Iridium-Catalyzed α-Selective Arylation of Styrenes by Dual C?H Functionalization

Article abstract of DOI:10.1002/anie.201808299

An Ir^I-system modified with a ferrocene derived bisphosphine ligand promotes α-selective arylation of styrenes by dual C?H functionalization. These studies offer a regioisomeric alternative to the Pd-catalyzed Fujiwara–Moritani reaction.

Full text of DOI:10.1002/anie.201808299

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Title: Iridium-Catalyzed α-Selective Arylation of Styrenes by Dual C-H
Functionalization
Authors: Phillippa Cooper, Giacomo Crisenza, Lyman Feron, and John
Bower
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10.1002/anie.201808299
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Iridium-Catalyzed α-Selective Arylation of Styrenes by Dual C-H
Functionalization
Phillippa Cooper, Giacomo E. M. Crisenza, Lyman J. Feron, and John F. Bower*
Abstract: An Ir(I)-system modified with
a
ferrocene derived
styrenes. Note that products mechanistically related to 4 have
been observed as minor components in enamide C-H alkylation
reactions.[11]
bisphosphine ligand promotes α-selective arylation of styrenes by
dual C-H functionalization. These studies offer a regioisomeric
alternative to the Pd-catalyzed Fujiwara-Moritani reaction.
The intermolecular Heck reaction is the foremost method
available for the C-H arylation of alkenes.[1] For processes
involving styrenes, arylation occurs predominantly at the β-
position.[1,2] In electronically predisposed cases, significant levels
of α-arylation are observed,[3] but complete selectivity for C-C
bond formation at this position can be achieved only under
specialized conditions.[4] The related intermolecular Fujiwara-
Moritani reaction, which is most effective in the presence of
directing groups, operates under oxidative conditions and is
attractive because it achieves C-H arylation of alkenes by dual C-
H functionalization, thereby circumventing the preparation of an
aryl (pseudo)halide (Scheme 1A).[1c,5] The regioselectivity trends
of this process mirror the Heck reaction, such that the method also
does not provide a general approach to the α-selective arylation
of styrenes. This type of selectivity has been observed in rare
cases involving heteroarenes, but substrate scope is severely
limited.[6] The paucity of general methods for direct styrene α-
arylation often mandates multistep synthetic workarounds,
thereby increasing cost, effort and waste.[7]
Scheme 1. Introduction.
We have previously described Ir-catalyzed branch selective
hydroarylations of styrenes with acetanilides 1 (DG = NHAc,
Scheme 1B).[8a] These processes were posited to occur via a
sequence of carbonyl directed C-H activation (to I), alkene
hydrometallation (to II) and C-C reductive elimination (to 3). In this
report, we show that modification of the Ir-center with specific
bisphosphine ligands alters the reaction outcome to provide a
method for the α-selective arylation of styrenes (1 to 4). This new
dual C-H functionalization method is regioisomeric with respect to
the Fujiwara-Moritani and Heck reactions,[1,5] and previous Ir-
catalyzed C-H alkenylation processes,[9,10] thereby providing
proof-of-concept for a unique approach to the α-arylation of
Natural abundance 13C kinetic isotope effect (KIE) experiments
on our previously developed alkene hydroarylation reaction (1 to
3, DG = NHAc) are suggestive of a C-C reductive elimination
pathway for the formation of 3 (see the SI).[8a,b,12,13] Accordingly,
we reasoned that the proposed C-H alkenylation process outlined
in Scheme 1B (1 to 4) requires a catalyst system that can enforce
access to an alkene carbometallation manifold at the expense of
the prevailing C-C reductive elimination pathway. It has previously
been shown by Shibata and co-workers that styrene
carbometallation occurs with complete branch selectivity using
bisphosphine-ligated iridacycles derived from C-C bond activation
of biphenylene.[14] Accordingly, if a carbometallative manifold
could be accessed, then we expected high regioselectivity for the
formation of III, which, in turn, would provide α-arylated styrene 4,
rather than the corresponding β-arylated isomer (not depicted).
P. Cooper, G. E. M. Crisenza, Prof. J. F. Bower
School of Chemistry,
University of Bristol,
An assay of potential ligand systems was undertaken on the
coupling of acetanilide 1a and styrene 2a using [Ir(cod)2]OTf as
precatalyst and dioxane as solvent. From these studies, we
observed that the use of dppf (L-1) afforded a 3:7 mixture of
alkene 4aa and hydroarylation product 3aa, with the former
generated in 23% yield. This prompted the evaluation of a variety
of related ligand systems L2-L6, which were prepared in three
steps from ferrocene (see the SI).[15] In general, the selectivity for
alkenylation vs hydroarylation, and the yield of 4aa increased as
the aromatic unit of the ligand became more electron poor, with
Bristol, BS8 1TS, United Kingdom
E-mail: john.bower@bris.ac.uk
L. J. Feron
Medicinal Chemistry, Oncology,
IMED Biotech Unit
AstraZeneca
Cambridge
United Kingdom
Supporting information for this article is given via a link at the end
of the document. X-ray data is available under CCDC 1838966-
1838967.
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Table 2. Scope of the anilide component.a
L-4 providing 4aa in 24% yield and 8:2 selectivity over 3aa.
However, L-5, which possesses highly electron withdrawing
pentafluorophenyl units, did not provide 4aa, and instead a
mixture of branched and linear hydroarylation products 3aa and
iso-3aa formed.[16] Ligand systems with more electron rich
aromatic units, such as L-6, were not effective, and resulted in
hydroarylation only. As L-4 provided the highest selectivity for
4aa, further optimization studies were undertaken using this
ligand. Pleasingly, by increasing the reaction time to 72 hours we
found that 4aa could be formed in 62% yield. The conversion of
III to 4 releases an Ir(III)-dihydride, and, as indicated by GCMS
analysis of crude reaction mixtures, turnover is achieved by
reduction of a sacrificial equivalent of styrene to ethyl benzene.
As such, we reasoned that oxidants other than styrene might offer
additional improvements. In the event, by using 200 mol% t-
butylethylene as an exogenous oxidant[9] and increasing the
catalyst loading to 7.5 mol%, 4aa was formed with 10:2 selectivity
over 3aa and could be isolated in pure form in 74% yield (further
optimization studies with respect to the oxidant are detailed in the
SI). For clarity, the product numbering system used in Table 1 is
retained throughout subsequent discussion: 3 = hydroarylation
product; 4 = C-H arylation product; first letter specifies anilide
precursor; second letter specifies styrene precursor.
With optimized conditions in hand, we sought initially to explore
scope with respect to the directing group (R1, Table 2A). These
studies revealed that a wide range of sterically distinct anilide-
based systems can be employed (1b-i), such that 4aa-ia were all
formed in good to excellent yield, with high selectivity over the
corresponding hydroarylation product (3).[17] Note that systems
where R1 = aryl are not suitable because competing ortho-
selective hydroarylation of this unit predominates.[8c] The process
tolerates diverse substitution on the anilide partner (Table 2B).
Indeed, para-substituted systems engage efficiently (4oa-rb), and
arenes
possessing
meta-substitution
undergo
highly
regioselective C-H alkenylation at the less hindered ortho-
Table 1. Selected optimization results.
position; for example, C-H arylation of styrene 2a with acetanilide
1m provided 4ma (65% yield) as a single regioisomer and with
good selectivity over the corresponding hydroarylation product
(5:1). The functional group compatibility of the process is good,
with, for example, the potentially labile C-Br bond of 4oa
remaining intact for further diversification. Ortho-substitution can
impact selectivity; 4ra was formed with only 2:1 selectivity over
3ra, but generation of 4vb was highly selective. In all cases, the
target products were easily separated from the minor
hydroarylation products by column chromatography.
Using anilide 1f, we have assessed the scope of the
alkenylation process with respect to the styrene partner (Table 3).
Electronically diverse systems all participate with acceptable
levels of efficiency; for example, para-fluoro system 4fd and para-
methyl system 4fb were generated in 75% and 77% yield,
respectively. An electronic trend is evident for alkenylation vs
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hydroarylation selectivity (cf. 4fb vs 4fe), however, steric effects
are more pronounced. Indeed, ortho-substitution on the styrene
lowers product selectivity, such that fluoro system 4fj was formed
with 2:1 selectivity over the corresponding hydroarylation product.
Despite this modest selectivity, analytically pure 4fj could still be
isolated in 50% yield. At the present stage, the process is
applicable to styrenes only; alkyl substituted alkenes participate
with low levels of efficiency with respect to both yield and product
selectivity.
Table 3. Scope of the styrene.a
Scheme 2. Product derivatizations.
The anilide-based C-H alkenylation products are useful
intermediates for synthesis, especially in heterocyclization
processes. Treatment of the alkenylation products with POCl3
effects smooth cycloaromatization to provide quinolines,[18] as
exemplified by the synthesis of 5a-d (Scheme 2A). Note that this
de novo heteroaromatization strategy offers high levels of
modularity, and its suitability for the construction of challenging
polycyclic systems, such as 5c and 5d, is significant. The protocol
even extended to the two-step conversion of estrone derived
acetanilide 1w to the unusual quinoidal steroid 5e. Other classes
of heterocyclization can also be achieved; treatment of 4aa with
SelectFluor[19] or iodine[20] provided adducts 6 and 7, respectively
(Scheme 2B). Free aniline 8 was accessed by acid hydrolysis of
4ha and could be converted in high yield to cinnoline 9 or
dihydroquinoline 10, which possesses
a
tetrasubstituted
stereocenter.
The C-H alkenylation processes outlined here represent proof-
of-concept for a broader family of styrene α-arylation protocols. In
preliminary efforts to extend the scope of our approach, we have
assayed a selection of other aromatic partners leading to the
observation that α-selective arylation using pyrrole 11a is feasible
(Scheme 3A). Here, L-4 was not a suitable ligand, but, instead,
Scheme 3. Extensions of the C-H alkenylation process.
we found that use of ferrocene-based system (S,S)-f-
Binaphane[21] provided targets 12a-c in 62-74% yield. The
seemingly fickle nature of the ligand requirements highlights a
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future challenge in the development of new processes. For pyrrole
11b, which is arylated at C3, C-H alkenylation to provide 12d was
highly regioselective. Using L-4 we have also found that
dehydrogenative C-C bond formation can be combined with a
further dehydrogenation event. When enamide 13 was exposed
to optimized conditions dehydrogenative aromatization (to 1n)
was followed by C-H alkenylation, which provided 4na in 60%
yield (Scheme 3B).[22]
funded by the EPSRC (EP/G036764/1) (studentship to G.E.M.C).
J.F.B. is indebted to the Royal Society for a University Research
Fellowship.
Keywords: iridium, C-H activation, arylation, styrene
[1] Reviews: a) R. F. Heck, Acc. Chem. Res. 1979, 12, 146-151; b) W. Cabri,
I. Candiani, Acc. Chem. Res. 1995, 28, 2-7; c) The Mizoroki-Heck Reaction;
M. Oestreich, Ed.; Wiley: Chichester, U.K., 2009.
[2] For example, see: a) A. F. Littke, G. C. Fu, J. Am. Chem. Soc. 2001, 123,
6989-7000; b) P. M. Murray, J. F. Bower, D. K. Cox, E. K. Galbraith, J. S.
Parker, J. B. Sweeney, Org. Process Res. Dev. 2013, 17, 397-405.
[3] Selected examples: a) W. Cabri, I. Candiani, A. Bedeschi, R. Santi, J. Org.
Chem. 1992, 57, 3558-3563; b) J. Ruan, J. A. Iggo, N. G. Berry, J. Xiao, J.
Am. Chem. Soc. 2010, 132, 16689-16699.
It is pertinent to comment on mechanistic details of the
processes described here.
A control experiment involving
resubjection of hydroarylation product 3aa to optimized C-H
arylation conditions did not provide alkene 4aa. This result
supports the idea that 4aa is generated via a carbometallative
[4] a) L. Qin, X. Ren, Y. Lu, Y. Li, J. Zhou, Angew. Chem. Int. Ed. 2012, 51,
5915-5919; b) Y. Zou, L. Qin, X. Ren, Y. Lu, Y. Li, J. Zhou, Chem. Eur. J.
2013, 19, 3504-3511; c) L. Qin, H. Hirao, J. Zhou, Chem. Commun. 2013,
49, 10236-10238.
pathway (I to III to
4 in Scheme 1B) rather than via
dehydrogenation of 3aa. C-H arylation of deuterio-2c with
acetanilide 1q resulted in scrambling of the deuterium labels in
product deuterio-4qc and in recovered deuterio-2c and 1q. This
suggests that reversible styrene hydrometallation (I to II) is also
operative under optimized conditions (Scheme 4). Accordingly,
the minor alkene hydroarylation products (e.g. 3aa) might arise
via either C-C reductive elimination from II or C-H reductive
elimination from III. At the present stage we have been unable to
[5] Seminal studies: a) I. Moritani, Y. Fujiwara, Tetrahedron Lett. 1967, 8,
1119-1122; b) Y. Fujiwara, I. Moritani, M. Matsuda, S. Teranishi,
Tetrahedron Lett. 1968, 9, 3863-3865; c) Y. Fujiwara, I. Moritani, S. Danno,
R. Asano, S. Teranishi, J. Am. Chem. Soc. 1969, 91, 7166-7169. Reviews:
d) L. Zhou, W. Lu, Chem. Eur. J. 2014, 20, 634-642; e) J. L. Bras, J. Muzart,
Chem. Rev. 2011, 111, 1170-1214; f) E. M. Beccalli, G. Broggini, M.
Martinelli, S. Sottocornola, Chem. Rev. 2007, 107, 5318-5365. Examples
of high yielding styrene β-(hetero)arylation: g) C. Aouf, E. Thiery, J. L. Bras,
J. Muzart, Org. Lett. 2009, 11, 4096-4099; h) A. García-Rubia, M. ꢀ.
Fernández-Ibáñez, R. Gómez Arrayás, J. C. Carretero, Chem. Eur. J. 2011,
17, 3567-3570; i) M. Yu, Z. Liang, Y. Wang, Y. Zhang, J. Org. Chem. 2011,
76, 4987-4994; j) C. Huang, B. Chattopadhyay, V. Gevorgyan, J. Am.
Chem. Soc. 2011, 133, 12406-12409; k) P. Gandeepan, C.-H. Cheng, J.
Am. Chem. Soc. 2012, 134, 5738-5741; l) X. Cong, J. You, G. Gao, J. Lan,
Chem. Commun. 2013, 49, 662-664; m) Wang, P.; Verma, P.; Xia, G.; Shi,
J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung,
K.-S.; Yu, J.-Q. Nature 2017, 551, 489. Metals other than palladium can
also be used (see reference 10).
discriminate
these
pathways,
such
that
meaningful
rationalizations for product selectivity in each case cannot be
made.
[6] a) M. Ghosh, A. Naskar, S. Mitra, A. Hajra, Eur. J. Org. Chem. 2015, 715-
718; b) Y. Yang, K. Cheng, Y. Zhang, Org. Lett. 2009, 11, 5606-5609.
[7] For the processes described here, a classical alternative requires a) the
preparation of an acid chloride, b) its use in ortho-selective Friedel-Crafts
acylation of an anilide and c) olefination of the F/C product. For selected
recent alternative approaches to α-arylated styrenes, see: a) J. Tang, D.
Hackenberger, L. J. Goossen, Angew. Chem. Int. Ed. 2016, 55, 11296-
11299; b) S. Agasti, A. Dey, D. Maiti, Chem. Commun. 2016, 52, 12191-
12194.
[8] a) G. E. M. Crisenza, O. O. Sokolova, J. F. Bower, Angew. Chem. Int. Ed.
2015, 54, 14866-14870; b) S. Grélaud, P. Cooper, L. Feron, J. F. Bower, J.
Am. Chem. Soc. 2018, 140, DOI: 10.1021/jacs.8b04627. For related ketone
and benzamide directed processes, see: c) G. E. M. Crisenza, N. G.
McCreanor, J. F. Bower, J. Am. Chem. Soc. 2014, 136, 10258-10261.
[9] A mechanistically similar process allows the internal C-H heteroarylation of
α-olefins, but styrenes afford β-heteroarylation products: C. S. Sevov, J. F.
Hartwig, J. Am. Chem. Soc. 2014, 136, 10625-10631.
Scheme 4. A deuterium labelling study.
In summary, we outline a unique Ir-catalyzed method for the α-
selective C-H arylation of styrenes. This dual C-H
functionalization protocol offers a regioisomeric alternative to the
well-established Pd-catalyzed Fujiwara-Moritani reaction. Efforts
to broaden the utility of the method are ongoing and the results of
these studies will be reported in due course.
[10] For a review on oxidative couplings of C-H bonds, see: C. Liu, J. Yuan, M.
Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015, 115, 12138-12204.
[11] D. Xing, G. Dong, J. Am. Chem. Soc. 2017, 139, 13664-13667.
[12] D. A. Singleton, A. A. Thomas, J. Am. Chem. Soc. 1995, 117, 9357-9358.
[13] This interpretation must be treated with caution because we have been
unable to devise an acceptable computational model; using a styrene (2c)
as the limiting component, a significant 13C KIE is observed for C2 but not
C1 (see the SI).
ACKNOWLEDGMENTS
We thank the University of Bristol School of Chemistry X-ray
crystallography service for analysis of 4ba and 5e. We thank the
EPSRC (EP/M507994/1) and AstraZeneca (studentship to P.C.),
and the Bristol Chemical Synthesis Doctoral Training Centre,
[14] H. Takano, K. S. Kanyiva, T. Shibata, Org. Lett. 2016, 18, 1860-1863.
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[15] L-3 and L-4 have been reported previously: a) O. R. Hughes, D. A. Young,
J. Am. Chem. Soc. 1981, 103, 6636-6642; b) B. C. Hamann, J. F. Hartwig,
J. Am. Chem. Soc. 1998, 120, 3694-3703.
[16] We speculate that the distinct outcome with this ligand may reflect a switch
to a C-C reductive elimination pathway enforced by the highly electron
withdrawing pentafluorophenyl units.
[17] The higher selectivities observed with bulkier directing groups might
indicate that DG dissociation precedes -hydride elimination to 4 (cf. 4ua
vs 4vb); this interpretation must be treated with caution because the
pathway to byproducts 3 has not been established.
[18] L. Ni, Z. Li, F. Wu, J. Xu, X. Wu, L. Kong, H. Yao, Tetrahedron Lett. 2012,
53, 1271-1274.
[19] J.-F. Zhao, X.-H. Duan, H. Yang, L.-N. Guo, J. Org. Chem. 2015, 80,
11149-11155.
[20] K. Kazuhiro, M. Kazuna, M. Osamu, K. Hisatoshi, Bull. Chem. Soc. Jpn.
2005, 78, 886-889.
[21] D. Xiao, X. Zhang, Angew. Chem. Int. Ed. 2001, 40, 3425-3428.
[22] For a recent report on Ir-catalyzed dehydrogenation processes, see: Z.
Wang, Z. He, L. Zhang, Y. Huang, J. Am. Chem. Soc. 2018, 140, 735-740.
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Phillippa Cooper, Giacomo E. M.
Crisenza, Lyman J. Feron and John F.
Bower*
Page No. – Page No.
Iridium-Catalyzed α-Selective
Arylation of Styrenes by Dual C-H
Functionalization
An Ir(I)-system modified with a ferrocene derived bisphosphine ligand promotes α-
selective arylation of styrenes by dual C-H functionalization. These studies offer a
regioisomeric alternative to the Pd-catalyzed Fujiwara-Moritani reaction.
This article is protected by copyright. All rights reserved.