Solvent-controlled photocatalytic divergent cyclization of alkynyl aldehydes: access to cyclopentenones and dihydropyranols

Article abstract of DOI:10.1039/d1sc03416b

Divergent synthesis is a powerful strategy for the fast assembly of different molecular scaffolds from identical starting materials. We describe here a solvent-controlled photocatalytic divergent cyclization of alkynyl aldehydes with sulfonyl chlorides for the direct construction of highly functionalized cyclopentenones and dihydropyranols that widely exist in bioactive molecules and natural products. Density functional theory calculations suggest that a uniqueN,N-dimethylacetamide-assisted 1,2-hydrogen transfer of alkoxy radicals is responsible for the cyclopentenone formation, whereas a C-C cleavage accounts for the selective production of dihydropyranols in acetonitrile and water at 50 °C. Given the simple and mild reaction conditions, excellent functional group compatibility, forming up to four chemical bonds, and tunable selectivity, it may find wide applications in synthetic chemistry.

Full text of DOI:10.1039/d1sc03416b

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Solvent-controlled photocatalytic divergent
cyclization of alkynyl aldehydes: access to
Cite this: DOI: 10.1039/d1sc03416b
cyclopentenones and dihydropyranols†‡
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Haiqian Zhu,§a Hanliang Zheng,§b Junhua Zhang,§a Jian Feng,a Lichun Kong,a
a
b
a
*
*
Fang Zhang, Xiao-Song Xue and Gangguo Zhu
Divergent synthesis is a powerful strategy for the fast assembly of different molecular scaffolds from
identical starting materials. We describe here a solvent-controlled photocatalytic divergent cyclization of
alkynyl aldehydes with sulfonyl chlorides for the direct construction of highly functionalized
cyclopentenones and dihydropyranols that widely exist in bioactive molecules and natural products.
Density functional theory calculations suggest that a unique N,N-dimethylacetamide-assisted 1,2-
hydrogen transfer of alkoxy radicals is responsible for the cyclopentenone formation, whereas a C–C
cleavage accounts for the selective production of dihydropyranols in acetonitrile and water at 50 ꢀC.
Given the simple and mild reaction conditions, excellent functional group compatibility, forming up to
four chemical bonds, and tunable selectivity, it may find wide applications in synthetic chemistry.
Received 23rd June 2021
Accepted 26th July 2021
DOI: 10.1039/d1sc03416b
rsc.li/chemical-science
methods are limited to aryl or alkenyl aldehydes (R1 ¼ Ar,
alkenyl), and the transformation of alkyl aldehydes (R1 ¼ alkyl)
Introduction
is still unknown owing to the lack of spin delocalization in the
formed ketyl radical. Recently, Liu4 and Zhu5 reported an
elegant intramolecular formyl migration reaction via the b-
scission of alkoxy radicals. Key to this transformation is the
release of a much more stable radical (R1c), and therefore, it is
a substrate-dependent process. So far, only a-hydroxy aldehydes
work for this reaction, and the formyl shi from the more
common alkyl aldehydes remains unexplored.
Nucleophilic addition to carbonyl groups represents one of the
most classic reactions for accessing ubiquitous C–C bonds. The
C–O double bonds accept the attack of nucleophiles to form an
alkoxide intermediate, followed by protonation to afford
alcohol products (Scheme 1a). In contrast, the radical addition
to carbonyls can generate a more reactive and versatile alkoxy
radical intermediate that may undergo a reduction, 1,2-
hydrogen atom transfer (1,2-HAT), or b-fragmentation to
produce structurally diverse products (Scheme 1b), such as
alcohols,1 ketones,2,3 or aldehydes.4,5 In addition, the radical-
mediated reaction usually occurs under mild, neutral condi-
tions, thus tolerating many sensitive functional groups which
are incompatible with the ionic reaction. Despite its apparent
advantages, the addition of radicals to carbonyl compounds has
been much less investigated due to the production of thermo-
dynamically unfavorable alkoxy radicals.6 In this respect, we
have established an aldehyde-to-ketone methodology2 with 1,2-
HAT of alkoxy radicals as the key step. However, the known
As fundamental structural scaffolds, cyclopentenones7 and
dihydropyranones8 widely exist in numerous natural products
and biologically active compounds, such as the inhibitor of
cyclooxygenase-2 (COX-2) A,9a potent anticancer agent B,9b and
herbicides C9c (Scheme 1c). Consequently, the development of
efficient methods for assembling these two motifs is highly
desirable. Pursuing our recent interests in the aldehyde-to-
ketone methodology,2 we envisioned that an intramolecular
addition of alkenyl radicals to alkyl aldehydes would allow us to
access the more reactive alkoxy radicals (Scheme 1d). If we
could control the reaction pathways of the in situ generated
alkoxy radicals, a divergent synthesis of cyclopentenones and
dihydropyranols would be established. Herein, we disclose
a visible light-induced sulfonylative cyclization of alkynyl alde-
hydes using commercially available sulfonyl chlorides as the
sulfonylation reagent.10 The reaction offers a facile access to
various structurally diverse cyclopentenones, dihydropyranols,
and dihydropyranones under very mild conditions. Density
Functional Theory (DFT) calculations provide insights into this
unique solvent-controlled divergent transformation. Speci-
cally, the cyclopentenone formation proceeds via a novel DMA-
aKey Laboratory of the Ministry of Education for Advanced Catalysis Materials,
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua
321004, P. R. China. E-mail: gangguo@zjnu.cn
bState Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P. R. China. E-mail: xuexs@nankai.edu.cn
† In memory of Prof. Ei-ichi Negishi.
‡ Electronic supplementary information (ESI) available: Data for all the products,
experimental procedures, and computational data. CCDC 2060837 and 2060838.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc03416b
§ These authors contributed equally.
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Table 1 Conditions optimization for the divergent cyclizationa
Entry
Base
Solvent
Yield of 3ab (%)
Yield of 4ab (%)
1
2
3
4
5
6
7
8
K2CO3
K2HPO4
K3PO4
DMA
DMA
DMA
DMA
66
65
66
74
76
5
30
10
Trace
Trace
Trace
Trace
Trace
57
30
25
51
48
Et3N
Na2CO3
Na2CO3
Na2HPO4
K3PO4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMA
MeCN
MeCN
MeCN
MeNO2
DCM
DMSO
DMF
MeCN
9
5
10
11
12
13c
Trace
NR
31
NR
Trace
73
Trace
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), fac-Ir(ppy)3
(2 mol%), base (0.4 mmol), H2O (0.4 mmol), solvent, 25 ꢀC, 5 h.
b
c
Isolated yield. Run at 50 ꢀC. DMA ¼ N,N-dimethylacetamide, DCM
¼
dichloromethane, DMSO
¼
dimethyl sulfoxide, DMF
¼
N,N-
dimethylformamide, NR ¼ no reaction.
Switching the solvent from DMA to MeCN led to 3a in only 5%
yield, and interestingly, the 4-sulfonyl dihydropyranol 4a was
isolated in 57% yield (entry 6). Encouraged by the result, we
examined other bases and solvents for the dihydropyranol
production, however, the reaction yields were not improved
(entries 7–12). To our delight, running the reaction at 50 ꢀC
resulted in full conversion of 1a and produced 4a in 73% yield
(entry 13).
With the optimized reaction conditions in hands, we set
about evaluating the scope of this cyclopentenone formation
protocol with DMA as the solvent (Table 2). In general, the
transformation proceeded efficiently to form densely
substituted cyclopentenones in moderate to high yields (3a–
3w). A broad array of functional groups, such as F, Cl, Br, CN, Ac,
OMe, quinoline, pyridine, and thiofuran, are well tolerated
under the reaction conditions, which may be utilized for the
downtown transformations. Although both the electron-rich
and -decient substituents were accommodated on the
benzene ring of 1, relatively lower yields were observed for the
latter cases (3g and 3h). In addition to arylalkynyl substrates (G
¼ Ar), the thioalkynyl aldehyde 1o reacted with 2a as well to
produce the desired product 3o in 73% yield. Direct construc-
tion of spirocyclopentenones was also feasible, as exemplied
by the production of 3p. The alkylalkynyl aldehyde 1q (G ¼ Me)
served as a viable substrate, while aldehydes 1r and 1s (G ¼ SiEt3
and H) were not engaged in this reaction (3q–3s). The reaction
of 1u, a dicarbonyl substrate, took place uneventfully to afford
3u in 69% yield. Substitution at the propargyl position with two
methyl groups led to 3x in a low yield, which may be attributed
to the increased hindrance for the radical sulfonylation of C–C
triple bonds. Aer succeeding in synthesizing tetrasubstituted
Scheme 1 Background and summary of this work.
assisted 1,2-hydrogen transfer, while the b-scission of alkoxy
radicals accounts for the selective production of dihydropyr-
anols with MeCN as the solvent. In contrast to the existing
photocatalysis divergent synthesis11–13 which is generally
restricted to the substrate-11 or catalyst-controlled12 system, the
solvent-controlled strategy developed here provides an opera-
tionally simple and highly efficient means for divergent
synthesis.
Results and discussion
Initially, alkynyl aldehyde 1a and TsCl (2a) were chosen as
model substrates for evaluating the reaction conditions. In the
presence of 2 mol% of fac-Ir(ppy)3 and 2.0 equiv. of K2CO3, the
3-sulfonyl cyclopentenone 3a was isolated in 66% yield aer 5 h
of irradiation with 15 W of blue LEDs in DMA at 25 ꢀC (Table 1,
entry 1). Base screening revealed that Na2CO3 was the most
efficient choice, delivering 3a in 76% yield (entries 2–5).
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Table 2 Scope of the cyclopentenone formationa
not engaged in this reaction (3zj). The X-ray crystallographic
analysis of 3g14 clearly indicated the structure of 3-sulfonyl
cyclopentenones.
The generality of photoredox-catalyzed synthesis of dihy-
dropyranols was then explored with MeCN as the solvent (Table
3). Alkynyl aldehydes bearing different substituents such as Me,
F, Cl, Br, CN, Ac, and OMe served as competent substrates,
delivering a variety of 4-sulfonyl dihydropyranols in moderate to
high yields (4a–4i). The electron effects appeared to have an
impact on the reaction efficiency. Specically, the trans-
formation of substrates 1g and 1h, having electron-withdrawing
CN and Ac substituents on the benzene ring, produced the
desired products 4g and 4h in 70% and 76% yield, respectively,
while a moderate yield (42%) was observed in the case of 1i,
bearing an electron-donating OMe group (4i). Substituents at
the a-position of aldehydes were evaluated. In particular, a-
tertiary aldehydes worked well for this reaction (4m–4q),
whereas the a-secondary aldehyde failed to provide the corre-
sponding product (4r), presumably due to the reduced stability
of secondary alkyl radicals. Aldehydes 1q–1s were ineffective for
the dihydropyranol formation. Additionally, the scope with
respect to sulfonyl chlorides was investigated. A wide range of
arylsulfonyl chlorides, substituted by groups such as F, CF3, Br,
Table 3 Scope of the dihydropyranol formationa
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), fac-Ir(ppy)3 (2 mol%),
Na2CO3 (0.4 mmol), H2O (0.4 mmol), DMA, 25 ꢀC, 5 h. Isolated yields are
given.
cyclopentenones, we then examined the feasibility of assem-
bling tri- or disubstituted cyclopentenones. Starting from the a-
secondary and a-primary aldehydes 1y and 1z, the 2,3,5-
trisubstituted and 2,3-disubstituted cyclopentenones were
successfully constructed (3y and 3z). The reaction was also
amenable to the access of sulfonylated cyclohexenones, albeit in
a moderate yield (3za). In contrast, construction of cyclo-
butenone or cycloheptenone via this method was unsuccessful
at the current stage. In the meantime, sulfonyl chlorides 2 were
varied with 1i as the coupling partner. Pleasingly, various aryl-
sulfonyl chlorides proved to be efficient substrates and
produced the corresponding sulfonyl cyclopentenones in
medium to high yields (3zb–3zi). Unfortunately, MeSO2Cl was
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), fac-Ir(ppy)3 (2 mol%),
Na2CO3 (0.4 mmol), H2O (0.4 mmol), MeCN, 50 ꢀC, 5 h. Isolated yields
are given.
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OMe, i-Pr, and CN, underwent the reaction smoothly to generate of the Ts group of 3a by a methyl group with MeMgCl cata-
functionalized dihydropyranols in promising yields (4s–4z). lyzed by Ni(acac)2 afforded 6a in 54% yield.15 Michael addition
Similarly, 2-furansulfonyl chloride served as an efficient sulfo- of BnSH or NaOEt to 3a followed by an elimination of sul-
nylation reagent (4za). It's noteworthy that four new chemical nate formed 6b and 6c in 86% and 99% yield, respectively.
bonds are concurrently created under the reaction conditions, Following Orita's protocol,16 photocatalytic desulfonylation of
thus highlighting the high bond-forming efficiency of this both 3a and 5a occurred readily to give 6d and 6e in high
method.
yields. Bromination at the allylic position of 5a with NBS and
Meanwhile, the one-pot synthesis of polysubstituted dihy- BPO produced 6f in a good yield. Given the signicant
dropyranones was explored (Table 4). As expected, the reaction importance of tetrasubstituted alkenes in organic synthesis,
furnished a set of sulfonylated dihydropyranones in medium to the attempts to establish stereodened tetrasubstituted
high yields with good functional group tolerance (5a–5e). The alkenes were also performed. Nucleophilic attack of MeMgCl
structure of 4-sulfonyl dihydropyranones was unambiguously to 5a delivered the tetrasubstituted (E)-alkene 6g in 82% yield.
identied by the X-ray crystallographic analysis of 5a.14
Furthermore, the (E)-enol 6h was selectively assembled in
To demonstrate the synthetic utility of this divergent almost quantitative yield upon treatment of 5a with K2CO3 in
ꢀ
transformation of alkynyl aldehydes, we carried out the MeOH at 55 C for 10 h.
derivatization of obtained products (Scheme 2). Substitution
To gain insights into the reaction mechanism, some control
experiments were performed, and the results are summarized in
Scheme 3. In the presence of butylated hydroxytoluene (BHT,
2.0 equiv.), neither 3a nor 4a could be obtained in a noticeable
yield, and instead, the sulfonyl compound 7 was isolated in 11%
and 48% yield, respectively. Likewise, adding 2,2,6,6-tetrame-
thylpiperidinooxy (TMEPO, 2.0 equiv.) to the standard condi-
tions shut down the reaction (not shown). These results
suggested a radical pathway. Additionally, the 18O isotope
labeling experiments were conducted. With the addition of 5.0
Table 4 One-pot synthesis of dihydropyranonesa
equiv. of H218O, 4a-18O was isolated in 69% yield with 89% 18
O
incorporation. In addition to the signal of [M + Na]+ ion of
4a-18O, a signal matched with [M + Na–H218O]+ ion was observed
by the HRMS analysis, thus indicating that the hydroxy group of
a
Reaction conditions: (i) see Table 3. (ii) Jones reagent (0.4 mmol),
MeCN, 25 ꢀC, 5 h. Isolated yields are given.
Scheme 2 Transformation of selected products. Reaction conditions:
(a) MeMgCl (1.2 equiv.), Ni(acac)2 (10 mol%), THF, 25 ꢀC, 10 h; (b) BnSH
(2.0 equiv.), DBU (2.0 equiv.), CHCl3, 25 ꢀC, 10 h; (c) NaOEt (2.0 equiv.),
THF, 25 ꢀC, 10 h; (d) perylene (5 mol%), i-Pr2NEt (8.0 equiv.), MeCN/
THF (5 : 1), blue LEDs, 25 ꢀC, 10 h; (e) BPO (20 mol%), NBS (3.0 equiv.),
CCl4, 95 ꢀC, 24 h; (f) MeMgCl (3.0 equiv.), THF, 10 h; (g) K2CO3 (4.0
equiv.), MeOH, 55 ꢀC, 10 h. THF ¼ tetrahydrofuran, DBU ¼ 1,8-dia-
zabicyclo[5,4,0]undec-7-ene, BPO ¼ dibenzoyl peroxide, NBS ¼ N-
bromosuccinimide.
Scheme 3 Mechanistic studies.
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4a is originated from water (see ESI‡ for details). Under the Parallel intermolecular kinetic isotopic effect experiments were
standard conditions, the reaction of aldehyde 1a-D performed then conducted, and a KIE value of 1.0 was determined,
well to deliver 3a and 4a-D in 73% and 75% yield, respectively. implying that the aldehydic C–H cleavage may not be the rate-
determing step.
Based on the above results and previous reports,2,4,5 a mech-
anistic proposal for the divergent cyclization of 1a is summa-
rized in Scheme 4. Initially, the single electron transfer (SET)
between the excited photocatalysis Ir(III)* and TsCl affords
a Ir(IV) species and sulfonyl radical Tsc.10d Radical sulfonylation
of the C–C triple bond of 1a and a subsequent addition of vinyl
radical I to the intramolecular CHO group produces a cyclo-
pentenyloxy radical II. It may undergo a 1,2-HAT to deliver the
neutral ketyl radical III, followed by SET with Ir(IV) and depro-
tonation to provide 3a (path 1a). Alternatively, the b-C-C
cleavage of II17 may take place to form a tertiary alkyl radical
IV (path 1b), which can be converted into the oxonium ion VI via
a 6-endo radical cyclization (path 2a)/SET oxidation sequence.
Additionally, a radical oxidation to the cation VII (path 2b) fol-
lowed by intramolecular nucleophilic attack may also lead to
the generation of VI. Finally, the nucleophilic attack of VI by
H2O generates 4a as the product.
To shed light on the unique role of solvent in tuning the
reaction pathways, we carried out computational studies using
DFT calculations, and the results are presented in Scheme 5. As
Scheme 4 Proposed mechanism.
Scheme 5 The calculated relative Gibbs free energies for the intermediates and transition-states of the model reaction in DMA (in blue) and
MeCN (in pink) at the wb97xd/def2tzvp-SMD//B3LYP-D3(BJ)/6-31G(d,p) level of theory.
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for the reaction performed in DMA, radical sulfonylation of 1a
occurring via transition state TS1 requires an activation free
energy of 14.3 kcal molꢁ1, which is viable under the reaction
conditions. Subsequently, radical addition to the intra-
molecular CHO group proceeds via a ve-membered ring tran-
sition state TS2 to give the radical II. This step has a free energy
barrier of 9.3 kcal molꢁ1. Starting from II, an unprecedented
DMA-assisted 1,2-hydrogen transfer18 (via TS3-DMA, with a free
energy of 7.6 kcal molꢁ1) is favoured over the 6-endo radical
cyclization (via TS5, with a free energy of 9.4 kcal molꢁ1) by
1.8 kcal molꢁ1, thus giving rise to the ketyl radical III. Forma-
tion of III is highly exergonic by 30.7 kcal molꢁ1 and is therefore
an irreversible process. Followed by SET oxidation and depro-
tonation, 3a can be constructed together with the regeneration
of photocatalysis Ir(III), which is strongly exergonic by
Author contributions
H. Z., J. Z., and J. F. conducted the experiments. H. Z., and X.-S.
X. carried out the theoretical calculations and wrote the
manuscript. L. K., and F. Z. characterized the compounds and
analyzed the data. G. Z. designed the project, analyzed the
results and wrote the manuscript.
Conflicts of interest
There are no concts to declare.
Acknowledgements
63.2 kcal molꢁ1
.
This work is supported by the Natural Science Foundation of
Zhejiang Province (LZ20B020002) and National Natural Science
Foundation of China (22071218, 21672191, 21772098 and
21933004). We thank Dr Z. Zhang, Z. Yuan, and L. Zhou for their
helpful discussions and Miss X. Wang for her support in the X-
ray crystallographic analysis.
With MeCN as the solvent, the MeCN-assisted 1,2-hydrogen
transfer of II (via TS3-NCMe) has a higher energy barrier of
15.3 kcal molꢁ1, which is unlikely to compete with the b-C-C
cleavage/6-endo cyclization sequence. Moreover, the 6-endo
radical cyclization of IV requiring a free energy barrier of
4.5 kcal molꢁ1 is favoured over the SET oxidation, with a free
energy barrier of 9.6 kcal molꢁ1, by 5.1 kcal molꢁ1. Therefore,
a stable allyl radical V that lies 25.8 kcal molꢁ1 lower in energy
than IV is selectively formed. Spin delocalization to the neigh-
boring C–C double bond should be responsible for the
increased stability of V, which provides a driving force for the
C–C bond cleavage and uncommon addition of alkyl radical to
the carbonyl oxygen atom19 in the 6-endo radical cyclization
step. Subsequently, the radical V is oxidized by Ir(IV) to form an
oxonium ion intermediate VI, followed by nucleophilic attack of
water to produce 4a, which is strongly exergonic by
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39.1 kcal molꢁ1
.
Conclusions
In conclusion, a photocatalytic divergent coupling of alkynyl
aldehydes with sulfonyl chlorides is developed. The reaction
provides a straightforward and highly selective method for the
assembly of structurally diverse cyclopentenones, dihydropyr-
anols, and dihydropyranones that are important building
blocks in organic and medicinal chemistry. Up to four new
chemical bonds are concurrently constructed under mild reac-
tion conditions, thus highlighting the high efficiency of this
method. DFT calculations reveal that a DMA-assisted 1,2-HAT of
alkoxy radicals is responsible for the production of cyclo-
pentenones, whereas a b-C–C cleavage followed by 6-endo
radical cyclization to formyl group accounts for the generation
of dihydropyranols in MeCN. Tuneable selectivity for 1,2-HAT
and b-fragmentation of alkoxy radicals is realized by change of
the solvent, thus providing a novel strategy for the selective
activation of inert C–H and C–C bonds.
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Data availability
The data supporting this article have been uploaded as part of
the ESI.‡
6 S. Wilsey, P. Dowd and K. N. Houk, J. Org. Chem., 1999, 64,
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© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci.