Tandem Alkyne Hydroacylation and Oxo-Michael Addition: Diastereoselective Synthesis of 2,3-Disubstituted Chroman-4-ones and Fluorinated Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b01447

Tandem reactions involving Rh-catalyzed intermolecular hydroacylations of alkynes with salicylaldehydes followed by intramolecular oxo-Michael additions are described for the diastereoselective synthesis of 2,3-disubstituted chroman-4-ones. The tandem hydroacylation/oxo-Michael additions occur to form 2,3-disubstituted chroman-4-ones in high yields from a range of 1,2-disubstituted acetylenes and substituted salicylaldehyes. The resulting 2,3-disubstituted chroman-4-ones are readily fluorinated to form trans-3-fluoro-2,3-disubstituted chroman-4-ones in high yields with excellent diastereoselectivity. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01447

Letter
pubs.acs.org/OrgLett
Tandem Alkyne Hydroacylation and Oxo-Michael Addition:
Diastereoselective Synthesis of 2,3-Disubstituted Chroman-4-ones
and Fluorinated Derivatives
Xiang-Wei Du and Levi M. Stanley*
Department of Chemistry, Iowa State University, 1605 Gilman Hall, Ames, Iowa 50014, United States
S
* Supporting Information
ABSTRACT: Tandem reactions involving Rh-catalyzed inter-
molecular hydroacylations of alkynes with salicylaldehydes
followed by intramolecular oxo-Michael additions are described
for the diastereoselective synthesis of 2,3-disubstituted chroman-
4-ones. The tandem hydroacylation/oxo-Michael additions occur
to form 2,3-disubstituted chroman-4-ones in high yields from a
range of 1,2-disubstituted acetylenes and substituted salicylaldehyes. The resulting 2,3-disubstituted chroman-4-ones are readily
fluorinated to form trans-3-fluoro-2,3-disubstituted chroman-4-ones in high yields with excellent diastereoselectivity.
Scheme 1. Synthesis of Dihydroquinolones and Chroman-4-
ones by Hydroacylation of Alkynes
andem processes involving atom-economic, transition-
Tmetal-catalyzed alkene or alkyne hydroacylation have been
developed as efficient routes to a variety of ketones.1 However,
examples of these tandem processes to form valuable
heterocyclic ketones are rare.1i The paucity of tandem reactions
involving alkene and alkyne hydroacylation to form heterocyclic
ketones is surprising because a variety of heteroatom-function-
alized aldehydes, particularly 2-hydroxybenzaldehydes (salicy-
laldehydes),2 2-aminobenzaldehydes,3 2-mercaptobenzalde-
hydes, and derivatives,4 are established as privileged substrates
in transition-metal-catalyzed alkene and alkyne hydroacylation
reactions.
The presence of heteroatom substitution in the aldehyde
substrates is often viewed as a limitation of alkene and alkyne
hydroacylation necessary to suppress catalyst deactivation
pathways and minimize the formation of undesired products
often observed in reactions of simple aldehydes.5 However,
these heteroatom functional groups offer a handle to rapidly
generate complex heterocycles when olefin hydroacylation
reactions are coupled with additional reaction manifolds
(Scheme 1).6 To this end, Willis developed a stepwise protocol
for hydroacylation of alkynes with 2-aminobenzaldehydes
followed by Lewis acid catalyzed, intramolecular aza-Michael
addition to rapidly generate dihydroquinolones (Scheme 1A).3
The development of related intermolecular hydroacylation of
alkynes with salicylaldehydes followed by intramolecular oxo-
Michael addition offers the potential to streamline traditional
syntheses of chroman-4-ones.7 However, tandem alkyne
hydroacylation/oxo-Michael addition processes to form chro-
man-4-ones are limited to two examples reported by Miura.2b,c
Hydroacylations of activated alkynes, ethyl hept-2-ynoate and
1-phenylhept-2-yn-1-one, and the subsequent oxo-Michael
additions occur to form approximately 1:1 mixtures of
chroman-4-one and benzofuran-3-(2H)-one products. To our
knowledge, a general catalyst system to generate chroman-4-
ones with high regio- and diastereoselectivity by a tandem
alkyne hydroacylation/oxo-Michael addition strategy has not
been reported.
We now report a one-pot process to synthesize 2,3-
disubstituted chroman-4-ones by hydroacylation of 1,2-
disubstituted alkynes with salicylaldehydes followed by an
intramolecular oxo-Michael addition (Scheme 1B). The 2,3-
disubstituted chroman-4-one products of these tandem
reactions are readily converted to trans-3-fluoro-2,3-disubsti-
Received: May 18, 2015
© XXXX American Chemical Society
A
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Letter
tuted chroman-4-ones by a highly diastereoselective enolate
fluorination.
The scope of the tandem reaction sequence with regard to
1,2-disubstituted alkynes was then examined (Scheme 2).
2,3-Diarylchroman-4-ones are core structures present in a
wide variety of biflavonoids8 and are valuable precursors to 2,3-
diaryl-2H-1-benzopyrans that exhibit potent antiestrogenic
activity.9 To develop a rapid entry into the 2,3-diarylchro-
man-4-one core, we studied the reaction of salicylaldehyde 1a
with 1,2-diphenylacetylene 2a in the presence of a variety of
bases and 5 mol % of catalyst prepared in situ from
[Rh(COD)Cl]2 and dppf (Table 1). The hydroacylation of
Scheme 2. Scope of Tandem Alkyne Hydroacylation/Oxo-
Michael Addition with 1,2-Disubstituted Acetylenes
Table 1. Identification of Reaction Conditions for Tandem
a
Alkyne Hydroacylation/Oxo-Michael Addition
yield 3a
dr
yield 4a
b
b,
c
b
entry base (mol %)
solvent
toluene
(%)
(trans:cis)
(%)
1
Na2CO3
(200)
14
1.8:1
76
2
3
4
5
K3PO4 (200) toluene
78
84
85
65
3.6:1
3.9:1
3.2:1
2.6:1
15
7
CsF (20)
CsF (20)
CsF (20)
toluene
DCE
1,4-
10
22
dioxane
a
6
CsF (20)
CsF (20)
CsF (20)
CsF (20)
CsF (10)
CsF (8)
DMF
91
93
81
70
95
3.8:1
5.7:1
1.8:1
3.0:1
5.0:1
5.0:1
5.4:1
5
1
0
8
4
4
4
Isolated yield reported as mixtures of trans-3 and cis-3. Yields in
7
MeCN
MeNO2
MeCN
MeCN
MeCN
MeCN
parentheses represent isolated yield of >20:1 trans-3 after column
chromatography. Reaction conducted with 1.0 equiv of 1,2-bis(3-
methoxyphenyl)ethyne.
b
8
9
10
11
12
94
d
e
CsF (8)
94 (92)
Reactions of 1a with a variety of 1,2-diarylacetylenes occur to
form the corresponding 2,3-diarylchroman-4-ones 3a−f in good
to excellent yields (55−92%). The diastereomeric ratio of 2,3-
diarylchroman-4-ones 3a−f was influenced by substitution on
the alkyne. 2,3-Diarylchroman-4-ones derived from 1,2-diary-
lacetylenes with electron-neutral (R = Ph, 4-ClC6H4) or bulky
(R = 2-MeOC6H4) aryl groups were isolated with greater than
5:1 diastereomeric ratios favoring trans-3a, 3b, and 3f. Tandem
reactions of 1a with 1,2-diarylacetylenes containing strongly
electron-withdrawing (R = 4-F3CC6H4), strongly electron-
donating (R = 4-MeOC6H4), and meta-substituted (R = 3-
MeOC6H4) aryl groups formed the corresponding 2,3-diary-
lchroman-4-ones 3c−e with modest diastereoselectivities (2.0−
3.1:1 trans-3:cis-3).
Although the tandem reactions form mixtures of trans:cis
diastereoisomers, pure trans-3 (>20:1) can be isolated by
recrystallization or column chromatography. For example,
trans-3a was isolated in 74% yield (2.22 g) after recrystallization
from the reaction of 1a (10.0 mmol, 1.22 g) with 2a. trans-3b
and trans-3c were isolated in 74% yield and 48% yield after
column chromatography.
A tandem alkyne hydroacylation and oxo-Michael addition
involving an unsymmetrical alkyne also occurs to form 2,3-
disbustituted chroman-4-ones with modest levels of regio- and
diastereoselectivity (eq 1). The reaction of 1-phenyl-1-propyne
with salicylaldehyde occurs to form a 3.4:1 mixture of
regioisomeric products 3-methyl-2-phenylchroman-4-one and
2-methyl-3-phenylchroman-4-one in 88% combined yield.10 3-
Methyl-2-phenylchroman-4-one is formed with a 3.8:1
diastereomeric ratio of trans and cis isomers, and 2-methyl-3-
a
Reaction conditions: 1a (1.0 equiv), 2a (1.2 equiv), [Rh(COD)Cl]2
(2.5 mol %), dppf (5 mol %), base, solvent (0.20 M), 100 °C. dppf =
b
1,1′-bis(diphenylphosphine)ferrocene. Determined by 1H NMR
spectroscopy of the crude reaction mixture with dibromomethane as
c
the internal standard. Combined yield of trans-3a and cis-3a.
d
Reaction conducted with 2 mol % of Rh catalyst (0.5 M in
e
MeCN). Combined isolated yield of trans-3a and cis-3a.
2a in the presence of a variety of inorganic bases occurs in high
yields (entries 1−3). These reactions form 2,3-diphenylchro-
man-4-one 3a and (E)-1-(2-hydroxyphenyl)-2,3-diphenylprop-
2-en-1-one 4a in combined yields of ≥90% with 2 equiv of
Na2CO3, K3PO4, or CsF as the base. However, the efficiency of
the oxo-Michael addition to form 3a is significantly impacted by
the identity of the base. Product 3a was generated in higher
yield and with higher diastereoselectivity when CsF (20 mol %)
was used as the base (entry 3).
The improved yield and diastereoselectivity observed with
CsF as the base guided attempts to improve the yield and
selectivity of the model reaction. To improve the diaster-
eoselectivity of the intramolecular oxo-Michael addition of 4a
to 3a, we evaluated the tandem reaction in a range of solvents
(entries 4−9) and found the yield (93%) and diastereomeric
ratio (5.7:1) of 3a to be the highest in acetonitrile (entry 7).
Conducting the model reaction in acetonitrile enabled us to
lower the loading of CsF to 8 mol % with only a modest
decrease in selectivity (entry 11). The loading of the Rh catalyst
was reduced from 5 to 2 mol % without significantly impacting
the yield or diastereoselectivity of the tandem reaction
sequence (compare entry 12 with entry 11).
B
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Letter
naphthaldehyde with 2a formed 3p with 3.5:1 dr. Trans
diastereomers (>20:1 dr) of 3 are readily obtained by column
chromatography or recrystallization. trans-3i and trans-3p were
isolated in 64% yield and 79% yield after recrystallization. trans-
3o was isolated in 36% after column chromatography.
With a tandem reaction strategy to form trans-2,3-
disubstituted chroman-4-ones 3 in hand, we sought to develop
a fluorination protocol to access pseudodiastereomeric trans-3-
fluoro-2,3-disubstituted chroman-4-ones in which the 2,3-diaryl
or 2,3-dialkyl substituents reside on the same face of the
chromanone core. A direct fluorination protocol to synthesize
trans-3-fluoro-2,3-disubstituted chroman-4-ones 5 is summar-
ized in Scheme 4.12 Deprotonation of diastereomeric mixtures
phenylchroman-4-one is formed with a 2.5:1 diastereomeric
ratio of trans and cis isomers.
Reactions of salicylaldehyde with 1,2-dialkylacetylenes occur
to form the corresponding 2,3-dialkylchroman-4-ones, which
are found in a variety of naturally occurring chroman-4-ones11
in higher yields than analogous reactions of 1,2-diarylacetylenes.
For example, reactions of 3-hexyne and 4-octyne with
salicylaldehyde occur to form 2,3-dialkylchroman-4-ones 3g
and 3h in 92% and 94% yield. However, the diastereoselectivity
of these reactions is modest, and the resulting 2,3-
dialkylchromanones 3g and 3h were isolated as 1.8:1 and
1.3:1 mixtures of the trans:cis diastereomers.
Scheme 4. Synthesis of 3-Fluoro-2,3-disbustituted Chroman-
b
4-ones
The scope of tandem reactions of a variety of substituted
salicylaldehydes with 1,2-diphenylacetylene 2a is summarized in
Scheme 3. Reactions of salicylaldehydes containing both
Scheme 3. Scope of Tandem Alkyne Hydroacylation/Oxo-
Michael Addition with Substituted Salicylaldehydes
a
NFSI = N-fluorobenzenesulfonimide. Isolated yields are reported as
mixtures of diastereomers. Diastereomeric ratios determined by 19F
NMR spectroscopy. Reaction conducted with 3.0 equiv of LiHMDS
b
and 4.8 equiv of NFSI.
of chroman-4-ones 3 with LiHMDS and fluorination of the
resulting enolate with NFSI from the opposite face of the C2
substituent selectively generates trans-5 in high yields with
excellent selectivities. Fluorinations of a variety of 2,3-
diphenylchroman-4-ones 3 occur to form trans-5a−f in 67−
91% yield with nearly perfect diastereoselectivity (>20:1). The
relative stereochemistry of 5a was confirmed by X-ray
crystallographic analysis (Figure 1). Fluorinations of 2,3-
dialkylchroman-4-ones form the corresponding trans-3-fluoro-
2,3-dialkylchroman-4-ones 5g (R1 = Et) and 5h (R1 = n-Pr) in
88% and 93% yield as 14:1 and 9:1 diastereomeric mixtures.
a
Yield of trans-3 with >20:1 diastereomeric ratio after recrystallization.
The uncyclized hydroacylation product 4o was isolated in 17% yield.
b
trans-3o was isolated in 36% yield.
electron-withdrawing and electron-donating substituents with
2a occur to form 2,3-diphenylchroman-4-ones in good yields
with moderate diastereoselectivities. Reactions of 4-NO2-, 4-F-,
and 4-Cl-salicylaldehyde with 2a form the corresponding 2,3-
diphenylchroman-4-ones 3i−k in 64−86% yield with diaster-
eoselectivities ranging from 2.6:1 to 5.3:1. Reactions of 3-
MeO-, 4-MeO-, 5-MeO-, and 6-MeO-salicylaldehydes with 1,2-
diphenylacetylene generate 2,3-diphenylchroman-4-ones 3l−o
in 55−90% yield with 2.9:1 to 4.6:1 dr. The reaction of 6-
methoxysalicylaldehyde with 2a formed only 55% yield of 2,3-
diarylchroman-4-one 3n, while the initial alkyne hydroacylation
product was isolated in 17% yield. The reaction of 2-hydroxy-1-
Figure 1. Relative stereochemistry and structure of 5a.
C
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Letter
(g) Chaplin, A. B.; Hooper, J. F.; Weller, A. S.; Willis, M. C. J. Am.
Chem. Soc. 2012, 134, 4885.
In conclusion, we have developed a tandem alkyne
hydroacylation/oxo-Michael addition process to synthesize
trans-2,3-disubstituted chroman-4-ones from readily accessible
starting materials in the presence of simple catalyst precursors.
The 2,3-disubstituted chroman-4-one products are transformed
to trans-3-fluoro-2,3-disubstituted chroman-4-ones in high
yields and with excellent diastereoselectivities by a straightfor-
ward fluorination procedure. Studies to expand the scope of the
tandem reaction to encompass unsymmetrical alkynes and to
apply these reactions in total syntheses of natural products are
ongoing in our laboratory.
(5) For recent reviews of alkene and alkyne hydroacylation, see:
(a) Willis, M. C. Hydroacylation of Alkenes, Alkynes and Allenes.
Comprehensive Organic Synthesis II; Molander, G. A., Knochel, P., Eds.;
Elsevier: Oxford, 2014; Vol. 4, pp 961. (b) Willis, M. C. Chem. Rev.
2010, 110, 725. (c) Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3,
2202.
(6) For selected examples, see: (a) Arambasic, M.; Hooper, J. F.;
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(7) (a) Kabbe, V. H.-J.; Widdig, A. Angew. Chem., Int. Ed. 1982, 21,
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(b) Harborne, J. B.; Williams, C. A. Phytochemistry 2000, 55, 481.
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(10) Under identical reaction conditions, the analogous reaction of
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chroman-4-one (34%), 3-phenylchroman-4-one (13%), and uncyclized
1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one in 21% yield.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data for all new
compounds, and crystallographic data for compound 5a. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01447.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lstanley@iastate.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (GM95697) for financial support and Dr.
Arkady Ellern (ISU) for X-ray diffraction data collection and
structure determination.
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