Synthesis of Phenylpropanoids via Matsuda-Heck Coupling of Arene Diazonium Salts

Article abstract of DOI:10.1021/acs.joc.7b00447

The Pd-catalyzed Heck-type coupling (Matsuda-Heck reaction) of electron rich arene diazonium salts with electron deficient olefins has been exploited for the synthesis of phenylpropanoid natural products. Examples described herein are the naturally occurring benzofurans methyl wutaifuranate, wutaifuranol, wutaifuranal, their 7-methoxy derivatives, and the O-prenylated natural products boropinols A and C.

Full text of DOI:10.1021/acs.joc.7b00447

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Article
Synthesis of phenylpropanoids via Matsuda-
Heck coupling of arene diazonium salts
Bernd Schmidt, and Felix Wolf
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00447 • Publication Date (Web): 10 Apr 2017
Downloaded from http://pubs.acs.org on April 10, 2017
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Synthesis of phenylpropanoids via Matsuda-Heck coupling of arene diazonium salts
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Bernd Schmidt* and Felix Wolf
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Universitaet Potsdam, Institut fuer Chemie, KarlꢀLiebknechtꢀStraße 24ꢀ25, Dꢀ14476 Potsdamꢀ
Golm, Germany.
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eꢀmail: bernd.schmidt@uniꢀpotsdam.de
Table of contents graphic:
Abstract: The Pdꢀcatalyzed Heckꢀtype coupling (MatsudaꢀHeck reaction) of electron rich
arene diazonium salts with electron deficient olefins has been exploited for the synthesis of
phenylpropanoid natural products. Examples described herein are the naturally occurring
benzofurans methyl wutaifuranate, wutaifuranol, wutaifuranal, their 7ꢀmethoxy derivatives
and the Oꢀprenylated natural products boropinols A and C.
Introduction
Phenylpropanoids are natural products with an oxygenated aromatic core substituted with a
three carbon tail.1 Biosynthetically phenylpropanoids are derived from Lꢀphenylalanine and
occasionally from Lꢀtyrosine through the action of phenylalanine ammoniaꢀlyase,2 an enzyme
that catalyzes the elimination of ammonia and thus yields Eꢀcinnamic acid. Further down the
biosynthetic pathway phenylpropanoids may be converted to other secondary metabolites,
such as chalcones, flavones, coumarins or stilbenes.3 Metabolites 1 with free phenols can
undergo Oꢀprenylation under the action of prenyltransferases, giving prenylethers 2,4ꢀ6
whereas a sequence of enzymatic reverse Oꢀprenylation to gemꢀdimethylallylethers 3 and
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Claisen rearrangement is a feasible route to Cꢀprenylated phenylpropanoids 4.7 From these Cꢀ
prenylated derivatives benzofurans 6 may arise via oxidative cyclization to 5 and cytochrom
Pꢀ450 induced hydrogen abstraction, followed by homolytic scission of the exocyclic CꢀCꢀ
bond with formation of acetone (Scheme 1).8
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Scheme 1. Biosynthetic relationship between phenols, prenylethers and benzofurans.8
There is evidence that phenylpropanoids are formed in plants in response to heat and excess
light stress. They play a major role in the antioxidant defense system of plants by trapping
reactive oxygen species.9 These antioxidant and radical scavenging properties are also
believed to contribute to several pharmacological activities reported for phenylpropanoids and
their glycoconjugates or for medicinal plants containing these secondary metabolites, such as
antibacterial and antiviral activities, antiinflammatory activity or antitumor activity.10
Several secondary plant metabolites of the general structure 2, i. e. phenylpropanoids with
prenyloxy side chains, have been isolated from the shrub Boronia pinnata Sm., which is
native to New South Wales, Australia.11 Preliminary bioactivity studies revealed a notable
activity against the EpsteinꢀBarr virus early antigen for boropinic acid (7), one of the
prenyloxyphenylpropanoids described in this study. Later, antibacterial activity against
Helicobacter pylori,12 antiꢀinflammatory activity,13 inhibitory activity against
prenyltransferases,14 farnesoidꢀXꢀreceptor agonistic activity,15 neuroprotective activity16 and
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an activating effect on the transient receptor potential protein TRPA117 were discovered for
boropinic acid (7) and its reduced derivatives boropinal C (8) and boropinol A (9). The
methyl ester of boropinic acid has also been isolated from a natural source, the plant Hortia
longifolia which is native to Brazil. This compound was found to inhibit αꢀglucosidase and αꢀ
amylase moderately.18 Related natural products with a benzofuranpropanoid structure have
been isolated from the shrub Zanthoxylum wutaiense.19 These compounds, named methyl
wutaifuranate (10a), 7ꢀmethoxywutaifuranal (11b), wutaifuranol (12a) and 7ꢀ
methoxywutaifuranol (12b), respectively, are active against Mycobacterium tuberculosis at a
ꢀg/mL level (Figure 1).
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Figure 1. Secondary plant metabolites from Boronia pinnata and Zanthoxylum wutaiense.
Four publications report the synthesis of boropinic acid (7)13,14,20 or its methyl ester21 and one
reports the syntheses of boropinal C (8) and boropinol A (9).20 These syntheses proceed via
Oꢀprenylation of vanillin and subsequent carbonyl olefination or via direct Oꢀprenylation of
ferulic acid. No syntheses of benzofuranpropanoids 10 – 12 have been published so far.
In continuation of our studies on Pdꢀcatalyzed Heckꢀtype coupling reactions with electron rich
phenol and alkoxyarene diazonium salts22,23 we investigated the synthesis of benzofuranꢀ and
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prenyloxyphenylpropanoids shown in figure 1, using this approach. The Heckꢀtype coupling
of arene diazonium salts is often described as “MatsudaꢀHeckꢀreaction”.24ꢀ36 Originally
discovered by Matsuda and coworkers in the late 1970’s,37ꢀ39 the synthetic value of this
variant of the MizorokiꢀHeck reaction remained underrated for several decades. As for Heck
reactions in general,40 the MatsudaꢀHeck variant is synthetically particularly useful and high
yielding when applied to electron deficient olefins, such as acrylates. At the outset of this
project it was unclear whether prenyloxyarene and benzofuran moieties tolerate the strongly
acidic conditions normally required to generate the respective diazonium salts, and if so,
whether undesired Pdꢀcatalyzed side reactions would occur. For instance, the prenylether
might be cleaved or undergo a double bond migration, and in the case of benzofurans a Pdꢀ
catalyzed arylation at C2, similar to a recently reported C2ꢀarylation of indoles with arene
diazoniums salts,41 is a conceivable competing reaction.
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Results and discussion
Boropinic acid derivatives. Commercially available nitrophenol 13 was prenylated under
standard conditions to furnish prenyl ether 14 in nearly quantitative yield. Chemoselective
reduction of the nitrogroup to aniline 15 was accomplished with zinc and acetic acid.
Diazotation of 15 with HBF4 and tertꢀbutyl nitrite worked well and led to the 4ꢀprenyloxy
arene diazonium salt 16, which precipitated from the reaction mixture and could be isolated
and characterized. For the MatsudaꢀHeck coupling of 16 and methyl acrylate we first tested
methanol as a solvent without added base, because these baseꢀfree conditions had previously
been identified to be superior for alkoxyarene diazonium salts in most cases.22,42 A cinnamate
coupling product 17 was indeed isolated in excellent yield, but quantitative deprenylation had
occurred. The deprenylation could be fully suppressed by addition of NaOAc as a base, and
the desired coupling product methylboropinate (18) was isolated in high yield. Both methanol
and acetonitrile are suitable solvents for this transformation, but in combination with a base
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the isolated yield is significantly higher in acetonitrile. Reduction of methylboropinate (18)
with DIBAlꢀH furnished boropinol A (9) in good yield. Oxidation of 9 with DessꢀMartin
periodinane43 worked well and gave boropinal C (8). The analytical data obtained by us for
the synthetic compounds 8,11 911 and 1818,21 match those reported for the natural products
(Scheme 2).
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Scheme 2. Syntheses of methylboropinate, boropinal C and boropinol A.
Prenyl ethers have been reported to be stable only at very low concentrations of in situ
generated Brønstedꢀacids44 but are cleaved in the presence pꢀtoluenesulfonic acid45 or the
Lewisꢀacid Yb(OTf)3.46 For these reasons it appears to be inconsistent that the equimolar
amount of HBF4 generated during a baseꢀfree MatsudaꢀHeck reaction is sufficient to induce a
quantitative deprenylation, whereas an excess of HBF4 is tolerated during the diazotation of
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prenyloxy aniline 15. This observation suggests that the deprenylative MatsudaꢀHeck reaction
leading to 17 is cooperatively catalyzed by Pd(0) and Brønsted acid (Scheme 3): after
protonation of the ether oxygen the cleavage of the Oꢀprenyl bond by oxidative addition to the
Pdꢀcatalyst is facilitated. The solvent methanol subsequently attacks the dimethylallyl ligand,
leading to prenylmethyl ether and the deprenylation product methylferulate (17), with
regeneration of the Pd(0) catalyst and the Bronstedꢀacid.
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Scheme 3. Cooperatively Pd/H+ꢀcatalyzed deprenylation.
H
Pd(0)
H
O
O
Ar
Ar
PdII
H
O
MeOH
Ar
OMe
Ar OH
+
Pd(0) + H
Methylwutaifuranate, wutaifuranal and wutaifuranol. Construction of the benzofuran was
accomplished along a sequence previously described by van Otterlo and coworkers for other
benzofurans:47 Oꢀallylation of paracetamol (19) gave allyl ether 20, which was converted to
21 by microwaveꢀpromoted Claisenꢀrearrangement48 and repetition of the Oꢀallylation step.
Compound 21 was subjected to a Ruꢀhydride catalyzed isomerization.49,50 Vinylether 22 was
obtained in nearly quantitative yield, but as a mixture of all four geometrical isomers, without
a clear preference for one of these. Ring closing metathesis51ꢀ53 of 22 catalyzed by second
generation Grubbs’ catalyst A54 furnished 5ꢀacetamidobenzofuran (23) in quantitative yield.
Originally, we envisaged the deacetylationꢀdiazotationꢀcoupling (DDC)ꢀsequence recently
developed in our laboratories for the synthesis of methylwutaifuranate (10a) from acetamide
23.55 This oneꢀpot sequence involves a deacetylation mediated by borontrifluorideꢀmethanol,
a diazotation with tertꢀbutyl nitrite and a Pdꢀcatalyzed MatsudaꢀHeckꢀcoupling of the in situ
generated arene diazonium salt. The latter step is initiated by addition of methyl acrylate and a
catalytic amount of Pd(OAc)2 to the deacetylationꢀdiazotation reaction mixture. Surprisingly,
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the DDCꢀsequence was unsuccessful in this case, giving the desired product 10a reproducibly
in yields lower than 10%. Monitoring the oneꢀpot reaction by TLC revealed that the
deacetylation works well, but that the diazotation step appears to be inhibited under these
conditions. For these reasons the transformation of 23 to methylwutaifuranate (10a) was
performed step by step, starting with the deacetylation of acetamide 23 to 5ꢀaminobenzofuran
(24a), which was diazotized to 25a, followed by MatsudaꢀHeck coupling with methyl acrylate
under baseꢀfree conditions to furnish 10a in 36% total yield based on acetamidobenzofuran
23. Reduction of 10a with DIBAlꢀH gave the natural product wutaifuranol (12a). This could
be oxidized to the aldehyde “wutaifuranal” (11a), which has, in contrast to its 7ꢀmethoxy
analogue 11b, not yet been isolated from a natural source. Analytical data recorded for
synthetic 10a and 12a match those reported for the natural products methyl wutaifuranate
(10a)19 and wutaifuranol (12a)19 (Scheme 4).
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Scheme 4. Methylwutaifuranate, wutaifuranol and wutaifuranal from paracetamol.
7-Methoxy derivatives of wutaifuranal and wutaifuranol and their ring-expanded
analogues. For the synthesis of 7ꢀmethoxy methyl wutaifuranate (10b) and its reduced
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derivatives 11b and 12b we chose commercially available 4ꢀnitroguaiacol (26) as the starting
material (Scheme 5). 4ꢀNitroguaiacol was first Oꢀallylated, and the resulting allyl ether 27
was subjected to microwave irradiation in N,Nꢀdiethyl aniline at the same temperature (250
°C) and for the same reaction time (1 h) as the acetamide 20. These conditions had previously
been successfully applied in Claisen rearrangements by us56 and we were therefore surprised
to find that a complex mixture of products was formed in this particular case, which contained
a large amount of highly polar products but apparently not the desired rearrangement product
28 (Table 1, entry 1). In order to improve the selectivity and increase the yield of 28 we
varied the reaction time and temperature (Table 1).
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Table 1. Optimization of reaction conditions for microwave promoted Claisen rearrangement.
entry
T
Reaction time/minutes
Yield of 28
ꢀꢀa)
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10
250 °C
250 °C
250 °C
250 °C
220 °C
220 °C
220 °C
220 °C
220 °C
220 °C
60
7
54%
7.5
15
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20
30
60
90
62%
51%
52%
61%
72%
76%
72%
70%
a)Complex mixture of products.
Compared to the standard conditions (entry 1) the yield of 28 was substantially improved to
62% by reducing the reaction time to 7.5 minutes (entry 3). Slightly shorter (entry 2) or longer
(entry 4) reaction times resulted in lower yields. Controlling the selectivity through the
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reaction time was unsatisfactory, and we therefore investigated a reduced temperature. At 220
°C the yield could be improved from 52% after microwave irradiation for 10 minutes (entry
5) to 76% after irradiation for 30 minutes (entry 8). Further prolongation of the reaction time
was neither detrimental nor beneficial (entries 9 and 10).
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Scheme 5. 7ꢀMethoxywutaifuranate and congeners from 4ꢀnitroguaiacol.
Phenol 28 was Oꢀallylated under standard conditions and the resulting allyl ether 29 was
converted to the 5ꢀnitrosubstituted benzofuran 31 by Ruꢀcatalyzed isomerization followed by
RCM. Reaction conditions and yields are very similar to those for the acetamidobenzofuran
23, apart from the Claisen rearrangement which required a reduced reaction temperature and
proceeded in somewhat lower yields. In the next step the nitro group in compound 31 was
reduced to an amino group by Pd/Cꢀcatalyzed hydrogenation, followed by diazotation and
baseꢀfree MatsudaꢀHeck coupling to furnish 7ꢀmethoxy methyl wutaifuranate (10b).
Reduction of 10b with DIBAlꢀH gave the natural product 7ꢀmethoxy wutaifuranol (12b),
which could be oxidized with DessꢀMartin’s reagent to 7ꢀmethoxy wutaifuranal (11b). In
contrast to methyl wutaifuranate (10a) its 7ꢀmethoxy analogue (10b) has not been isolated
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from natural sources so far and has not been described in the literature. The analytical data
recorded for synthetic compounds 11b and 12b match those previously reported in the
literature for the natural products from Zanthoxylum wutaiense.19
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The convenient access to diallyl compound 29 prompted us to investigate whether the
RCM/MatsudaꢀHeckꢀapproach is a feasible route to ringꢀexpanded analogues of the
benzofuran propanoid natural products. We expected some difficulties along the way. The
formation of benzoxepines by RCM57ꢀ60 has been described in the literature but is known to be
not as facile as that of fiveꢀ and sixmembered analogues. It normally requires higher dilution
and is occasionally hampered by competing double bond migration.61 More serious problems
were expected during the diazotation step and the MatsudaꢀHeck reaction, because the double
bond generated by RCM is isolated and not part of an aromatic system, as in the benzofurans.
This might result in acidꢀmediated isomerization, electrophilic addition or elimination
reactions under diazotation conditions. Under MatsudaꢀHeck conditions Pdꢀcatalyzed double
bond migrations or arylations at the oxacycle might interfere with the intended coupling
reaction.
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In the first step 29 was subjected to RCM using second generation Grubbs’ catalyst A. Under
the conditions used for the RCM of 22 and 30 (initial substrate concentration 0.3 M, toluene,
90 °C) a complex mixture of products was formed, presumably because of uncontrolled
double bond isomerizations. However, the expected benzoxepine 32 was obtained in high
yield in dichloromethane at ambient temperature and with an initial substrate concentration of
0.1 M. Reduction of the nitro group in the presence of the endocyclic CꢀCꢀdouble bond was
achieved with zinc in the presence of aq. NH4Cl. The intermediate aniline 33 was isolated, but
immediately diazotized without further purification to give the benzoxepin diazonium salt 34
in 83% yield over two steps. While the acidic diazotation conditions are tolerated without any
problems, attempted MatsudaꢀHeck coupling of 34 with methyl acrylate under the standard
conditions used for the benzofuran diazonium salts resulted in the formation of a complex
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mixture of products. The desired coupling product 35 could be isolated from this mixture, but
it was contaminated with impurities and the yield was lower than 10% (Table 2, entry 1). In
an attempt to optimize this step, the addition of NaOAc as a base was tested. The product was
indeed formed, but the conversion was lower than 10% (entry 2). In the next steps acetonitrile
was tested as a solvent. In the absence of NaOAc no conversion was observed (entry 3),
whereas addition of the base resulted again in a conversion below 10% (entry 4). For these
reasons we returned to the solvent methanol and baseꢀfree reaction conditions, but reduced the
initial substrate concentration from 0.1 M to 0.05 M, increased the excess of methyl acrylate
to four equivalents and reduced the catalyst loading to 2.5 mol %. We reasoned that these
measures should suppress the assumed competing MatsudaꢀHeck coupling at the endocyclic
double bond. Gratifyingly, the alkenylated benzoxepine 35 was formed in high selectivity and
isolated in good yield (entry 5).
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Table 2. Optimization of reaction conditions for the MatsudaꢀHeck coupling of 34.
entry methyl
acrylate
Pd(OAc)2 solvent
[mol %]
concentrationa) NaOAc Yield
[mol•L−1]
[equiv.] of 35
[equiv.]
1
2
3
4
5
2
2
2
2
4
5.0
5.0
5.0
5.0
2.5
methanol 0.10
methanol 0.10
ꢀꢀ
ꢀꢀb)
ꢀꢀc)
3.0
ꢀꢀ
CH3CN
CH3CN
0.10
0.10
ꢀꢀd)
ꢀꢀc)
3.0
ꢀꢀ
methanol 0.05
78%
a)Initial concentration of diazonium salt 34. b)Complex mixture of products. c)Conversion
<10%. d)No conversion.
Reduction of the ester group in 35 to the allylic alcohol 36 was accomplished with DIBAlꢀH,
but surprisingly the conversion remained unsatisfactory in methylene chloride for this
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particular substrate. A solvent switch to THF led to a substantially improved yield of 91%.
Oxidation of 36 with DessꢀMartin’s reagent furnished the ringꢀexpanded 7ꢀmethoxy
wutaifuranal analogue 37 in high yield (Scheme 6).
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Scheme 6. Synthesis of ringꢀexpanded 7ꢀmethoxy wutaifuranate analogues.
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Conclusions
In summary, naturally occurring phenylpropanoids isolated from the plants Boronia pinnata
and Zanthoxylum wutaiense have been synthesized from paracetamol and 4ꢀnitroguaiacol,
respectively, using Pdꢀcatalyzed couplings of prenyloxyareneꢀ and benzofuran diazonium
salts. Both types of arene diazonium salts have previously not been used in MatsudaꢀHeck
reactions. The synthetic approach to benzofuran propanoids can be extended to ringꢀexpanded
analogues by using a benzoxepin diazonium salt. However, this coupling partner requires
some modification of the reaction conditions, presumably because the endocyclic double bond
of the oxepine moiety undergoes competing Pdꢀcatalyzed reactions under the standard
conditions.
Experimental Section
General methods. All experiments were conducted in dry reaction vessels under an
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atmosphere of dry nitrogen. Solvents were purified by standard procedures. H NMR spectra
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were obtained at 300 MHz, 500 MHz or 600 MHz in CDCl3 with CHCl3 (δ = 7.26 ppm) as an
internal standard. Coupling constants are given in Hz. 13C NMR spectra were recorded at 75
MHz, 125 MHz or 151 MHz in CDCl3 with CDCl3 (δ = 77.1 ppm) as an internal standard.
Whenever the solubility or stability of the sample or signal separation were insufficient in
CDCl3, it was replaced by one of the following solvents: DMSOꢀd6 (DMSOꢀd5 as internal
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standard for H NMR spectroscopy, δ = 2.50 ppm, DMSOꢀd6 as internal standard for 13C
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NMR spectroscopy, δ = 39.5 ppm); acetoneꢀd6 (acetoneꢀd5 as internal standard for H NMR
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spectroscopy, δ = 2.05 ppm, CD3COCD3 as internal standard for C NMR spectroscopy, δ =
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29.8 ppm); methanolꢀd4 (CD2HOD as internal standard for H NMR spectroscopy, δ = 3.31
ppm, CD3OD as internal standard for 13C NMR spectroscopy, δ = 49.2 ppm). IR spectra were
recorded as ATRꢀFTIR spectra. Wavenumbers (ν
) are given in cm−1. The peak intensities are
defined as strong (s), medium (m) or weak (w). Lowꢀ and high resolution mass spectra were
obtained by EIꢀTOF or ESIꢀTOF. Microwave reactions were carried out in an AntonꢀPaarꢀ
monowaveꢀ300 reactor at 250 °C (monowave, maximum power 850 W, temperature control
via external IRꢀsensor) in sealed reaction vessels (volume of vials: 20 mL). Although most
arene diazonium tetrafluoroborates are stable at elevated temperature, we generally advise
against heating these compounds or recording melting points. Hexanes/MTBE mixtures of
increasing polarity were used for column chromatography, starting with a hexanes : MTBE
ratio of 10 : 1 (v/v), which was gradually reduced to 2 : 1 (v/v), if necessary.
2-Methoxy-1-((3-methylbut-2-en-1-yl)oxy)-4-nitrobenzene (14). A suspension of 13 (2.06
g, 12.1 mmol), K2CO3 (6.62 g, 48.0 mmol) and prenylbromide (2.68 g, 18.0 mmol) in acetone
(60 mL) was heated at 65 °C for 12 h. The resulting suspension was filtered through a pad of
celite which was washed with acetone. The filtrate was evaporated and the residue was
purified by column chromatography on silica, using hexane/MTBE mixtures as eluent, to
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furnish 14 (94%, 2.69 g, 11.3 mmol): yellow solid; mp 88ꢀ89 °C; H NMR (300 MHz,
CDCl3) δ 7.90 (dd, J = 8.9, 2.6 Hz, 1H), 7.75 (d, J = 2.6 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H),
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5.51 (tm, J = 6.8 Hz, 1H), 4.70 (d, J = 6.7 Hz, 2H), 3.96 (s, 3H), 1.81 (s, 3H), 1.78 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 154.0, 149.2, 141.4, 139.4, 118.6, 117.8, 111.1, 106.6, 66.4,
56.4, 26.0, 18.5; IR (ATR) ν 1587 (m), 1504 (s), 1335 (s), 1272 (s), 1254 (s); HRMS (EI)
calcd for C12H15NO4 [M+] 237.1001, found 237.1002.
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3-Methoxy-4-((3-methylbut-2-en-1-yl)oxy)aniline (15). A suspension of 14 (95 mg, 0.4
mmol), Znꢀdust (390 mg, 6.0 mmol) and acetic acid (344 µL, 6.0 mmol) in ethanol (5 mL)
was heated to reflux for 10 minutes. After cooling to ambient temperature, the reaction
mixture was filtered through a pad of celite, which was washed with ethanol. The filtrate was
evaporated and the residue was purified by column chromatography on silica, using
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hexane/MTBE mixtures as eluent, to furnish 15 (87%, 67 mg, 0.32 mmol): brownish oil; H
NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 2.6 Hz, 1H), 6.18 (dd, J =
8.4, 2.6 Hz, 1H), 5.49 (tm, J = 6.8 Hz, 1H), 4.46 (d, J = 6.7 Hz, 2H), 3.79 (s, 3H), 1.74 (s,
3H), 1.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 150.7, 141.2, 141.1, 137.2, 120.6, 116.1,
106.5, 100.8, 66.9, 55.7, 25.8, 18.2; IR (ATR) ν 3349 (bw), 1625 (w), 1506 (s), 1450 (m),
1223 (s); HRMS (ESI) calcd for C12H18NO2 [M+H]+ 208.1338, found 208.1327. According to
a SciFinder search the compound is known and commercially available, but no references are
listed and no data have been reported.
3-Methoxy-4-((3-methylbut-2-en-1-yl)oxy)phenyldiazonium tetrafluoroborate (16). A
solution of 15 (508 mg, 2.51 mmol) and HBF4 (aq., 48 wtꢀ%, 656 µL, 5.02 mmol) in ethanol
(5 mL) was stirred for 5 minutes at ambient temperature and then cooled to 0 °C. tertꢀBuONO
(668 µL, 5.02 mmol) was added dropwise. After 15 minutes at 0 °C the reaction mixture was
warmed to ambient temperature and stirred for 1 h. Diethyl ether (50 mL) was added and the
precipitate was filtered through a Büchner funnel. The solid was washed with diethyl ether
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and dried in vacuo to furnish 16 (62%, 475 mg, 1.55 mmol): colourless solid; H NMR (300
MHz, DMSOꢀd6) δ 8.41 (dd, J = 8.1, 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 9.2
Hz, 1H), 5.47 (tm, J = 6.3 Hz, 1H), 4.84 (d, J = 6.9 Hz, 2H), 3.88 (s, 3H), 1.77 (s, 3H), 1.73
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(s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δ 164.1, 154.4, 145.5, 135.9, 122.9, 119.5, 118.0,
107.6, 72.2, 61.8, 30.6, 23.3; IR (ATR) ν 2254 (m), 1568 (m), 1504 (m), 1245 8s), 1070 (s);
HRMS (ESI) calcd for C12H15N2O2 [M+] 219.1134, found 219.1133.
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Ferulic acid methyl ester (17).62 To a solution of 16 (76.5 mg, 0.25 mmol) and Pd(OAc)2
(2.8 mg, 5 mol%) in methanol (2.5 mL) was added methyl acrylate (45 µL, 0.50 mmol) at
ambient temperature and the reaction mixture was stirred until the gas evolution had ceased.
The solvent was evaporated and the residue was dissolved in MTBE (10 mL). The soluton
was washed with water (10 mL), the organic layer was separated and the aqueous layer was
extracted three times with MTBE (10 mL each). The combined organic extracts were dried
with MgSO4, filtered and evaporated. The residue was purified by column chromatography on
silica, using hexane/MTBE mixtures as eluent, to furnish 17 (96%, 49 mg, 0.24 mmol):
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colorless oil; H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 15.9 Hz, 1H), 7.07 (dd, J = 8.2, 1.7
Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 15.9 Hz, 1H), 6.10 (s,
1H), 3.92 (s, 3H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 148.3, 147.2, 145.4,
127.3, 123.4, 115.5, 115.2, 109.8, 56.3, 52.0; IR (ATR) ν 3387 (w), 2950 (w), 1510 (s), 1263
(s), 1156 (s); HRMS (EI) calcd for C11H12O4 [M+] 208.0736, found 208.0741.
Methyl-(E)-3-(3-Methoxy-4-((3-methylbut-2-en-1-yl)oxy)phenyl)acrylate (18).18,21 To a
solution of 16 (76.5 mg, 0.25 mmol), NaOAc (61.5 mg, 0.75 mmol) and Pd(OAc)2 (2.8 mg, 5
mol%) in CH3CN (2.5 mL) was added methyl acrylate (45 µL, 0.50 mmol) and the reaction
mixture was stirred until the gas evolution had ceased. The solvent was evaporated and the
residue was dissolvend in MTBE (10 mL). The solution was washed with water (5 mL), the
organic layer was separated and the aqueous layer was extracted three times with MTBE (5
mL each). The combined organic extracts were dried with MgSO4, filtered and evaporated.
The residue was purified by column chromatography on silica, using hexane/MTBE mixtures
as eluent, to furnish 18 (90%, 61 mg, 0.23 mmol). Following the same procedure but
replacing CH3CN by methanol also gave compound 18 (72%, 50 mg, 0.18 mmol): yellow
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solid, mp 56ꢀ58 °C; 1H NMR (300 MHz, acetoneꢀd6) δ 7.61 (d, J = 16.0 Hz, 1H), 7.33 (d, J =
1.7 Hz, 1H), 7.20 (dd, J = 8.3, 1.8 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 15.9 Hz,
1H), 5.50 (tm, J = 6.6 Hz, 1H), 4.62 (d, J = 6.6 Hz, 2H), 3.89 (s, 3H), 3.74 (s, 3H), 1.78 (s,
3H), 1.76 (s, 3H); 13C NMR (75 MHz, acetoneꢀd6) δ 166.9, 150.9, 150.0, 144.6, 137.3, 127.3,
122.6, 120.0, 115.2, 112.9, 110.4, 65.2, 55.2, 50.6, 24.9, 17.3; IR (ATR) ν 1712 (s), 1636 (m),
1510 (s), 1253 (s); HRMS (ESI) calcd for C16H20O4Na [M+Na]+ 299.1259, found 299.1267.
Boropinol A (9).11 To a solution of 18 (42 mg, 0.15 mmol) in THF (5 mL) was added DIBAlꢀ
H (1.0 M in CH2Cl2, 335 µL, 0.35 mmol) at −78 °C. After 30 minutes the reaction mixture
was warmed to ambient temperature and stirred until the starting material was fully
consumed. The reaction was quenched by addition of satd. aq. solution of NH4Cl (10 mL) and
the mixture was diluted with diethyl ether (10 mL). The organic layer was separated and the
aqueous layer was extracted twice with diethyl ether (10 mL each). The combined organic
extracts were dried with MgSO4, filtered and evaporated. The residue was purified by column
chromatography on silica, using hexane/MTBE mixtures as eluent, to furnish 9 (78%, 29 mg,
0.12 mmol): colourless oil; 1H NMR (300 MHz, CDCl3) δ 6.96 (d, J = 1.6 Hz, 1H), 6.92 (dd,
J = 8.3, 1.7 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 6.26 (dt, J = 15.8, 5.9
Hz, 1H), 5.53 (tm, J = 6.6 Hz, 1H), 4.60 (d, J = 6.6 Hz, 2H), 4.32 (dd, J = 5.9, 1.1 Hz, 2H),
3.90 (s, 3H), 1.79 (s, 3H), 1.75 (s, 3H), 1.57 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 149.9,
148.6, 138.1, 131.6, 130.1, 126.8, 120.3, 120.0, 113.3, 109.5, 66.2, 64.3, 56.2, 26.2, 18.6; IR
(ATR) ν 3471 (bw), 2918 (w), 1510 (s), 1261 (s), 1223 (m); HRMS (ESI) calcd for
C15H20O3Na [M+Na]+ 271.1310, found 271.1305.
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Boropinal C (8).11 To a solution of 9 (11.6 mg, 0.046 mmol) in CH2Cl2 (2 mL) was added
DessꢀMartin’s reagent (23.4 mg, 0.55 mmol) at 0 °C. The reaction mixture was stirred until
the starting material was fully consumed, warmed to ambient temperature and diluted with
CH2Cl2 (10 mL). It washed three times with satd. aq. solution of NaHCO3 and Na2SO3 (5
mL each) and once with brine (5 mL). The organic layer was dried with MgSO4, filtered and
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evaporated. The residue was purified by column chromatography on silica, using
hexane/MTBE mixtures as eluent, to furnish 8 (89%, 10.1 mg, 0.041 mmol): colourless oil;
1H NMR (500 MHz, acetoneꢀd6) δ 9.67 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 15.8 Hz, 1H), 7.38 (d,
J = 2.0 Hz, 1H), 7.27 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.70 (dd, J = 15.8,
7.7 Hz, 1H), 5.50 (tm, J = 6.7 Hz, 1H), 4.65 (d, J = 6.7 Hz, 2H), 3.90 (s, 3H), 1.79 (s, 3H),
1.77 (s, 3H); 13C NMR (125 MHz, acetoneꢀd6) δ 193.4, 153.3, 151.9, 150.4, 137.8, 127.6,
127.0, 123.8, 120.2, 113.2, 110.9, 66.7, 55.6, 25.3, 17.7; IR (ATR) ν 1669 (s), 1595 (m), 1507
(s), 1267 (s); HRMS (ESI) calcd for C15H19O3 [M+H]+ 247.1334, found 247.1341
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N-(4-(Allyloxy)phenyl)acetamide (20).63,64 A suspension 20 (4.50 g, 30 mmol), K2CO3 (8.30
g, 60.0 mmol) and allyl bromide (3.90 mL, 45 mmol) in acetone (90 mL) was stirred at 55 °C
for 12 h. After cooling to ambient temperature, the suspension was filtered through a pad of
celite and washed with acetone. The filtrate was evaporated to furnish 20 (99%, 5.70 g, 30
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mmol): colourless solid, mp 94ꢀ95 °C; H NMR (300 MHz, CDCl3) δ 7.39 (d, J = 9.0 Hz,
2H), 6.88 (d, J = 8.8 Hz, 2H), 6.06 (ddt, J = 17.1, 10.5, 5.3 Hz, 1H), 5.42 (dd, J = 17.3, 1.5
Hz, 1H), 5.31 (s, 1H), 5.30 (dm, J = 10.5 Hz, 1H), 4.52 (d, J = 5.3 Hz, 2H), 2.16 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 168.3, 155.4, 133.2, 131.1, 121.9, 117.7, 115.0, 69.1, 24.3; IR
(ATR) ν 3285 (bm), 1658 (s), 1513 (s), 1259 (m); HRMS (EI) calcd for C11H13NO2 [M+]
191.0946, found 191.0940.
N-(3-Allyl-4-(allyloxy)phenyl)acetamide (21).64 A solution of 20 (1.00 g, 5.2 mmol) in N,Nꢀ
diethylaniline (15 mL) was placed in a vessel suited for microwave irradiation and heated in a
dedicated microwave reactor to 250 °C for 1 h. After cooling to ambient temperature, the
solution was diluted with ethyl acetate (20 mL) and washed three times with aq. NaOH (2 M,
10 mL each). The organic layer was acidified to pH = 1 with aq. HCl (6 M) and extracted
three times with ethyl acetate (20 mL). The combined organic extracts were dried with
MgSO4, filtered and evaporated. The crude product, Nꢀ(3ꢀallylꢀ4ꢀhydroxyphenyl)acetamide,
was used without further purification and characterization in the next step: the residue from
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the previous step was dissolved in acetone (25 mL) and K2CO3 (1.65 g, 12.0 mmol) and allyl
bromide (1.04 mL, 12.0 mmol) were added. The reaction mixture was heated to 55 °C for 12
h, filtered through a short pad of celite which was washed with acetone. The combined
organic solutions were evaporated in vacuo to furnish 21 (82%, 0.80 g, 3.5 mmol) without
further purification: colourless solid, mp 111ꢀ113 °C; 1H NMR (300 MHz, acetoneꢀd6) δ 7.52
(dd, J = 8.8, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 6.88, (d, J = 8.8 Hz, 1H), 6.09 (ddt, J =
17.3, 10.6, 5.0 Hz, 1H), 5.98 (ddt, J = 16.9, 10.0, 6.7 Hz, 1H), 5.43 (dq, J = 17.3, 1.8 Hz, 1H),
5.24 (dq, J = 10.6, 1.6 Hz, 1H), 5.06 (dq, J = 17.2, 1.6 Hz, 1H), 5.00 (dm, J = 10.1 Hz, 1H),
4.56 (dt, J = 4.9, 1.5 Hz, 2H), 3.37 (d, J = 6.7 Hz, 2H), 2.05 (s, 3H); 13C NMR (75 MHz,
acetoneꢀd6) δ 167.4, 152.2, 136.9, 134.1, 132.8, 128.7, 121.0, 118.1, 115.9, 114.8, 112.0, 68.8,
34.2, 23.2; IR (ATR) ν 1521 (s), 1351 (s), 1123 (m), 736 (s); HRMS (EI) calcd for C14H17NO2
[M+] 231.1259, found 231.1260.
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N-(3-(Prop-1-en-1-yl)-4-(prop-1-en-1-yloxy)phenyl)acetamide (22). To a solution of 21
(693 mg, 3.00 mmol) in dry and degassed toluene (30 mL) was added [RuHCl(CO)(PPh3)3]
(142 mg, 5 mol%) and the solution was stirred at 65 °C for 12 h. After cooling to ambient
temperature, the solvent was evaporated and the residue was purified by column
chromatography on silica, using hexane/ethyl acetate mixtures as eluent, to furnish 22 (96%,
663 g, 2.90 mmol) as a mixture of isomers: colourless oil; selected NMRꢀdata of the major
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E,Eꢀisomer: H NMR (300 MHz, CDCl3) δ 7.76 (s(br.), 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.30
(dd, J = 8.6, 2.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.66 (dm, J = 15.6 Hz, 1H), 6.35 – 6.15
(m, 2H), 4.85 (dq, J = 6.5, 6.5 Hz, 1H), 2.15 (s, 3H), 1.88 (dd, J = 6.6, 1.3 Hz, 3H), 1.74 (dd,
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J = 7.0, 1.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ 168.6, 150.9, 141.7, 132.8, 128.2, 127.6,
124.7, 119.9, 118.5, 116.0, 106.8, 24.3, 18.9, 9.4.
N-(Benzofuran-5-yl)acetamide (23). The isomeric mixture of 22 (622 mg, 2.70 mmol) was
dissolved in dry and degassed toluene (30 mL) and second generation Grubbs’ catalyst A (114
mg, 5 mol%) was added. The solution was stirred at 90 °C until the starting material was fully
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consumed (TLC), cooled to ambient temperature and all volatiles were evaporated. The
residue was purified by column chromatography on silica, using hexane/ethyl acetate
mixtures as eluent to furnish 23 (quant., 486 mg, 2.70 mmol): colourless solid, mp 67ꢀ69 °C;
1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 2.0 Hz,
1H), 7.37 (d, J = 8.7 Hz, 1H), 7.25 (dd, J = 8.8, 2.0 Hz, 1H), 6.69 – 6.64 (m, 1H), 2.15 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 169.0, 151.9, 145.8, 133.2, 127.7, 118.0, 113.3, 111.3,
107.8, 24.2; IR (ATR) ν 3285 (bm), 1658 (s), 1554 (s), 1467 (s), 1199 (m); HRMS (EI) calcd
for C10H9NO2 [M+] 175.0633, found 175.0632.
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Benzofuran-5-amine (24a).65 To a solution of 23 (88 mg, 0.50 mmol) in ethanol (5 mL) was
added aq. HCl (6 M, 1.50 mL, 9.00 mmol), and the mixture was heated to reflux until the
starting material was fully consumed (TLC). The solution was cooled to ambient temperature,
the solvent was evaporated and the residue was partitioned between ethyl acetate (5 mL) and
aq. NaOH (2 M, 5 mL). The aqueous layer was extracted three three times with ethyl acetate
(5 mL), the combined organic extracts were dried with MgSO4, filtered and evaporated. The
residue was purified by column chromatography on silica, using hexane/ethyl acetate
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mixtures as eluent, to furnish 24a (59%, 39 mg, 0.30 mmol): brownish oil; H NMR (300
MHz, CDCl3) δ 7.56 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H),
6.70 (dd, J = 8.6, 1.8 Hz, 1H), 6.63 (d, J = 1.5 Hz, 1H), 3.58 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 149.6, 145.4, 142.0, 128.3, 113.6, 111.6, 106.1, 106.0; IR (ATR) ν 3285 (bm), 1658
(s), 1554 (s), 1467 (s), 1199 (m); HRMS (EI) calcd for C8H8NO [M+H]+ 134.0606, found
134.0613.
Benzofuran-5-diazonium tetrafluoroborate (25a). To a solution of 24a (90 mg, 0.67 mmol)
in ethanol (1.5 mL) was added aq. HBF4 (48 wtꢀ%, 177 µL, 1.35 mmol). The mixture was
stirred at ambient temperature for five minutes and then cooled to 0 °C. tertꢀBuONO (179 µL,
1.35 mmol) was added and the mixture was stirred for 15 minutes at 0 °C, warmed to ambient
temperature and then stirred for 1 h. Diethyl ether (20 mL) was added to precipitate the
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diazonium salt, which was isolated by filtration through a Buchner funnel. The solid was
washed with diethyl ether and dried in vacuo to furnish 25a (70%, 107 mg, 0.47 mmol): redꢀ
brown solid; 1H NMR (300 MHz, DMSOꢀd6) δ 9.13 (d, J = 1.8 Hz, 1H), 8.61 (dd, J = 9.1, 1.9
Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H); 13C
NMR (75 MHz, DMSOꢀd6) δ 160.2, 152.4, 129.8, 129.7, 129.6, 115.8, 109.8, 108.6; IR
(ATR) ν 2279 (m), 1571 (w), 1255 (w), 1031 (s); HRMS (ESI) calcd for C8H5N2O [M+]
145.0402, found 145.0417.
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Methylwutaifuranate (10a).19 To a solution of 25a (89 mg, 0.38 mmol) in methanol (4 mL)
was added Pd(OAc)2 (4.2 mg, 5 mol%) and methyl acrylate (69 µL, 0,76 mmol). The reaction
mixture was stirred at ambient temperature until the gas evolution had ceased, the solvent was
evaporated and the residue redissolvend in MTBE (10 mL). The solution was washed with
water (10 mL), the organic layer was separated and the aqueous layer was extracted three
times with MTBE (10 mL each). The combined organic extracts were dried with MgSO4,
filtered and evaporated. The residue was purified by column chromatography on silica, using
hexane/MTBE mixtures as eluent, to furnish 10a (87%, 68 mg, 0.33 mmol): colourless solid,
mp 84ꢀ86 °C; 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 16.0 Hz, 1H), 7.78 (s, 1H), 7.67 (d,
J = 2.1 Hz, 1H), 7.55 – 7.48 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H),
3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.6, 156.0, 146.0, 145.3, 129.5, 128.0, 124.2,
121.7, 116.6, 111.9, 106.8, 51.7; IR (ATR) ν 1707 (s), 1639 (m), 1176 (s); HRMS (EI) calcd
for C12H10O3 [M+] 202.0630, found 202.0624.
Wutaifuranol (12a).19 To a solution of 10a (30 mg, 0.15 mmol) in CH2Cl2 (5 mL) was added
DIBAlꢀH (1.0 M in CH2Cl2, 311 µL, 0.31 mmol) at −78 °C and the solution was stirred for
0.5 h. It was then warmed to ambient temperature and stirred until the starting material was
fully consumed. The reaction was quenched by addition of aq. satd. solution of NH4Cl (10
mL), the organic layer was separated and the aqueous layer was extracted three times with
CH2Cl2 (10 mL). The combined organic extracts were dried with MgSO4, filtered and
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evaporated. The residue was purified by column chromatography on silica, using
hexane/MTBE mixtures as eluent, to furnish 12a (92%, 24 mg, 0.14 mmol): colourless solid,
mp 64ꢀ66 °C; 1H NMR (600 MHz, acetoneꢀd6) δ 7.84 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 1.7 Hz,
1H), 7.50 (d, J = 8.6 Hz, 1H), 7.46 (dd, J = 8.6, 1.8 Hz, 1H), 6.90 (dd, J = 2.2, 0.9 Hz, 1H),
6.73 (dt, J = 15.9, 1.6 Hz, 1H), 6.41 (dt, J = 15.9, 5.4 Hz, 1H), 4.27 (ddd, J = 5.5, 5.5, 1.7 Hz,
2H), 3.88 (t, J = 5.7 Hz, 1H); 13C NMR (150 MHz, acetoneꢀd6) δ 154.5, 145.9, 132.6, 129.3,
129.2, 127.9, 122.8, 119.0, 111.1, 106.7, 62.4; IR (ATR) ν 3327 (bw), 1468 (s), 1089 (m), 972
(s); HRMS (ESI) calcd for C11H9O2 [MꢀH+] 173.0608, found 173.0645.
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(E)-3-(Benzofuran-5-yl)acrylaldehyde (11a). To a solution of wutaifuranol 12a (14.0 mg,
0.08 mmol) in CH2Cl2 (3 mL) was added DessꢀMartin’s reagent (34 mg, 0.79 mmol) at 0 °C.
The reaction mixture was warmed to ambient temperature and stirred until full conversion of
the starting material. It was then diluted with CH2Cl2 (5 mL) and washed three times with a
satd. aq. solution of NaHCO3 and Na2SO3 (5 mL each), and once with brine. The organic
layer was dried with MgSO4, filtered and evaporated. The residue was purified by column
chromatography on silica, using hexane/MTBE mixtures as eluent, to furnish 11a (83%, 11
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mg, 0.07 mmol): colourless solid, mp 83ꢀ84 °C; H NMR (500 MHz, acetoneꢀd6) δ 9.74 (d, J
= 7.7 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 15.9 Hz, 1H),
7.76 (dd, J = 8.6, 1.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.01 (dd, J = 2.2, 0.9 Hz, 1H), 6.81
(dd, J = 15.9, 7.7 Hz, 1H); 13C NMR (125 MHz, acetoneꢀd6) δ 193.5, 156.8, 153.5, 147.3,
130.1, 128.8, 128.2, 125.3, 122.8, 112.3, 107.3; IR (ATR) ν 1659 (s), 1617 (s), 1464 (m),
1106 (s); HRMS (ESI) calcd. for C11H9O2 [M+H+] 173.0603, found 173.0616.
1-(Allyloxy)-2-methoxy-4-nitrobenzene (27). A suspension of 26 (845 mg, 5.00 mmol),
K2CO3 (1.38 g, 10.0 mmol) and allyl bromide (658 µL, 7.50 mmol) in acetone (25 mL) was
stirred at 55 °C for 12 h. The resulting suspension was filtered through a pad of celite, which
was washed with acetone. The combined filtrates were evaporated to furnish the title
compound 27 (quant., 1.040 g, 5.00 mmol): yellow solid, mp 50ꢀ52 °C; 1H NMR (300 MHz,
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CDCl3) δ 7.88 (dd, J = 8.9, 2.6 Hz, 1H), 7.75 (d, J = 2.6 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H),
6.08 (ddt, J = 17.1, 10.7, 5.4 Hz, 1H), 5.45 (dq, J = 17.3, 1.3 Hz, 1H), 5.36 (dq, J = 1.05, 1.3
Hz, 1H), 4.72 (dt, J = 4.1, 1.3 Hz, 2H), 3.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 153.6,
149.3, 141.6, 132.0, 119.2, 117.7, 111.5, 106.8, 70.2, 56.4; IR (ATR) ν 1590 (m), 1505 (s),
1338 (m), 1275 (m); HRMS (EI) calcd for C10H11NO4 [M+] 209.0688, found 209.0676. Anal.
calcd for C10H11NO4 (209.20): C, 57.4; H, 5.3; N, 6.7. Found: C, 57.2; H, 5.4; N, 7.0.
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2-Allyl-6-methoxy-4-nitrophenol (28). A solution of 27 (209 mg, 1.00 mmol) in N,Nꢀ
diethylaniline (5 mL) was placed in a vessel suited for microwave irradiation and placed in a
microwave reactor at 220 °C for 0.5 h. The solution was cooled to ambient temperature,
diluted with ethyl acetate (10 mL) and washed three times with aq. HCl (2 M, 10 mL each).
The organic layer was separated, and the combined washing solutions were extracted three
times with ethyl acetate (15 mL each). The combined organic extracts were dried with
MgSO4, filtered and evaporated. The residue was purified by column chromatography on
silica, using hexane/MTBE mixtures as eluent, to furnish 28 (76%, 159 mg, 0.76 mmol):
yellow solid, mp 72ꢀ74 °C; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 2.5 Hz, 1H), 7.67 (d, J
= 2.5 Hz, 1H), 6.35 (s, 1H), 6.08 – 5.87 (m, 1H), 5.19 – 5.08 (m, 2H), 4.00 (s, 3H), 3.46 (d, J
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= 6.6 Hz, 2H); C NMR (75 MHz, CDCl3) δ 149.5, 146.0, 140.7, 134.9, 126.3, 119.2, 117.1
104.5, 56.7, 33.6; IR (ATR) ν 3456 (bw), 1519 (m), 1490 (m), 1337 (s); HRMS (EI) calcd for
C10H11NO4 [M+] 209.0688, found 209.0687. Anal calcd for C10H11NO4 (209.20): C, 57.4; H,
5.3; N, 6.7. Found: C, 57.4; H, 5.4; N, 6.8.
1-Allyl-2-allyloxy-3-methoxy-5-nitrobenzene (29). A suspension of 28 (1.26 g, 6.0 mmol),
K2CO3 (1.65 g, 12.0 mmol) and allyl bromide (1.04 mL, 12.0 mmol) in acetone (60 mL) was
heated at 55 °C for 12 h. The suspension was cooled to ambient temperature, filtered through
a pad of celite and washed with acetone. All volatiles were evaporated and the residue was
purified by column chromatography on silica, using hexane/MTBE mixtures as eluent, to
furnish 29 (94%, 1.40 g, 5.6 mmol): yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J =
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2.6 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 6.06 (ddt, J = 16.2, 10.4, 5.9 Hz, 1H), 5.94 (ddt, J =
16.8, 10.3, 6.6 Hz, 1H), 5.37 (dm, J = 17.2 Hz, 1H), 5.25 (dm, J = 10.4, 1H), 5.12 (dm, J =
10.4 Hz, 1H), 5.10 (d, J = 16.9 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 3.94 (s, 3H), 3.46 (d, J =
6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 152.6, 151.4, 143.6, 135.6, 134.7, 133.6, 118.3,
117.9, 117.0, 105.9, 75.1, 56.2, 34.3; IR (ATR) ν 1552 (s), 1474 (m), 1339 (s), 1289 (s);
HRMS (EI) calcd for C13H15NO4 [M+] 249.1001, found 249.1012.
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1-Methoxy-5-nitro-3-(prop-1-en-1-yl)-2-(prop-1-en-1-yloxy)benzene (30). To a solution of
29 (747 mg, 3.00 mmol) in dry and degassed toluene (15 mL) was added
[RuHCl(CO)(PPh3)3] (142 mg, 5.0 mol %) and the solution was heated at 65 °C for 12 h.
After cooling to ambient temperature, the solvent was evaporated and the residue was purified
by column chromatography on silica, using hexane/MTBE mixtures as eluent, to furnish 30
(96%, 720 g, 2.89 mmol) as a mixture of isomers: colourless, waxy solid; NMRꢀdata of the
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major E,Eꢀisomer: H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 2.6 Hz, 1H), 7.63 (d, J = 2.6
Hz, 1H), 6.63 (dm, J = 16.0 Hz, 1H), 6.39 (dq, J = 16.0, 6.4 Hz, 1H), 6.12 (dm, J = 6.0 Hz,
1H), 4.70 (dq, J = 6.0, 6.0 Hz, 1H), 3.91 (s, 3H), 1.93 (dd, J = 6.6, 1.3 Hz, 3H), 1.80 (dd, J =
6.9, 1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 152.3, 148.0, 144.4, 144.2, 132.2, 130.6,
123.4, 113.9, 105.5, 103.9, 56.4, 18.9, 9.1.
7-Methoxy-5-nitrobenzofuran (31). To a solution of 30 (249 mg, 1.0 mmol) in dry and
degassed toluene (10 mL) was added second generation Grubbs’ catalyst A (42 mg, 5 mol %).
The solution was heated to 90 °C until the starting material was fully consumed (TLC). After
cooling to ambient temperature, the solvent was evaporated and the residue was purified by
column chromatography on silica, using hexane/MTBE mixtures as eluent, to furnish 31 (95
%, 183 mg, 0.95 mmol): colourless solid, mp 123ꢀ126 °C; 1H NMR (300 MHz, CDCl3) δ 8.20
(d, J = 1.8 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 6.93 (d, J = 2.0 Hz,
1H), 4.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 147.7, 147.5, 145.4, 145.0, 128.6, 110.7,
108.2, 102.1, 56.7; IR (ATR) ν 1516 (s), 1330 (s), 1299 (m); HRMS (EI) calcd for C9H7NO4
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[M+] 193.0375, found 193.0382. Anal calcd for C9H7NO4 (193.16): C, 56.0; H, 3.7. Found: C,
55.6; H, 3.6.
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7-Methoxy-5-aminobenzofuran (24b). A suspension of 31 (48 mg, 0.25 mmol) and Pd/C (5
mg, 10 wtꢀ%) in methanol (5 mL) was stirred under an atmosphere of hydrogen (1 bar) for 12
h. The suspension was filtered through a pad of celite and washed with methanol, all volatiles
were evaporated and the residue was purified by column chromatography on silica, using
hexane/MTBE mixtures as eluent, to furnish 24b (81%, 33 mg, 0.20 mmol): brownish oil; 1H
NMR (300 MHz, methanolꢀd4) δ 7.58 (d, J = 2.1 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 6.53 (d, J
= 1.9 Hz, 1H), 6.39 (d, J = 1.7 Hz, 1H), 3.91 (s, 3H); 13C NMR (75 MHz, methanolꢀd4) δ
146.8, 146.3, 144.7, 140.5, 131.0, 107.4, 99.7, 99.1, 56.5; IR (ATR) ν 3421 (bw), 1598 (s),
1478 (m); HRMS (ESI) calcd for C9H10NO2 [M+H]+ 164.0712, found 164.0716.
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7-Methoxy-5-diazoniumbenzene tetrafluoroborate (25b). A solution of 24b (100 mg, 0.61
mmol) and HBF4 (aq., 48 wtꢀ%, 160 µL, 1.22 mmol) in ethanol (2 mL) was stirred for 5 min
at ambient temperature and then cooled to 0 °C. At this temperature tertꢀBuONO (163 µL,
1.22 mmol) was added and the mixture was stirred at 0°C for 0.25 h. It was warmed to
ambient temperature and stirred for 1 h, followed by addition of diethyl ether (20 mL) to
precipitate the diazonium salt. The precipitate was filtered through a Buchner funnel, the solid
was washed with diethyl ether and dried in vacuo to furnish 25b (78%, 123 mg, 0.48 mmol):
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redꢀbrown solid; H NMR (300 MHz, DMSOꢀd6) δ 8.83 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H),
7.42 (s, 1H), 4.07 (s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δ 151.8, 150.4, 146.7, 130.4, 123.8,
109.9, 109.7, 109.1, 58.2; IR (ATR) ν 2272 (m), 1600 (m), 1482 (m), 1029 (s); HRMS (ESI)
calcd for C9H7N2O2 [M+] 175.0508, found 175.0508.
Methyl-(E)-3-(7-methoxybenzofuran-5-yl)acrylate (10b). To a solution of 25b (173 mg,
0.66 mmol) and Pd(OAc)2 (7.4 mg, 5 mol%) in methanol (6 mL) was added methyl acrylate
(110 µL, 1.32 mmol) and the reaction mixture was stirred until the gas evolution had ceased.
All volatiles were evaporated, the residue was dissolved in MTBE (20 mL) and the solution
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was washed with water (10 mL). The organic layer was separated and the aqueous layer was
extracted three times with MTBE (20 mL). The combined organic extracts were dried with
MgSO4, filtered and evaporated. The residue was purified by column chromatography on
silica, using hexane/MTBE mixtures as eluent, to furnish 10b (78%, 119 mg, 0.51 mmol):
yellow solid, mp 94ꢀ97 °C; 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 15.9 Hz, 1H), 7.66 (d,
J = 2.1 Hz, 1H), 7.39 (d, J = 1.1 Hz, 1H), 7.00, d, J = 1.2 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H),
6.43 (d, J = 15.9 Hz, 1H), 4.06 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.9,
146.3, 146.1, 146.0, 145.9, 130.9, 129.8, 117.0, 115.5, 107.8, 105.5, 56.5, 52.1; IR (ATR) ν
1708 (s), 1635 (m), 1470 (m), 1277 (s); HRMS (EI) calcd for C13H12O4 [M+] 232.0736, found
232.0741. Anal calcd for C13H12O4 (232.24): C, 67.2; H, 5.2. Found: C, 67.2; H, 5.3.
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7-Methoxywutaifuranol (12b).19 To a solution of 10b (48 mg, 0.20 mmol) in CH2Cl2 (5 mL)
was added DIBAlꢀH (1.0 M in DCM, 500 µL, 0.50 mmol) at ꢀ78 °C. After 0.5 h the reaction
mixture was warmed to ambient temperature and stirred until the starting material was fully
consumed (TLC). The reaction was quenched by addition of a satd. aq. solution of NH4Cl (10
mL) and diluted with CH2Cl2 (10 mL). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3 times 10 mL). The combined organic extracts were dried with
MgSO4, filtered and evaporated. The residue was purified by column chromatography on
silica, using hexane/MTBE mixtures as eluent, to furnish 12b (83 %, 34 mg, 0.17 mmol):
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colourless solid, mp 58ꢀ60 °C; H NMR (300 MHz, acetoneꢀd6) δ 7.80 (d, J = 2.1 Hz, 1H),
7.23 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 1.3 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.69 (dt, J = 15.9,
1.4 Hz, 1H), 6.40 (dt, J = 15.9, 5.3 Hz, 1H), 4.26 (td, J = 5.5, 1.6 Hz, 2H), 4.02 (s, 3H), 3.86
(t, J = 5.6 Hz, 1H); 13C NMR (75 MHz, acetoneꢀd6) δ 146.1, 146.0, 144.4, 134.0, 130.1,
129.8, 129.5, 112.1, 107.3, 104.5, 62.8, 55.8; IR (ATR) ν 3344 (bw), 1597 (s), 1467 (m), 1357
(m), 1146 (s); HRMS (EI) calcd for C12H12O3 [M+] 204.0786, found 204.0782.
7-Methoxywutaifuranal (11b).19 To a solution of 12b (9.4 mg, 0.046 mmol) in CH2Cl2 (2
mL) was added DessꢀMartin’s reagent (23.4 mg, 0.550 mmol). The reaction mixture was
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stirred until the starting material was fully consumed (TLC) and then diluted with CH2Cl2 (5
mL). The solution was washed with a satd. aq. solution of NaHCO3/Na2SO3 (3 times 5 mL)
and once with brine. The organic layer was dried with MgSO4, filtered and evaporated. The
residue was purified by column chromatography on silica, using hexane/MTBE mixtures as
eluent, to furnish 11b (97%, 9.0 mg, 0.044 mmol): colourless solid, mp 106ꢀ108 °C; 1H NMR
(500 MHz, acetoneꢀd6) δ 9.73 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 15.8
Hz, 1H), 7.45 (d, J = 1.3, Hz, 1H), 7.03 (d, J = 1.4 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.73
(dd, J = 15.8, 7.7 Hz, 1H), 4.07 (s, 3H); 13C NMR (125 MHz, acetoneꢀd6) δ 193.7, 153.7,
146.2, 146.2, 146.0, 130.2, 129.6, 127.8, 111.5, 107.2, 105.3, 56.2; IR (ATR) ν 1666 (s), 1591
(m), 1464 (s), 1340 (m); HRMS (EI) calcd for C12H10O3 [M+] 202.0630, found 202.0620.
9-Methoxy-7-nitro-2,5-dihydrobenzo[b]oxepine (32). To a solution of 29 (124 mg, 0.50
mmol) in CH2Cl2 (5 mL) was added second generation Grubbs’ catalyst A (21 mg, 5 mol %)
and the reaction mixture was stirred at ambient temperature until full conversion of the
starting material (TLC). The solvent was evaporated and the residue was purified by column
chromatography on silica, using hexane/MTBE mixtures as eluent, to furnish 32 (91%, 101
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mg, 0.45 mmol): offꢀwhite solid, mp 105ꢀ107 °C; H NMR (300 MHz, CDCl3) δ 7.71 (d, J =
2.6 Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H), 5.91 (dm, J = 11.4 Hz, 1H), 5.55 (dm, J = 11.4 Hz,
1H), 4.71 – 4.66 (m, 2H), 3.96 (s, 3H), 3.59 – 3.53 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
152.6, 152.4, 143.5, 137.7, 127.3, 125.4, 116.5, 106.0, 70.3, 56.4, 31.4; IR (ATR) ν 1521 (m),
1484 (s), 1338 (s), 1272 (m), 1091 (m); HRMS (EI) calcd for C11H11NO4 [M+] 221.0688,
found 221.0676.
9-Methoxy-2,5-dihydrobenzo[b]oxepine-7-diazonium tetrafluoroborate (34). 9ꢀMethoxyꢀ
2,5ꢀdihydrobenzo[b]oxepinꢀ7ꢀamine (33): A solution of 32 (816 mg, 3.70 mmol) in
methanol/water (220 mL, 10 : 1 (v/v)) was cooled to 0 °C and NH4Cl (3.27 g, 61.3 mmol) and
Znꢀdust (19.20 g, 295 mmol) were added in portions. The resulting suspension was warmed to
ambient temperature und stirred until the starting material was fully consumed (TLC). The
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reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The
filtrate was concentrated and the residue was dissolved in ethyl acetate (10 mL) and washed
with brine. The organic layer was dried with MgSO4, filtered and evaporated to furnish crude
33, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3)
δ 6.21 (d, J = 2.6 Hz, 1H), 6.07 (d, J = 2.6 Hz, 1H), 5.81 (dm, J = 11.5 Hz, 1H), 5.45 (dm, J
= 11.5 Hz, 1H), 4.56 – 4.51 (m, 2H), 3.82 (s, 3H), 3.66 (s (br.), 2H), 3.40 – 3.34 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 152.6, 142.4, 139.8, 138.7, 127.8, 125.3, 107.1, 98.6, 70.8, 55.8,
31.6; IR (ATR) ν 3438 (m), 3362 (m), 1598 (m), 1500 (s), 1227 (m), 1163 (m); HRMS (EI)
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calcd for C11H13NO2 [M+H]+ 192.1025, found 192.1015.
9ꢀMethoxyꢀ2,5ꢀ
dihydrobenzo[b]oxepineꢀ7ꢀdiazonium tetrafluoroborate (34): The residue from the previous
step was dissolved in ethanol (7.4 mL) and cooled to 0 °C, followed by addition of aq. HBF4
(48 wtꢀ%, 970 µL, 7.40 mmol). tertꢀBuONO (982 µL, 7.40 mmol) was then added and the
mixture was stirred at 0 °C for 0.25 h. The reaction mixture was warmed to ambient
temperature, stirred for 1 h and diluted with diethyl ether (100 mL) to precipitate the
diazonium salt. The resulting suspension was filtered through a Buchner funnel, the
precipitate was washed with diethyl ether (10 mL) and dried in vacuo to furnish 34 (83%, 888
mg, 3.00 mmol): offꢀwhite solid; 1H NMR (300 MHz, DMSOꢀd6) δ 8.20 – 8.16 (m, 2H), 6.15
(dt, J = 10.6, 5.9 Hz, 1H), 5.85 (dt, J = 10.6, 4.8 Hz, 1H), 4.93 (dm, J = 4.8 Hz, 2H), 3.87 (s,
3H), 3.68 (d, J = 5.7 Hz, 2H); 13C NMR (75 MHz, DMSOꢀd6) δ 158.8, 152.5, 134.7, 130.1,
128.7, 127.6, 113.8, 105.6, 69.1, 57.3, 30.7; IR (ATR) ν 2255 (m), 1568 (m), 1469 (m), 1273
(m), 1028 (s); HRMS (ESI) calcd for C11H11N2O2 [M+] 203.0821, found 203.0820.
Methyl-(E)-3-(9-methoxy-2,5-dihydrobenzo[b]oxepine-7-yl)acrylate (35). To a solution of
34 (145 mg, 0.5 mmol) in methanol (10 mL) were added Pd(OAc)2 (2.8 mg, 2.5 mol %) and
methyl acrylate (180 µL, 2.0 mmol) and the reaction mixture was stirred until the gas
evolution had ceased. All volatiles were evaporated and the residue was dissolvend in MTBE
(10 mL). The solution was washed with water (10 mL), the organic layer was separated and
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the aqueous layer was extracted three times with MTBE (10 mL each). The combined organic
extracts were dried with MgSO4, filtered and evaporated. The residue was purified by column
chromatography on silica, using hexane/MTBE mixtures as eluent, to furnish 35 (78%, 102
mg, 0.39 mmol): colourless oil; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 16.0 Hz, 1H), 6.95
(d, J = 1.7 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 5.84 (dm, J = 11.6
Hz, 1H), 5.46 (dm, J = 11.6 Hz, 1H), 4.62 – 4.56 (m, 2H), 3.87 (s, 3H), 3.78 (s, 3H), 3.49 –
3.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.5, 152.3, 149.2, 144.7, 138.2, 130.5, 127.5,
125.6, 121.3, 117.1, 109.9, 70.5, 56.1, 51.7, 31.5; IR (ATR) ν 1709 (m), 1635 (m), 1492 (m),
1265 (s), 1149 (s); HRMS (ESI) calcd for C15H17O4 [M+H]+ 261.1127, found 261.1118.
(E)-3-(9-Methoxy-2,5-dihydrobenzo[b]oxepine-7-yl)prop-2-en-1-ol (36). To a solution of
35 (30 mg, 0.12 mmol) in THF (5 mL) was added DIBAlꢀH (1.0 M in CH2Cl2, 480 µL, 0.48
mmol) at ꢀ78 °C. The reaction mixture was allowed to warm to ambient temperature, stirred
until the starting material was fully consumed (TLC) and then quenched by addition of a satd.
aq. solution of NH4Cl (2 mL). It was diluted with diethyl ether, the organic layer was
separated and the aqueous layer was extracted with diethyl ether (3 times 5 mL). The
combined organic extracts were dried with MgSO4, filtered and evaporated. The residue was
purified by column chromatography on silica, using hexane/MTBE mixtures as eluent, to
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furnish 36 (91%, 24 mg, 0.10 mmol): colourless oil; H NMR (600 MHz, acetoneꢀd6) δ 6.97
(d, J = 1.9 Hz, 1H), 6.77 (d, J = 1.9 Hz, 1H), 6.51 (dt, J = 15.9, 1.7 Hz, 1H), 6.32 (dt, J =
15.9, 5.3 Hz, 1H), 5.81 (dtt, J = 11.6, 5.4, 2.3 Hz, 1H), 5.46 (dm, J = 11.6 Hz, 1H), 4.48 –
4.46 (m, 2H), 4.21 (ddd, J = 5.4, 5.4, 1.5 Hz, 2H), 3.98 (t, J = 5.6 Hz, 1H), 3.83 (s, 3H), 3.41
13
– 3.38 (m, 2H); C NMR (150 MHz, acetoneꢀd6) δ 152.9, 147.2, 138.4, 133.9, 129.9, 129.4,
128.2, 125.7, 119.0, 109.3, 70.4, 62.7, 55.7, 31.4; IR (ATR) ν 3404 (bm), 1587 (m), 1498 (s),
1343 (m), 1150 (s), 1091 (s); HRMS (ESI) calcd for C14H16O3 [M+] 232.1099, found
232.1098.
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