Branch-selective, Iridium-catalyzed hydroarylation of monosubstituted alkenes via a cooperative destabilization strategy

Article abstract of DOI:10.1021/ja505776m

Highly branch-selective, carbonyl-directed hydroarylations of monosubstituted alkenes are described. The chemistry relies upon a cationic Ir(I) catalyst modified with an electron deficient, wide bite angle bisphosphine ligand. This work provides a regioisomeric alternative to the Murai hydroarylation protocol.

Full text of DOI:10.1021/ja505776m

Communication
pubs.acs.org/JACS
Branch-Selective, Iridium-Catalyzed Hydroarylation of
Monosubstituted Alkenes via a Cooperative Destabilization Strategy
Giacomo E. M. Crisenza, Niall G. McCreanor, and John F. Bower*
School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
S
* Supporting Information
Scheme 1
ABSTRACT: Highly branch-selective, carbonyl-directed
hydroarylations of monosubstituted alkenes are described.
The chemistry relies upon a cationic Ir(I) catalyst modified
with an electron deficient, wide bite angle bisphosphine
ligand. This work provides a regioisomeric alternative to
the Murai hydroarylation protocol.
n 1993, Murai and co-workers demonstrated that Ru-catalyzed
Ialkene hydroarylation can be achieved by carbonyl-directed
arylC−Hactivation (Scheme1A).1 Thisprotocol provides access
to linear hydroarylation products and is considered a milestone in
the development of atom-economical methodology.2 In the
ensuing years, a wide range of related π‑bond insertion protocols
haveemerged that use avariety oflate transition metal catalysts.3,4
For intermolecular processes involving monosubstituted alkenes,
linearselectivitydominates andbranchedproductsarenotusually
accessible. Branch selectivity has been achieved under Co- or Ru-
catalyzed conditions but requires aniline, pyridine, or imine
directing groups and is limited to styrenes as the olefinic
partner.5−9 To date, a regioisomeric alternative to the original
Murai protocol, which enables carbonyl-directed, branch-
selective hydroarylation, remains elusive. This represents a
surprising gap in synthetic technology, especially given that
such a process would provide direct and potentially enantio-
selective access to products that are difficult to obtain using
conventional cross-coupling chemistry.10,11 In this report, we
detail the design of a catalyst system that achieves high branch
selectivity for carbonyl-directed hydroarylation of aryl- and alkyl-
substituted alkenes. The protocol has wide scope, is highly
selective for mono-ortho-alkylation, and opens the door to the
development of related processes, including enantioselective
variants.11
At the outset of our investigations, we were drawn to cationic
BINAP-ligated Ir(I) catalysts that were reported by Shibata for
ketone-directed hydroarylation of styrenes.4c These systems
preferentially provide linear products but are less discriminating
than Ru-based catalysts and deliver significant quantities of
branched adducts (7:1 to 3:1 selectivity). The relatively low
selectivities hinted that appropriate modifications could lead to a
catalyst system that favors branched products. Related studies on
directed hydroheteroarylation indicate that alkene coordination
and hydrometalation are reversible and that these steps do not
determine product regioselectivity.8 The predominance of linear
products likely reflects a higher equilibrium preference for linear
Ir(III) intermediate 1a over sterically disfavored isomer 1b
(Scheme 1A).12 Access to a branch-selective manifold thus
requires acceleration of reductive elimination Path b over Path a.
Our reaction design was guided by two observations that are
common in the organometallic literature. First, reductive elimin-
ation is accelerated by wide bite angle bisphosphine ligands in a
range of transition-metal-catalyzed C−C bond formations.13
There is some debate on the origin of this effect, but an appealing
explanation is that an increase in the P−M−P bond angle
compresses theC−M−CbondangleandthusrendersC−Cbond
formation more facile.14 Second, it has been observed that bulkier
alkyl groups undergo faster reductive elimination, perhaps due to
sterically induced destabilization.15 We considered whether these
two effects could be combined to promote branch-selective
alkene hydroarylation (Scheme 1B, cartoon representation).16
Specifically, wide bite angle ligand systems should compress bond
angle xa/b, which may accentuate steric destabilization of adduct
1b (2° alkyl ligand) relative to 1a (1° alkyl ligand) such that
reductive elimination via Path b is amplified. In this approach, the
wide bite angle bisphosphine and the branched alkyl ligand of 1b
provide “cooperative destabilization”, thereby accelerating
reductive elimination and, at the same time, controlling product
Received: June 9, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja505776m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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a
Table 1. Catalyst System Optimization
Table 2. Scope of the Carbonyl-Based Directing Group
a
a
entry
ligand
styrene equiv (mol%)
yield (%)
3a:4
1
2
3
4
5
6
7
8
rac-BINAP
dppm
dppe
450
450
450
450
450
450
450
200
100
73
29:71
8:92
82
23:77
60:40
100:0
36:64
100:0
100:0
dppp
52
dppb
28
b
dFppe
100
100
100
c
dFppb
dFppb
c
a
1
Yields and selectivities were determined by H NMR using 1,3,5-
b
trimethoxybenzene as a standard. dFppe = 1,2-bis(di(pentafluoro-
c
phenyl)phosphino)ethane. dFppb = 1,4-bis(di(pentafluorophenyl)-
phosphino)butane.
selectivity. As such, branched products are potentially accessed by
ligand-controlled exploitation of the Curtin−Hammett scenario.
As a benchmark reaction, hydroarylation of styrene with N,N-
diethylbenzamide was conducted under Shibata’s conditions
using rac-BINAP as ligand (Table 1, entry 1).4c The process was
chemically efficient but delivered a 29:71 mixture of branched to
linear products (3a vs 4). To probe the idea that bite angle might
be important, we systematically studied the effects of using dppm,
dppe, dppp, or dppb as ligand (entries 2−5). As the size of the
alkyl linker was increased, a gradual progression from linear to
complete branch selectivity was observed.17 However, this
selectivity came at the expense of decreased chemical efficiency
(e.g.,only28%yieldusingdppb).Basedupontheobservationthat
commercial electron-deficient aryl phosphines increase reaction
yields (cf. entries 3 and 6), we prepared dFppb, a previously
unreported ligand that is the pentafluorophenyl analogue of dppb
(see the Supporting Information). Gratifyingly, this system
provided adduct 3a in quantitative yield and with complete branch
selectivity.17,18 With dFppb as ligand, the loading of styrene can be
decreased from 450 to 200 mol% and reaction efficiency is
maintained (entry 7 vs 8).
a
1
Selectivites were determined by H NMR analysis of crude material.
b
The reaction was run at 150 °C.
a
Table 3. Substitution on the Arene
Further directing group scope was explored using 450 mol% of
the alkene partner because these conditions provide faster
reactions in more-challenging cases (Table 2). The protocol
tolerates a range of amide-based directing groups, including
secondary amide 2c. In all cases, the products 3a−d were isolated
ingoodto excellent yields and with complete or veryhigh levels of
branch selectivity. Aryl and alkyl ketones 2e−h are also viable
directing groups; again, products 3e−h wereisolated inuniformly
good yields and with high levels of branch selectivity. Esters will
also direct branch-selective hydroarylation but provide lower
yields of the product compared to amide- and ketone-based
directing groups. For example, hydroarylation using 2i provided
adduct 3i with 9:1 selectivity but inonly 18% yield. In all cases, the
mass balance of the reactions consisted of unreacted starting
material, and bis-ortho-alkylation wasnot observed. Atthe current
level of development, primary amides and aldehydes are not
suitable directing groups.19
a
1
Selectivites were determined by H NMR analysis of crude material.
product regioselectivity clearly highlights the stronger directing
ability of amides vs esters. The effects of substitution meta to the
directing group are more subtle. For electronically neutral or
bulky groups, substitution appears to be sterically controlled and
occurs at the less hindered ortho site (e.g., 3n and 3p). If the meta
substituent is small and inductively withdrawing, then high
selectivity for the more hindered ortho position is achieved (3m
and 3q).20 In the case of adduct 3o, a balance between these two
control factors seemingly results in low ortho positional
selectivity. Finally, if the arene already possesses substitution
ortho to the directing group (e.g., 2r to 3r), then functionalization
at the remaining ortho site is not achievable (vide infra). This
We have examined the effects of arene substitution using a
range of N,N-diethylbenzamide derivatives 2j−r (Table 3).
Substitution para to the directing group is well tolerated, and
potentially sensitive functionality, such as aryl bromides (3k) and
esters (3l), survives the catalysis conditions. In the case of 3l,
B
dx.doi.org/10.1021/ja505776m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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a
Table 4. Scope of the Alkene
Scheme 2
a
1
Selectivites were determined by H NMR analysis of crude material.
b
c
The reaction was run at 120 °C. A propene atmosphere was used.
aspectprovides alimitationinscope but isalsoabeneficialcontrol
factor that prevents bis-ortho-functionalization in other cases.
Importantly, the protocol also exhibits good scope with respect
to the alkene partner (Table 4). Electronically distinct styrenes
5a−d are tolerated, and targets 6a−d were produced in moderate
to excellent yield and with complete branch selectivity. Alkyl-
substituted alkenes also participate, and hydroarylation of pent-1-
ene 5e with amide 2a provided 6e in 78% yield and, again, with
completebranchselectivity. Theprocess can beextended toother
systems, although bulky substituents on the alkene do result in
lower chemical efficiency (e.g., 2a to 6h). However, even for
sterically demanding examples, high branch selectivity is
maintained. In the case of 6g, introduction of an isopropyl
group was achieved under an atmospheric pressure of propene.
This represents a simple alternative to notoriously challenging
Pd-catalyzed cross-couplings of isopropyl organometallics.10a
Electron-deficient alkenes do not participate, and attempted
hydroarylation of ethyl acrylate with 2a did not deliver adduct 6i.
Deuterium labeling and exchange experiments have elucidated
keymechanistic features ofthecurrentprocess. Hydroarylation of
deuterio-5a, which is labeled at the terminal vinylic positions, with
benzamide 2a provided deuterio-6a, where deuterium is trans-
ferred to the methyl, methine, and ortho positions (Scheme 2A).
The observed scrambling indicates that both oxidative addition
and alkene hydrometalation are reversible and supports reductive
elimination as the product-determining step (cf. Scheme 1A).
Subjecting 2q to the catalysis conditions in the absence of alkene,
but in the presence of D2O, showed deuterium incorporation at
both ortho positions and also at the methylene sites of the
directing group (Scheme 2B).21 The greater level of ortho
incorporation suggests that oxidative addition into the aryl
C(sp2)−H bonds is easier than that into the C(sp3)−H bonds of
the directing group.22 Equal levels of deuterium incorporation at
both ortho positions indicate that site-selective reductive
elimination (and not site-selective oxidative addition) determines
the regioselectivity of hydroarylation, which occurs selectively at
C-6 (see Table 3). An analogous experiment on reaction product
3q showed no detectable exchange at the remaining ortho site and
preferential deuterium incorporation at the methylene positions
of the directing group. Directed oxidative addition into the
C(sp2)−H bond of 3q requires coplanar alignment of the NEt2
moiety with the secondary alkyl substituent on the arene.
Presumably, this is disfavored on steric grounds; consequently,
bis-ortho alkylation is not observed in any of the cases we have
examined to date. An analogous rationalization accounts for the
lack of reactivity observed with ortho-substituted amide 2r (see
Table 3).
In summary, we report an efficient system for branch-selective,
carbonyl-directed alkene hydroarylation based upon the counter-
intuitive strategy of “cooperative destabilization”. This offers a
regioisomeric alternative to the Murai hydroarylation protocol
and is the first step toward the development of related
enantioselective processes. Notable features of the current system
includeitscompatibility withausefulrangeofdirectinggroups, an
ability to hydroarylate aryl- or alkyl-substituted alkenes, and
completeselectivityformono-ortho-alkylation.Futurestudieswill
focus upon the design of effective chiral ligands and the
generalization of this approach to regioselective hydroarylations
of 1,1- and 1,2-disubstituted alkenes. Evidently further validation
of our catalysis design is still required, but, in broader terms, the
strategy outlined here may enable the development of other
contrasteric alkene functionalization processes.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
john.bower@bris.ac.uk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
G.E.M.C. and N.G.M. thank the Bristol Chemical Synthesis
Doctoral Training Centre, funded by the EPSRC (EP/G036764/
■
C
dx.doi.org/10.1021/ja505776m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
achieve formal ortho-selective Friedel−Crafts alkylation of electron-
deficient arenes.
1), for a Ph.D. studentship. J.F.B. is indebted to the Royal Society
for a University Research Fellowship.
(11) Enantioselective hydroarylation/hydroheteroarylation protocols
have been developed, but efficient processes are limited to strained
bicycloalkenes: (a) Dorta, R.; Togni, A. Chem. Commun. 2003, 760.
(b) Sevov, C. S.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2116. Seealso
refs 4c and 8.
REFERENCES
■
(1) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529. See also: (b) Lewis, L.
N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108, 2728.
(12) For a discussion of factors that affect this type of equilibrium, see:
Harvey, J. N. Organometallics 2001, 20, 4887.
(2) Atom-economic processes are a key ideal of green chemistry: Trost,
B. M. Science 1991, 254, 1471.
(13)Selected examples:(a) Kohara, T.;Yamamoto, T.;Yamamoto, A. J.
Organomet. Chem. 1980, 192, 265. (b) Brown, J. M.; Guiry, P. J. Inorg.
Chim. Acta 1994, 220, 249. (c) Marcone, J. E.; Moloy, K. G. J. Am. Chem.
Soc. 1998, 120, 8527. Bulky ligands can achieve the same outcome:
(d) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 3224. (e) Culkin, D. A.; Hartwig, J. F. Organometallics
(3) Selected reviews: (a) Kakiuchi, F.; Murai, S. Top. Organomet. Chem.
1999, 3, 47. (b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
(c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(d) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (e) Kakiuchi, F.;
Chatani, N. Adv. Synth. Catal. 2003, 345, 1077. (f) Park, Y. J.; Jun, C.-H.
Bull. Korean Chem. Soc. 2005, 26, 871. (g) Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (h) Kakiuchi, F.; Kochi, T.
Synthesis 2008, 3013. (i) Kitamura, T. Eur. J. Org. Chem. 2009, 1111.
(j) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(k) Nakao, Y. Chem. Rec. 2011, 11, 242. (l) Colby, D. A.; Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814.
(m) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879. (n) Zheng, Q.-Z.; Jiao, N. Tetrahedron Lett. 2014, 55, 1121.
(4) Selected recent examples: (a) Lim, S.-G.; Ahn, J.-A.; Jun, C.-H. Org.
Lett. 2004, 6, 4687. (b)Kuninobu, Y.;Tokunaga, Y.;Kawata, A.;Takai, K.
J. Am. Chem. Soc. 2006, 128, 202. (c) Tsuchikama, K.; Kasagawa, M.;
Hashimoto, Y.-K.; Endo, K.; Shibata, T. J. Organomet. Chem. 2008, 693,
3939. (d) Zhang, Y. J.; Skucas, E.; Krische, M. J. Org. Lett. 2009, 11, 4248.
(e) Schinkel, M.; Marek, I.; Ackermann, L. Angew. Chem., Int. Ed. 2013,
52, 3977. (f) Schinkel, M.; Wallbaum, J.; Kozhushkov, S. I.; Marek, I.;
Ackermann, L. Org. Lett. 2013, 15, 4482. (g) Ilies, L.; Chen, Q.; Zeng, X.;
Nakamura, E. J. Am. Chem. Soc. 2011, 133, 5221.
́ ́
2004,23,3398.(f)Bakhmutov, V.I.;Bozoglian, F.;Gomez, K.;Gonzalez,
G.; Grushin, V. V.; Macgregor, S. A.; Martin, E.; Miloserdov, F. M.;
Novikov, M. A.; Panetier, J. A.; Romashov, L. V. Organometallics 2012,
31, 1315.
(14) For discussions, see: (a) Dierkes, P.; van Leeuwen, P. W. N. M. J.
Chem. Soc., Dalton Trans. 1999, 1519. (b) van Leeuwen, P. W. N. M.;
Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev. 2000, 100, 2741.
(c) Freixa, Z.; van Leeuwen, P. W. N. M. Dalton Trans. 2003, 1890.
(d) Birkholz (nee Gensow), M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M.
́
Chem. Soc. Rev. 2009, 38, 1099.
(15) Alkyl-ligand-induced ground-state destabilization has been
invoked to explain the rates of C−H bond-forming reductive elimination
from a series of zirconocene complexes: (a) Pool, J. A.; Lobkovsky, E.;
Chirik, P. J. Organometallics 2003, 22, 2797. Bulkier alkyl groups increase
the rate of C−H bond-forming reductive elimination from phosphine-
ligated Pt complexes: (b) Abis, L.; Sen, A.; Halpern, J. J. Am. Chem. Soc.
1978, 100, 2915. (c) Halpern, J. Acc. Chem. Res. 1982, 15, 332. For
insightfulstudiesontheeffectsofstericsandelectronicsontherateofC−
C bond-forming reductive elimination from phosphine-ligated Pd
complexes, see ref 13e. For examples where steric crowding inhibits
reductive elimination, see: (d) Ghosh, R.; Zhang, X.; Achord, P.; Emge,
T. J.; Krigh-Jespersen, K.; Goldman, A. S. J. Am. Chem. Soc. 2007, 129,
853.
(16) In Scheme 1B, the structures of 1a and 1b are illustrative and have
not been confirmed experimentally. In the Murai hydroarylation,
computational studies support reductive elimination from a complex
where the alkyl ligand is perpendicular to the plane of the arene:
Matsubara, T.; Koga, N.; Musaev, D. G.; Morokuma, K. Organometallics
2000, 19, 2318.
(17) The following bite angles are reported in ref 14a: BINAP, 92.4°;
dppm, 72°; dppe, 85°; dppp, 91°; and dppb, 97.7°. A wide bite angle
ligand may provide destabilization by compressing the aryl−Ir−alkyl
bond angle and/or by providing a more sterically demanding
coordination sphere. A better correlation to ligand bite angle than to
ligand buried volume is observed. This latter parameter quantifies ligand
steric properties: Clavier, H.; Nolan, S. P. Chem. Commun. 2010, 46, 841.
(18) (R)-SDP, which was used by Shibata to promote branch-selective
hydroheteroarylation at the 2-position of indoles (see ref 8), is not a
suitable ligand and provides only traces (<5%) of 3a/4.
(5) Cobalt: (a) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 400.
(b) Lee, P.-S.; Yoshikai, N. Angew. Chem., Int. Ed. 2013, 52, 1240. In this
latter report, formal carbonyl-directed, branch-selective hydroarylation
can be achieved but requires the formation and subsequent hydrolysis of
the imine directing group. Bis-alkylation was problematic in cases where
two ortho sites were available.
(6) Ruthenium: Uchimaru, Y. Chem. Commun. 1999, 1133.
(7) Branch-selective, nondirected alkene hydroheteroarylation reac-
tions enable the coupling of specific heterocycles and styrenes:
(a) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
6410. (b) Nakao, Y.; Kashikara, N.; Kanyiva, K. S.; Hiyama, T. Angew.
Chem., Int. Ed. 2010, 49, 4451.
(8) Specific combinations of N-based directing group and phosphine
ligand promote linear- or branch-selective hydroheteroarylation at the 2-
position of indoles: Shibata, T.; Ryu, N.; Pan, S. J. Am. Chem. Soc. 2012,
134, 17474.
(9) Styrenes represent “special cases” and often lead to significant levels
of branched products: (a) Tanaka, M.; Watanabe, Y.; Mitsudo, T.-a.;
Takegami, Y. Bull. Chem. Soc. Jpn. 1974, 47, 1698. (b) Casey, C. P.;
Petrovich, L. M. J. Am. Chem. Soc. 1995, 117, 6007. (c) Jiang, Y.-Y.; Li, Z.;
Shi, J. Organometallics 2012, 31, 4356. See also ref 4g.
(10) Secondary alkyl organometallics (e.g., organoboron derivatives)
give intermediates that undergo competitive and reversible β-hydride
elimination during Pd-catalyzed cross-coupling, which leads to linear
products. For selected examples that circumvent this problem, see:
(a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257. (b) Imao, D.; Glasspoole, B. W.; Laberge, V.
S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024. For selected
examples of alternative cross-coupling approaches, see: (c) Iwai, Y.;
Gligorich, K. M.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47, 3219.
(d) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem.
Soc. 2011, 133, 389. (e) Wisniewska, H. M.; Swift, E. C.;Jarvo, E. R. J. Am.
Chem. Soc. 2013, 135, 9083. For the products described here, a
conventional Pd-catalyzed cross-coupling strategy involves pre-install-
ation of the stereocenter on either the nucleophilic or electrophilic
partner. An asymmetric hydroarylation strategy combines stereocenter
creation with C−C bond formation and provides greater step/atom
economy. We note that processes of this type provide a method to
(19) Our qualitative observations indicate the following ranking of
directing group efficiency: tertiary amides > secondary amides ∼ ketones
> esters. A detailed study will be reported in due course.
(20) Secondary directing effects of fluoro and methoxy substituents
have been noted in other metal-catalyzed hydroarylation processes. For
example, see: Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 17283 and references cited therein.
(21) Hydroarylation of styrene with 2q under “standard” conditions,
but with H2O (3000 mol%) as an additive, afforded 3q in 59% yield with
selectivities comparable to those shown in Table 3.
(22) Carbonyl-directed metal insertion into C(sp3)−H bonds adjacent
to nitrogen has been exploited in catalysis: Shibata, T.; Hirashima, H.;
Kasagawa, M.; Tsuchikama, K.; Endo, K. Synlett 2011, 2171.
D
dx.doi.org/10.1021/ja505776m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX