Organocatalytic tandem three-component reaction of imine, alkyl vinyl ketone, and imide via aza-baylis-hillman reaction

Article abstract of DOI:10.1021/jo102143r

A highly chemoselective PPh₃-catalyzed three-component reaction of an imine, alkyl vinyl ketone, and phthalimide or succinimide is developed. Various highly functional adducts with high diastereoselectivities can be generated via aza-Morita-Baylis-Hillman reactions of aryl-substituted imines and alkyl vinyl ketones followed by Michael additions of imides and then epimerization.

Full text of DOI:10.1021/jo102143r

NOTE
pubs.acs.org/joc
Organocatalytic Tandem Three-Component Reaction of Imine, Alkyl
Vinyl Ketone, and Imide via aza-BaylisꢀHillman Reaction
Siang-en Syu, Yu-Ting Lee, Yeong-Jiunn Jang, and Wenwei Lin*
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Tingchow Road, Taipei 11677, Taiwan, Republic of China
S Supporting Information
b
ABSTRACT: A highly chemoselective PPh3-catalyzed three-compo-
nent reaction of an imine, alkyl vinyl ketone, and phthalimide or
succinimide is developed. Various highly functional adducts with high
diastereoselectivities can be generated via aza-MoritaꢀBaylisꢀHill-
man reactions of aryl-substituted imines and alkyl vinyl ketones
followed by Michael additions of imides and then epimerization.
ulticomponent reactions are of great importance in organic
synthesis due to generation of an adduct in a single
Scheme 1. Tandem Three-Component Reaction of Imine 1,
Alkyl Vinyl Ketone 2, and Imide 3
M
operation from three or more reactants with high atom economy
and bond-forming efficiency.1 In addition, good chemoselectiv-
ities in the presence of all the reactants make the multicompo-
nent reaction a useful methodology to construct complex
molecules.2 The aza-BaylisꢀHillman adducts,3 starting from
imines and alkyl vinyl ketones, are excellent Michael acceptors
due to the ketone functionality activated by the neighboring
sulfonimide group via hydrogen bonding interaction. Their
application in the Michael addition reactions with nucleophiles
can further provide various highly functional products.3,4
Recently, we reported an EtPPh2- or PPh3-catalyzed tandem
three-component reaction of aldehyde, alkyl acrylate (or alkyl
vinyl ketone), and amide.5 Since the aza-BaylisꢀHillman adducts
are better Michael acceptors than alkyl vinyl ketones, it should be
possible to conduct a phosphine-catalyzed three-component
reaction starting from the aza-BaylisꢀHillman reaction of imine
1 and alkyl vinyl ketone 2, followed by the Michael addition of
imide 3 to the resulting adduct. Herein, we wish to report a highly
diastereoselective and chemoselective three-component reaction
of 1, 2, and 3 catalyzed by PPh3 and methyl acrylate (4) or 1,4-
diazabicyclo[2.2.2]octane (DABCO), affording the adducts 5
and 6 (Scheme 1).
The imine 1a, methyl vinyl ketone (2a) (1.5 equiv), and
phthalimide (3a) (1.1 equiv) in the presence of PPh3 (20 mol %)
in tetrahydrofuran (THF) reacted successfully at 27 °C within 7
h (t1, full conversion of 1a), providing the highly functional
three-component adduct 5a in high isolated yield (96%), albeit
with poor diastereoselectivity (54:46) (entry 1, Table 1). In
order to improve the diastereoselectivity of 5a, several additives
such as DABCO, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or
4 were evaluated (Figure 1). The additive 4 was chosen because
the in situ formed enolate 10, which resulted from the Michael
addition of PPh3 to 4, could be an effective base.6 In addition,
different solvents were examined (entries 2ꢀ10). DABCO (20
mol %) catalyzed the aza-BaylisꢀHillman reaction of 1a and 2a,
giving the corresponding adduct 5a more efficiently (t1 = 2 h)
with improved diastereoselectivity (74:26, entry 2). Interest-
ingly, with slightly less 2a (1.3 equiv), the dr of 5a increased
slightly (t1 = 2 h; 75%; 80:20 dr; entry 3). When DABCO (40
mol %) was used without PPh3, it took longer (t1 = 12 h) to
furnish 5a (85% yield; 75:25 dr) (entry 4). Furthermore, we
found a slightly increased dr of 5a (80:20) after 48 h (t2) under
the same reaction conditions. Different solvents, such as CH2Cl2,
dimethylformamide (DMF), or CH3CN, were screened when
both PPh3 (20 mol %) and DABCO (20 mol %) were used, and
CH3CN turned out to be the best one for the formation of 5a
(0.5 h; 95% isolated yield) (entries 5ꢀ7). Even reduced PPh3
(10 mol %) and DABCO (10 mol %) can efficiently catalyze the
reaction of 1a, 2a (1.3 equiv), and 3a (1.1 equiv), affording 5a
within 0.5 h (100% yield; 50:50 dr) (entry 8). DBU (20 mol %)
gave an inferior result to that of DABCO (entries 7 and 9).
Surprisingly, in the presence of methyl acrylate (4) (20 mol %)
and PPh3 (20 mol %), the reaction of 1a, 2a (1.3 equiv), and 3a
(1.1 equiv) in CH3CN took place effectively within 0.5 h,
providing 5a in 95% isolated yield with 45:55 dr, and the
diastereoselectivity of 5a was up to 88:12 after 48 h (entry 10).7
Received: October 28, 2010
Published: March 14, 2011
r
2011 American Chemical Society
2888
dx.doi.org/10.1021/jo102143r J. Org. Chem. 2011, 76, 2888–2891
|

The Journal of Organic Chemistry
NOTE
Table 1. Optimization of Reaction Conditions for an Orga-
nocatalytic Three-Component Reaction of 1a, 2a, and 3aa
Figure 1. Possible bases in our designed condition for deprotonation of
the R-position of ketone function of 5 or 6 facilitating the change of the
ratio of two diastereomers of 5 or 6.
entry additive solvent t1; t2 (h) NMR yield of 5a (t1) (%)b; dr (t1; t2)c
1d none
2d DABCO THF
DABCO THF
4f DABCO THF
THF
7; 48
2; 48
2; 48
12; 48
96e; (54:46; 54:46)
95; (74:26; 75:25)
75; (80:20; 80:20)
85; (75:25; 80:20)
90; (66:34; 80:20)
85e; (50:50; 50:50)
100g; (60:40; 75:25)
100; (50:50; 75:25)
80; (50:50; 73:27)
100g; (45:55; 88:12)
Table 2. Three-Component Reaction of Imine 1, 2, and
3aa
3
5
6
7
DABCO CH2Cl2 2; 48
DABCO DMF 1; 48
DABCO CH3CN 0.5; 48
8h DABCO CH3CN 0.5; 48
9
DBU
CH3CN 0.5; 48
10
4
CH3CN 0.5; 48
a Reactions were carried out using 1a (1.0 mmol), 2a (1.3 equiv), and 3a
(1.1 equiv) in solvent (1.0 mL) at 27 °C. b DMF was used as the internal
standard. c Diastereoselectivities (erythro/threo) of 5a at t1 and t2 were
entry
R; R0
time (h)
yield (%)b; drc
1
determined by crude H NMR analysis. d 1.5 equiv of 2a was used.
e Isolated yield. f The reaction proceeded only with DABCO (40 mol %).
g 95% isolated yield. h PPh3 (10 mol %) and DABCO (10 mol %) were used.
1d
2d
3e
4d
5d
6e
7d
8e
4-CH3C6H4; Me
4-CH3OC6H4; Me
C6H5; Me
48
24
48
48
4
5a, 95; 88:12
5b, 90; 2:98
5c, 92; 83:17f
5d, 93; 2:98f
5e, 93; 6:94f
5f, 90; 9:91
5g, 95; 3:97f
5h, 91; 15:85
5i, 85; 90:10f
5j, 90; 90:10
5k, 87; 88:12g
5l, 87; 5:95g
5m, no reaction
5n, 87; 4:96
5o, 95; 17:83
The broad reaction scope of our optimized protocol was
demonstrated in Table 2 (condition A, PPh3 (20 mol %) and 4
(20 mol %); condition B, PPh3 (10 mol %) and DABCO (10 mol
%)). It showed that, under condition A, highly chemoselective
three-component reactions of various aryl-substituted imines
such as 1aꢀ1b, 1dꢀ1f, 1g, or 1iꢀ1j, 2a or 2b (1.3 equiv), and
3a (1.1 equiv) completed in 0.5ꢀ1 h, leading to the correspond-
ing adducts 5aꢀ5b, 5d, 5g, 5iꢀ5j, or 5n, 5o with poor to
moderate diastereoselectivities (50:50 to 30:70), except for 5e
(8:92 dr).8 When the reactions proceeded with prolonged time
(3ꢀ48 h), high diastereoselectivities of 5aꢀ5b, 5dꢀ5e, 5g,
5iꢀ5j or 5nꢀ5o were obtained (5a, 5iꢀ5k, 90:10 to 83:17 dr;
5b, 5dꢀ5e, 5g, 5nꢀ5o, 17:83 to 2:98 dr) (entries 1ꢀ2, 4ꢀ5, 7,
9ꢀ10, and 14ꢀ15). The reactions of 1c, 1f, or 1h, 2a (1.3 equiv)
and 3a (1.1 equiv), which gave unsatisfactory results under
condition A, were carried out in the presence of PPh3 (10 mol
%) and DABCO (10 mol %) within 8ꢀ48 h with good results
(5c, 92%, 87:13 dr; 5f, 90%, 9:91 dr; 5h, 91%, 15:85 dr) (entries
3, 6, and 8). A heteroaryl-subsitituted imine, such as 1k or an
imine 1l, reacted successfully with 2a and 3a according to our
protocol (1k, condition A; 1l, condition B), affording the
corresponding adduct 5k or 5l in high yields and with good
diastereoselectivities (5k, 87%, 88:12 dr; 5l, 87%, 5:95 dr)
(entries 11 and 12). An alkyl-substituted imine like 1m was
examined; however, no reaction of 1m, 2a, and 3a occurred
(entry 13).
2-naphthyl; Me
4-NO2C6H4; Me
4-CF3C6H4; Me
4-BrC6H4; Me
4-ClC6H4; Me
2-BrC6H4; Me
2-ClC6H4; Me
2-thienyl; Me
8
48
8
9d
48
48
24
24
10d
11d
12e
13d
14d
15d
trans-PhCHdCH; Me
i-Pr; Me
4-BrC6H4; Et
12
3
4-CF3C6H4; Et
a Reactions were carried out using 1 (1.0 mmol), 2 (1.3 equiv), and 3a
(1.1 equiv) in CH3CN (1.0 mL) at 27 °C. b Yield of isolated product.
c Diastereoselectivities (erythro/threo) of 5 were determined by crude 1H
1
NMR analysis; the stereochemistry of 5 was determined by H NMR
analysis in comparison to 5e, 5g, and 5i. d Condition A. e Condition B.
f The relative configuration was confirmed by X-ray crystallography.
g The relative configuration was not determined.
On the basis of experimental results (Tables 1ꢀ3), a plausible
reaction mechanism for this highly chemoselective three-com-
ponent reaction was proposed (Scheme 2).9,10 First, a PPh3-
catalyzed aza-BaylisꢀHillman reaction took place, giving rise to
the corresponding adduct 11. Deprotonation of an imide 3
occurred, and 12 underwent the Michael addition toward 11
followed by protonation, affording the corresponding adduct 5 or
6 with the regeneration of PPh3. The different solubilities of
erythro-5 and threo-5 (or erythro-6 and threo-6) in CH3CN
probably accounted for the diastereoselectivities of 5 (or 6).
The base, such as DABCO or an in situ formed base resulting
from the addition of PPh3 toward 4, deprotonated the R-position
Furthermore, a different imide, such as succinimide (3b)
(1.1 equiv), also worked nicely with an aryl-substituted imine
like 1b, 1c, 1e, or 1g (R = 4-CH3OC6H4, C6H5, 4-NO2C6H4,
4-BrC6H4) and 2a (1.3 equiv) in the presence of PPh3 (20 mol
%) and 4 (20 mol %) within 3ꢀ36 h, providing 6aꢀ6d
with high to excellent diastereoselectivities (13:87 to <1:99)
(entries 1ꢀ4, Table 3).8
2889
dx.doi.org/10.1021/jo102143r |J. Org. Chem. 2011, 76, 2888–2891

The Journal of Organic Chemistry
NOTE
Table 3. Three-Component Reaction of Imines 1, 2a,
and 3ba
nitrogen-flushed 10 mL Schlenk flask, equipped with a magnetic stirring
bar and a septum, was charged with a solution of 1a (273.1 mg, 1.0
mmol), 3a (161.7 mg, 1.1 equiv), and PPh3 (52.4 mg, 20 mol %) in dry
CH3CN (1.0 mL). Methyl vinyl ketone (2a) (105.4 μL, 1.3 equiv) and
methyl acrylate (4) (18.0 μL, 20 mol %) were added, and the reaction
mixture was stirred for 48 h at 27 °C. Thereafter, the solvent was
removed by evaporation in vacuo. Purification by flash chromatography
(CH2Cl2/CH3OH 100:1) furnished the adducts erythro-5a and threo-5a
as a white solid (419.0 mg) and a white solid (46.7 mg), respectively
(overall 95% yield).
erythro-5a: Rf 0.19 (CH2Cl2/CH3OH, 120/1); mp, 171.2ꢀ
171.5 °C; 1H NMR (400 MHz, CDCl3) δ/ppm, 7.76ꢀ7.68 (m, 2H),
7.68ꢀ7.61 (m, 2H), 7.55 (d, 2H, J = 8.0 Hz), 7.10 (d, 2H, J = 8.0 Hz),
6.86 (d, 2H, J = 7.8 Hz), 6.77 (d, 2H, J = 7.8 Hz), 5.86 (d, 1H, J = 9.2 Hz),
4.73 (pseudo t, 1H, J = 8.4 Hz), 4.11 (dd, 1H, J = 14.6, 6.4 Hz), 4.0 (dd,
1H, J = 14.6, 7.6 Hz), 3.65ꢀ3.54 (m, 1H), 2.33 (s, 3H), 2.06 (s, 3H),
1.92 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ/ppm, 207.2, 168.0,
142.9, 137.5, 137.2, 134.4, 133.9, 131.6, 129.1, 128.9, 127.0, 126.4, 123.1,
57.1, 56.1, 36.7, 30.0, 21.3, 20.7; MS (20 eV, EI) m/z (%), 335 [M ꢀ
154]þ (10), 273 (100), 217 (70), 174 (89), 155 (68), 118 (96), 92 (16);
IR (CH2Cl2) v (cmꢀ1), 3210 (s), 2922 (m), 1775 (s), 1723 (s), 1325
(m), 1155 (m), 938 (m), 717 (s); HRMS (ESI) m/z calcd for
C27H26N2O5SNa, [M þ Na]þ (513.1460), found, 513.1458. Anal.
Calcd. for C27H26N2O5S: C, 66.10; H, 5.34; N, 5.71; S, 6.54. Found:
C, 65.88; H, 5.31; N, 6.04; S, 6.67.
entry
R
time (h)
yield (%)b; drc
1
2
3
4
4-CH3OC6H4
C6H5
36
36
3
6a, 88; 13:87
6b, 93; 9:91
6c, 94; <1:99
6d, 91; 5:95
4-NO2C6H4
4-BrC6H4
12
a Reactions were carried out using 1 (1.0 mmol), 2a (1.3 equiv), and 3b
(1.1 equiv) in CH3CN (1.0 mL) at 27 °C. b Yield of isolated product.
c Diastereoselectivities (erythro/threo) of 6 were determined by crude 1H
NMR analysis; the relative configuration of 6aꢀ6d was confirmed by
X-ray crystallography.
Scheme 2. Proposed Mechanism of the Three-Component
Reaction of 1, 2, and 3 Catalyzed by PPh3
threo-5a: Rf 0.15 (CH2Cl2/CH3OH, 120/1); mp, 172.1ꢀ172.9 °C;
1H NMR (400 MHz, CDCl3) δ/ppm, 7.85ꢀ7.72 (m, 2H), 7.72ꢀ7.60
(m, 2H), 7.40 (d, 2H, J = 8.0 Hz), 6.97 (d, 2H, J = 8.0 Hz), 6.89 (d, 2H, J
= 7.8 Hz), 6.83 (d, 2H, J = 7.8 Hz), 6.20 (d, 1H, J = 9.7 Hz), 4.68 (pseudo
t, 1H, J = 8.6 Hz), 4.00ꢀ3.86 (m, 1H), 3.61ꢀ3.47 (m, 2H), 2.26 (s, 3H),
2.16 (s, 3H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ/ppm,
209.6, 167.8, 142.7, 137.6, 137.4, 134.5, 134.1, 131.6, 129.1, 129.0, 126.9,
126.5, 123.3, 58.1, 55.7, 37.8, 30.7, 21.3, 20.8; MS (20 eV, EI) m/z (%),
336 [M ꢀ 154]þ (100), 275 (80), 218 (25), 188 (28), 155 (18), 118
(30), 92 (7); IR (CH2Cl2) ν (cmꢀ1), 3210 (s), 2922 (m), 1775 (s), 1723
(s), 1325 (m), 1155 (m), 938 (m), 717 (s); HRMS (ESI) m/z calcd for
C27H26N2O5SNa, [M þ Na]þ (513.1460); found, 513.1464.
Preparation of N-[2-Acetyl-1-(4-trifluoromethyl-phenyl)-3-phthali-
midopropyl]-p-toluenesulfonamide 5f: A dry and nitrogen-flushed
10 mL Schlenk flask, equipped with a magnetic stirring bar and a
septum, was charged with a solution of 1f (327.0 mg, 1.0 mmol), 3a
(161.7 mg, 1.1 equiv), PPh3 (26.2 mg, 10 mol %), and DABCO (11.2
mg, 10 mol %) in dry CH3CN (1.0 mL). Methyl vinyl ketone (2a)
(105.4 μL, 1.3 equiv) was added, and the reaction mixture was stirred for
8 h at 27 °C. Thereafter, the solvent was removed by evaporation in
vacuo. Purification by flash chromatography (CH2Cl2/CH3OH 100:1)
furnished the adducts erythro-5f and threo-5f as a white solid and a white
solid, respectively (erythro-5f, 33.5 mg; threo-5f, 439.6 mg; mixture of 5f,
16.6 mg; overall 489.7 mg, 90%).
of ketone function of 5 or 6 and facilitated the change of the ratio
of the two diastereomers of 5 or 6.
In summary, we have developed a general procedure for the
highly diastereoselective and chemoselective three-component
reaction of imine 1, alkyl vinyl ketone 2, and imide 3 catalyzed by
PPh3 and DABCO or methyl acrylate (4). The reaction condi-
tions are very mild, and numerous aryl-substituted imines 1 can
react efficiently with 2 and 3 in high yields. The reaction
mechanism is proposed to undergo the aza-MoritaꢀBaylisꢀHillman
reaction of 1 and 2 followed by the Michael addition of 12 toward
the corresponding adduct 11. Our study indicated that in
combination with PPh3, 4 can improve the diastereoselectivities
of 5 or 6 when two diastereomers of 5 or 6 have different
solubilities in CH3CN. Further studies and the extensions of this
work in other activated alkenes, as well as the use of other
nucleophilic reagents, are currently underway.
erythro-5f: Rf 0.19 (CH2Cl2/CH3OH, 120/1); mp, 179.1ꢀ180.0 °C;
1H NMR (400 MHz, CDCl3) δ/ppm, 7.71ꢀ7.65 (m, 4H), 7.53 (d, 2H,
J = 8.0 Hz), 7.19 (d, 2H, J = 8.3 Hz), 7.15 (d, 2H, J = 8.3 Hz), 7.10 (d, 2H,
J = 8.0 Hz), 6.05 (d, 1H, J = 9.0 Hz), 4.93 (pseudo t, 1H, J = 7.8 Hz), 4.11
(dd, 1H, J = 14.8, 7.2 Hz), 3.99 (dd, 1H, J = 14.8, 7.2 Hz), 3.67ꢀ3.62 (m,
1H), 2.33 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ/
ppm, 206.0, 168.2, 143.6, 141.6, 137.4, 134.3, 131.4, 129.8 (J = 32.0 Hz),
129.4, 127.1, 126.9, 125.2 (J = 3.0 Hz), 123.5 (J = 271.0 Hz), 123.3, 56.3,
55.4, 35.7, 29.9, 21.3; MS (20 eV, EI) m/z (%), 389 [M ꢀ 155]þ (98),
328 (52), 242 (100), 217 (75), 174 (22), 155 (74), 147 (10); IR (KBr) ν
(cmꢀ1), 3276 (s), 3070 (w), 2929 (w), 1775 (s), 1719 (s), 1329 (s),
1170 (s), 894 (m), 676 (m), 565 (m); HRMS (ESI) m/z calcd for
C27H23F3N2O5SNa [M þ Na]þ 567.1177; found, 567.1169.
’ EXPERIMENTAL PROCEDURE
threo-5f: Rf 0.14 (CH2Cl2/CH3OH, 120/1); mp, 187.9ꢀ189.0 °C;
1H NMR (400 MHz, CDCl3) δ/ppm, 7.83 (dd, 2H, J = 5.3, 3.0 Hz), 7.72
General Procedure. Preparation of N-[2-Acetyl-1-(4-methyl-
phenyl)-3-phthalimidopropyl]-p-toluenesulfonamide 5a: A dry and
2890
dx.doi.org/10.1021/jo102143r |J. Org. Chem. 2011, 76, 2888–2891

The Journal of Organic Chemistry
NOTE
(dd, 2H, J = 5.3, 3.0 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0
Hz), 7.10 (d, 2H, J = 8.0 Hz), 6.97 (d, 2H, J = 8.0 Hz), 6.27 (d, 1H, J = 9.6
Hz), 4.81 (dd, 1H, J = 9.6, 6.4 Hz), 4.00 (dd, 1H, J = 14.2, 8.4 Hz), 3.64
(dd, 1H, J = 14.2, 5.5 Hz), 3.58ꢀ3.55 (m, 1H), 2.33 (s, 3H), 1.99 (s,
3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ/ppm, 2209.5, 167.8, 143.3,
141.8, 137.5, 134.3, 131.6, 129.9 (J = 32.0 Hz), 129.2, 127.2, 126.9, 125.4
(J = 3.0 Hz), 123.7 (J = 270.0 Hz), 123.6, 57.8, 55.2, 37.9, 31.4, 21.2; MS
(20 eV, EI) m/z (%), 389 [M ꢀ 155]þ (100), 328 (32), 242 (67), 217
(48), 174 (36), 155 (93); IR (KBr) ν (cmꢀ1), 3276 (s), 3070 (w), 2929
(w), 1775 (s), 1719 (s), 1329 (s), 1170 (s), 894 (m), 676 (m), 565 (m);
HRMS (ESI) m/z calcd for C27H24F3N2O5S [M þ H]þ 545.1358;
found, 545.1364.
Syu, S.; Wang, D.-W.; Chen, P.; Hung, Y.-T.; Jhang, Y.-W.; Kao, T.-T.;
Lee, Y.-T.; Lin, W. Tetrahedron Lett. 2010, 51, 5943.
(6) For the Henry reaction of aryl aldehyde and nitroalkane, in which
the zwitterion 10 was more efficient than 7 or PPh3 as a base, see (a)
Wang, X.; Fang, F.; Zhao, C.; Tian, S.-K. Tetrahedron Lett. 2008,
49, 6442. For a chemoselective Michael addition of nitroalkane toward
4 in the presence of aryl aldehyde and DBU, see (b) Wang, W.; Yu, M.
Tetrahedron Lett. 2004, 45, 7141.
(7) The different solubilities of erythro-5 and threo-5 (or erythro-6
and threo-6) in CH3CN probably accounted for the diastereoselectivities
of 5 (or 6). We found that the solubilities of 5 or 6 were not good, and all
of 5 or 6 precipitated during the reaction progress. The dr of 5 or 6 was
determined by crude 1H NMR analysis when all the products were well
dissolved in solution by adding excess of the corresponding solvent
(Tables 1ꢀ3). The base, such as DABCO or an in situ formed base 10,
accelerated the change of the ratio of two diastereomers of 5 or 6 in the
solution.
(8) For more details, please see the Supporting Information.
(9) Because PPh3 was a better catalyst than DABCO in our designed
three-component reaction and the corresponding aza-BaylisꢀHillman
reaction (Table 1), PPh3 was used as the representive catalyst for the
reaction of 1, 2, and 3 in the proposed reaction mechanism, and even
DABCO can also catalyze this process.
(10) In order to elucidate how DABCO influences the change of dr
of 5, two controlled experiments of erythro-5f or threo-5f with CD3OD in
the presence of DABCO in CDCl3 were carried out. It was found that
DABCO smoothly deprotonated the R-position of the ketone function
of both erythro-5f and threo-5f. For mechanism studies, please see the
Supporting Information.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dures, compound characterization data, X-ray crystallographic
data (CCDC numbers threo-5c (785230), threo-5d (785231),
threo-5e (748322), threo-5g (785232), threo-5i (785233), threo-
6a (785234), threo-6b (785235), threo-6c (785236), and threo-
6d (785237)), and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: wenweilin@ntnu.edu.tw.
’ ACKNOWLEDGMENT
We thank the National Science Council of the Republic of
China (NSC Grant No. 99-2113-M-003-004-MY2) and National
Taiwan Normal University (Grant 99T3030-6) for financial
support.
’ REFERENCES
(1) For an overview, see (a) Multicomponent Reactions; Zhu, J.,
Bienaymꢀe, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. For
excellent reviews, see (b) D€omling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3168. (c) Bienaymꢀe, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem.—Eur. J. 2000, 6, 3321. (d) Orru, R. V. A.; de Greef, M. Synthesis
2003, 10, 1471. (e) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(f) Ramꢀon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (g)
D€omling, A. Chem. Rev. 2006, 106, 17. (h) Nair, V.; Rajesh, C.; Vinod,
A. U.; Bindu, S.; A. R. Sreekenth, A. R.; Balagopal, L. Acc. Chem. Res.
2003, 36, 899. (i) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org.
Chem. 2003, 21, 4101. (j) Zhu, J. Eur. J. Org. Chem. 2003, 7, 1133. (k)
Weber, L. Curr. Med. Chem. 2002, 9, 1241.
(2) For an overview, see (a) Domino Reactions in Organic Synthesis;
Tietze, L. F., Brasche, G., Gericke, K., Eds.; Wiley-VCH: Weinheim,
Germany, 2006. Also see (b) Posner, G. H. Chem. Rev. 1986, 86, 831. (c)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134.
(3) For recent reviews for aza-BaylisꢀHillman reactions and appli-
cation of aza-BaylisꢀHillman adducts, see (a) Declerck, V.; Martinez, J.;
Lamaty, F. Chem. Rev. 2009, 109, 1 and references cited therein. (b) Shi,
Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 18, 2905. For aza-BaylisꢀHillman
reactions of aryl-substituted imines and 2a catalyzed by PPh3, see (c)
Shi, M.; Xu, Y.-M. Eur. J. Org. Chem. 2002, 4, 696.
(4) For selected literature about the addition of the carbon nucleo-
phile to the aza-BaylisꢀHillman adduct, see (a) Raheem, I. T.; Jacobsen,
E. N. Adv. Synth. Catal. 2005, 347, 1701. (b) Sergeeva, N. N.; Golubev,
A. S.; Burger, K. Synthesis 2001, 2, 281.
(5) (a) Wang, D.-W.; Syu, S.; Hung, Y.-T.; Chen, P.; Lee, C.-J.;
Chen, K.-W.; Chen, Y.-J.; Lin, W. Org. Biomol. Chem. 2011, 9, 363. (b)
2891
dx.doi.org/10.1021/jo102143r |J. Org. Chem. 2011, 76, 2888–2891