Selective lithiation of bis(furan-2-yl)methane: an efficient protocol for novel meso-functionalised synthons

Article abstract of DOI:10.1016/j.tetlet.2008.08.040

Bis(furan-2-yl)methane can be lithiated at the inter-ring carbon atom (meso-position) to give carbanions, which react with a variety of electrophiles to yield meso-elaborated derivatives in high yield and regioselectivity. This constitutes the first general approach to the title compounds.

Full text of DOI:10.1016/j.tetlet.2008.08.040

Tetrahedron Letters 49 (2008) 6234–6236
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective lithiation of bis(furan-2-yl)methane: an efficient protocol
for novel meso-functionalised synthons
*
Kamaljit Singh , Amit Sharma
Organic Synthesis Laboratory, Department of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Bis(furan-2-yl)methane can be lithiated at the inter-ring carbon atom (meso-position) to give carbanions
which react with a variety of electrophiles to yield meso-elaborated derivatives in high yield and regiose-
lectivity. This constitutes the first general approach to the title compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 June 2008
Revised 7 August 2008
Accepted 11 August 2008
Available online 14 August 2008
Dedicated to Professor Harjit Singh on the
occasion of his 70th birthday
Keywords:
Lithiation
Bis(furan-2-yl)methane
Carbanion
Regioselectivity
meso-Functionalisation
1. Introduction
Recently, these were found to be good substrates for cycloaddition
reactions with oxyallyl cations.11
Functional elaboration of the meso-position of bis(hetero-
cyclyl)methanes poses a challenge in view of non-availability of
methods for obtaining potentially useful meso-elaborated deriva-
tives.1 meso-Elaboration of bis(furan-2-yl)methane 1 has not been
reported, and the available routes for the synthesis of meso-substi-
tuted 1 generally rely on the acid-catalysed condensation of furan
with functionalised aldehydes2–4 or furfuryl alcohol,4 which in
addition to the limitation of their availability, often result in lower
yields of the desired compounds. Further, the separation of 1 from
the complex product mixture is often tedious which is dominated
by the oligomers encompassing up to six furan units.2,4 Alterna-
tively, condensation of (2-furyl)lithium5 with furfuraldehyde, fol-
lowed by NaBH4 reduction also furnishes 1 (R1 = R2 = H).6 Indeed,
a general route to obtain a number of meso-elaborated derivatives
1 has been elusive. Meso-elaboration of 1 is relevant in the context
of natural and unnatural porphyrinoids7,8 using biomimetic routes,
which has led to the synthesis of fundamental porphyrin structural
variants, such as dicationic tetraoxaporphyrins8 as well as other
categories of macrocycles such as calix[n]furans.6 Compounds 1
are also useful as flavouring agents and find industrial application,9
with some derivatives exhibiting interesting biological effects.10
Lithiation of five-membered heterocycles and their derivatives
is well known.12,13 Depending upon the reaction conditions and
the nature of the electrophiles, incorporation of substituents
occurs at a ring or benzylic position or in particular at meso-posi-
tions of bis(azol-1-yl)methanes. Recently, in case of bis(pyrrole-
2-yl)methanes, we reported14 exclusive substitution of the meso-
position. We now report the metallation of bis(furan-2-yl)methane
1 (R1 = R2 = H) with a lithium base, with selective deprotonation of
a meso-hydrogen, generating a carbanion.
2. Results and discussion
The meso-unsubstituted 1 was synthesised through condensa-
tion of furan with formaldehyde in an acid-catalysed reaction,
following conditions of a reported protocol.2 We initially examined
the metallation of 1 with 1.0–1.2 equiv of n-BuLi (À78 °C to 0 °C) in
anhydrous THF or diethyl ether and subsequent quenching with
1.0–2.0 equiv of benzaldehyde. Unreacted 1 (50–60%) along with
polymeric material was obtained after quenching the reaction mix-
ture with a saturated solution of ammonium chloride. Even the use
of near equimolar or excess quantities of the high solvating TMEDA
in combination with n-BuLi (À78 °C to 0 °C) did not improve the
process. Treatment of 1 with n-BuLi (1.2 equiv) in THF in the
presence of excess (1.5 equiv) of diisopropylamine (0 °C), which
* Corresponding author. Tel.: +91 1832258853; fax: +91 1832258819/20.
E-mail address: kamaljit19in@yahoo.co.in (K. Singh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.040

K. Singh, A. Sharma / Tetrahedron Letters 49 (2008) 6234–6236
6235
Table 1
allowed successful metallation of the central methyl carbon in
tris(2-thienyl)methane,15 failed to metallate the meso-carbon of
1. Even LDA (1.2 equiv) showed no reaction with 1. To determine
the optimal conditions for metallation at the meso-position, we
sought to employ THF–DMSO as solvent with the hope of generat-
ing a more basic methylsulfinylmethyl (dimsyl) anion,16 which
being ‘soft’ should effect metallation of the relatively ‘soft’ meso-
carbon of 1 as compared to the comparatively ‘hard’ C-5 position,
as previous literature results suggest. Additionally, a comparison
of the pKa values of carbon acids: diphenylmethane (pKa = 32.2),
2-benzylfuran (pKa = 30.2) suggested that the meso-methylene of
1 should be more acidic (pKa < 30.2) than C-5 position (pKa of fur-
an = 35).17,18 Thus, 1 was expected to be metallated at the more
acidic and ‘soft’ meso-position by the ‘soft’ dimsyl anion, generated
in situ by the reaction of n-BuLi and DMSO (pKa = 35), with the
excess DMSO assisting in dispersing anion aggregates.19 Moreover,
the meso-position in 1 may draw activation for deprotonation as
depicted in Figure 1. On the other hand, this type of activation shall
impede the deprotonation and subsequent substitution of the
furan (C-5) position, imparting regioselectivity to the process in
favour of meso-substitution. The failure of the non-coordinative
LDA to deprotonate either the meso- or C-5 positions further sup-
ports this hypothesis.
Synthesis of meso-substituted bis(furan-2-yl)methane 3/4
Entry
Substrate 1/2
Electrophile
Product 3
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
PhCHO
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
4a
4b
72
65
70
65
72
45
40
65b
56b
83b
69
51
30
68
70
4-Cl-C6H4CHO
3,4-(MeO)2-C6H3CHO
b-C10H7CHO
MeCOMe
PhCOMe
2-Acetylthiophene
EtBr
n-PrBr
n-BuBr
PhCH2Br
PhNCO
PhNCS
PhCHO
3,4-(MeO)2-C6H3CHO
a
Isolated purified (column chromatography: silica gel 60–120 mesh, ethyl
acetate/hexane as eluents) yields.
b
Based on 1H NMR (ureacted 1 in 3h:35%; 3i:44%; 3j:17%).
dehyde), ketones (acetone, acetophenone and 2-acetylthiophene),
alkyl halides (ethyl bromide, n-propyl bromide, n-butyl bromide
and benzyl bromide), isocyanates and isothiocyanates to furnish
the corresponding meso-elaborated products. In the reactions of
alkyl halides the isolation of the corresponding products 3h–j
(Table 1) was tedious owing to their low polarity and matching
Rf (TLC) with the starting 1 and the isolated products were often
accompanied by the starting 1, as revealed from the 1H NMR spec-
tra of the ‘purified’ compounds obtained after column chromatog-
raphy. In none of these reactions was the ring (C-5)-substituted
product detected by 1H NMR inspection of the crude reaction prod-
ucts. Only when the meso-position of 1 was blocked as dimethyl
derivative 2, does the lithiation-substitution occur at the C-5 posi-
tion. Thus, deprotonation of 2 using n-BuLi (1.2 equiv) at À78 °C in
anhydrous THF furnished a red coloured carbanion solution, which
upon trapping with benzaldehyde and subsequent reaction with
iodomethane furnished C-5 substituted ether 4a in 68% isolated
yield. Likewise, reaction of anion of 2 with 3,4-dimethoxybenzal-
dehyde followed by protection with iodomethane furnished corre-
sponding product 4b in 70% yield.
The following examples demonstrate the successful and occa-
sionally nearly quantitative trapping of the meso-anionic species
with a variety of electrophiles (Table 1).
Typically, treatment of 1 (Scheme 1) with 1.2 equiv of freshly
prepared n-BuLi (2.1 N in hexane) in anhydrous THF/DMSO (7:3,
v/v) solution at 0 °C (15 min), under a blanket of dry nitrogen
gas, followed by stirring at ambient temperature for 15 min fur-
nishes a turbid reddish brown anion solution. Addition of 1.5 equiv
of benzaldehyde dissolved in THF (10 ml) at 0 °C, followed by
stirring and monitoring the progress of the reaction (TLC),
and quenching by saturated NH4Cl solution furnished the meso-
substituted product 3a in 72% yield, after chromatographic
purification.
The synthesis of various meso-substituted bis(furan-2-yl)meth-
anes 3 is summarised in Table 1. The reactions proceeded smoothly
with a range of electrophiles such as aldehydes (benzaldehyde, 4-
chlorobenzaldehyde, 3,4-dimethoxybenzaldehyde and b-naphthal-
All compounds were fully characterised by NMR (1H and 13C)
spectroscopy, mass spectrometry and microanalytical analysis
(selected data are presented).
O
H
CH2
H
In summary, we have shown that the meso-position of the bis-
(furan-2-yl)methane 1 can be elaborated using a metallation-sub-
stitution sequence. The methodology is simple and furnishes the
products in good to high yields. The meso-elaboration of 1 has
not been reported earlier,20 so our approach provides a route to
O S
Li
Me
O
Figure 1. Proposed transition state in deprotonation of the meso-position of 1.
R1 R2
R3
O
H
Me Me
iii, iv, v
i, ii
O
O
O
O
O
R4
4a: R4 = C(OMe)HPh
4b: R4 = C(OMe)H-3,4-(MeO)2-C6H3
3a: R3 = PhCH(OH); 3b: R3 = 4-ClC6H4CH(OH)
3c: R3 = 3,4-(MeO)2-C6H3CH(OH);
1 : R1 = R2 = H
2 : R1 = R2 = Me
3d: R3 = β-C10H7CH(OH);
3e: R3 = MeCMe(OH); 3f: R3 = PhCMe(OH);
3g: R3 = (2-thienyl)CMe(OH); 3h: R3 = Et;
3i: R3
= =
n-Pr; 3j: R3 n-Bu; 3k: R3 = CH2Ph;
3l: R3 = CONHPh; 3m: R3 = CSNHPh;
Scheme 1. Synthesis of meso-substituted bis(furan-2-yl)methanes. Reagents and conditions: (i) n-BuLi (1.2 equiv), THF/DMSO (7:3 v/v), 0 °C; (ii) electrophile (1.5 equiv),
NH4Cl quenching; (iii) n-BuLi (1.2 equiv), THF, À78 °C; (iv) electrophile (1.5 equiv) (v) KOBut (1.2 equiv), MeI (1.5 equiv), NH4Cl quenching.

6236
K. Singh, A. Sharma / Tetrahedron Letters 49 (2008) 6234–6236
otherwise inaccessible meso-elaborated derivatives 3 with the pos-
sibility of further transformations at the newly incorporated meso-
substituent.
160.19 ppm. Anal. Calcd for C19H20O3: C, 77.00; H, 6.80. Found C,
76.85; H, 6.90. MS: m/z, 319.2 (M++23).
Acknowledgements
3. Selected data
We are thankful to CSIR, New Delhi, for the project 01(1960)/
04/EMR-II and a senior research fellowship (F. No. 9/254(160)/
2005-EMR-1) to A.S.
Compound 3a: Yellow oil. Rf: 0.27 (10% ethyl acetate/hexane). 1H
NMR (300 MHz, CDCl3): d 2.44 (s, 1H, OH, exchanged with D2O),
4.41 (d, 1H, J = 7.2 Hz), 5.28 (d, 1H, J = 7.2 Hz), 6.11 (m, 1H), 6.22
(m, 1H), 6.29 (m, 1H), 6.35 (m, 1H), 7.24 (m, 5H), 7.22 (m, 1H),
7.40 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d 47.76, 107.72,
108.21, 110.26, 110.45, 126.11, 127.70, 128.04, 141.58, 142.01,
151.82 ppm. Anal. Calcd for C16H14O3: C, 75.57; H, 5.55. Found C,
75.32; H, 5.24. MS: m/z, 276.8 (M++23).
Compound 3e: Viscous oil. Rf: 0.36 (10% ethyl acetate/hexane).
1H NMR (300 MHz, CDCl3): d 1.21 (s, 6H), 1.61 (s, 1H, OH, ex-
changed with D2O), 4.19 (s, 1H), 6.26 (m, 2H), 6.34 (m, 2H), 7.38
(m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d 27.66, 50.43, 108.23,
110.33, 141.60, 152.60 ppm. Anal. Calcd for C12H14O3: C, 69.88;
H, 6.84. Found C, 69.62; H, 6.64. MS: m/z, 228.8 (M++23).
Compound 3l: White solid. Rf: 0.25 (15% ethyl acetate/hexane).
Mp 78–80 °C (DCM/hexane); 1H NMR (300 MHz, CDCl3): d 5.17
(s, 1H), 6.39 (m, 4H), 7.11 (m, 1H), 7.27 (m, 1H), 7.30 (m, 3H),
7.48 (m, 2H), 7.53 (s, 1H, NH, exchanged with D2O) ppm. 13C
NMR (75 MHz, CDCl3): d 48.43, 108.93, 110.87, 119.80, 124.65,
128.97, 142.86, 149.23 ppm. Anal. Calcd for C16H13NO3: C, 71.90;
H, 4.90; N, 5.24. Found C, 71.65; H, 4.74; N, 5.35. MS: m/z, 289.8
(M++23).
References and notes
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Compound 4a: Yellow viscous oil. Rf: 0.70 (10% ethyl acetate/
hexane). 1H NMR (300 MHz, CDCl3): d 1.61 (s, 6H), 3.55 (s, 3H),
5.21 (s, 1H), 5.89 (m, 1H), 5.96–5.97 (m, 2H), 6.24–6.25 (m, 2H),
7.22–7.38 (m, 6H) ppm. 13C NMR (75 MHz, CDCl3): d 26.29,
26.40, 37.52, 56.90, 78.90, 104.16, 104.74, 109.13, 109.96, 126.75,
127.24, 127.87, 128.32, 139.34, 141.13, 153.03, 159.97,
16. Corey, E. J.; Chaykovsky, M. J. Org. Chem. 1965, 87, 1345.
17. Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63, 1568.
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Am. Chem. Soc. 1975, 97, 3226.
19. Kingsbury, C. A. J. Org. Chem. 1964, 29, 3262.
20. A single example of incorporation of a trimethylsilyl substituent at the meso-
position employed t-BuLi as base.6