Rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes

Article abstract of DOI:10.1002/anie.201407935

A rhodium-catalyzed chemo-, regio-, and enantio-selective addition of 2-pyridones to terminal allenes to give branched N-allyl 2-pyridones is reported. Preliminary mechanistic studies support the hypothesis that the reaction was initiated from the more acidic 2-hydroxypyridine form, and the initial kinetic O-allylation product was finally converted into the thermodynamically more stable N-allyl 2-pyridones.

Full text of DOI:10.1002/anie.201407935

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DOI: 10.1002/anie.201407935
Pyridone Allylation
Rhodium-Catalyzed Chemo-, Regio-, and Enantioselective Addition of
2-Pyridones to Terminal Allenes**
Changkun Li, Matthias Kꢀhny, and Bernhard Breit*
Abstract: A rhodium-catalyzed chemo-, regio-, and enantio-
selective addition of 2-pyridones to terminal allenes to give
branched N-allyl 2-pyridones is reported. Preliminary mech-
anistic studies support the hypothesis that the reaction was
initiated from the more acidic 2-hydroxypyridine form, and the
initial kinetic O-allylation product was finally converted into
the thermodynamically more stable N-allyl 2-pyridones.
C
hiral N-substituted 2-pyridones can be found in many
biologically active natural products and medicinally interest-
ing molecules (Figure 1).[1] They are usually prepared by
multistep synthesis in which chiral electrophiles or chiral
amines are needed.[2] The straightforward enantioselective
Scheme 1. Synthesis of chiral N-substitued 2-pyridones.
ambident nucleophile in organic synthesis.[6] The alkylation of
2-pyridone under basic condition suffers from the N vs. O
selectivity, which normally depends on solvents, bases,
substrates, and additives.[2a] Our group recently developed
the rhodium-catalyzed atom-economic and regioselective
addition of different pronucleophiles to alkynes or allenes
to generate the branched allylic products.[7] The pronucleo-
philes need to show pronounced acidity or the ability to
undergo an oxidative addition with the rhodium catalyst to be
applicable in this transformation. Thus, we anticipated the
more acidic 2-hydroxypyridine tautomer, rather than the
lactam form, to undergo a rhodium-catalyzed addition to
allenes under neutral conditions. Furthermore, there might be
an opportunity, based upon the choice of the phosphine
ligand, to control the N vs. O chemo- and enantioselectivity
(Scheme 2).
Figure 1. Biologically active molecules with N-chiral 2-pyridone moiet-
ies.
functionalization of 2-pyridones by the aid of a chiral catalyst
from achiral starting materials is still very rare.[3,4] Herein, we
report a rhodium-catalyzed chemo-, regio-, and enantioselec-
tive addition of 2-pyridones to terminal allenes to furnish a-
chiral N-allyl 2-pyridones (Scheme 1).
The molecule 2-pyridone exists as a mixture of two
tautomers, namely 2-pyridone and the corresponding 2-
hydroxypyridine.[5] The 2-pyridone anion is a well-known
[*] Dr. C. Li, M. Kꢀhny, Prof. Dr. B. Breit
Scheme 2. The rhodium catalyst differentiates two tautomers and
Institut fꢁr Organische Chemie, Albert-Ludwigs-Universitꢀt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
determines the O vs. N ratio.
Homepage: http://portal.uni-freiburg.de/oc-breit
Our study commenced with 5-chloropyridone 1a and
linear 3-phenylpropyl allene 2a as model substrates (Table 1).
In the presence of 2.5 mol% of [{Rh(cod)Cl}2] and 7.5 mol%
of DPEphos, O-allylated product 3aa and N-allylated 4aa
were isolated in a ratio of 1:1 (entry 1). Further ligand
screening revealed that electron-rich diphosphine ligands
(DTBM ligands) increased both the reactivity and the N vs. O
[**] This work was supported by the DFG, the International Research
Training Group “Catalysts and Catalytic Reactions for Organic
Synthesis” (IRTG 1038), and the Krupp Foundation. We thank Dr.
Manfred Keller for the X-ray diffraction analysis. C.L. thanks the
Alexander von Humboldt Foundation for a postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407935.
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Table 1: Screening of ligands for the rhodium-catalyzed chemo-, regio-,
and enantioselective addition of 2-pyridone to allene.[a]
Entry
Ligand
Ratio 3 vs. 4[b]
Yield of 4[c] (%)
ee (%)[d]
1
2
3
4
DPEphos (L1)
1:1
1:2
1:9
1:9
1:3.1
<1:20
17
47
73
80
78
86
–
92
L2
L3
L4
L5
L4
À78
92
5
93
92
6[e]
[a] 0.3 mmol of 1a and 0.45 mmol of 2a in 1.0 mL of DCE. [b] The ratio
was determined by 1H NMR. [c] Yield of isolated product. [d] The ee
values were determined by chiral-phase HPLC analysis. [e] 5.0 mol% of
[{Rh(cod)Cl}2] and 10.0 mol% of L4 were used.
selectivity.[8] When (R)-DTBM-BINAP (L2) and (R)-3,5-i-Pr-
4-NMe2-MeObiphep (L5) were used, moderate N : O ratios
(2:1 and 3.1:1) and high levels of enantioselectivity (92% and
93% ee) were obtained, while (S)-DTBM-segphos (L3) gave
a high N vs. O ratio (9:1), but a relatively low 78% ee
(entries 2, 3, and 5). Finally, (R)-DTBM-MeObiphep (L4)
showed the best combination of N vs. O selectivity (9:1) and
enantioselectivity (92% ee). When 5.0 mol% of [{Rh-
(cod)Cl}2] and 10.0 mol% of L4 were used, only N-allylated
Scheme 3. Scope of 2-pyridones in the rhodium-catalyzed chemo-,
regio-, and enantioselective addition of 2-pyridones to allenes.
[a] 5.0 mol% [{Rh(cod)Cl}2] and 10.0 mol% L4 were used.
[b] 2.5 mol% [{Rh(cod)Cl}2] and 5.0 mol% L4 were used. [c] 5.0 mol%
L5 was used. [d] The ee value was obtained from the corresponding
alcohol.
products in high yields and enantioselectivities (4aj and 4ak).
However, 6-chloropyridone gave only the O-allylated prod-
uct, presumably for steric reasons.[9] The reaction is not only
limited to electron-withdrawing pyridones. Electron-neutral
and electron-donating groups can also be tolerated (4am and
4ao), although 4-benzoxylpyridone showed only a moderate
conversion (4an).
After our investigation of pyridone substrates was com-
plete, we moved on to determine the scope of allene coupling
partners (Scheme 4). With 5-chloropyridone as the model
substrate, different allenes were tested under the standard
condition. A linear n-alkyl substituted allene without any
functional group worked smoothly to provide the N product
in high yield but with a slightly diminished enantioselectivity
(4ba). Different functional groups such as free hydroxy,
phenyl ether, ester, cyano, and phthalimide can all be
tolerated in this reaction (4ca–4ga). The bulky a-branched
cyclohexylallene showed lower reactivity to form the N-
1
product 4aa could be observed in the H NMR spectrum of
the crude reaction mixture (entry 6). In all cases, only
branched O and N allylated products can be detected.
With the optimized conditions in hand, we then examined
the scope of 2-pyridones (Scheme 3). Halogenated 2-pyri-
dones gave similar N vs. O ratios, yields, and ee values as the
model substrate 1a (4ab and 4ac). 5-Iodopyridone gave 1:1 N
vs. O ratio, perhaps because the active iodo group competes
with the O-allylated product to react with rhodium complex
(4ad). Strong electron-withdrawing groups (trifluoromethyl,
ester, nitro, aldehyde, and cyano) accelerated the reaction,
and a catalyst loading of 2.5 mol% [{Rh(cod)Cl}2] was
sufficient in these cases (4ae–4ah and 4al). A Weinreb
amide can also be tolerated in the reaction, which allows for
further reactions with organometallic reagents to furnish
ketones (4ai). Besides 5-substituted 2-pyridones, 4- and 3-
chloropyridones reacted smoothly to give the N-allylated
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These results suggest that the O-allylated product is the
kinetic product and it can be converted into the thermody-
namically more stable N-allylated product. Furthermore,
from 3ga to 4ga, it is most likely that an achiral intermediate
is produced and the final enantioselectivity of 4ga is
controlled by the chiral catalyst (see below).[13]
In situ IR spectroscopy was used to gain further insights
into the reaction mechanism. Because L3 showed similar
reactivity and is less expensive than L4, it was selected as the
ligand for these studies. This experiment shows that the O-
allylated product is formed quickly and is the primary kinetic
product. Subsequently, we hypothesize that the kinetic O-
allylation product is re-introduced to allylic insertion by
rhodium and progresses through a common intermediate to
give the thermodynamic N-alkylated product.[8]
This assumption was confirmed by DFT calculation on the
MP2/6-311 + G(2d,p) level (Scheme 6), as the N-branched-
Scheme 6. DFT calculation on the stability for O- and N-allylated 2-
pyridones in the gas phase.
Scheme 4. Scope of allenes in the rhodium-catalyzed chemo-, regio-,
allylated pyridone (4lo) was 6.6 kcalmolÀ1 more stable than
the corresponding O-product (3lo).[6a] An electron-withdraw-
ing group (aldehyde CHO) at the 5-position of the pyridone
ring increased the energy difference to 8.3 kcalmolÀ1 (3lh to
4lh).
and enantioselective addition of 2-pyridones to allenes.
allylated product (4ha).[10] To our surprise, an allene equipped
with a tertiary alcohol function displayed high reactivity to
give the corresponding amino alcohol derivative in excellent
yield and enantioselectivity (4ia). The absolute configuration
of compound 4jo was assigned to be (R) through comparison
to known literature examples.[3] The structure of N-allylated
(R)-4da was further confirmed by a single-crystal X-ray
diffraction analysis (see the Supporting Information).[11]
When 1a and 2g reacted in the presence of 1.0 mol%
[{Rh(cod)Cl}2] and 2.0 mol% L4, along with the expected N-
allylated product 4ga, O-allylated product 3ga was isolated in
61% yield with a 76% ee as the main product (Scheme 5).
Both the racemic and the scalemic 76% ee 3ga were subjected
to the standard conditions to furnish 4ga with 88% ee.[12]
On the basis of these observations, the following reaction
mechanism is proposed (Scheme 7). The rhodium catalyst
Scheme 7. Proposed mechanism.
reacts with the hydroxypyridine tautomer of 1 to form the
intermediate A.[14,15] A inserts into allene 2 to give the key
allyl rhodium intermediate B. Reductive elimination from B
can either form the O-allylated or the N-allylated products 3
and 4, respectively. Our experimental observations suggest
À
that formation of the C O product
3 is kinetically
Scheme 5. Conversion of O-allylated product into N-allylated product.
favored.[16,17] However, this process becomes reversible
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Liu, J. W. Meador, III, R. A. Ferre, J. Med. Chem. 2003, 46,
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equilibrium with the s-allylcomplex C, which might even be
the resting state of this catalytic cycle, in agreement with
similar observation we have made in the related reaction of
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allylated product 3 is lost, and once again the chiral catalyst
has control of the enantioselectivity en route to the thermo-
dynamic product 4 by way of a dynamic kinetic asymmetric
transformation.[18]
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The new pyridone allylation can be applied to the
synthesis of the known glucokinase activators 6 (Scheme 8).
[3] For the only example with two-step asymmetric Overman-type
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Scheme 8. The synthesis of glucokinase activators 6.
Rhodium-catalyzed selective addition of 2-pyridone 1p to
allene 2k afforded the key intermediate 4kp in 98% yield and
94% ee. Subsequent oxidation and methylation gave com-
pound 5 with 96% ee, which can be converted into com-
pounds 6 by aluminum-mediated amide formation with
a variety of aminoheterocycles.[1b]
In conclusion, we have developed the rhodium-catalyzed
direct chemo-, regio- and enantioselective allylation of 2-
pyridones with allenes in an atom-economic manner under
neutral conditions.[19] A broad range of 2-pyridones coupled
with functionalized allenes to give a-chiral N-allylic pyri-
dones. This reaction can be used in the synthesis of
biologically active molecules. Further studies will focus on
the selective allylation of other ambident nucleophiles.
[8] For details, see the Supporting Information.
[9] For a related steric effect on rearrangement of 6-substituted
alkoxylpyridine, see: a) C. S. Yeung, T. H. H. Hsieh, V. M. Dong,
Chem. Sci. 2011, 2, 544 – 551; b) S. Pan, N. Ryu, T. Shibata, Org.
Lett. 2013, 15, 1902 – 1905.
[10] In Ref. [3], the cyclohexyl group stops the palladium-catalyzed
rearrangement for steric reasons. Phenyl allene was tested and it
gave low conversion. 1,3-Disubstituted allene gave low con-
version, and only O-allyl product was detected.
[11] For the crystal structure, see the Supporting Information.
CCDC 1016609 (R-4da) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[12] Full conversion was obtained. Besides the N-allylated product,
the elimination products 2-pyridone and 1,3-diene were
observed in the 1H NMR of the crude mixture.
Received: August 4, 2014
Published online: October 8, 2014
Keywords: allenes · asymmetric allylation ·
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reaction mechanisms · 2-pyridones · rhodium
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