The intramolecular 5-: Exo, 7- endo -dig transition metal-free cyclization sequence of (2-alkynylphenyl) benzyl ethers: Synthesis of seven-membered fused benzo [b] furans

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Carmo, J. Neto, T. Acunha, B. A. Iglesias, D. F. Back and G. Zeni, Green Chem., 2016, DOI:

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Intramolecular 5-exo, 7-endo-dig Transition Metal-Free Cyclization

Sequence of (2-Alkynylphenyl) Benzyl Ethers: Synthesis of Seven-

Membered Fused Benzo[b]furans

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DOI: 10.1039/x0xx00000x

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Rafaela Gai,^aRoberto do Carmo Pinheiro,^aJosé S. S. Neto,^aBernardo A. Iglesias,^bThiago V.

Acunha,^bDavi F. Back^band Gilson Zeni*^,a

Base-promoted cyclization of (2-alkynylphenyl) benzyl ethers was studied in details. The effects of solvent, base,

temperature, reaction time and amount of base on the efficacy of the cyclization reaction was analyzed and a new base-

solvent system (tert-BuOK/DMSO) for effective cyclization of (2-alkynylphenyl) benzyl ethers was reported. The results

showed that the cyclization reactions proceeded cleanly and smoothly under mild reaction conditions, employing a tert-

BuOK as base, DMSO as solvent, at room temperature in a short reaction time (1 h). Under these conditions, a number of

different substituted (2-alkynylphenyl) benzyl ethers were cyclized to the corresponding fused heterocycle

cyclohepta[b]furans. This one-pot, two-steps procedure occurred regioselectively giving only the cyclohepta[b]furans as

the unique regioisomer via an initial intramolecular 5-exo-dig mode followed by an intramolecular 7-endo-dig mode. The

cyclohepta[b]furan derivatives absorbed in the UV region (300-350 nm range) with molar absorptivity coefficient values

attributed to spin and symmetry allowed π-π* electronic transitions. An emission located in the purple region (380-440

nm range), with a Stokes shift between 65-100 nm is probably associated to the charge transfer character of the excited

state. The electrochemical analysis (CV) of the cyclohepta[b]furans showed an oxidation and reduction process, probably

due to the presence of the selenium atom and π-anion radical species.

cyclohepta[b]furans are interesting building blocks and important

synthetic intermediates. For example, studies have shown that

they have been used as substrate for [8+2] cycloaddition

Introduction

reactions.¹¹These higher order conjugate additions have been

extensively used to directly entry to a large number of fused-

polycyclic compounds, which are part of numerous natural and non-

natural compounds. Cyclohepta[b]furans have multi-π-bonds and

the structural rigidity that leads to fast multistep electron transfer

as well as to physicochemical features, such as radical spin-trapping

therapeutic agents,¹²near-infrared dark quenchers,¹³color-tags for

the chromophore-supported purification technique¹⁴and

The derivatives of fused heterocycles are valued not only for their

rich and varied chemistry but also for many important biological

properties.¹In contrast to the numerous studies developed for the

chemistry and preparation of fused five- and six-membered

heterocycles, the preparation of seven-membered derivatives is

limited and generally involves a multistep synthesis.²However, the

discovery of several new families of cyclohepta[b]furan ring

containing different biological activities has generated an interest in

the development of new methodologies for the synthesis of these

heterocycles.³Representative examples of different biological

activities include antimicrobial,⁴cytotoxic,⁵antiulcer,⁶and anti-

inflammatory activities.⁷Cyclohepta[b]furans isolated from natural

sources also have a broad spectrum of biological activities, for

example, interleukin-8 receptor antagonist,⁸inhibitory activity

against PI3K⁹and neuroprotective effects.¹⁰Besides, substituted

electrochromic materials.¹⁵

Up to now, the most useful

methodology described to the preparation of these heterocycles is

the transition-metal-mediated cycloaddition reactions. In spite of

these methods, the cycloaddition reactions,¹⁶ring expansion

reactions,¹⁷ring-closing metathesis¹⁸and domino cyclization

reactions¹⁹have emerged as powerful tools to the preparation of

wide range of seven-membered heterocycles. Recently, there has

been enormous interest in the development of new methods

avoiding the use of transition metals.²⁰A green alternative to

transition metals in intramolecular cyclization is the base-promoted

annulations of unsaturated substrates.²¹This methodology has

signiﬁcant advantages over others, particularly in terms of

functional group tolerance, high levels of chemo-, regio-, and

stereoselectivity. In addition, the base-promoted annulation has

emerged as a powerful tool in organic synthesis due to the

^aLaboratório de Síntese, ꢀeaꢁꢂidade, Aꢂaliação Farmacológica e Toxicológica de

Organocalcogênios CCNE, UFSM, Santa Maria, ꢀio Grande do Sul, Brazil 97105-900.

E-mail: gzeni@ufsm.br; Fax: (+55)55-3220-8978; Tel: (+55)55-3220-9611.

^bLaboratório de Materiais Inorgânicos, Departamento de Química, UFSM, Santa

Maria, ꢀio Grande do Sul, Brazil 97105-900.

Electronic Supplementary Information (ESI) available: [details of any

supplementary information available should be included here]. See

DOI: 10.1039/x0xx00000x

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reduction of generation of chemical wastes, reaction time, solvent,

and energy, demonstrating the clear economic impacts and

environmental benefits. In this paper, our aim was to develop

conditions for the base promoted annulation of (2-alkynylphenyl)

benzyl ethers 1, bearing a nucleophilic center an appropriate

distance to the alkyne, for the selective synthesis of naphtha

chromenes 3 (Scheme 1). These cascade annulation reactions

generally proceed through double intramolecular endo-dig

cyclization mode.²²However, after initial reactions to determine

the feasibility of this project, we found that the product obtained

was the cyclohepta[b]furans 2. The reactions probably proceed via

an intramolecular exo-dig/endo-dig sequence (Scheme 1). Thus, in

order to develop a versatile method for the preparation of

cyclohepta[b]furans 2, we performed a systematic study of the

base-promoted cyclization reaction of (2-alkynylphenyl) benzyl

ethers 1 varying different reaction parameters and these results will

presented below.

.

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Scheme 2

Due to the fact that the acidity of the t-BuOH is similar to that of

DMSO,²³the system DMSO/tert-BuOK would facilitate the

formation and stabilization of the anion intermediates. For this

reason, we began our investigation using tert-BuOK as base and

DMSO as solvent. The results show that the use of a catalytic

amount of tert-BuOK did not convert the (2-alkynylphenyl) benzyl

ether 1a in the desired product even under extended reaction time

(24 h) and high temperature (100 ^oC) (Table 1, entries 1 and 2). The

increase of tert-BuOK amount to 2.0 equiv led to a significant

increase of 2a yield, reaching 88%, in a short reaction time (Table 1,

entry 3). We subsequently examined the effect of solvent on the

cyclization of (2-alkynylphenyl) benzyl ether 1a. The type of solvent

had significant effect and almost all of the solvents tested, except

DMF, did not afford the product (Table 1, entries 5-10). The use of

protic solvent would quench the anions preventing the conversion

of the (2-alkynylphenyl) benzyl ether 1a. To check this hypothesis

we carried out an experiment using tert-BuOH as solvent. With this

reaction conditions, there was no formation of cyclohepta[b]furan

2a and the (2-alkynylphenyl) benzyl ether 1a was completely

recovered (Table 1, entry 11). This is also assumed by us as an

additional evidence for the anionic pathway (see mechanism

discussion). It was found that various bases, such as Cs₂CO₃, NaOH,

DBU, NaH, and KOH, were not effective to mediate the cyclization

of 2-alkynylphenyl) benzyl ether 1a, although KOH gave moderated

yield of cyclohepta[b]furan 2a at a high temperature (Table 1,

entries 12-16). The amount of base was then optimized; the yields

were not significantly changed by decreasing from 2.0 to 0.5 equiv

amount (Table 1, entries 17 and 18). For economic reason, 0.5

equiv of tert-BuOK was adopted for further studies. At various

interval times, during the optimization reactions, samples of the

reaction mixture were analyzed by TLC, which showed that 1 h was

the reaction time necessary to the complete consume of starting

material. In accordance with these results, we concluded that the

optimum set of conditions for the cyclization reaction of (2-

alkynylphenyl) benzyl ether 1a were the addition of tert-BuOK (50

mol%) to a solution of (2-alkynylphenyl) benzyl ether 1a (0.25

mmol) in DMSO (2.0 mL) at room temperature for 1 h. To

demonstrate the generality of the methodology, various (2-

alkynylphenyl) benzyl ethers 1 were cyclized using the optimized

reaction conditions and the results are listed in Table 2.

Scheme 1

Results and Discussion

General Conditions

The starting material (2-alkynylphenyl) benzyl ethers

1 was

prepared by Sonogashira reaction involving terminal alkynes 4

reacting with aryl bromides 5 (Scheme 2).²⁴The terminal alkynes 4

were synthesized by the reaction of 2-bromophenol with

corresponding benzyl bromides followed by Sonogashira²⁵and

retro-Favorskii²⁶reactions, respectively. The aryl bromides 5 were

prepared reacting 2-bromoiodo-benzene with terminal alkynes via

Sonogashira reaction.²⁷

In order to optimize the reaction

conditions, we initiated our study by using (2-alkynylphenyl) benzyl

ether 1a (0.25 mmol), screening the action of bases, solvents,

temperature and reaction time and the results are summarized in

Table 1.

2 | J. Name., 2012, 00, 1-3

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observed. The cyclization conditions also worked well with

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electron-withdrawing groups at the aromatic rings of benzyloxy

Table 1. Effect of different reaction parameters on the preparation of

cyclohepta[b]furan 2a^a

affording the corresponding products 2f and 2g in 65 and 87%

yields, respectively.

We also studied the introduction of

substituents on the alkyne terminus. We observed that both

electron-rich and electron-deficient aryl groups directly bonded to

alkyne afforded the products in high yields, even though the aryl

containing a CF₃, a strong electron-withdrawing substituent, gave

only moderated 54% yield (Table 2, cyclohepta[b]furans 2h-2p).

Furthermore, the experiments showed that the cyclization reactions

were not influenced by effects of adding substituents on the two

aromatic systems given that the expected products were obtained

in similar good yields (Table 1, cyclohepta[b]furans 2q-2t). An

exception to the other results was observed for the case of (2-

alkynylphenyl) benzyl ether having a 1-naphthyl group bonded to

alkyne. The reaction of this substrate with standard conditions

gave a mixture of cyclohepta[b]furan 2u and the product formed via

a double exo-dig cyclization 2u'. In this case, the formation of 2u'

may be attributed to the steric hindrance offered by the 1-naphthyl

substituent to the nucleophilic attack at the C1 of alkynes.

Concerning the substrate having an alkyl group attached to the

carbon-carbon triple bond, we did not observe the formation of

cyclohepta[b]furan 2v. In this case, only the starting material was

recovered even under various reaction conditions (Table 2,

cyclohepta[b]furan 2v). This lower reactivity is probably due to the

absence of pi (π) bonds next to the alkyne, which becomes the

carbon-carbon triple bond less reactive towards nucleophilic attack.

entry

1

base (equiv)

tert-BuOK (0.2)

tert -BuOK (2)

tert-BuOK (2)

Cs₂CO₃(2)

solvent

DMSO

DMF

time (h)

24

1

yield (%)^b

N.R.^c

N.R.^c,d

88

2

3

4

1

83

5

THF

24

11

1

N.R.

45^d

6

dioxane

CH₂Cl₂

CH₃CN

toluene

DMA

7

8

9

10

11

12

13

14

15

16

17

18

tert-BuOH

DMSO

NaOH (2)

DBU (2)

NaH (2)

KOH (4)

Mechanism Proposal

tert-BuOK (1)

89

We assumed that the cyclization proceeds through; a) the

tert-BuOK (0.5)

1

90

^[a]The reaction was performed by the addition of tert-BuOK to a solution of

formation of benzyl anion I via abstraction of benzylic hydrogen

(2-alkynylphenyl) benzyl ether 1a (0.25 mmol) in DMSO (2.0 mL) under from (2-alkynylphenyl) benzyl ethers 1 by tert-BuOK; b) the

argon atmosphere, at room temperature for the time indicated.

intramolecular anionic addition to the carbon-carbon triple bond

^[b]Yields of purified products.

gives the vinyl anion II, via a 5-exo-dig mode; c) protonation of the

^[c]The substrate 1a was not consumed.

^[d]The reaction was performed at 100 °C.

vinyl anion by tert-BuOH, generated in situ, affords the benzofuran

intermediary III that upon further deprotonation gives IV. Next, in

the second cyclization step, the 6-exo-dig mode competes with 7-

Scope of the Reaction

endo-dig mode, therefore a mixture of cyclohepta[b]furans 2 and

dihydrobenzo-naphthofuran 2' would be produced (Scheme 3). The

nucleophilic attack of benzyl anion at the carbon-carbon bonds of

alkyne produces the anion V. The protonation/deprotonation

sequence gives the cyclized cyclohepta[b]furans 2. There is no way

to isolate any intermediates, such as bezofuran II and IV; however,

we presented herein some results of the experiments performed to

support this hypothesis. When (2-alkynylphenyl) benzyl ether 1a

reacted under optimized reaction, in the dark, to prevent the light-

induced formation of the radical, or in the presence of TEMPO a

radical inhibitor, the cyclohepta[b]furan 2a was obtained in 85%

and 89% yields, respectively (Schemes 4 and 5). This indicates that

the pathway does not follow the typical radical mechanism. When

the same reaction was carried out using hydrated THF or a protic

solvent instead of anhydrous THF, no cyclohepta[b]furan 2a was

detected and the (2-alkynylphenyl) benzyl ether 1a was completely

Because the yields varied with both electronic and steric effects,

any clear relationship between the structure of the (2-

alkynylphenyl) benzyl ether 1a and the reaction yield could not be

established. However, some results deserve a detailed analysis; for

example, in respect to the effect of the substituent on the

benzyloxy function we observed that the aryl group having no

substitution gave the highest yield for cyclohepta[b]furan 2a. The

electron-donating groups in the aromatic rings of benzyloxy

function were compatible with the reaction conditions, giving the

corresponding cyclohepta[b]furans 2c-2f in moderated to good

yields, although additional reaction time and an increase in

temperature were required. An exception to this behavior was

observed for cyclohepta[b]furan 2b, which was not obtained, even

though we made several modifications in the standard reaction

conditions. In this example, only unreacted starting material was

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recovered. This suggests that water and protic solvent may quench

the anions formed, hindering the reaction. In this context, our

cyclization methodology showed to be regioselective, providing the

desired cyclohepta[b]furan 2 via an intramolecular 5-exo-dig mode

followed by a 7-endo-dig mode.

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Table 2. Synthesis of cyclohepta[b]furans 2^a

Scheme 4

Ph

tert-BuOK (0.5 equiv)

DMSO (2 mL), r.t., 1 h

O

2

R¹

O

1

R¹

R²

1) radical scavenger (1.0 eq)

2) t-BuOK (0.5 eq)

O

Ph

DMSO, rt, 1 h

O

Ph

O

2a - 89%

O

1a

O

Me

Ph

O

Ph

Me

MeO

Me

2b ( - )

2c (70 %)^b,c

2d (55 %)^b

2e (81 %)^b

2a (90 %)

Scheme 5

The formation of six-membered ring via intramolecular 6-endo-dig

mode, in the first cyclization, or six-membered ring via a 6-exo-dig

process, in the second cyclization, was not observed in any case.

This high regioselectivity can be explained by the stability of the

new sigma-bond system formed, the formation of the more stable

vinyl carbanion from original alkyl anion and due to the carbon, the

nucleophilic cyclization normally goes on via 5-exo-dig over 6-endo

closure in the substrate with these interatomic distances.²⁸In the

second cyclization step, the 7-endo-dig mode was preferred over 6-

exo-dig, albeit the both processes are acceptable according to the

Baldwin rule.²⁸It is reasonable to assume that steric and electronic

factors over the competitive cyclization modes are involved in this

reaction.²⁹

O

Me

Ph

Me

F

Cl

Me

2f (65 %)^c

2h (70 %)^b,c

2i (80 %)^b,c

2j (90 %)^b

2g (87 %)

O

OMe

Ph

MeO

OMe

F

Cl

2k (79 %)^c

2l (70 %)^b,c

2m (82 %)^c

2n (83 %)^b

2o (88 %)

O

Ph

O

Ph

MeO

S

F₃C

F

OMe

2q (75 %)^c

OMe

2r (60 %)^c

2p (54 %)^b,c

2s (75 %)^b,c

2t (90 %)^b

Characterization of Cyclohepta[b]furan Derivatives

O

Ph

+

O

Ph Bu

H

In our methodology, except for the reaction of (2-alkynylphenyl)

benzyl ether having a 2-naphthyl group bonded to alkyne, which

gave a mixture of isomer derivatives, only the product resulting

from 5-exo-dig/7-endo-dig intramolecular sequence was obtained.

The presence of a unique isomer was confirmed by spectral ¹³C

NMR data from crude reaction mixture to avoid error in the

2v ( - )

2u

2u'

78 % (2u:2u' / 5:1)

^[a]The reaction was performed in the presence of (2-alkynylphenyl) benzyl

ethers 1 (0.25 mmol) and tert-BuOK (50 mol%) in DMSO (2.0 mL) under an

argon atmosphere at room temperature for 1 h.

^[b]The reaction was performed with tert-BuOK (1.0 equiv).

^[c]The reaction was performed at 100 ^oC.

1

detection isomer peaks by H NMR. The structures of all products 2

were unambiguously elucidated by their NMR data and confirmed

by single crystal X-ray diffraction for compound 2f (Figure 1, CCDC

1485830 ), 2g (CCDC 1485827, Figure S1 Supporting Information)

and 2m (CCDC 1485825, Figure S1 Supporting Information).

Figure 1. The molecular structure with the atom-labeling scheme of the

compound 2f with 50% thermal ellipsoids (using ORTEP software) (CCDC

1485830)

Scheme 3

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UV-Vis and Emission Fluorescence Analysis of Cyclohepta[b]furan

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Derivatives 2a-2t

The comparative absorption spectra of compounds 2a-2t, using

CHCl₃as solvent, are shown in Figure 2 and the optical properties

are listed in Table 3. The cyclohepta[b]furan derivatives showed

absorption maxima located around 250-400 nm range, at the UV

region. The values for the molar absorptivity coefficient (ε) for

these compounds indicate that spin and symmetry allowed

electronic transitions, which could be related to π-π* and n→π*

transitions (Figure 2). We did not observe significant changes on

the absorption maxima location associated with different

substituent groups in the cyclohepta[b]furan compounds. The

fluorescence emission spectra of some cyclohepta[b]furans are

illustrated in Figure 3. The emission curves were obtained exciting

the compounds at the absorption maxima wavelength at λ_exc= 350

nm. Cyclohepta[b]furan compounds presented fluorescence

emission in the purple region (380-450 nm range). As already

observed in the ground state, they presented comparable location

to the emission maxima, which indicates that the different organic

Figure 2. Comparative electronic UV-Vis absorption spectra of

cyclohepta[b]furan compounds 2a-2t, containing different substituted

groups in chloroform solution

moieties in the cyclohepta[b]heterocycles did not play

a

fundamental role on the excited state of these compounds. In

addition, the fluorescent emission of cyclohepta[b]furans

containing methoxyl substituent (2k and 2q) can be attributed to

the electronic nature of this electron donor group (Figure 3). These

results probably can be attributed to the nature of the π-π*

electronic transition, indicating that these compounds allow better

electronic delocalization in the excited state. The Stokes shifts

observed in the excited state can indicate that cyclohepta[b]furans

present some charge separation, in special compounds 2e and 2k

(both with CH₃O group). These results could be assigned to an

intramolecular charge transfer character in the excited state (Table

3). Moreover, they showed good fluorescence quantum yields if

compared to that of the DPA standard or cyclohepta[b]furan

compounds with donating substituents in meta or ortho position

(Table 3). This suggests that the presence of both oxygen atoms

and electronic donating groups enhance significantly the

fluorescent emission in these cyclohepta[b]furan derivatives.

Evidence also was found to correlate the higher fluorescence

quantum yields with the heterocyclic ring planarities.

Figure 3. Emission fluorescence spectra of compounds 2a-2t, in CHCl₃

solution

The oxidation peaks observed in these compounds can be assigned

to the cation radical species of cyclohepta[b]furans in solution.

Analyzing the donor/acceptor groups in these derivatives, we

observed that they did not influence the changes in the redox

potential (Supplementary Information, Figure S2 and S3). An

exception was the derivatives 2q and 2r, which had lower oxidation

potentials when to compare to those of the other compounds

(Table 4). This may be related to the electronic properties of the

molecule.

Cyclic Voltammetry Analysis of Cyclohepta[b]furans 2a-2t

In order to better evaluate the redox properties of

cyclohepta[b]furans CV experiments were performed to verify the

redox potential values of compounds, in dry dichloromethane

solutions (Table 4). In general, at -2.00 to +2.00 V potential range,

the cyclic voltammograms of cyclofuran-derivatives displayed one

reversible reduction peak (E_pc) between -0.90 V to -1.30 V versus

SHE redox couple (Figure 4). This reduction process can be

attributed to a C-O bond cleavage located in the furan unit, which

form an anion radical type species. Moving to the positive region,

all derivatives exhibit irreversible oxidation waves in the anodic

range (E_pa) at +1.20 V to +1.80 V (Table 4).

Figure 4. Comparative cyclic voltammogram of compounds 2a, 2h, 2k, 2n, 2s

and 2t, in dichloromethane containing 0.1 M TBAPF₆, as support electrolyte,

using scan rate at 100 mV/s, respectively.

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Table 3. UV-vis and emission data analysis of cyclohepta[b]furans 2a-2t

UV-vis, nm (ε; M^-1cm^-1)^a

272 (3.469); 360 (1.435)

272 (5.437); 358 (1.485)

269 (7.513); 352 (2.891)

273 (6.940); 359 (1.064)

270 (6.956); 358 (1.067)

271 (4.373); 358 (1.784)

274 (6.333); 359 (1.040)

271 (3.633); 359 (1.507)

248 (6.954); 357 (1.323)

280 (4.487); 358 (2.079)

269 (5.988); 358 (1.226)

253 (4.195); 355 (2.018)

274 (9.871); 358 (2.787)

270 (4.007); 359 (1.605)

270 (7.955); 357 (2.143)

280 (3.122); 357 (1.287)

281 (3.177); 357 (1.461)

276 (3.053); 358 (1.136)

267 (6.507); 358 (2.169)

emission (nm)^b

391

φ_fl

Stokes shifts (nm)^d

E_0-0(eV)^e

3.444

3.445

3.271

3.229

3.387

3.171

3.378

3.324

3.289

3.155

3.342

3.246

3.406

3.342

3.425

3.333

3.246

3.406

3.425

c

compound

2a

2c

2d

2e

2f

0.135

0.230

0.321

0.308

0.129

0.275

0.290

0.143

0.100

0.187

0.247

0.214

0.060

0.059

0.046

0.255

0.115

0.079

0.144

31

37

69

100

56

97

43

66

75

102

73

80

42

94

37

52

93

45

46

395

421

459

415

2g

2h

2i

455

402

425

2j

432

2k

2l

460

431

2m

2n

2o

2p

2q

2r

435

400

453

394

409

450

2s

403

2t

404

^[a]Measured in CHCl₃. ^[b]Measured in CHCl₃solution at 298K (λ_exc.= 350 nm). ^[c]9,10-Diphenylanthracene (DPA) in CHCl₃as standard (φ_fl= 0.65). ^[d]Stokes Shift

equation: Δλ´= λ_em- λ_abs(Δλ´ = 1/λ_abs– 1/λ_emx 10⁷cm^-1). ^[e]E_0-0= 1240 / λ (in eV).

Table 4. Electrochemical data of cyclohepta[b]furans 2a-2t

a

b

compound

E₁

E₂

E₃

HOMO (eV)^c

-6.277

-5.986

-5.950

-6.179

-6.289

-6.256

-6.268

-5.937

-5.964

-6.234

-6.232

-6.360

-6.292

-6.160

-6.256

LUMO (eV)^d

-2.833

-2.541

-2.679

-2.950

-2.902

-3.085

-2.890

-2.613

-2.675

-3.079

-2.890

-3.114

-2.886

-2.818

-2.831

ΔE (eV)

3.444

3.445

3.271

3.229

3.387

3.171

3.378

3.324

3.289

3.155

3.342

3.246

3.406

3.342

3.425

2a

2c

2d

2e

2f

+1.477 V

+1.186 V

+1.150 V

+1.379 V

+1.489 V

+1.456 V

+1.468 V

+1.137 V

+1.164 V

+1.434 V

+1.432 V

+1.560 V

+1.492 V

+1.360 V

+1.456 V

-----

-1.045 V

-0.994 V

-1.022 V

-1.148 V

-1.023 V

-1.048 V

-1.062 V

-1.041 V

-1.022 V

-1.026 V

-1.200 V

-1.126 V

-1.007 V

-1.099 V

-1.171 V

+1.489 V

+1.471 V

+1.661 V

+1.769 V

+1.739 V

-----

2g

2h

2i

+1.481 V

+1.453 V

-----

2j

2k

2l

+1.675 V

-----

2m

2n

2o

2p

+1.768 V

+1.654 V

+1.761 V

This journal is © The Royal Society of Chemistry 2016

J. Name., 2013, 00, 1-3 | 6

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Page 7 of 12

Green Chemistry

Journal Name

ARTICLE

2q

2r

2s

2t

+0.698 V

+0.675 V

+1.338 V

+1.469 V

+1.155 V

-0.309 V

-----

-1.054 V

-0.913 V

-1.228 V

-5.498

-2.165

-2.229

-2.732

-2.844

3.333

View Article Online

DOI: 10.1039/C6GC02423H

-5.475

3.246

-6.138

3.406

+1.704 V

-1.046 V

-6.269

3.425

[a]

[b]

E

[c]

E

[d]

E

= Anodic peak (versus SHE).

= Cathodic peak (versus SHE).

= -[4.8 + E_1ox(versus SHE)]eV.

E

LUMO

= [E_HOMO+ E_0-0]. ^[e]ΔE = E_LUMO- E_HOMO

.

pa

pc

HOMO

using Gel GF₂₅₄, 0.25 mm thickness. For visualization, TLC plates

were either placed under ultraviolet light, or stained with iodine

vapor, or acidic vanillin. Most reactions were monitored by TLC for

disappearance of starting material. The following solvents were

dried and purified by distillation from the reagents indicated:

tetrahydrofuran from sodium with a benzophenone ketyl indicator.

All other solvents were ACS or HPLC grade unless otherwise noted.

Air- and moisture-sensitive reactions were conducted in flame-dried

or oven dried glassware equipped with tightly fitted rubber septa

and under a positive atmosphere of dry nitrogen or argon.

Reagents and solvents were handled using standard syringe

techniques. Spectroscopic grade solvents (Sigma-Aldrich) were

used for fluorescence and UV-Vis measurements. UV-Vis electronic

absorption spectra in solution were performed on a UV-2600

Conclusions

To summarize, we showed that the (2-alkynylphenyl) benzyl ethers

1 react with tert-BuOK in DMSO to give the corresponding

cyclohepta[b]furans 2, via a sequential regioselective 5-exo-dig

mode followed by a 7-endo-dig mode. A systematic study to

determine the best reaction conditions of the cyclization system

revealed that the amount of base and solvent played an essential

role in this reaction. The reaction afforded cyclohepta[b]furans in

moderate to good yields and various functional groups were readily

accommodated in the final structure. We consider that this method

has significant advantages, such as a short reaction time, the

reactions were carried out under room temperature and given that

tert-BuOK is easily available commercially, less expensive and

relative non-toxic, our method could be considered an economic

and eco-friendly protocol. Another feature of this protocol is the

atom economy because two new carbon-carbon bonds were

formed in a one-pot procedure, which is an important concept of

green chemistry philosophy. The cyclohepta[b]furans 2 was

identified by their NMR data and the structures were confirmed by

single crystal X-ray diffraction. Furthermore, the cyclohepta[b]furan

derivatives absorbed the UV region (π-πꢀ and nꢁπꢀ transiꢂons)

and present fluorescence emission in the purple region (380-450

nm range) as well as redox potentials which can be attributed to the

anion/cation radical species.

spectrophotometer at a concentration of 1.0 x 10^-4- 1.0 x 10^-5

M

range. Steady state fluorescence spectra were taken with an Cary

Eclipse spectrofluorometer. The maximum absorption wavelength

was used as excitation wavelength for fluorescence measurements.

The quantum yield of fluorescence (φ_F) was measured at 25 ^oC

using spectroscopic grade solvents within solutions with

absorbance intensity lower than A = 0.2. 9,10-Diphenylanthracene

(DPA, Aldrich) in CHCl₃was used as fluorescence quantum yield

standard (φ_F= 0.65). Cyclic voltammograms were recorded on

potenciostat/galvanostat system at room temperature under argon

atmosphere, using dry dichloromethane solution (Sigma-Aldrich).

Electrochemical grade tetrabutylammonium hexafluorophosphate

(TBAPF₆, Sigma-Aldrich) was used as supporting electrolyte. These

experiments were carried out by employing a standard three

component system: a glassy carbon working electrode; a platinum

wire auxiliary electrode and a platinum wire pseudo-reference

electrode. To monitor the reference electrode, the Fc/Fc⁺couple

was used as an internal reference. All measurements were

performed at room temperature (25 ^oC).

Experimental Section

General Methods

Proton nuclear magnetic resonance spectra (¹H NMR) were

obtained on a NMR spectrometer at 400 MHz. Spectra were

recorded in CDCl₃solutions. Chemical shifts are reported in ppm,

referenced to the solvent peak of CDCl₃or tetramethylsilane (TMS)

as the external reference. Data are reported as follows: chemical

shift (δ), multiplicity, coupling constant (J) in Hertz and integrated

intensity. Carbon-13 nuclear magnetic resonance spectra (¹³C NMR)

were obtained on a 400 NMR spectrometer at 100 MHz. Spectra

were recorded in CDCl₃solutions. Chemical shifts are reported in

ppm, referenced to the solvent peak of CDCl₃. Abbreviations to

denote the multiplicity of a particular signal are s (singlet), d

(doublet), t (triplet), q (quartet), quint (quintet), sex (sextet), dt

(double triplet), td (triple doublet) and m (multiplet). High

resolution mass spectra were recorded on a mass spectrometer

using electrospray ionization (ESI). Column chromatography was

performed using Silica Gel (230-400 mesh) following the methods

described by Still. Thin layer chromatography (TLC) was performed

General Procedure

General

Procedure

for

the

Preparation

of

H-

benzo[4,5]cyclohepta[1,2-b]benzofurans Derivatives 2a-u

To a tube, under argon, containing the substrate 1 (0.25 mmol) and

DMSO (2 mL), was added t-BuOK. The reaction mixture was

allowed to stir for 1 h. After this time, the mixture was diluted with

ethyl acetate (20 mL) and washed saturated solution of NH₄Cl (2 x

20 mL). The organic phase was separated, dried over MgSO₄and

concentrated under vacuum. The residue was purified by column

chromatography on silica gel.

J. Name., 2013, 00, 1-3 | 7

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Green Chemistry

Page 8 of 12

ARTICLE

Journal Name

Characterization

(4). HRMS (ESI-TOF) m/z calcd for C₃₀H₂₃O₂[M + H]⁺: 415.1698.

View Article Online

DOI: 10.1039/C6GC02423H

Found: 415.1704.

6-diphenyl-5aH-benzo[4,5]cyclohepta[1,2-b]benzofuran

(2a):

Isolated by column chromatography (hexane as eluent) as a white 5a-(4-chlorophenyl)-6-phenyl-5aH-benzo[4,5]cyclohepta[1,2-

yellow solid. Yield: 0.086 g (90 %), mp 76-79 °C. ¹H NMR (CDCl₃, 400 b]benzofuran (2f): Isolated by column chromatography (hexane as

MHz): δ 7.52-7.50 (m, 1H), 7.48-7.40 (m, 2H), 7.30-7.23 (m, 7H), eluent) as a white yellow solid. Yield: 0.068 g (65 %), mp 174-176 °C.

7.20 (s, 1H), 7.17-7.02 (m, 6H), 6.93-6.90 (m, 2H), 6.71 (d, J = 8.0 Hz, ¹H NMR (CDCl₃, 400 MHz): δ 7.54 (ddd, J = 7.6 Hz, J = 1.3 Hz, J = 0.6

1H). ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 161.3, 142.6, 140.9, 140.6, Hz, 1H), 7.46-7.40 (m, 2H), 7.38-7.11 (m, 11H), 7.03 (d, J = 9.0 Hz,

140.4, 135.0, 134.1, 131.3, 130.6, 129.9, 129.4, 129.3, 128.1, 127.9, 2H), 6.98-6.92 (m, 2H), 6.77-6.72 (m, 1H). ¹³C{¹H} NMR (CDCl₃, 100

127.5, 127.3, 126.8, 126.2, 126.1, 126.0, 121.0, 120.7, 116.5, 110.5, MHz): δ 161.1, 142.3, 140.6, 140.3, 139.1, 134.9, 134.0, 133.9,

91.5. MS (EI, 70 eV; m/z (relative intensity)): 385 ([M + 1], 8), 384 131.3, 130.8, 130.0, 129.5, 129.3, 128.1, 127.8, 127.6, 127.4, 127.0,

(28), 307 (100), 276 (10), 205 (3), 169 (3), 153 (11), 138 (4). HRMS 126.4, 125.9, 121.2, 120.8, 116.7, 110.5, 90.8. MS (EI, 70 eV; m/z

(ESI-TOF) m/z calcd for C₂₉H₂₁O [M + H]⁺: 385.1592. Found: (relative intensity)): 420 ([M + 2], 13), 419 ([M + 1], 13), 418 (38),

385.1602.

383 (3), 341 (72), 307 (100), 276 (22), 207 (8), 152 (16). HRMS (ESI-

TOF) m/z calcd for C₂₉H₂₀ClO [M + H]⁺: 419.1203. Found: 419.1210.

6-phenyl-5a-(m-tolyl)-5aH-benzo[4,5]cyclohepta[1,2-b]benzofuran

(2c): Isolated by column chromatography (hexane as eluent) as a 5a-(4-fluorophenyl)-6-phenyl-5aH-benzo[4,5]cyclohepta[1,2-

1

white yellow viscous oil. Yield: 0.069 g (70 %). H NMR (CDCl₃, 400 b]benzofuran (2g): Isolated by column chromatography (hexane as

MHz): δ 7.56-7.52 (m, 1H), 7.49-7.42 (m, 2H), 7.36-7.25 (m, 5H), eluent) as a white yellow solid. Yield: 0.087 g (87 %), mp 183-185 °C.

7.22 (s, 1H), 7.20-7.07 (m, 5H), 6.99-6.91 (m, 3H), 6.90-6.86 (m, 1H), ¹H NMR (CDCl₃, 400 MHz): δ 7.54 (ddd, J = 7.6 Hz, J = 1.3 Hz, J = 0.5

6.74 (d, J = 8.0 Hz, 1H), 2.12 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100 MHz): Hz, 1H), 7.47-7.42 (m, 2H), 7.36-7.25 (m, 7H), 7.23 (s, 1H), 7.21-7.11

δ 161.3, 142.6, 140.9, 140.7, 140.3, 137.5, 135.1, 134.2, 131.2, (m, 3H), 6.97-6.92 (m, 2H), 6.78-6.69 (m, 3H). ¹³C{¹H} NMR (CDCl₃,

130.6, 129.9, 129.4, 129.3, 128.9, 127.7, 127.5, 127.2, 126.9, 126.7, 100 MHz): δ 162.3 (d, J = 247.0 Hz), 161.0, 142.5, 140.7, 140.3,

126.2, 126.1, 123.4, 121.0, 120.7, 116.4, 110.5, 91.5, 21.4. MS (EI, 136.3 (d, J = 3.0 Hz), 134.8, 134.0, 131.2, 130.7, 129.8, 129.4, 129.3,

70 eV; m/z (relative intensity)): 400 ([M + 2], 3), 399 ([M + 1], 19), 128.2 (d, J = 8.0 Hz), 127.6, 127.4, 126.9, 126.3, 125.8, 121.1, 120.7,

398 (60), 383 (4), 321 (68), 307 (100), 276 (11), 205 (4), 160 (10), 116.5, 114.7 (d, J = 21.0 Hz), 110.5, 90.8. MS (EI, 70 eV; m/z (relative

138 (4). HRMS (ESI-TOF) m/z calcd for C₃₀H₂₃O [M + H]⁺: 399.1749. intensity)): 403 ([M + 1], 20), 402 (61), 325 (100), 307 (95), 276 (12),

Found: 399.1752.

205 (5), 162 (11), 153 (12). HRMS (ESI-TOF) m/z calcd for C₂₉H₂₀FO

[M + H]⁺: 403.1498. Found: 403.1503.

6-phenyl-5a-(o-tolyl)-5aH-benzo[4,5]cyclohepta[1,2-b]benzofuran

(2d): Isolated by column chromatography (hexane as eluent) as a 5a-phenyl-6-(p-tolyl)-5aH-benzo[4,5]cyclohepta[1,2-b]benzofuran

yellow viscous oil. Yield: 0.054 g (55 %). ¹H NMR (CDCl₃, 400 MHz): δ (2h): Isolated by column chromatography (hexane as eluent) as a

1

7.51-7.42 (m, 4H), 7.35-7.21 (m, 5H), 7.20-7.02 (m, 4H), 6.99-6.87 white yellow solid. Yield: 0.069 g (70 %), mp 170-173 °C. H NMR

(m, 4H), 6.85-6.79 (m, 1H), 6.65 (d, J = 8.0 Hz, 1H), 2.19 (s, 3H). (CDCl₃, 400 MHz): δ 7.56 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H),

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 161.9, 141.8, 141.7, 139.9, 138.2, 7.33-7.24 (m, 4H), 7.23 (s, 1H), 7.21-7.01 (m, 8H), 6.99-6.90 (m, 2H),

135.3, 135.2, 134.3, 132.2, 130.6, 130.2, 129.4, 129.1, 129.0, 128.7, 6.75 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100 MHz):

128.2, 127.5, 127.2, 126.4, 126.3, 125.8, 124.6, 121.1, 120.5, 114.6, δ 161.3, 142.5, 140.7, 140.4, 137.8, 137.0, 135.0, 134.0, 131.2,

109.9, 92.7, 21.7. MS (EI, 70 eV; m/z (relative intensity)): 400 ([M + 130.5, 129.8, 129.2, 128.9, 128.2, 128.0, 127.8, 126.6, 126.2, 126.1,

2], 3), 399 ([M + 1], 33), 398 (100), 383 (7), 321 (24), 307 (67), 276 120.9, 120.6, 116.5, 110.5, 91.5, 21.1. MS (EI, 70 eV; m/z (relative

(17), 205 (11), 176 (12). HRMS (ESI-TOF) m/z calcd for C₃₀H₂₃O [M + intensity)): 399 ([M+1], 10), 398 (47), 321 (100), 307 (72), 276 (14),

H]⁺: 399.1749. Found: 399.1755.

253 (16), 207 (15), 177 (9). HRMS (ESI-TOF) m/z calcd for C₃₀H₂₃O

[M + H]⁺: 399.1749. Found: 399.1758.

5a-(3-methoxyphenyl)-6-phenyl-5aH-benzo[4,5]cyclohepta[1,2-

b]benzofuran (2e): Isolated by column chromatography (hexane as 5a-phenyl-6-(m-tolyl)-5aH-benzo[4,5]cyclohepta[1,2-b]benzofuran

1

eluent) as a white yellow viscous oil. Yield: 0.083 g (81 %). H NMR (2i): Isolated by column chromatography (hexane as eluent) as a

1

(CDCl₃, 400 MHz): δ 7.52 (ddd, J = 7.6 Hz, J = 1.3 Hz, J = 0.5 Hz, 1H), white yellow viscous oil. Yield: 0.080 g (80 %). H NMR (CDCl₃, 400

7.48-7.42 (m, 2H), 7.35-7.26 (m, 5H), 7.21 (s, 1H), 7.20-7.11 (m, 3H), MHz): δ 7.57-7.47 (m, 1H), 7.36-6.99 (m, 15H), 6.97-6.89 (m, 2H),

6.99 (t, J = 8.0 Hz, 1H), 6.96-6.92 (m, 2H), 6.90 (ddd, J = 7.8 Hz, J = 6.77-6.71 (m, 1H), 2.33 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ

1.7 Hz, J = 1.1 Hz, 1H), 6.86-6.83 (m, 1H), 6.77-6.73 (m, 1H), 6.62 161.3, 142.7, 140.9, 140.5, 140.4, 137.1, 135.0, 134.1, 131.2, 130.6,

(ddd, J = 8.0 Hz, J = 3.0 Hz, J = 1.0 Hz, 1H), 3.52 (s, 3H). ¹³C{¹H} NMR 129.9, 129.8, 129.2, 128.1, 128.0, 127.9, 127.4, 126.7, 126.6, 126.3,

(CDCl₃. 100 MHz): δ 161.2, 159.2, 142.3, 142.2, 140.9, 140.7, 135.0, 126.1, 126.0, 121.0, 120.7, 116.4, 110.5, 91.5, 21.4. MS (EI, 70 eV;

134.1, 131.3, 130.6, 130.0, 129.5, 129.3, 128.9, 127.5, 127.3, 126.8, m/z (relative intensity)): 399 ([M + 1], 13), 398 (47), 321 (100), 307

126.2, 126.0, 121.0, 120.8, 118.5, 116.6, 113.6, 112.1, 110.5, 91.2, (83), 276 (15), 207 (11), 163 (6), 153 (8). HRMS (ESI-TOF) m/z calcd

55.0. MS (EI, 70 eV; m/z (relative intensity)): 415 ([M + 1], 14), 414 for C₃₀H₂₃O [M + H]⁺: 399.1749. Found: 399.1755.

(42), 337 (58), 321 (10), 307 (100), 276 (10), 207 (4), 163 (6), 138

8 | J. Name., 2012, 00, 1-3

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Page 9 of 12

Green Chemistry

Journal Name

5a-phenyl-6-(o-tolyl)-5aH-benzo[4,5]cyclohepta[1,2-b]benzofuran

ARTICLE

6-(4-chlorophenyl)-5a-phenyl-5aH-benzo[4,5]cyclohe_Vp_iet_wa[_A1_rt,_i2_cl-_{e Online}

DOI: 10.1039/C6GC02423H

(2j): Isolated by column chromatography (hexane as eluent) as a b]benzofuran (2n): Isolated by column chromatography (hexane as

1

white yellow viscous oil. Yield: 0.089 g (90 %). H NMR (CDCl₃, 400 eluent) as a white yellow viscous oil. Yield: 0.086 g (83 %). H NMR

MHz): δ 7.53 (d, J = 7.6 Hz, 1H), 7.40-7.10 (m, 12H), 7.09-6.98 (m, (CDCl₃, 400 MHz): δ 7.55-7.51 (m, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.34-

3H), 6.91 (td, J = 7.6 Hz, J = 0.7 Hz, 1H), 6.74-6.67 (m, 2H), 1.96 (s, 7.23 (m, 6H), 7.22-7.00 (m, 7H), 6.94 (td, J = 7.5 Hz, J = 0.9 Hz, 1H),

3H). ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 161.5, 142.0, 140.9, 140.5, 6.91 (s, 1H), 6.77-6.72 (m, 1H). ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ

140.0, 137.1, 134.8, 134.4, 131.3, 130.7, 130.2, 129.8, 129.5, 128.9, 161.1, 142.5, 140.2, 139.5, 138.9, 134.7, 134.1, 133.3, 131.3, 130.7,

127.9, 127.8, 127.2, 126.9, 126.3, 126.1, 125.9, 124.9, 121.0, 120.8, 130.6, 129.9, 129.6, 128.2, 128.0, 127.7, 127.0, 126.3, 126.1, 126.0,

117.0, 110.5, 91.7, 20.2. MS (EI, 70 eV; m/z (relative intensity)): 400 121.2, 120.8, 116.6, 110.5, 91.2. MS (EI, 70 eV; m/z (relative

([M + 2], 3), 399 ([M + 1], 19), 398 (59), 321 (100), 307 (39), 276 intensity)): 420 ([M + 2], 18), 419 ([M + 1], 18), 418 (56), 341 (100),

(10), 205 (3), 169 (6), 138 (4). HRMS (ESI-TOF) m/z calcd for C₃₀H₂₃O 307 (85), 276 (27), 205 (9), 176 (12), 153 (25). HRMS (ESI-TOF) m/z

[M + H]⁺: 399.1749. Found: 399.1753.

calcd for C₂₉H₂₀ClO [M + H]⁺: 419.1203. Found: 419.1225.

6-(4-methoxyphenyl)-5a-phenyl-5aH-benzo[4,5]cyclohepta[1,2-

6-(4-fluorophenyl)-5a-phenyl-5aH-benzo[4,5]cyclohepta[1,2-

b]benzofuran (2k): Isolated by column chromatography (hexane as b]benzofuran (2o): Isolated by column chromatography (hexane as

eluent) as a white yellow solid. Yield: 0.081 g (79 %), mp 163-166 °C. eluent) as a yellow viscous oil. Yield: 0.088 g (88 %). ¹H NMR (CDCl₃,

¹H NMR (CDCl₃, 400 MHz): δ 7.50 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.7 400 MHz): δ 7.53 (ddd, J = 7.6 Hz, J = 1.3 Hz, J = 0.6 Hz, 1H), 7.45-

Hz, 2H), 7.34-7.22 (m, 4H), 7.20 (s, 1H), 7.18-7.00 (m, 6H), 6.95-6.88 7.38 (m, 2H), 7.33-7.24 (m, 4H), 7.22 (s, 1H), 7.21-7.12 (m, 3H),

(m, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.0 Hz, 1H), 3.76 (s, 3H). 7.11-7.04 (m, 3H), 7.03-6.91 (m, 3H), 6.91 (s, 1H), 6.75-6.72 (m, 1H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 161.2, 159.0, 142.4, 140.5, 140.3, ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 162.2 (d, J = 247.0 Hz), 161.1,

135.1, 134.0, 133.2, 131.2, 130.6, 130.5, 129.8, 128.5, 128.0, 127.9, 142.5, 140.2, 139.6, 136.5 (d, J = 3.0 Hz), 134.8, 134.1, 131.3, 131.0

126.5, 126.2, 126.1, 126.0, 121.0, 120.7, 116.5, 113.0, 110.4, 91.6, (d, J = 8.0 Hz), 130.7, 129.9, 129.3, 128.2, 128.0, 126.9, 126.2, 126.1,

55.2. MS (EI, 70 eV; m/z (relative intensity)): 415 ([M + 1], 15), 414 126.0, 121.1, 120.7, 116.6, 114.4 (d, J = 21.0 Hz), 110.4, 91.3. MS

(48), 337 (100), 307 (65), 293 (19), 276 (8), 207 (7), 163 (7). HRMS (EI, 70 eV; m/z (relative intensity)): 403 ([M + 1], 16), 402 (50), 325

(ESI-TOF) m/z calcd for C₃₀H₂₃O₂[M + H]⁺: 415.1698. Found: (100), 307 (58), 276 (8), 205 (5), 176 (4), 153 (13). HRMS (ESI-TOF)

415.1708.

m/z calcd for C₂₉H₂₀FO [M + H]⁺: 403.1498. Found: 403.1503.

6-(3-methoxyphenyl)-5a-phenyl-5aH-benzo[4,5]cyclohepta[1,2-

5a-phenyl-6-(3-(trifluoromethyl)phenyl)-5aH-

b]benzofuran (2l): Isolated by column chromatography (hexane as benzo[4,5]cyclohepta[1,2-b]benzofuran (2p): Isolated by column

eluent) as a yellow viscous oil. Yield: 0.072 g (70 %). ¹H NMR (CDCl₃, chromatography (hexane as eluent) as a white yellow solid. Yield:

1

400 MHz): δ 7.56-7.50 (m, 1H), 7.34-7.02 (m, 13H), 7.00-6.97 (m, 0.061 g (54 %), mp 59-61 °C. H NMR (CDCl₃, 400 MHz): δ 7.71 (s,

1H), 6.96-6.90 (m, 2H), 6.85 (ddd, J = 8.2 Hz, J = 2.6 Hz, J = 1.0 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 2H), 7.46-7.37 (m,

1H), 6.75 (d, J = 8.0 Hz, 1H), 3.73 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100 1H), 7.36-7.02 (m, 11H), 7.01-6.90 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H).

MHz): δ 161.3, 159.0, 142.7, 142.1, 140.8, 140.5, 134.9, 134.3, ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 161.1, 142.8, 141.3, 140.2, 139.5,

131.4, 130.7, 130.0, 129.4, 128.5, 128.1, 128.0, 126.9, 126.3, 126.2, 134.7, 134.5, 132.9, 131.4, 130.9, 130.3 (quart, J = 32.0 Hz), 130.2,

126.1, 122.1, 121.1, 120.8, 116.6, 115.1, 113.1, 110.6, 91.5, 55.3. 130.0, 128.3, 128.0, 127.9, 127.2, 126.3, 126.2 (2C), 126.0, 124.3

MS (EI, 70 eV; m/z (relative intensity)): 415 ([M + 1], 18), 414 (65), (quart, J = 272.0 Hz), 124.0 (quart, J = 4.0 Hz), 121.3, 120.8, 116.7,

337 (99), 307 (100), 293 (17), 276 (11), 207 (13), 163 (9). HRMS (ESI- 110.6, 91.2. MS (EI, 70 eV; m/z (relative intensity)): 453 ([M + 1],

TOF) m/z calcd for C₃₀H₂₃O₂[M + H]⁺: 415.1698. Found: 415.1703.

14), 452 (45), 375 (100), 307 (69), 276 (11), 205 (5), 176 (5), 153

(20). HRMS (ESI-TOF) m/z calcd for C₃₀H₂₀F₃O [M + H]⁺: 453.1466.

Found: 453.1471.

6-(2-methoxyphenyl)-5a-phenyl-5aH-benzo[4,5]cyclohepta[1,2-

b]benzofuran (2m): Isolated by column chromatography (hexane as

1

eluent) as a white solid. Yield: 0.084 g (82 %), mp 138-140 °C. H 5a-(3-methoxyphenyl)-6-(4-methoxyphenyl)-5aH-

NMR (CDCl₃, 400 MHz): δ 7.57 (d, J = 7.3 Hz, 1H), 7.42 (s_l, 1H), 7.36- benzo[4,5]cyclohepta[1,2-b]benzofuran (2q): Isolated by column

7.23 (m, 5H), 7.21 (d, J = 7.5 Hz, 1H), 7.18-6.88 (m, 8H), 6.79 (s, 1H), chromatography (hexane as eluent) as a yellow solid. Yield: 0.083 g

1

6.74 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 3.19 (s, 3H). ¹³C{¹H} (75 %), mp 156-159 °C. H NMR (CDCl₃, 400 MHz): δ 7.52 (ddd, J =

NMR (CDCl₃, 100 MHz): δ 162.4, 157.8, 142.9, 139.9, 139.2, 134.8, 7.6 Hz, J = 1.3 Hz, J = 0.6 Hz, 1H), 7.41 (d, J = 8.9 Hz, 2H), 7.35-7.26

134.7, 130.7, 130.6, 130.5, 130.3, 129.7, 128.8, 128.2, 127.6, 127.5, (m, 2H), 7.21 (s, 1H), 7.20-7.10 (m, 3H), 7.02-6.96 (m, 1H), 6.95-6.89

126.4, 126.3, 125.8, 120.6, 120.4, 120.1, 115.9, 110.1, 109.8, 91.4, (m, 3H), 6.88-6.82 (m, 3H), 6.78-6.74 (m, 1H), 6.62 (ddd, J = 8.0 Hz, J

54.6. MS (EI, 70 eV; m/z (relative intensity)): 416 ([M + 2], 4), 415 = 2.6 Hz, J = 1.0 Hz, 1H), 3.80 (s, 3H), 3.53 (s, 3H). ¹³C{¹H} NMR

([M + 1], 23), 414 (69), 337 (100), 321 (52), 307 (60), 292 (8), 276 (CDCl₃, 100 MHz): δ 161.2, 159.1, 159.0, 142.2, 142.1, 140.4, 135.1,

(8), 207 (6), 168 (9). HRMS (ESI-TOF) m/z calcd for C₃₀H₂₃O₂[M + 134.0, 133.3, 131.3, 130.6, 130.5, 129.9, 128.9, 128.6, 126.6, 126.2,

H]⁺: 415.1698. Found: 415.1700.

126.1, 121.0, 120.7, 118.6, 116.6, 113.5, 113.0, 112.2, 110.4, 91.4,

55.2, 55.0. MS (EI, 70 eV; m/z (relative intensity)): 446 ([M + 2], 2),

445 ([M + 1], 16), 444 (50), 429 (2), 413 (3), 337 (100), 321 (6), 293

J. Name., 2013, 00, 1-3 | 9

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(15), 265 (4), 163 (4). HRMS (ESI-TOF) m/z calcd for C₃₁H₂₅O₃[M + 1H), 7.52-6.84 (m, 20.7H), 6.67-6.62 (m, 0.2H), 6.39-6.33 (m, 1H).

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13

1

H]⁺: 445.1804. Found: 445.1810.

DOI: 10.1039/C6GC02423H

C{ H} NMR (CDCl₃, 100 MHz): δ 161.5, 161.0, 142.1, 140.4, 139.7,

139.3, 139.0, 138.5, 138.1, 134.8, 134.7, 134.5, 133.9, 133.3, 132.9,

132.6, 131.3, 131.1, 130.7, 130.6, 130.3, 130.2, 130.1, 130.0, 128.6,

128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.1, 127.0, 126.9,

126.8, 126.7, 126.4, 126.2, 126.1, 126.0, 125.9, 125.8, 125.4, 125.3,

124.9, 124.6, 121.1, 121.0, 120.9, 120.7, 117.1, 116.8, 110.6, 110.5,

91.8. MS (EI, 70 eV; m/z (relative intensity)): 436 ([M + 2], 4), 435

([M + 1], 26), 434 (75), 357 (100), 326 (11), 307 (35), 217 (3), 178

(13), 163 (10). HRMS (ESI-TOF) m/z calcd for C₃₃H₂₃O [M + H]⁺:

435.1749. Found: 435.1760.

5a-(4-fluorophenyl)-6-(4-methoxyphenyl)-5aH-

benzo[4,5]cyclohepta[1,2-b]benzofuran (2r): Isolated by column

chromatography (hexane as eluent) as a white yellow solid. Yield:

0.064 g (60 %), mp 75-78 °C. ¹H NMR (CDCl₃, 400 MHz): δ 7.53 (ddd,

J = 7.6 Hz, J = 1.3 Hz, J = 0.5 Hz, 1H), 7.40 (d, J = 8.9 Hz, 2H), 7.35-

7.09 (m, 8H), 6.94 (td, J = 7.6 Hz, J = 0.9 Hz, 1H), 6.91 (s, 1H), 6.86 (d,

J = 8.9 Hz, 2H), 6.78-6.70 (m, 3H), 3.81 (s, 3H). ¹³C{¹H} NMR (CDCl₃,

100 MHz): δ 162. 3 (d, J = 247. 0 Hz), 161.1, 159.1, 142.5, 140.3,

136.4 (d, J = 3.0 Hz), 135.0, 133.9, 133.0, 131.2, 130.7, 130.6, 129.8,

128.5, 128.2 (d, J = 8.0 Hz), 126.7, 126.2, 125.9, 121.1, 120.7, 116.5,

114.7 (d, J = 22.0 Hz), 113.0, 110.5, 91.0, 55.2. MS (EI, 70 eV; m/z

(relative intensity)): 434 ([M + 2], 4), 433 ([M + 1], 30), 432 (96), 417

(3), 401 (3), 337 (100), 325 (99), 294 (20), 276 (4), 168 (11). HRMS

(ESI-TOF) m/z calcd for C₃₀H₂₂FO₂[M + H]⁺: 433.1604. Found:

433.1609.

Acknowledgements

We are grateful to FAPERGS, CAPES and CNPq for financial support.

CNPq and CAPES are also acknowledged for the fellowships (R.G.

and G. Z.).

5a-phenyl-6-(thiophen-3-yl)-5aH-benzo[4,5]cyclohepta[1,2-

Notes and references

b]benzofuran (2s): Isolated by column chromatography (hexane as

1

eluent) as a white yellow viscous oil. Yield: 0.073 g (75 %). H NMR

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DOI: 10.1039/C6GC02423H

Table of Contents

We present the results on the intramolecular transition metal-free cyclization of (2-

alkynylphenyl) benzyl ethers promoted by sodium tert-butoxide.

Article Doi

The intramolecular 5-: Exo, 7- endo -dig transition metal-free cyclization sequence of (2-alkynylphenyl) benzyl ethers: Synthesis of seven-membered fused benzo [b] furans

DOI: 10.1039/c6gc02423h

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Full text of DOI:10.1039/c6gc02423h

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