Enantio- and Regioselective Ir-Catalyzed Hydrogenation of Di- and Trisubstituted Cycloalkenes

Article abstract of DOI:10.1021/jacs.6b07291

A number of cyclic olefins were prepared and evaluated for the asymmetric hydrogenation reaction using novel N,P-ligated iridium imidazole-based catalysts (Crabtree type). The diversity of these cyclic olefins spanned those having little functionality to

Full text of DOI:10.1021/jacs.6b07291

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Article
Enantio- and Regioselective Ir-catalyzed
Hydrogenation of Di- and Trisubstituted Cyclohexenes
Byron K. Peters, Jianguo Liu, Cristiana Margarita, Wangchuk Rabten, Sutthichat
Kerdphon, Alexander Orebom, Thomas Morsch, and Pher G. Andersson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07291 • Publication Date (Web): 22 Aug 2016
Downloaded from http://pubs.acs.org on August 22, 2016
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Enantio- and Regioselective Ir-catalyzed Hydrogenation of Di-
and Trisubstituted Cyclohexenes
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Byron K. Peters,a, ‡ Jianguo Liu,a, ‡ Cristiana Margarita,a, ‡ Wangchuk Rabten,a, ‡ Sutthichat Kerdphon,a, ‡
Alexander Orebom,a Thomas Morsch,a and Pher G. Andersson*,a.
aDepartment of Organic Chemistry, Stockholm University, Arrhenius-laboratory, 10691 Stockholm, Sweden.
‡These authors contributed equally.
ABSTRACT: A number of cyclic olefins were prepared and evaluated for the asymmetric hydrogenation reaction using novel N,P-
ligated iridium imidazole based catalysts (Crabtree type). The diversity of these cyclic olefins spanned those having little function-
ality to others bearing strongly coordinating substituents and heterocycles. Excellent enantioselectivities were observed both for
substrates having little functionality (up to >99 % ee) as well as substrates possessing functional groups several carbons away from
the olefin. Substrates having functionalities such as carboxyl groups, alcohols or heterocycles in the vicinity of the C=C bond,
where hydrogenated in high enantiomeric excess (up to >99 % ee). The hydrogenation was also found to be regio-selective and by
control of the reaction conditions, selective hydrogenation of one of two tri-substituted olefins can be achieved. Furthermore, tri-
substituted olefins can be selectively hydrogenated in the presence of tetra-substituted olefins.
efficient method to hydrogenate olefins for the preparation of
chiral molecules, typically in high enantiomeric excess. More
Introduction
The substituted cyclohexane unit is an important scaffold in
natural products and total synthesis.[1] The majority of these
motifs have stereogenic centers on the cyclohexane, for exam-
ple: sesquiterpenes Eudesmane, Ere-mophilan, and Frovatrip-
tan, a drug for the treatment of migraines (Figure 1).[2]
importantly, using N,P-ligands, minimally functionalized chi-
ral molecules can be prepared in high optical purity and yield.
In more recent studies these Ir-N,P catalysts have been suc-
cessfully used for hydrogenation of substrates having a wide
range of functional groups at the olefin. Therefore, one could
envisage using the Ir-N,P strategy in the hydrogenation of
easily prepared cyclohexene precursors.
The asymmetric hydrogenation as a means of installing ste-
reogenic centers in cyclic systems has been investigated to
some extent.[6] In particular, heterocycles have been hydrogen-
ated with high levels of enantioselectivity.[7] On the other
hand, there are surprisingly few examples for the hydrogena-
tion of unsaturated carbocycles. The asymmetric hydrogena-
tions of 2,3-benzofused derivatives (Figure 2) having 1[8] and
6[8f, 9] substitution, resulted in moderate to good enantioselec-
tivity.
Figure 1: Chiral cyclohexanes in nature
A number of stereoselective methods have been developed
to prepare chiral carbocycles including cyclohexanes. The
most successful are using a chiral catalyst, such as: Diels-
Alder[3], polyene cyclization, Robinson annulation, and or-
ganocatalyzed domino or cascade reactions[1, 4]. While these
reactions are important and have been used to prepare a num-
ber of natural products and pharmaceuticals[5], their generality
in terms of their substrate scope is not optimal. For example, a
high degree of functionality in the starting materials is re-
quired (domino and to a lesser extent the Diels-Alder), some
are only amenable to the preparation of two or more fused
rings (polyene and Robinson annulation), not to mention the
high catalyst loading that accompanies a majority of the or-
ganocatalytic methods (> 5 mol%).
R
1
R
2
3
H2
6
5
4
Figure 2: Chiral cyclohexanes by hydrogenation
Successful examples for the asymmetric hydrogenation of
compounds possessing more than one prochiral olefin are very
rare[8d] and have been mainly focused on conjugated 1,3-
dienes[10], hence convergent approaches are sometimes em-
ployed in total synthesis.[11] Therefore, 1,4-cyclohexadiene
substrates afford an interesting opportunity for the preparation
of multiple stereogenic centers.
In this work, we have developed a facile and enantioselec-
tive method to prepare a diversity of chiral cyclic molecules
from their corresponding cyclohexenes (Class 1-3, Figure 3).
In short, there lacks a general method to prepare these im-
portant structures having either minimal functionality or those
which are functionalized and even bearing heterocyclic units.
The iridium catalyzed asymmetric hydrogenation is a mild and
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Having both 2- and 4-methyl substitution (cat-v) offered high
1
2
3
4
5
6
7
8
selectivity. Comparably high and in some cases significantly
higher selectivity was observed compared to catalysts ii-iv.
Interestingly, having a 4-methoxy substituent (cat-vi) did not
result in the same benefits as the 4-methyl (cat-iii) and lower
selectivity is obtained compared to cat-ii. The 2- and 4-
dimethoxy version (cat-vii), however, furnished the hydrogen-
ated products in excellent enantioselectivity, similarly to the
2,4-dimethyl counterpart, cat-v.
Figure 3: Substrate classes
BArF24
Ph
Ph
Ph
Ph
9
Ph Ph
P
Discussion
Ph
Ph
BArF24
BArF24
BArF24
P
P
P
Ir
10
11
12
13
14
15
16
17
18
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60
Ir
Ir
Ir
Ligand design has always been a challenge for asymmetric
catalysis. It is often necessary that the electronic and steric
properties of the substituents on the ligand can be varied in
order to gain optimal enantioselectivity.[12] We have shown
previously that substrates of class 1 are hydrogenated in high
yield and enantiomeric excess with catalysts i and ii, bearing a
thiazole and imidazole ligand, respectively (Figure 4).[13]
Moreover, acid labile substrates such as enol ethers were tol-
erated by catalyst ii. A surprising outcome since related N,P-
ligated iridium catalysts have been shown to produce Ir-
N
N
N
N
N
N
N
S
Ph
Me
Me
i
ii
iii
iv
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ir
Ph
BArF24
BArF24
BArF24
BArF24
P
P
P
P
Ir
Ir
Ir
N
N
N
N
N
N
N
N
MeO
Me
polyhydride species in solution when treated with hydrogen[14]
,
OMe
OMe
F
Me
v
vi
vii
viii
which more recently have been revealed to be appreciably
acidic.[15] This prompted us to investigate the influence of the
substituent on the imidazole in the asymmetric hydrogenation
reaction. The imidazole ligand is biaryl in nature, and biaryls
possess an interesting chemistry, particularly with respect to
substituent effects.[16] In this study we present the hydrogena-
tion of a broad range of cyclohexene substrates having various
degrees of functionalization (Figure 3) with novel imidazole-
based N,P-iridium catalysts (Figure 4).
Figure 4: Catalysts used in this study
Other substrates, having a minimal functionalization were
screened (Table 2). High enantioselectivities were obtained
regardless of the substituent on the substrate (Me, i-Bu, OMe,
n-Pent, i-Pr, Bn). The 2,4-dimethyl imidazole catalyst v per-
formed well, being the most selective catalysts for a majority
of the substrates (entries 1-11, 13-16, 18-20 and 22-23). In
only a few instances did other catalysts such as the thiazole
cat-i (entries 12, 17 and 21), and the 2,4-dimethoxy cat-vii
(entries 24-25), produce higher enantioselectivities than cat-v.
In each case, the hydrogenations with cat-v proceeded smooth-
ly, tolerating even acid labile substrates (entries 8-14 and 17-
22), problematic substrates for many iridium N,P catalysts.
Furthermore, the thermodynamically less stable trans isomers
are predominantly formed for 1,3-substitutions. This is in line
with catalyst control over substrate control, typically observed
for N,P-ligated Ir-catalysts.[17]
Some model substrates were chosen to evaluate the imidaz-
ole catalysts (Table 1). Monocyclic dihydrobenzene 1a and
tetrahydronaphthalenes 2a and 3a are hydrogenated in essen-
tially full conversion using 0.5 mol % catalyst loading. While
the reactivity of the catalysts was independent of the substitu-
ent on the imidazole, the enantioselectivity showed a strong
dependence. Having a 4-methyl substitution (cat-iii) is benefi-
cial, compared to 4-H (cat-ii). Somewhat higher enantioselec-
tivity is observed in most cases. The 2-methyl substituent (cat-
iv), has higher enantioselectivity for the naphthalene type sub-
strates than catalysts ii and iii, however, significantly lower
selectivity was observed for the dihydrobenzene type substrate
(compare entries 2 and 3, cat-ii and cat-iii with entry 1, cat-iv).
Table 1: Evaluation of catalysts in the asymmetric hydrogenation of unsaturated carbocyclesa,b,c
i
ii
iii
iv
v
vi
vii
viii
Entry
1
Substrate
Product
conv. ee (%) conv. ee (%) conv. ee (%) conv. ee (%) conv. ee (%) conv. ee (%) conv. ee (%) conv. ee (%)
Ph
Me
Me
Ph
Me
Me
*
99 92
99 87
99 79
99 65
99 81
99 62
99 67
99 81
99 93
99 86
99 65
99 43
59d 94
99 94
99 35
99 17
1a
2a
1b
Me
Me
*
2
3
2b
3b
i-Bu
i-Bu
*
99 92
99 65
99 78
99 88
99 84
99 59
99 92
99 26
3a
aReaction conditions: 0.125 mmol of substrate, 0.5 mol % catalyst, 1 mL of CH2Cl2, 50 bar of H2, 17 h, rt, unless stated otherwise in the
supplementary information. bAll examples are hydrogenated to full conversion where enantioselectivity is reported, which was determined
1
c
d
by H NMR spectroscopy. No side products were detected. Determined by HPLC or GC analyses using a chiral stationary phase. Only
starting material was detected other than the product.
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aReaction conditions: 0.125 mmol of substrate, 0.5 mol % cata-
Table 2: Asymmetric hydrogenation of minimally func-
tionalized carbocycles (Class 1)a
1
lyst, 1 mL of CH2Cl2, 50 bar of H2, 17 h, rt, unless stated other-
b
wise in the supporting information. Predicted absolute stereo-
2
3
4
5
6
7
8
9
Productb
Catalyst Yield (%)c
ee (%)d
chemistry for the major product (>90% trans observed where
Entry
1
Substrate
c
applicable, unless otherwise stated). Isolated yield unless other-
Me
Me
Me
Me
d
99e
99e,f
99e,f
76f
wise specified. Determined by HPLC or GC analyses using a
v
v
v
v
v
v
99
4a
5a
4b
5b
6b
7b
8b
9b
chiral stationary phase. eConversion determined by 1H NMR spec-
troscopy. fSelectivity to trans <80 %.
Et
i-Pr
i-Pr
Me
Et
Et
i-Pr
i-Pr
Me
Et
2
3
94
96
99
99
99
Substrates with side chains bearing functional groups such
as OH, OTBDMS and COOMe (Table 3) were also tolerated
and furnished the saturated products in high enantiomeric ex-
cess (trans isomer). Catalyst v provided the best selectivity in
most cases, with ee’s exceeding 90 %.
Et
Et
6a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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49
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57
58
59
60
i-Pr
Ph
i-Pr
Ph
4
5
7a
Table 3: Asymmetric hydrogenation of unsaturated carbo-
cycles having non-ring bound functional groups (Class 1
extended)a
91
8a
Me
Ph-4-Me
Ph-4-CF3
Me
Me
Ph-4-Me
Ph-4-CF3
6
81
Entry
Substrate
Productb
Catalyst Yield (%)c
ee (%)d
9a
Me
Me
Me
Me
Me
Me
OH
OH
99e
99e
7
v
v
v
v
v
i
99
99
99
98
99
98
99
99
94
99
98
92
1
v
v
v
84
99
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
26a
26b
27b
28b
MeO
MeO
Me
i-Pr
OTBDMS
Me
OTBDMS
8
86e
87e
97e
2
3
4
99
99
92
27a
MeO
i-PrO
MeO
i-Pr
MeO
i-PrO
MeO
MeO
MeO
Me
OTBDMS
OTBDMS
99e,f
9
28a
Me
Me
Me
OMe
Me
OMe
71f
68
O
O
ixf
v
10
11
12
13
14
15
16
17
18
29a
29b
i-Bu
i-Bu
Pentyl
MeO
O
Me
MeO
O
Me
79e
5
97
OMe
OMe
30a
30b
MeO
Pentyl
81
95
aReaction conditions: 0.125 mmol of substrate, 0.5 mol % cata-
lyst, 1 mL of CH2Cl2, 50 bar of H2, 17 h, rt, unless stated other-
MeO
Cy
b
v
v
v
v
i
wise in the supporting information. Predicted absolute stereo-
chemistry for the major product (>90% trans observed where
MeO
Me
Me
OMe
MeO
Me
Me
Me
OMe
c
d
applicable, unless otherwise stated). Isolated yield. Determined
99e
99e
99e
99e
99e
e
by HPLC or GC analyses using a chiral stationary phase. Selec-
tivity to trans <80 %. fSee supporting information.
Me
Me
Et
Me
Me
Substrates having functional groups directly attached to the
carbocycle were also screened. Interestingly, despite the steric
encumbrance that the carboxyl groups impose, fantastic enan-
tioselectivity could be maintained using cat-v.
Et
Et
Et
Me
Me
OMe
Me
OMe
Me
Table 4: Asymmetric hydrogenation of unsaturated carbo-
cycles having ring bound functional groups (Class 2)a
20a
21a
OMe
Me
OMe
i-Pr
v
i-Pr
21b
Entry
1
Substrate
Productb
Catalyst
Yield (%)c
91e
ee (%)d
i-Pr
OMe
Me
i-Pr
OMe
Me
COOH
COOH
99e
82
98
72
97
98
98
19
v
v
98
i
99
22a
23a
24a
25a
22b
23b
24b
25b
Me
Me
Me
Me
Me
Me
MeO
MeO
31b
31a
20
21
22
23
24
25
98
99
99
93
94
92
COOH
Me
COOH
Me
O
xf
98e
99
99
2
3
OMe
OMe
i
32b
32a
O
MeO
OMe
MeO
OMe
v
Me
Me
Me
Me
Me
Me
98g
33b
v
+
O
+
O
Ph
Me
Ph
Me
v
Me
Me
33c
1a
2a
3a
1b
2b
3b
rac-33a
Me
Me
COOMe
COOMe
COOMe
COOMe
v
99h
97
vii
vii
4
34a
34b
i-Bu
i-Bu
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aReaction conditions: 0.125 mmol of substrate, 0.5 mol % cata-
regioselectivity in the hydrogenation of two different trisubsti-
1
2
3
4
5
6
7
8
lyst, 1 mL of CH2Cl2, 50 bar of H2, 17 h, rt, unless stated other-
tuted olefins. This is in contrast to the relatively non-bulky
Crabtree catalyst, which readily hydrogenates even more hin-
dered olefins such as tetra-substituted C=C groups.[18] Com-
pound 10a (Table 6), bearing two trisubstituted olefins, was
hydrogenated in full conversion to the corresponding saturated
alkane 10b with 50 bar H2 over 17 hours. If the reaction time
is lowered to 30 min, the reaction is nearly complete, however,
a small amount the styrene like intermediate 10c is observed.
If the pressure is reduced to 5 bar of H2 and the reaction al-
lowed to proceed for 5 hours, substantially more of the styrene
intermediate 10c is observed.
b
wise in the supporting information. Predicted absolute stereo-
chemistry for the major product (>90% trans observed where
c
applicable, unless otherwise stated). Isolated yield unless other-
d
wise specified. Determined by HPLC or GC analyses using a
e
f
chiral stationary phase. >95% trans-dimethyl product. See sup-
poring information. gFor both cis-fused diastereomers (1:1).
hConversion determined by 1H NMR spectroscopy.
A number of heterocyclic substrates were also evaluated
(Table 5). These substrates were found to require higher cata-
lyst loading (1-2 mol %), nevertheless high ee’s were obtained
(up to 99 %) for both 5- and 6- substitutions (indole nomencla-
ture). Catalyst v had good selectivity for the Me and OMe
substituted indoles and carbazoles (entries 1, 4, 5 and 7).
However, the longer carbon chains (n-Bu, n-Hex) on the in-
dole type substrates were handled better with the thiazole cata-
lyst i (entries 2 and 3), except in the case of the carbazole,
where catalyst ii performed more satisfactorily (entry 6). Hav-
ing a thiophene unit as a substituent was well tolerated by
catalyst i (entry 8). No reduction of the pyrrole (entries 1-6),
indole (entry 7) or thiophene (entry 8) was observed in any
case.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The hydrogenation of compound 42a was also observed to
be amenable to regioselectivity reduction by varying the con-
ditions of the reaction. At 50 bar of H2, hydrogenation of both
olefins takes place in 17 hours. However, by lowering the re-
action time, the intermediate 42c bearing the vinyl thiophene
unit is obtained exclusively with good selectivity.
Table 6: Regioselective hydrogenationsa
Me
R
Me
R
pH2/ bar time/ min
10c
42c
10b
42b
Table 5: Asymmetric hydrogenation of unsaturated carbo-
cycles having fused heterocycles (Class 3)a
Me
Me
Ph-4-CF3
5
30
94 (99% ee)
83 (99% ee)
6
1
2
10a
42a
S
Entry
Substrate
Productb
Catalyst
Yield (%)c ee (%)d
50
300
17
Me
Me
1
v
98
85
99
90
N
H
N
H
35a
35b
n-Bu
n-Bu
aReaction conditions: 0.125 mmol of substrate, 0.5 mol % cata-
2
i
N
N
lyst v, 1 mL of CH2Cl2, Conversion determined by 1H NMR spec-
troscopy. Enantioselectivity determined by HPLC or GC analyses
using a chiral stationary phase.
H
H
36a
37a
36b
37b
n-Hex
n-Hex
3
4
5
i
83
92
99
99
N
N
H
H
Aside from the obvious synthetic advantages to this regiose-
lectivity, the relatively simple means to bring it about further
caters to the utility of the methodology.
MeO
MeO
v
v
99e
99e
N
H
N
H
38a
39a
38b
N
H
N
H
MeO
MeO
Mechanism and stereoselectivity
39b
n-Bu
n-Bu
The mechanism of the asymmetric hydrogenation of trisub-
stituted olefins mediated by iridium N,P and C,N cationic
catalysts has been extensively studied by means of DFT calcu-
lations and a catalytic cycle involving IrIII/IrV has been pro-
posed.[19] The likelihood of this reaction pathway has been
supported both by more recent computational investigations[20]
and experimental NMR studies by Pfaltz[21], reporting the iden-
tification of a fundamental intermediate, an IrIII dihydride al-
kene complex. This species was shown to represent a resting
state of the catalyst, requiring the coordination of an additional
dihydrogen molecule, prior to the enantioselective migratory
insertion step, generating intermediate A (Figure 5a).
6
ii
98
90
N
N
n-Bu
n-Bu
Ts
Ts
40a
40b
OMe
OMe
7
8
v
i
99e
99e
99
99
N
N
Ts
Ts
41a
41b
S
S
Me
Me
42a
42b
aReaction conditions: 0.125 mmol of substrate, 0.5 mol % cata-
lyst, 1 mL of CH2Cl2, 50 bar of H2, 17 h, rt, unless stated other-
b
wise in the supporting information. Predicted absolute stereo-
chemistry for the major product (>90% trans observed where
c
applicable, unless otherwise stated). Isolated yield unless other-
d
wise specified. Determined by HPLC or GC analyses using a
chiral stationary phase. eConversion determined by 1H NMR spec-
troscopy.
Regioselectivity
Hydrogenations were observed to be regioselective, affect-
ing only the di- and trisubstituted olefins at 50 bar of H2. In
addition to these findings, it was observed that control of the
conditions using these new imidazole catalysts allowed for
Figure 5. Selectivity model
The understanding of the reaction mechanism and the ob-
servation of the structure of intermediate A enabled the devel-
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opment of a selectivity model, aimed to rationalize the stereo-
chemical outcome of the asymmetric hydrogenation.[22] This
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
Corresponding Author
quadrant model has proven able to predict the absolute config-
uration of the major enantiomer for a wide variety of saturated
products. It is also suitable to explain the trans preference
observed in the hydrogenation of cyclohexadienes.[13] The
results suggest that the first hydrogenation product is dissoci-
ated and then coordinated again from the favored face of the
second double bond, hence generating preferentially the trans
isomer of the corresponding cyclohexane (Figure 5b).
* E-mail: pher.andersson@su.se
Present Addresses
†If an author’s address is different than the one given in the affili-
ation line, this information may be included here.
Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manu-
script. / ‡These authors contributed equally.
9
The absolute configuration of three different cyclohexanes
(Table 7) was assigned comparing their values of optical rota-
tion to those available in the literature.[23] For all of the three
cases, it was found that the major produced enantiomer match-
es the configuration estimated according to the selectivity
model.
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Funding Sources
Any funds used to support the research of the manuscript should
be placed here (per journal style).
Table 7. Assigned absolute configurationsa
Notes
Any additional relevant notes should be placed here.
ACKNOWLEDGMENT
Energimyndigheten (The Swedish Energy Agency), Nordic Ener-
gy Research (N-INNER II), The Swedish Research Council (VR),
The Knut and Alice Wallenberg Foundation, Stiftelsen Olle
Engkvist Byggmästare and VR/SIDA for supporting this work.
Mr. Jianguo Liu thanks the Guangzhou Elite Scholarship Council
for a Ph.D. fellowship.
ABBREVIATIONS
CCR2, CC chemokine receptor 2; CCL2, CC chemokine ligand 2;
CCR5, CC chemokine receptor 5; TLC, thin layer chromatog-
raphy.
aAfter hydrogenation employing catalyst (S)-v (Entry 1 and
b
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1
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EWG
R
R
FG
R
R
R
Het
R
R
n
6
7
Minimally
functionalised
Functionality on
an extended chain
Ring tethered
functionality
Heterocycle containing or
heterocycle functionalised
8
9
R
= Me, n-Bu, Ph, i-Pr, OMe
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FG
= OH, OSiR3, NHCOCF3
44 examples, up to 99 % ee
Regioselective and high yielding
EWG = COOH, COOMe, CONR2
Het = Pyrrole, Indole
7
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134x396mm (300 x 300 DPI)
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31
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42
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44
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Table 3
92x57mm (300 x 300 DPI)
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30
31
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42
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44
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124x105mm (300 x 300 DPI)
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Table 5
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Table 6
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Table 7
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