Organic Letters
Letter
elegant study from the Yin group, ketones were utilized to
generate (Z)-δ-vinyl tertiary homoallylic alcohols D (Scheme
1b).5 By using the combination of the mesitylcopper catalyst
and a chiral bidentate phosphine ligand, (R)-DTBM-
SEGPHOS, tertiary homoallylic alcohols D were obtained
with high stereoselectivities and enantioselectivities from 1,4-
pentadiene C.
Table 1. Evaluation of Reaction Conditions for Cu-
Catalyzed Allylation of Benzaldehyde with α-Vinyl
a b c
, ,
Allylboronate 1
Along the line of our research interests in reaction
development using organoboron compounds,6 we were
intrigued whether α-vinyl allylboronate A can be utilized to
synthesize (E)-δ-vinyl-homoallylic alcohols. Inspired by prior
work on Cu-catalyzed allylation from the Shibasaki group,7,8
we envisioned that a base-promoted transmetalation of α-vinyl
allylboronate 1 with a copper catalyst should generate an
allylcopper species. Subsequent addition of the Cu inter-
mediate to aldehydes or ketones could provide δ-vinyl-
homoallylic alcohol products.9 However, several challenges
are present in this approach. First, the transmetalation step
could form a mixture of allylcopper intermediates such as I, II,
and III (Scheme 1). In theory, these Cu intermediates could all
react with carbonyl compounds to complicate the allylation
process. Moreover, a vast majority of prior work on Cu-
catalyzed carbonyl allylation utilized allylcopper species that do
not have any α-substituent.8,9 It is not apparent whether it is
feasible to achieve E-selective allylation with α-substituted
allylic copper using the proposed approach. With these
considerations in mind, we developed and report herein
stereoselective syntheses of (E)-δ-vinyl-homoallylic alcohols.
As shown in Scheme 1, in the presence of a copper catalyst and
an appropriate phosphine ligand, addition of α-vinyl
allylboronate 1 to aldehydes produces (E)-δ-vinyl-homoallylic
alcohols 2 with excellent E-selectivities. Ketones can also be
utilized under similar reaction conditions to deliver (E)-δ-vinyl
tertiary homoallylic alcohols 5 with high E-selectivities.
We began our studies by evaluating the reaction conditions
for E-selective allylation of benzaldehyde with α-vinyl
allylboronate 1. A shown in Table 1, the best results were
achieved with 10 mol % of CuCl as the catalyst, 12 mol % of
Xantphos as the ligand, and NaOtBu (1.5 equiv) as the base.
Under these conditions, the reaction of benzaldehyde with α-
vinyl allylboronate 1 (1.5 equiv) at ambient temperature in
THF provided (E)-δ-vinyl-homoallylic alcohol 2a in 86% yield
with excellent stereoselectivity (>20:1). Variation of the
catalyst, ligand, or base gave inferior results. For instance,
although the reaction with KOtBu as the base gave product 2a
exclusively, the yield was significantly lower than the one with
NaOtBu as the base (entry 2). When LiOtBu was employed as
the base, a 1:2 mixture of 2a and 4a was obtained in a
combined 81% yield (entry 3). The reaction with other
bidentate phosphine ligands such as BINAP gave a 2:1 mixture
of E- and Z-isomers, 2a and 3a, in 67% yield (entry 4). When
Xantphos was replaced by a monodentate NHC ligand IMes·
HCl, the reaction under otherwise identical conditions
produced a 2:1 mixture of 2a and 4a in a combined 71%
yield (entry 5). A similar selectivity (1:1) was observed when
SIPr·BF4 was used as the ligand (entry 6). The reaction with
10 mol % of Cu(OMe)2 as the catalyst in the absence of any
base gave a 1:2 mixture of 2a and 3a in 81% yield (entry 7).
The reaction of benzaldehyde with allylboronate 1 can proceed
in the absence of any catalyst, ligand, and base, affording a 1:2
mixture of E- and Z-isomers, 2a and 3a, in 92% yield (entry 8).
Resubjecting Z-isomer 3a or branched product 4a to the
catalytic reaction conditions did not produce any detectable
c
entry
variation of conditions
selectivity
yield (%)
1
2
3
4
5
6
7
8
none
2a only
2a only
86
53
81
67
71
78
81
92
KOt-Bu as the base
LiOt-Bu as the base
rac-BINAP as the ligand
IMes·Cl as the ligand
SIPr·BF4 as the ligand
Cu(OMe)2, no NaOt-Bu
no catalyst, ligand, base
2a:4a = 1:2
2a:3a = 2:1
2a:4a = 2:1
2a:4a = 1:1
2a:3a = 1:2
2a:3a = 1:2
a
Reaction conditions: boronate 1 (0.15 mmol, 1.5 equiv), CuCl (10
mol %), ligand (12 mol %), base (0.15 mmol, 1.5 equiv), aldehyde
b
(0.10 mmol, 1.0 equiv), THF (0.5 mL), rt. The selectivities were
determined by 1H NMR analysis of the crude reaction products.
c
Yields of isolated products are listed (as a mixture of isomers for
entries 3−8).
amount of E-isomer 2a, indicating that the C−C bond-forming
event is not reversible, and 3a or 4a cannot isomerize to 2a.
The scope of aldehyde that undergoes the Cu-catalyzed
allylation with boronate 1 was explored next. As summarized in
Scheme 2, a variety of aldehydes participated in the reaction to
give the corresponding (E)-δ-vinyl-homoallylic alcohols 2 with
excellent E-selectivities. Reactions with aromatic aldehydes
bearing a substituent at the para-position regardless of the
electronic properties gave products 2b−f in 78−86% yields.
Aromatic aldehydes with other substitution patterns reacted
under the developed conditions to generate products 2g−j in
77−98% yields. While the reactions with pyridyl aldehydes
suffered low conversions, several other heteroaromatic
aldehydes are suitable substrates for the reaction, affording
(E)-δ-vinyl-homoallylic alcohols 2k,l in 83−87% yields.
Moreover, the reactions with aliphatic aldehydes worked
smoothly to deliver alcohols 2m,n in 71−78% yields. In all
cases, >20:1 E-selectivities were observed. The olefin geometry
of homoallylic alcohols 2 was assigned as E on the basis of 1H
NMR analysis of the coupling constant of the olefinic protons.
In general, the reactions are complete within 12 h. Background
reactions with boronate 1 did not occur under these
conditions, as the formation of any Z-isomer 3 was not
detected.
Ketones are known to be suitable substrates in reactions
with allylic organometallics.8,9 To evaluate whether (E)-δ-vinyl
tertiary homoallylic alcohols 5 can be selectively synthesized
under the developed conditions, reactions of boronate 1 with
an array of ketones were examined. However, the reaction rates
are much slower compared to the ones from the reactions with
aldehydes. After some experimentation, CuOAc was identified
as the catalyst with optimal reaction rates, albeit with slightly
lower E-selectivities. As summarized in Scheme 3, CuOAc-
catalyzed reaction of acetophenone with boronate 1 gave
tertiary homoallylic alcohol 5a in 85% yield with 14:1 E-
selectivity. The reaction with propiophenone formed 5b in
79% yield with 10:1 E-selectivity. Aromatic ketones with a
6036
Org. Lett. 2021, 23, 6035−6040
Liu, Jiaming
