G. Toth, A. Kovacs, I. Bitter, H. Duddeck 1215

Heterocyclization with Iminium Chlorides, V

Condensation of 1,3-Dichlorotrirnethinecyanines with 1,3- and 1,2-Dinucleophiles Gabor Toth" ', Attila KOVBCS', Istvan Bitter" b, and Helmut Duddeck'

Technical Analytical Research Group of the Hungarian Academy of Sciences, Institute for General and Analytical Chemistry of the Technical University ', Gellert ter 4, H-1 11 1 Budapest, Hungary

Department of Organic Chemical Technology, Technical University b,

Miiegyetem rkp. 3, H-1 11 1 Budapest, Hungary

Lehrstuhl fur Strukturchemie der Ruhr-Universitat ', P. 0. Box 102148, W-4630 Bochum, Germany

Received June 4, 1991

Key Words: N-Heterocycles, condensed, regioselective synthesis of, structure elucidation of

Cyclic 1,3-dichlorotrimethinecyanines 1 were used for the preparation of condensed polycycles 2 - 13 with high regio- selectivity. In the case of five-membered cyanines the exclu- sive formation of the linear-type products was observed, while with six- and seven-membered cyanines the linear or angular

type of products were obtained, depending on the character of the nucleophile. The structures of the products were sup- ported by 'H-, I3C- and 15N-NMR data, NOE difference spec- troscopy, and different two-dimensional carbon-proton cor- relation measurements.

We have recently reported on the reaction of a symmetric 1,3- dichlorotrimethinecyanine with aromatic dinucleophiles affording heterocycles of potential biological activities 1*2). Since the 1,3-di- chlorotrimethinecyanines contain two carbon atoms of different electrophilic character, their nucleophilic attack may result in the formation of either a linear (A) or an angular (B) type of condensed heterocycle. 'H- and "C-NMR spectroscopic studies revealed the

Scheme 1

2, 3. 4

Ph-NH,

F'

CHJ aih/ : l a b c \ 0 1 2

8, 9. 10 X-

11. 12. 13

8 9 10 I- 11 12 13

x-: (210,-

formation of a single product proving that the ring closure is highly regioselective. The structure of the reaction products has been elu- cidated by additional 'H-NOE difference measurements corrobo- rating the linear anellation (type A) in each case '2').

For the sake of a better understanding of this reaction, various electrophiles and nucleophiles have been investigated, e.g. 1,3-di- chlorotrimethinecyanines with a five-, six-, and seven-membered ring "a" and phenylhydrazine as an aromatic dinucleophile (Scheme 1).

Structures of the expected reaction products are shown in Scheme 2. Letters A and B together with the appropriate numbers indicate the type of compounds formed in the reaction. It should also be mentioned that the numbering applied in the tables and in Scheme 2 is not in accordance with the IUPAC nomenclature but this modification, however, facilitates the comparison of the spectro- scopically analogous atoms in compounds 2- 13.

NMR-spectroscopic investigations of the crude reaction products revealed the exclusive formation of one substance with high regio- selectivity as observed in our previous studies. A pairwise compar- ison of the linear (A) and angular (B) structures shows very similar 'H- and ',C-NMR chemical shift values in both cases which are, therefore, insufficient to an unambiguous assignment of the struc- tures expected. For this purpose, the NOE difference method was utilized ' x 2 ) since the NOE intensity enhancement is dependent on the distance between the proton^"^). Irradiation of the 'H signals of the N(CH& and NCH, groups makes possible the determination of the steric surroundings of the 8-H (2'-H in compounds 10- 12) proton which is an unambiguous consequence of structures A or B.

The structure of each reaction product has been elucidated in this way. The measured NOE values are summarized in Table 1. It can be seen that the reaction with aniline affords a linear product

Liebigs Ann. Chem. 1991, 1215- 1219 OVCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1991 0170-2041/91/1111--1215 .$ 3.50+.25/0

1216 G. T6th, A. Kovacs, I. Bitter, H. Duddeck

Scheme 2

n = O 2A n = l 3A

n = 2 4A

5A

6A

7A

in all cases proving the site of the primary reaction preceding ring closure at C-2.

All reaction products formed with 2-aminopyridine were linear as well. In contrast to this, in reactions with 2-aminobenzthiazole and phenylhydrazine a linear structure A was found only if n = 0 (viz. in the case of a five-membered ring “a”), and B-type substances were obtained if n = 1 or n = 2.

These results may be attributed to the fact that in the six- and seven-membered cyanines the steric hindrance at the endocyclic electrophilic centre (C-2) is increasing parallel with the enhancement of the ring size which, depending on the characteristics of the nu- cleophilic reagent, may result in the formation of the angular prod- uct as well.

Table 1. Results of proton-proton 1 D NOE difference experiments (400 MHz)

Irradiated Compound proton Observed NOE in %“I

2 b)

3

4 5 6 ci I 8 9

10 11

12c) 13

NMe2 NMe 5-H, 8-H

NMez NMe2 NMe2 NMe2 NMe2 NMe NMe NMe2 NMe NMe NMe

8-H (13%), 12-H (4%) 14-H (10%) NMe2 (17%), 6-H (28%), 7-H (28%) 8-H (8%). 12-H (6%) 8-H (21%) 8-H (24%) 8-H (20%) 8 - ~ (io%j 8-H (15%) 8-H (9%) ’ 2’-H (lo%), 12-H (11.5%) 14-H (10.5%) 2’-H (10%) ’ 2’-H (5.5%)

a) The NOE (YO) refers to 1 H. - b, 2, base. - MHz. - dl Measured at 300 MHz.

Measured at 100

Characteristic ‘H- and ‘3C-chemical shift data of compounds 2 - 13 are summarized in Tables 2 and 3. Besides the utilization of the known substituent effects 5i the assignment has been corrobo- rated by NOE difference and decoupling experiments, coupling pat- tern (‘H NMR) and two-dimensional carbon-proton6’ correlation

OA

98

108

1 1 A

128

138

measurements as well. COLOC” measurements have been per- formed for the assignment of the quaternary carbon atoms, and the characteristic carbon-proton correlations are shown in Table 4.

It is noteworthy that comparing the chemical shifts of NCH, and N(C‘H3)2 signals in each compound of linear structure the NCH, and in the case of the angular isomers the N(CH,), proton signals appeared at lower field. This observation is of diagnostic value in the differentiation of the isomers.

Ring inversion of the saturated compounds 9 and 10 should be slow since the signals of the axial and equatorial methylene protons are separated in the ‘H-NMR spectra. Both molecules belong to type B where an unfavourable steric interaction occurs between the NCH, moiety and 8-H. A favourable conformation of ring “a” is supposed to exist as a result of this interaction. In the case of the two angular compounds 12 and 13, where the benzthiazole moiety is replaced by a phenyl group which can rotate around the N-C bond, the signals of the axial and equatorial methylene protons are averaged.

In some cases the COLOC spectrum optimized for the J(C,Hi = 6 Hz long-range coupling was utilized for the assignment of the quaternary carbon signals since the C-2, C-4, and C-10 signals appear within a close range and, therefore, they cannot be unam- biguously assigned by application of the known substituent effects alone. Characteristic cross-peaks were observed between the signals of the NCH, protons and the C-2 and between the N(CH3)2 and C-10 signals, which made possible an unambiguous assignment of these two carbons. Assignment of C-4 was further corroborated by the correlation with 8-H and 6-H taking into consideration the fact that no cross-peak is expected between this carbon atom and the NCH, and N(CHJ2 protons.

In the case of compounds 5, 8, and 9, ”N-NMR measurements have also been performed. Chemical shift data are summarized in Table 5.

It is known that signals of pyridine-type nitrogen atoms appear strongly downfield shifted comparing to that of aniline-type nitrogens8), that is, signals appearing at higher field belong to N(CH& and NCH3. Effects appearing on the protonation of the ring nitrogen have been utilized for the assignment of the methyl- amino nitrogen9). The protonation of the ring nitrogen atom in 4- aminopyridine results in a 20-30 ppm downfield shift of the NH, signal while the salt formation of 2-aminopyridine causes much less

Liebigs Ann. Chem. 1991, 1215-1219

Heterocyclization with Iminium Chlorides, V 1217

Table 2. ‘H-chemical shifts in [D,]DMSO (400 MHz)

4 5 6 7 9 10 11”’ 12b.c) 12a.c) 13“)

NMe 3.28 3.21 3.30 3.28 2.68 2.71 2.85 2.51 2.40 2.47 NMez 3.1 1 2.89 2.93 2.96 3.32 3.28 2.74 3.07 2.75 2.65 5-H 7.86 7.63 7.60 7.56 8.08 8.07 6-H 7.65 8.08 8.02 7.97 7.57 7.56

7.36 7.29 7.62 7.60 7 -H 7.38 7.40 8-H 7.89 8.74 8.67 8.53 8.15 7.97 -

12-H 2.68 3.49 2.85 2.73 3.07 2.93 3.08 2.71 2.48 2.45 2.67 2.55

13-H 1.82 - 1.93 1.86 1.68 1.79 - 1.88 1.65 1.68 1.92

- 1.86 3 3a-H 1.89 - - 1.95 - 2.10 1.79

14-H 3.68 3.83 3.59 3.73 3.35 3.73 3.96 3.24 3.06 3.16 3.52

2’-H - - - - - - 7.39 7.4- 7.6 7.63 7.65 3’-H - - - - - - 7.54 7.4 - 7.6 7.38 7.38 4 - H - - - - - - 7.45 7.4 - 7.6 7.12 7.16

- - - - - - - - - - - -

- - -

- -

a) In CDC13. - b, 12, HC104 salt. - Measured at 100 MHz.

Table 3. I3C-chemical shifts in [D,]DMSO (100 MHz)

4 5 6 7 8 a’ 9 10 11” 12a.b) 13” ~~~ ~

NMe 39.7 30.9 37.1 37.8 31.5 42.8 38.4 33.0 41.2 38.8 NMe2 44.1 40.9 40.4 40.9 41.4 41.1 40.8 40.4 40.3 41.8

163.2 157.2 161.5 164.2 154.2 155.2 164.8 148.3 149.8 c -2 156.1 c-4 C-4b c-5 118.2 124.3 C-6 131.4 140.3 139.2 138.8 c-7 124.2 116.6

126.0 130.7 130.0 c- 8 C-8a c-9 119.7 - c-10 160.0 147.5 148.6 148.5 151.1 160.9 163.8 154.6 156.6 157.1 c - I 1 114.7 114.3 112.5 112.0 110.2 100.4 104.5 94.1 93.6 104.3

22.7 25.5 22.9 24.9 27.6 22.4 21.0 22.6 - 17.5 26.6

c-12 28.3 22.7

- 26.0 C-13 22.4 C-23a 24.0 - - 23.6

49.2 49.7 52.0 49.8 51.1 59.5 51.9 52.5 - - 140.9 140.6 140.2

C-14 c-1‘

- - - - - - - 125.4 120.7 121.3 - - - - - - - 130.2 128.9 128.7

c-2‘

c-4’ - - - - - - - 129.2 124.5 124.7 c-3’

- - - 151.5 168.3 160.9 163.8 - - - - 124.3 124.0 124.1

124.3 124.2 123.9 123.8 123.7 128.0 127.1 127.0

116.4 11 5.6 127.1 127.2 127.2 130.5 118.9 118.2 118.2

- - - 135.6 134.2 134.5

- - - 137.1 152.6 149.5

- - - - - - - - - - - - - - - -

- - - - - - - -

21.8 - 17.0 23.1 - - 23.4 -

- 19.1

52.3 50.9 - - - - -

a’ Measured at 25 MHz. - b, In CDC13.

downfield shift (0-8 ppm) in the chemical shift of the amino ni- trogen.

The chemical shift of 6 = -341.6 measured for 8 changed to - 321.2 in compound 9 as a result of the displacement of the pos- itive charge proving that this signal belongs to the N(CH& group in p-position to N-3. At the same time, the signal observed at 6 = -269.1 was shifted to -281.5 indicating that the NCH, group is now in o-position (B) to the positive charge instead of the p-position

It can be concluded that the ‘H-, I3C- and ‘SN-chemical shifts are also characteristically different and therefore, besides the NOE re- sults give further support for the differentiation of the linear- and angular-type structures.

The authors express their gratitude to the Hungarian Academy of Sciences (OTKA) and to the Deutsche Forschungsgemeinschaft for the financial support of these studies. Special thanks are due to Dr. L. Weber for the measurement of the ”N-NMR spectrum of compound 8 and to Prof. Dr. G. Snatzke for valuable discussions.

(‘4).

Experimental The ‘H- and I3C-NMR measurements were carried out at 400

and 100 MHz, respectively, by using a Bruker AM-400 spectro- meter. Measurements were performed at room temp. (internal stan- dard TMS) utilizing a 32 K data memory. For NOE measurements a delay time of 3 s and an irradiation time of 1.5 s were used. IsN- NMR spectra were measured at 10, 30 and 40 MHz, respectively, in a 10-mm sample tube by using broad-band proton decoupling. Chemical shift values were measured for external K”N03 aqueous standard [6(K”NO3) = - 3.551 and then converted to the external nitromethane. Characteristic parameters of the measurements are: pulse angle 30” and pulse repetition time 8 s.

Melting points are uncorrected. Unless specified otherwise, rea- gent grade reactants and solvents were obtained from commercial supplies and used as received. 1,3-Dichlorotrimethinecyanines (la, b,c) were prepared by reaction of the appropriate N-methyl- lactams with N,N-dimethyldichloromethyleneiminium chloride ”) according to ref. ”) and used without further purification.

Liebigs Ann. Chem. 1991, 1215-1219

1218 G. Tbth, A. Kovacs, 1. Bitter, H. Duddeck

Table 4. Observed 'H-I3C long-range correlations for 5, 6, 9, 10, 11 and 13

2J ' J 4J 5J 5 9 10 11 13 5 6 9 10 11 13 9 10 13

NMe2 c-2

c-4 C-4b

C-5 C-6 c-7 C-8 C-8a

c-10

c - I 1 (2-14 c-1' c-2' C-4'

6-H

7-H 7-H

NMe NMe 14-H 8-H 6-H

7-H 8-H 8-H 5-H 5-H

NMe2 8-H

NMe NMe

NMe2 12-H 12-H 12-H

NMe NMe 14-H

8-H 8-H 6-H 7-H 7-H 8-H 8-H 5-H 5-H 6-H 5-H 5-H 7-H NMe2 NMe2

13-H

12-H NMe

6-H

NMe2 NMez NMe

NMe NMe

3'-H 4'-H 2'-H

Table 5. 15N-chemical shifts (6 values) of 4, 7 and 8 in [D6]DMS0 ration of the solvent the residue was triturated with 25 ml of water and two different work-up procedures were used,

a) The insoluble oily material was dissolved in 10 ml of ethanol, 5 a' 8 b, 9 and the salts were precipitated with 70% aqueous HC104. The free

"CH3)2 -355.6 -341.6 -321.2 bases were liberated from the salts with aqueous NaOH (11, 12, N-I (NCH3) -331.7 -269.1 -281.5 13). N-3 - 188.8 - 176.9 -212.8 N-9 -271.2 -205.9 - 159.8 b) The aqueous solution was clarified with charcoal, and the salts

were precipitated with 70% aqueous NaCIO, (4-7, 9, 10) and recrystallized from methanol, a) Measured at 10 MHz. - b, Measured at 40 MHz. -

at 30 MHz. Measured

Preparation of Iminium Salts la,b,c: To a stirred suspension of 16.5 g (0.1 mol) of N,N-dimethyldichloromethyleneiminium chlo- ride in 150 ml of dichloromethane 0.05 mol of N-methyllactam was added and boiled until HC1 evolution ceased (2 - 3 h). The solvent was evaporated in vacuo and the oily residue triturated with dry diethyl ether to remove the N,N-dimethylcarbamoyl chloride formed. The washing ether was decanted, the remaining thick sub- stance was weighed (11 -12 g, 0.045 mol) and dissolved in 150 ml of dichloromethane. After measuring the total volume of this stock solution, aliquote parts were used for the reactions.

Newly synthesized compounds (m.p., YO yield): 6-Dimethyl- amino-2,3,4,5-tetrahydro-l -methyl-1 H-azepino[6,7-b]quinolinium hydrogen perchlorate (4 . c104) (216-218°C dec., 68%). - 4-Di- methylamino-2,3-dihydro-l -methylpyrrolo[4,5-d]pyrimido[2,3-a]- pyridinium perchlorate (5 . C104) (258°C dec., 75%). - 5-Dimethyl- amino- 1.2,3,4-tetrahydro-l -methylpyrido(5,6-d]pyrimidino[2,3-a]- pyridinium perchlorate (6 . c104) (188-190"C, 58%). - 6- Dimethylamino-2,3,4,5-tetrahydro-l -methyl-1 H-azepino[6,7-d]pyr- imidino[2,3-a]pyridinium perchlorate (7 . C104) (180- 182"C, 61 YO). - 5-Dimethylamino-l,2,3,4-tetrahydro-l-methylpyrido[5,6-d]pyr- imidino[l,2-a]benzthiazolium perchlorate (9 . C104) (210-212"C, 78%). - 6-Dimethylamino-2,3,4,5-tetrahydro-l-methyl-lH-azepi-

Preparation of Heterocycles 4 - 7, 9 - 13. - General Procedure: To a dichloromethane solution of 10 mmol of la,b,c 10 mmol of the amine (hydrazine) and 3.05 g (30 mmol) of triethylamine were added, and the mixture was heated at reflux for 2 h. After evapo-

no[6,7-d]pyrimidino[l ,2-a]benzthiazolium perchlorate -(lo . C104) (168 - 17OoC, 64%). - 4-Dimethylamino-2.3-dihydro-f-methyl-5- phenylpyrrolo[4,5-d]pyrazole (11) (142- 143 "C, 56%). - 5-Dime- thylamino-1,2,3,4-tetrahydro-l-methyl-7-phenylpyrido[5,6-d]pyra-

Table 6. Elemental analysis data of compounds 4-7 and 9-13

C % H % Found Calcd. Found Mol. mass Calcd. Empirical

formula No Calcd. N %

Found

4 Ct6H22C1N304 355.83 54.01 53.78 6.23 6.17 5 C13H17C1N404 328.79 47.49 47.05 5.21 5.12

7 CiJLiClN404 356.81 50.49 49.95 5.93 5.82 9 Ci6HiGN04S 398.87 48.1 8 47.65 4.80 4.72

10 C17H21C1N404S 412.90 49.45 49.01 5.13 5.10 11 G H i J ' b 242.96 69.21 68.89 7.47 7.36 12 Ci s H ~ o N ~ 256.35 70.28 69.65 7.86 7.75 13 CtciH22N4 270.38 71.08 69.58 8.20 8.09

6 Ci&i9CN04 342.96 49.08 48.42 5.58 5.49

11.81 17.04 16.34 15.70 14.05 13.57 23.06 21.86 20.72

11.65 16.89 16.21 15.53 13.89 13.36 22.83 21.55 20.45

Liebigs Ann. Chem. 1991, 1215-1219

Heterocyclization with Iminium Chlorides, V 1219

zole (12) (130- 131 "C, 48%). - 6-Dimethylamino-2,3,4,5-tetrahy- dro-I-methyl-8-phenyl-iH-azepino[6,7-d]pyrazole (13) (100- 102"C, 63%).

CAS Registry Numbers

l a : 50860-24-7 / l b : 106808-48-4 / l c : 136088-94-3 / 2A: 106808- 35-9 / 3A: 106808-38-2 / 4A: 136088-80-7 / 5A: 136088-82-9 / 6 A : 136088-84-1 / 7 A : 136088-86-3 / 8A: 106808-40-6 / 9B: 136088- 88-5 / 10B: 136088-90-9 / 11A: 136088-91-0 / 12B: 136088-92-1 / 13B: 136088-93-2 / aniline: 62-53-3 / 2-aminopyridine: 504-29-0 / 2-aminobenzothiazole: 136-95-8 / phenylhydrazine: 100-63-0

Part IV: G. Toth, I. Bitter, G. Bigam, 0. Strausz, Magn. Reson. Chem. 24 (1986) 137.

*)G. Toth, I. Bitter, G. Bigam, 0. Strausz, Magy. Kem. Foly. 95 (1989) 26.

3, J. H. Noggle, R. E. Schirmer, The Nuclear Ouerhauser Effect, Academic Press, New York 1971.

4, R. A. Bell, K. Saunders, Can. J. Chem. 48 (1970) 11 14. 5, E. Pretsch, T. Clerk, J. Seibl, W. Simon, Tabellen zur Struktur-

aujklarung Organischer Verbindungen mit Spektroskopischen Methoden, Springer-Verlag, Berlin 1981.

6, A. Bax, J. Magn. Reson. 53 (1983) 517. ') H. Kessler, G. Griesinger, J. Zarbock, H. R. Loosli, J. Magn.

Reson. 57 (1984) 331. 8, G. A. Webb, Annual Reports on NMR Spectroscopy, vol. 18,

Academic Press, London, New York, Boston 1986. 9, W. Stadely, Helu. Chim. Acta 63 (1980) 504.

lo) H. Bohme, H. G. Viche, Zminium Salts in Organic Chemistry, part 1, p. 373, London 1976.

I f ) G. J. De Voghel, T. L. Egguichs, Z. Janousek, H. G. Viche, J. Org. Chem. 39 (1974) 1233.

[123/91]

Liebigs Ann. Chem. 1991, 1215-1219