Regio- and stereoselective synthesis of cyclobutanes by nickel-catalyzed homodimerizative [2 + 2] cycloaddition using allenamides

Article abstract of DOI:10.1016/j.tetlet.2021.152974

Highly regio- and stereoselective homodimerizative [2 + 2] cycloaddition of allenamides under nickel catalysis was developed. Xantphos is an essential ligand to give “tail to tail” products and DFT studies revealed that oxidative addition between a nickel

Full text of DOI:10.1016/j.tetlet.2021.152974

Tetrahedron Letters 69 (2021) 152974
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Tetrahedron Letters
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Regio- and stereoselective synthesis of cyclobutanes by nickel-catalyzed
homodimerizative [2 + 2] cycloaddition using allenamides
Yuna Kawata , Shigeru Arai a,b, , Masaya Nakajima , Atsushi Nishida
a
⇑
a
a
a
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly regio- and stereoselective homodimerizative [2 + 2] cycloaddition of allenamides under nickel
catalysis was developed. Xantphos is an essential ligand to give ‘‘tail to tail” products and DFT studies
revealed that oxidative addition between a nickel(0) complex and two distal C@C bonds of the allena-
mides would be a key process. Sequential formation of the metallacycle intermediate would proceed
in both a regio- and stereoselective manner to give the corresponding cyclobutane as a single isomer.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 7 February 2021
Revised 26 February 2021
Accepted 1 March 2021
Available online 9 March 2021
Keywords:
Nickel
Cycloaddition
Allenamides
DFT study
Homodimerization
Introduction
choice of xantphos is essential to achieve higher selectivity and
efficacy, which could be reasonably explained by DFT studies.
Cyclobutanes are important structural motifs for biologically
important compounds and natural products [1,2]. Their efficient
synthesis has been a major topic in synthetic organic chemistry
and one of the most reliable strategies for obtaining them has been
the [2 + 2] cycloaddition reaction [3–5]. In particular, the use of
allenes (C@C=C) as C2 components has been attractive because of
their higher reactivity compared to simple olefins and the syn-
thetic utility of the products involving additional C@C bonds [6–
These suggest that the initial metallacycle formation would deter-
mine both the regio- and stereoselectivity of the products. This
unprecedented ‘‘tail to tail” mode of cycloaddition through homod-
imerization of allenamides would also provide a new synthetic
option in metal catalysis, since Saito and co-workers have used
the simple allenes for the nickel-catalyzed [2 + 2] cycloaddition
reaction [25].
Our previous and preliminary studies on nickel- catalyzed
[2 + 2] cycloaddition effectively discriminated C@C bonds in
allenes and allenamides (Scheme 2). For example, bisallene (1a)
smoothly underwent an intramolecular reaction to give ‘‘head to
1
3]. To enhance the synthetic utility of allenes, the use of allena-
mides (N-C@C=C) has been option to give nitrogen-functionalized
cyclobutanes [14,15], and various metal species [16] including gold
complexes [17–22] have been shown to be effective catalysts for
heterodimerizative [2 + 2] cycloaddition.
On the other hand, the catalytic applications of a homodimer-
izative strategy for [2 + 2] cycloaddition using allenamides have
been limited to only 2 modes of cycloaddition (Scheme 1). One of
these is rhodium catalysis, which connects two proximal bonds
(
red) to give ‘‘head to head” trans-cycloadducts (Eq. (1a)) [23],
whereas gold catalysis promotes ‘‘head to tail” dimerization (eq.
b) [24]. An alternative synthetic method to an as yet unknown
1
carbon skeleton would be highly desirable and we herein describe
a new application of ‘‘tail to tail” homodimerization (eq. 1c). The
⇑
Corresponding author.
E-mail address: araisgr@chiba-u.jp (S. Arai).
Scheme 1. Metal-Catalyzed Homodimerizative [2
Allenamides.
+
2] Cycloaddition of
https://doi.org/10.1016/j.tetlet.2021.152974
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0

Y. Kawata, S. Arai, M. Nakajima et al.
Tetrahedron Letters 69 (2021) 152974
indicates that the distal bond of allenamides favorably dimerized
to the cyclobutene, regioselectively (Eq. (2b)) [26]. When a mixture
of 1a and 3a was subjected to similar conditions, 2a and 4a were
isolated in respective yields of 64% and 60% without any further
cycloaddition products such as 5 and 6 (eq. 2c). The regio- and
stereochemistry of 4a was confirmed to be (E,E) by X-ray crystallo-
graphic analysis [28]. These results prompted us to better under-
stand the behavior and reactivity of 3a and to continue further
investigations for the establishment of a new catalysis.
Scheme 2. Reactivity of Allenes and Allenamides under Nickel-Catalyzed [2 + 2]
Cycloaddition.
head” products (2a) exclusively (eq. 2a) [26,27], whereas the
allene-allenamide (1b) promoted a [2 + 2]/[4 + 2] cycloaddition
sequence to give a single ‘‘tail to tail” product (2b). Its structure
Table 1
Optimization of reaction conditions.
Entry Change from standard conditions
Yield of
Recov. of
3a %
a
4
a %
1
2
3
4
5
6
7
8
9
70 °C, 5 min
rt, 16 h
No xantphos, 70 °C, 30 min
75
7
2
44
14
81
67
0
0
87
0
3
9
0
0
90
92
PPh
dppb (10 mol%), 50 °C, 5 min
CH Cl , 50 °C, 5 min
3
(20 mol%), 50 °C, 5 min
2
2
THF, 50 °C, 5 min
No nickel catalyst, 50 °C, 30 min
No nickel catalyst,, no xantphos, 50 °C,
0
3
0 min
P(OPh)
catalyst, 50 °C, 30 min
NiCl (10 mol%) with xantphos (10 mol%),
0 °C, 30 min
1
0
1
3
(40 mol%) instead of nickel
0
0
46
98
1
2
5
a
Chemical yields of 4a were determined by 1H NMR analysis using Ph
3
CH as an
Scheme 3. Substrate Scope for Homodimerizative [2 + 2] Cycloaddition using
internal standard.
a)
3b-j
.
2

Y. Kawata, S. Arai, M. Nakajima et al.
Tetrahedron Letters 69 (2021) 152974
Fig. 1. Energy Diagram for Ni-Catalyzed Homodimerizative [2 + 2] Cycloaddition.
We initiated our studies by investigating the cycloaddition of 3a
under standard conditions [Ni[P(OPh) (10 mol%), xantphos
10 mol%), toluene, 50 °C). The reaction went to completion in
fonyl group on nitrogen was investigated to give 4 g in 97% yield.
In all cases, the reaction proceeded to exclusively give the corre-
sponding cycloadducts as a single isomer. A reactive moiety of
the aromatic bromide bond in 3h was unsuitable due to its reactiv-
ity toward Ni(0) species and the messy reaction gave no cycload-
ducts. The substituents around the allenyl double bonds in 3
gave a serious decrease in reactivity; for example, a methyl group
3 4
]
(
5
min to give 4a in 82% yield without any regio- or stereoisomeric
products. Higher temperature (70 °C) was also effective to com-
plete the reaction in 5 min, however the yield of 4a was slightly
decreased (entry 1). A room temperature condition was ineffective
and gave 4a in only 4% yield and 3a was recovered in 87% yield
even after 16 h (entry 2). The absence of xantphos prevented both
the conversion to 4a and the recovery of 3a, and unidentified prod-
2
(R ) in 3i and an aryl group in 3j both prevented cycloaddition and
the expected adducts were not obtained at all even after 5 h. This
would be because the steric bulk of substituents would be unsuit-
able for interacting with a nickel complex and the reaction resulted
in recovery of the starting allenamides in respective yields of 93%
and 87%.
ucts were observed (entry 3). Other phosphines such as PPh
1
4
3
and
,4-diphenylphosphinobutane (dppb) gave lower conversion to
a during the decomposition of 3a (entries 4 and 5). The use of
dichloromethane and THF as solvents at 50 °C gave the exclusive
formation of 4a in respective yields of 81% and 67% (entries 6
and 7). This reaction did not proceed without nickel(0) species
with/without xantphos (entries 8 and 9). The eliminated phosphite
To obtain insights into the mechanism of this catalytic transfor-
mation, we performed density functional theory (DFT) calculations
(M06/LANL2DZ/6-31G*) with I as a model substrate (Fig. 1). These
DFT studies suggested that the reaction is initiated by the forma-
tion of CP1a. The key feature for promotion of CAC bond formation
is tetrahedral approach by a Ni(0)-xantphos complex [29], and the
metallacycle formation would be help to overcome the activation
energy through TS1a (9.8 kcal/mol). Other possible transition-state
models such as TS1b and TS1c would be unlikely to form the cor-
responding metallacycles because of their higher activation ener-
gies of 25.7 kcal/mol and 24.3 kcal/mol, respectively (see the
Supporting Information). After distortion of the P-Ni-P angle is
released to INT1a’ (from 136° to 106°), the subsequent reductive
elimination step to TS2a requires 9.0 kcal/mol, which could be
accelerated by the larger bite angle of xantphos [30]. Finally, the
dissociation of II from CP2a generates a Ni-xantphos complex to
promote catalytic turnover. The tetrahedral nickel center in both
would not give any influence because the reaction using P(OPh)
3
(
40 mol%) did not work act as a promotor at all (entry 10). Finally,
2
a catalytic amount of NiCl instead of Ni(0) also gave the recovery
of 3a. The results summarized in Table 1 show the Ni(0)-xantphos
is an essential combination to promote the [2 + 2] cycloaddition
reaction of 3a.
The optimum condition (toluene, 50 °C) were next applied with
various substrates (Scheme 3). The electronic effect of the para
substituents in 3b and 3c did not influence the reaction efficacy
and gave the corresponding products 4b and 4c in respective yields
of 82% and 78%. N-Alkyl groups instead of aryl groups were also
effective for a smooth cycloaddition reaction; for example, N-Ben-
zyl substrate gave 4d in 76% yield. Substrates bearing phenethyl
and isopropyl groups were both quickly transformed to give 4e
and 4f in respective yields of 63% and 68%. Finally, a methanesul-
TS1a and TS2a could minimize the steric repulsion between PPh
and N(Ms)Me groups, and their activation energies (less than
2
3

Y. Kawata, S. Arai, M. Nakajima et al.
Tetrahedron Letters 69 (2021) 152974
1
0 kcal/mol) are much smaller than those of the reverse processes
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Appendix A. Supplementary data
[
(
2000) 2741–2769.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152974.
4