Bismuth(iii)-catalyzed cycloisomerization and (hetero)arylation of alkynols: Simple access to 2-(hetero)aryl tetrahydrofurans and tetrahydropyrans

Article abstract of DOI:10.1039/c8ob00368h

2-(Hetero)aryl tetrahydrofurans and tetrahydropyrans were successfully synthesized using Bi(OTf)₃-catalyzed hydroalkoxylation (cycloisomerization) of alkynols (via 5 or 6 exo-dig cyclization) and intermolecular (hetero)arylation. This reaction involves a highly efficient cascade process, where initially the alkynol undergoes a cycloisomerization step via activation of the triple bond and generates the oxocarbenium ion, which subsequently participates in the (hetero)hydroarylation step with electron-rich arenes. Simple to complex suitably functionalized alkynols (4-pentyn-1-ols and 5-hexyn-1-ols) and electron-rich aromatic compounds were found to be reliable substrates in this cascade transformation and furnished a wide range of oxygen heterocycles. This practical tandem process provides a means to build libraries related to pharmacologically active molecules and natural product like scaffolds.

Full text of DOI:10.1039/c8ob00368h

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Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Bismuth(III)-catalyzed cycloisomerization and (hetero)arylation of
alkynols: a simple access to 2-(hetero)aryl tetrahydrofurans and
tetrahydropyrans
Received 00th January 20xx,
Accepted 00th January 20xx
Ashwini K. Nakate,ab Madhukar S. Pratapureab and Ravindar Kontham*ab
DOI: 10.1039/x0xx00000x
2-(hetero)aryl tetrahydrofurans and tetrahydropyrans were successfully synthesized using Bi(OTf)3-catalyzed
hydroalkoxylation (cycloisomerization) of alkynols (via 5 or 6 exo-dig cyclization) and intermolecular (hetero)arylation. This
reaction involves a highly efficient cascade process, where initially the alkynol undergoes a cycloisomerization step via
activation of the triple bond and generates the oxocarbenium ion, which subsequently participates in
(hetero)hydroarylation step with electron-rich arenes. Simple to complex suitably functionalized alkynols (4-pentyn-1-ols
and 5-hexyn-1ols) and electron-rich aromatic compounds were found to be reliable substrates in this cascade
transformation and furnished a wide range of oxygen heterocycles. This practical tandem process provides a means to
build libraries related to pharmacologically active molecules and natural product like scaffolds.
www.rsc.org/
2-(hetero)aryl tetrahydrofurans and tetrahydropyrans is very
limited. Recently, Fañanás et al., reported an elegant approach
to construct the benzofused cyclic ethers via gold or platinum
Introduction
Saturated oxygen heterocycles, such as tetrahydrofurans and
tetrahydropyrans are ubiquitous core structures of bioactive
natural products and pharmaceutical drugs.1 From the
perspective of drug discovery research, still, there is a much
scope for the development of chemical space derived from
medium-sized heterocyclic frameworks. In this context, the
limitations of conventional heterocycle synthetic protocols
have fueled considerable interest in developing new and
efficient catalytic methods. In recent years, the catalytic
hydroalkoxylation/cycloisomerization of alkynols have
emerged as a powerful tool, which represents a direct means
for the synthesis of enol-ethers and diverse oxygen-containing
heterocycles via inter or intra-molecular reaction modes.2
These cascade/tandem processes offer great potential from
the synthetic point of view because, reactions of this type can
be performed with step and atom efficiency, with negligible
waste generation, which fulfills green chemistry requirements.
In the last three decades, inter and intra-molecular
bis(hydroalkoxylation),3 bis(arylation),4 hydroalkoxylation-
catalyzed intramolecular hydroalkoxylation-hydroarylation of
alkynols.7
It’s noteworthy to mention the Gordan et al., report of
GaCl3 induced hydroalkoxylation followed by Friedel-Crafts
type addition using alkynol and anisole, however, it is limited
to a single example.8 Some other miscellaneous reports also
present in the literature having constraints such as the use of
prefunctionalized starting materials and multiple steps.9
Hence, the development of an efficient synthetic method using
readily available starting materials, environmentally benign
and affordable main group element derived catalysts is of
considerable interest in the field of diversity-oriented synthesis
and in turn in drug discovery research.
Het/Ar
OH
catalyst ([M])
solvent
R3
R2
[M]
n = 1 (1); n = 2 (4)
O
R1
Het/Ar
R3
R1
+
n
n
R2
racemic
2
arene ( )
heteroarene ( )
n = 1 (3), (7); n = 2 (5)
6
alkylation5 of suitably functionalized alkynes using
π-acidic
1
transition metal (especially noble metals) derived catalysts are
well studied.6 In contrast, studies on tandem intramolecular
5/6-exo-dig
R2
R2
O
O
+[M]
-[M]
R1
R1
5/6
hydroalkoxylation
hydro-(hetero)arylation
[M]
n
hydroalkoxylation
(cycloisomerization)
followed
by
n
(cycloisomerization)
intermolecular hydro-(hetero)arylation of alkynols, which gives
Scheme 1. Strategy for synthesis of 2-(hetero)aryl tetrahydrofurans and
tetrahydropyrans from alkynols
a.Organic Chemistry Division, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune-411008 (India).
As part of our interest in the development of new synthetic
methodologies involving cycloisomerization of internal
alkynols,10,11 we have recently reported the synthesis of oxa-
b.Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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spirolactones via an intermolecular cascade annulation of Hexyn-1-ol derived secondary alcohol also well tolerated and
alkynols with α-ketoesters using Bi(OTf)3 as a dual activating (σ gave 5ba as a single diastereomer. Lactone fused alkynol also
and π) catalyst, which proceeds through an oxocarbenium ion found good substrate and furnished the corresponding pyran
intermediate (via 5-exo-dig hydroalkoxylation of alkynol) and 5ca in moderate yield of 30%. Propargyl ether derived alkynol
subsequent cascade annulation process.12 In light of these was proceeded smoothly, and delivered the product 5da in
observations, we envisioned that the same oxocarbenium ion good yield. Exclusive alpha-substituted products in the case of
species would undergo Friedel-Crafts type addition (hydro- α and β-naphthols is attributed to the probable chelation of
(hetero)arylation) under identical reaction conditions to give 2- the catalyst with the free hydroxyl functionality of arenes and
(hetero)aryl-tetrahydrofurans and pyrans from suitably the oxocarbenium ion in the probable transition state.14,9
functionalized alkynols and (hetero)arenes (Scheme 1).
Relative stereochemistry of 3la, 5ba and 5ca was confirmed by
NOE analysis (Scheme 2).13
Table 1. Optimization studiesa
Results and discussion
To investigate the feasibility of this hypothesis, known alkynol
1a (0.36 mmol) and α-naphthol (2a) (0.36 mmol) were treated
with Bi(OTf)3 (10 mol %, 0.036 mmol), in anhydrous CH2Cl2
under argon atmosphere. The reaction proceeded smoothly
and gave the desired 2-naphthyl tetrahydrofuran 3aa in the
good yield of 80% in 6 h at room temperature (entry 1) (Table
1). To identify effective catalyst and reaction conditions,
several Lewis acids (entries 4-15) and Brønsted acids (entries
16-20) were screened, in which some found moderately active.
Among all, Bi(OTf)3 turned out to be the preeminent catalyst. A
brief solvent screen (entries 1-3) prompts us to replace the
chlorinated solvent (CH2Cl2) with relatively benign toluene
(entry 2, 87% yield). Further tuning of the reaction parameters
like molar ratios of the substrates, catalyst loading did not lead
to any noticeable improvement in the outcome of the
reaction. Control experiments verified that the reaction did
not proceed in the absence of Bi(OTf)3 (entry 21) and very little
conversion observed with TfOH (a usual contaminant in
Bi(OTf)3 catalyst) (entry 20) (Table 1).13
entry
1
catalyst
Bi(OTf)3
Bi(OTf)3
solvent
CH2Cl2
yield (%)b
80
87
65
60
58
62
80
55
60
62
40
45
42
50
10
10
20
25
10
15
-
2
toluene
toluene
toluene
CH2Cl2
c
3
Bi(OTf)3
BiCl3
4
5
In(OTf)3
Yb(OTf)3
Hg(OTf)2
HgCl2
6
CH2Cl2
7
toluene
toluene
toluene
toluene
toluene
CH2Cl2
8
9
Hg(OAc)2
Pd(OTf)2
Pd(OAc)2
Ph3PAuCl, AgOTf
AgOTf
10
11
12
13
14
15
16
17
18
19d
20 d
21d
With the optimal conditions at hand, we then investigated
the substrate scope of this tandem process (Scheme 2). Firstly,
the reaction of diverse terminal/internal-alkynols and arenes
were tested. The known cyclopentane fused 4-pentyn-1-ol
CH2Cl2
Cu(OTf)2
FeCl3
CH2Cl2
CH3CN
(CH2)2Cl2
toluene
CH2Cl2
PTSA
worked well with
α
diphenylamine to afford corresponding adducts 3aa
/
β
-naphthols, phenol, o-cresol and
ae in
PTSA
-
CF3COOH
TfOH
excellent yields (50-92%). Cyclopentane fused internal alkynols
(having methyl, phenyl and benzyl substituents on alkyne
CH2Cl2
TfOH
toluene
toluene
termini) were also well condensed with
α
-naphthol and
3ca and 3da
cyclohexane fused
-naphthols gave 3ea
no catalyst
furnished corresponding tetrahydrofurans 3ba
,
aAll reactions were carried out with 0.36 mmol of 1a and 0.36 mmol of 2a in 2 mL
of the solvent unless otherwise specified. bIsolated yield of 3aa. c5 mol %.
dControl Experiments. rt = room temperature, Tf = triflate (CF3SO2).
respectively.
terminal/internal alkynols with
3eb
tolerated and gave 3ha in 69% yield. The reaction of 2,2-
diphenyl substituted primary alkynol with -naphthol and p-
cresol provided 3ia and 3if in good yield. Secondary alkynols
with -naphthol furnished 3ja and 3ka. Conformationally
Condensation
of
α
and
β
,
,
3fa and 3ga in good yields. Tertiary alkynol also well
Next, we were curious to verify the reactivity of alkynols with
heteroarenes in this tandem process, which provides the
access to 2-heteroaryl tetrahydrofurans and the results are
summarized in Scheme 3. Among several heterocycles (furan,
thiophene, pyrrole, pyridine, benzoxazole, and benzothiazole)
tested for this reaction, furan, indole and 1-methylindole were
found to be good substrates. Interestingly, the reaction of
cyclopentane fused alkynol with furan afforded mono-
arylation and double-arylation products 7aa and 7aa1 (dr, 1:3,
confirmed by HPLC analysis)13 in 45% and 51% yield
respectively. Internal alkynol with furan gave an inseparable
α
α
confined tetralin derived alkynol with α-naphthol furnished 3la
as a single diastereomer.13 Cyclohexane derived secondary
alkynols (having trans/cis fusion) with
3ma and 3na in good yield. The reaction of 4-pentyn-1-ol with
-naphthol gave 3oa (71%) in little longer reaction time (10 h).
To our delight, 5-hexyn-1-ol also reacted well with -naphthol
α-naphthol provided
α
α
and furnished the expected tetrahydropyran 5aa (via the 5-
exo-dig mode of cyclization) in the good yield of 58% in 10 h.
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mixture of 7ba and 7ba1 (dr, 1:1) in 60% yield. Cyclohexane As observed in our previous studies,12 The reactivity of
fused alkynol and furan in 1:2 molar ratio furnished 7ea unsubstituted 4-pentyn-1-ols is slightly slower compared to
exclusively, whereas with 1:1 molar ratio afforded 7ea and substituted analogs (Thorpe-Ingold effect)15 and 5-hexyn-1-ols
7ea1 (dr, 1:1) as an inseparable mixture. Diphenyl substituted compared to 4-pentyn-1-ols, which is in agreement with
alkynol provided mono and double arylated adducts 7ia and Baldwin rules.16 Electron-deficient arenes (nitroarenes, aryl
1
7ia1 (dr, 1:1, confirmed by H NMR and HPLC analysis).13 The carboxylates, cyanoarenes, haloarenes and pseudo-
reaction of indane derived alkynol with furan furnished 7pa haloarenes) and anisoles did not participate in the reaction,
and 7pa1. In contrast, benzyl group extended alkynol and which could be due to the unfavorable hydroarylation (Friedel-
secondary (benzylic) alkynols furnished corresponding mono- Crafts) step of the tandem process (Scheme 2 and 3).
furylated products 7ka and 7qa as a mixture of diastereomers
1
(confirmed by H NMR analysis). To our surprise, the reaction
of 2-methylfuran with 4-pentyn-1ol failed to deliver the mono
substituted product. Moreover, indole and 1-methylindole also
well reacted with primary and secondary alkynols to give 7ab
,
7ac and 7rc in good yields. (Scheme 3).
Scheme 3. Synthesis of 2-heteroaryl tetrahydrofurans from 4-pentyn-1-ols and
heteroarenes; aSeparated and characterized, bInseparable mixture, NMR Yields
provided. All yields mentioned above are isolated yields unless otherwise specified.
Scheme 2. Synthesis of 2-aryl tetrahydrofurans/pyrans from 4-pentyn-1-ols & 5-hexyn-
1-ols and arenes; Reaction time is 6 h, unless otherwise specified, a10 h, bOrtho/para
isomers obtained from the same reaction. All yields mentioned above are isolated
yields.
Scheme 4. Plausible reaction mechanism
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A plausible mechanism of this transformation based on our KBr pellet (IR grade). HRMS data were recorded on a Thermo
(and other’s) earlier mechanistic investigations and the results Scientific Q-Exactive, Accela 1250 pump. Experimental
obtained in this work is shown in Scheme 4.7,8,12 The reaction is procedures for all new compounds and known compounds
initiated by the π-coordination of Bi(OTf)3 to the C-C triple without published experimental procedures are described
bond of alkynol 1, 4 to form intermediate A, which triggers the below. Compounds that are not presented in the main text
hydroalkoxylation (cycloisomerization) via 5 or 6-exo-dig mode (manuscript) are numbered starting from S1.
of addition on to the alkyne triple bond, which lead to the
intermediate
cyclic enol ether
generate the oxocarbenium ion
(hetero)arylation with arenes or heteroarenes
Concomitant second protodebismuthination step in
B
. Protodebismuthination of
, further activation of enol ether
, which undergo hydro-
to give
leads to
B
affords the exo-
General procedure for the synthesis of 2-
(hetero)aryl tetrahydrofurans and
tetrahydropyrans
C
C
to
D
2
6
E.
E
Alkynol1a (0.36 mmol) α-naphthol 2a (0.36 mmol) were taken
the desired products 3, 5, 7 (Scheme 4).
in to a single neck 10 mL round bottom flask equipped with
positive argon flow, then dissolved in 2 mL of anhydrous
toluene. Bi(OTf)3 (0.036 mmol) was added under argon
atmosphere at room temperature (rt). The resulting reaction
mixture was stirred at rt for 6 h. After completion of the
reaction (monitored by TLC, visualized using UV, anisaldehyde,
and KMnO4 staining solutions), quenched with saturated
aqueous NaHCO3 solution, then extracted with CH2Cl2 (2x5 mL)
and washed with brine solution (10 mL). The combined organic
layers were dried over anhydrous Na2SO4, and filtered through
sintered glass funnel. The filtrate was concentrated under
reduced pressure and purified using silica-gel column
chromatography (100-200 mesh) to afford the corresponding
Conclusions
In summary, hydroalkoxylation (cycloisomerization) and hydro-
(hetero)arylation cascade reaction of alkynols with
(hetero)arenes mediated by main group element derived
borderline metal catalyst Bi(OTf)3 is identified. Diverse alkynols
and electron rich arenes/heteroarenes, which proceeds cleanly
under ambient reaction conditions and furnished a series of
novel 2-(hetero)aryl tetrahydrofurans and tetrahydropyrans in
good to excellent yields in an atom and step economic way. A
further expansion of this work in building libraries related to
pharmacologically active molecules and their biochemical
evaluation is in progress and will be communicated in due
course.
tetrahydrofuran 3aa
.
2-(3-Methyl-2-oxaspiro[4.4]nonan-3-yl)naphthalen-1-ol (3aa)
Following the General Procedure, to the mixture of (1-(prop-2-
yn-1-yl)cyclopentyl) methanol
(1a) (0.050 g, 0.36 mmol)
andnaphthalen-1-ol (2a) (0.052 g, 0.36 mmol) in anhydrous
Experimental
toluene (2 mL) was added Bi(OTf)3 (0.023 g, 0.036 mmol)
under argon atmosphere at room temperature and reaction
mixture was stirred for 6 h at rt. Purification of the crude
product by column chromatography (SiO2, 2% EtOAc/hexanes)
afforded 3aa as a brown liquid (0.089 g, 87%). Ortho
substitution of 3aa was confirmed by 1H NMR, 2D NMR
(HMBC, HSQC, COSY & NOESY) analysis.13 TLC: Rf = 0.7 (SiO2,
All reactions were performed under argon atmosphere with
oven (80 oC) or flame-dried glassware with septum seal.
Tetrahydrofuran (THF) was distilled from sodium-
benzophenone under argon atmosphere immediately prior to
use. Dichloromethane and acetonitrile were freshly distilled
over calcium hydride under argon atmosphere. 30 °C
corresponds to the room temperature (rt) of the laboratory
when the experiments were carried out. Reaction
temperatures are reported as the temperature of the bath
surrounding the reaction vessel. Analytical thin layer
chromatography (TLC) was performed on TLC Silica gel 60
F254. Visualization was accomplished with short wave UV light,
anisaldehyde or KMnO4 staining solutions followed by heating.
Chromatography was performed on silica gel (100-200 mesh)
by standard techniques eluting with solvents as indicated. 1H
and 13C NMR spectra were recorded on Bruker AV 200, 400
and 500 in solvents as indicated. Chemical shifts (δ) are given
in ppm. The residual solvent signals were used as references
and the chemical shifts converted to the TMS scale (CDCl3: δ H
= 7.26 ppm, δ C = 77.16 ppm), the following abbreviations
were used: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; AB q, AB quartet; dd, doublet of doublet; td, triplet
doublet; and br, broad. IR spectra were recorded on an FT-IR
instrument (Bruker Alpha Model) at normal temperature with
a
1
20% EtOAc/hexanes); H NMR (CDCl3, 500 MHz): δ 10.57 (s,
1H), 8.36-8.21 (m, 1H), 7.78-7.66 (m, 1H), 7.52-7.40 (m, 2H),
7.30 (d, J = 8.72 Hz, 1H), 7.03 (d, J = 8.59 Hz, 1H), 3.84 (d, J =
8.21 Hz, 1H), 3.74 (d, J = 8.21 Hz, 1H), 2.57 (d, J = 12.51 Hz, 1H),
2.19 (d, J = 12.51 Hz, 1H), 1.65 (s, 3H), 1.63-1.38 (m, 8H); 13C
NMR (CDCl3, 126 MHz): δ 150.2, 133.5, 127.1, 126.1, 125.6,
125.1, 124.9, 122.9, 122.5, 118.6, 89.2, 78.7, 52.7, 51.08,
37.75, 36.8, 30.9, 24.8, 24.7; IR (KBr, cm−1): ν 3209, 3061, 3016,
2963, 2865, 1733, 1633, 1503, 1380, 1024, 801, 762; HRMS
(ESI) m/z calcd for C19H23O2 [M+H]+ 283.1693
, found 283.1690.
2-(3-Methyl-2-oxaspiro[4.4]nonan-3-yl)naphthalen-1-ol (3aa)
Following the General Procedure, to the mixture of (1-
(prop-2-yn-1-yl)cyclopentyl) methanol
(1a) (0.050 g, 0.36
mmol) andnaphthalen-1-ol (2a) (0.052 g, 0.36 mmol) in
anhydrous toluene (2 mL) was added Bi(OTf)3 (0.023 g, 0.036
mmol) under argon atmosphere at room temperature and
reaction mixture was stirred for 6h at rt. Purification of the
crude product by column chromatography (SiO2, 2%
EtOAc/hexanes) afforded 3aa as a brown liquid (0.089 g, 87%).
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1
Ortho substitution of 3aa was confirmed by H NMR, 2D NMR 8.3 Hz, 1H), 3.64 (d, J = 8.3 Hz, 1H), 2.26 (d, J = 12.38 Hz, 1H),
(HMBC, HSQC, COSY & NOESY) analysis.13 TLC: Rf = 0.7 (SiO2, 2.08 (d, J = 12.38 Hz, 1H), 1.85-1.28 (m, 11H); 13C NMR (CDCl3,
1
20% EtOAc/hexanes); H NMR (CDCl3, 500 MHz): δ 10.57 (s, 50 MHz): 154.2, 141.2, 125.9, 114.9, 84.7, 78.5, 53.2, 51.7,
1H), 8.36-8.21 (m, 1H), 7.78-7.66 (m, 1H), 7.52-7.40 (m, 2H), 38.4, 37.2, 31.4, 24.7; HRMS (ESI) m/z calcd for C15H21O2
7.30 (d, J = 8.72 Hz, 1H), 7.03 (d, J = 8.59 Hz, 1H), 3.84 (d, J = [M+H]+ 233.1536, found 233.1535.
8.21 Hz, 1H), 3.74 (d, J = 8.21 Hz, 1H), 2.57 (d, J = 12.51 Hz, 1H), 2-Methyl-6-(3-methyl-2-oxaspiro[4.4]nonan-3-yl)phenol (3ad):
2.19 (d, J = 12.51 Hz, 1H), 1.65 (s, 3H), 1.63-1.38 (m, 8H); 13C
Following the General Procedure, to the mixture of(1-(prop-2-
NMR (CDCl3, 126 MHz): δ 150.2, 133.5, 127.1, 126.1, 125.6,
yn-1-yl) cyclopentyl) methanol (1a) (0.050 g, 0.036 mmol) and
125.1, 124.9, 122.9, 122.5, 118.6, 89.2, 78.7, 52.7, 51.08,
o-cresol (2d) (0.039 g, 0.036 mmol) in anhydrous toluene (2
37.75, 36.8, 30.9, 24.8, 24.7; HRMS (ESI) m/z calcd for C19H23O2
mL) was added Bi(OTf)3 (0.023 g, 0.036 mmol) under argon
[M+H]+ 283.1693, found 283.1690.
atmosphere at room temperature and reaction mixture was
1-(3-Methyl-2-oxaspiro[4.4]nonan-3-yl)naphthalen-2-ol (3ab)
stirred for 6h at rt. Purification of the crude product by column
Following the General Procedure, to the mixture of(1- chromatography (SiO2, 2% EtOAc /hexanes) afforded 3ad as a
(prop-2-yn-1-yl) cyclopentyl) methanol (1a) (0.050 g, 0.36 brown liquid (0.040 g, 45%). TLC: Rf = 0.7 (SiO2, 20%
mmol) and naphthalen-2-ol (2b) (0.052 g, 0.36 mmol) in EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz): δ 9.92 (s, 1H),
anhydrous toluene (2 mL) was added Bi(OTf)3 (0.023 g, 0.036 7.12-6.63 (m, 3H), 3.70 (d, J = 8.21 Hz, 1H), 3.72 (d, J = 8.21 Hz,
mmol) under argon atmosphere at room temperature and 1H ), 2.56 (d, J = 12.63 Hz 1H), 2.37-2.09 (m, 4H), 1.92-1.34 (m,
reaction mixture was stirred for 6h at rt. Purification of the 11H); 13C NMR (CDCl3, 50 MHz): δ 155.2, 130.6, 128.3, 126.8,
crude product by column chromatography (SiO2, 2% EtOAc 119.3, 117.4, 88.6, 78.6, 52.4, 51.0, 37.9, 36.9, 30.8, 24.7, 24.6;
/hexanes) afforded 3ab as a brown liquid (0.073 g, 71%). TLC: HRMS (ESI) m/z calcd for C16H23O2 [M+H]+ 247.1693, found
Rf = 0.7 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz): 247.1685.
δ
11.20 (s, 1H), 7.78-7.65 (m, 2H), 7.61 (d, J = 8.84 Hz, 1H), 3-Methyl-4-(3-methyl-oxaspiro[4.4]nona3-yl)phenol (3ad1):
7.39 (ddd, J = 8.62, 6.92, 1.52 Hz, 1H), 7.29-7.19 (m, 1H), 7.04
(d, J = 8.84 Hz, 1H), 3.81 (d, J = 8.08 Hz, 1H), 3.67 (d, J = 8.08
Hz, 1H), 2.72 (d, J= 12.51 Hz, 1H), 2.55 (d, J = 12.51 Hz, 1H),
1.88 (s, 3H), 1.67-1.48 (m, 8H); 13C NMR (CDCl3, 50 MHz): δ
153.2, 131.2, 129.6, 129.4, 129.2, 125.6, 124.3, 122.1, 120.9,
120.5, 89.9, 54.8, 51.2, 37.8, 35.7, 29.8, 25, 24.6; HRMS (ESI)
m/z calcd for C19H23O2 [M+H]+ 283.1693,found 283.1689.
2-(3-Methyl-2-oxaspiro[4.4]nonan-3-yl)phenol (3ac):
Following the General Procedure, to the mixture of (1-(prop-2-
yn-1-yl) cyclopentyl) methanol (1a) (0.050 g, 0.36 mmol) and o-
cresol (2d) (0.039 g, 0.36 mmol) in anhydrous toluene (2 mL)
was added Bi(OTf)3 (0.023 g, 0.036 mmol) under argon
atmosphere at room temperature and reaction mixture was
stirred for 6 h at rt. Purification of the crude product by
column chromatography (SiO2, 2% EtOAc /hexanes) afforded
3ad1 as a brown liquid (0.042 g, 47%). TLC: Rf = 0.4 (SiO2, 20%
Following the General Procedure, to the mixture of (1-(prop-2- EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz): δ 7.15 (s, 1H), 7.10
yn-1-yl) cyclopentyl) methanol (1a) (0.050 g, 0.36 mmol) and (d, J = 7.94 Hz, 1H), 6.74 (d, J = 8.54 Hz, 1H), 6.16 (br. s., 1H),
phenol (2c) (0.033 g, 0.36 mmol) in anhydrous toluene (2 mL) 3.80 (d, J = 7.93 Hz, 1H), 3.67 (d, J = 7.93 Hz, 1H), 2.23 - 2.33
was added Bi(OTf)3 (0.023 g, 0.036 mmol) under argon (m, 4H), 2.10 (d, J = 12.2 Hz, 1H), 1.71-1.47(m, 8H), 1.45-1.26
atmosphere at room temperature and reaction mixture was (m, 2H); 13C NMR (CDCl3, 101 MHz): δ 152.5, 140.8, 127.3,
stirred for 6h at rt. Purification of the crude product by column 123.6, 123.0, 114.5, 84.8, 78.4, 53.2, 51.6, 38.4, 37.2, 31.5,
chromatography (SiO2, 2% EtOAc /hexane) afforded 3ac as a 24.7, 24.7, 16.1; HRMS (ESI) m/z calcd for C16H23O2 [M+H]+
brown liquid (0.042 g, 50%). TLC: Rf = 0.7 (SiO2, 20% 247.1693, found 247.1689.
EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz): δ 9.72 (s, 1H), 2-(3-Methyl-2-oxaspiro[4.4]nonan-3-yl)-N-phenylaniline (3ae)
7.02 (m, 1H), 6.93-6.85 (m, 1H), 6.74 (m, 2H), 3.72 (d, J = 8.01
Following the General Procedure, to the mixture of (1-(prop-2-
Hz, 1H), 3.61 (d, J = 8.39 Hz, 1H), 2.46 (d, J = 12.59 Hz, 1H), 2.08
yn-1-yl)cyclopentyl) methanol (1a) (0.050 g, 0.36 mmol) and
(d, J = 12.59 Hz, 1H), 1.61-1.46 (m, 11H); 13C NMR (CDCl3, 126
diphenylamine (2e) (0.061 g, 0.36 mmol) in anhydrous toluene
MHz): δ 155.2, 130.6, 128.3, 126.8, 119.2, 117.4, 88.6, 78.6,
(2 mL) was added Bi(OTf)3 (0.023 g, 0.036 mmol) under argon
52.4, 51.0, 37.9, 36.9, 30.8, 24.7, 24.6; HRMS (ESI) m/z calcd
atmosphere at room temperature and reaction mixture was
for C15H21O2 [M+H]+ 233.1536, found 233.1536.
4-(3-Methyl-2-oxaspiro[4.4]nonan-3-yl)phenol (3ac1):
stirred for 6h at rt. Purification of the crude product by column
chromatography (SiO2, 2% EtOAc/hexanes) afforded 3ae as a
Following the General Procedure, to the mixture of(1-(prop-2- brown liquid (0.063 g, 57%). TLC: Rf = 0.5 (SiO2, 20%
yn-1-yl) cyclopentyl) methanol (1a) (0.050 g, 0.36 mmol) and EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz): δ 7.33-7.21 (m,
phenol (2c) (0.033 g, 0.36 mmol) in anhydrous toluene (2 mL) 4H), 7.12-6.97 (m, 4H), 6.96–6.83 (m, 1H), 5.67 (s, 1H), 3.77 (d,
was added Bi(OTf)3 (0.023 g, 0.036 mmol) under argon J = 8.21 Hz, 1H), 3.64 (d, J = 8.21 Hz, 1H), 2.27 (d, J = 12.38 Hz,
atmosphere at room temperature and reaction mixture was 1H), 2.08 (d, J = 12.38 Hz, 1H), 1.82-1.56 (m, 6H), 1.52 (s, 3H),
stirred for 6h at rt. Purification of the crude product by column 1.44-1.35 (m, 2H); 13C NMR (CDCl3, 50 MHz): δ 143.5, 142.2,
chromatography (SiO2, 2% EtOAc/hexanes) afforded 3ac1 as a 141.1, 129.3, 125.6, 120.6, 117.8, 117.4, 84.4, 78.5, 53.1, 51.8,
brown liquid (0.035 g, 41%). TLC: Rf = 0.4 (SiO2, 20% 38.4, 37.2, 31.4, 24.7; HRMS (ESI) m/z calcd for C21H26NO
1
EtOAc/hexanes); H NMR (CDCl3, 200 MHz): δ 7.26(d, J = 8.59 [M+H]+ 308.2009, found 308.2006.
Hz, 2H), 6.78 (d, J = 8.59 Hz, 2H), 5.65 (br. s., 1H), 3.78 (d, J = 2-(3-Ethyl-2-oxaspiro[4.4]nonan-3-yl)naphthalen-1-ol (3ba)
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DOI: 10.1039/C8OB00368H
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Following the General Procedure, to the mixture of (1-(but-2- 30.6, 24.7; HRMS (ESI) m/z calcd for C26H29O2 [M+H]+ 373.2162,
yn-1-yl) cyclopentyl) methanol (1b) (0.050 g, 0.32 mmol) and found 373.2155.
naphthalen-1-ol (2a) (0.047 g, 0.32 mmol) in anhydrous 2-(3-Methyl-2-oxaspiro[4.5]decan-3-yl)naphthalen-1-ol (3ea)
toluene (2 mL) was added Bi(OTf)3 (0.021 g, 0.032 mmol)
Following the General Procedure, to the mixture of(1-(prop-2-
under argon atmosphere at room temperature and reaction
yn-1-yl) cyclohexyl) methanol (1e) (0.050 g, 0.032 mmol) and
mixture was stirred for 6h at rt. Purification of the crude
naphthalen-1-ol (2a) (0.049 g, 0.32 mmol) in anhydrous
product by column chromatography (SiO2, 2% EtOAc /hexanes)
toluene (2 mL) was added Bi(OTf)3 (0.020 g, 0.0032 mmol)
afforded 3ba as a brown liquid (0.079 g, 81%). TLC: Rf = 0.7
(SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz): δ 10.68
under argon atmosphere at room temperature and reaction
mixture was stirred for 6h at rt. Purification of the crude
(s, 1H), 8.29 (d, J = 8.55 Hz, 1H), 7.75 (d, J = 7.32 Hz, 1H), 7.54-
product by column chromatography (SiO2, 2% EtOAc /hexanes)
7.43 (m, 2H), 7.30 (d, J = 8.55 Hz, 1H), 7.01 (d, J = 8.54 Hz, 1H),
afforded 3ea as a brown liquid (0.068 g, 70%). TLC: Rf = 0.8
(SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz): δ 10.37
3.86-3.78 (m, 2H), 2.54 (d, J = 12.82 Hz, 1H), 2.24 (d, J = 12.21
Hz, 1H),2.06-1.86 (m, 2H), 1.74-1.47 (m, 8H), 0.88 (t, J = 7.32
Hz, 3H); 13C NMR (CDCl3, 101 MHz): δ 151.4, 133.4, 127.0,
(s, 1H), 8.27-8.14 (m, 1H), 7.71-7.57 (m, 1H), 7.44-7.30 (m, 2H),
7.22 (d, J = 8.59 Hz, 1H), 6.98 (d, J = 8.59 Hz, 1H), 3.79 (d, J =
126.1, 125.4, 125.3, 125.0, 122.4, 120.6, 118.4, 92.5, 78.6,
51.8, 50.7, 37.4, 37.0, 36.6, 24.7, 24.6, 8.6; IR (KBr, cm−1): ν
8.59 Hz, 1H), 3.63 (d, J = 8.59 Hz, 1H), 2.43 (d, J = 12.88 Hz, 1H),
1.93 (d, J = 12.76 Hz, 1H), 1.56 (s, 3H), 1.50-1.11 (m, 10H); 13C
3200, 2061, 2955, 2866, 1634, 1502, 1382, 807, 758, 671;
NMR (CDCl3, 126 MHz): δ 150.0, 133.5, 127.1, 126.1, 125.5,
HRMS (ESI) m/z calcd for C20H25O2 [M+H]+ 297.1849, found
125.1, 124.9, 122.6, 122.4, 118.7, 88.9, 77.8, 51.7, 44.3, 36.9,
297.1848.
35.9, 31.1, 25.8, 23.8, 23.7; HRMS (ESI) m/z calcd for C20H25O2
[M+H]+ 297.1849, found 297.1847.
2-(3-Benzyl-2-oxaspiro[4.4]nonan-3-yl)naphthalen-1-ol (3ca)
Following the General Procedure, to the mixture of (1-(3- 1-(3-Methyl-2-oxaspiro[4.5]decan-3-yl)naphthalen-2-ol (3eb)
phenylprop-2-yn-1-yl) cyclopentyl) methanol (1c) (0.050 g,
Following the General Procedure, to the mixture of (1-(prop-2-
0.23 mmol) and naphthalen-1-ol (2a) (0.033 g, 0.23 mmol) in
yn-1-yl) cyclohexyl) methanol (1ea) (0.050 g, 0.32 mmol) and
anhydrous toluene (2 mL) was added Bi(OTf)3 (0.015 g, 0.023
naphthalen-2-ol (2b) (0.049 g, 0.32 mmol) in anhydrous
mmol) under argon atmosphere at room temperature and
toluene (2 mL) was added Bi(OTf)3 (0.020 g, 0.032 mmol)
reaction mixture was stirred for 6h at rt. Purification of the
under argon atmosphere at room temperature and reaction
crude product by column chromatography (SiO2, 2% EtOAc
mixture was stirred for 8 h at rt. Purification of the crude
/hexanes) afforded 3ca as a brown liquid (0.050 g, 60%). TLC:
Rf = 0.7 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz):
product by column chromatography (SiO2, 2% EtOAc/hexanes)
afforded 3eb as a brown liquid (0.065 g, 60%). TLC: Rf = 0.7
1
(SiO2, 20% EtOAc/hexanes); H NMR (CDCl3, 400 MHz): δ 11.1
δ 10.30 (s, 1H), 8.26-8.11 (m, 1H), 7.80-7.63 (m, 1H), 7.48-7.38
(m, 2H), 7.30-7.22 (m, 2H), 7.18-7.08 (m, 3H), 7.02-6.86 (m,
(s, 1H), 7.75-7.74 (m, 1H), 7.64 (d, J = 9.16 Hz, 1H), 7.48-7.40
2H), 3.79-3.64 (m, 2H), 3.79-3.64 (m, 2H), 2.51 (d, J = 12.63 Hz,
(m, 2H), 7.30-7.27 (m, 1H), 7.06 (d, J = 8.54 Hz, 1H), 3.91 (d, J =
1H), 2.32 (d, J = 12.63 Hz, 1H), 1.69 - 1.44 (m, 8H); 13C NMR
8.54 Hz 1H), 3.72 (d, J = 8.54 Hz, 1H), 2.58 (d, J = 12.82 Hz, 1H ),
2.46 (d, J = 12.82 Hz, 1H) 1.90 (s, 3H), 1.73-1.59 (m, 10H); 13C
(CDCl3, 50 MHz): δ 151.3, 137.5, 136.5, 133.6, 130.8, 130.3,
127.7, 127.0, 126.5, 126.2, 125.6, 125.4, 124.9, 122.5, 120.8,
NMR (CDCl3, 101 MHz): δ 152.9, 131.2, 129.6, 129.3, 129.1,
118.2, 91.8, 78.8, 50.8, 50.1, 49.0, 37.3, 37.1, 29.7, 24.7, 24.6;
125.5, 124.4, 122, 120.9, 120.4, 89. 63, 77.34, 54.08, 44.4,
IR (KBr, cm−1): ν 3229, 3060, 2948, 2863, 1632, 1499, 1382,
35.9, 35.5, 30.3, 29.7, 25.9, 23.8, 23.5; HRMS (ESI) m/z calcd
805, 754, 702; HRMS (ESI) m/z calcd for C25H27O2 [M+H]+
for C20H25O2 [M+H]+ 297.1849, found 297.1846.
359.2006, found 359.2003.
2-(3-Ethyl-2-oxaspiro[4.5]decan-3-yl)naphthalen-1-ol (3fa)
2-(3-Phenethyl-2-oxaspiro[4.4]nonan-3-yl)naphthalen-1-ol (3da)
Following the General Procedure, to the mixture of (1-(but-
Following the General Procedure, to the mixture of (1-(4-
2-yn-1-yl) cyclohexyl) methanol (1f) (0.050 g, 0.30 mmol) and
phenylbut-2-yn-1-yl) cyclopentyl) methanol (1d) (0.050 g,
naphthalen-1-ol (2a) (0.043 g, 0.30 mmol) in anhydrous
0.021 mmol) and naphthalen-1-ol (2a) (0.031 g, 0.021 mmol) in
toluene (2 mL) was added Bi(OTf)3 (0.019 g, 0.030 mmol)
anhydrous toluene (2 mL) was added Bi(OTf)3 (0.013 g, 0.0021
under argon atmosphere at room temperature and reaction
mmol) under argon atmosphere at room temperature and
mixture was stirred for 6h at rt. Purification of the crude
reaction mixture was stirred for 8 h at rt. Purification of the
product by column chromatography (SiO2, 2% EtOAc /hexanes)
crude product by column chromatography (SiO2, 2% EtOAc
afforded 3fa as a brown viscous liquid (0.047 g, 49.88%). TLC:
Rf = 0.7 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz):
/hexanes) afforded 3da as a brown liquid (0.045 g, 51%). TLC:
Rf = 0.7 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz):
δ 10.56 (s, 1H), 8.35 - 8.26 (m, 1H), 7.79-7.71 (m, 1H), 7.51-
δ 10.58 (s, 1H), 8.30 (d, J=7.9 Hz, 1H), 7.76 (d, J = 9.16 Hz 1H),
7.42 (m, 2H), 7.34 (d, J = 8.77 Hz, 1H), 7.06 (d, J = 8.77 Hz, 1H),
7.55-7.42 (m, 2H), 7.39-7.17 (m, 4H), 7.17-6.96 (m, 3H), 3.91-
3.84 (d, J = 8.77 Hz, 1H), 3.79 (d, J = 8.77 Hz, 1H), 2.48 (d, J =
3.15 (m, 2H), 2.68-2.54 (m, 1H), 2.27-2.22 (m, 1H), 1.71-1.44
(m, 12H); 13C NMR (CDCl3, 101 MHz): 150.1, 142.1, 133.5
12.59 Hz, 1H), 2.01 (d, J = 12.97 Hz, 1H), 2.0-1.83 (m, 2H), 1.62-
1.45 (m, 5H), 1.43-1.26 (m, 5H), 0.88 (t, J = 7.44 Hz, 3H); 13C
128.3, 127.0, 126.1, 125.1, 124.9, 122.4, 118.7, 118.6, 91.9,
NMR (CDCl3, 126 MHz): δ 151.18, 133.5, 127.05, 126.1, 125.4,
89.2, 78.7, 52.7, 51.1, 50.07 46.1, 37.7, 37.3,36.9, 36.8, 30.9,
125.0, 122.4, 120.6, 118.4, 92.1, 77.7, 50.8, 43.9, 36.8, 36.7,
6 | J. Name., 2012, 00, 1-3
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35.9, 29.7, 25.8, 23.9, 23.6, 8.7; HRMS (ESI) m/z calcd for 4H), 7.14-7.10 (m, 2H), 5.02-4.86 (d, J = 9.16 Hz, 1H), 4.3 (d, J =
C21H27O2 [M+H]+ 311.2006, found 311.2003.
9.16 Hz, 1H), 3.43 (d, J = 12.59 Hz, 1H), 3.18-3.03 (d, J = 12.59
Hz, 1H), 1.49 (s, 3H); 13C NMR (CDCl3, 126 MHz): δ 149.5,
145.8, 145.03, 133.4, 128.6, 128.4, 127.1, 127.07, 126.9, 126.5,
126.2, 125,5, 125.23, 124.7, 123.44, 122.5, 119.1, 89.4, 76.1,
55.7, 52.3, 30.7; HRMS (ESI) m/z calcd for C27H25O2 [M+H]+
381.1849, found 381.1846.
2-(3-Propyl-2-oxaspiro[4.5]decan-3-yl)naphthalen-1-ol (3ga):
Following the General Procedure, to the mixture of 2-(1-(pent-
2-yn-1-yl)cyclohexyl)ethan-1-ol (1g) (0.050 g, 0.27 mmol) and
naphthalen-1-ol (2a) (0.039 g, 0.27 mmol) in anhydrous
toluene (2 mL) was added Bi(OTf)3 (0.018 g, 0.027 mmol)
under argon atmosphere at room temperature and reaction
mixture was stirred for 6 h at rt. Purification of the crude
5-Methyl-2-(2-methyl-4,4-diphenyltetrahydrofuran-2-yl)phenol
(3if)
product by column chromatography (SiO2, 2% EtOAc/hexanes) Following the General Procedure, to the mixture of (1-(prop-2-
afforded 3ga as a brown viscous liquid (0.058 g, 64%). TLC: Rf = yn-1-yl) cyclopentyl) methanol (1i) (0.050 g, 0.21 mmol) and p-
1
0.7 (SiO2, 20% EtOAc/hexanes); H NMR (CDCl3, 500 MHz): δ cresol (2f) (0.022 g, 0.21 mmol) in anhydrous toluene (2 mL)
10.57 (s, 1H), 8.38-8.26 (m, 1H), 7.82-7.74 (m, 1H), 7.54-7.44 was added Bi(OTf)3 (0.013 g, 0.021 mmol) under argon
(m, 2H), 7.33 (d, J = 8.77 Hz, 1H), 7.06 (d, J = 8.77 Hz, 1H), 3.86 atmosphere at room temperature and reaction mixture was
(d, J = 8.39 Hz, 1H), 3.79 (d, J = 8.39 Hz, 1H), 2.51 (d, J = 12.97 stirred for 6h at rt. Purification of the crude product by column
Hz, 1H), 2.05 (d, J = 12.59 Hz, 1H), 1.91-1.98 (m, 1H), 1.85 (td, J chromatography (SiO2, 2% EtOAc/hexanes) afforded 3if as a
= 12.78, 4.58 Hz, 1H), 1.45-1.60 (m, 6H), 1.40 (m, 2H), 1.29- brown liquid (0.050 g, 68%). TLC: Rf = 0.66 (SiO2, 20%
1.34 (m, 4H), 0.85 (t, J = 7.25 Hz, 3H); 13C NMR (CDCl3, 126 EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz): δ 9.13 (s, 1H),
MHz): δ 150.9, 133.4, 127.05, 126.1, 125.4, 125.04, 122.4, 7.43-7.27 (m, 4H), 7.22-7.09 (m, 6H), 6.92-6.83 (m, 1H), 6.80-
120.9, 118.4, 91.7, 77.7, 51.2, 46.5, 43.9, 36.8, 35.9, 29.7, 25.8, 6.73 (m, 1H), 6.73-6.65 (d, J = 8.21 Hz, 1H), 4.88 (d, J = 9.2 Hz,
23.9, 23.6, 17.6, 14.3; HRMS (ESI) m/z calcd for C22H29O2 1H), 4.23 (d, J = 9.09 Hz, 1H), 3.36 (d, J = 12.63 Hz, 1H), 3.06 (d,
[M+H]+ 325.2162, found 325.1908.
J = 11.62 Hz, 1H), 2.23 (s, 3H), 1.36 (s, 3H); 13C NMR (CDCl3, 50
2-(1,1,3-Trimethyl-2-oxaspiro[4.5]decan-3-yl)naphthalen-1-ol
(3ha)
MHz): δ 152.2, 145.8, 145.2, 130.9, 128.9, 128.5, 128.4, 127.1,
126.9, 126.5, 117.1, 88.7, 75.9, 55.7, 52.0, 30.7, 20.6; HRMS
(ESI) m/z calcd for C24H24O2 [M]+ 344.1771, found 344.2276.
Following the General Procedure, to the mixture of2-
methyl-1-(1-(prop-2-yn-1-yl)cyclohexyl)propan-2-ol (1h) (0.050
2-(2,5-Dimethyltetrahydrofuran-2-yl)naphthalen-1-ol (3ja)
g, 0.39 mmol) and naphthalen-1-ol (2a) (0.039 g, 0.39 mmol) in Following the General Procedure, to the mixture of hex-5-yn-2-
anhydrous toluene (2 mL) was added Bi(OTf)3 (0.018 g, 0.039 ol (1j) (0.050 g, 0.50 mmol) and naphthalen-1-ol (2a) (0.073 g,
mmol) under argon atmosphere at room temperature and 0.50 mmol) in anhydrous toluene (2 mL) was added Bi(OTf)3
reaction mixture was stirred for 6 h at rt. Purification of the (0.032 g, 0.050 mmol) under argon atmosphere at room
crude product by column chromatography (SiO2, 2% EtOAc temperature and reaction mixture was stirred for 6 h at rt.
/hexanes) afforded 3ha as a brown liquid (0.062 g, 69%). TLC: Purification of the crude product by column chromatography
Rf = 0.8 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz): (SiO2, 2% EtOAc /hexanes) afforded (3ja, dr. 2:1) as a mixture
δ 10.79 (s, 1H), 8.43-8.28 (m, 1H), 7.77 (m, 1H), 7.57-7.44 (m, of two diastereomers (0.080 g, 65%) as a brown liquid. TLC: Rf
2H), 7.35 (d, J = 8.55 Hz, 1H), 7.15 (d, J = 8.54 Hz, 1H), 2.76 (d, J = 0.7 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz):
= 13.43 Hz, 1H), 2.45 (d, J = 12.82 Hz, 1H), 1.81-1.69 (m, 4H),
δ 10.64 (s, 1H, major isomer), 10.49 (s, 1H, minor isomer),
1.66 (s, 3H), 1.58-1.40 (m, 4H), 1.33 (s, 3H), 1.21 (s, 3H), 1.18- 8.18-8.34 (m, 2H), 7.66-7.79 (m, 2H, major & minor isomers),
1.11 (m, 2H); 13C NMR (CDCl3, 101 MHz): δ 150.2, 133.3, 127.1, 7.39-7.51 (m, 4H, major & minor isomers), 7.30 (d, J = 8.72 Hz,
125.9, 125.6, 125.4, 124.9, 124.3, 122.5, 118.5, 87.9, 85.4, 2H, major & minor isomers), 7.01-7.13 (m, 2 H, major & minor
77.4, 47.7, 46.8, 33.3, 32.05, 31.9, 26.2, 24.4, 23.3, 23.28, 23.1; isomers), 4.49–4.36 (m, 1H, minor isomer), 4.31-4.11 (m, 1H,
IR (KBr, cm−1): ν 3218, 3019, 2933, 1597, 1381, 1216, 760, 666; major isomer), 2.6-1.9 (m, 6H, major & minor isomers), 1.61 (s,
HRMS (ESI) m/z calcd for C22H29O2 [M+H]+ 325.2162, found 3H, major isomer), 1.6 (s, 3H, minor isomer), 1.38 (d, J = 6.06
325.2161.
Hz, 3H, major isomer), 1.34 (d, J = 6.1 Hz, 3H, minor isomer);
13C NMR (CDCl3, 50 MHz): δ (two diastereomers) 150.84,
150.51, 133.57, 127.09, 126.12, 125.71, 125.52, 125.12,
125.07, 124.88, 124.40, 124.15, 122.67, 122.49, 122.40,
118.79, 118.62, 88.64, 88.42, 76.43, 39.66, 39.30, 32.84, 32.78,
30.53, 29.74, 29.52, 21.53, 21.13; HRMS (ESI) m/z calcd for
C16H19O2 [M+H]+ 243.1380, found 243.1377.
2-(2-Methyl-4,4-diphenyltetrahydrofuran-2-yl)naphthalen-1-ol
(3ia)
Following the General Procedure, to the mixture of
2,2diphenylpent-4-yn-1-ol
(1i) (0.050 g, 0.21 mmol) and
naphthalen-1-ol (2a) (0.031 g, 0.21 mmol) in anhydrous
toluene (2 mL) was added Bi(OTf)3 (0.013 g, 0.021 mmol)
under argon atmosphere at room temperature and reaction
mixture was stirred for 8 h at rt. Purification of the crude
2-(5-Benzyl-2-methyltetrahydrofuran-2-yl)naphthalen-1-ol (3ka)
Following the General Procedure, to the mixture of 2-
product by column chromatography (SiO2, 2% EtOAc/hexanes) phenylpent-4-yn-1-ol (1k) (0.100 g, 0.062mmol) and 1-Napthol
afforded 3ia as a brown liquid (0.054 g, 67%). TLC: Rf = 0.7 1a) (0.089 g, 0.062mmol) in anhydrous toluene (5 mL) was
10.25 added Bi(OTf)3 (0.04 g, 0.0062mmol) under argon atmosphere
(
1
(SiO2, 20% EtOAc/hexanes); H NMR (CDCl3, 500 MHz):
δ
(s, 1H), 8.31-8.17 (m, 1H), 7.7-7.61 (m, 1H), 7.53-7.47 (m, 4H), at room temperature and reaction mixture was stirred for 2h.
7.43-7.34 (m, 3H), 7.28 (d, J = 8.77 MHz, 1H), 7.23-7.16 (m, Purification of the crude product by column chromatography
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(SiO2, 2% EtOAc/hexanes) afforded (3ka, dr, 1:1.6) as a mixture 21.5; HRMS (ESI) m/z calcd for C19H23O2 [M+H]+ 283.1693,
of two diastereomers (0.120 g, 66%) as a brown liquid. TLC: Rf found 283.1691.
1
= 0.9 (SiO2, 20% EtOAc/hexanes); H NMR (CDCl3, 400 MHz): δ 2-(2-Methyloctahydrobenzofuran-2-yl)naphthalen-1-ol (3na)
(two diastereomers) 10.34 and 10.18 (s, 1H), 8.4-8.34 and
Following the General Procedure, to the mixture of 2-(prop-2-
8.33-28 (m, 1H), 7.82-7.71 (m, 1H), 7.5-7.4 (m, 2H), 7.39-7.24
yn-1-yl)cyclohexan-1-ol
(1n) (0.050 g, 0.36 mmol) and
(m, 5H), 7.17-7.03 (m, 1H), 4.67-4.51 and 4.45-4.25 (m,
1H),3.1-3.05 (m, 1H), 3.02-2.93 and 2.86-2.79 (m, 1H), 2.61-
2.41 (m, 1H), 2.30-1.92 (m, 2H), 1.89-1.75 (m, 1H), 1.63 (s, 3H);
13C NMR (CDCl3, 101 MHz): δ (two diastereomers) 150.8,
150.5, 138.1, 137.9, 133.5, 129.5, 129.1, 128.5, 128.4, 127.1,
126.5, 126.5, 126.1, 125.5, 125.1, 124.4, 122.2, 118.8, 88.8,
88.5, 81.4, 80.8, 42.2, 42.01, 38.9, 38.8, 30.6, 30.4, 30.2, 29.3;
HRMS (ESI) m/z calcd for C22H23O2 [M+H]+ 319.1693, found
319.1688.
naphthalen-1-ol (2a) (0.062 g, 0.36 mmol) in anhydrous
toluene (2 mL) was added Bi(OTf)3 (0.023 g, 0.036 mmol)
under argon atmosphere at room temperature and reaction
mixture was stirred for 8 h at rt. Purification of the crude
product by column chromatography (SiO2, 2% EtOAc/hexanes)
afforded 3na (0.062 g, 59%). as mixture of two diastereomers
(dr, 1:1) and as a brown liquid. TLC: Rf = 0.8 (SiO2, 20%
EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz):
δ (two
diastereomers) 10.85 (s, 1H), 10.67 (s, 1H), 8.37 & 8.22 (m,
2H), 7.75 & 7.65 (m, 2H), 7.46-7.40 (m, 4H), 7.29 (d, J = 8.59
Hz, 2H), 7.04 (dd, J = 8.53, 4.61 Hz, 2H), 4.25 (d, J = 4.93 Hz,
2-(2-Methyl-3a-(prop-2-yn-1-yl)-2,3,3a,4,5,9b-
hexahydronaphtho[1,2-b]furan-2-yl)naphthalen-1-ol (3la)
Following the General Procedure, to the mixture of 2,2- 1H), 4.07 (d, J = 4.04 Hz, 1H), 2.64 (dd, J = 11.62, 6.32 Hz, 1H),
di(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-ol 1l 2.43 & 2.24 (m, 5H), 1.91 & 2.16 (m, 5H), 1.71 & 1.58 (s, 3H) &
(
)
(0.050 g, 0.22 mmol) and naphthalen-1-ol (2a) (0.032 g, 0.22 (s, 3H), 1.24 - 1.50 (m, 12H); 13C NMR (CDCl3, 50 MHz): δ (two
mmol) in anhydrous toluene (2 mL) was added Bi(OTf)3 (0.014 diastereomers) 150.3, 149.8,149.7, 133.4, 133.3, 127, 126.1,
g, 0.022 mmol) under argon atmosphere at room temperature 126, 125.7, 125.5, 125.2, 125.1, 125, 124.9, 124.5, 123.9,
and reaction mixture was stirred for 6 h at rt. Purification of 123.6, 122.6, 122.4, 118.9, 118.7,118.5, 87.8, 87.6, 86.3, 81.1,
the crude product by column chromatography (SiO2, 2% EtOAc 80.5, 78.6, 77.8, 77.4, 77.1,76.7, 70.4, 52.4, 45.9, 45.8, 43.2,
/hexanes) afforded 3la as a single diastereomer (0.045 g, 55%) 37.9, 37.9, 32.1, 32.1, 31.9, 31.6, 30.2, 28.5, 28.1, 28.0, 26.6,
as a brown liquid. Diastereo-selectivity was confirmed by 2D 25.9, 24.9, 23.8, 22.6, 21.6, 21.5, 20.9, 20; HRMS (ESI) m/z
NMR analysis (COSY, HMBC, HSQC and NOE).13 TLC: Rf = 0.9 calcd for C19H23O2 [M+H]+ 283.1693, found 283.1690.
(SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz): δ 10.46 2-(2-Methyltetrahydrofuran-2-yl)naphthalen-1-ol (3oa)
(s, 1H), 8.43-8.31 (m, 1H), 7.81-7.71 (m, 1H), 7.53-7.34 (m,
Following the General Procedure, to the mixture of pent-4-yn-
4H), 7.29 (m, 2H), 7.25-7.15 (m, 2H), 4.59 (s, 1H), 3.07 (d, J =
1-ol (1o) (0.050 g, 0.59 mmol) and naphthalen-1-ol (2a) (0.085
13.26 Hz, 1H), 2.83 (m, 1H), 2.37–1.91 (m, 5H), 1.67 (s, 3H),
g, 0.59 mmol) in anhydrous toluene (2 mL) was added Bi(OTf)3
1.46-1.21 (m, 2H); 13C NMR (CDCl3, 126 MHz): δ 150.3, 137.5,
(0.038 g, 0.059 mmol) under argon atmosphere at room
133.7, 132.4, 131.2, 128.78, 128.76, 127.2, 126.7, 126.3, 125.5,
temperature and reaction mixture was stirred for 8 h at rt.
125.2, 124.8, 122.6, 121.9, 119.1, 87.1, 81.9, 80.9, 70.4, 51.04,
Purification of the crude product by column chromatography
44.1, 31.4, 30.7, 25.9, 25.8; HRMS (ESI) m/z calcd for C26H25O2
(SiO2, 2% EtOAc /hexanes) afforded 3oa as a brown liquid
[M+H]+ 369.1849, found 369.1847.
(0.096 g, 71%). TLC: Rf = 0.7 (SiO2, 20% EtOAc/hexanes); 1H
2-(2-Methyloctahydrobenzofuran-2-yl)naphthalen-1-ol (3ma)
NMR (CDCl3, 400 MHz): δ 10.44 (s, 1H), 8.39-8.26 (m, 1H),
Following the General Procedure, to the mixture of 2-(prop- 7.83-7.71 (m, 1H), 7.56-7.44 (m, 2H), 7.35 (d, J = 8.55 Hz, 1H),
2-yn-1-yl)cyclohexan-1-ol (1m, 1,2-trans substituted) (0.050 g, 7.13 (d, J = 8.55 Hz, 1H), 4.21-4.11 (m, 1H), 4.04-3.97 (m, 1H),
0.36 mmol) and naphthalen-1-ol (2a) (0.062 g, 0.36 mmol) in 2.59-2.46 (m, 1H), 2.24-2.16 (m, 1H), 2.15-2.06 (m, 1H), 2.04-
anhydrous toluene (2 mL) was added Bi(OTf)3 (0.023 g, 0.0036 1.94 (m, 1H), 1.66 (s, 3H); 13C NMR (CDCl3, 101 MHz): δ 150.7,
mmol) under argon atmosphere at room temperature and 133.6, 127, 126.1, 125.5, 125.1, 124.3, 122.4, 121.9, 118.8,
reaction mixture was stirred for 8 h at rt. Purification of the 88.5, 68.6, 38.8, 29.1, 25.3; IR (KBr, cm−1): ν 3205, 2973, 1501,
crude product by column chromatography (SiO2, 2% EtOAc 1455, 1304, 1216, 1030; 804, 757; HRMS (ESI) m/z calcd for
/hexanes) afforded 3ma (0.059 g, 56%) as mixture of two C15H17O2 [M+H]+ 229.1223, found 229.1222.
diastereomers (dr, 1:2) as a brown liquid. TLC: Rf = 0.8 (SiO2, 2-(2-Methyltetrahydro-2H-pyran-2-yl)naphthalen-1-ol (5aa)
20% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz): δ (two
Following the General Procedure, to the mixture of hex-5-yn-
diastereomers) 10.95 and 10.78 (s, 1H), 8.34-8.22 (m, 1 H),
1-ol (4a) (0.050 g, 0.50 mmol) and naphthalen-1-ol (2a) (0.073
7.76-7.64 (m, 1H), 7.52-7.31 (m, 2H), 7.34-7.23 (m, 1 H), 7.08-
g, 0.50 mmol) in anhydrous toluene (2 mL) was added Bi(OTf)3
6.99 (m, 1H), 3.52-3.23 (m, 1H), 2.61-2.30 (m, 2H), 2.28-2.10
(0.033 g, 0.0050 mmol) under argon atmosphere at room
(m, 1H), 2.02-1.78 (m, 2H), 1.75 and 1.60 (s, 2H), 1.54-1.01 (m,
temperature and reaction mixture was stirred for 10 h at rt.
6H); 13CNMR (CDCl3, 101 MHz): δ (two diastereomers) 151.3,
Purification of the crude product by column chromatography
149.7, 133.4, 129.1, 128.3, 127.1,127.03, 126.2, 126.1, 125.8,
(SiO2, 2% EtOAc /hexanes) afforded 5aa as a brown liquid
(0.072 g, 58%). TLC: Rf = 0.70 (SiO2, 20% EtOAc/hexanes); 1H
125.5, 125.3, 125.2, 125.1, 125.1, 124.7, 124.1, 122.5, 122.3,
118.9, 118.4, 89.2, 87.6, 84.1, 83.9, 47.4, 46.3, 45.1, 44.1. 31.4,
NMR (CDCl3, 200 MHz): δ 9.68 (s, 1H), 8.29 (dd, J = 6.19, 3.41
31.3, 31.01, 30.08, 30.26, 28.8, 28.6, 25.5, 25.4, 24.3, 24.1,
Hz, 1H), 7.75 (dd, J = 5.81, 3.03 Hz, 1H ), 7.46 (dd, J = 6.19,
3.28 Hz, 1H), 7.36 (d, J = 8.46 Hz, 1H), 7.17 (d, J = 8.72 Hz, 1H),
8 | J. Name., 2012, 00, 1-3
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4.01–3.82 (m, 1H), 3.67-3.46 (m, 1H), 2.49 (d, J = 11.37 Hz, 1H), 7.45 (m, 2H), 7.42-7.35 (m, 1H), 7.27-7.19 (m, 1H), 4.41 (d, J =
1.86-1.78 (m, 1H), 1.77-1.64 (m, 4H), 1.56 (s, 3H); 13C NMR 12.38 Hz, 1H), 3.86-3.66 (m, 5H), 1.56 (s, 3H); 13C NMR (CDCl3,
(CDCl3, 50 MHz): δ 152.1, 133.9, 127, 126.3, 125.4, 125, 124.5, 50 MHz): δ 151.9, 134.1, 127.1, 126.5, 125.5, 125.1, 124.3,
122.3, 119.4, 118.9, 80.1, 63.6, 34.7, 29.3, 25.4, 19.6; IR (KBr, 122.3, 119.3, 118.1 78.6, 72.6, 66.5, 62, 23.6; IR (KBr, cm−1): ν
cm−1): ν 3239, 3019, 2935, 1577, 1379, 1275, 760, 669; HRMS 3259, 3016, 2965, 2858, 1631, 1578, 1458, 1110, 803, 757;
(ESI) m/z calcd for C16H19O2 [M+H]+ 243.1380, found 243.1378.
HRMS (ESI) m/z calcd for C15H17O3 [M+H]+ 245.1172,found
245.1169.
2-(2,6-Dimethyltetrahydro-2H-pyran-2-yl)naphthalen-1-ol (5ba)
3-(Furan-2-yl)-3-methyl-2-oxaspiro[4.4]nonane (7aa):
Following the General Procedure, to the mixture of hept-6-yn-
2-ol (4b) (0.050 g, 0.40 mmol) and naphthalen-1-ol (2a) (0.058 Following the General Procedure, to the mixture of (1-(prop-2-
g, 0.40 mmol) in anhydrous toluene (2 mL) was added Bi(OTf)3 yn-1-yl) cyclopentyl) methanol (1a) (0.50 g, 0.36 mmol) and
(0.026 g, 0.0040 mmol) under argon atmosphere at room furan (6a) (0.024 g, 0.36 mmol) in anhydrous toluene (2 mL)
temperature and reaction mixture was stirred for 10 h at rt. was added Bi(OTf)3 (0.023 g, 0.036 mmol) under argon
Purification of the crude product by column chromatography atmosphere at room temperature and reaction mixture was
(SiO2, 2% EtOAc /hexanes) afforded 5ba as a brown liquid stirred for 4 h at rt. Purification of the crude product by
(0.063 g, 55%). TLC: Rf = 0.7 (SiO2, 20% EtOAc/hexanes); 1H column chromatography (SiO2, 2% EtOAc /hexanes) afforded
NMR (CDCl3, 400 MHz): δ 9.79 (s, 1H), 8.38-8.33 (m, 1H), 7.79 7aa as a brown liquid (0.033 g, 45%). TLC: Rf = 0.9 (SiO2, 20%
(dd, J = 5.91, 3.62 Hz, 1H), 7.53-7.47 (m, 2H), 7.39 (d, J = 8.77 EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz): δ 7.35 (s, 1H), 6.63
Hz, 1H), 7.20 (d, J = 8.39 Hz, 1H), 3.62 (ddd, J=12.21, 6.10, 2.29 (s, 1H), 6.20 (d, J = 3.05 Hz, 1H); 3.69 (m, 2H), 2.40 (d, J = 12.82
Hz, 1H), 2.60-2.54 (m, 1H), 1.81-1.67 (m, 4H), 1.60 (s, 3H), Hz, 1H), 1.90 (d, J = 12.21 Hz, 1H), 1.68-1.52 (m, 11H); 13C NMR
1.43-1.33 (m, 2H), 1.29 (d, J = 6.49 Hz, 3H); 13C NMR (CDCl3, (CDCl3, 50 MHz): δ 159.5, 141.5, 109.8, 104.3, 80.3, 78.6, 51.6,
101 MHz): δ 152.4, 133.9, 127.1, 126.2, 125.4, 124.9, 124.5, 50.2, 38.5, 36.9, 27.2, 24.7, 24.6;HRMS (ESI) m/z calcd for
122.4, 119.5, 118.8, 80.5, 69.4, 33.9, 32.6, 30.5, 22.5, 20.06, C13H19O2 [M+H]+ 207.1380, found 207.1166.
19.7; HRMS (ESI) m/z calcd for C17H21O2 [M+H]+257.1536, 2,5-Bis(3-methyl-2-oxaspiro[4.4]nonan-3-yl)furan (7aa1):
found 257.1532.
Following the General Procedure, to the mixture of (1-
5-(1-Hydroxynaphthalen-2-yl)-5-methylhexahydro-2H-furo[3,2-
(prop-2-yn-1-yl) cyclopentyl) methanol (1a) (0.50 g, 0.36
b]pyran-2-one (5ca)
mmol) and furan (6a) (0.024 g, 0.36 mmol) in anhydrous
Following the General Procedure, to the mixture of5-(but-3-yn- toluene (2 mL) was added Bi(OTf)3 (0.023 g, 0.036 mmol)
1-yl)-4-hydroxydihydrofuran-2(3H)-one
(4c) (0.050 g, 0.32 under argon atmosphere at room temperature and reaction
mmol) andnaphthalen-1-ol (2a) (0.047 g, 0.32 mmol) in mixture was stirred for 4hat rt. Purification of the crude
anhydrous toluene (2 mL) was added Bi(OTf)3 (0.021 g, 0.0032 product by column chromatography (SiO2, 2% EtOAc/hexanes)
mmol) under argon atmosphere at room temperature and afforded 7aa1 as a brown liquid (0.064 g, 51%) as a mixture of
reaction mixture was stirred for 10 h at rt. Purification of the two diastereomers (dr, 1:3, confirmed by HPLC analysis).13 TLC:
crude product by column chromatography (SiO2, 2% Rf = 0.8 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz):
EtOAc/hexanes) afforded 5ca as a colourless liquid (0.029 g, δ (two diastereomers) 6.10 (s, 2H), 3.69 (d, J = 1.4 Hz, 4H), 2.42
30%) as a single diastereomer. TLC: Rf = 0.4 (SiO2, 20% (d, J = 12.8 Hz, 2H), 1.88 (d, J = 12.8 Hz, 2H), 1.58 (s, 22H); 13C
EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz): δ 8.88 (s, 1H), NMR (CDCl3, 101 MHz): δ (two diastereomers) 158.3, 158.3,
8.34-8.24 (m, 1H), 7.84-7.77 (m, 1H), 7.59-7.49 (m, 2H), 7.43 104.7, 104.7, 80.2, 80.1, 78.53, 51.6, 50.1, 38.4, 36.8, 36.8,
(d, J = 8.77 Hz, 1H), 7.15 (d, J = 8.39 Hz, 1H), 4.28 (d, J = 3.05 27.0, 26.9, 24.7, 24.7, 24.5; HRMS (ESI) m/z calcd for C22H33O3
Hz, 2H), 2.79 (dd, J = 17.17, 3.81 Hz, 1H), 2.69 (d, J = 17.17 Hz, [M+H]+ 345.2424, found 345.2423.
1H) , 2.40 (m, 1H), 2.34-2.26 (m, 1H), 2.01- 2.07 (m, 2H), 1.62 3-Ethyl-3-(furan-2-yl)-2-oxaspiro[4.4]nonane(7ba) and 2,5-Bis(3-
(s, 3H); 13C NMR (CDCl3, 126 MHz): δ 175.3, 151.8, 134.1, ethyl-2-oxaspiro[4.4]nonan-3-yl)furan (7ba1)
127.1, 126.8, 125.5, 125.3, 123.7, 122.2, 119.8, 116.9, 79.6,
75.6, 69.9, 38.9, 29.8, 27.1, 21.6; IR (KBr, cm−1): ν 3685, 3345,
Following the General Procedure, to the mixture of (1-
(prop-2-yn-1-yl) cyclopentyl) methanol (7b) (0.50 g, 0.32
3022, 2931, 1784, 1580, 1379, 1215, 763, 672; HRMS (ESI) m/z
calcd for C18H19O4 [M+H]+ 299.1278, found 299.1276.
mmol) and furan (6a) (0.022 g, 0.32 mmol) in anhydrous
toluene (2 mL) was added Bi(OTf)3 (0.021 g, 0.032 mmol)
2-(2-Methyl-1, 4-dioxan-2-yl)naphthalen-1-ol (5da):
under argon atmosphere at room temperature and reaction
Following the General Procedure, to the mixture of 2-(prop-2- mixture was stirred for 4 h at rt. Purification of the crude
yn-1-yloxy)ethan-1-ol
(
4d
)
(0.050 g, 0.49 mmol) and product by column chromatography (SiO2, 2% EtOAc /hexanes)
7ba1 as a brown liquid (0.085 g,
naphthalen-1-ol (2a) (0.072 g, 0.49 mmol) in anhydrous afforded the mixture of 7ba
&
toluene (2 mL) was added Bi(OTf)3 (0.032 g, 0.0049 mmol) 86%). TLC: Rf = 0.9 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3,
under argon atmosphere at room temperature and reaction 200 MHz): δ 7.40 - 7.31 (m, 1 H), 6.34 - 6.24 (m, 1 H), 6.20 (d, J
mixture was stirred for 10 h at rt. Purification of the crude = 3.16 Hz, 1 H), 6.12 (s, 2H), 3.82 - 3.44 (m, 5H), 2.31 (d, J =
product by column chromatography (SiO2, 2% EtOAc /hexanes) 12.76 Hz, 3H), 1.97-1.37 (m, 34H), (td, J = 7.45, 1.77 Hz, 9H);
afforded 5da as a brown liquid (0.055 g, 45%). TLC: Rf = 0.8 13C NMR (CDCl3, 50 MHz): δ 158.1, 156.8, 141.4, 109.7, 106.36,
1
(SiO2, 20% EtOAc/hexanes); H NMR (CDCl3, 200 MHz): δ 9.20 105.9, 105.6, 84.2, 78.3, 72.4, 71.1, 51.2, 48.4, 48.2, 41.5, 38.5,
(s, 1H), 8.37-8.24 (m, 1H), 7.76 (dd, J = 5.87, 3.47 Hz, 1H), 7.55- 38.4, 37.3, 37.3, 37.2, 36.3, 34.5, 33.3, 33., 31.7, 29.6, 28.8,
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24.9, 24.6, 24.5, 24.4, 8.9; HRMS (ESI) m/z calcd for (7ba) HRMS (ESI) m/z calcd for C21H20O2 [M+Na]+ 327.1356, found
C14H21O2, [M+H]+ 221.1536, found 221.1534, HRMS (ESI) m/z 327.1352.
calcd for (7ba1) C24H37O3, [M+H]+ 373.2737, found 373.2735.
2-(2-Methyl-4,4-diphenyltetrahydrofuran-2-yl)-5-(2-methyl-4,4-
diphenyltetrahydrofuran-2-yl)furan (7ia1)
3-(Furan-2-yl)-3-methyl-2-oxaspiro[4.5]decane (7ea)
Following the General Procedure, to the mixture of (1-
Following the General Procedure, to the mixture of
(prop-2-yn-1-yl) cyclohexyl) methanol (1e) (0.050 g, 0.32 2,2diphenylpent-4-yn-1-ol (1f) (0.050 g, 0.21 mmol) and furan
mmol) and furan (6a) (0.042 g, 0.64 mmol) in anhydrous 6a) (0.014 g, 0.21 mmol) in anhydrous Toluene (2 mL) was
(
toluene (2 mL) was added Bi(OTf)3 (0.020 g, 0.032 mmol) added Bi(OTf)3 (0.013 g, 0.021mmol) under argon atmosphere
under argon atmosphere at room temperature and reaction at room temperature and reaction mixture was stirred for 4h
mixture was stirred for 4 h at rt. Purification of the crude at rt. Purification of the crude product by column
product by column chromatography (SiO2, 2% EtOAc /hexanes) chromatography (SiO2, 2% EtOAc /hexanes) afforded 7ia1 as a
afforded 7ea as a brown liquid (0.043 g, 60%). TLC: Rf = 0.9 viscous yellow liquid (0.067g, 59%), as a mixture of two
1
(SiO2, 20% EtOAc/hexanes); H NMR (CDCl3, 200 MHz): δ 7.39- inseparable diastereomers (confirmed by 1H NMR and HPLC
7.31 (m, 1H), 6.33-6.25 (m, 1H), 6.18 (d, J = 2.65 Hz, 1H), 3.73 analysis). TLC: Rf = 0.8 (SiO2, 20% EtOAc/hexanes); 1H NMR
(d, J = 8.72 Hz, 1H), 3.62 (d, J = 8.72 Hz, 1H), 2.26 (d, J = 12.88 (CDCl3, 200 MHz): δ 7.36-7.09 (m, 20H), 6.03–5.84 (d, J = 0.63
Hz, 1H), 1.76 (d, J = 13.0 Hz, 1H), 1.59 (s, 3H), 1.56-1.36 (m, Hz, 2H), 4.68 (dd, J = 8.84, 4.80 Hz, 2H), 4.26 (dd, J = 9.35, 1.01
10H); 13C NMR (CDCl3, 50 MHz): δ 159.4, 141.5, 109.8, 104.4, Hz, 2H), 3.22 (dd, J = 13.01, 7.33 Hz, 2H), 2.64 (d, J = 13.01 Hz,
80.1, 49.3, 44.7, 37.2, 36, 27.6, 25.9, 23.9, 23.7; HRMS (ESI) 2H), 1.38 (d, J = 2.53 Hz, 6H); 13C NMR (CDCl3, 50 MHz): δ
m/z calcd for C14H21O2 [M+H]+ 221.1536, found 221.1534.
158.1, 158, 147.3, 145.9, 128.3, 127.2, 126.2, 126.1, 105, 105,
3-(Furan-2-yl)-3-methyl-2-oxaspiro[4.5]decane (7ea) and 2,5-Bis(3- 80.6, 80.6, 76.5, 76.5, 56.5, 56.5, 49.7, 26.6, 26.4; IR (KBr,
methyl-2-oxaspiro[4.5]decan-3-yl)furan (7ea1)
cm−1): ν 3376, 3016, 1599, 1444, 1216, 760, 702; HRMS (ESI)
m/z calcd for C38H37O3 [M+H]+ 541.2737, found 541.2737.
2-(Furan-2-yl)-2-methyl-3a-(prop-2-yn-1-yl)-3,3a,4,8b-tetrahydro-
2H-indeno[1,2-b]furan (7pa) and 2-(2-Methyl-3a-(prop-2-yn-1-yl)-
3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]furan-2-yl)-5-(2-methyl-3a-
(prop-2-yn-1-yl)-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]furan-2-
yl)furan (7pa1)
Following the General Procedure, to the mixture of and (1-
(prop-2-yn-1-yl)cyclopentyl) methanol
(1e) (0.050 g, 0.32
mmol) and furan (6a) (0.021 g, 0.32 mmol) in anhydrous
toluene (2 mL) was added Bi(OTf)3 (0.22 g, 0.032 mmol) under
argon atmosphere at room temperature and reaction mixture
was stirred for 4 h at rt. Purification of the crude product by
column chromatography (SiO2, 2% EtOAc /hexanes) afforded Following the General Procedure, to the mixture of 2,2-
the inseparable mixture of 7ea 1p (0.050 g,
7ea1 as a brown viscous di(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-ol
&
(
)
liquid (0.070 g, 74%). TLC: Rf = 0.9 (SiO2, 20% EtOAc/hexanes); 0.23 mmol) and furan (6a) (0.016 g, 0.23 mmol) in anhydrous
1H NMR (CDCl3, 200 MHz): δ 7.36 - 7.30 (m, 1H), 6.28 (dd, J = toluene (2 mL) was added Bi(OTf)3 (0.015 g, 0.023 mmol)
3.28, 1.89 Hz, 1H), 6.18 (d, J = 3.28 Hz, 1H), 6.07 (d, J = 0.88 Hz, under argon atmosphere at room temperature and reaction
2H), 3.76-3.58 (m, 6H), 2.33-2.22 (m, 3H), 1.80-1.68 (m, 3H), mixture was stirred for 4 h at rt. Purification of the crude
1.56 (d, J = 2.02 Hz, 8H), 1.52-1.36 (m, 30H); 13C NMR (CDCl3, product by column chromatography (SiO2, 2% EtOAc /hexanes)
50 MHz): δ 159.4, 158.3, 158.2, 141.6, 109.8, 104.8, 104.4, afforded mixture of 7pa
&
7pa1 as a viscous brown liquid
80.1, 80, 77.8, 49.2, 44.6, 37.2, 36, 29.7, 27.6, 27.5, 27.4, 25.9, (0.085 g, 92%). TLC: Rf = 0.9 (SiO2, 20% EtOAc/hexanes); 1H
23.9, 23.7; HRMS (ESI) m/z calcd for (7ea) C14H21O2, [M+H]+ NMR (CDCl3, 200 MHz): δ 7.44 (d, J = 2.53 Hz, 1H), 7.40-7.37
221.1536, found 221.1533; HRMS (ESI) m/z calcd for (7ea1) (m, 2H), 7.28-7.20 (m, 10H), 6.32-6.31 (m, 2H), 6.00 (dd, J =
C24H37O3 [M+H]+ 373.2737, found 373.2733.
3.22, 1.83 Hz, 1H), 5.64-5.60 (m, 1H), 5.31-5.26 (m, 3H), 3.13
(d, J = 6.06 Hz, 4H), 2.92 (d, J = 2.53 Hz, 2H), 2.79 (d, J = 13.39
Hz, 3H), 2.53-2.48 (m, 3H), 2.41 (dd, J = 4.93, 2.65 Hz, 4H), 2.33
(t, J = 4.23 Hz, 2H), 2.07-1.96 (m, 4H), 1.92 (t, J = 2.59 Hz, 2H),
1.64 (s, 3H), 1.43 (s, 6H); 13C NMR (CDCl3, 50 MHz): δ 159,
142.7, 141.7, 141.5, 141, 128.7, 127.1, 125.8, 125.7, 125.2,
124.7, 110.1, 109.8, 104.6, 91.7, 91.6, 82.8, 82.4, 82.2,69.8,
69.5, 54.7, 54.5, 49.4, 48.8, 43.7, 43.5, 29.7, 28.8, 28.5, 28.3,
27.5; HRMS (ESI) m/z calcd for (7pa) C19H19O2, [M+H]+
279.1380, found 279.1375; HRMS (ESI) m/z calcd for (7pa1)
C34H33O3, [M+H]+ 489.2424, found 489.2418.
2-(2-Methyl-4,4-diphenyltetrahydrofuran-2-yl)furan (7ia):
Following the General Procedure, to the mixture of
2,2diphenylpent-4-yn-1-ol (1f) (0.050 g, 0.21 mmol) and furan
(
6a) (0.014 g, 0.21 mmol) in anhydrous toluene (2 mL) was
added Bi(OTf)3 (0.13 g, 0.021mmol) under argon atmosphere
at room temperature and reaction mixture was stirred for 4h
at rt. Purification of the crude product by column
chromatography (SiO2, 2% EtOAc/hexanes) afforded 7ia as a
viscous yellow liquid (0.028g, 40%). TLC: Rf = 0.9 (SiO2, 20%
EtOAc/hexanes); 1H NMR (CDCl3, 200 MHz): δ 7.42-7.09 (m,
11H), 6.29-6.16 (m, 1H), 6.07 (d, J = 3.03 Hz, 1H), 4.76 (d, J =
9.22 Hz, 1H), 4.31 (d, J = 9.35 Hz, 1H), 3.30 (d, J = 12.88 Hz, 1H),
2-(5-Benzyl-2-methyltetrahydrofuran-2-yl)furan (7ka)
Following the General Procedure, to the mixture of 2-
2.73 (d, J = 12.88 Hz, 1H), 1.42 (s, 3H); 13C NMR (CDCl3, 50 phenylpent-4-yn-1-ol (1k) (0.100 g, 0.062mmol) and furan (6a
)
MHz): δ 159.1, 147, 145.9, 141.7, 128.4, 127.2, 126.2, 126.1, (0.042 g, 0.062 mmol) in anhydrous toluene (5 mL) was added
109.9, 104.6, 80.6, 56.5, 49.6, 26.6; IR (KBr, cm−1): ν 3057, Bi(OTf)3 (0.04 g, 0.006 mmol) under argon atmosphere at
2975, 2862, 1596, 1493, 1448, 1292, 1155, 1057, 755, 698; room temperature and reaction mixture was stirred for 2 h.
Purification of the crude product by column chromatography
10 | J. Name., 2012, 00, 1-3
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(SiO2, 2% EtOAc/hexanes) afforded two inseparable mixture of /hexanes) afforded 7ac as a viscous brown liquid (0.057 g,
diastereomers of 7ka (dr, 1:2) as a viscous and colourless liquid 59%). TLC: Rf = 0.5 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3,
(0.072 g, 51%). TLC: Rf = 0.9 (SiO2, 20% EtOAc/hexanes); 1H 400 MHz): δ 7.65 (d, J = 7.83 Hz, 1H), 7.34-7.18 (m, 2H), 7.18-
NMR (CDCl3, 500 MHz): δ 7.4-7.1 (m, 6H), 6.37-6.28 (m, 1H), 7.02 (m, 1H), 6.97 (s, 1H), 3.81-3.29 (m, 5H), 2.45 (d, J = 12.38
6.26-6.17 (m, 1H), 4.39-4.30 (m, 1H), 3.15-3.01 (m, 1H), 2.83- Hz, 1H), 2.14 (d, J = 12.25 Hz, 1H), 1.68 (s, 3H), 1.67-1.36 (m,
2.70 (m, 1H), 2.05-1.96 (m, 1H), 1.9-1.7 (m, 2H), 1.60 and 1.59 8H); 13C NMR (CDCl3, 101 MHz): δ 137.7, 125.5, 124.7, 123,
(s, 1:2, 3H); 13C NMR (CDCl3, 126 MHz): δ 159.6, 159.3, 141.6, 121.3, 120.3, 118.7, 109.3, 82.2, 78.1, 52.3, 51.9, 38.6, 37.3,
141.4, 138.8, 138.5, 129.5, 129.3, 128.3, 128.2, 126.2, 109.9, 32.6, 30.3, 24.7, 24.7; HRMS (ESI) m/z calcd for C18H24NO
109.8, 104.5, 104.4, 80.7, 80.4, 80.3, 80.2, 42.5, 42.2, 37.6, [M+H]+ 270.1852, found 270.1851.
36.7, 31.6, 30.8, 26.9, 26.5. HRMS (ESI) m/z calcd for C16H19O2 3-(5-(4-Methoxybenzyl)-2-methyltetrahydrofuran-2-yl)-1-methyl-
[M+H]+ 243.1380, found 243.1376.
1H-indole (7rc):
2-(2-Methyl-5-phenyltetrahydrofuran-2-yl)furan (7qa)
Following the General Procedure, to the mixture of 2-(4-
Following the General Procedure, to the mixture of 1- methoxybenzyl)pent-4-yn-1-ol
(1r) (0.100 g, 0.048 mmol)
phenylpent-4-yn-1-ol (1q) (0.1 g, 0.062 mmol) and furan (6a) and1-methyl-1H-indole (6c) (0.064 g, 0.048 mmol) in
(0.042 g, 0.062 mmol) in anhydrous toluene (2 mL) was added anhydrous toluene (5 mL) was added Bi(OTf)3 (0.031 g, 0.004
Bi(OTf)3 (0.040 g, 0.006 mmol), under argon atmosphere at mmol) under argon atmosphere at room temperature and
room temperature and reaction mixture was stirred for 2 h. reaction mixture was stirred for 2 h. Purification of the crude
Purification of the crude product by column chromatography product by column chromatography (SiO2, 2% EtOAc/hexanes)
(SiO2, 2% EtOAc/hexanes) afforded inseparable mixture of afforded 1:1 diastereomers 7rc as a viscous colourless liquid
diastereomers of 7qa (dr, 1:1) as a viscous colourless liquid (0.081 g, 59%). TLC: Rf = 0.7 (SiO2, 20% EtOAc/hexanes); 1H
(0.078 g, 51%). TLC: Rf = 0.9 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz):
δ 7.67 (d, J = 8.01 Hz 1H), 7.15-6.98 (m,
NMR (CDCl3, 200 MHz): δ 7.46-7.02 (m, 6H), 6.38-6.29 (m, 1H), 3H), 7.15-7.01 (m, 3H), 6.82 (t, J = 8.77 Hz, 2H), 4.11 (dt, J =
6.28-6.20 (m, 1H), 4.41-4.22 (m, 1H), 4.01-3.82 (m, 1H), 3.75- 8.01, 7.63 Hz, 1H), 3.83-3.66 (m, 6H), 2.73-2.52 (m, 3H), 2.37-
3.49 (m, 1H), 2.85-2.69, (m, 1H), 2.66-2.30 (m, 1H) 2.05 (dd, J 2.07 (m, 1H), 1.75 and 1.66 (two singlet, 3H); (CDCl3, 126 MHz):
= 10.74, 10.61 Hz, 1H), 1.69 and 1.66 (two s, 3H); 13C NMR
δ 157.9, 137.7, 133.0, 129.5, 125.4, 124.6, 121.4, 121.3, 120.5,
(CDCl3, 50 MHz): δ 158.8, 142, 141.7, 140.5, 128.6, 127.5, 120.3, 118.8, 118.8, 113.8, 109.3, 82.6, 82.1, 72.7, 72.4, 55.2,
127.3, 126.7, 126.6, 110, 104.8, 104.7, 81.2, 80.4, 74.5, 74.4, 45.6, 45.3, 42.1, 41.6, 38.8, 38.3, 32.6, 29.6, 29.3. HRMS (ESI)
46.1, 45.3, 44.8, 26.6. HRMS (ESI) m/z calcd for C15H17O2 m/z calcd for C22H26NO2 [M+H]+ 336.1958, found 336.1954.
[M+H]+ 229.1223, found 229.1585.
3-(3-Methyl-2-oxaspiro[4.4]nonan-3-yl)-1H-indole (7ab)
Conflicts of interest
Following the General Procedure, to the mixture of(1-(prop-2-
There are no conflicts to declare.
yn-1-yl) cyclopentyl) methanol (1a) (0.050 g, 0.36 mmol) and
1H-indole-1-carboxylic pivalic anhydride (6b
) (0.078 g, 0.36
mmol) in anhydrous toluene (2 mL) was added Bi(OTf)3 (0.023
g, 0.036 mmol) under argon atmosphere at room temperature
and reaction mixture was stirred for 6 h at rt. Purification of
the crude product by column chromatography (SiO2, 2% EtOAc
/hexanes) afforded 7ab as a viscous brown liquid (in this case -
BOC deprotected in situ) (0.048 g, 52%). TLC: Rf = 0.6 (SiO2,
Acknowledgements
We are thankful to the SERB (Science & Engineering Research
Board), New Delhi, India for financial support (Grant No.
YSS/2015/000725). A. K. N thanks DST-India for INSPIRE
Fellowship (JRF), and M. S. P thanks CSIR-India for the award of
Junior Research Fellowship (JRF). The authors thank Dr. C. V.
Ramana and Dr. D. Srinivasa Reddy for their support and
encouragement.
1
20% EtOAc/hexanes); H NMR (CDCl3, 400 MHz): δ 8.11 (br. s,
1H), 7.72 (m, 1H), 7.37 (m, 1H), 7.22-7.18 (m, 3H), 3.85 (d, J =
8.34 Hz, 1H), 3.77 (d, J = 8.21 Hz, 1H), 2.46 (d, J = 12.25 Hz, 1
H), 2.15 (d, J = 12.25 Hz, 1H), 1.75 (s, 3H) , 1.71–1.49 (m, 8H);
13C NMR (CDCl3, 101 MHz): δ 137.1, 125.1, 124.3, 121.7, 120.2,
119.9, 119.2, 111.2, 82.2, 78.2, 52.1, 51.8, 38.6, 37.3, 30, 24.7, Notes and references
24.7; IR (KBr, cm−1): ν 3618, 3475, 3416, 3011, 2957, 2863,
1
(a) J. Cossy, Synthesis of Saturated Oxygenated Heterocycles
1544, 1340, 1216, 1040, 764; HRMS (ESI) m/z calcd for
C17H22NO [M+H]+ 256.1696, found 256.1694.
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anhydrous toluene (2 mL) was added Bi(OTf)3 (0.037 g, 0.036
mmol) under argon atmosphere at room temperature and
reaction mixture was stirred for 6 h at rt. Purification of the
crude product by column chromatography (SiO2, 2% EtOAc
7
Uddin, V. M. Ramdeen, N. A. Cochrane, G. C. Fortman, T. B.
Gunnoe, T. R. Cundari, M. Sabat and W. H. Myers, ACS
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ARTICLE
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