Palladium-Catalyzed Carboamination of Allylic Alcohols Using a Trifluoroacetaldehyde-Derived Tether

Article abstract of DOI:10.1021/acs.orglett.7b01524

The selective palladium-catalyzed carboamination of allylic alcohols is reported on the basis of the use of an easily introduced trifluoroacetaldehyde-derived tether. Aminoalkynylation reactions were realized using alkynyl bromides and commercially available phosphine ligands. For aminoarylations, a new biaryl phosphine ligand, "Fu-XPhos", was introduced to overcome a competitive Heck pathway. The carboamination products were obtained in high yields and diastereoselectivity. The tether could be easily removed to give value-added amino alcohol building blocks.

Full text of DOI:10.1021/acs.orglett.7b01524

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Carboamination of Allylic Alcohols Using a
Trifluoroacetaldehyde-Derived Tether
Bastian Muriel, Ugo Orcel, and Jerome Waser*
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fed
́ ́
erale de
Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: The selective palladium-catalyzed carboamination of
allylic alcohols is reported on the basis of the use of an easily introduced
trifluoroacetaldehyde-derived tether. Aminoalkynylation reactions were
realized using alkynyl bromides and commercially available phosphine
ligands. For aminoarylations, a new biaryl phosphine ligand, “Fu-XPhos”,
was introduced to overcome a competitive Heck pathway. The
carboamination products were obtained in high yields and diaster-
eoselectivity. The tether could be easily removed to give value-added
amino alcohol building blocks.
allowing the simultaneous formation of a carbon−nitrogen and
a carbon−carbon bond have been less investigated, despite
their high potential for the synthesis of more complex building
blocks. Important breakthroughs have been achieved by the use
of carbamate- or imidate-based tethers on the alcohol (Scheme
1, eq 2).6 Nevertheless, the reported scope of these
transformations remains narrow, and the tethers often require
harsh conditions for cleavage. In this respect, the use of
hemiaminal tethers would appear highly attractive for the
functionalization of allylic alcohols, as they can be more easily
removed. In fact, Hiemstra and co-workers and Stahl and co-
workers have pioneered the use of such tethers for Wacker-type
oxidative cyclization reactions (Scheme 1, eq 3).7 Nevertheless,
several separated steps were still needed to install and remove
such tethers, and they were never used for more complex
transformations involving multiple bond-forming events.
Recently, our group introduced (hemi)aminal tethers derived
from trifluoroacetaldehyde for the carboamination of allylic
amines to give amino alcohols and diamines.8 We wondered if
the same strategy could be applied to allylic alcohols. In this
case, the lower nucleophilicity of alcohols compared to amines
was expected to be a major challenge for the efficiency of tether
installation.
llylic alcohols are broadly available and versatile building
1
Ablocks in organic synthesis. The inductive or directing
effect of the alcohol or its derivatives can be used to achieve
selective functionalization of the alkene double bond. In
particular, amination reactions have been intensively inves-
tigated as they give access to 1,2- and 1,3-amino alcohols,2
which are essential building blocks for the synthesis of bioactive
natural and synthetic compounds.3 Palladium catalysis has been
especially successful in this respect, leading to synthetically
highly useful multifunctionalization reactions such as amino-
hydroxylation4 or diamination5 (Scheme 1, eq 1). Reactions
Scheme 1. Palladium-Catalyzed Functionalization of Allylic
Alcohol Derivatives
Herein, we report the successful implementation of this
strategy for the synthesis of amino alcohols, which are
structurally complementary to those obtained from allylic
amines. Both aminoalkynylation and aminoarylation reactions
were achieved in high yields starting from preformed
hemiaminal ethers. In situ formation of the tether was also
possible with a slightly lower yield. In the case of amino-
arylation, a new phosphine ligand (“FuXPhos”, 1) had to be
designed to overcome a competitive Heck pathway. The
Received: May 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01524
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Organic Letters
Letter
introduced tether could be easily removed under mild acidic
conditions to give the free amino alcohols.
To begin our studies, we first synthesized hemiaminal ethers
4 and 6 from allylic alcohol 2 using either the reported tether
precursor 3 derived from formaldehyde7b or the trifluorace-
taldehyde derivative 5 used in our previous studies (Scheme 2,
formation of the Heck product 11a became again favored. At
this point, we wondered if the favorable effect of the furyl
substituent on the phosphine could be also important for
Buchwald-type phosphines. The new Fu-DavePhos ligand 17
could be easily accessed in two steps. The use of 17 indeed led
to an increase in selectivity and 10a could be isolated in 42%
yield. The selectivity could be further increased by using the
sterically more hindered Fu-XPhos ligand 1. Finally, the desired
product 10a could be obtained in 92% with less than 5%
formation of the Heck product 11a using cesium triflate as
additive.11
Scheme 2. Preliminary Results on Tether Introduction,
Carboamination, and Ligand Effect on Aminoarylation
The scope of the aminoalkynylation and arylation of
hemiaminal ether 6 was then examined (Scheme 3).
Scheme 3. Scope of the Carboamination of Hemiaminal
a b
,
Ether 6
a
Obtained as a 50:50 mixture of diastereoisomer at the propropargylic
b
center. NMR yield.
Propargylic silyl ethers 8b−e could be obtained in good yields
in this transformation with XPhos 18 as ligand. Fu-Xphos 1 was
confirmed as the best ligand for arylation. Benzene derivatives
10a−d bearing electron-withdrawing groups such as fluorine,
bromine, cyano, or nitro were isolated in high yields. The
electron-withdrawing group was required to obtain good yields.
Only 38% 10e could be observed when using phenyl bromide
as reagent. In this case, it was not possible to overcome
completely the Heck pathway. Furthermore, both multi-
substituted benzene rings 10f−h and heterocycles 10i−j
could be accessed from hemiaminal 6.
Substituted allylic alcohols were then examined in the
aminoalkynylation and -arylation reactions (Table 1). When
branched hemiaminal ether 19 was used as a 50:50 mixture of
diastereoisomers, amino alcohol derivative 20 was obtained in
73% yield and 67:33 dr (Table 1, entry 1).12 The synthesis of
the corresponding aminoarylation product 21 was also
successful (Table 1, entry 2). When symmetrical bisallylic
hemiaminal ether 22 was used, aminoalkynylation product 23
was formed in 65% yield as a single diastereoisomer (Table 1,
entry 3). The use of α,α-disubstituted olefins was also possible:
Both aminoalkynylation and -arylation products 25 and 26
were obtained in good yield and diastereoselectivity (Table 1,
entries 4 and 5). Finally, the more complex amino alcohol
derivative 28 could be also accessed in 57% yield but with lower
diastereoselectivity (Table 1, entry 6).
eq 1).8b Interestingly, the presence of the trifluoromethyl group
allowed a more efficient formation of the hemiaminal ether
(91% vs 37%). The conditions developed for allylic amines
were then applied to the carboalkynylation of hemiaminal ether
4 with alkynyl bromide 7, but no product formation could be
observed (Scheme 2, eq 2). In contrast, carboamination
product 8a could be obtained in 90% yield as a single
diastereoiosmer after only minor optimization of the reaction
conditions (Scheme 2, eq 3).9 However, only a moderate yield
of arylation product 10a could be obtained, due to the
competitive formation of Heck product 11a (Scheme 2, eq 4).
As the yield of arylation product 10a could not be improved
by changing the reaction conditions, we decided to examine
other phosphine ligands. Bidentate phosphine ligands 12 and
13, which had been successful in our previous work with
allylamines,8 gave low yields and selectivity. A good combined
yield of 10a and 11a was obtained with electron-deficient
arylphosphine 14, but formation of the Heck product 11a was
favored. We then investigated the use of Buchwald-type biaryl
monophosphine ligands.10 Interestingly, the use of DavePhos
15 led to an increased selectivity for aminoarylation but with
low overall yield. Replacing the cyclohexyl groups by benzene
groups (Ph-DavePhos, 16) restored the reactivity, but
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Letter
observed when compared to the use of isolated hemiaminal 6.
Finally, the introduced tether could be removed easily by
treatment with trifluoroacetic acid (TFA) followed by
methanolysis to give the ammonium salt in quantitative yield
(Scheme 4, eq 3).
Table 1. Amino-Alkynylation and -Arylation of Substituted
Allylic Alcohols
In conclusion, we have reported the first carboamination of
allylic alcohols based on the use of a trifluoroacetaldehyde
tether. Both alkynylation and arylation products could be
obtained in good yield and diastereoselectivity, giving amino
alcohol derivatives with complementary substitution patterns
compared to those obtained from allylic amines. The
hemiaminal tethers were easily introduced and could be
removed in a single step to give amino alcohols in quantitative
yields. These results further highlight the versatility of tethers
derived from trifluoroacetaldehyde and set the basis for the
development of further highly selective transformations of
olefins in future works.
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.7b01524.
Experimental procedures and analytical data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jerome.waser@epfl.ch.
ORCID
Jerome Waser: 0000-0002-4570-914X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by the Swiss National Science
Foundation (Grant No. 200021_159920).
■
To further increase the efficiency of the carboamination
process, we then investigated if the hemiaminal tether could be
installed in situ. Both the aminoalkynylation and -arylation were
indeed successful in the one-pot process, and products 8a and
10f were obtained in 64% and 62% yield, respectively (Scheme
4, eqs 1 and 2). Nevertheless, a significant decrease in yield was
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DOI: 10.1021/acs.orglett.7b01524
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