Efficient synthesis of structurally novel diaryl ethers by regioselective functionalization

Article abstract of DOI:10.1080/00397910802326547

Synthesis of structurally novel and biologically useful 3'-substituted diaryl ethers employing Cu(0) as a catalyst, followed by regioselective either sulfonylation or carbonylation, is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802326547

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Efficient Synthesis of
Structurally Novel Diaryl
Ethers by Regioselective
Functionalization
Rajendra K. Kharul a , Archana Gite a , Amitgiri
Goswami a , Mukul Jain a , Bipin Pandey a & Pankaj
R. Patel a
a Zydus Research Center , Ahmedabad, Gujrat, India
Published online: 31 Oct 2008.
To cite this article: Rajendra K. Kharul , Archana Gite , Amitgiri Goswami , Mukul
Jain , Bipin Pandey & Pankaj R. Patel (2008) Efficient Synthesis of Structurally Novel
Diaryl Ethers by Regioselective Functionalization, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:23,
4282-4294, DOI: 10.1080/00397910802326547
To link to this article: http://dx.doi.org/10.1080/00397910802326547
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Synthetic Communications1, 38: 4282–4294, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802326547
Efficient Synthesis of Structurally Novel Diaryl
Ethers by Regioselective Functionalization
Rajendra K. Kharul, Archana Gite, Amitgiri Goswami, Mukul Jain,
Bipin Pandey, and Pankaj R. Patel
Zydus Research Center, Ahmedabad, Gujrat, India
Abstract: Synthesis of structurally novel and biologically useful 30-substituted
diaryl ethers employing Cu(0) as a catalyst, followed by regioselective either
sulfonylation or carbonylation, is described.
Keywords: Chlorosulfonic acid, diaryl ether, hexamethylene tetraamine,
regioselective sulfonylation and carbonylation
INTRODUCTION
Diaryl ether linkage is present in many important classes of organic
molecules (e.g., ligands for inorganic complexes and polyphenylene oxide
polymer). Diaryl ether motif is also present in a number of natural
compounds as well as biologically active compounds.[1]
RESULTS AND DISCUSSION
In continuation of our efforts to synthesize biologically active diaryl
ethers[2] for a new drug discovery program supported by molecular mod-
eling studies, we required 30-substituted diaryl ethers (1 and 2). Although
simple diaryl ethers can be obtained by coupling the suitable fragments,
Received May 4, 2008.
ZRC Communication No. 243.
Address correspondence to Rajendra K. Kharul, Zydus Research Center,
Sarkhej Bavala N. H. 8A, Moraiya, Ahmedabad, 382210 Gujarat, India. E-mail:
rajendrakharul@zyduscadila.com
4282

Structurally Novel Diaryl Ethers
4283
Scheme 1. Reagents and conditions: a) Cu, Et3N, CH2Cl2, rt, 4 days, 80%.
there are few reports related to regioselective electrophilic substitution at
the 30-position.[3] The present communication describes regioselective
functionalization at the 30-position by using simpler reaction conditions
and readily available reagents, which makes the approach scalable. To
execute this, we needed various diaryl ethers. The literature describes var-
ious ways to assemble the ether backbone,[4] of which the Cu(0)-catalyzed
reaction[5] appeared to be the most effective.
Initially, bis-(4-methoxyphenyl) iodoniumtetrafluoroborate (3) was
coupled with methyl 3,5-dichloro-4-hydroxybenzoate (4) by using Cu(0)
as catalyst to get coupled product (5) (Scheme 1).[6] Subsequent regiose-
lective functionalization of (5) followed by functional group transforma-
tions furnished 1 and 2 (Schemes 2 and 3).
hus, diaryl ether (5) was sulfonylated at 0 ꢀC by using chlorosulfonic
acid to furnish corresponding arylsulfonyl chloride, which was obtained
by carefully quenching the excess of chlorosulfonic acid present in the
reaction mixture by slow addition of water at ꢁ5 to 0 ꢀC. The spectral
analysis indicated monosulfonylation in the prime ring (1H NMR, electro-
spray ionization-mass spectrometry [ESI-MS]). It is important and inter-
esting to note that the 30-position was regioselectively sulfonylated.
The regioselectivity was conceptualized and established based on
`
enhanced inductive effect of OMe group vis-a-vis OAr group for ortho
0
substitution followed by spectroscopic evidence. Thus, H2 proton (7.33
Scheme 2. Reagents and conditions: (a) ClSO3H, ꢁ10 to 0 ꢀC, 30 min; (b)
R1R2NH, CH2Cl2, 0 ꢀC to rt, 2 h, 70–80% (combined yield for two steps); (c)
KOH, MeOH:H2O (1:1), rt, 90–94%; (d) EDCI, HOBT, Et3N, CH2Cl2, 0 ꢀC to
rt, 15 h, 72–75%; (e) BBr3, CHCl3, ꢁ78 ꢀC, 58–75%.

4284
R. K. Kharul et al.
Scheme 3. Reagents and conditions: (a) HMTA, TFA, 80%; (b) Jones reagent,
acetone, 0 ꢀC, 30 min, 70%; (c) i) (COCl)2, cat. DMF, CH2Cl2, 0 ꢀC to rt, 2 h;
ii) R1R2NH, Et3N, CH2Cl2, 0 ꢀC to rt, 30 min, 75–85%; (d) KOH, MeOH:H2O
(1:1), rt, 85–90%; (e) EDCI, HOBT, Et3N, CH2Cl2, 0 ꢀC to rt, 15 h, 50–60%; (f)
BBr3, CHCl3, ꢁ78 ꢀC, 53–80%.
d, d, J ¼ 3 Hz) was flanked by sulfonyl and aryloxy groups and deshielded
0
0
0
0
as compared to H5 and H6 proton (Fig. 2). H5 and H6 appear at 6.95 d
(d, J ¼ 9 Hz) and 7.02 d (dd, J ¼ 3, 9 Hz) respectively. The reason for
exclusive monosubstitution at the 30-position can also be attributed to
the steric hindrance at either 20 or 60 position.
The sulfonyl chloride thus obtained was treated either with primary
or secondary amine to yield sulfonamides esters (7a–f). The sulfonamide
ester (7) was hydrolyzed to the corresponding acids (8a–f), and the acids
were coupled with (L)-proline by using 3-ethyl-1(N,N-dimethyl)amino-
propylcarbodiimide (EDCI).[7] The aryl ethers (9a–f) thus obtained, when
subjected to demethylation with BBr3,[8] furnished the desired diaryl
ethers (1a–f) in one pot (Fig. 1 and Table 1).
To synthesize caboxamides (2a–c), the diaryl ether (5) was regioselec-
tively carbonylated at the 30-position with hexamethylene tetraamine[9]
(HMTA) to furnish aldehyde (10). The aldehyde thus obtained was
oxidized with Jones reagent[10] to give the corresponding acid (11). The
Figure 1. Various sulfonamides (1a–f) and carboxamides (2a–c).

Structurally Novel Diaryl Ethers
4285
Figure 2.
carboxylic acid was converted to the amides (12a–c) via its acid chlorides,
which were prepared using oxalyl chloride. The amides (12) were regiose-
lectively hydrolyzed to the acid and then coupled with (L)-proline using
Table 1. Different substituents, absolute configuration, melting point, and yields
for products (1a–f) and (2a–c)
Absolute
configuration
Mp
(ꢀC)
Yield
(%)
Compound
R1
H
R2
R3
of ꢁCOOHa
1a
H
(S)
147–148
58
1b
1c
–(CH2)5–
–(CH2)5–
H
H
(S)
(R)
121–122
122–124
75
72
1d
H
H
H
(S)
147–148
61
1e
H
(S)
139–140
66
1f
2a
–(CH2)5–
–(CH2)5–
OH (R)
H
(S)
(S)
163–165
145–146
60
80
2b
2c
H
H
H
(S)
210–212
53
–(CH2)5–
(R)
122–123
66
Note. We have used L- and D-proline as well as trans-3-hydroxy-(L)-proline as
obtained from Aldrich & Co. We did not determine specific optical rotation of the
final compounds though they are chiral.

4286
R. K. Kharul et al.
EDCI to furnish diaryl ethers (14a–c). After demethylation with BBr3, dia-
ryl ether (14) furnished the desired polysubstituted diaryl ethers (2a–c).
CONCLUSION
Thus, a successful methodology for regioselective sulfonylation as well as
carbonylation at the 30-position of the polysubstituted diaryl ether has
been established. The further exploration of this methodology to prepare
differently functionalized complex diaryl ethers is under way.
EXPERIMENTAL
General Methods
1H NMR was recorded on the NMR spectrometer (M-300) at 300 MHz
in CDCl3 or DMSO-d6 solvent. Chemical shifts were reported as parts
per million downfield from an internal tetramethylsilane standard
1
(d ¼ 0.00 for H NMR). Mass spectra were recorded on a Perkin-Elmer
Sciex API 3000. IR spectra were recorded on FT-IR 8300 Shimadzu in
KBr pellets or CHCl3 or CCl4 as solvent. The compounds were analyzed
for purity by analytical HPLC at kmax 220 nm using column ODS C-18,
150 mm ꢂ 4.6 mm ꢂ 4 m on an Agilent 100 series. Melting points were
taken on a Scientific melting-point apparatus and are uncorrected.
Thin-layer chromatography (TLC) was performed by using 25 DC-
Alufolien 20 ꢂ 20 cm Kieselgel 60 F254 Merck plates.
Glassware was oven or flame dried prior to use. Reactions were per-
formed under an argon or nitrogen inert atmosphere whenever needed.
Crude products were purified by flash chromatography using 100- to
200-mesh silica gel, 230- to 400-mesh silica gel, or neutral aluminum oxide.
Preparation of 3,5-Dichloro-4-(4-methoxy-phenoxy)-benzoic Acid,
Methyl Ester (5)
To a stirred solution of bis-(4-methoxyphenyl) iodoniumtetrafluoroborate
(3) (20 g, 46.72 mmol, 1.5 equiv.) in dry dichloromethane (40 mL), copper
bronze (3.95g, 62.30mmol, 2 equiv.) was added at 0–5ꢀC. To this solution,
a mixture of methyl 3,5-dichloro-4-hydroxybenzoate (4) (6.88 g, 31.15 mmol,
1.0 equiv.) and triethyl amine (3.46 g, 34.26 mmol, 1.1 equiv.) in dichloro-
methane (60 mL) was added dropwise over a period of 1 h. The resulting
mixture was warmed to room temperature, stirred for 96 h, and filtered
through Celite1, and the residual copper bronze was washed thoroughly

Structurally Novel Diaryl Ethers
4287
with dichloromethane. The combined organic extracts were concentrated in
vacuo to obtain a crude, brown, thick liquid. The crude product was purified
by flash-column chromatography using (100- to 200-mesh) silica gel as sta-
tionary phase and ethyl acetate and n-hexane (2:98) as mobile phase to
1
obtain methyl ester (5) as white solid (8.3 g, 82%). H NMR (CDCl3,
300 MHz): d 8.06 (s, 2H), 6.83 (dd, J ¼ 9, 3 Hz, 2H), 6.76 (dd, J ¼ 9, 3 Hz,
2H), 3.94 (s, 3H), 3.77 (s, 3H); mp: 67–68ꢀC; HPLC purity: 99.33%.
General Procedure for Preparation of 7a–7f
3,5-Dichloro-4-[4-methoxy-3-(piperidine-1-sulfonyl)-phenoxy]-benzoic
Acid, Methyl Ester (7b)
Powdered 3,5-dichloro-4-(4-methoxy-phenoxy)-benzoic acid, methyl
ester (5) (1 g, 3.06 mmol, 1.0 equiv.) was taken in a round-bottomed flask,
and chlorosulfonic acid (1.78 g, 15.3 mmol, 5 equiv.) was carefully added
drop wise at 0–5 ꢀC. The resulting mixture was warmed to room tempera-
ture and stirred for 1 h. The reaction mixture was cooled to 0–5 ꢀC, and
excess chlorosulfonic acid was carefully quenched by dropping cold water
along the walls of the flask. The white precipitate obtained was extracted
with ethyl acetate (2 ꢂ 25 mL). The combined organic phase was washed
with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to furnish methyl ester (6) (1.1 g, crude). To the
stirred solution of methyl ester (6) (1.08 g, 2.55 mmol, 1 equiv.) in
dichloromethane (20 mL), piperidine (0.54 g, 6.37 mmol, 2.5 equiv.) was
added at 0–5 ꢀC dropwise. The resulting mixture was warmed to room
temperature and stirred for 2 h. The solvent was removed in vacuo, to
give a light yellow solid (1.12 g, 93% crude). The crude solid was treated
with methanol (10 mL) and stirred at room temperature for 10 min. The
obtained white solid was filtered in vacuo, to give methyl ester (7b)
(0.87 g, 72%). 1H NMR (CDCl3, 300 MHz): d 8.07 (s, 2H), 7.33 (d,
J ¼ 3 Hz, 1H), 7.01 (dd, J ¼ 9, 3 Hz, 1H), 6.94 (d, J ¼ 9 Hz, 1H), 3.95 (s,
3H), 3.89 (s, 3H), 3.20–3.17þ(m, 4H), 1.64–1.55 (m, 4H), 1.54–1.50 (m,
2H); ESI-MS: 497 [M þ Na] ; mp 139–140 ꢀC; HPLC purity: 94.25%.
General Procedure for Preparation of 8a–8f
3,5-Dichloro-4-[4-methoxy-3-(piperidine-1-sulfonyl)-phenoxy]-benzoic
Acid (8b)
NaOH (0.14 g, 3.65 mmol, 5 equiv.) dissolved in water (3 mL) was added
to a stirred solution of methyl ester (7b) (0.34 g, 0.73 mmol, 1.0 equiv.) in

4288
R. K. Kharul et al.
methanol (3 mL) at 26 ꢀC. The resulting mixture was stirred at room tem-
perature for 6 h. The reaction mixture was concentrated in vacuo. The
residue was dissolved in water (10 mL) and washed with ethyl acetate
(2 ꢂ 10 mL); the aqueous layer was acidified using 10% HCl solution
(5 mL) to furnish a white solid product. The white solid product was fil-
tered under suction, washed with n-hexane (20 mL), and dried in vacuo to
1
obtain acid (8b) (0.27 g, 82%). H NMR (CDCl3, 300 MHz): d 8.11 (s,
2H), 7.50 (d, J ¼ 3 Hz, 1H), 7.02 (dd, J ¼ 9, 3 Hz, 1H), 6.94 (d, J ¼ 9 Hz,
Hz, 1H), 3.96 (s, 3H), 3.20–3.12 (m, 4H), 1.60–1.50 (m, 6H); ESI-MS: 459
[Mꢁ1]; mp: 206–207 ꢀC; HPLC purity: 96.66%.
General Procedure for Preparation of 9a–9f
1-{3,5-Dichloro-4-[4-methoxy-3-(piperidine-1-sulfonyl)-phenoxy]-
benzoyl}-pyrrolidine-2-carboxylic Acid, Methyl Ester (9b)
EDC ꢃ HCl (0.216 g, 1.13 mmol, 2 equiv.) and HOBT (0.076g, 0.565 mmol,
1 equiv.) were added to a stirred solution of acid (8b) (0.26 g, 0.56 mmol, 1.0
equiv.) in dichloromethane (10 mL) at 0–5 ꢀC. L-Proline methyl ester
hydrochloride (0.108g, 0.565 mmol, 1 equiv.) was added followed by addi-
tion of triethyl amine (0.058g, 0.565 mmol, 1 equiv.), and the resulting mix-
ture was stirred at 26 ꢀC for 24h. The reaction mixture was diluted with
dichloromethane (10 mL), washed with water (2ꢂ 10 mL) and brine
(1 ꢂ 10 mL), dried over anhydrous sodium sulfate, filtered, and concen-
trated in vacuo to obtain the crude product. The crude product was purified
by flash-column chromatography using alumina as stationary phase and
ethyl acetate in n-hexane (4:6) as mobile phase to obtain the methyl ester
1
(9b) (0.186 g, 58%) as low melting solid. H NMR (CDCl3, 300 MHz): d
7.62 (s, 2H), 7.41 (d, J ¼ 3 Hz, 1H), 7.01 (dd, J ¼ 9, 3 Hz, 1H), 6.94 (d,
J ¼ 9 Hz, 1H), 4.68–4.64 (m, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.73–3.60 (m,
2H), 3.21–3.12 (m, 4H), 2.38–2.35 (m, 1H), 2.09–1.99 (m, 3H), 1.60–1.50
(m, 6H); ESI-MS: 571.6 [M þ H]þ; mp: 62–64 ꢀC; HPLC purity: 98.14%.
General Procedure for Preparation of 1a–1f
1-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-1-sulfonyl)-phenoxy]-
benzoyl}-pyrrolidine-2-carboxylic Acid (1b)
To a stirred solution of methyl ester (9b) (0.206 g, 0.36 mmol, 1.0 equiv.)
in chloroform (8 mL) at ꢁ78 ꢀC, BBr3 (0.541 g, 2.16 mmol, 6 equiv., 1 M
solution in CHCl3) were added. The resulting brown-colored reaction
mixture was stirred at 26 ꢀC for 16 h. The reaction mixture was quenched

Structurally Novel Diaryl Ethers
4289
with water (10 mL) and stirred at room temperature for 1 h. The organic
layer was separated and washed with saturated NH4Cl solution
(1 ꢂ 10 mL), dried over anhydrous sodium sulfate, filtered, and concen-
trated in vacuo to obtain crude product. The crude product was purified
by treating it with saturated solution of NaHCO3, washing the aqueous
layer with ethyl acetate (2 ꢂ 10 mL), and acidifying the aqueous layer
with 10% HCl solution (5 mL). The aqueous layer was extracted with
ethyl acetate (2 ꢂ 20 mL); the chloroform layer was washed with water
(2 ꢂ 20 mL) and brine (1 ꢂ 20 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to obtain acid (1b) (0.16 g, 95%).
1
Compound (1a): 58% yield; H NMR (DMSO-d6, 300 MHz): d 10.65
(br s, 1H), 7.73 (s, 2H), 7.05–6.92 (m, 3H), 4.39–4.25 (m, 1H), 3.55–
3.50 (m, 3H), 2.26–2.16 (m, 1H), 2.06–1.86 (m, 3H), 0.94 (d, J ¼ 6.51 Hz,
6H); ESI-MS: 516 [Mꢁ 1]; mp: 147–148 ꢀC; HPLC purity: 97.80%.
1
(1b): 95% yield; H NMR (CDCl3, 300 MHz): d 8.60 (br s, 1H), 7.65 (s,
2H), 7.09–7.03 (m, 2H), 6.94 (d, J ¼ 9 Hz, 1H), 4.74 (t, J ¼ 6.7 Hz, 1H),
3.69–3.63 (m, 2H), 3.06–3.02 (m, 4H), 2.36–2.29 (m, 2H), 2.14–1.97 (m,
3H), 1.64–1.56 (m, 4H), 1.48–1.42 (m, 2H); ESI-MS: 507.1 [Mþ H]þ; mp:
1
121–122 ꢀC; HPLC purity: 97.28%. (1c): 72% yield; H NMR (DMSO-d6,
300 MHz): d 12.66 (br s, 1H), 10.46 (s, 1H), 7.74 (s, 2H), 7.08–6.97 (m,
3H), 4.44–4.35 (m, 1H), 3.58–3.56 (m, 2H), 3.05 (s, 4H), 2.28–2.24 (m,
1H), 2.04–1.82 (m, 3H), 1.49–1.40 (m, 6H); ESI-MS: 543.5 [Mþ H]þ; mp:
1
122–124 ꢀC; HPLC purity: 97.18%. (1d): 61% yield: H NMR (DMSO-d6,
300 MHz): d 12.64 (br s, 1H), 10.72 (s, 1H), 10.1 (s, 1H), 7.72 (s, 2H),
7.15 (t, J ¼ 8.0 Hz, 2H), 7.04–6.89 (m, 6H), 4.43–4.36 (m, 1H), 3.59–3.56
(m, 2H), 2.28–2.26 (m, 1H), 2.06–1.86 (m, 3H); ESI-MS: 551 [Mꢁ 1]; mp:
1
147–148 ꢀC; HPLC purity: 98.73%. (1e): 66% yield; H NMR (DMSO-d6,
300 MHz): d 12.66 (br s, 1H), 10.45 (s, 1H), 7.72 (s, 2H), 7.27–7.24 (m,
1H), 7.09–6.95 (m, 3H), 4.38–4.36 (m, 1H), 3.59–3.56 (m, 2H), 3.16–3.14
(m, 1H), 2.28–2.26 (m, 1H), 2.06–1.86 (m, 3H), 1.60–1.56 (m, 3H), 1.44–
1.42 (m, 1H), 1.18–1.09 (m, 6H); ESI-MS: 557 [M]þ; mp 139–140 ꢀC; HPLC
purity: 96.46%. (1f): 60% yield; 1H NMR (DMSO-d6, 300 MHz): d 12.73 (br
s, 1H), 10.45 (s, 1H), 7.75–7.64 (m, 2H), 7.08–6.97 (m, 3H), 5.20–5.14 (m,
1H), 4.47 (t, J ¼ 8.1 Hz, 1H), 4.29–4.26 (m, 1H), 3.89–3.79 (m, 1H), 3.05
(s, 4H), 2.26–2.15 (m, 1H), 2.06–1.96 (m, 1H), 1.47–1.42 (m, 6H); ESI-
MS: 557 [M]ꢁ ; mp: 163–165 ꢀC; HPLC purity: 97.34%.
Preparation of 3,5-Dichloro-4-(3-formyl-4-methoxy-phenoxy)-
benzoic Acid, Methyl Ester (10)
To a stirred solution of methyl ester (5) (4.0 g, 12.23 mmol, 1.0 equiv.) in
trifluoroacetic acid (40 mL), hexamethyl tetramine (4.28 g, 30.58 mmol,

4290
R. K. Kharul et al.
2.5 equiv.) was added at 26 ꢀC. The resulting brown-colored reaction mix-
ture was heated at 70–80 ꢀC and stirred for 4 h. Trifluoroacetic acid was
removed in vacuo, and the resulting solid residue was stirred with water
(60 mL) for 16 h. The aqueous solution was carefully neutralized using
solid sodium bicarbonate, and pH was adjusted to 8. The aqueous layer
was extracted with dichloromethane (3 ꢂ 40 mL). The combined organic
extracts were washed with water (2 ꢂ 40 mL) and brine (1 ꢂ 40 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo to
obtain a crude yellow solid (4.2 g, 100%). The crude product was purified
by flash column chromatography using silica gel (100–200 mesh size), and
the pure product was eluted using ethyl acetate and n-hexane (7:93) to
1
obtain methyl ester (10) (3.4 g, 78%). H NMR (DMSO-d6, 300 MHz):
d 10.27 (s, 1H), 8.12 (s, 2H), 7.34 (dd, J ¼ 9.12 and 3 Hz, 1H), 7.27 (d,
J ¼ 9.15 Hz, 1H), 6.95 (d, J ¼ 3 Hz, 1H), 3.91 (s, 3H), 3.9 (s, 3H); mp:
145–147 ꢀC; HPLC purity: 96.12%.
Preparation of 3,5-Dichloro-4-(3-carboxy-4-methoxy-phenoxy)-
benzoic Acid (11)
Jones reagent (9 mL) was added to a stirred solution of methyl ester (10)
(3.0 g, 8.45 mmol, 1.0 equiv.) in acetone (50 mL) at 0–5 ꢀC until brown
color persisted. The resulting brown-colored reaction mixture was
warmed to room temperature and stirred for 4 h. The reaction mixture
was quenched with isopropanol (8.0 mL); the green inorganic salts preci-
pitated were removed by filtration under suction. The colored solution
was concentrated in vacuo to obtain crude off-white solid, which was
stirred with water (50 mL) for 30 min at room temperature and filtered
off. Thus the free-flowing acid (11) (1.9 g, 61%) was obtained. 1H
NMR (DMSO-d6, 300 MHz): d 12.88 (br s, 1H), 8.11 (s, 2H), 7.12–7.04
(m, 3H), 3.89 (s, 3H), 3.78 (s, 3H); ESI-MS: 372.2 [M þ H]þ; mp: 199–
200 ꢀC; HPLC purity: 93.77%.
General Procedure for Preparation of 12a–12c
3,5-Dichloro-4-[4-methoxy-3-(piperidine-1-carbonyl)-phenoxy]-benzoic
Acid, Methyl Ester (12a)
A catalytic amount of N,N-dimethylformamide (2 drops) was added
to the stirred solution of methyl ester (11) (0.9 g, 2.42 mmol, 1.0 equiv.)
in dichloromethane (5 mL) followed by oxalyl chloride (0.64 mL,
7.26 mmol, 3 equiv.) at 0–5 ꢀC. The resulting mixture was warmed to

Structurally Novel Diaryl Ethers
4291
room temperature and stirred for 1 h. The reaction mixture was concen-
trated and dried in vacuo to obtain the corresponding acid chloride
(0.94 g, crude). To the stirred solution of acid chloride (0.94 g, 2.42 mmol,
1 equiv.) in dichloromethane (10 mL), piperidine (0.41 g, 4.85 mmol, 2.0
equiv.) at 0–5 ꢀC was added dropwise. The resulting mixture was warmed
to room temperature and stirred for 1 h. The reaction mixture was diluted
with dichloromethane (5 mL), washed with water (1 ꢂ 20 mL) and brine
(20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo
to obtain methyl ester (12a) in the form of a light-yellow, thick liquid
1
(1.13 g, 98% crude). H NMR (CDCl3, 300 MHz): d 8.05 (s, 2H), 6.83–
6.82 (m, 2H), 6.68–6.67 (m, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 3.69–3.65
(m, 2H), 3.19–3.16 (m, 2H), 1.64–1.50 (m, 6H); ESI-MS: 437.9 [M]þ;
HPLC purity: 93.27%.
General Procedure for Preparation of 13a–13f
3,5-Dichloro-4-[4-methoxy-3-(piperidine-1-carbonyl)-phenoxy]-
benzoic Acid (13a)
To the stirred solution of methyl ester (12a) (1.0 g, 2.28 mmol, 1.0 equiv.)
in methanol (5 mL), NaOH (0.45 g, 11.41 mmol, 5 equiv.) dissolved in
water (5 mL) was added at room temperature. The resulting mixture
was stirred at room temperature for 6 h. The reaction mixture was con-
centrated in vacuo. The residue was dissolved in water (10 mL), washed
with ethyl acetate (2 ꢂ 10 mL); the water layer was acidified using 10%
HCl solution (5 mL) to yield a white solid. The white solid was filtered
under suction, washed with n-hexane (20 mL), and dried in vacuo to
1
obtain acid (13a) (0.9 g, 93%). H NMR (DMSO-d6, 300 MHz): d 13.65
(br s, 1H), 7.98 (s, 2H), 6.97 (d, J ¼ 9.12 Hz, 1H), 6.82 (dd, J ¼ 9, 3 Hz,
1H), 6.60 (d, J ¼ 3.12 Hz, 1H), 3.68 (s, 3H), 3.47–3þ.43 (m, 2H), 3.02–
2.98 (m, 2H), 1.48–1.29 (m, 6H); ESI-MS: 423.9 [M] ; mp: 147–148 ꢀC;
HPLC purity: 95.04%.
General Procedure for Preparation of 14a–14c
1-{3,5-Dichloro-4-[4-methoxy-3-(piperidine-1-carbonyl)-phenoxy]-
benzoyl}-pyrrolidine-2-carboxylic Acid, Methyl Ester (14a)
EDC ꢃ HCl (0.76 g, 4.00 mmol, 2 equiv.) and HOBT (0.27 g, 2.00 mmol,
1 equiv.) were added to the stirred solution of acid (13a) (0.85 g,
2.00 mmol, 1.0 equiv.) in dichloromethane (10 mL), at 0–5 ꢀC. L-Proline

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R. K. Kharul et al.
methyl ester hydrochloride (0.26 g, 2.00 mmol, 1 equiv.) was added fol-
lowed by addition of triethyl amine (0.20 g, 2.00 mmol, 1 equiv.). The
resulting mixture was stirred at room temperature for 24 h and then
diluted with dichloromethane (10 mL), washed with water (2 ꢂ 10 mL)
and brine (1 ꢂ 10 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo to obtain crude product. The crude product
was purified by flash-column chromatography using silica gel (100–
200 mesh) as stationary phase and ethyl acetate in n-hexane (1:1) as
mobile phase to obtain methyl ester (14a) as a white solid (0.60 g,
1
60%). H NMR (CDCl3, 300 MHz): d 7.61 (s, 2H), 6.83–6.79 (m, 2H),
6.70–6.69 (m, 1H), 4.68–4.64 (m, 1H), 3.79 (s, 6H), 3.70–3.62 (m, 4H),
3.19–3.16 (m, 2H), 2.40–2.30 (m, 1H), 2.09–1.99þ(m, 3H), 1.65–1.60 (m,
4H), 1.52–1.44 (m, 2H); ESI-MS: 557.4 [M þ Na] ; mp: 71–73 ꢀC; HPLC
purity: 99.32%.
General Procedure for Preparation of 2a–2c
1-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-
benzoyl}-pyrrolidine-2-carboxylic Acid (2a)
To the stirred solution of methyl ester (14a) (0.44 g, 0.82 mmol, 1.0
equiv.) in chloroform (8 mL) at ꢁ78 ꢀC BBr3 (1.23 g, 4.93 mmol, 6 equiv.
1 M solution in CHCl3) was added. The resulting brown-colored reaction
mixture was stirred at room temperature for 16 h, then quenched with
water (10 mL) and stirred at 26 ꢀC for 1 h. The organic layer was sepa-
rated, washed with saturated NH4Cl solution (1 ꢂ 10 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain
crude product. The crude product was purified by treating it with a
saturated solution of NaHCO3 and washing the aqueous layer with
diethyl ether (2 ꢂ 10 mL). The aqueous layer was acidified with 10%
HCl solution (5 mL). The white solid product that precipitated was
filtered in vacuo, washed with water (2 ꢂ 25 mL) and n-hexane
1
(2 ꢂ 25 mL), and dried in vacuo to obtain acid (2a) (0.35 g, 84%). H
NMR (CDCl3, 300 MHz): d 9.19 (br s, 1H), 7.64–7.61 (m, 2H),
6.98–6.90 (m, 2H), 6.62 (d, J ¼ 2.55 Hz, 1H), 4.73 (t, J ¼ 6.64 Hz, 1H),
3.65–3.57 (m, 6H), 2.35–2.28 (m, 2H), 2.17–2.07 (m, 1H), 2.02–1.94 (m,
1H), 1.68–1.63 (m, 2H), 1.60–1.54, (m, 4H); ESI-MS: 507.0 [M þ H]þ;
mp: 145–146 ꢀC; HPLC purity: 99.12%. (2b): 53% yield; 1H NMR
(DMSO-d6, 300 MHz): d 12.62 (br s, 1H), 11.59 (s, 1H), 8.18 (s, 1H),
7.72 (s, 2H), 7.44–7.40 (m, 1H), 6.86–6.73 (m, 2H), 4.44–4.36 (m, 1H),
3.58–3.56 (m, 2H),þ2.03 (s, 10H), 1.91–1.83 (m, 3H), 1.64 (s, 6H); ESI-
MS: 573.8 [M þ H] ; mp: 210–212 ꢀC; HPLC purity: 99.84%. (2c): 66%

Structurally Novel Diaryl Ethers
4293
1
yield; H NMR (DMSO-d6, 300 MHz): d 12.8 (br s, 1H), 9.56 (s, 1H),
7.70 (s, 1H), 6.82–6.72 (m, 2H), 6.54–6.50 (m, 1H), 4.41–4.35 (m,
1H), 3.57–3.52 (m, 3H), 3.32–3.26 (m, 3H), 1.89–1.85 (m, 4H), 1.53 (s,
2H), 1.43 (s, 4H); ESI-MS: 507.1 [M þ H]þ; mp: 122–123 ꢀC; HPLC pur-
ity: 98.29%.
ACKNOWLEDGMENT
We thank the management of Zydus Cadila Group for encouragement
and our analytical department for support.
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