Organocatalytic three-component reactions of pyruvate, aldehyde and aniline by hydrogen-bonding catalysts

Article abstract of DOI:10.1002/ejoc.200800491

Hydrogen-bonding catalysts have been found to catalyze one-pot three-component reactions of pyruvate, anilines and aldehydes to afford versatile 3-amino-1,5-dihydro-2H-pyrrol-2-ones in high yields. Both, thioureas and phosphoric acids are viable catalysts

Full text of DOI:10.1002/ejoc.200800491

FULL PAPER
DOI: 10.1002/ejoc.200800491
Organocatalytic Three-Component Reactions of Pyruvate, Aldehyde and
Aniline by Hydrogen-Bonding Catalysts
Xin Li,[a] Hui Deng,[b] Sanzhong Luo,*[a] and Jin-Pei Cheng*[a,b]
Keywords: Hydrogen bonds / Multicomponent reactions / Chirality / Phosphoric acids / Thioureas / Asymetric catalysis
Hydrogen-bonding catalysts have been found to catalyze
one-pot three-component reactions of pyruvate, anilines and
aldehydes to afford versatile 3-amino-1,5-dihydro-2H-pyrrol-
2-ones in high yields. Both, thioureas and phosphoric acids
are viable catalysts for these reactions and have comparable
activity. The corresponding chiral thioureas and phosphoric
acids have also been used in these three-component reac-
tions to give pyrrol-2-ones in high yields and with moderate
enantioselectivities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
promising biological properties.[5–7] Accordingly, synthetic
efforts have been made towards the construction of this
class of molecules. In general, 3-aminopyrrol-2-ones are ob-
tained by the two-component condensation of anilines with
pyrrolidine-2,3-diones[6c] or β,γ-unsaturated α-oxo esters.[7]
As pyrrolidinediones and β,γ-unsaturated α-oxo esters are
normally prepared from the corresponding aldehydes and
pyruvate derivatives, a one-pot three-component coupling
of aniline, aldehyde and pyruvate would be the ideal process
for the synthesis of these targeted lactams. In this regard, a
single example of such a three-component coupling reac-
tion in the presence of sulfuric acid has recently been re-
ported.[7b] An asymmetric catalytic one-pot three-compo-
nent coupling of aniline, aldehyde and pyruvate, to the best
of our knowledge, is hitherto unknown. In the process of
our study on the direct aldol reaction of pyruvate,[8] we
found that the reaction of pyruvate and aldehyde in the ca-
talysis of a primary amine unexpectedly afforded trace
amounts of the three-component-coupling product [Equa-
tion (1)] instead of the desired aldol product. This interest-
ing MCR reaction was next explored, and hydrogen-bond-
ing organocatalysts such as thioureas and phosphoric acids
were found to be effective catalysts for the reaction. Pro-
vided with the easily accessible chiral hydrogen-bonding or-
ganocatalysts, an asymmetric catalytic one-pot three-com-
ponent condensation of pyruvate, aldehyde and aniline has
been attempted for the first time. Herein we present the re-
sults of this study.
Introduction
Multicomponent reactions (MCRs) are convergent reac-
tions in which three or more starting materials react to form
a product,[1] thus making possible the speedy synthesis of
molecular libraries that have a high degree of structural di-
versity. Such processes are therefore of great value in the
search for new drugs. Accordingly, the development of new
catalytic MCR pathways, particularly enantioselective ones,
has received increasing attention in the past few years.
Breakthroughs in this area include the identification of sev-
eral asymmetric catalysts for highly enantioselective MCRs.
For example, Zhu and co-workers have developed a chiral
lanthanide complex for the asymmetric Biginelli reaction.[2]
Later, Wang et al. found that chiral (salen)Al complexes
served as efficient and effective asymmetric catalysts for
truncated Ugi reactions.[3] Recently, Gong reported that
chiral phosphoric acids were able to catalyze some MCR
reactions with excellent stereoselectivity.[4] Despite these
successes, the development of further catalytic asymmetric
MCRs is still highly desirable when considering the vast
number of MCRs and the potential of their optically pure
products.
1,5-Dihydro-2H-pyrrol-2-ones, particularly their 3-
amino-substituted derivatives, are an interesting type of lac-
tams that are found in many natural products and exhibit
[a] Beijing National Laboratory for Molecular Sciences (BNLMS),
Center for Chemical Biology, Institute of Chemistry, Chinese
Academy of Sciences,
Beijing 100190, China
Fax: +86-10-62554449
E-mail: luosz@iccas.ac.cn
[b] Department of Chemistry and State Key Laboratory of Ele-
mento-Organic Chemistry, Nankai University,
Tianjin 300071, China
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
(1)
4350
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4350–4356

Organocatalytic Three-Component Reactions
A and imine B followed by the intramolecular amidation
and loss of ethanol afforded the 3-aminopyrrol-2-one prod-
uct. In this process, hydrogen-bonding catalysts would acti-
vate the imine by forming hydrogen bonds with the nitrogen
atoms, thereby promoting the formation of enamine A and
imine B as well as the key coupling step. It is envisaged that
the overall reaction is accelerated by using typical hydrogen-
bonding catalysts such as thioureas or phosphoric acids
and, to the best of our knowledge, the use of these types
of catalysts has not been examined in the present reaction.
Indeed, both phosphoric acids and thioureas were found to
promote the three-component reactions (Table 1).
Results and Discussion
Through the pioneering work of Sigman and Jacobsen,[9]
hydrogen-bonding donors have recently become a promi-
nent type of organocatalyst that have enabled the realiza-
tion of a range of transformations. Among the hydrogen-
bonding organocatalysts explored so far, thioureas[10] and
phosphoric acids[11] have attracted the most attention due
to their success in a number of versatile transformations,
particularly in reactions involving the activation of carbonyl
groups or imines. In the three-component reaction of pyr-
uvate, aldehyde and aniline, aniline first reacts with the pyr-
uvate and aldehyde to form enamine A and imine B, respec-
As revealed in Table 1, the reaction of ethyl pyruvate,
tively (Scheme 1). The subsequent condensation of enamine benzaldehyde and p-anisidine was very sluggish in the ab-
Scheme 1. Proposed mechanism for the reaction of pyruvate, p-anisidine and aldehyde.
Table 1. Catalyst screening.[a]
Entry
Catalyst
Solvent
Yield[b] [%]
pKa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
none
1
toluene
THF
1,4-dioxane
CH3CN
CHCl3
6
33
5
–
ca. 10
–
–
–
–
–
–
1
1
5
1
52
57
64
70
38
50
54
54
58
61
62
69
86[e]
82[e]
1
CH2Cl2
benzene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1
1
2
21.1[c]
14.0[d]
13.9[d]
13.4[c]
12.8[d]
12.7[d]
10.8[d]
8.4[d]
–
3a
3b
3c
3d
3e
3f
4
1
4
–
[a] The reactions were carried out on a 0.1 mmol scale in 200 µL of toluene at room temperature with a molar ratio of pyruvate/p-
anisidine/benzaldehyde of 3:2:1. [b] Isolated yield based on the aldehyde. [c] Reference: F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456.
[d] Determined in this work with an uncertainty of Ϯ0.1. [e] 0.3 mmol Na2SO4 was added to the reaction mixture.
Eur. J. Org. Chem. 2008, 4350–4356
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X. Li, H. Deng, S. Luo, J.-P. Cheng
FULL PAPER
sence of any catalysts, affording only 6% yield after 18 h.
Under the optimized conditions, reactions were per-
In comparison, the use of phosphoric acid 1 for the same formed with both phosphoric acid 1 and thiourea 4 to ex-
reaction in toluene gave 70% yield, showing significant plore the substrate scope with regard to the anilines and
catalytic activity. Further investigations indicated that the aldehydes (Table 2). As shown in Table 2, various substi-
catalysis of phosphoric acid 1 was highly solvent-depend- tuted anilines bearing either electron-withdrawing or -do-
ent. Although the reaction occurred smoothly in non-polar nating groups were used in the reaction which led to the
solvents such as toluene and benzene (Table 1, Entries 7 desired products in high yields (Table 2, Entries 1–5). The
and 8), the same reaction barely occurred in polar solvents reaction was also quite general with regard to the aldehydes.
such as dioxane and CH3CN (Table 1, Entries 3 and 4). A variety of aromatic aldehydes underwent the reaction
With toluene as the optimal solvent, the reaction with thio- with ethyl pyruvate and p-anisidine to afford the desired
urea-type catalysts was also examined. A series of thioureas products in yields ranging from 57 to 81% with thiourea 4
with different substituents were synthesized and their corre- as catalyst (Table 2, Entries 6–15). Notably, the reaction
sponding pKa values were determined by using “overlap- also accommodated aliphatic aldehydes such as isovaleral-
ping indicator methods”.[12] As shown in Table 1 (En- dehyde, affording the desired 3-aminopyrrol-2-one product
tries 10–16), a correlation between the catalytic activity of in a moderate yield (Table 2, Entry 16). Among the cases
the thiourea and its corresponding pKa is evident, with examined, phosphoric acid 1 and thiourea 4 demonstrated
lower pKa values, that is, higher acidity, leading to better similar catalytic behaviour, which suggests they are both vi-
yields. Following this trend, the most acidic thiourea exam- able catalysts for this three-component reaction.
ined, thiourea 4, gave the best result with 69% yield in 18 h
With a mild three-component reaction protocol in hand,
(Table 1, Entry 16). With the identified optimal catalysts 1 we next briefly examined the asymmetric catalysis of this
and 4 further improvements in the reaction were achieved reaction by using readily available chiral thioureas[13] and
by using molecular sieves (4 Å) or anhydrous sodium sulfate phosphoric acids.[14] A series of known chiral thioureas 6–
as an additive. In the presence of anhydrous Na2SO4, the 10 and chiral phosphoric acids 11a–i were tested in the reac-
yields increased to 86 and 82% with the catalysts 1 and 4, tion of ethyl pyruvate, benzaldehyde and p-anisidine. After
respectively.
many attempts, our initial efforts led to only moderate
Table 2. Synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones catalyzed by 1 or 4.[a]
Entry
R1
R2NH2
R3CHO
5
Yield[b] [%]
Yield[c] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4-CH3OC6CH4
4-CH3C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
82
84
85
79
78
57
81
65
80
79
79
77
58
81
75
48
86
84
85
81
77
64
80
71
90
81
82
75
62
89
71
51
C6H5
4-ClC6H4
4-BrC6H4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
4-CH3OC6CH4
2,4-(CH3O)2C6H4
4-CH3C6H4
3-CH3C6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
3-BrC6H4
2-BrC6H4
4-O2NC6H4
3-O2NC6H4
(CH3)2CHCH2
[a] The reactions were carried out on a 0.1 mmol scale in 200 µL of toluene at room temperature with a molar ratio of pyruvate/p-
1
anisidine/benzaldehyde of 3:2:1. All new compounds were characterized by H and 13C NMR spectroscopy and MS. [b] Isolated yield
with catalyst 4. [c] Isolated yield with catalyst 1.
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Eur. J. Org. Chem. 2008, 4350–4356

Organocatalytic Three-Component Reactions
with a moderate level of enantioselectivity (44% ee, Table 4,
Entry 9). These results suggest that the use of chiral hydro-
gen-bonding catalysts is indeed a viable strategy for the
asymmetric catalytic three-component coupling reaction,
but new designs of catalysts are clearly required for better
stereocontrol.
enantioselectivities, as shown in Tables 3 and 4. Of the chi-
ral thioureas, Takemoto’s catalyst 10[13a] seemed to be the
best, providing 5a in 20% ee (Table 3, Entry 5). Of the chi-
ral phosphoric acids studied, 11i with the large steric bulk
at the 3,3Ј-positions, which was first used in asymmetric
catalysis by List and co-workers,[14c] gave the best results
Conclusions
We have demonstrated that hydrogen-bonding donors
such as phosphoric acid and thiourea derivatives are ef-
ficient catalysts for the three-component reactions of pyr-
uvate, anilines and aldehydes. This study has provided a
rather mild procedure for the synthesis of versatile 3-amino-
1,5-dihydro-2H-pyrrol-2-ones. Asymmetric catalysis with
chiral phosphoric acids and thioureas was also explored but
gave only moderate enantioselectivity. The development of
more stereoselective catalysts for three-component reac-
tions is currently underway in our laboratory.
Table 3. Reaction of ethyl pyruvate, p-anisidine and benzaldehyde
catalyzed by chiral thioureas.[a]
Entry
Catalyst
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
57
72
85
82
78
11
5
2
7
20
8
9
10
Experimental Section
General Information: Commercial reagents were used as received
unless otherwise stated. 1H and 13C NMR spectra were recorded
with a Bruker DPX 300 spectrometer. Chemical shifts are reported
in ppm from tetramethylsilane with the solvent resonance as the
internal standard. The following abbreviations were used to desig-
nate chemical shift mutiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, sept = septet, m = multiplet, br. = broad. All first-
order splitting patterns were assigned on the basis of the appear-
ance of the multiplet. Splitting patterns that could not be easily
interpreted are designated as multiplet (m) or broad (br.). Mass
spectra were obtained by using an electrospray ionization (EI) mass
spectrometer (Surveyor MSQ PLUS). IR spectra were recorded
with an FT/IR-480Plus spectrometer. Catalyst 2 was purchased
from Aldrich. Catalysts 1,[15] 3a,[16] 3b,[17] 3c,[18] 3d,[19] 3e,[20] 4,[16]
6,[21] 7,[22] 8,[13e] 9,[23] 10[13a] and 11[14] were prepared according to
literature procedures. Catalyst 3f was synthesized in this work.
[a] The reaction was carried out on a 0.1 mmol scale in 200 µL of
toluene at room temperature with a ratio of 1/2/3 = 3:2:1. [b] Isolated
yield based on the aldehyde. [c] Determined by HPLC analysis.
Table 4. Reaction of ethyl pyruvate, p-anisidine and benzaldehyde
catalyzed by chiral phosphoric acids.[a]
Entry
Catalyst
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11f
11g
11h
11i
78
88
83
80
85
87
85
81
77
11
13
3
7
6
6
19
22
44
Preparation of Catalyst 3f: 5-Isothiocyano-1,3-bis(trifluoromethyl)-
benzene (3 mmol) was added to a solution of aniline (3 mmol) in
dichloromethane (20 mL). The mixture was stirred at room tem-
[a] The reaction was carried out on a 0.1 mmol scale in 200 µL of
toluene at room temperature with a ratio of 1/2/3 = 3:2:1. [b] Isolated
yield based on the aldehyde. [c] Determined by HPLC analysis.
Eur. J. Org. Chem. 2008, 4350–4356
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X. Li, H. Deng, S. Luo, J.-P. Cheng
FULL PAPER
perature for 8 h (TLC) and concentrated. The crude product was
purified by flash chromatography to afford 980 mg (90%) of 3f as
a white solid. 1H NMR (300 MHz, CDCl3): δ = 7.32–7.41 (m, 3 H,
3 CH Ar), 7.48–7.53 (m, 2 H, 2 CH Ar), 7.68 (s, 1 H, CH Ar), 7.79
(br., NH, NHC), 7.98 (s, 2 H, 2 CH Ar), 8.66 (br., NH, NHC)
ppm. 13C NMR (75 MHz, CDCl3): δ = 119.50, 121.10, 124.72,
125.56, 128.35, 130.57, 131.37, 131.82, 132.27, 132.71, 135.55,
H enamine), 1672 (s, C=O amide) cm–1. MS (EI+): m/z = 400.
HRMS (EI+): calcd. for [C25H24N2O3] 400.1787; found 400.1790.
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-
amino]-1H-pyrrol-2(5H)-one (5i): Yield: 37.8 mg (90%). 1H NMR
(300 MHz, CDCl3): δ = 3.74 (s, 3 H, CH3O), 3.77 (s, 3 H, CH3O),
5.54 (d, 3J = 2.47 Hz, 1 H, CHN), 5.89 (d, 3J = 2.47 Hz, 1 H,
3
CH=), 6.49 (s, 1 H, NH), 6.80–6.87 (m, 4 H, 4 CH Ar), 7.03 (d, J
139.54, 179.72 ppm. IR (KBr): ν
= 1604 (s, C=S) cm–1. MS
˜
3
max
= 8.51 Hz, 2 H, 2 CH Ar), 7.11 (d, J = 8.51 Hz, 2 H, 2 CH Ar),
(EI+): m/z = 364. HRMS (EI+): calcd. for [C15H10F6N2S] 363.0469;
7.22–7.26 (m, 2 H, 2 CH Ar), 7.32 (d, 3J = 9.06 Hz, 2 H, 2 CH
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.37, 55.60, 64.07,
105.44, 114.25, 114.71, 118.55, 123.89, 128.35, 129.12, 129.93,
133.28, 133.84, 134.69, 136.31, 154.53, 157.12, 167.02 ppm. IR
found 364.0472.
(KBr): ν
= 3313 (s, N–H enamine), 1675 (s, C=O amide) cm–1.
˜
max
MS (EI+): m/z = 420. HRMS (EI+): calcd. for [C24H21ClN2O3]
420.1241; found 420.1244.
5-(3-Chlorophenyl)-1-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-
amino]-1H-pyrrol-2(5H)-one (5j): Yield: 34.0 mg (81%). 1H NMR
(300 MHz, CDCl3): δ = 3.75 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O),
5.53 (d, 3J = 2.47 Hz, 1 H, CHN), 5.89 (d, 3J = 2.47 Hz, 1 H,
CH=), 6.52 (s, 1 H, NH), 6.81–6.88 (m, 4 H, 4 CH Ar), 7.02–7.08
(m, 3 H, 3 CH Ar), 7.19–7.20 (m, 3 H, 3 CH Ar), 7.35 (d, 3J =
9.33 Hz, 2 H, 2 CH Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
55.38, 55.60, 64.13, 105.26, 114.28, 114.70, 118.59, 123.77, 125.08,
127.04, 128.36, 129.95, 130.22, 133.29, 134.66, 134.73, 140.00,
General Experimental Procedure: The pyruvate (0.3 mmol), aniline
(0.2 mmol), aldehyde (0.1 mmol) and catalyst (0.01 mmol) were
placed in a 5-mL vial equipped with a Teflon-coated stirring bar.
The solvent (200 µL) was added under air. The vial was capped
with a white polyethylene stopper, and the resulting mixture was
stirred at room temperature for the indicated time. Then the reac-
tion solution was concentrated in vacuo, and the crude product
was purified by flash chromatography to afford the product. Com-
pounds 5a,[7a] 5b,[7a] 5c,[24] 5d[7a] and 5g[7a] are already known.
154.54, 157.11, 167.06 ppm. IR (KBr): ν
= 3315 (s, N–H en-
˜
max
amine), 1673 (s, C=O amide) cm–1. MS (EI+): m/z = 420. HRMS
(EI+): calcd. for [C24H21ClN2O3] 420.1241; found 420.1243.
1-(4-Bromophenyl)-3-[(4-bromophenyl)amino]-5-phenyl-1H-pyrrol-
2(5H)-one (5e): Yield: 37.6 mg (78 %). 1H NMR (300 MHz,
CDCl3): δ = 5.62 (d, 3J = 2.74 Hz, 1 H, CHN), 6.04 (d, 3J =
5-(2-Chlorophenyl)-1-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-
1
amino]-1H-pyrrol-2(5H)-one (5k): Yield: 34.4 mg (82%). H NMR
3
2.74 Hz, 1 H, CH=), 6.72 (s, 1 H, NH), 6.94 (d, J = 9.06 Hz, 2 H,
(300 MHz, CDCl3): δ = 3.74 (s, 3 H, CH3O), 3.77 (s, 3 H, CH3O),
5.98 (d, 3J = 2.47 Hz, 1 H, CHN), 6.19 (d, 3J = 2.47 Hz, 1 H,
CH=), 6.52 (s, 1 H, NH), 6.82–6.87 (m, 4 H, 4 CH Ar), 6.98–7.05
2 CH Ar), 7.17–7.19 (m, 2 H, 2 CH Ar), 7.25–7.30 (m, 3 H, 3CH
Ar), 7.35–7.39 (m, 3 H, 3CH Ar), 7.43–7.46 (m, 3 H, 3 CH Ar)
ppm. 13C NMR (75 MHz, CDCl3): δ = 64.13, 108.85, 113.46,
118.05, 118.28, 122.77, 126.62, 128.49, 129.22, 131.65, 131.98,
3
(m, 3 H, 3 CH Ar), 7.08–7.18 (m, 2 H, 2 CH Ar), 7.35 (dd, J =
3
2.47, 7.96 Hz, 1 H, CH Ar), 7.47 (d, J = 9.06 Hz, 2 H, 2 CH Ar)
ppm. 13C NMR (75 MHz, CDCl3): δ = 54.31, 54.54, 59.31, 103.30,
113.19, 113.64, 117.51, 121.51, 126.22, 126.60, 127.99, 128.76,
129.26, 132.15, 132.43, 133.68, 133.95, 153.43, 155.65, 166.14 ppm.
132.25, 136.18, 136.72, 140.19, 166.99 ppm. IR (KBr): νmax = 3327
˜
(s, N–H enamine), 1674 (s, C=O amide) cm–1. MS (EI+): m/z =
482, 484, 486. HRMS (EI+): calcd. for [C22H16Br2N2O] 481.9629,
483.9609, 485.9588; found 481.9619, 483.9603, 485.9597.
IR (KBr): ν
= 3318 (s, N–H enamine), 1683 (s, C=O amide)
˜
max
c m– 1 . M S (E I + ) : m / z = 4 2 0 . H R M S ( E I + ) : c a l c d . fo r
5-(2,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)-3-[(4-methoxy-
[C24H21ClN2O3] 420.1241; found 420.1244.
1
phenyl)amino]-1H-pyrrol-2(5H)-one (5f): Yield: 28.5 mg (64%). H
NMR (300 MHz, CDCl3): δ = 3.73 (s, 3 H, CH3O), 3.75 (s, 3 H,
5-(3-Bromophenyl)-1-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-
amino]-1H-pyrrol-2(5H)-one (5l): Yield: 35.7 mg (77%). 1H NMR
(300 MHz, CDCl3): δ = 3.75 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O),
5.52 (d, 3J = 2.74 Hz, 1 H, CHN), 5.89 (d, 3J = 2.74 Hz, 1 H,
CH3O), 3.77 (s, 3 H, CH3O), 3.87 (s, 3 H, CH3O), 5.96 (d, 3J =
3
2.74 Hz, 1 H, CH-N), 6.07 (d, J = 2.47 Hz, 1 H, CH=), 6.33 (dd,
3J = 2.74, 8.23 Hz, 1 H, NH), 6.44 (t, 3J = 2.47 Hz, 2 H, 2 CH
Ar), 6.81–6.86 (m, 5 H, 5 CH Ar), 7.03 (d, 3J = 9.33 Hz, 2 H, 2
CH Ar), 7.48 (d, J = 9.33 Hz, 2 H, 2 CH Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.31, 55.35, 55.61, 57.23, 98.55, 104.97,
106.28, 114.00, 114.64, 117.49, 118.25, 122.72, 127.44, 130.79,
132.79, 135.19, 154.18, 156.46, 158.10, 160.32, 167.28 ppm. IR
3
CH=), 6.51 (s, 1 H, NH), 6.82–6.88 (m, 4 H, 4 CH Ar), 7.04 (d, J
= 9.06 Hz, 2 H, 2 CH Ar), 7.09–7.16 (m, 2 H, 2 CH Ar), 7.34–7.36
(m, 4 H, 4 CH Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.38,
55.61, 64.10, 105.27, 114.30, 114.71, 118.60, 122.88, 123.80, 125.54,
129.95, 130.51, 131.29, 133.29, 134.64, 140.24, 154.55, 157.13,
(KBr): ν
= 3330 (s, N–H enamine), 1674 (s, C=O amide) cm–1.
˜
167.07 ppm. IR (KBr): ν
= 3313 (s, N–H enamine), 1673 (s,
˜
max
max
MS (EI+): m/z = 446. HRMS (EI+): calcd. for [C26H26N2O5]
C=O amide) cm–1. MS (EI+): m/z = 464, 466. HRMS (EI+): calcd.
446.1842; found 446.1844.
for [C24H21BrN2O3] 464.0736, 466.0715; found 464.0731, 466.0720.
1-(4-Methoxyphenyl)-3-[(4-methoxyphenyl)amino]-5-(m-tolyl)-1H- 5-(2-Bromophenyl)-1-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-
1
1
pyrrol-2(5H)-one (5h): Yield: 28.4 mg (71%). H NMR (300 MHz, amino]-1H-pyrrol-2(5H)-one (5m): Yield: 28.8 mg (62%). H NMR
CDCl3): δ = 2.28 (s, 3 H, CH3), 3.74 (s, 3 H, CH3O), 3.77 (s, 3 H, (300 MHz, CDCl3): δ = 3.74 (s, 3 H, CH3O), 3.77 (s, 3 H, CH3O),
CH3O), 5.53 (d, J = 2.47 Hz, 1 H, CHN), 5.93 (d, J = 2.47 Hz, 5.99 (d, 3J = 2.47 Hz, 1 H, CHN), 6.17 (d, 3J = 2.47 Hz, 1 H,
3
3
1 H, CH=), 6.50 (s, 1 H, NH), 6.80–6.87 (m, 4 H, 4 CH Ar), 7.00–
CH=), 6.51 (s, 1 H, NH), 6.82–6.87 (m, 4 H, 4 CH Ar), 6.97–7.10
3
7.05 (m, 4 H, 4 CH Ar), 7.14–7.18 (m, 1 H, 1 CH Ar), 7.39 (d, J (m, 4 H, 4 CH Ar), 7.13–7.18 (m, 1 H, CH Ar), 7.47 (d, 3J =
= 8.51 Hz, 2 H, 2 CH Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.41, 55.35, 55.60, 64.71, 106.41, 114.13, 114.66, 118.40, 123.65,
9.06 Hz, 2 H, 2 CH Ar), 7.54 (dd, J = 1.37, 7.96 Hz, 1 H, 1 CH
3
Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ = 55.35, 55.59, 62.87,
124.01, 127.42, 128.76, 128.91, 130.41, 132.83, 134.92, 137.59, 104.42, 114.24, 114.69, 118.56, 122.54, 123.28, 127.41, 128.29,
138.64, 154.35, 156.88, 167.26 ppm. IR (KBr): ν = 3317 (s, N– 129.38, 130.30, 133.07, 133.43, 134.71, 136.54, 154.49, 156.67,
˜
max
4354
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4350–4356

Organocatalytic Three-Component Reactions
Chem. Soc. 2007, 129, 3790; d) J. Jiang, J. Yu, X.-X. Sun, Q.-
Q. Rao, L.-Z. Gong, Angew. Chem. Int. Ed. 2008, 47, 2458.
167.21 ppm. IR (KBr): ν
= 3319 (s, N–H enamine), 1679 (s,
˜
max
C=O amide) cm–1. MS (EI+): m/z = 464, 466. HRMS (EI+): calcd.
[5]
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a) V. L. Gein, A. V. Popov, V. E. Kolla, N. A. Popova, K. D.
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4370; b) Y. S. Andreichikov, V. L. Gein, O. I. Ivanenko, A. N.
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c) S. T. Kocharyan, N. P. Churkina, T. L. Razina, V. E. Karape-
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a) Y. C. Wu, L. Liu, D. Wang, Y. J. Chen, J. Heterocycl. Chem.
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10, 1775; b) S. Z. Luo, H. Xu, L. Zhang, J. Y. Li, J.-P. Cheng,
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J.-P. Cheng, J. Am. Chem. Soc. 2007, 129, 3074.
for [C24H21BrN2O3] 464.0736, 466.0715; found 464.0732, 466.0712.
1-(4-Methoxyphenyl)-3-[(4-methoxyphenyl)amino]-5-(4-nitrophenyl)-
1H-pyrrol-2(5H)-one (5n): Yield: 38.4 mg (89 %). 1H NMR
(300 MHz, CDCl3): δ = 3.74 (s, 3 H, CH3O), 3.77 (s, 3 H, CH3O),
5.68 (d, 3J = 2.47 Hz, 1 H, CHN), 5.88 (d, 3J = 2.47 Hz, 1 H,
3
CH=), 6.53 (s, 1 H, NH), 6.80–6.88 (m, 4 H, 4 CH Ar), 7.03 (d, J
= 8.51 Hz, 2 H, 2 CH Ar), 7.32–7.37 (m, 4 H, 4 CH Ar), 8.12 (d,
3J = 9.06 Hz, 2 H, 2 CH Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
55.38, 55.59, 63.84, 104.14, 114.42, 114.74, 118.78, 123.66, 124.27,
127.78, 129.62, 133.84, 134.35, 145.55, 147.69, 154.75, 157.25,
[7]
[8]
166.89 ppm. IR (KBr): ν
= 3311 (s, N–H enamine), 1680 (s,
˜
max
C=O amide) cm–1. MS (EI+): m/z = 431. HRMS (EI+): calcd. for
[C24H21N3O5] 431.1481; found 431.1483.
1-(4-Methoxyphenyl)-3-[(4-methoxyphenyl)amino]-5-(3-nitrophenyl)-
1H-pyrrol-2(5H)-one (5o): Yield: 32.3 mg (75 %). 1H NMR
(300 MHz, CDCl3): δ = 3.74 (s, 3 H, CH3O), 3.77 (s, 3 H, CH3O),
5.69 (d, 3J = 2.47 Hz, 1 H, CHN), 5.90 (d, 3J = 2.47 Hz, 1 H,
[9]
M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120,
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For recent reviews, see: a) A. G. Doyle, E. N. Jacobsen, Chem.
Rev. 2007, 107, 5713; b) M. S. Taylor, E. N. Jacobsen, Angew.
Chem. Int. Ed. 2006, 45, 1520.
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5744; b) S. J. Connon, Angew. Chem. Int. Ed. 2006, 45, 3909;
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For recent studies on the use of chiral thioureas as catalysts,
see: a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc.
2003, 125, 12672; b) Y. Hoashi, T. Yabuta, Y. Takemoto, Tetra-
hedron Lett. 2004, 45, 9185; c) T. Okino, Y. Hoashi, T. Furu-
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d) S. H. McCooey, S. J. Connon, Angew. Chem. Int. Ed. 2005,
44, 6367; e) B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org.
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Takemoto, Tetrahedron 2006, 62, 365; k) H. B. Huang, E. N.
Jacobsen, J. Am. Chem. Soc. 2006, 128, 7170; l) R. P. Herrera,
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44, 6576; m) M. T. Robak, M. Trincado, J. A. Ellman, J. Am.
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129, 1878.
3
CH=), 6.50 (s, 1 H, NH), 6.81–6.88 (m, 4 H, 4 CH Ar), 7.04 (d, J
3
= 8.51 Hz, 2 H, 2 CH Ar), 7.34 (d, J = 8.51 Hz, 2 H, 2 CH Ar),
7.42–7.51 (m, 2 H, 2 CH Ar) ppm. 13C NMR (75 MHz, CDCl3): δ
= 55.39, 55.60, 63.85, 104.27, 114.45, 114.74, 118.80, 122.17,
123.29, 123.90, 129.48, 130.01, 132.86, 133.81, 134.36, 140.38,
[11]
148.57, 154.75, 157.32, 166.90 ppm. IR (KBr): ν
= 3333 (s, N–
˜
max
[12]
[13]
H enamine), 1683 (s, C=O amide) cm–1. MS (EI+): m/z = 431.
HRMS (EI+): calcd. for [C24H21N3O5] 431.1481; found 431.1478.
5-Isobutyl-1-(4-methoxyphenyl)-3-[(4-methoxyphenyl)amino]-1H-
1
pyrrol-2(5H)-one (5p): Yield: 18.7 mg (51%). H NMR (300 MHz,
CDCl3): δ = 0.86 (d, 3J = 6.86 Hz, 3 H, CH3-CH), 0.98 (d, 3J =
6.86 Hz, 3 H, CH3CH), 1.17–1.26 (m, 2 H, CH2CH), 1.55–1.65 (m,
1 H, CHCH3), 3.80 (s, 3 H, CH3O), 3.83 (s, 3 H, CH3O), 4.62–4.68
(m, 1 H, CHN), 6.02 (d, 3J = 2.47 Hz, 1 H, CH=), 6.41 (s, 1 H,
3
NH), 6.88–6.98 (m, 4 H, 4 CH Ar), 7.06 (d, J = 8.51 Hz, 2 H, 2
CH Ar), 7.36 (d, 3J = 8.78 Hz, 2 H, 2 CH Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.05, 23.92, 25.18, 41.77, 55.48, 55.62,
58.92, 104.36, 114.37, 114.71, 118.38, 124.74, 129.76, 133.87,
135.17, 154.28, 157.30, 166.08 ppm. IR (KBr):ν = 3305 (s, N–H
˜
enamine), 1676 (s, C=O amide) cm–1. MS (EI+): m/z = 366. HRMS
(EI+): calcd. for [C22H26N2O3] 366.1943; found 366.1941.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for new compounds and HPLC trace for 5a.
Acknowledgments
[14]
For pioneering studies on the use of chiral phosphoric acid
catalysts, see: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe,
Angew. Chem. Int. Ed. 2004, 43, 1566; b) D. Uraguchi, M. Ter-
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This work was supported by the Natural Science Foundation of
China (NSFC) (20421202, 20632060 and 20702052), the Ministry
of Science and Technology (MoST) and the Institute of Chemistry
of the Chinese Academy of Sciences.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4355

X. Li, H. Deng, S. Luo, J.-P. Cheng
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Received: May 20, 2008
Published Online: July 21, 2008
4356
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4350–4356