Regioselective Access to 3-Ethylideneflavanones via Rhodium(I)-Catalyzed 1,3-Enyne Hydroacylation/Annulation Cascades

Article abstract of DOI:10.1002/adsc.202001565

The highly efficient synthesis of 3-ethylideneflavanones through sequential rhodium(I)-catalyzed hydroacylation of terminal aryl-substituted 1,3-enynes with chelating aldehydes and annulation is described. This straightforward protocol highlights an unprecedented C3-regioselective hydroacylation of 1,3-enynes, excellent functional group compatibility, and complete atom economy. (Figure presented.).

Full text of DOI:10.1002/adsc.202001565

UPDATES
DOI: 10.1002/adsc.202001565
Regioselective Access to 3-Ethylideneflavanones via Rhodium(I)-
Catalyzed 1,3-Enyne Hydroacylation/Annulation Cascades
Zhi-Xin Chang,a Fu-Rong Li,a,* Chengcai Xia,a Fei Li,a and Hong-Shuang Lia,*
a
Institute of Pharmacology, School of Pharmaceutical Sciences, Shandong First Medical University & Shandong Academy of
Medical Sciences, 619 Changcheng Road, Taian 271016, People’s Republic of China
Phone: +86 538 6229755
Fax: +86 538 6229751
E-mail: frli@sdfmu.edu.cn; hsli@sdfmu.edu.cn
Manuscript received: December 17, 2020; Revised manuscript received: January 17, 2021;
Version of record online: Februar 9, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001565
impressive Ru(II)-catalyzed 1,2-anti-Markovnikov for-
mal hydroalkylation of 1,3-enynes with umpolung
Abstract: The highly efficient synthesis of 3-ethyl-
ideneflavanones through sequential rhodium(I)-cata-
carbonyls to deliver the linear products with remark-
lyzed hydroacylation of terminal aryl-substituted
able regioselectivity (Scheme 1a).[4] Several site-selec-
1,3-enynes with chelating aldehydes and annulation
tive carbonyl propargylation reactions from the alde-
is described. This straightforward protocol high-
hyde oxidation level through Ru(II) or Ir(I)-catalyzed
lights an unprecedented C3-regioselective hydro-
transfer hydrogenation were accomplished by the
acylation of 1,3-enynes, excellent functional group
Krische group (Scheme 1b).[5] Meanwhile, a C2-
compatibility, and complete atom economy.
regioselective and enantioselective transformation of
1,3-enynes with aldehydes and bis(pinacolato)diboron
facilitated by a chiral bis-phosphine-Cu complex was
Keywords: Rhodium catalysis; Hydroacylation; 1,3-
Enyne; Regioselective synthesis; 3-Ethylideneflava-
none
documented
by
Hoveyda
and
co-workers
(Scheme 1c).[6] Besides the C1- and C2-regiospecific
transformations described above, a few precedents
detailed the development of C4-regioselective reduc-
tive coupling of 1,3-enynes with aldehyde-containing
The successful implementation of transition-metal- components relying on various Ni(0)[7] and Rh(I)[8]
catalyzed hydroacylation protocols enables synthetic complexes to provide the conjugated dienols
chemists to readily transform a diverse range of (Scheme 1d). It is noteworthy that a comprehensive
unsaturated feedstocks into more elaborated molecular mechanistic pathway involving oxidative cyclization
architectures with ideal and fabulous step-, and atom- was proposed in the case of the rhodium(I)-catalyzed
economy.[1] In terms of the conjugated hydrocarbons coupling reactions.[8] Despite these significant enyne-
encompassing several reactive sites for the hydro- aldehyde reductive coupling advancements, to the best
acylation, such as 1,3-dienes[2] and enynes, controlling of our knowledge, illustrations on achieving C3-
reaction selectivity remains a paramount challenge to regioselective hydrofunctionalization of 1,3-enynes
deliver the desired linear and branched carbonyl with aldehydes have rarely been reported, especially in
compounds. The elegant selection of a transition-metal the hydroacylation arena.
catalyst in combination with an appropriate ligand
Our group has been focusing on the rhodium(I)-
would provide a promising platform for achieving an catalyzed completely atom-economical hydroacylation
exquisitely regioselective catalytic transformation,[3] reactions of unsaturated hydrocarbons for the prepara-
which represents a perpetual pursuit in the field of tion of versatile functionalized ketones and enones.[9]
organometallic chemistry.
In 2018, we disclosed the synthesis of chromanones
In the last two decades, meticulous efforts have through Rh-catalyzed hydroacylation of aryl-substi-
been exerted to the regioselective reductive coupling tuted 1,3-dienes with the salicylaldehyde precursors.[9c]
of 1,3-enynes with simple aldehydes enabled by an However, no remarkable regioselectivity was observed
array of metallic catalytic systems (Scheme 1).[2f] For in this process. Consequently, it would be of great
instance, Li and co-workers very recently developed an significance to elaborate a new catalytic blueprint
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Table 1. Reaction Optimization Studies.[a]
entry deviation from the standard conditions
yield[b,c]
(%)
1
2
3
4
None
86 (2.4:1)
0
0
CoBr2 instead of [Rh(COD)OH]2
Ni(COD)2 instead of [Rh(COD)OH]2
RhH(CO)(PPh3)3 instead of [Rh(COD)
OH]2
35 (2.2:1)
5
6
[Rh(COD)Cl]2 instead of [Rh(COD)OH]2 81 (2.2:1)
[Rh(C2H4)2Cl]2 instead of [Rh(COD)OH]2 77 (2.5:1)
7
Rh(PPh3)3Cl instead of [Rh(COD)OH]2
76 (2.2:1)
8
9
10
Rh(COD)2SbF6 instead of [Rh(COD)OH]2 75 (1.7:1)
Rh(COD)2OTf instead of [Rh(COD)OH]2 79 (2.3:1)
Rh(COD)2BF4 instead of [Rh(COD)OH]2 69 (2.1:1)
11[d] 2.5 mol% of [Rh(COD)OH]2
64 (2.4:1)
Scheme 1. Transition-Metal-Catalyzed Regioselective Hydro-
functionalization of 1,3-Enynes with Aldehydes.
[a] Unless specified otherwise, each reaction was run with 1a
(0.2 mmol, 1.0 equiv.) and 2a (1.5 equiv.) in 1.0 mL of
anhydrous toluene (0.2 M).
based on site-selective transformations of the conju-
gated hydrocarbons. In this context, we speculated that
the coupling reaction of a terminal aryl-substituted 1,3-
enyne with a chelating aldehyde, in the presence of a
suitable organocatalyst, might proceed through an
unusual C3-regioselective hydroacylation/annulation
sequence (Scheme 1e). In view of the fact that the
resulting 3-alkylideneflavanones have gathered consid-
[b] Combined isolated yield of (E)- and (Z)-3aa.
[c] The value in parentheses indicates the ratio of (E)-isomer to
(Z)-isomer.
[d]
The reaction was performed with [Rh(COD)OH]2
(2.5 mol%), PPh3 (10 mol%), and K2CO3 (5 mol%).
erable momentum in the field of medicinal chemistry [Rh(COD)OH]2, PPh3, and K2CO3 in toluene (0.2 M)
(Figure 1),[10] this appealing but challenging regiocon- at 80 C for 24 h under N2 atmosphere, providing the
°
trolled strategy would offer a valuable synthetic trans- annulation product 3aa in 86% yield with a E:Z ratio
formation. Furthermore, in contrast with the conven- of 2.4:1 (Table 1, entry 1).[11] However, the use of
tional methods for the synthesis of 3- different catalysts such as CoBr2 and Ni(COD)2 proved
alkylideneflavanones from 2-hydroxyacetophenones to be completely inefficient (Table 1, entry 2–3).
and
aromatic
aldehydes
involving
tedious Switching [Rh(COD)OH]2 to the rhodium hydride
procedures,[10b,c,d] this one-pot protocol achieved 100% complex gave a relatively low yield of the product
atom-economy efficiency and displayed excellent func- (Table 1, entry 4). It should be mentioned that other
tional group tolerance and remarkable regioselectivity Rh(I) catalysts also afforded 3-ethylideneflavanone in
under mild reaction conditions.
good yields (Table 1, entry 5–9), with the exception of
To investigate the feasibility of such a regioselec- Rh(COD)2BF4, which was found to be slightly inferior
tive transformation, we evaluated the coupling reaction for this regioselective transformation (Table 1, en-
between salicylaldehyde 1a and but-3-en-1-yn-1- try 10). Finally, the product yield was lowered to 64%
ylbenzene 2a under various transition-metal catalysis upon decreasing the rhodium catalyst loading from
(Table 1). Indeed, the optimal results were obtained 5 mol% to 2.5 mol% (Table 1, entry 11).
when the reaction was performed in the presence of
With the optimized catalytic conditions established,
we next investigated the scope of the terminal aryl-
substituted 1,3-enynes for this regioselective reaction
(Scheme 2). Initially, under slightly modified reaction
conditions, the flavanone 3aa could be prepared on a
2 mmol scale in a synthetically useful yield of 66%
(see the Supporting Information). Excellent substitu-
tion pattern compatibility was observed for the one-pot
synthesis of diverse 3-ethylideneflavanones. Although
the substrate bearing an ortho-methyl group delivered
Figure 1. Selected 3-Alkylideneflavanone Molecules with Di-
verse Pharmaceutical Activities.
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the tolerance of other carbonyl functionalities such as
ketone (3am) and ester (3an) potentially allows for
subsequent functionalization. Different electron-with-
drawing groups on the benzene ring of the enynes,
including OCF3 (3ao), CF3 (3ap), and NO2 (3aq),
were not susceptible to the standard reaction condi-
tions. Gratifyingly, when the enyne substituted with a
3-thienyl group was evaluated in the coupling reaction,
the desired flavanone 3ar was isolated in 58% yield,
highlighting the feasibility of this protocol for con-
structing functionalized flavanones. On the other hand,
although 1-methyl- and 1-phenyl-substituted enynes
(2s–2t) as well as the aliphatic enyne with a terminal
phenethyl substituent (2u) could be converted into the
1
target flavanones by H NMR analysis of the crude
mixture, it is difficult to isolate the products due to the
poor regioselectivity.
As depicted in Scheme 3, we turned our attention to
evaluate the generality of salicylaldehydes for the
formation of a variety of 3-ethylideneflavanones.
Substrates bearing electron-donating groups including
methyl (3ba), tert-butyl (3ca), and methoxy (3da) all
gave the anticipated flavanones in good yields. In the
case of salicylaldehyde 1e possessing a diethylamino
group, the sequential hydroacylation and cyclization
reaction proceeded smoothly with an abnormal geo-
metric isomerism observed. Additionally, various halo-
gen substituents, including fluoro (3fa), chloro (3ga–
3ha), bromo (3ia), and iodo (3ja), remained intact in
this cascade reaction, thereby keeping the feasibility
for further derivatization over the CÀ X bonds. The
Scheme 2. Scope with Respect to 1,3-Enynes.
the desired product 3ab in only 47% yield because of
the steric repulsion effect, the enyne derivatives
containing various electron-donating groups, such as
ethyl (3ac), methoxy (3ad), and trimethylsilyl (3ae),
participated in the coupling reactions smoothly to
produce the corresponding ketones in 65–81% yield. 2-
Naphthyl- and biphenyl-substituted enynes could be
employed as suitable reactants to furnish the flava-
nones 3af and 3ag in 72% and 74% yield, respec-
tively. In addition, the substrates substituted with 4-
fluoro (3ah), 3,5-difluoro (3ai), 3-chloro (3aj), and 4-
bromo groups (3ak) were all compatible with the mild
catalytic system, thus isolating the corresponding 3-
ethylideneflavanones in good yields. To our surprise,
this regioselective protocol could be extended to the
substrate bearing an aldehyde group (2l). Meanwhile,
Scheme 3. Scope with Respect to Salicylaldehydes.
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mild rhodium-catalyzed system also tolerated diverse
functional groups, such as ester (3ka), trifluoromethyl
(3la), and nitro (3ma), providing the corresponding
flavanone derivatives in 57–65% yield.
To illuminate the mechanism of the regiospecific
cascade reaction, several control experiments were
performed (Scheme 4). In accordance with our obser-
vation in the transformation of the substrate 2l with an
aldehyde group, benzaldehyde (4) was not amenable
for this coupling reaction (Scheme 4a). When 2-amino-
benzaldehyde (5) was subjected to the standard
reaction conditions, no desired products were detected
either (Scheme 4b). These results highlight the impor-
tance of the phenolic hydroxy group of the salicylalde-
hydes in initiating the coupling reactions. Subse-
quently, mechanistic investigations on the isotopic
labeling experiments, in association with the kinetic
isotope effect (KIE), are described. We found that
approximately 74% deuterium was incorporated into
the 2-position of the flavanone d-3ca determined by
1H NMR analysis (Scheme 4c). Finally, a KIE (kH/kD)
of 2.1 is detected from an intermolecular competition
experiment between 1c and d-1c (Scheme 4d).[12] This
result suggests that β-hydride or reductive elimination
might be involved in the rate-determining step, which
Scheme 5. Plausible Reaction Mechanism.
is consistent with the previously reported Co-catalyzed by Krische,[8] which upon β-hydride elimination gen-
1,3-diene hydroacylation.[2a]
erates intermediate IIa. Subsequent reductive elimina-
On the basis of preliminary experimental evidences tion provides IIIa along with the rhodium catalyst to
as well as the transition-metal-catalyzed coupling complete the catalytic cycle. Note that 6-endo oxo-
reactions of 1,3-enynes[8] and dienes[2a,9c] with simple Michael cyclization onto carbon prevails over 6-exo
aldehydes, a putative mechanistic pathway is proposed cyclization, thus leading to the formation of β,γ-
for the regiospecific synthesis of 3-ethylideneflava- unsaturated ketone IVa. The final double bond isomer-
nones. As shown in Scheme 5, oxidative cyclization ization delivers the more stable flavanone 3aa (Path
between the aldehyde 1a and 1,3-enyne 2a promoted A). Alternatively, if oxidative cyclization between the
by the cationic rhodium catalyst gives rise to a five- two substrates proceeds through the indicated Path B, a
membered rhodiumacyclic intermediate Ia established thermodynamically unstable seven-membered rhodiu-
macycle Ib would have been formed, which can be
further transformed into the product 3aa’. However,
this isomerized ketone was not observed in the
catalytic system. It can be inferred from these results
that the alkyne expresses better reactivity than the
intramolecular alkene moiety under the rhodium(I)-
catalyzed hydroacylation conditions.
In summary, the first rhodium(I)-catalyzed C3-
regioselective hydroacylation of readily available 1,3-
enynes with abundant salicylaldehydes with subse-
quent 6-endo oxo-Michael cyclization for the construc-
tion of a variety of 3-ethylideneflavanones has been
developed. This completely atom-economical protocol
tolerates a broad range of functionalities, providing a
rational platform for further development of the
remarkably site-selective processes involving 1,3-
enynes. Preliminary mechanistic investigations re-
vealed that the hydroacylation of the alkyne moiety is
more favorable than that of the intramolecular alkene.
These findings will enrich the applications of the
transition-metal-catalyzed hydroacylation reactions of
Scheme 4. Mechanistic Studies.
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Chem. Sci. 2012, 3, 2202; f) M. Holmes, L. A. Schwartz,
M. J. Krische, Chem. Rev. 2018, 118, 6026, See also
references cited therein.
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To an oven-dried sealed tube (10 mL) equipped with a stirrer
bar in the glove box (filled with N2) was added [Rh(COD)OH]2
(4.6 mg, 0.01 mmol, 5 mol%), PPh3 (10.5 mg, 0.04 mmol,
20 mol%), K2CO3 (2.8 mg, 0.02 mmol, 10 mol%), salicylalde-
hyde 1a (24.4 mg, 0.2 mmol, 1.0 equiv.), and but-3-en-1-yn-1-
ylbenzene 2a (38.5 mg, 0.3 mmol, 1.5 equiv.). Then anhydrous
toluene (1.0 mL, 0.2 M) was added. The tube was sealed and
removed from the glove box. The resulting mixture was stirred
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°
at room temperature for 15 min, and heated at 80 C for 24 h.
Upon completion, the reaction mixture was cooled to room
temperature and concentrated. The residue was purified by
preparative thin-layer chromatography (n-hexane/EtOAc=
30:1) to afford the desired (E)-3aa and (Z)-3aa.
[6] F. Meng, F. Haeffner, A. H. Hoveyda, J. Am. Chem. Soc.
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Acknowledgements
This work was supported by the Key Research and Development
Program
of
Shandong
Province
(2018GGX109010,
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