Aerobic alcohol oxidation coupled to palladium-catalyzed alkene hydroarylation with boronic esters

Article abstract of DOI:10.1002/anie.200705317

(Chemical Equation Presented) An oxidation exercise: An aerobic alcohol oxidation coupled with a regioselective palladium-catalyzed reductive functionalization of styrenes and arylboronic esters has been developed (see scheme). The mechanism is thought to proceed by initial oxidation of the solvent to generate a Pd^II-hydride species, which subsequently reacts with the alkene and arylboronic ester to ultimately generate a new C-C bond.

Full text of DOI:10.1002/anie.200705317

Angewandte
Chemie
DOI: 10.1002/anie.200705317
Palladium Catalysis
Aerobic Alcohol Oxidation Coupled to Palladium-Catalyzed Alkene
Hydroarylation with Boronic Esters**
Yasumasa Iwai, Keith M. Gligorich, and Matthew S. Sigman*
The Suzuki reaction, which couples an organohalide and an
organoboron compound,[1] is an attractive cross-coupling
reaction for use in the synthesis of natural products[2] and
pharmaceuticals.[3] This utility is mainly because of the
excellent functional group compatibility, ease of preparation
of boronic acid derivatives, and the low toxicity of the boron
byproducts.[2] The mechanistic details have been widely
investigated and the reaction is thought to proceed through
0
À
oxidative addition of the organohalide (R X) to Pd to form
II
1
À
R–Pd –X and then transmetalation of the organoborane (R
B(OR)2).[1] The resulting R–PdII–R1 intermediate undergoes
reductive elimination to form the product.An exogenous
base is required to activate the boronic acid derivative for
transmetalation, which is proposed to occur through a four-
centered transition state (intermediate C, Scheme 1a).[4]
Our group has been developing an alterative route to
generate the requisite R–PdII–X intermediate by using an
alkene as a synthon for an alkylhalide.To this end, we have
recently reported the coupling of an alcohol oxidation to the
functionalization of an alkene.[5] Specifically, styrene deriva-
tives and organostannanes undergo a Pd-catalyzed reductive
cross-coupling reaction in isopropyl alcohol (IPA) under an
aerobic atmosphere to yield hydroarylation product 3a in
76% yield (Scheme 1b).The proposed mechanism proceeds
by initial oxidation of the alcoholic solvent to generate PdII-
hydride E, which reacts with the alkene to yield Pd-alkyl F
Scheme 1. a) Base facilitated transmetalation with boronic esters.
b) Reductive coupling with organostannanes. c) Mechanistic hypothe-
sis.
(Scheme 1c).The addition of a base can also promote a
base-mediated reductive elimination of the proposed PdII-
hydride intermediate (E) to form Pd0.[8] Herein, we report the
development of a catalyst system for the reductive coupling of
arylboronic esters and styrenes, and studies that highlight the
mechanistic complexity of the reaction.
(Scheme 1c).Subsequent transmetalation forms
G and
reductive elimination yields the reductive coupling product
and Pd0 (H), which is oxidized by O2 to regenerate the active
catalyst (D).[6] As discussed above, boronic acids offer
significant practical advantages in cross-coupling reactions
with respect to organostannane compounds.[1] However, the
development of a reductive coupling of alkenes with boronic
acid derivatives was thought to be a significant challenge
compared to the use of organostannanes because the strong
exogenous base needed to facilitate transmetalation[4] will
simultaneously affect the rate of the alcohol oxidation[7]
By using the reaction conditions developed for the Pd-
catalyzed reductive coupling with organostannanes[5] and the
commercially available boronic acid (PhB(OH)2) the desired
hydroarylation product (3a) was observed in 11% yield (GC)
as a greater than 25:1 ratio of regioisomers (Table 1,
entry 1).[9] However, we observed catalyst decomposition
and competitive initial transmetalation, which generates the
oxidative Heck product (4).[10] The poor stability of [Pd{(À)-
sparteine}Cl2] under these conditions prompted us to identify
a more robust catalyst system.Previously, our group demon-
strated that Pd complexes with N-heterocyclic carbene
(NHC) ligands are excellent catalysts for alcohol oxidation
in which high turnover numbers are achieved at low concen-
trations of O2.[11] Also, Pd(NHC) complexes have been widely
employed in a variety of cross-coupling reactions.[12] Thus,
[{Pd(IiPr)Cl2}2] was evaluated by using (À)-sparteine (sp) as
an exogenous base and an improved ratio of hydroarylation to
Heck reaction was observed with only a 63% conversion of
the substrate (Table 1, entry 2).Stronger bases are often used
in Suzuki reactions,[4] prompting us to evaluate the addition of
tBuOK, which led to additional improvement in the ratio of
[*] Y. Iwai, K. M. Gligorich, Prof. M. S. Sigman
Department of Chemistry, University of Utah
315 South 1400 East, Salt Lake City, UT 84112 (USA)
Fax: (+1)801-581-8433
E-mail: sigman@chem.utah.edu
[**] This work was supported by the National Institutes of Health (Grant
NIGMS RO1 GM3540). M.S.S. thanks the Dreyfus Foundation
(Teacher-Scholar) and Pfizer for their support. Y.I. thanks Kyorin Co.,
Ltd. for financial support. K.M.G. thanks Sanofi-Aventis for a
graduate research fellowship. We are grateful to Johnson Matthey
for the gift of various Pd salts.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 3219 –3222
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3219

Communications
Table 1: Optimization for the reductive coupling product with boronic
esters/acids.
(Table 1, entry 8).Additional optimization of the reaction
conditions, including an increase to three equivalents of EG,
produces 3a in 91% yield (GC) with [{Pd(SiPr)Cl2}2] as the
catalyst; these conditions were found to be the optimal
conditions for the transformation (Table 1, entry 9).[{Pd-
(IiPr)Cl2}2] is also a proficient catalyst under these conditions
yielding 3a in 89% yield (GC) (Table 1, entry 10).Interest-
ingly, under these conditions [Pd{sp}Cl2] is also an effective
catalyst (Table 1, entry 11).Finally, the reaction was per-
formed under the optimal conditions without sp, leading to
rapid Pd0 metal precipitation with only 2% conversion of 1a
(Table 1, entry 12).In contrast, performing the reaction
without tBuOK leads to a 78% yield (GC) of 3a, suggesting
that the combination of both sp and tBuOK is required to
achieve excellent catalysis (Table 1, entry 13).However, the
use of more tBuOK led to diminished yields of 3a.[16]
Diaryl methine units are prevalent in biologically active
small molecules and this method should allow the rapid highly
regioselective synthesis of this functionality.[13] To explore the
scope of the reductive coupling of boronic esters and styrenes
we utilized the optimized conditions to synthesize a variety of
diaryl methine-containing products (Table 2).All of the
reductive coupling reactions are highly regioselective
(> 25:1), and the reactions of simple coupling partners give
high yields (78–91%) of isolated diaryl methine-containing
products (Table 2, entries 1–3).The results demonstrate that
substrates containing acid-sensitive functional groups are
stable to the reductive coupling reaction conditions;[14] for
example, acetal protecting groups, which are readily removed
upon work up, are compatible with the reaction conditions
(Table 2, entries 5–7).Arylboronic esters containing electron-
donating groups react more slowly, thereby requiring a higher
catalyst loading (Table 2, entries 8 and 9), and ortho substi-
tution on the arylboronic acid is tolerated (Table 1, entry 10).
The ester functionality is also compatible, however an
increase in [sp] is required to achieve a 63% yield of 3k
(Table 2, entry 11).On the basis of our previous mechanistic
hypothesis that the formation of a p-benzyl intermediate is
responsible for the outstanding regioselectivity,[5,15] a diene
substrate, which can form a similar p-allyl species, was
evaluated and yielded the reductive coupling product 3l in
41% yield as a greater than 25:1 mixture of regioisomers
(Table 2, entry 12).Under these conditions both vinylboronic
esters and simple alkenes, which rapidly isomerize, do not
undergo an effective reductive coupling reaction.Even
though a chiral additive (sp) is used, less than 5% ee is
observed for the product.[16]
Entry Ligand PhB(OR)2 Base (mol%)
(equiv)
Conv. [%][a] 3a [%][b]
(t [h])
(3a:4)[c]
1[d] sp
BA (1.3) sp (40)
BA (1.3) sp (20)
BA (1.3) sp (20), tBuOK
(5)
35 (24) 11 (1.4:1)
63 (24) 13 (3.2:1)
2
3
IiPr
IiPr
18 (24)
8 (6.4:1)
4
5
IiPr
IiPr
PE (1.3) sp (5), tBuOK (5)
PE (2.5) sp (7.5), tBuOK
(7.5)
99 (24) 30 (2.7:1)
>99 (24) 64 (17:1)
6
7
8
IiPr
EG (2.5) sp (7.5), tBuOK
(7.5)
EG (2.5) sp (7.5), tBuOK
(7.5)
PD (2.5) sp (7.5), tBuOK
(7.5)
>99 (4)
>99 (8)
49 (27:1)
SiPr
SiPr
68 (>30:1)
46 (24) 32 (>30:1)
9[e] SiPr
10[e] IiPr
11[f] sp
EG (3)
EG (3)
EG (3)
EG (3)
EG (3)
sp (6), tBuOK(6) >99 (24) 91 (>30:1)
sp (6), tBuOK(6) >99 (24) 89 (>30:1)
sp (6), tBuOK(6) >99 (24) 89 (>30:1)
tBuOK (6)
sp (6)
12[e] SiPr
13[e] SiPr
2 (24)
>99 (24) 78 (23:1)
1 (4.3:1)
[a] Percent conversion determined with GC methods by using an internal
standard. [b] Yield determined by GC methods. [c] Ratio of yields
determined by GC methods. [d] 2.5 mol% [Pd(sp)Cl2]. [e] 0.75 mol%
[{Pd(Ligand)Cl2}2] and 558C. [f] 1.5 mol% [Pd(sp)Cl2] and 558C.
3a to 4.The low conversion of these reactions may arise from
PhB(OH)2 inhibiting the catalysis; exogenous acid can
decrease the rate of alcohol oxidation.[7] Therefore, the
pinacol-derived phenylboronic ester (PE) was submitted to
the reaction conditions with both sp and tBuOK, which led to
a 30% yield (GC) of 3a (Table 1, entry 4).The reaction was
monitored by GC methods and PE was fully consumed before
the reaction of the olefin was complete, suggesting that
remaining 1a undergoes an undesired reaction that does not
involve the boronic ester.On the basis of this hypothesis the
amount of PE was increased to 2.5 equivalents to produce 3a
in 64% yield (GC) with a 17:1 ratio of 3a to 4 (Table 1,
entry 5).
To further the optimize the reaction, ethylene glycol-
derived boronic ester EG, which was expected to undergo
faster transmetalation because of its smaller size, was
submitted to the reaction conditions and a 49% yield (GC)
of 3a was measured after 4 hours (Table 1, entry 6).Evaluat-
ing other NHC ligands revealed that the combination of SiPr
and EG produces 3a in 68% yield within 8 hours (Table 1,
entry 7).Interestingly, when propanediol-derived boronic
ester PD was used under the same reaction conditions a
32% yield of 3a was observed, demonstrating the sensitivity
of the transformation to the nature of the boronic ester
There were three mechanistic questions that we wanted to
address: 1) What is the efficiency of alcohol oxidation
compared to product formation? 2) Why are 3 equivalents
of the arylboronic ester required for good product yields? and
3) Why is exogenous sp required for catalysis? To investigate
the first question, a higher molecular weight alcohol (sec-
BuOH) was used as the solvent to enable GC analysis to
effectively measure the amount of ketone being formed by
alcohol oxidation.A time course analysis of the reaction was
performed and the yields (GC) of the hydroarylation product
3a and butan-2-one (5), as well as the percent of styrene 1a
remaining, were plotted as a function of time (Figure 1a).[16]
3220 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3219 –3222

Angewandte
Chemie
Table 2: Substrate scope of the reductive coupling reaction with boronic
esters.
Entry
1
R2
Product
Yield [%][a]
81
2
3
91
78
4
90
5[b]
77
68
6[b]
7[b]
71
8[c]
58
65
Figure 1. a) The amount of butan-2-one and hydroarylation product
generated compared to styrene consumed over time; measured by GC
9[c]
&
methods based upon 1 equiv of 1a: =4-methylstyrene (1a),
~
*
=hydroarylation (3a), =butan-2-one (5). b) The quantity of bor-
10[c]
68
onic ester consumed compared to phenol, hydroarylation product, and
!
biphenyl (6) produced over time: =boronic ester (2a), ”=phenol
*
(7), =hydroarylation (3a), =biphenyl.
11[d]
12
63
41
The yield (GC) of 3a was 78% in sec-BuOH compared to
91% in IPA, indicating a modest solvent dependence.
To investigate why 3 equivalents of 2a are required, the
fate of the boronic ester was observed as the reaction
progressed (Figure 1b).More than one equivalent of 2a was
consumed within 30 minutes and then a relatively linear
decrease in concentration was observed (the scatter can be
attributed to hydrolysis of 2a on silica gel before GC
analysis).In addition to hydroarylation product 3a, two
major byproducts, biphenyl (6) and phenol (7), were
observed.A 10% yield (GC) of biphenyl, the product of
oxidative boronic acid homocoupling,[17] is formed within
2 hours, but a 14% yield of biphenyl (ca.02.8 equiv of 2a
consumed) is observed overall.Phenol is the major byproduct
that is formed consistently throughout the reaction (ca.
1.3 equiv of 2a consumed); it is likely to be formed from
the reaction of the boronic ester with H2O2 produced from the
reduction of O2 during catalyst regeneration.[10b,18] Together
these data account for the undesired pathways that consume
the excess arylboronic ester required.
[a] Average yield of isolated product for two experiments performed on
0.5-mmol scale. [b] Treated with p-toluenesulfonic acid in acetone/H2O
upon work up. [c] 1.5 mol% [{Pd(SiPr)Cl2}2] and 658C. [d] 15 mol% sp.
Initially, the yield of 3a and 5 are equivalent until approx-
imately 60% conversion; this is consistent with the oxidation
of one alcohol directly yielding product, and suggests that the
PdII-hydride species formed by alcohol oxidation reacts with
the alkene faster than it reductively eliminates.[8] In contrast,
as the reaction progresses to higher substrate conversion, the
yield of 5 increases at a rate that differs from that of product
formation.This difference implies that as the concentration of
the alkene decreases, the PdII-hydride species can undergo
other competitive reactions, including reductive elimination.
Angew. Chem. Int. Ed. 2008, 47, 3219 –3222
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3221

Communications
The final mechanistic question addressed the role(s) of sp
Keywords: cross-coupling · homogeneous catalysis ·
molecular oxygen · palladium · reaction mechanisms
.
since performing the reaction without exogenous sp leads to
poor catalysis.Several functions of sp can be envisioned,
including performing as a ligand to stabilize Pd0 during
catalyst regeneration, acting as a ligand on PdII during the
reductive coupling process, or breaking up the dimeric
[{Pd(SiPr)Cl2}2] complex.The first two roles are difficult to
probe directly, however, an experiment was performed to
investigate the feasibility of sp breaking up the dimer
complex.The experiment involved dissolving [{Pd( SiPr)Cl2}2]
and 2 equivalents of sp in 1,2-dichloroethane (DCE) and
heating the resulting mixture to reflux for 2 hours (Figure 2).
[1] J.Tsuji, Palladium Reagents and Catalysts, Wiley, Hoboken, NJ,
2004, pp.288 – 313.
[2] a) S.Kotha, K.Lahiri, D.Kashinath, Tetrahedron2002, 58, 9633 –
9695; b) K.C.Nicolaou, P.G.Bulger, D.Sarlah,
Angew. Chem.
2005, 117, 4516 – 4563; Angew. Chem. Int. Ed. 2005, 44, 4442 –
4489.
[3] N.Yasuda, J. Organomet. Chem. 2002, 653, 279 – 287.
[4] a) S.R.Chemler, D.Trauner, S.J.Danishefsky,
Angew. Chem.
2001, 113, 4676 – 4701; Angew. Chem. Int. Ed. 2001, 40, 4544 –
4568; b) N.Miyaura, J. Organomet. Chem. 2002, 653, 54 – 57.
[5] K.M.Gligorich, S.A.Cummings, M.S.Sigman,
J. Am. Chem.
Soc. 2007, 129, 14193 – 14195.
[6] a) S.S. Stahl, Angew. Chem. 2004, 116, 3480 – 3501; Angew.
Chem. Int. Ed. 2004, 43, 3400 – 3420; b) K.M.Gligorich, M.S.
Sigman, Angew. Chem. 2006, 118, 6764 – 6767; Angew. Chem. Int.
Ed. 2006, 45, 6612 – 6615.
[7] M.S.Sigman, D.R.Jensen, Acc. Chem. Res. 2006, 39, 221 – 229.
[8] I.D.Hills, G.C.Fu, J. Am. Chem. Soc. 2004, 126, 13178 – 13179.
[9] For a Rh-catalyzed hydroarylation reaction of vinyl pyridine
with an arylboronic acid, see: a) M.Lautens, A.Roy, K.
Figure 2. Reaction of [{Pd(SiPr)Cl2}2] and sp yields complex 8
[(MH)+ =801.36] characterized by ESI-MS methods.[16]
Fukuoka, K.Fagnou, B.Martin-Matute,
J. Am. Chem. Soc.
2001, 123, 5358 – 5359.For examples of Pd-catalyzed hydro-
arylations of Michael acceptors with organoboranes, see: b) T.
Nishikata, Y.Yamamoto, N.Miyaura, Organometallics 2004, 23,
4317 – 4324; c) S.C.Pellegrinet, J.M.Goodman, J. Am. Chem.
Soc. 2006, 128, 3116 – 3117.
An aliquot of the mixture was analyzed by ESI-MS methods.
Excitingly, the major Pd complex observed in solution
corresponds to [Pd(SiPr)(sp)Cl2] [m/z (MH)+ = 801.3]. On
the basis of the trans geometry of related [Pd(NHC)-
(pyridine)Cl2] complexes,[19] we propose that complex 8 is
formed and that the NHC ligand is trans to the monodendate
sp ligand.Unfortunately, attempts to isolate complex 8 only
led to the [{Pd(SiPr)Cl2}2] complex and free sp, suggesting
that complex 8 is in equilibrium with the dimer.Notably,
[Pd{sp}Cl2] is not observed by ESI-MS methods.Other simple
amine bases do not lead to an effective catalytic system for
reductive coupling,[16] possibly because the large size of sp
facilitates ligand dissociation or the free nitrogen center of sp
acts as an intramolecular base.[7]
[10] a) For an example of an oxidative Heck reaction with an
arylboronic acid, see: M.M.S. Andappan, P. Nilsson, H. Von
Schenck, M.Larhed, J. Org. Chem. 2004, 69, 5212 – 5218; b) For
a recent mechanistic study of the oxidative Heck reaction, see:
P-.A.Enquist, P.Nilsson, P.Sjoberg, M.Larhed,
J. Org. Chem.
2006, 71, 8779 – 8786.
[11] D.R.Jensen, M.J.Schultz, J.A.Mueller, M.S.Sigman,
Angew.
Chem. 2003, 115, 3940 – 3943; Angew. Chem. Int. Ed. 2003, 42,
3810 – 3813.
[12] a) M.S.Viciu, S.P.Nolan in Topics in Organometallic Chemistry,
Vol. 14, Springer, Berlin, 2005, pp.241 – 278; b) N.M.Scott, S.P.
Nolan in N-Heterocyclic Carbenes in Synthesis (Ed.: S. P. Nolan),
Wiley-VCH, Weinheim, 2006, pp.55 – 72; c) E.A.B.Kantchev,
In conclusion, we have developed a catalyst system for a
highly regioselective reductive coupling of arylboronic esters
and styrenes under aerobic conditions to yield a variety of
diaryl methine-containing products.The proposed mecha-
C.J.OꢀBrien, M.G.Organ,
Angew. Chem. 2007, 119, 2824 –
2870; Angew. Chem. Int. Ed. 2007, 46, 2768 – 2813.
[13] J.Kischel, I.Jovel, K.Mertins, A.Zapf, M.Beller,
2006, 8, 19 – 22.
Org. Lett.
À
nism couples an alcohol oxidation with C C bond formation,
[14] Acid sensitive functional groups are not compatible with
previously reported Lewis acid catalyzed hydroarylation reac-
tions of alkenes.For an example, see: M.Rueping, BJ..
Nachtsheim, T.Scheidt, Org. Lett. 2006, 8, 3717 – 3719.
in which an alkene can be thought of as an alkyl halide that is
used in classic cross-coupling reactions.Careful analysis of the
reaction progress reveals that excess arylboronic ester is
required for effective catalysis because there is some oxida-
tion of the boronic ester, by H2O2 from O2 reduction, to
generate phenol as the major by-product.Also, the require-
ment of two bases, sp and tBuOK, was explored and revealed
that sp may promote the formation of a monomeric catalyst.
Future efforts will be focused upon expanding the scope of
this new transformation, exploring new Pd-catalyzed reduc-
tive coupling processes integrated with alcohol oxidation, and
extending the method to include asymmetric catalytic var-
iants.
[15] A.M. Johns, M. Utsunomiya, C.D. Incarvito, J.F. Hartwig,
Am. Chem. Soc. 2006, 128, 1828 – 1839.
J.
[16] See the Supporting Information for details.
[17] For examples of Pd-catalyzed oxidative homocoupling of
boronic acids, see: a) D.J. Koza, E. Carita, Synthesis 2002,
2183 – 2186; b) H.Yoshida, Y.Yamaryo, J.Ohshita, A.Kunai,
Tetrahedron Lett. 2003, 44, 1541 – 1544; c) C.Adamo, C.
Amatore, I.Ciofini, A.Jutand, H.Lakmini, J. Am. Chem. Soc.
2006, 128, 6829 – 6836.
[18] a) C.Adamo, C.Amatore, I.Ciofini, A.Jutand, H.Lakmini,
J.
Am. Chem. Soc. 2006, 128, 6829 – 6836; b) K.S.Yoo, C.P.Park,
C.H.Yoon, S.Sakaguchi, J.OꢀNeill, K.W.Jung,
Org. Lett. 2007,
9, 3933 – 3935.
[19] C.J.OꢀBrien, E.A.B.Kantchev, C.Valente, N.Hadei, G.A.
Received: November 19, 2007
Revised: January 15, 2008
Published online: March 17, 2008
Chass, A.Lough, A.C.Hopkinson, M.G.Organ,
Chem. Eur. J.
2006, 12, 4743 – 4748.
3222
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3219 –3222