Convenient synthesis of pharmacologically active ortho-substituted biaryl oxazolines via the suzuki reaction

Article abstract of DOI:10.1080/00397910903162817

We describe an efficient protocol for the Suzuki-Miyaura synthesis of ortho-substituted biphenyl oxazolines from 2-(2-bromophenyl)-4,4-dimethyl-2- oxazoline and aryl boronic acids or aryl boronates. The Suzuki coupling is carried out in the presence of Pd

Full text of DOI:10.1080/00397910903162817

1
Synthetic Communications , 40: 1907–1914, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903162817
CONVENIENT SYNTHESIS OF PHARMACOLOGICALLY
ACTIVE ORTHO-SUBSTITUTED BIARYL OXAZOLINES
VIA THE SUZUKI REACTION
1
A. Sanjeev Kumar, Samir Ghosh, R. Soundararajan, and
1
1
2
G. N. Mehta
1
Chemical Research and Development Department, Pfizer Ltd.,
Mumbai, India
2
Chemistry Section, Applied Sciences and Humanities Department, SVNIT,
Surat, India
We describe an efficient protocol for the Suzuki–Miyaura synthesis of ortho-substituted
biphenyl oxazolines from 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline and aryl boronic
3 4
acids or aryl boronates. The Suzuki coupling is carried out in the presence of Pd(PPh )
and sodium carbonate in aqueous tetrahydrofuran. The scope and limitations of the reaction
are discussed.
Keywords: Biaryls; cross-coupling; oxazolines; palladium catalyst; Suzuki coupling
INTRODUCTION
Biaryls are important substructures found in many biologically active
compounds (Fig. 1). The special utility of ortho-biaryls may arise from the gauche
conformation imposed by repulsive unbonded interactions and the ability of this
twisted architecture to interact with some conserved protein structure, which results
in broad pharmacological activity. Biaryls have been successfully utilized as lipo-
philic peptidomimetics and as replacements for more complex hydrocarbon skele-
[
1]
tons. These include the angiotensin II receptor antagonists exemplified by
[
2–4]
telmisartan
(1), losartan (2), and the hypolipidemic xenalipin (3).
RESULTS AND DISCUSSION
In the course of our research efforts, we required access to novel biaryl
5–11]
[
oxazolines. Adapting published methods based on oxazoline chemistry
and
[12]
preparation of these biaryl oxazolines resulted in multistep sequences, which often
involved chromatographic separations and gave poor overall yields. Until now, these
biaryl oxazolines have been synthesized by nucleophilic aromatic substitution on
Received March 30, 2009.
Address correspondence to R. Soundararajan, Chemical Research and Development Department,
Pfizer Ltd., Mumbai, India. E-mail: soundara1959@yahoo.com
1
907

1908
A. S. KUMAR ET AL.
Figure 1. Angiotensin II receptor antagonists telmisartan, losartan, and hypolipidemic agent, xenalipin.
aryloxazolines, but we thought that these could also be prepared by the Suzuki
coupling reaction. The Suzuki reaction has evolved as a powerful tool for the con-
struction of C–C bonds in organic chemistry.
We initially chose the oxazoline moiety as a carboxy synthon because of its
ortho-metalling properties, its stability to many common reaction conditions, its
use as a versatile synthetic intermediate, and the recovery of the parent acid under
mild conditions. With 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (4) in hand, sev-
eral Suzuki coupling reactions were carried out. This compound was prepared by
standard methods in a very good yield As part of our initial strategy toward the syn-
.
thesis of biaryl oxazolines derivatives, we first planned to apply a Suzuki coupling
between 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline 4 (which was prepared from
[
5]
commercially available 2-bromo benzoic acid as per literature procedure ) and
-(hydroxymethyl) phenyl boronic acid as shown in Scheme 1. Under optimal
reaction conditions [5 mol% Pd (PPh ) , 2 equiv of 2 M Na CO , and aqueous tetra-
4
3
4
2
3
methylsilane (THF) as solvent], Suzuki coupling afforded biaryl product 6 in more
than 90% yield.
With the success of the Suzuki coupling reaction, biaryl oxazoline (6) was pre-
pared efficiently in multigram quantities via this route as shown in Scheme 1. After
ꢀ
Suzuki coupling, the biaryl oxazoline (6) on reaction with thionyl chloride at 0–5 C
0
for 2 h gave the key intermediate 2-(4 -chloromethyl-biphenyl-2-yl)-4,4-dimethyl-
4
,5-dihydrooxazole (7) in more than 99% yield.
0
Scheme 1. Convergent scheme for 2-(4 -chloromethyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydrooxazole.

ORTHO BIARYL OXAZOLINES VIA SUZUKI REACTION
1909
Scheme 2. Ortho-substituted biaryl oxazolines synthesis via Suzuki coupling.
The two-step sequence has greatly improved the synthesis of biaryl oxazoline
[
12]
(
7) over the literature procedure : it gave better yield (overall yield 90%), needed
less preparation time, and required only one-column separation. With these Suzuki
coupling conditions, we were able to access other functionalized biaryl oxazolines.
We applied this method to prepare a set of substituted biaryl oxazolines using similar
reaction conditions (Table 1). In general, these Suzuki coupling conditions worked
well between aryl boronic acids (entries 1–6) or aryl boronates (entries 7 and 8) with
2
-(2-bromophenyl)-4,4-dimethyl-2-oxazoline.
With 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline in hand, several Suzuki
coupling reactions were carried out. First, the coupling reaction with 4-(hydroxy-
methyl)phenylboronic acid was examined, mainly because the coupling reaction
0
would provide a two-step method to synthesize 2-(4 -chloromethyl-biphenyl-
-yl)-4,4-dimethyl-4,5-dihydrooxazole, which is key intermediate of telmisartan, an
2
angiotensin II receptor antagonist useful in the treatment of hypertension, heart dis-
eases, heart strokes, and bladder diseases. The reaction indeed gave the intermediate
(Table 1, entry 1) in 90% yield using 5% Pd(PPh ) and in 75% yield using 1%
Pd(PPh ) catalyst.
3 4
3
4
To examine the scope of the reaction, 2-(2-bromophenyl)-4,4-dimethyl-2-
oxazoline was subjected to similar conditions with 4-chloro phenylboronic acid
and gave the desired product in about 82% yield (entry 2). The effect of substituents
was investigated with various aryl boronic acids and aryl boronates. In entries 2–6,
the reactions with electron-rich and electron-poor substituents proceeded smoothly
to give corresponding biphenyl oxazolines in moderate to good yields. Under these
conditions, 4-(methoxycarbonyl)benzene boronicacid pinacol ester did not react with
2
-(2-bromophenyl)-4,4-dimethyl-2-oxazoline in aqueous THF conditions even after
prolonged stirring; substituting aqueous THF with dimethylformamide (DMF) gave
the product in only 5% yield (entry 7). The poor yield is probably due to the presence
of the polar carboxyl group. When the carboxylic acid group was converted to
methyl ester, the reaction proceeded smoothly with 65% yield (entry 8). para-Substi-
tuted boronic acids or boronates (entries 1–4, 6, and 8) effectively coupled with
2
-(2-bromophenyl)-4,4-dimethyl-2-oxazoline to give the product in moderate to
good yields, better than the meta-substituted boronic acids.
In summary, we have described a simple and efficient method for the prep-
aration of ortho-substituted biphenyl oxazolines. This method provides a ready
alternative to the synthesis of a wide variety of biaryl carboxylic acids and biaryl
nitriles.

1910
A. S. KUMAR ET AL.
Table 1. Coupling reactions of 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline with aryl boronic acids and
aryl boronates
Entry
Arylboronic acid
Product
Time (h)
Yield (%)
1
3
90
2
3
2
3
82
80
4
8
76
5
6
8
6
60
85
7
8
24
5
4
65

ORTHO BIARYL OXAZOLINES VIA SUZUKI REACTION
1911
EXPERIMENTAL
Materials and Instruments
All aryl boronic acids, aryl boronates, solvents, and reagents were purchased
from Aldrich and Alfa Aesar suppliers and were used without further purification.
All nonaqueous reactions were performed in dry glassware under an atmosphere
of dry nitrogen. Organic solutions were concentrated under reduced pressure.
Thin-layer chromatography (TLC) was performed on Merck precoated silica-gel
1
13
6
(
0F254 plates. H and C NMR spectra were recorded in dimethylsulfoxide
DMSO-d ) at 400 MHz on a Varian Gemini 400-MHz Fourier transform (FT)
6
NMR spectrometer. The chemical shifts were reported in d ppm relative to tetra-
methylsilane (TMS). The mass spectra were recorded on Shimadzu LCMS-QP 800
liquid chromatography–mass spectrometry (LC-MS) and AB-4000 Q-trap
LC-MS=MS instruments. Elemental analyses were performed on a Flash EA-1112
instrument. Melting points were obtained by using the open capillary method and
are uncorrected.
Typical Procedure for Suzuki Coupling
Pd(PPh ) (5 mol%) was added to a degassed solution of aryl boronic acid or
4
3
aryl boronates (1.0 equiv) and 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (1.5
equiv) in 2.0 M sodium carbonate solution (10 mL) and THF (10 mL). The mixture
ꢀ
was heated at 60 C under N for the time indicated in Table 1 [reaction progress was
2
monitored by thin-layer chromatography (TLC)]. After cooling to rt, the solution
was diluted with ethyl acetate, washed with H O and brine, dried over anhydrous
2
MgSO , and concentrated under reduced pressure. The concentrate was purified
4
by silica-gel column chromatography using ethyl acetate and heptanes as an eluent
to give the coupling products.
0
Data for [2 -(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-yl]-
methanol (Entry 1)
ꢀ
[12]
ꢀ
mp 97–100 C); H NMR (CDCl ) (d ppm):
3
1
Melting point: 98–100 C (lit.
.74 (m, 1H, ArH, J ¼ 7.4 Hz), 7.49 (m, 1H, ArH, J ¼ 7.4 Hz), 7.40–7.39 (m, 2H,
7
ArH), 7.38 (d, 2H, ArH, J ¼ 8.0 Hz), 7.35 (d, 2H, ArH, J ¼ 8.0 Hz), 4.75 (s, 2H,
1
3
–
2
1
CH ), 3.80 (s, 2H, –CH ), 1.30 (s, 6H, 2 ꢁ –CH ); C NMR (CDCl ) (d ppm):
2
2
3
3
8.7, 66.3, 68.1, 78.9, 127.1, 126.9, 127.7, 128.5, 129.4, 129.4, 130.2, 137.2, 140.2,
41.2, 164.9; MS (m=z): 282 [M þ 1]. Anal. calcd. for C H NO (281): C, 76.84;
þ
1
8
19
2
H, 6.81; N, 4.98; O, 11.37. Found: C, 77.02; H, 6.81; N, 4.90.
0
Data for 2-(4 -Chloro-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-
oxazole (Entry 2)
1
An oil; H NMR (CDCl ) (d ppm): 7.60–7.43 (m, 3H, ArH), 7.41 (m, 1H, ArH,
3
J ¼ 7.4 Hz), 7.39 (d, 2H, ArH, J ¼ 8.4 Hz), 7.24 (d, 2H, ArH, J ¼ 8.4 Hz), 3.81 (s, 2H,
1
3
–
1
CH ), 1.3 (s, 6H, 2 ꢁ –CH ); C NMR (CDCl ) (d ppm): 28.6, 68.2, 78.9, 126.7
2
3
3
27.1, 127.7, 128.5, 129.1, 129.7, 130.2, 134.2, 137.7, 139.7, 164.9; MS (m=z): 286

1912
A. S. KUMAR ET AL.
þ
[
O, 5.60. Found: C, 71.51; H, 5.62; N, 4.90.
M þ 1]. Anal. calcd. for C H ClNO (285): C, 71.45; H, 5.64; Cl, 12.41; N, 4.90;
1
7
16
0
Data for 2-(4 -tert-Butyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-
oxazole (Entry 3)
1
An oil; H NMR (CDCl ) (d ppm): 7.57–7.40 (m, 3H, ArH), 7.39 (m, 1H, ArH,
3
J ¼ 7.4 Hz), 7.37 (d, 2H, ArH, J ¼ 8.4 Hz), 7.22 (d, 2H, ArH, J ¼ 8.4 Hz), 3.76 (s, 2H,
1
3
–
2
1
8
CH ), 1.26 (s, 9H, 3 ꢁ –CH ), 1.18 (s, 6H, 2 ꢁ –CH ); C NMR (CDCl ) (d ppm):
2
3
3
3
8.6, 31.3, 35.2, 68.1, 78.9, 127.27, 127.28, 127.78, 129.4, 129.5, 130.2, 136.6, 137.8,
40.2, 151.6, 164.8; MS (m=z): 308 [M þ 1]. Anal. calcd. for C H NO (307): C,
þ
2
1
25
2.04; H, 8.20; N, 4.56; O, 5.20. Found: C, 82.09; H, 8.29; N, 4.55.
0
Data for 2 -(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-
carbaldehyde (Entry 4)
1
An oil; H NMR (DMSO-d ) (d ppm): 10.0 (s, 1H, –CHO), 7.91 (d, 2H, ArH,
6
J ¼ 8.4 Hz), 7.73 (d, 1H, ArH, J ¼ 8.4 Hz), 7.48 (d, 2H, ArH, J ¼ 7.8 Hz), 7.44–7.34
(
–
1
m, 2H, ArH), 7.30 (m, 1H, ArH, J ¼ 7.4 Hz), 3.80 (s, 2H, –CH ), 1.12 (s, 6H, 2 ꢁ
2
1
3
CH ); C NMR (DMSO-d ) (d ppm): 28.0, 68.0, 78.9, 128.0, 128.5, 129.5, 129.6,
3 6
þ
30.4, 130.5, 131.2, 135.3, 140.2, 147.0, 161.8, 193.2; MS (m=z): 280 [M þ 1]. Anal.
calcd. for C H NO (279): C, 77.40; H, 6.13; N, 5.01; O, 11.46. Found: C, 77.02; H,
17
1
8
2
6
.30; N, 5.04.
0
Data for 2 -(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-
3-carbaldehyde (Entry 5)
1
An oil; H NMR (DMSO-d ) (d ppm): 10.05 (s, 1H, –CHO), 7.92 (s, 1H, ArH),
6
7
.86 (d, 1H, ArH, J ¼ 7.6 Hz), 7.80 (d, 1H, ArH, J ¼ 7.2 Hz), 7.68 (d, 1H, ArH,
J ¼ 7.6 Hz), 7.59–7.53 (m, 2H, ArH), 7.51–7.40 (m, 2H, ArH), 3.80 (s, 2H, –CH ),
2
1
3
1
1
1
6
.27 (s, 6H, 2 ꢁ –CH ); C NMR (DMSO-d ) (d ppm): 28.6, 68.1, 78.9, 128.0,
3
6
28.7, 129.0, 129.5, 129.6, 130.4, 130.5, 130.8, 131.2, 133.3, 140.2, 141.7, 166.9,
91.6; MS (m=z): 280 [M þ 1]. Anal. calcd. for C H NO (279): C, 77.40; H,
þ
1
8
17
2
.13; N, 5.01; O, 11.46. Found: C, 77.02; H, 6.30; N, 5.04.
0
Data for 4,4-Dimethyl-2-(4 -methyl-biphenyl-2-yl)-4,5-dihydro-
oxazole (Entry 6)
ꢀ
[12]
ꢀ
mp 57–59 C); H NMR (CDCl ) (d ppm):
3
1
Melting point: 56–58 C (lit.
.57–7.37 (m, 3H, ArH), 7.35 (m, 1H, ArH, J ¼ 7.4 Hz), 7.22 (d, 2H, ArH,
7
J ¼ 8.4 Hz), 7.19 (d, 2H, ArH, J ¼ 8.4 Hz), 3.82 (2H, s, –CH ), 2.32 (s, 3H, –CH ),
2
3
1
3
1
1
.30 (s, 6H, 2 ꢁ –CH ); C NMR (CDCl ) (d ppm): 21.2, 28.6, 68.1, 78.9, 127.2,
3
3
27.2, 127.7, 129.3, 129.4, 129.5, 130.2, 136.6, 137.8, 140.2, 164.9; MS (m=z): 266
þ
[
Found: C, 81.41; H, 7.20; N, 5.25.
M þ 1]. Anal. calcd. for C H NO (265): C, 81.48; H, 7.22; N, 5.28; O, 6.03.
1
8
19

ORTHO BIARYL OXAZOLINES VIA SUZUKI REACTION
1913
0
Data for 2 -(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-
4-carboxylic Acid (Entry 7)
ꢀ
[12]
ꢀ
1
Melting point: 191–193 C (lit. mp 191–193 C); H NMR (DMSO-d ) (d ppm):
6
1
2.9 (broad-s, 1H, –COOH), 7.94 (d, 2H, ArH, J ¼ 8.4 Hz), 7.64 (m, 1H, ArH,
J ¼ 7.4 Hz), 7.56 (m, 1H, ArH, J ¼ 7.4 Hz), 7.45–7.42 (m, 2H, ArH), 7.41 (d, 2H,
1
3
ArH, J ¼ 8.4 Hz), 3.76 (s, 2H, –CH ), 1.15 (s, 6H, 2 ꢁ –CH ); C NMR (DMSO-d )
2
3
6
(d ppm): 28.1, 68.0, 78.9, 128.0, 128.3, 128.9, 129.5, 130.0, 130.4, 130.5, 131.2, 140.4,
þ
1
7
45.2, 162.1, 167.7; MS (m=z): 296 [M þ 1]. Anal. calcd. for C H NO (295): C,
1
8
17
3
3.20; H, 5.80; N, 4.74; O, 16.25. Found: C, 73.30; H, 5.79; N, 4.70.
0
Data for 2 -(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-
4-carboxylic Acid Methyl Ester (Entry 8)
1
An oil; H NMR (CDCl ) (d ppm): 7.96 (d, 2H, ArH, J ¼ 8.4 Hz), 7.66 (m, 1H,
3
ArH, J ¼ 7.4 Hz), 7.56 (m, 1H, ArH, J ¼ 7.4 Hz), 7.48–7.44 (m, 2H, ArH), 7.42 (d,
2
–
1
H, ArH, J ¼ 8.4 Hz), 3.84 (s, 3H, –CH ), 3.76 (s, 2H, –CH ), 1.15 (s, 6H, 2 ꢁ
3
2
1
3
CH ); C NMR (CDCl ) (d ppm): 24.6, 47.4, 62.8, 74.7, 123.0, 123.1, 123.6,
3 3
24.0, 124.5, 125.2, 125.5, 125.8, 135.8, 141.1, 158.3, 162.3; MS (m=z): 310
þ
[
Found: C, 73.56; H, 6.23; N, 4.59.
M þ 1]. Anal. calcd. for C H NO (309): C, 73.77; H, 6.19; N, 4.53; O, 15.51.
1
9
19
3
ACKNOWLEDGMENT
We are grateful to SVNIT, Surat, and the Indian Institute of Chemical
Technology, Hyderabad, for supporting this work.
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