Rh-Catalyzed asymmetric hydroaminomethylation of α-Substituted acrylamides: Application in the synthesis of RWAY

Article abstract of DOI:10.1021/acs.orglett.0c03433

The successful rhodium-catalyzed asymmetric hydroformylation and hydroaminomethylation of α-substituted acrylamides is described using 1,3-phosphite-phosphoramidite ligands based on a sugar backbone. A broad scope of chiral aldehydes and amines were afforded in high yields and excellent enantioselectivities (up to 99%). Furthermore, the synthetic potential of this method is demonstrated by the single-step synthesis of the brain imaging molecule RWAY.

Full text of DOI:10.1021/acs.orglett.0c03433

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Letter
Rh-Catalyzed Asymmetric Hydroaminomethylation of α‑Substituted
Acrylamides: Application in the Synthesis of RWAY
́
̀
̀
̈
Roger Miro, Anton Cunillera, Jessica Margalef, Domke Lutz, Armin Borner,* Oscar Pamies,
́
Montserrat Dieguez, and Cyril Godard*
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ABSTRACT: The successful rhodium-catalyzed asymmetric hydroformylation and hydroaminomethylation of α-substituted
acrylamides is described using 1,3-phosphite-phosphoramidite ligands based on a sugar backbone. A broad scope of chiral aldehydes
and amines were afforded in high yields and excellent enantioselectivities (up to 99%). Furthermore, the synthetic potential of this
method is demonstrated by the single-step synthesis of the brain imaging molecule RWAY.
disubstituted olefins. The hydroformylation of 1,1′-disubsti-
he Rh-catalyzed hydroaminomethylation (HAM) of
Talkenes into amines is a sustainable, atom-economic, tuted olefins has been less studied than other mono- and
single-step alternative to classical multistep synthetic routes.1
disubstituted olefins, with only a few successful reported
examples8,10 and earlier ligands that were efficient for mono-
Although the enantioselective version of this reaction has a
and 1,2-disubstituted olefins (e.g., Binaphos, diazaphospho-
lane, and Kelliphite), did not work well for 1,1′-disubstituted
olefins.10a In addition, small structural changes from one type
of 1,1′-disubstituted olefin to another may require significant
changes in ligand structure and reaction conditions. Therefore,
an approach based on fine-tuning modular ligands can be
advantageous to advance in the hydroformylation of 1,1′-
disubstituted olefins, and therefore in the HF of α-substituted
acrylamides.
high potential, there are only a few examples reported to date
and all of them require either sacrificial reagents or cocatalysts
to access the chiral amines (Scheme 1A). In consequence, the
efficiency and interest regarding the reaction are undermined.2
Recently, we reported the efficient Rh-catalyzed asymmetric
HAM of α-alkyl acrylates to access chiral γ-aminobutyric esters
using a single Rh-catalyst (Rh/(R,R-QuinoxP*) (Scheme 1B).3
This work provided a straightforward access to chiral γ-
aminobutyric acid (GABA) derivatives.4,5
To the best of our knowledge, the asymmetric hydro-
formylation of α-substituted acrylamides has been reported
only for two substrates, with ee’s up to 86%, using a Rh/
DTBN-YanPhos system.8,9 Apart from this very recent work,
no other catalytic systems have been reported that can
hydroformylate a large series of α-substituted acrylamides.
We first searched for appropriate ligands for the hydro-
formylation of α-substituted acrylamides. The results are
Among the GABA derivatives, those that contain an amide
group are of paramount importance because this motif is
present in CCR2 antagonists for chronic inflammatory
processes such as atherosclerosis, multiple sclerosis, and
rheumatoid arthritis6 and CCR5 antagonists for HIV drug,7a
or for brain imaging.7b
In this work we present a new, direct atom-efficient route to
obtain amide-based GABA derivatives based on the Rh-
catalyzed asymmetric HAM of α-substituted acrylamides
(Scheme 1C). Since enantioselectivity in this process is
induced during the hydroformylation (HF) step, the discovery
of an efficient chiral catalyst is fundamental to economically
achieve those amide-based GABA derivatives. The complexity
of this problem can be understood by noticing that α-
substituted acrylamides are a particular case of 1,1′-
Received: October 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03433
© XXXX American Chemical Society
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A

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Scheme 1. Selected Precedents in Rh-Catalyzed Asymmetric
HAM of Alkenes
Table 1. Screening of Ligands for the Asymmetric
Hydroformylation of N,N-Diethylmethacrylamide 1a
a
b
b
c
Entry
Ligand
% Conv
% 2a [IY]
l/b ratio
% ee
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
8
0
0
64
74
99
38
−
−
76 [44]
83 [53]
90 [86]
5
−
−
25
28
100/0
−
−
−
4
8
73
a
Reaction conditions: 1a (0.5 mmol), Rh = [Rh(acac)(CO)2] (1 mol
%), L (1.2 mol %), P = 10 bar (H2/CO, 1:1), toluene (0.4 mL), T =
b
90 °C, t = 16 h, 900 r.p.m. % Conversions and yields determined by
1H NMR spectroscopy using naphthalene as internal standard; values
c
in brackets refer to isolated yields. % ee of 2a determined by chiral
GC after reduction into the alcohol.
high enantioselectivity (73%) were obtained with the sugar
based phosphite-phosphoramidite L6 (entry 6).
described in Table 1. We tested ligands that were previously
presented as efficient in the hydroformylation of 1,1-
disubstituted olefins (L1−L3)10a and mono- and 1,2-
disubstituted olefins (L4−L5).10a Inspired by the phosphine-
phosphoroamidite YanPhos-based ligands that were success-
fully used in the hydroformylation of some 1,1′-disubstituted
olefins, we also considered the new phosphite-phosphorami-
dite ligand L6 that contains a sugar backbone and is air
stable.11 Ligands L1−L6 were tested using the commercially
available substrate N,N-diethylmethacrylamide 1a, [Rh(acac)-
(CO)2] as the Rh precursor, and toluene as the solvent, under
10 bar of H2/CO (1:1), at 90 °C for 16 h (Table 1).
Under these conditions, the catalysts bearing the diphos-
phines (R,R)-QuinoxP* L1 (entry 1), (R,R)-BenzP* L2 (entry
2), and (S,S)-Ph-BPE L3 (entry 3) were barely active
(conversions <5%). It is noteworthy that L2 had provided
high yields (up to 91%) and high enantioselectivities (up to
94%) in the hydroformylation of α-alkyl acrylates.10c,d This
stresses the comments in the introduction that small structural
changes in the 1,1′-disubstituted olefin may require significant
changes in ligand structure. Electronic and/or steric differences
between the esters and the amides thus make the hydro-
formylation of the latter more difficult. Using the phosphine-
phosphite (Sax,S,S)-Bobphos L4 (entry 4) and the sugar based
diphosphite L5 (entry 5), the conversion increased to 64% and
74% respectively, with good regio- and chemoselectivity of the
linear product 2a. However, enantioselectivities were poor (ca.
8%) in both cases. Interestingly, full conversion, high regio-
and chemoselectivity of the desired linear aldehyde 2a, and
We next studied the effect of temperature, total pressure,
and CO/H2 ratio on the selectivity in the hydroformylation of
N,N-diethylmethacrylamide 1a (see Table S1 for details).
Under optimized reaction conditions (T = 60 °C, 20 bar, H2/
CO = 1:1), the enantioselectivity increased up to 90%,
maintaining high regio- and chemoselectivity for the desired
linear aldehyde 2a (Table 2, entries 1 and 2).
We next studied the effects of several ligand parameters.12
Since previous reports on the hydroformylation of 1,1′-
disubstituted substrates showed that small variations in the
ligands can significantly affect the catalytic performance, we
first modified the substituent at the nitrogen atom (Table 2).
The enantioselectivity decreased with the less sterically
hindered ligands L7 and L8 (entries 3 and 4). Ligands
containing an (S)- isopropyl group L9 and a methyl benzyl
group L10 also decreased the catalytic performance, but high
yields (up to 76%) and high enantioselectivities (up to 85%)
could still be obtained (entries 5 and 6). Finally, with ligand
L11, that contained a tert-butyl group, 92% enantioselectivity
was achieved but at the cost of conversion (49%, entry 7),
which suggests that alkene coordination is more difficult when
steric hindrance is increased. In conclusion, the ligand L6
provided the best compromise between activity and
enantioselectivity. Finally, the effect of the binaphthol’s
configurations was studied (see Table S2 for details). The
best results were obtained with S configurations in both biaryl
moieties while (SN, RO), (RN, SO), and (RN, RO) configurations
provided very low conversion as well as low regio- and
chemoselectivity for the linear aldehyde 2a.
B
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compared. For the substrate 1b, bearing a diphenyl amide
moiety, a 50% yield of 2b with 80% ee was obtained. Better
results, 80% yield and an excellent 99% ee, were obtained for
the formation of the linear aldehyde 2c that contains a
diisopropyl amide substituent. Next, the effect of the
substituent in the α-position was investigated. Products 2d
and 2e bearing ethyl and benzyl groups were obtained in high
yields (up to 74%), together with 90% and 86% ee, respectively
(Scheme 2). A lower yield and poor enantioselectivity were
obtained with a more sterically hindered alkene (linear
aldehyde 2f). For this substrate, we conducted a brief
screening with ligands L6−L11 (see Tables S3 and S4 in
SI), and using ligand L10 instead of L6, the linear product 2f
could be obtained in 66% yield and 74% ee. As in the case of
2f, L10 also provided high yields and enantioselectivities (up
to 82%) for the linear aldehyde 2g bearing a cyclopentyl group
and the linear aldehyde 2h containing a phenyl group. Finally,
2i bearing a phenyl group in the α-position and an
azepanamide group was also obtained in good yield (52%)
and high enantioselectivity (74%). The results for 2h and 2i
are particularly relevant since important biologically active
molecules include a phenyl substituent in α-position (Scheme
2) and the catalysts reported to date3,8,10c were only efficient
for α-alkyl substituted substrates. The catalytic systems based
on phosphite-phosphoramidite ligands L6 and L10 are thus
efficient in the Rh-catalyzed asymmetric hydroformylation of
α-substituted acrylamides (ee up to 99%), even for substrates
with a phenyl group in α-position. It is noteworthy that, in all
cases, only a small amount of branched product was formed
(<5%).
Based on these results, our Rh/phosphite-phosphoroamidite
catalysts were tested in the one-pot asymmetric HAM of α-
substituted acrylamides to directly yield chiral amines.1 A brief
optimization of the reaction conditions was first conducted
with alkene 1a and morpholine 3a as the nucleophile (see
Table S5 in SI). With ligand L6 and [Rh(acac)(CO)2] in a
mixture of 1,2-dichloroethane (DCE)/toluene as solvent under
20 bar of H2/CO (2:1) at 90 °C, the GABA derivative 4a was
obtained in 79% yield and 85% ee (Scheme 3).13 Note that this
experiment was performed at 1 mmol scale without affecting
the yield or the enantioselectivity (see Section SXVI in the SI).
Next, a series of other secondary amines were also tested in the
asymmetric HAM of 1a (Scheme 3), and the products 4b−d
were obtained in good-to-high yields (up to 75%) and high
enantioselectivities (up to 85%). Interestingly, protecting
groups such as benzyl and Boc (4b and 4c) were perfectly
tolerated. Even for primary amines such as aniline, the product
4e was afforded in 56% yield and 78% ee. When other
acrylamides were used (Scheme 3 bottom), the GABA
derivatives 4 were invariably obtained in good-to-high yields
(up to 78%) and high enantioselectivities (up to 84%), and the
trends observed in hydroformylation were again observed in
the HAM reaction (Scheme 3). Thus, a slight decrease in
enantioselectivity was observed for the product 4g that
contains two phenyl groups in the amide, while dialkyl
substituted acrylamides (4f,h,i) provided the best results.
Substrates 4d and 4k are of particular interest (Scheme 3)
since they contain either the amine (4d) or the amide (4k)
that are present in the brain imaging molecule RWAY (Scheme
1), and for both cases the product was obtained in high
enantioselectivities (up to 84%). In view of these results, we
envisioned the synthesis of RWAY in a single step via the Rh-
catalyzed asymmetric hydroaminomethylation (Scheme 4).
Table 2. Influence of Ligand Variations on the Asymmetric
Hydroformylation of 1a
a
b
b
c
Entry
Ligand
% Conv
% 2a [IY]
% ee
1
2
3
4
5
6
7
L6
L6
L7
L8
L9
L10
L11
72
99
54
76
70
68
49
89 [64]
88 [87]
84 [45]
82 [60]
86 [60]
82 [53]
84 [38]
90
90
d
74
70
81
85
92
a
Reaction conditions: 1a (0.5 mmol), Rh = [Rh(acac)(CO)2] (1 mol
%), L (1.2 mol %), P = 20 bar (H2/CO, 1:1), toluene (0.4 mL), T =
b
60 °C, t = 16 h, 900 r.p.m. % Conversions and yields determined by
1H NMR spectroscopy using naphthalene as internal standard; values
in brackets refer to isolated yields. In all cases, the % of branched
c
products was <5%. % ee of 2a determined by chiral GC after
d
reduction into the alcohol. t = 48 h.
At this stage, the asymmetric hydroformylation of a set of α-
substituted acrylamides was tested using ligand L6 (Scheme
2). Three substrates with distinct amide substituents were first
a b
,
Scheme 2. Asymmetric Hydroformylation of Acrylamides
a
As Table 2 (entry 2), lsolated yields, average of two independent
b
runs. % ee determined by chiral GC or HPLC after reduction into
c
d
the alcohol. 1 (0.25 mmol), Rh (2 mol %). T = 90 °C, t = 16 h.
e
Isolated yield corresponds to alcohol after reduction of the crude.
C
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high yields with high to excellent enantioselectivities. The
system could tolerate different substituents at the acrylamide
for both reactions, and in the case of HAM, various secondary
amines and aniline could be applied. Furthermore, the
synthesis of RWAY was performed in one step, with good
yield and high enantioselectivity. These results open up the use
of new air stable, readily available, and modular ligands to
advance in the hydroformylation of 1,1′-disubstituted olefins.
Mechanistic studies are currently ongoing.
Scheme 3. Rh-Catalyzed Asymmetric HAM of
Acrylamides
a b
,
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03433.
Experimental details for the preparation and character-
ization of ligands L6−L11 and of acrylamide substrates
1, and for the catalytic testing (optimization and
analytical methods) are included. (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
̈
Armin Borner − Leibniz-Institut für Katalyse e.V. Universität
Rostock, 18059 Rostock, Germany; orcid.org/0000-0002-
0381-8639; Email: cyril.godard@urv.cat
Cyril Godard − Departament de Química Física i Inorgànica,
Universitat Rovira I Virgili, 43007 Tarragona, Spain;
orcid.org/0000-0001-5762-4904;
Email: Armin.Boerner@catalysis.de
Authors
́
Roger Miro − Departament de Química Física i Inorgànica,
Universitat Rovira I Virgili, 43007 Tarragona, Spain
Anton Cunillera − Departament de Química Física i
Inorgànica, Universitat Rovira I Virgili, 43007 Tarragona,
Spain
a
1 (0.5 mmol), 3 (0,5 mmol), Rh = [Rh(acac)(CO)2] (1 mol %), L6
(1.2 mol %), P = 20 bar (H2/CO, 2:1), T = 90 °C, t = 16 h. Isolated
b
yields, average of two independent runs. % ee determined by chiral
HPLC. 1 (0.25 mmol), 2 (0.25 mmol), Rh (2 mol %), L6 (2.4 mol
%).
c
̀
Jessica Margalef − Departament de Química Física i
Inorgànica, Universitat Rovira I Virgili, 43007 Tarragona,
Spain
a b
,
Scheme 4. Synthesis of RWAY 4l via HAM Reaction
Domke Lutz − Leibniz-Institut für Katalyse e.V. Universität
Rostock, 18059 Rostock, Germany
̀
Oscar Pamies − Departament de Química Física i Inorgànica,
Universitat Rovira I Virgili, 43007 Tarragona, Spain;
orcid.org/0000-0002-2352-8508
́
Montserrat Dieguez − Departament de Química Física i
Inorgànica, Universitat Rovira I Virgili, 43007 Tarragona,
Spain; orcid.org/0000-0002-8450-0656
a
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03433
lb (0.25 mmol), 3b (0.25 mmol), Rh = [Rh(acac)(CO)2] (2 mol
%), L6 (2.4 mol %), P = 20 bar (H2/CO, 2:1), T = 90 °C, t = 16 h.
Isolated yields, average of two independent runs. % ee determined by
b
chiral HPLC.
Notes
The authors declare no competing financial interest.
Under previous optimized conditions (Scheme 3), a precipitate
was generated and the conversion dropped significantly.
However, when a mixture of 2-methyl-tetrahydrofuran (2-
Me-THF) and toluene was used, the RWAY compound 4l was
obtained in 64% isolated yield and 82% ee (Scheme 4).14
In summary, we have developed an efficient system for the
Rh-catalyzed asymmetric HF and HAM of α-substituted
acrylamides using chiral phosphite-phosphoramide ligands. In
both reactions, the products 2 and 4 were obtained in good to
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Spanish
Ministry of Economy and Competitiveness (CTQ2016-75016-
R, CTQ2016-74878-P), European Regional Development
Fund (AEI/FEDER, UE), the Catalan Government
(2017SGR1472), and the ICREA Foundation (ICREA
Academia award to M.D.).
D
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Li, X.; Yang, J.; Lv, H.; Zhang, X. Rhodium-Catalyzed Enantiose-
lective Anti-Markovnikov Hydroformylation of α-Substituted Acryl
Acid Derivatives. Org. Lett. 2020, 22, 1108−1112.
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optimization of the reaction conditions.
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(8) During the writing of this paper a new report on the use of the
Rh/DTBN-YanPhos complex in the asymmetric hydroformylation of
α-alkyl acryl acid derivatives, with three examples of acrylamides, one
of them with poor results, has been published. Li, S.; Li, Z.; You, C.;
E
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