Cobalt-Catalyzed Regioselective Olefin Isomerization under Kinetic Control

Article abstract of DOI:10.1021/jacs.8b01815

Olefin isomerization is a significant transformation in organic synthesis, which provides a convenient synthetic route for internal olefins and remote functionalization processes. The selectivity of an olefin isomerization process is often thermodynamically controlled. Thus, to achieve selectivity under kinetic control is very challenging. Herein, we report a novel cobalt-catalyzed regioselective olefin isomerization reaction. By taking the advantage of fine-tunable NNP-pincer ligand structures, this catalytic system features high kinetic control of regioselectivity. This mild catalytic system enables the isomerization of 1,1-disubstituted olefins bearing a wide range of functional groups in excellent yields and regioselectivity. The synthetic utility of this transformation was highlighted by the highly selective preparation of a key intermediate for the total synthesis of minfiensine. Moreover, a new strategy was developed to realize the selective monoisomerization of 1-alkenes to 2-alkenes dictated by installing substituents on the γ-position of the double bonds. Mechanistic studies supported that the in situ generated Co-H species underwent migratory insertion of double bond/β-H elimination sequence to afford the isomerization product. The less hindered olefin products were always preferred in this cobalt-catalyzed olefin isomerization due to an effective ligand control of the regioselectivity for the β-H elimination step.

Full text of DOI:10.1021/jacs.8b01815

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Article
Cobalt-Catalyzed Regioselective Olefin Isomerization Under Kinetic Control
Xufang Liu, Wei Zhang, Yujie Wang, Ze-Xin Zhang, Lei Jiao, and Qiang Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01815 • Publication Date (Web): 21 May 2018
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Cobalt-Catalyzed Regioselective Olefin Isomerization Under Kinetic
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Xufang Liu, Wei Zhang, Yujie Wang, Ze-Xin Zhang, Lei Jiao* and Qiang Liu*
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, China.
ABSTRACT: Olefin isomerization is a significant transformation in organic synthesis, which provides a convenient syn-
thetic route for internal olefins and remote functionalization processes. The selectivity of an olefin isomerization process
is often thermodynamically controlled. Thus, to achieve selectivity under kinetic control is very challenging. Herein, we
report a novel cobalt-catalyzed regioselective olefin isomerization reaction. By taking the advantage of fine-tunable NNP-
pincer ligand structures, this catalytic system features high kinetic control of regioselectivity. This mild catalytic system
enables the isomerization of 1,1-disubstituted olefins bearing a wide range of functional groups in excellent yields and re-
gioselectivity. The synthetic utility of this transformation was highlighted by the highly selective preparation of a key in-
termediate for the total synthesis of minfiensine. Moreover, a new strategy was developed to realize the selective monoi-
somerization of 1-alkenes to 2-alkenes dictated by installing substituents on the γ-position of the double bonds. Mecha-
nistic studies supported that the in-situ generated Co-H species underwent migratory insertion of double bond/β-H elim-
ination sequence to afford the isomerization product. The less hindered olefin products were always preferred in this co-
balt-catalyzed olefin isomerization due to an effective ligand control of the regioselectivity for the β-H elimination step.
isomerization. Notably, a number of effective transition-
metal catalysts have been developed for this selective
INTRODUCTION
Olefin isomerization is an atom-economical and syn-
thetically useful transformation.1 Two prominent features
of this reaction are: (1) convenient synthesis of internal
olefins via the isomerization of easily accessible terminal
alkenes2 (e.g. introducing an alkenyl group via isomeriza-
tion of an allyl group); and (2) remote functionalization of
the original C=C double bond, which is driven by a ther-
modynamically favored termination step.3 As shown in
Figure 1a, olefin isomerizations are thermodynamically
driven to produce more stable alkene isomers. Although a
wide range of efficient olefin isomerization reactions have
been developed, the selectivity control of this process is
still challenging. When the more stable isomerized olefin
is the desired product, it is less problematic due to the
easily accessible selectivity under thermodynamic control.
For example, the isomerization of alkenyl alcohols to car-
bonyl compounds is a thermodynamically driven chain-
walking process of double bonds (Figure 1b).3f,3j,4 Thus, as
long as the chain walking process is fast and reversible,
the most stable carbonyl product will dominate the prod-
uct distribution. In case the desired isomerization prod-
uct is not the most stable isomer, to control the regiose-
lectivity becomes rather challenging.5 A typical example is
the selective monoisomerization of 1-alkenes to 2-alkenes
(Figure 1c). It is difficult to avoid overisomerization to
generate other isomers with similar stability.6 To achieve
the desired selectivity, the catalysts utilized in such reac-
tions should well distinguish the different reactivity be-
tween 1-alkenes and 2-alkenes leading to a smaller activa-
tion energy barrier ΔG≠ compared with ΔG≠ for over-
monoisomerization process, which represents an attrac-
tive route to 2-alkenes from readily available 1-alkenes.7
From a synthetic point of view, other regioselective olefin
isomerizations under kinetic control would also be highly
desired because the target products for isomerization
reactions may be thermodynamically disfavored com-
pared with other possible isomerized products.
Figure 1. Typical energy profiles for the olefin isomeri-
zation reactions.
A representative case is the selective isomerization of
1,1-disubstituted olefins to afford the less hindered double
1
2
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bond shifted products (Figure 1d). In this case, the double methods for olefin isomerization, this system achieves
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bond migration process of substrate S has essentially two
unpredictable directions, and the desired product P1 may
further isomerize to the other isomer P2 with similar sta-
bility. As a result, the control of regioselectivity is very
demanding. To achieve a high regioselectivity, it is neces-
sary that the catalyst have a means to precisely differenti-
ate the steric hindrance of positions a and b on the sub-
strate S, which will require a kinetically-controlled sce-
nario. In this scenario, the isomerization process ought to
effective kinetic control of the isomerization process via
the repulsion interaction between the bulky substituents
on the substrates and the ligand spheres of catalysts. This
effect ensures the isomerization occurs only on the less
sterically hindered site. The catalytic system works well
not only for the regioselective isomerization of 1,1-
disubstituted olefins, but also for the selective monoi-
somerization of terminal olefins with a blocking substitu-
ent at the γ-position of the C=C bond. These cobalt-based
catalysts enable steric-selective shift of the C=C bond and
enrich the selectivity mode of catalytic olefin isomeriza-
tion.
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be irreversible, and the energy barrier ΔG≠ for the for-
2
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mation of desired isomer P1 is smaller than both ΔG≠ and
1
ΔG≠ . To date this type of olefin isomerization reaction
3
has not been studied in detail, and an efficient catalytic
system is still missing from the repertoire that could pro-
vide effective kinetic control of regioselectivity for olefin
isomerizations.
RESULTS AND DISCUSSION
In the total synthesis of minfinsine, we planned to ob-
tain olefin 2a by isomerizing exocyclic olefin 1a. Unfortu-
nately, the major product was undesired regioisomer 3a
under the classic acid promoted olefin isomerization.8
Independent isomerization experiment of isolated 2a un-
der identical conditions afforded the same product distri-
bution with a ratio of 1:2.2 for 2a/3a (Eq 1). These results
demonstrated that under Brønsted acid-catalyzed condi-
tions, the olefin isomerization is under thermodynamic
control, and the desired isomer 2a is thermodynamically
disfavored (DFT calculation confirmed that 2a is less sta-
ble than 3a by 0.5 kcal/mol in terms of Gibbs free energy).
This problem motivated us to develop a kinetically con-
trolled olefin isomerization via cobalt catalysis to access
the desired but less stable product 2a in a high regioselec-
tivity.
In fact, such an olefin isomerization is of potential syn-
thetic value, in particular in natural product synthesis. In
a recent synthesis of an indole alkaloid nature product,
minfiensine, accomplished by one of our groups, the regi-
oselective isomerization of the exocyclic olefin 1a stood
out as a key step for the originally designed late-stage
oxidation strategy (Scheme 1).8 It perfectly represents the
reaction scenario in Figure 1d involving two possible reac-
tion sites a and b with different steric hindrance. Howev-
er, the undesired regioisomer 3a was thermodynamically
more stable and thus isomerization to 3a dominated the
reaction under classic acidic conditions for olefin isomer-
ization. The lack of efficient olefin isomerization catalysts
that could selectively deliver the desired isomer 2a ham-
pered our original synthetic plan. This showcase example
prompted us to systematically study olefin isomerization
under kinetic control and therefore to develop an efficient
and selective catalytic system based on our experience in
the development of pincer cobalt catalysts.9
Scheme 1. A Synthetically Useful Olefin Isomeriza-
tion.
Catalyst Screening
We commenced this study by investigating the catalytic
activities of a series of cobalt complexes developed by us9
in the olefin isomerization of 1a (Table 1). These reactions
were performed in the presence of 1 mol% cobalt catalyst
and 10 mol% of ammonia borane as the additive in meth-
anol. Cobalt catalysts I and II supported by P-tertbutyl
and P-isopropyl PNP ligands displayed no reactivity (en-
tries 1 and 2). We envisioned that a modification from
PNP to NNP pincer ligands would give rise to hemilabile
cobalt catalysts, which may facilitate the isomerization
process, owing to the fact that the pyridine coordination
site would create a less sterically hindered metal center to
promote its interaction with the olefin substrate. Interest-
ingly, these NNP pincer cobalt catalysts III-VI indeed
exhibited much higher activity (entries 3-6). The P-
tertbutyl NNP ligand gave better conversion and yield
compared with the results of P-isopropyl and P-phenyl
NNP ligands. Moreover, the 5,6 NNP cobalt catalysts VII
and VIII with an enlarged metallacycle were more effec-
tive, leading to a higher regioselectivity of 2a (up to 17:1).
Herein, we report a series of cobalt pincer complexes
with well-defined structures as effective catalysts to real-
ize olefin isomerizations under kinetic control in excellent
regioselectivity. Distinguishing itself from other reported
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c
Specifically, 93% isolated yield of 2a was obtained using
bThe ratio of 2a : 3a were determined by H NMR. NMR
yields. dReaction time was 1 h. Isolated yield was shown.
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5
6
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8
cobalt catalyst VIII (entry 9). There was no reaction using
bulkier ortho-Me substituted 5,6 NNP cobalt catalyst IX,
whereas it shows high reactivity for other more reactive
olefin substrates (Scheme 6). A change of counterion of
the cobalt complexes from chloride to iodide resulted in
similar yield and regioselectivity for 2a (entry 11). Catalyst
with an imine donor, complex XI, led to higher regiose-
lectivity but lower conversion compared with the result of
the corresponding catalyst III, which is supported by an
amine ligand (entry 12). N-methyl-substituted catalyst XII
resulted in much lower conversion, albeit with a ratio of
2a:3a up to 23:1. These results revealed the crucial role of
catalyst structures in controlling of regioselectivity.
To make a comparison with other known catalysts for
olefin isomerization, we tested 10 reported catalytic sys-
tems based on different transition metals, including
Pd,3f,7g, Rh,2c Ru,3j,10 Ir,4 Fe2e,7f and Co7b,11, for the isomeriza-
tion reaction of 1a (Table 2). The optimized reaction con-
ditions reported in the literatures were directly applied
without modification.12 Among these known isomeriza-
tion catalysts, only the Co(SaltBu,tBu)Cl/silane catalytic
system reported by the Shenvi group11 was active enough
to give high conversion. However, even in that system,
only 67% selectivity for 2a was achieved (entry 9). Other
tested catalysts provided much lower conversion and se-
lectivity. This comparison highlighted the unique ad-
vantage of our pincer cobalt catalysts for this regioselec-
tive olefin isomerization reaction.
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Table 1. Pincer Cobalt Complexes Catalyzed Olefin Isom-
erization Reaction of 1a.a
Me
Me
1 mol% [Co]
10 mol% NH3BH3
Table 2. Performance of Representative Known Catalysis
Systems in Olefin Isomerization Reaction of 1a.a
+
N
MeOH, RT, 30 min
N
N
N
H
N
N
H
H
MeO2C
MeO2C
MeO2C
Me
Me
1a
2a
3a
Cat.
c
+
entry
1
[Co]
conv.
1a
[%]
2a : 3ab
yield
2a
[%]
N
N
N
N
N
N
H
H
H
MeO2C
MeO2C
MeO2C
I
0
-
0
1a
2a
3a
2
3
II
0
-
0
entry
1
standard conditions
1a : 2a : 3a
ref.
7g
III
98
8 : 1
87
1 mol% Pd(dba)2,1 mol% P(tBu)3,
4
5
IV
V
71
30
99
99
96
99
0
11 : 1
13 : 1
6 : 1
8 : 1
17 : 1
17 : 1
-
65
24
83
88
90
93
0
100 : 0 : 0
i
1 mol% PrCOCl, Toluene, 80 °C, 24 h
5 mol% Mazet's Catalyst, 5.5 mol% NaBArF,
50 mol% cyclohexene, DCE, 85 °C, 18 h
2
3
86 : 8 : 5
3f
6
VI
7
VII
VIII
VIII
IX
5 mol% [Rh(CO)2Cl]2,
12 mol% dppm, DCE, 75 °C, 24 h
100 : 0 : 0
2c
8
5 mol% Crabtree's catalyst,
H2 (1 min) then degassed, THF, RT, 4 h
9d
10
11
12
13
4
5
6
100 : 0 : 0
72 : 26 : 3
100 : 0 : 0
4
2 mol% Grotjahn's catalyst,
Acetone, RT, 15 h
3j
X
91
10 : 1
82
10 mol% Grubbs II catalyst,
MeOH, 60 °C, 3 h
XI
86
42
15 : 1
23 : 1
79
39
10
2e
7f
XII
5 mol% Fe(acac)3,
50 mol% PhMgBr, THF, RT, 15 h
7b
8
1 mol% Fe3(CO)12
,
H
N
H
N
H
N
100 : 0 : 0
0 : 2 : 1
KOH/H2O, Diglyme, 80 °C, 15 h
tBu
2P
iPr
2P
Co
Cl Cl
Co-I
PiPr2
Co PtBu2
N
Co PtBu2
10 mol% CoIII(Salen)Cl,
9
7b
11
Cl Cl
Cl Cl
Co-II
20 mol% PhSiH3, PhH, RT, 24 h
Co-III
10 mol% CoBr2(BDPP)
20 mol% ZnI2, 20 mol% Zn
5 mol% Ph2PH, DCM, RT
H
N
H
N
10
100 : 0 : 0
H
N
N
5
5
5
5
5
5
N
Co PiPr2
N
Co PPh2
N
Co PtBu2
Cp
Cl Cl
Co-IV
Cl Cl
Co-V
Cl Cl
Co-VI
PF6
Cy3P
Cy
Cy
Cy
Ru
H3CCN
N
P
P
Ir
P
N
Cy
N
Pd
H
N
H
N
H
N
Me
Cl
5
6
5
6
5
6
Co PiPr2
N
Co PtBu2
N
Co PtBu2
N
Cl Cl
Cl Cl
Cl
Cl
Mazet's catalyst
Crabtree's catalyst
Grotjahn's catalyst
Me
Co-VII
Co-VIII
Co-IX
Me
H
N
N
N
Mes
Mes
Ph
N
N
N
O
N
O
Cl
N
Co PtBu2
Ph2P
PPh2
N
Co PtBu2
N
Co PtBu2
Co
Cl
Co
Ru
Cl Cl
I
I
tBu
tBu
Cl Cl
Co-XII
Cl
Br Br
PCy3
Co-X
Co-XI
tBu
tBu
CoIII(Salen)Cl
aReaction conditions: 1a (0.05 mmol), NH3BH3 (5*10-3
Grubbs II catalyst
CoBr2(BDPP)
mmol) and Co catalyst (5*10-4 mmol) in 0.5 mL of MeOH.
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b
aThe ratio of 1a : 2a : 3a were determined by H NMR. A
complicated reaction mixture was generated with full
conversion of 1a.
products homoallylic ether 2t, allylic amine 2u and ,
1
2
3
4
5
6
7
8
unsaturated ester 2v in over 90% yields, albeit the E/Z
ratio of the internal olefin products could not be com-
pletely controlled. Remarkably, the thermodynamically
more stable isomerization products, vinyl ether and
enamine, were not observed in these transformations.
These above results highlighted the superior performance
of these pincer cobalt catalysts in accomplishing a precise
regioselectivity control, which also revealed the pivotal
role of steric factor, rather than the thermodynamic sta-
bility, in such olefin isomerizations.
Substrate Scope
Furthermore, the isomerization of other tetracyclic ole-
fin substrates 1b and 1c with different N-protecting
groups were also investigated under the optimized condi-
tions (Scheme 2). Different N-substituents and free amine
functionality on the substrates afforded similarly good
regioselectivity and yields for the desired less bulky olefin
product 2.
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Scheme 3. Substrate Scope for the Regioselective Ole-
fin Isomerization of 1.a
Scheme 2. Co-Catalyzed Regioselective Isomerization
of Tetracyclic Olefin 1.a
2 mol% [Co]
10 mol% NH3BH3
R
R
R
MeOH, RT, 3 h
1
2
3
CO2Et
CO2Et
CO2Et
Ph
CO2Et
2e
2d
99% (8 : 1)d
2f
97% (10 : 1)d
18% (2 : 1)b
98% (26 : 1)d
Boc
Ph
Ph
N
H
2g
2h
2i
99% (37 : 1)e
96% (1 : 1)b
97% (40 : 1)e
87% (2 : 1)b
99% (> 99 : 1)e
aReaction conditions: 0.05 mmol substrate, 1 mol% Co-
VIII, 10 mol% H3NBH3, 0.5 mL MeOH, at RT for 1 h. Iso-
lated yields of 2 were shown. NMR yield. 5 mol% Co-
VIII was used.
b
c
OTBS
SPh
Br
2j
99% (> 99 : 1)e
2k
2l
99% (> 99 : 1)f
97% (> 99 : 1)g
To demonstrate the generality of this regioselective ole-
fin isomerization reaction, we firstly prepared a variety of
β-substituted exocyclic olefin substrates 1 with different
ring size. The regioselective isomerization of exocyclic
olefins 1 were then systematically studied (Scheme 3).
Delightfully, the reactions of six-membered ring sub-
strates gave excellent yields of desired olefin products 2 in
high regioselectivity (2d-2m). It was found that the more
sterically hindered substituent on β-position of the dou-
ble bond gave rise to a larger ratio of 2:3 (2d-2h). Moreo-
ver, a wide range of functional groups including, ester,
amide, silyl ether, thio ether, bromo, hydroxyl, and
amine, were well tolerated. The olefin substrates with
seven- or eight-membered ring 1o-1s resulted in similarly
remarkable yields and regioselectivity. The exocyclic ole-
fin 1n bearing an additional substituent at the α-position
of the double bond was also a suitable substrate for this
transformation, which afforded a single isomer 2n in 90%
isolated yield. In contrast, much worse regioselectivity
(2:3 = 2:1 or 1:1) was obtained under classic acid promoted
olefin isomerization conditions for the reaction of 1e, 1g,
1h and 1m, clearly revealing that the cobalt-catalyzed ole-
fin isomerization was under kinetic control. Notably, the
isomerization of 1,1-disubstituted acyclic olefin substrates
1t, 1u and 1v proceeded in high regioselectivity as well.
These reactions led to the formation of less bulky olefin
CO2Et
OH
CO2Et
2n
2m
95% (> 99 : 1)g
50% (2 : 1)b
90% (> 99 : 1)g
OTBS
OH
CO2Et
CO2Et
2o
97% (9 : 1)h
2p
94% (> 99 : 1)g
2q
94% (> 99 : 1)i
OTBS
CO2Et
CO2Et
2r
97% (12 : 1)i
2s
99% (> 99 : 1)i
Ph
Ph
CO2Et
CO2Et
Si Ph
N
O
Ph
2t
97% (6 : 1)c, h
2u
90% (> 99 : 1)c, j
2v
93% (5 : 1)c, k
a>97% Conversions were achieved for all reactions. Isolat-
ed yields for a mixture of 2 and 3 were shown. The ratio of
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2:3 were determined by H NMR and shown in the paren-
Scheme 5. Derivatization of Testosterone.
b
1
2
3
4
5
6
7
8
theses. The yield and regioselectivity for olefin isomeri-
zation promoted by TsOH were shown in red. E/Z selec-
tivity for 2t, 2u and 2v was 2:1, 3:1 and 3:1, respectively.
dCo-VII was used. e1 mol% Co-IV was used. f5 mol% Co-IV
was used and the reaction temperature was 50 C. A se-
OH
OH
c
Pd/C
H
H
limonene
H
H
H
H
o
O
O
Testosterone
38%
cond portion of Co-IV (5 mol%) and NH3BH3 (10 mol%)
were added into the reaction system after 3 h and the re-
OH
g
4 mol% Co-IV
20 mol% H3NBH3
action was conducted for another 3 h. Co-IV was used
H
PPh3-CH3 Br
KOtBu
and the reaction temperature was 50 oC. hCo-VIII was
9
MeOH, RT 3 h
H
H
used. iCo-IV was used. 0.5 mol% Co-IV was used and the
j
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o
k
1z 69%
reaction temperature was 50 C. 2 mol% Co-VI was used
and the reaction temperature was 50 oC.
OH
OH
H
H
The cobalt-catalyzed isomerization of γ-substituted ex-
ocyclic olefin 1w-1y were also investigated (Scheme 4).
Remarkably, the double bonds selectively monoisomer-
ized to afford the desired isomers 2w-2y in over 90% iso-
lated yields. The double bond migration to the conjugated
positions of 4-Ph, 4-CO2Et and 4-NHBoc groups did not
happen for all these reactions, although the correspond-
ing conjugated olefin isomers are thermodynamically
more stable. It indicated that this Co-catalyzed highly
regioselective isomerization of γ-substituted exocyclic
olefin was also under kinetic control.
H
H
H
H
2z
3z
87% yield for (2z/3z), 2z : 3z = 3 : 1
Designed Strategy for Monoisomerization
Selective monoisomerization of 1-alkenes to 2-alkenes is
also a challenging kinetically controlled transformation as
shown in Figure 1c. According to those informative re-
sults discussed above, we designed a new strategy for mo-
noisomerization of 1-alkenes (Scheme 6). Knowing the
fact that the substituent on β-positon of the double bond
could effectively inhibit the olefin migration to the more
sterically hindered side of the 1,1-disubstituted olefins, we
expect to turn off the isomerization process by simply
installing a substituent R on the β-position of 1-alkene
(Scheme 6, eq. 2). In contrast, selective monoisomeriza-
tion of 1-alkenes to 2-alkenes could be turned on when an
R group is installed at the γ position of double bond
(Scheme 6, eq. 3). In this case, the R group would be in
the β-position of the resulting monoisomerized product
2-alkene, which would prevent further olefin migration to
other internal positions. To verify this hypothesis, a series
of control experiments were implemented. In fact, this
cobalt catalytic system was effective for the chain walking
reaction of 6-phenyl-1-hexene 4a, affording the most sta-
ble conjugated olefin product 5a in 78% yield and 100%
conversion, in which other olefin isomers were also pro-
duced (Scheme 6, eq. 1). However, much lower conversion
was indeed obtained under the same reaction conditions
for the isomerization of β-siloxy-1-alkene 6 along with the
generation of reduced alkane product (Scheme 6, eq. 2).
Furthermore, the monoisomerization of γ-substituted 1-
alkenes was investigated. Compound 8a, γ-Hydroxyl-7-
phenyl-1-heptene, was selected as the model substrate for
the monoisomerization reaction. Normally this com-
pound can be easily converted into the more stable isom-
erized ketone product since the hydroxyl group is an effi-
cient directing group for chain walking reaction. After a
systematic survey of pincer cobalt catalysts, we found that
the selectivity of this reaction was enhanced by increasing
the steric hindrance of the ligand and the most bulky cat-
alyst IX gave the best result (94% isolated yield) for the
monoisomerized 2-alkene 9a. It is noteworthy that other
isomerization products were not observed under these
Scheme 4. Olefin Isomerization of para-Substituted
Exocyclic Olefin Substrates 1.a
1 mol% [Co]-III
10 mol% NH3-BH3
R
R
MeOH, RT, 0.5 h
1
2
HN
Boc
Ph
Ph
EtO2C
2w
2x
2y
91%b
94%
99%
HN
Boc
EtO2C
3w
3x
3y
not observed
aReaction conditions: 0.5 mmol substrate, 1 mol% Co-III,
10 mol% NH3BH3 in 2 mL of MeOH at RT for 0.5 h. b0.5
mol% Co-III and 5 mol% NH3BH3 were used.
To further demonstrate the synthetic utility of this re-
gioselective olefin isomerization reaction, we performed a
derivatization of a steroid hormone, testosterone (Scheme
5). A functionalized exocyclic olefin 1z could be easily
prepared from testosterone in two steps, including a Pd-
catalyzed transfer hydrogenation and a Wittig reaction
step. The regioselective olefin isomerization of 1z could
be achieved with full conversion in the presence of 4
mol% of cobalt catalyst IV. 87% isolated yield for a mix-
ture of isomerized products 2z and 3z was attained in 3:1
regioselectivity. The isolation of the major product 2z in
high purity could be realized by preparative HPLC.
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reaction conditions. These results implied that the R
disubstituted double bond to form a thermodynamically
more stable product.13
1
2
3
group could indeed act as a switch to control the process
of 1-alkene isomerization with the assistance of cobalt
catalysts.
Scheme 7. Cobalt-Catalyzed Monoisomerization of γ-
Substituted 1-Alkenes 8 to 2-Alkenes 9. a
4
5
6
Scheme 6. A Designed Strategy for Monoisomeriza-
tion of 1-Alkenes to 2-Alkenes
7
8
9
10
11
12
13
14
15
16
17
18
19
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60
aReaction conditions: 0.125 mmol substrate, 1 mol% [Co],
10 mol% NH3BH3 in 0.5 mL of MeOH at RT for 3 h. bCo-IX
c
was used. Co-VIII was used. d2 mol% Co-VIII was used.
e2 mol% Co-IV was used.
Mechanistic Studies
In general, there are mainly three possible reaction
mechanisms for transition metal-catalyzed olefin isomeri-
zation process (Scheme 8).3b 1) The insertion/elimination
mechanism starts with a metal-hydride species possessing
a free coordination site. The coordination of olefin sub-
strate to the metal center and the following insertion of
double bond into the M-H bond gives the key alkyl-metal
intermediate, which undergoes the subsequent β-hydride
elimination to generate the isomerized olefin product
(Scheme 8, eq. 1).3d 2) The π-allyl metal mechanism may
proceed through either inner-sphere or outer-sphere hy-
drogen transfer process. The inner-sphere mechanism is
initiated by an oxidative addition of the low valent metal
with C-H bond in the allylic position to generate π-allyl
metal-hydride complex. The following reductive elimina-
tion taking place on the other site furnishes with the ole-
fin isomer (Scheme 8, eq. 2, up).14 Alternatively, in the
outer-sphere mechanistic pathway the ligand acts as a
base to deprotonate the allylic position, leading to the
formation of a π-allyl metal complex. This key intermedi-
ate gives the isomerization product after rotation over the
allyl bond and the subsequent reprotonation of the M-C
bond (Scheme 8, eq. 2, down).3j 3) The hydrogen atom
transfer (HAT) mechanism proceeded by initial HAT from
a metal-hydride complex to the alkene substrate, which
provided a carbon-centered radical and a metalloradical
species M• with a reduced valence.15 Finally, removal of H•
from alkyl radical by M• affords the isomerized olefin and
regenerates the meta-hydride species (Scheme 8, eq. 3).11
aThe yield of 5a was determined by GC using biphenyl as
b
1
internal standard. The yield of 7 was determined by H
NMR and the reduced alkane product was also obtained
in 13% yield. cThe ratio of 9a : other isomerization
1
products were determined by H NMR and shown in the
parentheses.
The scope for the selective monoisomerization of γ-
substituted 1-alkenes 8 to 2-alkenes 9 were investigated
(Scheme 7). Over 90% isolated yields for 2-alkene prod-
ucts (a mixture of E/Z isomers) were obtained for all the
tested substrates (9a-9g). Notably, there were no over-
isomerized internal olefins observed. The substituted
group R on the γ-position of double bonds could be diver-
sified,
including
hydroxyl,
bromo,
tert-
butyldiphenylsiloxy (OTBDPS), methyl group and even
fluro group. These results demonstrated the excellency in
regioselectivity and generality of this novel strategy for
the monoisomerization of 1-alkenes.
Moreover, the installing of R group on the γ position,
along with the uniqueness of kinetic control ability of our
catalytic systems, further enables challenging site-
selective monoisomerization of diene substrate. When
diene substrate 8h was subjected to the optimized condi-
tion, we observed only the predicted isomerization of
terminal double bond (eq. 2). This result is in contrast to
a similar substrate previously reported by Norton and
coworkers, where the isomerization occurred on the 1,1-
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1 mol% Co-IV
10 mol% H3NBH3
1 equiv. Additive
Scheme 8. Different Mechanisms for Transition-
Metal-Catalyzed Olefin Isomerization.
1
2
OTBS
OTBS
MeOH, RT
1j
2j
3
4
5
6
no
99% yield
99% yield
99% yield
99% yield
1,1-diphenyl ethene
dibutylhydroxytoluene
9,10-dihydroanthracene
7
8
9
5 mol% Co-IV
10 mol% H3NBH3
Ph
Ph
MeOH, 50 C, 3 h
11a
12a
61% conversion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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M-H
M
H
H
H
M-H
M
•
•
Ph
Ph
Ph
13a
14a
15a
not observed
A series of control experiments were carried out to dis-
tinguish these mechanistic pathways. A mixture of D4-1h
containing ortho- CD2 and the non-deuterated substrate
1m was treated under the standard isomerization reaction
conditions (Scheme 9). The isomerized products generat-
ed from this scrambling experiment were isolated and
In view of the above experimental observations, we
proposed an insertion/elimination mechanism for this
cobalt-catalyzed olefin isomerization reaction (Figure 2).
The catalytic cycle started with the coordination of 1 to
cobalt(I) hydride complex A, which could be generated by
reducing the cobalt dichloride complex using ammonia
borane.9b Chirik and co-workers synthesized an analogous
pincer cobalt (I) hydride complex by treating the
(PNP)CoCl2 complex with NaHBEt3, which supports the
reliability of such a cobalt hydride species.17 The insertion
of double bond into the Co-H bond gave the alkyl cobalt
intermediate C. The following β-hydride elimination of Ha
or Hb would lead the formation of isomerized olefin
products 2 or 3. The applied pincer cobalt catalyst could
precisely differentiate the steric hindrance of reaction
sites a and b due to the existence of R- substituted group,
which determined the excellent regioselectivity of this
isomerization process via kinetic control.
1
analyzed by H NMR. The isomerization products derived
from D4-1h displayed a decreased deuterium incorpora-
tion, while the allylic position of isomerized product 10b
was partially deuterated. This result excluded an intramo-
lecular 1,3-hydrogen shift reaction pathway via the π-allyl
metal mechanism.
Scheme 9. Scrambling Deuterium-Labeling Experi-
ment.
The reactions of 1j with different radical scavengers, 1,1-
diphenyl ethene, ditert-butylhydroxytoluene and 9,10-
dihydroanthracene, were further examined (Scheme 10,
up). There was no influence in the presence of one equiv-
alent of these radical inhibitors. Furthermore, a radical
clock reaction was designed using 1,6-diene 11a as sub-
strate (Scheme 10, down). If this reaction followed the
HAT mechanism, phenyl substituted 5-hexenyl radical 13a
would be generated, which could undergo a very fast cy-
clization to produce a cycloisomerization product 15a.13,16
In fact, the cyclization product was not obtained under
these standard reaction conditions. These results demon-
strated that the HAT mechanistic pathway was very un-
likely.
Figure 2. Proposed reaction mechanism.
DFT Computational Study
In order to elucidate the role of the NNP-Co based
catalytic system in the kinetic control of olefin isomeriza-
tion more comprehensively, we performed DFT computa-
tional studies employing the isomerization reaction cata-
Scheme 10. Radical Trap Experiments.
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lyzed by complex Co-IV. We have previously studied the Given that enolates and enamines are thermodynami-
1
2
3
4
5
6
7
8
mechanism of transfer hydrogenation reaction of alkynes
and the isomerization of the corresponding alkene prod-
uct catalyzed by the same series of NNP-Co pincer com-
plexes, and the results revealed that the spin states of Co-
containing intermediates and transition structures were
triplet rather than singlet, and there is no change in spin
state along the reaction pathways.18 Therefore, in the pre-
sent study the reaction mechanism is discussed on the
basis of the triplet potential energy surfaces.
Because exocyclic olefins served as major type of repre-
sentative substrates in this study, we first studied the
isomerization mechanism of olefin 1g. As revealed by DFT
calculation, for exocyclic alkene 1g, the isomerization to
its endocyclic isomers 2g and 3g is thermodynamically
favorable, with 2g being more stable by 0.6 kcal/mol in
terms of Gibbs free energy (Figure 3). Therefore, the
isomerization under thermodynamic control would pro-
duce a mixture of 2g and 3g with a low selectivity, which
is in agreement with the observed product distribution in
Brønsted-acid-catalyzed isomerization of 1g (see Scheme
3).
The potential energy surface of the Co-catalyzed isom-
erization of 1g is shown in Figure 3. Cobalt(I) hydride
complex IN1, derived from Co-IV under the reaction con-
ditions, coordinates with exocyclic alkene 1g to form
complex IN2. The coordination step is endergonic by 9.1
kcal/mol, which forms a tetracoordinated cobalt(I) center
with the dissociation of the pyridine ligand, in agreement
with the proposed hemilabile NNP ligand design. The
subsequent insertion of the exocyclic C=C bond into the
Co-H bond takes place via TS1 with an activation Gibbs
free energy of 23.7 kcal/mol. The insertion step affords
alkylcobalt(I) species IN3, and the transformation from
IN1 to IN3 is slightly endergonic (by 4.6 kcal/mol) from
IN1. In intermediate IN3, there are two sites, Ha and Hb,
accessible for β-hydride elimination, where Hb site is in a
close proximity to the quaternary carbon and is more
hindered. DFT calculation indicated that, β-hydride elim-
ination from Ha (via TS2a) is indeed more favorable than
from Hb (via TS2b), and thus leading to the preferred
isomerization product 2g (ΔΔG≠ = 1.0 kcal/mol).19 Analysis
of the two transition states shows that, in TS2b the coor-
dinating pyridine unit has a repulsion interaction with the
phenyl group attached to the quaternary carbon (the dis-
tance between the pyridine α-CH and the phenyl CH is
2.65 Å), while such interaction is absent in TS2a, because
the reaction center is distal to the quaternary carbon. It is
notable that both β-hydride elimination pathways require
higher activation barriers than the first insertion step,
indicating that the insertion step is reversible, while the
β-hydride elimination step is irreversible and rate-
determining. After β-hydride elimination, the formed
olefin-Co(I) hydride complexes, IN4a and IN4b, undergo
olefin dissociation to deliver the isomerized product and
release the Co(I) hydride IN1. The computed potential
energy surface exemplified the proposed scenario of ki-
netic control shown in Figure 1d, though the kinetically
preferred product is also thermodynamically more stable.
cally more favorable compared with other alkene isomers,
we sought to investigate the isomerization of alkene 1u as
another representative model, where complete kinetic
control dictated the regioselectivity and thermodynami-
cally disfavored alkene isomer 2u was produced as the
sole product (Scheme 3). Our computational result con-
firmed that the isomerization of 1u to enamine 3u is
thermodynamically more favorable than to allylic amine
2u by 0.6 kcal/mol in terms of Gibbs free energy (Figure
4). The isomerization pathway is similar to that of olefin
1g. After coordination to Co-H complex IN1 and alkene
insertion, substrate 1u was transformed to IN6, from
which two different β-hydride elimination transition
states lead to two regioisomers 2u and 3u, respectively.
Hydride elimination from the methylene moiety of the
ethyl group via TS4a requires 20.0 kcal/mol activation
energy, while hydride elimination from the methylene
adjacent to the amine group via TS4b requires 23.6
kcal/mol (starting from intermediate IN6).19 Analysis of
these transition structures revealed that TS4b involves
more steric repulsions between the isopropyl groups on
the phosphorus atom and the N-benzyl group, because
the reaction center is close to the bulky NBn2 substituent.
In the favored transition structure TS4a, the reaction cen-
ter is distal to the bulky part of the molecule and thus
with much less steric repulsion. After β-hydride elimina-
tion, olefin-Co(I) hydride complexes IN7a and IN7b are
generated, and olefin dissociation occurs to deliver the
isomerized product as well as release the Co(I) hydride
IN1. In this case, the steric interaction in the hydride
elimination process, rather than the thermodynamic sta-
bility of the isomerization products, predominate the re-
gioselectivity, which nicely showcased the catalyst-
enabled kinetic control of olefin isomerization.
9
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For both substrates under study, the Co-catalyzed ole-
fin isomerization is under kinetic control, despite that
exocyclic and acyclic olefin substrates exhibit different
reactivities and steric control factors. The selectivity is
dictated by the relative activation free energy of the two
regiomeric β-hydride elimination transition states, rather
than the relative thermodynamic energy of the two prod-
ucts. By employing carefully designed NNP-Co complexes
as catalysts, the isomerization pathway with less steric
hindrance would be more favorable, as exemplified above.
CONCLUSIONS
We have demonstrated a kinetically-controlled regiose-
lective olefin isomerization reaction catalyzed by a series
of well-defined cobalt complexes. Ammonia borane was
used as a bench stable and mild reagent to activate cobalt
catalyst precursors. The current catalytic system operates
under mild conditions and allows for the isomerization of
a variety of 1,1-disubstituted olefins and γ-substituted 1-
alkenes with good yields and regioselectivity. Notably, by
applying this protocol we enabled the efficient prepara-
tion of a key intermediate towards the total synthesis of
minfiensine and a convenient derivatization of testos-
terone. A combined experimental and theoretical mecha-
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Journal of the American Chemical Society
erization via kinetic control would provide useful insights
nistic studies uncovered an insertion/elimination reaction
1
2
pathway and the mechanism for regioselectivity control.
We believe this strategy for the regioselective olefin isom-
for the development of other types of practical olefin
isomerization processes.
3
4
5
6
7
8
9
Me
Competing -hydride elimination TSs
Gsolv(298 K)
in kcal/mol
Me
Me
Me
H
Ph
N
Ph
N
N
H
Co
Hb
Co
Ha
iPr
N
Me
H
N
P
iPr
iPr
Ph
P
iPr
iPr
iPr
Co
N
P
10
11
12
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14
15
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60
H
TS2b
26.4
Me
1.64 Å
1.65 Å
Me
Ph
N
TS2a
N
N
H
TS1
25.4
Co
P
N
H
Me
Ph
Hb
iPr
23.7
Co
TS2a (favored)
IN4b
10.3
H
iPr
P
iPr
iPr
1g
9.1
IN4a
IN2
2.65 Å
IN1
7.7
4.6
IN3
0
3g
-3.5
Ph
H
N
IN1
Me
Me
H
N
1.69 Å
Ph
N
-4.1
2g
Co
P
1.63 Å
N
Co PiPr2
Hb
Me
Ha
iPr
Ph
Me
H
iPr
Ph
N
H
N
Co
P
Ha
TS2b (disfavored)
iPr
iPr
Figure 3. Potential energy surface for the Co-catalyzed isomerization of exocyclic olefin 1g.
Figure 4. Potential energy surface for the Co-catalyzed isomerization of acyclic olefin 1u.
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D. B. J. Am. Chem. Soc. 2014, 136, 1226; (d) Chen, C.; Dugan, T. R.;
ASSOCIATED CONTENT
Brennessel, W. W.; Weix, D. J.; Holland, P. L. J. Am. Chem. Soc. 2014,
136, 945; (e) Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. 2012, 134,
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(9) (a) Shao, Z.; Fu, S.; Wei, M.; Zhou, S.; Liu, Q. Angew. Chem. Int.
Ed. 2016, 55, 14653; (b) Fu, S.; Chen, N.-Y.; Liu, X.; Shao, Z.; Luo, S.-
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(10) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481.
(11) Crossley, S. W. M.; Barabé, F.; Shenvi, R. A. J. Am. Chem. Soc.
2014, 136, 16788.
(12) We repeated the standard reactions reported in the literatures
successfully before applying these known catalysis systems for the
olefin isomerization of 1a. See Supporting Information for more
details.
(13) Li, G.; Kuo, J. L.; Han, A.; Abuyuan, J. M.; Young, L. C.; Norton, J.
R.; Palmer, J. H. J. Am. Chem. Soc. 2016, 138, 7698.
(14) Sawyer, K. R.; Glascoe, E. A.; Cahoon, J. F.; Schlegel, J. P.; Harris,
C. B. Organometallics 2008, 27, 4370.
1
2
3
4
5
6
7
8
The Supporting Information is available free of charge on the
ACS Publications website. Experimental details, Spectra and
crystallographic data were included.
AUTHOR INFORMATION
Corresponding Author
*qiang_liu@mail.tsinghua.edu.cn.
*leijiao@mail.tsinghua.edu.cn.
9
Author Contributions
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The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This article is dedicated to Prof. Jin-Pei Cheng from CBMS of
Tsinghua University on the occasion of his 70th birthday.
This project was supported by the National Natural Science
Foundation of China (21702118), the National Program for
Thousand Young Talents of China and the 111 project. We
thank Prof. Herbert Mayr from Ludwig-Maximilians-
Universität München and Dr. Gang Li from Princeton Uni-
versity for the helpful discussions.
(15) (a) Obradors, C.; Martinez, R. M.; Shenvi, R. A. J. Am. Chem. Soc.
2016, 138, 4962; (b) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley,
S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300.
(16) (a) Li, G.; Han, A.; Pulling, M. E.; Estes, D. P.; Norton, J. R. J. Am.
Chem. Soc. 2012, 134, 14662; (b) Griller, D.; Ingold, K. U. Acc. Chem.
Res. 1980, 13, 317.
(17) Semproni, S. P.; Milsmann, C.; Chirik, P. J. J. Am. Chem. Soc.
2014, 136, 9211.
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