Lewis acid promoted C-C and copper-catalyzed C-O bond formation: Synthesis of neoflavans

Article abstract of DOI:10.1039/c4ra00048j

An intramolecular [Cu]-catalyzed C-O bond formation for the synthesis of neoflavans is presented. Lewis acid promoted Friedel-Crafts Michael addition of electron rich aromatic systems onto the double bond of the cinnamate ester was employed to furnish a β-diaryl ester. Electrophilic aromatic bromination of the β-diaryl ester and reduction/Grignard addition furnished the required precursor alcohols. The method is applicable to the synthesis of neoflavans containing tertiary as well as quaternary carbon centers. Significantly, the neoflavan substructures are present in biologically active compounds.

Full text of DOI:10.1039/c4ra00048j

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Lewis acid promoted C–C and copper-catalyzed
C–O bond formation: synthesis of neoflavans†
Cite this: RSC Adv., 2014, 4, 13941
*
B. Suchand, J. Krishna, K. Mritunjoy and G. Satyanarayana
Received 3rd January 2014
Accepted 30th January 2014
DOI: 10.1039/c4ra00048j
www.rsc.org/advances
An intramolecular [Cu]-catalyzed C–O bond formation for the and cyclization of 1-naphthol and a,b-unsaturated aldehydes.10c
synthesis of neoflavans is presented. Lewis acid promoted Friedel– Benzopyrans were produced by Pettus and co-workers using
Crafts Michael addition of electron rich aromatic systems onto the enantioselective [4 + 2] cycloaddition between ortho-quinone
double bond of the cinnamate ester was employed to furnish a b-diaryl methides (o-QM) and enol ethers.10f The research group of
ester. Electrophilic aromatic bromination of the b-diaryl ester and Sames et al. developed new method for the construction of the
reduction/Grignard addition furnished the required precursor alco- chromene core by means of Pt(IV)-catalyzed intramolecular
hols. The method is applicable to the synthesis of neoflavans con- hydroarylation of arene–alkyne substrates.10g The research
taining tertiary as well as quaternary carbon centers. Significantly, the group of Tunge disclosed a three-step stereoselective reduction
neoflavan substructures are present in biologically active compounds. as the key step for the synthesis of diarylchromans from
phenols and cinnamic acid.10h To the best of our knowledge,
thus far there is no report on the synthesis of neoavans pos-
sessing a quaternary C-4 carbon atom.
In continuation of our research interest in transition-metal
catalysis,11 recently we have disclosed an efficient three-
Introduction
The
neoavans
(4-aryl-3,4-dihydro-2H-chromenes)
or
step strategy for the synthesis of avans and benzoxepines
by employing [Pd]-catalyzed C–C and [Cu]-catalyzed C–O
substituted chromans are ubiquitous substructures present in
biologically active natural compounds.1–3 For example, the
Dalbergia plant species are used in traditional Chinese medi-
cine for curing inammation, blood disorders and ischemia.4
Similarly, the simple neoavene dalbergichromene, isolated
from the stembark of Dalbergia species,5,6 shows medicinal
activity. Also, the chroman natural product centchroman
exhibits antifertility properties as an estrogen antagonist, which
was isolated from the methanolic extracts of A. indicum.7 In
addition, 3-hydroxy-4-arylchroman is also observed as
a
substructure in 4-arylavan-3-ol, isolated from the South
African plant Nelia meyeri.8 Further, the avonoid myristinin A
possessing the 4-arylchroman part structure is a potent poly-
merase beta inhibitor (Fig. 1).9
Owing to the interesting structural features and important
biological properties of neoavans/avenes, there are a number
of reports towards their synthesis.10 Notably, Wang
et al.reported enantioselective synthesis of chromans and
dihydrobenzopyrans by employing Friedel–Cras alkylation
Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Ordnance
Factory Estate Campus, Yeddumailaram - 502 205, Medak District, Andhra Pradesh,
India. E-mail: gvsatya@iith.ac.in; Fax: +91 40 2301 6032; Tel: +91 40 2301 6054
† Electronic supplementary information (ESI) available: See DOI:
10.1039/C4RA00048J/
Fig.
1 Representative examples of naturally occurring neoflavan
natural products containing neoflavan scaffolds.
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bond-forming reactions as the key steps.12 Herein, we present
a practical method for the synthesis of neoavans, wherein
Lewis acid (FeCl3) promoted Friedel–Cras Michael addition
and an intramolecular [Cu]-catalyzed Buchwald–Hartwig
coupling reaction are the key transformations involved in the
strategy.
Results and discussion
We envisioned that the substituted neoavans 5 and 7 can be
obtained by a key [Cu]-mediated intramolecular Buchwald–
Hartwig C–O bond formation between aryl bromide and
hydroxy (primary/tertiary) functionality of 4 and 6 respectively.
The required primary/tertiary alcohols 4 and 6 were produced
from the corresponding esters, which were in turn accessed by
Scheme 1 Retrosynthetic plan for flavans 5 and 7 from cinnamates 1.
Table 1 Synthesis of primary alcohols 4a–4f starting from cinnamates 1a–1e via b-diaryl esters 2a–2f and bromo-esters 3a–3fa
a
Isolated yields of chromatographically pure products.
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Table 2 [Cu]-catalyzed synthesis of neoflavans 5a–5f from primary Table 3 Synthesis of tertiary alcohols 6am–6fe from bromo-esters
alcohols 4a–4fa,b
3a–3f using alkyl Grignard reactiona,b,c
a
b
Isolated yields of chromatographically pure products. Reaction was
carried out on alcohols 4a–4f (0.30 mmol) in DMF (3 mL).
a
Isolated yields of chromatographically pure products. b The rst letter
(a–f) for compounds 6indicates the starting material, while the second
c
letter (m or e) refers to methyl or ethyl groups, respectively. 8 equiv.
of alkyl Grignard reagent was used.
employing Lewis acid (FeCl3) induced controlled Friedel–Cras
alkylation (Michael addition type) of an electron rich external
arene on ethyl cinnamates 1 followed by preferential electro-
philic bromination of the electron rich aromatic ring particu- bromination was not selective and gave a mixture of bromi-
larly at the ortho-position to the ester tether (Scheme 1). It is nated products. Next, reduction of the ester function was
worth mentioning that the controlled Friedel–Cras alkylation required to provide the corresponding alcohols for the planned
was observed, particularly, by the Lewis acid (FeCl3) in our metal mediated cyclization. The esters 3a–3f were reduced with
previous study, which formed the basic foundation for this LiAlH4, and the precursor primary alcohols 4a–4f yielded in
work.13
near quantitative yields, in a controlled manner without
The synthetic study began with the controlled Friedel–Cras affecting the bromo-substituent (Table 1).
alkylation (i.e. the reaction impeded aer Friedel–Cras
With the precursor alcohols 4 in hand, the key transition
Michael addition without allowing it to proceed to subsequent metal catalyzed intramolecular C–O bond formation was
intramolecular acylation) of ethyl cinnamates 1 with electron explored. In this regard, we employed the same reaction
rich aromatic systems such as 1,2-dimethoxybenzene or 1,2,3- conditions [CuI (20 mol%)/2,2-bipyridyl (20 mol%), base KOtBu
trimethoxybenzene. Thus, treatment of simple as well as b-alkyl (3 equiv.) in hot DMF (120 ꢀC) for 24 h] which were successful in
substituted ethyl cinnamates 1 with the external arene in the our previous reports for the synthesis of avans.12 As expected,
presence of Lewis acid (FeCl3, 3 equiv.), at ambient tempera- the reaction was quite successful and furnished the neoavan
ture, furnished the b-arylated esters 2a–2f, containing tertiary/ 5a in very good yield.
quaternary carbon atom, in fair to very good yields (Table 1).13 It
Since the above [Cu]-catalyzed C–O bond forming reaction
is worth mentioning that the use of DCE as a medium was conditions were successful for the construction of neoavan 5a
found to be more general than CH2Cl2 in order to give good (Table 2), these conditions were applied to the other alcohols
yields of the products 2. However, the same Friedel–Cras 4b–4f as well. Agreeably, these conditions were found to be
Michael addition either with external arene on 2-bromocinna- versatile and gave the cyclized neoavans 5b–5f (Table 2) pos-
mate or with external bromoarene on simple cinnamate failed sessing tertiary and quaternary C-4 carbon centers, in very good
to furnish the corresponding product.14 Preferential bromina- yields.
tion of the electron rich aromatic ring under the standard
Aer successful synthesis of various neoavan derivatives
electrophilic bromination conditions, provided the esters 3a–3f 5a–5f with varied functionalities on either aromatic ring start-
in excellent yields as shown in Table 1. It is worth mentioning ing from primary alcohol precursors 4a–4f, to check the scope
that when both the aromatic rings were electron rich, the and limitations of the method, we turned our attention to the
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Table 4 [Cu]-catalyzed synthesis of neoflavans 7am–7fe from tertiary
alcohols 6am–6fea,b
acknowledged. J. K. thanks CSIR, New Delhi, for the award of a
research fellowship.
Notes and references
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esters 3 with Grignard reagents furnished the corresponding
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Finally, the key intramolecular C–O bond formation cata-
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as well and generated the cyclized neoavans, 7am–7fe, in very
good yields (Table 4).
Conclusions
In summary, we have developed a simple and practically
applicable four-step strategy for the synthesis of functionalized
neoavans. Intermolecular Friedel–Cras alkylation (C–C bond
formation) and intramolecular [Cu]-catalyzed C–O bond
formation were applied as key steps of the strategy. The strategy
is efficient and amenable to the synthesis of neoavans con-
taining tertiary as well quaternary carbon centers.
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Acknowledgements
Financial support by the Department of Science and Technology
[(DST), CHE/2010-11/006/DST/GSN], New Delhi is gratefully
13944 | RSC Adv., 2014, 4, 13941–13945
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