Catalytic asymmetric conjugate addition of Grignard reagents to chromones

Article abstract of DOI:10.1039/c3cc43105c

A highly regio- and enantioselective copper catalysed direct conjugate addition of Grignard reagents to chromones has been developed taking advantage of the reduced reactivity of the resulting magnesium enolates. This methodology tolerates a broad scope of alkyl Grignards including secondary alkyl magnesium reagents as well as functionalised chromones.

Full text of DOI:10.1039/c3cc43105c

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Catalytic asymmetric conjugate addition of Grignard
reagents to chromones†
Cite this: Chem. Commun., 2013,
4
9, 5933
Carlos Vila, Valent ´ı n Hornillos, Mart ´ı n Fa n˜ an a´ s-Mastral and Ben L. Feringa*
Received 26th April 2013,
Accepted 16th May 2013
DOI: 10.1039/c3cc43105c
www.rsc.org/chemcomm
A highly regio- and enantioselective copper catalysed direct conjugate
addition of Grignard reagents to chromones has been developed
taking advantage of the reduced reactivity of the resulting magnesium
enolates. This methodology tolerates a broad scope of alkyl Grignards
including secondary alkyl magnesium reagents as well as function-
alised chromones.
The chromanone skeleton is present in a large number of natural
products, which show a wide range of biological activities includ-
ing anticancer, antitumor, antibacterial, antioxidant or anti-
1
microbial properties. The enantioselective synthesis of chiral
2
-aryl substituted chromanones is well described in the literature
2
and several examples have been published. However, the synthesis
of chiral chromanones bearing an aliphatic substituent at C-2 has
been reported in a limited number of studies. Two general strategies
for the catalytic synthesis of chiral 2-alkylchromanones have
been reported: an intramolecular oxa-Michael reaction and an
3
4
,5
intermolecular conjugate addition of organometallic reagents Scheme 1 General catalytic methods for the synthesis of chiral 2-alkylchromanones.
6,7
(
Scheme 1). Examples of the first methodology are the synthesis
of (R)-2-(cyclohexyl)chroman-4-one and (S)-flindersiachromanone
4
a
by the group of Scheidt using cinchona alkaloids (Scheme 1a).
2-alkyl chromanones can subsequently be obtained with excel-
5
Similarly, Feng and coworkers reported the synthesis of (S)-2- lent ee’s by a retroaldol reaction. However, a direct enantio-
ethylchromanone (85% ee) using a chiral N,N -dioxide nickel(II) selective synthesis via catalytic conjugate addition to chromones
0
complex. Finally, Wallace et al. described the synthesis of enantio- remains a significant challenge in the preparation of valuable
enriched 2-methylchroman-4-one derivatives by a diastereoselec- 2-alkylchromanones.
6
tive intermolecular addition to chiral 3-sulfinylchromones. As far
Copper catalysed asymmetric conjugate addition (ACA) repre-
as we know the only example of catalytic enantioselective conjugate sents an important and versatile methodology for the enantio-
8
addition to prepare optically active 2-alkylchromanones was selective formation of C–C bonds. Based on our previous reported
7
described by Hoveyda and co-workers in 2005. They reported an methodology, we envisioned the possibility of using alkyl Grignard
enantioselective copper-catalysed conjugate addition of dialkylzinc reagents for the synthesis of chiral 2-alkylchromanones through a
reagents to chromones (Scheme 1b), providing good yields when direct asymmetric conjugate addition. Taking advantage of the
the reaction was performed in the presence of benzaldehyde to trap lower reactivity of magnesium enolates, we envisioned that one
the zinc enolate and avoid undesired reactions. The corresponding could avoid enolate condensation and other side reactions, thus
eliminating the need of benzaldehyde as an enolate trapping
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG
reagent. The addition of Grignard reagents catalysed by copper
Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl; Fax: +31 50 363 4278;
Tel: +31 50 3634296
9
10
has been successfully applied to acyclic and cyclic enones.
Recently, our group reported the Cu-catalysed 1,4-addition of
†
Electronic supplementary information (ESI) available: General procedures,
1
1
1
13
Grignard reagents to unsaturated heterocycles such as coumarins
characterization data, H and C NMR spectra, and chiral analysis of all the
products. See DOI: 10.1039/c3cc43105c
12
and 2H-pyran-2-ones. We envisioned that this approach might
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a
Table 1 Optimisation of the reaction conditions
b
c
d
Entry
Ligand
Solvent
Conversion (yield)
ee
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L3
L3
L3
L3
L3
MTBE
MTBE
MTBE
MTBE
THF
Toluene
Ether
DCM
60% (49%)
87% (83%)
Full (93%)
35% (34%)
Full (95%)
Full (76%)
96% (84%)
Full (90%)
Full (98%)
0
86
91
4
0
75
73
94
95
e
9
DCM
a
Reaction conditions: CuBrꢁSMe
2
(0.01 mmol, 5 mol%, 2.02 mg) and
mol% (0.012 mmol) of ligand, 1.25 eq. of EtMgBr and 0.2 mmol of 1a
6
b
in 2 mL of solvent at ꢀ80 1C. Conversions were determined by GC.
c
d
Isolated yields obtained after column chromatography. Determined
by chiral HPLC analysis. (R) configuration assigned by comparison of
e
the optical rotation with literature data (ref. 5). 2.5 mol% of CuBrꢁ
2
SMe and 3 mol% of L3 were used at 0.4 mmol scale.
provide a direct, efficient and versatile method for the synthesis of
-alkylchromanones in an enantioselective way. Herein, we present
the copper catalysed asymmetric conjugate addition of Grignard
reagents to chromones using ferrocenyl-based bisphosphine
ligands. The corresponding 2-alkylchromanones are obtained in 2 mL of dry DCM at ꢀ80 1C; chromone (0.4 mmol) in 1 mL of DCM was added
high yields and with excellent regio- and enantioselectivities.
The reaction between 4H-chromen-4-one (1a) and ethylmagne-
sium bromide was chosen as a model reaction for the optimisa-
tion of this conjugate addition (Table 1). First we tested different
2
Scheme 2 Substrate scope for the enantioselective addition of Grignard
2
reagents to chromones. Reaction conditions: R MgBr (0.5 mmol, 1.25 eq.) was
2
added to a stirred solution of CuBrꢁSMe (0.01 mmol) and L3 (0.012 mmol) in
dropwise over 1 h. Isolated yields obtained after column chromatography.
a
Enantiomeric excess was determined by chiral HPLC. 2 mmol scale, 1 mol% of
b
c
CuBrꢁSMe
2
and 1.5 mol% of L3. Full conversion was not achieved. (R) configu-
ration assigned by comparison of the optical rotation with literature data of
compounds 2a (ref. 5) and 2g (ref. 4a), and on the assumption of a uniform
chiral diphosphine ligands using MTBE as a solvent at ꢀ80 1C. mechanistic pathway for the rest of the compounds.
With (R)-BINAP (L1), the corresponding 2-ethylchroman-4-one 2a
was isolated in 49% yield (60% conversion) as a racemic mixture.
Interestingly, when (R,S)-Josiphos (L2) was used as a ligand Finally, the best solvent turned out to be dichloromethane
(Table 1, entry 2) the conversion was much higher, providing affording product 2a in 90% yield with an excellent enantioselec-
the product 2a in 83% yield and high enantioselectivity (86% ee). tivity of 94% (entry 8). Furthermore, the catalyst loading could be
The regioselectivity of the reaction was excellent, and only the lowered to 2.5 mol% without compromising the yield (98%) or the
formation of the 1,4-addition product was observed. Ligand L3, enantiomeric excess (95%) (entry 9).
1
3
(
R,S)-Rev-Josiphos, used previously in the successful asymmetric
We next examined a broad range of alkyl Grignard reagents
11,12
conjugate addition to other unsaturated heterocycles,
proved and different substituted chromones to demonstrate the potential
to be the best ligand in terms of both reactivity and enantioselec- of this new transformation (Scheme 2). The use of linear alkyl
tivity. Thus, the use of L3 afforded 2a in 93% yield and with 91% reagents such as pentyl, hexyl or dodecylmagnesium bromide
9b
ee (entry 3). However, when L4 (R,R)-Taniaphos, which has been afforded the corresponding chromones 2b–d with good yields
applied in the conjugate addition to cyclic enones, was used and high enantioselectivities, although with a longer linear alkyl
product 2a was obtained in low yield and as a nearly racemic chain (R = dodecyl) a lower conversion was observed. The addition
2
i
mixture (entry 4). Next, we turned our attention to the effect of the of a branched Grignard reagent (R = Bu) provided the alkylated
solvent on the enantioselectivity of the reaction. 2-Ethylchroman- chromanone 2e with an excellent enantioselectivity of 98%.
4-one was obtained as a racemic compound when THF was used A functionalized Grignard reagent bearing an alkene moiety
as a solvent (entry 5), probably, due to the coordinating nature also worked well and the corresponding product 2f was obtained
of THF. When diethyl ether or toluene were used as a solvent with good yield and enantiomeric excess (79% and 85%, respec-
(entries 6 and 7) a decrease in the enantioselectivity was observed. tively). The use of 2-phenethylmagnesium bromide afforded the
5
934 Chem. Commun., 2013, 49, 5933--5935
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(Contract number: 300826). We thank T. D. Tiemersma-Wegman
(HRMS) and M. Smith (GC and HPLC) for technical assistance.
Notes and references
Scheme 3 Trapping of enolate 8 with benzaldehyde.
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3
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Scheme 4 Baeyer–Villiger oxidation of compound 2a.
14
corresponding natural product ent-flindersiachromanone (2g) in
7% yield and 75% ee. Remarkably, the catalytic system tolerates
the use of more challenging secondary alkyl Grignard reagents
affording the corresponding products 2h, i with good yields and
enantioselectivities.
Different substituted chromones bearing electron-donating
and electron-withdrawing groups at the 6 or 7 position were
also studied. Under the optimised reaction conditions, good
yields and high enantiomeric excesses were obtained indepen-
dently of the electronic character of the substituent in the
aromatic ring of the chromone. In addition, the reaction could
be carried out on a 2.0 mmol scale with 1 mol% of the catalyst
to afford the corresponding (R)-2-ethylchroman-4-one 2a in
7
5
4, 93–102.
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1
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81% yield and 94% ee.
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7 M. K. Brown, S. J. Degrado and A. H. Hoveyda, Angew. Chem., Int. Ed.,
2
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8
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1
5
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2
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7
aldol product in excellent yield. The trans-substituted product 9
(
was exclusively obtained in 90% yield, as a mixture of only 2
diastereomers as determined by H NMR analysis.
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9
1
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(
2
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to chromones. The corresponding chiral 2-alkylchromanones are
obtained in good yields (up to 98%) and with high enantioselec-
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2
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2 B. Mao, M. Fa n˜ an ´a s-Mastral and B. L. Feringa, Org. Lett., 2013, 15,
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for the synthesis of versatile optically active building blocks.
Financial support from The Netherlands Organization for
1
2
Scientific Research (NWO-CW) and Dutch National Research 13 When MeMgBr was used a low yield and low enantiomeric excess
were obtained.
School Combination Catalysis Controlled by Chemical Design
1
4 K. Picker, E. Ritchie and W. C. Taylor, Aust. J. Chem., 1976, 29,
023–2036.
by Intra-European Marie Curie fellowship (FP7-PEOPLE-2011-IEF) 15 Z. Gale ˇs tokov ´a and R. ˇS ebesta, Eur. J. Org. Chem., 2012, 6688–6695.
(NRSC-Catalysis) is gratefully acknowledged. C.V. was supported
2
This journal is c The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5933--5935 5935