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

Article abstract of DOI:10.1021/jo030266z

Reaction of isocyanates XNCO (X = Ar, i-Pr, t-Bu) with CH ₂(Y)CO₂CH₂CCl₃ (Y = CO ₂Me, CO₂-CH₂CCl₃, CN) gave 15 amides XNHCOCH(Y)CO₂CH₂CCl₃ (6) or enols of amides XNHC(OH)=C(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 CCl ₄ > 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-d ₆. 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), K_enol, and E/Z enol ratios from the analogues with CF₃ instead of CCl₃ are discussed.

Full text of DOI:10.1021/jo030266z

En ols of Am id es Activa ted by th e 2,2,2-Tr ich lor oeth oxyca r bon yl
Gr ou p
Ahmad Basheer and Zvi Rappoport*
Department of Organic Chemistry, The Hebrew University, J erusalem 91904, Israel
zr@vms.huji.ac.il
Received August 18, 2003
Reaction of isocyanates XNCO (X ) Ar, i-Pr, t-Bu) with CH2(Y)CO2CH2CCl3 (Y ) CO2Me, CO2-
CH2CCl3, 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
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 function-
alize the enols in solution, and for this the order of Kenol
values as a function of Y and Y′ is important.
-
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.
We have recently shown that when Y,Y′ are two ester
groups COOR and COOR′, R, R′ ) CH3, CH2CF3,
(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.
(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, J uly 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
1151

Basheer and Rappoport
or when Y ) CO2R, Y′ ) CN groups,4,5 the
S1 in the Supporting Information. On standing for a long
time the enols decomposed, presumably by “ketone cleav-
age”, and the small signals due to decomposition after a
relatively short time in solution are not given in Tables
1 and 2.
3-5
CH(CF3)2
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 chlorine-
containing 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) sys-
tems, studied their KEnol values (eq 1), their configura-
tions and their hydrogen bonding, and compared the
values with those of the corresponding CF3-analogues.
Str u ctu r e in Solu tion . Structural assignment of the
1
various species in solution was based mostly on H 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, integra-
tion 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
1
CH, recognized by its J CH 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.
1H 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.
Resu lts
Syn th esis. 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.
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 de-
pendent. 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
1
NMR Da ta . Selected H 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 Z-
isomers. The complete 13C NMR data are given in Table
1152 J . Org. Chem., Vol. 69, No. 4, 2004

Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group
TABLE 1. 1H NMR Da ta (δ, p p m , a t Room Tem p er a tu r e) for th e XNHCOCH(Y)CO2CH2CCl3/
XNHC(OH)dC(Y)CO2CH2CCl3 System s in Sever a l Solven tsa
E-enolb
δ(NH)
Z-enolb
δ(NH)
amide or anionb
compd
solvent
CCl4
CDCl3
δ(OH)
δ(CH2)
δ(OH)
δ(CH2)
δ(CH)
δ(NH)
δ(CH2)
5a /6a , X ) i-Pr
5a /6a , X ) Ph
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
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
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
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
c
4.87
4.87
4.80
4.78
4.76
4.96
5a /6a , X ) t-Bu
10.05
10.11
5a /6a X ) i-Pr
C6D6
5b/6b, X ) Ph
5c/6c, X ) p-MeOC6H4
5c/6c, X ) Ph
CCl4
CDCl3
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
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
4.51
4.89
4.89
4.88
4.88
4.88
4.84
4.83
c
c
c
c
c
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
d
10.49
4.85
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
THF-d8
17.20
17.16
17.06
17.44
16.56
16.69
11.57
11.72
11.47
11.63
9.59
c
c
c
c
4.67
4.79
4.68
4.72
4.45
4.67
4.92
c
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
4.92
4.93
4.92
4.93
4.87
4.87
5.02
5.00
4.97
4.91
c
4.85
4.84
5a /6a , X ) t-Bu
9.85
c
5c/6c, X) p-MeC6H4
5c/6c, X ) p-MeOC6H4
5c/6c, X ) p-BrC6H4
5c/6c, X ) C6F5
4.97
4.96
4.98
5.00
4.91
4.89
9.73
10.04
7.79
5.06
c
5c/6c, X ) i-Pr
14.27
14.38
4.77
4.98
4.76
4.74
4.71
4.70
4.75
4.48
4.45
4.87
c
5c/6c, X ) t-Bu
6.96
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
5a /6a , X ) Ph
CD3CN
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
17.02
16.45
16.54
11.48
9.41
9.68
c
c
16.00
15.52
15.66
11.78
9.82
10.10
c
c
c
5a /6a , X ) t-Bu
4.69
5b/6b, X ) Ph
5c/6c, X ) Ph
14.29
14.19
14.26
14.25
c
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
5c/6c X) p-MeC6H4
5c/6c, X ) p-MeOC6H4
5c/6c, X) p-BrC6H4
5c/6c, X ) C6F5
c
5.20
4.73
4.71
4.97
4.97
4.93
4.92
5.20
4.65
4.67
4.95
5c/6c, X ) i-Pr
14.07
14.23
5c/6c, X ) t-Bu
5a /6a , X ) Ph
DMSO-d6
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
e
e
8.87
7.57
c
11.74f
13.03
11.06
11.74f
10.20
11.90f
5c/6c, X ) i-Pr
5c/6c, X ) t-Bu
4.76
a
b
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. CO2Me
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. Not observed.
d
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 Da ta (δ, p p m ) for th e XNHCOCH(Y)CO2CH2CCl3/XNHC(OH)dC(Y)CO2CH2CCl3 System s in
Differ en t Solven ts
CH or Câ
b
a
solvent
CCl4
Y
X
species
or C- a
CH2
CCl3
Yc
COO
CON
162.4
166.4 ( 0.2
CO2Me
i-Pr, p-Tol
amide 57.6 ( 0.3d 73.9 ( 0.05 94.6 ( 0.1
E-enol 73.5 ( 0.2
Z-enol 75.3 ( 0.3
51.3 ( 1.1 164.6; 169.1
51.1 ( 0.2 170.6 ( 0.3;
173.8 ( 0.1
51.1 ( 1.1 170.3 ( 0.3;
171.6 ( 0.2
73.2 ( 0.15 94.0 ( 0.05
74.1 ( 0.5
94.9
168.2
C6D6
CO2Me
CO2Me
i-Pr
amide 58.6d
E-enol 76.1
Z-enol 74.5
74.3
73.7
74.2
94.4
96.4
95.5
50.7
51.6
51.3
163.8; 165.8
172.0; 175.1
171.65; 172.7
160.2
169.5
169.5
159.2 ( 1.0
CDCl3
Ar, i-Pr, t-Bu amide 59.1 ( 0.7d 74.5 ( 0.5
94.0 ( 0.05
53.6 ( 0.2 163.7 ( 0.3;
165.8 ( 0.2
E-enol 75.7 ( 0.6
Z-enol 75.5 ( 0.1
amide 59.1d
74.2 ( 0.4
74.6 ( 0.3
95.4 ( 0.2
95.0 ( 0.2
52.4 ( 0.4 171.5 (0.9;
175.0 ( 0.1
167.4 ( 0.2
169.5 ( 0.4
51.7 ( 0.7 171.2 ( 1.1;
173.0 ( 0.5
CO2CH2CCl3 Ph
75.1
73.8
93.7
94.8
-
-
163.4
172.2
158.1
171.2
171.0 ( 0.2
enol
76.3
CN
Ar, i-Pr, t-Bu Z-enol 58.0 ( 2.0d 74.0 ( 0.4
94.5 ( 0.4
95.6
115.1 ( 0.7 171.8 ( 0.6
E-enol
-
74.3
THF-d8
CO2Me
Ar, i-Pr, t-Bu amide 59.2 ( 0.5d 74.4 ( 0.1
94.8 ( 0.1
52.2 ( 0.2 163.4 ( 0.3;
164.9 ( 0.5
51.7 ( 0.8 168.2 ( 2.6;
173.1 ( 2.1
159.5 ( 0.9
165.0 ( 2.0
E-enol 76.1
73.5 ( 0.1
96.3 ( 0.4
CN
Ar
amide 48.9 ( 2.8
Z-enol 57.6 ( 1.7
74.9 ( 0.3
73.6 ( 0.3
95.6
95.2 ( 0.3
94.3 ( 0.05
112.8 ( 1.3 166.3 ( 3.1
113.3 ( 0.8 171.2 ( 0.4
52.9 ( 0.2 163.5 ( 0.3;
165.0 ( 0.4
162.2 ( 4.6
172.0 ( 0.4
160.2 ( 0.4
CD3CN
CO2Me
Ar, i-Pr, t-Bu amide 59.1 ( 0.4d 74.4 ( 0.1
CO2CH2CCl3 Ph
CN
Ar, i-Pr, t-Bu amide 46.3 ( 0.4d 75.2 ( 0.2
Z-enol 57.6 ( 1.7 73.6 ( 0.4
amide 59.3d
74.6
94.1
74.6
162.9
159.6
93.8 ( 0.1
94.7 ( 0.3
94.9 ( 0.4
94.5
112.6 ( 0.6 161.1 ( 0.5
114.6 ( 1.0 171.25 ( 0.05
53.2 ( 0.2 163.6 ( 0.5
197.9 ( 0.3
171.2 ( 0.3
160.8 ( 0.5
159.5
160.8 ( 7.3
(153.5)
DMSO-d6 CO2Me
CO2CH2CCl3 Ph
Ar, i-Pr, t-Bu amide 59.4 ( 0.6d 74.5 ( 0.5
amide 59.1d
amide
74.1
73.2
74.1
118.4
162.7
169.3 ( 0.8
CN
i-Pr, t-Bu
96.4
Ar, i-Pr, t-Bu ion
58.2 ( 1.8
72.4 ( 0.4
96.5 ( 0.8
117.7 ( 3.8 167.2 ( 1.6
167.1 ( 0.9
153.5
a
b
d
Singlet. Triplet, J ) 154.3-158.4 Hz. c Quartet, J ) 146.2-149.0 Hz. Doublet, J ) 133.4-137.6 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.
7.9-8.1 ppm, except for X ) C6F5 at 8.6 ppm, whereas
for X ) i-Pr and t-Bu the values are significantly lower
(δ 6.4 and 6.0). The highest values are in THF-d8, for X
) Ar (δ ∼ 9.6), but for X ) i-Pr, δ 7.8. In CD3CN, the
δ(NH) are between those in THF-d8 and CDCl3, again
with those for i-Pr, t-Bu being much lower than for X )
Ar.
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 CD3-
CN, the values differ by <0.16 ppm; i.e., the solvent effect
on δ(OH) is negligible.
The δ(OH) values for enols 5c are at a considerably
higher field and are available mostly for the Z-isomers.
In CDCl3, for X ) Ar, δ(OH) ) 14.4-14.6 (exception: Ar
) C6F5 at 14.1 ppm). For X ) i-Pr, t-Bu the δ(OH) values
are slightly lower (14.1 and 14.3). In CCl4 for X )
p-MeOC6H4 δ(ÃΗ) is lower than in CDCl3. In THF-d8 and
CD3CN the values are close, being 14.00-14.40 for X )
Ar, i-Pr, t-Bu.
The δ(CH2) values are nearly constant, being 4.8-4.9
in CDCl3 (5b, 5.0), and in THF, CD3CN 4.9-5.0 (E-5a ,
X ) i-Pr, 4.85 in THF). Values for Z-5a are similar.
The δ(CH) for the amides is of interest. For 6a , X )
Ar, δ ) 4.6 (CDCl3), 4.7 (THF), 4.7-4.75 (CD3CN). When
X ) i-Pr, δ ) 4.3, 4.5, and 4.4 in CCl4, CDCl3, and THF-
d8 and for X ) t-Bu δ(CH) 4.4 (CDCl3), 4.45 (CD3CN),
5.0 (DMSO-d6). For amide 6b δ(CH) ) 4.8 (CDCl3), 4.95
(CD3CN), 5.0 (DMSO-d6). For 6c, X ) Ar, i-Pr, t-Bu, δ-
(CH) ) 4.85-4.96 in CDCl3 and THF-d8. For 6c in
DMSO-d6 no C-H coupling is observed in the 13C NMR
spectra.
13C NMR. The 13C NMR spectra confirm the presence
of the enol(s) and amide species. The most significant
indication for the presence of the enols is the appearance
of two signals, which show no coupling to hydrogen, at δ
73-76 for 5a and one signal at this region for 5b. These
signals are assigned to Câ (dC(Y)CO2CH2CCl3) of the
enols, and from their intensities the signal for the major
enol appears at the higher field.
The δ(NH) signals in CDCl3 for E-5a , X ) Ar (11.3-
11.55), and for Z-5a , X ) Ar (11.9-12.0) display the same
aryl-substituent effect as δ(OH). They are significantly
higher than those for X ) i-Pr (9.40, 9.83) and t-Bu (9.7,
10.1) which resemble the value for X ) i-Pr in CCl4. In
THF-d8 and CD3CN the ranges are similar.
For Z-5c, δ(NH) is at a significantly higher field than
for E-5a and 5b. In CDCl3 and CCl4 for X ) Ar it is at
1154 J . Org. Chem., Vol. 69, No. 4, 2004

Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group
TABLE 3. 5/6 a n d E-5/Z-5 Ra tios in Va r iou s Solven ts
a
%
compd
Y
solvent
6
E-5
Z-5
anion
Kenol
pKenol
E-5/Z-5
5a /6a
Ph
CDCl3
68
100
100
78
100
100
62
23
9
0.47
e0.02
e0.02
0.28
e 0.02
e 0.02
0.61
0.33
g1.7
g1.7
0.55
g 1.7
g 1.7
0.21
2.6
CD3CN
DMSO-d6
CDCl3
CD3CN
DMSO-d6
CDCl3
THF-d8
CD3CN
DMSO-d6
CDCl3
THF-d8
CD3CN
DMSO-d6
CDCl3
p-BrC6H4
p-MeC6H4
15.5
6.5
2.4
26
6.5
12
2.5
2.2
2.6
91
0.1
1.0
100
100
66
e0.02
e0.02
0.52
g1.7
g1.7
0.28
p-MeOC6H4
2,4-(MeO)2C6H3
i-Pr
25
8
9
4
2.8
2.0
88
0.14
0.87
100
100
77
80
97
100
15
50
64
95
100
30
58
76
97
100
39
100
100
0
e0.02
e0.02
0.30
g1.7
g1.7
0.52
0.60
1.51
g1.7
-0.75
0.0
0.25
1.28
g1.7
-0.37
0.14
0.50
1.51
g1.7
-0.19
g1.7
g1.7
e-1.7
0
g 1.7
e-1.7
0.75
16
15
2
7
5
1
2.3
3
2
THF-d8
CD3CN
DMSO-d6
CCl4
0.25
0.031
e0.02
5.67
1.0
0.56
0.053
e0.02
2.33
0.72
0.32
0.031
e0.02
1.56
e0.02
e0.02
g50
1.0
e 0.02
g50
59
33
25
4
26
17
11
1
2.3
1.9
2.3
4
CDCl3
THF-d8
CD3CN
DMSO-d6
C6D6
CDCl3
THF
CD3CN
DMSO-d6
CDCl3
CD3CN
DMSO-d6
CDCl3
CD3CN
DMSO-d6
CDCl3
DMSO-d6
THF-d8
CD3CN
CCl4
0
0
48
27
17
2
22
15
7
2.2
1.8
2.4
t-Bu
1
2
5b/6b
5c/6c
Ph
61
Ph
100
50
50
100
85
p-BrC6H4
0
0
31
53
0
0
11
38
12
0
88
15
69
0.14
0.18
2.2
0.89
-0.35
0.05
0
47
p-MeOC6H4
100
100
89
g50
g50
8.1
1.63
e0.02
g50
2.2
0.89
e0.02
g50
7.33
1.56
e0.02
g50
e-1.7
e-1.7
-0.91
-0.21
g1.7
e-1.7
-0.35
0.05
g-1.7
e-1.7
-0.87
-0.19
g1.7
e-1.7
-0.75
e-1.7
CDCl3
THF-d8
CD3CN
DMSO-d6
CDCl3
THF-d8
CD3CN
DMSO-d6
CDCl3
THF-d8
CD3CN
DMSO-d6
CDCl3
CD3CN
THF-d8
DMSO-d6
CDCl3
62
100
C6F5
0
31
53
0
5
0
0
0
95
69
47
0
100
88
61
0
0.05
0
0
100
p-MeC6H4
i-Pr
0
12
39
0
0
15
0
0
0
100
0
100
85
96
5.6
g50
4
0.04
100
t-Bu
0
13
45
100
87
55
g50
6.7
1.22
e0.02
e-1.7
-0.83
-0.09
g1.7
THF-d8
CD3CN
DMSO-d6
100
a
Average value based on integration of several signals. The full data are in Table S2, Supporting Information.
The amide-Câ at 58-59 ppm is identified in the C-H
the enols display three signals at δ >167 ppm, two for
the ester carbonyls and one for CR. The latter apparently
appears at such a low field due to the contribution of
hybrid 1a , and display a narrow doublet of doublets due
to different couplings with the OH and the NH.
For systems 5c the two signals appearing at δ >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.
1
coupled spectra by a doublet, J CH of 132-137 Hz, the
range of J for sp3-hybridized carbon.
Although the shifts are solvent dependent, the fact that
the enols are not observed at all in DMSO-d6 and to a
very minor extent in CD3CN enabled to clearly distin-
guish between the amide and the enol signals in the low
field region at 155-175 ppm. The amide three CdO
signals for 6a and the two signals for 6b are at δ <166
ppm, with the CONH signal at the lowest field. Each of
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 Câ 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 Câ to the
conjugate base of 6c, (i.e., 6c-) which probably broadens
due to exchange of 6c and 6c-.
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) a n d δ(NH) Va lu es. In CCl4, δ(OH) for the E-
and 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) (5c-
3c) 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.
Solid -Sta te Str u ctu r e of 5c, X ) i-P r . 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 notewor-
thy. (a) The compound has an enol structure. (b) The CR-
Câ 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 CRdCâ bond lengths of other
systems 1, ascribed to the significant contribution of
hybrid 1a with the single CR-Câ 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 CN-
nitrogen 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 Câ 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 lengthen-
ing 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 Câ (N)CCâC(dO) of 120.4(4)° due to the lower bulk of
substituents at CR compared with those at Câ.
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 CD3-
CN. For 6c and 4c δ(NH) is almost the same in CD3CN.
K
en ol a n d E/Z Va lu es. 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.
Discu ssion
Str u ctu r es of th e En ols in Solu tion . 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 ana-
logues 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/
Com p a r ison of CO2CH2CHa l3, Ha l ) F , Cl Acti-
va ted System s. 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

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.
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 ob-
served.
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 re-
semble that of Z-5a , provided that the effect of the
â-EWG not involved in the O-H‚‚‚O bond (CN or CO2-
CH2CCl3) 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 nonpartici-
pating 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.
Th e N-Su bstitu en t Effect. The effect of substituents
in the aromatic ring of ArN-substituted systems on Kenol
was found previously to be relatively small.3 Electron-
donating 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 CD3-
CN 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 <1 ppm at a higher field and δ(NH) at ca. 2 ppm to a
higher field for the aliphatic substituents except for δ-
(OH) for Z-5c in THF-d8 and CD3CN. Since the substitu-
ent is bonded to the nitrogen and delocalization of the
nitrogen lone pair to the aromatic ring makes the
nitrogen more positive, the higher field δ(NH) is reason-
able. We note that in Z-5c where the NH is not intramo-
lecularly hydrogen bonded it is probably hydrogen bonded
to the THF-d8 or the CD3CN solvent, thus shifting the
NH signal to a lower field. The smaller effect on δ(OH)
is due to the larger distance of the O-H group from the
site of the substitution. The N-alkyl substituents mostly
show higher Kenol values than the N-Ar-substituted
systems. For 5a /6a , Kenol (X ) i-Pr)/Kenol (X ) Ph) ) 2.12
(CDCl3), and 0.053 compared with e0.02 in CD3CN. In
THF-d8, Kenol (X ) i-Pr) ) 0.56 whereas Kenol (X ) Ar) )
0.1, 0.14, and 0.25 for X ) p-tolyl, p-anisyl, and X ) 2,4-
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 as-
sumption 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, con-
sisting >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. J udging 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.
J . Org. Chem, Vol. 69, No. 4, 2004 1157

Basheer and Rappoport
(MeO)2C6H3, respectively. For X ) t-Bu, Kenol (X ) t-Bu)/
Kenol (X ) Ph) ) 1.5 (CDCl3) and Kenol (X ) t-Bu)/Kenol (X
) Ar) ) 3.2 (X ) p-tolyl), 2.3 (X ) p-anisyl), and 1.3 (X
) 2,4-(MeO)2C6H3) in THF-d8, and KEnol (X ) t-Bu) of
0.031 is higher than for p-tolyl and p-anisyl (e0.02) and
identical with that for 2,4-(MeO)2C6H3 in CD3CN.
A similar effect is shown for X ) i-Pr in the 5c/6c
system, but the effect is sometimes reversed for X ) t-Bu.
it is not observed in CD3CN. In contrast, systems 5c are
completely enolic in CDCl3, and they are either predomi-
nately 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 broad-
ening.
K
Enol (X ) i-Pr)/KEnol (X ) Ar) ) 6.3 (Ar ) p-BrC6H4), 3.4
(Ar ) p-anisyl), 3.6 (Ar ) p-tolyl) in CD3CN and g22.7,
g6.2, and g6.8 in THF-d8. The KEnol (X ) t-Bu)/KEnol (X
) Ar) ) 1.4, 0.75, and 0.79 in CD3CN and 3.0, 0.83, and
0.91 in THF-d8 for the same aryl groups.
The effect of i-Pr is ascribed to its higher electron
donation than of the aryl groups which contribute via
hybrid 1a . The smaller effect for t-Bu indicates that an
opposite effect is superimposed on the electron-donating
effect.
DFT calculations (B3LYP/6-31G**)9b show that CO2-
CH2CCl3-substituted systems should give stable (i.e.,
observable) enols. For 5a , X ) Ph, i-Pr, the calculated
pKenol values are -3.9 and -4.7, which are more negative
than the observed values (pKenol ) 0.33 and 1.0, respec-
tively in CDCl3, cf. Table 3). The differences which are
similar to those observed in other systems2,3,9b reflect the
fact that the calculations are for an isolated molecule in
the gas phase. However, the differences between the X
) Ph and X ) i-Pr derivatives are similar in the
calculations and in the solvent.
Likewise, the small differences between the CO2CH2-
CCl3 (5a ) and the CO2CH2CF3 (3a ) derivatives are shown
by comparison of the calculated values given above and
those calculated for 3a , X ) Ph, i-Pr, which are -4.4 and
-4.3, respectively.
Solven t a n d â-Su bstitu en t Effect on Ken ol Va lu es.
The data of Table 3 show a strong dependence of Kenol on
the polarity of the solvent. A decreased Kenol with the
increased polarity of the solvent according to the order
CCl4 > 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.
Finally, the comparison of the CO2CH2CCl3-substituted
systems with the previously studied CO2CH2CF3 ana-
logues3-5 does not show large differences in the Kenol
values. Moreover, the changes are not systematic.
Exp er im en ta l Section
Ma ter ia ls a n d Solven ts. Meth yl 2,2,2-Tr ich lor oeth yl
Ma lon a te (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(tr ich lor oeth yl) Ma lon a te (7b). The ester was pre-
pared in analogy to the procedure of Raha.13 To a mixture
containing trichloroethanol (80 g, 0.53 mol) and dry N,N-
dimethylaniline (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 H2-
SO4 (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.
Tr ich lor oeth yl Cya n oa ceta te (7c). The compound was
prepared by a modification of the Ireland method.14
(i) Cya n oa cetyl Ch lor id e. 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
The Kenol values strongly depend on the nature of the
â-substituent. When one CO2CH2CCl3 group remains
constant the Kenol values decrease with the change of the
second â-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
(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.
1158 J . Org. Chem., Vol. 69, No. 4, 2004

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.
R ea ct ion of Met h yl 2,2,2-Tr ich lor oet h yl Ma lon a t e
w ith Ar yl Isocya n a tes. 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 sepa-
rated 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-trichloroethoxy-
carbonyl 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 precipi-
tated 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).
mg, 5.2 mmol) in dry ether (30 mL) was added dropwise during
40 min at room temperature a solution of methyl 2,2,2-
trichloroethyl malonate (1.25 g, 5 mmol) in dry ether (10 mL).
After disappearance of the Na, a solution of isopropyl isocy-
anate (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:
1H 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, J d ) 23.3 Hz, J q
) 127.0 Hz, CH3 of i-Pr), 42.2 (dm, J d ) 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, J d ) 143 Hz, CH of i-Pr), 52.1 (q, J )
147.5, OCH3), 73.8 (t, J ) 155.1 Hz, CH2), 74.3 (s, Câ), 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, Câ), 95.1 (s, CCl3), 169.2 (m, CON), 171.2
(m, CdO of CO2CH2CCl3), 173.4 (m, CdO of CO2CH3).
R ea ct ion of Met h yl 2,2,2-Tr ich lor oet h yl Ma lon a t e
w ith ter t-Bu tyl Isocya n a te. To a suspension of Na (0.12 g,
5.2 mmol) in dry ether (30 mL) was added methyl 2,2,2-
trichloroethyl 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).
R ea ct ion of Met h yl 2,2,2-Tr ich lor oet h yl Ma lon a t e
w ith 2,4-Dim eth oxyp h en yl Isocya n a te. 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 (Na2-
SO4). 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.
Rea ction of Bis(2,2,2-tr ich lor oeth yl) Ma lon a te w ith
P h en yl Isocya n a te. 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).
Rea ction of 2,2,2-Tr ich lor oeth yl Cya n oa ceta te (7c)
w ith Ar yl Isocya n a tes. The reaction is demonstrated for the
reaction with phenyl isocyanate.
R ea ct ion of Met h yl 2,2,2-Tr ich lor oet h yl Ma lon a t e
w ith Isop r op yl Isocya n a te. (i) To a suspension of Na (120
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
J . Org. Chem, Vol. 69, No. 4, 2004 1159

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 Informa-
tion): 1H NMR (CDCl3, 298 K) δ 4.89 (2H, s), 7.39 (5H, m),
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 tert-
butyl 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).
Rea ction of 2,2,2-Tr ich lor oeth yl Cya n oa ceta te (7c)
w ith P en ta flu or op h en yl Isocya n a te. 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).
1
7.94 (1H, s, NH), 14.64 (1H, s, OH); H 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, Câ), 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, ipso-
1
C), 171.0 (s, CON), 171.2 (s, CdO); H 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,
1
NH); 13C NMR (DMSO-d6, 298 K, H-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).
Rea ction of 2,2,2-Tr ich lor oeth yl Cya n oa ceta te w ith
Isop r op yl a n d ter t-Bu tyl Isocya n a tes. (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 pink-
white solid (2.43 g, 81%), mp 150 °C, which after crystallization
Cr ysta llogr a p h ic Da ta for 5c, X ) i-P r . The data are
given in Tables S3-S7 of the Supporting Information.
Ack n ow led gm en t. We are indebted to Dr. Shmuel
Cohen for the X-ray structure determination and to the
Israel Science Foundation for support.
Su p p or tin g In for m a tion Ava ila ble: 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.
J O030266Z
1160 J . Org. Chem., Vol. 69, No. 4, 2004