Palladium-Catalyzed Carbo-Oxygenation of Propargylic Amines using in Situ Tether Formation

Article abstract of DOI:10.1002/chem.201900020

1,2-Amino alcohols and α-aminocarbonyls are frequently found in natural products, drugs, chiral auxiliaries, and catalysts. This work reports a new method for the palladium-catalyzed oxyalkynylation and oxyarylation of propargylic amines. The reaction is perfectly regioselective based on the in situ introduction of a hemiacetal tether derived from trifluoroacetaldehyde. cis-Selective carbo-oxygenation was achieved for terminal alkynes, whereas internal alkynes gave trans-carbo-oxygenation products. The obtained enol ethers could be easily transformed into 1,2-amino alcohols or α-amino ketones using hydrogenation or hydrolysis, respectively.

Full text of DOI:10.1002/chem.201900020

A Journal of
Accepted Article
Title: Palladium-Catalyzed Carbo-oxygenation of Propargylic Amines
using In Situ Tether Formation
Authors: Phillip D. G. Greenwood, Erwann Grenet, and Jerome Waser
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10.1002/chem.201900020
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Palladium-Catalyzed Carbo-oxygenation of Propargylic Amines
using In Situ Tether Formation
Phillip D. G. Greenwood, Erwann Grenet and Jerome Waser*[a]
Dedication ((optional))
Abstract: 1,2-Amino alcohols and α-aminocarbonyls are
frequently found in natural products, drugs, chiral auxiliaries and
catalysts. Herein, we report a new method for the palladium-
catalyzed oxyalkynylation and oxyarylation of propargylic amines. The
reaction is perfectly regioselective based on the in situ introduction of
a hemiacetal tether derived from trifluoroacetaldehyde. Cis-selective
carbo-oxygenation was achieved for terminal alkynes, whereas
internal alkynes gave trans-carbo-oxygenation products. The
obtained enol ethers could be easily transformed into 1,2-amino
alcohols or -amino ketones using hydrogenation or hydrolysis
respectively.
particularly attractive, but leads to formidable challenges in
reactivity, regio- and stereo-selectivity.[6] The use of tethering
groups installed onto existing functional groups such as alcohols
or amines allows the functionalization of  bonds under mild
conditions with high regioselectivity, but several steps are usually
required to install and remove the tether.[7] Inspired by pioneering
works of Beauchemin,[8] Hiemstra,[9] Stahl[10] and Menche,[11] our
group has developed new tethers based on acetaldehydes for the
palladium-catalyzed functionalization of allylic alcohols and
amines.[12] In particular, a one-pot tether introduction/olefin carbo-
oxygenation of allyl amines was developed for the synthesis of
aminoalcohols (Scheme 1A).[12a] Nevertheless, important
limitations remain for this transformation due to the challenging
carbon-carbon formation on a sp3 center: only alkyne and
electron-deficient arene halogenides could be used as
electrophiles and only primary positions could be functionalized.
Therefore, products bearing a stereocenter in  position to the
amine could not be accessed.
Compounds containing vicinal oxygen- and nitrogen-
functionalities are highly represented among bioactive molecules.
Examples of -amino ketones include the protease inhibitor
Rupintrivir (1)[1] and the antidepressant Bupropion (2).[2] Bioactive
amino alcohols are even more widespread, with a broad range of
bioactivities, as shown by the well-known stimulant
pseudoephedrine (3), the gastroprotective AI-77-B (4)[3] or the
antidepressant 5.[4] Chiral amino alcohols have also found
applications as ligands or organocatalysts in asymmetric
synthesis, as exemplified by the Jorgensen-Hayashi catalyst 6.[5]
Figure 1. Important organic compounds containing amino ketones and amino
alcohols.
The synthesis of amino alcohols from broadly available
unsaturated hydrocarbons such as alkenes and alkynes is
Scheme 1. Allyl and propargyl amines as precursors for the tethered
carbooxygenation of olefins.
[a]
Phillip Greenwood, Dr. Erwann Grenet and Prof. Dr. Jerome Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (CH)
Fax: (+)41 21 693 97 00
To overcome these limitations, we considered propargylic amines
as widely available starting materials.[13] After oxypalladation, the
formed palladium-Csp2 intermediate should undergo reductive
elimination more efficiently, leading to
a broader scope.
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
Furthermore, both amino ketones and amino alcohols could be
accessed from the products via hydrolysis and hydrogenation
respectively. Such a transformation will also give access to highly
Supporting information for this article is given via a link at the end of
the document.
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substituted enol ethers, which are challenging to synthesize
stereoselectivity, in particularly starting from non-heteroatom
substituted alkynes.[14] When considering the synthetic versatility
of enol derivatives, new synthetic methods are urgently needed.
In comparison to olefins, the tethered multi-functionalization of
alkynes has been less investigated. Most success has been met
using CO2 as tether precursor from propargylic amines for the
synthesis of oxazolidinones.[15] However, only one new C-O bond
is formed in these processes. Using palladium catalysis, an
important breakthrough was reported by Nevado and co-workers
in 2016, with the oxyarylation of propargylic amines using CO2 as
[a]NMR yields using p-difluorobenzene as internal standard.[19]
These reactions conditions were then applied to the more
challenging internal alkyne 8a. We were pleased to see that the
desired product 12a could be obtained in 40% yield (entry 4),
whereas -substituted allyl amines could not be used in our
previous work.[12a] Interestingly, formation of the E product was
now favored. Attempts to increase the yield by changing the
solvent or ligand were not successful (entries 5 and 6). In contrast,
a strong effect of the base was observed: the use of cesium
acetate led to low yield (entry 7), but 67% of 12a could be obtained
using potassium phosphate (entry 8). Finally, using XantPhos as
ligand allowed increasing both yield and selectivity (entry 9).
With optimized conditions in hand, we investigated first the
functional group tolerance on the amine substituent with terminal
propargylic alkynes and bromide 10a as electrophile (Scheme 2A).
Methoxy- and chloro- substituted benzyl amines 11b-d were
obtained in more than 80% yield with good Z selectivity. In
addition, a furyl, a methyl and a phenyl group were also tolerated
(products 11e-g). When a bis-propargylic amine was used as
starting material, enyne 11h was obtained as the Z isomer only.
The moderate yield was due to the formation of diyne 13 as side
product through sp-sp coupling. The formation of 13 could be
increased to 41% by doubling the number of equivalents of
bromide 10a. The carbo-oxygenation was also successful in case
of an aliphatic alkynyl bromide as partner to give product 11i
(Scheme 2B).
We then turned to the more challenging internal alkynes (Scheme
2C), which are a particular interesting class of substrates, as the
corresponding olefins did not react in our previous work.
Gratifyingly, primary, secondary, tertiary and cyclic alkyl groups
were all well tolerated on the alkyne (products 12a-f). With bulky
alkyl groups, only the E isomer was obtained. Aryl-substituted
enynes 12g-j were also obtained with perfect E selectivity. When
substituents were introduced at the propargylic position of the
amine, the reaction was too slow with bidentate phosphine ligands.
Fortunately, useful yields could be still obtained using tris(2-
furyl)phosphine as ligand (Scheme 2D). Enynes 14a-b were
obtained as mixtures of two diastereoisomers.
tether
precursor
(Scheme
1B).[16] Multi-functionalized
oxazolidinones were obtained as products, but no transformation
into other valuable building blocks was reported.
Herein, we report the first successful use of acetaldehyde-derived
tethers for both the oxy-alkynylation and -arylation of propargylic
amines (Scheme 1C). In contrast to our previous work with allyl
amines, substituted alkynes could also be used, resulting in the
highly stereoselective synthesis of tetrasubstituted alkenes. The
tether could be easily removed, enabling the synthesis of amino
ketones, amino alcohols and furan heterocycles.
We started our investigations with the oxyalkynylation of simple
benzylated propargylic amine 7a (Table 1). Using silylated
bromoalkyne 10a and the conditions developed previously for
allylic amines (Pd(0) catalyst,[17] hemiacetal 9, DPEPhos as ligand,
cesium carbonate as a base, in toluene), the desired product
could be obtained in 82% yield and 4:1 Z:E ratio (entry 1).[18] In
contrast, P(2-furyl)3, which was one of the best ligands in the case
of allylic amines, led to inferior results (entry 2). An improvement
in Z:E selectivity could be achieved using dichloroethane (DCE)
as solvent (entry 3).
Table 1. Optimization of the oxyalkynylation of amine 7a and 8a
Next, aryl iodides were examined as electrophiles (Scheme 2E).
Only low yields were obtained with DPEPhos or XantPhos as
ligands, but better results were obtained with RuPhos.[19] The
reaction of propargylamine 8a with phenyl iodide gave enol ether
15a in 78% yield and complete E selectivity.[20] This result is
noteworthy, as only electron-poor aryl electrophiles could be used
in our previous work on allyl amines. Aryl electrophiles bearing
electron-rich or –poor substituents could be used to give the
desired products 15b-f in good yields. Only in the case of an
ortho-methyl substituent the yield decreased to 45% (product
15c). A cyclopropyl substituent on the alkyne was also well
tolerated to give alkene 15g. Finally, difficult to access
tetrasubstituted olefins 15h-j bearing two aryl groups were also
Entry
R
H
Ligand
Base/solvent
Cs2CO3/toluene
Cs2CO3/toluene
Cs2CO3/DCE
Cs2CO3/DCE
Cs2CO3/toluene
Cs2CO3/DCE
CsOAc/DCE
K3PO4/DCE
Yield[a]/ Z:E ratio
82%/4:1
23%/3:1
83%/9:1
40%/1:7
20%/1:5
-
1
2
3
4
5
6
7
8
9
DPEPhos
P(2-furyl)3
DPEPhos
DPEPhos
DPEPhos
P(2-furyl)3
DPEPhos
DPEPhos
XantPhos
H
H
Me
Me
Me
Me
Me
Me
19%/ND
67%/1:6
73%/1:10
obtained with perfect
E selectivity. Such compounds are
important pharmacophores: for example, the drug tamoxifen (16),
which is used to treat breast cancer, bears an olefin with the same
two aryl substituents as compound 15j.
K3PO4/DCE
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Scheme 2. Scope of the carbooxygenation reaction with alkynyl bromides and aryl iodides. The olefins are obtained with >20:1 stereoselectivity, unless noted
otherwise. The major isomer obtained is drawn. [a]DPEPhos as (7.5 mol%) ligand, Cs2CO3 as base. [b]13 also isolated in 13% yield. [c]2.6 equiv.
bromoalkyne used. [d]XantPhos (7.5 mol%) as ligand, K3PO4 as base. [e]P(2-furyl)3 (15 mol%) as ligand, K3PO4 as base. [f]RuPhos (7.5 mol%) as ligand,
K3PO4 as base.
With a broad range of enynes and styrene derivatives in hand,
we turned to the functionalization of the obtained products.
Deprotection of product 12a with TBAF gave surprisingly stable
electron-rich terminal enyne 17 in 89% yield (Scheme 3). Enyne
17 could be easily further modified to give products 18 and 19 via
[3+2] addition and Sonogashira coupling respectively. The main
objective of this work was to access both amino ketone and amino
alcohol building blocks. Therefore, the removal of the acetal
functionality was investigated next. Hydrolysis in presence of
trifluoroacetic acid (TFA) was successful, but hydration of the
alkyne occurred upon isolation to give diketone 20 in 90% yield.
When a gold catalyst was added directly after acetal removal,
furan 21a was obtained in 88% yield. This transformation was also
successful with a cyclopropyl or phenyl substituent on the alkyne
(products 21b-c). Finally, hydrogenation of enyne 12a gave
protected amino alcohol 22 in 76% yield. In the case of styrene
Scheme 3. Transformations of enyne products 12. Reaction conditions: a)
derivatives 15, hydrogenation was completely stereoselective
with both alkyl and aryl substituents to give 23a and 23b in 91%
and 80% yield respectively (Scheme 4). The latter is especially
interesting, due to the importance of diarylmethane derivatives as
bioactive compounds, such as antidepressant 5. Compound 23a
was easily deprotected to give amino alcohol 24 in 96% yield.
TBAF, THF, 0 °C; b) pBr-BnN3, CuSO4; Na-ascorbate, THF:H2O, rt; c) pNO2-
Ph-I, Pd(OAc)2, DABCO, MeCN; d) TFA, H2O, CHCl3, rt; e) TFA, H2O, CHCl3, rt
then Au(PPh3)2Cl2, Ag(SbF6), rt; f) H2, Pd/BaSO4, EtOH, 55 °C.
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oxygenation of propargylic amines using palladium catalysis. The
reaction was successful with trifluoroacetaldehyde derived tethers
with both alkynyl bromides and aryl iodides as nucleophiles and
could be used for the stereoselective synthesis of tri- and tetra-
substituted olefins with high stereoselectivity. The switch of Z- to
E- selectivity observed when going from terminal to internal
alkynes as starting material may indicate a switch from syn- to
anti- palladation in the C-O bond forming step, but further
mechanism studies will be required to fully understand the
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blocks, such as amino ketones, amino alcohols or furans. Further
studies are currently ongoing for applying the tether strategy to
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Acknowledgements
This work is supported by the Swiss National Science Foundation
(No. 200021_159920) and EPFL. We thank Dr. R. Scopelliti and
Dr. F. F. Tirani from ISIC at EPFL for X-ray analysis.
Keywords: alkynes • tethers • amino alcohols • stereoselective
synthesis • palladium catalysis
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Phillip Greenwood, Erwann Grenet and
Jerome Waser*
Page No. – Page No.
Palladium-Catalyzed Carbo-
oxygenation of Propargylic Amines
using In Situ Tether Formation
Tether control: In-situ tether formation allows the selective palladium-catalyzed
oxyalkynylation and oxyarylation of propargyl amines in high yield and selectivity.
The obtained products are easily transformed into useful building blocks, such as
amino ketones, amino alcohols and furans.
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