Highly Enantioselective Synthesis of Propargyl Amide with Vicinal Stereocenters through Ir-Catalyzed Hydroalkynylation

Article abstract of DOI:10.1002/anie.201916088

Chiral propargyl amines are valuable synthetic intermediates for the preparation of biologically active compounds and functionalized amines. Catalytic methods to access propargyl amines containing vicinal stereocenters with high diastereoselectivity are particularly rare. We report an unprecedented strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centres. An iridium complex, ligated by a phosphoramidite ligand, catalyzes the hydroalkynylation of β,β-disubstituted enamides to afford propargyl amides in a highly regio-, diastereo-, and enantioselective fashion. Stereodivergent synthesis of all four possible stereoisomers was achieved using this strategy.

Full text of DOI:10.1002/anie.201916088

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Accepted Article
Title: Highly Enantioselective Synthesis of Propargyl Amide with Vicinal
Stereocenters through Ir-Catalyzed Hydroalkynylation
Authors: Wen-Wen Zhang, Su-Lei Zhang, and Bi-Jie Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201916088
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10.1002/anie.201916088
Angewandte Chemie International Edition
RESEARCH ARTICLE
Highly Enantioselective Synthesis of Propargyl Amide with
Vicinal Stereocenters through Ir-Catalyzed Hydroalkynylation
Wen-Wen Zhang‡, Su-Lei Zhang‡, and Bi-Jie Li*
[a]
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing, 100084, China
Email: bijieli@mail.tsinghua.edu.cn
‡Contributed equally to this work
Supporting information for this article is given via a link at the end of the document.
Abstract: Chiral propargyl amines are valuable synthetic
intermediates for the preparation of biologically active compounds
and functionalized amines. Catalytic methods to access propargyl
amines containing vicinal stereocenters with high diastereoselectivity
are particularly rare. We report an unprecedented strategy for the
synthesis of enantioenriched propargyl amines with two stereogenic
centres. An iridium complex, ligated by a phosphoramidite ligand,
catalyses the hydroalkynylation of β,β-disubstituted enamides to
challenge.[12] Previously, we have developed Rh- and Ir-
catalyzed enantioselective hydroalkynylation of enamide to
access chiral propargyl amides and homopropargyl amides with
a single stereocenter, respectively.[13] A prominent feature of this
chemistry is that it proceeds through
a
stereospecific
hydroalkynylation of the alkene rather than alkynylation of an
imine (as in A3 coupling). This intrinsic stereospecificity provides
a previously unrecognized opportunity to access stereodefined
propargyl amide containing multiple stereocenters. More
importantly, the stereospecificity of the hydroalkynylation
strategy would enable the diastereoselectivity to be precisely
controlled. In addition, reversal of the diastereoselectivity could
be achieved by switching the olefin geometry. Therefore, a novel
stereodivergent synthesis of all the possible stereoisomers could
be achieved through this strategy, which is not viable by
previous methods.
afford propargyl amides in
a highly regio-, diastereo-, and
enantioselective fashion. Stereodivergent synthesis of all four
possible stereoisomers was achieved using this strategy.
Introduction
Chiral amines, including those containing vicinal
stereocenters, frequently occur in a range of natural products
and drug molecules.[1] In particular, enantioenriched propargyl
amines are valuable synthetic intermediates frequently used for
the preparation of various bioactive molecules.[2] This is due to
the rich chemistry of the alkyne group, enabling the
transformation of propargyl amines to diverse chiral amine
compounds.[3]
Several important strategies have been developed for the
catalytic asymmetric synthesis of propargyl amines (Scheme 1).
The prevailing strategy involves the coupling of an aldehyde, an
amine, and
a
terminal alkyne (A3 coupling).[4],[5] While
synthetically useful, this method generates propargyl amine with
a single stereocenter through the alkynyl addition step.[6] The
second strategy, namely propargylic substitution,[7] delivers
chiral propargyl amines through catalytic substitution of
propargylic electrophile with an amine.[8] Similarly, only one
stereocenter is formed in the propargylic amine product.
Alternatively, enantioselective Mannich reaction between
carbonyl compound and C-alkynyl imine has been developed
using metal or small molecule catalyst.[9],[10] Enantioenriched
propargyl amines with vicinal stereocenters were produced
through this strategy. However, the diastereoselectivity is highly
dependent on the substrate, and modest diastereoselectivities
were observed in many cases. In addition, reversal of the
Scheme 1. Strategies for the preparation of propargyl amines.
However, our previous Rh- and Ir-based catalyst systems
did not work for β,β-disubstituted enamide because the reactivity
of the β,β-disubstituted enamide is significantly lower than that
of β-monosubstituted enamide due to the increased steric
hindrance. Therefore, identification for a new catalytic system is
necessary. In addition, the regioselectivity must be controlled
because the alkene has two potential reaction sites.
Furthermore, the catalyst effective for the hydroalkynylation
must not catalyze alkene isomerization,[14] as it would lead to
erosion of enantioselectivity and diastereoselectivity. In fact,
despite the progress made in enantioselective alkynyl addition
reactions,[15],[16],[17] catalytic asymmetric hydroalkynylation of
nonactivated tri-substituted olefins is rare,[18] and no such
diastereoselectivity
to
selectively
afford
the
other
diastereoisomer was not possible through this method. Despite
the important synthetic value of propargyl amines with vicinal
stereocenters, a general catalytic method to access these
compounds with both high diastereo- and enantio-control
remains to be developed.[11]
We envisioned that a catalytic asymmetric hydroalkynylation
of enamide could provide a potential solution to this synthetic
1
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Table 1. Evaluation of Ligandsa
example has been reported for the diastereoselective generation
of two stereocenters.
Here, we report an iridium-catalyzed asymmetric
hydroalkynylation of β,β-disubstituted enamides for the synthesis
of propargyl amides with vicinal stereocenters. In addition to
high enantioselectivity, complete diastereo-control was observed
by leveraging the stereospecificity of the hydrofunctionalization
event. Moreover, this strategy enables stereodivergent synthesis
of all possible stereoisomers by changing the olefin geometry
and ligand configuration.[19] Computational studies support a
mechanism involving C-C forming reductive elimination at the
iridium center.
Results and Discussion
Reaction development. The catalytic reaction of enamide
1a with terminal alkyne 2 was evaluated in the presence of a
rhodium catalyst with a variety of phosphine ligands. However,
none of these reactions provided significant amount of the
product (see Supporting Information). Thus, we turned our
attention to iridium based catalyst (Table 1). With L1 as a ligand,
the hydroalkynylation product was observed in low yield and
diastereoselectivity. The yield and diastereoselectivity were
slightly improved with BINAP (L2) as a ligand. A reversal of the
diastereoselectivity was observed with Ph-BPE ligand (L3),
indicating that significant alkene isomerization occurred.
Reactions with phosphoramidite ligands provided promising
results. Although catalytic hydroalkynylation with ligand L4-L6
delivered the product in low yield, reaction with L7 provided the
product
in
high
yield.[20]
Furthermore,
complete
diastereoselectivity and excellent enantioselectivity were
observed. The importance of the pendent olefin in L7 was
demonstrated by the reaction with L9 as a ligand, which formed
the product with diminished yield, diastereo- and
enantioselectivity.
Substrate scope. We further probed the scope of this
method (Table 2). The substituent on the amide group does not
have a significant impact on the yield and selectivity, as
demonstrated by the catalytic hydroalkynylations with i-Pr, t-Bu,
and phenyl substituted enamides (3b-3d). However, the
hydroalkynylation product was not observed for substrates
containing a carbamate or an N-methyl amide group (3e-3f). The
catalytic system worked well for a range of dialkyl substituted
enamides, affording the corresponding propargyl amides in high
yields, diastereo-, and enantioselectivities (3h-3r). Slightly
For less reactive β-aryl substituted enamides, a H8-binol
based ligand was used because of the higher activity of the
catalyst formed from this ligand. An array of propargyl amides
with a β-aryl substituent were produced in good yields (3s-3z).
Similarly, high diastereo- and enantioselectivities were observed
in all cases. The absolute configurations of the products 3c and
3s were determined by X-ray analysis (see Supporting
Information).
Stereodivergent synthesis. Next, we investigated the
stereodivergent synthesis through this method (Scheme 2).
Catalytic hydroalkynylation of E-1a with (S)-L7 generated the
syn-product (S,R)-3a. The anti-product (S,S)-3a was obtained by
switching the enamide geometry. Unlike our previous
observation,[13] the olefin geometry does not have a significant
impact on the yield and enantioselectivity. With (R)-L7 as a
ligand, hydroalkynylations of E- and Z-1a afforded the other two
stereoisomers. Thus, this hydroalkynylation strategy provides
access to all possible stereoisomers through catalyst control and
tuning substrate geometry.
decreased diastereoselectivity was
observed in the
hydroalkynylation of β-ethyl enamide (3q), due to the increase of
the temperature to 80 oC.
2
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RESEARCH ARTICLE
Table 2. Substrate Scope of Ir-Catalyzed Hydroalkynylationa
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RESEARCH ARTICLE
was obtained with a 1:1 metal to ligand ratio (Equation 1).
Therefore, it is likely that only one phosphoramidite ligand
coordinates to the metal center during catalysis.[21]
To provide further support for the 1:1 metal to ligand ratio
during catalysis, experiments were conducted to probe the non-
linear effect. However, no non-linear effect was observed
(Figure 1). The absence of a non-linear effect is consistent with
1:1 metal to ligand ratio in this alkynylation reaction.
Scheme 2. Stereodivergent synthesis.
100
Transformation of products. After deprotection of the silyl
group, the resulting propargyl amide 4 underwent diverse
subsequent functionalizations (Scheme 3). For example, a Pd-
catalyzed Sonogashira coupling of 4 generates 5a in high yield.
Hydrogenation, semi-hydrogenation, and hydroarylation of 4
deliver the alkyl and allyl amine compounds 5b-5d. Finally, the
amide group could be deprotected to form a free propargyl
amine 5e. Thus, the asymmetric hydroalkynylation enables facile
preparation of various chiral amine compounds from easily
available starting materials.
y = 1.0186x + 0.8539
R² = 0.993
80
60
40
20
0
0
20
40
60
80
100
The ee value of ligand L7 (%)
Figure 1. Absence of non-linear effect
Computational studies. Previously, we have showed that
catalytic hydroalkynylation of enamide occurs at the α position
with a rhodium catalyst and at the β position with an iridium
catalyst.[13] Our experimental and computation studies
suggested that a Chalk-Harrod mechanism is operative in the
Rh-catalyzed α-alkynylation. For the Ir-catalyzed β-alkynylation,
computational studies by Lin and co-workers indicated that a
modified Chalk-Harrod mechanism is more favorable.[22]
To distinguish which mechanism is operative for the current
Ir-catalyzed α-alkynylation, computational studies were
conducted (see Supporting Information for more details). First,
the energy profile of a catalytic cycle through the modified
Chalk-Harrod mechanism was computed. The reaction pathway
with the lowest activation barrier was shown in Figure 2A. It
starts with oxidative addition of the C-H bond to the metal center
to afford an enamide bound iridium acetylide Int-2a. Migratory
insertion of the alkene into the Ir-C bond followed by C-H
forming reductive elimination delivers the hydroalkynylation
product. Similar to the computation by Lin and co-workers,
migratory insertion of the alkene into the Ir-C bond has the
highest activation barrier (TS-2a). However, an activation free
energy of 33.7 kcal/mol is unusually high for a reaction
conducted at 60 oC. This high activation barrier likely reflects the
difficulty associated with the migratory insertion into a sterically
more hindered, trisubstituted alkene.
Scheme 3. Derivatization of hydroalkynylation product.
Metal to ligand ratio. To gain information about the metal to
ligand ratio of the active catalyst, we conducted the catalytic
hydroalkynylation by varying the amount of the ligand. Although
the enantioselectivity did not change significantly, the best yield
Subsequently, the energy profile of a catalytic cycle through
the Chalk-Harrod mechanism was computed. The pathway with
the lowest activation barrier was shown in Figure 2B. Oxidative
4
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RESEARCH ARTICLE
addition of the alkyne forms intermediate Int-2b. It undergoes an
intramolecular isomerization[23] to generate an octahedral
complex Int-3b. Subsequent migratory insertion of the alkene
into the iridium hydride occurs, furnishing an iridacycle Int-4b.
Finally, C-C forming reductive elimination at the iridium center
generates the hydroalkynylation product. The computed
energies indicated that migratory insertion of the alkene into the
iridium hydride bond is a relatively fast step, possibly due to the
chelation assistance[18] (no such chelation in TS-2a) and the
higher intrinsic reactivity of a metal hydride compared to a metal
carbon bond.[22] C-C forming reductive elimination at the iridium
center has the highest activation barrier (TS-3b). This activation
barrier is significantly lower than that for the modified Chalk-
Harrod catalytic cycle (TS-2a). Therefore, the computed
energies indicated that the Chalk-Harrod mechanism is more
favorable. The low activation barrier observed for C-C forming
reductive elimination at the iridium center is likely a result of the
ligand effect. Because the phosphoramidite is less electron-
donating than a bisphosphine ligand, the electron density at the
metal center is reduced, thus facilitating the reductive elimination
to occur more rapidly.[24]
Figure 2. Computed energies for Chalk-Harrod and modified Chalk-Harrod mechanisms. Calculations were carried out at the M06/6-
311++g(d,p)/SDD//B3LYP/6-31g(d,p)/Lanl2dz level of theory.
be formed in moderate ee. Therefore, the Chalk-Harrod
mechanism is more consistent with our experimental
observation.
In transition state structure TS-3b’, the lower naphthyl ring
on the ligand positions in a way that it compels the alkyl group to
tilt toward the amide group. Significant steric interaction was
observed between the ethyl group and the NH moiety. This
repulsive interaction likely contributes to the higher energy
observed for this competing transition state and consequently
leads to excellent enantioselectivity.
Conclusion
In summary, we have developed an iridium-catalyzed
enantioselective hydroalkynylation of β,β-disubstituted enamides.
Excellent regio-, diastereo-, and enantioselectivities were
observed for the hydroalkynylation products. The diastereo-
control by the stereospecificity and enantio-control by the
catalyst provided an opportunity for the stereodivergent
synthesis. Computational studies indicated that a Chalk-Harrod
mechanism is operative under the current reaction conditions.
Further investigation into the detailed mechanism is currently
ongoing in our laboratory.
Scheme 4. Competing transition states.
The Chalk-Harrod mechanism not only is lower in computed
energy, but also predicts the correct enantiomer observed in the
experiment (Scheme 4). The competing transition state TS-3b’
has an activation energy of 29.6 kcal/mol. Thus, the product was
predicted to be formed in more than 99% ee. This is in good
agreement with the experiment. In contrast, the modified Chalk-
Harrod mechanism predicts that the opposite enantiomer would
5
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Top200%20Pharmacetical%20Products%20by%20US%20Retail%20S
a les%20in%202012_0.pdf.
Experimental Section
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Preparation of E-enamide 1c: AlMe3 (2.0 M in hexane, 20
mmol) was added dropwise to a solution of Cp2ZrCl2 (10 mmol)
in DCE (15 mL) at 0 °C. After stirring for 1 h, 4-phenyl-1-butyne
(10 mmol) was added at 0 °C. The reaction mixture was stirred
for 24 h at room temperature and then cooled to 0 ºC before I2
(12 mmol) in THF (15 mL) was added. After 5 h, the mixture was
quenched with H2O carefully. The organic layer was extracted
with DCM, washed with Na2S2O3, dried with Na2SO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography to afford vinyl iodide as a single isomer (76%
yield).
A Schlenk tube was charged with pivalamide (20 mmol),
copper iodide (20 mmol), and Cs2CO3 (20 mmol). Vinyl iodide
(10 mmol) and N,N’-dimethylethylenediamine (20 mmol) in THF
were added under argon. The mixture was stirred at 60 ℃ for 12
h. After filtration over Celite, the mixture was diluted with DCM
and washed with water. The organic extract was dried over
Na2SO4 and concentrated in vacuo. The crude product was
purified by flash chromatography to afford E-enamide 1c (92%
yield).
Preparation of Z-enamide 1a’: To a cooled mixture (-78 °C) of
bromomethyltriphenylphosphonium bromide (10.5 mmol) in THF
(80 mL) under N2 was added t-BuOK (10.7 mmol). After 1 h at -
78 °C, a solution of benzylacetone (10 mmol) in 5.0 mL of dry
THF was added dropwise and the mixture was stirred for 1 h.
The reaction mixture was warmed up to room temperature and
poured into 50 mL of pentane while Ph3PO precipitated out of
the solution. After filtration, the solution was concentrated and
the residue was purified by flash chromatography to afford vinyl
bromide as an E and Z mixture (1:1 ratio, 60%). Further
amidation of the vinyl bromide using the procedure described
above afforded a mixture of E-1a and Z-1a’ from which Z-1a’
was separated by column chromatography (30% over two
steps).
Procedure for catalytic hydroalkynylation: In an N2-filled
glovebox, enamide 1a (0.10 mmol, 1.0 equiv), Ir(COD)2BF4 (2.5
mg, 0.0050 mmol), (S)-L7 (2.5 mg, 0.0050 mmol) were weighed
into a one-dram screw-capped vial. Subsequently, DCE (0.30
mL) and alkyne (0.20 mmol, 2.0 equiv) were added via syringes.
The vial was capped with a Teflon-lined screw cap, and the
resulting solution was then removed from the glovebox, placed
in a pre-heated aluminum block at 60 °C for 12 h. The reaction
mixture was concentrated and the residue was purified directly
by column chromatography to afford 38.2 mg of propargyl amide
3a as an oil (99%).
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This work was supported by the National Natural Science
Foundation of China (Grant No. 91856107 and No. 21672122)
and 111 Project (B16028). Prof. Nian-Kai Fu at Institute of
Chemistry, CAS is acknowledged for the help of HPLC analysis.
Keywords: propargyl amide • alkynylation • enamide •
asymmetric catalysis • vicinal stereocenters
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10.1002/anie.201916088
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
We have developed a hydroalkynylation strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centers.
The diastereo-control by the stereospecificity and enantio-control by the catalyst provided an opportunity for the stereodivergent
synthesis.
8
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