Acetonitrile Activation: An Effective Two-Carbon Unit for Cyclization

Article abstract of DOI:10.1002/anie.201900947

A novel activation of acetonitrile for the construction of cyclobutenones by [2+2] cyclization was developed. Acetonitrile is utilized for the first time as two-carbon (C2) cyclization building block. The present protocol successfully inhibits the competitive cycloaddition with the C≡N bond of acetonitrile, but enables the in situ formation of an unsaturated carbon–carbon bond and the subsequent cycloaddition as a C2 unit. This chemistry features simple reaction conditions, high chemoselectivities, wide substrate scope, and offers a new and practical approach to cyclobutenones and cyclobuteneimines.

Full text of DOI:10.1002/anie.201900947

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Accepted Article
Title: Acetonitrile Activation: An Effective C2 Cyclization Unit
Authors: Ning Jiao, Qixue Qin, Xiao Luo, Jialiang Wei, Yuchao Zhu,
Xiaojin Wen, and Song Song
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900947
Angew. Chem. 10.1002/ange.201900947
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Acetonitrile Activation: An Effective C2 Cyclization Unit
Qixue Qin, Xiao Luo, Jialiang Wei, Yuchao Zhu, Xiaojin Wen, Song Song, Ning Jiao*
Abstract:
A
novel acetonitrile activation for construction of
unknown and very challenging (Scheme 1b), because there is no
required unsaturated carbon-carbon bond. In addition, the
potential competitive cycloaddition with the C≡N triple bond also
restrict its possibility as a C2 cyclization unit.
cyclobutenones via [2+2] cyclization is developed. Acetonitrile is
utilized for the first time as C2 cyclization building block. The present
protocol successfully inhibits the competitive cycloaddition with the C
≡N triple bond, but enables the in situ formation of unsaturated
carbon-carbon bond and the subsequent cycloaddition as a C2 unit.
This chemistry features simple reaction conditions, high
chemoselectivities, wide substrate scopes, and offers a new and
practical approach to cyclobutenones and cyclobuteneimines.
Herein, we describe a novel metal-free triflic anhydride (Tf2O)
mediated [2+2] cycloaddition reaction using acetonitrile as C2
building block under mild reaction conditions (Scheme 1c). The
unsaturated C=C bond was generated in situ by this metal-free
strategy and selectively participated in this cycloaddition reaction
for construction of four-membered carbon rings. Remarkably,
through the reaction conditions selection, this chemistry can
provide a general and highly efficient approach to cyclobutenones
and cyclobuteneimines respectively (Scheme 1c), which are
widely used as versatile synthon in organic synthesis including
the total synthesis of naturally occurring or biologically target
molecules.[12]
Of the various types of reactions, cyclization and cycloaddition
reactions have been widely used in synthetic chemistry for the
construction of (hetero)cyclic compounds.[1] C2 unit presents a
versatile synthon for direct incorporation of two carbon chain in
cyclization reactions. In the past decades, the simplest and
abundant two-carbon molecules, ethylene,[2] acetylene[3] have
been employed as C2 building blocks for the formation of small-
and medium-sized cyclic compounds especially through
cyclometallation reactions (Scheme 1a). Despite their
significance, the direct incorporation of ethylene or acetylene into
cyclic compounds is still very limited[4] due to the gas-phase
reactants. Alternatively, trihaloethenes[5] were used as C2
building block in cycloaddition reactions, such as Diels-Alder
reactions,[6] [2+2] cycloaddition[7] and 1,3-Dipolar cycloaddition[8]
(Scheme 1a). However, the toxicity and the multiple-step
preparation of trihaloethene substrates restrict their further
application. For example, 1,1,2-trichloroethene has been
classified as human carcinogen.[9] Furthermore, most of the
cycloaddition processes still require harsh conditions or photo-
irradiation with the generation of halogenated products. Therefore,
it is highly attractive and very challenging to develop new reagents
that could be used as a mild C2 building block in cycloaddition
reactions.
Due to its abundance, low cost and low toxicity, acetonitrile has
been widely used as common solvent in laboratory and industry.
In addition, its inherent nitrile group and the relative active α-
C(sp3)-H bond enable it a valuable reactant used in a series of
Scheme 1. Cyclizations with C2 Building Blocks.
chemical transformations.[10] Among them,
a
variety of
cycloaddition reactions including [4+2]/[2+2+2] cyclization with
the nitrile group of the acetonitrile were developed to construct
nitrogen-containing cyclic compounds (Scheme 1b).[11] To the
best of our knowledge, however, the cycloaddition with the two
carbons of acetonitrile serving as a new C2 building block is still
For our continuous research interest in the construction of
nitrogen- or oxygen-containing cyclic compounds,[13] we started
the initial study towards the [2+2] cyclization by using 1a and
acetonitrile as the model reaction. We initially investigated this
reaction by employing (PPh3)AuCl as catalyst to activate the
alkyne in the mixed solvent of CH3CN/Toluene under Ar
o
atmosphere at 70 C (entry 1). Unfortunately, no product was
[*]
Q. Qin, X. Luo, J. Wei, Y. Zhu, X. Wen, S. Song, and Prof. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University,
Xue Yuan Rd. 38, Beijing 100191, China
obtained even with other catalysts such as Pd(OAc)2 and
Cu(OTf)2 (see Table S1, SI). To our delight, when triflic
anhydride (Tf2O) was used as an additive, the cycloaddition with
the two carbons of acetonitrile serving as a new C2 building
block occurred, and yielded the mixture of 4-membered carbon
ring products cyclobutenone 2a and cyclobuteneimine 3a (entry
2). In contrast, no product was detected when Trifluoroacetic
anhydride (TFAA) and Bis(trifluoromethanesulfonyl)imide
(Tf2NH) were used instead of Tf2O (entry 3 and entry 4). Further
investigation indicated that this transformation could proceed
Prof. N. Jiao
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, East China Normal University, Shanghai 200062, China
Fax: (+) 86-10-82805297
E-mail: jiaoning@pku.edu.cn
Homepage: http://sklnbd.bjmu.edu.cn/nj
Supporting information for this article is given via a link at the end of
the document.
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under metal free conditions, producing the mixture of 2a and 3a
in 53% yield (2a:3a = 1:17, entry 5). Interestingly, 62% yield of 2a
and 3a (2a:3a = 1:8) could be achieved with proton sponge (PS)
as base (entry 6). Furthermore, when decreased the loading of
PS to 25 mol%, the reaction produced cyclobuteneimine 3a as the
almost sole product in 66% yield (entry 7). It is noteworthy that the
reaction did not work in the absence of Tf2O (entry 8). Since the
2a might be originated from 3a by hydrolysis, 0.3 mL of H2O was
added in this reaction which afforded cyclobutenone 2a as the
sole product in 68% yield (entry 9). The efficiency and selectivity
were not affected in dark reaction (entry 10).
corresponding cyclobutenone product 2u in 71% yields.
Unfortunately, the efficiency of the terminal alkyl alkyne (1v) was
low under these conditions. Moreover, other nitriles, such as
butyronitrile and benzeneacetonitrile were not suitable for this
transformation, which gave only trace amount of desired products
(2w, 2x). It is noteworthy that these cyclobutenones could not be
obtained by the protocols with amides as the precursor (see
SI),[15] which demonstrate that the present approach would be
complementary to the amide-based routes to cyclobutenones
which could not be used in the preparation of α-unsubstituted
cyclobutenones.
Table 1. Reaction Conditions Investigation[a]
Entry
Cat.
Additive
-
base
DBU
DBU
DBU
DBU
DBU
PS
Yield(2a/3a)[b]
1
(PPh3)AuCl
0
2
(PPh3)AuCl
Tf2O
TFAA
Tf2NH
Tf2O
Tf2O
Tf2O
-
57% (1:16)
0
3
(PPh3)AuCl
4
(PPh3)AuCl
0
5
-
-
-
-
-
-
53% (1:17)
62% (1:8)
66% (1:20)
0
6
7[c]
PS
8[c]
PS
9[c,d]
10[c, d, f]
Tf2O
Tf2O
PS
68% (>20:1)[e]
63% (>20:1)[e]
PS
[a] Reaction conditions: 1a (0.5 mmol), Tf2O (3.0 equiv), base (1,0 equiv),
CH3CN/Toluene (2.5 mL/2.5 mL), stirred at 70 oC under Ar for 24 h. [b] Yields
were determined by 1H NMR using 1,1,2,2-Tetrachloroethane as an internal
standard. [c] The loading of PS was decreased to 25 mol%. [d] When 1a was
consumed, H2O (30.0 eq) was added for another 2 h reaction. [e] Isolated yields.
[f] The reaction was conducted in dark.
Under the optimized reaction conditions, we next studied the
generality of this transformation for the preparation of
cyclobutenones by exploring the scope of alkynes (Scheme 2). A
variety of aryl and alkyl substituted alkynes were tolerated in this
transformation. In addition, both terminal alkynes and internal
alkynes performed well under these conditions. Notably, this
transformation proceeded in good efficiency and high
regioselectivity when aryl internal alkynes (1a-1j) were explored
(2a-2j). Some functional groups, such as -Cl, -OTs, -OBz, -NPhth,
-Br were tolerated in this transformation (2d-2h). The structure of
2k was confirmed by X-ray analysis.[14] It was noteworthy that
when enynes which could cause the competitive reactions with
alkene or alkyne group were used as the substrates (1s, 1t), the
C=C bonds were not touched by this protocol, but producing the
desired conjugated cyclobutenone products in moderate yields
still with high regioselectivities (2s, 2t). The cyclic alkyne also
performed well under the standard conditions giving the
Scheme 2. Scope of Alkyne Partners for Cyclobutenones. Reaction conditions:
1 (0.5 mmol), Tf2O (3.0 equiv), ProntonSponge (25 mol%), CH3CN/Toluene (2.5
mL/2.5 mL), stirred at 70 oC under Ar for 24 h, followed by addition of H2O (30.0
eq) at 70 oC for 2 h. Isolated yields. rr is regioisomeric ratio. [a] The reaction
was conducted in 10.0 mmol.
Notably, these transformations could be stopped at the stage of
imine in the absence of H2O. For some selected examples
(Scheme 3), varies of cyclobuteneimines (3b-3g) were obtained
with good yields and regioselectivities, which indicated the
product diversity of this transformation. The structure of 3e was
also confirmed by X-ray analysis.[16]
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To get insight into the mechanism, the reaction with CD3CN
was investigated, which afforded the desired deuterated product
D-3b’ in 82% yield (Eq. 4). This result demonstrates that the two
carbons of cyclobutenones were derived from acetonitrile.
Interestingly, we found the hydrogen atoms at one allyl position
were also deuterated. Further deuterium exchange control
experiments indicated that this process may occur after the [2+2]
Scheme 3. Scope of Alkyne Partners for Cyclobuteneimines. Reaction
conditions:
1 (0.5 mmol), Tf2O (3.0 equiv), ProntonSponge (25 mol%),
CH3CN/Toluene (2.5 mL/2.5 mL), stirred at 70 oC under Ar for 24 h. Isolated
yields.
Moreover, this reaction was applied to late stage modification
of complex bioactive molecules containing alkyne group (Scheme
4). To be specific, 4 bearing a steroid scaffold was subjected to
standard conditions and afforded the corresponding product 5 in
52% yield. Additionally, 6 derived from Borneol produced the
desired product 7 in 54% yield under these mild conditions. These
two products may present potential biological activity in medicinal
chemistry.
cyclization reaction through
a
keto-enol/imine-enamine
tautomerism process (Eq. 5, also see SI). On the basis of the
above results, a plausible reaction pathway was proposed in
Scheme 5. As Tf2O is a widely used in synthetic chemistry to
generate triflate moieties with carbonyl substrates.[18] We believe
that the acetonitrile is initially activated by Tf2O to afford the key
intermediate I, which subsequently undergoes formal [2+2]
cyclization reaction with alkyne to produce the cyclobutene imine
3. The further hydrolysis of 3 in the presence of H2O yields the
final cyclobutenone product 2.
Scheme 4. Late-stage Modification of Estrone and Borneol Derivatives.
Due to their inherent ring strains and the great electrophilicity of
carbonyl unit, cyclobutenones usually possess unique
reactivity.[12] It was interesting that the epoxidized product 8 was
produced in 83% yield from 2b in the presence of m-CPBA (Eq.
1). 2b also executed Horner–Wadsworth–Emmons reaction well
to give four membered cyclic diene product 9 in 66% yield (Eq. 2).
Furthermore, owing to their inherent high ring strain, 2b readily
underwent nucleophilic addition/4π-ring opening/6π-ring closing
cascade reactions to give more versatile cyclohexenone 10 in
73% yield (Eq. 3).[17] These reactions demonstrate that
cyclobutenones could serve as versatile synthons for the further
synthesis of various structurally attractive and biologically
important molecules.
Scheme 5. Proposed Mechanism
In conclusion, we discovered a novel Tf2O mediated acetonitrile
activation for the construction of cyclobutenones via [2+2]
cyclization. In contrast to the reported cycloaddition reaction with
the nitrile group of acetonitrile, we realized the cycloaddition
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first time. This chemistry provides an efficient approach to
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construction of complex molecules. Further investigation of this
cyclization using acetonitrile as C2 unit is ongoing in our
laboratory.
Acknowledgements
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Financial support from the National Basic Research Program of
China (973 Program) (No. 2015CB856600), the National Natural
Science Foundation of China (21632001, 21772002, 81821004),
and the Major changes in the central level support projects
(2060302) are greatly appreciated. We thank Weijin Wang in this
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Keywords: Acetonitrile activation • C2 cyclization unit • [2+2]
cyclization • cyclobutenones
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Qixue Qin, Xiao Luo, Jialiang Wei,
Yuchao Zhu, Xiaojin Wen, Song Song
and Ning Jiao*
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Acetonitrile Activation: An Effective
C2 Cyclization Unit
Text for Table of Contents
Text for Table of Contents
In contrast to the reported cycloaddition reaction with the nitrile group of acetonitrile, this work realized a novel [2+2] cycloaddition
reaction for construction of cyclobutenones using acetonitrile as a C2 cyclization building block for the first time.
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