Synthesis of β-amino esters by bismuth triflate catalyzed three-component Mannich-type reaction

Article abstract of DOI:10.1055/s-2005-923594

We have developed an efficient, bismuth-catalyzed, Mannich-type three-component reaction by combining the corresponding aldehyde, amine, and silyl ketene acetal. The reaction proceeds rapidly and affords the corresponding β-amino esters in high yields (up

Full text of DOI:10.1055/s-2005-923594

LETTER
219
Synthesis of b-Amino Esters by Bismuth Triflate Catalyzed Three-Component
Mannich-Type Reaction
Synthesis of
b
-A
h
minoEstersierry Ollevier,* Etienne Nadeau
Département de Chimie, Université Laval, Québec, Québec G1K 7P4, Canada
Fax +1(418)6565034; E-mail: thierry.ollevier@chm.ulaval.ca
Received 31 October 2005
attractive because it is commercially available or can be
Abstract: We have developed an efficient, bismuth-catalyzed,
Mannich-type three-component reaction by combining the corre-
sponding aldehyde, amine, and silyl ketene acetal. The reaction pro-
ceeds rapidly and affords the corresponding b-amino esters in high
yields (up to 90%).
easily prepared from commercially available starting ma-
terials.14
As a part of our ongoing interest in bismuth(III)-catalyzed
multicomponent reactions involving silyl nucleophiles
(allyl silanes and silyl enol ethers),7,15 we report herein a
three-component bismuth(III)-catalyzed Mannich-type
reaction of silyl ketene acetals. A major merit of the three-
component reaction is indeed that many unique structures
can be afforded rapidly when three or more reactants are
combined in a single step to afford new compounds. We
wish to disclose our results in this area: the development
of an efficient, bismuth-catalyzed Mannich-type three-
component reaction that combines an aldehyde, aniline,
and a silyl ketene acetal to afford compounds with a b-
amino ester core structure. b-Amino esters are obtained
efficiently in the presence of 2 mol% of Bi(OTf)3·nH2O
(with 1 < n < 4).
Key words: amino esters, bismuth, green chemistry, Mannich-type
reaction, multicomponent reactions (MCR), silyl enolates
The development of new methods for the synthesis of b-
amino carbonyl derivatives is an important area of syn-
thetic efforts. b-Amino ketones and esters are extremely
important compounds as biologically active molecules.1
The Lewis acid-mediated reactions of imines with silyl
enolates are among the most efficient for the synthesis of
b-amino carbonyl compounds. Therefore, the develop-
ment of new catalytic methods for their preparation is of
first importance in organic synthesis. Catalytic Mannich-
type reactions have been reported by several groups as an
efficient method to prepare b-amino carbonyl com-
pounds.1,2 However, many imines tend to be unstable dur-
ing purification by chromatography, distillation, or
prolonged storage. Thus, it is desirable from a synthetic
point of view that imines, formed in situ from aldehydes
and amines, immediately react with silyl enolates and pro-
vide b-amino esters in a one-pot process.3,4 Nevertheless,
most Lewis acids cannot be used in this reaction because
they decompose or deactivate in the presence of the
amines and water produced during imine formation.
Recently, synthetic methods involving rare-earth and
lanthanide triflates as catalysts for Mannich-type reac-
tions have been reported.4 High catalytic activity, low
toxicity, and moisture- and air-tolerance make lanthanide
triflates attractive catalysts. However, the high cost of
these catalysts restricts their use.
Table 1 Optimization of the Three-Component Bi(OTf)3-Catalyzed
Mannich-Type Reaction Involving Benzaldehyde, Aniline, and
(1-Phenoxyvinyloxy)trimethylsilanea
O
Bi(OTf)3·nH2O
(x mol%)
OSiMe3
Ph
Ph
+
NH
O
PhNH2
+
Ph
H
OPh
conditions
OPh
1a
2
3a
4a
Entry Catalyst Solvent
(mol%)
Temp
(°C)
Time
(h)
Yield of 4a
(%)b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
5
MeCN
Et2O
0
–78
–78
–78
1
64c
75
80
66
45
65
53
84
81
3.5
3.5
1.3
3.2
2
THF
CH2Cl2
ClCH2CH2Cl –11
Bismuth compounds too have attracted recent attention
due to their low toxicity, low cost, and good stability.5
Bismuth salts have been reported as catalysts for opening
of epoxides,6 allylation of imines,7 Mukaiyama aldol reac-
tions,8 formation and deprotection of acetals,9 Friedel–
Crafts reactions,10 Diels–Alder reactions,11 Fries rear-
rangement,12a Claisen rearrangement,12b and intramolecu-
lar Sakurai cyclizations.13 Bi(OTf)3 is particularly
THFd
THFe
THF
THF
–78
–78
–78
–78
5.5
3.5
2
a Conditions: benzaldehyde (1.0 equiv), aniline (1.0 equiv),
(1-phenoxyvinyloxy)trimethylsilane (3a, 1.2 equiv), Bi(OTf)3·nH2O,
benzaldehyde concentration = 0.50 M.
b Isolated yield.
c Conversion according to 1H NMR.
SYNLETT 2006, No. 2, pp 0219–0222
0
1.
0
2.
2
0
0
6
d Benzaldehyde concentration = 1.0 M.
e Benzaldehyde concentration = 0.25 M.
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923594; Art ID: S10405ST
© Georg Thieme Verlag Stuttgart · New York

220
T. Ollevier, E. Nadeau
LETTER
Initially, we screened various conditions for the one-pot (phenylamino)propanoate (4a) was obtained with the best
Mannich-type reaction of imine derived from benzalde- yield [1% mol of Bi(OTf)3·nH2O, –78 °C, 3.5 h, 80% of
hyde (1a) and aniline (2) with (1-phenoxyvinyloxy)tri- 4a; Table 1, entry 3]. With further optimization of the re-
methylsilane (3a) in the presence of Bi(OTf)3·nH2O action conditions, we found that either a lower or a higher
(Table 1). Among various polar solvents tested, acetoni- substrate concentration gave a decreased yield of the
trile, diethyl ether, dichloromethane, and dichloroethane product due to lower conversion (Table 1, compare en-
gave moderate to good yields of the expected product tries 6 and 7 with entry 3). Next, the effect of the catalyst
(Table 1, entries 1, 2, 4, 5). The best solvent was found to loading was examined in the test reaction, using tetrahy-
be tetrahydrofuran. In this solvent, phenyl 3-phenyl-3- drofuran at –78 °C. When the reaction was carried out
Table 2 Three-Component Bi(OTf)3-Catalyzed Mannich-Type Reactions with Various Silyl Ketene Acetalsa
Ph
Bi(OTf)3·nH2O
(2 mol%)
OSiMe3
XR3
NH
O
O
+
+
R1
PhNH2
Ph
XR3
THF
Ph
H
R1 R2
R2
1a
2
3
4a–j
Entry
3
Methodb
Time (h)
syn/antic
Product 4
Yield of 4 (%)d
OSiMe3
OPh
1
2
A
B
3.5
3
–
–
4a
4a
84
63
OSiMe3
3
4
A
B
8
1.5
–
–
4b
4b
67
83
OEt
OSiMe3
5
6
B
A
0.8
2.5
–
4c
85
81
OMe
OSiMe3
OEt
78:22
4d
Ph
E/Z = 78:22
OSiMe3
7
8
A
B
2.5
2
74:26
73:27
4e
4e
80
74
OMe
E/Z = 80:20
OSiMe3
9
B
1.7
–
4f
59
OMe
OSiMe3
SEt
10
11
B
B
1
24:76
78:22
4g
4h
89
83
E/Z = 5:95
OSiMe3
1.8
SEt
E/Z = >99:1
OSiMe3
12
13
B
B
1
1
–
–
4i
4j
85
90
StBu
OSiMe3
SEt
a Conditions: benzaldehyde (1.0 equiv), aniline (1.0 equiv), silyl ketene acetal (1.2 equiv), Bi(OTf)3·nH2O (0.02 equiv).
b Method A: reaction performed at –78 °C. Method B: addition of silyl ketene acetal at –78 °C, then reaction mixture was allowed to reach r.t.
after 0.15 h.
c The diastereoisomers were not separable by chromatography and the yield is of the mixture.
d Isolated yield.
Synlett 2006, No. 2, 219–222 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino Esters
221
with 2 mol% of Bi(OTf)3·nH2O, the product 4a was ob-
tained in better yield (Table 1, entry 8). An increased cat-
alyst loading (5 mol%) gave decreased yields (Table 1,
entry 9).
Table 3 Three-Component Bi(OTf)3-Catalyzed Mannich-Type
Reactions with Various Aldehydesa
Ph
NH
O
Bi(OTf)3·nH2O
(2 mol%)
OSiMe3
OMe
O
R
OMe
Several examples of Bi(OTf)3-catalyzed Mannich-type
reactions with various silyl ketene acetals are summarized
in Table 2. Silyl ketene acetals derived from various esters
were reacted with an equimolar mixture of benzaldehyde
(1a) and aniline (2). The corresponding b-amino esters 4
were obtained in good yields (Table 2). Silyl enolates
derived from esters as well as thioesters reacted smoothly
to give the adducts. No adducts between aldehydes and
the silyl enolates were observed in any reaction according
to NMR analysis of the crude reaction mixture. As for the
diastereoselectivity of the reaction, good results were
obtained with the following substrates. Moderate syn
selectivity was observed with [(E)-1-ethoxy-2-phenyl-
vinyloxy]trimethylsilane (Table 2, entry 6). [(E)-1-
Methoxyprop-1-enyloxy]trimethylsilane afforded the ex-
pected product with syn stereoselectivity (Table 2, entries
7, 8). While the anti adduct was produced preferentially
+
+
PhNH2
R
H
THF, –78 °C
to 25 °C
1
2
3c
4k–n
Entry
Aldehyde
Time
(h)
Product 4 Yield of 4
(%)b
CHO
CHO
1
2
4k
82
O2N
2
3
4
2
4l
70
61
38
MeO
Ph
2.5
1
4m
4n
CHO
CHO
with
[(Z)-1-(ethylthio)prop-1-enyloxy]trimethylsilane
a Conditions: aldehyde (1.0 equiv), aniline (1.0 equiv), (1-methoxy-2-
methylprop-1-enyloxy)trimethylsilane (1.2 equiv), Bi(OTf)3·nH2O
(0.02 equiv), addition of silyl ketene acetal at –78 °C, then reaction
mixture allowed to reach r.t. after 0.15 h.
(Table 2, entry 10), the syn adduct was obtained with [(E)-
1-(ethylthio)prop-1-enyloxy]trimethylsilane (Table 2, en-
try 11).
b Isolated yield.
Next, other aldehydes were tested and the results are sum-
marized in Table 3. Generally, excellent yields of b-ami-
no ester were obtained with 1.2 equivalents of (1-
methoxy-2-methylprop-1-enyloxy)trimethylsilane (3c)
and 0.02 equivalent of Bi(OTf)3·nH2O at –78 °C in THF.
Aromatic aldehydes as well as an a,b-unsaturated alde-
hyde reacted smoothly to give the corresponding b-amino
ester derivatives 4 in high yield (Table 3, entries 1–4). The
reaction worked well with a variety of aldehydes includ-
ing those bearing an electron-withdrawing group, and the
corresponding b-amino ester 4 was obtained with good
yields (Table 3, entry 1). Electron-rich p-methoxybenzal-
dehyde led to the desired product in moderately good
yield (Table 3, entry 2). Conjugated aldehydes were good
substrates as well (Table 3, entry 3). Aliphatic aldehydes
do not react under such conditions probably due to en-
amine formation, except cyclohexane carboxaldehyde,
protocol does not require prior isolation of the imine. The
b-amino ester is directly obtained, usually as a crystalline
product, in a one-pot process. Because of its numerous
benefits, this method for the one-pot synthesis of b-amino
esters using bismuth triflate catalysis should find utility in
the synthesis of biologically active compounds.
Acknowledgment
This work was financially supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the Fonds
Québécois de la Recherche sur la Nature et les Technologies
(FQRNT, Québec, Canada), the Canada Foundation for Innovation
(CFI), and Université Laval. E.N. thanks NSERC for a postgraduate
which afforded product 4n in poor yield (Table 3, entry scholarship. We thank Rhodia (Lyon, France) for a generous gift of
triflic acid and Sidech s.a. (Tilly, Belgium) for bismuth oxide.
4). Product 4n was obtained in a good crude yield, but a
decreased isolated yield was obtained due to decomposi-
tion on silica gel chromatography. Interestingly, we never
observed side reaction products such as aldol and deami-
nation products.
References and Notes
(1) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(2) For reviews of catalytic Mannich-type reactions:
In summary, we have found that the Mannich-type
reaction of in situ prepared imines proceeds smoothly
with silyl ketene acetals and a catalytic amount of
Bi(OTf)3·nH2O.16 This method offers several advantages
including mild reaction conditions, highly catalytic (2%)
process, and no formation of by-products. Moreover, our
(a) Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric
Catalysis, Supplement, Vol. 1; Springer: Berlin, 2004, 143–
150. (b) Cordova, A. Acc. Chem. Res. 2004, 37, 102.
(c) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int.
Ed. 1998, 37, 1044. (d) Kobayashi, S.; Sugiura, M.;
Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102, 2227.
(e) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
Synlett 2006, No. 2, 219–222 © Thieme Stuttgart · New York

222
T. Ollevier, E. Nadeau
LETTER
(15) Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292.
(16) General Procedure for the Bismuth-Catalyzed Mannich-
Type Reaction.
(3) For reviews of multicomponent reactions:
(a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Syamala, M. Org. Prep.
Proced. Int. 2005, 37, 103. For recent examples of
multicomponent reactions: (c) Chen, S.-L.; Ji, S.-J.; Loh, T.-
P. Tetrahedron Lett. 2003, 44, 2405. (d) Kobayashi, S.;
Iwamoto, S.; Nagayama, S. Synlett 1997, 1099.
Under an inert atmosphere of argon, the silyl ketene acetal
(1.2 mmol) in 1 mL of dry THF was added dropwise to a
solution of Bi(OTf)3·nH2O (0.02 mmol), the aldehyde
(distilled, except p-nitrobenzaldehyde; 1 mmol), and the
aniline (1 mmol) in 1 mL of dry THF at –78 °C. The mixture
was stirred at –78 °C (Method A) or stirred at –78 °C for
0.15 h and then allowed to reach r.t. (Method B). The
mixture was stirred until the reaction was completed as
indicated by TLC. The reaction was quenched with H2O (4
mL) and extracted with Et2O (3 × 20 mL). The organic phase
was washed with H2O and sat. aq NaCl, dried over MgSO4,
and concentrated under vacuum (rotary evaporator). If the
crude product was a solid, it was triturated with hexane (10
mL) and filtered; otherwise, it was purified by column
chromatography (eluent hexane–EtOAc). The spectral data
for 4b–h,j–n match with those reported in the literature.
Phenyl 3-Phenyl-3-(N-phenylamino)propanoate (4a).
Reagents: benzaldehyde (102 mL, 106 mg, 1.0 mmol),
aniline (91 mL, 93 mg, 1.0 mmol), (1-phenoxyvinyloxy)tri-
methylsilane (250 mg, 1.2 mmol), and Bi(OTf)3·nH2O (14
mg, 0.02 mmol). The reaction was stirred for 3.5 h at –78 °C
(Method A). The crude product was washed with hexane to
afford 265 mg (84%) of 4a as a white solid; mp 129–130 °C;
Rf = 0.55 (hexane–EtOAc = 4:1). IR (KBr): n = 3401, 1735
cm–1. 1H NMR (CDCl3): d = 7.44 (2 H, d, J = 7.6 Hz), 7.26–
7.38 (5 H, m), 7.21 (1 H, tt, J = 7.4, 1.3 Hz), 7.12 (2 H, dd,
J = 8.6, 7.4 Hz), 6.89–6.91 (2 H, m), 6.70 (1 H, t, J = 7.3
Hz), 6.61 (2 H, dd, J = 8.6, 1.0 Hz), 5.00 (1 H, t, J = 6.3 Hz),
4.59 (1 H, s), 3.07 (2 H, d, J = 6.6 Hz). 13C NMR (CDCl3):
d = 170.0, 150.6, 146.9, 141.9, 129.7, 129.5, 129.2, 128.00,
126.6, 126.3, 121.7, 118.3, 114.0, 55.3, 43.0. HRMS:
m/z calcd for C21H19NO2 [M+]: 317.1416; found: 317.1421.
(S)-tert-Butyl 3-Phenyl-3-(N-phenylamino)propane-
thioate (4i).
Reagents: benzaldehyde (102 mL, 106 mg, 1.0 mmol),
aniline (91 mL, 93 mg, 1.0 mmol), [1-(tert-butylthio)vinyl-
oxy]trimethylsilane (245 mg, 1.2 mmol), and Bi(OTf)3·nH2O
(14 mg, 0.02 mmol). The reaction was stirred for 0.15 h at
–78 °C, then allowed to reach r.t. for 1 h (Method B). The
crude product was washed with hexane to afford 265 mg
(85%) of 4i as an orange solid; mp 99–101 °C. Rf = 0.75
(hexane–EtOAc = 4:1). IR (KBr): n = 3391, 1664 cm–1. 1H
NMR (CDCl3): d = 7.29–7.38 (4 H, m), 7.24 (1 H, tt, J = 7.0,
2.4 Hz), 7.09 (2 H, dd, J = 8.4, 7.4 Hz), 6.67 (1 H, t, J = 7.3
Hz), 6.56 (2 H, d, J = 8.0 Hz), 4.79 (1 H, t, J = 6.7 Hz), 2.90
(2 H, d, J = 6.8 Hz), 1.40 (9 H, s). 13C NMR (CDCl3):
d = 198.3, 147.1, 142.3, 129.3, 129.0, 127.7, 126.5, 117.9,
113.9, 56.1, 52.3, 48.9, 29.9. HRMS: m/z calcd for
C19H23NOS [M+]: 313.1500; found: 313.1508.
(e) Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett 1999,
1426. (f) Iimura, S.; Nobutou, D.; Manabe, K.; Kobayashi,
S. Chem. Commun. 2003, 1644. (g) Lock, S.; Miyoshi, N.;
Wada, M. Chem. Lett. 2004, 33, 1308.
(4) (a) Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.;
Hachiya, I. Synlett 1995, 233. (b) Kobayashi, S.; Araki, M.;
Yasuda, M. Tetrahedron Lett. 1995, 36, 5773.
(c) Kobayashi, S.; Busujima, T.; Nagayama, S. Synlett 1999,
545. (d) Kobayashi, S.; Moriwaki, M.; Akiyama, R.; Suzuki,
S.; Hachiya, I. Tetrahedron Lett. 1996, 37, 7783.
(5) (a) Organobismuth Chemistry; Suzuki, H.; Matano, Y., Eds.;
Elsevier: Amsterdam, 2001. (b) Gaspard-Iloughmane, H.;
Le Roux, C. Eur. J. Org. Chem. 2004, 2517. (c) Leonard,
N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58,
8373.
(6) (a) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett. 2004,
45, 49. (b) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett.
2002, 43, 7891.
(7) Ollevier, T.; Ba, T. Tetrahedron Lett. 2003, 44, 9003.
(8) (a) Ollevier, T.; Desyroy, V.; Debailleul, B.; Vaur, S. Eur. J.
Org. Chem. 2005, 4971. (b) Le Roux, C.; Ciliberti, L.;
Laurent-Robert, H.; Laporterie, A.; Dubac, J. Synlett 1998,
1249.
(9) (a) Leonard, N. M.; Oswald, M. C.; Freiberg, D. A.; Nattier,
B. A.; Smith, R. C.; Mohan, R. S. J. Org. Chem. 2002, 67,
5202. (b) Carrigan, M. D.; Sarapa, D.; Smith, R. C.;
Wieland, L. C.; Mohan, R. S. J. Org. Chem. 2002, 67, 1027.
(10) (a) Le Roux, C.; Dubac, J. Synlett 2002, 181. (b) Desmurs,
J. R.; Labrouillère, M.; Le Roux, C.; Gaspard, H.;
Laporterie, A.; Dubac, J. Tetrahedron Lett. 1997, 38, 8871.
(c) Répichet, S.; Le Roux, C.; Dubac, J.; Desmurs, J. R. Eur.
J. Org. Chem. 1998, 2743.
(11) (a) Garrigues, B.; Oussaid, A. J. Organomet. Chem. 1999,
585, 253. (b) Laurent-Robert, H.; Garrigues, B.; Dubac, J.
Synlett 2000, 1160.
(12) (a) Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M. C.
Synlett 2004, 2794. (b) Ollevier, T.; Mwene-Mbeja, T. M.
Tetrahedron Lett. submitted.
(13) (a) Leroy, B.; Markó, I. E. Org. Lett. 2002, 4, 47. (b)Leroy,
B.; Markó, I. E. Tetrahedron Lett. 2001, 42, 8685.
(14) (a) Répichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.;
Dubac, J. Tetrahedron Lett. 2002, 43, 993. (b) Labrouillère,
M.; Le Roux, C.; Gaspard, H.; Laporterie, A.; Dubac, J.;
Desmurs, J. R. Tetrahedron Lett. 1999, 40, 285.
(c) Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Org. Process
Res. Dev. 2001, 5, 84. (d) Peyronneau, M.; Arrondo, C.;
Vendier, L.; Roques, N.; Le Roux, C. J. Mol. Catal. A:
Chem. 2004, 211, 89. (e) Bi(OTf)3·nH2O has been prepared
from Bi2O3 according to ref. 14a.
Synlett 2006, No. 2, 219–222 © Thieme Stuttgart · New York