Enantioselective synthesis of coumarin derivatives catalyzed by primary amines

Article abstract of DOI:10.1002/adsc.201300450

Cinchona alkaloid-derived primary amines were used as organocatalysts for the preparation of enantioenriched coumarin derivatives. A series of optically active coumarin derivatives was obtained in good yields with excellent enantioselectivities (up to 98%

Full text of DOI:10.1002/adsc.201300450

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DOI: 10.1002/adsc.201300450
Enantioselective Synthesis of Coumarin Derivatives Catalyzed by
Primary Amines
Yen-Te Lee,a Utpal Das,a Yi-Ru Chen,a Chia-Jui Lee,a Chi-Han Chen,a
Mei-Chun Yang,a and Wenwei Lina,*
a
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan, R.O.C.
Fax : (+886)-2-2932-4249; e-mail: wenweilin@ntnu.edu.tw
Received: May 23, 2013; Revised: August 17, 2013; Published online: November 4, 2013
Abstract: Cinchona alkaloid-derived primary
amines were used as organocatalysts for the prepa-
ration of enantioenriched coumarin derivatives. A
series of optically active coumarin derivatives was
obtained in good yields with excellent enantioselec-
tivities (up to 98% ee).
antiviral activities.[2] Coumarin derivatives have also
found applications in fluorescent sensors for fluoride
anions as well as for chromogenic and fluorescent
turn-on type signaling.[2g,h] Thus, there has been a con-
tinuous effort towards the synthesis of coumarin and
its derivatives.[3] Over the last decade, organocatalysis
has emerged as one of the promising and rapidly ex-
panding fields in organic synthesis and has become
a parallel method to the conventional approaches uti-
lized in asymmetric catalysis.[4] In particular, aminoca-
talytic approaches[5] have gained much attention in
this regard. The iminium or H-bond catalyzed[6] Mi-
chael reaction of 4-hydroxycoumarin to a,b-unsaturat-
ed carbonyls has been widely investigated because the
Keywords: asymmetric catalysis; coumarin deriva-
tives; Michael addition; organocatalysis; primary
amines
Coumarin is a well-known oxygen heterocycle that obtained products are direct precursors to various
can be found as a structural motif in numerous natu- biologically active compounds such as warfarin, ace-
ral products.[1] Modification of this class of com- nocoumarol [Scheme 1, Eq. (1)].[7] However, the alter-
pounds has been of great importance due to their native approach to prepare coumarin derivatives via
broad spectrum of pharmacological properties, includ- a Michael addition of ketones (1) to 3-aroylcoumarins
ing antioxidant, anti-inflammatory, antibacterial and (2) has not been reported. This led us to evaluate the
Scheme 1. Organocatalyst-mediated preparation of coumarin derivatives.
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Enantioselective Synthesis of Coumarin Derivatives Catalyzed by Primary Amines
tioselectivity was observed by using either polar or
non-polar solvents (entries 8–11). Employment of
neat conditions was also disappointing (52% ee,
entry 12). An improvement of chemical yield was no-
ticed on lowering the reaction concentration or on in-
creasing the concentration of cyclohexanone (1a,
2 mmol), but the enantioselectivity remained moder-
ate (53% ee, entries 13 and 14). A significant im-
provement of enantioselectivity (73% ee) was ob-
tained by carrying out the reaction at 08C (entry 15).
Further lowering of the reaction temperature
(À258C) turned to be beneficial, as the enantioselec-
tivity was further improved to 95% ee (entry 16). It is
worth mentioning that both the diastereoselectivity
and enantioselectivity of 3a dropped upon lowering
Figure 1. Identification of catalysts for the organocatalytic
Michael addition.
enantioselective Michael addition of ketones to di- the catalyst loading (10 mol%) under these reaction
versely substituted 3-aroylcoumarins (2) [Scheme 1, conditions (entry 17). The presence of an acidic co-
Eq. (2)].
catalyst to ensure an effective process (primary amine
Herein we present a new approach for the synthesis is engaged in efficient enamine formation) is well
of optically active coumarin derivatives by using read- documented.[8] However, a very poor result was ob-
ily available Cinchona alkaloid-derived primary tained by using benzoic acid as co-catalyst (see the
amines.[8] The research group of Connon has demon- Supporting Information). Interestingly, use of
strated that Cinchona alkaloid-derived primary 20 mol% phenol furnished the product in improved
amines are efficient catalysts for the enamine activa- diastereoselectivity (>20:1 dr, 92% ee, see the Sup-
tion of ketones.[9] We have also recently demonstrated porting Information). We have recently observed that
enantioselective synthesis of substituted pyrans via the presence of precise quantities of water (as co-sol-
a Cinchona alkaloid-derived primary amine-catalyzed vent) were critical for such a reaction to proceed.[11]
Michael addition and subsequent enolization/cycliza- Eventually, when the reaction was carried out in an-
tion of cyclohexanone and trans-2-aroyl-3-arylacrylo- hydrous ethyl acetate, both the yield and enantiose-
nitriles.[10]
On the basis of these considerations, we envisioned yield and 90% ee, entry 16 vs. 18).
lectivity were dropped to a considerable extent (76%
that the Cinchona alkaloid-derived primary amines
Finally, we choose entry 16 (Table 1) as the opti-
(Figure 1) may catalyze a direct enantioselective Mi- mized reaction conditions and explored the scope and
chael addition of ketones to 3-aroylcoumarin deriva- limitations of the asymmetric Michael addition with
tives.
respect to different electrophiles and nucleophiles. A
We began our investigation by using cyclohexanone broad range of 3-aroylcoumarins (2a–k) having differ-
(1a) and 3-benzoyl-6-bromocoumarin (2a) as model ent substitution patterns were converted to the corre-
substrates. Initial catalyst screening confirmed our ex- sponding coumarin derivatives (3a–k) in moderate to
pectation that the secondary amines are ineffective high yields and selectivities with cyclohexanone (1a)
catalysts for this process probably because of their as the nucleophilie (Table 2). 6-Cl-substituted Michael
lower reactivity with 1a. Thus, use of 20 mol% of (S)- acceptor 2b afforded the product 3b in equal ease as
proline (I) or diphenylprolinol silyl ether (II) resulted in the case of 2a, and the corresponding coumarin de-
in only trace amounts of product (Table 1, entries 1 rivative was obtained in 86% yield and 91% enantio-
and 2). In contrast, the quinidine-derived primary meric excess along with a 19:1 diastereomeric ratio.
amine catalyst III (20 mol%) promoted the reaction In the case of electronically neutral Michael acceptor
with an improved yield (61%), and complete conver- 3-benzoylcoumarin (2c), the corresponding product 3c
sion of 2a was observed in ethyl acetate at room tem- was furnished with very good chemical yield (93%)
perature within 24 h (entry 3). However, the product and diastereomeric ratio (18:1) albeit with slightly
3a was obtained with moderate enantioselectivity lower enantioselectivity (84% ee). The presence of an
(63% ee) and a 4:1 diastereomeric ratio. Encouraged electron-donating group was also tolerated in the
by this result, we decided to further optimize the re- present reaction conditions. 3-Benzoylcoumarin deriv-
action conditions. Primary amine catalysts IV–VII atives (2d–f) bearing 6-, 7- and 8-methoxy substituents
were also investigated. Although all the catalysts (IV– delivered the corresponding products 3d–f in moder-
VII) promoted the reaction, the enantioselectivity re- ate to good yields (30–87%) and good to excellent
mained low to moderate (entries 4–7). A screen of enantioselectivity (67–96% ee). 6,8-Dichloro-substitut-
solvents indicated that several solvents were suitable ed Michael acceptor (2g) was also examined in our
for this reaction. However, no improvement of enan- protocol. Gratifyingly, the coumarin adduct (3g) was
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Table 1. Screening of catalysts and condition for the organocatalytic Michael addition of 1a and 2a.[a]
Entry
Catalyst
Solvent
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
I
II
III
IV
V
ethyl acetate
ethyl acetate
ethyl acetate
ethyl acetate
ethyl acetate
ethyl acetate
ethyl acetate
THF
CH2Cl2
toluene
MeOH
neat
ethyl acetate
ethyl acetate
ethyl acetate
ethyl acetate
ethyl acetate
ethyl acetate
trace
trace
61
80
76
22
76
48
39
58
69
68
88
84
91
95
51
–
–
–
–
4:1
3:1
2.5:1
4.5:1
3:1
2:1
3:1
3:1
4:1
2:1
4:1
2:1
4:1
10:1
4:1
17:1
63
20
47
nd
43
60
58
59
16
52
53
53
73
95
88
90
4
5[e]
6
VI
VII
III
III
III
III
III
III
III
III
III
III
III
7
8
9
10
11
12
13[f]
14[g]
15[h]
16[i]
17[i,j]
18[i,k]
76
[a]
Unless noted, all reactions were carried out with 1a (1 mmol), 2a (0.2 mmol) and catalyst (20 mol%) in the indicated sol-
vent (0.2 mL, laboratory grade solvent) for 24 h.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR analysis of the crude reaction mixture using Ph3CH as an internal standard.
1
Determined by H NMR analysis of the crude reaction mixture.
Determined by HPLC analysis.
ent-3a was obtained.
0.4 mL ethyl acetate was used.
2 mmol of 1a were used.
The reaction was carried out at 08C, t=1.5 days.
The reaction was carried out at À258C, t=1.5 days.
10 mol% of III was used.
[g]
[h]
[i]
[j]
[k]
Anhydrous ethyl acetate was used. nd=not determined.
afforded in excellent yield (98%) and enantioselectiv-
Having demonstrated the suitability of this process
ity (95% ee) coupled with a very good diastereomeric for the Michael addition of cyclohexanone (1a) to dif-
ratio (12:1). The presence of a substituent at the 3- ferent Michael acceptors (2a–k), we then turned our
benzoyl group of the Michael acceptor was also com- attention toward various cyclic and acyclic ketones
patible to our reaction condition. 4-Chlorophenyl- or (1b–e) with 2a or 2b as the electrophilic part in our
naphthyl-substituted compounds (2h–k) provided the optimized reaction conditions to provide the corre-
corresponding products 3h–k in moderate to excellent sponding coumarin derivatives 3l–o (Table 3). Moder-
yields (36–95%) and enantioselectivities (72–98% ee). ate diastereoselectivity (4:1) but good enantioselectiv-
The moderate yield in the case of adduct 3h was ity (77% ee) and good yield (85%) were obtained
partly because of the low solubility of the correspond- when cyclopentanone (1b) was used as nucleophile
ing starting material (2h). A re-examination of sol- with 2a (entry 1). Acetone (1c) was also a suitable
vents revealed that the yield and diastereomeric ratio substrate in our protocol. The adduct 3m was ob-
(58%, dr >20:1) can be improved by employing tetra- tained in excellent yield (93%) and high diastereose-
hydrofuran as solvent albeit with somewhat dimin- lectivity (>20:1) but with a poor enantioselectivity
ished enantioselectivity (87%, see the Supporting In- (14% ee, entry 2). The scope of using acyclic aliphatic
formation). As a limitation to the present method, the ketones was further extended by employing 2-hexan-
product containing a 3-acetyl substituent was ob-
ACHTUNGTRENNUNG
tained in poor chemical yield (<10%).
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Enantioselective Synthesis of Coumarin Derivatives Catalyzed by Primary Amines
Table 2. Substrate scope for the organocatalytic Michael addition of cyclohexanone (1a) and
3-aroylcoumarins 2.[a–d]
[a]
Unless noted, all reactions were carried out with 1 (1.5 mmol), 2 (0.3 mmol) and catalyst
(20 mol%) in ethyl acetate (0.3 mL) for 1.5–10 days.
[b]
Isolated yield.
[c]
[d]
[e]
1
Diastereomeric ratio was determined by H NMR analysis of the crude reaction mixture.
Enantiomeric excess was determined by HPLC analysis (major isomer).
Value in parenthesis indicates the ee value after a single recrystallization.
and 68% ee) but only in 10% chemical yield (entry 3). those of the other products were assigned by analo-
Tetrahydropyran-4-one (1e) turned out to be a very gy.[12] We believe that the reaction proceeds via enam-
good substrate for the present conditions and the ine formation between cyclohexanone and primary
adduct 3o was obtained with an excellent diastereose- amine (III), which performs a Michael addition with
lective ratio (>20:1) and enantioselectivity (94% ee) 2a–k, leading to the product 3a–o. In addition, it is
albeit with moderate yield (41%, entry 4).
necessary to use an excess amount of cyclohexanone
The absolute configurations of 3a, 3g and 3l were (1a, up to 5 equiv.) to have full conversion of 2a into
determined by single crystal X-ray data analyses and 3a because the reverse reaction of 3a does indeed
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Table 3. Substrate scope for the organocatalytic Michael ad-
dition of ketones 1 and 3-aroylcoumarins 2.[a]
Scheme 3. Organocatalytic one-pot approach to 3a.
for the Knoevenagel condensation of the representa-
tive 5-bromosalicylaldehyde and ethyl benzoylacetate
were found to be compatible with the enantioselective
route developed herein (see the Supporting Informa-
tion). The coumarin derivative 3a was obtained in
good yield and notably the level of enantioselectivity
mentioned in Table 2 was maintained.
To illustrate the synthetic potential of the catalytic
protocol, a gram-scale synthesis of coumarin deriva-
tive 3a was performed. Accordingly, by treatment of
3.0 mmol of 2a using the optimized conditions, the
corresponding product 3a was obtained in 94% yield
(1.20 g) with 96% ee. (Scheme 4).
Entry
1
2
3, Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
1b
1c
1d
1e
2a
2a
2a
2b
3l, 85
4:1
77
14
68
94
3m, 93
3n, 10
3o, 41
>20:1
>20:1
>20:1
[a]
Unless noted, all reactions were carried out with
1 (1.5 mmol), 2 (0.3 mmol) and catalyst (20 mol%) in
ethyl acetate (0.3 mL) for 10 days.
[b]
[c]
Isolated yield.
1
Determined by H NMR analysis of the crude reaction
mixture.
[d]
Determined by HPLC analysis (major isomer).
Next we turned our attention towards inclusion of
take place to provide 2a and 1a in the presence of cat- aliphatic aldehydes to further extend the substrate
alyst III.[13]
scope. In our preliminary study, the reaction of
Because the biological activities of the enantiomers propanal (4a) and 2a in the presence of catalyst II
AHCTUNGTRENNUNG
are quite different in some cases, development of effi- and benzoic acid in tetrahydrofuran followed by PCC
cient methods for the preparation of these enantio- oxidation provided a rearranged product mixture of
meric coumarin units is strongly desired. Indeed, ent- 5a and 5a’ in 53% isolated yield (2.2:1 dr; 5a: 4% ee;
3a can be prepared by using the same optimized reac- 5a’: 43% ee) (Scheme 5).[14]
tion conditions employing quinine-derived primary
amine catalyst V. The product was obtained with high an unprecedented chiral amine-catalyzed Michael ad-
enantioselectivity (88% ee; Scheme 2). dition reaction of cyclic and acyclic ketones with sub-
In conclusion, we have successfully demonstrated
Furthermore, the enantioselective one-pot ap- stituted coumarin derivatives. A series of substituted
proach to the synthesis of coumarin derivative 3a was coumarin compounds was obtained in 98% isolated
investigated (Scheme 3). Typical reaction conditions
Scheme 2. Organocatalytic approach to ent-3a.
Scheme 4. Gram-scale synthesis of 3a.
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Enantioselective Synthesis of Coumarin Derivatives Catalyzed by Primary Amines
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yield with up to 98% ee and >20:1 diastereomeric
ratio. Cyclic ketones showed excellent tolerance in
the process, which explored a new strategy for the
synthesis of optically active coumarin derivatives. Fur-
ther investigations on asymmetric organocatalytic re-
actions of 3-aroylcoumarins with other interesting nu-
cleophiles are currently ongoing in our laboratory.
[4] For general reviews on asymmetric organocatalysis,
see: a) Enantioselective Organocatalysis, (Ed.: P. I.
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Experimental Section
General Procedure
In a capped glass vial equipped with a magnetic stirring bar
was added 3-benzoyl-6-bromocoumarin (2a, 98.8 mg,
0.3 mmol) and catalyst III (20.3 mg, 20 mol%). Ethyl acetate
(0.3 mL) was added and the vial was cooled to À258C. Cy-
clohexanone (1a, 147.8 mg, 1.5 mmol) was added and the re-
action mixture was stirred for 1.5 days under the same con-
ditions. The reaction was monitored by using TLC and or
1H NMR data analysis. The reaction mixture was diluted
with ethyl acetate and then washed with 2N HCl. The or-
ganic layer was concentrated on a rotary evaporater and the
residue thus obtained was purified by flash column chroma-
tography on silica gel (hexanes:ethyl acetate=6:1) to afford
the adduct 3a; yield: 121.8 mg (95%).
Acknowledgements
We are grateful to the NSC of the Republic of China (NSC
101-2113M-003-001-MY3) and National Taiwan Normal Uni-
versity (NTNU100-D-06) for financial support.
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