Engaging 1,7-diynes in a photocatalytic Kharasch-type addition/1,5-(SN′′)-substitution cascade toward β-gem-dihalovinyl carbonyls

Article abstract of DOI:10.1039/d0cc07880h

A new and general photocatalytic Kharasch-type addition/1,5-(S_N′′)-substitution cascade of 1,7-diynes with alkyl halides such as BrCCl₃and CBr₄was reported for the first time, and used to produce 65 hitherto unreported β-gem-dihalovinyl ketones/aldehydes with moderate to excellent yields in a highly regioselective manner. This reaction tolerates a wide scope of substrates, which offers a green and efficient entry to fabricate synthetically important β-gem-dihalovinyl carbonyl scaffolds. Notably, the late-stage application of these resulting β-gem-dihalovinyl carbonyls shows high and unique reactivity profiles and demonstrates the versatility of their derivatization.

Full text of DOI:10.1039/d0cc07880h

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Engaging 1,7-diynes in a photo0c0 atalytic
Kharasch-type addition/1,5-(SN )-substitution
Cite this: Chem. Commun., 2021,
57, 1911
cascade toward b-gem-dihalovinyl carbonyls†
Received 3rd December 2020,
Accepted 14th January 2021
Dan Wu, Wen-Juan Hao, * Qian Rao, Yi Lu, Shu-Jiang Tu * and Bo Jiang
*
DOI: 10.1039/d0cc07880h
rsc.li/chemcomm
A
new and general photocatalytic Kharasch-type addition/ incorporated with a gem-dihaloalkene unit and carbonyl group
1,5-(SN00)-substitution cascade of 1,7-diynes with alkyl halides such remains challenging, presumably due to the huge difficulty in the
as BrCCl3 and CBr4 was reported for the first time, and used to control of selective gem-dihalogenation of two carbonyl groups of
produce 65 hitherto unreported b-gem-dihalovinyl ketones/aldehydes aldehydes or/and ketones (Scheme 1b).1a Accordingly, developing a
with moderate to excellent yields in a highly regioselective manner. new, practical and mechanistically distinct approach for their
This reaction tolerates a wide scope of substrates, which offers a synthesis is highly desirable.
green and efficient entry to fabricate synthetically important b-gem-
Visible-light-driven photoredox catalysis (VLPC) has been
dihalovinyl carbonyl scaffolds. Notably, the late-stage application identified as a flourishing and powerful tool for initiating
of these resulting b-gem-dihalovinyl carbonyls shows high and unique various organic transformations under mild conditions due to
reactivity profiles and demonstrates the versatility of their derivatization. its intrinsic characteristics of safety, greenness and sustain-
ability as well as availability.6 Such reactions offer a unique and
As readily available and versatile feedstocks, gem-dihaloalkenes direct approach to construct intricate architectures not available
exhibit unusual reactivity profiles and thus have been extensively from other methods.7 Since Kharasch pioneered atom trans-
applied in various transformations for the synthesis of impor- fer radical addition (ATRA) of CX4 across terminal olefins
tant molecular scaffolds.1 In particular, such molecules, due to
the two geminal halogen atoms linked by one alkenyl carbon,
demonstrate more reactivity toward oxidative addition of transi-
tion metal complexes than the corresponding monohaloalkenes
and could serve as attractive bidentate electrophiles in modern
cross-coupling reactions.2 Moreover, the carbonyl moiety of
aldehydes or/and ketones represents one of the most basic
functional groups in organic synthesis and occupies a vital
position in developing an array of notable reactions.3 Merging
a gem-dihalovinyl functionality with a carbonyl group into one
molecular skeleton, because of their respective high reactivities,
will render these compounds with distinct reactivity through
mutual activation with each other. At present, numerous efforts
have been contributed to establish effective methods for producing
gem-dihaloalkenes,4 of which traditional Wittig-type reactions of
aldehydes with carbon tetrahalides (CX4) mediated by stoichio-
metric PPh3 is one of the most commonly used appro-
aches (Scheme 1a).5 In contrast, the synthesis of compounds
School of Chemistry & Materials Science, Jiangsu Normal University,
Xuzhou, 221116, P. R. China. E-mail: wjhao@jsnu.edu.cn, laotu@jsnu.edu.cn,
jiangchem@jsnu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 2044615–2044618.
For ESI and crystallographic data in CIF or other electronic format see DOI:
Scheme 1 Photocatalytic synthesis of b-gem-dihalovinyl carbonyls.
Chem. Commun., 2021, 57, 1911ꢀ1914 | 1911
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(Scheme 1c),8 various transition metal-catalyzed and/or photoredox-
catalyzed versions have been developed to build up numerous
polyhalomethylated compounds from polyhalomethyl-containing
synthons and unsaturated systems.9 Inspired by these impressive
transformations, we designed and planned the preparation of
1,7-diyne-anchored starting materials 1 by taking advantage of an
ATRA strategy invented by Kharasch in which the CX3 radical adds
to the terminal triple bond of 1,7-diynes under photocatalytic
conditions, leading to the formation of b-gem-dihalovinyl carbonyls
3 through a radical-induced Kharasch-type addition of diynes, 1,5-
(SN00)-substitution and dehydrohalogenation cascade (Scheme 1d).
As depicted in Scheme 1e, it is particularly attractive and rare that
the new type of b-gem-dihalovinyl ketones/aldehydes can be readily
generated via photocatalytic benzannulation cascade under mild
and green conditions. Late-stage transformations of b-gem-dihalo-
vinyl ketones reveal that these compounds show a unique and
outstanding reactivity, providing great possibilities for the synthesis
of important molecules serving for organic and medicinal research.
Here, we report these interesting discoveries (Scheme 1).
To begin our studies, we chose 1-(2-ethynylphenyl)-4-
phenylbut-3-yn-1-ol (1a) and CBrCl3 (2a) as the model sub-
strates under blue LED irradiation. In the presence of 1
red
1/2
mol% [Ir(ppy)2(dtbbpy)]PF6 (E
[IrIV/*IrIII] = ꢀ0.96 V vs.
SCE)10 and 2.0 equivalents of NaOAc at room temperature
under an argon atmosphere in CH3CN, the reaction of 1a with
2a proceeded under 10 W blue LED irradiation, providing an
unprecedented b-gem-dichlorovinyl carbonyl product 3aa in
45% yield (Table S1, entry S1, ESI†). After careful screening of
the reaction conditions, we found that the reaction catalyzed by
fac-Ir(ppy)3 in EtOH at room temperature under argon condi-
tions afforded product 3aa in 80% yield (entry S10, ESI†).
With these established reaction conditions in hand, we then
evaluated the scope of photocatalysis by using a broad range of
1,7-diyne derivatives. Overall, all tested substrates could enable
photocatalytic Kharasch addition/1,5-(SN00)-substitution cascade
to access the desired b-gem-dihalovinyl carbonyls 3 in synthetically
useful yields, which were not available from conventional
Scheme 2 Scope with respect to the b-gem-dihalovinyl carbonyls 3.
methods1a (Schemes 2–4). As depicted in Scheme 2, CBrCl3 (2a) investigated (Scheme 2). Diverse substituents such as methyl, fluoro
was first reacted with various 1,7-diynes 1 to evaluate the effects of and chloro at the C4 or C5 position of the internal phenyl ring were
changing the electronic properties and positions of substituents in all particularly adapted to achieving this photoredox catalysis since
the arylalkynyl moiety, and all of them were successfully engaged it offered the products 3sa–3dda in satisfactory yields. Subse-
in the current catalytic annulation with comparable efficiency. quently, the generality of this protocol was further assessed by
A variety of substituents, such as methyl (1b–1e), methoxy (1f), exploiting carbon tetrabromide (CBr4) as the gem-dibromination
amide (1g), fluoro (1h), chloro (1i–1k), bromo (1l–1m), cyano (1n), reagent to assemble b-gem-dibromovinyl ketones. As expected, 1,7-
and nitro (1o), residing in different positions of the arene ring can diynes 1 with varied functionalities and substitution patterns could
all tolerate this catalytic system, furnishing the desired products effectively participate in the present reactions, delivering a series of
3ba–3ra in good to excellent yields (Scheme 2). Of these groups, the products 3ac–3ffc in 42%–87% yields. Among them, the presence
sterically crowded o-tolyl (1d) and o-chlorophenyl (1k) counterparts of a strong electron-withdrawing nitro (1o) group seems to hinder
exhibited good compatibility, suggesting that the increased steric the process, delivering a poor yield (3oc, 42%); in contrast, an
congestion does not impair the reactivity. The 2-thienyl-containing electron-donating TsO (1ff) group worked more efficiently, leading
substrate 1p was adopted to prove the compatibility of this to a 76% yield. Notably, 1,7-diynes bearing two terminal alkynyl
benzannulation, producing the corresponding product 3pa in an moieties (1gg–1kk) were found to show good reactivities, as evident
acceptable yield. Remarkably, alkyl substituents such as cyclopropyl by the corresponding b-gem-dihalovinyl aldehydes 3gga–3kkc being
and cyclohexyl could be engaged in this reaction process (3qa and obtained, albeit with moderate yields.
3ra). Next, a brief survey of the possible variation in the R1
substituents relative to the internal arene ring of substrates 1 was derived 1,7-diynes including epiandrosterone (1ll), estrone
This chemistry was also well accommodated by naturally
1912 | Chem. Commun., 2021, 57, 1911ꢀ1914
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(1mm), pregnenolone (1nn), estradiol(1oo), L-menthol (1pp),
L(ꢀ)-borneol (1qq), and D-a-tocopherol (1rr), confirming the
efficiency of the photocatalysis with 2a and 2c, as the corres-
ponding products 3lla–3rra and 3lla–3qqc were furnished with
48%–92% yields, thus highlighting the versatility of this protocol
in building up molecular complexity in a photocatalytic fashion.
(Scheme S14, ESI†). Note that this is the first reported procedure
for the assembly of these new b-gem-dihalovinyl carbonyls
through a conceptually new photocatalytic Kharasch addition/
SN00-substitution cascade.
To further demonstrate the viability of the photocatalytic
annulation process, we turned our attention to checking 1,7-
diynes 1ss–1xx with exchanging substituents linked by alkyne
moieties.11 As depicted in Scheme 4, the effects of changing the
electronic properties and positions of the substituents in the R1
moiety of 1,7-diynes was first investigated by combining with
CBrCl3 (2a), and all of them were smoothly engaged in the
current photocatalytic annulation with acceptable yields. Either
electronically neutral (H, 1ss), rich (methyl, 1tt and 1xx), or poor
(chloro 1uu and bromo 1vv) groups residing in various posi-
tions of the arene ring could be well-tolerated with this catalytic
system, accessing the corresponding products 3ssa–3vva in
43%–60% yields. Notably, 1,7-diyne 1ww with a C4 chloro group
in the internal arene also exhibited a good reactivity (3wwa).
Similarly, CBr4 (2c) was found to be favorable for this reaction
system, and products 3ssc, 3xxc, 3vvc and 3wwc were provided,
albeit with moderate obtainable yields.
Scheme 4 Scope with respect to the b-gem-dihalovinyl ketones 3.
afforded the corresponding b-alkynyl ketone 4 in 90% yield.12
Alternatively, the Pd-catalyzed cross coupling between 3ac and
p-tolyl boronic acid in toluene gave cyclopenta[a]naphthalen-3-
ol 5a in 75% yield.13 Interestingly, diethyl phosphite-mediated
intramolecular cyclization of 3ac provided brominated
cyclopenta[a]naphthalen-3-ol 5b in 93% yield.14 Moreover, the
SNV-type reaction of 3ac with p-toluenethiol occurred smoothly
in the presence of NaH, leading to the product 6 in 87% yield.15
On the basis of the above observations and control experi-
ments (See the ESI†) as well as literature reports,8,9,16 a reason-
able mechanism for product 3 was proposed in Scheme 6. First,
the Ir(III) complex is converted into the excited state of the
*Ir(III) complex under visible light irradiation. Radical inter-
mediate A is formed via a single electron transfer (SET) process
from the *Ir(III) complex and CBrCl3, together with Ir(IV) species.
Next, the addition of A to the terminal C–C triple bond of 1,7-
diynes 1 and the following 6-exo-dig cyclization produces
alkenyl radical C, followed by the radical cross coupling with
the Br radical from the oxidation of Brꢀ by Ir(IV) species17 to
intermediate D (detected by HRMS). Tꢀhen, intermediate D
undergoes 1,5-(SN00)-substitution of OH from H2O in the
presence of the base, giving intermediate E (detected by
HRMS), which removes HBr in the presence of the base to
afford F (detected by HRMS). Intermediate F is converted into
the final gem-dihalovinyl ketone 3aa through dehydration.
In summary, we have discovered a general and practical
photocatalytic Kharasch addition/SN00-substitution cascade of
The presence of the gem-dihalovinyl and the carbonyl moi-
eties offers flexible late-stage modifications (Scheme 5). For
instance, treatment of 3ac with TBAFꢁ3H2O in toluene cleanly
Scheme 3 Scope with respect to the naturally derived products 3.
Scheme 5 Synthetic elaboration of the b-gem-dibromovinyl ketones.
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21871112, and 21971090), the Graduate Education Innovation
Project of Jiangsu Province (No. KYCX20_2250) and the Top-
Notch Academic Programs Project of Jiangsu Higher Education
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Conflicts of interest
There are no conflicts to declare.
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