Functional group manoeuvring for tuning stability and reactivity: Synthesis of cicerfuran, moracins (D, E, M) and chromene-fused benzofuran-based natural products

Article abstract of DOI:10.1039/c7ob02459b

The protecting group manoeuvring as a strategy was applied for tuning the stability and reactivity of 4-(2,2-dibromovinyl)benzene-1,3-diol (12a) and 6-(2,2-dibromovinyl)-2,2-dimethylchroman-7-ol (22) in the domino synthesis of benzofuran-based natural products (1-8). The functional group demands and their impact on the reactivity driven by electronic effects were successfully managed by varying the protecting groups with substituted gem-dibromovinylphenols in domino couplings and triarylbismuth reagents under palladium-catalyzed conditions. This approach paved the way for the synthesis of moracin M (1) and cicerfuran (2), and the first time synthesis of moracin D (3) and moracin E (4) along with chromene-fused benzofuran-based natural products (5-8) in overall good yields.

Full text of DOI:10.1039/c7ob02459b

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Functional group manoeuvring for tuning stability
and reactivity: synthesis of cicerfuran, moracins
(D, E, M) and chromene-fused benzofuran-based
natural products†
Cite this: DOI: 10.1039/c7ob02459b
Maddali L. N. Rao, * Venneti N. Murty and Sachchida Nand
The protecting group manoeuvring as a strategy was applied for tuning the stability and reactivity of
4-(2,2-dibromovinyl)benzene-1,3-diol (12a) and 6-(2,2-dibromovinyl)-2,2-dimethylchroman-7-ol (22) in
the domino synthesis of benzofuran-based natural products (1–8). The functional group demands and
their impact on the reactivity driven by electronic effects were successfully managed by varying the pro-
tecting groups with substituted gem-dibromovinylphenols in domino couplings and triarylbismuth
reagents under palladium-catalyzed conditions. This approach paved the way for the synthesis of moracin
M (1) and cicerfuran (2), and the first time synthesis of moracin D (3) and moracin E (4) along with
chromene-fused benzofuran-based natural products (5–8) in overall good yields.
Received 4th October 2017,
Accepted 21st October 2017
DOI: 10.1039/c7ob02459b
rsc.li/obc
Introduction
Heterocyclic benzofuran scaffolds are bestowed with abundant
biological and medicinal properties. As privileged scaffolds,
benzofuran derivatives are associated with anticancer, anti-
microbial, immunomodulatory, antioxidant and anti-inflam-
matory properties.1a,b Furthermore, moracins A–Z and their
derivatives are the major source for the development of
drugs.1c–n A few related benzofuran natural products are
shown in Fig. 1. Among these, moracin M (1) and moracin D
(3) were isolated from M. alba L.,2a,b whereas moracin E (4) was
isolated from the acetone extracts of the cortex and phloem
tissues of mulberry shoots infected with F. solani f. sp. mori.2c
Furthermore, cicerfuran (2) was isolated from the root of the
wild species C. bijugum.2d Gramniphenols F (8) and G (7) were
recently isolated from Arundina gramnifolia2e and morunigrol
C (5) was isolated from the bark of Morus nigra.2f From the
structural similarity point of view, this family of benzofuran
natural products possesses 6-hydroxy substitutions and related
chromene-fused arene scaffolds along with functionalized
2-aryl substitutions. However, a common pool strategy for the
synthesis of this family of target skeletons has not been rea-
lized so far. A few known methods reported largely focused on
the synthesis of individual benzofuran skeletons employing
Fig. 1 6-Hydroxy or chromene-fused 2-arylbenzofuran based natural
products.
the Wittig-, Sonogashira-, Suzuki- and McMurry-based coup-
ling approaches.3 For example, Kotschy et al. synthesized cicer-
furan (2) employing the Sonogashira coupling of halogenated
phenols. This coupling reaction step became complicated due
to the presence of a phenolic group in the coupling partner.
This led to the usage of diacetate derivatives with either
4-bromoresorcinol or aryl alkynes in Sonogashira coupling, and
the corresponding aryl acetylenes were obtained although in
poor yields [(a), Scheme 1].3a Stevenson et al. reported Pd-cata-
lyzed coupling of arylacetylenes with 4-iodoresorcinol or its dia-
cetate derivative which also failed to undergo the Sonogashira
reaction cleanly under the conditions employed. In this case,
the final cicerfuran (2) product was identified only by GC-MS
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208 016,
India. E-mail: maddali@iitk.ac.in; Fax: +91 (0)512 259 7532;
Tel: +91 (0)512 259 7532
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7ob02459b
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Fig. 2 Strategy for 2-arylbenzofurans with 5- or 5,7-disubstitutions.
(Fig. 1). This strategy mainly revolves around the presence of a
2,6-disubstituted benzofuran core and in turn involves 2-aryl
and 6-OH substitutions (Fig. 3). The requirement of 6-OH sub-
stitution in the arene part earlier headed to serious difficulties
whenever the Sonogashira coupling was employed (vide supra).
It was addressed in different ways with (i) the use of special-
ized palladium catalytic protocols and (ii) differently functio-
nalized organometallic coupling reagents (Scheme 1).3a,b,e,g
With this background, a pooled approach was conceived to
bring out a viable strategy as outlined in Scheme 2. The tar-
geted benzofuran-based natural products (1–8) were divided
into two different groups (1–4) and (5–8) to envisage a pooled
synthetic strategy using resorcinol (9) as a common starting
material. The overall process involves the desired functionali-
zations in the preparation of substituted 2-(2,2-dibromovinyl)-
phenols, followed by domino coupling with an appropriate
triarylbismuth reagent to generate the benzofuran core.
As is well established, triarylbismuth reagents were chosen
as organometallic coupling partners as these reagents provide
threefold atom-economical coupling in a one-pot operation
with sub-stoichiometric loading of the bismuth reagent.5
The success of the proposed strategy heavily depends on
the relative stability and reactivity of the 4-(2,2-dibromovinyl)
benzene-1,3-diol (12a) in domino couplings in the preparation
of the first set of benzofuran products (1–4). Similarly, the
stability and reactivity of the related 6-(2,2-dibromovinyl)-2,2-
dimethylchroman-7-ol (22) is also crucial in the development
of a concise synthetic strategy for the second set of benzofuran
products (5–8). In fact, this adventure strenuously allowed us
to develop a synthetically advantageous pooled approach for
the preparation of benzofuran-based natural products (1–8)
with careful manoeuvring of the functional group and these
efforts are described below.
Scheme 1 Application of Sonogashira coupling in synthesis.
[(b), Scheme 1]3b without isolation. This poor reactivity was
attributed to the most probable instability of the Sonogashira
coupled acetylenic intermediates. To circumvent this, another
approach involving the formation of styrene derivatives through
the Wittig reaction was adopted in the synthesis of cicerfuran
(2).3b Furthermore, Duan et al. in 2007 reported a two-step
sequence using the McMurry cross-coupling of a substituted
salicylaldehyde and an aromatic aldehyde followed by oxidative
cyclization to obtain a benzofuran core.3c Furthermore, Jiang
et al. showed a one-pot method with propargyl substrates in
combination with aryl bromide and 4-bromoresorcinol invol-
ving a double Sonogashira reaction for the synthesis of cicer-
furan [Scheme 1, (c)].3d A few other methods have been reported
in the literature utilizing Suzuki3e and Wittig3f reactions as key
transformations in the preparation of cicerfuran (2).
Further difficulty in the application of the Sonogashira
reaction was also encountered by Jun et al. in the synthesis
of moracin M [Scheme 1 (d)].3g It was carried out initially
by the Sonogashira coupling of acetylated 4-bromoresorcinol
and an aryl alkyne followed by base mediated cyclization. As
this reaction was dictated by electronic constraints, ligand
P(tBu)3-HBF4 was employed for the Sonogashira coupling of
either 4-bromoresorcinol or its acetyl derivative under palla-
dium conditions. A few other methods have also been reported
for the synthesis of moracin M (1).3h–o
This enumeration of the literature approaches clearly high-
lighted the associated difficulties in the synthesis of benzo-
furan-based natural products. This motivated us to explore the
possibility for new avenues taking a cue from our experience in
the development of a concise synthetic strategy for 2,5-di-
substituted benzofuran scaffolds (Fig. 2)4a and its application
in the synthesis of ailanthoidol (A), egonol (B), homoegonol
(C), demethoxyegonol (D) and demethoxyhomoegonol (E).
This led us to plan for a pooled approach for the prepa-
ration of the present set of benzofuran-based natural products Fig. 3 Strategy for 2-arylbenzofurans with 6 or 5,6-disubstitutions.
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Hence, the protection of the phenol group with benzyl and/or
acetyl groups was invoked to obtain thermally stable gem-
dibromide suitable for the domino cyclization/coupling proto-
col. For this, 2,4-dihydroxybenzaldehyde (10) was selectively
benzylated (11b) and converted to the corresponding mono-
benzylated gem-dibromide (12b). This benzyl protection gave
stability as we could obtain a pure product through routine
purification procedures. Furthermore, the acetyl derivative (11)
and its conversion to dibromide also gave stable monoacety-
lated gem-dibromide (12c). Furthermore, we have also prepared
bis-protected stable gem-dibromides with an acetyl and benzyl
combination (12ba and 12ca). This preparation of mono and
bis-protected gem-dibromides was primarily to check their suit-
ability to generate the benzofuran core under domino coupling
conditions in a one-pot operation.
In addition, triarylbismuth reagents (TAB-1, TAB-2 and
TAB-3) required to carry out domino cross-coupling studies
were prepared using literature procedures as given in
Scheme 4 and these bismuth reagents were obtained in high
yields.4a,c
Scheme 2 A pooled synthetic strategy for benzofuran-based natural
products (1–8).
With the availability of various gem-dibromides and triaryl-
bismuth reagents in hand, it was time to establish the standar-
dized conditions involving the domino cyclization/coupling
reaction. To check the compatibility of gem-dibromides for this
purpose, a two-step procedure was followed initially for the
preparation of benzofurans. The benzyl protected gem-dibro-
mide (12b) was subjected to copper-catalyzed cyclization6d and
this afforded 2-bromobenzofuran 13a in 81% yield (2.1,
Scheme 5). It was then cross-coupled with a triarylbismuth
reagent (TAB-2) under palladium-catalyzed conditions7a to
afford benzofuran 13b in 81% yield. This initial attempt under
two-step conditions gave the desired benzofuran (13b) in 66%
overall yield. Encouraged by this, it was decided to check this
prospect under one-pot domino coupling conditions.
Accordingly, mono- and bis-protected gem-dibromides were
tested under one-pot domino coupling conditions4b with a
bismuth reagent (TAB-2) (2.2, Scheme 5).
Results and discussion
Our strategy was commenced with the readily available resorci-
nol (9) as given in Scheme 3. To start with, it was formylated
using the Vilsmeier–Haack reaction to obtain 2,4-dihydroxy-
benzaldehyde (10)6a and then transformed to the corres-
ponding gem-dibromide (12a) using Ramirez olefination.6b–d
However, this compound 12a was found to be thermally
unstable and decomposed during workup and purification
procedures. The possible reason could be due to the presence
of free phenolic groups in conjunction with gem-dibromide.
A domino test was carried out with monobenzylated gem-
dibromide (12b) under palladium coupling conditions (2.2, i)
and this delivered benzofuran 13b in 5% poor yield. This was
Scheme 3 Synthetic efforts to obtain thermally stable gem-bromides.
Scheme 4 Preparation of triarylbismuth reagents.
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deprotection step, as the domino coupling conditions directly
gave 6-hydrxoybenzofuran (13) in good yield, (iv) the dual role
played by acetyl as a stabilizer and labile protecting group
proved promising. This investigation helped us to realize that
gem-dibromide (12c) is more suitable to carry out domino
coupling to directly generate 6-hydroxybenzofuran (13) in a
one-pot operation. Note that gem-dibromide with a free
hydroxyl (12a) was found to be unstable initially and this with
benzyl protection (12b) although found to be thermally stable,
but failed to provide an efficient domino coupling process. In
such a scenario, the constructive role played by the acetyl
group was very positive and synthetically advantageous.
With successful generation of benzofuran 13, it was directly
treated with BBr3 following the literature procedure3g,h and the
desired moracin M (1) was obtained in 25% yield (Scheme 6).
Being not satisfied, further efforts were made to improve
this step. To fine-tune the reactivity, the free phenolic group
was converted to acetate (13c) and then subjected to demethyl-
ation using BBr3. This procedure gave moracin M (1) in 75%
overall high yield. Our investigation so far assisted us in
finding the right combination of protecting groups, and suc-
cessfully established a domino cyclization/coupling protocol
with gem-dibromide and its application in the synthesis of
moracin M (1). It encouraged us to further extend gem-dibro-
mide (12c) as a key intermediate in the synthesis of the much
studied cicerfuran (2),3a–f a benzofuran-based natural product
Scheme 5 Optimization of the key domino step.
disappointing as monobenzylated gem-dibromide (12b) failed (Scheme 6). However, this required cross-coupling with an
to survive to give the benzofuran product under the conditions ortho substituted sterically congested triarylbismuth reagent
employed. An additional test with doubly protected acetyl and (TAB-3). This reaction was then carried out in the presence of
benzyl derived gem-dibromide (12ba) demonstrated much CuI under palladium coupling conditions7b and cicerfuran (2)
improved reactivity and gave the corresponding benzofuran was obtained in a one-pot operation. It involved firstly the
(13b) in 54% yield (2.2, ii). Most probably, the deactivating domino cyclization/coupling of gem-dibromide (12c) with the
nature of the acetyl group electronically increased the stability bismuth reagent TAB-3 under palladium-catalyzed conditions,
of 12ba and it survived the reaction course to give the benzo- followed by in situ acetyl deprotection in the second step
furan product.
affording cicerfuran (2) in 42% yield.
To further fine-tune the reactivity, monoacetylated gem-
After successfully completing the synthesis of moracin M
dibromide (12c) was tested with acetyl alone as a deactivator, (1) and cicerfuran (2), we then focused on the synthesis of
which may further increase the substrate stability in compari- moracin D (3) and moracin E (4). The 6-hydroxybenzofuran
son with benzyl and acetyl double protection in 12ba. (13) obtained above was protected with the mesyl group using
Amazingly, this gem-dibromide 12c with monoacetyl protection MsCl and this gave the corresponding derivative 14 in 81%
demonstrated much improved reactivity and directly gave the yield (Scheme 7).
deacetylated benzofuran (13) in 64% yield (2.2, iii). The for-
Selective demethylation using BBr3 provided mesyl deriva-
mation of deacetylated benzofuran is notable as in situ acetyl tive 15 exclusively in 94% yield. The treatment of this with a
deprotection underwent smoothly without an additional step masked aldehyde8a (15a) in the presence of 3-picoline under
in a one-pot operation. Furthermore, a curiosity test with bis-
acetylated gem-dibromide (12ca) gave benzofuran (13) in 30%
yield (2.2, iv). From this, it was realized that the outcome
obtained with gem-dibromide 12c is highly useful synthetically
as it directly afforded deacetylated benzofuran 13 in good
yield. In fact, this benzofuran intermediate 13 is a useful
precursor for moracin M (1), moracin C3q and moracin N.3g
Overall, (i) the labile acetyl protection (12c) served in a better
way in comparison with benzyl protection (12b), (ii) mono-
protection with the acetyl group in 12c proved to be the best
choice in comparison with the bis-protected dibromides (12ba,
12ca), (iii) more labile acetyl did not require an additional Scheme 6 Synthesis of moracin M (1) and cicerfuran (2).
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We then continued our efforts towards other set of benzo-
furan-based natural products, morunigrol C (5), 3′,5′-di-O-
methylmorunigrol C (6), gramniphenol G (7) and gramniphe-
nol F (8) as given in Scheme 2. The substrates required for this
were prepared following the known procedures (Scheme 9).
The strategy adopted here involved the initial formation of
chroman-fused salicylaldehyde (20) starting from resorcinol
through a simple and straightforward means in two different
sequential operations. In route A, resorcinol (9) was subjected
to Vilsmeier–Haack formylation6a to obtain compound 10 in
high yield. It was subjected with 2-methyl-3-buten-2-ol in the
presence of BF3·OEt2 (2 equiv.) to directly obtain chroman-
fused salicylaldehyde (20) involving initial prenylation, fol-
lowed by acid-mediated cyclization. This attempt gave the
desired product (20) in 20% yield.8c
Scheme 7 Towards the synthesis of moracin D (3) and moracin E (4).
To improve the yield, in route B, firstly acid mediated
cyclization9 of resorcinol (9) was carried out to obtain the
corresponding chroman-fused derivative 19 in 60% yield. In
fact, the formylation of this under Vilsmeier–Haack or Duff’s
conditions initially gave poor yield. However, the desired for-
mylation underwent smoothly with paraformaldehyde in the
heating conditions gave two isomeric chromene derivatives as
an inseparable mixture (16) in 78% yield. This mixture was
subjected to mesyl deprotection8b under basic conditions,
which gave a mixture (17) of moracin D (3) and moracin E (4)
in 91% yield. At this stage, our attempts to separate this
mixture through column chromatography and other methods
miserably failed. Hence, derivatization with acetyl chloride was
carried out to obtain the corresponding acetates 18a and 18b
(Scheme 8) and this helped us in their separation in 61% and
28% yields, respectively, using silica gel column chromato-
graphy. Furthermore, the deprotection of the acetyl group was
carried out initially under acidic conditions using methanolic
HCl and this gave decomposed products. However, an
additional run under mild basic conditions using aqueous
ammonia in methanol gave moracin D (3) and moracin E (4)
in 92% and 93% yields, respectively (Scheme 8).
These synthetic efforts have so far successfully delivered
moracin M (1), cicerfuran (2), moracin D (3) and moracin E (4)
in a divergent manner from a common gem-dibromide 12c.
Our investigation also gave a few important clues about the
stability of gem-dibromides (12a–c, 12ba and 12ca) and their
suitability in the domino coupling process. In addition,
protection with acetyl group served in a great way to fine-tune
electronic properties and stabilize gem-dibromide substrates.
All these were achieved successfully with a few functional
manoeuvrings, which provided a concise and pooled synthetic
approach in a facile manner.
10
presence of MgCl2/NEt3 and the chroman-fused salicylalde-
hyde 20 was obtained in 55% yield. Thereafter, it was con-
verted to the corresponding gem-dibromide 22 and then sub-
jected to the domino cyclization/coupling protocol with the
bismuth reagent TAB-2. This attempt afforded the chroman-
fused benzofuran 23 in 15% poor yield. The crude product
mixture analysis did not show the presence of unreacted gem-
dibromide (22), indicating the most probable unstable nature
of the substrate which gave poor yield (Scheme 10).
To overcome this problem, it was decided to protect gem-
dibromide with the acetyl group to stabilize the substrate
during the cross-coupling course as the stability accrued in the
presence of acetyl led to high domino coupling yield as men-
tioned above (Scheme 11). The chroman-fused salicylaldehyde
Scheme 9 Synthetic routes for chroman-fused salicylaldehyde 20.
Scheme 8 Separation of moracin D (3) and moracin E (4).
Scheme 10 Coupling of gem-dibromide 22 with bismuth TAB-2.
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Scheme 11 Preparation of acetyl protected gem-dibromide 22a.
Scheme 13 Attempts for the demethylation of compound 6.
(20) was first acetylated (21) in 92% yield and it was converted
to dibromide (22a) in 82% yield following the usual
procedures.
tion of a double bond in the chromene (20a), followed by
acetylation (21a), and its conversion to gem-dibromide (22b)
followed by coupling with the bismuth reagent furnished di-
methylated morunigrol C (6) in overall good yields.
The gem-dibromide 22a was subjected to domino cross-
couplings with bismuth TAB-2 under palladium coupling con-
ditions (Scheme 12). Encouragingly, this reaction with acetyl
protected gem-dibromide (22a) afforded benzofuran 23 in 65%
yield with much improved reactivity. It was dehydrogenated
with DDQ to obtain 3′,5′-di-O-methylmorunigrol C (6) in 90%
yield. The intermediate benzofuran 23 was later demethylated
with BBr3 in DCM to afford intermediate 24 in 85% yield.
Further dehydrogenation with 2 equiv. of DDQ afforded moru-
nigrol C (5) in 30% yield.
To further improve the yield, an alternate pathway was envi-
saged through a diacetate followed by dehydrogenation. In the
first step, compound 24 was acetylated to obtain diacetate 25
in 95% yield and its dehydrogenation using 1 equiv. of DDQ
afforded the acetyl derivative of morunigrol C 26 in 89% yield.
This upon hydrolysis using aqueous ammonia in methanol
afforded morunigrol C (5). Amazingly, this three step pro-
cedure afforded morunigrol C (5) in 76% overall yield.
It is to be mentioned here that an alternative way of intro-
ducing a double bond in an early stage was evidenced to be a
futile exercise. As given in Scheme 13, an early stage introduc-
However, our attempts to demethylate compound 6 follow-
ing literature procedures with either BBr3 or NaSEt11 did not
provide the desired demethylation in a facile manner. This is
in tune with literature observations in the preparation of
compound 5.3e In this sense, our attempt with chroman-fused
benzofuran 23 successfully gave demethylation product 24
with BBr3 in high yield. It was indeed achieved more directly
without protecting group modifications in organometallic
coupling partners.3e Evidently, late stage functionalization
with a double bond adopted in Scheme 12 evolved as the best
synthetic option in this regard.
To achieve other natural products (7 and 8) containing the
2-p-anisyl group, the gem-dibromide 22a was reacted with tri(p-
anisyl)bismuth (TAB-1) under Pd-catalyzed conditions, which
gave the benzofuran intermediate 27 in 70% yield
(Scheme 14). From this, the required gramniphenol G (7) was
readily obtained with direct dehydrogenation using the DDQ
reagent in 93% yield.
This concise strategy allowed the synthesis of gramniphenol
G (7) in a short pathway involving six short steps from resorci-
Scheme 12 Synthesis of morunigrol (5) and 3’,5’-di-O-methyl-
morunigrol (6).
Scheme 14 Synthesis of gramniphenol G (7) and gramniphenol F (8).
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nol (9).3e,p Furthermore, gramniphenol F (8) was prepared
through demethylation, and converted to an acetate derivative
(29) followed by dehydrogenation and hydrolysis. These steps
proceeded very smoothly under the given conditions with high
conversion to provide gramniphenol F (8) in overall high yield.
Note that Jun et al. recently reported the synthesis of benzo-
furan-based natural products (5–8) applying the Suzuki coup-
ling of 2-bromobenzofuran derivatives under Pd-coupling con-
ditions.3e Furthermore, Natu et al. reported the synthesis of
gramniphenol G (7) involving the oxidative cyclization of ortho-
vinylphenol as a key transformation to obtain the corres-
ponding 2-arylbenzofuran.3p However, our pooled and concise
approach elegantly delivered a series of benzofuran-based
natural products, moracin M (1) and cicerfuran (2), and the
first time synthesis of moracin D (3) and moracin E (4) along
with chromene-fused benzofuran-based natural products (5–8).
In terms of the reactivity of two gem-dibromides (12c, 22a)
employed in the coupling process, it was expected that they
involve in different ways to give benzofuran, as illustrated in
Fig. 4. As is known, in the case of A, the presence of a free
hydroxyl group allows base mediated in situ cyclization to give
2-bromobenzofuran followed by cross-coupling with the
bismuth reagent affording 2-arylbenzofuran.4b However, this
possibility need not be the same in the case of B, where free
hydroxyl was protected with the acetyl group. It could involve
vide infra either through the 2-bromobenzofuran/cross-coup-
ling process or the formation of a diarylalkyne intermediate
and its cyclization.
Table 1 Screening with different base amounts
Entry
Cs2CO3
Time (h)
Product 27a (%)
Product 27 (%)
1
2
3
4
9 equiv.
9 equiv.
6 equiv.
6 equiv.
7
4
4
2
0
29
44
69
70
30
20
5
proposed in Scheme 15. The acetyl protected gem-dibromide
(p) undergoes base mediated elimination to give 1-bromoalk-
yne (q). This further involves cross-coupling with the bismuth
reagent involving r and s under palladium coupling conditions
to give a diarylalkyne intermediate (t).12 The base mediated
in situ deprotection of the acetyl group followed by cyclization
was expected to deliver benzofuran (u) in a one-pot domino
process.
Overall, the above synthetic efforts brought out a few impor-
tant aspects to the fore. For example, (i) the functional group
manoeuvring and the dual role of acetyl as a labile protecting
group and a stabilizer for 1,1-dibromide delivered fruitful
domino cross-coupling reactivity, (ii) the route adopted via
acetyl protection for efficient demethylations using BBr3 is
another highlight, (iii) the strategic use of mesyl protection
and selective demethylations applied in the synthesis of
moracin D (3) and moracin E (4) is notable, (iv) the acetyl
derived stability also helped the cross-coupling reactivity of
chroman-fused 1,1-dibromide (22a) under palladium coupling
conditions, (v) acetyl protection also gave facile oxidation
using DDQ to obtain morunigrol C (6) and gramniphenol F
(8), (vi) late stage introduction of a double bond evolved as the
best synthetic option during demethylation using the BBr3
reagent, (vii) the presence of a double bond or a free phenolic
To know this, a few control reactions were conducted with
different amounts of a base under palladium-catalyzed con-
ditions, as summarized in Table 1.
Firstly, the domino coupling reaction carried out with a
base (9 equiv.) for 7 h afforded benzofuran (27) exclusively
(entry 1, Table 1). Further modifications in the conditions with
the amount of base and reaction time gave mixed results. As is
given, the formation of the diarylalkyne 27a gradually
increased with decreasing the base amount and reaction time
(entries 2–4, Table 1). This investigation thus clearly estab-
lished the formation of diarylalkyne as an intermediate during
the reaction course. Based on this, a probable mechanism is
Fig. 4 Pathways for benzofuran formation.
Scheme 15 Domino elimination/coupling/cyclization.
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group was demonstrated to be detrimental during BBr3
mediated demethylations, and (viii) in the formation of
chroman-fused 2-arylbenzofurans (23 and 27), a domino
sequence involving elimination/cross-coupling/deprotection/
cyclization was proposed as a probable pathway.
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Conclusions
The application of the protecting group manoeuvring as a syn-
thetic strategy was demonstrated in conjunction with the
domino coupling process in the synthesis of benzofuran-based
natural products (1–8). The electronic demands of functional
groups and their tuning to derive the desired reactivity were
successfully managed by employing acetyl protected 4-(2,2-
dibromovinyl)benzene-1,3-diol (12a) and 6-(2,2-dibromovinyl)-
2,2-dimethylchroman-7-ol (22) in domino couplings with triar-
ylbismuth reagents. This approach in short paved the way for
the total synthesis of moracin D (3) and moracin E (4) for the
first time along with natural products (1, 2 and 5–8) in good
yields.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We acknowledge the financial support from the Council of
Scientific and Industrial Research (CSIR), New Delhi [02(0091)/
12/EMR-II]. V. N. M. and S. N. acknowledge the research fellow-
ship support of CSIR, New Delhi.
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