Nickel-catalyzed [4+2] cycloaddition for highly substituted arenes

Article abstract of DOI:10.1039/c2cc30801k

Nickel(0) catalyzed [4+2] cycloaddition of electron-deficient dienes to alkynes and subsequent aromatization gave highly substituted arenes. This formal inverse electron-demand Diels-Alder cycloaddition is attributed to the formation of a seven-membered n

Full text of DOI:10.1039/c2cc30801k

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COMMUNICATION
Nickel-catalyzed [4+2] cycloaddition for highly substituted arenesw
Hiroaki Horie, Takuya Kurahashi* and Seijiro Matsubara*
Received 4th February 2012, Accepted 28th February 2012
DOI: 10.1039/c2cc30801k
Nickel(0) catalyzed [4+2] cycloaddition of electron-deficient
dienes to alkynes and subsequent aromatization gave highly
substituted arenes. This formal inverse electron-demand Diels–
Alder cycloaddition is attributed to the formation of a seven-
membered nickelacycle from a diene and an alkyne.
We have studied nickel-catalyzed reactions between a,b-
unsaturated carbonyl compounds and alkynes.1,2 In the course
of our work, we reported on the co-oligomerization of acrylates
Scheme 2 Nickel-catalyzed [4+2] cycloaddition of diene 1a to alkyne
with alkynes giving 1,3-dienes.1 We attributed these reactions
to the oxidative cyclization of an acrylate and an alkyne with
2a and sequential aromatization.
resultant cycloadducts results in the creation of highly sub-
stituted arenes.8,9
Initially, we examined the reaction of diene 1a with alkyne
nickel(0), which results in the formation of a C–Ni bond at the
a-position of the acrylate with the nickel complex and a C–C
bond at the b-position with the alkyne (Scheme 1a). Based on
2a in the presence of Ni(cod)2 (10 mol%) and PPh3 (20 mol%)
our observations, we anticipated that a diene, which comprises
two enoate moieties, could form a C–Ni bond at the a-position
in toluene at 100 1C for 6 h. This reaction afforded several
isomers of cyclohexadienes and aromatized cycloadduct 3aa as
of one of the enoate moieties and form simultaneously a C–C
an inseparable mixture. To our satisfaction, vigorous stirring
bond at the b-position of the other enoate moiety to create a
seven-member nickelacycle intermediate. Following reductive
elimination, this intermediate would change into a six-member
carbocycle (Scheme 1b).2b We performed experiments to prove
this hypothesis and found that nickel-catalyzed [4+2] cyclo-
addition between a diene bearing two ester groups at positions
of the resulting reaction mixture under air in the presence of
1,8-diazabicyclo[5.4.0]-7-undecene (DBU) produced 3aa as
single product in a yield of 69% (Scheme 2).10
To improve the yield of 3aa, the use of several phosphine
ligands was examined (Table 1). Alkyl-substituted phosphines
Table 1 Optimization of reaction conditionsa
1 and 3 and an alkyne results in the creation of cycloadducts.
Although many transition-metal complexes have also been
catalyzed successfully through the [4+2] cycloaddition of
dienes with alkynes,3–7 most studies on this topic are limited
to reactions with electron-rich or electronically neutral dienes.
On the other hand, a reaction with electron-deficient dienes,
namely inverse electron-demand Diels–Alder type cyclo-
addition, is rare.4g,5b In this communication, we report that
the nickel-catalyzed [4+2] cycloaddition of electron-deficient
dienes to alkynes and subsequent aromatization of the
Entry Ni(cod)2 (mol%) Ligand
mol% Yieldb (%)
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
5
PPh3
PCy3
PCyPh2
PMePh2
P(4-MeC6H4)3
20
20
20
20
20
69
49
57
16
70
67
P(4-MeOC6H4)3 20
P(4-FC6H4)3
PPh3
PPh3
PPh3
PPh3
20
12
30
6
31
68
47
68
Scheme 1 Formation of nickelacycles from an enoate and an alkyne.
9
10
11c
5
6
84 (82)
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 615-8510, Japan.
E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp,
matsubar@orgrxn.mbox.media.kyoto-u.ac.jp; Fax: +81 75 383 2461;
Tel: +81 75 383 2462
a
Reactions were carried out using Ni(cod)2, ligand, diene 1a (0.50 mmol)
and 4-octyne (2a; 1.0 mmol, 2 equiv.) in 1 mL of toluene at 100 1C for 6 h,
then DBU (1.0 mmol, 2 equiv.) at room temperature under air for 2 h.
b
Yield was determined by NMR spectroscopy. The yield of the isolated
c
product is given in parentheses. 2a (1.5 mmol, 3 equiv.).
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/c2cc30801k
c
3866 Chem. Commun., 2012, 48, 3866–3868
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Table 2 Nickel-catalyzed [4+2] cycloaddition of electron-deficient dienes with alkynesa
Entry
1
R1
R2
2
R3
R4
3
Yieldb (%)
1c
2c
3
4
5
1b
1c
1d
1e
1f
4-MeOC6H4
3-MeOC6H4
4-FC6H4
4-F3CC6H4
2-MeC6H4
Me
Me
Me
Me
Me
2a
2a
2a
2a
2a
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
3ba
3ca
3da
3ea
3fa
(X = 4-OMe)
(X = 3-OMe)
(X = 4-F)
(X = 4-CF3)
(X = 2-Me)
54
56
81
77
70
6
1g
1-Naphthyl
tBu
2a
Pr
Pr
3ga
68
7
8
1a
1a
Ph
Ph
Me
Me
2b
2c
Et
Et
3ab
3ac
71
78
C5H11
C5H11
9
1a
1a
Ph
Ph
Me
Me
2d
2e
3ad
3ae
44
81
10d
11
12
1a
1h
Ph
Ph
Me
Et
2f
iPr
Me
Ph
3af
61e (1/1)f
2g
Ph
3hg
56
13
1h
Ph
Et
2h
Me
Ph
3hh
43
14
15
1a
1a
Ph
Ph
Me
Me
2i
2j
C5H11
C5H11
4-MeOC6H4
4-FC6H4
3ai
3aj
(Y = OMe)
(Y = F)
67
46
a
Reactions were carried out using Ni(cod)2 (5 mol%), PPh3 (6 mol%), diene 1 (0.50 mmol) and alkyne 2 (1.5 mmol, 3 equiv.) in 1 mL of toluene at
d
b
c
100 1C for 6 h, then DBU (1.0 mmol, 2 equiv.) at room temperature under air for 2 h. Yield of the isolated product. PPh3 (10 mol%). The
reaction with DBU under air was carried out for 15 h. The combined yield of the two regioisomers is given. Ratio of the regioisomers.
e
f
c
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were less effective than PPh3 (Table 1, entries 2–4) while
electron-rich triarylphosphines gave the product in similar
yields (entries 5 and 6). On the contrary, an electron-deficient
ligand resulted in a poor yield (entry 7). Decreasing the
amount of ligand to 12 mol% did not affect the reaction
(entry 8), while a low reaction rate was observed when the
amount of ligand was increased to 30 mol% (entry 9).
Decreasing the amount of Ni(cod)2 to 5 mol% did not lower
the yield (entry 10). Finally, we found that the use of 3 equiv.
of 2a drastically improved the yield and 3aa was obtained in a
yield of 84% (entry 11).
methoxy group or fluorine also reacted stereoselectively to
afford arene 3 (entries 14 and 15). However, terminal alkynes
failed to participate in the reaction. As shown in Scheme 3, the
[4+2] cycloaddition of (E)-isomer 4a with alkyne 2a also
resulted in 3aa with a yield of 83%.
We propose the reaction mechanism of the [4+2] cyclo-
addition as shown in Scheme 4. The reaction is initiated by the
coordination of two double bonds of diene 1 and alkyne 2 to
nickel(0). Although 1 and (E)-isomer 4 are in an equilibrium,
less sterically hindered 1 would give intermediate 5. Sub-
sequent oxidative cyclization and reductive elimination give
cyclohexadiene 7 and regenerate the starting nickel(0) catalyst.
Then, the aromatization of 7 affords arene 3.
With the optimized reaction conditions in hand, we examined
the substrate scope of this cycloaddition reaction (Table 2).
Dienes with an aryl substituent at R1 were effective participants.
In the reactions of methoxyphenyl-substituted dienes 1b and 1c,
deactivation of the nickel catalyst was observed. This was
prevented by using 10 mol% of phosphine ligand (Table 2,
entries 1 and 2). Among the aryl-groups that we examined, the
electron-deficient groups afforded aromatized cycloadduct 3 in
higher yields (entries 3 and 4). The sterically bulky o-tolyl
and 1-naphthyl groups also participated in the cycloaddition
(entries 5 and 6). Various internal alkynes were also examined
for their reactivity. Alkyl-substituted symmetrical alkynes 2b
and 2c reacted with 1a to afford 3ab and 3ac in good yields
(Table 2, entries 7 and 8). The reaction with cycloalkynes gave
ring-fused arenes. Whereas strained 12-membered cycloalkyne
2d resulted in a relatively low yield (entry 9), less strained
cyclopentadecyne (2e) gave arene 3ae in a yield of 81%. Of
note, the aromatizing step of this reaction was time intensive
(entry 10). Unsymmetrical alkyne 2f gave two corresponding
regioisomers in a yield of 61% but its selectivity was low
(entry 11). Aryl-substituted alkynes also participated in the
[4+2] cycloaddition. Diphenylacetylene (2g) reacted with diene
1h to afford 3hg in a yield of 56% (entry 12). Although two
regioisomers were possible outcomes in the reaction with
1-phenyl-1-propyne (2h), the product was obtained as a single
isomer (entry 13). Similar unsymmetrical alkyne bearing a
In conclusion, we developed a nickel-catalyzed [4+2] cyclo-
addition reaction that centers on electron-deficient dienes with
alkynes. This reaction corresponds to an inverse electron-
demand Diels–Alder reaction. In addition, subsequent aroma-
tization by using a base in air produces highly functionalized
arenes. Activation of both olefins of the diene is essential for
the cycloaddition reaction.
Notes and references
1 (a) H. Horie, T. Kurahashi and S. Matsubara, Chem. Commun.,
2010, 46, 7229; (b) H. Horie, I. Koyama, T. Kurahashi and
S. Matsubara, Chem. Commun., 2011, 47, 2658.
2 (a) I. Koyama, T. Kurahashi and S. Matsubara, J. Am. Chem.
Soc., 2009, 131, 1350. The reaction of a,b,g,d-unsaturated ketones
with alkynes afforded bicyclo[3.1.0]hexene; (b) H. Horie,
T. Kurahashi and S. Matsubara, Angew. Chem., Int. Ed., 2011,
123, 9118.
3 For iron-catalyzed [4+2] cycloaddition, see: (a) A. Carbonaro,
A. Greco and G. Dall’Asta, J. Org. Chem., 1968, 33, 3948;
(b) J. P. Genet and J. Ficini, Tetrahedron Lett., 1979, 20, 1499;
(c) H. Tom Dieck and R. Diercks, Angew. Chem., Int. Ed. Engl.,
1983, 22, 778.
4 For rhodium-catalyzed [4+2] cycloaddition, see: (a) I. Matsuda,
M. Shibata, S. Sato and Y. Izumi, Tetrahedron Lett., 1987,
28, 3361; (b) R. S. Jolly, G. Luedtke, D. Sheehan and
T. Livinghouse, J. Am. Chem. Soc., 1990, 112, 4965;
(c) M. Murakami, M. Ubukata, K. Itami and Y. Ito, Angew.
Chem., Int. Ed., 1998, 37, 2248; (d) S.-J. Paik, S. U. Son and
Y. K. Chung, Org. Lett., 1999, 1, 2045; (e) D. Motoda,
H. Kinoshita, H. Shinokubo and K. Oshima, Angew. Chem., Int.
Ed., 2004, 43, 1860; (f) W.-J. Yoo, A. Allen, K. Villeneuve and
W. Tam, Org. Lett., 2005, 7, 5853; (g) A. Saito, T. Ono,
A. Takahashi, T. Taguchi and Y. Hanzawa, Tetrahedron Lett.,
2006, 47, 891.
5 For nickel-catalyzed [4+2] cycloaddition, see: (a) P. A. Wender
and T. E. Jenkins, J. Am. Chem. Soc., 1989, 111, 6432;
(b) P. A. Wender and T. E. Smith, Tetrahedron, 1998, 54, 1255.
6 For cobalt-catalyzed [4+2] cycloaddition, see: (a) G. Hilt and
F.-X. du Mesnil, Tetrahedron Lett., 2000, 41, 6757; (b) G. Hilt
and T. J. Korn, Tetrahedron Lett., 2001, 42, 2783. See also following
review: (c) W. Hess, J. Treutwein and G. Hilt, Synthesis, 2008, 3537.
7 For other transition-metal-catalyzed [4+2] cycloaddition, see the
Scheme 3 Reaction of (E)-isomer 4a with alkyne 2a.
following. Ti: (a) K. Mach, H. Antropiusova, L. Petrusova,
´ ´
F. Turecek and V. Hanus, J. Organomet. Chem., 1985, 289, 331.
Pd: (b) K. Kumar and R. S. Jolly, Tetrahedron Lett., 1998,
39, 3047. Cu and Au: (c) A. Furstner and C. C. Stimson, Angew.
¨
Chem., Int. Ed., 2007, 46, 8845. Au: (d) S. M. Kim, J. H. Park and
Y. K. Chung, Chem. Commun., 2011, 47, 6719.
8 (a) P. A. Wender and T. E. Smith, J. Org. Chem., 1996, 61, 824;
(b) G. Hilt, J. Janikowsky and W. Hess, Angew. Chem., Int. Ed.,
2006, 45, 5204; (c) G. Hilt and M. Danz, Synthesis, 2008, 2257.
9 For reviews on preparation of arenes via [4+2] cycloaddition, see:
(a) V. Gevorgyan and Y. Yamamoto, J. Organomet. Chem., 1999,
576, 232; (b) S. Saito and Y. Yamamoto, Chem. Rev., 2000,
100, 2901.
Scheme 4 Plausible reaction mechanism.
10 S. Ikeda, N. Mori and Y. Sato, J. Am. Chem. Soc., 1997, 119, 4779.
c
3868 Chem. Commun., 2012, 48, 3866–3868
This journal is The Royal Society of Chemistry 2012