Efficient formation of benzylic quaternary centers via palladium catalysis

Article abstract of DOI:10.1002/cssc.201300276

Four's a crowd: An efficient protocol for the formation of benzylic quaternary centers via arylation of enones using a catalyst made from Pd(O ₂CCF₃)₂ and 2,2′-bipyridine is developed. For cyclic substrates, catalyst loadi

Full text of DOI:10.1002/cssc.201300276

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DOI: 10.1002/cssc.201300276
Efficient Formation of Benzylic Quaternary Centers via
Palladium Catalysis
Aditya L. Gottumukkala,[a] Jasmin Suljagic,[a] Kiran Matcha,[a] Johannes G. de Vries,*[a, b] and
Adriaan J. Minnaard*[a]
The benzylic quaternary center is a widely prevalent motif[1] in
a multitude of biologically active natural products,[2] drug can-
didates, and fragrances. The challenge of installing these cen-
ters in a straightforward and selective manner continues to re-
ceive much attention in recent literature.[3] Transition-metal
catalysis offers a spectrum of reactions to address this chal-
lenge.[4] In this respect, few reactions have enjoyed the success,
tenability, and reliabilty of conjugate addition reactions to
b,b-disubstituted enones. For this reaction, whilst catalysis by
copper[5] has been successful for the use of reactive organome-
tallics such as Grignard,[6] organozinc,[7] and organoalumini-
um[7,8] reagents, excellent reactivity with soft organometallics
such as boronic acids,[9] borates,[10] and boroxines[11] has been
achieved with rhodium.[12]
pending on their substitution pattern, and essentially all litera-
ture examples are limited to cyclic substrates (Scheme 1).
We adopted the reaction of 3-methyl cyclohexenone (1)
with phenylboronic acid (2; Table 1) as a model for studying
the various reaction parameters . Our initial efforts focused on
the study of N,N’-bis-2,6-xylyl-acenaphthenequinonediimine
(BIAN), a ligand we had previously found to be highly active
for oxidative Heck reactions under mild conditions,[21] and has
been documented to strongly ligate cationic late-transition
metal species. While no reactivity was observed with Pd(OAc)2
(entries 1,2), full conversion was achieved using 5 mol% of
Pd(O2CCF3)2 (entry 6). Disappointingly, the conversion dropped
significantly when the catalyst loading was lowered (entry 7),
warranting a search for another catalyst providing high conver-
sions at low catalyst loadings. We were delighted to find that
full conversion was obtained with 1 mol% of Pd(O2CCF3)2 and
1.5 mol% of 2,2’-bipyridine, when the reaction was performed
at 608C (entry 10). Performing the reaction at lower tempera-
ture, or with an increased proportion of water, resulted in
a lower conversion (entry 11, 12). Substituting phenylboronic
acid by potassium phenyltrifluoroborate (4, entry 13), potassi-
um trihydroxyphenylborate (6, entry 14) or phenyl N-methyl-
iminodiacetic acid MIDA boronate (7, entry 15) did not lead to
product formation.
As a complementary strategy, benzylic quaternary center for-
mation using boronic acids via palladium catalysis would be an
important addition to the toolbox of the synthetic chemist, es-
pecially in view of scale-up. Following a pioneering disclosure
by Lin and Lu,[13] this area has witnessed a flurry of investiga-
tions, such as the development of asymmetric versions by
Stoltz et al.[14] and ourselves,[15] the application of boroxines for
diastereoselective conjugate additions to substituted
enones,[16] desulfitative couplings of aryl sulfinic acids,[17] g-ary-
lation of a,b-unsaturated aldehydes,[18] in addition to a thor-
ough study of the mechanism by computational chemistry.[19]
Arylboronic acids[20] have emerged as the reagents of choice
for the introduction of aryl moieties by transition-metal cataly-
sis, especially owing to their commercial availability, easy
handling under ambient conditions, and functional-group
compatibility. Thus, a practical strategy that affords benzylic
quaternary centers employing arylboronic acids, with accept-
able palladium loadings would be highly beneficial. This would
alleviate the need to dehydrate boronic acids to boroxines or
use forcing and strongly acidic conditions to allow loss of SO2,
as in the desulfitative reactions. Furthermore, no studies have
documented trends in reactivity of enones or boronic acids de-
With the optimized conditions [1 mol% Pd(O2CCF3)2,
1.5 mol% 2,2-bipyridine, 608C, MeOH:H2O (9:1)] at hand, we
went on to explore the scope and limitations of the reaction
with a series of cyclic substrates. We were pleased to note that
isolated yields exceeding 90% were observed for most of the
products resulting from 3-methyl-cyclohexenone and 3-methyl
cyclopentenone (Scheme 1). 3-Methyl-cycloheptenone afforded
9 in 80% yield. When comparing the reactions of 3-methyl-
cylopentenone and 3-methyl-cyclohexenone with identical ar-
ylboronic acids, products resulting from the 5-membered ring
substrate usually formed in a higher yield, and the reactions
proceeded faster (Scheme 1; 3–3i and 8a–8g). This may be
due to the larger release of ring strain from a 5-membered
cyclic enone as compared to a 6-membered cyclic enone,
upon conjugate addition. Nonetheless, substrates 10 and 11
bearing bulky substituents were found to be unreactive under
these reaction conditions. This was recently explained by Houk
et al.,[19] who calculated that this reaction faces a large barrier
for the insertion step, if bulky substituents are present at the
b-position. Compared to the catalyst system of Lu et al., our
system employs the same Pd loading (1 mol% Pd), but allevi-
ates the low-yielding route to preform the cationic hydroxo-
complex.[13] Compared to the system of Lee et al., our protocol
employs 5-fold lower loading in Pd.[16]
[a] Dr. A. L. Gottumukkala, J. Suljagic, Dr. K. Matcha, Prof. Dr. J. G. de Vries,
Prof. Dr. A. J. Minnaard
Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 7, 9747 AG, Groningen (The Netherlands)
E-mail: a.j.minnaard@rug.nl
[b] Prof. Dr. J. G. de Vries
DSM Innovative Synthesis BV
P.O. Box 18, 6160 MD, Geleen (The Netherlands)
E-mail: hans-jg.vries-de@dsm.com
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201300276.
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fluoroantimonate (KSbF6) to the reaction afforded full
conversion (entry 4). The choice of KSbF6 was based
on our previous studies on the enantioselective con-
jugate addition to cyclic enones[15] in which the use
À
of SbF6 as a counter-ion for the cationic Pd complex
resulted in improved yield and selectivity. Therefore,
we surmised that adding KSbF6 to the current reac-
tion system could have a similar influence, and this
was indeed found to be the case. The improved ac-
À
tivity upon the addition of SbF6 may be attributed
to a salt metathesis between the trifluoroacetate
À
(CF3CO2À) ion and SbF6 leading to catalytically more
active species.[23] Alternatively, decomposition of the
anion would provide fluoride that can activate the ar-
ylboronic acid for transmetallation. However, lower-
ing the catalyst loading to 1 mol% in the presence of
the additive, gave diminished conversions (entry 5),
though still higher than in the case where no addi-
tive was present (entry 5 vs. entry 1). Hence it was
decided to use 5 mol% of Pd for subsequent
experiments.
Scheme 2 represents a study of the scope and limi-
tations of the reaction with acyclic substrates. Phenyl-
boronic acid afforded 13 in 72% yield, while p-tolyl-
boronic acid gave 13b in 75% yield. p-Fluorophenyl-
boronic acid gave 13c in 70% yield. In general, bor-
onic acids bearing alkoxy functionalities performed
well in the reaction. Compounds 13d–13h were all
obtained in yields between 72–78%. Substrate E-14,
bearing a benzyl moiety was also found to be appli-
cable in conjugate addition under the optimized re-
action conditions. Phenylboronic acid and m-tolylbor-
onic acid afforded 15a and 15b in 74% and 90%
yield, respectively. Substrate Z-14 also afforded 15a,
albeit in a slightly reduced yield of 68%. In order to
ascertain whether the observed success of substrates
12 and 14 was due to the coordination of the allylic
oxygen atom to the metal center during the catalysis,
and additionally to test the amenability of a nitro-
gen-containing substituent in the reaction, substrate 16 was
designed. However, this substrate was found to be unreactive.
Thus it remains unclear whether the observed influence of the
allylic oxygen on the reaction is due to a coordination of the
substrate to the metal or due to an electronic influence.
In summary, we report a simple and highly active catalyst
system for the formation of benzylic quaternary centers from
arylboronic acids and b-disubstituted enones. For cyclic sub-
strates, only 1 mol% of palladium is required for full conver-
sion, and a variety of arylboronic acids could be reacted with
yields exceeding 90%. 5-Membered cyclic enones were found
to be most reactive, followed by 6-membered rings and then
7-membered rings. This trend may be explained by the release
of ring strain upon conjugate addition. Among the arylboronic
acids studied, in general, electron-rich boronic acids provided
the highest yields. In the case of acyclic substrates 5 mol% Pd
was found to be necessary, along with the addition of
20 mol% KSbF6 to afford the highest conversion, along with
Scheme 1. Conjugate addition of arylboronic acids to cyclic enones.
Following the success of the cyclic substrates, we proceeded
to investigate whether acyclic substrates could undergo aryla-
tion using this catalytic system. In practice, reaction conditions
for the conjugate addition to acyclic substrates are usually con-
siderably different from those of cyclic substrates. This could
originate from the presence of different conformations in acy-
clic substrates.[5,22] In addition, release of (ring) strain as in
cyclic substrates is absent.
Based on earlier studies from our group,[15] in which we re-
ported that the presence of an allylic oxygen moiety was criti-
cal for the success of the reaction, we chose to evaluate the re-
action using 12 as test substrate (Table 2). The use of the opti-
mized conditions for cyclic substrates only led to 20% conver-
sion after 36 h (entry 1). Increasing the catalyst loading to
5 mol% led to an improved conversion, though it remained in-
complete, even at higher temperature (entries 2 and 3). At this
point, we considered the use of additives to improve the con-
version. We found that adding 20 mol% of potassium hexa-
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a
higher temperature (808C).
Table 1. Reaction of 3-methyl cyclohexenone with phenylboronic acid.[a]
Both and alkenes were
E
Z
found to react under the reac-
tion conditions described.
Experimental Section
Conjugate addition to cyclic enones:
To a Schlenk tube equipped with
Entry
Pd catalyst
Amount
[mol%]
Ligand
Amount
[mol%]
Solvent
T
[8C]
Conv.[b]
[%]
a
magnetic stirring bar and
a septum was added palladium tri-
fluoroacetate (3.3 mg, 1 mol%,
0.01 mmol), and 2,2’-bipyridine
(2.34 mg, 1.5 mol%, 0.015 mmol).
The Schlenk tube was capped and
alternated through 3 cycles of
vacuum and dinitrogen. The mix-
ture was dissolved in 2 mL of a so-
lution of MeOH/H2O (9:1) and the
tube was placed in a preheated oil
bath at 608C and allowed to stir
for 15 min. The tube was removed
from the oil bath, cooled to RT, fol-
lowed by the addition of the
enone (1 mmol, 1.0 equiv) via sy-
ringe or pipette and the boronic
acid (2 mmol, 2 equiv), in one por-
tion. The septum was replaced by
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
14[e]
15[f]
Pd(OAc)2
Pd(OAc)2
5
5
5
5
5
5
1
5
5
1
1
1
1
1
1
BIAN
BIAN
BIAN
BIAN
BIAN
BIAN
BIAN
dmphen
bipy
bipy
bipy
bipy
bipy
bipy
7
7
7
7
7
7
1.5
7
7
1.5
1.5
1.5
1.5
1.5
1.5
MeOH/H2O
MeOH/H2O
MeOH
RT
40
RT
RT
RT
60
60
60
60
60
RT
60
60
60
60
0
0
Pd(MeCN)4(BF4)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
14
33
43
full
35
–
full
full
32
40
0
MeOH
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O[c]
MeOH/H2O
MeOH/H2O
MeOH/H2O
0
0
bipy
[a] 3-Methyl cyclohexenone (0.5 mmol), phenylboronic acid (1 mmol), Pd precursor, ligand, solvent [MeOH/H2O
(9:1) or MeOH] 1 mL, 12 h. [b] Conversion determined by GC analysis. [c] MeOH/H2O (4:1). [d] 4 used instead of
2. [e] 5 used instead of 2. [f] 6 used instead of 2.
Table 2. Evaluation of the reaction parameters for acyclic substrates.[a]
Entry Pd catalyst Amount Ligand
[mol%]
Amount Additive
[mol%]
T
Conv.[b]
[8C] [%]
1
2
3
4
5
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
1
3
5
5
1
BIAN
dmphen
bipy
bipy
bipy
1.5
5
7
7
1.5
–
–
–
60
80
80
80 full
80 45
20
38
63
KSbF6
KSbF6
[a] 12 (0.25 mmol), phenylboronic acid (0.5 mmol), Pd(O2CCF3)2, ligand,
MeOH/H2O (9:1) 1 mL, 12 h. Conversion determined by GC analysis.
a screw cap. Upon complete consumption of the enone (moni-
tored by TLC/GC), the reaction mixture was allowed to cool to RT
and filtered through a pad of silica. The filtrate was dried over
MgSO4, concentrated in vacuo, and adsorbed onto silica before
being loaded on a silica-gel column. Elution with a mixture of
n-pentane/ether afforded the corresponding product.
Conjugate addition to acyclic enones: To a Schlenk tube equipped
with a magnetic stirring bar and a septum was added palladium
trifluoroacetate (8.3 mg, 5 mol%, 0.05 mmol), 2,2’-bipyridine
(11 mg, 7 mol%) and KSbF6 (27.5 mg, 20 mol%, 0.2 equiv). The
Schlenk tube was capped and alternated through 3 cycles of
vacuum and dinitrogen. The mixture was dissolved in 2 mL of a so-
lution of MeOH/H2O (9:1). The tube was placed in a preheated oil
bath at 808C and allowed to stir for 15 min. The tube was removed
from the oil bath, cooled to RT, followed by the addition of the
enone (0.5 mmol, 1.0 equiv) via syringe or pipette and the boronic
Scheme 2. Substrate scope for conjugate addition to acyclic enones.
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being loaded on a silica-gel column. Elution with a mixture of
n-pentane/ether afforded the corresponding product.
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Acknowledgements
This research was performed within the framework of the Catch-
Bio Program (053.70.206). The authors gratefully acknowledge
support from the SmartMix Program of the Netherlands Ministry
of Economic Affairs and the Netherlands Ministry of Education,
Culture and Science. J.S. is thankful to the European Union for an
Erasmus Fellowship.
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Received: March 28, 2013
Published online on July 2, 2013
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