Base-promoted synthesis of coumarins from salicylaldehydes and aryl-substituted 1,1-dibromo-1-alkenes under transition-metal-free conditions

Article abstract of DOI:10.1039/c4cc04377d

Facile synthesis of coumarin via the tandem reaction of salicylaldehyde with aryl-substituted 1,1-dibromo-1-alkene was developed. This new protocol proceeds smoothly under mild and transition-metal-free conditions, it allows rapid access to coumarins containing various heteroatoms that are more difficult to prepare by traditional methods. Based on the isolated intermediate of 4-(diethylamino)-3-phenylchroman-2-one and detailed mechanistic studies, a credible tandem pathway was proposed.

Full text of DOI:10.1039/c4cc04377d

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Base-promoted synthesis of coumarins from
salicylaldehydes and aryl-substituted 1,1-dibromo-
1-alkenes under transition-metal-free conditions†
Cite this: Chem. Commun., 2014,
50, 9887
Received 9th June 2014,
Accepted 3rd July 2014
Jianming Liu,*a Xin Zhang,a Lijun Shi,b Muwen Liu,a Yuanyuan Yue,a Fuwei Li*b and
Kelei Zhuo*a
DOI: 10.1039/c4cc04377d
www.rsc.org/chemcomm
Facile synthesis of coumarin via the tandem reaction of salicylaldehyde should be appreciated.11,12 Therefore, developing a new syn-
with aryl-substituted 1,1-dibromo-1-alkene was developed. This new thetic route that is not dependent on precious metals or ligands
protocol proceeds smoothly under mild and transition-metal- would be ideal in terms of cost and simplicity.
free conditions, it allows rapid access to coumarins containing
Recently, the tandem reactions of aryl-substituted 1,1-dibromo-
various heteroatoms that are more difficult to prepare by traditional 1-alkenes have emerged as powerful and versatile synthetic
methods. Based on the isolated intermediate of 4-(diethylamino)-3- intermediates.13,14 1,1-Dibromo-1-alkenes, owing to their high
phenylchroman-2-one and detailed mechanistic studies, a credible regioselectivity and easy accessibility from available starting
tandem pathway was proposed.
materials, have been exploited, notably as key units for the
construction of various heterocycles and carbocycles.15–18 Herein, we
The coumarin scaffold has been found in many natural products report a general and facile procedure for the preparation of coumar-
and pharmaceuticals, and it has also been considered as a valuable ins by the base-promoted tandem reaction of 1,1-dibromo-1-alkene
synthetic building block in material sciences.1–3 3-Arylcoumarins with salicylaldehyde derivatives. This development is based on the
are mainly prepared by the following five strategies: (a) the earliest retrosynthetic analysis depicted in Scheme 1. 3-Arylcoumarins
condensation of salicylaldehyde with phenylacetic acid or aryl- should be prepared by base-promoted intramolecular cyclization
acetonitrile;4 (b) Pd-catalysed cross coupling of simple coumarin of aryl-substituted 1,1-dibro-1-alkenes, which act as synthetic equiva-
with aryl halide or arylboronic acid;5,6 (c) Pd-catalysed carbonylative lents to the phenylacetyl compounds (Scheme 1). We envisaged
annulation;7 (d) base promoted three-component coupling using that aryl-substituted 1,1-dibromo-1-alkenes were possibly sui-
arynes, malonates and DMF;8 and (e) the oxidative hydrolysis table synthetic equivalents to the phenylacetyl synthons, since
of 3-phenylspiro[chroman-2,20-[1,3]dithiane].9 Although these they could act as C–O cross coupling acceptors and then the
methods exhibited their individual advantages, they generally bromine group was attacked by OHꢀ. Lastly, the desired
involved multistep procedures, sometimes harsh reaction condi- product was prepared by elimination. In this context, we now
tions, preparation of special starting materials, the combination developed a new base-promoted protocol for the intramolecular
with strong bases, the difficult synthesis of coumarins containing cyclization of salicylaldehydes and aryl-substituted 1,1-dibromo-
various heteroatoms, and the requirement of transition metal 1-alkenes to generate substituted coumarins. This method is not
complexes.10 To avoid the drawbacks of the above processes, such only a new route for coumarin synthesis but also a new type of
as toxicity and noble transition metal remaining in final products base-promoted tandem reaction.
as a trace impurity, transition-metal-free cross coupling reactions
Our evaluation started with the reaction of salicylaldehyde
(1a) and (2,2-dibromovinyl)benzene (2a) in the presence of base
under an air atmosphere in DMF at 110 1C (Table S1, see ESI†).
Although only a trace yield of the desired 3a was obtained with
Na2CO3 as the promoter, it could initiate such a transformation
a Collaborative Innovation Center of Henan Province for Green Manufacturing of
Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, P. R. China.
E-mail: jmliu@htu.cn, klzhuo@263.net
b State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou,
730000, P. R. China. E-mail: fuweili@licp.cas.cn
† Electronic supplementary information (ESI) available. CCDC 947235. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc04377d
Scheme 1 Retrosynthetic analysis of coumarins.
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(Table S1, ESI,† entry 1). Surprisingly, a perfect 85% yield was It was found that both electron-withdrawing groups and electron-
realized only by the addition of Et2NH into the above system donating groups at the para position of 1,1-dibromo-1-alkenes gave
(Table S1, ESI,† entry 2). However, Et2NH alone gave no reaction the desired products in good yield from 50% to 85% (3g–3l). The
(Table S1, ESI,† entry 3). These obvious differences indicated structure of 3h was unambiguously confirmed by single-crystal
that the synergetic function of inorganic Na2CO3 and organic X-ray diffraction analysis (see ESI†). Meanwhile, the tandem reac-
Et2NH led to such an efficient conversion. Among the screened tion of 2-hydroxy-1-naphyadehyde and 1,1-dibromo-1-alkenes with
inorganic bases (Table S1, ESI,† entries 4–8), Na2CO3 was various electron-rich and electron-poor groups also provided the
the most efficient base. The trace yield of the desired product substituted coumarins in good yields under the optimized reaction
was observed when DMAc, toluene and 1,4-dioxane were used conditions (3m–3s). In all, the ability to incorporate the different
as solvents (Table S1, ESI,† entries 9–11). NMP was also an substituents makes this reaction more attractive for increasing the
effective solvent, and promoted smoothly the reaction in 84% coumarin complexity.
yield (Table S1, ESI,† entry 12). The decrease and increase of the
temperature resulted in relatively low yield of the desired these base-promoted tandem reaction conditions to construct a
product (Table S1, ESI,† entries 13 and 14). variety of important nitrogen- and sulfur-containing heterocyclic
Encouraged by these promising results, we further applied
With the optimized conditions in hand, we started to investi- compounds (Scheme 3). To our delight, 1,1-dibromo-1-alkenes with
gate other substrates in base-promoted tandem reaction. First of an ortho-substituent on the pyridine ring were selectively treated
all, various salicylaldehydes were employed to construct the cou- with salicylaldehydes, affording the corresponding products in 45%
marins with (2,2-dibromovinyl)benzenes (Scheme 2). For salicylal- to 70% yields (4a–4e). Similarly, 2-(2,2-dibromovinyl)furans were
dehydes, a series of functional groups on the phenyl ring (e.g., coupled with salicylaldehydes to produce the substituted coumarins
methyl, methoxyl, chloro, and tertiary butyl) were compatible with in moderate yields (5a–5e). Lastly, various salicylaldehydes were also
the present catalytic system, and the desired products were shown to couple with 2-(2,2-dibromovinyl)thiophenes in moderate
isolated in excellent yields (3a–3f). This indicates that the present to good yields (5f–5j).
reaction has good functional-group tolerance. To our delight,
To explore the mechanism for this reaction, control experi-
both the o-methyl and o-t-butyl substituted salicylaldehydes were ments were carried out under the standard reaction conditions
similarly found to be suitable substrates for this transformation (Scheme 4). Firstly, radical trapping experiments were also con-
and gave the desired products in 80% and 78% yields, respectively. ducted by employing 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
Furthermore, various functional groups can be tolerated in to elucidate whether the reaction involves radical species.
1,1-dibromo-1-alkenes with a phenyl fragment, including a large
range of methoxyl, methyl, fluoro, halo and brine substituents.
Scheme 2 Base-promoted tandem reactions of salicylaldehydes with
1,1-dibromoalkenes. Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol),
Na2CO3 (2.0 mmol), and Et2NH (0.50 mL) in DMF (5.0 mL) at 110 1C for
12 h in air. Isolated yields.
Scheme 3 Base-promoted tandem reactions of salicylaldehydes with
other challenging substrates. Reaction conditions: (1.0 mmol),
1
2
(1.5 mmol), Na2CO3 (2.0 mmol), and Et2NH (0.50 mL) in DMF (5.0 mL) at
110 1C for 12 h in air. Isolated yields.
9888 | Chem. Commun., 2014, 50, 9887--9890
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to give intermediate III. In the presence of base, intermediate
III eliminated HBr to generate intermediate A. Finally, inter-
mediate A could undergo the elimination of Et2NH by the
driving force of aromatization to form the target product 3a.
In conclusion, we have demonstrated for the first time the
base-promoted cascade reaction of 1,1-dibromo-1-alkenes with
salicylaldehydes under mild conditions. Several substituted
salicylaldehydes and various aryl-substituted 1,1-dibromo-1-
alkenes were found to be suitable substrates for the tandem
reaction. This work opens up a new approach for the construc-
tion of heteroaromatic coumarins from available starting mate-
rials which show promising potential in biological activities and
pharmaceutical applications. Based on the isolated intermediate
of 4-(diethylamino)-3-phenylchroman-2-one and detailed mecha-
nistic studies, a credible tandem pathway was proposed.
We are grateful for financial support from National Natural
Science Foundation of China (21103044, 21173070, and 21205029),
Project funded by China Postdoctoral Science Foundation,
and Plan for Scientific Innovation Talent of Henan Province
(No. 124200510014).
Scheme 4 Preliminary mechanistic study.
The result showed that no radical species were involved in the tandem
reaction (see ESI† for details). Furthermore, the reaction between 1a
and 2a in the presence of H2O18 afforded the 18O-labeled product 3a
in 20% yield (Scheme 4a), demonstrating that the carbonyl oxygen
atom of coumarin originated from H2O produced by the reaction as
our initial assumption. When 4-hydroxybenzaldehyde was subjected
to be employed under the optimized reaction conditions, N,N-diethyl-
2-phenylacetamide was obtained in 30% yield (Scheme 4b), thus
demonstrating that the aldehyde group was essential for the tandem
reaction. At an early stage (2.0 h) of the reaction of 1a with 2a in DMF
under standard conditions, a large amount (80%) of intermediate
(4-(diethylamino)-3-phenylchroman-2-one) was expectedly detected
along with 3a by LC-MS analysis of the reaction mixture. Once
formed, the intermediate was converted into the desired product
during the progress of the reaction. Fortunately, 4-(diethylamino)-
3-phenylchroman-2-one could be isolated from the mixture, and
the structure was unambiguously confirmed by NMR and LC-MS
(Scheme 4c). The treatment of A under standard conditions
gave 3a in 90% yield (Scheme 4d). These results indicated that
the present reaction proceeded directly involving the formation
of intermediate A.
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