Intermolecular C-O addition of carboxylic acids to arynes: Synthesis of o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones

Article abstract of DOI:10.1016/j.tet.2013.01.078

An efficient and simple route to biologically and pharmaceutically important o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones has been developed utilizing readily available carboxylic acids and commercially available o-(trimethylsilyl)aryl tr

Full text of DOI:10.1016/j.tet.2013.01.078

Tetrahedron 69 (2013) 2789e2798
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intermolecular CeO addition of carboxylic acids to arynes: synthesis
of o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones
*
Anton V. Dubrovskiy, Richard C. Larock
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and simple route to biologically and pharmaceutically important o-hydroxyaryl ketones,
xanthones, 4-chromanones, and flavones has been developed utilizing readily available carboxylic acids
and commercially available o-(trimethylsilyl)aryl triflates.
Received 9 December 2012
Received in revised form 23 January 2013
Accepted 25 January 2013
Available online 4 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
corresponding CeO insertion products.9 Later, Ma and co-workers
reported an interesting cascade sequence that starts from 2,3-
Aryne insertions into CeN,1,2 CeC,3 CeSi,4 CeSn,5 and CeHal6
bonds and the C]O bond of aldehydes7 have been well docu-
mented in the literature. The formal insertion of a benzyne ring into
the CeO bond of a carboxylic acid would provide a powerful syn-
thetic transformation to access a range of biologically important
molecules. In our previous work, we have reported that the re-
action of arenecarboxylic acids with arynes in MeCN provides the
corresponding aryl esters in excellent yields, i.e., the product is
formed by formal benzyne insertion into the OeH bond of the
starting material (Scheme 1).8 Following up on this chemistry, we
found and reported in an earlier communication reaction condi-
tions, which allow one to obtain good to excellent yields of the
allenoic acids and affords chromones in good to excellent yields
using KF/18-crown-6 in THF.10 The present manuscript provides
a complete account of the scope and limitations of the synthesis of
o-hydroxyaryl ketones starting from carboxylic acids, as well as its
applications to the synthesis of xanthones, 4-chromanones, and
flavones.
2. Results and discussion
2.1. Synthesis of o-hydroxyaryl ketones
We allowed a simple aliphatic carboxylic acid (butyric acid, 1) to
react with the Kobayashi benzyne precursor o-(trimethylsilyl)
phenyl triflate11 (2) in the presence of CsF in acetonitrile (Table 1).
At both room temperature and at 65 ꢀC, as expected,8 the O-ary-
lation product, ester 4, was predominately formed (entries 1 and 2).
To avoid the formation of the latter product, we switched to a far
less acidic solvent, THF. To our delight, together with the mono-
arylation product 4, the o-hydroxyaryl ketone 3 was formed in
a 26% yield (entry 3).
A closer examination of the reaction mixture revealed that ad-
ditional products inseparable by chromatography, namely tertiary
alcohol 5 and xanthene 6, both bisearyne insertion products, are
produced (Scheme 2). Based on our findings, we propose the fol-
lowing mechanism for the formation of products 3e6. The aryl
anion intermediate 8, formed after nucleophilic attack of the car-
boxylate group of the carboxylic acid on the highly electrophilic
benzyne (7) generated in situ, undergoes a formal anionic Fries
rearrangement to the phenoxide 10 by a four-membered ring in-
termediate 9.12 This results in formation of the desired o-hydrox-
yaryl ketone 3 after proton abstraction from the reaction media.
The monoarylation product 4 can be formed by protonation of the
O
O
TMS
OTf
4 equiv CsF
MeCN, rt
O
O
HO
X
+
X
2 equiv
O
MeCN
O
O
X
X
H
66 - 98%
Scheme 1. Known reaction of arenecarboxylic acids and arynes in MeCN.
* Corresponding author. E-mail address: larock@iastate.edu (R.C. Larock).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.078

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A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
Table 1
Optimization of benzyne insertion into the CeO bond of an aliphatic carboxylic acida
O
O
F- source
solvent
TMS
TfO
O
Et
Et
Et
+
+
OH
OPh
HO
4
1
2
3
Entry
Equiv of 2
Fluoride source (equiv)
Solvent, mL
Temp (ꢀC)
% Yield of 3b
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.5
1.75
2
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (4)
CsF (4.7)
CsF (6)
TBAT (2)
MeCN, 5
MeCN, 5
THF, 5
rt
65
65
125
65
125
125
125
125
125
125
125
50
0c
0c
26
43
20c
27c
14c
4c
50
77
70
34
34c
THF, 5
DME, 5
DME, 5
THF, 5
7d
8e
9
10
11
12
13
THF, 5
THF, 15
THF, 15
THF, 15
THF, 15
Tol, 5
1.5
Bold values depict the optimized conditions that were used for investigation of the reaction’s scope.
a
All reactions were carried out on a 0.25 mmol scale in 5 mL of solvent during a 24 h period.
b
Isolated yields, unless stated otherwise.
c
1H NMR spectroscopic yields using an internal standard.
d
K2CO3 (1 equiv) was added to the reaction mixture.
Cs2CO3 (1 equiv) was added to the reaction mixture.
e
O
OH
O
O
TMS
TfO
O
CsF
Et
+
+
+
O
OH
Et
THF, Δ
Et
Et
1
2
4
6
3
Et
F-
O
NuH
NuH
O
-H2O
O
O
O
Et
O
Et
5
HO
Et
7
O
8
10
7
O
O
Et
Et
11
O
9
O
Scheme 2. Proposed mechanism for the reaction of butyric acid and benzyne.
aryl anion 8. The by-product 5 is likely formed from reaction of the
phenoxide 10 with an additional benzyne intermediate 7,13 which
followed by dehydration, leads to formation of the xanthene 6. The
proposed four-membered ring intermediate 9 is consistent with
similar intermediates reported recently by Greaney’s group in
a related study of primary aromatic amides.2
Isolation of the CeO insertion product 3 prompted us to pursue
this project, as it constitutes an expeditious route to o-hydroxyaryl
ketones, often used as precursors for the synthesis of biologically
important flavones and chalcones,14 starting from cheap and easily
accessible carboxylic acids. Most traditional synthetic approaches to
o-hydroxyaryl ketones ultimately proceed by the FriedeleCrafts ac-
ylation of phenols with acyl chlorides in the presence of Lewis
acids,15 or the Fries rearrangement of suitable phenyl esters.16 Both of
these procedures suffer from regioselectivity issues and proceed in
the presence of strong Lewis acids, which limits the potential of this
transformation. It is noteworthy that o-hydroxyaryl ketones are an
important class of biologically interesting structures,17 and some of
them, such as cotoin and hydrocotoin, have been found in nature.18
Unexpectedly, running the reaction at higher temperatures
allowed us to achieve higher yields of the desired hydroxyaryl ke-
tone, at the same time lowering the relative ratios of the major
side-products 4e6. Running the reaction at 125 ꢀC (sealed vial)
allowed us to isolate the desired hydroxyaryl ketone 3 in a 43% yield
(Table 1, entry 4). Changing the solvent to 1,2-dimethoxyethane
(DME) resulted in lower yields of the desired product 3 and

A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
2791
higher ratios of the arylation product 4 at both 65 ꢀC and 125 ꢀC
(entries 5 and 6). To test the possibility that the undesired pro-
tonation of the intermediate 8 is caused by the proton of the
starting acid, we attempted to run the reaction in the presence of
a stoichiometric amount of different bases. Unfortunately, the use
of K2CO3 as an additive resulted in a lower (14%) yield, which might
be caused by the poor solubility of the butyrate formed (entry 7).
Running the reaction in the presence of Cs2CO3 resulted in a still
lower (4%) yield of the desired product with significant amounts of
the ester 4 and the alkene 6 being detected (entry 8). Other bases
(e.g., NaH, Na2CO3, KOPiv, sym-collidine) failed to improve the yield
of the desired hydroxyaryl ketone. Using the sodium salt of the
butyric acid or its TMS-ether resulted in lower yields of the desired
product 3 and higher relative ratios of the alkene 6.
Increasing the amount of the benzyne precursor 1 from 1.0 to
1.2 equiv and diluting the reaction mixture resulted in an increased
(50%) yield of the desired product (entry 9). A further increase in the
amount of the benzyne precursor (up to 2 equiv) revealed that the
highest yield (entry 10, 77%) is achieved with a 1.5-fold excess of the
benzyne precursor to the starting butyric acid (entries 9e12).
A further increase in the amount of benzyne results in higher ratios
of the bis-arylated products 5 and 6, thus lowering the yield of the
desired product 3. Extending the time of the reaction and using more
CsF does not have any significant effect on the yield of the desired
ketone 3. We also attempted to run the reaction under Greaney’s
conditions, tetrabutylammonium triphenyldifluorosilicate (TBAT) in
toluene at 50 ꢀC.2 However, only a 34% yield of the product 3 was
observed in this case, while the undesired ester 4 was detected in
a 54% yield (entry 13). We subsequently applied our optimized
conditions (Table 1, entry 10) to other carboxylic acids (Table 2).
product 14 was successfully isolated in a 72% yield (entry 4). The
ester- and ketone-containing carboxylic acids provided the desired
products 15 and 16 in lower 58% and 39% yields, respectively (en-
tries 5 and 6).
A number of
indoleacetic acid, N-acetylglycine, succinimidoacetic acid, and
-bromophenylacetic acid were examined under our optimized
a-substituted carboxylic acids, such as N-methyl-
a
reaction conditions. Unfortunately, presumably due to either the
increased acidity of the protons next to the reacting carboxylic acid
functionality and/or the low solubility of some of these substrates
in THF, most of these reactions resulted in the formation of in-
separable mixtures of by-products with the undesired O-arylation
products often being formed in considerable amounts. One of the
more successful examples of this type of carboxylic acid is
3-thiopheneacetic acid, which resulted in formation of the
hydroxyaryl ketone 17 in a 30% yield (entry 7).
In the case of arenecarboxylic acids, perhaps due to the in-
creased acidity of the resulting hydroxyaryl ketones, over-arylation
products were a major concern not only because of decreased
yields of the desired insertion products, but also because of com-
plications during their isolation. Thus, in the case of p-nitrobenzoic
acid, the corresponding tertiary alcohol analogous to intermediate
5 could be isolated in a 54% yield and none of the desired
hydroxyaryl ketone was detected. Changing the electronic proper-
ties of the substituents on the phenyl ring had little effect on the
outcome of the reaction. The desired products of p-methoxy- and
p-methylbenzoic acids were formed in less than 30% yields (as
measured by 1H NMR spectroscopic analysis using an internal
standard). Unfortunately, none of these products could be isolated
due to a number of side-products with similar polarities. One of the
more successful reactions was with
afforded the corresponding o-hydroxyaryl ketone 18 in a 44% yield
(entry 8).
Allowing butyric acid to react with an excess (3 equiv) of the
benzyne precursor in DME, the bisearyne insertion xanthene
product 6 was obtained in a 50% yield (Scheme 3).19 Xanthenes are
a pharmaceutically important scaffold with many members shown
to possess antimalarial,20 antitrypanosomal,21 antileishmanial,21
and antitumor22 activities.
b-naphthoic acid, which
Table 2
Reaction of carboxylic acids with arynesa
O
O
TMS
TfO
4.0 equiv CsF
THF, 125 oC
24 h
R
+
R
OH
HO
1.5 equiv
Entry
R
Product
Yieldb (%)
77
Et
1
2
3
12
68
Ph
3
4
13
14
62
72
Scheme 3. Synthesis of a xanthene.
MeO
Ph
5
15
58
O
We also examined the reaction of butyric acid with the un-
symmetrical dimethoxy-substituted benzyne precursor 19.23 We
were delighted to observe the regioselective formation of the de-
sired isomer 20 in a 49% yield (Scheme 4). The regioselectivity is
consistent with that reported by the Stoltz group.23 The product 20
is a natural product that has been found in an Indian shrub Dyso-
phylla stellata Benth.24
6
7
16
17
39
30
O
8
18
44
a
Reaction conditions: 0.25 mmol of acid, 1.5 equiv of benzyne precursor and
4.0 equiv of CsF in 15 mL of THF were heated in a closed vial at 125 ꢀC for 24 h.
b
Isolated yield.
This methodology tolerates cycloalkyl and benzyl groups. The
corresponding products 12 and 13 were obtained in 68% and 62%
yields, respectively (entries 2 and 3). The alkene-containing
Scheme 4. Synthesis of a naturally-occurring hydroxyaryl ketone.

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A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
Table 3 (continued)
2.2. Synthesis of xanthones
Entry
Hal
Product
Yieldb (%)
While the low efficiency of the reaction of arenecarboxylic acids
with arynes is likely due to the high reactivity of the phenolic OH
group of the resulting o-hydroxyaryl ketones toward arynes, trap-
ping the phenol by an intramolecular SNAr reaction could provide
an interesting route to xanthones and analogues, which are very
important ring systems in biology and pharmacy.25
7
Br
49c,d,e
Indeed,
a close examination of the reaction between
o-methoxybenzoic acid and benzyne revealed that about 58% of the
starting material has been converted to the xanthone 21 and only
12% could be assigned as the expected o-hydroxyaryl ketone. When
o-halobenzoic acids are allowed to react with the benzyne pre-
cursor and CsF under our previously optimized conditions, we were
delighted to see formation of the xanthone 21 (Table 3). While
o-chloro and o-iodobenzoic acids provided poor yields (30% and
38%, respectively), the o-fluorobenzoic acid afforded the desired
xanthone in an 80% yield (entry 1).
8
9
F
F
47f
71g
O
O
OMe
Table 3
Reaction of o-haloarenecarboxylic acids with arynesa
O
O
O
29
TMS
TfO
4.0 equiv CsF
THF, 125 oC
24 h
OH
+
R2
a
R1
R2
R1
Reaction conditions: 0.25 mmol of the carboxylic acid, 1.5 equiv of the benzyne
precursor and 4.0 equiv of CsF in 15 mL of THF were heated in a closed vial at 125 ꢀC
for 24 h.
Hal
1.5 equiv
b
Isolated yield.
c
Reaction conditions: 0.25 mmol of the carboxylic acid, 1.5 equiv of the aryne
Entry
Hal
F
Product
Yieldb (%)
precursor, and 2.0 equiv of TBAT in 5 mL of toluene were heated at 60 ꢀC for 24 h.
d
The isolated o-hydroxyaryl ketone was heated in MeCN in the presence of
O
2 equiv of K2CO3 at 100 ꢀC for 24 h to provide the desired xanthone.
e
3,5-Dimethoxy-2-(trimethylsilyl)phenyl triflate was used as the aryne
precursor.
1
2
80
79
f
4,5-Dimethyl-2-(trimethylsilyl)phenyl triflate was used as the aryne precursor.
3-Methoxy-2-(trimethylsilyl)phenyl triflate was used as the aryne precursor.
g
O
21
O
Our xanthone process tolerates other halides present in the
benzoic acid moiety. Thus, the bromo-substituted xanthone 22 was
isolated in a 79% yield (entry 2). The presence of the bromide func-
tionality provides a useful handle for further diversification of the
system if a combinatorial library of these compounds is desired.26
We could obtain 4-aza-xanthone (23), albeit in only a 22% yield
(entry 3), starting from 2-chloronicotinic acid. The poor yield in this
reaction can be attributed to the high reactivity of the nucleophilic
pyridine nitrogen toward benzyne, an often reported process in the
literature.27 The reaction of the electron-poor nitro-substituted
carboxylic acid under our optimized reaction conditions provided
the desired xanthone 24 in only a 48% yield, with complications
during isolation of the desired product. However, running this re-
action under reaction conditions reported by the Greaney group for
a related insertion into the CeN bond of aromatic amides2 afforded
the xanthone 24 in a high 87% yield (entry 4). Running the reaction
of 1-bromo-2-naphthoic acid under analogous conditions afforded
the tetracyclic xanthone 25 in a 55% yield (entry 5).
The reaction of electron-rich 2-bromo-4,5-dimethoxybenzoic
acid with benzyne afforded only trace amounts of the desired
product 26 in both THFand DME. Employing the reaction conditions
reported by the Greaney group, in this case provided the uncyclized
o-hydroxyaryl ketone that upon cyclization in acetonitrile at ele-
vated temperatures in the presence of K2CO3 afforded the desired
xanthone 26 in a 59% overall yield (entry 6). Interestingly, the bis-
demethylated version of xanthone 26 has been shown to signifi-
cantly inhibit the growth of melanoma cancer cells and the mito-
genic response of human lymphocytes to a common mitogen PHA.28
Our standard xanthone protocol has also been used for the re-
action of 2-bromo-4,5-dimethoxybenzoic acid with the un-
symmetrical dimethoxybenzyne precursor 19. After the benzyne
insertion and subsequent induced SNAr reaction, the final
Br
F
O
22
O
3
4
5
6
Cl
22
N
O
23
O
O2N
Cl
Br
Br
87c
55c
59c,d
O
24
O
O
25
O
O
MeO
MeO
26

A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
2793
Table 4
tetraoxygenated xanthone 27 was isolated in a 49% overall yield
Reaction of acrylic acids with arynesa
(entry 7). It is noteworthy that the compound 27 is found in nature,
as well as partially demethylated analogues.29 The tetrademethy-
lated version, norathyriol, has been found in at least 19 different
natural sources and has been shown to possess hypotensive ac-
tivity.30 It is also an effective inhibitor of cutaneous plasma ex-
travasation31 and a monoamine oxidase inhibitor.32
Reacting o-fluorobenzoic acid with 4,5-dimethylbenzyne and
unsymmetrical 3-methoxybenzyne under our CsF/THF optimized
conditions afforded the corresponding xanthones 28 and 29 in 47%
and 71% yields, respectively (entries 8 and 9). The low yield in the
former case may be attributed to the poor solubility (and hence
isolation complications) of the desired product 28. The un-
symmetrical benzyne precursor provided the product 29 as a single
regioisomer.33
Entry R1
R2
R3
H
Product
Yieldb (%)
1
Me
H
30
31
84
2
H
H
85
3
4
5
H
H
H
nPr
H
H
32
33
82
71
77
NC(CH2)3
Me
Me 34
2.3. Synthesis of 4-chromanones and flavones
Me
Me
6
H
Me 35
64
The phenolate anion (see intermediate 10 in Scheme 2) formed
in situ could also be potentially trapped with a Michael acceptor in
an intramolecular fashion. This would open up a novel route to
biologically interesting 4-chromanones, flavones, and chromones
from readily available acrylic and propiolic acids.34
7
8
9
10
Ph
H
H
Ph
Me Me
Me Ph
H
H
H
H
36
37
38
39
56
74c
76d
67e
Indeed, in the reaction of methacrylic acid with benzyne
under the optimized reaction conditions used in the synthesis of
o-hydroxyaryl ketones, the 4-chromanone 30 was formed in
a moderate 58% yield. Surprisingly, none of the dihydrocoumarin
product that could result from the ring closure of an intermediate
like 8 was detected, which suggests that the formation of the four-
membered ring intermediate is a more favorable pathway. None of
the uncyclized hydroxyaryl ketone product was detected either,
suggesting a very fast rate of cyclization for the final Michael addi-
tion reaction. Running the methacrylic acid reaction in the presence
of various bases (e.g., Cs2CO3, Et3N, iPr2NEt, sym-collidine) failed to
improve the yield of the reaction. Substituting the substrate with
either the TES- or TBDMS-esters of methacrylic acid both afforded
the desired product in lower yields. Running the reaction at de-
creased temperatures and/or switching the solvent to DME resulted
in a lower yield of the desired product. After additional optimiza-
tion, we have found that diluting the reaction mixture helps to
improve the yield of the 4-chromanone 30 by w10%. Apparently,
one of the side reactions involves an intermolecular process. One of
the significant challenges observed in this transformation is the
poor reactivity of the starting carboxylic acid. As a result, running
the reaction with <1.5 equiv of the benzyne precursor does not lead
to complete conversion of the starting carboxylic acid.35 Running
the reaction with >2.0 equiv of the precursor 2 allows the carboxylic
acid to react completely. However, it also results in increased
amounts of over-arylation products (e.g., an alcohol analogous to
intermediate 5 in Scheme 2). Running the reaction under dilute
conditions with 1.75 equiv of the benzyne precursor provides an
80% yield of the desired product 30. Finally, adding the benzyne
precursor and CsF in two separate portions allowed us to improve
the yield up to 84%.36 The latter reaction conditions were applied to
a number of other 2-alkenoic acids (Table 4).
11
12
H
H
40
41
78
0
H
H
CO2Me
13
Me
Ph
Me
53f
14
H
H
29c,g
a
Reaction conditions: 0.25 mmol of the carboxylic acid, 1.5 equiv of aryne pre-
cursor and 4.0 equiv of CsF in 15 mL of THF were heated in a closed vial at 125 ꢀC for
18 h. Then an additional 0.5 equiv of the aryne precursor and 1.0 equiv of CsF were
added and the heating continued at 125 ꢀC for 6 h.
b
Isolated yield.
c
The yield includes the product obtained after base-induced cyclization of the o-
hydroxyaryl ketone (see the Supplementary data).
d
The E/Z ratio is w1.8/1.
The E/Z ratio is w5.1/1.
e
f
4,5-Dimethoxy-2-(trimethylsilyl)phenyl triflate was used as the aryne
precursor.
g
3,5-Dimethoxy-2-(trimethylsilyl)phenyl triflate was used as the aryne
precursor.
o-hydroxyaryl chalcone. Treating the reaction mixture with a base
(piperidine/THF/H2O)37 cyclized the hydroxyaryl ketone to the de-
sired flavanone 37 in a 74% overall yield (entry 8). 2,3-Disubstituted
acrylic acids provided diastereomeric mixtures of chromanones 38
and 39 in 76% and 67% yields, respectively (entries 9 and 10).
Cyclopentene-1-carboxylic acid afforded the tricyclic product 40 in
a 78% yield with exclusively a cis configuration at the 5,6-ring junc-
tion (entry 11). Unfortunately, monomethyl fumarate (as well as
monomethyl maleate), bearing an ester group on the carbon-carbon
double bond, did not provide any of the expected chromanone
product (entry 12). One possible explanation might be the decreased
nucleophilicity of the carboxylic group toward the benzyne caused
by the presence of the two electron-withdrawing groups. Other
carboxylic acids that provided low yields (less than 30%) of the
3-Alkyl-substituted acrylic acids successfully provided the cor-
responding
cyclohexyl-substituted
and
propyl-substituted
4-chromanones 31 and 32 in 85% and 82% yields, respectively (en-
tries 2 and 3). The carboxylic acid with a nitrile substituent at the end
of an alkyl chain provided the 4-chromanone 33 in a 71% yield (entry
4). 3,3-Dialkyl-substituted acrylic acids (3-methyl-2-butenoic acid
and geranic acid) provided the corresponding chromanones 34 and
35 in good yields (77% and 64%, respectively) (entries 5 and 6).
a-Phenylacrylic acid provided the cyclized product 36 in a 56% yield
(entry 7). Interestingly, in the case of cinnamic acid, a 60% yield of the
desired product 37 was obtained along with the uncyclized

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A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
Table 5
expected products include 2,4-alkadienoic (2,4-hexadienoic and
5-phenyl-2,4-pentadienoic) acids and 3-heteroaryl-substituted
(2-thienyl and 3-indolyl) acrylic acids. These substrates could
potentially engage in DielseAlder reactions with the dienophilic
benzyne at such high temperatures.
Reaction of 2-alkynoic acids with arynesa
We have also examined the reaction of alkenoic acids with other
benzyne precursors. The symmetrical 4,5-dimethoxybenzyne,
when allowed to react with 3,3-dimethylacrylic acid, provided the
cyclized product 42 in a 53% yield.38 It is noteworthy that an ana-
logue of this compound, precocene II, exhibits significant anti-
juvenile hormone activity in insects.39
Entry
R
Product
Yieldb (%)
1
2
3
Ph
Me
H
48
49
50
56
64
71c
When cinnamic acid was allowed to react with the un-
symmetrical dimethoxybenzyne precursor 19, at first the uncycl-
ized o-hydroxychalcone was isolated in a 68% yield. Subjecting the
latter compound to a piperidine-promoted intramolecular Michael
addition reaction resulted in formation of the desired chromanone
43 in a 48% yield, along with 42% of the unreacted starting material.
A chiral version of compound 43 is a natural product found in
Caesalpinia pulcherrima,40 and the monodemethylated version of
the latter, known as pinostrobin, is reported to be an effective
aromatase inhibitor.41
The reaction of itaconic acid methyl ester 44 with benzyne under
our optimized conditions did not result in formation of the expected
flavanone. Instead, the 3-coumaranone derivative 45 was isolated in
a 79% yield (Scheme 5). Since monomethyl fumarate did not provide
any isolable product under identical reaction conditions (Table 4,
entry 12), this reaction is best explained mechanistically as follows:
(a) the carboxylic acid undergoes the expected insertion with
benzyne to provide intermediate 46; (b) the latter isomerizes to
a more stable isomer 47 under the reaction conditions; (c) intra-
molecular Michael addition in the substrate 47 results in formation
of the five-membered ring product 45.
a
Reaction conditions: 0.25 mmol of the carboxylic acid, 1.5 equiv of the aryne
precursor and 2.0 equiv of TBAT in 5 mL of toluene were heated at 60 ꢀC for 24 h.
b
Isolated yield.
c
Reaction conditions: 0.25 mmol of the carboxylic acid, 1.5 equiv of the aryne
precursor and 2.0 equiv of TBAT in 15 mL of THF were heated at 65 ꢀC for 24 h.
Using these optimized reaction conditions, we have examined
the reaction of several 2-alkynoic acids with benzyne. 2-Butynoic
acid provided the chromone 49 in a 64% yield (entry 2). The re-
action of the unsubstituted propiolic acid with CsF in THF did not
provide any recognizable products. However, running the reaction
in the presence of TBAT provided the desired chromone 50 in a 71%
yield (entry 3). Unfortunately, acetylenedicarboxylic acid provided
mixtures of unidentified products using either the CsF- or TBAT-
mediated protocols.
It is noteworthy that we can also obtain chromones in the reaction
of 2- and 3-haloalkenoic acids with benzyne. Apparently, the chro-
manones produced with 2-bromoacrylic and 2-bromocyclohexenoic
acids undergo an elimination reaction furnishing the chromones 50
and 53in 18% and 85%yields, respectively (Scheme 6). The low yield of
the former product might be due to a less favorable dehydrohaloge-
nation reaction, as well as the possible low stability of the starting
material under the reaction conditions that we have employed.
2.3.1. Further mechanistic considerations. Some further mechanistic
considerations follow. An acid-catalyzed Fries rearrangement
leading from ester 4 (see Scheme 2) to an o-hydroxyaryl ketone
(analogous to compound 3) has been considered as a mechanistic
possibility for our overall transformation. Based on literature ac-
counts, however, strong acidic media is absolutely necessary for
such a rearrangement to occur.42 Nevertheless, we allowed phenyl
methacrylate (54) to react with methacrylic acid in THF in
the presence of CsF at 120 ꢀC (Scheme 7). As expected, no
4-chromanone was detected under these reaction conditions after
24 h. Replacing the basic CsF media with 1 equiv of BF3ꢁEt2O did not
result in the formation of the target compound 30 either. However,
the benzyne intermediate or molecules that result from its gener-
ation might play the role of a Lewis acid in this transformation. In
a crossover experiment, we have allowed cinnamic acid to react
with 2 equiv of the benzyne precursor in the presence of CsF and
phenyl methacrylate at 125 ꢀC. Unexpectedly, the chromanone 30,
that could only be formed from the ester 54, was detected in the 1H
NMR spectrum of the crude reaction mixture, albeit in only trace
amounts. This suggests that the cationic Fries mechanism is, at the
most, a very minor pathway for the transformation of acrylic acids
into the corresponding chromanones.
We have also examined the possibility that methyl esters can en-
gage in a similar CeO insertion process with a benzyne. While no
traces of any reaction were observed in the case of methyl benzoate,
methyl methacrylate unexpectedly resulted in the formation of two
stable products in w10% yields. Once the structures of these products
were established, it became evident that no CeO insertion had taken
place in the starting ester 55. Instead, because of the favorable con-
figuration of the methacrylate unit, a set of two ene-reactions appar-
ently occurs to produce the two ester products 56 and 57 (Scheme 8).
Scheme 5. Mechanism for the formation of coumaranone 45.
We have also examined the reaction of phenylpropiolic acid
with benzyne in THF under our optimized reaction conditions.
Unfortunately, due to the high temperature of the reaction, the
major product observed was the decarboxylated starting material.
To minimize the side reaction observed in the reaction of phenyl-
propiolic acid, we attempted to decrease the temperature to 90 ꢀC.
Gratifyingly, the yield of the product increased to 48%. If we
employed TBAT, the desired product 48 could be isolated in a sim-
ilar 49% yield, while running the reaction at only 65 ꢀC. We then
replaced THF with toluene, essentially employing reaction condi-
tions analogous to those reported by Greaney’s group using am-
ides.2 Running the reaction in toluene at 60 ꢀC allowed us to obtain
the flavone 48 in increased yields, with the optimal conditions
employing 1.5 equiv of the benzyne precursor (56% yield; Table 5,
entry 1).

A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
2795
Scheme 6. Reaction of haloalkenoic acids with benzyne.
O
O
Me
Me
O
HO
1 equiv
no rxn after 24 h
4 equiv CsF
THF, 125 oC
54
O
Me
PhO
1 equiv
O
O
O
O
O
O
TMS
Me
Me
OH
PhO
+
+
+
6.7 equiv CsF
THF, 125 oC
TfO
Ph
Ph
2 equiv
1 equiv
54
37
30
~1
~1
traces
Scheme 7. Mechanistic investigation of the possible cationic Fries rearrangement.
Scheme 8. Mechanism of the double ene reaction.
After optimization studies, it was found that running the methyl
methacrylate reaction in acetonitrile at room temperature in the
presence of an excess of the benzyne (3 equiv), the diarylated
product 57 can be isolated in an 80% yield.
accessible carboxylic acids and subsequent reactions. Various
functional groups have proven to be compatible with the reaction
conditions. The method should prove useful and reliable for
accessing these biologically and pharmaceutically important het-
erocyclic structures.
Other methods leading to stereodefined trisubstituted alkenes
usually utilize multiple synthetic steps and require the use of
expensive rhodium catalysts.43 We therefore examined the scope
of our aryne ene reaction. Unfortunately, allylic systems similar
to methyl methacrylate, such as methacrylonitrile, methyl trans-
2-butenoate, 3-methyl-2-cyclohexenone, allyl, and benzyl cya-
nides, resulted in only a very low conversion of the starting
material or in the formation of mixtures of unidentified products.
While a few ene reactions with a benzyne intermediate have
been observed before,43 our reaction of methyl methacrylate
proceeds under very mild conditions (MeCN, room temperature)
and allows one to obtain the diarylated product 57 in a high
yield.
4. Experimental section
4.1. General
The 1H NMR spectra were recorded at 300, 400, and 600 MHz as
specified for particular compounds. The 13C NMR spectra were
recorded at 75, 100, and 150 MHz. Chemical shifts are reported in
d
units (parts per million) by assigning the TMS resonance in the 1H
NMR spectrum as 0.00 ppm and the CDCl3 resonance in the 13C
NMR spectrum as 77.23 ppm. All coupling constants (J) are reported
in Hertz (Hz). Thin layer chromatography was performed using
60 mesh silica gel plates, and visualization was effected by short
wavelength UV light (254 nm). All melting points are uncorrected.
High resolution mass spectra (HRMS) were recorded using EI at
70 eV or using a QTOF mass spectrometer (APCI at a voltage of
70 eV). All reagents were used directly as obtained commercially,
unless otherwise noted.
3. Conclusions
In conclusion, we have developed an efficient and simple route
to o-hydroxyaryl ketones, xanthones, 4-chromanones, flavones and
their analogues by aryne incorporation into the CeO bond of easily

2796
A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
The characterization of compounds 3, 6, 12e15, 18, 21, 23,
24 h. After allowing the reaction mixture to cool to room tem-
perature, the mixture was extracted with EtOAc (20 mLꢂ2) from
the brine solution (40 mL), the organic fractions were combined,
and the solvent was evaporated under reduced pressure. The
residue was purified by flash chromatography on silica gel using
hexanes/EtOAc as the eluent to afford the desired xanthone 24 as
a pale brown solid in an 87% yield: mp 203e205 ꢀC (lit. mp46
29, 30, 32, 34, 36e40, 42, 48, and 49can be found inourearlier report.9
4.2. General procedure for the reaction of carboxylic acids
with arynes
The aryne precursor (1.5 equiv) was added to a mixture of car-
boxylic acid (0.25 mmol) and CsF (4.0 equiv) in 15 mL of freshly
distilled THF, and the reaction mixture was then stirred in a closed
vial at 125 ꢀC for 18 h. After the reaction mixture was allowed to
cool to room temperature, it was eluted through a plug of silica gel
with ethyl acetate and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography on
silica gel using hexanes/EtOAc as the eluent to afford the desired
o-hydroxyaryl ketone.
202e203 ꢀC); 1H NMR (400 MHz, CDCl3)
d
7.47 (t, J¼7.6 Hz, 1H),
7.55 (d, J¼8.5 Hz, 1H), 7.64 (d, J¼9.2 Hz, 1H), 7.81 (ddd, J¼8.7, 7.1,
1.7 Hz, 1H), 8.33 (dd, J¼7.9, 1.7 Hz, 1H), 8.54 (dd, J¼9.2, 2.8 Hz, 1H),
9.19 (d, J¼2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 118.2, 119.7,
121.3, 121.6, 123.5, 125.3, 126.9, 129.0, 135.9, 155.8, 159.1, 175.7;
HRMS (APCI) calcd for [MþH]þ C13H8NO4 242.0448, found
242.0452. The 1H and 13C NMR spectral data are in good agree-
ment with the literature data.47
4.2.1. 1-(2-Hydroxyphenyl)-4-phenylbutane-1,4-dione
compound was obtained as a white solid in a 39% yield: mp
107e108 ꢀC 1H NMR (400 MHz, CDCl3)
3.43e3.54 (m, 4H), 6.94 (t,
(16). This
4.2.7. Synthesis of benzo[c]xanthone (25). o-(Trimethylsilyl)phenyl
triflate (1.5 equiv) was added to a mixture of 1-bromo-2-naphthoic
acid (0.25 mmol) and TBAT (2.0 equiv) in 5 mL of toluene, and the
reaction mixture was then stirred at 60 ꢀC for 24 h. After allowing the
reaction mixture to cool to room temperature, the mixture was
extracted with EtOAc (20 mLꢂ2) from the brine solution (40 mL), the
organic fractions were combined, and the solvent was evaporated
under reduced pressure. The residue was purified by flash chro-
matography on silica gel using hexanes/EtOAc as the eluent to afford
the desired xanthone 25 as a white solid in a 55% yield: mp
d
J¼7.6 Hz, 1H), 6.99 (d, J¼8.1 Hz, 1H), 7.46e7.53 (m, 3H), 7.60 (t,
J¼7.3 Hz, 1H), 7.91 (d, J¼8.0 Hz, 1H), 8.04 (d, J¼7.5 Hz, 2H), 12.12 (s,
1H); 13C NMR (150 MHz, CDCl3)
d
32.3 (ꢂ2),118.7,119.2,119.5,128.3,
128.9, 130.1, 133þ.5, 136.6, 136.8, 162.5, 198.4, 204.8; HRMS (APCI)
calcd for [MþH] C16H15O3 255.1016, found 255.1014.
4.2.2. 1-(2-Hydroxyphenyl)-2-(thiophen-3-yl)ethanone
compound was obtained as a yellow semisolid in a 30% yield: 1H
NMR (400 MHz, CDCl3)
(17). This
149e151 ꢀC (lit. mp48 147e149 ꢀC); 1H NMR (600 MHz, CDCl3)
d 7.43
d
4.34 (s, 2H), 6.91 (t, J¼7.6 Hz, 1H), 7.00 (d,
(s, 1H), 7.61e7.80 (m, 5H), 7.90e7.94 (m, 1H), 8.27 (d, J¼8.2 Hz, 1H),
J¼8.8 Hz, 1H), 7.03 (d, J¼5.7 Hz, 1H), 7.15 (s, 1H), 7.33 (dd, J¼4.9,
8.40 (d, J¼6.4 Hz, 1H), 8.66 (d, J¼6.5 Hz, 1H); 13C NMR (150 MHz,
3.0 Hz, 1H), 7.48 (t, J¼8.4 Hz, 1H), 7.85 (d, J¼8.0 Hz, 1H), 12.20 (s,
CDCl3)
d 117.6, 118.1, 121.5, 122.5, 122.9, 124.0, 124.1, 124.4, 126.6,
1H); 13C NMR (100 MHz, CDCl3)
d
39.8, 118.7, 118.9, 119.0, 123.1,
126.9, 128.1, 129.6, 134.4, 136.6, 153.7, 155.8, 176.9; HRMS (APCI)
126.1, 128.5, 130.3, 133.4, 136.6, 162.9, 203.3; HRMS (EI) calcd for
C12H10O2S 218.0396, found 218.0391.
calcd for [MþH]þ C17H11O2 247.0754, found 247.0751. The 1H and 13
C
NMR spectral data are in good agreement with the literature data.13
4.2.3. 1-(2-Hydroxy-4,6-dimethoxyphenyl)butan-1-one (20). This
4.2.8. Synthesis of 2,3-dimethoxyxanthone (26). o-(Trimethylsilyl)
phenyl triflate (1.5 equiv) was added to a mixture of 2-bromo-4,5-
dimethoxybenzoic acid (0.25 mmol) and TBAT (2.0 equiv) in 5 mL
of toluene, and the reaction mixture was then stirred at 60 ꢀC for
24 h. After allowing the reaction mixture to cool to room tem-
perature, the mixture was extracted with EtOAc (20 mLꢂ2) from
the brine solution (40 mL), the organic fractions were combined,
and the solvent was evaporated under reduced pressure. The res-
idue was purified by flash chromatography on silica gel using
hexanes/EtOAc as the eluent to afford the corresponding hydrox-
yaryl ketone. The latter was dissolved in 4 mL of MeCN and heated
in the presence of K2CO3 (2 equiv) at 100 ꢀC for 24 h. After allowing
the reaction mixture to cool to room temperature, the solvent was
evaporated under reduced pressure. The residue was purified by
flash chromatography on silica gel using hexanes/EtOAc as the el-
uent to afford the desired xanthone 26 as a light brown solid in
a 59% yield: mp 161e162 ꢀC (lit.49 mp 163e164 ꢀC); 1H NMR
compound was obtained as a white solid in a 49% yield: mp
69e72 ꢀC (lit.44 mp 70 ꢀC); 1H NMR (400 MHz, CDCl3)
d 0.98 (t,
J¼7.4 Hz, 3H), 1.59e1.65 (m, 2H), 2.96 (t, J¼7.3 Hz, 2H), 3.81 (s, 3H),
3.85 (s, 3H), 5.92 (d, J¼2.4 Hz, 1H), 6.06 (d, J¼2.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
14.0, 18.1, 46.1, 55.5 (ꢂ2), 90.7, 93.6, 105.8, 162.7,
165.7, 167.6, 205.8; HRMS (APCI) calcd for [MþH]þ C12H17O4
225.1121, found 225.1122.
4.2.4. 2-Bromoxanthone (22). This compound was obtained as
1
a white solid in a 79% yield: mp 148e150 ꢀC (lit.45 mp 150 ꢀC); H
NMR (400 MHz, CDCl3)
7.69e7.79 (m, 2H), 8.29 (dd, J¼7.9,1.7 Hz,1H), 8.42 (d, J¼2.5 Hz,1H);
13C NMR (75 MHz, CDCl3)
117.3, 118.3, 120.2, 121.7, 123.3, 124.5,
d
7.33e7.42 (m, 2H), 7.47 (d, J¼8.5 Hz, 1H),
d
127.0, 129.4, 135.4, 137.9, 155.1, 156.2, 176.2; HRMS (APCI) calcd for
[MþH]þ C13H8BrO2 274.9702, found 274.9706. The 1H and 13C NMR
spectral data are in good agreement with the literature data.13
(400 MHz, CDCl3)
J¼7.6 Hz, 1H), 7.44 (d, J¼8.3 Hz, 1H), 7.63e7.70 (m, 2H), 8.30e8.35
(m, 1H); 13C NMR (100 MHz, CDCl3)
56.3, 56.5, 99.6, 105.3, 114.9,
d 3.99 (s, 3H), 4.01 (s, 3H), 6.90 (s, 1H), 7.36 (t,
4.2.5. 2,3-Dimethylxanthone (28). This compound was obtained as
a white solid in a 47% yield: mp 156e158 ꢀC; 1H NMR (400 MHz,
d
CDCl3)
d
2.35 (s, 3H), 2.38 (s, 3H), 7.24 (s, 1H), 7.34 (t, J¼7.5 Hz, 1H),
117.6, 121.5, 123.7, 126.5, 133.9, 146.7, 152.4, 155.4, 156.0, 176.0;
HRMS (APCI) calcd for [MþH]þ C15H13O4 257.0808, found 257.0809.
The 1H and 13C NMR spectral data are in good agreement with the
literature data.13
7.44 (d, J¼8.3 Hz, 1H), 7.68 (t, J¼7.8 Hz, 1H), 8.04 (s, 1H), 8.32 (d,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 19.5, 20.8, 118.1, 118.3,
119.9, 122.1, 123.8, 126.5, 126.9, 133.3, 134.6, 145.7, 154.9, 156.3,
177.3. HRMS (APCI) calcd for [MþH]þ C15H13O2 225.0910, found
225.0911. The 1H and 13C NMR spectral data are in good agreement
with the literature data.13
4.2.9. Synthesis of 1,3,6,7-tetramethoxyxanthone (27). The corre-
sponding dimethoxyaryne precursor (1.5 equiv) was added to
a mixture of 2-bromo-4,5-dimethoxybenzoic acid (0.25 mmol) and
TBAT (2.0 equiv) in 5 mL of toluene, and the reaction mixture was
then stirred at 60 ꢀC for 24 h. After allowing the reaction mixture to
cool to room temperature, the mixture was extracted with EtOAc
(20 mLꢂ2) from the brine solution (40 mL), the organic fractions
4.2.6. Synthesis of 2-nitroxanthone (24). o-(Trimethylsilyl)phenyl
triflate (1.5 equiv) was added to
a mixture of 2-chloro-5-
nitrobenzoic acid (0.25 mmol) and TBAT (2.0 equiv) in 5 mL of
toluene, and the reaction mixture was then stirred at 60 ꢀC for

A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
2797
were combined and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography on
silica gel using hexanes/EtOAc as the eluent to afford the corre-
sponding hydroxyaryl ketone. The latter was dissolved in 4 mL of
MeCN and heated in the presence of K2CO3 (2 equiv) at 100 ꢀC for
24 h. After allowing the reaction mixture to cool to room temper-
ature, the solvent was evaporated under reduced pressure. The
residue was purified by flash chromatography on silica gel using
hexanes/EtOAc as the eluent to afford the desired xanthone 27 as
a light brown solid in a 49% yield: mp 202e203 ꢀC (lit.50 mp
unsymmetrical dimethoxy-substituted benzyne precursor 19, the
uncyclized o-hydroxyaryl ketone was isolated in a 68% yield as
a yellow solid: mp 71e74 ꢀC: 1H NMR (400 MHz, CDCl3)
d 3.84 (s,
3H), 3.92 (s, 3H), 5.96 (s, 1H), 6.11 (s, 1H), 7.33e7.47 (m, 4H),
7.58e7.65 (m, 3H), 7.78 (d, J¼15.6 Hz, 1H), 7.91 (d, J¼15.6 Hz, 1H);
HRMS (APCI) calcd for [MþH]þ C17H17O4 285.1121, found 285.1129.
The latter was dissolved in 5 mL of THF, then 10 mL of water and
10 mL of piperidine were added, and the mixture was stirred for 2 h
at 40 ꢀC. After allowing the reaction mixture to cool to room tem-
perature, the mixture was extracted with EtOAc (20 mLꢂ2), the
organic fractions were combined, and the solvent was evaporated
under reduced pressure. Flash chromatography on silica gel using
hexanes/EtOAc as the eluent afforded 42% of the unreacted starting
material and 48% of the desired 4-chromanone 43 as a white solid:
mp 144e146 ꢀC (lit.53 mp 145e146 ꢀC); 1H NMR (400 MHz, CDCl3)
202 ꢀC); 1H NMR (400 MHz, CDCl3)
9H), 6.29 (d, J¼2.1 Hz, 1H), 6.40 (d, J¼2.1 Hz,1H), 6.74 (s, 1H), 7.60 (s,
1H); 13C NMR (100 MHz, CDCl3)
55.6, 56.2, 56.3, 56.3, 92.5, 95.0,
d 3.86 (s, 3H), 3.92e3.95 (m,
d
98.9, 105.7, 106.9, 116.0, 146.4, þ150.7, 154.3, 159.7, 161.8, 164.2, 174.6;
HRMS (APCI) calcd for [MþH] C17H17O6 317.1020, found 317.1023.
The 1H and 13C NMR spectral data are in good agreement with the
literature data.51
d
2.80 (dd, J¼16.4, 2.7 Hz, 1H), 2.97e3.07 (m, 1H), 3.82 (s, 3H), 3.90
(s, 3H), 5.41 (d, J¼14.8 Hz,1H), 6.10 (s,1H), 6.16 (s,1H), 7.31e7.49 (m,
5H); 13C NMR (150 MHz, CDCl3)
45.6, 55.6, 56.2, 79.3, 93.2, 93.6,
d
4.3. General procedure for the reaction of 2-alkenoic acids
with arynes
106.0, 126.1, 128.7, 128.8, 138.8, 162.3, 165.0, 166.0, 189.2; HRMS
(APCI) calcd for [MþH]þ C17H17O4 285.1121, found 285.1124. The 1H
and 13C NMR spectral data are in good agreement with the litera-
ture data.53
The aryne precursor (1.5 equiv) was added to a mixture of 2-
alkenoic acid (0.25 mmol) and CsF (4.0 equiv) in 15 mL of freshly
distilled THF, and the reaction mixture was then stirred in a closed
vial at 125 ꢀC for 18 h. After allowing the reaction mixture to cool,
additional aryne precursor (0.5 equiv) and CsF (1.0 equiv) were
quickly added and heating was continued at 125 ꢀC for 6 h. After the
reaction mixture was allowed to cool to room temperature, it was
eluted through a plug of silica gel with ethyl acetate and the solvent
was removed under reduced pressure. The residue was purified by
flash chromatography on silica gel using hexanes/EtOAc as the el-
uent to afford the desired 4-chromanones.
4.3.5. Methyl 2-(2-methyl-3-oxo-2,3-dihydrobenzofuran-2-yl)ace-
tate (45). This compound was obtained as a yellow solid in a 79%
yield starting from the monomethyl ester of itaconic acid: mp
127e130 ꢀC; 1H NMR (400 MHz, CDCl3)
d 1.46 (s, 3H), 2.93 (d,
J¼16.4 Hz, 1H), 3.02 (d, J¼16.4 Hz, 1H), 3.53 (s, 3H), 7.08 (t, J¼8.1 Hz,
2H), 7.59 (t, J¼7.8 Hz, 1H), 7.69 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 22.6, 41.5, 52.1, 86.5, 113.5, 120.6, 122.2, 124.8, 138.0, 169.3,
171.1, 202.8; HRMS (APCI) calcd for [MþH]þ C12H13O4 221.0808,
found 221.0809.
4.3.1. 2-Cyclohexylchroman-4-one (31). This compound was ob-
4.4. Procedure for the reaction of 2-alkynoic acids with
arynes
tained as a pale yellow oil in an 85% yield: 1H NMR (400 MHz,
CDCl3)
d
1.06e1.34 (m, 5H), 1.64e1.85 (m, 5H), 1.98 (d, J¼12.3 Hz,
1H), 2.60e2.77 (m, 2H), 4.14e4.24 (m, 1H), 6.94e7.01 (m, 2H), 7.46
The aryne precursor (1.5 equiv) was added to a mixture of
2-alkynoic acid (0.25 mmol) and TBAT (2.0 equiv) in 5 mL of an-
hydrous toluene, and the reaction mixture was then stirred in
a closed vial at 60 ꢀC for 24 h. After the reaction mixture was
allowed to cool to room temperature, the reaction mixture was
then poured into brine (15 mL) and the organic layer was sepa-
rated. The aqueous layer was extracted with ethyl acetate
(2ꢂ15 mL) and the organic layers were combined and concentrated
in vacuo. The residue was purified by flash chromatography on
silica gel using hexanes/EtOAc as the eluent to afford the desired
chromone derivatives.
(ddd, J¼8.7, 7.2, 1.8 Hz, 1H), 7.86 (dd, J¼7.8, 1.8 Hz, 1H); 13C NMR
(150 MHz, CDCl3) d 25.9, 26.0, 26.3, 28.2, 28.3, 40.3, 41.8, 82.0, 117.9,
121.0, 126.9, 135.9, 161.9, 193.2 (doubled signals at 25.9e26.0 and
28.2e28.3 are likely due to different electronic environments of the
corresponding carbons); HRMS (APCI) calcd for [MþH]þ C15H19O2
231.1380, found 231.1382. The 1H and 13C NMR spectral data are in
good agreement with the literature data.52
4.3.2. 4-(4-Oxochroman-2-yl)butanenitrile (33). This compound
was obtained as a pale yellow oil in a 71% yield: 1H NMR (400 MHz,
CDCl3)
d
1.82e2.08 (m, 4H), 2.48 (t, J¼6.6 Hz, 2H), 2.63e2.78 (m,
2H), 4.41e4.51 (m, 1H), 6.96 (d, J¼8.4 Hz, 1H), 7.02 (t, J¼7.5 Hz, 1H),
4.4.1. Chromone (50). This compound was obtained as a yellow
semisolid in a 71% yield running the reaction in 15 mL of THF at
65 ꢀC, instead of toluene at 60 ꢀC. The same compound was also
obtained in an 18% yield starting from 2-bromoacrylic acid (51)
using the CsF/THF protocol at 125 ꢀC: 1H NMR (400 MHz, CDCl3)
7.48 (t, J¼7.8 Hz, 1H), 7.87 (d, J¼7.9 Hz, 1H); 13C NMR (150 MHz,
CDCl3)
d 17.1, 21.3, 33.7, 42.9, 76.9, 117.9, 119.2, 120.9, 121.6, 127.1,
136.2, 161.2, 191.8; HRMS (APCI) calcd for [MþH]þ C13H14NO2
216.1019, found 216.1021.
d
6.34 (d, J¼6.0 Hz, 1H), 7.40 (t, J¼7.6 Hz, 1H), 7.45 (d, J¼8.4 Hz, 1H),
7.67 (t, J¼7.8 Hz, 1H), 7.85 (d, J¼6.0 Hz, 1H), 8.20 (d, J¼8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3)
113.3, 118.4, 125.1, 125.5, 126.0, 134.0,
4.3.3. 2-Methyl-2-(4-methylpent-3-en-1-yl)chroman-4-one(35). This
compound was obtained as a colorless oil in a 64% yield: 1H NMR
d
(400 MHz, CDCl3)
d
1.41 (s, 3H), 1.57 (s, 3H), 1.63e1.73 (m, 4H),
155.5, 156.7, 177.8; HRMS (EI) calcd for C9H6O2 146.0368, found
146.0370. The 1H and 13C NMR spectral data are in good agreement
with the literature data.54
1.75e1.85 (m, 1H), 2.05e2.17 (m, 2H), 2.66 (d, J¼16.4 Hz, 1H), 2.79 (d,
J¼16.4 Hz, 1H), 5.02e5.10 (m, 1H), 6.89e7.01 (m, 2H), 7.46 (ddd,
J¼8.6, 7.2, 1.8 Hz, 1H), 7.84 (dd, J¼7.8, 1.8 Hz,1H); 13C NMR (100 MHz,
CDCl3)
d
17.8, 22.5, 24.2, 25.9, 39.5, 47.7, 81.3,118.5,120.6,120.8,123.5,
4.4.2. 3,4-Dihydro-1H-xanthen-9(2H)-one (53). This compound
was obtained as a white solid in an 85% yield starting from
2-bromocyclohexenoic acid (52) using the CsF/THF protocol at
125 ꢀC: mp 87e88 ꢀC (lit.55 mp 91e92 ꢀC); 1H NMR (400 MHz,
126.6, 132.5, 136.3, 160.0, 192.9; HRMS (APCI) calcd for [MþH]þ
C16H21O2 245.1536, found 245.1541.
4.3.4. Synthesis of 5,7-dimethoxy-2-phenylchroman-4-one
(43). After the reaction between cinnamic acid and the
CDCl3) d 1.71e1.91 (m, 4H), 2.56e2.68 (m, 4H), 7.29e7.39 (m, 2H),
7.59 (ddd, J¼8.6, 7.1, 1.7 Hz,1H), 8.19 (dd, J¼8.0, 1.7 Hz, 1H); 13C NMR

2798
A.V. Dubrovskiy, R.C. Larock / Tetrahedron 69 (2013) 2789e2798
17. See Katritzky, A. R.; Le, K. N. B.; Mohapatra, P. P. Synthesis 2007, 3141 and ref-
(150 MHz, CDCl3)
d 21.0, 21.7, 21.9, 28.2, 117.6, 118.4, 123.2, 124.4,
erences therein for the biological activity of o-hydroxyaryl ketones.
125.7, 132.9, 155.9, 163.9, 177.8; HRMS (APCI) calcd for [MþH]þ
C13H13O2 201.0910, found 201.0916. The 1H and 13C NMR spectral
data are in good agreement with the literature data.56
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yield: 1H NMR (400 MHz, CDCl3)
7.17e7.41 (m, 10H), 7.95 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
3.76 (s, 3H), 3.97 (s, 2H),
33.4,
d
52.3, 126.3, 128.1, 128.7, 128.8, 129.0, 129.4, 130.9, 135.6, 139.6, 141.2,
168.8; HRMS (EI) calcd for C17H16O2 252.1150, found 252.1170. The
1H and 13C NMR spectral data are in good agreement with the lit-
erature data.43b
29. See: Peres, V.; Nagem, T. J.; de Oliveira, F. F. Phytochemistry 2000, 55, 683 and
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Acknowledgements
We thank the National Science Foundation, the National In-
stitute of General Medical Sciences (GM079593) and the National
Institutes of Health Kansas University Center of Excellence in
Chemical Methodology and Library Development (P50 GM069663)
for their generous financial support. We also thank Dr. Feng Shi,
while at Iowa State University, for the preparation of some aryne
precursors.
33. For similar reactivity of 3-methoxybenzyne, see: Dubrovskiy, A. V.; Larock, R. C.
Org. Lett. 2010, 12, 1180.
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35. Running the reaction with TBAT in THF ensures the complete conversion of the
acid, but also results in higher yields of undesired overarylated products
(analogous to products 5 and 6).
36. Apparently, an excess of the benzyne intermediate is more likely to engage in
the reaction with the phenoxide formed as a result of the opening of a four-
membered ring in an intermediate like 9, rather than with the starting, less
reactive carboxylic acid. Ideally, the slow addition technique could be beneficial
to the yield of the reaction. However, running the reaction in an overheated
solvent in a pressurized vial makes this hypothesis difficult to test.
37. Tanaka, K.; Sugino, T. Green Chem. 2001, 3, 133.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.01.078.
38. The only detected by-product was the O-monoarylation product.
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