A new entry of copper-catalyzed four-component reaction: Facile access to α-Aryl β-hydroxy imidates

Article abstract of DOI:10.1021/ol900023t

α-Aryl β-hydroxy imidates are efficiently obtained by the four-component reaction of ethyl glyoxylates, aryl acetylenes, sulfonyl azides, and alcohols using a copper catalyst. The developed procedure is characterized by high selectivity, mild reaction con

Full text of DOI:10.1021/ol900023t

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1155-1158
A New Entry of Copper-Catalyzed
Four-Component Reaction: Facile
Access to r-Aryl ꢀ-Hydroxy Imidates
Eun Jeong Yoo,† Sae Hume Park,† Sang Hyup Lee,‡ and Sukbok Chang*,†
Department of Chemistry and School of Molecular Science (BK21), Korea AdVanced
Institute of Science and Technology (KAIST), Daejeon 305-701, Korea, and College of
Pharmacy, Duksung Women’s UniVersity, Seoul 132-714, Korea
sbchang@kaist.ac.kr
Received January 7, 2009
ABSTRACT
r-Aryl ꢀ-hydroxy imidates are efficiently obtained by the four-component reaction of ethyl glyoxylates, aryl acetylenes, sulfonyl azides, and
alcohols using a copper catalyst. The developed procedure is characterized by high selectivity, mild reaction conditions, a wide substrate
scope, and an excellent functional group tolerance. Facile transformations of the obtained sulfonylimidate moiety to other carbonyl groups
such as sulfonamides or esters were also demonstrated.
Multicomponent reactions (MCRs)1 constitute an ideal
approach to transformations for generating complex molec-
ular skeletons in one pot. The Ugi four-component reaction
(4-CR),2 in which primary amines, oxo species, carboxylic
acids, and isocyanides react, is one of the most representative
MCRs leading to R-acylamino amides (peptoids) under
ambient conditions. It can be regarded that the isocyanide-
based Ugi 4-CR is an expansion of the Passerini three-
component reaction (3-CR),3 which affords depsipeptides and
ꢀ-peptide analogs from the coupling of ketones, carboxylic
acids, and isocyanides. This example offers an insightful
demonstration that a modification of reacting components
in previously established MCRs may lead to a new version
of transformations with great additional significance.
philes such as amine, alcohol, water, and pyrrole to afford
amidines, imidates, amides, and 2-iminopyrrole derivatives,
respectively.4 The reactions are featured to show a wide
substrate scope, a high tolerance to various functional groups,
and very mild reaction conditions.
Although a wide range of biologically interesting com-
pounds are readily obtained with good efficiency, selectivity,
and synthetic applicability, a limitation in our catalytic 3-CR
procedure has been pointed out: a substituent R to the imino
or carbonyl position cannot be directly introduced.5,6
The mechanistic pathway of the Cu-catalyzed 3-CR was
proposed to proceed via a reactive ketenimine intermediate
(A), generated in situ by the catalytic cycloaddition of
(4) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038–
2039. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046–16047. (c) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang,
S. Org. Lett. 2006, 8, 1347–1350. (d) Chang, S.; Lee, M.; Jung, D. Y.;
Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Chem. Soc. 2006, 128, 12366–
12367. (e) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1897–
1900. (f) Cho, S. H.; Hwang, S. J.; Chang, S. Org. Synth. 2008, 85, 131–
137. (g) Kim, J. Y.; Kim, S. H.; Chang, S. Tetrahedron Lett. 2008, 49,
1745–1749. (h) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47,
2836–2839. (i) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163–1166.
(5) For an example of R-substitution of N-phosphryl amidines, see: Kim,
We have recently developed the Cu-catalyzed 3-CR of
1-alkyne, sulfonyl- or phosphoryl azide, and various nucleo-
† Korea Advanced Institute of Science and Technology.
‡ Duksung Women’s University.
(1) For recent reviews, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168–3210. (b) Do¨mling, A. Chem. ReV. 2006, 106, 17–
89.
(2) (a) Ugi, I.; Steinbru¨ckner, C. Angew. Chem. 1960, 72, 267–268. (b)
Ugi, I. Angew. Chem. 1962, 74, 9–22.
S. H.; Jung, D. Y.; Chang, S. J. Org. Chem. 2007, 72, 9769–9771
.
(3) (a) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126–129.
(b) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int.
Ed. 2008, 47, 388–391.
(6) For a recent example of R-substitution of preisolated N-sulfonyl
imidates, see: Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 1804–1805
.
10.1021/ol900023t CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society

Table 1. Examination of Various Combinations for the Development of Cu-Catalyzed 4-CRa
a 1a (0.5 mmol), 2a (0.6 mmol), nucleophile (0.75 mmol), electrophile (1.0 mmol), and CuI (10 mol %) were stirred under the mentioned reaction
conditions at 25 °C for 12 h. b 1H NMR yield (internal standard was 1,1,2,2-tetrachloroethane). c Number in the parenthesis is the ratio of two diastereomers
determined by H NMR. d When the reaction was carried out in CHCl3, the same yield of the 4-CR adduct was obtained.
1
1-alkyne and sulfonyl azide followed by ring opening of the
corresponding triazole species (Scheme 1).7 On the basis of
two components would be highly important for the successful
realization of 4-CRs.
In fact, an adduct B derived from the reaction of
ketenimine A with a nucleophile will end up with a 3-CR
product C if a proton transfer process from B to C becomes
irreversible. In addition, selective reactivity of employed
electrophiles would be another key issue of consideration
because a direct cycloaddition of those species with the
ketenimine intermediate A is also possible as an undesired
reaction, thereby leading to a 3-CR product E and inhibiting
the formation of the 4-CR product D. Indeed, elegant
examples of this direct cyclization were already demon-
strated.8 It should be mentioned that the products obtainable
from the prospective 4-CR would be highly valuable from
the aspect of organic synthesis and combinatorial approach
because they bear elaborate neighboring functional groups.9
Scheme 1
At the outset of our studies, we first screened plausible
combinations of potential nucleophiles and electrophiles in
test reactions with phenylacetylene (1a) and p-toluenesulfo-
nyl azide (2a) under various conditions (Table 1). When an
anhydride was employed, the desired 4-CR product was not
observed and only 3-CR products were obtained in varied
this mechanistic consideration, it was envisioned that a new
type of 4-CR protocol could be plausible by the simultaneous
employment of pronucleophiles (Nu-H) and electrophiles in
one pot. It was predicted that a suitable combination of the
(8) (a) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45,
3157–3161. (b) Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007,
9, 1585–1587.
(9) For recent examples of R-aryl carbonyl compounds, see: (a)
Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am.
Chem. Soc. 1999, 121, 2147–2155. (b) Yokoshima, S.; Ueda, T.; Kobayashi,
S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem.
Soc. 2002, 124, 2137–2139. (c) Hoffmann, S.; Nicoletti, M.; List, B. J. Am.
Chem. Soc. 2006, 128, 13074–13075.
(7) (a) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int.
Ed. 2006, 45, 3154–3157. (b) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.;
Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46,
1730–1733. (c) Yoo, E. J.; Ahlquist, M.; Bae, I.; Fokin, V. V.; Sharpless,
K. B.; Chang, S. J. Org. Chem. 2008, 73, 5520–5528.
1156
Org. Lett., Vol. 11, No. 5, 2009

efficiencies depending on the nature of nucleophiles (entries
1 and 2). Interestingly, when ethyl glyoxylate and amine were
used, only a slight amount of 4-CR adduct was produced
along with a major 3-CR adduct, amidine (entry 3). However,
the yield of 4-CR product was significantly increased with
the use of alcohol nucleophile (entry 4). The obtained
R-phenyl ꢀ-hydroxy imidate displayed no diastereoselectiv-
ity, giving almost the same ratio of syn/anti isomers. On the
other hand, a simple aldehyde such as benzaldehyde did not
participate in the 4-CR reaction (entry 5). The use of other
electrophiles such as nitrosobenzene or imine derivatives did
not provide significant outcomes (entries 6 and 7).
Table 3. Various R-Aryl Imidates by Cu-Catalyzed 4-CRa
On the basis of the promising results obtained above, we
further attempted to optimize the 4-CR conditions using
phenylacetylene (1a), p-toluenesulfonyl azide (2a), methanol,
and ethyl glyoxylate (3a) (Table 2). Choice of solvents and
Table 2. Reaction Optimization of 4-CRa
,
entry
catalyst
solvent
additive
DBUd
2,6-lutidine
Et3N
yield (%)b c
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
Cu(OTf)2
CuI
CuI
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
THF
THF
THF
THF
<1
<1
11 (52:48)
59 (53:47)
47 (55:45)
71 (51:49)
66 (53:47)
71 (52:48)
67 (52:48)
Et3N
Et3N
a A solution of 1 (1.2 equiv), 2a (1.2 equiv), 3a (0.5 mmol), methanol
(5.0 equiv), Et3N (3.0 equiv), and CuI (10 mol %) in THF (1.0 mL) was
stirred at 25 °C for 24 h. b Isolated yield. c Diastereomeric ratio determined
Et3N
by H NMR. d Corresponding 4-CR product was detected in less than 5%
1
TBTAe f
,
f
yield.
Sc(OTf)3
a A solution of 1a (0.6 mmol), 2a (0.6 mmol), 3a (0.5 mmol), methanol
(2.5 mmol), additive (1.5 mmol), and catalyst (10 mol %) in solvent (1.0
mL) was stirred for 12 h at 25 °C. b 1H NMR yield (internal standard was
moderate ratio of diastereoselectivity was observed with a
substrate of 4-ethynylbenzaldehyde (entry 6). Whereas
heteroaromatic acetylenes readily participated in the 4-CR
(entry 8), aliphatic alkynes were less efficient, giving only
poor yields of 4-CR products along with a major 3-CR
product, imidate (entry 9).
1,1,2,2-tetrachloroethane). c Diastereomeric ratio determined by H NMR.
1
d When a stoichiometric amount of DBU was used, no 3-CR or 4-CR adduct
was observed. e TBTA ) tris(benzyl-triazolylmethyl)amine. f Et3N (1.5
mmol) was also added.
The scope of other counterparts of sulfonyl azides and
alcohols was then investigated (Table 4). All types of sulfonyl
azides examined worked with high efficiency, affording the
desired 4-CR products in satisfactory yields. Indeed, elec-
tronic or steric variation on the azide component exhibited
small effects on the reaction efficiency, and the corresponding
R-aryl ꢀ-hydroxy imidates were obtained in good yields. In
addition, the new 4-CR reaction was highly facile with a
wide range of primary alcohols to provide the corresponding
products in good yields. However, when secondary alcohols
were used, the reaction became sluggish, affording 4-CR
products in only poor yields (entry 11).
The Cu-catalyzed 4-CR reaction could also be successfully
expanded to include electrophiles other than ethyl glyoxylate.
For example, under the identical reaction conditions, phenyl
glyoxal (5) readily participated in the coupling reaction with
phenylacetylene (1a), p-toluenesulfonyl azide (2a), and
base additives was important for achieving high efficiency,
and THF and triethylamine were selected, respectively
(entries 4-6).10 However, the effect of copper species and
external ligands was less visible. In addition, the combined
use of copper catalyst and Lewis acid additive did not affect
the reaction efficiency (entry 9).
The optimized reaction conditions were subsequently
applied to a range of alkyne substrates (Table 3). In general,
the reaction with aryl acetylenes proceeded smoothly to
afford the desired 4-CR products in moderate to high yields.
Efficiency of this procedure was not much influenced by the
electronic variation of substituents. The reaction conditions
were completely tolerated to various functional groups
examined. The products were obtained with almost the same
ratio of two diastereomers in most cases. However, a
(10) See Supporting Informationfor details.
Org. Lett., Vol. 11, No. 5, 2009
1157

Scheme 2
Table 4. Substrate Scope of Sulfonyl Azides and Alcoholsa
with our earlier transformation protocol from simple al-
lylimidates to amides,4c a Pd-catalyzed [3,3]-sigmatropic
rearrangement of ꢀ-hydroxy allylimidate (7) was found
highly efficient under mild conditions to give N-allyl
N-sulfonamide in a good yield (8).12 In addition, upon
treatment of 7 with catalytic amounts of DBU under
hydrolytic conditions, an aldol product of R-aryl ꢀ-hydroxy
ester (9) was readily obtained, thus demonstrating that the
present approach can be utilized as an aldol surrogate.6
In summary, we have developed a new Cu-catalyzed 4-CR
of aryl acetylenes, sulfonyl azides, alcohols, and conjugated
aldehydes leading to R-aryl ꢀ-hydroxy imidates in good
yields.13 The process appears to represent a high efficiency
and selectivity, mild reaction conditions, and an excellent
functional group tolerance. Since the developed procedure
readily offers an R-aryl ꢀ-hydroxy imino moiety, which is a
highly important synthetic building block ranging from
simple and readily avaliable compounds, it might serve as a
new preparative alternate to replace the conventional meth-
ods.
a A solution of 3a (0.5 mmol), 1a (1.2 equiv), 2 (1.2 equiv), indicated
alcohol (5.0 equiv), Et3N (3.0 equiv), and CuI (10 mol %) was stirred in
THF (1.0 mL) at 25 °C for 24 h. b Isolated yield. c Diastereomeric ratio
d
determined by 1H NMR. 1H NMR yield (internal standard was
1,1,2,2,-tetrachloroethane).
Acknowledgment. This research was supported by the
KOSEF grant R01-2007-000-10618-0.
methanol to provide the corresponding R-aryl ꢀ-hydroxy
imidate (6) in synthetically acceptable yield (eq 1).11
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900023T
(12) (a) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910. (b)
Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224.
(13) Representative Experimental Procedure (Table 3). To a stirred
mixture of 3a (0.5 mmol), 1a (0.6 mmol), 2a (0.6 mmol), methanol (2.5
mmol), and CuI (10 mol %) in THF (1 mL) was added Et3N (1.5 mmol)
under N2. After the mixture was stirred for 24 h at 25 °C, it was quenched
by adding saturated NH4Cl solution and 1 N HCl. Then, the aqueous layer
was extracted with CH2Cl2. The crude residue was purified by flash column
chromatograph to give the desired product.
Synthetic applicability of the obtained R-aryl ꢀ-hydroxy
imidates was next briefly invesigated (Scheme 2). In analogy
(11) Matsubara, R.; Doko, T.; Uetake, R.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2007, 46, 3047–3050.
1158
Org. Lett., Vol. 11, No. 5, 2009