Communication
not proceed from the copper enolate obtained upon conju-
gate reduction, but via the enolborate or enolsilane intermedi-
ates obtained upon metathesis.
Table 1. Screening of reaction conditions.
Although PinBH facilitated a rapid reductive rearrangement
in a good overall yield, the d.r. was low (Table 1, entries 1 and
2).[12] Phenylsilanes also promoted the reaction with low diaste-
reoselectivities (entries 3 and 4). On the other hand, the use of
(EtO)2MeSiH (DEMS) facilitated a more diastereoselective reduc-
tive rearrangement for anti-3a, but the yield was disappoint-
ingly low (entry 6). Surmising that the poor yield resulted from
a lower turnover rate in the metathesis with (EtO)2MeSiH,
which would allow the unsequestered copper enolate inter-
mediate to engage in side reactions, the reductant concentra-
tion was increased and maximized by adding (E)-1a slowly to
the reaction mixture. Using this inverse addition protocol, the
yield was dramatically improved (entry 6 vs. 7). Under these
conditions, the copper catalyst loading could be decreased to
3 mol% without any detrimental effects. A screening of ligands
showed that sterically unhindered phosphites, such as P(OEt)3
and P(OMe)3, were the optimal ligands, providing the highest
yields and diastereoselectivity for anti-3a (entries 9 and 10),
while bulkier phosphites (e.g. P(OPh)3 and P(OiPr)3) failed to fa-
cilitate the regeneration of copper hydride and arrested the
catalytic cycle (entries 11 and 12). Toluene was found to be the
best solvent. THF and benzene could also be used, but anti-3a
was obtained with a slight decrease in d.r. (10:1, see the Sup-
porting Information). Small amounts of moisture are tolerated
in the reaction but results in lower yields of rearrangement
product (entry 10 vs. 13).[13] Decreasing the reaction tempera-
ture to 08C led to lower yields with only a marginal increase in
d.r. (entry 14).
Entry
Conc.
Ligand[b]
Reductant
Yield [%]
(anti/syn)
1[a]
1.0 M
0.5 M
1.0 M
1.0 M
1.0 M
1.0 M
1.6 M
1.6 M
1.6 M
1.6 M
1.6 M
1.6 M
1.6 M
1.6 M
PPh3
–
PPh3
PPh3
PPh3
PPh3
PPh3
Ph2PMe
P(OMe)3
P(OEt)3
P(OPh)3
P(OiPr)3
P(OEt)3
P(OEt)3
PinBH
PinBH
PhSiH3
Ph2SiH2
76 (1.6:1)
85 (1:1.3)
66 (1.2:1)
51 (1:1.5)
33 (5:1)
18 (6:1)
92 (8:1)
90 (8:1)
90 (11:1)
92 (11:1)
trace
2[b]
3[a]
4[a]
5[a]
(EtO)3SiH
6[a]
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
7[a]
8[a]
9[c]
10[c]
11[c]
12[c]
13[d]
14[e]
trace
78 (10:1)
86 (12:1)
[a] Cu(OAc)2.H2O (5 mol%), ligand (10 mol%). [b] [(Ph3P)CuH]6 (5 mol%)
[c] Cu(OAc)2 (3.3 mol%), ligand (6.6 mol%), slow addition of substrate.
[d] Cu(OAc)2.H2O (3.3 mol%), ligand (6.6 mol%), slow addition of sub-
strate. [e] Cu(OAc)2 (3.3 mol%), ligand (6.6 mol%), slow addition of sub-
strate, at 08C
particularly prone to intermolecular reactions (Table 3, entry 3),
or when sensitive functional groups are present (e.g. OAc,
Table 2, entry 4).
Mechanistically (Scheme 3), the reductive Claisen rearrange-
ment did not proceed from the copper enolate 4, but from the
corresponding enolsilane or enolborate. This was inferred from
the experiment in Scheme 1. This precluded the possibility to
use chiral copper complexes to induce an enantioselective
Claisen rearrangement. Other metal enolates are well-prece-
dented to undergo Claisen rearrangements.[2b] The fact that no
rearrangement followed the copper-catalyzed conjugate reduc-
tion could be experimental evidence supporting suggestions
that the copper enolate 4 is predominantly a C-bound eno-
late.[15]
After having surveyed the reaction conditions, the scope of
the copper-catalyzed reductive Claisen rearrangement was in-
vestigated. The reaction proceeded smoothly for all allylic acry-
late substrates (Table 2). The reductive rearrangement reactions
of the corresponding crotonate and cinnamate substrates
were less efficient (Table 3).
Substitution at all positions (C1, C4, C5, and C6) was tolerat-
ed. A higher diastereoselectivity was observed in the reactions
of substrates with bulky substituents at C4 (Table 2, entry 1 vs.
9, 7 vs. 8). Those substrates with a bulky R1 reacted with even
higher diastereoselectivity (Table 2, entry 9 vs. 10; Table 3,
entry 1 vs. 2). Notably, anti-3d could be obtained from the re-
ductive Claisen rearrangement of 1d (Table 2, entry 4), a prod-
uct that would be challenging to obtain chemoselectively by
a typical Ireland–Claisen rearrangement approach. E- and Z
substrates (C5–C6 geometry) provided complementary diaste-
reoselectivities (Table 2, entry 1 vs. 5, 2 vs. 6), with Z substrates
undergoing the rearrangement at a much slower rate (3 days
vs. 2 h).
The diastereoselectivity observed is consistent with copper
hydride reduction forming selectively (E)-silyl ketene acetals
((E)-5) that undergo the Claisen rearrangement via a chair tran-
sition state (E)-6, resulting in anti-3 (Scheme 3). Indeed, the re-
duction of acrylate 7, which cannot proceed to rearrangement,
yielded predominantly (E)-8 as observed by NMR (Scheme 4).
The stereospecificity of the rearrangement with respect to
the C5–C6 double-bond geometry[1b] is consistent with the
chair transition-state model proposed by Ireland.[1b] It also ex-
plains the less efficient reductive rearrangements of 1l–n, be-
cause the b-substituents would occupy axial positions in the
chair transition state (E)-6 (Scheme 3).
Starting from optically enriched acrylate 1o, perfect chirality
transfer[16] from C4 to C6 yielded 3o (Scheme 5). The partial
loss in chirality in the reductive rearrangement of 1p can be
explained by the fact that silyl ketene acetals (E)-5 and (Z)-5 re-
arrange to give opposite enantiomers, respectively (Scheme 3).
The reaction can be conducted at lower substrate concen-
trations in good yields, provided that the other reagents are
scaled up correspondingly, that is, by maintaining a high
copper hydride concentration for fast reduction of substrates
and a high silane concentration for fast trapping of copper
enolates. In fact, this is necessary for the reductive rearrange-
ment of substrates that are reduced slowly and are therefore
Chem. Eur. J. 2016, 22, 3709 – 3712
3710
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