Bronsted acid catalyzed, conjugate addition of β-dicarbonyls to in situ generated ortho-quinone methides - Enantioselective synthesis of 4-aryl-4H-chromenes

Article abstract of DOI:10.1002/anie.201403573

We describe herein a catalytic, enantioselective process for the synthesis of 4H-chromenes which are important structural elements of many natural products and biologically active compounds. A sequence comprising a conjugate addition of β-diketones to in situ generated ortho-quinone methides followed by a cyclodehydration reaction furnished 4-aryl-4H-chromenes in generally excellent yields and high optical purity. A BINOL-based chiral phosphoric acid was employed as a Bronsted acid catalyst which converted ortho-hydroxy benzhydryl alcohols into hydrogen-bonded ortho-quinone methides and effected the carbon-carbon bond-forming event with high enantioselectivity. Chiral phosphoric acids permit the in situ generation of hydrogen-bonded ortho-quinone methides which react with β-diketones and β-keto esters with excellent enantioselectivity and furnish valuable 4-aryl-4H-chromenes and related heterocycles upon subsequent cyclodehydration. These observations extend the substrate scope of enantioselective phosphoric acid catalysis towards an important additional class of compounds.

Full text of DOI:10.1002/anie.201403573

Angewandte
Chemie
DOI: 10.1002/anie.201403573
Asymmetric Catalysis
Brønsted Acid Catalyzed, Conjugate Addition of b-Dicarbonyls to
In Situ Generated ortho-Quinone Methides—Enantioselective
Synthesis of 4-Aryl-4H-Chromenes**
Osama El-Sepelgy, Stefan Haseloff, Santosh Kumar Alamsetti, and Christoph Schneider*
Abstract: We describe herein a catalytic, enantioselective
process for the synthesis of 4H-chromenes which are important
structural elements of many natural products and biologically
active compounds. A sequence comprising a conjugate addi-
tion of b-diketones to in situ generated ortho-quinone methides
followed by a cyclodehydration reaction furnished 4-aryl-4H-
chromenes in generally excellent yields and high optical purity.
A BINOL-based chiral phosphoric acid was employed as
a Brønsted acid catalyst which converted ortho-hydroxy
benzhydryl alcohols into hydrogen-bonded ortho-quinone
methides and effected the carbon–carbon bond-forming event
with high enantioselectivity.
addition of aryl and vinyl boronates to in situ generated ortho-
quinone methides proceeding under very mild conditions.[5]
Most recently, the groups of Ye and Scheidt independently
reported N-heterocyclic carbene catalyzed enantioselective
[4+3]-cycloadditions of a,b-unsaturated aldehydes and ortho-
quinone methides in the synthesis of benzoxopinones.[6]
The chromane skeleton belongs to the privileged struc-
tural motifs in the field of natural products as well as in the
area of pharmaceutically active compounds which exhibit
cytotoxic, antibacterial, antiviral, antiinflammatory, and anti-
oxidant activities.[7] Previous synthetic strategies specifically
towards the synthesis of 4H-chromenes furnished racemic
products in most cases.[8] Only in the last years a few
enantioselective processes have been developed which are,
however, limited to very special substrates.[9] Only the
palladium-catalyzed, enantioselective, conjugate addition of
aryl boronic acids to enones developed by Miyaura and co-
workers gave rise to some pharmacologically valuable 4-aryl-
4H-chromenes with high optical purity.[9a]
o
rtho-Quinone methides are highly reactive intermediates
in organic chemistry which have only recently been used
synthetically to a greater extent, in particular in the synthesis
of chromane systems. They are easily available from a variety
of precursors and react as polarized, electron-poor 1-oxa-
butadienes mostly with electron-rich [2p]-components in
hetero-Diels–Alder reactions with inverse electron demand
and with nucleophiles in conjugate additions, both with
reconstitution of the aromatic p-system.[1]
We report herein the first Brønsted acid catalyzed,
conjugate addition of b-dicarbonyls to in situ generated
ortho-quinone methides, which proceed with good to excel-
lent enantioselectivity and through a subsequent cyclodehy-
dration reaction furnish optically highly enriched 4-aryl-4H-
chromenes with a broad substitution pattern (Scheme 1). As
substrates for the in situ formation of the ortho-quinone
Catalytic, enantioselective reactions of ortho-quinone
methides have been reported only rarely.[2] Thus, Sigman
and co-workers showed that a chiral palladium–Quinox
complex successfully catalyzed the enantioselective dialkox-
ylation and carboalkoxylation of vinyl phenols and they
postulated a palladium ortho-quinone methide complex as
reactive intermediate.[3] Lectka et al. reported a formal,
cinchona alkaloid catalyzed [4+2]-cycloaddition of a stable
ortho-quinone methide with various silylketene acetals to
furnish 3,4-dihydrocoumarins with moderate to good enan-
tioselectivity.[4] Schaus and co-workers employed a chiral 1,1’-
binaphthol as catalyst to effect a highly enantioselective
[*] M. Sc. O. El-Sepelgy, M. Sc. S. Haseloff, Dr. S. K. Alamsetti,
Prof. Dr. C. Schneider
Scheme 1. Conceptualization of the synthesis of 4-aryl-4H-chromenes.
Institut fꢀr Organische Chemie, Universitꢁt Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
E-mail: schneider@chemie.uni-leipzig.de
methides we have employed ortho-hydroxy benzhydryl alco-
hols which had previously been employed in Lewis acid
catalyzed syntheses of racemic 4H-chromenes.[8h–j] We rea-
soned that a chiral Brønsted acid would not only generate the
catalyst-bound ortho-quinone methide, but at the same time
also remain attached to the enol tautomer of the b-dicarbonyl
compound through hydrogen bonding such that an enantio-
selective reaction would occur via a highly ordered transition
state.[10]
M. Sc. O. El-Sepelgy
Permanent Address: Faculty of Chemistry
Jagiellonian University Krakow
Ingardena 3, 30060 Krakow (Poland)
[**] O.E.-S. is grateful to the MPD Program of the Polish Science
Foundation (cofinanced through the European Regional Develop-
ment Fund) for a doctoral fellowship. We are grateful to Chemetall,
Evonik, and BASF for the donation of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403573.
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Our studies are conceptually related to the work of
Rueping[11] and Bach[12] in which secondary ortho-hydroxy-
benzylic alcohols were employed under similar conditions as
substrates for enantioselective allylic alkylation reactions and
for the addition of indole nucleophiles, respectively.[13]
We started our investigations with the reaction of ortho-
hydroxy benzhydryl alcohol 1a (1 equiv) and acetylacetone
(2a; 3 equiv) in CH2Cl2 in the presence of various chiral,
BINOL-based phosphoric acids 3 (20 mol%; Table 1). The
addition product 4a was obtained in good yields within 24 h at
room temperature and was subsequently cyclodehydrated to
(entries 6 and 7). The catalyst loading could be lowered to
only 5 mol% and the amount of diketone was reduced to
1.2 equiv as well without compromising yield or selectivity of
this reaction. When this conditions were applied 4H-chro-
mene 5a was isolated in 82% overall yield and 88:12 e.r.
(entry 8).
Additional ortho-hydroxy benzhydryl alcohols 1 were
submitted to the reaction with acetylacetone (2a) under these
optimized conditions and converted into the corresponding 4-
aryl-4H-chromenes 5a–d in good yields and high optical
purity (Figure 1).
Table 1: Optimization of the phosphoric acid catalyzed addition of
acetylacetone (2a) to ortho-quinone methides generated in situ.[a]
Figure 1. Phosphoric acid catalyzed, enantioselective synthesis of 4-
aryl-4H-chromenes 5 (reaction conditions see Table 1, entry 8).
Entry
Product
Catalyst
Yield [%]
e.r.[e]
1
2
3
4
4a
4a
4a
4a
4a
4a
4a
5a
3a
3b
3c
3d
3e
3e
3e
3e
70
95
97
97
97
88
95
82
56:44
78:22
84:16
81:19
85:15
86:14
89:11
88:12
This process could easily be extended to other b-diketones
as well. In particular, cyclic diketones turned out to be
excellent substrates. Thus, 1,3-cyclohexanedione (2b) was
converted into tetrahydroxanthenone 6a in 95% overall yield
and with 95:5 e.r. (Scheme 2). Reaction of 2b with other aryl-
substituted ortho-quinone methides furnished products 6b–
i in excellent overall yields and with high enantioselectivity of
at least 95:5 e.r. It is noteworthy that ortho-substituted and
even ortho-disubstituted aryl substituents within the ortho-
quinone methide were readily tolerated and delivered
xanthenones 6e,f and 6h with excellent yield and selectivity.
A substitution within the quinone methide fragment was
possible as well and the corresponding xanthenones 6j–m
were obtained in almost quantitative yields and up to 98:2 e.r.
Moreover, the bromo-substituted xanthenone 6m gave crys-
tals suitable for X-ray crystallography which proved the
absolute configuration of the reaction products (Figure 2).[14]
Reactions with 1,3-cyclopentanedione (2c) went equally
well and delivered cyclopenta[b]benzopyranones 7a–e
directly with high enantioselectivity of up to 97:3 e.r. The
addition of para-toluenesulfonic acid to effect the subsequent
dehydrative cyclization was not necessary here as the
intermediate conjugate addition product cyclized directly to
give the final benzopyranone 7. Again, ortho-aryl-substituted
quinone methides underwent particularly enantioselective
reactions (7b–d).
5
6[b]
7[c]
8[c,d]
[a] Reaction conditions: 0.20 mmol (1.0 equiv) ortho-hydroxy benzhy-
drylic alcohol 1, 0.60 mmol (3.0 equiv) acetylacetone (2a), catalyst 3
(20 mol%), 1 mL CH2Cl2, RT, 24 h. [b] Solvent 1 mL toluene. [c] Solvent
1 mL CHCl3 [d] 0.24 mmol (1.2 equiv) acetylacetone (2a), catalyst 3
(5 mol%). [e] Determined by HPLC on a chiral stationary phase (see the
Supporting Information).
give the desired 4H-chromene 5a through addition of para-
toluenesulfonic acid (20 mol%) at 408C. Control experiments
revealed that the optical purity of 4a and 5a was identical in
each case. Whereas the 3,3’-diphenyl-substituted BINOL
phosphoric acid 3a gave rise to low enantioselectivity in this
reaction (entry 1), higher selectivity was observed with steri-
cally more demanding 3,3’-aryl substituents in the BINOL
backbone of the Brønsted acid catalyst. The highest selectiv-
ity was eventually obtained with phosphoric acid 3e (Ar=
2,6-Me2-4-tBuC6H2) which delivered the addition product 4a
with 97% yield and 85:15 e.r. (entry 5). In toluene and CHCl3
as solvent this selectivity was further enhanced to 86:14 e.r.
and 89:11 e.r., respectively, while maintaining excellent yields
Through simple structural modification within the dike-
tone component the corresponding oxa- and thiaxanthenones
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Figure 2. Crystal structure of the bromo-substituted xanthenone 6m.
Thermal ellipsoids at 50% probability.
were easily accessible as well (Scheme 3). Thus, 3,5-pyrane-
dione (2d) reacted with various ortho-hydroxy benzhydryl
alcohols 1 under the optimized reaction conditions to furnish
Scheme 2. Phosphoric acid catalyzed, enantioselective synthesis of 9-
aryl-1H-xanthen-1-ones 6 and cyclopenta[b]benzopyranones 7. Reaction
conditions: 0.20 mmol (1.0 equiv) ortho-hydroxy benzhydryl alcohol 1,
0.24 mmol (1.2 equiv) 1,3-cycloalkanedione 2b/2c, catalyst 3e
(5 mol%), 1 mL CHCl3, 24 h. Reaction temperature: [a] 08C, [b] 108C,
[c] RT. Reactions with 1,3-cyclopentanedione (2c) delivered cyclopenta-
[b]benzopyranone 7 directly without the addition of pTsOH. e.r. values
were determined through HPLC on a chiral stationary phase (see the
Supporting Information).
Scheme 3. Phosphoric acid catalyzed, enantioselective synthesis of
heterosubstituted xanthenones 8/9. Reaction conditions see Scheme 2.
Reaction temperature: [a] 08C, [b] RT. Reactions with 3,5-pyranedione
(2d) delivered 3-oxaxanthenons 8a–e directly without the addition of
pTsOH. e.r. values were determined by HPLC on a chiral stationary
phase (see the Supporting Information).
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3-oxaxanthenones 8a–e; likewise 3,5-thiapyrandione (2e)
gave rise to the corresponding 3-thiaxanthenones 9a–e by
means of this annulation process. Both reactions proceeded in
typically good yields and excellent enantioselectivities as well.
The entire process was readily extended to reactions with
b-ketoesters as substrates. Thus, ethyl acetoacetate (2 f) and
ortho-hydroxy benzhydryl alcohol 1a reacted under standard
conditions to furnish 4-para-methoxyphenyl-4H-chromene 10
in 70% yield and with 92:8 e.r. (Scheme 4).
In conclusion, we have developed a broadly applicable,
phosphoric acid catalyzed, enantioselective, conjugate addi-
tion of b-dicarbonyl compounds to in situ generated ortho-
quinone methides and subsequently converted the addition
products into synthetically valuable 4-aryl-4H-chromenes and
related heterocycles through a cyclodehydration reaction.
Products were obtained in typically excellent yields and high
optical purity, and the practicality of the process was
documented in a large-scale experiment in which only
3 mol% of the Brønsted acid catalyst was required for
identical results. This study significantly broadens the scope of
chiral phosphoric acid catalysis and we expect that other
nucleophiles may be submitted to reactions with hydrogen-
bonded ortho-quinone methides according to this scheme as
well. The detailed investigation of the reaction described
herein and extension of this methodology are currently in
progress in our laboratories.
Scheme 4. Phosphoric acid catalyzed reaction with ethyl acetoacetate
(2 f).
Received: March 21, 2014
Published online: && &&, &&&&
Keywords: asymmetric synthesis · benzhydrylic alcohols ·
.
chiral phosphoric acids · chromenes · xanthenones
In order to demonstrate the practicality of this process we
conducted the synthesis of xanthenone 6m on a gram-scale.
With only 3 mol% of Brønsted acid catalyst 3e the conjugate
addition reaction proceeded to completion within 24 h at
room temperature and after subsequent acid-catalyzed cyclo-
dehydration 1.37 g (89%) of product 6m was obtained with
97:3 e.r. which was further enhanced to > 99:1 e.r. through
recrystallization (Scheme 5).
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both the ortho-quinone methide and the enol tautomer of the
b-diketone through hydrogen bonds and guides both compo-
nents in a highly ordered transition
state. On the basis of the absolute
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configuration of the products
secured through the crystal struc-
ture analysis we propose a transition
structure similar to the one depicted
in Figure 3. The 3-aryl group within
the BINOL backbone of the catalyst
(Ar2), which is positioned in close
proximity to where the reaction
occurs, effectively shields the upper
side of the ortho-quinone methide
and directs the incoming enol nucle-
ophile to its lower side.
Figure 3. Proposed transi-
tion structure of the reac-
tion.
4
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[14] CCDC 969295 (6m) contains the supplementary crystallo-
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crystal structure of 6m see the Supporting Information as well.
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Communications
Asymmetric Catalysis
O. El-Sepelgy, S. Haseloff, S. K. Alamsetti,
C. Schneider*
&&&& — &&&&
Brønsted Acid Catalyzed, Conjugate
Addition of b-Dicarbonyls to In Situ
Generated ortho-Quinone Methides—
Enantioselective Synthesis of 4-Aryl-4H-
Chromenes
Chiral phosphoric acids permit the in situ
generation of hydrogen-bonded ortho-
quinone methides which react with b-
diketones and b-keto esters with excellent
enantioselectivity and furnish valuable 4-
aryl-4H-chromenes and related hetero-
cycles upon subsequent cyclodehydra-
tion. These observations extend the sub-
strate scope of enantioselective phos-
phoric acid catalysis towards an impor-
tant additional class of compounds.
6
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