A highly selective synthesis of 3-hydroxy-2-methylpropionamide involving a one-pot tandem hydroformylation-hydrogenation sequence

Article abstract of DOI:10.1039/b510813f

3-Hydroxy-2-methylpropionamide, an important intermediate in the synthesis of methyl methacrylate, has been obtained with excellent conversion and high selectivity from acrylamide by a tandem hydroformylation-hydrogenation sequence catalysed by Rh/PPh₃ and Raney Ni, respectively. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b510813f

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COMMUNICATION
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A highly selective synthesis of 3-hydroxy-2-methylpropionamide
involving a one-pot tandem hydroformylation–hydrogenation sequence{
Luis Garc´ıa, Carmen Claver, Montserrat Die´guez* and Anna M. Masdeu-Bulto´*
Received (in Cambridge, UK) 29th July 2005, Accepted 11th October 2005
First published as an Advance Article on the web 16th November 2005
DOI: 10.1039/b510813f
We started by studying the best conditions for the hydro-
formylation part of the tandem hydroformylation–hydrogenation
sequence. So far, hydroformylation has been mainly investigated
for simple olefinic hydrocarbons6 and less so for functionalised
substrates such as 3. In recent years, however, great efforts have
been made to hydroformylate functionalised substrates which are
of interest for the synthesis of both chemical commodities and
biologically-active compounds.7 For example, unsaturated amides
can be hydroformylated as a tool for the synthesis of a-amino-
acids8 and lactams.9 Despite of this interest, few examples are
known.8,9 This is due to the difficulties of controlling simulta-
neously the chemo- and regioselectivity of the reaction for these
kinds of substrate. These substrates are also prone to hydrogena-
tion and polymerization under hydroformylation conditions.9,10
For example, the hydroformylation of methacrylamide gives an
equimolar mixture of hydrogenated and intramolecular condensa-
tion products, together with high amounts of polymerized
material.9
3-Hydroxy-2-methylpropionamide, an important intermediate
in the synthesis of methyl methacrylate, has been obtained with
excellent conversion and high selectivity from acrylamide by a
tandem hydroformylation–hydrogenation sequence catalysed
by Rh/PPh3 and Raney Ni, respectively.
Methyl methacrylate is an important industrial product for
preparing acrylic resins and custom plastics, among other
products.1 The industrial process for producing methyl methacry-
late is the reaction of acetone with hydrogen cyanide to form the
corresponding cyanohydrin, which is then transformed to methyl
acrylamide and then esterified.2 The problems of this process are
associated with the handling of highly toxic HCN and the
generation of high amounts of waste. Alternative high-performing
processes are constantly being sought, one of them being through
facile and highly selective catalytic routes. Methyl methacrylate can
alternatively be obtained from 3-hydroxy-2-methylpropionamide
(1, Scheme 1) by reaction with methyl formate. Compound 13 can
be obtained by hydroformylation of acrylonitrile with a Rh-based
catalyst,4 hydrogenation of the aldehyde and hydrolysis to the
amide (Scheme 1). However, even with the best Rh/P(OPh)3
catalytic systems, the selectivity (chemo- and regioselectivity) of the
hydroformylation processes are not satisfactory. Thus, the
selectivity in aldehydes can be up to 85% and the branched/linear
product ratio .40 : 1.4
The Rh-catalyzed asymmetric hydroformylation of acrylamide 3
was initially tested with triphenylphosphite (P(OPh)3). The
catalysts were prepared in situ by adding the corresponding
phosphite ligand to [Rh(acac)(CO)2] as a catalyst precursor (0.6%
molar ratio substrate/catalyst). The results are shown in Table 1.{
At 70 uC and 95 atm CO/H2 (1 : 1), the desired aldehyde 4b11 was
obtained as the major product (Table 1, entry 1) in the ratio 4b/4l
of 93 : 7, with high activity. However 6% of propylamide (5), the
product of hydrogenation reaction, and 7% of the dimerized
product 612 were also detected (Scheme 3).
In this communication we report a highly selective new route to
1 which involves the hydroformylation of acrylamide 3, an
available and inexpensive substrate, and a subsequent hydrogena-
tion step (Scheme 2). To our knowledge, the hydroformylation of
acrylamide has yet to be reported. Tandem sequences, like the one
described here, are becoming increasingly important in organic
synthesis for the rapid preparation of high value compounds.5
We next studied the effect of several parameters (nature of the
solvent, P/Rh ratio, temperature, CO/H2 ratio and ligand) on the
selectivity of the hydroformylation of acrylamide.
The results show that the efficiency of the process depended on
the nature of the solvent (Table 1, entries 1–3). Acetonitrile (ACN)
was found to be more regioselective for the branched aldehyde 4b
than THF, while DMF showed the highest regioselectivity but the
lowest chemoselectivity (Table 1, entries 2 and 3).
A decrease in the P/Rh ratio has an extremely positive effect on
the regioselectivity while the chemoselectivity was slightly lowered
(Table 1, entry 4).
Scheme 1 Synthesis of methyl methacrylate 2 starting from acrylonitrile.
Varying the temperature had an important effect on both the
chemo- and regioselectivity (Table 1, entries 1, 5–7). Increasing the
Departament de Qu´ımica F´ısica i Inorga`nica, Universitat Rovira i
Virgili, Campus Sescelades, c/Marcel?l´ı Domingo, s/n, E-43007,
Tarragona, Spain. E-mail: montserrat.dieguez@urv.net;
annamaria.masdeu@urv.net; Fax: (+34) 977559563;
Tel: (+34) 977558779
{ Electronic Supplementary Information (ESI) available: Detailed spectro-
scopic data of 4b and experimental procedures for the derivatization of 4b
to its dinitrophenylhydrazone derivative and to 1. See DOI: 10.1039/
b510813f
Scheme 2 New route for the synthesis of methyl methacrylate 2.
Chem. Commun., 2006, 191–193 | 191
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Table 1 Hydroformylation of acrylamide 3 with [Rh(acac)(CO)2] and various ligandsa
Entry
Ligand
T/uC
P/Rh
Solvent
% Conversionb
% Aldehyde (ratio 4b/4l)c
% 5d
% 6e
1
2
3
4
5
6
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
—
PPh3
PPh3
PPh3
PPh3
70
70
70
70
85
115
60
70
70
70
70
60
115
7 : 1
7 : 1
7 : 1
2 : 1
7 : 1
7 : 1
7 : 1
7 : 1
—
7 : 1
2 : 1
7 : 1
7 : 1
THF
ACN
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
100
100
100
100
100
100
80
100
0
100
99
87 (93 : 7)
88 (98 : 2)
74 (100 : 0)
83 (100 : 0)
86 (100 : 0)
77 (100 : 0)
75 (96 : 4)
86 (93 : 7)
—
86 (100 : 0)
70 (100 : 0)
97 (100 : 0)
17 (100 : 0)
6
7
2
10
2
4
17
3
7
—
8
11
0
10
16
15
10
6
2
7
—
6
19
3
7
8f
9
10
11
12g
13
a
100
100
46
37
Conditions: Total pressure P 5 95 atm of CO/H2 (1 : 1), substrate 5 7 mmol, [[Rh(acac)(CO)2]] 5 5.9 6 1023 mol l21, 7.5 ml solvent,
b
reaction time 5 20 min. Total conversion measured by GC using undecane as the internal standard. Conversion into aldehydes measured
c
by GC. Ratios of 4b to 4l measured by 1H NMR. Hydrogenation measured by GC. Dimerization measured by GC. PCO/PH 5 2 : 1.
Isolated yield of 4b was 93%.
d
e
f
2
g
Once the hydroformylation step was optimised, Raney Nickel
(25% with respect to acrylamide) was added to the THF final
reaction mixture without purification.§ The solution was pres-
surised to 95 atm and stirred for 20 h at 70 uC. GC analysis of the
final solution showed that no 4b was present and it was totally
converted to 3-hydroxy-2-methylpropionamide (1).
The Pt/C system (25% with respect to acrylamide) in ethanol
produced moderate conversion to 1 (up to 25% at 95 atm, 25 uC,
20 h). Other catalysts such Ru/C, PtO2/FeCl2 and Pd/C were not
active under the conditions studied.
In summary, the tandem catalysed sequence hydroformylation/
Scheme 3 Hydroformylation of acrylamide 3.
hydrogenation of acrylamide using [Rh(acac)(CO)2]/PPh3 and
Raney Nickel allows alcohol 1 to be obtained with high selectivity
temperature had an extremely positive effect on regioselectivity
and activity.
(4b/4l ratio is .99) but the chemoselectivity decreased (Table 1,
The authors acknowledge Dr. Juan Antonio Delgado and
entry 1 vs. 5 and 6). Lowering the temperature to 60 uC had an
extremely positive effect on both the regio- and chemoselectivity
REPSOL-YPF for fruitful suggestions and discussion.
of the desired product 4b (Table 1, entry 1 vs. 7). The best trade-
off between chemo- and regioselectivity was therefore achieved
Notes and references
at 60 uC.
{ Standard hydroformylation experiments. In a typical hydroformylation
In order to suppress the formation of hydrogenated product, we
experiment, a mixture of the acrylamide (7 mmol), [Rh(acac)(CO)2] (4.3 6
1022 mmol), ligand (3.1 61021 mmol, P/Rh 5 7 : 1) and undecane (0.5 ml)
(as GC internal standard) in 7.5 ml solvent was charged into a evacuated
performed a hydroformylation experiment under a reduced H2
partial pressure (Table 1, entry 8). However, the rate of
stainless steel autoclave. Then the reactor was pressurized up to 95 atm of
hydrogenation vs. hydroformylation was not affected.
syn-gas and heated to the convenient temperature. Stirring was initiated
Reaction without ligand using [Rh(acac)(CO)2] did not proceed
(Table 1, entry 9).
when thermal equilibrium had been reached. After 20 min, the reactor was
cooled to room temperature and depressurised. Analyses of samples were
performed by GC and NMR spectroscopy. 4b was isolated by flash
chromatography using AcOEt/MeOH (10 : 0.3) as eluent.
§ Standard hydrogenation experiments. In a typical hydrogenation
experiment, to the final reaction mixture of the hydroformylation reaction
of acrylamide was added the desired amount of catalyst. Then the reactor
was then pressurized up to a suitable hydrogen pressure and heated to the
appropriate temperature. Stirring was initiated when thermal equilibrium
had been reached. After the appropriate reaction time, the reactor was
cooled to room temperature and depressurised. Analyses of samples were
performed by GC and NMR spectroscopy.
We next used triphenylphosphine as the ligand for the Rh-
catalyzed hydroformylation of acrylamide 3. Under the initial
conditions (i.e. 70 uC, 95 atm of CO/H2 (1 : 1), P/Rh 5 7 : 1, THF
solvent), the use of triphenylphosphine provided higher regioselec-
tivity than the use of triphenylphosphite, while the chemoselectivity
remained almost unaffected (Table 1, entries 1 vs. 10).
As previously observed with P(OPh)3, the effect of lowering the
P/Rh ratio decreased the chemoselectivity for aldehydes (Table 1,
entries 10 vs. 11). As expected, lowering the temperature had a
extremely positive effect on the chemoselectivity (Table 1, entries
10 and 13 vs. 12). Thus, the reaction carried out at 60 uC showed
no condensation product combined with practically zero hydro-
genation and excellent regioselectivity. However, further lowering
of the temperature (T ¡ 50 uC) has a dramatically negative effect
on both conversion and selectivity, 5 being the major product.
1 The world consumption of methyl methacrylate in 2002 was estimated
at 2 million metric tons (http://www.plastunivers.com/Tecnica/
Hemeroteca/PlasticosUniversales/37/).
2 R. Perrin and J. P. Scharff, in Chimie Industrielle, Dunod, Paris, 2nd
edn, 1999, pp. 559.
3 Compound 1 is also useful as a intermediate for the synthesis of drugs
and pharmaceutical agents. See, for example: R. E. Moore, M. A. Tius,
R. A. Barrow, J. Liang, T. H. Corbett, F. A. Valeriote and
192 | Chem. Commun., 2006, 191–193
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