An arylative ring expansion cascade of fused cyclobutenes via short-lived intermediates with planar chirality

Article abstract of DOI:10.1021/jacs.5b06576

An arylative ring expansion cascade has been developed for the synthesis of medium-sized carbocycles from fused cyclobutenes. This reaction proceeds through a short-lived cis,trans-cycloalkadiene intermediate that is formed by thermal 4η electrocyclic ring opening. Chirality transfer experiments provide direct evidence for the transient generation of the intermediate.

Full text of DOI:10.1021/jacs.5b06576

Communication
pubs.acs.org/JACS
An Arylative Ring Expansion Cascade of Fused Cyclobutenes via
Short-Lived Intermediates with Planar Chirality
Norihito Arichi, Ken-ichi Yamada, Yousuke Yamaoka, and Kiyosei Takasu*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
*
S Supporting Information
that the thermal ring opening of a substituted bicyclo[6.2.0]-
decene proceeded at room temperature to give a 10-membered
carbocycle, whereas the use of smaller bicyclo[n.2.0] ring
systems (n = 3−5) did not result in any of the ring-opened
products, even at temperatures up to 200 °C. The authors went
on to suggest that the formation of medium-sized rings
containing a trans double bond would be impossible because of
their severe strain. Despite this assertion, we believe that
cis,trans-cycloalkadienes could potentially be generated as short-
ABSTRACT: An arylative ring expansion cascade has
been developed for the synthesis of medium-sized
carbocycles from fused cyclobutenes. This reaction
proceeds through a short-lived cis,trans-cycloalkadiene
intermediate that is formed by thermal 4π electrocyclic
ring opening. Chirality transfer experiments provide direct
evidence for the transient generation of the intermediate.
lived intermediates, even from substituted bicyclic com-
edium-sized rings form the core skeletons of many
natural products. Despite their importance, the synthesis
6,7
pounds.
Krenske, Houk, and Hsung recently provided
M
computational evidence to support the formation of such
transient intermediates in the thermal rearrangements of fused
of this class of compounds is a long-standing challenge in
1
organic chemistry. Intramolecular cyclization for the con-
6
cyclobutenes. We envisioned that intermolecular trapping of
struction of medium-sized rings is generally difficult because of
2
the short-lived intermediate 2 using a palladium catalyst would
afford medium-sized carbocycles (Scheme 1B). Notably, our
attention was directed toward the possibility of chirality transfer
through the inherent planar chirality of 2, which could provide
direct experimental evidence for the formation of this transient
intermediate.
the large entropic and enthalpic costs. An alternative strategy is
ring expansion of fused bicyclic units. The main advantage of
this approach is that it does not require high dilution or slow
addition conditions, which are generally employed to prevent
undesired dimerization during the cyclization process.
The thermal 4π electrocyclic reaction of syn-3,4-disubstituted
cyclobutenes proceeds in a stereospecific conrotatory manner
The trapping of 2 was initially attempted using an
intermolecular Heck reaction (Table 1). When 1a was treated
with iodobenzene (3a) in toluene at 100 °C in the presence of
Pd(OAc) , PPh , and N,N-diisopropylethylamine (DIPEA), the
3
to give cis,trans-1,3-butadienes (Scheme 1A). The thermal ring
Scheme 1. cis,trans-Cycloalkadienes as Possible
Intermediates for the Synthesis of Medium-Sized Carbocyles
2
3
8
cis,cis-cyclooctadiene 4aa was obtained in 34% yield (entry 1).
When Cs CO was used, formation of the olefinic isomer 5aa
2
3
Table 1. Selected Optimization of the 4π Electrocyclic Ring
a
Opening−Heck Arylation Cascade
b
c
entry
base (equiv)
ligand (mol %)
yield (%)
4aa/5aa
1
2
3
4
5
6
DIPEA (2.0)
Cs CO (2.0)
PPh (20)
34
30
83
90
64
>20:1
9:1
3
PPh (20)
2
3
3
AgOAc (2.0)
Ag CO (1.0)
PPh (20)
8:1
3
PPh (20)
14:1
1:2
2
3
3
Ag CO (1.0)
PCy (20)
2
3
3
Ag CO (1.0)
dppb (10)
61
b
1:1
2
3
opening of cis-fused cyclobutenes could therefore generate
cis,trans-cycloalkadienes. It has been reported that non-
substituted bicyclo[4.2.0]octene can undergo thermal ring
opening at 110 °C to give cis,trans-cyclooctadiene, but this
compound could not be isolated because of a rapid reverse
a
The reactions were run on a 0.2 mmol scale. Combined isolated
yields. Determined by H NMR analysis of the isolated products.
c
1
Received: June 25, 2015
4
5
reaction to the starting material. Clark and Untch reported
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b06576
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
was observed (entry 2). The use of silver salts had a positive
Table 2. Substrate Scope for the Synthesis of Medium-Ring-
Fused Indolines 6
a
impact on the yield of 4aa, with Ag CO being the most
2
3
suitable (entries 3 and 4). No improvements were observed in
the yield or selectivity using other ligands (entries 5 and 6). It is
noteworthy that no ring-opening compounds were obtained
when 1a was heated under the same conditions in the absence
of the palladium catalyst.
With the optimized conditions in hand, we investigated the
substrate scope of the ring expansion−arylation cascade
(Scheme 2). The reaction of cyclobutenes bearing an alkyl or
Scheme 2. Substrate Scope of the 4π Electrocyclic Ring
, ,
a b c
Opening−Heck Arylation Cascade
a
The reactions were run on a 0.2 mmol scale, unless noted otherwise.
Isolated yields. The reaction was run on a 0.1 mmol scale.
b
c
a
The reactions were run on a 0.2 mmol scale, unless noted otherwise.
b
c
d
Isolated yields are shown. 4/5 > 20:1, unless noted otherwise. 4ca/
e
Scheme 3. Working Mechanistic Hypothesis for the
Synthesis of Medium-Ring-Fused Indoline 6 with Chirality
Transfer
5
ca = 16:1. The reaction was run on a 1.2 mmol scale.
alkoxycarbonyl group proceeded smoothly (4ba and 4ca). The
use of an aryl iodide bearing an electron-withdrawing group
(
4ab) or an electron-donating group (4ac) was well-tolerated.
Heteroaryl iodides, including 2-iodothiophene and 3-iodopyr-
idine, also reacted smoothly (4ad and 4ae). Pleasingly, this
reaction was also successfully applied to seven-membered-ring-
fused cyclobutenes to afford the corresponding cyclonona-
dienes (4da and 4ef). The structure of 4ef was unambiguously
determined by X-ray crystallographic analysis.
We then investigated the use of N-tosyl-2-iodoaniline (3g) as
the aryl iodide to obtain medium-ring-fused trans-indolines 6
(
Table 2). After screening of several ligands, P(2-furyl) was
3
identified as the most appropriate ligand for this transformation
see the Supporting Information). The reaction of six-
(
membered-ring-fused cyclobutenes provided eight-membered-
ring-fused indolines as single diastereomers (entries 1 and 2).
Using 1a led to the simultaneous elimination of the methoxy
group to give 6a in 54% yield (entry 3). The use of the seven-
membered-ring-fused cyclobutenes 1g and 1h furnished the
corresponding nine-membered-ring-fused indolines (entries 4
and 5). The reaction of tricyclic cyclobutenes also proceeded
smoothly to afford the corresponding products with increased
reaction rates (entries 6−8).
of 2, which would be generated as a transient intermediate by
the thermal 4π electrocyclic reaction of 1. The resulting Pd
complex II would be converted to the six-membered
II
palladacycle III at a higher rate than the β-hydride elimination
9
to give 4. Subsequent reductive elimination from III would
10
Our proposed mechanism for the formation of 6 is shown in
give 6. We envisaged that this reaction would result in
chirality transfer through the planar chirality of 2. Certain
medium-sized-ring trans-cycloalkenes have been reported to
possess planar chirality. As a representative example, trans-
0
Scheme 3. Oxidative addition of Pd to 3g in the presence of
Ag CO would generate the cationic aryl Pd species I. This Pd
2
3
species would then undergo a syn insertion into the trans olefin
B
DOI: 10.1021/jacs.5b06576
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
cyclooctene exhibits stable planar chirality at ambient temper-
Scheme 4. Experimental Support for the Formation of the
Transient Intermediate 2
11
ature because of its highly rigid structure. For chirality
transfer to occur, the addition of 2 to I must occur at a higher
rate than the racemization of 2 by ring flip.
The chirality transfer was examined using optically pure
substrates (Table 3), which were prepared by preparative chiral
Table 3. Chirality Transfer in the Synthesis of Indoline 6
a
using Enantiopure Cyclobutenes
b
c
entry
1
T (°C)
time
4 h
yield of 6 (%)
ee of 6 (%)
1
2
3
4
5
6
(−)-1c
(−)-1g
(−)-1i
(−)-1i
(−)-1k
(−)-1k
100
100
100
50
79 ((+)-6c)
81 ((±)-6g)
73 ((+)-6i)
72 ((+)-6i)
78 ((+)-6k)
78 ((+)-6k)
>99
0
4 h
10 min
24 h
74
85
84
94
100
50
30 min
24 h
a
The reactions were run on a 0.1 mmol scale using enantiopure
substrate 1 (>99% ee), 3g (1.2 equiv), Pd(OAc) (10 mol %), P(2-
2
b
furyl)3 (20 mol %), and Ag CO3 (1.0 equiv). Isolated yields.
Determined by chiral HPLC.
2
c
the transient intermediate was trapped to form adduct 8 in 87%
yield. Most notably, this reaction resulted in complete chirality
transfer, which confirmed that the chirality transfer in the
synthesis of indoline 6 occurred via a planar-chiral inter-
1
2
HPLC. When (−)-1c was subjected to the reaction at 100 °C,
+)-6c was obtained without any loss of optical purity (entry
). The absolute configuration of (+)-6c was determined by X-
19
(
1
mediate. The intermediacy of 2 was further supported by the
inert behavior of bicyclo[3.2.0]heptane 1m, which can be
rationalized by assuming that the transient cis,trans-cyclo-
heptadiene is highly strained because of the smaller ring
ray analysis, and the stereochemical outcome was found to be
in reasonable agreement with our hypothesis (Scheme 3).
When (−)-1c was heated in toluene at 100 °C for 12 h in the
absence of the palladium catalyst, there was no decrease in the
enantiomeric purity of the recovered 1c, which suggested that
the eight-membered transient intermediate has a high energy
barrier to racemization. In sharp contrast, the use of seven-
membered-ring-fused (−)-1g provided 6g as a racemic mixture
6b,20
size.
In summary, we have developed a ring-expansion cascade of
fused cyclobutenes via short-lived cis,trans-cycloalkadiene
intermediates. Chirality transfer was observed in the synthesis
of indolines, and the extent of this transfer was highly
dependent on the ring size of the transient intermediate and
increased by the introduction of a benzene ring or an oxygen
atom. Further work is currently underway in our laboratory to
explore the novel reactions of fused cyclobutenes and develop
the memory of chirality through transient planar chirality.
(
entry 2). Furthermore, complete racemization was observed
during the formation of 6g even at 60 °C. The dramatic
difference in the extent of the chirality transfer reflects the fact
that the increased ring size significantly facilitates the
13
racemization by ring flip. Interestingly, the chirality was
retained in the reaction of the seven-membered-ring-fused
tricyclic cyclobutene (−)-1i, which gave (+)-6i with 74% ee
ASSOCIATED CONTENT
Supporting Information
Spectral data for all of the new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b06576.
■
*
S
(
entry 3). The introduction of a benzene ring could lead to an
increase of the stereochemical stability of the cis,trans-
cyclononadiene intermediate. When the reaction was
1
4
conducted at 50 °C for 24 h, the enantiomeric excess of
(
+)-6i improved to 85% ee (entry 4). Notably, the oxygen-
AUTHOR INFORMATION
Corresponding Author
*kay-t@pharm.kyoto-u.ac.jp
Notes
■
containing substrate (−)-1k was converted to (+)-6k with a
higher degree of chirality transfer than in the case of 1i (entries
3
and 4 vs entries 5 and 6). The stereochemical stability of 2
may be enhanced by the replacement of the methylene group
The authors declare no competing financial interest.
with an oxygen atom because of the shorter length of the C−O
15
bond compared with the C−C bond. The results of these
chirality transfer experiments therefore provide direct evidence
for the transient generation of 2. Consequently, these reactions
can be classified as a rare example of the memory of chirality
ACKNOWLEDGMENTS
This work was financially supported by JSPS KAKENHI
25293002), “Platform for Drug Design, Discovery and
Development” from MEXT, and a Fellowship for Young
■
(
16,17
involving transient planar-chiral intermediates.
Further
Scientists (26-7573 to N.A.) from JSPS.
research toward the development of this phenomenon could
therefore make a significant contribution to the area of
asymmetric synthesis.
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DOI: 10.1021/jacs.5b06576
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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(
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(
(
(
2
(
(
1
D
DOI: 10.1021/jacs.5b06576
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX