Palladium-catalyzed reactions of halogen derivatives of N,N-Dimethyl-1-Phenylethanamine with arylboronic acids as a novel approach to the synthesis of biaryls with central and axial chirality

Full text of DOI:10.1134/S0012500812080083

ISSN 0012ꢀ5008, Doklady Chemistry, 2012, Vol. 445, Part 2, pp. 166–169. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © I.N. Shishkina, I.A. Dotsenko, V.M. Demyanovich, N.A. Bumagin, N.S. Zefirov, 2012, published in Doklady Akademii Nauk, 2012, Vol. 445, No. 6,
pp. 639–642.
CHEMISTRY
PalladiumꢀCatalyzed Reactions of Halogen Derivatives
of
N
,
N
ꢀDimethylꢀ1ꢀPhenylethanamine with Arylboronic Acids
as a Novel Approach to the Synthesis of Biaryls
with Central and Axial Chirality
I. N. Shishkina, I. A. Dotsenko, V. M. Demyanovich,
N. A. Bumagin, and Academician N. S. Zefirov
Received February 21, 2012
DOI: 10.1134/S0012500812080083
Biaryls with axial chirality (atropoisomerism), [10], and 3 and 4 were obtained from the correspondꢀ
which appears due to hindered rotation around the ing acetophenones [11].
Ar–Ar bonds in the presence of at least one bulky subꢀ
For studying the reactivities of these synthons, the
stituent in the orthoꢀposition, occur as structural units
in some natural molecules [1]. Examples of these
compounds are the antibiotic vancomycin [2], the
antitumor lignan steganacin [3], and the antiꢀHIV
agent Michelamine B [4]. Furthermore, biaryl derivaꢀ
tives with axial chirality are widely used in the catalytic
asymmetric synthesis as efficient ligands [5].
model reaction of 1ꢀ(2'ꢀbromophenyl)ꢀ
ylethanamine ( ) with arylboronic acids 6a
chosen. In view of the low reactivity of aryl bromide
N
,
N
ꢀdimethꢀ
2
, 6d–6f was
2
caused by steric hindrance created by the orthoꢀdimeꢀ
thylaminoethyl group, we modified the classical
Suzuki procedure, in particular, rejected the use of
organic solvents. The reaction was carried out in water
Currently, substituted biaryls are synthesized most at the boiling point of the solution in the presence of
often by the palladiumꢀcatalyzed reaction of aryl 1 mol % of the palladium complex PdCl2(dppf) (dppf =
halides with arylboronic acids (Suzuki reaction) [6].
This reaction is also used for the synthesis of axially
chiral biaryls [7, 8]. The most significant results were
obtained by using a central chirality unit present in the
aryl halide for stereoinduction or by using complexes
with chiral ligands as catalysts.
1,1ꢀbis(diphenylphosphino)ferrocene) and 1 mol % of
a phase transfer agent, ꢀBu4NBr. This gave the prodꢀ
uct of crossꢀcoupling of aryl bromide with arylboꢀ
ronic acid 6e, aminoꢀbiaryl 7e, in a 30% yield, while
symmetric biaryl 8e was formed as the major reaction
product in a 60% yield (Scheme 1).
n
2
An important problem is practical accessibility of
the initial chiral compounds and the possibility of
obtaining them as both enantiomers. One of such
Unlike orthoꢀisomer
and paraꢀsubstituted aryl bromides (
2
, the corresponding metaꢀ
3
and ) react
4
quantitatively with arylboronic acids 6b–6d to give
unsymmetrical aminobiaryls 9b–9d and 10b–10d
(Scheme 2). The structures of the obtained comꢀ
pounds were confirmed by 1H NMR spectroscopy. For
identification, compounds 9b–9d and 10b–10d were
converted to their iodomethylates.
compounds is 1ꢀphenylethanamine (
1), which has
already been used to prepare chiral compounds, as
described in a review [9]. However, there are still no
publications on the use of this amine in the synthesis
of atropoisomeric biaryls.
We studied catalytic crossꢀcoupling reactions of 1ꢀ
(2', 3', 4'ꢀbromoꢀ and 2'ꢀiodoꢀphenyl)ꢀN,Nꢀdimethꢀ
ylethanamines (2–5) as electrophilic synthons with
arylboronic acids R–С6Н4В(ОН)2 as nucleophilic synꢀ
thons. All halogen derivatives were prepared by known
When the reaction of aryl bromide
2 with arylboꢀ
ronic acids 6a, 6d–6f was carried out by the classical
procedure in dioxane (60°C, 10 h) in the presence of
palladium(0) triphenylphosphine complex, Pd(PPh3)4,
only traces of crossꢀcoupling products 7a
detected in the reaction mixtures, the initial aryl broꢀ
mide remained unreacted, and arylboronic acids
were converted to symmetric biaryls 8a, 8d–8f (see
Scheme 1). Dimers are apparently formed via oxidaꢀ
tive coupling of arylboronic acids. The possible mechꢀ
, 7d–7f were
procedures:
2 and 5 were obtained from N,Nꢀdimeꢀ
thylꢀ1ꢀphenylethanamine via the orthoꢀlithiation step
2
8
Moscow State University, Moscow, 119992 Russia
166

PALLADIUMꢀCATALYZED REACTIONS OF HALOGEN DERIVATIVES
167
)ꢀ5a
Characteristics of the reaction products of haloꢀsubstituted
with arylboronic acids (6b 6e
N
,N
ꢀdimethylꢀ1ꢀphenylethanamines (
2
–5
,
5a, (S)ꢀ5, (
S
)
–
)
Reactants; reaction products
(yield, %)
1H NMR,
Elemental analysis data
δ
, ppm
Biaryl mp,
–
°
C
2
+
6e
;
7e (30) + 8e (60)
ABA: 1.32 d (J 6.8 Hz, 3H, CH3CH), 2,10 s (6H, (CH3)2N), 3.33 q
6.8 Hz, 1H, OH3CH), 3.86 s (3H,
(J
pꢀCH3O), 6.92–7.59 m (8H, arom).
3
+
6b
;
9b (~100)
IM: 215 (dec.) ABA: 1.53 d (
J
6.6 Hz, 3H, CH3CH), 2.32 s (6H, (CH3)2N), 2.37 s (3H,
6.6 Hz, 1H, OH3CH), 7.30–7.46 m (8H, arom).
6.8 Hz, 3H CH3CH), 2.26 s (3H, ꢀCH3), 3.03 s (9H,
(CH3)3NI), 4.87 q ( 6.8 Hz, 1H, CH3CH), 7.25–7.58 m (8H, arom).
o
ꢀCH3), 3.46 q (
J
IM: 1.78 d (
J
o
J
3
+
6c
;
9c (~100)
IM: 229 (dec.) ABA: 1.52 d (J 6.8 Hz, 3H, CH3CH), 2.31 s (6H, (CH3)2N), 2.43 s (3H,
m
ꢀCH3), 3.56 q ( 6.8 Hz, 1H, OH3CH); 7.18–7.52 m (8H, arom).
IM: 1.79 d ( 6.8 Hz, 3H, CH3CH,), 2.41 s (3H, ꢀCH3), 3.04 s (9H,
(CH3)3NI), 4.88 q ( 6.8 Hz, 1H, OH3CH), 7.21–7.84 m (8H, arom).
J
J
m
J
Found, %: O 56.62, H 6.44, N 3.79.
C18H24IN.
Calculated, %: O 56.70, H 6.34, N 3.67.
3
4
4
4
+
+
+
+
6d
;
10d (~100)
10b (~100)
10c (~100)
10d (~100)
IM: 239 (dec.) ABA: 1.57 d (
ꢀCH3), 3.49 q (
IM: 1.79 d ( 6.9 Hz, 3H, CH3CH), 2.37 s (3H,
(CH3)3NI), 4.87 q ( 6.9 Hz, 1H, OH3CH), 7.29–7.83 m (8H, arom).
J
6.9 Hz, 3H, CH3CH), 2.37 s (6H, (CH3)2N), 2.53 s (3H,
6.9 Hz, 1H, OH3CH), 7.24–7.67 m (8H, arom).
ꢀCH3), 3.04 s (9H,
p
J
J
p
J
6b
;
ABA: 231
(dec.)
ABA: 1.52 d (J 6.8 Hz, 3H CH3CH), 2.25 s (6H, (CH3)2N), 2.34 s (3H,
o
ꢀCH3), 3.54 q ( 6.8 Hz, 1H, OH3CH), 7.20–7.34 m (8H, arom).
IM: 1.78 d ( 6.6 Hz, 3H, CH3CH), 2.26 s (3H, ꢀCH3), 3.04 s (9H,
(CH3)3NI), 4.89 q ( 6.6 Hz, 1H, OH3CH), 7.22–7.68 m (8H, arom).
J
J
o
J
6c
;
IM: 243 (dec.) ABA: 1.53 d (J 6.6 Hz, 3H, CH3CH), 2.33 s (6H, (CH3)2N), 2.51 s (3H,
m
ꢀCH3), 3.49 q ( 6.6 Hz, 1H, OH3CH), 7.21–7.63 m (8H, arom).
IM: 1.76 d ( 6.9 Hz, 3H, CH3CH), 2.39 s (3H, ꢀCH3), 3.05 s (9H,
(CH3)3NI), 4.92 q ( 6.9 Hz, 1H, OH3CH), 7.18–7.77 m (8H, arom).
J
J
m
J
6d
;
IM: 247 (dec.) ABA: 1.52 d (J 6.8 Hz, 3H, CH3CH), 2.35 s (6H, (CH3)2N), 2.49 s (3H,
p
ꢀCH3), 3.43 q ( 6.8 Hz, 1H, OH3CH), 7.29–7.64 m (8H, arom).
IM: 1.76 d ( 6.8 Hz, 3H CH3CH), 2.36 s (3H, ꢀCH3), 3.03 s (9H,
(CH3)3NI), 4.87 q ( 6.8 Hz, 1H, OH3CH), 7.28–7.77 m (8H, arom).
J
J
p
J
Found, %: O 56.95, H 6.61, N 3.82.
C18H24IN.
Calculated, %: O 56.70, H 6.34, N 3.67.
5
+
6c
;
7c (70)
IM: 208 (dec.) ABA: 1.40 d (
ꢀCH3), 3.60 q (
IM: 1.82 d ( 6.6 Hz, 3H, CH3CH), 2.37 s (3H,
(CH3)3NI), 4.77 q ( 6.6 Hz, 1H, OH3CH), 7.25–8.06 m (8H, arom).
J
6.6 Hz, 3H, CH3CH), 2.19 s (6H, (CH3)2N), 2.47 s (3H,
6.6 Hz, 1H, OH3CH), 7.11–7.71 m (8H, arom).
ꢀCH3), 2.75 s (9H,
m
J
J
m
J
5
5
+
+
6d
6e
;
7d (87)
7e (80)
–
ABA: 1.33 d (
p
J
ꢀCH3), 3.44 q ( 6.8 Hz, 1H, OH3CH), 7.01–7.62 m (8H, arom).
6.8 Hz, 3H, CH3CH), 2.17 s (6H, (CH3)2N), 2.43 s (3H,
J
;
–
ABA: 1.32 d (
J
6.8 Hz, 3H, CH3CH), 2.10 s (6H, (CH3)2N), 3.33 q
ꢀCH3O), 6.92–7.59 m (8H, arom).
(J
6.8 Hz, 1H, OH3CH), 3.86 s (3H,
p
5а
+
6d
;
11 (~100)
IM: 238 (dec.) IM: 1.82 d (J 6.6 Hz, 3H, CH3CH), 2.39 s (3H, pꢀCH3), 2.76 s (9H,
(CH3)3NI), 4.80 q (J 6.6 Hz, 1H, OH3CH), 7.19–7.81 m (8H, arom).
(
S
)ꢀ5
+
stereomer mixture)
6b 12 (~100, 1 : 1 diaꢀ
;
–
–
ABA: 1.25 d (J 6.6 Hz, 3H, CH3CH), 2.04 and 2.08 s (3H, ꢀCH3),
2.11 and 2.13 s (6H, (CH3)2N), 2.90 and 3.05 q (
7.05–7.67 m (8H, arom).
o
6.6 Hz, 1H, OH3CH),
J
( +
stereomer mixture)
S)ꢀ5a
6b
;
13 (~100, 2 : 1 diaꢀ
IM: 1.96 d (3H, CH3CH), 2.20 and 1.97 s (3H, oꢀCH3), 3.20 s (9H,
(CH3)3NI), 4.71 and 4.21 q (1H, OH3CH), 6.91–7.66 m (8H, arom).
Note: ABA is amino biaryl, and IM is iodomethylate.
DOKLADY CHEMISTRY Vol. 445
Part 2
2012

168
SHISHKINA et al.
Me
H
R
Me
H
B(OH)2
NMe2
1
NMe2
1'
2'
“Pd”, Na2CO3
+
+
4'
Br
R
3'
R
2
6a, 6d f
ꢀ6
R
7a
,
7d
ꢀ7f
8а, 8d f
ꢀ8
[R = H(
a
), 2'ꢀMe(
b
), 3'ꢀMe(
c
), 4'ꢀMe(
d
), 4'ꢀOMe(
e
), 4'ꢀCl(f)]
Scheme 1.
Me
H
NMe2
Me
H
PdCl2(dppf)/Pd(PPh3)4
B(OH)2
Na2CO3,
nꢀBu4NBr
NMe2
+
H2O, 100°C
Br
R
R
3, 4
6b
ꢀ6d
9б
ꢀ9d, 10bꢀ10d
Scheme 2.
H
Me
H
Me
X
PdCl2(dppf)/Pd(PPh3)4
B(OH)2
Na2CO3,
nꢀBu4NBr
X
+
H2O, 100°C
I
R
5
5
(X = NMe2)
(X = NMe3I)
6cꢀ6e
R
а
Scheme 3.
anism may include the oxidative addition of arylboꢀ
Of most interest are biaryls for which the axial
ronic acid to the Pd(0) complex, symmetrization of chirality is possible. We carried out the reaction of the
optically active aryl iodide (S)ꢀ5 with 2ꢀmethylpheꢀ
the Ar–Pd–B(OH)2 complexes (the ligands are omitꢀ
ted) to give Ar–Pd–Ar and (HO)2B–Pd–B(OH)2
complexes, which then undergo reductive elimination
to give biaryls and diboronic acids and to recover the
Pd(0) complex.
nylboronic acid 6b, which afforded a 1 : 1 mixture of
diastereomeric aminobiaryls 12 in a quantitative yield,
i.e., the reaction lacks stereoselectivity (Scheme 4).
1
The diastereomer ratio was determined by H
NMR spectroscopy from the integrated intensity ratio
of the corresponding proton signals: СHCH3, NMe2,
ArCH3. We failed to separate the diastereomers by
either crystallization or chromatography on silica gel.
Since iodides are most reactive among aryl halides,
we used 1ꢀ(2'ꢀiodophenyl)ꢀ ꢀdimethylethanamine
N,N
(5
), instead of aryl bromide 2, in the crossꢀcoupling
reactions. As a result, irrespective of the type of the
catalyst used, PdCl2(dppf) or Pd(PPh3)4, the reactions
were completed over a period of 5–10 min and gave
high yields of the expected crossꢀcoupling products,
aminobiaryls 7c–7e (Scheme 3), which were characꢀ
terized as iodomethylates.
The increase in the substituent bulk on going from
(S)ꢀ5 to its iodomethylate (S)ꢀ5a resulted in stereoseꢀ
lective reaction with quantitative formation of iodomꢀ
ethylates of diastereomeric aminobiaryls 13 (Scheme 4)
in a 2 : 1 ratio.
Furthermore, we demonstrated that not only free
amine but also its iodomethylate can be introduced
into the crossꢀcoupling reaction: iodomethylate of
Thus, we carried out and optimized the first crossꢀ
coupling reactions of orthoꢀ, metaꢀ, and paraꢀhaloꢀ
genꢀsubstituted
N,Nꢀdimethylꢀ1ꢀphenylethanamines
iodoamine
5 (5a) quantitatively reacts with arylboꢀ
and their iodomethylates with arylboronic acids. In
ronic acid 6d to give the iodomethylate of the correꢀ
the case of orthoꢀsubstituted aryl halides, high yields of
sponding biaryl 11 (Scheme 3). The iodomethylate of aminobiaryls were observed only when aryl iodide
5 or
aryl bromide
2
does not react under these conditions. its iodomethylate 5a was used.
DOKLADY CHEMISTRY Vol. 445
Part 2
2012

PALLADIUMꢀCATALYZED REACTIONS OF HALOGEN DERIVATIVES
169
H
Me
X
(
S)
(S)
PdCl2(dppf)
X
X
B(OH)2
Me
(
S
)
Na2CO3,
nꢀBu4NBr
+
+
H
Me
H
H2O, 100°C
Me
Me
Me
I
(
S
)ꢀ
)ꢀ
5
5
(X = NMe2)
6b
12 (X = NMe2)
13 (X = NMe3I)
(S
а
(X = NMe3I)
Scheme 4.
EXPERIMENTAL
The physicochemical characteristics of the
obtained biaryls 8a 8d–8f (yields 67–87%) correꢀ
,
1H NMR spectra were recorded on a Varian XLꢀ400
spectrometer (400 MHz) in CDCl3 (for iodomethyꢀ
lates, in DMSOꢀd6) with internal TMS. The elemental
analysis was performed in the microanalysis laboratory
of the Department of Chemistry, Moscow State Uniꢀ
versity.
spond to published data.
The structure of amino biaryls 7c–7e, 9c, 9d, 10c,
10d, 12, and 13 and their iodomethylates were conꢀ
firmed by 1H NMR spectroscopy (table).
ACKNOWLEDGMENTS
This work was supported by the Russian Foundaꢀ
tion for Basic Research, project no. 11–08–00353a.
Synthesis of Biaryls
Procedure A. Aryl halide or iodomethylate
(1 mmol), arylboronic acid (1.3 mmol), nꢀBu4NBr
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(0.01 mmol), Na2CO3 (2.5 mmol), and water (5 mL)
were charged into a reactor equipped with a magnetic
stirrer and an argon supply system. PdCl2(dppf) (0.01
mmol) or Pd(PPh3)4 (0.01 mmol) was added with stirꢀ
ring under argon. The mixture was heated to 100°C
with stirring. The reaction was continued until the
organic layer floatedꢀup (5 to 10 min). The reaction
mixture was extracted with diethyl ether and the comꢀ
bined ethereal extracts were passed through a silica gel
layer. Evaporation of the solvent gave the correspondꢀ
ing biaryls as colorless oils, which were characterized
as iodomethylates.
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and the aqueous layer was extracted with CH2Cl2 (2
×
10 mL). The combined organic extracts were washed
with brine and dried with MgSO4. The solvent was
evaporated and the residue was chromatographed on
silica gel (elution with hexane–ethyl acetate, 10 : 1).
DOKLADY CHEMISTRY Vol. 445
Part 2
2012