Pd(quinox)-catalyzed allylic relay Suzuki reactions of secondary homostyrenyl tosylates via alkene-assisted oxidative addition

Article abstract of DOI:10.1039/c4sc00602j

Pd-catalyzed allylic relay Suzuki cross-coupling reactions of secondary alkyl tosylates, featuring a sterically-hindered oxidative addition and precise control of β-hydride elimination, are reported. The identification of a linear free energy relationship between the relative rates of substrate consumption and the electronic nature of the substrate alkene suggests that the oxidative addition requires direct alkene involvement. A study of the effect of alkyl chain length on the reaction outcome supports a chelation-controlled oxidative addition. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00602j

Chemical
Science
View Article Online
View Journal | View Issue
EDGE ARTICLE
Pd(quinox)-catalyzed allylic relay Suzuki reactions
of secondary homostyrenyl tosylates via alkene-
assisted oxidative addition†
Cite this: Chem. Sci., 2014, 5, 2336
*
Benjamin J. Stokes, Amanda J. Bischoff and Matthew S. Sigman
Pd-catalyzed allylic relay Suzuki cross-coupling reactions of secondary alkyl tosylates, featuring a sterically-
hindered oxidative addition and precise control of b-hydride elimination, are reported. The identification of
a linear free energy relationship between the relative rates of substrate consumption and the electronic
nature of the substrate alkene suggests that the oxidative addition requires direct alkene involvement. A
study of the effect of alkyl chain length on the reaction outcome supports a chelation-controlled
oxidative addition.
Received 25th February 2014
Accepted 13th March 2014
DOI: 10.1039/c4sc00602j
www.rsc.org/chemicalscience
catalyzed relay Suzuki reactions of this challenging electrophile
class (1, Scheme 1B), as well as preliminary mechanistic
Introduction
evidence as to why such secondary electrophiles are capable of
undergoing oxidative addition.
The Pd-catalyzed Suzuki cross-coupling is among the most
widely-used transition metal-catalyzed carbon–carbon bond-
forming reactions because of the ease with which a vast array of
coupling partners can be combined from commercially-avail-
able reactants under mild conditions.1 Despite the diversity of
coupling partners commonly employed in these reactions,
including many sp2 and sp3 nucleophiles and electrophiles,
secondary sp3 electrophiles remain difficult to utilize.2,3 This is
chiey a result of the SN2-type oxidative addition of secondary
halides and pseudohalides to Pd(0), which is severely limited
through presumed steric interactions.4
Since mixtures of allylic (relay) and homoallylic (non-relay)
cross-coupling products were routinely observed in reactions of
primary homostyrenyl tosylates (Scheme 1A),5 secondary
homostyrenyl tosylates such as 1 were anticipated to afford
mixtures of three cross-coupling products (Scheme 1B). Mech-
anistically, these products could result from divergent reaction
following oxidative addition. Specically, from Pd–alkyl B,
transmetallation of a boronic acid and subsequent reductive
We recently reported an unusual example of such an oxida-
tive addition in the context of exploring the reaction depicted in
Scheme 1A.5 In this report, primary homoallylic tosylates were
found to undergo oxidative addition followed by the relay of Pd
to the allylic position via a proposed sequential b-hydride
elimination and migratory insertion.6 The resultant stabilized
Pd–allyl intermediate then undergoes cross-coupling to an aryl
boronic acid to afford difficult-to-access secondary allylic
Suzuki products3 with generally good selectivity (>10 : 1) over
the less-hindered linear homoallylic cross-coupling product.
Through two mechanistic experiments employing secondary
homostyrenyl tosylates, oxidative addition was found to proceed
through a stereoinvertive, SN2-type mechanism – a rare example
of a Pd-catalyzed oxidative addition of an unactivated secondary
electrophile.7 Herein, we present an improved procedure for Pd-
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah, USA. E-mail: sigman@chem.utah.edu; Fax: +1 801-581-8433; Tel: +1 801-585-
0774
Scheme
1 (A) Previous relay Suzuki cross-coupling of primary
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, reaction optimization data, and spectroscopic data of all new
compounds. See DOI: 10.1039/c4sc00602j
homostyrenyl tosylates. (B) Mechanistic rationale to account for three
potential products resulting from the reaction of a secondary homo-
styrenyl tosylate under Pd(quinox) catalysis.
2336 | Chem. Sci., 2014, 5, 2336–2339
This journal is © The Royal Society of Chemistry 2014

View Article Online
Edge Article
Chemical Science
elimination could give homoallylic cross-coupling product 3; acid results in noticeably attenuated yields. For example, 3-
alternatively, b-hydride elimination/migratory insertion could uoro-4-isopropoxyphenylboronic acid gives 2e in just 36%
transpose the Pd atom to either the stabilized allylic position, A, yield, 4-chlorophenylboronic acid couples to give 42% yield of
or to the terminal alkyl position, C, which, aer transmetallation 2f, and 3-carbomethoxyphenylboronic acid affords 41% yield of
and reductive elimination, could afford the allylic cross-coupling the corresponding relay product 2g (although the methyl ester
product 2 or the bishomoallylic cross-coupling product 4, may be sensitive to the hydrolytic reaction conditions). Inter-
respectively. Using Pd(quinox) as catalyst, we now report that estingly, 3-methoxyphenylboronic acid, which also possesses a
relay Suzuki reactions of secondary homostyrenyl tosylates afford relatively electron-decient boron-bearing carbon atom, is
the allylic cross-coupling product, 2, exclusively, thus showcasing coupled in good yield (2h). Electron-rich 3-ethylphenylboronic
the control of b-hydride elimination in addition to the surprising acid also affords a good yield of the corresponding relay product
oxidative addition of a secondary electrophile.
2i. Polycyclic heteroaromatic boronic acids were also investi-
gated for their propensity to undergo relay cross-coupling. To
this end, ortho-substituted 2-dibenzofuranyl boronic acid gave
2j in reasonable yield, and indole-incorporated relay product 2k
was accessed in 60% yield.
Results and discussion
Our previous relay Suzuki cross-coupling conditions, which
employed KF$2H2O as base in isopropanol (Scheme 1A),
necessitated the use of 10–15 mol% of Pd(quinox)Cl2 to achieve
sufficient conversion of secondary homostyrenyl tosylates for
mechanistic studies.5 In an effort to decrease the precatalyst
load for secondary tosylates, we identied Cs2CO3 and THF–
H2O to be a suitable base–solvent combination, allowing the
reaction to be carried out at ambient temperature with just 5
mol% load of Pd(quinox)Cl2.8 Under these conditions, the scope
of boronic acid coupling partners in the relay Suzuki cross-
coupling of 1 was probed using three equivalents of boronic
acid (Table 1). Unsubstituted (2a) and 4-alkoxy-substituted
phenylboronic acids (2b–2d) were found to afford good yields of
the corresponding desired products. On the other hand, the
presence of electron-decient substituents on the arylboronic
An important observation based on crude NMR analyses of
each of these reactions is that the yield is generally comparable
to substrate conversion. That is to say, substrate 1 is not fully
consumed in these reactions, even upon doubling the amount
of reactants, reagents, and catalyst.8,9 The conversion is not
improved substantially by the addition of a second batch of
catalyst aer 16 h, which suggests that boronic acid decompo-
sition, rather than catalyst decomposition, prevents substrate
conversion under these conditions.10 This may also explain the
lower yields observed in relay cross-couplings of electron-de-
cient boronic acids as shown in Table 1.11
Turning our attention towards substrate scope, we next eval-
uated a series of electronically-disparate alkene substrates
through the preparation of para-substituted secondary homo-
styrenyl tosylates (5a–5f, Table 2). Isolated yields were fair for
triuoromethyl-, chloro-, uoro-, and methyl-containing prod-
ucts (6a–6d), while the 4-methoxy-substituted variant resisted
reaction almost entirely, resulting in less than 5% yield of
product 6e by NMR analysis. Finally, substrate 5f, containing an
aryl bromide functional group, afforded 20% yield of 6f. In this
reaction, both 1 and 2a were observed as byproducts, thus illus-
trating that aryl bromides are prone to oxidative addition to Pd(0)
under these conditions, while aryl chlorides are not (cf., 6b).
Table 1 Scope of aryl boronic acids in the relay Suzuki reactiona
Table 2 Scope of substrates containing para-substituentsa
a
b
Isolated yields are reported.
Yield determined by 1H NMR
c
spectroscopy using CH2Br2 as an ex situ internal standard. In
addition, 1 and 2a were isolated in 10% and 23% yield, respectively.
a
Isolated yields are reported.
This journal is © The Royal Society of Chemistry 2014
Chem. Sci., 2014, 5, 2336–2339 | 2337

View Article Online
Chemical Science
Edge Article
Based on the observed sensitivity of the reaction to the
electronics of the alkene, we became intrigued by the possibility
that the styrenyl portion of the substrate may facilitate the
oxidative addition of the hindered tosylate.12 To probe this
hypothesis, a relative rate experiment was designed to compare
the rate of conversion of homostyrenyl tosylates 5a–5e to that of
1.13 This revealed that the relative rates correlate to the Ham-
mett s values14 of the arene substituent (Scheme 2). The positive
r value observed implies a buildup of negative charge in the
transition state of the conversion-inuencing step, which
suggests an inverse-electron-demand ligand substitution of the
alkene onto Pd(0) that would be enabled by a more electron-
decient alkene.15,16 This evidence supports the hypothesis that
the substrate alkene is required for the oxidative addition step
in relay Suzuki cross-coupling reactions.17
A proposed mechanism for the relay Suzuki cross-coupling
reaction of secondary homostyrenyl tosylates is summarized in
Scheme 3. Initially, the alkene of 1 coordinates Pd(0) (7) and
brings Pd into proximity to the tosylate for the SN2-type oxidative
addition, leading to destabilized Pd–alkyl 8. Then, b-hydride
elimination may generate the diene–Pd–H intermediate 9, which
undergoes migratory insertion to afford the stabilized allyl–Pd
intermediate 10.18 Boronic acid transmetallation and reductive
elimination may then give rise to the cross-coupling product 2a.
Based on this newfound insight regarding the alkene-
dependent oxidative addition, we sought to investigate the
inuence that the number of carbon atoms separating the
alkene from the tosylate might have on oxidative addition. This
was accomplished by rst subjecting bishomostyrenyl tosylate
12 to the optimized conditions (Scheme 4). This resulted in
reasonable substrate conversion, and all three of the possible
cross-coupling products (2a, 3a, and 4a) were observed despite
having only observed the allylic relay product (2) in the afore-
mentioned reactions of homostyrenyl tosylates 1 and 5a–5f.
Interestingly, under our previously-reported reaction conditions,
Scheme 3 Proposed mechanism for the relay Suzuki cross-coupling
of a secondary homostyrenyl tosylate to phenylboronic acid.
the major reaction product is not the allylic relay product 2a, but
rather the linear arylation product 4a.5 This selectivity reversal
signies the sensitivity of relay Suzuki cross-couplings to reaction
conditions.
Scheme 4 Investigation of the relay cross-coupling of bishomostyr-
enyl tosylate.
Incorporating an additional carbon between the alkene and
tosylate, as in substrate 13, resulted in no reaction (eqn (1)).
This implies that the olen and tosylate are not able to bind to
the metal simultaneously in order for oxidative addition to be
achieved. This could be due to excessive strain in the oxidative
addition transition state (14) arising from the increased length
of the aliphatic chain, which may reasonably be expected to
prohibit a requisite chelation.
(1)
Conclusions
Scheme 2 Hammett correlation to the relative rates of consumption
of para-substituted and -unsubstituted secondary homostyrenyl
tosylates.
We have developed an allyl-selective relay Suzuki cross-coupling
reaction of secondary homostyrenyl tosylates at ambient
2338 | Chem. Sci., 2014, 5, 2336–2339
This journal is © The Royal Society of Chemistry 2014

View Article Online
Edge Article
Chemical Science
temperature. Linear free energy relationship analysis is consis-
tent with a mechanism whereby the substrate alkene coordinates
Pd prior to oxidative addition. Systematic evaluation of the
distance between the alkene and the electrophile reveals that the
alkene must be within three carbon atoms of the oxidant. Thus,
homostyrenyl and bishomostyrenyl substituents may now be
considered directing groups for oxidative additions of unac-
tivated alkyl electrophiles to Pd(0). New cross-coupling reactions
exploiting alkene-assisted oxidative addition of traditionally inert
alkyl electrophiles are currently being explored.
2012, 51, 10808; (e) E. W. Werner, T.-S. Mei, A. J. Burckle
and M. S. Sigman, Science, 2012, 338, 1455; (f) R. J. DeLuca
and M. S. Sigman, Org. Lett., 2012, 15, 92; (g) Y. Shang,
X. Jie, J. Zhou, P. Hu, S. Huang and W. Su, Angew. Chem.,
´
´
Int. Ed., 2013, 52, 1299; (h) S. Aspin, L. Lopez-Suarez,
P. Larini, A.-S. Goutierre, R. Jazzar and O. Baudoin, Org.
Lett., 2013, 15, 5056; (i) A. Millet, P. Larini, E. Clot and
O. Baudoin, Chem. Sci., 2013, 4, 2241; (j) T.-S. Mei,
E. W. Werner, A. J. Burckle and M. S. Sigman, J. Am. Chem.
Soc., 2013, 135, 6830; (k) V. Saini, L. Liao, Q. Wang, R. Jana
and M. S. Sigman, Org. Lett., 2013, 15, 5008.
7 B. Xiao, Z.-J. Liu, L. Liu and Y. Fu, J. Am. Chem. Soc., 2013,
135, 616.
Acknowledgements
The research reported in this publication was supported by the
National Institute of General Medical Science of the National
Institutes of Health under award numbers R01GM063540 and
8 For complete optimization data, please refer to the ESI.†
9 The secondary tosylates were not observed to undergo
hydrolysis under the reaction conditions.
F32GM099254 (B.J.S.), as well as a UROP undergraduate assis- 10 Substantial quantities of boronic acid homocoupling and
tantship from the University of Utah (A.J.B.).
protodeboronated products are observed in the crude
reaction mixtures.
11 Aqueous basic conditions such as these promote boronic
acid protodeboronation, especially of electron-decient
arylboronic acids. For a review, see: D. G. Hall, in Boronic
Acids, ed. Wiley-VCH Verlag GmbH & Co. KGaA, 2011, pp.
1–133.
Notes and references
1 For reviews on transition metal-catalyzed cross-coupling
reactions, see: (a) Metal-Catalyzed Cross-Coupling Reactions,
ed. F. Diederich and P. J. Stang, Wiley-VCH, Weinheim,
1998; (b) Metal-Catalyzed Cross-Coupling Reactions, 2nd 12 Homobenzylic tosylates do not react under these conditions,
Completely Revised and Enlarged ed., ed. A. de Meijere and
F. Diederich, Wiley-VCH, Weinheim, 2004.
or those previously reported (ref. 5).
13 While individual kinetic analysis for each substrate may
provide more accurate results, NMR analysis of
competition experiments can provide kinetic data that
agrees with individual analyses. For a recent example, see:
H. M. Yau, A. K. Cro and J. B. Harper, Chem. Commun.,
2012, 48, 8937.
2 For reviews on cross-coupling reactions of alkyl halides, see:
(a) M. R. Netherton and G. C. Fu, Top. Organomet. Chem.,
2005, 14, 85; (b) A. C. Frisch and M. Beller, Angew. Chem.,
Int. Ed., 2005, 44, 674; (c) F. Glorius, Angew. Chem., Int. Ed.,
2008, 47, 8347; (d) A. Rudolph and M. Lautens, Angew.
Chem., Int. Ed., 2009, 48, 2656; (e) M. Nakamura and S. Ito, 14 C. Hansch, A. Leo and R. W. Ta, Chem. Rev., 1991, 91, 165.
in Modern Arylation Methods, Wiley-VCH Verlag GmbH & 15 While Pd0(quinox)–alkene complexes have not previously
Co. KGaA, 2009, pp. 155–181; (f) N. Kambe, T. Iwasaki and
J. Terao, Chem. Soc. Rev., 2011, 40, 4937.
been implicated as reactive intermediates, PdII(quinox)
and PdII(pyrox) catalysts are well-known to engage alkenes.
For mechanistic studies, see: (a) B. W. Michel,
L. D. Steffens and M. S. Sigman, J. Am. Chem. Soc., 2011,
133, 8317; (b) A. B. Weinstein and S. S. Stahl, Angew.
Chem., Int. Ed., 2012, 51, 11505; (c) J. C. Holder, L. Zou,
A. N. Marziale, P. Liu, Y. Lan, M. Gatti, K. Kikushima,
K. N. Houk and B. M. Stoltz, J. Am. Chem. Soc., 2013, 135,
14996.
3 Secondary allylic electrophiles are a particularly challenging
substrate class in Pd-catalyzed Suzuki cross-couplings. For
leading reports, see: (a) C. Li, J. Xing, J. Zhao, P. Huynh,
W. Zhang, P. Jiang and Y. J. Zhang, Org. Lett., 2012, 14,
390; (b) J. Zhao, J. Ye and Y. J. Zhang, Adv. Synth. Catal.,
2013, 355, 491.
4 (a) R. G. Pearson and P. E. Figdore, J. Am. Chem. Soc., 1980,
102, 1541; (b) I. D. Hills, M. R. Netherton and G. C. Fu, 16 For leading reports on inverse-electron-demand alkene
Angew. Chem., Int. Ed., 2003, 42, 5749; (c) A. Ariafard and
Z. Lin, Organometallics, 2006, 25, 4030.
5 B. J. Stokes, S. M. Opra and M. S. Sigman, J. Am. Chem. Soc.,
2012, 134, 11408.
ligand substitution on Pd(0) complexes, see: (a) S. S. Stahl,
J. L. Thorman, N. de Silva, I. A. Guzei and R. W. Clark, J.
Am. Chem. Soc., 2002, 125, 12; (b) B. V. Popp,
J. L. Thorman, C. M. Morales, C. R. Landis and S. S. Stahl,
J. Am. Chem. Soc., 2004, 126, 14832.
6 For a review on selective catalytic C–C bond-forming
reactions involving unstabilized Pd–alkyl intermediates, 17 For alkene involvement in Ni(0)-catalyzed Negishi cross-
¨
see: (a) R. J. DeLuca, B. J. Stokes and M. S. Sigman, Pure
Appl. Chem., 2014, 86, 395. For recent reports, see: (b)
R. J. DeLuca and M. S. Sigman, J. Am. Chem. Soc., 2011,
133, 11454; (c) V. Saini and M. S. Sigman, J. Am. Chem.
coupling reactions, see: (a) A. Devasagayaraj, T. Studemann
and P. Knochel, Angew. Chem., Int. Ed. Engl., 1995, 34,
2723; (b) D. K. Nielsen, C.-Y. Huang and A. G. Doyle, J. Am.
Chem. Soc., 2013, 135, 13605.
Soc., 2012, 134, 11372; (d) S. Aspin, A.-S. Goutierre, 18 L. Liao and M. S. Sigman, J. Am. Chem. Soc., 2010, 132,
P. Larini, R. Jazzar and O. Baudoin, Angew. Chem., Int. Ed.,
10209.
This journal is © The Royal Society of Chemistry 2014
Chem. Sci., 2014, 5, 2336–2339 | 2339