Selective Preparation of Xanthones from 2-Bromofluorobenzenes and Salicylaldehydes via Palladium-Catalyzed Acylation-SNAr Approach

Article abstract of DOI:10.1055/s-0035-1561563

A regioselective pathway for the preparation of xanthones from 2-bromofluorobenzenes and salicylaldehydes has been developed. The reaction proceeded through palladium-catalyzed acylation-S_NAr sequence. Good to moderate yields of the desired xanthones were prepared in one step. Based on the results of control experiments, a possible reaction mechanism has been proposed.

Full text of DOI:10.1055/s-0035-1561563

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
C. Shen, X.-F. Wu
Letter
Synlett
Selective Preparation of Xanthones from 2-Bromofluorobenzenes
and Salicylaldehydes via Palladium-Catalyzed Acylation–SNAr Ap-
proach
Chaoren Shen
O
Br
Pd(OAc)2, BuPAd2, DMF, K2CO3
120 °C, 12 h
O
Xiao-Feng Wu*
+
R2
F
R2
HO
R1
O
Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
xiao-feng.wu@catalysis.de
R1
up to 81% yield
R1 = H, Me, Cl, F
R2 = H, OMe, Cl, NO2, CO2Me
Received: 25.11.2015
Accepted: 12.01.2016
Published online: 04.02.2016
ly available substrates and to achieve the regioselective syn-
thesis of xanthones.
Using 2-bromofluorobenzene (1a) and salicylaldehyde
(2a) as the standard substrates, conditions were investigat-
ed (Table 1). Initially, we found that 41% yield of the desired
product was obtained with 2.5 mol% PdCl2(PPh3)2 as the
precatalyst and 2.0 equivalents K2CO3 as the base in DMF at
120 °C (Table 1, entry 1). Besides the xanthone product, 25%
of 2,2′-difluoro-1,1′-biphenyl as the major side product
were isolated as well. The biaryl byproduct was generated
from the palladium-catalyzed homocoupling of 1a. The
generation of homocoupling byproduct also leads to the in-
complete conversion of salicylaldehyde. Besides the side re-
action, the premature decomposition of palladium catalyst
and formation of palladium black in the solution of reduc-
tive salicylaldehyde contributed to the low yield. Therefore
various measures including changing solvents (Table 1, en-
tries 2–4) and bases (Table 1, entries 5 and 6), employing
Pd(PPh3)4 (Table 1, entry 7) and adjusting reaction tempera-
ture (Table 1, entries 8 and 9) were attempted to inhibit the
side reaction and palladium black precipitation. Neverthe-
less none of them can further improve the yield and inhibit
the side reaction or generation of palladium black. The ele-
vated temperature accelerated the deposition of palladium
black. Increasing the palladium loading also has no signifi-
cant promotion on the yield (Table 1, entry 10). To exclude
the potential catalytic activity of deposed palladium black,
palladium on activated charcoal was also examined (Table
1, entry 11). It proves that palladium black has no catalytic
activity. Trials of Pd(OAc)2 with BINAP and DPPF ligands
show that bidentate phosphine ligand is not suitable for
this reaction (Table 1, entries 12 and 13). Although elec-
tron-rich tributylphosphine ligand is able to effectively in-
hibit the generation of palladium black, it prohibits the re-
action as well (Table 1, entries 14 and 15). Tris(4-methoxy-
phenyl)phosphine, more electron-rich analogue of
DOI: 10.1055/s-0035-1561563; Art ID: st-2015-b0915-l
Abstract A regioselective pathway for the preparation of xanthones
from 2-bromofluorobenzenes and salicylaldehydes has been devel-
oped. The reaction proceeded through palladium-catalyzed acylation–
SNAr sequence. Good to moderate yields of the desired xanthones were
prepared in one step. Based on the results of control experiments, a
possible reaction mechanism has been proposed.
Key words xanthone, palladium catalyst, coupling, heterocycle syn-
thesis, acylation, nucleophilic substitution
As the central core of a variety of naturally occurring or-
ganic compounds and secondary metabolites produced by
many bacteria,1 xanthone is one of the ‘privileged’ hetero-
cycle skeletons in organic chemistry.2 Thus, the construc-
tion of xanthone scaffold has always been synthetically at-
tractive due to the practical application3 and diverse bio-
logical activities4 of xanthones and their derivatives.5
Traditionally, Friedel–Crafts acylation is the classical ap-
proach to construct xanthones via benzophenone interme-
diates.6 However Friedel–Crafts acylation not only suffers
from low regioselectivity and poor functional-group toler-
ance but also requires overstoichiometric Lewis acid. Re-
cently, various new methodologies have been developed for
the preparation of xanthones.7 Palladium-catalyzed acyla-
tion of aryl halides with aldehydes is one of the procedures
for building the benzophenone unit.7l,8 To the best of our
knowledge, only one example of utilizing palladium-cata-
lyzed acylation to synthesize xanthones has been reported7l
by employing 1,2-dibromoarenes as starting material
which leads to the issue on regionselectivity and limited
substrate scope. Therefore we intended to develop a palla-
dium-catalyzed acylation–SNAr approach with commercial-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
C. Shen, X.-F. Wu
Letter
Synlett
triphenylphosphine, cannot manage to improve the yield
(Table 1, entry 16). To our delight, when bulky electron-rich
trialkylphosphine ligand n-BuPAd2 was employed, no palla-
dium black precipitated (Table 1, entry 17). Further increas-
ing the palladium and ligand loading can boost the yield,
though the homocoupling side product of 1a and uncon-
verted salicylaldehyde still can be detected by GC–MS.
Having established the optimized reaction conditions,
we investigated the substrate scope of this reaction
(Scheme 1).9 We found that the optimized reaction condi-
tions are also applicable with 2-iodofluorobenzene as sub-
strate (3a). For substituted salicylaldehydes with an elec-
tron-neutral or electron-donating group, good to moderate
yields can be achieved with the protocol (3b–d). The reac-
tion conditions displayed tolerance to the chlorine substitu-
ent on salicylaldehyde (3e and 3f). However, for salicylalde-
hydes with a strong electron-withdrawing group, such as
nitro and methoxycarbonyl, on the para position of hydrox-
yl group, no desired xanthone product 3g or 3h was ob-
tained. For various substituted o-bromofluorobenzenes ex-
cept 1-bromo-2,4-difluorobenzene (1k) and 1-bromo-4-
chloro-2-fluorobenzene (1l), the desired substituted xan-
thone products can be obtained in moderated yields. For 1k
and 1l, besides homocoupling byproduct biaryls and trace
target products, several kinds of unidentified side products
were observed on GC–MS. Moreover moderate yields were
achieved with the protocol on the reaction between substi-
tuted o-bromofluorobenzenes and salicylaldehydes in gen-
eral.
In order to have an insight into the reaction mechanism,
a set of control reactions were conducted (Scheme 2). First-
ly, it was found that both phenyl bromide and iodobenzene
can react smoothly with salicylaldehyde under the standard
reaction conditions to generate the corresponding 2-hydroxy-
benzophenone while homocoupling side product biphenyl
was detected on GC–MS as well (Scheme 2, a). When o-bro-
mofluorobenzene reacted with phenol instead of salicylal-
dehyde, the conversion of o-bromofluorobenzene was less
than 5%. No 1-fluoro-2-phenoxybenzene or 1-bromo-2-
phenoxybenzene but trace amount of 2,2′-difluoro-1,1′-bi-
Table 1 Optimization of Conditionsa
O
[Pd], ligand,
base (2 equiv.)
Br
F
O
F
F
+
+
under argon
sovent (2 mL), temp., 12 h
OH
O
3a
1a
2a
Entry
[Pd] (mol%)
Ligand (mol%)
Base
K2CO3
Solvent
Temp (°C)
Yield (%)b
1
2
PdCl2(PPh3)2 (2.5)
PdCl2(PPh3)2 (2.5)
PdCl2(PPh3)2 (2.5)
PdCl2(PPh3)2 (2.5)
PdCl2(PPh3)2 (2.5)
PdCl2(PPh3)2 (2.5)
Pd(PPh3)4 (2.5)
PdCl2(PPh3)2 (2.5)
PdCl2(PPh3)2 (2.5)
PdCl2(PPh3)2 (5.0)
Pd/C (5 wt%) (2.5)
Pd(OAc)2 (2.5)
–
DMF
120
120
120
120
120
120
120
130
105
120
120
120
120
120
120
120
120
120
41
0
–
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1,4-dioxane
toluene
DMAc
DMF
3
–
0
4
–
21
0
5
–
6
–
DMF
0
7
–
DMF
38
21
35
51
0
8
–
DMF
9
–
DMF
10
11
12
13
14
15
16
17
18
–
DMF
–
DMF
rac-BINAP (3.0)
DPPF (3.0)
t-Bu3P·HBF4 (5.5)
n-Bu3P·HBF4 (5.5)
(p-MeOC6H4)3P (5.5)
n-BuPAd2 (5.5)
n-BuPAd2 (8.8)
DMF
0
Pd(OAc)2 (2.5)
DMF
0
Pd(OAc)2 (2.5)
DMF
13
0
Pd(OAc)2 (2.5)
DMF
Pd(OAc)2 (2.5)
DMF
42
43
76
Pd(OAc)2 (2.5)
DMF
Pd(OAc)2 (4.0)
DMF
a Ad = 1-adamantyl; rac-BINAP = (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene; DPPF = 1,1′-bis(diphenylphosphino)ferrocene; DMF = N,N-dimethylforma-
mide; DMAc = N,N-dimethylacetamide.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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C. Shen, X.-F. Wu
Letter
Synlett
O
Br
O
Pd(OAc)2 (4.0 mol%)
+
R2
HO
DMF (2 mL), BuPAd2 (8.8 mol%)
K2CO3 (2.0 equiv.)
R2
F
R1
O
R1
1
2
3
O
O
O
O
O
O
O
O
O
O
O
O
Me
Me
OMe
Me
Me
O
3a, 76% (79%a)
3b, 81%
3b, 72%
3c, 52%
3c, 61%
3d, 69%
O
O
O
O
O
Cl Cl
Cl
NO2
CO2Me
O
O
O
O
O
Me
O
Cl
3e, 65%
3e, 56%
3f, 57%
3g, 0%
3h, 0%
3i, 64%
O
O
O
O
O
O
F
Me
Me
O
F
O
Cl
O
O
O
O
F
Me
Me
3j, 57%
3k, 0%
3l, 0%
3m, 79%
3n, 77%
3o, 41%
O
O
O
O
Me
Cl Cl
Cl
F
Cl Cl
Cl
O
O
O
O
Cl
3p, 73%
3q, 64%
3r, 51%
3s, 47%
Scheme 1 Substrate scope of the reaction. Unless otherwise stated, reaction conditions: 1 (0.50 mmol), 2 (0.50 mmol), K2CO3 (2.0 equiv.), 4 mol%
Pd(OAc)2, 8.8 mol% n-BuPAd2, DMF (2 mL), Ar, 120 °C, 12 h. Isolated yields are given. a 1-Fluoro-2-iodobenzene instead of 1-bromo-2-fluorobenzene.
phenyl was observed on GC–MS (Scheme 2, b). It indicates
that palladium-catalyzed acylation is prior to SNAr. No 2-
fluorobenzophenone but still trace amount of 2,2′-difluoro-
1,1′-biphenyl was observed in the reaction of o-bromofluo-
robenzene with benzaldehyde on GC–MS (Scheme 2, c).
When we attempted to exchange the sequence of acylation
and SNAr, although both 2-halogen phenol and 2-fluoro-
benzaldehyde are consumed, only the molecular ion peak of
SNAr product can be observed on GC–MS (for X = Br, m/z =
276 and 278, for X = I, m/z = 324) and no desired xanthone
or even homocoupling byproduct was detected (Scheme 2,
e). Intramolecular acylation can proceed with neither 2-(2-
iodophenoxy)benzaldehyde nor 2-(2-bromophenoxy)benz-
aldehyde (Scheme 2, f). These suggest that ether cannot re-
place the role of hydroxyl group in the palladium-catalyzed
acylation. Further investigation on the reaction of iodoben-
zene with benzaldehyde revealed that although neither
conversion of benzaldehyde nor generation of benzophe-
none was observed on GC, iodobenzene was consumed and
biphenyl was formed from the homocoupling of phenyl io-
dide10 (Scheme 2, g). Similar result was also obtained in the
reaction between bromobenzene and benzaldehyde, but
the conversion of bromobenzene is much lower (Scheme 2,
h). The above results of control reactions imply that the hy-
droxyl group plays an important role in palladium-cata-
lyzed acylation of aryl bromide or aryl iodide with salicylal-
dehyde.
Based on the results of control experiments and the
properties of acyl–palladium(II) complex,11 we proposed a
plausible reaction mechanism that is different from the
previous reported plausible reaction mechanism involving
acyl–palladium(II) and acyl–palladium(IV) complexes.7l,8b
Our proposed plausible mechanism is a Heck-like process
(Scheme 3).8c,e Compound 1a first undergoes oxidative ad-
dition of palladium(0) complex to generate the aryl–palla-
dium(II) intermediate. Then the aryl–palladium(II) inter-
mediate coordinates with salicylaldehyde anion to form
complex A in the basic solution and followed by the forma-
tion of complex B through the addition of aryl–palladi-
um(II) onto the C=O double bond. After β-hydrogen elimi-
nation and following intramolecular SNAr, xanthone is gen-
erated. When transmetalation between aryl–palladium(II)
intermediates takes place and reductive elimination fol-
lows, the biaryl side product forms.12
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
C. Shen, X.-F. Wu
Letter
Synlett
a)
O
X
standard conditions
O
+
+
HO
HO
for X = Br, 74%a
for X = I, 83%a
X = Br or I
O
b)
c)
Br
OPh
Br
F
HO
standard conditions
standard conditions
O
+
+
F
X
F
< 5% conversionb
X = F or Br
< 5% conversionb
0%
O
O
f)
e)
X
standard conditions
standard conditions
O
+
no reaction
O
X = Br or I
F
OH
O
X = Br or I
X
> 98% conversionb
X = Br or I
X
O
g)
I
standard conditions
+
O
+
> 99% conversionb
0%
h)
O
Br
standard conditions
O
+
+
ca. 11% conversionb
0%
Scheme 2 Control reactions. Unless otherwise stated, standard reaction conditions: aryl bromide or aryl iodide (0.50 mmol), salicylaldehyde or benz-
aldehyde or phenol (0.50 mmol), K2CO3 (2.0 equiv.), Pd(OAc)2 (4 mol%), n-BuPAd2 (8.8 mol%), DMF (2 mL), Ar, 120 °C, 12 h. a Isolated yield. b Conversion
determined with n-hexadecane as internal standard.
In conclusion, we have achieved the selective prepara-
tion of xanthone from commercially available 2-bromofluo-
robenzenes and salicylaldehydes utilizing palladium-cata-
lyzed acylation–SNAr approach. Moderate to good yields
with excellent regioselectivity can be achieved. Based on
our control reactions, a plausible mechanism with a Heck-
like process has been proposed.
Br
Pd(0)Ln
F
O
1a
PdHLn-1
O
F
O
Pd(II)LnX
F
PdLn-1
O
F
O
O
F
F
H
F
3a
O
Pd
Ln-1
O
Scheme 3 A plausible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
C. Shen, X.-F. Wu
Letter
Synlett
Acknowledgment
Gerbino, D. C. Org. Lett. 2014, 16, 2846. (l) Wang, S.; Xie, K.; Tan,
Z.; An, X.; Zhou, X.; Guo, C.-C.; Peng, Z. Chem. Commun. 2009,
6469. (m) Rao, H.; Ma, X.; Liu, Q.; Li, Z.; Cao, S.; Li, C.-J. Adv.
Synth. Catal. 2013, 355, 2191. (n) Suzuki, Y.; Fukuta, Y.; Ota, S.;
Kamiya, M.; Sato, M. J. Org. Chem. 2011, 76, 3960. (o) Jiang, N.;
Li, S.-Y.; Xie, S.-S.; Yao, H.; Sun, H.; Wang, X.-B.; Kong, L.-Y. RSC
Adv. 2014, 4, 63632. (p) Barbero, N.; SanMartin, R.; Domínguez,
E. Green Chem. 2009, 11, 830. (q) Hintermann, L.; Masuo, R.;
Suzuki, K. Org. Lett. 2008, 10, 4859. (r) Woydziak, Z. R.; Fu, L.;
Peterson, B. R. J. Org. Chem. 2012, 77, 473. (s) Johnson, M. M.;
Naidoo, J. M.; Fernandes, M. A.; Mmutlane, E. M.; van Otterlo, W.
A. L.; de Koning, C. B. J. Org. Chem. 2010, 75, 8701.
The authors thank the state of Mecklenburg-Vorpommern, the
Bundesministerium für Bildung und Forschung (BMBF), and the Deut-
sche Forschungsgemeinschaft for financial support. Thanks also go to
China Scholarship Council (CSC) for their financial support to C. Shen
(No. 201406230040). We also thank Dr. C. Fischer, S. Schareina, A.
Koch, and S. Buchholz for their excellent technical and analytical sup-
port. We also appreciate the general support from Prof. Matthias Bel-
ler.
Supporting Information
(8) (a) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett. 1996,
823. (b) Álvarez-Bercedo, P.; Flores-Gaspar, A.; Correa, A.;
Martin, R. J. Am. Chem. Soc. 2010, 132, 466. (c) Solé, D.; Mariani,
F. J. Org. Chem. 2013, 78, 8136. (d) Nowrouzi, N.; Motevalli, S.;
Tarokh, D. J. Mol. Catal. A: Chem. 2015, 396, 224. (e) Solé, D.;
Mariani, F.; Fernández, I. Eur. J. Org. Chem. 2015, 3935.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561563.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(9) General Procedure for the Synthesis of Xanthone
To an oven-dried 25 mL Schlenk tube containing a stirring bar
was added Pd(OAc)2 (4.5 mg, 0.02 mmol), n-BuPAd2 (15.7 mg,
0.44 mmol), 2-bromofluorobenzene (0.50 mmol), salicylalde-
hyde (0.50 mmol), K2CO3 (1.0 mmol). The Schlenk tube was vac-
uumed and then purged with argon before DMF (2.0 mL) was
injected using a syringe. Afterwards the Schlenk tube in the ice
bath was degassed by evacuation and backfilling with argon
three times. The reaction mixture was then stirred for 12 h at
120 °C. After the reaction was complete, the reaction mixture
was diluted with H2O (5 mL), extracted with EtOAc (3 × 10 mL)
and dried with anhydrous Na2SO4. After filtration and addition
of silica gel into the solution, the organic solvent was reduced
evaporated. The crude product was purified by column chroma-
tography using EtOAc–n-pentane.
(1) (a) Roberts, J. C. Chem. Rev. 1961, 61, 591. (b) Masters, K.-S.;
Bräse, S.Chem. Rev. 2012, 112, 3717.
(2) Lesch, B.; Bräse, S.Angew. Chem. Int. Ed. 2004, 43, 115.
(3) (a) Steiner, L. F.; Summerland, S. A. J. Econ. Entomol. 1943, 36,
435. (b) Engel, M. G.; Engel, F. L. J. Biol. Chem. 1947, 167, 535.
(c) Obot, I. B.; Obi-Egbedib, N. O. Curr. Appl. Phys. 2011, 11, 382.
(4) For selected recent examples, see: (a) Palmer, B. D.; Henare, K.;
Woon, S.-T.; Sutherland, R.; Reddy, C.; Wang, L.-C. S.; Kieda, C.;
Ching, L.-M. J. Med. Chem. 2007, 50, 3757. (b) Omolo, J. J.;
Johnson, M. M.; van Vuuren, S. F.; de Koning, C. B. Bioorg. Med.
Chem. Lett. 2011, 21, 7085. (c) Guo, N.; Liu, J.; Qin, L.; Jiang, D.;
You, X.; Lu, K.; Teng, Y.-O.; Yu, P. J. Asian Nat. Prod. Res. 2015, 17,
377.
(5) Sousa, E.; Pinto, M. M. Curr. Med. Chem. 2005, 12, 2447.
(6) Holleman, A. F. Org. Synth. 1927, 7, 84.
Xanthenone (3a)
White solid; yield: 74.5 mg (76%). 1H NMR (300 MHz, CDCl3):
δ = 8.35 (2 H, ddd, J = 8.0, 1.7, 0.5 Hz), 7.73 (2 H, ddd, J = 8.7, 7.1,
1.8 Hz), 7.52–7.48 (2 H, m), 7.38 (2 H, ddd, J = 8.1, 7.1, 1.1 Hz).
13C NMR (75 MHz, CDCl3): δ = 177.27, 156.20, 134.86, 126.77,
123.94, 121.88, 118.02. GC–MS (EI, 70 eV): m/z (%) = 196 (100),
168 (75), 139 (58), 113 (6), 92 (8), 74 (11), 63 (20). HRMS (EI):
m/z calcd for C13H8O2 [M]+: 196.05188; found: 196.05185.
(10) (a) Wang, L.; Lu, W. Org. Lett. 2009, 11, 1079. (b) Li, C.-L.; Qi, X.;
Wu, X.-F. J. Mol. Catal. A: Chem. 2015, 406, 94.
(7) For some recent representative synthetic pathways of xantho-
nes, see: (a) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273.
(b) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583. (c) Wertz,
S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928. (d) Yang, J.;
Dong, C.; Li, H.; Li, H.; Li, Y. Chin. Sci. Bull. 2012, 57, 2364.
(e) Wang, P.; Rao, H.; Hua, R.; Li, C.-J. Org. Lett. 2012, 14, 902.
(f) Manna, S. K.; Lavanya, S.; Manda, K.; Panda, G. Tetrahedron
Lett. 2014, 55, 5759. (g) Zhang, H.; Shi, R.; Gan, P.; Liu, C.; Ding,
A.; Wang, Q.; Lei, A. Angew. Chem. Int. Ed. 2012, 51, 5204. (h) Xu,
Y.; Zhou, J.; Zhang, C.; Chen, K.; Zhang, T.; Du, Z. Tetrahedron
Lett. 2014, 55, 6432. (i) Genovese, S.; Fiorito, S.; Specchiulli, M.
C.; Taddeo, V. A.; Epifano, F. Tetrahedron Lett. 2015, 56, 847.
(j) Hu, J.; Adogla, E. A.; Ju, Y.; Fan, D.; Wang, Q. Chem. Commun.
2012, 48, 11256. (k) Menéndez, C. A.; Nador, F.; Radivoy, G.;
(11) (a) Stephan, M. S.; Teunissen, A. J. J. M.; Verzijl, G. K. M.; de Vries,
J. G. Angew. Chem. Int. Ed. 1998, 37, 662. (b) Jutand, A.; Négri, S.;
de Vries, J. G. Eur. J. Inorg. Chem. 2002, 1711.
(12) Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Nature 2015, 524,
454.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E