Palladium-catalyzed asymmetric conjugate addition of arylboronic acids to heterocyclic acceptors

Article abstract of DOI:10.1002/chem.201203643

Flava Flavanone: Asymmetric conjugate additions to chromones and 4-quinolones are reported utilizing a single catalyst system formed in situ from Pd(OCOCF₃)₂ and (S)-tBuPyOX. Notably, these reactions are performed in wet solvent under ambient atmosphere, and employ readily available arylboronic acids as the nucleophile, thus providing ready access to these asymmetric heterocycles (see scheme).

Full text of DOI:10.1002/chem.201203643

DOI: 10.1002/chem.201203643
Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids
to Heterocyclic Acceptors
Jeffrey C. Holder, Alexander N. Marziale, Michele Gatti, Bin Mao, and
Brian M. Stoltz*[a]
Palladium-catalyzed asymmetric conjugate additions are
an increasingly versatile class of enantioselective reactions
that allow stereoselective alkylation and arylation of a,b-un-
saturated conjugate acceptors.[1] These processes often uti-
lize easily-handled, air- and water-stable boron nucleophiles
that render these reactions highly tolerant of oxygen and
moisture.[2] Recently, our group disclosed the asymmetric
conjugate addition of arylboronic acids to cyclic enones fa-
cilitated by a palladium catalyst derived in situ from palla-
dium(II) trifluoroacetate and a chiral pyridinooxazoline
(PyOX) ligand (5).[3] Notably, our catalyst system was gener-
ally applicable for five-, six-, and seven-membered carbocy-
clic enones. The numerous advantages of this system encour-
aged us to seek application to heterocyclic molecules to
demonstrate the broad utility of this reaction for the synthe-
sis of pharmaceutically relevant molecules. Herein, we
report the first general enantioselective conjugate addition
of arylboronic acids to heterocyclic conjugate acceptors de-
rived from chromones and 4-quinolones utilizing the Pd/
PyOX catalyst system. These reactions are performed under
an atmosphere of air and deliver a large variety of asymmet-
ric products with high enantioselectivity in moderate to ex-
cellent yields. The stereoselective conversion of chromones
through conjugate addition renders access to flavanones, a
class of heterocyclic molecules that has demonstrated nu-
merous medicinal properties.[4] Recent literature suggests
that intramolecular oxa-Michael additions are among the
best-studied synthetic methods for asymmetric flavanone
synthesis.[5] However, examples for the retrosynthetic dis-
connection of flavanones by conjugate addition of an aryl
moiety to a chromone derivative remain scarce.[6,7] While
chromones have been successfully employed in rhodium-cat-
alyzed conjugate addition,[7] to the best of our knowledge,
no palladium-catalyzed asymmetric conjugate addition syn-
theses of flavanones have been reported.[8] We identified
chromone as a functioning conjugate acceptor with our Pd/
PyOX system during a screen developed to analyze the
effect of a b-substituent on reactivity and enantioselectivity
(Table 1). As reported in our initial communication,[3] 3-
Table 1. Comparison of asymmetric conjugate additions to various enone
substrates.[a]
Entry
Product
Yield [%][b]
ee [%][c]
1
2
3
4
1 (R=H)
2 (R=Me)
3 (R=H)
4 (R=Me)
87[d]
99
18
93
94
–
91
trace
[a] Conditions: chromone (0.25 mmol), arylboronic acid (0.50 mmol), Pd-
AHCNUTTGERG(NUNN OCOCF3)2 (5 mol%), ligand (6 mol%), NH4PF6 (30 mol%), H2O
(5 equiv), ClCH2CH2Cl (1 mL), 608C, 12 h. [b] Isolated yield. [c] ee deter-
mined by chiral SFC or HPLC. [d] No NH4PF6 was used.
methylcyclohexenone reacts with phenylboronic acid to give
nearly quantitative yield of the conjugate addition adduct 2
in 93% ee (Table 1, entry 2). With only hydrogen in the b-
position, enantioselectivity drops precipitously to 18% ee
(Table 1, entry 1). Interestingly, 2-methyl-4-chromone reacts
poorly, with only trace conjugate addition adduct detected
[a] J. C. Holder,+ Dr. A. N. Marziale,+ Dr. M. Gatti, B. Mao,
Prof. B. M. Stoltz
Warren and Katharine Schlinger Laboratory for
Chemistry and Chemical Engineering
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 E California Blvd, MC 101-20
Pasadena, CA 91125 (USA)
1
by H NMR spectroscopy (Table 1, entry 4), yet chromone
reacts with high yield and excellent enantioselectivity (94%
ee, Table 1, entry 3).
We sought to explore the scope of the asymmetric conju-
gate addition of arylboronic acids to chromones with respect
to the range of substrates and functional groups tolerated.
Moderate yields and enantioselectivity were realized with
E-mail: stoltz@caltech.edu
[+] These authors have contributed equally.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203643.
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Chem. Eur. J. 2013, 19, 74 – 77

COMMUNICATION
Table 2. Asymmetric conjugate addition of arylboronic acids to chromo-
ne.[a]
flavanone products 13 and 11, respectively, with moderate
yield (60% and 65%) and high ee (86% and 95%). Nota-
bly, with the present catalytic protocol 7-hydroxychromone
could be successfully applied, yielding flavanones 18, 19,
and 20 without protection of the phenol (Table 3). To our
knowledge, this is the first example of an unprotected
phenol reacted in asymmetric conjugate additions and
serves to highlight the high functional group tolerance as
compared to other systems.[7] 7-Hydroxychromone under-
went smooth conjugate addition with a range of boronic
acids in good yield and enantioselectivity: phenylboronic
acid (18, 77% yield, 93% ee), 3-methylphenylboronic acid
(19, 66% yield, 90% ee), and 4-fluorophenylboronic acid
(20, 50% yield, 93% ee). Finally, we found reaction of phe-
nylboronic acids with substituted chromones to be general
for a number of other substituted chromones including 5,7-
dimethylchromone (flavanones 15 and 16, 92% ee and 95%
ee), 7-acetoxychromone (flavanone 17, 93% ee) and 7-me-
thoxychromone (flavanones 21 and 22, 94% ee and 96%
ee).
We next turned our attention to 4-quinolones as a class of
potential substrates. Like flavanones, 4-quinolones have
been reported as potential pharmaceutical agents.[9] Yet, de-
spite their promising antimitotic and antitumor activity, the
enantioselective synthesis of 2-aryl-2,3-dihydro-4-quinolones
remains a challenge in asymmetric conjugate addition. Hay-
ashi and co-workers reported a rhodium-catalyzed asymmet-
ric conjugate addition, which utilized 3 equivalents of aryl-
zinc chloride nucleophiles and superstoichiometic chlorotri-
Entry
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
H
91
50
66
72
40
77
52
64
36
51
69
64
94
76
90
93
89
98
94
94
85
90
95
77
2-F-C6H4
3-Me-C6H4
3-CO2Me-C6H4
3-Br-C6H4
3-NH(CO)CF3-C6H4
3-Cl-C6H4
4-Me-C6H4
4-Et-C6H4
4-F-C6H4
9
10
11
12
3,5-OMe-C6H3
4-dibenzofuran
[a] Conditions: chromone (0.25 mmol), arylboronic acid (0.50 mmol), Pd-
ACHTUNGTRENNUNG(OCOCF3)2 (5 mol%), ligand (6 mol%), NH4PF6 (30 mol%), H2O
(5 equiv), ClCH2CH2Cl (1 mL), 608C, 12 h. [b] Isolated yield. [c] ee deter-
mined by chiral SFC.
sterically challenging 2-fluorophenylboronic acid (Table 2,
entry 2). Arylboronic acid substitution at the meta position
is generally tolerated with high enantioselectivity and mod-
erate to good yields (Table 2, entries 3–7). Notably, arylbor-
onic acids with halogen substitutents in the para position
(Table 2, entry 10) and 3-carbomethoxyphenylboronic acid
underwent conjugate addition with high enantioselectivity
(Table 2, entry 4). Furthermore, nitrogen-containing substi-
tution was well tolerated when protected as a trifluoroaceta-
mide, producing the flavanone in 77% yield and 98% ee
(Table 2, entry 6). Other para-substituted arylboronic acids
also reacted with high enantioselectivity: alkyl substituents
on the phenylboronic acid yielded 94% and 85% ee
(Table 2, entries 8 and 9, respectively). With 3,5-dimethoxy-
phenylboronic acid, bearing multiple substituents, high
enantioselectivity (95% ee) was obtained (Table 2,
entry 11). Remarkably, a heteroarylboronic acid was suc-
cessfully reacted with chromone as the conjugate acceptor
for the first time (Table 2, entry 12), as 4-dibenzofuranbor-
onic acid was converted with 64% yield and 77% ee in this
case.
Substituted chromones were also found to perform well
with the Pd/PyOX catalytic system. 5,7-Dimethyl-6-acetyl-
chromone was successfully reacted with a variety of arylbor-
onic acids (Table 3, i.e., 6–8). Addition of phenylboronic
acid gave nearly quantitative yield and 90% ee (6), while 3-
methylphenylboronic acid displayed diminished yield with a
comparable ee of 88% (7), and 4-ethylphenylboronic acid
reacted with modest yield and 86% ee (8). Furthermore, a
variety of para- and meta-substituted arylboronic acids were
successfully converted with the corresponding 5,7-dimethyl-
8-acetylchromone as well (i.e., 9–14). Nucleophiles bearing
functional group handles such as 3-carbomethoxyphenylbor-
onic acid and 3-bromophenylboronic acid reacted to yield
methylsilane to react with carboxybenzylACTHNUTRGNE(NUG Cbz)-protected 4-
quinolones.[10] While Hayashi notes that phenylboronic acid
is a particularly poor nucleophile in reactions with protected
4-quinolones, giving the desired conjugate addition adduct
in only 10% yield, Liao and co-workers reported rhodium-
catalyzed asymmetric 1,4-addition of sodium tetraarylborate
reagents to N-substituted 4-quinolones.[11] To the best of our
knowledge, there are no literature reports of palladium-cata-
lyzed conjugate additions to 4-quinolones, nor are there any
robust examples of additions to the latter utilizing simple
boronic acid nucleophiles.
To our delight, Cbz-protected 4-quinolone reacted with
phenylboronic acid to yield conjugate addition adduct 23 in
modest yield and 80% ee (Table 4). Investigation of further
N-protecting groups demonstrated that the Cbz-protected
substrates gave the best results in terms of reactivity and
stereoselectivity. Gratifyingly, a range of addition products
could be prepared in up to 65% yield and 89% ee (Table 4).
Nitrogen-containing, heteroaromatic and simpler boronic
acid derivatives were successfully employed as nucleophiles
in the 1,4-addition to 4-quinolones. For the corresponding
alkyl- and halogen-substituted boronic acids, reasonable
yields (45–65%) and enantioselectivities (67–89% ee) were
observed.
Disubstituted boronic acids were well tolerated and gave
similar results (24 and 26). Both compounds were obtained
in 85% ee. For addition products 27, 30, and 31 yields and
enantioselectivities ranging from 31% to 36% and 40% to
Chem. Eur. J. 2013, 19, 74 – 77
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75

B. M. Stoltz et al.
Table 3. Asymmetric conjugate addition of arylboronic acids to substituted Table 4. Asymmetric conjugate addition of arylboronic acids to 4-quinolo-
chromones.[a]
nes.[a]
6
7
8
23
24
25
98% yield
90% ee
76% yield
88% ee
45% yield
86% ee
50% yield
80% ee
45% yield
85% ee
51% yield
85% ee
9
10
11
79% yield
95% ee
84% yield
86% ee
65% yield
95% ee
26
27
28
50% yield
85% ee
34% yield
60% ee
65% yield
89% ee
12
13
14
68% yield
91% ee
60% yield
86% ee
70% yield
83% ee
29
30
31
45% yield
67% ee
36% yield
54% ee
31% yield
40% ee
[a] Conditions: 4-quinolone (0.25 mmol), arylboronic acid (0.50 mmol), Pd-
AHCNUTTGERG(NUNN OCOCF3)2 (5 mol%), ligand (6 mol%), NH4PF6 (30 mol%), H2O
15
16
17
(5 equiv), ClCH2CH2Cl (1 mL), 608C, 12 h, yields given are isolated yields,
ee determined by chiral SFC.
84% yield
92% ee
80% yield
95% ee
77% yield
93% ee
palladium nanoparticles, a mercury drop test was performed.
The addition of mercury to a catalytic reaction is widely
used to exclude catalysis by palladium nanoparticles as the
amalgamation should only deactivate heterogeneous metal
particles.[12] For the conversion of chromone with phenylbor-
onic acid in the presence of 200 equiv of mercury, with re-
spect to the catalyst, only a slight drop of the yield from
91% to 80% was observed, while the ee of 94% remained
unaltered. Addition of mercury to the reaction of 3-methyl-
cyclohexenone and phenylboronic acid resulted in quantita-
tive yield and a slightly reduced ee of 90% for addition
product 2, which is within error margins. Hence, the forma-
tion of zerovalent palladium nanoparticles could be exclud-
ed.
18
19
20
77% yield
93% ee
66% yield
90% ee
50% yield
93% ee
21
22
96% yield
94% ee
81% yield
96% ee
[a] Conditions: chromone (0.25 mmol), arylboronic acid (0.50 mmol), Pd-
ACHTUNGTRENNUNG(OCOCF3)2 (5 mol%), Ligand (6 mol%), NH4PF6 (30 mol%), H2O (5 equiv),
ClCH2CH2Cl (1 mL), 608C, 12 h, yields given are isolated yields, ee determined
by chiral SFC.
In conclusion, we report the palladium-catalyzed conju-
gate addition of arylboronic acids to chromones and 4-qui-
nolones using a single, easily prepared catalyst system. To
our knowledge this is the first report of a palladium-cata-
lyzed asymmetric conjugate addition to chromones and 4-
quinolones using either palladium catalysis or arylboronic
acid nucleophiles. Overall, a total of 38 addition products
could be synthesized in moderate to excellent yield and high
enantioselectivity. The present catalytic protocol exhibits
particularly mild reaction conditions and renders the use of
60% ee were achieved (Table 4). While the decreased yield
of quinolone 31 can be rationalized by the sterically de-
manding nature of the boronic acid, the lower ee could not
be readily explained.
To confirm the homogeneous nature of our catalyst
system and exclude the possibility of erosion of enantiomer-
ic excess due to the presence of catalytically active, achiral
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Chem. Eur. J. 2013, 19, 74 – 77

Asymmetric Conjugate Addition
COMMUNICATION
silver salts for catalyst activation obsolete. Furthermore,
moisture and air are well tolerated; this results in an unpre-
cedented functional group tolerance. Hence, the direct syn-
thesis of flavanones bearing free hydroxyl groups by conju-
gate addition and the application of N-substituted, as well as
heterocyclic boronic acids, is realized. We are currently con-
ducting kinetic and computational studies to elucidate the
present catalytic reaction mechanism. Furthermore, contin-
ued study of the substrate scope of the Pd/PyOX system and
its reactivity, as well as the application of these operationally
simple asymmetric conjugate addition reactions to total syn-
thesis are underway in our laboratory.
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Experimental Section
Representative general procedure for the enantioselective 1,4-addition of
arylboronic acids to heteroaromatic conjugate acceptors: A screw-top 1
dram vial was charged with
a stir bar, PdCATHUNTGRENUGN(OCOCF3)2 (4.2 mg,
0.0125 mmol, 5 mol%), (S)-tBuPyOX (3.1 mg, 0.015 mmol, 6 mol%),
NH4PF6 (12.5 mg, 0.075 mmol, 30 mol%), and the corresponding arylbor-
onic acid (0.50 mmol, 2.0 equiv). The solids were suspended in dichloro-
ethane (0.5 mL) and stirred for 2 min at ambient temperature, after
which time a yellow color was observed. Not all solids were dissolved at
this time. Conjugate acceptor substrate (0.25 mmol, 1.0 equiv) and water
(0.025 mL, 1.25 mmol, 5.0 equiv) were added. The walls of the vial were
rinsed with an additional portion of dichloroethane (0.5 mL). The vial
was capped and the mixture was stirred at 608C in an oil bath for 12 h.
Upon complete consumption of the starting material (monitored by TLC,
4:1 hexanes/EtOAc, p-anisaldehyde or iodine/silica gel stain) the reaction
mixture was eluted through a pipet plug of silica gel, using CH2Cl2 as the
eluent, and concentrated in vacuo. The crude residue was purified by
column chromatography (hexanes/EtOAc) to afford a colorless solid.
[8] For an isolated example of a Pd-catalyzed non-enantioselective con-
jugate addition to a chromone, see: S.-H. Huang, T.-M. Wu, F.-Y.
Tasi, Appl. Organomet. Chem. 2010, 24, 619–624.
Acknowledgements
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The authors thank NIH-NIGMS (R01M080269–01), Caltech, Amgen,
and the Deutsche Akademie der Naturforscher Leopoldina (postdoctoral
fellowship A.N.M.) for financial support. J. C. H. thanks the American
Chemical Society Division of Organic Chemistry for a predoctoral fel-
lowship. M.G. is grateful to the Swiss National Science Foundation for fi-
nancial support through a postdoctoral fellowship. B. M. thanks the
China Scholarship Council (No.2008618001) and the University of Gro-
ningen for financial support. Anton A. Toutov is acknowledged for ex-
perimental assistance. Jinglan Zhou and Mike DeNinno (Vertex Pharma-
ceuticals) are acknowledged for helpful discussions and suggestions.
Keywords: arylboronic acids
·
asymmetric catalysis
·
Received: September 19, 2012
conjugate addition · heterocycles · palladium
Published online: December 3, 2012
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