Intermolecular C-O addition of carboxylic acids to arynes

Article abstract of DOI:10.1021/ol101017z

(Figure Presented) A novel, efficient, and expedient route to biologically and pharmaceutically important o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones has been developed starting from readily available carboxylic acids and commercially available o-(trimethylsilyl)aryl triflates.

Full text of DOI:10.1021/ol101017z

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3117-3119
Intermolecular C-O Addition of
Carboxylic Acids to Arynes
Anton V. Dubrovskiy and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received May 3, 2010
ABSTRACT
A novel, efficient, and expedient route to biologically and pharmaceutically important o-hydroxyaryl ketones, xanthones, 4-chromanones, and
flavones has been developed starting from readily available carboxylic acids and commercially available o-(trimethylsilyl)aryl triflates.
The insertion of arynes into C-N,1 C-C,2 C-Si,3 C-Sn,4
and C-Hal5 bonds and the CdO of aldehydes6 is now a
well-known reaction. The insertion of a benzene ring into
the C-O bond of a carboxylic acid would afford a powerful
synthetic approach to a range of complex and biologically
important molecules. However, we have previously reported
that the reaction of arenecarboxylic acids and arynes in
MeCN affords excellent yields of the corresponding aryl
esters, i.e., the reaction occurs by insertion into the O-H
bond of the carboxylic acid.7 In a closer examination of this
chemistry, we have now found reaction conditions that afford
good to excellent yields of the corresponding C-O insertion
products. Subsequent chemistry of the resulting o-hy-
droxyaryl ketones affords a novel approach to xanthones,
chromanones, and flavones.
We allowed butyric acid (1) to react with the benzyne
precursor 2 in the presence of fluoride ion at an elevated
temperature (Scheme 1). To avoid the formation of monoary-
lation product 5, rather than using relatively acidic acetoni-
trile as the solvent,8 we turned to far less acidic THF. To
our delight, together with the ester 5 the C-O insertion
product 8 was formed, as well as an inseparable mixture of
bis-aryne addition products 10 and 11.
The proposed reaction mechanism (Scheme 1) is consistent
with a related study of amides reported recently by Greaney’s
group.1b The aryl anion intermediate 4 apparently undergoes
rearrangement to the phenoxide 7 by a four-membered ring
intermediate 6, resulting in formation of the desired o-
hydroxyaryl ketone 8 after proton abstraction from the
reaction media. Monoarylation product 5 can arise from
protonation of the aryl anion 4. Byproduct 10 is presumably
(1) (a) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112. (b)
Pintori, D. G.; Greaney, M. F. Org. Lett. 2009, 12, 168.
(2) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
(3) Sato, Y.; Kobayashi, Y.; Sugiura, M.; Shirai, H. J. Org. Chem. 1978,
43, 199.
(4) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem. Comm.
2001, 1880.
(5) Yoshida, H.; Mimura, Y.; Ohshita, J.; Kunai, A. Chem. Commun.
2007, 2405.
(6) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita, J.; Kunai, A.
Org. Lett. 2004, 6, 4049.
(8) See ref 7. Acetonitrile leads to almost exclusive formation of
monoarylation products.
(7) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99.
10.1021/ol101017z  2010 American Chemical Society
Published on Web 06/14/2010

product 25 in a 71% yield. Only one regioisomer was
observed in this case, which suggests that the reaction is
controlled electronically rather than sterically.12
Scheme 1
.
Proposed Mechanism for the Reaction of Butyric
Acid and Benzyne
Table 1. Reaction of Carboxylic Acids with Arynesa
formed from reaction of phenoxide 7 with a second
equivalent of benzyne, which after dehydration forms the
xanthene 11.
The formation of product 8 encouraged us to pursue this
project, since it provides an expeditious route to o-hy-
droxyaryl ketones, important precursors for the synthesis of
biologically useful flavones and chalcones,9 from readily
available carboxylic acids. Optimization studies revealed that
elevated temperatures (125 °C), dilution of the reaction media
(0.017 M), and the addition of 1.5 equiv of the aryne
precursor 2 and 4 equiv of CsF allow isolation of the desired
product 8 in a 77% yield (Table 1, entry 1). We applied our
optimized conditions to other carboxylic acids (Table 1).
If the benzyne precursor is employed in excess (3 equiv),
it is possible to obtain the dehydrated bis-aryne insertion
product 11 in a 50% yield.10 This method well tolerates
alkene, cycloalkyl, ester, and benzyl functional groups; the
corresponding products 19-22 have been isolated in 58-72%
yields. However, the yields from arenecarboxylic acids are
typically low, with inseparable mixtures of products formed.
One of the most successful reactions is with ꢀ-naphthoic acid
(16), which affords the corresponding o-hydroxyaryl ketone
23 in a 44% yield.
We also envisioned that the in situ formed phenolate anion
7 could potentially undergo a nucleophilic aromatic substitu-
tion reaction. This could provide an interesting route to
xanthones and analogues, which are very important ring
systems in biology and pharmacy.11 Indeed, when o-
halobenzoic acids are allowed to react with the benzyne
precursor and CsF under our optimized conditions, we were
delighted to see formation of the xanthone, with an o-fluoro
substituent being the most efficient among the halogens,
furnishing xanthone (24) in an 80% yield. The 3-methoxy-
benzyne precursor 3-methoxy-2-(trimethylsilyl)phenyl tri-
flate, when reacted with the same acid, provided cyclized
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. c 3.0 equiv of benzyne precursor, 6.0 equiv of
CsF, and 5 mL of DME were used. d 3-Methoxy-2-(trimethylsilyl)phenyl
triflate was used as the aryne precursor.
We were also delighted to obtain 4-aza-xanthone (26),
albeit in only a 22% yield, starting from 2-chloronicotinic
acid (18), since the majority of the reported reactions
involving benzynes, even under milder reaction conditions,
do not tolerate the nucleophilic nitrogen of a pyridine ring.13
The in situ formed phenolate anion 7 could also potentially
undergo a Michael addition reaction. This would provide a
novel route to biologically important 4-chromanones and
flavones from readily available acrylic and propiolic acids.14
Indeed, when methacrylic acid (27) was allowed to react
under the optimized conditions, 4-chromanone 37 was
formed, but only in a 58% yield. Optimization studies
revealed that addition of the aryne precursor 2 and CsF in
two portions favors formation of the product 37, increasing
(12) For a related observation, see: Dubrovskiy, A. V.; Larock, R. C.
Org. Lett. 2010, 12, 1180.
(9) Kotali, A.; Harris, P. A. Org. Prep. Proc. Int. 1994, 26, 159.
(10) Okuma, K.; Nojima, A.; Matsunaga, N.; Shioji, K. Org. Lett. 2009,
11, 169.
(13) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H. Chem. Asian J.
2010, 5, 153.
(11) (a) Na, Y. J. Pharm. Pharmacol. 2009, 61, 707. (b) El-Seedi, H. R.;
El-Ghorab, D. M. H.; El-Barbary, M. A.; Zayed, M. F.; Goeransson, U.;
Larsson, S.; Verpoorte, R. Curr. Med. Chem. 2009, 16, 2581. (c) Diderot,
N. T.; Silvere, N.; Etienne, T. AdV. Phytomed. 2006, 2, 273.
(14) (a) Brahmachari, G. Nat. Prod. Commun. 2008, 3, 1337. (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893. (c) Birt,
D. F.; Hendrich, S.; Wang, W. Pharm. Ther. 2001, 90, 57. (d) Kim, H. P.;
Son, K. H.; Chang, H. W.; Kang, S. S. J. Pharmacol. Sci. 2004, 96, 229.
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Org. Lett., Vol. 12, No. 14, 2010

substituted aryne precursor 4,5-dimethoxy-2-(trimethylsi-
lyl)phenyl triflate, when reacted with the same acid, provided
cyclized product 39 in a 53% yield.15
Table 2. Reaction of Acrylic and Propiolic Acids with Arynesa
This method well tolerates alkyl and aryl functional
groups, with products 40-45 being produced in moderate
to good yields (56-82%). In the case of cinnamic acid,
additional treatment with base (piperidine/THF/H2O)16 was
required to cyclize the hydroxyaryl ketone to the desired
flavanone 45 in a 74% overall yield.
Under our optimized conditions, the major product ob-
served in the case of propiolic acids was the decarboxylated
starting material. To decrease this side reaction, we utilized
a procedure analogous to that reported by Greaney’s group,
which employs triphenyldifluorosilicate (TBAT) in toluene
at 60 °C.1b,17 This afforded flavone (46) and its alkyl
analogue 47 in 56% and 64% yields, respectively.
In summary, we have developed a novel, efficient, and
expedient route to o-hydroxyaryl ketones, xanthones, 4-chro-
manones, flavones, and their analogues by aryne insertion
into the C-O bond of readily available carboxylic acids and
subsequent rearrangements. The method should prove useful
for the preparation of these biologically and pharmaceutically
important structures. A variety of functional groups are
compatible with the reaction conditions. Further studies on
the scope of the method and its applications are in progress.
Acknowledgment. We thank the National Science Foun-
dation, the National Institute 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 gener-
ous financial support. We also thank Dr. Feng Shi at Iowa
State University for the preparation of some aryne precursors.
a Reaction conditions: 0.25 mmol of acid, 1.5 equiv of aryne precursor,
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 aryne precursor and 1.0 equiv
of CsF were added, and the heating was continued at 125 °C for 6 h.
b Isolated yield. c 4,5-Dimethoxy-2-(trimethylsilyl)phenyl triflate was used
as the aryne precursor. d The E/Z ratio is ∼1.8/1. e The E/Z ratio is ∼5.1/1.
f The yield also includes the product obtained after base-induced cyclization
of the o-hydroxyaryl ketone (see Supporting Information). g Reaction
conditions: 0.25 mmol of acid, 1.5 equiv of aryne precursor, and 2.0 equiv
of TBAT in 5 mL of toluene were heated at 60 °C for 24 h.
Supporting Information Available: Detailed experimen-
tal procedure and characterization data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101017Z
its yield to 84% (Table 2, entry 1). The latter reaction
conditions were applied to other 2-alkenoic acids (Table 2).
3-Methyl-2-butenoic acid (28) afforded 4-chromanone 38
in a 77% yield (entry 2). The symmetrical dimethoxy-
(15) The only detected by-product was the O-monoarylation product.
(16) Tanaka, K.; Sugino, T. Green Chem. 2001, 3, 133.
(17) It is noteworthy that this procedure did not work efficiently with
substituted acrylic acids.
Org. Lett., Vol. 12, No. 14, 2010
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