Metal-free access to 3-allyl-2-alkoxychromanonesviaphosphine-catalyzed alkoxy allylation of chromones with MBH carbonates and alcohols

Article abstract of DOI:10.1039/d1ob00215e

A metal-free access to 3-allyl-2-alkoxychromanones by PPh₃-catalyzed alkoxy allylation of chromones with MBH carbonates and alcohols is described. This reaction is performed under mild conditions and it shows good functional group tolerance, providing a series of functionalized chromanones in moderate to high yields with excellent diastereoselectivities. Deuterium-labeling experiments to probe a possible mechanism and scale-up reaction were also conducted.

Full text of DOI:10.1039/d1ob00215e

Organic &
Biomolecular Chemistry
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Metal-free access to 3-allyl-2-alkoxychromanones
via phosphine-catalyzed alkoxy allylation of
chromones with MBH carbonates and alcohols†
a,c
Cite this: Org. Biomol. Chem., 2021,
19, 2663
Received 3rd February 2021,
Accepted 2nd March 2021
Ling Meng,a,b Xiaoyong Chang,a Zhenyang Lin *b and Jun (Joelle) Wang
*
DOI: 10.1039/d1ob00215e
rsc.li/obc
A metal-free access to 3-allyl-2-alkoxychromanones by PPh3-cata- side chain is important for the VKER inhibition compound.6
lyzed alkoxy allylation of chromones with MBH carbonates and Thus, it is of great importance to develop a synthetic method
alcohols is described. This reaction is performed under mild con- for this kind of chromanone derivative.
ditions and it shows good functional group tolerance, providing a
Allylic moieties are not only essential substructures in
series of functionalized chromanones in moderate to high yields organic compounds but also versatile functional groups in
with excellent diastereoselectivities. Deuterium-labeling experi- organic synthesis.7 To enrich the diversity of flavonoids, incor-
ments to probe a possible mechanism and scale-up reaction were poration of allylic moieties into chromanones has become one
also conducted.
of the efficient and useful strategies. In 2013, McErlean and
co-workers reported an intramolecular vinylogous Stetter reac-
tion of unsaturated ketones in the presence of triazolium salt
and DBU, providing 3-allylchromanones in 70–88% yields with
84–96% ee.8 In 2015, Jørgensen and co-workers synthesized
branched and linear 3-allylchromans via an asymmetric
γ-allylation of 2-(chroman-4-ylidene)acetaldehyde by combin-
ing organocatalysis and transition-metal catalysis.9 Two years
later, Song and co-workers disclosed an enantioselective proto-
nation of silyl enol ethers catalyzed by Song’s oligoEG catalyst
with CsF as a fluoride source for access to 3-allylic chroma-
nones and thiochromanones.10 Although these elegant
approaches to the synthesis of 3-allychromanones have been
successfully established, the search for metal-free methods
under mild conditions is highly desirable.
Flavonoids are one of the largest and best investigated groups
of plant secondary metabolites, which have shown a broad
spectrum of biological activities.1 Through searching the
library of flavonoids, it was found that the 2-alkoxychroma-
none scaffold which contains an alkoxyl group at the 2-posi-
tion of the basic structure of flavonoid exists in many biologi-
cally active natural products. As shown in Fig. 1, compound I
is obtained from the seeds of Psoralea corylifolia.2
Erigeroflavanone II isolated from E. annuus flowers exhibits
inhibitory activities towards protein glycation and aldose
reductase.3 Compound III has been isolated from the leaves of
Cassia grandis and it shows antioxidant and cytotoxic activi-
ties.4 Apart from naturally occurring products, synthetic com-
pounds also have potential biological applications. For
instance, the synthetic 2-alkoxychromanones IV are potent and
selective inhibitors of human and rat ecto-50-nucleotidase,
alkaline phosphatases (TNAP and IAP) and ectonucleotidases.5
In addition, the natural ferulenol V and the synthetic com-
pounds VI were employed in the investigation of the structure–
activity relationship, showing that the length of the isoprenyl
So far, significant progress has been made in organocata-
lyzed allylic alkylation reaction of MBH carbonates with
aDepartment of Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
bDepartment of Chemistry, The Hong Kong University of Science & Technology,
Clear Water Bay, Kowloon, Hong Kong. E-mail: chzlin@ust.hk
cDepartment of Chemistry, Hong Kong Baptist University, Kowloon TongKowloon,
Hong Kong. E-mail: junwang@hkbu.edu.hk
†Electronic supplementary information (ESI) available. CCDC 2060387. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob00215e
Fig. 1 Examples of biologically active compounds containing 2-alkoxyl
or 3-allylchromanone cores.
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various nucleophiles (Scheme 1).11 The plausible mechanism alkoxy allylation of 3-cyanochromones with MBH carbonates
of the reaction is that a nucleophilic attack of a Lewis base and alcohols, which provides a metal-free access to a series of
(organocatalyst) on MBH carbonate takes place, releasing CO2 3-allyl-2-alkoxychromanones (Scheme 2(c)).
and (tBuO)− anions that undergo hydrogen abstraction of the
We began our investigation by using 3-cyanochromone and
nucleophile. The nucleophilic anion attacks the allylic salt to unsubstituted MBH carbonate as model substrates. In light of
generate a γ-substituted product. Alternatively, the nucleophi- the initial results (see the ESI†), different symmetric phos-
lic anion attacks MBH carbonate via an SN2′ pathway or the phines were tested and the results are shown in Table 1.
allylic salt through an SN2 pathway to give an α-substituted 20 mol% of the commonly used weak nucleophilic PPh3
product. Thus, we expected that the allylic reaction of MBH resulted in the targeted product in 95% yield at room tempera-
carbonates with chromones could provide the corresponding ture (entry 1). When tricyclohexylphosphine and triisopropyl-
3-allyl-2-alkoxychromanone via a nucleophilic attack of the phosphine were used as catalysts, the conversion of the reac-
chromone-based nucleophile formed through a conjugate tion was low and the desired products were obtained in 35%
addition of the chromone with alcohol.
and 18% yields, respectively (entries 2 and 3). This might be
To the best of our knowledge, approaches to the synthesis attributed to the poor leaving ability of these two phosphines,
of 3-allyl-2-alkoxychromanones are rare. In 2007, the albeit with good donating ability. The reaction gave a full con-
Yamamoto group reported a palladium catalyzed three-com- version but only 12% yield of the desired product in the pres-
ponent coupling reaction of chromones, allylic acetates and ence of DPPE, accompanying an unrecognized by-product gen-
alcohols, generating a series of 3-allyl-2-alkoxychromanones in erated in the reaction (entry 4). Monophosphine XPhos furn-
51–99% yields (Scheme 2(a)).12 In 2012, Plietker and co- ished the product in 78% yield while bisphosphine rac-
workers reported a regioselective alkoxy allylation of activated BIPHEP showed lower reactivity with 51% yield (entries 5 and
olefins in the presence of an iron complex.13 6). Notably, all the catalysts provided high diastereoselectivities
3-Cyanochromone was also used as a substrate and the corres- (>20 : 1). Thus, PPh3 was identified as the best catalyst (entry
ponding product was obtained in 51% yield with no selectivity 1). Next examinations of catalyst loading and reaction tempera-
(Scheme 2(b)). These reported methods for the synthesis of ture were performed. When the reaction was carried out at
3-allyl-2-alkoxychromanones are limited to transition metal room temperature, lowering the catalyst loading led to incom-
catalysis, and organocatalysis has not been well developed. plete conversions, hence the observation of decreased yields
With the continuing work of our group in the synthesis of fla- from 95% to 64% (entry 1 and entries 7 and 8). In contrast, an
vonoids,14 we decided to investigate a phosphine-catalyzed increase in reactivity from 74% to 98% was observed when the
reactions were performed with the catalyst loading varying
from 20 mol% to 5 mol% (entries 9–11), accompanied by the
formation of an undetermined byproduct. Further decreasing
the catalyst loading led to lower yields of the products which
Table 1 Optimization of the reaction conditionsa
Scheme 1 Allylic alkylations of MBH carbonates with nucleophiles and
the proposed mechanism.
Entry
Catalyst
Cat. loading
Temp.
Yieldb
1
2
3
4
5
6
7
8
PPh3
PCy3
P(iPr)3
DPPE
XPhos
BIPHEP
PPh3
PPh3
PPh3
PPh3
PPh3
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
10 mol%
5 mol%
20 mol%
10 mol%
5 mol%
2.5 mol%
1 mol%
rt
rt
rt
rt
rt
rt
rt
rt
50
50
50
50
50
95
35
18
12
78
51
89
64
74
82
98
91
90
9
10
11
12
13
PPh3
PPh3
a Unless otherwise specified, all the reactions were carried out with 1a
(0.2 mmol) and 2a (0.3 mmol) in methanol (2.0 mL) in the presence of
a catalyst at a specific temperature for 12–24 h. The diastereomeric
ratio (dr) was determined by crude 1H NMR spectroscopy. All the
examples were with >20 : 1 dr. b Isolated yield.
Scheme 2 Synthesis of 3-allyl-2-alkoxychromanones.
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may be because the reduced catalyst loadings cannot promote ished 4laa in 89% yield. 3-Ester substituted chromone also
the reaction as effectively as that with 5 mol% catalyst (entries worked well to give the desired product 4maa in 82% yield.
12 and 13). Finally, we chose the reaction conditions shown in Chromone without a cyano group at the 3-position showed no
entry 11 as the optimized conditions for further evaluation. reactivity under the current catalytic system (4naa). To our
The enantioselective version of the reaction was also investi- delight, all the examples gave high diastereoselectivities
gated. Various chiral organocatalysts including bifunctional (>20 : 1). Besides, the relative configuration of the major dia-
phosphines and cinchonidine-derived catalysts were employed stereoisomer was unambiguously determined by single crystal
in the reactions of 3-cyanochromones, unsubstituted MBH car- X-ray diffraction of the product 4kaa (CCDC 2060387†),15 and
bonates and methanol as solvent. Disappointingly, no or only the two newly formed bonds were found to be trans to each
trace enantioselectivity was observed (Scheme S1(a)†).
other.
Next, we tested the scope of MBH carbonates under the
With the optimized reaction conditions in hand, the sub-
strate scope of 3-cyanochromones was then explored to evalu- standard reaction conditions (Scheme 4). When MBH carbon-
ate the efficiency of the catalytic system (Scheme 3). Generally, ates bearing different ester groups (CO2Me, CO2Et, CO2Bn, and
3-cyanochromones containing electron-donating groups pro- CO2tBu) were employed as substrates, the corresponding chro-
vided higher reactivities than those bearing electron-withdraw- manones (4aaa–da) were furnished in good to excellent yields
ing groups (4baa–caa (94–95% yields) vs. 4daa-faa (82–89% (90–98%). The bulky group (CO2tBu) slightly decreased the
yields)). 3-Cyanochromone incorporated with a strong elec- reactivity of the reaction. The reactions can take place success-
tron-withdrawing group (–NO2) showed decreased reactivity, fully in the solvents ethanol, isopropanol and butanol, provid-
and the targeted product 4gaa was obtained in only 61% yield. ing the targeted products in 87–95% yields (4abb–d). We also
The reaction could also proceed smoothly when there is an examined the phenyl substituted MBH carbonate. The
unprotected hydroxyl group at the 6-position of 3-cyanochro- α-regioselective product was obtained as a major product with
mone, generating the product 4haa in 80% yield. The position 1 : 4 diastereoselectivity (Scheme S1(b)†). Other Brønsted acids,
of the substituent on the benzene ring of 3-cyanochromone such as phenol, thiophenol, phenylmethanol, phenylacetylene
has no significant impact on the reactivity of the reaction, and and acetic acid, also have been tested. However, no desired
the corresponding chromanones were generated in 86–96% product was obtained, and only the [3 + 2] cycloaddition pro-
yields (4iaa–kaa). Naphthalene-containing chromone furn- ducts were observed. Besides, a gram-scale reaction was per-
formed in the presence of 5 mol% PPh3. The 3-cyanochromone
1a (685 mg, 4 mmol) reacted with the MBH carbonate 2b
(1.38 g, 6 mmol) in methanol, providing the targeted product
4aba in 91% yield (1.14 g) with >20 : 1 diastereoselectivity after
12 hours. No significant loss in the yield and diastereomeric
ratio was observed when compared with 0.2 mmol scale reac-
tion (Scheme 4).
To gain insight into the mechanism, deuterium-labeling
experiments were carried out (Scheme 5). As shown in
Scheme 5(a), the 3-allyl-2-methoxychromanone 4aba was
dissolved in the solvent tetradeuteromethanol. No isotopic
Scheme 3 Scope of 3-cyanochromones. Reactions were carried out
with 1b–n (0.2 mmol) and 2a (0.3 mmol) with 5 mol% PPh3 in methanol
Scheme 4 Scope of MBH carbonates and alcohols. Reactions were
carried out with 1a (0.2 mmol) and 2a–d (0.3 mmol) with 5 mol% PPh3
in alcohol 3a–d (2.0 mL) at 50 °C for 12–36 h. The dr was determined by
crude 1H NMR spectroscopy. All examples were with >20 : 1 dr. Isolated
yields were provided.
°
(2.0 mL) at 50 C for 12–36 h. The dr was determined by crude 1H NMR
spectroscopy. All examples were with >20 : 1 dr. Isolated yields were
provided.
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carbonates was proposed as shown in Scheme 6. The reaction
is initiated by the formation of the phosphonium 9. Then, the
released (tBuO)− anion abstracts a proton from alcohol, gener-
ating an alkoxy anion that undergoes conjugate addition to
3-cyanochromone 1a to form the nucleophilic species 10.
Finally, an SN2′ nucleophilic addition of 3-cyano-2-methoxy-4-
oxochroman-3-ide 10 to the phosphonium 9 takes place,
releasing the final product 4aba′ and regenerating the catalyst.
Conclusions
In summary, phosphine-catalyzed alkoxy allylation of 3-cyano-
chromones with MBH carbonates and alcohols has been devel-
oped under mild reaction conditions, providing a metal-free
access to various 3-allyl-2-alkoxychromanones in good to high
yields with excellent diastereoselectivity. The deuterium experi-
ments demonstrate that the reaction takes place via an SN2′
nucleophilic addition of the formed 3-cyano-2-methoxy-4-oxo-
chroman-3-ide to phosphonium rather than an SN2 nucleophi-
lic addition to phosphonium or an SN2′ nucleophilic addition
to MBH carbonate. Other catalytic asymmetric transformations
of chromones and MBH carbonates are currently underway in
our laboratory.
Scheme 5 Deuterium-labeling experiments.
exchange was observed, indicating that the final product has
no active hydrogen that can conduct the hydrogen exchange
process. When methanol-d4 was used as solvent, the hydro-
gens on the double bond of the allylic moiety of the product
were deuterated, which shows that hydrogen exchange occurs
between alcohol and phosphonium 5 (Scheme 5(b)). The phos-
phonium 5 can be deprotonated by tert-butoxy or methoxy
anions, and the resulting phosphorus ylide 6 is protonated
quickly by methanol-d4 to form the species 7. On the other
hand, the nucleophilic attack of the methoxy anion on 3-cyano-
chromone 1a is much faster than that of the phosphorus ylide
6. Thus, the 3-allyl-2-methoxychromanone 4aaa′ is the major
product observed in the reaction. Finally, we synthesized and
employed the deuterated MBH carbonate 8 in the alkoxy allyla-
tion (Scheme 5(c)). The deuterium only appeared in the
methylene group of the product 4aba′, and the product 4aba″
was not observed, suggesting that the nucleophilic addition of
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge Shenzhen Overseas High-level
Talents Innovation Plan of Technical Innovation Project
(KQJSCX20180319114439973) for financial support.
3-cyano-2-methoxy-4-oxochroman-3-ide
to
phosphonium
Notes and references
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possibility of nucleophilic addition of 3-cyano-2-methoxy-4-
oxochroman-3-ide to MBH carbonate to form the product can
also be excluded.
On the basis of the above experimental results, a mecha-
nism for the alkoxy allylation of 3-cyanochromones with MBH
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