SYNTHESIS OF QUINOLIN-2-ONES FROM ortho-vinylcarbonylamino-substituted ACYLBENZENES BY TANDEM MICHAEL AND KNOEVENAGEL REACTIONS

Transcription

1 Chemistry of eterocyclic Compounds, Vol. 49, No. 10, January, 2014 (ussian riginal Vol. 49, No. 10, ctober, 2013) SYNTESIS F QUINLIN-2-NES FM ortho-vinylcabnylamin-substituted ACYLBENZENES BY TANDEM MICAEL AND KNEVENAGEL EACTINS S. S. Mochalov 1 *, A. N. Fedotov 1, E. V. Trofimova 1, and N. S. Zefirov 1 Consecutive Michael addition and Knoevenagel intramolecular condensation reactions provide 3-alkoxymethyl-, 3-aminomethyl-, and 3-benzylquinolin-2-ones from o-(vinylcarbonylamino)acylbenzenes. The synthesis of 3-alkoxymethylquinolin-2-ones may be carried out in a one-pot procedure directly from o-(vinylcarbonylamino)acylbenzenes. Aminomethylquinolin-2-ones are formed in one-pot approach only from corresponding o-(vinylcarbonylamino)benzophenones. Their analogs with o-alkylcarbonyl groups form Michael adducts under these conditions. Keywords: N-(7-acyl-2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-enamides, N-(2-acylphenyl)prop-2-enamides, quinolin-2-ones, intramolecular Knoevenagel condensation. The biological activity of quinolin-2-one derivatives is a function of the nature and position of the substituents existing in the heterocyclic fragment. For example, 4-substituted 3-phenylquinolin-2-ones have strong affinity for the glycine site of the N-methyl-D-aspartate receptor [1-3], while 3-(1-indol-2-yl)quinolin- 2-ones is a kinase insert domain receptor (KD) inhibitor [4], and 4-aryl-3-hydroxyalkylquinolin-2-ones are effective for the treatment of erectile dysfunction [5]. ence, having the possibility of varying the substituents in the heterocycle would permit the synthesis of quinolin-2-one derivatives with potentially promising biological activity, which might allow the development of new drugs. In our previous work [6] on the intramolecular cyclization of o-(n-acylamino)benzophenones to give quinolin-2-ones by the action of equimolar amounts of sodium ethylate in ethanol, we showed that o-( -bromopropionylamino)benzophenones, in contrast to their analogs lacking - or -haloalkyl groups in the amide fragment of the molecule, do not form quinolin-2-ones, but rather are converted into elimination products of a hydrogen halide from the haloalkyl fragment and nucleophilic substitution of the bromine atom by the alkoxy group. Furthermore, as it was specially shown in this same study, obtained o-(vinylcarbonylamino)benzophenones upon heating with two equivalents of sodium ethylate in ethanol are capable to transform into 3-(ethoxymethyl)quinolin-2-ones. It this case, evidence that the transformations of o-(vinylcarbonylamino)benzophenones into the corresponding quinolin-2-ones are accomplished through a step involving Michael addition of ethanol to the double bond of the unsaturated fragment and subsequent Knoevenagel cyclization of the formed adduct was obtained. *To whom correspondence should be addressed, ssmoch@org.chem.msu.ru. 1 M. V. Lomonosov Moscow State University, 1, Build. 3, Leninskie Gory, Moscow , ussia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp , ctober, riginal article submitted June 20, 2013 revision submitted ctober 2, /14/ Springer Science+Business Media New York 1469

2 1 2 =CCCl, 3 N Na Dioxane, 20 С N 2 2 NCC= 1, 2, 3a j, 4 5, 6, 7a j, 8 1 1, 5 = Me, 1 =, 2 = t-bu 2, 6 = Et, 1 =, 2 = Br 3, 7 a j = 3, 7 a = Me, b = i-pr, c = c-pr, d = 4-MeC 6, e = 4-FC 6, f = 4-ClC 6, g = 3-FC 6, h = 2-FC 6, i = 2-ClC 6, j = 2-BrC 6 4, 8 = 2-BrC 6, 1 = 2 = Me n the basis of these results, we proposed that o-(vinylcarbonylamino)acylbenzenes may be used in the synthesis of quinolin-2-ones with the possibility of broad variation of the nature of the substituents at position 3 of the heterocycle. Actually, if these vinylcarbonylaminobenzenes would undergo the Michael reaction and give the corresponding addition products and these products, in turn, would undergo intramolecular cyclization, then quinolin-2-ones with substituents introduced by the Michael donors could be obtained by tandem Michael and Knoevenagel reactions. In order to elucidate whether such synthesis scheme can be realized, we obtained a series of o-(vinylcarbonylamino)acylbenzenes and studied their conversions to quinolin-2-ones. The required o-(vinylcarbonylamino)acylbenzenes 5, 6, 7a-j, and 8 were obtained by the acylation of o-aminoacylbenzenes 1, 2, 3a-j, and 4 using acryloyl chloride (Tables 1 and 2). TABLE 1. Physicochemical Characteristics of Compounds 5, 6, 7a-j, and 8 Compound Empiriclal formula Found, % Calculated, % С N Mp, С (Et) Yield, % 5 C 15 19N C 12 12BrN a C 13 13N b C 15 17N c C 15 15N d C 19 17N e C 18 14FN f C 18 14ClN g C 18 14FN h C 18 14FN i C 18 14ClN j C 18 14BrN C 18 16BrN

3 TABLE 2. 1 NM Spectra of Compounds 5, 6, 7a-j, and 8 Compound Chemical shifts (CDCl 3), δ, ppm (J, z) (9Н, s, С(С 3) 3) 2.66 (3Н, s, СН 3) 5.79 (1Н, d, J = 10.1, C=-cis) 6.34 (1Н, dd, J = 17.3, J = 10.1, C=) 6.45 (1Н, d, J = 17.3, C=-trans) 7.16 (1Н, dd, J = 8.6, J = 1.8, Н Ar) 7.86 (1Н, d, J = 8.6, Н Ar) 9.01 (1, d, J = 1.8, Н Ar) (1, s, N) (3Н, t, J = 5.9, СН 2С 3) 3.04 (2Н, q, СН 2СН 3) 5.83 (1Н, d, J = 9.4, C=-cis) 6.32 (1Н, dd, J = 9.4, J = 16.7, C=) 6.46 (1Н, d, J = 16.7, C=-trans) 7.26 (1Н, dd, J = 9.3, J = 1.7, Н Ar) 7.74 (1, d, J = 9.3, Н Ar) 9.12 (1Н, d, J = 1.7, Н Ar) (1, s, N) 7a 2.59 (3Н, s, СН 3) (2, m) and (2Н, m, ) 5.76 (1Н, dd, J = 9.8, J = 1.4, C=-cis) 6.28 (1Н, dd, J = 16.9, J = 9.8, C=) 6.41 (1Н, dd, J = 16.9, J = 1.4, C=-trans) 7.41 (1Н, s, Н Ar) 8.43 (1, s, Н Ar) (1, s, N) 7b 1.21 (6Н, d, J = 7.4, СН(СН 3) 2) 3.53 (1Н, sept, J = 7.4, СН(СН 3) 2) (2, m) and (2Н, m, ) 5.55 (1Н, dd, J = 9.8, J = 1.5, C=-cis) 6.31 (1Н, dd, J = 16.8, J = 9.8, C=) 6.38 (1Н, dd, J = 16.8, J = 1.5, C=-trans) 7.46 (1Н, s, Н Ar) 8.45 (1, s, Н Ar) (1, s, N) 7c (2Н, m), (2Н, m) and (1Н, m, Н c-pr) (2, m) and (2Н, m, ) 5.74 (1Н, d, J = 10.2, C=-cis) 6.27 (1Н, dd, J = 17.4, J = 10.2, C=) 6.38 (1Н, d, J = 17.4, C=-trans) 7.66 (1Н, s, Н Ar) 8.41 (1, s, Н Ar) (1, s, N) 7d 2.44 (3Н, s, СН 3) (2, m) and (2Н, m, ) 5.76 (1Н, d, J = 9.9, C=-cis) 6.31 (1Н, dd, J = 17.3, J = 9.9, C=) 6.41 (1Н, d, J = 17.3, C=-trans) 7.14 (1Н, s, Н Ar) 7.29 (2Н, d, J = 8.2, Н Ar) 7.57 (2Н, d, J = 8.2, Н Ar) 8.36 (1, s, Н Ar) (1, s, N) 7e (2, m) and (2Н, m, ) 5.77 (1Н, d, J = 10.2, C=-cis) 6.30 (1Н, dd, J = 16.8, J = 10.2, C=) 6.41 (1Н, d, J = 16.8, C=-trans) 7.08 (1Н, s, Н Ar) (2Н, m, Н Ar) (2Н, m, Н Ar) 8.36 (1, s, Н Ar) (1, s, N) 7f (2, m) and (2Н, m, ) 5.78 (1Н, d, J = 10.2, C=-cis) 6.31 (1Н, dd, J = 17.6, J = 10.2, C=) 6.42 (1Н, d, J = 17.6, C=-trans) 7.08 (1Н, s, Н Ar) 7.46 (2Н, d, J = 8.6, Н Ar) 7.61 (2Н, d, J = 8.6, Н Ar) 8.38 (1, s, Н Ar) (1, s, N) 7g (2, m) and (2Н, m, ) 5.78 (1Н, d, J = 10.3, C=-cis) 6.31 (1Н, dd, J = 17.2, J = 10.3, C=) 6.45 (1Н, d, J = 17.2, C=-trans) 7.10 (1Н, s, Н Ar) (1Н, m, Н Ar) (3Н, m, Н Ar) 8.39 (1, s, Н Ar) (1, s, N) 7h (2, m) and (2Н, m, ) 5.79 (1Н, d, J = 10.4, C=-cis) 6.33 (1Н, dd, J = 17.7, J = 10.4, C=) 6.44 (1Н, d, J = 17.7, C=-trans) 7.03 (1Н, d, J = 1.8, Н Ar) 7.17 (1Н, t, J = 8.6, Н Ar) 7.26 (1Н, t, J = 8.6, Н Ar) 7.41 (1Н, dt, J = 7.7, J = 1.4, Н Ar) (1Н, m, Н Ar) 8.47 (1, s, Н Ar) (1, s, N) 7i (2, m) and (2Н, m, ) 5.81 (1Н, dd, J = 10.1, J = 1.3, C=-cis) 6.36 (1Н, dd, J = 17.2, J = 10.1, C=) 6.46 (1Н, dd, J = 17.2, J = 1.3, C=-trans) 6.88 (1Н, s, Н Ar) 7.30 (1Н, dd, J = 7.4, J = 1.7, Н Ar) 7.37 (1Н, td, J = 7.4, J = 1.7, Н Ar) 7.43 (1Н, td, J = 7.4, J = 1.7, Н Ar) 7.46 (1Н, dd, J = 7.4, J = 1.7, Н Ar) 8.50 (1, s, Н Ar) (1, s, N) 7j (2, m) and (2Н, m, ) 5.79 (1Н, d, J =10.1, C=-cis) 6.36 (1Н, dd, J = 16.8, J = 10.1, C=) 6.45 (1Н, d, J = 16.8, C=-trans) 6.85 (1Н, s, Н Ar) 7.27 (1Н, dd, J = 7.9, J = 1.7, Н Ar) 7.34 (1Н, td, J = 7.9, J = 1.7, Н Ar) 7.41 (1Н, td, J = 7.7, J =1.4, Н Ar) 7.63 (1Н, dd, J = 7.7, J = 1.4, Н Ar) 8.50 (1, s, Н Ar) (1, s, N) (3Н, s, ОСН 3) 4.03 (3Н, s, ОСН 3) 5.84 (1Н, dd, J = 9.9, J = 1.4, C=-cis) 6.40 (1Н, dd, J = 17.1, J = 9.9, C=) 6.49 (1Н, dd, J = 17.1, J = 1.4, C=-trans) 6.76 (1Н, s, Н Ar) 7.32 (1Н, dd, J = 8.2, J = 1.4, Н Ar) 7.36 (1Н, td, J = 8.2, J = 1.4, Н Ar) 7.45 (1Н, td, J =8.3, J =1.2, Н Ar) 7.67 (1Н, dd, J = 8.3, J = 1.2, Н Ar) 8.72 (1, s, Н Ar) (1, s, N) We then established that o-(vinylcarbonylamino)acylbenzenes 7a-h and 8 may undergo the Michael reaction and add, in one case, alcohols in the presence of alcoholates of the same name and, in the other, amines. The amines undergo the Michael reaction even at 20 C, while the reaction with alcohols requires heating. In both cases, the addition proceeds with high yields and without complications. 1471

4 1 X Et 2 NC X 20 C 3 h 11a g, 12a,b, 13, 14a 7a h, equiv., 3 h 1 2 NC 3 9a c, 10a c = 9a c 3 = Me, a = i-pr, b = 4-MeC 6, c = 2-FC 6 10a c 3 = Et, a = 4-MeC 6, b = 4-FC 6, c = 2-FC 6 11a g X = pyrrolidin-1-yl, a = Me, b = i-pr, c = c-pr, d = 4-MeC 6, e = 4-ClC 6, f = 3-FC 6, g = 2-FC 6 12a,b X = 4-morpholyl, a = 4-ClC 6, b = 3-FC 6 13 = 4-ClC 6, X = NPr 14a = 2-BrC 6, 1 = 2 = Me, X = pyrrolidin-1-yl In addition to aminoacylbenzenes 9a-c, 10a-c, 11a-g, 12a,b, 13, and 14a, which are adducts of the direct Michael reaction, 2-( -phenylethylcarbonylamino)acylbenzenes 15a-g and 16, which are structural analogs of these Michael adducts, were also synthesized using the reaction of o-acylaminobenzenes 3a-e,g,i and 4 with -phenylpropionyl chloride. 3a e,g,i, 4 Ph CCl, 3 N Na Dioxane, 20 C, 1 h a g, 16 NC Ph 15a g = ОСН 2 CН 2 О, a = Me, b = i-pr, c = c-pr, d = 4-MeC 6, e = 4-FC 6, f = 3-FC 6, g = 2-ClC 6 16 = 2-BrC 6, 1 = 2 = Me All -alkoxy-, -amino-, and -phenylethyl-substituted anilides 9a-c, 10a-c, 11a-g, 12a,b, 13, 14a, 15a-g, and 16 were obbained for the first time. The chemical yields of these compounds and their physicochemical characteristics are presented in Tables 3 and 4. 9a c, 10a c, 11e g, 12a,b, 13, 15a f NC Y 1 equiv. Me (or Et) Me (or Et), 9 12 h N C Y C2 Y + + Y 2 N N 17a c, 18a c, 19d f, 20a,b, 21, 22a f 17a c Y = Me, a = i-pr, b = 4-MeC 6,c = 2-FC 6 18a c Y = Et, a = 4-MeC 6, b = 4-FC 6, c = 2-FC 6 19d f Y = pyrrolidin-1-yl, d = 4-ClC 6, e = 3-FC 6, f = 2-FC 6 20a,b Y = morpholin-4-yl, a = 4-ClC 6, b = 3-FC 6 21 Y = NPr, = 4-ClC 6 22a f Y = Ph, a = Me, b = i-pr, c = c-pr, d = 4-MeC 6, e = 4-FC 6, f = 3-FC

5 TABLE 3. Physicochemical Characteristics of -Substituted 2-Propionylaminobenzophenones 9a-c, 10a-c, 11a-g, 12a,b, 13, 14a, 15a-g, and 16 Compound Empirical formula 9a C 16 21N b C 20 21N c C 19 18FN a C 21 23N b C 20 20FN c C 20 20FN a C 17 22N b C 19 26N c C 19 24N d C 23 26N e C 22 23ClN f C 22 23FN g C 22 23FN a C 22 23ClN b C 22 23FN * 2 C 21 24Cl 2N a C 22 25BrN a C 19 19N b C 21 23N c C 21 21N d C 25 23N e C 24 20FN f C 24 20FN g C 24 20ClN C 24 22BrN Found, % Calculated, % С Н N Mp*, С Yield, % *Products 9a,c, 11a-e, 11g, 12b, and 13 were recrystallized from ether, while products 9b, 11f, 12a, and 15a-g were recrystallized from ethanol products 10a-c, 14, and 16 are viscous oils. * 2 The elemental analysis and melting point for compound 13 are given for the hydrochloride. In a study of the cyclization of the obtained Michael adducts to give the corresponding quinolin-2-ones under the conditions adopted in our previous work [6], we found that the possibility of an intramolecular Knoevenagel reaction may depend decisively on the nature and steric factors of the o-acyl substituent in the 1473

6 TABLE 4. 1 NM Spectra of -Substituted 2-Propionylaminobenzophenones 9a-c, 10a-c, 11a-g, 12a,b, 13, 14a, 15a-g, and 16 Com- Chemical shifts (CDCl pound 3), δ, ppm (J, z) a 1.20 (6Н, d, J = 7.6, СН(С 3) 2) 2.67 (2Н, t, J = 5.8, СОСН 2) 3.39 (3Н, s, ОСН 3) 3.50 (1Н, sept, СН(С 3) 2) 3.76 (2, t, J = 5.8, СН 2ОСН 3) (2, m) and (2Н, m, ) 7.43 (1Н, s, Н Ar) 8.36 (1, s, Н Ar) (1, s, N) 9b 2.44 (3Н, s, СН 3) 2.67 (2Н, t, J = 5.8, СОСН 2) 3.40 (3Н, s, ОСН 3) 3.75 (2, t, J = 5.8, СН 2ОСН 3) (2, m) and (2Н, m, ) 7.09 (1, s, Н Ar) 7.26 (2Н, d, J = 8.1, Н Ar) 7.59 (2Н, d, J = 8.1, Н Ar) 8.24 (1, s, Н Ar) (1, s, N) 9c 2.70 (2Н, t, J = 5.8, СОСН 2) 3.41 (3Н, s, ОСН 3) 3.77 (2Н, t, J = 5.8, СН 2ОСН 3) (2, m) and (2Н, m, ) 6.98 (1Н, d, J = 2.4, Н Ar) 7.15 (1Н, dt, J = 9.6, J = 1.0, Ar) 7.24 (1Н, dt, J = 8.0, J = 1.2, Н Ar) 7.40 (1Н, dt, J = 8.0, J = 1.8, Н Ar) 7.49 (1Н, m, Н Ar) 8.37 (1, s, Н Ar) (1, s, N) 10a 1.19 (3, t, J = 5.8, ОСН 2СН 3) 2.42 (3Н, s, СН 3) 2.65 (2Н, t, J = 6.2, СОСН 2) 3.55 (2Н, q, J = 6.9, ОСН 2СН 3) 3.77 (2Н, t, J = 6.2, СОСН 2) (2, m) and (2Н, m, ) 7.07 (1, s, Ar) 7.25 (2Н, d, J = 8.2, Ar) 7.55 (2Н, d, J = 8.2, Ar) 8.22 (1, s, Ar) (1, s, N) 10b 1.19 (3, t, J = 6.9, ОСН 2СН 3) 2.67 (2Н, t, J = 5.9, СОСН 2) 3.55 (2Н, q, J = 6.9, ОСН 2СН 3) 3.78 (2Н, t, J = 5.9, СН 2ОСН 3) (2, m) and (2Н, m, ) 7.06 (1, s, Ar) (2Н, m, Ar) (2Н, m, Ar) 8.23 (1Н, s, Ar) (1, s, N) 10c 1.21 (3, t, J = 7.2, ОСН 2СН 3) 2.72 (2Н, t, J = 5.9, СОСН 2) 3.59 (2Н, q, J = 7.2, ОСН 2СН 3) 3.82 (2Н, t, J = 5.9, СН 2О 2СН 3) (2, m) and (2Н, m, ) 6.99 (1Н, d, J = 2.3, Ar) 7.16 (1Н, t, J = 9.1, Ar) 7.25 (1Н, t, J = 8.0, Ar) 7.40 (1Н, td, J =8.0, J =1.2, Ar) (1Н, m, Ar) 8.37 (1, s, Ar) (1, s, N) 11a (4, m, N(СН 2СН 2) 2) 2.50 (3Н, s, СН 3) 2.78 (2Н, t, J = 6.3, СОСН 2) (4Н, m, N(СН 2СН 2) 2) 3.12 (2Н, t, J = 6.3, СН 2N(СН 2СН 2) 2) (2, m) and (2Н, m, ) 7.29 (1, s, Ar) 8.16 (1Н, s, Ar) (1, s, N) 11b 1.17 (6Н, d, J = 7.0, СН(С 3) 2) (4, m, N(СН 2СН 2) 2) (4Н, m, N(СН 2СН 2) 2) 2.63 (2Н, t, J = 5.8, СОСН 2) 2.88 (2Н, t, J = 5.8, СН 2N(СН 2СН 2) 2) 3.47 (1Н, sept, J = 7.0, СН(С 3) 2) (2, m) and (2Н, m, ) 7.40 (1Н, s, Ar) 8.29 (1, s, Ar) (1, s, N) 11c (2Н, m), (2Н, m) and (1Н, m, Н c-pr) (4, m, N(СН 2СН 2) 2) (6Н, m, СН 2N(СН 2СН 2) 2) 2.89 (2Н, t, J = 6.4, СОСН 2) (2, m) and (2Н, m, ) 7.57 (1Н, s, Ar) 8.22 (1, s, Ar) (1, s, N) 11d (4, m, N(СН 2СН 2) (3, s, C 3) (6Н, m, N(СН 2СН 2) 2) 2.83 (2, t, J = 6.0, СОСН 2) (2, m) and (2Н, m, ) 7.03 (1Н, s, Ar) 7.25 (2Н, d, J = 8.4, Ar) 7.61 (2Н, d, J = 8.4, Ar) 8.08 (1, s, Ar) (1, s, N) 11e (4, m, N(СН 2СН 2) 2) (6Н, m, СН 2N(СН 2СН 2) 2) 2.84 (2Н, t, J = 6.4, СОСН 2) (2, m) and (2Н, m, ) 6.97 (1Н, s, Ar) 7.44 (2Н, d, J = 8.3, Ar) 7.65 (2Н, d, J = 8.3, Ar) 8.07 (1, s, Ar) (1, s, N) 11f (4, m, N(СН 2СН 2) 2) (6Н, m, СН 2N(СН 2СН 2) 2) 2.82 (2Н, t, J = 5.8, СОСН 2) (2, m) and (2Н, m, ) 6.99 (1Н, s, Ar) (1Н, m, Ar) (3Н, m, Ar) 8.08 (1, s, Ar) (1, s, N) 11g (4, m, N(СН 2СН 2) 2) (4Н, m, N(СН 2СН 2) (2Н, t, J = 6.4, CН 2N(СН 2СН 2) (2Н, t, J = 6.4, СОСН 2) (2, m) and (2Н, m, ) 6.99 (1Н, d, J = 2.0, Ar) 7.16 (1Н, td, J = 9.5, J = 1.0, Ar) 7.25 (1Н, td, J = 7.8, J = 1.1, Ar) 7.41 (1Н, td, J = 7.8, J = 1.8, Ar) (1Н, m, Ar) 8.30 (1, s, Ar) (1, s, N) 12a (4, m, N(СН 2СН 2) 2О) 2.60 (2Н, t, J = 6.4, СОСН 2СН 2N) 2.77 (2Н, t, J = 6.4, СОСН 2) 3.74 (4Н, t, J = 4.8, N(СН 2СН 2) 2) (2, m) and (2Н, m, ) 7.01 (1Н, s, Ar) 7.46 (2Н, d, J = 8.2, Ar) 7.64 (2Н, d, J = 8.2, Ar) 8.10 (1, s, Ar) (1, s, N)

7 TABLE 4 (continued) b (4, m, N(СН 2СН 2) 2О) 2.61 (2Н, t, J = 5.8, СОСН 2СН 2N) 2.76 (2Н, t, J = 5.8, СОСН 2) 3.73 (4Н, t, J = 4.8, N(СН 2СН 2) 2) (2, m) and (2Н, m, ) 7.04 (1Н, s, Ar) (1Н, m, Ar) (3Н, m, Ar) 8.12 (1, s, Ar) (1, s, N) 13* 0.96 (3Н, t, J = 7.8, СН 2СН 2СН 3) 1.81 (2Н, m, СН 2СН 2СН 3) 2.87 (2Н, t, J =7.8, NСН 2СН 2СН 3) 3.03 (2Н, t, J = 5.8, СОСН 2) 3.25 (2Н, t, J = 5.8, СОСН 2СН 2NН + 2 ) (2, m) and (2Н, m, ) 6.91 (2Н, br.s, N + 2 ) 6.92 (1Н, s, Ar) 7.36 (2Н, d, J = 8.0, Ar) 7.52 (2Н, d, J = 8.0, Ar) 7.90 (1, s, Ar) (1, s, NСО) 14a (4, m, N(СН 2СН 2) 2) (4Н, m, N(СН 2СН 2) 2) 2.73 (2, t, J = 6.9, СН 2N(СН 2СН 2) 2) 2.94 (2Н, t, J = 6.9, СОСН 2) 3.63 (3, s, ОСН 3) 4.01 (3, s, ОСН 3) 6.73 (1Н, s, Ar) 7.33 (1Н, dd, J = 8.0, J = 1.3, Ar) 7.36 (1Н, td, J = 7.8, J = 1.4, Ar) 7.44 (1Н, t, J = 7.8, Ar) 7.67 (1Н, d, J = 8.0, Ar) 8.49 (1, s, Ar) (1, s, N) 15a 2.56 (3, s, СН 3) 2.73 (2Н, t, J = 6.1, СН 2Ph) 3.07 (2Н, t, J = 6.1, CОСН 2) (2, m) and (2Н, m, ) (1, m, Ar) (4Н, m, Ar) 7.38 (1Н, s, Ar) 8.35 (1Н, s, Ar) (1, s, N) 15b 1.19 (6Н, d, J = 7.4, СН(С 3) 2) 2.74 (2Н, t, J = 7.2, СН 2Ph) 3.07 (2, t, J = 7.2, СОСН 2) 3.50 (1Н, sept, J = 7.4, СН(С 3) 2) (2, m) and (2Н, m, ) (1Н, m, Ar) (4Н, m, Ar) 7.43 (1Н, s, Ar) 8.37 (1, s, Ar) (1, s, N) 15c (2Н, m), (2Н, m) and (1Н, m, Н c-pr) 2.71 (2Н, t, J = 7.4, СН 2Ph) 3.06 (2Н, t, J = 7.4, CОСН 2) (2, m) and (2Н, m, ) (1, m, Ar) (4Н, m, Ar) 7.62 (1Н, s, Ar) 8.32 (1Н, s, Ar) (1, s, N) 15d 2.45 (3, s, СН 3) 2.73 (2Н, t, J = 7.2, СН 2Ph) 3.08 (2Н, t, J = 7.2, CОСН 2) (2, m) and (2Н, m, ) 7.11 (1, s, Ar) (1Н, m, Ar) (6Н, m, Ar) 7.56 (2Н, d, J = 8.0, Ar) 8.25 (1Н, s, Ar) (1, s, N) 15e 2.73 (2Н, t, J = 7.4, СН 2Ph) 3.07 (2Н, t, J = 7.4, CОСН 2) (2, m) and (2Н, m, ) 7.05 (1, s, Ar) (3Н, m, Ar) (4Н, m, Ar) (2Н, m, Ar) 8.25 (1Н, s, Ar) (1, s, N) 15f 2.75 (2Н, t, J = 7.5, СН 2Ph) 3.08 (2Н, t, J = 7.5, CОСН 2) (2, m) and (2Н, m, ) 7.07 (1, s, Ar) (1Н, m, Ar) (8Н, m, Ar) 8.29 (1Н, s, Ar) (1, s, N) 15g 2.81 (2Н, t, J = 7.3, СН 2Ph) 3.12 (2Н, t, J = 7.3, CОСН 2) (2, m) and (2Н, m, ) 6.85 (1, s, Ar) (1Н, m, Ar) (8Н, m, Ar) 8.42 (1Н, s, Ar) (1, s, N) (2Н, t, J = 7.8, СН 2Ph) 3.09 (2Н, t, J = 7.8, CОСН 2) 3.58 (3, s, ОСН 3) 3.97 (3, s, ОСН 3) 6.68 (1, s, Ar) (1Н, m, Ar) (5Н, m, Ar) 7.32 (1Н, td, J = 7.8, J =1.6, Ar) 7.40 (1Н, dt, J = 8.0, J =1.0, Ar) 7.62 (1Н, d, J = 8.0, Ar) 8.58 (1Н, s, Ar) (1, s, N) * 1 Н NM spectrum recorded for hydrochloride. starting anilides. Thus, N-( -alkoxypropionyl)- and N-( -phenyl)propionylaminobenzenes with ortho-alkyl- and ortho-cyclopropylcarbonyl substituents 9a, 15a-c and -alkoxy-, -amino-, and -phenylpropionylaminobenzenes 9b, 10a,b, 11e,f, 12a,b, 13, and 15d-f with meta- or para-substituted benzoyl fragments in the ortho position are converted by the action of equimolar amounts of sodium alcoholate upon heating in an alcohol to give the corresponding 3-alkoxymethyl-, 3-aminomethyl- and 3-benzylquinolin-2-ones 17a,b, 18a,b, 19d,e, 20a,b, 21, and 22a-f in high yields (Tables 5 and 6). Under the same conditions, N-( -aminopropionyl)aminoacylbenzenes 11a-c, which contain alkyl- or cyclopropylcarbonyl groups in the ortho position, form quinolin-2-ones 19a-c in low yields (11-37%, Table 5). Considerable amounts of anilides 11a-c are converted into the corresponding ortho-substituted anilines 3a-c and into 3-alkoxymethylquinolin-2-ones 23a-c. 1475

8 1 equiv. Et 11a c Et, 10 h C N 2 Et + + 3a c N N 19a c 23a c a = Me, b = i-pr, c = c-pr In all likelihood, this transformation of aminoacylbenzenes 11a-c results from: 1) the lower activity of the carbonyl group of the ortho-acyl substituent in the Knoevenagel reaction in comparison with the activity of substrates 11e,f and 2) the capacity of compounds 11a-c to convert to the corresponding N-( -ethoxypropionyl)acylaminobenzenes, which, similar to analog 9a, may cyclize to give 3-ethoxymethylquinolin-2-ones 23a-c. In this case, the alternative variant for formation of quinolin-2-ones 23a-c through nucleophilic substitution of the amine fragment in quinolones 19a-c, formed during the reaction, by an ethoxy group apparently does not occur. therwise, such a substitution should be observed in the cyclization, for example, of acylaminobenzenes 11e,f. TABLE 5. Physicochemical Characteristics of Quinolin-2-ones 17a-c, 18a-c, 19a-g, 20a,b, 21, 22a-f, 23a-c, 24, 25, 26a-c, 27a,b, 28, and 29 Compound Empirical formula Found, % Calculated, % С N Mp*, С Yield* 2, % a C N b C N c C FN a C N b C FN c C FN a C N b C N c C N d C ClN e C FN f C FN g С 23 Н 24 N a C ClN b C FN C ClN a C N b C N c C N (79) (81) (78) (82) (87) (91) (45) (42) (28)

9 TABLE 5 (continued) d C N e C FN f C FN a C N b C N c C N C N C BrN a C ClN b C ClN (84) (81) (77) (79) (92) (87) (79) 26c C ClN a C FN b C FN C FN C BrN (81) (90) (87) (56) (45) *Compounds 17a-c, 18a-c, 19f, 20a, 22a-e, 23b, 24, 26a-c, 28, and 29 were recrystallized from ethanol, compound 9c was recrystallized from 60% aq. ethanol, compounds 19d,e and 27a were recrystallized from methanol, compound 19g was recrystallized from ether, compound 25 was recrystallized from chloroform, compounds 21, 23a, and 27b were recrystallized from 1:3 chloroform-ether, and compounds 19a,b, 20b, and 22f were recrystallized from DMS. * 2 The yields of these quinolin-2-ones obtained by one-pot procedures are given in parentheses. Evidence for the effect of steric factors of the substituents on the formation of quinolin-2-ones from the Michael adducts is found for examples of Knoevenagel cyclization of anilides of ortho-fluoro-, chloro-, and bromobenzophenones 9c, 10c, 11g, 14a, 15g, and 16. Thus, 2-fluorobenzoylanilides 9c, 10c, and 11g were found to be capable of cyclizing to give the corresponding quinolin-2-ones 17c, 18c, and 19f in high yields and require only a longer time for complete conversion of the starting substrates (see Experimental). In contrast, 2-chloro- and 2-bromoanilides 14a, 15g, and 16 do not form the corresponding quinolones at all, even upon prolonged heating at reflux with alcoholate in alcohol solution. In this case, o-[( -phenylethylcarbonyl)- amino]benzophenones 15g and 16 undergo virtually quantitative cleavage at the amide bond to give the corresponding anilines 3i, 4, and -phenylpropionic acid (see Experimental), while o-bromo-substituted anilide 14a gives the product of nucleophilic substitution of the amine fragment by an alkoxy group, namely, N-{2-[(4- bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-3-methoxyprop-2-enamide (14b) in addition to the cleavage products. 1477

10 TABLE 6. 1 NM Spectra of Quinolin-2-ones 17a-c, 18a-c, 19a-g, 20a,b, 21, 22a-f, 23a-c, 24, 25, 26a-c, 27a,b, 28, and 29 Compound Chemical shifts*, δ, ppm (J, z) a 1.47 (6Н, d, J = 6.5, СН(С 3 ) 2 ) 3.36 (3Н, s, ОСН 3 ) 3.70 (1Н, sept, J = 6.5, СН(С 3 ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 4.63 (2Н, s, СН 2 ОСН 3 ) 7.05 (1Н, s, Ar) 7.48 (1, s, Ar) (1, s, N) 17b 2.41 (3Н, s, С 3 ) 3.08 (3Н, s, ОСН 3 ) 3.96 (2Н, s, СН 2 ОСН 3 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.32 (1Н, s, Ar) 6.82 (1Н, s, Ar) 7.15 (2, d, J = 7.9, Ar) 7.32 (2, d, J = 7.9, Ar) (1, s, N) 17c 3.03 (3Н, s, ОС 3 ) 3.89 (1Н, d, J = 19.9) and 4.16 (1Н, d, J = 19.9, СН 2 ОСН 3 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.23 (1Н, s, Ar) 6.84 (1Н, s, Ar) (3, m, Ar) 7.60 (1, m, Ar) (1, s, N) 18a 1.17 (3Н, t, J = 6.9, ОСН 2 С 3 ) 2.45 (3Н, s, С 3 ) 3.47 (2Н, q, J = 6.9, ОСН 2 С 3 ) 4.21 (2Н, s, СН 2 ОEt) (4Н, m, ОСН 2 СН 2 О) 6.64 (1Н, s, Ar) 6.95 (1Н, s, Ar) 7.21 (2, d, J = 7.4, Ar) 7.27 (2, d, J = 7.4, Ar) (1, s, N) 18b 1.19 (3Н, t, J = 6.3, ОСН 2 С 3 ) 3.48 (2Н, q, J = 6.3, ОСН 2 С 3 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 4.28 (2Н, s, СН 2 ОEt) 6.58 (1Н, s, Ar) 6.98 (1Н, s, Ar) (2, m, Ar) (2, m, Ar) (1, s, N) 18c 0.91 (3Н, t, J = 7.5, ОСН 2 С 3 ) 3.19 (2Н, q, ОСН 2 С 3 ) 3.98 (1Н, d, J = 11.1) and 4.15 (1Н, d, J = 11.1, СН 2 ОEt) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.23 (1Н, s, Ar) 6.84 (1Н, s, Ar) (3, m, Ar) (1, m, Ar) (1, s, N) 19a (4Н, m, N( ) 2 ) 2.40 (3Н, s, С 3 ) (4Н, m, N( ) 2 ) (2Н, m, СН 2 N( ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.74 (1Н, s, Ar) 7.16 (1Н, s, Ar) (1, s, N) 19b 1.21 (6Н, d, J = 6.8, СН(СН 3 ) 2 ) (4Н, m, N( ) 2 ) (4Н, m, N( ) 2 ) 3.45 (1Н, sept, J = 6.8, СН(СН 3 ) 2 ) 4.21 (2Н, s, СН 2 N( ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.83 (1Н, s, Ar) 7.25 (1Н, s, Ar) (1, s, N) 19c (2Н, m), (2Н, m) and (1Н, m, Н c-pr) (4Н, m, N( ) 2 ) (4Н, m, N( ) 2 ) 4.11 (2Н, s, СН 2 N( ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.83 (1Н, s, Ar) 7.70 (1Н, s, Ar) (1, br. s, N) 19d (4Н, m, N( ) 2 ) (4Н, m, N( ) 2 ) 3.49 (2Н, s, СН 2 N( ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.52 (1Н, s, Ar) 6.96 (1Н, s, Ar) 7.31 (2, d, J = 8.2, Ar) 7.46 (2, d, J = 8.2, Ar) (1, s, N) 19e (4Н, m, N( ) 2 ) (4Н, m, N( ) 2 ) 3.46 (1Н, d, J = 12.2) and 3.52 (1Н, d, J = 12.2, СН 2 N( ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.56 (1Н, s, Ar) 6.97 (1Н, s, Ar) (3, m, Ar) (1, m, Ar) (1, br. s, N) 19f (4Н, m, N( ) 2 ) (4Н, m, N( ) 2 ) 3.46 (1Н, d, J = 3.4) and 3.59 (1Н, d, J = 3.4, СН 2 N( ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.54 (1Н, s, Ar) 6.92 (1Н, s, Ar) (2, m, Ar) (2, m, Ar) (1, br. s, N) 19g 1.72 (4Н, br. s, N( ) 2 ) 2.45 (3Н, s, СН 3 ) 2.61 (4Н, br. s, N( ) 2 ) 3.62 (2Н, s, СН 2 N(СН 2 СН 2 ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.59 (1Н, s, Ar) 6.96 (1, s, Ar) 7.21 (2, d, J = 8.1, Ar) 7.29(2Н, d, J = 8.1, Ar) (1Н, br. s, N) 20a (4Н, m, N( ) 2 О) (2Н, m, СН 2 N( ) 2 О) (4Н, m, N( ) 2 О) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.54 (1Н, s, Ar) 6.94 (1Н, s, Ar) 7.33 (2, d, J = 8.3, Ar) 7.46 (2, d, J = 8.3, Ar) (1, br. s, N) 20b (4Н, m, N( ) 2 О) 3.04 (1Н, d, J = 12.1) and 3.16 (1Н, d, J = 12.1, СН 2 N( ) 2 О) (4Н, m, N( ) 2 О) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.27 (1Н, s, Ar) 6.83 (1Н, s, Ar) 7.14 (1, d, J = 7.4, Ar) (2, m, Ar) (1Н, m, Ar) (1, s, N) (3Н, t, J = 7.1, СН 2 СН 2 СН 3 ) (2Н, m, СН 2 СН 2 СН 3 ) (2Н, m, NНC2Et) 3.51 (1Н, br. s, СН 2 NPr) 3.72 (2Н, s, СН 2 NPr) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.48 (1Н, s, Ar) 7.04 (1Н, s, Ar) 7.34 (2, d, J = 8.2, Ar) 7.51 (2, d, J = 8.2, Ar) 20a 2.31 (3Н, s, СН 3 ) 3.92 (2Н, s, СН 2 Ph) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.78 (1Н, s, Ar) (6Н, m, Ar) (1, br. s, N)

11 TABLE 6 (continued) b 1.34 (6Н, d, J = 7.6, СН(СН 3 ) 2 ) 3.62 (1Н, sept, J = 7.6, СН(СН 3 ) 2 ) 4.24 (2Н, s, СН 2 Ph) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.88 (1Н, s, Ar) (1Н, m, Ar) (4Н, m, Ar) 7.45 (1Н, s, Ar) (1, br. s, N) 22c (2Н, m), (2Н, m) and (1Н, m, Н c-pr) 4.14 (2Н, s, СН 2 Ph) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.77 (1Н, s, Ar) (3Н, m, Ar) (2Н, m, Ar) 7.54 (1Н, s, Ar) (1, s, N) 22d 2.37 (3Н, s, СН 3 ) 3.63 (2Н, s, СН 2 Ph) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.25 (1Н, s, Ar) 6.84 (1Н, s, Ar) 6.96 (2, d, J = 7.8, Ar) (3Н, m, Ar) (2Н, m, Ar) 7.29 (2, d, J = 7.8, Ar) (1, s, N) 22e 3.63 (2Н, s, СН 2 Ph) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.21 (1Н, s, Ar) 6.85 (1Н, s, Ar) 6.92 (2, d, J = 7.6, Ar) (3Н, m, Ar) (2Н, m, Ar) 7.31 (2, t, J = 7.6, Ar) (1, s, N) 22f 3.62 (1Н, d, J = 17.6) and 3.64 (1Н, d, J = 17.6, СН 2 Ph) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.21 (1Н, s, Ar) 6.85 (1Н, s, Ar) 6.92 (2, d, J = 7.8, Ar) (2Н, m, Ar) (3Н, m, Ar) (1, m, Ar) (1, m, Ar) (1, s, N) 23a 1.09 (3Н, t, J = 7.0, ОСН 2 С 3 ) 2.38 (3Н, s, СН 3 ) 3.46 (2Н, q, J = 7.0, ОСН 2 С 3 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 4.45 (2Н, s, СН 2 ОEt) 6.75 (1Н, s, Ar) 7.20 (1Н, s, Ar) (1, s, N) 23b 1.09 (3Н, t, J = 6.6, ОСН 2 С 3 ) 1.39 (6Н, d, J = 6.9, СН(СН 3 ) 2 ) 3.42 (2Н, q, J = 6.6, ОСН 2 С 3 ) 3.62 (1Н, sept, J = 6.9, СН(СН 3 ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 4.49 (2Н, s, СН 2 ОСН 2 СН 3 ) 6.79 (1Н, s, Ar) 7.36 (1Н, s, Ar) (1, s, N) 23c (2Н, m), (2Н, m) and (1Н, m, Н c-pr) 1.29 (3Н, t, J = 7.2, ОСН 2 С 3 ) 3.71 (2Н, q, J = 7.2, ОСН 2 С 3 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 4.77 (2Н, s, СН 2 ОСН 2 СН 3 ) 6.87 (1Н, s, Ar) 7.67 (1Н, s, Ar) (1, s, N) (3Н, t, J = 6.2, СН 2 СН 3 ) 1.39 (9Н, s, С(СН 3 ) 3 ) 2.61 (3Н, s, СН 3 ) 3.65 (2Н, q, J = 6.2, ОСН 2 СН 3 ) 4.76 (2Н, s, СН 2 ОСН 2 СН 3 ) 7.29 (1, dd, J = 8.1, J = 1.9, Ar) 7.37 (1Н, s, Ar) 7.69 (1, d, J = 8.1, Ar) (1, s, N) (3Н, t, J = 6.2, СН 2 СН 3 ) 3.04 (2Н, q, J = 6.2, СН 2 СН 3 ) 3.52 (3Н, s, ОСН 3 ) 4.68 (2, s, СН 2 ОСН 3 ) 7.36 (1, d, J = 8.2, Ar) 7.58 (1Н, br. s, Ar) 7.63 (1, d, J = 8.2, Ar) (1, s, N) 26a 3.08 (3Н, s, ОСН 3 ) 3.96 (2Н, s, СН 2 ОС 3 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.28 (1Н, s, Ar) 6.83 (1Н, s, Ar) 7.31 (2Н, d, J = 8.3, Ar) 7.59 (2Н, d, J = 8.3, Ar) (1, s, N) 26b 0.92 (6Н, d, J = 6.8, СН(СН 3 ) 2 ) 3.36 (1Н, sept, J = 6.8, ОСН(СН 3 ) 2 ) 4.04 (2Н, s, СН 2 ОСН(СН 3 ) 2 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.23 (1Н, s, Ar) 6.78 (1Н, s, Ar) 7.29 (2Н, d, J = 8.4, Ar) 7.55 (2Н, d, J = 8.4, Ar) (1, s, N) 26c 4.08 (2Н, s, СН 2 Ph) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 4.33 (2Н, s, СН 2 ОСН 2 Ph) 6.29 (1Н, s, Ar) 6.84 (1Н, s, Ar) (2Н, m, Ar) (3Н, m, Ar) 7.31 (2Н, d, J = 8.3, Ar) 7.56 (2Н, d, J = 8.3, Ar) (1, s, N) 27a 3.35 (3Н, s, ОСН 3 ) (4Н, m, ОСН 2 СН 2 О, СН 2 ОСН 3 ) (2Н, m, ОСН 2 С 2 О) 6.59 (1Н, s, Ar) 7.00 (1Н, s, Ar) (3Н, m, Ar) (1Н, m, Ar) (1, s, N) 27b 1.14 (6Н, d, J = 6.4, СН(СН 3 ) 2 ) 3.58 (1Н, sept, J = 6.4, ОСН(СН 3 ) 2 ) (3Н, m) and (3Н, m, ОСН 2 СН 2 О, СН 2 ОСН(СН 3 ) 2 ) 6.59 (1Н, s, Ar) 6.97 (1Н, s, Ar) (3Н, m, Ar) (1Н, m, Ar) (1, s, N) (1Н, d, J = 9.8) and 4.24 (1Н, d, J = 9.8, СН 2 ОСН 2 Ph) (2Н, m, СН 2 Ph) (4Н, m, ОСН 2 СН 2 О) 6.25 (1Н, s, Ar) 6.86 (1Н, s, Ar) (2Н, m, Ar) (3Н, m, Ar) (3Н, m, Ar) (1Н, m, Ar) (1, s, N) (3Н, t, J = 6.7, ОСН 2 С 3 ) (1Н, m) and (1Н, m, ОСН 2 С 3 ) 3.98 (1Н, d, J = 10.3) and 4.58 (1Н, d, J = 10.3, СН 2 ОСН 2 СН 3 ) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 6.43 (1Н, s, Ar) 7.01 (1Н, s, Ar) (2Н, m, Ar) 7.45 (1Н, t, J = 7.7, Ar) 7.72 (1Н, d, J = 7.8, Ar) (1, br. s, N) *The 1 NM spectra of 17a, 18a,b, 19b-f, 20a, 21, 22b, 23c, 24, 25, 27a,b, and 29 were recorded in CDCl 3, while the spectra for 17b,c, 18c, 19a,g, 20b, 22a,c-f, 23a,b, 26a-c, and 28 were recorded in DMS-d

12 In a study of the transformations of o-(vinylcarbonylamino)acylbenzenes to quinolin-2-ones through separate consecutive Michael and Knoevenagel reactions, we attempted to elucidate whether it is possible to synthesize quinolones from alkenylanilides in a one-pot procedure. We found that the action of two equivalents of sodium alcoholate in the corresponding alcohol on, -unsaturated anilides 5, 6, and 7a-h,j over the time required for the cyclization of o-( -alkoxypropionylamino)acylbenzenes 9a-c and 10a-c leads to conversion to 3-alkoxymethylquinolones 17a-c, 18a-c, 23a-c, 24, 25, 26a-c, 27a,b, 28, and 29 in high yields (Table 5). 5, 6, 7a h,j 2 equiv. 3, C, 8 10 h 1 2 N 3 17a c, 18a c, 23a c, 24, 25, 26a c, 27a,b, 28, = Me, 1 =, 2 = t-bu, 3 = Et 25 = Et, 1 =, 2 = Br, 3 = Me = 26a c = 4-ClC 6, a 3 = Me, b 3 = i-pr, c 3 = Ph 27a,b = 3-FC 6, a 3 = Me, b 3 = i-pr 28 = 2-FC 6, 3 = Ph 29 = 2-BrC 6, 3 = Et It is important to note that, -unsaturated substrates containing fluorine or bromine atoms in the ortho position of the benzoyl fragments behave in the one-pot procedures identically to the corresponding Michael adducts upon cyclization by the action of an equivalent of alcoholate in alcohol. For example, 2-fluorobenzoyl derivative 7h is converted into 3-(alkoxymethyl)quinolin-2-ones 17c, 18c, and 28 in high yields. In contrast, 2-bromobenzoyl derivative 7j gives the corresponding quinolone 29 only in 39% yield. The major product, amine 3j (61% yield), results from cleavage of the amide bond. n the other hand, N-[2-(2-bromobenzoyl)- 4,5-dimethoxyphenyl]prop-2-enamide (8) does not form any intramolecular cyclization products, and only the corresponding aniline 4 was obtained in 93% yield. In a study of the feasibility of a one-pot synthesis of 3-(alkylamino)quinolin-2-ones from the corresponding alkenylanilides, it was we found that anilides with o-alkylcarbonyl groups 7a-c are converted by the action of 2.5 equivalents of pyrrolidine in ethanol into the Michael addition products 11a-c only. Under the same conditions, o-(vinylcarbonylamino)benzophenones 7d,f,g give a mixture of an addition product 11d,e,f and 3-(pyrrolidinylmethyl)quinolin-2-one 19g,d,e, respectively, in approximately equal amounts. 7d,f,g 2.5 equiv. N Et,, 10 h N N + 11d,e,f 19g = 4-MeC 6 19d,e,g It is interesting that the reaction of anilide 7d with morpholine, in contrast to the analogous reaction with pyrrolidine, provides only Michael adduct 12c. 7d 2.5 equiv. N Et,, 10 h N 12c N Me 1480

13 Thus, 3-alkoxymethyl- or 3-alkylaminomethylquilinolin-2-ones may be obtained from 2-alkenylcarbonylaminoacylbenzenes using both one-pot and two-step procedures involving the addition of Michael donors and intramolecular Knoevenagel cyclization. EXPEIMENTAL The 1 NM spectra were recorded on a Varian XL-400 spectrometer (400 Mz) in DMS-d 6 with TMS as internald standard or in CDCl 3 using the residual signals of the solvent as an internal reference (δ 7.26 ppm). The elemental analysis was carried out on a Vario-11CN analyzer. The melting points were determined on an Electrothermal Digital Melting Point Apparatus (model 1А9100). The separation and analysis of the reaction mixtures were carried out on thick or thin layer Al 2 3 plates (Brokman activity II), eluents: А) Et 2 CCl 3 petroleum ether, 1:1:3, B) Et 2 CCl 3 petroleum ether Me, 1:1:2:0.1. The petroleum ether with bp С was used. 2-Aminoacylbenzenes 1 [7], 2 [8], 3a,f [9], 3b,d,h [10], 3c,d [11], 3i,j [12] were obtained following methods published earlier. (2-Amino-2,3-dihydro-1,4-benzodioxin-6-yl)(4-fluorophenyl)methanone (3е) was synthesized by the reduction of (2-nitro-2,3-dihydro-1,4-benzodioxin-6-yl)(4-fluorophenyl)methanone following the method described in [10]. Yield 86% mp С (Et). 1 Н NM spectrum (CDCl 3 ), δ, ppm (J, z): (2, m) and (2Н, m, ОСН 2 СН 2 О) 6.33 (1Н, s, Ar) 6.71 (1, s, Ar) 6.82 (2, br. s, N 2 ) (2, m, Ar) (2, m, Ar). Found, %: С Н 4.33 N С 15 Н 12 FN 3. Calculated, %: С Н 4.43 N (2-Amino-4,5-dimethoxyphenyl)(2-bromophenyl)methanone (4) was obtained similarly by reducing (2-bromophenyl)(4,5-dimethoxy-2-nitrophenyl)methanone following the method described in [4]. Yield 77% mp С (Et). 1 Н NM spectrum (CDCl 3 ), δ, ppm (J, z): 3.59 (3Н, s, СН 3 О) 3.91 (3Н, s, СН 3 О) 6.21 (1Н, s, Ar) 6.48 (2, br. s, N 2 ) 6.55 (1, s, Ar) (2, m, Ar) 7.42 (1Н, t, J = 7.9, Ar) 7.64 (1, d, J = 7.9, Ar). Found, %: С Н 4.28 N С 15 Н 14 BrN 3. Calculated, %: С Н 4.20 N N-(2-Acylphenyl)prop-2-enamides 5, 6, 7a-j, 8 (General Method). Freshly distilled acrylic chloride (0.91 g, 10 mmol) and 3 N Na solution (3.5 ml, 3.73 g, 10 mmol) were simultaneously added portionwise to the corresponding 2-acylaniline 1, 2, 3a-j, 4 (10 mmol) in dioxane (40 ml). The reaction mixture was stirred for 1 h at 20 C and poured into water (250 ml). The precipitate was filtered off, washed with water, dried in air, and recrystallized from an appropriate solvent. N-(7-Acyl-2,3-dihydro-1,4-benzodioxin-6-yl)-3-alkoxypropanamides 9a-c and 10a-c (General Method). N-[7-Acyl-2,3-dihydro-1,4-benzodioxin-6-yl]prop-2-enamide 7b,d,e,h,i (2.0 mmol) was gradually added at 20 С to ethanolic solution of sodium alcoholate, prepared from metallic sodium (46 mg, 2.0 mmol) and methanol or ethanol (30 ml). The reaction mixture was then refluxed for 3 h, cooled to 20 C, poured into water (250 ml). The formed oily substance was extracted with CCl 3 (2 40 ml), the extract was washed with water, dried over MgS 4, and, after evaporation of the solvent, the residue was recrystallized from a suitable solvent or purified by chromatography on Al 2 3 (compounds 10a-c, eluent А). N-(7-Acyl-2,3-dihydro-1,4-benzodioxin-6-yl)-3-aminopropanamides 11a-g, 12a,b, 13 and N-{2-[(2-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-3-(pyrrolidin-1-yl)propanamide 14а (General Method). Pyrrolidine, morpholine, or propylamine (3.0 mmol) was added to a suspension of N-arylprop-2-enamide 7a-h, 8 (3.0 mmol) in Me or Et (40 ml). The mixture was stirred for 1 h at 20 C and poured into water (200 ml). The formed oily substance was extracted with CCl 3 (2 35 ml), the extract was washed with water, dried over MgS 4, and, after evaporation of the solvent, the residue was purified by chromatography on Al 2 3 (eluent А). N-(7-Acyl-2,3-dihydro-1,4-benzodioxin-6-yl)-3-phenylpropanamides 15a-g and N-{2-[(4-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-3-phenylpropanamide (16) were obtained by the interaction of 1481

14 equimolar amounts of the corresponding 2-aminoacylbenzenes 3a-e,g,i, 4 and β-phenylpropionyl chloride in procedure analogous to the synthesis of N-(2-acylphenyl)propen-2-amides 5, 6, 7a-j, 8 (see above). Cyclization of Compounds 9a-c, 10a-c, 11е-g, 12a,b, 13, 15a-f into Quinoline-2-ones (General Method). The corresponding Michael adduct (1.0 mmol) was added to a sodium ethylate or methylate solution, prepared from metallic sodium (23 mg, 1.0 mmol) and ethanol or methanol (25 ml). The mixture was refluxed for 9-12 h (18 h for compounds 9c, 10c, 11g), cooled to 20 C, and poured into water (200 ml). The precipitated crystalls were filtered off, washed with water, dried in air, and afterwards recrystallized from suitable solvents or purified by chromatography on Al 2 3 (compounds 19а-c, eluent B) and recrystallized. 3-Alkoxymethyl-, 3-aminomethyl-, or 3-benzyl-substituted quinolin-2-ones 17a-c, 18a-c, 19d-f, 20a,b, 21, 22a-f were obtained as a result. N-{2-[(4-Bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-3-methoxypropanamide (14b) was obtained from compound 14а (0.46 g, 1.0 mmol) following the described general method of the cyclization in Me. The separation of the reaction mixture on Al 2 3 yielded the starting compound 14а (0.11 g, 24%), aniline 4 (0.06 g, 22%), and compound 14b (0.17 g, 53%). Viscous oil. 1 Н NM spectrum (CDCl 3 ), δ, ppm (J, z): 2.78 (2Н, t, J =7.1, CОСН 2 ) 3.44 (3, s, ОСН 3 ) 3.63 (3, s, ОСН 3 ) 3.82 (2, t, J =7.1, СН 2 ОСН 3 ) 4.01 (3, s, ОСН 3 ) 6.74 (1, s, Н Ar) 7.33 (1Н, td, J = 7.9, J = 1.6, Ar) 7.37 (1Н, d, J = 7.9, Н Ar) 7.44 (1Н, t, J = 7.9, Н Ar) 7.67 (1Н, d, J = 7.9, Н Ar) 8.64 (1Н, s, Ar) (1, s, N). Found, %: С Н 4.58 N С 19 Н 20 BrN 5. Calculated, %: С Н 4.77 N (2-Amino-4,5-dimethoxyphenyl)(2-chlorophenyl)methanone (3i) was obtained by the method described above from (2-chlorophenyl)(4,5-dimethoxy-2-[(2-phenylethyl)amino]phenyl)methanone (15g) (0.42 g, 1.0 mmol). The separation of the reaction mixture on Al 2 3 plates yielded the starting compound 15g (0.06 g, 14%), compound 3i (0.2 g, 81%), and β-phenylpropionic acid (0.1 g, 77%). An analogous treatment of compound 16 (0.47 g, 1.0 mmol) yielded aniline 4 (0.28 g, 89%) and β-phenylpropionic acid (0.1 g, 71%), along with the recovered starting material 16 (0.05 g, 10%). 9-Methyl-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (19a) and 8-(ethoxymethyl)-9-methyl-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (23а) were obtained from compound 11a (0.32 g, 1.0 mmol) by means of cyclization in Et following the general procedure. The separation of the reaction mixture on Al 2 3 plates yielded compounds 3а (0.045 g, 18%), 19a (0.11 g, 37%), and 23а (0.12 g, 43%). 9-Isopropyl-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (19b) and 8-(Ethoxymethyl)-9-isopropyl-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (23b). An analogous treatment of compound 11b (0.27 g, 0.78 mmol) yielded compounds 3b (0.062 g, 41%), 19b (0.025 g, 11%), and 23b (0.082 g, 39%), along with the recovered starting anilide 11b (0.03 g, 11%). 9-Cyclopropyl-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (19c) and 9-Cyclopropyl-8-(ethoxymethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (23c). The treatment of compound 11c (0.35 g, 1.0 mmol) as described above yielded compounds 3c (0.023 g, 11%), 19c (0.059 g, 19%), and 23c (0.128 g, 45%)%), along with the recovered starting anilide 11c (0.025 g, 7%). ne-pot Synthesis of 3-Alkoxymethylquinolin-2-ones 17a-c, 18a-c, 23a-c, 24, 25, 26a-c, 27a,b, 28, 29 from N-(2-Acylphenyl)prop-2-enamides 5, 6, 7a-h,j (General Method). о-(vinylcarbonyl)acylbenzene 5, 6, 7a-h, 7j (1.0 mmol) was added to an corresponding sodium alcoholate solution prepared from sodium (0.046 mg, 2.0 mmol) and MеОН, Еt, 2-Pr, or Bn (25 ml). The reaction mixture was heated to C, stirred at that temperature for 10 h, cooled to 20 C, poured into water (200 ml), and neutralized with 2 N Cl. The prepicitate was separated by filtration, washed with water, dried in air, and recrystallized from a suitable solvent or purified by chromatography on Al 2 3 plates (compounds 28, 29, eluent B) and recrystallized. ne-pot Synthesis of 3-Alkylaminomethylquinolin-2-ones from Compounds 7d,f,g (General Method). A mixture of о-(vinylcarbonyl)acylbenzene 7d,f,g (1.0 mmol) and pyrrolidine or morpholine (2.5 mmol) in Et (15 ml) was refluxed for 10 h. The solvent was evaporated in vacuo, and the residue was separated by chromatography on Al 2 3 plates (eluent B). 1482

15 9-(4-Methylphenyl)-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (19g) (0.103 g, 28%) was obtained from compound 7d (0.320 g, 1.0 mmоl) along with compound 11d (0.270 g, 71%). 9-(4-Chlorophenyl)-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (19d) (0.32 g, 45%) was obtained from compound 7f (0.61 g, 1.8 mmol) along with compound 11e (0.29 g, 39%). 9-(3-Fluorophenyl)-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-7(6Н)-one (19e) (0.16 g, 42%) was obtained from compound 7g (0.33 g, 1.0 mmol) along with compound 11f (0.15 g, 38%). N-{7-[(4-Bromophenyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-3-(morpholin-4-yl)propanamide (12c) was obtained in an analogous way from compound 7d (0.323 g, 1.0 mmol) and morpholine (0.220 g, 2.5 mmol). Yield g (95%) mp С (Еt). 1 Н NM spectrum (CDCl 3 ), δ, ppm (J, z): 2.44 (3Н, s, СН 3 ) (6Н, m, СН 2 N(СН 2 СН 2 ) 2 О) 2.82 (2Н, br. s, СОСН 2 ) 3.76 (4, br. s, N( )) (2Н, m) and (2Н, m, ОСН 2 СН 2 О) 7.07 (1Н, s, Ar) 7.29 (2Н, d, J = 8.2, Ar) 7.61 (2Н, d, J = 8.2, Ar) 8.10 (1Н, s, Ar) (1Н, br. s, N). Found, %: С Н 6.43 N С 23 Н 26 N 2 5. Calculated, %: С Н 6.39 N This work was supported by the Council of the President of the ussian Federation for the Leading Scientific School Supporting Grants (grant NSh ). EFEENCES 1. L. A. McQuaid, E. C. Smith, D. Lodge, E. Pralong, J.. Wikel, D.. Calligaro, and P. J.. 'Malley, J. Med. Chem., 35, 3423 (1992). 2. J. J. Kugalowski, M. owley, P. D. Leeson, and Z. M. Mawer, EP Pat. Appl W. Carling, P. D. Leeson, K. W. Moore,. Baker, A. C. Foster, S. Grimwood, J. A. Kemp, G.. Marshall, M. D. Tricklebank, and K. I. Saywell, J. Med. Chem., 40, 754 (1997). 4. Y.-Q. Fang,. Karisch, and M. Lautens, J. rg. Chem., 72, 1341 (2007). 5. P. ewawasam, W. Fan, M. Ding, K. Flint, D. Cook, G. D. Goggins,. A. Myers, V. K. Gribkoff, C. G. Boissard, S. I. Dworetzky, J. E. Starett, and N. J. Lodge, J. Med. Chem., 46, 2819 (2003). 6. S. S. Mochalov, M. I. Khasanov, A. N. Fedotov, and N. S. Zefirov, Khim. Geterotsikl. Soedin., 1345 (2011). [Chem. eterocycl. Compd., 47, 1105 (2011)]. 7.. A. Gazzaeva, M. I. Khasanov, S. S. Mochalov, and N. S. Zefirov, Khim. Geterotsikl. Soedin., 941 (2007). [Chem. eterocycl. Compd., 43, 799 (2007)]. 8. A. N. Fedotov, S. S. Mochalov, and Yu. S. Shabarov, Zh. Prikl. Khim., 50, 1860 (1977). 9. S. S. Mochalov, M. I. Khasanov, E. V. Trofimova, A. N. Fedotov, and N. S. Zefirov, Khim. Geterotsikl. Soedin., 1507 (2009). [Chem. eterocycl. Compd., 45, 1208 (2009)]. 10. S. S. Mochalov, M. I. Khasanov, and N. S. Zefirov, Khim. Geterotsikl. Soedin., 252 (2009). [Chem. eterocycl. Compd., 45, 201 (2009)]. 11. S. S. Mochalov and M. I. Khasanov, Khim. Geterotsikl. Soedin., 788 (2008). [Chem. eterocycl. Compd., 44, 628 (2009)]. 12. S. S. Mochalov, D. V. Kosynkin, I. D. Yudin, V. N. Atanov, Yu. S. Shabarov, and N. S. Zefirov, Khim. Geterotsikl. Soedin., 601 (1994). [Chem. eterocycl. Compd., 30, 527 (1994). 1483