Versatile synthesis of 2-(substituted phenyl)-6,7-dihydro-1H-indol-4(5H)- ones from Morita-Baylis-Hillman acetates of 2-oxo-2-(substituted phenyl)acetaldehyde

Article abstract of DOI:10.1002/ejoc.201200107

A versatile synthesis of 2-(substituted phenyl)-6,7-dihydro-1H-indol-4(5H)- ones from adducts of the Morita-Baylis-Hillman reaction between 2-oxo-2-(substituted phenyl)acetaldehydes and cyclohex-2-enone under mild conditions is described. Application of adducts prepared by the Morita-Baylis-Hillman reaction between 2-oxo-2-(substituted phenyl)acetaldehydes and cyclohex-2-enone for the synthesis of 2-(substituted phenyl)-6,7-dihydro- 1H-indol-4(5H)-ones has been described. Copyright

Full text of DOI:10.1002/ejoc.201200107

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DOI: 10.1002/ejoc.201200107
Versatile Synthesis of 2-(Substituted phenyl)-6,7-dihydro-1H-indol-4(5H)-ones
from Morita–Baylis–Hillman Acetates of
2-Oxo-2-(substituted phenyl)acetaldehyde[‡]
Harikrishna Batchu[a] and Sanjay Batra*[a]
Keywords: Nitrogen heterocycles / Synthetic methods / Indole Derivatives / Morita–Baylis–Hillman
A versatile synthesis of 2-(substituted phenyl)-6,7-dihydro-
1H-indol-4(5H)-ones from adducts of the Morita–Baylis–Hill-
man reaction between 2-oxo-2-(substituted phenyl)acetalde-
hydes and cyclohex-2-enone under mild conditions is de-
scribed.
hydroxy-enamines.[13] Recently, during studies towards de-
velopment of new anticancer agents, Huang’s group synthe-
sized this scaffold from 1,3-cyclohexanedione and 5-amino-
levulinic acid hydrochloride.[14] More recently, Li’s group re-
ported a multi-component approach for this moiety
through a microwave-promoted reaction between differently
substituted enamines, phenylglyoxal monohydrate and
acetic acid.[15,16]
The Morita–Baylis–Hillman (MBH) reaction has been
used extensively in heterocyclic synthesis during the last
decade.[17] In one of our research programs we have been
exploring the synthetic potential of MBH derivatives for
realizing aza-heterocycles.[18] We envisaged the synthesis of
6,7-dihydro-1H-indole-4(5H)-ones from the adduct of the
MBH reaction between 2-oxo-2-phenylacetaldehyde and cy-
clohex-2-enone (Figure 1). A SN2Ј reaction of a primary
amine on the double bond of the cycloalkene unit of the
MBH acetate followed by intramolecular cyclization involv-
ing the keto group is anticipated to afford the desired prod-
uct. Here, we have developed a facile synthesis of substi-
tuted 6,7-dihydro-1H-indole-4(5H)-ones. The advantage of
this method is that it is versatile and a wide range of pri-
mary amines can be used to give the N-substituted 6,7-dihy-
dro-1H-indole-4(5H)-one unit.
Introduction
6,7-Dihydro-1H-indole-4(5H)-one is an important struc-
tural motif because it serves as the starting material for con-
struction of several indole-based compounds.[1] In addition,
derivatives bearing this core are of considerable pharmaco-
logical interest and possess an array of biological activities
including HSP90 inhibition,[2] soluble guanylate cyclase in-
hibition,[3] kv 1.5 blocking,[4] anti-psychotic,[5] GABAA-α5
receptor ligands,[6] antiproliferation and aurora kinase inhi-
bition.[7] Furthermore 4-oxo-4,5,6,7-tetrahydroindole is a
sub-structural unit of the biologically important alkaloids,
mitomycins,[8] and several elegant syntheses of this struc-
tural unit have been reported. The first synthesis, reported
in 1962 by Stetter and Lauterbach, involved treatment of
1,3-cyclohexadiones with α-haloketones leading to triones
that upon reaction with ammonia or primary amines af-
forded substituted 4-oxo-4,5,6,7-tetrahydroindoles.[9]
A
variant to the procedure included alkylation of cyclohexa-
1,3-dione with ethyl bromopyruvate to generate 4-oxote-
trahydrobenzofuran-3-carboxylic acid that reacted with am-
monia at high temperature to give the product.[10] In an-
other strategy electro-oxidative coupling of cyclohexa-1,3-
dione with ethyl vinyl ether followed by aminolysis was re-
ported.[11] Heravi et al. disclosed that a potassium hydrogen
sulfate catalyzed Ugi reaction between cyclohexylisocy-
anide, an aldehyde, a cyclic 1,3-dicarbonyl compound and
ammonium acetate in acetonitrile produced 2,3-disubsti-
tuted 6,7-dihydro-1H-indole-4(5H)-ones.[12] Aoyagi et al.
generated the same core through Pd-catalyzed oxidation of
[‡] CDRI Communication No. 8223
[a] Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute,
PO Box 173, Lucknow 226 001, India
Fax: +91-522-2623405, 2623938
E-mail: batra_san@yahoo.co.uk
Figure 1. Retrosynthetic plan for the formation of 6,7-dihydro-1H-
indole-4(5H)-one from the MBH adduct of 2-oxo-2-phenylacetal-
dehyde.
s_batra@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200107.
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sired 2-(substituted phenyl)-6,7-dihydro-1H-indole-4(5H)-
ones 22a–25a as solids in excellent yields without the need
for purification.
Results and Discussion
The initial step of this study was to investigate the MBH
reaction of 2-oxo-2-phenylacetaldehyde with cyclohex-2-en-
one (Scheme 1). 2-Oxo-2-phenylacetaldehyde monohydrate
(6) was treated with cyclohex-2-enone in the presence of 4-
dimethylaminopyridine (DMAP) or imidazole in THF/
water or dioxane/water as solvent. Following optimization,
we found that performing the reaction in the presence of
0.4 equiv. of DMAP in THF/H2O (1:1, v/v) gave MBH ad-
duct 11 in 58% yield. Although the use of imidazole as
catalyst also afforded 11, the yield was relatively low. Ad-
duct 11 was then efficiently transformed into the corre-
sponding MBH acetate 16 through reaction with acetyl
chloride in the presence of pyridine in dichloromethane for
3 h at room temperature. Subsequently 16 was treated with
saturated methanolic ammonia at room temperature. The
reaction was complete in 10 min to give the required 2-
phenyl-6,7-dihydro-1H-indole-4(5H)-one (21a) as a solid
product in 89% yield. Encouraged by this result we per-
formed MBH reactions on 2-oxo-2-(substituted phenyl)-
acetaldehydes[19] 7–10 with cyclohex-2-enone in the pres-
ence of DMAP in aqueous medium affording the respective
adducts 12–15 in 58–63% yields. Treating compounds 12–
15 with acetyl chloride under the optimized conditions af-
forded acetates 17–20 in 85–96% yields, respectively. Reac-
tions of 17–20 with methanolic ammonia produced the de-
At this stage we proposed that the reaction sequence
could be accomplished in a one-pot protocol. In order to
investigate this possibility, 2-oxo-2-phenylacetaldehyde
monohydrate (6) was added to a solution of cyclohex-2-
enone and DMAP in dichloromethane and stirred at room
temperature for 2 d. Thereafter, triethylamine and acetic an-
hydride were added and the reaction mixture was stirred for
15 min. Further methanolic ammonia was added, and the
reaction was continued for a another 15 min before workup.
Interestingly, this protocol resulted in the isolation of 21a
in 27% yield. Based on this result, it was considered best to
isolate the MBH acetate before reaction with the primary
amine.
Having optimized the conditions with ammonia, we set
out to investigate the scope of this methodology for a vari-
ety of primary amines and MBH acetates. The results of
the study are summarized in Table 1. The reactions of am-
monia with MBH acetates 16–20 were complete in 10 min
(Table 1, Entries 1–5), whereas those with isopropylamine
(Table 1, Entries 6–10) or with N-(2-aminoethyl)morph-
oline took 30 min or 4 h, respectively, for completion
(Table 1, Entries 11–15). The reactions of amino acids were
also fast and complete within 30 min (Table 1, Entries 16–
17). Similarly, the reaction with phenyl hydrazine was com-
plete in 4 h to provide the product in 61% yield (Table 1,
Entry 25). Due to our interest in development of new anti-
malarials, three quinoline derivatives were also prepared in
good yields (Table 1, Entries 22–24).[20] In contrast to the
previous results obtained, the reactions of anilines and
hydrophobic amines were sluggish and the products were
isolated in moderate to low yields only (Table 1, Entries 21,
26 and 28). In addition, 2-nitroaniline failed to react to fur-
nish the expected product 21o (Table 1, Entry 27). 1,3-Prop-
anediamine gave mono- (21r) and di-indolone (21s) deriva-
tives in almost equal quantities (Table 1, Entry 30).
Amongst the MBH acetates, it was observed that the pres-
ence of an electron donating substitution on the aromatic
ring (from the α-ketobenzaldehyde) significantly enhances
the yields of the corresponding indolone derivatives
(Table 1, Entries 3, 8, 13).
The chloroformylation of such indolones is already re-
ported in the literature.[21] It was envisaged that the forma-
tion of the chloroformyl derivative of these indolones fol-
Scheme 1. Synthesis of substituted 6,7-dihydro-1H-indole-4(5H)-
ones.
Scheme 2. Synthesis of 6,7-dihydro-5H-pyrrolo[2,3-h]quinazolines.
2
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Synthesis of 2-(Substituted phenyl)-6,7-dihydro-1H-indol-4(5H)-ones
Table 1. Scope of the protocol with different primary amines.
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Table 1. (continued)
4
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Synthesis of 2-(Substituted phenyl)-6,7-dihydro-1H-indol-4(5H)-ones
Table 1. (continued)
[a] Isolated yield after column chromatography. [b] No column chromatography was required.
lowed by copper-mediated coupling reaction with amidines duced the expected 6,7-dihydro-5H-pyrrolo[2,3-h]quinazol-
would furnish new pyrroloquinazolines (Scheme 2). In a ines 29 and 30 in good yields.
representative study tetrahydroindolones 21b and 21h were
subjected to Vilsmeier Haack reactions in the presence of
DMF/POCl3 resulting in the isolation of chloroformyl de-
rivatives 27 and 28, respectively. Treating compounds 27
Conclusions
and 28 with acetamidine hydrochloride in the presence of
In summary, we have developed a new synthesis of tetra-
CuI, l-proline and Cs2CO3 at 90 °C in DMSO for 12 h pro- hydroindolones from MBH adducts in good yields. This
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solid (35 mg, 89%). M.p. 245–246 °C. Rf = 0.30 (hexanes/EtOAc,
protocol is attractive because it employs readily-available
starting materials and allows diverse functionality to be in-
stalled on the nitrogen atom of the indole.
3:2, v/v). IR (KBr): ν = 1630 (CO), 3441 (NH) cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 2.18–2.24 (m, 2 H, CH2), 2.52 (t, J =
6.3 Hz, 2 H, CH2), 2.88 (t, J = 6.1 Hz, 2 H, CH2), 6.82 (d, J =
1.5 Hz, 1 H, ArH), 7.26 (s, 1 H, ArH), 7.36–7.48 (m, 4 H, ArH),
8.65 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.0,
24.0, 38.0, 102.5, 121.9, 124.3, 127.2, 129.1, 131.9, 133.3, 145.1,
195.1 ppm. MS (ESI+): m/z = 212.2. HRMS: calcd. for C14H14NO
[M + H]+ 212.1075; found 212.1083.
Experimental Section
Melting points were determined in capillary tubes with a Precision
melting point apparatus containing silicon oil. IR spectra were re-
corded by using a Perkin–Elmer RX I FTIR spectrophotometer.
1H NMR and 13C NMR spectra were recorded with either a Bruker
DPX-200 or a Bruker Avance DRX-300 spectrometer with tet-
ramethylsilane as an internal standard. MS (ESI) were recorded
with a Thermo Finnigan LCQ Advantage, Ion Trap Mass spec-
trometer. HRMS spectra were recorded in the EI mode with an
Agilent 6520 Q-TOF, LC-MS–MS mass spectrometer.
1-Isopropyl-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (21b): 88%
as brown oil (45 mg from 55 mg). Rf = 0.32 (hexanes/EtOAc, 3:2,
v/v). IR (neat): ν = 1648 (CO) cm–1. 1H NMR (300 MHz, CDCl ):
˜
3
δ = 1.46 (d, J = 7.0 Hz, 6 H, 2 CH3), 2.20 (t, J = 6.1 Hz, 2 H,
CH2), 2.50 (t, J = 6.4 Hz, 2 H, CH2), 3.00 (t, J = 6.0 Hz, 2 H,
CH2), 4.44–4.53 (m, 1 H, CH), 6.49 (s, 1 H, ArH), 7.31–7.41 (m, 5
H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 22.4, 24.4, 24.6,
38.0, 48.5, 105.7, 121.5, 128.0, 128.6, 130.0, 133.3, 136.4, 143.5,
194.5 ppm. MS (ESI+): m/z = 254.1. HRMS: calcd. for C17H20NO
[M + H]+ 254.1545; found 254.1549.
General Procedure for the Preparation of 6–10 as Exemplified for 2-
Oxo-2-phenylacetaldehyde (6): Water (2.5 mL) was added to a
stirred solution of SeO2 (16.64 g, 150 mmol) in dioxane (40 mL)
and heated to reflux until the SeO2 dissolved. Compound 1 (10.0 g,
83.3 mmol) was added to the solution and the reaction was main-
tained at reflux temperatures. After the reaction was complete, as
monitored by TLC, the mixture was filtered through a filter paper
and then filtered through a pad of Celite. The filtrate was evapo-
rated to afford a crude product that was purified by distillation
under reduced pressure. The fraction separated at 95–97 °C/25 Torr
yielded the product as a yellow liquid. This liquid was dissolved in
hot water (40 mL) and allowed to crystallize to afford 6 as a white
solid (10.39 g, 82%).
1-(2-Morpholin-4-ylethyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-
one (21c): 73% as a brown solid (217 mg from 250 mg). M.p. 93–
95 °C. R = 0.26 (CHCl /MeOH, 9:1, v/v). IR (KBr): ν = 1642
˜
f
3
(CO) cm–1. H NMR (300 MHz, CDCl3): δ = 2.20–2.26 (m, 6 H,
3ϫ CH2), 2.41 (t, J = 7.0 Hz, 2 H, CH2), 2.52 (t, J = 6.4 Hz, 2 H,
CH2), 2.86 (t, J = 5.8 Hz, 2 H, CH2), 3.58 (t, J = 4.2 Hz, 4 H, 2ϫ
CH2), 4.00 (t, J = 7.0 Hz, 2 H, CH2), 6.55 (s, 1 H, ArH), 7.39–7.42
(m, 5 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 22.6, 23.9,
38.0, 42.1, 53.9, 58.5, 66.8, 105.9, 120.7, 128.1, 128.7, 129.5, 132.5,
136.0, 144.8, 194.5 ppm. MS (ESI+): m/z = 325.2. HRMS: calcd.
for C20H25N2O2 [M + H]+ 325.1916; found 325.1920.
1
General Procedure for the Preparation of 11–15 with Cyclohex-2-
enone as Exemplified for 11: 4-Dimethylaminopyridine (36 mg,
0.30 mmol) was added to a stirred solution of cyclohex-2-enone
(87 mg, 0.905 mmol) in THF/water (2 mL, 1:1, v/v) at room tem-
perature and stirred for 20 min. Compound 6 (100 mg, 0.66 mmol)
was added to the mixture and the reaction was stirred for 12 h. The
reaction mixture was diluted with water (5 mL) and extracted with
EtOAc (3ϫ5 mL). The combined organic layers were washed with
brine (6 mL), dried with anhydrous Na2SO4 and concentrated un-
der reduced pressure to afford the crude product. Purification of
the crude material by column chromatography (EtOAc/hexanes,
20:80, v/v) gave pure product 11 as brown oil (88 mg, 58%).
Methyl 2-(4-Oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)acetate
(21d): 80% as an off-white solid (166 mg from 200 mg). M.p. 103–
105 °C. R = 0.26 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1647
˜
f
(CO) cm–1. H NMR (300 MHz, CDCl3): δ = 2.20–2.26 (m, 2 H,
1
CH2), 2.53 (t, J = 6.2 Hz, 2 H, CH2), 2.72 (t, J = 5.9 Hz, 2 H,
CH2), 3.79 (s, 3 H, CH3), 4.58 (s, 2 H, CH2), 6.60 (s, 1 H, ArH),
7.26 (s, 1 H, ArH), 7.30 (d, J = 1.7 Hz, 1 H, ArH), 7.37–7.41 (m,
3 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.2, 23.7, 37.9,
46.2, 53.0, 105.7, 121.2, 128.4, 128.9, 129.4, 131.8, 136.5, 145.3,
168.8, 194.3 ppm. MS (ESI+): m/z = 284.2. HRMS: calcd. for
C17H18NO3 [M + H]+ 284.1287; found 284.1280.
General Procedure for the Preparation of 16–20 as Exemplified for
16: Pyridine (1.5 mL, 18.42 mmol) was added to a stirred solution
of 11 (1.82 g, 7.91 mmol) in dichloromethane (30 mL) at 0 °C and
stirred for 10 min. Acetyl chloride (1.4 mL, 19.74 mmol) was added
and the reaction mixture was stirred at room temperature for 3 h.
After completion of the reaction, as monitored by TLC, water
(25 mL) was added and the reaction was extracted with dichloro-
methane (3ϫ25 mL). The combined organic layers were washed
with brine (25 mL), dried with anhydrous Na2SO4 and concen-
trated under reduced pressure to afford the crude product. Purifica-
tion of the crude material by column chromatography (EtOAc/hex-
anes, 10:90, v/v) gave pure product 16 as an off-white solid (1.83 g,
85%).
1-[2-(1H-Indol-3-yl)ethyl]-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-
one (21e): 74% as an off-white solid (192 mg from 200 mg). M.p.
197–198 °C. R = 0.15 (CHCl /MeOH, 9:1, v/v). IR (KBr): ν =
˜
f
3
1
1633 (CO). H NMR (300 MHz, CDCl3): δ = 2.46 (s, 6 H, CH2),
2.86 (t, J = 6.9 Hz, 2 H, CH2), 4.17 (t, J = 7.0 Hz, 2 H, CH2), 6.62
(s, 1 H, ArH), 6.69 (s, 1 H, ArH), 7.00–7.06 (m, 1 H, ArH), 7.11–
7.19 (m, 2 H, ArH), 7.34 (d, J = 8.2 Hz, 1 H, ArH), 7.41 (d, J =
2.7 Hz, 5 H, ArH), 8.11 (s, 1 H, NH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 22.4, 23.7, 26.7, 37.9, 45.5, 106.1, 111.5, 118.2, 119.6,
120.3, 122.2, 122.5, 127.1, 128.1, 128.8, 129.5, 132.8, 135.9, 136.3,
145.5, 194.8 ppm. MS (ESI+): m/z = 355.1. HRMS: calcd. for
C24H23N2O [M + H]+ 355.1810; found 355.1804.
1-Allyl-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (21f): 71% as a
white solid (164 mg from 250 mg). M.p. 167–169 °C. Rf = 0.28
General Procedure for the Preparation of 21a–s and 22–25a–c as
Exemplified for 2-Phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (21a):
Methanolic ammonia (1 mL) was added to a stirred solution of 16
(50 mg, 0.18 mmol) in methanol (10 mL) and allowed to stir at
room temperature for 10 min. After completion of reaction, as
monitored by TLC, the solvent was evaporated under reduced pres-
sure to afford the crude product that was purified by triturating
with an EtOAc/hexanes mixture to give pure product 16a as a white
(hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1650 (CO) cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 2.19–2.20 (m, 2 H, CH2), 2.52 (t, J
= 5.8 Hz, 2 H, CH2), 2.77 (t, J = 5.6 Hz, 2 H, CH2), 4.48 (d, J =
1.7 Hz, 2 H, CH2), 4.89 (d, J = 17.0 Hz, 1 H, CH), 5.24 (d, J =
10.4 Hz, 1 H, CHH), 5.85–5.97 (m, 1 H, CHH), 6.61 (s, 1 H, ArH),
7.38 (s, 5 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 22.2,
23.9, 38.0, 46.9, 105.3, 116.8, 120.7, 128.0, 128.7, 129.1, 132.2,
6
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Synthesis of 2-(Substituted phenyl)-6,7-dihydro-1H-indol-4(5H)-ones
133.5, 136.3, 145.1, 194.4 ppm. MS (ESI+): m/z = 252.1. HRMS:
= 430.3. HRMS: calcd. for C26H25ClN3O [M + H]+ 430.1686;
found 430.1685.
calcd. for C17H18NO [M + H]+ 252.1388; found 252.1383.
Methyl 2-[(4-Oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)(phen-
1-[4-(7-Chloroquinolin-4-ylamino)butyl]-2-phenyl-6,7-dihydro-1H-
yl)methyl]acrylate (21g): 52% as a brown oil (147 mg from 200 mg). indol-4(5H)-one (21l): 75% as a brown solid (366 mg from 300 mg).
1
R = 0.27 (hexanes/EtOAc, 3:2, v/v). IR (neat): ν = 1653 (CO). H
R = 0.48 (CHCl /MeOH, 9:1, v/v). M.p. 73–75 °C. IR (KBr): ν =
˜
f 3
˜
f
NMR (300 MHz, CDCl3): δ = 1.98–2.04 (m, 2 H, CH2), 2.14–2.16 1639 (CO), 3241 (NH) cm–1. H NMR (300 MHz, [D6]DMSO): δ
1
(m, 2 H, CH2), 2.39–2.43 (m, 2 H, CH2), 3.66 (s, 3 H, OCH3), 6.50
(s, 1 H, ArH), 6.57 (d, J = 1.2 Hz, 1 H, ArH), 6.63 (s, 1 H, ArH),
= 1.47–1.49 (m, 2 H, CH2), 1.56–1.58 (m, 2 H, CH2), 2.03–2.07
(m, 2 H, CH2), 2.31–2.36 (m, 2 H, CH2), 2.82–2.86 (m, 2 H, CH2),
7.02–7.04 (m, 2 H, ArH) 7.27 (d, J = 5.0 Hz, 1 H, ArH), 7.32–7.33 3.12 (d, J = 5.1 Hz, 2 H, CH2), 3.95–3.99 (m, 2 H, CH2), 6.31 (s,
(m, 1 H, ArH) 7.34–7.36 (m, 7 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 24.4, 25.1, 37.8, 52.5, 60.0, 106.1, 124.3, 127.7, 128.2,
1 H, CH2), 6.36 (d, J = 5.5 Hz, 1 H, ArH), 7.28–7.34 (m, 5 H,
ArH), 7.43–7.47 (m, 1 H, ArH), 7.78 (d, J = 1.8 Hz, 1 H, ArH),
128.4, 128.6, 128.8, 128.9, 129.1, 129.7, 137.4, 139.6, 145.1, 8.21 (d, J = 9.0 Hz, 1 H, ArH), 8.37 (d, J = 4.6 Hz, 1 H, ArH) ppm.
194.9 ppm. MS (ESI+): m/z = 386.1. HRMS: calcd. for C25H24NO3
13C NMR (50 MHz, [D6]DMSO): δ = 21.7, 23.4, 24.5, 27.4, 37.6,
41.7, 43.7, 98.7, 104.8, 117.1, 119.7, 124.3, 124.5, 126.2, 127.7,
128.6, 128.7, 132.3, 134.1, 135.1, 144.9, 150.4, 150.8, 192.7 ppm.
MS (ESI+): m/z = 444.2. HRMS: calcd. for C27H27ClN3O [M +
H]+ 444.1843; found 444.1849.
[M + H]+ 386.1756; found 386.1750.
1-Benzyl-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (21h): 90% as
an off-white solid (996 mg from 1.00 g). M.p. 104–106 °C. Rf =
0.31 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1650 (CO), 3441
˜
1
(NH) cm–1. H NMR (300 MHz, CDCl3): δ = 2.11–2.15 (m, 2 H,
1-Anilino-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (21m): 61% as
dark brown oil (20 mg from 30 mg). Rf = 0.30 (hexanes/EtOAc,
CH2), 2.51 (t, J = 6.2 Hz, 2 H, CH2), 2.62 (t, J = 5.8 Hz, 2 H,
CH2), 5.13 (s, 2 H, CH2), 6.68 (s, 1 H, ArH), 6.93 (d, J = 6.7 Hz, 3:2, v/v). IR (neat): ν = 1642 (CO), 3453 (NH) cm–1. 1H NMR
˜
2 H, ArH), 7.26 (s, 1 H, ArH), 7.27–7.34 (m, 7 H, ArH) ppm. 13C (300 MHz, CDCl3): δ = 2.08–2.16 (m, 2 H, CH2), 2.50–2.54 (m, J
NMR (50 MHz, CDCl3): δ = 22.5, 23.8, 38.0, 48.1, 105.6, 121.0,
125.7, 127.7, 128.0, 128.7, 129.1, 136.8, 137.3, 145.2, 194.5 ppm.
MS (ESI+): m/z = 302.1. HRMS: calcd. for C21H20NO [M + H]+
302.1545; found 302.1439.
= 6.0 Hz, 2 H, CH2), 2.70 (t, J = 6.1 Hz, 2 H, CH2), 6.50 (d, J =
7.7 Hz, 2 H, ArH), 6.62 (s, 1 H, NH), 6.73 (s, 1 H, ArH), 6.92 (t,
J = 7.3 Hz, 1 H, ArH), 7.20–7.30 (m, 5 H, ArH), 7.36–7.40 (m, 2
H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5, 23.6, 29.9,
38.2, 103.7, 112.6, 118.8, 121.6, 127.9, 128.2, 128.6, 129.8, 130.8,
136.0, 146.2, 146.8, 194.4 ppm. MS (ESI+): m/z = 303.1. HRMS:
calcd. for C20H19N2O [M + H]+ 303.1497; found 303.1492.
1-Adamantyl-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (21i): 48%
as a white solid (122 mg from 200 mg). M.p. 217–219 °C. Rf = 0.32
(hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1651 (CO), 3410
˜
(NH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.60 (s, 6 H, 3ϫ 1,2-Diphenyl-1,5,6,7-tetrahydro-4H-indol-4-one (21n): 35 % as a
CH2), 2.05 (s, 3 H, 3ϫ CH), 2.13–2.18 (m, 8 H, CH2), 2.48 (t, J =
white solid (74 mg from 200 mg). M.p. 232–234 °C. Rf = 0.27 (hex-
6.1 Hz, 2 H, CH2), 3.21 (t, J = 5.8 Hz, 2 H, CH2), 6.33 (s, 1 H, anes/EtOAc, 3:2, v/v). IR (KBr): ν = 1652 (CO). 1H NMR
˜
ArH), 7.30 (s, 5 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = (300 MHz, CDCl3): δ = 2.14 (s, 2 H, CH2), 2.54–2.55 (m, 2 H,
25.3, 29.2, 30.3, 35.9, 37.8, 43.8, 62.5, 109.6, 121.7, 127.5, 127.6,
130.6, 136.8, 138.5, 144.9, 194.8 ppm. MS (ESI+): m/z = 346.3.
HRMS: calcd. for C24H28NO [M + H]+ 346.2171; found 346.2168.
CH2), 2.67 (t, J = 5.5 Hz, 2 H, CH2), 6.80 (s, 1 H, ArH), 7.05–
7.08 (m, 2 H, ArH) 7.16–7.17 (m, 5 H, ArH), 7.39–7.40 (m, 3 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.2, 23.9, 38.2,
105.9, 121.2, 127.1, 127.8, 128.3, 128.3, 128.4, 129.4, 131.9, 136.3,
137.7, 146.1, 194.8 ppm. MS (ESI+): m/z = 288.2. HRMS: calcd.
for C20H18NO [M + H]+ 288.1388; found 288.1382.
1-[2-(7-Chloroquinolin-4-ylamino)ethyl]-2-phenyl-6,7-dihydro-1H-
indol-4(5H)-one (21j): 75 % as an off-white solid (343 mg from
300 mg). M.p. 52–54 °C. Rf = 0.40 (CHCl3/MeOH, 9:1, v/v). IR
(KBr): ν = 1636 (CO), 3247 (NH) cm–1. 1H NMR (300 MHz, [D ]-
1-(2,3-Dimethylphenyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one
(21p): 22 % as a brown solid (51 mg from 200 mg). M.p. 132–
˜
6
DMSO): δ = 1.94–1.99 (m, 2 H, CH2), 2.28–2.31 (m, 2 H, CH2),
2.49 (s, 2 H, CH2), 2.82 (t, J = 5.5 Hz, 2 H, CH2), 4.17–4.19 (m, 2
H, CH2), 5.92 (d, J = 5.3 Hz, 1 H, ArH), 6.32 (s, 1 H, CH2), 7.35–
134 °C. R = 0.37 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1651
˜
f
(CO) cm–1. H NMR (300 MHz, CDCl3): δ = 1.76 (s, 3 H, CH3),
1
7.36 (m, 5 H, ArH), 7.43–7.47 (m, 1 H, ArH), 7.76 (d, J = 2.1 Hz, 2.07–2.15 (m, 2 H, CH2), 2.26 (s, 3 H, CH3), 2.32–2.41 (m, 2 H,
1 H, ArH), 8.05 (d, J = 9.2 Hz, 1 H, ArH), 8.19 (d, J = 5.3 Hz, 1
H, ArH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 21.1, 21.6,
23.3, 37.6, 42.2, 98.1, 105.0, 119.9, 123.8, 124.3, 127.3, 127.8, 128.5,
CH2), 2.52–2.59 (m, 2 H, CH2), 6.83 (s, 1 H, ArH), 7.06–7.23 (m,
8 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 20.4, 22.7,
24.0, 38.2, 105.2, 121.0, 126.3, 127.1, 127.7, 128.3, 128.8, 128.9,
129.3, 131.9, 132.8, 133.6, 135.2, 145.0, 148.7, 149.5, 151.4, 130.6, 132.2, 133.9, 134.9, 136.7, 138.8, 152.5, 194.8 ppm. MS
192.6 ppm. MS (ESI+): m/z = 416.2. HRMS: calcd. for (ESI+): m/z = 316.2 [M + H]+. HRMS: calcd. for C22H22NO [M
C25H23ClN3O [M + H]+ 416.1530; found 416.1536.
+ H]+ 316.1701; found 316.1705.
1-[3-(7-Chloroquinolin-4-ylamino)propyl]-2-phenyl-6,7-dihydro-1H-
indol-4(5H)-one (21k): 76% as a brown solid (359 mg from 300 mg).
Phenyl tert-Butyl 4-(4-Oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-
yl)butylcarbamate (21q): 88% as a brown oil (308 mg from 250 m
M.p. 62–64 °C. R = 0. 42 (CHCl /MeOH, 9:1, v/v). IR (KBr): ν = g). R = 0.28 (hexanes/EtOAc, 3:2, v/v). IR (neat): ν = 1643 (CO),
˜
˜
f
3
f
1639 (CO), 3242 (NH) cm–1. H NMR (300 MHz, [D6]DMSO): δ
= 1.84–1.89 (m, 2 H, CH2), 1.99–2.04 (m, 2 H, CH2), 2.31–2.35 2 H, CH2), 1.42 (s, 9 H, 3 CH3), 1.48–1.56 (m, 2 H, CH2), 2.18–
(m, 2 H, CH2), 2.50 (t, J = 1.7 Hz, 2 H, CH2), 2.85 (t, J = 5.5 Hz, 2.24 (m, 2 H, CH2), 2.49–2.53 (m, 2 H, CH2), 2.81 (t, J = 6.1 Hz,
3378 (NH) cm–1. H NMR (300 MHz, CDCl3): δ = 1.26–1.35 (m,
1
1
2 H, CH2), 4.08–4.13 (m, 2 H, CH2), 6.26 (d, J = 5.3 Hz, 1 H, 2 H, CH2), 2.97 (d, J = 5.9 Hz, 2 H, CH2), 3.90 (t, J = 7.6 Hz, 2
ArH), 6.33 (s, 1 H, CH2), 7.20–7.23 (m, 3 H, ArH), 7.33–7.36 (m, H, CH2), 4.36 (s, 1 H, NH), 6.54 (s, 1 H, ArH), 7.35–7.42 (m, 5 H,
2 H, ArH), 7.42–7.45 (m, 1 H, ArH), 7.78–7.82 (m, 1 H, ArH), ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.6, 23.9, 27.2, 27.8,
8.12 (d, J = 9.0 Hz, 1 H, ArH), 8.32–8.36 (m, 1 H, ArH) ppm. 13C 28.5, 38.0, 39.8, 44.1, 66.1, 79.4, 105.8, 120.6, 128.0, 128.8, 129.3,
NMR (75 MHz, [D6]DMSO): δ = 21.7, 23.4, 28.5, 31.6, 37.6, 41.9,
98.7, 105.0, 119.8, 124.2, 124.4, 126.7, 127.6, 128.5, 128.6, 129.3,
132.1, 133.9, 135.2, 145.2, 150.4, 151.1, 192.9 ppm. MS (ESI+): m/z
132.7, 135.9, 144.5, 156.1, 194.4 ppm. MS (ESI+): m/z = 383.2.
HRMS: calcd. for C23H31N2O3 [M + H]+ 383.2335; found
383.2340.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20107
/KAP1
Date: 17-04-12 15:20:07
Pages: 11
B. Harikrishna, S. Batra
FULL PAPER
1-(3-Aminopropyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one
J = 8.7 Hz, 2 H, ArH), 7.40 (d, J = 8.7 Hz, 2 H, ArH), 8.62 (s, 1
(21r): 20% as brown oil (48 mg from 250 mg). Rf = 0.24 (CHCl3/ H, NH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 22.2, 23.6,
MeOH, 9:1, v/v). IR (neat): ν = 1631 (CO), 3434 (NH) cm–1. 1H 37.7, 55.1, 100.2, 114.3, 120.7, 124.7, 125.2, 132.3, 144.7, 158.1,
˜
NMR (300 MHz, CDCl3): δ = 2.19–2.25 (m, 2 H, CH2), 2.50–2.53 192.8 ppm. MS (ESI+): m/z = 242.2. HRMS: calcd. for C15H16NO2
(m, 4 H, 2ϫ CH2), 2.83–2.88 (m, 3 H, 2 H of one CH2 and 1 H
of other CH2), 2.96 (s, 1 H, 1 H of other CH2), 3.98–4.02 (m, 2 H,
CH2), 6.55 (s, 1 H, ArH), 7.38–7.42 (m, 5 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.6, 24.0, 34.2, 38.0, 39.0, 42.3, 76.8, 105.8,
120.7, 128.1, 128.8, 129.4, 132.7, 136.0, 194.4 ppm. MS (ESI+): m/z
= 269.2. HRMS: calcd. for C17H20N2O[M + H]+ 269.1654; found
269.1650.
[M + H]+ 242.1181; found 242.1176.
1-Isopropyl-2-(4-methoxyphenyl)-1,5,6,7-tetrahydro-4H-indol-4-one
(23b): 86 % as a brown solid (161 mg from 200 mg). M.p. 103–
108 °C. R = 0.32 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1645
˜
f
1
(CO) cm–1. H NMR (300 MHz, CDCl3): δ = 1.44 (d, J = 6.6 Hz,
6 H, 2 CH3), 2.20 (s, 2 H, CH2), 2.52 (s, 2 H, CH2), 2.99 (s, J =
6.0 Hz, 2 H, CH2), 3.85 (s, 3 H, CH3), 4.43–4.54 (m, 1 H, CH),
6.45 (s, 1 H, ArH), 6.94 (d, J = 7.8 Hz, 2 H, ArH), 7.22–7.26 (m,
2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.4, 24.4, 24.5,
37.9, 48.3, 55.4, 105.3, 114.0, 121.3, 125.6, 131.3, 136.1, 143.1,
159.5, 194.4 ppm. MS (ESI+): m/z = 284.2. HRMS: calcd. for
C18H22NO2 [M + H]+ 284.1651; found 284.1648.
1,1Ј-(Propane-1,3-diyl)bis[2-phenyl-6,7-dihydro-1H-indol-4(5H)-one]
(21s): 19% as brown oil (39 mg from 250 mg). Rf = 0.84 (CHCl3/
1
MeOH, 9:1, v/v). IR (neat): ν = 1647 (CO). H NMR (300 MHz,
˜
CDCl3): δ = 1.41 (s, 2 H, CH2), 2.12 (s, 4 H, CH2), 2.47 (s, 4 H,
2ϫ CH2), 2.54 (s, 4 H, 2ϫ CH2), 3.71 (s, 4 H, 2ϫ CH2), 6.55 (s,
2 H, ArH), 7.20 (s, 3 H, ArH), 7.37 (s, 7 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.3, 22.3, 22.8, 23.8, 29.1, 29.3, 29.5, 29.7,
29.8, 31.5, 31.8, 32.1, 34.0, 37.9, 41.4, 76.8, 106.2, 114.2, 121.0,
128.2, 129.0, 129.1, 132.2, 135.6, 139.4, 144.0, 194.2 ppm. MS
(ESI+): m/z = 463.2. HRMS: calcd. for C31H31N2O2 [M + H]+
463.2386; found 463.2380.
2-(4-Methoxyphenyl)-1-(2-morpholinoethyl)-6,7-dihydro-1H-indol-
4(5H)-one (23c): 90% as brown oil (53 mg from 50 mg). Rf = 0.28
(CHCl /MeOH, 9:1, v/v). IR (neat): ν = 1647 (CO) cm–1. 1H NMR
˜
3
(300 MHz, CDCl3): δ = 2.18–2.24 (m, 4 H, 2ϫ CH2), 2.33 (s, 2 H,
CH2), 2.49–2.53 (m, 4 H, 2ϫ CH2), 2.90 (s, 2 H, CH2), 3.66 (s, 4
H, 2ϫ CH2), 3.85 (s, 5 H, CH3 and CH2), 6.50 (s, 1 H, ArH), 6.96
(d, J = 8.4 Hz, 2 H, ArH), 7.29 (d, J = 8.7 Hz, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 22.7, 23.9, 29.8, 38.0, 53.8, 55.5,
66.6, 105.7, 114.2, 120.7, 124.8, 130.9, 144.4, 159.7, 194.3 ppm. MS
(ESI+): m/z = 355.2. HRMS: calcd. for C21H27N2O3 [M + H]+
355.1810; found 355.1804.
2-(4-Bromophenyl)-1,5,6,7-tetrahydro-4H-indol-4-one (22a): 74% as
a brown solid (55 mg from 90 mg). M.p. Ͼ250 °C. Rf = 0.28 (hex-
anes/EtOAc, 3:2, v/v). IR (KBr): ν = 1638 (CO), 3259 (NH) cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 2.19 (t, J = 6.2 Hz, 2 H, CH2),
2.49–2.53 (m, 2 H, CH2), 2.87 (t, J = 6.1 Hz, 2 H, CH2), 6.81 (d,
J = 2.0 Hz, 1 H, ArH), 7.33 (d, J = 8.5 Hz, 2 H, ArH), 7.50 (d, J
= 8.4 Hz, 2 H, ArH), 8.68 (s, 1 H, NH) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ = 22.2, 23.4, 37.4, 101.7, 119.3, 120.7, 125.2, 130.7,
131.2, 131.4, 145.2, 193.8 ppm. MS (ESI+): m/z = 290.1. HRMS:
calcd. for C14H13BrNO [M + H]+ 290.0181; found 290.0185.
2-(4-Methylphenyl)-1,5,6,7-tetrahydro-4H-indol-4-one (24a): 76% as
a white solid (120 mg from 200 mg). M.p. Ͼ250 °C. Rf = 0.29 (hex-
anes/EtOAc, 3:2, v/v). IR (KBr): ν = 1631 (CO), 3257 (NH) cm–1.
˜
1H NMR (300 MHz, [D6]DMSO): δ = 2.01–2.05 (m, 2 H, CH2),
2.30 (s, 3 H, CH3), 2.31 (s, 2 H, CH2), 2.80 (t, J = 5.7 Hz, 2 H,
CH2), 6.6 (d, J = 1.7 Hz, 1 H, ArH), 7.17 (d, J = 7.8 Hz, 2 H,
ArH), 7.53 (d, J = 7.9 Hz, 2 H, ArH), 11.7 (s, 1 H, NH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 20.7, 22.2, 23.6, 37.7, 65.4, 100.9,
120.7, 123.8, 129.2, 129.4, 132.3, 135.7, 144.9, 192.8 ppm. MS
(ESI+): m/z = 226.1. HRMS: calcd. for C15H16NO [M + H]+
226.1232; found 226.1226.
2-(4-Bromophenyl)-1-isopropyl-1,5,6,7-tetrahydro-4H-indol-4-one
(22b): 85% as brown oil (48 mg from 60 mg). Rf = 0.32 (hexanes/
EtOAc, 3:2, v/v). IR (neat): ν = 1630 (CO) cm–1 1H NMR
.
˜
(300 MHz, CDCl3): δ = 1.45 (d, J = 7.1 Hz, 6 H, 2 CH3), 2.17–
2.24 (m, 2 H, CH2), 2.48–2.52 (m, 2 H, CH2), 2.99 (t, J = 6.2 Hz,
2 H, CH2), 4.39–4.50 (m, 1 H, CH), 6.49 (s, 1 H, ArH), 7.18 (d, J
= 8.3 Hz, 2 H, ArH), 7.54 (d, J = 8.3 Hz, 2 H, ArH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 22.4, 24.3, 24.5, 37.7, 48.6, 106.3,
116.0, 121.5, 122.4, 131.5, 131.8, 132.1, 132.8, 133.0, 135.2, 144.1,
195.0 ppm. MS (ESI+): m/z = 332.1. HRMS: calcd. for
C17H19BrNO [M + H]+ 332.0650; found 332.0647.
1-Isopropyl-2-(4-methylphenyl)-1,5,6,7-tetrahydro-4H-indol-4-one
(24b): 73% as a white solid (170 mg from 250 mg). Rf = 0.32 (hex-
anes/EtOAc, 3:2, v/v). IR (KBr): ν = 1657 (CO) cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 1.45 (d, J = 7.1 Hz, 6 H, 2 CH3), 2.17–
2.21 (m, 2 H, CH2), 2.40 (s, 3 H, CH3), 2.51 (t, J = 6.4 Hz, 2 H,
CH2), 3.00 (t, J = 6.1 Hz, 2 H, CH2), 4.46–4.50 (m, 1 H, CH), 6.46
(s, 1 H, ArH), 7.21 (s, 4 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.4, 22.4, 24.4, 24.6, 38.0, 48.4, 105.5, 121.5, 129.3,
130.0, 130.4, 136.4, 138.0, 143.2, 194.4 ppm. MS (ESI+): m/z =
268.1. HRMS: calcd. for C18H22NO [M + H]+ 268.1701; found
268.17011.
2-(4-Bromophenyl)-1-(2-morpholin-4-ylethyl)-1,5,6,7-tetrahydro-4H-
indol-4-one (22c): 73% as a white solid (104 mg from 124 mg). M.p.
125–128 °C. R = 0.26 (CHCl /MeOH, 9:1, v/v). IR (KBr): ν =
˜
f
3
1
1628 (CO) cm–1. H NMR (300 MHz, CDCl3): δ = 2.19–2.22 (m,
2 H, CH2), 2.29 (t, J = 4.5 Hz, 4 H, 2ϫ CH2), 2.42 (t, J = 6.9 Hz,
2 H, CH2), 2.49–2.54 (m, 2 H, CH2), 2.86 (t, J = 6.1 Hz, 2 H,
CH2), 3.58–3.61 (m, 4 H, 2ϫ CH2), 3.99 (t, J = 7.0 Hz, 2 H, CH2),
6.55 (s, 1 H, ArH), 7.26 (d, J = 8.3 Hz, 2 H, ArH), 7.55 (d, J =
8.4 Hz, 2 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 21.6,
22.6, 23.8, 24.9, 37.9, 42.3, 50.0, 54.0, 58.5, 66.8, 106.3, 120.8,
130.9, 131.5, 132.0, 134.7, 145.2, 194.4 ppm. MS (ESI+): m/z =
403.1. HRMS: calcd. for C20H24BrN2O2 [M + H]+ 403.1021; found
403.1018.
1-(2-Morpholinoethyl)-2-p-tolyl-6,7-dihydro-1H-indol-4(5H)-one
(24c): 70% as an off-white solid (207 mg from 250 mg). M.p. 122–
124 °C. R = 0.28 (CHCl /MeOH, 9:1, v/v). IR (KBr): ν = 1643
˜
f
3
1
(CO) cm–1. H NMR (300 MHz, CDCl3): δ = 2.47–2.51 (m, 2 H,
CH2), 2.55 (s, 4 H, 2ϫ CH2), 2.68 (s, 3 H, CH3), 2.71–2.74 (m, 2
H, CH2), 2.77–2.82 (m, 2 H, CH2), 3.14 (t, J = 6.1 Hz, 2 H, CH2),
3.89 (s, 4 H, 2ϫ CH2), 4.29 (s, 2 H, CH2), 6.80 (s, 1 H, ArH), 7.51–
7.54 (m, 4 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4,
22.6, 23.9, 30.4, 34.3, 38.0, 42.2, 53.9, 58.6, 66.9, 105.6, 120.6,
125.6, 129.4, 135.9, 136.0, 138.0, 144.6, 194.3 ppm. MS (ESI+): m/z
= 339.2. HRMS: calcd. for C21H27N2O2 339.2073; found 339.2078.
2-(4-Methoxyphenyl)-1,5,6,7-tetrahydro-4H-indol-4-one (23a): 92%
as a brown solid (44 mg from 60 mg). M.p. 247–248 °C. Rf = 0.28
(hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1634 (CO), 3257
˜
1
(NH) cm–1. H NMR (300 MHz, CDCl3): δ = 2.16–2.22 (m, 2 H,
CH2), 2.50 (t, J = 6.3 Hz, 2 H, CH2), 2.86 (t, J = 6.0 Hz, 2 H,
CH2), 3.82 (s, 3 H, CH3), 6.68 (d, J = 2.2 Hz, 1 H, ArH), 6.92 (d,
2-(2,4-Dimethylphenyl)-1,5,6,7-tetrahydro-4H-indol-4-one (25a):
93% as an off white solid (148 mg from 200 mg). M.p. 242–244 °C.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20107
/KAP1
Date: 17-04-12 15:20:07
Pages: 11
Synthesis of 2-(Substituted phenyl)-6,7-dihydro-1H-indol-4(5H)-ones
R = 0.29 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1629 (CO),
HRMS: calcd. for C22H19ClNO [M + H]+ 348.1155; found
˜
f
3414 (NH) cm–1. H NMR (300 MHz, CDCl3): δ = 2.16–2.24 (m, 348.1160.
1
2 H, CH2), 2.34 (s, 3 H, CH3), 2.40 (s, 3 H, CH3), 2.52 (t, J =
General Procedure for the Preparation of Compounds 29–30 as Ex-
6.3 Hz, 2 H, CH2), 2.87 (t, J = 6.1 Hz, 2 H, CH2), 6.59 (d, J =
2.4 Hz, 1 H, ArH), 7.03–7.09 (m, 2 H, ArH), 7.20 (d, J = 7.7 Hz,
1 H, ArH), 8.31 (s, 1 H, NH) ppm. 13C NMR (50 MHz, CDCl3/
[D6]DMSO): δ = 20.4, 20.6, 22.0, 23.4, 37.4, 69.4, 70.0, 103.8,
120.0, 125.9, 127.7, 128.7, 131.0, 131.5, 134.6, 136.0, 144.0,
193.8 ppm. MS (ESI+): m/z = 240.2. HRMS: calcd. for C16H18NO
[M + H]+ 240.1338; found 240.1442.
emplified for 7-Isopropyl-2-methyl-8-phenyl-6,7-dihydro-5H-pyr-
rolo[2,3-h]quinazoline (29): Acetamidine hydrochloride (76 mg,
0.80 mmol) and Cs2CO3 (436 mg, 1.34 mmol) were added to a
stirred solution of 27 (200 mg, 0.67 mmol) in DMSO (5 mL), and
the mixture was purged with nitrogen for 10 min. CuI (13 mg,
0.068 mmol) and l-proline (15 mg, 0.13 mmol) were then added
and the reaction was stirred at 90 °C for 12 h under a nitrogen
atmosphere. After completion of the reaction, water (15 mL) was
added to the reaction mixture and extracted with EtOAc
(3ϫ10 mL). The combined organic layers were washed with brine
(10 mL), dried with anhydrous Na2SO4 and concentrated under re-
duced pressure to afford the crude product. Purification of the
crude material by column chromatography (EtOAc/hexanes, 20:80,
v/v) furnished the pure 29 (154 mg, 76%) as an off-white solid.
M.p. 72–74 °C. Rf = 0.27 (hexanes/EtOAc, 3:2, v/v). 1H NMR
(300 MHz, CDCl3): δ = 1.48 (d, J = 7.0 Hz, 6 H, CH3), 2.66 (s, 3
H, CH3), 2.94–3.00 (m, 2 H, CH2), 3.05–3.09 (m, 2 H, CH2), 4.48–
4.58 (m,1 H, CH), 6.70 (s, 1 H, ArH), 7.37–7.42 (m, 5 H, ArH)
8.24 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.6,
23.0, 25.4, 26.1, 48.2, 104.9, 119.2, 121.2, 127.6, 128.5, 129.7, 133.7,
136.2, 136.7, 153.1, 159.2, 166.6 ppm. MS (ESI+): m/z = 304.2.
2-(2,4-Dimethylphenyl)-1-isopropyl-1,5,6,7-tetrahydro-4H-indol-4-
one (25b): 91% as a brown solid (170 mg from 200 mg). M.p. 178–
179 °C. R = 0.29 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1651
˜
f
(CO) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.33–1.43 (m, 6 H, 2
CH3), 2.13 (s, 3 H, CH3), 2.21 (s, 2 H, CH2), 2.36 (s, 3 H, CH3),
2.52 (s, 2 H, CH2), 2.98 (s, 2 H, CH2), 4.07–4.08 (m, 1 H, CH2),
6.37 (s, 1 H, ArH), 7.01–7.09 (m, 3 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.3, 21.3, 22.3, 24.4, 24.5, 29.8, 37.9, 48.4,
105.5, 121.4, 126.4, 130.0, 130.9, 131.6, 134.7, 138.5, 138.6, 142.5,
194.5 ppm. MS (ESI+): m/z = 282.2. HRMS: calcd. for C19H24NO
[M + H]+ 282.1858; found 282.1864.
2-(2,4-Dimethylphenyl)-1-(2-morpholinoethyl)-6,7-dihydro-1H-indol-
4(5H)-one (25c): 92% as brown oil (216 mg from 200 mg). Rf =
0.28 (CHCl /MeOH, 9:1, v/v). IR (neat): ν = 1648 (CO) cm–1. H HRMS: calcd. for C20H22N3 [M + H]+ 304.1814; found 304.1819.
1
˜
3
NMR (300 MHz, CDCl3): δ = 2.14 (s, 3 H, CH3), 2.19–2.27 (m, 7
7-Benzyl-2-methyl-8-phenyl-6,7-dihydro-5H-pyrrolo[2,3-h]quinazol-
H, 2ϫ CH2 and CH3), 2.36 (s, 4 H, 2ϫ CH2), 2.52 (t, J = 6.3 Hz,
ine (30): 75% as an off-white solid (151 mg from 200 mg). M.p. 73–
2 H, CH2), 2.86 (t, J = 6.1 Hz, 2 H, CH2), 3.60 (s, 4 H, CH2), 3.80
75 °C. Rf = 0.17 (hexanes/EtOAc, 3:2, v/v). 1H NMR (300 MHz,
(s, 2 H, CH2), 6.42 (s, 1 H, ArH), 7.02–7.05 (m, 1 H, ArH), 7.08–
CDCl3): δ = 2.68 (s, 5 H, CH2 & CH3), 2.91 (s, 2 H, CH2), 5.17 (s,
7.10 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.2,
2 H, CH2), 6.89 (s, 1 H, ArH), 6.96 (s, 2 H, ArH), 7.27–7.34 (m, 8
21.4, 22.6, 23.9, 30.5, 38.0, 53.8, 58.5, 66.7, 105.9, 120.5, 125.7,
H, ArH), 8.21 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ
126.5, 128.9, 131.2, 131.4, 134.2, 138.2, 138.8, 143.8, 194.4 ppm.
= 20.8, 25.1, 26.0, 48.0, 105.0, 118.6, 121.5, 125.8, 127.6, 127.7,
MS (ESI+): m/z = 353.1. HRMS: calcd. for C22H29N2O2 [M +
128.7, 129.1, 132.6, 137.2, 137.8, 138.1, 153.2, 159.2, 166.5 ppm.
H]+ 353.2229; found 353.2235.
MS (ESI+): m/z = 352.2. HRMS: calcd. for C24H22N3 [M + H]+
352.1814; found 352.1819.
General Procedure for the Preparation of Compounds 27–28 as Ex-
emplified for 4-Chloro-1-isopropyl-2-phenyl-6,7-dihydro-1H-indole-
5-carbaldehyde (27): POCl3 (0.5 mL, 5.36 mmol) was added to a
stirred solution of 21b (500 mg, 1.98 mmol) in DMF (5 mL) at 0 °C
and stirred for 10 min. The reaction mixture was then poured onto
crushed ice and extracted with EtOAc (3ϫ20 mL). The combined
organic layers were washed with brine (30 mL), dried with anhy-
drous Na2SO4 and concentrated under reduced pressure to afford
the crude product. Purification of the crude material by column
chromatography (EtOAc/hexanes, 10:90, v/v) furnished the pure
product 27 (485 mg, 82%) as a yellow solid. M.p. 129–131 °C. Rf
Supporting Information (see footnote on the first page of this arti-
1
cle): Spectroscopic data of remaining compounds and H and 13C
NMR spectra of all compounds are included.
Acknowledgments
H. B. gratefully acknowledges the financial assistance from the
Council of Scientific and Industrial Research, New Delhi in the
form of a fellowship. S. B. acknowledges the financial support from
the Department of Science and Technology, New Delhi. The au-
thors also acknowledge Dr. K. Srivastava for carrying out the anti-
malarial bioassay.
= 0.76 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1644 (CO) cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 1.46 (d, J = 7.0 Hz, 6 H, CH3),
2.80–2.86 (m, 2 H, CH2), 2.95–3.01 (m, 2 H, CH2), 4.43–4.53 (m,
1 H, CH), 6.37 (s, 1 H, ArH), 7.32–7.45 (m, 5 H, ArH), 10.15 (s,
1 H, CHO) ppm. 13C NMR (50 MHz, CDCl3): δ = 22.6, 22.9, 23.0,
27.5, 29.8, 48.6, 106.4, 119.8, 122.7, 128.1, 128.7, 129.8, 132.9,
135.6, 136.4, 145.6, 189.3 ppm. MS (ESI+): m/z = 300.2. HRMS:
calcd. for C18H19ClNO [M + H]+ 300.1155; found 300.1159.
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(28): 80% as a yellow solid (1.44 g from 1.56 g). M.p. 163–165 °C.
R = 0.73 (hexanes/EtOAc, 3:2, v/v). IR (KBr): ν = 1645 (CO) cm–1.
˜
f
1H NMR (300 MHz, CDCl3): δ = 2.58–2.64 (m, 2 H, CH2), 2.75–
2.81 (m, 2 H, CH2), 5.13 (s, 2 H, CH2), 6.53 (s, 1 H, ArH), 6.94
(d, J = 6.6 Hz, 2 H, ArH), 7.28–7.34 (m, 8 H, ArH), 10.15 (s, 1 H,
CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6, 22.6, 48.3,
106.4, 119.2, 123.1, 125.8, 127.8, 128.0, 128.8, 129.1, 129.2, 132.0,
136.9, 137.2, 137.4, 145.4, 189.2 ppm. MS (ESI+): m/z = 348.2.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 11
B. Harikrishna, S. Batra
FULL PAPER
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Received: January 30, 2012
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20107
/KAP1
Date: 17-04-12 15:20:07
Pages: 11
Synthesis of 2-(Substituted phenyl)-6,7-dihydro-1H-indol-4(5H)-ones
Nitrogen Heterocycles
B. Harikrishna, S. Batra* ............... 1–11
Versatile Synthesis of 2-(Substituted phen-
yl)-6,7-dihydro-1H-indol-4(5H)-ones from
Morita–Baylis–Hillman Acetates of 2-Oxo-
2-(substituted phenyl)acetaldehyde
Application of adducts prepared by the
Morita–Baylis–Hillman reaction between
2-oxo-2-(substituted phenyl)acetaldehydes
and cyclohex-2-enone for the synthesis of
2-(substituted phenyl)-6,7-dihydro-1H-ind-
ol-4(5H)-ones has been described.
Keywords: Nitrogen heterocycles / Synthetic
methods / Indole Derivatives / Morita–
Baylis–Hillman
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11