Suzuki-Miyaura cross-couplings of secondary allylic boronic esters

Article abstract of DOI:10.1039/c2cc16076e

Palladium-catalyzed cross-coupling reactions of secondary allylic boronic esters with iodoarenes were demonstrated under the conditions previously described for the coupling of benzylic substrates. The regioselectivity of the process was largely dictated by the pattern of olefin substitution. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc16076e

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COMMUNICATION
Suzuki–Miyaura cross-couplings of secondary allylic boronic esterswz
Ben W. Glasspoole, Kazem Ghozati, Jonathon W. Moir and Cathleen M. Crudden*
Received 29th September 2011, Accepted 25th November 2011
DOI: 10.1039/c2cc16076e
Palladium-catalyzed cross-coupling reactions of secondary
allylic boronic esters with iodoarenes were demonstrated under
the conditions previously described for the coupling of benzylic
substrates. The regioselectivity of the process was largely dictated
by the pattern of olefin substitution.
Remarkably, not only are the aforementioned conditions
effective for the coupling of benzylic boronic ester 1, they also
exhibit essentially perfect chemoselectivity for the coupling of
this substructure in the presence of its linear isomer 3. Even in
the absence of any competing substrate, 3 failed to undergo
any coupling under our silver-oxide-mediated conditions,
which is noteworthy because linear branched boronic esters
are considered to be more reactive than their more substituted
counterparts.3
The Pd-catalyzed Suzuki-Miyaura cross-coupling reaction1,2
represents one of the most important methods for the metal-
catalyzed formation of carbon–carbon bonds developed to
date, and is currently the most frequently employed method
for the construction of C–C bonds in the pharmaceutical
industry.2 Although the Suzuki-Miyaura coupling has been
primarily employed for the construction of C–C bonds between
sp2-hybridized carbons, primary sp3-hybridized partners can also
be employed.3 The final frontier for this reaction now appears to
be the use of nucleophiles with stereochemistry, such that the
Suzuki-Miyaura reaction would result in chiral, non-racemic
products.4–9
In 2009,4 we reported the first example of the stereospecific
coupling of acyclic boronic esters (eqn (1) top).10 This synthetic
sequence provides facile access to enantiomerically enriched
1,1-diarylalkanes, which are extremely difficult to prepare by
other methods.11,12 The use of silver oxide as a base, proposed
by Kishi to promote difficult transmetalations,13 was critical for
the successful Suzuki-Miyaura coupling of chiral boronic ester
1. Subsequent advances in the area have been described by
Suginome, Molander, and Hall.5,7,8
In order to probe the reasons for this unusual chemoselectivity,
we began by subjecting a series of representative boronic esters to
our standard conditions (Fig. 1). Compound 5 provides an
interesting test as it is both linear like the unreactive isomer 3
and benzylic like 1. In the event, 5 reacts in good yield to give the
corresponding diaryl methane. Although an unsubstituted
benzylic species like 5 might be expected to have high reactivity,
the contrast between its reactivity and the complete inertness of
its one-carbon homologue 3 hints at the importance of the
benzylic nature of compound 1. Furthermore, this substrate
illustrates that the increased reactivity of 1 relative to 3 is not
due to a more facile reductive elimination from the more
sterically hindered substrate 1.
To test this idea further, we examined boronic ester 6, which
is benzylic but more substituted than 3. This compound was
unreactive, indicating that steric hindrance does not enhance
the activity of the boronic esters. Fully aliphatic branched
boronic esters 7 and 8 gave no product when subjected to typical
silver oxide-mediated reaction conditions, further indicating that
the benzylic nature of substrates 1 and 5 is critical. In order to
assess whether other unsaturated groups can act similarly, we
prepared allylic substrate (ꢀ)-2-cyclohexenyl boronic acid
pinacolate ester 9.14 Remarkably, the introduction of the single
ð1Þ
Herein we describe our studies into understanding the
chemoselectivity of this reaction, and expanding its scope,
specifically to include secondary allylic boronic esters. This
class of coupling partners has been virtually unknown in the
Suzuki-Miyaura cross coupling reaction.
Department of Chemistry, Queen’s University, 90 Bader Lane,
Kingston, ON, K7L 6N3 Canada.
E-mail: cruddenc@chem.queensu.ca; Fax: (613) 533-6669;
Tel: (613)533-6000 x36755
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc16076e
Fig. 1 Evolution of reactivity in boronic esters with p-iodoacetophenone
z This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
under standard Pd/Ag2O conditions.
c
1230 Chem. Commun., 2012, 48, 1230–1232
This journal is The Royal Society of Chemistry 2012

site of unsaturation resulted in a 58% isolated yield of the
corresponding arylated species.
As recently noted,15 allylic cross-coupling reactions are
remarkably under represented on the cross-coupling landscape.
Although Szabo 16 Yamamoto17 and others18 have shown the
´
,
great versatility of the coupling of achiral primary allylboronates,
virtually no couplings have been carried out with secondary
allylic boronic esters or boranes.19 Indeed there is only one
example of a racemic methallyltrifluoroborate coupling to the
best of our knowledge.17 Thus, we were interested in developing a
general method for the cross-coupling of substituted allylic
boronic esters.
Scheme 1 Regioselectivity in the coupling of allylic organometallics.
However, the use of bidentate phosphines at a 6 : 1 P : Pd ratio
completely inhibited the reaction, consistent with our previous
observations in the case of benzylic derivative 1. Similarly, the
use of Pd(dba)2 alone, without added PPh3, gave no reaction.23
We began with the preparation of several unsymmetrical
boronic esters. A variety of methods were explored for the
synthesis of these potentially sensitive allylic boronic esters. Of
these, Matteson, Ito and Aggarwal-type20 homologations
proved effective for the majority of substrates (eqn (2)–(4)).
In the particular case where R = aryl, the Matteson protocol
proved the most versatile.
0
In addition to the SE mechanism, Szabo
´
has proposed an
addition/elimination mechanism for the cross coupling of
primary allylboronic acids.16 Since this mechanism does not
require transmetalation of the allyl boronate, we also carried
out our coupling in the absence of silver oxide, using Cs2CO3
as the base, but found no reaction. Thus it seems as though
our previously developed conditions, which require the
presence of monodentate triaryl phosphines as virtually the
only effective ligands for Pd, and the use silver oxide to affect
transmetalation, are also critical for the success of the secondary
allylic coupling described herein.
ð2Þ
ð3Þ
Using the aforementioned silver-mediated reaction conditions,
we examined the viability of a variety of secondary allylic boronic
esters as coupling partners (Table 1). The Suzuki-Miyaura cross-
coupling proceeds in good to moderate yield, regardless of the
aryl iodide employed. For propenyl substrates, the reaction
proceeds with ca. 85 (ꢀ5) : 15 (ꢀ5) selectivity for the g-isomer.
However, when the substituent on the boron-bearing carbon was
smaller than that on the olefin (i.e. substrate 10c), an equal
mixture of the two possible isomers was observed. This illustrates
two important features of this reaction. Firstly, that a symme-
trical p-allyl species is not involved, otherwise the same product
distribution would be expected. Secondly, that the regioselec-
tivity seems to be highly sensitive to the sterics involved.
As further evidence of this, substrates 10d and e in which the
olefin is conjugated to an aromatic substituent, undergo
coupling with high a-selectivity (Table 1, entries 8–10). Since
the phenyl substituent has a higher A-value than an n-alkyl
substituent (3 vs. 1.75), it is conceivable that the high
a-selectivity is due to steric differences between the two
substituents, however electronic effects could also be at play
for this substituent. Studies are underway to differentiate these
possibilities.
ð4Þ
With a variety of allylic boronic esters in hand, we attempted
their coupling with p-iodoacetophenone under our standard
conditions (eqn (5)). The reaction proceeded to give the expected
product in good yield, as a mixture of g- and a-arylated products,
favouring the g-isomer by ca. 9:1.
ð5Þ
Although the coupling of this type of nucleophile is unprece-
dented, g-selectivity is regularly observed in the cross coupling of
0
allyl silanes, and is explained by an SE transmetalation reaction
In conclusion, we have provided insight into the chemo-
selectivity of the silver-mediated cross coupling of secondary
boronic esters in terms of substrate specificity and reaction
specificity. We have developed the first protocol for the
regioselective cross-coupling of chiral racemic secondary
allylic boronic esters, with the regioselectivity dictated by the
pattern of olefin substitution. Current efforts are directed
towards the synthesis of enantiomerically enriched and geo-
metrically defined secondary allylic boronic esters and affecting
their enantiospecific cross-coupling. Preliminary results indicate
the reaction proceeds with high levels of stereoretention. These
results will be reported in due course.
followed by a (largely) stereospecific reductive elimination.16–17,21
Leakage into the a-isomer is presumed to occur by s–p
interconversion of the transmetalated intermediate prior to
reductive elimination (Scheme 1). Thus conditions that promote
facile reductive elimination result in higher g-selectivity, in the
case of allylic silanes (Scheme 1).15,22,23
Bidentate phosphines with large bite angles and phosphine-free
catalysts with highly electron deficient dba-type ligands have been
employed to maximize g-selectivity with allylic silanes.15,17,23
Therefore, in an attempt to improve the selectivity for the
g-isomer, we examined the effect of the bidentate phosphine dppb.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1230–1232 1231

Table 1 Selective coupling of allylic boronate estersa
D. Trauner and S. J. Danishefsky, Angew. Chem., Int. Ed., 2001,
40, 4544.
4 D. Imao, B. W. Glasspoole, V. S. Laberge and C. M. Crudden,
J. Am. Chem. Soc., 2009, 131, 5024.
5 T. Ohmura, T. Awano and M. Suginome, J. Am. Chem. Soc., 2010,
132, 13191.
6 D. L. Sandrock, L. Jean-Gerard, C.-Y. Chen, S. D. Dreher and
G. A. Molander, J. Am. Chem. Soc., 2010, 132, 17108.
7 J. C. H. Lee and D. G. Hall, Nat. Chem., 2011, 3, 894.
8 T. Ohmura, T. Awano and M. Suginome, Chem. Lett., 2009,
38, 664.
Entry
Boronic ester
Aryl iodide
Yieldb
g : a
9 The Fu group has made breakthroughs in the coupling of second-
ary aliphatic electrophiles: C. Fischer and G. C. Fu, J. Am. Chem.
Soc., 2005, 127, 4594; S. L. Zultanski and G. C. Fu, J. Am. Chem.
Soc., 2011, 133, 15362.
1
84
87 : 13
10 Cyclopropyl boronic esters undergo stereospecific couplings.
M. Rubina, M. Rubin and V. Gevorgyan, J. Am. Chem. Soc.,
2003, 125, 7198. Symmetrical cyclic boronic esters couple with b-
hydride elimination S. D. Dreher, P. G. Domer, D. L. Sandrock
and G. A. Molander, J. Am. Chem. Soc., 2008, 130, 9257;
A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000,
122, 4020.
11 Racemic 1,1-diarylethanes: (a) A. Lopez-Perez, J. Adrio and
J. C. Carretero, Org. Lett., 2009, 11, 5514; (b) K. Balan Urkalan
and M. S. Sigman, Angew. Chem., Int. Ed., 2009, 48, 3146;
(c) Y. Iwai, K. M. Gligorich and M. S. Sigman, Angew. Chem.,
Int. Ed., 2008, 47, 3219; (d) H.-B. Sun, B. Li, R. Hua and Y. Yin,
Eur. J. Org. Chem., 2006, 4231; (e) M. Rueping, B. J. Nachtsheim
and T. Scheidt, Org. Lett., 2006, 8, 3717; (f) J. Kischel, I. Jovel,
K. Mertins, A. Zapf and M. Beller, Org. Lett., 2006, 8, 19.
12 Enantioenriched diaryl ethanes: (a) T. C. Fessard, S. P. Andrews,
H. Motoyoshi and E. M. Carreira, Angew. Chem., Int. Ed., 2007,
46, 9331; (b) K. Okamoto, Y. Nishibayashi, S. Uemura and
A. Toshimitsu, Angew. Chem., Int. Ed., 2005, 44, 3588;
10a
10a
11a
11b
2
3
83
70
79 : 21
86 : 14
10a
10a
11c
4
72
90 : 10
11d
11a
11c
11a
(c) L. Prat, G. Dupas, J. Duflos, G. Queguiner, J. Bourguignon
´
and V. Levacher, Tetrahedron Lett., 2001, 42, 4515;
(d) J. A. Wilkinson, S. B. Rossington, S. Ducki, J. Leonard and
J. Hussain, Tetrahedron, 2006, 62, 1833; (e) J. A. Wilkinson,
S. B. Rossington, S. Ducki, J. Leonard and J. Hussain,
Tetrahedron: Asymmetry, 2004, 15, 3011; (f) S. M. Podhajsky,
Y. Iwai, A. Cook-Sneathen and M. S. Sigman, Tetrahedron, 2001,
67, 4435; (g) S. Nave, R. P. Sonawane, T. G. Elford and
V. K. Aggarwal, J. Am. Chem. Soc., 2010, 132, 17096.
5
6
7
81
82
65
84 : 16
91 : 9
10b
10b
13 J. Uenishi, J. M. Beau, R. W. Armstrong and Y. Kishi, J. Am.
Chem. Soc., 1987, 109, 4756.
50 : 50
14 G. Dutheuil, N. Selander, K. J. Szabo
Synthesis, 2008, 2293.
´
and V. K. Aggarwal,
10c
10d
15 S. E. Denmark and N. S. Werner, J. Am. Chem. Soc., 2010,
132, 3612.
´
16 S. Sebelius, V. J. Olsson, O. A. Wallner and K. J. Szabo, J. Am.
Chem. Soc., 2006, 128, 8150.
17 Y. Yamamoto, S. Takada, N. Miyaura, T. Iyama and
H. Tachikawa, Organometallics, 2009, 28, 152.
8
9
11a
58
8 : 92
18 K. Nilsson and A. Hallberg, Acta Chem. Scand., Ser. B, 1987,
41, 569.
19 Substituted allyl boranes in p-allyl Pd chemistry: E. F. Flegeau,
U. Schneider and S. Kobayashi, Chem.–Eur. J., 2009, 15, 12247;
P. Zhang, L. A. Brozek and J. P. Morken, J. Am. Chem. Soc., 2010,
132, 10686.
20 (a) D. S. Matteson, Tetrahedron, 1998, 54, 10555; (b) V. K. Aggarwal,
M. Althaus, A. Mahmood, J. R. Suarez and S. P. Thomas, J. Am.
Chem. Soc., 2010, 132, 4025; (c) H. Ito, C. Kawakami and
M. Sawamura, J. Am. Chem. Soc., 2005, 127, 16034.
21 Selectivity is dependent on the type of phosphine used:
Y. Hatanaka, K.-I. Goda and T. Hiyama, Tetrahedron Lett.,
1994, 35, 6511.
22 (a) Y. Hatanaka, K. Goda and T. Hiyama, Tetrahedron Lett.,
1994, 35, 1279; (b) Y. Hatanaka, Y. Ebina and T. Hiyama, J. Am.
Chem. Soc., 1991, 113, 7075.
11a
11c
53
55
19 : 81
16 : 84
10e
10e
10
a
b
For experimental details see supporting information. Isolated
yields after silica gel chromatography.
Notes and references
1 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
(b) N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett.,
1979, 20, 3437.
2 J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
Biomol. Chem., 2006, 4, 2337.
3 (a) Z. Lu and G. C. Fu, Angew. Chem., Int. Ed., 2010, 49, 6676;
(b) H. Doucet, Eur. J. Org. Chem., 2008, 2013; (c) S. R. Chemler,
23 Previous studies showed that excess PPh3 was needed for high
yields.4
c
1232 Chem. Commun., 2012, 48, 1230–1232
This journal is The Royal Society of Chemistry 2012