine (1111.2.58 g of NaBr and 3.34 g of N-chlorosuccinimide (NCS) in 30 mL of absolute ethanol, following the recently ~ublishedprocedure of Wilbur et al. ( l o b ) ,was obtained 3.26 g (75%yield) of 2-amino-5-hromopyrimidine(11).mp 241-243'C dee. The IR and UV spectra of this material were identical with those of a sample prepared by the above procedure (NaBr/CI*,H20)and with those of a sample prepared according to Englishet al. (3).Mixture melting points of these samples were not depressed.
2-Amino-5-bromopyrimidine hydrochloride (11. HCI) 2-Amino-5-hromopyrimidine (II), 1.0 g (0.006 mol), was dissolved in 5 mL of hot concentrated hydrochloric acid. The solution was cooled in an ice hath while absolute alcohol was added to the solution until precipitation of the hydrochloride was complete (-10 mL). The salt was collected in a Buchner funnel, washed with absolute alcohol, and dried over PzOs in a vacuum dessieator. The pure product, 0.9 g, was obtained in 75%yield; mp 190°Cdee. Neutral equivalent: Cdcd. 210.5; found 209.6. 2-Amino-5-cyanopyrimidine ( I )
Experimental
2-Amino-5-bromopyrirnidine (10 This preparation must be carried out under an efficientfume hood3 In a 600-mL beaker. a solution of 9.5 e (0.10 mol) of 2-aminoovrimi~~~~~~~--- mT, nfwater .dine (111) mol) of sodium bromide in 225 . . and 11.3 ~'(0.11 ". at 20°C was prepared. The beaker was placed in a water hath maintained at &2O0Cby allowing tap water to flow in and out of it a t a moderate rate. The solution was vigorously stirred, either by hand with a sturdy glass rod, or preferably by means of a magnetic stirrer under an efficientfume hood3 while a slow stream of chlorine ga$ was introduced into it through a fritted glass inlet tube. The addition rate of chlarinewas controlled by (1) not allowing the temperatureof the reaction mixture to exceed 30%. and (21 not allowine the color of
A mixturs uf 3.1 g l(l.021)moll of?-amin.>-bn,rnopyritnidine 111). 2 UI: ~~10?2mol,of freihrupmuicvunidr in 5(lml.oifrrshl\~diitill~d dirncthd suli.,xidr rDhlSO, was healed under r d h x ior 4 hand rhrn ~~~.~~ ~
added to 3M)mL of cold water. The mixture war -- allowed ~ . .-t. ~ n. stand ~until . it cooled to room temperature. The precipitate was collected in a Buchner funnel hy suction filtration and then dried in a desiccator. A crude yield of 1.6 g (67%)was ohtained. Recrystallization from 50 mL of alcohol yielded 1.4 g (58%)of colorless prisms, mp 4 7 5 T dec., lit. (2) 300-310'C dec., lit. ( 1 ) -260°C. IR spectrum (Nujol mull), 3100,2220,1680,1600,1527,1385.1235.1070.969.805.661cm-l: UV spectrum, 257 nm (lob c 4.46); 296 nm(logr 3.54). Anal. calcd. for C5HaNa:C. 50.0:, H., 3.3fi: N., 4fi.R. Found: C.,....601: ~~, ., H, 3.42; N, 46.4. T ~ ~ and I Ruv spectrawere identical with those of authenticsamples prepared by the method of Takamizawa et al. (I) and by the quinoline procedure of English et al. (2). ~
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Acknowledgment The addition of chlorine gas was continued for 15-20 min and then stopped. The suspension was stirred for an additional 15-min period before it was filtered under a hood by suction filtration using a Biichner funnel fitted with a suction filtering flask with theside tube attached to a water aspirator operating at full water pressure. The pale yellow product was washed with several portions of cold water and dried in a desiccator over PzOs. The dry product, 14.5 g (83%yield) melted at 23&241°C. Recrystallization from boiling 70% ethanol with a charcoal treatment yielded 13.9 g (80%)of analytically pure white lustrous plates, mp 241-243°C dec5 (lit. mp 242-244-C (3)).The IR and UV spectra were identical with those of an authentic sample prepared by the method of English, et al. (3).
We are indebted to t h e Research Committee of Long Island UniversityIC. W. Post Center for partial support of t h e work reported here. Literature Cited 111 Takamiraws,A., Hirai, K.. Sato, Y., and Tori. K., J Org. Chem.,23,1740 119M). 12) English,J.P..Clark, J.H.,Shepherd,R.G.,Marron,H. W.,Krapcho.J.,sndRahlin,
R.O.,Jr.,J. Amsr. Chem. Soc.. 6R. 1039(1946). I31 English. J. P., C1ark.J. H.,Clapp,J. W.,Seeger,D.,sndEbe1.R. H..J.Amer.Chem. Soc.. 68,453 (19661.
(41 TsPamirawa,A..Ikawa.K.,and Narisda,M.. JPhann. Soc Jopon.78,632 (1958). (5) Hartman, W. W.,and Dickey, J. B.,"OrganieSynfheses," VolII, John Wiiey andsons, Inc.. New York. 1943, p. 173. 16) Britton,E., and Tree, R.,U.S. Pat. 2,607.802 (19521 to Dow Chemical Co. 17) Knawles, W. S.. and Alh G. H.. U.S. Pat. 3,012,035 11961) to Monsanto Chemical
....... ,...-,. (10) la1 Wi1hur.D. S.,andAndemon.K. W. J . Or&
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Journal of Chemical Education
Chem..47.358(1982):lbi Wi1hur.D.
