MAGNETIC RESONANCE IN CHEMISTRY, VOL. 24, 137-144 (1986)

Condensation of 1,3=Trimethinecyanines with Arylamines. Structural Assignment of the Products by NOE Difference Spectroscopy?

Gtibor T6th" NMR Laboratory of the Institute for General and Analytical Chemistry, Technical University, Budapest H-1521, Hungary

Istvtin Bitter" Institute of Organic Chemistry and Technology, Technical University, Budapest H-1521, Hungary

Glen Bigam and Ott6 Strausz Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada

-

The condensation of 1,3-dichlorotrimethinecyanines and arylamines was found to be highly regioselective. Nuclear Overhauser effect difference experiments proved a linear structure for the formed perchlorates of l-aza-9-azonia-lll-benz~indene, l-aza-9-azouiaanthracene, l,l0-diaza-4a-azonia-9-thiacyclopenta[b]fluo- rene, 6-aza-%azoniabenz[u]anthracene and 6,7-diaza-lla-azoniabenz[u]anthracene derivatives. NOE difference experiments, together with 2D proton-proton and proton-carbon correlation measurements, allowed the complete 'H and -C assignment.

heterocycles, the investigation of the reaction INTRODUCTION mentioned above was continued using unsymmetrical

cyclized 1,3-dichlorotrimethinecyanines. These com- We have earlier reported the reaction of anilines and pounds can be readily prepared from lactams with 2-aminopyridine with symmetrical l73-dich1orotri- dichloromethyleneiminium salts (PIC) ,3 in a manner methinecyanines, affording pyrido[172-a]triazinium similar to that described by De Voghel et aL4 for the salts.' Since we were interested in the preparation of linear derivatives (Scheme 1). new potentially biologically active nitrogen-containing Secondary lactams are expected to react with PIC at

CI

" F 2 +

1 0

q \ O R -t

c6H 5

30 R = H 3b R = C H 3

C H 3

2a 2b

CgH5

40 4 b

Scheme 1

the unsubstituted nitrogen atom. In contrast, 3a * Authors to whom correspondence Should be addressed: NMR, G. behaved like tertiary lactams, owing to the steric T6th; synthesis, I. Bitter. f Heterocyclization with Iminium Chlorides, Part IV. For Part 111, see Ref. 1. smoothly with aniline and different heterocyclic

0749-1581/86/020137-08$05 .OO Received 4 April 1985 0 1986 by John Wiley & Sons, Ltd. Revised 1 July 1985

hindrance at the nitrogen- and reacted

138 G. TOTH E T A L .

1 9 . 2 - 5 20 I- a i i l i n e

- 6 2b + m i l i n e

20 i- 2-cutlinobenz-thiazofe - 7

- 8 40 +- a n i l i n e

40 i 2-aminopyridine - 9

4b +- 2-aininopyridine - 10 Reaction c o n d i t i o n s : I. CH2C12, 40°C,Et3N

2. EtOH + HCl0,oraqueous NaCIO,

A Me, ,Me N

Me, ,Me dza I

Me

5 n = O

50 : base

7 8 9 R = H

10 R = Me

6 n = l

Scheme 2

primary amines in the presence of triethylamine, yielding condensed heterocycles. Since the un- symmetrical 1,3-dichlorocyanines 2 and 4 each have two different electrophilic carbon atoms, in the exocyclic and endocyclic positions, linear A-type or angular B-type annelation can be expected as a result of the nucleophilic attack (Scheme 2).

'H and 13C NMR analysis. The numbering of the hydrogen and carbon atoms used in the Schemes and Tables is not in accordance with IUPAC nomen- clature. This choice, however, facilitates the com- parison of spectroscopically analogous atoms in 5-10. A pairwise comparison of linear (type A) and angular (type B) structures shows that similar lH and 13C chemical shifts can be expected in both types of structures. Chemical shifts alone have therefore not allowed an unambiguous structure determination of 5-10. Inspection of Dreiding models indicates that, for structures of type A, unfavourable steric interactions occur between NMe, and H-12 or H-12a and H-8. In the case of the angular structures of type B, non-bonding interaction between NMe, and H-7 does not occur, but instead a new, similarly

RESULTS AND DISCUSSION

The lH and 13C NMR spectra of the products indicated that the cyclization was highly regio- selective, because only one main product was formed in all cases investigated. We report here the synthesis and determination of the structure of 5-10 and their

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0

rci

I3

r,

‘c3

* Ln d-

0

in

Ln

Ln 0

1O

in

Lo

0

r.

in

r. 0

(x3

3N -4

1” -4

I

W 5 Y-

c O

0 il

0 c 0 V

- L a Y

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2 a ii: W

i

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140 G. TOTH ET AL.

unfavourable steric crowding appears around the NMe group. Utilizing the different steric environments and interactions of NMe, and NMe groups in structures of types A and B, NOE difference experiments seemed to be inappropriate for the determination of structure in 5-10, since the NOE data are extremely sensitive to the inter-proton distances.' These experiments involve the measurement of the intensity change of a proton resonance upon saturating another proton. A strong NOE indicates that the two protons are in close proximity. Two-dimensional (2D) NOE experiments allow the simultaneous observation of all the NOES between closely spaced protons in a molecule.6

In the NOESY spectrum of 8 (see Fig. l ) , the appearance of cross-peaks A1 and A2 proves that the NMe, group is close to H-12a and H-8. At the applied plotting level, the NMe group exhibits only one steric interaction, with H-14 (see cross-peak B1 in Fig. 1). These observations prove the linear A-type structure for 8.

In spite of the advantages of the 2D over the 1D NOE experiment, the latter allows the measurement of the intensity enhancement with a higher accuracy and, in this way, a better estimate of the inter-proton distances in the molecule. The results of the 1D NOE experiments are presented in Table 1. Saturation of the NMe, protons results in simultaneous intensity enhancements of two different protons. This experi- ment allows the assignment of the linear structure (type A) to 5 and 7-10. Owing to the hindered rotation of the NMe, group at room temperature, its signal is broadened in 8-10. At an elevated temperature of 60 or 70"C, because of the rapid rotation of NMe, group, the signal became sharp. To keep a minimum saturation power level, and to avoid the partial saturation of the NMe and other signals, the NOE difference experiment with saturation of the NMe, protons was performed at elevated tempera- ture. Changes in temperature and concentration caused small changes in the chemical shifts of several signals. The high selectivity of the NOE experiment upon irradiation of the NMe, protons of 10 at 60 "C is shown in Fig. 2. Accidental isochrony of H-5 and H-8 was observed for 6, which prohibited the structure determination by exploiting the NOE enhancement

Table 1. Results of proton-proton 1D NOE difference experiments on 5-10 in DMSO-11, at 25 "C

Proton irradiated Proton observed, NOE (%la 5ab NMe, H-8 (13%), H-12 (4%)

NMe H-14 6 H-5, H-8 NMe, (17%), H-6 (28%), H-7 (28%) 7 NMe, H-8(-10%) 8 NMe," H-8 (22%), H-12a (23%)

9 NMe, H-8 (16%), H-12a (18%) 10 NMeZd H-8 (22%), H-12a (23.6%)

NMe H-5 (2%), H-14 (8%)

'The NOE enhancement % refers to 1H. 5-base, solvent CDCI,.

" At 70 "C. At 60 "C.

NMe H-5 (3.5%), H-14b (2.7%), H-14 (10%)

upon saturation of the NMe, signal. Irradiation of the 2H intensity doublet at 7.94 resulted in a characteristic NOE enhancement of the NMe, protons, and no effect was measured for the NMe signal. This experiment gives evidence of a linear A-type structure for 6. Saturation of the NMe protons in 8 and 10 resulted in enhancements of 8-10% for H-14, but at the same time the NOE effect for H-5 on the condensed aromatic ring did not exceed 4%. After considering the corresponding inter-proton distances in these molecules, this experiment gives further support for the linear A-type structure and excludes the angular B-type alternative.

The IH chemical shifts, assignments and selected 3J coupling constants for 5-10 are summarized in Table 2. Even at 400MHz, owing to the overlap of multiplets in the aromatic region, standard decoupling experiments alone could not be used to assign all the proton resonances. The complete assignment was made possible by means of the combined decoupling 2D proton-proton correlation (COSY45) and NOE difference experiments. The advantage of the latter method is the separate observation of coincident signals.

The COSY45 spectrum of 8 allows the determina- tion of proton-proton J connectivities. It is evident from this experiment that the H-12a signal, which is crucial to the structure determination, appears at 7.20 under the extensively overlapped region of the Ph-C-14 proton signals. Irradiation of the NMe protons produced a NOE to the H-14b ortho-protons; the corresponding signal can be separately observed in the NOE difference spectrum of 8 (see Fig. 3).

A comparison of the chemical shifts of 5 with those obtained for the corresponding free base 5a, prepared from the perchlorate salt with aqueous sodium hydroxide, indicates that the positive charge is strongly delocalized, since almost all the signals experience a small downfield protonation shift. The pyrrolidine or piperidine rings in 5-7 are flexible, and rapid interconversion of the conformers at room temperature causes averaging of the methylene protons. The Ph-(2-14 group in 8-10 prefers the quasi-axial position. An analogous behaviour of the phenyl group was observed in the l-phenyltetrahydro- isoquinolinones 3a and 3b used as starting materials in the synthesis of these compound^.^ This follows from the extremely high chemical shift of H-14 (>6 ppm) and the appearance of the H-12d signal in the range 7.58-7.62. For a quasi-equatorial disposition of the Ph-C-14 group, owing to its diamagnetic anisotropy, a pronounced upfield shift would be expected for the H-12d signaL7

The 13C NMR measurements provided further evidence for the structures deduced for 5 , 6 and 8-10. The characteristic chemical shifts and assignments are listed in Table 3 . In the signal assignment we utilized broad band decoupled and proton coupled I3C spectra, selective 13C{1H} decoupling, established additivity ruless and the two-dimensional proton- carbon correlated spectrum of 8 (see Fig. 4). Unambiguous 13C assignment of the C-l4d, C-12b, C-12c and the C-12d, C-8 signals, appearing in close proximity to each other at 128.0, 127.8, 127.7 and

CONDENSATION OF 1,3-TRIMETHINECYANIN WITH ARYLAMINES 141

Table 2. 'H chemical shifts and selected 'J coupling Table 3. =C chemical sh&s of 5. 6 and 8-10

H

NMe NMe, 5 6 7 8

12 12a 12b 12c 12d 13 14 14b 14c 14d NH+

3J 5,6 6-7 7,8 12a,l2b 14,NH

constants (Hz) for 5-10 in DMSO-d,P 5ab 5 6 7 8 9

3.11 3.20 3.36 3.12 3.65 2.99 3.06 3.10 2.91 3.05' 2.97' 7.70 7.71 7.94 8.16 8.04 7.66 7.41 7.63 7.67 7.59 7.80 8.05 7.16 7.40 7.44 7.64 7.51 7.41 7.84 7.85 7.94 8.33 8.29 8.71 3.26 3.40 3.10 3.43

7.20 7.37 7.52

7.58 7.62 7.43 7.50-

1.91 3.59 3.83 3.61 3.94 6.16

7.21 6.03 7.24- 7.35 7.30 7.20-

10.36 11.70 12.20 7.30 10.38

8.0 8.4 8.4 7.7 8.5 8.5 7.0 7.1 7.3 7.7 7.3 6.7 8.3 8.4 8.4 8.2 8.5 6.7

7.9 7.9 4.3

a 4J(68) and 4J(57) values are between 1 .O and 1.6 Hz.

' Broad. Solvent: CDCI,.

- -

l o 3.41 2.98' 7.78 8.1 1 7.48 8.77

7.36

7.50- 7.62

6.18 7.36

7.30 7.20-

8.5 7.0 6.8 7.7

C NMe NMe, 2 4 5 6 7 8 9

10 11 12 12a 12b 12c 12d 13 14 14a 14b 14c 14d

in DMSO-dG 5 6 8

32.6 39.1 38.6 42.8 43.0 44.7

152.7 151.0 151.5 136.4 136.2 137.2 117.4 117.8 118.7 130.4 130.8 131.5 123.8 124.1 124.3 125.4 125.1 126.2, 119.0 118.4 119.8 156.0 155.8 154.3 112.9 113.1 104.9 25.0 24.0 128.0

125.7 127.8 127.7, 126.3

19.7 134.2 52.4 50.9 66.3

139.0 125.7 128.8 128.0

9

41.2 148.8 150.8 124.0 139.1 11 5.9 131.0

159.0 104.2 124.0 126.5 129.6 127.8 127.4 136.6 57.3

141.7 126.3 128.8 128.2

8.25 8.0 7.75 7.5 7.25 I 1 I l l 1 I l l 1 I I ~ I I l l 1 1 ' 1 1

PPrn

Figure 3. Control spectrum and I D NOE difference spectrum of 8 upon saturating NMe. DMSO-&,70 "C, 400 MHz.

10

35.4 41.4

148.1 150.8 124.3 139.5 116.4 131.0

157.2 105.0 124.0 126.3 129.7 128.2 126.9 136.7 65.8

139.6 126.0 129.0 128.2

126.3, 126.25, respectively, was possible on the basis of the complete 'H assignment. The proton-carbon correlated spectrum of 8 is shown in Fig. 4. The similar chemical shifts of the C-4, C-5, C-6, C-7, C-8 and C-9 signals in 8, 5 and 6 suggest that the structure alteration in relatively remote parts of the molecules does not significantly affect their shifts, as expected. In addition to the analogy for the chemical shifts of the C-7 and C-8 signals in 8 to 5 and 6, selective 13C{ IH} decoupling experiments were utilized to support their assignments. It was proved that, for these two closely spaced signals, C-7 appears at higher field than C-8.

A characteristic feature of the spectra of the cycloadducts is the strong deshielding of C-6. A similar phenomenon was observed with the cor- responding carbon atom of 9-substituted acridinium salts9

In the proton coupled 13C spectra of the products, the quaternary C-4 and C-9 atoms exhibit a triplet splitting pattern of 7 Hz, due to the two 3J(CH) ortho couplings.

Structure 10 can be formally derived from 8 by replacing C-9 by N-9. As a consequence of this relationship, the two compounds will show different chemical shifts only in the neighbourhood of the bridgehead position 9. In accord with this expectation, all the other signals of the two compounds occur at almost identical fields.

The assignment of the C-5 to C-8 signals in 9 and 10 was also confirmed by selective 13C{ 'H} decoupling experiments. It follows from these measurements that the sequence is C-6>C-8>C-5>C-7. It should be noted that C-8, despite the attached nitrogen atom bearing a positive charge, is less shielded than C-6. A further characteristic feature of these spectra (9,lO) is the strong shielding of C-7. This signal is shifted about 8ppm to higher field than in 5, 6 and 8. A similar,

142 G. TOTH ET AL.

H-12a

~-14r7? d

"i H-12d

H-6

H-5

H-8

130 I

120 ppm

I I

I

I

I

Figure 4. 2 0 proton-carbon correlated spectrum of 8. DMSO-c&, 25"C, 400/100 MHz.

extremely high shielding of the corresponding carbon atom was observed with 1,2,3,4-tetrahydro-llH-py- rido[2,1-b]quinazolin-ll-one, where the depicted canonical formulae can be regarded as close analogues to 9 and 1 O 1 O (Scheme 3) .

The high deshielding for C-6 and shielding for C-7 in 9 and 10 can be better understood by considering the canonical forms I and 11; in I1 a positive Scheme 3

( y - ~&Pc&ll 6.2 - 134.3

CONDENSATION OF 1,3-TRIMETHINECYANIN WITH ARYLAMINES 143

I I1

Scheme 4

polarization occurs on C-6 (Scheme 4). At the same time, the N-%C-8=C-7 moiety in I1 represents an enamine unit, where the known delocalization along this strucure element can lead to enhanced electron density at C-7, which is in a ,6 position to N-9.

In summary, the reaction of 1,3-dichlorocyanines and arylamines yielded, with high selectivity, linearly condensed products. The structure determination was made by means of 1D and 2D NOE experiments. The complete 'H and 13C assignments were achieved, in addition to the standard 'H{lH} and 13C{'H) decouplings, by 2D proton-proton (COSY45) and proton-carbon correlated experiments.

EXPERIMENTAL

All the compound investigated were characterized via correct elemental analysis data and their IR spectra, in addition to their NMR spectra. Melting points are uncorrected.

Preparation of the heterocyclic salts 5-10

General procedure. To a solution of 10 mmol of 2 or 4 in 25 cm3 of dry dichloromethane were added 10 mmol of amine and 30mmol of triethylamine, and the mixture was boiled for 2-3 h. After evaporating the solvent, the residue was triturated with 25cm3 of water and two different work-up methods were used, as follows. (a) The insoluble oily material was dissolved in 10cm3 of ethanol and the salts were precipitated with 70% perchloric acid (5 ,6) . The free base 5a was liberated from the salt 5 with aqueous sodium hydroxide. (b) The aqueous solution was clarified with charcoal and the salt was precipitated with 30% aqueous sodium perchlorate (7-10).

All salts were recrystallized from methanol.

Compounds (yield %) l-Methyl-2,3-dihydro-4-di- methylamino-l-aza-9-azonia-1H-benzlf]indene per-

chlorate (S ) , m.p. 206-208°C (52%); Sa, m.p. 161-162 "C (80%); l-methyl-1,2,3,4-tetrahydr0-10- dimethylamino-l-aza-9-azoniaanthracene perchlorate (6), m.p. 202-204 "C (41%); l-methyl-2,3-dihydro-4- dimethylamino-l,l0-diaza-4a-azonia-9-thiacyclopenta- [blfluorene perchlorate (7), m.p. 255-256 "C (72%); 5-phenyl- 5,6-dihydro-6-methyl- 12-dimethylamino-6- aza-7-azoniabenz[a]anthracene perchlorate (8), m.p. 288-290 "C (45%) ; 5-phenyl-5,6-dihydro-12-dimethyl- amino-6,7-diaza-l1a-azoniabenz[a]anthracene perchlo- rate (9), m.p. 290 "C (42%); 5-phenyl-5,6-dihy- dro-6-methyl- 12-dimethylamino-6,7- diaza -1 1 a- azonia benz[a]anthracene perchlorate (lo), m.p. 290 "C (48%).

NMR spectroscopy

The 'H and 13C NMR measurements were carried out in the Fourier transform mode at 400 and 100MHz, respectively, using a Bruker WH-400/DS NMR spectrometer and the Aspect 2000 data system utilizing 32K of data memory. All experiments were carried out at ambient temperature (298K). The deuterium resonance of the solvents was used for the lock signal. The 'H chemical shifts and coupling constants were calculated as first order at 400 MHz, and are reported with an accuracy of approximately rtO.01 ppm and f0.20 Hz, respectively. For maximum accuracy, the spectra were expanded to a width of 5 Hz cm-'. The solutions used for the NOE difference experiments were degassed four times using the freeze-pump-thaw technique, and then sealed under vacuum. All glassware was cleaned extensively, including a nitric acid wash to diminish paramagnetic impurities. For NOE measurements a delay time of 8 s was used. The 2D COSY45 measurements were carried out using the Bruker software package (2D spectral width 3200Hz, delay time 2.0s, mixing time 0.5s, no. of repetitions 8, no. of increments 512, FT size 1K X 1K). The NOESY experiment was per- formed on a Varian XL-400 spectrometer in the NMR Applications Laboratory of the Varian Co. (Zug, Switzerland).

Acknowledgements

The authors are grateful to Dr G. Kotovych for helpful discussions, Dr. Gy. De6k and Dr L. Hazai for providing samples 3a and 3b and Dr R. Kyburz for the NOESY spectrum. One of us (G.T.) thanks the Natural Sciences and Engineering Research Council of Canada for a visiting fellowship.

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