Enantioselective Synthesis of 4-Substituted Dihydrocoumarins through a Zinc Bis(hydroxyamide)-Catalyzed Conjugate Addition of Terminal Alkynes

Article abstract of DOI:10.1002/adsc.201201120

A new enantioselective catalyst for the conjugate addition of terminal alkynes has been developed. Terminal alkynes react with 3- alkoxycarbonylcoumarins in the presence of diethylzinc and bis(hydroxyamide) ligands to give chiral non-racemic dihydrocoumarins substituted with an alkynyl group on the C-4 position with good yields and enantiomeric excesses up to 95%. Copyright

Full text of DOI:10.1002/adsc.201201120

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DOI: 10.1002/adsc.201201120
Enantioselective Synthesis of 4-Substituted Dihydrocoumarins
through a Zinc Bis(hydroxyamide)-Catalyzed Conjugate Addition
of Terminal Alkynes
Gonzalo Blay ,a,* M. Carmen MuÇoz,b Josꢀ R. Pedro,a,* and Amparo Sanz-Marcoa
a
Departament de Quꢁmica Orgꢂnica, Facultat de Quꢁmica, Universitat de Valꢃncia, C/Dr. Moliner 50, E-46100 Burjassot
(Valꢃncia), Spain
Fax : (+34)-96-354-4328; phone: (+34)-96-354-4329; e-mail: gonzalo.blay@uv.es or jose.r.pedro@uv.es
Departament de Fꢁsica Aplicada, Universitat Politꢃcnica de Valꢃncia, Camꢁ de Vera s/n, E-46022 Valꢃncia, Spain
b
Received: December 22, 2012; Revised: February 6, 2013; Published online: April 8, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201120.
Abstract: A new enantioselective catalyst for the
conjugate addition of terminal alkynes has been de-
veloped. Terminal alkynes react with 3-alkoxycar-
bonylcoumarins in the presence of diethylzinc and
bis(hydroxyamide) ligands to give chiral non-race-
mic dihydrocoumarins substituted with an alkynyl
group on the C-4 position with good yields and
enantiomeric excesses up to 95%.
plexes has been reported by Hayashi[12] and Car-
reira.[13] The Cu-catalyzed conjugate addition of di-
AHCTUNGTREGaNNUN lkylzinc reagents to 3-acyl- and 3-nitrocoumarins
using phosphoramidite ligands has been described by
Woodward[14] and Feringa,[15] respectively. This latter
author has reported recently the asymmetric addition
of Grignard reagents catalyzed by copper.[16] Finally,
Feng has developed a catalytic asymmetric conjugate
allylation of 3-acylcoumarins with tetraallyltin via
Keywords: alkynylation; asymmetric catalysis; N,O
ligands; nucleophilic addition; oxygen heterocycles
a dual activation strategy using N,N-dioxide-YbACHTUNGTRENNUNG(OTf)3
and (CuOTf)2·C7H8.[17] However, an asymmetric con-
jugate alkynylation of coumarins has never been
achieved, to the best of our knowledge.
The asymmetric conjugate alkynylation of unsatu-
rated ketones has been carried out by using BINOL-
The 3,4-dihydrocoumarin ring system constitutes the derived chiral alkynylboronates[18] or alkynylalanes in
core of many natural products[1] and biologically the presence of a nickel catalyst.[19] Hayashi and Nish-
active compounds. Over the past decades, numerous imura have described the conjugate alkynylation of
dihydrocoumarin derivatives and related compounds enones with silylacetylenes catalyzed by either rhodi-
have been discovered or obtained synthetically, which um[20] or cobalt complexes.[21] Recently, our group has
exhibited estrogen-like,[2] protein transacetylase,[3] re- also developed an asymmetric conjugate alkynylation
ductase inhibitory,[4] protein kinase,[5] antiherpetic,[6] of enones mediated by Et2Zn and VANOL.[22] On the
cytotoxic,[7] antioxidant and antiproliferative,[8] or other hand the conjugate alkynylation of unsaturated
blocking of ATP-sensitive potassium channels activi- esters has been only possible with double-activated
ties,[9] among others. Natural dihydrocoumarins are substrates such as 5-alkylidene-Meldrum acid deriva-
also of great interest as flavouring agents in the food tives. Thus, Carreira[23] and Fillion[24] have reported
industry.[10] Furthermore, dihydrocoumarins have separately the conjugate addition of terminal alkynes
been used as building blocks for the synthesis of other to these substrates catalyzed by copper or rhodium,
bioactive compounds.[11] For these reasons, the devel- respectively, whilst Cui and Walker have used alkyn-
opment of new synthetic procedures for the construc- yl-Grignard reagents in the presence of a chiral
tion or modification of this scaffold has attracted con- amino alcohol for this purpose.[25] Herein, we describe
siderable attention among chemists. The conjugate the asymmetric alkynylation of 3-alkoxycarbonylcou-
addition of carbon nucleophiles to coumarins is one marins using a new Zn-bis(hydroxyamide) catalyst. To
of most straightforward methods for the synthesis of the best of our knowledge, this is the first reported
3,4-dihydrocoumarins bearing a substituted stereogen- example of the alkynylation of coumarins, but also
ic center at the 4-position of the heterocycle.
the first example of a zinc-mediated alkynylation of
The enantioselective conjugate addition of arylbor- unsaturated esters that requires substoichiometric
onic acids to coumarins employing chiral Rh com- amounts of chiral inducer.
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Table 1. Conjugate addition of phenylacetylene (5a) to 3-
ethoxycarbonylcoumarin (1a) according to Scheme 1.
Screening of ligands.[a]
At the onset of our investigation we studied the re-
action between 3-ethoxycarbonylcoumarin (1a) and
phenylacetylene (5a) to give compound 6aa
(Scheme 1) under identical conditions to those used
previously by us for the conjugate alknylation of
enones (Et2Zn-binaphthol ligands).[22] However, with
this system the alkynylation product 6aa was obtained
in racemic form with low yield, together with the 4-
ethyl derivative. Then, we screened the use of bis(hy-
droxyamide) ligands L1 and L2 that we had success-
fully used in the past for the enantioselective diethyl-
zinc addition to aldehydes (Table 1, entries 1 and
2).[26] Although L1 led to the expected product in rac-
emic form, the encouraging result obtained with
ligand L2 prompted us to synthesize and test other
C2-symmetrical bis-hydroxyamides L3–L12.
Entry
L
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
4
2
2
5
2
4
1
2
1
1
1
1
34
73
78
63
66
55
76
79
86
61
80
72
0
50
67
10
40
0
47
34
37
20
68
55
9
L9
10
11
12
L10
L11
L12
In general, bis(hydroxyamide) L3 derived from 2-
amino-1,1,2-triphenylethanol and isophthalic acid
[a]
1a (0.125 mmol), 5a (0.9 mmol), L (0.025 mmol), Et2Zn
(0.25 mmol), N-Me-piperidine (0.05 mmol).
Isolated yield of 6aa.
[b]
[c]
Determined by HPLC.
gave better results than amides derived from the
same amino alcohol and other acid scaffolds (en-
tries 1–5). The presence of diarylmethanol units in the
ligand was essential to obtain enantioselectivity
(entry 6 vs. entries 5, 7–12), the best result being ob-
tained when R’=Ph (entry 3 vs. entries 7, 8). Finally,
the highest yield and enantioselectivity were obtained
with ligands L3 and L11 (entries 3 and 11).
Next we continued the optimization process with
L11 and studied the effect of the 3-alkoxycarbonyl
group (Table 2). With the bulkier 3-tert-butoxycarbon-
Table 2. Conjugate addition of phenylacetylene (5a) to 3-
alkoxycarbonylcoumarins (1a–4a) according to Scheme 1.[a]
Entry
R
Co-solvent
T
[8C]
Yield ee
[%][b] [%][c]
1
2
3
1a Et
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
0
6aa 65
68
58
65
72
68
66
64
54
72
72
65
2a Me
3a i-Pr
4a t-Bu
4a t-Bu
4a t-Bu hexane
4a t-Bu CH2Cl2
4a t-Bu toluene
4a t-Bu
7aa 80
8aa 75
9aa 82
9aa 69
9aa 87
9aa 99
9aa 83
9aa 60
9aa 60
9aa 58
4
5[d]
6
7
9
10
11[e]
12[f]
4a t-Bu
4a t-Bu
r.t.
r.t.
[a]
1a–4a (0.125 mmol), 5a (0.9 mmol), L11 (0.025 mmol),
Et2Zn (0.25 mmol), N-Me-piperidine (0.05 mmol).
Isolated yield.
Determined by HPLC.
Me2Zn was used instead of Et2Zn.
10 mol% of L11 was used.
[b]
[c]
[d]
[e]
[f]
Scheme 1. Conjugate addition of phenylacetylene to 3-alk-
oxycarbonylcoumarins and ligands used in this study.
5 mol% of L11 was used.
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Enantioselective Synthesis of 4-Substituted Dihydrocoumarins
Table 3. Conjugate addition of alkynes 5 to 4-tert-butoxycar-
bonylcoumarins 4 according to Scheme 2.[a]
yl derivative 4a we observed an increase in both yield
and enantioselectivity with respect to other alkoxy
groups, compound 9aa being obtained with 82% yield
and 72% ee (entry 4). The use of Me2Zn instead of
Et2Zn, as well as the use of other co-solvents or reac-
tion temperatures did not bring about any improve-
ment (entries 5–10). We also tested the effect of the
catalyst load. The reaction could be carried out in the
presence of only 10 mol% of ligand L11 without any
effect on the enantioselectivity (entry 11), although
compound 9aa was obtained with lower yield (60%).
A further decrease of the catalytic load to 5 mol%
(entry 12) brought about a decrease of both enantio-
selectivity and yield with respect to 20 mol% catalyst
load.
Despite the fair results attained in the test reaction
with ligand L11 (Table 2, entry 4, footnote [a]),[27] we
were encouraged to continue with the study of the
scope of the reaction under the best reaction condi-
tions. A number of substituted 3-tert-butoxycarbonyl-
coumarins 9a–j were synthesized and reacted with
phenylacetylene 5a (Scheme 2, Table 3, entries 1–10).
The presence of substituents with either electron-do-
nating or electron-withdrawing nature on the aromat-
ic ring of the coumarin favoured higher enantioselec-
tivities with respect to the unsubstituted coumarin.
The highest enantioselectivities were obtained with
coumarins substituted on the C-7 or C-8 positions (en-
tries 2, 3 vs. entries 4, 5). In particular, excellent enan-
tioselectivities (ee above 90%) were obtained with
Entry
4
R
5
R’
9
Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
H
a
a
a
a
a
a
a
a
a
a
b
b
c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9aa 82
9ba 76
9ca 70
9da 80
9ea 70
9fa 97
9ga 85
9ha 78
9ia 82
9ja 85
9ab 36
9ab 40
9fc 92
72
76
75
85
84
91
95
80
89
93
60
66
87
81
92
92
–
5-MeO
6-MeO
7-MeO
8-MeO
8-Me
8-t-Bu
6-Br
6,8-(t-Bu)2
6-Cl, 8-Me
H
H
8-Me
8-Me
6-Cl, 8-Me
6-Cl, 8-Me
H
9
10
11
12[d]
13
14
15
16
17
18
j
a
a
f
f
j
j
a
f
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
3-FC6H4
4-MeOC6H4 9fd 99
3-FC6H4
4-FC6H4
CO2Me
Me3Si
d
c
e
f
9jc 77
9je 73
–
–
NR[e]
8-Me
g
95[f]
–
[a]
4 (0.125 mmol), 5 (0.9 mmol), L11 (0.025 mmol), Et2Zn
(0.25 mmol), N-Me-piperidine (0.05 mmol).
Isolated yield.
Determined by HPLC.
Ligand L3 was used.
[b]
[c]
[d]
[e]
[f]
Compound 4a was recovered unreacted.
Product of ethyl 1,4-addition.
coumarins bearing an alkyl group (Me or t-Bu) at the of trimethylsilylacetylene (5g) with alkoxycarbonyl-
C-8 position (entries 6, 7).[28] We also tested some di- coumarin 4f was also tested. However, under the opti-
ACHTUNGTRENNUNG
Next, we tested the use of other terminal alkynes. 5g and diethylzinc from 1.5 h to 3 h prior to addition
Aliphatic alkynes such as 4-phenyl-1-butyne (5b) of the substrate 4f gave a non-reactive species and
were tolerated, although the addition product was ob- compound 4f was recovered unaltered under these
tained with lower yield and enantiomeric excess (en- conditions. Other substituted arylacetylenes reacted
tries 11, 12). Ethyl propiolate (5f) did not react with with a number of coumarins with excellent yields and
4a under the optimized conditions, the starting mate- high enantioselectivities. In particular, (3-fluorophe-
rial being recovered unaltered (entry17). The reaction nyl)ethyne (5c) and (4-fluorophenyl)ethyne (5e) re-
acted with disubstituted coumarin 4j to give the ex-
pected products 9jc and 9je with 92% ee in both cases
(entries 15 and 16).
In all the cases products 9 were obtained as a single
diastereomer that was identified as that having the
trans disposition between the tert-butoxycarbonyl and
alkynyl groups as it was shown by X-ray analysis of
compound 9ha.[29] Unfortunately, these crystals were
not suitable for a determination of the absolute ste-
reochemistry. Nevertheless, we were able to deter-
mine the absolute stereochemistry of compound 9aa
by chemical correlation with compound 11 of known
stereochemistry (Scheme 3). A sample of compound
9aa (72% ee) was hydrogenated over Pd/C to give
compound 10 with quantitative yield, which after hy-
Scheme 2. Conjugate addition of alkynes to coumarins.
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Gonzalo Blay et al.
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Scheme 5. Synthetic transformations from dihydrocoumarin
13. All the reactions took place without lost of optical
purity.
Scheme 3. Determination of the absolute stereochemistry of
compound 9aa.
TsOH in toluene to give 4-alkynylated coumarin 13.
Therefore, the alkoxycarbonyl group on C-3 can be
considered as an auxiliary that increases the reactivity
drolysis and decarboxylation gave 3-(2-phenylethyl)- of the double bond, which can be later removed from
dihydrocoumarin 11. By comparison of the optical ro- the molecule.[31]
tation sign and chiral chromatography retention times
Alkynylcoumarin 13 can be reduced upon treat-
of compound 11 obtained in this way with those de- ment with LiAlH4 to give alcohol 14 (Scheme 5),
scribed in the literature for the (R)-enantiomer of which after Mitsunobu reaction yields the chromane
compound 11,[16] we could establish that our prepared 15, which is the starting material for the synthesis of
compounds 10 and 11 should be of S configuration at other 4-(phenylethynyl)chromanes with antihyperten-
C-4 and compound 9aa should have the R configura- sive activity.[32] On the other hand, gold-catalyzed cy-
tion at this stereogenic center.[30] For the rest of com-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
tially hydrogenated with Lindlar catalyst to give the
In summary, we have developed a procedure for
alkenylated coumarin 12 having a Z-double bond in the enantioselective synthesis of 4-substituted dihy-
quantitative yield without detriment on the optical drocoumarins via the enantioselective alkynylation of
purity (Scheme 4). On the other hand, the tert-butoxy- 3-alkoxycarbonylcoumarins. The reaction is carried
carbonyl group at C-3 can be removed by selective out by a novel catalytic system that uses C2-symmetri-
hydrolysis-decarboxylation after treatment with cal bis-hydroxyamides, diethylzinc and terminal al-
kynes. The alkynylated products are obtained with
good yields and with enantiomeric excesses between
60 and 94%, depending on the substitution of both
the alkyne and the coumarin. Although most of the
study has been carried with 20 mol% catalyst loading,
this can be reduced to 10 mol% without affecting the
enantioselectivity of the reaction, although with a de-
crease of yield. The potential synthetic applicability
of the resulting products has been shown by diverse
transformations. Further studies to enlarge the scope
of the reaction as well as new synthetic applications
of the resulting products are underway.
Scheme 4. Partial hydrogenation of the triple bond and de-
carboxylation of compound 9aa. All the reactions took
place without lost of optical purity.
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Enantioselective Synthesis of 4-Substituted Dihydrocoumarins
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General Procedure for the Enantioselective
Conjugate Alkynylation of Coumarins
A 1.5M solution of Et2Zn in toluene (0.17 mL, 0.25 mmol)
was added dropwise to a solution of ligand L11 (11.3 mg,
0.025 mmol) and alkyne 5 (0.94 mmol) in dry toluene
(0.48 mL) at room temperature under nitrogen. The mixture
was stirred at 708C for 1.5 h, during this time a white precip-
itate was formed. After cooling to room temperature, a solu-
tion of coumarin 4 (0.125 mmol) and N-methylpiperidine
(6.1 mL, 0.05 mmol) in toluene (1.0 mL) was added via sy-
ringe and the solution was stirred until the reaction was
complete (1–4 h, TLC). During this time the precipitate
slowly dissolved. The reaction mixture was quenched with
20% aqueous NH4Cl (1.0 mL), extracted with CH2Cl2 (2ꢅ
15 mL), washed with brine (15 mL), dried over MgSO4 and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel eluting with hexane:EtOAc
mixtures afforded compound 9.
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Lett. 2004, 6, 3873–3876.
[14] X. Tang, A. J. Blake, W. Lewis, S. Woodward, Tetrahe-
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Financial support from the Ministerio de Economꢀa y Com-
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Union) (CTQ2009-13083) and from Generalitat Valenciana
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Gonzalo Blay et al.
COMMUNICATIONS
tivities with or without this base. However, the use of
N-methylpiperidine provided better yields.
[31] The presence of the 3-alkoxycarbonyl moiety is manda-
tory. The reaction of phenylacetylene with unsubstitut-
ed coumarin does not take place under the optimized
conditions.
[28] A similar effect has been found by Fillion in the enan-
tioselective 1,4-addition of dialkylzinc reagents to 5-(1-
arylalkylidene)-Meldrumꢇs acid derivatives, where the
location and nature of the substituent on the aryl group
determined the enantioselectivity of the reaction, see:
a) E. Fillion, A. Wilsily, J. Am. Chem. Soc. 2006, 128,
2774–2775; b) A. Wilsily, E. Fillion, Org. Lett. 2008, 10,
2801–2804; c) A. Wilsily, E. Fillion, J. Org. Chem. 2009,
74, 8583–8594.
[29] Crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposit-
ed with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 916051. These
data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif or on application to CCDC, 12
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Arslan, O. T. Komesli, I. Aydin, E. Yildirim, Cent. Eur.
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Saepua, K. Srichomthong, S. Supothina, C. Thongpan-
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Union Road, Cambridge CB2 1EZ, UK [fax.:
1223/336-033; e-mail: deposit@ccdc.cam.ac.uk].
ACHTUNGTRNE(NUNG +44)-
[30] This change in the stereochemical notation is due to
a change in the priority order of the substituents from
9aa to 12 when applying the Cahn–Ingold–Prelog rules.
1076
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ꢄ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1071 – 1076