Solvent-free imino-aldol three-component couplings on a conveniently-prepared and reusable phosphoric acid-silica gel support

Article abstract of DOI:10.1246/cl.2004.1308

A new solvent-free procedure for the synthesis of β-amino carbonyl compounds in generally moderate to excellent yields has been developed. Three-component Mannich-type couplings between aldehydes (aromatic, aliphatic, alicyclic, and heterocyclic), aromatic amines and silyl enol equivalents proceeded smoothly on a conveniently prepared and reusable phosphoric acid-silica gel solid support.

Full text of DOI:10.1246/cl.2004.1308

1308
Chemistry Letters Vol.33, No.10 (2004)
Solvent-free Imino-Aldol Three-component Couplings on a Conveniently-prepared
and Reusable Phosphoric Acid-Silica Gel Support
Sandra Lock, Norikazu Miyoshi, and Makoto Wadaꢀ
Department of Chemistry, Faculty of Integrated Arts and Sciences, University of Tokushima,
Minami-Josanjima, Tokushima, 770-8502
(Received July 22, 2004; CL-040861)
A new solvent-free procedure for the synthesis of ꢀ-amino
encourage uniform stirring characteristics as far as possible in
the presence of the liquid organic reagents. Thus, silica gel
(1200 mg) containing approximately 4 mmol of phosphoric acid
was vigorously stirred and then strongly heated in situ for 10 min
before adding 1a (1 mmol), 2a (1.1 mmol), and 3a (1.2 mmol)
in quick succession, but stirring overnight at 15 ꢁC under argon
afforded 2,2-dimethyl-3-phenyl-3-phenylaminopropionic acid
methyl ester (4a) in low yield (Entry 1, Table 1). In a similar re-
action, increasing the amount of 3a to 2.2 mmol gave little im-
provement (Entry 2, Table 1) but when we repeated this reaction,
having first extended the support heating period to 30 min, 4a
was obtained in 67% yield (Entry 3, Table 1).
carbonyl compounds in generally moderate to excellent yields
has been developed. Three-component Mannich-type couplings
between aldehydes (aromatic, aliphatic, alicyclic, and heterocy-
clic), aromatic amines and silyl enol equivalents proceeded
smoothly on a conveniently prepared and reusable phosphoric
acid-silica gel solid support.
The Lewis-acid catalyzed imino-aldol coupling of alde-
hydes with amines and silylated enol equivalents to form ꢀ-ami-
no carbonyl compounds is a key facet of organic synthesis.1 De-
velopment of aldol-type reactions, in recent years, has been in-
fluenced by an increasing pressure on the fine chemical industry
to adopt cleaner, more eco-friendly production methods2 and this
has resulted in the use of more benign solvents3 as well as new
procedures with solid-supported acid catalysts which can offer
ease of work up and opportunities for recycling.4,5
The combination of phosphoric acid with silica for use as a
solid acid catalyst is not a new one. Phosphoric acid immobilized
on silica produces a liquid-phase catalyst that has been widely
exploited over many years6 in reactions such as the isomerisation
of 1,2-epoxyalkanes,7 dehydration of alcohols,8 and the industri-
al hydration of ethylene.9 The form of the silica (often a gel or
diatomaceous earth), amount of phosphoric acid and preparation
method vary to meet the different acid strength requirements of
the individual reactions but an extensive period of heat treat-
ment, generally in a calcining oven at temperatures of 120 ꢁC
and above, tends to be a common step within each process.
As part of our continuing interest in the development of
imino-aldol reactions10 we chose to try a solvent-free approach,
using phosphoric acid supported on silica gel as a solid acid
catalyst and wish to disclose the results herewith.11
Table 1. The influence of varying the pre-heating time, acid
content of the support, and the amount of 3a on the synthesis
of 4a according to Eq 1
Heatinga
Time/min
Yield of
4a/%b
Entry
H3PO4/equiv.
3a/equiv.
1
2
3
4
5
6
7
8
9
10
00
4
00
1.2
2.2
00
28
37
67
30
00
00
2
1.9
00
84
00
00
86c
71d
60
00
00
00
00
1
00
—
30
2
—
00
40e
42f
00
aUsing a Hakko Heating Gun, No. 880B, AC 100 V ꢂ 800 W, 50/
60 Hz. bIsolated yield. cReaction performed at ꢂ5 ꢁC. dReaction per-
formed at 25 ꢁC. eUsing phosphoric acid alone. fUsing silica gel alone.
A further improvement in yield (to 84%, Entry 4, Table 1)
was obtained when the content of phosphoric acid in the support
was halved, while maintaining the same period of pre-reaction
heat treatment using the hot air gun, and a similar amount of silyl
reagent. It is noteworthy that reducing the amount of phosphoric
acid would also have reduced the initial water content that nat-
urally accompanies the reagent. Thus it is possible that the lower
water content at the outset may have contributed to the fairly
substantial increase in yield.14 Reducing the reaction tempera-
ture had a beneficial effect (Entry 5, Table 1) but an increase
in the reaction temperature was disadvantageous (Entry 6,
Table 1). A further decrease in the amount of phosphoric acid
in the support also had a detrimental effect (Entry 7, Table 1)
and poor yields of the required product were obtained when each
of the components of the support was used alone (Entries 8 and
9, Table 1).15
OSiMe
3
Ph
OMe
HN
O
3a
PhCHO + PhNH
2
Ph
OMe
(1)
H PO -SiO
3
4
o
2
1 equiv.
Ar, 15 C, 16 h
1a
2a
4a
We began the investigation with a test reaction between
benzaldehyde (1a), aniline (2a) and [(1-methoxy-2-methyl-1-
propenyl)oxy]trimethylsilane (3a) (Eq 1). The support was pre-
pared simply by vigorously stirring chromatography grade silica
12
ꢀ
gel (60 A, 230–400 mesh) with the required amount of phos-
phoric acid (supplied by the manufacturer, Wako Pure Chemical
Industries, as an 85% aqueous solution) and then subjecting it to
a period of intense heating with a hot air gun before adding the
organic reagents when the support had cooled. A 1200-mg por-
tion13 was used in order to preserve a powdery consistency and
Encouraged by the higher yields obtained by using 2 mmol
of phosphoric acid in the support and by extending the pre-reac-
tion heating period, we examined the efficacy of recycling
(Table 2). The phosphoric acid-silica gel recovered from the ex-
periment that gave the product in 84% yield (Entry 4, Table 1)
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.10 (2004)
1309
was successfully recycled in three further identical experiments
with only a 10% loss of activity on the third occasion (Entry 3,
Table 2) compared to its initial use. For each repetition a period
of preliminary in situ heating of the support (20 min) was used
to drive off organic reagents remaining from the previous
experiment.
with the exception of 1i which coupled with 2a and 3a to give
4i in 82% yield (Entry 9, Table 3), more modest amounts result-
ed from the reactions between 2a, 3a, and aliphatic aldehydes
1h–1k (Entries 8–11, Table 3). The use of aromatic amines
2l–2n with 1a and 3a proved moderately successful under the re-
action conditions (Entries 12–14, Table 3) but a reaction be-
tween 1a, 3a, and 2o, the more strongly basic aliphatic amine,
gave none of the desired product.
The silyl enol ether 3p also behaved very poorly (Entry 16,
Table 3) giving acetophenone as the major product when it
was reacted with 1a and 2a. However, greater success was
achieved in reactions between 1a, 2a, and silyl reagents 3q
and 3r, giving 64 and 69% respectively, of the desired coupling
products (Entries 17 and 18, Table 3).
In conclusion, a convenient solvent-free procedure for per-
forming imino-aldol couplings, using a phosphoric acid-silica
gel solid acid support, has been developed which affords the re-
spective ꢀ-amino carbonyl compounds in generally moderate to
excellent yields. The reaction has demonstrated that a functional
and reusable solid acid can be readily produced from combining
phosphoric acid and silica gel without the need for extensive
preparation steps and we continue to investigate its synthetic
capabilities.
Table 2. The efficacy of recycling the support used in the
synthesis of 4a according to Eq 1, in the conditions shown in
Entry 4, Table 1a
Entry
Use of Support
Yield of 4a/%b
1
2
3
1st recycling
2nd recycling
3rd recycling
79
80
76
aRecovered phosphoric acid-silica gel (used initially in the experiment
that gave 84% of 4a (Entry 4, Table 1)) was strongly heated in situ with
a hot air gun for 20 min and stirred with 1a (1 mmol), 2a (1.1 mmol),
and 3a (1.9 mmol) under argon for 16 h at 15 ꢁC. bIsolated yield.
OSiMe
3
3
R
2
5
R
R
4
HN
O
4
R
3a,p−r.
1
2
R CHO + R NH
2
5
1
R
R
H PO -SiO
3
4
o
2
(2)
3
R
R
Ar, −5 C, 16 h
References and Notes
1a−k 2a,l−o
4a−r
1
E. F. Kleinman in ‘‘Comprehensive Organic Synthesis,’’ ed. by B. M. Trost,
Pergamon, Oxford (1991), Vol. 2, p 733.
P. Anastas and R. Lankey, Chem. Br., 37, 26 (2001).
a) T. Akiyama, J. Takaya, and H. Kagoshima, Tetrahedron Lett., 42,
4025 (2001). b) T. Akiyama, J. Itoh, and K. Fuchibe, Synlett, 2002, 1269.
c) T.-P. Loh, L.-C. Feng, and L.-L. Wei, Tetrahedron, 56, 7309 (2000).
S. Kobayashi and S. Nagayama, J. Am. Chem. Soc., 120, 2985 (1998).
S. Iimura, D. Nobutou, K. Manabe, and S. Kobayashi, Chem. Commun.,
2003, 1644.
The scope of the reaction using phosphoric acid-silica gel
was investigated with a range of aromatic and aliphatic alde-
hydes 1b–1k [p-methoxybenzaldehyde (1b), o-methoxybenzal-
dehyde (1c), p-tolualdehyde (1d), o-chlorobenzaldehyde (1e),
2-furaldehyde (1f), 2-thiophenecarboxaldehyde (1g), cyclohex-
anecarboxaldehyde (1h), isovaleraldehyde (1i), trans-cinnamal-
dehyde (1j), n-butyraldehyde (1k)], amines 2l–2o [o-anisidine
(2l), p-anisidine (2m), o-chloroaniline (2n), benzylamine (2o)]
and silyl reagents 3p–3r [1-phenyl-1-(trimethylsiloxy)ethylene
(3p), 1-methoxy-1-trimethylsilyloxypropene (3q), 1-trimethylsi-
lyloxycyclohexene (3r)] according to Eq 2.16
2
3
4
5
6
7
T. R. Krawietz, P. Lin, K. E. Lotterhos, P. D. Torres, D. H. Barich, A.
Clearfield, and J. H. Haw, J. Am. Chem. Soc., 120, 8502 (1998).
G. D. Yadav and D. V. Satoskar, J. Chem. Technol. Biotechnol., 69, 438
(1997).
8
9
G. P. Babu, R. S. Murthy, and V. Krishnan, J. Catal., 166, 111 (1997).
C. M. Fougret and W. F. Holderich, Appl. Catal., A, 207, 295 (2001).
¨
10 a) M. Wada, Chem. Lett., 1981, 153. b) H. Ohki, M. Wada, and K. Akiba,
Tetrahedron Lett., 29, 4719 (1988). c) M. Wada, J. Synth. Org. Chem.
Jpn., 11, 960 (1990). d) M. Wada, E. Takeichi, and T. Matsumoto, Bull.
Chem. Soc. Jpn., 64, 990 (1991). e) We found that solvent-free imino-aldol
reactions proceeded on a B2O3-SiO2 support and results were presented at
the 83rd Annual Meeting of the Chemical Society of Japan, Tokyo, March
2003, Abstr., No. 3H6-45.
The corresponding ꢀ-amino carbonyl compounds 4, were
obtained in good to excellent yields from coupling aromatic al-
dehydes, 1a–1g with 2a and 3a (Entries 1–7, Table 3) while,
Table 3. The synthesis of 4 according to Eq 2 in the presence of
a phosphoric acid-silica gel solid support
11 Presented at the 84th Annual Meeting of the Chemical Society of Japan,
Kobe, March 2004, Abstr., No. 3K2-11.
Entry
R1
R2
R3
R4
R5
4/%a
12 Reactions using silica gels of various pore and mesh sizes revealed that
reducing the mesh size reduced the product yield, whereas changing the
pore size had comparatively little effect.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
C6H5
p-MeOC6H4
o-MeOC6H4
p-MeC6H4
o-ClC6H4
2-furyl
2-thiophene
cyclohexyl
Ph
00
Me Me OMe
4a/86
4b/84
4c/94
4d/90
4e/71
4f/88
4g/82
4h/59
4i/82
4j/60
4k/49
4l/69
4m/60
4n/53
4o/—
4p/7
4q/64b
4r/69b
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
H
00
00
00
00
13 R. Hiroi, N. Miyoshi, and M. Wada, Chem. Lett., 2002, 274.
14 In a reaction performed at ꢂ5 ꢁC, deliberate addition of water (1 mmol) to
the prepared support, before adding the organic reagents, afforded only
40% of 4a. When no water was added, but the pre-formed imine, N-ben-
zylidineaniline was used, coupling with 3a gave 4a in 84% yield.
15 Presented at the 81st Annual Meeting of the Chemical Society of Japan,
Tokyo, March 2002, Abstr., No. 2G9-09. Silica gel is an established
dehydrating reagent but its effect, in the present study, is unknown.
16 A typical reaction procedure: To a mixture (1200 mg) of H3PO4 (2 mmol)
and silica gel, vigorously stirred, then strongly heated in situ with a
hot air gun for 30 min under vacuum and cooled to ꢂ5 ꢁC in argon, were
added aniline (110.8 mg, 1.19 mmol), p-tolualdehyde (114.5 mg, 0.95 mmol)
and [(1-methoxy-2-methyl-1-propenyl)oxy]trimethylsilane (345.8 mg, 1.98
mmol) in quick succession. After stirring for 16 h at ꢂ5 ꢁC the mixture
was washed with diethyl ether (20 cm3), filtered through a plug of cotton
wool and, after evaporation of solvent, the organic residue was purified
by TLC (n-hexane:ethyl acetate = 7:1 as an eluent) to give 2,2-dimethyl-
3-phenylamino-3-p-tolylpropionic acid methyl ester (255 mg, 90%) as a
yellow solid.
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
(CH3)2CHCH2
C6H5CH=CH
CH3CH2CH2
00
00
00
00
00
00
00
o-MeOC6H4
p-MeOC6H4
o-ClC6H4
benzyl
Ph
00
00
Ph
00
00
00
00
00
00
00
00
00
00
00
00
H
Me
H
Ph
OMe
00
00
00
00
–(C4H8)–
aIsolated yield. bsyn:anti ratio, 50:50.
Published on the web (Advance View) September 11, 2004; DOI 10.1246/cl.2004.1308