A defunctionalization concept for the convenient synthesis of bis(5-arylfuran-2-yl)methane scaffolds

Article abstract of DOI:10.1002/ejoc.201301319

The bis(5-arylfuran-2-yl)methane framework has been obtained through defunctionalization of aryl ketones, derived from abundantly available L-(+)-tartaric acid, under the influence of acid. The stereocomponents present in these starting aryl ketones have been found to be insignificant for this transformation. Formation of bis(5-arylfuran-2-yl)methane scaffold 1 has been achieved by using a defunctionalization concept involving aryl ketones 2 under the influence of acid. Ketones 2 are easily accessible from L-(+)-tartaric acid through an umpolung strategy using α-amino nitriles as acyl anion equivalents. The stereocomponent (threo/erythro) present in 2 was not significant for this transformation. Copyright

Full text of DOI:10.1002/ejoc.201301319

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301319
A Defunctionalization Concept for the Convenient Synthesis of Bis(5-arylfuran-
2-yl)methane Scaffolds
Praveen Kumar Tiwari,[a] Tufan Mukhopadhyay,[a] and Indrapal Singh Aidhen*[a]
Keywords: Alkylation / Biomass / Oxygen heterocycles / Carbocations / Dimerization / Ketones
The bis(5-arylfuran-2-yl)methane framework has been ob-
tained through defunctionalization of aryl ketones, derived
from abundantly available L-(+)-tartaric acid, under the influ-
ence of acid. The stereocomponents present in these starting
aryl ketones have been found to be insignificant for this
transformation.
polymer manufacturing.[4d] In this context, an ambitious
defunctionalization scheme entailing the use of tartaric acid
and/or erythritol from nature’s biomass was envisaged for
the synthesis of bis(furyl)methanes 2 in particular. The ob-
jective necessitated assembling architecture 3, before em-
barking upon exhaustive defunctionalization. The four-car-
bon fragment, C2–C5 in the general structure 3 was visual-
ized to originate from erythritol or tartaric acid as renew-
able materials (Figure 1). The work presented in this paper
provides proof of concept for this objective.
Introduction
The use of biomass as renewable feedstock for the pro-
duction of valuable chemicals is one of the most ambitious
projects around the world.[1] Defunctionalization of carbo-
hydrates, in particular, has been most attractive.[2] Difuryl-
methanes 1a or aryl(furyl)methanes 1b[3] have attracted the
attention of synthetic organic chemists due to their indus-
trial importance.[4] Such compounds have been identified in
licorice flavors,[4a] coffee volatiles,[4b] convenient precursors
in the synthesis of various condensed heterocyclic sys-
tems[4c] and as monomers and cross-linking reagents in
Results and Discussion
Presuming the intrinsic stereocomponent originating
from the starting material is inconsequential during de-
functionalization and generation of the target bis(5-aryl-
furan-2-yl)methane derivatives 2, the synthesis of 4a as an
equivalent and representative of general structure 3 was
planned. Because the two hydroxy groups in l- or d-tartaric
acid are equivalent due to C2-symmetry, we chose to use
the known threitol derivative 5, which can be easily ob-
tained from abundant l-(+)-tartaric acid[5] in a few steps,
as a convenient building block for the synthesis of 4a
(Scheme 1).
Figure 1. Hydroxylated architecture 3 from tartaric acid or erythrit-
ol for defunctionalization.
Scheme 1. Synthesis of bromide 6 via 5 from l-(+)-tartaric acid.
(a) Triphenylphosphine (PPh3), N-bromosuccinimide (NBS), N,N-
dimethylformamide (DMF), 60 °C, 2.5 h, 83%.
[a] Department of Chemistry, Indian Institute of Technology
Madras
Chennai 600036, India
E-mail: isingh@iitm.ac.in
The incorporation of the arylacyl residue was envisaged
through the use of α-amino nitrile as an acyl anion equiva-
lent.[6] The α-amino nitrile 7, which is an example of an
http://chem.iitm.ac.in/professordetails/profsingh/index.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301319.
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8083

P. K. Tiwari, T. Mukhopadhyay, I. S. Aidhen
SHORT COMMUNICATION
arylacyl anion precursor, underwent clean alkylation with gested the isolated product was bis[5-(4-chlorophenyl)-
bromide 6 to afford the alkylated products 8 as diastereo- furan-2-yl]methane (2a). X-ray diffraction studies on the
isomeric mixtures in 80–85% yield (Scheme 2). The pro- crystal finally confirmed the structure of 2a (Figure 2).
gress of the reaction could be easily monitored by the grad-
ual decrease of the deep-yellow color of the carbanion after
addition of the electrophile. The alkylated diastereoisomeric
mixture of 8a was directly subjected to hydrolysis using
CuSO4·5H2O in aqueous methanol at 60 °C.[7] Clean un-
masking of the oxo functionality occurred, furnishing the
desired aryl ketone 4a in 76% yield. The reaction sequence
afforded the other threo-configured aryl ketones 4b–f with
1
equal ease and in good yields (Table 1). The H and 13C
NMR spectra for aryl ketone 4 were recorded in [D6]-
DMSO.
Figure 2. ORTEP diagram of 2a.
The formation of 2a is a result of dimerization of the
initially formed furan derivative 9a via a highly stable benz-
ylic carbocation intermediate and concomitant loss of a
formaldehyde molecule (Scheme 3). The transformation
was independently effected with the use of 15 equiv. of tri-
fluoroacetic acid (TFA) in aqueous tetrahydrofuran (THF)
(THF/H2O, 3:1) at 40–45 °C in 3–4 h.
Scheme 2. Synthesis of threo-configured aryl ketones 4 through alk-
ylation of α-amino nitriles 7 with bromide 6 and subsequent direct
hydrolysis of the alkylated products 8.
Table 1. Synthesis of threo-configured aryl ketones 4 through alkyl-
ation of α-amino nitriles 7.
Entry
Ar
Aryl ketone 4
Yield [%][a]
1
2
3
4
5
6
4-chlorophenyl
4-methylphenyl
phenyl
3,4-dichlorophenyl
4-fluorophenyl
4-methoxyphenyl
4a
4b
4c
4d
4e
4f
76
71
80
81
63
66
[a] Isolated yield.
The anticipated potential of architecture 3 towards de-
functionalization and transformation into substituted furan
derivatives was clearly revealed during our attempts to re-
cord the H NMR spectrum of aryl ketone 4a in CDCl3.
Apparently, the trace acidity and the moisture content of
Scheme 3. Aryl ketone 4a cascade reaction to bis(5-arylfuran-2-yl)
methane on exposure to acid. (a) Traces of aqueous protic acid,
slow conversion to 2a through 9a; (b) CF3COOH, THF/H2O (3:1),
40–45 °C, 3–4 h.
1
CDCl3 were sufficient to induce hydrolysis of the isoprop-
The generality of the acid-promoted defunctionalization
ylidene ketal protection in 4a and subsequent annulation. was demonstrated when other aryl ketones 4b–f underwent
Isolation and purification of the newly formed compound equally facile transformation into the corresponding bis(5-
in CDCl3 solution of 4a was indeed found to be a furan arylfuran-2-yl)methanes 2b–f under the same reaction con-
derivative, as evident from two prominent doublet signals ditions (Table 2).
1
[δ = 6.21 (J = 3. 2 Hz), 6.57 (J = 3.2 Hz) ppm] in the H
The successful cascade of threo-configured aryl ketones
NMR spectrum corresponding to the unsubstituted posi- 4 to bis(5-arylfuran-2-yl)methane derivatives 2 under the
tions in the furan ring. A sharp singlet (δH = 4.12 ppm) acidic conditions validated the original proposal of synthe-
correlating with an upfield carbon signal (δC = 27.9 ppm) sizing 2 through exhaustive defunctionalization of biomass
in the HSQC spectrum (see the Supporting Information) material. To address the presumed insignificance of the ste-
and a careful analysis of the integration values indeed sug- reocomponent of the starting ketones 4, erythro-configured
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Eur. J. Org. Chem. 2013, 8083–8086

Synthesis of Bis(5-arylfuran-2-yl)methane Scaffolds
Table 2. Bis(5-arylfuran-2-yl)methanes 2 from threo-configured aryl tion studies.[12] As expected, compound 9a, prepared by an
alternative route,[13] converged to product 2a under the
ketones 4, respectively.
Yield [%][a]
same reaction conditions.
Entry
Bis(5-arylfuran-2-yl)methane 2
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
63
74
71
55
65
75
Conclusions
Bis(5-arylfuran-2-yl)methane compounds have been suc-
cessfully obtained through defunctionalization of readily
accessed derivatives from abundantly available l-(+)-tar-
taric acid as renewable biomass. With the advent of solid
acid catalysis,[14] the acid-promoted defunctionalization dis-
closed herein should be of great value for the industrial pro-
duction of bis(5-arylfuran-2-yl)methane frameworks.
[a] Isolated yield.
aryl ketones 12 were synthesized by using the same strategy
described for the threo-configured aryl ketones 4. Although
enantiopure erythritol derivative 10[8–11] was used for the
synthesis of 12 via bromide 11, this is certainly not required.
To our delight, erythro-configured aryl ketones 12 under-
went equally facile conversion into bis(5-arylfuran-2-yl)-
methanes 2 (Scheme 4), thereby demonstrating the insignifi-
cance of the stereocomponent in the starting aryl ketones
and confirming the importance of functional architecture
for defunctionalization and convergence to bis(5-arylfuran-
2-yl)methane scaffold 2 (Table 3).
Experimental Section
General Procedure for the Preparation of (S)-4-[(R)-1-(Benzyloxy)-
2-bromoethyl]-2,2-dimethyl-1,3-dioxolane (6):[10] To a solution of 5[5]
(0.87 g, 3.43 mmol) in anhydrous DMF (8 mL), solid PPh3 (2.25 g,
8.58 mmol) and NBS (1.53 g, 8.58 mmol) were added (addition of
NBS was exothermic) under nitrogen. The reaction mixture was
heated at 60 °C with constant stirring under an inert gas for 2.5 h
(the progress of the reaction was monitored by TLC). Upon total
consumption of reactant, the mixture was cooled to room tempera-
ture, water was added, and the mixture was extracted with ethyl
acetate (3ϫ 10 mL). The combined organic layers were washed
with water (10 mL), dried with anhydrous Na2SO4, and concen-
trated under reduced pressure to give a solid crude residue, which
was further purified by silica gel column chromatography to give 6
(0.89 g, 83%) as a colorless liquid.
General Procedure for the Preparation of threo-Configured Aryl
Ketones: To a suspension of NaH (94 mg, 2.35 mmol) in DMF
(2 mL), a solution of previously azeotropically (toluene, 3ϫ 3 mL)
dried α-amino nitrile 7a (464 mg, 1.96 mmol) in DMF (4 mL) was
added dropwise at 0 °C under nitrogen. The mixture was stirred for
30 min, then a solution of 6 (614 mg, 1.96 mmol) in DMF (2 mL)
was added slowly at 0 °C. The reaction mixture was stirred at room
temperature for 4 h (TLC analysis revealed the formation of a dia-
stereomeric mixture of alkylated product 8a). Finally, the reaction
was quenched by the addition of a saturated aqueous solution of
NH4Cl and extracted with ethyl acetate. The organic layer was
washed with water (4ϫ 5 mL), dried with anhydrous Na2SO4, and
the solvent was evaporated under reduced pressure followed by
flash chromatography with silica gel. The diastereomeric mixture
of alkylated product 8a (560 mg, 1.19 mmol) was subjected to hy-
drolysis with CuSO4·5H2O (1.2 g, 4.80 mmol) dissolved in MeOH/
H2O (6 mL, 3:1) at 60 °C for 2 h. Upon completion of the reaction,
the reaction mixture was concentrated under reduced pressure, and
the organic compound was extracted with ethyl acetate (3ϫ 5 mL).
The organic layer was dried with anhydrous Na2SO4, and the sol-
vent was evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography (ethyl acetate/
hexanes) to give 4a (339 mg, 76%) as a colorless liquid.
Scheme 4. Synthetic route for bis(5-arylfuran-2-yl)methanes 2 from
erythritol 10.
Table 3. Bis(5-arylfuran-2-yl)methanes 2 from d-erythro-configured
aryl ketones 12.
Entry
12
Yield [%][a]
2
Yield [%][a]
1
2
3
4
5
12a
12b
12c
12d
12e
68
63
67
61
66
2a
2b
2c
2d
2e
65
67
66
60
64
[a] Isolated yield.
The proposed intermediacy of 9a during the formation
of bis(5-arylfuran-2-yl)methane derivatives 2 from both the
erythro- and threo-configured aryl ketones 4 and 12, respec-
tively, under acidic conditions, was unequivocally estab-
lished by its isolation when the reaction was quenched be-
fore reaching completion. Thus, the deacetalization reaction
of 4a, using trifluoroacetic acid in THF/H2O (3:1) at 40–
45 °C, was quenched after 1.5 h (before its convergence to
the final product 2a) to furnish the proposed intermediate
9a in 47% yield together with product 2a in 10% yield.
General Procedure for the Preparation of Bis(5-arylfuran-2-yl)meth-
ane 2 from threo-Configured Aryl Ketone 4 and erythro-Configured
Aryl Ketone 12: Aryl ketone 4a (298 mg, 0.79 mmol) was dissolved
in THF/H2O (3:1; 4 mL) followed by TFA (11.9 mmol), and the
reaction mixture was stirred at 40–45 °C. Upon complete consump-
tion of starting material (reaction monitored by TLC), the mixture
Intermediate 9a was isolated from reaction mixture and
fully characterized by H and 13C NMR and X-ray diffrac- was concentrated under vacuum to dryness. Saturated aqueous
1
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P. K. Tiwari, T. Mukhopadhyay, I. S. Aidhen
SHORT COMMUNICATION
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ethyl acetate (3ϫ 5 mL). The organic layer was dried with anhy-
drous Na2SO4 and concentrated to give a crude mass, which was
purified by silica gel column chromatography (ethyl acetate/hex-
anes) to obtain 2a (94 mg, 63%) as a colorless crystalline com-
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X-ray Crystallography: CCDC-915971 (2a), -915970 (2b), -915972
(2c), and -915969 (9a) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental details, copies of the H and 13C NMR spectra,
HRMS of all key intermediates and final products, X-ray crystal
data for compounds 2a–c and 9a.
Acknowledgments
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We thank the Department of Science and Technology (DST) New
Delhi for funding towards the 400 MHz NMR spectrometer, the
Department of Chemistry, Indian Institute of Technology Madras
(IIT Madras) under the Intensification of Research in High Priority
Areas (IRPHA) Scheme and ESI-MS facility under the Fund for
Improvement of Science & Technology Infrastructure (FIST) pro-
gram. The Board of Research in Nuclear Science (BRNS) is ac-
knowledged for funding of project 2008/37/BRNS. P. K. T. is
thankful to the Council of Scientific and Industrial Research
(CSIR)/University Grants Commission (UGC) New Delhi for a
Junior Research Fellowship. The authors thank Mr. V. Ramkumar
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[12] Compound 9a: Yield: 20 mg (47%); colorless crystalline solid;
m.p. 80–82 °C; Rf = 0.2 (hexane/EtOAc, 9:1). 1H NMR
(400 MHz, CDCl3): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.34 (d, J =
8.8 Hz, 2 H), 6.58 (d, J = 3.2 Hz, 1 H), 6.38 (d, J = 3.2 Hz,
1 H), 4.66 (s, 2 H), 1.65 (br. s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 154.0 (ArC), 153.1 (ArC), 133.2 (ArC), 129.2
(ArC), 129.0 (ArCH), 125.1 (ArCH), 110.2 (ArCH, furan),
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Published Online: November 19, 2013
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