Ruthenium-catalyzed intramolecular hydrocarbamoylation of allylic formamides: Convenient access to chiral pyrrolidones

Article abstract of DOI:10.1021/ja4026787

An attractive strategy for the synthesis of saturated nitrogen-containing heterocycles is described herein, involving the implementation of ruthenium-catalyzed intramolecular hydrocarbamoylation of olefins. The process proceeds by formal C-H bond cleavage

Full text of DOI:10.1021/ja4026787

Communication
pubs.acs.org/JACS
Ruthenium-Catalyzed Intramolecular Hydrocarbamoylation of Allylic
Formamides: Convenient Access to Chiral Pyrrolidones
Nicolas Armanino and Erick M. Carreira*
Laboratorium fur Organische Chemie, ETH Zurich, CH-8093 Zurich, Switzerland
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̈
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S
* Supporting Information
hydroacylation.11 Although hydroacylation reactions have been
extensively studied, the related hydroesterification12 and
particularly the hydrocarbamoylation reactions, which one
could also contemplate for heterocycle synthesis, have been
the subject of only limited investigations. In this regard, the
inherent difficulties finding catalysts able to perform hydro-
esterification or carbamoylation without suffering competitive,
irreversible decarbonylation have hampered their development
in complex molecule synthesis.
To date, two catalyst manifolds to effect hydrocarbamoyl-
ation have been investigated. The first involves the use of
ruthenium−carbonyl complexes for intermolecular coupling of
formamides and simple alkenes under harsh conditions and
high pressures of CO.13 The narrow substrate scope observed
has limited their utility largely to the manufacture of industrial
bulk chemicals. Milder conditions for the intermolecular
reaction are achieved by Chang’s insightful use of a pyridine
directing group.12e,14 This auxiliary-based approach, however,
precludes its employment in an atom-economical, intra-
molecular fashion. The second venue developed for this
transformation involves the use of nickel catalysts, which has
been largely limited to alkyne substrates.15 This method,
however, is not compatible with amides bearing a free N−H
bond due to the highly reactive nature of the catalyst and the
requirement for use of a protecting group.
ABSTRACT: An attractive strategy for the synthesis of
saturated nitrogen-containing heterocycles is described
herein, involving the implementation of ruthenium-
catalyzed intramolecular hydrocarbamoylation of olefins.
The process proceeds by formal C−H bond cleavage of an
allylic formamide followed by construction of a new C−C
bond in a reaction that is characterized by complete atom-
economy. The method is particularly valuable in
conjunction with the numerous efficient strategies available
for the preparation of optically active allylic formamides.
yrrolidones and the related pyrrolidines are common
Pmotifs in a variety of important structures including
alkaloids,1 top-selling drugs, and other bioactive molecules
(Figure 1).2 Despite their broad applications, methods for their
synthesis rely heavily on a well-established set of C−C bond-
forming reactions3 and, more recently, hydroamination
reactions.4 Propelled by our interest in identifying and
investigating new bond-forming catalytic reactions, we now
report a ruthenium-catalyzed hydrocarbamoylation for the
construction of substituted pyrrolidones from easily accessible
allylic formamides (Figure 1).
Recognizing the power of this transformation for the
synthesis of heterocycles from readily available allylic
formamides, we set out to explore this reaction with 1a as a
test substrate (Table 1). Initial screening of a range of
complexes based on Rh, Fe, Os, Pd, and Ru identified
Ru3(CO)12 as a competent catalyst in combination with halide
additives.16 As expected, no reaction took place in the absence
of the ruthenium catalyst (entry 2). The amount of iodide
additive was optimized to 15 mol% (entries 1, 3−5), and both
NaI and Bu4NI could be used interchangeably (entry 6). While
we found it was not necessary to perform the reaction in a
carbon monoxide-filled autoclave, initial purging of the reaction
mixture with CO by sparging dramatically increased the
conversion and consistently resulted in cleaner product
formation (entry 7). A screen of solvents over a range of
temperatures revealed DMF as the optimal choice for the
reaction, while other solvents such as DMSO (entry 8) gave
lower yields. The catalyst loading and temperature of the
reaction could also be lowered (entries 9, 10), albeit at a cost in
yield.
Figure 1. Intramolecular hydrocarbamoylation and potential synthetic
applications.
Hydroacylation reactions constitute an important set of
transformations that have a long history.5 These reactions allow
the formation of C−C bonds in a single step with complete
atom-economy.6 Since the pioneering work of Bosnich7 and
Sakai8 on intramolecular hydroacylation for the synthesis of
cyclopentanones, recent advances in intra- and intermolecular
hydroacylation have led to the discovery of efficient catalyst
systems for this reaction on a range of substrates.9 Of particular
interest for fine chemicals synthesis, intramolecular hydro-
acylation has been studied for the preparation of heterocycles.10
Most notably, Dong’s approach of replacing the olefin moiety
with a ketone allowed the preparation of lactones by carbonyl
Received: March 15, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4026787 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
ab
,
a
Table 1. Optimization of the Cyclization Reaction
Table 2. Substrate Scope under Standard Conditions
entry
deviation from the standard conditions
conv (%)
yield (%)
a
1
2
3
4
5
6
7
8
9
10
standard conditions
>99
0
92
−
trace
no Ru3(CO)12
0% Bu4NI
15
5% Bu4NI
40
36
10% Bu4NI
84
78
NaI instead of Bu4NI
no CO (under Ar)
DMSO as solvent
only 3% Ru3(CO)12
reaction at 120 °C
>99
53
92
10
>99
>99
>99
51
87
77
a
Standard conditions: suspension of 1a (0.08 mmol), Ru3(CO)12 (5
mol%) and Bu4NI (15 mol%) in DMF (0.25 mL) in a septum-capped
vial was purged with CO (balloon) and the vial then heated to 150 °C
b
1
for 4 h. Conversion and yield were determined by H NMR against
1,4-dimethoxybenzene as an added standard.
With the optimal conditions in hand, we turned our attention
to the scope of the reaction (Table 2). The cyclization to
pyrrolidones could be performed on an array of substrates
including both alkyl- and aryl-substituted secondary form-
amides. Aryl groups bearing both electron-withdrawing (entries
3, 4) and electron-donating groups (entry 6) at various
positions of the ring were well tolerated. In those cases, no side
reactions arising from insertion into the aryl C−H bonds were
observed. The reaction was also compatible with substrates
where the amine is positioned at a fully substituted carbon
(entries 7−11), allowing easy access to spirocycles and chiral
pyrrolidones (entry 11) that contain tetrasubstituted stereo-
genic carbon centers.
We were pleased to find that both 1,2- and 1,1-disubstituted
olefins were competent substrates in the reaction and furnished
the desired pyrrolidones in good yields (entries 12−14).17 It is
noteworthy that 1,1-disubstituted substrates gave the product in
high diastereoselectivity, favoring the thermodynamically more
stable trans-substituted pyrrolidone. This stands in contrast
with the observations made by Sakai for rhodium-catalyzed
intramolecular hydroacylation, in which the cis-product is
preferentially formed.8a When employing homoallylic (entry
15) and bis-homoallylic (entry 16) formamides as substrates,
we observed exclusive formation of the pyrrolidones and no
sign of the corresponding piperidones. In the case of
homoallylic formamide this can be explained by an exo-type
cyclization. By contrast, in the bis-homoallylic substrate this
must arise from an olefin transposition that precedes the
cyclization event. In no case, however, did we observe
isomerization of the olefin toward conjugation with the
formamide.
We then explored the preparation of enantioenriched
pyrrolidones. The impressive collection of strategies developed
for the preparation of optically enriched allylic amines has
rendered them readily available,18 in particular through allylic
amination19,20 and addition to sulfinyl-imines21 as well as
enzymatic methods.22 To demonstrate the convenience of our
combined method, we synthesized the enantioenriched chiral
pyrrolidone (S)-2d in two steps from the known racemic allylic
alcohol (Scheme 1). The intermediate allylic amine generated
a
b
See Supporting Information for reaction conditions. Isolated yield of
c
the product after column chromatography. Product obtained as a 1:1
mixture of diastereomers. Product obtained in 20:1 dr. Product
obtained in 8:1 dr.
d
e
from the iridium-catalyzed asymmetric amination20 was
converted directly in a single pot into the formamide, which
was obtained in 88% ee. This was then conveniently cyclized
utilizing ruthenium-catalyzed hydrocarbamoylation to give the
B
dx.doi.org/10.1021/ja4026787 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Preparation of Chiral Pyrrolidone (S)-2d
Scheme 2. Deuterium Labeling Experiments
product pyrrolidone with complete conservation of optical
purity.
no deuterium loss from the formyl position, indicating that
breaking of the formyl C−H bond is irreversible in the catalytic
cycle. In the product pyrrolidone, this label was only found to a
minor extent on C(3) and not at all on C(4); the appearance of
less than complete incorporation at C3 is consistent with the
fact that C3 proton and deuterium in the product would be
susceptible to exchange with the starting amide N−H (Figure
2).26 In summary, the observations are in line with the
mechanism involving initial activation of the N−H bond, as
opposed to a direct activation of the formamide C−H bond.
In conclusion, we have reported a new intramolecular
cyclization of allylic formamides. The reaction involves formal
ruthenium-catalyzed insertion into the formamide C−H bond
and concomitant C−C bond formation by olefin hydro-
carbamoylation. The reaction exemplifies complete atom-
economy since all atoms of the starting material are present
in the product. Finally, the reaction presents a convenient
method for the preparation of enantioenriched chiral
pyrrolidones, particularly when used in conjunction with
asymmetric allylic amination protocols.
The pyrrolidones obtained also feature a convenient
synthetic handle in the form of the free amide N−H bond
for further functionalization. In fact, we found that ruthenium-
catalyzed cyclization requires a free amide N−H bond.
Attempts involving cyclization with various tertiary amides
failed to yield cyclized product. This indicates that a free N−H
bond plays an important role in the mechanism of the reaction,
a feature that complements the nickel-catalyzed reactions.
On the basis of these observations and in accordance with
previous reports,13b we propose a possible mechanism that
involves initial insertion of the active ruthenium catalyst into
the N−H bond of I to give II (Figure 2). This process has been
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectroscopic data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
Figure 2. Proposed catalytic cycle.
AUTHOR INFORMATION
Corresponding Author
carreira@org.chem.ethz.ch
Notes
■
reported for ruthenium−carbonyl clusters and has been shown
to benefit from the additive effect of electron-rich ligands,23 in
particular halides.24 Intermediate II is poised to undergo
reversible insertion of the olefin to give III. This ruthenacycle
can undergo β-hydride abstraction of the proximal formamide
C−H bond to give IV, which is suggested to undergo attack of
the nucleophilic alkyl moiety onto the electrophilic carbonyl
carbon to give V. Finally, release of the product with proton
transfer regenerates the active catalyst.
To gain additional mechanistic insight, we conducted a
number of experiments with deuterium-labeled substrates
(Scheme 2).25 The use of the substrate with N−D in the
cyclization reaction (Scheme 2, experiment A) afforded product
with significant deuterium incorporation (45%) at C2 and C3.
This observation suggests that olefin hydrometalation is
reversible and nonselective, leading to label scrambling.
Consistent with this result, when the reaction was interrupted
at 50% conversion (experiment B), the olefin in the recovered
starting material was shown to incorporate 31% deuterium
label. We then repeated the same process for the substrate
bearing C−D at the formyl carbon (experiments C and D). In
the experiments, recovered substrate at 50% conversion showed
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
N.A. thanks the SSCI for a fellowship.
■
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Journal of the American Chemical Society
Communication
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D
dx.doi.org/10.1021/ja4026787 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX