Organocatalytic annulation of aldehydes and o-quinone methides: A facile access to dihydrocoumarins

Article abstract of DOI:10.1016/j.tetlet.2016.11.006

A [4+2] annulation of aldehydes and o-quinone methides catalyzed by a secondary amine is developed. This process leads to biologically important dihydrocoumarins in moderate to good yields after oxidation. In addition, the employment of a chiral secondary amine catalyst allows access to optically active dihydrocoumarins with up to 64% ee.

Full text of DOI:10.1016/j.tetlet.2016.11.006

Accepted Manuscript
Organocatalytic Annulation of Aldehydes and o-Quinone Methides: A Facile
Access to Dihydrocoumarins
Ding Zhou, Kaizhe Mao, Jian Zhang, Bingliang Yan, Wei Wang, Hexin Xie
PII:
S0040-4039(16)31456-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.006
TETL 48292
Reference:
Tetrahedron Letters
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28 October 2016
2 November 2016
Please cite this article as: Zhou, D., Mao, K., Zhang, J., Yan, B., Wang, W., Xie, H., Organocatalytic Annulation
of Aldehydes and o-Quinone Methides: A Facile Access to Dihydrocoumarins, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.11.006
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Tetrahedron Letters
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Organocatalytic Annulation of Aldehydes and o-Quinone Methides: A Facile Access
to Dihydrocoumarins
Ding Zhou,#,a Kaizhe Mao,#,a Jian Zhang,a Bingliang Yan,a Wei Wanga,b,* and Hexin Xiea,*
a
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
b
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A [4+2] annulation of aldehydes and o-quinone methides catalyzed by a secondary amine is
developed. This process leads to biologically important dihydrocoumarins in moderate to good
yields after oxidation. In addition, the employment of a chiral secondary amine catalyst allows
access to optically active dihydrocoumarins with up to 64% ee.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
o-Quinone methide
Dihydrocoumarin
ortho-Quinone methides (o-QMs) are a class of highly
reactive intermediates and have been employed in the synthesis
of a wide variety of natural products and biologically intriguing
molecules.1 Recently, by the ingenious combination of
organocatalysis,2 the chemistry of o-QMs was further expanded,
especially in the field of asymmetric catalysis.3 Chiral Brøsted
acids have proved to be among the most useful catalysts in the
enantioselective reactions of o-QMs, presumably due in large
part to their ability to accelerate the generation of o-QMs and
activate nucleophiles simultaneously.4 N-Heterocyclic carbene
(NHC) catalysts,5 as well as cinchona alkaloids-based catalysts6
and substituted chiral binapthols,7 have also been demonstrated
as efficient promoters. The well-established aminecatalysts,
however, were surprisingly less explored in the o-QMs-involved
processes.
Dihydrocoumarins are structurally important motifs found in a
large number of pharmaceuticals and natural occurring
compounds.8 Attracted by the intriguing biological properties of
dihydrocoumarin-containing molecules (e.g., anti-cancer, anti-
microbial, anti-aging, etc.),9 organic chemists have devoted
considerable efforts on the development of new synthetic
methods and great progress has been achieved, particularly on the
construction of dihydrocoumarins mediated by organocatalysts.
The use of NHC-based catalysts has been extensively
investigated.5a,10,5b Furthermore, chiral amines were also explored
Scheme. 1. Organocatalytic synthesis of dihydrocoumarins
for the preparation of 3,4-disubstituted hydrocoumarins from
# These authors contributed equally.
*Corresponding authors.
E-mail addresses: wwang@unm.edu (W. Wang), xiehexin@ecust.edu.cn (H.
Xie)

Table 1 Optimization of reaction conditionsa
Entry
1
Cat.
[F-] (equiv.)
KF (0.5)
Additive (equiv.)
18-C-6 (0.1)
-
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
THF
Time (h) Yield (%)b
I
I
I
I
I
II
I
I
I
I
I
12
12
5
<5c
2
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.05)
TBAF (0.1)
36
3
TFA (0.1)
82
4
p-Nitrophenol (0.1)
AcOH (0.1)
AcOH (0.1)
AcOH (0.1)
AcOH (0.1)
AcOH (0.1)
AcOH (0.1)
AcOH (0.1)
5
70
5
5
87 (40)d
74
6
5
8
5
77
9
5
49
10
11
12e
CH3CN
DCM
DCM
5
46
6
85
5
69
a
Unless otherwise noted, reactions were conducted with 1a (0.073 mmol), 2a (0.22 mmol, 3 equiv.), amine catalyst (0.015 mmol, 20 mol%), additive (0.007
mmol, 10 mol%) and fluoride reagent in solvent (0.4 mL) at rt. b Isolated yields for two steps. Yield of hemiacetal estimated by TLC With Fetizon’s
reagent instead of PCC as oxidant. With 2a (0.11 mmol, 1.5 equiv.). TBAF: Tetrabutylammonium fluoride; PCC: pyridinium chlorochromate; TFA:
c
d
e
trifluoroacetic acid.
aldehydes and nitroalkenes (Scheme 1)11. Very recently
Scheidt et al. described an elegant NHC-catalyzed asymmetric
annulation of o-QMs and acyl imidazoles, resulting in optically
active dihydrocoumarins with up to 86% ee.5d In this context,
taking advantage of the o-QM chemistry, we wish to report a new
secondary amine-catalyzed [4 + 2] annulation of aldehydes for
the synthesis of dihydrocoumarins.
Table 2 Scope of reactions
Entry
R1
R2
Product Yield (%)a
As illustrated in Scheme 1, we envision that in situ-forming o-
QM and enamine intermediates synergistically react in [4 + 2]
annulation manner. To achieve this goal, we selected fluoro-
containing 1a as o-QM precursor, which can be conveniently
transformed to o-QM in the presence of a catalytic amount of
fluoride, while aldehyde 2a was activated by pyrrolidine. Initial
attempt using potassium fluoride and 18-crown-6 to trigger the
formation of o-QM failed to deliver the desired product likely
due to the low solubility of potassium fluoride in
dichloromethane (Table 1, entry 1). Therefore, we switched to
organic solvable tetrabutylammonium fluoride (TBAF) (entry 2).
We were delightful to observe the formation of hemiacetal, and
1
2
4-Cl, 1a
4-Cl, 1a
Bn, 2a
PMB, 2b
3aa
3ab
87
66
CH2Ph(4’-
COOEt), 2c
Me, 2d
n-Bu, 2e
n-C8H17, 2f
i-Pr, 2g
Ph, 2h
3
4-Cl, 1a
3ac
58
4
4-Cl, 1a
4-Cl, 1a
4-Cl, 1a
4-Cl, 1a
4-Cl, 1a
4-F, 1b
4-F, 1b
4-Br, 1c
4-Br, 1c
4-Me, 1d
6-Me, 1e
4-tBu, 1f
H, 1g
3ad
3ae
3af
79
77
66
76
62
81
75
81
75
55
48
54
71
63
65
82
71
75
5
6
7
3ag
3ah
3ba
3be
3ca
3ce
3da
3ed
3fd
3ga
3gd
3gh
3ge
3gg
3gi
8
9
Bn, 2a
n-Bu, 2e
Bn, 2a
n-Bu, 2e
Bn, 2a
Me, 2d
Me, 2d
Bn, 2a
Me, 2d
Ph, 2h
n-Bu, 2e
i-Pr, 2g
Et, 2i
10
11
12
13
14
15
16
17
18
19
20
21
upon
oxidation
by
pyridiniumchlorochromate
(PCC),
dihydrocoumarin 3aa was obtained in 36% yield over two steps.
The addition of trifluoroacetic acid (TFA) to the reaction
significantly increased the yield of dihydrocoumarin to 82%
(entry 3). Further screening identified acetic acid as the optimal
additive (entry 5). On the other hand, proline (II) proved to be
less efficient for this transformation, affording 3aa in lower yield
(74%, entry 6). Besides DCM, other solvents (e.g. toluene, THF,
CH3CN, etc.) were also examined, but all failed to show any
significant improvements (entries 8-10).
H, 1g
H, 1g
H, 1g
H, 1g
Having established the optimal reaction conditions, we then
explored the generality of this [4 + 2] annulation process. A
survey of aldehydes revealed that this pyrrolidine-mediated
H, 1g
a Isolated yields for two steps.
reaction is compatible with
a range of substituents on
with electron-rich (2b) or electron-deficient (2c) groups were all
acetaldehydes (Table 2). in addition to aldehyde 2a, analogues

tolerated, giving dihydrocoumains 3ab and 3ac in 66% and 58%
yield, respectively (entries 2, and 3). Aliphatic aldehydes (2d-
2g), as well as 2-phenylacetaldehyde (2h), can also furnish
substituted dihydrocoumarins in moderate to good yields over the
two-step transformation (entries 4-8). 2-Ethylhaxanal,
substituted aldehyde, however, is incompatible with current
protocol, resulting in no desired production formation.
a α-
Scheme. 3 Proposed transition state model for enantioselection.
The scope of o-QM precursor was also investigated. o-QM
precursors with both electron-neutral (R1 = H) and electro-
withdrawing groups (R1 = F, Cl, Br) can all participate the [4 + 2]
annulation process smoothly, leading to substituted dihydro-
coumarins in comparable yields after oxidation (entries 9-12, 16-
21). On the other hand, o-QM precursors with electron-donating
yields. Furthermore, the application of chiral secondary amine
catalyst in this process can furnish optically active
dihydrocoumarins with up to 64% ee.
t
groups (R1 = Me, Bu) gave slightly lower yields (entries 13-15).
Acknowledgments
But o-QM precursors with stronger electron-donating groups
(e.g., R1 = OMe) were not amenable to this pyrrolidine-catalyzed
transformation as current synthetic method failed to produce this
type of less stable precursors.
This work was financially supported by the “Thousand Plan”
Youth Program, the Fundamental Research Funds for the Central
Universities, and East China University of Science
Technology.
&
Supplementary data
1
Experimental procedures, characterizations, H NMR and 13C
NMR spectra, HPLC traces are available in the online version.
References and notes
Scheme. 2 Asymmetric synthesis of dihydrocoumarins catalyzed by
Click here to remove instruction text...
chiral amine
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17 General procedure: To a solution of o-QM precursor 1 (0.21
mmol), aldehyde 2 (0.63 mmol) and AcOH (0.021 mmol) in
dichloromethane (0.9 mL)were added pyrrolidine (0.042 mmol) and
TBAF (1M in THF, 0.021 mmol), subsequently. The reaction
mixture were then stirred at room temperature until completion of
the reaction (monitored by TLC). Chromatography on a short silica
gel column (eluting with petroleum ether/ethyl acetate) was used to
give the [4 + 2] annulation adduct as crude product, which was then
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the reaction, dihydrocoumarin3 was obtained after chromatography
on silica gel column (eluting with petroleum ether/ethyl acetate).

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Organocatalytic Annulation of Aldehydes
and o-Quinone Methides: A Facile Access to
Dihydrocoumarins
Ding Zhou,a Kaizhe Mao,a Bingliang Yan,a Wei Wang*a,b and Hexin Xie*a

Revised Highlights
Research highlights
 [4 + 2] Annulation of aldehydes and o-quinone methides
 Facile synthesis of dihydrocoumarins
 Use of simple secondary amine as catalyst