A visible-light mediated ring opening reaction of alkylidenecyclopropanes for the generation of homopropargyl radicals

Article abstract of DOI:10.1039/d1sc01889b

Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher's attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester activation chemistry has witnessed significant blooming developments and provided new synthetic routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis, providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives. The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile synthesis of bioactive molecules or their derivatives and medicinal substances.

Full text of DOI:10.1039/d1sc01889b

Chemical
Science
View Article Online
View Journal | View Issue
EDGE ARTICLE
A visible-light mediated ring opening reaction of
alkylidenecyclopropanes for the generation of
homopropargyl radicals†
Cite this: Chem. Sci., 2021, 12, 9088
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
b
ab
Xiao-Yu Zhang,a Chao Ning,a Ben Mao,a Yin Wei
and Min Shi
*
*
Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic
studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have
a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher's
attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester
activation chemistry has witnessed significant blooming developments and provided new synthetic
routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock
reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis,
providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives.
The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile
synthesis of bioactive molecules or their derivatives and medicinal substances.
Received 6th April 2021
Accepted 27th May 2021
DOI: 10.1039/d1sc01889b
rsc.li/chemical-science
can undergo further transformations (Scheme 1A, b). As for
thermally induced cyclizations, heating would facilitate the
Introduction
double bond of ACPs to react with a dienophile or dipole to
afford spirocyclic derivatives (Scheme 1A, c).
Furthermore, the application of alkylidenecyclopropanes in
radical C–C bond forming reactions has also received much
Over the past few decades, the ring-opening reactions of alky-
lidenecyclopropanes (ACPs) have been vigorously explored, due
to their high reactivity endowed by ring strain.1 In general, the
reaction modes of alkylidenecyclopropanes can be mainly
classied into the following: transition metal-catalyzed reac-
tions,2 Lewis or Brønsted acid-catalyzed/mediated reactions,3
thermal induced cyclizations4 and free radical additions
(Scheme 1A).5 Since the 1970s, the research on the chemistry of
ACPs upon transition metal catalysis has been in progress, and
four different reaction patterns have been disclosed thus far
(Scheme 1A, a). The distal bond (C3–C4) and proximal bond
(C2–C3 or C2–C4) of ACPs can be inserted by transition metal M
to undergo the subsequent reactions. On the other hand, the
organo-transition metal reagent R–MLn can be added into
alkylidenecyclopropanes via anti-Markovnikov or Markovnikov
addition, leading to the ring opening of cyclopropane or other
transformations. In the reaction of ACPs with Lewis or Brønsted
acids, the cyclopropyl ring can be activated to undergo ring
opening to form two different zwitterionic intermediates, which
aKey Laboratory for Advanced Materials and Institute of Fine Chemicals, Key
Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research
Center, School of Chemistry & Molecular Engineering, East China University of
Science and Technology, Meilong Road No. 130, Shanghai, 200237, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: weiyin@sioc.ac.cn; mshi@mail.sioc.ac.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, NMR spectra and computational details. See DOI:
10.1039/d1sc01889b
Scheme 1 Traditional reaction modes of alkylidenecyclopropanes and
unknown reaction mode of alkylidenecyclopropanes.
9088 | Chem. Sci., 2021, 12, 9088–9095
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
attention. The addition of radicals into alkylidenecyclopro- conducted preliminary density functional theory (DFT) calcu-
panes could generate cyclopropyl radicals or cyclo- lations to predict whether the envisaged process is kinetically
propylcarbinyl radicals. The former can be further transformed feasible (Scheme 2A) (see the ESI† for the details). The calcu-
to achieve the difunctionalization of alkenes, and the latter can lation results showed that the energy barrier for the ring-
undergo b-scission in the cyclopropyl ring to afford the homo- opening process of the alkylidenecyclopropane radical
allyl radical known as a classical radical clock (Scheme 1A, d). ðDG‡1 ¼ 5:4 kcal molꢀ1Þ is lower than that for the ring-opening
These synthetic methods provide an efficient access to the rapid process of the CPC radical ðDG‡2 ¼ 7:1 kcal molꢀ1Þ; indicating
generation of molecular complexity. However, with increasing that the ring-opening process of the alkylidenecyclopropane
exploration on research means and technologies, nearly no radical is kinetically favorable. In addition, the ring-opening
breakthrough on the chemical transformation of alkylidenecy- process of the alkylidenecyclopropane radical is an exergonic
clopropanes has been made for a long time. More efforts to process (DG1 ¼ ꢀ13.4 kcal molꢀ1), suggesting that this is
develop new reaction modes of alkylidenecyclopropanes are a thermodynamically favorable process. Based on these calcu-
highly desired in current research.
The ring opening of the cyclopropylcarbinyl (CPC) radical to process of the alkylidenecyclopropane radical is feasible.
the 3-butenyl radical is a fast radical rearrangement that holds Recently, NHPI (N-hydroxyphthalimide) esters, as stable and
lation results, developing reactions involving the ring opening
a position of distinction in mechanistic studies involving readily accessible compounds, have emerged as a novel and
“radical clocks” and “mechanistic probes”. Numerous research efficient synthon to undergo a number of interesting and
studies have adopted potential precursors of this radical or its practical transformations.8 Due to their redox reactivity, NHPI
analogues in attempts to implicate radical intermediates in esters can serve as a radical precursor to accept an electron to
a reaction pathway by the detection of the products from the trigger a consecutive domino of events that release phthalimidyl
radical ring opening process.6 At the same time, it is found that anions, CO2 and the corresponding radicals applied for a variety
this methodology and the nal detected products bearing of reactions.9 Photoredox catalysis induced by visible light,
alkenyl groups can be applied to diverse organic synthesis.7 owing to the advantages of ease of handling, application safety
Since alkylidenecyclopropanes (ACPs) have a similar molecular and natural abundance, is utilized as one of the accesses ful-
structure to methylcyclopropane and the release of ring strain lling the described process.10 Visible-light induced carbon–
can provide a potent thermodynamic driving force, we designed carbon bond-forming reactions involving NHPI esters were
an unknown radical reaction mode, in which the C(sp2)–X bond identied as an ideal strategy to construct various interesting
of alkylidenecyclopropane can be selectively cleaved to afford compounds. Such reactions can be categorized as follows: (i)
the alkylidenecyclopropane radical (Scheme 1B). This radical C(sp3)–C(sp3) bond formation; (ii) C(sp3)–C(sp2) bond forma-
can further undergo the same ring opening rearrangement tion; (iii) C(sp3)–C(sp) bond formation; (iv) C(sp3)–B or Se/S
process to generate the corresponding radical species contain- bond formation.8 However, in these reactions, NHPI esters
ing an alkynyl moiety and subsequently play a vital role in directly release the C(sp3) radicals applied for the bond forma-
mechanistic studies and diverse organic synthesis. Thus, we tion. No examples of releasing the highly reactive vinyl radicals
as C(sp2) radicals have been reported to date. With regard to this
aspect, we skillfully take advantage of the high reactivity of
C(sp2) radicals to fulll our design. Building on the widely
investigated eld of classical ring opening radical clock reac-
tions and the successes of photocatalytic NHPI esters in
decarboxylative activity chemistry, we are inspired by the
possibility of an innovative non-classical ring opening radical
clock reaction to provide both terminal and internal alkynes
(Scheme 2B). Notably, it is convinced that different levels of
saturation of small molecules can cause a broad spectrum of
transformations, especially applicable in the areas of pharma-
ceutical and agrochemical production. Therefore, the trans-
formations of alkynes into alkenes and alkanes fullled by our
envisaged method would provide a practical synthetic route
(Scheme 2B).
Results and discussion
Experimental investigations
We began our investigation with easily available NHPI ester 1b
(0.075 mmol, 1.5 equiv.) and phenyl vinyl ketone 2a (0.05 mmol,
1.0 equiv.) as the model substrates, Ru(bpy)3(PF6)2 as the
Scheme 2 DFT calculations of the ACP radical clock vs. classical CPC
ring opening radical clock process. Alkylidenecyclopropanes and this
photosensitizer, and Hantzsch ester and iPr2NEt as additives in
work.
dichloromethane (0.75 mL) at room temperature upon the
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 9088–9095 | 9089

View Article Online
Chemical Science
Edge Article
Table 1 Optimization of the reaction conditionsa
Table
2
Substrate
scope
of
NHPI
esters
bearing
alkylidenecyclopropanesa
Entry
Condition
Yieldb (%)
1
2
3
4
5
6
7
8
Standard condition
Without Ru(bpy)3(PF6)2
87
NR
NR
15
34
NR
21
13
71
57
66
84
Without blue LED
Without iPr2NEt
Ru(bpz)3(PF6)2 instead of Ru(bpy)3(PF6)2
fac-lr(ppy)3 instead of Ru(bpy)3(PF6)2
i
DBU instead of Pr2NEt
i
DABCO instead of Pr2NEt
9
THF instead of DCM
DCE instead of DCM
1.0 equiv. 1b
10
11
12
12 h instead of 3 h
a
Reaction conditions: 1b (0.075 mmol, 1.5 equiv.), 2a (0.05 mmol, 1.0
a
Reaction conditions: 1 (0.3 mmol, 1.5 equiv.), 2a (0.2 mmol, 1.0
equiv.), Hantzsch ester (HEH) (0.3 mmol, 1.5 equiv.), iPr2NEt (0.44
mmol, 2.2 equiv.), Ru(bpy)3(PF6)2 (2 mol%), DCM (3 mL), rt, 3 h, Ar,
and 15 W blue LED. Yields were determined from isolated products.
i
equiv.), Hantzsch ester (HEH) (0.075 mmol, 1.5 equiv.), Pr2NEt (0.11
mmol, 2.2 equiv.), Ru(bpy)3(PF6)2 (2 mol%), DCM (0.75 mL), rt, 3 h,
Ar, and 15 W blue LED. All the reactions were carried out on a 0.05
mmol scale in solvent (0.75 mL) at rt for 3 h unless otherwise
specied. b Isolated yield.
corresponding internal alkynes 3ia, 3ja and 3ka in good yields
ranging from 80–94%. Notably, the substrate 1la having an
aromatic heterocycle was also suitable for this reaction,
affording the desired product 3la in 85% yield.
irradiation of a 15 W blue LED for 3 h, giving the desired alkyne
3ba in 87% yield (Table 1, entry 1). The optimization of reaction
conditions revealed that the photosensitizer, light and additive
were indispensable in this reaction (Table 1, entries 2–4). Other
metal-polypyridyl complex photosensitizers were also screened,
and the results showed that Ru(bpz)3(PF6)2 was less effective as
compared with Ru(bpy)3(PF6)2, but the use of fac-Ir(ppy)3 did
not afford the desired product (Table 1, entries 5-6). Instead of
iPr2NEt, other additives such as DBU and DABCO were tested,
which resulted in decreased yields (Table 1, entries 7-8). We
further investigated other solvents, such as THF and DCE,
providing 3ba in 71% and 57% yields (Table 1, entries 9-10),
respectively, identifying DCM as the most suitable solvent.
Using 1.0 equiv. of 1b or prolonging the reaction time to 12 h
could not effectively improve the yield of 3ba (Table 1, entries
11-12).
With the optimal reaction conditions in hand, we attempted
to investigate the substrate scope of various NHPI esters bearing
alkylidenecyclopropanes and the results are shown in Table 2.
When the substituent R was a hydrogen atom, the reaction
could proceed smoothly to provide the terminal alkyne 3aa in
75% yield. For substrates 1c and 1d, ethyl group and propyl
group substituted NHPI esters were compatible in this reaction,
generating the corresponding internal alkynes 3ca and 3da in
89% and 92% yields, respectively. When the R group was
changed into the benzyl group bearing different substituents,
such as 4-H, 4-OMe, 4-Cl and 3,5-Br (1e–1h), the desired prod-
ucts 3ea–3ha were obtained in 89–93% yields. Moreover, we
attempted to introduce featured substituents, such as allyl,
propargyl and cinnamyl groups, into the substrates, and found
that the reactions also proceeded smoothly to afford the
Next, we focused on the generality of this protocol regarding
a,b-unsaturated carbonyl compounds. As outlined in Table 3,
most of the reactions proceeded smoothly under well-estab-
lished conditions to generate the expected products in
moderate to good yields. First, we examined aryl substituted
a,b-unsaturated ketones (2b–2i). The mild conditions enabled
the tolerance to important functional groups, such as halide,
cyano, ester, alkoxy and so on, affording the corresponding
alkynes 3bb–3bi, in the yields ranging from 75% to 92%.
Moreover, alkyl substituted a,b-unsaturated ketones (2j–2n)
were also compatible in this reaction, affording the desired
alkynes 3bj–3bn, albeit with moderate yields (36–43%). For the
a,b-unsaturated amide 2o, the reaction could also proceed
smoothly to produce the desired product 3bo in 33% yield.
When the a position of a,b-unsaturated ketones was substituted
by ester and phenyl groups, the reaction occurred smoothly to
give the expected products 3bp and 3bq in 87% and 81% yields,
respectively. For conjugated diene substrate 2r, in which the
d position was substituted by a methyl group, the corresponding
product 3br was obtained in 92% yield, probably due to the
radical addition taking place at the d position and the relative
stability of key radical intermediates. It is well known that
aromatic heterocycles play an important role in medicinal
chemistry; therefore, a,b-unsaturated ketones bearing furyl,
thienyl, pyrrole, indolyl, benzofuryl and imidazolyl groups were
applied to this reaction to generate alkynes having aromatic
heterocycles. To our delight, these reactions also proceeded very
well to provide the corresponding alkynes 3bs–3bx in moderate
9090 | Chem. Sci., 2021, 12, 9088–9095
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
Table 3 Substrate scope of a,b-unsaturated ketonesa
a
i
Reaction conditions: 1b (0.3 mmol, 1.5 equiv.), 2 (0.2 mmol, 1.0 equiv.), Hantzsch ester (HEH) (0.3 mmol, 1.5 equiv.), Pr2NEt (0.44 mmol, 2.2
equiv.), Ru(bpy)3(PF6)2 (2 mol%), DCM (3 mL), rt, 3 h, Ar, and 15 W blue LED. Yields were determined from isolated products.
to good yields. For cyclic exo-methylene ketones 2y and 2z, the resulting alkynes can act as versatile forging blocks for diversity-
desired products 3by and 3bz were obtained in both 78% yields. oriented synthesis. A rhodium-catalyzed hydrosilylation reac-
Notably, when the alkenyl sulfone 2aa was utilized as the tion and gold-catalyzed cyclization of 3baf were conducted to
substrate, the desulfonylative cross-coupling reaction occurred, afford the corresponding products, silylated compound 4 and
resulting in the formation of product 3baa in 97% yield. Finally, cyclized product 5 in 87% and 90% yields, respectively. The
we illustrated the utility of this novel non-classical radical clock Sonogashira cross-coupling reaction of 3baf with vinyl bromide
reaction using the core structures of several bioactive mole- also proceeded smoothly, giving the enyne 6 in 99% yield, which
cules, such as geraniol (2ab), estrone (2ad) and vanillin (2ae), could be utilized for the construction of valuable building
and a mesogenic compound (2ac). All the desired alkynylated blocks, such as pyrroles. The click reaction of 3baf with tosyl
products were obtained in good yields (78–88%), irrespective of azide via copper catalysis afforded the [3 + 2] cycloaddition
existing complex molecular structures. In addition, acrylesters, product 7 in 95% yield, demonstrating the potential practica-
acrylamides, exo-cyclic lactone and simple crotonyl or cinna- bility of the resulting alkynes in medicinal chemistry. Hydro-
moyl substrates were also attempted to use as the radical genation or partial hydrogenation of the obtained alkyne 3baf
acceptors to proceed this reaction; however, no desired prod- effectively generated the corresponding alkane 8 and alkene 9.
ucts were obtained (for unsuccessful examples, see Page S3 in As for the immediate potential in biochemistry and medicinal
the ESI†). Unfortunately, we did not succeed in obtaining an chemistry, we have easily synthesized ve different synthetic
aryl-substituted substrate aer several attempts.
precursors 10, 11, 12, 15 and 16 on a gram scale through this
methodology (Scheme 3B). Compound 10 was synthesized from
3ba through a two-step reduction procedure in 65% yield (0.91
g), which was regarded as the key intermediate for the synthesis
of Fingolimod, mainly available for the treatment of Multiple
Synthetic applications
To demonstrate the preparative utility of our methodology,
product transformations were conducted (Scheme 3A). The
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 9088–9095 | 9091

View Article Online
Chemical Science
Edge Article
Scheme 3 Synthetic applications of the non-classical ring opening radical clock reaction. (A) Product transformations of 3baf. (a) NaBH4, MeOH,
0 ꢁC – rt; DMAP, imidazole, TBSCl, DCM, 0 ꢁC – rt, and 12 h; Rh(COD)2BF4, PPh3, Et3SiH, acetone, rt, and 20 h. (b) AuCl3, AgOTf, toluene, rt, and 8
h. (c) Pd(PPh3)2Cl2, CuI, Et3N, THF, rt, 12 h. (d) CuTc, toluene, rt, and 8 h. (e) Pd/C, MeOH, H2, rt, and 4 h. (f) Lindlar catalyst, MeOH, H2, rt, and 8 h.
(B) Synthesis of drugs applying our methodology. (g) Pd/C, MeOH, H2, rt, and 4 h; NaBH4, AlCl3, THF, and 0 ꢁC - 65 ꢁC. (h) ethylene glycol, p-
TsOH, toluene, and 110 ꢁC; n-BuLi, propyl chloroformate, THF, and ꢀ78 ꢁC; Pd/C, MeOH, H2, rt, and overnight; LiOH, THF, H2O, and rt; DMAP,
DCC, Et3N, DCM, DMF, and 0 ꢁC – rt; 6-(1-aminoethyl)pyridazin-3(2H)-one S6, POCl3, DCE, reflux, and 3 h. (i) BH3$THF, cyclohexene, THF, 0 ꢁC,
and 2 h; NaBO3$4H2O, H2O, and 2 h. (j) Pd/C, MeOH, H2, rt, and 4 h; TiCl4, (CH3)2Zn, DCM, ꢀ50 ꢁC, and 2 h; BBr3, DCM, 0 ꢁC, and 12 h.
Sclerosis (MS).11 Starting from 3aa, the two vital precursors 11 by serving as a weak m-opioid receptor agonist;13 therefore, we
and 12 were synthesized in 46% (0.56 g) and 43% (0.49 g) yields, synthesized the vital precursor 15 through a one-pot selective
respectively. Precursors 11 and 12 could be further transformed hydroboration and oxidation of alkyne 3baf in 59% yield (0.69
into substituted imidazo [1,5-b] pyridazine 13 and its analogue g). Furthermore, on the basis of Razdan's protocol,14 we
14, which are proved to be exceptionally active against the prepared the building block 16 in 79% yield (0.63 g) through the
reverse transcriptase of HIV-1, in 64% (0.68 g) yield and 62% reduction and demethylation of alkyne 3baf, which could be
(0.64 g) yield, respectively12 (for details on the formal synthesis applied to assemble the novel tetrahydrocannabinol/ananda-
or total synthesis of bioactive molecules, see Pages S13 and S14 mide (THC/AEA) hybrid ligand. This modied ligand could
in the ESI†). Since 1977, Tramadol has been used as a painkiller signicantly improve its binding affinity to the CB1 receptor in
9092 | Chem. Sci., 2021, 12, 9088–9095
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
generating terminal or internal alkynes and their derivatives,
which would be synthetically very useful along with excellent
functional group tolerance.
Mechanistic studies
To gain more insights into the reaction mechanism, the uo-
rescence quenching experiments of Ru(bpy)3(PF6)2 with 1b were
performed and its Stern–Volmer analysis is depicted in Fig. 1,
indicating that 1b could not be photo-excited by the photo-
catalyst effectively. In addition, we carried out several control
experiments (Scheme 4). First, when TEMPO as a radical scav-
enger was subjected to our model reaction, the non-classical
radical clock reaction was inhibited completely and a new
product 17 generated from the resultant alkyl radical trapped by
TEMPO was obtained in 49% yield (Scheme 4, a). Subsequently,
a reaction using deuterium-labeled Hantzsch ester d3-2af was
conducted, and the deuterium atom was incorporated exclu-
sively at the a position of alkyne d1-3ba, showing that SET and
HAT processes were both involved in the last step15 (Scheme 4,
b). Substrate 1a (E1/2 ¼ ꢀ1.18 V vs. SCE, see Page S18 in the ESI†)
and radical clock substrate 1m (E1/2 ¼ ꢀ1.24 V vs. SCE, see Page
S18 in the ESI†) were mixed together to undergo the reaction,
affording the corresponding products 3aa and 18 in 48% and
16% yield, respectively (Scheme 4, c). This reaction outcome
basically agrees with the prediction of DFT calculations, which
indicate that the ring-opening process of the alkylidenecyclo-
propane radical is kinetically more favorable.
Fig. 1 Stern–Volmer quenching experiment.
On the basis of generally accepted mechanisms for NHPI
ester's decarboxylative activity,8,15 a plausible catalytic cycle is
proposed in Scheme 5. The initial excitation of Ru(bpy)3(PF6)2
Scheme 4 Mechanistic investigations.
*
produces the excited state RuðbpyÞ3ðPF6Þ2; which undergoes
SET with iPr2NEt or Hantzsch ester to generate the Ru(I), amine
radical cation or Hantzsch ester radical cation. The N-(acyloxy)
phthalimide 1 receives an electron from Ru(I) (E1/2 ¼ ꢀ1.33 V vs.
biological research. In summary, these diverse transformations
exhibit the strong capability of our non-classical radical clock
reaction coupled with various subsequent manipulations for
Scheme 5 Proposed reaction mechanisms.
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 9088–9095 | 9093

View Article Online
Chemical Science
Edge Article
SCE), to transiently form radical anionic intermediate A. Next,
an entropically favored decarboxylation can proceed via two
plausible pathways to generate the desired radical intermediate
D: (i) rapid homolytic fragmentation and decarboxylation from
A to release the phthalimide anion, CO2 and the radical inter-
mediate B. As a central design element, we postulated that B
would undergo the ring-opening process to produce the nucle-
ophilic carbon-centered radical bearing alkynyl D, or (ii)
homolytic fragmentation of the N–O bond to furnish interme-
diate C, which can further undergo decarboxylation and radical
rearrangement to D. The addition of this nucleophilic radical to
a conjugate acceptor 2 generates a stabilized radical E, which
then undergoes SET and HAT processes to successfully form the
functionalized alkyne 3. Notably, the radical intermediate E was
not engaged in a fast 5-exo-dig-cyclization to afford the cyclized
product; therefore, we assumed that the cyclization is reversible
and reduction only occurred on the ring-opened isomer.
References
1 (a) A. Brandi and A. Goti, Chem. Rev., 1998, 98, 589–636; (b)
A. Brandi, S. Cicchi, F. M. Cordero and A. Goti, Chem. Rev.,
2003, 103, 1213–1270; (c) G. Audran and H. Pellissier, Adv.
Synth. Catal., 2010, 352, 575–608; (d) M. Shi, J.-M. Lu,
Y. Wei and L.-X. Shao, Acc. Chem. Res., 2012, 45, 641–652;
(e) D.-H. Zhang, X.-Y. Tang and M. Shi, Acc. Chem. Res.,
2014, 47, 913–924; (f) L.-Z. Yu, K. Chen, Z.-Z. Zhu and
M. Shi, Chem. Commun., 2017, 53, 5935–5945; (g)
X.-Y. Zhang, P.-H. Li and M. Shi, Asian J. Org. Chem., 2018,
7, 1924–1933.
2 (a) N. Tsukada, A. Shibuya, I. Nakamura and Y. Yamamoto, J.
Am. Chem. Soc., 1997, 119, 8123–8124; (b) M. Shi, L.-P. Liu
and J. Tang, J. Am. Chem. Soc., 2006, 128, 7430–7431; (c)
¨
¨
C. Aıssa and A. Furstner, J. Am. Chem. Soc., 2007, 129,
14836–14837; (d) S. Cui, Y. Zhang and Q. Wu, Chem. Sci.,
2013, 4, 3421–3426; (e) J. C. Timmerman, B. D. Robertson
and R. A. Widenhoefer, Angew. Chem., Int. Ed., 2015, 54,
2251–2254; (f) W. Fang, Y. Wei and M. Shi, Org. Lett., 2018,
20, 7141–7144; (g) W. Fang and M. Shi, Chem. –Eur. J.,
2018, 24, 9998–10005; (h) B. Cao, Y. Wei and M. Shi, Chem.
Commun., 2018, 54, 14085–14088.
Conclusions
In conclusion, we have successfully established a robust
methodology to access alkynes via the versatile and practical
non-classical ring-opening radical clock reactions of NHPI
esters bearing ACPs inspired by conventional photocatalytic
NHPI ester's activation and classical radical clock reactions.
Compared with the traditional reaction modes of alkylidene-
cyclopropanes, this method is totally new and its prospect will
be prosperous for the rapid generation of molecular complexity
in organic synthesis. Most importantly, since the carbon–
carbon triple bond can serve as a versatile functional group for
diverse organic synthesis, the resulting alkynes can be trans-
formed into a variety of bioactive molecules and natural prod-
ucts. Further studies for discovering detailed mechanisms and
novel reaction types to synthesize other useful compounds are
underway.
3 (a) M. Shi and B. Xu, Org. Lett., 2002, 4, 2145–2148; (b) M. Shi,
B. Xu and J.-W. Huang, Org. Lett., 2004, 6, 1175–1178; (c)
L.-X. Shao, B. Xu, J.-W. Huang and M. Shi, Chem. –Eur. J.,
2006, 12, 510–517; (d) M. E. Scott, Y. Bethuel and
M. Lautens, J. Am. Chem. Soc., 2007, 129, 1482–1483; (e)
J.-W. Huang and M. Shi, Synlett, 2004, 2004, 2343–2346.
4 (a) I. Nakamura, T. Nemoto, Y. Yamamoto and A. de Meijere,
Angew. Chem., Int. Ed., 2006, 45, 5176–5179; (b) X.-Y. Tang
and M. Shi, J. Org. Chem., 2009, 74, 5983–5986; (c) K. Chen,
R. Sun, Q. Xu, Y. Wei and M. Shi, Org. Biomol. Chem., 2013,
11, 3949–3953; (d) X.-Y. Zhang, S. Yang, Y. Wei and M. Shi,
Org. Biomol. Chem., 2018, 16, 6399–6404.
5 (a) B. Xu, Y. Chen and M. Shi, Tetrahedron Lett., 2002, 43,
2781–2784; (b) J.-W. Huang and M. Shi, J. Org. Chem., 2005,
70, 3859–3863; (c) T. Kippo, K. Hamaoka and I. Ryu, J. Am.
Chem. Soc., 2013, 135, 632–635; (d) L. Yu, Y. Wu, T. Chen,
Y. Pan and Q. Xu, Org. Lett., 2013, 15, 144–147; (e)
Z.-Z. Zhu, K. Chen, L.-Z. Yu, X.-Y. Tang and M. Shi, Org.
Lett., 2015, 17, 5994–5997; (f) Y.-C. Yuan, H.-L. Liu,
X.-B. Hu, Y. Wei and M. Shi, Chem. –Eur. J., 2016, 22,
13059–13063; (g) X. Fan, L.-Z. Yu, Y. Wei and M. Shi, Org.
Lett., 2017, 19, 4476–4479; (h) X.-Y. Zhang, C. Ning,
Y.-J. Long, Y. Wei and M. Shi, Org. Lett., 2020, 22, 5212–5216.
6 (a) L. Huang, A. M. Olivares and D. J. Weix, Angew. Chem., Int.
Ed., 2017, 56, 11901–11905; (b) W. Zhang, F. Wang,
S. D. McCann, D. Wang, P. Chen, S. S. Stahl and G. Liu,
Science, 2016, 353, 1014–1018; (c) W. Zhao, R. P. Wurz,
J. C. Peters and G. C. Fu, J. Am. Chem. Soc., 2017, 139,
12153–12156; (d) Q. Fu, Z.-Y. Bo, J.-H. Ye, T. Ju, H. Huang,
L.-L. Liao and D.-G. Yu, Nat. Commun., 2019, 10, 3592–
3595; (e) J. H. Blackwell, R. Kumar and M. J. Gaunt, J. Am.
Chem. Soc., 2021, 143, 1598–1609.
Author contributions
X.-Y. Z., C.N. and B. M. contributed to the experimental work; Y.
W. contributed to the computational work. X.-Y. Z., Y. W. and
M. S. contributed to ideation and writing of the paper.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful for the nancial support from the Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant No. XDB20000000), the National Natural Science Foun-
dation of China (21372250, 21121062, 21302203, 20732008,
21772037, 21772226, 21861132014 and 91956115), the Project
supported by Shanghai Municipal Science and Technology
Major Project (Grddant No. 2018SHZDZX03) and the Funda-
mental Research Funds for the Central Universities
222201717003.
9094 | Chem. Sci., 2021, 12, 9088–9095
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
7 (a) S. Handa and G. Pattenden, Chem. Commun., 1998, 311–
T. Nishikawa, K. Yamada, D. Ravelli, M. Fagnoni and
I. Ryu, Org. Lett., 2017, 19, 6436–6439; (f) Y. Zhao,
J.-R. Chen and W.-J. Xiao, Org. Lett., 2018, 20, 224–227; (g)
M.-C. Fu, R. Shang, B. Zhao, B. Wang and Y. Fu, Science,
2019, 363, 1429–1434.
¨
312; (b) G. Ruedi and H.-J. Hansen, Tetrahedron Lett., 2004,
45, 5143–5145; (c) Y. Takekawa and K. Shishido, J. Org.
Chem., 2001, 66, 8490–8503; (d) T. Fukuyama, T. Kippo,
K. Hamaoka and I. Ryu, Sci. China Chem., 2019, 62, 1525–
1528.
11 R. U. Maruthi, R. B. Venkateswara and V. Siddaiah, Der
Pharma Chemica, 2017, 9, 36–40.
8 (a) S. Murarka, Adv. Synth. Catal., 2018, 360, 1735–1753; (b)
K. Okada, K. Okamoto, N. Morita, K. Okubo and M. Oda, J. 12 D. G. H. Livermore, R. C. Bethell, N. Cammack,
Am. Chem. Soc., 1991, 113, 9401–9402.
A. P. Hancock, M. M. Hann, D. V. S. Green, R. B. Lamont,
9 (a) H. Subramanian, Y. Landais and M. P. Sibi, Radical
S. A. Noble and D. C. Orr, J. Med. Chem., 1993, 36, 3784–3794.
Addition Reactions, in Comprehensive Organic Synthesis II, 13 F. Lecerf-Schmidt, R. Haudecoeur, B. Peres, M. M. Ferreira
ed. P. Knoche, Elsevier, Amsterdam, 2nd edn, 2014, pp.
699–741; (b) M. P. Sibi, S. Manyem and J. Zimmerman,
Chem. Rev., 2003, 103, 3263–3296.
Queiroz, L. Marcourt, S. Challal, E. Ferreira Queiroz,
G. Sotoing Taiwe, T. Lomberget, M. Le Borgne,
J. L. Wolfender, M. De Waard, R. J. Robins and
A. Boumendjel, Chem. Commun., 2015, 51, 14451–14453.
10 (a) J. Xuan, Z.-G. Zhang and W.-J. Xiao, Angew. Chem., Int.
Ed., 2015, 54, 15632–15641; (b) M. H. Shaw, J. Twilton and 14 C. Bourne, S. Roy, J. L. Wiley, B. R. Martin, B. F. Thomas,
D. W. C. MacMillan, J. Org. Chem., 2016, 81, 6898–6926; (c)
N. Vallavoju, S. Selvakumar, B. C. Pemberton, S. Jockusch,
A. Mahadevan and R. K. Razdan, Bioorg. Med. Chem., 2007,
15, 7850–7864.
M. P. Sibi and J. Sivaguru, Angew. Chem., Int. Ed., 2016, 55, 15 G. Pratsch, G. L. Lackner and L. E. Overman, J. Org. Chem.,
5446–5451; (d) L. Candish, M. Teders and F. Glorius, J. Am.
Chem. Soc., 2017, 139, 7440–7443; (e) T. Fukuyama,
2015, 80, 6025–6036.
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 9088–9095 | 9095