Zinc-mediated addition of diethyl bromomalonate to alkynes for the cascade reaction towards polysubstituted pyranones and tetracarbonyl derivatives

Article abstract of DOI:10.1039/c3cc46788k

The zinc-mediated regioselective addition reactions of diethyl bromomalonate and aromatic and aliphatic alkynes were investigated for the synthesis of vinyl malonates. When the vinyl organo-zinc intermediates were reacted with acid chlorides 2H-pyran-2-ones were obtained while the application of oxalyl chloride and an amine led to tetracarbonyl derivatives in a one-pot multi-step reaction sequence. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc46788k

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Zinc-mediated addition of diethyl bromomalonate
to alkynes for the cascade reaction towards
polysubstituted pyranones and tetracarbonyl
derivatives†
Cite this: Chem. Commun., 2014,
50, 542
Received 5th September 2013,
Accepted 2nd November 2013
Anne Miersch, Klaus Harms and Gerhard Hilt*
DOI: 10.1039/c3cc46788k
www.rsc.org/chemcomm
The zinc-mediated regioselective addition reactions of diethyl bromo-
malonate and aromatic and aliphatic alkynes were investigated for the
synthesis of vinyl malonates. When the vinyl organo-zinc intermediates
were reacted with acid chlorides 2H-pyran-2-ones were obtained while
the application of oxalyl chloride and an amine led to tetracarbonyl
derivatives in a one-pot multi-step reaction sequence.
Organo-zinc species have been investigated intensively by many
groups for their application in various carbon–carbon bond formation
processes.1 The zinc-mediated addition of organo-zinc species
generated in situ to carbon–carbon double and triple bond
systems has been investigated in the past as well.2 The mild
reaction conditions and the comparable low reactivities of organo-
zinc species make them highly interesting regarding the high
compatibility towards a variety of functional groups.3
Scheme 1 Zinc-mediated addition of diethyl bromomalonate to phenyl-
acetylene and quenching experiments of the intermediate.
Recently, we described the regiodiverse addition of benzylic
bromides to alkynes mediated by varying amounts of zinc powder for
the control of the double bond geometry.4 When the benzylic bromide
was replaced by diethyl bromomalonate (1) the addition of the in situ
generated organo-zinc species to phenyl acetylene led to the vinyl
zinc intermediate 2 which was then quenched by electrophiles. The
work-up of intermediate 2 after a reaction time of 3 h led to the mild
generation of a vinyl malonate ester 3 without isomerisation of the
double bond (Scheme 1). Also, the addition of the organo-zinc species
was highly regioselective and only the 1,1-disubstituted alkenes
of type 3 were obtained (see Fig. 1).
However, when bromine was used for the work-up of 2 the
double bond migrated from a vinyl bromide to the allyl bromide
position as in 4. Interestingly, products of type 4 would be accessible
by the well-known Knoevenagel condensation,5 whereas the thermo-
dynamically less stable products of type 3 are not accessible under
the original conditions of the Knoevenagel condensation.6
Fig. 1 Results for the zinc-mediated addition of diethyl bromomalonate 1
to alkynes.
The reaction worked best in dichloromethane as solvent giving
the desired product 3 in 97% yield when the alkyne was applied in
slight excess (1.5 equiv.) (Scheme 2). Only 62% product was isolated
when toluene was used as solvent and in this case three isomers with
the same molecular mass were observed in the inseparable mixture
of products. When many zinc-mediated reactions were performed in
Fachbereich Chemie, Hans-Meerwein-Str., 35043 Marburg, Germany.
E-mail: Hilt@chemie.uni-marburg.de; Fax: +49 6421 2825677;
Tel: +49 6421 2825601
† Electronic supplementary information (ESI) available. CCDC 957488–957490.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3cc46788k
542 | Chem. Commun., 2014, 50, 542--544
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Table 1 Results for the zinc-mediated cascade reaction sequence for the
synthesis of 2H-pyran-2-ones of type 8
Entry
RCOCl
Product
Yielda (%)
Scheme 2 Regioselective synthesis of vinyl malonates of type 5.
ethereal solvents such as diethyl ether or tetrahydrofuran,7 no conver-
sion was observed in these solvents and only traces of the desired
product 3 could be detected by GCMS when acetonitrile was applied as
solvent. The reaction also failed when catalytic amounts of zinc powder
(10 mol%) were used. However, with an excess of zinc (150 mol%) and
a 1 : 1 ratio of the starting materials already 71% yield was obtained and
an excess of alkyne (1.5 equiv.) was found to be optimal.
Under these reaction conditions we investigated the scope of the
reaction toward a number of functionalized terminal alkynes. The
results of these reactions are summarized in Fig. 1. For electron-rich
phenyl acetylene derivatives (5a/5c) good yields were obtained. How-
ever, the more electron rich the arene substituent, the higher the ratio
of double bond migration toward the Knoevenagel-type product
(comparable to 4, Scheme 1). In the case of the 4-methoxyphenyl
substituent (5c), already 25% of the double bond migrated within 24 h
after isolation.8 Nevertheless, when aliphatic substituted alkynes were
applied (5e–5g) these double bond migration products were not
observed within a reaction time of 3–4 h. The yields for most products
were good leaving the functional groups involved in the starting
material intact.
Incorporation of heteroatoms into allylic positions in the products
could be realized (5h/5i/5k) and the vinyl cyclopropane derivative
(5g) and the vinyl silane derivative (5j) are also of similar interest
for follow-up reactions.
In the next step of the investigation, the intermediates of
type 2 were reacted with acid chlorides (6) as the most reactive
carbonyl derivative for direct carbon–carbon bond formation
with vinylic organo-zinc species (Scheme 3). The conversion
with the acid chloride led to intermediates 7 which could not
be isolated but led to a condensation reaction yielding the
2H-pyran-2-ones of type 8 as products.9
1
R = Bn
76
2
3
4
5
6
7
8
R = cyclohexyl
R = tertBu
R = Me
69
66
62
60
55
52
R = Et
R = 4-ClC3H6
R = C10H15
In this series of experiments the alkyne was kept constant
(phenylacetylene) and the acid chloride derivative was altered
to investigate the scope of the substituents (R) compatible
with the reaction sequence. The results of the zinc-mediated
synthesis of 2H-pyran-2-ones are summarized in Table 1.
The one-pot multi-step synthesis of 2H-pyran-2-one derivatives
could be realized for a series of acid chlorides in acceptable to
R = C3H5
45
42
9
R = (CH2)2CHQCH2
a
Conditions: diethyl bromomalonate (1.0 eq.), phenylacetylene
(1.5 eq.), zinc dust (150 mol%), CH2Cl2 (1 mL), 40 1C, 3 h, then acid
chloride (3.0 eq.), ꢀ40 1C–rt, 16 h.
good yields. However, the reaction seems to be limited to aliphatic
acid chlorides because aromatic acid chlorides gave the desired
products only in low yields.
Nevertheless, simple aliphatic acid chlorides (8d/8e), sterically
hindered acid chlorides (8c/8g), as well as functionalized aliphatic
acid chlorides (8f/8h/8i) are well accepted. Thereby, the construc-
tion of trisubstituted and polyfunctionalised 2H-pyran-2-ones in a
Scheme 3 Cascade reaction sequence for the synthesis of 2H-pyran-2-ones. straightforward fashion was accomplished.
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accessible in a one-pot procedure. Additionally, the reaction
with oxalyl chloride led to a diverse reaction sequence to
form highly functionalized tetracarbonyl derivatives (10) with
unexplored synthetic potential.
Notes and references
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Scheme 4 Zinc-initiated cascade reaction sequence for the synthesis of
tetracarbonyl derivatives of type 10.
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8b, 8c and 8e.10 The X-ray structure of 8c is given in Fig. 2.
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different type of product was obtained (Scheme 4). The zinc-
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reactive oxalyl chloride reacts at the malonate position to form
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544 | Chem. Commun., 2014, 50, 542--544
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