Branch-Selective and Enantioselective Iridium-Catalyzed Alkene Hydroarylation via Anilide-Directed C-H Oxidative Addition

Article abstract of DOI:10.1021/jacs.8b04627

Tertiary benzylic stereocenters are accessed in high enantioselectivity by Ir-catalyzed branch selective addition of anilide ortho-C-H bonds across styrenes and α-olefins. Mechanistic studies indicate that the stereocenter generating step is reversible.

Full text of DOI:10.1021/jacs.8b04627

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Branch-Selective and Enantioselective Iridium-Catalyzed Alkene
Hydroarylation via Anilide-Directed C−H Oxidative Addition
†
†
‡
,†
́
Simon Grelaud, Phillippa Cooper, Lyman J. Feron, and John F. Bower*
†School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
‡Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
S
* Supporting Information
boronic acid derivatives (Scheme 1B).2a,c,g,h,4 Within this
ABSTRACT: Tertiary benzylic stereocenters are ac-
cessed in high enantioselectivity by Ir-catalyzed branch
selective addition of anilide ortho-C−H bonds across
styrenes and α-olefins. Mechanistic studies indicate that
the stereocenter generating step is reversible.
context, Pd-catalyzed Suzuki couplings with aryl halides have
been developed; however, isomerization of the alkyl-Pd(II)
intermediate often leads to isomeric products.1a,b,2a,g,h Metal-
free cross-couplings of aryl lithium reagents with alkyl boronic
esters, which require external oxidants, circumvent this
problem and offer good scope.4 For all of these approaches,
step and atom economy are imperfect because of the
requirement for prefunctionalization and/or the need for
additional reagents in the coupling step. For example, alkyl
boronic esters are often accessed by enantioselective hydro-
boration of an alkene precursor,6 whereas aryl halides are
usually prepared by regioselective halogenation of an aryl C−H
bond.
ertiary benzylic stereocenters are of recognized value in
T
the design of pharmaceuticals (Scheme 1A). The most
Scheme 1
The fact that alkenes and aryl C−H bonds can be considered
feedstock precursors for the approaches summarized in
Scheme 1B raises the question of whether tertiary benzylic
stereocenters might be accessed directly via C−H activation-
triggered enantioselective addition of an aryl C−H bond across
an alkene. In this context, the most challenging processes are
likely to be those that harness nonpolarized acyclic alkenes
(i.e., styrenes and α-olefins), because these offer minimal
electronic control for achieving regioselective C−C bond
formation. Indeed, synthetically useful intermolecular enantio-
selective alkene hydroarylations invariably exploit polarized
alkenes to enforce regiocontrol.7−9 Enantioselective alkene
hydroheteroarylations have also been developed under a range
of mechanistic regimes, but are limited to specific classes of
heteroarene or alkene.7a,10 To our knowledge, no general
protocol exists for the highly enantioselective addition of aryl
C−H bonds across styrenes and α-olefins.
Building on seminal studies from Togni,7c,d Shibata,11a and
Krische,11b we previously identified Ir-catalysts that overturn
the usual linear selectivity of Murai-type alkene hydroarylation
reactions to provide branched products (Scheme 1C).7a,12,13
Here, cationic systems modified with dFppb, a wide bite angle
and electron poor achiral bisphosphine ligand, were effective
for branch selective hydroarylations of styrenes and α-olefins,
whereas narrow bite angle ligands (e.g., dppm) afforded linear
products.13 The efficacy of these methods provided the
impetus for the development of enantioselective variants.14
In particular, anilide-based processes (DG = NHAc) emerged
as a key objective because (a) a large number of anilines are
commercially available at low cost and (b) derivatizations of
powerful methodologies to access these motifs establish the
stereocenter via a C−C bond forming fragment union step.1
Commonly, this is achieved by cross-coupling of a nucleophile
with an electrophile;2 however, effective methods that harness
two electrophiles3 or two nucleophiles have also emerged.4
Recent methods that allow the direct use of alkenes as a
coupling partner are notable.5 Arguably, the most general
approaches exploit arylation of stereodefined secondary alkyl
Received: May 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b04627
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Journal of the American Chemical Society
Communication
Table 1. Optimization of an Enantioselective Alkene Hydroarylation Process Using a Modular Ligand Design
a
b
c
entry
R
X
ligand
solvent (M)
B:L
yield
44%
71%
11%
31%
99%
e.r.
1
2
3
4
5
6
7
8
3-Me
3-Me
3-Me
3-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
BF4
Josiphos SL-J418-1
(S,S)-BDPP
(R)-SDP
(R,R)-Kelliphite
dioxane (1.5)
dioxane (1.5)
dioxane (1.5)
dioxane (1.5)
dioxane (0.25)
dioxane (0.25)
dioxane (0.25)
dioxane (0.025)
dioxane (0.05)
dioxane (0.05)
toluene (0.05)
hexyl acetate (0.05)
DME (0.05)
2:1
1:1
73:27
37:63
48:52
33:67
90:10
n.d.
d
d
19:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
L-1
L-2
L-3
L-3
L-4
L-5
L-5
L-5
L-5
L-5
<20%
87%
39%
87%
100%
83%
100%
83%
87%
52%
92:8
93:7
91:9
9
10
11
12
13
94.5:5.5
95:5
93.5:6.5
94:6
e
14
toluene (0.05)
toluene (0.05)
96:4
f
15
L-5
96.5:3.5
a
b
c
1
Branched to linear (B:L) ratio determined by H NMR analysis of the crude reaction mixture. Isolated yields. Determined by chiral SFC
d
e
f
analysis. Vinylation product was observed in 11% and 4% for entries 2 and 3 (see later). The reaction was performed at 110 °C for 72 h. The
reaction was performed at 105 °C for 72 h.
the products can be achieved via the anilide unit. However, the
development of an enantioselective alkene hydroarylation
process was considered challenging because of the prescriptive
ligand features required for achieving high branch selectivity.
As described below, we have now succeeded in identifying a
modular ligand family that allows alkene hydroarylation of
styrenes and α-olefins to be used for the efficient and highly
enantioselective synthesis of tertiary benzylic stereocenters.
We began by undertaking an exhaustive screen of
commercially available chiral ligands for the hydroarylation
of styrene with acetanilide 1a. These studies failed to reveal a
system that could provide both high enantioselectivity and
high branched to linear (B:L) regioselectivity, with the most
promising results shown in Table 1, entries 1−4. Accordingly, a
library of new chiral ligands was required, and we were drawn
to variants of Kelliphite15 because the modularity of this
system leads to general structure L, where one or both of the
blue and red components is a homochiral unit. An attractive
feature of this design is that it allows tuning of the ligand
substructure to provide an effective system for any given
substrate. For the conversion of 1b to 2b, this approach led
initially to BiPhePhos-like16 ligand L-1, which afforded 2b in
90:10 e.r., >25:1 B:L selectivity, and 99% yield. Further
refinement was sought by altering the blue BINOL unit of L-1,
and we found that L-3, which contains a conformationally
flexible biphenol moiety,17 generated 2b in 92:8 e.r. Here,
increased enantioselectivity was observed using higher dilution
(entry 7 vs 8). Further studies revealed that t-Bu-substituted
variant L-5 could generate 2b in 96:4 e.r. and high B:L
selectivity using toluene as solvent (entry 14). L-5 is a novel,
bench stable bisphosphite ligand that can be prepared in two
steps.
As outlined in Table 2A, the method tolerates a wide range
of interesting and sensitive acetanilides, including indole-based
system 2e and halogen-substituted systems 2l and 2m. For
anilides with two available ortho-positions competing bis-ortho-
alkylation was observed in certain cases using 250 mol %
styrene (e.g., 2c), but high selectivity for mono-ortho-alkylation
was achieved by using 110 mol % of this component. C−C
bond formation is highly selective for the less hindered ortho-
position of meta-substituted substrates (e.g., 2g), which
presumably reflects the steric demands of the ligand. The
reaction conditions tolerate protic functionality (2i), and can
be extended to elaborate substrates, such as steroid-derived
system 2ac (Table 2D). The protocol offers good scope with
respect to the styrene component (Table 2B), with para- (2q)
and meta-substituted systems (e.g., 2r) participating efficiently.
Hydroarylation of ortho-substituted styrenes is more demand-
ing, but adduct 2p was still formed in 53% yield. Significantly,
the process extends to α-olefins (Table 2C), as demonstrated
by the hydroarylation of hex-1-ene, which provided 2t in 96%
yield and 94:6 e.r. Even very sterically demanding alkenes are
tolerated, such that hydroarylation of tert-butylethylene led to
2aa in 81% yield and 95:5 e.r. The absolute stereochemistry of
B
DOI: 10.1021/jacs.8b04627
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Communication
a
Table 2. Scope of the Enantioselective Alkene Hydroarylation Process
a
1
Alkene equivalents and branched to linear selectivities are indicated in parentheses (determined by H NMR analysis of the crude mixture).
b
c
d
Ortho-regioselectivity was 93:7. The reaction was performed at 120 °C. Concentration was 0.025 M.
2b was determined by X-ray analysis of (+)-CSA salt 2b″, and
stereochemical assignments of the other products were
tentatively made on this basis.
The scalability of the process is demonstrated by the
hydroarylation of styrene (250 mol %) with 1f on 2 mmol
scale, which formed 2f in 88% yield and 98.5:1.5 e.r. using only
0.25 mol % Ir-catalyst (Table 2E). Similarly, 1.61 g of 2b was
prepared with satisfactory levels of efficiency on a 10 mmol
scale. In these examples, the lower catalyst loading (vs Table
2A) allowed the processes to be run at higher concentration
with respect to the substrate (1.0 M vs 0.05 M), while
maintaining the same concentration with respect to the
C
DOI: 10.1021/jacs.8b04627
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Communication
catalyst. The protocol also tolerates low level contaminants:
hydroarylation of styrene with pharmacy grade anilide 1i,
sourced directly from acetaminophen (paracetamol) tablets,
gave 2i in 91.5:8.5 e.r. This result, although less efficient than
from pure 1i, shows that the conditions are tolerant to
additives (e.g., magnesium stearate) used in the commercial
formulation process. Finally, manipulation of the anilide unit of
the products allows easy access to heterocycles (3 and 4),
iodoarenes (7), and cross-coupled products (6) (Table 2F).
The results in Table 2 show that the protocol offers very good
levels of scope for enantioselective hydroarylations of styrenes
and α-olefins. Another significant aspect is that the method
provides a formal enantioselective alternative to Friedel−Crafts
alkylation. Processes of this type are highly challenging, even
without factoring in other issues that our method addresses,
such as ortho vs para regiocontrol and high monoalkylation
selectivity.18
V and VI; exposure of styrene deuterio-9 to optimized reaction
conditions resulted in scrambling of the deuterium labels in
product deuterio-2q and recovered deuterio-9 (Scheme 2A).
C−C bond formation could occur either via C−C reductive
elimination from VI or via carbometalation from π-complex
IV. Support for the latter is provided by the observations that
(a) bulky alkene substituents are tolerated (cf. 2aa) and (b)
trace amounts (1−5%) of C−H vinylation adducts (cf. VII)
form in certain cases; these are most easily rationalized by
invoking β-hydride elimination from carbometalation product
VIII. Natural abundance 13C KIE experiments have been used
to distinguish unequivocally between C−C reductive elimi-
nation and carbometalation pathways;19 this method shows
which alkene carbon centers are involved in the first
irreversible step. When the hydroarylation of styrene 9 (100
mol %) with acetanilide 1f (150 mol %) was run to
approximately 75% conversion, analysis of recovered 9
revealed a significant KIE at the terminal alkene carbon only
(Scheme 2B). This effectively discounts C−C reductive
elimination as the productive pathway, while indicating that
(a) C−H reductive elimination is the first irreversible step and
(b) carbometalation from IV to VIII is reversible. To gain
further evidence, we sought to generate intermediate VIII via a
distinct pathway. To this end, we exposed alkene 10 (cf. VII)
to optimized conditions, but under an atmosphere of hydrogen
on the presumption that hydrometalation by an in situ
generated iridium-dihydride species would provide an
intermediate akin to VIII.20 This experiment generated 2f
(6% e.e.) and anilide 1f in a 3:2 ratio (Scheme 2C). The
formation of 1f seemingly confirms that the stereocenter
generating carbometalation step (IV to VIII) is reversible; this
is rather unusual given that high enantioselectivity is observed
in Table 2. Two mechanistic extremes could account for this.
In one scenario, alkene carbometalation (IV to VIII) exhibits
low (or inconsequential) facial selectivity but C−H reductive
elimination to the major enantiomer is faster than to the
minor. In the second scenario, carbometalation facial
selectivity is high and subsequent C−H reductive elimination
is less discriminating for both enantiomers. The low
enantioselectivity obtained for product 2f in Scheme 2C
suggests the second option predominates, although this
interpretation assumes that reduction of 10 proceeds solely
via intermediates of type VIII. The mechanism in Scheme 2D
is distinct from that proposed in our earlier work using
dFppb,13b where 13C KIE experiments are suggestive of a C−C
reductive elimination pathway (see the SI).
A series of experiments have led to the mechanistic outline
given in Scheme 2D. As supported by deuterium exchange
experiments (see the Supporting Information (SI)), the
process likely commences with reversible N-acetyl directed
C−H oxidative addition to form III. From IV, reversible
hydrometalation generates linear and branched intermediates
Scheme 2. Mechanistic Studies
A key feature of the ligand design outlined here is that its
modularity allows tailoring to specific substrate classes. To
demonstrate this, we optimized the hydroheteroarylation of
styrene with thiophene 11a to provide 12a; this process
performed poorly using L-5 (44% yield, >25:1 B:L, 26:74 e.r.)
(Table 3), and the low enantioselectivity necessitated a
redesign of the ligand system. In the event, we found that
ferrocene-based bisphosphonite systems incorporating SPI-
NOL-derived units as the blue component are effective. Ligand
L-6 (R = H) provided 12a in 77% yield, >25:1 B:L selectivity,
and 91:9 e.r. Substituted variants L-7 (R = Ph) and L-8 (R =
mesityl) can be accessed via earlier stage Suzuki cross-coupling.
The latter offered increased selectivity, with 12a formed in
77% yield and 97.5:2.5 e.r. using 120 mol % styrene. This new
ligand was applied to thiophenes 12b−f, with satisfactory
results achieved for hydroarylations of styrenes and α-olefins,
and in the diastereoselective hydroarylation that forms steroid
D
DOI: 10.1021/jacs.8b04627
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Table 3. Reoptimization for a Challenging Substrate Class
AUTHOR INFORMATION
■
Corresponding Author
*john.bower@bris.ac.uk
ORCID
John F. Bower: 0000-0002-7551-8221
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
EPSRC (EP/M507994/1) and AstraZeneca (studentship to
P.C.), the European Research Council (ERC Grant 639594),
the Royal Society (URF to J.F.B.) and the Leverhulme Trust
are thanked for funding. The EPSRC UK National Mass
Spectrometry Facility at Swansea University is thanked for
analysis. G.E.M. Crisenza (Bristol) is thanked for substrate
synthesis.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b04627.
■
S
Experimental details, characterization data (PDF)
Crystallographic data for 2b′′ (CIF)
Crystallographic data for 12a (sample 1) (CIF)
Crystallographic data for 12a (sample 2) (CIF)
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