Palladium-catalyzed conjugate addition of arylboronic acids to 2-substituted chromones in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2016.10.084

Palladium-catalyzed conjugate additions of arylboronic acids to 2-alkylchromones are reported. The conjugate additions occur in aqueous media in the presence of a catalyst generated from palladium trifluoroacetate and 1,10-phenanthroline, and the flavanone derivatives containing a fully-substituted carbon center are formed in up to 90% yield.

Full text of DOI:10.1016/j.tetlet.2016.10.084

Accepted Manuscript
Palladium-catalyzed conjugate addition of arylboronic acids to 2-substituted
chromones in aqueous media
Anthony L. Gerten, Levi M. Stanley
PII:
S0040-4039(16)31406-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.084
TETL 48254
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 August 2016
20 October 2016
21 October 2016
Please cite this article as: Gerten, A.L., Stanley, L.M., Palladium-catalyzed conjugate addition of arylboronic acids
to 2-substituted chromones in aqueous media, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.10.084
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Palladium-catalyzed conjugate addition of
arylboronic acids to 2-substituted chromones
in aqueous media
Leave this area blank for abstract info.
Anthony L. Gerten, Levi M. Stanley
Iowa State University, Department of Chemistry, Ames, Iowa 50011, United States
R2
B(OH)2
O
O
O
Pd(II) Catalyst
R2
aq. NaTFA
60 °C
O
R1
R1
Up to 90% yield

1
Tetrahedron Letters
Palladium-catalyzed conjugate addition of arylboronic acids to 2-substituted
chromones in aqueous media
Anthony L. Gerten, Levi M. Stanley*
Iowa State University, Department of Chemistry, Ames, Iowa 50011, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Palladium-catalyzed conjugate additions of arylboronic acids to 2-alkylchromones are reported.
The conjugate additions occur in aqueous media in the presence of a catalyst generated from
palladium trifluoroacetate and 1,10-phenanthroline, and the flavanone derivatives containing a
fully-substituted carbon center are formed in up to 90% yield.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Conjugate Addition
Palladium
Flavanones
Protodeboronation
Catalysis
Recent work from our laboratory showed that conjugate
additions of arylboronic acids to sterically demanding β-aryl
cycloalkenones catalyzed by a palladium(II) complex of 2,2-
bipyridine (2,2-bpy) occur in high yields when carried out in
aqueous sodium trifluoroacetate (NaTFA).5 This work built upon
studies by Stoltz that demonstrate the presence of water in
palladium-catalyzed conjugate additions of arylboronic acids to
β-substituted cyclic enones is important to protonate the
palladium enolate intermediate and facilitate catalyst turnover.6
We sought to leverage the increased reactivity toward
challenging enone substrates when palladium-catalyzed
conjugate additions of arylboronic acids are carried out in
aqueous media. To this end, palladium-catalyzed conjugate
additions of arylboronic acids to 2-substituted chromones are
disclosed herein (Scheme 1b).
Introduction
Flavanone-containing scaffolds are present in an array of
natural products, and the biological activity associated with many
of these compounds renders them attractive synthetic targets.1a-f
Conjugate additions of organometallic reagents to chromones
have emerged as a powerful means to access these structures.1a In
2010, Huang and coworkers reported conjugate additions of
arylboronic acids to chromones catalyzed by palladium
complexes.2 Since then, numerous reports of conjugate additions
of arylboronic acids to chromones catalyzed by palladium3a-c and
rhodium4a-d complexes have been disclosed (Scheme 1a).
Previous Studies
O
O
Pd or Rh
catalyst
ArB(OH)2
ArB(OH)2
+
(a)
(b)
R1
R1
Results and Discussion
O
O
O
O
Ar
Ar
This Work
We began our studies by evaluating the model conjugate
addition of phenylboronic acid (1a) to 2-methylchromone (2a) to
form 2-methyl-2-phenylchroman-4-one (3a) as the desired
product (Scheme 2). The reaction conditions and catalyst
identified for conjugate additions of arylboronic acids to β-aryl
cycloalkenones were initially evaluated in the current model
reaction.5 The addition of 1a (4 equiv) to 2a catalyzed by a
complex prepared from 2,2-bipyridine and palladium
trifluoroacetate (Pd(TFA)2) occurs to form 3a in low yield (29%)
when the reaction is run at 100 °C in aqueous NaTFA. In
addition to the desired product, we observed >90%
protodeboronation of phenylboronic acid (1a) to form benzene
and a small amount biphenyl from homocoupling of 1a.
Pd(II) catalyst
+
R1
R1
aqueous NaTFA
O
R2
O
R2
Scheme 1. Synthesis of flavanone derivatives by conjugate
additions of arylboronic acids to chromones.
However, there are currently no reports of conjugate additions
of arylboronic acids to 2-substituted chromones. In fact, a report
by the Stoltz group demonstrated that 2-methylchromone was
unreactive under their conditions as a conjugate addition acceptor
in palladium-catalyzed conjugate additions of arylboronic acids.3a

2
Tetrahedron Letters
2,2 -bpy (6 mol %)
Pd(TFA)2 (5 mol %)
O
O
O
2,2-bpy, occurred to form product 3a in 38% yield when the
OH
OH
reaction was run at 60 °C with a 1:4 ratio of 2a:1a (entry 1).
However, we still observed 70% protodeboronation under these
reaction conditions. When the reaction was run with a 1:1 ratio of
2a:1a, we observed 27% yield of product 3a, 35%
protodeboronation, and 21% biphenyl formation (entry 2).
Encouraged by the lower relative rate of protodeboronation
versus desired conjugate addition observed under these
conditions, we ran the reaction with a 2:1 ratio of 2a:1a. This
reaction delivered product 3a in 56% yield and decreased
protodeboronation and biphenyl formation to 19% and 12%,
respectively (entry 3).
+
Ph
B
50 mM NaTFA (3 M)
100 °C, time
O
Ph
1a
4 equiv.
2a
1 equiv.
3a
+ Ph-H + Ph-Ph
Table 1
Identification of reaction conditions to minimize
protodeboronation
O
O
O
O
C1-C4
(5 mol %)
OH
OH
+
Ph
B
50 mM NaTFA (3 M)
60 °C, 15-22 h
Ph
Scheme 2. Reaction profile for conjugate addition of
phenylboronic acid (1a) to 2-methylchromone (2a). Reaction
conditions: 1a (2.00 mmol), 2a (0.500 mmol), Pd(TFA)2 (0.025
mmol), 2,2-bpy (0.030 mmol), 50 mM aq. NaTFA (0.167 mL),
100 °C, 8 h. Yields are determined by GC using tridecane as an
internal standard.
1a
2a
3a
R
R
N
N
N
N
Pd
Pd
(TFA)2
(TFA)2
The low yield of conjugate addition product 3a and the
undesired protodeboronation and homocoupling pathways
prompted us to follow the reaction over time. After two hours,
we observed 28% yield of 3a with 69% protodeboronation. The
yield of 3a did not increase after approximately two hours, while
protodeboronation continued to occur. After 8 hours, the
phenylboronic acid was completely consumed, and 93%
protodeboronation was observed. Initial efforts to mitigate the
undesired protodeboronation reaction, including evaluation of a
variety of arylboron nucleophiles, reaction temperatures, and
reaction concentrations were largely unproductive (see ESI for
details).7
After our early efforts to reduce protodeboronation did not
lead to an acceptable solution, we next examined the issue of
biphenyl formation in our reactions. The generally accepted
mechanism for palladium-catalyzed conjugate additions of
arylboronic acids to enones is a non-redox process involving
Pd(II) intermediates.6 The observed homocoupling of
phenylboronic acid led us to believe that this undesired side
reaction was removing the requisite Pd(II) from the catalytic
cycle by reductive elimination from a PdAr2 species to form a
Pd(0) species.8 Greatly diminished yields of 3a under rigorously
oxygen-free conditions lent even greater evidence to the
formation of an off-cycle Pd(0) species (see ESI for details). The
inclusion of oxygen is necessary to reoxidize Pd(0) species to
Pd(II) species to ensure that the desired conjugate addition
pathway remains operative.
C4
C1: R = H
C2: R = OMe
C3: R = CF3
Yield 3a
Ph-H
(%)a
Ph-Ph
Ratio
2a:1a
Entry
Catalyst
(%)a,b
(%)a
1c
2
3
4
5
1:4
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
3:1
38
27
56
49
53
68
65
49
82 (76)
70
35
19
30
13
16
22
25
14
6
7
C1
C1
C1
C2
C3
C4
C4
C4
C4
C4
21
12
12
15
13
12
11
10
6
6
7d
8e
9f
10f
84 (87)
a Yields determined by GC using tridecane as internal standard.
b Isolated yields in parentheses.
c Catalyst C1 generated in situ from Pd(TFA)2 and 2,2-bpy.
d Reaction run at 80 °C.
e Reaction run at 100 °C.
f 4.5 M in 50 mM aq. NaTFA.
To further improve upon our reaction conditions, we
examined the impact of electronically distinct bipyridine ligands
on the activity of the palladium catalyst (entries 3-5). A more
electron-rich palladium center led to a higher relative rate of
protodeboronation (compare entry 4 with entry 3). The outcome
of the reaction conducted in the presence of the electron-poor
catalyst complex C3 (R = CF3) was essentially unchanged from
that observed with complex C1 (compare entry 5 with entry 3).
Notably, the complex derived from 1,10-phenanthroline
(C4) led to higher yield of product 3a relative to the palladium
complexes of bipyridine ligands. Complex C4 catalyzed the
addition of 1a to 2a to form 3a in 68% yield with 16%
protodeboronation and 13% biphenyl formation (entry 6). We
hypothesize that the palladium complex of 1,10-phenanthroline
eliminates the potential for rollover C-H activation of 2,2-
bipyridine ligands that may remove palladium from the catalytic
cycle.10
The observation that the yield of product 3a does not
increase after two hours led us to hypothesize that once the
concentration of 2-methylchromone (2a) was low relative to the
concentration of phenylboronic acid (1a), the desired conjugate
addition reaction ceases and protodeboronation becomes the
dominant reaction pathway for phenylboronic acid (1a). With
this hypothesis in mind and further inspired by a report from
Minaard,9 we examined the impact of increasing the
concentration of chromone 2a relative to phenylboronic acid (1a)
in an attempt to minimize protodeboronation.
The results presented in Table 1, entries 1-3 demonstrate that
the relative rate of protodeboration versus conjugate addition is
highly dependent on the concentration of 2a. The model reaction
catalyzed by complex C1, prepared in situ from Pd(TFA)2 and

3
Encouraged by the results of reactions catalyzed by complex
C4, we sought to identify reaction conditions to further increase
the yield of 3a and limit protodeboronation. Increasing the
temperature of the reaction to 80 or 100 °C led to a decrease in
the yield of 3a and an increase in protodeboronation (entries 7
and 8). Increasing the concentration of the reaction to 4.5 M
based on phenylboronic acid led to the formation of 3a in 76%
isolated yield (entry 9). Protodeboronation and biphenyl
formation could be further suppressed by conducting the reaction
fluorophenylboronic acid to 2a formed 3p in <5% yield. o-
Methoxyphenylboronic acid displayed increased reactivity
toward the desired conjugate addition reaction relative to o-
fluorophenylboronic acid and led to the formation of 3q in 35%
yield. The addition of 2-fluoro-4-methoxyphenylboronic acid
provides further evidence to the impact of o-substitution on the
arylboronic acid. This reaction generated the corresponding 2-
methyl-2-arylchromanone 3r in 25% yield. In contrast, the
addition of an electronically similar arylboronic acid, 3-fluoro-4-
methoxyphenylboronic acid, led to the formation of 3o in high
yield.
with
a 3:1 ratio of 2a:1a (entry 10), and 2-methyl-2-
phenylchroman-4-one (3a) was isolated in 87% yield.
O
O
C4
O
O
C4
(5 mol %)
(5 mol %)
R2
R2
ArB(OH)2
+
PhB(OH)2
+
50 mM NaTFA (4.5 M)
Ar
50 mM NaTFA (4.5 M)
O
O
60 °C,15-20 h
Ar
R1 60 °C,15-20 h
O
3s-v
O
2b-e
2a
3a-s
R1
1a
2b: R1 = Et, R2 = H
2c: R1 = iPr, R2 = H
2d: R1 = Cy, R2 = H
2e: R1 = Me, R2 = OMe
3b (R = OMe): 79%
3c (R = MOM): 68%
3d (R = Me): 77%
3e (R = Ph): 83%
3f (R = F): 51%
3g (R = Cl): 57%
3h (R = Br): 19%
3i (R = CF3): 8%
O
O
O
O
O
O
O
O
O
O
R
3a: 87%
O
Ph
Ph
Ph
O
O
O
O
O
Ph
3s: 79%
3t: 43%
3u: 15%
3v: 81%
R
O
O
O
O
Scheme 4. Palladium-catalyzed conjugate additions of
PhB(OH)2 to chromones 2b-e. Reaction conditions:
PhB(OH)2 (0.250 mmol), chromone 2b-e (0.750 mmol), C4
(0.0125 mmol), 50 mM aq. NaTFA (0.056 mL, 4.5 M), 60 °C,
15-20 h. Isolated yields are reported after purification by
flash column chromatography. Yields reported are the
average of two runs.
O
3j (R = OMe): 68%
3k (R = Me): 69%
3l (R = Cl): 21%
O
3m: 90%
3n: 60%
O
R1
F
O
O
O
R2
3p (R1 = F, R2 = H): 5%
3q (R1 = OMe, R2 = H): 35%
3r (R1 = F, R2 = OMe): 25%
To further expand the scope of this reaction, we evaluated
conjugate additions of phenylboronic acid to a variety of 2-
alkylchromones. The reaction of 2-ethylchromone (2b) with
phenylboronic acid formed chromanone 3s in 79% yield.
Increasing the steric volume of the substituent at the 2-position of
the chromone resulted in decreased acceptor reactivity toward
conjugate addition: the reaction of 2-isopropylchromone (2c)
occurred to give chromanone 3t in 43% yield, and the reaction of
2-cyclohexylchromone (2d) formed chromanone 3u in 15%
yield. 2-Phenylchromone (flavone) did not react under our
reaction conditions. This trend of decreased acceptor reactivity
with increasing steric volume at the 2-position of the chromone is
consistent with a slower rate of turnover-limiting insertion of the
enone into the palladium-arene bond.6 Substitution on the 2-
alkylchromone backbone is also tolerated. The reaction of 6-
methoxy-2-methylchromone with phenylboronic acid formed
chromanone 3v in 81% yield.
3o: 83%
Scheme 3. Palladium-catalyzed conjugate additions of
arylboronic acids to 2a. Reaction conditions: ArB(OH)2
(0.250 mmol), 2a (0.750 mmol), C4 (0.0125 mmol), 50 mM
aq. NaTFA (0.056 mL, 4.5 M), 60 °C, 15-20 h. Isolated
yields are reported after purification by flash column
chromatography. Yields reported are the average of two runs.
With a practical catalyst system identified, we proceeded to
evaluate conjugate additions of a variety of arylboronic acids to
2-methylchromone (2a). These results are summarized in
Scheme 3. Additions of arylboronic acids containing electron-
donating and electron-neutral groups at the para-position to 2a
formed the corresponding 2-methyl-2-arylchroman-4-ones 3b-3e
in 68-83% yield. Moderately electron-deficient p-fluorophenyl
and p-chlorophenylboronic acids reacted with 2a to generate 2-
methyl-2-arylchroman-4-ones 3f and 3g in 51% and 57% yield,
respectively. However, the additions of p-bromophenylboronic
acid and electron-poor p-trifluoromethylphenylboronic acid to 2a
formed 3h and 3i in low yields. Additions of m-methoxy- and m-
methylphenylboronic acid generated 3j and 3k in good yields
(68-69%), while a m-halogenated arylboronic acid led to low
yields of the corresponding 2-methyl-2-arylchroman-4-one 3l.
Additions of electron-rich 3,4- and 3,5-disbustituted arylboronic
acids to 2a formed 2-methyl-2-arylchroman-4-ones 3m-3o in
good-to-excellent yields (60-90%).
Conclusion
In conclusion, we developed the first conjugate additions of
arylboronic acids to 2-substituted chromones. Additions of
arylboronic acids to these challenging substrates are enabled by
the use of a readily accessible palladium(II) catalyst in aqueous
media. This catalyst system overcomes the low reactivity of 2-
alkylchromones, and maintaining a low concentration of the
arylboronic acid relative to the 2-alkylchromone electrophile
reduces undesired protodeboronation and homocoupling
pathways. The scope of these reactions encompasses a variety of
arylboronic acids and 2-alkylchromones and enables the formation
of an array of 2-alkyl-2-arylchromanone products. Studies are
ongoing in our laboratory to develop an enantioselective variant of
Notably, o-substituted arylboronic acids displayed decreased
reactivity in conjugate additions to 2a. The addition of o-

4
Tetrahedron Letters
4.
(a) He, Q.; So, C. M.; Bian, Z.; Hayashi, T.; Wang, J. Chem. Asian. J.
this reaction and to expand these conjugate addition reactions to
2015, 10, 540. (b) Korenaga, T.; Hayashi, K.; Akaki, Y.; Maenishi, R.;
Sakai, T. Org. Lett. 2011, 13, 2022. (c) Han, F.; Chen, G.; Zhang, X.;
Liao, J. Eur. J. Org. Chem. 2011, 2928. (d) Lang, F.; Li, D.; Chen, J.;
Chen, J.; Li, L.; Cun, L.; Zhu, J.; Deng, J.; Liao, J. Adv. Synth. Catal.
2010, 352, 843.
additional classes of acceptors.
Acknowledgement
5.
6.
Van Zeeland, R.; Stanley, L. M. ACS Catal. 2015, 5, 5203.
(a) Boeser, C. L.; Holder, J. C.; Taylor, B. L. H.; Houk, K. N.; Stoltz, B.
M.; Zare, R. N. Chem. Sci. 2015, 6, 1917. (b) Holder, J. C.; Zou, L.;
Marziale, A. N.; Liu, P.; Lan, Y.; Gatti, M.; Kikushima, K.; Houk, K.
N.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 14996.
We thank Iowa State University, the Iowa State University
Center for Catalysis (CCAT), and the Research Corporation for
Science Advancement for supporting our studies.
7.
(a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J.
Am. Chem. Soc. 1998, 120, 5579. (b) Hayashi, T.; Takahashi, M.;
Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052. (c)
Lennox, A. J. J.; Lloyd-Jones, G. C. Isr. J. Chem. 2010, 50, 664.
Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J. Am.
Chem. Soc. 2006, 128, 6829.
Referenes and notes
1.
(a) Wang, J.; Meng, L. Synlett 2015, 27, 656. (b) Emami, S.;
Ghanbarimasir, Z. Eur. J. Med. Chem. 2015, 93, 539. (c) Chang, L. C.;
Kinghorn, A. D., Bioactive Compounds from Natural Sources:
8.
9.
Isolation, Characterisation and Biological Properties. Taylor
&
Buter, J.; Moezelaar, R.; Minnaard, A. J. Org. Biomol. Chem. 2014, 12,
5883.
Francis: London, 2001. (d) Pietta, P. J. Nat. Prod. 2000, 63, 1035. (e)
Harbone, J. B.; Williams, C. A. Nat. Prod. Rep. 1995, 12, 639. (f)
Harborne, J. B., The Flavonoids: Advances in Research Since 1980.
Chapman and Hall: New York, 1988.
10. Butschke, B.; Schlangen, M.; Schroder, D.; Schwarz, H. Chem. Eur. J.
2008, 14, 11050.
2.
3.
Huang, S.-H.; Wu, T.-M.; Tsai, F.-Y. Appl. Organometal. Chem. 2010,
24, 619.
(a) Holder, J. C.; Marziale, A. N.; Gatti, M.; Mao, B.; Stoltz, B. M.
Chem. Eur. J. 2013, 19, 74. (b) Kim, D.; Ham, K.; Hong, S. Org.
Biomol. Chem. 2012, 10, 7305. (c) Gottumukkala, A. L.; Matcha, K.;
Lutz, M.; de Vries, J. G.; Minnaard, A. J. Chem. Eur. J. 2012, 18, 6907.

5
Highlights



A catalytic method for synthesis of substituted flavanone derivatives is reported.
The catalyst system minimizes protodeboronation and biaryl formation processes.
The reactions encompass a range of arylboronic acids and 2-alkylchromanones.