Organic Letters
Letter
concept with the use of malononitriles and newly designed
vinyl carbonates as substrates toward the formation of
synthetically challenging functionalized carbocycles under
palladium catalysis; the kinetics of the catalytic system proved
to be controllable under different reaction conditions giving
rise to either cycloheptenones (k > k ) or cyclopentanones (k
Table 1. Selected Ligand Screening Data toward the
Formation of Carbocycles of 3aa and 4a
d
1
2
1
<
k2), adding further to the attractiveness of this methodology
(Scheme 1c).
The cycloheptenone and vinyl cyclopentanone products
prevailed in a number of natural products, bioactive
compounds, and pharmaceuticals, and their diverse and
10−13
efficient synthesis is the continuous endeavor of chemists.
Considering the excellent reactivities of this new vinyl
carbonate, we believed the present work opens up windows for
the construction of novel and valuable functionalized cyclic
structures.
Initial investigation suggested vinyl carbonate 1 could be
14
easily prepared from CO and is air-stable and scalable. We
2
began our research by exploring the reaction between phenyl-
substituted carbonate 1a and benzylidene malononitrile 2a in
the presence of Pd(PPh ) catalyst and a batch of different
3
4
phosphine ligands in toluene at 60 °C (Table 1). To our
delight, the precursor 1a exhibited excellent reactivity
producing either cycloheptenone 3aa or cyclopentanone 4a
(
Table 1). As expected, the formation of vinyl pentanone 4a
was more favored and could be obtained in 86% yield at rt
indicating the reactive nature of the newly designed carbonate
(
°
(
Table 1, Entry 1). Increasing the reaction temperature to 60
C did not improve the diastereoselectivity of 4a significantly
Table 1, Entries 2−3). Then we investigated the ligand effect
on the product distribution (3aa vs 4a) via systematic variation
of different phosphine ligands (Table 1, Entries 4−20).
Notably, the use of ligand L15 gave rise to strained product
3
aa in 10% yield comparing with <1% in most cases.
Afterward, the effect of the palladium species, reaction
temperature, and solvent were investigated utilizing L15 as
ligand in order to achieve the regioselective formation of
product 3aa (Table 2). Surprisingly, the use of other palladium
catalysts did not produce any of the target product at all (Table
a
b
c
Performed at rt. Performed at 40 °C. The dr value and yield
1
determined by H NMR using 2-methylnaphthalene as internal
standard. The reactions were carried out with 1a (0.12 mmol), 2a
d
(
(
0.10 mmol), Pd catalyst (5 mol %), and ligand (10 mol %) in toluene
1.0 mL).
2
, Entries 1−4), suggesting subtle intrinsic nature of the
Pd(PPh ) precatalyst. The reaction performed in dioxane at
3
4
1
00 °C gave affirmative results (Entries 5−11). Interestingly,
the kinetics of the reaction was remarkably affected when
proved to be efficient using different malononitrile derivatives
and carbonates equipped with both electron-withdrawing
(3af−3ag, 3aj, 3ea−3ha, 3ja−3ka) or donating (3ab−3ad,
3ah−3ai, 3ak, 3ba−3da) groups on the para-, ortho-, or meta-
position of the phenyl substituent. Incorporation of a
heterocycle fragment (3am−3an) in the target product was
feasible. Alkyl-substituted malononitriles (3ao−3ap) showed
satisfactory reactivities toward the product formation. The
installation of clumsy group on the substrates (3al, 3ao, 3la,
and 3ma) was also possible, albeit the cyclohexyl-substituted
ones gave rise to the desired products in a slightly reduced
yield. It is noteworthy that the use of phenylsulfonyl
acrylonitrile as acceptor in the reaction was well tolerated,
affording the corresponding sulfone 3aq in excellent
diastereoselectivity. The use of an enantioenriched L15
under the standard conditions gave rise to a racemic product
3aa. The X-ray analysis of product 3aa (inset in Figure 1),
apart from the spectroscopic analysis data, further supported
performed in a mixture of dioxane and toluene, illustrating the
non-negligible solvent effect in current system (Entry 15).
15
Addition of molecular sieves helped further to improve the
regioselectivity resulting in target product 3aa in 95% yield
with only trace amount of vinyl pentanone 4a (Entry 18). In
contrast, previously reported cycloadditions between vinyl
cyclic carbonate A/carbamate B and malononitrile derivatives
only gave rise to five-membered products with the seven-
16,4b,c,5a
membered products undetected.
It was believed that
the exceptional reactivity of carbonate 1 was related to its
structural characteristics. Comparing with intermediate t1, the
introduction of an extra double bond in t3 changed the
3
2
hybridization mode of the α-carbon from sp to sp and
simultaneously varied the bond angle θ (θ ≠ θ ) (marked in
1
2
Scheme 1a,c); this structural difference of the intermediates
might facilitate the formation of larger rings from t3.
With the optimized reaction conditions in hand, we set out
to evaluate the generality of the transformations toward the
formation of otherwise synthetically challenging seven-
membered cycloheptenones (Figure 1). The catalytic system
17,18
the seven-membered structures.
We then focused on the condition screening in order to
synthesize the vinyl pentanone products in a diastereoselective
3
52
Org. Lett. 2021, 23, 351−357
Yan, Biwei
