Catalytic three-component Ugi reaction

Article abstract of DOI:10.1002/anie.200800494

(Chemical Equation Presented) Perfect atomeconom y characterizes a novel catalytic three-component Ugi reaction (see example). Different α-amino amides are formed in good yields from aldehydes, primary amines, and isocyanides in the presence of phenyl phosphinic acid as the catalyst. The products will be useful for the synthesis of α-amino acid derivatives and in diversity-oriented synthesis.

Full text of DOI:10.1002/anie.200800494

Communications
DOI: 10.1002/anie.200800494
Multicomponent Reactions
Catalytic Three-Component Ugi Reaction**
Subhas Chandra Pan and Benjamin List*
Dedicated to Professor Elias J. Corey on the occasion of his 80th birthday
Multicomponent reactions (MCRs) are one-pot processes
that combine three or more substrates simultaneously.[1] Such
processes are of great interest in diversity-oriented synthesis,
especially to generate compound libraries for screening
purposes. The Ugi four-component reaction (Ugi 4CR)[2] is
one of the milestones in this field and great efforts have been
devoted to the exploration of the potential of this trans-
formation.[3] A primary amine,a carbonyl compound,a
carboxylic acid,and an isocyanide react to give a-amido
amides in this remarkable reaction. In recent years several
modifications of the classical Ugi 4CR have been described;
these include variations of one of the components or the
introduction of a linkage between two of them.[4] In particular,
the groups of Zhu[5] and Dömling[6] have contributed signifi-
cantly to the advancement of this transformation.[7] Mecha-
nistically,the Ugi reaction is believed to proceed via a
nitrilium ion intermediate (A),which results from the
addition of the isocyanide to an in situ generated iminium
ion (Scheme 1). Nucleophilc addition of the carboxylate ion
Scheme 1. Ugi 4CR and new three-component reaction.
followed by Mumm rearrangement leads to the final product
and water as the only by-product (Scheme 1,path a). We
reasoned that it should be possible to intercept the nitrilium
ion A not with the carboxylate ion but rather with the water
molecule generated in the course of imine formation. This
would require using acids (HX) other than carboxylic acids
and possibly result in a catalytic cycle (Scheme 1,path b). To
the best of our knowledge such a three-component Ugi
reaction,which transforms an aldehyde,a primary amine,and
an isocyanide to an a-amino amide is unknown.[8] Given the
potential of these products for the synthesis of a-amino acids
and their derivatives,we became interested in developing this
new reaction. Here we report the first catalytic three-
component Ugi reaction in which water acts as the internal
nucleophile. We identified phenyl phosphinic acid (10) as the
best catalyst for this perfectly atom-economic reaction,thus
introducing a new motif for organocatalysis.
The newly designed reaction does not proceed in the
absence of catalyst. Stirring benzaldehyde (1a), p-anisidine
(2a),and tert-butyl isocyanide (3a) at room temperature for
three days in toluene resulted in no detectable quantities of
the desired product (4a). Even heating the reaction mixture
to 808C for 24 h did not result in the formation of product 4a.
At this point we started to investigate different Brønsted acid
catalysts for this reaction (Table 1). p-Toluenesulfonic acid (5)
gave no conversion to the product either at room temperature
or at 808C (Table 1,entry 1). The desired product was
obtained in poor yields when phenyl boronic acid (6) or
diphenyl phosphate (7) were used as the catalysts (Table 1,
entries 2 and 3). Sc(OTf)3 (8) could also promote this reaction
but with low conversion (Table 1,entry 4). Phenyl phosphonic
acid (9) gave moderate conversion (Table 1,entry 5).
Remarkably,we found phenyl phosphinic acid ( 10) to be a
highly active catalyst for the reaction,giving the desired
[*] S. C. Pan, Prof. Dr. B. List
[9]
product in 95% conversion (Table 1,entry 6),
whereas
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
diphenyl phosphinic acid (11) and diphenyl phosphine oxide
(12) were proved to be inactive (Table 1,entries 7 and 8).
Decreasing the catalyst loading of 10 to 5 mol% resulted in
considerably lower yield. Other solvents were also screened
but toluene generally gave the best yields (see Supporting
Information for details).
Using phenyl phosphinic acid (10) as the catalyst and
toluene as solvent,we initiated a study to explore the scope of
this new three-component reaction. First,the reaction of a
variety of different aldehydes 1 with p-anisidine (2a) as the
E-mail: list@mpi-muelheim.mpg.de
[**] This work was funded in part by the DFG (Priority program
“Organocatalysis” SPP1179). Generous support by the Max Planck
Society, Novartis (Young Investigator Award to B.L.), the Fonds der
Chemischen Industrie (Silver Award to B.L.), and AstraZeneca
(Research Award in Organic Chemistry to B.L.) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3622
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3622 –3625

Angewandte
Chemie
Table 1: Identification of an efficient catalyst for the three-component
Ugi reaction.
aliphatic a-branched aldehydes and an a-unbranched alde-
hyde gave good yields (Table 2,entries 8–11).
A variety of amines was investigated next using benzal-
dehyde (1a) as the aldehyde component and tert-butyl
isocyanide (3a) as the other component (Table 3). It turned
Table 3: Catalytic three-component Ugi reaction of benzaldehyde with
different amines and tert-butyl isocyanide.
Entry[a]
R2
Product
Time [h]
Yield [%][b]
1
2
3
4
5
6
2-naphthyl
4-CF3C6H4
4-CO2EtC6H4
3-ClC6H4
3-pyridyl
4l
4m
4n
4o
4p
4q
4r
20
20
20
20
20
20
36
20
36
83
81
88
74
81
42
36
40
41
Entry
Catalyst
Conversion [%][a]
1
2
3
4
5
6
7
8
5
6
7
8
9
10
11
12
0
8
PhCH2
(Ph)2CH
7[c]
8
9
15
30
35
95
8
Allyl
4s
4t
2
=
R NH (Ph)2NH
2
[a] Reaction conditions analogous to those described in Table 2. [b] Yield
of the product after silica gel column chromatography. [c] Using
20 mol% of catalyst 10.
0
[a] Determined by gas chromatography.
out that different aromatic amines can be used to give
products in high yields (Table 3,entries 1–4). The electronic
properties of the aromatic system of the amine component do
not seem to influence the yield of the reaction. Even the
heteroaromatic pyridylamine gave the desired product in
good yield (Table 3,entry 5). The reaction also works with
benzylamine and benzhydrylamine; however,slightly lower
yields were obtained (Table 3,entries 6 and 7). Furthermore,
an (allyl)amine undergoes the reaction to give the desired
product in moderate yield (Table 3,entry 8). Finally a
secondary amine was probed and provided product 4t in
41% yield (Table 3,entry 9).
amine component and tert-butyl isocyanide (3a) was exam-
ined (Table 2). The reactions took place efficiently in good
yields for all the aldehydes studied. Particularly high yields
were observed with aromatic aldehydes (Table 2,entries 1–5)
and an a,b-unsaturated aldehyde (Table 2,entry 6). Hetero-
aromatic 3-pyridyl carbaldehyde can be employed in this
reaction with moderate yield (Table 2,entry 7),and even
Table 2: Catalytic three-component Ugi reaction of different aldehydes
with tert-butyl isocyanide and p-anisidine.
The isocyanide component of our reaction can also be
varied: both cyclohexyl isocyanide and benzyl isocyanide
gave the corresponding products in high yields (Table 4,
entries 1 and 2). Good results were also obtained with a
Entry[a]
R1
Product
Time [h]
Yield [%][b]
1
2
3
4
5
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
12
12
20
20
20
20
20
20
20
20
20
91
88
78
82
87
83
51
74
81
52
61
Table 4: Catalytic three-component Ugi reaction of benzaldehyde with
p-anisidine and different isocyanides.
4-MeOC6H4
4-ClC6H4
2-ClC6H4
2-naphthyl
(E)-CH CHPh
3-pyridyl
iPr
cHex
tBu
nBu
6[c]
7
8
9
10
11
=
Entry[a]
R3
Product
Time [h]
Yield [%][b]
4j
4k
1
2
3
4
5
cHex
Bn
tBuCH2C(Me2)
EtO2CCH2
pTsCH2
4u
4v
4w
4x
4y
20
36
20
20
20
78
64
62
83
68
[a] Reaction conditions: Aldehyde
1 (0.5 mmol), p-anisidine (2a,
0.5 mmol), tert-butyl isocyanide (3a, 0.5 mmol), and catalyst 10
(0.05 mmol) were stirred at 808C in toluene (0.5 mL). [b] Yield of the
product after silica gel column chromatography. [c] Using 20 mol% of
catalyst 10.
[a] Reaction conditions analogous to those described in Table 2. [b] Yield
of the product after silica gel column chromatography.
Angew. Chem. Int. Ed. 2008, 47, 3622 –3625
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3623

Communications
longer chain isocyanide (Table 4,entry 3) and even with
functionalized isocyanides (Table 4,entries 4 and 5).
Although no detailed mechanistic studies have been
carried out at this point,a catalytic cycle leading to the a-
amino amide product can be envisaged (Scheme 2). Phenyl
ceutical and agrochemical substance libraries. Further studies
in our laboratory are underway to develop an asymmetric
catalytic version,[12] to obtain a better understanding of the
role of the phosphinic acid catalyst,and to explore other
catalytic reactions with isocyanides.
Experimental Section
Aldehyde 1 (0.5 mmol),amine 2 (0.5 mmol),isocyanide 3 (0.5 mmol),
and catalyst 10 (10 mol%) were placed into a dry flask and dry
toluene (0.5 mL) was added. The mixture was stirred for 12–36 h at
808C and then directly subjected to silica gel column chromatography
(ethyl acetate/hexane) to give pure product 4.
Received: January 30,2008
Published online: March 28,2008
Keywords: a-amino amides · phosphinic acids · Ugi reactions
.
[1] a) Multicomponent Reactions (Eds.: J. Zhu,H. BienaymØ),
Wiley-VCH,Weinheim, 2005,and references therein; b) D. J.
Ramón,M. Yus, Angew. Chem. 2005, 117,1628 – 1661; Angew.
Chem. Int. Ed. 2005, 44,1602 – 1634; c) J. Zhu, Eur. J. Org. Chem.
2003,1133 – 1144; d) R. V. A. Orru,M. de Greef, Synthesis 2003,
1471 – 1499; e) H. BienaymØ,C. Hulme,G. Oddon,P. Schmitt,
Chem. Eur. J. 2000, 6,3321 – 3329; f) L. Weber,K. Illgen,M.
Almstetter, Synlett 1999,366 – 374.
Scheme 2. Proposed mechanism for the catalytic three-component Ugi
reaction.
[2] I. Ugi, Angew. Chem. 1962, 74, 9 – 22; Angew. Chem. Int. Ed.
1962, 1,8 – 21.
[3] a) A. Dömling, Chem. Rev. 2006, 106,17 – 89; b) S. Marcaccini,
T. Torroba, Nat. Protoc. 2007, 2,632 – 639; c) A. Dömling,I. Ugi,
Angew. Chem. 2000, 112,3300 – 3344; Angew. Chem. Int. Ed.
2000, 39,3168 – 3210; d) I. Ugi,B. Werner,A. Dömling,
Molecules 2003, 8,53 – 56.
[4] a) R. W. Armstrong,A. P. Combs,P. A. Tempest,S. D. Brown,
T. A. Keating, Acc. Chem. Res. 1996, 29,123 – 131; b) L. Weber,
Curr. Med. Chem. 2002, 9,1241 – 1253; c) C. Hulme,V. Gore,
Curr. Med. Chem. 2003, 10,51 – 80.
phosphinic acid (10) can be considered a Brønsted acid and,in
the form of its phenylphosphonous acid tautomer (13),a
Lewis base. It is tempting to speculate that both properties
may be required for effective catalysis. Thus,the catalytic
cycle may be initiated by protonation of the in situ generated
imine. Subsequently,the nitrilium ion that is formed after the
addition of the isocyanide could be trapped by the nucleo-
philic phosphinate anion to give intermediate 14. Finally,
H2O,which is released in the imine formation,reacts with
intermediate 14 to generate 15,which fragments to a-amino
amide 4 and catalyst 10. Although we have no evidence for
this particular mechanism,after the submission of this
manuscript Goulioukina et al.[10] reported an interesting
synthetic study on a-iminophosphonates that provides some
support for our mechanistic hypothesis. They observed the
hydrolysis of an a-iminophosphonate to the corresponding
amide as an unwanted side reaction in their studies,providing
at least some support for our proposal of a-iminophosphinate
14 as an intermediate and its rapid hydrolysis to amide 4 via
intermediate 15. Nevertheless,other plausible mechanisms
cannot be ruled out at this point.
In summary,we have developed an efficient and poten-
tially useful new reaction,the phosphinic acid catalyzed
three-component Ugi reaction. The desired products 4 are
formed in good yields upon mixing readily available sub-
strates with catalyst 10. The broad scope,operational
simplicity,practicability,and mild reaction conditions render
it an attractive approach for the generation of different a-
amino amides. In addition to its obvious use for the synthesis
of a-amino acid derivatives,our reaction may also find use in
diversity-oriented synthesis[11] and for the design of pharma-
[5] a) X. Sun,P. Janvier,G. Zhao,H. BienaymØ,J. Zhu,
Org. Lett.
J.
2001, 3,877 – 880; b) G. Zhao,X. Sun,H. BienaymØ,J. Zhu,
Am. Chem. Soc. 2001, 123,6700 – 6701; c) E. Gonzµlez-Zamora,
A. Fayol,M. B. Choussy,A. Chiaroni,J. Zhu, Chem. Commun.
2001,1684 – 1685; d) P. Cristau,J. P. Vors,J. Zhu, Org. Lett. 2001,
3,4079 – 4082; e) P. Janvier,X. Sun,H. BienaymØ,J. Zhu, J. Am.
Chem. Soc. 2002, 124,2560 – 2567; f) A. Fayol,J. Zhu, Angew.
Chem. 2002, 114,3785 – 3787; Angew. Chem. Int. Ed. 2002, 41,
3633 – 3635; g) P. Janvier,H. BienaymØ,J. Zhu, Angew. Chem.
2002, 114,4467 – 4470; Angew. Chem. Int. Ed. 2002, 41,4291 –
4294; h) P. Janvier,M. Bois-Choussy,H. BienayamØ,J. Zhu,
Angew. Chem. 2003, 115,835 – 838; Angew. Chem. Int. Ed. 2003,
42,811 – 814; i) A. Fayol,C. Housseman,X. Sun,P. Janvier,H.
BienaymØ,J. Zhu, Synthesis 2005,161 – 165; j) A. Fayol,J. Zhu,
Org. Lett. 2005, 7,239 – 242; k) D. Bonne,M. Dekhane,J. Zhu, J.
Am. Chem. Soc. 2005, 127,6926 – 6927; l) C. Housseman,J. Zhu,
Synlett 2006,1777 – 1779; m) T. Pirali,G. C. Tron,J. Zhu, Org.
Lett. 2006, 8,4145 – 4148; n) D. Bonne,M. Dekhane,J. Zhu,
Angew. Chem. 2007, 119,2537 – 2540; Angew. Chem. Int. Ed.
2007, 46,2485 – 2488; o) T. Ngouansavanh,J. Zhu, Angew. Chem.
2007, 119,5877 – 5880; Angew. Chem. Int. Ed. 2007, 46,5775 –
5778; p) J-M. Grassot,G. Masson,J. Zhu, Angew. Chem. 2008,
120,961 – 964; Angew. Chem. Int. Ed. 2008, 47,947 – 950.
[6] a) B. Beck,M. Magnin-Lachaux,E. Herdtweck,A. Dömling,
Org. Lett. 2001, 3,2875 – 2878; b) B. Beck,G. Larbig,B. Mejat,
M. Magnin-Lachaux,A. Picard,E. Herdweck,A. Dömling, Org.
Lett. 2003, 5,1047 – 1050; c) J. Kolb,B. Beck,M. Almstetter,S.
3624 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3622 –3625

Angewandte
Chemie
Heck,E. Herdtweck,A. Dömling, Mol. Diversity 2000, 6,297 –
313; d) B. Henkel,B. Westner,A. Dömling, Synlett 2003,2410 –
kamp,K. Lꢂmmerhirt, Angew. Chem. 1968, 80,394 – 395; Angew.
Chem. Int. Ed. Engl. 1968, 7,372 – 373; e) Y. Tanaka,T. Hasui,
M. Suginome, Org. Lett. 2007, 9,4407 – 4410. For a recent three-
component Ugi reaction with ammonium chloride,see: f) L. B.
Mullen,J. D. Sutherland, Angew. Chem. 2007, 119,8209 – 8212;
Angew. Chem. Int. Ed. 2007, 46,8063 – 8066.
2412; e) B. Beck,A. Picard,E. Herdtweck,A. Dömling,
Org.
Lett. 2004, 6,39 – 42; f) A. Dömling,K. Illgen, Synthesis 2005,
662 – 667; g) A. Dömling,B. Beck,T. Fuchs,A. Yazbak, J. Comb.
Chem. 2006, 8,872 – 880; h) A. Dömling,E. Herdtweck,S. Heck,
Tetrahedron Lett. 2006, 47,1745 – 1747; i) A. Dömling,B. Beck,
U. Eichelberger,S. Sakamuri,S. Menon,Q-Z Chen,Y Lu,L. A.
Wessjohann, Angew. Chem. 2006, 118,7393 – 7397; Angew.
Chem. Int. Ed. 2006, 45,7235 – 7239.
[9] For recent use of phenyl phosphinic acid as Brønsted acid
catalyst,see: a) G. B. Rowland,H. Zhang,E. B. Rowland,S.
Chennamadhavuni,Y. Wang,J. C. Antilla, J. Am. Chem. Soc.
2005, 127,15696 – 15697; b) S. C. Pan,J. Zhou,B. List,
2006,3275 – 3276.
Synlett
[7] For selected recent contributions from other groups,see: a) C.
Masdeu,E. Gómez,N. A. O. Williams,R. Lavilla, Angew. Chem.
2007, 119,3103 – 3106; Angew. Chem. Int. Ed. 2007, 46,3043 –
3046; b) W.-M. Dai,H. Li, Tetrahedron 2007, 63,12866 – 12876;
c) L. El Kaꢀm,L. Grimaud,J. Oble, Angew. Chem. 2005, 117,
8175 – 8178; Angew. Chem. Int. Ed. 2005, 44,7961 – 7964; d) L.
El Kaꢀm,M. Gageat,L. Gaultier,L. Grimaud, Synlett 2007,500 –
502; e) G. B. Giovenzana,G. C. Tron,S. D. Paola,I. G. Mene-
gotto,T. Pirali, Angew. Chem. 2006, 118,1117 – 1120; Angew.
Chem. Int. Ed. 2006, 45,1099 – 1102; f) L. J. Diorazio,W. B.
Motherwell,T. D. Sheppard,R. B. Waller, Synlett 2006,2281 –
2283; g) W. Keung,F. Bakir,A. P. Patron,D. Rogers,C. D.
Priest,V. Darmohusodo, Tetrahedron Lett. 2004, 45,733 – 737;
[10] N. S. Goulioukina,G. N. Bondarenko,S. E. Lyubimov,V. A.
Davankov,K. N. Gavrilov,I. P. Beletskaya, Adv. Synth. Catal.
2008, 350,482 – 492.
[11] Reviews discussing diversity-oriented synthesis: a) S. L.
Schreiber, Science 2000, 287,1964 – 1969; b) P. Arya,D. T. H.
Chou,M-G. Baek, Angew. Chem. 2001, 113,351 – 358; Angew.
Chem. Int. Ed. 2001, 40,339 – 346; c) M. D. Burke,S. L.
Schreiber, Angew. Chem. 2004, 116,48 – 60; Angew. Chem. Int.
Ed. 2004, 43,46 – 58; d) P. Arya,R. Joseph,Z. Gan,B. Rakic,
Chem. Biol. 2005, 12,163 – 180; e) D. S. Tan, Nat. Chem. Biol.
2005, 1,74 – 84.
[12] By using the chiral phosphoric acid catalyst 3,3’-bis [(2,4,6-
h) K. Rikimaru,A. Yanagisawa,T. Kan,T. Fukuyama,
Synlett
tris(isopropyl)phenyl)]binaphthyl
hydrogen
phosphate
2004,41 – 44.
(10 mol%),the product 4a was obtained in 15% yield with
59:41 e.r. and by using the new chiral phosphinic acid catalyst
1,1’-binaphthyl-2,2’-diyldiphosphinic acid (10 mol%) the prod-
uct 4a was obtained in 90% yield with 52:48 e.r.
[8] Previously only secondary amines were used in a non-catalytic
variant,see: a) I. Ugi,C. Steinbrꢁckner,DE 1103337, 1959; b) I.
Ugi,S. Cornelius, Chem. Ber. 1961, 94,734 – 742; c) J. W.
McFarland, J. Org. Chem. 1963, 28,2179 – 2181; d) N. Kreutz-
Angew. Chem. Int. Ed. 2008, 47, 3622 –3625
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3625