M.K. Das, A. Yadav, S. Majumder et al.
Tetrahedron 82 (2021) 131928
Scheme 1. Synthesis of 1,6-diene 1 via deacylative allylation.
Scheme 3. The rationale of deacylative allylations (DaA) of enolcarbonate 2.
(ꢀ)-crinane (4a) and (þ)-crinane (ent-4a) (Scheme 3) utilizing DaA
methodology.
3. Results and discussions
The deacylative allylations (DaA) using unfunctionalized allyl
alcohol is an attractive strategy for allylation of
a-position of a
carbonyl group. For optimization studies we selected enolcarbonate
2a and allylalcohol as the pronucleophile and proelectrophile,
respectively. A number of different bases were screened in com-
bination of with catalytic Pd(0). Following exhaustive optimization,
it was found that, 2.5 mol% Pd(PPh3)4 in combination with NaH (2.0
equiv) in THF furnished product 7a in 92% yield in 5 h. Therefore,
this condition was chosen for the studies of substrate scope.
Our optimized condition could be extended to various enolcar-
bonates 2 with allylalcohol as pro-electrophiles and the results are
summarized in Scheme 4. Applying the DaA strategy, we could
synthesize a wide range of 2-aryl cyclohexanones 7a-g with a C2-
quaternary center in good to excellent yields (Scheme 4). Impor-
tantly, aromatic ring containing both electron-donating (see, 7a-f)
and electron-withdrawing (see, 7g) functional groups were well
tolerated for DaA reaction with allyl alcohol (Scheme 4). Further,
methallyl alcohol as pro-electrophile afforded products 2-aryl 20-
methallyl cyclohexanones 7h-k in 85e87% yields in 4e6 h (Scheme
4). Gratifyingly, phenallylalcohol could also be employed as pro-
electrophile to access products 7l-m in 95e97% yields under the
Fig. 1. Representative Amaryllidaceae alkaloids.
formaldehyde equivalent (Scheme 2). The latter could be accessed
via a sequential reductive amination of intermediate g-ketoalde-
hyde, which in turn could be obtained from 2-aryl-20-allyl cyclo-
hexanones of type 7f.
2. Retrosynthetic analysis
2-Nitrocyclohexanone derivatives having an electron with-
drawing group could undergo a retro-Claisen type activation in
the presence of in-situ generated allyl alkoxide, thereby breaks
we would require the synthesis of 2-aryl-20-allyl cyclohexanone for
the synthesis of Amaryllidaceae alkaloids shown in Fig. 1.
The mechanistic rationale of deacylative allylations (DaA) of
enolcarbonate 2 is shown in Scheme 3. It is envisioned that an
allylic alkoxide may induce a deacylative process of aryl substituted
enolcarbonate 2 to form carbanion II (Scheme 3), which would then
Further,
a number of substituted allylalcohols as pro-
electrophiles were tested under optimized conditions to afford
compounds 8a-h in up to 95% yields (Scheme 5). Most importantly,
we found that the DaA reaction was highly regioselective in nature,
where linear products (such as 8a-h) were obtained in excellent
yields and no traces of branched products were obtained (Scheme
react with Pd(II)-p-allyl complex [generated in situ by reaction of
Next, a number of enolcarbonates with an aromatic ring con-
taining electron-withdrawing groups were tested to afford com-
pounds 9a-i in 80e96% yields in 3e5 h (Scheme 6). Once again, a
number of substituted allylalcohols, such as crotyl alcohol, and
cinnamyl alcohol with E-geometry, as pro-electrophiles furnished
only linear products (9b-c, 9e-f, 9j, and 9m) under the optimized
condition. Further, 3,3-dimethyl allyl alcohol (prenyl alcohol) as
pro-electrophile afforded only linear products 9i and 9l (Scheme 6).
Interestingly, cyclohexane sharing an ethylester at C-2 position,
which is a challenging substrate due to the possibilities of
sequential allylations, also afforded product 9j in 68% yield, thereby
allylacetate and Pd(0)] to furnish various 2-arylated cyclohexa-
nones 7e9. Based on this hypothesis, we recently reported an
efficient Pd(0)-catalyzed deacylative allylation (DaA) and utilized
for a total synthesis of ( )-crinane [14a]. Herein, we report a
detailed studies of our methodology of Pd(0)-catalyzed deacylative
allylation (DaA) of enolcarbonates and the total syntheses of
clearly
indicating
mild
nature
of
our
process.
2-
Arylcyclopentanones (9k-n) and 2-arylcycloheptanones (9o-p)
based enolcarbonates furnished various structural scaffolds as
We then look forward for the utilization of 2,3-disubstituted
allyl alcohol as pro-electrophile in Pd(0)-catalyzed deacylative
Scheme 2. Retrosynthetic analysis of Amaryllidaceae alkaloids sharing 5,10b-
ethanophenathridines.
2