Microwave-enhanced rhodium-catalyzed conjugate-addition of aryl boronic acids to unprotected maleimides

Article abstract of DOI:10.1016/j.tetlet.2007.04.084

Various boronic acids were treated with a rhodium (I) catalyst enabling their 1,4-conjugate addition to unprotected maleimide. The scope of the reaction was explored to include both electron-rich and electron poor boronic acids. These reactions were also

Full text of DOI:10.1016/j.tetlet.2007.04.084

Tetrahedron Letters 48 (2007) 4413–4418
Microwave-enhanced rhodium-catalyzed conjugate-addition
of aryl boronic acids to unprotected maleimides
Pravin S. Iyer,* Meaghan M. O’Malley and Matthew C. Lucas
Department of Medicinal Chemistry, Roche Palo Alto, LLC 3431 Hillview Avenue, Palo Alto, CA 94304, USA
Received 14 December 2006; revised 13 April 2007; accepted 17 April 2007
Available online 22 April 2007
Abstract—Various boronic acids were treated with a rhodium(I) catalyst enabling their 1,4-conjugate addition to unprotected malei-
mide. The scope of the reaction was explored to include both electron-rich and electron poor boronic acids. These reactions were
also performed in the microwave resulting in reduced reaction times and improved efficiencies. Additionally, substrates that were
recalcitrant under conventional conditions were successfully reacted under microwave conditions. The reaction worked satisfactorily
with boronic acids having a free OH or NH group.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Rhodium-catalyzed conjugate carbon–carbon bond
forming reactions are garnering widespread attention
due to their broad applicability.1–3 Miyaura and co-
workers used rhodium catalysts to promote conjugate
addition reactions to a,b-unsaturated amides and lac-
tams.4–6 Hayashi and co-workers have extended the con-
jugate addition reaction scope to include maleimides
(Scheme 1), pioneered the enantioselective conjugate-
addition of aryl boronic acids to N-protected malei-
mides7 and proposed a mechanism for the rhodium
catalysis in a recent paper.8
Our initial test reaction, the addition of 4-methoxy-
phenyl boronic acid 5 to maleimide 4 proceeded cleanly
and in a 70% yield (Scheme 2). Encouraged by this re-
sult, we sought to investigate the scope and limitations
of this reaction by testing a range of boronic acids.
As expected, we found that electron-rich boronic acids
were very reactive and worked in good yields, usually
within 3 h at 50 °C in an oil bath. In an effort to further
broaden the applicability of this reaction, we investi-
gated electron-deficient boronic acids. They reacted
slowly (4–6 h) and in poor yields. Analysis confirmed
that the boronic acids were undergoing competitive
hydrolysis resulting in cleavage of boron from the aryl
ring.9 A higher proportion of the decomposed boronic
acids were found in the slower or incomplete reactions.
To circumvent this problem, we sought to increase the
rate of the reaction and thereby minimize the time avail-
able for hydrolysis to occur.
In the course of a total synthesis project, we sought to
use the rhodium-catalyzed conjugate-addition reaction
of an aryl boronic acid to an N-protected maleimide.
While the reaction itself was successful, we faced chal-
lenges in choosing a suitable protecting group for malei-
mide that was both facile to introduce and remove.
Nitrogen protection of maleimide was inconsistent and
the yields were usually low. In order to circumvent these
problems, we decided to explore the direct rhodium-cat-
alyzed conjugate additions to unprotected maleimide. A
survey of the literature revealed that such additions to
unprotected maleimides are, to the best of our knowl-
edge, novel and heretofore unexplored.
In our efforts to speed up the reaction, we turned to
microwave chemistry.10 Optimization efforts allowed
us to shorten the reaction time to 5 min from 3 to 6 h
while increasing the temperature from 50 °C to 100 °C.
We observed no decomposition of the maleimide or
the rhodium catalyst at these elevated temperatures.
Test reactions were run to directly compare microwave
heating to conventional heating at 100 °C keeping all
other parameters (including heating time) identical.
*
Corresponding author. E-mail: pravin.iyer@roche.com
Summer intern at Roche Palo Alto.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.084

4414
P. S. Iyer et al. / Tetrahedron Letters 48 (2007) 4413–4418
PG
N
O
O
PG
N
B(OH)2
O
O
Rhodium catalyst
+
R
R
1
2
3
Scheme 1.
H
N
O
O
H
N
B(OH)2
O
O
[RhCl(cod)] ,
2
+
KOH, Dioxane/H O
2
O
50 °C, 70%
O
4
5
6
Scheme 2.
Conventional heating at 100 °C resulted in significantly
lower yields.11 Table 1 shows a comparison between
conventional heating and microwave heating. Electron-
deficient systems like the p-fluorophenyl and the p-triflu-
orophenyl boronic acids (entries 6, 7) that had given
poor yields or failed under conventional conditions
now proceeded in acceptable yields in the microwave.
Electron-rich boronic acids (entries 1–5) gave consis-
tently high yields both conventionally and in the micro-
wave. Good yields were also obtained using bulky
boronic acids (entries 10, 11), such as naphthyl and
biphenyl. To our delight, additions using boronic acids
Table 1.
H
N
O
O
H
B(OH)2
N
O
O
[RhCl(cod)] ,
+
2
KOH, Dioxane/H O
2
R
R
4
2
7
Rxn #
Boronic acid
Product
Method A
Yield (%) Time (min)
Method B
Yield (%) Time (min)
H
N
O
O
B(OH)2
1
70
180
69
5
O
5
O
6
H
N
O
O
B(OH)2
2
45
360
58
15
O
8
9
O

P. S. Iyer et al. / Tetrahedron Letters 48 (2007) 4413–4418
4415
Table 1 (continued)
Rxn # Boronic acid
Product
Method A
Yield (%) Time (min)
Method B
Yield (%) Time (min)
H
N
O
O
B(OH)2
3
62
360
82
5
10
11
H
N
O
O
B(OH)2
4
5
6
68
80
34
360
360
360
78
85
62
5
5
5
12
13
H
N
O
O
B(OH)2
N
14
N
15
H
N
O
O
B(OH)2
F
16
F
17
H
N
O
O
B(OH)2
7
0
360
64
15
F3C
18
F3C
19
H
N
O
O
B(OH)2
8
40
360
55
15
HO
20
HO
21
H
N
O
O
B(OH)2
9
63
360
65
5
N
H
22
N
(continued on next page)
23
H

4416
P. S. Iyer et al. / Tetrahedron Letters 48 (2007) 4413–4418
Table 1 (continued)
Rxn # Boronic acid
Product
Method A
Yield (%) Time (min)
Method B
Yield (%) Time (min)
H
N
O
O
B(OH)2
10
59
360
60
5
24
25
H
N
O
O
B(OH)2
11
78
360
80
5
26
27
Method A: Conventional heating (50 °C, 3–6 h).
Method B: Microwave heating (100 °C, 5–15 min).
with potentially labile functionalities (entries 8, 9) such
as a free OH or a free NH (4-hydroxyphenyl boronic
acid and 5-indoleboronic acid) were also successful.
While this reaction methodology has broad scope, one
limitation is the use of highly hindered boronic acids.
ortho-Substituted boronic acids faired poorly under
both conventional and microwave conditions (data not
shown).
1.0 equiv) in water (0.5 mL) followed by the boronic
acid (3.09 mmol, 3.0 equiv). After 3 min maleimide
(0.100 g, 1.03 mmol, 1.0 equiv) in dioxane (2.6 mL)
was added and the reaction mixture was heated in an
oil bath at 50 °C for 3–6 h. The reaction mixture was
cooled to room temperature, the solvents were removed
in vacuo and the residue was purified by column
chromatography.
In summary, the novel reaction of boronic acids with
unprotected maleimide is a robust reaction and a useful
contribution to organic synthesis. We have demon-
strated the microwave-adaptability of this reaction and
developed conditions to improve the rates and yields
of these reactions. The methodology described herein
allows rapid access to the pyrrolidine-2,5-dione (malei-
mide) core that is found in several natural products
and marketed drug molecules.12
3.3. Method B: microwave-assisted synthesis
To a solution of chloro(1,5-cyclooctadiene)rhodium (I)
dimer (0.025 g, 0.05 mmol, 5 mol%) in 1,4-dioxane
(0.9 mL) was added KOH (0.058 g, 1.03 mmol,
1.0 equiv) in water (0.18 mL) followed by the addition
of boronic acid (3.09 mmol, 3.0 equiv). After 3 min
maleimide (0.100 g, 1.03 mmol, 1.0 equiv) in dioxane
(0.9 mL) was added and the reaction mixture was heated
at 100 °C for 5–15 min in a microwave. The reaction
mixture was cooled to room temperature, the solvents
were removed in vacuo and the residue was purified by
column chromatography.
3. Experimental
3.1. General procedure
All reactions were performed in sealed tubes. Solvents
were purchased from commercial sources and used with-
out further purification. Microwave reactions were per-
formed using a Personal Chemistry EmrysTM Optimizer
EXP. All 1H and 13C NMR spectra were obtained using
a Bruker Avance 300 MHz and all chemical shifts are
reported in ppm relative to tetramethylsilane. Mass spectra
were obtained using a Waters Micromass spectrometer.
3.4. 3-(4-Methoxyphenyl)pyrrolidine-2,5-dione (6)
Method A: The reaction mixture was heated for 3 h and
yielded 70% of pure product. Method B: The reaction
mixture was heated for 5 min and yielded 69% of pure
product. The material was purified by column chroma-
tography using a gradient of 10–50% ethyl acetate/hex-
anes: Mp: 136.5–138.5 °C; 1H NMR (300 MHz, CDCl3,
d, ppm) d 2.85 (dd, J = 5.1 Hz, 18.6 Hz, 1H), 3.23 (dd,
J = 9.6 Hz, 18.6 Hz, 1H), 3.80 (s, 3H), 4.04 (dd,
J = 5.1 Hz, 9.6 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.17
(d, J = 8.7 Hz, 2H), 8.34 (br s, 1H); 13C NMR
(100 MHz, CDCl3, d, ppm) d 38.3, 46.6, 55.4, 114.7
(2C), 128.5 (2C), 128.6, 159.4, 176.1, 178.1; MS m/z
3.2. Method A: conventional synthesis
To a solution of chloro(1,5-cyclooctadiene)rhodium (I)
dimer (0.025 g, 0.05 mmol, 5 mol % equiv) in 1,4-diox-
ane (2.6 mL) was added KOH (0.058 g, 1.03 mmol,

P. S. Iyer et al. / Tetrahedron Letters 48 (2007) 4413–4418
4417
MH+ 206; Anal. Calcd for C11H11NO3: C, 64.38; H,
5.40; N, 6.83. Found: C, 64.70; H, 5.32; N, 6.93.
d, ppm) d 2.84 (dd, J = 5.0 Hz, 18.6 Hz, 1H), 2.94 (s,
6H), 3.19 (dd, J = 9.6 Hz, 18.6 Hz, 1H), 3.98 (dd,
J = 5.0 Hz, 9.6 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H), 7.10
(d, J = 8.8 Hz, 2H), 8.42 (br s, 1H); 13C NMR
(100 MHz, CDCl3, d, ppm) d 38.3, 40.5 (2C), 46.6,
113.0 (2C), 124.0, 128.0 (2C), 150.3, 176.5, 178.7;
MS m/z MH+ 219; Anal. Calcd for C12H14N2O2: C,
66.04; H, 6.47; N, 12.84. Found: C, 66.01; H, 6.44; N,
12.72.
3.5. 3-(3-Methoxyphenyl)pyrrolidine-2,5-dione (9)
Method A: The reaction mixture was heated for 6 h and
yielded 45% of pure product. Method B: The reaction
mixture was heated for 15 min and yielded 58% of pure
product. The material was purified by column chroma-
tography using a gradient of 25–55% ethyl acetate/hex-
anes: Mp: 104.5–106.0 °C; 1H NMR (300 MHz, CDCl3,
d, ppm) d 2.89 (dd, J = 5.1 Hz, 18.6 Hz, 1H), 3.24 (dd,
J = 9.7 Hz, 18.6 Hz, 1H), 3.81 (s, 3H), 4.06 (dd,
J = 5.1 Hz, 9.7 Hz, 1H), 6.78–6.88 (m, 3H), 7.30 (t,
J = 8.0 Hz, 1H), 8.10 (br s, 1H); 13C NMR (100 MHz,
CDCl3, d, ppm) d 38.2, 47.3, 55.3, 113.3, 113.5, 119.5,
130.4, 138.1, 160.2, 175.7, 177.3; MS m/z MH+ 206;
Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40; N,
6.83. Found: C, 64.28; H, 5.25; N, 6.85.
3.9. 3-(4-Fluorophenyl)pyrrolidine-2,5-dione (17)
Method A: The reaction mixture was heated for 6 h
and yielded 34% of pure product. Method B: The reac-
tion mixture was heated for 5 min and yielded 62% of
pure product. The material was purified by column
chromatography using a gradient of 25–60% ethyl
acetate/hexanes: Mp: 110.9–111.3 °C; 1H NMR
(300 MHz, CDCl3, d, ppm) d 2.85 (dd, J = 5.3 Hz,
18.6 Hz, 1H), 3.25 (dd, J = 9.7 Hz, 18.6 Hz, 1H), 4.08
(dd, J = 5.3 Hz, 9.7 Hz, 1H), 7.04–7.11 (m, 2H), 7.20–
7.27 (m, 2H), 8.43 (br s, 1H); 13C NMR (100 MHz,
CDCl3, d, ppm) d 38.2, 46.5, 116.3 (d, J = 22 Hz, 2C),
129.2 (d, J = 8 Hz, 2C), 132.3, 162.5 (d, J = 248 Hz,
1C), 175.7, 177.6; MS m/z MH+ 194; Anal. Calcd for
C10H8FNO2: C, 62.17; H, 4.17; N, 7.25. Found: C,
62.58; H, 4.17; N, 7.26.
3.6. 3-Phenylpyrrolidine-2,5-dione (11)
Method A: The reaction mixture was heated for 6 h
and yielded 62% of pure product. Method B: The reac-
tion mixture was heated for 5 min and yielded 82% of
pure product. The material was purified by column
chromatography using a gradient of 25–60% ethyl ace-
tate/hexanes: Mp: 80.5–83.5 °C; 1H NMR (300 MHz,
CDCl3, d, ppm) d 2.88 (dd, J = 5.1 Hz, 18.6 Hz, 1H),
3.25 (dd, J = 9.6 Hz, 18.6 Hz, 1H), 4.09 (dd,
J = 5.1 Hz, 9.6 Hz, 1H), 7.23–7.42 (m, 2H), 7.35 (m,
3H), 8.50 (br s, 1H); 13C NMR (100 MHz, CDCl3, d,
ppm) d 38.6, 47.7, 127.8 (2C), 128.5, 129.6 (2C), 137.0,
175.5, 176.3; MS m/z MH+ 176; Anal. Calcd for
C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C,
68.83; H, 5.14; N, 8.12.
3.10. 3-(4-Trifluoromethylphenyl)pyrrolidine-2,5-dione
(19)
Method A: The reaction mixture was heated for 6 h and
yielded no product. Method B: The reaction mixture
was heated for 15 min and yielded 64% of pure product.
The material was purified by column chromatography
using a gradient of 25–55% ethyl acetate/hexanes: Mp:
1
125.5–127.0 °C; H NMR (300 MHz, CDCl3, d, ppm)
3.7. 3-(3-Tolyl)pyrrolidine-2,5-dione (13)
d 2.89 (dd, J = 5.3 Hz, 18.6 Hz, 1H), 3.29 (dd,
J = 9.7 Hz, 18.6 Hz, 1H), 4.17 (dd, J = 5.3 Hz, 9.7 Hz,
1H), 7.40 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H),
8.51 (br s, 1H); 13C NMR (100 MHz, CDCl3, d, ppm)
d 37.8, 47.0, 125.0 (q, J = 313 Hz, 447 Hz, 1C), 126.2
(d, J = 4 Hz, 2C), 128.0 (3C), 140.3, 175.4, 176.9; MS
m/z MH+ 244; Anal. Calcd for C11H8F3NO2: C,
54.33; H, 3.32; N, 5.76. Found: C, 54.14; H, 3.30; N,
5.76.
Method A: The reaction mixture was heated for 6 h and
yielded 68% of pure product. Method B: The reaction
mixture was heated for 5 min and yielded 78% of pure
product. The material was purified by column chroma-
tography using a gradient of 25–50% ethyl acetate/hex-
anes: Mp: 97.0–99.5 °C; 1H NMR (300 MHz, CDCl3, d,
ppm) d 2.36 (s, 3H), 2.88 (dd, J = 5.0 Hz, 18.6 Hz, 1H),
3.24 (dd, J = 9.6 Hz, 18.6 Hz, 1H), 4.05 (dd, J = 5.0 Hz,
9.6 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 7.05 (s, 1H), 7.14
(d, J = 7.3 Hz, 2H), 7.24–7.30 (m, 1H), 8.20 (br s, 1H);
13C NMR (100 MHz, CDCl3, d, ppm) d 21.4, 38.4,
47.3, 124.4, 128.1, 128.9, 129.2, 136.6, 139.1, 175.9,
177.8; MS m/z MH+ 190; Anal. Calcd for C11H11NO2:
C, 69.83; H, 5.86; N, 7.40. Found: C, 69.90; H, 5.83;
N, 7.49.
3.11. 3-(4-Hydroxyphenyl)pyrrolidine-2,5-dione (21)
Method A: The reaction mixture was heated for 6 h and
yielded 40% of pure product. Method B: The reaction
mixture was heated for 15 min and yielded 55% of pure
product. The material was purified by column chroma-
tography using a gradient of 35–65% ethyl acetate/hex-
anes: Mp: 196.3–198.4 °C; 1H NMR (300 MHz,
acetone-d6, d, ppm) d 2.72 (dd, J = 5.3 Hz, 18.1 Hz,
1H), 3.21 (dd, J = 9.6 Hz, 18.1 Hz, 1H), 4.10 (dd,
J = 5.3 Hz, 9.6 Hz, 1H), 6.82–6.87 (m, 2H), 7.15–7.20
(m, 2H), 8.33 (br s, 1H), 10.00 (br s, 1H); 13C NMR
(100 MHz, acetone-d6, d, ppm) d 39.6, 47.9, 116.8
(2C), 130.1 (2C), 130.5, 158.0, 177.8, 179.9; MS m/z
MH+ 192; Anal. Calcd for C10H9NO3: C, 62.82; H,
4.75; N, 7.33. Found: C, 62.42; H, 4.67; N, 7.19.
3.8. 3-(4-Dimethylaminophenyl)pyrrolidine-2,5-dione (15)
Method A: The reaction mixture was heated for 6 h and
yielded 80% of pure product. Method B: The reaction
mixture was heated for 5 min and yielded 85% of pure
product. The material was purified by column chroma-
tography using a gradient of 25–55% ethyl acetate/hex-
anes: Mp: 140.8–141.5 °C; 1H NMR (300 MHz, CDCl3,

4418
P. S. Iyer et al. / Tetrahedron Letters 48 (2007) 4413–4418
3.12. 3-(1H-Indol-5-yl)pyrrolidine-2,5-dione (23)
product. The material was purified by column chroma-
tography using a gradient of 25–50% ethyl acetate/hex-
anes: Mp: 179.0–180.0 °C; 1H NMR (300 MHz, CDCl3,
d, ppm) d 2.86 (dd, J = 5.4 Hz, 18.1 Hz, 1H), 3.30 (dd,
J = 9.6 Hz, 18.1 Hz, 1H), 4.28 (dd, J = 5.4 Hz, 9.6 Hz,
1H), 6.92–7.38 (m, 2H), 7.39–7.51 (m, 4H), 7.65–7.70
(m, 3H), 10.10 (br s, 1H); 13C NMR (100 MHz, CDCl3,
d, ppm) d 39.2, 48.3, 128.1 (2C), 128.5 (2C), 128.7, 129.6
(2C), 130.1 (2C), 138.9, 141.4, 141.7, 177.7, 179.5; MS
m/z MH+ 252; Anal. Calcd for C16H13NO2: C, 76.48;
H, 5.21; N, 5.57. Found: C, 77.02; H, 5.15; N, 5.66.
Method A: The reaction mixture was heated for 3 h and
yielded 63% of pure product. Method B: The reaction
mixture was heated for 5 min and yielded 65% of pure
product. The material was purified by column chroma-
tography using a gradient of 30–60% ethyl acetate/hex-
anes: Mp: 188.5–190.0 °C; 1H NMR (300 MHz,
acetone-d6, d, ppm) d 2.65 (dd, J = 5.0 Hz, 18.2 Hz,
1H), 3.14 (dd, J = 9.6 Hz, 18.2 Hz, 1H), 4.08 (dd,
J = 5.0 Hz, 9.6 Hz, 1H), 6.32 (d, J = 3.1 Hz, 1H), 6.91
(dd, J = 1.8 Hz, 8.4 Hz, 1H), 7.19–7.21 (m, 1H), 7.28
(d, J = 8.4 Hz, 1H), 7.39 (d, J = 1.3 Hz, 1H), 10.10 (br
s, 1H); 13C NMR (100 MHz, acetone-d6, d, ppm) d
40.3, 48.9, 102.8, 113.0, 120.6, 122.1, 126.7, 129.8,
130.6, 136.9, 178.1, 180.3; MS m/z MH+ 215; Anal.
Calcd for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08.
Found: C, 67.22; H, 4.75; N, 12.88.
Acknowledgement
We are grateful to the analytical chemistry department
of Roche for help with compound characterization.
References and notes
3.13. 3-Naphthalen-2-ylpyrrolidine-2,5-dione (25)
1. Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
2. Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169.
3. Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
4. Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics
1997, 16, 4229.
5. Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944.
6. Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem.
2001, 66, 6852.
7. Hayashi, T.; Shintani, R.; Duan, W.-L. J. Am. Chem. Soc.
2006, 128, 5628.
8. Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M.
J. Am. Chem. Soc. 2002, 124, 5052.
9. Chromatography and analysis of reaction products (exem-
plified by entry 9) confirmed recovery of the indole formed
by hydrolysis of the corresponding boronic acid.
10. (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250;
(b) Adam, D. Nature 2003, 421, 571.
Method A: The reaction mixture was heated for 6 h and
yielded 59% of pure product. Method B: The reaction
mixture was heated for 5 min and yielded 60% of pure
product. The material was purified by column chroma-
tography using a gradient of 25–55% ethyl acetate/hex-
anes: Mp: 154.0–154.6 °C; 1H NMR (300 MHz, CDCl3,
d, ppm) d 2.98 (dd, J = 5.1 Hz, 18.6 Hz, 1H), 3.31 (dd,
J = 9.6 Hz, 18.6 Hz, 1H), 4.24 (dd, J = 5.1 Hz, 9.6 Hz,
1H), 7.32 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.45–7.53 (m,
2H), 7.72 (s, 1H), 7.80–7.88 (m, 3H), 8.45 (br s, 1H);
13C NMR (100 MHz, CDCl3, d, ppm) d 38.2, 47.5,
124.7, 126.5, 126.68, 126.72, 126.73, 127.8, 129.4,
132.8, 133.4, 133.8, 176.0, 177.8; MS m/z MH+ 226;
Anal. Calcd for C14H11NO2: C, 74.65; H, 4.92; N,
6.22. Found: C, 74.91; H, 4.91; N, 6.34.
11. Entry 7 gave a 38% yield of desired addition product,
compared to 0% (conventional 50 °C) and 64% (micro-
wave, 100 °C). Entry 9 gave a 39% yield of the desired
addition product, compared to 63% (conventional, 50 °C
heating) and 65% (microwave heating, 100 °C).
12. Tonnaer, J.; Alphons, D. M. (Organon Ireland Ltd, Ire.)
PCT Int. Appl., 2004, WO2004110437.
3.14. 3-Biphenyl-4-ylpyrrolidine-2,5-dione (27)
Method A: The reaction mixture was heated for 6 h and
yielded 78% of pure product. Method B: The reaction
mixture was heated for 5 min and yielded 80% of pure