Rh(I)-bisphosphine-catalyzed asymmetric, intermolecular hydroheteroarylation of α-substituted acrylate derivatives

Article abstract of DOI:10.1021/ja511445x

Asymmetric hydroheteroarylation of alkenes represents a convenient entry to elaborated heterocyclic motifs. While chiral acids are known to mediate asymmetric addition of electron-rich heteroarenes to Michael acceptors, very few methods exploit transition metals to catalyze alkylation of heterocycles with olefins via a C-H activation, migratory insertion sequence. Herein, we describe the development of an asymmetric, intermolecular hydroheteroarylation reaction of α-substituted acrylates with benzoxazoles. The reaction provides 2-substitued benzoxazoles in moderate to excellent yields and good to excellent enantioselectivities. Notably, a series of mechanistic studies appears to contradict a pathway involving enantioselective protonation of a Rh(I)-enolate, despite the fact that such a mechanism is invoked almost unanimously in the related addition of aryl boronic acids to methacrylate derivatives. Evidence suggests instead that migratory insertion or beta-hydride elimination is enantiodetermining and that isomerization of a Rh(I)-enolate to a Rh(I)-heterobenzyl species insulates the resultant α-stereocenter from epimerization. A bulky ligand, CTH-(R)-Xylyl-P-Phos, is crucial for reactivity and enantioselectivity, as it likely discourages undesired ligation of benzoxazole substrates or intermediates to on- or off-cycle rhodium complexes and attenuates coordination-promoted product epimerization.

Full text of DOI:10.1021/ja511445x

Article
pubs.acs.org/JACS
Rh(I)−Bisphosphine-Catalyzed Asymmetric, Intermolecular
Hydroheteroarylation of α‑Substituted Acrylate Derivatives
Claire M. Filloux and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: Asymmetric hydroheteroarylation of alkenes
represents a convenient entry to elaborated heterocyclic
motifs. While chiral acids are known to mediate asymmetric
addition of electron-rich heteroarenes to Michael acceptors,
very few methods exploit transition metals to catalyze
alkylation of heterocycles with olefins via a C−H activation,
migratory insertion sequence. Herein, we describe the
development of an asymmetric, intermolecular hydroheteroar-
ylation reaction of α-substituted acrylates with benzoxazoles.
The reaction provides 2-substitued benzoxazoles in moderate
to excellent yields and good to excellent enantioselectivities. Notably, a series of mechanistic studies appears to contradict a
pathway involving enantioselective protonation of a Rh(I)−enolate, despite the fact that such a mechanism is invoked almost
unanimously in the related addition of aryl boronic acids to methacrylate derivatives. Evidence suggests instead that migratory
insertion or beta-hydride elimination is enantiodetermining and that isomerization of a Rh(I)−enolate to a Rh(I)−heterobenzyl
species insulates the resultant α-stereocenter from epimerization. A bulky ligand, CTH-(R)-Xylyl-P-Phos, is crucial for reactivity
and enantioselectivity, as it likely discourages undesired ligation of benzoxazole substrates or intermediates to on- or off-cycle
rhodium complexes and attenuates coordination-promoted product epimerization.
INTRODUCTION
■
Catalytic, enantioselective addition of a C−H bond of a
heterocycle across an alkene represents a conceptually simple
and atom economical method for the preparation of elaborated
heterocyclic scaffolds. This concept has been implemented in a
formal sense in the asymmetric Friedel−Crafts alkylation of
electron-rich heteroarenes, such as indoles, with Michael
acceptors.1 Yet methods exploiting transition metals to mediate
asymmetric hydroheteroarylation (HH) of alkenes via a C−H
activation, insertion sequence remain quite elusive.2,3 This
deficiency is somewhat surprising given the diverse methods for
asymmetric hydroarylation of olefins with activated arenes4 or
with arenes containing directing groups for C−H functionaliza-
tion.5 In the early 2000s, Bergman and Ellman pioneered the
achiral, intramolecular HH of unactivated alkenes with a
Rh(I)−phosphine catalyst.3a This discovery was expanded in a
great body of work to the intermolecular HH reaction of
alkenes6 and to several discrete asymmetric, intramolecular HH
reactions.7 In 2012, Shibata provided an early example of an
asymmetric intermolecular HH reaction mediated by a
transition metal (TM):8 an Ir(I)−SDP-catalyst promotes the
branched-selective alkylation of N-benzoylindole and styrene in
42% ee (Figure 1, eq 1). Notably, alkylation occurs at the
indole 2-position, whereas functionalization typically proceeds
at the 3-position under Friedel-Craft conditions.1 Though only
modestly selective, Shibata’s example foreshadows that TM-
catalyzed HH may eventually serve as a selective and general
complement to established methods using chiral acids. Indeed,
Figure 1. TM-catalyzed, asymmetric, intermolecular hydroheteroar-
ylation reactions previously reported in the literature.
Hartwig and Sevov described in short succession the
asymmetric HH of norbornene with diverse heterocycles
using a chiral Ir(I) catalyst (Figure 1, eq 2).9 Most recently,
Hou and co-workers reported the enantioselective alkylation of
2- substituted pyridines with unactivated, terminal alkenes using
a chiral, half-sandwich scandium complex. (Figure 1, eq 3).10
Received: November 13, 2014
© XXXX American Chemical Society
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Figure 2. Our HH reaction of benzoxazoles and α-substituted acrylates and precedent inspiring its development.
While the work of Hartwig and Hou provides a powerful
proof of concept, room for complementary asymmetric HH
methods remains. Specifically, we sought to expand the scope
of the olefin coupling partner. Hartwig’s HH reaction is
demonstrated only with the strained cyclic alkene, norbornene,9
and Hou’s pyridine alkylation appears limited to relatively
unfunctionalized, electron neutral alkenes.10 Herein, we
describe a Rh(I)-catalyzed asymmetric alkylation of benzox-
azoles with acrylate derivatives (Figure 2, eq 4). To our
knowledge, this work represents the first example of an
enantioselective, transition-metal-mediated, intermolecular HH
of acyclic, electron-deficient alkenes. Moreover, the described
reaction makes products of potential medicinal value; isosteres
for purine bases and certain amino acids, 2-substituted
benzoxazoles are known to exhibit tremendous biological
activity.11
We found inspiration for the described HH reaction in
chemistry developed by Chang et al.3j This group reported the
HH of acrylates and acrylate derivatives with benzheterocycles
or pyridine oxides (Figure 2, eq 5). Chang et al. invoke catalysis
by a Rh(I)−acetate speciesacetate counterion mediates C−H
activation, while liberated acetic acid protonates an eventual
C−Rh bond (Figure 2, eq 6). We envisioned that use of a
substituted acrylate in a system related to Chang’s would enable
the asymmetric preparation of branched products (Figure 2, eq
7). Notably, the Rh(I)−dppe system used by Chang et al. lends
itself to enantioselective modification: in contrast to relatively
scarce chiral cyclopentadienyl ligands ubiquitous in Rh(III)
catalysis,5d,e,h chiral bisphosphine ligands abound.12
Despite the overt similarity between the known and
proposed reactions, several complications could accompany
the envisioned asymmetric method. The mechanism proposed
by Chang invokes protonation of Rh−enolate II (Figure 2).3j
While protonation of C-bound II could provide enantioen-
riched products, protonation or ligand exchange of O-bound III
at oxygen would give racemic product. Additionally, β-H
elimination and dissociation of resultant conjugated alkene
would furnish undesired Heck product.3j Indeed, success of
Hartwig’s and Hou’s chemistry may be understood in light of
these anticipated difficulties; the privileged nature of
norbornene in eq 2 (Figure 1) likely derives in part from the
fact that presumed intermediate I cannot undergo β-H
elimination. Hou’s pyridine alkylation (Figure 1, eq 3) is also
presumably more insulated from β-H elimination than a Rh(I)-
system, since the enhanced thermodynamic stabilization of
metal−hydrogen bonds over metal−carbon bonds is smaller for
early TMs than for late ones.13
While we were aware that the described pitfalls could plague
our desired reaction with low stereo- or product-selectivity,
work by Reetz, Genet, and others offered hope that these
obstacles would not be insurmountable.14 These groups report
that a Rh(I)−chiral bisphosphine system mediates the
asymmetric hydroarylation of α-substituted acrylates with
boronic acid derivatives (Figure 2, eq 8). Importantly, this
reaction is presumed to intercept analogous Rh−enolate
intermediate IV.14b−d Similar opportunities for stereochemical
scrambling or Heck reactivity exist for IV as for our presumed
Rh−enolate II. Yet these pathways must not be competitive in
the described systems, since saturated products are obtained in
good to excellent enantioselectivities.14 These groups invoke
asymmetric protonation of Rh−enolate IV or O-bound Rh-
isomer to explain high product enantioselectivities,14,15 but
aside from Genet et al.,14e none provide rigorous mechanistic
evidence in favor of this claim (vide infra).
RESULTS AND DISCUSSION
■
Encouraged that our asymmetric HH could succeed, we
decided to begin by investigating mechanistic aspects of the
parent, achiral reaction (Figure 2, eq 5). The first question we
sought to address was the role of the CsOAc. If, as Chang and
co-workers postulated, CsOAc serves to generate a Rh(I)−
acetate catalyst in situ, then perhaps the same reactivity could
be accomplished with a premade Rh(I)−acetate catalyst.
Chatani and co-workers have indeed observed that [Rh(cod)-
OAc]2 can be used in place of a KOAc−[Rh(cod)Cl]2 system
in the directed hydroarylation of acrylates with 8-aminoquino-
line-derived benzamides.16,17 We prepared [Rh(cod)OAc]2 by
treating [Rh(cod)Cl]2 with KOAc in refluxing acetone
according to a known procedure.18 Recrystallization from
EtOAc provided X-ray quality crystals of the air-stable, orange
solid. These were characterized by X-ray crystallography to
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provide what we believe is the first reported crystal structure of
the complex (see Supporting Information).19 As predicted,
[Rh(cod)OAc]2 performs with equal efficiency as Chang’s in
situ generated catalyst in the HH of several benzheterocycles 1
with tert-butyl acrylate (Chart 1). CsOAc thus appears to serve
primarily as an acetate source in Chang’s chemistry.
Table 1. Initial Reaction Optimization
a
b
Chart 1. HH Using Chang’s Established Conditions (Red)3j
or [Rh(cod)OAc]2 (Blue)
equiv
T
time
(h)
4ca
ee
a,b
entry ligand
solvent
3a
(°C)
(%)
(%)
1
2
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CH3CN
TFE
4
4
4
4
4
4
4
6
8
4
4
4
4
4
4
4
4
8
120
120
120
120
120
120
120
120
120
100
100
100
100
100
100
100
160
100
60
60
60
60
60
60
24
24
24
24
24
24
24
24
24
24
24
24
100
95
39
9
29
−47
57
3
4
−78
84
5
20
56
19
29
58
17
15
<5
<5
6
6
85
7
89
8
85
9
77
10
11
12
13
14
15
16
88
95
16
DCE
95
DME
91
DMF
22
10
7
88
PhCF3
o-DCB
CH3CN
95
a
17
17
To ensure uniformity for comparison, all reactions were performed
b
c
18
58
95
by the first author. Yields were determined with respect to 4,4′-di-tert-
butylbiphenyl (DTBB) by H NMR of the reaction mixture.
1
With [Rh(cod)OAc]2 in hand, we screened the asymmetric
HH of ethyl methacrylate (3a) and 4-methylbenzoxazole (1c)
(Table 1), since this heterocycle proved most reactive in the
achiral reaction with tert-butyl acrylate (Chart 1, vide supra).
Ligands resembling dppe were chosen at the outset. In PhMe at
120 °C, 1c and 3a react in the presence of a Rh(I)−prophos
(L1) catalyst to deliver α-substituted product 4ca in
quantitative yields and 29% ee (Table 1, entry 1). Ees remain
modest with Chiraphos (L2) and Me−Duphos (L3) (entries 2
and 3). Significant improvement in ee is achieved with Binap
(L4), but yields of 4ca suffer. Since bite angle is known to have
a pronounced effect on reaction selectivity and efficiency,20 we
examined Binap derivatives, Synphos (L5) and Segphos (L6),
whose bite angles we hoped would compare more favorably to
dppe.21,22 Gratifyingly, a Rh(I)−Segphos system delivers
product 4ca in acceptable 56% yield, and good selectivity
(85% ee, entry 6). A twofold increase in acrylate concentration
further increases reactivity, providing comparable yields in 24 h
to what is obtained in 60 h with lower acrylate concentrations
(entries 6−9). Concurrently, a solvent and temperature screen
(entries 9−17) revealed acetonitrile (CH3CN) to be optimal
for selectivity (95% ee, entry 11). Combining results, execution
of the HH reaction in CH3CN with 8 equiv of acrylate 3a and 5
mol % rhodium dimer provides satisfactory yields of 4ca in
excellent enantioselectivity (entry 18).
a
Determined with respect to DTBB by LC analysis of the reaction
b
mixture on a chiral stationary phase. Determined at the same time as
% yield by LC analysis of the crude reaction mixture on a chiral
stationary phase. Reaction conducted with 5 mol % [Rh(cod)OAc]2
and 10 mol % L6.
c
parts (Chart 1, 1a−1b, and 1d). Yields displayed in Chart 1 fail
to adequately capture this striking reactivity differencewhile
reaction of 1c is complete in 3 h, reaction of 1a, 1b, and 1d stall
at about 50% after 60 h. To gain insight into this disparate
reactivity, we performed two competition experimentsone
between 1b-D and 1c-H (Figure 3 and eq 10),23 and one
between 1b-H and 1c-H (eq 11).
Although we were pleased with this result, we anticipated
that reaction efficiency would need to be further improved in
order to extend the substrate scope to less reactive heterocycles.
For instance, when benzoxazole 1a is reacted under the
conditions shown in entry 2 of Table 1 (which provide nearly
quantitative yields of 4ca), no discernible product 4aa is
obtained (eq 9). Before refining our conditions, we sought to
understand what made 4-methylbenzoxazole (1c) so much
more reactive than its unsubstituted or 6-substituted counter-
From the former, the following significant observations are
made: (a) crossover substrates 1b-H and 1c-D are observed by
1H and H NMR (Figure 3); (b) H is incorporated into the
alkyl backbone of both products 2b and 2c (eq 10); and (c) 2H
is incorporated predominantly at the β-position of both
products (eq 10). From this data, we propose a mechanistic
2
2
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a β-H elimination, hydrorhodation sequence to heterobenzyl-
Rh VIII (observation c). Protonation appears to occur
predominantly from VIII (or the N-bound isomer, vide
infra). Protonation likely proceeds via an outer-sphere
mechanism (observation b), but an inner-sphere mechanism
after D−H exchange cannot be ruled out.
Competition between 1b-H and 1c-H provides further
mechanistic insights (eq 11). When reactive 1c and sluggish 1b
(Chart 1) are subjected to the standard conditions, products 2b
and 2c form in roughly equal rates (eq 11). We rationalize the
identical rates of formation of 2b and 2c in one of two ways,
both of which invoke the different ligating abilities of 1b and 1c.
Given that C−H activation is reversible, one explanation
assumes that there exists one or more irreversible steps before
the turnover-limiting step (TLS) of sluggish substrate 1b.25 In
the context of the mechanism shown in Figure 4, we assume
that MI is irreversible and therefore product determining and
that protonation of 1b-derived intermediates VI or VIII is
turnover limiting. Sluggish protonation of 1b-derived VI or
VIII is understood by invoking coordination of the heterocycle
to rhodium in 1b-derived intermediate VI. Ligation blocks a
free coordination site necessary for either protonation of VI or
isomerization to VIII via β-H elimination. While unhindered
azoles such as 1b, 1a, and 1d can presumably bind in the
fashion described, A[1,3]-strain would disfavor analogous
coordination of 1c-derived IX, accelerating the reactivity of
1c relative to its unsubstituted counterparts. Indeed, 15N NMR
studies suggest that bulky substitution adjacent to the
coordinating nitrogen of various oxazoles impedes their
coordination to Rh(II)-complexes.26 To sum up, then, so
long as the C−H activation, MI sequence proceeds at roughly
equal rates for both substrates, products 2b and 2c will form in
a one-to-one ratio, since all catalyst will eventually funnel to 1b-
derived VI.
1
2
Figure 3. H and H NMR of competition experiment between 1c-H
and 1b-D in PhMe implicates reversible C−H activation.
In perhaps a more simple explanation, strongly coordinating
1b (and 1a and 1d) but not weakly coordinating 1c acts as a
competitive ligand toward important intermediates on or off
the catalytic cycle, slowing catalysis of both 1b and 1c.
Although it would be difficult to discriminate between these
two explanationsone invoking an intramolecular coordina-
tion event and one invoking an intermolecular coordination
eventboth suggest similar avenues for reaction optimization.
Specifically, if deleterious coordination of the heteroarene were
responsible for low reactivity of 1a−1b and 1d, then perhaps it
could be discouraged by increasing the bulk of the bi-
sphosphine ligand. We were optimistic that increasing ligand
bulk might offer additional advantages. A congested coordina-
tion environment could also encourage a difficult MI event for
steric reasons, since MI necessarily reduces the metal
coordination number by one.27
cycle similar to that offered by Chang et al. (Figure 4).3j,24
A
Rh−acetate catalyst mediates reversible C−H activation of
heteroarene 1 (observation a) to provide Rh−heteroaryl
complex V. Migratory insertion (MI) across the terminal
acrylate (R = H) furnishes Rh−enolate VI, which isomerizes via
To this end, we sought to further optimize the reaction of
ethyl methacrylate (3a) and 1c by screening bulky Segphos
derivatives (Table 2). While DTBM-Segphos (L8) is fairly
unreactive (entry 3), DM-Segphos (L7) improves yields by
about 20% relative to Segphos (Table 2, entries 1 vs 2). With
the arene held constant, exploration of the phosphine backbone
revealed CTH-(R)-Xylyl-P-Phos (L11) to be a superior
ligand.28 It provides quantitative yield of product 4ca in
excellent enantioselectivity after 24 h (entry 6). A control
reaction confirms that the acetate counterion is crucial for
reactivityno product is obtained under optimal conditions
when [Rh(cod)Cl]2 is used.29
Figure 4. Proposed mechanistic cycle for the HH of terminal (R = H)
or α-substituted (R ≠ H) acrylates.
D
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crotonate (3e). Acrylates with benzyl, n-butyl, and sterically
bulky isobutyl substituents at the α-position react in good yield
to give products 4cf−4ch in very high enantioselectivities
despite the opportunity for β-H elimination into the alkyl
backbone. Dimethyl itaconate (3i) provides good yields of
functionalized product 4ci albeit in modest enantioselectivity.
Acrylate 3j containing a protected alcohol reacts without
difficulty to give silyl ether 4cj in excellent enantioselectivity.
Notably, it was found that addition of 25 mol % CsOAc is
necessary to promote reactivity for these more hindered
acrylatesindeed, no product is obtained from the reaction of
benzyl-substituted 3f in its absence (Chart 2).31 While the
beneficial effect of CsOAc is not fully understood, acetate rather
than cesium ion appears to be responsible for the yield
improvement, since no product is obtained from the reaction of
3f and 1c when CsI is used in the place of CsOAc.
Table 2. Reaction Optimization with Second Generation,
Bulky Bisphosphine Ligands
Finally, and much to our gratification, variation of the
benzoxazole backbone is possible with bulky P-Phos ligand
L11. Unsubstituted benzoxazole 1a reacts smoothly; chloro-
and fluoro-products 4ea−4fa are assembled in high ees albeit in
diminished yields. Isomeric methoxy products 4ga−4ha are
obtained in moderate yield and moderate to high enantiose-
lectivities. While addition of 25 mol % CsOAc also appears to
accelerate reactions with these benzoxazole substrates, its effect
is less pronounced (4aa, 50% vs 67%). The HH reaction is not
without limitations. Acrylates substituted with aryl or secondary
alkyl groups do not participate effectively, nor do α,β-
disubstituted acrylates or acrylates containing β-leaving groups
(Figure 5).
a,b
c
See footnotes for Table 1. With 2 mol % [Rh(cod)OAc]2, 4 mol %
L8, 4 equiv 3a in PhMe at 120 °C for 60 h: these conditions give 4ca
in 56% yield and 85% ee when L6 is used as a ligand.
With these second-generation conditions in hand, we sought
to examine the substrate scope of our HH reaction (Chart 2).30
Variation of the ester group provides products 4ca−4cc in
excellent yields and selectivities. Methacrylonitrile (3d)
participates in moderate yield and good enantioselectivity.
The HH reaction is also tolerant of diverse acrylate backbones,
although α-substitution appears crucialracemic product 4ce
is obtained in low yield from the reaction of 1c and ethyl
Figure 5. Acrylates that do not provide product in the HH reaction
with benzoxazoles.
a,b
Chart 2. Scope of the Rh(I)−P-Phos-Catalyzed HH of Benzoxazoles and Methacrylate Derivatives
a
b
c
Isolated yields after column chromatography on silica gel. Ees of isolated products determined by LC analysis on chiral stationary phase. Reaction
d
run for 24 h. Yield determined with respect to 4,4′-di-tert-butylbiphenyl by LC analysis of the crude reaction mixture on a chiral stationary phase.
e
f
g
Reaction run for 80 h. Yield determined with respect to 4,4′-di-tert-butylbiphenyl by 1H NMR of the crude reaction mixture. Ee determined by LC
analysis of the crude reaction mixture on a chiral stationary phase.
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At this point in our studies, we wanted to better understand
the origin of enantioselectivity of our HH reaction. Asymmetric
protonation of a Rh−enolate (e.g., IV or O-bound isomer,
Figure 2, eq 8) is classically invoked as the enantio-determining
step of the Rh(I)−bisphosphine-mediated addition of boronic
acids to α-substituted acrylates, although mechanistic evidence
is sparse.14 We chose to test plausibility of this enantio-
determining step with a labeling study using deuterated 1c (1c-
D) (Figure 6, eq 12). Were our HH mechanism to proceed via
workers for the hydroheteroarylation of terminal acrylates
(Figure 4, R ≠ H).3j Reversible C−H activation liberates a
molecule of acetic acid and gives a Rh−heteroaryl complex V,
which undergoes MI across the acrylate. At this point, a β-H
elimination, hydrorhodation sequence isomerizes resultant Rh−
enolate VI to alkyl−Rh VIII, which is protonated by acetic acid,
regenerating RhOAc complex.
We believe that the proposed isomerization event is crucial
for the high enantioselectivities obtained in our reaction. In our
preferred mechanism, enantiodetermining MI delivers C-bound
Rh−enolate X in a stereodefined fashion (Figure 7). One might
Figure 7. Rationale for isomerization of a rhodium enolate
intermediate.
Figure 6. Labeling experiments rule out a mechanism involving
enantioselective protonation of a rhodium enolate.
imagine that C-bound X could equilibrate with O-bound
isomer XI(1−2). Protonation or ligand exchange of XI on O
would deliver racemic product, and ees would suffer to the
extent that this path is operative. Isomerization of Rh−enolate
X to isomer XII, then, insulates the α-stereocenter from
epimerization, as long as isomerization is stereospecific.
Stereospecificity is guaranteed if the β-H elimination, hydro-
rhodation steps take place from the same face of alkene XIII, or
said another way, if Rh−H intermediate XIII stays bound to the
alkene in a sigma fashion. Indeed, β-H-elimination, hydro-
metalation sequences mediated by late transition metals have
been shown to preserve with high fidelity the stereochemistry
set by MI events.4m
This mechanism may also help explain why α-substituted
acrylates are privileged substrates for our HH reaction and
perhaps even for the Rh(I)−bisphosphine-mediated asymmet-
ric hydroarylation reported by Darses and others.14 When an α-
substituted acrylate is used, C-bound Rh−enolate X is
tetrasubstituted (Figure 7), and O-bound isomer XI experi-
ences significant allylic strain, either between the ester OR
group and the heterobenzylic carbon (red, XI-1) or between
rhodium and the α-R substituent (blue, XI-2). Sterics may thus
discourage formation of XI and promote isomerization to less
hindered trisubstituted alkyl rhodium XII. Trisubstituted XII is
further stabilized as the heterobenzyl complex. Protonation or
ligand exchange may be facilitated by isomerization to Rh−
enamido complex XIV.33
protonation of a Rh-enolate (e.g., II or III, Figure 2; or VI,
Figure 4), then we should see D-incorporation at the α-position
of product 4ca, since 1c is the terminal proton source. Contrary
to this expectation, reaction of 1c-D with 3a to 42% conversion
under standard conditions provides product 4ca, in which D is
incorporated exclusively at the β-position (eq 12). 1c is
recovered with 33% H incorporation, consistent with a
reversible C−H activation event. The proton source respon-
sible for formation of 1c-H in eq 12 is presumably solvent:
indeed, when the experiment is repeated in CD3CN, virtually
no H−D exchange in 1c-D is observed (eq 13). All 2H from 1c-
D is accounted for in product 4ca, since CH3CN cannot serve
as a competitive proton source (eq 13). β-deuterium
incorporation in 4ca does not likely arise from in situ
generation and subsequent preferential reaction of β-deutero
3a, since the reciprocal reaction of 1c-H and 3b-d8 gives 4ba
1
with H-incorporation at the β-position exclusively (eq 14).
These labeling studies provide considerable insight into the
reaction mechanism. First, they give grounds for dismissal of
several possible elementary steps. For instance, protonation of a
Rh−enolate cannot be enantiodetermining, as protonation
takes place predominantly at the β- rather than the α-position.
The labeling study also seems to contradict a mechanism
involving migratory insertion of a Rh(III)−heteroarene (in a
3,2 sense) or a Rh(III)−hydride (in a 2,3 sense) across acrylate
3 followed by reductive elimination to form a C−H or C−C
bond respectivelythis mechanism, too, would deliver
products deuterated at the α- not the β-position.32 To account
for the results of our labeling experiment, then, we propose a
mechanism analogous to that proffered by Chang and co-
Final evidence for our proposed mechanism is provided by
epimerization studies (Figure 8). We wanted to know why the
reaction of 1c appeared significantly more selective than the
reaction of other benzoxazole substrates, particularly 1h. We
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Figure 8. Epimerization experiments of 4ha, 4ga, and 4ca.
speculated that epimerization over the long reaction time might
be partially responsible, but we struggled to rationalize why 4ha
would epimerize more quickly than other products: the most
simple racemization pathway that can be imagined is
deprotonation−reprotonation of the α-stereocenter by an
acetate−acetic acid couple. Yet electronics of the benzoxazole
backbone should not affect acidity of the remote stereocenter.
Nevertheless, we resubjected low (4ha), intermediate (4ga),
and high (4ca) ee products to the reaction of 1c and an
appropriate acrylate (Figure 8, eqs 15−17). When low ee
product 4ha is resubjected to the reaction of 1c and 3a under
standard conditions, it is indeed found to epimerize to 50% ee
(eq 15). In contrast, the ee of product 4ca drops to only 93%
ee when it is resubjected to the reaction of 1c and benzyl
methacrylate 3c under identical conditions (eq 17).34 Yet
epimerization does not appear to be solely responsible for the
low ees of 4ha, since intermediate ee product 4ga also shows
significant stereochemical scrambling under the reaction
conditions (eq 16).
Figure 9. Proposed epimerization mechanism.
We tested credence of this mechanism by treating product
4ha (75% ee) with [Rh(cod)OAc]2 and CTH-(R)-xylyl-P-Phos
in CD3CN (Figure 10, eq 18), since we knew CD3CN to be a
That rates of epimerization of product 4 depend crucially on
the benzoxazole backbone challenges an epimerization
mechanism via traditional base-assisted deprotonation of the
α-stereocenter. Tenuousness of this racemization pathway is
reinforced by the fact that product 4ha epimerizes at the same
rate in the presence or absence of added base (eq 15)35 and
that CsOAc alone fails to epimerize product 4ha even after
prolonged heating (data not shown).
In light of insights gained from labeling studies in eqs 12−14,
we wondered whether epimerization takes place by the
microscopic reverse of the mechanism proposed in Figure 7:
coordination of the benzoxazole nitrogen to rhodium acidifies
the heterobenzylic H of product 4, which is abstracted by
acetate (Figure 9, step 1).36 Resultant Rh−enamido complex
XVI, which is in equilibrium with C-bound XVII (step 2),
isomerizes back into the acrylate backbone via a series of β-H-
elimination, hydrorhodation events (steps 3−5) to eventually
give O-bound Rh−enolate XX. Enolate XX is shown as, but
need not exist as, the rhodacycle. Protonation or ligand
exchange of XX at oxygen epimerizes the α-stereocenter of
product 4 (step 6).37 While intermediate XVII is shown with a
specific stereochemistry at the carbon bearing rhodium, this is
only intended to illustrate that no stereochemical scrambling of
the α-stereocenter occurs prior to formation of O-bound XX if
alkene XVIII remains coordinated to rhodium (i.e., the
stereochemistry of the starting material is relayed to the
stereochemistry of C-bound XIX).
Figure 10. Epimerization−labeling experiment.
competent proton source (Figure 6, eqs 12−13). If
epimerization were occurring via a typical deprotonation−
reprotonation sequence at the α-carbon, then we should see 2H
incorporation at the α-position of product 4ha. On the other
hand, if the epimerization mechanism depicted in Figure 9 were
2
operative, we would see H incorporation at both β- and α-
positions of product. In accord with our hypothesis, 4ha is
isolated from the reaction in eq 18 in 20% ee with significant
deuterium incorporation at the α-position and predominant
deuterium incorporation at the β-position.
While this data cannot unequivocally debunk a mechanism
by which deuteration at the α- and β-positions occurs by
independent deprotonation−reprotonation events at vicinal
carbons, the level of D incorporation at the α-position of
product 4ca strongly suggests that the two incorporation events
are coupled by a common intermediate. Specifically, 21% 2H at
the α-position of 4ca does not nearly account for a 55% loss in
ee of 4ca (eq 18).38 Thus, 4ca must epimerize by at least one
other mechanism besides protonation. We propose that Rh−
enolate intermediate XX has two opportunities to scramble α-
stereochemistry. It can, as already discussed, protonate or
undergo ligand exchange on oxygen to give enantiomeric
product (Figure 9, step 6). Yet protonation is not necessary for
epimerization to occur. To the extent that the α-stereo-
G
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Journal of the American Chemical Society
Article
chemistry of C-bound XIX is lost in O-bound XX, then
isomerization back to the C-bound isomer should be able to
deliver diastereomeric complex XXI in which α-stereochemistry
is inverted (step 7). A reverse sequence of elimination, addition
events relays XXI to enantiomeric product (step 8).
deleterious coordination of benzoxazole substrates to on- or off-
cycle intermediates, accelerates a difficult MI step, and
discourages coordination-initiated epimerization. In short,
careful mechanistic analysis has enabled the development of
an efficient and highly selective catalytic, asymmetric HH of
readily accessible reagents to produce chiral compounds of high
biological importance.
We wondered how the epimerization mechanism depicted in
Figure 9 could account for the very different fates of low ee
product 4ha and high ee product 4ca when they are resubjected
to our Rh−bisphosphine system. Interestingly, when highly
enantioenriched product 4ca (95% ee) is treated with rhodium
and ligand under identical conditions to those described for
4ha, it also deuterates considerably at the β-position (Figure 10,
eq 19). In contrast to 4ha, however, product 4ca epimerizes
quite slowly (to 91%) even at high dimer loading, and it shows
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures; characterization data, H NMR, 13C
1
NMR, and HPLC spectra for new compounds; crystallographic
data for [Rh(cod)OAc]2. This material is available free of
charge via the Internet at http://pubs.acs.org.
2
no discernible H incorporation at the α-position. We provide
AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu.
Notes
two possible explanations to account for the data in eqs 18−19,
but alternatives are possible. As illustrated in Figure 9,
deprotonation of 4 gives Rh−enamido complex XVI (step 1).
It is possible that A[1,3]-strain between the axial methyl of 4ca
and rhodium shortens the lifetime of XVI such that a rapid
backward reactionprotonation of XVIoutcompetes iso-
merization into the acrylate backbone (step 2).
An alternative explanation invokes differential stability of 4ha
and 4ca Rh−enolate complexes XX (Figure 9). Whereas
coordination of the heterocyclic nitrogen to rhodium could
stabilize a 4ha-derived Rh−enolate XX, A[1,3]-strain would
prevent analogous stabilization of 4ca-derived XX. In either
case, relative coordinating abilities of 4ca and other
benzoxazoles appear to crucially influence product epimeriza-
tion rates. If this is true, then our bulky P-Phos ligand may serve
an additional service: it may discourage ligation-promoted
racemization.
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIGMS (GM80442) for support of this research and
Johnson Matthey for a generous loan of Rh salts. We thank Dr.
Kevin M. Oberg for X-ray analysis. C.M.F. thanks Genentech
(Organic Division Fellowship) for funding.
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imine precursor, see: Zhao, P.; Krug, C.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 12066−12073.
(37) For simplicity, this figure shows only formation of (R)-product
from O-bound XX (step 6), yet (S)-product is presumably also
formed.
(38) Since the amount of deuterium in CD3CN presumably
overwhelms the amount of H+ liberated from product 4, we
approximate that 1% 2H will incorporate into the α-position for
each protonation event. Each (R) → (S) conversion contributes 2% ee,
which means we would need (75% starting ee − 20% final ee)/2 ∼ 28
protonation events if all were selective for the minor enantiomer. In
reality, protonation should give both enantiomers of product. A
significant excess of protonation events is needed, then, to account for
the observed 55% ee difference. The deuterium incorporation in 4ca
should reflect this excess.
J
DOI: 10.1021/ja511445x
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX