Michael Reactions of Arylidenesulfonylacetonitriles. A New Route to Polyfunctional Benzo[a]quinolizines

Abstract

Arylidenesulfonylacetonitriles react in acetonitrile with 1-methylisoquinoline and isoquinolin-1-yl-acetonitrile in the presence of piperidine to give benzo[a]quinolizines 6,9 and 7,10, respectively. The structures of the products were established on the basis of elemental and spectral analyses and their chemical reactivity.

Introduction

High yielding syntheses of polyfunctional benzo[a]quinolizines are well documented [1,2,3,4,5,6,7,8,9]. As a continuation of our work on the use of isoquinoline and its derivatives for the synthesis of fused heterocyclic compounds [10,11], we now report a new and general one step route affording polyfunctional substituted benzo[a]quinolizines in good yield from readily available inexpensive starting materials, which competes favorably with the methods previously reported for the preparation of the title compounds.

Results and Discussion

Treatment of 1-methylisoquinoline (1) [12] with arylidenesulfonylacetonitriles 3a-c [13] in boiling acetonitrile in the presence of an equimolar amount of piperidine leads, in each case, to the formation of only one product 6a-c, as indicated by TLC and ¹H-NMR analyses (Scheme 1).

Scheme 1.

The structures of the products 6a-c were established on the basis of their elemental analyses and spectral data (IR, ¹H-NMR, MS). For example, the IR spectrum of compound 6a shows a stretching frequency at 3350 cm^-1 (NH) in addition to characteristic bands at 1315 and 1155 cm^-1 (asymmetric and symmetric stretching vibrations of a SO₂ group). Its ¹H-NMR spectrum reveals a singlet at δ = 6.9 assignable to the C-1 proton and a singlet at δ = 8.8, which disappears upon deuterium exchange, assignable to the NH proton, in addition to the typical signals of the isoquinoline moiety. The formation of 6 may be explained by cyclization of the initially formed Michael addition product 4 to the unisolated product 5. Subsequent autoxidation of the latter leads to the final product 6 (cf. Scheme 1). When the reaction of 1 with 3a-c was carried out in the presence of excess piperidine (2 moles) then the products 7a-c were formed directly. The structures of the products 7 were also inferred from their elemental analyses and spectral data. For example, the IR spectra show a characteristic peak near 3320 cm^-1 due to a NH group. The mass spectra of the products also show a molecular ion peak of high intensity, and the ¹H-NMR and chemical reactivity also support the proposed structures of the products. In light of the previous results, it may be suggested that the unisolated products 5 afford the end products 7 via loss of benzenesulfinic acid (Scheme 1). Similarly, isoquinolin-1-yl-acetonitrile (2) [14] reacts with 3a,b to give 9a,b (cf. Scheme 2). The structures of the latter products were confirmed by elemental analysis and spectroscopic data. Upon treatment of p-nitrobenzylidene phenylsulfonylacetonitrile 3c in this fashion a product 10c was formed directly due to elimination of benzenesulfinic acid from the intermediate 8 (Scheme 2). The structure of the product 10c was confirmed by its independent synthesis via reaction of 2 with 11 (Scheme 3).

Scheme 2.

Scheme 3.

The structures of 10b,c were also confirmed by their chemical reactions as described in Scheme 4. For example, acylation of 10b,c with acetic anhydride or benzoylation with benzoyl chloride in pyridine affords the corresponding N-acetylimino or N-benzoylimino compounds 12b,c and 13b,c, respectively. Nitrosation of 10c with sodium nitrite in acetic acid gives the corresponding N-nitroso compound 14c. Thermolysis of 14c in xylene gives the carbonyl compound 15c. The structure of 15c was confirmed by its alternative synthesis by hydrolysis of 10c with dilute hydrochloric acid. Also, hydrolysis of 10b with dilute hydrochloric acid leads to the formation of 15b. Their elemental analyses and spectral data (cf. Table 1 and Table 2) confirmed the structures of 12, 13, 14 and 15.

Scheme 4.

Table 1.

Analytical data of the synthesized compounds

Compd. no.	Color	Yield %	m.p.°C solvent	Mol. formula Mol. Wt.	% Analysis Calcd. (Found)
					C	H	N	S
6a	yellow	80	225-226	C27H24N2O4S	68.64	5.08	5.93	6.78
			DMF	472.23	(68.72)	(5.02)	(5.83)	(6.66)
6b	dark	82	264-266	C27H23N2O4SCl	63.96	4.54	5.53	6.32
	yellow		DMF	506.72	(64.23)	(4.44)	(5.52)	(6.38)
6c	orange	78	276-277	C27H23N3O6S	62.67	4.45	8.12	6.19
			DMF	517.23	(62.52)	(4.24)	(8.03)	(6.08)
9a	dark	84	258-259	C28H23N3O4S	67.61	4.63	8.45	6.44
	yellow		DMF	497.23	(67.43)	(4.52)	(8.62)	(6.27)
9b	bright	77	320-322	C28H22N3O4SCl	63.22	4.14	7.90	6.02
	brown		DMF	531..72	(63.04)	(4.03)	(7.84)	(6.14)
7a	yellow	81	329-331	C21H20N2O2	75.90	6.02	8.43	-
			DMF	332.19	(75.63)	(6.14)	(8.63)	-
7b	yellow	85	206-207	C21H19N2O2Cl	68.76	5.18	7.64	-
			DMF	366.68	(68.64)	(5.02)	(7.83)	-
7c	yellow	88	214-215	C21H19N3O4	66.84	5.04	11.14	-
			DMF	377.19	(66.90)	(5.13)	(11.24)	-
10a	dark	86	214-216	C22H19N3O2	73.95	5.32	11.76	-
	yellow		DMF	357.19	(73.63)	(5.21)	(11.54)	-
10b	bright	79	223-224	C22H18N3O2Cl	67.43	4.60	10.73	-
	brown		DMF	391.68	(67.13)	(4.73)	(10.94)	-
10c	dark	89	275-277	C22H18N4O4	65.67	4.48	13.93	-
	yellow		DMF	402.19	(65.51)	(4.32)	(13.83)	-
12b	dark	84	153-155	C24H20N3O3Cl	66.44	4.61	9.69	-
	yellow		EtOH	433..70	(66.12)	(4.51)	(9.82)	-
12c	dark	78	150-151	C24H20N4O5	64.86	4.50	12.61	-
	yellow		EtOH	444.21	(64.84)	(4.32)	(12.41)	-
13b	dark	77	241-242	C29H22N3O3Cl	70.23	4.44	8.48	-
	yellow		DMF	495.72	(70.13)	(4.24)	(8.21)	-
13c	brown	79	260-262	C29H22N4O5	68.77	4.35	11.07	-
			DMF	506.23	(68.63)	(4.11)	(10.90)	-
14c	red	81	250-251	C22H17N5O5	61.25	3.94	16.24	-
			DMF	431.19	(61.21)	(3.67)	(16.42)	-
15b	yellow	78	294-295	C22H17N2O3Cl	67.26	4.33	7.13	-
			DMF	392.67	(67.13)	(4.12)	(7.34)	-
15c	yellow	83	244-246	C22H17N3O5	65.51	4.22	10.42	-
			DMF	403.17	(65.23)	(4.12)	(10.35)	-

Table 2.

IR and ¹H-NMR spectroscopic data

Compd. no.	IR (cm-1)	1H NMR (δ ppm)	M+
6a	3350	2.6 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 6.9 (s, 1H); 7.0-	472
	(NH)	7.7 (m, 10H); 7.8 (s, 1H); 7.9 (s, 1H), 8.8 (s, 1H)
6b	3380	3.0 (m, 2H); 3.8 (s, 6H); 4.1 (m, 2H); 7.0 (s, 1H);	507
	(NH)	7.2-7.6 (m, 10H); 7.9 (s, 2H).
6c	3446	3.1 (m, 2H); 3.8 (s, 6H); 4.1 (m, 2H); 6.9 (s, 1H); 7.1-8.5 (m,	517
	(NH)	12H).
9a	2216 (CN),	3.0 (m, 2H); 3.8 (s, 6H); 4.1 (m, 2H); 6.9 (s, 1H); 7.0-7.6 (m,	497
	3417 (NH)	11H); 7.7 (s, 1H)
9b	2219 (CN),	2.8 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 7.2 (s, 1H); 7.3-	532
	3415 (NH)	7.7 (m, 10H); 7.9 (s, 1H)
7a	3386	2.9 (m, 2H); 3.3 (s, 3H); 3.4 (s, 3H); 3.8 (m, 2H); 6.7 (s, 1H); 6.8	332
	(NH)	(s, 1H); 6.9 (s, 1H), 7.1 (s, 1H) 7.2-7.6 (m, 6H)
7b	3252	2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 6.3 (s, 1H); 6.4	367
	(NH)	(s, 1H); 6.7 (s,1H); 7.1 (s, 1H); 7.4-7.8 (m, 5H)
7c	3323	2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.2 (m, 2H); 6.4 (s, 1H); 6.5	377
	(NH)	(s, 1H); 6.7 (s, 1H), 6.9 (s, 1H) 7.1-7.6 (m, 5H)
10a	2221 (CN),	2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.0 (m, 2H); 6.3 (s, 1H); 6.4	357
	3316 (NH)	(s, 1H); 6.7 (s, 1H); 7.2-7.6 (m, 5H)
10b	2225 (CN),	2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.0 (m, 2H); 6.8 (s, 1H); 6.9	392
	3420(NH)	(s, 1H); 7.1 (s, 1H); 7.4-8.2 (m, 5H)
10c	2200 (CN),	2.8 (m, 2H); 3.6 (s, 3H); 3.7 (s, 3H); 4.0 (m, 2H); 6.4 (s, 1H); 6.9	402
	3307(NH)	(s, 1H); 7.1 (s, 1H); 7.4-8.2 (m, 5H)
12b	1656(CO),	2.8 (m, 2H); 3.7 (s, 3H); 3.9 (s, 6H); 4.0 (m, 2H); 6.7 (s, 1H); 7.0	434
	2217 (CN)	(s, 1H); 7.4-8.2 (m, 5H)
12c	1658(CO),	2.0 (s, 3H); 2.9 (m, 2H); 3.9 (s, 6H); 4.0 (m, 2H);	444
	2210(CN)	6,5 (s, 1H); 6.8 (s, 1H); 7.4-7.6 (m, 4H); 7.9 (s, 1H)
13b	1654(CO),	2.9 (m, 2H); 3.8 (s, 3H); 3.9 (s, 3H); 4.1 (m, 2H); 6.7 (s, 1H); 7.3-	496
	2211(CN)	8.2 (m, 11H)
13c	1672 (CO),	3.0 (m, 2H); 3.9 (s, 6H); 4.6 (m, 2H); 6.8 (s, 1H), 7.3 (s, 1H); 7.4-	506
	2210(CN)	8.2 (m, 10H)
14c	2218(CN)	2.7 (m, 2H); 3.8 (s, 6H); 4.0 (m, 2H); 6.7 (s, 1H); 6.8 (s, 1H); 7.4-	431
		8.2 (m, 5H)
15b	1659 (CO),	2.8 (m, 2H); 3.7 (s, 3H); 3.9 (s, 3H); 4.0 (m, 2H); 6.7 (s, 1H); 6.8	393
	2216 (CN)	(s, 1H); 7.4-8.2 (m, 5H)
15c	1666(CO),	2.7 (m, 2H); 3.8 (s ,3H); 4.0 (s, 3H); 4.1 (m, 2H); 6.7 (s, 1H); 6.9	403
	2218 (CN)	(s, 1H); 7.4-8.2 (m, 5H)

• Compound 10c: ¹³C-NMR 27.54, 41.51, 56.78, 56.92, 100.73, 112.06, 113.92, 118.62, 119.82, 120.05, 123.40, 124.31, 130.70, 133.72, 135.31, 139.32, 142.12, 147.82, 148.65, 157.69.
• Compound 9a: ¹³C-NMR 28.95, 47.44, 58.31, 58.39, 95.67, 108.45, 112.09, 114.03, 115.60, 119.22, 119.72, 126.32, 130.29, 130.79, 130.96, 132.51, 133.62, 136.76, 150.08, 152.21, 155.38, 155.94, 157.48, 158.58.

Experimental

General

All melting points were determined on an Electrothermal melting point apparatus and are uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer. ¹H NMR spectra were recorded in CDCl₃ and (CD₃)₂SO solutions on a Varian Gemini 200 MHz spectrometer and chemical shifts are expressed in δ units using TMS as internal reference. Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer, operating at 70 eV. Elemental analyses were carried out at the Microanalytical Center of the University of Cairo, Giza, Egypt. The analytical and spectral data of the compounds prepared is summarized in Table 1 and Table 2.

Synthesis of 2-aryl-6,7-dihydro-9,10-dimethoxy-4-imino-2-phenylsulphonyl-benzo[a]quinolizines 6 and 9.

Piperidine (0.5 mL, 0.005 mol) was added at room temperature to a solution of arylidene-sulfonylacetonitriles 3 (0.005 mol) and 1-methylisoquinoline (1) (1.02 g, 0.005 mol) or isoquinolin-1-yl-acetonitrile (2) (1.15 g, 0.005 mol) in acetonitrile (40 mL). The reaction mixture was refluxed for 8 h. The solvent was evaporated under reduced pressure and the residue was triturated with methanol (10 mL) whereupon it solidified. The crude product was collected and crystallized from DMF.

Synthesis of 2-aryl-6,7-dihydro-9,10-dimethoxy-4-iminobenzo[a]-quinolizines 7 and 10

These compounds were prepared by the same procedure described for the synthesis of compounds 6 and 9 using (1mL, 0.01 mol) of piperidine. The precipitated compounds were crystallized from DMF.

Nitrosation of 10c.

Cold sodium nitrite solution (0.7 g in 10 mL water) was added dropwise to a stirred solution of 10c (2.01 g, 0.005 mol) in acetic acid (30 mL). The mixture was left in an ice bath for 4 h., then the reddish solid that precipitated was collected. Crystallization of the crude product from DMF gave the corresponding N-nitroso derivative 14c.

Thermolysis of 14c.

The N-nitroso compound 14c (2.16 g, 0.005 mol) was refluxed in xylene (20 mL) until its red color disappeared (ca. 20 min). The reaction mixture was then cooled, the crude product was collected, washed with water and crystallized from DMF.

Acylations of 10b,c.

A solution of 10b,c (0.005 mol) in acetic anhydride (25 mL) was refluxed for 1 h. The solvent was removed under reduced pressure and the residue was triturated with water. The solid formed was collected, washed with water and crystallized from ethanol to give N-acetylimino derivatives 12b,c.

Treatment of 10b,c (0.005 mol) with benzoyl chloride (0.58 mL, 0.005 mol) in pyridine (30 mL) at reflux for 30 min. and workup of the reaction mixture in usual way gave the corresponding N-benzoyl-imino derivatives 13b,c.

Hydrolysis of 10 b,c.

A suspension of 10 b,c (2.01g, 0.005 mol) in 10% hydrochloric acid (20 mL) was refluxed for 30 min. The reaction mixture was cooled and the solid that precipitated out was collected and crystallized from DMF to give 15b,c.