C5-Disubstituted Meldrum's Acid Derivatives as Platform for the Organocatalytic Synthesis of C3-Alkylated Dihydrocoumarins

Article abstract of DOI:10.1002/adsc.201801453

C5-disubstituted Meldrum's acid precursors were shown to be a useful platform for the synthesis of an array of 3-alkylated dihydrocoumarins with up to 93:7 er, thanks to an enantioselective domino cyclization-decarboxylative-protonation reaction triggered by an unprecedented benzhydryl-derived cupreine organocatalyst. This cyclization sequence was extended to an emerging organocatalytic decarboxylative-chlorination reaction in the presence of trichloroquinolinone and by means of a bifunctional cinchona derived Br?nsted base which gave rise to the formation of dihydrocoumarins (up to 79:21 er) with a tertiary chlorinated stereocenter. (Figure presented.).

Full text of DOI:10.1002/adsc.201801453

Title: C5-Disubstituted Meldrum’s Acid Derivatives as Platform for the
Organocatalytic Synthesis of C3-Alkylated Dihydrocoumarins
Authors: Thomas Martzel, Julien Annibaletto, Vincent Levacher, jean-
François Brière, and Sylvain Oudeyer
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801453
Link to VoR: http://dx.doi.org/10.1002/adsc.201801453

10.1002/adsc.201801453
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
C5-Disubstituted Meldrum’s Acid Derivatives as Platform
for the Organocatalytic Synthesis of C3-Alkylated
Dihydrocoumarins
Thomas Martzel, Julien Annibaletto, Vincent Levacher, Jean-François Brière*
and Sylvain Oudeyer*
a
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France.
E-mail: jean-francois.briere@insa-rouen.fr, sylvain-oudeyer@univ-rouen.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201######.((Please delete if not appropriate))
a small proton atom to ketene dithioacetals.[5f] One of
Abstract. C5-disubstituted Meldrum’s acid precursors
were shown to be a useful platform for the synthesis of an the obtained product was hydrolyzed into an α-phenyl
array of 3-alkylated dihydrocoumarins with up to 93:7 er,
thanks to an enantioselective domino cyclization-
decarboxylative- protonation reaction triggered by an
unprecedented benzhydryl-derived cupreine organocatalyst.
This cyclization sequence was extended to an emerging
organocatalytic decarboxylative-chlorination reaction in the
presence of trichloroquinolinone and by means of a
bifunctional cinchona derived Brønsted base which gave
rise to the formation of dihydrocoumarins (up to 79:21 er)
with a tertiary chlorinated stereocenter.
dihydrocoumarin with high enantiomeric excess. In
view of this background, an expedious synthetic
sequence furnishing C3-substituted dihydrocoumarin
remains desirable.
Very recently, the group of Guiry achieved the
synthesis of a series of 3-aryl dihydrocoumarins with
er ranging from 65:35 to 94:6 (Scheme 1b).[6] This
functionalization strategy takes advantage of the
palladium-catalyzed decarboxylative protonation
reaction[7] in the presence of ephedrine as a chiral
stoichiometric source of proton. Although several
teams ventured into this convenient enantioselective
protonation (EP) strategy, mostly from hemimalonic
esters in organocatalysis, only the groups of Brunner,
Rouden, Zhang and Song succeeded in getting good
er (rarely > 95:5) albeit at the expense of the use of
high catalyst loading (up to 1 equiv).[8],[9]
Keywords: Coumarin; organic catalysis; synthetic method;
Meldrum’s acid; Decarboxylative protonation
Amongst the privileged coumarin scaffolds in
medicinal chemistry, the dihydrocoumarin derivatives
are widely distributed within naturally occurring
molecules and bioactive compounds.[1] Consequently,
several
groups
have
developed
catalytic
enantioselective syntheses of 3,4-disubstituted
chroman-2-ones[2] and, to a much lesser extent, 3,3-
disubstituted
homologues
(Scheme
1).[3]
Nevertheless, the construction of enantioenriched 3-
substituted derivatives turned out to be more
challenging. To the best of our knowledge, the group
of Scheidt has reported the single one-step
asymmetric
construction
of
3-substituted
dihydrocoumarins upon NHC organocatalysis
eliciting a (4+2)-cycloaddition reaction with er
ranging from 75:25 to 93:7.[4] Beside the elegant but
two steps enamine-based approaches developed by
Xie and Liu,[5a-e] requiring the final oxidation of a
lactol intermediate, List and co-workers have
pioneered the challenging enantioselective delivery of
1
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10.1002/adsc.201801453
Advanced Synthesis & Catalysis
Scheme 1. Context of the investigation.
We recently introduced disubstituted Meldrum’s
acid (MA) derivatives as stable alternatives to
hemimalonic esters for the enantioselective
decarboxylative protonation reaction upon phase-
transfer catalytic conditions,[10] while this architecture
also affords new synthetic opportunities in
heterocycle formation.[11] We reasoned that a novel
and readily available MA platform 1 (Scheme 2),[12]
may undergo the intramolecular nucleophilic addition
of the phenol moiety thanks to the electrophilic
character of the carbonyl groups. Then, the
fragmentation-decarboxylation events would afford a
transient enolate species A which would undergo the
key enantioselective protonation. Overall, an original
organocatalytic proton shuttle from the phenol part to
the final product 2 would occur. We are pleased to
report herein that a novel bifunctional organocatalyst
(R3N*) allows this unprecedented catalytic route to
enantioenriched 3-alkylated dihydrocoumarins 2.
Furthermore, by means of these MA-based platforms,
a proof of concept of a sparingly reported asymmetric
Scheme 2. Proof of principle.
During the rapid survey of reaction conditions
(Table 1 and see SI), THF proved to be the most
suitable solvent both for er and the reaction
efficiency (entries 1-5). Eventually, the enantiomeric
ratio was improved to 93:7 er by carrying out the
reaction at 5 °C (entries 8-10) in a more concentrated
fashion (0.5 M –entries 6-7). This outcome provides
one of the highest enantioselection for the synthesis
of 3-benzyl dihydrocoumarin derivatives of type
2a,[4],[5d] while successfully demonstrating the
challenging enantioselective delivery of a small
proton atom to an enolate intermediate along a
complex domino process.
decarboxylative
chlorination
reaction
was
demonstrated allowing the construction of chiral C3-
chlorinated dihydrocoumarins.[13]
This investigation began with the phenol 1a as a
model substrate (Scheme 2, see SI for full-details). A
screening of an array of chiral Brønsted bases
revealed that quinine 3a achieved the domino
transformation into the desired 2a in smooth
conditions (rt, 2 hours), in a complete conversion and
promising 37.5:62.5 er. The functional group
modulation on catalysts 3 highlighted that cupreine
bifunctional
organocatalysts
provided
better
Table 1. Conditions optimization. [a]
selectivity with er increasing from 74.5:25.5 to 82:18
in line with steric hindrance at the C9-ether moiety
(see R1 for 3c-3f).[14] Eventually, a novel benzhydryl-
derived cupreine 3g was synthesized and furnished
excellent 90:10 er. Preliminary structure activity
investigations by modulating the benzhydryl moiety,
by para-fluorophenyl (3h) or 2-naphtyl (3i) pendants,
together with the evaluation of the N-oxide catalyst 3j
led to lower selectivities.
Entry Solvent T, time Conc. Conv.[b]
er[c]
(°C, h)
(mol/l)
(%)
1
2
3
4
5
6
7
8
9
THF
PhMe
MeCN
CH2Cl2
Et2O
THF
THF
THF
THF
rt, 2
rt, 2
rt, 2
rt, 2
rt, 2
rt, 2
rt, 2
10, 20
5, 20
-5, 64
0.1
0.1
0.1
0.1
0.1
0.2
0.5
0.5
0.5
0.5
99
25
56
27
64
90:10
71:29
71:29
61.5:38.5
87:13
91:9
92:8
92.5:7.5
93:7
98
98
99[d]
99[d]
78[e]
10
THF
93:7
[a] Reaction performed on 0.05 mmol of phenol 1a. [b]
Determined on the crude product by 1H NMR. [c]
Determined by chiral HPLC.
2
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10.1002/adsc.201801453
Advanced Synthesis & Catalysis
As depicted in Scheme 3a, one could envisage the
annulation process between a transient unsubstituted
ortho-quinone methide and benzyl MA C to give C-3
benzyl coumarin 2a. Interestingly, Fochi and
Bernardi reported the synthesis of C-4-arylated
dihydrocoumarins,[15]
based
on
the
key
enantioselective conjugate addition of unsubstituted
Meldrum’s acid to substituted ortho-quinone
methides generated from benzylic sulfones in basic
conditions.
However,
the
non-asymmetric
decarboxylative-cyclization final steps required a
heating step (APTS, toluene, 100 °C). In our
conditions (catalyst 3g, THF, 5 °C), making use of
the in-situ fluoride-promoted formation of the
unsubstituted ortho-quinone methide generated from
OTES-benzyl bromide B (Scheme 3a),[4],[5d] a smooth
formal (4+2) cycloaddition and the subsequent
Scheme 4. Proposed catalytic cycle and transition state.
decarboxylative-protonation
reaction
occurred.
As phenol 1a was difficult to purify, the readily
available silylated precurors 4 (see SI) were used to
study the scope and limitations of this novel
transformation (Scheme 5). Indeed, the corresponding
phenols 1 were thus generated after a simple acidic
deprotection of the O-silyl moiety of 4 and used
without further purification. By means of cupreine
catalyst 3g for 20 hours at 5 °C, C3-benzylated
dihydrocoumarin derivatives 2a-2f and 2h, with
phenyl-moiety flanked by para- or meta-substituents,
were uneventfully formed with 61-99% yields over
two-steps and er between 90.5:9.5 to 93:7. The yield
of the para-methoxy derivative 2f was improved
from 61 to 99% in 60 hours of reaction albeit with a
slight decrease in er to 91:9 (previously 92.5:7.5).
Ortho-methoxy aryl derivative 2g led to 86% yield
with a 86:14 er. Heterocyclic pendants were tolerated
but the corresponding products 2i-2k were obtained
with er ranging from 85:15 to 89.5:10.5. Precursors
with alkyl-chain substituents led to moderate er (2l-
2n, 79-95%, 74:26-82.5:17.5 er) except the
counterpart 2o, bearing a versatile ester functional
group, which was synthesized in 85% yield and 91:9
er. The precursors having substituents on the phenol
moiety were cyclized into products 2p-2q[18] in
89.5:10.5 and 88.5:11.5 er respectively and excellent
yields (86-92%). However, although this strategy
allows the straightforward construction of 3-phenyl
derivative 2r, a low enantiomeric ratio (59:41 er) was
measured due to racemization events of this more
acidic product.
Unfortunately, the product 2a was obtained in 64%
yield and only 65:35 er. Contrary to the successful
strategy from the suitable phenol platform 1a
(Scheme 2), the final stereoselective protonation
during the (4+2) cycloaddition approach (Scheme 3a)
may compete with other processes among which the
racemic protonation by the rather acidic MA starting
material C (pKa = 4.8).[12] Eventually, it was shown
that neither the intermolecular addition of phenol nor
the direct addition event of catalyst 3g occurred
(Scheme 3b).[16]
Scheme 3. Reactivity investigations.
In this context, we propose that the intramolecular
attack of the phenol moiety to the electrophilic MA
platform 1a is promoted by the Brønsted base 3g
(Scheme 4), and the facile fragmentation-
decarboxylation process via D to lead to the rather
stable tetrasubstituted enolate intermediate
A
(Scheme 1).[17] Then, the bifunctional protonated-
cupreine organocatalyst 3g-H would deliver the
proton to the rear-face of the enolate A to give 2a,
through a hydrogen-bonding manifold by means of
the hydroxyl-quinoline part in the Transition State
(see SI for TS-proposal discussion).[14]
3
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10.1002/adsc.201801453
Advanced Synthesis & Catalysis
Scheme 7. A decarboxylative chlorination approach [a-b]
Pleasingly, the chlorination reaction occurred with
more efficiency with the bifunctional organocatalyst
7,[21] derived from 9-epi-aminoquinine. Next, better
enantiomeric excesses were observed in the presence
of the trichloroquinolinone 8, originally developed by
Bartoli, Melchiorre and co-workers as chlorinated
agent (see SI).[22] Under these conditions (THF,
15 °C, 40 hours) a series of novel chlorinated
coumarin derivatives 6a-6g were obtained as major
products with isolated yields between 51 to 74%. The
presence of the minor protonated products 2 was
observed on the crude reaction mixture (6:2  80:20).
Worthy of note, it was proven that the catalytic
chlorination reaction did not occur on the coumarin
product 2a. At that stage, albeit moderate, the er were
uniformly measured between 76:24 to 79:21 (6a-6g)
for this proof of principle and novel domino
cyclization-decarboxylative chlorination reaction.
Furthermore, this approach allows the elaboration of
unprecedented α,α-disubstituted coumarins[3] with a
versatile tertiary chlorinated stereocenter.[20]
Scheme 5. Scope and limitations of the decarboxylative
protonation reaction.[a-b]
In order to illustrate the utility of these
dihydrocoumarins, the unprecedented synthesis of the
enantioenriched C3-benzyl chroman
5
was
undertaken, as these derivatives (as racemic) have
potent antirhinovirus properties (Scheme 6).[19] To
our delight, the desired chroman 5 was obtained in
58% yield over a two-step reduction sequence of
coumarin 2a with virtually no erosion of er.
Scheme 6. Useful synthetic transformation.
In conclusion, we have highlighted the reactivity of
C5-disubstituted Meldrum’s acid derivatives as novel
platforms for the enantioselective organocatalytic
synthesis of medicinally relevant 3-alkylated
dihydrocoumarins in up to 93:7 er, thanks to a
Next, we wondered whether it could be possible to
take advantage of the reactivity of the readily
available Meldrum’s acid platforms 4, for the
construction of more substituted dihydrocoumarin
derivatives. At the onset, we considered the beautiful
and unprecedented enantioselective decarboxylative
chlorination reaction recently reported by Shibatomi
et al.[13],[20] This strategy applied to our domino
cyclization-decarboxylative process would provide an
unprecedented entry to dihydrocouramins 6 having a
C3-chlorinated tetrasubstituted stereocenter (Scheme
7).
domino
cylization-decarboxylative
protonation
reaction trigerred by a novel cuprein organocatalyst.
The versatility of these platforms was demonstrated
through an original (second report to date)
enantioselective decarboxylative chlorination reaction
towards the construction of chroman-2-ones with a
tertiary chlorinated stereocenter with up to 79:21 er.
The synthesis of other heterocycles based upon the
4
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10.1002/adsc.201801453
Advanced Synthesis & Catalysis
Meldrum’s acid platforms is currently under
Synth. Catal. 2018, 360, 1128; d) L. Cui, D. Lv, Y.
Wang, Z. Fan, Z. Li, Z. Zhou, J. Org. Chem. 2018, 83,
4221; e) M. Spanka, C. Schneider, Org. Lett. 2018, 20,
4769; f) Z. Cao, G.-X. Zhou, C. Ma, K. Jiang, G.-J.
Mei, Synthesis 2018, 50, 1307 and references cited
therein.
investigation.
Experimental Section
General decarboxylative protonation reaction procedure:
5-Benzyl-2,2-dimethyl-5-(2-((triethylsilyl)oxy)benzyl)-
1,3-dioxane-4,6-dione 4a (68.1 mg, 0.15 mmol) was
diluted in EtOH (3 mL) and 37% aqueous HCl solution
(0.06 mL) was added dropwise at room temperature. The
reaction mixture was stirred at room temperature for 1
hour. The mixture was quenched with water and extracted
twice with CH2Cl2. The combined organic phases were
dried over MgSO4, and concentrated in vacuo. The residue
was diluted in dry THF (0.5 M), stirred at 5 °C for 10
minutes, then organocatalyst 3g (20 mol%) was added. The
mixture was stirred at 5 °C for 20 hours, filtered on a pad
of silica gel [eluent: Petroleum Ether/EtOAc (8/2) and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel to afford the desired
enantioenriched (S)–3–Benzylchroman–2–one 2a in 85%
yield and 93:7 er.
[3] a) M. Murakata, T. Jono, Y. Mizuno, O. Hoshino, J.
Am. Chem. Soc. 1997, 119, 11713; b) M. Murakata, T.
Jono, T. Shoji, A. Moriya, Y. Shirai, Tetrahedron:
Asymmetry 2008, 19, 2479; c) B. Teng, W. Chen, S.
Dong, C. W. Kee, D. A. Gandamana, L. Zong, C.-H.
Tan, J. Am. Chem. Soc. 2016, 138, 9935; d) R. Akula,
P. J. Guiry, Org. Lett. 2016, 18, 5472; e) X.-H. Li, S.-
L. Wan, D. Chen, Q. R. Liu, C.-H. Ding, P. Fang, X.-L.
Hou, Synthesis 2016, 48, 1568; f) H. Jin, S. M. Cho,
G.-S. Hwang, D. H. Ryu, Adv. Synth. Catal. 2017, 359,
163; g) Y. Zhu, W.-Z. Zhang, L. Zhang, S. Luo, Chem.
Eur. J. 2017, 23, 1253; h) H. Jin, J. Lee, H. Shi, J. Y.
Lee, E. J. Yoo, C. E. Song, D. H. Ryu, Org. Lett. 2018,
20, 1584.
General decarboxylative chlorination reaction: 5-Benzyl-
2,2-dimethyl-5-(2-((triethylsilyl)oxy)benzyl)-1,3-dioxane-
4,6-dione 4a (68.1 mg, 0.15 mmol) was diluted in EtOH (3
mL) and 37% aqueous HCl solution (0.06 mL) was added
dropwise at room temperature. The reaction mixture was
stirred at room temperature for 1 hour. The mixture was
quenched with water and extracted twice with CH2Cl2. The
combined organic phases were dried over MgSO4, and
concentrated in vacuo. The residue was diluted in dry THF
(0.25 M), stirred at 15 °C for 10 minutes, then 5,7,7-
trichloro-7H-quinolin-8-one 8 (1.5 equiv), NaHCO3 (1
equiv) and organocatalyst 7 (20 mol%) were added. The
mixture was stirred at 15 °C for 40 hours, filtered on a pad
of silica gel [eluent: Petroleum Ether/EtOAc (8/2)] and
concentrated in vacuo. A ratio of chlorinated:protonated
products 6a:2a of 80:20 was measured on the crude
[4] A. Lee, K. A. Scheidt, Chem. Commun. 2015, 51, 3407.
[5] a) D. Zhou, X. Yu, J. Zhang, W. Wang, H. Xie, Org.
Lett. 2018, 20, 174; b) Y.-K. Liu, Z.-L. Li, J.-Y. Li, H.-
X. Feng, Z.-P. Tong, Org. Lett. 2015, 17, 2022; c) X.-
L. Sun, Y.-H. Chen, D.-Y. Zhu, Y. Zhang, Y.-K. Liu,
Org. Lett. 2016, 18, 864; d) D. Zhou, K. Mao, J. Zhang,
B. Yan, W. Wang, H. Xie, Tetrahedron Lett. 2016, 57,
5649; e) Y.-H. Chen, X.-L. Sun, H.-S. Guan, Y.-K. Liu,
J. Org. Chem. 2017, 82, 4774; f) J.-W. Lee, B. List, J.
Am. Chem. Soc. 2012, 134, 18245.
[6] During the preparation of this manuscript: J. James, R.
1
reaction mixture by H NMR. The residue was purified by
Akula, P. J. Guiry, Adv. Synth. Catal. 2018, 360, 3138.
column chromatography on silica gel to afford the desired
enantioenriched 3-Benzyl-3-chlorochroman-2-one 6a in
56% yield and 78:22 er.
[7] For
a
pioneering Pd-catalyzed decarboxylative
protonation approach, see: S. C. Marinescu, T.
Nishimata, J. T. Mohr, B. M. Stoltz, Org. Lett. 2008,
10, 1039.
Acknowledgements
[8] For reviews on decarboxylative protonation, see: a) J.
Blanchet, J. Baudoux, M. Amere, M.-C. Lasne, J.
Rouden, Eur. J. Org. Chem. 2008, 5493; b) J. T. Mohr,
A. Y. Hong, B. M. Stoltz, Nat. Chem. 2009, 1, 359; c)
S. Oudeyer, J.-F. Brière, V. Levacher, Eur. J. Org.
Chem. 2014, 6103; d) S. Nakamura, Org. Biomol.
Chem. 2014, 12, 394.
This work has been partially supported by INSA Rouen, Rouen
University, CNRS, EFRD and Labex SynOrg (ANR-11-LABX-
0029) and region Normandie (CRUNCh network). We wish to
thank Dr. Morgane Sanselme (University of Rouen Normandy,
SMS laboratory) for the X-ray diffraction analysis.
References
[9] For leading publications, see: a) H. Brunner, Markus A.
Baur, Eur. J. Org. Chem. 2003, 2854; b) M. Amere,
M.-C. Lasne, J. Rouden, Org. Lett. 2007, 9, 2621; c) M.
Pigeaux, R. Laporte, D. C. Harrowven, J. Baudoux, J.
Rouden, Tetrahedron Lett. 2016, 57, 4599; d) S. Some,
H. Y. B. Kim, Mun Jong, Y. J. Zhang, C. E. Song, Eur.
J. Org. Chem. 2017, 4562.
[1] a) F. Borges, F. Roleira, N. Milhazes, L. Santana, E.
Uriarte, Curr. Med. Chem. 2005, 12, 887Curr. Med.
Chem; b) V. Semeniuchenko, U. Groth, V. Khilya,
Synthesis 2009, 3533; c) D. P. Kamat, S. G. Tilve, V. P.
Kamat, J. K. Kirtany, Org. Prep. Proced. Int. 2015, 47,
1; d) Z. Leitis, Chemistry of Heterocyclic Compounds
(New York, NY, United States) 2016, 52, 527Chemistry
of Heterocyclic Compounds (New York, NY, United
States).
[10] F. Legros, T. Martzel, J.-F. Brière, S. Oudeyer, V.
Levacher, Eur. J. Org. Chem. 2018, 1975.
[11] T. Tite, M. Sabbah, V. Levacher, J.-F. Brière, Chem.
Commun. 2013, 49, 11569.
[2] For selected recent publications, see: a) B. Wu, Z. Yu,
X. Gao, Y. Lan, Y.-G. Zhou, Angew. Chem. Int. Ed.
2017, 56, 4006; b) J.-H. Jin, X.-Y. Li, X. Luo, J. S.
Fossey, W.-P. Deng, J. Org. Chem. 2017, 82, 5424; c)
T. Zhang, C. Ma, J.-Y. Zhou, G.-J. Mei, F. Shi, Adv.
[12] For reviews on Meldrum's acid in catalysis, see: a) A.
M. Dumas, E. Fillion, Acc. Chem. Res. 2009, 43, 440;
5
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10.1002/adsc.201801453
Advanced Synthesis & Catalysis
b) E. Pair, T. Cadart, V. Levacher, J.-F. Brière,
ChemCatChem 2016, 8, 1882.
[18] CCDC 1870775 (2q) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre.
[13] First enantioselective decarboxylative chlorination of
β-ketocarboxylic acids: K. Shibatomi, K. Kitahara, N.
Sasaki, Y. Kawasaki, I. Fujisawa, S. Iwasa, Nat.
Commun. 2017, 8, 15600.
[19] C. Conti, N. Desideri, Bioorg. Med. Chem. 2009, 17,
3720.
[14] For reviews on Cupreines, see: a) T. Marcelli, J. H.
van Maarseveen, H. Hiemstra, Angew. Chem. Int. Ed.
2006, 45, 7496; b) L. A. Bryant, R. Fanelli, A. J. A.
Cobb, Beilstein J. Org. Chem. 2016, 12, 429.
[20] For reviews on catalytic chlorination reaction, see: a)
K. Shibatomi, A. Narayama, Asian J. Org. Chem. 2013,
2, 812; b) M. Gómez-Martínez, D. A. Alonso, I. M.
Pastor, G. Guillena, A. Baeza, Asian J. Org. Chem.
2016, 5, 1428.
[15] L. Caruana, M. Mondatori, V. Corti, S. Morales, A.
Mazzanti, M. Fochi, L. Bernardi, Chem. Eur. J. 2015,
21, 6037.
[21] Negligible ee were obtained for the chlorination
reaction of 4a either with cupreine catalyst 3g or
Shibatomi's organocatalyst (see reference 13).
[16] Indeed, the previously developed decarboxylative
protonation reaction, triggered by the intermolecular-
addition of phenol to C5-arylated MA, required the use
of a stronger phosphate base in the presence of a
quaternary ammonium salt upon phase-transfer
conditions to occur, see reference 10.
[22] G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P.
Melchiorre, L. Sambri, Angew. Chem. Int. Ed. 2005,
44, 6219.
[17] For an example of mechanistic investigation of
cyclocondensation reaction with Meldrum's acid, see:
N. Lespes, E. Pair, C. Maganga, M. Bretier, V.
Tognetti, L. Joubert, V. Levacher, M. Hubert-Roux, C.
Afonso, C. Loutelier-Bourhis, J.-F. Brière, Chem. Eur.
J. 2018, 24, 4086.
6
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10.1002/adsc.201801453
Advanced Synthesis & Catalysis
COMMUNICATION
C5-Disubstituted Meldrum’s Acid Derivatives as
Platform for the Organocatalytic Synthesis of C3-
Alkylated Dihydrocoumarins
Adv. Synth. Catal. Year, Volume, Page – Page
Thomas Martzel, Julien Annibaletto, Vincent
Levacher, Jean-François Brière* and Sylvain
Oudeyer*
7
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