Synthesis and kinetic investigation of the selective acidolysis of para-substituted N-benzyl- or N-phenyl-N-phenylacetyl-α,α-dialkylglycine cyclohexylamides

Article abstract of DOI:10.1016/j.tet.2006.05.078

Several derivatives of N-phenylacetyl-N-benzyl-α,α-dimethylglycine cyclohexylamide and their α,α-dibenzylglycine analogues were synthesised by a Ugi-Passerini reaction. In addition, a few analogues of the former but having an N-phenyl instead of a benzyl

Full text of DOI:10.1016/j.tet.2006.05.078

Tetrahedron 62 (2006) 8184–8198
Synthesis and kinetic investigation of the selective acidolysis
of para-substituted N-benzyl- or N-phenyl-N-phenylacetyl-
a,a-dialkylglycine cyclohexylamides
a
Filipa C. S. C. Pinto, Sılvia M. M. A. Pereira-Lima, Cristina Ventura,
a
b
´
Lıdia Albuquerque, Raquel Gonc¸alves-Maia and Hernani L. S. Maia
c
c
a,
*
´
^
a
´
Centro de Quımica, University of Minho, Gualtar, P-4710-057 Braga, Portugal
bAdvanced Institute of Education and Sciences, Alameda das Linhas de Torres 179, P-1750-142 Lisboa, Portugal
cDepartment of Chemistry and Biochemistry, Faculty of Science, University of Lisbon, Campo Grande, P-1749-016 Lisboa, Portugal
Received 25 February 2006; revised 25 May 2006; accepted 29 May 2006
Available online 23 June 2006
Abstract—Several derivatives of N-phenylacetyl-N-benzyl-a,a-dimethylglycine cyclohexylamide and their a,a-dibenzylglycine analogues
were synthesised by a Ugi–Passerini reaction. In addition, a few analogues of the former but having an N-phenyl instead of a benzyl group
at the nitrogen atom were synthesised. The compounds in each of these three sets differed from each other at position 4 of the N-benzyl (and
N-phenyl) group. These adducts were submitted to acidolysis with TFA to obtain the corresponding free acids, the reactions being monitored
by HPLC and data collected for kinetic purposes. The kinetic data were submitted to Hammett uni- and biparametric relationships and the
results were analysed in terms of structure–reactivity in connection with the sensitivity of the reaction rates to the electronic contributions
of the various substituents at position 4 of the aromatic rings. The results allowed comparison with information obtained in previous inves-
tigations and rationalise the contribution of the substituent at the nitrogen atom to the lability of the C-terminal amide bond.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
compounds. In most cases these amino acids are not com-
mercially available and their synthesis is usually difficult
due to steric hindrance of the required reactions. Neverthe-
less, the interest these amino acids have raised in late
years led to the recent development of a few interesting
and sometimes ingenious approaches for preparation of
either symmetric10–12 or asymmetric compounds.13,14 Hav-
ing obtained the required amino acids is not sufficient to
reach one’s goal, as again steric crowding makes their inser-
tion into a peptide chain even more problematic than the
amino acid synthesis; thus, conventional methods of peptide
synthesis become unpractical as reflected by the low yields
observed in the rare cases where a product is obtained. A
promising way to overcome these difficulties would consist
in synthesising the a,a-dialkylglycine unit already incorpo-
rated into the peptide chain, a route that is in principal
offered by the four-component Ugi-Passerini reaction.16
This is particularly appropriate when no concern for asym-
metric induction is required, such as in the case of symmetric
a,a-dialkylglycines, which are among the simplest and most
widely used structural units in the construction of peptides
with a predetermined secondary structure.15 However, the
above strategy is not exempt of difficulties, as it requires that
(i) the unwanted alkyl group bound to the nitrogen atom of
the dialkylated centre be removed and (ii) the unavoidable
racemisation of the amino acid residue that follows the
Conformational rigidity increases potency and selectivity
of bioactive peptides, improving their bioavailability and
enhancing resistance to peptidases.1 Consequently, design
of conformationally constrained peptides is one of the
approaches for development of bioactive species with high
activity and selectivity towards a specific receptor.2,3 Owing
to steric crowding within the neighbourhood of the a-carbon
atom of a,a-dialkylglycines, conformational rigidity can be
obtained by inserting one or more residues of these amino
acids into the peptide chain. In addition, special conforma-
tional features imparted to the peptide backbone by these
amino acid residues4–7 may be used to modulate the activity
and selectivity. This can be best achieved by previous para-
metrisation of these amino acids8 followed by molecular
dynamics simulations of the bioactive peptides9 as modified
at strategic positions by one or more residues of these amino
acid units. Once the most promising peptide sequences
are predicted, it is necessary to synthesise the selected
Keywords: Acidolysis; a,a-Dialkylglycines; a,a-Trialkylglycines; Peptide
synthesis; Ugi–Passerini reaction; Rate constant; Structure–reactivity rela-
tionships.
* Corresponding author. Tel.: +351 967 096 958; fax: +351 253 617 959;
e-mail: h.maia@netcabo.pt
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.078

F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
8185
R1 R1
R1 R1
R1 R1
O
O
H
N
H2O
TFA
R2
O
OH
PhCH2
N
PhCH2
N
N
R2
O
R2
O
O
PhCH2
1-3
4-6
2a, 5a R1 = Bn, R2 = 4-MeO-C6H4CH2
2b, 5b R1 = Bn, R2 = 4-Me-C6H4CH2
2c, 5c R1 = Bn, R2 = C6H5CH2
1a, 4a R1 = Me, R2 = 4-MeO-C6H4CH2
1b, 4b R1 = Me, R2 = 4-Me-C6H4CH2
1c, 4c R1 = Me, R2 = C6H5CH2
3a, 6a R1 = Me, R2 = 4-MeO-C6H4
3b, 6b R1 = Me, R2 = C6H5
3c, 6c R1 = Me, R2 = 4-Cl-C6H4
3d, 6d R1 = Me, R2 = 4-CN-C6H4
3e, 6e R1 = Me, R2 = 4-NO2-C6H4
2d,5d R1 = Bn, R2 = 4-F-C6H4CH2
2e, 5e R1 = Bn, R2 = 4-Cl-C6H4CH2
2f, 5f R1 = Bn, R2 = 4-CF3O-C6H4CH2
2g, 5g R1 = Bn, R2 = 4-CF3-C6H4CH2
2h, 5h R1 = Bn, R2 = 4-NO2-C6H4CH2
1d, 4d R1 = Me, R2 = 4-F-C6H4CH2
1e, 4e R1 = Me, R2 = 4-Cl-C6H4CH2
1f, 4f R1 = Me, R2 = 4-CF3O-C6H4CH2
1g, 4g R1 = Me, R2 = 4-CF3-C6H4CH2
1h, 4h R1 = Me, R2 = 4-NO2-C6H4CH2
Scheme 1.
newly synthesised unit be overcome. We have shown that the
former can be achieved if the unwanted N-substituent is
methoxybenzyl,17 and that the latter can be overcome by
taking advantage of the lability of the amide bond at the
C-terminus of the a,a-dialkyl glycine unit.18–20 This allows
obtaining the amino acid unit at the peptide C-terminus,
ready for further elongation of the chain without any risk
of racemisation. The above can be achieved by treatment
of Ugi–Passerini adduct with trifluoroacetic acid (TFA),
but this approach will prove useful only if the double cleav-
age can be performed under acceptable selectivity and in
good yield, which depends on the nature and structure of
this adduct. In order to assess the selectivity of the amide
bond cleavage, we have further investigated its mechanism
and evaluated the effect of the substituent bulk and structure
at the N- and C-terminus, and also at the a-carbon atom of
the fully substituted amino acid (Scheme 1).21,23 In order
to complete this investigation, we now present the results
of a similar evaluation concerning the nature of the alkyl
substituent bound to the N-terminal nitrogen atom of Ugi–
Passerini adduct.
rate of the acidolyses but also the path of the reactions in-
volved.20 Compounds with methyl group at the side chain
reacted faster and behaved better when compared with
the corresponding benzyl analogues where a larger steric
effect had to be expected. Thus, for the present investiga-
tion we designed one set of compounds with methyl (sub-
strates 1) and another with benzyl (substrates 2) at the
amino acid side chain, with eight substrates in each set
(Scheme 1). As in our previous work R2 was always
4-methoxybenzyl, for these two sets we chose differently
substituted benzyl groups (including the nonsubstituted
group). In addition, we have also devised a third set of
substrates with methyl at the amino acid side chain but
in which R2 was a phenyl, substituted or not in position
4 (substrates 3); in this case only five compounds were
envisaged. All the compounds were synthesised by Ugi–
Passerini reaction using phenylacetic acid, cyclohexyl
isonitrile, the appropriate amine and acetone (compounds
1a–1h and 3a–3e) or dibenzyl ketone (compounds 2a–2h)
according to the methodologies described elsewhere
(Table 1).19,20 As shown previously18,20 and is depicted in
Scheme 1, these substrates undergo acidolysis, which pro-
ceeds via an oxazolone derivative to yield the correspond-
ing open-chain N-acyl-N,a,a-trialkylglycine. Thus, each
of the above substrates was treated at room temperature
with 5% TFA in acetonitrile to give three new sets of com-
pounds (4, 5 and 6) homologous to the previous ones (1, 2
and 3, respectively) and the yields are presented also in
Table 1.
2. Results and discussion
2.1. Syntheses
In our previous work it was found that the bulk of the
amino acid side chains may affect seriously not only the
Table 1. Synthesis of Ugi–Passerini adducts PhCH2CO-N(4-X-C6H4-CH2)-C(R1)2CO-NHC6H11 (1a–1h and 2a–2h) and PhCH2CO-N(4-X-C6H4)-
C(CH3)2CO-NHC6H11 (3a–3e) and of their cleavage products (4a–4h, 5a–5h and 6a–6e, respectively)
X
Compound
R1
Yield
(%)
Compound
R1
Yielda
(%)
Compound
R1
Yield
(%)
Compound
R1
Yielda
(%)
Compound
R1
Yield
(%)
Compound
R1
Yield
(%)
No.
No.
No.
No.
No.
No.
CH3O
CH3
H
F
Cl
CF3O
CF3
CN
NO2
Me
Me
Me
Me
Me
Me
Me
1a
1b
1c
1d
1e
1f
91
90
71
95
86
91
98
Me
Me
Me
Me
Me
Me
Me
4a
4b
4c
4d
4e
4f
84
89
76
97
89
90
92
Bn
Bn
Bn
Bn
Bn
Bn
Bn
2a
2b
2c
2d
2e
2f
82
60
44
85
76
63
78
Bn
Bn
Bn
Bn
Bn
Bn
Bn
5a
5b
5c
5d
5e
5f
68
93
98
88
85
92
95
Me
3a
92
86
71
Me
6a
98b
77b
66a
Me
Me
3b
3c
Me
Me
6b
6c
1g
4g
2g
5g
Me
Me
3d
3e
24
9
Me
Me
6d
6e
56a
48c
Me
1h
50
Me
4h
89
Bn
2h
47
Bn
5h
62
a
Treatment with TFA in acetonitrile (5%) at room temperature.
Treatment with neat TFA at room temperature.
Treatment with boiling neat TFA.
b
c

8186
F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
Table 3. Rate constants, k, and mean deviations, dk, for the acidolysis of
PhCH2CO-N(4-X-C6H4-CH2)-CMe2CO-NHC6H11 (1a–1g) at different
temperatures
2.2. Acquisition and treatment of kinetic information
As will be discussed below, even in the case of the lower
yields obtained in the acidolyses with 5% TFA no signs
have been detected for the reagent undergoing any reaction
other than acidolytic cleavage of the C-terminal amide
bond as depicted in Scheme 1. Thus, each substrate was sub-
mitted to acidolysis with 2% TFA under controlled con-
ditions for collection of kinetic data; this was assisted by
HPLC to monitor the reagent peak according to the proce-
dure described below in Section 4. As expected,21–23 an
excellent linear relationship between substrate concentration
and HPLC peak areas was found, which allowed calculation
of reaction rate constants directly from peak areas. All reac-
tions exhibited pseudo-first order behaviour with respect
to the amino acid derivative, which is shown by the linear
variation of ln A, where A is an HPLC peak area, as a function
of time. As an example, ln A versus t plots for experiments
concerning substrates 1a at two temperatures (25.00 and
40.00 ꢀC) and 2a at 25.00 ꢀC are presented in Fig. 1. The
observed rate constants, k, were calculated by the linear least
squares methodology for a straight line. Four to five experi-
ments were performed for each substrate in reactions carried
out at 25.00 ꢀC, while only two to three were performed
for reactions at other temperatures. The results presented in
Tables 2 and 3 are the mean rate constant values (k) and their
mean deviations (dk).
X
Compound
no.
(kꢁdk)ꢂ104 (sꢃ1
)
20.00 ꢀC
30.00 ꢀC
35.00 ꢀC
40.00 ꢀC
CH3O 1a
2.54ꢁ0.05 6.23ꢁ0.18 9.44ꢁ0.22 12.99ꢁ0.48
2.20ꢁ0.06 4.62ꢁ0.18 6.68ꢁ0.25 11.99ꢁ0.45
1.50ꢁ0.06 3.32ꢁ0.09 5.13ꢁ0.18 8.16ꢁ0.40
1.06ꢁ0.03 2.35ꢁ0.07 3.45ꢁ0.11 5.76ꢁ0.23
0.84ꢁ0.02 1.84ꢁ0.06 2.95ꢁ0.10 4.06ꢁ0.16
0.68ꢁ0.01 1.55ꢁ0.04 2.20ꢁ0.06 3.53ꢁ0.18
0.53ꢁ0.02 1.14ꢁ0.03 1.68ꢁ0.10 2.40ꢁ0.08
CH3
H
F
Cl
1b
1c
1d
1e
CF3O 1f
CF3 1g
acidolyses, s being the Hammett substituent constant and
r the reaction constant reflecting the sensitivity of the reac-
tion rate to the total electronic effect of the substituents. The
values of Hammett constants for para-substituents (sp) used
to fit the observed rate constants (k) are listed in Table 4;25
although the number of substituents used in each set of com-
pounds is not large, it is worthwhile to note that they provide
a wide range of electronic effects. Table 5 shows the para-
meters estimated (a0 and a1) for Hammett plots by the least
squares methodology for a straight line. The correlation
coefficient (r) and the standard deviation (s) of the fits are
also presented together with the standard deviations of the
estimated parameters. The confidence levels for the esti-
mated parameters as well as those for the fits obtained in a
test-F24 were always better than 99.99%, except for the reac-
tions with compounds 3a–3e, which was 99.8%; this dif-
ference is most probably due to the small number of
compounds (N¼5) available in the latter case. Fig. 2 shows
the corresponding plots. The success obtained in the above
treatment of the electronic effect of substituents on the rate
of our reactions leads us to investigate the possibility to
quantify field/inductive and resonance contributions. For
this purpose, we extended our analysis of rate constants
As in all compounds now under investigation R2 is con-
nected to the rest of the molecule through an aromatic
moiety, it is appropriate to analyse the kinetic results at the
light of a Hammett treatment. For this purpose, the uni-
parametric correlation log k¼log ko+rs was applied to all
11
2a
Table 4. Hammett constants and their constituent contributions24
T = 25.00°C
Substituent
sP
sR
sI
9
1a
CH3O
CH3
H
F
Cl
CF3O
CF3
CN
NO2
ꢃ0.268
ꢃ0.170
0.000
0.063
0.227
0.350
0.540
0.660
0.778
ꢃ0.56
ꢃ0.18
0
ꢃ0.39
ꢃ0.19
ꢃ0.04
0.16
0.29
0.01
0.003
0.45
0.42
0.39
0.38
—
T = 25.00°C
1a
T = 40.00°C
7
0
100
200
300
t / min
—
0.13
Figure 1. Plots of values of ln Aversus time for acidolysis of compounds 1a
(25.00 and 40.00 ꢀC) and 2a (25.00 ꢀC).
0.65
Table 2. Rate constants, k, and mean deviations, dk, at 25.00 ꢀC for the acidolysis of PhCH2CO-N(4-X-C6H4-CH2)-C(R1)2CO-NHC6H11 (1a–1h and 2a–2h)
and PhCH2CO-N(4-X-C6H4)-C(CH3)2CO–NHC6H11 (3a–3e)
X
Compound
(kꢁdk)ꢂ104 sꢃ1
Compound
(kꢁdk)ꢂ104 sꢃ1
Compound
(kꢁdk)ꢂ106 sꢃ1
R1
No.
R1
No.
R1
No.
CH3O
CH3
H
F
Cl
CF3O
CF3
CN
NO2
Me
Me
Me
Me
Me
Me
Me
1a
1b
1c
1d
1e
1f
4.513ꢁ0.051
3.333ꢁ0.042
2.530ꢁ0.078
1.711ꢁ0.017
1.417ꢁ0.059
1.190ꢁ0.050
0.727ꢁ0.004
Bn
Bn
Bn
Bn
Bn
Bn
Bn
2a
2b
2c
2d
2e
2f
1.567ꢁ0.019
1.306ꢁ0.034
1.005ꢁ0.013
0.692ꢁ0.002
0.512ꢁ0.002
0.439ꢁ0.003
0.322ꢁ0.003
Me
Me
Me
3a
10.14ꢁ0.02
6.833ꢁ0.022
1.729ꢁ0.014
3b
3c
1g
2g
Me
Me
3d
3e
0.347ꢁ0.018
0.334ꢁ0.017
Me
1h
0.497ꢁ0.010
Bn
2h
0.196ꢁ0.010

F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
8187
Table 5. Application of the Hammett equationa log k¼a0+a1sp
Compound
1a–1h
2a–2h
3a–3e
1a–1g
T (ꢀC)
25.00
25.00
25.00
20.00
30.00
35.00
40.00
a0
a1
N
r
ꢃ3.63ꢁ0.02
ꢃ0.91ꢁ0.05
8
0.993
0.04
ꢃ4.05ꢁ0.02
ꢃ0.86ꢁ0.04
8
0.993
0.04
ꢃ5.34ꢁ0.07
ꢃ1.56ꢁ0.15
5
0.986
0.13
ꢃ3.85ꢁ0.02
ꢃ0.89ꢁ0.08
7
0.981
0.05
ꢃ3.50ꢁ0.02
ꢃ0.91ꢁ0.07
7
0.987
0.05
ꢃ3.32ꢁ0.02
ꢃ0.92ꢁ0.07
7
0.985
0.05
ꢃ3.13ꢁ0.02
ꢃ0.96ꢁ0.06
7
0.990
0.04
s
a
Estimated parameters, a0 and a1, number of points, N, correlation coefficient, r, and standard deviation, s.
the nitro group, which would decrease substantially the
nucleophilicity of the amine nitrogen atom when compared
with the other substituents. This was so enhanced in the case
of nitroanilide 3e that it could not be obtained in a yield
better than 9%. Acidolyses of the dimethylglycine deriva-
tives 1 with 5% TFA were faster than those with the
corresponding dibenzylglycine compounds 2 (2.5–4 h for
substrates 1a–1g and 20–27 h for compounds 2a–2e, respec-
tively). The acidolyses of the nitrobenzyl derivatives were
much slower, requiring 26 and 48 h for 1h and 2h, respec-
tively. As shown in Table 1, good to very good yields were
obtained in the acidolysis of compounds 1b–1g and 2b–
2g. We have shown20 that (i) when treated with TFA at low
concentration and room temperature the 4-methoxybenzyl
group is not cleaved, but (ii) the partial cleavage may occur
by prolonged treatment with 5% TFA and (iii) the full cleav-
age is usually achieved on boiling in neat TFA for 5 min.
Thus, full selective cleavage of the amide bond was observed
with compound 1a to give a yield of 91% of the required
product. However, as the acidolysis of 2a was about three
times slower than that of 1a, subsequent partial cleavage
of the N-methoxybenzyl group took place to allow only
68% of the required product. This did not affect the kinetic
measurements not only because these are referred to the dis-
appearance of 2a, which occurs prior to further cleavage, but
also because no secondary peaks were found overlapping
with the reagent peak in the chromatograms. When 1b and
1d were boiled in neat TFA for 20 min the substituent at
R2 was not eliminated, the corresponding N-phenylacetyl-
trialkylglycine being the only product obtained; this dif-
ferentiates methoxybenzyl group from the remaining
compounds investigated. It was already known26 that the
N-substituent of N,a,a-tribenzylglycine resists to boiling in
concentrated aqueous HBr for several hours and that its
cleavage requires hydrogenation in hot butanol for 12 h.
The reactions of the N-phenyl derivatives with 5% TFA at
room temperature were so slow (27–168 h for 3a–3d) that
in most cases partial decomposition of the product was ob-
served on completion, thus contributing to lower the final
yield. Nevertheless, the acidolysis of compound 3a was still
sufficiently fast to avoid decomposition even when it was
treated with neat TFA; so, this gave the best results for com-
pound 3a and also 3b (Table 1). However, with the other sub-
strates of this set their reactions with neat TFAwere still slow
and showed considerable decomposition of the product,
the best results being then obtained with 5% TFA at room
temperature; in the case of the nitrophenyl derivative (3e)
boiling in neat TFA for more than 1 h was required for an ac-
ceptable progress but a yield of only 48% could be obtained.
T (ºC)
-3
-5
-7
40
35
30
CH3O
CH3
25
25
20
H
F
Cl
CF3O
CF3
CN
1a-1h
2a-2h
3a-3e
NO2
25
0.8
-0.4
0.2
Figure 2. Hammett plots (log k vs sp) for compounds 1a–1h, 2a–2h and
3a–3e at 25.00 ꢀC and 1a–1g at other temperatures.
taking advantage of a biparametric relationship in order to
evaluate these two main part components as follows: log k¼
a0+a1sR+a2sI (where sR and sI are the resonance constant
and the field/inductive constant, respectively).25 This treat-
ment was applied only to those cases where the number of
results available allowed the most meaningful statistical
analysis, i.e., compounds 1a–1h and 2a–2h at 25.00 ꢀC.
The values of the constants used in the regression analysis,
sR and sI, are listed also in Table 4. It should be noted that
for the range of the substituents studied these two constants
are not collinear and can be used as independent variables
since their correlation coefficient is as low as 0.148 (N¼8).
The results of the biparametric equations are presented in
Table 6.
2.3. Discussion of results
The yields obtained in Ugi–Passerini reaction (Table 1) were
usually good to very good, except in the case of nitro deriv-
atives. The behaviour observed with the nitro derivatives
is possibly due to the large electron withdrawing effect of
Table 6. Application of the biparametric Hammett equationa log k¼
a0+a1sR+a2sI at 25.00 ꢀC (N¼8 points)
Compound a0
a1
a2
r
s
1a–1h
2a–2h
ꢃ3.61ꢁ0.04 ꢃ0.86ꢁ0.07 ꢃ0.95ꢁ0.08 0.993 0.05
ꢃ4.00ꢁ0.02 ꢃ0.78ꢁ0.04 ꢃ0.96ꢁ0.05 0.996 0.03
a
In general, the values of the rate constants for the compounds
of N-benzyl derivatives of a,a-dimethylglycine 1a–1h are
Estimated parameters, a0, a1 and a2, correlation coefficient, r, and stan-
dard deviation, s.

8188
F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
about 2.5 times larger than those for their analogues in the
a,a-dibenzylglycine series (2a–2h). This difference must
be related to a larger steric contribution of the amino acid
side chains (R1) to the reaction rates in the case of com-
pounds 2. Nevertheless, both sets have approximately the
same sensitivity to electronic contributions, which is parti-
cularly visible by comparing thevalues for a1 in the Hammett
plots (ꢃ0.91 and ꢃ0.86 for set 1 and set 2, respectively, at
25.00 ꢀC; Table 5 and Fig. 2). However, a different behav-
iour is observed in the case of the N-phenyl derivatives of
a,a-dimethylglycine 3a–3e, where the rate constants are
40–150 times smaller than those found for similar com-
pounds in set 1. Now, the reactions are not only much slower
but also much more sensitive to the electronic contribution
of the substituent at the nitrogen atom than in the above case.
This different behaviour becomes evident from the value of
a1 in the corresponding Hammett plot (ꢃ1.56), which differs
significantly from those of the previous sets. The absence of
a methylene group between the nitrogen atom and the aro-
matic ring allows the electronic contribution of the substitu-
ent to be passed onto the oxygen atom of the vicinal carbonyl
group, thus tuning its nucleophilicity. It is clear that conjuga-
tion of the side chain phenyl ring of compounds 3 with the
reaction centre contributes to its stabilisation, thus decreas-
ing the nucleophilicity of the oxygen atom to make the reac-
tions slower than with the benzyl derivatives. In their
investigation of the effect of the substituent on the rate of
acidolysis under similar conditions of various para-sub-
stituted N-benzoyl derivatives of N,a,a-trimethylglycine,
Creighton et al.18 have found that the value is ꢃ1.335.
This suggests that the nucleophilicity of the oxygen atom
is more sensitive to the electronic contribution of the sub-
stituent at the nitrogen atom (Scheme 2A) than that at the
N-carbonyl carbon atom (Scheme 2B). This may be inter-
preted as resulting from the additional interaction in our case
between the substituent and the nucleophilic oxygen atom
through the formation of an N–C double bond during the
cyclisation process. The results presented in Table 5 and
Figure 2 for compounds 1 at different temperatures show
a slope varying, although not much but steadily, with tem-
perature, in agreement with what one would expect from
the properties of Hammett reaction constant. Fluorine deriv-
atives 1d and 2d are the less well behaved compounds;
in fact, in the plots obtained at different temperatures they
show systematic deviations to the same side of the lines
(Fig. 2).
-3.5
1a-1h
2a-2h
-4.8
-4.8
-3.5
log k (calc)
Figure 3. Plot of observed log k values for acidolysis of compounds 1a–1g
against those calculated with log k¼ꢃ3.61ꢃ0.86sRꢃ0.95sI and of
compounds 2a–2g against those calculated with log k¼ꢃ4.00ꢃ0.78sRꢃ
0.96sI.
significance of the estimated parameters and of the fit ob-
tained by the test-F were always better than 99.99%. In order
to further demonstrate the validity of these correlations, the
values observed for log k were plotted against those calcu-
lated by the equations, as shown in Fig. 3. The 16 points
(eight for 1a–1h and eight for 2a–2h) fall very closely to
the bisectrix of perfect correlation. The successful decompo-
sition of substituent electronic effects places the discussion
of field/inductive and resonance components in numerical
terms. Since in our case a1 and a2 have a similar magnitude
(Table 6), one might conclude that, as an average, both
effects contribute significantly to the reactivity. Now, fluo-
rine derivative 1d is again less well behaved. It can be
seen in Table 4 and Fig. 4 that the field/inductive constant
and resonance constant can be very different from each
other for every substituent. Fluorine, where these two
constants are large, have opposite signs and are almost of
the same size is the exception; in this case the resonance
contribution can almost cancel the field/inductive con-
tribution if the reaction under consideration is equally
sensitive to both, as has already been discussed by others.27
However, if in our case the sensitivities concerning the
fluorine derivatives are different, these compounds should
diverge from the average, which might explain the deviant
behaviour.
X
X
R1 R1
R1 R1
CH3O
O
O
O
O
A
N
N
σR
σI
σp
YH
YH
CH3
Y
O
R3
R3
O
R3
R3
H
F
R1 R1
R1 R1
Cl
N
N
B
Y
O
CF3O
CF3
O
X
X
NO2
Scheme 2.
-0.8
-0.4
0
0.4
0.8
The biparametric relationships presented above for com-
pounds 1a–1h and 2a–2h at 25.00 ꢀC are excellent, the
Figure 4. Plot of Hammett constant (sp), field/inductive constant (sI) and
resonance constant (sR) for the different substituents.

F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
8189
3. Conclusions
60 (230–400 mesh). All melting points were measured on
a Gallenkamp melting point apparatus and are uncorrected.
1H NMR spectra were recorded at 25 ꢀC inw5% solutions on
a Varian Unity Plus-300 spectrometer; all shifts are given in
parts per million using Me4Si¼0; J-values are given in hertz,
and assignments were made by comparison of chemical
shifts, peak multiplicity and J-values. 13C NMR spectra
were recorded with the same instrument at 75.4 MHz and
using the solvent peak as internal reference; assignments
were carried out using DEPT 135, HMBC, HMQC and NOE
techniques. Elemental analyses were preformed on a Leco
CHNS 932 instrument. HPLC measurements were carried
out with a Jasco PU-980 intelligent HPLC Pump, a Shimadzu
SPD-6AV UV–vis Spectrophotometric Detector and a
Shimadzu C-R6A Chromatopac Printer. A reverse phase
LiChrospher 100 RP-18 (5 m) column was used throughout
the work. Temperature stability was maintained throughout
the kinetic work with a HAAKE Circulator DL30 thermo-
static bath, the temperatures being set with the aid of Preci-
sion thermometers allowing an accuracy of 0.01 ꢀC.
The kinetic results obtained in this investigation show that
the reaction rate constants differ sufficiently from compound
to compound to allow their interpretation in terms of struc-
ture–reactivity considerations. The sensitivity of the mea-
sured reaction rates to the nature (electronic contribution)
of the substituent at the nitrogen atom of the anilides
3a–3e is larger than that reported19 for the N-acyl group
and this may be related to the formation of C–N double
bond required for cyclisation and consequent cleavage of the
C-terminal amide bond, as depicted in Scheme 2. N-Benzyl
derivatives of either a,a-dimethyl- or a,a-dibenzylglycine
(1a–1h and 2a–2h, respectively) exhibit a lesser sensitivity,
which is in agreement with the existence of a methylene
group between the nitrogen atom and the phenyl ring. Simi-
larly to what we have previously found, a,a-dimethylgly-
cine derivatives react much faster than the corresponding
a,a-dibenzylglycines. However, these two sets of com-
pounds show a very similar behaviour in what concerns
sensitivity to the electronic contribution of the substituent
R2 to acidolysis and to its main components (resonance
and field/inductive effect). Although acidolytic cleavage of
the C-terminal amide bond of a,a-dialkylglycine derivatives
requires an alkyl/aryl substituent at the amino acid nitrogen
atom,19–23 it occurs independent of the size of the electronic
contribution, which contributes only to the rate of acidolysis.
This suggests that such requirement is essentially related
to steric effect and not so much to a polar effect, possibly
by assisting the molecules to assume a bent conformation
and facilitating internal nucleophilic attack in support of
what we had already suggested.21 Our results showed that
anilides substituted with electron withdrawing groups such
as N-(4-chlorophenyl) and N-(4-cyanophenyl) exhibit a com-
paratively high resistance of the C-terminal amide bond of
a,a-dialkylglycine amides to acidolysis. This suggests that
either of these groups would seem appropriate to impart
useful conformational restrictions in combination with
a,a-dialkylglycine peptides while preventing unwanted
cleavage of the C-terminal peptide bond of the amino acid
residue bearing the two side chains. Finally, it is noteworthy
that while the 4-methoxybenzyl group can be cleaved from
Ugi–Passerini substrate together with the C-terminal amide
bond if sufficient forcing conditions are used (boiling with
neat TFA), all the other 4-substituted benzyl groups tested
do not. Thus, when cleavage of the N-alkyl group from
Ugi–Passerini adducts is required, only 4-methoxybenzyl
compounds suit this purpose, which was the group we
have used with success in our previous work.
4.1.1. General method for the synthesis of Ugi–Passerini
adducts (1, 2 and 3). For the preparation of the a,a-di-
methylglycine derivatives, a 0.5 M solution of the required
amine in dry acetone containing anhydrous sodium sulfate
(0.12 g cmꢃ3) was prepared and stirred for 15 min; then,
1 equiv of a 2 M solution of phenylacetic acid in dry metha-
nol was added and the mixture was stirred for further
15 min. Finally, 1 equiv of cyclohexyl isocyanide was also
added and the mixture was stirred at room temperature for
1–4 weeks in the dark and under nitrogen. To the suspension
thus obtained dichloromethane was added to dissolve the
product that meanwhile had precipitated and the sodium
sulfate was filtered off. The filtrate was concentrated under
reduced pressure and the residue was purified by column
chromatography using the following eluent sequence:
dichloromethane/n-hexane 2:1, dichloromethane, dichloro-
methane/methanol 200:1, 100:1 and 50:1. For the prepara-
tion of a,a-dibenzylglycine derivatives, to a 1 M solution
of 1,3-diphenylpropanone in dry methanol containing anhy-
drous sodium sulfate (0.12 g cmꢃ3) 1 equiv of the required
amine was added. After stirring for 45–60 min, 1 equiv of
cyclohexyl isocyanide was mixed and the preparation was
continued as above.
4.1.1.1. N-Phenylacetyl-N-(4-methoxybenzyl)-a,a-di-
methylglycine cyclohexylamide (1a). The reaction was
carried out on a 0.05-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 1a (19.17 g,
91%) as a white solid, mp 168.9–169.8 ꢀC (lit.20 168.4–
169.8 ꢀC). 1H NMR (300 MHz, CDCl3): 1.08–1.21 (3H, m,
C6H11), 1.42 (6H, s, 2ꢂCH3), 1.64–1.73 (5H, m, C6H11),
1.95 (2H, m, C6H11), 3.68 (2H, s, CH2CO), 3.71–3.80 (1H,
m, C6H11-H1), 3.82 (3H, s, OCH3), 4.53 (2H, s, NCH2),
5.50 (1H, d, J¼8.1 Hz, NH), 6.94 (2H, d, J¼8.7 Hz,
NCH2Ph-H3,5), 7.21–7.31 (5H, m, COCH2Ph), 7.38 (2H,
d, J¼9.0 Hz, NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3):
d 24.21 (2ꢂCH3), 24.81 (C6H11-C3,5), 25.56 (C6H11-C4),
32.87 (C6H11-C2,6), 42.05 (CH2CO), 47.06 (CH2N), 48.25
(C6H11-C1), 55.18 (OCH3), 62.36 (Ca), 114.21 (NCH2Ph-
C2,6), 126.71 (COCH2Ph-C4), 127.08 (NCH2Ph-C3,5),
128.39 (COCH2Ph-C2,6), 128.62 (COCH2Ph-C3,5),
4. Experimental
4.1. Syntheses
Tri-distilled and de-ionised water was used in HPLC ex-
periments. Methanol and acetone were dried by standard
procedures. All other solvents and reagents were used as
obtained from commercial sources. TLC analyses were
carried out on 0.25 mm thick precoated silica plates (Merck
Fertigplatten Kieselgel 60 F254) and spots were visualised
under UV light or by exposure to vaporised iodine. Prepara-
tive chromatography was carried out on Merck Kieselgel

8190
F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
130.23 (NCH2Ph-C4), 134.86 (COCH2Ph-C1), 158.74
(NCH2Ph-C4), 171.74 (COCH2), 172.65 (CONH). Anal.
Calcd for C26H34N2O3: C, 73.90; H, 8.11; N, 6.63. Found:
C, 73.98; H, 8.08; N, 6.69.
32.94 (C6H11-C2,6), 42.06 (CH2CO), 46.80 (CH2N), 48.39
(C6H11-C1), 62.29 (Ca), 115.70 (d, JC–F¼21.3 Hz,
NCH2Ph-C3,5), 126.81 (COCH2Ph-C4), 127.56 (d, JC–F
¼
8.1 Hz, NCH2Ph-C2,6), 128.33 (COCH2Ph-C2,6), 128.32
(COCH2Ph-C3,5), 134.13 (d, JC–F¼3.2 Hz, NCH2Ph-C1),
134.70 (COCH2Ph-C1), 161.93 (d, JC–F¼245.6 Hz,
NCH2Ph-C4), 171.77 (COCH2), 173.80 (CONH). Anal.
Calcd for C25FH31N2O2: C, 73.14; H, 7.61; N, 6.82. Found:
C, 73.10; H, 7.67; N, 6.86.
4.1.1.2. N-Phenylacetyl-N-(4-methylbenzyl)-a,a-di-
methylglycine cyclohexylamide (1b). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 1b (3.68 g,
90%) as a white solid, mp 157.5–158.7 ꢀC. 1H NMR
(300 MHz, CDCl3): 1.03–1.21 (3H, m, C6H11), 1.29–1.39
(2H, m, C6H11), 1.42 (6H, s, 2ꢂCH3), 1.57–1.72 (3H, m,
C6H11), 1.94 (2H, m, C6H11), 2.36 (3H, s, Ph-CH3), 3.67
(2H, s, CH2CO), 3.70–3.81 (1H, m, C6H11-H1), 4.55 (2H,
s, NCH2), 5.52 (1H, d, J¼8.1 Hz, NH), 7.19–7.44 (9H, m,
COCH2Ph+NCH2Ph); 13C NMR (75 MHz, CDCl3):
d 20.93 (Ph-CH3), 24.22 (2ꢂCH3), 24.21 (2ꢂCH3), 24.80
(C6H11-C3,5), 25.56 (C6H11-C4), 32.85 (C6H11-C2,6),
42.06 (CH2CO), 47.45 (CH2N), 48.22 (C6H11-C1), 62.40
(Ca), 125.84 (NCH2Ph-C2,6), 126.71 (COCH2Ph-C4),
128.39 (COCH2Ph-C2,6), 128.62 (COCH2Ph-C3,5), 129.50
(NCH2Ph-C3,5), 134.82 (COCH2Ph-C1), 135.29 (NCH2Ph-
C1), 136.88 (NCH2Ph-C4), 171.77 (COCH2), 173.75
(CONH). Anal. Calcd for C26H34N2O2: C, 76.81; H, 8.43;
N, 6.89. Found: C, 76.98; H, 8.14; N, 7.03.
4.1.1.5.
N-Phenylacetyl-N-(4-chlorobenzyl)-a,a-di-
methylglycine cyclohexylamide (1e). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 1e (3.69 g,
86%) as a white solid, mp 140.4–141.5 ꢀC. 1H NMR
(300 MHz, CDCl3): 1.07–1.22 (3H, m, C6H11), 1.30–1.39
(2H, m, C6H11), 1.41 (6H, s, 2ꢂCH3), 1.59–1.74 (3H, m,
C6H11), 1.96–1.99 (2H, m, C6H11), 3.60 (2H, s, CH2CO),
3.75–3.80 (1H, m, C6H11-H1), 4.52 (2H, s, NCH2), 5.51
(1H, d, J¼7.8 Hz, NH), 7.17–7.29 (5H, m, COCH2-Ph),
7.35 (2H, d, J¼8.4 Hz, NCH2Ph-H3,5), 7.47 (2H, d,
J¼8.4 Hz, NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3):
d 24.14 (2ꢂCH3), 24.86 (C6H11-C3,5), 25.54 (C6H11-C4),
32.82 (C6H11-C2,6), 42.05 (CH2CO), 46.87 (CH2N),
48.39 (C6H11-C1), 62.26 (Ca), 126.82 (COCH2Ph-C4),
127.36 (NCH2Ph-C2,6), 128.30 (COCH2Ph-C2,6),
128.72 (COCH2Ph-C3,5), 128.96 (NCH2Ph-C3,5), 132.95
(NCH2Ph-C4), 134.60 (COCH2Ph-C1), 137.03 (NCH2Ph-
C1), 171.76 (COCH2), 173.73 (CONH). Anal. Calcd for
C25ClH31N2O2: C, 70.32; H, 7.32; N, 6.52. Found: C,
70.15; H, 7.29; N, 6.66.
4.1.1.3. N-Phenylacetyl-N-benzyl-a,a-dimethylglycine
cyclohexylamide (1c). The reaction was carried out on
a 0.015-molar scale and the crude product was purified by
column chromatography as described above and recrystal-
lised from ethyl acetate to yield 1c (4.06 g, 71%) as a white
1
solid, mp 161.1–162.0 ꢀC. H NMR (300 MHz, CDCl3):
1.04–1.22 (3H, m, C6H11), 1.29–1.42 (3H, m, C6H11), 1.43
(6H, s, 2ꢂCH3), 1.67–1.74 (2H, m, C6H11), 1.96 (2H, m,
C6H11), 3.67 (2H, s, CH2CO), 3.72–3.82 (1H, m, C6H11-
H1), 4.59 (2H, s, NCH2), 5.52 (1H, d, J¼7.8 Hz, NH),
7.21–7.34 (6H, m, COCH2Ph+NCH2Ph-H4), 7.41 (2H,
t, J¼7.5 Hz, NCH2Ph-H3,5), 7.48 (2H, d, J¼7.5 Hz,
NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3): d 24.22
(2ꢂCH3), 24.84 (C6H11-C3,5), 25.56 (C6H11-C4), 32.90
(C6H11-C2,6), 42.07 (CH2CO), 47.60 (CH2N), 48.29
(C6H11-C1), 62.39 (Ca), 125.91 (NCH2Ph-C2,6), 126.76
(COCH2Ph-C4), 127.23 (NCH2Ph-C4), 128.39 (COCH2Ph-
C2,6), 128.67 (COCH2Ph-C3,5), 128.86 (NCH2Ph-C3,5),
134.77 (COCH2Ph-C1), 138.40 (NCH2Ph-C1), 171.82
(COCH2), 173.78 (CONH). Anal. Calcd for C25H32N2O2:
C, 76.50; H, 8.22; N, 7.14. Found: C, 76.44; H, 8.11; N, 7.19.
4.1.1.6. N-Phenylacetyl-N-(4-trifluoromethoxybenzyl)-
a,a-dimethylglycine cyclohexylamide (1f). The reaction
was carried out on a 0.006-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 1f (2.61 g, 91%)
1
as a white solid, mp 143.2–144.0 ꢀC. H NMR (300 MHz,
CDCl3): 1.08–1.23 (3H, m, C6H11), 1.32–1.36 (2H, m,
C6H11), 1.43 (6H, s, 2ꢂCH3), 1.60–1.74 (3H, m, C6H11),
1.98 (2H, m, C6H11), 3.61 (2H, s, CH2CO), 3.74–3.84 (1H,
m, C6H11-H1), 4.56 (2H, s, NCH2), 5.52 (1H, d, J¼8.1 Hz,
NH), 7.17–7.32 (7H, m, COCH2Ph+NCH2Ph-H3,5), 7.59
(2H, d, J¼8.4 Hz, NCH2Ph-H2,6); 13C NMR (75 MHz,
CDCl3): d 24.14 (2ꢂCH3), 24.86 (C6H11-C3,5), 25.54
(C6H11-C4), 32.93 (C6H11-C2,6), 42.06 (CH2CO), 46.75
(CH2N), 48.42 (C6H11-C1), 62.26 (Ca), 120.37 (q, JC–F
¼
257.4 Hz, OCF3), 121.31 (NCH2Ph-C3,5), 126.82 (COCH2Ph-
C4), 127.35 (NCH2Ph-C2,6), 128.30 (COCH2Ph-C2,6),
128.72 (COCH2Ph-C3,5), 134.57 (COCH2Ph-C1), 137.25
(NCH2Ph-C1), 148.25 (q, JC–F¼1.8 Hz, NCH2Ph-C4),
171.76 (COCH2), 173.77 (CONH). Anal. Calcd for
C26F3H31N2O3: C, 65.53; H, 6.56; N, 5.88. Found: C,
65.49; H, 6.42; N, 5.91.
4.1.1.4.
N-Phenylacetyl-N-(4-fluorobenzyl)-a,a-di-
methylglycine cyclohexylamide (1d). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 1d (3.90 g,
95%) as a white solid, mp 162.5–163.5 ꢀC. 1H NMR
(300 MHz, CDCl3): 1.06–1.22 (3H, m, C6H11), 1.29–1.40
(2H, m, C6H11) 1.42 (6H, s, 2ꢂCH3), 1.58–1.74 (3H, m,
C6H11), 1.97 (2H, m, C6H11), 3.61 (2H, s, CH2CO), 3.71–
3.84 (1H, m, C6H11-H1), 4.53 (2H, s, NCH2), 5.51 (1H, d,
J¼8.1 Hz, NH), 7.07 (2H, t, J¼8.7 Hz, NCH2Ph-H3,5),
7.18–7.32 (5H, m, COCH2Ph), 7.49 (2H, dd, J¼5.4,
9.0 Hz, NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3):
d 24.17 (2ꢂCH3), 24.88 (C6H11-C3,5), 25.57 (C6H11-C4),
4.1.1.7. N-Phenylacetyl-N-(4-trifluoromethylbenzyl)-
a,a-dimethylglycine cyclohexylamide (1g). The reaction
was carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described
above and recrystallised from ethyl acetate to yield 1g
(4.51 g, 98%) as a white solid, mp 126.9–128.0 ꢀC. 1H
NMR (300 MHz, CDCl3): 1.09–1.23 (3H, m, C6H11),

F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
8191
1.31–1.40 (2H, m, C6H11) 1.43 (6H, s, 2ꢂCH3) 1.59–1.75
(3H, m, C6H11), 1.99 (2H, m, C6H11), 3.58 (2H, s, CH2CO),
3.73–3.85 (1H, m, C6H11-H1), 4.60 (2H, s, NCH2), 5.53
(1H, d, J¼8.1 Hz, NH), 7.17–7.32 (5H, m, COCH2Ph),
7.67 (4H, dt, J¼8.4, 14.4 Hz, NCH2Ph); 13C NMR
(75 MHz, CDCl3): d 24.16 (2ꢂCH3), 24.90 (C6H11-C3,5),
25.57 (C6H11-C4), 32.97 (C6H11-C2,6), 42.13 (CH2CO),
47.11 (CH2N), 48.48 (C6H11-C1), 62.29 (Ca), 124.02 (q,
JC–F¼272.1 Hz, CF3), 125.81 (q, JC–F¼3.7 Hz, NCH2Ph-
C3,5), 126.34 (NCH2Ph-C2,6), 126.90 (COCH2Ph-C4),
128.30 (COCH2Ph-C2,6), 128.79 (COCH2Ph-C3,5), 129.55
(q, JC–F¼32.5 Hz, NCH2Ph-C4), 134.49 (COCH2Ph-C1),
142.79 (NCH2Ph-C1), 171.80 (COCH2), 173.73 (CONH).
Anal. Calcd for C26F3H31N2O2: C, 67.81; H, 6.78; N, 6.08.
Found: C, 67.72; H, 6.84; N, 5.92.
(C6H11-C1), 55.17 (OCH3), 69.15 (Ca), 114.17 (NCH2Ph-
C3,5), 126.85, 126.88 (2ꢂCCH2Ph-C4+COCH2Ph-C4),
127.07 (NCH2Ph-C2,6), 128.11 (2ꢂCCH2Ph-C3,5), 128.54
(COCH2Ph-C3,5), 129.49 (COCH2Ph-C2,6), 130.97
(2ꢂCCH2Ph-C2,6+NCH2Ph-C1), 134.71 (COCH2Ph-C1),
135.33 (2ꢂCCH2Ph-C1), 158.47 (NCH2Ph-C4), 170.86
(CONH), 172.64 (COCH2). Anal. Calcd for C38H42N2O3:
C, 79.41; H, 7.37; N, 4.87. Found: C, 79.07; H, 6.94; N, 4.94.
4.1.1.10. N-Phenylacetyl-N-(4-methylbenzyl)-a,a-di-
benzylglycine cyclohexylamide (2b). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 2b (3.36 g,
60%) as a white solid, mp 201.8–202.9 ꢀC. 1H NMR
(300 MHz, CDCl3): 0.86–1.12 (3H, m, C6H11), 1.27–1.35
(2H, m, C6H11), 1.54–1.63 (5H, m, C6H11), 2.35 (3H, s,
CH3Ph), 2.94 (2H, d, J¼12.0 Hz, CCH2Ph), 3.35 (2H, br
d, J¼11.7 Hz, CCH2Ph), 3.52–3.56 (1H, m, C6H11-H1),
3.56 (2H, s, COCH2), 3.72 (2H, br s, NCH2), 5.07 (1H, d,
J¼7.5 Hz, NH), 7.16–7.26 (12H, m, NCH2Ph-H3,5+
2ꢂCCH2Ph), 7.33 (5H, m, COCH2Ph), 7.62 (2H, d,
J¼7.8 Hz, NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3):
d 20.99 (CH3Ph), 24.84 (C6H11-C3,5), 25.55 (C6H11-C4),
32.56 (C6H11-C2,6), 36.07 (2ꢂCCH2Ph), 42.08 (CH2CO),
47.60 (CH2N), 48.35 (C6H11-C1), 69.13 (Ca), 125.84
(NCH2Ph-C2,6), 126.85 (2ꢂCCH2Ph-C4+COCH2Ph-
C4), 128.08 (2ꢂCCH2Ph-C3,5), 128.52 (COCH2Ph-C3,5),
129.48 (COCH2Ph-C2,6+NCH2Ph-C3,5), 130.95 (2ꢂ
CCH2Ph-C2,6), 134.68 (COCH2Ph-C1), 135.33 (2ꢂCCH2Ph-
C1), 136.00 (NCH2Ph-C1), 136.37 (NCH2Ph-C4), 170.78
(CONH), 172.63 (COCH2). Anal. Calcd for C38H40N2O2:
C, 81.68; H, 7.58; N, 5.01. Found: C, 81.84; H, 7.41; N, 5.15.
4.1.1.8.
N-Phenylacetyl-N-(4-nitrobenzyl)-a,a-di-
methylglycine cyclohexylamide (1h). The reaction was
carried out on a 0.005-molar scale, starting with 4-nitro-
benzylamine hydrochloride (3 equiv, 5.658 g), which was
neutralised with triethylamine (2.9 equiv, 4.01 ml) in dry di-
ethyl ether (30 ml) at room temperature and under stirring
for 90 min. The reaction mixture was filtered and the filtrate
was concentrated under reduced pressure; the residue was
dissolved in freshly distilled acetone (25 ml) and used ac-
cording to the general procedure described above. The final
product was purified by column chromatography and recrys-
tallised from ethyl acetate to yield 1h (1.09 g, 50%) as a pale
yellow solid, mp 141.8–143.0 ꢀC. 1H NMR (300 MHz,
CDCl3): 1.10–1.24 (3H, m, C6H11), 1.31–1.40 (2H, m,
C6H11), 1.42 (6H, s, 2ꢂCH3), 1.60–1.75 (3H, m, C6H11),
1.99 (2H, m, C6H11), 3.55 (2H, s, CH2CO), 3.77–3.80 (1H,
m, C6H11-H1), 4.62 (2H, s, NCH2), 5.55 (1H, d, J¼7.8 Hz,
NH), 7.14 (2H, d, J¼6.3 Hz, COCH2Ph-H2,6), 7.22–7.28
(3H, m, COCH2Ph-H3,4,5), 7.80 (2H, d, J¼8.7 Hz,
NCH2Ph-H2,6), 8.22 (2H, d, J¼9.0 Hz, NCH2Ph-H3,5);
13C NMR (75 MHz, CDCl3): d 24.08 (2ꢂCH3), 24.88
(C6H11-C3,5), 25.52 (C6H11-C4), 32.94 (C6H11-C2,6),
42.13 (CH2CO), 46.95 (CH2N), 48.54 (C6H11-C1), 62.23
(Ca), 124.03 (NCH2Ph-C3,5), 126.91 (NCH2Ph-C2,6),
126.91 (COCH2Ph-C4), 128.20 (COCH2Ph-C2,6), 128.81
(COCH2Ph-C3,5), 134.22 (COCH2Ph-C1), 146.32
(NCH2Ph-C1), 147.17 (NCH2Ph-C4), 171.65 (COCH2),
173.68 (CONH). Anal. Calcd for C25H31N3O4: C, 68.63;
H, 7.14; N, 9.60. Found: C, 68.49; H, 7.07; N, 9.61.
4.1.1.11. N-Phenylacetyl-N-benzyl-a,a-dibenzylglycine
cyclohexylamide (2c). The reaction was carried out on
a 0.01-molar scale and the crude product was purified by col-
umn chromatography as described above and recrystallised
from ethyl acetate to yield 2c (2.40 g, 44%) as a white crys-
tals, mp 206.5–207.4 ꢀC. 1H NMR (300 MHz, CDCl3):
0.66–1.16 (3H, m, C6H11), 1.21–1.42 (2H, m, C6H11),
1.50–1.82 (5H, m, C6H11), 2.94 (2H, d, J¼11.7 Hz,
CCH2Ph), 3.34 (2H, br d, J¼10.5 Hz, CCH2Ph), 3.54
(3H, s, COCH2+C6H11-H1), 3.74 (2H, br s, NCH2), 5.05
(1H, d, J¼7.5 Hz, NH), 7.12–7.23 (11H, m, 2ꢂCCH2Ph+
NCH2Ph-H4), 7.35–7.42 (7H, m, NCH2Ph-H3,5+
COCH2Ph), 7.75 (2H, d, J¼9.0 Hz, NCH2Ph-H2,6); 13C
NMR (75 MHz, CDCl3): d 24.85 (C6H11-C3,5), 25.54
(C6H11-C4), 32.55 (C6H11-C2,6), 36.12 (2ꢂCCH2Ph),
42.09 (CH2CO), 47.73 (CH2N), 48.38 (C6H11-C1), 69.10
(Ca), 125.92 (NCH2Ph-C2,6), 126.83, 126.89 (2ꢂCCH2Ph-
C4+NCH2Ph-C4+COCH2Ph-C4), 128.12 (2ꢂCH2Ph-C3,5),
4.1.1.9. N-Phenylacetyl-N-(4-methoxybenzyl)-a,a-di-
benzylglycine cyclohexylamide (2a). The reaction was
carried out on a 0.05-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 2a (18.78 g,
82%) as a white solid, mp 129.0–130.1 ꢀC (lit.20 87.3–
1
87.9 ꢀC). H NMR (300 MHz, CDCl3): 0.84–1.07 (3H, m,
128.56
(NCH2Ph-C3,5),
128.79
(COCH2Ph-C3,5),
C6H11), 1.19–1.29 (2H, m, C6H11), 1.57–1.61 (5H, m,
C6H11), 2.93 (2H, d, J¼12.0 Hz, CCH2Ph), 3.34 (2H, br d,
J¼10.8 Hz, CCH2Ph), 3.48–3.52 (1H, m, C6H11-H1), 3.55
(2H, s, COCH2), 3.68 (2H, br s, NCH2), 3.80 (3H, s,
OCH3), 5.05 (1H, d, J¼7.5 Hz, NH), 6.93 (2H, d, J¼
8.7 Hz, NCH2Ph-H3,5), 7.12–7.25 (10H, m, 2ꢂCCH2Ph),
7.32–7.38 (5H, m, COCH2Ph), 7.65 (2H, d, J¼8.4 Hz,
NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3): d 24.86
(C6H11-C3,5), 25.56 (C6H11-C4), 32.57 (C6H11-C2,6),
36.05 (2ꢂCCH2Ph), 42.08 (CH2CO), 47.25 (CH2N), 48.39
129.46 (COCH2Ph-C2,6), 130.94 (2ꢂCH2Ph-C2,6), 134.58
(COCH2Ph-C1), 135.25 (2ꢂCCH2Ph-C1), 139.05 (NCH2Ph-
C1), 170.79 (CONH), 172.65 (COCH2). Anal. Calcd for
C37H40N2O2: C, 81.58; H, 7.40; N, 5.14. Found: C, 81.56;
H, 7.27; N, 5.27.
4.1.1.12. N-Phenylacetyl-N-(4-fluorobenzyl)-a,a-di-
benzylglycine cyclohexylamide (2d). The reaction was car-
ried out on a 0.01-molar scale and the crude product was
purified by column chromatography as described above

8192
F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
and recrystallised from ethyl acetate to yield 2d (4.80 g,
85%) as a white solid, mp 190.9–192.2 ꢀC. 1H NMR
(300 MHz, CDCl3): 0.85–1.11 (3H, m, C6H11), 1.22–1.35
(2H, m, C6H11), 1.53–1.62 (5H, m, C6H11), 2.91 (2H, d,
J¼12.0 Hz, CCH2Ph), 3.34 (2H, br d, J¼10.8 Hz, CCH2Ph),
3.51 (2H, s, COCH2), 3.49–3.58 (1H, m, C6H11-H1), 3.72
(2H, br s, NCH2), 5.04 (1H, d, J¼7.5 Hz, NH), 7.08
(2H, t, J¼8.7 Hz, NCH2Ph-H3,5), 7.13–7.29 (10H, m,
2ꢂCCH2Ph), 7.33–7.37 (5H, m, COCH2Ph), 7.75 (2H, dd,
J¼5.4, 8.4 Hz, NCH2Ph-H2,6); 13C NMR (75 MHz,
CDCl3): d 24.81 (C6H11-C3,5), 25.52 (C6H11-C4), 32.52
(C6H11-C2,6), 36.00 (2ꢂCCH2Ph), 42.07 (CH2CO), 47.12
36.09 (2ꢂCCH2Ph), 42.07 (CH2CO), 47.16 (CH2N), 48.49
(C6H11-C1), 69.14 (Ca), 120.41 (q, JC–F¼257.1 Hz, OCF3),
121.21 (NCH2Ph-C3,5), 126.98, 127.01 (2ꢂCCH2Ph-
C4+COCH2Ph-C4), 128.44 (NCH2Ph-C2,6), 128.19 (2ꢂ
CCH2Ph-C3,5), 128.62 (COCH2Ph-C3,5), 129.40 (COCH2Ph-
C2,6), 130.92 (2ꢂCCH2Ph-C2,6), 134.33 (COCH2Ph-C1),
135.07 (2ꢂCCH2Ph-C1), 137.79 (NCH2Ph-C1), 148.11
(q, JC–F¼1.8 Hz, NCH2Ph-C4), 170.86 (CONH), 172.50
(COCH2). Anal. Calcd for C38F3H39N2O3: C, 72.59; H, 6.25;
N, 4.46. Found: C, 72.72; H, 5.89; N, 4.53.
4.1.1.15. N-Phenylacetyl-N-(4-trifluoromethylbenzyl)-
a,a-dibenzylglycine cyclohexylamide (2g). The reaction
was carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 2g (4.79 g,
78%) as a white solid, mp 213.5–214.5 ꢀC. 1H NMR
(300 MHz, CDCl3): 0.87–1.12 (3H, m, C6H11), 1.24–1.36
(2H, m, C6H11), 1.59 (5H, m, C6H11), 2.89 (2H, d,
J¼11.7 Hz, CCH2Ph), 3.34 (2H, br s, CCH2Ph), 3.50 (2H,
s, COCH2), 3.52–3.60 (1H, m, C6H11-H1), 3.80 (2H, br s,
NCH2), 5.05 (1H, d, J¼7.5 Hz, NH), 7.14–7.30 (10H, m,
2ꢂCCCH2Ph), 7.31–7.38 (5H, m, COCH2Ph), 7.65 (2H,
d, J¼8.1 Hz, NCH2Ph-H3,5), 7.92 (2H, d, J¼8.1 Hz,
NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3): d 24.81
(C6H11-C3,5), 25.48 (C6H11-C4), 32.49 (C6H11-C2,6),
36.01 (2ꢂCCH2Ph), 42.15 (CH2CO), 47.45 (CH2N), 48.46
(C6H11-C1), 69.11 (Ca), 124.07 (q, JC–F¼272.0 Hz, CF3),
125.68 (q, JC–F¼3.8 Hz, NCH2Ph-C3,5), 126.39 (NCH2Ph-
C2,6), 126.98, 127.01 (2ꢂCCH2Ph-C4+COCH2Ph-
C4), 128.17 (2ꢂCCH2Ph-C3,5), 128.61 (COCH2Ph-C3,5),
129.33 (COCH2Ph-C2,6), 129.20 (q, JC–F¼32.5 Hz,
NCH2Ph-C4), 130.87 (2ꢂCCH2Ph-C2,6), 134.17 (COCH2Ph-
C1), 134.96 (2ꢂCCH2Ph-C1), 143.32 (NCH2Ph-C1), 170.79
(CONH), 172.41 (COCH2). Anal. Calcd for C38F3H39N2O2:
C, 74.49; H, 6.42; N, 4.57. Found: C, 74.46; H, 6.07; N, 4.63.
(CH2N), 48.23 (C6H11-C1), 69.13 (Ca), 115.58 (d, JC–F
¼
21.3 Hz, NCH2Ph-C3,5), 126.90, 126.94 (2ꢂCCH2Ph-C4+
COCH2Ph-C4), 127.58 (d, JC–F¼7.8 Hz, NCH2Ph-C2,6),
128.14 (2ꢂCCH2Ph-C3,5), 128.56 (COCH2Ph-C3,5),
129.40 (COCH2Ph-C2,6), 130.91 (2ꢂCCH2Ph-C2,6),
134.47 (COCH2Ph-C1), 134.70 (d, JC–F¼2.9 Hz, NCH2Ph-
C1), 135.15 (2ꢂCCH2Ph-C1), 161.79 (d, JC–F¼245.0 Hz,
NCH2Ph-C4), 170.84 (CONH), 172.51 (COCH2). Anal.
Calcd for C37FH39N2O2: C, 78.97; H, 6.99; N, 4.98. Found:
C, 79.11; H, 6.68; N, 4.94.
4.1.1.13. N-Phenylacetyl-N-(4-chlorobenzyl)-a,a-di-
benzylglycine cyclohexylamide (2e). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 2e (4.37 g,
76%) as a beige solid, mp 180.6–181.5 ꢀC. 1H NMR
(300 MHz, CDCl3): 0.84–1.07 (3H, m, C6H11), 1.20–1.30
(2H, m, C6H11), 1.53–1.62 (5H, m, C6H11), 2.90 (2H, d,
J¼12.0 Hz, CCH2Ph), 3.33 (2H, br d, J¼10.8 Hz, CCH2Ph),
3.48–3.55 (1H, m, C6H11-H1), 3.50 (2H, s, COCH2), 3.69
(2H, br s, NCH2), 5.02 (1H, d, J¼7.5 Hz, NH), 7.13–7.26
(10H, m, 2ꢂCCH2Ph), 7.30–7.37 (7H, m, COCH2Ph+
NCH2Ph-H3,5), 7.72 (2H, d, J¼8.4 Hz, NCH2Ph-H2,6);
13C NMR (75 MHz, CDCl3): d 24.83 (C6H11-C3,5), 25.52
(C6H11-C4), 32.53 (C6H11-C2,6), 35.97 (2ꢂCCH2Ph),
42.11 (CH2CO), 47.19 (CH2N), 48.44 (C6H11-C1), 69.11
(Ca), 126.95, 127.00 (2ꢂCCH2Ph-C4+COCH2Ph-C4),
127.45 (NCH2Ph-C2,6), 128.17 (2ꢂCCH2Ph-C3,5),
128.61 (NCH2Ph-C3,5), 128.91 (COCH2Ph-C3,5), 129.39
(COCH2Ph-C2,6), 130.91 (2ꢂCCH2Ph-C2,6), 132.66
(NCH2Ph-C4), 134.38 (COCH2Ph-C1), 135.08 (2ꢂ
CCH2Ph-C1), 137.66 (NCH2Ph-C1), 170.81 (CONH),
172.49 (COCH2). Anal. Calcd for C37ClH39N2O2: C, 76.73;
H, 6.79; N, 4.84. Found: C, 76.73; H, 6.73; N, 4.90.
4.1.1.16.
N-Phenylacetyl-N-(4-nitrobenzyl)-a,a-di-
benzylglycine cyclohexylamide (2h). The reaction was
carried out on a 0.003-molar scale, starting with 4-nitro-
benzylamine hydrochloride (1.3 equiv, 2.45 g), which was
neutralised with triethylamine (1.2 equiv, 1.66 ml) in dry di-
ethyl ether (20 ml) at room temperature and under stirring
for 90 min. The reaction mixture was filtered and the filtrate
was concentrated under reduced pressure; the residue was
dissolved in dry MeOH (5 ml) and used according to the
general procedure described above. The final product was
purified by column chromatography and recrystallised from
ethyl acetate to yield 2h (0.84 g, 47%) as a pale yellow solid,
4.1.1.14. N-Phenylacetyl-N-(4-trifluoromethoxybenzyl)-
a,a-dibenzylglycine cyclohexylamide (2f). The reaction
was carried out on a 0.0056-molar scale and the crude prod-
uct was purified by column chromatography as described
above and recrystallised from ethyl acetate to yield 2f
(2.23 g, 63%) as a white solid, mp 169.0–170.0 ꢀC. 1H
NMR (300 MHz, CDCl3): 0.85–1.11 (3H, m, C6H11),
1.22–1.35 (2H, m, C6H11), 1.54–1.63 (5H, m, C6H11), 2.91
(2H, d, J¼11.7 Hz, CCH2Ph), 3.35 (2H, br d, J¼10.8 Hz,
CCH2Ph), 3.48–3.59 (1H, m, C6H11-H1), 3.51 (2H, s,
COCH2), 3.75 (2H, br s, NCH2), 5.04 (1H, d, J¼7.5 Hz,
NH), 7.14–7.27 (12H, m, 2ꢂCCH2Ph+NCH2Ph-H3,5),
7.31–7.38 (5H, m, COCH2Ph), 7.81 (2H, d, J¼9.0 Hz,
NCH2Ph-H2,6); 13C NMR (75 MHz, CDCl3): d 24.84
(C6H11-C3,5), 25.53 (C6H11-C4), 32.53 (C6H11-C2,6),
1
mp 211.8–212.8 ꢀC. H NMR (300 MHz, CDCl3): 0.88–
1.11 (3H, m, C6H11), 1.24–1.35 (2H, m, C6H11), 1.53–1.63
(5H, m, C6H11), 2.87 (2H, d, J¼11.7 Hz, CCH2Ph), 3.34
(2H, br s, CCH2Ph), 3.48 (2H, s, COCH2), 3.52–3.58 (1H,
m, C6H11-H1), 3.82 (2H, br s, NCH2), 5.04 (1H, d,
J¼7.8 Hz, NH), 7.17–7.25 (10H, m, 2ꢂCCH2Ph), 7.30–
7.38 (5H, m, COCH2Ph), 8.00 (2H, d, J¼8.1 Hz, NCH2Ph-
H2,6), 8.24 (2H, d, J¼8.7 Hz, NCH2Ph-H3,5); 13C NMR
(75 MHz, CDCl3): d 24.80 (C6H11-C3,5), 25.49 (C6H11-C4),
32.48 (C6H11-C2,6), 35.93 (2ꢂCCH2Ph), 42.22 (CH2CO),
47.46 (CH2N), 48.54 (C6H11-C1), 69.15(Ca), 124.01
(NCH2Ph-C3,5), 127.02, 127.12 (2ꢂCCH2Ph-C4+NCH2Ph-
C2,6+COCH2Ph-C4), 128.25 (2ꢂCCH2Ph-C3,5), 128.70
(COCH2Ph-C3,5), 129.28 (COCH2Ph-C2,6), 130.85

F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
8193
(2ꢂCCH2Ph-C2,6), 133.91 (COCH2Ph-C1), 134.80
(2ꢂCCH2Ph-C1), 146.85 (NCH2Ph-C4), 147.06 (NCH2Ph-
C1), 170.78 (CONH), 172.27 (COCH2). Anal. Calcd for
C37H39N3O4: C, 75.36; H, 6.67; N, 7.13. Found: C, 75.05;
H, 6.60; N, 6.92.
(C6H11-C2,6), 42.83 (CH2), 48.54 (C6H11-C1), 62.54 (Ca),
126.54 (CH2Ph-C4), 128.28 (CH2Ph-C3,5), 128.76
(CH2Ph-C2,6), 129.17 (NPh-C3,5), 131.87 (NPh-C2,6),
134.42 (NPh-C4), 134.93 (CH2Ph-C1), 138.35 (NPh-C1),
170.74 (CON), 173.50 (CONH). Anal. Calcd for
C24ClH29N2O2: C, 69.80; H, 7.08; N, 6.75. Found: C,
69.58; H, 7.07; N, 6.81.
4.1.1.17. N-Phenylacetyl-N-(4-methoxyphenyl)-a,a-
dimethylglycine cyclohexylamide (3a). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from diethyl ether to yield 3a (3.77 g,
4.1.1.20.
N-Phenylacetyl-N-(4-cyanofenyl)-a,a-di-
methylglycine cyclohexylamide (3d). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 3d (0.96 g,
1
92%) as a white crystals, mp 105.7–106.8 ꢀC. H NMR
(300 MHz, CDCl3): 1.06–1.21 (3H, m, C6H11), 1.31 (6H,
s, 2ꢂCH3), 1.37–1.39 (2H, m, C6H11), 1.58–1.72 (3H, m,
C6H11), 1.93 (2H, m, C6H11), 3.33 (2H, s, CH2), 3.69–3.81
(1H, m, C6H11-H1), 3.84 (3H, s, OCH3), 5.64 (1H, d,
J¼8.1 Hz, NH), 6.86 (2H, d, J¼9.0 Hz, NPh-H3,5), 6.99
(2H, m, CH2Ph-H2,6), 7.06 (2H, d, J¼8.7 Hz, NPh-H2,6),
7.20 (3H, m, CH2Ph-H3,4,5); 13C NMR (75 MHz, CDCl3):
d 24.75 (C6H11-C3,5), 25.29 (2ꢂCH3), 25.51 (C6H11-C4),
32.75 (C6H11-C2,6), 42.59 (CH2), 48.30 (C6H11-C1),
55.33 (OCH3), 62.61 (Ca), 113.99 (NPh-C3,5), 126.35
(CH2Ph-C4), 128.11 (CH2Ph-C3,5), 128.83 (CH2Ph-C2,6),
131.27 (NPh-C2,6), 132.33 (NPh-C1), 135.23 (CH2Ph-
C1), 159.21 (NPh-C4), 171.23 (CON), 173.71 (CONH).
Anal. Calcd for C25H32N2O3: C, 73.50; H, 7.90; N, 6.86.
Found: C, 73.24; H, 7.91; N, 6.97.
1
24%) as a white crystals, mp 166.0–167.1 ꢀC. H NMR
(300 MHz, CDCl3): 1.08–1.21 (3H, m, C6H11), 1.32 (6H,
s, 2ꢂCH3), 1.34–1.42 (2H, m, C6H11), 1.59–1.74 (3H, m,
C6H11), 1.96 (2H, m, C6H11), 3.29 (2H, s, CH2), 3.70–3.82
(1H, m, C6H11-H1), 5.65 (1H, d, J¼7.8 Hz, NH), 6.90
(2H, m, CH2Ph-H2,6), 7.16–7.20 (3H, m, CH2Ph-H3,4,5),
7.34 (2H, d, J¼8.1 Hz, NPh-H2,6), 7.62 (2H, d, J¼8.4 Hz,
NPh-H3,5); 13C NMR (75 MHz, CDCl3): d 24.79 (C6H11-
C3,5), 25.49 (2ꢂCH3), 25.54 (C6H11-C4), 32.81 (C6H11-
C2,6), 43.09 (CH2), 48.68 (C6H11-C1), 62.60 (Ca), 112.46
(NPh-C4), 117.82 (NPh-CN), 126.68 (CH2Ph-C4), 128.37
(CH2Ph-C3,5), 128.55 (CH2Ph-C2,6), 131.77 (NPh-C2,6),
132.76 (NPh-C3,5), 134.46 (CH2Ph-C1), 143.99 (NPh-
C1), 170.15 (CON), 173.22 (CONH). Anal. Calcd for
C25H29N3O2: C, 74.41; H, 7.24; N, 10.41. Found: C,
74.26; H, 7.22; N, 10.38.
4.1.1.18. N-Phenylacetyl-N-phenyl-a,a-dimethylgly-
cine cyclohexylamide (3b). The reaction was carried out
on a 0.02-molar scale and the crude product was purified
by column chromatography as described above and recrys-
tallised from diethyl ether to yield 3b (6.53 g, 86%) as
4.1.1.21.
N-Phenylacetyl-N-(4-nitrophenyl)-a,a-di-
methylglycine cyclohexylamide (3e). The reaction was
carried out on a 0.04-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from diethyl ether to yield 3e (1.47 g,
1
a white crystals, mp 127.2–128.3 ꢀC. H NMR (300 MHz,
CDCl3): 1.03–1.23 (3H, m, C6H11), 1.34 (6H, s, 2ꢂCH3),
1.35–1.40 (2H, m, C6H11), 1.66–1.71 (3H, m, C6H11), 1.94
(2H, m, C6H11), 3.33 (2H, s, CH2), 3.70–3.83 (1H, m,
C6H11-H1), 5.66 (1H, d, J¼7.5 Hz, NH), 6.98 (2H, m,
CH2Ph-H2,6), 7.16–7.22 (5H, m, NPh-H2,6+CH2Ph-
H3,4,5), 7.39 (3H, m, NPh-H3,4,5); 13C NMR (75 MHz,
CDCl3): d 24.78 (C6H11-C3,5), 25.37 (2ꢂCH3), 25.55
(C6H11-C4), 32.79 (C6H11-C2,6), 42.69 (CH2), 48.36
(C6H11-C1), 62.56 (Ca), 126.41 (CH2Ph-C4), 128.16
(CH2Ph-C3,5), 128.46 (NPh-C4), 128.84 (CH2Ph-C2,6),
129.03 (NPh-C3,5), 130.43 (NPh-C2,6), 135.16 (CH2Ph-
C1), 139.67 (NPh-C1), 170.83 (CON), 173.62 (CONH).
Anal. Calcd for C24H30N2O2: C, 76.16; H, 7.99; N, 7.40.
Found: C, 76.17; H, 7.90; N, 7.51.
1
9%) as a yellow crystals, mp 100.9–101.9 ꢀC. H NMR
(300 MHz, CDCl3): 1.11–1.24 (3H, m, C6H11), 1.36 (6H,
s, 2ꢂCH3), 1.42–1.46 (2H, m, C6H11), 1.58–1.76 (3H, m,
C6H11), 2.00 (2H, m, C6H11), 3.33 (2H, s, CH2), 3.74–3.85
(1H, m, C6H11-H1), 5.64 (1H, d, J¼7.8 Hz, NH), 6.93
(2H, m, CH2Ph-H2,6), 7.20–7.22 (3H, m, CH2Ph-H3,4,5),
7.41 (2H, d, J¼9.0 Hz, NPh-H2,6), 8.20 (2H, d, J¼9.0 Hz,
NPh-H3,5); 13C NMR (75 MHz, CDCl3): d 24.86 (C6H11-
C3,5), 25.56 (C6H11-C4), 25.64 (2ꢂCH3), 32.90 (C6H11-
C2,6), 43.19 (CH2), 48.79 (C6H11-C1), 62.68 (Ca), 124.14
(NPh-C3,5), 126.80 (CH2Ph-C4), 128.47 (CH2Ph-C3,5),
128.61 (CH2Ph-C2,6), 131.93 (NPh-C2,6), 134.45
(CH2Ph-C1), 145.82 (NPh-C4), 147.41 (NPh-C1), 170.14
(CON), 173.27 (CONH). Anal. Calcd for C24H29N3O4: C,
68.06; H, 6.90; N, 9.92. Found: C, 67.98; H, 6.88; N, 9.85.
4.1.1.19. N-Phenylacetyl-N-(4-chlorophenyl)-a,a-di-
methylglycine cyclohexylamide (3c). The reaction was
carried out on a 0.01-molar scale and the crude product
was purified by column chromatography as described above
and recrystallised from ethyl acetate to yield 3c (2.93 g,
4.1.2. General method for the preparative acidolysis of
Ugi–Passerini adducts (4, 5 and 6). Compounds 1a–1h,
2a–2h and 3a–3d (0.20 or 0.25 g, depending on the solubil-
ity) were dissolved in 25 ml of 5% TFA in dry acetonitrile
and the solutions were kept at room temperature until TLC
(dichloromethane/MeOH, 25:1) showed no more starting
material (2–168 h). The solvent was concentrated under
reduced pressure at 30 ꢀC and the pH of the residue was
adjusted to 3 by treatment with 2 M aqueous NaOH. The
mixture was stirred overnight and the resulting suspension
was extracted into chloroform (3ꢂ15 ml). The combined
organic layers were washed with water (2ꢂ20 ml) and dried
1
71%) as a white crystals, mp 118.9–119.7 ꢀC. H NMR
(300 MHz, CDCl3): 1.05–1.22 (3H, m, C6H11), 1.31 (6H,
s, 2ꢂCH3), 1.34–1.43 (2H, m, C6H11), 1.57–1.73 (3H, m,
C6H11), 1.95 (2H, m, C6H11), 3.32 (2H, s, CH2), 3.71–3.80
(1H, m, C6H11-H1), 5.63 (1H, d, J¼7.8 Hz, NH), 6.96
(2H, m, CH2Ph-H2,6), 7.11 (2H, d, J¼8.7 Hz, NPh-H2,6),
7.18–7.21 (3H, m, CH2Ph-H3,4,5), 7.31 (2H, d, J¼8.4 Hz,
NPh-H3,5); 13C NMR (75 MHz, CDCl3):
d 24.82
(C6H11-C3,5), 25.48 (2ꢂCH3), 25.56 (C6H11-C4), 32.85

8194
F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
over anhydrous MgSO4; this was filtered off and the filtrate
was concentrated under reduced pressure. The residue thus
obtained was purified by column chromatography and/or re-
crystallisation; in the former case the desired fraction was
evaporated to dryness to give the corresponding compound
(4, 5 and 6).
4.1.2.4.
N-Phenylacetyl-N-(4-fluorobenzyl)-a,a-di-
methylglycine (4d). The reaction was carried out with
compound 1d (0.25 g) and the product was purified by
recrystallisation from diethyl ether/petroleum ether (40–
60 ꢀC) to yield 4d (191 mg, 97%) as white crystals, mp
1
191.4–192.2 ꢀC. H NMR (300 MHz, CDCl3): 1.45 (6H, s,
2ꢂCH3), 3.67 (2H, s, CH2CO), 4.56 (2H, s, NCH2), 7.10
(2H, t, J¼8.7 Hz, NCH2Ph-H3,5), 7.18–7.33 (5H, m,
COCH2Ph), 7.41 (2H, dd, J¼5.4, 8.4 Hz, NCH2Ph-H2,6),
9.43 (1H, br s, OH); 13C NMR (75 MHz, CDCl3): d 23.47
(2ꢂCH3), 41.41 (CH2CO), 46.68 (CH2N), 61.47 (Ca),
115.81 (d, JC–F¼21.6 Hz, NCH2Ph-C3,5), 126.90
(COCH2Ph-C4), 127.41 (d, JC–F¼7.8 Hz, NCH2Ph-C2,6),
128.52 (COCH2Ph-C2,6), 128.72 (COCH2Ph-C3,5),
133.59 (d, JC–F¼3.2 Hz, NCH2Ph-C1), 134.29 (COCH2Ph-
C1), 162.01 (d, JC–F¼245.6 Hz, NCH2Ph-C4), 172.15
(COCH2), 178.83 (COOH). Anal. Calcd for C19FH20NO3:
C, 69.29; H, 6.12; N, 4.25. Found: C, 69.14; H, 6.10; N,
4.03. Compound 4d was also obtained, in 66% yield, when
0.25 g of 1d was submitted to the forcing reaction conditions
described below for the preparation of 6e.
4.1.2.1. N-Phenylacetyl-N-(4-methoxybenzyl)-a,a-di-
methylglycine (4a). The reaction was carried out with com-
pound 1a (0.20 g) and the product was purified by
recrystallisation from ethyl acetate to yield 4a (140 mg,
84%) as a white solid, mp 201.1–202.1 ꢀC (lit.20 168.6–
1
169.2 ꢀC). H NMR (300 MHz, DMSO-d6): 1.27 (6H, s,
2ꢂCH3), 3.57 (2H, s, CH2CO), 3.76 (3H, s, OCH3), 4.59
(2H, s, NCH2), 6.94 (2H, d, J¼8.7 Hz, NCH2Ph-H3,5),
7.11–14 (2H, m, COCH2Ph-H2,6), 7.17–7.29 (3H, m,
COCH2Ph-H3,4,5), 7.36 (2H, d, J¼8.7 Hz, NCH2Ph-H2,6),
12.02 (1H, br s, OH); 13C NMR (75 MHz, DMSO-d6): d 23.33
(2ꢂCH3), 40.34 (CH2CO), 46.12 (CH2N), 55.06 (OCH3),
60.69 (Ca), 113.99 (NCH2Ph-C3,5), 126.40 (COCH2Ph-
C4), 127.03 (NCH2Ph-C2,6), 128.27 (COCH2Ph-C3,5),
128.92 (COCH2Ph-C2,6), 130.92 (NCH2Ph-C1), 135.58
(COCH2Ph-C1), 158.20 (NCH2Ph-C4), 170.78 (COCH2),
175.20 (COOH). Anal. Calcd for C20H23NO4: C, 70.36; H,
6.79; N, 4.10. Found: C, 69.87; H, 6.82; N, 4.21.
4.1.2.5.
N-Phenylacetyl-N-(4-chlorobenzyl)-a,a-di-
methylglycine (4e). The reaction was carried out with com-
pound 1e (0.21 g) and the product was purified by column
chromatography (dichloromethane/MeOH, 25:1) followed
by recrystallisation from diethyl ether/petroleum ether
(40–60 ꢀC) to yield 4e (154 mg, 89%) as a white solid, mp
4.1.2.2. N-Phenylacetyl-N-(4-methylbenzyl)-a,a-di-
methylglycine (4b). The reaction was carried out with com-
pound 1b (0.21 g) and the product was purified by column
chromatography (dichloromethane/MeOH, 25:1) followed
by recrystallisation from ethyl acetate to yield 4b (152 mg,
89%) as a white solid, mp 160.7–161.7 ꢀC. 1H NMR
(300 MHz, CDCl3): 1.46 (6H, s, 2ꢂCH3), 2.39 (3H, s, Ph-
CH3), 3.70 (2H, s, CH2CO), 4.57 (2H, s, NCH2), 7.21–7.35
(9H, m, COCH2Ph+NCH2Ph), 9.81 (1H, br s, OH); 13C
NMR (75 MHz, CDCl3): d 21.01 (Ph-CH3), 23.50 (2ꢂCH3),
41.36(CH2CO), 47.12(CH2N),61.40(Ca), 125.76(NCH2Ph-
C2,6), 126.76 (COCH2Ph-C4), 128.57 (COCH2Ph-C2,6),
128.63 (COCH2Ph-C3,5), 129.56 (NCH2Ph-C3,5), 134.54
(COCH2Ph-C1), 134.86 (NCH2Ph-C1), 136.92 (NCH2Ph-
C4), 172.11 (COCH2), 179.05 (COOH). Anal. Calcd for
C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.64;
H, 7.01; N, 4.41. Compound 4b was also obtained, in 79%
yield, when 0.25 g of 1b was submitted to the forcing reac-
tion conditions described below for the preparation of 6e.
1
168.8–169.8 ꢀC. H NMR (300 MHz, CDCl3): 1.44 (6H, s,
2ꢂCH3), 3.65 (2H, s, CH2CO), 4.56 (2H, s, NCH2), 7.18–
7.38 (9H, m, COCH2-Ph+NCH2Ph-H2,3,5,6), 10.01 (1H,
br s, OH); 13C NMR (75 MHz, CDCl3): d 23.43 (2ꢂCH3),
41.40 (CH2CO), 46.72 (CH2N), 61.45 (Ca), 126.90
(COCH2Ph-C4), 127.21 (NCH2Ph-C2,6), 128.47 (COCH2Ph-
C2,6), 128.71 (COCH2Ph-C3,5), 129.05 (NCH2Ph-C3,5),
133.08 (NCH2Ph-C4), 134.18 (COCH2Ph-C1), 136.49
(NCH2Ph-C1), 172.11 (COCH2), 178.81 (COOH). Anal.
Calcd for C19ClH20NO3: C, 65.99; H, 5.83; N, 4.05. Found:
C, 65.68; H, 5.93; N, 4.01.
4.1.2.6. N-Phenylacetyl-N-(4-trifluoromethoxybenzyl)-
a,a-dimethylglycine (4f). The reaction was carried out
with compound 1f (0.25 g) and the product was purified by
recrystallisation from diethyl ether/petroleum ether (40–
60 ꢀC) to yield 4f (153 mg, 90%) as a white solid, mp
1
149.9–150.7 ꢀC. H NMR (300 MHz, CDCl3): 1.45 (6H,
4.1.2.3.
N-Phenylacetyl-N-benzyl-a,a-dimethylgly-
s, 2ꢂCH3), 3.66 (2H, s, CH2CO), 4.59 (2H, s, NCH2),
7.19–7.32 (7H, m, COCH2Ph+NCH2Ph-H3,5), 7.49 (2H,
d, J¼8.4 Hz, NCH2Ph-H2,6), 9.32 (1H, br s, OH); 13C
NMR (75 MHz, CDCl3): d 23.47 (2ꢂCH3), 41.47 (CH2CO),
46.69 (CH2N), 61.49 (Ca), 120.4 (q, JC–F¼257.1 Hz,
OCF3), 121.45 (NCH2Ph-C3,5), 126.96 (COCH2Ph-C4),
127.21 (NCH2Ph-C2,6), 128.50 (COCH2Ph-C2,6), 128.76
cine (4c). The reaction was carried out with compound 1c
(0.20 g) and the product was purified by column chromato-
graphy (dichloromethane/MeOH, 25:1) followed by recrys-
tallisation from ethyl acetate to yield 4c (121 mg, 76%) as
a white solid, mp 196.9–197.9 ꢀC. 1H NMR (300 MHz,
CDCl3): 1.47 (6H, s, 2ꢂCH3), 3.69 (2H, s, CH2CO), 4.61
(2H, s, NCH2), 7.21–7.31 (6H, m, COCH2Ph+NCH2Ph-
H4), 7.41–7.45 (4H, m, NCH2Ph-H2,3,5,6), 9.41 (1H, br s,
OH); 13C NMR (75 MHz, CDCl3): d 23.50 (2ꢂCH3),
41.36 (CH2CO), 47.31 (CH2N), 61.44 (Ca), 125.79
(NCH2Ph-C2,6), 126.78 (COCH2Ph-C4), 127.26 (NCH2Ph-
C4), 128.56 (COCH2Ph-C2,6), 128.63 (COCH2Ph-C3,5),
128.88 (NCH2Ph-C3,5), 134.44 (COCH2Ph-C1), 137.93
(NCH2Ph-C1), 172.16 (COCH2), 178.99 (COOH). Anal.
Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found:
C, 73.35; H, 6.59; N, 4.61.
(COCH2Ph-C3,5),
134.15
(COCH2Ph-C1), 136.71
(NCH2Ph-C1), 148.39 (q, JC–F¼1.9 Hz, NCH2Ph-C4),
172.17 (COCH2), 178.80 (COOH). Anal. Calcd for
C20F3H20NO4: C, 60.76; H, 5.10; N, 3.54. Found: C,
60.67; H, 5.36; N, 3.28.
4.1.2.7. N-Phenylacetyl-N-(4-trifluoromethylbenzyl)-
a,a-dimethylglycine (4g). The reaction was carried out
with compound 1g (0.25 g) and the product was purified
by recrystallisation from ethyl acetate to yield 4g (161 mg,

F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
8195
92%) as white crystals, mp 180.9–181.8 ꢀC. 1H NMR
(300 MHz, CDCl3): 1.46 (6H, s, 2ꢂCH3), 3.65 (2H, s,
CH2CO), 4.64 (2H, s, NCH2), 7.18 (2H, m, COCH2-H2,6),
7.24–7.33 (3H, m, COCH2Ph-H3,4,5), 7.60 (2H, d,
J¼8.4 Hz, NCH2Ph-H2,6), 7.67 (2H, d, J¼8.4 Hz,
NCH2Ph-H3,5), 9.00 (1H, br s, OH); 13C NMR (75 MHz,
CDCl3): d 23.48 (2ꢂCH3), 41.54 (CH2CO), 47.03 (CH2N),
61.54 (Ca), 124.03 (q, JC–F¼274.0 Hz, CF3), 125.93 (q,
JC–F¼3.7 Hz, NCH2Ph-C3,5), 126.20 (NCH2Ph-C2,6),
127.02 (COCH2Ph-C4), 128.48 (COCH2Ph-C2,6), 128.80
(COCH2Ph-C3,5), 129.75 (q, JC–F¼32.5 Hz, NCH2Ph-C4),
134.06 (COCH2Ph-C1), 142.25 (NCH2Ph-C1), 172.17
(COCH2), 178.67 (COOH). Anal. Calcd for C20F3H20NO3:
C, 63.32; H, 5.31; N, 3.69. Found: C, 63.38; H, 5.04;
N, 3.62.
60 ꢀC) to yield 5b (200 mg, 93%) as a white solid, mp
1
212.5–213.7 ꢀC. H NMR (300 MHz, CDCl3): 2.34 (3H, s,
CH3Ph), 3.02 (2H, d, J¼13.2 Hz, CCH2Ph), 3.43 (2H, br
d, J¼12.9 Hz, CCH2Ph), 3.61 (2H, s, COCH2), 3.82 (2H,
br s, NCH2), 7.17–7.30 (12H, m, 2ꢂCCH2Ph+NCH2Ph-
H3,5), 7.33–7.44 (7H, m, COCH2Ph+NCH2Ph-H2,6), 8.45
(1H, br s, OH); 13C NMR (75 MHz, CDCl3): d 20.98
(CH3Ph), 36.13 (2ꢂCCH2Ph), 41.31 (CH2CO), 48.11
(CH2N), 68.88 (Ca), 125.57 (NCH2Ph-C2,6), 127.01
(COCH2Ph-C4), 127.06 (2ꢂCCH2Ph-C4), 128.40 (2ꢂ
CCH2Ph-C3,5), 128.58 (COCH2Ph-C3,5), 129.62 (NCH2Ph-
C3,5), 129.72 (COCH2Ph-C2,6), 130.87 (2ꢂCCH2Ph-C2,6),
134.42 (COCH2Ph-C1), 135.14 (NCH2Ph-C1), 135.37
(2ꢂCCH2Ph-C1), 136.68 (NCH2Ph-C4), 173.42 (COCH2),
175.66 (COOH). Anal. Calcd for C32H31NO3: C, 80.47; H,
6.54; N, 2.93. Found: C, 80.64; H, 6.64; N, 3.10.
4.1.2.8.
N-Phenylacetyl-N-(4-nitrobenzyl)-a,a-di-
methylglycine (4h). The reaction was carried out with com-
pound 1h (0.20 g) and the product was purified by column
chromatography (dichloromethane/MeOH, 25:1) followed
by recrystallisation from diethyl ether/petroleum ether
(40–60 ꢀC) to yield 4h (146 mg, 89%) as pale yellow crys-
tals, mp 194.7–195.8 ꢀC. 1H NMR (300 MHz, CDCl3):
1.45 (6H, s, 2ꢂCH3), 3.64 (2H, s, CH2CO), 4.68 (2H,
s, NCH2), 7.17 (2H, d, J¼6.6 Hz, COCH2Ph-H2,6),
7.22–7.32 (3H, m, COCH2Ph-H3,4,5), 7.66 (2H, d, J¼
8.7 Hz, NCH2Ph-H2,6), 8.26 (2H, d, J¼8.7 Hz, NCH2Ph-
H3,5), 9.03 (1H, br s, OH); 13C NMR (75 MHz, CDCl3):
d 24.44 (2ꢂCH3), 41.60 (CH2CO), 47.00 (CH2N), 61.59
(Ca), 124.19 (NCH2Ph-C3,5), 126.73 (NCH2Ph-C2,6),
127.14 (COCH2Ph-C4), 128.41 (COCH2Ph-C2,6), 128.87
(COCH2Ph-C3,5), 133.75 (COCH2Ph-C1), 145.65
(NCH2Ph-C1), 147.32 (NCH2Ph-C4), 172.12 (COCH2),
178.51 (COOH). Anal. Calcd for C19H20N2O5: C, 64.04;
H, 5.66; N, 7.86. Found: C, 63.89; H, 5.65; N, 7.59.
4.1.2.11. N-Phenylacetyl-N-benzyl-a,a-dibenzylglycine
(5c). The reaction was carried out with compound 2c
(0.25 g) and the product was purified by recrystallisation
from ethyl acetate to yield 5c (207 mg, 98%) as a white
1
solid, mp 228.6–229.7 ꢀC. H NMR (300 MHz, DMSO-
d6): 2.76 (2H, d, J¼12.9 Hz, CCH2Ph), 3.26 (2H, d, J¼
12.9 Hz, CCH2Ph), 3.43 (2H, s, COCH2), 3.94 (2H, s,
NCH2), 7.13 (2H, br dd, J¼1.5, 6.6 Hz, COCH2Ph-H2,6),
7.23–7.30 (14H, m, 2ꢂCCH2Ph+NCH2Ph-H4+COCH2Ph-
H3,4,5), 7.37 (2H, t, J¼7.8 Hz, NCH2Ph-C3,5), 7.53 (2H, d,
J¼7.5 Hz, NCH2Ph-H2,6), 12.35 (1H, br s, OH); 13C NMR
(75 MHz, DMSO-d6): d 36.28 (2ꢂCCH2Ph), 40.50 (CH2CO),
47.58 (CH2N), 68.23 (Ca), 125.66 (NCH2Ph-C2,6), 126.57
(NCH2Ph-C4), 126.78, 126.82 (2ꢂCCH2Ph-C4+COCH2Ph-
C4), 128.19 (2ꢂCH2Ph-C3,5+COCH2Ph-C3,5), 128.63
(NCH2Ph-C3,5), 129.60 (COCH2Ph-C2,6), 130.75 (2ꢂ
CH2Ph-C2,6), 134.98 (COCH2Ph-C1), 135.67 (2ꢂ
CCH2Ph-C1), 139.34 (NCH2Ph-C1), 171.61 (COCH2),
172.27 (COOH). Anal. Calcd for C31H29NO3: C, 80.32; H,
6.31; N, 3.02. Found: C, 80.23; H, 6.14; N, 3.14.
4.1.2.9. N-Phenylacetyl-N-(4-methoxybenzyl)-a,a-di-
benzylglycine (5a). The reaction was carried out with com-
pound 2a (0.14 g) and the product was purified by PLC
(dichloromethane/MeOH, 15:1) followed by recrystallisa-
tion from ethyl acetate to yield 5a (81 mg, 68%) as a white
solid, mp 208.2–209.3 ꢀC (lit.20 158.2–159.2 ꢀC). 1H NMR
(300 MHz, DMSO-d6): 2.77 (2H, d, J¼12.9 Hz, CCH2Ph),
3.26 (2H, d, J¼13.2 Hz, CCH2Ph), 3.44 (2H, s, COCH2),
3.72 (3H, s, OCH3), 3.80 (2H, s, NCH2), 6.94 (2H, d,
J¼8.7 Hz, NCH2Ph-H3,5), 7.13–7.15 (2H, m, COCH2Ph-
H2,6), 7.19–7.34 (13H, m, 2ꢂCCH2Ph+COCH2Ph-
H3,4,5), 7.44 (2H, d, J¼8.7 Hz, NCH2Ph-H2,6), 12.34
(1H, br s, OH); 13C NMR (75 MHz, DMSO-d6): d 36.22
(2ꢂCCH2Ph), 40.50 (CH2CO), 47.02 (CH2N), 55.03
(OCH3), 68.18 (Ca), 114.04 (NCH2Ph-C3,5), 126.54
(2ꢂCCH2Ph-C4), 126.75 (NCH2Ph-C2,6+COCH2Ph-C4),
128.16 (2ꢂCCH2Ph-C3,5), 128.19 (COCH2Ph-C3,5),
129.59 (COCH2Ph-C2,6), 130.74 (2ꢂCCH2Ph-C2,6),
130.96 (NCH2Ph-C1), 135.04 (COCH2Ph-C1), 135.68
(2ꢂCCH2Ph-C1), 158.11 (NCH2Ph-C4), 171.57 (COCH2),
172.29 (COOH). Anal. Calcd for C32H31NO4: C, 77.87; H,
6.33; N, 2.84. Found: C, 77.44; H, 6.05; N, 2.86.
4.1.2.12. N-Phenylacetyl-N-(4-fluorobenzyl)-a,a-di-
benzylglycine (5d). The reaction was carried out with
compound 2d (0.25 g) and the product was purified by
recrystallisation from ethyl acetate to yield 5d (190 mg,
88%) as a white solid, mp 193.9–195.0 ꢀC. 1H NMR
(300 MHz, CDCl3): 3.01 (2H, d, J¼13.2 Hz, CCH2Ph),
3.45 (2H, br d, J¼12.6 Hz, CCH2Ph), 3.60 (2H, s,
COCH2), 3.84 (2H, br s, NCH2), 7.08 (2H, t, J¼9.0 Hz,
NCH2Ph-H3,5), 7.25–7.33 (10H, m, 2ꢂCCH2Ph), 7.35–
7.41 (5H, m, COCH2Ph), 7.43–7.50 (2H, m, NCH2Ph-
H2,6), 8.81 (1H, br s, OH); 13C NMR (75 MHz, CDCl3):
d 36.12 (2ꢂCCH2Ph), 41.31 (CH2CO), 47.68 (CH2N), 68.93
(Ca), 115.84 (d, JC–F¼21.6 Hz, NCH2Ph-C3,5), 127.16
(2ꢂCCH2Ph-C4+COCH2Ph-C4), 127.28 (d, JC–F¼7.8 Hz,
NCH2Ph-C2,6), 128.45 (2ꢂCCH2Ph-C3,5), 128.64
(COCH2Ph-C3,5), 129.64 (COCH2Ph-C2,6), 130.82
(2ꢂCCH2Ph-C2,6), 133.82 (d, JC–F¼3.2 Hz, NCH2Ph-C1),
134.12 (COCH2Ph-C1), 135.17 (2ꢂCCH2Ph-C1), 161.88
(d, JC–F¼245.6 Hz, NCH2Ph-C4), 173.41 (COCH2),
175.62 (COOH). Anal. Calcd for C31FH28NO3: C, 77.32;
H, 5.86; N, 2.91. Found: C, 76.97; H, 5.79; N, 2.92.
4.1.2.10. N-Phenylacetyl-N-(4-methylbenzyl)-a,a-di-
benzylglycine (5b). The reaction was carried out with
compound 2b (0.25 g) and the product was purified by
recrystallisation from diethyl ether/petroleum ether (40–
4.1.2.13. N-Phenylacetyl-N-(4-chlorobenzyl)-a,a-di-
benzylglycine (5e). The reaction was carried out with
compound 2e (0.25 g) and the product was purified by

8196
F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
recrystallisation from diethyl ether/petroleum ether (40–
60 ꢀC) to yield 5e (186 mg, 85%) as a white solid, mp
by recrystallisation from ethyl acetate to yield 5h (108 mg,
62%) as pale yellow crystals, mp 213.3–214.5 ꢀC. 1H
NMR (300 MHz, DMSO-d6): 2.73 (2H, d, J¼12.9 Hz,
CCH2Ph), 3.29 (2H, d, J¼13.2 Hz, CCH2Ph), 3.44 (2H, s,
COCH2), 4.15 (2H, br s, NCH2), 7.13 (2H, dd, J¼1.5,
9.3 Hz, COCH2Ph-H2,6), 7.21–7.29 (13H, m, 2ꢂ
CCH2Ph+COCH2Ph-H3,4,5), 7.78 (2H, d, J¼8.7 Hz,
NCH2Ph-H2,6), 8.21 (2H, d, J¼9.0 Hz, NCH2Ph-H3,5),
12.47 (1H, br s, OH); 13C NMR (75 MHz, DMSO-d6):
d 36.41 (2ꢂCCH2Ph), 40.49 (CH2CO), 47.51 (CH2N),
68.39 (Ca), 123.63 (NCH2Ph-C3,5), 126.57 (COCH2Ph-
C4), 126.83 (2ꢂCCH2Ph-C4), 127.15 (NCH2Ph-C2,6),
128.16 (COCH2Ph-C3,5), 128.22 (2ꢂCCH2Ph-C3,5),
129.65 (COCH2Ph-C2,6), 130.75 (2ꢂCCH2Ph-C2,6),
134.76 (COCH2Ph-C1), 135.54 (2ꢂCCH2Ph-C1), 146.50
(NCH2Ph-C4), 147.52 (NCH2Ph-C1), 171.68 (COCH2),
172.28 (COOH). Anal. Calcd for C31H28N2O5: C, 73.21;
H, 5.55; N, 5.51. Found: C, 72.91; H, 5.46; N, 5.52.
1
207.9–209.1 ꢀC. H NMR (300 MHz, CDCl3): 2.98 (2H, d,
J¼13.2 Hz, CCH2Ph), 3.43 (2H, br d, J¼12.9 Hz, CCH2Ph),
3.57 (2H, s, COCH2), 3.81 (2H, br s, NCH2), 7.26–7.45 (19H,
m, 2ꢂCCH2Ph+COCH2Ph+NCH2Ph), 8.22 (1H, br s, OH);
13C NMR (75 MHz, CDCl3): d 36.06 (2ꢂCCH2Ph), 41.36
(CH2CO), 47.74 (CH2N), 68.91 (Ca), 127.11 (NCH2Ph-
C2,6), 127.17 (2ꢂCCH2Ph-C4+COCH2Ph-C4), 128.47 (2ꢂ
CCH2Ph-C3,5), 128.67 (NCH2Ph-C3,5), 129.12 (COCH2Ph-
C3,5), 129.63 (COCH2Ph-C2,6), 130.82 (2ꢂCCH2Ph-C2,6),
132.99 (NCH2Ph-C4), 134.03 (COCH2Ph-C1), 135.13
(2ꢂCCH2Ph-C1), 136.76 (NCH2Ph-C1), 173.32 (COCH2),
175.48 (COOH). Anal. Calcd for C31ClH28NO3: C, 74.76;
H, 5.67; N, 2.81. Found: C, 74.48; H, 5.84; N, 2.94.
4.1.2.14. N-Phenylacetyl-N-(4-trifluoromethoxy-
benzyl)-a,a-dibenzylglycine (5f). The reaction was carried
out with compound 2f (0.25 g) and the product was purified
by column chromatography (dichloromethane/MeOH, 25:1)
followed by recrystallisation from ethyl acetate to yield 5f
4.1.2.17. N-Phenylacetyl-N-(4-methoxyphenyl)-a,a-
dimethylglycine (6a). The reaction was carried out with
compound 3a (0.38 g) in neat TFA at room temperature
and the product was purified by column chromatography (di-
chloromethane/MeOH, 25:1) followed by recrystallisation
from ethyl acetate to yield 6a (0.30 g, 98%) as white crys-
tals, mp 164.2–165.5 ꢀC. 1H NMR (300 MHz, CDCl3):
1.36 (6H, s, 2ꢂCH3), 3.40 (2H, s, CH2), 3.85 (3H, s,
OCH3), 6.87 (2H, d, J¼9.0 Hz, NPh-H3,5), 7.04 (2H, m,
CH2Ph-H2,6), 7.09 (2H, d, J¼8.7 Hz, NPh-H2,6), 7.20
(3H, m, CH2Ph-H3,4,5), 8.91 (1H, br s, OH); 13C NMR
(75 MHz, CDCl3): d 24.84 (2ꢂCH3), 42.08 (CH2), 55.43
(OCH3), 61.69 (Ca), 114.17 (NPh-C3,5), 126.93 (CH2Ph-
C4), 128.14 (CH2Ph-C3,5), 129.03 (CH2Ph-C2,6), 131.26
(NPh-C2,6), 131.79 (NPh-C1), 135.08 (CH2Ph-C1),
159.47 (NPh-C4), 171.60 (CON), 179.08 (COOH). Anal.
Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found:
C, 69.52; H, 6.43; N, 4.35.
1
(201 mg, 92%) as white crystals, mp 175.4–176.4 ꢀC. H
NMR (300 MHz, CDCl3): 3.00 (2H, d, J¼12.9 Hz,
CCH2Ph), 3.45 (2H, br d, J¼12.9 Hz, CCH2Ph), 3.59 (2H,
s, COCH2), 3.86 (2H, br s, NCH2), 7.22–7.43 (17H, m,
2ꢂCCH2Ph+NCH2Ph-H3,5+COCH2Ph), 7.53 (2H, d,
J¼8.7 Hz, NCH2Ph-H2,6), 8.51 (1H, br s, OH); 13C NMR
(75 MHz, CDCl3): d 36.13 (2ꢂCCH2Ph), 41.37 (CH2CO),
47.71 (CH2N), 68.96 (Ca), 121.46 (NCH2Ph-C3,5), 120.41
(q, JC–F¼257.1 Hz, OCF3), 127.12 (NCH2Ph-C2,6), 127.20,
127.22 (2ꢂCCH2Ph-C4+COCH2Ph-C4), 128.49 (2ꢂ
CCH2Ph-C3,5), 128.68 (COCH2Ph-C3,5), 129.63 (COCH2Ph-
C2,6), 130.83 (2ꢂCCH2Ph-C2,6), 133.98 (COCH2Ph-C1),
135.09 (2ꢂCCH2Ph-C1), 136.91 (NCH2Ph-C1), 148.28 (q,
JC–F¼1.8 Hz, NCH2Ph-C4), 173.41 (COCH2), 175.61
(COOH). Anal. Calcd for C32F3H28NO4$1/3H2O: C, 69.43;
H, 5.22; N, 2.53. Found: C, 69.53; H, 5.41; N, 2.58.
4.1.2.15. N-Phenylacetyl-N-(4-trifluoromethylbenzyl)-
a,a-dibenzylglycine (5g). The reaction was carried out with
compound 2g (0.25 g) and the product was purified by re-
crystallisation from ethyl acetate to yield 5g (207 mg,
95%) as white crystals, mp 201.9–203.0 ꢀC. 1H NMR
(300 MHz, CDCl3): 2.99 (2H, d, J¼12.9 Hz, CCH2Ph),
3.45 (2H, br d, J¼12.6 Hz, CCH2Ph), 3.57 (2H, s,
COCH2), 3.91 (2H, br s, NCH2), 7.27–7.42 (15H, m, 2ꢂ
CCCH2Ph+COCH2Ph), 7.64 (4H, s, NCH2Ph-H2,3,5,6),
8.44 (1H, br s, OH); 13C NMR (75 MHz, CDCl3): d 36.21
(2ꢂCCH2Ph), 41.44 (CH2CO), 48.01 (CH2N), 68.96 (Ca),
124.00 (q, JC–F¼272.0 Hz, CF3), 125.96 (q, JC–F¼3.8 Hz,
NCH2Ph-C3,5), 126.12 (NCH2Ph-C2,6), 127.24 (2ꢂ
CCH2Ph-C4+COCH2Ph-C4), 128.51 (2ꢂCCH2Ph-C3,5),
128.71 (COCH2Ph-C3,5), 129.59 (q, JC–F¼32.5 Hz,
NCH2Ph-C4), 129.60 (COCH2Ph-C2,6), 130.82 (2ꢂ
CCH2Ph-C2,6), 133.85 (COCH2Ph-C1), 135.03 (2ꢂCCH2Ph-
C1), 142.45 (NCH2Ph-C1), 173.33 (COCH2), 175.40
(COOH). Anal. Calcd for C32F3H28NO3$1/3H2O: C, 71.50;
H, 5.37; N, 2.61. Found: C, 71.33; H, 5.25; N, 2.55.
4.1.2.18. N-Phenylacetyl-N-phenyl-a,a-dimethylgly-
cine (6b). The reaction was carried out with compound 3b
(0.25 g) in neat TFA at room temperature and the product
was purified by column chromatography (dichloro-
methane/MeOH, 12:1) followed by recrystallisation from
ethyl acetate to yield 6b (72 mg, 77%) as a white solid, mp
1
154.8–155.7 ꢀC. H NMR (300 MHz, CDCl3): 1.38 (6H, s,
2ꢂCH3), 3.39 (2H, s, CH2), 7.01 (2H, m, CH2Ph-H2,6),
7.19–7.22 (5H, m, NPh-H2,6+CH2Ph-H3,4,5), 7.39 (3H,
m, NPh-H3,4,5), 9.38 (1H, br s, OH); 13C NMR (75 MHz,
CDCl3): d 24.86 (2ꢂCH3), 42.13 (CH2), 61.58 (Ca), 126.41
(CH2Ph-C4), 128.14 (CH2Ph-C3,5), 128.70 (NPh-C4),
128.99 (CH2Ph-C2,6), 129.14 (NPh-C3,5), 130.33 (NPh-
C2,6), 134.94 (CH2Ph-C1), 139.08 (NPh-C1), 171.16
(CON), 179.08 (COOH). Anal. Calcd for C18H19NO3: C,
72.71; H, 6.44; N, 4.71. Found: C, 72.63; H, 6.48; N, 4.65.
4.1.2.19. N-Phenylacetyl-N-(4-chlorophenyl)-a,a-di-
methylglycine (6c). The reaction was carried out with com-
pound 3c (0.21 g) in 5% TFA at room temperature and the
product was purified by column chromatography (dichloro-
methane/MeOH, 25:1) followed by recrystallisation from di-
ethyl ether/petroleum ether (40–60 ꢀC) to yield 6c (109 mg,
66%) as white crystals, mp 170.4–171.5 ꢀC. 1H NMR
(300 MHz, CDCl3): 1.36 (6H, s, 2ꢂCH3), 3.39 (2H, s,
4.1.2.16.
N-Phenylacetyl-N-(4-nitrobenzyl)-a,a-di-
benzylglycine (5h). The reaction was carried out with com-
pound 2h (0.20 g) and the product was purified by column
chromatography (dichloromethane/MeOH, 100:1) followed

F. C. S. C. Pinto et al. / Tetrahedron 62 (2006) 8184–8198
8197
CH2), 7.00 (2H, m, CH2Ph-H2,6), 7.11 (2H, d, J¼8.4 Hz,
NPh-H2,6), 7.20–7.22 (3H, m, CH2Ph-H3,4,5), 7.35 (2H,
d, J¼8.7 Hz, NPh-H3,5), 9.35 (1H, br s, OH); 13C NMR
(75 MHz, CDCl3): d 24.88 (2ꢂCH3), 42.29 (CH2), 61.65
(Ca), 126.60 (CH2Ph-C4), 128.28 (CH2Ph-C3,5), 128.88
(CH2Ph-C2,6), 129.36 (NPh-C3,5), 131.66 (NPh-C2,6),
134.58 (CH2Ph-C1), 134.74 (NPh-C4), 137.59 (NPh-C1),
171.05 (CON), 178.94 (COOH). Anal. Calcd for
C18ClH18NO3: C, 65.16; H, 5.47; N, 4.22. Found: C,
65.10; H, 5.59; N, 4.33.
Ugi–Passerini adduct in 4.5 ml of acetonitrile contained in
a dilution flask; this was followed by addition of 0.4 ml of
25% TFA in acetonitrile and adjustment of the volume to
5 ml with acetonitrile. The above operations were carried
out with the reaction vessel and all reagent solutions were
kept in a thermostatic bath at a temperature stabilised within
0.01 ꢀC of the required value, the same was applied through-
out the reaction. At regular intervals of time samples were
collected for HPLC monitoring and injected as quickly as
possible to minimise errors caused due to temperature fluc-
tuations. A mixture of acetonitrile/water 3:1 (v/v) was used
as eluent and in most cases the detection was performed at
the wavelength of 260 nm.
4.1.2.20. N-Phenylacetyl-N-(4-cyanophenyl)-a,a-di-
methylglycine (6d). The reaction was carried out with com-
pound 3d (0.20 g) in 5% TFA at room temperature and the
product was purified by column chromatography (dichloro-
methane/MeOH, 50:1) followed by recrystallisation from
ethyl acetate to yield 6d (90 mg, 56%) as a white solid,
mp 167.6–168.7 ꢀC. 1H NMR (300 MHz, CDCl3): 1.37
(6H, s, 2ꢂCH3), 3.37 (2H, s, CH2), 6.93 (2H, m, CH2Ph-
H2,6), 7.19–7.21 (3H, m, CH2Ph-H3,4,5), 7.29 (2H, d,
J¼8.1 Hz, NPh-H2,6), 7.66 (2H, d, J¼8.4 Hz, NPh-H3,5),
9.56 (1H, br s, OH); 13C NMR (75 MHz, CDCl3): d 24.96
(2ꢂCH3), 42.66 (CH2), 61.91 (Ca), 112.89 (NPh-C4),
117.75 (NPh-CN), 126.83 (CH2Ph-C4), 128.43 (CH2Ph-
C3,5), 128.69 (CH2Ph-C2,6), 131.52 (NPh-C2,6), 133.01
(NPh-C3,5), 134.12 (CH2Ph-C1), 143.20 (NPh-C1),
170.50 (CON), 178.85 (COOH). Anal. Calcd for
C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.50;
H, 5.67; N, 8.65.
Acknowledgements
We wish to acknowledge Miss Elisa Pinto for running the
NMR spectra and for the elemental analyses and also the
~
Fundac¸ao para a Ciencia e Tecnologia (Portugal) for finan-
cial support to the Centro de Quımica Fina (University of
^
´
Minho) and for a scholarship to one of us (F.C.S.C.P.).
References and notes
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in 5 ml of neat TFA and the solution was refluxed for 1 h.
The solvent was concentrated under reduced pressure at
30 ꢀC and the pH of the residue was adjusted to 3 by treat-
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