Nickel-catalyzed [2 + 2 + 2] cycloaddition of arynes and an unactivated alkene: Synthesis of 9,10-dihydrophenanthrene derivatives

Article abstract of DOI:10.1039/b907476g

A nickel-catalyzed [2 + 2 + 2] cycloaddition of two molecules of aryne and an alkene moiety in a α,ω-diene afforded 9,10-dihydrophenanthrene derivatives in good yields.

Full text of DOI:10.1039/b907476g

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Nickel-catalyzed [2 + 2 + 2] cycloaddition of arynes and an unactivated
alkene: synthesis of 9,10-dihydrophenanthrene derivativesw
Nozomi Saito, Kengo Shiotani, Atsushi Kinbara and Yoshihiro Sato*
Received (in College Park, MD, USA) 14th April 2009, Accepted 11th May 2009
First published as an Advance Article on the web 10th June 2009
DOI: 10.1039/b907476g
A nickel-catalyzed [2 + 2 + 2] cycloaddition of two molecules
of aryne and an alkene moiety in a a,x-diene afforded
9,10-dihydrophenanthrene derivatives in good yields.
A transition metal-catalyzed [2 + 2 + 2] cycloaddition of
multiple bonds has been an atom-economical and useful
methodology for the synthesis of polycylclic compounds.1
Since the first report on triphenylene synthesis via palladium-
catalyzed [2 + 2 + 2] cyclotrimerization of benzynes in
1998,2a arynes have been utilized in transition-metal catalyzed
[2 + 2 + 2] cycloadditions as coupling partners.2–5 Recently,
we have reported a palladium-catalyzed [2 + 2 + 2]
Scheme 2
cycloaddition of a,o-diyne and arynes and its application to
the synthesis of arylnaphthalene lignans, Taiwanins C and E,
To date, there have been only two examples in the literature
and dehydrodesoxypodophyllotoxin.6
of [2 + 2 + 2] cycloaddition of two arynes and one alkene
catalyzed by a nickel or palladium complex.9 It was stated in
In this context, we envisaged that if a transition metal-
both reports that only activated alkenes such as strained
catalyzed [2 + 2 + 2] cycloaddition of an a,o-diene and aryne
bicyclic alkenes9a or alkenes having an electron-withdrawing
could proceed,
a 1,2,3,4-tetrahydronaphthalene skeleton,
group on the sp2 carbon9b are suitable for the cycloaddition
with an aryne. Thus, the [2 + 2 + 2] cycloaddition of arynes
and an unactivated alkene as shown in Scheme 2 has not been
demonstrated previously. This unprecedented result prompted
us to investigate the nickel-catalyzed [2 + 2 + 2] cycloaddition
of unactivated alkenes and arynes.
which is one of the important frameworks found in a variety
of biologically active natural products such as podophyllotoxin,
could be efficiently constructed (Scheme 1).7
To examine the feasibility of the above plan, the reaction of a
diene 1a and benzyne, which was generated from the precursor 4a
and CsF,8 in the presence of 10 mol% of Ni(cod)2 and 40 mol%
of PPh3 was carried out in MeCN at 50 1C (Scheme 2). The
expected product 3aa was not obtained, but a 9,10-dihydro-
phenathrene derivative 5aa was produced in 17% yield along
with a diene having a biphenyl moiety 6aa in 5% yield. The results
suggested that 5aa is formed by [2 + 2 + 2] cycloaddition of two
molecules of benzyne and an alkene part in the diene 1a.
First, we examined the reaction of 1a and 4a using various
ligands in the presence of Ni(cod)2 and CsF in MeCN
(Table 1). When 40 mol% of P(p-tol)3 was used instead of
Table 1 Optimization of reaction conditions of [2 + 2 + 2] cyclo-
addition of diene 1a and benzyne
Yield (%)a
5aa
E-6aa
Z-6aa
Entry
Ligand (x mol%)
Time/h
1
2
3
4
5
P(p-tol)3 (40)
P(o-tol)3 (40)
P(o-tol)3 (20)
IMesÁHCl (10)
SIMesÁHBF4
(10)
24
18
4
4
2
24
54
7
13
2
5
5
6
70
67
11
9
77 (71)b
11 (9)bc
5 (4)bc
Scheme 1
Yields were determined by 1H NMR analysis of the mixture of 5aa
a
Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0812, Japan. E-mail: biyo@pharm.hokudai.ac.jp;
Fax: +81 11 706 4982; Tel: +81 11 706 4982
w Electronic supplementary information (ESI) available: Detailed
experimental procedure and spectral data. See DOI: 10.1039/b907476g
b
c
and 6aa. Yields in parentheses are isolated yields. The yields of
E- and Z-6aa were determined by 1H NMR analysis of the mixture of
E- and Z-6aa.
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PPh3, the phenanthrene derivative 5aa and diene (E/Z)-6aa
were obtained in 24% yield and 9% yield, respectively
(entry 1). On the other hand, the cycloaddition in the presence
of P(o-tol)3 as a ligand improved the yield of 5aa to 54%, and
diene (E/Z)-6aa was also obtained in 18% yield (entry 2).
Interestingly, decreasing the loading of P(o-tol)3 to 20 mol%
accelerated the cycloaddition, and the starting diene 1a was
consumed within 4 h, giving 5aa and (E/Z)-6aa in 70% yield
and 16% yield, respectively (entry 3). From these results, it
was thought that a bulky and electron-sufficient ligand is
suitable for the cycloaddition. After screening such ligands,
N-heterocyclic carbene (NHC) was found to be good ligand
for the [2 + 2 + 2] cycloaddition (entries 4 and 5). The
reaction using SIMes as a ligand gave dihydrophenanthrene
derivative 5aa in 77% yield (isolated yield of 71%) and 16%
yield (isolated yield of 13%), respectively (entry 5).
Scheme 3
phenanthrene derivatives 5ab or 5ac and dienes 6ab or 6ac,
respectively (entries 5 and 6).
Next, we investigated the reaction of a mono-alkene 8 with
4a instead of diene 1 (Scheme 3, eqn (1)). The [2 + 2 + 2]
cycloaddition of 8 did not proceed, and only 9 was obtained in
11% yield along with recovered 8 in 53% yield. This result
strongly suggested that the unreacted alkene part in the diene 1
is necessary for the [2 + 2 + 2] cycloaddition. Thus, we
examined the chain length between two alkene parts in the
diene (eqn (2)). When 1,6-heptadiene (1f) was used as a
coupling partner, the [2 + 2 + 2] cycloaddition proceeded
to give the phenanthrene derivative 5fa in 31% yield along
with diene having a biphenyl part 6fa in 3% yield. On
the other hand, no significant products were obtained when
1,7-octadiene (1g) was used as a substrate. From these results,
it was thought that the positional relationship of the two
alkene parts in the diene also affects the co-trimerization of
alkene and two arynes.
Next, the [2 + 2 + 2] cycloaddition of various dienes and
arynes under optimal conditions was investigated (Table 2).
The reaction of 1b, having a cyclic acetal moiety, and 4a gave
5ba and (E/Z)-6ba in 36% yield and 12% yield, respectively
(entry 1). Dienes having a heteroatom in a chain 1c and 1d
were also applicable to the cycloaddition, and the corresponding
5ca or 5da and 6ca or 6da were produced in slightly moderate
yields (entries 2 and 3, respectively). Interestingly, when an
unsymmetrical diene 1e was used as a coupling partner
of 4a, the cycloaddition proceeded chemoselectively to give
the phenanthrene derivative 5ea and diene 6ea, which were
obtained by the reaction of a less-hindered allyl group and
benzyne (entry 4). The reaction of 1a and substituted aryne
precursors 4b and 4c also proceeded smoothly to afford the
Table 2 Reactions of various dienes and arynesa
Yieldsb
5
6 (E/Z)c
Entry Diene 1
Aryne precursor 4
1
1b
4a
5ba: 36%
6ba: 12% (1/99)
2
3
1c (X = NTs)
1d (X = O)
4a
4a
5ca: 25%
5da: 25%
6ca: 12% (1.5/1)
6da: 9% (1.3/1)
4
1e (E = CO2Me)
4a
5ea: 46%
6ea: 7% (3.0/1)
5
6
1a
1a
4b (R = OMe)
4c (R = –OCH2O–)
5ab: 68%
5ac: 57%
6ab: 14% (2.5/1)
6ac: 21% (2.6/1)
a
Reaction conditions: diene 1 (1 equiv.), 4 (3 equiv.), Ni(cod)2 (10 mol%), SIMesÁHBF4 (10 mol%), CsF (6 equiv.), MeCN, 50 1C. Reaction time:
b
4 h (entries 1–5) or 2 h (entry 6). Isolated yield. The ratio of E- and Z-6 was determined by H NMR analysis of the mixture of E- and Z-6.
c
1
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Part of this work was supported by a Grant-in-Aid for
Scientific Research (B) (No. 19390001) from JSPS and by
The Novartis Foundation (Japan) for the Promotion of
Science, The Uehara Memorial Foundation, and Akiyama
Foundation, which are gratefully acknowledged.
Notes and references
1 For recent reviews on transition metal-catalyzed cycloaddition,
see: (a) S. Saito and Y. Yamamoto, Chem. Rev., 2000, 100, 2901;
(b) J. A. Varela and C. Saa, Chem. Rev., 2003, 103, 3787;
´
(c) S. Kotha, E. Brahmachary and K. Lahiri, Eur. J. Org. Chem.,
2005, 4741; (d) P. R. Chopade and J. Louie, Adv. Synth. Catal.,
2006, 348, 2307.
2 For Pd-catalyzed [2 + 2 + 2] co-trimerization of arynes, see:
(a) D. Pena, S. Escudero, D. Pe
Angew. Chem., Int. Ed., 1998, 37, 2659; (b) D. Pena, D. Pe
E. Guitian and L. Castedo, Org. Lett., 1999, 1, 1555; (c) D. Pena,
A. Cobas, D. Perez, E. Guitian and L. Castedo, Org. Lett., 2000, 2,
1629; (d) D. Pena, A. Cobas, D. Perez, E. Guitian and L. Castedo,
Org. Lett., 2003, 5, 1863; (e) C. Romero, D. Pena, D. Perez and
E. Guitian, Chem.–Eur. J., 2006, 12, 5677; (f) H. S. Kim,
´
rez, E. Guitia
´
n and L. Castedo,
´
rez,
´
´
´
´
´
Scheme 4
´
´
S. Gowrisankar, E. S. Kim and J. N. Kim, Tetrahedron Lett.,
2008, 49, 6569.
3 For Pd- or Ni-catalyzed [2 + 2 + 2] cycloaddition of aryne-aryne-
Based on the above results, we propose a possible mechanism
of the [2 + 2 + 2] cycloaddition of alkene and benzyne as
shown in Scheme 4. First, coordination of two alkene parts of
1 and a triple bond of benzyne (2) to nickel(0) complex gave
p-complex 10, from which oxidative cycloaddition of one
alkene part and benzyne would proceed to afford nickelacycle
11 (Path A). It was thought that stabilization of complex 11 by
coordination of tethered alkene to the nickel(II) center is the
driving force for progress of oxidative cycloaddition from 10.
Then insertion of another benzyne into the nickel-carbon bond
of 11 would afford seven-membered nickelacycle 12. Finally,
reductive elimination of the nickel complex from 12 would
proceed to give the phenanthrene derivative 5. On the other
hand, b-elimination from 12 (depicted as 13) followed by
reductive elimination would produce diene having a biphenyl
part 6. Because a small amount of triphenylene formed
by co-trimerization of three molecules of benzyne (2) was
obtained in some cases (data not shown), an alternative
pathway that involves the formation of nickelacycle 14 by
oxidative cycloaddition of two benzynes to nickel(0) is also
possible (Path B). In this pathway, the intermediate 15 would
be formed from the coordinately unsaturated nickelacycle
14 and diene 1 accompanied by ligand (L) dissociation.
Then insertion of alkene into the nickel-carbon bond and
re-coordination of the ligand would occur to produce the
seven-membered nickelacycle 12. Although the detailed
mechanism is still not clear, the [2 + 2 + 2] cycloaddition
might proceed through both reaction pathways.10
alkyne or aryne-alkyne-alkyne, see: (a) D. Pena, D. Pe
E. Guitian and L. Castedo, J. Am. Chem. Soc., 1999, 121, 5827;
(b) K. V. Radhakrishnan, E. Yoshikawa and Y. Yamamoto,
Tetrahedron Lett., 1999, 40, 7533; (c) D. Pena, D. Perez,
E. Guitian and L. Castedo, J. Org. Chem., 2000, 65, 6944;
(d) D. Pena, D. Perez, E. Guitian and L. Castedo, Synlett, 2000,
1061; (e) D. Pena, D. Perez, E. Guitian and L. Castedo, Eur. J.
Org. Chem., 2003, 1238; (f) J.-C. Hsieh and C.-H. Cheng, Chem.
Commun., 2005, 2459; (g) J. Caeiro, D. Pena, A. Cobas, D. Perez
and E. Guitian, Adv. Synth. Catal., 2006, 348, 2466; (h) C. Romero,
D. Pena, D. Perez and E. Guitian, J. Org. Chem., 2008, 73, 7996See
also, ref. 2e.
´
rez,
´
´
´
´
´
´
´
´
´
´
´
4 For Ni-catalyzed [2 + 2 + 2] cycloaddition of aryne-aryne-allene,
see: J.-C. Hsieh, D. K. Rayabarapu and C.-H. Cheng, Chem.
Commun., 2004, 532.
5 For Pd-catalyzed [2 + 2 + 2] cycloaddition of aryne-aryne-alkene
or aryne-alkyne-alkene, see: (a) E. Yoshikawa and Y. Yamamoto,
Angew. Chem., Int. Ed., 2000, 39, 173; (b) E. Yoshikawa,
K. V. Radhakrishnan and Y. Yamamoto, J. Am. Chem. Soc.,
2000, 122, 7280.
6 (a) Y. Sato, T. Tamura and M. Mori, Angew. Chem., Int. Ed., 2004,
43, 2436; (b) Y. Sato, T. Tamura, A. Kinbara and M. Mori, Adv.
Synth. Catal., 2007, 349, 647.
7 A transition metal-catalyzed [2 + 2 + 2] cycloaddition of alkene-
alkene-alkyne is still limited to several examples, see:
(a) B. M. Trost, K. Imi and A. F. Indolese, J. Am. Chem. Soc.,
1993, 115, 8831; (b) J. Seo, H. M. P. Chui, M. J. Heeg and
J. Montgomery, J. Am. Chem. Soc., 1999, 121, 476;
(c) T. Shibata and Y.-k. Tahara, J. Am. Chem. Soc., 2006, 128,
11766; (d) K. Tanaka, G. Nishida, H. Sagae and M. Hirano,
Synlett, 2007, 1426; (e) D. Tanaka, Y. Sato and M. Mori, J. Am.
Chem. Soc., 2007, 129, 7730. There have been no reports on
cycloaddition of alkene-alkene-aryne.
8 For in situ formation of benzyne from 4 with fluoride ion, see:
Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983,
1211.
9 (a) T. T. Jayanth, M. Jeganmohan and C.-H. Cheng, J. Org.
Chem., 2004, 69, 8445; (b) I. Quintana, A. J. Boersma, D. Pena,
In summary, during the course of our study on the
[2 + 2 + 2] cycloaddition of a,o-dienes and arynes, we
found a novel nickel-catalyzed [2 + 2 + 2] cycloaddition
of one unactivated alkene and two arynes, giving
9,10-dihydrophenanthrene derivatives in good yields. Moreover,
it was suggested that the unreacted tethered alkene played an
important role in the progress of the co-trimerization of
substrates.11 Further studies along this line are in progress.
D. Pe
10 For a similar mechanism of [2 + 2 + 2] cycloaddition of acrylate
and aryne proposed by Pena and Perez et al., see, ref. 9b.
rez and E. Guitian, Org. Lett., 2006, 8, 3347.
´ ´
´
11 Recent review on the effect of olefin ligands on transition metal
catalysis, see: J. B. Johnson and T. Rovis, Angew. Chem., Int. Ed.,
2008, 47, 840.
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This journal is The Royal Society of Chemistry 2009
4286 | Chem. Commun., 2009, 4284–4286