Mannich-type reaction of (1-methoxy-2-methylpropenyloxy)trimethylsilane with arylaldehydes and aromatic amines catalyzed by perfluorinated rare earth metal salts in fluorous phase

Article abstract of DOI:10.1016/j.tet.2005.03.059

In this paper, we describe a useful Mannich-type reaction in fluorous phase. By use of perfluorodecalin (C₁₀F₁₈, cis- and trans-mixture) as a fluorous solvent and perfluorinated rare earth metal salts such as Sc(OSO₂C

Full text of DOI:10.1016/j.tet.2005.03.059

Tetrahedron 61 (2005) 4965–4970
Mannich-type reaction of
(1-methoxy-2-methylpropenyloxy)trimethylsilane with
arylaldehydes and aromatic amines catalyzed by perfluorinated
rare earth metal salts in fluorous phase
*
Min Shi, Shi-Cong Cui and Ying-Hao Liu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
Received 4 January 2005; revised 8 March 2005; accepted 10 March 2005
Available online 2 April 2005
Abstract—In this paper, we describe a useful Mannich-type reaction in fluorous phase. By use of perfluorodecalin (C10F18, cis- and trans-
mixture) as a fluorous solvent and perfluorinated rare earth metal salts such as Sc(OSO2C8F17)3 or Yb(OSO2C8F17)3 (2.0 mol%) as a catalyst,
the Mannich-type reaction of arylaldehydes with aromatic amines and (1-methoxy-2-methylpropenyloxy)trimethylsilane can be performed
for many times without reloading the catalyst and the fluorous solvent.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
perfluoro-alkanes, have some unique properties that make
them attractive alternatives for conventional organic
solvents.5 They have limited miscibility with conventional
organic solvents. Compounds functionalized with perfluori-
nated groups often dissolve preferentially in fluorous
solvents. This character can be used to extract fluorous
components from reaction mixtures.6 The ‘Fluorous
Biphase System’ (FBS) technique was first reported by
Horvath and Rabai.6a It allows the catalysis to be performed
in a two-phase reaction mixture consisting of a perfluori-
nated solvent and an organic solvent. Therefore, by
introducing a perfluorinated catalyst in a catalytic reaction
system, the catalyst is solubilized and simultaneously
immobilized in the ‘Fluorous Phase’. By elevating the
temperature the biphasic system forms a homogenous
solution and the catalytic process can take place. Cooling
down the reaction mixture leads to the reformation of two
separate phases. Afterwards, easy product isolation and the
recovery of the perfluoro-tagged metal catalyst can be
achieved by simple phase separation.7 The isolation and
recovery of perfluorinated components can be accomplished
not only by a phase separation of immiscible liquid layers
but also by solid–liquid extraction using a perfluorinated
non-polar stationary phase.6a
Mannich reaction is one of the most important fundamental
reactions in organic chemistry. It is a powerful tool in the
routes for the synthesis of various b-amino ketones or esters,
which are versatile synthetic building blocks for the
preparation of many nitrogen-containing, biologically
important compounds.1 In the bimolecular version of the
classical Mannich reaction the use of preformed or in situ
generated iminium2 or N-acyliminium ions3 and carbon
nucleophiles has greatly expanded the versatility of this
methodology allowing the use of milder reaction conditions.
Recently, some significant progresses have been made in a
number of Lewis acid or transition metal catalyzed Mannich
reactions of (1-methoxy-2-methylpropenyloxy) trimethyl-
silane with imines in organic solvents. For example, the
application of zirconium [Zr(OPri)4], palladium complexes,
and rare earth metal triflates [Ln(OTf)n, LnZYb, Sc, Y, La]
in Mannich reaction has enlarged its utility in organic
synthesis.4
On the other hand, perfluorocarbon fluids, especially
Keywords: Mannich-type reaction; Perfluorinated rare earth metal salt;
Perfluorinated alkali metal salt; (1-Methoxy-2-methylpropenyloxy)tri-
methylsilane; Perfluorodecalin (C10F18 cis- and trans-mixture); Fluorous
biphase system.
Based on this concept, we attempted the application of
fluorous phase separation techniques to the one-pot ‘three-
component’ Mannich reaction of (1-methoxy-2-methyl-
propenyloxy)trimethylsilane with arylaldehydes and
*
Corresponding author. Tel.: C86 21 5492 5137; fax: C86 21 64166128;
e-mail: mshi@pub.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.059

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M. Shi et al. / Tetrahedron 61 (2005) 4965–4970
Scheme 1.
M(OSO2C8F17), MZLi, Na]9 and used them as catalysts in
the one-pot ‘three-component’ Mannich-type reaction of
(1-methoxy-2-methyl propenyloxy)trimethylsilane 3 with
benzaldehyde 1a and aniline 2a in hexane10 and perfluoro-
decalin (C10F18, cis- and trans-mixture) fluorous solvent
(Scheme 1). At 60 8C (upon heating), the organic phase is
miscible with fluorous phase to give a homogeneous phase.
At 20 8C (room temperature), it becomes a biphasic system.
The results are summarized in Table 1 and as can be seen,
Ln(OSO2C8F17)3 Lewis acid catalysts are more effective
than Ln(OSO2CF3)3 (Table 1, entries 3–6) while perfluori-
nated alkali metal salts are ineffective in this FBS catalytic
reaction system (Table 1, entries 7–9). It should be
emphasized here that no reaction occurred in the absence
of catalyst. In addition, the Bronsted acids HOSO2CF3 and
HOSO2C8F17 themselves can catalyze this reaction as well,
with HOSO2C8F17 being more effective than HOSO2CF3
under identical conditions (Table 1, entries 1 and 2). These
results suggest that a long perfluorinated alkyl chain, so
called ‘pony tail’, could indeed allow more efficient transfer
of the catalyst into the fluorous phase. Overall, Sc(OSO2-
C8F17)3 is the most active catalyst in this reaction. Although
HOSO2C8F17 itself can effectively catalyze this reaction as
well, its salt Sc(OSO2C8F17)3 is more stable under ambient
atmosphere and can be easily handled (Table 1, entries 1 and
2). It should be noted that in consideration of cost of
Table 1. Mannich-type reaction of 1a, 2a, and 3 in hexane and fluorous
phase per fluorodecalin for 2 h
Entry
Catalyst
Yield (%)a
4a
1
2
3
4
5
6
7
8
9
HOSO2CF3
50
63
47
65
55
71
24
14
28
HOSOC8F17
Yb(OSO2CF3)3
Yb(OSO2C8F17 3
Sc(OSO2CF3)3
Sc(OSO2C8F17 3
Na(OSO2C8F17
Na(OSO2CF3)
Li(OSO2C8F17
)
)
)
)
a Isolated yields.
aromatic amines using perfluorinated rare earth metal salts
or other metal salts as catalysts. By this technology, the
efficiency of the synthetic process of this Mannich-type
reaction can be increased because the recovery of
perfluorinated rare earth metal salt or other metal salt
catalysts from the reaction solution can be avoided.
In order to perform this Mannich-type reaction in fluorous
phase, we prepared several perfluorinated rare earth metal
salts [Ln(OSO2CF3)3 and Ln(OSO2C8F17)3, LnZYb, Sc]8
and perfluorinated alkali metal salts [M(OSO2CF3) and
Table 2. Mannich-type reaction of 1a, 2a, and 3 in different fluorous solvents for 2 h
Entry
Fluorous phase
Yield (%)a
4a
1
2
71
54
3
40
46
72
4
CF3(CF2)4CF3
5b
6b
7b
71
65
a Isolated yields.
b The catalyst in fluorous phase was reused.

M. Shi et al. / Tetrahedron 61 (2005) 4965–4970
4967
catalyst, Yb(OSO2C8F17)3 is also an active and cheap
catalyst in this reaction.
could be recovered during the purification of the adducts by
column chromatography.
Next, we screened several other fluorous solvents, such as
perfluoroheptane (C7F8), perfluoro (methylcyclohexane)
(C7F14) and perfluorohexane (C6F14) in this FBS catalytic
system. The results are summarized in Table 2. We found
that during the Mannich-type reaction process, the loss of
fluorous solvent is very serious at 60 8C when using
perfluorohexane (C7F8), perfluoro(methylcyclohexane)
(C7F14) and perfluorohexane (C6F14) as solvent because
they are volatile (bp 58–76 8C). Perfluorodecalin (C10F18,
cis- and trans-mixture) is the best fluorous solvent for this
reaction (Table 2, entries 1–4). This new fluorous phase is
not volatile because it has higher boiling point (bp 142 8C).
Based on the 19F NMR spectroscopic data and GC–MS, no
loss of catalyst or perfluorodecalin to the organic and water
phase during workup can be detected.
In addition, we utilized relatively cheaper Yb(OSO2C8F17)3
as a Lewis acid to catalyze the reaction of (1-methoxy-2-
methylpropenyloxy)trimethylsilane 3 with arylaldehydes 1
and 2-aminophenol 5 in a biphasic way of hexane and
perfluorodecalin. The results are summarized in Table 4.
The initial examination of this reaction was performed at
60 8C using arylaldehyde 1a as the substrate under the same
conditions as those described above. Unfortunately, the
corresponding Mannich-type adduct 6a was formed in lower
yield (40%) because of the oxidization of 2-aminophenol 5
at this high temperature (60 8C) (Table 4, entry 1). We found
that with the addition of tetrahydrofuran (THF) (0.5 mL)
into this hexane (1.0 mL) and perfluorodecalin (1.0 mL)
system to dissolve the solid powders of 2-aminophenol 5,
the reactions proceeded smoothly at 20 8C to give 6a in
higher yield (Table 4, entry 2), although this catalytic
reaction system is not a homogenous phase at 20 8C. For
other arylaldehydes, these reactions proceeded smoothly
under the same conditions to give the corresponding
Mannich-type adducts 6 in good yields (Table 4, entries
3–6). The fluorous phase containing the employed Lewis
acid Yb(OSO2C8F17)3 can also be easily recovered and
reused for three times to give the adduct 6a in similar yields
without reloading the catalyst and fluorous solvent (Table 4,
entries 7–9).
The perfluorodecalin fluorous phase containing Sc(OSO2-
C8F17)3 catalyst can be easily isolated by simple separation
of the fluorous phase. This catalytic phase can be reused for
three times to give similar results without reloading fluorous
solvent and the catalyst (Table 2, entries 5–7).
Using Sc(OSO2C8F17)3 as a catalyst and perfluorodecalin
(C10F18, cis- and trans-mixture) as the fluorous solvent in a
biphasic way, Mannich-type reaction of (1-methoxy-2-
methylpropenyloxy)trimethylsilane 3 with other arylalde-
hydes 1 and aromatic amines 2 were examined as well. The
results are shown in Table 3. These Mannich-type reactions
proceeded smoothly at 60 8C to give the corresponding
adducts 4b-f in good yields (Table 3, entries 1–5). Thus, a
novel FAB catalytic process of Mannich reaction of
(1-methoxy-2-methylpropenyloxy)trimethylsilane with
arylaldehydes and aromatic amines has been explored.
This is the first example of an Mannich reaction of
arylaldehydes with aromatic amines and (1-methoxy-2-
methylpropenyloxy)trimethylsilane in a fluorous phase. It
should be also emphasized here that no reaction occurred
when using aliphatic aldehydes as substrates with aromatic
amines in this reaction under the same conditions. This is
because the corresponding imines formed in situ are not
stable in the presence of Lewis acids. In these cases, the
reactions gave no other by-products. The starting materials
In summary, we reported in this paper a new process to carry
out the Mannich-type reaction of (1-methoxy-2-methyl-
propenyloxy)trimethylsilane, arylaldehydes and aromatic
amines in fluorous phase. Using perfluorodecalin (C10F18,
cis- and trans-mixture) as a fluorous solvent and Sc(OSO2-
C8F17)3 or Yb(OSO2C8F17)3 as a catalyst, this Mannich
reactions can be repeated several times without reloading
fluorous solvent and the catalyst. By the conventional Lewis
acid catalyzed reaction, the water-stable Lewis acids,
Yb(OPf)3, Sc(OTf)3 or Sc(OPf)3 could be recovered from
the water phase after the usual workup. Obviously, the water
must be evaporated and this will consume a lot of energy.
By this technology, the catalytic phase can be easily
recovered and can be reused for the next reaction without
any treatment. Further investigations to develop other types
Table 3. Results of Mannich-type reaction of aryladehyde 1, aromatic amine 2, and 3 in fluorous phase for 2 h
Entry
R1
R2
Yield (%)a
4
1
2
3
4
5
1b, R1Zp-Cl
1c, R1Zp-NO2
1d, R1Zp-Ome
1a, R1ZH
2a, R2ZH
4b, 65
4c, 65
4d, 70
4e, 66
4f, 58
2a, R2ZH
2a, R2ZH
2b, R2Zp-F
2c, R2Zo-CF3
1a, R1ZH
a Isolated yields.

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M. Shi et al. / Tetrahedron 61 (2005) 4965–4970
Table 4. Results of Mannich-type reaction of arylaldehydes 1, 2-aminophenol 5 and 3 in fluorous phase for 8 h
Entry
R1
Yield (%)a
6
1b
2
3
4
1a, R1ZH
6a, 40
6a, 93
6b, 73
6c, 63
6d, 79
6e, 66
6a, 60
6a, 64
6a, 68
1a, R1ZH
1b, R1Zp-Me
1c, R1Zp-OMe
1d, R1Zp-Cl
1e, R1Zp-Br
1a, R1ZH
5
6
7c
8c
9c
1a, R1ZH
1a, R1ZH
a Isolated yields.
b The reaction was performed at 60 8C.
c The recovered catalyst in fluorous phase was used.
of reactions in fluorous phase with perfluorinated metal salt
are now in progress.
methanol at 0 8C. The reaction mixture was stirred at room
temperature for 30 min, then at reflux for 2 h. The clear
solution concentrated under reduced pressure. The resulting
white cake was dried at 125 8C for 2 h. The production was
recrystallized from methanol or ethanol/diethyl ether.
2. Experimental
2.4. Typical reaction procedure for the Mannich-type
reaction in fluorous phase
2.1. General remarks
MPs were obtained with a Yanagimoto micro melting point
apparatus and are uncorrected. 1H NMR spectra were
recorded on a Bruker AM-300 spectrometer for solution in
CDCl3 with tetramethylsilane (TMS) as internal standard;
J-values are in Hz. All of the solid compounds reported in
this paper gave satisfactory CHN microannalyses with a
Carlo–Erba 1106 analyzer. Mass spectra were recorded with
a HP-5989 instrument and HRMS was measured by a
Finnigan MAC mass spectrometer. Organic solvents were
dried by standard methods when necessary. Commercially
obtained reagents were used without further purification. All
reactions were monitored by TLC with Huanghai GF254
silica gel coated plates. The orientation of nitration was
determined by NMR analysis. Flash column chromato-
graphy was carried out using 300–400 mesh silica gel.
To a solution of Sc(OPf)3 [(C8F17SO3)3Sc] (10 mg,
0.006 mmol) in perfluorodecalin (C10F18, cis- and trans-
mixture) (solvent, 1.0 mL) was added a solution of aniline
(27 mL, 0.3 mmol) and benzaldehyde (30 mL, 0.3 mmol) in
toluene (solvent, 1.0 mL). Then, (1-methoxy-2-methyl-
propenyloxy)trimethylsilane (90 mL, 0.45 mmol) was
added in the mixture under stirring. The mixture was stirred
at 60 8C for 20 h. The fluorous layer was separated for the
next reaction. The reaction mixture (organic layer) was
washed by water (5 mL) and extracted with dichloro-
methane (2!15 mL). The combined organic layers were
dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by
column chromatography on silica gel (EtOAc–hexaneZ
1:10) to give the product as a colorless solid 60 mg, yield
71%.
2.2. Preparation of perfluorinated rare earth metal
catalysts [Ln(OSO2C8F17)3, LnZYb, Sc]
2.4.1. 2,2-Dimethyl-3-phenyl-3-phenylaminopropionic
acid methyl ester 4a. A white solid, 60 mg, yield 71%;
This is a known compound. Its 1H NMR spectroscopic data
are in consistent with those reported in literature (Ref. Loh,
T.-P.; Liung, S. B. K. W.; Tan, K.-L.; Wei, L.-L.
Tetrahedron 2000, 56, 3227–3238). 1H NMR (CDCl3,
TMS, 300 MHz): d 1.16 (3H, s, CH3), 1.27 (3H, s, CH3),
3.65 (3H, s, OCH3), 4.49 (1H, s, CH), 4.79 (1H, s, NH), 6.49
(2H, dd, JZ1.2, 8.7 Hz, ArH), 6.59 (1H, t, JZ7.5 Hz, ArH),
7.04 (2H, dd, JZ7.5, 8.7 Hz, ArH), 7.17–7.29 (5H, m,
ArH).
The reaction procedure: an excess amount of
a
lanthanide(III) oxide (99.9% purity) was added to an
aqueous solution of C8F17SO3H (50% v/v) and heating at
boiling for 30 min to 1 h. The mixture was filtered to
remove the unreacted oxide. The water was then removed
from the filtrate under reduced pressure. The resulting
hydrate was dried by heating under vacuum at 180–200 8C
for 48 h.
2.3. Preparation of perfluorinated alkali metal salt
catalysts [M(OSO2C8F17), MZLi, Na, K]
2.4.2. 3-(4-Chlorophenyl)-2,2-dimethyl-3-phenylamino-
propionic acid methyl ester 4b. A white solid, 62 mg,
yield 65%. Mp 108–110 8C. IR (CHCl3): n 1732, 1613,
The reaction procedure: trifluoromethanesulfonic acid was
added dropwise to a solution of the carbonate salt in

M. Shi et al. / Tetrahedron 61 (2005) 4965–4970
4969
1510, 1533, 1442, 1149, 873 cmK1. 1H NMR (CDCl3, TMS,
300 MHz): d 1.15 (3H, s, CH3), 1.27 (3H, s, CH3), 3.65 (3H,
s, OCH3), 4.45 (1H, s, CH), 4.79 (1H, s, NH), 6.46 (2H, dd,
JZ1.0, 8.8 Hz, ArH), 6.62 (1H, t, JZ7.4 Hz, ArH), 7.05
(2H, dd, JZ7.4, 8.8 Hz, ArH), 7.20–7.28 (4H, m, ArH). 13C
NMR (CDCl3, 75 MHz): d 20.8, 24.4, 46.9, 52.1, 65.8,
113.3, 117.5, 128.2, 129.0, 129.6, 133.2, 137.9, 146.6,
176.7. MS (EI) m/z: 317 (MC, 4.63), 216 (MCK101, 100),
180 (MCK137, 4.27), 104 (MCK213, 13.22), 77 (MCK
240, 19.37). Anal. Calcd for C18H20ClNO2 requires C,
68.03; H, 6.34; N, 4.41. Found: C, 68.26; H, 6.33; N, 4.40%.
phenylamino)propionic acid methyl ester 4f. A white
solid, 61 mg, yield 58%. Mp 108–110 8C. IR (CHCl3): n
1
1714, 1616, 1519, 1495, 1437, 1266, 1124, 785 cmK1. H
NMR (CDCl3, TMS, 300 MHz): d 1.17 (3H, s, CH3), 1.30
(3H, s, CH3), 3.66 (3H, s, OCH3), 4.46 (1H, s, CH), 5.14
(1H, s, NH), 6.60 (1H, d, JZ8.1 Hz, ArH), 6.72 (1H, s,
ArH), 6.82 (1H, d, JZ8.1 Hz, ArH), 7.11 (1H, t, JZ8.1 Hz,
ArH), 7.21–7.33 (5H, m, ArH). 13C NMR (CDCl3,
75 MHz): d 21.1, 25.0, 47.1, 52.4, 64.9, 110.0 (q, JZ
4.1 Hz), 114.1 (q, JZ4.2 Hz), 116.2, 117.7 (q, JZ
277.5 Hz), 127.9, 128.4, 128.4, 129.7, 129.9 (q, JZ
10.1 Hz), 138.7, 147.3, 177.1. MS (EI) m/z: 351 (MC,
2.16), 250 (MCK101, 100), 172 (MCK179, 11.97), 145
(MCK206, 15.63). Anal. Calcd for C19H20F3NO2 requires
C, 64.95; H, 5.74; N, 3.99. Found: C, 65.06; H, 5.88; N,
3.95%.
2.4.3. 2,2-Dimethyl-3-(4-nitrophenyl)-3-phenylamino-
propionic acid methyl ester 4c. A yellow solid, 64 mg,
yield 65%. Mp 103–105 8C. IR (CHCl3): n 1728, 1603,
1507, 1523, 1438, 1266, 1139, 853 cmK1. 1H NMR (CDCl3,
TMS, 300 MHz): d 1.18 (3H, s, CH3), 1.32 (3H, s, CH3),
3.67 (3H, s, OCH3), 4.57 (1H, d, JZ7.1 Hz, CH), 4.90 (1H,
d, JZ7.1 Hz, NH), 6.45 (2H, d, JZ8.6 Hz, ArH), 6.64 (1H,
t, JZ7.5 Hz, ArH), 7.06 (2H, dd, JZ7.5, 8.6 Hz, ArH), 7.49
(2H, d, JZ8.9 Hz, ArH), 8.16 (2H, d, JZ8.9 Hz, ArH). 13C
NMR (CDCl3, 75 MHz): d 21.1, 24.5, 46.8, 52.3, 64.2,
113.3, 118.0, 123.3, 129.1, 129.2, 146.1, 147.4, 147.5,
176.2. MS (EI) m/z: 328 (MC, 5.74), 227 (MCK101, 100),
181 (MCK147, 37.21), 168 (MCK160, 8.99), 77 (MCK
251, 19.42). Anal. Calcd for C18H20N2O4 requires C, 65.84;
H, 6.14. N, 8.53. Found: C, 65.99; H, 6.14; N, 8.44%.
2.5. Typical reaction procedure for the Mannich-type
reaction in fluorous phase
A solution of Yb(OPf)3 [(C8F17SO3)3Yb] (25 mg,
0.025 mmol) in perfluorodecalin (C10F18, cis- and trans-
mixture) (1.0 mL) was added to a solution of 2-aminophenol
(33 mg, 0.3 mmol) and benzaldehyde (31 mL, 0.3 mmol) in
a mixture solvent of hexane (1.0 mL) and tetrahydrofuran
(0.5 mL). Then, (1-methoxy-2-methyl-propenyloxy)tri-
methylsilane (90 mL, 0.45 mmol) was added to the reaction
mixture under stirring. The mixture was stirred at 20 8C for
8 h. Then, the reaction mixture was washed by dichloro-
methane (3!2 mL). And the fluorous phase was separated
for the next reaction. The solvent of organic layer was
removed under reduced pressure and the residue was
purified by column chromatography on silica gel (EtOAc–
hexaneZ1:10) to give the product.
2.4.4. 3-(4-Methoxyphenyl)-2,2-dimethyl-3-phenyl-
aminopropionic acid methyl ester 4d. A yellowish oil,
66 mg, yield 70%. IR (CHCl3): n 1727, 1603, 1510, 1265,
1
1178, 1034 cmK1. H NMR (CDCl3, TMS, 300 MHz): d
1.15 (3H, s, CH3), 1.25 (3H, s, CH3), 3.65 (3H, s, OCH3),
3.76 (3H, s, OCH3), 4.44 (1H, s, CH), 4.74 (1H, s, NH), 6.49
(2H, d, JZ8.4 Hz, ArH), 6.59 (1H, t, JZ7.4 Hz, ArH), 6.81
(2H, d, JZ8.7 Hz, ArH), 7.04 (2H, dd, JZ7.4, 8.4 Hz,
ArH), 7.18 (2H, d, JZ8.7 Hz, ArH). 13C NMR (CDCl3,
75 MHz): d 20.9, 24.7, 47.4, 52.3, 55.4, 64.0, 113.6, 113.7,
117.4, 129.2, 129.5, 131.4, 147.2, 159.1, 177.3; MS (EI)
m/z: 313 (MC, 3.08), 212 (MCK101, 100), 168 (MCK145,
6.10), 104 (MCK209, 15.95), 77 (MCK236, 14.87).
HRMS (Maldi) calcd for C19H24O3N (MCC1) requires
314.1756. Found: 314.1751.
2.5.1.
3-(2-Hydroxyphenylamino)-2,2-dimethyl-3-
phenyl-propionic acid methyl ester 6a. A white solid;
84 mg, yield 93%. This is a known compound. Its 1H NMR
spectroscopic data are in consistent with those reported in
literature (Ref. Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am.
1
Chem. Soc. 2000, 122, 34, 8180–8186). H NMR (CDCl3,
TMS, 300 MHz): d 1.21 (3H, s, CH3), 1.24 (3H, s, CH3),
3.69 (3H, s, OCH3), 4.55 (1H, s, CH), 4.87 (1H, s, NH), 5.21
(1H, s, OH), 6.38–6.70 (4H, m, ArH), 7.22–7.29 (4H, m,
ArH).
2.4.5. 3-(4-Fluorophenylamino)-2,2-dimethyl-3-phenyl-
propionic acid methyl ester 4e. A white solid, 59 mg,
yield 66%. Mp 89–91 8C. IR (CHCl3): n 1727, 1591, 1493,
2.5.2. 3-(4-Methylphenyl)-3-(2-hydroxyphenylamino)-
2,2-dimethylpropionic acid methyl ester 6b. A white
solid; 68 mg, yield 73%. This is a known compound. Its 1H
NMR spectroscopic data are in consistent with those
reported in literature (Ref. Yamashita, Y.; Ueno, M.;
Kuriyama, Y.; Kobayashi, S. Adv. Synth. Catal. 2002,
1
1265, 1150 cmK1. H NMR (CDCl3, TMS, 300 MHz): d
1.15 (3H, s, CH3), 1.28 (3H, s, CH3), 3.66 (3H, s, OCH3),
4.41 (1H, d, JZ7.3 Hz, CH), 5.02 (1H, d, JZ7.3 Hz, NH),
6.15 (1H, dt, JZ2.8, 11.8 Hz, ArH), 6.25–6.31 (2H, m,
ArH), 6.96 (1H, dd, JZ8.1, 15.0 Hz, ArH), 7.23–7.29 (5H,
m, ArH). 13C NMR (CDCl3, 75 MHz): d 21.1, 24.9, 47.1,
52.3, 64.6, 100.3 (d, JZ25.5 Hz), 104.0 (d, JZ22.1 Hz),
109.5 (d, JZ2.4 Hz), 127.9, 128.4 (d, JZ3.6 Hz), 130.2,
130.3, 139.0, 149.0 (d, JZ11.0 Hz), 164.0 (d, JZ
254.7 Hz), 177.1. MS (EI) m/z: 301 (MC, 3.40), 200
(MCK101, 100), 122 (MCK179, 21.75), 95 (MCK206,
20.93), 77 (MCK224, 9.22). Anal. Calcd for C18H20FNO2
requires C, 71.74; H, 6.69; N, 4.65. Found: C, 71.80; H,
6.40; N, 4.53%.
1
344, 929–931). H NMR (CDCl3, TMS, 300 MHz): d 1.20
(3H, s, CH3), 1.24 (3H, s, CH3), 2.28 (3H, s, CH3), 3.68 (3H,
s, OCH3), 4.55 (1H, s, CH), 4.99 (1H, s, NH), 6.31–6.70
(4H, m, ArH), 7.20–7.26 (4H, m, ArH).
2.5.3. 3-(4-Methoxyphenyl)-3-(2-hydroxyphenylamino)-
2,2-dimethyl-propionic acid methyl ester 6c. A yellow
solid; 62 mg, yield 63%. IR (thin film): n 3421, 2954, 2926,
2853, 1712, 1610, 1514, 1487, 1448, 1392, 1369, 1269,
1
1193, 1140, 1120, 1104, 1010 cmK1. H NMR (CDCl3,
2.4.6.
2,2-Dimethyl-3-phenyl-3-(3-trifluoromethyl-
TMS, 300 MHz): d 1.20 (3H, s, CH3), 1.23 (3H, s, CH3),

4970
M. Shi et al. / Tetrahedron 61 (2005) 4965–4970
1994. (c) Pilli, R. A.; Russowsky, D. Trends Org. Chem. 1997,
6, 101. (d) Risch, N.; Arend, M.; Westermann, B. Angew.
Chem., Ind. Ed. 1998, 37, 1044–1070. (e) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856.
2. Pilli, R. A.; Russowsky, D. J. Chem. Commun. 1987,
1053–1054.
3.68 (3H, s, OCH3), 3.75 (3H, s, OCH3), 4.53 (1H, s, CH),
4.98 (1H, s, NH), 5.76 (1H, s, OH), 6.36–6.70 (4H, m, ArH),
7.17–7.24 (4H, m, ArH). 13C NMR (CDCl3, 75 MHz): d
19.9, 24.3, 47.4, 52., 55.1, 63.9, 113.3, 113.7, 114.1, 117.7,
120.9, 129.3, 130.9, 135.6, 144.2, 158.7, 177.9. MS (EI)
m/z: 65 (11.32), 73 (16.81), 80 (10.75), 115 (12.65), 120
(27.24), 197 (14.72), 276 (100), 277 (16.98), 278 (96.68),
279 (14.45), 377 (MC, 2.11). HRMS (MALDI): calcd for
C18H21NO3Br (MCC1) requires 378.0704, found:
378.0699.
3. (a) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem.
1995, 60, 717–722. (b) Pilli, R. A.; Russowsky, D. J. Org.
Chem. 1996, 61, 3187–3190.
4. (a) Kobayashi, S.; Ishitani, H.; Nagayama, S. Chem. Lett.
1995, 423–424. (b) Kobayashi, S.; Busujima, T.; Nagayama, S.
Synlett 1999, 545–546. (c) Ali, T.; Chauham, K. K.; Frost,
C. G. Tetrahedron Lett. 1999, 40, 5621–5624. (d) Iimura, S.;
Nobutou, D.; Manabe, K.; Kobayashi, S. Chem. Commun.
2003, 1644–1645. (e) Yamashita, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2002, 124, 3292–3392. (f) Ueno, M.; Kobayashi,
S. Org. Lett. 2002, 4, 3395–3397.
2.5.4. 3-(4-Chlorophenyl)-3-(2-hydroxyphenylamino)-
2,2-dimethylpropionic acid methyl ester 6d. A white
solid; 78 mg, yield 79%. This is a known compound. Its 1H
NMR spectroscopic data are in consistent with those
reported in literature (Ref. Ishitani, H.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180–8186).
1H NMR (CDCl3, TMS, 300 MHz): d 1.19 (3H, s, CH3),
1.24 (3H, s, CH3), 3.68 (3H, s, OCH3), 4.55 (1H, s, CH),
4.99 (1H, s, NH), 6.31–6.70 (4H, m, ArH), 7.20–7.26 (4H,
m, ArH).
5. (a) Zhu, D. W. Synthesis 1993, 953–954. (b) Wolf, E. D.;
Koten, G. V.; Deelman, B. Chem. Soc. Rev. 1999, 28, 37–41.
6. (a) Horvath, I. T.; Rabai, J. Science 1994, 266, 72–75. (b)
Horvath, I. T.; Kiss, G.; Cook, R. A.; Bond, J. E.; Stevens,
P. A.; Rabai, J.; Mozeliski, E. J. J. Am. Chem. Soc. 1998, 120,
3133–3143. (c) Fawcett, J.; Hope, E. G.; Kemmitt, R. D. W.;
Paige, D. R.; Russell, D. R.; Stuart, A. M.; Cole-Hamilton,
D. J.; Payne, M. J. Chem. Commun. 1997, 1127–1128. (d)
Curran, D. P. Angew. Chem. Int. Ed. 1998, 37, 1174–1196. (e)
Nakamura, H.; Linclau, B.; Curran, D. P. J. Am. Chem. Soc.
2001, 123, 10119–10120.
2.5.5. 3-(4-Bromophenyl)-3-(2-hydroxyphenylamino)-
2,2-dimethylpropionic acid methyl ester 6e. A yellow
solid; 74 mg, yield 66%. IR (thin film): n 3415, 2955, 2925,
1713, 1610, 1512, 1451, 1248, 1178, 1139, 1107, 1036 cmK1
.
1H NMR (CDCl3, TMS, 300 MHz): d 1.20 (3H, s, CH3),
1.24 (3H, s, CH3), 3.68 (3H, s, OCH3), 4.54 (1H, s, CH),
4.98 (1H, s, NH), 5.75 (1H, s, OH), 6.31–6.70 (4H, m, ArH),
7.15–7.41 (4H, m, ArH). 13C NMR (CDCl3, 75 MHz): d
20.0, 24.2, 47.1, 52.4, 63.9, 113.3, 114.2, 117.9, 121.1,
121.3, 130.0, 131.1, 135.3, 138.2, 143.9, 177.5. MS (EI)
m/z: 65 (1.99), 73 (4), 80 (2.01), 109 (3.07), 151 (3.60), 161
(2.45), 221 (2.46), 228 (100), 229 (17.11), 329 (MC, 2.11).
HRMS (MALDI): calcd for C19H24NO4(MCC1) requires
330.1705, found: 330.1708.
7. (a) Schneider, S.; Bannwarth, W. Angew. Chem. 2000, 112,
4292–4295. (b) Schneider, S.; Bannwarth, W. Helv. Chim.
Acta 2001, 84, 735–742.
8. For the preparation of perfluorinated rare earth metal catalysts
[Ln(OSO2C8F17)3, LnZYb, Sc], please see: Hanamoto, Y.;
Sugimoto, Y.; Jin, Y. Z.; Imanaga, J. Bull. Chem. Soc. Jpn.
1997, 70, 1239–1244. The reaction procedure: an excess
amount of a lanthanide(III) oxide (99.9% purity) was added to
an aqueous solution of C8F17SO3H (50% v/v) and the mixture
was heated at boiling temperature for 30 min to 1 h. The
mixture was filtered to remove the unreacted oxide. The water
was then removed from the filtrate under reduced pressure.
The resulting hydrate was dried by heating under vacuum at
180 to 200 8C for 48 h.
Acknowledgements
We thank the State Key Project of Basic Research (Project
973) (No. G2000048007), Chinese Academy of Sciences
(KGCX2-210-01), Shanghai Municipal Committee of
Science and Technology, and the National Natural Science
Foundation of China for financial support (20025206,
203900502, and 20272069).
9. For the preparation of perfluorinated alkali metal salt catalysts
[M(OSO2C8F17), MZLi, Na, K], please see: Corey, E. J.;
Shimoji, K. Tetrahedron Lett. 1983, 24, 169–172. The reaction
procedure: trifluoromethanesulfonic or heptadecafluoro-
octanesulfonic acid was added dropwise to a solution of the
carbonate salt in methanol at 0 8C. The reaction mixture was
stirred at room temperature for 30 min, then it was refluxed for
2 h. The clear solution was concentrated under reduced
pressure. The resulting white cake was dried at 125 8C for
2 h. The obtained product was recrystallized from methanol or
ethanol/diethyl ether.
References and notes
1. (a) Kleinman, E. F. In Trost, B. M., Fleming, I., Eds.;
Comprehensive Organic Synthesis; Pergamon: Oxford, 1991;
Vol. 2, pp 893–951. (b) Tramontini, M.; Angiolini, L. In
Mannich Bases. Chemistry and Uses; CRC: Boca Raton, FL,
10. The organic substrates in hexane is miscible with various
fluorous solvents upon heating at 60 8C.