Substituent-Controlled Divergent Cascade Cycloaddition Reactions of Chalcones and Arylalkynols: Access to Spiroketals and Oxa-Bridged Fused Heterocycles

Article abstract of DOI:10.1002/adsc.202100523

Herein, we report substituent-controlled divergent cascade cycloaddition reactions of chalcones and arylalkynols in the presence of PtI₂. Depending on the substituent on the chalcone, either spiroketals or oxa-bridged fused heterocycles could be obtained in the ranges of 86–97% and 87–95% yields under identical reaction conditions. Control experiments were carried out to elucidate the origin of the high chemoselectivity. These provide a method for the synthesis of a diverse array of structurally complex oxygen-containing heterocycles. (Figure presented.).

Full text of DOI:10.1002/adsc.202100523

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100523
Substituent-Controlled Divergent Cascade Cycloaddition
Reactions of Chalcones and Arylalkynols: Access to Spiroketals
and Oxa-Bridged Fused Heterocycles
Tianlong Zeng,a Jingyang Kong,a Hongkai Wang,a Lingyan Liu,a,*
Weixing Chang,a and Jing Lia, b,*
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071,
People’s Republic of China
E-mail: liulingyan@nankai.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Weijin Road 94#, Nankai District, Tianjin,
b
300071, People’s Republic of China
E-mail: lijing@nankai.edu.cn
Manuscript received: April 30, 2021; Revised manuscript received: May 24, 2021;
Version of record online: ■■■, ■■■■
Dedicated to the 100th anniversary of Chemistry at Nankai University
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100523
Abstract: Herein, we report substituent-controlled divergent cascade cycloaddition reactions of chalcones and
arylalkynols in the presence of PtI2. Depending on the substituent on the chalcone, either spiroketals or oxa-
bridged fused heterocycles could be obtained in the ranges of 86–97% and 87–95% yields under identical
reaction conditions. Control experiments were carried out to elucidate the origin of the high chemoselectivity.
These provide a method for the synthesis of a diverse array of structurally complex oxygen-containing
heterocycles.
Keywords: Chalcones; Arylalkynols; Cascade cycloaddition reaction; Spiroketals; Oxa-bridged fused hetero-
cycles
Introduction
Spiroketals and oxa-bridged heterocycles are present in
many natural products and synthetic pharmaceuticals
(Figure 1).[1] For example, paeciloketal A, which was
isolated from the jellyfish Nemopilema nomurai and
displays antibacterial activity against the marine
pathogen Vibrio ichthyoenteri, has a spiroketal struc-
ture, as does eleganketal A, which has antiviral activity
against H1 N1. Representative oxa-bridged heterocy-
clic compounds include laurenditerpenol, which inhib-
its tumor cell survival under hypoxic conditions, and
Figure 1. Compounds with spirocyclic and oxa-bridged hetero-
cyclic skeletons.
commiphoroid A, which inhibits adipocyte prolifera-
tion and differentiation. Because of the ubiquity of
these scaffolds, methods for their construction have
attracted considerable attention from the organic syn-
thesis community.[2] Arylalkynols 1, bifunctional com- used for this purpose. These compounds act as
pounds bearing hydroxy and alkynyl groups, have been precursors for benzoisofurans, which are formed in situ
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by means of intramolecular 5-exo-dig hydroalkoxyla- arylalkynols 1.[4a] As part of our ongoing work in this
tive cyclization reactions (Scheme 1). Benzoisofuran area, we have been exploring the use of linear α,β-
intermediates Int1, which have an exocyclic double unsaturated ketones, which are relatively inert and
bond, can act as electron-rich alkenes (C2 synthons) flexible, as oxaza-four-atom synthons in reactions with
and undergo [2+n] cycloaddition reactions with a 1. In the process, we unexpectedly discovered that we
synthon containing n atoms to form spirocycles. In could obtain a diverse array of spiroketals and oxa-
addition, Int1 can isomerize to Int2, C4 synthons that bridged heterocycles in high yields by means of
can undergo [4+n] cycloaddition reactions to form substituent-controlled divergent cycloadditions of ary-
oxa-bridged fused heterocycles. A number of cyclo- lalkynols and chalcones
2 and 3, respectively
addition reactions of Int1 have been reported,[3] but to (Scheme 2). Interestingly, subtle differences between
our knowledge, there have been only a few reports of the substituents on the two different types of chalcone
cycloadditions of Int2.[4] The lack of examples of the substrates resulted in completely different chemo-
latter may be due to the predominance of competitive selectivity under identical reaction conditions.
side reactions of pre-formed Int1.
We were interested in the reactions of arylalkynols
1 with two- and four-atom synthons, such as chalcones.
Results and Discussion
Chalcones are widely used as Michael acceptors We began by carrying out reactions of model substrates
because of their α,β-unsaturated structure. They have (2-ethynylphenyl)methanol (1a) and α-cyanochalcone
also been used as C2 synthons or oxaza-four-atom (2a) under various conditions, as shown in Table 1.
synthons for [2+n] or [4+n] cycloaddition reactions, Reaction at room temperature in toluene (PhMe) in the
respectively.[5] Our research group has developed presence of PtI2 and 4 Å molecular sieves for 36 h
methods for substrate- and cocatalyst-controlled diver- gave a 40% yield of spiroketal 4aa as a mixture of two
gent cascade cycloaddition reactions of arylalkynols diastereoisomers in a 1:1 diastereoisomeric ratio (dr)
1.[4] In one of these reactions, cyclic α,β-unsaturated (entry 1). This result indicates that the reaction
ketones derived from dioxo-pyrrolidine were employed proceeded via a formal [2+4] cascade cycloaddition
as oxaza-four-atom synthons in cycloadditions with and that 1a acted as a dienophile and 2a as an oxaza-
four-atom synthon. Increasing the reaction temperature
°
to 40 C markedly increased the yield of 4aa (entry 2).
°
At 60 C, the yield reached 97% (entry 3), but
°
increasing the temperature further (to 80 or 100 C)
decreased the yield precipitously (entries 4 and 5).
Changing the solvent to PhOMe was deleterious to the
yield (entry 6). When PtCl2 was used as a catalyst, 1a
decomposed, and 2a was recovered unchanged (en-
try 7). The reaction was sluggish in the presence of
Ph3PAuCl/AgNTf2/Y(OTf)3 at room temperature, both
in PhMe and in MeCN (entries 8 and 9). To improve
the diastereoselectivity, we tested combinations of PtI2
with other Lewis acids such as Ni(OTf)2 and the rare
earth metal salts Y(OTf)3 and Sc(OTf)3 and with
Scheme 1. Possible cycloaddition modes of arylalkynols 1.
ligands such as l-proline, 1,5-cyclooctadiene, (rac)-PA
((�)-1,1’-binaphthyl-2,2’-diylhydrogenphosphate), BI-
NAP ((�)-2,2’-bis(diphenylphosphino)-1,1’-binaphtha-
lene), and 2,2’-bipyridinyl. Unfortunately, these experi-
ments yielded no obvious improvements in the
diastereoselectivity (entries 10–19). In summary, the
optimal reaction conditions were as follows: 1a
(1.5 equiv.), 2a (1.0 equiv.), 5 mol% PtI2, 4 Å molec-
°
ular sieves (40 mg), PhMe (0.1 M), 60 C, 36 h.
With the optimal conditions in hand (Table 1,
entry 3), we evaluated the scope of the reaction with
respect to substrates 1 and 2 (Table 2). In almost all
cases, the desired spiroketal products were obtained in
excellent yields (86–97%). Specifically, 1a reacted
with α-cyanochalcones bearing various R2 and R3
Scheme 2. Substituent-controlled divergent cascade cycloaddi-
tion reactions of arylalkynols 1 and chalcones 2 or 3.
groups; substrates with an unsubstituted phenyl group
(2a), an electron-deficient phenyl group (2b–2i, 2l),
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Table 1. Optimization of conditions for the cascade cycloaddition reaction of 1a and 2a.[a]
°
Entry
Cat.
Temp. ( C)
Solv.
% Yield (dr)[b]
1
2
3
4
5
6
7
8
PtI2
PtI2
PtI2
PtI2
PtI2
PtI2
PtCl2
rt
PhMe
PhMe
PhMe
PhMe
PhMe
PhOMe
PhMe
PhMe
MeCN
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
40 (1:1)
80 (1:1)
97 (1.2:1)
66 (9:1)
54 (10:1)
76 (2:1)
decomp
trace
40
60
80
100
60
60
rt
Ph3PAuCl/AgNTf2/Y(OTf)3
Ph3PAuCl/AgNTf2/Y(OTf)3
PtI2/Y(OTf)3
PtI2/Sc(OTf)3
PtI2/Ni(OTf)2
PtI2/l-Proline
PtI2/l-Proline
PtI2/COD
9
rt
trace
10
11
12
13
14[c]
15[d]
16[e]
17
18
19
60
60
60
60
60
60
60
60
60
60
68 (1:0.7)
33 (1:0.8)
30 (1:0.8)
NR
N. R.
34 (1:1)
23 (1:1)
decomp
20 (3:2)
26 (1:1)
PtI2/COD
PtI2/(rac)-PA
PtI2/BINAP
PtI2/2,2’-bipyridinyl
[a] Reaction conditions, unless otherwise noted: 1a (39.6 mg, 0.3 mmol); 2a (46.7 mg, 0.2 mmol); 4 Å molecular sieves (40 mg);
metal catalyst (5 mol%); Lewis acid catalyst, additive, or ligand (20 mol%); solvent (1 mL); 36 h. Abbreviations: NR, no
reaction; decomp, decomposition; COD, 1,5-cyclooctadiene; (rac)-PA, (�)-1,1’-binaphthyl-2,2’-diylhydrogenphosphate; BINAP,
(�)-2,2’-bis(diphenylphosphino)-1,1’-binaphthalene.
[b] Isolated yields are reported. The dr values were determined from the 1H NMR spectrum of crude product 4aa.
[c] l-proline, 1.0 equiv.
[d] COD, 5 mol%.
[e] COD, 10 mol%.
or an electron-rich phenyl group (2j, 2k, 2m) afforded
the corresponding spiroketals (4aa–4am) in >90%
yields. Moreover, 2-thienyl chalcone gave 4an in 93%
yield. Reactions of 2a with arylalkynols 1b–1f gave
good yields of corresponding products 4ba–4fa. A
reaction of methyl-substituted arylalkynol 1g gener-
ated four diastereoisomers of 4ga under the standard
conditions. The relative configuration of 4ac was
determined by X-ray single-crystal diffraction (Fig-
ure 2).[6a]
Unexpectedly, reaction of (2-ethynylphenyl) meth-
anol (1a) with o-hydroxychalcone 3a generated an
oxa-bridged fused six-membered cyclic ether (5) in
yields up to 94% under the conditions used for reaction
of α-cyanochalcone 2a (Table 3, entry 1). In this
reaction, 1a acted as a precursor of a C4 synthon
rather than a C2 synthon. Owing to the four prochiral
centers of 5, product 5aa was obtained as a mixture of
three diastereoisomers, which were inseparable. To
improve the diastereoselectivity of the cascade cyclo-
addition reaction between 1a and 3a, we systemati-
Figure 2. The ORTEP drawing of 4ac (30% propability)
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are summarized in Table 4. Gratifyingly, various o-
hydroxychalcones 3 bearing either an electron-with-
drawing substituent (F, Cl, Br, CF3) or an electron-
donating substituent (Me, MeO) at the para, meta, or
ortho position on the aromatic ring were tolerated,
delivering mixtures of corresponding oxa-bridged
heterocycles 5aa–5am and 5aa’–5am’ in good to
excellent yields; these results indicate that the aryl
substituents had no significant electronic or steric
effects on the reaction outcome. Furthermore, 2-
thienyl-substituted o-hydroxychalcone was also a good
substrate, affording a 1:1.3 mixture of 5an and 5an’ in
91% yield. In addition, arylalkynols 1b–1f reacted
with o-hydroxychalcone 3a to give mixtures of oxa-
bridged heterocycles 5ba–5fa and 5ba’–5fa’ in high
yields. Notably, the two major diastereoisomers of 5ah
and 5ah’ were separable, and thus their structures were
unambiguously confirmed by X-ray single-crystal
diffraction (Figures 3 and 4).[6b,c] All the products were
mixtures of three diastereoisomers, namely, 5 as a
single diastereomer and 5’ as a mixture of two
diastereoisomers. Although we expended considerable
Table 2. Substrate scope of the cascade cycloaddition reactio-
n.[a]
[a] Reactions of 1 (0.3 mmol, 1.5 equiv.) and 2 (0.2 mmol,
1.0 equiv.) were carried out in the presence of PtI2 (5 mg,
5 mol%) and 4 Å molecular sieves (40 mg) in PhMe
°
(2.0 mL) at 60 C for 36 h. Isolated yields are reported. The
dr values were determined from the H NMR spectra of the
crude products.
1
Figure 3. The ORTEP drawing of 5ah (30% propability)
cally varied the ligand or additive, temperature,
solvent, and amounts of reactants and additives
(Table S1, entries 1–17). However, we were unable to
improve the results. In addition, we tested bimetallic
catalyst systems, as well as other metal catalysts, but
again the results were unsatisfactory (Table 3, entries
2–23). For example, when commonly used Au or Pd
catalysts were evaluated, the reactions were sluggish
(entries 14–20 and 23), for reasons that are unclear at
present. Thus, the optimal reaction conditions were the
same as those used for the reactions of the arylalkynols
and α-cyanochalcones: that is, 1 (1.5 equiv.), 3
°
(1.0 equiv.), 5 mol% PtI2, PhMe (1.0 mL), 60 C, 36 h.
To demonstrate the generality of this Pt-catalyzed
heteroannulation reaction, we subjected a variety of
arylalkynols 1 and o-hydroxychalcones 3 to the
optimized reaction conditions; representative results
Figure 4. The ORTEP drawing of 5ah’ (30% propability)
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Table 3. Screening of conditions for reaction of phenylalkynol 1a and o-hydroxychalcone 3a.[a]
°
Entry
Cat.
Temp. ( C)
Solv.
% Yield (dr)[b]
1
2
3
4
5
6
7
8
PtI2
PtI2/Y(OTf)3
PtI2/Sc(OTf)3
PtI2/Ni(OTf)3
60
60
60
60
60
60
60
60
60
60
60
60
60
rt
rt
rt
rt
rt
rt
rt
60
60
60
PhMe[c]
PhMe[c]
PhMe[c]
PhMe[c]
PhMe[c]
PhMe[c]
PhMe[c]
PhMe[c]
PhMe[c]
PhMe
PhMe
PhMe
PhMe
PhMe
THF
PhMe
PhMe
PhMe
94 (1:1.4)
24 (1:2.4)
68 (1:1.2)
56 (1:1.3)
11 (1:1.1)
31 (1:1.6)
20 (1:1.7)
22 (1:1.3)
37 (1:1.2)
NR
PtI2/Zn(OTf)2
PtI2/Zn(OTf)2/bisoxazoline
PtI2/Zn(OTf)2/2,2’-bipyridinyl
PtI2/BINAP
PtI2/trimethyl borate
PtI2/1,2-cyclohexadiamine
PtI2/NaBARF
PtI2/NaBARF
PtI2/BF3 OEt2
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl/rac-PA
Ph3PAuCl/AgNTf2/Y(OTf)3
BINAPAuCl/Y(OTf)3
(4-CF3Ph)3PAuCl/Y(OTf)3
(2-tBuPhO)3PAuCl/Y(OTf)3
Cu(OTf)2 (20 mol%)
CuI (20 mol%)
9
10
11[d]
12[e]
13[f]
14
15
16
17
18[g]
19[g]
20[g]
21
22
23
decomp
decomp
complex mixture
NR
.
NR
decomp
complex mixture
decomp
decomp
NR
decomp
NR
decomp
PhMe
PhMe
PhMe
PhMe
(Ph3P)2PdCl2
PhMe
[a] Reactions of 1a (39.6 mg, 0.3 mmol, 1.5 equiv.) and 3a (46.7 mg, 0.2 mmol, 1.0 equiv.) were carried out in the presence of PtI2
°
or Ph3PAuCl/AgNTf2 (5 mol%) and a Lewis acid catalyst or additive or ligand (20 mol%) in 1 mL of solvent for 36 h at 60 C or
room temperature (rt). Abbreviations: NR, no reaction; decomp, decomposition; bisoxazoline, 2,2’-(1-methylethylidene) bis[4,5-
dihydro]-oxazole; NaBARF, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; (rac)-PA, ((�)-1,1’-binaphthyl-2,2’-diylhy-
drogenphosphate).
1
[b] Isolated yields are reported. The dr values were determined from the H NMR spectra of crude product. The product was a
mixture of three diastereoisomers in all cases.
[c] PhMe, 2 mL.
[d] NaBARF, 5 mol%.
[e] NaBARF, 10 mol%.
.
[f] BF3 OEt2, 1.0 equiv.
[g] Au catalyst, 2.5 mol%.
effort in trying to separate these diastereoisomers by yield; Scheme 4, eq. 1, condition I). The fact that no
means of various methods, we were unsuccessful.
5aa was observed indicates that 2a was more reactive
Gram-scale reactions of 1a (5.25 mmol) and either than 3a and that 1a preferred kinetically as a C2
2a (3.5 mmol) or 3a (3.5 mmol) in the presence of synthon (Int1, Scheme 1). In contrast, a reaction of a
°
PtI2 (5 mol%) at 60 C for 16 h in PhMe produced 4aa 3:1:1 1a/2a/3a mixture afforded 4aa (87%) and 5aa
(1.14 g, 89%) or 5aa (1.15 g, 93%), respectively (87%) in a 1:1 molar ratio (Scheme 4, eq. 1, condition
(Scheme 3).
II). These two results demonstrate that the reactions of
To ascertain the influence of the CN and OH groups both α-cyanochalcone and o-hydroxychalcone were
of the chalcone substrates, we conducted a number of highly chemoselective despite the fact that the pathway
control experiments (Scheme 4). First, we found that involving the C4 synthon (Int2) of arylalkynol 1a is
when a mixture of (2-ethynylphenyl)methanol (1a), α- thermodynamically more challenging; these results
cyanochalcone (2a), and o-hydroxychalcone (3a) in a also indicate that the [2+4] and [4+2] cycloaddition
°
1:1:1 molar ratio was stirred at 60 C in the presence of reactions predominated over the disfavored [2+2] and
PtI2 in PhMe for 16 h, 4aa was the only product (80% [4+4] cycloadditions. Furthermore, the unsubstituted
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Table 4. Substrate scope of the cascade cycloaddition reaction
of arylalkynols 1 and o-hydroxychalcones 3.[a]
Scheme 3. Gram-scale cascade cycloaddition reactions of (2-
ethynylphenyl)methanol (1a) and α-cyanochalcone 2a or o-
hydroxychalcone 3a.
gen-bonding interaction with the carbonyl group of the
o-hydroxychalcone. Such an interaction would result in
a preference for o-hydroxychalcone to act as a C2
synthon and would force arylalkynol 1a to undergo the
challenging isomerization to Int2 via an intramolecular
5-exo-dig hydroalkoxylation cyclization-1,5-H shift
reaction. Moreover, when o-aminochalcone 10 was
used as the substrate, no reaction occurred (eq. 3,
condition III). We surmised that the combination of the
weak basicity of the arylamine group and the weak
acidity of the phenol group of the o-hydroxychalcone
changed the overall pKa of the reaction system. In
addition, when 68% deuterated 2’-OD-chalcone 11 was
1
allowed to react with 1a, the H NMR spectrum of the
crude product showed a 1.2:1 ratio of 2’-OH-chalcone
(integration area, 0.48) and oxa-bridged heterocycle
(total integration area, 0.18+0.05+0.15+0.02=
0.40) (eq. 3, condition IV; see also Figure S4). This
result indicates that 2’-OD-chalcone 11 was less
reactive than the 2’-OH-chalcone and that the hydro-
gen-bonding interaction was weaker in the case of the
former. Notably, some HÀ D exchange was observed
during the reaction between 2’-OD-chalcone 11 and
1a, with 68% of 2’-OD-chalcone 11 exchanged to 88%
2’-OH-chalcone (0.48+0.40). We speculated that 1a
and traces of water in the PhMe solvent might have
provided the active H even though we used dried
solvent and carried out the reaction under argon. Taken
together, these results indicate that 2’-OD-chalcone 11
[a] Reactions of arylalkynols 1 (0.3 mmol, 1.5 equiv.) and o-
hydroxychalcones 3 (0.2 mmol, 1.0 equiv.) were carried out
in the presence of PtI2 (5 mg, 5 mol%) and 4 Å molecular
°
sieves (40 mg) in PhMe (2.0 mL) at 60 C for 36 h. Isolated
yields are provided. The dr values were determined from the
1H NMR spectra of the crude products. In all cases, the
product was a mixture of three diastereoisomers: one
diastereoisomer of 5 and two diastereoisomers of 5’.
chalcone 6 gave a 45% overall yield of oxa-bridged was unreactive in this cascade reaction. Surprisingly,
fused heterocycles 7 and 7’ as the sole products under reaction of 4’-OH-chalcone 14 delivered corresponding
the standard reaction condition (Scheme 4, eq. 2).
products 15 and 15’ in a 71% overall yield (Scheme 4,
Reactions of o-methoxychalcone (8) and o-meth- eq. 4). This result demonstrates that an intermolecular
ylchalcone (9) were sluggish, and only traces of the hydrogen bond with the 4’-OH group accelerated the
corresponding oxa-bridged heterocycles (12 and 12’, [4+2] cascade cycloaddition of 1a and 14.
13 and 13’, respectively) were generated (Scheme 4,
In addition, replacing the CN group of the α-
eq. 3, conditions I and II). These results demonstrate cyanochalcone with a NO2 group (16; Scheme 4, eq. 5,
that the OH group played a key role in the reaction, condition I) led to a complex mixture, whereas no
perhaps by participating in an intramolecular hydro- reaction occurred when the CN group was replaced
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nature of the substituent were key factors for this [2+
4] cascade cycloaddition reaction.
To determine whether the CN group coordinated
with the PtI2 catalyst, we carried out a reaction of
hydroxychalcone 20, which has a CN group on the
aromatic ring that does not have the hydroxyl group.
This reaction afforded the oxa-bridged heterocycles 21
and 21’ in an overall yield of 90% (Scheme 4, eq. 6),
indicating that the CN group did not affect the reaction
rate or chemoselectivity. Moreover, no spiroketal was
produced in the reaction of (2-ethynylphenyl)methanol
(1a) and o-hydroxychalcone 3a in a PhMe/CH3CN
mixture or in CH3CN alone (eq. 7). These results
demonstrate that both the nature and the position of the
substituent on the chalcone were important and that the
electronic and steric effects of the substituent played a
decisive role.
On the basis of the above-described experiments,
we proposed the following mechanisms for these two
cascade cycloaddition reactions (Scheme 5). First, PtI2
activates (2-ethynylphenyl)methanol (1a), which
undergoes an intramolecular 5-exo-dig hydroalkoxyla-
tion to give the benzoisofuran Int1, which has an
exocyclic double bond. Int1 then attacks α-cyanochal-
cone 2a via a Michael addition pathway to give Int3.
Product 4aa is generated by an oxygen anion
annulation reaction of Int3. Alternatively, Int1 can
isomerize to thermodynamically stable intermediate
Int2 via a 1,5-H-migration, and subsequent Michael
addition with hydroxychalcone 3a (which has an
intramolecularly hydrogen bonded form) gives Int4.
The [4+4] oxygen anion annulation reaction is
disfavored, so the carbanion attacks the oxonium ion in
a [4+2] cycloaddition reaction, giving oxa-bridged
fused heterocycle 5aa.
Conclusion
In conclusion, we have described substituent-con-
trolled divergent cascade cycloaddition reactions be-
Scheme 4. Control experiments.
with a COOEt group (17; eq. 5, condition II). When α-
Ph-chalcone 18 was used as a substrate, 1a decom-
posed, and 18 was recovered unchanged (eq. 5,
condition III); whereas no reaction was observed when
α-methylchalcone 19 was the substrate (eq. 5, con-
dition IV). We surmised that the results for 16 may
have been due to competitive Michael reactions of the
α,β-unsaturated ketone and α,β-unsaturated nitro com-
pound and that the latter reaction predominated. In
contrast, the COOEt and Ph groups of chalcones 17
and 18 are less electron withdrawing than the CN
group, and the methyl group of 19 is electron donating,
which can explain the lower reactivities of 17, 18, and
19 via Int1 relative to the reactivity of 2a. All of these
results demonstrate that both the size and the electronic
Scheme 5. Proposed mechanisms for the cascade cycloaddition
reactions of arylalkynol 1a with α-cyanochalcone 2a and o-
hydroxychalcone 3a.
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tween chalcones and arylalkynols. Specifically, α-
cyano- and o-hydroxychalcones gave two completely
different products, spiroketals and oxa-bridged fused
heterocycles, respectively, in high yields under identi-
cal reaction conditions. Control experiments demon-
strated that the chemoselectivity was controlled by the
nature and position of the substituent on the chalcone
as well as by electronic and steric effects. The α-
cyanochalcones preferred to act as oxaza-four-atom
synthons, whereas the o-hydroxychalcones acted as C2
synthons. In addition, we confirmed that the arylalky-
nol reaction partner acted as the kinetically preferred
C2 synthon precursor and that the thermodynamically
stable C4 synthon had the great challenging. On the
basis of control experiments, we proposed mechanisms
for these two cascade reactions. Further transforma-
tions of the products and assessment of their biological
activities are underway in our laboratory.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (no. 21873051) and the National
Key Research and Development Program of China (no.
2017YFD0201404). We also acknowledge support from the
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin).
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Supporting Information
The Supporting Information is available free of charge
on the ACS Publications website.
NMR spectra for all novel compounds (PDF), X-
ray single-crystal diffraction ORTEP drawings of 4ac,
5ah, and 5ah’ (PDF).
Experimental Section
General Information
1H NMR and 13C NMR spectra were recorded on a Bruker AV
1
400 MHz instrument. H and 13C NMR chemical shifts were
calibrated to tetramethylsilane as an internal reference. Chem-
ical shifts are given in ppm, and coupling constants (J) are
given in Hz. The following multiplicity abbreviations are used:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; High-
resolution mass spectra were recorded under electrospray
ionization conditions on a Varian 7.0T FTMS spectrometer.
Synthesis and Characterization of Annulation Prod-
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Adv. Synth. Catal. 2021, 363, 1–10
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RESEARCH ARTICLE
asc.wiley-vch.de
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Goodness-of-fit on F2) 1.035. Supplementary crystallo-
graphic data have been deposited at the Cambridge
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(7) Å, V) 1897.31 (14) Å3, T) 113 K, Z) 2. Reflections
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observations [>2ó(I)] 5231, parameters) 255, Goodness-
of-fit on F2) 1.047. Supplementary crystallographic data
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0.0562, wR2=0.0856, a=10.8068 (8) Å, b=18.6072 (8)
R indices [I>2ó(I)], R1=0.0374, wR2=0.0838,
R
indices (all data) R1=0.0495, wR2=0.0374, a=10.8492
(5) Å, b=11.7736 (4) Å, c=15.5739 (7) Å, V) 1897.31
(14) Å3, T) 113 K, Z) 4. Reflections collected/unique:
7682/6377 [R(int)=0.044], number of observations [>
2ó(I)] 7682, parameters) 510, Goodness-of-fit on F2)
1.037. Supplementary crystallographic data have been
deposited at the Cambridge Crystallographic Data Center.
CCDC 2063720.
Adv. Synth. Catal. 2021, 363, 1–10
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© 2021 Wiley-VCH GmbH
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RESEARCH ARTICLE
Substituent-Controlled Divergent Cascade Cycloaddition
Reactions of Chalcones and Arylalkynols: Access to Spiroke-
tals and Oxa-Bridged Fused Heterocycles
Adv. Synth. Catal. 2021, 363, 1–10
T. Zeng, J. Kong, H. Wang, L. Liu*, W. Chang, J. Li*