CHEMISTRY OF NITROALKANES LXXXIII 1 *

Transcription

1 Tetrahedron. Vol. 25, pp to Pergamon Press Printed in Great Britain CHEMSTRY OF NTROALKANES LXXX 1 * HETEROCYCLC DERVATVES OF METHAZONC ACD. FORMATON OF 5-NTRO-l,2,3,4-TETRAHYDROPYRMDNE DERVATVES H. DABROWSKA-URBAŃSKA nstitute of Organic Chemistry, Polish Academy of Sciences, Warsaw 42, Poland A. R. KATRTZKY School of Chemical Sciences. University of East Anglia. Norwich, England and T. URBAŃSK Warsaw nstitute of Technology (Politechnika), Warsaw 10, Poland. (Received in the UK 22 October 1968 ; accepted for publication 28 October 1968) Abstract The derivative produced by the reaction of methazonic acid with p-chloraniline reacts with formaldehyde and primary amines to form 1,3-disubstituted 5-nitro-l,2,3,4-tetrahydropyrimidines. These are readily transaminated at the 1- or 1,3-positions by warming with primary amines. Transamination involves (1) ring opening with loss of a mole of formaldehyde to form a SchifTś base zwitterion, (2) replacement of the amine forming the SchifTs base, and (3) reclosure of the ring by formaldehyde. OUR researches on the formation of heterocyclic systems from primary nitroparaffins, formaldehyde and amines, 2 are now extended to methazonic acid (). 3 Compound is an oxime as well as a primary nitroparaffm which could lead to products more complicated than previously. To avoid the instability of methazonic acid, we used the derivative (), obtained by reaction with p-chloroaniline. 4 Spectroscopic properties of related compounds 5 " suggest revision of the originally proposed SchifTs base structure (S) to a nitroenamine with (cf. also Ref. 5b) resonance structures HE NCH 2CH=N0H NCH 2CH=N^4 Л-С1 S NCH=CHNH^^KC1 ' N=CH-CH=NHA^JbCl HE S z (enamine) and Sz (Schiffs base zwitterion), and this is confirmed by the NMR spectra, see below. Nitroolefins do not normally undergo aldol reactions with formaldehyde, 6 but the enamine function could modify this behaviour. ndeed, reacted with formaldehyde in aqueous ethanol at ph of ca. 8 to yield the carbinol (lia) together with * Also considered as Part XXX in the series "Applications of Proton Magnetic Resonance Spectroscopy to Structural Problems." 1617

2 1618 H. DABROWSKA-URBAŃSKA, A. R. KATRTZKY and T. URBAŃSK a little of the 1,2,3,4-tetrahydropyrimidine (Va). The origin of the cyclized product (Va) can be explained by partial hydrolysis of lia to give p-chloroaniline which then reacts with more lia and formaldehyde to yield Va. Although direct evidence is not available, diamine Va is probably an intermediate ; the conversion (lia -* Va) may involve either dehydration followed by a Michael addition, or fission of lia back to followed by a Mannich reaction. :=сн NH-(/ v- ( N-C=CH-NH-R 0,N-C=CH-NH-(7 7~С1 CH 2 OH CH,NHR V lia: R = p-cl C 6 Va: R = p-cl C 6 llb: R = Me Vb: R = Me Vc: R = Et Vd : R = CH,Ph 0,N s C 6 C1<>) N ^R V Va: R = p-cl-c 6 Vb: R = Me Vc: R = Et Vd: R = CH 2 Ph Treatment of the nitroolefin () with formaldehyde and the appropriate primary amine gave the four 5-nitro-l,2,3,4-tetrahydropyrimidines (Va-Vd). The yield was highest when the molar proportions of, formaldehyde, and the amine were 1:3:2 These reactions may be of the Mannich type or they may involve the formation of the carbinol (lia). As expected lia also reacts with formaldehyde and the amine in the proportions 1:2:2 to give products of type V. V: R = R' Via: R = R' = Me Vb: R = R' = CH,Ph V Vila Vllb R # R' R = Et, R' = Me With amounts of the amine larger than 2 molar, transamination products (V) were formed in addition to V; with formaldehyde and benzylamine in boiling ethanol also gave both Vb and Vd. Transmination of preformed 5-nitrotetrahydropyrimidines (V -» V) occured on treatment with various amines (see Scheme 1). The substituents at position 1 or at both positions 1 and 3 were changed depending on the amine used and the temperature : as a rule, both substituents were replaced in boiling ethanol. We did not examine closely the transaminating ability of amines, but the 1,3-dibenzyl derivative (Vb) was formed particularly readily when benzylamine was used. Transaminations also occur with the amines formed by fission of the original tetrahydro pyrimidine

3 Chemistry of nitroalkanes LXXX 1619 (V). Thus, heating Vb in boiling ethanol (basified with triethylamine to ph 8), rearranges Vb into Va (a type of "semi-disproportionation"). Boiling Vd in ethanol and methylamine gave some Vb by a similar "semi-disproportionation", although at 20 the intermediate product Vllb was formed. С 6 Н 4 -С1(/>) SCHEME 1 C 6 Cl</>> Vllb Reaction mechanisms. Carbinol lia was transaminated by heating with ethanolic methylamine to give p-chloroaniline and the new carbinol Hb which reacted with formaldehyde and various primary amines to form 5-nitro-l,2,3,4-tetrahydropyrimidines (V). We did not succeed in transaminating compound by any of the methods successful with compounds V-V. Transaminations of carbinols of type are analogous to the well-known properties of SchifTs bases. 7 Compound is mesomeric with enamine (HE) and SchifTs base zwitterion (Sz) canonical forms.

4 1620 H. DABROWSKA-URBANSKA, A. R. KATRTZKY and T. URBAŃSK 0,N-C=CH NHR CH,OH ШЕ 0,N = C-CH=NHR CH.OH Sz n anhydrous media, the tetrahydropyrimidines (V) form hydrochlorides, these are readily hydrolyzed by water to formaldehyde and the diamine hydrochlorides (V). The latter reform the tetrahydropyrimidines by treatment with formaldehyde at ph 8 (cf. Scheme 2). The hydrochloride (V) gives an N-nitroso compound (V) with sodium nitrite. SCHEME 2 C 6 -Cl(/>) N. N N H \ C 1 " Ç 6 Cl(p) JH H Jl *NH 2 C' O j N " ^ ^ \ NaNO, N C 6 CH/>) N H R NO V The novel transaminations of the hydropyrimidine derivatives (V-V) probably involve preliminary ring opening of these tautomeric N-p-chlorophenyl-N'-alkyl (or aralkyl)-2-nitro-l,3-diaminopropenes, where each of the two enamine forms (VEa, b) is mesomeric with a Schiffs base zwitterion (VSza, b) contributing to the resonance hybrid. Each tautomer can react with amines at the C=N + HR group and thus transamination can occur successively at both positions 1 and 3. The formulae (VEa, b and VSza, b) also illustrate the possible formation of potentially tautomeric cyclic products (V) ; the double bond shift in V is of a different type from the known tautomerism of enamines. 8 N-C=CH NHR CH.NHR VEa N-C -CH, NHR CHNHR' VEb O' :N=C-CH=NHR CH.NHR VSza o; o"' = C-CH,-NHR CH=NHR VSzb

5 Chemistry of nitroalkanes LXXX 1621 Spectroscopic proof of structure. Nitroolefins do not normally undergo aldol reactions with formaldehyde 6 which seemed originally to indicate addition to the primary nitro group of Sz to give the hypothetical diol (X) converted by a primary amine to an azetidine (X), which was transaminated by R'NH 2 to yield compounds of type X and X. However, the diol (X) could not be isolated, and firm evidence for the tetrahydropyrimidine structure was later obtained from ultraviolet and NMR spectra. N^ /CH=NC 6 -Cl(/>) HOH 2 C / ^CH 2 OH X N. CH=NC 6 CK/» N R N CH=NR R X: R Ф R' X: R = R' TABLE 1. UV SPECTRA OF DOXAN SOLUTONS Compound mu mu , ,500 lia , ,750 Va" , ,700 V , ,250 Va 254, ,100 Vb 250, ,500 Vd , ,750 Via 220* с ,210 Vb 220* с ,900 " Hydrochloride b n n-hexane Not determined owing to the low solubility in n-hexane.

6 1622 H. DABROWSKA-URBAŃSKA, A. R. KATRTZKY and T. URBAŃSK UV spectral data are recorded in Table 1. Compounds, lia, Va and V, which all contain the p-chlorophenyl group, show two band spectra almost identical with those of the ring compounds (Va-d) containing the same substituent in position 1 (or both 1 and 3) (Fig. 1). The bands are hypsochromically shifted in Via and Vb which do not contain conjugated aromatic rings =21500 fa ł\\ % FG. 1 UV spectra of dioxan solutions of ( -) and Vb(x x x). n the infrared spectra (Table 2), the heterocyclic compounds V, V and V show two characteristic bands in the region cm" 1 which do not appear in the ring opened derivatives V and V, nor the acyclic starting materials. We assigned these bands to tetrahydropyrimidine ring stretching modes. The other bands agree with the suggested structures. The nitro symmetric and asymmetric modes occur at the lower frequencies characteristic for conjugated systems. The NMR spectrum of (Fig. 2) clearly indicates the olefinic structure. The tetrahydropyrimidine spectra (Figs 3-5) show the signals from the CH 2 groups as singlets : this is a result of rapid inversion of the rings (deformed chair ^ deformed chair). 0 ŁN-CH = C H - N H - ^ - CL a b e d a+d TMs r(pprrt) ю FG. 2 NMR spectrum of in deuteriochloroform : a, 2-72 т ; b, 3-31 т ; с 0-60 x ; d, ; J 6-5 c/s.

7 Chemistry of nitroalkanes LXXX 1623 >у is 2? U e e o o -3-1Л!Л 1Л [A V) 1Л V) У1 (Я >>>>>>> O v D O l N Q O O O ^ ^ O ( N O N - - N r O N C f O i r i - O f N f N r n f N n i N l N r n t N - H И!/1 И И И W > > > > > > О С М т ч т ^ г ^ ^ - а ч О _ ( N M f N f N r S M M m i m N s o\ S 8 8 <fl И (Л в е в e O O O O O O O O O Q O O O O O Q r - 88 >л <л E и и и Vi (Л (Л (Л (Л В в 8888S И И (Л (Л > > > > > > О О О О О О О v> «n m О <N «n «*п. ЧО «Л V) «Н чочочочочочочочочочо ч ч ч ч ч ЧО чо S3 U и О " OO»-H <N ON JO гч Os 0Й ръ -В > > ГЧ (N os \ гч гч > * * s > > О О О гч ГЧ ГЧ О О О m m m 8 VO Os Os ГЧ СЧ * > * m ч o o GO OS OO ГЧ in SO О О О О О О О г m г г г m г О m vo ON Os Os гч гч О "* ГЧ О О ГО ГО с N С е е е * е в е i n O O O O O m O O 0N(N04OOt>000vO ON ON in in члч01п«п»п1п*п1п»л i*» S * * 5t ОС ОС 'Л N (N "Л (N П (N (N (N ГЧ n-, m m m m m в г- (N S E ta з. е Я Л "D м H S > > > >>>>>>> я и X ca. Я К > > > > О ТЗ i i i i i i < i

8 1624 H. DABROWSKA-URBAŃSKA, A. R. KATRTZKY and T. URBAŃSK («1 Ç 6Cl * 1- < ( t Tlppm) FlG. 3 NMR spectrum of Vb in deuteriochloroform:a, 1-57 T; b, 5-55 r; c, 6-09 T; d, 7-47 x; e, т. (f) Ç 6 Cl (а)н-с^сн2 (Ы l O 2 N-C^ >-CH 2 -C 6 H5 (d) (c) CH (C) 2 T M S -4-4 T(ppm) 2 10 L 4 NMR spectrum of Vd in deuteriochloroform: a, 1-55 t; b, 5-62 T; c, 6 06 T; d, 6-32 T; e, 2-73 т; f, т.

9 Chemistry of nitroalkanes LXXX 1625 (f) FG. 5 NMR spectrum of Vila in deuteriochloroform: a, 1-91 т; b, 5-92 т; с, 615 т; d, 7-39 т; e, 8.84 т; f т. EXPERMENTAL M.ps, crystal shapes and analytical data are collected in Table 3. Mol wts were determined by the ebulliometric method of Swietoslawski in benzene or dioxan as solvents. Water of crystallization was determined by the Karl Fischer reagent. Spectroscopy. UV spectra were obtained with a Unicam SP-700 spectrophotometer in cuvettes of 1 cm with dioxan or n-hexane as solvents. R spectra were recorded for nujol mulls or KBr discs with Unicam SP-200 and Hilger 800 spectrophotometers fitted with a NaC prism. NMR spectra were recorded on a Varian 4300-C (generator frequency 60 MHz) in deuteriochloroform or deuterioacetone with TMS as internal standard. ^^p-chlor<mhenyl)amino-2-hydroxy-2-nitromethylethylene(ula.) Compound lia was obtained from methazonic acid and p-chloroaniline, J m.p (lit.* 165 ). Compound Ha (3-9 g, 0 02 molx EtOH (60 ml), and aqueous 27% formaldehyde (20-4 ml, 0-2 mol), were mixed and brought to ph ca. 8, with Et 3 N or 2% NaOHaq. After 12 hr the nitroenamine lia (3-8 g, 84%) separated. t crystallized from EtOH or nitromethane and is soluble also in acetone and (sparingly) in water. After 24 hr the by-product Va (0-04 g. 1%) crystallized, see below. 1-Substituted 1,2,3,4-tetrahydro-1 Ąp-chlorophenyly-b-nitropyrimidines (V). Method \,from Ha. Aqueous (27%) formaldehyde (15-4 ml, 015 mol) and the appropriate primary amine (01 mol) (mcthylamine, ethylaminc, p-chloroaniline or benzylamine) was added to Ha (9-9 g, 005 mol) suspended in EtOH (120 ml) (or MeOH for the preparation of Vc). For Va and Vd it was necessary to basify the mixture with Et,N to ph ca. 8. The soin was stirred for 1 hr, left for 10 hr, and the resulting ppt recrystallized ; Vb and Vd from EtOH, Vc from MeOH and Va from benzene. The yields were 81-84%. Method 2,/rom lia. To a suspension of lia (1 14 g, mol) in EtOH (15 ml) aqueous (27%) formaldehyde (102 ml mol) and a primary amine (001 mol) as in method 1, were added. The mixture was heated on a steam-bath until the solid dissolved, and was kept 10 hr at 20'. The ppts were crystallized as in method 1. The yields were 60-75%.

10 1626 H. DĄBROWSKA--URBAŃSKA, A. R. KATRTZKY and T. URBAŃSK я X - rn Ô\ <Ь rt *H <N ~н *8 Z os^r--mot7-r^v^(n^oooofn-h40 u m m (N h Ю ГП ГО Tt 5 N 0\ гл ós à\»-н СО ГЧ C7\ ^ ^ 10 ^ OO СО y Ó ГЛ '«f n t 4 О V"t in u- s e Ю OO fn OO ^ VD ON СО СО rf ^ (N Ю vi = 4J Л CX - O U U m х ООО, ~ /*\ r*i с-) >7 м w n m m «À' «o Z П Zł! «o"ss z^zzzzz Z U и X "-^ *.,,. i «la,. M O U U U U O U U U U U C J C J U U U O U в в > > > и ж X >>>>>>>>>> > > и

11 Chemistry of nitroalkanes LXXX 1627 The tetrahydropyrimidines V form bright yellow crystals, readily soluble in benzene, chloroform and dioxan, and sparingly soluble in water. 2-Hydroxymethy-1 -N-methylamine-2-nitroethylene ( lb) Aqueous MeNH 2 (40%, 1-5 g, 002 mol) was added to a suspension of lia (2-28 g, 001 mol) in EtOH (15 mol). The yellow enamine Hlb (1-2 g, 90%) soon crystallized. \2,3,4-Tetrahydro-\,3-dimethyl-5-nitropyrimidine (Via). Aqueous formaldehyde (27%, 0-4 ml, 0004 mol) and aqueous MeNH 2 (40%, 0-3 ml, 0004 mol) were added to a suspension of Hlb (0-26 g, 0002 mol) in EtOH (5 ml). The mixture was heated on a steam-bath until the solid dissolved, then left at room temp for a few hr. The product Via separated and was recrystallized from MeOH or EtOH, m.p (01 g, 30%). Transamination of the tetrahydropyrimidines V, V and V 1. Reaction o/vb or Vd with methylamine. Aqueous MeNH 2 (40%, 1-5 ml, 002 mol) was added to a suspension of Vb or Vd (001 mol ; 2-5 g or 3-3 g, respectively) in EtOH (30 ml). The solid dissolved rapidly and immediately a yellow product, Via (1-5 g, 90%) or Vllb (1-95 g, 85%) precipitated. 2. Reaction of Ус or Va with methylamine. Aqueous MeNH 2 (40%, 1-5 ml, 0 02 mol) was added to a suspension of Vc or Va (2-67 g, and 3-5 g respectively, 001 mol) in MeOH (30 ml). For Va the mixture was refluxed for 45 min. When the solid had dissolved, the solvent was evaporated at 20 and ether was added. Yellow crystals of Vila (1-2 g, 70%) or Via (0-4 g, 50%) resulted. 3. Reaction o/vb with p-chloraniline. p-chloroaniline (1-27 g, 001 mol) was added to a suspension of Vb (1-26 g, mol) in EtOH (15 ml) and the whole made alkaline with Et 3 N to ph ca. 8, and refluxed for 30 min. Two products (Vb and Va) were detected by TLC; the latter was isolated by its lower solubility. 4. Reaction of Va, Vd, Via or Vllb with benzylamine. Benzylamine (002 mol) was added to a suspension of Va, Vd, Via or Vllb (001 mol) in EtOH. With Va, Via and Vllb, the mixture was refluxed for 30 min, but with Vd the reaction occurred at room temp. After cooling, yellow crystals of Va, Vd, Vllb (70-90%) or Via (15%) were collected. 5. Reaction o/vb in basic medium. A suspension of Vb (1 g) in EtOH was brought by Et 3 N to ph ca. 8 and refluxed for 40 min. After cooling, the product (0-8 g) was collected and identified as Vb with a smaller amount of Va by TLC. 6. Reaction o/vd with an excess of methylamine. A suspension of Vd (0-66 g, 0002 mol) in MeOH and aqueous MeNH 2 (40%, 1-5 ml, 0-02 mol) were refluxed for lj hr. The product, Vb (005 g, 25%) was collected. Hydrochlorides of the tetrahydropyrimidines V and V Compounds Vb, Vc or Via (1 g) were kept overnight in anhyd EtOH and ethereal HC (5 ml). Light yellow hydrochlorides of Vb or Vc, or the colourless hydrochloride of Via were collected (yields 11 g, 1-1 g and 1-2 g respectively). The hydrochloride of Via was recrystallized from MeOH, the others could not be purified by crystallization because of low solubility, rapid decomposition when heated, and easy hydrolysis. To the suspension of hydrochloride Vb, Vc or Via (00025 mol) in EtOH, NHC0 3 aq (0005 mol) was added, slightly warmed and filtered : Vb. Vc or Via precipitated. Hydrolysis of the tetrahydropyrimidines V Compound Vb, Vc or Vd (1 g), EtOH (15 ml) and cone HC (0-3 ml) were boiled until the solid dissolved. The hydrochlorides Vb, Vc or Vd resulted (yields 0-7 g, 64%; 0-8 g, 75%; 0-6 g, 53%, respectively), and were crystallized from EtOH. Reaction of the diamine hydrochloride Vb with sodium nitrite Saturated NaN aq (0-5 g) was added to the soin of Vb (0-9 g) in water (30 ml). A crystalline yellow ppt of V (0-7 g) was collected. t gave a positive Liebermann test. Reaction of the diamine hydrochlorides V with formaldehyde Aqueous formaldehyde (27%, 102 ml, 001 mol) was added to a suspension of hydrochlorides Vb, Vc or Vd (0 005 mol, 1-4 g and 1-85 g respectively) in EtOH, and NaHC0 3 aq or Et 3 N was added to ph ca. 8. The products were identified as Vb. Vc or Vd (yields 1 g. 11 g and 1-4 g. respectively; ca. 85%). Acknowledgements The authors are much indebted to Miss S. Kwiatkowska, M.Sc. for measuring the UV spectra, to Dr. U. Dąbrowska for measuring the R spectra, and to Drs.. Dąbrowski and M. Witanowski for help in interpreting the NMR spectra.

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