An efficient synthesis of symmetric and unsymmetric bis-(β- aminoamides) via Ugi multicomponent reaction

Article abstract of DOI:10.1021/ol302935y

A library of symmetrical and unsymmetrical bis-(β-aminoamides) has been prepared starting from symmetrical secondary diamines by using a double Ugi four-component reaction. A sacrifical Mumm rearrangement, thanks to the use of 2-hydroxymethyl benzoic acid, is necessary to suppress the competing split-Ugi reaction, increasing the yield and simplifying the purification step. The scope, the reaction conditions, and the role of water in trapping the nitrilium intermediate are also discussed.

Full text of DOI:10.1021/ol302935y

ORGANIC
LETTERS
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Vol. XX, No. XX
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An Efficient Synthesis of Symmetric and
Unsymmetric Bis-(β-aminoamides) via Ugi
Multicomponent Reaction
Fabio La Spisa, Alberto Feo, Riccardo Mossetti, and Gian Cesare Tron*
ꢀ
Dipartimento di Scienze del Farmaco, Universita degli Studi del Piemonte Orientale
“A. Avogadro”, Largo Donegani 2, 28100 Novara, Italy
tron@pharm.unipmn.it
Received October 24, 2012
ABSTRACT
A library of symmetrical and unsymmetrical bis-(β-aminoamides) has been prepared starting from symmetrical secondary diamines by using a
double Ugi four-component reaction. A sacrifical Mumm rearrangement, thanks to the use of 2-hydroxymethyl benzoic acid, is necessary to
suppress the competing split-Ugi reaction, increasing the yield and simplifying the purification step. The scope, the reaction conditions, and the
role of water in trapping the nitrilium intermediate are also discussed.
Symmetrical compounds have played an important role
in several branches of chemistry including medicinal chem-
istry.1 For example the symmetry of the binding site of
HIV protease has brought a plethora of C-2 symmetrical
protease inhibitors with low nanomolar activity, which
paved the way for the nonsymmetrical protease inhibitors
currently on the market.2 For this reason the ability to
Figure 1. Bis-(β-aminoamide) scaffold.
synthesize symmetrical compounds in a simple manner
and in a one-pot operation is a surplus value for the
medicinal chemists involved in drug discovery and it is
A four-component bis-Ugi-like reaction,3 using water as
an acid component, was recognized as a valuable, faster
worth being continually investigated. For one of our
alternative strategy for the synthesis of these compounds
compared to the reported methods.4
medicinal chemistry programs we needed to synthesize a
library of symmetrical and unsymmetrical bis-(β-amino-
amides) (1) as shown in Figure 1.
€
(3) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
3210. (b) Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632–639. (c)
Symmetrical compounds using a double Ugi reaction have been pre-
pared; see for example: Michalik, D.; Schaks, A.; Wessjohann, L. A.
Eur. J. Org. Chem. 2007, 149–157. Westermann, B.; Michalik, D.;
Schaks, A.; Kreye, O.; Wagner, C.; Merzweiler, K.; Wessjohann, L. A.
Heterocycles 2007, 73, 863–872.
(1) Conreas, J. M.; Sippl, W. Homo and heterodimer ligands: the
twin drug approach. In The practice of medicinal chemistry, 3rd ed.;
Wermuth, C. G., Ed.; Elsevier Ltd.: The Netherlands, 2008; pp 380À414.
(2) Greer, J.; Erickson, J. W.; Baldwin, J. J.; Varney, M. D. J. Med.
Chem. 1994, 37, 1035–1054.
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10.1021/ol302935y
XXXX American Chemical Society

Also, a survey in the literature showed us the lack of a
general and valid one-pot procedure using water as an acid
component in the Ugi reaction. A main reason can explain
the lack of such a reaction: the poor nucleophilicity of
water in attacking the nitrilium ion.
Indeed, even if the attack of water to the nitrilium ion is
considered possible and it is reported in both books and
papers,5 there is a paucity of such examples in the literature
and the reaction didnot appearof general use. Fora deeper
insight, this reaction always requires the presence of a
Lewis or Brønsted acid pointing out a different mechanism
of action. The most puzzling situation is in the first
example of an Ugi reaction in which a carboxylic acid
has been replaced with water, reported by Ugi himself, in
order to obtain the local anesthetic xylocaine (5) in an one-
pot process. To accomplish this reaction a strong excess of
hydrochloric acid was used6 (Scheme 1).
used.11 Very recently Sugimone et al., in order to bypass
the problem of the lack of reactivity of water in the Ugi
reaction, reported the use of an aminoborane to give the
desired R-aminoamides using secondary amines.12
Another way to overcome this problem was the use of an
acid such as trifluoroacetic acid. The corresponding amide
can then be easily hydrolyzed under basic conditions.13
Also, when symmetrical secondary diamines react with a
carbonyl compound, an isocyanide, and a carboxylic acid,
a novel competing reaction, named split-Ugi, occurs14
(Scheme 2). In this case, the second secondary amine
intercepts the imino-anhydride intermediate. Even in the
presence of 2 equiv of acid, a carbonyl group and isocya-
nide, and 1 equiv of the diamine, the intramolecular split-
Ugi reaction still competes and prevails over the classical
Ugi reaction being the major component of the mixture.
Scheme 2. Split-Ugi Reaction
Scheme 1. Ugi’s Synthesis of Xylocaine
Because of the limitations cited above, in this paper we
wish to present a novel strategy to synthesize, in an easy
and straightforward manner, symmetrical and unsymme-
trical bis-(β-aminoamides) suppressing the competing
split-Ugi reaction, and without using an excess of mineral
or Lewis acids and aminoboranes. In order to demon-
strate, once more, the poor nucleophilicity of water, at the
beginning, wecarried out a reactionbetween a symmetrical
secondary diamine (6), paraformaldehyde (3), water (7),
and pentyl isocyanide (8) in methanol both at room
temperature and at reflux. In both cases we were able to
recover only the aminal (9) (Scheme 1). The use of the
diamine as dichloridrate6a did not change the result of the
reaction as well as the use of phenylphosphonic acid (10) as
the catalyst.11b These results confirm once again the poor
nucleophilicity of water and its low propensity to attack
the nitrilium ion, opening up other reaction pathways. The
presence of a carboxylic acid is therefore necessary both to
hydrolyze the aminal and to give the iminoanhydride
intermediate. In this particular situation the imidate
should be attacked by the nucleophilic solvent of the
reaction (methanol) to release the desired compound.
Unfortunately, when 2 equiv of acetic acid (11), pentyl
isocyanide, and praraformaldeyde were used, the product
of the split-Ugi reaction (12) was always the major com-
ponent compared to the symmetrical bis-(β-aminoamide)
13 (Scheme 3).
The mechanism of the reaction can be rationalized by
the fact that the more nucleophilic chloride ion attacks the
nitrilium ion instead of water.7 At this point the unstable
chloroimidate is then converted into the desired amide by
reaction with water.8 Note the presence of a secondary
amine which directly gives an iminium ion, ruling out the
use of the acid to activate the imine.9,10
Other works in which water was the fourth component
of the Ugi reaction have been and are continuously
reported, but in all cases a Lewis or Brønsted acid is always
(4) See for example: (a) Katritzky, A.; Qi, M.; Feng, D. J. Org. Chem.
1998, 63, 6712–6714. (b) Tsukube, H.; Adachi, H.; Morosawa, S. J. Org.
Chem. 1991, 25, 7102–7108.
(5) (a) Isonitrile Chemistry; Ugi, I., Ed.; Academic Press: New York,
€
1971. (b) Ugi, I.; Werner, B.; Domling, A. Molecules 2003, 8, 53–66.
€
(6) (a) Ugi, I.; Steinbruckner, C. U.S. Patent 3247200, 1966. (b) Ugi,
I; Werner, B. The four-component reaction and other multicomponent
reactions of the isocyanides. In Methods and reagents for green chem-
istry; Tundo, P., Perosa, A., Zecchini, F., Eds.; John Wiley & Sons, Inc.:
Hoboken, NJ, 2007; pp 3À22.
(7) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84, 16–24.
(8) The formation of a chloroimidate intermediate has been reported.
See for example: (a) Yue, T.; Wang, M. X.; Wang, D. X.; Zhu, J. Angew.
Chem., Int. Ed. 2008, 47, 9454–9457. (b) Giustiniano, M.; Pirali, T.;
Massarotti, A.; Biletta, B.; Novellino, E.; Campiglia, P.; Sorba, G.;
Tron, G. C. Synthesis 2010, 23, 4107–4118.
(9) Paraformaldeyde reacts with diethylamine without the need of an
acid as catalyst; see: Bhat, A. R.; Bhat, A. I.; Athar, F.; Azam, A. Helv.
Chim. Acta 2009, 92, 1644–1656.
(10) The acid could also be important to hydrolize back the aminal.
(11) (a) McFarland, J. J. Org. Chem. 1963, 28, 2179–2181. For more
recent exemples, see: (b) Pan, C. S.; List, B. Angew. Chem., Int. Ed. 2008,
47, 3622–3625. (c) Ramazani, A.; Rezai, A.; Mahyari, A.; Rouhani, M.;
Khoobi, M.; Yaaghubi, E.; Shabrendi, H.; Vessally, E.; Azizkhani, V.;
Amini, I.; Lashgari, H.; Noohi, G.; Shaghaghi, Z.; Sadri, F. Synth.
Commun. 2001, 41, 1444–1454. (d) Shaabani, A.; Keshipour, S.;
Shaabani, S.; Mahyari, M. Tetrahedron Lett. 2012, 53, 1641–1644. (e)
(12) (a) Tanaka, Y.; Hasui, T.; Sugimone, M. Org. Lett. 2007, 9,
4407–4410. (b) Tanaka, Y.; Hidaka, K.; Hasui, T.; Suginome, M. Eur. J.
Org. Chem. 2009, 1148–1151.
(13) Carniato, D.; Jaillardon, K.; Busnel, K.; Gutmann, M.; Briand,
J. F.; Deprez, B.; Thomas, D.; Bougeret, C. WO 2009150248.
(14) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I.;
Pirali, T. Angew. Chem., Int. Ed. 2006, 45, 1099–1102.
€
Domling, A. Amino Group Chemistry. In From Synthesis to the Life
Science; Ricci, A., Ed.; Wiley-VCH: 2008; pp 149À182.
B
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The scope of this reaction was next examined, and dif-
ferent isocyanides and bis-amines were used in order to
demonstrate the generality of the reaction.
The symmetrical bis-(βaminoamides) synthesized (21À30)
are listed in Figure 3 showing the generality of this novel
procedure.
Scheme 3. Failed Attempts To Prepare the Symmetrical
Bis-(β-aminoamides)
Even with the sterically hindered pivalic acid (14) we
could only recover the split-Ugi adduct along with the
Passerini reaction product (15). At this point, given the
importance of the presence of a carboxylic acid to attack
the nitrilium intermediate, we thought to use a functiona-
lized carboxylic acid with a nucleophilic arm. This moiety
should be able to compete withthe other amine component
for reaction with the imino-anhydride intermediate to give
a sacrifical Mumm rearrangement. To accomplish our
task, we thought that 2-hydroxymethyl benzoic acid (16)
could be the right partner (Figure 2).
Figure 3. Symmetrical bis-(βaminoamides) synthesized.
Then, we wondered, using only 1 equiv of acid 16,aldehyde,
and isocyanide, if the sacrifical Mumm rearrangement
could still prevail over the competing split-Ugi reaction.
Satisfactorily, reaction among piperazine, paraformalde-
hyde, benzylisocyanide, and 16 gave the desired Ugi pro-
duct (31) in 60% yield along with the symmetrical bis-
(β-aminoamide) in 10% yield. After chromatographic
purification, the compound can undergo a similar reaction
using a different isocyanide (32) to give in 90% yield the
desired unsymmetrical bis-(β-aminoamide) (33) (Scheme5).
Figure 2. Sacrifical Mumm rearrangement.
To our satisfaction, when piperazine (18) was mixed with
2 equiv of acid (16), benzyl isocyanide (19), and parafor-
maldehyde (3) in methanol at reflux, we obtained the desired
product (20) in 90% yield (Scheme 4). It is important to
highlight that the 2-hydroxymethyl benzoic acid behaves
like a pseudo water molecule by first trapping the nitrilium
ion as in a normal Ugi reaction. This acid then undergoes an
intramolecular cyclization to deliver only one oxygen atom
to the product, as water would, producing the aromatic
lactone phthalide (17). This latter can be easily recovered by
column chromatography due to its lipophilic nature and can
be used again to prepare 16 (see Supporting Information).
Scheme 5. Formation of the Unsymmetrical Bis-(β-
aminoamide) 33
Scheme 4. Formation of the Symmetrical Bis-(β-aminoamide) 20
Even in this case a library of unsymmetrical bis-(β-amino-
amides) has been prepared (Figure 4).
Finally, we applied our methodology for the formal
synthesis of the antianginal agent ranolazine (46) (Figure 5).
Org. Lett., Vol. XX, No. XX, XXXX
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Figure 5. Formal synthesis of ranolazine.
In conclusion we developed a novel methodology for the
preparation of symmetrical and unsymmetrical bis-(β-ami-
noamides) using available starting materials and avoid-
ing the use of protective groups. The use of 16 is man-
datory to suppress the competing split-Ugi reaction
and circumvent the poor reactivity of water on the
nitrilium ion. As the piperazine ring is considered a
privileged structure in medicinal chemistry with at least
73 drug entries of piperazine-related drugs deposited in
the Drug Bank,16 this novel strategy may be an added
value for medicinal chemists. Use of these compounds
as potential calcium channel inhibitors17 and applica-
tion of this reaction to the synthesis of symmetrical
polyamines18 will be reported in due course.
Figure 4. Unsymmetrical bis-(βaminoamides) synthesized.
Indeed, the advanced intermediate 44 can be prepared with
our chemistry in 70% yield under optimized conditions
and can then be coupled with the epoxy derivative (45) as
already shown.15
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Acknowledgment. Financial support from Universita del
Piemonte Orientale and M.I.U.R. PRIN 2010W7YRLZ_002
is gratefully acknowledged.
(15) Aalla, S.; Gilla, G.; Anumula, R. R.; Kurella, S.; Padi, P. P.;
Vummenthla, P. R. Org. Process Res. Dev. 2012, 16, 748–754.
€
(16) Huang, Y.; Khoury, K.; Domling, A. Top. Heterocycl. Chem.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds
synthesized. This material is available free of charge via
the Internet at http://pubs.acs.org.
2010, 23, 85–127.
(17) Yang, Z. Q.; Barrow, J. C.; Shipe, W. D.; Schlegel, K. A.; Shu,
Y.; Yang, F. V.; Lindsley, C. W.; Rittle, K. E.; Bock, M. G.; Hartman,
G. D.; Uebele, V. N.; Nuss, C. E.; Fox, S. V.; Kraus, R. L.; Doran, S. M.;
Connolly, T. M.; Tang, C.; Ballard, J. E.; Kuo, Y.; Adarayan, E. D.;
Prueksaritanont, T.; Zrada, M. M.; Marino, M. J.; Graufelds, V. K.;
DiLella, A. G.; Reynolds, I. J.; Vargas, H. M.; Bunting, P. B.;
Woltmann, R. F.; Magee, M. M.; Koblan, K. S.; Renger, J. J. J. Med.
Chem. 2008, 51, 6471–6477.
(18) Pirali, T.;Callipari, G.;Ercolano, E.;Genazzani, A. A.;Giovenzana,
G. B.; Tron, G. C. Org. Lett. 2008, 10, 4199–4202.
The authors declare no competing financial interest.
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