Regioselective cross-coupling of allylboronic acid pinacol ester derivatives with aryl halides via Pd-PEPPSI-IPent

Article abstract of DOI:10.1021/ja308613b

The cross-coupling reactions of allylboronic acid pinacol ester derivatives with aryl and heteroaryl halides occurred with high selectivity (>97%) at the α-carbon of the allylboron reagent in the presence of Pd-PEPPSI-IPent precatalyst and 5 M KOH in refluxing THF. In the case of trisubstituted allylboronates with different substituents on the olefin, minor olefin geometry isomerization was observed (E/Z & 80/20).

Full text of DOI:10.1021/ja308613b

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Communication
Regioselective Cross-Coupling of Allylpinacol Boronic
Ester Derivatives with Arylhalides via Pd-PEPPSI-IPent.
Jennifer Lynn Farmer, Howard N. Hunter, and Michael G. Organ
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Oct 2012
Downloaded from http://pubs.acs.org on October 9, 2012
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Regioselective Cross-Coupling of Allylpinacol Boronic Ester Deriva-
tives with Arylhalides via Pd-PEPPSI-IPent.
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Jennifer L. Farmer, Howard N. Hunter and Michael G. Organ.
Department of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
KEYWORDS: cross-coupling, palladium, PEPPSI, allylation.
Supporting Information Placeholder
no catalyst system to date has been developed that is selective
ABSTRACT: The cross-coupling reactions of allylpinacol-
for the linear product (i.e., the α-isomer). This is unfortunate
since most natural products contain prenyl and geranyl side
chains attached at the α-carbon. Armed with this information,
we set out to find conditions that were selective for the linear
product, thus providing access to cathafurans A and B.
boronic ester derivatives with aryl and heteroaryl halides oc-
curred with high selectivity (>97%) at the α-carbon of the
allylboron reagent in the presence of Pd-PEPPSI-IPent
precatalyst and 5M KOH in refluxing THF. In case of trisub-
stituted allylboronates with different substituents on the olefin,
minor olefin geometry isomerization was observed (E/Z ~
80/20).
SCHEME 2. Formation of α– and γ–Coupling Products via
Pd-Catalyzed Cross-Coupling Reactions.
Isoprenylated arenes are found in the structure of many
natural products, of which several demonstrate biological and
pharmacological activities.1 Among these compounds are
cathafurans A and B, which have antimicrobial, antioxidative,
anti-inflammation and cytotoxic activities (Scheme 1).2 The
retrosynthetic route that we have developed to prepare these
compounds is based on the introduction of prenylated-side
chains to an advanced benzofuran building block via Suzuki-
Miyaura cross-coupling (Scheme 1).
Optimal conditions for α-selective allylation with
Pd(PPh3)4 have been reported by Podesta and co-workers for
the cross-coupling of aryliodides with prenylpinacolboronic
ester (2a).5g,6 Using this as a starting point, we wanted to eval-
uate our most active Pd-NHC complex, Pd-PEPPSI-IPent (3),
in the coupling of 4-iodoanisole (1). While 3 has performed
well in sp2-sp2 and sp3-sp3 Suzuki-Miyaura7 and Negishi8
cross-coupling reactions, its application in sp2-sp3 coupling
reactions involving allylic metals with aryl and/or alkenyl
electrophiles has not yet been explored. Interestingly, in our
hands Pd(PPh3)4 actually generated the branched (γ) product
almost exclusively, and not the linear (α) one as we anticipat-
ed. However, 3 did show very high selectivity for the linear
product.
SCHEME 1. Synthetic Approach to Cathafurans A and B.
SCHEME 3. Comparison of Pd(PPh3)4 and Pd-PEPPSI-
IPent (3) in the Allylation of 4-Iodoanisole with Prenyl-
boronic Ester (2a).
While cross-coupling has proven to be one of the most
powerful and direct methods for introducing prenyl and gera-
nyl side chains into aromatic systems, controlling regioselec-
tivity has proven challenging. The catalyst ligand and structure
of the organometallic reagent employed impacts this selectivi-
ty (Scheme 2).3,4,5 Despite the many advantages of organobo-
ron reagents, including air and moisture stability and low tox-
icity, few studies have yielded high and reliable regioselectivi-
ty with allylic derivatives. While Miyaura5a-c and Szabo5d-f
have developed conditions using phosphine ligands to achieve
for high selectivity for the branched product (i.e., the γ-isomer)
with allyltrifluoroborates and allylboronic acids, respectively,
While selectivity was very high with 1, reduction of the
iodide and homocoupling was unavoidable, leading to low
yield of allylated products 4. Consequently, we opted to con-
duct further studies using an aryl bromide instead. 1-Bromo-4-
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(tert-butyl)benzene (5) and 2a were chosen to optimize reac- (Table 3). The reactions proceeded smoothly under these con-
1
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3
4
5
6
7
8
tion conditions and to study the kinetics for this transformation
since 5 showed no steric or electronic bias9 and was suitable
for analysis by GC/MS (Table 1). After a short base/solvent
optimization study, it was found that 5M KOH (4 equiv.) in
THF provided optimal results (Table 1, entry 8); under anhy-
drous conditions, conversion was poor (Table 1, entries 1-6).
Although CsF was better than KF, switching to TBAF, which
was fully soluble, led to poorer conversion (Table 1, entries 1-
3). Interestingly, K2CO3, one of the most common bases used
in a variety of Suzuki-Miyaura cross-coupling applications led
to poor conversion, both with (entry 7), and without (entry 4)
water.
ditions regardless of how sterically or electronically deactivat-
ed the aryl halide. With the aryl bromides showing good reac-
tivity, attention was then focused on aryl chlorides, as there
are no such couplings reported in the literature. The reactions
proceeded smoothly and in most cases were higher yielding
than the corresponding aryl bromides, which we attribute to
less reduction. We were also pleased to see that the reaction
conditions could be extended to dihaloarenes, such as 18. In
all cases, heterocyclic halides coupled uneventfully.
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Table 3. Allylation of Arylhalides with Prenylboronic Ester
2a Catalyzed by Pd-PEPPSI-IPent.[a,b]
Table 1. Optimization of Suzuki-Miyaura Reaction Condi-
tions – Base Study.
Entry
Base
Conv. (%)[a]
6a/6b
1
2
3
4
5
6
7
8
KF
CsF
TBAF
0
42.5
<4
<4
10
0
18.5
81
0
98/2
100/0
100/0
100/0
0
K2CO3
KOH
KOtBu
2M K2CO3
5M KOH
96/4
97/3
[a] Conversions determined by GC/MS using a calibrated in-
ternal standard (undecane); reactions were performed in duplicate.
To be certain the IPent ligand was responsible for the ob-
served regioselectivity, we screened several other ligands re-
ported to produce the α-isomer preferentially (Table 2). Dppe
and dppp were unselective despite their difference in bite an-
gles (entries 1-2). This was surprising since other groups have
shown significant differences between the two ligands in other
Pd-catalyzed cross-couplings.3,4,5 Once again, Pd(PPh3)4
showed high selectivity for the γ-isomer 6b while both the IPr
and IPent ligands displayed high selectivity for α-isomer 6a,
with IPent providing slightly higher α-selectivity.10
[a] Yields are reported on isolated products following silica gel
chromatography; isolated yields are the average of two runs. [b]
Product ratios determined by H-NMR spectroscopy of the crude
reaction mixture and are >99/1 (α/γ) unless otherwise indicated.
[c] 3 equiv. of 2a and 8 equiv. of 5M KOH were used.
1
Table 2. Effect of Ligands.
While the exact mechanism by which allylboranes are
transmetallated remains unclear, there is evidence to support
either addition-elimination5f or an inversion (SE2’) process5c
for γ-selective coupling reactions. An SE2’ mechanism would
be promoted by bulky phosphine ligands that could facilitate
fast reductive elimination for the observed γ regioselectivity.
In both cases, formation of a (π–allyl)palladium(II) intermedi-
ate, (e.g., 26, Scheme 4) leading to α-coupling, was ruled
out.5c,5f
Entry
Cat
Conv. (%)[a]
6a/6b
1
2
3
4
5
Pd(OAc)2/dppe
Pd(OAc)2/dppp
Pd(PPh3)4
90
76
90
86
81
56/44
54/46
5/95
93/7
97/3
Pd-PEPPSI-IPr
Pd-PEPPSI-IPent (3)
To examine the possible formation of 26, we carried out a
classical allylic substitution reaction of prenylbromide 19 with
20 in the presence of Pd(PPh3)4 and 3 (Eq. 1). Both catalysts
provided marginal regioselectivity, which was surprising since
other Suzuki-type allylations were reported to proceed prefer-
entially to give the linear product (e.g., 4a).11 The results in
[a] Conversions determined by GC/MS using a calibrated in-
ternal standard (undecane); reactions performed in duplicate.
With optimization completed, 3 was evaluated in the al-
lylation of a variety of aryl and heteroaryl halides with 2a
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Eq. 1 could be interpreted that following ionization, the less
hindered σ-complex is slightly favoured in the equilibrium due
1
2
3
4
5
6
7
8
to steric interactions with the ligands. Presuming that reduc-
tive elimination is relatively fast with both catalysts, the α-
and γ-isomers are produced in the same ratio as their corre-
sponding Pd σ-complexes. In other words, while there is
σ−π−σ interconversion following ionization of the bromide
leading to an equilibrium of σ-complexes, there is no such
interconversion following transmetallation, which would be
consistent with proposals by Miyaura5c and Szabo5f. However,
the results in Eq. 1 are in stark contrast to those in Eq. 2 that
produces the identical product through similar, if not identical
intermediates. Here Pd(PPh3)4 gives primarily the γ−product
(4b) while 3 gives exclusively the α−product (4a), as was the
case for all earlier examples in the manuscript.
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[a] Yields are reported on isolated products following silica gel
chromatography; isolated yields are the average of two runs. [b]
1
Product ratios determined by H-NMR spectroscopy of the crude
reaction mixture and are >99/1 (α/γ) unless otherwise indicated.
E/Z product ratios determined by 1D and 2D NMR spectroscopy
(see Supporting Information). [c] For the preparation of al-
lylboronates 2c and 2d see to references 6 and 13, respectively.
For the preparation of 2e and 2f see the Supporting Information.
[d] The yields and isomer ratios produced by Pd(PPh3)4 are in
parenthesis. Yield of combined products was 93%.
To further probe the existence of a post-transmetallation π-
allyl complex resembling 26, we substituted one of the methyl
groups on 2a with different groups and different olefin geome-
tries to look for scrambling of olefin stereochemistry (Table
4). Indeed there appears to be a small amount of leakage of
olefin stereochemistry that presumably must take place
through the formation of a Pd π-allyl complex. In all cases
starting with the E-allylboronate the same 80/20 ratio (E/Z)
was observed. However, the results in entry 1 are instructive.
Whereas the E-geranylborane gives 80/20 E/Z 22a, the Z iso-
mer leads to only 45 percent scrambling of the Z stereochemis-
try (i.e., Z to E). These results show that there is limited
σ−π−σ interconversion occurring via π-allyl complex 26 with
catalyst 3 as the two different boronate isomers do not reach
equilibrium before reductive elimination occurs. What this
experiment does confirm is that reductive elimination with
catalyst 3 is relatively fast.
To investigate this, we reacted 2b12 with 5 in the presence of 3
and this yielded very little product (Eq. 3). This suggests that
transmetallation, at least with the IPent ligand on Pd, does not
proceed SE2’. One might expect that if transmetallation first
involved olefin coordination that 2b might actually transmetal-
late faster, or at least as well as 2a. That it scarcely reacts sug-
gests that transmetallation with 3 is SE2 and the borane is
simply now too hindered to allow it to be activated. This also
suggests that coordination of the olefin in 2a to the catalyst
metal during transmetallation is not likely since the olefin in
2b is sterically less hindered than 2a. Now, when one com-
pares this result with 3 vs. Pd(PPh3)4, a different outcome is
obtained (Eq. 3). The reaction proceeds to ~30 percent conver-
sion, so while it did not go to completion, it proceeded signifi-
cantly farther than with 3. Taken together, this suggests that
transmetallation with 3 does proceed SE2, but with Pd(PPh3)4,
it may well proceed SE2’.
As this manuscript focuses primarily on the regioselectivi-
ty aspect of this allylation with allylboronates, it is noteworthy
that more complex substrates in Table 4, some of which pos-
sess coordinating functionality, still rigorously provide α-
selectivity with 3; none of the γ-isomer was observed. To this
point, when Pd(PPh3)4 was used (entry 1) the primary product
was again the γ-isomer, further demonstrating the unique se-
lectivity that can be achieved with catalyst 3 relative to any
other catalyst in the literature.
The remaining issue to try to shed light on was the mecha-
nism of transmetallation itself. Since 3 has shown in other
cross-coupling reactions to facilitate fast reductive elimination
due to its bulky nature,8 we believe transmetallation to be pro-
ceeding without allylic transposition (SE2) (Scheme 4).
SCHEME 4. Proposed Mechanism.
Table 4. Allylation of 5 with Allylboronic Ester Derivatives
Catalyzed by Pd-PEPPSI-IPent.[a,b]
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R
[1] (a) Sun, S. G.; Chen, R. Y.; Yu, D. Q. J. Asian Nat. Prod. Res.
Ar
R
Ar
Pd0Ln
2001, 3, 253. (b) Du, J.; He, Z. D.; Wang, R.; Ye, W. C.; Xu, H. X.;
But, P. H. Phytochemistry, 2003, 62, 1235. (c) Sohn, H.-Y.; Son, K.
H.; Kwon, C.-S.; Kwon, G.-S.; Kang, S. S. Phytomedicine, 2004, 11,
666.
[2] Ni, G.; Zhang, Q.-J.; Zheng, Z.-F.; Chen, R.-Y.; Yu, D.-Q. J. Nat.
Prod. 2009, 72, 966.
[3] For Pd-catalyzed reactions with allylfluorosilanes, see: (a) Hat-
anaka, Y.; Ebina, Y.; Hiyama, T. J. Am. Chem. Soc. 1991, 113, 7076.
(b) Hatanaka, Y.; Goda, K.; Hiyama, T. Tetrahedron Lett. 1994, 35,
6511.
[4] For Pd-catalyzed reactions with allylstannanes, see: (a) Echavar-
ren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478. (b) Farina,
V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585. (c) Obora, Y.;
Tsuji, Y.; Kobayashi, M.; Kawamura, T. J. Org. Chem. 1995, 60,
4647. (d) Takaoka, S.; Nakade, K.; Fukuyana, Y. Tetrahedron Lett.
2002, 43, 6919. (e) Takemura, S.; Hirayama, A.; Tokunaga, J.; Ka-
wamura, F.; Inagaki, K.; Hashimoto, K.; Nakata, M. Tetrahedron
Lett. 1999, 40, 7501. (f) Mattson, A. E.; Scheidt, K. A. J. Am. Chem.
Soc. 2007, 129, 4508. (g) Takaoka, S.; Takaoka, N.; Minoshima, Y.;
Huang, J.-M.; Kubo, M.; Harada, K.; Hioki, H.; Fukuyama, Y. Tetra-
hedron, 2009, 65, 8354.
[5] For Pd-catalyzed reactions with allylboron derivatives, see: (a)
Yamamoto, Y.; Takada, S.; Miyaura, N. Chemistry Letters 2006, 35,
704. (b) Yamamoto, Y.; Takada, S.; Miyaura, N. Chemistry Letters
2006, 35, 1368. (c) Yamamoto, Y.; Takada, S.; Miyaura, N. Organo-
metallics 2009, 28, 152. (d) Sebelius, S; Olsson, V. J.; Szabó, K. J. J.
Am. Chem. Soc. 2005, 127, 10478. (e) Olsson, V. J.; Sebelius, S.;
Selander, N.; Szabó, K. J. J. Am. Chem. Soc. 2006, 128, 4588. (f)
Sebelius, S; Olsson, V. J.; Wallner, O. A.; Szabó, K. J. J. Am. Chem.
Soc. 2006, 128, 8150. (g) Gerbino, D. C.; Mandolesi, S. D.; Schmalz,
H.-G.; Podestá, J. C. Eur. J. Org. Chem. 2009, 3964. (h) For a recent
publication on secondary allylic boronic esters see: Glasspoole, B.
W.; Ghozati, K.; Moir, J. M.; Crudden, C. M. Chem. Commun. 48,
1230.
1
2
3
4
5
6
7
8
Ar-X
γ
-product
α
-product
Oxidative
Addition
Reductive
Elimination
Reductive
Elimination
R
PdIINHC
NHC
Ar
NHC
NHC
Ar PdII
26
R
Ar via 26
σ-π
PdII
Ar
PdII
X
π-allyl complex
25b
25a
R
interconversion
9
Transmetallation
SE2
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Transmetallation
OR
K
Bpin
R
SE2'
R
Bpin
+ KOHaq
In conclusion, sterically bulky Pd-PEPPSI-IPent 3 has
shown to be extremely reactive in the metal-catalyzed allyla-
tion of allylboronate derivatives. The high α-selectivity
demonstrated by 3 over all other Pd- catalysts in the Suzuki-
Miyaura cross-coupling of prenylboronic ester 2a with a varie-
ty of arylhalides illustrates that this process can now be used
with high reliability to produce such allylated aromatics. This
is especially important because isomeric allylated products
typically cannot be separated. We attribute the observed regi-
oselectivity primarily to both the significant steric bulk of the
NHC ligand and the substitution of the allylboronic ester. This
new protocol will serve to complement the usefulγ−selectivity
demonstrated by Miyaura5a-c and Szabo.5f While reactive al-
lylmetal species such as Mg,[14] Zn[15], and In[16] can be cou-
pled under mild conditions, those systems have failed to
demonstrate high selectivity in metal-catalyzed allylation.
Further, while allylstannanes[4] have demonstrated good linear
selectivity, the coupling requires harsh conditions and con-
fronts the chemist with tin waste and purification problems
that the boronate system does not.
[6] For the preparation of prenylpinacolboronic ester 2a and 2c, see:
Dutheuil, G.; Selander, N.; Szabo, K., J.; Aggarwal, V., K. Synthesis,
2008, 14, 2293.
[7] Organ, M. G.; Calimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J.
Angew. Chem. 2009, 121, 2419; Angew. Chem. Int. Ed. 2009, 48,
2383.
ASSOCIATED CONTENT
[8] (a) Calimsiz, S.; Sayah, M.; Mallik, D.; Organ, M. G. Angew.
Chem. 2010, 122, 2058; Angew. Chem. Int. Ed. 2010, 49, 2014; (b)
Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org.
Chem. 2010, 4343; (c) Calimsiz, S.; Organ. M. G. Chem. Commun.
2011, 47, 5181.
[9] Miyaura and co-workers reported unanticipated α–selectivity
when coupling 4- and 2-bromoanisoles (see reference 5b).
[10] For the purpose of comparison and the creation of standard
curves for GCMS analysis, these compounds were also prepared via a
Wittig reaction (see Supporting Information).
Supporting Information. Experimental procedures and charac-
terization of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Michael G. Organ, organ@yorku.ca
ACKNOWLEDGMENT
[11] Pigge, F. C. Synthesis, 2010, 11, 1745.
[12] For the preparation of 4,4,5,5-tetramethyl-2-(2-methylbut-3-en-
2-yl)-1,3,2-dioxaborolane 2b, see: Hoffmann, R. W.; Wolff, J. J.
Chem. Ber. 1991, 124, 563.
[13] Zhang, P.; Roundtree, I. A.; Morken, J. P. Org. Lett. 2012, 14,
1416.
[14] (a) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed.
2002, 41, 4137. (b) Ohmiya, H.; Tsuji, T.; Yorimitsu, H.; Oshima, K.
Chem. Eur. J. 2004, 10, 5640.
The authors are grateful to the National Science and Engineering
Council of Canada (NSERC), the Ontario Research and Devel-
opment Challenge Fund (ORDCF), the Ontario Graduate Scholar-
ship Program (OGS), and the Ontario Centre of Excellence
(OCE).
[15] Xu, Z.; Negishi, E.-I. Org. Lett. 2008, 10, 4311.
[16] P. D.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201.
REFERENCES
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