Enols as feasible acid components in the Ugi condensation

Article abstract of DOI:10.1021/ol302976g

Heterocyclic enols are used for the first time as acid components in an Ugi-type multicomponent condensation. For that purpose, we have chosen enols containing a Michael acceptor, in order to facilitate an irreversible rearrangement of the primary Ugi adduct. The new four-component process leads readily and efficiently to heterocyclic enamines containing at least six elements of diversity.

Full text of DOI:10.1021/ol302976g

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6218–6221
Enols as Feasible Acid Components
in the Ugi Condensation§
Teresa G. Castellano,† Ana G. Neo,† Stefano Marcaccini,*,‡ and Carlos F. Marcos*,†
´
Laboratorio Quımica Organica y Bioorganica (L.O.B.O.), Departamento Quımica
Organica e Inorganica, Facultad de Veterinaria, Universidad de Extremadura,
ꢀ
ꢀ
´
ꢀ
ꢀ
ꢀ
ꢁ
10071 Caceres, Spain, and Dipartimento Chimica ‘Ugo Schiff’, Universita di Firenze,
50019 Sesto Fiorentino (FI), Italy
cfernan@unex.es
Received October 29, 2012
ABSTRACT
Heterocyclic enols are used for the first time as acid components in an Ugi-type multicomponent condensation. For that purpose, we have chosen
enols containing a Michael acceptor, in order to facilitate an irreversible rearrangement of the primary Ugi adduct. The new four-component
process leads readily and efficiently to heterocyclic enamines containing at least six elements of diversity.
Multicomponent reactions (MCR)1 are highly conver-
gent processes that lead to complex molecules with great
efficiency and atom economy.2 Particularly useful are
MCR of isocyanides (IMCRs), as the Ugi four-component
condensation (U4CC), in which carboxylic acids, carbonyl
compounds, amines and isocyanides afford diversely
functionalized R-acylamino amides.3 Further structural
diversity can be achieved through a wide variety of post-
condensation transformations,4 and we have successfully
used this strategy for the synthesis of biologically relevant
heterocycles,5 β-dicarbonylic compounds,6 amino acid
derivatives7 and retro-peptide building blocks.8
A conceivably even more powerful approach to scaffold
diversity replaces one of the components by a new reagent
that mimics its reactivity and chemical behavior.9
† Universidad de Extremadura.
‡
ꢁ
Universita di Firenze.
§ Dedicated to the memory of our friend Stefano Marcaccini, who died
October 1, 2012.
€
(1) (a) Domling, A. Chem. Rev. 2006, 106, 17. (b) Domling, A.; Ugi, I.
Significantly, the carboxylic acid is involved in several
key steps of the classical U4CC, and hence its substitution
leads tomajorstructuralchanges.1b,10 Forexample, theuse
€
€
Angew. Chem., Int. Ed. 2000, 39, 3169. (c) Ugi, I.; Domling, A.; Horl, W.
Endeavour 1994, 18, 115.
(2) Isambert, N.; Lavilla, R. Chem.;Eur. J. 2008, 14, 8444.
€
(3) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
1959, 71, 386.
(6) (a) Carrillo, R. M.; Neo, A. G.; Lopez-Garcia, L.; Marcaccini, S.;
Marcos, C. F. Green Chem. 2006, 8, 787. (b) Neo, A. G.; Delgado, J.;
Polo, C.; Marcaccini, S.; Marcos, C. F. Tetrahedron Lett. 2005, 46, 23.
(7) Faggi, C.; Neo, A. G.; Marcaccini, S.; Menchi, G.; Revuelta, J.
Tetrahedron Lett. 2008, 49, 2099.
(8) Neo, A.; Carrillo, R.; Delgado, J.; Marcaccini, S.; Marcos, C.
Mol. Diversity 2011, 15, 529.
(9) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(4) Marcaccini, S.; Torroba, T. Post-Condensation Modifications of
the Passerini and Ugi Reactions. In Multicomponent Reactions; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2005; p 33.
(5) (a) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetra-
hedron Lett. 1997, 38, 2519. (b) Bossio, R.; Marcos, C. F.; Marcaccini, S.;
Pepino, R. Synthesis 1997, 1389. (c) Bossio, R.; Marcaccini, S.; Pepino,
R.; Marcos, C. F. J. Chem. Educ. 2000, 77, 382. (d) Marcaccini, S.;
Pepino, R.; Marcos, C. F.; Polo, C.; Torroba, T. J. Heterocycl. Chem.
2000, 37, 1501. (e) Marcos, C. F.; Marcaccini, S.; Pepino, R.; Polo, C.;
Torroba, T. Synthesis 2003, 691. (f) Neo, A. G.; Marcos, C. F.;
Marcaccini, S.; Pepino, R. Tetrahedron Lett. 2005, 46, 7977. (g) Marcos,
C. F.; Marcaccini, S.; Menchi, G.; Pepino, R.; Torroba, T. Tetrahedron
Lett. 2008, 49, 149. (h) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino,
R. Heterocycles 1997, 45, 1589. (i) Neo, A. G.; Carrillo, R. M.; Barriga,
S.; Moman, E.; Marcaccini, S.; Marcos, C. F. Synlett 2007, 327. (j)
Marcaccini, S.; Neo, A. G.; Marcos, C. F. J. Org. Chem. 2009, 74, 6888.
(10) (a) Ugi, I.; Steinbruckner, C. Angew. Chem., Int. Ed. 1960, 72,
€
267. (b) Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 2802. (c) Ugi, I.
Angew. Chem., Int. Ed. 1962, 1, 9. (d) Rosendahl, K. H.; Ugi, I. Liebigs
Ann. Chem. 1963, 65. (e) Ugi, I.; Steinbruckner, C. Chem. Ber. Recl.
1961, 94, 734. (f) Heck, S.; Domling, A. Synlett 2000, 424. (g) Bossio, R.;
Marcaccini, S.; Pepino, R. Liebigs Ann. Chem. 1993, 1229.
(11) Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R.; Polo, C.
Synthesis 1991, 999.
r
10.1021/ol302976g
Published on Web 11/30/2012
2012 American Chemical Society

Table 1. Ugi Condensation with Heterocyclic Enols
Figure 1. X-ray structure of Ugi adduct 13a.
Scheme 1. Synthesis of Pyrrolidine-2,3-diones
an irreversible last reaction step,3,12 we hypothesize that
the viability of such processes would lie in the presence of
specific structural motifs in the enol that make possible an
irreversible transformation of the primary adduct. Here we
demonstrate the viability of this novel alternative and its
successful use for the straightforward synthesis of amino
acid-derived heterocyclic enamines.15
Accordingly, we selected different 5- and 6-membered
enolic heterocycles containing R,β-unsaturated electron-
withdrawing groups (1À6).16 Expectedly, they would react
with Schiff bases and isocyanides to give Ugi-type primary
adducts that would subsequently suffer a Michael-retro-
Michael rearrangement to stable heterocyclic enamines
(Table 1).
Thus, heterocyclic enols (1À6), (E)-N-benzylidene-1-
phenylmethanamine (7a) and cyclohexyl or terc-butyl
isocyanide (8; R6 = c-C6H11 or t-Bu) were mixed in
methanol at rt. The reaction was followed by tlc, and the
consumption of the starting enol and the formation of a new
product was evident after a few hours. In all cases, the
products were isolated in moderate or good yields and were
successfully identified, according to their spectral data, as the
expected Ugi-type adducts (9À14, Table 1). The structure of
3-amino-1H-pyrrol-2(5H)-one (13a; Table 1, entry 5), ob-
tained as an almost equimolar mixture of the two possible
a General procedure: equimolar amounts of the reagents were stirred
in methanol at rt for 72 h. b Yields are non optimized.
of phenols as acid surrogates was successfully introduced
by Marcaccini,11 and then applied by El Kaim to a series of
reactions in which the primary adduct is stabilized through
a Smiles rearrangement.12 Enols have pKa values compar-
able to that of phenols,13 being sufficiently acidic to
protonate imines. Furthermore, enolates are more nucleo-
philic than carboxylates, and thus able to trap the nitrilium
intermediates formed in Ugi-type condensations. Surpris-
ingly, with the only exception of a very recently published
double Ugi reaction with highly acidic bis-enolic squaric
acid,14 the use of enols in such reactions is unprecedented.
We anticipate that the use of heterocyclic enol deriva-
tives would provide a simple approach to the synthesis of
libraries of compounds containing biologically privileged
heterocyclic structures. As efficient IMCRs always include
(15) Jourdan, F.; Kaiser, J. T.; Lowe, D. J. Synth. Commun. 2005, 35,
2453.
(16) (a) Zhong, Y.-L.; Zhou, H.; Gauthier, D. R., Jr.; Askin, D.
Tetrahedron Lett. 2006, 47, 1315. (b) Stefanou, V.; Matiadis, D.; Melagraki,
G.; Afantitis, A.; Athanasellis, G.; Igglessi-Markopoulou, O.; McKee, V.;
Markopoulos, J. Molecules 2011, 16, 384. (c) Savel’ev, V. L.; Artamonova,
O. S.; Troitskaya, V. S.; Vinokurov, V. G.; Zagorevskii, V. A. Chem.
Heterocycl. Compd. 1973, 9, 816. (d) Gein, V.; Gein, L.; Bezmaternykh, E.;
Voronina, E. Pharm. Chem. J. 2000, 34, 254. (e) Wasserman, H. H.; Koch,
R. C. J. Org. Chem. 1962, 27, 35.
(12) (a) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed.
2005, 44, 7961. (b) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J.
J. Org. Chem. 2007, 72, 4169. (c) Marcaccini, S.; Menchi, G.; Trabocchi,
A. Tetrahedron Lett. 2011, 52, 2673.
(13) Werstiuk, N. H.; Andrew, D. Can. J. Chem. 1990, 68, 1467.
(14) Aknin, K.; Gauriot, M.; Totobenazara, J.; Deguine, N.; Deprez-
Poulain, R.; Deprez, B.; Charton, J. Tetrahedron Lett. 2012, 53, 458.
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Org. Lett., Vol. 14, No. 24, 2012
6219

Table 2. Three-component Synthesis of 4-Aminoacil-pyrrolidones
entry
R1
Ph
R2
R3
R4
R5
R6
producta (% Yield) diastereomeric ratio (A:B)
1
Ph
Ph
Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
cC6H11
13a (95)
13b (92)
13c (81)
13d (93)
13e (72)
13f (88)
13g (91)
13h (92)
13i (90)
13j (84)
13k (94)
13l (94)
13m (84)
13n (80)
13o (83)
13p (88)
13q (29)
13r (85)
13s (68)
13t (66)
13u (86)
13v (82)
14a (70)
14b (67)
55:45b
60:40
50:50
60:40
67:33
63:37
50:50
55:45
50:50
50:50
50:50
50:50
56:44
63:37
50:50
50:50
60:40
55:45
50:50
55:45
50:50
64:36
60:40
63:37
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
tBu
3
2,6-Me2Ph
cC6H11
4
4-ClC6H4
4-ClC6H4
4-FC6H4
5
CH2CO2tBu
cC6H11
6
7
4-FC6H4
tBu
8
4-FC6H4
2,6-Me2Ph
CH2CO2tBu
PhCH2
9
4-FC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-MeOC6H4
4-MeOC6H4
C5H11
3,4-(OCH2O)C6H3 Et Ph
cC6H11
Ph
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
3,4-(OCH2O)C6H3CH2 cC6H11
3,4-(OCH2O)C6H3CH2 tBu
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-MeOC6H4
3,4-(OCH2O)C6H3CH2 CH2CO2tBu
3,4-(OCH2O)C6H3CH2 CH2CO2tBu
3,4-(OCH2O)C6H3CH2 TOSMIC
3,4-(OCH2O)C6H3CH2 C5H11
3,4-(OCH2O)C6H3 Et Ph
4-MeOC6H4
Et 2-furil PhCH2
cC6H11
tBu
Ph
Et 2-furil PhCH2
4-MeOC6H4
4-MeOC6H4
Me Ph
Me Ph
Et Ph
Et Ph
PhCH2
cC6H11
3,4-(OCH2O)C6H3CH2 tBu
PhCH2 Ph
PhCH2 Ph
PhCH2
PhCH2
cC6H11
tBu
a For optimized reaction conditions, see Supporting Information. b RS:RR ratio.
diastereomers, was further confirmed by fractional crystal-
lization and X-ray diffraction analysis of the R,S diaster-
eomer (Figure 1).
alternatively, alkyl oxalacetates (17),16e,20 or acetylenedi-
carboxylates (18; Scheme 1),21 which exponentially
increases the diversity of products attainable from the
Ugi-type condensation. Furthermore, the presence of a
stereogenic center at position 5 of the ring could be advan-
tageous, as it would lead to the formation of two readily
separable diastereomeric products in the Ugi-type reaction.
After some optimization, successive addition of cyclo-
hexyl isocyanide (8, R6 = c-C6H11; 2 equiv) and the enol
(5a, 1 equiv) to a solution of the imine (7a, 2 equiv) in
methanol, and stirring the resulting mixture at 26 °C for 48
h afforded 13a in 95% yield and a 55:45 RS:RR diaster-
eomeric ratio.
To optimize the new reaction, we selected pyrrolidine-
2,3-diones17 with carboxyl substituents on position 4 (5, 6;
Scheme 1), which have drawn our attention as they are in
the core of many natural products and drugs.15,18 Impor-
tantly, the pyrrolidone scaffold have been demonstrated
to be a privileged structure in the design of modulators of
proteinÀprotein interactions.18,19 Advantageously, pyrrolidine-
2,3-diones (5, 6) are readily accessible through three-
component reactions of aldehydes (15), amines (16) and,
To further explore the scope of this new condensation,
we applied the optimized reaction conditions to different
isocyanides (8), imines (7) and pyrrolidinodiones (5, 6;
Table 2). The reaction proceeds as expected, giving in all
the cases the corresponding pyrrolidinonamines (13, 14) in
good to excellent yields. Remarkably, although the dia-
stereomeric ratio was always close to 1:1, in many cases
(17) Vaughan, W. R.; Covey, I. S. J. Am. Chem. Soc. 1958, 80, 2197.
(18) (a) Thiel, P.; Kaiser, M.; Ottmann, C. Angew. Chem., Int. Ed.
2012, 51, 2012. (b) Rose, R.; Erdmann, S.; Bovens, S.; Wolf, A.; Rose,
M.; Hennig, S.; Waldmann, H.; Ottmann, C. Angew. Chem., Int. Ed.
2010, 49, 4129. (c) Armisheva, M.; Kornienko, N.; Gein, V.; Vakhrin, M.
Russ. J. Gen. Chem. 2011, 81, 1893.
(19) (a) Reddy, T. R. K.; Li, C.; Guo, X.; Myrvang, H. K.; Fischer,
P. M.; Dekker, L. V. J. Med. Chem. 2011, 54, 2080. (b) Zhuang, C.;
Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.; Wang, S.; Zhang, Y.; Wu, Y.;
Yao, J.; Sheng, C.; Zhang, W. J. Med. Chem. 2012, 55 (22), 9630.
(20) Metten, B.; Kostermans, M.; Van Baelen, G.; Smet, M.; Dehaen,
W. Tetrahedron 2006, 62, 6018.
(21) (a) Taylor, W.; Vadasz, A. Aust. J. Chem. 1982, 35, 1227. (b) Sun,
J.; Wu, Q.; Xia, E.-Y.; Yan, C.-G. Eur. J. Org. Chem. 2011, 2011, 2981.
6220
Org. Lett., Vol. 14, No. 24, 2012

ring, followed by β-elimination of the imidate oxygen
(Scheme 2). Similar intramolecular Michael additionÀ
elimination processes have been observed in other systems,22
but in the present case, this is especially favored, as an
unstable imidate rearranges to a stable amide. This rearran-
gement plays a similar role to the usual O to N acyl migration
in the classical U4CC, making the whole process irreversible
and ensuring the efficiency of the reaction. As in the classic
U4CC, the condensation with enols seems to be favored in
polar solvents. However, surprisingly, it also takes place in
toluene, although at a slower rate than in methanol.
Scheme 2. Proposed Mechanism of the MCR with Enols
We finally explored the possibility of performing the
four-component condensation of isocyanides (8), enols
(5), aldehydes (15) and amines (16), instead of using
preformed imines (7). Consequently, benzaldehyde (15;R4 =
C6H5), benzylamine (16; R5 = CH2C6H5), cyclohexylisocya-
nide (8;R6 =c-C6H11) and pyrrolidinodione (5a) were mixed
in methanol in the usual reaction conditions. The expected
aminopyrrolidine (13a) was isolated in a 70% yield, after 6
days. The reaction was then performed in the presence of
anhydrous sodium sulfate to favor the formation of the imine.
In this case, the yield was improved to 86% after only 48 h.
Representative examples of this four-component condensa-
tion were also performed, and the expected products
were obtained with good or excellent yields in all the cases
(Table 3). Indeed, the operationally simpler four component
condensation can be conveniently performed, with a minimal
detriment on the yield.
Table 3. Four-component Synthesis of 4-Aminoacil-
pyrrolidones
In conclusion, we have developed a novel, efficient and high
yielding IMCR in which, for the first time, heterocyclic enols
are used as the acid partners in an Ugi type condensation. The
reaction takes place smoothly at room temperature, with no
need of catalysis. The success of this transformation lies in the
structure of the enols that makes possible a conjugate addi-
tion-β-elimination rearrangement on the primary adduct.
This approach constitutes a general, convenient and highly
convergent synthesis of amino acid-derived enamines, which
has been optimized for the preparation of biologically relevant
3-amino-1H-pyrrol-2(5H)-ones containing six elements of
diversity. Further studies are underway to improve diaster-
eoselectivities and to extend this new MCR to the synthesis of
other heterocyclic and nonheterocyclic enamines.
product
(% yield)
entry R1
R2
R3 R4
R5
R6
1
2
3
Ph Ph
Et Ph CH2Ph
Et Ph CH2Ph
cC6H11 13a (86)
tBu 13b (85)
Ph Ph
Ph Ph
Et Ph 3,4-(OCH2O)- cC6H11 13m (78)
PhCH2
4
Ph 4-MeOPh Me Ph CH2Ph
cC6H11 13u (90)
only one of the diastereoisomers spontaneously precipi-
tates from the reaction mixture, and can be cleanly isolated
by filtration. The NMR data suggest that the precipitate is
always the R,S diastereoisomer, although an unequivocal
assignation is not possible. Moreover, both diastereomers
give distinctive spots on tlc and can be readily separated either
by fractional crystallization or column chromatography.
In agreement with our initial hypothesis, the formation of
pyrrolidinones 13 and 14 can be rationalized considering
that the primary Ugi adducts 20 suffer an intramolecular
conjugate addition of the amine nitrogen to the heterocyclic
Acknowledgment. We are thankful for support from
Instituto de Salud Carlos III (PI081234), Junta de Extre-
madura and FEDER. T.G.C. thanks UEx for a predoc-
toral fellowship.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds and the CIF of 13a. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) (a) Okuda, K.; Watanabe, N.; Hirota, T.; Sasaki, K. Tetrahedron
Lett. 2010, 51, 903. (b) Stiasni, N.; Kappe, C. O. ARKIVOC 2002, 71.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
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