Rhodium-catalysed enantioselective synthesis of 4-arylchroman-2-ones

Article abstract of DOI:10.1039/c1ob06586f

The rhodium-catalysed enantioselective 1,4-addition of organoboron reagents to arylidene Meldrum's acids as acceptors, allows convenient access to 4-arylchroman-2-ones with good to excellent levels of enantioselectivity. The use of silyl-protected dioxabo

Full text of DOI:10.1039/c1ob06586f

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Rhodium-catalysed enantioselective synthesis of 4-arylchroman-2-ones†
Joseph C. Allen, Gabriele Kociok-Ko¨hn and Christopher G. Frost*
Received 16th September 2011, Accepted 5th October 2011
DOI: 10.1039/c1ob06586f
The rhodium-catalysed enantioselective 1,4-addition of
organoboron reagents to arylidene Meldrum’s acids as ac-
ceptors, allows convenient access to 4-arylchroman-2-ones
with good to excellent levels of enantioselectivity. The use
of silyl-protected dioxaborinanes as donors was found to
be advantageous to achieving good yields of product under
anhydrous conditions.
diversification. The lack of literature reports for the addition
of organoboron reagents reflects a greater challenge due to the
sterically-hindered nature of the trisubstituted alkene and the
sensitivity of the malonate functionality in the product to attack
by nucleophiles (e.g. water).10 Indeed, our initial investigation
into the rhodium-catalysed addition of phenylboronic acid 3
to the 4-methoxyphenyl alkylidene Meldrum’s acid derivative
1a in dioxane at room temperature afforded low conversion to
product 2. The anhydrous conditions and low temperature proved
detrimental to the application of potassium trifluoroborate salt 4
and hydroxymethyl dioxaborinane 6 (Scheme 1).11
The enantioselective construction of C–C bonds using the
rhodium-catalysed 1,4-addition of organometallics is established
as an important tool for organic synthesis.1 For the addition of
aryl and alkenylboronic acids, the reaction is routinely carried
out in aqueous solvents and can afford excellent enantioselec-
tivities across a wide-range of alkene acceptors. In the majority
of applications, boronic acids are the coupling partners of
choice for conjugate addition reactions. However, there can be
issues with purification and manipulation. Often, an excess of
reagent has to be used due to competing protodeboronation
processes and by competing formation of trimeric cyclic anhy-
drides (boroxines) in solution, leading to difficulties in being
able to accurately measure reaction stoichiometry.2 A number of
elegant solutions to this problem have been presented involving
the use of preformed boronate reagents that can be isolated
and stored prior to use including tris(hydroxy)borates,3 lithium
trimethoxyboronate species,4 trifluoroborate salts5 (such as 4) and
N-methyliminodiacetic acid (MIDA) boronates.6 An important
addition to this range of donors are the cyclic triolborates 5
synthesised by Miyaura.7 These boronate reagents are reported
to be stable in air and water and more soluble in organic solvents
than potassium trifluoroborates. In this paper we describe the
utility of silyl-protected dioxaborinanes in rhodium-catalysed 1,4-
addition reactions under anhydrous conditions. This allows the
enantioselective addition to arylidene Meldrum’s acid derivatives
and a subsequent asymmetric synthesis of 4-arylchroman-2-ones.
Fillion and co-workers have shown that arylidene Meldrum’s
acid derivatives such as 1a are useful substrates for the rhodium-
catalysed 1,4-addition of organozinc8 and organotin9 donors
generating a range of products with significant scope for further
Scheme 1 The addition of arylboron reagents to arylidene Meldrum’s
acids.
Pleasingly, the cyclic triolborate 5 and the silyl-protected
dioxaborinane 7 gave the desired product 2 with no traces of
decomposition products. The superior conversions and good iso-
lated yield obtained with 7 prompted further investigation of this
novel organoboron reagent. The silyl-protected dioxaborinanes
are readily prepared in high yield by heating an arylboronic acid
with 2-(hydroxymethyl)-2-methylpropane-1,3-diol under Dean–
Stark conditions followed by treatment with chlorotrimethylsilane
in the presence of triethylamine (See Supporting Information for
full details†). The arylboron products are easily purified by flash
chromatography and can be stored on the bench for several months
with no evidence of decomposition. With a range of silyl-protected
dioxaborinane reagents in hand, the scope of the rhodium-
catalysed addition to arylidene Meldrum’s acid acceptors was
explored (Scheme 2).
Department of Chemistry, University of Bath, Bath, UK, BA2 7AY.
E-mail: c.g.frost@bath.ac.uk; Fax: +44 1225 386231; Tel: +44 1225 386142
† Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data, and copies of NMR spectra for com-
pounds synthesised in this study. CCDC reference number 836829. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06586f
32 | Org. Biomol. Chem., 2012, 10, 32–35
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yield. The 4-arylchroman-2-one system is of synthetic interest as
it features in a number of natural flavonoid structures or as inter-
mediates in drug synthesis.12 The rhodium-catalysed 1,4-addition
of boronic acids to coumarin derivatives has been demonstrated
to afford 4-arylchroman-2-ones with high enantioselectivity.13
However, coumarins tend to be relatively poor substrates for
conjugate additions, thus up to ten equivalents of boronic acid
donor were required for successful conversion to product. Our
alternative strategy shown in Fig. 1 is based on an enantioselective
rhodium-catalysed 1,4-addition to (2-benzyloxy)phenyl arylidene
Meldrum’s acid derivative followed by hydrolysis/decarboxylation
of the cyclic malonate, deprotection of the benzyl ether and in-
tramolecular esterification to provide the desired 4-arylchroman-
2-one products.
Scheme 2 Scope of addition using silyl-protected dioxaborinanes.
Fig. 1 Enantioselective synthesis of 4-arylchroman-2-ones.
Employing the optimised set of reaction conditions, the isolated
yields were consistently good for arylidene Meldrum’s acid accep-
tors that possessed electron-donating ether substituents (Scheme
2, 9–16).
The development of an enantioselective rhodium-catalysed
1,4-addition to (2-benzyloxy)phenyl alkylidene Meldrum’s acid
derivative proved to be challenging. Preliminary attempts using
a [Rh(C2H4)2Cl]2 precatalyst in the presence of atropisomeric
bidentate phosphine ligands afforded no desired product, both the
silyl-protected dioxaborinane donor and the alkene were recovered
intact.
In contrast, arylidene Meldrum’s acid derivative 8 with the para-
F group on the aryl ring was unreactive under the standard reac-
tion conditions. Similarly, other electron-withdrawing substituents
(Br and NO2) were not tolerated on the acceptor. This observation
can be rationalised by the inductive deactivation of the hindered
trisubstituted alkene derivative to carbometallation. Substitution
of the silyl-protected dioxaborinane was possible at the ortho,
meta, and para positions. However, yields were compromised
when both donor and acceptor were ortho-substituted (Scheme
2, 11–13). With the optimised set of reaction conditions, we next
established that silyl-protected dioxaborinane 7 could be employed
for the addition to typical cyclic activated alkenes (Scheme 3).
Enantiopure diene ligands can substitute for chiral phosphines
in enantioselective processes and often show superior reactivity
and enantioselectivity.14 Fortunately, the enantiopure diene (R,R)-
Ph-bod* introduced by Hayashi and co-workers allowed the
arylation to proceed with good reactivity and enantioselectivity
under anhydrous conditions (Scheme 4).15 The isolated yields
obtained with the enantiopure diene ligand (R,R)-Ph-bod* were
consistent with the racemic protocol. Substitution of the silyl-
protected dioxaborinane at the para position afforded excellent
yields of product (Scheme 4, 11, 14 and 15) with lower yields
for the meta substituted aryl group in 12 and poor yields for
the ortho,ortho substituted product 13. The enantioselectivity was
determined after conversion to the 4-arylchroman-2-one products
16–21. Thus, the enantioenriched Meldrum’s acid derivative 10–
15 was heated in a stirring mixture of DMF and aqueous HCl to
afford the carboxylic acid. Hydrogenation of the crude reaction
mixture in ethyl acetate in the presence of palladium impregnated
on carbon led to deprotection of the benzyl ether. The resulting
phenol was then heated in the presence of a catalytic amount
of para-toluenesulfonic acid to afford the desired product 16–
21 over three steps (Scheme 5). The enantioselectivity was good
for a range of silyl-protected dioxaborinane donors (up to 97%
ee for 20). The enantioselectivity was significantly lower when
both donor and acceptor were ortho-substituted (Scheme 5, 9).
The absolute configuration of 20 was determined to be (R)-
by X-ray crystallography (Fig. 2). A recent density functional
Scheme 3 The addition to cyclic activated alkenes.
The new organoboron reagent proved to be remarkably effective
for the rhodium-catalysed 1,4-addition to cyclic substrates under
anhydrous conditions at room temperature. The stoichiometry of
the organoboron donor could be reduced to just 1.1 equivalents
and the products (Scheme 3 17–20) were obtained in high isolated
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Fig. 2 ORTEP drawing of (R)-4-(4-chlorophenyl)chroman-2-one 20.†
alkene acceptors and to explain their unique properties are in
progress.
Notes and references
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Scheme 4 Enantioselective additions with (R,R)-Ph-bod*.
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Conclusions
In conclusion, we have shown that silyl-protected dioxaborinanes
perform exceptionally well as donors in rhodium-catalysed 1,4-
addition reactions under anhydrous conditions. In the scenario
presented here, this allowed an enantioselective addition to aryli-
dene Meldrum’s acid derivatives and a subsequent asymmetric
synthesis of 4-arylchroman-2-ones. Further studies to explore the
application of these new donors in additions to other challenging
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