Ugi four-component reaction of alcohols: Stoichiometric and catalytic oxidation/MCR sequences

Article abstract of DOI:10.1021/ol401181a

A new, simple, and efficient procedure for the one-pot Ugi four-component reaction of alcohols instead of aldehydes is described. Using a stoichiometric amount of IBX or only 1-2% of sodium 2-iodobenzenesulfonate in the presence of Oxone, a wide range of primary alcohols were oxidized to the aldehyde that were directly engaged in the Ugi four-component reaction to afford α-acetamidoamides in good to excellent yields.

Full text of DOI:10.1021/ol401181a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ugi Four-Component Reaction of
Alcohols: Stoichiometric and Catalytic
Oxidation/MCR Sequences
†
Fleur Drouet, Geraldine Masson,* and Jieping Zhu*
,†
,‡
ꢀ
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, ICSN, CNRS,
91198 Gif-sur-Yvette Cedex, France, and Institut of Chemical Sciences and Engineering,
Ecole Polytechnique Federale de Lausanne, EPFL-SB-ISIC-LSPN, CH-1015
Lausanne, Switzerland
geraldine.masson@cnrs.fr; jieping.zhu@epfl.ch
Received April 26, 2013
ABSTRACT
A new, simple, and efficient procedure for the one-pot Ugi four-component reaction of alcohols instead of aldehydes is described. Using a
stoichiometric amount of IBX or only 1À2% of sodium 2-iodobenzenesulfonate in the presence of Oxone, a wide range of primary alcohols were
oxidized to the aldehyde that were directly engaged in the Ugi four-component reaction to afford R-acetamidoamides in good to excellent yields.
The Ugi four-component reaction (Ugi-4CR)1 is with-
out a doubt one of the most investigated multicomponent
reactions (MCR).2 This reaction allows for a one-step
synthesis of highly functionalized R-acetamidoamide 1, a
structure found in many biologically active compounds,
from an aldehyde, an amine, a carboxylic acid, and an
isocyanide.3 Itsapplication inpharmaceutical industryand
in academic research underwent a dramatic increase over
the past 20 years.3,4 Furthermore, because of the increasing
need for always more economic and environmentally
friendly syntheses, the development of tandem oxidative
processes5 combining alcohol oxidation with multicompo-
nent reactions is actually of great interest.2,6,7 Indeed, most
(5) (a) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem.
Res. 2005, 38, 851–869. (b) Ekoue-Kovi, K.; Wolf, C. Chem.;Eur. J.
2008, 14, 6302–6315. (c) Tietze, L. F.; Brasche, G.; Gericke, K. M.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(6) For reviews on isocyanide-based multicomponent reactions, see:
(a) Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471–1499. (b) Nair, V.;
Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899–907. (c) Zhu, J. Eur. J. Org.
† Institut de Chimie des Substances Naturelles.
‡ Ecole Polytechnique Federale de Lausanne.
€
(1) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
€
1959, 71, 386–386. (b) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72,
267–268.
(2) For recent reviews on multicomponent reactions, see: (a) Muli-
ꢀ
component Reaction; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005.
(b) Domling, A. Chem. Rev. 2006, 106, 17–89. (c) Ruijter, E.; Scheffelaar,
R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234–6246.
(3) (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995,
117, 7842–7843. (b) Weber, L.; Wallbaum, S.; Broger, C.; Gubernator,
K. Angew. Chem., Int. Ed. 1995, 34, 2280–2282. (c) Zhang, J. D.; Rivers,
G.; Zhu, Y. Y.; Jacobsen, A.; Peyers, J.; Grundstrom, G.; Burch, P.;
Hussein, S.; Marolewski, A.; Herlihy, W.; Rusche, J. Bioorg. Med.
Chem. 2001, 9, 825–836. (d) Weber, L. Drug Discovery Today 2002, 7,
143–147. (e) Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12,
324–331. (f) Evans, C. G.; Smith, M. C.; Carolan, J. P.; Gestwicki, J. E.
Bioorg. Med. Chem. Lett. 2011, 21, 2587–2590. (g) Endo, A.;Yanagisawa,
A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002,124,
6552–6554.
€
Chem. 2003, 1133–1144. (d) Domling, A. Chem. Rev. 2006, 106, 17–89.
(e) Isambert, N.; Lavilla, R. Chem.;Eur. J. 2008, 14, 8444–8454.
(f) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153–2171. (g)
Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Chem. Rev. 2009, 109,
796–814.
(7) For recent examples, see: (a) Khosropour, A. R.; Khodaei,
M. M.; Beygzadeh, M.; Jokar, M. Heterocycles 2005, 65, 767–773. (b)
Ngouansavanh, T.; Zhu, J. P. Angew. Chem., Int. Ed. 2006, 45, 3495–
3497. (c) Leon, F.; Rivera, D. G.; Wessjohann, L. A. J. Org. Chem. 2008,
73, 1762–1767. (d) Garima; Srivastava, V. P.; Yadav, L. D. S. Tetra-
hedron Lett. 2010, 51, 6436–6438. (e) De Moliner, F.; Crosignani, S.;
Banfi, L.; Riva, R.; Basso, A. J. Comb. Chem. 2010, 12, 613–616. (f)
Brioche, J.; Masson, G.; Zhu, J. Org. Lett. 2010, 12, 1432–1435. (g) De
Moliner, F.; Crosignani, S.; Galatini, A.; Riva, R.; Basso, A. ACS
Comb. Sci. 2011, 13, 453–457. (h) Ye, X.; Xie, C.; Huang, R.; Liu, J.
Synlett 2012, 409–412.
(4) For reviews on the Ugi reaction, see: (a) Ugi, I.; Werner, B.;
Domling, A. Molecules 2003, 8, 53–66. (b) El Kaim, L.; Grimaud, L.
Tetrahedron 2009, 65, 2153–2171.
r
10.1021/ol401181a
XXXX American Chemical Society

of the classic multicomponent reactions are based on the
reactivity of aldehydes which are known to be unstable or
difficult to handle. Moreover, when they are not commer-
cially available, aldehydes are traditionally synthesized
from the corresponding alcohols. Hence, the direct use of
alcohols instead of aldehydes significantly increases the
versatility and efficiency of these reactions.
p-chlorobenzyl alcohol 2a in the presence of IBX followed
by Ugi-4CR of the in situ generated 4-chlorobenzaldehyde
with allylamine 3a, tert-butyl isocyanide 4a, and acetic acid
5a (Table 1) was examined. On the basis of the work of
More and Finney on the IBX-promoted oxidation of
alcohols to their corresponding aldehydes, we initially
chose acetonitrile as solvent.12 Conducting the oxidation
in refluxing MeCN, followed by the Ugi-4CR at room
temperature over 64 h, the desired R-acetamidoamide 1a
was obtained in 50% yield (entry 1). Although modifica-
tions of the reaction conditions were limited by the neces-
sity to be compatible with both the oxidation step and the
Ugi multicomponent reaction, slight variations of the
parameters were studied. First, the concentration proved
to be a key factor to the success of the reaction. Although
the Ugi reaction required high concentrations (0.5À2 M),13
the oxidation step required more dilute conditions in
order to keep the reaction mixture homogeneous. This is
due to the poor solubility of the oxidant and its reduced
form 2-iodosobenzoic acid (IBA). A concentration of
0.5 M furnished the best result (entry 2). Then, in accordance
with previous observations on the Ugi reaction,7 the
preformation of the imine allowed us to significantly
increase the yield (entry 3). Finally, the addition of metha-
nol after the oxidation step permitted not only anincreased
yield of 80% but also a decrease of the reaction time from
64 to 40 h (entry 5).
Table 1. Optimization of the IBX-Mediated Alcohol Oxidation/
Ugi-4CR Sequencea
entry
solvent
MeCN
C (mol/L)
time (h)
yieldc (%)
1
0.3
0.5
0.5
0.5
0.5
64
64
64
64
40
50
57
64
61
78
2
MeCN
3b
4b
5b
MeCN
MeCN/THF (1:1)
MeCN/MeOH (1:1)
a General conditions: alcohol 2a (1.0 equiv), IBX (1.2 equiv), MeCN
at reflux for 3 h, then addition of 3a, 4a, and 5a (molar ratio: 3a/4a/5a =
1.2/1.5/1.5) at rt. b Imine preformed for 1 h. c Yields refer to chromato-
graphically pure products.
With the optimum conditions in hand, the scope of the
reaction was next examined using different alcohols,
amines, carboxylic acids and isocyanides. The results are
listed in Table 2. First, benzyl alcohols carrying either
electron-donating or electron-withdrawing substituents
have been successfully engaged in this sequence and
afforded the Ugi-4CR adducts in good to excellent yields
(1aÀe). We then extended the procedure to various pri-
mary non activated alcohols. Although these substrates
present a low reactivity under certain oxidative con-
ditions7a,d or lead to side reactions such as overoxidation,
aldol or Tishchenko reaction, a wide range of R-acetamido-
amides was isolated in moderate to excellent yields from
aliphatic alcohols (entries 5À11). It is noteworthy that
unlike benzyl alcohols, the reaction is best to be performed
in pure acetonitrile (entry 5). Another important feature of
this procedure is the functional group compatibility. In-
deed, in addition to the amine, isocyanide, and carboxylic
acid functions implied in the reaction, other functional
groups such as ethers (2b,c), halides (2e), ester (entry 9),
alkene (2f), and hemiacetal (2l) functionalities were all
tolerated. Finally, the enantiopure alcohol 2l whose corre-
sponding Garner aldehyde is known to be sensitive and
difficult to handle was successfully engaged in this se-
quence (entry 11). Chiral HPLC analysis indicated that
only a negligible amount of racemization occurred during
the reaction, leading to two separable diastereomers in
82% yield (dr = 2:1) with 95% ee.
However, to the best of our knowledge, the Ugi-4CR
from alcohols under oxidative conditions has never been
studied.8 This reaction, which presents many potentially
oxidizable intermediates and reactants, such as amine 3 or
isocyanide 4, presents a synthetic challenge and so we
decided to investigate this reaction. We report herein the
first IBX-mediated tandem oxidative Ugi four-component
reaction of alcohols.9 Furthermore, we also document
that the same oxidative MCR proceeds efficiently using a
catalytic amount of sodium 2-iodobenzenesulfonate and a
stoichiometric amount of Oxone as a co-oxidant.
Knowing the compatibility of o-iodoxybenzoic acid (IBX)10
with multicomponent reactions,4b,7f,8a,11 the oxidation of
(8) For examples starting from amines, see: (a) Ngouansavanh, T.;
Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 5775–5778. (b) Jiang, G.; Chen,
J.; Huang, J.-S.; Che, C.-M. Org. Lett. 2009, 11, 4568–4571. (c) Ye, X.;
Xie, C.; Pan, Y.; Han, K.; Xie, T. Org. Lett. 2010, 12, 4240–4243.
(9) For a review on hypervalent iodine-mediated oxidation of alco-
hols, see: Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086–2099.
(10) (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178.
(b) Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic
Press: London, 1997. (c) Topics in Current Chemistry; Wirth, T., Ed.;
Springer: Berlin, 2003; p 224. (d) Tohma, H.; Kita, Y. Adv. Synth. Catal.
2004, 346, 111–124. (e) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656–
3665. (f) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358.
(g) Ladziata, U.; Zhdankin, V. V. ARKIVOC 2006, ix, 26–58. (h)
Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2011, 50, 1524–
1552. (i) Satam, V.; Harad, A.; Rajule, R.; Pati, H. Tetrahedron 2010, 66,
7659–7706. (j) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185–1197.
(11) (a) Fontaine, P.; Chiaroni, A.; Masson, G.; Zhu, J. P. Org. Lett.
2008, 10, 1509–1512. (b) Gualtierotti, J.-B; Schumacher, X.; Fontaine,
P.; Masson, G.; Wang, Q.; Zhu, J. Chem.;Eur. J. 2012, 18, 14812–
14819.
(12) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003.
(13) Marcaccini, S.; Torroba, T. Nat. Protocols 2007, 2, 632–639.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope and Limitations of IBX-Mediated Ugi-4CR
of Alcohols
Table 3. Optimization of the Catalytic Alcohol Oxidation/
Ugi-4CR Sequencea
entry
solvent
MeCN
3d (equiv)
yieldb (%)
1
1.2
17
12
37
65
2
MeCN/MeOH (1/1)
MeCN/MeOH (4/1)
MeCN/MeOH (4/1)
1.2.
1.2
3
4b
2.5.
a General conditions: alcohol 2a (1.0 equiv), 6 (0.01 equiv), and
Oxone (0.6 equiv) in MeCN at reflux for 3 h, then addition of 3d and
MeOH at rt. After 2 h, 4a (1.5 equiv) and 5a (1.5 equiv) were added.
b Yields refer to chromatographically pure products.
using a catalytic amount of IBX in combination with a
stoichiometric amount of Oxone (2KHSO5ÀKHSO4À
K2SO4). More recently, Ishihara established that the 2-io-
doxybenzenesulfonic acid (IBS) is a stronger oxidant than
IBX under nonaqueous conditions.16 Although IBS is not
stable enough to be isolated, it can be in situ generated
from sodium 2-iodobenzenesulfonate (6) and Oxone al-
lowing the selective oxidation of primary alcohols to
aldehydes. Furthermore, we expected that the controlled
addition of Oxone, a nontoxic, environmentally safe, in-
expensive, stable and easy to handle co-oxidant,17 will
avoid side reactions such as an overoxidation of the
aldehyde or oxidation of other reactants or intermediates
of the Ugi-4CR. Hence, we investigated the Ugi-4CR from
alcohols using 1À2% of sodium 2-iodobenzenesulfonate
in the presence of Oxone. Using our previously optimized
conditions, the Ugi-4CR product was obtained with 12%
yield. A brief optimization study was performed and the
results are summarized in table 3. The best conditions
consisted of using an excess of amine (2.5 equiv) in a mixed
solvent (acetonitrile/methanol = 4:1) in the presence of 6
(0.01 equiv) and Oxone (0.6 equiv). Under these condi-
tions, the R-acetamido amide 1d was isolated in a 65%
yield.
a Reaction conditions: alcohol 2 (1.0 equiv), IBX (1.2 quiv), MeCN
at reflux for 2À4 h, then addition of molar ratio 3/4/5 =1.2/1.5/1.5 and
methanol at rt. b Yields referred to chromatographycally pure product.
c Reaction in MeCN. d The imine was preformed for 2 h. e Determined
based on the 1H NMR spectrum of the crude material. f 5À6% of partial
epimerization was measured by chiral HPLC analysis.
With these conditions in hand, the protocol was applied
to the synthesis of various R-acetamido amides 1. Examples
for this catalytic one-pot process are given in Scheme 1.
First, the substituent effect on the aromatic ring of various
benzyl alcohols was studied. We observed that benzyl
alcohols bearing moderate electron-donating or electron-
withdrawing substituents successfully afforded the corre-
sponding Ugi-4CR products. However, with p-methoxy-
benzyl alcohol, the desired Ugi-adduct 1b was isolated in
Confident of the efficiency of this Ugi-4CR from alco-
hols using IBX as oxidant, we next explored the possibility
of using a catalytic amount of hypervalent iodine. Vinod14
and Giannis15 have reported the oxidation of alcohols
(16) Uyanik, M.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2009,
131, 251–262.
(17) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org.
Lett. 2003, 5, 1031–1034.
(14) Thottumkara, A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett.
2005, 7, 2933–2936.
(15) Schulze, A.; Giannis, A. Synthesis 2006, 257–260.
Org. Lett., Vol. XX, No. XX, XXXX
C

only 38% yield. Nevertheless, we were pleased to observe
that this method was also applicable to aliphatic alcohols.
The catalytic oxidation of these nonactivated alcohols to
aldehydes is known to be highly sensitive as it generally
leads to the corresponding carboxylic acid or ester.14 How-
ever, Ishihara showed that, using 2% of sodium 2-iodo-
benzenesulfonate 6 in nitromethane, a slow addition of the
aliphatic alcohols to the oxidant could lead to the desired
aldehyde.16 In our case, we found that acetonitrile was the
best solvent and R-acetamido-amides 1 were obtained in
moderate to good yields when starting with β-substituted
aliphatic alcohols (1k,n). Linear alcohols such as octanol
also afforded the desired compound 1g but with a low
yield.
Scheme 1. Ugi-4CR of Alcohols under Catalytic Oxidative
Conditions: Scopea
In summary, we have developed a highly efficient IBX-
mediated Ugi-four component reaction of primary alco-
hols. The first example of an efficient MCR reaction of
alcohols was documented in the presence of a catalytic
amount of sodium 2-iodobenzenesulfonate using Oxone as
the terminal oxidant. We believed that this eco-friendly
tandem oxidative process could be extended to other MCRs.
Acknowledgment. Financial support from CNRS and
ANR are gratefully acknowledged. F.D. thanks ICSN for
a doctoral fellowship.
Supporting Information Available. Experimental de-
tails, characterization data, HPLC enantiomer analysis,
and 1H and 13C NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reaction conditions: alcohol 2 (1.0 equiv) and 6 (0.01 equiv) in
MeCN at reflux for 2À4 h, then addition of molar ratio 3/4/5 = 2.5/1.5/
1.5 and methanol at rt. b Reaction conditions: alcohol 2 (1.0 equiv), 6
(0.02 equiv), and anhydrous Na2SO4 in MeCN at reflux for 2À4 h, then
addition of molar ratio 3/4/5 = 2.5/1.5/1.5 at rt.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX