Direct enantioselective allylic substitution of 4-hydroxycoumarin derivatives with branched allylic alcohols: Via iridium catalysis

Article abstract of DOI:10.1039/d0cc02832k

A highly efficient direct asymmetric allylic substitution (AAS) reaction of 4-hydroxycoumarin derivatives with branched allylic alcohols was realized by combining a chiral iridium complex catalyst with a Lewis acid under mild reaction conditions, delivering various chiral allylation products in remarkably high yields and excellent enantioselectivities. The salient features of this transformation include mild reaction conditions, general substrate scope, good functional group tolerance, high yields, excellent selectivities and easy scale-up. Furthermore, the obtained products can be readily transformed into several kinds of bioactive compounds.

Full text of DOI:10.1039/d0cc02832k

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DOI: 10.1039/D0CC02832K
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Direct Enantioselective Allylic Substitution of 4-Hydroxycoumarin
Derivatives with Branched Allylic Alcohols via Iridium Catalysis
Ruigang Xu,a Kai Li,a Jiaqi Wang,a Jiamin Lu,a Lina Pan,a Xiaofei Zenga* and Guofu Zhonga*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A highly efficient direct asymmetric allylic substitution (AAS) in the catalytic asymmetric allylic substitution (AAS) reactions
reaction of 4-hydroxycoumarin derivatives with branched with the direct use of allylic alcohol derivatives remains an
allylic alcohols was realized by combining a chiral iridium unexplored challenge.
O
complex catalyst with Lewis acid under mild reaction
conditions, delivering various chiral allylation products in
OH
OH
OH
remarkably high yields and excellent enantioselectivities. The
salient features of this transformation include mild reaction
conditions, general substrate scope, good functional-group
tolerance, high yields, excellent selectivities and easy scale-up.
Furthermore, the obtained products can be readily
transformed into several kinds of bioactive compounds.
O
O
O
O
R
O
O
4-Hydroxycoumarin
I. Phenprocoumon
II. R = H, Warfarin
III. R = NO2, Acenocouma
IV. R = Cl, Coumachlor
OH
OH
X
O
O
Coumarin derivatives are important chemicals in the perfume,
cosmetic, agricultural and pharmaceutical industries, and have
been well recognized as the key structural scaffolds in many
bioactive compounds.1 They have always fascinated synthetic and
O
O
CF3
V. Coumatetralyl
VI. X = O, Flocoumafen
VII. X = S, Difethialone
Figure 1. Drugs and Bioactive Molecules Containing (Thio)Coumarin
medicinal
chemists
because
of
their
comprehensive
(a) Michael addition of 4-hydroxycoumarin to electron-deficient C=C double
pharmacological profiles such as analgesic,2 anti-arthritis,3 anti-
inflammatory,4 anti-platelet,5 anti-bacterial,6 anti-viral,7 and anti-
cancer8 properties. (Figure 1) For example, Phenprocoumon, a
coumarin derived long-acting oral anticoagulant drug, is a well-
known vitamin K antagonist that inhibits coagulation by blocking
synthesis of coagulation factors II, VII, IX and X.9 Warfarin and
acenocoumarol, medications that are used as anticoagulants, are
commonly used to treat blood clots such as deep vein thrombosis
and pulmonary embolism and to prevent stroke in people who have
atrial fibrillation, valvular heart disease or artificial heart valves.10
Therefore, much attention has been paid towards the syntheses and
structural modifications of coumarins and their analogues.
EWG
R
bonds
OH
OH
catalyst
EWG
+
R
conditions
O
O
O
O
EWG = aldehyde, ketone, NO2, ketoester
(b) This work:
OH
OH
OH
[Ir]/L
Ar
+
Lewis acid
-H2O
Ar
X
O
X
O
X = O, S, NCH3
wide substrate scope
remarkably high chemo- and regio- selectivities
excellent yields and enantioselectivities
In spite of a wide range of literature reports towards the
synthesis of coumarin derivatives,11 it is still highly desirable to
explore enantioselective approaches to the synthesis of optically
pure coumarin derivatives. The use of 4-hydroxycoumarin as the
starting material has been demonstrated as an important strategy
ascribed to its bifunctional character. The organocatalytic or
transition-metal catalyzed direct asymmetric Michael addition of
4-hydroxycoumarin to electron-deficient C=C double bonds has
proved to be one of the most convenient approaches to furnish
coumarin derived chiral compounds (Scheme 1, a).12 However, to
the best of our knowledge, the utilization of 4-hydroxycoumarin
application to synthesis of chiral drugs and bioactive compounds
OH
O
OH
O
OH
O
OH
O
Ph
Ph
Ar
Ph
O
O
O
O
O
coumarin containing bioactive compounds
Scheme 1. 4-Hydroxycoumarins in asymmetric reactions
Iridium-catalyzed enantioselective allylic substitution has been
established as a powerful synthesis strategy for the formation of
carbon-carbon and carbon-heteroatom bonds, with both excellent
regio- and stereoselectivities. Largely due to the pioneering work
of Takeuchi,13 Helmchen,14 Hartwig,15 Carreira,16 Krische,17
You,18 Zhang19 and other research groups,20 a wide variety of
nucleophiles have been successfully employed in iridium-
a. College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 311121, China
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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catalyzed AAS reactions. We thus envisioned that the use of 4- yield with >99% ee when the reaction was carried out in THF at
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hydroxycoumarin as the nucleophile in iridium-catalyzed AAS room temperature for 18 hours in the pDreOsIe: n10c.e10o39f/D20CmCo0l2%832oKf
reaction would provide a highly efficient method to enantiomeric [Ir(COD)Cl]2, 8 mol% of (R)-L1 and 10 mol% of Yb(OTf)3 as acid
enriched coumarin containing allylation products, which could act promoter (entry 1).
OH
as the key synthetic intermediate for further conversion to several
kinds of bioactive privileged scaffolds. The major challenges in
achieving this goal are threefold. First, a mode of activation must
be identified that could avoid the O-allylation reaction. Second, an
optimal reaction condition must be found to control the
branched/linear (b:l) selectivity of the allylation reaction. Third, a
powerful asymmetric catalytic system must be established to
ensure the substitution in a highly stereoselective manner. Thus, it
is a formidable task to develop a highly efficient direct catalytic
AAS reaction of 4-hydroxycoumarins.
OH
[Ir(COD)Cl]2
L1
Yb(OTf)3
OH
(R)-
+
R
R
O
1a
O
THF, r.t., 18 h
O
3
O
2a
(±)-
OH
OCH3
OH
OH
OCH3
O
O
O
O
O
3c
O
OCH3
3b
3d
: 98% yield
: 91% yield
>25:1 b:l
>99% ee
: 94% yield
>25:1 b:l
99% ee
>25:1 b:l
>99% ee
OCH3
In line with our recent research21 on the selectivity controllable
allylic substitution reactions with allylic alcohols,22 we considered
whether the catalytic strategy pioneered by Carreira and co-
workers would be suitable for this catalytic asymmetric allylic
transformation, which involves iridium/chiral ligand as the
catalyst together with an acid as the promotor in the reaction.23
Herein, we report a cooperative iridium/Lewis acid catalyzed AAS
reaction of 4-hydroxycoumarin with racemic branched allylic
alcohols in good yields and excellent enantioselectivities (Scheme
1, b). In addition, the corresponding allylation products could be
easily transformed to useful pharmaceutical molecules.
OH
OH
F
OH
O
O
O
O
CO2CH3
O
O
OCH3
3e
3f
3g
: 88% yield
>25:1 b:l
97% ee
: 89% yield
>25:1 b:l
>99% ee
: 76% yield
>25:1 b:l
94% ee
Br
Cl
OH
OH
OH
O
O
O
O
O
O
F
[b]
[b]
3h
3i
3j
: 87% yield
: 69% yield
>25:1 b:l
>99% ee
: 71% yield
>25:1 b:l
>99% ee
>25:1 b:l
>99% ee
OH
OH
OH
Table 1. Reaction conditions optimizationa
OH
OH
OH
[Ir(COD)Cl]2
L1
O
O
CH3
O
O
O
O
Et
i-Bu
OH
(R)-
Ph
Ph
+
+
3k: 87% yield
>25:1 b:l
>99% ee
3l: 89% yield
>25:1 b:l
>99% ee
3m: 98% yield
>25:1 b:l
>99% ee
Ph
Yb(OTf)3
THF, r.t., 18 h
O
1a
O
O
3a
O
O
4
O
(
)-2a

OH
OH
OH
O
P N
O
O
P N
O
O
P
O
N
S
O
3n
O
O
3o
O
O
O
Ph
3p
: 98% yield
>25:1 b:l
99% ee
: 93% yield
>25:1 b:l
99% ee
: 89% yield
8:1 b:l
L1
L1
L2[b]
(R)-
(R)-
(S)-
97% ee
Scheme 2. Substrate scope of allylic alcohols.a
Yield(%) 3a/4c ee[%]
Entr
1
2
3
4
5
6
7
8
Change in condition
none
93
n.r.
n.r.
<5
92
78
53
n.r.
66
26
74
>25/
-
-
>99
-
-
The reaction could not proceed in the absence of any of iridium
catalyst, chiral ligand or acid promoter (entries 2, 3 and 8). The
use of other chiral ligands (R)-L2 instead of (R)-L1 could not
promote the reaction at all (entry 4). It is noteworthy that the
alkylated product with inversed absolute configuration could be
afforded in almost the same yield and ee value when (S)-L1 was
employed (entry 5). Other acid promoters, such as (PhO)2PO2H
and Sc(OTf)3 were also investigated (entries 6 and 7), the
stereoselectivities were maintained in excellent levels, however,
the yields were decreased. A massive number of documents
evidenced that the reaction solvents could significantly impact the
stereoselectivity and yield of many reactions. Hence, different
reaction solvents, such as DCM and dioxane (entries 9 and 10),
were screened and all resulted in lower ee values and yields. In
addition, water, a general and green solvent, was also tested in the
reaction, and the desired 3a was still isolated in high yield (entry
11), which demonstrated the potential of aqueous mediated AAS
reaction. Additionally, slightly lowering the load of Yb(OTf)3 or
allylic alcohol resulted in reduction of the yield (entry 12).
without [Ir(COD)Cl]2 catalyst
without Ligand
(R)-L2 instead of (R)-L1
(S)-L1 instead of (R)-L1
DPP instead of Yb(OTf)3
Sc(OTf)3 instead of Yb(OTf)3
no acid promoter was added
DCM instead of THF
dioxane instead of THF
water instead of THF
5 mol% of Yb(OTf)3 was used
n.d.
>25/
>25/
>25/
-
>25/
>25/
>25/
>25/
n.d.
<-99
>99
98
-
96
97
84
>99
9
10
11
12
83
a
General conditions: 1a (0.2 mmol), (±)-2a (0.4 mmol),
[Ir(COD)Cl]2 (2 mol%), chiral ligand (8 mol%), and acid promoter
b
(10 mol%) in 1.3 mL solvent under the argon protection, 18 h.
Yields of isolated product. c Measured by H NMR of the crude
1
d
reaction mixture. Determined by chiral HPLC using chiralpak
AD-H column. fReaction time: 36 h. DPP = diphenyl phosphate.
With the optimized reaction conditions in hand, the scope of the
reaction was explored with a range of allylic alcohols. The results
are summarized in Scheme 2. From Scheme 2, it could be seen that
allylic alcohols bearing either electron-donating or withdrawing
groups at the ortho-, meta-, or para-position of the phenyl group
participated in this reaction to give the desired products (3b−3n)
in remarkably high yields with excellent stereoselectivities
(94−>99% ee’s). Notice that the reaction was slightly affected by
To verify our hypothesis, we initiated our studies by using
commercially available 4-hydroxycoumarin (1a) and racemic
branched allylic alcohol (±)-2a as model substrates. We were
engaged in examining an array of reaction parameters and
exploring a range of iridium/phosphoramidite complex as extrinsic
chiral catalysts to provide a possible mode of stereocontrol (Table
1). It was found that the desired product 3a was obtained in 93%
2 | J. Name., 2012, 00, 1-3
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the electronic effects of substituents in the aromatic ring of allylic converted to different functionalities, which greatly VfaiecwilAirttiactleeOdntlhinee
alcohols. The substrates bearing stronger electron-donating groups construction of coumarin derived opticallyDaOcIt:i1v0e.1s0m39a/lDl0mCoCl0e2c8u3l2aKr
(OCH3 group, 3b, 3c, 3d and 3e) in the aromatic ring provided the libraries. For example, the 4-hydroxy group was firstly treated
expected products in higher yields than those bearing with TsCl, and then functionalized by thiophenol to give
electroneutral or electron-deficient groups. The absolute enantiomeric enriched compound 10.
stereochemistry of 3a was determined to be R by comparison of
its optical rotation with the known compound reported in the
literature (see the Supporting Information).26 Furthermore, the
reactions of naphthyl and heteroaryl substituted allyl alcohols
were successfully carried out to give their respective products in
good yields with excellent enantioselectivities (3o-3p), which
opened up the possibility of diverse synthesis of coumarin-based
3a
a) Gram scale synthesis of
OH
OH
[Ir(COD)Cl]2 (2 mol%)
L1
OH
(R)-
(8 mol%)
Ph
+
Ph
Yb(OTf)3 (10 mol%)
THF (0.15 M), r.t., 24 h
O
O
O
3a
O
(
)-2a

(1.66 g, 12.4 mmol)
1a
(1.63 g, 94% yield)
>25:1 b:l
(1.00 g, 6.2 mmol)
drugs for the future.
3a
b) Transformationso of
>99% ee
OH
OH
[Ir(COD)Cl]2
L1
OH
OH
(R)-
OH
OH
O
+
Ph
R
R
Yb(OTf)3
THF, r.t., 24 h
Ph
Ph
(±) -2a
X
O
Ph
Ph
X
O
X = O, S, NCH3
i
ii
O
O
O
O
3
1
O
7:
96% yield
>99% ee
8:
99% yield
3a
: >99% ee
OH
OH
OH
O
>99% ee
(R)-Phenprocoumon
Cl
iii
HIV protease inhibitor
SPh
O
O
H3CO
OTs
O
O
O
3q: 98% yield
>25:1 b:l
>99% ee
3r: 96% yield
>25:1 b:l
97% ee
3a: 93% yield
>25:1 b:l
>99% ee
Ph
Ph
iv
O
O
O
O
OH
OH
OH
10:
87% yield
9:
95% yield
98% ee
CH3
Br
F
>99% ee
Scheme 4. Gram scale synthesis and transformation of 3a. (i)
TsNHNH2, NaOAc, EtOH, reflux, 6 h; (ii) CH2I2, Et2Zn, TFA, 0 °C to
rt., 4-6 h; (iii) TsCl, Et3N, DCM, 0 °C to rt., 4-6 h; (iv) PhSH, Et3N,
DCM, rt., 6-8 h.
O
O
O
O
O
O
3t: 63% yield
>25:1 b:l
93% ee
3u: 57% yield
>25:1 b:l
>99% ee
3s: 62% yield
>25:1 b:l
98% ee
OH
OH
In summary, we have disclosed a highly efficient direct iridium-
catalyzed AAS reaction between 4-hydroxycoumarins/
thiocoumarins/quinolones and allylic alcohols for the first time, to
the best of our knowledge. A variety of allylic alcohols as well as
substituted coumarin derivatives were utilized to access
biologically interesting coumarin-based chiral allylated
compounds with remarkably high yields (up to 98%) and excellent
regio- and enantioselectivities (>25:1 b:l, >99% ee for most cases)
under mild reaction conditions. Notably, the biologically
important quinoline-2,4-dione derivatives and thiocoumarin were
both suitable substrates in the reaction. Furthermore, the reaction
could be enlarged to gram-scale and this crafted synthetic
approach greatly facilitates the synthesis of different chiral
pharmaceuticals and precursors in comparison to the traditional
method.
N
CH3
5: 88% yield
8:1 b:l
98% ee
O
S
O
6: 87% yield
>25:1 b:l
98% ee
Scheme 3. Substrate scope of 4-hydroxycoumarinsa
Encouraged by the excellent results achieved with different
allylic alcohols, the scope of a series of 4-hydroxycoumarin
derivatives was next investigated. As can be seen from Scheme 3,
variation of the coumarin derivatives was suitable for the reaction
and corresponding compounds 3q-3u were afforded in good to
excellent yields with excellent regio- and stereoselectivities.
During the past several decades, quinoline-2,4-diones and
thiocoumarins played important role in natural and synthetic
chemistry due to their biological and pharmacological activities.27
We gratefully acknowledge the Natural Science Foundation of
China (No. 21672048), the Natural Science Foundation of
Zhejiang Province (LY18B020015), and Hangzhou Normal
University for financial support. X. Z. acknowledges a Xihu
Scholar award from Hangzhou City, and G. Z. acknowledges a
Qianjiang Scholar from Zhejiang Province in China.
Subsequently,
4-hydroxy-1-methyl-2(1H)-quinolone
and
thiocoumarin were employed as substrates in this reaction. We are
very pleased to find that both types of compounds were suitable
for the reaction, providing the allylation products 5 and 6 in
excellent results.
To verify the practicality and synthetic potential of the newly
developed synthetic methodology, a scale-up synthesis of product
3a was conducted. Under the standard conditions, the reaction of
1a with 2a on a 6.2 mmol scale delivered 1.63 g of 3a (94% yield)
without any erosion of ee value, which demonstrated the efficacy
of this protocol (Scheme 4, a). Moreover, the long-acting oral
anticoagulant drug, (R)-Phenprocoumon (7),24 could be easily
afforded by reduction of (R)-3a under TsNHNH2, excellent yield
and enantioselectivity were obtained (Scheme 4, b). Furthermore,
the HIV protease inhibitor 825 could also be synthesized efficiently
from the cyclopropanation of the terminal alkene of 3a with CH2I2
(Simmons-Smith Reaction), delivering the corresponding
cyclopropanation product in excellent results without any loss of
ee value. In addition, the 4-hydroxyl group of 3a could be easily
Conflicts of interest
There are no conflicts to declare.
Notes and references
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Grover and S. M. Jachak, RSC Adv. 2015, 5, 38892. (d) H. Wei,
J.-L. Ruan and X.-J. Zhang, RSC Adv. 2016, 6, 10846.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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