Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group

Design, Synthesis, and Biological Evaluation of New Diaminoquinazolines as β-Catenin/Tcf4 Pathway Inhibitors. Yongjun Mao , Nan Lin , Wang Tian , Xia...
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Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group Ahmad Basheer and Zvi Rappoport* Department of Organic Chemistry, The Hebrew University, Jerusalem 91904, Israel [email protected] Received August 18, 2003

Reaction of isocyanates XNCO (X ) Ar, i-Pr, t-Bu) with CH2(Y)CO2CH2CCl3 (Y ) CO2Me, CO2CH2CCl3, CN) gave 15 amides XNHCOCH(Y)CO2CH2CCl3 (6) or enols of amides XNHC(OH)dC(Y)CO2CH2CCl3 (5) systems. The amide/enol ratios in solution depend strongly on the substituent Y and the solvent and mildly on the substituent X. The percentage of enol for group Y increases according to Y ) CN > CO2CH2CCl3 > CO2Me and decreases with the solvent according to CCl4 > C6D6 > CDCl3 > THF-d8 > CD3CN > DMSO-d6. With the most acidic systems (Y ) CN) amide/enol exchange is observed in moderately polar solvents and ionization to the conjugate base is observed in DMSO-d6. The solid-state structure of the compound with Y ) CN, X ) i-Pr was found to be that of the enol. The reasons for the stability of the enols were discussed in terms of polar and resonance effects. Intramolecular hydrogen bonds result in a very low δ(OH) and contribute to the stability of the enols and are responsible for the higher percentage of the E-isomers when Y ) CO2Me and the Z-isomers when Y ) CN. The differences in δ(OH), δ(NH), Kenol, and E/Z enol ratios from the analogues with CF3 instead of CCl3 are discussed. In recent years, we have studied the preparation and properties, especially the enol/amide equilibria, of enols of carboxamides activated by electron-withdrawing groups (EWGs)Y,Y′ 1.1-5 Many of these enols become as stable as and even more stable than their tautomeric amides 2, due to the important contribution of the dipolar structure 1a to the structure of 1, resulting from the resonative negative charge delocalization by Y and Y′. One goal of our study is to arrange the groups Y and Y′ in their order of enol stabilizing ability, measured formally by Kenol. Whereas parameters measuring the negative charge resonative delocalizing ability such as σR- or pKa(CH2YY′) are qualitatively and sometimes quantitatively correlated with the pKenol value within small groups of related compounds, such correlations do not cover systems with Y,Y′ groups belonging to different families. Two reasons exist for this: (i) The pKa(CH2YY′) are not linearly correlated with the gas-phase acidities of XNHC(OH)dCYY′ for all Y,Y′ but only for closely related families.6 (ii) In the comparison of 1 and 2, the Y,Y′ groups have a significant effect also on the amide form, e.g., by a dipole/dipole interaction between Y and/ * Corresponding author. (1) Mukhopadhyaya, J. K.; Sklenak, S.; Rappoport, Z. J. Am. Chem. Soc. 2000, 122, 1325. (2) Mukhopadhyaya, J. K.; Sklenak, S.; Rappoport, Z. J. Org. Chem. 2000, 65, 6856. (3) Lei, Y. X.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2001, 66, 8379. (4) Lei, Y. X.; Casarini, D.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2003, 68, 947. (5) Lei, Y. X.; Casarini, D.; Cerioni, G.; Rappoport, Z. J. Phys. Org. Chem. 2003, 16, 525. (6) Mishima, M.; Matsuoka, M.; Lei, Y. X.; Rappoport, Z. Manuscript submitted.

or Y′ and the carbonyl (or the C-O-) group in hybrids 2 and 2a (eq 1). Moreover, with certain Y,Y′ (e.g., keto groups) the enolization sites are the groups Y and/or Y′ themselves rather than the amido CdO group.2,7 Whereas we approach the question of the effect of Y,Y′ on Kenol by calculations, which also enable to dissect the effect of Y,Y′ on the amide and the enol forms,2,8,9 an experimental ordering or confirmation of the calculated order are of importance. In addition, a long-range goal is to functionalize the enols in solution, and for this the order of Kenol values as a function of Y and Y′ is important.

We have recently shown that when Y,Y′ are two ester groups COOR and COOR′, R, R′ ) CH3, CH2CF3, (7) Toullec, J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley Interscience: New York, 1990; Chapter 6, pp 357 and 359. (8) For calculations on the acids/enols of acid systems and dissection of the effect on Kenol to the effects on the two species, see: Yamataka, H.; Rappoport, Z. J. Am. Chem. Soc. 2000, 122, 9818. (9) (a) Rappoport, Z.; Yamataka, H. ESOR 9 Conference, Oslo, Norway, July 12-17, 2003. Abstract book, OR 59, p 128. (b) Yamataka, H.; Rappoport, Z. Unpublished results.

10.1021/jo030266z CCC: $27.50 © 2004 American Chemical Society

Published on Web 01/15/2004

J. Org. Chem. 2004, 69, 1151-1160

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Basheer and Rappoport

CH(CF3)23-5 or when Y ) CO2R, Y′ ) CN groups,4,5 the percentage of enol increases systematically with the increased number of fluorine atoms in R + R′, i.e., for R ) CH2CF3, in the order R′ ) CH(CF3)2 > CH2CF3. In the present work, we extend this study to the chlorinecontaining ester group Y ) CO2CH2CCl3 since it relates to the CO2CH2CF3 group already studied, but the steric and electronic differences between CF3 and CCl3 groups may affect the percentage of enols in the 1/2 mixtures, as well as other parameters. For this purpose, we have prepared 15 XNHC(OH)d C(Y)CO2CH2CCl3 (5)/XNHCOCH(Y)CO2CH2CCl3 (6) systems, studied their KEnol values (eq 1), their configurations and their hydrogen bonding, and compared the values with those of the corresponding CF3-analogues.

Results Synthesis. The amide/enol of amide systems were prepared from the three active methylene compounds 7a-c with the aryl or alkyl isocyanates 8. For obtaining system 5a/6a the sodium salt of 7a was first prepared and then reacted with 8. The 5b/6b and 5c/6c systems were prepared in one step from 6c and 7c with 8 in DMF containing Et3N (eq 2). The reaction of pentafluorophenyl isocyanate with the salt of 7a gave the required salt, but on acidification it led to cleavage of the enol, giving CH2(CO2Me)CONHC6F5.

NMR Data. Selected 1H and 13C NMR spectral data for the enols and the amides are given in Tables 1 and 2. These are the characteristic signals relevant for structure assignments (OH, NH, CH2, CH in the 1H NMR and CO, CO2, CdC in the 13C spectra) or used for assigning or confirming the assignment of E- and Zisomers. The complete 13C NMR data are given in Table 1152 J. Org. Chem., Vol. 69, No. 4, 2004

S1 in the Supporting Information. On standing for a long time the enols decomposed, presumably by “ketone cleavage”, and the small signals due to decomposition after a relatively short time in solution are not given in Tables 1 and 2. Structure in Solution. Structural assignment of the various species in solution was based mostly on 1H NMR data, which gave also the quantitative enol/amide ratios (i.e., pKenol ) -log Kenol), from the integration of the OH(enol) vs CH(amide) or the NH(enol) vs NH(amide) signals. When both E- and Z-enols were formed, integration of the OH and NH signals and occasionally (in the absence of overlap) of other signals gave the E/Z enol ratios. The 13C NMR data qualitatively corroborated the assignments. The most significant signal being the amide CH, recognized by its 1JCH coupling, which is lost in the ionization of the most acidic carbon acids. The product distributions in solution are structure- and solvent-dependent. The enol(s)/amide ratios and when available the ratios of the two enols were determined in the solvents CDCl3, CD3CN, THF-d8, and DMSO-d6 and occasionally in C6D6. The average distributions and KEnol values are given in Table 3, and the full data are in Table S2 of the Supporting Information. 1 H NMR. All the compounds investigated had shown in the 1H NMR spectrum in CDCl3 at least two and frequently four low field signals. Systems 5a/6a, X ) Ar, displayed four signals: two in the 15.9-17.3 ppm region and two in the 11.3-12.1 ppm region. In these cases, the lowest and the highest field signals have identical integration, and the other two have also identical but lower integration. On shaking with excess D2O all the four signals decrease in intensity and disappear relatively rapidly, with formation of a HDO signal, but the two at the lower field disappear much faster. This behavior and analogies with other enolic systems3-5 assign the two lower field signals as enolic OH signals and the higher field ones as NH signals. The major enol is the one with the largest δ(OH) - δ(NH) difference. A fifth low field (but not always observed) signal, at δ 8.7-9.5 ppm (but 9.7-10.6 ppm in DMSO-d6), is assigned to the amide NH signal and has an integration similar to that of a signal at δ ca. 4.6, assigned to the CH signal. With the 5b/6b system only three low field signals were observed: those at δ 16.3 and 11.7 are ascribed to the OH and NH groups of the symmetrical enol, 5b, and that at δ 8.8-8.9 (10.5 in DMSO-d6) is ascribed to the amide NH. The low field region of the cyano ester systems 5c/6c differs from those of 5a/6a and 5b/6b. In CDCl3 there are three signals. The lowest field signal at δ 14.0-14.6 is broad and has an approximate integration as that of the signal at δ 7-8. Both signals are ascribed to the major enol. A low intensity signal at δ 9 is ascribed to the NH group of the minor enol, but its OH signal is not observed, possibly due to exchange with the main enol. The NH and CH signals of the amide were not observed. A similar pattern was observed in CD3CN. The chemical shifts are substituent and solvent dependent. For enols E-5a, X ) Ar δ(OH) ) 16.89-17.25 in CDCl3 with a small systematic decrease in δ(OH) with the increased electron donation by the para substituent. However, δ(OH) is slightly higher for X ) 2,4-(MeO)2C6H3

Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group TABLE 1.

1H NMR Data (δ, ppm, at Room Temperature) for the XNHCOCH(Y)CO CH CCl / 2 2 3 XNHC(OH)dC(Y)CO2CH2CCl3 Systems in Several Solventsa

E-enolb compd 5a/6a, X ) i-Pr 5a/6a, X ) Ph 5a/6a, X ) p-BrC6H4 5a/6a, X) p-MeC6H4 5a/6a, X ) p-MeOC6H4 5a/6a, X ) 2,4-(MeO)2C6H3 5a/6a, X ) i-Pr 5a/6a, X ) t-Bu 5a/6a X ) i-Pr 5b/6b, X ) Ph 5c/6c, X ) p-MeOC6H4 5c/6c, X ) Ph 5c/6c, X ) p-BrC6H4 5c/6c, X )p-MeC6H4 5c/6c, X)p-MeOC6H4 5c/6c, X)C6F5 5c/6c, X ) i-Pr 5c/6c, X ) t-Bu 5a/6a, X) p-MeC6H4 5a/6a, X ) 2,4-(MeO)2C6H3 5a/6a, X ) p-MeOC6H4 5a/6a, X ) p-BrC6H4 5a/6a, X ) i-Pr 5a/6a, X ) t-Bu 5c/6c, X) p-MeC6H4 5c/6c, X ) p-MeOC6H4 5c/6c, X ) p-BrC6H4 5c/6c, X ) C6F5 5c/6c, X ) i-Pr 5c/6c, X ) t-Bu 5a/6a, X ) Ph 5a/6a, X ) p-BrC6H4 5a/6a, X) p-MeC6H4 5a/6a, X ) p-MeOC6H4 5a/6a, X) 2,4-(MeO)2C6H3 5a/6a, X ) i-Pr 5a/6a, X ) t-Bu 5b/6b, X ) Ph 5c/6c, X ) Ph 5c/6c X) p-MeC6H4 5c/6c, X ) p-MeOC6H4 5c/6c, X) p-BrC6H4 5c/6c, X ) C6F5 5c/6c, X ) i-Pr 5c/6c, X ) t-Bu 5a/6a, X ) Ph 5a/6a, X ) p-BrC6H4 5a/6a, X) p-MeC6H4 5a/6a, X ) p-MeOC6H4 5a/6a, X) 2,4-(MeO)2C6H3 5a/6a, X ) i-Pr 5a/6a, X ) t-Bu 5b/6b, X ) Ph 5c/6c, X ) Ph 5c/6c, X ) p-BrC6H4 5c/6c, X) p-MeC6H4 5c/6c, X ) p-MeOC6H4 5c/6c, X ) C6F5 5c/6c, X ) i-Pr 5c/6c, X ) t-Bu

solvent CCl4 CDCl3

C6D6

Z-enolb

δ(OH)

δ(NH)

δ(CH2)

δ(OH)

δ(NH)

δ(CH2)

δ(CH)

δ(NH)

δ(CH2)

16.37 17.08 17.25 16.96 16.89 16.94 16.30 16.35 16.98 16.27

9.44 11.52 11.54 11.42 11.33 11.55 9.40 9.65 9.66 11.67

4.65 4.89 c c 4.87 4.87 4.80 4.78 4.76 4.96

15.45 16.09 16.22 15.99 15.93 16.00 15.44 15.51 16.00

9.88 11.95 11.99 11.85 11.76 11.87 9.83 10.05 10.11

4.72 c 4.88 4.88 c 4.88 4.85 4.83 4.67

4.25 4.64 4.62 4.62 4.62 4.62 4.46 4.39 4.37 4.79

6.90 9.17 9.24 9.08 9.06 9.43 7.02 7.01 6.87 8.91

ca. 4.72 4.87 4.86 4.86 4.85 4.86 4.84 4.83 4.38 4.89

14.02 14.64 14.61 14.44 14.53 14.11 14.05 14.25 16.15 16.17 16.09 16.41 15.68 15.82 14.40 14.30 14.00 d 14.27 14.38

8.29 7.94 8.01 8.10 7.86 8.59 6.37 5.95 11.97 12.04 11.89 12.05 9.91 10.15 9.62 9.59 9.73 10.04 7.79 6.96

4.51 4.89 4.89 4.88 4.88 4.88 4.84 4.83 c c c c c c 4.97 4.96 4.98 5.00 4.91 4.89

16.00 15.52 15.66

11.78 9.82 10.10

c c c

14.29 14.19 14.26 14.25 c 14.07 14.23

8.52 8.46 8.25 8.51 8.44 6.70 6.21

4.96 4.96 4.95 4.97 4.98 4.91 4.91

4.67 4.79 4.68 4.72 4.45 4.67 4.92 c 5.06 c 4.77 4.98 4.76 4.74 4.71 4.70 4.75 4.48 4.45 4.87 c

e

8.87

c

e

7.57

4.76

9.28 9.31 9.24 9.51 7.24 7.14 10.88 10.78 9.83 10.43 8.98 7.40 8.86 8.90 8.74 8.69 8.98 6.84 6.74 8.84 8.91 8.83 8.78 8.98 8.79 6.91 6.82 10.45 10.59 10.35 10.30 9.69 8.21 7.98 10.54 10.48 10.41 10.38 10.30 9.80 8.81 8.56

CCl4 CDCl3 d

THF-d8

amide or anionb

10.49

4.85

17.20 17.16 17.06 17.44 16.56 16.69

11.57 11.72 11.47 11.63 9.59 9.85

c c c c 4.85 4.84

17.02 16.45 16.54

11.48 9.41 9.68

c c 4.69

CD3CN

DMSO-d6

c 5.20 4.73 4.71 4.97 4.97 4.93 4.92 5.20 4.65 4.67 4.95 11.74f 13.03 11.06 11.74f 10.20 11.90f

4.92 4.93 4.92 4.93 4.87 4.87 5.02 5.00 4.97 4.91 c 4.76 4.91 4.91 4.92 4.92 4.91 4.88 4.87 4.95 4.96 4.96 4.94 4.93 4.98 4.91 4.85 5.00 5.00 5.01 5.01 5.00 4.96 4.95 5.04 4.83 4.82 4.85 4.85 4.81 4.90 4.89

a All signals are singlets. For the E-enol/Z-enol/amide ratios, see Table 3. When data are not given the signal was not observed. b CO Me 2 signals are at δ 3.70-3.84 for the enols; in 6a, at δ 3.80-3.88. Aromatic MeO signals are at δ 3.77-3.83; aromatic Me signals are at δ 2.30-2.36; i-Pr signals are at δ 1.07-1.28 (Me), 3.62-4.14 (CH); t-Bu signals are at δ 1.30-1.44. c Overlaps another signal. d Not observed. A broad signal at δ 10.5 ppm probably indicates a rapid exchange on the NMR time scale. e Not observed. Probably due to a rapid exchange. f Probably the proton of the ionized species.

than for X ) p-MeOC6H4. The behavior is identical for Z-5a, except that δ(OH) is at 15.93-16.22, ∆δ(OH) [E-5a - Z-5a] being ca. 1 ppm. In THF, for X ) Ar, δ(OH) E-5a

) 17.06-17.20, Z-5a ) 16.09-16.15 ppm. In CD3CN only one pair of values is available for X ) 2,4-(MeO)2C6H3: δ(OH) ) 17.02 (E-5a) and 16.00 (Z-5a). J. Org. Chem, Vol. 69, No. 4, 2004 1153

Basheer and Rappoport TABLE 2. Selected 13C NMR Data (δ, ppm) for the XNHCOCH(Y)CO2CH2CCl3/XNHC(OH)dC(Y)CO2CH2CCl3 Systems in Different Solvents solvent CCl4

Y CO2Me

X i-Pr, p-Tol

C6D6

CO2Me

i-Pr

CDCl3

CO2Me

Ar, i-Pr, t-Bu

THF-d8

CD3CN

DMSO-d6

a

CO2CH2CCl3

Ph

CN

Ar, i-Pr, t-Bu

CO2Me

Ar, i-Pr, t-Bu

species

CH or Cβ or C- a

CH2b

CCl3a

Yc

COO

CON

amide E-enol

57.6 ( 0.3d 73.5 ( 0.2

73.9 ( 0.05 73.2 ( 0.15

94.6 ( 0.1 94.0 ( 0.05

51.3 ( 1.1 51.1 ( 0.2

162.4 166.4 ( 0.2

Z-enol

75.3 ( 0.3

74.1 ( 0.5

94.9

51.1 ( 1.1

amide E-enol Z-enol amide

58.6d 76.1 74.5 59.1 ( 0.7d

74.3 73.7 74.2 74.5 ( 0.5

94.4 96.4 95.5 94.0 ( 0.05

50.7 51.6 51.3 53.6 ( 0.2

E-enol

75.7 ( 0.6

74.2 ( 0.4

95.4 ( 0.2

52.4 ( 0.4

Z-enol

75.5 ( 0.1

74.6 ( 0.3

95.0 ( 0.2

51.7 ( 0.7

amide enol Z-enol E-enol amide

59.1d 76.3 58.0 ( 2.0d 59.2 ( 0.5d

75.1 73.8 74.0 ( 0.4 74.3 74.4 ( 0.1

93.7 94.8 94.5 ( 0.4 95.6 94.8 ( 0.1

115.1 ( 0.7

164.6; 169.1 170.6 ( 0.3; 173.8 ( 0.1 170.3 ( 0.3; 171.6 ( 0.2 163.8; 165.8 172.0; 175.1 171.65; 172.7 163.7 ( 0.3; 165.8 ( 0.2 171.5 (0.9; 175.0 ( 0.1 171.2 ( 1.1; 173.0 ( 0.5 163.4 172.2 171.8 ( 0.6

E-enol

76.1

73.5 ( 0.1

96.3 ( 0.4

51.7 ( 0.8

amide Z-enol amide

48.9 ( 2.8 57.6 ( 1.7 59.1 ( 0.4d

74.9 ( 0.3 73.6 ( 0.3 74.4 ( 0.1

95.6 95.2 ( 0.3 94.3 ( 0.05

112.8 ( 1.3 113.3 ( 0.8 52.9 ( 0.2

59.3d 46.3 ( 0.4d 57.6 ( 1.7 59.4 ( 0.6d 59.1d

74.6 75.2 ( 0.2 73.6 ( 0.4 74.5 ( 0.5 74.1 73.2

94.1 93.8 ( 0.1 94.7 ( 0.3 94.9 ( 0.4 94.5 96.4

74.6 112.6 ( 0.6 114.6 ( 1.0 53.2 ( 0.2 74.1 118.4

163.4 ( 0.3; 164.9 ( 0.5 168.2 ( 2.6; 173.1 ( 2.1 166.3 ( 3.1 171.2 ( 0.4 163.5 ( 0.3; 165.0 ( 0.4 162.9 161.1 ( 0.5 171.25 ( 0.05 163.6 ( 0.5 162.7 169.3 ( 0.8

58.2 ( 1.8

72.4 ( 0.4

96.5 ( 0.8

117.7 ( 3.8

167.2 ( 1.6

CN

Ar

CO2Me

Ar, i-Pr, t-Bu

CO2CH2CCl3 CN

Ph Ar, i-Pr, t-Bu

CO2Me CO2CH2CCl3 CN

Ar, i-Pr, t-Bu Ph i-Pr, t-Bu

amide amide Z-enol amide amide amide

Ar, i-Pr, t-Bu

ion

Singlet. b Triplet, J ) 154.3-158.4 Hz. c Quartet, J ) 146.2-149.0 Hz.

It is significant that for the symmetrical 5b, X ) Ph, δ(OH) resembles more that for Z-5a and δ(NH) resembles that for E-5a than vice versa. For 5a, X ) i-Pr, t-Bu δ(OH) ) 16.30, 16.35 (E) and 15.44, 15.51 (Z) ppm, i.e., lower than for X ) Ar, and for 5a, X ) i-Pr the ∆δ(OH) and ∆δ(NH) values of the two enols are lower than for X ) Ar. The values are close to those in CCl4, although for the CF3-analogues, X ) Ar, δ(OH) [CDCl3] - δ(OH) [CCl4] ∼ 1 ppm. In THF and CD3CN, the values differ by 170 ppm are due to the major enol. The lower field signal is ascribed to COO and the higher field to CR. The signals for the other enol are not observed presumably due to their lower intensities. J. Org. Chem, Vol. 69, No. 4, 2004 1155

Basheer and Rappoport

A unique behavior is observed for the seven 5c/6c systems in DMSO-d6, a solvent where the enols are not observed. In the region where Cβ is observed in other solvents, the signal is broad at a relatively higher field, and coupling to hydrogen is absent in the C-H coupled spectrum. This is ascribed to ionization at Cβ to the conjugate base of 6c, (i.e., 6c-) which probably broadens due to exchange of 6c and 6c-. Solid-State Structure of 5c, X ) i-Pr. The solid-state structure of the enol 5c, X ) i-Pr, was determined by X-ray diffraction. The ORTEP and the stereoview are given in Figures S1 and S2 and general crystallographic data, bond lengths, bond angles, positional and thermal parameters are given in Tables S3-S7 in the Supporting Information. The following structural data are noteworthy. (a) The compound has an enol structure. (b) The CRCβ bond length of 1.426(7) Å is much longer than a typical CdC bond (1.35 Å)10 being between a single and a double bond. It resembles the CRdCβ bond lengths of other systems 1, ascribed to the significant contribution of hybrid 1a with the single CR-Cβ bond.1-5 (c) The former amidic carbonyl bond at 1.325(6) Å is much longer than this bond in typical amides (1.23 Å) but is somewhat shorter than the C-O bond length of 1.362 Å in enols.10 This is ascribed to delocalization of the positive charge at CR to the oxygen, which gives a partial double bond character to the C-O bond. However, the bond length is consistent with structure 5c and not with the amide 6c. (d) The CR-N bond length of 1.325(6) Å is somewhat shorter than that in enamines (1.33-1.35 Å),10 for the same reason described in (c) above. (e) The O-H group is cis to the CO2CH2CCl3 group, and intramolecularly hydrogen bonded to the ester carbonyl. The bonded O-H and the hydrogen bonded O‚‚‚H bond lengths are 1.00 and 1.70 Å, respectively; i.e., the hydrogen bond is asymmetric. (f) An intramolecular N-H‚‚‚NC bond of the cis NH and CN groups is impossible due to the long N‚ ‚‚N distance, but the compound exists as a dimer in which the N-H group is intermolecularly bonded to the CNnitrogen of a second molecule. The intermolecular bond length is 2.11 Å, longer and hence weaker than the intramolecular O-H‚‚‚O bond. (g) The bonds of Cβ to the ester and the cyano carbons of 1.420(7) and 1.426(7) Å, respectively are shorter than the typical bond length between two sp2 carbons (1.46-1.48 Å) or sp2 and sp carbons (1.427-1.431 Å).10 The bond shortenings are due to the double bond character of the CdY and CdY′ bonds resulting from negative charge delocalization (cf. hybrid 1a). (h) The CdO bond in the ester of 1.246(6) Å is longer than usual CdO bonds in esters (e.g., 1.175 Å in PhNHCOCH(CO2Me)2).1 This is ascribed to the lengthening expected both from the contribution of hybrid 1a, and the hydrogen bonding. A similar explanation applies to the lengthening of the CtN bond to 1.147(6) Å. The OCRN bond angle at CR of 116.8(5)° is smaller than that at Cβ (N)CCβC(dO) of 120.4(4)° due to the lower bulk of substituents at CR compared with those at Cβ. Comparison of CO2CH2CHal3, Hal ) F, Cl Activated Systems. The present work complements and extends an earlier work on the CO2CH2CF3 analogues (10) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2, 1987, S1.

1156 J. Org. Chem., Vol. 69, No. 4, 2004

3a/4a of our system,3-5 and it is of interest to compare the δ(OH), δ(NH), Kenol, and E/Z ratios in both systems. δ(OH) and δ(NH) Values. In CCl4, δ(OH) for the Eand Z-enol, X ) i-Pr for 5a, are 0.75 and 0.85 ppm higher than for 3a, and the corresponding δ(NH) values are 0.77 and 0.73 ppm higher for 5a than for 3a. In CDCl3, the δ(OH) and δ(NH) values for the E-isomer and δ(NH) for the Z-isomer are almost the same for 3a and 5a, and δ(OH) for Z-5a is 0.10 higher than for 3a. In CD3CN, only E-3a was observed with δ(OH) and δ(NH) 0.03 and 0.09 ppm higher for 5a.Only one enol was observed for 5c, X ) i-Pr, at 298 K. The δ(OH) and δ(NH) values are higher for 5c than for 3c by 0.10 and 0.17 ppm in CDCl3 and by 0.09 and 0.0 ppm in CD3CN. For X ) p-Me, p-MeO, p-H, p-BrC6H4, and 2,4-(MeO)2C6H3 in CDCl3 the ∆δ(OH) and ∆δ(NH) [5a-3a] are 0.00-0.05 except for ∆δ(OH) for the Z-isomer which is 0.11-0.15. For the four para-substituents in the 5c systems, δ(OH) data are known for only one isomer for both 5c and 3c at room temperature. In CD3CN, the ∆δ(NH) (5c3c) values are mostly 0.01 (-0.17 for X ) p-MeOC6H4) and ∆δ(OH) ) 0.10-0.22 (X ) p-BrC6H4 ) -0.03). In CDCl3, ∆δ(NH) ) -0.04-0.32 and ∆δ(OH) ) 0.0-0.27. In THF-d8 the spread in the values is larger. All the ∆δ(NH) values are negative (-0.02 to -1.89) and the ∆δ(OH) values are -0.51 to +0.51. For X ) i-Pr, the amide δ(NH) is 0.04-0.09 ppm higher for 6a than for 4a in CCl4, DMSO-d6, CDCl3, and CD3CN. For 6c and 4c δ(NH) is almost the same in CD3CN. Kenol and E/Z Values. For the diester systems 5a and 3a only values in CDCl3 can be compared due to low solubility. The Kenol values for the five N-aryl substituted 5a are 12-34% higher for 5a/6a than for 3a/4a except for X ) p-MeOC6H4 where the values are the same. The E/Z enol ratios are 17-26% higher for 5a/6a. For X ) i-Pr in CDCl3, the Kenol and the E/Z ratio are almost the same for 5a/6a and 3a/4a and the corresponding values in CCl4 are only 57% and 92% for 5a/6a. For both X ) i-Pr and 2,4-(MeO)2C6H3, 3-5% of enols were observed for the CCl3 system but none for the CF3-substituted analogues in CD3CN. The low solubility does not allow determination of Kenol for 3c/4c in CDCl3. In THF-d8, Kenol (5c)/Kenol (3c) ) 0.44, 0.62, 1.05 for X ) p-BrC6H4, p-MeOC6H4, and p-MeC6H4, respectively. The corresponding ratios in CD3CN are 0.62, 0.70, and 0.88, respectively. For X ) i-Pr the ratio is 1.06. Consequently, Kenol is mostly somewhat higher for the CF3 derivatives. Since only one enol was mostly observed at room temperature for the cyanoester systems, E/Z enol ratios are not available. Discussion Structures of the Enols in Solution. A priori the enolization can take place on either the amide or the ester carbonyl group. Previous studies with systems having the RCH(CO2R′)CONHX moiety,1-5 including the CF3 analogues of our compounds, had shown that the enolization is always on the amido carbonyl. This is corroborated in our system by the solid-state structure of enol 5c, X ) i-Pr, and is consistent with the δ(CH2CCl3) value of the ester group in solution. The strongest evidence is the number of observed isomers in systems 5a/6a and 5b/

Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group

6b. System 5b/5b with the two identical CO2CH2CCl3 groups will give only one enol 5b if enolization is on the amide, but enolization on an ester group will give E- and Z-isomers. With the C(CO2Me)CO2CH2CCl3 systems the number of isomers will be two and four for enolization on the amide and the ester, respectively. The observation of two enols for systems 5a/6a and one for 5b/6b, corroborates the enolization on the amide carbonyl. Consequently, we assign the two enols of 5a with various X groups to a pair of E- and Z-isomers. Each of them display sharp signals, indicating that their mutual isomerization which may proceed by rotation around the CdC bond, is slow on the NMR time scale under our conditions.

The assignment to E- and Z-configuration is analogous to that used previously for the analogous series with a CO2CH2CF3 instead of a CO2CH2CCl3 group.3 The assumption is that the isomer with the stronger hydrogen bond to OH has the lower δ(OH) value and the stronger hydrogen bond to NH have the lower δ(NH) value.11 In the 5a series the CO2Me group is a better hydrogen bond acceptor than the CO2CH2CCl3, and hence, the O-H‚‚‚O bond will be stronger in E-5a than in Z-5a. At the same time, the N-H‚‚‚O bond in Z-5a will be stronger than that in E-5a. Consequently, δ(OH) will be at a lower field and δ(NH) will be at a higher field for E-5a than for Z-5a. The more abundant isomer shows the lower δ(OH) and higher δ(NH) value, i.e., the largest difference between δ(OH) and δ(NH) and was therefore assigned the E-5a configuration. The isomers with the δ(OH) and δ(NH) signals at δ values between those for the E-5a are assigned to Z-5a. The E-isomers are more abundant since the O-H‚‚‚O hydrogen bond is stronger than a N-H‚‚‚ O hydrogen bond making E-5a more stable than Z-5a. The energy difference between the two isomers which mainly reflects the opposing effects of these two bonds is rather small, being 0.1-0.8 kcal/mol as calculated from the E-5/Z-5 ratios of 1.2-4 in Table 3. The assignments are corroborated by the δ(OH) and δ(NH) values of 5b in which both hydrogen bonds are to a CO2CH2CCl3 group. The values resemble those for Z-5a and E-5a, respectively, where similar hydrogen bonds are formed. The configurations are likewise determined for the two isomers of 5c. One isomer strongly predominates, consisting >88%, but mostly 100% of the enols mixture. Due to the linearity of the CN group only Z-5c forms an O-H‚ ‚‚O bond, and only E-5c forms an intramolecular N-H‚ ‚‚O bond. Judging by the solid-state structure of 5c, X ) i-Pr there may be also intermolecular N-H‚‚‚N bonds in (11) Perrin, C. L.; Nelson, J. B. Annu. Rev. Phys. Chem. 1997, 48, 511.

solution as observed in the solid. We have no evidence for this but since this bond is longer and hence weaker than the intramolecular bond, if it exists in solution, it should be less stabilizing. Hence, the Z-5c configuration was assigned to the major (or exclusive) isomers observed.

We note, however, that when E-5c is observed the difference in δ(OH) of the two isomers of the 5c system is much smaller than for the 5a system. Moreover, if the O-H‚‚‚O bond is dominant, δ(OH) of Z-5c should resemble that of Z-5a, provided that the effect of the β-EWG not involved in the O-H‚‚‚O bond (CN or CO2CH2CCl3) will be small. This is not the case; e.g., for X ) i-Pr, δ(OH) in CDCl3 for Z-5c is 13.95 and 15.9-16.2 for Z-5a , X ) Ar. This situation resembles that with the CO2CH2CF3 analogues, suggesting that the nonparticipating group in the hydrogen bond have an effect on the stability of the hydrogen bond when YdCN. This may be due to the different steric effects of Y,Y′ in the isomeric enols. The N-Substituent Effect. The effect of substituents in the aromatic ring of ArN-substituted systems on Kenol was found previously to be relatively small.3 Electrondonating aryl substituents increased log Kenol as expected from the contribution of structure 1a.3 In the present work, an N-C6F5 substituent was investigated for the first time in the 5c system and showed an identical effect to that of a p-BrC6H4 group. For substituted aryl groups in the 5c system in CDCl3, the enol(s) were the only species obtained. In the more ionizing solvents THF-d8 and CD3CN Kenol values are not much different for X ) C6F5 and p-MeC6H4. The effect of the N-Ar substituent is therefore not large. The N-alkyl substituents i-Pr and t-Bu mostly show a significant effect on δ(OH) and δ(NH) values when compared with the N-Ar systems. In most cases, δ(OH) is CDCl3 > CD3CN > DMSO-d6 was found earlier for other systems.1,3-5 In the present case, CCl4 was not studied due to the low solubility of systems 5c, but a single experiment with C6D6 had shown that it appears between CCl4 and CDCl3 in this sequence. THF-d8 was also investigated, and the percentage of enol 5c, X ) p-Tol (88%, Kenol ) 7.33), is between that for CDCl3 (100%, Kenol g 50) and CD3CN (61%, Kenol ) 1.56), thus closing the gap in solvents previously existing between CDCl3 and CD3CN. This is reminiscent of the Kenol value of the i-PrNHC(OH)dC(CN)CO2CH(CF3)2/i-PrNHCOCH(CN)CO2CH(CF3)2 system which is also between those in CDCl3 and in CD3CN.5 The extended order of Kenol values is therefore CCl4 > C6D6 > CDCl3 > THF-d8 > CD3CN > DMSO-d6, DMF-d7. This order is the order of polarity of these solvents and is ascribed to a lower polarity of the intramolecularly hydrogen bonded enol compared with that of the amide and to the preference of the more polar species in the more polar solvents. The Kenol values strongly depend on the nature of the β-substituent. When one CO2CH2CCl3 group remains constant the Kenol values decrease with the change of the second β-substituent in the order CO2Me < CO2CH2CCl3 < CN. Thus, for systems 5a the amide is the predominant tautomer in CDCl3 and the exclusive one in CD3CN, whereas the enol predominates for 5b in CDCl3, but again 1158 J. Org. Chem., Vol. 69, No. 4, 2004

it is not observed in CD3CN. In contrast, systems 5c are completely enolic in CDCl3, and they are either predominately enolic or have similar percentages of enol and amide in CD3CN. DMSO-d6 is a solvent in which enols were not observed in many systems including 5a and 5b.2,3 For systems 5c the situation is unclear. A broad amide C1H signal is observed only for 5c, X ) p-BrC6H4, and in the 13C NMR spectrum the signal is broad but it does not appear for the other compounds 5c and the C-H coupling cannot be evaluated. We ascribe this behavior to acidification of the carbon acid by the CN group which in the higher dielectric solvent leads to ionization of the CH (or OH) hydrogen, leading to the enolate ion. Although there is no direct evidence for it, we think that exchange of the latter with the neutral amide leads to the signal broadening. Finally, the comparison of the CO2CH2CCl3-substituted systems with the previously studied CO2CH2CF3 analogues3-5 does not show large differences in the Kenol values. Moreover, the changes are not systematic.

Experimental Section Materials and Solvents. Methyl 2,2,2-Trichloroethyl Malonate (7a) [1H NMR (CDCl3, 298K) δ 3.54 (2H, s), 3.77 (3H, s), 4.80 (2H, s)] was prepared according to Danieli.12 Bis(trichloroethyl) Malonate (7b). The ester was prepared in analogy to the procedure of Raha.13 To a mixture containing trichloroethanol (80 g, 0.53 mol) and dry N,Ndimethylaniline (72 mL, 0.56 mol) at ice temperature was added a solution of malonyl dichloride (25 g, 177 mmol) in dry chloroform (60 mL) dropwise during 1 h. The solution was then refluxed for 6 h and cooled, and cold 6 N H2SO4 (150 mL) was added with stirring. The solution was extracted with ether (3 × 200 mL), and the organic layer was washed with 6 N H2SO4 (200 mL), twice with water (2 × 200 mL), twice with 10% aqueous K2CO3 solution (2 × 100 mL), and three times with saturated NaCl solution (100 mL). The ether phase was dried on Na2SO4, the solvent was evaporated, and dry MgO (2 g) was added to the remainder. The product was distilled at 130 °C/8 Torr, giving 11.5 g (31 mmol, 17.5%) of bis(trichloroethyl) malonate: 1H NMR (CDCl3, 298 K) δ 3.70 (2H, s, CH2), 4.82 (4H, s); 13C NMR (CDCl3, 298 K) δ 40.6 (t, J ) 133.3 Hz, CH2), 74.6 (t, J ) 156.4 Hz, CH2CCl3), 94.2 (s, CCl3), 160.1 (m, Cd O). Anal. Calcd for C7H6Cl6O4: C, 22.98; H, 1.63. Found: C, 23.01; H, 1.58. Trichloroethyl Cyanoacetate (7c). The compound was prepared by a modification of the Ireland method.14 (i) Cyanoacetyl Chloride. To an ice-cooled solution of cyanoacetic acid (17 g, 0.2 mL) in dry ether (100 mL) was added PCl5 (41.7 g, 0.2 mol) during 20 min. The reaction mixture was kept for an additional 1 h at room temperature until the PCl5 was completely dissolved. The ether was evaporated, the POCl3 was distilled at 60 °C at reduced pressure, and when most of the ether and POCl3 were removed, benzene (20 mL) was added, and the benzene with the remaining POCl3 were distilled. This procedure was repeated. The residue was cooled to room temperature and used in the following stage. (ii) To a cold solution of 2,2,2-trichloroethanol (29.9 g, 0.2 mol) and N,N-dimethylaniline (24.2 g, 0.2 mol) in methylene chloride (30 mL) was added the solution prepared in step (i) dropwise during 2 min. The reaction mixture was refluxed for (12) Danieli, B.; Dertario, A. Helv. Chim. Acta 1993, 76, 2981. (13) Raha, C. Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 263. (14) Ireland, R. E.; Chaykovsky, M. Organic Syntheses; Wiley: New York, 1973; Collect. Vol. V, p 171.

Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group 4 h and then left overnight at room temperature. Water (100 mL) was added, and heat was evolved. The aqueous layer was washed with methylene chloride (3 × 20 mL), and the combined organic layer was washed consecutively with 2 N H2SO4 solution (10 × 50 mL), water (3 × 50 mL), and 10% aqueous Na2CO3 solution (50 mL) and dried (Na2SO4). The solvent was evaporated, and the product was distilled at 82 °C/10 Torr, giving 14.5 g (55 mol, 28%) of yellow trichloroethyl cyanomalonate (7c): 1H NMR (CDCl3, 298 K) δ: 3.67 (2H, s), 4.85 (2H, s); 13C NMR (CDCl3, 298 K) δ 24.5 (t, J ) 137.3 Hz, CH2), 75.0 (t, J ) 157.1 Hz, CH2CH3), 93.7 (CCl3), 112.2 (t, J ) 10.6 Hz, CN), 161.8 (m, CdO). Anal. Calcd for C5H4Cl3NO2: C, 27.71; H, 1.85; N, 6.47. Found: C, 28.06, H, 1.97; N, 6.24. Reaction of Methyl 2,2,2-Trichloroethyl Malonate with Aryl Isocyanates. The reaction which is demonstrated for phenyl isocyanate was also used for the p-bromo, p-methyl, and p-methoxy phenyl isocyanates. (i) To a suspension of Na (0.12 g, 5.2 mmol) in dry ether (30 mL) was added a solution of methyl 2,2,2-trichloroethyl malonate (1.25 g, 5 mmol) in dry ether (20 mL) dropwise during 1 h. The aryl isocyanate was then added, and the reaction mixture was refluxed for 3 h and then cooled to room temperature. The white solid formed was filtered and washed with ether (50 mL), giving 1.65 g (84%) of the sodium salt of amide 7a: 1H NMR (DMSO-d6, 298 K) δ 3.51 (3H, s), 4.74 (2H, s), 6.85 (1H, t, J ) 7.3 Hz), 7.18 (2H, t, J ) 7.92 Hz), 7.52 (2H, d, J ) 8.2 Hz), 11.0 (1H, s). (ii) A solution of the salt (1.5 g, 3.84 mmol) in dry DMF (5 mL) was added slowly into a cold solution of 2 N HCl (50 mL) with stirring and cooling, giving an oily solid which was extracted with EtOAc (40 mL). The organic layer was separated and dried (Na2SO4), the solvent was evaporated, and the remaining oily solid was solidified after standing overnight in a refrigerator. It was filtered and dried at room temperature giving 1.1 g (78%) of methoxycarbonyl 2,2,2-trichloroethoxycarbonyl benzanilidomethane (5a/6a, X ) Ph), mp 97-98 °C. Attempts to get suitable crystals for X-ray diffraction were unsuccessful. The spectral and analytical data are given in Tables 1 and 2 and Table S8 (Supporting Information). The p-methoxyphenyl derivative (1.21 g, 61%) was similarly obtained from 1.25 g (5 mmol) diester and 0.65 mL (5 mmol) of 4-methoxyphenyl isocyanate. The following two derivatives were obtained similarly but without extraction by ethyl acetate since the product precipitated on cooling: 1.8 g (80%) of the p-bromo derivative 5a/6a, X ) p-BrC6H4 from 1.25 g (5 mmol) of 7a and 1 g (5 mmol) 4-bromophenyl isocyanate, and 1.6 g (78%) of the p-methyl derivative 5a/6a, X ) p-Tol from 1.25 g (5 mmol) of 7a and 0.63 mL (5 mmol) of p-tolyl isocyanate. The analytical and spectral data are in Tables 1 and 2 and Table S8 (Supporting Information). Reaction of Methyl 2,2,2-Trichloroethyl Malonate with 2,4-Dimethoxyphenyl Isocyanate. To a suspension of Na (70 mg, 3 mmol) in dry ether (30 mL) was added methyl 2,2,2-trichloroethyl malonate (0.625 g, 2.5 mmol), and the mixture was stirred overnight. After complete disappearance of the sodium, 2,4-dimethoxyphenyl isocyanate (0.45 g, 2.5 mmol) was added. The reaction mixture was stirred for 2 h at room temperature and refluxed for 3 h, and after cooling to room temperature a white solid was formed. It was filtered, washed with ether (20 mL), and dissolved in DMF (5 mL), and the solution was added slowly into a cooled solution of 2 N HCl with stirring and cooling. The oily solid obtained was extracted with EtOAc (2 × 50 mL). The organic phase was separated, washed with water (3 × 70 mL), and dried (Na2SO4). The solvent was evaporated, the oily solid formed was dissolved in 3 mL EtOAc + 5 mL petroleum ether, and the solution was kept for 48 h at 0 °C. The solid obtained was filtered and dried giving 0.58 g (1.4 mmol, 56%) of 5a/6a, X ) 2,4-(MeO)2C6H3, mp 102 °C. Reaction of Methyl 2,2,2-Trichloroethyl Malonate with Isopropyl Isocyanate. (i) To a suspension of Na (120

mg, 5.2 mmol) in dry ether (30 mL) was added dropwise during 40 min at room temperature a solution of methyl 2,2,2trichloroethyl malonate (1.25 g, 5 mmol) in dry ether (10 mL). After disappearance of the Na, a solution of isopropyl isocyanate (0.5 mL, 5 mmol) in dry ether (10 mL) was added dropwise. The mixture was refluxed for 2 h and cooled, and after 2 h at room temperature the white solid formed was filtered and washed with dry ether (50 mL), giving 1.0 g (56%) of the sodium salt of 5a/6a, X ) i-Pr: 1H NMR (DMSO-d6, 298 K) δ 1.03 (6H, d, J ) 6.7 Hz), 3.44 (3H, s), 3.90 (1H, sextet, J ) 6.7 Hz), 4.66 (2H, s), 8.47 (1H, d, J ) 7.2 Hz). (ii) To a solution of the salt (1 g, 2.8 mmol) in DMF (8 mL) was added water (100 mL), and to the ice-cooled formed solution was added dropwise 32% HCl (5 mL). After standing overnight in the refrigerator, 5a/6a, X ) i-Pr (0.78 g, 83%), mp 92-3 °C, was obtained. The analytical data are in Tables 1 and 2 and Table S8 (Supporting Information), and the NMR spectra are given below as an example of the appearance of amide/enol mixtures: 1 H NMR (CDCl3, 298 K) 6a (50%) δ 1.25 (3.1 H, d, J ) 6.6 Hz), 3.83 (2.5 H, s, OCH3 overlap signals of E-5a), 4.10 (1H, hep, J ) 6.3 Hz, CH of i-Pr overlap signals of E-5a), 4.46 (0.51 H, s), 4.84 (1H, s), 7.02 (0.5H, s, NH), E-5a (33%) δ 1.2 (2.9H, d, J ) 6.6 Hz, CH3 of i-Pr, overlap signals of Z-5a), 4.80 (0.7H, s), 9.4 (0.33H, s, NH), 16.3 (0.34H, s, OH), Z-5a (17%) δ 3.74 (0.5H, s), 4.85 (0.3H, s), 9.83 (0.17 H, s, NH), 15.44 (0.16H, s, OH); 13C NMR (CDCl3, 298 K) 6a δ 22.6 (qd, Jd ) 23.3 Hz, Jq ) 127.0 Hz, CH3 of i-Pr), 42.2 (dm, Jd ) 139 Hz, CH of i-Pr), 53.4 (t, J ) 148.6 Hz, OCH3), 58.4 (d, CH, J ) 135.9 Hz), 74.7 (t, J ) 156.8 Hz, CH2), 94.0 (s, CCl3), 160.2 (m, CON), 163.8 (m, CdO of CO2CH2CCl3), 165.7 (m, CdO of CO2CH3), E-5a δ 22.2 (overlap), 42.8 (dm, Jd ) 143 Hz, CH of i-Pr), 52.1 (q, J ) 147.5, OCH3), 73.8 (t, J ) 155.1 Hz, CH2), 74.3 (s, Cβ), 95.5 (s, CCl3), 167.2 (m, CON), 171.5 (m, CdO of CO2CH2CCl3), 174.7 (m, CdO of CO2CH3), Z-5a δ 22.3 (overlap), 42.8 (dm, J ) 137.6 Hz, CH of i-Pr), 51.0 (q, J ) 146.5, OCH3), 74.3 (t, J ) 155.9 Hz, CH2), 76.2 (s, Cβ), 95.1 (s, CCl3), 169.2 (m, CON), 171.2 (m, CdO of CO2CH2CCl3), 173.4 (m, CdO of CO2CH3). Reaction of Methyl 2,2,2-Trichloroethyl Malonate with tert-Butyl Isocyanate. To a suspension of Na (0.12 g, 5.2 mmol) in dry ether (30 mL) was added methyl 2,2,2trichloroethyl malonate (1.25 g, 5 mmol), and the mixture was stirred overnight. A solution of tert-butyl isocyanate (0.57 mL, 5 mmol) in dry ether (10 mL) was added, and the mixture was refluxed for 2 h. After an additional 1 h at room temperature, the solid Na salt formed was filtered and dried. The salt was dissolved in DMF (5 mL), and the solution was added slowly into a cold solution of 2 N HCl (100 mL) with stirring and cooling. The white oily solid solidified on standing overnight at 0 °C and was filtered and dried giving 0.87 g (50%) of 5a/ 6a, X ) t-Bu, mp 103 °C. Analytical and spectral data are in Tables 1 and 2 and Table S8 (Supporting Information). Reaction of Bis(2,2,2-trichloroethyl) Malonate with Phenyl Isocyanate. To a CaCl2 moisture-protected mixture of bis(2,2,2-trichloroethyl) malonate (3.67 g, 10 mmol) and dry Et3N (6 mL, 20 mmol) in dry DMF (10 mL) which was stirred for 5 min was added phenyl isocyanate (1.1 mL, 10 mmol) with stirring, which continued for 1 h. The orange mixture obtained was added dropwise to a cold 2 N HCl solution (200 mL), and the oily solid obtained was extracted with ethyl acetate (2 × 100 mL). The organic layer was separated and dried (Na2SO4), and the solvent was evaporated giving 3.21 g of a crude product. It was crystallized by adding petroleum ether to its solution in ethyl acetate, to give 2.60 g (54%) of the product 5b/6b, mp 135 °C. Analysis and spectral data are in Tables 1 and 2 and Table S8 (Supporting Information). Reaction of 2,2,2-Trichloroethyl Cyanoacetate (7c) with Aryl Isocyanates. The reaction is demonstrated for the reaction with phenyl isocyanate. To a stirred mixture of 2,2,2-trichloroethyl cyanoacetate (1.08 g, 5 mmol) and dry Et3N (1.02 g, 10 mmol) in dry DMF

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Basheer and Rappoport (5 mL) was added phenyl isocyanate (0.5 mL, 5 mmol), and the mixture was stirred for 1 h at room temperature. The orange solution formed was added slowly to a cold solution of 2 N HCl (50 mL). The white solid formed was filtered, washed with cold water, and dried, giving enol 5c, X ) Ph (1.2 g, 72%), mp 160 °C. Analysis is given in Table S8 (Supporting Information): 1H NMR (CDCl3, 298 K) δ 4.89 (2H, s), 7.39 (5H, m), 7.94 (1H, s, NH), 14.64 (1H, s, OH); 1H NMR (CDCl3, 220 K) δ 4.93 (2H, s), 7.44 (5H, m), 8.92 (1H, s, NH), 10.8 (0.04H, s, OH), 14.44 (1H, s, OH); 13C NMR (CDCl3, 298 K, 1H decoupled) δ 58.1 (s, Cβ), 74.0 (s, CH2), 94.5 (s, CCl3), 115.2 (s, CN), 122.7 (s, m-Ph-C), 126.9 (s, p-Ph-C), 129.4 (s, o-Ph-C), 134.3 (s, ipsoC), 171.0 (s, CON), 171.2 (s, CdO); 1H NMR (DMSO-d6, 298 K) ionized amide δ 4.83 (2H, s), 6.92 (1H, t, J ) 7.4 Hz), 7.23 (2H, t, J ) 8 Hz), 7.48 (2H, d, J ) 8.0 Hz), 10.41 (0.8H, s, br, NH); 13C NMR (DMSO-d6, 298 K, 1H-coupled) ionized amide δ 59.0 (s, br, C-), 72.0 (t, J ) 154.1 Hz, CH2), 96.7 (s, CCl3), 118.8 (d, J ) 162.3 Hz, Ph), 121.9 (d, J ) 160.8 Hz, Ph), 128.7 (d, J ) 159.3 Hz, Ph), 139.8 (s, ipso-C), 166.41 (s, br, CON), 167.6 (s, br, COO). The p-methoxy derivative (0.69 g, 1.9 mmol, 76%) was similarly obtained from 0.54 g (2.5 mmol) of 7c and 0.38 mL (2.5 mmol) of 4-methoxyphenyl isocyanate; 0.835 g (2 mmol, 80%) of the p-bromo derivative from 0.54 g (2.5 mmol) of 7c and 495 mg (2.5 mmol) of p-bromophenyl isocyanate, 0.78 g (83%) of the p-methylphenyl derivative from 0.54 g (2.5 mmol) of 7c and 4-methylphenyl isocyanate. The analytical and spectral data are in Tables 1 and 2 and Table S8 (Supporting Information). Reaction of 2,2,2-Trichloroethyl Cyanoacetate with Isopropyl and tert-Butyl Isocyanates. (i) To a mixture of 7c (2.16 g, 10 mmol) and Et3N (2.1 g, 20 mmol) in dry DMF (10 mL) was added isopropyl isocyanate (1 mL, 10 mmol) at room temperature. The brown solution formed was added slowly to a cold 2 N HCl solution (100 mL), giving a pinkwhite solid (2.43 g, 81%), mp 150 °C, which after crystallization

1160 J. Org. Chem., Vol. 69, No. 4, 2004

from 1:1 EtOAc-petroleum ether gave crystals of the enol 5c, X ) i-Pr, suitable for X-ray diffraction. (ii) A similar procedure, starting from 0.54 g (2.5 mmol) of 7c, 0.75 g (5 mmol) of Et3N and 285 mg (2.5 mmol) of tertbutyl isocyanate, gave 0.58 g (1.84 mmol, 74%) of 5c, X ) t-Bu, mp 158 °C. The analytical and spectral data are given in Tables 1 and 2 and Table S8 (Supporting Information). Reaction of 2,2,2-Trichloroethyl Cyanoacetate (7c) with Pentafluorophenyl Isocyanate. To a stirred mixture of 7c (0.54 g, 25 mmol) and Et3N (0.75 mL, 5 mmol) in dry DMF (5 mL) was added pentafluorophenyl isocyanate (0.33 mL, 2.5 mmol), and the mixture was stirred overnight. The brown-red solution was added dropwise to a cold 2 N HCl solution (100 mL), and the white oily solid obtained crystallized after standing overnight in the refrigerator, giving 0.52 g (1.22 mmol, 49%) of the product, mp 156 °C. Crystallization from EtOAc-petroleum ether gave colorless crystals: 1H NMR (CDCl3) δ 4.86 (2H, s), 8.59 (1H, s, NH), ca. 14 (0.46H, very br, OH). Other data are in Tables 1 and 2 and Table S8 (Supporting Information). Crystallographic Data for 5c, X ) i-Pr. The data are given in Tables S3-S7 of the Supporting Information.

Acknowledgment. We are indebted to Dr. Shmuel Cohen for the X-ray structure determination and to the Israel Science Foundation for support. Supporting Information Available: Figures S1 and S2 of the ORTEP structure and the stereoviews of 5c, X ) i-Pr. Tables S1 and S2 giving the full 13C NMR data and the Kenol and E/Z ratios, Tables S3-S7 giving the crystallographic data for 5c, X ) i-Pr, and Table S8 giving mp’s, yields, and microanalysis of the new enols/amides. This material is available free of charge via the Internet at http://pubs.acs.org. JO030266Z