Chain-walking strategy for organic synthesis: Catalytic cycloisomerization of 1,n-dienes

Article abstract of DOI:10.1021/ja308377u

The catalytic construction of carbon-carbon bonds in small organic molecules via chain walking is described. Catalytic cycloisomerization of 1,n-dienes via chain walking was achieved using a palladium-1,10-phenanthroline catalyst to form five-membered-ring products. By means of a cycloisomerization/ hydrogenation protocol, 1,7- to 1,14-dienes were selectively converted to bicyclo[4.3.0]nonane derivatives. The use of chain walking provides a new method in organic synthesis to functionalize unreactive carbon-hydrogen bonds by letting the catalyst look for preferable bond-forming sites by moving around on the substrate.

Full text of DOI:10.1021/ja308377u

Communication
pubs.acs.org/JACS
Chain-Walking Strategy for Organic Synthesis: Catalytic
Cycloisomerization of 1,n‑Dienes
Takuya Kochi,* Taro Hamasaki, Yuka Aoyama, Junichi Kawasaki, and Fumitoshi Kakiuchi
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa
223-8522, Japan
S
* Supporting Information
carbon−carbon bond formation in small organic molecules has
rarely been investigated.4 Long-distance olefin isomerization,
which involves olefin dissociation processes, has been used for
many carbon−carbon bond formations.5 However, the
reactions are often not regioselective or form new bonds only
on carbons where carbon−carbon double bonds or metal−
carbon bonds are relatively stabilized (i.e., bonds stabilized by
functional groups or the least hindered carbon−metal bonds).
Under the situation where chain walking occurs, bond-forming
sites can be controlled by the catalyst, which looks for
preferable sites to form bonds by walking around on the
substrate. In addition, if two or more isomerizable carbon−
carbon double bonds are present, olefin isomerization may
occur at each olefin part, and selective bond formation is even
more difficult to achieve.
ABSTRACT: The catalytic construction of carbon−
carbon bonds in small organic molecules via chain walking
is described. Catalytic cycloisomerization of 1,n-dienes via
chain walking was achieved using a palladium−1,10-
phenanthroline catalyst to form five-membered-ring
products. By means of a cycloisomerization/hydrogenation
protocol, 1,7- to 1,14-dienes were selectively converted to
bicyclo[4.3.0]nonane derivatives. The use of chain walking
provides a new method in organic synthesis to function-
alize unreactive carbon−hydrogen bonds by letting the
catalyst look for preferable bond-forming sites by moving
around on the substrate.
hain walking is a mechanism in which an alkylmetal
To examine the use of chain walking for organic synthesis,
cycloisomerization of 1,n-dienes was chosen as our target
reaction.6 Cycloisomerization of 1,5- or 1,6-dienes has been
extensively studied by many researchers using a variety of
transition-metal catalysts to form five-membered-ring products.
If we could incorporate the chain-walking mechanism into the
cycloisomerization reaction, dienes other than 1,5- or 1,6-
dienes would also be transformed to five-membered-ring
products. There have been only a limited number of reports
on cycloisomerization of 1,n-dienes to form five-membered
rings when n is larger than 6 (e.g., 1,7- and 1,8-dienes).7 For
these examples, the reactions are considered to proceed via
stepwise olefin isomerization pathways where both olefin
isomerization and exchange rapidly occur.
C
species undergoes rapid β-hydride elimination and
reinsertion to change the position of the metal on the alkyl
chain without dissociation of the olefin during the process
(Scheme 1).1 Ever since the development of palladium−α-
Scheme 1. Mechanism of Chain Walking
Here we report the use of the chain-walking process for the
palladium-catalyzed synthesis of small organic molecules
containing carbocycles. Cycloisomerization of several dienes
other than 1,6-dienes proceeded in the presence of a
palladium−1,10-phenanthroline catalyst to form five-mem-
bered-ring products.
For our initial investigation, 1,8-diene 1a was reacted with
catalysts previously used for cycloisomerization of 1,6-dienes.
When palladium−1,10-phenanthroline complex 2a8 was
employed as a catalyst in the presence of NaBArf4 [Arf = 3,5-
(CF3)2C6H3], cycloisomerization proceeded to give five-
membered-ring products, including 3a as the major product
along with 4a (Table 1, entry 1). Reactions of several other
palladium and ruthenium catalysts were also conducted for the
reaction but resulted in poor yields or no detection of cyclized
diimine catalysts by Brookhart and co-workers, olefin polymer-
ization via chain walking has provided various unique polymers2
such as highly branched polyethylenes2a and their copolymers
with polar monomers.2b The palladium−α-diimine catalysts can
also polymerize olefins other than ethylene.2c−f For example,
polymerization of 1-hexene provides products with much less
branching than normal poly(1-hexene).2a Osakada and co-
workers also reported on chain-walking polymerization of 1,6-
dienes possessing only one terminal vinyl group.2d In these
examples, many bond formations occurred at both terminal
carbons of the substrate including unactivated methyl carbons.
These results essentially indicate that chain walking may be
used to functionalize unactivated carbon−hydrogen bonds by
letting the catalyst move around on parts of the substrate
carbon chain distant from the olefin moiety.3
Although the chain-walking mechanism has been incorpo-
rated into many olefin polymerization processes, its use for
Received: August 23, 2012
Published: September 21, 2012
© 2012 American Chemical Society
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Communication
Table 1. Optimization of the Pd-Catalyzed
Cycloisomerization of 1,8-Diene 1a via Chain Walking
Table 2. Time Dependence of Pd-Catalyzed
Cycloisomerization of 1a via Chain Walking
a
a
c
yield (%)
b
entry
1
cyclohexene (equiv)
time (h)
conv. (%)
3a
4a
−
−
−
−
2
3
96
>99
>99
>99
>99
99
83
84
76
70
63
76
78
77
76
75
6
10
13
22
33
3
b
2
3
4
4
c
yield (%)
8
DCE
(mL)
conv.
b
5
−
24
2
entry
2
amount of 2 (mol %)
(%)
3a
4a
6
10
10
10
10
10
1
2
3
4
5
6
2a
2b
2c
2d
2a
2a
10
10
10
10
2.5
2.5
2
2
2
2
2
5
98
>99
>99
99
69
4
18
nd
82
58
7
7
3
99
4
d
8
4
>99
>99
>99
5
15
28
82
84
9
8
5
10
24
6
a
Reaction conditions: 1a (0.1 mmol), 2 (0.0025 mmol), NaBArf4
99
b
>99
10
(0.003 mmol), DCE (5 mL), rt. Determined by GC analysis.
c
a
Reaction conditions: 1a (0.1 mmol), 2, NaBArf4 (1.2 equiv to 2),
DCE, rt, 3 h. Determined by GC analysis. Determined by GC
analysis using 5a for calibration. Not determined.
Determined by GC analysis using 5a for calibration.
b
c
d
(Table 3, entry 1). Although tetrasubstituted olefin 4a in the
product was not reduced, the rest of the products were
successfully hydrogenated to give bicyclo[4.3.0]nonane deriv-
ative 5a along with its minor diasteromer in high yields with
high diastereoselectivity, whether cyclohexene was used for
cycloisomerization or not.
products even at high conversion.9 Modification of the ligand of
the palladium catalyst was then examined. Installation of methyl
groups at the 2- and 9-positions of 1,10-phenanthroline to
increase the steric bulk seriously lowered the product yield, and
considerable olefin isomerization without cyclization was
observed (entry 2). On the other hand, when ligands such as
3,4,7,8-tetramethyl-1,10-phenanthroline and 2,2′-bipyridine
were used, tetrasubstituted olefin product 4a became the
major product (entries 3 and 4). After optimization of the
reaction conditions using 1,10-phenanthroline as a ligand, the
reaction with 2.5 mol % 2a in 5 mL of dichloroethane (DCE)
was found to give the highest yield of 3a (entry 6).
Next, the cycloisomerization reaction was monitored by GC
analysis (Table 2, entries 1−5). The reaction was fast in the
beginning, and the amount of the product gradually increased
until the reaction time reached 3 h. After this point, however,
the yield of 3a was suddenly reduced. In contrast, the amount
of 4a kept increasing for up to 24 h. These results indicate that
some amount of 3a was converted to 4a during the reaction.
The time dependence of the yield of 3a led us to investigate
additives that would suppress the isomerization of 3a to 4a. For
this purpose, we chose cyclohexene as an additive, reasoning
that additives such as this, whose coordinating ability is stronger
than that of 4a but weaker than that of 3a, may be effective for
inhibiting the recoordination of 3a by competitive coordina-
tion. Indeed, addition of 10 equiv of cyclohexene suppressed
the formation of 4a (Table 2, entries 6−10). The product yield
was slightly lowered, probably because of somewhat accelerated
olefin exchange before cyclization. However, the use of an
additive would allow us to run the cycloisomerization without
closely monitoring the reaction by GC analysis for each
substrate.
The reactions of several other 1,n-dienes were then
examined, and the product yields were determined using the
cycloisomerization/hydrogenation protocol. 1,7-Diene 1c was
similarly converted to bicyclo[4.3.0]nonane 5c in high yield
with or without using cyclohexene (entry 2). The reaction was
also applicable to substrates with two olefin parts connected by
longer carbon linkages. While the reaction of 1,9-diene 1d
provided the corresponding five-membered-ring products in
good yields with high diastereoselectivity in either case (entry
3), the cyclization product from 1,10-diene 1e was obtained in
as high as 80% yield only when the reaction was performed
without cyclohexene (entry 4). The cycloisomerization also
proceeded efficiently in the absence of cyclohexene with 1,14-
diene 1f, which gave the product in 75% yield (entry 5). 1,8-
Dienes with ethyl (1g) and tert-butyl (1h) malonate moieties
were also converted to the corresponding bicyclo[4.3.0]nonane
derivatives 5g and 5h in good yields (entries 6 and 7).
Substrates other than malonate derivatives were also applicable
to this reaction. Meldrum’s acid derivative 1i was converted to
tricyclic compound 5i (entry 8). X-ray diffraction analysis of 5i
unambiguously showed the formation of the bicyclo[4.3.0]-
nonane backbone, and the stereochemistry of 5i was also
confirmed. The reaction also proceeded with nitrogen-tethered
substrate 1j, and the corresponding pyrrolidine derivative 5j
was obtained in 57% yield when cyclohexene was used as an
additive (entry 9).
The proposed mechanism is shown in Figure 1a. First, the
terminal olefin reacts with the catalyst because of its small size
relative to the disubstituted olefin, and an alkylpalladium
species is formed. Then chain walking starts to get to a position
where the other olefin coordinates to the metal and inserts into
the palladium−carbon bond the most easily. Syn β-hydride
Although 3a was found to be the major product in the
reaction of 1a, small amounts of several isomers of 3a were also
formed. To determine the efficiency of the cyclization, the
products were hydrogenated using platinum oxide as a catalyst
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Communication
Table 3. Chain-Walking Cycloisomerization/Hydrogenation
a
of Various 1,n-Dienes
Figure 1. Mechanism of (a) catalytic cycloisomerization of 1,8-diene
1a to 3a via chain walking and (b) further isomerization of 3a to 4a.
To obtain highly branched polymers by olefin polymerization
via chain walking, the relative order of the rates should be chain
walking > intermolecular carbon−carbon bond formation >
olefin exchange. For the palladium−α-diimine catalysts, olefin
exchange is suppressed considerably by the large substituents
on both sides of the square-planar palladium faces. In contrast,
the use of the chain-walking process for organic synthesis may
be achieved when intermolecular carbon−carbon bond
formation is slower and chain walking is still faster than olefin
exchange. Widenhoefer and co-workers reported that complex
2a isomerized a 1,6-diene into a five-membered-ring product
containing a trisubstituted olefin, indicating that the chain-
walking process and other intramolecular processes with
catalyst 2a are much faster than olefin exchange.8
a
Reaction conditions: 1a (0.5 mmol), 2 (0.0125 mmol), NaBArf4
b
(0.015 mmol), DCE (25 mL), rt. Combined yields of diastereomers,
as determined by GC analysis. Numbers in parentheses are those
To gain further understanding of the mechanism, we
performed the reaction with 1,6-diene 1b (trans:cis = 93:7),
an isomer of 1a, but only a trace amounts (or less) of products
3a and 4a were observed (eq 1). When a 1:1 mixture of 1a and
c
obtained for the reaction in the presence of 10 equiv of cyclohexene.
d
e
Performed with 0.025 mmol of 2 and 0.03 mmol of NaBArf4. The
yield of the major diastereomer is given because the peak of the minor
diastereomer overlapped with that of a trace amount of a non-
hydrogenated product. Not determined. Performed for 24 h.
f
g
elimination occurs, forming the initial product 3a. While there
is enough substrate that can react with the palladium,
recoordination of 3a is suppressed because the terminal olefin
reacts much more readily than 3a, which contains only a
disubstituted olefin surrounded by a bulky group. However,
after the reaction system runs out of the substrate,
recoordination of 3a occurs from the face opposite to the
one originally bound to the palladium before dissociation
(Figure 1b). Olefin insertion into the palladium−hydrogen
bond followed by chain walking gives the more stable
tetrasubstituted olefin product, 4a.
1b was used for the reaction, 1b was mostly recovered after 3 h,
while most of 1a was converted to 3a or 4a (eq 2). If the
reaction of 1b occurred via a stepwise olefin isomerization
pathway, internal olefins such as 1b should have a reactivity
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Journal of the American Chemical Society
Communication
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high enough to be at least comparable to that of 1a. In fact, in a
previously reported example of cycloisomerization of a 1,7-
diene to form a five-membered ring, isomerized 1,6-diene
intermediates were shown to have higher reactivities than the
original 1,7-diene.7c,e This strongly suggests that the reaction
proceeds via a chain-walking mechanism.
(4) For carbon−carbon bond formation at an allylic position
considered to proceed by chain walking of one carbon−carbon bond,
see: Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644.
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Hiersemann, M. Org. Lett. 2012, 77, 4980.
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In summary, we have demonstrated the remarkable potential
of the chain-walking strategy in organic synthesis by enabling
the selective formation of five-membered-ring products from
various 1,n-dienes. We believe that the use of the chain-walking
strategy will offer diverse novel methods in organic synthesis to
construct carbon−carbon bonds that are otherwise difficult to
form. Transition-metal-catalyzed direct functionalization of
unreactive carbon−hydrogen bonds has become a powerful
tool for carbon−carbon bond formation,3 but there are still
limitations in scope, particularly in terms of functionalization of
sp3-hybridized carbon−hydrogen bonds. In addition, the site
selectivity of the functionalization generally relies upon that of
carbon−hydrogen bond cleavage controlled by electronics,
sterics, and/or directing groups. Therefore, the use of chain
walking should provide an alternative approach for the
functionalization of unreactive sp3-hybridized carbon−hydro-
gen bonds. Further investigation of the chain-walking strategy
to develop new types of carbon−carbon bond-forming
reactions is underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details, characterization data, and crystallo-
graphic data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(9) See Table S1 in the Supporting Information for details.
AUTHOR INFORMATION
Corresponding Author
kochi@chem.keio.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, and a grant from the Keio
Leading-Edge Laboratory of Science and Technology.
REFERENCES
■
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exchange occur rapidly, but in this paper, we refer to chain walking
only as a mechanism in which olefin exchange is much slower than β-
hydride elimination/reinsertion, considering the mechanism of the
chain-walking polymerization and what the term really represents.
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