HBF4 catalyzed Mannich-type reaction in aqueous media

Article abstract of DOI:10.1055/s-1999-2789

HBF₄ catalyzed Mannich-type reaction took place smoothly in aqueous media to afford β-amino carbonyl compounds in high yields. One-pot synthesis of β-amino carbonyl compounds from aldehyde and amine also worked well.

Full text of DOI:10.1055/s-1999-2789

LETTER
1045
HBF4 Catalyzed Mannich-Type Reaction in Aqueous Media
Takahiko Akiyama,* Jun Takaya, Hirotaka Kagoshima
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax+81-3-5992-1029; E-mail: takahiko.akiyama@gakushuin.ac.jp
Received 19 April 1999
Ph
Abstract: HBF4 catalyzed Mannich-type reaction took place
smoothly in aqueous media to afford b-amino carbonyl compounds
in high yields. One-pot synthesis of b-amino carbonyl compounds
from aldehyde and amine also worked well.
PhNH
Ph
O
OTMS
Acid
0 °C
N
+
Ph
Ph
Ph
1
2
Key words: Mannich-type reaction, aqueous reaction, HBF4, imino
aldol, aldimine
Table 1 Effect of acid
Entry Acid Amount
Solvent
Reaction timeYield/%
Lewis acid promoted addition of silyl enolates to imine,
Mannich-type reaction, is an efficient method for the
preparation of b-amino ketone or b-amino esters.1 It is one
of the most important basic reaction types in organic
chemistry. Nevertheless, because imines are generally
less reactive than ketone moiety, addition to imines have
been less extensively studied.2 Furthermore, equimolar
amount of Lewis acid was required quite often as a pro-
moter due to stronger basicity of nitrogen. Several novel
types of activator for the imine moiety have been reported
recently and have been applied to Mannich-type reaction.
For example, Kobayashi and co-workers found that scan-
dium and lanthanide triflates,3 which are water tolerant
Lewis acids, activate aldimines highly effectively and
Mannich-type reaction proceeded smoothly to afford b-
amino carbonyl compounds in high yields.4,5 Asymmetric
Mannich-type reaction employing Zr(IV),5 transition met-
al catalyst,6 and chiral acyl chloride have been reported.7
1
2
3
4
5
HBF4
HBF4
HBF4
HCl
0.1 CH3OH–H2O (30/1) 30 min
0.1 CH3CN–H2O (30/1) 30 min
96
84
79
54
16
89
0.1 CH3OH–H2O (4/1)
2 h
0.5 CH3CN–H2O (30/1) 30 min
0.2 CH3CN–H2O (30/1) 48 h
HF
6 p-TsOH 0.1 CH3OH–H2O (30/1) 30 min
a) 1.0 equiv of 1 was employed.
0 °C furnished a b-amino ketone (2) in 96% yield (Entry
1). Catalytic amount of HBF4 (10 mol%) promoted the
Mannich-type reaction smoothly. It is noted that present
addition reaction took place smoothly even in the pres-
ence of large amount of water (Entry 3). Aqueous HCl and
p-TsOH also worked well.
On the other hand, modern organic reactions are frequent-
ly promoted by Lewis acid in anhydrous organic solvent.8
Restraint on the use of organic solvents, in particular ha-
logenated solvents, is desired from the environmental
point of view. Aqueous media thus have attracted consid-
erable attention in the fields of synthetic organic chemis-
try.9,10 Except lanthanide triflate,3 common Lewis acids
are not compatible with aqueous media, and hence
Brønsted acid is a logical candidate as an activator in
aqueous media. Along the line, HCl catalyzed allylation
of carbonyl compounds with allyltin has been reported.11
Selected examples of the HBF4 catalyzed Mannich-type
reaction in aqueous media are shown in Table 2. Aldi-
mines derived from aromatic aldehyde and aniline under-
went addition reaction with 1 to afford b-amino ketones in
high yields (Entries 1, 2, and 4). An a,b-unsaturated aldi-
mine afforded exclusively 1,2-adduct and 1,4-adduct was
not observed (Entry 5). For the present addition reaction,
aldimine derived from aromatic amine must be employed
and an aldimine derived from aliphatic amine was not ef-
fective (Entry 3). Other silyl enol ethers worked well to
afford the corresponding b-amino ketones in high yields
though the stereoselectivity was modest (Entries 6 and 7).
Ketene silyl acetals were found to be effective as nucleo-
phile if the reactions were run at lower temperature (En-
tries 8, 9, and 10). An aldimine derived from glyoxylate
also worked well to give the corresponding adduct, which
is an amino acid derivative, in a high yield (Entry 11).
We wish to report herein that catalytic amount of HBF4 ef-
ficiently activate aldimines and addition of silyl enolate to
aldimine took place smoothly in aqueous media.12,13 Fur-
thermore, one-pot synthesis of b-amino ketone and b-ami-
no ester from aldehyde, amine, and a silyl enolate has
been achieved.
At the outset, benzylideneaniline and a trimethylsilyl enol
ether of acetophenone (1) (1.0 equiv) were allowed to re-
act with Brønsted acid in aqueous media and the results
are shown in Table 1. Simple addition of diluted aqueous
HBF4 to the solution of the aldimine and 1 in methanol at
Synlett 1999, No. 07, 1045–1048 ISSN 0936-5214 © Thieme Stuttgart · New York

1046
T. Akiyama et al.
LETTER
R1NH
R1
O
OTMS
R5
R2
HBF4 (10 mol%)
R3
N
+
R5
ROH-H2O (30:1 v/v)
R1
R4
R3 R4
Table 2 HBF4 catalyzed Mannich-type reaction
Entry
R1
Ph
Ph
R2
Ph
R3
H
R4
H
R5
Ph
Ph
Solvent
CH3OH
CH3OH
Conditions
Yield/%
1
2
0 °C, 30 min
0 °C, 1 h
96
88
p-CH3OC6H4
H
H
3
4
5
6
Ph
p-CH3C6H4
PhCH=CH
Ph
PhCH2
Ph
H
H
H
H
H
H
Ph
Ph
Ph
Ph
CH3OH
CH3OH
i-PrOH
CH3OH
0
0 °C, 3.5 h
0 °C, 30 min
85
Ph
H
0 °C, 3 h
0 °C, 3 h
69
Ph
Mea)
83d)
94e)
91
7
8
Ph
Ph
Ph
H
-(CH2)4-
CH3OH
i-PrOH
CH3OH
i-PrOH
i-PrOH
0 °C, 1 h
–40 °C, 1 h
–20 °C, 1.5 h
Ph
Ph
Me
Me
Phb)
Mec)
H
OMe
OMe
OEt
Ph
9
Ph
H
H
98f)
91g)
89
10
11
Ph
Ph
H
H
–40 °C, 30 min
0 °C, 1 h
EtOCO
p-CH3OC6H4
a) E:Z=3:97. b) E:Z= 76:24. c) E:Z=88:12. d) syn: anti= 63:37. e) syn:anti = 50:50. f) syn:anti= 52:48.
g) syn:anti =54:46. h) The amount of silyl enolate follows; 1.0 equiv for entry 1, 1.5 equiv fo entries
2–7, 11. 3.0 equiv for entries 8–10.
transition metal catalysis16 though common Lewis acids
(10 mol%)
Ph
activate aldehyde preferentially. Aldol reaction toward al-
dehyde did not proceed by means of HBF4. High
chemoselectivity is rationalized by considering the higher
basicity of nitrogen over oxygen.
OTMS
Ph
O
HBF4
N
+
+
CH3OH-H2O
(30:1, v/v)
0 °C, 30 min
Ph
Ph
1.0 eq.
1.0 eq.
1.0 eq.
Since imines, in particular aliphatic aldimines, are not sta-
ble and are difficult to purify, it would be synthetically
quite useful if imines, generated in situ from aldehyde and
amine, react with silyl enolates to afford b-amino carbon-
yl compounds in one vessel. Judging from the high
chemoselectivity of the present reaction towards aldimine
in the presence of aldehyde, we expected that three-com-
ponent synthesis of b-amino ketone could be achieved.
Results of the one-pot Mannich-type reaction is shown in
Table 3. Aliphatic aldimines as well as aromatic aldimine
underwent Mannich-type reaction smoothly to afford the
corresponding adducts in good to high yields.17 It is noting
that imines were formed even in the presence of water
quickly4a,18 and silyl enolates were stable enough to react
under the present reaction conditions. Phenylglyoxal
monohydrate, which possesses water of crystallization,
afforded the addition product in 91% yield (entry 12). As
PhNH
O
HO
O
+
Ph
Ph
Ph
Ph
96%
0%
Scheme 1
Another characteristic feature of the present addition reac-
tion is high chemoselectivity toward aldimine in the pres-
ence of aldehyde as shown in Scheme 1. It was found
recently that selective activation of imine could be
achieved under the influence of lanthanide triflates14,15 or
Synlett 1999, No. 07, 1045–1048 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
HBF4 Catalyzed Mannich-Type Reaction in Aqueous Media
1047
the operation is very simple, 5) use of halogenated solvent
is avoided and environmentally-conscious.
OTMS
R4
R2
R1CHO
+ PhNH2 +
R3
References and Notes
3; R2=R3=H, R4=Ph
(1) a) Kleinman, E. F.; Volkmann. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon Press:
Oxford, 1991; Vol. 2; pp. 975. b) Overman, E.; Ricca, D., J. In
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Ed. Engl. 1998, 37, 1044.
(2) a) Ojima, I.; Inaba, S.; Yoshida, K. Tetrahedron Lett. 1977,
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Kashiwagi, K.; Matsui, S. Chem. Lett. 1989, 1397.
e) Mukaiyama, T.; Akamatsu, H.; Han, J. S. Chem. Lett. 1990,
889. f) Onaka, M.; Ohno, R.; Yanagiya, N.; Izumi, Y. Synlett
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M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc.
1994, 116, 10520.
4; R2=H, R3=Ph, R4=OMe (E:Z=88:12)
5; R2= R3= Me, R4=OMe
PhNH
O
HBF4 (10 mol%)
ROH-H2O (30:1/v:v)
R1
R4
R2
R3
Table 3 Three-Component Synthesisa)
R1 Silyl enolate Solvent Conditions Yield/%
Entry
0 °C, 1.5 h
0 °C, 1.5 h
CH3OH
CH3OH
CH3CN
i-PrOH
90
84
89
69
Ph
3
3
1
2
p-CH3C6H4
(3) For reviews; a) Kobayashi, S. Synlett 1994, 689.
b) Kobayashi, S. Eur. J. Org. Chem 1999, 15. c) Kobayashi,
S. Chem. Soc. Rev. 1999, 28, 1.
p-NO2C6H4
PhCH=CH
3
3
3
4
5
0 °C, 2 h
0 °C, 3 h
(4) a) Kobayashi, S.; Ishitani, H. J. Chem. Soc., Chem. Commun.
1995, 1379. b) Kobayashi, S.; Araki, M.; Yasuda, M.
Tetrahedron Lett. 1995, 36, 5773. c) Kobayashi, S.; Ishitani,
H.; Komiyama, S.; Oniciu, D. C.; Katritzky, A. R.
Tetrahedron Lett. 1996, 37, 3731. d) Kobayashi, S.; Iwamoto,
S.; Nagayama, S. Synlett 1997, 1099. e) Kobayashi, S.; Furuta,
T.; Sugita, K.; Oyamada, H. Synlett 1998, 1019. f) Kobayashi,
S.; Furuta, T.; Sugita, K.; Okitsu, O.; Oyamada, H.
Tetrahedron Lett. 1999, 40, 1341.
(5) a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
1997, 119, 7153. b) Kobayashi, S.; Ishitani, H.; Ueno, M. J.
Am. Chem. Soc. 1998, 120, 431. c) Ishitani, H.; Kitazawa, T.;
Kobayashi, S. Tetrahedron Lett. 1999, 40, 2161.
c-C6H11
3
3
CH3CN
i-PrOH
79
60
0 °C, 1 h
0 °C, 6 h
PhCH2CH2
PhCH2OCH2
PhCO
6
7
8
9
i-PrOH
i-PrOH
i-PrOH
i-PrOH
70
3
3
3
4
0 °C, 2 h
0 °C, 3.5 h
0 °C, 1.5 h
–20 °C, 1 h
91
EtOCO
55
10 PhCH2CH2
81b)
(6) a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc.
1998, 120, 2474. b) Ferraris, D.; Young, B.; Dudding, T.;
Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548.
(7) Müller, R.; Goesmann, H.; Waldmann, H. Angew. Chem., Int.
Ed. Engl. 1999, 38, 184.
11
12
Ph
5
5
i-PrOH
CH3CN
99
89
–40 °C, 1 h
–40 °C, 1 h
c-C6H11
13 PhCH2CH2
PhCH2OCH2
5
5
i-PrOH
i-PrOH
80
82
–40 °C, 1 h
–40 °C, 1 h
(8) Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in
Organic Synthesis, CRC Press: Boca Raton 1995.
(9) For reviews; a) Reissig, H. -U. In Organic Synthesis
Highlights; VCH, Weinheim 1991; pp. 71. b) Li, C.-J. Chem.
Rev. 1993, 93, 2023. c) Li, C.-J.; Chan, T.-H. Organic
Reactions in Aqueous Media, John Wiley, New York 1997.
d) Lubineau, A.; Augé, J.; Queneau, Y. Synthesis 1994, 741.
d) Li, C.-J. Tetrahedron 1996, 52, 5643.
14
a) The molar ratio of aldehyde, amine, and silyl enolate
is 1.0:1.0:1.5 for entries 1–9,1.0:1.0:3.0 for entries
10–14. b) syn:anti=73:27.
(10) Recent examples of the synthetic reactions in aqueous media;
a) Li, C.-J. Tetrahedron 1996, 52, 5643. b) Li, X.; Loh,
T.Tetrahedron: Asymmetry 1996, 7, 1535. c) Loh, T.-P.; Pei,
J.; Cao, G.-Q. J. Chem. Soc., Chem. Commun. 1996, 1819.
d) Loh, T. P.; Pei, J.; Lin, M. J. Chem. Soc., Chem. Commun.
1996, 2315. e) Wada, M.; Fukuma, T.; Morioka, M.;
Takahashi, T.; Miyoshi, N. Tetrahedron Lett. 1997, 38, 8045.
f) Kobayashi, S.; Nagayama, S.; Busujima, T. Chem. Lett.
1997, 959. g) Li, C. J.; Zhang, W. C. J. Am. Chem. Soc. 1998,
120, 9102. h) Kobayashi, S.; Nagayama, S.; Busujima, T.
Chem. Lett. 1999, 71.
a nucleophile, not only silyl enol ether as well as ketene
silyl acetal were found to be quite effective if the reactions
were carried out at lower temperature.
In summary, we found the first Brønsted acid promoted
Mannich-type reaction in aqueous media. Salient features
of the present reactions are; 1) aqueous HBF4, which is a
cheap Brønsted acid, could be used, 2) aldimine may be
formed in situ in the presence of water, 3) aldimine de-
rived from aliphatic aldehyde worked pretty well, 4) thus
(11) a) Yanagisawa, A.; Inoue, H.; Morodome, M.; Yamamoto, H.
J. Am. Chem. Soc. 1993, 115, 10356. b) Yanagisawa, A.;
Morodome, M.; Nakashima, H.; Yamamoto, H. Synlett 1997,
1309.
Synlett 1999, No. 07, 1045–1048 ISSN 0936-5214 © Thieme Stuttgart · New York

1048
T. Akiyama et al.
LETTER
(12) Brønsted mediated Mannich reaction; see, Blatt, A. H.; Gross,
N. J. Org. Chem. 1964, 29, 3306.
(13) Sodeoka and co-workers recently reported a example of
Mannich-type reaction, which proceeded under the influence
of HBF4, generated by mixing AgBF4, TMSCl, and trace
amount of H2O.6a
(14) a) Kobayashi, S.; Nagayama, S. J. Org. Chem. 1997, 62, 232.
b) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1997, 119,
10049.
for 30 min. To the solution was added a silyl ketene acetal (3)
(0.1 mL, 0.492 mmol) and 4.3 wt% solution HBF4 in water
(34.0 mL, 0.167 mM) at that temperature. After being stirred at
that temperature for 45 min, the reaction was quenched by
addition of water. The aqueous layer was extracted with
CH2Cl2 and the combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated to
dryness. Purification of the crude mixture by preparative TLC
(SiO2, hexane:ethyl acetate = 5:1, v/v) gave a b-amino ester
(42.7 mg, 0.166 mM) in a quantitative yield.
(15) Akiyama, T.; Iwai, J. Synlett 1998, 273.
(16) Preferencial activation of aldimine in the presence of
aldehyde; a) Nakamura, H.; Asao, N.; Yamamoto, Y. J. Chem.
Soc., Chem. Commun. 1995, 1273. b) Nakamura, H.; Iwama,
H.; Yamamoto, Y.J. Am. Chem. Soc. 1996, 118, 6641.
(17) A typical experimental procedure for Entry 10 of Table 3. A
solution of aniline (15.0 mL, 0.165 mM) and benzaldehyde
(17.0 mL, 0.167 mM) in i-PrOH (1.0 mL) was stirred at –40 °C
(18) Kobayashi, S.; Busujima, T.; Nagayama, S. J. Chem. Soc.,
Chem. Commun. 1998, 19.
Article Identifier:
1437-2096,E;1999,0,07,1045,1048,ftx,en;Y09699ST.pdf
Synlett 1999, No. 07, 1045–1048 ISSN 0936-5214 © Thieme Stuttgart · New York