Trifluoroacetylated N,N-dialkylanilines react in refluxing 1-butanol to benzoxazine derivatives via an intramolecular] [1, 5] hydrogen shift and subsequent cyclization of the dipolar intermediate

Dijk, B.G. van

Reinhoudt, D.N.

Verboom, W.

English

Verboom, Willem

van Dijk, B.G.

Reinhoudt, David

NARCIS 

Novel applications of the “t-amino effect” in heterocyclic chemistry; synthesis of 5H-pyrrolo- and 1H,6H-pyrido[1,2-a][3,1]benzoxazines

University of Twente Research Information

Tetrahedron Letters,Vo1.24,No.36,pp 3923-3926,1983 oo40-4039/83 $3 00 + .Oo Printed In Great Brltaln 01983 Pergamon Press Ltd NOVEL APPLICATIONS OF THE "t-AMINO EFFECT" IN HETEROCYCLIC CHEMISTRY; SYNTHESIS OF 5H-PYRROLO- AND 1H,6H-PYRIDOC1,2-alC3,llBENZOXAZINES 17. Verboom, B.G. van Dl]k and D.N. Relnhoudt* Laboratory of Organic Chemistry, Twente University of Technology, Enschede, The Netherlands Abstract. TrzfluoroacetyZated N,N-dzalkylanzlznes react zn refZuxzng I-butanol to benzoxazzne derzvatzves vza an zntramolecular Cl,51 hydrogen shzft and subsequent cycltzatzon of the dzpoZar zntermedzate Hltherto 1,2,3,3a-tetrahydro-5H-pyrrolo~l,2-alC3,llbenzoxazine and 2,3,4,4a- tetrahydro-1H,6H-pyrIdoC1,2-alC3,llbenzoxaz~ne were unknown classes of heterocy- cles However, Kienzle' very recently published the preparation of these types of compounds by oxidation of the appropriate benzyl alcohols with Mn02. This publi- cation prompts us to report the prellmlnary results of an alternative approach to these types of heterocycles. In the course of our investigations of the "t-amino effect" 2 in heterocyclic chemistry we have reported previously the formation of N-heterocycles by ring clo- 3 sure reactions of substituted 2-vznyZ-N,N-dlalkylanlllnes . We have subsequently investigated the reactivity of 2-acyZ-N,N-dlalkylanlllnes (e.g. 2). In a previous paper we have described the reactlon of pyrrolldlne and piperi- dine enamines with trlfluoroacetlc anhydrlde. The trlfluoroacetylated enamlnes were found to undergo thermal isomerizatlon to 1,3-oxazlnes 4 Reaction of the l- (4-methyl-, and 4-methoxyphenyl)pyrrolldlnes 5 (lc) and (Lb) with trlfluoroacetlc anhydrlde In tetrahydrofuran at room temperature for 2 days or for 18 h at 40 OC gave in yields of more than 90% the 2,2,2-trlfluoro-l-C5-methyl- and 5-methoxy- 2-(l-pyrrolld1nyl)phenyllethanones (22) and (2b), respectively6 The correspond- ing plperidlne analogues &s-d_ yielded, after aqueous work up, mixtures of the R OH ? 2 3 a R = CH3, X = (CH& c R =CH3, X=(CH& e R=CH3, X= HC=CH b R q OCH3, X q (Cti,), d R =OCH,,X =(CH2j3 3923 3924 trlfluoroacetylated compounds 22-2 and of the corresponding hydrates 7 &-_d. The latter were isolated as pure crystalline materials' after trlturatlon of the crude reaction mixture with dllsopropyl ether in yields of 38% Cmp 78-85 OC (dec)l and 35% Cmp 105-112 'C (dec)l, respectively. 2,5-Dihydro-1-(4-methylphenyl)-lH-pyrrole (Le) reacted with trifluoroacetlc anhydrlde in a slmllar way to give 2s in high yield. Tr:chloroacetylatlon of la with trlchloroacetlc anhydrlde could not be a- chleved neither In refluxlng tetrahydrofuran nor In refluxlng 1,2-dlchloroethane. Heating of 22 in 1-butanol at 118 OC for 45 h gave a quantltatlve conversion into 5-(tr~fluoromethyl~-1,2,3,3,3a-tetrahydro-7-methyl-5~-pyrrolo~l,2-~l~3,llbenzo- xazlne (4%). This compound was isolated after column chromatography [alumina (III- IV), chloroform/petroleum ether (bp 60-80 OC)l as an 011 In a yield of 91%. The 1 H NMR spectrum showed the presence of two Isomers In a ratlo of about 4.5:1. Upon addltlon of a few drops of methanol the malor isomer crystallized Cmp 60-60.5 OC (methanol ); m/e 257.102 CM+); 'H NMR (CDC13) 6 5.25-5.05 (m, 1 H, NCHO), 4.95 (q, J = 8.3 Hz, 1 H, HCCF3), 3.8-3.1 (m, 4 H, NCH2), 2.28 (s, 3 H, CH3); 13C NMR (CDC13) 6 84.7 (d, NCHO), 72.1 (dq, J = 30 Hz, HCCF3), 50.8 (t, NCH2), 22.6 (q, CH3)l. The minor isomer showed in the 1 H NMR spectrum the characteristic HCCF3-ab- sorption at 6 5.20 (q, J = 6.3 Hz) and the NCHO-signal at 6 4.8-4.65 (m). Heating of the pure malor isomer ln 1-butanol for 3 days gave according to the 'H NMR spectrum the thermodynamic Isomer mixture with a ratio of the Isomers of about 4.5:1. RJ$y .q? H3cJ$z3 H CF3 H CF3 t!i 4 5 6 a R=CHJ b R=OCH3 Heating of the hydrate 3~ or a mixture of 2_c and 3~ In l-butanol for 90 h gave after chromatography a 1:l isomer mixture of 6-(trlfluoromethyl)-2,3,4,4a_tetrahy- dro-8-methy1-1H,6H-pyrldoU,2-u1[3,1]benzoxaz~ne (5%) as an 011 In a yield of 95% from which one isomer crystallized spontaneously [mp 66.5-68 OC (methanol); 'H NMR (CDC13) .5 5.03 (q, J = 8.1 Hz, 1 H, HCCF3), 4.6-4.4 (m, 1 H, NCHO); 13C NMR (cDc13) 6 82.0 (d, NCHO), 71.8 (dq, J = 30 Hz, HCCF3)1. The other isomer showed character- lstlc absorptlons In the 'H NMR spectrum at 6 5.28 (q, J = 6.3 Hz, 1 H, HCCF3) and 4.4-4.2 (m, 1 H, NCHO) and In the 13C NMR spectrum at 6 84.0 (d, NCHO) and 74.0 (dq, J = 30 Hz, HCCF3). The methoxy analogues 2b and 32 reacted slmllarly. After heating In 1-butanol at 118 OC for only 20 h Isomer mixtures of & (2.5:1) and & (2:l) were obtained as 011s In yields of 77 and 908, respectively. Starting from 2s the ring closure could not be accomplished in refluxing l-bu- tanol. Instead 2,2,2-tr~fluoro-1-C5-methyl-2-(1H-pyrrol-l-yl~phenyllethanol (6) 3925 was Isolated as an 011 from the reaction mixture In a yield of 60% CIR (NaCl) 3450 -1 cm (OH); m/e 255.087 (M+); 'H NMR (CDC13) 6 6.73 and 6.28 (t, J = 2 Hz, 2 H, pyrrole H'S), 4.79 (br q, J = 6.6 Hz, 1 H, xC(OH)CF3), 2.75 (br s, 1 H, OH); 13C NMR (CDC13) 6 124.3 (q, J = 283 Hz, CF3), 66.9 (dq, J = 33 Hz, HC(OH)CF3)1. The formatlon of 4 and 2 can be explalned by two consecutive reactions as de- plcted In the Scheme. The first step comprises a thermal suprafacial Cl,51 hydro- gen shift producing the zwitterion 2. Subsequently, intramolecular addition of the negative charged oxygen atom to the lmlnium double bond gives rise to compounds 2 and 2. We have obtained strong evidence that the hydrogen shift indeed 1s a con- certed process, because when the reactlon of 22 was performed In l-deuterlo-l-bu- tanol no incorporation of deuterlum was detected at C-3a and C-5 of !_a. Besides, no loss of deuterlum was observed starting from & In which the hydrogens of the carbon atoms adlacent to nitrogen were replaced by deuterlum. It 1s likely that In the cases of the hydrates &-CJ under the conditions used firstly dehydration takes place to &-fi. Scheme In order to allow the hydrogen shift to take place the strongly electron-wpth- drawing CF3-group adlacent to the carbonyl moiety seems to be crucial, because starting from methyl 2-(l-pyrrolldlnyl)benzoate and 1-[2-(l-pyrrolldlnyl)phenyll- ethanone the ring closure could not be achieved. The effect of the substltuent R in compound 2 on the rate of reactlon (kOCH > kc, ) can be explalned In terms of a more effective stablllzatlon of the posltlve cha:ge at the nitrogen atom in the zwltterlon 2 by the methoxy group. The formation of 5 comprises aromatlzatlon to a pyrrole by deprotonatlon of the lntermedlate 2 which is obviously faster than the cycllzatlon reaction. This synthesis of benzoxazlnes (4 and 2) is a further example of the potential use of the "t-amino effect" of 2-substituted N,N-dialkylanlllnes in heterocycllc chemistry. Acknowledgement. We are grateful for the flnanclal support of this work by the "Koningin Wllhelmlna Fends". 3926 1. 2. 3. 4. 5. 6. 7. 8. 9. References and Notes F. Klenzle, Tetrahedron Lett. 24, 2213 (1983). 0. Meth-Cohn and H. Suschltzky, Adv. Heterocyclic Chem. 14, 211 (1972). W. Verboom, D. N. Relnhoudt, R. Vlsser and S. Harkema, J. Org. Chem. submitted for publlcatlon. W. Verboom, D. N. Relnhoudt, S. Harkema and G. J. van Hummel, J. Org. Chem. 47, 3339 (1982). Compounds A were prepared by dlalkylatlon of the corresponding anllines with 1,4-dlbromobutane, 1,5-dlbromopentane and czs-1,4-dlchlorobutene, respective- ly, in refluxlng toluene in the presence of ethyldllsopropylamine. For other examples of the facile trlfluoroacetylation of activated aromatic compounds see: W. Verboom, G. W. Visser and D. N. Relnhoudt, Tetrahedron 3_8_, 1831 (1982), and references cited therein. Stewart et al. 8 have recently published several other examples of the forma- tion of hydrates of trlfluoromethyl phenyl ketones. R. S. McDonald, K.-C. Teo and R. Stewart, J. Chem. Sot., Perkln Trans. 2 1983 ,,,,r 297, and references cited therein. Satisfactory elemental analyses were obtained for all new crystalline com- pounds (C,H,N + 0.3%). (Received in UK 1 July 1983) 

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Novel applications of the “t-amino effect” in heterocyclic chemistry; synthesis of 5H-pyrrolo- and 1H,6H-pyrido[1,2-a][3,1]benzoxazines

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