Extrapolation of the gold-catalyzed cycloisomerization to the palladium-catalyzed cross-coupling/cycloisomerization of acetylenic alcohols for the synthesis of polysubstituted furans: Scope and application to tandem processes

Article abstract of DOI:10.1016/S1872-2067(15)60994-9

This paper describes the development of an integrated approach for the preparation of diverse furan derivatives from acetylenic alcohols by gold and palladium catalyzed π-activation chemistry. Notably, this new method was found to be amenable to cycloocty

Full text of DOI:10.1016/S1872-2067(15)60994-9

Chinese Journal of Catalysis 37 (2016) 288–299
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
Extrapolation of the gold‐catalyzed cycloisomerization to the
palladium‐catalyzed cross‐coupling/cycloisomerization of
acetylenic alcohols for the synthesis of polysubstituted
furans: Scope and application to tandem processes
Chandrasekar Praveena,*, Paramasivan T. Perumalb
a Functional Materials Division, Central Electrochemical Research Institute (CSIR Laboratory), Karaikudi 630003, India
b Organic Chemistry Division, Central Leather Research Institute (CSIR Laboratory), Adyar, Chennai 600020, India
A R T I C L E I N F O
A B S T R A C T
Article history:
This paper describes the development of an integrated approach for the preparation of diverse
furan derivatives from acetylenic alcohols by gold and palladium catalyzed π‐activation chemistry.
Notably, this new method was found to be amenable to cyclooctyl‐containing substrates, which
represents a significant extension to this methodology compared with our previous reports. Fur‐
thermore, this newly developed method allowed for the direct construction of cyclooctyl furans
from their synthetic precursors under Sonogashira conditions. Experimental results revealed that
palladium played two major functions in these reactions, including (1) an essential catalyst in the
cross‐coupling reaction of the substrates; and (2) facilitating the cyclization of the acetylenic alcohol
intermediates through a typical π‐activation process. The scope of this chemistry was highlighted by
the one‐pot synthesis of 3‐iodofuran, which provided an opportunity for further functionalization
(via coupling methods). Finally, the AuBr3 protocol was also elaborated to domino cyclization/C–H
activation reactions, as well as the cyclization of acyclic precursors. Taken together, the results of
this study demonstrate that gold and palladium catalysts can be used to complement each other in
cyclization reactions.
Received 9 September 2015
Accepted 12 October 2015
Published 5 February 2016
Keywords:
Furan derivatives
Cycloisomerization
Gold catalysis
Palladium catalysis
One‐pot operation
Tandem reactions
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
1. Introduction
cient construction of diverse structural frameworks and mo‐
lecular architectures [20,21]. The strong σ‐donor and weak
Homogeneous gold catalysts continue to attract increasing
levels of interest in organic chemistry because of the efficiency,
mild nature and unique properties [1–15]. Our collective un‐
derstanding of gold catalysis has been facilitated by the theo‐
ries of frontier molecular orbitals [16], relativistic effects
[17,18] and π‐acidity [19]. The unusual reactivity of gold cata‐
lysts, namely the activation of C–C triple bonds, has led to the
development of a wide range of powerful methods for the effi‐
π‐acceptor properties of alkynes render gold‐complexed al‐
kynes electrophilic and therefore opens the door for the dis‐
covery of new reactions [22,23]. In contrast to the vast majority
of transition metal‐catalyzed processes, the high oxidation po‐
tential of Au(I) to Au(III) allows most Au(I)‐catalyzed reactions
to proceed without the requirement for an inert atmosphere.
We have initiated a program to exploit the unique reactivity of
alkyne precursors towards gold catalysis for the synthesis of
* Corresponding author. Tel: +91‐9677733808; E‐mail: chandrasekar.praveen@gmail.com
This work was supported by the Department of Science and Technology (INSPIRE Faculty Program), India.
DOI: 10.1016/S1872‐2067(15)60994‐9 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 37, No. 2, February 2016

Chandrasekar Praveen et al. / Chinese Journal of Catalysis 37 (2016) 288–299
289
carbo‐ and heterocyclic compounds [24–30]. Furans fused to
cycloalkyl ring systems (e.g., cyclopentyl, cyclohexyl, cyclohep‐
tyl and cyclooctyl rings) have found numerous applications in a
variety of different areas ranging from natural products to me‐
dicinal chemistry [31–38]. Consequently, contemporary syn‐
thetic chemistry has witnessed the development of a plethora
of highly efficient synthetic strategies for the construction of
these sub‐structures [39–56]. However, despite significant
advances in this area, there are still some challenging sub‐
strates for this reaction, including cyclooctyl derivatives. As
part of our ongoing interest in the development of transi‐
tion‐metal catalysts for the synthesis of carbo‐ and heterocyclic
systems [24–30,57–63], we recently reported the gold‐cata‐
lyzed preparation of fused‐furans containing five, six and seven
member rings [24]. In a continuation of this work, it was en‐
visaged that furans fused to an eight member ring could also be
prepared in a similar manner. During our study towards the
preparation of the requisite synthons, we found that the expo‐
sure of 2‐bromocyclooct‐2‐enol to terminal acetylenes under
Sonogashira conditions led to a sequential cross‐coupling/
cycloisomerization process, which resulted in the formation of
the fused furans. In other words, this process provided direct
access to the desired cyclooctyl furans through a ‘‘gold‐free’’
protocol. In this paper, we provide a detailed account of our
work, including the synthetic elaboration of commercially
available starting materials to give complex cyclooctyl furans,
as well as the exploitation of tandem processes and the syn‐
thetic potential of these fused furan systems.
the current study gave C, H and N results that were within
±0.5% of the theoretical values. Purifications by column
chromatography were conducted over silica gel (100–200
mesh, SRL, Mumbai, India) using a mixture of petroleum ether
and ethyl acetate (EtOAc) as the eluent. Analytical thin‐layer
chromatography (TLC) was performed on pre‐coated plastic
sheets of silica gel G/UV‐254 of 0.2 mm in thickness
(Macherey‐Nagel, Düren, Germany) using analytical grade
solvents. The TLC plates were visualized with iodine spray
(10% w/w I2 in silica gel), UV light (λ = 254 and 365 nm) and
alkaline KMnO4 solution.
2.2. General procedure for the synthesis of the
2‐alkynyl‐cycloalk‐2‐enols (5a–5l)
Dry triethylamine (5 mL) was added to a mixture of iodo
compound 3 (1.0 mmol), Pd(PPh3)2Cl2 (5 mol%) and CuI (5
mol%) in an oven‐dried flask under N2, and the resulting sus‐
pension was magnetically stirred for 5 min. Terminal alkyne 4
(1.2 mmol) was then added to the reaction in a drop‐wise
manner, and the resulting mixture was stirred at room tem‐
perature until TLC analysis showed the disappearance of the
2‐iodo‐cycloalk‐2‐enol starting material (~6 h). The reaction
mixture was diluted with water (50 mL) and extracted with
ethyl acetate (4 × 15 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure to give the crude product as a residue.
The residue was subsequently purified by column chromatog‐
raphy over silica gel eluting with a 9:1 (v/v) mixture of EtOAc
and petroleum ether to afford the pure product (5a–5l).
2. Experimental
2‐(Phenylethynyl)‐cyclohept‐2‐enol (5a). Brown oil; IR
(CH2Cl2): 3395, 2923, 2354, 1595, 1438, 752 cm–1. 1H NMR
(500 MHz, CDCl3): δH 1.67–1.71 (m, 4H), 1.93–1.97 (m, 2H),
2.13–2.20 (m, 1H), 2.30–2.40 (m, 2H), 6.43 (t, 1H, J = 6.8 Hz),
7.29–7.30 (m, 4H), 7.42–7.44 (m, 2H). 13C NMR (125 MHz,
CDCl3): δC 25.7, 27.2, 28.6, 35.1, 71.3, 87.6, 91.2, 123.1, 128.3,
128.4, 131.2, 131.5, 138.9. GC‐MS: m/z = 212. Anal. Calcd. for
C15H16O: C, 84.87%; H, 7.60%. Found: C, 84.80%; H, 7.64%.
2‐(4‐Pentylphenylethynyl)‐cyclohept‐2‐enol (5b). Brown
2.1. Materials, methods and instruments
All of the commercially available solvents and reagents were
used as supplied without further purification. Solutions in
organic solvents were dried over anhydrous Na2SO4. Solvents
were evaporated under reduced pressure. Melting points (MP)
were obtained using open capillaries and have been reported
as the uncorrected values. Infrared (IR) spectra were recorded
on a Perkin‐Elmer FTIR spectrophotometer (Hopkinton, MA,
USA). The IR spectra were recorded as KBr pellets for solid
oil; IR (CH2Cl2): 3435, 2927, 1679, 1595, 1438, 838 cm–1. H
1
NMR (500 MHz, CDCl3): δH 0.87 (t, 3H, J = 6.9 Hz), 1.28–1.32 (m,
5H), 1.51–1.68 (m, 5H), 1.93–1.95 (m, 2H), 2.15–2.18 (m, 2H),
2.25–2.30 (m, 1H), 2.58 (t, 2H, J = 8.4 Hz), 4.43 (brs, 1H), 6.40 (t,
1H, J = 6.1 Hz), 7.10 (d, 2H, J = 7.6 Hz), 7.34 (d, 2H, J = 8.4 Hz).
13C NMR (125 MHz, CDCl3): δC 14.1, 22.6, 26.0, 27.3, 28.5, 31.0,
31.5, 35.1, 35.9, 71.3, 86.8, 91.6, 120.1, 123.2, 128.6, 131.4,
138.4, 143.5. GC‐MS: m/z = 282. Anal. Calcd. for C20H26O: C,
85.06%; H, 9.28%. Found: C, 84.98%; H, 9.30%.
2‐Thiophen‐2‐ylethynyl‐cyclohept‐2‐enol (5c). Brown oil;
IR (CH2Cl2): 3421, 2925, 2842, 1654, 1444, 1079, 850, 698
cm–1. 1H NMR (500 MHz, CDCl3): δH 1.35–1.40 (m, 1H),
1.58–1.72 (m, 3H), 1.77–1.83 (m, 1H), 1.90–1.98 (m, 2H),
2.28–2.40 (m, 2H), 4.43 (brs, 1H), 6.41 (t, 1H, J = 1.5 Hz), 6.94 (t,
1H, J = 5.3 Hz), 7.16 (d, 1H, J = 3.8 Hz), 7.23 (d, 1H, J = 5.3 Hz).
13C NMR (125 MHz, CDCl3): δC 25.7, 27.1, 28.6, 35.0, 71.4, 84.0,
91.6, 123.2, 127.1, 127.2, 131.0, 131.8, 139.4. GC‐MS: m/z =
218. Anal. Calcd. for C13H14OS: C, 71.52%; H, 6.46%. Found: C,
compounds and neat sample for liquid compounds. 1H and 13
C
NMR spectra were recorded on a JEOL spectrometer (Peabody,
MA, USA) at 500 and 125 MHz, respectively. The samples for
NMR spectroscopy were prepared in DMSO‐d6 and CDCl3. The
chemical shifts () for the 1H NMR spectra have been reported
relative to tetramethylsilane (TMS,  = 0.00), which was used as
an internal reference standard, and expressed in parts per
million (ppm). The number of protons (n) for a given resonance
has been indicated as nH and the spin multiplicities have been
given as follows: s (singlet), d (doublet), t (triplet), dd (doublet
of doublets), dt (doublet of triplets), ddd (doublet of doublet of
doublets) and m (multiplet). The coupling constants (J) have
been given in hertz. GC‐MS spectra were recorded on a
Perkin‐Elmer system. Elemental analyses were recorded on a
Thermo Finnigan FLASH EA 1112CHN analyzer (Niulab
Equipments, Mumbai, India). All of the compounds analyzed in

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71.40%; H, 6.50%.
6H), 1.63–1.73 (m, 3H), 1.79–1.91 (m, 3H), 2.00–2.05 (m, 1H),
2.08–2.15 (m, 1H), 2.80–2.99 (m, 1H), 3.35 (brs, 1H), 4.14 (brs,
1H), 6.15 (t, 1H, J = 3.8 Hz). 13C NMR (125 MHz, CDCl3): δC 18.3,
23.5, 25.2, 25.7, 25.8, 30.7, 40.0, 68.9, 83.3, 92.9, 123.9, 129.9.
GC‐MS: m/z = 220. Anal. Calcd. for C14H20O2: C, 76.33%; H,
9.15%. Found: C, 76.44%; H, 9.12%.
2‐Hex‐1‐ynyl‐cyclohept‐2‐enol (5d). Colorless oil; IR
(CH2Cl2): 3368, 2928, 2851, 1707, 1447, 1065, 909, 732 cm–1.
1H NMR (500 MHz, CDCl3): δH 0.96 (t, 3H, J = 6.8 Hz), 1.28–1.34
(m, 6H), 1.36–1.48 (m, 4H), 1.97–2.10 (m, 4H), 2.50 (m, 1H),
4.17 (brs, 1H), 6.07 (t, 1H, J = 3.8 Hz). 13C NMR (125 MHz,
CDCl3): δC 13.5, 18.3, 19.1, 22.5, 24.7, 25.8, 29.8, 30.1, 69.4, 80.0,
92.0, 130.2, 137.5. GC‐MS: m/z = 192. Anal. Calcd. for C13H20O:
C, 81.20%; H, 10.48%. Found: C, 81.31%; H, 10.54%.
2‐(Phenylethynyl)‐cyclopent‐2‐enol (5k). Brown oil; IR
1
(CH2Cl2): 3368, 2924, 2363, 1485, 1309, 1048, 756 cm–1. H
NMR (500 MHz, CDCl3): δH 1.82–1.84 (m, 1H), 2.14 (s, 1H),
2.34–2.37 (m, 2H), 2.58–2.60 (m, 1H), 4.87 (brs, 1H), 6.29 (t,
1H, J = 3.05 Hz), 7.29–7.31 (m, 2H), 7.45–7.46 (m, 3H). 13C NMR
(125 MHz, CDCl3): δC 31.0, 32.9, 77.1, 84.7, 92.1, 123.1, 128.2,
128.4 (2C), 131.7, 140.5. GC‐MS: m/z = 184. Anal. Calcd. for
C13H12O: C, 84.75%; H, 6.57%. Found: C, 84.80%; H, 6.55%.
2‐(4‐Pentylphenylethynyl)‐cyclopent‐2‐enol (5l). Brown oil;
IR (CH2Cl2): 3377, 2914, 2363, 1491, 1313, 1041, 759 cm–1. 1H
NMR (500 MHz, CDCl3): δH 0.87 (t, 3H, J = 6.9 Hz), 1.27–1.34 (m,
4H), 1.58–1.63 (m, 2H), 1.80–1.84 (m, 1H), 2.03 (s, 1H),
2.33–2.37 (m, 2H), 2.56–2.62 (m, 3H), 4.86 (s, 1H), 6.26 (s, 1H),
7.11 (d, 2H, J = 7.6 Hz), 7.36 (d, 2H, J = 8.4 Hz). 13C NMR (125
MHz, CDCl3): δC 14.1, 22.6, 30.9, 31.0, 31.5, 32.9, 35.9, 79.1, 83.9,
92.5, 120.2, 128.4, 128.5, 131.6, 139.9, 143.5. GC‐MS: m/z =
254. Anal. Calcd. for C18H22O: C, 84.99%; H, 8.72%. Found: C,
84.85%; H, 8.78%.
2‐(1‐Hydroxy‐cyclohexylethynyl)‐cyclohept‐2‐enol
(5e).
Colorless oil; IR (CH2Cl2): 3500, 3450, 2930, 1640, 1435, 1199,
1
799 cm–1. H NMR (500 MHz, CDCl3): δH 1.12–1.18 (m, 4H),
1.35–1.51 (m, 6H), 1.59–1.65 (m, 4H), 1.69–1.77 (m, 4H),
1.91–1.99 (m, 1H), 3.30 (brs, 1H), 4.20 (brs, 1H), 6.16 (t, 1H, J =
3.9 Hz). 13C NMR (125 MHz, CDCl3): δC 14.1, 18.2, 22.6, 24.6,
25.2, 25.6, 30.5, 39.0, 67.3, 69.4, 75.1, 82.9, 93.0, 124.4, 139.0.
GC‐MS: m/z = 234. Anal. Calcd. for C15H22O2: C, 76.88%; H,
9.46%. Found: C, 77.00%; H, 9.44%.
2‐(Phenylethynyl)‐cyclohex‐2‐enol (5f). Brown oil; IR
(CH2Cl2): 3383, 2928, 1592, 1053, 755 cm–1. 1H NMR (500 MHz,
CDCl3): δH 1.60–1.62 (m, 1H), 1.75–1.78 (m, 3H), 1.87–1.90 (m,
1H), 2.12–2.21 (m, 2H), 4.26 (brs, 1H), 6.30 (t, 1H, J = 4.6 Hz),
7.28–7.29 (m, 3H), 7.43–7.44 (m, 2H). 13C NMR (125 MHz,
CDCl3): δC 18.1, 26.0, 30.6, 66.9, 88.4, 89.3, 123.2, 124.2, 128.2,
128.3, 131.6, 137.8. GC‐MS: m/z = 198. Anal. Calcd. for C14H14O:
C, 84.81%; H, 7.12%. Found: C, 84.91%; H, 7.09%.
2‐(4‐Pentylphenylethynyl)‐cyclohex‐2‐enol (5g). Brown oil;
IR (CH2Cl2): 3400, 2928, 2363, 1509, 1461, 1047, 980 cm–1. 1H
NMR (500 MHz, CDCl3): δH 0.87 (t, 3H, J = 6.9 Hz), 1.25–1.32 (m,
4H), 1.57–1.60 (m, 3H), 1.74–1.76 (m, 2H), 1.88–1.90 (m, 1H),
2.11–2.22 (m, 3H), 2.57 (t, 2H, J = 7.6 Hz), 4.22 (brs, 1H), 6.28 (t,
1H, J = 4.6 Hz), 7.11 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz).
13C NMR (125 MHz, CDCl3): δC 14.1, 18.2, 22.6, 26.0, 30.6, 31.0,
31.5, 35.9, 67.0, 87.5, 89.6, 120.2, 124.4, 128.5, 131.5, 137.3,
143.4. GC‐MS: m/z = 268. Anal. Calcd. for C19H24O: C, 85.03%; H,
9.01%. Found: C, 85.18%; H, 8.96%.
2‐Pyridin‐2‐ylethynyl‐cyclohex‐2‐enol (5h). Yellow oil; IR
(CH2Cl2): 3450, 3398, 2929, 2369, 1500, 1450, 1055, 977 cm–1.
1H NMR (500 MHz, CDCl3): δH 1.58–1.60 (m, 1H), 1.75–1.77 (m,
2H), 1.86–1.88 (m, 1H), 2.12–2.18 (m, 2H), 2.21–2.24 (m, 1H),
4.31 (brs, 1H), 6.41 (t, 1H, J = 4.6 Hz), 7.17 (t, 1H, J = 7.6 Hz),
7.39 (d, 1H, J = 6.8 Hz), 7.61 (t, 1H, J = 7.6 Hz), 8.53 (d, 1H, J =
5.3 Hz). 13C NMR (125 MHz, CDCl3): δC 18.1, 26.2, 30.7, 66.5,
88.3, 89.1, 122.6, 124.1, 127.0, 136.2, 139.6, 143.4, 149.8.
GC‐MS: m/z = 199. Anal. Calcd. for C13H13NO: C, 78.36%; H,
6.58%; N, 7.03%. Found: C, 78.47%; H, 6.56%; N, 7.00%.
2‐Hex‐1‐ynyl‐cyclohex‐2‐enol (5i). Colorless oil; IR (CH2Cl2):
Experimental procedure for the synthesis of compound
(5m). A mixture of compound 3a (205 mg, 1 mmol), phe‐
nylethynylcopper(I) (164 mg, 1 mmol) and dry Et3N (5 mL)
was heated at 80 °C under an atmosphere of N2 for 6 h. The
mixture was then poured into ice‐cold water (25 mL) and ex‐
tracted with Et2O (3 × 10 mL). The combined organic extracts
were washed sequentially with 2M HCl (5 mL), 5% NaHCO3 (5
mL) and water (10 mL), and then dried over anhydrous MgSO4.
The solvent was removed under reduced pressure to afford the
crude product, which was purified by column chromatography
over silica gel eluting with a 1:4 (v/v) mixture of EtOAc and
petroleum ether to afford the pure product 5m as a light yellow
1
solid. IR (KBr): 3390, 2921, 2352, 1595, 1431, 748 cm–1. H
NMR (500 MHz, CDCl3): δH 1.62–1.77 (m, 6H), 1.99–2.08 (m,
2H), 2.17–2.23 (m, 1H), 2.34–2.43 (m, 2H), 6.45 (t, 1H, J = 6.9
Hz), 7.32–7.40 (m, 4H), 7.48–7.52 (m, 2H). 13C NMR (125 MHz,
CDCl3): δC 24.3,25.9, 27.5, 28.9, 35.4, 71.7, 87.9, 91.6, 123.6,
128.5, 128.9, 131.7, 131.9, 140.4. GC‐MS: m/z = 226. Anal.
Calcd. for C16H18O: C, 84.80%; H, 8.02%. Found: C, 84.95%; H,
7.96%.
2.3. General procedure for the synthesis of fused furans
(6a–6l and 6q)
3430, 2930, 1501, 1455, 990, 803 cm–1. H NMR (500 MHz,
1
CDCl3): δH 0.96 (t, 3H, J = 6.8 Hz),, 1.32–1.44 (m, 4H), 1.60–1.79
(m, 4H), 1.90–2.15 (m, 5H), 4.09 (brs, 1H), 5.91 (t, 1H, J = 4.3
Hz). 13C NMR (125 MHz, CDCl3): δC 13.6, 19.2, 21.5, 25.0, 28.4,
31.2, 36.8, 69.9, 78.7, 90.3, 132.3, 137.8. GC‐MS: m/z = 178.
Anal. Calcd. for C12H18O: C, 80.85%; H, 10.18%. Found: C,
80.99%; H, 10.12%.
2‐(1‐Hydroxy‐cyclohexylethynyl)‐cyclohex‐2‐enol (5j). Col‐
orless oil; IR (CH2Cl2): 3505, 3451, 2929, 1513, 1219, 782 cm–1.
1H NMR (500 MHz, CDCl3): δH 1.18–1.23 (m, 2H), 1.43–1.59 (m,
AuBr3 (5 mol%) was added a stirred solution of 2‐acetylenic
alcohol 5 (1.0 mmol) in dichloroethane (1 mL) under N2, and
the resulting mixture was stirred at the specified temperature
and the specified time (see Table 2 and Schemes 2 and 7). Upon
completion of the reaction, as indicated by TLC, the reaction
mixture was quenched with 10 mL of water and extracted with
dichloromethane (3 × 5 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to afford the crude product, which was

Chandrasekar Praveen et al. / Chinese Journal of Catalysis 37 (2016) 288–299
291
purified by column chromatography over silica gel (100–200
mesh) eluting with a mixture of cyclohexane and EtOAc to af‐
ford pure product (6a–6l and 6q).
2‐(4‐Pentylphenyl)‐4,5,6,7‐tetrahydro‐benzofuran
(6g).
Colorless liquid; IR (CH2Cl2): 2928, 2851, 2354, 1495, 1452,
909, 838 cm–1. 1H NMR (500 MHz, CDCl3): δH 0.92 (t, 3H, J = 6.8
Hz), 1.30–1.36 (m, 5H), 1.64–1.66 (m, 3H), 1.80–1.88 (m, 2H),
1.99–2.28 (m, 2H), 2.59–2.77 (m, 4H), 6.35 (s, 1H), 7.18 (d, 1H, J
= 8.4 Hz), 7.25 (d, 1H, J = 7.6 Hz), 7.52–7.57 (m, 2H). 13C NMR
(125 MHz, CDCl3): δC 14.2, 22.1, 22.9, 23.1, 23.5, 30.7, 31.2, 31.6,
35.8, 105.2, 118.8, 123.3, 126.6, 141.5, 147.7, 150.1, 152.1.
GC‐MS: m/z = 268. Anal. Calcd. for C19H24O: C, 85.03%; H,
9.01%. Found: C, 84.98%; H, 9.03%.
2‐(4,5,6,7‐Tetrahydro‐benzofuran‐2‐yl)‐pyridine (6h). Yel‐
low oil; IR (CH2Cl2): 3400, 2930, 2850, 1680, 1450, 823 cm–1. 1H
NMR (500 MHz, CDCl3): δH 1.65–1.74 (m, 3H), 2.21–2.24 (m,
2H), 2.38–2.40 (m, 1H), 2.44 (t, 1H, J = 7.6 Hz), 2.66 (t, 1H, J =
6.1 Hz), 6.36 (s, 1H), 7.14–7.17 (m, 1H), 7.56 (t, 1H, J = 7.6 Hz),
7.63–7.65 (m, 1H), 8.57 (d, 1H, J = 3.8 Hz). 13C NMR (125 MHz,
CDCl3): δC 19.7, 24.6, 27.7, 29.7, 82.9, 104.2, 113.7, 120.1, 123.0,
136.4, 143.2, 149.6, 160.1. GC‐MS: m/z = 199. Anal. Calcd. for
C13H13NO: C, 78.36%; H, 6.58; N, 7.03%. Found: C, 78.25%; H,
6.60%; N, 7.07%.
2‐Butyl‐4,5,6,7‐tetrahydrobenzofuran (6i). Colorless oil; IR
(CH2Cl2): 2935, 2853, 1675, 1447, 799, 763 cm–1. 1H NMR (500
MHz, CDCl3): δH 0.93 (t, 3H, J = 6.9 Hz), 1.33–1.69 (m, 8H),
2.35–2.60 (m, 6H), 6.01 (s, 1H). 13C NMR (125 MHz, CDCl3): δC
13.4, 20.9, 21.2, 29.5, 31.1, 32.3, 35.4, 36.0, 106.3, 112.6, 149.5,
151.1. GC‐MS: m/z = 178. Anal. Calcd. for C12H18O: C, 80.85%; H,
10.18%. Found: C, 80.74%; H, 10.22%.
1‐(4,5,6,7‐Tetrahydro‐benzofuran‐2‐yl)‐cyclohexanol (6j).
Colorless oil; IR (CH2Cl2): 3480, 2935, 2929, 1669, 1447, 1250,
800, 713 cm–1. 1H NMR (500 MHz, CDCl3): δH 1.20–1.25 (m, 2H),
1.49–1.61 (m, 6H), 1.65–1.69 (m, 4H), 1.72–1.75 (m, 2H),
1.89–2.10 (m, 4H), 3.95 (brs, 1H), 6.51 (s, 1H). 13C NMR (125
MHz, CDCl3): δC 17.2, 17.4, 18.0, 18.2, 19.0, 20.1, 22.6, 35.7,
105.2, 118.0, 141.9, 151.2. GC‐MS: m/z = 220. Anal. Calcd. for
C14H20O2: C, 76.33%; H, 9.15%. Found: C, 76.25%; H, 9.17%.
2‐Phenyl‐5,6‐dihydro‐4H‐cyclopenta[b]furan (6k). Colorless
2‐Phenyl‐5,6,7,8‐tetrahydro‐4H‐cyclohepta[b]furan
(6a).
Colorless oil; IR (CH2Cl2): 2924, 2851, 1676, 1450, 803 cm–1. 1H
NMR (500 MHz, CDCl3): δH 1.75–1.82 (m, 6H), 2.53 (t, 2H, J = 5.3
Hz), 2.86 (t, 2H, J = 6.1 Hz), 6.45 (s, 1H), 7.21 (t, 1H, J = 7.6 Hz),
7.36 (t, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 7.6 Hz). 13C NMR (125
MHz, CDCl3): δC 26.3, 26.7, 28.8, 29.1, 30.9, 108.8, 123.0, 123.2,
126.5, 128.6, 131.4, 149.8, 153.4. GC‐MS: m/z = 212. Anal.
Calcd. for C15H16O: C, 84.87%; H, 7.60%. Found: C, 85.00%; H,
7.55%.
2‐(4‐Pentylphenyl)‐5,6,7,8‐tetrahydro‐4H‐cyclohepta[b]furan
(6b). Colorless liquid; IR (CH2Cl2): 2926, 2851, 1676, 1450, 803
1
cm–1. H NMR (500 MHz, CDCl3): δH 0.90 (t, 3H, J = 6.9 Hz),
1.33–1.36 (m, 5H), 1.62 (t, 2H, J = 7.6 Hz), 1.72–1.79 (m, 5H),
2.51 (t, 2H, J = 6.1 Hz), 2.59 (t, 2H, J = 7.6 Hz), 2.83 (t, 2H, J = 6.1
Hz), 6.37 (s, 1H), 7.15 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 7.6 Hz).
13C NMR (125 MHz, CDCl3): δC 14.1, 22.6, 26.3, 26.7, 28.8, 29.1,
30.9, 31.2, 31.6, 35.7, 108.0, 122.8, 123.2, 128.6, 128.9, 141.3,
150.1, 152.9. GC–MS: m/z = 282. Anal. Calcd. for C20H26O: C,
85.06%; H, 9.28%. Found: C, 85.00%; H, 9.30%.
2‐Thiophen‐2‐yl‐5,6,7,8‐tetrahydro‐4H‐cyclohepta[b]furan
(6c). Brown oil; IR (CH2Cl2): 2921, 2847, 1663, 1573, 1443,
1218, 1080, 840, 691 cm–1. 1H NMR (500 MHz, CDCl3): δH
1.72–1.73 (m, 4H), 1.77–1.79 (m, 2H), 2.49 (t, 2H, J = 6.1 Hz),
2.81 (t, 2H, J = 6.1 Hz), 6.29 (s, 1H), 7.00 (dd, 1H, J1 = 3.8 Hz, J2 =
3.8 Hz), 7.14–7.15 (m, 2H). 13C NMR (125 MHz, CDCl3): δC 26.2,
26.6, 28.7, 29.0, 30.8, 108.8, 121.3, 122.9, 123.1, 127.6, 134.5,
145.5, 153.0. GC–MS: m/z = 218. Anal. Calcd. for C13H14OS: C,
71.52%; H, 6.46%. Found: C, 71.58%; H, 6.45%.
2‐Butyl‐5,6,7,8‐tetrahydro‐4H‐cyclohepta[b]furan
(6d).
Colorless liquid; IR (CH2Cl2): 2919, 2850, 1660, 1565, 1435,
1211, 1075, 850 cm–1. 1H NMR (500 MHz, CDCl3): δH 0.95 (t, 3H,
J = 6.8 Hz), 1.27–1.34 (m, 4H), 1.55–1.65 (m, 6H), 2.31–2.55 (m,
6H), 6.03 (s, 1H). 13C NMR (125 MHz, CDCl3): δC 14.0, 20.2, 20.3,
24.4, 29.9, 30.1, 31.2, 32.6, 32.8, 106.4, 112.8, 149.8, 152.0.
GC‐MS: m/z = 192. Anal. Calcd. for C13H20O: C, 81.20%; H,
10.48%. Found: C, 81.30%; H, 10.44%.
1‐(5,6,7,8‐Tetrahydro‐4H‐cyclohepta[b]furan‐2‐yl)‐cyclo‐
hexanol (6e). Colorless liquid; IR (CH2Cl2): 3477, 2940, 2935,
1652, 1439, 1231, 799, 702 cm–1. 1H NMR (500 MHz, CDCl3): δH
1.19–1.26 (m, 2H), 1.55–1.63 (m, 6H), 1.72–1.79 (m, 4H),
1.75–1.81 (m, 4H), 1.92–2.15 (m, 4H), 3.99 (brs, 1H), 6.49 (s,
1H). 13C NMR (125 MHz, CDCl3): δC 16.9, 17.3, 18.5, 18.9, 19.9,
20.1, 22.8, 31.2, 35.3, 105.9, 117.8, 140.7, 151.0. GC‐MS: m/z =
234. Anal. Calcd. for C15H22O2: C, 76.88%; H, 9.46%. Found: C,
77.01%; H, 9.44%.
2‐Phenyl‐4,5,6,7‐tetrahydro‐benzofuran (6f). Colorless liq‐
uid; IR (CH2Cl2): 2934, 2851, 1669, 1447, 1247, 760, 690 cm–1.
1H NMR (500 MHz, CDCl3): δH 1.75–1.78 (m, 2H), 1.84–1.89 (m,
2H), 2.46 (t, 2H, J = 6.1 Hz), 2.67 (t, 2H, J = 6.1 Hz), 6.47 (s, 1H),
7.20 (t, 1H, J = 7.6 Hz), 7.35 (t, 2H, J = 7.6 Hz), 7.62 (d, 2H, J = 6.9
Hz). 13C NMR (125 MHz, CDCl3): δC 22.2, 23.1, 23.2, 23.4, 106.1,
119.0, 123.3, 126.6, 128.6, 131.5, 150.9. GC‐MS: m/z = 198.
Anal. Calcd. for C14H14O: C, 84.81%; H, 7.12%. Found: C,
84.75%; H, 7.15%.
oil; IR (CH2Cl2): 2935, 2859, 1681, 1453, 810 cm–1. H NMR
1
(500 MHz, CDCl3): δH 1.79–1.83 (m, 2H), 1.95 (t, 2H, J = 6.3 Hz),
2.56 (t, 2H, J = 6.2 Hz), 6.50 (s, 1H), 7.15 (t, 1H, J = 7.6 Hz), 7.34
(t, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 7.6 Hz). 13C NMR (125 MHz,
CDCl3): δC 23.5, 23.7, 24.2, 105.1, 118.0, 122.3, 125.5, 127.6,
130.5, 150.7, 151.9. GC‐MS: m/z = 184. Anal. Calcd. for C13H12O:
C, 84.75%; H, 6.57%. Found: C, 84.86%; H, 6.54%.
2‐(4‐Pentylphenyl)‐5,6‐dihydro‐4H‐cyclopenta[b]furan (6l).
Colorless oil; IR (CH2Cl2): 2931, 2856, 1680, 1455, 892, 800
1
cm–1. H NMR (500 MHz, CDCl3): δH 0.94 (t, 3H, J = 6.8 Hz),
1.36–1.41 (m, 5H), 1.68–1.71 (m, 3H), 1.76–1.80 (m, 2H), 1.93
(t, 2H, J = 6.2 Hz), 2.56 (t, 2H, J = 6.3 Hz), 6.43 (s, 1H), 7.22 (d,
2H, J = 7.6 Hz), 7.34 (d, 2H, J = 7.6 Hz). 13C NMR (125 MHz,
CDCl3): δC 14.3, 22.0, 22.8, 23.0, 30.6, 31.1, 31.6, 35.8, 104.9,
117.9, 123.4, 123.8, 128.7, 148.0, 150.0, 152.0. GC‐MS: m/z =
254. Anal. Calcd. for C18H22O: C, 84.99%; H, 8.72%. Found: C,
85.10%; H, 8.67%.
2,3‐Dimethylfuran (6q). Colorless liquid; IR (neat): 3150,
3115, 1501, 1164, 1075, 801 cm–1. 1H NMR (500 MHz, CDCl3):
δH 1.91 (s, 3H), 2.29 (s, 3H), 6.19 (d, 1H, J = 6.0 Hz), 7.41 (d, 1H, J
= 6.0 Hz). 13C NMR (125 MHz, CDCl3): δC 9.3, 11.0, 113.3, 114.5,

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140.5, 147.9. GC‐MS: m/z = 96. Anal. Calcd. for C6H8O: C,
74.97%; H, 8.39%. Found: C, 75.15%; H, 8.26%.
2‐bromo‐cyclooct‐2‐enol 3d (10.0 mmol), Pd(PPh3)2Cl2 (5
mol%), and CuI (5 mol%) in an oven‐dried flask under N2, and
the resulting suspension was stirred for 5 min. Phenylacetylene
4a (1.2 eq.) was then added to the reaction in a dropwise
manner, and the resulting mixture was stirred at room tem‐
perature for 6 h. Molecular iodine (1.0 eq.) was then added to
the reaction, and the resulting mixture was stirred for further 2
h. The mixture was then quenched with a saturated solution of
sodium thiosulfate and extracted with EtOAc (3 × 50 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to
afford the crude product, which was purified by column chro‐
matography over silica gel (100–200 mesh) eluting cyclohex‐
ane/EtOAc to afford pure 8a as a colorless liquid. IR (neat):
3084, 3059, 2929, 2851, 1635, 1610, 1549, 1489, 1449 cm–1. 1H
NMR (500 MHz, CDCl3): δH 1.65–1.79 (m, 4H); 1.81–1.92 (m,
4H); 2.37 (t, 2H, J = 6.1 Hz); 2.72 (t, 2H, J = 6.2 Hz); 7.34 (t, 1H, J
= 7.6 Hz); 7.48 (t, 2H, J = 7.6 Hz); 8.02 (d, 2H, J = 7.6 Hz). 13C
NMR (125 MHz, CDCl3): δC 20.7, 21.9, 22.9, 23.4, 23.6, 66.9,
123.7, 126.5, 128.0, 128.9, 129.0, 131.2, 150.1, 151.5. GC‐MS:
m/z = 352. Anal. Calcd. for C16H17IO: C, 54.56%; H, 4.86%.
Found: C, 53.91%; H, 4.95%.
2.4. General procedure for the synthesis of the
cycloocta[b]furans(6m–6o)
Dry triethylamine (5mL) was added to a mixture of
2‐bromo‐cyclooct‐2‐enol 3d (1.0 mmol), Pd(PPh3)2Cl2 (5
mol%) and CuI (5 mol%) in an oven‐dried flask under N2, and
the resulting suspension was stirred for 5 min. Terminal alkyne
4 (1.2 mmol) was then added to the reaction in a dropwise
manner, and the resulting mixture was stirred at room tem‐
perature until it reached completion, indicated by the disap‐
pearance of 2‐bromo‐cyclooct‐2‐enol by TLC (~6 h). The reac‐
tion was diluted with water (50 mL) and extracted with ethyl
acetate (4 × 15 mL). The combined organic extracts were dried
over anhydrous sodium sulfate and concentrated under re‐
duced pressure to give the crude product. The crude was then
purified by column chromatography over silica gel eluting with
a 1:9 (v/v) mixture of EtOAc and petroleum ether to afford the
pure product (6m–6o). Compound 6m was synthesized in the
way using the catalyst and conditions depicted in Scheme 3.
2‐Phenyl‐4,5,6,7,8,9‐hexahydrocycloocta[b]furan
(6m).
Colorless oil; IR (CH2Cl2): 3081, 3055, 2927, 2844, 1625, 1606,
1541, 1485, 1455, 1351, 895, 797 cm–1. 1H NMR (500 MHz,
CDCl3): δH 1.49–1.55 (m, 4H), 1.65–1.70 (m, 2H), 1.75–1.80 (m,
2H), 2.55 (t, 2H, J= 6.2 Hz), 2.85 (t, 2 H, J = 6.2 Hz), 6.41 (s, 1H),
7.15–7.20 (m, 1H),7.30–7.35 (m, 2H), 7.60–7.64 (m, 2H). 13C
NMR (125 MHz, CDCl3): δC 23.8, 25.3, 26.1, 27.4, 28.9, 108.1,
120.5, 123.1, 126.4, 128.5, 131.3, 150.5, 151.7. GC‐MS: m/z =
226. Anal. Calcd. for C16H18O: C, 84.91%; H, 8.02%. Found: C,
85.11%; H, 7.98%.
2.6. Experimental procedure for the Negishi coupling of 8a
A solution of organozinc reagent 7a (1.05 eq.) in THF was
added to a stirred solution of 8a (1.0 mmol) and Pd(Ph3P)4 (10
mol%) in dry dioxane at 0 °C, and the resulting mixture was
stirred at 25 °C for 30 min. The reaction was quenched with 0.5
mol/L HCl and extracted with Et2O. The combined organic ex‐
tracts were then washed sequentially with saturated NaHCO3
solution and brine, and dried over anhydrous Na2SO4. The sol‐
vent was then removed under reduced pressure to give the
crude product, which was purified by column chromatography
over silica gel (100–200 mesh) eluting with a mixture of hexane
and EtOAc to give the pure product 9a as a colorless solid. MP
72–74 °C; IR (KBr): 3069, 3025, 2935, 1519, 1489, 1449, 1375,
2‐Pentyl‐4,5,6,7,8,9‐hexahydrocycloocta[b]furan (6n). Col‐
orless oil; IR (CH2Cl2): 2927, 2860, 1733, 1520, 1455, 1345,
1
1257, 1165, 1090, 1010, 930, 850 cm–1. H NMR (500 MHz,
CDCl3): δH 0.89 (t, 3H, J = 6.4 Hz), 1.30–1.35 (m, 4H), 1.44–1.68
(m, 10 H), 2.44–2.55 (m, 4H), 2.70 (m, 2H), 5.69 (s, 1H). 13C
NMR (125 MHz, CDCl3): δC 14.1, 22.3, 23.8, 25.3, 26.0, 26.1, 27.5,
28.0, 28.1, 28.9, 31.5, 107.5, 118.5, 149.5, 152.9. GC‐MS: m/z =
220. Anal. Calcd. for C15H24O: C, 81.76%; H, 10.98%. Found: C,
81.91%; H, 10.92%.
1
781 cm–1. H NMR (500 MHz, CDCl3): δH 1.34–1.45 (m, 4H),
1.67–1.77 (m, 4H). 2.36 (s, 3H), 2.47 (t, 2H, J = 7.6 Hz), 2.89 (t,
2H, J = 8.1 Hz), 6.95–7.04 (m, 2H), 7.12 (t, 1H, J = 7.6 Hz),
7.29–7.40 (m, 4H), 7.51–7.67 (m, 2H). 13C NMR (125 MHz,
CDCl3): δC 21.5, 22.9, 24.1, 25.5, 27.0, 30.5, 57.4, 115.1, 116.5,
119.5, 120.2, 124.1, 127.9, 129.8, 130.4, 132.5, 131.9, 146.7,
150.9, 160.1. GC‐MS: m/z = 316. Anal. Calcd. for C23H24O: C,
87.30%; H, 7.64%. Found: C, 88.11%; H, 7.55%.
2‐(3‐(Benzyloxy)propyl)‐4,5,6,7,8,9‐hexahydrocycloocta[b]
furan (6o). Colorless oil; IR (CH2Cl2): 2925, 2853, 1572, 1495,
1476, 1450, 1410, 1361, 1305, 1280, 1250, 1210, 1145, 1100,
1
1074, 1025, 983, 960, 905, 881, 858, 800 cm–1. H NMR (500
MHz, CDCl3): δH 1.35–1.70 (m, 8H), 1.85 (q, 2H, J = 6.7 Hz), 2.39
(t, 2H, J = 6.3 Hz), 2.55–2.65 (m, 6H), 3.45 (t, 2H, J = 6.7 Hz),
5.65 (s, 1H),7.20–7.29 (m, 5H). 13C NMR (125 MHz, CDCl3): δC
23.7, 24.6, 25.3, 25.8, 26.0, 27.3, 28.2, 28.7, 69.4, 73.0, 108.0,
118.6, 127.5, 127.6, 127.7, 128.4, 128.5, 138.5, 149.7, 152.0.
GC‐MS: m/z = 321. Anal. Calcd. for C20H26O2: C, 80.50%; H,
8.78%. Found: C, 80.21%; H, 8.85%.
2.7. Experimental procedure for the Sonogashira coupling of 8a
Dry triethylamine (5mL) was added to a mixture of com‐
pound 8a (1.0 mmol), Pd(PPh3)2Cl2 (5 mol%) and CuI (5 mol%)
were placed in an oven‐dried flask under N2, and the resulting
suspension was stirred for 5 min. Phenylacetylene 4a (1.1 eq.)
was added to the reaction in a dropwise manner, and the re‐
sulting mixture was stirred at room temperature for 3 h. The
reaction was diluted with water (50 mL) and extracted with
ethyl acetate (4 × 15 mL). The combined organic extracts were
dried over anhydrous sodium sulfate and concentrated to dry‐
2.5. Experimental procedure for the preparation of
3‐iodo‐2‐phenyl‐4,5,6,7,8,9‐hexahydrocycloocta[b]furan 8a
Dry triethylamine (50 mL) was added to a mixture of

Chandrasekar Praveen et al. / Chinese Journal of Catalysis 37 (2016) 288–299
293
ness to give the crude product, which was purified by column
chromatography over silica gel eluting with a mixture of EtOAc
and petroleum ether to afford the pure product 10a as a yellow
solid. MP 110–112 °C; IR (KBr): 3060, 3018, 2939, 2855, 2219,
1642, 1608, 1556, 1499, 1351 cm–1. 1H NMR (500 MHz, CDCl3):
δH 1.66–1.79 (m, 4H), 1.85–1.93 (m, 4H), 2.55 (t, 2H, J = 6.7 Hz),
2.69 (t, 2H, J = 6.4 Hz), 7.29 (t, 1H, J = 7.6 Hz), 7.35–7.41 (m,
5H), 7.51–7.55 (m, 2H), 8.05 (d, 2H, J = 8.1 Hz). 13C NMR (125
MHz, CDCl3): δC 20.7, 21.0, 21.3, 22.8, 23.1, 23.4, 84.1, 97.5,
105.2, 123.6, 124.5, 124.9, 127.9, 128.4, 128.8, 129.6, 131.5,
132.2, 151.1, 153.4. GC–MS: m/z = 326. Anal. Calcd. for C24H22O:
C, 88.31%; H, 6.79%. Found: C, 88.91%; H, 6.65%.
To a stirred solution of iodofuran 8a (1.0 mmol) in DMAc
(1.5 mL) at room temperature was added ethylacrylate (1.1
eq.), Pd(OAc)2 (5 mol%), nBu3P (25 mol%) and pyridine (3.0
eq.), and the resulting mixture was stirred at 50 °C for 1 h. The
mixture was then diluted with brine (10 mL) and extracted
with EtOAc (3 × 15 mL). The combined organic extracts were
washed with brine (20 mL) and dried over anhydrous MgSO4.
The solvent was then removed under reduced pressure to give
a residue, which was purified by column chromatography over
silica gel eluting with a mixture of hexane and EtOAc to give
16a as a pale yellow liquid. IR (neat): 3095, 3061, 2941, 2841,
1717, 1635, 1621, 1542, 1480, 1455, 1425, 1341, 781 cm–1. 1H
NMR (500 MHz, CDCl3): δH 1.29 (t, 3H, J = 7.6 Hz), 1.66–1.78 (m,
4H), 1.81–1.92 (m, 4H), 2.67–2.75 (m, 4H), 3.96 (q, 2H, J = 7.6
Hz), 6.52 (d, 1H, J = 16.4 Hz), 7.30 (t, 1H, J = 7.6 Hz), 7.45 (t, 2H, J
2.8. Experimental procedure for the Suzuki coupling of 8a
To a stirred solution of iodofuran 8a (1.0 mmol) in di‐
methoxyethane at room temperature was added phenylboronic
acid 11a (1.0 eq.), Pd(PPh3)4 (10 mol%) and Cs2CO3 (1.0 eq.),
and the resulting mixture was stirred at 60 °C for 1 h. The mix‐
ture was cooled to room temperature and filtered through a
sintered crucible. The filtrate was collected and concentrated to
dryness under reduced pressure to give the crude product,
which was purified by column chromatography over silica gel
eluting with a mixture of EtOAc and petroleum ether to afford
the pure product 12a as a colorless solid. MP 88–90 °C; IR
(KBr): 3068, 3025, 2932, 1515, 1475, 1381, 763 cm–1. 1H NMR
(500 MHz, CDCl3): δH 1.65–1.78 (m, 4H), 1.83–1.92 (m, 4H),
2.39 (t, 2H, J = 6.7 Hz), 2.75 (t, 2H, J = 6.6 Hz),6.78–6.89 (m, 2H),
7.17–7.35 (m, 5H), 7.44–7.55 (m, 3H). 13C NMR (125 MHz,
CDCl3): δC 20.9, 21.3, 22.7, 22.9, 23.1, 23.4, 55.7, 114.1, 114.2,
119.8, 122.1, 125.6, 126.5, 126.6, 127.4, 128.5, 130.8, 131.9,
146.8, 150.5, 158.9. GC‐MS: m/z = 302. Anal. Calcd. for C22H22O:
C, 87.38%; H, 7.33%. Found: C, 86.97%; H, 7.45%.
= 7.6 Hz), 7.65 (t, 2H, J = 7.6 Hz), 7.95 (d, 1H, J = 16.4 Hz). 13
C
NMR (125 MHz, CDCl3): δC 13.8, 21.8, 22.4, 22.7, 23.0, 23.3, 51.5,
61.7, 117.1, 117.5, 117.9, 127.2, 128.0, 128.6, 130.8, 137.5,
151.8, 153.8, 167.1. GC‐MS: m/z = 324. Anal. Calcd. for
C21H24O3: C, 77.75%; H, 7.46%. Found: C, 77.57%; H, 7.53%.
2.11. Experimental for the one‐pot synthesis of compound 18a
AuBr3 (5 mol%) was added to a solution of compound 6f
(1.0 mmol) in dichloroethane (1 mL) under N2 at room temper‐
ature, and the resulting mixture was heated at 70 °C for 30 min.
Butenone 17a (1.2 eq.) was then added to the reaction, and the
resulting mixture was stirred for 20 min. Upon completion of
the reaction, as indicated by TLC, the reaction mixture was
quenched with water (10 mL) and extracted with dichloro‐
methane (3 × 5 mL). The combined organic extracts were dried
over anhydrous Na2SO4, filtered and concentrated under re‐
duced pressure to afford the crude product, which was purified
by column chromatography over silica gel (100–200 mesh)
eluting with a mixture of cyclohexane and EtOAc to afford pure
product 18a as a yellow liquid. IR (neat): 3098, 3055, 2946,
1685, 1586, 1355 cm–1. 1H NMR (500 MHz, CDCl3): δH 1.78–1.85
(m, 2H), 1.88–1.95 (m, 2H), 2.19 (s, 3H), 2.45 (t, 2H, J = 6.9 Hz),
2.61 (t, 2H, J = 6.7 Hz), 2.81 (t, 2H, J = 3.4 Hz), 2.95 (t, 2H, J = 2.8
Hz), 7.29 (t, 1H, J = 7.6 Hz),7.45 (t, 2H, J = 7.6 Hz), 7.66–7.77 (m,
2H). 13C NMR (125 MHz, CDCl3): δC 19.5, 20.5, 21.4, 22.9, 23.6,
30.1, 44.2, 118.2, 119.1, 120.1, 121.1, 123.5, 124.3, 128.5, 150.3,
151.4, 208.8. GC‐MS: m/z = 268. Anal. Calcd. for C18H20O2: C,
80.56%; H, 7.51%. Found: C, 81.07%; H, 7.39%.
2.9. Experimental procedure for the Stille coupling of 8a
To a stirred solution of iodofuran 8a (1.0 mmol) in dry THF
(10 mL) at room temperature was added Pd(PPh3)4 (10 mol%),
LiCl (3.0 eq.) and tributyl(vinyl)tin (2.0 eq.), and the resulting
mixture was stirred at room temperature for 12 h. The mixture
was filtered through a pad of Celite and the filtrate was con‐
centration under reduced pressure to give a residue, which was
purified by column chromatography over silica gel (100–200
mesh) eluting with a mixture of hexane and EtOAc to afford
14a as a colorless liquid. IR (neat): 3091, 3061, 3035, 2935,
2849, 1631, 1614, 1591, 1471, 1455, 1425, 1345, 781 cm–1. 1H
NMR (500 MHz, CDCl3): δH 1.65–1.79 (m, 4H), 1.85–1.94 (m,
4H), 2.55–2.67 (m, 4H), 5.35 (dd, 1H, J1 = 12.2 Hz; J2 = 2.1 Hz),
5.47 (dd, 1H, J1 = 18.4 Hz; J2 = 12.2 Hz), 6.91 (dd, 1H, J1 = 18.2
Hz, J2 = 12.2 Hz), 7.29–7.34 (m, 1H), 7.40–7.45 (m, 2H), 7.67 (t,
2H, J = 7.6 Hz). 13C NMR (125 MHz, CDCl3): δC 21.5, 22.6, 22.9,
23.4, 115.2, 118.3, 127.1, 128.8, 129.6, 130.1, 130.3, 131.9,
149.5, 150.6. GC‐MS: m/z = 252. Anal. Calcd. for C18H20O: C,
85.67%; H, 7.99%. Found: C, 86.07%; H, 7.87%.
2.12. Experimental procedure for the one‐pot synthesis of
compound 19a
To a mixture of AuBr3 (5 mol%) and AgSbF6 (5 mol%) in dry
dichloroethane (1 mL) under N2 was added a solution of com‐
pound 6f (1.0 mmol) in dichloroethane (1 mL), and the result‐
ing mixture was heated at 70 °C for 30 min. Phenylacetylene 4a
(1.2 eq.) was added to the reaction, and the resulting mixture
was stirred for 3 h. The reaction was then cooled to room tem‐
perature and quenched with water (10 mL). The resulting
mixture was extracted with dichloromethane (3 × 5 mL) and
the combined organic layers were dried over anhydrous
2.10. Experimental procedure for the Heck coupling of 8a

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Chandrasekar Praveen et al. / Chinese Journal of Catalysis 37 (2016) 288–299
Na2SO4. The solvent was then removed under reduced pressure
to afford the crude product, which was purified by column
chromatography over silica gel (100–200 mesh) eluting with a
mixture of cyclohexane and EtOAc to afford pure product 19a
as colorless liquid. IR (neat): 3095, 3054, 2941, 1685, 1609,
1450, 1355, 898, 747 cm–1. 1H NMR (500 MHz, CDCl3): δH
1.77–1.85 (m, 2H), 1.89–1.96 (m, 2H), 2.65 (t, 2H, J = 6.4 Hz),
2.78 (t, 2H, J = 6.6 Hz), 5.41 (d, 1H, J = 2.3 Hz), 5.67 (d, 1H, J =
2.0 Hz), 7.15–7.29 (m, 4H), 7.35–7.48 (m, 5H), 7.49–7.54 (m,
1H). 13C NMR (125 MHz, CDCl3): δC 19.5, 22.5, 23.4, 23.9, 105.5,
120.1, 121.2, 124.4, 127.5, 127.9, 128.1, 128.3, 128.6, 129.3,
141.2, 145.8, 150.4, 150.6. GC‐MS: m/z = 300. Anal. Calcd. for
C22H20O: C, 87.96%; H, 6.71%. Found: C, 88.17%; H, 6.63%.
Table 1
Synthesis of acetylenic alcohols.
Entry
1
2
3
4
5
6
7
8
n
3
3
3
3
3
2
2
2
2
2
1
1
R 4
5 a Yieldb (%)
phenylacetylene (4a)
5a
5b
5c
5d
5e
5f
90
92
88
89
77
91
94
79
89
79
80
81
1‐ethynyl‐4‐pentylbenzene (4b)
2‐ethynylthiopene (4c)
1‐hexyne (4d)
1‐ethynylcyclohexanol (4e)
phenylacetylene (4a)
1‐ethynyl‐4‐pentylbenzene (4b)
2‐ethynylpyridine (4f)
1‐hexyne (4g)
1‐ethynylcyclohexanol (4e)
phenylacetylene (4a)
5g
5h
5i
9
10
11
12
5j
5k
5l
1‐ethynyl‐4‐pentylbenzene (4b)
a All of the products were characterized by IR, H NMR, 13C NMR and
1
GC‐MS analyses.
b Isolated yield after column chromatography.
3. Results and discussion
We previously reported a convenient method for the syn‐
thesis of fused furans via AuBr3‐catalyzed cycloisomerization of
2‐alkynyl‐cycloalk‐2‐enols (Scheme 1) [24]. The requisite
2‐alkynyl‐cycloalk‐2‐enols were synthesized via the
α‐iodination of the corresponding cycloalken‐2‐ones 1 with
I2/pyridine, which afforded the 2‐iodocycloalk‐2‐enones 2
[64–66]. Subsequent 1,2‐reduction of these 2‐iodocycloalk‐2‐
enones 2 with a stoichiometric mixture of NaBH4 and
CeCl3·7H2O gave the 2‐iodoenols 3 [67,68]. These iodoenols
were then treated with a variety of terminal alkynes 4 under
Sonogashira conditions [69,70] to give the hitherto unknown
2‐alkynyl‐cyclo‐alk‐2‐enols 5 in excellent yields. A wide range
of coupling products were successfully synthesized under these
conditions, including those bearing aliphatic, aromatic and het‐
eroaromatic substituents, with yields ranging from good to
excellent (Table 1).
The results of a series of optimization studies revealed that
all of the substrates underwent the desired cycloisomerization
reaction in the presence of 5 mol% AuBr3 in 1,2‐dichloroethane
(Table 2). As shown in Table 2, the yields of the fused furans
varied from good to excellent depending on the nature of the
substituent attached to the alkyne moiety and the reaction
temperature. Furthermore, the results indicated that the effi‐
ciency of the cyclization was dependent on the nature and the
size of the ring attached to the alkyne moiety for substrates
5a–5l. For example, substrates bearing a cycloheptyl ring, the
reaction proceeds smoothly over a short reaction time, even at
room temperature (Table 2, entries 1–5). Substrates bearing a
cyclohexyl ring also reacted rapidly to produce the desired
products in good yields when the reaction was carried out for
30 min at 70 °C (Table 2, entries 6–10). However, substrates
with a cyclopentyl ring reacted slowly to give low yields of the
desired products, even when the reaction time was extended to
45 min (Table 2, entries 11 and 12). These observations can be
rationalized in terms of the greater degree of strain associated
with the resulting cyclopenta[b]furan products compared with
the cyclohexa[b]furan and cyclohepta[b]furan products. The
results of these experiments also revealed that the nature of the
substituent on the alkyne of the 2‐alkynylcycloalk‐2‐enol sub‐
strate did not play a significant role in determining the success
of the cyclization, because aliphatic, aromatic and heteroaro‐
matic groups were well tolerated at this position to give almost
identical yields of the products. The formation of the products
was confirmed by the appearance of a singlet peak in their 1H
NMR spectra in CDCl3 with a δH value in the range of 6.20–6.30
ppm, which was attributed to the C3‐H of the furan ring. More‐
over, the 13C NMR spectra of these products all contained a
peak with a δC value in the range of 104–109 ppm, which con‐
Table 2
Synthesis of furans 6a–6l.
Entry
1
2
3
4
5
6
7
8
5
6 a
6a
6b
6c
6d
6e
6f
6g
6h
6i
Yieldb (%)
.
CeCl3 7H2O (1.0 eq.)
O
O
I2 (1.0 eq.)
OH
5a
5b
5c
5d
5e
5f
5g
5h
5i
90
91
89
95
79
86
88
70
92
83
60
66
NaBH4 (1.0 eq.)
Pyridine (1.0 eq.)
n( )
n( )
n( )
I
I
CH2Cl2
MeOH
-
-
-
1a 1c 0 oC to rt, 2 h
2a 2c
0 oC to rt, 1 h
3a 3c
n = 1, 2, 3
Pd(Ph3P)2Cl2 (5 mol%)
CuI (5 mol%), Et3N
(1.2 eq.)
rt, 6 h
R
9
4
10
11
12
5j
5k
5l
6j
6k
6l
OH
-
R
AuBr3 (5 mol%)
(CH2)2Cl2
6a 6e: 25 oC, 5 min
O
n( )
-
6f 6j: 70 oC, 30 min
R
n( )
a All of these products were characterized by IR, 1H NMR, 13C NMR and
GC‐MS analyses
b Isolated yield after column chromatography.
-
-
-
6k 6l: 70 oC, 45 min
5a 5l
6a 6l
Scheme 1. AuBr3‐catalyzed synthesis of furans 6a–6l.

Chandrasekar Praveen et al. / Chinese Journal of Catalysis 37 (2016) 288–299
295
firmed the presence of the C3 carbon of the furan ring.
coupling of 2‐bromoenol 3d with phenylethynylcopper(I) [82]
(Scheme 3). This reaction led to the stable alkyne 5m in excel‐
lent yield without the formation of any of the corresponding
cyclized product 6m, which suggested that Et3N and CuBr
(formed as by‐product) were not acting as catalysts for the
cyclization. We subsequently investigated the cyclization of 5m
using 5 mol% PdCl2(Ph3P)2 and found that the reaction pro‐
ceeded smoothly to afford the cyclization product 6m in excel‐
lent yield. PdCl2 also gave the cyclized product 6m in excellent
yield, which indicated that this reaction did not require a neu‐
tral phosphine ligand. These two test reactions clearly indicat‐
ed that Pd(II) was the active catalytic species involved in this
transformation. Notably, the reaction of 5m with CuI
(co‐catalyst in the Sonogashira reaction) under the same condi‐
tions led to only trace quantities of the cyclization product 6m
with 80% of starting material being recovered unchanged. This
result therefore precluded the participation of CuI in the cy‐
clization reaction. Finally, the reaction of 5m with a catalytic
amount of AuBr3 also afforded a clean conversion to product
6m, which suggested that our gold‐based methodology was
indeed applicable to cyclooctyl systems.
In light of their biological significance and their prevalence
as the core substructures in numerous crenulide diterpenoid
natural products, we became interested in extending the scope
of our study to cyclooctyl‐fused furan ring systems [71,72].
Using the optimized reaction conditions, we initially explored
the general scope of our methodology by investigating the syn‐
thesis of a series of cyclooctyl furans (Scheme 2). According to
the literature, the precursors for this cyclization reaction could
be synthesized from commercially available cycloheptene (1d)
[73,74]. Thus, the cyclopropanation of 1d with CHBr3 afforded
cycloadduct 2d, which underwent a ring expansion reaction
with AgClO4 in aqueous acetone to furnish the 2‐bromoenol 3d
[75]. Surprisingly, the subsequent alkynylation of 3d under the
standard Sonogashira conditions did not lead to the expected
alkynylated product 5. In contrast to other ring systems (n = 1,
2, 3), we found that the eight‐membered ring 3d reacted rap‐
idly under the Sonogashira condition to afford the cyclized
product 6 directly without the isolation of the cross‐coupled
intermediate 5.
At this stage in the study, the identity of the catalytic species
involved in this one‐pot operation was unknown. As well as
playing an important role in oxidative addition reactions
[76,77], palladium salts can catalyze the intramolecular cycliza‐
tion reactions of alkynes bearing a hydroxyl tether [78–81].
Prompted by this literature survey, we assumed that palladium
was the catalyst involved in this tandem process. To test this
hypothesis, we investigated the synthesis and isolation of al‐
kyne 5m, which was readily prepared by the Castro‐Stephens
Based on these results, we proposed a mechanism for the
formation of fused furans, which is shown in Scheme 4. Thus,
the initial coordination of the soft Lewis acidic metal [M] to
alkyne 5 would lead to π‐complex 5I. The increased electro‐
philicity of the alkyne would allow for the nucleophilic attack of
the adjoining hydroxyl group to give the cyclized intermediate
5II. The subsequent proto‐deauration of 5II would results in
the formation of 5III, which would undergo an isomerization
Br
Br
tBuOK (1.1 eq.),
CHBr3 (1.05 eq.)
Pd(Ph3P)2Cl2 (5 mol%)
Br
AgClO4 (2.0 eq.)
CuI (5 mol%),
Et3N
pentane, 0 oC,
6 h, N2
(1.2 eq.)
rt, 6 h
R
acetone/H2O (1:9)
rt, 1 h
OH
4
3d
1d
2d
R
6m: R = Ph; 95%
R
6n: R = C5H11; 92%
6o: R = C3H6OBn; 90%
in situ
cyclization
O
OH
5
6
Scheme 2. Synthesis of cyclooctylfurans 6m–6o.
6m
5 mol% PdCl2
(CH2Cl)2 , rt, 10 min
92% yield
Ph
Et3N, 80 oC, N2
Br
5 mol% AuBr3
Cu
+
Ph
6 h
O
(CH2Cl)2, rt, 10 min
96% yield
Ph
OH
5m
OH
91% yield
6m
3d
5 mol% CuI
(CH2Cl)2, rt, 10 min
5 mol% PdCl2(Ph3P)2
(CH2Cl)2, rt, 10 min
97% yield
12% yield
6m
6m
Scheme 3. Cyclization of 5m by several transition metal catalysts.

296
Chandrasekar Praveen et al. / Chinese Journal of Catalysis 37 (2016) 288–299
OH
R
R
R
5
(
)
O
O
proto-deauration
-activation
n
isomerization
[M]
6
5III
(
)
(
)
n
n
n = 1, 2, 3, 4; M = Au(III)
n = 4; M = Pd(II), Au(III)
H
OH
R
R
O
+
_
[M]
(
)
5II
n
[M]
(
5I
)
n
cyclization
Scheme 4. Tentative mechanism for the formation of furans 6.
reaction to produce the fused furan 6.
tributyl(vinyl)tin (13a) and ethylacrylate (15a), respectively,
to give the corresponding 3‐vinyl derivatives 14a and 16a in
moderate to good yields [86,87].
At this stage in the study, we decided to delineate the scope
of our chemistry through a series of synthetic elaborations.
Keeping in mind the versatility of the iodide functionality in
organometallic transformations, we attempted the one‐pot
synthesis of 3‐iodofuran 8a (Scheme 5). Pleasingly, this
sequential process provided the desired iodide 8a in 84% yield.
The subsequent Negishi coupling reaction of compound 8a
with the arylzinc reagent 7a in the presence of 10 mol%
Pd(Ph3P)4 allowed for the introduction of an aryl group, with
the tetra‐substituted furan product 9a being isolated in 79%
yield [83,84]. Furthermore, the Sonogashira reaction of 8a with
phenylacetylene (4a) provided the functionalized alkyne 10a
in 88% yield [69]. The Suzuki‐Miyaura coupling reaction of 8a
with phenylboronic acid 11a afforded the 2,3‐diphenyl
substituted furan 12a in 90% yield [85]. Lastly, compound 8a
also underwent Stille and Heck coupling reactions with
Having demonstrated the catalytic application of this newly
developed palladium‐catalyzed tandem process, we turned our
attention back towards the possibility of using AuBr3 to
facilitate other interesting one‐pot procedures with particular
emphasis on Michael‐ [88] and Friedel–Crafts‐type reactions
[89] (Scheme 6). For example, the cyclization of substrate 5f
under the optimized conditions followed by the in situ addition
of methyl vinyl ketone 17a resulted in the formation of the
Michael adduct 18a in 80% yield. Furthermore, the tandem
Friedel–Crafts alkenylation of 5f with phenylacetylene (4a) in
the presence of a silver co‐catalyst resulted in product 19a
bearing a C=C bond, albeit in a low yield of 22%. It is
noteworthy, however, that this reaction proceeded
regioselectively, with the addition only occurring at the internal
Br
Ph
+
4a
OH
3d
i) PdCl (Ph P) (5 mol%)
2
3
2
CuI (5 mol%), Et N, rt, 6 h
3
''one-flask''
Me
ii) I (1.0 eq.), rt, 2 h
2
Ph
84% overall yield
ZnCl
7a
(1.05 eq.)
Ph
I
4a
(1.1 eq.)
Me
Ph
Ph
Ph
PdCl (Ph P) (5 mol%)
10 mol% Pd(Ph P)
3 4
O
2
3
2
O
O
CuI (5 mol%), Et N, rt, 3 h
9a
3
8a
dioxane, rt, 30 min
79% yield
10a
88% yield
COOEt
SnBu
PhB(OH) 11a (1.0 eq.)
2
3
15a
(1.1 eq.)
Pd(Ph P) (10 mol%)
3
4
13a
o
Cs CO , DME, 60 C, 1 h
2
3
Pd(OAc) (5 mol%), nBu P (25 mol%)
2
3
(1.2 eq.)
90% yield
o
pyridine, DMAc, 50 C; 1 h
83% yield
Pd(Ph P) (10 mol%)
3
4
Ph
LiCl, THF, rt, 12 h
64% yield
COOEt
Ph
O
12a
Ph
Ph
O
O
14a
16a
Scheme 5. Pd‐catalyzed organometallic transformations of 8a.

Chandrasekar Praveen et al. / Chinese Journal of Catalysis 37 (2016) 288–299
297
O
Ph
i) AuBr3 (5 mol%)
(CH2Cl)2, 70 oC, 30 min
i) AuBr3/AgSbF6 (5 mol%)
(CH2Cl)2, 70 oC, 30 min
OH
Ph
Ph
Ph
Ph (1.0 eq.), 70 oC, 3 h
70 oC, 20 min
O
ii)
O
ii)
4a
22% yield
5f
19a
18a
80% yield
17a
(1.2 eq.)
O
''one-flask''
''one-flask''
Scheme 6. AuBr3‐catalyzed sequential processes.
Pd(Ph P) Cl (5 mol%)
SiMe
3
2
2
Me
3
i) Red-Al (1.7 eq.),
o
Me
CuI (5 mol%), Et N
3
Me
K CO (1.0 eq.)
Et O, 0 C, 1 h
2
Me
I
2
3
1.0 eq. TMS-acetylene 4h
OH
ii) I (1.2 eq.),
2
OH
OH
MeOH, 1 h, rt
rt, 1 h, N , 82% yield
2
o
5q
AuBr (5 mol%)
-78 C to rt, 1 h
5p
OH
20a
3e
3
AuBr (5 mol%)
3
(CH Cl) , rt, 30 min
2
2
(CH Cl) , reflux
2
2
78%
1 h
Me
SiMe
3
Me
Me
O
O
6p
6q
Scheme 7. AuBr3 catalyzed cyclization of acyclic substrates.
carbon of alkyne 4a, as indicated by NMR analysis of the crude
mixture. This observation was consistent with those of
previous studies, in that the Au π‐acid drove the addition of an
arene/heteroarene to the internal carbon of the terminal
acetylene [89].
was the active catalytic species involved in this process. This
methodology was also applied to a series of tandem processes,
which provided access to a wide range of functionalized furan
molecules. Given that most of these substrates are commer‐
cially available or synthetically accessible this new method
could be used for the synthesis of furan‐based libraries for de‐
tailed SAR studies in medicinal chemistry. Further studies to‐
wards identifying new applications for this process to generate
furan‐based chemical libraries of potential pharmacological
interest are currently underway.
Finally, we were intrigued by the prospect of applying this
methodology to acyclic acetylenic alcohols for the synthesis of
non‐fused furan rings (see Scheme 7). The requisite
(Z)‐iodoallylic alcohol 3e was prepared by the reaction of
commercially available butyn‐1‐ol (20a) with Red‐Al
[NaAlH2(OCH2CH2OMe)2], followed by quenching of the
resulting carbanion with I2 [90]. Subsequent Sonogashira
coupling of 3e with ethynyltrimethylsilane 4h gave alkyne 5p
[91]. Disappointingly, the reaction of silylated alkyne 5p under
our validated conditions did not provide the expected product
6p, even under reflux conditions. This result was attributed to
the reduced aurophilicity of alkyne 5p as a result of the
deactivating effect of the silyl group. However, substrate 5q
Acknowledgments
C. Praveen acknowledges the Department of Science and
Technology for providing INSPIRE faculty award. C. Praveen
also thanks Dr. Vijayamohanan K. Pillai and Dr. D. Jeyakumar of
CSIR‐CECRI for providing infrastructure facilities.
bearing an unsubstituted terminal alkyne underwent
a
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Graphical Abstract
Chin. J. Catal., 2016, 37: 288–299 doi: 10.1016/S1872‐2067(15)60994‐9
Extrapolation of the gold‐catalyzed cycloisomerization to the palladium‐catalyzed cross‐coupling/cycloisomerization of
acetylenic alcohols for the synthesis of polysubstituted furans: Scope and application to tandem processes
Chandrasekar Praveen*, Paramasivan T. Perumal
Central Electrochemical Research Institute (CSIR laboratory), India; Central Leather Research Institute (CSIR laboratory), India
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