6-nitro-1,2,3,4-tetrahydroquinoline-4-carboxylic esters and 7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylic esters by a tandem reductive amination-SNAr reaction

Full text of DOI:10.1080/00304940903517506

Organic Preparations and Procedures International, 42:71–82, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903517506
6-Nitro-1,2,3,4-tetrahydroquinoline-4-carboxylic
Esters and 7-Nitro-3,4-dihydroquinoxaline-
1(2H)-carboxylic Esters by a Tandem Reductive
Amination-SNAr Reaction
Richard A. Bunce and James E. Schammerhorn
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma,
USA
The tandem reductive amination-SNAr reaction sequence has recently been reported for
the efficient synthesis of 1,2,3,4-tetrahydroquinolines.1 As part of our effort to develop
new routes to biologically active heterocyclic compounds having diverse substitution, we
wished to extend this methodology to the synthesis of tetrahydroquinolines and tetrahydro-
quinoxalines bearing carboxyl groups on the saturated ring, and possibly to dihydroben-
zoxazines as well.2 In the tetrahydroquinoline series, this would provide compounds that
have been shown to have useful activities in the treatment of inflammatory diseases such
as asthma.3 Tetrahydroquinoxaline derivatives have been shown to express useful activity
as anticancer drugs4 and cell adhesion agents.5 Dihydrobenzoxazines have demonstrated
activity as antihypertensives6 and neuroprotective agents.7
The substrates for this annulation reaction are trisubstituted aromatic systems bearing
a 3-oxo side-chain at C1, a F (or Cl) at C2 and a NO2 group at C5. We expected that the
electronic nature of the atom linking the 3-oxo side chain to the ring would be critical to
the success of the final SNAr ring closure. While the alkyl side-chain of the tetrahydro-
quinoline precursors should not pose a problem, the alkylamino group in the tetrahydro-
quinoxaline precursors and the alkoxy side chain required to prepare dihydrobenzoxazines
would deactivate the ring toward the final SNAr cyclization. In the tetrahydroquinoxaline
precursors, the electron donating character of the nitrogen could be decreased by protect-
ing it as a carbamate. Derivatization, however, would not be possible in the case of the
dihydrobenzoxazine precursors and we anticipated difficulties in the ring closure step using
these substrates.
The synthesis of the cyclization substrates is shown in Scheme 1. The tetrahydro-
quinoline precursors were prepared from methyl 2-fluoro-5-nitrophenylacetate obtained
by esterification of the corresponding acid;8 the tetrahydroquinoxaline precursors were
Received July 17, 2009; in final form October 23, 2009.
Address correspondence to Richard A. Bunce, Department of Chemistry, Oklahoma State Uni-
versity, Stillwater, OK 74078-3071. E-mail: rab@okstate.edu
71

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Bunce and Schammerhorn
Scheme 1
Synthesis of the cyclization substrates.
generated from 2-fluoro-5-nitroaniline protected as its methyl carbamate; and finally, a
dihydrobenzoxazine precursor was prepared from 2-chloro-5-nitrophenol.9 The acidity of
the benzylic CH, the anilide NH and the phenolic OH in these structures facilitated depro-
tonation and allylation α to the aromatic ring. Ozonolysis10 then converted the side-chain
double bonds to the necessary carbonyl functions.
The reductive amination-SNAr sequences were carried out by dissolving 1.00 eq of
the carbonyl compound in CH3OH, adding 1.20 eq of the amine, stirring for 30 min and
finally adding (in three portions) 1.40 eq of NaBH3CN. In the preparation of tetrahydro-
quinolines, the aldehyde precursors gave the best results (70–90% yields of 12–15). The
ketone substrates, however, yielded inseparable mixtures of cis and trans isomers and were
not pursued. In the tetrahydroquinoxaline ring closures, the aldehydes11 were generally
observed to give lower yields (36–62% of 16–19) than the ketone substrates (57–83%
yields of 17–20). Finally, in our one attempt to close a dihydrobenzoxazine derivative, we
observed only the simple reductive amination product 24 (46%) along with recovered start-
ing material (28%); none of the ring-closed product 25 was formed, presumably due to the

6-Nitro-1,2,3,4-tetrahydroquinoline-4-carboxylic Esters
73
unfavorable electronics of the system.12 In the current reaction, primary amines were more
successful than secondary amines while tertiary amines gave complex mixtures containing
little if any of the cyclized product. The results of our reductive amination-SNAr reactions
are summarized in Schemes 2 and 3.
Scheme 2
Synthesis of tetrahydroquinoline and dihydroquinoxaline carboxylic esters.
Scheme 3
Attempted synthesis of dihydrobenzoxazines.
In conclusion, we have developed a new route to nitro-substituted tetrahydroquinoline-
4- and dihydroquinoxaline-1(2H)-carboxylic esters based on a tandem reductive amination-
SNAr reaction. In this sequence, an electron deficient aromatic ring is critical to the final
SNAr ring closure. The reaction is also sensitive to steric hindrance in the amine, with
primary amines giving the highest yields. Though the current approach to the tetrahydro-
quinoline systems is not as diastereoselective as our earlier-reported reduction-reductive
amination,10 it does offer a relatively direct route to the title compounds. We are contin-
uing our studies to develop efficient approaches to heterocyclic structures of biological
interest.
Experimental Section
All reactions were run in dry glassware under N2. The saturated NH4Cl, saturated NaCl,
5% NaHCO3, 5% Na2S2O3 and 0.5 M HCl, used in work-up procedures refer to aqueous
solutions. Reactions were monitored by TLC on silica gel GF plates (Analtech 21521).

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Bunce and Schammerhorn
Preparative separations were performed by one of the following methods: (1) flash column
chromatography13 on silica gel (grade 62, 60–200 mesh) containing UV-active phosphor
(Sorbent Technologies UV-05) packed into quartz columns or (2) PTLC on 20-cm × 20-cm
silica gel GF plates (Analtech 02015). Band elution for all chromatographic separations
was monitored using a hand-held UV lamp. Melting points were uncorrected. IR spectra
were run as thin films on NaCl disks. 1H and 13C NMR spectra were measured in CDCl3
at 300 MHz and 75 MHz, respectively, using (CH3)4Si as the internal standard; coupling
constants (J) are given in Hz. Mass spectra (EI/DP) were obtained at 70 eV.
Methyl 2-Fluoro-5-nitrophenylacetate (2)
A solution of 5.00 g (25.1 mmol) of 2-fluoro-5-nitrophenylacetic acid (1)8 in 100 mL
of CH3OH containing 2 mL of concentrated H2SO4 was refluxed for 24 h, then cooled,
concentrated, poured into ice water and extracted with ether (3x). The combined ether
extracts were washed with 5% NaHCO3 (2x) and saturated NaCl (1x), then dried (MgSO4)
and concentrated under vacuum to give the ester as a light yellow oil that slowly crystallized.
The crude solid was triturated with 1% ether in pentane and filtered to give 4.74 g (89%) of
2 as a light yellow solid, mp 52–55◦C. IR: 1743, 1529, 1350, 1250 cm−1; 1H NMR: δ 8.22
(m, 2 H), 7.23 (t, J = 8.8 Hz, 1 H), 3.77 (d, J = 1.1 Hz, 2 H), 3.75 (s, 3 H); 13C NMR: δ
169.7, 164.6 (d, J = 257.9 Hz), 144.1, 127.5 (d, J = 6.1 Hz), 125.1 (d, J = 10.7 Hz), 123.1
(d, J = 18.3 Hz), 116.4 (d, J = 24.4 Hz), 52.5 (d, J = 3.8 Hz), 34.0 (d, J = 2.3 Hz); MS:
m/z 213 (M+).
Anal. Calcd for C9H8FNO4: C, 50.70; H, 3.76; N, 6.57. Found: C, 50.73; H, 3.77; N,
6.53.
Methyl N-(2-Fluoro-5-nitrophenyl)carbamate (6)
To a stirred solution of 5.00 g (32.0 mmol) of 2-fluoro-5-nitroaniline (5) in 50 mL of
pyridine at 0◦C was slowly added 3.35 g (2.74 mL, 35.4 mmol) of methyl chloroformate
over 30 min. The reaction was stirred for 2 h with gradual warming to 22◦C. The crude
reaction mixture was added to water and ether extracted (3x). The combined ether extracts
were washed with 0.5 M HCl (4x), water (1x) and NaCl (1x), then dried (MgSO4) and
concentrated under vacuum to give a brown powder. Trituration of this solid with ether
gave 5.75 g (91%) of 6 as tan crystals, mp 116–118◦C (lit14 mp 116–118◦C). IR: 3401,
1740, 1533, 1348, 1245 cm−1; 1H NMR: δ 9.08 (br d, J = 4.8 Hz, 1 H), 7.94 (ddd, J = 9.1,
4.2, 2.7 Hz, 1 H), 7.23 (t, J = 9.1 Hz, 1 H), 7.02 (br s, 1 H), 3.86 (s, 3 H); 13C NMR: δ
154.9 (d, J = 254.1 Hz), 153.1, 144.7, 127.5 (d, J = 11.4 Hz), 118.9 (d, J = 9.2 Hz), 115.6
(d, J = 3.4 Hz), 115.4 (d, J = 22.1 Hz); MS: m/z 214 (M+).
Anal. Calcd for C8H7FN2O4: C, 44.86; H, 3.27; N, 13.08. Found: C, 44.77; H, 3.31;
H, 13.16.
Alkylation Procedure for the Ester: Methyl 2-(2-Fluoro-5-nitrophenyl)-4-pentenoate
(3a)
The general procedure of Makosza and Tyrala was followed.15 In a 100 mL three-necked
round-bottomed flask, a solution of 1.07 g (5.00 mmol) of 2 in 10 mL of dry CH3CN

6-Nitro-1,2,3,4-tetrahydroquinoline-4-carboxylic Esters
75
was added to a suspension of 5.80 g (42.0 mmol) of anhydrous K2CO3 and 10 mg of
18-crown-6in40mLofdryCH3CN. Totheresultingredmixturewasadded1.01g(0.55mL,
6.00 mmol) of 3-iodo-1-propene. The reaction was stirred under reflux for 6 h, then cooled
to 22◦C and filtered to remove the solids. The solids were washed with ether and the filtrate
was concentrated under vacuum. The remaining oil was purified by flash chromatography
on a 30 cm × 2 cm silica gel column eluted with 5–10% ether in hexanes to give 1.15 g
1
(91%) of 3a as a light yellow oil. IR: 1738, 1646, 1529, 1350, 1245 cm−1; H NMR: δ
8.30 (dd, J = 6.2, 2.7 Hz, 1 H), 8.18 (ddd, J = 9.0, 4.4, 2.7 Hz, 1 H), 7.21 (t, J = 9.0 Hz,
1 H), 5.70 (ddt, J = 17.0, 10.2, 7.0 Hz, 1 H), 5.05 (m, 2 H), 4.07 (t, J = 7.1 Hz, 1 H), 3.72
(s, 3 H), 2.90 (m, 1 H), 2.59 (m, 1 H); 13C NMR: δ 171.9, 164.0 (d, J = 257.9 Hz), 144.4,
133.7, 127.4 (d, J = 9.0 Hz), 125.6 (d, J = 6.1 Hz), 124.8 (d, J = 9.9 Hz), 118.2, 116.5 (d,
J = 25.1 Hz), 52.5, 43.5, 36.3; MS: m/z 253 (M+).
Anal. Calcd for C12H12FNO4: C, 56.92; H, 4.74; N, 5.53. Found: C, 56.99; H, 4.77; N,
5.49.
Methyl 2-(2-Fluoro-5-nitrophenyl)-4-methyl-4-pentenoate (3b)
This compound (1.20 g, 90%) was prepared as above from 1.07 g (5.00 mmol) of 2 and 1.09
g (6.00 mmol) of 3-iodo-2-methyl-1-propene. IR: 1738, 1651, 1533, 1350, 1248 cm−1; 1H
NMR: δ 8.32 (dd, J = 6.2, 2.7 Hz, 1 H), 8.18 (m, 1 H), 7.21 (t, J = 9.0 Hz, 1 H), 4.74 (s,
1 H), 4.64 (s, 1 H), 4.23 (t, J = 7.7 Hz, 1 H), 3.71 (s, 3 H), 2.88 (dd, J = 14.4, 7.3 Hz, 1
H), 2.54 (dd, J = 14.4, 8.4 Hz, 1 H), 1.74 (s, 3 H); 13C NMR: δ 172.2, 164.0 (d, J = 257.1
Hz), 144.3, 141.1, 127.5 (d, J = 16.8 Hz), 125.5 (d, J = 6.1 Hz), 124.6 (d, J = 9.9 Hz),
116.4 (d, J = 25.9 Hz), 113.5, 52.5, 42.0, 40.3, 22.0; MS: m/z 267 (M+).
Anal. Calcd for C13H14FNO4: C, 58.42; H, 5.24; N, 5.24. Found: C, 58.49; H, 5.26; N,
5.18.
Alkylation Procedure for the Amide: Methyl N-(2-Fluoro-5-nitrophenyl)-N-(2-
propenyl)carbamate (7a)
In a 50 mL three-necked round-bottomed flask, 0.24 g of 60% NaH in mineral oil (6.00
mmol) was washed with hexanes (3x) and suspended in 15 mL of dry DMF. To the stirred
suspension at 22◦C was slowly added a solution of 1.07 g (5.00 mmol) of 6 in 5 mL of dry
DMF. Stirring was continued for 30 min and a solution of 1.01 g (0.55 mL, 6.00 mmol)
of 3-iodo-1-propene in 1 mL of dry DMF was added. The reaction was stirred for 8 h at
22◦C, quenched with saturated NH4Cl and extracted with ether (3x). The combined ether
extracts were washed with 5% Na2S2O3 (1x) and saturated NaCl (1x), then dried (MgSO4)
and concentrated under vacuum. The crude 7a (1.19 g, 93%) was spectroscopically pure
1
and was used directly in the next reaction. IR: 1718, 1643, 1528, 1348, 1255 cm−1; H
NMR: δ 8.20 (m, 2 H), 7.28 (t, J = 8.9 Hz, 1 H), 5.86 (ddt, J = 17.4, 10.8, 6.0 Hz,
1 H), 5.17 (s, 1 H), 5.13 (dd, J = 7.3, 1.3 Hz, 1 H), 4.28 (d, J = 6.1 Hz, 2 H), 3.74
(br s, 3 H); 13C NMR: δ 161.2 (d, J = 261.1 Hz), 155.0, 144.1, 132.4, 130.2, 125.7 (d,
J = 2.9 Hz), 124.4 (d, J = 9.7 Hz), 118.7, 117.1 (d, J = 23.2 Hz), 53.5, 52.7; MS:
m/z 254 (M+).

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Bunce and Schammerhorn
Anal. Calcd for C11H11FN2O4: C, 51.97; H, 4.36; N, 11.02. Found: C, 51.89; H, 4.39;
N, 11.18.
Methyl N-(2-Fluoro-5-nitrophenyl)-N-(2-methyl-2-propenyl)carbamate (7b)
This compound (1.18 g, 88%) was prepared as above from 1.07 g (5.00 mmol) of 6 and 1.09
g (6.00 mmol) of 3-iodo-2-methyl-1-propene. IR: 1723, 1659, 1533, 1348, 1256 cm−1; 1H
NMR: δ 8.18 (m, 2 H), 7.27 (t, J = 9.0 Hz, 1 H), 4.85 (s, 1 H), 4.78 (s, 1 H), 4.26 (s, 2 H),
3.74 (br s, 3 H), 1.77 (s, 3 H); 13C NMR: δ 162.0 (d, J = 261.0 Hz), 155.2, 144.1, 140.1,
130.1, 125.1 (d, J = 2.9 Hz), 124.2 (d, J = 10.0 Hz), 117.1 (d, J = 23.5 Hz), 114.0, 55.7,
53.5, 19.9; MS: m/z 268 (M+).
Anal. Calcd for C12H13FN2O4: C, 53.69; H, 4.89; N, 10.44. Found: C, 53.58; H, 4.86;
N, 10.52.
1-Chloro-2-(2-methyl-2-propenyloxy)-4-nitrobenzene (10)
In a 100 mL three-necked round-bottomed flask, a solution of 0.87 g (5.00 mmol) of 2-
chloro-5-nitrophenol (9)9 in 10 mL of dry acetone was added to a suspension of 5.80 g
(42.0 mmol) of anhydrous K2CO3 in 25 mL of dry acetone. To the resulting mixture was
added 1.09 g (6.00 mmol) of 3-iodo-2-methyl-1-propene. The reaction was stirred under
reflux for 6 h, then cooled to 22◦C and filtered to remove the solids. The solids were washed
with ether and the filtrate was concentrated under vacuum. The remaining oil was purified
by flash chromatography on a 30 cm × 2 cm silica gel column eluted with 5–10% ether
in hexanes to give 0.98 g (92%) of 10 as a light yellow oil that solidified on standing, mp
59–60◦C. IR: 1652, 1528, 1353 cm−1; 1H NMR: δ 7.80 (dd, J = 8.5, 2.4 Hz, 1 H), 7.77 (d,
J = 2.4 Hz, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 5.19 (dd, J = 1.3, 0.9 Hz, 1 H), 5.07 (dd, J
= 2.6, 1.6 Hz, 1 H), 4.61 (s, 2 H), 1.87 (s, 3 H); 13C NMR: δ 154.4, 147.1, 139.0, 130.4,
116.3, 113.94, 113.93, 108.1, 73.0, 19.2; MS: m/z 227, 229 (ca 3:1, M+)
Anal. Calcd for C10H10ClNO3: C, 52.75; H, 4.40; N, 6.15. Found: C, 52.81; H, 4.44;
N 6.11.
Representative Ozonolysis Procedure: Methyl 2-(2-Fluoro-5-nitrophenyl)-4-
oxobutanoate (4a)
The general procedure of Bunce and co-workers was adapted.10 In a 250 mL round-
bottomed flask, a solution of 1.00 g (3.95 mmol) of 3a in 100 mL of MeOH was ozonized
at –78◦C until TLC indicated complete consumption of the starting material. Excess ozone
was purged with a stream of dry N2 and 5.00 g (5.91 mL, 80.6 mmol) of dimethyl sulfide
was added. The mixture was warmed to 0◦C and 5 mL of acetic acid was added. The
solution was stirred at 0◦C for 1 h, then warmed to 22◦C and stirred for 8 h. The reaction
was concentrated, diluted with ether, washed with 5% NaHCO3 (3x) and saturated NaCl
(1x) and then dried (MgSO4). Removal of the ether gave 0.94 g (93%) of 4a as a light yellow
oil that solidified on standing, mp 63–64◦C. The crude product was spectroscopically pure
and was used directly in the next reaction. IR: 2842, 2731, 1738, 1724, 1530, 1350, 1249
cm−1; 1H NMR: δ 9.08 (s, 1 H), 8.21 (m, 2 H), 7.25 (t, J = 9.0 Hz, 1 H), 4.54 (dd, J = 8.4,
5.7 Hz, 1 H), 3.73 (s, 3 H), 3.48 (dd, J = 18.8, 8.4 Hz, 1 H), 2.91 (dd, J = 18.8, 5.7 Hz,

6-Nitro-1,2,3,4-tetrahydroquinoline-4-carboxylic Esters
77
1 H); 13C NMR: δ 198.0, 171.3, 163.8 (d, J = 257.9 Hz), 144.4, 127.0 (d, J = 16.8 Hz),
125.6 (d, J = 6.1 Hz). 125.3 (d, J = 9.9 Hz), 116.9 (d, J = 24.4 Hz), 52.9, 45.3, 38.2; MS:
m/z 255 (M+).
Anal. Calcd for C11H10FNO5: C, 51.76; H, 3.92; N, 5.49. Found: C, 51.81; H, 3.93; N,
5.45.
Methyl 2-(2-Fluoro-5-nitrophenyl)-4-oxopentanoate (4b)
This compound (0.96 g, 95%) was prepared as above from 1.00 g (3.75 mmol) of 3b. IR:
1738, 1717, 1533, 1350, 1250 cm−1; 1H NMR: δ 8.19 (m, 2 H), 7.23 (t, J = 9.0 Hz, 1 H),
4.51 (dd, J = 8.8, 5.3 Hz, 1 H), 3.71 (s, 3 H), 3.45 (dd, J = 18.8, 8.8 Hz, 1 H), 2.80 (dd,
J = 18.8, 5.3 Hz, 1 H), 2.22 (s, 3 H); 13C NMR: δ 204.7, 171.7, 163.9 (d, J = 258.6 Hz),
144.6, 127.4 (d, J = 17.5 Hz), 125.6 (d, J = 5.3 Hz), 125.1 (d, J = 9.9 Hz), 116.7 (d, J =
24.4 Hz), 52.8, 45.1, 39.5, 29.8; MS: m/z 269 (M+).
Anal. Calcd for C12H12FNO5: C, 53.53; H, 4.46; N, 5.20. Found: C, 53.61; H, 4.44; N,
5.11.
Methyl N-(2-Fluoro-5-nitrophenyl)-N-(2-oxoethyl)carbamate (8a)
This compound (0.85 g, 84%) was prepared as above from 1.00 g (3.95 mmol) of 7a. IR:
1713, 1533, 1352, 1256 cm−1; 1H NMR: δ 9.70 (s, 1 H), 8.31 (br s, 1 H), 8.21 (m, 1 H),
7.33 (t, J = 9.1 Hz, 1 H), 4.45 (s, 2 H), 3.76 (br s, 3 H); 13C NMR: δ 196.2, 161.4 (d, J =
260.8 Hz), 155.0, 144.0, 130.1, 125.7, 124.6 (d, J = 8.9 Hz), 117.1 (d, J = 23.2 Hz), 59.1,
53.9; MS: m/z 256 (M+).
Anal. Calcd for C10H9FN2O5: C, 46.88; H, 3.54; N, 10.93. Found: C, 47.02; H, 3.59;
N, 10.82.
Methyl N-(2-Fluoro-5-nitrophenyl)-N-(2-oxopropyl)carbamate (8b)
This compound (0.90 g, 89%) was prepared as above from 1.00 g (3.73 mmol) of 7b, mp
98–100◦C. IR: 1718, 1533, 1348, 1256 cm−1; 1H NMR: δ 8.37 (br s, 1 H), 8.18 (ddd, J =
9.2, 4.1, 3.2 Hz, 1 H), 7.28 (t, J = 9.2 Hz, 1 H), 4.43 (s, 2 H), 3.73 (br s, 3 H), 2.20 (s, 3 H);
13C NMR: δ 202.0, 161.5 (d, J = 260.8 Hz), 155.0, 144.1, 130.3, 126.1, 124.5 (d, J =
9.1 Hz), 117.1 (d, J = 23.2 Hz), 58.9, 53.8, 26.8; MS: m/z 270 (M+).
Anal. Calcd for C11H11FN2O5: C, 48.89; H, 4.10; N, 10.37. Found: C, 48.92; H, 4.10;
N, 10.36.
1-(2-Chloro-5-nitrophenoxy)-2-propanone (11)
This compound (0.95 g, 94%) was prepared as above from 1.00 g (4.38 mmol) of 10, mp
85–87◦C. IR: 1728, 1525, 1348 cm−1; 1H NMR: δ 7.86 (dd, J = 8.8, 2.4 Hz, 1 H), 7.64 (d,
J = 2.4 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 4.74 (s, 2 H), 2.39 (s, 3 H); 13C NMR: δ 202.7,
153.6, 147.1, 130.8, 130.5, 117.3, 107.9, 73.4, 26.7; MS: m/z 229, 231 (ca 3:1, M+)
Anal. Calcd for C9H8ClNO4: C, 47.06; H, 3.49; N, 6.10. Found: C, 47.11; H, 3.52; N,
6.07.

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Bunce and Schammerhorn
Representative Procedure for Reductive Amination-SNAr Cyclizations: ( )-Methyl
1-Benzyl-6-nitro-1,2,3,4-tetrahydroquinoline-4-carboxylate (12)
The procedure of Bunce and Nago was used.1 In a 50 mL one-necked round-bottomed flask,
a solution of 100 mg (0.39 mmol) of 4a and 51 mg (0.52 mL, 0.47 mmol) of benzylamine
in 4 mL of CH3OH was stirred for 30 min and 21 mg (0.33 mmol) of NaBH3CN was
added. This was followed by two additional 7 mg (0.11 mmol)-portions of NaBH3CN at
12 h intervals. Stirring was continued for 48 h and the crude reaction mixture was added
to saturated NaCl and extracted with ether (3x). The combined ether extracts were dried
(MgSO4), concentrated under vacuum and purified by PTLC using 20% ether in hexanes.
Band 1 gave 114 mg (90%) of 12 as a yellow oil. IR: 1734, 1522, 1348 cm−1; 1H NMR: δ
8.06 (d, J = 2.7 Hz, 1 H), 7.93 (dd, J = 9.3, 2.7 Hz, 1 H), 7.36 (t, J = 7.3 Hz, 2 H), 7.28 (t,
J = 7.3 Hz, 1 H), 7.18 (d, J = 7.3 Hz, 2 H), 6.51 (d, J = 9.3 Hz, 1 H), 4.63 (s, 2 H), 3.89
(apparent t, J = 4.2 Hz, 1 H), 3.75 (s, 3 H), 3.74 (m, 1 H), 3.44 (dddd, J = 12.6, 4.8, 3.7,
1.3 Hz, 1 H), 2.39 (dq, J = 13.5, 3.7 Hz, 1 H), 2.09 (ddt, J = 13.5, 11.7, 4.8 Hz, 1 H); 13C
NMR: δ 173.2, 149.8, 136.7, 136.0, 129.0, 127.5, 126.7, 126.1, 125.5, 117.1, 110.2, 55.0,
52.5, 46.7, 42.1, 23.4; MS: m/z 235 (M+−C7H7).
Anal. Calcd for C18H18N2O4: C, 66.26; H, 5.52; N, 8.59. Found: C, 66.33; H, 5.56; N,
8.51.
( )-Methyl 1-Hexyl-6-nitro-1,2,3,4-tetrahydroquinoline-4-carboxylate (13)
This compound (92 mg, 74%) was prepared as above from 100 mg (0.39 mmol) of 4a and
47 mg (0.062 mL, 0.47 mmol) of hexylamine, mp 60–62◦C. IR: 1735, 1522, 1346 cm−1
;
1H NMR: δ 8.02 (m, 2 H), 6.55 (d, J = 9.9, Hz, 1 H), 3.80 (apparent t, J = 4.1 Hz, 1 H),
3.73 (s, 3 H), 3.61 (td, J = 12.6, 3.7 Hz, 1 H), 3.35 (m, 3 H), 2.33 (dq, J = 13.6, 3.6 Hz,
1 H), 1.96 (ddt, J = 13.6, 11.6, 4.9 Hz, 1 H), 1.63 (m, 2 H), 1.33 (m, 6 H), 0.90 (t, J =
6.6 Hz, 3 H); 13C NMR: δ 173.3, 149.5, 135.9, 126.9, 125.5, 116.7, 109.5, 52.4, 51.7, 46.2,
41.9, 31.5, 26.6, 26.2, 23.2, 22.5, 13.9; MS: m/z 249 (M+−C5H11).
Anal. Calcd for C17H24N2O4: C, 63.75; H, 7.50; N, 8.75. Found: C, 63.74; H, 7.51; N,
8.73.
( )-Methyl 1-Isobutyl-6-nitro-1,2,3,4-tetrahydroquinoline-4-carboxylate (14)
This compound (101 mg, 89%) was prepared as above from 100 mg (0.39 mmol) of 4a and
34 mg (0.047 mL, 0.47 mmol) of isobutylamine. IR: 1735, 1522, 1347 cm−1; 1H NMR: δ
8.02 (d, J = 2.7 Hz, 1 H), 7.99 (dd, J = 9.2, 2.7 Hz, 1 H), 6.55 (d, J = 9.2 Hz, 1 H), 3.81
(apparent t, J = 4.2 Hz, 1 H), 3.73 (s, 3 H), 3.65 (td, J = 11.7, 3.7 Hz, 1 H), 3.36 (dm, J
= 12.6 Hz, 1 H), 3.19 (ddd, J = 23.6, 14.6, 7.3 Hz, 2 H), 2.32 (dq, J = 13.6, 3.7 Hz, 1
H), 2.13 (nonet, J = 6.7 Hz, 1 H), 1.98 (ddt, J = 13.6, 11.7, 4.9 Hz, 1 H), 0.96 (d, J = 6.7
Hz, 3 H), 0.95 (d, J = 6.7 Hz, 3 H); 13C NMR: δ 173.3, 149.8, 135.9, 126.9, 125.3, 116.7,
109.9, 59.4, 52.4, 47.4, 42.0, 26.7, 23.2, 20.2, 20.1; MS: m/z 249 (M+−C3H7).
Anal. Calcd for C15H20N2O4: C, 61.64; H, 6.85; N, 9.59. Found: C, 61.75; H, 6.88; N,
9.53.

6-Nitro-1,2,3,4-tetrahydroquinoline-4-carboxylic Esters
79
( )-Methyl 1-Cyclohexyl-6-nitro-1,2,3,4-tetrahydroquinoline-4-carboxylate (15)
This compound (87 mg, 70%) was prepared as above from 100 mg (0.39 mmol) of 4a
and 47 mg (0.054 mL, 0.47 mmol) of cyclohexylamine, mp 73–75◦C. IR: 1735, 1511,
1326 cm−1; 1H NMR: δ 8.01 (m, 2 H), 6.64 (d, J = 10.0 Hz, 1 H), 3.78 (apparent t, J =
4.5 Hz, 1 H), 3.72 (s, 3 H), 3.71 (dm, J = 12.7 Hz, 1 H), 3.40 (m, 1 H), 3.36 (td, J = 12.8,
3.8 Hz, 1 H), 2.34 (dq, J = 13.4, 3.8 Hz, 1 H), 1.95–1.69 (complex, 6 H), 1.62–1.30
(complex, 3 H), 1.26–1.09 (complex, 2 H); 13C NMR: δ 173.2, 149.7, 135.6, 126.9, 125.5,
117.5, 109.6, 57.4, 52.3, 42.3, 38.8, 29.7, 29.4, 25.9, 25.7, 25.5, 23.5; MS: m/z 318 (M+).
Anal. Calcd for C17H22N2O4: C, 64.13; H, 6.97; N, 8.80. Found: C, 64.17; H, 6.99; N,
8.76.
Methyl 4-Benzyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (16)
This compound (66 mg, 52%) was prepared as above from 100 mg (0.39 mmol) of 8a and
51 mg (0.052 mL, 0.47 mmol) of benzylamine, mp 102–103◦C. IR: 1709, 1522, 1330 cm−1
;
1H NMR δ 8.41 (br s, 1 H), 7.86 (dd, J = 9.3, 2.6 Hz, 1 H), 7.38–7.25 (complex, 3 H),
7.18 (d, J = 6.6 Hz, 2 H), 6.60 (d, J = 9.3 Hz, 1 H), 4.65 (s, 2 H), 3.92 (t, J = 5.3 Hz,
2 H), 3.85 (s, 3 H), 3.58 (t, J = 5.3 Hz, 2 H); 13C NMR: δ 154.3, 143.4, 136.9, 135.7, 129.1,
127.7, 126.2, 123.1, 122.2, 120.7, 110.1, 54.7, 53.5, 49.2, 40.7; MS: m/z 236 (M+-C7H7).
Anal. Calcd for C17H17N3O4: C, 62.39; H, 5.20; N, 12.84. Found: C, 62.42; H, 5.23;
N, 12.81.
Methyl 4-Hexyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (17)
This compound (78 mg, 62%) was prepared as above from 100 mg (0.39 mmol) of 8a and
47 mg (0.062 mL, 0.47 mmol) of hexylamine. IR: 1710, 1522, 1331 cm−1; 1H NMR δ 8.35
(br s, 1 H), 7.93 (dd, J = 9.3, 2.7 Hz, 1 H), 6.60 (d, J = 9.3 Hz, 1 H), 3.83 (s, 3 H), 3.83
(t, J = 5.3 Hz, 2 H), 3.49 (t, J = 5.3 Hz, 2 H), 3.38 (apparent t, J = 7.7 Hz, 2 H), 1.63
(quintet, J = 7.2 Hz, 2 H), 1.40–1.28 (complex, 6 H), 0.90 (distorted t, J = 6.8 Hz, 3 H);
13C NMR: δ 155.1, 143.1, 136.2, 125.5, 122.3, 120.8, 109.3, 53.5, 51.6, 48.8, 40.5, 31.5,
26.6, 26.3, 22.6, 14.0; MS: m/z 250 (M+−C5H11).
Anal. Calcd for C16H23N3O4: C, 59.81; H, 7.17; N, 13.08. Found: C, 59.90; H, 7.14;
N, 12.99.
Methyl 4-Isobutyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (18)
This compound (63 mg, 55%) was prepared as above from 100 mg (0.39 mmol) of 8a and
34 mg (0.047 mL, 0.47 mmol) of isobutylamine. IR: 1709, 1524, 1328 cm−1; 1H NMR δ
8.37 (br s, 1 H), 7.92 (dd, J = 9.3, 2.4 Hz, 1 H), 6.61 (d, J = 9.3 Hz, 1 H), 3.84 (s, 3 H),
3.84 (t, J = 5.3 Hz, 2 H), 5.51 (t, J = 5.3 Hz, 2 H), 3.21 (d, 2 H, J = 7.7 Hz, 2 H), 2.14
(nonet, J = 6.8 Hz, 1 H), 0.97 (d, J = 6.6 Hz, 6 H); 13C NMR δ 154.4, 143.4, 136.3, 122.6,
122.1, 120.9, 109.8, 59.5, 53.5, 50.1, 40.4, 26.8, 20.3; MS: m/z 250 (M+-C3H7).
Anal. Calcd for C14H19N3O4: C, 57.34; H, 6.48; N, 14.33. Found: C, 57.27; H, 6.44;
N, 14.38.

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Bunce and Schammerhorn
Methyl 4-Cyclohexyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (19)
This compound (45 mg, 36%) was prepared as above from 100 mg (0.39 mmol) of 8a and
47 mg (0.054 mL, 0.47 mmol) of cyclohexylamine. IR: 1710, 1518, 1329 cm−1; 1H NMR:
δ 8.33 (br s, 1 H), 7.93 (dd, J = 9.3, 2.8 Hz, 1 H), 6.68 (d, J = 9.3 Hz, 1 H), 3.83 (s, 3
H), 3.78 (t, J = 5.2 Hz, 2 H), 3.72 (tt, J = 11.4, 3.3 Hz, 1 H), 3.43 (t, J = 5.2 Hz, 2 H),
1.98–1.70 (complex, 5 H), 1.58–1.32 (complex, 3 H), 1.20 (m, 2 H); 13C NMR: δ 154.2,
143.4, 135.9, 123.3, 122.4, 120.9, 109.5, 57.1, 53.4, 42.2, 40.7, 29.4, 25.7, 25.5; MS: m/z
319 (M+).
Anal. Calcd for C16H21N3O4: C, 60.18; H, 6.58; N, 13.17. Found: C, 60.31; H, 6.62;
N, 13.05.
( )-Methyl 4-Benzyl-3-methyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (20)
This compound (110 mg, 83%) was prepared as above from 105 mg (0.39 mmol) of 8b and
51 mg (0.52 mL, 0.47 mmol) of benzylamine, mp 101–103◦C. IR: 1710, 1520, 1348 cm−1
;
1H NMR: δ 8.47 (br s, 1 H), 7.81 (dd, J = 9.3, 2.7 Hz, 1 H), 7.39–7.24 (complex, 3 H),
7.15 (d, J = 7.0 Hz, 2 H), 6.48 (d, J = 9.3 Hz, 1 H), 4.70 (d, J = 17.4 Hz, 1 H), 4.61 (d,
J = 17.4 Hz, 1 H), 4.38 (br d, J = 13.2 Hz, 1 H), 3.88 (s, 3 H), 3.80 (m, 1 H), 3.37 (dd, J
= 13.2, 2.9 Hz, 1 H), 1.26 (d, J = 6.4 Hz, 3 H); 13C NMR: δ 154.8, 142.9, 136.8, 136.1,
129.0, 127.6, 125.9, 122.9, 122.1, 120.1, 110.5, 54.3, 53.6, 52.9, 45.8, 17.6; MS: m/z 250
(M+-C7H7).
Anal. Calcd for C18H19N3O4: C, 63.34; H, 5.57; N, 12.32. Found: C, 63.29; H, 5.58;
N, 12.35.
( )-Methyl 4-Hexyl-3-methyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (21)
This compound (90 mg, 69%) was prepared as above from 105 mg (0.39 mmol) of 8b
and 47 mg (0.062 mL, 0.47 mmol) of hexylamine. IR: 1710, 1522, 1353 cm−1; 1H NMR:
δ 8.41 (br s, 1 H), 7.92 (dd, J = 9.3, 2.8 Hz, 1 H), 6.55 (d, J = 9.3 Hz, 1 H), 4.34 (dd,
J = 13.1, 1.8 Hz, 1 H), 3.85 (s, 3 H), 3.69 (m, 1 H), 3.43 (m, 1H), 3.27 (m, 1 H), 3.16
(dd, J = 13.1, 3.0 Hz, 1 H), 1.63 (m, 2 H), 1.40–1.28 (complex, 6 H), 1.20 (d, J = 6.4
Hz, 3 H), 0.91 (distorted t, J = 7.0 Hz, 3 H); 13C NMR: δ 154.7, 142.4, 135.9, 122.4,
122.0, 120.2, 109.3, 53.7, 53.4, 49.7, 45.5, 31.5, 26.7, 26.6, 22.5, 17.6, 13.9; MS: m/z 264
(M+−C5H11).
Anal. Calcd for C17H25N3O4: C, 60.90; H, 7.46; N, 12.54. Found: C, 61.01; H, 7.49;
N, 12.49.
( )-Methyl 4-Isobutyl-3-methyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (22)
This compound (90 mg, 75%) was prepared as above from 105 mg (0.39 mmol) of 8b and
34 mg (0.047 mL, 0.47 mmol) of isobutylamine, mp 109–110◦C. IR: 1709, 1521, 1354
cm−1; 1H NMR: δ 8.46 (br s, 1 H), 7.90 (dd, J = 9.3, 2.7 Hz, 1 H), 6.56 (d, J = 9.3 Hz,
1 H), 4.39 (dd, J = 13.0, 1.9 Hz, 1 H), 3.86 (s, 3 H), 3.70 (m, 1 H), 3.46 (dd, J = 14.5,
5.3 Hz, 1 H), 3.23 (dd, J = 13.1, 2.8 Hz, 1 H), 2.91 (dd, J = 14.8, 9.5 Hz, 1 H), 2.15 (m,
1 H), 1.17 (d, J = 6.4 Hz, 3 H), 0.964 (d, J = 6.8 Hz, 3 H), 0.960 (d, J = 6.6 Hz, 3 H); 13C

6-Nitro-1,2,3,4-tetrahydroquinoline-4-carboxylic Esters
81
NMR: δ 154.8, 142.4, 136.0, 122.2, 121.8, 120.2, 109.9, 56.9, 53.9, 53.4, 45.2, 26.6, 20.1,
16.6; MS: m/z 264 (M+−C3H7).
Anal. Calcd for C15H21N3O4: C, 58.63; H, 6.84; N, 13.68. Found: C, 58.59; H, 6.82;
N, 13.73.
( )-Methyl 4-Cyclohexyl-3-methyl-7-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate
(23)
This compound (74 mg, 57%) was prepared as above from 105 mg (0.39 mmol) of 8b and
47 mg (0.054 mL, 0.47 mmol) of cyclohexylamine. IR: 1709, 1511, 1346 cm−1; 1H NMR:
δ 8.50 (br s, 1 H), 7.91 (dd, J = 9.5, 2.8 Hz, 1 H), 6.71 (d, J = 9.5 Hz, 1 H), 4.43 (d, J =
12.7 Hz, 1 H), 3.93 (m, 1 H), 3.86 (s, 3 H), 3.72 (tt, J = 11.4, 3.3 Hz, 1 H), 2.89 (dd, J =
13.0, 2.4 Hz, 1 H), 2.10–1.62 (complex, 5 H), 1.60–1.32 (complex, 3 H), 1.21 (m, 2 H),
1.14 (d, J = 6.4 Hz, 3 H); 13C NMR: δ 154.7, 141.8, 135.9, 122.6, 121.6, 120.4, 110.3,
58.0, 53.4, 47.3, 45.9, 31.1, 29.6, 26.0, 25.9, 25.5, 19.5; MS: m/z 318 (M+−CH3).
Anal. Calcd for C17H23N3O4: C, 61.26; H, 6.91; N, 12.61. Found: C, 61.39; H, 6.94;
N, 12.51.
( )-N-Benzyl-1-(2-chloro-5-nitrophenoxy)-2-propanamine (24)
This compound (58 mg, 46%) was prepared as above from 90 mg (0.39 mmol) of 11 and
1
51 mg (0.52 mL, 0.47 mmol) of benzylamine. IR: 3321, 1525, 1345 cm−1; H NMR: δ
7.78 (dd, J = 8.6, 2.6 Hz, 1 H), 7.74 (d, J = 2.4 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 1 H), 7.39-
7.20 (complex, 5 H), 4.12 (m, 2 H), 3.97 (d, J = 13.6 Hz, 1 H), 3.86 (d, J = 13.6 Hz, 1 H),
3.25 (m, 1 H), 2.04 (br s, 1 H), 1.25 (d, J = 6.4 Hz, 3 H); 13C NMR: δ 154.6, 147.2, 140.2,
130.3, 128.4, 128.1, 127.9, 127.0, 116.3, 107.7, 73.7, 51.2, 51.1, 17.2,; MS: m/z 320, 322
(ca 3:1, M+).
Anal. Calcd for C16H17ClN2O3: C, 59.91; H, 5.30; N, 8.74. Found: C, 60.02; H, 5.34;
N 8.66.
Acknowledgment
J. E. S. thanks the Department of Chemistry at Oklahoma State University for a teaching
assistantship. Funding for the 300 MHz NMR spectrometer of the Oklahoma Statewide
Shared NMR Facility was provided by 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.
References
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Herron and L. Y. Hale, J. Heterocycl. Chem., 40, 1031 (2003).

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