Observation of O→N type smiles rearrangement in certain alkyl aryl nitro compounds

Article abstract of DOI:10.1055/s-2002-35227

Smiles rearrangements on some alkyl aryl nitro compounds having NH₂ group as the nucleophile and oxygen as the leaving group are reported.

Full text of DOI:10.1055/s-2002-35227

PAPER
2421
Observation of O N Type Smiles Rearrangement in Certain Alkyl Aryl Nitro
Compounds1
O
N Type Smiles
a
R
earrange
t
ment esan Selvakumar,* Deekonda Srinivas, Azagarsamy Malar Azhagan
Department of Discovery Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 050, India
Fax +91(40)3045438; E-mail: selvakumarn@drreddys.com
Received 15 July 2002; revised 19 August 2002
57 was added to the 3,4-difluronitrobenzene (2) to yield
Abstract: Smiles rearrangements on some alkyl aryl nitro com-
the compound 6, which upon deacetylation resulted in the
nitro-amine 7 as its hydrochloride salt. However, the at-
tempted cyclization of compound 7 under identical condi-
tions employed for the cyclization of 3 resulted only in the
linear tricycle 4 instead of the expected angular tricycle 8.
The overall transformation of the conversion of amine 7 to
pounds having NH2 group as the nucleophile and oxygen as the
leaving group are reported.
Key words: rearrangement, nucleophilic addition, cyclization,
isomerization, nitro compound
the tricyclic compound 4 involves a smooth Smiles rear-
rangement of amine 7 presumably leading to the rear-
ranged alcohol 3 that in turn underwent further
cyclization, as before, resulting in compound 4.
Smiles rearrangement falls under a broad category of in-
tramolecular aromatic nucleophilic substitution of an ap-
propriately placed nucleophile (YH) onto aromatic rings
possessing a strong electron withdrawing group and a
leaving group (X) properly positioned as shown in the
F
F
Figure 1.2 While the rearrangement is well studied on
compounds having the two carbon atoms joining groups X
and Y being part of an aromatic ring, it has not been well
documented for compounds having aliphatic carbons in
between X and Y groups although there have been reports
of amides being used as nucleophiles while converting a
phenolic hydroxyl group to an anilinic amine functional-
ity.3 Chromium tricarbonyl catalyzed Smiles rearrange-
ments on certain unactivated aromatic systems have also
been reported.4 There was a recent report outlining the use
of Smiles rearrangement in the preparation of certain het-
erocyclic pyridine derivatives.5 As this type of rearrange-
ment is not adequately explored, often products resulting
out of this rearrangement are discarded as side products in
literature.6 In this report, we record our observations on
Smiles rearrangements on some hitherto unknown sub-
strates that possess two or three alkyl carbons in between
X and Y groups.
NH
a
+
NO2
N
F
NO2
OH
OH
b
1
3
2
O
NO2
NO2
N
N
O
F
e
8
4
e
F
O
O
NO2
O
NO2
N
c
d
O
NH HCl
N
OH
5
6
7
Scheme 1 Reagents and conditions: (a) Et3N, CH3CN, r.t., 5 h (b)
KOH, DMSO, H2O, r.t., 4 h (c) 2, NaH, THF, 0 °C to r.t., 9 h (d) con-
cd HCl, reflux, 8 h (e) KOH, H2O, 3:1 THF DMSO, r.t., 8 h.
X
Y
C
C
C
C
EWG
EWG
YH
XH
Figure 1
It is believed that the amine nitrogen in compound 7, be-
ing more nucleophilic than oxygen, undergoes an in-
tramolecular aromatic nucleophilic addition resulting in
an intermediate of type 9 as shown in Scheme 2. The in-
termediate 9 further opens up as shown leading eventually
to the alcohol 3, which in turn cyclizes under the basic re-
action conditions yielding the tricycle 4. The occurrence
of Smiles rearrangement was confirmed by isolating the
intermediate 3 in high yields under controlled conditions
of exposing compound 7 to aqueous potassium hydroxide
in THF DMSO, 3:1 for a lesser period of time (ca. 2
hours) at room temperature.
In an ongoing program in our laboratory on the prepara-
tion of a variety of aromatic tricyclic compounds, we
wished to make the angular tricyclic compound 8
(Scheme 1). Addition of prolinol 1 to 3,4-difluoroni-
trobenzene (2) afforded the linear tricycle 4 under basic
conditions via the intermediate 3. In an attempt to prepare
the target tricyclic compound 8, the N-protected prolinol
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2421,2425,ftx,en;P03602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2422
N. Selvakumar et al.
PAPER
experiment clearly demonstrates the vulnerability of the
above compounds to undergo Smiles rearrangement.
F
F
O
NO2
O
O
O
To explore the occurrence of Smiles rearrangement on a
primary acyclic amine,8 compound 21 was synthesized as
shown in Scheme 4. The compound 19, prepared as per
the literature procedure for compound 5,7 afforded the ni-
tro-acetamide 20 under standard conditions that under-
went deacetylation resulting in the nitro-amine 21 as its
hydrochloride salt. Subjecting the salt 21 to the usual ba-
sic conditions lead to the rearranged product 22 in 82%
yield as the sole product.9
N
aq.KOH
N
NH
DMSO
7
9
F
NO2
N
NO2
N
O
F
OH
OH
4
3
O
NO2
a
b
Scheme 2
NH
NH
O
O
19
20
In order to assess the feasibility of the Smiles rearrange-
ment in these substrates, experiments were carried out on
compounds having different aromatic rings. Thus, the
amines 11, 14 and 17, prepared respectively from 4-fluor-
onitrobenzene, 2-fluoronitrobenzene and 1-fluoro-2,4-
dinitrobenzene as their hydrochlorides by a route analo-
gous to the preparation of compound 7 (Scheme 3), were
exposed to basic conditions to result in rearranged com-
pounds as expected.
F
F
O
NO2
HN
NO2
c
NH2 HCl
OH
22
21
NO2
NO2
NO2
R1
R1
R1
O
O
NO2
O
NO2
R2
HN
NO2
O
R2
O
N
R2
b
c
a
O
b
N
NH HCl
NH
NH2 HCl
OH
OH
24
25
23
11:R1=H, R2=NO2
14:R1=NO2, R2=H
17:R1, R2=NO2
12:R1=H, R2=NO2
15:R1=NO2, R2=H
18:R1,R2=NO2
10:R1=H, R2=NO2
13:R1=NO2, R2=H
16:R1, R2=NO2
Scheme 4 Reagents and conditions: (a) 2, NaH, THF, r.t. (b) concd
HCl, reflux (c) KOH, DMSO, H2O, 60 °C, 4 h.
In order to understand the reactivity of substrates with
three aliphatic carbons in between X and YH groups,
compound 23 was prepared as usual from N-acetyl-3-hy-
droxypropylamine and 1-chloro-2,4-dinitrobenzene. It
was deacetylated to yield the amine 24. The compound 24
underwent smooth Smiles rearrangement to give the rear-
ranged compound 25.
Scheme 3 Reagents and conditions: (a) concd HCl, reflux (b) KOH,
DMSO, H2O, 60 °C.
While the mononitro compounds 11 and 14 needed sever-
al hours to complete the rearrangement leading to nitro
compounds 12 and 15 respectively, the highly electron de-
ficient dinitro compound 17 rearranged in 15 minutes to
give rise to the isomerized dinitro compound 18. Further
confirmation for the feasibility of Smiles rearrangement
was derived from a NMR experiment that was conducted
on compound 11. Addition of 5 equivalents of potassium
carbonate to an NMR tube containing a sample of 11 in
DMSO-d6 resulted in appreciable isomerization to com-
pound 12 within 30 minutes. This was confirmed by the
appearance of a new set of doublets corresponding to aro-
matic protons of 12. The conversion of the angular com-
pound 11 to the rearranged compound 12 was completed
up to 50% upon leaving 11 in the NMR tube for 15 hours
and the conversion was nearly complete after 6 days. This
The above experiments have clearly established the feasi-
bility of Smiles rearrangement in substrates having two or
three aliphatic carbon atoms in between groups X and Y
wherein NH2 group plays the role of YH and oxygen atom
plays the role of group X. We believe that this account
would caution those who are attempting to prepare com-
pounds of this nature.
Melting points are uncorrected. Unless otherwise mentioned, all 1H
NMR spectra were recorded in CDCl3 at 200 MHz. All 13C NMR
spectra were done at 50 MHz in DMSO-d6. Chemical shifts are re-
ported in units with respect to TMS and DMSO-d6 as internal stan-
1
dard respectively for H NMR and 13C NMR. Unless otherwise
Synthesis 2002, No. 16, 2421–2425 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
O
N Type Smiles Rearrangement in Alkyl Aryl Nitro Compounds
2423
mentioned, all the solvents used were of LR grade. Flash chroma-
tography was performed using silica gel (100–200 mesh). All the
organic extracts were dried over Na2SO4 after work up. Petroleum
ether (PE) with a bp range of 60–80 °Cwas used.
1H NMR: = 8.07–7.94 (m, 2 H), 7.28–7.20 (m, 1 H), 4.50–4.20 (m,
3 H), 3.60–3.40 (m, 2 H), 2.30–2.00 (m, 7 H).
13C NMR: = 168.9 and 168.6 (1 C), 152.3 and 152.1 (1 C), 150.2
(d, J = 246.8 Hz, 1 C), 140.0 (d, J = 7.3 Hz, 1 C), 121.2 (d, J = 2.7
Hz, 1 C), 113.9, 111.8 (d, J = 22.8 Hz, 2 C), 70.6 and 68.8 (2 C),
56.2 and 54.8 (1 C), 47.4 and 45.2 (1 C), 28.2 and 27.3 (1 C), 23.6
and 22.0 (1 C), 22.5 and 21.7 (1 C).
(2S)-1-(2-Fluoro-4-nitrophenyl)azolan-2-ylmethanol (3)
To a soln of L-prolinol (1) (76 mg, 0.75 mmol) in anhyd CH3CN (5
mL) was added dropwise Et3N (159 mg, 1.57 mmol) followed by
3,4-difluoronitrobenzene (2) (100 mg, 0.63 mmol) at r.t. under Ar.
After stirring for 5 h at the same temperature, the reaction mixture
was worked up by addition of H2O and extraction with EtOAc
(3 × 25 mL). The combined organic extracts were washed with
H2O, brine and dried. The evaporation of solvent afforded the nitro-
alcohol 3 as a yellow solid (120 mg, 80%) that was suitable for the
next step. An analytical sample was obtained by further purification
on a column of silica gel; mp 92–94 °C.
MS-CI: 283 [M+ + 1], 126, 112.
(2S)-2-(2-Fluoro-4-nitrophenoxymethyl)azolaneHydrochloride
(7)
A soln of the nitro-amide 6 (200 mg, 0.71 mmol) in concd HCl (10
mL) was refluxed for 8 h and then the volatiles were evaporated.
The resultant solid was suspended in toluene and the volatiles were
removed under reduced pressure. This process was repeated once
again to remove traces of HCl to afford the nitro-amine 7 as its hy-
drochloride salt (150 mg, 76%).
IR (KBr): 1609, 1522, 1309 cm–1.
1H NMR: = 7.80–8.00 (m, 2 H), 6.67 (t, J = 9.4 Hz, 1 H), 4.27 (br
IR (KBr): 2880, 2721, 1523, 1345, 1295 cm–1.
s, 1 H), 3.40–3.74 (m, 4 H), 1.90–2.20 (m, 4 H).
1H NMR: = 9.94 (br s, 1 H), 9.60 (br s, 1 H), 8.30–8.10 (m, 2 H),
7.55–7.35 (m, 1 H), 4.49 (b, J = 4.9 Hz, 2 H), 3.99 (br s, 1 H), 3.21
(br s, 2 H), 2.15–1.65 (m, 4 H).
13C NMR: = 150.0 (d, J = 241.7 Hz, 1 C), 141.6 (d, J = 8.2 Hz, 1
C), 134.9 (d, J = 8.2 Hz, 1 C), 121.7, 114.3 (d, J = 6.3 Hz, 2 C),
112.2 (d, J = 26.4 Hz, 1 C), 61.51, 61.39, 50.4 (d, J = 5.7 Hz, 1 C),
27.6, 22.4.
MS-CI: m/z (%) = 241 [M+ + 1], 170, 91.
MS-EI: m/z (%) = 240 [M+], 209, 163.
Rearrangement of (7)
Anal. Calcd for C11H13N2O3F: C, 55.00; H, 5.45; N, 11.66. Found:
C, 55.00; H, 5.40; N, 11.58.
To a stirred suspension of the nitro-amine 7 (150 mg, 0.54 mmol) in
a mixture of THF (10 mL) and DMSO (3.5 mL) at r.t. was added
powdered KOH (91 mg, 1.63 mmol) followed by few drops of H2O.
The progress of the reaction was monitored by TLC that revealed
the completion of reaction after 8 h of stirring. The reaction mixture
was diluted with H2O and extracted with EtOAc (3 × 30 mL). The
combined organic extracts were washed with H2O, brine and dried.
The evaporation of solvent afforded a yellow solid (90 mg, 69%).
The TLC and the spectral data obtained for this compound was
identical to the rearranged product 4 as prepared earlier.
(6aS)-3-Nitro-6a,7,8,9-tetrahydro-6H-azolo[1,2-d]benzo[b]-
[1,4]oxazine (4)
To a soln of the nitro-alcohol 3 (100 mg, 0.42 mmol) in DMSO (8
mL) at r.t. was added powdered KOH (70 mg, 1.24 mmol) followed
by few drops of H2O. After stirring for 4 h at the same temperature,
the reaction mixture was worked up by addition of H2O and extrac-
tion with EtOAc (3 × 25 mL). The combined organic extracts were
washed with H2O, brine and dried. The evaporation of solvent af-
forded product 4 as a yellow solid (70 mg, 77%). An analytical sam-
ple was obtained by recrystallization in EtOH.
10
Yellowish gum, exists as rotamers.
Mp 158–160 °C.
IR (neat): 1640, 1341, 1265 cm–1.
IR (KBr): 1600, 1487, 1292 cm–1.
1H NMR: = 8.19 (d, J = 9.3 Hz, 2 H), 7.04 (d, J = 9.3 Hz, 2 H),
4.50–3.90 (m, 3 H), 3.60–3.40 (m, 2 H), 2.20–1.95 (m, 7 H).
1H NMR: = 7.85 (dd, J = 8.8, 2.4 Hz, 1 H), 7.72 (d, J = 2.4 Hz, 1
H), 6.42 (d, J = 9.3 Hz, 1 H), 4.55 (dd, J = 10.3, 3.4 Hz, 1 H), 3.28–
3.72 (m, 4 H), 2.22–1.94 (m, 3 H), 1.53–1.39 (m, 1 H).
13C NMR: = 141.0, 140.7, 135.1, 119.9, 110.3, 109.6, 67.6, 55.4,
47.1, 27.8, 23.0.
13C NMR: = 169.0 and 168.5 (2 C), 163.8 and 163.5 (2 C), 141.0
and 140.8 (2 C), 125.8 (2 C), 114.9 (2 C), 69.7 and 67.9 (2 C), 56.4
and 55.0 (2 C), 47.4 and 45.2 (2 C), 28.2 and 27.3 (2 C), 23.5 and
22.1 (2 C), 22.5 and 21.7 (2 C).
MS-CI: m/z (%) = 265 [M+ + 1], 126, 112.
MS-EI: m/z (%) = 220 [M+], 190, 174.
Anal. Calcd for C11H12N2O3: C, 59.98; H, 5.50; N, 12.73. Found: C,
59.86; H, 5.35; N, 12.55.
11
Hygroscopic solid.
IR (KBr): 2907, 2746, 1594, 1345 cm–1.
1-[(2S)-2-(2-Fluoro-4-nitrophenoxymethyl)azolan-1-yl]-1-etha-
none (6)
1H NMR: (DMSO-d6): = 9.92 (br s, 1 H), 9.40 (br s, 1 H), 8.25 (d,
J = 9.3 Hz, 2 H), 7.20 (d, J = 9.3 Hz, 2 H), 4.50–3.80 (m, 3 H),
3.30–3.10 (m, 2 H), 2.30–1.60 (m, 4 H).
To a soln of N-acetyl-L-prolinol (5) (200 mg, 1.39 mmol) in anhyd
THF (15 mL) at 0 °C under Ar was added NaH (60% in oil, 40 mg,
1.67 mmol) followed by 3,4-difluoronitrobenzene (2) (222 mg, 1.39
mmol). The reaction mixture was stirred while warming to r.t. over
9 h and then worked up by addition of H2O followed by extraction
with EtOAc (3 × 40 mL). The combined organic extracts were
washed with H2O, brine and dried. The residue obtained upon evap-
oration of the solvents was chromatographed over silica gel. The ni-
tro-amide 6 was obtained upon elution with PE–EtOAc, 1:1 as a
yellowish gum (210 mg, 53%) that exists as rotamers.
MS-CI: m/z (%) = 223 [M+ + 1].
12
Yellow solid; mp 107–109 °C.
IR (neat): 3457, 1600, 1307 cm–1.
1H NMR: (DMSO-d6): = 8.05 (d, J = 9.1 Hz, 2 H), 6.69 (d, J = 9.1
Hz, 2 H), 4.91 (t, J = 5.4 Hz, 1 H), 3.92 (br s, 1 H), 3.60–3.20 (m, 4
H), 2.20–1.80 (m, 4 H).
13C NMR: = 151.6, 135.4, 125.7 (2 C), 111.0 (2 C), 60.5, 60.3,
48.3, 27.7, 22.5.
IR (neat): 1640, 1525, 1347 cm–1.
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2424
N. Selvakumar et al.
PAPER
MS-CI: m/z (%) = 223 [M+ + 1], 191, 145.
1H NMR: (DMSO-d6): = 9.89 (br s, 1 H), 9.45 (br s, 1 H), 8.79 (d,
J = 2.4 Hz, 1 H), 8.56 (dd, J = 9.3, 2.9 Hz, 1 H), 7.62 (d, J = 9.3 Hz,
1 H), 4.70–3.90 (m, 3 H), 3.30–3.00 (m, 2 H), 2.30–1.70 (m, 4 H).
Anal. Calcd for C11H14N2O3: C, 59.45; H, 6.35; N, 12.61. Found: C,
59.51; H, 6.35; N, 12.52.
MS-CI: m/z (%) = 268 [M+ + 1], 102.
13
Light yellow solid, exists as rotamers; mp 91–93 °C.
18
Thick gum.
IR (neat): 3419, 1605, 1524, 1325 cm–1.
IR (neat): 1641, 1526, 1417 cm–1.
1H NMR: (400 MHz): = 7.81 (dd, J = 8.3, 2.0 Hz, 1 H), 7.53–7.49
(m, 1 H), 7.19 (d, J = 8.3 Hz, 1 H), 7.00 (t, J = 7.8 Hz, 1 H), 4.43–
4.21 (m, 3 H), 3.62–3.43 (m, 2 H), 2.07 (s, 3 H), 2.23–1.92 (m, 4 H).
13C NMR: = 168.9 and 168.6 (2 C), 151.2 and 149.9 (2 C), 139.5,
134.4 and 134.3 (1 C), 124.9 and 124.8 (1 C), 120.8 and 120.6 (1
C), 115.1 and 114.9 (1 C), 70.2 and 68.4 (1 C), 56.3 and 55.0 (1 C),
47.5 and 45.2 (1 C), 28.2 and 27.3 (1 C), 23.5 and 22.0 (1 C), 22.5
and 21.6 (1 C).
1H NMR: (400 MHz): = 8.70 (d, J = 2.4 Hz, 1 H), 8.20 (dd,
J = 9.8, 2.4 Hz, 1 H), 7.15 (d, J = 9.8 Hz, 1 H), 4.28–4.23 (m, 1 H),
3.85 (dd, J = 11.7, 4.4 Hz, 1 H), 3.70 (dd, J = 11.7, 3.4 Hz, 1 H),
3.59–3.53 (m, 1 H), 2.90–2.85 (m, 1 H), 2.32–2.25 (m, 1 H), 2.15–
2.05 (m, 2 H), 1.88–1.80 (m, 1 H).
13C NMR: = 145.7, 134.7, 134.5, 127.0, 123.4, 117.5, 61.6, 61.3,
52.8, 27.8, 24.3.
MS-CI: m/z (%) = 265 [M+ + 1], 142, 112, 100.
MS-CI: m/z (%) = 268 [M+ + 1], 236, 220.
Anal. Calcd for C13H16N2O4: C, 59.08; H, 6.10; N, 10.60. Found: C,
59.04; H, 6.19; N, 10.53.
20
Light yellow solid; mp 109–111 °C.
14
IR (neat): 1658, 1525, 1348, 756 cm–1.
Hygroscopic solid.
IR (KBr): 3424, 2883, 1522, 1282 cm–1.
1H NMR: = 8.15–7.95 (m, 2 H), 7.10–6.95 (m, 1 H), 6.29 (br s, 1
H), 4.23 (t, J = 5.1 Hz, 1 H), 3.74 (q, J = 5.4 Hz, 1 H), 2.04 (s, 3 H).
1H NMR: (DMSO-d6): = 9.80 (br s, 1 H), 9.22 (br s, 1 H), 7.95 (d,
J = 7.8 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 1 H),
7.18 (t, J = 7.3 Hz, 1 H), 4.55–3.90 (m, 3 H), 3.30–3.00 (m, 2 H),
2.20–1.70 (m, 4 H).
13C NMR: = 169.8, 152.3 and 152.1 (1 C), 150.3 (d, J = 247.2 Hz,
1 C), 140.0 (d, J = 7.7 Hz, 1 C), 121.2 (d, J = 2.7 Hz, 1 C), 113.9,
111.8 (d, J = 22.8 Hz, 1 C), 68.3, 38.0, 22.4.
MS-CI: m/z (%) = 243 [M+ + 1].
MS-CI: m/z (%) = 223 [M+ + 1], 91.
21
15
Hygroscopic solid.
Orange solid; mp 82–84 °C.
IR (neat): 3398, 1604, 1511, 1276 cm–1.
1H NMR: (400 MHz): = 7.78 (dd, J = 8.3, 1.5 Hz, 1 H), 7.41–7.37
(m, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 6.84–6.80 (m, 1 H), 4.17–4.11
(m, 1 H), 3.84 (dd, J = 11.2, 3.4 Hz, 1 H), 3.59–3.49 (m, 2 H), 2.75–
2.71 (m, 1 H), 2.19–1.97 (m, 3 H), 1.84–1.74 (m, 2 H).
IR (KBr): 3426, 2910, 1345, 1285.
1H NMR: (DMSO-d6): = 8.41 (br s, 3 H), 8.25–8.15 (m, 2 H),
7.50–7.40 (m, 1 H), 4.46 (t, J = 4.9 Hz, 1 H), 3.26 (t, J = 4.9 Hz, 1
H).
MS-CI: m/z (%) = 201 [M+ + 1].
13C NMR: = 142.0, 137.5, 132.9, 126.1, 117.2, 115.9, 62.0, 60.1,
52.3, 28.9, 24.3.
22
Light yellow solid; mp 98–100 °C.
MS-CI: m/z (%) = 223 [M+ + 1], 191, 175.
IR (KBr): 3526, 3296, 1615 cm–1.
Anal. Calcd for C11H14N2O3: C, 59.45; H, 6.35; N, 12.61. Found: C,
59.42; H, 6.50; N, 12.54.
1H NMR: = 8.01 (dd, J = 10.5, 1.3 Hz, 1 H), 7.89 (dd, J = 11.6, 2.4
Hz, 1 H), 6.73–6.64 (m, 1 H), 5.08 (br s, 1 H), 3.95 (t, J = 5.3 Hz, 1
H), 3.46 (t, J = 5.1 Hz, 1 H), 1.80 (br s, 1 H).
16
13C NMR: = 148.3 (d, J = 240.5 Hz, 1 C), 143.6 (d, J = 12.0 Hz, 1
C), 134.5 (d, J = 7.5 Hz, 1 C), 122.4, 110.3 (d, J = 22.6 Hz, 1 C),
109.5 (d, J = 4.4 Hz, 1 C), 59.4, 45.0.
Light yellow solid, exists as rotamers; mp 97–99 °C.
IR (neat): 1638, 1608, 1532, 1345 cm–1.
1H NMR: (400 MHz): = 8.73 (d, J = 2.4 Hz, 1 H), 7.42 (dd,
J = 9.3, 2.9 Hz, 1 H), 7.44 (d, J = 9.3 Hz, 1 H), 4.48–4.39 (m, 3 H),
3.60–3.46 (m, 2 H), 2.09 (s, 3 H), 2.18–1.97 (m, 4 H).
13C NMR: = 169.0 and 168.6 (1 C), 155.9 and 155.6 (1 C), 139.7
and 139.6 (1 C), 138.5, 129.3 and 129.1 (1 C), 121.1 and 121.0 (1
C), 115.9 and 115.6 (1 C), 71.4 and 69.8 (1 C), 56.1and 54.8 (1 C),
47.5 and 45.3 (1 C), 28.2 and 27.2 (1 C), 23.5 and 22.0 (1 C), 22.5
and 21.6 (1 C).
MS-EI: m/z (%) = 200 [M+], 169, 123.
Anal. Calcd for C8H9N2O3F: C, 48.00; H, 4.53; N, 14.00. Found: C,
47.87; H, 4.56; N, 13.92.
23
Yellow solid; mp 114–115 °C.
IR (KBr): 3273, 1646, 1343 cm–1.
1H NMR: = 8.82 (d, J = 2.4 Hz, 1 H), 8.47 (dd, J = 9.1, 2.4 Hz, 1
H), 7.26 (d, J = 9.1 Hz, 1 H), 6.40 (br s, 1 H), 4.36 (t, J = 5.6 Hz, 2
H), 3.56–3.48 (m, 2 H), 2.15 (q, J = 5.9 Hz, 2 H), 2.03 (s, 3 H).
13C NMR: = 169.1, 156.0, 139.3, 138.2, 129.2, 121.0, 115.5, 68.4,
35.2, 28.5, 22.5.
MS-EI: m/z (%) = 310 [M+], 126, 112, 100.
Anal. Calcd for C13H15N3O6: C, 50.49; H, 4.89; N, 13.59. Found: C,
50.45; H, 4.89; N, 13.48.
17
MS-CI: m/z (%) = 284 [M+ + 1].
Hygroscopic solid.
IR (KBr): 3423, 2873, 1611, 1345 cm–1.
Anal. Calcd for C11H13N3O6: C, 46.65; H, 4.63; N, 14.84. Found: C,
46.66; H, 4.52; N, 14.78.
Synthesis 2002, No. 16, 2421–2425 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
O
N Type Smiles Rearrangement in Alkyl Aryl Nitro Compounds
2425
24
References
Hygroscopic solid.
IR (KBr): 3424, 2926, 1521, 1354 cm–1.
1H NMR: (DMSO-d6): = 8.78 (d, J = 2.4 Hz, 1 H), 8.53 (dd,
J = 9.3, 2.4 Hz, 1 H), 8.16 (br s, 3 H), (d, J = 9.3 Hz, 1 H), 4.44 (t,
J = 5.4 Hz, 2 H), 3.00–2.90 (m, 2 H), 2.12 (t, J = 6.3 Hz, 2 H).
(1) DRF Publication No. 212.
(2) (a) Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React.
1971, 18, 99. (b) Bunnett, J. F.; Zahler, R. E. Chem. Rev.
1951, 49, 273.
(3) (a) Bayles, R.; Johnson, M. C.; Maisey, R. F.; Turner, R. W.
Synthesis 1977, 31. (b) Baker, W. R. J. Org. Chem. 1983,
48, 5140. (c) Neumeyer, J. L.; Gao, Y.; Kula, N. S.;
Baldessariu, R. J. J. Med. Chem. 1990, 33, 3124.
(4) Davies, S. G.; Hume, W. E. Tetrahedron Lett. 1195, 36,
2673.
MS-CI: m/z (%) = 242 [M+ + 1].
25
Yellow solid; mp 67–69 °C.
IR (KBr): 3374, 1623, 1339 cm–1.
(5) Soukri, M.; Lazar, S.; Akssira, M.; Guillaumet, G. Org. Lett.
2000, 2, 1557.
1H NMR: = 9.15 (d, J = 2.4 Hz, 1 H), 8.90 (br s, 1 H), 8.29 (dd,
J = 9.7, 2.7 Hz, 1 H), 6.99 (d, J = 9.7 Hz, 1 H), 3.91 (t, J = 5.4 Hz,
2 H), 3.61 (q, J = 6.5 Hz, 2 H), 2.05 (q, J = 6.2 Hz, 2 H), 1.68 (br s,
1 H).
13C NMR: = 148.0, 134.5, 129.7, 129.4, 123.4, 114.9, 58.8, 41.1,
30.9.
(6) For example see: Cao, B.; Park, H.; Joullie, M. M. J. Am.
Chem. Soc. 2002, 124, 520; during the preparation of the
compound 26 the authors report the formation of an
unidentified aryl amine. We believe that the undesired aryl
amine is presumably the structure 28 a product of Smiles
rearrangement via the intermediate 27 (Figure 2).
MS-CI: m/z (%) = 242 [M+ + 1].
CN
CN
CN
OMOM
H
N
O
Anal. Calcd for C9H11N3O5: C, 44.82; H, 4.60; N, 17.42. Found: C,
44.62; H, 4.68; N, 17.24.
O
Et
Et
N
Et
H
H2N
HO
OMOM
OMOM
Br
Br
Br
Acknowledgments
26
27
28
The support rendered by analytical research department of Discove-
ry Research, Dr. Reddy’s Laboratories Ltd. is greatly appreciated.
We also thank Dr. Sanjay Trehan and Professor Javed Iqbal for hel-
pful discussions. We appreciate the referees of this publication for
their useful suggestions.
Figure 2
(7) Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.;
Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org.
Chem. 1988, 53, 3457.
(8) Similar studies on primary acyclic amines have been
reported although under different conditions: (a) Knipe, A.
C.; Sridhar, N. Synthesis 1976, 606. (b) Mutai, K.;
Kobayashi, K. Bull. Chem. Soc. Jpn. 1981, 54, 462.
(9) A similar amino-ethanol substrate undergoing Smiles
rearrangement in a polyfunctional vinylthiohalobenzene
substrate has been reported: (a) Amosova, S. V.;
Gostevsgaya, V. I.; Gavrilova, G. M.; Afonin, A. V.;
Toryashinova, D. D. Zh. Org. Khim. 1993, 29, 2416.
(b) Yilmaz, I.; Shine, H. J. Gazz. Chim. Ital. 1989, 119.
Synthesis 2002, No. 16, 2421–2425 ISSN 0039-7881 © Thieme Stuttgart · New York