An expeditious route to eight-membered heterocycles by nickel-catalyzed cycloaddition: Low-temperature Csp2-Csp3 bond cleavage

Article abstract of DOI:10.1002/anie.201203521

A cool break: 3-Azetidinone and a variety of diynes undergo a cycloaddition reaction catalyzed by Ni/IPr to give dihydroazocine compounds (see scheme; IPr=1,3-bis(2,6-diisopropylphenyl)imidazolidene). The reaction involves a challenging CC bond cleavage step, yet, surprisingly, proceeds at low temperature.

Full text of DOI:10.1002/anie.201203521

Angewandte
Chemie
DOI: 10.1002/anie.201203521
Cycloaddition Reactions
An Expeditous Route to Eight-Membered Heterocycles By Nickel-
À
Catalyzed Cycloaddition: Low-Temperature Csp2 Csp3 Bond Cleavage**
Puneet Kumar, Kainan Zhang, and Janis Louie*
In the 21st century, chemists have witnessed immense growth
prone to polymerization and decomposition.[13] Furthermore,
self-condensation of heteroatom-substituted cyclobutanones
occurs under neutral as well as basic reaction conditions.
Despite these challenges, we successfully developed a Ni/IPr
catalyst that can effect the coupling of diynes and azetidi-
nones to afford dihydroazocines in excellent yield.[14] This
catalytic method not only provides medium-sized eight-
membered heterocycles that are normally challenging to
prepare but also represents a remarkable model system for
À
in the field of C H bond activation, which represents an
À
elegant method for constructing C C bonds in a manner that
minimizes waste.[1] Alternatively, C C bond activation pro-
vides another possible solution. Although significant progress
À
À
À
has been made in the area of C H bond activation, C C bond
activation is still in its infancy.[2] The paucity of developments
À
in this area can be attributed to the highly inert nature of C C
À
s bond and the poor interaction of the orbitals of C C
s bonds with transition metals.[2a]
the cleavage of Csp2 Csp3 bonds at low temperature.
À
There is a significant amount of literature that describes
the use of the inherent strain of cyclopropanes (strain
energy = 27.6 kcalmolÀ1) in transition-metal-catalyzed reac-
tions.[3] Before the remarkable finding of Murakami et al., the
use of cyclobutanes (strain energy = 26.4 kcalmolÀ1) in such
reactions remained largely unexplored.[4] Since then, appreci-
able efforts have been made in using various transition-metal
catalysts to harness the latent potential of cyclobutanones.[5]
Most of these studies focused on the development of methods
for accessing carbocycles that were, at the time, difficult to
synthesize
Our research group has been active in developing nickel-
catalyzed cycloaddition reactions. Recently, our research
group and those of others independently discovered a
Ni/PPh3-catalyzed method for coupling azetidinones and
alkynes to afford 3-piperidones; this method involves cleav-
At the outset, we reasoned that self-condensation of the
azetidinone could be minimized through the use of suitable
protecting groups on the nitrogen atom of 3-azetidinones. The
reaction between commercially available 3-Boc-protected
azetidinone (2a) and malonate diyne 1a was chosen as
a model reaction. Given our success in using catalytic
amounts of Ni/PPh3 in toluene as reaction conditions for the
coupling of azetidinones and alkynes, we initially evaluated
these reactions conditions for the reaction between 1a and 2a.
In the event, although moderate conversion of azetidinone 2a
was observed, no desired product was detected (Table 1,
entry 1). Other phosphine ligands were also evaluated
(Table 1, entries 2–8), but these reactions also led to little or
no desired product. Notably, the reactions where some
desired product was formed were those in which electron-
donating phosphines were used (P(nBu)3, PCy3, and P(Cyp)3;
Table 1, entries 5—7, respectively). A side reaction that
plagues many cycloaddition reactions is the oligomerization
of alkyne units to give aromatic products.[15] We feared that
this reaction was the cause of the low yields and therefore we
conducted the reaction using Ni/PCy3 as the catalyst and
employing slow addition of the diyne (Table 1, entry 6).
Unfortunately, a low yield of product 3aa was still obtained.
We then turned our attention to the highly s-donating
N-heterocyclic carbene (NHC) ligand, IPr, owing to our
previous success in using Ni/IPr in the cycloaddition of both
diyne and enynes and carbonyl compounds such as aldehydes
and ketones;[16] Murakami and co-workers also used a Ni/IPr
catalyst to facilitate the cycloaddition of diynes and cyclo-
butanones.[11] Ultimately, the use of IPr proved to be
advantageous because the product 3aa was obtained in
À
age of the C C bond attached to the carbonyl of the
azetidinone.[6] We surmised that if two tethered alkynes
were employed instead of one, insertion of both of the alkynes
À
into the azetidinone Csp2 Csp3 bond could occur, thus resulting
in the formation of eight-membered N-containing heterocy-
clic products [Eq. (1)]. Medium-sized heterocycles are prev-
alent among bioactive molecules.[7] Unfortunately, the syn-
thesis of eight-membered rings poses a serious challenge
because of enthalpic and entropic factors.[8–10] In contrast to
cyclobutanone, which was used by the research group of
Murakami,[11,12] heteroatom-substituted cyclobutanones are
[*] P. Kumar, K. Zhang, Prof. Dr. J. Louie
Department of Chemistry, University of Utah
315 South, 1400 East, Salt Lake City, Utah 84112-0850 (USA)
E-mail: louie@chem.utah.edu
Homepage: http://www.chem.utah.edu/faculty/louie/index.html
[**] We acknowledge the NIH (5R01GM076125) and the NSF (0911017)
for financial support. We thank Dr. J. Muller and Dr. A. Aarif of the
University of Utah for providing HRMS and single-crystal X-ray
crystallographic data, respectively. We also thank Ashish Thakur for
the preparation of diynes 1g and 1h, and for the partial synthesis of
1m.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203521.
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Table 1: Ligand evaluation for the Ni-catalyzed cycloaddition of diyne 1a
and azetidinone 2a.[a]
significantly when the reaction temperature was lowered to
08C (Table 2, entry 4).[17] The use of a more dilute reaction
mixture led to further improvement of the yield (Table 2,
À
entries 4–6). Because previous C C bond cleavage reactions
were facilitated when they were conducted at higher temper-
À
atures, the results herein are exceptional in that the C C bond
cleavage step proceeds at 08C.[18]
Other protecting groups on the nitrogen atom of
3-azetidinone were also evaluated (Table 3). The use of the
methoxycarbonyl protecting group (2b; Table 3, entry 2)
Entry
Ligand
2a
3aa
Conv. [%][b]
Yield [%][c]
1
2
3
4
5
6
7
PPh3
dppf
binap
PCy2Ph
P(nBu)3
PCy3
49
48
–
60
72
83
81
n.d.
n.d.
n.d.
n.d.
23
Table 3: Effect of azetidinone protecting group on the Ni/IPr-catalyzed
cycloaddition of 1a and 2a–d.
37 (28)[d]
30
P(Cyp)3
8
9
18
n.d.
70[e]
Entry
2
Protecting group (PG)
Product 3
Yield [%] 3
1
2
3
4
2a
2b
2c
2d
Boc
CO2Me
Ts
3aa
3ab
3ac
3ad
88
69
25
92
IPr
>99
[a] Azetidinone 2a (0.1m), diyne 1a (0.12m), 10 mol% [Ni(cod)2], ligand
(20 mol% for entries 1, and 4—8; 10 mol% for entries 2 and 3), toluene,
1008C, 12 h. [b] Conversion of diyne was determined by 1H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
[c] Yields of isolated product. [d] Diyne 1a was added dropwise to the
reaction mixture. [e] Reaction was run at RT. binap=2,2’-bis(diphenyl-
phosphino)-1,1’-binaphthyl, Boc=tert-butoxycarbonyl, cod=1,5-cyclo-
octadiene, Cy=cyclohexyl, Cyp=cyclopentyl, dppf=1,1’-bis(diphenyl-
phosphino)ferrocene, n.d.=not detected.
Bnh
Ts =p-toluenesulfonyl.
resulted in a lower yield than the use of Boc-protected
azetidinone (2a; Table 3, entry 2). The use of the tosyl (Ts)
protecting group afforded the product in poor yield (2c;
Table 3, entry 3). However, the use of the benzhydryl (Bnh)
protecting group (2d; Table 3, entry 4) led to an excellent
yield (92%) of the corresponding dihydroazocine 3ad.
70% yield when the reaction was conducted at room temper-
ature (Table 1, entry 9).
The substrate scope of this reaction was investigated with
various diynes (Scheme 1). The presence of a dioxolone
moiety in the diyne was well tolerated under the reaction
conditions and the dihydroazocine product 3bd was obtained
in good yield. Unsurprisingly, the presence of ether functional
groups was tolerated (Scheme 1; 3 cd and 3dd).[19] Notably,
the sulfonamide-based diyne, which is not always well
tolerated in Ni-catalyzed cycloaddition reactions, reacted
with azetidinone to provide the pyrrolidinyl-fused dihydroa-
zocine product 3ed in excellent yield.[20] The reaction of
a diyne containing a sulfonyl group (1 f) afforded product in
slightly lower yield than an ester-containing diyne (1a).
Interestingly, ketones and nitriles, which are functional
groups that also undergo cycloaddition reactions with
diynes, did not interfere with the coupling reaction involving
the azetidinone (3gd and 3hd, Scheme 1).[11,20c,e] The success
of the reaction is not dependent on the presence of the
Thorpe–Ingold effect because the use of a diyne with an
unsubstituted backbone afforded the corresponding dihy-
droazocine (3id) in good yield. Because ester-containing
compounds often cannot be used as therapeutics, we eval-
uated other substrates. Inspired by the recent work of
Carriera and co-workers, oxetanyl and azetidinyl diynes (1j
and 1k) were prepared and subjected to the optimized
reaction conditions;[21] the corresponding dihydroazocine
We surmised that the b-carbon-elimination step might be
slow because the slow addition of the diyne did not lead to
improved yields (see above). To facilitate this step, we
conducted the reaction at higher temperatures (Table 2).
Unfortunately, higher reaction temperatures proved to be
deleterious to the coupling reaction and resulted in increased
alkyne oligomerization. Specifically, when the reaction per-
formed at 608C and at 1008C the dihydroazocine product was
obtained in 35% and 21% yield, respectively (Table 2,
entries 2 and 3). These results suggested that lowering
rather than increasing the reaction temperature might result
in higher product yield. Indeed, the yield of 3aa improved
Table 2: Temperature-effect evaluation on the Ni/IPr-catalyzed cyclo-
addition of 1a and 2a to afford 3aa[a]
Entry
T [8C]
1a Conc. [m]
3aa Yield [%][b]
1
2
3
4
5
6
RT
60
100
0
0
0
0.10
0.10
0.10
0.10
0.20
0.05
70
35
21
84
68
88
[a] Reaction conditions: azetidinone 2a (1 equiv), diyne 1a (1.2 equiv),
10 mol% [Ni(cod)2], 20 mol% IPr, toluene, 8 h. [b] Yield of isolated
product.
2
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A proposed mechanism for the cycloaddition reaction is
shown in Scheme 2. Typically, such a cycloaddition would
begin with oxidative coupling between an alkyne and the
carbonyl group.[11,22,23] In this case, oxidative coupling would
Scheme 1. Products derived from the Ni-catalyzed cycloaddition of
diynes 1b–1k and azetidinone 2d. Reaction conditions: azetidinone
2 d (1 equiv), diyne 1b–1k (1.2 equiv), [Ni(cod)2] (10 mol%), IPr
(20 mol%), toluene, 8h.
products (3jd and 3kd, Scheme 1), which contain a spirocyclic
backbone, were obtained in good yield.
3-oxacyclobutanone (2e) and diyne 1a could also undergo
the Ni/IPr-catalyzed cycloaddition reaction using the standard
reaction conditions, thus giving dihydrooxocine 3ae in good
yield [Eq. (2)].
Scheme 2. Proposed mechanism of the cycloaddition reaction.
afford a spirocyclic intermediate M1. Subsequent insertion of
the pendant alkyne would give the intermediate M2, which
could then undergo either reductive elimination (to afford
products such as 3nd and 3od) or b-carbon elimination to
To address the question of regioselectivity when using an
unsymmetrical diyne, diyne 1l, which contains a terminal
alkyne and a methyl-substituted alkyne, was subjected to the
optimized reaction conditions; only one regioisomer was
observed [3ld; Eq. (3)]. Another unsymmetrical diyne, 1m,
the termini of which differ electronically rather than sterically,
was also evaluated; again, only one regioisomer was observed
[3md, Eq. (3)].
À
afford metallacycle M3. Finally, C C bond forming reductive
elimination occurs to give the dihydroazocine product and the
catalyst. In the cycloaddition of unsymmetrical diyne 1l, the
regioselectivity is governed by the difference in the size of the
substituents on the alkynes. That is, oxidative coupling
between the alkyne bearing the larger group occurs first to
minimize steric interactions between the group and the
ligand. Indeed, this type of regioselectivity has been found
in various cycloaddition reactions catalyzed by nickel com-
plexes. However, in the cycloaddition of unsymmetrical diyne
1m, the electronic nature of the alkyne, rather than steric
Interestingly, when diynes 1n and 1o, which were
expected to afford six-membered-ring-fused dihydroazocine
products, were evaluated, the expected products arising from
À
Csp2 Csp3 bond cleavage were not obtained. Instead, spirocy-
clic pyran products were formed in good yields [3nd and 3od,
Eq. (4)].[16]
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h) G. Zuo, J. Louie, J. Am. Chem. Soc. 2005, 127, 5798; i) G. Zuo,
J. Louie, Angew. Chem. 2004, 116, 2327; Angew. Chem. Int. Ed.
2004, 43, 2277; for iridium: j) N. Chatani, H. Inoue, T. Morimoto,
T. Muto, S. Murai, J. Org. Chem. 2001, 66, 4433.
factors, dictate the observed regioselectivity. That is, the
oxidative coupling of the alkyne bearing the methyl group
(R1 = Me) is more favored than the coupling of the alkyne
with perturbed electronics (R2 = OEt). This type of electroni-
cally driven regioselectivity has not been exploited exten-
sively in cycloaddition reactions.[24]
In conclusion, we have demonstrated that eight-mem-
bered heterocycles can be easily accessed through Ni/IPr-
catalyzed coupling of 3-azetidinone (or 3-oxetanone) and
diynes. The decomposition of these constrained heterocycles
could be avoided by using specific reaction conditions. This
[4] M. Murakami, H. Amii, Y. Ito, Nature 1994, 370, 540.
[5] For construction of carbocycles through transition-metal-cata-
lyzed activation of cyclobutanones, see: a) M. Murakami, S.
Ashida, Chem. Commun. 2006, 4599; b) T. Matsuda, M. Makino,
M. Murakami, Angew. Chem. 2005, 117, 4684; Angew. Chem. Int.
Ed. 2005, 44, 4608; c) L. Liu, N. Ishida, M. Murakami, Angew.
Chem. Int. Ed. 2012, 51, 2485; d) P. A. Wender, A. G. Correa, Y.
Sato, R. Sun, J. Am. Chem. Soc. 2000, 122, 7815; e) M. M.
Montero-Campillo, J. Rodrꢀguez-Otero, E. M. Cabaleiro-Lago,
Tetrahedron 2008, 64, 6215.
À
method involves an interesting C C bond cleavage step,
which operates smoothly at 08C. Further synthetic and
[6] For Ni-catalyzed coupling of azetidinone and alkynes, see: a) P.
Kumar, J. Louie, Org. Lett. 2012, 14, 2026; b) K. Y. T. Ho, C.
Aꢁssa, Chem. Eur. J. 2012, 18, 3486.
mechanistic analysis of this reaction is currently underway.
[7] For selected biologically important compounds containing
reduced azocine moieties, see: a) J. D. Winkler, A. T. Londre-
gan, M. T. Hamann, Org. Lett. 2006, 8, 2591; b) J. D. Winkler,
A. T. Londregan, J. R. Ragains, M. T. Hamann, Org. Lett. 2006,
8, 3407; c) E. Vedejs, R. J. Galante, P. G. Goekjian, J. Am. Chem.
Soc. 1998, 120, 3613.
Experimental Section
Representative procedure: In a nitrogen-filled glove box, a scintilla-
tion vial equipped with a magnetic stir bar, was charged with
a solution of azetidinone (1 equiv) in toluene (0.05m) and diyne
(1.2 equiv). At room temperature, a solution of the catalyst, which
was prepared by stirring a mixture of [Ni(cod)2] and IPr (1:2 molar
ratio) in toluene for at least 6 h, was added. The vial containing the
reaction mixture was immediately taken out of the glove box and
sealed; the reaction mixture was then stirred at 08C for 8 h. The
solvent was removed under vacuum and the product was purified by
silica-gel flash column chromatography.
[8] For construction of eight-membered carbocycles through tran-
sition metal catalyzed cycloaddition, see: a) P. A. Wender, N. C.
Ihle, J. Am. Chem. Soc. 1986, 108, 4678; b) P. A. Wender, M. J.
Tebbe, Synthesis 1991, 1089; c) P. A. Wender, J. M. Nuss, D. B.
Smith, A. Suꢂrez-Sobrino, J. Vꢃgberg, D. Decosta, J. Bordner, J.
Org. Chem. 1997, 62, 4908; d) P. A. Evans, J. E. Robinson, E. W.
Baum, A. N. Fazal, J. Am. Chem. Soc. 2002, 124, 8782; e) S. R.
Gilbertson, B. DeBoef, J. Am. Chem. Soc. 2002, 124, 8784;
f) J. A. Varela, L. Castedo, C. Saa, Org. Lett. 2003, 5, 2841;
g) P. A. Evans, E. W. Baum, J. Am. Chem. Soc. 2004, 126, 11150;
h) P. A. Evans, E. W. Baum, A. N. Fazal, M. Pink, Chem.
Commun. 2005, 63; i) S. I. Lee, S. Y. Park, Y. K. Chung, Adv.
Synth. Catal. 2006, 348, 2531; j) P. A. Wender, J. P. Christy, J. Am.
Chem. Soc. 2006, 128, 5354; k) B. DeBoef, W. R. Counts, S. R.
Gilbertson, J. Org. Chem. 2007, 72, 799; l) G. Hilt, J. Janikowski,
Angew. Chem. 2008, 120, 5321; Angew. Chem. Int. Ed. 2008, 47,
5243.
Received: May 7, 2012
Published online: && &&, &&&&
À
Keywords: azetidinones · C C activation · cycloaddition ·
.
dihydroazocines · nickel
[1] a) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; b) P.
Kumar, J. Louie, Angew. Chem. 2011, 123, 10956; Angew. Chem.
Int. Ed. 2011, 50, 10768; c) K. Chen, P. S. Baran, Nature 2009,
459, 824; d) C. J. Li, B. M. Trost, Proc. Natl. Acad. Sci. USA 2008,
105, 13197; e) J.-P. Corbet, G. Mignani, Chem. Rev. 2006, 106,
2651.
[9] For a ring-closing-metathesis route to medium-sized hetero-
cycles, see: a) A. Deiters, S. F. Martin, Chem. Rev. 2004, 104,
2199; for a Rh-catalyzed reaction forming dihydroazocines, see:
b) R. T. Yu, R. K. Friedman, T. Rovis, J. Am. Chem. Soc. 2009,
131, 13250.
À
[2] For discussion on the challenges involved in C C bond
[10] A. Michaut, J. Rodriguez, Angew. Chem. 2006, 118, 5870;
Angew. Chem. Int. Ed. 2006, 45, 5740.
activation, see: a) M. Murakami, Y. Ito, Top. Organomet.
Chem. 1999, 3, 97; b) B. Rybtchinski, D. Milstein, Angew.
Chem. 1999, 111, 918; Angew. Chem. Int. Ed. 1999, 38, 870; c) C.-
H. Jun, Chem. Soc. Rev. 2004, 33, 610; d) M. Miura, T. Satoh,
Top. Organomet. Chem. 2005, 14, 1; e) M. Murakami, Chem. Rec.
2010, 10, 326; f) M. Murakami, T. Matsuda, Chem. Commun.
2011, 47, 1100; g) T. Seiser, T. Saget, D. N. Tran, N. Cramer,
Angew. Chem. 2011, 123, 7884; Angew. Chem. Int. Ed. 2011, 50,
7740.
[11] For studies on the synthesis of carbocycles by methods involving
nickel-catalyzed b-carbon elimination, see: a) M. Murakami, S.
Ashida, T. Matsuda, J. Am. Chem. Soc. 2005, 127, 6932; b) M.
Murakami, S. Ashida, T. Matsuda, J. Am. Chem. Soc. 2006, 128,
2166; c) M. Murakami, M. Makino, S. Ashida, T. Matsuda, Bull.
Chem. Soc. Jpn. 2006, 79, 1315; d) S. Ashida, M. Murakami, Bull.
Chem. Soc. Jpn. 2008, 81, 885.
[12] For prior work with cyclobutenones, see: a) L. S. Liebeskind,
S. L. Baysdon, M. S. South, S. Iyer, J. P. Leeds, Tetrahedron 1985,
41, 5839; b) L. S. Liebeskind, R. Chidambaram, D. Mitchell, B.
Foster, Pure Appl. Chem. 1988, 60, 2734; c) M. A. Huffman, L. S.
Liebeskind, J. Am. Chem. Soc. 1991, 113, 2771; d) M. A.
Huffman, L. S. Liebeskind, J. Am. Chem. Soc. 1993, 115, 4895;
e) L. S. Liebeskind, A. Bombrun, J. Org. Chem. 1994, 59, 1149.
[13] a) Y. Dejaegher, N. M. Kuz’menok, A. M. Zvonok, N.
De Kimpe, Chem. Rev. 2002, 102, 29; b) D. De Smaele, Y.
Dejaegher, G. Duvey, N. De Kimpe, Tetrahedron Lett. 2001, 42,
2373.
[3] For transition-metal-catalyzed activation of cyclopropanes lead-
ing to carbocycles, see: for rhodium: a) P. A. Wender, A. J.
Dyckman, C. O. Husfeld, D. Kadereit, J. A. Love, H. Rieck, J.
Am. Chem. Soc. 1999, 121, 10442; b) P. A. Wender, C. M.
Barzilay, A. J. Dyckman, J. Am. Chem. Soc. 2001, 123, 179;
c) P. A. Wender, G. G. Gamber, R. D. Hubbard, L. Zhang, J. Am.
Chem. Soc. 2002, 124, 2876; d) P. A. Wender, L. O. Haustedt, J.
Lim, J. A. Love, T. J. Williams, J.-Y. Yoon, J. Am. Chem. Soc.
2006, 128, 6302; e) Y. Wang, J. Wang, J. Su, F. Huang, L. Jiao, Y.
Liang, D. Yang, S. Zhang, P. A. Wender, Z.-X. Yu, J. Am. Chem.
Soc. 2007, 129, 10060; for ruthenium: f) B. M. Trost, F. D. Toste,
H. Shen, J. Am. Chem. Soc. 2000, 122, 2379; g) B. M. Trost, J.
Waser, A. Meyer, J. Am. Chem. Soc. 2008, 130, 16424; for nickel:
[14] This synthetic technology is the subject of a patent application
submitted by us in Aug. 2011 (P. Kumar, J. Louie, 61-528,739.
4
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[15] P. A. Wender, J. P. Christy, J. Am. Chem. Soc. 2007, 129, 13402.
[16] For Ni-catalyzed cycloaddition of diynes and enynes with
carbonyl compounds, see: a) T. N. Tekevac, J. Louie, Org. Lett.
2005, 7, 4037; b) T. N. Tekavec, J. Louie, J. Org. Chem. 2008, 73,
2641.
Prescher, J. Louie, Angew. Chem. 2011, 123, 10882; Angew.
Chem. Int. Ed. 2011, 50, 10694.
[21] J. A. Burkhard, G. Wuitschik, M. Rogers-Evans, K. Mꢄller,
E. M. Carreira, Angew. Chem. 2010, 122, 9236; Angew. Chem.
Int. Ed. 2010, 49, 9052.
[17] When PCy3 was used as a ligand in a reaction conducted at 608C
and RT, yields of 1a were 47% and 24%, respectively.
[18] Y. Nakao, T. Hiyama, Pure Appl. Chem. 2008, 80, 1097.
[19] The structure of 3dd was unambiguously determined by single
crystal X-ray crystallography (see the Supporting Information).
CCDC 890696 (3dd) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif..
[20] For examples of where a diyne containing an NTs group in the
backbone can be a poorly effective coupling partner in nickel-
catalyzed cycloaddition reactions, see: a) J. Louie, J. E. Gibby,
M. V. Farnworth, T. N. Tekavec, J. Am. Chem. Soc. 2002, 124,
15188; b) T. N. Tekavec, A. M. Arif, J. Louie, Tetrahedron 2004,
60, 7431; c) M. M. McCormick, H. A. Duong, G. Zuo, J. Louie, J.
Am. Chem. Soc. 2005, 127, 5030; d) P. Kumar, D. M. Troast, R.
Cella, J. Louie, J. Am. Chem. Soc. 2011, 133, 7719; e) P. Kumar, S.
[22] a) K. M. Miller, W.-S. Huang, T. F. Jamison, J. Am. Chem. Soc.
2003, 125, 3442; b) J. Montgomery, G. J. Sormunen, Top. Curr.
Chem. 2007, 279, 1; c) H. A. Malik, G. J. Sormunen, J. Mont-
gomery, J. Am. Chem. Soc. 2010, 132, 5966; d) P. R. McCarren, P.
Liu, P. H.-Y. Cheong, T. F. Jamison, K. N. Houk, J. Am. Chem.
Soc. 2009, 131, 6654; e) P. Liu, P. McCarren, P. H.-Y. Cheong,
T. F. Jamison, K. N. Houk, J. Am. Chem. Soc. 2010, 132, 2050.
[23] Based on the recent DFT calculations, the possibility of initial
oxidative coupling of two alkyne units cannot be ruled out
completely. J.-Y. Tao, D.-C. Fang, G. A. Chass, Phys. Chem.
Chem. Phys. 2012, 14, 6937.
[24] a) F. E. McDonald, H. Y. H. Zhu, C. R. Holmquist, J. Am.
Chem. Soc. 1995, 117, 6605; b) J. Castro, H. Sorensen, A. Riera,
C. Morin, A. Moyano, M. A. Pericas, A. E. Greene, J. Am.
Chem. Soc. 1990, 112, 9388; c) T. Hanazawa, K. Sasaki, Y.
Takayama, F. Sato, J. Org. Chem. 2003, 68, 4980; d) Y. Komine,
A. Kamisawa, K. Tanaka, Org. Lett. 2009, 11, 2361.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Cycloaddition Reactions
A cool break: 3-Azetidinone and a variety
of diynes undergo a cycloaddition reac-
tion catalyzed by Ni/IPr to give dihy-
droazocine compounds (see scheme;
IPr=1,3-bis(2,6-diisopropylphenyl)imi-
dazolidene). The reaction involves a chal-
P. Kumar, K. Zhang,
J. Louie*
&&&& — &&&&
An Expeditous Route to Eight-Membered
Heterocycles By Nickel-Catalyzed
Cycloaddition: Low-Temperature Csp2 Csp3
À
lenging Csp2 Csp3 bond cleavage step, yet,
À
surprisingly, proceeds at low tempera-
ture.
Bond Cleavage
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!