Selective cine -arylation of tert -cyclobutanols with indoles enabled by nickel catalysis

Article abstract of DOI:10.1039/d1cc01233a

In previous literature, tert-cyclobutanols are widely studied for C-C bond activation exclusively leading to the formation of ordinary γ-substituted ketones. Herein, we first report a nickel-catalyzed cine-arylation of tert-cyclobutanols with indoles to access β-aryl ketones with an unusual site-selectivity at the C3-position of tert-cyclobutanols. The reaction features earth-abundant nickel catalysis, excellent regioselectivity, high atom-economy, and broad substrate scope.

Full text of DOI:10.1039/d1cc01233a

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Selective cine-arylation of tert-cyclobutanols
with indoles enabled by nickel catalysis†
Cite this: Chem. Commun., 2021,
7, 4686
5
Yuanyuan Hu, Honggen Luo, Xiangtu Tu, Han Xue, Hongwei Jin, Yunkui Liu
and
Received 7th March 2021,
Accepted 5th April 2021
Bingwei Zhou
*
DOI: 10.1039/d1cc01233a
rsc.li/chemcomm
In previous literature, tert-cyclobutanols are widely studied for C–C alkanes with a variable chain length dependent on the ring size.
bond activation exclusively leading to the formation of ordinary Among them, cyclobutanols are versatile building blocks that
c-substituted ketones. Herein, we first report a nickel-catalyzed cine- are capable of producing g-substituted ketones via either
7
arylation of tert-cyclobutanols with indoles to access b-aryl ketones with a radical b-fragmentaion or an organometallic b-carbon
8
an unusual site-selectivity at the C3-position of tert-cyclobutanols. The elimination enabling a ring-opening process (Scheme 1b). As
reaction features earth-abundant nickel catalysis, excellent regioselec- a result, a range of g-(or ipso-) functionalization reactions such
tivity, high atom-economy, and broad substrate scope.
as halogenation, azidation, cyanation, arylation, alkynylation,
etc. have been successfully developed over the past several
7
,8
Transition-metal catalyzed site-selective functionalization of decades.
In these events, however, the functional groups
inert C–H bonds is synthetically attractive yet challenging in are exclusively introduced into the C2 (or C4) position, and
organic chemistry. In this regard, great efforts have been the deconstructive functionalization of alicyclic hydrocarbons
devoted to the development of efficient strategies for selective incorporating substituents adjacent to the cleaved C–C bond
9
incorporation of functional groups from the proximal to more (cine-functionalization) remains unexplored.
challenging distal C–H bonds with or without the assistance of
directing groups. Notably, an expedient way to access selec- diverse catalytic reactivity of nickel salts, we envisioned an unpre-
In light of the fantastic chemistry of cine-functionalization and
1
,2
10
tive distal C–H functionalization relies on metal migration via cedented nickel-catalyzed formal dehydrogenative coupling
11
an iterative b-elimination/migratory reinsertion, also termed as reaction merging a C–C bond cleavage and migrated C–H
12
a ‘‘chain walking’’ process, which can be hardly achieved by functionalization. Such a cascade process was visualized operating:
3
other conventional methods (Scheme 1a). For instance, Martin (i) ring-opening of cyclobutanols via C–C bond cleavage; (ii) nickel-
and coworkers described an elegant nickel-catalyzed switchable induced olefin isomerization; (iii) cine-arylation via a Michael
4
site-selective carboxylation of alkyl bromides. The in situ
generated alkyl nickel species from bromoalkanes undergoes
a divergent migration depending on the reaction temperature,
leading to the formation of linear or branched carboxylic
acid selectively. Although an unusual site-selectivity towards C–H
bonds has been addressed, the transformations are often limited in
4,5
substrates, such as linear alkyl olefins and bromides. Further
extending the scope of available substrates and novel coupling
reactions merging selective C–H functionalization is still highly
desirable.
On the other hand, C–C bond cleavage is blossoming as an
alternative tool for the diversification of readily accessible cyclic
6
skeletons. This approach renders 1,n-bifunctionalized acyclic
College of Chemical Engineering Zhejiang University of Technology,
Hangzhou, 310014, China. E-mail: zhoubw@zjut.edu.cn
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc01233a
Scheme 1 Strategies for distal functionalization.
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addition. Furthering our continued research work on nickel examined under the standard reaction conditions. A range of phenyl
13
catalysis, we herein present the first nickel-catalyzed cine-arylative groups with electron donating groups were fairly tolerated giving the
ring-opening reaction of tert-cyclobutanols with indoles (Scheme 1c). products in good yields (3m–s, Scheme 3). The reaction of tert-
Note that the C3-position of tert-cyclobutanols instead of the cyclolbutanols bearing o-tolyl or 1-naphthyl groups proceeded slug-
ordinary C2 or C4-position can be selectively functionalized thus gishly, presumably due to the steric hindrance of alcohols (3t and 3v,
featuring excellent regioselectivity and high atom-economy in this Scheme 3). 1-(Benzo[d][1,3]dioxol-5-yl)cyclobutan-1-ol 1k and 1-(thio-
protocol.
phen-2-yl)cyclobutan-1-ol 1l were also viable substrates delivering the
The standard reaction conditions in Scheme 2 were obtained by corresponding product 3w and 3x in 51% and 40% yield, respec-
screening various reaction parameters (see the ESI† for details). We tively. In addition, less steric 1-alkyl substituted cyclobutanols under-
then commenced evaluating the substrate scope of indoles. As with went the transformation smoothly to provide the desired products
the model substrate 2a, other 2-methylindoles with different sub- in moderate yields (3y–z, Scheme 3). Finally, the reaction of 1,
stituents at the 5-position were subjected to the optimized reaction 2-disubstituted cyclobutanol 1q with 2a was examined and the
(conditions A) providing the corresponding products in moderate product 3A was isolated albeit in a low yield (3A, Scheme 3).
to good yields (3a–d, Scheme 2). To further extend the generality of Further experiments were carried out to shed light on the
indole, we employed parent indole 2e as a coupling partner instead plausible reaction mechanism. We first conducted a radi-
of 2a. Unfortunately, the desired product 3e was isolated in a low cal trapping experiment by using TEMPO, BHT, and 1,
yield (9%) under the standard reaction conditions. We again 1-diphenylethene as radical scavengers. As a result, all the
screened the reaction parameters and the yield of 3e could be reactions were thoroughly inhibited which suggested that a
improved significantly by employing conditions B. In general, radical pathway might be involved in this transformation
indoles bearing electron donating groups showed superior reactiv- (Scheme 4a). However, the TEMPO-adduct could not be isolated
ity over those with electron withdrawing ones (3f–l, Scheme 2). Of
note, the halogens such as Cl or Br and the BPin group were
compatible in the reaction (3j–l, Scheme 2). Eventually, a gram-
scale reaction of 1m and 2a was conducted. To our delight, the
reaction proceeded smoothly under the standard reaction condi-
tions affording the product 3a in 72% yield.
Next, we continued to investigate the substrate scope of
tert-cyclobutanols. First, 1-aryl substituted cyclobutanols were
Scheme 2 Substrate scope of indoles. Conditions (A): 1m (0.2 mmol), 2
t
(
0.4 mmol), Ni(PPh
3 2
) Br
2
(5 mol%), Ox2 (1.2 equiv.), NaO Bu (2 equiv.),
Toluene (0.5 mL), at 80 1C for 12 h. Conditions (B): 1m (0.2 mmol), 2
t
(
(
0.4 mmol), NiBr
2 equiv.), Toluene (0.5 mL), at 80 1C for 12 h. [a] Conducted on a 5 mmol
2
(20 mol%), L3 (20 mol%), Ox5 (1.2 equiv.), NaO Bu
Scheme 3 Substrate scope of tert-cyclobutanols. Conditions: 1 (0.2 mmol),
t
3 2 2
2a (0.4 mmol), Ni(PPh ) Br (5 mol%), Ox2 (1.2 equiv.), NaO Bu (2 equiv.),
scale. [b] Under the standard reaction conditions (conditions (A))
toluene (0.5 mL), at 80 1C for 12 h.
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Scheme 5 Deuterium experiments.
deuterium experiments indicated that the alkene isomerization
1
5
might take place via a Ni(I)-involved 1,3-H shift and the
resultant conjugated ketone was readily captured by the indole
t
with the assistance of NaO Bu.
A possible reaction mechanism is depicted in Scheme 6
based on the preliminary mechanistic experiments and pre-
1
5–18
vious literature.
We conjecture that a low-valent nickel
species Ni-II in situ generated from the nickel salt may trigger
1
6
the catalytic reaction. The oxidative addition of Ox2 to Ni-II
yields the intermediate Ni-III followed by ligand exchange with
tert-cyclobutanol. The formed Ni alcoholate Ni-IV undergoes a
ring opening process via C–C bond cleavage to produce an alkyl
Scheme 4 Preliminary mechanistic experiments.
17
nickel species Ni-V. A reductive b-H elimination reaction
takes place to generate an intermediate 7a-Ni which further
1
5
from the reaction. Next, we conducted the reaction of 1m with transforms to 6a-Ni via a radical alkene isomerization.
3
-bromoindole in the absence of an oxidant (Scheme 4b). As a Finally, the Michael addition of 6a with indole 2 provides the
result, both 3e and 4e could not be detected which indicated product 3 and releases the Ni-II.
1
8
that the intermediate Ni-I might not be involved in the catalytic
In conclusion, the first site-selective formal dehydrogenative
cycle, while the Ni-V in Scheme 6 was a plausible intermediate coupling reaction of tert-cyclobutanols with indoles has been
since the reaction of 1m with 2a produced the side product 5a successfully developed. Surprisingly, an array of b-indolyl
albeit in a low yield (Scheme 4c). Furthermore, we examined the ketones were obtained in moderate to good yields featuring
reaction of unsaturated ketones 6a and 7a with indole, respec- readily available nickel catalysis, excellent regioselectivity and a
tively (Schemes 4d and e). Consistent with our initial assump- high atom economy. Further investigations on the site-selective
tion, product 3a was isolated exclusively in both reactions. It
could be inferred that 6a and 7a are probably the key inter-
mediates in the migration reaction. However, no 3a could be
obtained if the reaction of 7a with 2a was conducted in the
absence of nickel salt (Scheme 4e).
Deuterium experiments were then performed to clarify the
detailed process for cine-arylation (Scheme 5). First, we pre-
pared the deuterated tert-cyclobutanol 1m-d
to the standard reaction by using Ox3 as an oxidant
Scheme 5a). The product 3a was isolated in 62% yield and
4
and subjected it
(
1
the H/D exchange was examined by H NMR analysis. It turned
out that the deuterium atoms at one C2-position of 1m-d
almost remained intact at the g-position of the product 3a-d
4
2
.
However, the deuterium atom at the other C2-position was fully
replaced by a hydrogen atom at the a-position of 3a-d due to
the rapid keto–enol tautomerism in the presence of a strong
2
1
4
base. This rapid H/D exchange was further supported by
conducting a model reaction treated with D O (Scheme 5b).
2
In addition, no deuterium was incorporated into the b-position
of 3a-d
and the 3-hexylthiophene 8a (Scheme 5a). These Scheme 6 Plausible reaction mechanism.
2
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functionalization of less strained cycloalcohols enabled by
nickel catalysis are underway in our laboratory.
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Conflicts of interest
8
9
There are no conflicts to declare.
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