Benzo-fused heterocycles and carbocycles by intramolecular SNAr and tandem SN2-SNAr reactions

Article abstract of DOI:10.1002/jhet.5570450239

(Chemical Equation Presented) Benzo-fused heterocyclic and carbocyclic systems have been synthesized by intramolecular S_NAr and tandem S_N2-S_NAr reactions. Treatment of 3-(2-fluoro-5- nitrophenyl)-1-propanol with sodium hydride in N,N-dimethylformamide gave 6-nitrochroman in 80% yield by an intramolecular S_NAr reaction. Treatment of 2-(3-bromopropyl)-1-fluoro-4-nitrobenzene with benzylamine in N,N-dimethylformamide gave 1-benzyl-6-nitrotetrahydroquinoline in 98% yield by a tandem S_N2-S_NAr reaction. Finally, in a similar process, reaction of this same bromide with dimethyl malonate under basic conditions gave 1,1-bis(methoxycarbonyl)-6-nitro-1,2,3,4-tetrahydronaphthalene in 80% yield. Further studies exploring ring size effects are also presented.

Full text of DOI:10.1002/jhet.5570450239

Mar-Apr 2008
551
Benzo-fused Heterocycles and Carbocycles by
Intramolecular SNAr and Tandem SN2-SNAr Reactions
Richard A. Bunce*, Takahiro Nago [1], Nathan Sonobe [1] and LeGrande M. Slaughter
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071
rab@okstate.edu
Received August 30, 2007
O2N
O2N
O2N
O2N
2 equivalents NaH
N,N-dimethylformamide
F
F
OH
Br
O
80%
C6H5CH2NH2
N,N-dimethylformamide
N
98%
CH2C6H5
Benzo-fused heterocyclic and carbocyclic systems have been synthesized by intramolecular SNAr and
tandem SN2-SNAr reactions. Treatment of 3-(2-fluoro-5-nitrophenyl)-1-propanol with sodium hydride in
N,N-dimethylformamide gave 6-nitrochroman in 80% yield by an intramolecular SNAr reaction. Treatment
of 2-(3-bromopropyl)-1-fluoro-4-nitrobenzene with benzylamine in N,N-dimethylformamide gave 1-
benzyl-6-nitrotetrahydroquinoline in 98% yield by a tandem SN2-SNAr reaction. Finally, in a similar
process, reaction of this same bromide with dimethyl malonate under basic conditions gave 1,1-
bis(methoxycarbonyl)-6-nitro-1,2,3,4-tetrahydronaphthalene in 80% yield. Further studies exploring ring
size effects are also presented.
J. Heterocyclic Chem., 45, 551 (2008).
known 2-fluoro-5-nitrobenzyl bromide (1) [6], two-carbon
chain extension was accomplished by a sequence involving
(1) alkylation of di-tert-butyl malonate to give 2, (2)
hydrolysis of the tert-butyl esters with trifluoroacetic acid
in the presence of triethylsilane [7] to give dicarboxylic
acid 3 and (3) decarboxylation at 160° to give mono-
carboxylic acid 4. Chemoselective reduction of the acid
with borane-tetrahydrofuran complex gave alcohol
substrate 5 [8], which was carried on to the corresponding
bromide 6 by conversion to the methanesulfonate ester and
treatment with lithium bromide [9]. The yields for all
procedures ranged from 82-96%.
INTRODUCTION
Tandem reactions initiated by reduction of
nitroaromatic substrates have provided an efficient route
to a variety of heterocyclic systems [2]. The synthesis of
these substrates has often required the use of nucleophilic
aromatic substitution to introduce functionality needed to
capture the resulting amino group in a ring-forming
process. In the course of our work, we became interested
in the possibility of generating heterocyclic systems by
tandem processes terminated by a nucleophilic aromatic
substitution. The current work describes our initial efforts
to explore this synthetic strategy and outlines the use of
an intramolecular SNAr route to benzo-fused oxygen
heterocycles and a tandem SN2-SNAr route to benzo-fused
nitrogen heterocycles and carbocycles.
Substrates for the evaluation of ring size effects were
prepared from bromides 1 and 6 using a five step
Scheme 1 [a]
The structures accessible using the current reaction
include substituted chromans, tetrahydroquinolines and
tetrahydronaphthalenes. These ring systems each contain
numerous derivatives that are known to express useful
biological activities [3,4,5]. While we have only prepared
compounds bearing substitution at C6, several other
substitution patterns should also be possible. The current
study also includes an evaluation of the method for the
closure of five- and seven-membered rings. The results
should serve to define the parameters needed for success
in these reactions.
O2N
CH2Br
F
O2N
CH2CH(CO2-t-C4H9)2
a
F
1
2
O2N
CH2CH(CO2H)2
O2N
(CH2)2CO2H
b
c
F
F
3
4
O2N
(CH2)3OH
F
O2N
(CH2)3Br
F
d
e
5
6
RESULTS AND DISCUSSION
[a] Key: (a) CH2(CO2-t-C4H9)2, K2CO3, acetone, 22o, 96%; (b) CF3CO2H,
(C2H5)3SiH, dichloromethane, 22o, 82%; (c) 160o, neat, 94%; (d) BH3·THF,
tetrahydrofuran 0!22o, 87%; (e) i. CH3SO2Cl, (CH3CH2)3N, CH2Cl2, 0o; ii.
LiBr, 3:1 ether:acetone, 40o, 90%.
The preparation of precursors for the closure of six-
membered rings is depicted in Scheme 1. Starting from the

552
R. A. Bunce, T. Nago, N. Sonobe and L. M. Slaughter
Vol 45
sequence that included (1) nucleophilic displacement of
the bromides by cyanide to give nitriles 7 and 8 [10], (2)
acid hydrolysis of the nitriles to generate carboxylic acids
9 and 10, (3) reduction of the acids to afford alcohols 11
and 12 [8], and (4-5) treatment of the alcohols with
methanesulfonyl chloride followed by lithium bromide to
give bromides 13 and 14 [9]. The yield for each step in
these syntheses ranged from 75-98% (Scheme 2).
Cyclizations to form five-membered rings were less
satisfactory. Treatment of alcohol 11 with sodium
hydride led to intermolecular reactions and decomposition
of the substrate; none of the desired oxygen heterocycle
18 was produced. Attempts to prepare 1-benzyl-5-nitro-
indoline (20) from bromide 13 and benzylamine led to
complex mixtures, which included the desired heterocycle
as well as elimination and substitution products 21 and 22
derived from the basic nucleophile. The best yield of
indoline 20 (31%) was achieved when the reaction was run
at 0−22°, but the conversion was only 82% and
elimination was still a major pathway (Scheme 4). These
outcomes presumably arise because the short three-atom
chain prevents the nucleophilic center from achieving the
optimum orientation for addition, which must come from
above (or below) the plane of the ring.
Scheme 2 [a]
O2N
(CH2)nBr
F
O2N
(CH2)nCN
F
a
b
1 (n = 1)
6 (n = 3)
7 (n = 1)
8 (n = 3)
O2N
(CH2)nCO2H
F
O2N
(CH2)nCH2OH
F
c
Scheme 4
9 (n = 1)
10 (n = 3)
11 (n = 1)
12 (n = 3)
O2N
2 equivalents NaH
(CH2)n
11
12
O2N
(CH2)nCH2Br
N,N-dimethylformamide
d
O
18 (n = 1) 0%
19 (n = 3) 77%
F
13 (n = 1)
14 (n = 3)
[a] Key: (a) For 1!7: KCN, aqueous ethanol, 22o, 91%; For 6!8: KCN, dimethyl-
sulfoxide, 22o, 98%; (b) 50% aqueous H2SO4, 110o; yield of 9, 75%, 10, 85%; (c)
BH3-THF, 0!22o; yield of 11, 86%, 12, 97%; (d) i. CH3SO2Cl, (CH3CH2)3N,
CH2Cl2, 0o; ii. LiBr, 3:1 ether:acetone, 40o; yield of 13, 87%, 14, 91%.
O2N
C6H5CH2NH2
+
13
N,N-dimethylformamide
N
CH2C6H5
31%
20
Our initial cyclization studies focused on the closure of
six-membered rings (Scheme 3). Treatment of alcohol 5
with a two-fold excess of sodium hydride in N,N-dimethyl-
formamide led to chroman 15 in 80% yield by an
intramolecular SNAr reaction [11]. Addition of two
equivalents of benzylamine to bromide 6 in N,N-dimethyl-
formamide led to a nearly quantitative yield of tetra-
hydroquinoline 16 by a tandem SN2-SNAr reaction [12].
Finally, in a similar process, carbocycle 17 was generated
in 80% yield by treating 6 with dimethyl malonate in the
presence of two equivalents of sodium hydride [13]. All
products were readily purified by chromatography.
O2N
CH=CH2
F
O2N
CH=CH2
+
NRCH2C6H5
21
(CH3CO)2O
pyridine
37%
22 (R = H)
23 (R = COCH3) 14%
O2N
C6H5CH2NH2
+
14
N,N-dimethylformamide
N
CH2C6H5
24
35%
O2N
(CH2)4NHCH2C6H5
Scheme 3
F
O2N
25 trace
2 equivalents NaH
5
N,N-dimethylformamide
O
80%
15
Seven-membered ring closures gave more variable
results. Treatment of 12 with sodium hydride as above
proceeded to give benzoxepin 19 in 77% yield. Attempts
to generate benzazepine 24 from 14 using benzylamine,
however, gave only 35% yield. The major product in
these reactions was 25, which arises from simple SN2
displacement of the side chain bromide without ring
closure. Even when 25 was heated to 120˚, little
additional cyclization was noted. These rings should form
more readily since the longer side chain permits approach
O2N
C6H5CH2NH2
N,N-dimethylformamide
N
98%
CH2C6H5
6
16
O2N
CH3O2C
CO2CH3
2 equivalents NaH
N,N-dimethylformamide
CH3O2C CO2CH3
80%
17

Mar-Apr 2008
Benzo-fused Heterocycles and Carbocycles
553
of the nucleophilic group with the proper trajectory for
addition to the aromatic ring (Figure 1), but evidently,
there is resistance to achieving the correct side chain
conformation to allow this angle of approach. It should
be noted that the isolation of 25 as a major product
suggests that displacement of the side chain halide occurs
prior to attack on the aromatic nucleus [6].
Six-membered rings have minimal strain and the longer
tether permits intramolecular attack by the nucleophile.
Seven-membered heterocycles require conformational
folding of the tether, which introduces torsional strain and
deters ring closure.
EXPERIMENTAL
All reactions were run under dry nitrogen in oven-dried
glassware. N,N-dimethylformamide from a freshly opened bottle
was stored under nitrogen over 4Å molecular sieves and
syringed into reactions as needed. Reactions were monitored by
thin layer chromatography on silica gel GF plates (Analtech
21521). Preparative separations were performed by one of the
following methods: (1) flash column chromatography [15] on
silica gel (grade 62, 60-200 mesh) containing ultraviolet-active
phosphor (Sorbent Technologies UV-5) packed into quartz
columns or (2) preparative thin layer chromatography on 20-cm
x 20-cm silica gel GF plates (Analtech 02015). Compound
elution in all cases was monitored using a hand-held ultraviolet
lamp. Hexanes used in chromatography had a boiling range of
65-70°; petroleum ether used in crystallization and trituration
procedures had a boiling range of 35-60°. Melting points were
uncorrected. Infrared spectra were run as thin films on sodium
chloride disks and referenced to polystyrene. Unless otherwise
X
X
X
O2N
F
O2N
F
O2N
F
X = O or NHCH2C6H5
Figure 1
Calculations on the oxygen systems indicate that the
five- and seven-membered heterocycles are more strained
than the six-membered structure by 2.24 kcal/mole and
5.13 kcal/mole, respectively [14]. Analysis of molecular
models confirms that the tether bearing the nucleophilic
oxygen in the benzofuran precursor is too short to permit
the optimum orientation for addition from above the plane
of the ring while the side chain in the benzoxepin
precursor is too long for efficient ring closure. Models
also indicate that the side chain conformations required
for cyclization of the five and seven-membered rings
suffer from C-H and C-C eclipsing interactions, which are
not present in the chair-like conformation that leads to the
chroman. Similar considerations should also apply in the
nitrogen series, with the added problem that basic
nucleophiles strongly promote elimination in the indoline
precursor.
1
indicated, H and 13C nuclear magnetic resonance spectra were
measured in deuteriochloroform at 300 MHz and 75 MHz,
respectively, using tetramethylsilane as the internal standard;
coupling constants (J) are given in Hertz. Unless otherwise
noted, mass spectra (electron impact/direct probe) were obtained
at 70 electron volts.
Di-tert-butyl 2-(2-Fluoro-5-nitrobenzyl)-1,3-propanedio-
ate (2). A stirred suspension of 15.0 g (109 mmoles) of
anhydrous potassium carbonate was prepared in 75 mL of
anhydrous acetone. To this suspension was added 2.94 g (13.6
mmoles) of di-tert-butyl malonate followed by 1.50 g (6.4
mmoles) of 1 [6]. The mixture was vigorously stirred for 2
days, then filtered through Celite® and concentrated. The
resulting oil was diluted with ether, washed with saturated
aqueous sodium chloride, dried (magnesium sulfate) and
concentrated under vacuum. The excess di-tert-butyl malonate
was removed at 55° under high vacuum and was recycled; the
remaining oil crystallized on cooling. Trituration of the crystals
with 5% ether in petroleum ether and filtration gave 2.27 g
(96%) of 2 as a light tan solid, mp 81-83°. The product from
three runs of this reaction were combined and used directly in
CONCLUSION
We have developed a new approach to the synthesis of
benzo-fused six- and seven-membered oxygen hetero-
cycles involving intramolecular SNAr addition of a three-
or four-carbon side chain alkoxide to an activated
aromatic fluoride positioned ortho to this substituent.
Nitrogen-containing rings have been prepared by a
tandem SN2-SNAr sequence involving intermolecular SN2
reaction of an amine with a side chain primary sp3
bromide followed by intramolecular SNAr displacement of
a similarly disposed activated aromatic fluoride. A six-
membered carbocycle has been prepared in an analogous
manner using the anion of dimethyl malonate. Ring size
studies indicate that the length of the tether linking the
aromatic ring to the nucleophile and conformational
effects in the chain are critical to the success of the
process. Five-membered rings are disfavored primarily
by the inability of the side chain nucleophile to approach
the aromatic ring with the correct geometry for addition;
additionally, elimination to form the styrene is a problem
in tandem SN2-SNAr reactions using basic nucleophiles.
1
the next step. ir: 1727, 1530, 1350, 1249 cm-1; H nmr: δ 8.22-
8.10 (complex, 2H), 7.17 (t, 1H, J = 8.7), 3.54 (t, 1H, J = 7.9),
3.23 (d, 2H, J = 7.9), 1.43 (s, 18H); 13C nmr: δ 167.4, 164.7 (d, J
= 257.4), 143.9, 127.1 (d, J = 6.6, obscures a second C signal),
124.5 (d, J = 10.0), 116.3 (d, J = 24.9), 82.2, 53.3, 27.8 (d, J =
2.3), 27.7. Anal. Calcd. for C18H24FNO6: C, 58.54; H, 6.50; N,
3.79. Found: C, 58.51; H, 6.46; N, 3.83.
2-(2-Fluoro-5-nitrobenzyl)-1,3-propanedioic Acid (3). To
solution 6.75 g (18.3 mmoles) of 2 in 75 mL of
a
dichloromethane was added 43.8 g (28.5 mL, 384 mmoles) of
trifluoroacetic acid and 10.6 g (14.6 mL, 91.5 mmoles) of
triethylsilane. The mixture was stirred for 3 hours and then
concentrated under vacuum to give a light yellow solid. The
solid was suspended in dichloromethane and filtered to give 3.86
g (82%) of 3 as an off-white powder, mp 144-146° (dec). This

554
R. A. Bunce, T. Nago, N. Sonobe and L. M. Slaughter
Vol 45
compound was dried under high vacuum and used directly in the
1
18.2), 126.5 (d, J = 7.2), 124.1 (d, J = 10.0), 116.3 (d, J = 24.9),
32.2, 32.1, 27.5 (d, J = 1.7); ms: m/z 261, 263 (M+, M++2).
Anal. Calcd. for C9H9BrFNO2: C, 41.22; H, 3.44; N, 5.34.
Found: C, 41.31; H, 3.48; N, 5.25.
next step. ir: 3691-2123, 1713, 1527, 1350, 1249 cm-1; H nmr
(deuteriodimethylsulfoxide-d6): δ 12.9 (br s, 2H), 8.24 (m, 1H),
8.16 (m, 1H), 7.43 (m, 1H), 3.64 (t, 1H, J = 7.6), 3.16 (t, 2H, J =
7.6); 13C nmr (deuteriodimethylsulfoxide-d6): δ 169.7, 164.2 (d,
J = 255.6), 143.7, 127.3 (d, J = 18.0), 126.8 (d, J = 6.9), 124.6
(d, J = 10.9), 116.6 (d, J = 25.2), 51.3, 27.2; ms (30 eV): m/z 257
(M+). Anal. Calcd. for C10H8FNO6: C, 46.69; H, 3.11; N, 5.45.
Found: C, 46.74; H, 3.13; N, 5.41.
2-(2-Fluoro-5-nitrophenyl)acetonitrile (7). To a stirred
solution of 1.00 g (15.4 mmoles) of potassium cyanide in 6 mL
of water at 22° was slowly added a solution of 2.34 g (10.0
mmoles) of 1 in 30 mL of ethanol [10]. The reaction mixture
was stirred for 4 hours, diluted with water and ether extracted
(three times). The combined ether extracts were washed with
saturated aqueous sodium chloride (three times), dried
(magnesium sulfate) and concentrated under vacuum to afford
1.63 mg (91%) of 7 as a yellow oil. This compound was
spectroscopically pure and used without further purification. ir:
2256, 1529, 1350, 1252 cm-1; 1H nmr: δ 8.41 (dd, 1H, J = 6.5,
2.7), 8.29 (ddd, 1H, J = 9.1, 4.5, 2.7), 7.32 (t, 1H, J = 9.0), 3.89
(s, 2H); 13C nmr: δ 163.6 (d, J = 259.4), 144.4, 126.2 (d, J =
10.3), 125.8 (d, J = 4.9), 119.5 (d, J = 17.8), 116.8 (d, J = 23.5),
115.4, 17.7 (d, J = 4.9); ms: m/z 180 (M+). Anal. Calcd. for
C8H5FN2O2: C, 53.33; H, 2.78; N, 15.56. Found: C, 53.38; H,
2.83; N, 15.51.
3-(2-Fluoro-5-nitrophenyl)propanoic Acid (4). A 100-mL
flask containing 4.00 g (15.6 mmoles) of powdered 3 was heated
at 160-170° under nitrogen using an oil bath. The solid liquefied
and carbon dioxide was released. After 30 minutes, the
evolution of gas ceased, the heat was removed and the brown
product solidified. The solid was recrystallized from ether-
petroleum ether to give 3.11 g (94%) of 4 as a tan solid, mp 109-
1
110°. ir: 3374-2282, 1520, 1348, 1249 cm-1; H nmr: δ 9.87 (br
s, 1H), 8.22-8.10 (complex, 2H), 7.18 (t, 1H, J = 9.0), 3.06 (t,
2H, J = 7.1), 2.76 (t, 2H, J = 7.1); 13C nmr: δ 177.8, 164.6 (d, J =
256.8), 144.2, 128.8 (d, J = 17.8), 126.5 (d, J = 6.9), 124.5 (d, J
= 10.3), 116.3 (d, J = 24.9), 33.6, 24.0; ms: m/z 213 (M+). Anal.
Calcd. for C9H8FNO4: C, 50.70; H, 3.76; N, 6.57. Found: C,
50.71; H, 3.76; N, 6.54.
4-(2-Fluoro-5-nitrophenyl)butanenitrile (8). To a solu-
tion of 310 mg (4.77 mmoles) of potassium cyanide in 10 mL of
dimethylsulfoxide at 22° was slowly added a solution of 940 mg
(3.59 mmoles) of 6 and the mixture was stirred for 3 hours [10].
The crude reaction mixture was added to saturated aqueous
3-(2-Fluoro-5-nitrophenyl)-1-propanol (5). A solution of
g (11.7 mmoles) of 4 in 25 mL of anhydrous
2.50
tetrahydrofuran was prepared and cooled to 0°. This solution
was stirred and 12.2 mL of 1 M borane tetrahydrofuran complex
(12.2 mmoles) in tetrahydrofuran was added slowly by syringe
over 20 minutes. The reaction was allowed to warm to room
temperature overnight. The reaction was quenched at 0° by slow
addition of 10 mL of water, then transferred to a separatory
funnel with ether and washed with saturated aqueous sodium
chloride (three times). The combined ether layers were dried
(magnesium sulfate) and concentrated under vacuum to give
2.16 g (87%) of 5 as a light yellow oil that was purified by flash
chromatography on a 30-cm x 2-cm silica gel column eluted
with 20% ether in hexanes. The resulting light yellow oil
crystallized to a waxy solid on standing at 0°, mp 35-36°. ir:
sodium chloride and ether extracted (three times).
The
combined ether layers were washed with saturated sodium
chloride (three times), dried (magnesium sulfate) and
concentrated under vacuum to give 734 mg (98%) of 8 as a
yellow oil. This compound was spectroscopically pure and used
without further purification. ir: 2247, 1527, 1351, 1243 cm-1;
1H nmr: δ 8.16 (m, 2H), 7.22 (t, 1H, J = 9.0), 2.92 (t, 2H, J =
7.0), 2.45 (t, 2H, J = 7.1), 2.05 (quintet, 2H, J = 7.1); 13C nmr: δ
164.5 (d, J = 257.1), 144.2, 128.5 (d, J = 18.3), 126.3 (d, J =
6.6), 124.4 (d, J = 10.0), 118.8, 116.5 (d, J = 25.2), 27.9 (d, J =
2.0), 25.2 (d, J = 1.4), 16.7; ms: m/z 208 (M+). Anal. Calcd. for
C10H9FN2O2: C, 57.69; H, 4.33; N, 13.46. Found: C, 57.65; H,
4.34; N, 13.44.
1
3365, 1525, 1350, 1243 cm-1; H nmr: δ 8.17 (dd, 1H, J = 6.5,
3.0), 8.05 (ddd, 1H, J = 9.0, 4.3, 3.0), 7.16 (t, 1H, J = 9.0), 3.72
(t, 2H, J = 6.3), 2.85 (t, 2H, J = 7.4), 1.92 (m, 2H), 1.77 (br s,
1H); 13C nmr: δ 164.7 (d, J = 256.2), 144.1, 130.5 (d, J = 18.3),
126.4 (d, J = 7.2), 123.7 (d, J = 10.3), 116.1 (d, J = 25.2), 61.7,
32.2, 25.3 (d, J = 2.3); ms: m/z 199 (M+). Anal. Calcd. for
C9H10FNO3: C, 54.27; H, 5.03; N, 7.04. Found: C, 54.22; H,
5.06; N, 7.05.
Acid Hydrolysis of Nitriles: 2-(2-Fluoro-5-nitrophenyl)-
acetic Acid (9). To 1.63 g (9.05 mmoles) of 7 was added 40 mL
of 50% aqueous sulfuric acid and the mixture was boiled for 1
hour. Upon cooling, the acid crystallized from the mixture and
was isolated by filtration. Drying under high vacuum gave 1.35
g (75%) of 9 as a tan solid, mp 143-144°. This compound was
spectroscopically pure and used without further purification. ir:
3304-2278, 1714, 1518, 1344, 1242 cm-1; 1H nmr (deuterio-
dimethylsulfoxide-d6): δ 10.96 (br s, 1H), 8.36 (dd, 1H, J = 6.3,
3.0), 8.23 (ddd, 1H, J = 8.8, 4.6, 3.0), 7.47 (t, 1H, J = 9.0), 3.81
(s, 2H); 13C nmr (deuteriodimethylsulfoxide-d6): δ 170.9, 164.4
(d, J = 255.9), 143.7, 127.5 (d, J = 6.6), 125.0 (d, J = 10.6),
124.5 (d, J = 18.6), 116.4 (d, J = 24.9), 33.8 (d, J = 1.7); ms: m/z
199 (M+). Anal. Calcd. for C8H6FNO4: C, 48.24; H, 3.02; N,
7.04. Found: C, 48.41; H, 3.09; N, 7.04.
2-(3-Bromopropyl)-1-fluoro-4-nitrobenzene (6). A solu-
tion of 2.00 g (10.1 mmoles) of 5 was converted to its
methanesulfonate ester according to the procedure of Crossland
and Servis [9], mp 58-60°. The crude ester was dissolved in 160
mL of 3:1 ether:acetone, 4.35 g (50.0 mmoles) of anhydrous
lithium bromide was added and the reaction was warmed at 40°
for 12 h. The reaction mixture was cooled, added to water and
ether extracted (three times). The combined ether layers were
washed with water and saturated aqueous sodium chloride, dried
(magnesium sulfate) and concentrated under vacuum. The
resulting light yellow oil was flash chromatographed on a 30-cm
x 2-cm silica gel column eluted with 5% ether in hexanes to give
2.38 g (90%, two steps) of bromide 6 as a light yellow oil. ir:
1525, 1349, 1243 cm-1; 1H nmr: δ 8.20-8.10 (complex, 2H), 7.18
(t, 1H, J = 8.7), 3.44 (t, 2H, J = 6.5), 2.92 (t, 2H, J = 7.5), 2.22
(m, 2H); 13C nmr: δ 164.6 (d, J = 256.8), 144.2, 129.3 (d, J =
4-(2-Fluoro-5-nitrophenyl)butanoic Acid (10). Using the
procedure outlined for the preparation of 9, 734 mg (3.53
mmoles) of 8 was hydrolyzed to give 682 mg (85%) of 10 as a
tan solid, mp 100-101°. ir: 3683-2256, 1708, 1527, 1350, 1243
1
cm-1; H nmr: δ 9.40 (br s, 1H), 8.14 (m, 2H), 7.17 (t, 1H, J =
8.7), 2.81 (t, 2H, J = 7.5), 2.45 (t, 2H, J = 7.3), 2.01 (quintet, 2H,
J = 7.5); 13C nmr: δ 179.0, 164.6 (d, J = 256.5), 144.2, 129.9 (d,
J = 18.6), 126.4 (d, J = 7.2), 124.1 (d, J = 10.3), 116.3 (d, J =

Mar-Apr 2008
Benzo-fused Heterocycles and Carbocycles
555
25.2), 33.1, 28.1 (d, J = 2.0), 24.4 (d, J = 1.1); ms: m/z 227 (M+).
Anal. Calcd. for C10H10FNO4: C, 52.86; H, 4.41; N, 6.17.
Found: C, 52.87; H, 4.42; N, 6.17.
The combined ether washes were washed with saturated aqueous
sodium chloride (three times), dried (magnesium sulfate) and
concentrated under vacuum. Purification by preparative thin
layer chromatography gave 72 mg (80%) of 15 as a light yellow
Reduction of the Carboxylic Acids: 2-(2-Fluoro-5-nitro-
phenyl)ethanol (11). Using the procedure described for the
preparation of 5, 1.86 g (9.35 mmoles) of acid 9 was reduced to
alcohol 11. Purification by flash chromatography on a 30-cm x
2-cm column of silica gel eluted with 20% ether in hexanes gave
1.49 g (86%) of 11 as a light yellow oil that solidified on
standing, mp 44-46°. ir: 3365, 1527.1350, 1243 cm-1; 1H nmr: δ
8.22 (dd, 1H, J = 6.3, 2.7), 8.13 (m, 1H), 7.18 (t, 1H, J = 9.0),
3.92 (q, 2H, J = 5.7), 2.99 (t, 2H, J = 6.3), 1.99 (br s, 1H); 13C
nmr: δ 164.8 (d, J = 256.5), 144.0, 127.6 (d, J = 18.6), 127.1 (d,
J = 7.2), 124.1 (d, J = 10.3), 116.2 (d, J = 25.2), 61.5, 32.0 (d, J
= 1.1); ms: m/z 185 (M+). Anal. Calcd. for C8H8FNO3: C,
51.89; H, 4.32; N, 7.57. Found: C, 51.94; H, 4.35; N, 7.49.
1
solid, mp 102-104° (lit [3b] mp 104°). ir: 1507, 1340 cm-1; H
nmr: δ 8.02-7.94 (complex, 2H), 6.84 (d, 1H, J = 9.8), 4.29 (t,
2H, J = 5.3), 2.86 (t, 2H, J = 6.5), 2.05 (m, 2H); 13C nmr: δ
160.4, 143.8, 125.9, 123.5, 122.6, 117.1, 67.2, 24.8, 21.5; ms:
m/z 179 (M+). Anal. Calcd. for C9H9NO3: C, 60.34; H, 5.03; N,
7.82. Found: C, 60.33; H, 5.05; N, 7.79.
1-Benzyl-6-nitro-1,2,3,4-tetrahydroquinoline (16). A sol-
ution of 100 mg (0.38 mmoles) of 6 in 3 mL of anhydrous N,N-
dimethylformamide was treated with 82 mg (0.76 mmoles) of
benzylamine in 1 mL of dry dimethylformamide. The reaction
was stirred for 30 min at room temperature and for 2 hours at
45°, quenched by addition to 30 mL of saturated aqueous
ammonium chloride and ether extracted (three times). The
combined organic extracts were washed with saturated aqueous
sodium chloride (three times), dried (magnesium sulfate) and
concentrated under vacuum. Purification by preparative thin
layer chromatography gave 100 mg (98%) of 16 as a bright
yellow solid, mp 71-73°. ir: 1518, 1309 cm-1; 1H nmr: δ 7.88 (s,
1H), 7.87 (m, 1H), 7.39-7.24 (complex, 3H), 7.18 (d, 2H, J =
7.1), 6.42 (d, 1H, J = 9.8), 4.60 (s, 2H), 3.50 (t, 2H, J = 6.0),
2.85 (t, 2H, J = 6.0), 2.04 (quintet, 2H, J = 6.0); 13C nmr: δ
150.6, 136.5, 136.4, 128.9, 127.4, 126.1, 125.0, 124.7, 121.4,
109.4, 54.8, 50.2, 27.9, 21.4; ms: m/z 177 (M+-C7H7). Anal.
Calcd. for C16H16N2O2: C, 71.64; H, 5.97; N, 10.45. Found: C,
71.69; H, 5.95; N, 10.51.
4-(2-Fluoro-5-nitrophenyl)butanol (12).
Using the
procedure outlined for the preparation of 5, 702 mg (3.09
mmoles) of acid 10 was reduced to alcohol 12. Purification by
flash chromatography on a 20-cm x 2-cm column of silica gel
eluted with 20% ether in hexanes gave 636 mg (97%) of 12, mp
39-40°; ir: 3348, 1527, 1350, 1243 cm-1; 1H nmr: δ 8.14 (dd, 1H,
J = 6.5, 2.7), 8.10 (m, 1H), 7.16 (t, 1H, J = 8.9), 3.70 (t, 2H, J =
6.5), 2.77 (t, 2H, J = 7.4), 1.86 (br s, 1H), 1.74 (m, 2H), 1.65 (m,
2H); 13C nmr: δ 164.6 (d, J = 256.5), 144.1, 130.9 (d, J = 18.3),
126.3 (d, J = 7.4), 123.6 (d, J = 10.3), 116.1 (d, J = 25.2), 62.3,
32.0, 28.5 (d, J = 1.7), 25.9 (d, J = 1.1); ms: m/z 213 (M+). Anal.
Calcd. for C10H12FNO3: C, 56.34; H, 5.63; N, 6.57. Found: C,
56.40; H, 5.67; N, 6.51.
2-(2-Bromoethyl)-1-fluoro-4-nitrobenzene (13). Using the
procedure described for the preparation of 6, 1.00 g (5.41
mmoles) of alcohol 11 was converted to bromide 13.
Purification by flash chromatography on a 20-cm x 2-cm silica
gel column using 10% ether in hexanes gave 1.17 g (87%) of 13
as a light yellow oil that crystallized on standing at 0°, mp 24-
25°. ir: 1529, 1350, 1243 cm-1; 1H nmr: δ 8.19 (m, 2H), 7.21 (t,
1H, J = 9.0), 3.63 (t, 2H, J = 7.0), 3.30 (t, 2H, J = 7.0); 13C nmr:
δ 164.6 (d, J = 257.4), 144.2, 127.4 (d, J = 17.8), 127.0 (d, J =
6.9), 124.8 (d, J = 10.3), 116.5 (d, J = 24.9), 32.3 (d, J = 1.7),
30.3; ms (30 eV): m/z 247, 249 (M+, M++2). Anal. Calcd. for
C8H7BrFNO2: C, 38.71; H, 2.82; N, 5.64. Found: C, 38.83; H,
2.87; N, 5.61.
1, 1-Bis(methoxycarbonyl)- 6- nitro-1, 2, 3, 4-tetrahydro-
naphthalene (17). To a suspension of 22 mg (0.90 mmoles)
of oil-free sodium hydride in 3 mL of anhydrous N,N-
dimethylformamide was added 60 mg (0.45 mmoles) of
dimethyl malonate in 2 mL of dry dimethylformamide. The
reaction mixture was stirred for 15 minutes and 100 mg (0.38
mmoles) of 6 was added as a solution in 2 mL of dry
dimethylformamide. The reaction was stirred for 2 hours at
room temperature and for 2 hours at 45°, then quenched by
addition to 30 mL of saturated aqueous ammonium chloride
and ether extracted (three times). The combined ether extracts
were washed with saturated aqueous sodium chloride (three
times), dried (magnesium sulfate) and concentrated under
vacuum. Purification by preparative thin layer chroma-
tography using 20% ether in hexanes gave 90 mg (80%) of 17
as a light yellow solid, mp 109-110°. ir: 1732, 1524, 1348
2-(4-Bromobutyl)-1-fluoro-4-nitrobenzene (14). Using the
procedure described for the preparation of 6, 1.00 g (4.69
mmoles) of alcohol 12 was converted to bromide 14.
Purification by flash chromatography on a 20-cm x 2-cm silica
gel column using 10% ether in hexanes gave 1.18 g (91%) of 14
1
cm-1; H nmr: δ 7.99 (m, 2H), 7.56 (d, 1H, J = 9.5), 3.78 (s,
6H), 2.93 (t, 2H, J = 6.5), 2.48 (m, 2H), 1.89 (m, 2H); 13C nmr:
δ 170.9, 147.1, 139.0, 138.9, 131.8, 124.1, 120.3, 59.1, 53.2,
30.6, 29.3, 19.4; ms (30 eV): m/z 293 (M+). Anal. Calcd. for
C14H15NO6: C, 57.34; H, 5.12; N, 4.78. Found: C, 57.35; H,
5.12; N, 4.74.
Attempted Synthesis of 5-Nitro-2,3-dihydrobenzofuran
(18). Attempts to cyclize 11 to 18 as described for the synthesis
of 15 led to a complex mixture of products resulting from
intermolecular reactions and decomposition of the substrate.
7-Nitro-2,3,4,5-tetrahydro-1-benzoxepin (19). Using the
procedure described for the preparation of 15, 100 mg (0.47
mmoles) of 12 yielded 70 mg (77%) of 19, mp 40-41° [16]. ir:
1520, 1347 cm-1; 1H nmr: δ 8.04 (d, 1H, J = 2.8), 8.01 (dd, 1H, J
= 8.6, 2.8), 7.05 (d, 1H, J = 8.6), 4.10 (t, 2H, J = 5.2), 2.91 (m,
2H), 2.01 (m, 2H), 1.80 (m, 2H); 13C nmr: δ 165.3, 143.1, 135.7,
126.2, 123.2, 121.9, 73.7, 34.1, 31.4, 25.4; ms: m/z 193 (M+).
1
as a light yellow oil. ir: 1525, 1350, 1242 cm-1; H nmr: δ 8.12
(m, 2H), 7.17 (t, 1H, J = 8.8), 3.45 (t, 2H, J = 6.3), 2.76 (t, 2H, J
= 7.6), 1.93 (m, 2H), 1.83 (m, 2H); 13C nmr: δ 164.6 (d, J =
256.2), 144.2, 130.4 (d, J = 18.3), 126.3 (d, J = 7.2), 123.8 (d, J
= 10.3), 116.2 (d, J = 25.5), 33.0, 32.0, 28.1 (d, J = 1.1), 28.0 (d,
J = 1.7); ms: m/z 275, 277 (M+, M++2). Anal. Calcd. for
C10H11BrFNO2: C, 43.48; H, 3.99; N, 5.07. Found: C, 43.44; H,
4.02; N, 5.10.
6-Nitrochroman (15). To a suspension of 24 mg (1.00
mmole) of oil-free sodium hydride in 2 mL of anhydrous N,N-
dimethylformamide was added 100 mg (0.50 mmoles) of 5 in 3
mL of dry dimethylformamide. The reaction immediately
turned brown. The mixture was stirred for 8 hours at room
temperature, quenched by addition to 20 mL of saturated
aqueous ammonium chloride and ether extracted (three times).

556
R. A. Bunce, T. Nago, N. Sonobe and L. M. Slaughter
Vol 45
Anal. Calcd. for C10H11NO3: C, 62.17; H, 5.70; N, 7.25. Found:
C, 62.18; H, 5.70; N, 7.27.
This procedure also yielded N-[4-(2-fluoro-5-nitrophenyl)-
butyl]benzylamine (25) as a minor product. However, using the
above procedure at 45° for 2 hours, 25 was produced as the
major product (89 mg, 80%). ir: 3325, 1525, 1350, 1241 cm-1;
1H nmr: δ 8.11 (m, 1H), 8.07 (m, 1H), 7.36-7.20 (complex, 5H),
7.13 (t, 1H, J = 9.0), 3.78 (s, 2H), 2.72 (t, 2H, J = 7.1), 2.67 (t,
2H, J = 7.1), 1.70 (m, 2H), 1.58 (m, 2H), 1.36 (br s, 1H); 13C
nmr: δ 164.6 (d, J = 256.2), 144.2, 140.3, 131.0 (d, J = 18.6),
128.3, 128.0, 126.9, 126.3 (d, J = 7.4), 123.5 (d, J = 10.3), 116.0
(d, J = 25.5), 54.0, 48.9, 29.6, 28.7 (d, J = 2.0), 27.3. Anal.
Calcd. for C17H19FN2O2: C, 67.55; H, 6.29; N, 9.27. Found: C,
67.59; H, 6.31; N, 9.22.
Attempted Synthesis of 1-Benzyl-5-nitroindoline (20).
Using the procedure for the preparation of 16, 100 mg (0.40
mmoles) of 13 was treated dropwise with benzylamine at 0° and
the reaction was slowly allowed to warm to room temperature
(24 hours). Workup gave a dark yellow oil that was purified by
preparative thin layer chromatography using 5-20% ether in
hexanes to give four bands: band 1, 2-fluoro-5-nitrostyrene
(21); band 2, recovered 13 (18 mg, 18%); band 3, a mixture of
20 and 2-(N-benzylamino)-5-nitrostyrene (22). The compounds
in band 3 were treated with excess acetic anhydride and pyridine
at 85° for 12 hours to acylate the aniline then separated by
preparative thin layer chromatography to give 2 bands: band 1,
20; band 2, N-benzyl-N-(2-ethenyl-4-nitrophenyl)acetamide
(23). The physical and spectral data for 20, 21 and 23 are given
below. Yields are based on 82% conversion of the starting
material.
Acknowledgment. T. N. thanks the Oklahoma State
University College of Arts and Sciences for a Wentz Project
Scholarship and the Department of Chemistry for a Skinner
Scholarship; N. S. thanks the Department of Chemistry for a
Moore Scholarship. Funding for the 300 and 400 MHz NMR
spectrometers of the Oklahoma Statewide Shared NMR Facility
was provided by the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Foundation, and
Conoco, Inc. Finally, the authors wish to thank the OSU College
of Arts and Sciences for funds to upgrade our departmental FT-
IR and GC-MS instruments.
1-Benzyl-5-nitroindoline (20). This compound (26 mg,
31%) was isolated as a yellow solid, mp 67-68° [17]. ir: 1608,
1
1518, 1490, 1320 cm-1; H nmr: δ 8.03 (dd, 1H, J = 8.8, 1.9),
7.90 (m, 1H), 7.40-7.23 (complex, 5H), 6.35 (d, 1H, J = 8.8),
4.43 (s, 2H), 3.63 (t, 2H, J = 8.7), 3.09 (t, 2H, J = 8.7); 13C nmr:
δ 157.0, 138.2, 136.2, 129.7, 128.8, 127.7, 127.4, 126.7, 120.8,
103.5, 52.4, 51.0, 27.0; ms: m/z 163 (M+-C7H7). Anal. Calcd.
for C15H14N2O2: C, 70.87; H, 5.51; N, 11.02. Found: C, 70.88;
H, 5.53; N, 10.98.
2-Fluoro-5-nitrostyrene (21). This compound (20 mg,
37%) was isolated as a light yellow oil. ir: 1620, 1529, 1346,
1241 cm-1; 1H nmr: δ 8.41 (dd, 1H, J = 6.3, 2.7), 8.13 (ddd, 1H, J
= 9.0, 4.4, 2.7), 7.19 (t, 1H, J = 9.0), 6.87 (dd, 1H, J = 17.7,
11.2), 5.99 (d, 1H, J = 17.7), 5.59 (d, 1H, J = 11.2); 13C nmr: δ
163.3 (d, J = 260.5), 144.4, 127.4 (d, J = 3.1), 126.6 (d, J =
17.1), 124.6 (d, J = 10.3), 122.9 (d, J = 6.0), 119.6 (d, J = 4.6),
116.8 (d, J = 24.9); ms: m/z 167 (M+). Anal. Calcd. for
C8H6FNO2: C, 57.49; H, 3.59; N, 8.38. Found: C, 57.47; H,
3.60; N, 8.34.
N- Benzyl- N- (2- ethenyl- 4- nitrophenyl) acetamide (23).
This compound (13 mg, 14%) was isolated as a colorless oil that
crystallized on standing. Trituration with 5% ether in petroleum
ether gave a light yellow solid, mp 80-82°. ir: 1669, 1610, 1525,
1346 cm-1; 1H nmr: δ 8.46 (d, 1H, J = 2.7), 8.02 (dd, 1H, J = 8.7,
2.7), 7.60-7.44 (complex, 3H), 7.38-7.25 (complex (2H), 6.94
(d, 1H, J = 8.7), 6.56 (dd, 1H, J = 17.4, 11.1), 5.93 (d, 1H, J =
17.4), 5.51 (d, 1H, J = 11.1), 5.34 (d, 1H, J = 14.0), 4.34 (d, 1H,
J = 14.0), 1.80 (s, 3H); 13C nmr: δ 169.6, 161.2, 145.0, 137.4,
136.1, 130.8, 129.8, 129.3, 128.6, 128.0, 123.2, 121.7, 120.2,
52.1, 22.6. Anal. Calcd for C17H16N2O3: C, 68.92; H, 5.41; N,
9.46. Found: C, 68.89; H, 5.44; N, 9.44.
REFERENCES AND NOTES
[1] Undergraduate research participants: T. N., 2006-present; N.
S., 2005-2006.
[2] See for example [a] Bunce, R. A.; Herron, D. M.; Ackerman,
M. L. J. Org. Chem. 2000, 65, 2847. [b] Bunce, R. A.; Herron, D. M.;
Johnson, L. B.; Kotturi, S. V. J. Org. Chem. 2001, 66, 2822. [c] Bunce,
R. A.; Randall, M. H.; Applegate, K. G. Org. Prep. Proced. Int. 2002,
34, 493. [d] Bunce, R. A.; Herron, D. M.; Lewis, J. R.; Kotturi, S. V.;
Holt, E. M. J. Heterocyclic Chem. 2003, 40, 101. [e] Bunce, R. A.;
Herron, D. M.; Hale, L. Y. J. Heterocyclic Chem. 2003, 40, 1031. [f]
Bunce, R. A.; Johnson, L. B.; Holt, E. M. J. Heterocyclic Chem. 2004,
41, 563. [g] Bunce, R. A.; Smith, C. L.; Lewis, J. R. J. Heterocyclic
Chem. 2004, 41, 963. [h] Bunce, R. A.; Schammerhorn, J. E. J.
Heterocyclic Chem. 2006, 43, 1031. [i] Bunce, R. A.; Schammerhorn, J.
E.; Slaughter, L. M. J. Heterocyclic Chem. 2006, 43, 1505.
[3] Oxygen heterocycles: [a] Chiou, W.-F.; Li, S.-Y.; Ho, L.-K.;
Hsien, M.-L.; Don, M.-J. Eur. J. Med. Chem. 2002, 37, 69. [b] Hodgetts,
K. J.; Kieltyka, A.; Brodbeck, R.; Tran, J. N.; Wasley, J. W. F.;
Thurkauf, A. Bioorg. Med. Chem. 2001, 9, 3207. [c] Hach, V; Leciva, D.
M. Coll. Czech. Chem. Commun. 1959, 24, 3136.
[4] Nitrogen heterocycles: [a] Sano, H.; Noguchi, T.; Tanatani,
A.; Hashimoto, Y.; Miyachi, H. Bioorg. Med. Chem. 2005, 13, 3079. [b]
Hanada, K.; Furuya, K.; Yamamoto, N.; Nejishima, H.; Ichikawa, K;
Nakamura, T.; Miyakawa, M.; Amano, S.; Sumita, Y.; Oguro, N. Biol.
Pharm. Bull. 2003, 26, 1563. [c] Stenkamp, D.; Mueller, S. G.; Roth, G.
J.; Lustenberger, P.; Rudolf, K.; Lehmann-Lintz, T.; Arndt, K.; Ralf, R.
H.; Lenter, M.; Wieland, H.-A. International Patent WO 2004039764,
2004; Chem. Abstr. 2004, 140, 406638. [d] Cho, I.-H.; Lim, J.-W.; Noh,
J.-Y.; Kim, J. H.; Park, S.-W.; Ryu, H.-C.; Kim, J.-H.; Chun, H.-O.;
Wang, S.-Y.; Lee, S.-H. International Patent WO 2003021409, 2003.;
Chem. Abstr. 2003, 138, 321129. [e] Reich, S. H.; Fuhry, M. A. M.
International Patent WO 9205173, 1992; Chem. Abstr. 1992, 117,
150985.
1-Benzyl- 7-nitro-2, 3, 4, 5-tetrahydro-1H- 1-benzazepine
(24). Using the procedure outlined for the preparation of 16,
100 mg (0.36 mmoles) of 14 was reacted with benzylamine at
20° for 3 hours and 120° for 12 hours to give 36 mg (35%) of 24
1
as a yellow oil. ir: 1503, 1312 cm-1; H nmr: δ 7.96 (d, 1H, J =
2.7), 7.92 (dd, 1H, J = 9.0, 2.7), 7.40-7.24 (complex, 5H), 6.75
(d, 1H, J = 9.0), 4.50 (s, 2H), 3.31 (distorted t, 2H, J = 5.5), 2.96
(distorted t, 2H, J = 5.5), 1.81 (m, 4H); 13C nmr: δ 157.0, 139.6,
137.5, 131.5, 128.7, 127.4, 127.3, 126.4, 123.4, 115.5, 57.6,
52.3, 33.7, 27.2, 24.6; ms: m/z 191 (M+-C7H7). Anal. Calcd. for
C17H18N2O2: C, 72.34; H, 6.38; N, 9.92. Found: C, 72.39; H,
6.40; N, 9.87.
[5] Carbocycles: [a] Nagata, R.; Tanno, N.; Ae, N. Canadian
Patent CA 2135811, 1995; Chem. Abstr. 1995, 124, 8615. [b] Nagata,
R.; Tanno, N.; Ae, N. European Patent EP 657427, 1995; Chem. Abstr.
1995, 123, 256515.
[6] Bunce, R. A.; Rogers, D.; Nago, T.; Bryant, S. A. J.
Heterocyclic Chem., 2008, 45, 547. This report presents another
application of the SN2-SNAr reaction.

Mar-Apr 2008
Benzo-fused Heterocycles and Carbocycles
557
[7] The use of trifluoroacetic acid and triethylsilane to remove
Org. Chem. 1997, 62, 2054. [c] Boger, D. L.; Miyazaki, S.; Kim, S. H.;
Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999,
121, 10004. [d] Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J.-H.; Rogel,
O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc. 2001, 123, 1862.
[12] For examples of SNAr reactions involving amines, see [a]
Bader, H.; Hansen, A. R.; McCarty, F. J. J. Org. Chem. 1966, 31, 2319.
[b] Pietra, F.; Del Cima, F. J. Org. Chem. 1968, 33, 1411. [c] Totered,
J.; Nilsson, U. J. Synlett 2004, 2517.
[13] For an example of the SNAr reaction involving malonate
anion, see [a] Perchinunno, M.; Guerrato, A.; Pregnolato, F. Org. Prep.
Proced. Int. 1977, 9, 303.
[14] Density functional theory calculations were performed using
the GAUSSIAN 03 package [Frisch, M. J., et. al, Gaussian 03,
Gaussian, Inc., Pittsburgh, PA, 2004] at the B3LYP/6-31+G** level of
theory with full vibrational analysis.
tert-butyl esters is described in Mehta, A.; Jaouhari, R.; Benson, T. J.;
Douglas, K. T. Tetrahedron Lett. 1992, 33, 5441. [b] See also Pearson,
D. A.; Blanchette, M.; Baker, M. L.; Guindon, C. A. Tetrahedron Lett.
1989, 30, 2739.
[8] The use of borane-tetrahydrofuran complex for the selective
reduction of acids in the presence of nitro groups is described in Yoon,
N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky, T. P. J.
Org. Chem. 1973, 38, 2786.
[9] Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35, 3195.
The two-step route via the mesylate occurred cleanly in all cases with no
elimination. The use of phosphorus tribromide in ether gave 10-25%
yields of the bromides from 5, 11 and 12 presumably due to competing
attack on the aromatic ring by the nucleophilic phosphorus. The use of
potassium bromide in 45% (w/w) aqueous sulfuric acid gave 70-80% of
the bromides from 5 and 12, but gave predominantly elimination from
11.
[15] Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
[10] Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A.
R. Vogel's Textbook of Practical Organic Chemistry, 5th Ed.; Longman
[16] This compound has been prepared in 56% yield by nitration
of 2,3,4,5-tetrahydrobenzoxepin. The bp was reported as 142-145° (1
mm Hg), but no mp was given, see Nilsson, J. L. G.; Selander, H.;
Sievertsson, H.; Skanberg, I.; Svensson, K. G. Acta Chem. Scand. 1971,
25, 94.
[17] This compound has also been prepared in 91% yield by
benzylation of 5-nitroindoline, but no mp was given, see Tsou, H.-R.;
Overbeek-Klumpers, E. G.; Hallett, W. A.; Reich, M. F.; Floyd, M. B.;
Johnson, B. D.; Michalak, R. S.; Nilakantan, R.; Discafani, C.; Golas, J.;
Rabindran, S. K.; Shen, R.; Shi, X.; Wang, Y.-F.; Upeslacis, J.; Wissner,
A. J. Med. Chem. 2005, 48, 1107.
Scientific and Technical:
New York, NY, 1989; pp 713-714.
Conversion to the nitrile proceeds best in ethanol for the benzylic halide
and in dimethylsulfoxide for the unactivated halide. The use of the more
basic conditions in dimethylsulfoxide for the benzylic halide resulted in
conversion to the nitrile followed by alkylation of the product to give
2,3-bis(2-fluoro-5-nitrophenyl)propionitrile.
[11] For examples of SNAr reactions involving alkoxides, see [a]
Bunce, R. A.; Easton, K. M. Org. Prep. Proced. Int. 2004, 34, 76. [b]
Boger, D. L.; Zhou, J.; Borzilleri, R. M.; Nukui, S.; Castle, S. L. J.