C. Taylor, Y. Bolshan / Tetrahedron Letters 56 (2015) 4392–4396
4393
R1
straightforward procedure for the preparation of ynones from acyl
chlorides and potassium alkynyltrifluoroborate salts (Scheme 2).28
This convenient, one-pot reaction proceeds rapidly in the presence
of boron trichloride without exclusion of air or moisture.
Furthermore, alkynyltrifluoroborate salts can be easily prepared
from terminal alkynes according to the published procedure.29
Given the interesting biological properties of aurone and flavone
natural products, we sought to develop a method for the prepara-
tion of 2-hydroxylated precursors of aurone and flavone scaffolds.
Unfortunately, the method highlighted in Scheme 2 is limited by
commercial availability of acyl chloride starting materials.
Limited access to good quality sterically hindered benzoyl chlo-
ride derivatives led us to seek an alternative method for the prepa-
ration of the o-alkynoylphenol precursors. Herein, we describe a
new method for the preparation of sterically hindered ynones from
potassium alkynyltrifluoroborate salts and mixed anhydrides and
its application to the synthesis of both natural and unnatural fla-
vone and aurone derivatives.
O
R1
O
O
R2
R2
R3
O
R3
aurone
flavone
Figure 1. Structure of substituted aurone and flavone.
manipulation of the conditions does affect which major product is
formed, accounts in the literature indicate the formation of a mix-
ture of both cyclization products.18 Silver(I) ion-catalyzed cycliza-
tion of o-alkynoylphenols results predominantly in the 5-exo
cyclized aurone product, however, trace amounts of the 6-endo
product are also formed.19 A similar outcome has been observed
when tributylphosphine was employed as a catalyst.20 Product
mixtures are problematic since separation of structurally similar
aurone and flavone products is not trivial. Fortunately, in the
course of our investigation we have discovered cesium carbonate
to promote the rapid and exclusive 5-exo cyclization of o-
alkynoylphenol compounds in high yields.
Results and discussion
It is possible to regioselectively promote the 6-endo cyclization
of o-alkynoylphenols by applying the principles of the Morita–
Baylis–Hillman reaction.21 Flavone synthesis may be achieved via
1,4-addition of a nucleophile to the b-carbon in the ynone system.
Intramolecular Michael addition followed by elimination of the
nucleophile results in the 6-endo cyclized flavone product.22
Specifically, we have employed a protocol reported by Doi and
coworkers, where trifluoromethanesulfonic acid (TfOH) promotes
the exclusive 6-endo cyclization to produce the desired flavone
product.22a A straightforward method for the preparation of o-
alkynoylphenols is particularly appealing given that they may be
Due to the limited commercial availability of substituted ben-
zoyl chloride derivatives, our first challenge was to find a way to
apply our methodology to the sterically hindered, ortho hydroxy
substituted benzoic acid 1. Scheme 3 illustrates initial efforts to
convert the carboxylic acid group to an acyl chloride, which could
subsequently be converted to an ynone. Direct conversion of the
acid to an acyl chloride using thionyl chloride was not successful.
Therefore, we sought to protect the acid and hydroxyl functionali-
ties of the starting material. This would allow for subsequent trans-
formation to the desired acyl chloride precursor.
Initially, allyl bromide was used to form a diprotected acid.
Subsequent exposure of the protected acid group to sodium
hydroxide followed by conversion to an acyl chloride using thionyl
chloride was expected to produce a protected benzoyl chloride 3.
Compound 3 could be converted to the desired ynone intermediate
(Scheme 3).28 Unfortunately, conditions for the conversion of 2–3
resulted in partial decomposition making isolation of clean product
a challenge. Additionally, this method is not ideal as a result of the
number of steps required for the preparation of acyl chloride.
As an alternative strategy, we silylated substituted carboxylic
acid 1 to allow for the direct conversion of the protected acid to
an acyl chloride. Scheme 4 illustrates the transformation of the
TBDMS protected intermediate 4 to an acyl chloride using oxalyl
chloride,30 followed by reaction with para-methoxy pheny-
lacetylenetrifluoroborate under the reported reaction conditions.
In addition to ynone formation, we observed the concurrent
demethylation of the ortho-methoxy group under the conditions
applied. Ynone product 6 was obtained in 16% yield. The low yield
of this particular reaction may be attributed to incomplete conver-
sion of 4 to the acyl chloride intermediate as well as steric bulk
associated with the silyl protecting group.
utilized as
a convenient starting material for the efficient
synthesis of both aurone and flavone scaffolds.
There are a number of synthetically useful methods for the
preparation of ynones.23 However, efficient methods for the prepa-
ration of sterically hindered examples, especially o-alkynoylphe-
nols, are scarce. Suzuki–Miyaura carbonylative coupling of
sterically hindered aryl iodides with boronic acids has been
reported.24 More recently, carbonylative Negishi coupling of an
alkynylzinc reagent to a 2,6-dimethoxy substituted aryl iodide
has been demonstrated in modest yields.25 The use of unstable
alkynylboronic acids and alkynylzinc reagents as well as the pres-
ence of unwanted direct coupling byproducts reduces the effi-
ciency of these methods. Moreover, selective monodemethylation
of an ortho-methoxy group is challenging.25 Alternative methods
for the synthesis of o-alkynoylphenols involve the addition of
metal acetylides to an aldehyde followed by oxidation of the sec-
ondary alcohol to
a
ketone.22a,d,26 These approaches for the
preparation of hindered o-alkynoylphenols suffer from low atom
economy, multistep procedures, and low yields.
Recently, transition-metal-free reactions of organoboranes have
gained considerable attention.27 Previously, we have developed a
The demethylation of an ortho-methoxy group under the devel-
oped conditions for ynone preparation led us to continue our
investigation using 2,4,6-trimethoxy substituted starting materi-
als. First, 2,4,6-trimethoxybenzoic acid was converted to benzoyl
chloride 7 using oxalyl chloride. The conversion to 7 was not com-
plete, however, we proceeded with the next step of the synthesis.
The boron trichloride-catalyzed reaction with para-methoxy
R1
O
O
R2
R1
O
R3
Flavones
R2
R3
OH
R3
O
R2
O
BCl3, DCM
rt, 30 min
O
R2
BF3K
+
R1
Aurones
R1 Cl
R1
O
R2
Scheme 1. Cyclization of o-alkynoylphenols.
Scheme 2. Straightforward preparation of ynones.