UPDATES
[a]
with excellent (Z)-alkene stereocontrol and good to Table 3. Chirality transfer experiments.
high levels of diastereoselectivity. For example, the
three-component reaction of anisaldehyde (1b), 2a,
and 3a afforded the desired product 4baa in 49%
yield. In addition, benzaldehyde derivatives with an
electron-withdrawing group at the para position
afforded (Z)-enynyl homoallylic alcohols 4caa–eaa in
7
6%–80% yields. As will be discussed, the stereo-
[
b]
[c]
entry
R (2)
4aaa
(%)
ee
es
chemistry of 4daa was corroborated by single-crystal
[22]
(%)
(%)
X-ray diffraction. 4-Pyridinecarboxaldehyde 1f was
also amenable to this reaction, giving 4faa in 81%
yield with high (Z)-selectivity and diastereoselectivity.
The reaction was effective for both aromatic and
aliphatic aldehydes. Although the present system
provided 4gaa–iaa with high (Z)-selectivity, lower
diastereoselectivities were observed.
To further evaluate the scope of this process,
various borylated allyl benzoates 2 were investigated.
Substrates with electron-neutral (2b), electron-rich
1
2
3
C H CO (2a)
63
48
60
59
63
64
66
70
71
6
5
2-CF C H CO (2l)
3
6
4
2-MeOC
H
CO (2m)
4
6
[a]
Reaction conditions: 1a (0.75 mmol), 2 (0.5 mmol), 3a
0.85 mmol), Pd(OAc) (0.025 mmol), and P(4-MeOC H )
(
2
6
4
3
(
0.05 mmol) in toluene (3 mL) in 120°C oil bath.
[b]
Enantiomeric excess was determined by HPLC.
[c]
es (enantiospecificity)=(ee% of product)/(ee% of starting
material).
(2c–2e), and electron-deficient (2f and 2g) substitu-
ents on the aromatic ring participated in the three-
component reaction. It is noteworthy that the reaction electronic and/or steric substituent effects of o-CF and
3
tolerates the readily modifiable bromo group. When o-MeO substituent were limited in our system and
2
h was reacted for 2 h, corresponding product 4aha improved the es slightly (entries 2 and 3). The absolute
was obtained in 62% yield and the bromo group stereochemistry of 4aaa was determined to be (1S,2R)
[17]
remained intact. However, longer reaction times based on derivatization to a known material.
resulted in subsequent Stille cross-coupling between Furthermore, when (R)-2a (95% ee) was treated with
three-component product 4aha and 3a, affording Pd(OAc) (5 mol%) and P(4-MeOC H ) (10 mol%) in
2
6
4 3
[23]
4
aha’ selectively in 66% yield.
These results toluene at 120°C for 4 h, (R)-2a was recovered in 34%
demonstrate the synthetic utility of the present method. yield with a significant loss of enantiomeric excess
However, this was not the case for other bromo- (80% ee).
substituted substrates. When ortho-bromo-substituted
To address the racemization process, we envisioned
substrate 2i was subjected to similar reaction con- that a competing reaction involving palladium-cata-
ditions, the reaction competed with double alkynyla- lyzed alkene isomerization of (R)-2a followed by
[27a]
tion, resulting in the production of 4aia and 4aia’ in allylboration of benzaldehyde may also occur
if the
3
9% and 15% yields, respectively. Moreover, a palladium-catalyzed coupling of homoaldol equivalent
prolonged reaction time and the addition of an excess 5 with 3a is feasible (Scheme 3a). This is because
amount of 3a allowed the selective formation of 4aia’, homoaldol equivalent 5 is known to be produced in its
[27b]
albeit in moderate yield. Substrate 2j bearing a 2- racemic form.
To test this hypothesis, we examined
thienyl group as a heteroaryl substituent was also the reaction between rac-2a and 1a in the absence of
examined, and provided 4aja in 50% yield. While this 3a (Scheme 3b). Although 5 was obtained in 48%
process tolerates a wide range of aryl substituents, an
attempt to use phenethyl-substituted substrate 2k
failed.
To gain further insights into the mechanism, we
conducted a chirality transfer experiment using (R)-2a
under the optimized reaction conditions (Table 3).
[5]
Compared to the results from our previous work and
those from a related study on Tsuji-Trost allylic
[24]
alkylation, lower chirality transfer was observed and
aaa was obtained in 63% yield with 66% es
entry 1).
Because it has been reported that ortho-substituent
4
(
on the benzoyloxy group could improve yield and
enantiospecificity in palladium-catalyzed allyl-aryl
[20,25,26]
coupling reactions,
we examined the effect of
Scheme 3. Mechanistic studies.
ortho-substituted benzoates as a leaving. However,
Adv. Synth. Catal. 2021, 363, 1–9
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!