Taming furfuryl cations for the synthesis of privileged structures and novel scaffolds

Article abstract of DOI:10.1039/c3ob40814k

Furfuryl cations are generated via a highly efficient bismuth-catalyzed reaction of furfuryl alcohols. This systematic study provides insight on the reactivity profile of furfuryl cations towards nucleophilic substitution reactions. Novel C-C, C-N, C-O and C-S bond forming reactions of furfuryl cations have been developed, thus providing access to a diverse array of building blocks for further manipulations. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40814k

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Taming furfuryl cations for the synthesis of privileged
structures and novel scaffolds†‡
Cite this: Org. Biomol. Chem., 2013, 11, 4299
Received 23rd April 2013,
Accepted 17th May 2013
Seema Dhiman and S. S. V. Ramasastry*
DOI: 10.1039/c3ob40814k
www.rsc.org/obc
Furfuryl cations are generated via a highly efficient bismuth-cata-
lyzed reaction of furfuryl alcohols. This systematic study provides
insight on the reactivity profile of furfuryl cations towards nucleo-
philic substitution reactions. Novel C–C, C–N, C–O and C–S bond
forming reactions of furfuryl cations have been developed, thus
providing access to a diverse array of building blocks for further
manipulations.
Fig. 1 General representation of Achmatowicz and Piancatelli rearrangement
reactions.
Furans are among the most extensively studied heterocyclic
systems and are an important class of compounds that exhibit
unique chemical reactivity patterns and significant biological
activity profiles.1 Many furan (and thiophene) derivatives are
found to possess phytocidal, antibacterial, antiviral, herbici-
dal, insecticidal and antioxidant activities,1e and exhibit
pharmacological properties that include serving as anti-
depressant and anti-inflammatory agents.1f Furanoid skeletons
are important components of many bioactive natural products
as well as primary structural motifs in several pharmaceuticals,
molecular electronics and functional polymers.2 Furan,
tetrahydrofuran and especially benzofuran (coumarone)
cores have been recognized as privileged structures in drug
discovery.3
Advantages of furan-based strategies for synthesis are the
ready availability of starting materials, ease of manipulation,
and high degree of synthetic flexibility. Among furan based
synthons, furyl alcohols occupy the distinction of generating
some of the most sought-after cores in organic synthesis; the
Achmatowicz4a,b and Piancatelli rearrangements4c are classic
examples where furfurylcarbinols are oxidatively converted to
functionalized pyrans and under acidic conditions to hydroxy
cyclopentenones, respectively, Fig. 1.
Though furfuryl cations are well-known reactive intermedi-
ates in organic synthesis, to our surprise, we realized that only
a handful of reports actually deal with the generation of fur-
furyl cations from the respective furfuryl alcohol precursors and
subsequent elaborations.5 With a growing emphasis on ‘green
chemistry’,6 direct nucleophilic substitution of the hydroxyl
group in an alcohol could be considered as an ideal strategy as
water is the only by-product. Another ‘green’ advantage of
employing such strategy would be the avoidance of organo-
metallic reagents and halides or analogous species. Brønsted
or Lewis acid-catalyzed generation of cations from benzyl alco-
hols, allyl alcohols and doubly activated systems like bis-
benzyl, bis-allyl, benzyl–allyl, benzyl-propargyl alcohols and
their reactivity with wide range of substrates is well-docu-
mented.7 However, a systematic study of generating furfuryl
cations from the respective α- or β-furylcarbinols and sub-
sequent exploitation of the cationic center (Fig. 2) was never
realized despite having huge potential for the synthesis of a
diverse range of natural products and medicinally important
compounds.
Department of Chemical Sciences, Indian Institute of Science Education and
Research (IISER) Mohali, Sector 81, S A S Nagar, Manuali 140 306, Punjab, India.
E-mail: ramsastry@iisermohali.ac.in; Fax: +91 172 2240266; Tel: +991 172 2240266
†This research work is dedicated to the memory of the late Prof. A. Srikrishna,
Department of Organic Chemistry, Indian Institute of Science (IISc), Bangalore.
‡Electronic supplementary information (ESI) available: Experimental procedures
for the synthesis of starting materials, copies of 1H and 13C NMR spectra of all
new compounds and crystallographic data of bicyclic ether 49. CCDC 931682.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40814k
Fig. 2 Acid promoted generation of furfuryl cations and proposed nucleophilic
substitution reactions.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4299–4303 | 4299

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 1 Lewis acid screeninga,b
Table 2 Solvent screening resultsa,b
Entry
Lewis acid (20 mol%)
Time (h)
Yieldc (%)
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
BF3·OEt2
FeCl3
InCl3
ZnCl2
Sc(OTf)3
CuOTf
BiCl3
BiCl3
BiCl3
Bi(OTf)3
—
12
0.5
1
3
1
16
1
2
4
78
81
75
38
69
49
85
82
80
84
—
1
2
3
4
CH2Cl2
Toluene
Xylene
CH3NO2
Water–CH3NO2
Water
1
4
2
85
66
57
85
—
—
—
<5
54
75
1
5c
6d
7e, f
8
24
36
60
75
72
6
Water
8d
9e
10
11f
Acetone
Acetonitrile
—
9
10
0.5
250
a A mixture of alcohol (0.1 mmol), acetylacetone (0.11 mmol), BiCl3
(20 mol%) in 1 mL solvent stirred for an appropriate time at room
temperature. b No trace of product observed (by TLC) in ethyl acetate or
THF even after 75 h. c 1 : 1 water, nitromethane as solvent (1 mL). d In
0.5 mL water, stirred in the presence of 20 mol% sodium dodecyl
sulfate (SDS) for 24 h, added additional 20 mol% and stirred for 12 h,
further added an additional 60 mol% and stirred for 24 h more. e In
0.5 mL water, stirred in the presence of 20 mol% Triton® X-100 for
24 h, added additional 20 mol% and stirred for 12 h, further added an
additional 60 mol% and stirred for 24 h more. f BiCl3 probably
underwent aqueous hydrolysis to BiOCl which is known as an
ineffective Lewis acid.
a A mixture of alcohol (0.1 mmol), acetylacetone (0.11 mmol), and
catalyst in 1 mL dichloromethane was stirred for an appropriate time.
b Either starting material recovered or traces of product observed with
TiCl4, MgBr2, SnCl4, AlCl3, Zn(OTf)2, PdCl2, CoCl2, CuCl2 as catalysts.
c Isolated yields after silica gel column chromatography. d 10 mol%
catalyst was used. e 5 mol% catalyst was used. f No catalyst was used,
no trace of product was observed by crude NMR.
Herein we delineate our efforts towards the generation of
furfuryl cations under Lewis acid catalysis, their reactions with
various nucleophiles and elaboration to some architecturally
novel scaffolds. At the outset, optimization studies for the
generation of furfuryl cation were performed. To identify
effective catalysts and reaction conditions, we chose furfuryl
alcohol 1 and acetylacetone as substrates for the model reac-
tion. The results are compiled in Table 1. From these experi-
ments FeCl3, BiCl3 and Bi(OTf)3 have emerged as effective
catalysts to afford 2 in terms of reaction time and yield.
However, when prolonged beyond 0.5 h, the acetylacetone
adduct 2 was found to be unstable under the FeCl3 catalyzed
reaction conditions.
Among many metal based Lewis acids, bismuth com-
pounds have been employed as effective green catalysts in
various organic transformations.8 BiCl3 represents the best
choice of catalyst for subsequent study as it is environmentally
friendly, cost-effective, and less toxic.9 Lowering the catalyst
loading prolonged the reaction times with marginal drop in
the yields, entries 8 and 9. Control experiments verified that
the reaction did not proceed in the absence of a Bi source,
entry 11.
A brief solvent screen (Table 2) prompted us to replace the
chlorinated solvent with relatively benign nitromethane. It is
interesting to note that, during the entire study, we never had
observed any side product originating from nitromethane as
nucleophile. Our efforts to develop a reaction on water were
unsuccessful, but solvent-free conditions were found to be
encouraging.
With the optimized reaction conditions in hand, we then
investigated the substrate scope with 2-, 3-furyl and thiophenyl
carbinols and nucleophiles, Scheme 1. Short reaction times
and excellent yields were observed in almost all cases. Some of
the noteworthy features of this methodology are: (i) very
simple and mild reaction conditions, (ii) it does not require
any further activation unlike the extensively studied bis-
benzylic, benzylic-allylic or benzylic-propargylic systems, (iii) a
unique method under which C–C, C–N, C–O, C–S bond for-
mation can be achieved.
Dehydrative alkylation of furfuryl and thiophenyl alcohols
with β-diketones and β-ketoesters as nucleophiles proceeded
in excellent yields (3–18). Quaternary carbon-containing furans
could be efficiently assembled through this methodology (14,
15). A range of aromatic and heteroaromatic compounds furn-
ished Friedel–Crafts alkylation products in very good yields,
entries 19–26. Significantly, compound 26 belongs to the
class of unsymmetrical trisubstituted methane derivatives
(TRSMs).10 TRSMs exhibit a wide range of biological activities
such as non-steroidal aromatase inhibition, anti-proliferative,
antitubercular, etc. A variety of alcohols and thiols as nucleo-
philes generate ethers (entries 27–30) in a transformation that
is parallel to Williamson or Mitsunobu etherification reac-
tions. Furfuryl alcohols can also be aminated11 under these
environmentally benign reaction conditions, viz., compounds
31 and 32. It is worth noting that azide 33 obtained in 82%
yield represents the first Bi(III)-catalyzed azidation12 of a
furfuryl alcohol with pronucleophile trimethylsilylazide.
Homoallylic furan derivatives (34) can be accessed via this
methodology using allyltrimethylsilane as a pronucleophile.
Tertiary alcohol 35 underwent elimination to the trisubstituted
olefin 36 in a 3 : 1 E/Z ratio, while the alcohol 37 bearing no
4300 | Org. Biomol. Chem., 2013, 11, 4299–4303
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Scheme 2 BiCl3-catalyzed intramolecular cyclization reactions and some
natural products under the purview of this methodology.
intramolecular version without any noticeable elimination
product (unlike tertiary alcohol 35) affording sterically
demanding mono- and bicyclic ethers 48 and 49,17 respecti-
vely. The complete carbon framework of linear furanopoly-
ketides 50 and 5118 has been incorporated in the bisether 52.19
Bisether 52 also constitutes the synthesis of C1–C8 fragment
(including C15 and C17) of bipinnatin K 53.20 While a general
approach to tetrahydropyrans can be established as exempli-
fied by the synthesis of the pyran 54, significance of this methodo-
logy is further elevated in the form of pyrrolidine 55, which
is an important synthon and is amenable in elaborating to
several bioactive natural products and pharmaceutics.
In conclusion, we have outlined efficient BiCl3 catalyzed
inter- and intramolecular furfurylation reactions. By virtue of
their generality, selectivity and efficiency, we believe that these
efficient transformations provide an easy and straightforward
access to structurally unique furan derivatives and pharmaceu-
tically intriguing compounds. Additional work on elaboration
of these methods to the total synthesis of relevant heterocycles
is in progress and will be communicated in due course.
We are thankful to the Department of Science and Technol-
ogy (DST), New Delhi (sanction order no. SR/FT/CS-156/2011)
and Indian Institute of Science Education and Research
(IISER) Mohali for funding. We thank NMR and X-ray facilities
of IISER-Mohali. S. D. thanks IISER-Mohali for a research
fellowship.
Scheme 1 BiCl3 catalyzed reactions of furfuryl and thiophenyl alcohols with
different nucleophiles.
substitution at the 5-position afforded a complex mixture as
expected (in contrast to 17 and 18).
After successfully demonstrating the generality of the BiCl3-
catalyzed intermolecular furfurylation reactions, we turned our
attention to investigate the entropically advantageous intra-
molecular version, Scheme 2. Diverse furan-containing natural
product-like tetrahydrofurans, tetrahydropyrans, and pyrroli-
dines can be accessed by this method, viz., the cyclic ether 39
is an advanced precursor to the monoterpene natural product
40, a secondary metabolite isolated from an extract of sun-
cured Greek tobacco leaves.13
Furans 39, 41 and 42 are part carbon skeletons of FD-838
43,14 naltriben 44,15 ligulacephalin B 45,16 and many others.
Isobenzofuran 46 is an important core present in several bio-
active compounds. Functionalized and strained bicyclic ether
47 can be generated easily via this methodology. It is worth
noting that tertiary alcohols react equally efficiently in the
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4299–4303 | 4301

View Article Online
Communication
Organic & Biomolecular Chemistry
Chem.–Asian J., 2013, 8, 546; (g) M. Noji, T. Ohno, K. Fuji,
N. Futaba, H. Tajima and K. Ishii, J. Org. Chem., 2003, 68,
9340.
Notes and references
1 (a) Z. N. Cui, Y. Li, Y. Ling, J. Huang, J. R. Cui, R. Q. Wang
and X. L. Yan, Eur. J. Med. Chem., 2010, 45, 5576;
(b) A. H. F. A. El-Wahab, Z. I. A. Al-Fifi, A. H. Bedair,
F. M. Ali, A. H. A. Halawa and A. M. El-Agrody, Molecules,
2011, 16, 307; (c) E. Lukevits and L. Demicheva, Chem. Hetero-
cycl. Compd., 1993, 29, 243; (d) K.-S. Yeung, Top. Hetero-
cycl. Chem., 2012, 29, 47; (e) F. C. Meotti, D. O. Silva,
A. R. S. dos Santos, G. Zeni, J. B. T. Rocha and
C. W. Nogueira, Environ. Toxicol. Pharmacol., 2003, 15, 37
and excellent references cited therein; (f) K. Dawood,
H. Abel-Gawad, M. Ellithey, H. A. Mohamed and B. Hegazi,
Arch. Pharm., 2006, 339, 133.
2 (a) T. Nagahara, Y. Yokoyama, K. Inamura, S. Katakura,
S. Komoriya, H. Yamaguchi, T. Hara and M. Iwamoto,
J. Med. Chem., 1994, 37, 1200; (b) X. Huang, B. Peng,
M. Luparia, L. F. R. Gomes, L. F. Veiros and N. Maulide,
Angew. Chem., Int. Ed., 2012, 51, 8886; (c) J. R. Hanson, Nat.
Prod. Rep., 1995, 12, 381; (d) J. M. Chambers,
D. C. S. Huang, L. M. Lindqvist, G. P. Savage, J. M. White
and M. A. Rizzacasa, J. Nat. Prod., 2012, 75, 1500;
(e) M. Watanabe, W.-T. Su, Y. J. Chang, T.-H. Chao,
Y.-S. Wen and T. J. Chow, Chem.–Asian J., 2013, 8, 60;
(f) D. Das, S. Pratihar and S. Roy, Org. Lett., 2012, 14, 4870
and references cited therein.
3 (a) B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo,
R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber,
P. S. Anderson, R. S. L. Chang, V. J. Lotti, D. J. Cerino,
T. B. Chen, P. J. Kling, K. A. Kunkel, J. P. Springer and
J. Hirshfield, J. Med. Chem., 1988, 31, 2235;
(b) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker,
G.-Q. Cao, S. Barluenga and H. J. Mitchell, J. Am. Chem.
Soc., 2000, 122, 9939; (c) D. A. Horton, G. T. Bourne and
M. L. Smythe, Chem. Rev., 2003, 103, 893; (d) H. Sunden
and R. Olsson, Org. Biomol. Chem., 2010, 8, 4831;
(e) M. S. Butler, J. Nat. Prod., 2004, 67, 2141;
(f) A. K. Ghosh, P. R. Sridhar, N. Kumaragurubaran,
Y. Koh, I. T. Weber and H. Mitsuya, ChemMedChem, 2006,
1, 939.
4 (a) O. Achmatowicz Jr., P. Bukowski, B. Szechner,
Z. Zwierzchowska and A. Zamojski, Tetrahedron, 1971, 27,
1973; (b) M. D. Burke, E. M. Berger and S. L. Schreiber,
J. Am. Chem. Soc., 2004, 126, 14095; (c) G. Piancatelli,
A. Scettri and S. Barbadoro, Tetrahedron Lett., 1976, 17,
3555.
6 R. A. Sheldon, Chem. Soc. Rev., 2012, 41, 1437.
7 Some selected references: (a) J. J.-K. Smith, L. A. Young and
F. D. Toste, Org. Lett., 2004, 6, 1325; (b) K. Motokura,
N. Fujita, K. Mori, T. Mizugaki, K. Ebitani and K. Kaneda,
Angew. Chem., Int. Ed., 2006, 45, 2605; (c) F. Xia, Z. L. Zhao
and P. N. Liu, Tetrahedron Lett., 2012, 53, 2828;
(d) Y. Nishibayashi, M. Yoshikawa, Y. Inada, M. Hidai and
S. Uemura, J. Am. Chem. Soc., 2002, 124, 11846; (e) Y. Inada,
M. Yoshikawa, M. D. Milton, Y. Nishibayashi and
S. Uemura, Eur. J. Org. Chem., 2006, 881; (f) R. Sanz,
D. Miguel, A. Martinez, J. M.-A. Gutierrez and F. Rodriguez,
Org. Lett., 2007, 9, 727; (g) M. Ikeda, Y. Miyake and
Y. Nishibayashi, Angew. Chem., Int. Ed., 2010, 49, 7289;
(h) P. N. Chatterjee and S. Roy, Tetrahedron, 2011, 67, 4569;
(i) T. Aoyama, S. Miyota, T. Takido and M. Kodomari,
Synlett, 2011, 2971; ( j) M. Noji, Y. Konno and K. Ishii,
J. Org. Chem., 2007, 72, 5161; (k) F. Bisaro, G. Prestat,
M. Vitale and G. Poli, Synlett, 2002, 1823; (l) P. N. Liu,
L. Dang, Q. W. Wang, S. L. Zhao, F. Xia, Y. J. Ren,
X. Q. Gong and J. Q. Chen, J. Org. Chem., 2010, 75, 5017;
(m) V. Terrasson, S. Marque, M. Georgy, J.-M. Campagne
and D. Prim, Adv. Synth. Catal., 2006, 348, 2063;
(n) T. Ohshima, J. Ipposhi, Y. Nakahara, R. Shibuya and
K. Mashima, Adv. Synth. Catal., 2012, 354, 2447;
(o) M. Yasuda, T. Somyo and A. Baba, Angew. Chem., Int.
Ed., 2006, 45, 793; (p) J. Fan, C. Wan, G. Sun and Z. Wang,
J. Org. Chem., 2008, 73, 8608; (q) P. G. Cozzi and L. Zoli,
Angew. Chem., Int. Ed., 2008, 47, 4162; (r) M. Rueping,
B. J. Nachtsheim and A. Kuenkel, Org. Lett., 2007, 9, 825;
(s) B. G. Das, R. Nallagonda and P. Ghorai, J. Org. Chem.,
2012, 77, 5577; (t) D. Stadler and T. Bach, Chem.–Asian J.,
2008, 3, 272; (u) S. Biswas and J. S. M. Samec, Chem.–Asian
J., 2013, 8, 974.
8 (a) J. M. Bothwell, S. W. Krabbez and R. S. Mohan, Chem.
Soc. Rev., 2011, 40, 4649; (b) H. Gaspard-Iloughmane and
C. Le Roux, Eur. J. Org. Chem., 2004, 2517.
9 From http://www.sigmaaldrich.com, the price per 25 g in
US dollars is $75 and $238 for BiCl3 and Bi(OTf)3, respecti-
vely. The LD50 of BiCl3 is listed as 3.3 g kg−1 (oral, rat) in
the MSDS provided by Sigma-Aldrich, which is lower than
that of NaCl (3.8 g kg−1). The low toxicity of bismuth is
attributed to the poor solubility of the metal in aqueous
solutions at moderate pH levels similar to biological systems.
5 PTSA catalysis: (a) M. O’Brien, S. Cahillb and L. A. Evans, 10 (a) S. K. Das, Shagufta and G. Panda, Tetrahedron Lett.,
Chem. Commun., 2008, 5559; (b) M. O’Brien, A. Leach,
R. J. Armstrong, K. Chonga and R. Sheridanb, Org. Biomol.
Chem., 2012, 10, 2392; (c) J. L. Princival, S. M. G. de Barros,
J. V. Comasseto and A. A. D. Santos, Tetrahedron Lett., 2005,
2005, 46, 3097; (b) V. Nair, S. Thomas, S. C. Mathew
and K. G. Abhilash, Tetrahedron, 2006, 62, 6731;
(c) P. Thirupathi and S. S. Kim, J. Org. Chem., 2010, 75,
5240 and relevant references cited therein.
46, 4423. CSA catalysis: (d) J. Zhang, L. Li, Y. Wang, 11 D. Hollmann, A. Tillack, D. Michalik, R. Jackstell and
W. Wang, J. Xue and Y. Li, Org. Lett., 2012, 14, 4528. Lewis
acid catalysis: (e) J. M. Winne, S. Catak, M. Waroquier and
M. Beller, Chem.–Asian J., 2007, 2, 403 and references cited
therein.
V. V. Speybroeck, Angew. Chem., Int. Ed., 2011, 50, 11990; 12 See ESI‡ for an elaboration to a medicinally important
(f) W. Gong, Y. Liu, J. Zhang, Y. Jiao, J. Xue and Y. Li,
compound.
4302 | Org. Biomol. Chem., 2013, 11, 4299–4303
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
13 T. Pettersson, A.-M. Eklund and I. J. Wahlberg, J. Agric.
Food Chem., 1993, 41, 2097.
Chinese folk medicine in the treatment of edema and
scrofula.
14 K. Mizoue, T. Okazaki, K. Hanada, T. Amamoto, 17 CCDC number: 931682. Structure confirmed by single
M. Yamagishi and S. Omura, Eur. Pat. Appl., 1987, EP crystal X-ray diffraction analysis (see ESI‡).
216607. FD-838 induces differentiation of leukemic cells in 18 T. Lin, X. Lin, C. Lu, Z. Hu, W. Huang, Y. Huang and
culture and inhibits growth of certain Gram-positive bac-
teria and true fungi.
15 J. Schutz, C. M. Dersch, R. Horel, M. Spetea, M. Koch,
Y. Shen, Eur. J. Org. Chem., 2009, 2975. Compounds 50
and 51 are known inhibitors of human pathogenic
microorganisms.
R. Meditz, E. Greiner, R. B. Rothman and H. Schmidhammer, 19 Efforts to convert 39 to 40 or 52 to 51 were unsuccessful,
J. Med. Chem., 2002, 45, 5378. Naltriben is a selective δ
opioid receptor antagonist.
16 T. Kazuki, Y. Yasunori and K. Masao, Chem. Pharm. Bull.,
2005, 53, 1555. Ligulacephalin B is a constituent of
see ESI.‡
20 J. Marrero, J. Benítez, A. D. Rodríguez, H. Zhao and
R. G. Raptis, J. Nat. Prod., 2008, 71, 381. Bipinnatin K is an
acetylcholine-binding protein (AChBP) inhibitor.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4299–4303 | 4303