2474
J. Org. Chem., Vol. 42, No. 14,1977
Chapman, Elwood, Heseltine, Hess, and Kurtz
Annelation of Pyridinium Rings onto Nitrogen Heterocycles D. D. Chapman,* J. K. Elwood, D. W. Heseltine, H. M. Hess, and D. W. Kurtz Research Laboratories, Eastman Kodak Company, Rochester, New York 14650 Received October 13,1976 Numerous, new fused pyridinium salts were synthesized by the interaction of protonated heterocycles with a,@unsaturated ketones. The mode of addition was shown to depend on the heterocycle used and sometimes on the reaction conditions. Dihydropyridinium intermediates could be isolated in many cases.
In a preliminary communication' we described a simple method for the synthesis of fused pyridinium salts by the reaction of protonated heterocycles with methyl vinyl ketone. In this paper we report, the extension of this method to other heterocycles and unsaturated ketones. The first example of this synthesis' was the preparation of 3-methyl-4-phenylpyrido[2,l-b]benzothiazolium bromide (4) according to Scheme 1. The formal Michael addition of 2benzylbenzothiazolium bromide (1) to methyl vinyl ketone (MVK) in acetonitrile gave the adduct 2. Additions of this type to salts of other nitrogen heterocyclic bases have been reported p r e v i o u ~ l y .Product ~,~ 2 was characterized by its IR, NMR spectra, and elemental analysis. Heating 2 in a variety of solvents caused ring closure of the active methylene and the carbonyl group to give the dihydropyridobenzothiazolium salt 3. The NMR spectrum (MeZSO-de) of this compound showed a methyl group at 6 2.03 and two methylene triplets centered at 6 3.18 and 4.85.The aromatization of 3 to 4 could be carried out in a variety of ways, e.g., prolonged heating in DMA or MeZSO, but most easily by heating with Pd/C in DMA. Characteristic peaks in the NMR spectrum (MezSO-ds) or 4 were a methyl group at 6 2.53 and a single proton doublet at 6 10.24 assigned to the hydrogen at position 1. The extension of this reaction sequence to the other nitrogen heterocyclic salts shown (5-8) gave varying results. Under
Scheme I
Br1
@ p 2 P h
Br-
J
I
CH,CH,COCH, 2
DMA, heat
Scheme I1
Br-
5
+ CH2=CHCOCH,
@CH2Ph
I
CH,CH,COCH,
Br10
clod-
6
c10,-
11
Br8
7
appropriate conditions salts 6 and 7 gave in turn Michael adducts (9 and 121, ring-closed dihydropyridinium salts (10 and 13), and the fully aromatic fused pyridinium salts (11 and 14) (Scheme 11).Although 8 successfully formed the Michael adduct 15 with MVK, it failed to give an appreciable amount
I
CH,CHICOCH, 12
13
14
Br-
&H2CH2COCH3 15
of ring-closed dihydropyridinium salt. This behavior was attributed to the low acidity of the benzylic methylene causing
the reverse Michael reaction to compete favorably with ring closure. When the Michael addition was carried out with 5 , the vinyl group of the MVK became attached to the benzylic carbon as opposed to the nitrogen, and cyclization and aromatization occurred to give 16 instead of the expected 17. The structure of 16 was established by its NMR spectrum, which showed a methyl peak at 6 3.32 which is at least 0.5 ppm toward lower field than that expected from structure 17. The
Annelation of Pyridinium Rings onto Heterocycles Me.
Me
Me
Me
(210,17
J . Org. Chem., Vol. 42, No. 14, 1977 2475 The dihydropyridinium ester 26 was prepared from 20 via the procedure used to prepare 23 from 19. Upon aromatization, loss of the ethoxycarbonyl group and substantial hydrogenolysis of the chlorine-carbon bond also occurred giving an inseparable mixture of 27 and 28. The mole percentages of the two salts present were estimated from the elemental analyses as both the perchlorate and fluoroborate salts. The NMR (Me2SO-ds) of mixed 27 and 28 showed a broadened
spectrum also lacked the doublet at 6 10.0 which is characteristic of a proton a to a positively charged pyridine nitrogen. This reversal of the mode of addition of MVK will be discussed later with reference to 2,3,3-trimethyl-3H-indolium salts and other unsaturated ketones. In order to facilitate ring closure of the Michael adducts from various benzimidazolium salts and MVK, the acidities of the hydrogens involved in the condensations were increased by activating with ethoxycarbonyl groups. When 18 was treated with MVK in acetonitrile, the Michael adduct was not Ph
Me
I
I
H
C10,-
H
18
C10,19
Et
I
20
isolated in crystalline form. The resulting syrup was boiled in 2,6-lutidine and subsequently treated with ethanol to give the dihydropyridinium salt 21. Aromatization to 22 was achieved by heating in DMA with Pd/C as before. When 19 Ph I
21
n (-80%)
28 (-20%)
doublet at 6 8.53 (J = 8 Hz) assigned to the proton at position 9 in 27; a small doublet at 6 8.76 ( J = 2 Hz) was assigned to the proton at position 9 in 28. The unexpected loss of the ester group during this reaction suggested that hot DMA containing HC1 might be an effective medium for carrying out the ester hydrolysis of compounds of this type. In support of this suggestion it was found that the dihydropyridinium ester 23 could be selectively aromatized or hydrolyzed and decarboxylated. The resulting quaternary salts 29 and 30 were then converted to 31. Boiling DMA con-
22
was reacted with MVK in acetonitrile, again a crystalline adduct was not isolated. Ring closure presumably occurred when the resulting syrup was subsequently boiled in pyridine. In addition to the expected product, 23, 24, or 25 was also
25, R = H
isolated depending upon whether the workup involved ethanol (to give 24) or acetic acid (to give 25). Evidently, the vinyl group of the MVK reacted partially at nitrogen and partially a t the activated methylene. The structures of 24 and 25 were assigned from the NMR spectra (90 MHz; 100 atom % Me?SO-de) using decoupling techniques.
taining 5%of concentrated hydrochloric acid was very effective a t hydrolyzing and decarboxylating the esters if part of the solvent was allowed to boil off. The use of a reflux condenser resulted in substantially lower yields. With Michael adducts containing a 2-methyl group of sufficient acidity, e.g., the 2-methylbenzothiazolium adduct 32, the ring closure reaction to form 33 does occur but only to the
2476 J. Org. Chem., Vol. 42, No. 14, 1977
Chapman, Elwood, Heseltine, Hess, and Kurtz Table Ia
R,
Calcd, %
Registry 55867-79-3
R, CH,
55868-11-6
H
62476-17-9
€I
55953-69-0
H
55953-76-9
H
62476-19-1
CH,
no.
a
Yield, CH,, PPm
R3
C
H
N
C
H
N
H
CH3
59.3
5.0
4.3
59.6
5.3
4.6
217
27
3.20
CH3
63.5
5.2
3.4
63.7
5.2
3.6
298-300
50
3.22
Ph
69.8
5.0
3.1
69.4
5.1
3.1
>310
30
Ph
67.8
5.1
2.9
67.8
5.3
2.9
258
26
67.8
5.1
2.9
67.5
5.3
2.9
245
43
67.3
5.9
3.4
67.1
5.9
3.3
290
25
CH;O*
Ph C
Found, %
R2
H
O
e
Ph
CH,O-@
CH3
CH,O-@
Satisfactory analytical data
(i 0.4%
2. c10,W
I CH2CHLCOCH,
CH,
*
c10,-
-U b C H ,
-
6
-
DMA Pd'C
3.32
2,3,3-Trimethylindolium perchlorate (35) also proved to be the most reactive of all the salts studied in terms of its reaction with other unsaturated ketones. When it was heated
33
32
Mp,"C
for C, H, N ) were reported for all new compounds listed in the table.
1. pyridine
Br-
(210,-
C10,-
c10,-
Ph
HjC
39
34 with benzylideneacetone at 100 "C, addition and cyclization occurred to form 39, the 8-phenyl analogue of 38. extent of a 17%yield owing to the competition with the reverse Some other pyridoindolium salts formed by the carbon alMichael reaction. Aromatization to 34 was carried out in the kylation of both the 2-methylindolium salt 35 and the 2normal manner. In the case of the reaction of 2,3,3-trimethyl-3H-indolium perchlorate (35) with MVK either neat or in acetonitrile the product was the open-chain adduct 36 which when heated in r n C 2 H 5 H,C CH, HjC CH3 H,C CH, H Br-
6
-1
&CH3
H 35
X-
5
CH,CH,COCH,
36
40
-
c10,-
& L H J
c10,-
37
ethylindolium salt 40 with unsaturated ketones are shown in Table I. The 3H-indolium salt 35 will also react with unsaturated ketones where the ketone function is contained in a ring; for
pyridine formed the aromatic compound 37. No dihydro intermediate was observed. If, however, the initial reaction of 35 with MVK was run in DMA at room temperature no 36 was obtained and the only 35
o?$ (210,-
-
R
38
product was 38 analogous to 16 in which carbon alkylation predominated. The two products 37 and 38 could readily be distinguished by the methyl resonances in their NMR spectra: 37 at 6 2.79 and 38 at 6 3.33.
42
example, 2-benzylidene-1-indanone41 (R = Ph; X = CH2) gives the indenopyridoindolium salt 42 (R = Ph; X = CH2).
J.Org. Chem., Vol. 42, No. 14, 1977 2477
Annelation of Pyridinium Rings onto Heterocycles Table
IP
Calcd, % Registry no.
R
X
5 5 9 53-7 1-4
Ph
6 2 4 76-21-5
-
61049-39-6
'1,4
61049-41-0
C
62476-23-7 a
H
O
C
G
Ph
Satisfactory analytical d a t a
(t 0.4%
C
H
N
C
H
N
Mp, "C
Yield, %
CH,
70.5
4.8
3.1
70.5
5.1
2.8
259-261
48
CH,
68.6
4.9
2.9
68.5
4.9
2.8
229-230
29
CH,
66.8
4.5
3.1
66.5
4.8
3.0
229-230
18
0
64.8
4.2
2.7
64.8
4.1
2.6
300
26
C=O
68.4
4.2
3.0
68.4
4.5
2.8
300
11
for C, H, N ) were reported for all new compounds listed in the table.
Table I11
R
Ph
CH ,O,C
+
Found, %
2-Benzyl-3-(3-oxo-1-butyl)benzothiazolium Bromide (2). 2Benzylbenzothiazolium bromide (1,24.5 g) in acetonitrile (100 mL) was treated with methyl vinyl ketone (6 g) and stirred overnight a t room temperature. The starting material dissolved and the product precipitated: yield 19.9 g (66%); mp 144 "C; IR 1710 cm-l; NMR (MeOD) 6 5.05 (s, 2 H, CH*Ph), 2.2 (s, 3 H, CH&O), 3.4 (t, 2 H, -CH2CO), 5.07 (t, 2 H, N+CH2). Anal. Calcd for ClaHlaBrNOS: C. 57.4: H. 4.8: N. 3.7. Found: C. 57.3: H, 5.1; N, 3.8. 1,2-Dihydro-3-methyl-4-phenylpyrido[2,1b]benzothiazolium Bromide (3). The adduct 2 (10 g) was heated to reflux in dimethyl- ' acetamide (50 mL). The solution was then cooled and the product collected, yield 8 g. Recrystallization from ethanol gave mp 208-210 "C: NMR (Me2So-d~)6 2.03 (s, 3 H, CH3), 3.18 (t,2 H, -CHzC=), 4.85 (t, 2 H, -CH2Nf), 7.4-8.4 (m, 9 H, aryl). Anal. Calcd for CIaHlGBrNS: C, 60.3; H, 4.5; N, 3.9; S, 8.9. Found: C, 60.0; H, 4.6; N, 3.9; S, 8.9. 3-Methyl-4-phenylpyrido[2,1-b]benzothiazoliumPerchlorate (4).The dihydro compound 3 (1g) was refluxed in dimethylacetamide (20 mL) in the presence of 10%palladium on charcoal (0.1 g) for 2 h. The product was isolated by filtration and converted to the perchlorate: yield 0.6 g after recrystallization from ethanol; mp 218-219 "C; NMR (MezSO-d6)62.53 (s,3H,CH3),7.7(~,5H,Ph),7.81-9.23(rn, 5 H, aryl), 10.24 (d, 1 H, J = 7 Hz, HI). Anal. Calcd for ClsH1&1NO& C, 57.5; H, 3.8; N, 3.7; S, 8.5. Found: C, 57.6; H, 3.9; N, 3.6; S, 8.6. 2-Benzyl-5-phenylbenzoxazole(Free Base of 6). 2-Arnino-4phenylphenol(89 g) and phenylacetic acid (65 g) were heated together at 200-220 "C for 3 h. The product was treated with aqueous sodium hydroxide and the mixture extracted with chloroform. Removal of the chloroform gave an oil which was crystallized from hexane (Norit carbon) to give white needles (67 g, 49%), mp 52-54 "C. Anal. Calcd for C ~ O H ~ B NC,O84.2; : H, 5.3; N, 1.9. Found: C, 84.2; H, 5.5; N, 4.9. 2-Benzyl-3-(3-oxo-1-butyl)-5-phenylbenzoxazolium Bromide (9). 2-Benzyl-5-phenylbenzoxazoliumbromide (6, 1.7 g) was suspended in acetonitrile (25 mL) and methyl vinyl ketone (0.7 g) added with rapid stirring. The solid dissolved and after 40 min the solution was poured into ether (150 mL). The product (0.8 g, 40%) was collected and had mp 106-108 "C, IR 1710 cm-l. Attempts to recrystallize this material led to decomposition. 1,2-Dihydro-4,8-diphenyl-3-methylpyrido[ 2,l-b] benzoxazolium Bromide (IO). 2-Benzyl-5-phenylbenzoxazoliumbromide (6, 6.7 g) and methyl vinyl ketone (2.8 g) in dry acetonitrile (100mL) were stirred at room temperature for 104 h. The product (4 g, 55%) was isolated by filtration and after recrystallization from chloroformhexane had mp 300-313 "C dec; NMR (MeOD) 6 2.12 ( s , 3 H, CH,
