Autotandem catalysis with Ruthenium: Remote Hydroesterification of Allylic Amides

Article abstract of DOI:10.1021/ol4034463

A one-pot tandem sequence involving olefin isomerization and hydroesterification has been developed that enables the incorporation of a C1-unit at the remote terminal position of allylic amides. Key observations suggest that generation of an active ruthenium hydride, formed by addition of acetic acid, allows both processes to take place under mild conditions in an autotandem catalytic, cascading fashion, which is characterized by the use of a single catalytic entity capable of promoting multiple distinct steps without operator intervention.

Full text of DOI:10.1021/ol4034463

Letter
pubs.acs.org/OrgLett
Autotandem Catalysis with Ruthenium: Remote Hydroesterification
of Allylic Amides
Nicolas Armanino, Marc Lafrance, and Erick M. Carreira*
Laboratorium fur Organische Chemie, ETH Zurich, CH-8093 Zurich, Switzerland
̈
̈
̈
S
* Supporting Information
ABSTRACT: A one-pot tandem sequence involving olefin isomerization and
hydroesterification has been developed that enables the incorporation of a
C1-unit at the remote terminal position of allylic amides. Key observations
suggest that generation of an active ruthenium hydride, formed by addition of
acetic acid, allows both processes to take place under mild conditions in an
autotandem catalytic, cascading fashion, which is characterized by the use of a
single catalytic entity capable of promoting multiple distinct steps without
operator intervention.
umerous approaches are available for the ready synthesis
of optically active allylic amines. These include
useful intermolecular counterparts.3b The paucity of these
N
second variants results from decarbonylative decomposition
pathways of the putative acyl- and formyl-metal species that
compete with the bimolecular processes.7 A recent approach to
effect intermolecular hydroacylation8 and hydroesterification9
reactions has been to employ substrates or reagents
incorporating directing groups with catalysts that can
transiently form covalent intermediates. This effectively
converts an intermolecular process into its intramolecular
counterpart.
diastereoselective reactions, most notably the additions that
have been described using Ellman’s auxiliary1 and catalytic
enantioselective methods.2 Hydroacylation and the related
hydroesterification reactions are recognized as powerful tools
for synthetic chemistry and are increasingly gaining attention.3,4
The processes provide direct means for C−C bond formation
with olefins as starting materials in transformations charac-
terized by high atom economy. Herein, we report a process
employing Ru3(CO)12 for the conversion of allylic amides to δ-
amido esters, a class of building blocks that are otherwise not
easily accessed (Figure 1). The process is noteworthy, as it
Since the seminal report of ruthenium catalyzed hydro-
esterification,10 Ru3(CO)12 and its derivatives have been used
for the homologative esterification of ethylene, cyclohexene,
norbornene, and methyl acrylates.11 Typically, the reactions
require a large excess of olefins (2−8 equiv), high temperatures
(170−230 °C), and elevated CO pressures (20−90 bar). One
of the most convenient hydroesterification reagents, reported
by Chang,9a is the formate ester derived from 2-pyridyl
carbinol. With this reagent, simple terminal and cyclic olefins
could be homologated when used in excess in the reaction
(1.2−3 equiv).9a,b The method was later extended to simple
allylic alcohols with modest success.12 However, it is far from
clear from this work whether hydroacylation could be relied
upon as a preparatively useful transformation of optically active
allylic and homoallylic alcohols, and whether the reaction could
be extrapolated to include protected nonracemic allylic amines.
In separate unrelated work, ruthenium(II) complexes, such
as [HRuCl(PPh3)3], as well as Ru3(CO)12 have been shown to
promote olefin isomerization via hydrometalation driven by the
stability of the resulting product.13,14 We hypothesized that the
putative [Ru−H] species proposed as an intermediate in
hydroesterification reactions might be competent in olefin
transposition, potentially enabling isomerization−hydroester-
ification cascade sequences (Figure 2). Prior work with metal-
Figure 1. Autotandem catalytic cascading sequence involving olefin
isomerization and hydroesterification.
involves a one-pot operation characterized as an autotandem
catalytic process with a cascading sequence of transformations
that includes olefin isomerization and hydroesterification by the
same Ru catalyst.5
One-pot processes that involve cascading reactions provide
attractive tools for organic synthesis.6 They simplify operations
and reduce the number of required isolations resulting in
greater economy of the overall synthetic process. Of particular
interest are autotandem catalytic reactions that are charac-
terized by the use of a single catalytic entity capable of
promoting multiple distinct steps without the need for operator
intervention. There have been a notable number of intra-
molecular hydroacylation reactions that have been studied and
developed.3a By contrast there are few examples of synthetically
Received: November 28, 2013
Published: December 18, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
Table 2. Isomerization−Hydroesterification of Allylic
a
Amines (Eq 1)
Figure 2. Strategic combination of ruthenium catalyzed isomerization
and hydroesterification.
catalyzed olefin isomerization would suggest that uncontrolled
isomerization could be problematic, as it would lead to a
potential loss of stereochemical information by formation of
achiral intermediates (e.g., an enamine, for X = nitrogen in
Figure 2). Nonetheless, the successful coupling of these two
reactions that otherwise have been only studied separately
would lead to a process furnishing remotely functionalized ester
building blocks.
In the initial investigations (Table 1), trifluoroacetamide 2a
was used as limiting substrate with a 2-fold excess of pyridin-2-
a
Table 1. Effect of Solvent and Acetic Acid Additive
entry
conditions
conv (%)
ratio 3a:4a
1
2
3
4
5
DMF
THF
15
40
5:1
10:1
3:1
THF, AcOH (5 mol %)
THF, AcOH (10 mol %)
THF, Bu4NOAc (10 mol %)
90
>95
35
3:1
3:1
a
2a (0.15 mmol), 1 (0.30 mmol), Ru3(CO)12 (5 mol %), and Bu4NI
(15 mol %) were stirred in a sealed vial with the given amount of
AcOH in the appropriate solvent (0.23 mL) for 40 h at 75 °C.
Conversion and ratios (3a:4a) were determined by integration of the
crude 19F NMR against a PhCF3 standard.
ylmethyl formate (1) in DMF. Under these conditions,
formation of the terminal products δ- (3a) and γ- (4a)
amino esters occurred with a preference for the unbranched
product 3a, while no β-amido ester was observed. Further
investigation revealed that the use of THF as solvent resulted
improved conversion (entry 2). In our efforts to optimize the
process, we found that the addition of substoichiometric
quantities of acetic acid (5−10 mol %) to the reaction mixture
resulted in a dramatic enhancement in activity (entries 3, 4).15
This effect was not observed when using Bu4NOAc as an
additive in lieu of acetic acid, underscoring the significance of
proton cocatalysis (entry 5). The use of Bu4NI was necessary,
even in the presence of acetic acid, and a control reaction where
this was omitted resulted in no observed conversion.16
a
Conditions: Substrate 2 (1 equiv), 1 (2 equiv), Ru3(CO)12 (5 mol
%), Bu4NI (15 mol %), and AcOH (10 mol %) in THF (0.67 M) for
b
48 h at 75 °C. Isolated yield of the major product (3) after
c
chromatography and of minor product in parentheses. In DMF (0.67
d
M) at 135 °C for 18 h. Combined yield of inseparable mixture of
e
major and minor products in 4:1 ratio. No racemization was observed.
Under the optimized conditions, a wide variety of substrates
bearing both alkyl and aryl groups could be used (Table 2).
Both E and Z olefins could be employed as substrates and
exhibited indistinguishable reactivity. In addition to the N-
trifluoroacetamides, other amine protecting groups could be
employed such as benzamides, acetamides, phthalimides
(entries 1−3), and N-Boc amines (entry 15). It is noteworthy
that more sterically hindered substrates required higher
temperatures (135 °C) for effective conversion to product.
(entries 4 and 11). At lower temperatures, the formation of
products was slower than the unproductive decarbonylation of
reagent 1, and 2-pyridyl methanol was the only observed
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Organic Letters
Letter
reaction product. In those cases, a switch to higher boiling
DMF as solvent was necessary. A wide variety of functional
groups were tolerated under the reaction conditions including
cyclopropanes (entry 8), nitriles (entry 9), acetals (entry 11),
silyl ethers (entry 16), ethers (entry 17), and cyclic carbamates
(entry 18). Trisubstituted olefins were also competent
substrates (entry 14) and lead to exclusive formation of the
isomerized, unbranched product. Notably, no erosion of
stereochemical information was observed (entries 12, 15) and
optically active products could ultimately be isolated in
enantiopure form when the reaction was conducted with
optically pure allylic amines. This observation is particularly
interesting given that, in most cases, ruthenium has been shown
to effect the isomerization of olefins toward conjugation with
heteroatoms,13 which in the cases presented would result in loss
of stereochemical information as shown in Figure 2. In the
present case, however, we hypothesize that the steric bulk of
the allylic amides is sufficient to inhibit unproductive
isomerization.
these are replaced over 12 h by a single dominant singlet
resonance at δ = −17.0 ppm. The observed signals are in good
accordance with hydrides of ruthenium carbonyl clusters and
are likely formed by metal cluster protonation. In contrast,
addition of reagent 1 to the catalyst mixture (in the absence of
acetic acid) at 70 °C results in only the very slow formation of
two main hydride signals over the course of several hours: δ =
−12.5, δ = −15.5. The appearance of these resonances can be
accelerated by the addition of acetic acid to the mixture, which
results in the formation of two dominant singlets at δ = −12.5
and δ = −17.0 ppm. The formation of ruthenium cluster
hydrides by protonation has been shown to benefit from
coordination of electron rich and particularly anionic ligands,17
including halides.18 Indeed, it is not surprising that in control
experiments no hydride signals were observed when Bu4NI was
not used. The dramatic improvement in reactivity observed
with the combination of Bu4NI and AcOH suggests that
formation of an active metal hydride promotes olefin
isomerization, and ultimately allows it to be coupled with
hydroesterification in an efficient tandem process.
In summary we have developed an operationally simple,
generally applicable, and efficient method for the generation of
remotely functionalized δ-amido esters commencing with allylic
amines. The reaction process benefits from a broad selection of
routes for the preparation of optically active allylic amines, and
the transformation enables ready access to enantioenriched
building blocks. The reactions can be carried out at high
concentrations, use inexpensive ruthenium as the catalyst, and
do not require a pressurized CO atmosphere. More broadly, the
process constitutes an example of autotandem catalysis, which
is characterized by the use of a single catalytic entity capable of
promoting multiple distinct steps without operator interven-
tion. Ongoing efforts in our group are now aimed at unraveling
other ruthenium-cluster catalyzed cascades as well as under-
standing the exact nature of the catalytic species. In this respect,
the observation concerning the benefits of added acetic acid
may prove useful in other Ru-cluster catalyzed isomerization
processes.
When an allylic amide was used as a substrate incorporating
both internal and terminal olefins (5), the hydroacylation
reaction occurred preferentially on the latter (Scheme 1). This
Scheme 1. Selective Hydroesterification of a Terminal Olefin
(5) and Remote Hydroesterification of 7
resulted in selective formation of the γ-amino ester product 6.
Multiple isomerizations could also be used to functionalize a
more remote terminal position of the substrate . Thus exposure
of 7 to the reaction conditions yielded ε-amino ester 8 by
double alkene isomerization, followed by selective homologa-
tion of the terminal position.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental procedures and characterization data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Intrigued by the dramatic benefits of added acetic acid, we
have conducted some mechanistic studies in order to gain
insight into the process. Accordingly, reaction of the catalyst
mixture (Ru3(CO)12/Bu4NI 1:3) with acetic acid and reagent 1
1
in d8-THF at 70 °C was monitored by H NMR spectroscopy
AUTHOR INFORMATION
■
(Figure 3). Upon addition of acetic acid (2 equiv relative to
Ru3(CO)12) to the catalyst mixture, resonances corresponding
to singlets at δ = −10.1 and δ = −12.5 ppm are formed, and
Corresponding Author
*E-mail: carreira@org.chem.ethz.ch.
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Boris Gaspar (ETH Zurich) and Hajer Abdelkafi
̈
(ETH Zurich) for initial experiments. N.A. thanks the SSCI for
̈
a fellowship. M.L. thanks the NSERC for a postdoctoral
fellowship. We are grateful for support from the Swiss National
Science Foundation.
1
Figure 3. Ruthenium hydride species observed by H NMR.
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Organic Letters
Letter
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