Substituted 2-Methylene-1,3-oxazolidines, -1,3-thiazolidines, -1,3-benzothiazines, -1,3-oxazines, and Substituted Imidazopyrimidinediones from Cl(CH2)nNCO and Cl(CH2)nNCS and Active Methylene Compounds Ahmad Basheer and Zvi Rappoport* Department of Organic Chemistry, The Hebrew UniVersity, Jerusalem 91904, Israel
[email protected] ReceiVed September 6, 2006
The reaction of ω-chloroalkyl isocyanates Cl(CH2)nNCO (n ) 2 (2), 3 (4)) and isothiocyanate Cl(CH2)2NCS (3) with active methylene compounds CH2YY′ 1 in the presence of Et3N or Na give 2-YY′-methylene1,3-oxazolidines, (E,Z)-1,3-thiazolidines, and 1,3-oxazines from 2, 3, and 4, respectively. 2-(Chloromethyl)phenyl isocyanate 8 gives with 1 the corresponding benzo-oxazines. Ethyl 2-isothiocyanatobenzoate 10 gives the corresponding benzothiazolinone, whereas the analogous isocyanate 12 gives noncyclic enols. Ethoxycarbonyl isothiocyanate 14 gives an open-chain thioenol or an enol-thioamide. The cyanoamides CH2(CN)CONHR, R ) H, Me, CHPh2, give with Et3N and 2 the bicyclic imidazopyrimidinediones 16, derived from two molecules of 2, but with their preformed Na salt they give the 1,3-oxazolidines. Reaction of cyanoacetamide with 3 in the presence of Na gave a tricyclic triaza(thia)indacene, derived from two molecules of 3. A reaction mechanism involving an initial attack of the anion 1- on the NdCdX (X ) O, S) moiety gives an anion 18, which cyclizes intramolecularly and after tautomerization gives the mono-ring heterocycle. With the cyanoamides, the N- site of the ambident ion 18 attacks another molecule of 2 giving the anion 20, which by intramolecular attack on the CN, followed by expulsion of the Clgives the bicyclic 16 after tautomerization.
Introduction Reaction of active methylene compounds carrying two strongly electron-withdrawing groups Y, Y′ with organic isocyanates1 and isothiocyanates2 under basic conditions frequently form the corresponding amides (thioamides) or their enols (thioenols) either as mixtures or as one of the pure species, (1) Mukhopadhyaya, J. K.; Sklenak, S.; Rappoport, Z. J. Am. Chem. Soc. 2000, 122, 1325. (2) Basheer, A.; Rappoport, Z. Kyushu International Conference on Physical Organic Chemistry (KISPOC 11), Sep 12-15, 2005, Abstract book, pp 1-2.
depending on Y and Y′. The reaction (eq 1) was extensively investigated by us.3 The enols or thioenols are polyfunctional dipolar species with vicinal NHR and OH or SH groups on an electrophilic vinylic carbon. We reasoned that if the alkyl group R of the RNCO or RNCS will carry a terminal leaving group (3) (a) Mukhopadhyaya, J. K.; Sklenak, S.; Rappoport, Z. J. Org. Chem. 2000, 65, 6856. (b) Lei, Y. X.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2001, 66, 8379. (c) Lei, Y. X.; Casarini, D.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2003, 68, 947. (d) Lei, Y. X.; Casarini, D.; Cerioni, G.; Rappoport, Z. J. Phys. Org. Chem. 2003, 16, 525. (e) Basheer, A.; Rappoport, Z. J. Org. Chem. 2004, 69, 1151.
10.1021/jo061835g CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/16/2006
J. Org. Chem. 2006, 71, 9743-9750
9743
Basheer and Rappoport TABLE 1. E/Z Ratio and δ(NH) Values (ppm) for Compounds 5 and 6 at Several Temperatures Y
such as chlorine, reaction of the CH2YY′ with the isocyanate or isothiocyanate, e.g., Cl(CH2)nNCX, n ) 2, 3, X ) O, S, will be followed or be coupled with Cl- expulsion by the X (or XH) functionality to give heterocyclic systems. We therefore reacted several active methylene compounds (1) with β-chloroethyl isocyanate (2), with β-chloroethyl isothiocyanate (3), and with γ-chloropropyl isocyanate (4) and related derivatives and obtained the corresponding 2-YY′-substituted methylene 1,3-N,O- and N,S-heterocyclic systems. Some other products were also formed.
COMe
Results
CO2Me
Reaction and Structure Assignment of the Monocyclic Hetereocycles. Reaction of 15 active methylene compounds 1a-o, where Y,Y′ are various combinations of ester, cyano, carbonyl, amido, and sulfonyl groups with 2 in the presence of Et3N or sometimes with a Na metal, resulted in a rapid formation of Et3NHCl or NaCl with the more acidic 1 and a slower formation with the less acidic 1. On addition of water the corresponding 2-substituted methylene-1,3-oxazolidines (5ao) precipitated in high yields (eq 2). When Y and/or Y′ are
potential enolization sites, such as COMe or a barbituric acid residue (i.e., 1c,f-j), the cyclization via reaction of the Y or Y′ could give an alternative 1,4-O,N-heterocyclic 7-membered ring, but this was not found. Table S1 (Supporting Information) indicates that apparently only one isomer, judged by the observed single NH ring signal, is formed. This can be due either to formation of only the most stable isomer or to a rapid interconversion of E and Z isomers, as found for highly dipolar push-pull systems resembling our compounds.4 Since E and Z isomers of enols formed according to eq 1, which are structurally related to compounds 5, are frequently observed, solutions of several compounds 5 where Y * Y′ were cooled. When a solution of 5f in CDCl3 which shows at rt one signal at δ 11.14 ppm was cooled to 220 Κ, the 1H NMR spectrum displayed two isomers (δ (NH) signals at 9.56 ppm for the E isomer and (4) (a) Oki, M. Applications of Dynamic NMR Spectroscopy to Organic Chemistry; VCH: Weinheim, 1985. (b) Sandstro¨m, J. In The Chemistry of Enamines; Rappoport, Z., Ed.; Wiley: Chichester, 1994; Chapter 6, p 405.
9744 J. Org. Chem., Vol. 71, No. 26, 2006
Y′ CO2Et
solvent CDCl3
X
T (K)
E or Z
% yield
δ(NH)
O
298 220
S
298
a Z E Z E a E Z a Z E a Z E a Z E
100 98 2 70 30 100 94 6 100 99 1 100 79 21 100 73 27
11.14 11.15 9.56 12.06 10.14 8.56 9.15 6.37 11.28 11.23 9.63 10.25b 11.17 10.31 9.24b 9.53 9.11
CN
CO2Me
O S
298 298
COMe
CONHPh
O
298 240
DMSO-d6 DMF-d7
S
298 220
CDCl3
O
298 240
a
CO2CH2CF3
Rapid E/Z interconversion takes place. b Broad signal.
11.15 for the Z isomer) in a Z/E ratio of 98:2. The assignment is based on the expected stronger H-bond for the Z isomer. Likewise, the two rt 1H NMR δ(NH) signals at 11.28 and 12.46 ppm of 5g appear at 240 K at 11.23 and 12.60 ppm with 99% intensity together with 1% of two new signals at 9.63 and 10.68 ppm. The major isomer was assigned as Z on the basis of its favorable NH‚‚‚OdCCH3 hydrogen bond. Cooling of 5n, which shows at rt only one broad δ(NH) signal at 9.25 ppm, to 240 K gave a 73:27 Z/E isomer ratio, with δ(NH) at 9.11 (E) and 9.53 (Z) ppm. The data are summarized in Table 1. The structures were consistent with the elemental analysis (Table S8, Supporting Information), with the 1H , 13C NMR and 2D NMR spectra, and with the known structures of compounds 5a,5 5d,6-8a 5e,7,8c and 5i.5 X-ray diffraction of compounds 5f and 5h corroborated the structures and the configuration assignments. In both cases, the NH is cis and hydrogen bonded (cf. the N‚‚‚O nonbonded distances in Table 2) to the CdO of the acetyl group, which is the stronger hydrogen bond acceptor among the pairs of Y and Y′ groups.9 The main bond lengths and angles are given in Table 2, and the full crystallographic data are given in the Supporting Information. The 1H NMR δ(NH) (Table S1, Supporting Information) indicates the importance of intramolecular hydrogen bonding in compounds 5. In CDCl3, it appears at 7.75-11.29 ppm with the lowest value of 7.75 ppm for 5e having two CN groups that are incapable of forming an intramolecular hydrogen bond. The next low value is 8.56 ppm for 5a, with one cyano and one ester group. The three higher values at 11.14-11.29 ppm are for 5f-i, where Y′ ) COMe, the strongest hydrogen bond acceptor among our Y and Y′.9 The δ(NH) of 5e in DMSO-d6 is at 2.38 ppm lower field than in CDCl3, presumably indicating a stronger intermolecular hydrogen bonding with the DMSOd 6. (5) Huang, Z-T.; Zhang, P.-C. Chem. Ber. 1989, 122, 2011. (6) Jeon, M. K.; Kim, K. J. Chem. Soc., Perkin Trans. 1 2000, 3107. (7) Huche´, M.; Lhommet, G. J. Heterocycl. Chem. 1986, 23, 701. (8) (a) Huang, Z-T.; Shi, X. Synth. Commun. 1990, 20, 1321. (b) Huang, Z.-T.; Shi, X. Synthesis 1990, 162. (c) Ishida, T.; Osaka, H.; Nogami, T.; Yamazaki, R.; Yasui, M.; Iwasaki, F.; Mizoguchi, A.; Kuhata, M.; Uemiya, T.; Nishimura, A. Synth. Met. 1993, 2013. (d) Gompper, R.; To¨pfl, W. Chem. Ber. 1962, 95, 182. (9) Laurent, C.; Berthelot, M.; Graton, J. In The Chemistry of Phenols; Rapoport, Z., Ed.; Wiley: Chichester, 2003; Chapter 8, p 529.
Reactions with ActiVe Methylene Compounds TABLE 2. Selected Crystallographic Data for 5f and 5h
methylene-1,3-thiazolidines (6a-g) (eq 3). For the three unsymmetrical products when Y * Y′, the 1H NMR spectra showed that 6a and 6f are formed as a mixture of E and Z isomers, whereas 6g apparently appeared only as a single isomer at rt (see below).
bond length (Å) 5f (R ) C7O2Et) C(1)-C(2) C(2)-C(3) C(2)-C(7) C(2)-S(1) C(1)-N (1) C(1)-O(1) C(3)-O(2) N(1)-H O(2)‚‚‚H N(1)‚‚‚O(2)
5h (R ) SO2C4F9)
1.393(9) 1.429(10) 1.481(9)
1.423(5) 1.467(5) 1.708(4) 1.294(5) 1.330(4) 1.229(6) 0.81(4), 0.81(4)a 2.03(4), 2.30(4)a 2.584(4), 2.909(5)a
1.326(8) 1.323(8) 1.236(8) 0.96(7), 0.96(7) 1.99(6), 2.11(7)a 2.560(8), 2.889(8)a
angle (deg) O(1)-C(1)-N(1) C(3)-C(2)-C(7) C(3)-C(2)-S(1)
5f (R ) C7O2Et)
5h (R ) SO2C4F9)
110.4(6) 119.9(6)
111.5(3) 122.9(3)
Symmetry transformations used to generate equivalents atom: -x + 1, -y + 1, -z + 1. a
FIGURE 1. Dipolar contribution to the hybrid 5 or 6.
The 13C NMR spectra (Table S2, Supporting Information) of compounds 5 (and of 6, 7, 9, 11, 13, and 15) indicate their high dipolar structures. As shown in Figure 1, CR (carrying X ) O, S and N) is highly positive while Cβ (carrying YY′) is highly negative. For compounds 5, CR appears at 170.11-173.96 ppm, an extremely low field for a vinylic carbon, with low structure sensitivity. Cβ appears at 34.79-99.46 ppm, a high field for a vinylic carbon, with higher sensitivity to the nature of Y and Y′. The higher field is for Y′Y ) (CN)2, at 34.79 ppm for 5e, followed by ca. 56 ppm for the cyano ester and cyano amide derivatives. Higher values at ca. 89-90 ppm are for 5f-h, where Y′ ) COMe. For 5i and 5j, the values are 99.46 (103.4)5 and 96.45 ppm, respectively. Consequently, the difference in ∆CRβ is mainly due to differences in δCβ. The extremes in ∆CRβ of ca. 139 ppm for 5e, and 81.3 for 5h, reflect contributions from both the dipolar structure and the hydrogen bonding.10 Large differences were observed earlier for enols.1-3 The partial single bond character of the formal C1-C2 double bond is shown by the bond lengths of 1.393 and 1.423 Å (Table 2) which are longer than a normal CdC bond. Compounds 5k-m were prepared from the sodium salt of 1k-m in THF. The reaction with Et3N gave different products (for details see below). Reaction of seven compounds 1 with the isothiocyanate 3 under similar conditions gave the corresponding 2-substituted (10) (a) Fischer, G.; Rudorf, W.-D.; Kleinpeter, E. Magn. Reson. Chem. 1991, 29, 212. Fischer, G.; Kleinpeter E. Magn. Reson. Chem. 1991, 29, 204. Klinepeter, E.; Schulenberg, A. Tetrahedron. Lett. 2005, 46, 5997. (b) Kleinpeter, E.; Klod, S.; Rudorf, W.-D. J. Org. Chem. 2004, 69, 4317.
The Y and Y′ signals in the two isomers differed by
