Synthesis of β2,2-Amino Esters via Rh-Catalysed Regioselective Hydroaminomethylation

Article abstract of DOI:10.1002/adsc.201900642

The synthesis of β^2,2-amino esters was successfully achieved via Rh-catalysed regioselective hydroaminomethylation of methyl methacrylate with secondary amines using the neutral precursor [Rh(acac)(CO)₂]. In this process, the presence of molecular sieves revealed crucial in order to access the final amino ester. For the synthesis of products containing aniline derivatives, the use of the cationic precursor [Rh(COD)₂]BF₄ and ^MeCgPPh phosphine as ligand was necessary in a mixture of toluene/DCE as solvent. Effects of the steric and electronic properties of the amines were observed during this study. Interestingly, poisoning effect of CO in the hydrogenation of the imine intermediate was observed when benzyl amine was used. (Figure presented.).

Full text of DOI:10.1002/adsc.201900642

Title: Synthesis of β2,2-amino esters via Rh-catalysed regioselective
hydroaminomethylation
Authors: Cyril Godard, Aurora Ruiz, and Anton Cunillera
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900642
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10.1002/adsc.201900642
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of β2,2-amino esters via Rh-catalysed regioselective
hydroaminomethylation
Anton Cunillera, Aurora Ruiz and Cyril Godard*
Department de Química Física i Inorgànica, Universitat Rovira i Virgili, C/Marcel·lí Domingo, n1, 43007, Tarragona,
Spain. E-mail: cyril.godard@urv.cat
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The synthesis of β2,2-amino esters was
successfully achieved via Rh-catalysed regioselective
hydroaminomethylation of methyl methacrylate with
secondary amines using the neutral precursor
[Rh(acac)(CO)2]. In this process, the presence of
molecular sieves revealed crucial in order to access the
final amino ester. For the synthesis of products
containing aniline derivatives, the use of the cationic
precursor [Rh(COD)2]BF4 and MeCgPPh phosphine as
ligand was necessary in a mixture of toluene/DCE as
solvent. Effects of the steric and electronic properties of
the amines were observed during this study. Interestingly,
poisoning effect of CO in the hydrogenation of the imine
intermediate was observed when benzyl amine was used.
best of our knowledge, there are no reports to the date
on the synthesis of β-amino acids or derivatives via
HAM reaction.
Keywords: Hydroaminomethylation; β-amino acids;
tandem; hydroformylation; hydrogenation
Figure 1. Examples of biologically active β2,2-amino acids.
β-amino acids are incorporated into secondary
metabolites in bacteria, plants, fungi and
cyanobacteria, and have potential biological and
physical activities.[1] Moreover, they are precursors
for the synthesis of β-lactams, which constitute an
important class of antibiotics.[2] Over the last years,
significant efforts have been devoted to the synthesis
of these building blocks as pharmaceutical
intermediates and peptidomedics.[3] Most of these
strategies are based on the hydrogenation of
unsaturated compounds[4], Mannich reaction[5], or
conjugated additions[6]. However, either high catalyst
loadings or the use of reagents that are not readily
available is required. β2,2-amino acids, which
containing a quaternary carbon centre in α-position of
the carbonyl, such as HY-2901 and H1/5-HT2A
antagonist are potential sleeping disorder drugs for
the insomnia treatment (Figure 1).[7] Due to the
interest for these target molecules, various strategies
have been reported for their synthesis such as
Mannich reaction and C-H amination.[8] However,
these processes require multi-step synthetic routes or
the presence of directing groups in the structure of the
substrate.
The synthesis of β2,2-amino acid derivatives via
tandem HAM reaction requires the formation of
quaternary carbon centre in the hydroformylation step
(Scheme 1), which is disfavoured according to
Keuleman’s rule.[10]
Scheme 1. Attempted HAM of acrylates in the synthesis of
β-amino esters and our work.
The hydroaminomethylation (HAM) of alkenes is a
powerful tool to access nitrogen containing molecules
from readily available reagents.[9] However, to the
1
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10.1002/adsc.201900642
Advanced Synthesis & Catalysis
However, Clarke and co-workers reported the
also favoured the formation of 3a (62% isolated
yield) (entry 5, Table 1). Moreover, when the
temperature was reduced to 50 °C the amino ester 3a
was isolated in 79% yield (entry 6, Table 1).
regioselective hydroformylation of α-substituted
acrylates using MeCgPPh L1 ligand (Scheme 1, top
reaction).[11] The branched aldehyde was afforded in
excellent yield with a wide variety of acrylates. In
this report, the synthesis of β2,2-amino ester was
performed in two steps using two distinct catalysts:
one Rh catalyst for the hydroformylation step and an
Ir species for the hydrogenation of the imine (Scheme
1). Similarly, the same group reported the
hydroaminovinylation of methyl acrylate and
obtained the corresponding enamine (Scheme 1).[12]
However, it was observed that depending on the
amine, the hydroamination product was the major one.
In view of these precedents, we envisioned the
Table 1. Optimisation of reaction conditions
Entry[a] MS(mg) T(°C) t(h) C(%)[b]
3a[b]
1
-
90
20
>99
-
regioselective
hydroaminomethylation
of
α-
2
3[c]
4
5
6
50
50
100
100
100
90
90
70
70
50
20
20
20
72
72
>99
>99
>99
>99
>99
36
21
42
67[62]
82[79]
substituted acrylates 1 with amines 2 as an efficient
method to access β2,2-amino esters 3 (Scheme 1).
First a screening of ligands was performed using
methyl methacrylate 1a and morpholine as model
substrates (See Table S1 in SI). The highest
regioselectivity towards the branched aldehyde 4a
was obtained using methyldiphenylphosphine L2
(Scheme 2). Nonetheless, no traces of the amino ester
product 3a were detected in these reactions and the
aldehyde was the main product.
[a]
Reaction conditions: 1a (0.5 mmol), morpholine (0.5
mmol), Rh = [Rh(acac)(CO)2] (2 mol%), toluene (0.4 mL).
[b] % Conversion and yield determined by GC-MS analysis
using naphthalene as external standard. Values between
brackets refer to isolated yield. [c] morpholine (0.75 mmol),
linear enamine and amino ester detected by GC.
We hypothesized that the presence of water formed
as a by-product could explain this result. Indeed, if
the hydroformylation takes place at internal position
of the alkene, the branched aldehyde 4a is generated
(Scheme 2). Next, condensation of the morpholine
produces the iminium cation 5a, which is expected to
be highly reactive, and could react with water and re-
form the branched aldehyde 4a.
Motivated by these result (entry 6, Table 1), a
series of β2,2-amino esters 3 was synthesised using
methyl methacrylate 1a as model substrate (Scheme
3). The steric hindrance revealed an important factor
since cyclic secondary amines such as morpholine
and 1-Boc-piperazine, provided the amino esters 3a-b
in high yield (up to 86%) while non-cyclic secondary
amines produced amino esters 3c-e in moderate to
low yields. In the case of diisopropylamine, the
corresponding amino ester 3f was not detected.
Interestingly, when primary amines such as aniline,
benzyl amine, butyl amine, and cyclohexylamine,
were applied under these conditions, the
corresponding imino esters 6a-d were isolated in
good to excellent yields (Scheme 3), but the
corresponding amino esters were not formed. These
results can be related with previous reports describing
the reduction of the unsaturated nitrogen intermediate
as the limiting step of the reaction. [10,12] In conclusion,
β2,2-amino ester 3a-e have been synthesised in low to
high yield via Rh-catalysed HAM of methyl
methacrylate 1a with various secondary amines 2
using L2 as ligands (Scheme 3). The reaction
conditions were appropriate to reduce the iminium 5
obtained with secondary amines, but not to reduce the
imino ester 6.
Scheme 2. Process for the synthesis of β2,2-amino ester 3a.
The reaction was therefore run in the presence of 4Å
molecular sieves (MS) (entry 1, Table 1) and under
these conditions, the amino ester product 3a was
obtained, although in moderate yield. This result
confirmed the importance of removing the water from
the reaction mixture. The use of an excess of
morpholine decreased the yield of 3a (entry 3, Table
1).
At this point, an optimisation of the reaction
conditions using methyl methacrylate 1a and aniline
as model substrates was performed (Table 2). Both
L1 and L2 were tested under the optimised
conditions for secondary amines, and in both cases,
the amine product 3g was not obtained (entries 1 and
2, Table 2).
When the temperature was decreased to 70°C and the
amount of MS increased (entry 4, Table 1), the yield
increased up to 42%. Increasing the time up to 72h
2
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10.1002/adsc.201900642
Advanced Synthesis & Catalysis
Interestingly, the use of the cationic precursor
[Rh(COD)2]BF4 in
a
mixture of toluene/1,2-
dichloroethane (tol/DCE) resulted in the formation of
amino ester 3g in moderate yield (entries 3 and 4,
Table 2). In the case of L2, high selectivity towards
alkene hydrogenation product 7 was observed (entry
3, Table 2), while with L1, the alkene hydrogenation
was substantially reduced, but both the branched
aldehyde 4a and the imine 6a were still detected
(entry 4, Table 2). Increasing the temperature to
70 °C afforded 3g in 67% yield (entry 5, Table 2).
Under higher total syngas pressure (up to 30 bar), the
formation of amino ester 3g was achieved in
excellent yield (entry 6, Table 2). When the catalyst
loading was 1 mol%, the high selectivity towards 3g
was maintained (entry 7, Table 2). Thus, the use of a
cationic precursor in a mixture of tol/DCE revealed
crucial to complete the HAM reaction when using
aniline.
In order to expand the scope of β2,2-amino esters 3,
various aniline derivatives 2 and acrylates 1 were
tested (Scheme 4). First, the electronic effect was
studied using para-substituted anilines. No
significant effect was observed when para-substituted
anilines bearing electron-donating methyl and
methoxy group, respectively, were used. In both
cases, the corresponding amino esters 3h and 3i were
afforded in high yields (up to 88%).
Scheme 3. Rh-catalysed HAM of methyl methacrylate 1a
with secondary and primary amines.
Table 2. Optimisation of reaction conditions for Rh-
catalysed HAM of 1a with aniline.
Entry[a]
1
L
L2
L1
L2
L1
L1
L1
L1
C(%)[b]
>99
>99
>99
>99
>99
>99
>99
3g[b]
-
-
25
31
67
90
94[87]
4a[b]
-
60
-
29
4
-
6a[b]
>99
40
-
34
11
-
7[b]
-
-
75
6
17
10
6
2[c]
3[d]
4[e]
5[f]
6[g]
7[h]
-
-
[a]
Reaction conditions: 1a (0.5 mmol), aniline (0.5 mmol),
Rh = [Rh(acac)(CO)2] (2 mol%), L2 (4 mol%), toluene
[b]
(0.4 mL), P = 10 bar (CO/H2, 1:1). % Conversion and
1
yield determined by H NMR analysis using naphthalene
as internal standard. Values between brackets refer to
isolated yield.[c] Rh = [Rh(acac)(CO)2] (2 mol%), L1 (4
[d]
mol%). Rh = [Rh(COD)2]BF4 (2 mol%), L2 (4 mol%),
[e]
tol/DCE (1:1, 0.4 mL). Rh = [Rh(COD)2]BF4 (2 mol%),
L1 (4 mol%), tol/DCE (1:1, 0.4 mL).[f] Rh
=
[Rh(COD)2]BF4 (2 mol%), L1 (4 mol%), T = 70 °C,
tol/DCE (1:1, 0.4 mL). [g] Rh = [Rh(COD)2]BF4 (2 mol%),
Scheme 4: Rh-catalysed HAM of acrylates 1a-b with
aniline derivatives 2. Values between brackets refer to
isolated yields.
L1 (4 mol%), T = 70 °C, P = 30 bar (CO/H2, 1:1), tol/DCE
[h]
(1:1, 0.4 mL).
Rh = [Rh(COD)2]BF4 (1 mol%), L1 (2
mol%), T = 70 °C, P = 30 bar (CO/H2, 1:1), tol/DCE (1:1,
0.4 mL).
In contrast, when the aniline derivative bearing
electron-withdrawing iodide group in para-position
3
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10.1002/adsc.201900642
Advanced Synthesis & Catalysis
was tested, the imine 6e was the main reaction
product. Using ortho-substituted anilines bearing
methyl and methoxy groups, the amino esters 3h and
3j were afforded in high isolated yield (up to 81%).
However, when the steric hindrance was further
increased using 2,6-dimethyl aniline, the imine 6f
was obtained. A possible explanation for this result is
that the coordination of this imine to the Rh catalyst
is disfavoured, and consequently, the hydrogenation
cannot take place.
detected (Scheme 5). These results therefore
indicated that carbon monoxide was poisoning the
hydrogenation step in the HAM reaction with benzyl
amine. The same result was obtained using other
primary amines such as butyl amine or cyclohexyl
amine. This could indicate that under syngas pressure,
coordination of CO competes with that of the imine
intermediates when primary amines are used, thus
inhibiting their hydrogenation.
Interestingly, when the ethyl benzylacrylate 1b
was used as substrate and aniline as nucleophile, the
corresponding amino ester 3l was afforded in 40%
isolated yield.
The results described thus demonstrated that under
appropriate conditions, β2,2-amino esters 3 can be
obtained by HAM reaction, either using secondary
amines or aniline derivatives.
Nevertheless, when the HAM of methyl
methacrylate 1a with benzyl amine was attempted
(Table 3) either using L1 or L2 in the presence of
cationic [Rh(COD)2BF4 in tol/DCE, the imine 6b was
mainly produced (entry 1 and 2, Table 3).
Scheme 5: Rh-catalysed hydrogenation of 6b.
Kalck and co-workers proposed the existence of an
equilibrium between neutral species involved in the
HF reaction, and cationic species, which are expected
to hydrogenate the imine.[13] In this equilibrium, a
dihydride intermediate is generated from the neutral
rhodium hydride species in the presence of a protic
source. Moreover, Beller and co-workers reported
that the use of tetrafluoroboric acid facilitated the
formation of amines in the HAM of vinylarenes.[14]
For this reason, the addition of tetrafluoroboric acid
In conclusion, a series of β2,2-amino esters 3 was
successfully synthesised through the regioselective
Rh-catalysed HAM of methyl methacrylate with
secondary amines and aniline derivatives. For the
secondary amines, the use of molecular sieves
resulted crucial to remove the water from the media.
For the aniline derivatives, the use of a cationic
rhodium precursor in tol/DCE was required to afford
the amino ester 3. Both electronic and steric
was tested in the reaction (entry 3, Table 3). However, properties of the amine reagents were highly
under these conditions, the addition of an acid did not
promote the hydrogenation of imine 6b.
important to obtain the corresponding amine. In this
case, ethyl benzylacrylate was successfully applied to
access amino ester containing benzyl substituent. For
other primary amines, such as benzyl amine, carbon
monoxide acted as a poison under the tested
conditions and the hydrogenation step could not be
completed, resulting in the formation of the
corresponding imines. The synthesis of the
biologically active β2,2-amino acids HY-2901 and
H1/5-HT2A using this methodology is currently on
going in our lab and will be reported in the near
future.
Table 3. Optimisation of reaction conditions for Rh-
catalysed HAM of 1a with benzyl amine.
Entry [a]
C(%)[b]
3m[b]
4a[b]
6b[b]
7[b]
L
1
2
>99
>99
95
-
-
-
-
-
6
85
>99
82
15
-
7
L1
L2
L2
3[c]
[a]
Reaction conditions: 1a (0.5 mmol), benzyl amine (0.5
mmol), Rh = [Rh(COD)2]BF4 (1 mol%), L (2 mol%),
tol/DCE (1:1, 0.4 mL), P = 10 bar (H2/CO, 1:1), 50 ºC.[b]
Conversion and yields determined by 1H NMR using
naphthalene as internal standard. [c] HBF4 (2 mol%).
Experimental Section
The Rh-catalysed HAM reaction was set up in a CAT24
autoclave from HEL Inc. and was stirred with a teflon-
coated magnetic stirring bar.
General procedure for the synthesis of β2,2-amino esters
using secondary amines.
A 2 mL glassware reactor tube was charged with methyl
methacrylate 1a (0.5 mmol), secondary amine 2 (0.5
mmol), 100 mg of 4Å MS, ligand L2 (3.7 µL, 0.02 mmol),
dicarbonyl(acetylacetonato)rhodium(I) (2.6 mg, 0.01
mmol) in toluene (0.4 mL). The reaction tube was placed
in the reactor which was pressurised with 10 bar of H2/CO
(1:1), heated at 50°C and left stirring at 800 rpm. The
reaction was stopped after 72 h by cooling the reactor in an
ice bath for 20 min followed by venting the system. The
At this point, two control experiments were
conducted (Scheme 5). First, the imine 6b was treated
with hydrogen in the presence of L2 and
[Rh(COD)2]BF4 in tol/DCE, and interestingly, the
amino ester 3m was obtained in good yield. It was
then concluded that the system is capable of reducing
the imine. Finally, the imine 6b was treated under
syngas mixture, and this time no amino ester 3m was
4
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10.1002/adsc.201900642
Advanced Synthesis & Catalysis
mixture was purified by chromatographic column with
Transition Metals for Organic Synthesis, Vol. 1 (Eds.:
M. Beller, C. Bolm) Wiley-VCH: Weinheim, 2004, pp
57−85. c) D. Crozet, M. Urrutigoïty, P. Kalck,
ChemCatChem, 2011, 3, 1102-1118. d) C. Chen, X-Q.
Dong, X. Zhang, Org. Chem. Front. 2016, 3, 1359-
1370. e) P. Kalck, M. Urrutigoïty, Chem. Rev.
2018,118, 3833-3861.
Al2O3 to afford the resulting β2,2-amino esters 3.
General procedure for the synthesis of β2,2-amino esters
using aniline and derivatives.
A 2 mL glassware reactor tube was charged with α-alkyl
acrylate 1 (0.5 mmol), aniline derivative 2 (0.5 mmol),
bis(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (2 mg,
0.005 mmol) in DCE (0.2 mL), and ligand L1 (2.9 mg,
0.01mmol) in toluene (0.2 mL). The reaction tube was
placed in the reactor which was pressurised with 30 bars of
H2/CO (1:1), heated at 70°C and left stirring at 800 rpm.
The reaction was stopped after 20 h by cooling the reactor
in an ice bath for 20 min followed by venting the system.
The mixture was purified by chromatographic column with
SiO2 to afford the resulting β2,2-amino esters 3.
[10] A. I. Keulemans, A. Kwantes, T. van Bavel, Rec. Trav.
Chim. Pays Bas. 1948, 67, 298-308.
[11] a) M. L. Clarke, Tetrahedron Lett. 2004, 45, 4043-
4035. M. L. Clarke, G. J. Roff, Chem. Eur. J. 2006, 12,
7978-7986.
[12] M. L. Clarke, G. J. Roff, Green Chem. 2007, 9, 792-
Acknowledgements
796.
[13] D. Crozet, A. Gual, D. McKay, C. Dinoi, C. Godard,
M. Urrutigoïty, J-C. Daran, L. Maron, C. Claver, P.
Kalck, Chem. Eur. J. 2012, 18, 7128-7140.
The authors are grateful to the Ministerio de Economia y Com-
petividad and the Fondo Europeo de Desarrollo Regional
FEDER (CTQ2016-75016-R, AEI/FEDER,UE) for funding and
PhD grant (BES-2014-069199) to AC.
[14] L. Routaboul, C. Buch, H. Klein, R. Jackstell, M.
Beller, Tetrahedron Lett. 2005, 46, 7401-7405.
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis of β2,2-amino esters via Rh-catalysed
regioselective hydroaminomethylation
Adv. Synth. Catal. Year, Volume, Page – Page
Anton Cunillera, Aurora Ruiz and Cyril Godard*
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