1368 D. Lloyd, C. Reichardt, and M . Struthers

Liebigs Ann. Chem. 1986, 1368- 1379

Experiments towards the Preparation of 6-Hydroxy-, 6-Methoxy-, and 6-(Hydroxyphenyl)-2,3-dihydro-1,4- diazepinium Salts and 1,2-Dihydr0-5-(hydroxyphenyl)-2- oxopyrimidinium Salts

Douglas Lloyd * ’, Christian Reichardt * b, and Margot Struthersa,b,‘)

Department of Chemistry, Purdie Building, University of St. Andrews ‘, St. Andrews, Fife, Scotland, KY16 9ST

Fachbereich Chemie der Universitat Marburgb, Hans-Meerwein-StraDe, D-3550 Marburg

Received February 4, 1986

The preparation of a number of 2,3-dihydro-6-(hydroxyphenyl)-1,4-diazepinium salts (11 c -f) and of 1,2-dihydro-5-(hydroxyphenyl)-2-oxopyri1nidinium salts (17a, b) from 3-(hydroxypheny1)vinamidinium salts (10 b, c) is described. Attempted preparation of a 3-(2- hydroxypheny1)vinamidinium salt gave instead a mixture of formyl-substituted benzofura- nones (15 and 16). Attempted preparation of 2,3-dihydro-6-hydroxy-1,4-diazepinium salts (1 a-c) provided products other than diazepinium salts, but 2,3-dihydro-6-methoxy-1,4- diazepinium salts (7a, b) were prepared.

Versuche zur Herstellung von 6-Hydroxy-, 6-Methoxy- und 6-(Hydroxyphenyl)-2,3-dihydro- 1,4-diazepinium-Salzen sowie von 1,2-Dihydro-5-(hydroxyphenyl)-2-oxopyrimidinium-Salzen

Die Herstellung einiger 2,3-Dihydro-6-(hydroxyphenyl)-1,4-diazepinium-Salze (11 c - f) und 1,2-Dihydro-5-(hydroxyphenyl)-2-oxopyrimidinium-Salze (17a, b) ausgehend von 3-(Hy- droxypheny1)vinamidinium-Salzen (10 b, c) wird beschrieben. Versuche zur Herstellung eines 3-(2-Hydroxyphenyl)vinamidinium-Salzes fiihrten stattdessen zu einer Mischung formylsub- stituierter Benzofuranone (15 and 16). Versuche zur Darstellung von 2,3-Dihydro-6-hydroxy- 1,4-diazepiniumsalzen (1 a - c) ergaben anstatt der gewiinschten 1,4-Diazepiniumsalze andere Produkte; 2,3-Dihydro-6-methoxy-1,4-diazepinium-Salze (7a, b) konnten jedoch erhalten werden.

Little attention has been paid to hydroxy-2,3-dihydro-1,4-diazepinium salts. Attempts have therefore been made to prepare 6-hydroxy and phenylogous 6-(hydroxyphenyl) derivatives and also a 1,2-dihydro-5-(hydroxyphenyl)-2-oxopy- rimidinium salt since the latter heterocyclic ring has a vinamidinium system’) similar to that present in the 2,3-dihydro-1,4-diazepinium ring.

2,3-Dihydro-6-hydroxy-l ,rl-diazepinium Salts 1 A large variety of substituted 2,3-dihydro-l,4-diazepinium salts has been in-

vestigated3’ but only one example of a hydroxy derivative has been described, namely the 6-hydroxy-1,4-diphenyl derivative 1 a, which was prepared by Eistert

0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1986 0170-2041/86/0808 - 1368 $ 02.50/0

6-Hydroxy-2,3-dihydro-1,4-diazepinium and Pyrimidinium Salts 1369

and Haupter') from hydroxymalonaldehyde and 1,2-bis(phenylamino)ethane in methanolic perchloric acid.

l a - c 2 a-c

Because of this dearth of information about the hydroxy derivatives 1, of their possible deprotonation to new zwitterionic vinamidinium systems 2, and of our interest in chemistry involving hydroxymalonaldehyde (triose-reductone)') and other substituted malonaldehydes6), it seemed worthwile to investigate the prep- aration of other hydroxy-diazepinium salts such as 1 b, c.

Reaction of hydro~ymalonaldehyde~) or its bis(diethy1 acetal)') with 1,2-diami- noethane in methanolic perchloric acid, designed to give 1 b, provided no tractable organic product. 1,2-Bis(methylamino)ethane gave no identifiable product with the bis(diethy1 acetal) but with hydroxymalonaldehyde itself, in the presence of methanolic perchloric acid, produced colourless needles of a product whose ele- mental analysis was consistent with structure l c , but whose NMR spectra could not be reconciled with a symmetrical 1,4-diazepinium structure l c . Instead of l c , the six-membered 2,3,4,5-tetrahydro-5-(hydroxymethylene)-1,4-dimethylpyrazin- ium salt 3a has unexpectedly been formed, i. e. the hydroxymalonaldehyde has reacted as a 1,2-bifunctional and not - as expected - as a 1,3-bifunctional com- pound.

The tetrahydropyrazinium structure of 3a derives from the following experimental results: (a) Two N-methyl signals appear in both the 'H and "C NMR spectrum. Altogether, the 'H NMR spectrum of 3a in [D6]DMS0 exhibits five signals for its twelve protons at room temperature, whereas l c should give only three signals (with the exception of the OH-signal, not available under these conditions due to its broadness)*! - (b) The IR spectrum exhibits a strong absorption band at 1650 cm ', characteristic of a (protonated) aldehyde carbonyl group. - (c) The mass spectrum shows a peak at in/z = 140, characteristic of the ion (M+ - HC104). - (d) An analogous tetrafluoroborate salt 3b was obtained when the re- action was carried out using HBF4 instead of HC104, giving the same peak at m/z = 140 in its mass spectrum, 1. e. the cation formed remained the same. - In order to confirm the structure of 3a unequivocally, an X-ray analysis of 3a has been tried to carry out'). However, unexpected difficulties have prevented a final solution up to now9).

Attempted preparations of 1 a - c from the corresponding 1,2-diaminoethanes and the bis(diethy1 acetal) of hydroxymalonaldehyde') provided only in the case

*' Note Added in Proqf(Ju1y 2, 1986): Furthermore, application of the DEPT technique, including fully coupled DEPT spectra, confirms the presence of two methyl, two me- thylene, two methine, and one quaternary carbon atoms as well as the assignment of the relevant signals, which are completely in accord with the presence of a 5-aza-1-oxapen- tadienium system in 3a,b; cf: also D. Lloyd, H . McNah, and D. R. Marshall, J. Chem. SOC., Perkin Trans. 1, 1978, 1453.

Liebigs Ann. Chem. 1986

1370 D. Lloyd, C . Reichardt, and M. Struthers

of 1,2-bis(phenylamino)ethane an isolable product, which again is not a 1,4-di- azepinium salt. From its elemental analysis, melting point, and NMR spectra this product appeared to be the 1,3-diphenylimidazolium salt S'O), but it was not col- ourless, as reported, but rather formed dark green, almost black, needles.

R L I I I I OH

[Ivn . .. . + E t O e E i L EtOH

R

R. H

LC6H5 H-""

0 CIO, 4 Not isolated

XQ

68 % traces

5 6

Mechanistic considerations of the formation of 5 via 4 (not isolated) lead to the assumption that it might have associated with it a small amount of the mono- methinium salt 6 and presumably also higher vinylogues of 6 which could provide the intense colouration"'.

2,3-Dihydro-6-methoxy-1,4-diazepinium Salts 7 Because of the failure of hydroxymalonaldehyde to provide 1,Cdiazepinium

salts, corresponding reactions of methoxymalonaldehyde'2) were investigated. Both 1,2-bis(methylamino)- and 1,2-bis(phenylamino)ethane provided the 6-meth- oxy-l,6diazepiniurn salts 7a, b4), but the N,W-dimethyl derivative 7a was only obtained with some difficulty and in low yield.

Liebigs Ann. Chem. 1986

6-Hydroxy-2,3-dihydro-1,4-diazepinium and Pyrimidinium Salts 1371

The observation that 6-methoxy but not 6-hydroxy derivatives were obtainable reflects the very different fine structure associated with hydroxymalonaldehyde 8a =$ 8bl3) on the one hand and methoxymalonaldehyde 914) on the other, which may in turn affect their modes of reaction in solution.

8a 8b 9

Both malonaldehydes are intramolecularly hydrogen-bonded but in different ways.

2,3-Dihydro-6-(hydroxyphenyl)-1,4-diazepinium Salts 1 1 The chemistry associated with the 6-position of 2,3-dihydro-1,4-diazepinium

salts can be transferred to the para-position of a phenyl group attached to the 6- position. Thus, dihydrodiazepinium salts are halogenated ‘ O J ~ ) and nitratedI6) at the 6-position, and the corresponding 6-phenyl derivative 11 a is brominated and nitrated at the para-position of the 6-phenyl ringI7).

Because of the difficulties encountered in preparing 6-hydroxy-dihydrodiaze- pinium salts it was decided to investigate the preparation of phenylogous 6-(hy- droxyphenyl) derivatives l l c - f , since the properties of the hydroxy groups in such compounds might give some indication of the behaviour of hydroxy groups attached directly to the 6-position of the dihydrodiazepinium ring.

?

YH CH t R

R - H,CH, 1Oa-c i l a - f

OH OH H H

Liebigs Ann. Chem. 1986

1372 D. Lloyd, C. Reichardt, and M. Struthers

Reaction of the vinamidinium salts lob-c (for their preparation see below) with either 1,2-diaminoethane or 1,2-bis(methylamino)ethane yields the 6-(4- or 6-(3-hydroxyphenyl)-substituted dihydrodiazepinium salts l l c - f as crystalline compounds in satisfactory yields (ca. 45 - 92%). For comparison (NMR spectra), the 6-phenyl-substituted dihydrodiazepinium salts 11 a and 11 b19) have been prepared analogously from the vinamidinium salt 10a2’).

The phenyl-substituted vinamidinium salt IOa was obtained by Vilsmeier reaction of phenylacetic acid with phosphorus oxytrichloride and dimethylformamide, followed by acid work-up”). The hydroxyphenyl-substituted vinamidinium salts 10 b, c were also prepared by this method using 4- or 3-hydroxyphenylacetic acid 12a, b as educts.

When Vilsmeier formylations were carried out on 12a, b, but work-up procedure involving alkali was used, the hydroxyphenyl-substituted 3-(dimethy1amino)acroleins 13a, b were ob- tained.

Hydrolysis of 13 b provided the (3-hydroxyphenyl)malonaldehyde 14 in good yield (74%), as a colourless, crystalline, stable compound, but hydrolysis of 13a resulted in the formation of a colourless powder which rapidly decomposed to a deep violet product which in turn became a black tar.

Reactions of the acroleins 13a, b or of the malonaldehyde 14 with 1,2-diami- noethane or 1,2-bis(methylamino)ethane provided an alternative method for the preparation of the hydroxyphenyl-substituted dihydrodiazepinium salts 11 c - f, but the yields obtained were lower than those starting from the vinamidinium salts lob , c.

Vilsmeier formylation of either (4-) or (3-hydroxyphenyl)acetic acid gave solid products only when the initial reaction mixture was subjected to acid or alkaline work-up, providing vinamidinium salts 10 b, c or 3-(dimethylamino)acroleins 13a, b, respectively.

On the other hand, Vilsmeier formylation of (2-hydroxypheny1)acetic acid led to the separation of a red precipitate during the course of the reaction. (2-Hydroxypheny1)acetic acid exists in solution in equilibrium with benzofuran-2(3H)-one, and consideration of the elemental analysis of the product obtained suggested that the benzofuranone might have been the species involved in formylation, leading to the benzofuran derivatives 15 and 16. No attempt was made to separate the two isomers.

One formylation has occured at thc 3-position of the furan ring and another in the benzene ring at sites ortho and para to the oxygen-linked position in the benzene ring. In work-up

Liebigs Ann. Chem. 1986

6-Hydroxy-2,3-dihydro-1,4-diazepinium and Pyrimidinium Salts 1373

the latter substituent is hydrolysed to a formyl group while the former, being part of an extended amide group, is not hydrolysed.

,OH

&CH,-COzH

flH CHO NMe2

f H

NMe,

15 16

Elemental analysis and 'H NMR spectrum are consistent with structures 15 and 16 and expansion of the 'H NMR spectrum indicates that both isomers are present, with one of them predominating. Thus, consistent with being associated with a P-aminoacrylic ester type of structure, the N-methyl groups provide two separated NMR-signals at 6 x 3.7 and 3.3. The lower field signal is a singlet but the higher field signal consists of a singlet with a much smaller singlet at its side. Similarly, the signal representing the aldehydic proton consists of a singlet flanked by a much smaller singlet. Furthermore, the complexity of the 'H NMR spectrum in the region 6 = 7.4 ... 7.7 is also in accord with the presence of a mixture of isomeric 15 and 16.

It would be expected that compounds 15 and 16 would provide similar but distinct CHO NMR-signals and that the N-methyl group directed away from the benzene ring should give superimposed signals for the two isomers whereas the N-methyl group directed towards the benzene ring would provide separated signals (see formulas 15a and 16a). A contribution from such mesomeric structures results in the non-equivalence of the two N-methyl signals of the vinylogous N,N-dimethylurethane system inherent in compounds 15 and 16.

1,2-Dihydro-5-(hydroxyphenyl)-2-oxopyrimidinium Salts 17 Using N,N'-dimethylurea instead of N,N'-disubstituted 1,2-diaminoethanes in

the reaction with hydroxyphenyl-substituted vinamidinium salts 10 b, c provided in methanolic perchloric acid the dihydro-0x0-pyrimidinium salts 17a, b as yellow, crystalline compounds in moderate yields.

y 3

+ lOb,c - /NH in H,O/CH,OH

L6 - 18 %

0-c \

Liebigs Ann. Chem. 2986

1374 D. Lloyd, C. Reichardt, and M . Struthers

The 5-phenyl derivative 17c had been made previously but from the sodium salt of phenylmalonaldehyde rather than from the appropriate 3-phenyl-vinamidinium salt 1Oa 2').

Attempted preparation of N,N-unsubstituted dihydro-0x0-pyrimidinium salts with urea itself and 10 b, c resulted in an intractable tar.

C. R. thanks the Deutschc. Forschungsyemeinschrlft and the Fonds der Chemischen Industrie for financial support. M. S. thanks the British Council for the award of a Scholarship in the Fed. Rep. Germany and the University of St. Andrews for a Research Studentship. We are grateful to Dr. H . McNah, University of Edinburgh, for carrying out the NMR-DEPT experiments.

Experimental Melting points: Kofler-Mikroheiztisch (Fa. Reicherl) and Gallenkamp apparatus, uncor-

rected. - Elemental analyses: Analytik-Servicelaboratorium of the Fachbcreich Chemie, University of Marburg, and Department of Chemistry, University of St. Andrews. - 'H NMR spectra: Bruker WP-80 spectrometer; "C NMR (with proton broad band decou- pling): Varian CFT-20 spectrometer, both with telrdmcthylsihne (6 = 0) as internal stand- ard. - Mass spectra: AEI MS-902 spectrometer, pcrfluoro-tris-n-butylamine as internal reference. - The yields for all reactions have usually not been optimised.

2,3-Dihydro-6-hydroxy-f ,I-dipltenyl-f ,I-diazepinium Perchlorate (1 a)": A solution of0.70 g (3.3 mmol) of 1,2-bis(phenylamino)ethanc and 1.00 g of perchloric acid (70%) in 10 ml of mcthanol was added to 0.20 g (2.3 mmol) of hydr~xymalonaldehyde~' in 10 ml of methanol and warmcd to ca. 60°C. When it had cooled to room temp., the precipitate was filtered off, washed with a little methanol and dicthyl ether, and recrystallised from methanol to give 0.65 g (77%) of l a as yellow needles with m. p. 197 - 198°C (Lit.4' 197°C). - 'H NMR ([D,]DMSO): 6 = 4.0 (m, broad; 4H, 2,3-H), 7.2 (m; IOH, Ph), 7.9 (s; 2H, 5,7-H), OH- signals not observcd. - "C NMR ([D,]DMSO): 6 = 56.1 (s; C-2,3), 122.8 (s; 0-C), 126.8 (s; i-C), 128.2 (s; p-C), 129.9 (s; m-C), 144.9 (s; C-6), 149.1 (s; C-5,7). - MS (70 eV): mjz =

265 (Mi - CIO4). CI7Hl7C1N2O5 (364.8) Calcd. C 55.97 H 4.70 N 7.68 Found C 56.11 H 4.52 N 7.59

2,3,4,S-Tetrahydro-5- (hydroxymethy1ene)- 1,4-dimrthylpyrnzinium Perchlorate (3a): A so- lution of 0.30 g (3.4 mmol) of 2,2-bis(methylamino)ethane and l .00 g of perchloric acid (70%) in 10 ml of methanol was added to 0.22 g (2.5 mmol) of hydro~ymalonaldehyde~) in 10 rnl of methanol and warmed to ca. 60°C. After being kept for 12 h at room temp., the precipitate was filtered off, washed with a little methanol and diethyl cther, and recrystallised from methanol to give 0.30 g (50%) of 3a as colourless necdles with m. p. 203-204°C. - IR (KBr): 1650 cm ~ ' (C = 0). - ' H NMR ([D,]DMSO): 6 = 2.9 (s; 3 H, CHI), 3.2 (s; 3 H, CHI), 3.5 (m; 4 H, 2,3-H), 7.9 (s; 1 H, 6-H), 8.8 (s; 1 H, CHOI-I); OH-signal not observed. - I3C NMR

177.5 (s; C-6). - MS (70 eV): m/z = 140 ( M + - HC104). C7HI3C1N2O5 (240.6) Found C 35.09 H 5.54 N 11.45

2,3,4,5-Tetruhydro-5-(hydroxynzethylene)-l,4-din~elk~~lpyrnzinium Tetrfluorohorate (3b) was preparcd analogously to 3a; 1.50 g of tetrafluoroboric acid (50%) was uscd, yielding 0.25 g (44%) of3b as colourless crystals with m. p. 194- 196 'C. - 'H NMR ([D6]DMSO):

6-H), 8.67 (s; 1 H, CNOH); OH-signal not obscrved. - "C NMR ([D6]DMSO): 6 = 41.26

Liebigs Ann. Chem. 1986

([DhlDMSO): 6 = 41.4 (s; CHJ, 42.8 (s; CHI), 47.6 (s; CH2), 112.9 (s; C-5), 149.9 (s; CHOH),

Calcd. C 34.94 H 5.45 N 11.64

6 = 2.89 (s; 3H, CH?), 3.20 (s; 3H, CH,), 3.38 ( t ; 2H, CH2), 3.62 (ti 2H, CHZ), 7.86 (s; 1 H,

6- Hydroxy-2,3-di hydro- 1,4-diazepinium and Pyrimidinium Salts 1375

(t; CHI), 42.65 (9; CH,), 42.74 (9; CH,), 47.48 (ti CH2), 11 3.00 (s; C-5), 149.99 (d; CHOH), 177.72 (d; C-6). - MS (70 cV): m/z = 140 (M' - HBF,).

C7H13BF4N20 (228.0) Calcd. C 36.88 H 5.75 Found C 36.98 H 5.66

f ,3-Diphenyliw2idazolin~~m Perchlorate (5)"): A solution of 0.51 g (2.4 mmol) of 1,2-bis- (pheny1amino)ethane and 0.50 g of perchloric acid (70%) in 10 ml of ethanol was added to 0.60 g (2.5 mmol) of hydroxymalonaldehyde bis(diethy1 acetal) (1,1,3,3-tetraethoxy-2- hydroxypropane)8J in 10 ml of ethanol and the mixture was heated under reflux for 30 min. On cooling, a dark green precipitate crystallised out. This was filtered off, washed with a little ethanol and diethyl ether, and recrystallised from ethanol which contained a fcw drops of perchloric acid, yielding 0.53 g (68%) of 5 as dark green needles with m. p. 238 - 240°C (Lit.'") 230°C). The colouration of 5 is due to the presence of trace amounts of 6'lJ and presumably higher vinylogues ''I which are difficult to remove by simple recrystallisation. - 'H NMR ([D6]DMSO): 6 = 4.6 (s; 4H, 4,5-H), 7.3-7.8 (m; 10H, Ph), 10.0 (s; I H, 2-H). -

NMR ([D,]DMSO): F = 48.7 (s; C-43, 118.8, 127.5, 130.1, and 136.3 (s; phenyl-C), 152.0 (s; C-2). CI5HlSC1N2O4 (322.7) Calcd. C 55.82 H 4.68 N 8.68 Found C 55.98 H 5.01 N 8.63

2,3-Dihydro-6-rnethoxy-f ,4-dimethyl-f ,4-diazepinium Perchlorate (7a): A solution of 0.30 g (3.4 mmol) of 1,2-bis(methylamino)ethane and 1.00 g of perchloric acid (70%) in 10 ml of methanol was added to 0.25 g (2.4 mmol) of methoxymalonaldehyde12) in 10 ml of methanol, heatcd under reflux for 20 min, and then left standing for 24 h at room temperature. Removal of the solvent left an oil. To this was added a little diethyl ether/methanol, and when scratched, a precipitate formed. This was filtered off, washed with a little methanol and diethyl ethcr, and recrystallised from methanol, yielding 0.10 g (16%) of 7a as yellow crystals with m. p. 138-142°C. - 'H NMR ([D,]DMSO): 6 = 3.3 (s; 6H, NCH3), 3.5 (s; 3H, OCH3), 3.6 (s; 4H, 2,3-H), 8.1 (s; 2H, 5,7-H). - MS (70 eV): m/z = 155 (M' - CIO,). C8H15C1N205 (254.7) Calcd. C 37.73 H 5.94 H 11.00 Found C 36.89 H 5.84 N 10.76 2,3-Dihydro-6-methoxy-1,4-diphenyl-f .4-diazepinium Perchlorate (7 b): A solution of 0.80 g

(3.8 mmol) of 1,2-bis(phenylamino)ethane and 1.00 g of perchloric acid (70%) in 10 ml of methanol was added to 0.25 g (2.4 mmol) of methoxymalonaldehyde") in 10 ml of methanol. The mixture was warmed to ca. 60°C and kept 24 h at room temperature. The precipitate was filtered off, washed with a little methanol and diethyl ether, and recrystallised from me- thanol, yielding 0.79 g (87%) of 7 b as yellow crystals with m. p. 214-216°C. - 'H NMR ([DJDMSO): 6 = 3.6 (s; 3H, OCH3), 4.2 (m; 4H, 2,3-H), 7.5 (m; 10H, Ph), 8.1 (s; 2H, $7- H). - I3C NMR ([D,]DMSO): 6 = 56.0 (s; C-2,3), 64.7 (s; OCHJ, 123.0, 128.3, 129.7, and 131.4 (s; phcnyl-C), 144.8 (s; C-6), 152.1 (s; C-5,7). - MS (70 eV): m/z = 278 (M+ - HC104). Cl8Hl9C1N2OS (378.8) Calcd. C 57.07 H 5.06 N 7.40 Found C 57.23 H 5.03 N 7.42

f ,1,5,5-Tetramethyl-3-phenyl-l,5-diazapen~adienium Perchlorate (10a)"! To 100 ml of chilled, dry dimcthylformamide was added, with stirring, 46.0 g (300 mmol) of POCI,. The solution was allowed to stand for 5 min, then 13.6 g (100 mmol) of phenylacctic acid was added. The mixture was gradually brought to 70°C (bath temp.) at which it was maintained, with stirring, for 2 h. The bath temp. was then raised to and maintained at 85°C until the evolution of gas was complctc (ca. 4 11). Exccss dimethylformamide was removed at reduccd pressure. To the cooled rcsidue, made homogeneous by the addition ofca. 100 nil of ethanol, was added a solution of 30 ml of perchloric acid (70%) in 100 ml of ethanol. After kecping the solution in a cool place for 48 h, the prccipitate was filtcrcd off and rccrystallised from ethanol, yielding 17.3 g (57%) of 10a as whitc needles with m. p. 200-202°C (Lit.20J 200-20lT). - 'H NMR ([DJDMSO): 6 = 2.6 (s; 6H, NCH3), 3.5 (s; 6H, NCH,), 7.6 (m;

Liebigs Ann. Chem. 1986

1376 D. Lloyd, C. Reichardt, and M . Struthers

5H, Ph), 8.0 (s; 2H, CH). - I3C NMR ([D,]DMSO): 6 = 39.1 (s; NCH?), 48.4 (s; NCHJ, 105.1 (s; C-Ar), 128.2, 128.6, 132.1, and 132.4 (s; phenyl-C), 162.8 (s; CH). - MS (70 eV): m/z = 203 (M+ - CIO,).

Cj3HI9C1N2O4 (302.8) Calcd. C 51.57 H 6.33 N 9.25 Found C 51.78 H 6.43 N 9.22

3-(4-Hydroxyphenyl)-l ,f ,S,5-tetramethyl-l,S-diazapentudienium Perchlorate (lob): As de- scribed for 10a, with 15.2 g (100 mmol) of (4-hydroxypheny1)acetic acid (12a): 22.2 g (70%) of 10b as colourless needles with m. p. 224-226°C. - 'H NMR ([D,]DMSO): 6 = 2.3 (s; 6H, NCH3), 3.1 (s; 6H, NCH,), 6.4-7.0 (m; 4H, C6H4), 7.5 (s; 2H, CH), 9.7 (s, broad; 1 H, OH). - I3C NMR ([D6]DMSO): 6 = 39.1 (s; NCH,), 48.5 (s; NCH3), 105.3 (s; C-Ar), 115.2, 122.1, and 133.2 (s; phenyl-C), 157.6 (s; COH), 163.2 (s; CH). - MS (70 eV): mjz = 219 (Mt - clod).

Cl3HI9C1N2OS (318.8) Calcd. C 48.99 H 6.01 N 8.79 Found C 49.12 H 5.82 N 8.91

3-(3-Hydroxyphenyl)-f ,f ,5,5-tetrumethyl-f ,S-diuzapentadienium Perchlorate (10c): As de- scribed for 10a, with 15.2 g (100 mmol) of (3-hydroxypheny1)acetic acid (12b): 14.9 g (47%) of 10c as colourless crystals with m. p. 194-196°C. - 'H NMR ([D6]DMSO): 6 = 2.4 (s; 6H, NCH,), 3.1 (s; 6H, NCH3), 6.6-7.4 (m; 4H, C6H4), 7.6 (s; 2H, CH); OH-signal not observed. - 13C NMR ([DJDMSO): 6 = 38.9 (s; NCH,), 48.5 (s; NCH,), 105.2 (s; C-Ar), 115.8, 118.9, 123.1, 129.6, and 133.7 (s; phenyl-C), 157.2 (s; COH), 162.8 (s; CH).

Calcd. C 48.99 H 6.01 N 8.79 Cl3Hl9CIN2O5 (318.8) Found C 48.97 H 5.94 N 8.72

2-(4-Hydroxyphenyl)-3-(dimethylamino)acrolein (13a): To 100 ml of chilled, dry dime- thylformamide was added, with stirring, 46.0 g (300 mmol) of P0Cl3. The solution was allowed to stand for 5 min, then 15.2 g (100 mmol) of (4-hydroxypheny1)acetic acid (12a) was added. The mixture was gradually brought to 70°C (bath temp.) at which it was main- tained, with stirring, for 2 h. The bath temp. was then raised to and maintained at 85°C until the evolution of gas was complete (ca. 4 h). The resulting cold solution was poured onto 300 g of ice, and to this was added 36.0 g (900 mml) of NaOH. The suspension was stirred until all the solid had dissolved. The solution was then made strongly alkaline by the addition of 200 ml of 10 M NaOH solution, with chilling to ensure that the temperature did not exceed 40°C. After 2 h, concentrated HCI was added, until a precipitate resulted. This was filtered off, washed with water, and recrystallised from ethanol to yield 17.8 g (92%) of 13a as yellow crystals with m. p. 192-194°C. - 'H NMR ([D6]DMSO): 6 = 2.6 (s; 6H, NMe2), 6.2-6.7 (m; 4H, C6H4), 6.8 (s; l H , CHN), 8.7 (s; lH, CH=O), 9.0 (s, broad; IH, OH). - I3C NMR ([D,]DMSO): 6 = 42.8 (s; NMe2), 113.0 (s; C-Ar), 114.3, 125.0, and 132.0 (s; phenyl-C), 155.8 (s; COH), 158.8 (s; CHN), 188.4 (s; CH=O). - MS (70 eV): m/z = 191 (M+).

CI1Hl3NO2 (191.2)

2-(3-Hj~droxyphenyl)-3-(dimethylumino/acrolein (13b): As given for 13a, with 15.2 g (100 mmol) of (3-hydroxypheny1)acetic acid (12b): 13.8 g (72%) of 13b as pale yellow crystals with rn. p. 206-209°C. - 'H NMR ([D,]DMSO): 6 = 2.7 (s; 6H, NMe2), 6.3-6.9 (m; 4H, C6H4), 7.0 (s; 1 H, CHN), 8.9 (s; 1 H, CH=O), 9.2 (s, broad; 1 H, OH). - 13C NMR ([D,]DMSO): 6 = 42.0 (s; NMe2), 124.1 (s; C-Ar), 113.2, 118.1, 121.9, 128.2, and 136.1 (s; phenyl-C), 156.4 (s; COH), 158.6 (s; CHN), 187.0 (s; CH=O). - MS (70 eV): m/z = 191

Calcd. C 69.09 H 6.85 N 7.32 Found C 69.06 H 6.83 N 7.22

(M+). Cl1HI3NO2 (191.2)

(3-Hydroxypheny1)malonaldehyde (14): 0.95 g (5.0 mmol) of 13b was suspended in 8 ml of ethanol and to this was added 10 ml of 10 M NaOH. This solution was heated under

Liebigs Ann. Chem. 1986

Calcd. C 69.09 H 6.85 H 7.32 Found C 69.00 H 6.89 N 7.22

6-Hydroxy-2,3-dihydro-l,4-diazepinium and Pyrimidinium Salts 1377

reflux for 3 h. To the cooled solution was added conc. HCI, ensuring that the temp. did not rise above 40°C. A brown solid formed. The reaction mixture was extracted three times with diethyl ether and the combined ethereal phases were dried with MgS04. The diethyl ether was removed in vacuo, leaving 0.61 g (74%) of 14 as fine white powder with m. p. 135°C (dec.). - 'H NMR ([D6]DMSO): 6 = 6.4-7.1 (m; 4H, C6H4), 8.7 (s; 2H, CH), 9.5 (s, broad; 2H, OH). - 13C NMR ([D6]DMSO): 6 = 113.7, 116.2, 120.1, 128.5, and 132.6 (s; phenyl-C), 121.0 (s; C-Ar), 156.7 (s; rneta-COH), 180.0 (s; CH). - MS (70 eV): m/z = 164 (M '1. C9Hs03 (164.2) Calcd. C 65.85 H 4.91 Found C 65.57 H 4.88

3-[(Dimethylarnino)methylene]-2,3-dihydro-2-oxo-5-benzofuranc~rboxaldehyde (15) and -7-benzofurancarboxaldehyde (16): To 100 ml of chilled, dry dimethylformamide was added, with stirring, 46.0 g (300 mmol) of POCI,. The solution was allowed to stand for 5 min, then 15.2 g (100 mmol) of (2-hydroxypheny1)acetic acid was added. The mixture was grad- ually brought up to 70°C (bath temp.) at which temp. it was maintained, with stirring, for 2 h. The bath temp. was then raised to and maintained at 85°C until the evolution of gas was complete (ca. 4 h). The red precipitate formed after this time was filtered off, recrystallised from acetone/water and dried in vdcuo, affording 8.8 g (41%) of a mixture of the isomers 15 and 16 as bright pink crystals with m. p. 138-139°C. No attempt was made to separate the two isomers. - 'H NMR ([D6]Acetone) (mixture of regio and E / Z isomers): 6 = 3.3, 3.5, and 3.7 (three s; 6H, NMe2), 7.4-7.7 (m; 3H, arene-H), 8.0 (s; IH, CHN), 9.8 and 9.9 (two s; 1 H, CH=O); cf: reference') for the full complex NMR-spectrum. - MS (70 ev): rnlz = 217(M+).

C12HllN03 (217.2) Calcd. C 66.35 H 5.10 N 6.45

2,3-Dihydro-6-phenyl-1,4-diazepinium Perchlorate (11 a)'? A solution of 0.75 g (2.5 mmol) of 10a in 10 ml of methanol, plus a few drops of perchloric acid (70%), was added to 0.15 g (2.5 mmol) of 1,2-diaminoethane in 10 ml of methanol. This solution was warmed to ca. 60°C and was then kept for 24 h at room temperature. The precipitate was filtered off and recrystallised from ethanol, affording 0.52 g (76%) of l l a as pale yellow crystals with m. p. 179-181 "C (Lit.") 179--180°C). If no precipitate formed, either trituration or the addition of diethyl ether encouraged formation of a solid. - 'H NMR ([D6]DMSO): 6 = 3.7 (s; 4H, 2,3-H), 7.4 (s, broad; 2H, 1,4-H), 7.45 (m; 5H, Ph), 8.0 (s; 2H, 5,7-H). - 13C NMR ([D,]DMSO): 6 = 48.9 (s; C-2,3), 102.7 (s; C-6), 126.2, 127.3, 128.7, and 138.8 (s; phenyl-C), 157.4 ((2-57). - MS (70 cV): rn/z = 173 (Mt - C104). CllHI3C1N2O4 (272.7) Calcd. C 48.45 H 4.81 N 10.27 Found C 48.29 H 4.75 N 10.17 2,3-Dihydro-l,4-dimethyl-6-phenyl-i,4-diazepiniurn Perchlorate (1 1 b) 19): As described for

Ila, with 0.22 g (2.5 mmol) of 1,2-bis(methylamino)ethane: 0.49 g (65%) of l l b as pale yellow crystals with m. p. 157-158"C(Lit.19) 154--156"C), - 'H NMR ([D,]DMSO): 6 = 3.2 (s; 6H, NCHJ, 3.6 (s; 4H, 2,3-H), 7.1 (s; 5H, Ph), 7.7 (s; 2H, 5,7-H). - I3C NMR ([D,]DMSO): 6 = 47.5 (s; NCH& 55.4 (s; C-2,3), 102.1 (s; C-6), 126.2, 127.6, 128.5, and 139.0 (s; phenyl-C), 157.5 (s; C-5,7). - MS (70 eV): rn/z = 201 (Mf - C104).

Found C 66.41 H 5.23 N 6.32

C13H17CIN204 (300.7) Calcd. C 51.92 H 5.70 N 9.31 Found C 51.64 H 5.65 N 9.26

2,3-Dihydro-6-(4-hydroxyphenyl)-l,4-diazepinium Perchlorate (11 c): As described for 11 a, with 0.80 g (2.5 mmol) of lob: 0.59 g (82%) of I l c as ycllow powdcr with m. p. 397-399°C. - 'H NMR ([D,]DMSO): 6 = 3.7 (s; 4H, 2,3-H), 6.7-7.3 (m; 4H, C6H4). 7.7 (s; 2H, 5,7-H), 9.3 (s, broad; 3H, NH and OH). - I3C NMR ([D,]DMSO): 6 = 50.6 (s; C-2,3), 104.0 (s; C-6), 116.1, 129.1, and 131.3 (s; phenyl-C), 156.0 (s; COH), 156.1 (s; C-5,7). - MS (70 cV): m/z = 189 (M ' - C104).

ClIH13ClN2O5 (288.7) Calcd. C 45.77 H 4.54 N 9.70 Found C 45.84 H 4.51 N 9.55

Liebigs Ann. Chem. 1986

1378 D. Lloyd, C. Reichardt, and M . Struthers

2,3-Dihydro-6- (4-hydroxyphenyl) -1,4-dimethyl-1,4-diazepinium Perchlorate (11 d): As given for l l a , with 0.22 g (2.5 mmol) of 1,2-bis(methylamino)ethane and 0.80 g (2.5 mmol) of lob: 0.50 g (63%) of l l d as yellow needles with m. p. 163-165°C. - 'H NMR ([D6]DMSO): 6 = 3.4 (s; NCH,), 3.7 (s; 4H, 2,3-H), 6.6-7.4 (m; 4H, CsH4), 7.9 (s; 5,7-H), 9.4 (s; broad;

115.2, 129.1, and 129.9 (s; phenyl-C), 156.1 (s; COH), 157.2 (s; C-5,7). - MS (70 eV): m/z = 217 (M' - C104).

IH, OH). - ',C NMR ([DhlDMSO): 6 = 47.3 (s; NCH3), 55.4 (s; C-2,3), 102.2 (s; C-6),

C13Hl7CIN2O5 (316.7) Calcd. C 49.30 H 5.41 N 8.84 Found C 49.42 H 5.43 N 8.93

2,3-Dihydro-6-(3-hydroxyphenylj-f ,I-diazepinium Perchlorate (11 e): As given for 11 a, with 0.80 g (2.5 mmol) of lOc: 0.32 g (45%) of l l e as colourless crystals with m. p. 159- 161 "C. - 'H NMR ([D6]DMSO): 6 = 3.7 (s; 4H, 2,3-H), 6.4 (s, broad; 3H, NH and OH), 6.6-7.3 (m; 4H, C&), 7.7 (s; 2H, 5,7-H). - I3c NMR ([D,]DMSO): 6 = 50.5 (s; C-2,3), 103.8 (s; C-6), 112.5, 113.6, 117.4, and 129.5 (s; phenyl-C), 154.7 (s; C-5,7), 157.5 (s; COH). - MS (70 eV): m/z = 189 (M+ - C10.J.

CIlH13CINZOS (288.7) Calcd. C 45.77 H 4.54 N 9.70 Found C 45.82 H 4.56 N 9.81

2,3-Dihydro-6-(3-hydroxyphenyl)-I,4-dimethyl-l,4-diazepinium Perchlorate (11 f): As de- scribed for l l a , with 0.22 g (2.5 mmol) of 1,2-(methy1amino)ethane and 0.80 g (2.5 rnrnol) of 1Oc: 0.73 g (92%) of l l f as yellow needles with m. p. 165-167°C. - 'H NMR ([D6]DMSO): 6 = 3.4 (s; 6H, NCH,), 3.7 (s; 4H, 2,3-H), 6.4-7.2 (m; 5H, CsH4 and OH),

C-6), 113.2, 114.7, 118.5, and 129.5 (s; phenyl-C), 157.4 (s; COH), 157.4 (s; C-57). - MS (70 eV): m/z = 217 (Mi - Clod.

7.9 (s; 2H, 5,7-H). - 13C NMR ([DsIDMSO): 6 = 47.4 (s; NCH,), 55.4 (s; C-2,3), 102.2 (s;

CI3Hl7CIN2O5 (316.7) Calcd. C 49.30 H 5.41 N 8.84 Found C 49.20 H 5.34 N 8.68

1,2-Dihydro-5- (4-hydroxyphenyl)-i.3-dimethyl-2-oxopyrimidiniuin Perchlorate (17 a): A so- lution of 0.22 g (2.5 mmol) of N,N-dimethylurea in 10 ml of methanol was added to 0.75 g (2.4 mmol) of 10b in 10 ml of methanol containing a few drops of pcrchloric acid (70°/0). This solution was warmed to ca. 60°C. After 24 h at room temp., the precipitate was filtered off and recrystallised from ethanol containing a few drops of perchloric acid (70%), affording 0.36 g (48%) of 17a as yellow plates with rn. p. 242-244°C. - 'H NMR ([D6]DMSO): 6 = 3.8 (s; 6H, NCH,), 6.9-7.7 (m; 4H, C6H4), 9.5 (s; 2H, 4,6-H); OH-Signal not observed. - I3C NMR ([D6]DMSO): 6 = 40.3 (s; NCH,), 116.0, 120.7, and 127.4 (s; phenyl-C), 116.5 (s; C-5), 147.2 (s; C=O), 157.2 (s; C-4,6), 158.2 (s; COH).

C12H13C1N206 (316.7) Calcd. C 45.51 H 4.14 N 8.85 Found C 44.85 H 4.19 N 8.76

1,2-Dihydro-5-(3-hydroxypheny1)-1,3-dimethy1-2-oxopyrimidiniu~ Perchlorate (17b): As above for 17a, with 0.75 g (2.4 mmol) of I0c: 0.35 g (46%) of 17b as yellow needles with m. p. 178-180°C. - 'H NMR ([D6]Acetone): 6 = 2.8 (s; 6H, NCH,), 6.8-7.4 (m; 4H, C&), 8.7 (s; 1H, OH), 9.5 (S; 2H, 4,6-H).

C12H13C1N206 (316.7) Calcd. C 45.51 H 4.14 N 8.85 Found C 45.24 H 4.00 N 8.71

M. Struthers, Thesis, Univ. of St. Andrews 1982 (the experimental work was carried out in Marburg and St. Andrews).

2, D. Lloyd and H . McNab, Angew. Chem. 88,496 (1976); Angew. Chem., Int. Ed. Engl. 15, 459 (1976); New Synthetic Methods, Vol. 5, p. 209ff., Verlag Chemie, Weinheim 1979. Sec . a ) D. Lloyd, H . P. Cleyhorn, and D. R. Marshall, Adv. Heterocycl. Chem. 17, I (1974). - 3b1 D. Lloyd and H. McNah, Heterocycles 11, 549 (1978).

4, B. Eistert and F. Haupter, Chem. Ber. 93, 264 (1960).

Liebigs Ann. Chem. 1986

6-Hydroxy-2,3-dihydro-l,4-diazepinium and Pyrimidinium Salts 1379

51 C. Reichardt and C. Rust, Synthesis 1980, 232. - See also 5b) H. v. Euler and B. Eistert, Chemie und Biochemie der Reduktone und Reduktonate, Verlag F. Enke, Stuttgart 1957. -

6, 6a1 C. Reichardt and K. Halbritter, Angew. Chem. 87, 124 (1975); Angew. Chem., Int. Ed. Engl. 14, 86 (1975); New Synthetic Methods, Vol. 2, p. 119ff., Verlag Chemie, Weinheim 2975. - 6b) C. Reichardt, K.-Y. Yun, W. Massa, R. E. Schmidt, 0. Exner, and E.-U. Wiirth- wein, Liebigs Ann. Chem. 1985, 1997.

B. Eistert, F. Arnemann, and F. Haupter, Chem. Ber. 88, 939 (1955). - 7b) K. Schank und D. Wessling, Liebigs Ann. Chem. 710, 137 (1967).

N. V. Kuznetsov and I. I. Krasavtsev, Ukrainsk. Khim. Zh. 42,404 (1976) [Chem. Abstr. 85,20550 (1976)l. - xb) N. V. Kuznetsov and I. I. Krasavtsev, USSR-Pat. 388533 (Feb. 15, 1976) [Chem. Abstr. 84, 1 6 4 1 6 9 ~ (1976)l.

') R. Allmann, Fachbereich Geowissenschaften, University of Marburg, unpublished results 1985/86 (preliminary crystal data for 3a: space group P212121, 765 reflections, a = 1497.0(7), b = 1030.0(5), c = 677.4(3) pm, Z = 4).

lo) Cf: inter alia C. Barnett, H . P. Cleghorn, G. E. Cross, D. Lloyd, and D. R. Marshall, J. Chem. SOC. C 1966, 93.

") For similar monomethine cyanine dyes and their higher vinylogues see ' l a ) F. M. Hamer, The Cyanine Dyes and Related Compounds, Interscience Publishers, New York, London 1964. - ' l b ) J. Fabian and H. Hartmann, Light Absorption of Organic Colorants, p. 167ff., Springer-Verlag, Berlin 1980.

B. Eistert and F. Haupter, Chem. Ber. 92, 1921 (1959). - IZbl H. Baganz and K. Praefcke, Chem. Ber. 96, 2661 (1969). - R. C. Moschel and N. J . Leonard, J. Org. Chem. 41, 294 (1976).

'3) '3a) H. Obata and T. Tokuyama, J. Chem. SOC. Jpn. 91 1098 (1970). - '3b) F. Frimmel and H . P. Fritz, Z. Naturforsch., Part B 25, 57 (1970). - "') F. Frimmel, H . P. Fritz, and C. G. Kreiter, J. Cryst. Mol. Struct. 1, 25 (1971) [Chem. Abstr. 75, 42898c (1971). - 13d) D. Semmingsen, Acta Chem. Scand., Part B 28, 141 (1974). - 13') B. Ya. Simkin, B. V. Go- lyanskii, and V. I. Minkin, Zh. Org. Khim. 17, 3 (1981); J. Org. Chem. USSR 17, 1 (1981).

14) The fine structure of methoxymalonaldehyde in solution has not particularly been studied, but the fine structures of malonaldehyde itself and of some other related substituted malonaldehydes are well known; cfi inter alia: 14a1 W. 0. George and V. G. Mansell, J. Chem. SOC. B 1968,132. - 14b) R. S. Noi, B. A. Ershov, and A. I. Kol'tsov, Zh. Org. Khim. 11, 1778 (1975) [Chem. Abstr. 83, 163444a (1975)l. - 14') S. L. Baughcum, R. W. Duerst, W. F. Rowe, Z. Smith, and E. B. Wilson, J. Am. Chem. SOC. 103, 6296 (1981). - 14d) C. J. Seliskar and R. E . HojJmann, J. Mol. Spectrosc. 96, 146 (1982). - 14e1N. D. Sanders, J. Mol. Spectrosc. 86, 27 (1981). -

Is) Isa) D. Lloyd and D. R. Marshall, J. Chem. Soc. 1958, 118. - lSbl D. Lloyd, R. H. Mc- Dougall, and D. R. Marshall, J. Chem. Soc. C 1966, 780. - '") A . M. Gorringe, D. Lloyd, F. I. Wasson, D. R. Marshall, and P. A. Duffield, J. Chem. SOC. C 1969, 1449.

16) C . Barnett, Chem. Commun. 1967, 637. - 16b) C. Barnett, J. Chem. SOC. C 1967, 2436. - A. M . Gorrin e, D. Lloyd, D. R. Marshall, and L. A . Mulligan, Chem. Ind.

C 1970, 617.

K. Schank, Synthesis 1972, 176.

7,

12) '

See also reference6").

(London) 1968, 130. - l 6 w A. M. Gorringe, D. Lloyd, and D. R. Marshall, J. Chem. Soc.

"I D. Lloyd, K. S. Tucker, and D. R. Marshall, J. Chem. SOC., Perkin Trans. 1 1981, 726. ") D. Lloyd, H. McNab, and D. R. Marshall, J. Chem. SOC., Perkin Trans. 1 1978, 1453. ") I% Tucker, Thesis, p. 132, Univ. of St. Andrews 1978.

2. Arnold, Collect. Czech. Chem. Commun. 26, 3051 $1961). - *Ob) C. Jutz, R. Kirch- lechner, and H.-J. Seidel, Chem. Ber. 102,2301 (1969). - G. M . Coppola, G. E. Hardt- mann, and B. S. Huegi, J. Heterocycl. Chem. 11, 51 (1974). - 'Od1 R. Knorr, P. Liiw, P. Hassel, and H. Bronberger, J. Org. Chem. 49, 1288 (1984). - See also reference'").

2 ' ) D. Lloyd, H. McNab, and K. S. Tucker, J. Chem. SOC., Perkin Trans. 1 1977, 1862.

~ ~ 8 6 1

Liebigs Ann. Chem. 1986