Catalytic performance of polystyrene-bound ChibaG derivatives as guanidine organobases in asymmetric Michael additions

Article abstract of DOI:10.1002/hlca.201300259

The guanidine organocatalyst, ChibaG, was bound via an ether linkage to the phenyl group of the 2-imino substituent to Merrifield resin. Polystyrene-bound ChibaG acted as an effective catalyst in the Michael reaction of tert-butyl N-(diphenylmethylidene)g

Full text of DOI:10.1002/hlca.201300259

Helvetica Chimica Acta – Vol. 97 (2014)
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Catalytic Performance of Polystyrene-Bound ChibaG Derivatives as
Guanidine Organobases in Asymmetric Michael Additions
by Tsutomu Ishikawa*, Takashi Heima, Makoto Yoshida, and Takuya Kumamoto
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675,
Japan (phone/fax: þ 81-43-2262944; e-mail: benti@faculty.chiba-u.jp)
The guanidine organocatalyst, ChibaG, was bound via an ether linkage to the phenyl group of the 2-
imino substituent to Merrifield resin. Polystyrene-bound ChibaG acted as an effective catalyst in the
Michael reaction of tert-butyl N-(diphenylmethylidene)glycinate with methyl vinyl ketone, and could be
recovered and reused many times.
Introduction. – Polymer-bound and polymeric reagents and catalysts are becoming
more common in organic synthesis. Compared with conventional solution reactions,
polymer-bound reagents are easier to handle for large-scale reactions, they are reusable
and less toxic. They play an important role in high-throughput chemistry [1] and ꢀgreen
chemistryꢁ [2]. Guanidine is a common organobase catalyst in organic synthesis [3]. We
have previously reported new preparation methods for a range of chiral guanidines [4],
some of which have been evaluated as homogeneous organobase catalysts for
asymmetric reactions, such as the Michael reaction [5a – 5e], kinetic silylation [5f],
TMS cyanation [5g], base-catalyzed epoxidation [5h], and alkylating esterification [5i].
(4R,5R)-2-{[(S)-1-(Hydroxymethyl)-2-phenylethyl]imino}-1,3-dimethyl-4,5-diphenyl-
imidazolidine ((ꢀ)-ChibaG; 1) and its enantiomer [5d] afforded the addition product in
intermolecular [5a – 5c] and intramolecular Michael reactions [5d][5e] with reasonable
enantioselectivity. In the intermolecular Michael reaction with N-(diphenylmethylide-
ne)glycinate as a Michael donor, it has been proposed that a transition state consisting
of a complex formed with ChibaG (1) is responsible for the excellent asymmetric
induction.
We report herein a polystyrene (PS)-bound chiral catalyst based on ChibaG which
exhibited satisfactory asymmetric induction in a Michael addition product. The ChibaG
catalyst was bound through an ether linkage to the phenyl group of the 2-imino
substituent to the Merrifield resin. Furthermore, the catalyst remained active after it
was reused repeatedly.
Results and Discussion. – We have previously designed polymer-supported and
polymeric chiral guanidines, 2 and 3, respectively, with a (R)-2-{[(S)-1-(hydroxy-
methyl)-2-phenylethyl]imino}-4-phenylimidazolidine core as heterogeneous guanidine
organobases and used them for the asymmetric Michael reaction of tert-butyl N-
(diphenylmethylidene)glycinate (4) with methyl vinyl ketone (MVK; 5; Table).
However, only moderate asymmetric induction was observed in the product for
ꢂ 2014 Verlag Helvetica Chimica Acta AG, Zꢃrich

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polymeric guanidine 3 [6]. Therefore, we designed PS-bound ChibaG derivatives 6 – 8
as alternative heterogeneous guanidine organobases (Fig.). Derivatives 6 and 7
incorporated HypoGelꢄ and TentaGelꢄ at N1 through an oxyethyl tether, whereas 8 was
bound to Merrifield resin through an ether linkage on the phenyl group of the 2-imino
substituent.
Figure. Structures of the guanidine organobases
The HypoGelꢄ and TentaGelꢄ ChibaG derivatives, 6 and 7, respectively, were
prepared from (4R,5R)-1-methyl-4,5-diphenylimidazolin-2-one (9) [7] (Scheme 1).
Because of the low reactivity of 9, the key 1-(2-hydroxyethyl)-3-methyl-4,5-diphenyl-
imidazoline-2-thione (12) intermediate was synthesized by converting 9 to thiourea 10
[8] with Lawessonꢁs reagent. A 2-silyloxyethyl group was introduced at the
unsubstituted N-atom of thiourea 10, and the silyl group of 11 was removed by
treatment with Bu4NF (TBAF) to afford 12. The Williamson reaction of 2-
hydroxyethyl-substituted thiourea 12 with HypoGelꢄ 200 bromide under sonication
furnished PS-bound thiourea 13. The latter was activated with oxalyl chloride (COCl)2,
and the 2-chloroamidinium chloride intermediate reacted with (S)-phenylalaninol, to
afford the desired HypoGelꢄ guanidine 6. The loading of 6 was estimated to be ca.
0.37 mmol/g by elemental analysis. The reaction of 12 with TentaGelꢄ 200 bromide
provided an alternative thiourea 14, which was similarly converted to TentaGelꢄ
guanidine 7. The loading efficiency was ca. 0.10 mmol/g.

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309
t
Scheme 1. Preparation of HypoGelꢄ and TentaGelꢄ Guanidines, 6 and 7, Respectively. TBS, BuMe2Si.
However, PS-bound guanidines 6 and 7 did not act as catalysts for the Michael
reaction of tert-butyl N-(diphenylmethylene)glycinate (4) with MVK (5). We have
already observed that replacing both Me substituents C(1) and C(3) in the ChibaG
skeleton with Bn groups leads to low yields of the Michael-addition product, although it
increases the enantioselectivity [5b]. The results for 6 and 7 also indicated that steric
bulk around the guanidine N-core in ChibaG derivatives affects the Michael reaction,
by reducing the activation of glycinate substrate 4 by the guanidine catalyst in the
transition state. Therefore, we focused on tyrosinol-based ChibaG derivative 8 as an
alternative PS-bound organobase carrying the same 2-(1-benzyl-2-hydroxyethyl)-1,3-
dimethylimino moiety as ChibaG (1) (Scheme 2).
ChibaG derivative 8 was prepared according to our standard method for synthesiz-
ing fully-substituted monocyclic chiral guanidines [4a]. 1,3-Dimethyl-4,5-diphenylimi-
dazolin-2-one (15) was treated with (COCl)2, and then the crude 2-chloroamidinium
chloride 16 formed was reacted with (S)-[4-(benzyloxy)phenyl]alaninol (O-benzyltyr-
osinol) [9] to afford guanidine 17 in 66% yield. Guanidine 17 was hydrogenated to
provide tyrosinol-substituted ChibaG (18). The immobilization of 18 on Merrifield
resin in acetone in the presence of K2CO3 afforded the desired PS-bound ChibaG
derivative 8. The loading of 8 was estimated to be ca. 0.14 mmol/g by elemental
analysis.
Prior to the heterogeneous Michael reaction using immobilized ChibaG derivative
8, the catalytic performance of tyrosinol-substituted guanidines 17 and 18, and the
original (ꢀ)-ChibaG (1) was examined for the previously reported homogeneous

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Scheme 2. Preparation of Tyrosinol-Based ChibaG Derivative 8
Michael reaction of 4 with MVK (5) [5c] (Table). The reaction using O-benzyltyr-
osinol-substituted ChibaG, 17, afforded the (S)-adduct 19 (R ¼ Me) with a similar yield
and enantioselectivity as the original (ꢀ)-ChibaG (1)-catalyzed reaction (Entries 1 and
2). The addition of K2CO3 as a dehydrating agent did not affect the reaction (Entry 3).
We have previously found that solvent-free conditions were critical for the completion
of the ChibaG (1)-catalyzed Michael reaction with a less reactive acrylate as a Michael
acceptor [5c]. O-Benzyltyrosinol-substituted ChibaG, 17, also served as an effective
catalyst in the solvent-free Michael reaction with acrylates (Entries 4 and 5). The
addition product 19 (R ¼ Me) was also formed, when a catalyst bearing a phenolic OH
group was used, or when a H-atom source, such as an alcohol or phenol, was used
(Entries 6 – 9). The catalytic activity was maintained even when an additional
substituent was introduced at C(4) of the Ph group of the phenylalaninol moiety in
ChibaG; therefore, the catalyst 8 was used in a heterogeneous Michael reaction.
A mixture of glycinate 4 and MVK (5) was stirred with PS-bound ChibaG
derivative 8, and the (S)-adduct 19 (R ¼ Me) was obtained in reasonable yields and
enantioselectivity (Entry 10). Furthermore, the insoluble catalyst was recovered from
the reaction mixture by filtration and was reused repeatedly (Entries 11 and 12).
Conclusions. – The ChibaG organocatalyst was bound via an ether linkage to the
phenyl group of the 2-imino substituent to Merrifield resin. The PS-bound catalyst
acted as a reusable heterogeneous guanidine organobase catalyst in the Michael
reaction of tert-butyl N-(diphenylmethylene)glycinate with MVK.

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Table. Michael Reactions Catalyzed by Tyrosinol-Substituted ChibaG Derivatives
Entry
R
X
Solvent
Additive
–
Time [d]
Yield of 19 [%]
ee [%]
1
2
3
4
5
6
7
8
9
Me
Me
Me
CO2Me
CO2Et
Me
Me
Me
Me
Me
Me
Me
H (1)
THF
THF
THF
–
THF
THF
THF
THF
THF
THF
THF
THF
4
4
4
3
7
2
4
4
4
2
2
2
93
89
88
90
23
83
87
89
90
87
72
70
85
82
88
92
86
83
85
93
92
85
80
83
BnO (17)
BnO (17)
BnO (17)
BnO (17)
HO (18)
H (1)
H (1)
H (1)
PS-CH2O (8)
PS-CH2O (8)
PS-CH2O (8)
–
a
K2CO3
)
–
–
–
MeOH
EtOH
PhOH
–
–
–
10
11b)
12c)
a) 0.6 mol of K2CO3 was added. b) Recycle use of a guanidine recovered in Entry 10 (2nd trial).
c) Recycle use of a guanidine recovered in Entry 11 (3rd trial).
Experimental Part
General. Anh. DMF and CH2Cl2 were used as purchased from Kanto Chemical, and anh. THF was
used as purchased from Wako Chemical. The org. extracts were dried (MgSO4), and evaporations were
conducted under reduced pressure. TLC: Merck Art 5715 DC-Fertigplatten Kieselgel 60 F254 and Fuji
Silicia NH-TLC plate. Column chromatography (CC): Kanto Chemical silica gel 60 (SiO2) spherical and
Fuji Silisia NH SiO2 (100 – 200 mesh). M.p.: Yanagimoto MPSI melting-point apparatus; uncorrected. IR
Spectra: Attenuated Total Reflectance (ATR) system on a JASCO FT/IR-300E spectrophotometer; ˜n in
cmꢀ1. 1H- and 13C-NMR spectra: JEOL JNM-ECP-400 and -500 instruments; in CDCl3; d in ppm rel. to
Me4Si as internal standard, J in Hz. MS: JEOL JNM HX-110 for FAB-MS; in m/z.
(4R,5R)-1-Methyl-4,5-diphenylimidazolidine-2-thione (10) [8]. A soln. of 9 [7] (1.03 g, 4.09 mmol)
and Lawessonꢁs reagent (2.15 g, 5.28 mmol) in toluene (14 ml) was heated to reflux for 14 h, and to the
resulting soln. were added MeOH (5 ml) and 10% aq. HCl (10 ml). The mixture was stirred at r.t. for 1 d,
poured into H2O, and extracted with AcOEt. The org. soln. was washed with sat. aq. NaHCO3, H2O, and
brine, and dried and evaporated to give 10 (0.893 g, 81%). Colorless prisms (recrystallized from hexane/
AcOEt). M.p. 177 – 1788. 1H-NMR (400 MHz): 2.98 (s, 3 H); 4.52 (d, J ¼ 7.9, 1 H); 4.70 (d, J ¼ 7.9, 1 H);
6.56 (s, 1 H); 7.20 – 7.44 (m, 10 H). 13C-NMR (125 MHz): 32.6; 66.5; 75.6; 126.2; 127.1; 128.6; 128.97;
129.00; 129.2; 137.6; 139.3; 183.5. FAB-MS: 269 ([M þ H]þ). Anal. calc. for C16H16N2S (268.368): C 71.60,
H 6.01, N 10.44; found: C 71.73, H 6.05, N 10.38.
(4R,5R)-1-(2-{[(tert-Butyl)(dimethyl)silyl]oxy}ethyl)-3-methyl-4,5-diphenylimidazolidine-2-thione
(11). A mixture of 10 (117 mg, 0.435 mmol) and Cs2CO3 (282 mg, 0.866 mmol) in DMF (0.8 ml) was
stirred at r.t. for 30 min, and to the resulting mixture was added (2-bromoethoxy)(tert-butyl)(dime-

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thyl)silane (0.1 ml, 0.466 mmol). The mixture was stirred at r.t. for 16 h, poured into H2O, and extracted
with AcOEt. The org. soln. was washed with H2O and brine, and dried and evaporated. Purification of the
residue by CC (SiO2; hexane/AcOEt 40 :1 ! 20 :1) gave 11 (79 mg, 43%). Colorless prisms (recrystal-
1
lized from hexane/Et2O). M.p. 77 – 788. H-NMR (400 MHz): ꢀ 0.04 (s, 6 H); 0.77 (s, 9 H); 3.01 – 3.07
(m, 1 H); 3.04 (s, 3 H); 3.63 – 3.67 (m, 1 H); 3.98 – 4.03 (m, 1 H); 4.21 – 4.26 (m, 1 H); 4.41 (d, J ¼ 6.7,
1 H); 4.92 (d, J ¼ 6.7, 1 H); 7.13 – 7.18 (m, 4 H); 7.34 – 7.39 (m, 6 H). 13C-NMR (125 MHz): ꢀ 5.6; ꢀ 5.5;
18.1; 25.8; 33.3; 47.6; 61.7; 71.9; 73.2; 126.8; 127.0; 128.6; 128.7; 129.13; 129.14; 138.6; 139.0; 182.6. FAB-
MS: 427 ([M þ H]þ). Anal. calc. for C24H34N2OSSi (426.701): C 67.56, H 8.03, N 6.57; found: C 67.51, H
7.99, N 6.45.
(4R,5R)-1-(2-Hydroxyethyl)-3-methyl-4,5-diphenylimidazolidine-2-thione (12). A soln. of 11
(583 mg, 1.37 mmol) in THF (4 ml) was stirred with a 1.0m soln. of Bu4NF in THF (1.5 ml, 1.50 mmol)
at r.t. for 18 h, poured into 10% aq. HCl, and extracted with AcOEt. The org. soln. was washed with sat.
aq. NaHCO3, H2O, and brine, and dried and evaporated. Purification of the residue by CC (SiO2, hexane/
AcOEt 20 :1 ! 4 :1) gave 12 (409 mg, 96%). Colorless prisms (recrystallized from hexane/AcOEt). M.p.
1
120 – 1218. IR: 3352 (OH). H-NMR (400 MHz): 2.62 – 2.68 (br. s, 1 H, exchangeable); 3.04 (s, 3 H);
3.29 – 3.34 (m, 1 H); 3.68 – 3.78 (m, 2 H); 4.18 – 4.23 (m, 1 H); 4.48 (d, J ¼ 7.8, 1 H); 4.69 (d, J ¼ 7.8, 1 H);
7.18 – 7.20 (m, 4 H); 7.36 – 7.41 (m, 6 H). 13C-NMR (125 MHz): 33.4; 47.7; 61.3; 71.6; 73.4; 126.9; 127.1;
128.87; 128.93; 129.21; 129.23; 137.9; 138.0; 183.9. Anal. calc. for C18H20N2OS (312.437): C 69.20, H 6.45,
N 8.97; found: C 69.03, H 6.45, N 8.90.
The HypoGelꢄ-Incorporated Thiourea 13. A suspension of 12 (699 mg, 2.24 mmol) and NaH (60% in
mineral oil, 130 mg, 3.25 mmol) in DMF (8 ml) was stirred at r.t. for 3 h. After addition of HypoGelꢄ 200-
Br (807 mg; loading, 0.8 mmol of Br/g) the mixture was sonicated at r.t. for 2 d (negative for Beilstein
test). After acidification with 10% aq. HCl, the mixture was filtered through a glass filter (G3),
successively washed with H2O (4ꢁ), MeOH (4ꢁ), AcOEt (4ꢁ), CH2Cl2 (8ꢁ), and MeOH (8ꢁ), and
dried under reduced pressure to give 13 (821 mg). Yellow powder. M.p. > 3008. 13C-NMR (125 MHz,
C6D6; gel phase): 33.2; 45.1; 67.7; 69.7; 70.3; 71.7; 73.2; 86.5; 127.3; 128.6; 129.2; 139.4; 139.6; 183.7. Anal.
calc. (based on the loading of HypoGelꢄ 200-Br): N 1.89; found: N 1.04.
The HypoGelꢄ-Incorporated Guanidine (6). A mixture of 13 (699 mg) and (COCl)2 (0.5 ml,
5.73 mmol) was heated to reflux for 20 h. The mixture was evaporated and suspended in CH2Cl2 (0.5 ml).
After addition of a soln. of (S)-phenylalaninol (130 mg, 0.858 mmol) and Et3N (0.5 ml, 3.59 mmol) in
CH2Cl2 (1.0 ml) at 08, the suspension was sonicated at r.t. for 24 h. After addition of H2O, the mixture was
filtered through a glass filter (G3), successively washed with 10% aq. HCl (2ꢁ), 20% aq. NaOH (2ꢁ),
H2O (4ꢁ), MeOH (4ꢁ), CH2Cl2 (8ꢁ), and MeOH (8ꢁ), and dried under reduced pressure to give 6
(821 mg, loading, ca. 0.37 mmol/g). Brown powder. M.p. > 3008. IR: 3302 (OH), 1655 (C¼N). 13C-NMR
(125 MHz, C6D6; gel phase): 14.4; 22.9; 37.3; 43.1; 45.9; 53.1; 53.8; 59.1; 61.7; 65.6; 68.1; 69.1; 73.2; 139.4;
157.6. Anal. calc. (based on the loading of HypoGelꢄ 200-Br): N 1.49; found: N 1.86.
The TentaGelꢄ-Incorporated Thiourea 14. A soln. of 12 (0.620 g, 1.99 mmol) and NaH (60% in
mineral oil, 0.150 g, 3.75 mmol) in DMF (7 ml) was stirred at r.t. for 3 h. After addition of TentaGelꢄ 200-
Br (1.53 g, loading: 0.125 mmol of Br/g), the mixture was sonicated at r.t. for 3 d (negative for Beilstein
test). After acidification with 10% aq. HCl, the mixture was filtered through a glass filter (G3),
successively washed with H2O (4ꢁ), MeOH (4ꢁ), AcOEt (4ꢁ), CH2Cl2 (8ꢁ), and MeOH (8ꢁ), and
dried under reduced pressure to give 14 (1.45 g). Yellow powder. M.p. > 3008. 13C-NMR (125 MHz, C6D6;
gel phase): 33.1; 40.9; 45.1; 67.7; 69.7; 71.7; 73.2; 86.5; 127.3; 128.3; 128.6; 129.2; 152.3; 183.7. Anal. calc.
(based on the loading of TentaGelꢄ 200-Br): N 0.34; found: N 0.28.
The TentaGelꢄ-Incorporated Guanidine (7). A mixture of 14 (220 mg) and (COCl)2 (0.8 ml,
9.17 mmol) was heated to reflux for 20 h. The mixture was evaporated and suspended in CH2Cl2 (1 ml).
After addition of a soln. of (S)-phenylalaninol (85 mg, 0.56 mmol) and Et3N (0.3 ml, 2.15 mmol) in
CH2Cl2 (1.5 ml) at 08, the suspension was sonicated at r.t. for 24 h. After addition of H2O, the mixture was
filtered through a glass filter (G3), successively washed with 10% aq. HCl (2ꢁ), 20% aq. NaOH (2ꢁ),
H2O (4ꢁ), MeOH (4ꢁ), CH2Cl2 (8ꢁ), and MeOH (8ꢁ), and dried under reduced pressure to give 7
(180 mg; loading, ca. 0.10 mmol/g). Brown powder. M.p. > 3008. IR: 1662 (C¼N). 13C-NMR (125 MHz,
C6D6; gel phase): 29.8; 37.2; 40.9; 41.8; 68.1; 69.2; 73.1; 138.6; 139.0; 139.5; 146.2; 160.8. Anal. calc. (based
on the loading of TentaGelꢄ 200-Br): N 0.43; found: N 0.62.

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(2S)-3-[4-(Benzyloxy)phenyl]-2-{[(4R,5R)-1,3-dimethyl-4,5-diphenylimidazolidin-2-ylidene]ami-
no}propan-1-ol (17). A soln. of (S)-O-benzyltyrosinol [9] (495 mg, 1.54 mmol) in CH2Cl2 (4.5 ml) was
added to an ice-cooled soln. of 16 (94% purity; 361 mg, 1.40 mm) and Et3N (1.0 ml, 7.18 mmol) in CH2Cl2
(2 ml) under Ar, and the mixture was stirred at r.t. for 3 h. After acidification (pH ca. 3) with 10% aq.
HCl (5 ml) under ice-cooling, the separated org. soln. was collected, and the aq. soln. was extracted with
CH2Cl2. The combined org. solns. were evaporated. After addition of H2O, the mixture was extracted
with toluene. The aq. soln. was basified (pH > 11) with 20% aq. NaOH and extracted with toluene. The
org. soln. was washed with H2O and brine, and dried (K2CO3) and evaporated to give 17 (466 mg, 60%).
A pale-yellow oil. [a]1D7 ¼ ꢀ49.2 (c ¼ 1.02, CHCl3). IR: 3600 – 3200 (br., OH), 1624 (C¼N). H-NMR
1
(400 MHz): 2.95 – 3.00 (m, 1 H); 3.06 (s, 6 H); 3.33 (dd, J ¼ 9.2, 4.0, 1 H); 3.95 (d, J ¼ 5.6, 2 H); 4.25 (s,
2 H); 4.55 (br. s, 1 H); 5.55 (s, 2 H); 7.39 (d, J ¼ 8.4, 2 H); 7.47 (d, J ¼ 7.2, 4 H); 7.63 (d, J ¼ 8.0, 2 H); 7.72 –
7.75 (m, 7 H); 7.80 (t, J ¼ 7.2, 2 H); 7.88 (d, J ¼ 8.4, 2 H). 13C-NMR (100 MHz): 39.0; 57.5; 65.8; 69.9; 77.3;
114.4; 127.3; 127.4; 127.8; 128.2; 128.5; 128.6; 130.5; 132.2; 137.0; 138.1; 157.2; 157.8. HR-FAB-MS:
506.2820 ([M þ H]þ, C33H36N3Oþ2 ; calc. 506.2808).
4-[(2S)-2-{[(4R,5R)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-ylidene]amino}-3-hydroxypropyl]-
phenol (18). A mixture of 17 (1.89 g, 3.74 mmol) and 5% Pd/C (200 mg) in MeOH (55 ml) was
hydrogenated at r.t. for 5 h under atmospheric pressure. After the catalyst was removed by filtration
through Celite, the filtrate was evaporated. The residue was purified by CC (NH-SiO2, toluene/MeOH
5 :1) to afford 18 (1.31 g, 85%). A pale-yellow oil. [a]2D0 ¼ ꢀ66.2 (c ¼ 1.01, CHCl3). IR: 3734 (OH), 1649
1
(C¼N). H-NMR (400 MHz, (D6)DMSO, 1508): 2.60 (s, 6 H); 2.70 – 2.85 (br. s, 2 H); 3.48 (d, J ¼ 6.0,
2 H); 3.79 (s, 2 H); 4.08 (br. s, 1 H); 6.72 (d, J ¼ 8.0, 2 H); 7.01 – 7.37 (m, 12 H). 13C-NMR (100 MHz):
38.6; 58.6; 64.9; 77.3; 116.7; 127.0; 128.5; 128.8; 130.2; 137.1; 159.0; 159.2. HR-FAB-MS: 416.2323 ([M þ
H]þ, C26H30N3Oþ2 ; calc. 416.2338).
Merrifield Resin-Incorporated ChibaG (8). After stirring a mixture of 18 (1.26 g, 3.02 mmol) and
K2CO3 (0.884 g, 6.39 mmol) in acetone (10 ml) at r.t. for 30 min under sonication, chloromethyl-
polystyrene resin (1.705 g, ca. 1.7 mmol/g) was added. The mixture was sonicated at r.t. for 24 h (negative
for Beilstein test). After addition of H2O, the mixture was filtered through a glass filter (G3), successively
washed with MeOH (4ꢁ) and Et2O (4ꢁ), and dried under reduced pressure to give 8 (1.98 g; loading, ca.
0.14 mmol/g). Colorless solids. IR: 3674 (br., OH). Anal. calc. (based on the loading of Merrifield resin):
N 4.41; found: N 0.60.
General Procedure for the Michael Reaction of tert-Butyl N-(Diphenylmethylidene)glycinate (4) and
MVK (5). To a soln. of 4 (ca. 30 mg, ca. 0.10 mmol) and the guanidine catalyst (0.2 mol equiv.) in THF
(0.5 ml), 5 (0.04 ml, 0.48 mmol) was slowly added at 208 under Ar either in the presence of an additive
(0.2 mol equiv.) or in the absence of an additive. After stirring at r.t. for an appropriate time, the mixture
was evaporated. The residue was purified by CC (SiO2; hexane/AcOEt 3 :1) to afford an adduct 19 (R ¼
Me) [5c] as a colorless oil. The ee value was estimated by chiral HPLC (DAICEL CHIRALCEL OD;
hexane/iPrOH 100 :1; flow rate, 1.0 ml/min; detection, at 254 nm): tR 11.0 (R) and 15.8 (S) min.
Using of a heterogeneous catalyst, the reaction was carried out in suspension, and the recovered
catalyst by filtration was reused for the next reaction after being successively washed with H2O, MeOH,
and Et2O, followed by drying under reduced pressure.
We are grateful for the partial financial support from Japan Science and Technology Cooporation
(JST).
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Received June 26, 2013