Ligand-controlled palladium-catalyzed regiodivergent suzuki-miyaura cross-coupling of allylboronates and aryl halides

Article abstract of DOI:10.1021/ja405950c

An orthogonal set of catalyst systems has been developed for the Suzuki-Miyaura coupling of 3,3-disubstituted and 3-monosubstituted allylboronates with (hetero)aryl halides. These methods allow for the highly selective preparation of either the α- or the

Full text of DOI:10.1021/ja405950c

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Communication
Ligand-Controlled Palladium-Catalyzed Regiodivergent Suzuki-
Miyaura Cross-Coupling of Allylboronates and Aryl Halides
Yang Yang, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja405950c • Publication Date (Web): 09 Jul 2013
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Ligand-Controlled Palladium-Catalyzed Regiodivergent Suzuki-
Miyaura Cross-Coupling of Allylboronates and Aryl Halides
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Yang Yang and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
responding branched σ–allylpalladium species (6)
through a π–allyl intermediate (7),4 thus producing
mixtures of isomers (3 and 4) following reductive
elimination. Moreover, transmetallation of a prenyl-
boron reagent (2) with oxidative addition complex 1
could proceed through either an SE2 or SE2’ pathway,
which may also contribute to the poor selectivity often
ABSTRACT: An orthogonal set of catalyst systems has
been developed for the Suzuki-Miyaura coupling of
3,3-disubstituted and 3-monosubstituted allylboronates
with (hetero)aryl halides. These methods allow for the
highly selective preparation of either the α- or the γ-
isomeric coupling product.
Scheme 2. Proposed Mechanism.
The broad spectrum of intriguing molecular architec-
tures and biological activities of prenylated and re-
verse-prenylated natural products1 has spurred exten-
sive efforts toward the development of efficient meth-
ods to prepare these compounds. In this context, the
selective syntheses of both of these isomers based on a
regiodivergent coupling methodology using a common
prenyl-metal species and an aryl halide is very appeal-
ing (Scheme 1).2 Among various types of organometal-
lic reagents, organoboron compounds are most fre-
quently used due to their air and moisture stability,
functional group compatibility, ready availability and
Scheme 1. Prenylated Natural Products and Pro-
posed Regioselective Allylation of Aryl Halides.
observed.5 Previously, Szabó6 and Miyaura7 have re-
ported good regioselectivity for the formation of the
branched product with 3-monosubstituted allylboron
reagents. However, a general and practical γ-selective
coupling of 3,3-disubstituted allylboronates to prepare
branched products that bear a sterically demanding
quaternary center (4), and in particular, a method for
tert-prenylation, remains to be developed.8 To date,
Organ’s well-tailored NHC-based catalyst remains the
only α-selective system to access the linear product
(3).9 However, this protocol necessitated the use of
strong aqueous base at high temperature (5 M aq. KOH
in refluxing THF for 24 h), thereby limiting the func-
tional group tolerance. More importantly, a unifying
regiodivergent method providing rapid access to both
the α- and the γ-regioisomers employing a set of cata-
lysts that are structurally similar but furnish orthogonal
selectivities continues to be a daunting challenge. In
addition, despite the fact that heterocycles are ubiqui-
tous structural motifs in biologically active compounds,
the regioselective allylation of heteroaryl halides has
rarely been studied.10
low toxicity.3 However, the successful development of
a
coupling process involving 3-substituted al-
lylboronates has been hampered by regioselectivity
issues (Scheme 2). In principle, linear σ–
allylpalladium complex (5) could isomerize to the cor-
a
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To overcome these challenges, we reasoned that the thyl ring of L3 with an isoproxy group resulted in infe-
1
choice of ligand would influence the transmetallation
mechanism, the rate of σ–π–σ interconversion and the
rate of reductive elimination, and thus represent the
key to achieving high regioselectivity. Over the past
decade, our research group has been engaged in the
design, development and utilization of bulky biar-
ylphosphine ligands that have proven effective for a
broad range of palladium-catalyzed cross-coupling
reactions.11,12 In general, the synthesis of these ligands
is simple, flexible and allows rational tuning of their
steric and electronic properties.13 Taken together, these
features could greatly facilitate the development of
highly α- and γ-selective allylation catalysts that are
broadly applicable to a diverse array of functionalized
aryl halides.
rior selectivity (L4). At this stage, we hypothesized
that the use of more sterically demanding ligands
would destabilize and/or inhibit the formation of the
branched σ–allylpalladium species 6, thus favoring the
formation of the linear product (10a). Indeed, the regi-
oselectivity could be reversed when bulkier di-tert-
butylbiarylphosphine ligands were employed. In par-
ticular, the catalyst generated from t-BuXPhos (L6)
was found to be highly selective for the production of
α-isomer, but further increasing the size of the t-
BuXPhos biaryl backbone (L7 and L8) led to less se-
lective catalysts. After extensive optimization, biphasic
MeCN/aq. K3PO4 was identified as the optimal reac-
tion media for the α-selective coupling. Thus, under
the optimized conditions, the t-BuXPhos-based catalyst
afforded the linear product in 83% yield with excellent
selectivity.
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Table 1. Ligand Evaluation.a
Utilizing both protocols, we examined the substrate
scope with respect to the aryl halide component (Table
2). A wide variety of aryl bromides, bearing electron-
donating or electron withdrawing substituents (11a-
11l), could be effectively converted to the linear or the
branched product with high level of regioselectivity. In
addition to aryl bromides, aryl chlorides and triflates
were also compatible substrates for this transformation
(11f and 11l). While various heteroaryl halides could
be transformed (Table 2 (B)), we were unable, in most
cases, to develop a set of regiodivergent conditions for
these substrates.14 Still the examples shown represent
the most general ones for transforming a variety of
difficult heterocyclic substrates.
entry
L
α/γ
yield of 10a
yield of 10b
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2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
<1:99
1:99
<1%
<1%
55%
42%
99%
80%
7%
<1:99
17:83
90:10
98:2
<1%
16%
63%
68% (84%)b
<1%
7%
Next, we sought to extend the scope of allylboronate
substrates that could be employed in the Suzuki-
Miyaura coupling (Table 3). In general, unsymmetrical
3,3-disubstituted allylboronates (12a-12c) could be
coupled with excellent regioselectivity. Starting from
an E/Z mixture of farnesylboronate15 (12c), either the
α- or the γ-isomer could also be accessed under these
conditions. Similarly, 3-monosubstituted allylboronates
(12d and 12e) represented suitable coupling partners
with both conditions. It is noteworthy that an α-
selective coupling protocol for 3-monosubstituted al-
lylboronates has not been previously described. Tether-
ing the terminal methyl group together with a (CH2)3
spacer (12f) imposed no detrimental effects on regiose-
lectivity. In addition, a cyclic allylboronate (12g) could
be successfully applied in this reaction, maintaining
both good yields and selectivities. Finally, 12g reacted
smoothly to provide 14g with high diastereocontrol
using the γ-selective system.
88:12
46:64
53%
6%
7%
aReactions with L1-L4 were carried out with 1 mol% [(allyl)PdCl]2
and 4 mol% L at 40 °C; reactions with L5-L8 were carried out with 1.5
mol% [(allyl)PdCl]2 and 6 mol% L at 70 °C. Yields were determined by
1H NMR spectroscopy of the crude reaction mixture. bReaction was
performed in MeCN.
We commenced our study by examining palladium
catalysts derived from dialkylbiarylphosphine ligands
(Table 1). Although catalysts generated from SPhos
(L1) and RuPhos (L2) provided good regioselectivity
for the branched product (10b), only moderate conver-
sion of the aryl bromide was observed using 2 mol%
Pd. However, the yield of 10b could be increased dra-
matically using a catalyst derived from L3. Interesting-
ly, replacing the methoxy group on the bottom naph-
Although these coupling processes are highly regi-
oselective, we observed scrambling of the olefin con-
figuration when unsymmetrical 3,3-disubstitued al-
lylboronates were subjected to system A (Table 3,
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Table 2. Substrate Scope of Aryl and Heteroaryl Halides.a
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aYields are of isolated product, see Supporting Information for details; α/γ ratio and yields in parentheses were determined by 1H NMR spectroscopy of
the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bL5 was used instead of L6. c60 °C.
aYields are of isolated product, see Supporting Information for details;
α/γ ratio was determined by 1H NMR spectroscopy of the crude reaction
mixture; E/Z ratio was determined by GC analysis. b60 °C. cStereochem-
istry was confirmed by NOESY NMR spectroscopy.
Table 3. Substrate Scope of Allylboronates.a
entry 1-2). For example, geranylboronate (12a) and
nerylboronate16 (12b) furnished the linear product with
different degrees of isomerization of olefin geometry
(13a and 13b). Interestingly, with catalyst system B,
12b delivered higher selectivity for the branched iso-
mer than 12a (14a and 14b). Taken together, these re-
sults suggest the intermediacy of
a
post-
transmetallation π–allylpalladium species (7);17 pre-
sumably, the two different (allyl)Pd(Ar)(L) species
generated from the transmetallation of (Ar)Pd(X)(L)
with 12a and 12b do not fully equilibrate via σ–π–σ
interconversion prior to reductive elimination. To gain
further insight into the origin of regioselectivity, ter-
tiary allylboronate 1518 was subjected to the coupling
conditions. With the catalyst derived from L3, reaction
of boronates 15 or 9 with 8 afforded drastically differ-
ent results with regard to regioisomer distribution (Ta-
ble 4, entry 1-2). Again, these results imply that σ-allyl
palladium complexes 5 and 6 do not reach equilibrium
via a π–allylpalladium intermediate before reductive
elimination occurs.19 In contrast, using L6-based cata-
lyst, both 15 and 9 provided excellent selectivity for
the linear product (entry 3-4). Therefore, if transmetal-
lation of (Ar)Pd(X)(L6) with 9 and 15 furnishes two
different σ–allylpalladium complexes (5 or 6), the rate
of σ–π–σ interconversion is faster relative to reductive
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(1) For recent reviews, see: (a) Williams, R. M.; Stocking, E. M.;
Sanz-Cervera, J. F. Top. Curr. Chem. 2000, 209, 97–173. (b) Li, S.
Nat. Prod. Rep. 2010, 27, 57–78.
(2) For a recent review on prenylation methods, see: Lindel, T.;
Marsch, N.; Adla, S. K. Top. Curr. Chem. 2012, 309, 67–130.
(3) For reviews, see: (a) Boronic Acids; Hall, D. G., Ed.; Wiley-
VCH: Weinheim, Germany, 2005. (b) Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, Germany, 2004.
(4) For selected reviews on the η3–η1–η3 interconversion of al-
lylpalladium intermediate, see: (a) Trost, B. M.; Van Vranken, D.
L. Chem. Rev. 1996, 96, 395–422. (b) Pregosin, P. S.; Salz-
mann, R. Coord. Chem. Rev. 1996, 155, 35–68.
elimination to form 10b. Alternatively, the transmetal-
lation of ArPd(X)(L6) with 9 and 15 proceeds via two
different pathways, SE2 and SE2’, respectively, to fur-
nish the same σ-allylpalladium complex (5), which
does not undergo σ-π-σ isomerization at a rate that is
competitive with reductive elimination to form 10a.
1
2
3
4
5
6
7
8
Table 4. Mechanistic Insights.
9
10
11
12
13
14
15
16
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(5) For a recent study on the Suzuki-Miyaura coupling of al-
lylboronates where regioselectivity was dictated by the substitution
pattern of substrates, see: Glasspoole, B. W.; Ghozati, K.; Moir, J.
M.; Crudden, C. M. Chem. Commun. 2012, 48, 1230–1232.
(6) Sebelius, S.; Olsson, V. J.; Wallner, O. A.; Szabó, K. J. J. Am.
Chem. Soc. 2006, 128, 8150–8151.
(7) (a) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem. Lett. 2006,
35, 704–705. (b) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem.
Lett. 2006, 35, 1368–1369. (c) Yamamoto, Y.; Takada, S.; Miyaura,
N. Organometallics 2009, 28, 152–160.
(8) An exception is the C2-tert-prenylation of indoles:
Schkeryantz, J. M.; Woo, J. C. G.; Danishefsky, S. J. J. Am. Chem.
Soc. 1995, 117, 7025–7026. For a recent example, see: Kuttruff, C.
A.; Zipse, H.; Trauner, D. Angew. Chem. Int. Ed. 2011, 50, 1402–
1405.
entry
yield of
10a
yield of
10b
L
boronate
α/γ
1a
2a
3b
4b
L3
L3
L6
L6
9
15
9
<1:99
25:75
98:2
< 1%
20%
84%
92%
99%
52%
<1%
<1%
15
>99:1
aReaction was carried out in THF/aq. K3PO4 at 40 °C for 12 h. bReac-
tion was carried out in MeCN/aq. K3PO4 at 70 °C for 12 h; yield and α/γ
ratio were determined by H NMR spectroscopy of the crude reaction
mixture using 1,3,5-trimethoxybenzene as an internal standard.
1
(9) Farmer, J. L.; Hunter, H. N.; Organ, M. G. J. Am. Chem. Soc.
2012, 134, 17470–17473.
In summary, we have developed a complementary
set of palladium-catalyzed regiodivergent protocols for
the Suzuki-Miyaura coupling of 3-substituted al-
lylboronates with aryl halides that allow for the rapid
construction of allylated arene architectures. This
method features excellent regioselectivity, enhanced
operational simplicity and a broad scope of aryl halides.
Notably, a number of allylated heteroaromatic com-
pounds prepared by the current method would be diffi-
cult or tedious to synthesize by other means. Further
mechanistic investigations aimed at determining the
origin of this regiochemical dichotomy and broadening
the application of this method in the context of natural
product synthesis are ongoing topics in our laboratory.
(10) For palladium-catalyzed coupling of other allylmetals, see:
Si: (a) Hatanaka, Y.; Ebina, Y.; Hiyama, T. J. Am. Chem. Soc. 1991,
113, 7076–7077. (b) Hatanaka, Y.; Goda, K.; Hiyama, T. Tetrahe-
dron Lett. 1994, 35, 1279–1282. (c) Hatanaka, Y.; Goda, K.; Hiya-
ma, T. Tetrahedron Lett. 1994, 35, 6511–6514. (d) Denmark, S. E.;
Werner, N. S. J. Am. Chem. Soc. 2010, 132, 3612–3620. Sn: (e)
Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21, 2595–2598. (f)
Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478–
5486. (g) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113,
9585–9595. (h) Obora, Y.; Tsuji, Y.; Kobayashi, M.; Kawamura, T.
J. Org. Chem. 1995, 60, 4647–4649. Zn: (i) Xu, Z.; Negishi, E.-i.
Org. Lett. 2008, 10, 4311–4314. (j) Wang, C.; Tobrman, T.; Xu, Z.;
Negishi, E.-i. Org. Lett. 2009, 11, 4092–4095.
(11) For recent reviews, see: (a) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2011, 2, 57–68. (b) Martin, R.; Buchwald, S. L. Acc.
Chem. Res. 2008, 41, 4695–4698.
(12) For recent work on sp2-sp2 Suzuki-Miyaura coupling, see:
(a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685–4696. (b) Billingsley, K. L.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–3366. (c)
Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073–14075.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures,
characterization and spectral data. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
(13) Kaye, S.; Fox, J. M.; Hicks, M. A.; Buchwald, S. L. Adv.
Syn. Catal. 2001, 343, 789–794.
(14) See Supporting Information for details.
(15) Raducan, M.; Alam, R.; Szabó, K. Angew. Chem. Int. Ed.
2012, 51, 13050–13053. Zhang, P.; Roundtree, I. A.; Morken, J. P.
Org. Lett. 2012, 14, 1416–1419.
AUTHOR INFORMATION
Corresponding Author
*sbuchwal@mit.edu
(16) For the syntheses of 12a and 12b, see: Zhang, P.; Roundtree,
I. A.; Morken, J. P. Org. Lett. 2012, 14, 1416–1419.
ACKNOWLEDGMENT
(17) To rule out the possibility that 3-substituted allylboronates
are configurationally unstable under these reaction conditions, 4-
tert-butyl-1-bromobenzene was treated with 1.5 equiv of 12b under
conditions A and B and the reaction was stopped at partial conver-
sion. Only 12b was recovered and no 12a was observed. Further,
the E/Z ratio of allylated products did not change over the course of
the reaction, indicating the coupling products were configurationally
stable under these conditions. For a review on the configurational
stability of allylmetals, see: Hoffmann, R. W. Angew. Chem. Int.
Ed. 1982, 21, 555–566.
We acknowledge the National Institutes of Health for
financial support of this work (Grant GM46059). We are
grateful to Drs. Nathan T. Jui and Jean-Baptiste Langlois
for insightful discussions. We thank Dr. J. Robb DeBergh
for help with the preparation of this manuscript.
REFERENCES
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(18) For the synthesis of 15, see: Clary, J. W.; Rettenmaier, T. J.;
Snelling, R.; Bryks, W.; Banwell, J.; Wipke, W. T.; Singaram, B. J.
Org. Chem. 2011, 76, 9602–9610.
(19) We found that 9 and 15 are not interconvertible under the
current reaction conditions.
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