Ugi four-component condensation with two cleavable components: the easiest synthesis of 2,N-diarylglycines

Article abstract of DOI:10.1016/j.tetlet.2008.01.134

The Ugi four-component condensation between anilines, aromatic aldehydes, isocyanides, and α-oxoacids afforded the expected adducts which were cleaved in mild conditions to give 2,N-diarylglycines in high yields.

Full text of DOI:10.1016/j.tetlet.2008.01.134

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2099–2102
Ugi four-component condensation with two cleavable components:
the easiest synthesis of 2,N-diarylglycines
Cristina Faggi a, Ana G. Neo b,c, Stefano Marcaccini b,*, Gloria Menchi b, Julia Revuelta b,d
a
`
CRIST, Centro Interdipartimentale di Cristallografia, Universita di Firenze, via della Lastruccia 3, I-50019 Sesto Fiorentino (FI), Italy
`
b
HeteroBioLab, Dipartimento di Chimica Organica, Universita di Firenze, via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy
c Departamento de Quı´mica Orga´nica, Facultad de Veterinaria, Universidad de Extremadura, Avenida de la Universidad s/n, E-10071 Ca´ceres, Spain
d Instituto de Quı´mica Orga´nica General—CSIC, Grupo de Quı´mica Orga´nica Biolo´gica, C/Juan de la Cierva 3, 28006 Madrid, Spain
Received 8 November 2007; revised 30 January 2008; accepted 30 January 2008
Available online 6 February 2008
Dedicated to the memory of Professor Ivar Ugi
Abstract
The Ugi four-component condensation between anilines, aromatic aldehydes, isocyanides, and a-oxoacids afforded the expected
adducts which were cleaved in mild conditions to give 2,N-diarylglycines in high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
The use of cleavable components in the Ugi four-com-
ponent condensation is of great importance since it allows
to broaden the scope of this important reaction.1 Although
the best known cleavable reagent is 1-isocyanocyclohex-1-
ene, reported more than 40 years ago by Ugi and Rosen-
dahl as a synthetic equivalent of the unknown ‘hydrogen
isocyanide’2 and then exploited by Keating and Arm-
strong,3 other cleavable isocyanides, acids, amines, and
carbonyl compounds are known.1,4
and converted into the corresponding a-amino acid 7a. The
same product 7a was obtained upon alkaline treatment of
the Ugi-4CC adducts 5b, prepared by employing benzyl
isocyanide (1b) in the place of cyclohexyl isocyanide, and
5c obtained by employing pyruvic acid (4b) in the place
of benzoylformic acid (4a). Thus, the basic cleavage of
the Ugi adducts appeared to be feasible, regardless of the
kind of the isocyanide and the a-ketoacid.
The general interest of a-amino acids5 and certain 2,N-
diarylglycines6 besides our interest in the post-condensa-
tion modifications of the isocyanide-based multicomponent
reactions1b prompted us to perform further studies on this
cleavage.
This Letter deals with a post-condensation transforma-
tion of Ugi-4CC adducts in which two components behave,
at the same time, as cleavable reagents.
The reaction between cyclohexyl isocyanide (1a), 4-chlo-
robenzaldehyde (2a), 4-chloroaniline (3a), and benzoyl-
formic acid (4a) afforded the expected Ugi-4CC adduct,
namely 2-[N-benzoylformyl-N-(4-chloro)phenyl]amino-2-
(4-chlorophenyl)-N-cyclohexyl acetamide (5a). Upon treat-
ment of 5a with methanolic potassium hydroxide, the
potassium salt of 2,N-di-(4-chlorophenyl)glycine (6a) was
isolated in high yield and purity from the reaction mixture
At first sight the transformations 5a,b,c?6a appeared
as a double amide bond hydrolysis, but we were doubtful,
since the reaction took place smoothly in mild conditions,
whereas the hydrolysis of amides requires, as it is well-
known, drastic conditions. A careful examination of the
basic cleavage of 5a showed that only one equivalent of
potassium hydroxide was consumed. In addition we were
able to isolate a product from the reaction mixture, which
was identified as N-cyclohexyl benzoylformamide (8a) by
comparison with an authentic specimen obtained by a
known method.7
*
Corresponding author. Tel.: +39 055 457 3510; fax: +39 055 457 3531.
E-mail address: stefano.marcaccini@unifi.it (S. Marcaccini).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.134

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C. Faggi et al. / Tetrahedron Letters 49 (2008) 2099–2102
In all of the cases studied, high yields of a-amino acids 7
were obtained from Ugi adducts 5 prepared from aromatic
aldehydes and anilines. It must be underlined that the iso-
lation of the Ugi adducts is unnecessary and the synthesis
of a-amino acids 7 was carried out in a more satisfactory
manner by employing a two-step one-pot procedure. The
one-pot procedure allowed us to obtain high yields of 7
by employing the cheap pyruvic acid (4b) in the place of
the relatively expensive benzoylformic acid (1a).8,9
Interestingly, the reaction did not afford a-amino acid
salts when Ugi-4CC adducts arising from aliphatic alde-
hydes, ketones, and alkylamines were subjected to metha-
nolic potassium hydroxide. When 1-(N-benzoylformyl-N-
phenyl)amino-N-cyclohexyl-1-cyclo-hexanecarboxamide (9)
Fig. 1. ORTEP Drawing of compound 11.
CHO
R1 NC
+
+
Ar
KOH
R2
Ar
HN
MeOH
2 h, rt
Cl
MeOH,
2d, rt
Ar
O
1
O
N
O
_
2a
R2
+
O
CO2
K
+
HN
R1
NH
Ar
6a
NH2
R2
O
R1
CO2H
+
5
8
O
Cl
Ar = 4-ClC6H4
3a
HCO2H, H2O
Ar
4
1) MeOH, 2d, rt
2) KOH, 2 h, rt
3) HCO2H, H2O
Ar1
Ar
OH
Ar2
OH
Ar2 NH2
Ar1 CHO
N
1a +
+
4b
+
N
H
H
87-93%
O
O
7a
7
Ph
KOH
1a, 4a,
MeOH
2d, rt
O
N
NH
MeOH
N
Ph
OH
O
rt
Ph
N
O
N
Ph
O
O
Ph
10
11
9
Cl
1a + 2a + 4a
MeOH
2d, rt
KOH,
MeOH
+
no reaction
O
Ph
N
Ph
NH2
O
HN
13
c-C6H11
O
Ph
12
1
a
b
R1
-C6H11
C6H5CH2
2
Ar1
4-ClC6H4
4-FC6H4
4-CH3OC6H4
C6H5
3
a
b
c
d
Ar2
4-ClC6H4
4-CH3OC6H4
4-CH3C6H4
C6H5
4
a
b
R2
C6H5
CH3
5,8
R1
-C6H11
C6H5CH2
-C6H11
R2
C6H5
C6H5
CH3
c
a
b
c
d
a
b
c
c
c
7
Ar1
Ar2
7
Ar1
Ar2
a
b
c
d
e
4-ClC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-ClC6H4
f
g
h
i
4-CH3OC6H4
C6H5
4-ClC6H4
4-FC6H4
4-FC6H4
C6H5
C6H5
C6H5
C6H5
4-CH3OC6H4
4-CH3OC6H4
4-CH3C6H4
4-CH3C6H4
j
4-CH3C6H4
Scheme 1. Behavior of Ugi-4CC adducts arising from a-oxoacids toward KOH.

C. Faggi et al. / Tetrahedron Letters 49 (2008) 2099–2102
2101
obtained from 1, 4a, and N-phenyl cyclohexanone imine
(10) was treated with the base, a cyclization to 2,5-dioxo-
1,3-diphenyl-3-hydroxy-1,4-diazaspiro[5.5]undecane (11)
whose structure was confirmed by X-ray analysis10
(Fig. 1) took place. Ugi adduct 12 arising from benzyl-
amine (13), cyclohexyl isocyanide (1a), 4-chlorobenzalde-
hyde (2a), and benzoylformic acid (4a) was recovered
unchanged after 2 days exposure to methanolic KOH
(Scheme 1).
the corresponding esters, which are not easily available.13
Another method consists of the hydrolysis of the corres-
ponding nitriles, in turn obtained via Strecker-type reac-
tions.14 Since the hydrolysis of a-aminonitriles is
generally carried out in strong acidic medium at high tem-
peratures, the survival of sensitive groups cannot be
ensured. Thus, the present method appears to be an alter-
native to the traditional Strecker synthesis and, at the same
time, similar. In fact the carbon atom of the carboxylic
group arises from the isocyanide and the inorganic cyanide,
respectively, whereas the amine and the aldehyde are the
same. In addition this route appears to be suitable for the
preparation of 2,N-diarylglycines in the solid phase by
using resin-bound isocyanides, such as polystyrene isocya-
nide resin.15
On the basis of the above observations we proposed a
cleavage mechanism (Scheme 2). The formation of the
reaction products can be explained by hypothesizing the
base-induced formation of the 5-membered intermediates
14 alone or in equilibrium with the 6-membered intermedi-
ates 15 in the reaction medium.11 The presence of an acid
hydrogen in position 5 of the imidazolidinone ring of 14
ensures the prosecution of the reaction. The failure of the
reaction with Ugi-4CC adducts arising from ketones can
be explained with the absence of acid hydrogens. When ali-
phatic amines and/or aldehydes are employed the H-5 is
not acidic enough to give anions 16. Rearrangement of
anions 16 leads to the formation of 8 and the intermediate
ketene anions 17 which give the a-amino acid salts 6
directly, via the addition of water or via the addition of
methanol followed by the hydrolysis of the corresponding
methyl esters. Thus, both the acid and the isocyanide act
as cleavable reagents. In the a-amino acids 7 only the iso-
cyanide carbon is retained and this is a typical feature of
convertible isocyanides. It is noteworthy that simple
aliphatic isocyanides such as 1, without multiple bonds or
additional functional groups, behave as convertible
isocyanides.12
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2008.01.134.
References and notes
1. (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210;
(b) Marcaccini, S.; Torroba, T. In Multicomponent Reactions; Zhu, J.,
´
Bienayme, H., Eds.; VCH: Weinheim, 2005; pp 33–75; Do¨mling, A.
Chem. Rev. 2006, 106, 17–89.
2. Ugi, I.; Rosendahl, F. K. Liebigs Ann. Chem. 1963, 666, 65–67.
3. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842–
7843; J. Am. Chem. Soc. 1996, 118, 2574–2583.
4. Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T. Synlett 2004,
41–44.
5. Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Eur. J. 2002, 8,
3646–3652.
6. Groebke Zbinden, K.; Obst-Sander, U.; Hilpert, K.; Kuhne, H.;
¨
In conclusion the present method allows the preparation
of 2,N-diarylglycines in a very simple manner: all the
reagents are commercially available, reagents and solvents
are used as supplied, the reactions are performed by simple
mixing of the reagents at room temperature, and no special
apparatus is required. It must be noted that 2,N-diaryl-
glycines are usually prepared via alkaline hydrolysis of
Banner, D. W.; Bo¨hm, H.-J.; Stahl, M.; Ackermann, J.; Alig, L.;
´
Weber, L.; Wessel, H. P.; Riederer, M. A.; Tschopp, T. B.; Lave, T.
Bioorg. Med. Chem. Lett. 2005, 15, 5344–5352.
7. Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116–1121.
8. The Ugi 4-CC adducts prepared from pyruvic acid are more soluble in
methanol than the corresponding adducts arising from benzoylformic
acid. Thus, lower overall yields of a-amino acids were obtained when
the cleavage was performed on the isolated Ugi adducts.
9. General procedure for one-pot synthesis of 2,N-diarylglycines 8: A
solution of the amine 3 (5.0 mmol) in MeOH (10 ml) was treated
under stirring with aldehyde 2 (finely powdered if solid) (5.0 mmol).
The resulting mixture was stirred for 10 min at room temperature and
then treated with pyruvic acid (4a) (440 mg, 5.0 mmol) and cyclohexyl
isocyanide (1a) (546 mg, 5.0 mmol). The resulting mixture was stirred
for 48 h at rt and then treated with a solution of KOH (337 mg,
6.0 mmol) in MeOH (4 ml). After 2 h stirring at room temperature (a
prolonged time has no detrimental effect on the yield and purity of the
reaction product) the solvent was removed under diminished pressure,
and the residue partitioned between H2O (30 ml) and CHCl3 (30 ml).
The layers were separated and the aqueous phase was acidified with
formic acid until pH 4. The resulting suspension was filtered and the
collected solid product washed with water and dried to give almost
pure 7 in 87–93% yield.
10. Crystal data for compound 11: C27H32N2O3, M = 432.55, triclinic,
ꢀ
˚
space group P1, a = 9.814(2), b = 10.705(2), c = 11.603(2) A,
3
˚
a = 79.17(1), b = 83.14(2), c = 88.94(1), V = 1188.7(4) A , Z = 2,
Scheme 2. Proposed mechanism for the formation of 2,N-diarylglycines
from Ugi-4CC adducts.
Dc = 1.208, l = 0.079 mmÀ1, F(000) = 464. In total 8157 reflections

2102
C. Faggi et al. / Tetrahedron Letters 49 (2008) 2099–2102
were collected with a 4.40 < h < 31.92° range; 6123 were independent;
C(22) and O(3) were found in the Fourier synthesis; all of them were
refined as isotropic. The X-ray CIF file for this structure has been
deposited at the Cambridge Crystallographic Data Center with the
deposition number CCDC 616531. Copies of the data can be
obtained, free of charge, from CCDC, 12 Union Road, Cambridge,
CB2 1EZ UK (e-mail: deposit@ccdc.cam.ac.uk, internet:
www.ccdc.cam.ac.uk).
the parameters were 298 and the final R index was 0.0571 for
reflections having I > 2r(I) and 0.0967 for all data. RX-analysis was
carried out with a Goniometer Oxford Diffraction KM4 Xcalibur2 at
room temperature. Graphite-monochromated Mo/Ka radiation
(40 mA/À40 kV) and a KM4 CCD/SAPPHIRE detector were used
for cell parameter determination and data collection. The integrated
intensities, measured using the x scan mode, were corrected for
Lorentz and polarization effects [Walker, N.; Stuart, D. Acta
Crystallogr., Sect. A 1983, 39, 158–166]. The substantial redundancy
in data allows empirical absorption corrections (SADABS) [Sheld-
rick, G. M. SADABS version 2.03, a Program for Empirical Absorption
Correction; Universita¨t Go¨ttingen, 1997–2001] to be applied using
multiple measurements of symmetry-equivalent reflections. The
structure was solved by direct methods of SIR97 [Altomare, A.; Burla,
M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Guagliardi,
A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr.
1999, 32, 115–119] and refined using the full-matrix least squares on
F2 provided by SHELXL97 [Sheldrick, G. M. SHELXL97: Program for
11. Both carbonyl groups are reactive enough to undergo base-promoted
nucleophilic attacks by the amide nitrogen. The formation of
orthoamides from Ugi-4CC adducts has been reported: Marcaccini,
´
S.; Miguel, D.; Torroba, T.; Garcıa-Valverde, M. J. Org. Chem. 2003,
68, 3315–3318; For another example of the reactivity of Ugi-4CC
´
adducts with additional carbonyl groups: Garcıa-Valverde, M.;
´
Macho, S.; Marcaccini, S.; Rodrıguez, T.; Rojo, J.; Torroba, T.
Synlett 2008, 33–36.
12. To our knowledge only an example has been reported in which a
saturated, unfunctionalized isocyanide behaves as a C1 synthon:
Henkel, B.; Weber, L. Synlett 2002, 1877–1879.
13. Recently a simple solution-phase access to these compounds based on
the method of Henkel and Weber has been reported. See Ref. 6.
14. See for example: Csongar, C.; Mueller, I.; Slezak, H.; Klebsch, H.-J.;
Tomaschewski, G. J. Prakt. Chem. 1988, 330, 1006–1014.
15. Arshady, R.; Ugi, I. Polymer 1990, 31, 1164–1169.
Crystal Structure Refinement; Institut fur Anorganische Chemie der
¨
Universita¨t Go¨ttingen: Go¨ttingen, Germany]. The non-hydrogen
atoms were refined anisotropically; aromatic and methylenic hydro-
gens were assigned in calculated positions, whereas hydrogens on