Sequential aldol Condensation-Transition metal-Catalyzed addition reactions of aldehydes, methyl ketones, and arylboronic acids

Article abstract of DOI:10.1021/ol200457q

Sequential aldol condensation of aldehydes with methyl ketones followed by transition metal-catalyzed addition reactions of arylboronic acids to form β-substituted ketones is described. By using the 1,1′;-spirobiindane- 7,7′;-diol (SPINOL)-based phosphite, an asymmetric version of this type of sequential reaction, with up to 92% ee, was also realized. Our study provided an efficient method to access β-substituted ketones and might lead to the development of other sequential/tandem reactions with transition metal-catalyzed addition reactions as the key step.

Full text of DOI:10.1021/ol200457q

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2058–2061
Sequential Aldol Condensation-Transition
Metal-Catalyzed Addition Reactions
of Aldehydes, Methyl Ketones, and
Arylboronic Acids
Yuan-Xi Liao, Chun-Hui Xing, Matthew Israel, and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the City
University of New York, Staten Island, New York 10314, United States
Qiaosheng.hu@csi.cuny.edu
Received February 19, 2011
ABSTRACT
Sequential aldol condensation of aldehydes with methyl ketones followed by transition metal-catalyzed addition reactions of arylboronic acids to
form β-substituted ketones is described. By using the 1,10-spirobiindane-7,70-diol (SPINOL)-based phosphite, an asymmetric version of this type
of sequential reaction, with up to 92% ee, was also realized. Our study provided an efficient method to access β-substituted ketones and might lead
to the development of other sequential/tandem reactions with transition metal-catalyzed addition reactions as the key step.
Transition metal-catalyzed addition reactions of arylboro-
nic acids with carbonyl-containing compounds and deriva-
tives have recently emerged as useful transformations for
organic synthesis in part due to the nature of low toxicity and
air/moisture stability of arylboronic acids.1,2 One of the most
noteworthy achievements in this field might be transition
metal-catalyzed addition reactions of arylboronic acids with
R,β-unsaturated ketones, which yield synthetically useful β-
substituted ketones as the products.2,3 While good to high
enantioselectivities have been achieved for this type of addi-
tion reaction, the prepurifed R,β-unsaturated ketones were
used. Although R,β-unsaturated ketones can be “readily”
obtained from the aldol condensation of aldehydes and/or
ketones, the use of prepurified R,β-unsaturated ketones
apparently posed some limits: they require an extra purifica-
tion/separation step from aldehydes/ketones and are less
available than aldehydes/ketones. During our study on
transition metal-catalyzed addition reactions of arylboronic
acids with carbonyl-containing compounds,4ꢀ7 we became
interested in combining the formation of R,β-unsaturated
ketones, the aldol condensation, with the addition reactions
in a tandem or sequential fashion.8 We reasoned that achiev-
ing such tandem/sequential reactions will minimize the effort
for the preparation of R,β-unsaturated ketones because
prepurification for such R,β-unsaturated ketones is elimi-
nated and may also expand the R,β-unsaturated ketone
substrate scope. Herein, we report our results on such new
sequential reactions, including an asymmetric Rh(I)-cata-
lyzed sequential reaction.
We began our study by mixing benzaldehyde, acetone and
p-tolylboronic acid together with palladacycle 11,9ꢀ11 or
[Rh(COD)Cl]2 as the catalyst. We found with toluene or
THF-MeOH as the solvent, the desired reaction product (A)
was the minor product and the major product was the 1,2-
addition product (B) (Table 1). We speculated that this
reaction outcome was likely due to the fact that transition
metal-catalyzed addition of p-tolylboronic acid with benzal-
dehyde occurred faster than the aldol condensation of ben-
zaldehyde with acetone under the reaction condition.
To overcome the fast 1,2-addition reaction issue, we
decided to carry out the reaction of aldehydes, methyl
ketones and arylboronic acids in a sequential fashion: the
arylboronic acids, and the catalyst were introduced into the
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r
10.1021/ol200457q
Published on Web 03/18/2011
2011 American Chemical Society

the solvent, the sequential reactions of acetone, aldehydes
and arylboronic acids occurred smoothly at room tempera-
ture (Table 2, entries 1ꢀ3). Different aldehydes and aryl-
boronic acids were tested for the sequential reaction, and
good yields were observed (Table 2, entries 1ꢀ9). We also
tested 2-butanone, 2-pentanone, acetophenone and 3-penta-
Table 1. Tandem Aldol Condensation-Transition Metal-Catalyzed
Reaction of Benzaldehyde, Acetone, and p-Tolylboronic Acid a
Table 2. Sequential Aldol Condensation-Transition Metal-
Catalyzed Addition Reactions of Aldehydes, Methyl Ketones,
and Arylboronic Acidsa
a Reaction condition: benzaldehyde (0.25 mmol), acetone (0.3 mL),
p-tolylboronic acid (2.0 equiv), toluene (0.7 mL) or THF/MeOH (1.0
mL/0.1 mL), base (3.0 equiv), 60 °C. b Based on GC-MS analysis. c H2O
(2.0 equiv) was added to the reaction system. d H2O (22 equiv) was added
to the reaction system. e Phenyl p-tolyl ketone (14%) was observed.
f Phenyl p-tolyl ketone (9%) was observed.
reaction system after the completion of the aldol condensa-
tion. We found with K2CO3 as the base and THF/MeOH as
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a Reaction condition: aldehyde (0.25 mmol,1.0 equiv), acetone (0.1
mL), H2O (0.1 mL) and K2CO3 (1.0 equiv), 50 °C for 30 min, then 1 or
[Rh(COD)Cl]2 (1 mol %), THF (1 mL) and arylboronic acids (0.5 mmol,
2.0 equiv) were added into the mixture at rt for another 6 h. b Isolated
yield. c Reaction was carried out in 2.5 mmol scale. d 1-Phenyl-2-methyl-
1-penten-3-one (16%) was observed.
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Org. Lett., Vol. 13, No. 8, 2011
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none for the reaction. We found that 2-butanone, 2-penta-
none and acetophenone were suitable ketones (Table 2,
entries 10ꢀ15). On the other hand, we also found that
3-pentanone was inefficient for the sequential reaction
(Table 2, entry 16), likely because the aldol condensation
between benzaldehyde and 3-pentanone occurred too slowly.
We also found aliphatic aldehydes, which can also undergo
aldol reactions with themselves, were suitable starting mate-
rials for the new sequential reaction (Table 2, entries 17, 18).
We next turned our attention to the asymmetric version
of this sequential β-aryl ketone formation process. We selec-
ted Rh(I) complexes for our study because Rh(I)/chiral
ligand-catalyzed 1,4-addition reactions of arylboronic acids
with R,β-unsaturated ketones have been established.1,3 We
examined four optically active ligands, 2,12 3,13 1,10-spiro-
biindane-7,70-diol (SPINOL)-based phosphite 414 and 5,15
that were available to us and our results are listed in Table 3.
We found while Rh(I)/ligand 3 and Rh(I)/ligand 5 were
poor catalysts for the sequential aldol condensation-addi-
tion reaction (Table 3, entries 2, 4), Rh(I)/(R)-BINAP 2 and
Rh(I)/ligand 4 exhibited good catalytic activities and
enantioselectivities (Table 3, entries 1, 3). Other factors that
could influence the enantioselectivity of the reaction were
then examined. We found that with 4as the ligand, K2CO3 as
the base and THF as the solvent, the enantioselectivity could
be improved to 89% (Table 3, entries 6- 11). Decreasing the
reaction temperature from room temperature to 0 °C further
improved the enantioselectivity to 92% (Table 3, entry 12).
Several aldehydes, methyl ketones and arylboronic acids
were examined for the asymmetric sequential aldol con-
densation-Rh(I)/4-catalyzed addition reaction. Optically
active β-arylated ketones were obtained in good yields and
good enantioselectivity (Table 4, entries 1ꢀ8). Because this
sequential reaction involvedR,β-unsaturated ketones, gen-
erated from the aldol condensation of aldehydes and methyl
ketones, and arylboronic acids, we reasoned that optically
active β-arylated ketones with opposite chiral configurations
could be obtained with the same Rh(I)/4 catalyst by simply
reversing the aryl groups on aldehydes and arylboronic
acids. We found indeed that (R)-4-phenyl-4-p-tolylbutan-
2-one, generated from benzaldehyde, acetone and p-tolyl-
boronic acid, and (S)-4-phenyl-4-p-tolylbutan-2-one, gener-
ated from p-tolualdehyde, acetone and phenylboronic
acid, were obtained in excellent enantioselectivity with
the same Rh(I)/4 catalyst (Table 4, entries 1, 9).
Table 3. Asymmetric Sequential Aldol Condensation-Rh(I)/
Ligand-Catalyzed Addition Reaction of Benzaldehyde, Acet-
one, and p-Tolylboronic Acid a
Table 4. Asymmetric Sequential Aldol Condensation-Rh(I)-
Catalyzed Addition Reactions of Aldehydes, Methyl Ketones,
and Arylboronic Acids a
a Reaction condition: aldehyde (0.25 mmol,1.0 equiv), arylboronic
acid (2.0 equiv), MeOH (0.1 mL), ketone (0.2 mL), H2O(0.1 mL), K2CO3
(3.0 equiv), 0 °C. b Isolatedyield. c Determined by HPLC analysis (Chiral
OD Column) d Established by comparison of the HPLC data with
reported ones.
a Reaction condition: benzaldehyde (0.25 mmol,1.0 eqiuv), p-tolyl-
boronic acid (2.0 equiv), solvent(1 mL), acetone (0.2 mL), H2O (0.1 mL),
base (1.0 equiv). b Isolated yield. c Determined by HPLC (Chiralcel OD
Column). d 4 (4 mol %) was used.
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Org. Lett., Vol. 13, No. 8, 2011

In summary, we demonstrated that the aldol condensa-
tion of aldehydes with methyl ketones followed by transi-
tion metal-catalyzed addition reactions with arylboronic
acids could occur efficiently in a sequential fashion, afford-
ing various β-arylated ketones. By using an optically active
1,10-spirobiindane-7,70-diol (SPINOL)-based phosphite as
the ligand, a Rh(I)-catalyzed asymmetric version of such a
sequential reaction has been realized and up to 92% ee was
achieved. Our study provided an efficient method to access
β-substituted ketones from readily available alde-
hydes with methyl ketones, and might lead to the
development of other new sequential/tandem reac-
tions with transition metal-catalyzed addition reac-
tions as part of the reaction sequence.
Acknowledgment. We gratefully thank the NSF (CHE-
0719311) and NIH (1R15 GM094709) for funding. Partial
support from PSCꢀCUNY Research Award Programs is
also acknowledged. We thank the Frontier Scientific for its
generous gifts of arylboronic acids.
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Supporting Information Available. General procedures
and product characterization for sequential aldol conde-
sation-transition metal-catalyzed addition reactions of
aldehydes, methyl ketones and arylboronic acids. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
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