Cyclization of ortho-hydroxycinnamates to coumarins under mild conditions: A nucleophilic organocatalysis approach

Article abstract of DOI:10.3762/bjoc.8.186

(E)-Alkyl ortho-hydroxycinnamates cyclize to coumarins at elevated temperatures of 140-250 °C. We find that the use of tri-nbutylphosphane (20 mol %) as a nucleophilic organocatalyst in MeOH solution allows cyclization to take place under much milder conditions (60-70 °C). Several coumarins were prepared, starting from ortho-hydroxyarylaldehydes, by Wittig reaction with Ph₃P=CHCO₂Me to (E)-methyl ortho-hydroxycinnamates, followed by the phosphane catalyzed cyclization.

Full text of DOI:10.3762/bjoc.8.186

Cyclization of ortho-hydroxycinnamates to
coumarins under mild conditions: A nucleophilic
organocatalysis approach
Florian Boeck, Max Blazejak, Markus R. Anneser and Lukas Hintermann*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1630–1636.
Department Chemie, Technische Universität München,
Lichtenbergstr. 4, 85748 Garching, Germany
doi:10.3762/bjoc.8.186
Received: 03 July 2012
Email:
Accepted: 20 August 2012
Published: 26 September 2012
Lukas Hintermann* - lukas.hintermann@tum.de
* Corresponding author
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Keywords:
catalysis; coumarins; heterocycles; mechanisms; organocatalysis;
phosphanes
© 2012 Boeck et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
(E)-Alkyl ortho-hydroxycinnamates cyclize to coumarins at elevated temperatures of 140–250 °C. We find that the use of tri-n-
butylphosphane (20 mol %) as a nucleophilic organocatalyst in MeOH solution allows cyclization to take place under much milder
conditions (60–70 °C). Several coumarins were prepared, starting from ortho-hydroxyarylaldehydes, by Wittig reaction with
Ph3P=CHCO2Me to (E)-methyl ortho-hydroxycinnamates, followed by the phosphane catalyzed cyclization.
Introduction
Coumarins are important structural motifs in natural products show, in part, a lack of regioselectivity [7-10]. Such problems
and bioactive compounds, in which they exhibit broad bio- may be circumvented by using ring-closing metathesis [11,12]
logical activity, e.g., as anticoagulants, antifungal agents, or other approaches [13-15]. In selective synthetic schemes, the
antioxidants, or as anthelmintic, hypnotic and cytotoxic agents generation of coumarins is typically realized by the cyclization
[1-4]. Due to their fluorescent properties, coumarins are also of ortho-hydroxycinnamates (Scheme 1).
widely used as agrochemicals, additives in cosmetics and food,
optical brighteners, and dispersed fluorescent and tunable laser- This reaction requires high temperatures (140–250 °C,
dye optical agents [5,6]. Classical synthetic approaches for Scheme 1a) [16,19-29] or photochemical double-bond isomer-
coumarins are based on the Perkin reaction or von Pechmann ization (Scheme 1b) [15,17,30,31]. An alternative boron tribro-
condensation, i.e., reactions under harsh conditions and at mide induced lactonization proceeds at a lower temperature
elevated temperatures [1]. Recent new methodologies based on (Scheme 1c), but is not compatible with acid-sensitive function-
CH-activation reactions still use acidic reaction media and ality [18,32]. It follows that synthetic methods converting
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Beilstein J. Org. Chem. 2012, 8, 1630–1636.
Scheme 2: Hypothetical catalytic cycle: Nucleophile-assisted cycliza-
tion of (E)-ethyl 2’-hydroxycinnamate (1) to coumarin (2).
Scheme 1: Conditions for the cyclization of 2’-hydroxycinnamate and
related precursors to coumarins. (a) Thermal cyclization [16]. (b)
Photochemical isomerization/cyclization [17]. (c) Lewis acid induced
demethylation/cyclization [18].
Results and Discussion
The reaction of (E)-ethyl 2’-hydroxycinnamate (1) to coumarin
(2) was chosen as the assay to find catalytic activity under mild
conditions (Table 1).
hydroxycinnamates to coumarins in the absence of acid under
mild conditions are very desirable, particularly for labile It was initially thought that hydro-heteroatomic nucleophiles
starting materials, as often found in the late stages of multistep such as thiols, which are known to easily undergo hetero-
natural-product syntheses.
Michael additions [38], could be suitable candidates for the
screen. However, coumarin was not formed in the presence of
The difficulty of cyclizing (E)-2’-hydroxycinnamates to thiols (Table 1, entry 1). We turned our attention to nucle-
coumarins can be traced to the (E)-configuration of the starting ophiles that are established catalysts in Morita–Baylis–Hillman
material, which places the ester carbonyl group out of reach of type reactions, where they add to conjugated acceptor systems
the phenolic nucleophile [33-35]. The starting material must
first be isomerized to a (Z)-configured intermediate, before
Table 1: Screening of catalysts for nucleophilic double-bond isomer-
cyclization can occur in a geometrically favored manner, but
there is a considerable kinetic and energetic barrier against this
isomerization process, provoking the observed high reaction
temperatures. We wondered whether this problem could be
circumvented by adding a nucleophile (HNu) to the reaction
mixture containing 1, which is capable of undergoing a revers-
ible conjugate addition to form an intermediate A devoid of an
alkene functionality (Scheme 2).
ization.a
Entry
Catalyst
Yield (%)b
1
2
3
4
5
6
7
8
PhSH
–
DABCO
cinchonine
DBU
–
Rotation around the single bond to give B should be a fast
process, and cyclization to a 2-chromanone C is then entropi-
cally favored. Eventually, the elimination to coumarin (2) could
be driven by aromatic stabilization (Scheme 2). In fact, a related
stoichiometric two-step protocol has been proposed [36]. It
appeared to us that the practical problem of developing a mild
and convenient catalytic conversion of ortho-hydroxycinna-
mates to the corresponding coumarins could be an ideal test
case to show the utility of using organocatalytic rationales for
solving a synthetic problem.
–
–
DMAP
IMesc
–
<1
–
PPh3
n-Bu3P
89
aReactions were performed on 0.5 mmol scale in 1 mL of solvent;
reaction time 20–23 h. bScreening yields were determined by GC and/
or HPLC analysis with N-pivaloylaniline as internal standard. cIMes
was generated in situ from IMes·HCl [37] and DBU.
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[39]. Tests with either nitrogen bases (Table 1, entries 2–5) or
N-heterocyclic carbenes (Table 1, entry 6) were not rewarded
with success. Finally, phosphanes were tested, and while tri-
phenylphosphane was not active (Table 1, entry 7), a change to
the smaller and more nucleophilic tri-n-butylphosphane, a
widely used nucleophilic catalyst [39-42], produced coumarin
in rather high yields. Concentrating on n-Bu3P as a very
successful catalyst, a solvent screen was performed at the lower
temperature of 60 °C (Table 2).
Table 2: Screening of solvents in catalyzed coumarin synthesis.a
Entry
Solvent
Time (h)
Yield (%)b
1
2
4
5
5
6
7
8
9
10
toluene
isopropanol
EtCN
28
28
28
28
20
28
22
22
22
16
26
19
8
Conversion to the product in toluene was now considerably
reduced (Table 2, entry 1). The broad solvent screening implied
that some protic solvents, in particular methanol (Table 2, entry
7), were superior to toluene or polar aprotic solvents. The alter-
native phosphane PCy3 was also briefly tested in that solvent,
but the reduced activity implied that there was a negative steric
influence with this catalyst (Table 2, entry 8).The scope and
utility of the optimal catalyst system n-Bu3P in MeOH was next
studied in preparative reactions with a range of substituted
2’-hydroxycinnamic esters 3, which were readily obtained by
reaction of substituted salicylaldehydes with methyl triphenyl-
phosphoranylidene acetate (Ph3P=CHCO2Me) [16,28]. They
were cyclized to the corresponding substituted coumarins 4
under the optimized conditions, involving 20 mol % of n-Bu3P
as the catalyst in methanol solution at 70 °C (Table 3).
dioxane
hexane
CHCl3
2
7
21
77
47c
3
MeOH
MeOH
glycol
glycerol
27
MeOH/H2O
(1:1)
11
16
30
12
13
14
15
CF3CH2OH
MeCN
16
16
16
23
43
6
DMSO
–
tert-butanol
36
aReactions were performed on a 0.5 mmol scale in 1 mL of solvent.
bScreening yields were determined by GC and/or HPLC analysis with
N-pivaloylaniline as the internal standard. cPCy3 was used as the cata-
lyst instead of n-Bu3P.
In these preparative experiments, the reaction mixtures were
quenched by the addition of a cocatalytic amount of 1,2-dibro-
Table 3: Substrate scope of the phosphane catalyzed coumarin synthesis.a
Entry
1
Substrate
Product
Yield (%)b
82
2
1
2
3
80
2
3a
3b
–c
4b
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Beilstein J. Org. Chem. 2012, 8, 1630–1636.
Table 3: Substrate scope of the phosphane catalyzed coumarin synthesis.a (continued)
4
96
3c
4c
5
88d
4d
4e
3d
6
83
96
3e
7
4f
3f
8
96
4g
4h
3g
9
75
99
3h
10
3i
4i
aReactions were performed on a 1 mmol scale in 1 mL of methanol at 70 °C for 20 h. 15 min prior to workup, the mixture was quenched by addition of
1,2-dibromoethane (20 μL, 0.23 equiv). bYields of pure isolated material. cNo reaction to coumarin observed; starting material (60%) was reisolated.
dReaction performed at 90 °C in a closed vessel.
moethane prior to work-up, as described below (see the experi- tions such as high temperatures (140–250 °C). We have consid-
mental section). The coumarins were generally obtained in good ered a strategy to perform a fast catalytic conjugate addition of
to excellent yields under the satisfactorily mild conditions of a heteronucleophile to the starting material in order to speed up
this catalysis. An exception was methyl 4’-nitro-2’-hydroxycin- the overall cyclization reaction. Initial experiments with neutral
namate, which did not cyclize to coumarin under the present thiols as nucleophiles were not successful. On the other hand,
conditions (Table 3, entry 3). Several of the products in Table 3, addition of a nucleophilic trialkylphosphane to (E)-ethyl
including the N,N-diethylamino- (Table 3, entry 7), and 2’-hydroxycinnamate (1) in methanol solution, immediately
methoxy-derivatives (Table 3, entries 5 and 6) show strong produced a yellow color indicative of the generation of a pheno-
fluorescence.
late anion. When this experiment was carried out in an NMR
tube in [D4]-methanol, 31P NMR spectroscopy indicated that
The cyclization of (E)-2’-hydroxycinnamates 1 and 3 to n-Bu3P (δ = −30 ppm) was indeed consumed by a conjugate
coumarins 2 and 4 is slow because it requires prior inversion of addition to 1, with generation of a tributylphosphonium salt (δ =
the double-bond geometry, a process that calls for harsh condi- +37 ppm) of the probable zwitterionic structure 5 (Scheme 3;
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Beilstein J. Org. Chem. 2012, 8, 1630–1636.
Scheme 3: Proposed catalytic cycle, based on 31P NMR spectroscopic and color evidence.
for the 31P NMR spectrum see the Supporting Information step syntheses of sensitive targets. This work also illustrates the
File 1).
utility of using organocatalytic rationales (mechanistic predic-
tions) for developing new solutions to synthetic problems.
Similar phosphonium phenolates are known to exist either as
Experimental
the zwitterionic (analogue to 5) or neutral phosphorane struc-
ture (analogue to 5’) [43,44]. Under the conditions of the General procedure for coumarin synthesis
catalytic reaction, phosphonium (+37 ppm) was the only species The starting hydroxycinnamate ester (1 mmol) was inserted in a
of importance and thus represents the resting state of the headspace vial containing a magnetic stirring bar. The vial was
catalytic reaction, which could be either 5 or 6. We did not flushed with argon and capped. Methanol (1 mL, degassed with
observe a 31P NMR signal for n-Bu3P, or a signal for the phos- argon) was added by syringe through the cap. After addition of
phorane structure 5’, which is not favored in the highly polar tri-n-butylphosphane (50 μL, 0.20 mmol; 20 mol %) with a
solvent methanol [43]. Interestingly, we noted that quenching of microliter syringe, the solution turned bright yellow. The reac-
the catalytic reaction mixtures with a cocatalytic amount of 1,2- tion mixture was heated to 70 °C and stirred for 20 h. The reac-
dibromoethane prior to work-up had a favorable effect on pro- tion was quenched by the addition of 1,2-dibromoethane
duct yield and purity: First, any of the catalyst n-Bu3P present (20 μL, 0.23 mmol, 0.23 equiv) and cooled to room tempera-
will be converted to a water-soluble phosphonium salt, which is ture. After evaporation, the crude mixture was purified by
easier to separate from the coumarin product than the neutral column chromatography.
phosphane is. Second, the yields of coumarins were higher
when the quenching procedure was used. This implies that part Reaction example: 7-(N,N-Diethylamino)coumarin
of the coumarin product may remain associated with the cata- (4f)
lyst after full conversion of the starting material, for example in Prepared according to the general procedure from (E)-methyl
the form of 6 or 6’. Addition of 1,2-dibromoethane will assist in 3-(2-hydroxy-4-N,N-diethylaminophenyl)propenoate (3f, 249
shifting the equilibrium away from 6/6’ to release product 2 and mg, 1 mmol) with n-Bu3P (50 μL, 0.20 mmol, 20 mol %) in
n-Bu3P, since the latter should react irreversibly with the alky- MeOH (1 mL). After work-up and column chromatography
lating reagent.
(EtOAc/hexanes 1:5 + 5% NEt3), the product was obtained as a
yellow crystalline solid (209 mg, 96%). CAS-Nr. 20571-42-0;
mp 90 °C; Rf = 0.32 (Hex/EtOAc 5:1 + 5% NEt3); 1H NMR
Conclusion
In conclusion, we have developed a new catalytic cyclization of (360 MHz, CDCl3) δ 7.54 (d, J = 9.4 Hz, 1H), 7.25 (d, J = 8.5
(E)-alkyl 2’-hydroxycinnamates to coumarins with the Hz, 1H), 6.60 (dd, J = 8.6, 2.6 Hz, 1H), 6.51 (d, J = 2.6 Hz,
aid of a nucleophilic alkyl phosphane catalyst, which allows 1H), 6.04 (d, J = 9.3 Hz, 1H), 3.42 (q, J = 7.1 Hz, 4H), 1.21 (t, J
this conversion to be carried out under much milder = 7.1 Hz, 1H) ppm; 13C NMR (90 MHz, CDCl3) δ 162.2
conditions compared to established procedures [16,19-29]. (C=O), 156.7 (C), 150.5 (C), 143.7 (CH), 128.7 (CH), 109.3
The reaction should be of particular utility in the (CH), 108.9 (CH), 108.5 (C), 97.7 (CH), 45.0 (2 × CH2), 12.4
generation of coumarin derivatives in the late stages of multi- (2 × CH3) ppm.
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