Chain Walking as a Strategy for Carbon-Carbon Bond Formation at Unreactive Sites in Organic Synthesis: Catalytic Cycloisomerization of Various 1,n-Dienes

Article abstract of DOI:10.1021/jacs.5b10804

Carbon-carbon bond formation at unreactive sp³-carbons in small organic molecules via chain walking was achieved for the palladium-catalyzed cycloisomerization of 1,n-dienes. Various 1,n-dienes (n = 7-14) such as those containing cyclic alkenes, acyclic internal alkenes, and a trisubstituted alkene can be used for the chain-walking cycloisomerization/hydrogenation process, and five-membered ring compounds including simple cyclopentane and pyrrolidine derivatives can easily be prepared. Chain walking over a tertiary carbon was also found to be possible in the cycloisomerization. It is not necessary for the linker portion of the diene to contain a quaternary center, and diene substrates with two alkene moieties linked by a tertiary carbon or a nitrogen atom can also be used as substrates. Column chromatography using silica gel containing silver nitrate was found to be effective for isolating some of the cycloisomerization products without hydrogenation. Deuterium-labeling experiments provided direct evidence to show that the reaction proceeds via a chain-walking mechanism.

Full text of DOI:10.1021/jacs.5b10804

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Article
Chain Walking as a Strategy for Carbon–Carbon Bond Formation at Unreactive
Sites in Organic Synthesis: Catalytic Cycloisomerization of Various 1,n-Dienes
Taro Hamasaki, Yuka Aoyama, Junichi Kawasaki, Fumitoshi Kakiuchi, and Takuya Kochi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10804 • Publication Date (Web): 03 Dec 2015
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Journal of the American Chemical Society
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Chain Walking as a Strategy for Carbon–Carbon Bond For-
mation at Unreactive Sites in Organic Synthesis: Catalytic
Cycloisomerization of Various 1,n-Dienes
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Taro Hamasaki, Yuka Aoyama, Junichi Kawasaki, Fumitoshi Kakiuchi, and Takuya Kochi*
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yoko-
hama, Kanagawa 223-8522, Japan
ABSTRACT: Carbon–carbon bond formation at unreactive sp3-carbons in small organic molecules via chain walking was
achieved for the palladium-catalyzed cycloisomerization of 1,n-dienes. Various 1,n-dienes (n = 7-14) such as those contain-
ing cyclic alkenes, acyclic internal alkenes, and a trisubstituted alkene can be used for the chain-walking cycloisomeriza-
tion/hydrogenation process, and five-membered ring compounds including simple cyclopentane and pyrrolidine deriva-
tives can easily be prepared. Chain walking over a tertiary carbon was also found to be possible in the cycloisomerization.
It is not necessary for the linker portion of the diene to contain a quaternary center, and diene substrates with two alkene
moieties linked by a tertiary carbon or a nitrogen atom can also be used as substrates. Column chromatography using
silica gel containing silver nitrate was found to be effective for isolating some of the cycloisomerization products without
hydrogenation. Deuterium-labeling experiments provided direct evidence to show that the reaction proceeds via a chain-
walking
mechanism.
Figure 1. Strategies for Carbon–Carbon Bond Formation
Introduction
Carbon–carbon bond formation constitutes the most
crucial and fundamental processes in organic synthesis. In
general, these bonds are formed utilizing reactive func-
tional groups that have been preinstalled at bond-forming
sites of substrates (Figure 1a). In search of more efficient
processes, transition-metal-catalyzed direct functionaliza-
tion of unreactive carbon–hydrogen bonds, which are
ubiquitous in organic molecules, has attracted considera-
ble attention and are now used as powerful tools for car-
bon–carbon bond formation (Figure 1b). However, there
are still limitations in scope, particularly in terms of func-
tionalization of sp3-hybridized carbon–hydrogen bonds.1
In addition, site selectivity generally relies upon that of
carbon–hydrogen bond cleavage controlled by electronics,
sterics and/or directing groups.2
We envisioned that the use of chain walking may pro-
vide an alternative approach for functionalizing unreac-
tive sp3-hybridized carbon–hydrogen bonds (Figure 1c).
Chain walking, a frequently-used term in olefin polymeri-
zation, is a mechanism in which an alkylmetal species
undergoes a rapid β-hydride elimination and reinsertion
to change the position of the metal on the alkyl chain
without dissociation of the alkene during the process
(Scheme 1). The term, chain walking, has also been used
for
a
mechanism where both β-hydride elimina-
tion/reinsertion and alkene exchange rapidly occur, but
we only refer to the term as a mechanism in which alkene
exchange is much slower than β-hydride elimina-
tion/reinsertion, considering the mechanism for chain-
walking polymerization and what the term really repre-
sents.
Scheme 1. Mechanism of Chain Walking
Ever since the development of α-diimine palladium
catalysts by Brookhart and coworkers, olefin polymeriza-
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reported on the arylation of methyl groups at the γ- and
tion via chain walking has permitted a wide variety of
unique polymers to be produced.3 In order to obtain these
polymers, chain walking must occur rapidly and at the
same time, alkene exchange must be much slower than
polymer formation. For the case of α-diimine palladium
catalysts, alkene exchange is suppressed to a considerable
extent by the presence of large substituents on both sides
of the square planar palladium faces. Therefore, we specu-
lated that the use of the chain-walking process for organic
synthesis would be possible, if removal of the large sub-
stituents would accelerate alkene exchange, thus making
it faster than that of polymer formation. In many exam-
ples of chain-walking polymerization, bond formations
occurs between carbons at the alkene moieties and unac-
tivated terminal sp3-carbons of the substrates.3a,d-i These
results essentially indicate that chain walking may be
used to functionalize unactivated carbon–hydrogen bonds
by allowing catalysts to move around on the carbon
chains from distant alkene moieties of substrates.
δ-positions of α-amino esters.4d Although the product
yields were moderate, the palladium center had effective-
ly migrated from the α-position to the γ- or δ-position.
Under the conditions where efficient chain walking oc-
curs, bond-forming sites can be controlled by catalysts,
which are selective for preferable sites to form bonds by
moving around on substrates (Figure 1c), and this type of
reactions may be difficult in the absence of the chain-
walking mechanism. Therefore, we examined catalytic
carbon–carbon bond formation taking advantages of this
feature of the chain-walking mechanism.
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In order to examine the use of chain walking in organic
synthesis, the cycloisomerization of 1,n-dienes was chosen
as our target reaction,9 because dienes contain two al-
kene moieties and selective bond formation would be
very difficult if rapid alkene exchange were to occur to
isomerize both alkene moieties. The cycloisomerization of
1,5- or 1,6-dienes has been extensively studied using vari-
ous transition metal catalysts to form five-membered
rings.9a-e,g If it were possible to incorporate the chain-
walking mechanism into the reaction, dienes other than
1,5- or 1,6-dienes might also be transformed into five-
membered ring products. There have been only a few re-
ports on the cycloisomerization of 1,n-dienes to form five-
membered rings where n is larger than 6, such as 1,7- and
1,8-dienes,10 but carbon–carbon bonds were formed via
stepwise alkene isomerization pathways where both al-
kene isomerization and exchange occur rapidly in these
examples.
We reported on the palladium-catalyzed chain-walking
cycloisomerization of 1,n-dienes in a communication as a
demonstration of the use of the chain-walking process for
the synthesis of small organic molecules.11 In this commu-
nication, substrates were limited to those bearing cyclo-
hexene moieties, and isolating the cycloisomerization
products was difficult at this point. In addition, no direct
evidence to support the chain-walking mechanism was
provided.
Although the chain-walking mechanism has been in-
corporated into many olefin polymerization processes, its
use in organic synthesis has remained limited and inves-
tigations of carbon–carbon bond formation in small or-
ganic molecules are particularly rare.4 Long-distance al-
kene isomerization,5 which involves rapid alkene dissocia-
tion processes, has been reported by several researchers
such as Grotjahn5b and Mazet.5d Alkene isomerization
after carbon–carbon bond formation has also been used
in some catalytic reactions.6, 7 Ozawa, Kubo, and Hayashi
reported an asymmetric Mizoroki-Heck type reaction of
2,3-dihydrofuran, which proceeds via enantioselective
carbon–carbon bond formation, followed by selective al-
kene isomerization.6 The combination of carbon–carbon
bond formation/alkene isomerization has recently be-
come a powerful tool in asymmetric synthesis, largely
based on the efforts of Sigman and coworkers, and the
isomerization processes are considered to proceed via
chain-walking mechanisms, in which only slow alkene
exchange occurs.7
The use of the long-distance alkene isomerization to
form carbon–carbon bonds at unreactive sites has been
studied as well, but these reactions are often not regiose-
lective or only form new bonds on carbons where carbon–
carbon double bonds or metal–carbon bonds are relative-
ly stabilized (i.e. those bonds that are stabilized by func-
tional groups or the least hindered carbon–metal bonds).8
For example, alkylzirconocenes are known to isomerize
and eventually form zirconocenes bearing primary alkyl
groups, which can be used for further bond formation,
and mechanistic studies by Labinger, Bercaw, and
coworkers suggested that alkene exchange reaction oc-
curs rapidly during the isomerization process.8a Excellent
regioselectivity to functionalize terminal sp3-carbons has
also been achieved for catalytic carbonylations such as
hydroformylation8c and hydroesterification8d via alkene
isomerization. Ryu and coworkers developed enone isom-
erization/addition reactions, in which carbon–carbon
bond formation occurred selectively at the α-position of
the carbonyl groups.8b Baudoin and coworkers recently
Here we provide a the full account of the chain-walking
cycloisomerization of 1,n-dienes including (i) a vastly ex-
panded substrate scope, (ii) an efficient isolation tech-
nique for the cycloisomerization products without the
need for hydrogenation, and (iii) the results of deuterium-
labeling experiments which strongly suggest the presence
of the chain-walking process for this reaction.
Results and Discussion
1.
Chain-Walking
Cycloisomeriza-
tion/Hydrogenation of Various 1,n-Dienes. We previ-
ously reported on the chain-walking cycloisomerization
of 1,n-dienes using a 1,10-phenanthroline palladium cata-
lyst 212 as a communication in 2012.11 The reaction of 1,8-
diene 1a gave 3a as the major product in high yield along
with 4a and small amounts of other byproducts (eq 1).
The substrate scope was then examined using a hydro-
genation/cyclization protocol in order to estimate the
efficiency of the cyclization and to simplify the product
analysis (eq 2).
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when the reaction was conducted for 24 h using 5 mol %
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of 2, the corresponding five-membered ring product 5c
was obtained in 65% yield with a 98:2 diastereoselectivity
(eq 4). The structure and the stereochemistry of product
5c were determined by NMR analysis including a NOESY
experiment. The results showed that the chain-walking
process in this cycloisomerization can proceed over a ter-
tiary carbon.
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In the previous communication, only a limited class of
substrates, namely, 1,n-dienes bearing a cyclohexene and
a linear terminal alkene moiety was used for the reaction.
In this section, we describe a significantly expanded sub-
strate scope including more simple substrates than the
previous ones.
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1-3
Chain-Walking
Cycloisomeriza-
tion/Hydrogenation of 1,n-Dienes Containing an
Acyclic Internal Alkene Moiety. The cycloisomeriza-
tion was also investigated with 1,8-diene 1d, which has an
acyclic internal alkene and a terminal alkene moiety. The
reaction of 1d for 6 h gave a complex mixture of com-
pounds in which the yield of none of the products ap-
peared to exceed 50% by GC analysis. It turned out, how-
ever, that the hydrogenation of the crude mixture in the
presence of a catalytic amount of platinum oxide gave
cyclopentane derivative 5d in 91% GC yield with 98:2 dia-
stereoselectivity (eq 5). This result indicated that the
1-1
Chain-Walking
Cycloisomeriza-
tion/Hydrogenation of 1,n-Dienes Containing a Cy-
clopentene and a Linear Terminal Alkene Moiety.
The reaction of 1,8-diene 1b, which contains a cyclopen-
tene ring, was first investigated. When the cycloisomeri-
zation was performed for 24 h using 10 mol % of 2, five-
membered ring formation via chain walking proceeded to
give bicyclo[3.3.0]octane derivatives 5b and 5b’ in 66%
total yield with 96:4 diastereoselectivity (eq 3). The struc-
tures of the major product 5b and the minor product 5b’
were similar to those obtained by Curran’s radical cycliza-
tion of dimethyl (3-cyclopentenyl)iodomalonate with 1-
hexene,13 except that Curran’s products contained n-butyl
groups instead of n-propyl groups. A comparison of the 1H
NMR data suggested that our major product 5b and mi-
nor product 5b’ have the same stereochemistry as Cur-
ran’s minor and major products, respectively.
chain-walking cycloisomerization to form
a
five-
membered ring proceeds efficiently in the case of a diene
substrate bearing an acyclic internal alkene moiety, but
without a cycloalkene moiety in the substrate, significant
alkene isomerization occurs after cyclization resulting in
the formation of an alkene moiety with cis and trans ge-
ometries in many positions of the product. The 13C NMR
spectrum of 5d showed that there is only one signal corre-
sponding to a carbonyl carbon, which strongly suggests
that 5d has a C2-symmetric structure. A comparison of
the 1H NMR data of 5d with those of similar cyclopentane
derivatives which contain two methyl groups instead of n-
propyl groups14 also showed that the signals on the cyclo-
pentane ring of product 5d appeared much closer to those
of the C2-symmetric analog14a than those of the Cs-
symmetric compound.14b
1-2
Chain-Walking
Cycloisomeriza-
tion/Hydrogenation of a 1,8-Diene Containing a Cy-
clic Alkene and a Branched Terminal Alkene Moiety.
The reaction was examined with 1,8-diene 1c, containing a
branch close to the terminal alkene moiety. The cycloi-
somerization of 1c is not as efficient as that of 1a, but
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alkene moieties had no effect on the product yield, and
1
the reactions of 1,9-diene 1g and 1,10-diene 1h gave cyclo-
pentane derivatives 5g and 5h, respectively in 89% yield
(entries 3 and 4). Further extension of the linker to 1,14-
diene 1i, which requires chain walking over 8 carbons,
still did not reduce the yield significantly and product 5i
was obtained in 80% yield (entry 5). Diethyl malonate
derivative 1j provided product 5s in 83% yield (entry 6),
and di-tert-butyl malonate derivative 1k was converted to
cyclopentane derivative 5k in 68% yield when 5 mol % of
the palladium catalyst was used (entry 7). The reaction of
nitrogen-tethered substrate 1l under the standard reac-
tion conditions only gave a 6% yield of pyrrolidine deriva-
tive 5l (entry 8). The use of cyclohexene as an additive11
was found to be effective for acyclic substrate 1l. The reac-
tion in the presence of 20 equiv of cyclohexene improved
the yield to 26% (entry 9), and when 10 mol % of palladi-
um catalyst 2 was used, pyrrolidine derivative 5l was ob-
tained in 62% yield (entry 10).
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The cycloisomerization/hydrogenation was found to be
applicable to various 1,n-dienes containing a crotyl group
and the corresponding cyclopentane derivative was ob-
tained with a degree of high diastereoselectivity (Table 1).
The cycloisomerization was slower and the reaction time
was extended to 24 h for this class of substrates, probably
because some of the cyclization products contain a termi-
nal alkene moiety, which may competitively coordinate to
the metal center. The reaction of 1,7-diene 1e gave prod-
uct 5e in 77% yield (entry 1), and a higher yield of 91% was
obtained for the reaction of 1,8-diene 1f (entry 2). On the
other hand, a slight elongation of the linker between the
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cycloisomeriza- 1-5 Chain-Walking
Table
1.
Chain-walking
Cycloisomeriza-
1
2
3
tion/hydrogenation of various 1,n-dienes containing an
tion/Hydrogenation of a 1,n-Diene without a Qua-
ternary Carbon. The substrates used so far contained a
quaternary carbon or a trisubstituted nitrogen atom at
the linker portion of the two alkene moieties, which in-
hibit the metal center from walking from one alkene moi-
ety to the other. In order to test the possible applicability
of substrates without a quaternary carbon, the reaction of
1,8-diene 1n, which has only one methoxycarbonyl group
on the linker portion was examined. The cycloisomeriza-
tion of 1n was less efficient than 1d and 5 mol % of 2 was
needed, but after hydrogenation, cyclization product 5n
was obtained in 65% yield (eq 7). It is unclear whether the
lower efficiency was caused by the chain walking of the
metal center beyond the tertiary carbon or the lack of a
quaternary center which may facilitate the cyclization by
the Thorpe-Ingold effect, but these findings at least show
that the cycloisomerization does not require the presence
of a linker atom with no hydrogen atom.
acyclic internal alkene moietya
4
5
6
7
8
9
en-
try
1 (E:Z)
Product 5
yield d.r.
(%)b
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1
1e (82:18)
1f (82:18)
1g (84:16)
1h (80:20)
1i (82:18)
77
92:8
97:3
96:4
96:4
93:7
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3
4
5
91
89
89
80
6
1j (80:20)
1k (81:19)
83
68
95:5
96:4
7c
The reactivity of a substrate with two alkene moieties
connected by a methylene chain without any substituent
was also examined. The reaction of 1,14-diene 1o under
the standard cycloisomerization conditions did not give
any observable amounts of cyclization products and most
of substrate 1o was recovered. The stoichiometric reaction
of 1o with the palladium catalyst was then investigated.
The reaction of palladium complex 2 and NaBArf4 with 2
equiv of 1o for 3 h at rt, followed by washing with hexane,
provided π-allylpalladium complex 6, whose structural
assignments were supported by ESI-MS and NMR anal-
yses (eq 8).15 A similar reaction of 1o with 2 and NaBArf4 in
CDCl3 also showed the signals corresponding to complex
6. These results indicate that in the absence of any sub-
stituents on the linker portion, the palladium center rap-
idly migrates over to the other alkene moiety and forms a
π-allyl complex without closing a five-membered ring.
8
9d
1l (84:16)
1l (84:16)
6
26
62
97:3
97:3
97:3
10d,e 1l (84:16)
a
Reaction conditions: 1 (0.5 mmol), 2 (0.0125 mmol, 2.5
mol %), NaBArf4 (0.015 mmol, 3 mol %), DCE (25 mL), rt, 24
b
h. Combined yields of diastereomers, determined by GC
analysis. c Performed with 0.025 mmol (5 mol %) of 2 and 0.03
mmol (6 mol %) of NaBArf4. Performed in the presence of
d
20 equiv of cyclohexene. e Performed with 0.05 mmol (10 mol
%) of 2 and 0.06 mmol (12 mol %) of NaBArf4.
1-4
Chain-Walking
Cycloisomeriza-
tion/Hydrogenation of a 1,n-Diene Containing a Tri-
substituted Alkene Moiety. The applicability of 1,n-
dienes containing
a
1,2-disubstited alkene moiety
prompted us to investigate a substrate involving a trisub-
stituted alkene moiety. The reaction of 1,8-diene 1m,
which contains a prenyl group for 24 h under the stand-
ard reaction conditions proceeded efficiently, and gave
five-membered ring product 5m in 88% yield with excel-
lent diastereoselectivity (eq 6). A notable feature of this
reaction is that a facile placement of an isopropyl group
on the cyclopentane ring was achieved by the simple use
of a prenyl group.
2. Isolation of the Chain-Walking Cycloisomeriza-
tion Products. As described above, the reaction of 1a
provided the major product 3a in high yield but also pro-
duced small amounts of other isomerization products
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such as 4a, alkene isomerization products, diastereomers
of 3a, and other cyclization products (eq 9), and when we
published our initial communication, it was difficult to
separate 3a from the mixture in high yield by simple silica
gel column or size exclusion chromatography. In this sec-
tion, we describe an efficient isolation technique for the
isolation of the cycloisomerization products.
5
1f
50
97:3
1
2
3
4
5
6
7
(n = 8)
a Reaction conditions: 1 (0.5 mmol), 2 (0.0125 mmol, 2.5
mol %), NaBArf4 (0.015 mmol, 3 mol %), DCE (25 mL), rt. b
Combined yields of diastereomers.
The isolation of cycloisomerization products in high
yields was generally difficult in cases of the reactions of
substrates without a cycloalkane moiety. However, in the
case of the reaction of 1m, the alkene moiety of the prod-
uct had a high tendency to be formed at the terminus,
and cyclopentane derivative 3m, which contains an iso-
propenyl group on the ring, was produced in 58% yield
(eq 10).
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After an examination of available purification methods,
column chromatography using silica gel containing 25%
silver nitrate16 was found to be effective for the isolation
of cyclization product 3 (Table 2). When 1,8-diene 1a was
used as a substrate, the corresponding five-membered
ring product 3a was obtained in 78% yield as a 96:4 dia-
stereomeric mixture (entry 1). The reaction of 1,7-diene 1p
also gave the corresponding product 3p but the isolated
yield was lower than that of 3a (entry 2). The reactions of
1,9-diene 3q, 1,10-diene 3r, and 1,14-diene 3s also provided
cycloisomerization products having the same bicy-
cle[4.3.0]non-2-ene core structure as the major products,
but as the length of the linker between the two alkene
moieties became longer, the isolated yield gradually de-
creased, partly because the separation of 3 from other
isomers became more difficult (entries 3-5).
3. Mechanistic Considerations of the Chain-
Walking Cycloisomerization. In the previous commu-
nication on the cycloisomerization of 1,n-dienes, we pos-
tulated that the reaction proceeds via chain walking.
However, little mechanistic information was obtained at
that time. Monitoring of the reaction of 1a indicated that
3a was the primary product and 4a was formed later via
the isomerization of 3a (Table S3, entries 1-6 in the Sup-
porting Information). The effect of the addition of cyclo-
hexene to suppress the formation of 4a can also be ex-
plained by the proposed mechanism (Table S3, entries 7-
11). The reaction in the presence of 1,6-diene 1t also indi-
cated a strong possibility that the reaction proceeded via
a chain-walking mechanism (eq 11).11 However, no direct
evidence in favor of chain-walking mechanism in this
cycloisomerization was provided. In this section, we de-
scribe the results obtained from a deuterium-labeling
experiment and mechanistic considerations based on the
experimental results.
Table 2. Isolation of chain-walking cycloisomerization
products 3a
en-
try
1
Product 3
isolated d.r.
yield
(%)b
1
1a
78
56
63
56
96:4
97:3
97:3
97:3
(n = 2)
3-1 Experiments Using Deuterium-Containing Sub-
strate 1a-d2. The reaction was examined using 1,8-diene
1a-d2, which contains two deuterium atoms at the termi-
nal carbon of the vinyl group. The cycloisomerization of
1a-d2 proceeded similar to that of 1a under the standard
conditions, and after silver nitrate/silica gel column
chromatography, the major diastereomer of 3a-d2 was
isolated in 40% yield in pure form (eq 12). The areas of the
peaks in the ESI-MS spectrum of the isolated product 3a-
d2 were similar to those of substrate 1a-d2, suggesting that
2
3
4
1c
(n = 1)
1d
(n = 3)
1e
(n = 4)
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no significant intermolecular H/D exchange had occurred
304.2
1%
2%
305.2
82%
77%
306.2
15%
16%
307.2
2%
4%
1
2
3
4
5
6
7
8
during the reaction, and most of the product molecules
retained two deuterium atoms located at the terminal
vinyl carbon (Figure 2 and Table 3). However, the NMR
spectra of 3a-d2 indicated that some of the deuterium
atoms had migrated to other positions in the product
molecule. The 1H NMR spectrum of 3a-d2 showed that the
terminal methyl group contained only 1.8 protons mean-
ing about 40% of the deuterium atoms at the terminal
1
2
1a-d2
3a-d2
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12
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Figure 3. 2H{1H} NMR spectrum of 3a-d2
(a)
(b)
Figure 4. DEPT90 spectrum of 3a-d2
The results of these deuterium-labeling experiments
provided important insights into the mechanism of the
cycloisomerization. Deuterium atoms at the terminal car-
bon can migrate to other positions via chain walking, but
the mechanism is somewhat complicated depending on
the position to which deuterium atoms migrate. Moving
the deuterium from position a to position b is relatively
facile as depicted in Scheme 2. Agostic intermediate A has
a palladium center at position b and β–deuteride elimina-
tion gives deuterido alkene complex B. Insertion of the
alkene into the Pd–D bond provides either the original
alkyl complex A or primary alkyl complex C, in which a
deuterium atom has migrated from position a to position
b. In order to move the palladium back from position a to
position b with keeping the deuterium at position b, bond
rotation to form another agnostic intermediate D is nec-
essary, and β-hydride elimination from D, followed by
reinsertion, gave secondary alkyl palladium complex F,
which has the same structure as A except that a deuteri-
um atom at position a and the hydrogen atom at position
b are exchanged with each other.
Figure 2. ESI-MS spectra of (a) 1a-d2 and (b) 3a-d2
carbon had been exchanged with hydrogens. The 2H NMR
spectra also suggested that there were observable
amounts of deuterium atoms on the three carbons (la-
beled b,c,d in Figure 3) next to the terminal methyl
groups. The presence of deuterium atoms on carbons at
a-c were also confirmed by the 13C NMR spectrum com-
bined with the DEPT90 spectrum, which showed 1:1:1 tri-
plet (CHDR2) signals corresponding to the carbons at po-
sitions b and c (Figure 4).
Table 3. ESI-MS area ratios of 1a-d2 and 3a-d2
entry compound
ESI-MS area ratios
m/z = m/z =
m/z =
m/z =
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verted to anti-L via a similar process, but this reaction
1
2
3
4
5
6
7
8
Scheme 2. Possible Mechanisms of H/D Exchange
between Positions a and b via Chain Walking
also involves both cis-H and trans-K, which means that
the formation of both trans and cis alkene intermediates
must occur. Therefore, the deuterium incorporation at
position c essentially shows that the chain-walking pro-
cess in this reaction proceeds through both trans and cis
alkene intermediates.
The results of the deuterium-labeling experiment also
revealed that the H/D exchange only occurred at posi-
tions a-d and the deuterium atoms did not spread out to
the cyclohexene ring, which is consistent with the propo-
sition that the reaction proceeds via a chain-walking
mechanism and not via a stepwise isomerization process.
The fact that the levels of deuterium incorporation dimin-
ished with distance from the original position a indicates
that chain walking does not occur at the level where the
H/D exchange reaches an equilibrium but only to some
extent and the desired alkene insertion can compete with
the chain-walking process.
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Deuterium incorporation at position c can be achieved
by a similar process to that shown in Scheme 3, but the
situation becomes slightly more complicated. Intermedi-
ate F is first converted to either anti- or syn-G by ex-
changing the hydrogen interacting with the metal from
the one at position a to one of the two hydrogens at posi-
tion c. β-Hydride elimination from anti-G forms interme-
diate trans-H which contains a trans alkene which
should be more stable than a cis alkene, and reinsertion
of the trans alkene in the opposite direction may provide
anti-I to place the metal at position c. In order to move
the deuterium atom from position b to position c, bond
rotation to form agostic intermediate syn-J is necessary.
Intermediate syn-J can be transformed into syn-L by β-
hydride elimination and reinsertion, but the reaction
must proceed through cis-K, which has a
3-2 A Proposed Mechanism for the Chain-Walking
Cycloisomerization of 1a. The proposed mechanism for
the formation of 3a is shown in Figure 5. The catalyst first
reacts with the terminal alkene moiety of diene 1a be-
cause it is smaller than the other alkene moiety, and hy-
drometalation results in the formation of an alkylpalladi-
um species. Chain walking of the alkylpalladium interme-
diate along the alkyl chain eventually makes it possible
for the other alkene moiety to coordinate to the metal
and easily be inserted into the palladium–carbon bond. In
this reaction, five-membered ring formation to place the
hydrogens around the newly formed carbon–carbon bond
in the anti orientation may be sufficiently favorable to
permit the reaction to proceed. After the ring formation,
syn β-hydride elimination occurs to form the primary
product 3a. While there is a sufficient amount of 1a, the
small terminal alkene moiety of 1a most frequently coor-
dinates to the catalyst to drive 3a out of the catalyst via an
associative exchange mechanism.12b
Scheme 3. Possible Mechanisms of H/D Exchange
between Positions b and c from Intermediate F via
Chain Walking (R = CH2R')
relatively unstable cis alkene structure. Therefore the
H/D exchange process from anti-G to syn-L needs to
proceed through both trans and cis alkene intermediates.
The other agostic intermediate syn-G can also be con-
Figure 5. A Proposed Mechanism for the Chain-Walking
Cycloisomerization of 1,8-Diene 1a.
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Chain-walking isomerization of alkylpalladium species
1
2
3
4
5
6
7
8
may not seem to be a facile process, but Brookhart and
coworkers conducted detailed experimental mechanistic
studies on the chain-walking isomerization of a butylpal-
ladium species bearing an α-diimine ligand and the re-
sults showed that less than 10 kcal/mol is required for the
reaction to proceed.17a Theoretical studies were also con-
ducted for the isomerization of the alkylpalladium species
via β-hydride elimination and reinsertion. For example,
Morokuma and coworkers theoretically studied the isom-
erization of an iso-propylpalladium complex possessing
an unsubstituted diimine ligand to an n-propyl complex
and reported that the energy barrier for this process was
6.9 kcal/mol.17b
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4. Synthesis of Prostane. One of the advantages of the
chain-walking cycloisomerization of 1,n-dienes is that two
different alkyl groups other than methyl groups can be
placed stereoselectively at two adjacent carbons in the
cyclopentane ring. In principle, the formation of similar
structures by the standard cycloisomerization of 1,6-
dienes may be achieved by the use of substrates pos-
sessing two internal alkene moieties, but few methods
have been reported for the corresponding transformation
in which only a limited number of substrates are used.18
Therefore, the cycloisomerization/hydrogenation pro-
tocol was applied to the first synthesis of prostane, which
is the basic framework of prostaglandins (Scheme 4). The
cycloisomerization of 1,12-diene 7 proceeded efficiently
and after hydrogenation using platinum oxide, cyclopen-
tane derivative 8 was isolated in 57% yield in 2 steps.
Treatment of 8 with sodium hydroxide in ethanol/water
hydrolyzed the ester moieties to give dicarboxylic acid 9
in 95% yield. Decarboxylation of 9 to form a monocarbox-
ylic acid, followed by Barton decarboxylation provided
prostane 10 in 61% yield.
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Asahi Glass Foundation. T. H. is grateful to the Japan Society
for the Promotion of Science (JSPS) for a Research Fellowship
for Young Scientists.
Scheme 4. Synthesis of prostane
1
2
3
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Conclusions
We achieved the synthesis of small organic molecules
via catalytic carbon–carbon bond formation reactions that
involve a chain walking mechanism. Palladium-catalyzed
cycloisomerization was found to be applicable to various
1,n-dienes from 1,7- to 1,14-dienes using the chain-walking
mechanism to move the palladium center to the position
where the carbopalladation of the other alkene forms a
five-membered ring. The applicable substrates were not
limited to those having a cyclohexene ring, but a wide
variety of 1,n-dienes such as those containing (i) a cyclo-
pentene ring, (ii) an acyclic 1,2-disubsituted alkene, and
(iii) a trisubstituted alkenes. Chain walking over a tertiary
carbon was found to be possible in the cycloisomerization
reaction. A diene substrate with two alkene moieties
linked by a tertiary carbon can also be used as a substrate.
The results of a deuterium-labeling experiment provided
direct evidence that the reaction proceeds via a chain-
walking mechanism.
We believe the chain-walking strategy provides a new
route to the construction of carbon–carbon bonds as de-
scribed in Figure 1, and further extensions of this strategy
including more innovative cycloisomerization and com-
binations of the chain-walking cyclization with other
types of reactions are currently under way.
ASSOCIATED CONTENT
Supporting Information. Full experimental details and
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kochi@chem.keio.ac.jp
ACKNOWLEDGMENT
This work was supported, in part, by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and grants from Keio
Leading-edge Laboratory of Science and Technology and the
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