Ligand-Controlled Regiodivergent Hydroformylation of Ynamides: A Stereospecific and Regioselective Access to 2- And 3-Aminoacroleins

Article abstract of DOI:10.1021/acs.orglett.9b03566

The rhodium-catalyzed hydroformylation of ynamides is described and gives selective access to 2- or 3-aminoacrolein derivatives. The regioselectivity of this carbonylation can be completely controlled at will thanks to the nature of the ligand used. This represents the first example of regiodivergent alkyne hydroformylation. The influence of the substituents on the different positions of the ynamide has been investigated, and it appears that this reaction is tolerant to a wide range of functional groups.

Full text of DOI:10.1021/acs.orglett.9b03566

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ligand-Controlled Regiodivergent Hydroformylation of Ynamides: A
Stereospecific and Regioselective Access to 2- and 3‑Aminoacroleins
Patrick Wagner,† Morgan Donnard,*,‡ and Nicolas Girard*,†
†
́
́
́
Universite de Strasbourg, CNRS (LIT UMR 7200), Faculte de Pharmacie, F-67000 Strasbourg, France
‡
́
́
́
̀
Universite de Strasbourg, CNRS, Universite de Haute-Alsace (LIMA UMR 7042), Ecole Europeenne de Chimie, Polymeres et
́
Materiaux (ECPM), F-67000 Strasbourg, France
S
* Supporting Information
ABSTRACT: The rhodium-catalyzed hydroformylation of
ynamides is described and gives selective access to 2- or 3-
aminoacrolein derivatives. The regioselectivity of this carbon-
ylation can be completely controlled at will thanks to the
nature of the ligand used. This represents the first example of
regiodivergent alkyne hydroformylation. The influence of the substituents on the different positions of the ynamide has been
investigated, and it appears that this reaction is tolerant to a wide range of functional groups.
ighty years after having been discovered by Roelen,1
Ehydroformylation reaction has demonstrated over the
decades its strong synthetic power and became the most
important homogeneous catalytic process in the industry.2,3
This reaction is highly atom economic, as it functionalizes a
carbon−carbon multiple bond with an aldehyde generated
from readily available gases (i.e., CO and H2), and its relatively
mild reaction conditions have allowed it to be used as the key
transformation in elegant tandem/domino processes.4 Since its
first report by Wender in 1957,5 alkyne hydroformylation has
been much less investigated than that of alkenes.6 In recent
years, major progress has been made in alkyne hydro-
formylation. One of the most notable is Buchwald’s
introduction of BiPhePhos as ligand in rhodium-catalyzed
hydrocarbonylation,7 allowing a significant decrease in the
overreduction of the newly formed α,β-unsaturated aldehyde.
Since then, significant efforts have been done by several groups
such as Alper,8 Hidai,9 le Floch and Sanchez,10 Breit,11
Beller,12 and Dong and Zhang13 in order to increase the
regio-/stereoselectivity and to suppress as much as possible the
byproducts coming from undesired hydrogenation processes.
In addition, very recently, You14 introduced the first syngas-
free alkyne hydroformylation. However, if the overreduction
can be now considered as controlled, in the case of internal
dissymmetric alkynes a lot of work remains to be done in terms
of regiocontrol of the reaction. To date, three possibilities of
control have been investigated (Figure 1). The first relies on
the classical steric control. In that case the metal center will be
introduced on the less hindered side of the alkyne. The second
is based on the use of phenylacetylene derivatives. In that
specific case, the reaction mainly drives to the introduction of
the formyl group on the same carbon as the aromatic moiety.
The third option is the use of a directing group that can
chelate the metal center of the catalytic species. And finally, the
last one has been recently reported by Breit and co-workers.15
They demonstrated that a rhodium-catalyzed tandem
Figure 1. Comparison between reported alkyne−hydroformylation
regioselectivity and this work reporting the ligand-controlled
regiodivergent hydroformylation of ynamides.
regioselective hydroformylation/hydrogenation of internal
alkynes can be performed thanks to the use of a guanidine-
based ligand that allows supramolecular interactions between
the organometallic complex and the substrate. If all these
approaches can lead from good to very good regioselectivity;
Received: October 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
notably, in all cases, its controlled inversion has never been
reported.
Table 1. Optimization of the Reaction Conditions
In this context, we have decided to focus our attention on
the use of particular alkynes directly linked to a nitrogen atom,
namely the ynamides.16 These compounds have emerged over
the last 15 years as remarkable building blocks. Notably, they
are precious precursors of polysubstituted enamines that can
be subsequently involved in the synthesis of valuable complex
molecules. In our opinion, this family of molecules could be
quite interesting as hydroformylation substrates for several
reasons. First, the use of these species in hydroformylation
could lead to efficient and general access to polyfunctionalized
aminoacrolein derivatives that are building blocks with high
synthetic potential but fairly difficult to synthesize.17 Second,
ynamides are particular unsymmetrical alkynes. On the one
hand, due to the presence of the nitrogen atom linked to the
carbon−carbon triple bond, this unsaturation is remarkably
electron rich. This activation could result in a high tendency to
be directly hydrogenated to form the corresponding enamine
4, but its strong polarization could also help to control the
regioselectivity of the hydroformylation reaction. On the other
hand, the electron-withdrawing group attached to the nitrogen
can act as a directing group and could also favor one
regioisomer over the other.18 All together, these parameters
represent as many challenges but, being tamed, they can be
regarded as an asset to regioselectively perform the hydro-
formylation to obtain at will an isomer or the other (2 or 3).19
In this paper, we demonstrate that ynamides undergo efficient
regiodivergent ligand-controlled hydroformylations with good
to very good selectivity. To the best of our knowledge, this is
the first example of a regiodivergent hydroformylation of
alkynes (Figure 1).
To begin our investigations, a simple ynamide 1a bearing an
alkyl chain on both the nitrogen and the alkyne and a tosyl
group as the electron-withdrawing group was chosen as the
substrate, and the most efficient conditions reported in the
literature for the hydroformylation of alkyne were first tested
(i.e., triphenylphosphine as ligand, toluene as solvent at 70 °C
under 5 bar of syngas overnight) (Table 2, entry 1). The
reaction took place with a very low conversion. The main
product formed was the reduced compound 4a (68% of the
converted material), but traces of the targeted aldehydes have
been detected, and the NMR analyses showed that the β
isomer 3a was clearly favored (ratio 2a/3a = 25/75). To
improve this first encouraging result, we have then decided to
test different ligands to evaluate their effect on the overall
reaction results. Remarkably, when the ligand was changed to
P(OPh)3 the conversion increased, but more interestingly, the
ratio 2a/3a was completely inverted (Table 2, entry 2). Taken
together these two results were validating our idea that the
regioselectivity of the hydroformylation of ynamides could be
controlled in one direction or the other. After testing of several
bidentate ligands (Xantphos,20 (R)-DM-SEGPHOS,21 BiPhe-
Phos,22 TriBiPhos,23 for structures see Table 1), only
Xantphos and BiPhePhos (BPP) confirmed this differential
selectivity between phosphine and phosphite ligands while
increasing the conversion to a synthetically useful level (Table
2, entries 3−6). However, if the reaction conditions seemed to
be optimal when using Xantphos as ligand (high regioselec-
tivity and only traces of direct hydrogenation), a significant
amount of the reduced compound 4a remained when
BiPhePhos was used. Notably, the isomerization of the newly
a
Table 2. Ligand and Solvent Optimization
(2a + 3a)/
yield ald
c
entry
ligand
P(Ph)3
P(OPh)3
Xantphos
(R)-DM-
SEGPHOS
solvent
2a/3a
4a
(%)
b
1
2
3
4
toluene
toluene
toluene
toluene
25/75
71/29
5/95
nd
32/68
54/46
92/8
nd
nd
38
75
nd
d
5
6
7
8
9
BiPhePhos
TriBiPhos
BiPhePhos
BiPhePhos
BiPhePhos
toluene
toluene
hexane
DCE
81/19
nd
76/24
76/24
82/18
63/37
nd
60/40
67/33
61/39
57
nd
d
56
59
42
CH3CN
a
Rh(CO)2(acac) (2 mol %), ligand (6 mol %), 1a (1 equiv, 0.03 mol·
L−1), CO/H2 (1:1, 5 bar), 70 °C, 16 h; ratios determined by H
1
b
c
NMR analysis of the crude. Conversion = 15%. Isolated yield of 2a
d
+ 3a. Conversion <5%. nd = not determined.
formed C−C double bond has never been observed as only the
Z isomer was systematically obtained.
To optimize the reaction conditions when BiPhePhos is
used as ligand, we have investigated diverse additional
parameters. First, to evaluate the effect of the solvent on the
chelation of the directing group, we performed a quick
screening (hexane, DCE, acetonitrile). Notably, the regiose-
lectivity remained relatively unaffected by the nature of it
(Table 2 entries 5−7). Then, pushing further our effort to
reduce the fraction of the hydrogenated product 4a, we have
focused our attention on the gaseous part of the reaction. First,
we demonstrated that the pressure of syngas (CO/H2 1:1) was
not significantly influencing the efficiency and the selectivity of
the reaction (Table 3 entries 1−3). Then we investigated the
effect of the proportion of carbon monoxide. For practical
reasons, we performed this study at 10 bar. Remarkably an
enrichment in CO of the gas mixture resulted in a significant
decrease of the quantity of 4a formed without affecting the
regioselectivity of the reaction (Table 3, entries 4 and 5). The
aldehydes could be obtained in more than 75% yield. Notably,
performing the reaction at 40 °C resulted in a very low
conversion of the starting material after 16 h (less than 3%),
while the reaction done at 100 °C gave the same results as at
70 °C. In addition, we determined that 16 h was required for
complete conversion in both cases.
B
DOI: 10.1021/acs.orglett.9b03566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Optimization of CO/H2 Ratio and Pressure when
BiPhePhos Used as Ligand
Table 4. Scope and Limitation of the Reaction
a
b
entry CO/H2 pressure (bar) 2a/3a (2a + 3a)/4a yield ald (%)
1
2
3
4
5
1:1
1:1
1:1
3:1
5:1
5
10
2.5
10
81/19
75/25
79/21
71/29
70/30
63/37
70/30
65/35
82/18
84/16
57
60
55
77
75
10
a
Rh(CO)2(acac) (2 mol %), BiPhePhos (6 mol %), 1a (1 equiv, 0.03
mol·L−1), toluene, 70 °C, CO/H2 (see table body), 16 h. Ratios
b
determined by 1H NMR analysis of the crude. Isolated yield of 2a +
3a.
With these two optimized reaction conditions in hand
(Xantphos and BiPhePhos), the scope of the reaction was
investigated by performing both regiodivergent hydroformyla-
tions of diversely substituted ynamides (Table 4).
First, the influence of the substitution at the β position of
the ynamides has been evaluated. The functionalization of the
alkyl chain with a protected alcohol for instance as in ynamide
1b did not affect the selectivity of the reaction (entries 3 and
4) but induced a slight decrease of the yield around 10%. This
could be potentially explained by the higher steric hindrance of
the OTBS group in comparison to the previous phenyl ring. An
aromatic ring such as a phenyl induced a remarkable increase
of the direct reduction of 1c to the corresponding enamine 4c
when BiPhePhos was used as ligand; however, the
regioselectivity was improved with an 8/2 ratio in favor of
2c (entry 5). Interestingly, apart from a slight increase of the
proportion of reduced side product 4c, the hydroformylation
of 1c using Xantphos as ligand gave similar results as 1a in
terms of yield and regioselectivity. A silylated substituent such
as TMS on the ynamides 1d led to complete inhibition of the
reaction in both cases (entries 7 and 8) as only starting
material was recovered after 16 h. To explain this
phenomenon, if the steric hindrance can be incriminated
when Xantphos is used as ligand, the additional electronic
effect induced by the silicon atom on the polarization of the
C−C triple bond has to be considered when BiPhePhos is
employed (electronic impoverishment at the α position of the
ynamide 1d).
The use of terminal ynamide 1e with BiPhePhos as ligand
led to a significant increase in the reduced product 4e. The low
26% yield observed and the apparent inversion of selectivity is
most probably due to the degradation of the unstable enaminal
2e (entry 9). In a second time, the influence of the protecting
group on the nitrogen has been evaluated. In our opinion, this
point was crucial as the selectivity of our catalytic systems is
based on the directing abilities of this moiety. Substrates
bearing a carbamate group such as Boc (1f), Moc (1g), or an
oxazolidone (1h and 1i) gave relatively similar results as the
tosylated ynamide 1a both in terms of selectivity and yield
(entries 11−18). Then the effect of the last point of diversity,
i.e., the second substituent on the nitrogen atom, was
investigated. A benzyl group did not affect significantly the
reactivity of the reaction as 1j gave similar results as 1a with
both ligands (entries 19 and 20). An aniline-based ynamide 1k
gave better results with both ligands in term of selectivity,
while the amount of the undesired reduction was significantly
reduced (entries 21 and 22). A bulky substituent such as a tert-
butyl group on the nitrogen of the ynamide 1l led to complete
inhibition of the reaction with both ligands (entries 23 and
b
ald/red
yield ald
(%)
entry substrate
ligand
2/3
(2+3)/4
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
BiPhePhos
Xantphos
70/30
5/95
68/32
13/87
80/20
7/93
84/16
92/8
86/14
91/9
62/38
86/14
75
75
67
62
54
84
nr
nr
c
9
22/78
5/95
78/22
7/93
73/27
11/89
70/30
13/87
57/43
5/95
45/55
93/7
26
c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
54
89/11
>95/<5
87/13
>95/<5
85/15
>95/<5
88/12
>95/<5
86/14
94/6
66
68
62
87
68
75
77
78
78
79
66
72
nr
1f
1g
1g
1h
1h
1i
1i
1j
1j
60/40
7/93
81/19
<5/>95
1k
1k
1l
93/7
>95/<5
1l
nr
1m
1m
1n
1n
1o
1o
1p
1p
1q
1q
63/37
6/94
67/33
92/8
50
73
69
74
43
54
62
79
73/27
25/75
57/43
25/75
75/25
62/38
>95/<5
>95/<5
82/18
79/21
43/57
74/26
80/20
91/9
d
72/28
89/11
47
d
61
a
Rh(CO)2(acac) (2 mol %), ligand (6 mol %), 1a (1 equiv, 0.03 mol·
L−1), CO/H2 (1:1, 5 bar with Xantphos and 1:5, 10 bar with
1
BiPhePhos), toluene, 70 °C, 16 h. Ratios determined by H NMR
analysis of the crude. Isolated yield of 2 + 3. Only 3e has been
b
c
d
isolated. Conversion = 70%.
24). Together with the observation made with the TMS group
on the terminal position of 1d , this seems to demonstrate that
C
DOI: 10.1021/acs.orglett.9b03566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Hypothesis about the control of regioselectivity depending on the type of ligand used.
the steric hindrance around the alkyne has a dramatic effect on
the conversion of the reaction as, in both cases (1d and 1l), the
starting material was fully recovered after 16 h.
rhodium center (Int. Ic) to install the catalyst at the α position
through an 5-exo-dig type hydrometalation (Int. Id) resulting
in the formation of enaminal 2a as the major product (Figure
2, path I).
The presence of an additional chelating moiety on the
nitrogen side such as morpholine (1m) induced a slight
decrease of the selectivity when BiPhePhos was used as ligand,
but notably the amount of reduced compound 4m was
significantly increased (entry 25). However, when the reaction
was performed with Xantphos, the reaction proceed with
results in the classical range of the previous substrates (entry
26).
Interestingly, the use of an amino acid derivative bearing a
carboxyl group as a chelating group (1n) induced in equivalent
proportion an increase of the regioselectivity (2 vs 3) with
BiPhePhos (entry 27) and a decrease of it with Xantphos
(entry 28). Remarkably, the latter was accompanied with an
increase of the undesired reduction leading to 4n.
Finally, the steric parameter in the β position was
investigated using the relatively low bulky oxazolidinone as
nitrogen moiety. Logically, with BiPhePhos as the ligand, the
major isomer is systematically the α one, with good to very
good selectivity. The steric control of the regioselectivity with
Xantphos as ligand has been demonstrated. Indeed, the more
the steric congestion increases, the more the proportion of α
isomer significantly increases ultimately going to a total
inversion of the selectivity in the case of a tert-butyl group.
A possible explanation for the regioselectivity observed is
based on the electronic richness of the phosphorus atom of the
two families of ligands (Figure 2). In our opinion, the
discriminating step is the hydrometalation one. In the case of
phosphine ligands, the phosphorus is relatively electron-rich
with a high σ-donating character24 resulting in a coordination
to the rhodium strong enough to avoid the competitive
coordination of the sulfonamide moiety of the ynamide. In that
case, only the polarization and the steric hindrance of the
alkyne is influencing the selectivity (Int. IIc) by installing the
rhodium at the most electron rich and the less hindered
position, namely the β one (Int. IId). Under these conditions,
the 3-aminoacrolein 3a is the major product of the reaction
(Figure 2, path II).
To conclude, we have developed a regiodivergent access to
2- and 3-amino acrolein derivatives based on the hydro-
formylation of ynamides. The stereospecificity is totally
conserved as the reaction is always leading to the product
resulting from the syn addition of the hydrogen and the formyl
group on the alkyne moiety. The regioselectivity can be
controlled by the ligand and can be inverted according to its
nature. The use of BiPhePhos mainly furnishes the α isomer,
while the use of Xantphos allows us to obtain quasi-exclusively
the β one. More broadly, this study opens the door to
regiodivergent hydroformylations of alkynes. The concept
used, i.e., chelation versus steric control, to access selectively
one or the other regioisomer could be generalized and is under
investigation in our laboratory. In addition, both experimental
and in silico investigations are in progress to better rationalize
the regioselectivity of the reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03566.
Experimental procedures; full spectroscopic data for all
1
new compounds; copies of H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: donnard@unistra.fr.
*E-mail: nicolas.girard@unistra.fr.
ORCID
Morgan Donnard: 0000-0002-9303-4634
Nicolas Girard: 0000-0003-4610-9872
Notes
Conversely, when the less σ-donating phosphite ligand is
used,10 the electron-withdrawing group can coordinate the
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b03566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We are grateful to the Centre National de la Recherche
Scientifique (CNRS) and the Universite de Strasbourg for
financial support. Paul Chatelain, Maryame Sy, and Pierre
Hansjacob (University of Strasbourg) are acknowledged for
preliminary investigations and substrate synthesis.
́
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