Stereoselective Palladium-Catalyzed 1,3-Arylboration of Unconjugated Dienes for Expedient Synthesis of 1,3-Disubstituted Cyclohexanes

Article abstract of DOI:10.1021/acscatal.9b02747

As significant pharmacophores, 1,3-disubstituted cyclohexanes are widespread in natural products and synthetic bioactive molecules. In this work, we describe a palladium-catalyzed arylboration of 1,4-cyclohexadienes, which allows expeditious access to an array of functionalized 1,3-disubstituted cyclohexanes from the readily available starting materials. Palladium catalysis enables the arylboration to proceed in a reversed regioselectivity compared with earlier nickel catalysis. The most striking feature of this protocol lies in the 1,3-regioselectivity and exclusive cis-diastereoselectivity. Intriguingly, the success of this three-component reaction does not rely on the application of dative ligands but a cheap ammonium chloride salt instead. The synthetic utility of this method is highlighted by a series of downstream stereospecific transformations and a drug molecule synthesis.

Full text of DOI:10.1021/acscatal.9b02747

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Letter
Stereoselective Palladium-Catalyzed 1,3-Arylboration of Unconjugated
Dienes for Expedient Synthesis of 1,3-Disubstituted Cyclohexanes
Hailiang Pang, Dong Wu, Hengjiang Cong, and Guoyin Yin
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 16 Aug 2019
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ACS Catalysis
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Stereoselective Palladium-Catalyzed 1,3-Arylboration of
Unconjugated Dienes for Expedient Synthesis of 1,3-Disubstituted
Cyclohexanes
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Hailiang Pang,† Dong Wu,† Hengjiang Cong,‡ and Guoyin Yin*†
† The Institute for Advanced Studies, Wuhan University, Wuhan 430072, China
‡ College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China
ABSTRACT: As a significant pharmacophore, 1,3-disubstituted cyclohexanes are widespread in natural products and synthetic
bioactive molecules. A palladium-catalyzed arylboration of 1,4-cyclohexadienes is reported, which allows expeditious access to an
array of functionalized 1,3-disubstituted cyclohexanes from the readily available starting materials. Palladium catalysis enables the
arylboration to proceed in a reversed regioselectivity compared with earlier nickel catalysis. The most striking feature of this protocol
lies in the 1,3-regioselectivity and exclusive cis-diastereoselectivity. Intriguingly, the success of this three-component reaction does
not rely on the application of dative ligands, but a cheap ammonium chloride salt instead. The synthetic utility of this method is
highlighted by a series of downstream stereospecific transformations and a drug molecule synthesis.
KEYWORDS: Alkenes, 1,3-Arylboration, Palladium, Metal migration, Stereoselectivity
A) Representive Bioactive Molecules Containing the Fragment of 1,3-Disubstituted Cyclohexane
Over the past few decades, fragment-based drug discovery
Me Me
O
(FBDD) has developed into an important strategy to identify the
lead pharmaceutical compounds.1 However, compared with the
sp2-rich, planar compounds, three-dimensional (3D) fragments
are highly limited in candidate libraries.1a In this context, the
1,3-disubstituted cyclohexane fragment is widely investigated
as a privileged scaffold in many significant, pharmaceutically
relevant molecules, such as anti-diabetic agent, cannabinoid
receptors, MAO-B inhibitor and so on, as depicted in Figure
1A.2 However, general synthetic approach towards this class of
compounds is quite scarce.2a, 2d, 3 Therefore, the development of
a general, efficient and stereoselective method for direct
synthesis of 1,3-disubstituted cyclohexanes from readily
available starting materials is a highly desirable yet challenging
task. On the other hand, the chemical dearomatization of
nonactivated arenes provides a powerful platform for rapid
assembly of value-added, complex molecules from inexpensive
fundamental aromatic compounds, which has attracted
extensive interest in the synthetic community in the past few
years.4 For example, a great advance in the transformation of
simple arenes into cyclohexane derivatives has been achieved
recently by the Sarlah group through a sequence of
photochemical arene-arenophile cycloaddition and metal
catalysis (Figure 1B, left).5 With this method, a set of 1,2- and
1,4-disubstituted cyclohexanes were selectively prepared.5b,d-f
Herein, we present a protocol which can convert benzene into a
diverse range of functionalized 1,3-disubstituted cyclohexanes
by combination of the well-known Birch reduction6 and an
unprecedented arylboration7 (Figure 1B, right). Remarkably,
the palladium catalysis allows the arylboration to proceed in an
extraordinarily 1,3-regioselective and cis-diastereoselective
manner.8-9 Furthermore, the incorporation of a boron group into
the products enables further stereospecific transformations to
afford a variety of highly functionalized 3D molecules.10
Ph
OH
OH
OPh
OH
OH
O
Me
OH
anti-diabetic agent
cannabinoid receptor
O
MAO-B inhibitor
Me Me
NaO
Cl
OH
O
O
OPh
H
N
Me
OH
O
OH
GPR120 modulator
Me
OH
cannabinoid receptor
type 2
beta-3 adrenoceptor
B) Dearomative Transformations (from planar to 3D):
1. Birch reduction
2. metal catalysis
1. RN=NR, hv
R
R'
R
R'
2. metal catalysis
(recent reports)
new strategy
feedstock
chemical
1.3-disub.
cyclohexane
1.2-disub.
or
R
R'
Ar
[Pd]
Bpin
1.4-disub.
1,3-arylboration
(this work)
cis-1,3-product


cheap starting material;
 diverse transformations;
excellent regioselectivity & exclusive diastereoselectivity.
Figure 1. Background Introduction and Reaction Design
As an extension of our interest in the application of nickel
migration,11-12we commenced this study by exploring a nickel-
catalyzed arylboration of 1,4-cyclohexadienes, with 1,4-
cyclohexadiene
(1a),
bromobenzene
(2a)
and
bis(pinacolato)diboron (B2pin2, 3) as model substrates. As
depicted in Table 1, the regio- and diastereo-selectivity would
be the main challenge of this arylboration reaction. For
example, it was found that with a nickel(II) salt and a 1,10-
phenanthroline derivative L1 as the catalyst, only the 3,1-
arylboration product 4a was isolated, albeit in lower yield with
a poor diastereoisomeric ratio (1:1) (entry 1). Without the
ligand, the 1,2-arylboration product cis-5a was isolated as a
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ACS Catalysis
single isomer in this three-component reaction (Table 1, entry
Page 2 of 6
experiments revealed that both the additive and the base played
an essential role for the success of this aryboration reaction
(Table 1, entries 13 and 14).
2), which is consistent with Brown’s ligand-free system.9i These
results reveal that the epimerization should derive from nickel
migration. After extensively screening reaction conditions, the
diastereoselectivity could not be improved, therefore we turned
our attentions to other transition metal catalysts.
1
2
3
4
5
6
7
8
TMAC
I
Ar PdII
II
Ar
2
I
Pd0
I
Bpin
Ar
Ar PdII
[
]
Table 1. Reaction Optimization
III
Bpin
Ar
6
Ar
Bpin
1,4-product
PdII
1a
chemo- and diastereo-selectivity
ArX
2
)
PdII Bpin
(
9
1,2-product
Ar
Ar
Bpin
1
3
[PdII]
Ar
B2pin2 (3)
Ar
Ar
Bpin
10
11
12
13
14
15
16
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21
22
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60
Bpin
Ar
VII
[M]
1a
IV
3,1-product
1,2-product
1,3-product
AcOBpin
VIII
4
5
6
( )
(
)
(
)
[PdII]
[PdII]H
Ar
Ar
Entry
Derivation from conditions A
Results
30%(1:1)a 4a
33% cis-5a
B2pin2/NaOAc
3
1
2
no change
no ligand
VI
V
Derivation from conditions B
cis-6a, [%]
Scheme 1. Proposed Mechanism
3
4
no change
82(78)b
57
0
23
20
6
Subsequently, a catalytic cycle involving cis-2,3-palladium
migration was proposed to rationalize this stereoselective
transformation. As shown in Scheme 1, the reaction is initiated
by oxidative addition of ArI with a Pd(0) species (I). In the
presence of the ammonium salt (TMAC), a new Pd(II) complex
III is probably generated from the Pd(II) complex II, which
reacts with the unconjuagated diene 1a to deliver intermediate
IV. Then the intermediate IV rapidly undergoes β-H
elimination and migratory insertion. The excellent
stereoselectivity observed in products suggest that the Pd-H
does not diassociate from the substrate in this process, which is
in accordance with Larock’s observations in the Pd-catalyzed
carboarylation reactions.14,15 Therefore, the migratory insertion
preceeds in a coplanar manner affording a stable π-allylPd(II)
complex VI. Subsequent transmetalation with B2pin2 forms
intermediate VII, which delivers the arylboration product 6 and
the Pd(0) catalyst by reductive elimination. Interestingly, the
migratory insertion of Pd-H also proceeds in a highly
regioselective manner, as no 1,2- and 1,4-products are
observed.
With the optimal reaction conditions in hand, we next turned
our attention to the investigation of the generality of this
palladium-catalyzed arylboration reaction. As outlined in Table
2, both electron-rich and electron-deficient aryl iodides
successfully yielded the cis-1,3-arylboration products in
moderate to good yields. Accordingly, a number of 1,3-
disubstituted cyclohexene derivatives were prepared.
Significantly, in all cases, the cis-1,3-arylboration products
were isolated as a single constitutional isomer. Remarkably, this
reaction exhibited extraordinary functional group compatibility.
A broad set of functional groups, such as ethers (OR), chlorides
(Cl), bromides (Br), esters (COOR), ketones (C=O), amides
(CONHR), cyano (CN), trifluoromethylsulfonates (OTf),
olefins (C=C), as well as arylamines (ArNH2), phenols (ArOH),
alcohols (ROH) and indoles are all well tolerated in this reaction.
Ortho-substituted (Cl and OBn) aryl iodides can also furnish the
desired products in good yields (6f, 6k and 6o). It is worthy
highlighting that this palladium-catalyzed arylboration shows
good chemoselectivity towards polyhalogenated arenes (6p-6s),
which provides further opportunities for iterative cross-
couplings.16 Moreover, this method could be used to directly
modify the complex bioactive molecules and their derivatives
(6x-6z and 6ab).
Pd(OAc)2 instead of Pd(acac)2
NiBr2·DME instead of Pd(acac)2
TBAC instead of TMAC
TMAB instead of TMAC
TMAI instead of TMAC
NaHCO3 instead of NaOAc
Na2CO3 instead of NaOAc
DCE instead of CHCl3
Dioxane instead of CHCl3
no TMAC
5
6
7
8
9
39
56
45
52
5
10
11
12
13
14
no NaOAc
2
Conditions A: NiBr2·DME (5 mol %), L1 (5 mol %), 1a (1.0 mmol),
2a (0.5 mmol), B2pin2 (3, 0.75 mmol), LiOMe (1.0 mmol), in DMF,
30 °C, 24 h. Isolated yield. a The ratio in parenthese is cis-/trans-
4a. Conditions B: Pd(acac)2 (5 mol %), 1a (0.4 mmol), 2b (0.2
mmol), B2pin2 (3, 0.2 mmol), TMAC (0.2 mmol), NaOAc (0.4
mmol), in anhydrous CHCl3, 60 °C, 24 h; GC yields against
naphthalene. b 1a (0.6 mmol), isolated yield.
O
Br
I
N
N
OMe
Me
2a
2b
L1
After carefully surveying a series of commonly used metal
catalysts, Pd(acac)2 proved to be most efficient in this three-
component transformation. As illustrated in Table 1, entry 3,
when aryl iodide 2b was used, the 1,3-arylboration product cis-
6a was isolated in 78% yield. Notably, only a single cis-isomer
was detected in this reaction. In addition, no 1,2-arylboration
products were observed in the Pd-catalyzed conditions. Further
catalyst evaluation indicated that Pd(acac)2 gave the best yield
(Table 1, entries 3 and 4). Replacing the palladium catalyst with
nickel salt resulted in no desired product formation (Table 1,
entry 5). The importance of tetramethylammonium chloride
(TMAC) additive was highlighted by replacing it with
tetrabuthylammonium
tetramethylammonium
chloride
bromide
(TBAC),
and
(TMAB)
tetramethylammonium iodide (TMAI) leading to dramatically
decreased yields (Table 1, entries 6-8). These results indicate
that both the cation and anion of the amounium salt are crucial
to this three-component reaction. The additive likely plays a
role to generate an active anionic palladium complex and/or
stablize the Pd(0) catalyst from precipitation.13 Moreover, the
examination of bases and solvents indicated that NaOAc and
CHCl3 were the best choices (Table 1, entries 9-12). Control
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ACS Catalysis
1
2
3
4
Table 2. Reaction Scopes a
Pd(acac)2 (5 mol %)
NaOAc (2 equiv)
Ar
Bpin
Ar
B2pin2
3
X
TMAC (1 equiv)
CHCl3 , 60 °C, 24 h
1
2
6
cis-
5
O
O
O
NC
H2N
H2N
Cl
6
7
MeO
MeHN
Bpin
Me
Bpin
Bpin
Bpin
Bpin
Bpin
8
9
6a
6b
61%b (81%)
6e
6d
50% (57%)
6f
6c
78%b (82%)
63% (67%)b
65% (83%)
84% (92%)
H
N
H
HO
Bpin
MeO
Cl
Ph
N
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
HO
Boc
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
O
MeO
6m
52%b (68%)
6g
6h
6i
6j
6k
6l
53%b (65%)
67%/64%c (75%)
71%b (83%)
80% (97%)
62% (78%)
45% (57%)
OMe
Br Cl
Br
TfO
Br
OBn
MeO
MeO
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Cl
Bpin
6q
6s
6t
6o
6p
6r
56%b (59%)
61%b (70%)
53%b (62%)
65%b (71%)
61%b (69%)
44% (58%)
6n
O
44% (60%)
O
Ph
N
H
N
Me
H
H
O
Bpin
F
H
Bpin
S
Bpin
Bpin
H
O
H
H
O
Bpin
Bpin
6z
6y
73%b (88%)
6u
6w
6v
6x
71%b (87%)
62%b (70%)
60%b (61%)
75%b (82%)
65%b (70%)
O
Bpin
O
MeO
MeO
H
Bpin
Bpin
Bpin
Me
+
O
H
H
Me
Bpin
O
1b
Me
6ac
47% (59%)
Bpin
substituted 1,4-diene
6ab
b
b
6aa
6ad:
33%
6ad':
24%
53%b (77%)
33% (78%)
other olefins
MeO
O
O
MeO
H2N
NH
MeHN
MeO
B(OH)2
N
Bpin
Bpin
Bpin
Bpin
1e
d
9
1c
: 79%
1,5-COD (
)
serotonin receptor
b
b
7a
7c
7d
: 51%
: 55%
: 38%
7b
: 53%
Me
Ph
MeO2C
Bpin
Bpin
MeO2C
F
1f
allylbenzene (
)
S
10:
75%
1d
4-VCH (
)
b
b
8b
8a
: 46%
+
: 78%
Me
Me
Me
Bpin
Bpin
Bpin
Bpin
Ph
1g
Bpin
+
Ph
Ph
1h
Isoprene (
)
1,3-diene (
)
1i
1,3-cyclohexadiene (
)
48%b (1.5:1)
12'
b
79%b (1:1)
11'
12
13:
72%
11
a Isolated yields on 0.5 mmol scale; the number in parentheses is NMR yield. b Yield of the corresponding alcohol after oxidation. c Isolated
yields on 6.0 mmol scale; d CsF instead of NaOAc, DCE instead of CHCl3.
Additionally, the carboboration product 6ac can be obtained in
a moderate yield as well, when 2-iodocyclohexenone was used
as the substrate. Finally, substituted 1,4-cyclohexadiene 1b was
also able to provide 1,3-arylboration products in a good yield,
albeit with a poor regioisomeric ratio (6ad and 6ad’).
Fortunately, the two isomers could be separated by flash
column chromatography.
To further demonstrate the synthetic value of this palladium-
catalyzed arylboration reaction, the scope of other dienes was
explored. As shown in Table 2, when 1,5-cyclooctadiene (1,5-
COD) was used as the reactant, surprisingly, a series of cis-1,2-
arylboration products were selectively obtained (7a-7d),
probably owing to the second double bond plays a role of ligand
to facilitate the reductive elimination at the original position.17
Moreover, the products of regioselective 1,2-arylboration only
occurred at the terminal double bond, when 4-vinylcyclohexene
(4-VCH) was used (8a and 8b). It is noteworthy that this is the
first example to achieve a selective 1,2-arylboration with
unactivated terminal olefins.9 Furthermore, replacing B2pin2
with arylboronic acid (1e) led to the formation of cis-1,3-
diarylation product (9) in a good yield by slightly optimizing
the reaction conditions. Heck product, rather than arylboration
product, were isolated from the reaction with allybenzene as the
substrate (10). This result indicated that the C-B bond could
only be constructed from π-allyl-palladium species, rather than
from the π-benzyl-palladium intermediates in this catalytic
system.8c Additionally, the arylboration products could also be
anticipated with acyclic conjugated dienes (1g and 1h), albeit
with poor selectivity between 1,2- and 1,4-regioisomers under
the current reaction conditions, which offers a different
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Page 4 of 6
regioselectivity from the previous dual metal catalysis
COD and 4-VCH, the downstream specific transformation and
the rapid synthesis of pharmaceutically relevant molecule
address the synthetic potentials of this protocol, and provide
valuable additions to the FBDD libraries. Therefore, we believe
this chemistry will greatly advance complex molecules
synthesis and medicinal chemistry candidates.
methods.9f-9g While the 1,3-cyclohexadiene 1i afforded the
single cis-1,4-arylboation product 13 with a good yield.
1
2
3
4
5
6
7
8
O
MeO
OH
MeO
F
O
16
: 79%
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.” Condition investigation, experimental
procedures and compound characterization (PDF), and
Crystallographic data (CIF)
15
Ph2PO2H
: 60%
CDCl3, RT
toluene
40°C
MeO
H2
Me
Ar
Bpin
Bpin
Pd/C
9
OH
F
S
EtOAc
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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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
18:
79%
14
: 81% (dr = 1:1)
O
H2O2, NaOH
THF
m-CPBA
DCM
MeO
O
MeO
AUTHOR INFORMATION
Ar
OH
MnO2
DCM
PPh3, DIAD
THF
O
N
Corresponding Author
O
17
21
: 77%
19
: 68%
* E-mail: yinguoyin@whu.edu.cn
Pd/C, H2
EtOH
O
O
ORCID
Me
MeHN
MeO
Guoyin Yin: 0000-0002-2179-4634
OH
F
OH
OH
S
20a
20b
20c
: 80%
: 85%
: 99%
Notes
Scheme 2. Stereospecific Transformations
The authors declare no competing financial interest.
To illustrate the potential of this 1,3-arylboration to create
diverse structures, we conducted subsequent transformations of
several products. As illustrated in Scheme 2, saturated product
14 was obtained first after hydrogenation of the olefin. Then the
C-B bonds were reacted with a benzoquinone and an aryl
aldehyde, providing 1518 and 1619 respectively. The C-B bonds
were converted to hydroxyl groups by oxidation with H2O2,
resulting in a series of cyclic allylalcohols (17). The alcohols
were further transformed to 18 by selective oxidation of the
double bond, 19 by a Mitsunobo reaction with phthalimide,20
and a plethora of saturated alcohols 20a-20c via hydrogenation.
In addition, a 5-arylsubstituted cyclohexenone 21 was provided
by a selective oxidation of the alcohol. Notably, except the
direct hydrogenation reaction (14), all other transformations are
stereospecific processes.
ACKNOWLEDGMENT
We thank Profs. Qianghui Zhou, Wen-Bo Liu and Aiwen Lei at
Wuhan University for lending lab space and sharing the basic
instruments. We are grateful for the financial support from National
Natural Science Foundation of China (21702151, 21871211) and
the Fundamental Research Funds for Central Universities
(2042019kf0208).
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I
1. NaOH, EtOH, RT
OEt
EtO
EtO
OH
PPh3, DIAD,THF
0 °C to RT
O
O
2. BH3•THF, -78 °C to RT
O
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(±)-
23
(±)- : 76%
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B2pin2
1. standard conditions
EtO
O
O
EtO
O
OH
O
1.
2. H2O2, NaOH, THF, 0°C to RT
3. Pd/C, H2, EtOAc
I
25
(±)- : 82%
24
(±)- : 97%
HO
O
PhOH
PPh3, DIAD,THF
0°C to RT
O
O
26
(±)- : 30%
2. NaOH, MeOH / H2O
anti-diabetic agent
Scheme 3. Synthesis of Bioactive Molecule
Finally, the synthetic utility of this palladium-catalyzed
arylboration reaction is further demonstrated in an efficient
synthesis of anti-diabetic agent 26,2f, using commercially
21
available 22 as the starting material (Scheme 3).
In summary, we have developed a novel strategy to access
1,3-disustituted cyclohexanes from benzene. This strategy
integrates the classical Birch reduction with a newly developed
palladium-catalyzed arylboration. 1,2-Arylboration of 1,5-
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Versatile Catalysts for One-pot Oxidation/Hydrogenation Reactions.
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OH
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Ar
Birch reduction
then
Bpin
[Pd]
79%
F
benzene
1,3-arylboration
cis-1,3-product
HO
O
O
OPh


cheap starting material;  stereospecific transformations;
excellent regioselectivity & exclusive diastereoselectivity.
anti-diabetic agent
multiple steps, 18%
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