Catalysis of Ugi four component coupling reactions by rare earth metal triflates

Article abstract of DOI:10.1021/jo800745a

(Chemical Equation Presented) Substoichiometric quantities of scandium and ytterbium triflate increase the yield of Ugi four component coupling reactions of aromatic aldehydes 2- to 7-fold. These rare earth metal triflates enhance the reaction yields prim

Full text of DOI:10.1021/jo800745a

SCHEME 1. Proposed Mechanism of the Ugi Four
Component Coupling Reaction
Catalysis of Ugi Four Component Coupling
Reactions by Rare Earth Metal Triflates
Babajide O. Okandeji, Jonathan R. Gordon, and
Jason K. Sello*
Department of Chemistry, Brown UniVersity, 324 Brook
Street, ProVidence, Rhode Island 02912
jason_sello@brown.edu
ReceiVed April 07, 2008
In recent years, there has been much interest in catalysis of
isocyanide-based multicomponent reactions.3,4 Because the Ugi
4CC reaction is generally high yielding (especially in protic
solvents like methanol and trifluoroethanol), there has been little
interest in catalysis of the Ugi four component reaction. Catalysts
for the Ugi 4CC reaction would be valuable in cases where
substrates have limited reactivity (e.g., aromatic aldehydes and
ketones). Moreover, catalysis is likely to provide the general
and much needed strategy that enables asymmetric Ugi 4CC
reactions.5 To the best of our knowledge, there are only two
catalysts reported to be useful in Ugi 4CC reactions.6 First, there
are a few examples in which stoichiometric quantities of ZnCl2
are used to both activate and rigidify chiral imines for asym-
metric additions of isocyanides.6a–c Second, Ciufolini and co-
workers reported that TiCl4 is a particularly effective Lewis acid
catalyst at 5 mol % for Ugi five center-four component reactions
of R-amino acids, aromatic aldehydes, isocyanides, and
methanol.6d They hypothesized that TiCl4 enhances these
reactions by activating the aldehydes for imine formation.
The multistep mechanism of the Ugi 4CC reaction makes it
an intriguing and challenging subject for catalysis. Of particular
interest is catalytic activation of the reaction’s imine intermediate
for the addition of the isocyanide. In situ Brønsted acid catalysis
via protonation of the imine by the carboxylic acid substrate is
believed to facilitate the addition of the isocyanide in the Ugi
4CC reaction.2 A Lewis acid catalyst could activate the imine
intermediate in a similar way. Further, a chiral catalyst that
activates the imine for isocyanide addition could also provide
stereocontrol over this stereogenic step of the Ugi 4CC reaction.
In an effort to identify catalysts that could activate the imine
intermediate of the Ugi 4CC reaction, we turned our attention
to the Lewis-acidic rare earth metals. Rare earth metal triflates,
like scandium and ytterbium triflate, are known to catalyze
reactions of imines, including allylations, aza Diels-Alder
reactions, cyanations, imino-aldol reactions and three-component
Substoichiometric quantities of scandium and ytterbium
triflate increase the yield of Ugi four component coupling
reactions of aromatic aldehydes 2- to 7-fold. These rare earth
metal triflates enhance the reaction yields primarily via
activation of the imine intermediate of this multicomponent
reaction.
From a mechanistic perspective, multicomponent reactions
are among the most peculiar in organic chemistry. In these
reactions, more than two reactants condense with retention of
most of their atoms to yield a defined product.1 In the most
preparatively useful multicomponent reactions, a sequence of
reversible steps is concluded by an enthalpically driven and
irreversible product-forming step.2 Beyond their mechanistic
interest, multicomponent reactions are extensively used in total
synthesis, drug discovery, and bioconjugation.3
One of the best known multicomponent reactions is the Ugi
four component coupling (4CC) reaction (Scheme 1).2 The
substrates for this reaction are an isocyanide, an amine, a
carboxylic acid, and either an aldehyde or a ketone. In this
reaction, these substrates spontaneously condense to yield an
R-acylamino carboxamide. The generally accepted mechanism
of the Ugi 4CC reaction involves four elementary steps, the
last of which is irreversible.2 In the first step, the carbonyl
compound condenses with an amine to form an imine. Next,
the isocyanide adds to the imine to yield a nitrilium ion. Then,
a reactive O-acylimidate is formed via the R-addition of the
carboxylate anion to the nitrilium ion. The fourth and final step
is the O- to N-acyl transfer (Mumm rearrangement) to yield
the R-acylamino carboxamide product.
(4) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825. (b)
Andreana, P. R.; Liu, C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231. (c) Henkel,
B.; Beck, B.; Westner, B.; Mejat, B.; Do¨mling, A. Tetrahedron Lett. 2003, 44,
8947. (d) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew.Chem., Int.
Ed. 2008, 47, 388–391.
(5) Ramo´n, D. J.; Yus, M. Angew. Chem., Intl. Ed. 2005, 44, 1602.
(6) (a) Kunz, H.; Pfrengle, W. J. Am. Chem. Soc. 1988, 110, 651–652. (b)
Oertel, K.; Zech, G.; Kunz, H. Angew. Chem., Int. Ed. 2000, 39, 1431–4333.
(c) Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58, 6127–6133. (d)
Godet, T.; Bonvin, Y.; Vincent, G.; Merle, D.; Thozet, A.; Ciufolini, M. A.
Org. Lett. 2004, 6, 3281.
(1) Zhu, J., Bienayme, H. Multicomponent Reactions; Verlag GmbH & Co.
KGaA: Weinheim, 2005.
(2) Do¨mling, A. Angew. Chem., Intl. Ed. 2000, 39, 3168–3210.
(3) Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
10.1021/jo800745a CCC: $40.75
Published on Web 06/21/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5595–5597 5595

TABLE 1. Metal Triflate Catalyzed Ugi 4CC Reactionsa
TABLE 2. Metal Catalysis of Ugi 4CC with Various Isocyanidesa
a All reactions were performed in CH2Cl2 (0.5 M) for 15 h at room
temperature, preceded by a 30 min precondensation of the aldehydes
and amines.
some cases, the modest yield of the desired R-acylamino
carboxamides (1) is a consequence of the competing Passerini
reaction of aldehydes, carboxylic acids, and isocyanides to yield
R-acyloxycarboxamides (2) (Table 1, entries a and d).12
However, in all cases, the remainder of material recovered from
the reactions was unreacted substrates. The reaction yields may
be limited by catalyst coordination to the secondary amine in
the product of the isocyanide addition (the nitrilium intermedi-
ate), which could interfere with the reaction’s O- to N-acyl shift.7
This possibility is consistent with our observation that reaction
yields are lower at catalyst loadings greater than 10 mol %.11
In examining the substrate scope of these metal triflate-
catalyzed reactions, we note that the catalysts are effective in
reactions with aromatic aldehydes. In contrast, Sc(OTf)3 and
Yb(OTf)3 suppressed Ugi 4CC reactions with aliphatic alde-
hydes under these conditions (Table 1, entries g and h). The
suppression of these reactions by the metal triflates is again
ascribed to inhibitory coordination of the metals to the secondary
amine of the nitrilium intermediate.7
Whereas the identity of the amine had subtle effects on the
degree of catalysis, the identity of the isocyanide component
proved more significant in the yields of Sc(OTf)3 and Yb(OTf)3-
catalyzed reactions (Table 2). For reasons that are not clear,
the influence of the catalysts was significantly higher in the
reaction with cyclohexyl isocyanide than with benzyl isocyanide
(Table 2, entries a and b).13
As Lewis acidic metals, Sc(OTf)3 and Yb(OTf)3 can be
expected to activate the aldehyde for imine formation and the
imine for addition of the isocyanide in the Ugi 4CC reaction.
We performed a series of experiments to determine which mode
a All reactions were performed in CH2Cl2 (0.5 M) for 15 h at room
temperature, preceded by a 30 min precondensation of the aldehydes
and amines.
reactions of aldehydes, amines, and various nucleophiles.7,8
Several recent reports of chiral scandium (III) complexes that
catalyze asymmetric reactions further piqued our interest in rare-
earth metal triflates for catalysis of the Ugi 4CC reaction.9 We
report here that Sc(OTf)3 and Yb(OTf)3 are effective catalysts
for Ugi 4CC reactions.
In our initial experiments, we explored the efficacy of
Sc(OTf)3 and Yb(OTf)3 as catalysts for the reaction of benzyl
isocyanide, 4-pentenoic acid, two amines (benzyl amine and
n-butyl amine) and a variety of aldehydes in CH2Cl2.10 At a 10
mol % catalyst loading,11 Sc(OTf)3 and Yb(OTf)3 increased the
yield of the desired R-acylamino carboxamides (1) from 2- to
5-fold (Table 1). In all cases, Sc(OTf)3 proved to be a better
promoter than Yb(OTf)3. While the yields of the catalyzed
reactions are consistently greater than those of the uncatalyzed
reactions, the yields of the catalyzed reactions are modest. In
(7) Kobayshi, S. Eur. J. Org. Chem. 1999, 1, 15–27.
(8) (a) Scandium triflate has also been used to catalyze a number of other
isocyanide-based multicomponent reactions Keung, W.; Bakir, F.; Patron, A. P.;
Rogers, D.; Priest, C. D. Tetrahedron Lett. 2004, 45, 733. (b) Ireland, S. M.;
Tye, H.; Whittaker, M. Tetrahedron Lett. 2003, 44, 4369. (c) Schwerkoske, J.;
Masquelin, T.; Perun, T.; Hulme, C. Tetrahedron Lett. 2005, 46, 8355.
(9) (a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J.
J. Am. Chem. Soc. 2003, 125, 10780. (b) Fukuzawa, S.; Komuro, Y.; Nakano,
N.; Obara, S. Tetrahedron Lett. 2003, 44, 3671. (c) Schneider, C.; Sreekanth,
A. R.; Mai, E. Angew. Chem., Int. Ed. 2004, 42, 5691. (d) Kobayashi, S.; Hachiya,
I; Ishitani, H.; Araki, M. Tetrahedron Lett. 1993, 34, 4535.
(12) In separate experiments, it was found that Sc(OTf)3 and Yb(OTf)3 did
not catalyze the Passerini reaction at 0.5 M in CH2Cl2.
(13) Cyclohexylisocyanide is reported to be slightly more reactive than benzyl
isocyanide in Ugi 4CC reactions: Portal, C.; Launay, D.; Merritt, A.; Bradley,
M. J. Comb. Chem. 2005, 7, 554.
(10) Sc(OTf)3 and Yb(OTf)3 facilitate unproductive reaction of aldehydes
with nucleophilic solvents like methanol and trifluoroethanol.
(11) A survey of catalyst loadings revealed that 10 mol% is optimal (see
Supporting Information).
5596 J. Org. Chem. Vol. 73, No. 14, 2008

TABLE 3. Evidence for Imine Activation by Sc(OTf)3 in Ugi 4CC
Reactionsa
the present case imine activation by Sc(OTf)3 is primarily
responsible for its enhancement of Ugi 4CC reaction yields.
In summary, catalytic quantities of Sc(OTf)3 and Yb(OTf)3
catalyze the Ugi four component coupling reactions. These rare
earth metal triflates most likely enhance the yield of this reaction
via activation of its imine intermediate. The apparent mechanism
of catalysis, the remarkable differences in yield between the
uncatalyzed and catalyzed reactions, and the availability of chiral
Sc(III) complexes bode well for realization of catalytic asym-
metric Ugi 4CC reactions. Studies toward this goal are in
progress.
Experimental Section
General Procedure for the Ugi 4CC Reactions. The amine
(0.25 mmol, 1 equiv), aldehyde (0.25 mmol, 1 equiv) and metal
triflate (0.025 mmol, 0.1 equiv) were added to 400 µL of CH2Cl2
in a 1/2 dram glass vial and mixed for 30 min by rotation. The
isocyanide (0.2375 mmol, 0.95 equiv) and the carboxylic acid (0.25
mmol, 1 equiv) were added and the resulting solution (0.5 M) was
allowed to rotate for 15 h. The solution was diluted to 2 mL with
CH2Cl2 and washed six times with 2 mL of a saturated NaHCO3
solution. The organic layer was dried over MgSO4, and the reaction
products were purified by flash column chromatography.
a All reactions were performed in CH2Cl2 at 0.5 M for 15 h at room
temperature.
Isolation and characterization of compound 1a-i (Table 1). Flash
chromatography conditions: CH2Cl2 until isocyanide and aldehyde
eluted then 20:1 (CH2Cl2:ethyl acetate). 1H NMR (400 MHz;
CDCl3): δ 8.20 (d, J ) 8.8, 2H), 7.56 (d, J ) 8.6, 2H), 7.36-7.24
(m, 5H), 6.84 (br, 1H), 5.88-5.79 (m, 2H), 4.48 (d, J ) 5.7, 2H),
3.36 (t, J ) 7.8, 2H), 2.54-2.50 (m, 2H), 2.45-2.39 (m, 2H),
1.54-1.48 (m, 1H), 1.26-1.14 (m, 3H), 0.83 (t, J ) 7.1, 3H).13C
NMR (101 MHz; CDCl3): δ 173.7, 169.0, 147.5, 143.2, 137.8,
136.93 129.6, 128.7, 127.7, 127.5, 123.6, 115.7, 62.2, 47.6, 43.7,
32.7, 31.9, 29.2, 20.0, 13.6. LRMS: calcd 423.5 for C24H29N3O4,
observed 446 [M + Na]+.
of activation was relevant in the enhanced yields of the metal-
catalyzed reactions. Initially, we used 1H NMR to establish that
condensation of n-butyl amine with either p-nitrobenzaldehyde
or benzaldehyde to form an imine is complete within 1 h in the
absence of the Sc(OTf)3.14 Accordingly, we observed that
condensation of these aldehydes and n-butyl amine for 3 h prior
to the addition of the 4-pentenoic acid and benzyl isocyanide
had no influence on the yield of the Ugi 4CC reactions (Table
3).15 These observations suggest that under these conditions
imine formation is rapid, but the addition of the isocyanide to
the imine is relatively slow. Because imine formation is rapid
in the absence of Sc(OTf)3 and the timing of Sc(OTf)3 addition
had little influence over the degree to which the reaction yields
were enhanced (Table 3, entries b and c), we propose that in
Acknowledgment. We thank Dr. Tun-Li Shen for mass
spectrometric analyses. This work was generously supported
by funds from Brown University and a Career Award at the
Scientific Interface from the Burroughs Wellcome Fund to J.K.S.
Supporting Information Available: Detailed experimental
procedures, compound characterization data, spectra, and ex-
panded discussion of peripheral findings. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) We observed that the imine formation within minutes of mixing the
aldehydes and n-butyl amine at 0.5 M in CDCl3. Sc(OTf)3 enhanced the rate of
imine formation under these conditions. See Supporting Information.
(15) Precondensation of the aldehyde and the imine is reported to improve
the yield of Ugi 4CC reactions. See ref 2.
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