.
Angewandte
Communications
Table 2: Scope of the etherification of N-hydroxyphthalimide with alkenyl boronic acids.
optimal catalyst when compared to
other CuI and CuII salts (entries 5–9)
and pyridine was shown to be the
optimal base when compared to
other amines and inorganic bases
(entries 10–13). Neither the copper-
mediated nor the copper-catalyzed
coupling reaction showed any con-
version to the desired product when
run in the absence of air, and both
transformations required the use of
a halogenated solvent. The cross-
coupling process was fairly insensi-
tive to the choice of desiccant; 4 ꢀ
molecular sieves and MgSO4 gave
the desired product in only slightly
attenuated yields.[14] The optimiza-
tion study concluded that treatment
of a 1:2 mixture of 1/2a in 1,2-
dichloroethane (DCE) with Cu-
(OAc)2 (1 equiv or 20 mol%), pyri-
Entry
1
Product
Yield [%]
Entry
12
Product
Yield [%]
of 3[a]
of 3[a]
98[b] (76)
82 (73)
2
3
4
81 (70)
87 (74)
88 (78)
13
14
15
83 (76)
73 (68)
91 (89)
5
6
7
81 (77)
47
16
17
18
86 (82)
84 (78)
41
dine
(3 equiv),
and
Na2SO4
(4 equiv) in air provided optimal
conversion of 2a to 3a.
With the optimal conditions for
the cross-coupling of 1 and 2a in
hand, the scope of the transforma-
tion was evaluated with a variety of
alkenyl boronic acids to determine
the tolerance for boronic acid sub-
stitution patterns. As shown in
Table 2, both copper-mediated and
copper-catalyzed conditions con-
verted 1- and 2-trans-substituted
vinyl boronic acids, Z-disubstituted
alkenyl boronic acids, and cyclic
alkenyl boronic acids to the desired
N-enoxyphthalimides 3 with reten-
tion of alkene geometry.[15] Both
alkyl- and aryl substituents were
tolerated for the boronic acid cou-
pling partner, as were common aryl
86 (77)
8
76 (67)
63 (66)
67 (55)
70 (71)
19
20
21
22
86 (80)
64
9
10
11
83
76 (52)
[a] Yield of isolated product using 1 equiv Cu(OAc)2 and (yield of isolated product using 20 mol%
Cu(OAc)2). [b] When run on a 1 mmol scale, the yield of isolated product using 1 equiv of Cu(OAc)2 was
74%. Cy=cyclohexyl, DCE=1,2-dichloroethane, PhthN=phthalimide, OAc=acetate, pyr=pyridine.
electron-withdrawing
functional
groups such as nitro, fluoro, and
trifluoromethyl, as well as common
protecting groups such as ketals. Trisubstituted alkenyl
boronic acids and alkenyl boronic acids with ortho-substituted
aryl groups currently represent a limitation of this method.
Unfavorable steric interactions also hinder the etherification
of 6-methyl cyclohexenyl boronic acid 2r; however, no similar
inhibition was observed for the fused system 2v. The broad
scope of the copper-mediated cross-coupling of N-hydroxy-
phthalimide 1 and alkenyl boronic acids 2 ultimately provided
an array of N-enoxyphthalimides 3 to screen for the [3,3]
rearrangement.
quantitative yields, as determined by comparison to an
internal standard by H NMR spectroscopy; however, imi-
1
dates 4 were unstable when subjected to silica gel chroma-
tography.[16] Isolation and purification of a-hydroxy ketones 5
was achieved in high yield after the hydrolysis of crude
samples of 4 (Table 3). An ion-exchange resin provided
optimal yields for the cleavage of phthalimide from 4, but
silica gel was similarly effective with longer reaction times. a-
Hydroxyketones 5 that were too volatile or hydrophilic to be
separated from phthalimide by extraction were protected in
solution and isolated as the corresponding a-benzoyloxy
ketones 6 (Table 3). The N-enoxyphthalimides 3b–3d, under-
went rearrangements to form a-oxygenated aldehydes 4b–4d,
which were isolated without further purification as the
Solutions of N-enoxyphthalimides 3 in C6D6 or toluene
were heated at 80–908C for 10–16 h to promote a [3,3]
rearrangement and afford dioxygenated alkenyl boronic acids
as imidates 4. These rearrangements occurred in almost
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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