Copper-Catalyzed Intermolecular Heck-Like Coupling of Cyclobutanone Oximes Initiated by Selective C?C Bond Cleavage

Article abstract of DOI:10.1002/anie.201707181

The first example of intermolecular olefination of cyclobutanone oximes with alkenes via selective C?C bond cleavage leading to the synthesis of nitriles in the presence of a cheap copper catalyst is reported. The procedure is distinguished by mild and safe reaction conditions that avoid ligand, oxidant, base, or toxic cyanide salt. A wide scope of cyclobutanones and olefin coupling components can be used without compromising efficiency and scalability. The alternative visible-light-driven photoredox process for this coupling reaction was also uncovered.

Full text of DOI:10.1002/anie.201707181

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Communications
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International Edition: DOI: 10.1002/anie.201707181
German Edition: DOI: 10.1002/ange.201707181
À
C C Activation
Copper-Catalyzed Intermolecular Heck-Like Coupling of
À
Cyclobutanone Oximes Initiated by Selective C C Bond Cleavage
Binlin Zhao and Zhuangzhi Shi*
Abstract: The first example of intermolecular olefination of
À
cyclobutanone oximes with alkenes via selective C C bond
cleavage leading to the synthesis of nitriles in the presence of
a cheap copper catalyst is reported. The procedure is distin-
guished by mild and safe reaction conditions that avoid ligand,
oxidant, base, or toxic cyanide salt. A wide scope of cyclo-
butanones and olefin coupling components can be used
without compromising efficiency and scalability. The alterna-
tive visible-light-driven photoredox process for this coupling
reaction was also uncovered.
À
T
he activation and functionalization of C C single bonds by
transition-metal complexes is of fundamental interest and
plays an important role in the synthesis of complex organic
molecules.[1] Because of the presence of multiple C C bonds
À
in an organic molecule with subtle difference in activation
barrier, controlling the positional selectivity is the key
challenge. Cyclobutanones and their derivatives are very
useful intermediates that are widely used in total synthesis of
nature products.[2] Considerable attention has been turned to
À
the selective functionalization via C C bond cleavage over
the years.[3] Transition-metal catalysts, mainly rhodium,[4]
palladium,[5] and nickel[6] complexes, have been successfully
À
Figure 1. Coupling of cyclobutanone derivatives with olefins via C C
bond cleavage.
[7]
À
used for the activation of C C bonds in these compounds.
Murakami and co-workers first reported an intramolecular
cyclization of cyclobutanones bearing styrene-type olefin
substituents to tricyclic ketone in good yields (Figure 1a).[8] In
2014, Dong and co-workers have developed a unique strategy
to enable intramolecular cyclobutanone-olefin coupling
For instance, in a seminal work by Nishimura and Uemura,
a Pd-catalyzed intramolecular olefination of cyclobutanone
oximes was described via b-carbon elimination, where the b-
H elimination and migration of the formed double bond led to
the conjugated a,b-unsaturated nitriles (Figure 1d).[11]
Accordingly, to develop a general intermolecular cyclobuta-
none oxime–olefin coupling reaction that is broadly appli-
cable for the synthesis of cyano-containing olefin products,
the b-H elimination must be overcome and the scope of the
cyclobutanones and olefins must be extended. Compared to
the Pd catalyst, Cu salt[12] is a promising redox catalyst for
Heck-like reaction[13] and free-radical addition of alkenes.[14]
We began our investigations by monitoring the reactivity
of cyclobutanone O-benzoyl oxime (1a) with 1,1-diphenyl-
ethylene (2a) in presence of copper catalysts (Table 1). While
the reaction was found to be facile with 1.2 equiv of 2a in the
presence of the Cu(OTf)2 catalyst (10 mol%) in a binary
solvent system, 1,4-dioxane and trifluorotoluene (v/v = 1:1) at
1008C which afforded the 6,6-diphenylhex-5-enenitrile (3aa)
in 90% isolated yield (entry 1). The copper salt is crucial for
the success (entry 2). Either 1,4-dioxane or trifluorotoluene as
sole solvent provided lower yield (entries 3,4). Intriguingly,
changing the ratio of two components 1a and 2a to 2:1 did not
influence the yield at all, which greatly improved the
practicality (entry 5). At a lower temperature, 708C the
À
through a Rh-catalysed cofactor-assisted C C activation
approach (Figure 1b).[9] Herein, we have reported the first
case on intermolecular Heck-like reaction of cyclobutanone
derivatives with olefins in which nitrile products are derived
À
by a formal Cu-catalyzed C C cleavage of the cyclobutanone
oximes avoiding the use of the toxic cyanide sources (Fig-
ure 1c).
Although the Heck reaction has been widely studied,
challenges in the field include the substrates that bear b-H,
because their alkylmetal intermediate has the strong tendency
to undergo a b-H elimination to generate conjugated olefin.[10]
[*] B. Zhao, Prof. Dr. Z. Shi
State Key Laboratory of Coordination Chemistry
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210093 (China)
E-mail: shiz@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/zzshi/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201707181.
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Table 1: Reaction development.[a]
Table 2: Scope of the olefins.[a]
Entry Variation from the “standard conditions”
Yield of 3aa [%][b]
1
none
95 (90)[c]
2
3
4
without Cu(OTf)2
only 1,4-Dioxane
only PhCF3
0
90
82
5
1a:2a=2:1
93
6
at 708C
73
7
CuI instead of Cu(OTf)2
Cu powder instead of Cu(OTf)2
1a’ instead of 1a
76
8
56
9[d]
96 (91)[c]
10[e] 1a’’ instead of 1a
92 (85)[c]
11
12
Pd2(dba)3·CHCl3/BINAP instead of Cu(OTf)2
[Ir(cod)Cl]2 instead of Cu(OTf)2
0
35
[a] Standard conditions: 1a (0.20 mmol, 1.0 equiv), 2a (0.24 mmol,
1.2 equiv) in 2 mL PhCF3 and 1,4-dioxane (1:1) at 1008C for 12 h, under
argon. [b] Determined by GC. [c] Isolated yields. [d] 1a’=cyclobutanone
O-(4-nitrobenzoyl) oxime. [e] 1a’’=Cyclobutanone O-perfluorobenzoyl
oxime.
results were found inferior than that observed under the
optimal conditions (entry 6). Interestingly, other copper
catalysts such as CuI and even copper powder were also
effective for this transformation albeit with lower yields
(entries 7,8). Further exploration showed that the cyclobuta-
none O-(4-nitrobenzoyl) oxime (1a’) and O-perfluorobenzoyl
oxime (1a’’) could also be converted into 3aa in very excellent
yield (entries 9,10). Synthesis of 3aa could not be observed
under palladium catalysis (entry 11).[11] However, the use of
an iridium complex [Ir(cod)Cl]2[15] instead of Cu(OTf)2 could
result formation of the desired product 3aa in 35% yield
(entry 12).
With the set of optimized reaction conditions in hand, we
À
first examined the scope of various olefin motifs in this C C
cleavage event (Table 2). Using this new method, the reaction
of 1a and 2a could be efficiently accessed on gram scale
without compromising its efficiency. Olefins 2b–2c delivered
the products 3ab and 3ac in moderate yields along with
a small amount of isomer formation. It is worth noting that
styrenes 2d–2g bearing methyl, Br, BPin, and 2-vinylnaph-
thalene (2h) only yielded trans-products. Importantly, diene
2i and enyne 2j reacted smoothly with 1a to produce the
nitriles 3ah–3aj in 58–64% yields. N-Acetyl-1-phenylethen-
amine (2k) delivered a mixture of Z/E isomers (Z/E = 83:17)
in 47% yield. Net benzofuran coupling adduct 3al was
obtained in 84% yield by reaction of 1a with 3-methylene-
2,3-dihydrobenzofuran (2l). Alkylcyanation of vinylestrone
2m could produce 3am in 65% yield. Late-stage modifica-
tion[16] of exemestane proceeded with 1a to form a double
bond migration endo-product 3an with the normal exo-
products in a 64:36 ratio. Trenbolone acetate (1o) is an
extremely powerful anabolic steroid with three different
double bonds, reacted smoothly to generate 3ao in 58% yield
with sole regioselectivity. Coumarin and its derivatives 1p–1t
with remarkable biological activities, such as antitumor, anti-
[a] Reaction conditions: 10 mol% Cu(OTf)2, 1a (0.20 mmol, 1.0 equiv),
2 (0.24 mmol, 1.2 equiv) in 2 mL PhCF3 and 1,4-dioxane (1:1) at 1008C
for 12 h, under argon, isolated yields. [b] 10 mol% Cu(OTf)2, 1a (1.1 g,
6.0 mmol), 2a (1.3 g, 7.2 mmol) in 60 mL PhCF3 and 1,4-dioxane (1:1) at
1008C for 12 h, under argon, isolated yield. [c] Determined by GC-MS
and/or 1H NMR. [d] Using 1a (2.0 equiv). [e] At 608C. [f] Using 1a
(4.0 equiv).
HIV, antioxidant, antibacterial, antiinflammatory, and anti-
psychotic activity,[17] were exposed to the reaction condition
affording the structural modified products 3ap–3at with sole
site-selectivity as well.
À
To further explore the potential of this novel C C
olefination reaction, a series of cyclobutanone derivatives
were examined (Table 3). Symmetrical cyclobutanone deriv-
atives with a wide array of functional groups including phenyl
(1b), benzyl (1c), ester (1d), cyano (1e), ether (1 f), and 4-
methoxy-2-methyl-4-oxobutan-2-yl (1g) could be transferred
to the products 3ba–3ga in 43–89% yields. Di-substituted
cyclobutanone derivatives 1h–1i underwent facile olefina-
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Table 3: Scope of the cyclobutanone oximes.[a]
[a] Reaction conditions: 10 mol% Cu(OTf)2, 1 (0.20 mmol, 1.0 equiv), 2 (0.24 mmol, 1.2 equiv) in 2 mL PhCF3 and 1,4-dioxane (1:1) at 1008C for 12 h,
under argon, isolated yields. [b] At 808C. [c] Determined by GC-MS and/or 1H NMR. [d] At 408C.
tion. The piperidine derivative 1j also showed comparable
reactivity. Remarkably, the reaction of a bulky oxime 1k
could provide a tertiary alkylation product 3ka in 58% yield.
Nonsymmetrical cyclobutanone derivatives 1l–1o delivered
the olefination products 3la–3oa in 68–91% yields, in which
with visible light in the presence of fac-[Ir(ppy)3], a common
visible light-mediated photoredox catalysis, the substrates 1a
and 1a’ were in poor conversion. However, we isolated the
desired product 3aa in 73% yield when employing O-
perfluorobenzoyl oxime 1a’’.[18] Further analysis of oximes
1a–1a’’ by cyclic voltammetry revealed irreversible reduction
profiles that are in accordance with our experimental results
(see the Supporting Information). According to the electro-
À
C C bond cleavage occurred selectively at the more hindered
position. Z/E isomers of bicyclo[4.2.0] type oxime 1p were
separable by column chromatography, which exhibited slight
difference in reactivity and generated trans-product 3qa as
a major product. Moreover, the conversion of bicyclo[3.2.0]
substrate 1q had same stereochemistry with excellent dia-
steroemeric ratio (93:7). Interestingly, oxetan-3-one oxime 1r
provided the corresponding nitrile 3ra in 55% yield. In
addition, benzocyclobutenone derivatives 1s–1u also worked
well under the standard reaction conditions forming the
benzonitrile products 3sa–3ua in 68–93% yields with sole
regioselectivity. Unfortunately, example of less-strained sub-
strates such as 1v only provided the desired product 3va in
trace amount under the current reaction conditions.
Several experiments were conducted to get insight into
the potential mechanism of this transformation. The reaction
with TEMPO, largely inhibited the reaction to form the
product 3aa. Formation of alkylated TEMPO 4 also sug-
gested the existence of radical species in the reaction
(Scheme 1a). Moreover, submitting the olefin 5 to the
standard conditions afforded dihydronaphthalene 7 in 35%
yield. The formation of 7 can be accounted by invoking the
benzylic radical 6 that underwent fragmentation and cycliza-
tion (Scheme 1b). When the reaction mixture was irradiated
Scheme 1. Mechanistic experiments.
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chemical scale, the E1/2 reduction potential of oxime 1a was
completely unsuitable for SET in the excited state of the *IrIII.
This photoredox process not only provided an alternative
approach for this coupling reaction, but also further demon-
strated the high reactivity of copper catalysis in this radical
chemistry (Scheme 1c).
On the basis of the above experimental results, a mecha-
nism has been proposed as shown in Figure 2. The reaction
starts with the generation of cyclobutylideneiminyl radical
Keywords: copper · cyclobutanone · olefination · oximes ·
radicals
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À
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À
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Manuscript received: July 14, 2017
Version of record online: && &&, &&&&
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Communications
À
C C Activation
B. Zhao, Z. Shi*
&&&& — &&&&
Copper-Catalyzed Intermolecular Heck-
Like Coupling of Cyclobutanone Oximes
À
Initiated by Selective C C Bond Cleavage
No construction without destruction: A
copper-catalyzed intermolecular olefina-
tion of cyclobutanone oximes with
ligand, oxidant, base, or toxic cyanide
salt, and a wide scope of cyclobutanones
and olefin coupling components can be
used without compromising efficiency
and scalability.
À
alkenes by C C activation has been
established. The method features mild
and safe reaction conditions that avoid
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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