Nickel-iminophosphine-catalyzed [4+2] cycloaddition of enones with allenes: Synthesis of highly substituted dihydropyrans

Article abstract of DOI:10.1039/c1cc10890e

Enones were found to react with allenes intermolecularly in the presence of a catalytic amount of a nickel-iminophosphine complex to provide dihydropyrans via oxidative cyclization of an enone and Ni(0).

Full text of DOI:10.1039/c1cc10890e

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COMMUNICATION
Nickel-iminophosphine-catalyzed [4+2] cycloaddition of enones with
allenes: synthesis of highly substituted dihydropyransw
Saori Sako, Takuya Kurahashi* and Seijiro Matsubara*
Received 15th February 2011, Accepted 5th April 2011
DOI: 10.1039/c1cc10890e
Enones were found to react with allenes intermolecularly in the
presence of a catalytic amount of a nickel-iminophosphine
complex to provide dihydropyrans via oxidative cyclization of
an enone and Ni(0).
Table 1 Nickel-catalyzed [4+2] cycloaddition of 1a with 2aa
The hetero Diels–Alder reactions of a,b-unsaturated carbonyl
compounds with carbon–carbon double bonds are a useful
method for the synthesis of dihydropyrans, which are privileged
structural subunits in numerous important natural products
and in pharmaceuticals.1,2 Although there are a large number of
examples for syntheses of dihydropyrans by hetero Diels–Alder
reactions, the use of an enol ether as an electron-rich hetero-
dienophile is mandatory for sufficient transformation, and an
example of utilization of other heterodienophiles has never been
appeared in the literature.3 Thus, the development of alternative
methodologies, which would allow for straightforward access
to structurally diverse dihydropyrans, remains an important
research topic. Herein, we wish to report an unprecedented
nickel-catalyzed [4+2] cycloaddition of enones with allenes to
afford highly substituted dihydropyrans.
Entry
Ligand
2a (equiv.)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
PMe3
PPh3
PCy3
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.5
3.0
2.5
2.5
2.5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
MeCN
15
o1
o1
23
4
5
6
7
8
7c
7
7
7
7
7
o1
72
95
We recently reported that the Ni(0)/PMe3 catalyst promotes
[4+2] cycloaddition of enones with alkyne.4 Thus, we first
presumed that the same reaction conditions might be available
for the cycloaddition of enones with allenes as well. Therefore,
ethyl benzylidene acetoacetate (1a) was treated with 1,1-
dipentylallene (2a), 10 mol% of Ni(cod)2 and 40 mol% of
PMe3 in toluene at 100 1C for 15 h. However, this led to
dihydropyran 3aa only in 15% yield (Table 1, entry 1). The
result prompted us to investigate efficient ligands for the
transformation. Phosphine ligands, such as PPh3, and PCy3,
did not afford cycloadduct 3aa. However, to our delight, it was
found through examination of various ligands that iminophos-
phines are highly efficient for the [4+2] cycloaddition.5,6
Among the iminophosphines examined, cyclohexylamine-
derived ligand 7 gave the best result (95% yield, entry 7). Trace
or lower amounts of 3aa were obtained in the cases of using 4,
5, and 8 in place of 7 (entries 4–8). Decreasing the amount of
o1
9
52
80
10
11
12
13
14
89
99
99
58
Pyridine
a
All reactions were carried out using 1a (0.2 mmol), 2a, Ni(cod)2
(10 mol%), and ligand (40 mol%) in 2 mL of solvent (100 1C) unless
otherwise noted. NMR yield base on enone 1a. 20 mol% of 7.
b
c
iminophosphine 7 to 20 mol% resulted in lowering the yield of
cycloadduct 3aa (entry 9). On screening the molecular ratio of
1a and 2a that was employed for cycloaddition, it was found
that a ratio of 1a/2a of 1 : 2.5 gave the highest yield of 3aa
(entries 7, 10, and 11). Finally, by changing the reaction
solvent to 1,4-dioxane or MeCN, we obtained 3aa in 99%
yield (entries 12 and 13).
A range of substrates 1 was also tested in the reaction with
allene 2a; results are summarized in Table 2. Enones 1b and 1c
also reacted with 2a to furnish dihydropyrans 3ba and 3ca in
70% and 24% yields respectively (entries 2 and 3). However,
cycloadduct 3ba was obtained in 18% isolated yield due to
decomposition during silica gel column chromatography.
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 2438;
Tel: +81 75 383 2440
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc10890e
c
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Table 2 The scope of the [4+2] cycloadditiona
Scheme 1 Formation of oxa-nickelacycle via oxidative cyclization.
Entry
R1
R2
1
3
Yieldb (%)
1
2
3
4
5
6
Me
Ph
tBu
Me
Me
Me
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
3aa
3ba
3ca
3da
3ea
3af
99 (98)
70 (18)
24 (23)
99 (73)
61 (60)
o1
4-MeO-C6H4
4-CF3-C6H4
Pr
a
All reactions were carried out using 1a (0.2 mmol), 2a (0.5 mmol),
Ni(cod)2 (10 mol%), and 7 (40 mol%) in 2 mL of 1,4-dioxane (100 1C)
for 15 h unless otherwise noted. NMR yield base on enone 1a.
Isolated yields are given in parentheses.
b
Fig. 1 ORTEP drawing of 8.
on the reaction were not observed, it was found that the
cycloaddition reaction of 1a with bulky cyclohexyl-substituted
allene 2h gave the dihydropyrans 3ah in 99% yield with high
regioselectivity (entry 8). The cis-configuration of 3ah was
confirmed by X-ray crystal structure analysis.8
Table 3 The [4+2] cycloaddition of 1a with various allenes 2a
We then conducted stoichiometric reactions of 1a with
Ni(cod)2 and iminophosphine 7 to obtain insight into the
reaction mechanism. The reaction of ethyl benzylidene aceto-
acetate (1a) with Ni(cod)2 and iminophosphine 7 at 25 1C
gave an oxa-nickelacycle 8 quantitatively (Scheme 1).9 The
molecular structure of 8 was confirmed by the X-ray crystal
structure analysis, which showed that the nickel(II) complex
has a square planar molecular geometry (Fig. 1). The coordi-
nation geometry of 8 with the oxygen atom trans to the
phosphorous atom is rationalized by trans influence, considering
that the phosphines are one of the strongest donor ligands.10
Treatment of oxanickelacycle 8 with allene 2h in toluene (100 1C,
15 h) afforded the dihydropyran 3ah in 85% isolated yield
consisting of regioisomers in 9/1 ratio. Thus, the catalytic
reaction to form dihydropyran 3ah can be rationalized as arising
Entry R3
R4
2
3
Yieldb (%)
1
2
3
4
5
6
7
8
C5H11 C5H11
Me
H
H
H
H
H
H
2a 3aa
2b 3ab
99 (98)
36 (40)
Me
C5H11
2c 3ac/3ac0 84 (91) (1/1)c
2d 3ad/3ad0 88 (80) (1/1)c
2e 3ae/3ae0 99 (95) (2/3)c
CH2CH2Ph
CH2CH2CN
CH2CH2OAc
2f 3af/3af0
87 (76) (2/3)c
CH2CH2OSitBuPh2 2g 3ag/3ag0 93 (94) (1/2)c
Cy
2h 3ah/3ah0 99 (94) (9/1)c
a
All reactions were carried out using 1a (0.2 mmol), 2a (0.5 mmol),
Ni(cod)2 (10 mol%), and 7 (40 mol%) in 2 mL of 1,4-dioxane (100 1C)
for 15 h unless otherwise noted. NMR yield base on enone 1a.
b
c
Isolated yields are given in parentheses. Ratio of cis 3/trans 30.
b-Aryl substituted enones possessing an electron-donating or
-withdrawing group on the phenyl ring also provided corres-
ponding cycloadducts in good to moderate yields (entries 4
and 5), whereas b-alkyl substituted enones fail to participate in
the reaction.7
We next investigated the scope of the reaction using various
allenes; results are summarized in Table 3. Under the same
reaction conditions, highly volatile 1,1-dimethylallene 2b also
reacted with 1a to furnish cycloadduct 3ab in 36% yield (entry 2).
The reaction of 1a with mono-substituted allenes, such as 2c
and 2d, gave the dihydropyrans consisting of regioisomers in
1/1 ratio (entries 3 and 4). Allenes possessing functional
groups, such as nitrile, acetoxy, and siloxy, also tolerated the
reaction conditions and afforded the correspondingly substituted
dihydropyrans in high yield (entries 5–7). Although distinct
directing effects of such functional groups in regioselectivity
Scheme 2 Plausible reaction mechanism for cycloaddition of 1a with 2h.
Chem. Commun., 2011, 47, 6150–6152 6151
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from oxidative cyclization of nickel(0) to an enone 1a to form
oxa-nickelacycle 8 (Scheme 2).11 Subsequent coordination of
allene 2h takes place to give intermediate 9a; here, the steric
repulsive interaction is minimal between two cyclohexyl groups
of both 2h and 8. Insertion of an allene into the C–Ni bond leads
to the seven-membered oxa-nickelacycle 10, which undergoes
reductive elimination to give 3ah and a Ni(0) complex.
(d) E. Shirakawa, H. Yoshida and H. Takaya, Tetrahedron Lett.,
1997, 38, 3759; (e) E. Shirakawa, H. Yoshida, T. Kurahashi,
Y. Nakao and T. Hiyama, J. Am. Chem. Soc., 1998, 120, 2975;
(f) K. R. Reddy, C.-L. Chen, Y.-H. Liu, S.-M. Peng, J.-T. Chen
and S.-T. Liu, Organometallics, 1999, 18, 2574; (g) S. M. Nobre
and A. L. Monteiro, J. Mol. Catal. A: Chem., 2009, 313, 65.
6 The use of other bidentate ligands, such as dppf, dppp, binap, bpy,
did not afford any product.
7 Neither benzylidene-substituted pentane-2,4-dione nor diethyl
malonate participated in the cycloaddition with allene 2a even
for prolonged reaction times, and both were recovered unchanged
quantitatively. A stoichiometric reaction of such enones with
Ni(cod)2 and iminophosphine 7 did not afford oxa-nickelacycle
and resulted in no reaction. Thus, a-ester-substituted a,b-unsatu-
rated ketone will be a suitable substrate for oxa-nickelacycle
formation and cycloaddition with allenes.
In summary, we have developed a new nickel-catalyzed
[4+2] cycloaddition reaction of enones with allenes to provide
highly substituted dihydropyrans. Iminophosphine was found
to be a highly active ligand for the reaction; enones are
susceptible to oxidative cyclization of nickel(0) in the presence
of an iminophosphine ligand, and such reactions allow inter-
molecular cycloaddition with allenes. Further investigations
on the potential of the developed cycloaddition and detailed
mechanistic studies of the catalytic reaction mechanism are
currently underway in our laboratory.12
8 For details see ESIw.
9 For crystallographic evidence for the formation of oxa-nickelacycles,
see: (a) H. H. Karsch, A. W. Leithe, M. Reisky and E. Witt,
Organometallics, 1999, 18, 90; (b) K. K. D. Amarasinghe,
S. K. Chowdhury, M. J. Heeg and J. Montgomery, Organometallics,
2001, 20, 370; (c) J. Montgomery, K. K. D. Amarasinghe,
S. K. Chowdhury, E. Oblinger, J. Seo and A. V. Savchenko, Pure
Appl. Chem., 2002, 74, 129; (d) S. Ogoshi, M. Oka and
H. Kurosawa, J. Am. Chem. Soc., 2004, 126, 11802;
(e) H. P. Hratchian, S. K. Chowdhury, V. M. Gutierrez-Garcia,
K. K. D. Amarasinghe, M. J. Heeg, H. B. Schlegel and
J. Montgomery, Organometallics, 2004, 23, 4636; (f) S. Ogoshi,
M. Ueta, T. Arai and H. Kurosawa, J. Am. Chem. Soc., 2005,
127, 12810; (g) S. Ogoshi, M. Nagata and H. Kurosawa,
J. Am. Chem. Soc., 2006, 128, 5350; (h) S. Ogoshi, K. Tonomori,
M. Oka and H. Kurosawa, J. Am. Chem. Soc., 2006, 128, 7077;
(i) S. Ogoshi, T. Arai, M. Ohashi and H. Kurosawa, Chem.
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This work was supported by Grants-in-Aid from MEXT,
Japan. T.K. also acknowledges Asahi Glass Foundation,
Kansai Research Foundation, and Mizuho Foundation.
Notes and references
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12 As a result of preliminary experiments, we found that cyclo-
addition of 1a with 2a in the presence of Ni(cod)2/(S,S)-iPr-foxap
afforded 3aa with 54% ee in 18% yield. Further modifications of
chiral iminophosphine ligands to improve enantioselectivity and
yield are underway.
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c
6152 Chem. Commun., 2011, 47, 6150–6152
This journal is The Royal Society of Chemistry 2011