Communication
tive elimination of an iron(III) species.[19] A 2,2’-bipyridine-type
ligand[12a] was ineffective. Without the oxidant (DCP), only one
catalytic turnover occurred, suggesting that DCP brings the
catalytic cycle back to the initial step by oxidizing the iron(I) in-
termediate to regenerate an iron(III) reactive species. 1,2-Di-
chloroethane and 1,2-dibromopropane behaved similarly,
albeit less efficiently (47% and 48% yield, respectively). Termi-
nal alkynes did not give the desired annulation product.
This reaction has a considerable synthetic scope, as exempli-
fied by the data in Table 1, Equations (1) and (2), and Figure 1.
Both cyclic and acyclic alkenes reacted well, and isomerization
of the starting acyclic substrates was not observed. The reac-
tion proceeded well with b-oxo- (Table 1, entry 1), b-alkyl
(Table 1, entry 3), and b-unsubstituted alkeneamides (Table 1,
entry 2), but a-unsubstituted substrates such as acrylamide
gave low yields (ca. 20%) with poor mass balance, possibly be-
cause of decomposition of the substrate. Internal alkynes pos-
sessing alkyl, alkenyl, aryl, heteroaryl, allyl, alkynyl, and silyl
groups could be successfully employed in the reaction. For an
unsymmetrical acetylene substituted by an aryl and an alkyl
group (Table 1, entry 4), 5-alkyl-6-aryl pyridone was obtained as
Figure 1. Dependence of regioselectivity on the b-substituent (R2).
The regioselectivity shown in Figure 1 suggests that the CÀC
bond-formation process is highly sensitive to the b-substituent
of the acrylamide, possibly owing to steric hindrance, as
shown by the transition in the product distribution from 3, 8,
9, to 10. For 3, where there is no substituent at the b-position,
the regioisomer A was favored over B, whereas, for b-methylat-
ed 8, the A/B ratio eroded to 35:65. Interestingly, a slight
change in the b-methyl group in 8 to an ethyl group (9) favors
B over A (4:96). Similarly, cyclohexenecarboxamide 10 was ob-
tained in a 2:98 (A/B) ratio. Assuming that the activation of the
CÀH bond by an iron catalytic intermediate is the first step of
the reaction, we can consider that the regioselectivity reflects
the steric effects in intermediate C or C’, and that the small
atomic radius enhances the selectivity.
1
the major isomer in 96:4 ratio, as confirmed by H NMR spec-
troscopy and single-crystal X-ray crystallographic analysis. As
also shown in Equation (1), trimethylsilyl alkynes having alkyl,
aryl (Table 1, entries 5–8), alkenyl (Table 1, entry 9), thienyl
(Table 1, entry 10), allyl (Table 1, entry 11), and alkynyl (Table 1,
entries 12 and 13) groups reacted with methacrylamide 1 in
high yield and good regioselectivity (Table 1, entries 5–13).
Chloride (Table 1, entry 6) and bromide (Table 1, entry 8)
groups were well tolerated. An enyne compound (Table 1,
entry 9) reacted in high yield and without isomerization on the
double bond. A 1,3-diyne (Table 1, entry 12) reacted cleanly to
give 6-alkynylpyridone quantitatively—a rare example of func-
tionalization of a CÀH bond with a 1,3-diyne.[20] 1,4-Bis(alkynyl)-
benzene reacted selectively at only one alkyne site, thus leav-
ing one alkyne group intact (Table 1, entry 13).
The study on the key parameters of this reaction (Equa-
tion (1)) is summarized below and described in the Supporting
Information. As previously observed,[12b,c,13] a bidentate direct-
ing group is essential, probably because of its ability to stabi-
lize the iron intermediate. Substrates such as N-methylbenza-
mide were unreactive. The nature of the organometallic base
is also important: a Grignard reagent or a monoorganozinc
halide instead of the diorganozinc afforded the desired prod-
uct 3 in low yield (33% and 40%, respectively). Out of the
4.5 equivalents of trimethylsilylmethylmagnesium chloride
used (98% yield, [Eq. (1)]), 1 equivalent deprotonates the
amide proton, and the remaining 3.5 equivalents contributes
to formation of a diorganozinc or a zincate intermediate by re-
action with zinc halide (1.5 equiv). A small amount of starting
material (2-methacrylamide) was recovered when 4.0 equiva-
lents of Grignard reagent was used (3 in 91% yield). This
might suggest participation of an ferrate species in the catalyt-
ic cycle of this reaction.[18] A diphosphine bearing a conjugated
backbone such as cis-1,2-bis(diphenylphosphino)ethylene
(dppen) is necessary to achieve high yields, the saturated ana-
logue, 1,2-bis(diphenyphosphino)ethane (dppe), gave 3 in only
43% yield. As previously suggested,[12b,c,13] dppen might stabi-
lize by single-electron transfer an intrinsically unstable iron(I)
intermediate formed after CÀC bond formation through reduc-
The reaction was found to be useful also for isoquinolone
synthesis (Table 2). Thus, the reaction of N-quinolin-8-yl-3-toly-
lamide (Table 2, entry 1) or N-picolinylbenzamide (Table 2,
entry 2) with 4-octyne under identical reaction conditions gave
the corresponding isoquinolones in high yield. The reaction of
the N-picolinylbenzamide with an unsymmetrical alkyne such
as 1-phenyl-1-propyne proceeded with high regioselectivity
[Eq. (2)], while the same reaction with a quinolylamide sub-
strate was very slow (Table 2, entries 3 and 4). The picolinyl
group in the product can be removed using the procedure re-
ported by Chatani and co-workers.[4e]
The reaction of benzamide 11 with 4-octyne gave either an
alkenylated product 12,[21] or the annulated product 13, de-
pending on the organometallic base used (Figure 2). When
a monoorganozinc halide was used as the base, the alkenylat-
ed product 12 was obtained as the major product regardless
of the presence or absence of the oxidant DCP. However, when
a diorganozinc was used in the presence of DCP, the cyclized
product 13 was formed exclusively. The results suggest
a common intermediate D for both paths and also that the di-
organozinc is a strong enough silylmethyl donor to iron and
Chem. Asian J. 2016, 11, 380 – 384
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Matsubara, Tatsuaki
