One-pot reactions of bicyclic zinc enolate generated from Ni-catalyzed reductive cyclization to furnish octahydro-4,7-ethanobenzofuran-9-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151148

The one-pot reactions of catalytically generated bicyclic zinc enolate with various electrophiles are reported. The zinc enolate as a key intermediate is efficiently delivered from Ni-catalyzed reductive cyclization of alkynyl cyclohexadienone. Employing aldehydes, imine, nitroalkene, and α,β-unsaturated carbonyl compounds as electrophiles, this new class of one-pot reactions gave multi-functionalized cis-hydrobenzofurans and octahydro-4,7-ethanobenzofuran-9-one derivatives in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2019.151148

Tetrahedron Letters 60 (2019) 151148
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot reactions of bicyclic zinc enolate generated from Ni-catalyzed
reductive cyclization to furnish octahydro-4,7-ethanobenzofuran-9-one
derivatives
a,
⇑
a
a
a
a
Tetsuya Tsujihara , Moriho Tomeba , Shigeaki Ohkubo-Sato , Kyoko Iwabuchi , Rino Koie ,
a
a
b
b
a,
⇑
Natsumi Tada , Satoru Tamura , Tsunayoshi Takehara , Takeyuki Suzuki , Tomikazu Kawano
a
Department of Medicinal and Organic Chemistry, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
Comprehensive Analysis Center, Institute of Scientific and Industrial Research, Osaka University, Mihogaoka, Ibaraki 567-0047, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2019
Revised 9 September 2019
Accepted 12 September 2019
Available online 13 September 2019
The one-pot reactions of catalytically generated bicyclic zinc enolate with various electrophiles are
reported. The zinc enolate as a key intermediate is efficiently delivered from Ni-catalyzed reductive
cyclization of alkynyl cyclohexadienone. Employing aldehydes, imine, nitroalkene, and
a,b-unsaturated
carbonyl compounds as electrophiles, this new class of one-pot reactions gave multi-functionalized
cis-hydrobenzofurans and octahydro-4,7-ethanobenzofuran-9-one derivatives in moderate to good
yields.
Keywords:
Ó 2019 Elsevier Ltd. All rights reserved.
One-pot reaction
Reductive cyclization
Cyclohexadienone
Zinc enolate
Introduction
the development of several kinds of transition metal catalysis in
such reactions, the nickel-catalyzed transformations of alkynyl
One-pot and domino reactions are the powerful synthetic
methodology for the construction of structurally complex mole-
cules [1]. This type of reactions requires an appropriate initiating
reaction, which provides a reactive intermediate for the following
steps. Involvement of transition metal-catalyzed or mediated steps
makes these processes much more effective. In this regard, copper-
catalyzed conjugate additions of organometallic reagents (e.g.,
cyclohexadienones are less explored [7]. We envisaged that
nickel-catalyzed reductive cyclization [8] of alkynyl cyclohexa-
dienone 1 with diethyl zinc yields bicyclic zinc enolate and subse-
quent trapped reactions with appropriate electrophiles afford a
variety of functionalized cis-hydrobenzofurans (Scheme 1a) and
octahydro-4,7-ethanobenzofuran-9-one derivatives (Scheme 1b).
Considering the wide applications to the asymmetric transforma-
tion of cyclohexadienones, development of the one-pot domino
processes is valuable for the synthesis of structurally complex chi-
ral molecules. Herein, we report nickel-catalyzed reductive cycliza-
tion of alkynyl cyclohexadienone and subsequent electrophilic
2
R Zn, RMgX) to a, b-unsaturated carbonyl compounds have been
successfully explored as an efficient fundamental reaction [2], in
which the reactive metal enolate is generated in situ. By employing
various electrophiles, several domino conjugate addition and
electrophilic trapped reactions have been reported to date [3–4].
4
,4-Disubstituted cyclohexadienones are recognized as
attractive substrates for conjugate additions as the products may
be subject to further 1,4-addition or may be employed in cycloaddi-
tions [5]. Recently, transition metal-catalyzed asymmetric cycliza-
tion of alkynyl cyclohexadienones have been extensively studied,
and the products have been utilized in the synthesis of cis-
hydrobenzofuran-based polycyclic compounds [6]. Compared to
⇑
Corresponding authors.
E-mail addresses: ttsujiha@iwate-med.ac.jp (T. Tsujihara), tkawano@iwate-med.
Scheme 1. Schematic representation of the Ni-catalyzed reductive cyclization of 1
ac.jp (T. Kawano).
followed by enolate trapped reactions in one-pot.
https://doi.org/10.1016/j.tetlet.2019.151148
0
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
T. Tsujihara et al. / Tetrahedron Letters 60 (2019) 151148
trapped reactions of the bicyclic zinc enolate with aldehydes, imine,
nitroalkene, and , b -unsaturated carbonyl compounds in one-pot.
did not improve the yield of 2a (entry 10). Finally, the employment
of (PMePh )NiCl [10] or [(TMEDA)Ni(o-tolyl)Cl] [11] afforded 2a in
2% and 93% isolated yield, respectively (entries 11 and 12).
After having identified the optimal reaction conditions, we
investigated the short scope of substrates regarding the sub-
stituent on the cyclohexadienone ring and alkyne moiety
a
2
2
9
Results and discussion
Initially, we investigated the reaction conditions of Ni-catalyzed
reductive cyclization of alkynyl cyclohexadienone 1a (Table 1).
Based on the reported procedure for Ni-catalyzed reductive
(Scheme 2). The reaction of methyl derivative 1b resulted in a
slightly diminished yield of 2b (83%) due to the relatively slow
reaction. On the other hand, 1c bearing isopropyl substituent
showed excellent reactivity to afford 2c in 99% isolated yield. Fur-
thermore, not only alkyl-substituted internal alkyne (1d) but also
the terminal alkyne (1e) participated in this cyclization to give
cyclization [8], treatment of 1a with 1.5 equiv of Et
2
Zn in the pres-
3
in THF at 30 °C
ence of 10 mol % of Ni(acac) and 20 mol % of PPh
2
afforded the cyclized product 2a in 82% yield (entry 1). In this reac-
tion, the ethylated product 3a via reductive elimination from ethyl
2
d and 2e in 90% and 89% isolated yields, respectively. The relative
(
alkenyl)nickel intermediate and 4-ethylphenol 4a [9] generated
configuration and the geometry of 2a and 2c were unequivocally
determined by X-ray analysis (Fig. 1) [12].
from the reduction of 1a were also observed in 3% and 8% yields,
respectively. As reported by Montgomery and co-workers, [8] the
addition of phosphine ligand largely affected the distribution of b
-H elimination and reductive elimination from ethyl(alkenyl)nickel
intermediate. The reaction without any phosphine ligands fur-
nished 3a and 4a as major components instead of 2a albeit in
low yields (entry 2). To realize the proposed one-pot reactions,
the high efficiency of Ni-catalyzed reductive cyclization of 1a is
necessary. Therefore, we defined 2a as the desired product and
investigated the effects of phosphine ligand to improve the yield
of 2a (entries 3–8). Upon conducting the reaction with 10 mol %
of bidentate ligands (dppe or rac-binap) under otherwise identical
conditions, the formation of 2a was suppressed (entries 3 and 4). P
(
n-Bu)
comparable results to the case using PPh
our delight, the desired reaction of 1a proceeded smoothly in the
presence of 10 mol % of PMePh to furnish 2a in 94% yield (entry
). When the reaction was conducted with bulkier alkyldiaryl
3
was also ineffective (entry 5). The use of PMe
2
Ph showed
3
(entries 1 and 6). To
Scheme 2. Short scope of the Ni-catalyzed reductive cyclization of 1.
2
7
2
phosphine (PCyPh ), the yield of 2a diminished and the formation
of 4a was increased (entry 8). Hence, it was suggested that the use
of methyldiphenylphosphine was essential to promote the desired
reductive cyclization smoothly and suppress the undesired reac-
tions of 1a. Encouraged by the result of entry 7, we next tried to
reduce the catalyst loading (entries 9–12). When 5 mol % of Ni
(
acac)
2
and 10 mol % of PMePh
2
were employed, the yield of 2a
Fig. 1. POV-ray drawing of a) 2a and b) 2c with probability ellipsoids drawn at the
50% level. Hydrogen atoms except for important ones are omitted for clarity.
decreased to 90% (entries 7 and 9). The use of 5 mol % of Ni(cod)
2
Table 1
a
Ni-catalyzed reductive cyclization of alkynyl cyclohexadienone 1a.
Entry
Ni catalyst (mol %)
Ni:Ligand
Time/min
Yield of 2a/%b
Yield of 3a/%b
Yield of 4a/%b
1
2
3
4
5
6
7
8
9
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
2
2
2
2
2
2
2
2
2
(10) + PPh
(10)
(10) + dppe (10)
3
(20)
1:2
1:0
1:1
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
15
15
15
15
15
15
15
15
25
25
25
25
82
trace
5
trace
6
81
94
28
90
3
37
8
12
trace
trace
trace
trace
trace
19
8
22
18
45
25
12
5
37
8
11
3
(10) + rac-binap (10)
(10) + P(n-Bu)
(10) + PMe Ph (20)
(10) + PMePh
(10) + PCyPh
(5.0) + PMePh
(5.0) + PMePh
NiCl
[(TMEDA)Ni(o-tolyl)Cl] (5.0) + PMePh
3
(20)
2
2
(20)
(20)
2
2
(10)
(10)
10
11
12
Ni(cod)
(PMePh
2
2
63
93 (92)
96 (93)
c
2
)
2
2
(5.0) + PMePh
2
(10)
trace
trace
c
2
(10)
3
a
b
c
All reactions were performed in the presence of Ni catalyst and ligand at 30 °C in THF (0.20 M) under an argon atmosphere.
Yields determined by NMR spectroscopy on the basis of hydroquinone dimethylether as an internal standard.
0
0
The values in parentheses are the isolated yields. dppe = 1,2-bis(diphenylphosphino)ethane, binap = 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl, acac = acetylacetonate,
0
0
cod = cycloocta-1,5-diene, TMEDA = N,N,N ,N -tetramethylethylenediamine.

T. Tsujihara et al. / Tetrahedron Letters 60 (2019) 151148
3
Scheme 3. One-pot Ni-catalyzed reductive cyclization of 1c and subsequent enolate trapped reactions.
Scheme 4. One-pot Ni-catalyzed reductive cyclization of 1 and subsequent [4 + 2] annulations.

4
T. Tsujihara et al. / Tetrahedron Letters 60 (2019) 151148
Having successfully optimized the reaction conditions and the
Appendix A. Supplementary data
substrate, we next examined the one-pot reactions of bicyclic zinc
enolate with various electrophiles (Scheme 3). Using 1c as a model
substrate, the one-pot electrophilic trapped reaction of the bicyclic
zinc enolate with benzaldehyde was carried out at 50 °C for 24 h
Supplementary data (crystallographic data (Figs. S1–S5) and full
details of structural parameters (Tables S1–S5) for 2a, 2c, 10, 16c,
and 17c, experimental procedures, characterization data, copies of
H and C NMR spectra for all new compounds) to this article can
be found online at https://doi.org/10.1016/j.tetlet.2019.151148.
1
13
(
Scheme 3a). The aldol condensation products 5a were obtained
in 76% yield as a mixture of (Z,E) and (Z,Z)-isomers in the ratio
9 : 11. In the case of propionaldehyde, the aldol condensation pro-
8
duct 5b and the epoxide 6b [13] were obtained in 50% and 20%,
respectively (Scheme 3b). At lower temperature (–40 °C), the
aldol-type alcoholic products 7 were obtained in 91% total yield
as a mixture of three diastereomers (Scheme 3c). The Mannich-
type reaction with N-tosylimine prepared from benzaldehyde also
proceeded to afford the b -amino product 8 in 98% total yield as a
mixture of three diastereomers (Scheme 3d). Moreover, the
Michael-type reaction with dimethyl benzylidenemalonate gave
References
[1] For relevant review and book: (a) Y. Hayashi Chem. Sci. 7 (2016) 866–880;
(b) L.F. Tietze, Domino Reactions: Concepts for Efficient Organic Synthesis,
Wiley-VCH, Weinheim, 2014.
[
2] For relevant reviews: (a) N. Krause, A. Hoffmann-Röder Synthesis (2001) 171–
96;
(b) A. Alexakis, C. Benhaim, Eur. J. Org. Chem. (2002) 3221–3236;
1
(
(
(
c) A. Alexakis, J.E. Bäckvall, N. Krause, O. Pàmies, M. Diéguez, Chem. Rev. 108
2008) 2796–2823;
d) T. Jerphagnon, M.G. Pizzuti, A.J. Minnaard, B.L. Feringa, Chem. Soc. Rev. 38
9
in 58% yield (Scheme 3e). Thus, the bicyclic zinc enolate gener-
ated from Ni-catalyzed reductive cyclization of 1c showed suffi-
cient reactivity toward the electrophiles and afforded various
functionalized cis-hydrobenzofurans in moderate to good yields.
To pursue the reactivity of the bicyclic zinc enolate generated
from 1c, we further explored the one-pot trapped reactions with
other electrophiles (Scheme 4). In the reaction with trans-b-nitros-
tyrene, the octahydro-4,7-ethanobenzofuran-9-one derivative 10
along with Michael adduct 11 could be acquired in 17% and 21%,
respectively (Scheme 4a). The relative configuration, as well as
the octahydro-4,7-ethanobenzofuran-9-one skeleton of 10, were
unequivocally determined by X-ray analysis [12]. This result
allowed us to presume that the bridged cyclic product 10 was
formed through a formal [4 + 2] annulation between the bicyclic
zinc enolate and trans-b-nitro styrene through double Michael
addition. Similarly, the reaction with methyl acrylate afforded
the bridged cyclic products 12 and 13 in 25% yield and 13% yield,
respectively (Scheme 4b). E-Chalcone also led to the [4 + 2] annula-
tion, and the diastereomeric products 14 and 15 were obtained in
(2009) 1039–1075;
(
(
e) T. Thaler, P. Knochel, Angew. Chem. Int. Ed. 48 (2009) 645–648;
f) D. Müller, A. Alexakis, Chem. Commun. 48 (2012) 12037–12049.
[
3] For relevant reviews: (a) H.-C. Guo, J.-A. Ma Angew. Chem. Int. Ed. 45 (2006)
354–366;
(
(
b) Z. Galeštoková, R. Šebesta, Eur. J. Org. Chem. (2012) 6688–6695;
c) D. Vargová, I. Némethová, K. Plevová, R. Šebesta, ACS Catal. 9 (2019) 3104–
3143.
[4] Selected reports: (a) B.L. Feringa, M. Pineschi, L.A. Arnold, R. Imbos, A.H.M. de
Vries Angew. Chem. Int. Ed. 36 (1997) 2620–2623;
(
1
b) R. Naasz, L.A. Arnold, M. Pineschi, E. Keller, B.L. Feringa, J. Am. Chem. Soc.
21 (1999) 1104–1105;
(c) M. Kitamura, T. Miki, K. Nakano, R. Noyori, Bull. Chem. Soc. Jpn. 73 (2000)
999–1014;
(
4
(
d) A. Alexakis, G.P. Trevitt, G. Bernardinelli, J. Am. Chem. Soc. 123 (2001)
358–4359;
e) K. Agapiou, D.F. Cauble, M.J. Krische, J. Am. Chem. Soc. 126 (2004) 4528–
4529;
(
(
f) X. Rathgeb, S. March, A. Alexakis, J. Org. Chem. 71 (2006) 5737–5742;
g) S. Guo, Y. Xie, X. Hu, C. Xia, H. Huang, Angew. Chem. Int. Ed. 49 (2010)
2
728–2731;
(h) S. Guo, Y. Xie, X. Hu, H. Huang, Org. Lett. 13 (2011) 5596–5599;
i) K. Kawamura, H. Fukuzawa, M. Hayashi, Bull. Chem. Soc. Jpn. 84 (2011)
40–647;
j) C.-Y. Ni, S.-S. Kan, Q.-Z. Liu, T.-R. Kang, Org. Biomol. Chem. 9 (2011) 6211–
6214;
k) N. Germain, L. Guénée, M. Mauduit, A. Alexakis, Org. Lett. 16 (2014) 118–
21;
l) N. Germain, D. Schlaefli, M. Chellat, S. Rosset, A. Alexakis, Org. Lett. 16
(
6
(
5
3% and 11% yield, respectively (Scheme 4c). Moreover, when
methyl 2-cyanocinnamate was employed as an electrophile, this
4 + 2] annulation proceeded smoothly under milder reaction con-
(
1
(
[
ditions (30 °C, 1.5 h), whereas methyl cinnamate proved no reac-
tion (Scheme 4d) [14]. Namely, the diastereomeric products 16c
and 17c were obtained in 75% and 14%, respectively. The substrates
(2014) 2006–2009;
(m) N. Germain, A. Alexakis, Chem. Eur. J. 21 (2015) 8597–8606;
(
n) Y.-M. Hung, C.-H. Tseng, B.-J. Uang, Tetrahedron: Asymmetry 26 (2015)
369–1374;
o) J.Y.J. Wang, T. Palacin, S.P. Fletcher, Org. Lett. 21 (2019) 378–381.
[5] For relevant reviews: (a) K.A. Kalstabakken, A.M. Harned Tetrahedron 70
1
d and 1e also gave the corresponding products 16d-e and 17d-e
1
(
in moderate yields. The structures of octahydro-4,7-ethanobenzo-
furan-9-one derivatives 12–17 were identified by NMR and HRMS.
Furthermore, single-crystal X-ray analysis of 16c and 17c unequiv-
ocally revealed the relative configurations [12].
(
(
(
2014) 9571–9585;
b) W. Sun, G. Li, L. Hong, R. Wang, Org. Biomol. Chem. 14 (2016) 2164–2176;
c) X.-P. Zeng, Z.-Y. Cao, Y.-H. Wang, F. Zhou, J. Zhou, Chem. Rev. 116 (2016)
7330–7396.
[
6] Selected recent reports: Pd catalysis (a) J. Chen, X. Han, X. Lu Angew. Chem. Int.
Ed. 56 (2017) 14698–14701;
Conclusion
(
b) W. Wu, T. Chen, J. Chen, X. Han, J. Org. Chem. 83 (2018) 1033–1040;
Rh catalysis (c) Z.-T. He, B. Tian, Y. Fukui, X. Tong, P. Tian, G.-Q. Lin, Angew.
Chem. Int. Ed. 52 (2013) 5314–5318;
We have developed the first example of the one-pot process
based on nickel-catalyzed reductive cyclization of alkynyl cyclo-
hexadienone and sequential trapped reactions of the bicyclic zinc
enolate with various electrophiles. Our protocol provides facile
access to structurally diverse cis-hydrobenzofurans and octahy-
dro-4,7-ethanobenzofuran-9-one derivatives in moderate to good
yields. Further investigation into the detailed reaction mechanism,
scope, and its application to the asymmetric catalysis are currently
ongoing, and these results will be reported in due course.
(
1
d) Y. Fukui, P. Liu, Q. Liu, Z.-T. He, N.-Y. Wu, P. Tian, G.-Q. Lin, J. Am. Chem. Soc.
36 (2014) 15607–15614;
(e) K.K. Gollapelli, S. Donikela, N. Manjula, R. Chegondi, ACS Catal. 8 (2018)
440–1447;
f) C.-L. Duan, Y.-X. Tan, J.-L. Zhang, S. Yang, H.-Q. Dong, P. Tian, G.-Q. Lin, Org.
1
(
Lett. 21 (2019) 1690–1693;
Cu catalysis (g) P. Liu, Y. Fukui, P. Tian, Z.-T. He, C.-Y. Sun, N.-Y. Wu, G.-Q. Lin, J.
Am. Chem. Soc. 135 (2013) 11700–11703;
(
h) Z.-T. He, X.-Q. Tang, L.-B. Xie, M. Cheng, P. Tian, G.-Q. Lin, Angew. Chem. Int.
Ed. 54 (2015) 14815–14818;
(i) T. Shu, L. Zhao, S. Li, X.-Y. Chen, C. von Essen, K. Rissanen, D. Enders, Angew.
Chem. Int. Ed. 57 (2018) 10985–10988.
[
[
7] Reports on Ni catalysis (a) C. Clarke, C.A. Incerti-Pradillos, H.W. Lam J. Am.
Chem. Soc. 138 (2016) 8068–8071;
Acknowledgments
(
(
b) R. Kumar, Y. Hoshimoto, E. Tamai, M. Ohashi, S. Ogoshi, Nat. Commun. 8
2017) 32–38.
8] For relevant review: (a) J. Montgomery Angew. Chem. Int. Ed. 43 (2004) 3890–
908;
We are grateful to the technical staff of the Comprehensive
Analysis Center of Institute of Scientific and Industrial Research
3
Selected reports: (b) J. Montgomery, A.V. Savchenko, J. Am. Chem. Soc. 118
(1996) 2099–2100;
(
Osaka University) for their assistance.

T. Tsujihara et al. / Tetrahedron Letters 60 (2019) 151148
5
(
4
c) J. Montgomery, E. Oblinger, A.V. Savchenko, J. Am. Chem. Soc. 119 (1997)
911–4920.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
[
9] The formation of phenol 4a occurred from the reduction of 1a by the zero-
valent nickel complex, presumably.
10] E.A. Standley, T.F. Jamison, J. Am. Chem. Soc. 135 (2013) 1585–1592.
11] (a) J. Magano, S. Monfette, ACS Catal 5 (2015) 3120–3123;
[13] The epoxide 6b might be formed from the corresponding enone. Zinc mediated
epoxidations of enones with oxygen were reported. (a) K. Yamamoto, N.
Yamamoto Chem. Lett. 18 (1989) 1149–1152;
[
[
(
b) J.D. Shields, E.E. Gray, A.G. Doyle, Org. Lett. 17 (2015) 2166–2169.
(b) D. Enders, J. Zhu, L. Kramps, Liebigs Ann. (1997) 1101–1113.
[14] When methyl cinnamate was used as electrophile (50 °C, 24 h), only the
reductive cyclization product 2c was obtained in 75%.
[
12] Complete crystallographic data for the structure analysis in this paper have
been deposited with the Cambridge Crystallographic Data Centre, CCDC No.
1
940186 (2a), 1940184 (2c), 1940185 (10), 1940188 (16c), 1940187 (17c).