Angewandte
Communications
Chemie
ing precursors to the polyhydroxytetralone natural products.
Here, we describe the development of a cyclobutanone a-
arylation reaction and realization of the ring-expansion
process shown in Scheme 2. Additionally, we demonstrate
this high yielding sequence in the first synthetic approach to
a member of the coniothyrinone family of natural products.
As depicted in Scheme 3, we began by examining the
reaction of cyclobutanone 17 with 4-bromotoluene using
Considering the key role base plays in determining the
fate of cyclobutanone 17, the a-arylation reaction was
t
t
repeated using LiO Bu and (D BPF)PdCl , and we were
2
delighted to find that the desired a-arylcyclobutanone 19 was
produced in good yield (55%), along with around 15% of the
diarylated cyclobutanone 22 (Table 1, entry 1). The effect of
Table 1: Pd-catalyzed a-arylation of cyclobutanone 17.
[
a]
[b]
Entry
Catalyst
Solvent
19/22 (yield)
t
1
2
3
4
5
6
7
8
(D BPF)PdCl
PhCH3
PhCH3
PhCH3
DME
1,4-dioxane
THF
6:1 (70%)
7.5:1 (n.d.)
4:1 (42%)
2
2
2
2
2
2
t
[c]
[e]
[d]
(D BPF)PdCl
t
(D BPF)PdCl
t
(D BPF)PdCl
2:1 (n.d.)
t
(D BPF)PdCl
3.5:1 (n.d.)
7.5:1 (59%)
17.5:1 (76%)
>19:1 (71%)
t
(D BPF)PdCl
PdCl /XPhos (1:1)
PdCl /XPhos (1:2)
THF
THF
2
2
Scheme 3. Pd-catalyzed a-arylation of cyclobutanone 20 and competing
aldol and fragmentation reactions promoted by various bases.
[a] 5 mol% catalyst used unless otherwise specified; [b] combined yield
of isolated product; [c] 1 mol% catalyst; [d] accompanied by ca. 35% of
the carboxylic acid 20; [e] 10 mol% catalyst.
standard conditions developed for the a-arylation of acyclic
[
11b]
ketones, cyclohexanone, and malonate,
which typically
II
0
comprise a Pd or Pd catalyst with a bulky, electron-rich
mono- or bidentate phosphine ligand, and excess base.
Unfortunately, after screening various combinations of palla-
catalyst loading was examined (entries 2 and 3), and although
[
10c,11b]
t
the use of 1 mol% of (D BPF)PdCl2 provided a slight
improvement in the ratio of monoarylation to diarylation
(entry 2), the necessarily increased reaction times coincided
with large amounts of cyclobutanone fragmentation and
decreased overall yield. A small screen of solvents (entries 4–
6) revealed THF to be optimal for this transformation. We
[11b]
[10d]
[11a]
dium catalysts and PCy3,
XPhos,
or (DPPF)PdCl2,
with K PO , LDA, or LiHMDS in THF, we did not observe
3
4
1
any of the a-arylcyclobutanone 19 by H NMR spectroscopic
[
20]
analysis of crude reaction mixtures. Colacot has reported
t
[10d]
that (D BPF)PdCl is a very active and air stable catalyst for
next re-examined the conditions reported by Buchwald,
2
[
16]
t
sterically challenging Suzuki coupling reactions, and that
this catalyst promotes the a-arylation of ketones with aryl
chlorides and bromides when used in combination with
NaO Bu.
< 5%) of a-arylcyclobutanone 19 could be isolated along
with the carboxylic acid 20 derived from Haller–Bauer
fragmentation, which was the major reaction product. To
gain insight into the effect of base on the a-arylation of 17 and
deleterious competing processes (e.g., aldol reaction or
using LiO Bu as the base (entry 7), and were delighted to find
that the a-arylcyclobutanone 19 was produced in excellent
yield (72%) with minimal formation of the diarylated product
t
[13a]
Using these conditions in toluene, small amounts
22 when using varying stoichiometries of PdCl /XPhos
2
(
(entry 8). The nature of the aryl halide was also briefly
explored and it was found that reactions involving the
corresponding 4-chlorotoluene did not provide any of the a-
[
21]
[20]
arylcyclobutanone 19. Use of aryl iodides (e.g., 4-iodoto-
luene) resulted in formation of the desired a-arylcyclobuta-
nones (e.g., 19) with favourable ratios of mono to diarylation
(ca. 20:1), albeit in much lower yield and accompanied by
fragmentation), we explored the reactions of cyclobutanone
t
1
7 with Li-, Na- and KO Bu in THF. As summarized in
t
t
[20]
Scheme 3, both NaO Bu and KO Bu promoted rapid frag-
a large number of unidentified byproducts.
mentation, providing the carboxylic acid 20 after workup.
Conversely, the reaction of cyclobutanone 17 with LiO Bu led
Having identified two sets of conditions for the a-
arylation of cyclobutanone 17 (Table 1, entries 6 and 7), we
evaluated the scope of this reaction using [3.2.0]-, [4.2.0]-, and
t
to rapid formation of diastereomeric aldol products 21.
Notably, after an extended reaction time (90 min), the
major product of this latter reaction was again the carboxylic
acid 20, thus suggesting that the formation of lithium aldolates
from 17 is a reversible process. This observation proved
critical, since the reversible formation of Li aldolates could
serve to protect the cyclobutanone from fragmentation, while
slowly releasing the Li enolate required for a-arylation.
[6.2.0]-bicycloalkanones and several aryl bromides. As high-
t
lighted in Figure 1, when using LiO Bu and either PdCl /
2
t
XPhos (conditions A) or (D BPF)PdCl2 (conditions B), a-
arylcyclobutanones 24–41 were prepared in good to excellent
yield. Notably, the Pd-catalyzed a-arylation is similarly
effective with cyclobutanones annulated to 5-, 6-, or 8-
membered rings. It was also found that aryl bromides bearing
electron-donating or electron-withdrawing (e.g., methyl,
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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