Catalytic Enantioselective Vinylogous Allylic Alkylation of Coumarins

Article abstract of DOI:10.1021/acs.orglett.7b02421

An unprecedented, organocatalytic enantioselective vinylogous γ-allylic alkylation of 4-methylcoumarins has been developed. Using allylic carbonates as the allyl source, this reaction is catalyzed by Lewis basic dimeric Cinchona alkaloid (QD)₂P

Full text of DOI:10.1021/acs.orglett.7b02421

Letter
pubs.acs.org/OrgLett
Catalytic Enantioselective Vinylogous Allylic Alkylation of Coumarins
Satavisha Kayal and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
S
* Supporting Information
ABSTRACT: An unprecedented, organocatalytic enantioselective vinylogous γ-allylic alkylation of 4-methylcoumarins has been
developed. Using allylic carbonates as the allyl source, this reaction is catalyzed by Lewis basic dimeric Cinchona alkaloid
(QD)2PHAL and proceeds exclusively in a γ- and branched-selective manner to produce densely functionalized coumarin
derivatives generally in good yields with good to high enantioselectivities (up to 97:3 er).
he principle of vinylogy, as described by Fuson, accounts
for the transmission of electronic effect of a given
We became interested in advancing the concept of distant
functionalization of coumarins to the domain of asymmetric
allylic alkylation.8 Introduction of an allyl group at the γ-
position of 4-methylcoumarin was first reported by Tunge et al.
in 2011 through a Pd-catalyzed migratory decarboxylative
coupling (Scheme 1A).9 However, enantioselective γ-allylation
T
functional group through a conjugated π-system.1 This concept
allows for the formation of bonds away from the parent
functional group, a phenomenon often termed as distant or
remote functionalization.2 In spite of its obvious advantages, the
scope of vinylogous nucleophilic reactivity has been restricted
to a handful of transformations3 and calls for new development.
Coumarins are a class of structural motif distributed in over
1000 natural products and various biologically active synthetic
targets (Figure 1).4 In addition, the photophysical properties of
Scheme 1. Catalytic Enantioselective Vinylogous Allylic
Alkylation of Coumarins
Figure 1. Bioactive compounds and natural products bearing coumarin
scaffold.
coumarins make them attractive components in dye industries.5
The popularity of coumarin-containing compounds as potential
drugs as well as polymeric materials has created a demand for
their enantioselective synthesis and functionalization.6 The
inherent electron-deficient nature of coumarins presents an
opportunity for distant functionalization of appropriately
substituted coumarins.
In this context, γ-functionalization of cyanocoumarins has
received special attention during the past few years. In 2010,
Xie et al. first disclosed the application of 3-cyano-4-
methylcoumarins as vinylogous nucleophiles for enantioselec-
tive γ-functionalization.7
of coumarins proved particularly challenging, possibly because
of the difficulty associated with remote regio- and enantiocon-
trol in the bond-formation step. The only known example of
enantioselective γ-allylation of cyanocoumarins is developed by
Lautens and co-workers using a Rh-catalyzed ring-opening
reaction of oxabicycles (Scheme 1A).10
Received: August 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02421
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Letter
Despite these examples of transition-metal-catalyzed γ-allylic
alkylation of coumarins9−11 and other nucleophiles,12 an
organocatalytic enantioselective γ-allylation of coumarins is
yet to be developed.13 In fact, organocatalytic enantioselective
γ-allylic alkylation reactions in general remain relatively
unexplored.14
Table 1. Evaluation of Catalyst and Reaction Conditions for
Vinylogous Allylic Alkylation
a
Herein, we present the first organocatalytic enantioselective
vinylogous γ-allylic alkylation of coumarins.
Our strategy relies upon the use of allylic carbonates (2,
Scheme 2) derived from Morita−Baylis−Hillman15 adducts as
Scheme 2. Mechanistic Hypothesis of Catalytic
Enantioselective Vinylogous γ-Functionalization Reaction
b
d
c
entry
cat.
solvent
CH2Cl2
additive
time
er
1
none
I
−
−
48 h
48 h
−
−
d
2
CH2Cl2
3
II
CH2Cl2
−
−
12 h
72 h
48 h
18 h
24 h
6 d
89:11
4
III
III
CH2Cl2
93:7
e
5
CH2Cl2
4 Å MS
94:6
f
6
III
CH2Cl2
−
90:10
94:6
e
e
7
III
III
III
III
CH3CN
4 Å MS
4 Å MS
−
the allyl source.16 The allylic carbonates of type 2 are known to
undergo decarboxylation through SN2′ attack of Lewis basic
tertiary amines (NR3) to generate the active allylating agent
A.16 The resulting tert-butoxide is then expected to deprotonate
cyanocoumarins (1) to produce the active vinylogous
nucleophile B. Addition of B to A can then take place either
in SN2′ fashion to furnish the desired branched γ-allylation
product 3 or in SN2 fashion to generate the linear (achiral) γ-
allylation product 4. Besides, B can also react directly through
its α-position. Overcoming the divergent regiochemical
possibilities on both nucleophile B (α- vs γ-) as well as on
electrophile A (SN2′ vs SN2) would be crucial to the success of
this vinylogous γ-allylic alkylation reaction.
While the attack from nucleophile B is likely to favor the less
sterically encumbered γ-position, we reasoned that the
regioselectivity arising out of the addition to electrophile A to
be catalyst-controlled.17 Previous reports from Lu and co-
workers16i as well as from our group16c demonstrated that
bifunctional tertiary amino(thio)urea catalysts promote SN2
addition on A. In contrast, SN2′ addition to A is facilitated
under the influence of dimeric Cinchona alkaloids, as described
by Chen and co-workers.16j
To put our design principles into practice, we initiated our
studies with the reaction between cyanocoumarin 1a and
phenyl-substituted allylic carbonate 2a in CH2Cl2 at 25 °C
(Table 1). Although no conversion was detected in the
presence of 10 mol % of unmodified quinidine (I) (entry 2),
the related dimeric Cinchona alkaloids were indeed found to
catalyze this vinylogous allylic alkylation reaction. Thus, with
(DHQD)2PHAL (II) as the catalyst, the branched γ-allylated
product 3aa was obtained as the sole regioisomer with
promising enantioselectivity (entry 3). As anticipated (vide
supra), neither α-addition product nor any linear γ-allylation
product (4 in Scheme 2) could be detected. The use of
(QD)2PHAL (III) as the catalyst led to enhanced enantiose-
lectivity at the expense of reaction rate (entry 4). Addition of 4
Å MS improved both the reaction rate as well as the
enantioselectivity (entry 5). Raising temperature to 50 °C
8
EtOAc
95.5:4.5
96:4
9
EtOAc/H2O (1:1)
EtOAc/brine (1:1)
5 d
10
−
5 d
96.5:3.5
a
Reactions were performed using 1.0 equiv of 1a and 1.1 equiv of 2a
b
on a 0.05 mmol scale. Time required for complete consumption of
1a. Enantiomeric ratio (er) as determined by HPLC analysis using a
column with a chiral stationary phase. No conversion after 48 h. MS
= molecular sieves. Reaction performed at 50 °C.
c
d
e
f
offered noticeable enhancement of the reaction rate but with
reduced enantioselectivity (entry 6). A survey of reaction
media, at this stage, revealed EtOAc to be the best with respect
to enantioselectivity of the reaction, albeit with significantly
slow conversion (entry 8). To our surprise, even better er was
observed in a heterogeneous mixture (1:1) of EtOAc and water
(entry 9). Following the same trend, 1:1 mixture of EtOAc and
brine turned out to be the optimum reaction medium, affording
the product with 96.5:3.5 er (entry 10). Tweaking various other
reaction parameters, including the ester substituent on the
allylic carbonate, neither improved the yield nor enantiose-
lectivity.18 Similarly, the use of allylic acetate instead of allylic
carbonate in the presence of stoichiometric amount of an
external base (Na2CO3) failed to generate the desired product,
even after 5 days.
The scope and limitations of this vinylogous allylic alkylation
reaction of cyanocoumarins were then evaluated under the
optimized catalyst and reaction conditions (Table 1, entry 10).
A variety of β-aryl-substituted allylic carbonates with diverse
steric and electronic demand on the aryl ring (2a−n) were well
tolerated, and the desired products (3aa−an) were obtained as
a single regioisomer in moderate to good yields and with good
to high enantioselectivities (Table 2A). Irrespective of the
position of the substituents on the aryl ring (o-, m-, or p-), the
products were generally formed with similar range of yields and
enantioselectivities. The same level of yield and er was also
observed for 2-naphthyl-substituted allylic carbonate 2o. β-
Heteroaryl-substituted allyl carbonate could also be used as the
substrate as shown for 2-thienyl-substituted allyl carbonate 2p:
B
DOI: 10.1021/acs.orglett.7b02421
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Letter
a
Table 2. Substrate Scope of Vinylogous Allylic Alkylation
Scheme 3. Reaction on a 1.0 mmol Scale and
Functionalization of the Product
known as antifungal agent and has also been used as an
intermediate in dye industries.20,21 Base-mediated retro-
Knoevenagel reaction followed by hydrolysis resulted in the
formation of acyclic compound 6 with 63% yield. Compound 6
may be considered as the α-allylic alkylation product of 2′-
hydroxyacetophenone.
In conclusion, a catalytic enantioselective vinylogous allylic
alkylation of 4-methylcoumarins has been developed using
ester-substituted allylic carbonates as the allyl source. Catalyzed
by a dimeric Cinchona alkaloid (QD)2PHAL, this reaction led
to the γ-allylic alkylation of cyanocoumarins in exclusively
branched-selective fashion to furnish densely functionalized
products in good yields with good to high enantioselectivities.
This report represents the first organocatalytic enantioselective
vinylogous γ-allylic alkylation of coumarins. Single-step
conversion of the product to useful motifs and building blocks
has also been demonstrated.
a
Yields correspond to the isolated yield. Enantiomeric ratios (er) were
b
determined by HPLC analysis using a chiral stationary phase. Values
in the parentheses indicate er of the product after a single
recrystallization.
While the resulting product 3ap was obtained in good yield,
enantioselectivity remain rather modest.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02421.
■
S
Our protocol was found to be equally efficient for substituted
cyanocoumarins (1b−d), and the desired products (3ba−da)
were obtained in moderate yields with good to high
enantioselectivities (Table 2B). However, β-alkyl-substituted
allylic carbonates were found to be completely unreactive under
the standard reaction conditions, which marks a prominent
limitation of our protocol.18 Similarly, removal or replacement
of the cyanide group in 1 with ester or amide group led to
complete attenuation of its reactivity.18
Experimental details, characterization data, and crystallo-
graphic data (PDF)
NMR spectra and HPLC data (PDF)
Crystallographic data for 3ag (CIF)
The absolute configuration of 3ag was established by the X-
ray diffraction analysis of its single crystals obtained from
petroleum ether/EtOAc mixture and found to be R (Table
2A).19 The absolute configurations of the other allylation
products were assigned by analogy as the same.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sm@orgchem.iisc.ernet.in.
ORCID
To confirm the scalability of our protocol, the reaction was
performed on a scale 10 times higher than that used for
evaluation of substrate scope (Table 2). Thus, a reaction
between 1a and 2a on a 1.0 mmol scale under otherwise
standard reaction conditions furnished the desired product 3aa
in 67% yield with the same level of enantioselectivity (96:4 er)
as obtained in the smaller scale reaction (Scheme 3).
The products of this allylic alkylation reaction are densely
functionalized and could be converted to useful building blocks.
For example, exposure of 3aa to sulfur under basic conditions20
led to the formation of a tricyclic aminothiophenocoumarin 5
with 76% yield and 95:5 er (Scheme 3). This structural motif is
Santanu Mukherjee: 0000-0001-9651-6228
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is funded by the Council of Scientific and
Industrial Research (CSIR), New Delhi [Grant No. 02(0207)/
14/EMR-II] and Science and Engineering Research Board
(SERB), New Delhi [Grant No. SB/S1/OC-63/2013]. S.K.
thanks CSIR for a doctoral fellowship. We express our sincere
thanks to Mr. Prodip Howlader (Department of Inorganic and
C
DOI: 10.1021/acs.orglett.7b02421
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