BF3-Catalyzed Skeletal Rearrangement of 7-En-2-ynones to endo-Type Cyclic Dienes

Article abstract of DOI:10.1021/acs.orglett.0c00949

Transition-metal-catalyzed cycloisomerization reactions with skeletal rearrangement of 1,n-enynes to afford cyclic dienes (particularly exo-cyclization products) have been well studied. However, there are few reports on the nonmetal-catalyzed skeletal rearrangement of enynes and skeletal rearrangement of electron-deficient enynes such as n-en-2-ynones. Here, we describe BF₃·MeCN-catalyzed synthesis of 3-alkylidenecyclohexenes from 7-en-2-ynones, representing the first nonmetal-catalyzed skeletal rearrangement of 1,6-enynes to endo-type cyclic dienes.

Full text of DOI:10.1021/acs.orglett.0c00949

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Letter
BF ‑Catalyzed Skeletal Rearrangement of 7‑En-2-ynones to endo-
3
Type Cyclic Dienes
Daisuke Sato, Yuichiro Watanabe, Keiichi Noguchi, Junichiro Kanazawa, Kazunori Miyamoto,
Masanobu Uchiyama,* and Akio Saito*
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ABSTRACT: Transition-metal-catalyzed cycloisomerization reactions with skeletal rearrangement of 1,n-enynes to afford cyclic
dienes (particularly exo-cyclization products) have been well studied. However, there are few reports on the nonmetal-catalyzed
skeletal rearrangement of enynes and skeletal rearrangement of electron-deficient enynes such as n-en-2-ynones. Here, we describe
BF ·MeCN-catalyzed synthesis of 3-alkylidenecyclohexenes from 7-en-2-ynones, representing the first nonmetal-catalyzed skeletal
3
rearrangement of 1,6-enynes to endo-type cyclic dienes.
atalytic cycloisomerization reactions with skeletal rear-
rangement of 1,n-enynes afford diverse cyclic products,
As an extension of our research on metathesis-type reactions
C
between alkynes and heteroenes catalyzed by σ-electrophilic
6
including cyclic conjugated dienes and bicyclic compounds, in
acids, we herein report catalytic skeletal rearrangement of 7-
1
a highly atom-economical manner. In particular, skeletal
en-2-ynones into six-membered endo-type dienes using BF3·
MeCN as a σ-electrophilic nonmetallic catalyst (Scheme 2).
rearrangement to form cyclic conjugated dienes, which can be
regarded as a formal enyne metathesis, has great potential for
application in the total synthesis of natural products and
Scheme 2. Cycloisomerization of 7-En-2-ynoates or -ynones
1
f,g
pharmaceuticals. Depending on the substitution pattern of
substrates and the nature of the catalysts, 1,6-enynes can be
converted into five-membered exo-type dienes I and II and six-
membered endo-type dienes (Scheme 1). However, although
Scheme 1. Skeletal Rearrangements to Afford Cyclic Dienes
Although Pd-catalyzed cycloisomerization without skeletal
rearrangement of 7-en-2-ynoates into six-membered 1,3-dienes
has been reported, six-membered 1,4-dienes or five-membered
dienes (including the rearranged dienes in Scheme 1) are
sometimes formed as byproducts (occasionally as the main
2
a−c,7
8
products
) (Scheme 2). Therefore, the selective for-
2
3
selective synthesis of exo-type I and II has been achieved by
using various π-acidic metal complexes (Pd, Ru, Pt, Au, etc.),
the exclusive formation of endo-type dienes has rarely been
Received: March 14, 2020
2
e,4
reported. Furstner et al. have disclosed a selective synthesis
̈
of exo-type I by the skeletal rearrangement of an ynone-
tethered cyclooctene using HBF or BF ·OEt . Nevertheless,
5
4
3
2
there has been no systematic study on nonmetal-catalyzed
skeletal rearrangement of enynes.
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00949
A
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mation of six-membered 1,3-dienes from 7-en-2-ynones
remains challenging.
Initially, we focused on the evaluation of catalysts (20 mol
mmol scale reaction (entry 17). It should be noted that the
9
endo-type diene 2a was obtained as a single stereoisomer
10
(Table 1).
%
) for the cycloisomerization of 7-en-2-ynone 1a in CH Cl
With the optimal conditions in hand, we next investigated
the scope of the present cycloisomerization, using various 7-en-
2
2
(Table 1). Our previous work on alkyne-carbonyl metathesis
2-ynones 1a−o and 8-en-2-ynone 1p (Scheme 3). Like phenyl
Table 1. Evaluation of Catalysts
a
Scheme 3. Scope of Substrates
a
a
entry
catalyst
t (h)
2a (%)
3a (%)
b
1
2
3
4
5
6
7
8
9
IPy BF -2HBF
4
8
8
24
5
3
1
1
1
24
24
24
24
24
24
24
4
38
27
46
48
45
41
37
36
23
0
23
20
17
10
13
4
20
30
22
2
4
b
NIS-HBF4
NIS-BF ·OEt
3
2
NIS-BF ·MeCN
3
BF ·OEt2
3
BF ·MeCN
3
b
HBF4
TfOH
Tf NH
2
c
10
11
12
13
14
15
16
17
MsOH
0 (1a: 98)
0 (1a: 73)
13 (1a: 70)
0 (1a: 97)
17
7
5
c
B(C F )
5 3
0
13
6
c
c
c
In(OTf)3
Sc(OTf)3
TMSOTf
TrBF4
c
0
43
50
60
58
d
d
BF ·MeCN
3
,
e
BF ·MeCN
4
c
6
3
a
b
1
d
Isolated yield. Et O complex. Determined by H NMR. BF3·
MeCN: 10 mol %, solvent: CH Br . 1a: 1 mmol.
2
e
2
2
showed that IPy BF (Py = pyridine) pretreated with HBF (2
2
4
4
equiv to IPy BF ) or a 1:1 mixture of N-iodosuccinimide
2
4
(
NIS) and acid was a more effective catalyst and exhibited a
a
Unless otherwise noted, only E-isomers of 1 were used. Reaction
stronger σ-acidity than widely used nonmetal catalysts such as
b
c
6
d
times are shown in parentheses. BF ·MeCN: 20 mol %. E/:Z ratio
HBF4 or BF ·OEt . Therefore, these superelectrophilic
3
3
2
d
e
of 1j = 84:16. E/Z ratio of 1k or 1m = 85:15. BF ·MeCN: 50 mol
3
iodine species were initially tested (entries 1−4). In contrast
f
g
h
5
%. Temp: 80 °C. E/Z ratio of 1o = 72:28. E/Z ratio of 1p = 80:20.
to Fu
̈
rstner’s report on the synthesis of exo-type dienes, we
i
BF ·MeCN: 30 mol %.
3
obtained endo-type dienes 2a in all cases in 27−48% yields at
room temperature with no detectable formation of the
corresponding exo-type dienes. Although cyclic ketone 3a
with cleavage of the triple bond was formed as a byproduct
ynone 1a, ethyl derivative 1b and 4-substituted aryl derivatives
1d−g were smoothly converted into the corresponding endo-
type dienes 2b and 2d−g in 43−79% yield. In the case of 3- or
2-substituted aryl derivatives 1h, 1i, ynals 1c, 1m, and 8-en-2-
(
10−23%) in these reactions, the NIS-BF ·MeCN catalytic
3
system led to the relatively selective formation of 2a (2a:3a =
8:10, entry 4). To check the effect of NIS, we examined the
sole use of BF complexes, Brønsted acids, or other Lewis acids
4
ynone 1s, increasing the amounts of BF ·MeCN (20 or 30 mol
3
3
(
entries 5−16). Even in the absence of NIS, BF ·MeCN gave
%) afforded the endo-type dienes 2, albeit in lower yield for 2c,
2i, and 2m (28−35%). Furthermore, the optimal conditions
were effective for the reaction of the ether-tethered 1j−m and
the malonate-tethered 1n and 1o. Unfortunately, the reaction
of ynoate 1p did not proceed even when 50 mol % of BF3·
MeCN was used at 80 °C for 24 h, and 1p was recovered
quantitatively. This may be due to the weaker electron-
withdrawing ability of the alkoxy carbonyl group. Regarding
3
endo-type diene 2a with high selectivity (2a:3a = 41:4, entry
). On the other hand, when strong Brønsted acids such as
HBF , TfOH, and Tf NH (Tf = CF SO ) were employed, the
6
4
2
3
2
yield of 2a was reduced to 23−37%, concomitantly with an
increased yield of cyclic ketone 3a (20−30%, entries 7−9).
Among the tested catalysts, TrBF (Tr = trityl) resulted in the
4
highest yield of 2a (50%, entry 15); unfortunately, this could
not be improved by changing the catalytic amount or solvent
1
substituents of alkenes, although the styrene derivative (R =
R = Ph, X = O) easily underwent intramolecular Diels−Alder
reaction, unsubstituted 1q and E-phenethyl-substituted 1r, as
well as E-Me-substituted 1a−o and 1s, all afforded endo-type
dienes 2 with no detectable formation of the corresponding
exo-type dienes.
2
(
see Supporting Information for details). However, by using 10
11
mol % of BF ·MeCN in CH Br , which showed better results
3
2
2
than many other solvents (see Supporting Information for
details), the yield of 2a was improved to 60% (entry 16).
Furthermore, this catalytic system could be applied to the 1
B
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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
pathways of the skeletal rearrangements of 1l without an acid
catalyst and with Brønsted acid, as shown in Figures S2−S4
(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
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Letter
2
a−c,7,8
methods,
we believe that our findings not only open a
ACKNOWLEDGMENTS
■
new window on nonmetal-catalyzed skeletal rearrangements
but also provide an attractive procedure for accessing six-
This work was supported partly by JSPS Grants-in-Aid for
Scientific Research (C) (No. 18K06573 for A.S.) and Scientific
Research (S) (No. 17H06173 for M.U.), and JST CREST
(No. JPMJCR19R2 for A.S. and M.U.). Allotment of
computational resources (Project G19012) from HOKUSAI
BigWaterfall (RIKEN) is gratefully acknowledged.
15
membered 1,3-dienes. Furthermore, based on DFT calcu-
lations and experimental data, we propose that the reaction
proceeds via the bifurcating zwitterionic intermediate (INT2)
in which the secondary carbocation at the C3 position is
partially stabilized by the C1−C2 double bond. Studies on
other skeletal rearrangements of n-en-2-ynones are underway.
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ASSOCIATED CONTENT
■
2
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00949.
2
Experimental procedures, compound characterization
data, and computational details (PDF)
Accession Codes
CCDC 1975901 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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Yuichiro Watanabe − Graduate School of Pharmaceutical
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