Mannich-type reaction in water in the presence of a surfactant

Article abstract of DOI:10.1055/s-2006-950344

The effect of sodium dodecyl sulfate (SDS) loading in fluoroboric acid catalyzed Mannich-type reactions of ketene silyl acetals with aldimines was studied. The reaction proceeded smoothly in the presence of 1 mol% of SDS. Formation of small particles was observed by transmission electron microscopy. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950344

SPECIAL TOPIC
4075
Mannich-Type Reaction in Water in the Presence of a Surfactant
Influence
uof Surfactant
n
on Mannich
j
-
Type
R
i
eactions in
W
I
ater toh, Kohei Fuchibe, Takahiko Akiyama*
Department of Chemistry, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax +81(3)59921029; E-mail: takahiko.akiyama@gakushuin.ac.jp
Received 3 August 2006
ketene silyl acetals were employed as a nucleophile. Here-
in we wish to report the results obtained using a Mannich-
type reaction in water, in the presence of catalytic
amounts of SDS.10
Abstract: The effect of sodium dodecyl sulfate (SDS) loading in
fluoroboric acid catalyzed Mannich-type reactions of ketene silyl
acetals with aldimines was studied. The reaction proceeded smooth-
ly in the presence of 1 mol% of SDS. Formation of small particles
was observed by transmission electron microscopy.
At the outset, loading of SDS was studied using the reac-
tion of the ketene silyl acetal 2a with aldimine 1 (Table 1).
When standard reaction conditions (40 mol% of SDS)7b,d
were employed, the b-amino ester 3a was obtained quan-
titatively (entry 1). Interestingly, the Mannich-type reac-
tion also proceeded smoothly in the presence of as low as
1 mol% of SDS (entry 3). Further decreases in the loading
of SDS dropped the yield of 3a significantly, though the
reaction still proceeded, though sluggishly, in the absence
of SDS (entry 4). An increase in the amount of HBF4 to 30
mol% led to the slow formation of the adduct in good
yield (entry 5). We thus selected two protocols with which
to further investigate the modified Mannich-type reaction;
Protocol 1: HBF4 (10 mol%) with SDS (1 mol%) and Pro-
tocol 2: HBF4 (30 mol%) in the absence of SDS.
Key words: Mannich-type reaction, water, imine, surfactant,
amino ester
The Mannich-type reaction of silyl enolates with aldi-
mines constitutes an important method with which to pre-
pare b-amino carbonyl intermediates that facilitate access
to many biologically active nitrogen containing com-
pounds.1 A number of Lewis acid catalysts have been de-
veloped that promote such Mannich-type reactions,2 and
enantioselective versions have also recently been devel-
oped.3,4,5 Organic reactions in aqueous media have attract-
ed much attention from synthetic organic chemists lately,
not only because water is the most abundant, cheapest and
most environmentally friendly solvent, but also because
water, when compared to conventional organic solvents,
possesses many unique characteristics.6 We have recently
found that Mannich-type reactions take place smoothly
under the influence of substoichiometric amounts of
Brønsted acid, typically fluoroboric acid (HBF4), to fur-
nish the corresponding b-amino carbonyl compounds, in
high yields, in aqueous organic solvents. Furthermore, the
HBF4-catalyzed Mannich-type reaction proceeded in the
presence of sodium dodecyl sulfate (SDS) in water, under
organic solvent-free conditions.7 Aza Diels–Alder reac-
tions in aqueous media have also been successfully
achieved.8 In the HBF4-catalyzed Mannich-type reaction
in water, we previously used 40 mol% of SDS to obtain
the corresponding b-amino carbonyl compounds in high
yields.9 Addition of SDS resulted in the generation of
small particles through the formation of micelles, thus in-
creasing the solubility of the substrates in water and facil-
itating a smooth reaction. Unfortunately, normal phase
separation during work-up was hampered by the forma-
tion of emulsions due to the presence of such large
amounts of SDS. In order to overcome this difficulty, an
anion-exchange resin was required which enabled the re-
action mixture to be worked up more efficiently. We sub-
sequently reinvestigated the loading of SDS and found
that the amount could be significantly reduced when
Table 1 Effect of the Loading of HBF4 and SDS
p-MeOC6H4
C6H4p-OMe
OSiMe3
NH
O
N
HBF4
+
SDS
H2O, r.t.
Ph
OMe
Ph
H
OMe
3a
2a (3.0 equiv)
1 (1.0 equiv)
Entry
SDS (mol%) HBF4 (mol%) Time (h) Yield (%)
1
2
3
4
5
40
10
1
10
10
10
10
30
0.5
0.5
1
100
99
94
0
4
20
0
4
81
The results of the Mannich-type reaction of silyl enol
ethers and those of the ketene silyl acetals (3.0 equiv) ob-
tained with Protocol 1 are shown in Table 2. The reaction
of ketene silyl acetals (2a–e) and the ketene thio acetal 2f
generally proceeded smoothly in the presence of as low as
1 mol% of SDS. In contrast, the Mannich-type reaction of
silyl enol ethers were not effective, with the exception of
the silyl enol ether 2i, derived from acetophenone. It
should be noted that both silyl enol ethers and ketene silyl
acetals reacted well when 40 mol% of SDS was em-
ployed. The use of anion-exchange resins could be avoid-
SYNTHESIS 2006, No. 23, pp 4075–4080
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950344; Art ID: C05106SS
© Georg Thieme Verlag Stuttgart · New York

4076
J. Itoh et al.
SPECIAL TOPIC
reaction presumably proceeded at the boundary between
substrates and water. Recently, Sharpless and co-workers
reported on the rate acceleration of organic reactions on
the water surface.12 In the present case, the Mannich-type
reaction is faster under micellar conditions than on the
conventional water surface.
Table 2 Results of the Mannich-Type Reactions
C6H4p(OMe)
p-MeOC6H4
N
HBF4 (0.1 equiv)
NH
O
silyl enolate
(3.0 equiv)
+
Ph
H
SDS (1 mol%)
H2O, r.t.
Ph
R2
1
R1
3
OTMS
OTMS
OTMS
OTMS
OEt
H
H
Me
H
OEt
CH2Ph
2b
OMe
OSiPh3
2d
OMe
Me
2a
Me
2c
(E/Z = 85:15)
(E/Z = 91:9)
(E/Z = 98:2)
OTMS
OTMS
OMe
OTMS
Ph
OTMS
SEt
OTMS
Ph
H
H
Ph
Me
2h
2g
2e
2f
2i
(E/Z = 96:4)
(E/Z = 72:28)
Entry
Nu
2a
2b
2c
2d
2e
2f
Time (h)
Product
3a
Yield (%) syn:anti
1
2
3
4
5
6
7
8
9
1
6
2
2
1
1
7
5
7
94
100
97
91
93
99
13
0
–
3b
19:81
70:30
85:15
16:84
–
3c
3d
3e
3f
2g
2h
2i
3g
38:62
–
3h
3i
89
–
Figure 1 Transmission electron microscopy of the reaction mixture
Finally, the stability of the ketene silyl acetal in water was
studied. As a model, the reaction of the ketene silyl acetal
2a with the aldimine 4, derived from pivalaldehyde, was
investigated (Figure 2). Since 4 does not form the Man-
nich adduct owing to its steric hindrance, the stability of
2a could be measured in the presence of 4. The amount of
2a was monitored by GC with dodecane as an internal
standard. As can be seen in Figure 2, when imine 4 was
absent, 2a decomposed almost instantaneously in HBF4 in
the presence of SDS (Exp. 1). In the presence of the ald-
imine 4, 2a decomposed quickly in water when SDS was
present (Exp. 2), whereas in the absence of SDS, 2a sur-
vived for more than five hours (Exp. 3). These observa-
tions demonstrate that the Mannich-type reaction must
proceed quite rapidly under micellar conditions since the
stability of the ketene silyl acetal is lower under micellar
conditions than in pure water, in which ketene silyl acetal
is separated from the water phase.
ed using 1 mol% of SDS since, despite the formation of a
turbid solution, clear phase separation was possible.
Three-component Mannich-type reactions11 were also
studied using protocols 1 and 2 (Table 3). Aliphatic alde-
hydes as well as aromatic aldehydes reacted smoothly to
afford the corresponding b-amino esters in good to high
yields.
The Mannich-type reaction in water, in the presence of
SDS, is considered to proceed under micellar conditions.
Transmission electron microscopic (TEM) observation of
the reaction mixture in the presence of 40 mol% of SDS,
both 10 minutes (left) and 30 minutes (right) after the re-
action started, clearly showed the formation of small par-
ticles, thus demonstrating that the reaction proceeded
under micellar conditions (Figure 1; top). The formation
of similar, small particles was also observed even in the
presence of just 1 mol% of SDS. In contrast, since the sub-
strates are not soluble in water, particle formation was not
observed by TEM in the absence of SDS. In this case, the
Synthesis 2006, No. 23, 4075–4080 © Thieme Stuttgart · New York

SPECIAL TOPIC
Influence of Surfactant on Mannich-Type Reactions in Water
4077
Table 3 Results of the Three-Component Mannich-Type Reactions
NH2
p-MeOC6H4
NH
OTMS
OMe
Me
Me
HBF4
H2O
O
+
+
RCHO
R
OMe
OMe
2a
3
Protocol 1
Protocol 2
HBF4 (10 mol%)
SDS (1 mol%)
HBF4 (30 mol%)
ketene silyl acetal (1.5 equiv)
ketene silyl acetal (1.2 equiv)
Entry
Aldehyde
Product
Protocol 1
Time (h)
Protocol 2
Yield (%)
Time (h)
Yield (%)
1
2
3
4
5
6
C6H5CHO
3a
3j
40 min
87
92
90
88
73
53
5
5
5
5
5
5
74
73
96
89
84
86
4-MeC6H4CHO
2-furfural
3
1
5
3
3
3k
3l
PhCOCHOa
BnOCH2CHO
PhCH2CH2CHO
3m
3n
a PhCOCHO·H2O was employed.
In conclusion, we have developed two methods for the
Brønsted acid catalyzed Mannich-type reaction of ketene
silyl acetals with aldimines, generated in situ from the cor-
responding aldehyde and amine, in water. This approach
enables a simple work-up that does not require the addi-
tion of ion-exchange resin.
NMR spectra were measured with a Varian Unity-INOVA 400
spectrometer in CDCl3. Tetramethylsilane (TMS) served as internal
standard (d = 0) for 1H NMR, and CDCl3 was used as internal stan-
dard (d = 77.0) for 13C NMR. All solvents were purified according
to standard procedures. Column chromatography (PSQ 60B, Fuji
Silysia Chemical Ltd.) and preparative TLC (Wakogel B-5F, Wako
Pure Chemical Industries ) were conducted on silica gel.
Typical Procedure
An aq soln of HBF4 (1.3598 M, 8 mL, 0.008 mmol) was added to a
r.t. mixture of N-benzylidene-p-anisidine (1; 17 mg, 0.0805 mmol),
ketene silyl acetal (2a; 48 mL, 0.241 mmol) and SDS (0.10027 M, 8
mL, 0.0008 mmol) in H2O (0.5 mL). After being stirred at r.t. for 0.5
h, the reaction was quenched by the addition of sat. NaHCO3 (2 mL)
and CH2Cl2 (5 mL). The aqueous layer was extracted with CH2Cl2
(3 × 10 mL) and the combined organic layers were washed with
brine (5 mL), dried over Na2SO4, and concentrated to dryness. Pu-
rification of the crude mixture by preparative TLC (SiO2, hexane–
EtOAc, 10:1) gave 3a (94%).
TEM Analysis
The sample was mounted on a grid with films of carbon-coated Par-
lodion by floating the grid on a drop of the reaction mixture. The
sample side of the grid was washed with ion-exchanged H2O and
negatively stained with freshly prepared 2% uranyl acetate. The
grid was examined with a JEOL JEM1010 transmission microscope
at 80 kV.
Figure 2 Stability of a ketene silyl acetal 2a in various solvent
systems; (Exp. 1) 2a, HBF4 (10 mol%), SDS (1 mol%), H2O, r.t.;
(Exp. 2) 4, 2a (3 equiv), HBF4 (10 mol%), SDS (1 mol%), H2O, r.t.;
(Exp. 3) 4, 2a (3 equiv), HBF4 (10 mol%), H2O, r.t.
Synthesis 2006, No. 23, 4075–4080 © Thieme Stuttgart · New York

4078
J. Itoh et al.
SPECIAL TOPIC
Methyl 3-[N-(4-Methoxyphenylamino)]-2,2-dimethyl-3-phenyl-
propionate (3a)
Rf = 0.3 (hexane–EtOAc, 10:1).
Methyl 3-[N-(4-Methoxyphenylamino)]-3-phenyl-2-triphenyl-
siloxypropionate (3d)
Mp 129.0–135.0 °C (MeOH); Rf = 0.3 (hexane–EtOAc, 10:1).
IR (CHCl3): 3422, 3015, 2953, 1724, 1514, 1236, 1138, 704, 665
cm–1.
IR (CHCl3): 3420, 3013, 2953, 1755, 1514, 1429, 1229, 1119, 739,
507 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.16 (s, 3 H), 1.24 (s, 3 H), 3.65
(s, 3 H), 3.66 (s, 3 H), 4.45 (s, 1 H), 4.45 (s, 1 H), 6.45 (d, J = 8.8
Hz, 2 H), 6.63 (d, J = 8.8 Hz, 2 H), 7.25–7.28 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 177.1, 151.9, 141.2, 139.3, 128.3,
127.9, 127.3, 114.6, 114.6, 65.1, 55.6, 52.0, 47.1, 24.5, 20.4.
MS: m/z (%) = 313(3) [M+], 212 (82), 196 (100), 167 (30), 77 (28),
41 (55).
1H NMR (400 MHz, CDCl3): d = 7.23–7.54 (m, 20 H), 6.64–6.67
(m, 2 H, syn), 6.63–6.66 (m, 2 H, anti), 6.45–6.48 (m, 2 H, syn),
6.36–6.38 (m, 2 H, anti), 4.84 (dd, J = 8.4 Hz, 2.5 Hz, 1 H, syn),
4.84 (dd, J = 8.1 Hz, 5.6 Hz, 1 H, anti), 4.71 (d, J = 8.4 Hz, 1 H,
syn), 4.71 (d, J = 8.1 Hz, 1 H, anti), 4.66 (d, J = 5.6 Hz, 1 H, anti),
4.65 (d, J = 2.5 Hz, 1 H, syn), 3.67 (s, 3 H, syn), 3.67 (s, 3 H, anti),
3.35 (s, 3 H, syn) 3.32 (s, 3 H, anti).
13C NMR (100 MHz, CDCl3): d (syn) = 171.5, 152.0, 140.8, 138.6,
135.5, 133.1, 130.0, 128.5, 127.7, 127.4, 127.4, 114.7, 114.7, 60.9,
60.4, 55.7, 51.8.
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.71; H, 7.25; N, 4.76.
13C NMR (100 MHz, CDCl3): d (anti) = 171.1, 152.2, 140.6, 138.7,
134.9, 133.1, 130.2, 128.3, 127.9, 127.4, 127.3, 115.1, 114.7, 61.7,
60.9, 55.6, 51.5.
MS: m/z (%) = 559 (2) [M+], 271 (2), 270 (2), 256 (6), 213 (16), 212
(100), 199 (2), 197 (3), 196 (3), 183 (2), 181 (3), 180 (3), 168 (5),
134 (4), 105 (2), 77 (2).
Methyl 2-Benzyl-3-[N-(4-methoxyphenylamino)]-3-phenyl-
propionate (3b)
Mp 111.0–113.0 °C (EtOH); Rf = 0.3 (hexane–EtOAc, 10:1).
IR (CHCl3): 3416, 3013, 2835, 1720, 1510, 1454, 1236, 1180, 1038,
820, 700, 519 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.08–7.40 (m, 10 H), 6.65–6.74
(m, 2 H), 6.45–6.50 (m, 2 H), 4.62 (d, J = 5.5 Hz, 1 H, anti), 4.47
(d, J = 5.3 Hz, 1 H, syn), 4.35 (s, 1 H, anti), 4.36 (s, 1 H, syn), 4.36
(br s, 1 H), 3.90 (q, J = 7.1 Hz, 2 H, anti), 3.93 (q, J = 7.1 Hz, 2 H,
syn), 3.69 (s, 3 H, anti), 3.68 (s, 3 H, syn), 3.00–3.14 (m, 2 H), 2.85–
2.96 (m, 1 H), 0.97 (t, J = 7.1 Hz, 3 H, anti), 0.95 (t, J = 7.1 Hz, 3 H,
syn).
Anal. Calcd for C35H33NO4Si: C, 75.10; H, 5.94; N, 2.50. Found: C,
74.88; H, 5.73; N, 2.48.
Methyl 3-[N-(4-Methoxyphenylamino)]-2,3-diphenyl-
propionate (3e)
Mp 145.5–147.0 °C (MeOH); Rf = 0.3 (hexane–EtOAc, 8:1).
IR (CHCl3): 3398, 3031, 2955, 2835, 1734, 1512, 1454, 1240, 1163,
1036, 822, 700, 665 cm–1.
13C NMR (100 MHz, CDCl3): d (anti) = 173.1, 152.2, 141.2, 140.7,
139.3, 128.8, 128.5, 128.4, 127.5, 127.0, 126.3, 115.0, 114.7, 60.6,
60.5, 55.7, 54.6, 33.7, 13.9.
13C NMR (100 MHz, CDCl3): d (syn) = 174.0, 151.8, 141.5, 141.0,
138.6, 128.9, 128.5, 128.4, 127.3, 126.7, 126.5, 114.7, 114.5, 60.5,
59.0, 55.7, 54.7, 36.4, 13.9.
1H NMR (400 MHz, CDCl3): d = 7.08–7.46 (m, 10 H), 6.62–6.67
(m, 2 H, syn), 6.56–6.60 (m, 2 H, anti), 6.52–6.55 (m, 2 H, syn),
6.31–6.35 (m, 2 H, anti), 4.87 (d, J = 8.6 Hz, 1 H, syn), 4.87 (d,
J = 9.9 Hz, 1 H, anti), 3.93 (d, J = 8.6 Hz, 1 H, syn), 3.87 (d, J = 9.9
Hz, 1 H, anti), 3.63 (s, 3 H, anti), 3.63 (s, 3 H, syn), 3.44 (s, 3 H,
syn), 3.44 (s, 3 H, anti).
MS: m/z (%) = 389 (6) [M+], 213 (13), 212 (100), 196 (11), 91 (12).
13C NMR (100 MHz, CDCl3): d (anti) = 171.9, 152.4, 141.7, 141.2,
135.1, 129.0, 128.8, 128.5, 128.2, 127.6, 127.3, 115.5, 114.5, 64.3,
60.0, 55.6, 51.9.
13C NMR (100 MHz, CDCl3): d (syn) = 172.9, 152.3, 140.8, 140.6,
135.5, 128.8, 128.3, 128.3, 127.5, 127.2, 127.9, 115.6, 114.6, 62.4,
58.9, 55.6, 52.2.
Anal. Calcd for C25H27NO3: C, 77.09; H, 6.99; N, 3.60. Found: C,
76.87; H, 6.71; N, 3.57.
Methyl 3-[N-(4-Methoxyphenylamino)]-2-methyl-3-phenyl-
propionate (3c)
Oil; Rf = 0.3 (hexane–EtOAc, 8:1).
IR (CHCl3): 3420, 3032, 2835, 1724, 1510, 1244, 1182, 1040, 820,
702, 521 cm–1.
MS: m/z (%) = 211 (82), 196 (100), 167 (25), 92 (11), 89 (12), 77
(20), 64 (17), 63 (18), 51 (16).
1H NMR (400 MHz, CDCl3): d = 7.19–7.32 (m, 5 H), 6.64–6.68 (m,
2 H), 6.46–6.50 (m, 2 H), 4.63 (d, J = 5.3 Hz, 1 H, syn), 4.41 (d,
J = 7.7 Hz, 1 H, anti), 4.32 (br s, 1 H), 4.11 (q, J = 7.1 Hz, 2 H, an-
ti), 4.06 (q, J = 7.1 Hz, 2 H, syn), 3.68 (s, 3 H, anti), 3.67 (s, 3 H,
syn), 2.91 (dq, J = 7.1 Hz, 5.3 Hz, 1 H, syn), 2.80 (dq, J = 7.7 Hz,
7.0 Hz, 1 H, anti), 1.16 (t, J = 7.1 Hz, 3 H, anti), 1.15 (d, J = 7.7 Hz,
3 H, syn), 1.14 (t, J = 7.1 Hz, 3 H, anti), 1.13 (d, J = 7.0 Hz, 3 H, an-
ti).
13C NMR (100 MHz, CDCl3): d (anti) = 175.0, 152.0, 141.4, 141.1,
128.5, 127.3, 126.9, 114.8, 114.7, 61.7, 60.6, 55.6, 46.9, 15.2, 14.1.
13C NMR (100 MHz, CDCl3): d (syn) = 174.3, 152.1, 141.3, 141.0,
128.4, 127.2, 126.9, 114.9, 114.7, 60.7, 60.5, 55.7, 46.2, 14.1, 11.9.
Anal. Calcd for C23H23NO3: C, 76.43; H, 6.41; N, 3.88. Found: C,
76.63; H, 6.63; N, 3.80.
Ethyl 3-[N-(4-Methoxyphenylamino)]-3-phenylpropanethioate
(3f)
Mp 76.0–77.0 °C (EtOH); Rf = 0.4 (hexane–EtOAc, 8:1).
1H NMR (400 MHz, CDCl3): d = 7.21–7.42 (m, 5 H), 6.66–6.70 (m,
2 H), 6.48–6.52 (m, 2 H), 4.76 (t, J = 6.8 Hz, 1 H), 4.27 (br s, 1 H),
3.68 (s, 3 H), 2.96 (d, J = 6.8 Hz, 2 H), 2.85 (q, J = 7.5 Hz, 2 H),
1.19 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 197.3, 152.3, 142.2, 140.9, 128.7,
127.44, 126.3, 115.1, 114.7, 56.6, 55.6, 51.6, 23.6, 14.5.
MS: m/z (%) = 313 (6) [M+], 213 (15), 212 (100), 211 (16), 196 (19),
91 (6), 77 (7), 57 (8).
IR (CHCl3): 3406, 3030, 2934, 1711, 1364, 665 cm–1.
MS (DI): m/z (%) = 315 (15) [M]+, 213 (12), 212 (100), 196 (16),
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.67; H, 7.68; N, 4.67.
122 (6), 104 (5), 77 (7).
Anal. Calcd for C18H21NO2S: C, 68.54; H, 6.71; N, 4.44; S, 10.17.
Found: C, 68.82; H, 6.96; N, 4.51; S, 9.83.
Synthesis 2006, No. 23, 4075–4080 © Thieme Stuttgart · New York

SPECIAL TOPIC
Influence of Surfactant on Mannich-Type Reactions in Water
4079
2-[Phenyl-N-(4-methoxyphenylamino)methyl]cyclohexanone
Methyl 3-[N-(4-Methoxyphenylamino)]-2,2-dimethyl-4-phenyl-
4-oxobutanoate (3l)14
(3g)13
Rf = 0.2 (Hexane–EtOAc, 5:1).
Rf = 0.5 (MeCN–toluene, 1:10).
1H NMR (400 MHz, CDCl3): d = 7.18–7.49 (m, 5 H), 6.62–6.65 (m,
2 H), 6.46–6.50 (m, 2 H), 4.73 (d, J = 4.2 Hz, 1 H, syn), 4.54 (d,
J = 7.3 Hz, 1 H, anti), 4.36 (br s, 1 H), 3.67 (s, 3 H, syn), 3.61 (s,
3 H, anti), 1.26–2.86 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 212.8, 211.4, 152.1, 152.1, 141.8,
141.7, 141.6, 141.4, 128.4, 128.3, 127.5, 127.3, 127.1, 126.9, 115.5,
115.1, 114.6, 114.6, 58.9, 58.2, 57.5, 56.7, 55.6, 55.6, 42.4, 41.7,
28.9, 28.4, 27.9, 27.0, 24.9, 23.6.
1H NMR (400 MHz, CDCl3): d = 1.18 (s, 3 H), 1.31 (s, 3 H), 3.56
(s, 3 H), 3.72 (s, 3 H), 4.49 (s, 1 H), 5.20 (s, 1 H), 6.73–6.75 (m,
4 H), 7.41–7.45 (m, 2 H), 7.52–7.56 (m, 1 H), 7.87–7.90 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 200.7, 153.1, 141.4, 137.4, 133.3,
128.6, 128.3, 116.2, 144.9, 47.6, 55.7, 52.0, 46.5, 46.0, 23.0, 21.9.
IR (CHCl3): 3528, 3381, 3030, 2953, 1732, 1682, 1514, 1240, 790,
716 cm–1.
MS (DI): m/z (%) = 341 (7) [M]+, 240 (12), 237 (15), 236 (100), 177
MS: m/z (%) = 211 (85), 196 (100), 167 (22), 141(7), 115 (8), 92
(8), 89 (9), 77 (13), 63 (12), 51 (10).
(12), 176 (61), 134 (17), 105 (15), 77 (23).
Methyl 4-Benzyloxy-3-[N-(4-methoxyphenylamino)]-2,2-di-
methylbutanoate (3m)
Rf = 0.7 (hexane–EtOAc, 3:1).
3-N-(4-Methoxyphenylamino)-1,3-diphenyl-1-propanone (3i)
Rf = 0.3 (hexane–EtOAc, 5:1).
IR (CHCl3): 3412, 3022, 2934, 1686, 1512, 1238, 775, 667 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.90–7.92 (m, 2 H), 7.54–7.58 (m,
1 H), 7.42–7.46 (m, 4 H), 7.30–7.34 (m, 2 H), 7.21–7.25 (m, 1 H),
6.66–6.69 (m, 2 H), 6.51–6.54 (m, 2 H), 4.92 (dd, J = 5.1 Hz, 7.7
Hz, 1 H), 4.29 (br s, 1 H), 3.68 (s, 3 H), 3.49 (dd, J = 5.1 Hz, 16.1
Hz, 1 H), 3.40 (dd, J = 7.7 Hz, 16.1 Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 7.23–7.37 (m, 5 H), 6.72–6.76 (m,
2 H), 6.60–6.64 (m, 2 H), 4.56 (d, J = 11.2 Hz, 1 H), 4.37 (d, J = 7.3
Hz, 1 H), 4.32 (d, J = 11.2 Hz, 1 H), 3.77 (dq, J = 6.2 Hz, 1 H), 3.73
(s, 3 H), 3.42 (d, J = 7.9 Hz, 1 H), 3.50 (s, 3 H), 1.27 (s, 3 H), 1.21
(s, 3 H), 1.17 (d, J = 6.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.6, 151.4, 144.3, 138.3, 128.3,
127.9, 127.5, 114.9, 114.0, 74.4, 70.5, 65.4, 55.8, 51.6, 47.2, 24.0,
22.9, 17.9.
13C NMR (100 MHz, CDCl3): d = 198.4, 152.4, 143.2, 141.2, 136.8,
133.4, 128.8, 128.7, 128.2, 127.3, 126.4, 115.4, 114.7, 55.7, 46.4.
MS: m/z (%) = 211 (80), 196 (100), 167 (24), 115 (10), 92 (10), 89
(11), 77 (16), 63 (16), 51 (14).
IR (CHCl3): 3423, 3030, 2875, 1724, 1514, 1456, 1236, 1138, 793,
675 cm–1.
Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C,
79.74; H, 6.66; N, 4.28.
MS (DI): m/z (%) = 371 (14) [M]+, 270 (23), 237 (19), 236 (100),
176 (45), 162 (22), 134 (9), 91 (39), 77 (6), 65 (7).
Methyl 3-[N-(4-Methoxyphenylamino)]-2,2-dimethyl-3-(4-
methylphenyl)propionate (3j)
Mp 110.5–111.0 °C (MeOH); Rf = 0.2 (hexane–EtOAc, 10:1).
Methyl 3-[N-(4-Methoxyphenylamino)]-2,2-dimethyl-5-phenyl-
pentanoate (3n)
oil; Rf = 0.4 (hexane–EtOAc, 5:1).
IR (CHCl3): 3422, 3026, 2953, 1724, 1512, 1236, 822 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.23–7.27 (m, 2 H), 7.17 (d,
J = 7.5 Hz, 1 H), 7.08 (d, J = 7.5 Hz, 2 H), 6.72–6.76 (m, 2 H),
6.57–6.59 (m, 2 H), 3.75 (s, 3 H), 3.54 (s, 1 H), 3.43 (s, 1 H), 2.77–
2.84 (m, 1 H), 2.51–2.59 (m, 1 H), 1.84–1.91 (m, 1 H), 1.55–1.60
(m, 1 H), 1.18 (s, 3 H), 1.17 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.4, 151.5, 143.4, 141.8, 128.4,
128.2, 125.8, 114.8, 114.0, 60.1, 55.7, 51.6, 48.0, 35.0, 33.2, 22.5,
21.8.
1H NMR (400 MHz, CDCl3): d = 7.14 (d, 2 H), 7.07 (d, 2 H), 6.61–
6.65 (m, 2 H), 6.43–6.47 (m, 2 H), 4.42 (2 × s, 2 H), 3.65 (2 × s,
6 H), 2.29 (s, 3 H), 1.23 (s, 3 H), 1.15 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.2, 151.8, 141.2, 136.9, 136.2,
128.7, 128.2, 114.7, 114.6, 64.8, 55.6, 52.0, 47.1, 24.4, 21.0, 20.4.
MS: m/z (%) = 327 (3) [M]+, 226 (100), 210 (56), 181 (6), 134 (9),
91 (10), 77 (12), 59 (8), 41 (22).
IR (CHCl3): 3530, 3425, 3013, 2835, 1724, 1506, 1456, 1215, 1040,
791, 719, 517 cm–1.
MS (DI): m/z (%) = 341 (10) [M]+, 240 (100), 149 (30), 134 (11),
Anal. Calcd for C20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found: C,
73.51; H, 7.63; N, 4.11.
91 (32).
Methyl 3-(2-Furyl)-3-[N-(4-methoxyphenylamino)]-2,2-di-
methylpropionate (3k)
Mp 75.5–76.5 °C (EtOH); Rf = 0.7 (hexane–EtOAc, 3:1).
Anal. Calcd for C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
73.70; H, 7.89; N, 4.08.
IR (CHCl3): 3408, 3009, 2953, 1724, 1512, 1232, 1148, 673 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.24 (s, 3 H), 1.25 (s, 3 H), 3.68
(s, 3 H), 3.70 (s, 3 H), 4.14 (br s, 1 H), 4.62 (s, 1 H), 6.12 (d, J = 3.1
Hz, 1 H), 6.25 (dd, J = 1.8 Hz, 3.1 Hz, 1 H), 6.58–6.60 (m, 2 H),
6.67–6.72 (m, 2 H), 7.30 (d, J = 1.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 176.8, 153.5, 152.6, 141.6, 141.2,
115.6, 114.6, 110.1, 108.0, 59.9, 55.6, 52.0, 47.3, 23.5, 20.8.
Acknowledgment
Partial financial support from the Ministry of Education, Science
and Culture of Japan is deeply acknowledged. J.I. is grateful to a
JSPS Research Fellowship for Young Scientists. We are grateful to
Dr Toshiaki Takei for TEM observations.
MS: m/z (%) = 303 (5) [M]+, 202 (95), 186 (15), 122 (20), 77 (22),
59 (23), 41 (100).
References
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Synthesis 2006, No. 23, 4075–4080 © Thieme Stuttgart · New York

4080
J. Itoh et al.
SPECIAL TOPIC
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Synthesis 2006, No. 23, 4075–4080 © Thieme Stuttgart · New York