Regio- And diastereoselective synthesis of: Trans -3,4-diaryldihydrocoumarins via metal-free [4+2] annulation of ynamides with o -hydroxybenzyl alcohols

Article abstract of DOI:10.1039/d1cc00687h

An efficient regio- and diastereoselective method for the construction of valuable trans-3,4-diaryldihydrocoumarins via metal-free [4+2] annulation of ynamides with o-hydroxybenzyl alcohols has been developed. Ynamides are first treated as 2-π partners to react with o-hydroxybenzyl alcohols via traceless sulfonamide directing groups, affording trans-3,4-diaryldihydrocoumarins in good yields with high regio- and diastereoselectivities. This metal-free methodology is also characterized by a wide substrate scope, good functional group tolerance, and efficiency on a gram scale.

Full text of DOI:10.1039/d1cc00687h

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Regio- and diastereoselective synthesis of
trans-3,4-diaryldihydrocoumarins via
metal-free [4+2] annulation of ynamides
with o-hydroxybenzyl alcohols†
b
Cite this: DOI: 10.1039/d1cc00687h
Received 5th February 2021,
Accepted 12th April 2021
Wen-Feng Luo,a Long-Wu Ye,
Long Li *a and Peng-Cheng Qian*a
DOI: 10.1039/d1cc00687h
rsc.li/chemcomm
An efficient regio- and diastereoselective method for the construction
of valuable trans-3,4-diaryldihydrocoumarins via metal-free [4+2]
annulation of ynamides with o-hydroxybenzyl alcohols has been
developed. Ynamides are first treated as 2–p partners to react with
o-hydroxybenzyl alcohols via traceless sulfonamide directing groups,
affording trans-3,4-diaryldihydrocoumarins in good yields with high
regio- and diastereoselectivities. This metal-free methodology is also
characterized by a wide substrate scope, good functional group
tolerance, and efficiency on a gram scale.
Fig. 1 Selected trans-3,4-diaryldihydrocoumarin derivatives in bioactive
and natural products.
Heterocyclic structural skeletons containing coumarins and
their derivatives widely exist in a series of natural products and
pharmaceuticals.1 In particular, trans-3,4-diaryldihydrocoumarin
derivatives have received much attention because of their promising
anti-breast cancer and anti-osteogen biological activities (Fig. 1).2
However, successful examples of straightforward synthesis of these
valuable O-heterocycles remain scarce.2g,h Thus, it is highly desirable
to develop novel synthetic strategies to construct trans-3,4-
diaryldihydrocoumarin skeletons in a flexible, efficient, and
good diastereoselective fashion.
Ortho-quinone methides (o-QMs), which are generated in situ
from the corresponding o-hydroxybenzyl alcohols by organo-
catalysts or transition-metal catalysts, have been proven as
powerful intermediates for the efficient synthesis of various
valuable functionalized heterocycles, especially O-heterocycles
through a diverse range of formal [4+2] annulations in the past
few decades.3,4 Among them, catalytic [4+2] annulations of
ortho-quinone methides (o-QMs) with carbonyl compounds have
shown unique advantages for constructing diarylcoumarin
motifs (Scheme 1a).5 These significant processes have been
achieved; however, most of the intermolecular formal [4+2]
annulations have so far been limited to cis-3,4-diaryldihydro-
coumarin frameworks, and important trans-products were rarely
reported.5b,c In addition, alkynes employed as two-carbon synthons
with o-QMs for the preparation of 3,4-diaryldihydrocoumarins
have not been explored.6
Owing to their unique reactivity and regioselectivity, ynamides,
which are special alkynes directly connected with N-atoms, have
attracted much attention in the past decade.7,8 Ynamides have
been regarded as versatile building blocks to react with diverse
bifunctional starting materials containing both nucleophilic and
a Institute of New Materials & Industry Technology, College of Chemistry &
Materials Engineering, Wenzhou University, Wenzhou 325035, China.
E-mail: qpc@wzu.edu.cn, longwzu1990@wzu.edu.cn
b State Key Laboratory of Physical Chemistry of Solid Surfaces and Key Laboratory
for Chemical Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China
Scheme 1 Catalytic [4+2] annulations for the synthesis of 3,4-diaryldihydro-
coumarins involving o-QMs.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1cc00687h
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Table 1 Brønsted acid-catalyzed formal [4+2] annulation of different
ynamides 1 with o-hydroxybenzyl alcohols 2aa
electrophilic moieties, providing a concise and flexible approach
to construct various valuable functionalized heterocycles, which
contained core scaffolds in many natural products and drugs.9
Inspired by the above-mentioned results, for the synthesis of
heterocycles, we envisioned that ynamides might be treated as
bifunctional 2–p partners to undergo catalytic tandem intermole-
cular formal [4+2] annulation/hydration with o-hydroxybenzyl
alcohols via traceless directing groups, rendering the formation
of 3,4-diaryldihydrocoumarins. Interestingly, after the treatment
with Cs2CO3, the annulation products were smoothly isomerized
into important trans-3,4-diaryldihydrocoumarins, which have been
found in an array of bioactive molecules and natural products
(Scheme 1b). Herein, we reported a novel Brønsted acid-catalyzed
formal [4+2] annulation of ynamides with o-hydroxybenzyl
alcohols, which allows a highly regioselective and diastereose-
lective synthesis of trans-3,4-diaryldihydrocoumarins. Notably,
ynamides were first treated as bifunctional 2–p partners with
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), HNTf2 (0.04 mmol),
ortho-quinone methides (o-QMs) to prepare useful trans-3,4- DCE (4 mL), 80 1C, 20 min, in vials; then, Cs2CO3 (1.5 equiv.), r.t., 3 h;
isolated yields and diastereoselectivities are reported.
diaryldihydrocoumarins, compared with well-established various
carbonyl compounds. Importantly, sulfonamide groups acted as
traceless directing groups resulting in different regioselectivities of trans-3,4-diaryldihydrocoumarins 3 in mostly good to excellent
ynamides in this metal-free [4+2] annulation, compared with AlCl3- yields with high regio- and diastereoselectivities, as shown in
catalyzed annulation by Chang.6e In addition, this metal-free Table 1. Diverse substituted groups, for example, electron-
methodology was also characterized by a wide substrate scope, donating groups such as Me and MeO (Table 1, entries 2, 3, 7
good functional group tolerance and efficiency on a gram scale.
and 8) or electron-withdrawing groups such as F, Cl, and Br
In order to test our initial design, ynamide 1a and o-hydroxy- (Table 1, entries 4–6 and 9–11) on the para- or meta-position of
benzyl alcohol 2a were employed as the model substrates and the aromatic ring, were suitable for this metal-free system
some screening results are summarized in Table S1 (ESI†).11 to smoothly deliver the corresponding trans-3,4-diaryldihydro-
Various non-noble metal catalysts were first examined includ- coumarins 3a–3k in 70–86% yields with 5 : 1–12 : 1 dr values.
ing AlCl3, Cu(OTf)2, Zn(OTf)2, Sc(OTf)3 and Fe(OTf)3 in the Interestingly, the ynamide 1l bearing a steric o-position methyl
presence of DCE as the solvent and 5 equiv. H2O as the additive group also proceeded well in this [4+2] annulation, affording the
(Table S1, ESI†, entries 1–5). Although the diastereoselectivities expected products 3l in 81% yield with 7 : 1 diastereoselectivity
were poor, most of the Lewis acid catalysts showed good catalytic (Table 1, entry 12). In addition, the effects of p–p conjugation of
reactivity for this formal [4+2] annulation, giving the regioselective the benzene and naphthalene rings might result in cis-3,4-
annulation product in 40–72% yields without the formation of diaryldihydrocoumarin 3m in 93% yield with excellent diastereo-
Chang’s product.6e Meanwhile, various typical Brønsted acid selectivity after the treatment with Cs2CO3 (Table 1, entry 13).
catalysts were investigated for this cascade reaction covering Notably, ynamides were first employed as 2–p partners in the
TsOH, MsOH, HOTf, and HNTf2 (Table S1, ESI†, entries 6–9). formation of 3,4-diaryldihydrocoumarins with ortho-quinone
Surprisingly, the expected annulation product could be obtained methides (o-QMs) via traceless directing sulfonamide groups.
in 90% yield using the strong Brønsted acid HNTf2 as the More importantly, no AlCl3-catalyzed annulation product was
catalyst.6b,10 In addition, the solvent, temperature and amount obtained in all examples.6e
of catalyst were screened, but the yield and diastereoselectivity
Then, an array of different o-hydroxybenzyl alcohols 2 were
could not be improved (Table S1, ESI†, entries 10–13). Further- also evaluated, as outlined in Table 2. A variety of o-hydroxy-
more, an array of different bases were evaluated to increase the benzyl alcohols 2 containing both electron-withdrawing and
diastereoselectivity of the annulation product (see the ESI† for electron-donating groups on the Ar2 at the para, meta, or steric
details).11 Gratifyingly, after the treatment with Cs2CO3, the o-position successfully underwent tandem intermolecular [4+2]
thermodynamically stable trans-3,4-diaryldihydrocoumarin 3a annulation/hydration under mild conditions, delivering the
was achieved in 86% isolated yield with 9: 1 diastereoselectivity desired trans-3,4-diaryldihydrocoumarins 3n–3t in 60–74%
(Table S1, ESI†, entry 14).12 It needs to be emphasized again that yields with 7 : 1–12 : 1 dr values (Table 2, entries 1–7). Finally,
the AlCl3-catalyzed regioselective annulation product was not the expected regio- and diastereoselective trans-3,4-diaryldi-
observed in this metal-free tandem reaction.6e
hydrocoumarins 3u–3w substituted with different groups such as
With the optimal reaction conditions in hand, we then Br, Me, and OMe were achieved in 63–78% yields with 6 : 1–7 : 1 dr
explored the scope of this metal-free [4+2] annulation of ynamides values, revealing that the electronic nature of substituents on the
1 with o-hydroxybenzyl alcohols 2a. First of all, a series of diverse phenyl ring had little effect on the yields and diastereoselectivities
ynamides 1 were investigated, and this tandem reaction showed (Table 2, entries 8–10). The cis-product 3x was also observed in
excellent functional group tolerance, leading to the desired 45% yield with 420 : 1 dr, probably because of the effect of p–p
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Table 2 Brønsted acid-catalyzed formal [4+2] annulation of ynamides 1a
with different o-hydroxybenzyl alcohols 2a
Scheme 3 Mechanism studies.
a N2 atmosphere without water, and isolated the annulation
product 3aa in 75% yield. Importantly, further hydration and
isomerization of 3aa could afford the expected product 3a by
treating with water and base, strongly supporting the notion
that 3aa was the key intermediate of this cascade reaction
(Scheme S1, ESI†, eqn (a)).9d,e In addition, 3ab, which was the
hydration product of ynamide 1a, was employed to react with 2a
under standard conditions, and no desired 3a was observed,
thus ruling out the enolate-type pathway (Scheme S1, ESI†, eqn
(b)).10 On the basis of the above-mentioned experimental observa-
tions, a plausible mechanism to rationalize this metal-free annula-
tion in the formation of trans-3,4-diarylcoumarins 3 is proposed
(Scheme 3). Initially, the Brønsted acid could smoothly activate the
o-hydroxybenzyl alcohols 2 to generate o-QM intermediates A,
releasing one molecular water. Then, intermolecular ynamides
1, serving as nucleophiles, rapidly attacked the o-QM intermedi-
ates A to deliver B via the intermolecular Michael addition, which
underwent another addition to keteniminiums, affording the [4+2]
annulation products C. Subsequently, the hydration of C afforded
the benzolactone frameworks D,9d,e along with the generation of
sulfonamide groups. Finally, the thermodynamically stable trans-
3,4-diarylcoumarins 3 could be achieved via enolization isomeriza-
tion in the presence of Cs2CO3.12
In summary, we have developed a novel Brønsted acid-catalyzed
formal [4+2] annulation reaction of ynamides with o-hydroxybenzyl
alcohols. This metal-free method provides a facile and practical
avenue to efficiently construct valuable trans-3,4-diaryldihydro-
coumarins in good to excellent yields with good regio- and
diastereoselectivities under mild reaction conditions. This tandem
reaction also shows a wide substrate scope, and excellent
functional group tolerance and efficiency on a gram scale.
Notably, ynamides are first treated as 2–p partners for direct
formal [4+2] annulation with o-hydroxybenzyl alcohols via trace-
less directing groups to the best of authors’ knowledge, which
not only significantly enriches the chemistry of o-QMs, but also
promotes further development of ynamides chemistry. Further
explorations into the synthetic applications of this metal-free
protocol are in progress in our lab.
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), HNTf2 (0.04 mmol),
DCE (4 mL), 80 1C, 20 min, in vials; then, Cs2CO3 (1.5 equiv.), r.t., 3 h;
isolated yields and diastereoselectivies are reported.
conjugation (Table 2, entry 11). The o-hydroxymethyl alcohol 2l
could successfully react with 1a and 1m, giving the corresponding
trans-products 3y and 3z in moderate yields with good diastereo-
selectivities (Table 2, entries 12 and 13).
To further examine the applicability of this metal-free [4+2]
annulation, a gram-scale reaction of ynamide 1a with o-hydroxy-
benzyl alcohol 2a was carried out under standard reaction
conditions, and 1.29 g of the desired trans-3,4-diaryldihydro-
coumarin 3a was readily obtained in 86% yield with 9 : 1
diastereoselectivity, as illustrated in Scheme 2. With 3a in hand,
the subsequent chemical transformations were explored. First, 4a
containing the core skeleton of coumarins could be successfully
achieved in 60% yield via oxidation using DDQ.1 In addition, the
3a could be smoothly converted into the valuable O-heterocycle 4b
in 94% yield with good diastereoselectivity by reduction/intra-
molecular Mitsunobu reaction, which was found in a series of
natural products and pharmaceuticals.2
To understand the reaction mechanism, several control
experiments were carried out (Scheme S1, ESI†). We first
performed this metal-free [4+2] annulation in dry DEC under
The authors are grateful for financial support from the National
Natural Science Foundation of China (No. 21828102) and the Foun-
dation of Wenzhou Science & Technology Bureau (No. ZY2020027).
Conflicts of interest
Scheme 2 Gram-scale synthesis and further transformations of 3a.
There are no conflicts to declare.
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