Structural and theoretical evidence of the reaction products of ethyl(ethoxymethylene)cyanoacetate with 5-phenoxymethyl-2-amino-2-oxazoline

Journal of Molecular Structure 508 (1999) 193–205

Structural and theoretical evidence of the reaction products of ethyl(ethoxymethylene)cyanoacetate with 5-phenoxymethyl-2-amino-2-oxazoline C. Chaimbault a, J.J. Bosc a, C. Jarry a, J.M. Leger b, N. Marchand-Geneste c, A. Carpy c,* a

Laboratoire de Chimie Physique et Mine´rale, Universite´ Victor Segalen Bordeaux 2, 146 rue Le´o Saignat, 33076 Bordeaux Cedex, France b Laboratoire de Chimie Analytique, Universite´ Victor Segalen Bordeaux 2, 3ter Place de la Victoire, 33076 Bordeaux Cedex, France c Laboratoire de Physico- et Toxico-Chimie des Syste`mes Naturels (LPTC), UPRES A 5472, CNRS, Universite´ de Bordeaux I, 351, Cours de la Libe´ration, 33405 Talence Cedex, France Received 16 November 1998; received in revised form 27 January 1999; accepted 27 January 1999

Abstract The reaction between ethyl(ethoxymethylene)cyanoacetate and 5-phenoxymethyl-2-amino-2-oxazoline leads to a 1,4-adduct and to a 2,3-dihydrooxazolo[3,2-a]pyrimidin-5-one. The structures were assigned by spectroscopy and, for the cyclocondensation compound, by X-ray crystallography. The question of regioselectivity was studied by a theoretical approach in order to determine the more reliable reaction pathways. An unexpected mechanistic scheme is proposed to explain the formation of the cyclocondensed compound. q 1999 Elsevier Science B.V. All rights reserved. Keywords: 2,3-dihydrooxazolo[3,2-a]pyrimidin-5-one, 2-amino-2-oxazoline; b-dielectrophile, reaction path

1. Introduction Condensation of non-substituted amidines with bdifunctional compounds is a general preparative method for pyrimidine derivatives [1]. The reaction using ethyl(ethoxymethylene)cyanoacetate (EMCA) begins with a 1,4-addition followed by subsequent cyclization giving pyrimidines [1–4]. In the course of our studies on 2-amino-2-oxazolines, we found that they are useful synthons for the preparation of various heterocyclic systems [5,6].

* Corresponding author. Tel.: 133-556-848944; fax: 133-557848948. E-mail address: [email protected] (A. Carpy)

Their amidine moiety is a versatile building block for cyclocondensation reactions leading to polycyclic compounds with a bridgehead nitrogen atom [7,8]. Moreover, the two nitrogen atoms are potent nucleophilic centres permitting the initiation of a concerted cyclocondensation with b-dielectrophilic reagents. In this work, the EMCA was selected to react with the 5-phenoxymethyl-2-amino-2-oxazoline. Under our experimental conditions, the reaction yielded two products, a cyclocondensation compound B23 and a non-cyclized one A2 (Scheme 1). Their structures were established by 1H, 13C NMR and by X-ray crystallography. In order to gain information about the possible mechanisms involved in this reaction, the reaction paths were studied, using computational methods.

0022-2860/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S0022-286 0(99)00059-9

194

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

Scheme 1. Schematic reaction.

2. Experimental 2.1. Synthesis EMCA (8.45 g; 50 mmol) is added dropwise to a solution of 5-phenoxymethyl-2-amino-2-oxazoline (9.6 g; 50 mmol) in ethanol (150 ml). The solution Table 1 Crystal data and structure refinement for B23 Chemical formula Formula weight Crystal size (mm) Crystal system Space group Unit-cell dimensions

˚ 3) Volume (A Z Density calculated (Mg/m 3) Absorption coefficient m F(000) Temperature (K) ˚) Wavelength (A u range for data collection Index ranges Reflections collected Independent reflections Observed reflections Refinement method Data/restraints/parameters Goodness-of-fit on F 2 Final R indices ‰I . 2s…I†Š R indices (all data) Extinction coefficient Largest diff. Peak and hole

C14H11N3O3 269.26 0.20 × 0.05 × 0.01 Monoclinic C 2/c ˚, b ˆ a ˆ 30.491(3) A ˚ , c ˆ 13.450(2) A ˚, 6.757(1) A b ˆ 112.75(1)8 2555.5(6) 8 1.40 0.844 mm 21 1120 296(2) 1.54178 3.148–59.928 0 , h , 34, 0 , k , 7, 214 , l , 13 1882 1882 [R(int) ˆ 0.0000] 1202 Full-matrix least-squares on F 2 1881/0/182 1.045 R1 ˆ 0.0428, Rw2 ˆ 0.1040 R1 ˆ 0.0923, Rw2 ˆ 0.1249 0.00087(10) 0.166 and 2 0.171 e A 23

is stirred magnetically at room temperature for 5 h. The white precipitate is collected and purified by column chromatography on silica gel (eluent CHCl3/ MeOH 90/10 v/v) to give white crystals of the monosubstituted product A2 (20.5 mmol, yield: 41%). The filtrate is stirred overnight, and a second solid precipitated. Collection by filtration and slow crystallization from methanol yielded B23 (23 mmol, yield: 46%). Melting points were determined with a SM-LUXPOL Leitz hot-stage microscope and were uncorrected. UV spectra were recorded in methanol on a Kontron Uvikon 940 spectrophotometer. The IR spectra were obtained with a Bruker IFS 25 spectrophotometer. NMR data were recorded with a Bruker AC-200 spectrometer. Chemical shifts (d in ppm) and coupling constants (J in Hz) were measured using tetramethylsilane as the internal standard. 2-ethyl(methylenecyanoacetate)-5-phenoxymethyl2-iminooxazolidine (A2): m.p. ˆ 1768 C, Rf ˆ 0.63 (eluent CHCl3/MeOH 90/10 v/v). UV (MeOH) 296 (e ˆ 3572), 217 (e ˆ 6928). IR (Bruker IFS-25) (KBr) n (cm 21): 2224 (CxN), 1706 (CyO), 1656 (CyN). 1H NMR (Bruker AC 200) (200.13 MHz, DMSO-d6), d : 1.20 (t, 3H, CH3, 3J ˆ 7.1 Hz), 3.64 (dd, 1H, OCH2aCH, 2J ˆ 10.0 Hz, 3J ˆ 7.1 Hz), 3.92 (t, 1H, OCH2bCH, 2J ˆ 10.0 Hz), 4.12 (q, 2H, CH2CH3, 3J ˆ 7.1 Hz), 4.24 (dd, 1H, CH2aN, 2J ˆ 11.6 Hz, 3J ˆ 5.3 Hz), 4.34 (dd, 1H, CH2bN, 2J ˆ 11.6 Hz, 3J ˆ 2.9 Hz), 5.36–5.30 (m, 1H, CHCH2), 6.92–7.34 (m, 5H, H-Ar), 8.47 (s, 1H, yCH), 9.97 (s, 1H, NH). 13C NMR (Bruker AC200) (50.32 MHz, DMSO-d6), d : 14.3 (CH3), 43.5 (CH2N), 60.1 (CH2CH3), 67.8 (OCH2CH), 79.6 (CH), 84.6

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205 Table 2 Atomic coordinates ( × 10 4) and equivalent isotropic displacement ˚ 2 × 10 3) for B23. U(eq) is defined as one third of the parameters (A trace of the orthogonalized Uij tensor x C(1) C(2) C(3) C(4) C(5) C(6) O(7) C(8) C(9) O(10) C(11) N(12) C(13) N(14) C(15) C(16) C(17) C(18) N(19) O(20)

y

2386(1) 2340(1) 1923(1) 1554(1) 1604(1) 2020(1) 2782(1) 3183(1) 3563(1) 3697(1) 4150(1) 4355(1) 4023(1) 4351(1) 4813(1) 5054(1) 4824(1) 5538(1) 5923(1) 4992(1)

z 639(5) 1908(5) 1906(6) 671(6) 2 596(5) 2 625(5) 516(3) 1711(5) 1231(5) 2 858(3) 2 960(5) 835(4) 2400(5) 2 2663(4) 2 2489(5) 2 751(5) 1109(5) 2 665(5) 2 559(5) 2765(4)

3735(2) 2902(3) 1997(3) 1919(3) 2756(3) 3667(3) 4681(2) 4786(3) 5852(3) 5837(2) 5978(2) 6126(2) 6096(3) 5960(2) 6097(2) 6220(2) 6220(2) 6326(2) 6391(2) 6282(2)

U(eq) 39(1) 49(1) 59(1) 58(1) 53(1) 46(1) 49(1) 45(1) 45(1) 49(1) 40(1) 36(1) 50(1) 48(1) 45(1) 36(1) 38(1) 42(1) 61(1) 51(1)

(Cy),116.6 (CxN), 114.6, 121.3, 129.6, 158.0 (C-Ar), 163.9 (yCH), 164.7, 164.8 (CyN, CyO). 6-cyano-2,3-dihydro-2-phenoxymethyl-5H-oxazolo [3,2-a]pyrimidin-5-one (B23): m.p. ˆ 1878C, Rf ˆ 0.73 (eluent CHCl3/MeOH 90/10 v/v). UV (MeOH) 291 (e ˆ 5194), 2187 (e ˆ 7231). IR (Bruker IFS-25) (KBr) n (cm 21): 2224 (CxN), 1704 (CyO). 1H NMR (Bruker AC 200) (200.13 MHz, DMSO-d6), d : 4.10 (dd, 1H, CH2aN, 2J ˆ 11.5 Hz, 3J ˆ 6.8 Hz), 4.38– 4.27 (m, 2H, OCH2CH), 4.40 (dd, 1H, CH2bN, 2J ˆ 11.5 Hz, 3J ˆ 2.8 Hz), 5.47–5.36 (m, 1H, CHCH2), Table 3 ˚ ) for B23 Bond lengths (A C(1)–C(2) C(1)–O(7) C(1)–C(6) C(2)–C(3) C(3)–C(4) C(4)–C(5) C(5)–C(6) O(7)–C(8) C(8)–C(9) C(9)–O(10) C(9)–C(13)

1.374(4) 1.377(3) 1.380(4) 1.379(5) 1.372(5) 1.376(5) 1.381(4) 1.424(3) 1.489(4) 1.472(4) 1.532(4)

O(10)–C(11) C(11)–N(14) C(11)–N(12) N(12)–C(17) N(12)–C(13) N(14)–C(15) C(15)–C(16) C(16)–C(18) C(16)–C(17) C(17)–O(20) C(18)–N(19)

1.320(3) 1.309(4) 1.344(4) 1.396(4) 1.454(4) 1.354(4) 1.361(4) 1.427(4) 1.440(4) 1.220(4) 1.147(4)

195

Table 4 Bond angles (8) for B23 C(2)–C(1)–O(7) C(2)–C(1)–C(6) O(7)–C(1)–C(6) C(1)–C(2)–C(3) C(4)–C(3)–C(2) C(3)–C(4)–C(5) C(4)–C(5)–C(6) C(1)–C(6)–C(5) C(1)–O(7)–C(8) O(7)–C(8)–C(9) O(10)–C(9)–C(8) O(10)–C(9)–C(13) C(8)–C(9)–C(13) C(11)–O(10)–C(9) N(14)–C(11)–O(10)

124.5(3) 120.5(3) 115.0(3) 119.1(3) 121.1(3) 119.3(3) 120.5(3) 119.5(3) 118.1(2) 106.9(2) 108.2(3) 105.1(2) 113.7(3) 109.2(2) 120.9(3)

N(14)–C(11)–N(12) O(10)–C(11)–N(12) C(11)–N(12)–C(17) C(11)–N(12)–C(13) C(17)–N(12)–C(13) N(12)–C(13)–C(9) C(11)–N(14)–C(15) N(14)–C(15)–C(16) C(15)–C(16)–C(18) C(15)–C(16)–C(17) C(18)–C(16)–C(17) O(20)–C(17)–N(12) O(20)–C(17)–C(16) N(12)–C(17)–C(16) N(19)–C(18)–C(16)

127.0(3) 112.1(3) 122.4(3) 111.8(2) 125.7(3) 101.6(2) 113.0(3) 125.2(3) 122.4(3) 120.8(3) 116.7(3) 121.1(3) 127.4(3) 111.5(3) 178.2(4)

6.86–7.33 (m, 5H, H-Ar), 8.53 (s, 1H, yCH). 13C NMR (Bruker AC200) (50.32 MHz, DMSO-d6), d : 44.4 (CH2N), 67.6 (OCH2CH), 79.1 (CH), 94.5 (Cy), 114.9 (CxN), 157.7 (CyO), 114.6, 121.4, 129.6, 157.8 (C-Ar), 162.4 (CyN), 164.4 (yCH).

2.2. X-ray analysis A white crystal of B23 (dimensions 0.2 × 0.05 × 0.01 mm) was mounted on an Enraf–Nonius CAD-4 diffractometer using graphite-monochromated CuKa radiation. The crystal data are listed in Table 1. Lattice parameters were determined by least-squares refinement of 25 reflections with 25 , u , 358. Intensities were collected with v 2 2u scan mode, up to u ˆ 59.98. The intensities of two standard reflections, measured every 90 min, showed no significant deviation. The data were corrected for Lorentz and polarization effects and for empirical absorption correction. A total of 1882 reflections were measured, of which 1202 with I $ 2s (I) were considered as observed. The structure was solved by direct methods (Shelx 86 [9]) and refined using Shelx 93 [10] suite of programs. In the final least-squares cycles, all atoms were allowed to vibrate anisotropically. Final residuals were R ˆ 0.0428 (Rw2 ˆ 0.1040). Final fractional coordinates for B23 and equivalent displacement parameters are listed in Table 2. Bond lengths and angles are given in Tables 3 and 4. Selected torsion angles are listed in Table 5.

196

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

Table 5 Selected torsion angles (8) for B23 C(6)–C(1)–O(7)–C(8) C(1)–O(7)–C(8)–C(9) O(7)–C(8)–C(9)–O(10) O(7)–C(8)–C(9)–C(13)

177.1 (3) 2177.7 (3) 63.6 (3) 180.0 (2)

Scheme 2. Summary of the theoretical reaction paths.

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

197

Fig. 1. Singlet reaction paths calculated at the MNDO level connecting the reagents (imino or amino form and EMCA) to the different product channels. The enthalpies DH at 298 K are in kcal mol 21.

2.3. Reaction paths analysis To investigate the possible products of a reaction, the reaction paths connecting the reagents to the different products can be determined theoretically. This theoretical section deals mainly with a determination of the topology of the singlet potential energy surface (PES), i.e. the search for minima and saddle points, using the semi-empirical MNDO method of Dewar and Thiel [11]. If it is well known that semiempirical approaches cannot give reliable quantitative values for energies it is also clear that the topological features of PES are correctly reproduced by the MNDO approach. Moreover, this method converges

rapidly towards the low energy geometries. One more reason to choose a semi-empirical approach is that the AMPAC 6.0 package [12] that was used, contains many convenient tools, e.g. powerful SCF convergers, efficient optimizers, saddle point and reaction path algorithms [13]. The search for stationary points on a PES has been limited to minima and saddle points, respectively characterized by zero and one negative eigenvalue of the Hessian matrix. Several techniques have been considered, e.g. the BFGS method [14–18], the eigenvector following (EF) algorithm [19–21] and the ‘‘Chain method’’ [22] to systematically explore the PES. The first two methods allow to reach all

198

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

Fig. 1. (continued)

stationary points (i.e. minima or saddle points) whilst the third method permits only the determination of saddle points. Once the saddle points are found, the reaction paths connecting each saddle point to their two related minima were determined by the exponential predictor corrector (EPC) method [13], based on the intrinsic reaction coordinates (IRC) approach of Fukui et al. [23]. The theoretical study concerns the reaction between EMCA and the non-substituted 2-amino-2-oxazoline. We took into account (1) the amino–imino tautomer equilibrium 1 (2) the 1,4-addition reaction type (attack 1 In the following paper, the 2-amino-2-oxazoline and the 2-iminooxazolidine are respectively called amino and imino forms.

on the carbon atom of the –C–OEt group of EMCA) or the 1,2-addition reaction type (attack on the carbon atom of the –COOEt group of EMCA). As A2 and B23 have a free nitrile function, the eventuality of an attack on the carbon atom of the nitrile function was discarded. Under these conditions, one could expect the formation of six products, four non-cyclized compounds A1, A2, A3, and A4 and two cyclized compounds B23 and B14 (Scheme 2). The molecular geometries (bond lengths, bond angles and torsion angles) of the structures associated with 15 minima (including the possible reactants) and 14 saddle points found on the singlet PES were deposited as supplementary material. Fig. 1(a)–(g) display the qualitative reaction paths

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

Fig. 1. (continued)

199

200

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

Fig. 1. (continued)

connecting the reagents (the amino or the imino form, plus the EMCA molecule), to the possible products. These figures show that rather high barriers exist along all the reaction paths. However, it is well known that the values of these barriers will drastically decrease at the ab initio level. As the probability to form the products depends on the complexity (number of intermediates) of the reaction path, the study focuses on the number of chemical steps which are necessary to reach these products.

3. Results and discussion At room temperature, 5-phenoxymethyl-2-amino-

2-oxazoline reacts with the b-dielectrophile EMCA in ethanol to give two products with similar yields. The first product is a non-cyclized compound corresponding to an 1,4-adduct and characterized as 2-ethyl(methylenecyanoacetate)-5-phenoxymethyl-2iminooxazolidine A2. The second product is the bicyclic compound 6-cyano-2,3-dihydro-2-phenoxymethyl-5H-oxazolo[3,2-a]pyrimidin-5-one B23. 3.1. Structure assignment The structures of the synthesized compounds were assigned either by spectroscopy or by diffraction methods. The IR spectrum of A2 shows the absorption of the CyO group of the ester moiety at 1706 cm 21

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

201

Fig. 1. (continued)

and the absorption of the nitrile group at 2224 cm 21. No sharp NH absorption band in the 3300 cm 21 region, corresponding to the isomeric 3-substituted2-iminooxazolidine structure, is observed [24]. In the 1H NMR spectrum, the protons CH2N and CHO form an ABX system as do the protons PhOCH2 and CHO. The D2O exchangeable signal at 9.97 ppm is assigned as the NH proton. Our research group already reported that, in 3-phenylcarbamoyl-2iminooxazolidines, the NH proton forms a singlet at , 6 ppm [24] whereas it appeared at , 10 ppm in 2phenylcarbamoyl-2-iminooxazolidines [25]. In the 13 C NMR spectrum the CH2N is shielded compared to the corresponding carbon atom in 2-amino-2oxazolines. This effect, due to the delocalization of the CyN exocyclic double bond [25], is confirmed

by the CyN IR absorption band located at 1656 cm 21. The UV spectrum of A2 presents an absorption at 296 nm, similar to the p -electrons conjugation in B23. The IR spectrum of B23 shows strong CxN and CyO absorptions at 2224 and 1704 cm 21, respectively. In the 1H NMR spectrum, the protons CH2N and CHO also formed an ABX system as they do in A2. Moreover, the ethylenic proton appeared as a singlet at 8.53 ppm, as in A2, indicating the same magnetic environment. The overall structure was established by X-ray diffraction on a single crystal. An ORTEP view of the molecule showing the atomic numbering is depicted in Fig. 2. As expected the fused oxazoline and pyrimidine rings are almost coplanar (dihedral angle 2.6 (1)8). The phenoxymethyl moiety

202

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

Fig. 1. (continued)

is trans-extended (C(6)–C(1)–O(7)–C(8) ˆ 177.1(3)8, C(1)–O(7)–C(8)–C(9) ˆ 2 177.7(3)8). Its orientation towards the heterocyclic system is defined by the torsion angle O(7)–C(8)–C(9)– O(10) ˆ 63.6(3)8 (Table 5). The two planar systems form an angle of 63.9(1)8.

3.2. Theoretical study of the reaction A 2-amino-2-oxazoline can theoretically react under this form or under its 2-iminooxazolidine tautomeric form [25]. In the amino form, the endo nitrogen atom is more nucleophilic than the exo nitrogen atom, whereas in the imino form, the contrary occurs.

Consequently, two nucleophilic attacks can be expected. It was reported that EMCA reacted with amidines at the enol ether function and, non-selectively, at one of the two acyl groups [1,4]. The reaction proceeded through a conjugate addition followed by a cyclization on the cyano or on the alkoxycarbonyl group. This one-step cyclocondensation reaction was achieved at temperatures higher than 1008C or on melt [1,3,4]. 1,4-Adducts were isolated under mild conditions and were cyclized under the same conditions as the one-step cyclocondensations. In this study, as both isolated compounds presented a nitrile group, the possibility of an attack on the cyano group was discarded. Two electrophilic centres

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

203

Table 6 Summary of the different reaction types

1,4-addition 1,2-addition

Starting reactant: amino form

Starting reactant: imino form

A1 A3

A2 A4

were considered, the alkoxycarbonyl group and the enol ether group. As both nitrogen atoms in 2amino-2-oxazolines are potent nucleophilic centres, the question of the regioselectivity had to be evoked. Four adducts could be theoretically expected (Scheme 2). As already observed, compounds A1 and A2 may be obtained from the amino/imino forms through a classical 1,4-addition, respectively [1,24]. Conversely, compounds A3 and A4 would result from a 1,2-addition. A summary of the different reaction types is presented in Table 6. Moreover, the N/N 0 transposition reaction between a 3-substituted-2iminooxazolidine and a 2-substituted-2-iminooxazolidine evidenced in a previous study [24] was also considered. The cyclization of both adducts A2 and A3 could lead to the observed cyclocondensed product B23. The stability of A2was studied. Heated A2 for 1 h at 2008C yielded B23 (35%). But as A2 is stable under mild conditions, it could not be assumed that A2 is an intermediate in the formation of the cyclic product B23 at room temperature. Thus, in order to gain information about the mechanism of the reaction of EMCA on 5-phenoxymethyl-2-amino-2-oxazoline (Scheme 1), a theoretical approach was undertaken. Fig. 1(a) shows the passage from the amino form to the imino form which requires a H transfer from the N exocyclic atom (amino tautomer) to the N endocyclic atom (imino tautomer), i.e. the tautomeric equilibrium between the two forms. The formation of the imino form is possible through the saddle point labelled

Fig. 2. ORTEP diagram of compound B23 showing the atomic numbering.

TS10 2 in which the H atom is bridged over the N (endocyclic)–N (exocyclic) bond. Recently, semiempirical (MNDO, AM1 and PM3) and ab initio calculations at the HF/6-31G level showed that the most stable form was the amino form [26]. This tautomeric equilibrium was also investigated by estimating the total energy difference between the two forms (,2 kcal mol 21) and the tautomer equilibrium constant with different ab initio methods using a large number of basis sets [27]. Fig. 1(b) and (c) presents the reaction paths leading to the products obtained through an 1,4-addition. Fig. 1(b) deals with the reaction path which leads to the formation of A1 from the amino form and EMCA. The evolution from the reactants to A1 occurs via a saddle point TS9 characterized by elongated N–H and O–H bonds. Then, the leaving of an HOEt molecule and the formation of A1 are straightforward. However, no way was found to make the cyclic product B14 from A1. Fig. 1(c) deals with the reaction path leading to the formation of the B23 molecule from the imino form. In this reaction pathway, three intermediates are found: A0, A2 and A2B23. First, the reactants undergo a molecular rearrangement into the structure A0 via a saddle point labelled TS1 where the OEt group is bridged between the two reactants. Then, by a progressive elongation of the C–OEt bond ˚ in TS1 and 2.83 A ˚ in A0) the minimum (1.480 A A0 is reached and directly gives A2. The passage from A2 to the less stable A2B23 intermediate would occur via the transition state TS2, corresponding to a H-bridged structure over the N–O bond. The formation of the product from A2B23 would require the passage over a saddle point labelled TS3, characterized by a shortening of the C–N bond ˚ in A2B23, 2.23 A ˚ in TS3 and 1.44 A ˚ in B23). (2.77 A This reaction path to reach B23, which would involve a rather unstable structure (A2B23) and a large

2

TS stands for Transition State.

204

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

number of molecular rearrangements, is unlikely, at least at room temperature. Fig. 1(d) and (e) presents the reaction paths leading to the products obtained through a 1,2-addition. Fig. 1(d) describes a way to form the stable B23 structure from the amino form and EMCA. Two intermediates labelled A3 and A3B23 were identified before reaching the structure B23. Along this pathway, the reactants evolve towards the formation of A3 through a saddle point labelled TS5 by a progressive decrease ˚ in TS5 and 1.43 A ˚ in A3) of the C–N bond (2.22 A and by the C–OEt and N–H bonds breaking. The saddle point TS5 corresponds to a H-bridged structure over the N–O bond. The structure A3 evolves into the A3B23 minimum via the transition state TS7 by a ˚ in A3, 1.92 A ˚ shortening of the C–N bond (3.26 A ˚ in A3B23). The formation of in TS7 and 1.50 A B23 requires the passage over the saddle point TS8 which allows the leaving of a HOEt molecule and the decrease of the C–N bond to obtain the cyclic compound B23. This reaction path involves less molecular rearrangements than the previous one (Fig. 1(c)). This makes the formation of the stable structure B23 from A3 more likely than from A2. Fig. 1(e). shows the pathway leading to the formation of the structure A4 from the imino form. The reactants undergo a molecular rearrangement into the structure A01 via a saddle point labelled TS4 corresponding to a OEt-bridged structure over the C–C bond. The formation of A4 requires the passage over a barrier corresponding to the saddle point TS6 in which the H atom is bridged over the N–O bond. Hence, following the cleavage of the C–OEt and N–H bonds, TS6 evolves towards the intermediate A4. However, no way was found to make the cyclic product B14 from A4. Fig. 1(f) and (g) suggests mechanisms for the possible N/N 0 rearrangements. Fig. 1(f) describes the rearrangement between the intermediates A1 and A2. The formation of A2 from A1 occurs via an intermediary minimum labelled A6. The A1 molecule undergoes a transfer of the EMCA group from the N endocyclic atom to the N exocyclic atom through the saddle point TS11. Once the structure A6 is reached, the formation of A2 requires a H transfer from the N exocyclic atom to the N endocyclic atom which corresponds to the transition state labelled TS12. Then, an equilibrium can be considered between the two species A1 and A2, in favour of the formation of A2

(DE ˆ 25.2 kcal mol 21). Fig. 1(g) deals with the conversion of the A3 intermediate into the A4 structure. The chemical rearrangements along this reaction path are similar to those considered in the preceding equilibrium (Fig. 1(f)). The present equilibrium exists if a stable structure labelled A5 is considered along the reaction path. In fact, the A3 and A5 molecules are connected by the transition state TS13 in which the EMCA group is bridged over the N (endocyclic)–N (exocyclic) bond. Then, the passage over the saddle point TS14 allows to transfer the H atom in order to reach the A4 structure. If this transposition exists (A3 $ A4), it would be in favour of A4 (DE ˆ 22.4 kcal mol 21). A summary of these theoretical reaction paths is presented in Scheme 2. As compounds A2 and B23 were isolated experimentally, the discussion is focused on the possible mechanisms of their formation. If the reaction starts with the amino form, the molecule B23 can be reached from the intermediate A3 formed via a 1,2-addition (Fig. 1(d)). The amino form can also give the intermediate A1 via a 1,4 addition (Fig. 1(b)) and A1 can be possibly transformed into the stable A2 molecule (Fig. 1(f)). As a result of the unstable A2B23 intermediate (Fig. 1(c)), the cyclization of A2 into B23 is unlikely in mild conditions (at room temperature, no cyclization of the monosubstituted compound A2 was observed; however, it was observed that A2 under melt at 2008C gives B23). Then, the stable A2 molecule can be considered as one of the possible products of the reaction. This A2 molecule can also be obtained from the imino form by a 1,4-addition via the intermediate A0 (Fig. 1(c)). Further, if the imino form is the reacting molecule, through a 1,2-addition the A4 species can be reached via the A01 intermediate, which could evolve towards A3 (Fig. 1(g)) and B23. This event is unlikely, because (1) the most direct pathway to form A3 is from the amino form, (2) the equilibrium A4 $ A3 is in favour of A4 as already observed in the course of substitution reactions of 2-amino-2-oxazolines with phenylisocyanate [24]. From this theoretical study it seems that the formation of B23 is much easier if the starting reactant is the amino form (via a 1,2-addition) than if the starting reactant is the imino form (via a 1,4-addition). According to the literature this result was unexpected. The reaction pathways leading to B23 and involving

C. Chaimbault et al. / Journal of Molecular Structure 508 (1999) 193–205

A1 (from the amino form) or A4 (from the imino form) are somewhat complicated. Moreover the second one is energetically unfavoured. On the contrary, the formation of the stable structure A2 is more direct if the starting reactant is the imino form than if it is the amino form. One can notice that A1 and A3 are easily accessible from the amino form whereas A2 and A4 are easily accessible from the imino form. This is in accordance with previous findings stating that, in the amino form, the most reactive nucleophilic centre is the endocyclic N atom, whereas in the imino form, the most reactive nucleophilic centre is the exocyclic N atom [25–27]. The impossibility to cyclize the intermediates A1 and A4 suggests that the product B14 is unlikely in this reaction according to what was observed experimentally.

4. Conclusions At room temperature, the reaction between 5-phenoxymethyl-2-amino-2-oxazoline and the b-dielectrophile EMCA, in ethanol, leads to a 1,4adduct, i.e. the 2-ethyl(methylenecyanoacetate)-5phenoxymethyl-2-iminooxazolidine A2 and to a cyclocondensed product, i.e. 6-cyano-2,3-dihydro2-phenoxymethyl-5H-oxazolo[3,2-a]pyrimidin-5one B23. Their structures were assigned either by spectroscopy or by diffraction methods. A computational study of the theoretical reaction paths reveals that the 1,4-adduct A2 can be obtained (1) from the imino form, or (2) from the amino form via a rearrangement of A1. As A2 is stable under mild conditions, A2 cannot be considered as an intermediate in the formation of B23 at room temperature. Nevertheless, B23 can be obtained from A2 under drastic conditions. Another mechanistic scheme suggests that B23 is preferably obtained from the amino form and EMCA (via the A3 structure) through a 1,2-addition reaction. This statement, which was unexpected referring to the literature, would explain the experimental findings, at least at room temperature. However, as we already stated in this article, one must keep in mind that semi-empirical methods cannot give reliable quantitative values for energies but that topological features of the PES, e.g. minima and saddle points would be reproduced by ab inition methods [28]. As

205

the height of the energy barriers could be modified using ab initio methods, the new mechanistic scheme that we proposed could be an artefact of the MNDO method and other mechanistic schemes cannot be ruled out.

References [1] A. Lorente, L. Vaquerizo, A. Martin, P. Go´mez-Sal, Heterocycles 41 (1995) 71. [2] C. Romano, E. Cuesta, C. Avendan˜o, Heterocycles 31 (1990) 267. [3] K. Nagahara, H. Kawano, S. Sasaoka, C. Ukawa, T. Hirama, A. Tadaka, H.B. Cottam, R.K. Robins, J. Heterocyclic Chem. 31 (1994) 239. [4] D. Ilavsky, J. Krechl, P. Trsˇka, J. Kuthan, Collect. Czechoslov. Chem. Comm. 44 (1979) 1423. [5] O. Adetchessi, D. Desor, I. Forfar, C. Jarry, J. Heterocyclic Chem. 34 (1997) 429. [6] I. Forfar, J.J. Bosc, J.M. Leger, C. Jarry, Pharm. Pharmacol. Commun. 4 (1998) 9. [7] K.D. Kampe, Liebigs Ann. Chem. (1974) 593. [8] I. Forfar, C. Jarry, J.M. Leger, A. Carpy, Arch. Pharm. Weinheim 323 (1990) 905. [9] G.M. Sheldrick, C. Kru¨ger, R. Goddard, SHELX 86 in Crystallographic Computing 3, Oxford University Press, New York, 1985 pp. 175–189. [10] G.M. Sheldrick, SHELX 93, Program for the Refinement of the Crystal Structures, University of Go¨ttingen, Germany, 1993. [11] M.J.S. Dewar, W.J. Thiel, J. Am. Chem. Soc. 99 (1977) 4899. [12] AMPAC 6.0, Semichem, 7128 Summit, Shawnee, KS 66216. [13] D.A. Liotard, Int. J. Quant. Chem. 44 (1992) 723. [14] C.G. Broyden, J. Inst. Math. Applic. 6 (1970) 222. [15] D.F. Shanno, J. Opt. Theory Applic. 46 (1985) 87. [16] D.F. Shanno, Math. Comp. 24 (1970) 647. [17] R. Fletcher, Comput. J. 13 (1970) 317. [18] D. Goldfarb, Math. Comp. 24 (1970) 23. [19] J. Simmons, A. Banerjee, N. Adams, R. Shepard, J. Phys. Chem. 89 (1985) 52. [20] J. Baker, J. Comp. Chem. 7 (1986) 385. [21] P. Culot, G. Dive, V.H. Nguyen, Theoret. Chim. Acta 82 (1992) 189. [22] D.A. Liotard, J.P. Perrot, Numerical Methods in the Study of Critical Phenomena, Springer, Berlin, 1981 p. 213. [23] K. Fukui, J. Phys. Chem. 74 (1970) 4161. [24] J. Bosc, C. Jarry, J. Ouhabi, M. Laguerre, A. Carpy, Can. J. Chem. 74 (1996) 1341. [25] J.J. Bosc, I. Forfar, C. Jarry, J. Ouhabi, J.M. Leger, A. Carpy, Arch. Pharm. Weinheim 323 (1990) 561. [26] J. Ouhabi, C. Jarry, A. Zouanate, A. Carpy, Arch. Pharm. Pharm. Med. Chem. 330 (1997) 367. [27] N. Marchand-Geneste, A. Carpy, J. Mol. Struct. (Theochem) 465 (1999) 209. [28] N. Marchand, P. Jimeno, J.C. Rayez, D. Liotard, J. Phys. Chem. 101 (1997) 6077.