Nickel-catalyzed [2?+?2] cycloaddition reaction using bisallenes

Article abstract of DOI:10.1016/j.tetlet.2019.151168

A nickel-catalyzed [2 + 2] cycloaddition of bisallenes has been described. Simple bisallenes are employed for the formation of “head to head” cycloadducts in the presence of Ni(0) with xantphos. The dienyl moiety in a product were applicable for various [

Full text of DOI:10.1016/j.tetlet.2019.151168

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nickel-catalyzed [2 + 2] cycloaddition reaction using bisallenes
Shigeru Arai a,b, Yuna Kawata a, Yuka Amako a, Atsushi Nishida a,b
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Chuo-ku, Inohana, Chiba 260-8675, Japan
b Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A nickel-catalyzed [2 + 2] cycloaddition of bisallenes has been described. Simple bisallenes are employed
for the formation of ‘‘head to head” cycloadducts in the presence of Ni(0) with xantphos. The dienyl moi-
ety in a product were applicable for various [4 + 2] cycloaddition reactions. Allene-allenamides under Ni-
xantphos system gave the tricyclic compounds through sequential [2 + 2]–[4 + 2] cycloaddition reaction
in highly stereoselective manner.
Received 10 August 2019
Revised 14 September 2019
Accepted 17 September 2019
Available online xxxx
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Allenes
Nickel
Cycloaddition
Allenamides
Introduction
nents for further application and investigated regio- and
stereocontrolled [2 + 2] cycloaddition.
Cyclobutanes are privileged structural motifs for biologically
important molecules [1], and their efficient synthesis has been
major topics in synthetic organic chemistry. One of the most rapid
and facile synthetic approaches to the functionalized cyclobutanes
has been [2 + 2] cycloaddition reaction under photo irradiation,
thermal conditions and metal catalysis [2,3]. In particular, allenes
as ‘‘activated olefins” have been utilized as versatile C2-components
due to their strong affinity to metal complexes and successfully
applied in [2 + 2] cycloaddition reaction mediated by various metal
species [4]. For example, symmetric bisallenes with a Pd(0) cata-
lyst gave ‘‘head to head” cycloadducts [5,6], whereas thermal con-
ditions [6] or Rh catalysis [7] give ‘‘tail to tail” cycloadducts.
Azabicyclo[3,1,1]heptane skeletons are effectively constructed
under Au(I) catalysis [8] (Scheme 1).
These results indicate that bisallenes dramatically change their
behavior and the observed reactivity and selectivity are highly
dependent on the nature of catalysts or conditions. Therefore,
other metal species would be an alternative tool for a new system.
Previously, we have reported that the bisallenes are suitable pre-
cursors for stereoselective hydrocyanative cyclization [9]. Herein
we focused on the reactivity of bisallenes with nickel species to
provide a new protocol of [2 + 2] cycloaddition reaction producing
highly functionalized cyclobutanes (Scheme 2). During the course
of study, we realized that the allenes were suitable substrates for
nickel-catalyzed cyclization [9,10] and cycloaddition [11]. There-
Results and discussion
In the beginning, 1a with a catalytic amount of Ni[P(OPh)3]4
(10 mol%) in toluene was employed under thermal condition
(Table 1). The reaction resulted in the formation of ‘‘head to head”
product of 2a in only 5% yield after 18 h (entry 1). To improve the
yield of 2a, ligand screening was next examined. The use of PCy3
did not complete the reaction to give 2a only in 2% with a recovery
of 1a in 53% yield (entry 2). On the other hand, PPh3 accelerated the
cycloaddition to complete within 1 h with affording 2a in 27% yield
(entry 3). Arylphosphine such as MePPh2 gave slight improvement
in the yield of 2a (entry 4). In the case of bidentate phosphines, sig-
nificant differences in their conversion were observed. For exam-
ple, the use of BINAP and dppe (1,2-diphenylphosphinoethane)
were resulted in low yield (entries 5 and 6), however dppb (1,2-
diphenylphosphinobutane) slightly improved the yield of 2a (entry
7). We were pleased to find that xantphos dramatically enhanced
the reaction efficacy to complete within 1.5 h and the yield of 2a
was increased to 87% (entry 8). Similar results were obtained when
the reaction period was 15 min or the temperature was lowered to
50 °C (entries 9 and 10). The solvent effect using THF, CH3CN, and
1,2-dichloroethane (DCE) was next investigated at 70 °C, however
the positive improvements in the reaction rate or the chemical
yield were not observed (entries 11–13). These results are summa-
rized in Table 1.
fore, we next focused on the reactivity of bisallenes as
p -compo-
https://doi.org/10.1016/j.tetlet.2019.151168
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Arai, Y. Kawata, Y. Amako et al., Nickel-catalyzed [2 + 2] cycloaddition reaction using bisallenes, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151168

2
S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Mode of [2 + 2] cycloaddition using bisallene.
Scheme 3. Substrate scope under optimum conditions.
gen atom such as 1b,c were both suitable for this intramolecular
cycloaddition to give 2b,c as a sole product in respective yields
of 29% and 47%. A phenyl group on R2 was also applicable and
highly stereocontrolled product (2d) was exclusively obtained in
61% yield. The construction of carbocycle using 1e was accom-
plished to give 2e in 53% yield. A cyanoacetate was also applicable
to give the corresponding adducts (2f) as a mixture of diastere-
omers (dr = 1:1). The substituent on R1 dramatically decreased
the reaction efficacy, and the reaction of 1g gave lower conversion
to 2g only in 5% yield.
Scheme 2. Ni-Catalyzed reaction using bisallene.
Table 1
Ligand effect in Ni-catalyzed [2 + 2] cycloaddition using 1a.
To study the reactivity of the two methylenes on a cyclobutane
ring, we next investigated the transformations using 2a (Scheme 4).
Conjugate diene in 2a shows enough reactivity to form cyclohex-
ene ring via thermal and stereoselective [4 + 2] cycloaddition reac-
tions, for example, the reaction with 3a at 120 °C gave tetracyclic
compound (4a) in 75% yield [6]. Benzyne generated from 3b acted
as a reactive dienophile to give 4b in 41% yield after recrystalliza-
tion. These structures were established by X-ray crystallographic
analysis [12]. Cu-mediated dehydro Diels-Alder reaction [13] using
3c gave 4c in 49% yield. Finally, regio- and stereoselective Ni-cat-
alyzed hydrocyanation [14] was investigated and gave a sole
HCN adduct of 4d in 54% yield [12].
Then, we next focused on allenamides [15] that have been uti-
lized in intra- [16] and intermolecular [2 + 2] cycloaddition [17–
23] using various metal catalysts. In the case of allene-allenamides
(5), their non-equivalent four C@C double bonds could be discrim-
inated through selective interaction with Ni(0) species, however
Ni-xantphos system using 5a was ineffective to give any ‘‘head to
head”, ‘‘head to tail” or ‘‘tail to tail” [2 + 2] cycloadducts (7a-c) at
all. On the other hand, intramolecular cycloaddition using 5b
smoothly proceeded to give a single product of 6b, of which struc-
ture was confirmed to have tricyclic core by X-ray crystallographic
analysis (Scheme 5) [12]. In case of 5c, similar cycloaddition pro-
ceeded to give 6c as a single diastereomer in 44% yield. Xantphos
was also an essential ligand for this cycloaddition because the reac-
tions without ligand or the use of PPh3 or dppe instead were all
ineffective to give any trace amount of 6 nor 7 at all.
Entry
Ligand
(mol%)
Conditiona
Time h
Yield
Recov.
of 2a %b
of 1a %b
1
2
3
4
5
6
7
8
none
PCy3 (20)
PPh3 (20)
MePPh2 (20)
(S)-BINAP (10)
dppe (10)
Toluene, 70 °C
Toluene, 70 °C
Toluene, 70 °C
Toluene, 70 °C
Toluene, 70 °C
Toluene, 70 °C
Toluene, 70 °C
Toluene, 70 °C
Toluene, 70 °C
Toluene, 50 °C
THF, 70 °C
18
20
1
1
11
20
16
1.5
0.25
0.25
0.25
0.25
0.25
5
2
27
36
7
0
53
0
0
19
45
43
0
0
0
0
0
0
6
dppb (10)
22
87c
80c
76c
73
16
39
xantphos (10)
xantphos (10)
xantphos (10)
xantphos (10)
xantphos (10)
xantphos (10)
9
10
11
12
13
CH3CN, 70 °C
DCE, 70 °C
a
The reaction concentration: 0.1 M.
Yields are estimated by H NMR analysis using 2,20-bipyridyl as an internal
standard except for entries 8–10.
b
1
c
Isolated yield
Under optimum conditions, substrate scope using 1b-g was
The plausible reaction pathways for above reactions are pro-
posed in Scheme 6. The [2 + 2] cycloaddition of 1a would be trig-
next investigated (Scheme 3). Substituents on
a position to nitro-
Please cite this article as: S. Arai, Y. Kawata, Y. Amako et al., Nickel-catalyzed [2 + 2] cycloaddition reaction using bisallenes, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151168

S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx
3
EtO2C
CO2Et
O
3c
Me
NCO2Me
3a
Cu(OAc)2 (1 eq)
O
H
CO2Et
CO2Et
H
H
H
H
2,2’-bipry
O
TEMPO
TsN
TsN
NCO2Me
tol. 120 °C PhCl, 120 °C
1 h
23 h
H
O
4a: 75%
4c: 49%
H
TsN
H
2a
TMS
Ni[P(OPh)3]4 (10 mol%)
xantphos (10 mol%)
TMSCN, CF3CH2OH
H
H
H
OTf
3b
TsN
TsN
Me
CN
4d: 54%
MeCN, rt, 24 h tol. 100 °C, 20 h
H
4b: 41%
Scheme 4. Synthetic transformation of 2a.
R
R
Ni[P(OPh)3]4 (10 mol%)
xantphos (10 mol%)
R
TsN
TsN
N
toluene, 70 °C
Ts
5a: R = H
5b: R = Me
5c: R = iPr
6a: R = H : 0% (0.5 h)
6b: R = Me: 62% (0.5 h)
6c: R = iPr : 44% (1 h)
R
R
TsN
TsN
7b: head to tail
7a: head to head
R
6b
Scheme 6. Plausible reaction mechanism.
TsN
not isolated
7c: tail to tail
would effectively promote the reductive elimination from the
intermediates A and B to the corresponding cycloadducts [28,29].
Scheme 5. Ni-Catalyzed cycloaddition using 5.
gered by the formation of A reacting with inner allenyl C@C bonds
of 1a via oxidative cyclization, and the following reductive elimina-
tion gives head to head product of 2a with a release of a Ni(0) cat-
alyst. The formation of A would be critically prevented by the steric
bulk of a substituent such as 1g to decrease the cyclization efficacy.
In case of allene-allenamide (5b), two possible nickelacycles B1
and B2 via homodimerization are proposed. The following reduc-
tive elimination would give ‘‘tail to tail” cycloadduct (C), [24] which
could be transformed to 6b through intramolecular Diels-Alder
reaction.[25–27] The exclusive formation of 6b,c suggests that
the stereochemistry of red C@C bonds in both B and C would be
critically controlled to be E-isomer for sequential [4 + 2] cycloaddi-
tion. In both cases, xantphos gave strong influence in conversion,
which would be caused by its larger bite angle. This bisphosphine
Conclusions
In conclusion, we have developed a nickel-catalyzed [2 + 2]
cycloaddition using bisallenes. The reaction pathways are highly
dependent on the substrates. Symmetric bisallenes predominantly
gave simple [2 + 2] adducts via ‘‘head to head” cycloaddition,
whereas allene-allenamide substrates show unique reactivity to
promote sequential [2 + 2]–[4 + 2] cycloaddition to give tricyclic
compounds with highly stereoselective manner. These observa-
tions among the nickel catalysis have enough impact on synthetic
chemistry, offering the alternative method for the synthesis of
functionalized cyclolobutanes, and the further application is cur-
rently undergoing in our laboratory.
Please cite this article as: S. Arai, Y. Kawata, Y. Amako et al., Nickel-catalyzed [2 + 2] cycloaddition reaction using bisallenes, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151168

4
S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx
[6] X. Jiang, X. Cheng, S. Ma, Angew. Chem. Int. Ed. 45 (2006) 8009–8013.
Experimental section
[7] F. Inagaki, S. Narita, T. Hasegawa, S. Kitagaki, C. Mukai, Angew. Chem. Int. Ed.
48 (2009) 2007–2011.
[8] S.M. Kim, J.H. Park, Y.K. Kang, Y.K. Chung, Angew. Chem. Int. Ed. 48 (2009)
4532–4535.
Represened procedure for Ni-catalyzed [2 + 2] cycloaddition of 1a
[9] Y. Amako, H. Hori, S. Arai, A. Nishida, J. Org. Chem. 78 (2013) 10763–10775.
[10] S. Arai, Y. Amako, X. Yang, A. Nishida, Angew. Chem. Int. Ed. 52 (2013) 8147–
8150.
[11] S. Arai, A. Izaki, Y. Amako, M. Nakajima, M. Uchiyama, M. Nishida, Adv. Synth.
Catal. (2019), https://doi.org/10.1002/adsc.201900719.
[12] CCDC 1936053 (4b), 1936034 (4d) and 1936055 (6b) contain the
supplementary crystallographic data for this paper.
[13] B. Jiang, Q.-J. Liang, Y. Han, M. Zhao, Y.-H. Xu, T.-P. Loh, Org. Lett. 20 (2018)
3215–3219.
[14] S. Arai, K. Nakazawa, X.-F. Yang, A. Nishida, Tetrahedron 75 (2019) 1145–1148.
[15] T. Lu, Z.-X. Ma, Y. Zhang, R.P. Hsung, Chem. Rev. 113 (2013) 4862–4904.
[16] T. Nada, Y. Yoneshige, Y. Ii, T. Matsumoto, H. Fujioka, S. Shuto, M. Arisawa, ACS
Catal. 6 (2016) 3168–3171.
A mixture of Ni[P(OPh)3]4 (23.5 mg, 0.018 mmol, 10 mol%),
xantphos (10.4 mg, 0.018 mmol, 10 mol%) and 1a (50.3 mg,
0.18 mmol) in toluene (1.8 mL, 0.1 M) was heated at 70 °C under
argon atmosphere for 90 min. After the filtration of the reaction
mixture through a celite pad, the organic solvents were removed
under the reduced pressure. The resulting mixture was poured into
silica gel and purified by column chromatography (hexane:
AcOEt = 80:1 to 10:1) to give 2a as colorless solid (43.6 mg,
0.16 mmol, 87%).
[17] R.-R. Liu, J.-P. Hu, J.-J. Hong, C.-J. Lu, J.-R. Gao, Y.-X. Jia, Chem. Sci. 8 (2017)
2811–2815.
Acknowledgments
[18] X. Zhong, Q. Tang, P. Zhou, Z. Zhong, S. Dong, X. Liu, X. Feng, Chem. Commun.
54 (2018) 10511–10514.
[19] H. Faustino, P. Bernal, L. Castedo, F. López, J.L. Mascareñas, Adv. Synth. Catal.
354 (2012) 1658–1664.
This work was supported by the Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (Grant No. 17K08205).
[20] S. Suárez-Pantiga, C. Hernández-Díaz, M. Piedrafita, E. Rubio, J.M. González,
Adv. Synth. Catal. 354 (2012) 1651–1657.
[21] W.-F. Zheng, G.-J. Sun, L. Chen, Q. Kang, Adv. Synth. Catal. 360 (2018) 1790–
1794.
Appendix A. Supplementary data
[22] W.-F. Zheng, P.P. Bora, G.-J. Sun, Q. Kang, Org. Lett. 18 (2016) 3694–3697.
[23] X.-X. Li, L.-L. Zhu, Z. Chen, Org. Lett. 14 (2012) 436–439.
[24] S. Saito, K. Hirayama, C. Kabuto, Y. Yamamoto, J. Am. Chem. Soc. 122 (2000)
10776–10780.
[25] S. Ma, P. Lu, L. Lu, H. Hou, J. Wei, Q. He, Z. Gu, X. Jiang, X. Jin, Angew. Chem. Int.
Ed. 44 (2005) 5275–5278.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151168.
References
[26] P. Lu, S. Ma, Org. Lett. 9 (2007) 2095–2097.
[27] Artgas, A; Vila, J.; Lledó, A.; Solà, M.; Pla-Quintana, A.; Roglans, A. Org. Lett.
DOI: 10.1021/acs.orglett.9b02032.
[28] M.-N. Birkholz, Z. Freixa, P.W.N.M. van Leeuwen, Chem Soc. Rev. 38 (2009)
1099–1118.
[29] N.D. Staudaher, R.M. Stolley, J. Louie, Chem. Commun. 50 (2014) 15577–
15580.
[1] V.M. Dembitsky, J. Nat. Med. 62 (2008) 1–33.
[2] T. Michinobu, F. Diederich, Angew. Chem. Ont. Ed. 57 (2018) 3552–3577.
[3] S. Poplata, A. Tröster, Y.-Q. Zou, Thorsten Bach, Chem. Rev. 116 (2016) 9748–
9815.
[4] B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Soc. Rev. 39 (2010) 783–816.
[5] S.-K. Kang, T.-G. Baik, A.N. Kulak, Y.-H. Ha, Y. Lim, J. Park, J. Am. Chem. Soc. 122
(2000) 11529–11530.
Please cite this article as: S. Arai, Y. Kawata, Y. Amako et al., Nickel-catalyzed [2 + 2] cycloaddition reaction using bisallenes, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151168