REACTION OF N-ACYL-a-AMINOKETONES WITH 2,5,6-TRIAMINO-4-

HYDROXYPYRIMIDINE

S. I. Zav'yalov and T. K. Budkova UDC 542.91:547.85

We have previously found that the condensation of acetamidoacetone (la) with 2,5,6-tri- amino-4-hydroxypyrimidine (II) in refluxing aqueous hydrazine leads to a mixture of 6- and 7-methylpterines (Ilia and b) in 8:2 ratio, while in aqueous EtaNH at IO0~ the reaction of ketone (la) with (II) is strictly selective with the formation of only isomer (lllb) [i]. In the present work, some features and limitations of the applicability of these reactions are examined.

O , O s N. 14~ H N ~ / ! I a'b'e') H~ (Ia-e)

(IIIb,c,e) ~ (II) (Illa,c~ d)

N2H 4

RCOCHR'NHCOR" (Ia--c)

R=W'=CH~,H'H (Ia); R = R ' = R " = C H 3 (Ib); R=C2H,. R ' = H . R~=CH8 (I~); R----CH.q. R ' = H .

R'--CsH5 (Id); R=C~Hs, R'=-H, R~=C~H5 (Ir

R=CH3. R'----H (llIa). (Ill I~; R = R ' ~ C H 3 (IIJ~);

R=C~Hs, R = H (IIld), (Ille)

Other N-acyl-a-aminoketones such as 3-acetamido-2-butanone (Ib) and l-benzamido-2-butanone (le) enter an analogous condensation with pyrimidine (II) under the action of Et2NH. 6,7- Dimethylpterine (lllc) and 7-ethylpterine (llle) are formed, respectively, with 61 and 68% yields. The position of the ethyl group at C(7) and the existence of (llle) as a single com- pound correlate with the presence of only one signal at C(6) (8.27 ppm) at low field in the PMR spectrum and the similarity of the IR spectrum of (llle) with the spectrum of a known sample of 7-methylpterine (lllb).

The regioselectivity of the reaction of (II) with ketones (la) and (le) may be explained by the initial formation of an equilibrium mixture of imino derivatives (IV) and (V) as a re- suit of the condensation of ketones (la) and (le) with the NH2 group at C(5) and C(6) in (II). Imine (IV) predominates in this mixture as a consequence of the enhanced nucleophilicity of the NH2 group at C(5) [2]. However, the capacity for subsequent cyclization should be more pronounced for the 7-isomer (V), in which there is a direct conjugation of three double bonds, which facilitates the deprotonation of the methylene group and formation of enamine (VI). The subsequent conversion of enamine (VI) into the 7-substituted pterine (lllb and e) may involve intermediate steps of hydrolysis of the enamine (Vl), cyclization of the aldehyde (VII), and dehydrogenation of 7,8-dihydropterine (VIII) by atmospheric oxygen. In comparison with imine (V), the deprotonation of the methylene group in the isomeric imine (IV) should be hindered as a consequence of the crossed conjugation of the double bonds in (IV). The irreversible conversion of the 6-imino derivative (V) into the 7-substituted pterine (lllb and e) causes a shift in the 5-imine (IV)~-6-imine (V) equilibrium towards the 6-isomer (V) and thus pro- vides for the regioselective formation of the 7-substituted pterine (lllb and e).

The loss of the acylamino derivative after the formation of the intermediate imino de- rivative (V) is supported by the stability of ketones (la-e) to the action of diethylamine un- der the conditions of pterine synthesis.

A more complicated case is observed in the condensation of ketones (la-e) with (II) in the presence of hydrazine (Table i). The reagent ratio, structure of the ketones (la-e), and

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow. Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1323-1326, June, 1979. Original article submitted January 16, 1978.

1236 0568-5230/79/2806-1236507.50 �9 1979 Plenum Publishing Corporation

some other factors affect the yields and regioselectivity of this reaction, condensation of acetamidoacetone (Is) with pyrimidine

o HN~N~9 JR 1"120

(It) 1L_, N/L\ '1~,i~,. \NH2 ~H2

(~V) NHCOR )

0 0 NHCORr J N H , , J~) - cHo jj NH~ .1

II2N/'X~'NNH/ \ R H._,N/~,/~NH / \ R (VII) N,x4 (VI)

0

H=N~&NH~\R 0.0> (IIIb, e)

(Vilt)

The study of the

NHGOR ~ IL~ NHo I

< [I20 H2N ~ / ~ , , ~ / / C , R

(v)

NHCOR t

H N 2 ~ NH~ ~Ii

sulfate (II) showed that the greatest yields of the mixtures of pterines (Ilia) and (lllb) and the greatest degree of regioselectivity is achieved by conducting the pterine synthesis in two steps: the preliminary treatment of ketone (Is) with excess hydrazine in aqueous solu- tion with the addition of catalytic amounts of acetic acid and subsequent heating with pyri- midine sulfate (II) in aqueous acetic acid at pH 5-6. In this process, the molar ratio of pyrimidine (II), ketone (la), and N2H~.H20 should be 1:2:13-20. A significant difference in the fraction of hydrazine from the ratio indicated above and the absence of acetic acid, and also carrying out the condensation of pyrimidine (II) with ketone (Is) and hydrazine in one step lead to a reduction in the yield of the mixture of pterines (Ilia) and (lllb) and in- crease in the fraction of the 7-methyl isomer (lllb). A decrease in the pterine yield and decrease in the regioselectivity also occur by introducing l-benzamidoketones (Id) and (le) and acetamidoacetone homologs (Ib) and (Ic) into the reaction with pyrimidine (II) (see Ta- ble i, runs 14-17).

A mechanism may be postulated for the regioselective formation of the 6-substituted pter- ines (Ilia) and (llld) from (II) and ketones (la), (Ic), (Id), and (le) which involves the prior conversion of the ketones (Is), (Ic), (Id), and (le) into osazone (X) and its subse- quent conversion with (II) by a scheme proposed by Pfleiderer et al. [2]:

NNH 2 (Ia, c, d e) x~II~ t', , " R--C--CH=NNH~

(•

O

{II) ( - ~ H ~ N%C/'RI

H~N / "lq" \NH= CH (XI) %NNH2

-N2H4 (Ilia, d) R=CH~, C~H 5

However, this proposal does not agree with the experimental data: a complex mixture of prod- ucts is formed upon heating ketones (la) and (Id) with hydrazine in aqueous solution, in which it was not possible to find significant amounts of the osazone of pyruvaldehyde (X) (R = CH3):

0 0 N R �9

RCOCH2X H 2 N ~ N ~ c / " R N2H4 H ~ ~ C / "~2H*> (XI) -N2~ (Iiia, d )

(xID X ----- NHCOCH~, NHCOC6Hs or other groups

Nevertheless, we may propose that the synthesis of pterines (Ilia) and (llld)proceeds through the intermediate hydrazone (XI) which arises in the reaction of ketones (Is, c-e) (or any oth-

1237

TABLE i. Condensation of N-Acyl-a-aminoketones (la-e) with 2,* 5,6-Triamino-4-hydroxypyrimidine (II) in the Presence of N2H4. HaO and Acetic Acid at pH 5-6

RII n �9

number* Starting (Ia-e), 2-~.5 moles per mole pyrimi- dine sulfate (II)

1 2 3 4 5 6 7

8 9

10 i l 12 t3 i4 15 16 t7

Aceta mldoacetone The sa me

)>

)

(Ia)

Benza midoacetone (Id) 3-A ce ta mido - 2-butanone fib) 1-Aceta mido- 2- buta ndn~(Ic) 1- Be nza mido-2- buta none (/e)

'Number of IYie lds of moles of NzH a. J mixtures of

IHzOper mole lisomeric I pvrimidine su I,I .terin,~s ,~

8,4 50 4,2 0

14 43 4~2 49

t2,6 . Traces 8,4 62

t2,7 60 i2,6 61 19,3 51 t6,8 50 16,8 61 2i 50 26,6 27 18 28 14,9 30 (IIIc) t5,9 30 t6,8 37

Ratio of 6- and q-substituted pterines (IIIa, d): (IIIb, e) (by PMR)r

I

F8 ( i l ia ~) :2 (IIIb)

8:2 5,5:4,5

7:3 7:3 8:2 9:i 9:i

>9,5:<0,5 9:t 8:2 7:3

(Hid)-3 (IIIe) 0:4

*Runs i, 2, 4, and 5 were carried out in the absence of acetic acid. Runs i, 2, 3, and 5 were carried out in one operation according to our earlier work [I], andin the other runs, ketones (la-e) were initially treated with hydrazine and then the con- densation with pyrimidine sulfate (II) was carried out. In run ii, the prior treatment of ketone (la) with hydrazine was car- ried out in the presence of catalytic amounts of acetic acid. In runs i, 2, 3, 5, 6, 8, i0, Ii, 12, and 13, N,N-diacetylam- inoacetone (IX), which is rapidly converted to (la) in aqueous hydrazine at 20~ (about 5 min), was used as a source of ketone (Ia). #PMR spectroscopy permits the detection of 25% impurity of structural isomer.

er acetone derivatives) with the more nucleophilic NHa group at C(5) of (II) and subsequent hydrazinolysis of the imine of type (Xll).

EXPERIMENTAL

The UV spectra were taken in 0.i N KOH on a Specord UV-VIS spectrometer, the IR spectra were taken in KBr pellets on a UR-20 spectrometer, and the PMR spectra were taken in i N KOH on a DA-60-1L spectrometer with TMS external standard. The thin-layer chromatography was car- ried out on Silufol UV-254 in a 7:2:1 i-PrOH-H20-NH40H system (the fluorescent spots were de- tected in UV light).

Reaction of 2,5,6-Triamino-4-hydroxypyrimidine (II) with N,N-Diacetylaminoacetone (IX) in the Presence of Diethylamine. A mixture of 0.5 g (0.0021 mole) pyrimidine sulfate (II), 0.75 gr(0.0048 mole) (IX) [3], and 1.2 ml EtaNH in i0 ml water was heated at reflux for 12 h, cooled to ~20~ acidified with acetic acid to pH ~5, and maintained at -20~ for 12 h. The precipitate was washed with water, acetone, and ether, and dried in vacuum at 100=C, A yield of 0.25 g (67%) 7-methylpterine (lllb)was obtained with Rf 0.47. UV spectrum (Amax): 251 and 358 nm. PMR spectrum (6, ppm): 2.60 s (CHa), 8,27 s (C(6)-H). IR spectrum (v, cm-1): 700, 735, 821, 890, 980, 1038, 1131, 1182, 1241, 1293, 1320, 1380, 1429, 1470, 1523, 1550, 1640, 1690, 1730, 2760, 2855, 3070, and 3265. An independently prepared sample of 7-methylpterine (lllb) [2, 4] had the same characteristics.

Reaction of (II) with 3-Acetamido-2-butanone (Ib) in the Presence of Et2NH: A mixture of 0.74 g (0.0031 mole) pyrimidine sulfate (II), 1 g (0.0077 mole)(Ib) [5], and 1,8 ml Et2NH in I0 ml water was heated at reflux for 12 h, cooled, and acidified with acetic acid to pH 5-6. The precipitate was washed with water, acetone, and ether, and dried in vacuum at 100~ A yield of 0.36 g (61%) 6,7-dimethylpterine (lllc) was obtained with Rf 0.48. UV spectrum (%max): 250 and 357 nm. PMR spectrum (6, ppm): 2.62 s (CHa). IR spectrum (~, cm-~): 690,

1238

722, 740, 820, 870, 990, 1020, 1075, ii00, 1180, 1219, 1270, 1285, 1365, 1390, 1420, 1445, 1475, 1520, 1550, 1572, 1640, 1690, 1725, 2780, 2850, 3080, 3220, and 3270. An independently prepared sample of 6,7-dimethylpterine (IIIc) [6] had the same characteristics.

Reaction of (II) withl-Benzamido-2-butanone (Ie) in the Presence of Et2NH. A mixture of 0.5 g (0.0021 mole) pyrimidine sulfate (II), 0.8 g (0.0042 mole) (Ie) [7], and 2.2 ml Et2N1 ! in i0 ml water was heated at reflux for 29 h and after treatment as discussed above, 7-ethyl- pterine (IIIe) [8] was obtained which was purified by dissolving in 0.5 N NaOH and subsequent acidification with acetic acid to pH 5. A yield of 0.23 g (67%) (IIIe) was obtained with Rf 0.53. UV spectrum (l~mx): 251 and 358 nm. PMR spectrum (~, ppm): 1.40 t (CH3), 2.88 q (CH2), and 8.27 s (C(6)-H). IRspectrum (~, cm-1): 700, 720, 735, 820, 827, 868, 965, 998, 1050, 1130, 1180, 1199, 1232, 1295, 1310, 1420, 1465, 1520, 1550, 1630, 1692, 1733, 2770, 2850, 2945, 2980, 3160, 3270, and 3470.

Reaction of (II) with N,N-Diacetylaminoacetone (IX) in the Presence of Hydrazine. A mixture of 1.5 g (0.0095 mole) (IX), 4 ml (0.07 mole) 88% N2H4.H20, and 0.i ml acetic acid in i0 ml water was heated at reflux for 4.5 h, and then 1 g (0.0042 mole) pyrimidine sulfate (II) was added, and the mixture was stirred for 3 h at 20~ and acidified with acetic acid to pH6. The mixture was then heatedat reflux for 6.5 h. After cooling at 20~ precipitate was washed with water, acetone, and ether, and dried in vacuum at 100~ A yield of 0.45 g (61%) 6-methylpterine (IIIa) was obtained with Rf 0.47. UV spectrum (%max!: 252 and 363 nm. PMR spectrum (~, ppm): 2.77 s (CH3), 8.52 s (C(7)-H). IR spectrum (~, cm- ): 680, 730, 770, 826, 865, 915, 953, 1008, 1059, 1138, 1185, 1248, 1299, 1310, 1340, 1357, 1400, 1445, 1490, 1540, 1585, 1615, 1670, 1705, 2740, 2802, 2837, 2935, 3180, and 3260. An independently pre- pared sample of 6-methylpterine (Ilia) had the same characteristics [2, 4].

The condensation of (II) with 3-acetamido-2-butanone (Ib) and benzamidoacetone (Id) was carried out analogously. 6,7-Dimethylpterine (lllc) and a mixture of 6- and 7-methylpterines (Ilia) and (lllb) were obtained, respectively (see Table i, runs 14 and 16).

Reaction of (II) with l-Acetamido-2-butanone (Ic) by the Action of Hydrazine, A mix- ture of 0.54 g (0.0042 mole) (Ic) [7] and 1.9 ml (0.033 mole) 88% N2H~.H20 in i0 ml water was heated at reflux for 3.5 h and then 0.5 g pyrimidine sulfate (II) was added; the mixture was stirred for 2 h at 20~ and then acidified to pH 5 with acetic acid and heated at reflux for 5 h. After the usual treatment, 0.12 g (30%) of a mixture of 6- and 7-ethylpterines (llld and e) [8] was obtained with Rf 0.53. UV spectrum (%max): 252 and 360 nm. PMR spec- trum (~, ppm): 1.40 t (CH3), 2.88 q (CH2), 8.27 s (C(6)-H), and 8.50 s (C(7)-H), with integral intensity ratio 3:2:0.3:0.7. IR spectrum (~, cm-1): 677, 720, 735, 792, 825, 861, 942, 999, 1055, 1130, 1181, 1246, 1293, 1370, 1418, 1488, 1540, 1625, 1690, 1726, 2800, 2850, 2880, 2940, 2980, 3150, and 3266.

Reaction of (II) withl-Benzamido-2-butanonebytheActionof Hydrazine. (Ie~ A mixture of 0.5 g (0.0026 mole) (le), 2 ml (0.035) 88% N2H4-H20, and two drops of acetic acid in 5 ml water was heated at reflux for 12 h in the presence of activated charcoal. After cooling to 20~ and filtration of the charcoal, the filtrate was stirred for i0 min with 0.5 g (0.0021 mole) pyrimidine sulfate (II) and then acidifiedwith 2ml acetic acid and heated at reflux for 5 h. After usual work-up, a mixture of 0.15 g (37%) 6- and 7-ethylpterines (llld and e) was obtained in 6:4 ratio.

CONCLUSIONS

7-Substituted pterines are formed in the condensation of N-acyl-a-aminoketones with 2,5,6-triamino-4-hydroxylpyrimidine in aqueous solution by the action of diethylamine, while a mixture of isomeric 6- and 7-substituted pterines with the predominance of the 6-isomer is obtained by the action of hydrazine and acetic acid.

LITERATURE CITED

i. S.I. Zav'yalov, T. K. Budkova, and G. I. Ezhova, Izv. Akad. Nauk SSSR, Ser. Khim., 2811 (1977).

2. W~ Pfleiderer, H. Zondler, and R. Mengel, Lieb. Ann. Chem., 741, 64 (1970), 3. S.I. Zav'yalov, I. F. Mustafaeva, and N. I. Aronova, Izv. Akad. Nauk SSSR, Ser. Khim.,

2091 (1973). 4. C.B. Storm, R. Shiman, and S. Kaufman, J. Org. Chem., 36,13925 (1971). 5. S.I. Zav'yalov, N. I. Aronova, and N. N. Makhova, in: Reactions and Research Methods

for Organic Compounds [in Russian], Vol. 22, Khimiya (1971), p. 9.

1239

.

7. 8.

F. Sachs and G. Meyerheim, Bet., 41, 3957 (1908). S. I. Zav'yalov and G. I. Ezhova, Izv. Akad. Nauk SSSR, Ser. Khim., 1044 (1979). J. Mirza, W. Pfleiderer, A. D. Brewer, A. Stuart, and H. C. S. Wood, J. Chem. Soc., C, 437 (1970).

SYNTHESIS AND SOME PROPERTIES OF 8,y-UNSATURATED 6-SULTONES

A. V. Semenovskii,* E. V. Polunin, I. M. Zaks, and A. M. Moiseenkov

UDC 542.91:547.315.2:547.368

In the present article, we examine the synthesis and Some properties of ~,y-unsaturated ~-sultones (II) with the aim of converting these compounds into cis-trisubstituted olefins. The first representative (lid) was obtained by the action of dioxanesulfotrioxide (O(CH2)40- SOs) on dimethylbutadiene (Id) [i]. The isoprene representative (llc) and its analog (lid) were recently isolated in our laboratory [2] from the mixture of compounds formed in the dis- proportionation of SOa in the presence of the corresponding 1,3-dienes (Ic and d). In this process, the cyclosulfonate (llc), similar to (lid), is obtained in good yield from isoprene (Ic) and dioxanesulfotrioxide [2]. The latter was found to convert divinyl (la) and piperyl- ene (Ib, mixture of isomers) to the corresponding sultones (lla and b). Dioxanesulfotrioxide was found the most suitable reagent of the usually recommended donor--acceptor SOs complexes [3] and the less common hexafluoromethylketenalsulfate type compounds which we have tested for the sulfonation of olefins [4]. In all cases studied, the cyclosulfonation is accompan- ied by the competing cationic oligomerization of the dienes, primarily of divinyl (la). The dominant factor which determines the yield of sultones (II) is carrying out the reaction from --20 to 0~ which is in accord with the observation that only dienesulfonic acids are formed from the same starting compounds at higher temperatures [5].

The asymmetrical dienes (Ib) and (Ic) react regiospecifically, yielding the correspond- ing sultones (lib) and (llc). This finding is in accord with consideration of the reaction as anonsynchronous dipolar [2 +4] cycloadditions [I, 2, 6] with the intermediate zwitterion (lllb and c), whose structure is determined by the polarization of the double bonds in the starting molecule (Ib and c) (see the work of Grummitt et al. [7]).

The structure of sultones (lla and b) was confirmed spectrally: the IR spectra feature intense bands in the region from 1200 to 1400 cm-* characteristic for cyclosulfonates: a CH2S proton multiplet is present in the PMR spectra of all four sultones (II) in the region from 3.5 to 4.8 ppm and a vinyl proton multiplet at from 5.5 to 5.8 ppm is present in the spectra of (lla-c).

Sultones (II) are thermally and chemically labile compounds. Thus, (llc) is stable for several months at 0-5~ but half decomposes in ~20 min at I05~ and vigorous exothermic de- composition occurs at I09-II0~ The presence of isoprene (Ic) in the products of this reac- tion indicates a thermal retro [2 + 4] process which is supported by the isolation of adduct (IV) with maleic anhydride (MA).

Sultone (IIc) is sensitive to the action of acids and, in particular, of bases and read- ily undergoes opening by the action of hydroxyl-containing nucleophiles (see the work of Bord- well et al. [I]). Hydrolysis and methanolysis yield sulfonic acids (V) and (VI) as Z and E

�9 ~ ' -~.-e R, R ' q / e

~(I) [I!) t i l l)

R = R I = R 2 = H (a); R = R I = H , RS=Me (b); R=Me, R1=RI=H (c); R=R*----Me, R~=H (d>

*Deceased.

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow. Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1327-1331, June 1979. Original article submitted January 17, 1978.

1240 0568-5230/79/2806-1240507,50 �9 1979 Plenum Publishing Corporation