Guanidine-catalyzed asymmetric addition reactions: Michael reaction of cyclopentenone with dibenzyl malonates and epoxidation of chalcone

Article abstract of DOI:10.3987/COM-05-S(K)32

Several kinds of modified guanidines designed by us were applied to two types of asymmetric synthesis as superbases: Michael reactions of cyclopentenone with dibenzyl malonates and epoxidation of chalcone. Good to moderate asymmetric inductions were obser

Full text of DOI:10.3987/COM-05-S(K)32

HETEROCYCLES, Vol. 66, 2005
347
HETEROCYCLES, Vol. 66, 2005, pp. 347 – 359. © The Japan Institute of Heterocyclic Chemistry
Received, 29thAugust, 2005, Accepted, 20th October, 2005, Published online, 21st October, 2005. COM-05-S(K)32
GUANIDINE-CATALYZED ASYMMETRIC ADDITION REACTIONS:
MICHAEL REACTION OF CYCLOPENTENONE WITH DIBENZYL
#
MALONATES AND EPOXIDATION OF CHALCONE
Takuya Kumamoto,a Keiko Ebine,a Miyuki Endo,a Yukari Araki,a Yuji
Fushimi,a Ikue Miyamoto,a Tsutomu Ishikawa,a* Toshio Isobe,b and Keiko
Fukudab
aGraduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi,
Inage, Chiba 263-8522, Japan
bCentral Research Laboratory, Shiratori Pharmaceutical Co. Ltd., 6-11-24
Tsudanuma, Narashino, Chiba 275-0016, Japan
benti@p.chiba-u.ac.jp
Abstract – Several kinds of modified guanidines designed by us were applied to
two types of asymmetric synthesis as superbases: Michael reactions of
cyclopentenone with dibenzyl malonates and epoxidation of chalcone. Good to
moderate asymmetric inductions were observed in these guanidine-catalyzed
reactions.
INTRODUCTION
Guanidines can be characterized as superbases1 in organic synthesis due to their strong basicity.2 We
have explored the possibility of readily available modified guanidines3 as re-useable chiral superbases in
asymmetric synthesis.4 Michael reaction is one of the most important organic reactions for C-C bond
formation. Therefore, several chiral catalysts,5 mainly metal bases, have been developed for asymmetric
Michael reaction, but the use of guanidine-type catalysts6 led to either ineffective or no chirality transfer
from the guanidines. We have independently explored the possibility of modified guanidines7 to organic
synthesis as chiral auxiliaries and observed excellent asymmetric induction in the Michael reaction
between activated vinyl compounds such as methyl vinyl ketone or acrylates with tert-butyl
diphenyliminoacetate.8 In this paper we present an alternative Michael reaction of cyclopentenone (1)

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with dibenzyl malonates (2) (Scheme 1a) and epoxidation of chalcone (4) with hydroperoxides (Scheme
1b) catalyzed with chiral guanidines.
Scheme 1. Examined Guanidine-catalyzed Asymmetric Synthesis
RESULTS AND DISCUSSION
In these asymmetric syntheses total twenty-six guanidines (6, 7-8,3a 9-12,4a 13,3a 14,4a 15-20,3a 21-22,3c 23-
26,3b 27-28 and 29-313b) shown in Fig. 1 were screened. Acyclic guanidine (6) and cyclic guanidines (27
and 28) were prepared from carbodiimide (323c) and carbamates (333c and 343c), respectively, according to
the reported procedures.3b, c In the former Michael reaction seventeen guanidines (6-22) and in the latter
epoxidation thirteen guanidines (10, 14, 17-18 and 23-31) were examined, respectively.
Figure 1. Modified Guanidines Examined as Chiral Auxiliaries

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349
Figure 1. Modified Guanidines Examined as Chiral Auxiliaries (continued)
REACTION OF CYCLOPENTENONE (1) WITH DIBENZYL MALONATES (2)
Reaction of cyclopentenone (1) with dibenzyl malonate itself (2a) has been often used as a model reaction
for asymmetric Michael reactions and successful results were reported in the uses of metal-BINOL
complex9 (93% yield; 91% ee), a quaternary ammonium salt10 (62% yield; 58% ee) and metal-chiral
aminodiol complex11 (78% yield; 83% ee). Thus, we examined this reaction for screening the effect of
modified guanidines as chiral superbases. The reaction was at first carried out in the presence of a
stoichiometric amount of guanidines (Table 1).
Table 1. Preliminary Experiments for Asymmetric Michael Reaction of 1 with 2a in the Presence of a
Stoichiometric Amount of a Chiral Guanidine
3a
run
guanidine
time (d)
a
yield (%)
b
ee (%)
12
0
conf.
1
2
3
4
5
6
7
8
9
6
7
9
80
47
36
45
98
51
57
61
65
S
-
14
10
20
10
20
16
14
21
8
0
-
9
8
R
R
R
S
S
R
10
11
12
13
14
15
11
19
28
43
a
b
Isolated yields.
Configuration.
Cyclopentenone (1) was stoichiometrically treated with dibenzyl malonate (2a) in refluxed chloroform
(CHCl3) in the presence of nine different types of chiral guanidines (6-14) (see, Figure 1). Acyclic

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guanidine (6) gave 3a in 80% yield with only 12% enantiomer excess (ee) (run 1). Cyclic guanidines (7
and 8) without chiral center in the cyclic part gave racemic 3a (runs 2 and 3). Next, we applied the
cyclic guanidines with diphenyl groups at 4,5-positions of imidazolidine part, which had been reported to
be good catalysts in the asymmetric Michael reaction of diphenyliminoacetate and α,β-unsaturated
carbonyl compounds.8 As expected, ee was slightly improved when this type of guanidines (9-11) were
used (runs 4-6). Moderate asymmetric induction was observed with the 1,3-dimethylimidazolidine-type
(NMe-type) guanidines (12-14) with a hydroxyethyl residue in a substituent on the external nitrogen
function (runs 7-9), especially (R)-phenylalaninol derivative (14) gave 3a in 65% yield with 43% ee, in
which (R)-isomer was formed as a major enantiomer. An absolute configuration of 3a was found to be
controlled by the stereochemistry of the substituent on the external nitrogen when NMe-guanidines (13
and 14) with (2-hydroxy-1-benzyl)ethyl residue were used as chiral auxiliaries (runs 8 and 9). The
guanidines used in this reaction were completely recovered as re-useable forms by acid-base extraction.
The ee and the absolute configuration of an addition product (3a) were determined by chiral HPLC
analysis followed by the procedure in the literature after conversion of 3a into a dioxolane derivative.9
The efficiency of a guanidine as a catalyst was evidenced because of no reaction in the absence of the
guanidine.
Table 2. Trials for Michael Reaction of 1 with 2a in the Presence of a Catalytic Amount of a Chiral
Guanidine with a Hydroxyethyl Function
3a
run
guanidine
time (d)
a
yield (%)
b
ee (%)
43
12
20
0
conf.
c
14
12
15
16
17
18
19
20
21
22
b
12
10
22
23
26
6
65
30
16
59
R
S
R
-
1
2
3
4
d
5
-
-
NR
d
6
-
-
NR
7
25
12
12
12
c
13
51
8
21
12
8
S
R
S
R
8
9
10
17
20
a
d
Isolated yields.
Configuration.
The data of run 9 in Table 1.
No reaction.
In Michael reaction a base used should act in a catalytic amount. We next attempted the guanidine-

HETEROCYCLES, Vol. 66, 2005
351
catalyzed (0.1 equiv.) Michael reaction of 1 with 2a using ten types of guanidines (12, 14-22) having a
hydroxyethyl substituent under the same conditions that in Table 1 (Table 2). Phenylalaninol derivative
(14) showed the highest asymmetric induction in this series, even in slow reactions (run 1). Varinol
derivatives (12 and 15) gave lower ee (runs 2 and 3). Guanidine (16), in which two phenyl groups were
introduced to the hydroxyethyl substituent of 14, improved chemical yield, but showed no asymmetric
induction (run 4). Phenylglycinol derivatives (17 and 18) gave no product (runs 5 and 6). Bicyclic
(19), cyclic (20) without chiral center in the cyclic part, and acyclic guanidines (21 and 22) gave 3a with
low ee (runs 7-10).
The guanidine (14)-catalyzed reactions were further examined in different solvent systems at 60-70 °C
(Table 3). In protic [ethanol (EtOH)] and non-protic polar [acetonitrile (MeCN)] solvents, reactions
were accelerated but no chiral induction was observed (runs 2 and 3). Reaction in tetrahydrofuran
(THF) gave no product (run 4). Reactions in aromatic solvents slightly improved ee but gave lowered
chemical yields (runs 5-7). No acceleration of the reaction in toluene was observed even addition of
tert-butyl alcohol as a proton source (run 8). Ee was improved to be 62% when the reaction in CHCl3
was carried out at room temperature albeit low chemical yield (run 9).
Table 3. Solvent Effects in the Guanidine (14)-Catalyzed Reaction of 1 with 2a at 60 - 70 °C
3a
run
solvent
time (d)
a
yield (%)
b
ee (%)
43
0
conf.
c
CHCl3
12
1
65
55
46
R
-
1
2
3
4
5
6
7
8
EtOH
MeCN
7
0
-
d
THF
7
-
-
NR
toluene
7
17
21
11
11
11
48
45
50
47
62
d
R
R
R
R
R
PhCF3
7
PhH
7
10% t-BuOH in toluene
7
e
CHCl3
41
9
a
e
b
c
Isolated yields.
Configuration.
The data of run 9 in Table 1.
No reaction.
Reaction was carried out in rt.

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Solvent-free reactions,12 in which rate acceleration is generally observed, have attracted much attention
from the ecological point of view. Thus, the Michael reaction was examined using the guanidine (14) as
a catalyst under the condition without a solvent (Table 4). Stirring a heterogeneous mixture of 1 and 2a
containing 0.1 equivalent of 14 at 20 °C resulted in completion of the reaction within 19 h, but
asymmetric induction was slightly lowered (run 2). No increase of ee was observed even in lower
temperature (run 3).
Table 4. A Guanidine (14)-catalyzed Asymmetric Michael Reaction of 1 with 2a without Solvent
3a
run
time
conditions
a
yield (%)
b
ee (%)
43
conf.
R
c
12 d
19 h
23 h
refluxed in CHCl3
neat, 20 °C
65
77
75
1
2
3
30
R
neat, 7-8 °C
31
R
a
b
c
Isolated yields.
Configuration.
The data of run 9 in Table 1.
Similar rate-acceleration was observed when dibenzyl methylmalonate (2b) was used as Michael donor
instead of 2a, in which moderate ee was observed. On the other hand, no reaction was observed in
chloroform solution (Scheme 2).
Scheme 2. A Guanidine (14)-catalyzed Michael Reaction of 1 with 2b
EPOXIDATION OF CHALCONE (4)
Chalcone (4) is a common substrate for epoxidation trials of α,β-unsaturated ketones. Thus, good
results were given in the use of poly-leucine,13 quaternary quinine derivatives,14 and metal complexes15 as
catalysts. Apart from these examples, there are no reports catalyzed with organic bases to our knowledge.
We decided to explore the ability of our chiral guanidines as catalysts for this reaction. Several
hydroperoxides were applied to the reaction in the presence of a catalytic amount (0.2 equiv.) of

HETEROCYCLES, Vol. 66, 2005
353
guanidine (23) with an N-unsubstituted imidazolidine ring (NH-guanidine) (Table 5).
Table 5. Trials for Epoxidation of 4 Using Various Hydroperoxides in Toluene at Room Temperature in
the Presence of a 0.2 Equivalent of 23
5
run
hydroperoxide
time (h)
a
yield (%)
ee (%)
30
1
2
3
4
5
6
7
70% TBHP aq
CMHP
24
24
24
24
3
43
24
33
19
50
44
3
65
TBHP in toluene
CMHP in toluene
30% H2O2 aq
H2O2-urea complex
mCPBA
49
68
17
24
96
15
1
a
Isolated yields.
Commercially available 70% tert-butyl hydroperoxide (TBHP) in water was added to the solution of
chalcone (4) and guanidine (23) in toluene. After 24 h, the corresponding epoxide (5) was obtained in
43% yield (run 1). The ee (30%) and the (2R,3S)-configuration of product (5) were determined by chiral
HPLC analysis.16 Utilization of commercially available cumene hydroperoxide (CMHP) improved ee
Table 6. Trials for Optimization of the Guanidine (23)-catalyzed Epoxidation of 4 with TBHP in
Toluene
5
23
(equiv.)
time
(d)
temp
(°C)
run
a
yield (%)
ee (%)
49
b
0.2
0.2
0.2
1
1
1
4
1
rt
50
rt
33
68
67
55
1
2
3
4
45
45
rt
47
a
b
Isolated yields.
The data of run 3 in Table 5.

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HETEROCYCLES, Vol. 66, 2005
(run 2). Purified hydroperoxides in toluene16 were applied and the selectivities were further improved
(runs 3 and 4). Hydrogen peroxides, both as an aqueous solution and as a complex with urea, lowered
enantioselectivities (runs 5 and 6). The reaction was sluggish when m-chloroperoxybenzoic acid
(mCPBA) was used (run 7). From these results, we chose TBHP in toluene as a standard oxidant and
tried to optimize this epoxidation reaction (Table 6).
Elevating reaction temperature from rt to 50 °C, prolongation of reaction time, and increasing the amount
of guanidine (23) led to increment of chemical yield, but did not affect to ee (runs 2-4). Thus, our
attention was turned to the epoxidation using different kinds of chiral guanidines (Table 7).
Increasing number of methyl substituents on the imidazolidine nitrogens in guanidine (23) lowered not
only reaction rate but also the selectivity (runs 2 and 3). Guanidine (25), a diastereomer of 23 with
enantiomeric substituent on the external nitrogen of guanidine skeleton, gave 5 in the same asymmetric
induction that 23 did (run 4). Interestingly, similar to Michael reaction discussed above, chirality of 5
was controlled by the absolute configuration of the imino substituent in the case of guanidines with
hydroxyethyl moitey (14, 17 and 18) (runs 5-7). Guanidine (26) with 1-naphthyl group instead of
phenyl group showed almost same ee (run 8). Utilization of the NH-guanidines, which possess 2-
hydroxyethyl (27), and 2-(tert-butyldimethylsilyloxy)ethyl moiety (28), ethyl (29), cyclohexyl (30), and
benzyl functions (31), enhanced chemical yields; however improvement of ee was not observed in each
case (runs 9-13).
Table 7. Trials for Epoxidation of 4 with TBHP in Toluene in the Presence of Various Types of
Guanidines
5
5
run guanidine
run
guanidine
a
yield (%) ee (%)
a
yield (%) ee (%)
b
1
23
24
10
25
14
17
18
33
17
20
44
36
35
49
49
7
8
26
27
28
29
30
31
49
96
90
78
59
59
41
23
22
31
34
37
2
9
3
4
5
6
7
6
10
11
12
13
46
c
32
22
c
41
a
b
c
Isolated yield.
The data of run 3 in Table 5.
An enantiomer was formed.

HETEROCYCLES, Vol. 66, 2005
355
MECHANISTIC CONSIDERATION FOR CHIRAL INDUCTIONS
It is found that the NMe-guanidine (14), which possesses a (2-hydroxy-1-benzyl)ethyl moiety, was
suitable as a catalyst for enantioselective Michael reaction of cyclopentenone (1) with dibenzyl malonates
(2), and that NH-guanidine (23) with 1-phenylethyl moiety was the best catalyst for epoxidation of
chalcone (4). Simple MM2 calculation (Chem3D) approach to ureas (35 and 36), the precursors of these
guanidines (14 and 23), allowed us to speculate possible transition states. Two phenyl groups located at
4 and 5 positions of imidazolidine ring share pseudoaxial positions each other because of steric repulsion
between the phenyl and the N-Me groups in 35. As a result, the two phenyl rings are perpendicular to
the imidazolidine ring in 35. On the other hand, no steric repulsion causes them to locate in
pseudoequatrial positions in 36 which takes rather flat conformation than 35 (Figure 2). These situations
1
can be supported by the difference of chemical shifts of phenyl group in the H-NMR spectrum of each
compound [7.12-7.15 (4H, m), 7.32-7.37 (6H, m) in 35, 7.27-7.38 (10H, m) in 36].17
Figure 2. Optimized Structures of Ureas (35 and 36) by MM2 Calculation. From the Left, Top, Side,
and Front Views.
From these results, mechanism of chiral induction in Michael reaction of 1 with 2a catalyzed by 14 is
considered as follows. Malonate anion would be tightly complexed with guanidinium salt via two
hydrogen bonds between the carbonyl oxygen of 2a and the hydroxy group of 14, and between the
enolate oxygen and the guanidinium proton. In addition each phenyl ring of 2a and 14 could be
interacted through π-π interaction (Figure 3). Under this situation re-face of 1 will approach from top
side to the malonate unit of the complex by the aid of another hydrogen bond formation between the
hydroxy group of 14 and the carbonyl oxygen of 1 to furnish (R)-3a as a major enantiomer.

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HETEROCYCLES, Vol. 66, 2005
Figure 3. Proposed Mechanism for Chiral Induction of Cyclopentenone (1) with Dibenzyl Malonate
(2a) Catalyzed by Guanidine (14).
In the case of the guanidine (23)-catalyzed epoxidation of chalcone (4) with TBHP, it could be reasonably
supposed that the acid-base interaction between TBHP and 23 forms a seven-membered ring through two
hydrogen bonds (Figure 4). The bottom side of the TBHP unit in the complex is shielded with the
phenyl group of 23 close to the seven-membered ring. So, si-face at β position of 4 will approach from
top side of this complex by the aid of hydrogen bond between the carbonyl oxygen of 4 and hydrogen on
guanidine to furnish (2R,3S)-5 as a major enantiomer.
Figure 4. Proposed Mechanism for Chiral Induction of the Guanidine (23)-catalyzed Epoxidation of
Chalcone (4) with TBHP
CONCLUSION
In summary, it was found that modified guanidines catalyzed the asymmetric Michael reaction of
cyclopentenone (1) with dibenzyl malonates (2) and the epoxidation of chalcone (4) even not satisfactory
results. Interestingly, in the former reaction, reaction was accelerated under solvent-less conditions.

HETEROCYCLES, Vol. 66, 2005
357
These guanidine-catalyzed asymmetric synthesis could contribute to development of green chemistry,14
because modified guanidines are considered to be re-useable (economically favored) and easily
functionalizable (widely applicable) artificial organic bases.
EXPERIMENTAL
General Experimental Procedures. IR spectrum was recorded on a JASCO IR-700 Infrared
13
Spectrophotometer. 1H- and C-NMR spectra were recorded on a JEOL JNM GSX-300 spectrometer
1
(300 MHz for H, 75 MHz for 13C) in CDCl3. High resolution fast-atom bombardment mass
(HRFABMS) spectrum was recorded on a JEOL JMS-HX110A mass spectrometer with a direct inlet
system. Specific rotation, [α]D, was recorded on a JASCO DIP-140 digital polarometer in CHCl3.
High performance liquid chromatography (HPLC) was performed on a Shimadzu CLASS-LC-10/M10A.
For column chromatography, silica gel 60 (Merck, 70-230 mesh) and FL-100D (Fuji Silysia) were used.
N,N’,N’’-Tris[(S)-1-phenylethyl]guanidine (6). This compound was prepared from carbodiimide
(323c) and (S)-1-phenethylamine following the procedure reported in reference 3c. A colorless oil: IR
1
(KBr) ν (cm-1): 3430, 1635; H-NMR δ (ppm): 1.31 (3H, d, J = 6.2 Hz), 1.41 (6H, d, J = 6.6 Hz), 4.51
13
(3H, brs), 6.75 (3H, brs), 7.15-7.26 (9H, m); C-NMR δ (ppm): 25.12, 52.34, 125.98, 126.34, 128.23,
146.44, 149.31; HRFABMS m/z: 372.2407, calcd for C25H30N3: 372.2440; [α]21D +209.5° (c 1.0).
(4S,5S)-2-[(1S)-1-Benzyl-2-(tert-butyldimethylsilyl)ethylimino]-4,5-diphenylimidazolidine (27) and
(4S,5S)-2-[(1S)-1-Benzyl-2-hydroxyethylimino]-4,5-diphenylimidazolidine (28). These compounds
were prepared by hydrolysis of carbamates (333c and 343c) following the procedure reported in reference
1
3b. 27: amorphous mass: IR (KBr) ν (cm-1): 1620, 1550; H-NMR δ (ppm): 0.05 (3H, s), 0.66 (3H, s),
0.92 (9H, s), 2.86 (1H, dd, J = 13.4, 7.5 Hz), 2.97 (1H, dd, J = 13.4, 6.2 Hz), 3.65 (1H, dd, J = 9.7, 3.7
Hz), 3.74 (1H, dd, J = 9.7, 4.4 Hz), 3.77 (3H, m), 4.44 (2H, br s), 7.17-7.30 (15H, m); 13C-NMR δ (ppm):
-5.40, -5.35, 18.35, 25.97, 38.45, 56.26, 64.66, 126.30, 126.52, 127.32, 128.46, 129.57, 139.04, 143.46,
159.83; HRFABMS 486.2925, calcd for C30H40N3OSi: 486.2941; [α]21 –73.6° (c 1.0). 28: amorphous
D
mass; IR (KBr) ν (cm-1): 3270, 1610; 1H-NMR δ (ppm): 2.58 (1H, dd, J = 13.5, 8.6 Hz), 2.68 (1H, dd, J =
13.5, 5.5 Hz), 3.41 (1H, dd, J = 11.2, 6.8 Hz), 3.54 (1H, d, J = 11.2 Hz), 3.62-3.73 (1H, m), 4.24 (2H, m),
13
5.67 (3H, br s), 7.02-7.19 (15H, m); C-NMR δ (ppm): 38.15, 56.93, 65.27, 72.13, 126.19, 126.29,
127.21, 128.32, 128.36, 129.18, 138.64, 142.97, 161.33; Anal. Calcd for C24H25N3O·1/3H2O: C, 76.36; H
6.85; N, 11.33. Found: C, 76.40; H; 6.80; N; 10.92; [α]21D –57.3° (c 1.0).

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HETEROCYCLES, Vol. 66, 2005
General procedure for Michael reaction of cyclopentenone (1) with dibenzyl malonate (2a) in the
presence of chiral guanidine (14) (run 9 in Table 1). A mixture of 1 (70 mg, 0.86 mmol), 2a (202 mg,
0.71 mmol) and 14 (201 mg, 0.50 mmol) in CHCl3 (10 mL) was refluxed for 16 days. After cooling to rt,
AcOEt was added and the whole was washed with 10% HCl and brine and dried over MgSO4. The
solvent was evaporated in vacuo and the residue was purified by column chromatography (SiO2, hexane-
Et2O = 1 : 1) to give 3a as a colorless oil (167 mg, 65%). 3a was converted to corresponding dioxolane
derivative,9 which was subjected to chiral HPLC analysis (CHIRALCEL OD, hexane – 2-propanol = 40 :
1, 1.0 mL/min, 254 nm) to be 43% ee. The former peak, which was assigned as (R)-isomer, is major
product.
General procedure for epoxidation of chalcone (4) and TBHP in toluene in the presence of chiral
guanidine. To a toluene solution (0.2 mL) of chalcone (ca. 30 mg, 0.14 mmol) and chiral guanidine
(0.2 equiv.), a toluene solution of TBHP (0.2 mL, 10 equiv.) was added at rt and the whole was stirred at
rt for 24 h. The reaction was quenched with 10% aq. Na2SO3 and was extracted with AcOEt. Organic
layer was washed with sat. aq. NaHCO3, H2O and brine and dried over MgSO4. The solvent was
evaporated in vacuo and the residue was purified by column chromatography (SiO2, hexane – AcOEt =
10 : 1) to give 5 as colorless prisms which was subjected to chiral HPLC analysis (CHIRALCEL OD,
hexane – 2-propanol = 40 : 1, 1.0 mL/min, 254 nm). The latter peak, which was assigned as (2R,3S)-
isomer, is major product.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research (14370717) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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