Nickel-catalyzed cycloadditions of unsaturated hydrocarbons, aldehydes, and ketones

Article abstract of DOI:10.1021/jo702508w

(Chemical Equation Presented) The nickel-catalyzed cycloaddition of unsaturated hydrocarbons and carbonyls is reported. Diynes and enynes were used as coupling partners. Carbonyl substrates include both aldehdyes and ketones. Reactions of diynes and aldeh

Full text of DOI:10.1021/jo702508w

Nickel-Catalyzed Cycloadditions of Unsaturated Hydrocarbons,
Aldehydes, and Ketones
Thomas N. Tekavec and Janis Louie*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850
louie@chem.utah.edu
ReceiVed NoVember 26, 2007
The nickel-catalyzed cycloaddition of unsaturated hydrocarbons and carbonyls is reported. Diynes and
enynes were used as coupling partners. Carbonyl substrates include both aldehdyes and ketones. Reactions
of diynes and aldehydes afforded the [3,3] electrocyclic ring-opened tautomers, rather than pyrans, in
high yields. The cycloaddition reaction of enynes and aldehydes afforded two distinct products. A new
carbon-carbon bond is formed, prior to a competitive â-hydrogen elimination of a nickel alkoxide, between
the carbonyl carbon and either one of the carbons of the olefin or the alkyne. The steric hindrance of the
enyne greatly affected the chemoselectivity of the cycloaddition of enynes and aldehydes. In some cases,
dihydropyran was also formed. The scope of the cycloaddition reaction was expanded to include the
coupling of enynes and ketones. No â-hydrogen elimination was observed in cycloaddition reaction of
enynes and ketones. Instead, C-O bond-forming reductive elimination occurred exclusively to afford
dihydropyrans in excellent yields. In all cases, complete chemoselectivity was observed; only dihydropyrans
where the carbonyl carbon forms a carbon-carbon bond with a carbon of the olefin, rather than of the
alkyne, were observed. All cycloaddition reactions occur at room temperature and employ nickel catalysts
bearing the hindered 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) or its saturated analogue,
1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolin-2-ylidene (SIPr).
Introduction
in several biologically important compounds. Thus a direct,
catalytic cycloaddition route utilizing simple starting materials
conducted under neutral reaction conditions would be a valuable
synthetic tool in the construction of pyrans.
Transition metal-catalyzed [2 + 2 + 2] cycloadditions are
an extremely powerful method for the synthesis of various
carbo- and heterocyclic compounds.1 Not only are the reactions
carried out catalytically under neutral conditions, but they offer
a great degree of flexibility in the compounds that can be
synthesized. For instance, one diyne can be transformed into a
benzene ring, pyridone, pyridine, pyrone, or pyran depending
on whether it is coupled with alkyne, isocyanate, nitrile, carbon
dioxide, or a carbonyl (aldehydes and ketones) (Scheme 1).2
While a great degree of success has been realized with [2 + 2
+ 2] cycloadditions of diynes with alkynes,3 isocyanates,4
nitriles,5 and carbon dioxide,6 far less success has been had with
aldehydes7 and ketones.8,9 The inability to efficiently couple
carbonyls with diynes via a transition metal-catalyzed [2 + 2
+ 2] cycloaddition is unfortunate due the prevalence of pyrans
The relative lack of success in the coupling of carbonyls and
diynes can be attributed to a combination of two factors. The
first is the increased steric bulk of carbonyls relative to alkynes,
isocyanates, nitriles, and carbon dioxide. The latter all possess
sp-hybridized carbons whereas carbonyl carbons are sp2-
hybridized. Such a simple change in hybridization severely limits
the “faces” from which an electrophile can be attacked from.
The linear molecules (those containing sp-hybridized carbons)
can easily be attacked from any face in their 360° radius.
Trigonal planar molecules (those containing sp2-hybridized
carbons) can only be easily attacked from one of two faces (i.e.,
the top face or the bottom face).
The second contributing factor is the energetically demanding
C-O bond-forming reductive elimination required for the pyran
formation. Indeed, the reductive elimination of ethers from
(1) Review: Chopade, P. R.; Louie, J. AdV. Synth. Catal. 2006, 348,
2307.
10.1021/jo702508w CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/05/2008
J. Org. Chem. 2008, 73, 2641-2648
2641

Tekavec and Louie
SCHEME 2. Previous Cycloadditions of Diynes and
SCHEME 1. [2+2+2] Cycloaddition of Diynes with Various
Electrophiles
Carbonyls
the alkoxide intermediate11 and to accelerate rate-determining
C-O bond-forming reductive elimination. Similar reductive
eliminations from Ni complexes appear to be more challenging.
Theoretical calculations have shown that in C-X bond-forming
reductive eliminations from (PH3)2Ni(CH3)(X) complexes (where
X ) C, O, or N), the C-O reductive elimination is 6.0 kcal/
mol higher than the C-N reductive elimination and 19.1 kcal/
mol higher than the C-C reductive elimination.12 In fact,
Hillhouse demonstrated Ni(II) alkoxide complexes require
oxidation to induce C-O reductive elimination through a one-
electron process. In contrast, thermolysis of the Ni complexes
favors â-hydrogen elimination of the alkoxide ligand followed
by C-H reductive elimination.13
In accordance with these difficulties, only two examples of
transition metal catalyzed [2 + 2 + 2] cycloadditions of diynes
with carbonyls have been reported (Scheme 2). Both reactions
require elevated temperatures and relatively reactive carbonyl
substrates (i.e., aldehydes and activated ketones). The first was
by Tsuda and co-workers who successfully coupled diynes with
aldehydes in the presence of a Ni/phosphine catalyst to generate
a pyran.7a The second was by Itoh and co-workers who used a
Ru catalyst to couple diynes with a tricarbonyl to afford a
dieneone, which is the3,3 electrocyclic ring-opened tautomer of
the pyran cycloadduct.8
transition metal complexes is a rare elementary reaction that is
generally limited to special cases. Of particular note are
processes catalyzed by Pd phosphine systems that afford aryl
ethers via key C-O reductive-elimination steps.10 Such systems
typically employ sterically hindered alkylphosphine or bidentate
arylphosphines. The efficacy of these ligands is believed to lie
in their ability to inhibit facile â-hydrogen elimination from
(2) (a) Schore, N. E. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, UK, 1991;
Vol. 5, pp 1129-1162. (b) Grotjahn, D. B. In ComprehensiVe Organome-
tallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Hegedus,
L., Eds.; Pergamon Press: Oxford, UK, 1995; Vol. 12, pp 741-770. (c)
Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (d) Gevorgyan, V.;
Radhakrishnan, U.; Takeda, A.; Rubina, M.; Rubin, M.; Yamamoto, Y. J.
Org. Chem. 2001, 66, 2835. (e) Yamamoto, Y. Curr. Org. Chem. 2005, 9,
503. (f) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 21,
2209.
(3) Review: (a) Kotha, S.; Brachmachary, K.; Lahiri, K. Eur. J. Org.
Chem. 2005, 4741. Recent reports: (b) Gandon, V.; Leca, D.; Aechter, T.;
Vollhardt, K. P. C.; Malacria, M.; Aubert, C. Org. Lett. 2004, 6, 3405. (c)
Kezuka, S.; Tanaka, T.; Ohe, Y.; Nakaya, Y.; Takeuchi, R. J. Org. Chem.
2006, 71, 543. (d) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am.
Chem. Soc. 2004, 126, 8382. (e) Takeuchi, R.; Nakaya, Y. Org. Lett. 2003,
5, 3659. (f) Novak, P.; Pohl, R.; Kotora, M.; Hocek, M. Org. Lett. 2006, 8,
2051. (g) Tanaka, K.; Sagae, H.; Toyoda, K.; Noguchi, K.; Hirano, M. J.
Am. Chem. Soc. 2007, 129, 1522.
(4) Recent reports: (a) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett.
2005, 7, 4737. (b) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc.
2004, 126, 11438. (c) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett.
2001, 3, 2117. (d) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.;
Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605.
(5) Review: (a) Varela, J. A.; Saa´, C. Chem. ReV. 2003, 103, 3787.
Recent reports: (b) Bonaga, L. V. R.; Zhang, H. C.; Moretto, A. F.; Ye,
H.; Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc.
2005, 127, 3473. (c) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H. J.;
Spannenberg, A.; Sunderman, B.; Sunderman, C. Angew. Chem., Int. Ed.
2004, 43, 3795. (d) Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc.
2001, 123, 6189. (e) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J.
J. Am. Chem. Soc. 2005, 127, 5030.
Previous results from our laboratory have shown that Ni/NHC
(NHC ) N-heterocyclic carbene) complexes efficiently catalyze
the [2 + 2 + 2] cycloaddition of diynes with isocyanates,
nitriles, and carbon dioxide.4b,5e,6c,d On the basis of these results
and the limited success in the coupling of diynes with carbonyls,
we sought to expand our Ni/NHC catalyst system to include
(10) (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 3224. (b) Mann, G.; Hartwig, J. Am. Chem. Soc.
1996, 118, 13109. (c) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L.
J. Am. Chem. Soc. 1997, 119, 6787. (d) Widenhoefer, R. A.; Buchwald, S.
L. J. Am. Chem. Soc. 1998, 120, 6504.
(6) (a) Tsuda, T.; Morikawa, S.; Saegusa, T. J. Chem Soc., Chem.
Commun. 1979, 982. (b) Tsuda, T.; Morikawa, S.; Sumiya, R.; Saegusa, T.
J. Org. Chem. 1988, 53, 3140. (c) Louie, J.; Gibby, J. E.; Farnworth, M.
V.; Tekavec, T. N. J. Am. Chem. Soc. 2002, 124, 15188. (d) Tekavec, T.
N.; Arif, A. M.; Louie, J. Tetrahedron 2004, 60, 7431.
(7) (a) Tsuda, T.; Kiyoi, T.; Miyane, T.; Saegusa, T. J. Am. Chem. Soc.
1988, 110, 8570. (b) Tekavec, T. N.; Louie, J. Org. Lett. 2005, 7, 4037.
(8) Yamamoto, Y.; Takagishi, H.; Itoh, K. J. Am. Chem. Soc. 2002, 124,
6844.
(11) (a) Zhao, J.; Hesslink, H.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 7220. (b) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 3124. (c) Ng, S. M.; Zhao, C.; Lin, Z. J. Organomet. Chem.
2002, 662, 120.
(12) Macgregor, S. A.; Neave, G. W.; Smith, C. Faraday Discuss. 2003,
124, 111.
(13) (a) Masunaga, P. T.; Hillhouse, G. L. J. Am. Chem. Soc. 1993, 115,
2075. (b) Koo, K.; Hillhouse, G. L. Organometallics 1995, 14, 456. (c)
Koo, K.; Hillhouse, G. L. Organometallics 1996, 15, 2669. (d) Koo, K.;
Hillhouse, G. L. Organometallics 1998, 17, 2924. (e) Han, R.; Hillhouse,
G. L. J. Am. Chem. Soc. 1997, 119, 8135. C-N reductive elimination: (f)
Koo, K.; Hillhouse, G. L. Organometallics 1995, 14, 4421.
(9) For stoichiometric examples with Co, see: (a) Harvey, D. F.; Johnson,
B. M.; Ung, C. S.; Vollhardt, K. P. C. Synlett 1989, 15-18. (b) Gleiter, R.;
Schehlmann, V. Tetrahedron Lett. 1989, 30, 2893.
2642 J. Org. Chem., Vol. 73, No. 7, 2008

Nickel-Catalyzed Cycloadditions
TABLE 1. Evaluation of Ligands in the Ni-Catalyzed
Cycloadditions of Diyne 1 and Benzaldehydea
only trace amounts of the desired pyran were observed (entry
8). When N-aryl carbenes were employed, a marked increase
in the ratio of pyran formation to diyne conversion was observed
(entries 9-11). The highest yields of pyran were observed with
N-aryl carbenes possessing increased steric hindrance (entries
10-11). Interestingly, the saturated SIPr ligand provided
significantly higher conversions of diyne in conjunction with
higher pyran yields than reaction run in the presence of the
sterically similar IPr ligand.
Ultimately, a protocol similar to the one found effective for
6c,d
the cycloaddition of alkynes and CO2
cleanly afforded
dienone 2, which is derived from electrolytic ring opening of
the initially formed pyran 2′ (eq 2).17 Excellent yields (as
determined using gas chromatography) were obtained with 5
mol % of Ni(COD)2, 10 mol % of SIPr, a diyne concentration
of 0.1 M in toluene, and a slight excess (1.25 equiv) of aldehyde
at room temperature.
a Reaction conditions: 0.1 M diyne 1, 0.125 M PhCHO, 5 mol %
Ni(COD)2, 10 mol % ligand, toluene, room temperature. b Determined by
GC based on napthalene as the internal standard.
the coupling of carbonyls with diynes. Herein, we report the
development of a Ni/NHC catalyst that effectively cyclizes
unsaturated hydrocarbons, such as diynes and enynes, with
carbonyl substrates, such as aldehydes and ketones, at ambient
temperature.
Cycloaddition of Diynes and Aldehydes: Formation of
Dienones.18 As illustrated in Table 2, the Ni/SIPr combination
catalyzes the cycloaddition reaction of diynes and various
aldehydes. For example, benzaldehyde cyclized smoothly at
Results and Discussion
Cycloaddition of Diynes and Aldehydes: Catalyst Devel-
opment. A variety of conditions were evaluated by using diyne
1 and benzaldehyde as model substrates for the cycloaddition
reaction (eq 1). Initially, several phosphines and carbenes were
screened as potential ligands for this reaction (Table 1). Since
Tsuda and Saegusa’s original report, several new bulky phos-
phine ligands, which have shown improved reactivity in C-N
and C-O bond-forming cross-couplings,14 have been developed
and were included in our ligand screen. Unfortunately, no diyne
conversion was observed with any of the phosphine ligands
(entries 2-7). Upon switching to the N-heterocyclic carbene
ligands,15 which we have successfully employed in other
cycloaddition reactions,4b,5e,6c-d,16 improved conversions and
yields were observed. High diyne conversion was observed when
a sterically hindered N-alkyl carbene was employed; however,
TABLE 2. Ni-Catalyzed Cycloadditions with a Variety of
Aldehydesa
dienone
product
yield
(%)b
entry
diyne
aldehyde
R2 ) C6H5
1
2
3
4
5
6
1 (R1 ) Me)
2
3
4
5
6
8
78
91
1
R2 ) 4-MeO-C6H4
R2 ) 4-CF3-C6H4
R2 ) i-Pr
1
1
1
65c
58d,e
72d,e
80
R2 ) n-Pr
7 (R1 ) Et)
R2 ) C6H5
a Reaction conditions: 0.1 M diyne, 0.125 M aldehyde, 5 mol %
Ni(COD)2, 10 mol % SIPr, room temperature. b Isolated yields (average of
two runs). c 10 mol % Ni(COD)2, 20 mol % SIPr. d 10 mol % Ni(COD)2,
10 mol % SIPr. e Product exists as an equilibrium mixture of dienone (major)
and pyran (minor).
(14) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L J. Am. Chem. Soc.
1996, 118, 7215. (b) Driver, S. M.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 7217. (c) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 3395. (d) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1,
35. (e) Torraca, K. E.; Huang, X.; Parrish, L. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 10770. (f) Kawatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2000, 122, 9546. (g) Harris, M. C.; Huang, X.; Buchwald, S.
L. Org. Lett. 2002, 4, 2885.
(15) ItBu ) 1,3-di-tert-butylimidazol-2-ylidene; IMes ) 1,3-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene; IPr ) 1,3-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene; SIPr ) 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroim-
idazolin-2-ylidene.
(17) The thermal electrocyclic ring opening of fused R-pyrans is common,
see: (a) Marvell, E. N.; Caple, G.; Gosink, T. A.; Zimmer, G. J. Am. Chem.
Soc. 1966, 88, 619. (b) Marvell, E. N.; Chadwick, T.; Caple, G.; Gosink,
T.; Zimmer, G. J. Org. Chem. 1972, 37, 2992. (c) Kluge, A. F.; Lillya, C.
P. J. Org. Chem. 1971, 36, 1979. (d) Trost, B. M.; Rudd, M. T.; Costa, M.
G.; Lee. P. I.; Pomerantz, A. E. Org. Lett. 2004, 6, 4235.
(16) (a) Zuo, G.; Louie, J. Angew. Chem., Int. Ed. 2004, 43, 2277. (b)
Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5798.
(18) Some of this work has been previously reported, see ref 7b.
J. Org. Chem, Vol. 73, No. 7, 2008 2643

Tekavec and Louie
room temperature with diynes 1 and 7 to afford dienones 2 and
8 in good yields (entries 1 and 6, respectively). The cycload-
dition of an aryl aldehyde bearing an electron-donating group
(p-OMe) afforded the dienone product in a higher yield than
the reaction of an aryl aldehyde possessing an electron-
withdrawing group (p-CF3) (entries 2 and 3, respectively).
Aliphatic aldehydes also underwent facile cycloaddition (entries
4 and 5) with slightly modified conditions (10 mol % Ni(COD)2
and 10 mol % SIPr). In addition, excess butyraldehyde (entry
5, 5 equiv) was necessary to ensure complete dienone forma-
tion.19
Diynes possessing a three-carbon linkage between alkynes
also underwent Ni-catalyzed cyclization with aldehydes. When
diynes 9 and 11 were subjected to benzaldehyde under standard
cyclization procedures, dieneones 10 and 12 were obtained in
20% and 91% yield, respectively (eqs 3 and 4). Interestingly,
nation and â-hydrogen elimination. It is likely that carbon-
oxygen bond-forming reductive elimination is more facile when
a less strained [6,6] ring system is being formed (i.e., when n
) 2), which explains the formation of electrocyclic ring-opened
cycloadducts (2-8). In contrast, the higher energy barrier to
form a relatively strained [5,6] ring system (i.e., when n ) 1)
prevents carbon-oxygen bond-forming reductive elimination
from occurring, and in turn, only dienone products arising from
â-hydride elimination are observed (e.g., dienones 10 and 12).
Cycloaddition of Enynes and Aldehydes. The cycloaddition
of enynes and carbonyls (or even heterocumulene deriva-
tives)20,21 remains a challenge in synthetic chemistry. Given the
dramatic increase in reactivity of the Ni-carbene catalysts in
the cycloaddition of diynes and aldehydes, enynes were evalu-
ated as potential substrates. Thus, enyne 14 was subjected to
benzaldehyde under optimized reaction conditions at room
temperature (eq 5). Cyclization led to the formation of two
products, enone 15 and ketone 16, which were isolated in a
1:1.6 ratio for a combined overall yield of 79%. The carbonyl
carbon of the aldehyde substrate is connected to the alkyne
portion in enone 15 whereas this carbon is connected to the
alkene portion in ketone 16.
the connectivity of dienones 10 and 12 was different than those
obtained from reactions involving diynes possessing a four-
carbon linkage (Table 2). Specifically, the C-C bond between
the carbonyl carbon and the Ph group of benzaldehyde is cleaved
in dienones 2-8 (Table 2). In contrast, this bond remains
connected in dienones 10 and 12. A similar outcome occurs in
Ni/PR3-catalyzed cycloadditions where reactions were run at
high temperatures.7a It is believed that products of this nature
arise from a [1,5] H shift.7a An alternative account of these
products involves â-hydrogen elimination from a Ni alkoxide
intermediate (13, Scheme 3).13 If nickelacycle 13 undergoes
C-O bond-forming reductive elimination, dienones where the
carbonyl-carbon bond has been cleaved are formed. On the
other hand, if nickelacycle 13 undergoes â-hydrogen elimination
and subsequent carbon-hydrogen reductive elimination, di-
enones where the carbonyl-carbon bond remains intact are
formed. The ratio of products would therefore depend on the
relative rates of carbon-oxygen bond-forming reductive elimi-
The cycloaddition reaction of benzaldehyde and enyne 17,
whose sole difference from enyne 14 is an ethyl substituent on
the terminal end of the alkyne, gave enone 18a exclusively under
identical reaction conditions (eq 6 and entry 1 of Table 3). Thus,
when enynes with slightly larger alkynes were used as the
substrates, only enone products were obtained (Table 3). In all
cases, products arising from the addition of the carbonyl carbon
to the alkene were not observed. Furthermore, addition of the
carbonyl carbon to the alkyne was observed regardless of the
aldehyde substrate. For example, both aryl and alkyl aldehydes
produced enone products (entries 1-6, Table 3). Increasing the
steric hindrance of the aldehyde had no effect on the chemose-
lectivity of the reaction (entries 2 and 5). Electron-donating and
electron-withdrawing aryl aldehydes both afforded enone prod-
ucts suggesting electronic effects of the aldehyde do not play a
major role in determining the chemoselectivity between enone
and ketone formation (as seen in Table 3). The cycloaddition
also proceeded smoothly in the presence of silyl and benzyl
protecting groups to give the corresponding enones in good to
SCHEME 3. Mechanistic Explanation for a Products
Dichotomy in the Cycloaddition of Diynes of Varying Length
(19) In some cases, excess aldehyde was necessary due to competitive
NHC-catalyzed aldehyde cyclotrimerization.
(20) (a) Takimoto, M.; Mizuno, T.; Mori, M.; Sato, Y. Tetrahedron 2006,
62, 7589. (b) Takimoto, M.; Mizuno, T.; Sato, Y.; Mori, M. Tetrahedron
Lett. 2005, 46, 5173.
(21) (a) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370. (b)
Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782.
2644 J. Org. Chem., Vol. 73, No. 7, 2008

Nickel-Catalyzed Cycloadditions
TABLE 3. Ni-Catalyzed Cycloadditions of Enynes and Aldehydesa
TABLE 4. Ni-Catalyzed Cycloadditions of Enynes with Varying
Alkyne Substituentsa
yield
entry
enyne
ratio A:Ba
product
(%)b
1
2
3
4
5
25 (R ) H)
<5:95
38:62
>95:5
>95:5
>95:5
26
57
79
87
89
91
14 (R ) Me)
17 (R ) Et)
27 (R ) i-Pr)
29 (R ) n-Pr)
15; 16
18a
28
30
a Determined by 1H NMR analysis of crude reaction mixture. b Isolated
yield, average of two runs.
the effect of olefin substitution on the chemoselectivity of the
cycloaddition. Thus, a series of enynes (31, 32, and 35) bearing
methyl substitution on the olefin were prepared and subjected
to benzaldehyde under standard cycloaddition conditions. Enyne
31 that possesses a trans-substituted olefin failed to react (eq
7), which may be due to a decreased ability of the olefin to
bind to the metal center. On the other hand, the analogous cis
enyne 32 cyclized with benzaldehyde to yield ketone 33 and
pyran 34 (eq 8). Likewise, the cyclization of enyne 35 with
benzaldehyde produced similar results. Ketone 36 and pyran
3722 were formed in 82% and 18%, respectively (eq 9). In all
cases, only products arising from the coupling of the carbonyl
carbon with the olefin were obtained.
a Reaction conditions: 0.1 M enyne, 0.125 M aldehyde, 5 mol %
Ni(COD)2, 10 mol % SIPr, room temperature. b Isolated yields (average of
two runs). c 7.5 mol % Ni(COD)2, 15 mol % SIPr.
excellent yield (entries 7 and 8). Enynes with a three-carbon
linkage also cyclized to afford the enone product as a five-
membered carbocycle (entry 9).
Chemoselectivity of the Cycloaddition of Substituted
Enynes: Alkyne Substituents. The difference in product ratio
(enone:ketone) obtained in the cycloaddition of enyne 14 versus
enyne 17 suggested the chemoselectivity could be influenced
by varying the steric bulk of the alkyne substituent. Thus, a
series of substituted enynes, containing one terminal olefin and
an internal alkyne bearing a terminal group of varying size (R
) H, Me, Et, i-Pr, and n-Pr), were prepared. These enynes (14,
17, 25, 27, 29) were subjected to benzaldehyde under the
standard cycloaddition conditions (Table 4). When the R group
at the terminal position of the alkyne was a hydrogen atom (entry
1), only ketone 26, arising from the addition of the aldehyde to
the olefin, was observed. Increasing the size of the R group to
methyl led to the formation of both enone (15) and ketone (16)
products in relatively equal amounts (1:1.6). When the alkyne
substituent was Et (entry 3) or larger (entries 4 and 5), a
complete reversal in product formation was observed. In these
cases, the carbonyl carbon preferentially reacted with the alkyne
portion of the enyne.
Interestingly, although ketone 33 was obtained as a mixture
of diastereomers, formation of the pyran products displayed
Chemoselectivity of the Cycloaddition of Substituted
Enynes: Olefin Substituents. The effect of olefin substitution
on the chemoselectivity was also investigated. When the alkyne
bears a methyl group at its terminus, a mixture of enone and
ketone products were obtained (entry 2, Table 4). This feature
suggested that enynes of this nature (i.e., R ) Me), but bearing
various substituted tethered olefins, would allow us to delineate
(22) The diastereoselectivity of pyran 37 could not be determined by
NMR analysis due to the conformation of the ring; pyran 37 possesses a
particularly flattened out structure due to the olefin and lacks any 1,3
interations in the NOE analysis. Unfortunately, we were unable to grow
suitable crystals for X-ray analysis to determine the structure of pyran 37.
J. Org. Chem, Vol. 73, No. 7, 2008 2645

Tekavec and Louie
higher selectivity. Both pyrans 34 and 37 were isolated as single
diastereomers (eqs 8 and 9). The trans configuration between
the methyl and phenyl substituents was confirmed by X-ray
analysis.23
used. At the onset, it was unclear whether ketones would be
suitable substrates for the cycloaddition. As seen with cycload-
ditions involving CO2 or aldehydes, the Ni/carbene-catalyzed
cycloadditions are sensitive to steric hindrance. Thus, it was
possible that ketones may be too sterically hindered to undergo
cyclization. Another concern was that simple alkyl ketones may
not have sufficient electrophilicity to undergo oxidative coupling
or insertion into a nickelacycle intermediate.24d,27 Indeed, Ru-
catalyzed cyclizations of diynes and ketones only provide
products when electron-deficient ketones were employed.8
Initially, the cycloaddition of a ketone, cyclohexanone, and
a diyne (1) was evaluated (eq 10). Gratifingly, cyclohexanone
reacted smoothly with diyne 1 under slightly modified conditions
to afford pyran 40a in 80% yield. As observed in the reaction
of diynes and aldehydes, pyran 40a also underwent spontaneous
electrolytic ring opening. However, in this case, the pyran (40a)
existed in thermal equilibrium with its ring-opened dienone
tautomer 40b in a ratio of 10:1.
Rationale for the Chemoselectivity of the Cycloaddition
of Enynes and Aldehydes. The chemoselectivity observed in
these cycloaddition reactions may be due to a similar rational
for the selectivity observed in cycloadditions between diynes
with CO2,6c,d isocyanates,4b and nitriles.5b In those reactions,
unsymmetrical diynes that possess a large TMS (or t-Bu) group
on one of the alkynyl units undergo regioselective cycloaddition.
The regioselectivity is most likely governed by an insertion step.
Thus, to minimize steric repulsion between the TMS group and
the sterically hindered NHC ligand, heterocyclic products that
bear the TMS group in the 3-position are formed. Similarly,
the chemoselectivity observed in the cycloaddition of enynes
and aldehydes may be dictated by the insertion step (Scheme
4).24-26 Increasing the steric hindrance of the alkyne substituent
(R) favors coupling between the alkyne and the aldehyde
through the preferential formation of oxanickelacycle 38. This
intermediate minimizes the steric repulsion between the alkyne
substituent and the NHC ligand. Similarly, enynes bearing
methyl substitution on the olefin lead to increased coupling
between the olefin and the aldehyde through the selective
formation of oxanickelacycle 39. This intermediate minimizes
the steric repulsion between the olefin substituent (i.e., a methyl)
and the NHC ligand. For both 38 and 39, facile â-H elimination
from the alkoxide ligand occurs to afford the carbonyl products.
Interestingly, substitution on the olefin appears to enhance C-O
bond-forming reductive elimination24 as pyran products are
observed (eqs 8 and 9).
Cycloaddition of Enynes and Ketones. Given the facile
nature of the cycloaddition between enynes and aldehydes, other
carbonyl substrates were examined in an effort to further expand
the scope of the reaction. Thus, ketones were used as coupling
partners in lieu of aldehydes. Not only would this exchange
open a relatively unexplored realm in [2 + 2 + 2] cycloaddi-
tions, but the use of ketones would also eliminate the possibility
of the â-hydrogen elimination that occurs when aldehydes are
The cycloaddition of ketones was then evaluated with enynes.
Enyne 14 and acetone were subjected to standard reaction
conditions and dihydropyran 41 was obtained, albeit in low
yield. However, the yield of dihydropyran could be increased
by the slow addition of the enyne to the reaction mixture.
Ultimately, the slow addition of enyne 14 at room temperature
to a stirring solution of Ni(COD)2 (10 mol %), IPr (15 mol %),
and acetone (1.25 equiv) in toluene afforded dihydropyran 41
as a single regioisomer in good isolated yield (Table 5). To
our knowledge, this is the first example in which both
anunactivated ketone and enyne participate in a cycloaddition
reaction.
SCHEME 4. Proposed Mechanism for the Cycloaddition of
Enynes and Aldehydes
Further optimization of the reaction conditions showed that
the addition of 3 Å molecular sieves (150 mg/mmol) led to
(23) See the Supporting Information for complete X-ray analysis.
(24) (a) Ho, C.-Y.; Jamison, T. F. Angew. Chem., Int. Ed. 2007, 46, 782.
(b) Ho, C.-Y.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 5362. (c) Ng,
S.-S.; Ho, C.-Y.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 11513. (d)
Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077. (e) Miller, K. M.;
Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342. (f) Miller, K. M.;
Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004,
126, 4130. (g) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2,
4221. (h) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc.
2003, 125, 3442. (i) Miller, K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron:
Asymmetry 2003, 14, 3619.
(25) (a) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441. (b)
Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (c) Mahandru, G.
M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (d) Ni,
Y.; Amarasinghe, K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743.
(26) (a) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc.
2005, 127, 12810. (b) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem.
Soc. 2004, 126, 11802.
(27) Trost has utilized acetone as a solvent in Ru-catalyzed cycloisomer-
izations of diynes and does not report any reactivity with the acetone, see
ref 17d.
2646 J. Org. Chem., Vol. 73, No. 7, 2008

Nickel-Catalyzed Cycloadditions
TABLE 5. Ni-Catalyzed Cycloadditions of Enynes and Ketonesa
TABLE 6. Ni-Catalyzed Cycloadditions of Various Enynes and
Acetonea
a Reaction conditions: 10 mol % Ni(COD)2, 15 mol % IPr, 150 mg/
mmol 3 Å molecular sieves, 0.1 M toluene, rt. b Isolated yields, average of
two runs. c Fewer equivalents could be used to obtain more modest yields.
d Isolated as a single diastereomer. e 3:1 syn:anti.
a Reaction conditions: 10 mol % Ni(COD)2, 15 mol % IPr, 150 mg/
mmol 3 Å molecular sieves, 0.1 M toluene, rt. b Isolated yield, average of
two runs. c Fewer equivalents of ketone could be used to obtain more modest
yields. d Isolated as a 1:1 mixture of diastereomers.
1), possessing a methyl group at the internal position of the
olefin, smoothly cyclized to yield pyran 48 as a single
diastereomer as confirmed by X-ray analysis.23 However,
placing substituents at the terminal position of the olefin proved
more problematic. While an internal olefin with cis geometry
required 10 equiv of acetone to obtain a high yield of the
dihydropyran (entry 2), internal olefins with a trans geometry
failed to produce any of the desired product. On the other hand,
increasing substituent length on the alkyne had little effect on
the reaction (entry 3). A fused [5,6] ring system was obtained
from the cyclization of enyne 51 (entry 4), although a slightly
higher amount of acetone was required. Enynes containing
functionalities such as ethers (entry 5) and amines (entry 6) also
cyclized proficiently.
Rationale for the Chemoselectivity of the Cycloaddition
of Enynes and Ketones. In contrast to the cycloaddition of
aldehydes and enynes, substitution on either the olefin or the
alkyne terminus had little effect on the chemoselectivity of pyran
formation. In all cases, the carbonyl carbon was bound to the
olefin, regardless of the alkyne substituent. For example, enyne
17 that has an ethyl terminus still provided pyran 50 (Table 6,
entry 3). Despite this difference, it is likely the cycloadditions
of carbonyls (i.e., ketones and aldehydes) and enynes have
improved yields.28 With use of these conditions, a variety of
unactivated ketones cyclized to afford pyrans in excellent yields
(>91%). As illustrated in Table 5, steric hindrance about the
carbonyl played a large role in determining the reaction
conditions. Both the ketone concentration and enyne addition
time needed to be adjusted accordingly to minimize oligomeric
side products. For instance, 1.25 equiv of acetone smoothly
reacted with enyne 14 by adding the enyne over 0.5 h (entry
1). However, when 3-pentanone was used (entry 2), 4.0 equiv
of ketone and an enyne addition time of 4 h was needed to
obtain a comparable yield. Unsymmetrical methyl ketones also
produced the cycloadducts in excellent yields (entries 3 and 4).
Cyclic ketones possessing 5-, 6-, and 7-carbon rings were also
suitable substrates for the reaction requiring 1.25-4 equiv of
ketone and enyne addition times of 0.5-2 h (entries 5-7).
As shown in Table 6, enynes with variable substitution
patterns and functionality were also tolerated. Enyne 35 (entry
(28) Without the addition of 3 Å molecular sieves, cyclization reactions
gave inconsistent isolated yields of dihydropyran, and yields ranged from
70% to 83%.
J. Org. Chem, Vol. 73, No. 7, 2008 2647

Tekavec and Louie
SCHEME 5. Cycloaddition of Enynes and Ketones
Experimental Procedures
General Procedure for the Cycloaddition of Diynes and
Aldehydes. In a glovebox, a solution of diyne (0.39 mmol) and
aldehyde (0.49 mmol) in 3 mL of toluene was added to an oven-
dried scintillation vial equipped with a magnetic stir bar. To the
stirring solution, a solution of Ni(COD)2 (5.4 mg, 0.020 mmol)
and SIPr (15.3 mg, 0.039 mmol) in 0.9 mL of toluene, which was
previously equilibrated for at least 6 h, was added. The reaction
mixture was stirred at room temperature for 2 h (or until complete
consumption of starting material was observed as judged by GC
or TLC) over which time the color changed from orange to brown.
Upon consumption of the diyne, the mixture was concentrated in
vacuo. The residue was purified by column chromatography on
silica gel. The reaction conditions and results are shown in
Table 2.
similar mechanisms. As such, mechanisms A and B (Schemes
4 and 5) can be used to rationalize the chemoselectivity observed
in the formation of all the pyrans (48-50, 52, 54, 56, 58).
However, in this case, the ability to undergo C-O bond-forming
reductive elimination governs the chemoselectivity. Reversible
oxidative coupling (to form an oxanickelacyclopentane24,25,26
or a nickelacyclopentene29) and insertion steps30 lead to the
formation of oxanickelacycloheptene intermediates 38 and 39
(Schemes 4 and 5). However, only complex 39 is likely to
undergo C-O bond-forming reductive elimination. Carbon-
oxygen bond-forming reductive elimination from complex 38
General Procedure for the Cycloaddition of Enynes and
Aldehydes. In a glovebox, a solution of diyne (0.32 mmol) and
aldehyde (0.40 mmol) in 3 mL of toluene was added to an oven-
dried scintillation vial equipped with a magnetic stir bar. To the
stirring solution was added a solution of Ni(COD)2 (4.4 mg, 0.016
mmol) and SIPr (12.5 mg, 0.032 mmol) in 0.2 mL of toluene, which
was previously equilibrated for at least 6 h. The reaction mixture
was stirred at room temperature for 2 h (or until complete
consumption of starting material was observed as judged by GC
or TLC) over which time the color changed from orange to brown.
Upon consumption of the enyne, the mixture was concentrated in
vacuo. The residue was purified by column chromatography on
silica gel. The reaction conditions and results are shown in Tables
3 and 4.
3
would require the formation of a Csp -O bond, which has only
been observed under oxidative conditions.13 Thus, regardless
of the size of the substituent, oxidative coupling and insertion
events may be reversible thereby allowing all the components
to rearrange and form complex 39 and, ultimately, pyran 39b
rather than 38b (Scheme 5).
General Procedure for the Cycloaddition of Enynes and
Ketones. In a glovebox, a solution of diyne (0.37 mmol) and
aldehyde (0.46 mmol) in 3 mL of toluene was added to an oven-
dried scintillation vial equipped with a magnetic stir bar. To the
stirring solution was added a solution of Ni(COD)2 (10.0 mg, 0.037
mmol) and IPr (15.3 mg, 0.055 mmol) in 0.6 mL of toluene, which
was previously equilibrated for at least 6 h. The reaction mixture
was stirred at room temperature for 2 h (or until complete
consumption of starting material was observed as judged by GC
or TLC) over which time the color changed from orange to brown.
Upon consumption of the enyne, the mixture was concentrated in
vacuo. The residue was purified by column chromatography on
silica gel. The reaction conditions and results are shown in Tables
5 and 6.
Conclusion
It was found that diynes can undergo a [2 + 2 + 2]
cycloaddition with aldehydes in the presence of a Ni/carbene
catalyst. While dienones were obtained for the cyclization of
1,6- and 1,7-diynes, their connectivity was different. It is
believed that in the cyclization of 1,6-diynes, the dienone arises
from a â-hydrogen elimination/C-H reductive elimination. In
the case of 1,7-diynes, the observed dienone arises from a C-O
reductive elimination/electrocyclic ring-opening sequence. This
methodology was expanded to include enynes as substrates to
generate ketones, enones, or pyrans. Evidence suggests that the
chemoselectivity of the reaction is governed by steric hindrance
about the enyne, with the aldehyde reacting preferentially with
the more sterically hindered unsaturated hydrocarbon. Finally,
it was found that pyrans can be obtained chemoselectively in
excellent yields from the cyclization of enynes and ketones. This
represents the first successful attempt at using enynes and
ketones as coupling partners in a [2 + 2 + 2] cycloaddition
reaction.
Acknowledgment. The authors thank Matt Snyder for the
synthesis of some of the NHC ligands used in this study. We
also thank Atta M. Arif for obtaining the X-ray crystallographic
data. We gratefully acknowledge Merck, NSF (Career Award),
the NIH-NIGMS, and the Alfred P. Sloan Foundation for
supporting this research.
Supporting Information Available: Full Experimental Section,
including characterization of all reaction products and demonstration
of purity. This material is available free of charge via the Internet
at http://pubs.acs.org.
(29) (a) Saito, A.; Oka, Y.; Nozawa, Y.; Hanzawa, Y. Tetrahedron Lett.
2006, 47, 2201. (b) Ikeda, S.; Miyashita, H.; Taniguchi, M.; Kondo, H.;
Okano, M.; Sato, Y.; Odashima, K. J. Am. Chem. Soc. 2002, 124, 12060.
(30) Carmona, E.; Gutie´rrez-Puebla, E.; Mar´ın, J. M.; Monge, A.;
Paneque, M.; Poveda, M. L.; Ruiz, C. J. Am. Chem. Soc. 1989, 111, 2883.
JO702508W
2648 J. Org. Chem., Vol. 73, No. 7, 2008