Organic Letters
On the other hand, complete consumption of the Z-isomer
of 1a required 1 equiv of BF ·MeCN, likely due to the low
3
reactivity of Z-alkene for electrophilic addition, and cyclic
ketone 3a was obtained as a major product (Scheme 4).
Scheme 4. Reactions of Z-Disubstituted or Trisubstituted
Alkenes
‡
Figure 1. Gibbs free energy profile (ΔG in kcal/mol) of skeletal
rearrangements of 7-en-2-ynone into cyclic dienes calculated by M06-
2X/6-31+G(d).
more favorable than TS2b by 3.8 kcal/mol, since the ring
contraction through C2−C4 bond scission causes a large
energy loss. Thus, the production of the endo-type diene is
favored kinetically and thermodynamically in this system.
Concerning the exo-type product, since the activation energy of
Regardless of the amount of BF ·MeCN, cyclic alkene 1t was
3
C3−C4 bond cleavage via TS3b to give INT4b is rather high
also not converted into endo-type diene 2t, but rather into exo-
‡
(
ΔG = 24.7 kcal/mol), INT3b would be more likely to
type diene 4t as the major product. Furstner et al. reported
̈
5
undergo sequential hydration and retro-aldol cleavage reaction
to give the 3a-type product in some cases (Scheme 5). In
similar results using BF ·Et O in toluene. The trisubstituted
3
2
13
1
u preferentially underwent Alder-ene type reaction under the
optimal conditions to give 5u in 91% yield.
Scheme 5. Proposed Mechanism for Formation of 3a
As mentioned above, ynone-tethered E-disubstituted alkenes
were selectively converted into endo-type dienes by the present
methods. To obtain mechanistic insight, DFT calculations
were conducted using 1l as a model substrate that reduces
computational cost. The pathways for the peculiar skeletal
rearrangements of 1l catalyzed by BF are summarized in
3
Figure 1.
Initial interaction between 1l and BF3 generates an
association complex INT1 with a stabilization energy of 2.2
kcal/mol, which undergoes BF -mediated annulation (C2−C4
3
bond formation) via TS1 to give INT2 with an activation
energy of 12.0 kcal/mol. As judged by the elongated C2−C3
bond distance (1.65 Å), as well as the near-linearity (168.9°) of
the allene moiety, we consider INT2 to be a zwitterionic
intermediate in which the secondary carbocation at the C3
position is partially stabilized by the C1−C2 double bond.
INT2 is the bifurcating intermediate for the endo- and exo-type
products. Notably, the delocalized cation species like INT2 has
been recognized as a reactive intermediate in various types of
contrast, the corresponding intermediate derived from 1t has a
3,4-cyclooctane-fused cyclobutene framework, whose C3−C4
bond is more easily cleaved than the case of unfused
14
cyclobutene, and thus would be transformed into exo-type
diene 4t (Scheme 4). On the other hand, the reaction
(see Supporting Information), are similar to those with BF .
3
However, (1) the activation energies without acid catalysts are
5
,12
enyne cycloisomerization reactions.
For the endo-type
much higher than those with BF and (2) the activation energy
3
product, the enolate anion (C1 carbon) in INT2 attacks the
difference at the bifurcating point with the Brønsted acid
becomes very small. These calculated results are consistent
with the experimental observations (Table 1).
C3 cation center, followed by BF -mediated C3−C4 bond
3
cleavage/C2−C4 π bond formation, thereby giving rise to
endo-type diene INT3a with a low activation energy (9.0 kcal/
mol). Alternatively, INT2 undergoes ring contraction (C−C
bond rearrangement) to yield a five-membered ring transition
state TS2b, and subsequently the enolate anion smoothly
approaches the C4 carbocation along the intrinsic reaction
coordinate to produce INT3b with a reasonably high
stabilization energy (34.0 kcal/mol). TS2a is energetically
In conclusion, we have developed a synthetic method for 3-
alkylidenecyclohexenes by BF ·MeCN-catalyzed skeletal re-
3
arrangement of 7-en-2-ynones. The present work is the first
report of nonmetal-catalyzed skeletal rearrangement of 1,6-
enyenes to afford endo-type cyclic dienes. Since the selective
formation of six-membered 1,3-dienes from electron-deficient
alkynes such as 7-en-2-ynoates is difficult by conventional
C
Org. Lett. XXXX, XXX, XXX−XXX