TETRAHEDRON Pergamon Tetrahedron 54 (1998) 6191--6200

Annulation of Imidazolines with bis-Electrophiles: Synthesis of Imidazo[1,2-a]pyridines

Raymond C. F. Jones* and Pravin Patel
Chemistry Department, The Open University, Walton Hall, Milton Keynes MK7 6AA, U.K.

Simon C Hlrst and Mark J Smallridge

Chemistry Department, University of Nottingham, Nottingham, NG7 2RD, U.K. Received 17 March 1998; revised 1 April 1998; accepted 2 April 1998
Abstract:

1-Benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole undergoesannulation with a varietyof 1,3-bis-eleetrophiles(a,ll-unsaturated acid derivatives, 13-ketoesters,a,lt-unsaturated aldehydes) to form imidazo[l,2-a]pyridines. 1998Elsevier Science Ltd. All rights reserved.

INTRODUCTION A theme of our studies with the 2-imidazoline (4,5-dihydroimidazole) heterocycle 1 has been the generation and utilisation of nucleophilic reactivity at the a-carbon atom. l Indeed, we have reported extensively on the reactivity of lithio-derivatives 2, including the realisation of the doubly nucleophilic synthon 3 by successive reactions at N(1) and C(a).ld,2 An alternative readily available source of nucleophilic properties at C(a) is found in the enaminoester 4. ta Prompted by the biological activity shown by many imidazolines, 3 and by the opportunity to access aza-analogues of the bicyclic indolizidine system (which is found in a number of bioactive natural products4), we have explored the annulation of the heterocyclic keteneaminal 4 in reaction with bis-electrophiles according to the general Scheme 1. We report herein details of successful imidazo[l,2-a]pyridone formation with a variety of carbonyl 1,3-bis-electrophiles, namely or,Itunsaturated carbonyl compounds (acid derivatives, aldehydes), ll-ketoesters and derivatives. 5 ct,13-Unsaturated ketones show a distinctive behaviour 5b that will be reported separately, and we have already reported on annulation with dihalloalkane electrophiles. 6 Brief trials with some carbonyl 1,2-bis-electrophiles are also described. Related annulation studies have been reported elsewhere. 7

R1
5 ~
4~.N 1 L a

CH2Ph N

CH2Ph N a

~ l

GH2Ph N .C02Et
~N
m

4 Scheme I

In=O, 1 J

0040-4020/98/$19.00 1998 Elsevier Science Ltd. All rights reserved. Plh S0040-4020(98)00312-3

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R. C. F. Jones et al./Tetrahedron 54 (1998) 6191--6200

RESULTS AND DISCUSSION The enaminoester 4 is easily prepared from C-acylation of lithio-imidazoline 2 with diethyl carbonate, or (more conveniently on a preparative scale) directly from N-benzyl-l,2-diaminoethane and the imidate obtained from ethyl cyanoacetate (EtOH, HCI). la Our intention when using ml3-unsaturated acid derivatives as 1,3-bis-electrophiles was to sufficiently activate the acid function to promote initial N-acylation with subsequent conjugate C-addition; this sequence has been observed with related cyclic enaminoesters. 8 Thus reaction of 4 with propenoyl chloride (pyridine, toluene at reflux) led to the hexahydroimidazo[1,2-a]pyridone 5a in good yield. A more convenient protocol, however, was developed based on in situ formation of (x,~-unsaturated acyl imidazolides. Thus the c~,[~unsaturated acid (propenoic, 2-butenoic, 3-pbenylpropenoic, propynoic) was treated with 1,1'-carbonyldiimidazole (THF, 25"C, 3h) before addition of the ketene aminal 4 and heating at reflux for 24h. Simple basic work-up by partition of the reaction mixture between chloroform and aqueous sodium hydrogencarbonate afforded the imidazopyridones 5a-c and 6, respectively, in excellent yields (Scheme 2). The acid component was used in excess. Interestingly, when chromatographed on silica, the imidazopyridones 5a and 5b underwent hydration to afford the cyclols 7a and 7b, respectively; the former was obtained as a mixture with 5a from which pure cyclol 7a could be isolated in low yield by further chromatography, whilst 7b was obtained in good yield but could not be fully characterized. In contrast, the imidazopyridones 5c and 6 were stable towards chromatography. It is known that acylamidines undergo hydration to form cyclols more readily than unsubstituted amidines, 9 and we have observed a related cyclol formation in other work. lc The cyclols 7 show the expected extra peaks in the IH NMR spectra for OH and CHCO2Et, and also exhibit an upfield shift of the benzylic protons of approx. 1 ppm relative to the corresponding imidazopyridines 5; the signals from the methylene protons at C-4 and C-5 of the imidazoline ring of cyclols 7 also show a much greater chemical shift separation (1-1.2 ppm) than the corresponding signals for imidazopyridones 5. ml3-Unsaturated esters were briefly examined as cyclocondensation partners. Treatment of enaminoester 4 with ethyl propenoate (ethanol at reflux), followed by chromatography on silica gave the expected cyclol 7a

C, H2Ph
N

RCH=CHCONJ~'N

~'N~'~'~CO2Et H CH2=CHCOCI pyridine ..~/N

CH2Ph N .CO2Et SiO2 column

0
5a;R=H 98%
5b; R = Me 89=/o 5 c ; R = P h 98%

CH2Ph [~1~ .OHCO2Et

0
7a;R=H
7b; R = Me

CH2Ph ~N .CO2Et
0
5a 82%

X=CCON
CH2Ph
0
6 93%

Scheme 2

R. C. F. Jones et al. / Tetrahedron 54 (1998) 6191-6200

6193

(Scheme 3). Reaction of 4 with methyl propynoate (ethanol, reflux) afforded the trans (J 16 Hz) C-addition product $ (95%); the illustrated enamine geometry is proposed based on spectroscopic similarities between 8 and starting material 4.]0 Isolation of this C-addition product implies, in line with the work of others, 10,11that annulation with conjugated esters proceeds via an initial C-addition, whereas we suggest (see above) that the more reactive conjugated acyl imidazolides proceed via initial N-acylation. It has been shown that the reaction of secondary enamines such as 4 with propynoate esters in non-protic solvents proceeds via an azaene pathway, I which can be viewed as a conjugate addition with concerted intramolecular proton transfer. CH2Ph N
8

~N~-'~ /

CO2Me

,,~H - C O MEO ~N C= C 2 e t H ,
N H

CH2Ph

k c

I.H2C=CHCO2Et, EtOH. ~I~I~O~co2Et

--N/~
O 7a

CH2Ph

CO2Et

O2Et 2. SiO2 chromatography

4

Scheme

Using 1,3-bis-electrophiles at a higher oxidation level, enaminoester 4 was found to react with 13-ketoesters, Scheme 4. Reflux in toluene with ethyl acetoacetate afforded an excellent yield of a separable mixture of the regioisomeric imidazopyridin-5-one 9a (79%) and imidazopyridin-7-one 10 (21%), arising from competing acylation at N(3) or at the enamine C(ct). The regiochemical assignment of 9a and 10 was based on n.O.e experiments; irradiation of the alkenyl-CH3 at ~ 2.21 in the 5-oxo isomer 9a gave enhancement only of the alkenyl-H (,~ 5.80), whereas irradiation of the corresponding signal in the 7-oxo isomer 10 produced enhancements of both the alkenyl-H and an imidazoline ring methylene signal. The 5-oxo isomer also exhibits more extended conjugation than the 7-oxo compound in the UV spectrum. When ethyl benzoylacetate was used as bis-electrophile, only the 5-oxo isomer 9b was obtained (72%). The enol ether, ethyl 3methoxy-2-butenoate 11, led to the 5-oxo compound 9a as the only imidazopyridone component of a complex reaction mixture. The related annulation of 2-benzyl-2-imidazoline with ethyl acetoacetate has been reported to afford an imidazopyridin-7-one,12 presumably via enamine formation with cyclisation by C-acylation. No reaction was observed between the ketene aminal 4 and pentan-2,4-dione or diethyl malonate under a variety of conditions: toluene at reflux, with or without catalytic tohiene-4-sulphonic acid; THF at reflux, sodium hydride. Starting materials were recovered in all cases.

CH2Ph N CO2Et H
4

R..~.CO2E t PhMeat reflux, p-TsOH (cat.)

CH2Ph ~ N CO2Et R
9a; R = Me 9b; R = Ph

CH2Ph J N CO2Et O

MeO O2Et 11

10

Scheme

Next we examined a,~-unsaturated aldehydes as 1,3-bis-electrophiles. Treatment of enaminoester 4 with enals in refluxing solvent (2-butenal in acetonitrile; 2-methyl-2-butenal, 2-methylpropenal, 3-pbenylpropenal in dioxan) gave annulation products 12,a-d, Scheme 5. The isolated yields of tetrahydroimidazopyridines 12

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R. C. F. Jones et al. I Tetrahedron 54 (1998) 6191--6200

were only moderate after chromatography; presumably water addition at C-8a to produce polar cyclols is intervening to lower recoveries. In the case of 12a a higher yield was secured by distillation rather than chromatography (62 vs. 53%), but this did not prove possible with 12b-d. We suggest that this annulation proceeds via initial conjugate C-addition followed by cyclocondensation to form the enamine function. This sequence is supported by the observation that no enamine formation takes place with simple aldehydes. In addition, the reaction of enaminoester 4 with propenal unexpectedly afforded the imidazoline-substituted cyclohexene 13 (60% based on 4, with 1.2 mol equiv, of propenal, i.e. quantitative based on the aldehyde). This structure is supported by 1H-IH and 1H-13C correlation spectroscopy, and rationalized by conjugate Caddition of enaminoester 4 to two molecules of aldehyde followed by intramolecular aldol condensation.
R1

G H2Ph

C, Ph H2

RI

12a;R I = H , R 2=Me 12b; R1 = R2 = Me 12c;R I = M e , R 2 = H 12d;R I = H , R 2=Ph Scheme 5

62% 32% 32% 27%

13

When a,l~-unsaturated ketones and lactones are reacted with ketene aminal 4, the initial Michael adducts are isolated and cyclocondensation does not occur. 5b These conjugate additions, and the further chemistry of the Michael adducts that leads inter alia to a novel piperidine synthesis, 13 will be reported separately. The above findings suggest that the enaminoester 4 shows a preference for conjugation addition of C(a) onto a,l~-unsaturated carbonyl systems, shown schematically in Fig. 1. We speculate that the reactions with lidicarbonyl compounds usually follow a similar pathway via conjugate addition onto their enol forms (Fig, 1; R 3 = OX). This would account for the preferred regiochemistry of 13-ketoester annulation and the reaction with enol derivative 11. The lack of reaction with 13-diesters may be related to their lower enol content (e.g. diethyl malonate 7.7 x 10-3% vs. ethyl acetoacetate 8.0% in pure compound), fI-Diketones have much higher enol content (pentane-2,4-dione 76.4%) and we propose that they may undergo ready conjugate addition (Scheme 6) but that the primary adduct 14 will resist cyclocondensation (cf. the results with a,l~-unsaturated ketonesSb), and our experience with 2-(2-hydroxyalkyl)-2-imidazolines suggests they will undergo 'retroaldol' fragmentation under the reaction conditions, Ic thus returning starting materials.

CH2Ph

.~OH

O
Fig. 1 Scheme 6

14

R. C. F. Jones et aL / Tetrahedron 54 (1998) 6191-6200

6195

As a representative of carbonyl 1,2-bis-electrophiles, we observed annulation of ketene aminal 4 with the ct-diester diethyl oxalate. Under neutral (toluene, reflux) or basic conditions (THF, reflux, sodium hydride) starting materials were recovered, whilst under acidic conditions (toluene, catalytic toluene-4-sulphonic acid, reflux 24 h) the dioxopyrrolo[1,2-a]imidazole 16 was isolated (50%). When the reaction was interrupted after 12 h, it was possible to obtain a low yield (28%) of N-acylation product 15 (Scheme 7); 6 5.5 (CH), no NH absorption in the IR spectrum, that was not fully charaeterised. These findings are consistent with a recent report on the reaction of oxalate esters with N-unsubstituted heterocyclic ketene aminals. 7

C, H2Ph N H
O2Et 4

EtO2C-CO2Et PhMeat reflux, p-TsOH(cat.)

r CH2Ph ] N ==CHCO2Et [ ~'~_ J CO2Et

CH2Ph ~ ~N
O

15 Scheme 7

16

We have thus shown that the enaminoester 4 is a synthetically useful 1,3-(C,N)-bis-nucleophile in annulation with a range of carbonyl 1,3-bis-electrophiles to form imidazo[1,2-a]pyridines, and with a 1,2diester to form a pyrrolo[ 1,2-a]imidazole. EXPERIMENTAL
General: Melting points were measured on a Kofler hot-stage and are uncorrected. IR spectra were

recorded on Perkin-Elmer 710B, 1710 FT-IR, Pye-Unicam SP3-100 or Philips PU 9706 spectrometers in chloroform unless otherwise stated. UV spectra were recorded in ethanol using a Pye-Unicam SP800 spectrometer. 1H NMR spectra were recorded in deuteriochloroform (internal standard TMS) at 90 MHz on a Perkin-Elmer R32 spectrometer, unless otherwise stated; spectra at 250 and 400 MHz were recorded on Bruker WM250 and JEOL EX400 spectrometers, respectively. 13C NMR spectra were measured on Jeol FX90Q or Bruker FX90 instruments at 22.5 MHz unless otherwise stated; spectra at 100 MHz were recorded on a JEOL EX400 spectrometer. Mass spectra were obtained using AEI MS902 or MM7070E spectrometers in EI-positive mode. Solvents were dried and distilled before use: acetonitrile distilled from P205 and stored over activated 4A molecular sieves; chloroform and dichloromethane distilled from Call2; dioxan (referring to 1,4-dioxan) dried over activated 4A molecular sieves and distilled; ethanol distilled from magnesium ethoxide and stored over activated 4A molecular sieves: tetrahydrofuran (THF) distilled from K immediately before use; toluene dried over sodium and distilled. Aqueous ammonia refers to ammonia solution, d 0.88. Column chromatography was carried out under medium pressure using Merck Kieselgel 60 (Art. 7729); flash column chromatography refers to chromatography using Merck Kieselgel 60 (Art. 9328). Organic extracts were dried over anhydrous magnesium sulphate for 10 min.
1-Ben~yl-8.ethoxycarbonyl-l,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-one

5a.

Method

A:

Propenoic acid (0.14 g, 1.94 mmol) and l,l'-carbonyldiimidazole (0.36 g, 2.2 mmol), were stirred together in THF (12 cm 3) for 3 h at 20"C before addition of 1-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydro-

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R. C. F. Jones et al. / Tetrahedron 54 (1998) 6191-6200

imidazole 4 (0.I0 g, 0.41 retool). The solution was heated at reflux for 24 h, allowed to cool and the solvent removed under reduced pressure. The residue was dissolved in chloroform and washed repeatedly with saturated sodium hydrogen carbonate solution to remove imidazolc. The chloroform solution was dried, filteredand concentrated under reduced pressure to afford tbe title compound (0.12 g, 98%) as an oil (Found: M + 300.1469. CI7H2oN203 requires M 300.1474); ~ 1.2 (3H, t,J 7 Hz, CH3), 2.4-2.8 (4H, m, CH2CH2CO), 3.3-3.9 (4H, m, NCH2CH2N), 4.15 (2H, q, J7 Hz, CH2CH3), 4.8 (2H, s, CH2Ph), 7.4 (5H, m, Ar-H); m/z 301 (MI-I+, 8%), 300 (M +, 33), 299 (14), 255 (13), 228 (12), 227 (52), 120 (11), 106 (12), 92 (I0), 91 (I00). Method B: To I-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole(0.25 g, 1.02 mrnol) 4 and pyridine (0.I g, 1.26 mmol) in toluene (5 c m 3) heated under reflux was added propenoyl chloride (0.09 cm 3, 1.11 rnmol) in toluene (I cm3). After 3 h the solution was cooled, poured into sodium hydroxide solution (5% w/v), and extracted into chloroform. The combined chloroform extracts were dried, filteredand concentrated under reduced pressure to give the titlecompound as an oil (0.25 g, 82%), identicalwith material prepared by method A. Column chromatography of a sample of the imidazo[I,2-a]pyridine 5a (0.59 g, 1.97 retool),prepared by Method A, on silicagel eluting with chloroform--ethanol (99.5:0.5 v/v) gave a 45:65 mixture (estimated by IH NMR spectroscopy) of 5a and the cyclol 7a (0.46 g). This mixture was re-chromatographed over silicagel

eluting with chloroform to give 1.benzyl,8-ethoxyearbonyl-Sa-hydroxy-l,2,3,5,6, 7,8,8a-octahydroimidazo,

[l,2-a]pyridin-5-one 7a (0.094 g, 15%) as an oil (Found: M + 318.1591. CI7H22N204 requires M 318.1580);

~I 1.3 (3H, t, J 7 Hz, CH3), 1.9 (1H, br s, OH), 2.1-3.0 (6H, m, CH2CH2CO, NCH2CH2NCO), 3.7 (IH, t, J 7 Hz, CHCO), 3.85 (2H, s, CH2Ph), 4.0 (2H, t, NCH2CH2NCO), 4.3 (2H, q, J 7 Hz, CH2CH3), 7.4 (5H, m, AtH); m/z 318 (M +, 1%), 317 (2), 301 (8), 300 (M+-H20, 40), 299 (17): the rest of the fragmentation pattern was the same as for 5a. No further material was isolated, indicating that these compounds decompose after prolonged exposure to silica during column chromatography. Compound 7a was also prepared by treatment of 1-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.15 g, 0.6 mmol) with ethyl propenoate (0.067 cm 3 g, 0.67 retool) in ethanol (25 cm 3) at reflux for 24 h. Removal of the solvent under reduced pressure and chromatography of the residue on silica gel eluting with ethyl acetate-triethylamine (99:1 v/v) afforded cyclol 7a (0.135 g, 70%), identical with material described above. (Yields were variable depending on the length of exposure to silica gel.) Benzyl-8-ethxyarbnyl7methyl-23567-hexahydrimidaz[2-apyridin-5-ne 5b: prepared by the method A described for 5a, using (E)-2-butenoic acid (0.17 g, 2.0 retool) and 1-benzyl-2-(cthoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.46 g, 1.9 retool). Work-up afforded the title compound (0.52 g, 89%) as an oil (Found: M + 314.1615. CIsH22N203 requires M 314.1630); Vmax/Cm (film) 2970, -1 1660 (C=O), 1580; 6H 1.05 (3H, d, J 8 Hz, CHCH3), 1.2 (3H, t, J 7 Hz, CH2CH3), 2.4-2.6 (2H, m, CH2CO), 3.1-3.8 (5H, m, NCH2CH2N, CHCH3), 4.1 (2H, q, J 7 Hz, CH2CH3), 4.7 (2H, 2 x d, CH2Ph), 7.3 (5H, br s, As-H); m/z 315 (MH+, 3%), 314 (M +, 21), 299 (35), 269 (10), 241 (34), 120 (30), 106 (15), 92 (13), 91 (100). Column chromatography of the imidazo[ 1,2-a]pyridine 5b on silica gel eluting with hexanc--cthyl acetate (4:6 v/v) afforded -bcnzy-8-thxycarbny-8a-hydrxy-7-mcthy-2356788a-ctahydrimidaz[2a]pyridin-5-onc 7b (0.45g, 73%) as an unstable oil that could not be fully characterized, Vmax/cm (film) -l 3320, 1725, 1665; ~H 1.1 (3H, d, J 8 Hz, CHCH3), 1.3 (3H, t, J 7 Hz, CH2CH3), 1.55 (1H, s, OH), 2.3-3.0 (5H, m, NCH2CH2NCO, CH2CO, CHCH3), 3.35 (1H, d, J 7 Hz, CHCO), 3.8 (2H, s, CH2Ph) 4.0 (2H, t, NCH2CH2NCO), 4.3 (2H, q, J 7 Hz, CH2CH3), 7.35 (5H, s, As-H); m/z 332 (M+, 1%), 331 (2), 314 (M+-

R. C. F. Jones et al. / Tetrahedron 54 (1998) 6191-6200

6197

H20, 12): the rest of the fragmentation pattern was the same as for 5b.

l.Benzyl.8-ethoxyearbonyl-7-phenyl, l,2,3,5,6, 7-herahydroimidazo[1,2-a]-py "ndin-5-one5c: prepared by the method A described for Sa, using 3-phenylpropenoic acid (0.30g, 2.02 mmol) and 1-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.50 g, 2.03 retool). Work-up afforded the title compound (0.75 g, 98%) as an oil (Found: M + 376.1775. C23H24N203 requires M 376.1787); Vmax/cm (film) 2980, -1 1665, 1585, 1380, 1110, 750, 700; ~I 1.15 (3H, t, J 7 Hz, CH3), 2.95 (2H, d, J 8 Hz, CH2CO), 3.35-3.75 (4H, m, NCH2CH2N), 4.15 (2H, q, J 7 Hz, CH2CH3), 4.45 (IH, t, J 8 Hz, CHPh), 4.85 (2H, 2 x d, CH2Ph), 7.157.45 (10H, m, At-H); ~C 14.4, 37.4, 38.0, 40.8, 48.0, 54.3, 59.2, 80.7, 126.1, 126.4, 127.8, 128.2, 128.5, 136.6, 143.0, 152.9, 166.5, 168.5 (one coincidence of signals); m/z 376 (M +, 27%), 304 (16), 303 (67), 299 (5), 285 (7), 105 (8), 92 (9), 91 (100).

1,Benzyl.8-ethoxycarbonyl-l,2,3,5.tetrahydroimidazo[1,2-alpyridin-5.one 6: prepared by the method A

described for 5a, using propynoic acid (0.142 g, 2.03 mmol) and 1-benzyl-2-(ethoxycarbonylmethylene)2,3,4,5-tetrahydroimidazole 4 (0.46 g, 1.9 mmol). Work-up afforded a residue that was chromatographed over silica gel eluting with chloroform to afford the title compound (0.52 g, 93%) as an oil (Found: M+ 298.1303. CITHIsN203 requires M 298.1317); Vmax/Cm (film) 1655, 1535, 1495; ~ 1.2 (3H, t, J 7 Hz, CH3), 3.5-3.7 -I (2H, m, NCH2CH2N), 3.95-4.3 (4H, m, CH2CH3, NCH2CH2N), 4.8 (2H, s, CH2Ph), 5.85 (1H, d, J 10 Hz, CH=CHCO), 7.3 (5H, s, Ar-H), 7.85 (1H, d, J 10 Hz, CH=CHCO); ~c 14.3, 42.6, 48.8, 54.2, 60.5, 91.1, 106.7, 127.8, 128.8, 136.0, 143.8, 154.5, 161.8, 164.8 (one coincidence of signals); m/z 298 (M +, 28%), 246 (9), 92 (8), 91 (100).

1-Benzyl-2-(1-eth~xycarb~nyl-3-meth~xycarb~ny~r~p-2-enylidene)-2~3~4~5-tetrahydr~imidaz~e
solution of 1-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole

8: A

4 (0.40 g, 1.63 mmol) and

methyl propynoate (0.145 cm3, 1.63 mmol) in ethanol (20 cm 3) was stirred at 20C for 48 h. The solvent was removed under reduced pressure to afford an oil (0.54 g, 100%) which was suspended in hot hexane and chloroform added until solution. On cooling the title compound was collected as crystals (0.5 g, 95%), m.p. 101-103C (Found: M 330.1580. CIsH22N204 requires M 330.1580); Vmax/Cm (nujol) 2927, 1701, 1663, -I 1651, 1605, 1589, 1549, 1497; ~ (400 MHz) 1,28 (3H, t, J 6 Hz, CH2CH3), 3.4-3.55 (4H, m, NCH2CH2N), 3.50 (3H, s, OCH3), 4.14 (2H, q, J 6 Hz, CH2CH3), 4.47 (2H, s, CH2Ph), 5.78 (1H, d, J 16 Hz, CH=CHCO), 7.2-7.3 (5H, m, Ar-H), 7.68 (1H, d, J 16 Hz, CH=CHCO), 8.46 (1H, br s, NH); e~c(100 MHz) 14.6, 42.0, 49.0, 50.6, 55.1, 59.5, 78.5, 105.1, 127.5, 127.9, 128.8, 136.2, 141.1, 167.9, 141.0, 141.1; m/z 330 (M, 1%), 246 (M-C4H402, 47), 201 (22), 173 (37), 91 (100).

-Benzyl-8-ethxycarbnyl--7-methy-235-tetrahydrimidaz[12-apyridin-5-ne 9a and 1-Benzyl8.ethoxycarbonyl.5-methyl, l,2,3,7-tetrahydroimidazo[1,2.a]pyridin-7-one 10: To l-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (2.0 g, 8.1 mmol) in toluene (100 cm 3) were added toluene-4-sulphonic acid (0.2 g, catalytic) and ethyl acetoacetate (1.05 cm 3, 8.24 retool). The solution was heated at reflux under a Dean and Stark separator for 12 h and the solvent removed under reduced pressure. The residual oil was purified by flash column chromatography on silica gel eluting with dichloromethaneethanol-aqueous ammonia (300:8:1 v/v/v) to give the imidazopyridin-7-one 10 as a white crystalline solid (0.52 g, 21%), m.p. 96-97C (Found: C, 65.70; H, 6.91; N, 8.56%; M 312.1482. CI8H20N203.H20 requires C, 65.44; H, 6.71; N, 8.48%; CIgH2oN203 requires M 312.1474); Vmax/Cm 2940, 2880, 1710 (ester C=O), -1 1640 (NC=O), 1540, 1360, 1225, 1100, 890; )l~nax/nm 230 (~dm3 mo1-1 cm-I 25 x 104); ~ (250 MHz) 1.14 (3H, t, J 7.1 Hz, CH2CH3), 2.19 (3H, s, CH3C=C), 3.55 & 4.03 (4H, 2 x m, NCH2CH2N), 4.15 (2H, q, J 7.1

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Hz, CH2CH3), 4.39 (2H, s, CH2Ph), 5.89 (1H, s, CH), 7.37 (5H, m, Ar-H); 6C 13.4, 44.3, 47.8, 51.3, 57.1, 60.7, 100.1 (C=CCO2), 111.4 (CH), 127.2, 127.4 and 128.3 (ARCH), 135.2 (ARC), 143.7, 151.5, 166.7 (CO2Et), 176.8 (CO keto); m/z 312 (M+, 39%), 267 (M+--OEt, 33), 266 (26), 239 (94), 119 (21), 91 (100). Further elution gave the imidazopyridin-5-one 9a as a pale yellow solid (2.0 g, 79%), m.p. 70-72"C (Found: M + 312.1486. ClgH20N203 requires M 312.1474); Vmaxlcm 2940, 2880, 1710 (ester C=O), 1645 (NC----O), -1 1590, 1510, 1370, 1300; )nnax/nm 284 (~dm 3 mo1-1 cm -1 4.8 x 104), 324 (7.2 x 104); ~ 1.15 (3H, t, J 7.2 Hz, CH2CH3), 2.21 (3H, s, CH3C=C), 3.60 and 4.15 (each 2H, m, NCH2), 4.25 (2I-I, q, J 7.2 Hz, CH2CH3), 4.43 (2H, s, CH2Ph), 5.80 (1H, s, CH), 7.35 (5H, m, Ar-H); t~C 13.6, 41,8, 48.4, 52.5, 57.2, 60.4, 92.6 (C=CCO2), 107.2 (CH), 126.9, 127.4 and 128.3 (ARCH), 135.1 (ARC), 151.0, 151.5, 160.0 (NCO), 166.3 (CO2Et); m/z 312 (M+, 14%), 246 (20), 201 (8), 173 (11), 92 (8), 91 (100). The imidazopyridin-5-one 9a was also observed using the method described above, using ethyl 3methoxy-2-butenoate 11 (1.2 g, 8.0 rnmol) instead of ethyl acetoacetate, and heating at reflux for 24 h. Purification of the residual oil by column chromatography on silica gel eluting with chloroform-ethanol (50:1 v/v) gave compound 9a in a mixed fraction with unchanged enarninoester 4, that was not further separated. 1-Benzyl-8-etxycarbyl-7-peny-1235-tetrahydrimidazl[12-a]pyridin-5-ne 9b: To l-benzyl~ 2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (2.03 g, 8.1 retool) in toluene (100 cm 3) was added toluene-4-sulphonic acid (0.2 g, catalytic) and ethyl benzoylacetate (1.4 cm3, 8.1 retool). The solution was heated at reflux under a Dean and Stark separator for 12 h and the solvent was removed under reduced pressure. The residual oil (4.3 g) was purified by flash chromatography eluting with chloroform to give the title compound as a clear oil (2.2 g, 72%) (Found: M + 374.1630. C23H22N203 requires M 374.1630); Vmax/Cm (film) 3061, 2983, 1704 (C--O ester), 1652 (NC=O), 1587, 1572, 1531, 1497; 2~nax/nm (CH3CN) -1 284 (eldm 3 mo1-1 cm-1 6.8 x 103), 335 (8.1 x 103); ~ (400 MHz) 0.55 (3H, t, J 8 Hz, CH3), 3.55 (2H, q, J 8 Hz, CH2CH3), 3.60 and 4.10 (each 2H, t, J 9 Hz, NCH2), 4.48 (2H, s, CH2Ph), 5.78 (1H, s, CH), 7.15-7.3 (10H, br s, Ar-H); t~C (100 MHz) 13.1, 42.2, 48.9, 52.2, 61.0, 93.2 (C=CCO2), 107.9 (CH), 126.9, 127.5, 127.9, 128.0, 128.1 and 128.8 (ARCH), 135.4 and 140.1 (ARC), 150.4, 155.4, 160.3 (NCO), 167.0 (CO2Et); m/z 374 (M+, 36%), 329 (5), 301 (9), 92 (10), 91 (100). l-Benzyl-8-ethoxycarbonyl-7-methyl.l,2,3,7-tetrahydroimidazo[1,2-a]pyridine 12a: l-Benzyl-2(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.30 g, 1.2 mmol) and (E)-2-butenai (0.12 cm 3, 1.4 retool) were heated together in acetonitrile (25 cm 3) at reflux for 24 h. After cooling, the solvent was removed under reduced pressure and the dark yellow oil purified by flash colum chromatography eluting with dichloromethane-ethanol-aqueous ammonia (300:8:1 v/v/v) to give the title compound (0.19 g, 53%). Purification by kugelrohr distillation (bulb temperatue 250'C, 2 mmHg) instead of chromatography increased the yield to 62% (Found: M+-Me 283.1440. CIaH22N202 requires M-Me 283.1447); Vmax/cm 2900, 2850, -! 1665 (C=O), 1640 (NC=C), 1535, 1425, 1270, 1175, 1110; ~I 1.00 (3H, d, J 8 Hz, CHCH3), 1.20 (3H, t, J 7 Hz, CH2CH3), 3.3-3.8 (5H, m, NCH2CH2N and CHCH3), 4.15 (2H, q, J 7 Hz, CH2CH3), 4.65 and 4.80 (each 1H, d, J 16 Hz, CHaHbPh), 5.15 (IH, t, J 8 Hz, NCH=C/'/), 6.0 (1H, d, J 8 Hz, NCH=CH), 7.45 (5H, m, AtH); ~C 14.5, 23.4, 28.7, 46.2, 48.3, 55.1, 58.4, 77.5, 111.2, 124.1, 127.0, 128.0, 128.2, 137.6, 157.6, 166.7; m/z (M+ not observed) 284 (3%), 283 (M+-Me, 13), 136 (65), 119 (59), 92 (18), 91 (100). l-Benzyl-8-ethoxycarbonyl-6,7.dimethyl-l,2,3,7-tetrahydroimidazo[1,2-alpyridine 12b: prepared by the method described for 12a, using 1-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.50 g, 2.0 mmol), (E)-2-methyl-2-butenal (0.14 cm3, 2.4 retool) and heating in dioxan (25 cm 3) at reflux for

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6199

24 h, to afford the title compound (0.20 g, 32%) as a yellow oil (Found: M 312.1840. C19H24N20 2 requires M 312.1838); Vraaxlcm 2940, 2860, 1660 (br, C=O and NC---C), 1550, 1430, 1285, 1110; ~ 1.00 (3H, d, J 6 -1 Hz, CHCH3), 1.20 (3H, t, J 7 Hz, CH2CH3), 1.80 (3H, s, C=CCH3), 3.3-3.8 (5H, m, NCH2CH2N and CHCH3), 4.15 (2H, q, J 7 Hz, CH2CH3), 4.60 and 4.80 (each I H, d, J 13 Hz, CHaHbPh), 5.80 (1H, s, C--CH), 7.40 (5H, m, Ar-H); t5 14.5, 17.8, 20.4, 34.1, 46.2, 48.5, 55.1, 58.3, 76.2, 119.4, 120.1, 126.9, 127.9, 128.0, C 137.7, 157.6, 166.6; m/z 312 (M +, 7%), 298 (31), 297 (M+-Me, 100), 267 (12), 134 (23), 91 (54). 1-Benzyl-8-ethoxycarbonyl-6.methyl.l,2,3,7.tetrahydroimidazo[l,2-aJpyridine 12: prepared by the method described for 12a, using 1-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.50 g, 2.0 mmol), 2-methylpropenal (0.17 cm 3, 2.0 mmol) and heating in dioxan (25 cm 3) at reflux for 96 h, to afford the title compound (0.19 g, 32%) as a yellow oil (Found: M + 298.1666. C18H22N20 2 requires M 298.1681); Vmax/Cm 2940, 2880, 1665 (C=O), 1645 (NC=C), 1540, 1450, 1180, 1110; ~ 1.20 (3H, t, J 7 -1 Hz, CH2CH3), 1.75 (3H, s, C--CCH3), 3.2-3.45 (4H, m, NCH2CH2N), 3.7 (2H, s, C=CCH2), 4.15 (2H, q, J 7 Hz, CH2CH3), 4.80 (2H, s, CH2Ph), 6.45 (IH, s, C=CH), 7.40 (5H, m, Ar-H); m/z 298 (M +, 35%), 297 (47), 269 (14), 253 (15), 176 (17), 134 (16), 133 (18), 132 (38), 125 (12), 120 (15), 92 (20), 91 (100). l-Benzyl-8-ethoxycarbonyl-7,phenyl-l,2,3,7-tetrahydroimidazo[l,2-a]pyridine 12d: To 1-benzyl-2(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.50 g, 2.0 mmol) and (E)-3-phenylpropenal (0.30 cm 3, 2.4 mmol) in dioxane (25 cm 3) were added powdered 4A molecular sieves (1 g, activated at 180C for 72 h) and the mixture was heated at reflux for 72 h. Removal of the solvent under reduced pressure gave a dark oil which was purified by flash column chromatography eluting with dichloromethane--ethanol-aqueous ammonia (300:8:1 v/v/v) to give the title compound (0.20 g, 27%) as a brown oil (Found: M+ 360.1832. C23H24N202 requires M 360.1838); Vmax/cm 2940, 2860, 1665 (C=O), 1640 (NC---'C), 1530, 1090; 5H 1.20 -1 (3H, t, J 7 Hz, CH2CH3), 3.50 (4H, m, NCH2CH2N), 4.15 (2H, q, J 7 Hz, CH2CH3), 4.70 (IH, d, J 8 Hz, CHPh), 4.75 (2H, s, CH2Ph), 5.35 (1H, t, J 8 Hz, NCH=CH), 6.15 (1H, d, J 8 Hz, NCH=CH), 7.40 (10H, m, Ar-H); ~C 14.6, 39.5, 46.4, 48.2, 55.2, 58.8, 76.6, 109.4, 124.9, 125.7, 127.2, 128.0, 128.3, 137.5, 148.0, 157.6, 166.8; m/z 360 (M +, 11%), 287 (M+-CO2Et), 283 (M+-Ph, 100), 269 (M+-CH2Ph, 29), 195 (16), 147 (7), 120 (15), 91 (77). 1-Benzyl-2-[4-ethoxycarbonyl-2-formylcyclohexen.4-yl]-4,5-dihydroimidazole 13: 1-Benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole 4 (0.50 g, 2.0 retool) and propenal (0.163 cm 3, 2.4 retool) were heated together in acetonitrile at reflux for 4 h. After removal of the solvent under reduced pressure the residual oil was purified by flash column chromatography eluting with dichloromethane-ethanol-aqueous ammonia (300:8:1 v/v/v) to give the title compound (0.41 g, 60% based on 4) as a colourless oil (Found: M+ 340.1783. C20H24N203 requires M 340.1787); Vmax/Cm 2950, 2880, 2850, 1730 (ester C--O), 1680 (C=O), -1 1600, 1390, 1170, 920; ~I (250 MHz) 1.27 (3H, t, J 7.1 Hz, CH2CH3), 2.32 (3H, m, CH2CCO2 and CHaHbCH2CH=C), 2.62 (1H, m, CHaHbCH2CH=C), 2.80 (2H, m, CH2CH=C), 3.14 and 3.72 (each 2H, m, NCH2CH2N), 4.22 (2H, q, J 7.1 Hz, CH2CH3), 4.25 (2H, s, CH2Ph), 6.81 (IH, dd, J 5.7, 3.5 Hz, CH=C), 7.30 (5H, m, At-H), 9.48 (1H, s, CH=O); ~5C 13.5, 17.8, 23.3, 28.2, 28.5, 45.7, 50.9, 51.5, 51.6, 56.8, 61.0, 126.6, 126.8, 128.0, 136.9, 138.2, 148.3, 164.7, 172.5, 192.2 (C=O); m/z 340 (M +, 15%), 311 (M+-CHO, 15%), 312 (12), 311 (M+-Et, 32), 268 (14), 267 (69), and 91 (100). The NMR assignments were confirmed by IH-IH and IH-13C correlation spectroscopy. -Benzyl-7-ethxycarbny-236-tetrahydr-5H-pyrrl[2-a]imidazle-56-dine 16: Diethyl oxalate (1.1 cm 3, 8.1 mmol) and toluene-4-sulphonic acid (I0 nag, catalytic) were added to 1-benzyl-2-

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(ethoxycarbonylmethylene)-2,3,4,5-tetrahydromidazole 4 (2.0 g, 8.1 retool) in toluene (100 cm 3) and the solution was heated at reflux under a Dean and Stark separator for 24 h. The solvent was removed under reduced pressure and the residual oil purified by flash column chromatography on silica gel eluting with chloroform ~ chloroform--ethanol (300:8 v/v) to give the title compound as a yellow solid (1.5 g, 50%), m.p. 154-156"C (decomp.) (Found: C, 63.95; H, 5.75; N, 9.22%. C16H16N204 requires C, 63.99; H, 5.37; N, 9.33%); Vmax/cm (nujol) 1751 and 1675 (C=O), 1617, 1483, 1456, 1409, 1377; 3,max/nm 248 (e/dm3 mo1-1 -1 cm-1 1.86 x 104), 348 (4.0 x 103); ~ (400 MHz) 1.24 (3H, t, CH2CH3), 3.82 and 3.93 (each 2H, m, CH2N), 4.20 (2H, q, CH2CH3), 5.40 (2H, s, CH2Ph), 7.2-7.35 (5H, m, Ar-H); t~C (100 MHz) 14.1, 37.8, 52.0, 53.3, 59.7, 86.5, 128.0, 128.4, 128.9, 133.6, 157.9, 162.4, 165.4, 177.0; m/z 300 (M , 4%), 272 (M+--CO, 4), 254 (M+--CO-~O, 6), and 91 (100). When the reaction was interrupted after 12 h, a yellow oil was isolated (0.8 g, 28%) and partially identified as 1-benzyl-2-(ethoxycarbonylmethylene)-3-ethoxycarbonyloxy-2,3,4,5-tetrahydroimidazole 15; Vmax/Cm (film) 2936, 1761 and 1673 (C=O), 1608, 1456, 1355, 1115; 2~aax/nm 244 -1 (e/dm3 mo1-1 cm-1 1.06 x 104), 270 (1.05 x 104), 348 (1.5 x 103); ~ (250 MHz) 1.3 (6H, m, 2 x CH2CH3), 3.45 and 4.15 (10H, m, 2 x CH2N, 2 x OCH2CH3, CH2Ph), 5.5 (1H, s, C=CH), 7.30 (5H, s, Ar-H). ACKNOWLEDGEMENTS We thank Drs. Eric W. Collington & Peter Hallett, and Dr Christopher B. Chapleo for helpful discussions; Rachel H. Lloyd & Jeffrey W. Hobbs for the isolation of intermediate 15; SERC and Glaxo Group Research for a CASE studentship (S.C.H.); SERC and Reckitt & Colman Pharmaceuticals for a CASE studentship (M.J.S.); the EPSRC National Mass Spectrometry Service Centre, Swansea, for some MS data.
REFERENCES AND FOOTNOTES

2 3 4 5

6 7 8 9 10 11 12 13

(a) Anderson, M. W.; Begley, M. J.; Jones, R. C. F.; Saunders, J. J. Chem. Soc., Perkin Trans. 1 1984, 2599-2602; (b) Anderson, M. W.; Jones, R. C. F.; Saunders, J. J. Chem. Soc., Perkin Trans. 1 1986, 205209; (c) Jones, R. C. F.; Anderson, M. W.; Smallridge, M. J. Tetrahedron Lett. 1988, 29, 5001-5004; (d) Jones, R. C. F.; Schofield, J. J. Chem. Soc., Perkin Trans. 1 1990, 375-383; (e) Jones, R. C. F.; Smallridge, M. J.; Chapleo, C. B. J. Chem. Soc., Perkin Trans. 1 1990, 385-391. For an alternative solution in 2-benzylic cases: Dalko, P. I.; Langlois, Y. Chem. Commun. 1988, 331-332. See, for example: Grout, R. J. in The Chemistry of Amidines and Imidates; Patai, S. Ed.; Wiley. London, 1975, p. 255 et seq.; Chapleo, C. B. Chem. Br. 1986, 313-314. See, for example: Michael, J. P. Nat. Prod. Rep, 1997, 14, 619-636, & refs. therein. For preliminary reports of part of this work, see: (a) Jones, R. C. F.; Anderson, M. W.; Smallridge, M. J. Tetrahedron Lett. 1988, 29, 5001-5004; (b) Jones, R. C. F.; Hirst, S. C. Tetrahedron Lett. 1989, 30, 53615364. Jones, R. C. F.; Patel, P.; Hirst, S. C.; Turner, I. Tetrahedron 1997, 53, 11781-11790. Yu, C.-L.; Wang, L.-B.; Li, W.-Y.; Huang, Z.-T. Synthesis 1996, 959-962, & refs. therein. Brunerie, P.; C~16rier, J.; Huch6, M.; Lhommet, G. Synthesis 1985, 735-738. Shemyakin, M. M.; Antonov, V. K.; Shkrob, A. M.; Shchelokov, V. I.; Agadzhanyan, Z. E. Tetrahedron 1965, 21, 3537-3572. Huang, Z.-T.; Wang, M.-X. J. Chem, Soc., Perkin Trans. 1 1993, 1085-1090. Huang, Z.-T.; Tzal, L.-H. Chem. Bet. 1986, 119, 2208-2219. Magatti, C. V.; Villani, F. J. J. Heterocyclic Chem. 1978, 15, 1021-1023. Jones, R. C. F.; Hirst, S. C. Tetrahedron Lett. 1989, 30, 5365-5368; Jones, R. C. F.; Turner, I.; Howard, K. J. Tetrahedron Lett. 1993, 39, 6329-6332.