Rhodium-Catalyzed Dynamic Kinetic Asymmetric Allylation of Phenols and 2-Hydroxypyridines

Article abstract of DOI:10.1002/chem.201603532

Inspired by the mechanistic studies of rhodium-catalyzed atom-economic addition of carboxylate acids to allenes, a rhodium-catalyzed dynamic kinetic asymmetric allylation of different nucleophiles with racemic allylic carbonates has been developed. High regio- and enantioselectivities can be obtained under neutral conditions and, furthermore, the chemoselectivities can be controlled by different diphosphine ligands. (R,R)-QuinoxP* leads to selective O-allylation of phenols, whereas when embedding (S,S)-DIOP as the ligand, 2-naphthol is ortho-C-allylated for the first time in high enantioselectivity. To this end, hydroxypyridines can be N-allylated by Rh^I/(S)-DTBM-Segphos via the same intermediate as in the previously reported atom-economic addition to allenes.

Full text of DOI:10.1002/chem.201603532

DOI: 10.1002/chem.201603532
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Enantioselectivity |Very Important Paper|
Rhodium-Catalyzed Dynamic Kinetic Asymmetric Allylation of
Phenols and 2-Hydroxypyridines
Changkun Li and Bernhard Breit*[a]
Abstract: Inspired by the mechanistic studies of rhodium-
catalyzed atom-economic addition of carboxylate acids to al-
lenes, a rhodium-catalyzed dynamic kinetic asymmetric allyl-
ation of different nucleophiles with racemic allylic carbon-
ates has been developed. High regio- and enantioselectivi-
ties can be obtained under neutral conditions and, further-
more, the chemoselectivities can be controlled by different
diphosphine ligands. (R,R)-QuinoxP* leads to selective O-al-
lylation of phenols, whereas when embedding (S,S)-DIOP as
the ligand, 2-naphthol is ortho-C-allylated for the first time in
high enantioselectivity. To this end, hydroxypyridines can be
N-allylated by RhI/(S)-DTBM-Segphos via the same intermedi-
ate as in the previously reported atom-economic addition to
allenes.
Introduction
employing a chiral rhodium catalyst is much less developed
(Scheme 1). The Hayashi group reported the first successful
rhodium-catalyzed asymmetric allylic alkylation with the help
of a chiral PÀN ligand, in which a single aliphatic example was
realized with moderate regioselectivity.[10] Vrieze realized the ki-
netic resolution of aliphatic allylic carbonates with benzyl
amine in the presence of rhodium and a chiral diphosphine
ligand.[11] Nguyen reported the dynamic kinetic asymmetric al-
Transition-metal-catalyzed allylic substitution reactions belong
to the most powerful methods to construct carbon–carbon
and carbon–heteroatom bonds.[1] For the unsymmetric mono-
substituted allylic substrates, many transition metals, such as
Pd,[2] Ir,[3] Ru,[4] Fe, Mo, W,[5] and Rh,[6] can selectively generate
the branched regioisomer providing the possibility to con-
struct a new chiral center. In the past decade, iridium- and
ruthenium-catalyzed asymmetric allylation reactions have
made great progress in highly regio-(branched) and enantiose-
lective allylic substitutions, especially for aryl-substituted allylic
precursors. Conversely, aliphatic allylic substrates have not
been examined thoroughly in many cases, perhaps due to the
lower reactivity, competing b-hydride elimination, and moder-
ate regioselectivities. Rhodium catalysts are known to perform
with excellent regioselectivities and may provide a solution to
these problems. The rhodium-catalyzed allylic substitution was
first reported by Tsuji[7] featuring its high branched regioselec-
tivity in contrast to palladium catalysis. Evans and co-workers
improved the regioselectivities in these reactions by employing
trialkoxyphosphite ligands and discovered that these reactions
were not only highly regioselective but also enantiospecific.[8]
From enantiomerically pure allylic electrophiles, the corre-
sponding chiral products were obtained with either retention
or inversion of configuration. However, the transformation of
racemic allylic substrates, which are easily prepared and highly
reactive,[9] to furnish enantioenriched substitution products
[a] Dr. C. Li, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstraße 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under http://dx.doi.org/10.1002/
chem.201603532.
Scheme 1. Rhodium-catalyzed asymmetric allylic substitutions.
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lylation of anilines with racemic allylic trichloroacetimidate in
the presence of rhodium and a chiral diene ligand with the re-
lease of trichloroacetamide as the driving force.[12] Herein, we
report a rhodium-catalyzed dynamic kinetic asymmetric O-, C-
and N-allylation of phenols and 2-hydroxypyridines with easily
available racemic allylic carbonates employing commercially
available chiral diphosphine ligands under neutral conditions.
Considering the mechanism of the rhodium-catalyzed allylic
substitution, ionization of the two enantiomers of racemic allyl-
ic substrate with a chiral rhodium complex would provide the
diastereomeric p-allylrhodium complexes (Scheme 2). A fast
equilibrium between these two diastereomers via a s-allyl rho-
dium complex prior to the attack of a nucleophile is necessary
to realize a dynamic kinetic asymmetric allylation. In case the
s-allyl rhodium complex is the more stable species and the
resting state of the reaction, the rhodium-catalyzed dynamic
kinetic asymmetric allylation shall, in principle, be the same as
if one would start the reaction from linear allyl precursors,
which are less reactive.[9]
tion might be achieved provided that a suitable chiral diphos-
phine ligand could be identified (Eq. (2), Scheme 3).
Results and Discussion
Rhodium-catalyzed dynamic kinetic asymmetric O-allylation
of phenols
To develop an efficient method for the asymmetric allylation of
phenols, we next turned our attention to a rhodium-catalyzed
allylic substitution, which may proceed via the same allylic rho-
dium intermediates as for the addition to allenes. An allylic car-
bonate was expected to have a higher reactivity than an ester
and hence allow for milder reaction conditions. Additionally,
the released carbonate anion can function as a base to deprot-
onate the neutral nucleophile precursors and hence to provide
a low concentration of the anionic nucleophile.
Initial reactivity assays were undertaken with the racemic al-
lylic carbonate 1a and 4-bromophenol 2a as model substrates
(Table 1). In the presence of 2.5 mol% of [Rh(cod)Cl]2 (cod=
1,5-cyclooctadiene) and 5.0 mol% of DPEphos, the branched
allylic phenol ether[15] 3aa was isolated in 72% yield with
a 29:1 branched/linear ratio (Table 1, entry 1). Further ligand
screening revealed that the more electron-rich diphosphine
ligand L2 gave an 84% yield and >50:1 B/L ratio (entry 2). Dif-
ferent chiral electron-rich ligands were tested and (R,R)-Qui-
Scheme 2. Rhodium-catalyzed dynamic kinetic asymmetric allylation.
Table 1. Condition screening of rhodium-catalyzed asymmetric O-allyla-
tion of phenols.[a]
Recently, our group developed the rhodium-catalyzed atom-
economic and regioselective addition of different nucleophiles
to alkynes or allenes.[13] Further mechanistic studies on carbox-
ylic acid nucleophiles showed that the generation of
a branched allylic ester product is reversible.[14] The calculated
and isolated linear h1-s-allyl rhodium complex is the resting
state of the reaction (Eq. (1), Scheme 3).
Based on this, we assumed that in a rhodium-catalyzed allyl-
ic substitution reaction, the chiral center starting from racemic
allylic substrates can be destroyed via such a s-allyl rhodium
intermediate and the formation of the new stereogenic center
can be determined by an appropriate chiral catalyst. In this
case, a rhodium-catalyzed dynamic kinetic asymmetric allyla-
Entry
Ligand
Solvent
Yield 3a [%][b]
ee 3a [%][d]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
Et2O
toluene
72
84
65
81
87
12[c]
88
23
4[c]
78
–
–
À92
97
82
–
96
91
–
10
99
[a] The reactions were carried out with 0.3 mmol of 1a and 0.36 mmol of
2a in 1.0 mL of dichloromethane. [b] Isolated yield. [c] NMR yield. [d] The
ee values were determined by chiral HPLC.
Scheme 3. The proposal of this work.
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noxP* was found to yield in the best reactivity and enantiose-
lectivity (entry 4). Additionally, a screening of the influence of
different solvents revealed that those derived from different
ethers such as THF or diethyl ether gave the lowest conversion
(entries 8 and 9), whereas toluene provided a moderate yield
and a better enantiomeric excess at the same time (entry 10).
Finally, with DCM as the solvent, 88% yield and 96% ee could
be accessed. The absolute configuration of the product was as-
signed to be R by comparing with a known structure in the lit-
erature.[15m]
strate than the carbonate starting material for the rhodium cat-
alyst.[16] Furthermore, electron-rich and -neutral phenols are
also good substrates in this transformation to furnish the cor-
responding allylic ethers (3aj to 3am). Even sterically more-de-
manding substrates such as 1-naphthol, 2-naphthol, and 2-
phenylphenol reacted well with 1a resulting in high yields and
high enantiomeric excess (3an to 3ap).
Next, the reactivity of different allylic carbonates as suitable
reaction partners was explored (Table 3).[17] The reaction of
With the optimized conditions in hand, we first explored the
scope of this reaction with regard to different phenols by
using 1a as the privileged allylic carbonate (Table 2). Halogen
groups are well-tolerated at different positions of the phenyl
ring (3ab to 3ad). Notably, phenols with stronger electron-
withdrawing groups (ester, cyano, trifluomethyl, ketone, and al-
dehyde) reacted smoothly to give the allylic ethers in high
yields and enantiomeric excess (3ae to 3ai). However, for 4-ni-
trophenol, less than 10% conversion could be observed. Per-
haps the product, allylic 4-nitrophenol ether, is a better sub-
Table 3. Scope of allylic carbonates in rhodium-catalyzed asymmetric O-
allylation of phenols.
Table 2. Scope of phenols in rhodium-catalyzed asymmetric O-allylation
of phenols.[a]
[a] The reaction was carried out at 358C. [b] The reaction was carried out
at 808C. [c] The ee was determined by subjecting the deprotected 3ka to
HPLC analysis. [d] The reaction was carried out at 358C and 4-vinyl-1, 3-di-
oxolan-2-one 1k was used as the substrate. [e] The substrate is a mixture
of 10:1 Z/E isomers and the ee was determined from the saturated aryl
ether after hydrogenation.
phenol 2m with longer chain branched allylic carbonate 1b af-
forded the ether in 86% yield and 97% ee. As the product
3 cm of 1c and 2m is volatile, we chose 2a as the model sub-
strate. Substrates with aliphatic chains devoid of any functional
groups behaved well in the reaction (3ca and 3da). b-
Branched allylic carbonate 1e reacted smoothly with 99% ee,
whereas an a-branched cyclohexyl substituent showed lower
reactivity (3 fa). The reaction of 1g needed to be carried out at
358C, showing no detrimental effect on the enantioselectivity
(ee=99%). A tert-butyl substituent makes the reaction more
sluggish and 3ha was isolated in 15% yield even at 808C.
Phenyl-substituted allylic carbonate also participated in this re-
action and 3ia was isolated in 92% yield with 90% ee. Func-
[a] The reactions were carried out with 0.3 mmol of 1a and 0.36 mmol of
2 in 1.0 mL of dichloromethane. [b] The ee was determined according to
the corresponding alcohol.
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tional groups, such as a TBS ether and an olefin, are also toler-
ated well in this reaction (3ja and 3la). An allylic ether with
a free hydroxyl function (3ka) was obtained in 97% ee, when
racemic 4-vinyl-1, 3-dioxolan-2-one (1k) was applied.
product 3da was determined by the ligands, and not by the
substrate, resulting in a reaction that is not stereospecific at
any time and making the use of chiral-appropriate ligands cru-
cial for high enantioselectivities within this process.
In order to explore the potential application of this method-
ology, we carried out a gram-scale reaction (Scheme 4). In the
presence of 1.0 mol% of [Rh(cod)Cl]2 and 2.0 mol% (R,R)-Qui-
noxP*, 5 mmol of rac-1d reacted with 6 mmol of p-methoxyl-
phenol 2j at 308C to furnish 1.27 g of allylic PMB ether 3dj in
95% yield and 92% ee. Oxidative deprotection with
(NH4)2Ce(NO3)6 afforded the chiral allylic alcohol 4 in 93% yield.
In this respect, the described rhodium-catalyzed allylic substi-
tution/oxidative deprotection sequence provides a practical
approach to prepare chiral allylic alcohols in gram-scale quanti-
ties.
To our surprise, when subjecting the linear isomeric carbon-
ate 5 (Scheme 6) to the indicated reaction conditions, only
13% of the branched product 3aa (97% ee) was isolated, with
most of 5 recovered. Conducting the reaction at 608C afforded
27% yield with 96% ee resulting in the suggestion that the
same rhodium allyl intermediates are passed by either starting
from the linear or the branched allylic carbonate. Furthermore,
it shows the lower reactivity of the linear allylic carbonate for
the rhodium-catalyzed allylic substitution. Increased levels of
substitution at the alkene function of the allylic carbonate
render the reaction sluggish: Compounds 6 and 7 gave less
than 5 mol% conversion, while the reaction with 8 afforded
43 mol% of product with 12.5:1 regioselectivity at 408C.
Scheme 4. A gram-scale application: preparation of enantioenriched allylic
alcohols.
To further elucidate the reaction mechanism, we conducted
a kinetic resolution and experimental studies regarding the ste-
reospecificity of the reaction (Scheme 5). When 2.0 equivalents
of rac-1d were reacted with 1.0 equivalent of 2a, the product
3da was generated in 94% yield and 98% ee, along with the
recovered allylic carbonate S-1d in 99% yield and only 56% ee.
Hence, enantiodifferentiation of the rhodium/(R,R)-QuinoxP*
complex is not very pronounced for the reaction with racemic
allylic carbonate. Furthermore, we next examined if the reac-
tion is stereospecific in the presence of rhodium/diphosphine
complexes. Enantioenriched R-1d reacted with 2a under the
catalysis of three different Rh/ligand complexes to give differ-
ent results. This study reveals that the configuration of the
Scheme 6. The reactivities of other substrates.
Rhodium-catalyzed dynamic kinetic asymmetric C-allylation
of electron-rich phenols
The selective allylation at the ortho-position of phenols can be
realized by a thermal or catalytic Claisen rearrangement of allyl
aryl ethers. The linear-selective allylation of naphthols or other
electron-rich phenols could also be catalyzed by palladium,
molybdenum, ruthenium, and other transition metals.[18] How-
ever, to the best of our knowledge, intermolecular[19] transi-
tion-metal-catalyzed branched and enantioselective allylation
of electron-rich phenols has never been reported before.
Herein, we describe the first rhodium-catalyzed regio- and
enantioselective C-allylation of naphthols and other electron-
rich phenols with racemic allylic carbonates (Scheme 7).
The O-allylation of 2-naphthol was obtained in 98% yield
and 97% ee by using (R,R)-QuinoxP* as the privileged chiral
ligand (Table 2, 3ao). Surprisingly, when (S,S)-DIOP was exam-
ined as the chiral ligand, the C-allylation product was predomi-
nant. With racemic allylic carbonate 1b and 2-naphthol 2o as
model substrates, we screened solvents and some DIOP-deriva-
tives in order to get a selective access to these types of C-allyl-
ated products (Table 4). The reaction in toluene led to a better
conversion as well as to an enhanced C/O ratio and enantiose-
lectivity compared to dichloromethane (Table 4, entry 2). THF
provided similar ee but much lower yield of 9bo (entry 3). The
Scheme 5. Kinetic resolution and stereospecificity studies.
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Table 5. Scope of rhodium-catalyzed asymmetric C-allylation of phenols[a]
Scheme 7. Transition-metal-catalyzed intermolecular C-allylation of 2-naph-
thol.
more polar acetonitrile directed the reaction in favor to the O-
allylation product 3bo (entry 4). In toluene, (R,R)-DTBM-DIOP
and (R,R)-Cp-DIOP were not able to give better enantioselectiv-
ities, while open-chain (R,R)-TBDM-SLIOP[20] exhibited less reac-
tivity and gave lower ee (entries 5–7).
Choosing toluene as the solvent and commercially available
(S,S)-DIOP as the chiral ligand in this reaction, we examined
the scope of this rhodium-catalyzed chemo-, regio-, and enan-
tioselective allylation of electron-rich phenols (Table 5). Allylic
carbonates with b-branch, phenyl and silyl ether substituents
were tolerated well and gave similar ee values (9do, 9eo, and
9jo). An a-branched cyclohexyl group increased the enantiose-
lectivity (9 fo, 89% ee). The sterically more hindered tert-butyl-
substituted allylic carbonate provided the C-allylation product
with 94% ee but a lower yield and C/O ratio (9ho). Applying
an aryl-substituted allylic carbonate, a lower 71% ee was ob-
tained (9io). Besides the carbonates, different phenols were
tested. Bromo and ester groups can be installed at the 6-posi-
Table 4. Condition screening of rhodium-catalyzed asymmetric C-allylation
of 2-naphthol.[a]
[a] The reactions were carried out with 0.3 mmol of 1 and 0.36 mmol of 2
in 1.0 mL toluene. [b] The racemate cannot be separated by chiral HPLC.
tion of the 2-naphthol (9bq and 9br). 1-naphthol reacted
smoothly to produce the 2-allyl-naphthol in high yield and
enantioselectivity (9bn). Sesamol and 3,4-dimethoxylphenol
could also be used in this reaction to give the ortho-allylation
products at the less hindered position (9bk and 9bs). Con-
versely, mono-methoxy-substituted phenols cannot produce
the corresponding C-allylation products (9bu). The C-allylation
of 1-bromo-2-naphthol (2v) could not be realized, with only
the O-allylation product detectable. Finally, the absolute con-
figuration of the product 9 fw was assigned to be R, based on
a single-crystal X-ray diffraction analysis.
Entry
Ligand
Solvent
C/O
9bo [%][b]
ee 9bo [%][c]
1
2
3
4
5
6
7
L7
L7
L7
L7
L8
L9
L10
DCM
toluene
THF
CH3CN
toluene
toluene
toluene
10:1
20:1
5:1
1:10
12:1
14:1
5:1
66
82
45
–
74
92
29
70
83
84
–
69
83
67
To test if the O-allyl product is a reaction intermediate of the
C-allyl product, control experiments were conducted. Submis-
sion of the O-allylation product rac-3ao to the same reaction
conditions did not show any reactivity at all. However, in the
presence of 0.5 equivalents of 2-naphthol, 11% conversion of
[a] The reaction was carried out using 0.3 mmol of 1b and 0.36 mmol of 2o
in 1.0 mL of solvent. [b] Isolated yield. [c] The ee was determined by chiral
HPLC.
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rac-3ao to the corresponding C-allyl product was observed.
5.0 equivalents of 2-naphthol further increased the conversion
of rac-3ao to 17%, and 14% of 9ao (Scheme 8) was isolated
finally furnish N-allyl pyridones with similar selectivities via the
O-allylated intermediate, employing the same catalyst as used
for the related allene addition reaction.
Indeed, racemic allylic carbonate 1a reacted with 5-chloro-
pyridone 10a in the presence of the rhodium/(R)-DTBM-MeO-
Biphep catalyst to give 83% yield of the N-allyl pyridone 11 aa
with 94% ee, which is the same level of enantioselectivity as
for the allene addition reaction.[13h] Further ligand examination
showed that the less-costly (S)-DTBM-Segphos operated with
a similar enantioselectivity, which caused us to choose this
ligand in further studies. Pyridones equipped with electron-
withdrawing substituents at the 3- or 5-position increased the
reactivities and enantioselectivities (11 ab and 11 ac, 2.5 mol%
[Rh(cod)Cl]2). For 3-nitropyridone, only 1 mol% of rhodium
dimer precursor (11 me) was needed for full conversion. Elec-
tron-neutral pyridone could also react smoothly to give the
corresponding N-allylated product with high ee (11 ad). The ab-
solute configuration was assigned to be S by comparison with
literature data.[22b] Then we examined the scope of racemic al-
lylic carbonates, especially those with small alkyl substituents,
which are not easily available for the corresponding allene
counterparts. In this way, simple methyl, ethyl, n-pentyl, and
isobutyl substituents can be easily installed at the a-position
to the nitrogen atom of 5-chloropyridone with high yields and
enantioselectivities (11 ea, 11 ba, and 11 ea, Table 6). Further-
more, an unprotected hydroxyl function can be obtained with
98% ee by starting from the commercially available racemic
vinyl ethylene carbonate (11 ka).
Scheme 8. Control experiments.
with 90% ee. The corresponding linear allyl 2-naphthol ether
was completely inert under the same reaction conditions even
in the presence of 2-naphthol. These experiments suggest that
the conversion of O-allyl-2-naphthol ether to the C-allyl-2-
naphthol needs extra 2-naphthol as a proton source and this
process is slow. The C-allyl product seems to be formed under
kinetic control determined by the nature of ligands and the
substrates.
Rhodium-catalyzed dynamic kinetic asymmetric N-allylation
of 2-hydroxypyridine
a-Chiral N-substituted 2-pyridones can be found in many natu-
ral products and as peptidomimetics in medicinally relevant
molecular structures.[21] Chiral electrophiles, which are usually
prepared by multistep synthesis, can be used as alkylating re-
agents under basic conditions. Methods for the efficient and
enantioselective construction of this structural motif with the
aid of a chiral catalyst from achiral starting materials are still
very rare.[22] We have reported the rhodium-catalyzed chemo-,
regio-, and enantioselective addition of 2-hydroxypyridine to
terminal allenes to prepare chiral N-allyl pyridones.[13h] The re-
action has been shown to proceed via the kinetic O-allyl inter-
mediates, which finally rearrange slowly to the thermodynami-
cally more stable N-allyl pyridones (Scheme 9). Inspired by the
asymmetric O-allylation and C-allylation of phenols, we expect-
ed that 2-hydroxypyridines could also serve as nucleophiles to
This highly enantioselective N-allylation method of 2-pyri-
dones can be applied in a formal synthesis of medicinally inter-
esting rhinovirus 3C-protease inhibitor (Scheme 10).[21c] The ni-
trogen atom in the 2-pyridone ring can be distinguished from
the normal amide nitrogen in 10g and selectively allylated in
Table 6. Scope of rhodium-catalyzed asymmetric N-allylation of 2-hydrox-
ypyridines.
[a] The reactions were carried out with 0.3 mmol of 10 with 5.0 mol% of
[Rh(cod)Cl]2. [b] 2.5 mol% of [Rh(cod)Cl]2. [c] 1.0 mol% of [Rh(cod)Cl]2.
Scheme 9. Rhodium-catalyzed asymmetric allylation of 2-pyridone.
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A with (for C-allylation) or without (for N-allylation) the help of
a proton source to reform complex D, and finally leads to the
thermodynamic C- or N-allyl products. Due to the fact that O-,
C-, or N-allylations need different chiral ligand environments,
this might be supportive for the proposed inner-sphere reduc-
tive elimination mechanism. This stands in contrast to the
known outer-sphere nucleophilic attack observed in palladium-
and iridium-catalyzed allylic substitutions,[23] in which one
metal/chiral ligand combination usually provides similar enan-
tioselectivities for different nucleophiles.
Conclusion
Scheme 10. The application: formal synthesis of rhinovirus 3C-protease in-
hibitor.
We have described rhodium-catalyzed dynamic kinetic asym-
metric allylations of phenols and 2-hydroxypyridines with race-
mic allylic carbonates under mild and neutral conditions. The
reactions are especially suitable for aliphatic-substituted allylic
carbonates, which complement known iridium- and rutheni-
um-catalyzed allylic substitution chemistry. Highly regio- and
enantioselective O-allylation of phenols was achieved. The re-
action can be performed on a gram-scale and used in chiral al-
lylic alcohol synthesis. For the first time, branched and enantio-
selective ortho-C-allylation of naphthols and other electron-rich
phenols was realized. Excellent chemo-, regio-, and enantiose-
lectivities were obtained for the N-allylation of 2-hydroxypyri-
dines. This reaction can be regarded as an alternative to our
previously reported atom-economic addition of 2-hydroxypyri-
dines to allenes, especially for smaller-alkyl substituted prod-
ucts, for which the corresponding allenes are not easily avail-
able. The method can be used in the formal synthesis of
a human rhinovirus 3C-protease inhibitor’s key intermediate.
The extension of this strategy to other neutral nucleophiles
and detailed mechanism studies are under investigation in our
laboratory.
92% yield and 98% ee to afford compound 11 mf. It was con-
verted to the key intermediate methyl ester 12 by a three-step
oxidation and methylation sequence in 63% yield.
Reaction mechanism
Based on the experiments above and the mechanism studies
on the regioselective coupling of carboxylic acids and terminal
alkynes,[14] we propose a plausible catalytic cycle for the rhodi-
um-catalyzed dynamic kinetic asymmetric O-, C-, and N-allyla-
tion of phenols and 2-hydroxypyridines, as shown in
Scheme 11. RhICl/chiral diphosphine monomer A reacts with
racemic allylic carbonate 1 to generate h1 s-allyl carbonate
rhodium complex B. At this stage, the chiral center of the allyl
electrophile is destroyed. Complex B is able to undergo
a ligand exchange with acidic phenol (or hydroxypyridine) to
form phenolate-bound s-allyl rhodium complex C, which is
perhaps the same intermediate as passed upon addition of
phenols or 2-hydroxypyridines to allenes. This is followed by
carbon dioxide and methanol release, which might be the driv-
ing force of this reaction. In analogy to previous mechanistic
investigations, s-allyl complex C might isomerize to the Rh-p-
allyl complex D, which then undergoes reductive elimination
to furnish the products with back-formation of the RhI species
A. The O-allyl product can react further with rhodium complex
Acknowledgements
This work was supported by the DFG. C.L. thanks the Alexand-
er von Humboldt Foundation for a postdoctoral fellowship. We
thank Dr. D. Kratzert and Dr. M. Keller for the X-ray diffraction
analysis.
Keywords: allylic substitution · dynamic kinetic asymmetric
transformations · enantioselectivity · phenol · rhodium
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Received: July 27, 2016
Published online on && &&, 0000
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FULL PAPER
Transform your chemistry: A rhodium-
catalyzed dynamic kinetic asymmetric
allylation of different nucleophiles with
racemic allylic carbonates has been de-
veloped. High regio- and enantioselec-
tivities can be obtained under neutral
conditions and, furthermore, the che-
moselectivities can be controlled by dif-
ferent diphosphine ligands (see
&
Enantioselectivity
C. Li, B. Breit*
&& – &&
Rhodium-Catalyzed Dynamic Kinetic
Asymmetric Allylation of Phenols and
2-Hydroxypyridines
scheme).
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ÝÝ These are not the final page numbers!