Ni(II)-catalyzed Conia-ene reaction of 1,3-dicarbonyl compounds with alkynes

Article abstract of DOI:10.1021/ol050532q

(Chemical Equation Presented) We have discovered a Ni(II)-catalyzed Conia-ene reaction of 1,3-dicarbonyl compounds with alkynes. In the presence of Ni(acac)₂ and Yb(OTf)₃, various acetylenic 1,3-dicarbonyl compounds underwent Conia-ene reaction to give mono- and bicyclic olefinic eye opentanes. A mechanism involving the enol-yne-Ni complex formation is proposed and supported by deuterium-labeling experiments.

Full text of DOI:10.1021/ol050532q

ORGANIC
LETTERS
2
005
Vol. 7, No. 11
185-2188
Ni(II)-Catalyzed Conia-Ene Reaction of
,3-Dicarbonyl Compounds with Alkynes
2
1
Qiang Gao, Bao-Fu Zheng, Jin-Heng Li, and Dan Yang*
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong,
P. R. China
yangdan@hku.hk
Received March 11, 2005
ABSTRACT
We have discovered a Ni(II)-catalyzed Conia-ene reaction of 1,3-dicarbonyl compounds with alkynes. In the presence of Ni(acac)
2 3
and Yb(OTf) ,
various acetylenic 1,3-dicarbonyl compounds underwent Conia-ene reaction to give mono- and bicyclic olefinic cyclopentanes. A mechanism
involving the enol
−yne−Ni complex formation is proposed and supported by deuterium-labeling experiments.
8
3
The R-alkylation of 1,3-dicarbonyl compounds is one of the
most common methodologies for the formation of carbon-
carbon bonds. Direct R-alkylation of 1,3-dicarbonyl com-
strong acid, or UV irradiation is still required. Recently,
Toste and co-workers reported an elegant gold(I)-catalyzed
Conia-ene reaction of â-ketoesters with alkynes under mild
and neutral conditions. In the presence of catalytic amounts
of (PPh )AuCl and AgOTf, a series of alkynic â-ketoesters
gave the cycloisomerization products in high yield. Here we
report the utilization of Ni(acac) -Yb(OTf) as the catalyst
1
5a
pounds without prior enolate formation represents a more
efficient approach.2 One example is Conia-ene reaction:
ketones undergo thermal cyclization onto alkynes to yield
-5
3
6
cyclic R-vinylated ketones. However, the high temperature
2
3
required for this reaction limits its application in organic
in the Conia-ene reaction of 1,3-dicarbonyl compounds with
synthesis. The use of transition-metal catalysts allows the
reaction to proceed at lower temperatures, but strong base,
alkynes.
7
Intramolecular cyclizations mediated by nickel complexes
have been extensively explored in recently years for sub-
strates such as dienes, enynes, dienynes, and bis-dienes. To
9
(
1) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, pp 1-63.
the best of our knowledge, nickel-catalyzed hydroalkylation
(
2) (a) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290-
1
2
2
1291. (b) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125,
056-2057. (c) Wang, X.; Pei, T.; Han, X.; Widenhoefer, R. A. Org. Lett.
003, 5, 2699-2701. (d) Yang, D.; Li, J. H.; Gao, Q.; Yan, Y. L. Org.
(7) (a) Pd-catalyzed: Balme, G.; Bouyssi, D.; Faure, R.; Gore, J.; Van
Hemelryck, B. Tetrahedron 1992, 48, 3891-3902. (b) Mo-catalyzed:
McDonald, F. E.; Olson, T. C. Tetrahedron Lett. 1997, 38, 7691-7692.
(c) Cu-catalyzed: Bouyssi, D.; Monteiro, N.; Balme, G. Tetrahedron Lett.
1999, 40, 1297-1300. (d) Ti-mediated: Kitagawa, O.; Suzuki, T.; Inoue,
T.; Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998, 63, 9470-9475.
(8) Boaventura, M. A.; Drouin, J.; Conia, J. M. Synthesis 1983, 801-
804.
(9) For reviews see: (a) Wilke, G. Angew. Chem., Int. Ed. Engl. 1988,
27, 185-206. (b) Tamao, K.; Kobayashi, K.; Ito, Y. Synlett 1992, 539-
546. (c) Trost, B. M.; Krische, M. J. Synlett 1998, 1-16. (d) Mortreux, A.
In Transition Metal Catalysed Reactions; Murahashi, S.-I., Davies, S. G.,
Eds.; Blackwell Science Ltd.: London, 1999; pp 159-167. (e) Montgomery,
J. Acc. Chem. Res. 2000, 33, 467-473. (f) Montgomery, J.; Amarasinghe,
K. K. D.; Chowdhury, S. K.; Oblinger, E.; Seo, J.; Savchenko, A. V. Pure
Appl. Chem. 2002, 74, 129-133. (g) Ikeda, S.-I. Angew. Chem., Int. Ed.
2003, 42, 5120-5122.
Lett. 2003, 5, 2869-2871. (e) Wang, X.; Widenhoefer, R. A. Chem.
Commun. 2004, 660-661. (f) Han, X.; Wang, X.; Pei, T.; Widenhoefer, R.
A. Chem. Eur. J. 2004, 10, 6333-6342.
(3) (a) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org. Chem.
1
996, 61, 2699-2708. (b) Cruciani, P.; Aubert, C.; Malacria, M. Tetrahe-
dron Lett. 1994, 35, 6677-6680. (c) Renaud, J.-L.; Petit, M.; Aubert, C.;
Malacria, M. Synlett 1997, 55, 931-932. (d) Renaud, J.-L.; Aubert, C.;
Malacria, M. Tetrahedron 1999, 55, 5113-5128.
(4) (a) Yao, X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884-6885. (b)
Nguyen, R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J. Org. Lett. 2005, 7, 673-
75.
5) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
6
(
Soc. 2004, 126, 4526-4527. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste,
F. D. Angew. Chem., Int. Ed. 2004, 43, 5350-5352.
(6) For a review see: Conia, J. M.; Le Perchec, P. Synthesis 1975, 1-19.
1
0.1021/ol050532q CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/06/2005

Table 1. Screening of the Reaction Conditionsa
Table 2. Ni(acac)
,3-Dicarbonyl Compounds with Alkynesa
2
-Catalyzed Conia-Ene Reaction of Various
1
Yb(OTf)3
(equiv)
T
(°C)
time
(h)
yieldb
(%)
entry
Ni (equiv)
1
2
3
4
5
6
7
8
Ni(PPh3)4 (0.2)
Ni(COD)2 (0.1)
NiCl2(dppe)2 (0.2)
Ni(acac)2 (0.2)
Ni(acac)2 (0.2)
Ni(acac)2 (0.1)
Ni(acac)2 (0.05)
Ni(acac)2 (0.1)
0.5
0.1
0.5
0.5
0.5
0.2
0.1
0
50
50
rt
15
4
c
d
d
4.5
4.5
15
12
30
30
rt
c
50
50
50
50
68
83
80
77
a
Reaction conditions: 1 (0.33 mmol), dioxane (15 mL), air atmosphere.
b
c
d
Isolated yield. No reaction. Complex mixture but no 2 was formed.
3
of unactived alkynes by sp -hybridized C-H bonds has not
1
0
been reported. In our initial study, we examined the
catalytic efficiency of various nickel reagents in the cycliza-
11
tion of â-keto ester 1 (Table 1). To increase the enol content
of the â-keto esters, we added Lewis acid Yb(OTf) as a
in dioxane
failed to give any reaction even at 50 °C (entry 1). On the
other hand, 1 was rapidly consumed by Ni(COD) or NiCl
dppe) , but a mixture of unidentified compounds were
produced with no desired cyclization product (entries 2 and
). While no reaction was observed using 20% Ni(acac)
and 50% Yb(OTf) at room temperature (entry 4), we
3
12
3 4
cocatalyst. Treatment of 1 with 20% Ni(PPh )
2
2
-
(
2
3
2
3
obtained desired product 2 in 68% yield by raising the
reaction temperature to 50 °C for 15 h (entry 5). When we
reduced the catalyst loading to 10% Ni(acac)
OTf) , a higher yield of 2 (83%) was observed (entry 6).
Further reducing the catalyst loading to 5% Ni(acac) and
0% Yb(OTf) did not obviously compromise the yield,
although a longer reaction time was needed (entry 7). We
found that a similar yield of 2 could be achieved even in the
2
and 20% Yb-
(
3
2
a
1
3
Reaction conditions: Yb(OTf)3 (0.2 equiv), Ni(acac)2 (0.1 equiv), 0.03
b
M substrate in dioxane, 50 °C, air atmosphere. 3 and 4, R ) Me, R′ )
t
i
Bu; 5 and 6, R ) Pr, R′ ) Me; 7 and 8, R ) Me, R′ ) allyl; 9 and 10,
c
R ) CH CH CHdCH , R′ ) Me; 11 and 12, R ) Ph, R′ ) Et. Isolated
2
2
2
d
yield. Yb(OTf)3 (0.5 equiv) and Ni(acac)2 (0.2 equiv) were used.
absence of Yb(OTf)
was required for completion (entry 8 vs entry 6). It should
be pointed out that all our Ni(acac) -catalyzed reactions were
3
; however, a much longer reaction time
e
Yb(OTf)3 (0.067 equiv) and Ni(acac)2 (0.1 equiv) were used.
2
carried out in open air without exclusion of oxygen from
decomposed quickly and only 20% of 2 was isolated. This
observation suggests that the presence of oxygen is beneficial
to the cyclization reaction, probably because it can reoxidize
any adventitiously reduced Ni(0) species that are generated
as the reaction proceeds.
Having established the suitable reaction conditions, we
then examined this Ni(II)-catalyzed cycloisomerization on
a wide range of ꢀ-acetylenic 1,3-dicarbonyl substrates (Table
the reaction flask.13 In contrast, when the cyclization was
2
conducted in argon atmosphere, i.e., Ni(acac) (0.1 equiv)/
Yb(OTf) (0.2 equiv)/Ar/dioxane/50 °C/6 h, substrate 1
3
(
10) A Ni(acac)2-catalyzed addition of â-dicarbonyl derivatives to R,â-
unsaturated nitriles has been reported. See: Veronese, A. C.; Callegari, R.;
Morelli, C. F.; Basato, M. T. J. Mol. Catal. A: Chem. 1999, 142, 373-
3
76.
(
11) Other transition-metal complexes, such as Pd(PPh3)4, Pd(OAc)2,
2
). Compared with the reaction of 1, a longer reaction time
PdCl2(PPh4)2, PdCl2(MeCN)2, CpCo(CO)2, Fe(acac)2, and Fe(acac)3 gave
either a complex mixture or no reaction.
(
12) (a) Yang, D.; Ye, X.-Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999,
(13) We also screened the effects of other solvents on this reaction. Under
1
21, 5579-5580. (b) Yang. D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung,
the same reaction condition, the reaction conducted in THF produced 2 in
poor yield (25%), whereas the reaction failed to proceed in MeCN. Although
2 was obtained in 40% yield in DCE, the conversion was relative low
compared with that in dioxane; even lower conversion (<5%) was observed
in toluene.
K.-K. J. Am. Chem. Soc. 2001, 123, 8612-8613. (c) Yang, D.; Gu, G.;
Yan, Y.-L.; Zhao, H.-W.; Zhu, N.-Y. Angew. Chem., Int. Ed. 2002, 41,
3
1
014-3017. (d) Yang, D.; Gao, Q.; Lee, O.-Y.; Org. Lett. 2002, 4, 1239-
241.
2186
Org. Lett., Vol. 7, No. 11, 2005

was needed when the size of substituents increased either
on the ester or the ketone moiety (substrates 3 and 5; entries
27 and 29.5a Cyclization of 27 gave product 28, in which
the deuterium predominately (77%:1% ) anti/syn) locates
anti to the â-ketoesters group (eq 2). In contrast, the Ni-
1
and 2). For substrates 7 and 9, which contain olefinic
groups, the cyclizations were completely chemoselective, and
the olefinic groups did not participate in the reaction (entries
(acac) -catalyzed cyclization of 29 afforded cyclopentanone
30 selectively (22%:5% ) syn/anti), with deuterium syn to
the â-ketoester moiety (eq 3).
2
3
and 4). â-Ketoester 11, in which the presence of a phenyl
group might cause 1,3-allylic strain for its enol form, was
also cyclized successfully in 73% yield (entry 5). Besides
â-ketoesters, the Ni(II)-catalyzed cyclization is also ap-
plicable for 1,3-diketones: the cyclizaiton of 13 provided
diketone 14 in 71% yield (entry 6). Interestingly, even the
cyclization of â-ketoamide 15 was achieved in moderate
yield (69%) (entry 7). However, the corresponding N,N-
dimethyl substituted â-keto amide failed to react due to
severe 1,3-allylic strain.5
a
The Ni(II)-catalyzed cyclization reactions are applicable
to the preparation of bicyclic compounds. While bicyclo-
[
3.2.1]octanone 18 was obtained in moderate yield from the
cyclization of â-ketoester 17 under the standard conditions
entry 8), cis-fused 6,5-bicyclic compound 20 was synthe-
These deuterium labeling results are in contrast with those
obtained by Toste et al. in the Au(I)-catalyzed Conia-ene
reactions, suggesting that a completely different mechanism
might be involved in our Ni(II)-catalyzed reactions. A
plausible mechanism is depicted in Scheme 1, which involves
(
15
sized from cyclohexanone 19 in good yield (entry 9).
Similarly, ene reaction of cyclopentanone 21 afforded cis-
fused 5,5-bicyclic keto 22 in 88% yield (entry 10). The
synthetic utility of this reaction is further demonstrated by
the preparation of bicyclic ring systems containing hetero-
cyclic units. For example, the cyclization of lactone 23
provided cis-fused 5,5-heterocyclic compound 24 in 86%
yield (entry 11), and the procedure was also employed in
the construction of a bicyclic lactam 26 (entry 12).
Scheme 1. Proposed Mechanism for the Ni(II)-Catalyzed
Conia-Ene Reaction
It is surprising that, as described above (Table 1, entries
4
and 5), longer reaction time and lower yield were obtained
when the amount of Yb(OTf) increased. To determine the
role that Yb(OTf) plays in the reaction, we repeated the
cyclization of 1 under the same reaction condition but
increased the loading of Yb(OTf) to 1 equiv. After 19 h,
only half of 1 was consumed and 2 was isolated in only
0% yield (eq 1). In contrast, when 0.067 equiv of Yb(OTf)
3
3
3
the formation of the enol-yne-Ni complex A. The insertion
of Ni enolate to the alkyne generates a Ni(II) vinyl species
B and then protonation of the C-Ni bond to give the
cyclization product 28.
2
3
In conclusion, we have developed a new Ni(II)-catalyzed
Conia-ene reaction of 1,3-dicarbonyl compounds with alkynes.
This represents the first example of nickel-catalyzed hy-
3
droalkylation of unactivated alkynes by sp hybridized C-H
bonds. The simple catalyst system provides various mono-
and bicyclic olefinic cyclopentanes in a highly regioselective
manner. A mechanism involving the enol-yne-Ni complex
formation is proposed and supported by deuterium labeling
experiments. The neutral and mild reaction condition should
make the Conia-ene reaction a valuable method to synthesize
was used, the reaction time was shortened dramatically to 6
h while the yield remained good. The 3:2 ratio of Ni(acac)
and Yb(OTf) indicates the more active catalyst may be the
in situ formed Ni(OTf) in the reaction system. Indeed, the
reaction can be catalyzed by Ni(OTf)
reaction rate but slightly lower yield. The excess amount of
Yb(OTf) may decrease the reaction rate by competing
complexation with the carbonyl groups of substrates.
To further probe the mechanism of our Ni(II)-catalyzed
Conia-ene reactions, we synthesized deuterated â-ketoesters
2
3
16
quaternary carbon centers.
2
14
2
with a higher
(15) Toste and co-workers have studied the mechanism of Au(I)-catalyzed
Conia-ene reaction and proved the pathway which involves the formation
of enyne-Au complex, followed by the nucleophilic attack of the enol on
the alkyne to give cyclic intermediate, and finally 2 after protonation. See
ref 5.
3
(16) For reviews, see: (a) Fuji, K. Chem. ReV. 1993, 93, 2037-2066.
b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 110,
(
3
88-401. (c) Christoffers, J.; Mann, A.; Angew. Chem., Int. Ed. 2001, 40,
4591-4597. (d) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003,
(14) Ni(OTf)2 was prepared according to the literature procedure:
42, 1688-1690. (e) Denissova, I.; Barriault, L. Tetrahedron 2003, 59,
10105-10146.
Byington, A. R.; Bull, W. E. Inorg. Chim. Acta 1977, 21, 239-244.
Org. Lett., Vol. 7, No. 11, 2005
2187

Acknowledgment. This work was supported by The
University of Hong Kong and the Hong Kong Research
Grants Council (Project No. HKU 7121/02P). D.Y. acknowl-
edges the Bristol-Myers Squibb Foundation for an Unre-
stricted Grant in Synthetic Organic Chemistry.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050532Q
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Org. Lett., Vol. 7, No. 11, 2005