Shifting the Reactivity of Bis-propargyl Ethers from Garratt-Braverman Cyclization Mode to 1,5-H Shift Pathway to Yield 3,4-Disubstituted Furans: A Combined Experimental and Computational Study

Article abstract of DOI:10.1021/acs.joc.5b02246

Aryl or vinyl substituted bis-propargyl ethers upon base treatment generally form phthalans via the Garratt-Braverman (GB) cyclization pathway. In a major departure from this usual route, several aryl/vinyl bis-propargyl ethers with one of the acetylenic

Full text of DOI:10.1021/acs.joc.5b02246

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Article
Shifting the Reactivity of Bis-propargyl ethers from Garratt-Braverman
Cyclization Mode to 1, 5- H shift Pathway to Yield 3, 4-Disubstituted
Furans: A Combined Experimental and Computational Study
Joyee Das, Eshani Das, Saibal Jana, Partha Sarathi Addy, Anakuthil Anoop, and Amit Basak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02246 • Publication Date (Web): 16 Dec 2015
Downloaded from http://pubs.acs.org on December 22, 2015
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The Journal of Organic Chemistry
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Shifting the Reactivity of Bis-propargyl ethers from
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Garratt-Braverman Cyclization Mode to 1, 5- H shift
Pathway to Yield 3, 4-Disubstituted Furans: A
Combined Experimental and Computational Study
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Joyee Das+, Eshani Das#, Saibal Jana, Partha Sarathi Addy, Anakuthil Anoop* and Amit
Basak*
Department of Chemistry, Indian Institute of Technology Kharagpur 721 302 India
*Corresponding author
+ major contributor to the experimental work; # major contributor to the computational work
Email: absk@chem.iitkgp.ernet.in, anoop@chem.iitkgp.ernet.in
Abstract
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Aryl or vinyl substituted bis-propargyl ethers upon base treatment generally form phthalans via the
Garratt-Braverman (GB) Cyclization pathway. In a major departure from this usual route, several
aryl/vinyl bis-propargyl ethers with one of the acetylenic arms ending up with 2-tetrahydropyranyloxy
methyl or ethoxy methyl have been shown to follow the alternative intramolecular 1, 5-H shift pathway
upon base treatment. The reaction has led to the formation of synthetically as well as biologically
important 3, 4-disubstituted furan derivatives in good yields. The initially formed E-isomer in solution
(CDCl3) slowly isomerizes to the Z-isomer indicating greater stability of the latter. The factors affecting
the interplay between the 1, 5-H shift and GB rearrangement have also been evaluated and the results
are supported by DFT based computational study.
Key Words: H-shift, Garratt-Braverman Cyclization, Furans, Bis-allene, Diradical, Propargyl
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Ethers
1
2
3
4
Introduction
5
The study of reactivity of bis-propargyl sulfones, ethers and sulfonamides has drawn interest in recent
years.1 The reaction involves the formation of 2 C-C bonds in high yields under mild conditions leading
to the formation of an aromatic ring and is popularly known as Garratt-Braverman (GB) cyclization.2
The synthetic utility of the reaction has recently been elaborated in a series of publications.3 The
involvement of a diradical intermediate from an in situ generated bis-allene intermediate (Scheme 1), as
proposed initially by Garratt and Braverman4 and later supported by computations and selectivity
profiles,5 is the generally accepted mechanism although other possibilities like an anionic intramolecular
Diels-Alder reaction has also been proposed.6 One interesting aspect of the reactivity of appropriately
substituted bis-propargyl systems is the possibility of 1, 5-H shift to internally quench the diradical
intermediate (Scheme 2). Normally this reaction occurs when there is no involvement of double bond
(from an alkene or an existing aromatic ring). For systems where this participation is possible, GB
cyclization pathway becomes dominant as that creates a stabilized aromatic ring. It is thus a challenge to
shift the reaction towards 1, 5-H shift pathway which creates a lesser stabilized furan system. We have
undertaken a project to study the parameters that might help in tilting the preference from GB to 1, 5-H
shift pathway. The present study has been restricted to bis-propargyl ether systems only as in these
cases, we have achieved fair amount of success in inducing predominant 1, 5-shift and the results are
described herein. Incidentally the 1, 5-H shift products are 3, 4-disubstituted furans which are important
in organic synthesis7 and are also present in various biologically interesting natural products.8 Our
method offers an alternative way to obtain these disubstituted furans in high yields.
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•
C
Ph
X
X
X
X
•
Ph
C
H
Ph
I
IV
II
III
X = SO2, O, N
H H
X
X
H
V
VI
Scheme 1: GB cyclization of aryl substituted bis-propargyl systems
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C
•
Ph
H
X
X
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X
C
VIII
R
•
VII
X = SO2, O, N
IX
X
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19
R
Scheme 2: 1, 5-H shift from the diradical intermediate
It was realized that to offset the participation of double bond for the GB cyclization, we may need to
weaken the C-H bond involved in the 1, 5-shift. Another possible strategy may involve the use of
different aryl systems with varying degree of resonance stability or double bond fixation. The latter is
important because in the process of generating an aromatic system in GB cyclization, the pre-existing
aromatic ring has to lose its aromaticity to participate in the mutual quenching of diradicals. Higher loss
may shift the preference towards the 1, 5-shift pathway. These possibilities are schematically
represented in Figure 1.
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Decrease double bond fixation
O
Increase aromatic stability
R
R1
•
A
X
•
R = alkene, aryl
R1 = OTHP, OEt, H
Weaken this bond
R
H
Figure 1: Strategies to tilt the preference towards 1, 5 H-shift pathway
Taking all these aspects into consideration, we decided to synthesize bis-propargyl ethers as
represented by general structure A (Figure 1). The R group at one arm was planned to be varied from
phenyl (or substituted phenyl) to naphthalene or even to a simple alkene. This will provide us an idea
about the influence of electron delocalization on the course of the reaction. At the other end, an ethereal
system (OTHP or OEt) was incorporated with the hope that the incipient radical generated during H
migration would be stabilized by electron donation from the adjacent oxygen.
Results and discussion
The synthesis of the target molecules 1a-8a is shown in Scheme 3 (for 9a, see reference 3d). The key
step involved O-alkylation of mono THP-protected butyne 1,4-diol 10 with the eneyne bromides 11a-
15a (prepared via eneyne coupling and functional group manipulations following published
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procedures1). The olefinic substrate 6a was obtained via Sonogashira coupling between the alkyne 16
1
2
3
and vinyl bromide.
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5
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8
9
O
O
R = Ph
Br
1. PPTS
OH
R
R
11a-15a
i
10
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2. i, CH3CH2I
OCH2CH3
OTHP
OTHP
1a-5a
7a
10
O
O
Me
O
iii
11a
i
OTHP
THPO
Me
OH
R
17
8a
16
6a
O
O
O
ii
R
+
R
X
X
X
18
19
For 1a,11a R = Phenyl For 2a,12a R = 2,4-Dimethoxy Phenyl For 3a,13a R = 4-
Methoxy Phenyl For 4a,14a R = 4- Methyl Phenyl For 5a, 15a R = Naphthyl
For 1a, 2a, 3a, 4a, 7a H-shift product (19) is exclusive
For 8a GB product (18) is only product
For 5a , 19 is major product
For 6a , 18 is major product
i) NaH, dry DMF, 0 oC to rt, ii) KOtBu, dry DMSO, rt
iii) Vinyl bromide, PdCl2(PPh3)2, CuI, dry Et3N, rt,
Scheme 3: Synthesis of target propargyl ethers
The substrates were then subjected to the conditions usually adapted for GB cyclization. Thus a DMSO
solution of the ethers was treated with KOtBu (1.2 eq) and the solution was stirred at room temperature
for 1 h by which time all the starting material was consumed. Usual work up (quenching with NH4Cl
and extracting into ethyl acetate) followed by column chromatography (Si-gel) afforded the products.
The results are shown in Table 1.
A thorough analysis of the results revealed several interesting outcomes. For phenyl or substituted
phenyl ethers, the reaction followed only the 1, 5-shift pathway. The presence of acetal/ethereal oxygen
at the other arm plays an important role as replacement with simple methyl forced the reaction to
proceed entirely through GB pathway. Another interesting aspect is in the case of naphthalene and vinyl
substituted propargyl ethers. In these cases, both GB and 1, 5-H shift products were produced in
different ratios. This validates our assertion that lesser sacrifice of aromaticity/delocalization energy
during self- quenching of the diradical via GB pathway may allow the GB product to be formed. This is
what was observed in naphthalene system which has less resonance energy per benzene ring as
compared to only phenyl thus allowing GB product to be formed, although in less amount (ratio of 1, 5-
H shift product and GB product was 1:0.2) as compared to no GB product in case of phenyl based
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systems. For the vinyl system, no such issue arises and hence the GB product became the predominant
product.
1
2
3
Double bond fixation also played an important role in deciding the favored pathway. This is exemplified
by the earlier reported isolation of only the 1, 5-H shift product from the 1, 4-dimethoxy naphthyl
substituted ether 9a. In naphthalene, there is non-equivalency of bond order due to partial bond fixation
which gives less double bond character to the C2-C3 bond.
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The structures of the various products were confirmed by NMR and mass spectroscopic data analysis.
For the 3, 4-disubstituted furan derivatives, the geometry of the double bond in the initially formed
product was found to be E (trans) (J = 12.6 Hz) which, however, got converted into the Z (cis) form (J =
6.6 Hz) upon keeping in CDCl3 (For Spectra see Supporting Information). This isomerization
generally took 5-6 days for completion; however, in case of dimethoxy derivative 2b, the isomerization
happened during chromatographic purification. This E to Z isomerization at room temperature clearly
indicated higher stability for the Z isomer! This is quite unprecedented and we believe that the Z form
achieves an extra stability via a C-H----O hydrogen bond involving the furan C2-H. It may be pointed
out that there are plenty of computational evidence regarding the existence of such a H-bond.9 We have
also done energy minimization of the two isomers which too indicated presence of intramolecular H-
bond involving furan H-2 (Figure 2). 1H NMR taken separately in CDCl3 and then in d6-DMSO showed
slight upfield shift (Δδ ≈ 0.1) of the furan H-2 in the Z-isomer (For Spectra see Supporting
Information). On the other hand, all other furan hydrogens (H-2 in E isomer and H-5 of both E and Z
isomers) showed downfield shift of Δδ > 0.2 indicating the possibility of involvement of H-2 in Z-
isomer in intramolecular H-bonding. Petrova et al.10 in their study of conformations of 1, 4-
dihydropyridine derivatives have shown upfield shift (CDCl3 vs d6-DMSO) of hydrogens involved in
similar intramolecular C-H----O bonding. It may be mentioned here that Schmittel et al.11 in a recent
paper have reported formation of both E and Z isomers in thermal Garratt−Braverman/[1, 5]-H Shift of
an ene-diallene system and observed (both experimentally and also based on computations) a
nonstatistical dynamics. In our case, the reaction always led to E isomer as the exclusive product which
isomerized to the Z form upon keeping in solution or during chromatographic purification.
Figure 2: Energy minimized structure [BP86-(D3-BJ)/def2-SVP] of 1b in Z and E configuration. The Z
configuration is more stable than the E configuration by ΔE= 3.9 kcal mol-1 (ΔG298 = 2.4 kcal mol-1).
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1
Entry
1
Reactant
Product
Yield (%)
80
2
3
4
5
O
O
6
7
8
9
1b
THPO
1a
OTHP
OMe
2
OMe
70
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O
O
MeO
MeO
2a
3a
4a
2b
OTHP
THPO
3
4
5
75
80
70
O
O
MeO
MeO
3b
THPO
OTHP
O
O
4b
OTHP
THPO
OTHP
O
O
+
O
THPO
OTHP
5a
5b
5c
1:0.2
6
7
72
85
O
O
+
O
THPO
6a
THPO
THPO
1:3.18
6c
6b
O
O
7b
OCH2CH3
H3CH2CO
7a
8
9
65
50
O
O
8c
OMe
8a
OMe
O
O
OMe
9a
9b
OMe
OTHP
THPO
The distance is in Angstorm (Å).
Reaction condition: KOtBu, dry DMSO, rt, 1h
Table 1: Results of base treatment of various propargyl ethers.
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We have also studied the mechanism of GB cyclization and 1,5-H shift using DFT calculations. The
first cyclization of bis-allenyl ether yields a diradical intermediate that undergoes self-quenching leading
to the products (furans via 1, 5-H shift and phthalans via GB). Although we have mapped the entire
reaction pathway starting from the bis-allene, this discussion is restricted to the diradical self-quenching
step. The relative activation energies for the two self-quenching processes should determine the
outcome of the reaction. This assumption is possibly justified as both the products originated from the
same diradical intermediate. It is true that 1, 5-H shift and the GB process involve different conformers
of the diradical intermediate. However, the computed energy difference between reacting conformers
has been found to be much less in comparison to the corresponding activation energies leading to the
products (except for the olefinic substrate 6a). This indicated rapid equilibration between the
conformers and hence the applicability of the Curtin-Hammett principle.12 The reason for higher
difference between the two reacting conformers in case of 6a may be attributed to the lower van der
Waals interaction between the olefin H and furan H-5 as compared to the aryl derivatives (Figure 3).
The same trend is also reflected in the TS that resembles the diradical intermediate. The reaction profile
for later stages of 1, 5-H shift and GB cyclization for substrate 1a is shown as a representative example
(Figure 4).
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Figure 3: Optimized structure [BP86-(D3-BJ)/def2-SVP] of diradical intermediates and TS’s of GB
cyclization and 1,5-H-shift for 1a and 6a. The distances are in Angstorm (Å).
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Figure 4: Reaction profile for later stages of 1, 5-H shift and GB cyclization for 1a. Relative free
energies [BP86-(D3-BJ)/def2-SVP] are given in kcal mol-1
The computed activation energies are shown in Table 2 which clearly indicated that for the phenyl
substituted systems (1a to 3a) the two activation energies (GB and H-shift) differ by more than 2 kcal
mol-1 with GB process having higher activation energy. These systems thus preferred to follow the 1, 5-
H shift pathway. For the naphthalene system 5a, this difference is less than 1 kcal mol-1 and hence both
the products were formed with 1, 5-H shift showed higher preference. For the vinyl system, the
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activation energy for the GB process is less than the 1, 5-H shift pathway thus making the GB process
the predominant reaction. In case of the methyl substituted propargyl ether, the stronger C-H bond as
compared to the ethereal system (like OTHP derivative) disfavored the 1, 5- H shift. In fact, the
calculated C-H bond energy (Scheme 4) for an ethereal system (94.2 kcal mol-1) is lower than the
corresponding bond energy for methyl substituted propargyl ether (107.2 kcal mol-1).
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Relative Free energy difference
(∆∆G) between the reactive
conformers (diradical
intermediates) for GB and H-
shift processes
Product Ratio
(H-Shift : GB)
Activation free
energy
Substrate Reaction type
(∆G‡)
(kcal mol-1)
(∆∆G =∆GGB - ∆GH-shift
)
(kcal mol-1)
H-shift
2.1
6.5
3.2
7.2
3.1
7.7
3.9
4.0
5.7
1.4
1:0
1:0
1a
2a
3a
5a
GB
H-shift
GB
1.9
1.3
1.4
5.2
H-shift
GB
1:0
H-shift
GB
1:0.2
1:3.18
H-shift
6a
GB
4.2
Table 2: Computational results [BP86-(D3-BJ)/def2-SVP]: The activation energy (∆G‡), energy
difference between the reactive diradical intermediates (∆∆G = ∆GGB - ∆GH-shift) and experimental
product ratio is given. Free energies were calculated at 298K. All energy values are in kcal mol-1.
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1
XI
XII
X111
XIV
2
3
4
5
6
O
O
O
O
7
8
-
+
+
H
-
E(94.2 kcal/mol)
H
E(107.2 kcal/mol)
OTHP
9
H
H
H
OTHP
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H
Scheme 4: Calculation of C-H bond energy from the optimized geometries [BP86-(D3-BJ) / def2-SVP].
Here the energies are electronic energy. The optimized geometries are included in SI.
In conclusion, we have succeeded in developing a general route to 3, 4-disubstituted furans by
successfully shifting the reactivity of bis-propargyl ethers towards the 1, 5-H shift pathway from the
usual GB mode. The parameters controlling this interplay of reactivity have also been identified and
rationalized by DFT based computations. Future studies will aim towards exploring the synthetic utility
of the furan derivatives and also carrying out a more elaborate study on the E to Z isomerization.
Experimental Section
1
All H-NMR and 13C-NMR spectra were obtained with 200 MHz, 400 MHz and 600 MHz NMR
instruments in CDCl3 unless mentioned otherwise. The following abbreviations are used to describe
peak patterns where appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, app. =
apparently and b = broad signal. All coupling constants (J) are given in Hz. Mass spectra were recorded
in ESI+ mode (ion trap). IR spectra were recorded as thin films and bands are expressed in cm-1.
All the dry solvents used for reactions were purified according to the standard protocols. Dimethyl
sulfoxide (DMSO), N, N-dimethylformamide (DMF), triethylamine (Et3N) were distilled from calcium
hydride. All the solvents for column chromatography were distilled prior to use. In most of the column
chromatographic purifications, ethyl acetate (EA/EtOAc) and petroleum ether (PE) of boiling range 60-
800C were used as eluents. Columns were prepared with silica gel (Si-gel, 60-120 and 230-400 mesh,
SRL).
General procedure for O-propargylation: Synthesis of compounds (1a-8a)
To an ice-cold solution of alcohol (1 mmol) in dry DMF (10 mL), NaH (2 eq, 60% suspension in
mineral oil) was added and the solution was stirred for 30 min at ice cold temperature under N2
atmosphere. After the alkoxide was generated, respective propargyl bromides (ethyl iodide in case of
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7a) (1.0 eq) diluted with dry DMF (5 mL) were added dropwise by maintaining the ice-cold temperature
and the mixture was stirred for 1h. It was then quenched with aqueous NH4Cl and partitioned between
ethyl-acetate and water. The organic layer was washed with brine solution and the combined organic
layer was dried with anhydrous sodium sulfate. The solvent was removed and the crude residue was
purified by column chromatography (Si- gel, petroleum ether-ethyl acetate mixture as eluent).
1
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3
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5
6
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9
Preparation of (6a) via Sonogashira Coupling
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To a degassed solution of 16 (1 mmol) and vinyl bromide (4 eq) in dry Et3N (10 mL) was added
PdCl2(PPh3)2 (3 mol %) and CuI (20 mol %) under inert atmosphere and the mixture was allowed to stir
at room temperature for 18 h. The mixture was then poured to ethyl acetate and the organic layer was
washed with saturated solution of NH4Cl and brine. The ethyl acetate layer was then dried over
anhydrous sodium sulfate, evaporated and the purified product was obtained via column
chromatography by using hexane-ethyl acetate as eluent.
Spectral data of cyclization products (for 9a, see reference 3d)
2-[4-(3-Phenyl-prop-2-ynyloxy)-but-2-ynyloxy]-tetrahydro-pyran (1a)
State: yellow oil; yield: 227 mg, 80%; IR (neat) νmax 2927, 2855, 2230, 1611, 1575, 1503, 1210, 1024,
752 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.45 - 7.43 (m, 2H), 7.32 - 7.26 (m, 3H), 4.82 (bs, 1H),
4.47 (s, 2H), 4.36 (s, 2H), 4.36 - 4.26 (m, 2H), 3.86 - 3.81 (m, 1H), 3.55 - 3.52 (m, 1H), 1.84 - 1.54 (m,
6H); 13C NMR (50 MHz, Chloroform-d) δ 131.8, 128.5, 128.3, 122.5, 96.8, 86.8, 84.3, 83.0, 81.3, 62.0,
+
57.3, 56.9, 54.3, 30.2, 25.4, 19.0. HRMS: Calcd. for C18H21O3 [M+H]+ 285.1491 found 285.1494.
2-{4-[3-(2,4-Dimethoxy-phenyl)-prop-2-ynyloxy]-but-2-ynyloxy}-tetrahydro-pyran (2a)
State: yellow oil; yield: 265 mg, 77%; IR (neat) νmax 2934, 2876, 2231, 1623, 1564, 1034, 750 cm-1; 1H
NMR (400 MHz, Chloroform-d) δ 7.32 (d, J = 8.0 Hz, 1H), 6.43 - 6.41 (m, 2H), 4.81 (t, J = 3.2 Hz,
1H), 4.49 (s, 2H), 4.36 (s, 2H), 4.32 - 4.25 (m, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.86 - 3.79 (m, 1H), 3.54
13
- 3.51 (m, 1H), 1.83 - 1.52 (m, 6H); C NMR (50 MHz, Chloroform-d) δ 161.6, 161.5, 134.8, 104.9,
104.3, 98.5, 97.0, 87.0, 83.3, 82.9, 81.7, 62.2, 57.9, 56.9, 55.9, 55.6, 54.5, 30.4, 25.5, 19.2. HRMS:
+
Calcd. for C20H25O5 [M+H]+ 345.1702 found 345.1705.
2-{4-[3-(4-Methoxy-phenyl)-prop-2-ynyloxy]-but-2-ynyloxy}-tetrahydro-pyran (3a)
State: yellow oil; yield: 235 mg, 75%; IR (neat) νmax 2977, 2875, 1576, 2231, 1613, 1045, 754 cm-1; 1H
NMR (400 MHz, Chloroform-d) δ 7.37 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.81 (t, J = 3.6 Hz,
13
1H), 4.45 - 4.25 (m, 6H), 3.86 - 3.79 (m, 4H), 3.54 - 3.50 (m, 1H), 1.83 - 1.51 (m, 6H); C NMR (50
MHz, Chloroform-d) δ 159.8, 133.3, 114.5, 113.9, 96.8, 86.8, 82.9, 82.8, 81.3, 61.9, 57.4, 56.8, 55.2,
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54.2, 30.2, 25.3, 19.0. HRMS: Calcd. for C19H23O4 [M+H]+ 315.1596 found 315.1597.
+
1
2
3
2-[4-(3-p-Tolyl-prop-2-ynyloxy)-but-2-ynyloxy]-tetrahydro-pyran (4a)
4
State: yellow oil; yield: 247 mg, 83%; IR (neat) νmax 3100, 2855, 1564, 2231, 1632, 1025, 765 cm-1; 1H
NMR (400 MHz, Chloroform-d) δ 7.29 (d, J = 7.2 Hz, 2H),7.05 (d, J = 6.8 Hz, 2H), 4.77 (bs, 1H), 4.40
(s, 2H), 4.30 (s, 2H), 4.30 - 4.21 (m, 2H), 3.78 - 3.76 (m, 1H), 3.49 - 3.47 (m, 1H), 2.28 (s, 3H), 1.77 -
5
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1.48 (m, 6H); C NMR (100 MHz, Chloroform-d) δ 138.8, 131.9, 129.2, 119.6, 97.0, 87.1, 83.8, 83.2,
81.5, 62.1, 57.5, 57.0, 54.4, 30.4, 25.6, 21.6, 19.2. HRMS: Calcd. for C19H23O3 [M+H]+ 299.1647
+
found 299.1643.
2-[4-(3-Naphthalen-2-yl-prop-2-ynyloxy)-but-2-ynyloxy]-tetrahydro-pyran (5a)
State: yellow oil; yield: 243 mg, 73%; IR (neat) νmax 3123, 2937, 2876, 2234, 1506, 1617, 1027, 765
cm-1; 1H NMR (600 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.83 - 7.79 (m, 3H), 7.52 - 7.49 (m, 3H), 4.86
(t, J = 3.6 Hz, 1H), 4.55 (s, 2H), 4.44 (s, 2H), 4.43 - 4.31 (m, 2H), 3.89 - 3.85 (m, 1H), 3.58 - 3.55 (m,
1H), 1.88 - 1.56 (m, 6H); 13C NMR (50 MHz, Chloroform-d) δ 133.0, 132.9, 131.9, 128.5, 128.1, 127.9,
126.9, 126.7, 119.8, 97.0, 87.2, 84.7, 83.2, 81.4, 62.1, 57.5, 57.1, 54.4, 30.3, 25.5, 19.2. HRMS: Calcd.
for C22H23O3 [M+H]+ 335.1647 found 335.1647.
+
2-(4-Pent-4-en-2-ynyloxy)-but-2-ynyloxy]-tetrahydro-pyran (6a)
State: yellow oil; yield: 168 mg, 72%; IR (neat) νmax 2937, 2876, 2234, 1523, 1623, 1025, 745 cm-1; 1H
NMR (400 MHz, Chloroform-d) δ 5.83 (dd, J = 11.8 Hz, 7.2 Hz, 1H), 5.68 (dd, J = 11.8 Hz, 1.2 Hz,
1H), 5.52 (dd, J = 7.4 Hz, 1.2 Hz, 1H), 4.82 (t, J = 2.0 Hz, 1H), 4.38 (s, 2H), 4.37 - 4.27 (m, 4H), 3.87 -
13
3.83 (m, 1H), 3.57 - 3.53(m, 1H), 1.88 - 1.55 (m, 6H); C NMR (50 MHz, Chloroform-d) δ 127.8,
+
116.6, 97.0, 85.5, 85.0, 83.1, 81.3, 62.1, 57.3, 57.0, 54.4, 30.3, 25.5, 19.1. HRMS: Calcd. for C14H19O3
[M+H]+ 235.1334 found 235.1332.
[3-(4-Ethoxy-but-2ynyloxy)-prop-1-ynyl]-benzene (7a)
State: yellow oil; yield: 198 mg, 87%; IR (neat) νmax 3069, 2985, 2852, 2251, 1731, 1604, 1495, 1088,
887, 761, 694 cm-1; H NMR (400 MHz, Chloroform-d) δ 7.45 (m, 2H), 7.32 - 7.31 (bm, 3H), 4.47 (s,
2H), 4.36 (s, 2H), 4.20 (s, 2H), 3.57 (dd, J = 7.2 Hz, 6.8 Hz, 2H), 1.23 (appt, J = 7.2 Hz, 3H); 13C NMR
1
(50 MHz, Chloroform-d) δ 131.8, 128.5, 128.3, 122.5, 86.8, 84.3, 83.2, 81.3, 65.5, 58.0, 57.3, 56.9,
15.0. HRMS: Calcd. for C15H17O2 [M+H]+ 229.1229 found 229.1223.
+
(3-But-2-ynyloxy-prop-1-ynyl)-benzene (8a)
State: yellow oil; yield: 154 mg, 84%; IR (neat) νmax 3066, 2960, 2932, 2859, 2230, 1963, 1611, 1499,
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1362, 1132, 926, 894, 764, 698 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.46 - 7.45 (bm, 2H), 7.32 -
1
2
3
4
13
7.31 (bm, 3H), 4.46 (s, 2H), 4.28 (apps, 2H), 1.88 (s, 3H); C NMR (50 MHz, Chloroform-d) δ 131.8,
128.5, 128.3, 122.6, 86.5, 84.6, 83.2, 74.5, 57.2, 57.1, 3.6. HRMS: Calcd. for C13H13O+ [M+H]+
5
6
185.0966 found 185.0965.
7
8
9
General procedure for furan ring formation: Synthesis of compounds (1b-8c)
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To an ice-cold solution of the ethers 1a-9a (0.2 mmol) in dry DMSO (5 mL) was added KOtBu (1.2 eq)
and the reaction was allowed to stir at room temperature for 1 h. It was then quenched with NH4Cl
solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate
and evaporated to get the crude product which was purified by column chromatography with hexane-
ethyl acetate mixture as eluent.
2-[2-(4-Benzyl-furan-3-yl)-vinyloxy]-tetrahydro-pyran (1b)
State: yellow oil; yield: 45 mg, 80%; IR (neat) νmax 2954, 2874, 2857, 1660, 1530, 1234, 1178, 1050,
767 cm-1; 1H NMR (600 MHz, Chloroform-d) δ 7.39 (s, 1H), 7.34 - 7.31 (m, 2H), 7.28 - 7.23 (m, 3H),
7.08 (s, 1H), 6.73 (d, J = 12.6 Hz, 1H), 5.80 (d, J = 13.2 Hz, 1H), 4.96 (app s, 1H), 3.86 - 3.83 (m, 1H),
13
3.81 (s, 2H), 3.59 - 3.57 (m, 1H), 1.90 - 1.57 (m, 6H); C NMR (150 MHz, Chloroform-d) δ 144.5,
141.0, 139.7, 138.4, 128.6, 128.4, 126.1, 123.1, 121.1, 98.7, 98.4, 62.0, 30.3, 29.6, 25.1, 18.6. HRMS:
+
Calcd. for C18H21O3 [M+H]+ 285.1491 found 285.1495.
2-{2-[4-(2,4-Dimethoxy-benzyl)-furan-3-yl]-vinyloxy}-tetrahydro-pyran (2b)
State: yellow oil; yield: 48 mg, 70%; IR (neat) νmax 2989, 2945, 2867, 1664, 1567, 1357, 1209, 1098,
756 cm-1; 1H NMR (600 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.10 (s, 1H), 6.97 (d, J =8.4 Hz, 1H), 6.49
(d, J = 2.4 Hz, 1H), 6.44 (d, J = 6.6 Hz, 1H), 6.42 (dd, J = 7.8 Hz, 2.4 Hz, 1H), 5.19 (d, J = 6.6 Hz, 1H),
5.13 (app t, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.70 (s, 2H), 3.71 - 3.70 (m, 1H), 3.62 - 3.60 (m,
1H), 1.95 - 1.69 (m, 6H); 13C NMR (150 MHz, Chloroform-d) δ 159.3, 157.9, 142.5, 142.0, 139.7,
129.9, 122.4, 120.8, 119.6, 103.8, 98.8, 98.3, 96.2, 61.6, 55.4, 55.3, 29.6, 25.1, 22.7, 18.6. HRMS:
+
Calcd. for C20H24NaO5 [M+Na]+ 367.1521 found 367.1541.
2-{4-[3-(4-Methoxy-phenyl)-prop-2-ynyloxy]-but-2-ynyloxy}-tetrahydro-pyran (3b)
State: yellow oil; yield: 47 mg, 75%; IR (neat) νmax. 2954, 2876, 1667, 1530, 1359, 1213, 1095, 789
cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.34 (s, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.02 (s, 1H), 6.83 (d,
J = 8.0 Hz, 2H), 6.70 (d, J = 12.8 Hz, 1H), 5.75 (d, J = 12.8 Hz, 1H), 4.93 (app s, 1H), 3.84 - 3.82 (m,
1H), 3.79 (s, 3H), 3.70 (s, 2H), 3.56 - 3.54 (m, 1H), 1.87 - 1.53 (m, 6H); 13C NMR (100 MHz,
Chloroform-d) δ 158.0, 144.4, 140.9, 138.4, 131.7, 129.5, 123.6, 121.0, 113.8, 98.8, 98.4, 62.0, 55.2,
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29.6, 29.5, 25.1, 18.6. HRMS: Calcd. for C19H23O4 [M+H]+ 315.1596 found 315.1591.
+
1
2
3
2-{2-[4-(4-Methyl-benzyl)-furan-3-yl]-vinyloxy}-tetrahydro-pyran (4b)
4
5
6
7
8
State: yellow oil; yield: 47 mg, 80%; IR (neat) νmax 2948, 2929, 2876, 2854, 1664, 1520, 1464, 1357,
1206, 1169, 1090, 786, 745 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.35 (s, 1H), 7.11 (s, 4H), 7.04
(s, 1H), 6.71 (d, J = 12.8 Hz, 1H), 5.77 (d, J = 12.8 Hz, 1H), 4.96 (app s, 1H), 3.85 - 3.81 (m, 1H), 3.73
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(s, 2H), 3.57 - 3.55 (m, 1H), 2.33 (s, 3H), 1.75 - 1.57 (m, 6H); C NMR (100 MHz, Chloroform-d) δ
144.6, 141.1, 138.5, 136.8, 135.8, 129.3, 128.7, 123.6, 121.2, 99.0, 98.6, 62.2, 30.1, 29.9, 25.3, 21.2,
18.8. HRMS: Calcd. for C19H22NaO3 [M+Na]+ 321.1467 found 321.1467.
+
2-[2-(4-Naphthalen-2-ylmethyl-furan-3-yl)-vinyloxy]-tetrahydro-pyran (5b)
State: yellow oil; yield: 39 mg, 58%; IR (neat) νmax.2950, 2786, 1669, 1465, 1208, 1178, 1098, 745
cm-1; 1H NMR (600 MHz, DMSO-d6) δ 7.87 - 7.81 (m, 3H), 7.68 (s, 1H), 7.65 (s, 1H), 7.49 - 7.44 (m,
3H), 7.38 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 12.6 Hz, 1H), 5.64 (d, J = 12.6 Hz, 1H), 4.91 (app s, 1H),
3.92 (s, 2H), 3.59 - 3.55 (m, 1H), 3.38 - 3.34 (m, 1H), 1.67 - 1.40 (m, 6H); 13C NMR (150 MHz,
Chloroform-d) δ 144.5, 141.1, 138.4, 137.2, 133.6, 132.2, 128.0, 127.6, 127.3, 126.8, 125.9, 125.3,
123.0, 121.1, 98.7, 98.3, 61.9, 30.5, 29.6, 25.0, 18.6. HRMS: Calcd. for C22H22NaO3 [M+Na]+
+
357.1467 found 357.1471.
7-((tetrahydro-2H-pyran-2-yloxy)methyl)-8,10-dihydrophenanthro[2,3-c]furan (5c)
State: yellow oil; yield: 9 mg, 13%; IR (neat) νmax 3069, 2965, 2867, 1645, 1475, 1145, 755 cm-1; H
1
NMR (600 MHz, Chloroform-d) δ 8.91 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 9.6 Hz, 1H), 7.74 - 7.71 (m,
3H), 7.64 - 7.63 (m, 2H), 5.50 (app s, 2H), 5.38 - 5.35 (m, 3H), 4.99 - 4.96 (m, 2H), 4.12 - 4.08 (m, 1H),
13
3.74 - 3.70 (m, 1H), 2.07 - 1.64 (m, 6H); C NMR (150 MHz, Chloroform-d) δ 141.4, 139.3, 137.8,
133.7, 133.3, 130.5, 130.3, 128.4, 128.0, 127.4, 127.1, 126.3, 125.9, 120.8, 98.9, 73.6, 73.5, 67.7, 62.6,
30.2, 25.5, 19.4. HRMS: Calcd. for C22H22NaO3 [M+Na]+ 357.1467 found 357.1469.
+
2-[2-(4-Allyl-furan-3-yl)-vinyloxy]-tetrahydro-pyran (6b)
State: yellow oil; yield: 9 mg, 18%; IR (neat) νmax.2947, 2875, 1667, 1525, 1234, 1095, 734 cm-1; H
1
NMR (400 MHz, Chloroform-d) δ 7.36 (s, 1H), 7.34 (s, 1H), 6.77 (d, J = 12.8 Hz, 1H), 6.60 (d, J = 8.0
Hz, 1H), 6.13 (d, J = 11.2 Hz, 1H), 5.86 - 5.78 (m, 2H), 5.02 - 4.91 (m, 2H), 4.73 (app s, 1H), 3.90 -
13
3.84 (m, 1H), 3.60 - 3.58 (m, 1H), 2.07 - 1.67 (m, 6H); C NMR (150 MHz, Chloroform-d) δ 137.7,
137.6, 136.3, 126.0, 118.4, 114.1, 99.0, 98.9, 62.2, 31.9, 30.7, 30.6, 22.7, 19.5. HRMS: Calcd. for
+
C14H18NaO3 [M+Na]+ 257.1154 found 257.1154.
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4-(Tetrahydro-pyran-2-yloxymethyl)-1,3-dihydro-isobenzofuran (6c)
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5
State: yellow oil; yield: 25 mg, 55%; IR (neat) νmax.2956, 2935, 2856, 1668, 1465, 1205, 1093, 786
1
cm-1; H NMR (600 MHz, Chloroform-d) δ 7.29 - 7.24 (m, 2H), 7.19 - 7.18 (d, J = 7.2 Hz, 1H), 5.20
6
7
8
9
(app s, 2H), 5.14 (s, 2H), 4.78 (d, J = 12.6 Hz, 1H), 4.71 (t, J = 3.0 Hz, 1H), 4.47 (d, J = 12.6 Hz, 1H),
13
3.93 - 3.89 (m, 1H), 3.59 - 3.56 (m, 1H), 1.9 - 1.56 (m, 6H); C NMR (150 MHz, Chloroform-d) δ
139.5, 137.8, 131.9, 127.5, 126.5, 120.1, 97.9, 73.5, 73.0, 67.3, 62.0, 30.5, 25.4, 19.2. HRMS: Calcd. for
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+
C14H18NaO3 [M+Na]+ 257.1154 found 257.1154.
3-Benzyl-4-(2-ethoxy-vinyl)-furan (7b)
State: yellow oil; yield: 39 mg, 85%; IR (neat) νmax.2987, 2956, 2867, 1669, 1356, 1189, 1067, 755
cm-1; H NMR (600 MHz, Chloroform-d) δ 7.35 (s, 1H), 7.33 - 7.31 (m, 2H), 7.24 -7.23 (m, 3H), 7.10
1
(s, 1H), 6.63 (d, J = 12.6 Hz, 1H), 5.46 (d, J = 12.6 Hz, 1H), 3.79 (app q, J = 8.4 Hz, 4H), 1.29 (dd, J =
13
7.2 Hz, 6.6 Hz, 3H); C NMR (50 MHz, Chloroform-d) δ 147.8, 141.1, 139.9, 138.1, 128.7, 128.6,
126.3, 123.3, 121.6, 95.0, 65.5, 30.4, 14.9. HRMS: Calcd. for C15H17O2 [M+H]+ 229.1229 found
+
229.1213.
4-Methyl-1,3-dihydro-naphtho[2,3-c]furan (8c)
State: sticky mass; yield: 24 mg, 65%; IR (neat) νmax.3100, 2986, 2934, 1667, 1523, 1356, 1189, 1098,
785, 747 cm-1; 1H NMR (600 MHz, Chloroform-d) δ 8.02 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H),
7.57 (s, 1H), 7.53 - 7.47 (m, 2H), 5.28 (s, 2H), 5.27 (s, 2H), 2.58 (s, 3H); 13C NMR (150 MHz,
Chloroform-d) δ 137.4, 136.6, 133.5, 132.1, 128.5, 126.2, 125.5, 125.3, 123.5, 117.3, 73.5, 72.8, 15.4.
HRMS: Calcd. for C13H13O+ [M+H]+ 185.0966 found 185.0968.
Computational Details:
All the computations were carried out with Orca 3.0.313 software package. Geometry optimizations were
done in gas phase using Density Functional Theory (DFT) using BP8614 fuctional, def2-SVP basis set15
with resolution of identity (RI) approximation16. Empirical dispersion correction17 (DFT-D3BJ) was
included in all calculations. Unrestricted formalism was used for open shell diradical intermediate. The
nature of stationary point was characterized by vibrational frequency analysis.
___________________________________________________________________________________
ASSOCIATED CONTENT
Supporting Information: Spectral data of all new compounds, copies of NMR (1H and 13C) spectra for
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all compounds and computational details. This material is available free of charge via the Internet at
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http://pubs.acs.org.
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AUTHOR INFORMATION
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*Corresponding Author
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E-mail: absk@chem.iitkgp.ernet.in, anoop@chem.iitkgp.ernet.in
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Notes
The authors declare no competing financial interest.
__________________________________________________________________________________
ACKNOWLEDGEMENT
Author A.B. is grateful to CSIR, Govt. of India, for funding and to DST, Govt. of India, for the JC Bose
fellowship. J.D. thanks CSIR, Govt. of India for a research fellowship (NET). ED thanks IIT Kharagpur
for an institute research fellowship. DST and IIT Kharagpur are also thanked for the funds for 400 MHz
(IRPHA program) and 600 MHz facilities respectively.
REFERENCES
1. (a) Basak, A.; Das, S.; Mallick, D.; Jemmis, E. D. J. Am. Chem. Soc. 2009, 131, 15695; (b) Das, J.;
Mukherjee, R.; Basak, A. J. Org. Chem. 2014, 79, 3789;
2. (a) Garratt, P. J.; Neoh, S. B. J. Am. Chem. Soc. 1975, 97, 3255; (b) Cheng, Y. S. P.; Dominguez, E.;
Garratt, P. J.; Neoh, S.B. Tetrahedron Lett. 1978, 19, 691; (c) Garratt, P. J.; Neoh, S. B. J. Org.
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Table of Contents
==========================================================================
O
O
H
Z isomer more stable!
R
X
X
R
E
DMSO
rt, 1 h
KOtBu
in solution
For R = aryl and X = OTHP, OEt
I is the exclusive product
O
O
+
For R = alkene and X = OTHP
For R = aryl and X = H,
II is the major product
R
R
X
I
II
X
3,4-disubstituted furans
Yield ranges from 50-85%
Substituted
Phthalans
Z
Energy minimized structures
=========================================================================
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