(±)-1,2-dialkyl-5-nitro-2,3-dihydro-1H-indoles by a tandem reductive amination-SNAr reaction

Article abstract of DOI:10.1002/jhet.82

(Chemical Equation Presented) A tandem reductive amination-S_NAr reaction has been applied to the synthesis of (±)-1,2-dialkyl-5-nitro-2, 3-dihydro-1H-indoles. Treatment of a series of 2-fluoro-5-nitrobenzyl ketones with primary amines and sodium cyanoborohydride in methanol at room temperature provided good yields of the target heterocycles. The reaction is sensitive to steric hindrance and proceeds best with less hindered ketone substrates using primary amines that are unbranched at the α carbon.

Full text of DOI:10.1002/jhet.82

July 2009
(ꢀ)-1,2-Dialkyl-5-nitro-2,3-dihydro-1H-indoles by a Tandem
629
Reductive Amination-SNAr Reaction
Richard A. Bunce,* Takahiro Nago [1], and Brian White [1]
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071
*E-mail: rab@okstate.edu
Received September 24, 2008
DOI 10.1002/jhet.82
Published online 2 July 2009 in Wiley InterScience (www.interscience.wiley.com).
A tandem reductive amination-SNAr reaction has been applied to the synthesis of (ꢀ)-1,2-dialkyl-5-
nitro-2,3-dihydro-1H-indoles. Treatment of a series of 2-fluoro-5-nitrobenzyl ketones with primary
amines and sodium cyanoborohydride in methanol at room temperature provided good yields of the
target heterocycles. The reaction is sensitive to steric hindrance and proceeds best with less hindered
ketone substrates using primary amines that are unbranched at the a carbon.
J. Heterocyclic Chem., 46, 629 (2009).
INTRODUCTION
nitrophenyl)acetic acid (1) [2(b)] with a series of car-
boxylic acid anhydrides in pyridine followed by reflux-
ing with acidic ethanol gave the 1-(2-fluoro-5-nitro-
phenyl)-2-propanone derivatives 3, 4, and 5 [12,13].
Yields of the ketone products correlated with the steric
hindrance of the anhydride with acetic anhydride giv-
ing the highest yield (82%) and isobutyric anhydride
the lowest (24%). Finally, the desoxybenzoin deriva-
tive 6 was prepared in 58% yield by a Friedel-Crafts
reaction of (2-fluoro-5-nitrophenyl)acetyl chloride
with benzene [14].
Over the past several years, our work has led to a
number of reductive cyclizations that yield 1,2,3,4-tetra-
hydroquinolines [2]. Recently, we reported a tandem
reductive amination-SNAr reaction for the preparation of
substituted 6-nitro-1,2,3,4-tetrahydroquinolines [3]. In
the current work, we have extended this sequence to the
preparation of (ꢀ)-dialkyl-5-nitro-2,3-dihydro-1H-indoles.
Earlier syntheses of dihydroindoles have involved photoly-
sis of N-aryl enamines [4]; reduction of indoles with bor-
ane-trimethylamine [5]; base-catalyzed spirocyclization of
aromatic imide imines [6]; base-catalyzed tandem hydro-
amination-aryne addition of chlorostyrenes [7]; and tandem
SN2-SNAr reaction of 2-(3-bromopropyl)-1-fluoro-4-nitro-
benzene [2(b)]. Each of these mechanistically diverse
routes provides access to a select group of dihydroindoles
but none constitutes a general synthesis.
Scheme 1
Dihydroindoles bearing
a 1,1,1,3,3,3-hexafluoro-2-
hydroxypropan-2-yl group in the C5 position have been
shown to exhibit significant biological activity as non-
steroidal liver X receptor-a agonists [8]. Liver X recep-
tors normally bind 24S,25-epoxycholesterol and have
been found to play an important role in lipid metabolism
[8]. These potent modulators of liver X receptor-a are
currently being investigated for the treatment of dyslipi-
demia, atherosclerosis, and diabetes [9]. While the com-
pounds prepared here possess a nitro group at C5, the
nitro group could be readily transformed [10,11] to per-
mit installation of the required substituent.
Our cyclization study sought to demonstrate the feasi-
bility of preparing selected dihydroindoles from alkyl 2-
fluoro-5-nitrobenzyl ketones and primary amines by a
tandem reductive amination-SNAr sequence. Initially, we
believed that the enolizability of the substrates might
lead to competitive condensation reactions under the
RESULTS AND DISCUSSION
The synthesis of our dihydroindole precursors is
shown in Scheme 1. Dakin-West reaction of (2-fluoro-5-
C
V
2009 HeteroCorporation

630
R. A. Bunce, T. Nago, and B. White
Vol 46
Table 2
neutral to basic reaction conditions. Another potential
problem was the strain associated with closing a benzo-
fused five-membered ring [15]. Neither of these con-
cerns, however, proved to be a significant deterrent to
the success of the reaction.
Reductive cyclization of ethyl ketone 4.
The reaction is run by dissolving 1.00 equivalent of
the ketone in methanol, then adding 1.20 equivalents of
the amine and 1.25 equivalents of sodium cyanoborohy-
dride, and stirring at room temperature for 48 h. Opti-
mum yields were obtained when two extra portions (0.18
equivalents each) of the amine and the reducing agent
were added at 12-h intervals during the first 24 h. The
major limitation of the current process is its sensitivity to
the steric environment surrounding the ketone and amine
functions. For example, the reaction was successful for
substrates 3 (R ¼ CH3) and 4 (R ¼ CH2CH3), but pro-
ceeded poorly for 5 (R ¼ CH(CH3)2). The phenyl ketone
6 proved to be inert to the reaction conditions at 22ꢁC,
but gave a low yield of the heterocycle, along with three
other products, at 65ꢁC. Bulky amines, branched at the
a-carbon, also gave lower yields.
R
Yield of 10 (%)a
a
b
c
d
e
C6H5CH2
C6H5CH2CH2
n-C6H13
i-C3H7OCH2CH2CH2
i-C4H9
60
62
61
61
64
a Each reaction also gave 11 in 18–20% yield and unreacted 4 in 10–
12% yield.
10–15% yield. More hindered amines, such as cyclo-
hexylamine, gave dihydroindole 7f in much lower yield
(22%), with the remainder being alcohol 8 (20%), sim-
ple reductive amination product 9 (32%) and recovered
3 (14%). Isolation of 9 in this case suggests that reduc-
tive amination initiates the two-step sequence. Finally,
tert-butylamine gave only alcohol 8 (20%) along with
unreacted 3 (75%).
The best results were achieved by reacting methyl ke-
tone 3 with unbranched primary amines (see Table 1).
These gave the target dihydroindoles 7a–e in 74–82%
yields. In each case, the ketone reduction product, 1-(2-
fluoro-5-nitrophenyl)-2-propanol (8), was also isolated in
For more sterically congested substrates 4 and 5, the
yield of the dihydroindole decreased and the proportion
of ketone reduction product (11 and 13, respectively)
and unreacted ketone increased (see Tables 2 and 3).
Ethyl ketone 4 gave the dihydroindoles in 60–64%
yield, which is still synthetically useful. Isopropyl
ketone 5, however, afforded less than 25% yields and
the desired products were difficult to separate from
unreacted ketone and other minor by-products. Finally,
Table 1
Reductive cyclization of methyl ketone 3.
R
Yield of 7 (%)a
Table 3
Unbranched
Reductive cyclization of isopropyl ketone 5.
a
b
c
C6H5CH2
C6H5CH2CH2
n-C6H13
78
76
82
74
82
d
e
i-C3H7OCH2CH2CH2
i-C4H9
Branched
f
g
c-C6H11
t-C4H9
22b
0c
a Each reaction also gave 8 in 10–13 % yield.
b This reaction also gave reductive amination product 9 in 32% yield,
8 in 20% yield, and unreacted 3 in 14% yield.
R
Yield of 12 (%)
c This reaction gave 8 in 20% yield and unreacted 3 in 75% yield.
a
c
C6H5CH2
n-C6H13
17a
22b
a This reaction also gave 13 in 15% yield and unreacted 5 in 58% yield.
b This reaction also gave 13 in 14% yield and unreacted 5 in 55%
yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
(ꢀ)-1,2-Dialkyl-5-nitro-2,3-dihydro-1H-indoles
631
Scheme 2
were run as thin films on sodium chloride disks and referenced
1
to polystyrene. 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 Hz. Mass spectra
(electron impact/direct probe) were obtained at 70 eV.
1-(2-Fluoro-5-nitrophenyl)-2-propanone (3). This com-
pound was prepared from 1 and acetic anhydride on a 13.2
mmol scale by adapting the method described by Schtacher
and Dayagi [12] for the synthesis of 1-(3-nitrophenyl)-2-propa-
none. The crude product was recrystallized from methanol to
give 2.13 g (82%) of 3, mp 113–114ꢁC. ir: 1725, 1522, 1352,
1
1246 cmꢃ1; H NMR: d 8.19 (ddd, 1H, J ¼ 8.8, 4.4, 2.7), 8.12
(dd, 1H, J ¼ 6.2, 2.7), 7.22 (t, 1H, J ¼ 8.8), 3.88 (d, 2H, J ¼
0.9), 2.31 (s, 3H); 13C NMR: d 202.7, 164.5 (d, J ¼ 257.4),
144.2, 127.4 (d, J ¼ 6.6), 124.9 (d, J ¼ 10.3), 123.4, (d, J ¼
18.6), 116.2 (d, J ¼ 24.9), 43.3, 29.7; ms: m/z 197 (Mþ).
Anal. Calcd. for C9H8FNO3: C, 54.82; H, 4.06; N, 7.11.
Found: C, 54.84; H, 4.07; N, 7.07.
phenyl ketone 6 and benzylamine in methanol reacted
only under forcing conditions (65ꢁC, 48 h) to give a low
yield of the desired dihydroindole 14 (11%), along with
indole 15 (13%) from a deprotonation of the intermedi-
ate imine and cyclization by the nitrogen of the delocal-
ized anion, methoxyketone 16 (7%) from solvent addi-
tion to the activated ring, alcohol 17 (14%) and
unreacted 6 (52%) (see Scheme 2).
1-(2-Fluoro-5-nitrophenyl)-2-butanone (4). This compound
was prepared from 1 and propionic anhydride on a 13.2 mmol
scale by adapting the method described by Schtacher and Day-
agi [12] for the synthesis of 1-(3-nitrophenyl)-2-propanone.
The crude product was flash chromatographed on a 30 cm ꢂ
2.5 cm silica gel column eluted with 5% ether in hexanes to
give 1.53 g (59%) of 4, mp 59–61ꢁC. ir: 1721, 1529, 1351,
1
1248 cmꢃ1; H NMR: d 8.18 (ddd, 1H, J ¼ 8.8, 4.5, 2.9), 8.13
(dd, 1H, J ¼ 6.2, 2.9), 7.21 (t, 1H, J ¼ 8.8), 3.85 (d, 2H, J ¼
0.8), 2.60 (q, 2H, J ¼ 7.2), 1.12 (t, 3H, J ¼ 7.2); 13C NMR: d
205.5, 164.5 (d, J ¼ 257.7), 144.1, 127.7 (d, J ¼ 6.6), 124.9
(d, J ¼ 9.6), 123.6 (d, J ¼ 19.1), 116.2 (d, J ¼ 24.3), 42.0 (d,
J ¼ 1.5), 35.9, 7.7; ms: m/z 211 (Mþ). Anal. Calcd. For
C10H10FNO3: C, 56.87; H, 4.74; N, 6.63. Found: C, 56.85; H,
4.73; N, 6.63.
CONCLUSION
We have developed an approach to the synthesis of
(ꢀ)-1,2-dialkyl-5-nitro-2,3-dihydro-1H-indoles based on
a tandem reductive amination-SNAr reaction. The reac-
tion gives good yields in many cases but is sensitive to
steric hindrance in the ketone and amine reacting part-
ners. Thus, while satisfactory conversions were achieved
from substrates 3 and 4, hindered ketone 5 gave low
yields and aromatic ketone 6 was unreactive. Branching
at the a-carbon of the amine also proved detrimental to
the reaction. We are pursuing further studies of this
transformation in systems bearing other electron with-
drawing groups at C5 and C7 of the dihydroindole
system.
1-(2-Fluoro-5-nitrophenyl)-3-methyl-2-butanone (5). This
compound was prepared from 1 and isobutyric anhydride on
an 11.5 mmol scale by adapting the method described by
Schtacher and Dayagi [11] for the synthesis of 1-(3-nitro-
phenyl)-2-propanone. The crude product was flash chromato-
graphed on a 30 cm ꢂ 2.5 cm silica gel column using 5%
ether in hexanes to give 0.62 g (24%) of 5, mp 46–48ꢁC.
1
ir: 1720, 1530, 1349, 1249 cmꢃ1; H NMR: d 8.18 (ddd, 1H,
J ¼ 8.8, 4.5, 2.9), 8.12 (dd, 1H, J ¼ 6.2, 2.9), 7.20 (t, 1H, J ¼
8.8), 3.90 (s, 2H), 2.79 (septet, 1H, J ¼ 6.8), 1.20 (d, 6H, J ¼
6.8); 13C NMR: d 208.8, 164.5 (d, J ¼ 256.9), 144.3, 127.8 (d,
J ¼ 6.6), 124.8 (d, J ¼ 10.7), 123.8 (d, J ¼ 18.4), 116.1 (d,
J ¼ 24.3), 41.0, 40.1 (d, J ¼ 1.5), 18.2; ms: m/z 182 (Mþ-
C3H7). Anal. Calcd. For C11H12FNO3: C, 58.67; H, 5.33; N,
6.22. Found: C, 58.71; H, 5.34; N, 6.17.
3-(2-Fluoro-5-nitrophenyl)-1-phenyl-1-ethanone (6). [Caution!
Benzene is a carcinogen. Thionyl chloride is an inhalation haz-
ard and is highly toxic. Both should be handled carefully in a
EXPERIMENTAL
All reactions were run under dry nitrogen unless otherwise
indicated. Methanol was used from a freshly opened bottle.
Reactions were monitored by thin layer chromatography on
silica gel GF plates (Analtech 21521) with ultraviolet detec-
tion. Preparative separations were performed by one of the fol-
lowing methods: (1) flash column chromatography [16] on
silica gel (grade 62, 60–200 mesh) containing ultraviolet-active
phosphor (Sorbent Technologies UV-5) packed into quartz col-
umns or (2) preparative thin layer chromatography on 20 cm
ꢂ 20 cm silica gel GF plates (Analtech 02015). Band elution
for both methods was monitored using a hand-held ultraviolet
lamp. Hexanes used in chromatography had a boiling range of
65–70ꢁC. Melting points were uncorrected. Infrared spectra
well-ventilated area.] In a round-bottomed flask protected by a
R
drying tube (DrieriteV), 2.97 g (1.82 mL, 25.0 mmol) of thi-
onyl chloride was added to a solution of 2.49 g (12.5 mmol)
of 1 in 40 mL of benzene and the mixture was stirred and
heated under reflux for 3 h. Solvent and excess thionyl chlo-
ride were removed by distillation and the resulting acid chlo-
ride in 10 mL of benzene was added dropwise to a suspen-
sion of 2.00 g (15.0 mmol) of aluminum chloride in 40 mL
of benzene [14]. The mixture was heated under reflux for 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

632
R. A. Bunce, T. Nago, and B. White
Vol 46
h, then cooled and quenched by addition to 10 mL of concen-
trated hydrochloric acid and 25 g of crushed ice. The product
was extracted with 1:1 benzene:ether (two times) and the
combined organic extracts were washed with saturated so-
dium chloride (one time), dried (magnesium sulfate), and
concentrated under vacuum. The crude product was recrystal-
lized from methanol to give 1.88 g (58%) of 6, mp 89–90ꢁC.
Alcohol 8 (12%) was also isolated.
(ꢀ)-1-Hexyl-2-methyl-5-nitro-2,3-dihydro-1H-indole
(7c). This compound (110 mg, 82%) was isolated as a yellow
;
oil. ir: 1508, 1314 cmꢃ1
1H NMR: d 8.04 (dd, 1H, J ¼ 8.8,
2.2), 7.84 (m, 1H), 6.20 (d, 1H, J ¼ 8.8), 4.02 (m, 1H), 3.21
(m, 3H), 2.65 (ddd, 1H, J ¼ 16.3, 7.5, 0.9), 1.56 (m, 2H),
1.40–1.23 (complex, 6H), 1.31 (d, 3H, J ¼ 6.2), 0.90 (t, 3H,
J ¼ 7.0); 13C NMR: d 156.6, 137.4, 128.4, 126.8, 120.6,
103.0, 59.2, 44.3, 35.7, 31.5, 27.1, 26.8, 22.6, 19.8, 14.0; ms:
m/z 262 (Mþ). Anal. Calcd. for C15H22N2O2: C, 68.70; H,
8.40; N, 10.69. Found: 68.68; H, 8.45; N, 10.63.
1
ir: 1691, 1527, 1352, 1249 cmꢃ1; H NMR: d 8.21 (superim-
posed ddd and dd, 2H), 8.05 (superimposed dd, 2H), 7.64 (tt,
1H, J ¼ 7.4, 1.2), 7.52 (t, 2H, J ¼ 7.4), 7.24 (t, 1H, J ¼ 8.2),
4.44 (d, 2H, J ¼ 0.8); 13C NMR: d 194.5, 164.7 (d, J ¼
256.9), 144.1, 135.9, 133.8, 128.9, 128.3, 127.9 (d, J ¼ 6.6),
125.0 (d, J ¼ 10.3), 123.8 (d, J ¼ 18.4), 116.2 (d, J ¼ 24.3),
38.6 (d, J ¼ 1.5); ms (30 eV): m/z 259 (Mþ). Anal. Calcd.
For C14H10FNO3: C, 64.86; H, 3.86; N, 5.41. Found: C,
64.87; H, 3.86; N, 5.42.
Alcohol 8 (10%) was also isolated.
(ꢀ)-1-(3-Isopropoxypropyl)-2-methyl-5-nitro-2,3-dihydro-
1H-indole (7d). This compound (105 mg, 74%) was isolated
as a yellow oil that solidified upon standing at 10ꢁC, mp 39–
1
40ꢁC. ir: 1507, 1316 cmꢃ1; H NMR: d 8.03 (dd, 1H, J ¼ 8.8,
Representative procedure for the reductive amination-
nucleophilic substitution reaction with 3: (ꢀ)-1-Benzyl-2-
methyl-5-nitro-2,3-dihydro-1H-indole (7a). To a stirred solu-
tion of 100 mg (0.51 mmol) of 3 and 64 mg (0.65 mL, 0.60
mmol) of benzylamine at 22ꢁC was added 40 mg (0.64
mmol) of sodium cyanoborohydride. The reaction was stirred
at 22ꢁC for 48 h; two additional portions of 10 mg (0.09
mmol) of benzylamine and 6 mg (0.09 mmol) of sodium cya-
noborohydride were added at 12-h intervals during the first
24 h. The crude reaction mixture was poured into saturated
sodium chloride and extracted with ether (three times). The
combined ether extracts were dried (magnesium sulfate), con-
centrated under vacuum, and purified by preparative thin
layer chromatography using 20% ether in hexanes. The bright
yellow band contained 106 mg (78%) of 7a as a yellow solid,
2.4), 7.84 (m, 1H), 6.29 (d, 1H, J ¼ 8.8), 4.02 (m, 1H), 3.52
(septet, 1H, J ¼ 6.2), 3.46–3.30 (complex, 4H), 3.23 (ddd, 1H,
J ¼ 16.1, 9.2, 1.1), 2.65 (ddd, 1H, J ¼ 16.1, 7.5, 1.3), 1.82
(quintet, 2H, J ¼ 6.8), 1.32 (d, 3H, J ¼ 6.2), 1.16 (d, 6H, J ¼
6.1); 13C NMR: d 156.8, 137.4, 128.3, 126.7, 120.5, 103.2,
71.6, 64.8, 59.4, 41.2, 35.7, 27.9, 22.1, 22.0, 19.8; ms: m/z 278
(Mþ). Anal. Calcd. for C15H22N2O3: C, 64.75; H, 7.91; N,
10.07. Found: C, 64.77; H, 7.94; N, 9.99.
Alcohol 8 (13%) was also isolated.
(ꢀ)-1-Isobutyl-2-methyl-5-nitro-2,3-dihydro-1H-indole
(7e). This compound (96 mg, 82%) was isolated as a yellow
1
oil. ir 1507, 1316 cmꢃ1; H NMR: d 8.02 (dd, 1H, J ¼ 8.8, 2.4),
7.84 (m, 1H), 6.21 (d, 1H, J ¼ 8.8), 4.01 (m, 1H), 3.25 (ddd, 1H,
J ¼ 16.2, 8.8, 2.4), 3.02 (d, 2H, J ¼ 7.5), 2.66 (ddd, 1H, J ¼
16.2, 7.0, 1.3), 2.01 (septet, 1H, J ¼ 7.0), 1.29 (d, 3H, J ¼ 6.2),
0.98 (d, 3H, J ¼ 6.8), 0.92 (d, 3H, J ¼ 6.8); 13C NMR: d 157.0,
137.5, 128.1, 126.7, 120.6, 103.2, 59.9, 52.3, 35.6, 27.5, 20.5,
20.3, 19.6; ms: m/z 234 (Mþ). Anal. Calcd. for C13H18N2O2: C,
66.67; H, 7.69; N, 11.97. Found: C, 66.63; H, 7.73; N, 11.95.
Alcohol 8 (10%) was also isolated.
1
mp 94–95ꢁC. ir: 1506, 1315 cmꢃ1; H NMR: d 8.00 (dd, 1H,
J ¼ 8.8, 2.4), 7.88 (m, 1H), 7.38–7.22 (complex, 5H), 6.23 (d,
1H, J ¼ 8.8), 4.55 (d, 1H, J ¼ 16.3), 4.35 (d, 1H, J ¼ 16.3),
4.02 (m, 1H), 3.29 (ddd, 1H, J ¼ 16.1, 9.1, 1.1), 2.72 (ddd, 1H,
J ¼ 16.1, 7.7, 0.9), 1.32 (d, 3H, J ¼ 6.2); 13C NMR: d 156.8,
138.1, 136.7, 128.8, 128.5, 127.6, 127.0, 126.6, 120.6, 103.7,
59.7, 48.5, 35.8, 19.8; ms: m/z 268 (Mþ). Anal. Calcd. for
C16H16N2O2: C, 71.64; H, 5.97; N, 10.45. Found: C, 71.64; H,
5.96; N, 10.42.
(ꢀ)-1-Cyclohexyl-2-methyl-5-nitro-2,3-dihydro-1H-indole
(7f). This compound (29 mg, 22%) was isolated as a yellow
;
oil. ir: 1506, 1313 cmꢃ1
1H NMR: d 8.02 (dd, 1H, J ¼ 8.8,
2.3), 7.83 (dt, 1H, J ¼ 2.3, 1.4), 6.24 (d, 1H, J ¼ 8.8), 4.14
(m, 1H), 3.30 (m, 2H), 2.61 (ddd, 1H, J ¼ 16.2, 4.5, 0.8), 1.89
(m, 4H), 1.73 (m, 2H), 1.54 (m, 1H), 1.30 (m, 3H), 1.30 (d,
3H, J ¼ 6.2); 13C NMR: d 155.3, 137.1, 128.5, 126.7, 120.8,
103.6, 57.2, 56.2, 36.0, 31.0, 30.1, 26.1, 26.0, 25.6, 23.2; ms:
m/z 245 (Mþ-CH3). Anal. Calcd. for C15H20N2O2: C, 69.23;
H, 7.69; N, 10.77. Found: C, 69.26; H, 7.71; N, 10.72.
This reaction also produced 12 mg (12%) of 1-(2-fluoro-5-
nitrophenyl)-2-propanol (8), mp 53–54.5ꢁC. ir: 3385, 1527,
1350, 1245 cmꢃ1
;
1H NMR: d 8.21 (dd, 1H, J ¼ 6.2, 2.9),
8.13 (ddd, 1H, J ¼ 8.8, 4.4, 2.9), 7.18 (t, 1H, J ¼ 8.8), 4.13
(d of sextets, 1H, J ¼ 6.2, 0.9), 2.91 (ddd, 1H, J ¼ 13.8, 4.8,
1.3), 2.83 (ddd, 1H, J ¼ 13.8, 7.5, 1.3), 1.61 (br s, 1H), 1.29
(d, 3H, J ¼ 6.2); 13C NMR: d 164.8 (d, J ¼ 256.2), 149.6,
128.3 (d, J ¼ 18.3), 127.6 (d, J ¼ 7.2), 124.1 (d, J ¼ 10.3),
116.2 (d, J ¼ 25.5), 67.4, 38.2, 23.3; ms: m/z 199 (Mþ). Anal.
Calcd. for C9H10FNO3: C, 54.27; H, 5.03; N, 7.04. Found: C,
54.31; H, 5.05; N, 7.01.
This reaction also produced 45 mg (32%) of N-cyclohexyl-
a-methyl-2-(2-fluoro-5-nitrophenyl)ethanamine (9) as a yellow
oil. ir: 3323, 1528, 1350, 1244 cmꢃ1 1H NMR: d 8.16 (dd,
;
1H, J ¼ 6.2, 2.7), 8.11 (ddd, 1H, J ¼ 9.0, 4.5, 2.7), 7.16 (t,
1H, J ¼ 9.0), 3.11 (sextet, 1H, J ¼ 6.3), 2.86 (dd, 1H, J ¼
13.5, 6.1), 2.64 (dd, 1H, J ¼ 13.5, 7.2), 2.55 (tt, 1H, J ¼ 10.3,
3.7), 1.85 (m, 2H), 1.70 (m, 2H), 1.60 (m, 1H), 1.32–1.15
(complex, 4H), 1.04 (d, 3H, J ¼ 6.3), 1.01 (m, 2H); 13C
NMR: d 164.8 (d, J ¼ 256.2), 144.3, 128.7 (d, J ¼ 17.7),
127.5 (d, J ¼ 7.4), 123.8 (d, J ¼ 10.3), 116.1 (d, J ¼ 25.8),
53.5, 49.7, 36.7, 34.2, 33.9, 26.1, 25.1, 25.0, 20.9; ms: m/z 265
(Mþ-CH3). Anal. Calcd. for C15H21FN2O2: C, 64.29; H, 7.50;
N, 10.00. Found: C, 64.38; H, 7.56; N, 9.95.
(ꢀ)-2-Methyl-5-nitro-1-(2-phenylethyl)-2,3-dihydro-1H-indole
(7b). This compound (110 mg, 76%) was isolated as a yellow
;
oil. ir: 1508, 1315 cmꢃ1
1H NMR: d 8.00 (dd, 1H, J ¼ 8.8,
2.2), 7.83 (m, 1H), 7.34–7.16 (complex, 5H), 6.16 (d, 1H, J ¼
8.8), 3.91 (m, 1H), 3.47 (m, 2H), 3.19 (ddd, 1H, J ¼ 16.3, 9.3,
0.9), 2.86 (m, 2H), 2.62 (ddd, 1H, J ¼ 16.3, 7.5, 0.9), 1.26 (d,
3H, J ¼ 6.2); 13C NMR: d 156.2, 138.6, 137.6, 128.7, 128.6,
128.4, 126.7, 126.6, 120.5, 103.0, 59.5, 46.2, 35.6, 33.5, 19.7;
ms: m/z 282 (Mþ). Anal. Calcd. for C17H18N2O2: C, 72.34; H,
6.38; N, 9.93. Found: C, 72.27; H, 6.40; N, 9.88.
Alcohol 8 (20%) and unreacted 3 (14%) were also isolated.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
(ꢀ)-1,2-Dialkyl-5-nitro-2,3-dihydro-1H-indoles
633
120.4, 102.9, 71.6, 64.8, 64.7, 41.3, 32.6, 27.8, 26.0, 22.1,
22.0, 8.8; ms: m/z 205 (Mþ-C5H11O). Anal. Calcd. for
C16H24N2O3: C, 65.75; H, 8.22; N, 9.59. Found: C, 65.79; H,
8.24. N, 9.52.
Alcohol 11 (18%) and unreacted 4 (11%) were also isolated.
(ꢀ)-2-Ethyl-1-isobutyl-5-nitro-2,3-dihydro-1H-indole
(10e). This compound (75 mg, 64%) was isolated as a yellow
Attempted preparation of (ꢀ)-1-tert-butyl-2-methyl-5-
nitro-2,3-dihydro-1H-indole (7g). Treatment of 3 as above
gave only alcohol 8 (20%) and unreacted 3 (75%).
Reductive amination-nucleophilic substitution reaction
with 4: (ꢀ)-1-Benzyl-2-ethyl-5-nitro-2,3-dihydro-1H-indole
(10a). This reaction was run on a 100 mg (0.47 mmol)-scale
using the general procedure given above for the preparation of
7a. This compound (80 mg, 60%) was obtained as a yellow
oil. ir: 1511, 1315 cmꢃ1
;
1H NMR: d 8.02 (dd, 1H, J ¼ 8.8,
1
solid, mp 47–48ꢁC. ir: 1509, 1316 cmꢃ1; H NMR: d 8.00 (dd,
2.3), 7.85 (m, 1H), 6.21 (d, 1H, J ¼ 8.8), 3.88 (m, 1H), 3.20
(ddd, 1H, J ¼ 16.4, 9.6, 1.0), 3.03 (m, 2H), 2.74 (ddd, 1H, J ¼
16.4, 6.6, 1.0), 2.02 (septet, 1H, J ¼ 6.7), 1.78 (sextet d, 1H, J ¼
7.4, 3.1), 1.53 (m, 1H), 0.97 (d, 3H, J ¼ 6.7), 0.91 (d, 3H, J ¼
6.7), 0.90 (t, 3H, J ¼ 7.4); 13C NMR: d 157.4, 137.1, 128.2,
126.8, 120.5, 102.9, 65.1, 52.3, 32.5, 27.4, 25.9, 20.5, 20.3, 8.8;
ms: m/z 205 (Mþ-C3H7). Anal. Calcd. for C14H20N2O2: C, 67.74;
H, 8.06; N, 11.29. Found: C, 67.69; H, 8.04; N, 11.30.
1H, J ¼ 8.9, 2.3), 7.89 (m, 1H), 7.36–7.22 (complex, 5H), 6.23
(d, 1H, J ¼ 8.9), 4.56 (d, 1H, J ¼ 16.4), 4.36 (d, 1H, J ¼
16.4), 3.89 (m, 1H), 3.24 (dd, 1H, J ¼ 16.5, 9.6), 2.81 (dd, 1H,
J ¼ 16.5, 3.1), 1.81 (sextet d, 1H, J ¼ 7.4, 3.1), 1.58 (m, 1H),
0.90 (t, 3H, J ¼ 7.4); 13C NMR: d 157.2, 138.0, 136.7, 128.8,
128.6, 127.5, 126.9, 126.7, 120.6, 103.5, 65.1, 48.7, 32.8, 26.2,
8.9; ms: m/z 191 (Mþ-C7H7). Anal. Calcd. for C17H18N2O2: C,
72.34; H, 6.38; N, 9.93. Found: C, 72.38; H, 6.41; N, 9.87.
This reaction also produced 19 mg (19%) of 1-(2-fluoro-5-
nitrophenyl)-2-butanol (11), mp 37–38ꢁC. ir: 3390, 1527, 1350,
Alcohol 11 (18%) and unreacted 4 (11%) were also isolated.
Reductive amination-nucleophilic substitution reaction
with 5: (ꢀ)-1-Benzyl-2-isopropyl-5-nitro-2,3-dihydro-1H-
indole (12a). This reaction was run on a 100 mg (0.44 mmol)-
scale using the general procedure given above for the prepara-
tion of 7a. This compound (22 mg, 17%) was isolated as a
yellow oil following preparative thin layer chromatography
1
1244 cmꢃ1; H NMR: d 8.23 (dd, 1H, J ¼ 6.2, 2.9), 8.13 (ddd,
1H, J ¼ 8.9, 4.2, 2.9), 7.18 (t, 1H, J ¼ 8.9), 3.84 (m, 1H), 2.95
(ddd, 1H, J ¼ 14.0, 4.1, 1.0), 2.79 (dd, 1H, J ¼ 14.0, 8.4), 1.60
(br s, 1H), 1.58 (m, 2H), 1.02 (t, 3H, J ¼ 7.4); 13C NMR: d
164.8 (d, J ¼ 256.9), 144.0, 127.8 (d, J ¼ 17.6), 127.6 (d, J ¼
7.4), 124.0 (d, J ¼ 10.3), 116.1 (d, J ¼ 25.8), 72.6, 36.2, 30.1,
9.8; ms: m/z 184 (Mþ-C2H5). Anal. Calcd. For C10H12FNO3: C,
56.34; H, 5.63; N, 6.57. Found: C, 56.40; H, 5.66; N, 6.51.
Unreacted 4 (12%) was also recovered.
1
using 15% ether in hexanes. ir: 1510, 1317 cmꢃ1; H NMR: d
8.01 (dd, 1H, J ¼ 9.0, 2.3), 7.89 (m, 1H), 7.38–7.20 (complex,
5H), 6.29 (d, 1H, J ¼ 9.0), 4.62 (d, 1H, J ¼ 16.4), 4.33 (d,
1H, J ¼ 16.4), 3.92 (ddd, 1H, J ¼ 10.3, 7.6, 3.9), 3.03 (dd,
1H, J ¼ 16.6, 10.2), 2.89 (dd, 1H J ¼ 16.6, 7.6), 2.17 (sextet
d, 1H, J ¼ 6.8, 3.9), 0.91 (d, 3H, J ¼ 6.8), 0.81 (d, 3H, J ¼
6.8); 13C NMR: d 157.7, 138.0, 136.4, 128.8, 127.7, 127.6,
127.1, 126.7, 120.6, 103.7, 68.0, 48.4, 28.3, 27.5, 18.6, 14.6;
ms: m/z 205 (Mþ-C7H7). Anal. Calcd. for C18H20N for
C18H20N2O2: C, 72.97; H, 6.76; N, 9.46. Found: C, 72.93; H,
6.72; N, 9.48.
(ꢀ)-2-Ethyl-5-nitro-1-(2-phenylethyl)-2,3-dihydro-1H-indole
(10b). This compound (87 mg, 62%) was isolated as a yellow
;
oil. ir: 1513, 1322 cmꢃ1
1H NMR: d 8.00 (dd, 1H, J ¼ 8.8,
2.1), 7.83 (m, 1H), 7.32–7.15 (complex, 5H), 6.15 (d, 1H, J ¼
8.8), 3.76 (m, 1H), 3.51 (ddd, 1H, J ¼ 14.8, 9.0, 6.1), 3.42
(ddd, 1H, J ¼ 14.8, 8.8, 6.8), 3.12 (dd, 1H, J ¼ 16.4, 9.6),
2.89 (ddd, 1H, J ¼ 14.6, 9.0, 6.8), 2.80 (ddd, 1H, J ¼ 14.6,
8.8, 6.1), 2.70 (dd, 1H, J ¼ 16.4, 7.4), 1.78 (sextet d, 1H, J ¼
7.4, 3.1), 1.50 (m, 1H), 0.88 (t, 3H, J ¼ 7.4); 13C NMR: d
156.6, 138.6, 137.5, 128.6 (2C), 128.5, 126.7, 126.6, 120.5,
102.8, 64.8, 46.3, 33.4, 32.6, 26.0, 8.8; ms: m/z 205 (Mþ-
C7H7). Anal. Calcd. for C18H20N2O2: C, 72.97; H, 6.76; N,
9.46. Found: C, 73.01; H, 6.74; N, 9.47.
This reaction also produced 15 mg (15%) of 1-(2-fluoro-5-
nitrophenyl)-3-methyl-2-butanol (13) as a dark yellow oil. ir:
1
3427, 1526, 1347, 1245 cmꢃ1; H NMR: d 8.24 (dd, 1H, J ¼
6.2, 2.9), 8.13 (ddd, 1H, J ¼ 8.8, 4.3, 2.9), 7.17 (t, 1H, J ¼
8.8), 3.66 (m, 1H), 2.96 (dd, 1H, J ¼ 14.1, 2.0), 2.73 (dd, 1H,
J ¼ 14.1, 9.8), 1.77 (septet, 1H, J ¼ 6.8), 1.48 (br s, 1H), 1.03
(d, 3H, J ¼ 6.8), 1.02 (d, 3H, J ¼ 6.8); 13C NMR: d 164.8 (d,
J ¼ 256.2), 144.1, 128.5 (d, J ¼ 18.5), 127.6 (d, J ¼ 7.4),
124.0 (d, J ¼ 10.3), 116.1 (d, J ¼ 25.0), 76.1, 33.9, 33.5,
18.7, 17.1; ms: m/z 184 (Mþ-C3H7). Anal. Calcd. for
C11H14FNO3: C, 58.15; H, 6.17; N, 6.17. Found: C, 58.23; H,
6.19; N, 6.12.
Alcohol 11 (19%) and unreacted 4 (10%) were also isolated.
(ꢀ)-2-Ethyl-1-hexyl-5-nitro-2,3-dihydro-1H-indole (10c). This
compound (80 mg, 61%) was isolated as a yellow oil. ir: 1511,
1
1313 cmꢃ1; H NMR: d 8.03 (dd, 1H, J ¼ 8.9, 2.3), 7.83 (m,
1H), 6.19 (d, 1H, J ¼ 8.9), 3.89 (m, 1H), 3.31–3.11 (complex,
3H), 2.73 (dd, 1H, J ¼ 17.1, 8.0), 1.80 (m, 1H), 1.57 (m, 3H),
1.31 (m, 6H), 0.91 (t, 3H, J ¼ 7.4), 0.90 (distorted t, 3H, J ¼
6.2); 13C NMR: d 157.0, 137.2, 128.4, 126.8, 120.4, 102.7,
64.6, 44.4, 32.6, 31.5, 27.0, 26.8, 26.0, 22.5, 14.0, 8.8; ms: m/z
205 (Mþ-C5H11). Anal. Calcd. for C16H24N2O2: C, 69.57; H,
8.70; N, 10.14. Found: C, 69.63; H, 8.75; N, 10.06.
Unreacted 5 (58%) was also recovered.
(ꢀ)-1-Hexyl-2-isopropyl-5-nitro-2,3-dihydro-1H-indole
(12c). This compound (28 mg, 22%) was isolated as a yellow
;
oil. ir: 1516, 1327 cmꢃ1
1H NMR: d 8.03 (dd, 1H, J ¼ 8.8,
2.1), 7.83 (m, 1H), 6.19 (d, 1H, J ¼ 8.8), 4.12 (t, 1H, J ¼
7.8), 3.93 (ddd, 1H, J ¼ 10.5, 7.3, 3.7), 3.30 (ddd, 1H, J ¼
14.8, 9.4, 6.3), 3.16 (ddd, 1H, J ¼ 14.8, 9.4, 5.8), 3.06 (septet,
1H, J ¼ 6.8), 2.98 (dd, 1H, J ¼ 16.6, 9.9), 2.82 (dd, 1H, J ¼
16.6, 7.2), 2.16 (m, 1H), 1.76 (m, 1H), 1.57 (m, 1H), 1.32 (m,
4H), 0.95 (d, 3H, J ¼ 6.8), 0.89 (m, 3H), 0.78 (d, 3H, J ¼
6.8); 13C NMR: d 157.3, 139.5, 128.5, 126.9, 120.4, 102.5,
67.9, 44.4, 43.6, 31.5, 28.5, 27.2, 26.8, 26.7, 22.6, 18.6, 14.4;
ms: m/z 219 (Mþ-C5H11). Anal. Calcd. for C17H26N2O2: C,
70.34; H, 8.97; N, 9.66. Found: C, 70.40; H, 9.01; N, 9.60.
Alcohol 13 (14%) and unreacted 5 (55%) were also isolated.
Alcohol 11 (20%) and unreacted 4 (10%) were also isolated.
(ꢀ)-2-Ethyl-1-(3-isopropoxypropyl)-5-nitro-2,3-dihydro-
1H-indole (10d). This compound (84 mg, 61%) was isolated
as a yellow oil. ir: 1515, 1315 cmꢃ1 1H NMR: d 8.03
;
(dd, 1H, J ¼ 8.8, 2.1), 7.84 (m, 1H), 6.28 (d, 1H, J ¼ 8.8),
3.85 (m, 1H), 3.53 (septet, 1H, J ¼ 6.2), 3.49–3.27 (complex,
4H), 3.18 (dd, 1H, J ¼ 16.4, 9.4), 2.74 (dd, 1H, J ¼ 16.4,
7.4), 1.82 (m, 3H), 1.55 (m, 1H), 1.15 (d, 6H, J ¼ 6.2), 0.91
(t, 3H, J ¼ 7.4); 13C NMR: d 157.2, 137.4, 128.3, 126.8,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

634
R. A. Bunce, T. Nago, and B. White
Vol 46
Skinner Scholarship. Funding for the 400 MHz NMR spectrome-
ter of the Oklahoma Statewide Shared NMR Facility was pro-
vided 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 FTIR and GC-
MS instruments.
Reductive amination-nucleophilic aromatic substitution
reactions with 6. Treatment of 100 mg (0.39 mmol) of 6 with
51.8 mg (0.48 mmol) of benzylamine using the general proce-
dure given above for the preparation of 7a afforded 98% re-
covery of unreacted 6.
Repeating this reaction in methanol at 65ꢁC for 48 h yielded
four products, in addition to recovered 6. These products were
separated by preparative thin layer chromatography using 10%
ether in hexanes to give: band 1: 16 mg (13%) of 15; band 2:
13 mg (11%) of 14; band 3: 52 mg (52%) of recovered 6;
band 4: 14 mg (14%) of 17; and band 5: 7 mg (7%) of 16.
The physical and spectral data for these products were as
follows:
REFERENCES AND NOTES
[1] Undergraduate research participants: T. N., 2006–2009;
B. W. 2008–2009.
[2] (a) Bunce, R. A.; Rogers, D.; Nago, T.; Bryant, S. A. J Het-
erocycl Chem 2008, 45, 547; (b) Bunce, R. A.; Nago, T.; Sonobe, N.;
Slaughter, L. M. J Heterocycl Chem 2008, 45, 551.
1-Benzyl-2-phenyl-5-nitroindole (15). Viscous yellow oil;
1
ir: 1513, 1332 cmꢃ1; H NMR: d 8.62 (d, 1H, J ¼ 2.2), 8.05
(dd, 1H, J ¼ 9.3, 2.2), 7.43 (apparent s, 5H), 7.30 (m, 1H),
7.28 (apparent t, 2H, J ¼ 6.6), 7.20 (d, 1H, J ¼ 8.8), 6.97 (dd,
2H, J ¼ 8.2, 2.2), 6.80 (s, 1H), 5.41 (s, 2H); 13C NMR: d
145.0, 142.1, 140.6, 136.9, 131.3, 129.2, 129.0, 128.9, 128.8,
127.7, 127.5, 125.8, 117.6, 117.5, 110.4, 104.3, 48.0; ms: m/z
237 (Mþ-C7H7). Anal. Calcd. for C21H16N2O2: C, 76.82; H,
4.88; N, 8.54. Found: C, 76.88; H, 4.91; N, 8.50.
[3] Bunce, R. A.; Nago, T. J Heterocycl Chem 2008, 45, 1155.
[4] Chapman, O. L.; Eian, G. L. J Am Chem Soc 1968, 90, 5329.
[5] Berger, J. Synthesis 1974, 508.
[6] Speckamp, W. N.; Veenstra, S. J.; Dijkink, J.; Fortgens, R.
J Am Chem Soc 1981, 103, 4643.
[7] (a) Beller, M. Breindl, C.; Riermeier, T. H.; Eichberger, M.;
Trauthwein, H. Angew Chem Int Ed 1998, 37, 3389; (b) Beller, M.;
Breindl, C.; Riermeier, T. H.; Tillack, A. J Org Chem 2001, 66, 1403.
[8] See for example (a) Collins, J. L.; Fivush, A. M.; Watson,
M. A.; Galardi, C. M.; Lewis, M. C.; Moore, L. B.; Parks, D. J.; Wil-
son, J. G.; Tippin, T. K.; Binz, J. G.; Plunket, K. D.; Morgan, D. G.;
Beaudet, E. J.; Whitney, K. D.; Kliewer, S. A.; Willson, T. M. J Med
Chem 2002, 45, 1963; (b) Miao, B.; Zondlo, S.; Gibbs, S.; Cromley,
D.; Hosagrahara, V. P.; Kirchgessner, T. G.; Billheimer, J.; Mukherjee,
R. J Lipid Res 2004, 45, 1410; (c) Li, L.; Liu, J.; Zhu, L.; Cutler, S.;
Hasegawa, H.; Shan, B.; Medina, J. C. Bioorg Med Chem Lett 2006,
16, 1638; (d) Dehmlow, H.; Kuhn, B.; Panday, N.; Ratni, H.; Schulz--
Gasch, T.; Wright, M. B. U.S. Pat. 20050245515 (2005), 45 pp; Chem
Abstr 2005, 143, 440259.
(ꢀ)-1-Benzyl-2-phenyl-5-nitro-2,3-dihydro-1H-indole
(14). Yellow solid, mp 137–139ꢁC; ir: 1510, 1313 cmꢃ1 1H
;
NMR: d 8.09 (dd, 1H, J ¼ 8.8, 2.2), 7.93 (s, 1H), 7.41–7.24
(complex, 8H), 7.12 (dd, 2H, J ¼ 7.7, 2.2), 6.39 (d, 1H, J ¼
8.8), 4.88 (dd, 1H, J ¼ 9.9, 7.7), 4.56 (d, 1H, J ¼ 15.9), 4.01
(d, 1H, J ¼ 15.9), 3.55 (dd, 1H, J ¼ 16.5, 9.9), 3.08 (dd, 1H,
J ¼ 16.5, 8.2); 13C NMR: d 156.8, 141.0, 138.6, 136.0, 129.0,
128.8, 128.4, 128.2, 127.7, 127.5, 127.1, 126.8, 120.8, 103.9,
67.6, 48.4, 37.7; ms: m/z 239 (Mþ-C7H7). Anal. Calcd. for
C21H18N2O2: C, 76.36; H, 5.45; N, 8.48. Found: C, 76.38; H,
5.46; N, 8.45.
(ꢀ)-1-Phenyl-2-(2-fluoro-5-nitrophenyl) ethanol (17). Viscous
[9] Collins, J. L. Curr Opin Drug Discov Dev 2004, 24, 1755.
[10] For examples of aniline diazotization in the presence of
amides, see (a) Dugave, C. J Org Chem 1995, 60, 601; (b) Vergne, C.;
Bois-Choussy, M.; Zhu, J. Synlett 1998, 1159.
1
yellow oil; ir: 3546, 3416, 1526, 1346, 1244 cmꢃ1; H NMR:
d 8.13 (m, 2H), 7.41–7.28 (complex, 5H), 7.16 (t, 1H, J ¼
8.8), 4.99 (t, 1H, J ¼ 6.6), 3.12 (d, 2H, J ¼ 6.6), 2.00 (br s,
1H); 13C NMR: d 164.8 (d, J ¼ 256.5), 144.0, 143.1, 128.7,
128.2, 127.8 (d, J ¼ 6.9), 127.2 (d, J ¼ 18.0), 125.7, 124.2 (d,
J ¼ 10.0), 116.1 (d, J ¼ 25.5), 73.7, 38.4; ms: m/z 243 (Mþ-
H2O). Anal. Calcd. for C14H12FNO3: C, 64.37; H, 4.60; N,
5.36. Found: C, 64.44; H, 4.64; N, 5.29.
[11] For examples of aniline diazotization in the presence of a
tertiary amine substituent, see (a) Gerson, F. Holy Chim Acta 1963,
46, 1109; (b) Gerson, F. Chem Abstr 1963, 59, 41106; (c) Chen, L.;
Du, J.; Wang, Y. Ganguang Kexue Yu Guang Huaxue 1985, 6; (d)
Chen, L.; Du, J.; Wang, Y. Chem Abstr 1986, 104, 35451; (e) Siegel,
H.; Erdmann, F.; Lutz, W. Eur. Pat. EP 333004 (1989), 10 pp; Chem
Abstr 1990, 112, 45744.
3-(2-Methoxy-5-nitrophenyl)-1-phenyl-1-ethanone (16). Light
yellow solid, mp 118–120ꢁC; ir: 2848, 1689, 1514, 1330
1
cmꢃ1; H NMR: d 8.22 (dd, 1H, J ¼ 9.3, 2.7), 8.11 (d, 1H, J
[12] Schtacher, G.; Dayagi, S. J Med Chem 1972, 15, 1174.
[13] Buchanan, G. L. Chem Soc Rev 1988, 17, 91.
¼ 2.7), 8.03 (d, 2H, J ¼ 7.7), 7.62 (t, 1H, J ¼ 7.7), 7.51 (t,
2H, J ¼ 7.7), 6.96 (d, 1H, J ¼ 9.3), 4.36 (s, 2H), 3.88 (s, 3H)
13C NMR: d 196.0, 162.5, 141.3, 136.5, 133.4, 128.7, 128.2,
127.0, 125.1, 124.9, 110.0, 56.2, 39.9; ms: m/z 166 (Mþ-
C7H5O). Anal. Calcd. for C15H13NO4: C, 66.42; H, 4.80; N,
5.17. Found: C, 66.44; H, 4.80; N, 5.19.
[14] Allen, C. F. H.; Barker, W. E. Organic Syntheses; Wiley:
New York, 1943; Vol. II, p 156.
[15] Strain in closing a benzo-fused five-membered ring was
cited as a contributing factor in the low yields obtained for 2,3-dihy-
dro-1H-indoles prepared by a tandem SN2-SNAr reaction. This now
appears unlikely. The primary problem in the SN2-SNAr approach to
this ring system is the tendency for the substrates to undergo elimina-
tion to the styrene in the presence of the basic amine nucleophile, see
ref. 1(b).
Acknowledgment. T. N. thanks Oklahoma State University for
a Niblack Scholarship and the Department of Chemistry for a
Moore Scholarship. B. W. thanks the 2008 NSF-REU program at
OSU (CHE-0649162) and the Department of Chemistry for a
[16] Still, W. C.; Kahn, M.; Mitra, A. J Org Chem 1978, 43,
2923.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet