Functionalized Benzofurans via Microwave-Promoted Tandem Claisen-Rearrangement/5-endo-dig Cyclization

Month 2019

Functionalized Benzofurans via Microwave-Promoted Tandem Claisen-

Rearrangement/5-endo-dig Cyclization

*

Christiane Schultze and Bernd Schmidt

Universitaet Potsdam, Institut fuer Chemie, Karl-Liebknecht-Straße 24-25, Potsdam-Golm D-14476, Germany

*E-mail: bernd.schmidt@uni-potsdam.de

Received May 7, 2019

DOI 10.1002/jhet.3671

Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).

Ortho-allyloxy alkinyl benzenes undergo, upon microwave irradiation in dimethylformamide, a tandem

sequence of Claisen-rearrangement and 5-endo-dig cyclization to furnish 7-allyl-substituted benzofurans.

With terminal alkynes, chroman-4-ones and enaminoketones become the main products. A mechanistic pro-

posal for this observation relies on a reaction of the starting material with the solvent dimethylformamide

under the microwave conditions.

J. Heterocyclic Chem., 00, 00 (2019).

INTRODUCTION

the present work, we aimed at an extension of the

microwave-promoted Claisen-rearrangement/cyclization

sequence to systems without an explicitly electrophilic

functional group FG. This is, for example, the case with

C─C-triple bonds directly attached to the ortho-position

of the masked phenol. Upon Claisen rearrangement, the

liberated O-nucleophile would undergo a 5-endo-dig

cyclization to benzofurans. The development of methods

for the synthesis of benzofurans has attracted continuous

interest for many decades. Some of the most recent

contributions include routes that involve the construction

Over the past few years, we investigated the

development and application of microwave-promoted

tandem sequences [1–3] for the synthesis of

benzoannellated oxacycles with an aliphatic substituent at

the benzo ring, starting from easily accessible acyclic

precursors (Scheme 1). In general, these transformations

start from allyl-protected ortho-substituted phenols (e.g.,

salicylic aldehyde derivatives) with

a

substituent

containing a reactive, normally electrophilic, functional

group FG. For the synthesis of the precursors, the allyl

ether plays the role of a protecting group to mask the

nucleophilic reactivity of the phenol. Instead of a

traceless deprotection, the allyl ether is used to install an

allyl side chain at the benzo ring, which can be further

elaborated in various ways as required for the target

structures to be addressed.

of the benzene ring as

a key step, either by

benzannulation to a preformed furan [12] or by a

dehydration/oxidative dehydrogenation sequence of an in

situ formed tetrahydrobenzofuran [13]. Many syntheses

of benzofurans use 5-endo-dig cyclizations of ortho-

alkinylphenols [14]. Traditionally, these reactions are

mediated by bases such as Cs₂CO₃in polar, aprotic

solvents at elevated temperatures [15,16], but only for

very few examples microwave irradiation was used to

accelerate the reaction [17,18]. In recent years, metal

catalysis has been intensively investigated for this

intramolecular heteroannulation, including, inter alia,

rhodium [19], palladium [20], and indium catalysts [21].

Transition metal catalysis offers the opportunity to

combine the heteroannulation with additional steps to

tandem sequences, which ultimately results in the

formation of 2,3-disubstituted benzofurans. Examples for

Along these lines, straightforward syntheses of

pyranocoumarins

[4],

prenylcoumarins

[5–7],

furanocoumarins [8], chroman-4-ones [9], and chromene-

4-ones [10,11] were developed and implemented in the

total synthesis of several natural products. In the above-

mentioned examples, the cyclization step proceeds

through a nucleophilic acyl substitution (for the synthesis

of coumarins) or through an addition across an

electronically biased C─C-multiple bond (for the

synthesis of chroman-4-ones and chromene-4-ones). In

C. Schultze, and B. Schmidt

Vol 000

Scheme 1. Generalized tandem Claisen-rearrangement/cyclization

sequence.

occurrence in natural products [30] and drugs [31].

Examples for bioactive naturally occurring benzofurans

are the moracins, which show antifungal and antibacterial

activity [32]. 7-Aminomethyl-substituted benzofurans,

such as the example shown in Figure 1 together with

moracins S and L, were identiﬁed as kinase inhibitors

and potent cytotoxic agents in a high throughput

screening [33].

such tandem sequences are a Rh-catalyzed cyclization of

alkinylphenols in the presence of electron deﬁcient

alkenes [22] or cyclizations of alkinylphenol allyl ethers,

which proceed through a metal catalyzed deallylation and

intramolecular transfer of the allyl substituent to the 3-

position of the benzofuran [23–26]. Allyl ethers of

alkinyl phenols are also the envisaged starting materials

for the tandem sequence investigated in this study, but in

contrast to the transition metal catalyzed reactions

mentioned earlier, the microwave-promoted Claisen-

rearrangement/5-endo-dig cyclization will result in the

formation of 7-allylbenzofurans, that is, the allyl

substituent is installed at the benzo ring, rather than the

furan part of the heterocycle [27]. We are aware of only

one example from the patent literature for such a tandem

Claisen-rearrangement/5-endo-dig cyclization, which

describes a total synthesis of the natural product moracin

S (Fig. 1) [28]. The authors used conventional heating in

water for 9 h in a closed reaction vessel to promote the

reaction, resulting in a yield of 31% of a 7-prenylated

benzofuran. During preparation of this manuscript, Mino

and coworkers published a closely related two-step

RESULTS AND DISCUSSION

We started the investigation into the microwave-

promoted tandem sequence with precursor 4a [24,26],

which was synthesized from 2-allyloxybenzaldehyde (1a)

[10] in two steps via carbonyl alkynylation using the

Bestmann–Ohira reagent 2 [34], followed by Sonogashira

coupling of 3a [35] with iodobenzene. For the latter step,

the copper-free reaction conditions published by Liang

et al. were used [36] (Scheme 2).

All microwave irradiation experiments were conducted

at 250°C, because we [9] and others [7] have previously

shown that the Claisen rearrangement remains incomplete

at lower temperatures. In a ﬁrst experiment (Table 1,

entry 1), we tested toluene as a solvent. After 1 h, the

starting material was completely consumed, but we could

only isolate the product of the Claisen rearrangement 6a

and not the expected benzofuran 7a. We reasoned that

replacing toluene by the polar aprotic solvent

dimethylformamide (DMF) should enhance the

nucleophilicity of the phenol and thereby facilitate the

ring closure. Benzofuran 5a was indeed the sole product

when the reaction was run in DMF. It could be isolated

in a yield of 92% (Table 1, entry 2). Addition of K₂CO₃

under these conditions did not improve the yield further

(Table 1, entry 3).

approach

to

7-allylbenzofurans

from

ortho-

allyloxyalkinyl benzenes that uses a Lewis acid-mediated

Claisen rearrangement, followed by a TBAF-catalyzed

5-endo-dig cyclization. Both steps can be conducted in

one pot, but in this case, overstoichiometric amounts of

TBAF are required to promote the cyclization [29].

The interest in the development of novel synthetic

methods for functionalized benzofurans and 2,3-

dihydrobenzofurans is stimulated by their ubiquitous

To explore the scope of the tandem sequence, three other

diarylacetylenes

4b–d

were

synthesized

from

Scheme 2. Synthesis of precursor 4a.

Figure 1. Natural and nonnatural bioactive C3-unsubstituted

benzofurans.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2019

Microwave-Promoted Benzofuran Synthesis

Table 1

Synthesis of 7-allyl-2-arylbenzofurans.

Entry

4

R¹

R²

R³

Solvent

t (min)

Product (yield, %)

1

2

3^a

4

5

6

7

8

9

4a

4b

4c

4d

H

OMe

H

OMe

H

OMe

H

OMe

Toluene

DMF

60

15

30

15

30

15

30

6a (45)

5a (92)

5a (90)

5b (n. d.)^b

5b (67)

5c (n. d.)^b

5c (63)

5d (n. d.)^b

5d (54)

DMF, dimethylformamide.

^aK₂CO₃(4 equiv.) used as an additive.

^bNot determined, incomplete conversion (thin-layer chromatography).

commercially available benzaldehydes 7 in three steps

(Table 2) and irradiated at 250°C in DMF in a

microwave reactor. In all cases, unreacted starting

material was detected by thin-layer chromatography

(TLC) after 15 min (Table 1, entries 4, 6, and 8), but the

conversion was quantitative after 30 min and the

expected benzofurans 5b–d were isolated in yields

between 54% and 67% (Table 1, entries 5, 7, and 9).

The optimized conditions for the tandem Claisen-

rearrangement/5-endo-dig cyclization sequence could also

be successfully applied to an acetylene substituted with

an electron-withdrawing group. The required precursor,

propiolate 4e, was synthesized from acetylene 3a by

lithiation and electrophilic trapping with methyl

chloroformiate [37]. Microwave irradiation at 250°C in

DMF furnished 7-allyl-2-methoxycarbonylbenzofuran

(5e) in 54% yield (Scheme 3).

We concluded our investigation into this microwave-

promoted tandem sequence with ﬁve monosubstituted

acetylenes 3a–e. Compound 3a is an intermediate en

route to the test substrate 4a and its synthesis from

aldehyde 1a via carbonyl alkynylation with the

Bestmann–Ohira reagent is shown in Scheme 2. The

other four arylacetylenes 3b–e were synthesized

analogously from the known ortho-allyloxybenzal-

dehydes 1b–e (Table 3).

In a ﬁrst experiment, 3a was subjected to microwave

irradiation in DMF for 15 min (Table 4, entry 1).

Surprisingly, neither the expected 7-allylbenzofuran (12a)

nor the Claisen rearrangement product 11a were detected,

although the starting material was fully consumed as

indicated by TLC. Instead, the enaminoketone 13a and 7-

allylchromene-4-one (14a) were isolated in more than

60% combined yield. The enaminoketone 13a must result

from a reaction between the starting material 3a and the

solvent DMF, and 14a is apparently formed from 13a via

an intramolecular conjugate addition followed by

elimination of dimethylamine [40]. In toluene as a solvent

(Table 4, entry 2), the reaction stops at the stage of the

Claisen rearrangement as previously observed for the

diarylacetylene 4a, and the phenol 11a was isolated in

moderate yield. The assumption that the chromene-4-one

14a results from 13a is supported by the observation that

its yield increases at longer reaction times at the expense

of the intermediary product 13a (Table 4, entry 3). From

the four other monosubstituted acetylenes tested in this

study, only 3b and 3d, both with an electron-donating

substituent in para-position to the allyloxy group, reacted

to benzofurans (Table 4, entries 4 and 6). While 7-allyl-

5-methoxybenzofuran (12b) was isolated in a fair yield of

47%, along with equal amounts of the enaminoketone

13b and its secondary product 14b, the MOM-protected

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

C. Schultze, and B. Schmidt

Vol 000

Table 2

Synthesis of precursors 4b–d.

Entry

7

R¹

R²

R³

8 (yield, %)

10 (yield, %)

4 (yield, %)

1

2

3

7b

7c

7d

H

OMe

H

OMe

H

OMe

8b (53)

8c (57)

8d (58)

10b (96)

10c (81)

10d (93)

4b (65)

4c (78)

4d (62)

Scheme 3. Tandem Claisen-rearrangement/cyclization sequence of

propiolate 4e.

accelerates the 5-endo-dig cyclization over the reaction

with the solvent DMF.

Enaminoketones are valuable intermediates for the

synthesis of heterocycles [41]. Precedence for their

preparation from DMF and alkynes is scarce, and we are

aware of only two examples remotely resembling the

transformation observed by us. One example is the Rh-

catalyzed reaction of DMF, sulfonylazides, and terminal

alkynes to α-amino enaminoketones [42,43]. In another

synthesis, ortho-hydroxy acetophenones undergo an acid

catalyzed, microwave-promoted condensation with the

dimethylacetal of DMF to furnish enaminoketones as

intermediates, which then undergo a cyclization to

chromene-4-ones [40]. A tentative mechanism to explain

the formation of enaminoketones 13 and their secondary

products 14 from alkynes 3 and DMF is outlined in

Scheme 4. We assume that the reaction with DMF occurs

after the Claisen rearrangement and that a hydrogen bond

between the phenol and the oxygen of DMF increases the

nucleophilicity at the terminal sp-carbon through an

ortho-quinonemethide structure. Nucleophilic attack at

the DMF carbon yields intermediate A, from which

aromaticity is restored via intramolecular nucleophilic

migration of the DMF-oxygen to the inner carbon of the

former C─C-triple bond.

derivative 12d was obtained only in a poor yield of 18%.

We could not observe any products resulting from a

reaction with DMF in this case. Without an electron-

donating substituent in para-position to the allyloxy group

(Table 4, entries

5 and 7), we observed either

decomposition of the starting material (in the case of 3c)

or the formation of a 5:1 mixture of enaminoketone 13e

and chromene-4-one 14e (in the case of 3e). These

observations suggest that an electron-donating group

para to the allyloxy substituent increases the

nucleophilicity of the phenol intermediate 11 and

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Microwave-Promoted Benzofuran Synthesis

Table 3

Synthesis of (o-allyloxyaryl)acetylenes 3b–d.

Entry

1^Ref.

1b [38]

1c [5]

1d [6]

1e [39]

R¹

R²

R³

3 (yield, %)

1

2

3

4

H

OMe

H

OMe

H

OMe

3b (39)

3c (16)

3d (35)

3e (39)

OMe

H

OMOM

OMe

H

Table 4

Microwave irradiation of (o-allyloxyaryl)acetylenes 3.

Entry

3

R¹

R²

R³

Solvent

t (min)

11 (yield, %)

12 (yield, %

13 (yield, %

14 (yield, %

1

2

3

4

5

6

7

3a

3b

3c

3d

3e

H

OMe

H

OMe

H

OMe

H

DMF

Toluene

DMF

15

60

30

11a (--)^a

11a (41)^a

11a (--)^a

11b (--)^a

--^b

12a (--)^a

12b (47)

--^b

13a (23)

13a (--)^a

13a (13)

13b (15)

--^b

14a (40)

14a (--)^a

14a (49)

14b (16)

--^b

H

OMe

OMOM

OMe

DMF

11d (--)^a

11e (--)^a

12d (18)

13d (--)^a

13e (52)

14d (--)^a

14e (10)

H

12e (--)^a

DMF, dimethylformamide.

--, Not detected.

^aNot detected

^bComplex mixture of products formed

Scheme 4. Tentative mechanism for the formation of products 13a and

14a.

tandem Claisen-rearrangement/5-endo-dig cyclization

sequence of ortho-allyloxy alkinyl arenes. For

monosubstituted alkynes, an unexpected and to the best

of our knowledge unprecedented reaction with the

solvent DMF was observed, which leads to

enaminoketones and in a subsequent step to chromene-4-

ones.

EXPERIMENTAL SECTION

General methods. All experiments were conducted in

CONCLUSIONS

dry reaction vessels under an atmosphere of dry nitrogen.

Solvents were puriﬁed by standard procedures. H NMR

1

In summary, we have devised a route to 7-allyl-

spectra were obtained at 300 or 600 MHz in CDCl₃with

substituted benzofurans via

a

microwave-promoted

CHCl₃(δ = 7.26 ppm) as an internal standard. Coupling

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

C. Schultze, and B. Schmidt

Vol 000

constants are given in Hz. ¹³C NMR spectra were recorded

at 75 or 150 MHz in CDCl₃with CDCl₃(δ = 77.1 ppm) as

an internal standard. Whenever the solubility or stability of

the sample or signal separation was insufﬁcient in CDCl₃,

it was replaced by acetone-d₆(acetone-d₅as internal

standard for ¹H NMR spectroscopy, δ = 2.05 ppm,

CD₃COCD₃as internal standard for ¹³C NMR

spectroscopy, δ = 29.8 ppm). IR spectra were recorded as

154.3, 153.5, 133.4, 118.7, 117.6, 116.3, 114.5, 112.8,

81.3, 80.1, 70.5, 55.9; IR (ATR) ν 3284 (m), 2938 (w),

2106 (w), 1579 (w), 1494 (s), 1463 (w), 1463 (m), 1277

(m), 1219 (s), 1159 (m); HRMS (ESI) calcd for

C₁₂H₁₃O₂[M + H]⁺189.0916, found 189.0927.

1-(Allyloxy)-2-ethynyl-3,5-dimethoxybenzene

(3c).

Following the general procedure, 1c (222 mg,

1.00 mmol) was converted to 3c (35 mg, 0.16 mmol,

1

ATR-FTIR spectra. Wavenumbers (ν) are given in cm^À1

.

16%): yellowish oil; H NMR (300 MHz, CDCl₃) δ 6.05

(s, 1H), 6.05 (s, 1H), 6.02 (ddt, J = 17.3, 10.5, 5.0 Hz,

1H), 5.43 (dq, J = 17.3, 1.7 Hz, 1H), 5.25 (dq, J = 10.6,

1.7 Hz, 1H), 4.57 (dt, J = 5.0, 1.7 Hz, 2H), 3.83 (s, 3H),

3.76 (s, 3H), 3.29 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ

163.0, 162.1, 161.7, 132.9, 117.5, 93.8, 92.0, 90.7, 83.9,

76.5, 69.5, 56.0, 55.4; IR (ATR) ν 3274 (m), 2940 (w),

2101 (m), 1601 (s), 1575 (s), 1456 (m), 1418 (m), 1337

(w), 1225 (m); HRMS (ESI) calcd for C₁₃H₁₅O₃

[M + H]⁺219.1021, found 219.1000.

The peak intensities are deﬁned as strong (s), medium

(m), or weak (w). Low-resolution and high-resolution

mass spectra were obtained by EI-TOF or ESI-TOF.

Microwave reactions were carried out in Anton-Paar-

monowave 300 or 400 reactors (monowave, maximum

power 850 W, temperature control by IR-sensor, 20-mL

vial volume).

General procedure for the synthesis of arylacetylenes 3 and

8. To a solution of the appropriate benzaldehydes 1 or 7

1-(Allyloxy)-2-ethynyl-4-methoxy-5-(methoxymethoxy)

(1.00 mmol) in methanol (10 mL) was added K₂CO₃

(276 mg, 2.00 mmol). Dimethyl (1-diazo-2-oxopropyl)

phosphonate (2, 307 mg, 1.60 mmol) was added and the

solution was stirred at ambient temperature until the

starting material was fully consumed (TLC). All volatiles

were evaporated and the residue partitioned between

brine (10 mL) and ethyl acetate (30 mL). The organic

layer was separated and the aqueous layer extracted with

ethyl acetate (twice, 30 mL each). The combined organic

extracts were dried with MgSO₄, ﬁltered, and evaporated.

The residue was puriﬁed by column chromatography,

using hexanes/MTBE mixtures of increasing polarity as

eluent.

benzene (3d).

Following the general procedure, 1d

(252 mg, 1.00 mmol) was converted to 3d (87 mg,

0.35 mmol, 35%): yellowish oil; ¹H NMR (300 MHz,

CDCl₃) δ 6.91 (s, 1H), 6.76 (s, 1H), 5.99 (ddt, J = 17.2,

10.4, 5.2 Hz, 1H), 5.39 (dm, J = 17.2 Hz, 1H), 5.22 (dm,

J = 10.4 Hz, 1H), 5.16 (s, 2H), 4.53 (dm, J = 5.2 Hz,

2H), 3.77 (s, 3H), 3.45 (s, 3H), 3.21 (s, 1H); ¹³C NMR

(75 MHz, CDCl₃) δ 154.8, 148.1, 143.7, 133.2, 117.6,

116.8, 104.8, 103.5, 95.5, 80.3, 80.1, 70.4, 56.4, 56.2; IR

(ATR) ν 3260 (s), 2937 (w), 2105 (w), 1604 (w), 1504

(s), 1463 (m), 1417 (m), 1390 (m), 1268 (s), 1212 (s);

HRMS (ESI) calcd for C₁₄H₁₆O₄[M + H]⁺249.1127,

found 249.1120.

1-(Allyloxy)-2-ethynylbenzene (3a) [44].

Following the

2-(Allyloxy)-1-ethynyl-4-methoxybenzene (3e) [45].

Following the general procedure, 1e (192 mg,

1.00 mmol) was converted to 3e (73 mg, 0.39 mmol,

general procedure, 1a (162 mg, 1.00 mmol) was

converted to 3a (103 mg, 0.65 mmol, 65%): yellowish

oil; H NMR (300 MHz, CDCl₃) δ 7.49 (dm, J = 7.6 Hz,

1

39%): yellowish oil; H NMR (300 MHz, CDCl₃) δ 7.38

1H), 7.35–7.27 (m, 1H), 6.94 (dm, J = 7.5 Hz, 1H),

6.92–6.87 (m, 1H), 6.09 (ddt, J = 17.3, 10.5, 5.0 Hz,

1H), 5.50 (dq, J = 17.3, 1.7 Hz, 1H), 5.32 (dq, J = 10.5,

1.7 Hz, 1H), 4.66 (dt, J = 5.0, 1.7 Hz, 2H), 3.32 (s, 1H);

¹³C NMR (75 MHz, CDCl₃) δ 159.8, 134.3, 133.0,

130.2, 120.7, 117.7, 112.5, 111.9, 81.3, 80.2, 69.4; IR

(ATR) ν 3283 (m), 2868 (w), 2106 (w), 1595 (m), 1575

(m), 1487 (s), 1444 (s), 1287 (m), 1249 (s), 1229 (s);

HRMS: no [M⁺] signal observed with different ionization

methods.

(dm, J = 7.8 Hz, 1H), 6.47–6.41 (2H), 6.05 (ddt,

J = 17.3, 10.6, 5.0 Hz, 1H), 5.47 (dq, J = 17.3, 1.7 Hz,

1H), 5.29 (dq, J = 10.6, 1.7 Hz, 1H), 4.61 (dt,

J = 5.0 Hz, 2H), 3.79 (s, 3H), 3.21 (s, 1H); ¹³C NMR

(75 MHz, CDCl₃) δ 161.4, 161.0, 135.0, 132.9, 117.7,

105.4, 104.5, 100.1, 80.3, 79.9, 69.5, 55.5; IR (ATR) ν

3281 (m), 2937 (w), 2103 (w), 1604 (s), 1571 (m), 1500

(s), 1462 (m), 1443 (m), 1420 (m), 1301 (s); HRMS

(ESI) calcd for C₁₂H₁₃O₂[M + H]⁺189.0916, found

189.0929.

1-(Allyloxy)-2-ethynyl-4-methoxybenzene (3b) [45].

Following the general procedure, 1b (192 mg,

1.00 mmol) was converted to 3b (73 mg, 0.39 mmol,

1-Ethynyl-4-methoxybenzene (8b) [46].

Following the

general procedure, 7b (136 mg, 1.00 mmol) was

converted to 8b (70 mg, 0.53 mmol, 53%): yellowish oil;

¹H NMR (300 MHz, CDCl₃) δ 7.44 (d, J = 8.9 Hz, 2H),

6.85 (d, J = 8.9 Hz, 1H), 3.80 (s, 3H), 3.01 (s, 1H); ¹³C

NMR (75 MHz, CDCl₃) δ 160.1, 133.7, 114.3, 114.1,

83.8, 75.9, 55.4; IR (ATR) ν 3286 (m), 2838 (w), 2106

(w), 1605 (s), 1571 (w), 1505 (s), 1464 (m), 1441 (m),

1

39%): yellowish oil; H NMR (300 MHz, CDCl₃) δ 7.00

(dd, J = 2.7, 0.6 Hz, 1H), 6.85 (dd, J = 9.0, 2.7 Hz, 1H),

6.80 (dd, J = 9.0, 0.6 Hz, 1H), 6.05 (ddt, J = 17.3, 10.3,

5.1 Hz, 1H), 5.44 (dq, J = 17.3, 1.7 Hz, 1H), 5.27 (dq,

J = 10.3, 1.7 Hz, 1H), 4.58 (dt, J = 5.1 1.6 Hz, 2H), 3.75

(s, 3H), 3.29 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ

Journal of Heterocyclic Chemistry

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Month 2019

Microwave-Promoted Benzofuran Synthesis

1289 (s), 1245 (s); HRMS (EI) calcd for C₉H₈O [M⁺]

132.0575, found 132.0573.

separated, dried with MgSO₄, ﬁltered, and evaporated.

The residue was puriﬁed by column chromatography on

silica, using hexanes/MTBE mixtures of increasing

1-Ethynyl-3,5-dimethoxybenzene (8c) [46].

Following

the general procedure, 7c (166 mg, 1.00 mmol) was

converted to 8c (92 mg, 0.57 mmol, 57%): yellowish oil;

¹H NMR (300 MHz, CDCl₃) δ 6.65 (d, J = 2.3 Hz, 2H),

6.47 (t, J = 2.3 Hz, 1H), 3.78 (s, 6H), 3.04 (s, 1H); ¹³C

NMR (75 MHz, CDCl₃) δ 160.7, 123.5, 110.1, 102.4,

83.8, 76.8, 55.5; IR (ATR) ν 3286 (m), 2838 (w), 2117

(w), 1587 (s), 1453 (m), 1419 (s), 1344 (m), 1321 (m),

1295 (m), 1204 (s), 1153(s); HRMS (EI) calcd for

C₁₀H₁₀O₂[M⁺] 162.0681, found 162.0678.

polarity as eluent.

2-((4-Methoxyphenyl)ethynyl)phenol (10b) [16,48].

Following the general procedure, 8b (132 mg,

1.00 mmol) was converted to 10b (215 mg, 0.96 mmol,

96%): yellowish oil; H NMR (300 MHz, CDCl₃) δ 7.52

1

(dm, J = 8.9 Hz, 2H), 7.44 (dd, J = 7.6, 1.7 Hz, 1H),

7.29 (ddd, J = 8.2, 7.5, 1.7 Hz, 1H), 7.01 (dd, J = 8.2,

1.0 Hz, 1H), 6.96–6.93 (m, 1H), 6.92 (dm, J = 8.9 Hz,

2H), 5.90 (s, 1H), 3.87 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 160.1, 156.5, 133.3, 131.6, 130.3, 120.5,

114.7, 114.5, 114.3, 110.0, 96.6, 81.8, 55.5; IR (ATR) ν

3504 (br), 2934 (w), 2836 (w), 2206 (w), 1602 (m), 1505

(s), 1483 (m), 1452 (m), 1287 (m), 1245 (s), 1174 (s);

HRMS (EI) calcd for C₁₅H₁₂O₂[M⁺] 224.0832, found

224.0842.

5-Ethynyl-1,2,3-trimethoxybenzene (8d) [47]. Following

the general procedure, 7d (196 mg, 1.00 mmol) was

converted to 8d (111 mg, 0.58 mmol, 58%): yellowish

1

oil; H NMR (300 MHz, CDCl₃) δ 6.72 (s, 2H), 3.84 (s,

3H), 3.85 (s, 6H), 3.02 (s, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 153.2, 139.5, 117.2, 109.6, 83.8, 76.3, 61.1,

56.3; IR (ATR) ν 3282 (m), 2939 (w), 2104 (w), 1575

(s), 1501 (s), 1449 (m), 1409 (s), 1331 (s), 1233 (s), 1183

(m), 1122(s); HRMS (EI) calcd for C₁₁H₁₂O₃[M⁺]

192.0786, found 192.0787.

2-((3,5-Dimethoxyphenyl)ethynyl)phenol (10c) [48].

Following the general procedure, 8c (162 mg,

1.00 mmol) was converted to 10c (206 mg, 0.81 mmol,

1

81%): yellowish oil; H NMR (300 MHz, acetone-d₆) δ

1-(Allyloxy)-2-(phenylethynyl)benzene (4a) [26]. Alkyne

3a (158 mg, 1.00 mmol), iodobenzene (204 mg,

1.00 mmol), and pyrrolidine (410 μL, 5.00 mmol) were

suspended in water (5 mL). PdCl₂(2 mg, 1 mol%) was

added and the mixture was heated to 50°C for 16 h and

then cooled to ambient temperature and diluted with ethyl

acetate (30 mL). The mixture was washed with brine, the

organic layer was separated, dried with MgSO₄, ﬁltered,

and evaporated. The residue was puriﬁed by column

chromatography on silica using hexanes/MTBE mixtures

of increasing polarity as eluent to furnish 4a (112 mg,

0.48 mmol, 48%): colorless oil; ¹H NMR (300 MHz,

CDCl₃) δ 7.59–7.54 (2H), 7.52 (dm, J = 7.6 Hz, 1H),

7.38–7.28 (m, 4H), 6.96 (tm, J = 7.5 Hz, 1H), 6.91 (d,

J = 8.3 Hz, 1H), 6.12 (ddt, J = 17.2, 10.6, 4.8 Hz, 1H),

5.56 (dq, J = 17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.6,

1.6 Hz, 1H), 4.66 (dt, J = 4.8, 1.6 Hz, 2H); ¹³C NMR

(75 MHz, CDCl₃) δ 159.5, 133.6, 133.4, 131.8, 129.7,

128.9, 128.4, 128.2, 124.1, 121.1, 117.2, 113.3, 93.8,

86.1, 69.8; IR (ATR) ν 3061 (w), 2918 (w), 1592 (w),

1572 (w), 1496 (m), 1482 (m), 1443 (m), 1276 (m), 1239

(m), 1225 (m); HRMS (EI) calcd for C₁₇H₁₄O [M⁺]

234.1045, found 234.1048.

8.51 (s, 1H), 7.42 (dd, J = 7.7, 1.7 Hz, 1H), 7.25 (ddd,

J = 8.6, 7.3, 1.7 Hz, 1H), 6.95 (dd, J = 8.5, 1.0 Hz, 1H),

6.88 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 6.71 (d, J = 2.3 Hz,

2H), 6.51 (t, J = 2.3 Hz, 1H), 3.81 (s, 6H); ¹³C NMR

(75 MHz, acetone-d₆) δ 161.8, 158.9, 133.7, 131.0,

125.8, 120.6, 116.5, 111.1, 110.0, 102.2, 94.5, 85.8,

55.8; IR (ATR) n 3436 (br), 2937 (w), 2838 (w), 2206

(w), 1585 (s), 1488 (m), 1451 (m), 1418 (m), 1356 (m),

1203 (s), 1150 (s); HRMS (EI) calcd for C₁₆H₁₄O₃[M⁺]

254.0943, found 254.0950.

2-((3,4,5-Dimethoxyphenyl)ethynyl)phenol (10d) [48].

Following the general procedure, 8d (192 mg,

1.00 mmol) was converted to 10d (264 mg, 0.93 mmol,

1

93%): yellowish oil; H NMR (300 MHz, acetone-d₆) δ

8.41 (s, 1H), 7.41 (dd, J = 7.7, 1.7 Hz, 1H), 7.24 (ddd,

J = 8.3, 7.4, 1.7 Hz, 1H), 6.95 (dd, J = 8.3, 1.0 Hz, 1H),

6.88 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 6.85 (s, 2H), 3.85 (s,

6H), 3.75 (s, 3H); ¹³C NMR (75 MHz, acetone-d₆) δ

158.8, 154.3, 140.2, 133.6, 130.9, 120.6, 119.3, 116.5,

111.3, 109.9, 94.8, 85.0, 60.7, 56.6; IR (ATR) ν 3407

(br), 2938 (w), 2837 (w), 1574 (s), 1504 (m), 1448 (m),

1409 (m), 1356 (m), 1233 (s), 1122 (s); HRMS (EI)

calcd for C₁₇H₁₆O₄[M⁺] 284.1043, found 284.1053.

General procedure for the synthesis of allyl ethers 4b–d.

To a solution of the corresponding phenol 10 (1.00 mmol)

in acetone (5 mL) were added allyl bromide (128 μL,

1.50 mmol) and K₂CO₃(280 mg, 2.00 mmol). The

mixture was heated to 50°C for 16 h and then cooled to

ambient temperature and partitioned between brine

(20 mL) and ethyl acetate (30 mL). The organic layer

was separated, and the aqueous layer was extracted with

ethyl acetate (twice, 30 mL each). The combined organic

General procedure for the synthesis of diarylacetylenes

10.

The corresponding alkyne 8 (1.00 mmol), 2-

iodophenol (219 mg, 1.00 mmol), and NEt₃(277 μL,

2.00 mmol) were dissolved in dry and degassed benzene

(5 mL). CuI (6 mg, 3 mol %) and Pd (PPh₃)₂Cl₂(21 mg,

3 mol %) were added and the mixture was heated to

50°C for 1 h. After cooling to ambient temperature, the

mixture was diluted with ethyl acetate (30 mL) and

washed with brine (10 mL). The organic layer was

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

C. Schultze, and B. Schmidt

Vol 000

extracts were dried with MgSO₄, ﬁltered, and evaporated.

The residue was puriﬁed by column chromatography on

silica, using hexanes/MTBE mixtures of increasing

polarity as eluent.

1-(Allyloxy)-2-((4-methoxyphenyl)ethynyl)benzene (4b).

À78°C for 2 h. The reaction was quenched by addition of

an aqueous saturated solution of NH₄Cl (5 mL) and then

warmed to ambient temperature. Ethyl acetate (30 mL)

was added, the organic layer was separated, and the

aqueous layer was extracted with ethyl acetate (twice,

30 mL each). The combined organic extracts were dried

with MgSO₄, ﬁltered, and evaporated. The crude product

was puriﬁed by column chromatography on silica, using

hexanes/MTBE mixtures of increasing polarity as eluent,

Following the general procedure, 10b (224 mg,

1.00 mmol) was converted to 4b (172 mg, 0.65 mmol,

65%): yellowish oil; ¹H NMR (300 MHz, CDCl₃) δ

7.52–7.47 (m, 3H), 7.26 (ddd, J = 8.7, 7.6, 1.8 Hz, 1H),

6.95 (dd, J = 7.5, 0.9 Hz, 1H), 6.92–6.86 (3H), 6.11 (ddt,

J = 17.2, 10.5, 4.8 Hz, 1H), 5.55 (dm, J = 17.2 Hz, 1H),

5.31 (dm, J = 10.5 Hz, 1H), 4.65 (dt, J = 4.8, 1.7 Hz,

2H), 3.83 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 159.7,

159.1, 133.4, 133.3, 133.2, 129.4, 120.9, 117.2, 116.0,

114.1, 113.7, 112.8, 93.7, 84.6, 69.5, 55.4; IR (ATR) ν

2933 (w), 2836 (w), 2214 (w), 1605 (m), 1571 (w), 1509

(s), 1443 (m), 1285 (s), 1243 (s), 1173 (m), 1104 (m);

HRMS (EI) calcd for C₁₈H₁₆O₂[M⁺] 264.1150, found

1

to furnish 4e (95 mg, 0.44 mmol, 44%): yellowish oil; H

NMR (300 MHz, CDCl₃) δ 7.51 (dd, J = 7.6, 1.7 Hz,

1H), 7.36 (ddd, J = 8.5, 7.5, 1.7 Hz, 1H), 6.92 (ddd,

J = 7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.04

(ddt, J = 17.3, 10.6, 4.8 Hz, 1H), 5.49 (dq, J = 17.3,

1.6 Hz, 1H), 5.30 (dq, J = 10.6, 1.6 Hz, 1H), 4.62 (dt,

J = 4.8, 1.6 Hz, 2H), 3.82 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 160.8, 154.7, 134.9, 132.6, 132.3, 120.8,

117.6, 112.5, 109.4, 84.5, 83.7, 69.3, 52.7; IR (ATR) ν

2953 (m), 2219 (s), 1704 (s), 1595 (m), 1574 (m), 1489

(s), 1446 (s), 1279 (s), 1162 (s); HRMS (ESI) calcd for

C₁₃H₁₂O₃Na [M + Na]⁺239.0684, found 239.0679.

264.1144.

1-((2-Allyloxy)phenyl)ethynyl)-3,5-dimethoxybenzene

(4c).

Following the general procedure, 10c (254 mg,

1.00 mmol) was converted to 4c (229 mg, 0.78 mmol,

1

General procedure for microwave-promoted reactions of

78%): yellowish oil; H NMR (300 MHz, CDCl₃) δ 7.51

alkynes 4.

The appropriate precursor 4 (1.00 mmol)

(dd, J = 7.6, 1.7 Hz, 1H), 7.28 (ddd, J = 8.4, 7.6, 1.7 Hz,

1H), 6.95 (td, J = 7.5, 1.0 Hz, 1H), 6.90 (d, J = 8.3 Hz,

1H), 6.72 (d, J = 2.3 Hz, 2H), 6.46 (t, J = 2.3 Hz, 1H),

6.11 (ddt, J = 17.2, 10.6, 4.8 Hz, 1H), 5.56 (dq, J = 17.2,

1.7 Hz, 1H), 5.31 (dq, J = 10.6, 1.7 Hz, 1H), 4.65 (dt,

J = 4.8, 1.7 Hz, 2H), 3.81 (s, 6H); ¹³C NMR (75 MHz,

CDCl₃) δ 160.7, 159.3, 133.6, 133.2, 129.8, 125.1,

120.9, 117.2, 113.2, 112.7, 109.5, 101.8, 93.7, 85.6,

69.4, 55.5; IR (ATR) ν 2936 (w), 2838 (w), 2214 (w),

1585 (s), 1493 (m), 1447 (m), 1419 (m), 1357 (m), 1259

(m), 1203 (s), 1152 (s); HRMS (EI) calcd for C₁₉H₁₈O₃

was dissolved in toluene (7 mL) or DMF (7 mL)

(Tables 1 and 4 or Scheme 2) in a vessel suited for

microwave irradiation. The vessel was sealed, placed in a

dedicated microwave reactor, and heated at 250°C for the

time period indicated in the respective tables and

schemes. After cooling to ambient temperature, the

solvent was evaporated and the residue puriﬁed by

column chromatography on silica with hexanes/MTBE

mixtures as eluent.

2-Allyl-6-(phenylethynyl)phenol (6a).

Table 1, entry 1

(solvent toluene; reaction time 60 min): following the

general procedure, 4a (234 mg, 1.00 mmol) was

converted to 6a (105 mg, 0.45 mmol, 45%): yellowish

[M⁺] 294.1256, found 294.1249.

5-((2-Allyloxy)phenyl)ethynyl)-1,2,3-trimethoxybenzene

(4d).

Following the general procedure, 10d (284 mg,

1

oil; H NMR (300 MHz, CDCl₃) δ 7.58–7.52 (2H), 7.41–

1.00 mmol) was converted to 4d (201 mg, 0.62 mmol,

1

7.36 (3H), 7.33 (dd, J = 7.7, 1.7 Hz, 1H), 7.16 (dm,

J = 7.6 Hz, 1H), 6.88 (dd, J = 7.6, 7.6 Hz, 1H), 6.04

(ddt, J = 17.3, 11.0, 6.6 Hz, 1H), 5.96 (s, 1H), 5.12 (dm,

J = 17.3 Hz, 1H), 5.11 (dm, J = 11.0 Hz, 1H), 3.46 (dm,

J = 6.5 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 154.7,

136.5, 131.8, 131.2, 129.9, 128.9, 128.7, 126.3, 122.8,

120.4, 115.9, 109.7, 96.4, 83.7, 34.4; IR (ATR) ν 3508

(m), 3059 (w), 2918 (w), 1638 (w), 1585 (w), 1491 (m),

1451 (s), 1334 (m), 1229 (s), 1069 (m); HRMS (EI)

calcd for C₁₇H₁₄O [M⁺] 234.1045, found 234.1040.

62%): yellowish oil; H NMR (300 MHz, CDCl₃) δ 7.49

(dd, J = 7.6, 1.7 Hz, 1H), 7.27 (ddd, J = 8.4, 7.5, 1.7 Hz,

1H), 6.95 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 6.90 (d,

J = 8.4 Hz, 1H), 6.79 (s, 2H), 6.11 (ddt, J = 17.2, 10.6,

4.8 Hz, 1H), 5.56 (dq, J = 17.2, 1.7 Hz, 1H), 5.30 (dq,

J = 10.6, 1.7 Hz, 1H), 4.65 (dt, J = 4.8, 1.7 Hz, 2H),

3.87 (s, 6H), 3.87 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ

159.2, 153.2, 133.4, 133.3, 129.7, 120.9, 118.8, 118.3,

117.1, 113.2, 112.7, 109.0, 93.7, 85.0, 69.4, 61.1, 56.3;

IR (ATR) ν 2938 (w), 2841 (w), 2252 (w), 1573 (s),

1504 (s), 1446 (m), 1409 (m), 1355 (m), 1261 (m), 1233

(s), 1126 (s); HRMS (EI) calcd for C₂₀H₂₀O₄[M⁺]

324.1356, found 324.1351.

7-Allyl-2-phenylbenzofuran (5a).

Table 1, entry 2

(solvent DMF; reaction time 15 min): following the

general procedure, 4a (234 mg, 1.00 mmol) was

converted to 5a (215 mg, 0.92 mmol, 92%): yellowish

Methyl-3-(2-allyloxy)phenyl)propiolate (4e) [37].

A

1

solution of 3a (158 mg, 1.00 mmol) was cooled to

À78°C. Butyllithium (2.5 M sol. in hexane, 0.60 mL,

1.50 mmol) was added and the mixture was stirred at

oil; H NMR (600 MHz, CDCl₃) δ 7.92–7.88 (m, 2H),

7.49–7.46 (3H), 7.38 (tt, J = 7.4, 1.3 Hz, 1H), 7.21 (dd,

J = 7.5, 7.5 Hz, 1H), 7.14 (dm, J = 7.3 Hz, 1H), 7.04 (s,

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2019

Microwave-Promoted Benzofuran Synthesis

1H), 6.17 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 5.26 (dm,

J = 17.0 Hz, 1H), 5.17 (dm, J = 10.0 Hz, 1H), 3.78 (d,

J = 6.8 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 155.7,

153.4, 136.1, 130.7, 129.1, 128.9, 128.6, 125.0, 124.4,

123.8, 123.3, 119.1, 116.3, 101.7, 34.2; IR (ATR) ν 3061

(w), 1638 (w), 1638 (w), 1608 (w), 1565 (w), 1480 (m),

1424 (m), 1289 (m), 1203 (s), 1172 (m); HRMS (EI)

calcd for C₁₇H₁₄O [M⁺] 234.1045, found 234.1053.

(m), 1251 (m), 1123 (s); HRMS (ESI) calcd for

C₂₀H₂₁O₄[M + H]⁺325.1440, found 325.1444.

Methyl-7-allylbenzofuran-2-carboxylate (5e).

Scheme 2

(solvent DMF; reaction time 30 min): following the

general procedure, 4e (216 mg, 1.00 mmol) was

converted to 5e (117 mg, 0.54 mmol, 54%): yellowish

1

oil; H NMR (300 MHz, acetone-d₆) δ 7.64 (dd, J = 7.1,

2.0 Hz, 1H), 7.64 (s, 1H), 7.33 (dm, J = 7.6 Hz, 1H),

7.29 (dd, J = 7.5, 7.5 Hz, 1H), 6.10 (ddt, J = 17.0, 10.0,

6.6 Hz, 1H), 5.15 (dq, J = 17.0, 1.7 Hz, 1H), 5.10 (dq,

J = 10.0, 1.7 Hz, 1H), 3.93 (s, 3H), 3.70 (dm,

J = 6.6 Hz, 2H); ¹³C NMR (75 MHz, acetone-d₆) δ

160.2, 155.1, 146.4, 136.5, 128.3, 127.8, 125.5, 125.0,

121.9, 116.8, 114.9, 52.5, 34.1; IR (ATR) ν 2952 (w),

1720 (s), 1639 (w), 1566 (m), 1435 (m), 1335 (w), 1293

(s), 1176 (s); HRMS (ESI) calcd for C₁₃H₁₃O₃[M + H]⁺

217.0865, found 217.0879.

2-Allyl-6-ethynylphenol (11a). Table 4, entry 2 (solvent

toluene; reaction time 60 min): following the general

procedure, 3a (158 mg, 1.00 mmol) was converted to 11a

(65 mg, 0.41 mmol, 41%): yellowish oil; ¹H NMR

(300 MHz, CDCl₃) δ 7.27 (dd, J = 7.7, 1.7 Hz, 1H), 7.15

(dm, J = 7.5 Hz, 1H), 6.83 (dd, J = 7.6, 7.6 Hz, 1H),

6.01 (ddt, J = 17.5, 9.6, 6.5 Hz, 1H), 5.90 (s, 1H), 5.14–

5.05 (m, 2H), 3.46 (s, 1H), 3.42 (dm, J = 6.5 Hz, 2H);

¹³C NMR (75 MHz, CDCl₃) δ 155.5, 136.4, 131.6,

130.2, 126.4, 120.3, 116.0, 108.4, 84.1, 79.0, 34.3; IR

(ATR) ν 3507 (w), 3284 (w), 2919 (w), 1637 (m), 1451

(s), 1328 (m), 1245 (m), 1213 (m), 1071 (m), 994 (m);

HRMS: no [M⁺] signal observed with different ionization

methods.

7-Allyl-2-(4-methoxyphenyl)benzofuran (5b).

Table 1,

entry 5 (solvent DMF; reaction time 30 min): following

the general procedure, 4b (264 mg, 1.00 mmol) was

converted to 5b (177 mg, 0.67 mmol, 67%): yellowish

1

oil; H NMR (300 MHz, CDCl₃) δ 7.81 (dm, J = 8.9 Hz,

2H), 7.43 (dd, J = 7.6, 1.1 Hz, 1H), 7.17 (dd, J = 7.5,

7.5 Hz, 1H), 7.09 (dm, J = 7.5 Hz, 1H), 6.99 (d,

J = 8.9 Hz, 2H), 6.89 (s, 1H), 6.16 (ddt, J = 16.8, 10.0,

6.7 Hz, 1H), 5.24 (dm, J = 17.0 Hz, 1H), 5.15 (dm,

J = 10.0 Hz, 1H), 3.87 (s, 3H), 3.76 (dm, J = 6.7 Hz,

2H); ¹³C NMR (75 MHz, CDCl₃) δ 160.1, 155.9, 153.3,

136.2, 129.4, 126.5, 123.9, 123.7, 123.6, 123.2, 118.8,

116.2, 114.4, 100.1, 55.5, 34.2; IR (ATR) ν 2933 (w),

2836 (w), 1614 (m), 1506 (s), 1482 (w), 1454 (w), 1429

(w), 1249 (s), 1173 (m); HRMS (ESI) calcd for

C₁₈H₁₇O₂[M + H]⁺265.1229, found 265.1245.

7-Allyl-2-(3,5-dimethoxyphenyl)benzofuran (5c). Table 1,

entry 7 (solvent DMF; reaction time 30 min): following the

general procedure, 4c (294 mg, 1.00 mmol) was converted

1

to 5c (185 mg, 0.63 mmol, 63%): yellowish oil; H NMR

(300 MHz, acetone-d₆) δ 7.50 (dd, J = 7.4, 1.5 Hz, 1H),

7.31 (s, 1H), 7.20 (dd, J = 7.4, 7.4 Hz, 1H), 7.17–7.12

(m, 3H), 6.55 (t, J = 2.3 Hz, 1H), 6.15 (ddt, J = 16.8,

10.0, 6.7 Hz, 1H), 5.25 (dq, J = 17.0, 1.8 Hz, 1H), 5.12

(dm, J = 10.0 Hz, 1H), 3.89 (s, 6H), 3.75 (dm,

J = 6.7 Hz, 2H); ¹³C NMR (75 MHz, acetone-d₆) δ

162.3, 156.3, 154.1, 137.1, 133.1, 129.9, 125.4, 124.4,

124.2, 120.0, 116.5, 103.8, 103.2, 101.5, 55.8, 34.6; IR

(ATR) n 2936 (w), 2836 (w), 1595 (s), 1571 (s), 1455

(m), 1420 (m), 1357 (w), 1203 (s), 1152 (s); HRMS

(ESI) calcd for C₁₉H₁₉O₃[M + H]⁺295.1334, found

295.1315.

(E)-1-(3-allyl-2-hydroxyphenyl)-3-(dimethylamino)prop-2-

ene-1-one (13a) and 8-allyl-4H-chromene-4-one (14a).

Table 4, entry 3 (solvent DMF; reaction time 30 min):

following the general procedure, 3a (158 mg, 1.00 mmol)

was converted to 13a (30 mg, 0.13 mmol, 13%) and 14a

(91 mg, 0.49 mmol, 49%). Analytical data for 13a:

1

yellowish oil; H NMR (600 MHz, acetone-d₆) δ 14.81

(s, 1H), 7.89 (d, J = 12.0 Hz, 1H), 7.74 (dm, J = 8.0,

1.8 Hz, 1H), 7.22 (dm, J = 7.3 Hz, 1H), 6.74 (dd,

J = 8.0, 7.5 Hz, 1H), 6.01 (ddt, J = 17.0, 10.0, 6.8 Hz,

1H), 5.98 (d, J = 12.1 Hz, 1H), 5.07 (dm, J = 17.1 Hz,

1H), 4.99 (dm, J = 10.0 Hz, 1H), 3.37 (d, J = 6.8 Hz,

2H), 3.27 (s, 3H), 3.04 (s, 3H); ¹³C NMR (150 MHz,

acetone-d₆) δ 192.1, 162.0, 156.0, 137.8, 134.3, 129.3,

127.4, 120.6, 118.1, 115.6, 90.3, 45.4, 37.6, 34.3; IR

(ATR) ν 2912 (w), 2811 (w), 1624 (s), 1592 (m), 1541

(s), 1471 (s), 1419 (s), 1343 (s), 1274 (s); HRMS (ESI)

calcd for C₁₄H₁₈NO₂[M + H]⁺232.1338, found

7-Allyl-2-(3,4,5-trimethoxyphenyl)benzofuran

(5d).

Table 1, entry 9 (solvent DMF; reaction time 30 min):

following the general procedure, 4d (324 mg, 1.00 mmol)

was converted to 5d (175 mg, 0.54 mmol, 54%):

1

yellowish oil; H NMR (300 MHz, acetone-d₆) δ 7.47

(dd, J = 7.5, 1.3 Hz, 1H), 7.26 (s, 2H), 7.25 (s, 1H), 7.18

(dd, J = 7.5, 7.5 Hz, 1H), 7.12 (dm, J = 7.5 Hz, 1H),

6.12 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 5.25 (dq, J = 17.0,

1.9 Hz, 1H), 5.12 (dm, J = 10.0 Hz, 1H), 3.94 (s, 6H),

3.79 (s, 3H), 3.74 (dm, J = 6.8 Hz, 2H); ¹³C NMR

(75 MHz, acetone-d₆) δ 156.4, 154.8, 154.0, 140.1,

137.1, 130.2, 126.8, 125.1, 124.3, 124.1, 119.8, 116.5,

103.4, 102.3, 60.7, 56.6, 34.7; IR (ATR) ν 2936 (w),

2836 (w), 1589 (m), 1568 (m), 1501 (m), 1414 (m), 1337

1

232.1345. Analytical data of 14a: [10] yellowish oil; H

NMR (600 MHz, acetone-d₆) δ 8.19 (d, J = 6.0 Hz, 1H),

7.98 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 (dm, J = 7.4 Hz,

1H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 6.29 (d, J = 6.0 Hz,

1H), 6.06 (ddt, J = 17.1, 10.1, 6.6 Hz, 1H), 5.12 (dq,

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

C. Schultze, and B. Schmidt

Vol 000

J = 17.1, 1.8 Hz, 1H), 5.09 (dm, J = 10.1 Hz, 1H), 3.64 (d,

J = 6.6 Hz, 2H); ¹³C NMR (150 MHz, acetone-d₆) δ 177.3,

156.7, 155.3, 136.6, 134.8, 130.8, 125.9, 125.7, 124.3,

116.9, 113.2, 34.1; IR (ATR) ν 3076 (w), 2913 (w), 1641

(s), 1597 (m), 1481 (m), 1437 (m), 1405 (m), 1346 (m),

1321 (m); HRMS (ESI) calcd for C₁₂H₁₁O₂[M + H]⁺

1H), 3.87 (s, 3H), 3.74 (dt, J = 6.2, 1.6 Hz, 2H), 3.62 (s,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 149.8, 148.6, 145.2,

142.3, 135.9, 122.6, 118.3, 115.6, 106.8, 101.1, 99.6,

57.7, 56.3, 29.1; IR (ATR) ν 2924 (m), 1638 (w), 1602

(m), 1456 (m), 1429 (m), 1295 (m), 1208 (m), 1155 (m);

HRMS (EI) calcd for C₁₄H₁₆O₄[M⁺] 248.1043, found

187.0759, found 187.0757.

248.1046.

7-Allyl-5-methoxybenzofuran (12b), (E)-1-(3-allyl-2-hydroxy-

(E)-1-(3-allyl)-2-hydroxy-4-methoxyphenyl)-3-

(dimethylamino)prop-2-ene-1-one (13e) and 8-allyl-7-methoxy-4

H-chromene-4-one (14e). Table 4, entry 7 (solvent DMF;

5-methoxyphenyl)-3-(dimethylamino)prop-2-ene-1-one

and 8-allyl-6-methoxy-4H-chromene-4-one (14b).

(13b),

Table 4,

entry 4 (solvent DMF; reaction time 30 min): following

the general procedure, 3b (188 mg, 1.00 mmol) was

converted to 12b (88 mg, 0.47 mmol, 47%), 13b (39 mg,

0.15 mmol, 15%), and 14b (35 mg, 0.16 mmol, 16%).

Analytical data for 12b: yellowish oil; ¹H NMR

(300 MHz, CDCl₃) δ 7.60 (d, J = 2.1 Hz, 1H), 6.93 (d,

J = 2.5 Hz, 1H), 6.78–6.75 (m, 1H), 6.71 (d, J = 2.2 Hz,

1H), 6.08 (ddt, J = 17.1, 10.0, 6.6 Hz, 1H), 5.17 (dq,

J = 17.1, 1.7 Hz, 1H), 5.12 (dm, J = 10.0 Hz, 1H), 3.84

(s, 3H), 3.65 (d, J = 6.6 Hz, 2H); ¹³C NMR (75 MHz,

CDCl₃) δ 156.3, 148.8, 145.5, 135.8, 127.8, 124.7,

116.5, 113.4, 107.0, 101.5, 56.0, 34.1; IR (ATR) ν 2927

(m), 1606 (m), 1474 (s), 1426 (s), 1298 (w), 1196 (s),

1141 (s), 1034 (m); HRMS (EI) calcd for C₁₂H₁₂O₂[M⁺]

188.0832, found 188.0836. Analytical data for 13b:

reaction time 30 min): following the general procedure,

3e (188 mg, 1.00 mmol) was converted to 13e (136 mg,

0.52 mmol, 52%) and 14e (22 mg, 0.10 mmol, 10%).

Analytical data for 13e: yellowish oil; ¹H NMR

(300 MHz, acetone-d₆) δ 14.93 (s, 1H), 7.83 (d,

J = 12.1 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 6.48 (d,

J = 9.0 Hz, 1H), 5.91 (ddt, J = 17.1, 10.0, 6.4 Hz, 1H),

5.88 (d, J = 12.1 Hz, 1H), 4.97 (dm, J = 17.1 Hz, 1H),

4.86 (dm, J = 10.0 Hz, 1H), 3.85 (s, 3H), 3.36 (d,

J = 6.4, 1.6 Hz, 2H), 3.22 (s, 3H), 3.00 (s, 3H); ¹³C

NMR (75 MHz, acetone-d₆) δ 191.5, 163.4, 162.4, 155.2,

137.4, 128.9, 115.5, 115.2, 114.4, 101.9, 90.2, 56.0,

45.3, 37.5, 27.4; IR (ATR) ν 2912 (w), 1613 (s), 1540

(s), 1485 (m), 1417 (m), 1348 (s), 1285 (m), 1244 (s);

HRMS (EI) calcd for C₁₅H₁₉NO₃[M⁺] 261.1359, found

261.1365. Analytical data for 14e: yellowish oil; ¹H

NMR (300 MHz, acetone-d₆) δ 8.10 (d, J = 6.0 Hz, 1H),

8.00 (d, J = 8.9 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H), 6.19

(d, J = 6.0 Hz, 1H), 5.94 (ddt, J = 17.1, 10.0, 6.4 Hz,

1H), 4.99 (dq, J = 17.1, 1.7 Hz, 1H), 4.94 (dq, J = 10.0,

1.7 Hz, 1H), 3.99 (s, 3H), 3.57 (dt, J = 6.2, 1.7 Hz, 2H);

¹³C NMR (75 MHz, acetone-d₆) δ 177.0, 162.1, 156.6,

156.1, 136.2, 125.6, 119.8, 116.7, 115.5, 112.8, 110.1,

56.8, 27.6; IR (ATR) ν 3077 (w), 2976 (w), 1636 (s),

1618 (s), 1592 (s), 1427 (m), 1405 (m), 1352 (m), 1267

(s); HRMS (EI) calcd for C₁₃H₁₂O₃[M⁺] 216.0781,

found 216.0783.

1

yellowish oil; H NMR (300 MHz, CDCl₃) δ 13.75 (s,

1H), 7.86 (d, J = 12.1 Hz, 1H), 7.07 (d, J = 3.0 Hz, 1H),

6.89 (d, J = 3.0 Hz, 1H), 6.02 (ddt, J = 17.1, 10.1,

6.6 Hz, 1H), 5.71 (d, J = 12.1 Hz, 1H), 5.14–5.04 (m,

2H), 3.78 (s, 3H), 3.42 (d, J = 6.6 Hz, 2H), 3.16 (s, 3H),

2.95 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 191.5, 155.3,

154.9, 150.8, 136.6, 130.0, 121.2, 119.7, 116.0, 110.4,

90.3, 56.2, 45.5, 37.5, 33.9; IR (ATR) ν 2910 (w), 1627

(s), 1539 (s), 1462 (m), 1362 (m), 1265 (s), 1194 (m),

1079 (s); HRMS (EI) calcd for C₁₅H₁₉NO₃[M⁺]

261.1359, found 261.1360. Analytical data for 14b:

1

yellowish oil; H NMR (300 MHz, CDCl₃) δ 7.87 (d,

J = 5.9 Hz, 1H), 7.45 (d, J = 3.1 Hz, 1H), 7.13 (d,

J = 3.1 Hz, 1H), 6.33 (d, J = 5.9 Hz, 1H), 5.98 (ddt,

J = 17.1, 10.3, 6.6 Hz, 1H), 5.16–5.07 (m, 2H), 3.87 (s,

3H), 3.58 (d, J = 6.6 Hz, 2H); ¹³C NMR (75 MHz,

CDCl₃) δ 177.9, 156.8, 154.9, 149.8, 135.0, 131.6,

125.8, 124.1, 117.3, 112.2, 103.2, 56.0, 33.7; IR (ATR) ν

3079 (w), 2935 (w), 1641 (s), 1607 (s), 1471 (s), 1430

(m), 1400 (m), 1327 (s), 1214 (m); HRMS (EI) calcd for

Acknowledgments. We thank Evonik Oxeno for generous

donations of solvents and Umicore (Hanau, Germany) for gener-

ous donations of catalysts.

REFERENCES AND NOTES

C₁₃H₁₂O₃[M⁺] 216.0781, found 216.0782.

[1] Kappe, C. O. Angew Chem Int Ed 2004, 43, 6250.

[2] Kappe, C. O. Chimia 2006, 60, 308.

7-Allyl-5-methoxy-6-(methoxymethoxy)benzofuran (12d).

[3] Kappe, C. O. Chem Soc Rev 2008, 37, 1127.

[4] Schmidt, B.; Schultze, C. Eur J Org Chem 2018, 2018, 223.

[5] Schmidt, B.; Riemer, M. Synthesis 2016, 48, 141.

[6] Schultze, C.; Schmidt, B. J Org Chem 2018, 83, 5210.

[7] Konrádová, D.; Kozubíková, H.; Doležal, K.; Pospíšil, J. Eur J

Org Chem 2017, 2017, 5204.

Table 4, entry 6 (solvent DMF; reaction time 30 min):

following the general procedure, 3d (248 mg, 1.00 mmol)

was converted to 12d (45 mg, 0.18 mmol, 18%):

1

yellowish oil; H NMR (300 MHz, CDCl₃) δ 7.58 (d,

J = 2.2 Hz, 1H), 6.96 (s, 1H), 6.67 (d, J = 2.1 Hz, 1H),

6.10 (ddt, J = 17.1, 10.0, 6.2 Hz, 1H), 5.11 (s, 2H), 5.09

(dq, J = 17.1, 1.6 Hz, 1H), 5.03 (dq, J = 10.1, 1.7 Hz,

[8] Schultze, C.; Schmidt, B. Beilstein J Org Chem 2018, 14,

2991.

[9] Schmidt, B.; Riemer, M.; Schilde, U. Synlett 2014, 25, 2943.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2019

Microwave-Promoted Benzofuran Synthesis

[10] Schmidt, B.; Riemer, M.; Schilde, U. Eur J Org Chem 2015,

2015, 7602.

[11] Schmidt, B.; Riemer, M. Synthesis 2016, 48, 1399.

[30] Chen, Z.; Pitchakuntla, M.; Jia, Y. Nat Prod Rep 2019, 36, 666.

[31] Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T.

J Med Chem 2018, 61, 10996.

[12] Liu, C.; Huang, W.; Wang, M.; Pan, B.; Gu, Y. Adv Synth

Catal 2016, 358, 2260.

[32] Naik, R.; Harmalkar, D. S.; Xu, X.; Jang, K.; Lee, K. Eur J

Med Chem 2015, 90, 379.

[13] Huang, W.; Xu, J.; Liu, C.; Chen, Z.; Gu, Y. J Org Chem

2019, 84, 2941.

[14] Halina, K.; Malgorzata, S.; Monika, K. Curr Org Synth 2012,

9, 529.

[15] Damera, K.; Ke, B.; Wang, K.; Dai, C.; Wang, L.; Wang, B.

RSC Adv 2012, 2, 9403.

[16] Liu, Y.; Lu, T.; Tang, W.-F.; Gao, J. RSC Adv 2018, 8, 28637.

[17] Sun, S.-X.; Wang, J.-J.; Xu, Z.-J.; Cao, L.-Y.; Shi, Z.-F.;

Zhang, H.-L. Tetrahedron 2014, 70, 3798.

[33] Salomé, C.; Narbonne, V.; Ribeiro, N.; Thuaud, F.; Serova,

M.; de Gramont, A.; Faivre, S.; Raymond, E.; Désaubry, L. Eur J Med

Chem 2014, 74, 41.

[34] Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett

1996, 1996, 521.

[35] Li, D.-Y.; Wei, Y.; Marek, I.; Tang, X.-Y.; Shi, M. Chem Sci

2015, 6, 5519.

[36] Liang, B.; Dai, M.; Chen, J.; Yang, Z. J Org Chem 2005, 70,

391.

[37] Fu, J.; Shang, H.; Wang, Z.; Chang, L.; Shao, W.; Yang, Z.;

Tang, Y. Angew Chem Int Ed 2013, 52, 4198.

[38] Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;

Nishida, A. J Org Chem 2006, 71, 4255.

[39] Miege, F.; Meyer, C.; Cossy, J. Angew Chem Int Ed 2011, 50,

5932.

[18] Jacubert, M.; Hamze, A.; Provot, O.; Peyrat, J.-F.; Brion, J.-D.;

Alami, M. Tetrahedron Lett 2009, 50, 3588.

[19] Sarbajna, A.; Pandey, P.; Rahaman, S. M. W.; Singh, K.;

Tyagi, A.; Dixneuf, P. H.; Bera, J. K. ChemCatChem 2017, 9, 1397.

[20] Singh, C.; Prakasham, A. P.; Gangwar, M. K.; Butcher, R. J.;

Ghosh, P. ACS Omega 2018, 3, 1740.

[40] Balakrishna, C.; Kandula, V.; Gudipati, R.; Yennam, S.; Devi,

P. U.; Behera, M. Synlett 2018, 29, 1087.

[41] Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463.

[42] Miura, T.; Funakoshi, Y.; Tanaka, T.; Murakami, M. Org Lett

2014, 16, 2760.

[21] Alonso-Marañón, L.; Martínez, M. M.; Sarandeses, L. A.;

Gómez-Bengoa, E.; Pérez Sestelo, J. J Org Chem 2018, 83, 7970.

[22] Isono, N.; Lautens, M. Org Lett 2009, 11, 1329.

[23] Fürstner, A.; Davies, P. W. J Am Chem Soc 2005, 127, 15024.

[24] Watanabe, K.; Mino, T.; Ishikawa, E.; Okano, M.; Ikematsu,

T.; Yoshida, Y.; Sakamoto, M.; Sato, K.; Yoshida, K. Eur J Org Chem

2017, 2017, 2359.

[43] Jung, D. J.; Jeon, H. J.; Kim, J. H.; Kim, Y.; Lee, S.-G. Org

Lett 2014, 16, 2208.

[44] Yoneyama, H.; Numata, M.; Uemura, K.; Usami, Y.;

Harusawa, S. J Org Chem 2017, 82, 5538.

[25] Ohno, S.; Takamoto, K.; Fujioka, H.; Arisawa, M. Org Lett

2017, 19, 2422.

[45] Xiao, Y.-C.; Moberg, C. Org Lett 2016, 18, 308.

[46] Cai, L.; Yang, D.; Sun, Z.; Tao, X.; Cai, L.; Pike, V. W. Chin J

Chem 2011, 29, 1059.

[47] Pelphrey, P. M.; Popov, V. M.; Joska, T. M.; Beierlein, J. M.;

Bolstad, E. S. D.; Fillingham, Y. A.; Wright, D. L.; Anderson, A. C. J

Med Chem 2007, 50, 940.

[26] Watanabe, K.; Mino, T.; Ikematsu, T.; Hatta, C.; Yoshida, Y.;

Sakamoto, M. Org Chem Front 2016, 3, 979.

[27] Schultze, C.. Dissertation, University of Potsdam, Germany,

2018.

[28] Jeon, J. G.; Lee, J. J.; Hallym University, Industry Academic

Cooperation Foundation, S Korea South Korea, 2015; p. 10.

[29] Watanabe, K.; Mino, T.; Masuda, C.; Yoshida, Y.; Sakamoto,

M. Eur J Org Chem 2019, 2019, 1635.

[48] Fischer, J.; Savage, G. P.; Coster, M. J. Org Lett 2011, 13,

3376.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Article Doi

Functionalized Benzofurans via Microwave-Promoted Tandem Claisen-Rearrangement/5-endo-dig Cyclization

DOI: 10.1002/jhet.3671

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Article abstract of DOI:10.1002/jhet.3671

Full text of DOI:10.1002/jhet.3671

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