Palladium-catalyzed mono-γ-arylation of 7-methoxy-4-methylcoumarin

Article abstract of DOI:10.1016/j.tetlet.2019.151057

Herein, we report the selective mono-γ-arylation of 7-methoxy-4-methylcoumarin under palladium-catalyzed conditions. The Buchwald G3 pre-catalyst in conjunction with either the Xantphos or N-Xantphos ligand proves to be highly reactive, engaging aryl iodides, bromides, chlorides, and triflates to effect the desired transformation. A wide range of functionality is tolerated, including the ability to activate heteroaryl halides in the transformation. The initial scope of aryl halides and limitations of this methodology are presented.

Full text of DOI:10.1016/j.tetlet.2019.151057

Journal Pre-Proof
Palladium-Catalyzed Mono-γ-Arylation of 7-Methoxy-4-methylcoumarin
Mary E. Sexton, Ami Okazaki, Zhuowen Yu, Alexis van Venrooy, Jason R.
Schmink, William P. Malachowski
PII:
S0040-4039(19)30817-2
DOI:
https://doi.org/10.1016/j.tetlet.2019.151057
TETL 151057
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 July 2019
12 August 2019
14 August 2019
Please cite this article as: Sexton, M.E., Okazaki, A., Yu, Z., van Venrooy, A., Schmink, J.R., Malachowski, W.P.,
Palladium-Catalyzed Mono-γ-Arylation of 7-Methoxy-4-methylcoumarin, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.151057
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JOURNAL PRE-PROOF
Palladium-Catalyzed Mono-γ-Arylation of 7-Methoxy-4-
methylcoumarin
Mary E. Sexton, Ami Okazaki, Zhuowen Yu, Alexis van Venrooy, Jason R. Schmink†, William P. Malachowski*
Department of Chemistry, Bryn Mawr College, 101 North Merion Avenue, Bryn Mawr, Pennsylvania, 19010-2899, United
States
† Current Address: Pennsylvania College of Health Sciences, 850 Greenfield Road, Lancaster, Pennsylvania 17601.
4% Xantphos G3
MeO
O
O
MeO
O
O
or
Selective mono--arylation of 7-methoxy-4-methylcoumarin
4% N-Xantphos G3
THF, 50-90 °C, 24 h
3.0 equiv, LiHMDS
+
ArX
25 examples
23-98% yield
Ar
Ar= substituted benzene, naphthalene, benzofuran, pyridine, benzophenone
X= I, Br,Cl, OTf
ABSTRACT: Herein, we report the selective mono-γ-arylation of 7-methoxy-4-methylcoumarin under palladium-catalyzed
conditions. The Buchwald G3 pre-catalyst in conjunction with either the Xantphos or N-Xantphos ligand proves to be highly
reactive, engaging aryl iodides, bromides, chlorides, and triflates to effect the desired transformation. A wide range of functionality
is tolerated, including the ability to activate heteroaryl halides in the transformation. The initial scope of aryl halides and limitations
of this methodology are presented.
Keywords: enolate -arylation, palladium-catalyzed, coumarin, Xantphos
Coumarins are of particular interest due to their wide
variety of therapeutic applications, such as their antibiotic
presence of Pd(PPh3)4 with high selectivity.11
Unfortunately, using stoichiometric amounts of tin
compounds make this method less attractive due to the
toxicity of tin and the limited availability of tin dienolates.
Fortunately in 1998, Miura and co-workers demonstrated
that α,β-unsaturated ketones and aldehydes react with aryl
bromides under basic conditions to selectively produce the
γ-arylated product using palladium acetate with
triphenylphosphine as the catalyst.12 (Fig. 1, Panel A) This
method eliminated the need for toxic metals and expanded
the scope of reagents that could be utilized at the γ-position
due to the wide variety of aryl bromides available.
Importantly, they were able to avoid Heck reactions of the
C-C double bond and alkene isomerization via β-hydride
elimination. By varying the amounts of aryl bromide, they
were also able to synthesize the diphenylated derivative.
In 2005, Varseev and Maier described the synthesis of 7-
aryltetralones (Fig. 1, Panel B).13 They initially desired to
mono-γ-arylate 3,4,4a,5,6,7-hexahydronaphthalen-1(2H)-
one; however, they were only able to isolate tetralone
derivatives. Their sequence included a sequential palladium
catalyzed γ-arylation and dehydrogenation for the synthesis
of substituted tetralones.
1
2
and antifungal,
anti-inflammatory,
and antiviral
activities.3 In addition, coumarin’ s strong fluorescence
under UV light leads to their frequent use in different laser
dyes and optical brighteners (410-470 nm).4 Indeed, the
range of applications for coumarin derivatives makes them
valuable to the chemistry community.
Over the past two decades, enolate α-arylation chemistry
has been studied extensively and comprehensively.5,6,7 γ -
Arylation, a related phenomenon in conjugated enolates,
has received considerable recent attention due to the
challenges of regioselectively arylating the γ -position,
selectively monoarylating, and avoiding potential
condensation side products.8 α,β-Unsaturated ketones and
esters are difficult to selectively mono-γ-arylate due to the
dienolate intermediate that forms in the reaction, which can
produce multiple unwanted products, including α-arylation,
β-arylation via Heck reaction, and polyarylation. In the
past, alkylation was utilized successfully to functionalize
the γ-position; however, the methods were limited in
scope.9,10,11
Despite these challenges, the alkylation of α,β-
unsaturated ketones and esters has been widely studied.
Regioselectivity in the alkylation of α,β-unsaturated
ketones and esters has been controlled by direct alkylation
at the -position using various metals such as copper9 and
tin.10 Yamamoto and co-workers cross-coupled tin
dienolates at the γ-position with aryl bromides in the
In 2008, Buchwald and Hyde described among the first
examples of palladium catalyzed γ-arylation of β,γ-
unsaturated ketones to create quaternary centers, which
previously had not been explored due to the difficulty of
14
this process.
Among the reasons this process is
dienolates are less
considered more difficult are:

JOURNAL PRE-PWRiOthOoFur desired substrate in hand, the reaction was
nucleophilic than enolates, dienolates are more prone to
self-condensation through Michael reactions, and there
exists the potential for the generation of regioisomeric
products. Buchwald and Hyde found that there was
subsequent isomerization to the α ,β-product when β,γ-
unsaturated ketones were utilized. Nevertheless, they were
able to produce the desired product with a sterically
congested quaternary center under basic conditions (Fig. 1,
Panel C). They were also able to apply their results to a
one-pot ketoinoline synthesis (Fig. 1, Panel D). In 2009,
Buchwald and Hyde constructed 5,5-disubstituted
optimized using the reaction conditions in Table 1.
Utilizing similar conditions to previous studies on α-
arylation chemistry,5,6,7 we were able to produce the desired
monoarylated product. Initially, cesium carbonate,
potassium-tert-butoxide, and lithium hexamethyldisilazide
were screened for reactivity. Both cesium carbonate (Table
1, Entry 1) and potassium-tert-butoxide (Table 1, Entry 2)
reactions showed trace amounts of product with mainly
starting material via GC analysis; however, lithium
hexamethyldisilazide produced the desired mono-γ-arylated
product (Table 1, Entry 3).
Utilizing the third generation (G3) Buchwald precatalyst
scaffold21 (Table S1, structures available in the ESI) and a
variety of readily available ligands, the catalyst was
screened for optimization (Table 1). All third generation
Buchwald precatalysts listed were prepared using the
general procedure described by Bruno, Tudge, and
Buchwald. N-Xantphos G3 (Entry 5)22 as well as DPEPhos
G3 (Entry 6) were promising due to their high yield of
product and minimal starting material remaining. DPPF G3
(Entry 7)23 was incomplete and produced more of B than 1.
MorDalPhos G3 (Entry 8), and PA-PPh G2 (Entry 9)
provided incomplete reactions with production of the
undesired polyarylated products B and C. Xantphos as the
ligand produced 100% of product with no remaining
starting materials at 70 °C (Entry 11). Reduction of the
precatalyst to 2% (Entry 14) did not hinder the amount of
product being produced. Ultimately, THF was found to be
the best solvent for the reaction in all of the trials
completed. Toluene, a non-polar solvent, provided an
incomplete reaction with small amounts of diarylated
product formed (Entry 12).
butenolides, which provided another example of
a
quaternary center being made from γ-arylation.15
12
A
, Miura and co-workers
R
CHO
R
CHO
Pd(OAc)2 / PPh3
Cs2CO3 / DMF
+
ArBr
R
Ar
O
R
13
B
, Varseev and Maier
O
R
ArX, DMF, rt
Pd(OAC)2, PPh3
Cs2CO3, TBAB
X=Br, I
14
C
, Buchwald and Hyde
O
O
2% Pd(OAc)2
4% dppe
ArBr or
+
VinylBr
1.5 equiv. Cs2CO3
toluene
100 °C, 8 h
R'
R'
Ar/Vinyl
R
R
15
D
, Buchwald and Hyde
R2
O
O
X
O
2% Pd(OAc)
4% MePhos
R2
O
+
R1
1.2 eq. K2CO3
R3
toluene/t-amyl alcohol
R1
100oC, 12 h
R3
E
, This work
4% Xantphos G3
or
Table 1: Optimization of the reaction conditions.
MeO
O
O
MeO
O
O
MeO
O
O
O
MeO
O
O
MeO
O
4% N-Xantphos G3
THF, 50-90 °C, 24 h
3.0 equiv, LiHMDS
MeO
O
O
Br
+
ArX
conditions
+
+
+
Ph
C
B
1
Ph
Ph
Ph
Ph
Ar
Figure 1. Survey of approaches toward γ-arylation.
Temp
(°C)
Catalyst
(loading)c
Entry
Base
Solvent
1a
Ba
Ca
s.m.
In 2015, Skrydstrup and co-workers reported the
Xantphos
G3 (4%)
Xantphos
G3 (4%)
Xantphos
G3 (4%)
Xantphos
G3 (4%)
NiXantphos
G3 (4%)
DPEPhos
G3 (4%)
DPPF G3
(4%)
1b
2b
3b
4
Cs2CO3
KOtBu
CPME
CPME
CPME
MeTHF
MeTHF
MeTHF
MeTHF
MeTHF
MeTHF
MeTHF
THF
90
90
r.t.
85
85
85
85
85
85
70
70
70
70
70
trace
trace
(TLC)
99
0
0
0
0
carbonylation of vinylogous esters at the γ-position.16 They
successfully produced the gamma product with no trace of
α-arylation present for 2,2,6-trimethyl-4H-1,3-dioxin-4-
one. These publications, in addition to the others reported
above, represent the few examples of γ-arylation of ketones
and esters.
100
100
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
nd
0
nd
0
(TLC)
Trace
8
5
92
0
0
Expanding on the work of Miura, Maier, Buchwald, and
Skrydstrup, we began our study to mono-γ -arylate 7-
methoxy-4-methylcoumarin (Fig. 1, Panel E). This
compound was considered to be electronically and
sterically favorable to form the γ-arylated product due to
the proton in the γ-position being most acidic. Breaking
aromaticity or conjugation is highly unfavorable. This
leaves strictly the α- and γ-positions being available for
cross coupling. Although there have been several Pd-
catalyzed approaches to -arylated coumarins,17-20 these
utilized Suzuki-Miyaura and Negishi cross-coupling
approaches, therefore, to the best of our knowledge, this is
the first report of an enolate arylation approach to -aryl
coumarins.
6
90
0
0
10
27
36
6
7
33
40
trace
30
0
0
MorDalPhos
G3 (4%)
PA-PPh G2
(4%)
8
64
0
9
52
10
0
Xantphos
G3 (4%)
Xantphos
G3 (4%)
Xantphos
G3 (4%)
Xantphos
G3 (4%)
Xantphos
G3 (2%)
10
11
12
13
14
98
2
100
62
0
0
0
toluene
CPME
THF
4
0
34
22
0
76
2
0
100
0
0
a
b
Values reported are GC yields using biphenyl as an internal standard; Used 4-
c
bromoanisole instead of bromobenzene; Ligands are listed in the Supporting
Information (S3)

JOURNAL PRE-PROOF
After initial optimization, we explored our substrate
optimal palladium precatalyst for the aryl bromides, iodides
and triflates. Entries 26-28 illustrate several substrates that
proved unreactive in our studies. For β-bromostyrene and
4-chloroanisole, the starting materials failed to react at all;
while for 3-bromobenzothiophene we obtained a complex
reaction mixture. The lack of reactivity in the aryl bromides
is difficult to explain, but the electron rich aryl chloride
likely made it a poor substrate for oxidative addition.
It is already known that oxidative addition of aryl
chlorides using bidentate phosphine ligands, such as N-
Xantphos, proceeds through a higher energy Pd-L2 pathway
than if a bulky monodentate phosphine were utilized.24
Consequently, higher temperatures are typically necessary
for palladium catalyzed reactions with aryl chlorides. N-
Xantphos is favored over Xantphos for aryl chlorides
because it can help lower the activation energy for
oxidative addition.
scope with a variety of aryl bromides, aryl chlorides, aryl
iodides, and an aryl triflate as shown in Table 2. γ-
Arylation worked very well for a range of electronically
and sterically diverse aryl bromides (Table 2, Entries 1-11).
The
electron
deficient
aryl
bromide,
4-
bromobenzotrifluoride (Entry 12), only afforded 22% yield
of trifluoromethyl derivative 12; and the significantly less
electron withdrawing cyano analog (Entry 13) was obtained
in 95% yield. A heteroaryl bromide (Entry 14) provided
excellent results with a yield of 92%. However, the
pyridine derivatives in entries 15 and 16 provided low
yields of 57% and 32% respectively. It is likely that the
pyridine nitrogen was binding to palladium and attenuating
catalysis as both reactions were incomplete due to
remaining 7-methoxy-4-methyl coumarin in the GCMS.
Table 2. Substrate scope and limitations.
N-Xantphos has been reported24 by Mao and Walsh and
co-workers to have an acidic phenoxazine N-H (pKa ~21 in
DMSO25), which under basic reaction conditions,
deprotonates and associates with a main group metal, in our
case lithium, and the ligand pi-system.22 Walsh and co-
workers had proposed that the main group metal cooperates
with the palladium center to help lower the barrier for the
oxidative addition of aryl chlorides, which they propose N-
Xantphos is superior to Xantphos for aryl chlorides. Our
results are consistent with this proposal.
Mechanistically, the desired cross coupling likely
proceeds through a traditional Pd0/PdII catalytic cycle. The
desired aryl halide should oxidatively add into the catalytic
cycle. Next, the base deprotonates the substrate and
substitutes for the bromide associated with the palladium.
Finally, reductive elimination occurs to produce the desired
gamma-arylated product.
In conclusion, we have reported a method to synthesize
γ-arylated 7-methoxy-4-methylcoumarin using a variety of
aryl halides. We were able to utilize the less expensive
Xantphos Pd G3 over the more expensive N-Xantphos Pd
G3 precatalyst for most of the aryl halides, except the aryl
chlorides. We were able to do so using lower temperatures
as well as only reacting for 24 hours. These compounds
were UV active and could be easily observed via TLC
analysis due to their highly fluorescent blue property.
These fluorescent compounds may have applications in
transistors, laser dyes, or even for medicinal purposes.
Future studies could explore utilizing these compounds in a
variety of ways as well as studying the diarylated product
for their fluorescent capabilities. Ultimately this method
provides a simple way of functionalizing 7-methoxy-4-
methylcoumarin at the γ-position and creating new
coumarin derivatives.
4% Xantphos G3
MeO
O
O
MeO
O
O
or
4% N-Xantphos G3
THF, 50-90 °C, 24 h
3.0 equiv, LiHMDS
+
ArX
Ar
Product
Yield
(%)a
Entry
Ar–X
aryl bromidesb
1
2
3
4
5
6
7
8
bromobenzene
4-bromoanisole
3-bromoanisole
2-bromoanisole
4-bromo-tert-butylbenzene
3-bromotoluene
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
90
88
93
98
75
70
65
81
74
68
70
22
95
92
57
32
70
4-bromotoluene
2-bromomesitylene
2-bromonaphthalene
2-bromo-4-tert-butyltoluene
4-bromo- N,N-dimethylaniline
4-bromobenzotrifluoride
4-bromobenzonitrile
5-bromobenzofuran
2-bromopyridinee
9
10
11
12
13
14
15
16
17
3-bromopyridinee
4-chlorobromobenzene
aryl iodidesc
18
19
20
21
4-iodoanisole
2
42
53
70
84
1-iodonaphthalene
4-bromoiodobenzene
2-iodotoluene
18
19
20
aryl chloridesd
chlorobenzene
1-chloronapthalene
4-chlorobenzophenone
aryl triflateb
22
23
24
1
18
21
70
58
23
25
4-methoxyphenyl-
trifluoromethanesulfonate
unsuccessful substrates
beta-bromostyrene
3-bromobenzothiophene
4-chloroanisole
2
84
26
27
28
a Isolated yield after column chromatography; 70 °C, Xantphos
b
c
e
G3; 50 °C, Xantphos G3; d 90 °C, N-Xantphos G3; Incomplete
Appendix A. Supplementary data.
reaction.
Full experimental details along with a table of ligand structures
tested in the reaction development are available in the Electronic
Supplementary Information (ESI). 1H and 13C NMR spectra for all
compounds (PDF) are also provided. Supplementary data to this
article can be found online at .
The aryl iodide, aryl chloride, and aryl triflate examples
shown in entries 18-25 also provided the desired products.
o
Aryl iodides reacted at lower temperature (50 C) than the
o
aryl bromides (70 C). The aryl chlorides required higher
o
temperatures (90 C) and N-Xantphos G3 rather than the
less expensive variant, Xantphos G3, which was the
Acknowledgements

JOURNAL PRE-P(R10O) SOtevFens RW, Mukaiyama T. Chem. Lett. 1985; 14: 851-854.
The authors acknowledge the Charles Casey Undergraduate
(11) a) Yamamoto Y, Hatsuya S, Yamada, J.. J. Chem. Soc. Chem.
Commun. 1988; 2: 86-87. b) Yamamoto Y, Hatsuya S, Yamada J. J.
Org. Chem. 1990; 55: 3118-3128.
(12) Terao Y, Satoh T, Miura M, Nomura M. Tetrahedron Lett.
1998; 39: 6203-6206.
(13) Varseev GN, Maier ME. Org. Lett. 2005; 7: 3881-3884.
(14) Hyde AM, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47:
177-180.
(15) Hyde AM, Buchwald SL. Org. Lett., 2009; 11: 2663-2665.
(16) Makarov IS, Kuwahara T, Jusseau X, Ryu I, Lindhardt AT,
Skrydstrup T. J. Am. Chem. Soc. 2015; 137: 14043-14046.
(17) Dikova A, Cheval NP, Blanc A, Weibel JM, Pale P. Adv.
Synth. Catal. 2015; 357: 4093-4100.
(18) Shah P, Santana D, García J, Serrano JL, Naik M, Pednekar S,
Kapdi AR. Tetrahedron, 2013; 69: 1446-1453.
(19) Wu J, Liao Y, Yang Z.. J. Org. Chem. 2001; 66: 3642-3645.
(20) Wu J, Yang Z.. J. Org. Chem. 2001; 66: 7875-7878.
(21) Bruno NC, Tudge MT, Buchwald SL. Chem. Sci. 2013; 4:
916-920.
(22) Zhang J, Bellomo A, Trongsiriwat N, Jia T, Carroll PJ, Dreher
SD, Tudge MT, Yin H, Robinson JR, Schelter EJ, Walsh PJ.. J. Am.
Chem. Soc. 2014; 136: 6276-6287.
(23) Driver MS, Hartwig JF. J. Am. Chem. Soc. 1996; 118: 7217-
7218.
Research Fellowship for funding support. Bryn Mawr College and
the Isabel H. Benham Fund for Faculty Research are thanked for
funding support. The authors acknowledge the National Science
Foundation for a Major Research Instrumentation Award (CHE-
0958996), which funded the acquisition of the NMR spectrometer
used in this work.
References
(1) a) Sardari S, Mori Y, Horita K, Micetich RG, Nishibe S,
Daneshtalab M. Bioorg. Med. Chem., 1999; 7: 1933-1940. b)
Montagner C, de Souza SM, Groposo C, Monache FD, Smânia EFA,
Smânia Jr A. Zeitschrift fur Naturforschung C. 2008; 63: 21-28.
(2) Kirsch G, Abdelwahab AB, Chaimbault P. Molecules 2016; 21:
1322.
(3) Xie L, Takeuchi Y, Cosentino LM, MacPhail AT, Lee HK. J.
Med. Chem. 2001; 44: 664-671.
(4) Coumarin and Coumarin Derivatives
| Thermo Fisher
Scientific-US. https://www.thermofisher.com/us/en/home/life-
science/cell-analysis/fluorophores/coumarin.html (accessed Sep 25,
2018).
(5) Uno M, Seto K, Takahashi S. J. Chem. Soc.,Chem. Commun.,
1984; 14: 932-933.
(6) a) Moradi WA, Buchwald SL. J. Am. Chem. Soc. 2001; 123:
7996-8002. b) Culkin DA, Hartwig JF.. Acc. Chem. Res. 2003; 36:
234-245. c) Palucki M, Buchwald SL. J. Am. Chem. Soc. 1997; 119:
11108-9.
(7) Hesp KD, Lundgren RJ, Stradiotto M. J. Am. Chem. Soc. 2011;
133: 5194-5197.
(8) Huang DS,.; Hartwig JF. Angew. Chem. Int. Ed. 2010; 49:
5757-5761.
(9) a) Savu PM, Katzenellenbogen JA. J. Org. Chem. 1981; 46:
239-250. b) Katzenellenbogen JA, Crumrine AL. J. Am. Chem. Soc.
1974; 96: 5662-5663.
(24) Mao J, Zhang J, Zhang S, Walsh PJ. Dalton Trans., 2018, 47,
8690-8696.
(25) Bordwell FG. Acc. Chem. Res., 1988, 21, 456-463.
(26) (a) Schmink JR, Baker Dockrey SA, Zhang T, Chebet N, van
Venrooy A, Sexton M, Lew SI, Chou S, Okazaki A. Org. Lett. 2016;
18: 6360-6363. (b) Munjanja L, Brennessel WW, Jones WD.
Organometallics 2015; 34: 1716-1724. (c) Munjanja L, Brennessel
WW, Jones WD. Organometallics 2015; 34: 4574-4580.

JOURNAL PRE-PROOF
Highlights:
-Regio- and chemoselective enolate gamma-arylation
-Xantphos ligand critical to reaction success
-Rapid synthesis of various C-4 benzyl coumarin derivatives
5