A convenient preparation of N-alkyl and N-arylamines by smiles rearrangement - Synthesis of analogues of diclofenac

Article abstract of DOI:10.1081/SCC-120021996

Smiles rearrangement of substituted aryloxyacetamides in which oxygen and nitrogen are separated by COCH₂ group has been successful even when the aryloxy ring carries weak or no electron withdrawing group. Earlier reports of such reactions involved either strong electron withdrawing groups or a special catalyst. The diphenylamines thus obtained gave analogues of diclofenac in only one case.

Full text of DOI:10.1081/SCC-120021996

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A Convenient Preparation of N-Alkyl and N-Arylamines
by Smiles Rearrangement—Synthesis of Analogues of
Diclofenac
M. S. Wadia a & D. V. Patil a b
a Department of Chemistry , University of Pune , India
b Chemistry Department , Cusrow Wadia Institute of Technology , Pune, India
Published online: 17 Aug 2006.
To cite this article: M. S. Wadia & D. V. Patil (2003) A Convenient Preparation of N-Alkyl and N-Arylamines by Smiles
Rearrangement—Synthesis of Analogues of Diclofenac, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:15, 2725-2736, DOI: 10.1081/SCC-120021996
To link to this article: http://dx.doi.org/10.1081/SCC-120021996
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 15, pp. 2725–2736, 2003
A Convenient Preparation of N-Alkyl and
N-Arylamines by Smiles
Rearrangement—Synthesis of
Analogues of Diclofenac
#
*
M. S. Wadia and D. V. Patil
Department of Chemistry, University of Pune, India
ABSTRACT
Smiles rearrangement of substituted aryloxyacetamides in which
oxygen and nitrogen are separated by COCH2 group has been suc-
cessful even when the aryloxy ring carries weak or no electron with-
drawing group. Earlier reports of such reactions involved either
strong electron withdrawing groups or a special catalyst. The
diphenylamines thus obtained gave analogues of diclofenac in only
one case.
*Correspondence: M. S. Wadia, Department of Chemistry, University of Pune,
411007, India; E-mail: mswadia@chem.unipune.ernet.in.
#Current address: Chemistry Department, Cusrow Wadia Institute of
Technology, Pune, India.
2725
DOI: 10.1081/SCC-120021996
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2726
Wadia and Patil
Diaryl amines are frequently difficult to prepare, especially if the two
aryl rings are different. One method for their preparation involves Smiles
rearrangement.[1,2a] The rearrangementof o-aminophenyl aryl ethers has
been reviewed.[2a]
Rearrangements are reported when the aryl rings carried strong
electron withdrawing substituents like nitro and three or more fluorine
atoms.[2a] The firstexample of Smiles rearrangementwhit a single
halogen atom as the activating group was carried out in this series of
compounds using excess NaNH2 in refluxing benzene.[2b]
For aryloxyacetamides where oxygen and nitrogen are separated by
CH2-CO group, the Smiles rearrangement has been successful in
NaH/DMF at50 ꢀC only when aryloxy ring contains strong electron
withdrawing groups such as NO2.[4] The only report[4] when phenoxy
ring carries two or three chlorines needs a special catalyst viz TDA.
The reaction is facilitated if the oxygen and nitrogen of the aryl-
oxyacetamides are separated by CMe2-CO group[3,5] since formation of
spirocyclic intermediate is aided by the presence of methyl groups. When
the reaction is carried out with NaH/DMF[3] the reaction was successful
only when the aryloxy ring contains strong electron withdrawing groups
such as NO2, COC6H5 or CF3. However in this class of compounds
reactions are successful even when the aryloxy ring contains no activating
groups provided the reaction are carried out in NaH in the carcinogenic
HMPA or NaH/DMF in presence of DMPU.[5] The present study reports
the Smiles rearrangement of aryloxyacetamides in which the oxygen and
nitrogen are separated by a CH2-CO group. Smiles reaction of the amide
1a has been reported[6] using NaOEt/EtOH at reflux. Under these con-
ditions it gave a product characterized (m.p., spectral data) as the desired
amine 2a in 95% yield. Similar reactions were then carried out on the
amides 1b–d to afford the expected amines 2b–d in 87,67, and 80% yields
respectively. Reaction of the dichloroamide 1e, under these conditions,
ꢀ
gave a productm.p.138–139 C (82% yield) characterized as the acid 3e.
[6]
Ithas been reporetd
that rearrangement using ꢁOH of less activated
amides 1f afforded the hydrolysis product 3f whereas that of the more
activated amides 1a or 1g under these conditions gave the rearranged
products 2a or 2g.
In order to avoid such type of hydrolytic cleavage, it was decided to
[3]
carry outfurhter reacitons in NaH/DMF.
Reaction of the amide 1d
afforded the product 2d m.p. 42–43ꢀC (characterized by the usual means)
in 76% yield. Similar reaction on 1e, 1h, and 1i provided the amines 2e,
ꢀ
2h, and 2i in 52, 50, and 47% yields. Reaction of 1e at125 C gave the
rearranged product 2e in 40% yield and another compound m.p.
154–155ꢀC (14%) which could have either structure 4a or 4b. In order

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Smiles Rearrangement of Aryloxyacetamides
2727
ArNHR
Ar-OCH CONHR
2
2
1
1-2
g
Ar = 2-nitrophenyl
R = Ph
a
R = Ph
Ar = 4- nitrophenyl
Ar = 4- nitrophenyl
Ar = 4- nitrophenyl
2,4,6-trichlorophenyl
Ar =
Ar =
h R = Et
i
b R = 3-tolyl
c R = 3-anisyl
d R = Ph
2,4-dichlorophenyl
R = Et
Ar =
Ar =
Ar =
j
2,4,6-trichlorophenyl
Ar = Ph
Ar = Ph
R = Ph
e
f
R = Ph
R = Ph
2,4- dichlorophenyl
3-nitrophenyl
R = 4- anisyl
k
l
R =
2,4,6-trichloro Ar = Ph
phenyl
ArOCH COOH
2
R
Cl
O
3
Cl
O
e Ar = 2,6 dichloropheny
f Ar = 3-nitrophenyl
COCH X
2
R'
N
N
Ph
Ph
5a X = Cl
4a R= Cl R'= H
4b R= H R'= Cl
5b X = OH
to decide between structure 4a and 4b, the amine 2e was converted to the
chloride 5a (reaction with chloroacetyl chloride, 93% yield) and then to
alcohol 5b (hydrolysis with Na2CO3, yield 61% based on 5a consumed).
In the hydrolysis reaction, the amine 2e characterized by direct compar-
ison (TLC, IR, NMR) was isolated in 16% yield. Attempted cyclization
of 5b using NaH/DMF at room temperature gave two products one of
which (28%) was identified as the amine 2e. The other compound had
m.p. 103–104ꢀC very differentfrom that(m.p. 154–155 ꢀC) isolated in the
reaction of 1e with NaH/DMF at high temperature. This initially led to
the conclusion that compound m.p. 103–104ꢀC was 4b and compound
m.p. 154–55ꢀC was 4a. However examination of its properties (TLC,
Spectra) established that compound m.p. 103–104ꢀC has structure 1e
and its formation involved a Smiles rearrangement occurring in 47%
yield. Since Smiles rearrangement had been obtained starting from
dichlorophenyl ethers 1e, 1i, 5b it became of interest to see whether the
rearrangement could be obtained in the unsubstituted phenyl ethers.
Reaction of 1j and 1k with NaH/DMF at room temperature resulted
in recovery of starting material. Reaction at 110ꢀC gave the rearranged
products 2j and 2k in 14 (65% based on 1j consumed) and 35% yield
respectively. This supported the idea that nucleophilicity of nitrogen is
one of the factors[1,2] that governs the Smiles rearrangement. In keeping

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2728
Wadia and Patil
with this the phenyl ether 1l, where the nitrogen has very low nucleophi-
licity failed to give the rearranged product.
The rearrangementof 1j–k representhte firstexamples of Smiles
rearrangement in which oxygen and nitrogen are separated by CH2CO
group and the phenoxy ring carries no substitutents.
Diclofenac 8e is perhaps the most widely used nonsteroidal antiin-
flammatory agent being the eighth largest selling drug overall.[7]
Interestingly only one patent[8] uses a Smiles rearrangementfor sit
synthesis (Sch. 1). The method reports[8] that R and R0 could be alkyl
or hydrogen .The patent does not clarify if the reaction to give alcohol 6
0
during rearrangementis possible when boht R and R are hydrogen. If
this is possible then the direct conversion of 6 to 7e (by SOCl2) would
make the process even more convenient.
Having obtained the amines 2a–e, it was planned to convert these to
compound 7a–e which could then be converted to analogues of diclofe-
nac 8e. To check the validity of this reasoning diphenyl amine was con-
verted via the chloroamide 7f to the cyclized product 9f which on
hydrolysis provided the desired acid 8f m.p. 114ꢀC (Lit.[18] m.p.
114–116ꢀC). The identity of 9f and 8f was confirmed by their spectral
properties. Similarly the amine 2d was transformed via 7d and 9d to 8d.
Since the conversion of 2e to 8e is reported, this was not carried out.
CH Cl
2
R'
O
O R'
i)Hydrolysis
Ph-NH-C-C-COOH
R
Ph-N-C-C-OH
CO
ii) ClCH COCl
2
R
Ar
N
7e
6
Ar
0
i) AlCl 60-160 C
3
-
ii) OH/H O
2
COOH
NH
Ar
8e
Ar= 2,6- dichlorophenyl
R = R'= H or C -C alkyl
,
1
4
Scheme 1.

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Smiles Rearrangement of Aryloxyacetamides
2729
Interestingly cyclizations of the chloroamides 7a–c (prepared from
the amines 2a–c) did not afford the desired cyclic products 9a–c under a
variety of conditions. The failure of cyclization of 7c was a greatsurprise
as it had a suitably placed methoxy group to aid the cyclization. The
reaction of 7c provided the compound 7g in which demethylation had
occurred. The identity of 7g was conformed by its spectral properties.
COOH
O
COCH Cl
2
N
R'
N
R'
NH
Ar
R'
Ar
Ar
7
9
8
7-9
R'= H
Ar= 2,4-dichlorophenyl
e
a
b
c
Ar= 4-nitrophenyl
Ar= 4-nitrophenyl
Ar= 4-nitrophenyl
R'= H
R'= H
R'=
CH
Ar= Ph
3
f
g
R'=
OCH
Ar= 4-nitrophenyl
R'= OH
3
Ar= 2,4,6-trichloro
phenyl
d
R'= H
EXPERIMENTAL
All melting points and boiling points are uncorrected. The yields of
all the compounds reported are of crystallized or distilled pure com-
pounds. All solvents were distilled and dried. Elemental analysis were
obtained using Hosli’s rapid carbon hydrogen analyzer. IR spectra
were recorded on Perkin-Elmer FT-IR Model (1615). NMR spectra
were recorded on Jeol FX 90Q (90 MHz) instrument in CDCl3, values
are given in ꢀ.
General Procedure for the Preparation of Aryloxyacetamide
A mixture of aryloxyacetic acid (1 equiv.) and excess thionyl chloride
was refluxed in an oil bath for 8–10 h. Excess thionyl chloride was
removed under vacuum. To a cooled solution of the above acid chloride
in dry benzene (20 mL), primary amine (2 equiv.) was added drop by drop
keeping the temperature between 0–5ꢀC. After addition, reaction was

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2730
Wadia and Patil
refluxed for 2–4 h. After addition of few drops of conc. HCl and water,
the aqueous layer was extracted with ether (3 Â 40 mL). The organic layer
was washed with brine and then with water. Organic layer was dried over
Na2SO4. Removal of ether by distillation afforded the product which was
further purified by passage through silica gel column. The yields, m.p.,
IR, and analysis are given below.
1a. Yield: 93%, m.p. 169–170ꢀC (Lit.[6] m.p. 170–71ꢀC). IR (nujol):
1
3386, 1681, 1595, 1542, 1511, 1336, 870 cmꢁ1. H NMR: ꢀ ¼ 4.83 (s, 2H,
OCH2-), 7.2 (d, 2H, J ¼ 8 Hz, ArH), 7.37 (d, 2H, J ¼ 9 Hz, ArH), 7.43 (t,
1H, J ¼ 8 Hz, ArH), 7.71 (m, 2H, ArH), 8.25 (d, 2H, J ¼ 9 Hz, ArH), 9.71
(bs, 1H, NH). Anal. calcd. for C14H12N2O4: C, 61.76; H, 4.41. Found: C,
61.85; H, 4.21.
1b. Yield: 95%, m.p. 93–94ꢀC. IR (nujol): 3284, 1680, 1593, 1554,
1
1339, 846 cmꢁ1. H NMR: ꢀ ¼ 2.37 (s, 3H, ArCH3), 4.88 (s, 2H, OCH2),
6.98 (bd, 1H, J ¼ 9 Hz, ArH), 7.28 (m, 5H, ArH), 8.28 (d, 2H, J ¼ 9 Hz,
ArH), 9.8 (bs, 1H, NH). Anal. calcd. for C15H14N2O4: C, 62.93; H, 4.89.
Found: C, 63.15; H, 5.06.
1c. Yield: 88%, m.p. 114ꢀC. IR (nujol): 3268, 1673, 1609, 1592, 1550,
1
1343, 858 cmꢁ1. H NMR: ꢀ ¼ 3.94 (s, 3H, OCH3), 4.83 (s, 2H, OCH2),
7.0 (bd, 1H, J ¼ 9 Hz, ArH), 7.4 (bs, 1H, NH), 7.51 (m, 5H, ArH), 8.6 (d,
2H, J ¼ 9 Hz, ArH). Anal. calcd. for C15H14N2O5: C, 59.60; 4.63. Found:
C, 59.45; H, 4.86.
1d. Yield: 80%, m.p. 109–110ꢀC (Lit.[9] m.p. 108–110ꢀC). IR (nujol):
3392, 1694, 1597, 859, 763, 696 cmꢁ1
.
1H NMR: ꢀ ¼ 4.66 (s, 2H,
-OCH2CO-), 7.11–7.60 (m, 5H, -NPh), 7.7 (s, 1H, ArH), 7.8 (s, 1H,
ArH), 8.8 (bs, 1H, -NH). Anal. calcd. for C14H10Cl3NO2: C, 50.83; H,
3.02. Found: C, 50.54; H, 2.96.
1e. Yield: 82%, m.p. 103–104ꢀC (Lit.[10] m.p. 105–106ꢀC). IR (nujol):
3381, 1689, 1602, 901, 867, 755, 689 cmꢁ1. H NMR: ꢀ ¼ 4.66 (s, 2H,
1
–CH2CO), 6.94 (d, 1H, J ¼ 8 Hz, ArH), 7.07–7.91 (m, 7H, ArH), 8.66
(bs, 1H, –NH). Anal. calcd. for C14H11Cl2NO2: C, 56.75; H, 3.72. Found:
C, 56.94; H, 3.74.
1h. Yield: 84%, m.p. 98–99ꢀC. IR (nujol): 3404, 1662, 1536, 856 cmꢁ1
.
1H NMR: ꢀ ¼ 1.24 (t, 3H, J ¼ 6.5 Hz, -CH3), 3.48 (quin, 2H, J ¼ 6.5 Hz,
NH-CH2), 4.57 (s, 2H, OCH2CO), 7.31 and 7.4 (s, 1H each, ArH). Anal.
calcd. for C10H10Cl3NO2: C, 42.48; H, 3.54. Found: C, 42.51; H, 3.47.
1i. Yield: 88%, m.p. 102–103ꢀC. IR (nujol): 3287, 1663, 1563, 935,
1
867 cmꢁ1. H NMR: ꢀ ¼ 1.23 (t, 3H, J ¼ 6.5 Hz, -CH3), 3.43 (quin, 2H,
J ¼ 6.5 Hz, NH-CH2), 4.54 (s, 2H, OCH2CO), 6.80, (bs, 1H, NH), 6.88 (d,
1H, J ¼ 9 Hz, ArH), 7.31 (bd, 1H, J ¼ 9 Hz, ArH), 7.51 (bs, 1H, ArH).
Anal. calcd. for C10H11Cl2NO2: C, 48.38; H, 4.43. Found: C, 48.35;
H, 4.58.

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Smiles Rearrangement of Aryloxyacetamides
2731
1j. Yield: 90%, m.p. 98–99ꢀC (Lit.[11] m.p. 101ꢀC). IR (nujol): 3185,
1
1659, 1598, 1494, 764, 689 cmꢁ1. H NMR: ꢀ ¼ 4.63 (s, 2H, OCH2CO),
6.88–7.86 (m, 10H, ArH), 8.37 (bs, 1H, NH). Anal. calcd. for
C14H13NO2: C, 74.00; H, 5.72. Found: C, 73.89; H, 5.55.
1k. Yield: 80%, m.p. 131ꢀC (Lit.[11] m.p. 130ꢀC). IR (nujol): 3254,
1
3198, 1664, 1615, 1494, 831, 753, 690 cmꢁ1. H NMR: ꢀ ¼ 3.83 (s, 3H,
OCH3), 4.66 (s, 2H, O-CH2CO), 6.94 (d, 2H, J ¼ 8 Hz, ArH), 7.1 (t, 1H,
J ¼ 8 Hz, ArH), 7.2 (d, 2H, J ¼ 8 Hz, ArH), 7.4 (d, 2H, J ¼ 8 Hz, ArH),
7.57 (t, 2H, J ¼ 8 Hz, ArH), 8.37 (bs, 1H, -NH). Anal. calcd. for
C15H15NO3: C, 70.04; H, 5.84. Found: C, 70.13; H, 5.99.
1l. Yield: 78%, m.p. 162ꢀC. IR (nujol): 3188, 1688, 1600, 1522,
1
875, 857, 770, 750, 688 cmꢁ1. H NMR: ꢀ ¼ 4.74 (s, 2H, -OCH2CO),
7.12 (m, 3H, ArH), 7.36 (m, 2H, ArH), 7.46 (s, 2H, ArH), 8.14 (bs,
1H, -NH). Anal. calcd. for C14H10Cl3NO2: C, 50.83; H, 3.02. Found:
C, 51.01; H, 3.26.
General Procedure for the Preparation of Amines
Using Smiles Rearrangement
I. A mixture of the amide (10 mmol) and alcoholic sodium ethoxide
(20 mmol, 1 N) was refluxed for 30 min. The orange red reaction mixture
was diluted with an equal volume of water and the precipitate of amine
was filtered off, washed with water and recrystallized.
2a. Yield: 95%, m.p. 131ꢀC (Lit.[6] m.p. 131–132ꢀC). IR (nujol): 3336,
1
1603, 1584, 1540, 1524, 1376, 1303, 843, 749, 702, 690 cmꢁ1. H NMR:
ꢀ ¼ 6.8 (bs, 1H, NH), 7.46 (d, 2H, J ¼ 9 Hz, ArH), 7.8 (m, 5H, ArH), 8.77
(d, 2H, J ¼ 9 Hz, ArH). Anal. calcd. for C12H10N2O2: C, 67.29; H, 4.67.
Found: C, 67.17; H, 4.88.
2b. Yield: 67%, m.p. 123–124ꢀC (Lit.[12] m.p. 125ꢀC). IR (nujol):
3320, 1581, 1540, 1498, 1323, 840 cmꢁ1
.
1H NMR: ꢀ ¼ 2.22 (s, 3H,
ArCH3), 6.48 (bs, 1H, NH), 7.2 (m, 6H, ArH), 8.37 (d, 2H, J ¼ 9 Hz,
ArH). Anal. calcd. for C13H12N2O2: C, 68.42; H, 5.26. Found: C, 68.55;
H, 5.54.
2c. Yield: 87%, m.p. 112–113ꢀC. IR (nujol): 3344, 1602, 1579, 1495,
1376, 1331, 842 cmꢁ1
1H, NH), 6.97 (m, 3H, ArH), 7.2 (d, 2H, J ¼ 9 Hz, ArH), 7.34
(t, 1H, J ¼ 8.5 Hz, ArH), 8.4 (d, 2H, J ¼ 9 Hz, ArH). Anal. calcd. for
C13H12N2O3: C, 63.93; H, 4.91. Found: C, 64.11; H, 5.23.
.
1H NMR: ꢀ ¼ 3.88 (s, 3H, OCH3), 6.48 (bs,
2d. Yield: 80%, m.p. 42–43 (Lit.[13] m.p. 43–44ꢀC). IR (nujol): 3391,
3079, 3051, 1601, 1553, 1497, 885, 856, 744, 691 cmꢁ1. 1H NMR: ꢀ ¼ 5.89
(bs, 1H, NH), 6.88 (d, 2H, J ¼ 8 Hz, ArH), 7.0 (t, 1H, J ¼ 8 Hz, ArH), 7.3

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(t, 2H, J ¼ 8 Hz, ArH), 7.46 (s, 2H, ArH). Anal. calcd. for C12H8Cl3N: C,
52.84; H, 2.93. Found: C, 52.60; H, 3.05.
Similar reactions of 1e gave two products identified as 3e (82%) m.p.
138–139ꢀC (Lit.[11] m.p. 140ꢀC) and aniline (46%) identified by direct
comparison (IR, m.p. b.p.) with authentic sample.
II. Hexane washed NaH (45 mmol) was added to a stirred solution
of amide (15 mmol) in dry DMF (20 mL). The reaction was stirred
at room temperature (in case of 2d, 2e, 2h, 2i) or at115 ꢀC (for
2i, 2j, 2k) for 24 h. After addition of water the product was extrac-
ted with ethyl acetate (3 Â 20 mL). The organic layer was washed first
with brine, then water and dried (Na2SO4). Removal of ethyl acetate
gave a productwhich was furhter purified by passage htrough silica
gel column using hexane–ethyl acetate (97:3) as eluent.
2d. Yield: 76%, m.p. 42–43ꢀC (Lit.[13] m.p. 43–44ꢀC). Identified
as 2d by directcomparison (IR. mmp) whit sample prepared
earlier.
2e. Yield: 52%, m.p. 58–59 (Lit.[14] m.p. 64ꢀC). IR (nujol): 3413,
1
1591, 1507, 872, 804, 734, 691, cmꢁ1. H NMR: ꢀ ¼ 6.1 (bs, 1H, NH),
6.88–7.57 (m, 8H, ArH). Anal. calcd. for C12H9Cl2N: C, 60.50; H, 3.78.
Found: C, 60.63; H, 3.95.
2h. Yield: 50%, b.p. 260–262 (Lit.[15] b.p. 148–153ꢀmm). IR (neat):
1
3537, 3382, 3055, 1569, 856, cmꢁ1. H NMR: ꢀ ¼ 1.2 (t, 3H, J ¼ 6.5 Hz,
–CH3), 4.25 (q, 2H, J ¼ 6.5 Hz, NCH2-), 6.07 (bs, 1H, NH), 7.4 (s, 2H,
ArH). Anal. calcd. for C8H8Cl3N: C, 42.76; H, 3.56. Found: C, 42.94;
H, 3.76.
2i. Yield: 47% thick liquid. IR (neat): 3418, 3070, 1600, 1507, 797,
.
750 cmꢁ1
1H NMR: ꢀ ¼ 1.28 (t, 3H, J ¼ 6 Hz, –CH3), 3.17 (q, 2H,
J ¼ 6 Hz, NCH2), 4.2 (bs, 1H, NH), 6.6 (d, 1H, J ¼ 9 Hz, ArH), 7.2 (d,
1H, J ¼ 9 Hz, ArH), 7.34 (s, 1H, ArH). Anal. calcd. for C8H9Cl2N: C,
50.52; H, 4.73. Found: C, 50.77; H, 5.02.
2j. Yield: 14% (65% based on 1j consumed), m.p. 53–54ꢀC (Lit [.16]
m.p. 54ꢀC). IR (nujol): 3376, 1593, 744, 690 cmꢁ1. 1H NMR: ꢀ ¼ 5.68 (bs,
1H, NH), 7.26 (m, 10H, ArH). Anal. calcd. for C12H11N: C, 85.20; H,
6.50. Found: C, 85.42; H, 6.42.
2k. Yield: 35%, m.p. 107–108ꢀC (Lit.[16] m.p. 108ꢀC). IR (nujol):
3384, 1596, 1510, 845, 750, 695 cmꢁ1.1H NMR: ꢀ ¼ 3.8 (s, 3H, OCH3),
5.48 (bs, 1H, NH), 7.0 (m, 9H, ArH). Anal. calcd. for C13H13NO: C,
78.39; H, 6.53. Found: C, 78.15; H, 6.39.
2l. Starting compound 1l recovered.
Reaction of the amide (2e) was then carried out with stirring at 125ꢀC
for 20 h. Usual workup gave two products.
2e. Yield: 40%, m.p. 58–59ꢀC.

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Smiles Rearrangement of Aryloxyacetamides
2733
4a or 4b. Yield: 14%, m.p. 154–155ꢀC. IR (nujol): 1690, 1593, 1492,
1
935, 852, 731 cmꢁ1. H NMR: ꢀ ¼ 4.77 (s, 2H, –OCH2CO), 6.37 (d, 1H,
J ¼ 8 Hz, ArH), 6.86 (dd, 1H, J ¼ 2 and 8 Hz, ArH), 7.1 (d, 1H, J ¼ 2 Hz,
ArH), 7.31 (m, 2H, ArH), 7.6 (m, 3H, ArH). Anal. calcd. for
C14H10ClNO2: C, 64.74; H, 3.85. Found: C, 64.62; H, 4.02.
Preparation of 5a
A mixture of 2e (1 g, 4 mmol) and chloroacetyl chloride (1.2 mL,
d-1.418, 12 mmol) was refluxed for 6 h, cooled and evaporated. The resi-
due was dissolved in ethyl acetate (40 mL). The organic phase was washed
with aq. KHCO3 (20 mL, 2N) and water (40 mL) and evaporated to
afford a thick liquid.
5a. Yield: (1.23 g) 93%, thick liquid. 1H NMR: ꢀ ¼ 4.02 (s, 2H,
–NCOCH2Cl), 7.13–7.71 (m, 8H, ArH). Anal. calcd. for C14H10Cl3NO:
C, 53.42; H, 3.18. Found: C, 53.12; H, 3.36.
Conversion of Chloroamide 5a to Hydroxyamide 5b
To the trichloride (1.1 g, 3.5 mmol), was added aq. Na2CO3 (10%,
20 mL). The reaction mixture was refluxed for 24 h, cooled and extracted
with ethyl acetate (3 Â 25 mL). Usual workup gave a thick gel, which was
purified by column chromatography using silica gel in hexane–ethyl acet-
ate system to provide products.
2e. Yield: (10%) and 5a: (40%) identified by usual means.
5b. Yield: (0.184 g) 37%, thick liquid. IR (neat): 3442, 1676, 1593,
1476, 981, 797, 737, 695 cmꢁ1. 1H NMR: ꢀ ¼ 3.4 (bs, 1H, exchanges, OH),
4.1 (bs, 2H, CH2), 7.0–7.7 (m, 8H, ArH).
Attempted cyclization of 5b in NaH/DMF.
Hexane washed NaH (0.66 mmol) was added to a stirred solution of
5b (100 mg, 0.33 mmol) in dry DMF (10 mL). Reaction was stirred at
room temperature for 20 h. Usual workup and purification gave two
products.
1e. Yield: (0.047 g) 47%, m.p. 103–104ꢀC, identical (TLC, IR, mmp)
with the compound prepared earlier.
2e. Yield: (0.028 g) 28%, m.p. 58–59ꢀC, identical (TLC, IR, mmp)
with the compound prepared earlier.

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General Procedure for the Preparation of 7a–f
A mixture of amine 2a–f (4 mmol), chloroacetyl chloride (1.2 mL,
d-1.418, 12 mmol) and pyridine (1 drop) was refluxed (for 12 h), cooled
and excess chloroacetyl chloride was removed. Usual workup using ethyl
acetate gave the product.
1
7a. Yield: 91%, thick liquid. H NMR: ꢀ ¼ 4.34 (s, 2H, CH2Cl), 7.31
(m, 7H, ArH), 8.83 (d, 2H, J ¼ 9 Hz, ArH). Anal. calcd. for
C14H11ClN2O3: C, 57.83; H, 3.78. Found: C, 57.71; H, 3.70.
7b. Yield: 95%, thick liquid. IR (neat): 1692, 1592, 1350, 948, 916,
1
904, 859, 792, 754 cmꢁ1. H NMR: ꢀ ¼ 2.57 (s, 3H, ArCH3), 4.34 (s, 2H,
CH2Cl), 7.88 (m, 6H, ArH), 8.88 (d, 2H, J ¼ 8 Hz, ArH). Anal. calcd. for
C15H13ClN2O3: C, 59.11; H, 4.27. Found: C, 58.97; H, 4.39.
7c. Yield: 68%, m.p. 105–106ꢀC. IR (nujol): 1682, 1592, 1552, 1519,
1
1494, 1336, 921, 851, 783, 754 cmꢁ1. H NMR: ꢀ ¼ 4.23 (s, 2H, CH2Cl),
4.25 (s, 3H, OCH3), 7.26 (m, 2H, ArH), 7.66 (bs, 1H, ArH), 7.86 (d, 3H,
J ¼ 9 Hz, ArH), 8.6 (d, 2H, J ¼ 9 Hz, ArH) Anal. calcd. for C15H13ClN2O4:
C, 56.16; H, 4.05. Found: C, 56.23; H, 4.24.
7d. Yield: 93%, thick liquid. IR (neat): 1711, 1654, 1595, 1496, 860,
1
764, 736, 688, cmꢁ1. H NMR: ꢀ ¼ 4.0 (s, 2H, CH2Cl of one conformer),
4.23 (s, 2H, CH2Cl of other conformer), 7.48 (m, 7H, ArH, of both
conformers). Anal. calcd. for C14H9Cl4NO: C, 48.14; H, 2.58. Found:
C, 48.20; H, 2.85.
7f. Yield: 94%, m.p. 117–118ꢀC. IR (nujol): 1680, 1591, 1489, 783,
1
732, 700 cmꢁ1. H NMR: ꢀ ¼ 4.08 (s, 2H, CH2Cl), 7.37 (bs, 10H, ArH).
Anal. calcd. for C14H12ClNO: C, 68.43; H, 4.89. Found: C, 68.56; H,
4.89.
General Procedure for the Cyclization of 7a–f
A mixture of chloroamide (0.3 mmol) anhydrous AlCl3 (46 mg,
0.35 mmol) and NaCl (20 mg) was heated at 160ꢀC for 30 min. Usual
work-up using ethyl acetate gave the product. 7a and 7b gave a tarry
product, while 7c gave the uncyclized hydroxy compound 7g.
7g. Yield: (0.080 g) 91%, thick liquid. IR (neat): 3316, 1679, 1594,
1
1518, 1487, 1348, 882, 857, 784 cmꢁ1. H NMR: ꢀ ¼ 4.26 (s, 2H, CH2Cl),
5.94 (bs, 1H, OH), 7.29 (m, 3H, ArH), 7.66 (bs, 1H, ArH), 7.88 (d, 2H,
J ¼ 9 Hz, ArH), 8.63 (d, 2H, J ¼ 9 Hz, ArH). Anal. calcd. for
C14H11ClN2O4: C, 54.81; H, 3.59. Found: C, 55.21; H, 3.96.
9d. Yield: 83%, m.p. 157–159ꢀC. IR (nujol): 1725, 1613, 1488, 872,
820, 753 cmꢁ1. 1H NMR: ꢀ ¼ 3.8 (s, 2H, CO-CH2), 6.46 (d, 1H, J ¼ 8 Hz,

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Smiles Rearrangement of Aryloxyacetamides
2735
ArH), 7.31 (m, 3H, ArH), 7.63 (s, 2H, ArH). Anal. calcd. for:
C14H8Cl3NO: C, 53.76; H, 2.56. Found: C, 53.49; H, 2.77.
9f. Yield: 60%, m.p. 120ꢀC (Lit.[17] m.p. 121ꢀC). IR (nujol): 1713,
1
1612, 1593, 1503, 1480, 857, 834, 750 cmꢁ1. H NMR: ꢀ ¼ 4.0 (s, 2H,
–COCH2), 7.37 (d, 1H, J ¼ 8 Hz, ArH), 8.0 (m, 8H, ArH). Anal. calcd.
for: C14H11NO: C, 80.38; H, 5.26. Found: C, 80.17; H, 5.54.
General Procedure for the Preparation of
Analogues of Diclofenac
A solution of 9d or 9f (1.6 mmol), aq. NaOH (2N, 1.5 mL) and
ethanol (15 mL) was refluxed for 4 h. The clear solution was cooled in
an ice bath and acidified with conc. HCl. The precipitated crystals were
collected and recrystallized from ethanol.
8d. Yield: 86%, m.p. 170ꢀC. IR (nujol): 3355, 2650, 1684, 1585, 1499,
1
946, 856, 772 cmꢁ1. H NMR: ꢀ ¼ 3.77 (s, 2H, CH2CO), 6.0 (broad, 1H
exchanges NH/OH), 6.54 (d, 1H, J ¼ 8 Hz, ArH), 7.2 (m, 3H, ArH), 7.37
(bs, 1H, exchanges OH/NH), 7.54 (s, 2H, ArH). Anal. calcd. for
C14H10NCl3O2: C, 50.83; H, 3.02. Found: C, 50.98; H, 3.23.
8f. Yield: 88%, m.p. 114ꢀC (Lit.[18] m.p. 114–116ꢀC). IR (nujol):
1
3396, 1711, 1611, 1592, 1502, 750, 696 cmꢁ1. H NMR: ꢀ ¼ 3.64 (s, 2H,
–CH2CO), 6.66 (bd, 1H, J ¼ 8 Hz, ArH), 6.77 to 7.68 (m, 10H, ArH,
NH, –COOH). Anal. calcd. for C14H13NO2: C, 74.00; H, 5.72. Found:
C, 74.25; H, 5.54.
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2736
Wadia and Patil
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Received in the UK July 26, 2002