COMMUNICATION
Table 2. Regioselective nickel-catalysed cycloaddition of N-Boc-3-azeti-
dinone 1 with unsymmetrical alkynes 4.
Entry
R1
R2
4
5/6[a]
87:13
89:11
89:11
Yield
[%][b]
1
2
3
4
5
6
7
8
Me
nBu
nBu
cHex
iBu
p-CF3C6H4
Me
Me
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
92
89
99
Scheme 1. Proposed rationale for the observed regioselectivity.
p-MeOC6H4
p-MeCOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
iPr
86:14
84:16
88[c]
91[c]
82
complexes.[13] Moreover, only one phosphine ligand would
be present on the metal during the regioselectivity-deter-
mining event[10] whereas the excess of phosphine required
under our optimised reaction conditions would promote the
final reductive elimination.
55:45[d]
60:40[d]
100:0[e]
88:12
90
tBu
87[f]
88
9
Et
C(Me)=CH2
p-PhC6H4
Ph
10
11
12
C(Me)=CH2
SiMe3
SiMe3
4j
4k
4l
60:40[d]
97:3[g]
80:20[d]
86
91[f]
80[h]
Although the regioselectivity observed with silylated al-
kynes 4k and 4l is in agreement with the results obtained in
other intermolecular nickel-catalyzed reactions of silylated
alkynes with electrophiles,[11b,d,g,14] it cannot be explained by
the same steric considerations. The axial strain values of
methyl, isopropyl, trimethylsilyl, and phenyl groups (1.74,
2.21, 2.5 and 2.8 kcalmolÀ1, respectively)[15] suggest that the
steric differentiation between substituents R1 and R2 is
larger in 4g than in 4k. Nevertheless, the regioselectivity ob-
served with 4k was excellent, whereas it was poor with 4g.
Similarly, steric effects appear inconsequential in the case of
4l, the major product displaying the larger silyl substituent
next to the carbonyl group, in contradiction to the trend ob-
served with 4a–4e. Hence, stereoelectronic effects appear
predominant in determining the regioselectivity of alkynes
4k and 4l. In this context, it is interesting to consider the re-
versed and significantly accentuated polarisation of the sily-
lated alkyne ligands in known complexes C and D as com-
pared with E, which has been established by 13C NMR spec-
troscopy.[16] Whereas steric effects would predominate in the
mechanistic pathway involving less polarized alkynes, the re-
gioselectivity of the reactions of 4k and 4l would be dictat-
ed by the polarity of the alkynes when coordinated to nickel
in a nucleophilic attack onto 1.[17,18]
It was also possible to observe reaction with N-Ts-3-azeti-
dinone 7 (Ts=para-tolylsulfonyl), although a greater excess
of alkynes, slightly higher reaction temperature, and
a higher catalyst loading (in the case of 4a) were required
to reach full conversion (Scheme 2). Hence, pyridinone 8
was isolated in 74% yield. The higher reaction temperature
might explain the slightly lower selectivity obtained for re-
gioisomers 9 and 10 in the cycloaddition of 4a with 7 as
compared with the result obtained with N-Boc-3-azetidinone
1 (Table 2, entry 1).
nOct
[a] Unless otherwise noted, this ratio was determined from the isolated
yields of separated products 5 and 6. [b] Combined isolated yields of 5
and 6. [c] Alkyne and azetidinone were premixed. [d] Ratio determined
1
by H NMR spectroscopy on an inseparable mixture of 5 and 6. [e] Com-
pound 6h could not be detected by 1H NMR spectroscopy of the crude
material. [f] Isolated yield of 5. [g] Ratio determined by 1H NMR spec-
troscopy of the crude. [h] 1.5 equiv of alkyne was used.
not vary greatly when one compares those two substrates.
This result is in good accordance with reports by Jamison
and co-workers, which propose that the alkene moiety of
1,3-enynes directs their intermolecular nickel-catalyzed re-
ductive coupling with aldehydes and ketones by coordina-
tion of the alkene to the metal.[8d,9] This is also in agreement
with recent theoretical investigations.[10] Evaluating the di-
recting effects of an alkene and a benzene ring with 1,3-
enyne 4j, we observed a decrease of the regioselectivity nor-
mally induced by aromatic substituents (Table 2, entry 10 vs.
1–5), confirming the influence of the alkenyl substituent. Fi-
nally, reactions of trimethylsilyl-substituted alkynes 4k and
4l gave predominantly regioisomers 5k and 5l, respectively,
which display the silyl group in the a position to the carbon-
yl.
In line with experimental results,[8d,9,11] recent theoretical
investigations suggest that the regioselectivity of nickel-cata-
lyzed reductive coupling of simple alkynes and aldehydes is
dictated by steric effects.[10] A similar model with N-Boc-3-
azetidinone 1 would favour the formation of metallacycle A
by minimisation of steric interactions (Scheme 1) and would
be consistent with the results presented in entries 1–8 of
À
Table 2. Hence, intermediate A would undergo C C bond
activation toward B and reductive elimination would afford
the major product 5. The diminished steric differentiation
between substituents R1 and R2 in alkynes 4 f and 4g would
explain the poor regioselectivity observed with these sub-
strates. The intermediates invoked in this postulated mecha-
nistic sequence are consistent with the isolation of h2,h2-1,5-
enone-nickel complexes[12] and dimeric nickeladihydrofuran
We then examined the regioselectivity of the ring-opening
of a-substituted azetidinone 11, which gave exclusively 12 in
91% yield (Scheme 3), indicating that only the less substi-
tuted bond of 11 is cleaved in the putative rearrangement of
F to G (Scheme 4). Presumably, the minimisation of steric
Chem. Eur. J. 2012, 18, 3486 – 3489
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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