TEMPO-Promoted Domino Heck-Suzuki Arylation: Diastereoselective Cis-Diarylation of Glycals and Pseudoglycals

Article abstract of DOI:10.1021/acs.orglett.5b01722

A palladium-catalyzed regio- and diastereoselective diarylation of glycals and pseudoglycals, which is a kind of Heck-Suzuki arylation, is described. A wide range of arylboronic acids reacted under these conditions smoothly. Selectivity was C1-C2(α,α) in

Full text of DOI:10.1021/acs.orglett.5b01722

Letter
pubs.acs.org/OrgLett
TEMPO-Promoted Domino Heck−Suzuki Arylation:
Diastereoselective Cis-Diarylation of Glycals and Pseudoglycals
Anil Kumar Kusunuru,† Chaitanya K. Jaladanki,‡ Madhu Babu Tatina,† Prasad V. Bharatam,‡
and Debaraj Mukherjee*,†
†Academy of Scientific and Innovative Research, Indian Institute of Integrative Medicine (CSIR), Jammu 180001, India
‡Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar Punjab
160062, India
S
* Supporting Information
ABSTRACT: A palladium-catalyzed regio- and diastereoselective diarylation of glycals and pseudoglycals, which is a kind of
Heck−Suzuki arylation, is described. A wide range of arylboronic acids reacted under these conditions smoothly. Selectivity was
C1−C2(α,α) in the case of glycals but C2−C3(β,β) for pseudoglycals. Quantum chemical analysis has been carried out to
establish the reaction mechanism, which may involve Pd(II)/Pd(O). TEMPO plays a key role in the formation of diaryl glycoside
due to its radical nature.
ifunctionalization of alkenes, where two new bonds are
syntheses of biologically significant molecules.5 The Larhed
Dformed from an alkene precursor in one pot, is a powerful research group has worked extensively on diarylation of chelating
synthetic method to impart molecular complexity.1,3,4 Such a
vinylic ether substituted by a (dimethylamino)ethyl group using
an excess of arylboronic acid in combination with p-
benzoquinone.4f−h However, the introduction of such chelating
groups is not possible for glycals. Because of our continuing
interest in glycal chemistry6 and the presence of many natural
products and biologically important compounds containing
diarylated furanose and pyranose moieties,7 we took up the task
of developing a regio- and stereospecific diarylation of glycals.
Glycals contain an enol ether double bond, thus making it a
challenging substrate for diarylation.
Recent advances in C-arylation of glycals have revealed
arylboronic acids to be efficient aryl coupling partners due to
their moisture stability and commercial availability. While
Maddaford et al. reported Ferrier C-arylation with arylboronic
acids under Pd catalysis, Ye et al. obtained diverse C-aryl
glycosides by varying the oxidants (Scheme 1).8 So far, the
arylation of glycals has been restricted to the monoarylation
stage9,6e,8a only, and no attempt has been made for the
stereoselective vicinal diarylation of glycals and pseudoglycals.
Herein, we disclose our efforts toward the development of an
efficient robust protocol for the regio- and diastereoselective
vicinal diarylation of glycals and pseudoglycals.
transformation becomes synthetically more challenging if the
two new adjacent chiral centers are to be formed in a highly
diastereoselective fashion.4 Palladium has become a popular
metal of choice for alkene difunctionalization due to the ease with
which Pd(II) facilitates the addition of nucleophiles to alkenes.2
When the nucleophiles come from arylorganometallics such as
arylboronic acid or arylstannanes, oxidative palladium catalysis
generates 1,1-, 1,2-, or 1,3-(allylic esters) diarylated products
depending on the type of alkene precursor.3 The success of
diarylation may be attributed to the stabilization of electrophilic
palladium species, thereby suppressing other competitive
reactions such as β-hydride/β-heteroatom elimination. One
way of achieving this is to use substrates that are unable to
undergo β-hydride elimination after initial Heck insertion such as
norbornenes, alkynes, allenes, and carbene precursors or employ
a three-component coupling to achieve the formation of two
sp2−sp3 carbon−carbon bonds from the alkene framework using
vinyl triflates as the organic electrophile and boronic acids as the
organometallic reagent.4 However, most of these methods are
substrate specific and have limitations in case of identical aryl
groups.
In order to effect diarylation, we thought of using 2 equiv of
phenylboronic acid with 1 equiv of tri-O-acetyl-D-glucal and
Glycals are important raw materials for the stereoselective
synthesis of natural products, their fragments, and analogues
because of their availability as inexpensive chiral building blocks.
Over the years, there has been a significant development in
glycal-based methodologies and their applications in the
Received: June 13, 2015
© XXXX American Chemical Society
A
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yields and excellent diastereoselectivities were observed for a
broad range of substituted arylboronic acids possessing diverse
electronic (Scheme 2, entries 1a, 2a, and 4a−9a) and steric
Scheme 1. Existing Method for C-Arylation of Glycals with
Arylboronic Acids
Scheme 2. Substrate Scope: Vicinal Diarylation of Glycals
carrying out the transformation with Pd reagents with or without
oxidants under Pd catalysis. A summary of this optimization
study is depicted in Table 1. To start with, tri-O-acetyl-D-glucal
Table 1. Optimization Studies for Diarylation of Glycals
product
Pd(OAc)2
(equiv)
time
(h)
1a/1b/1c
a
b
c
entry
oxidant
solvent
ACN
(% yield)
1
2
1
24
10
15
15
15
15
24
8
1c (70%)
1b (55%)
1b (45%)
1b (20%)
1a (20%)
1a (10%)
1
AcOH
AcOH
3
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
PhI(OAc)2
4
1,4-benzoquinone AcOH
5
K2S2O8
Oxone
AcOH
AcOH
6
7
DMSO
TEMPO
TEMPO
TEMPO
8
AcOH
1a (80%)
1a (30%)
1a (20%)
9
EtCOOH
10
10
10
isobutyric
acid
11
0.1
TEMPO
formic acid
14
ND
a
In all cases, 3 equiv of oxidant was used. All of the reactions were
properties (Scheme 2, entries 3a, 7a). A series of glycals (D-
glucal, D-galactal, L-rhamnal, and L-fucal) were also examined,
and all provided the desired products with excellent diaster-
eoselectivity (Scheme 2, entries 1a−18a), which demonstrates
the robustness of the catalytic system employed.
b
conducted at 30−40 °C. Solvent used was 2−3 mL for 100 mg of
glycal. Yield obtained after column chromatography.
c
and phenylboronic acid were allowed to react with 1 equiv of
Pd(OAc)2 in acetonitrile, whereupon formation of the Ferrier C-
aryl glycoside (1c) was observed. By changing the solvent to
acetic acid, we obtained a new product, which was characterized
as the β-hydride-eliminated C-aryl glycoside 1b (Table 1, entry
2). To the best of our knowledge, this is first report of β-hydride-
eliminated C-aryl glycoside formation from glycals with acetyl
protection, although the same product can be obtained from
benzyl/silyl-protected substrate. Continuing our study, we used
10 mol % of Pd(OAc)2 in the presence of PhI(OAc)2 or 1,4-
benzoquinone as oxidants (Table 1 entries 3 and 4). In both
cases, only β-hydride-eliminated C-aryl glycoside (1b) was
obtained as the major product. Gratifyingly, we found that the
treatment of tri-O-acetyl-D-glucal (1) with phenylboronic acid (2
equiv) in the presence of Pd(OAc)2 (10 mol %), TEMPO (3
equiv), and AcOH as solvent for 8 h at room temperature
furnished the targeted 1,2-(α,α)-diarylated-C-glycoside in 80%
yield.
So far we have described the successful stereoselective
diarylation of glycals with identical arylboronic acids. In order
to expand the scope of this reaction further, we became
interested in seeing if the regioselective addition of two
arylboronic acids having different reactivity toward glycals
could be performed. For this purpose, we chose 3,5-
dimethoxyphenylboronic acid along with phenylboronic acid.
Indeed, we obtained differentially substituted 1,2-arylated glucal
derivative (1d) with complete regiocontrol albeit in lower yield
and accompanied by compound 1a (Scheme 3). The
regiochemistry of the new diarylated product 1d was determined
from 2D NMR analysis. The HMBC (800 MHz) spectrum of 1d
showed cross peaks between the signals for ortho protons of the
3,5-dimethoxyaryl group at δ 6.91 ppm (CDCl3), which is upfield
of other aromatic proton signals (and thus easily distinguish-
able), and the anomeric carbon peak of the glycal partner at δ
77.0 ppm (CDCl3). This established the connectivity of the 3,5-
dimethoxyphenyl ring at C(1) and hence of the unsubstituted
phenyl ring at C(2) (see the Supporting Informaiton for 2D
NMR) of 1d. Similar results were obtained while working with 4-
methoxyarylboronic acid along with unsubstituted boronic acids
With the optimum conditions of stereoselective diarylation in
our hand, we attempted the reaction with other arylboronic acids.
A variety of arylboronic acids with different substituents were
observed to smoothly undergo the reaction. Generally, good
B
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Scheme 3. Regioselective Diarylation of Glycals
Scheme 5. Possible Catalytic Process along with Free Energy
Change Values and Activation Barrier (Ea) Values (Energies
in kcal/mol)
(Scheme 3). Experiments are in progress to improve the yield of
1d further.
Apart from glycals, pseudoglycals were also tested under the
optimized conditions (Scheme 4). We obtained 2,3-diarylated
glycosides with excellent stereoselectivity by diminishing the
temperature to 10 °C. The stereochemistry of the product is
cis(β,β) at C2−C3 as determined10 by 2D-NMR spectroscopic
studies (see the Supporting Information).
has been divided into four basic steps as follows: (i)
transmetalation of arylboronic acid to produce A (ArPdX), (ii)
syn addition reaction of A to the double bond of the glycal to
generate B, (iii) aryl exchange, and (iv) a second arylation and
reductive elimination of palladium to form F. In the first
transmetalation step, the arylboronic acid [ArB(OH)2] reacts
with palladium diacetate leading to the formation of A. The aryl
group exchanges with the acetate of palladium acetate in this step,
the enthalpy of this reaction being 0.36 kcal/mol. In Pd(OAc)2,
two bidentate interactions are present and all four coordination
centers are occupied, but in A only three coordination centers
around Pd are occupied.
Scheme 4. Diarylation of Pseudoglycals
The second step involves metal insertion reaction followed via
syn addition reaction. Compound A forms an initial complex
(RC) with the π cloud of the glycal, which is exergonic in nature,
by 14.27 kcal/mol. In RC, the palladium atom is almost at an
equal distance (η2-arrangement) from both the olefin carbon
atoms but slightly oriented toward C2 carbon; the distance of
C1−Pd is 2.30 Å, and that of C2−Pd is 2.18 Å.
In order to determine the stereochemistry of the aryl moieties
of the 1,2-diarylated glycosides produced, spectroscopic analyses
were performed. From a mechanistic consideration, the
stereochemistry of aryl moieties was expected to be cis (α−α
or β−β). In the NOESY spectrum of compound 1a, observed
correlations between H1/H6 and H2/H4 reveal that H-1, H-2, H-
4, and H-6 are cofacial. This confirms the stereochemistry of the
aryl groups as cis(α−α) at C(1)/C(2) (Figure 1). In the case of
3,4-di-O-acetyl-L-rhamnal, the stereochemistry of aryl groups is
cis(β−β) at C(1)/C(2).11
From the above observations, a plausible mechanism for the
palladium-catalyzed diarylation of glycals can be visualized as
outlined in Scheme 5. To provide support to the proposition,
density functional theory (DFT) calculations have been
performed. Two different pathways were explored on the
potential energy surface (Scheme 5). The entire pallodocycle
The RC has the possibility of forming either C(1)-arylated
product or C(2)-arylated product. The DFT studies showed that
the formation of C(1)-arylated product (B) is more favorable
than of the C(2)-arylated product (B′). The activation energy
(Ea) required for the formation of B from RC is 18.98 kcal/mol
(for B′ it is 23.31 kcal/mol). This reaction is exergonic in nature
by 6.95 kcal/mol to give B (B is more stable than B′ by 4.8 kcal/
mol). In B, the aryl group is in an axial position, and the Pd−OAc
is in an equatorial position at the C(2) center. It was also
observed that the acetate substituent at C(3) forms an O---Pd
coordinate bond (2.11 Å), giving a square-planar arrangement at
the Pd center. B may undergo anti elimination to give the
arylated product G, which is an exothermic process by 4.26 kcal/
mol. However, in this reaction, a diaryl product is formed that
may involve the intermediacy of E. Formation of E from B is an
endothermic process by 24.59 kcal/mol (though diaryl product is
stable by 1.26 kcal/mol). Hence, it can be concluded that diaryl
product formation can occur but not through E. Experimentally,
the reaction is carried out in the presence of TEMPO. The radical
character of TEMPO must be facilitating the reaction. To verify
this, quantum chemical calculations have been performed on
intermediates C and D. Formation of intermediate C (radical) is
an endergonic process by 8.76 kcal/mol. Radical C can yield
radical D in the presence of ArB(OH)2, with the energy required
Figure 1. 2D-NMR correlation diagrams of diaryl glycosides.
C
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for this reaction being only 0.80 kcal/mol. Hence, the formation
of D from B requires only 9.56 kcal/mol and is more favorable in
comparison to the formation of E from B (24.59 kcal/mol). D
can yield the diaryl product F by releasing 10.39 kcal/mol, with
an energy barrier of ∼14.40 kcal/mol. Overall, the diaryl product
formation follows a low energy pathway in the presence of
TEMPO. Hence, it can be concluded that the radical character of
TEMPO is facilitating the diaryl product formation through this
reaction (B + ArB(OH)2 + TEMPO →F + AcOB(OH)2 +
TEMPO) and is marginally exergonic by 1.26 kcal/mol. Figure 2
shows the 3D structures of the transition states TS (A → B) and
TS (D → F).
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(10) In NOESY of compound 19a we observed cross peaks between
H3(δ 3.46)/H5(δ 3.77) and no cross peak between H2(δ 3.1)/H4(δ
5.61), which confirms the stereochemistry of aryl groups as cis(β−β) at
C2-C3 (Figure 3).
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at C1-C2.
Figure 2. 3D structures of the transition states (i) (A → B)−C1-
arylation; (ii) (D → F)-C2-arylation.
From the complex B, three pathways appear likely: (i)
formation of G, (ii) formation of E (both in the absence of
TEMPO), and (iii) formation of C (in the presence of TEMPO).
Formation of G is much more favorable in the absence of
TEMPO; hence, diaryl product via E is not noticed. Only in the
presence of TEMPO can the formation of C−F be noticed. The
overall energy barrier for the formation of F from B in the
absence of TEMPO is 35 kcal/mol (via E). The same in the
presence of TEMPO is 23.5 kcal/mol.
In conclusion, we have established a highly diastereoselective
diarylation of glycals with arylboronic acids wherein a wide
vareity of glycals and arylboronic acids can participate. The
reaction is basically a type of Heck−Suzuki arylation. Here, the
oxidizing agent TEMPO plays a key role in blocking syn-and anti-
elimination. The diarylation can take place in the presence of the
radical oxidative agent TEMPO.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, 1H, 13C, and 2D- NMR spectra,
Cartesian coordinates, and characterization of all compounds.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01722.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dmukherjee@iiim.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to CSIR-IIIM (MLP4015, BSC0108) for
generous funding. A.K. and T.M.B. thank CSIR, New Delhi, for a
senior research fellowship. IIIM Publication No.: IIIM/1816/
2015.
D
DOI: 10.1021/acs.orglett.5b01722
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