Synthesis of indolines via a SmI2 promoted domino nitro reduction-intramolecular aza-Michael reaction

Article abstract of DOI:10.1002/jhet.1982

A simple and straightforward synthesis of substituted indolines based on a domino nitro reduction intramolecular aza-Michael reaction is described. The reaction employs Samarium diiodide under mild conditions for the addition of dibromoacetic acid to substituted 2-(2-nitrophenyl) acetaldehyde derivatives and their subsequent cyclization upon nitro group reduction to provide corresponding indoline heterocycles in good yields. This "one pot" strategy also permitted the expeditious synthesis of a 1,2,3,4-tetrahydroquinoline, whereas the seven-membered 2,3,4,5-tetrahydrobenzoazepines compounds were not formed under these reaction conditions.

Full text of DOI:10.1002/jhet.1982

Month 2014
Synthesis of Indolines via a SmI2 Promoted Domino Nitro Reduction–
Intramolecular aza-Michael Reaction
Josierika A. Ferreira Ramos, Carolina S. Araújo, Tanus J. Nagem, and Jason G. Taylor
a
a
a
a
*
Departamento de Química (DEQUI), ICEB, Universidade Federal de Ouro Preto, Campus Morro do Cruzeiro, CEP.
35400-000, Ouro Preto, Minas Gerais, Brazil
*
E-mail: jason@iceb.ufop.br
Received January 19, 2013
DOI 10.1002/jhet.1982
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Br
Br
O
OH
SmI2
O
H3CO2C
CO2CH3
(10 equiv)
R
R
R
THF-MeOH,
rt, 18h
N
NO2
H
NO2
A simple and straightforward synthesis of substituted indolines based on a domino nitro reduction intramolec-
ular aza-Michael reaction is described. The reaction employs Samarium diiodide under mild conditions for the
addition of dibromoacetic acid to substituted 2-(2-nitrophenyl) acetaldehyde derivatives and their subsequent cycli-
zation upon nitro group reduction to provide corresponding indoline heterocycles in good yields. This “one pot”
strategy also permitted the expeditious synthesis of a 1,2,3,4-tetrahydroquinoline, whereas the seven-membered
2,3,4,5-tetrahydrobenzoazepines compounds were not formed under these reaction conditions.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
intramolecular Michael addition protocol could efficiently
provide nitrogen heterocycles such as 2-(tetrahydroquinolin-
2-yl)-, 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)- and
2-(tetrahydroquinoxalin-2-yl) acetates in good yield when
simply employing iron powder in glacial acetic (Scheme 1)
[13]. In a similar fashion, the formation of five-membered
rings as part of a tricyclic molecule via a tandem reduction–
Michael addition from a nitro group has been developed for
the synthesis of hexahydrocarbazoles [14]. However, on this
occasion, the a,b-unsaturated carbonyl compound is a cyclic
enone, and the acyclic version was never explored.
Thus, proof of concept had been established for the
synthesis of aryl fused six-membered ring nitrogen
heterocycles and our curiosity lead us to investigate the
possibility of analogous five- and seven-membered com-
pounds being conveniently accessed in a similar manner.
Facile synthesis of the requisite precursor for the domino
reaction would render this approach synthetically useful
for its application in a longer multistep synthesis. In this
regard, herein, we report the application of a domino nitro
reduction–intramolecular aza-Michael strategy that occurs
in a one pot fashion upon coupling of dibromoacetic
acid with of substituted 2-(2-nitrophenyl) acetaldehyde
derivatives in the presence of SmI2 to afford substituted
indoline derivatives.
Compounds with biological activity that have found
applications as pharmaceuticals and agricultural chemicals
are often derived from nitrogen heterocyclic structures,
which also appear frequently in natural products [1,2].
Nitrogen heterocycles pertinent to this work include
indoline and 1,2,3,4-tetrahydroquinoline structures, and a
variety of synthetic methodologies for the synthesis of
these structures have been summarized in many reviews
[3,4]. Examples of the indoline structural framework can
be encountered in natural products such as JBIR-16 [5]
and (2S)-cyclo-Dopa-5-O-glucoside [6] (Fig. 1).
Despite the wide availability of synthetic methods, there
still exists a need to develop more efficient procedures,
particularly those that allow the synthesis of indoline
intermediates with pendant functional groups, which
could later be exploited for the preparation of other complex
azapolycyclic ring systems. The intramolecular aza-Michael
reaction offers a direct and atom-economical means of
efficiently synthesizing nitrogen heterocycles. It is known
that in the presence of triphenylphosphine, that azide func-
tional group bearing acyclic -a,b-unsaturated carbonyl and
cyano compounds spontaneously cyclize upon reduction
to afford pyrrolidines or piperidines in good yields [7].
Furthermore, carbamates and sulfonamides can undergo
intermolecular cyclizations with a,b-unsaturated carbonyl
compounds in the presence of a simple base such as sodium
tert-butoxide or sodium hydrogen carbonate [8–12]
(Scheme 1). An article relevant to this work was published
in the year 2000 in which Bunce and coworkers demonstrated
that the exploitation of a nitro group in a tandem reduction–
RESULTS AND DISCUSSION
The synthesis of the target precursor begins with a simple
nucleophilic substitution reaction of commercially available
substituted 2-nitrotoluenes 1a–f with paraformaldehyde in
© 2014 HeteroCorporation

J. A. Ferreira Ramos, C. S. Araújo, T. J. Nagem, and J. G. Taylor
Vol 000
Scheme 2. Synthesis of aldehydes 2a–f by a nucleophilic substitution –
OH
HO
HO
oxidation protocol.
OH
CH3
CH3
O
O
HO2C
(8 equiv)
H
1.
O
H
OH
KOH, DMSO, 40oC, 6h
CH3
NO2
CO2H
O
N
H CH3
N
HO
R
H
R
H
NO2
2. PCC, DCM, rt, 4-5h
(2S)-cyclo-Dopa 5-O-glucoside
JBIR-67
Yield over 2 steps
1a,R = H;
1b, R = 4-Cl;
1c,R = 6-Cl; 1d, R = 4-OCH3;
1e,R = 4-Br 1f, R = 2,5-(CH3)2
Figure 1. Indoline frameworks present in natural products.
Scheme 1. Examples of intramolecular aza-Michael reaction.
2a: 56%, 2b: 52%, 2c:55%,
2d: 57%, 2e: 45%, 2f: 43%
expected indolines 3a–f (entries 1–6). It appears that the
addition of dibromoacetic acid is significantly faster
than the nitro reduction and therefore allowing the
obtainment of the indoline product in good yields. The
slightly acidic nature of the reaction mixture is probably
responsible for the solvolysis of the product that results
in the formation of a pendant ester. Cyclization is easily
confirmed by absence of the olefinic hydrogen signals
and the appearance of a methine double doublet at
~3.30 ppm in the 1H NMR spectra. The purity of the
compounds was confirmed by elemental analysis and
high resolution mass spectrometry.
Ref 7
R1
X
R1
R2
R1
N3
R
Ph3P
H2N
R
NH
n
X
X
R2
n =1, 2
X = CO2CH3, CN
THF,H2O
n
R2
R
-50 o
C
n
60-86% Yield for 9 examples
Ref 9
CO2CH3
KOtBu (0.8 equiv)
THF, -78 o
Boc
R1
CO2CH3
NH
N
R1
R2
C
57-97% for 7 examples
O
Ref 11
OH
Our curiosity was drawn towards the application of this
strategy for the synthesis of six and seven-membered rings.
In contrast to the group of Bunce, we pursued the synthesis
of the necessary substrate for the intramolecular cyclization
reaction employing a palladium catalyzed coupling reac-
tion, which upon double bond migration yields the desired
aldehydes. This strategy was advantageous given that it
permitted extension of the alkyl chain by employing the
appropriate unsaturated alcohol (Scheme 3).
CO2CH3
Cbz
NaHCO3, MeOH
22 oC, 70% yield
H
CO3CH3
NHCbz
N
O
H
X
HO
Ref 13
R
O
X
NO2
CO2Et
Fe (6 equiv), HOAc
115 oC, 30min, N2
X = CH2, O, NH
N
H
OEt
R
86-98% for 7 examples
This now set the stage for the application of the present
methodology for the preparation of the desired heterocycle
compound. Heterocycle 5 was obtained in good yield as an
oil after purification, and it was fully characterized by
NMR spectroscopy with all 1H and 13C signals being
assigned and in agreement with the literature data [20]. In
contrast, substrate 4b furnished only the aniline 6, and
intramolecular aza-Michael addition did not proceed to
afford the expected tetrahydrobenzoazepine. Although the
7-exo-trig heterocyclization is favored under Baldwin’s
rules, the aza-Michael reaction is potentially reversible,
and the subtle interplay of entropic and stereo-electronic
factors seem to disfavor cyclization on this occasion.
In summary, we have developed a convenient methodol-
ogy for the synthesis of a variety of indolines via a domino
nitro reduction–intramolecular aza-Michael reaction. Using
10 equivalents of SmI2, modest to good yields could be
realized for the obtainment of both indoline and
1,2,3,4-tetrahydroquinoline heterocyles by this approach.
A limitation was encountered when an attempt was
made to extend this methodology to the synthesis of
2,3,4,5-tetrahydrobenzoazepines. Work is ongoing in
DMSO as solvent (Scheme 2). Upon purification, the alcohols
were subjected to mild PCC oxidation to afford the corre-
sponding aldehydes. All aldehydes are known compounds,
and their spectral data are in complete accordance with the
literature values. Synthesis of the a,b-unsaturated carbonyl
compound in which the neighboring methylene carbon is also
in a benzyilic position is often troublesome because of the
possibility for double bond migration [15].
Samarium diiodide has been shown to be effective in
the coupling of aldehydes to dibromoacetic acid [16],
ethyldibromoacetate [17] and dichloroacetamide [18] in
which the elimination reaction proceeds with very high
E diastereoselectivity. SmI2 is a well-known reducing agent
of arylnitro groups to anilines [19]; thus, we envisaged a
tandem reaction resulting in the corresponding indolines from
aldehydes 2a–e in a one-pot procedure. Our investigations
exploring the substrate scope are summarized in Table 1.
We opted for a THF–MeOH solvent mixture given that
the literature precedence indicated this to be the best in
which reduction of the nitro group occurs readily under this
condition. Generally, yields were good irrespectively of the
electronic or steric nature of the aryl substituent, to give the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Indolines via a SmI2 Promoted Domino Nitro Reduction–Intramolecular
aza-Michael Reaction
Table 1
Evaluation of substituted 2-(2-nitrophenyl)acetaldehyde derivatives.
Entry
1
Substrate
Product
Yield (%)
67
2a
2
2b
59
3
4
2c
61
64
2d
5
6
2e
2f
57
58
were recorded using samples that were either prepared as a
liquid film between NaCl plates or pressed into KBr discs.
Elemental analyses (C, H, N, S) were conducted using the
PerkinElmer 2400 Series; their results were found to be in
good agreement (Æ0.3%) with the calculated values. For
NMR data, the chemical shifts are reported in d (ppm)
referenced to residual protons and 13C signals in deuterated
chloroform. The coupling constants (J) are expressed in
Hertz (Hz).
Synthesis of aldehydes 2a–f. To a stirred solution of substituted
2-nitrotoluene (90 mmol) in DMSO (200mL) were added para-
formaldehyde (720mmol) and KOH (85% aqueous solution,
0.25 mol) dropwise over 10min at 0ꢀC, and then the reaction
our group to develop new strategies toward the synthesis
of medium sized benzo-fused nitrogen heterocycles.
EXPERIMENTAL
All commercial reagents were used as received. Anhydrous
solvents were purchased from Sigma Aldrich (St. Louis,
MO). Column chromatography was performed using silica
gel 200–400 mesh. TLC analysis was performed using silica
gel plates, using ultraviolet light (254 nm) or vanillin solution
for visualization. Melting points are uncorrected. IR spectra
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. A. Ferreira Ramos, C. S. Araújo, T. J. Nagem, and J. G. Taylor
Vol 000
Scheme 3. Synthesis of tetrahydroquinoline 5 and compound 6.
2727, 1715, 1609, 1527, 1480, 1409, 1347, 1244, 1166, 1144, 1054,
957, 859, 786, 743, 704, 665, 635; dH (400 MHz, CDCl3): 9.83
(1H, s), 7.95 (1H, d, J 8.4), 7.59 (1H, t, J 8.4), 7.41–7.44 (2H, m),
2.97 (2H, t, J 7.2), 2.60 (2H, t, J 7.2), 2.01 (2H, quintet, J 7.2); dC
(100 MHz, CDCl3): 201.8, 149.3, 136.4, 133.1, 131.9, 127.4, 124.9,
43.3, 32.2, 23.1; MS m/z (EI): calcd for C10H11NO3 193.0739, found
193.0745. Anal. Calcd for C10H11NO3: C, 62.17%; H, 5.74%; N,
7.25%. Found: C, 62.20%:;H, 5.79%; N, 7.26%.
General method for the synthesis of indoline derivatives. In
a Schlenk tube (25 mL) equipped with a magnetic stir bar was
charged dibromoacetate (2 mmol) and the corresponding
aldehyde (2 mmol) in 5 mL of a 1:1 mixture of THF–MeOH.
Next, 20 mmol of a 0.1M solution of SmI2 was added slowly by
syringe in THF, and the reaction mixture was stirred at room
temperature for 18 h. Upon completion as determined by TLC,
the reaction was quenched with aqueous 0.1M HCl (20 mL), and
the organic layer was extracted with chloroform (3Â 25 mL).
The combined organic extracts were dried over MgSO4, and
the solvent was removed under vacuum to afford an oily residue
that was purified by flash chromatography on silica gel (hexane/
EtOAc 8:1 to 4:1) providing the title compounds.
Methyl 2-(indolin-2-yl)acetate (3a). The product was obtained as
a pale yellow oil; Rf = 0.5 (hexanes/EtOAc, 7:3); υmax (thin film,
cmÀ1): 3356, 2940, 1622, 1456, 1315, 1262, 1157, 1043, 935,
869, 751; dH (400 MHz, CDCl3): 7.12 (1H, d, J 7.6), 7.09 (1H, t,
J 7.6), 6.79 (1H, t, J 7.6), 6.73 (1H, d, J 7.6), 5.67 (1H, br s, NH),
4.28–4.31 (1H, m), 3.66 (3H, s), 3.26 (1H, dd, J 8.4, 15.2),
2.77–2.68 (3H, m); dC (100 MHz, CDCl3): 172.1, 148.3, 128.8,
127.7, 124.8, 120.3, 110.9, 56.0, 51.8, 40.2, 35.7; MS m/z (EI):
calcd for C11H13NO2 191.0946, found 191.0942. Anal. Calcd
for C11H13NO2: C, 69.09%; H, 6.85%; N, 7.32%. Found:
C, 69.15%; H, 6.87%; N, 7.29%.
Methyl 2-(6-chloroindolin-2-yl)acetate (3b). The product was
obtained as a pale yellow oil; Rf = 0.4 (hexanes/EtOAc, 7:3); υmax
(thin film, cmÀ1): 3354, 2942, 1624, 1456, 1316, 1268, 1152,
1043, 934; dH (400 MHz, CDCl3): 7.01 (1H, d, J 7.6), 6.72
(1H, d, J 7.6), 6.56 (1H, s), 5.72 (1H, br s, NH), 4.23–4.30
(1H, m), 3.64 (3H, s), 3.27 (1H, dd, J 8.5, 15.0), 2.76–2.68
(3H, m); dC (100 MHz, CDCl3): 172.4, 143.3, 133.5, 124.7,
122.8, 120.5, 110.3, 56.2, 51.8, 40.5, 35.9; MS m/z (EI): calcd
for C11H12ClNO2 225.0557, found 225.0552. Anal. Calcd for
C11H12ClNO2: C, 58.54%; H, 5.36%; N, 6.21%. Found:
C, 58.55%; H, 5.39%; N, 6.25%.
Methyl 2-(4-chloroindolin-2-yl)acetate (3c). The product was
obtained as a pale yellow solid mp 57–59ꢀC; Rf = 0.37 (hexanes/
EtOAc, 7:3); υmax (KBr disc, cmÀ1): 3350, 2941, 1627, 1447,
1310, 1269, 1174, 1157, 1051, 1040, 934; dH (400 MHz, CDCl3):
7.06–7.02 (2H, m), 6.58 (1H, s), 5.72 (1H, br s, NH), 4.23–4.30
(1H, m), 3.69 (3H, s), 3.29 (1H, dd, J 8.5, 15.0), 2.76–2.68
(3H, m); dC (100 MHz, CDCl3): 170.9, 151.3, 135.2, 127.9,
122.6, 118.5, 112.0, 55.5, 51.1, 40.0, 34.5; MS m/z (EI): calcd
for C11H12ClNO2 225.0557, found 225.0555. Anal. Calcd
for C11H12ClNO2: C, 58.54%; H, 5.36%; N, 6.21%. Found:
C, 58.50%; H, 5.34%; N, 6.22%.
Methyl 2-(6-methoxyindolin-2-yl)acetate (3d). The product was
obtained as a pale yellow oil; Rf = 0.35 (hexanes/EtOAc, 7:3); υmax
(thin film, cmÀ1): 3345, 2949, 1620, 1466, 1310, 1275, 1172,
1163, 1100, 974; dH (400 MHz, CDCl3): 7.11 (1H, d, J 7.6), 6.14
(1H, d, J 7.6), 6.02 (1H, s), 5.51 (1H, br s, NH), 4.23–4.30
(1H, m), 3.72 (3H, s), 3.65 (3H, s), 3.29 (1H, dd, J 8.5, 15.0),
2.76–2.68 (3H, m); dC (100MHz, CDCl3): 173.3, 153.7, 145.3,
Pd(OAc)2 (2 mol%)
Bu4NCl (1 equiv),
NaHCO3 (2.5 equiv)
NO2
NO2
I
OH
H
n
n
DMF, 40 oC, 24 h
O
4a, n = 1: 77%
4b, n = 2: 71%
H
N
Br
Br
O
OCH3
n = 1
O
OH
NO2
SmI2
5
68% Yield
(10 equiv)
H
O
n
THF-MeOH,
rt, 18h
NH2
O
n = 2
OCH3
6
64% Yield
mixture was stirred for an additional 18 h. The reaction mixture was
poured into sat. NH4Cl and extracted with chloroform (4Â 100 mL).
The extracts were washed with brine, dried over Na2SO4, filtered,
and evaporated in vacuo. The crude product was purified by flash
column chromatography on silica gel (5–50% EtOAc in hexane)
to give substituted 2-(2-nitrophenyl)ethanol 1a–e. Spectroscopic
data are in accordance with reported values: 1a [21], 1b [22],
1c [23], 1d [24], and 1e [25].
To a solution of the substituted 2-nitrophenethyl alcohols 1a–e
(1 g, 6 mmol) in dry DCM (50mL) was added PCC (1.9g, 9 mmol).
The resultant mixture was stirred at room temperature for 3 h and
dried over MgSO4. The filtrate was concentrated to dryness under
reduced pressure, and the residual material was purified by column
chromatography to give substituted 2-nitrophenylacetaldehyde
2a–e (43–57% over two steps). Spectroscopic data are in accor-
dance with reported values: 2a [26], 2b [27], 2c [28], and 2d,f [29].
Synthesis of aldehydes 4a and 4b. In a typical procedure for
the synthesis of the aldehyde, a Schlenk tube equipped with a stir
bar was charged with 2-nitroiodobenzene (8 mmol), allylalcohol or
3-buten-1-ol (18 mmol), sodium hydrogencarbonate (35.0 mmol),
tetra-n-butylammonium chloride (8 mmol), and palladium acetate
(2 mol%). Anhydrous DMF (15 mL) was added, and the black
reaction mixture was heated to 40ꢀC for 24 h. Upon completion, the
solution was cooled to room temperature, diluted with EtOAc
(25 mL), and filtered, and the solvent was removed under reduced
pressure. The oily residue was purified by column chromatography
to afford either 4a (77%) or 4b (71%) depending on the unsaturated
alcohol employed.
3-(2-Nitrophenyl)propanal (4a). Pale yellow oil; Rf = 0.1
(hexanes/EtOAc, 4:1). Spectroscopic data are in accordance
with the literature values [24]. υmax (thin film, cmÀ1): 3422,
3067, 2897, 2829, 2727, 1721, 1609, 1576, 1519, 1452,
1344, 1199, 1164, 1143, 1054, 1022, 850, 785, 742, 704, 662,
635; dH (400MHz, CDCl3): 9.85 (1H, s), 7.98 (1H, d, J 8.0),
7.58 (1H, t, J 8.0), 7.43–7.46 (2H, m), 3.25 (2H, t, J 7.6),
2.94 (2H, t, J 7.6); dC (100 MHz, CDCl3): 200.4, 149.2, 135.8,
133.4, 128.5, 127.7, 125.0, 44.5, 25.8; MS m/z (EI): calcd
for C9H9NO3 179.0582, found 179.0567. Anal. Calcd for
C9H9NO3: C, 60.33%; H, 5.06%; N, 7.82%. Found: C,
60.30%; H, 5.09%; N, 7.86%.
4-(2-Nitrophenyl)butanal (4b). Pale yellow oil; Rf = 0.4 (hexanes/
EtOAc, 13:7); υmax (thin film, cmÀ1): 3427, 2940, 2873, 2878, 2827,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Indolines via a SmI2 Promoted Domino Nitro Reduction–Intramolecular
aza-Michael Reaction
Acknowledgments. Authors gratefully acknowledge the generous
financial support from the Brazilian funding agencies Fundação
de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG),
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq), and Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior (CAPES).
124.1, 123.8, 124.5, 115.0, 56.2, 55.2, 51.8, 40.5, 36.0; MS m/z
(EI): calcd for C12H15NO3 221.1052, found 221.1059. Anal. Calcd
for C12H15NO3: C, 65.14%; H, 6.83%; N, 6.33%. Found: C,
65.18%; H, 6.89%; N, 6.29%.
Methyl 2-(6-bromoindolin-2-yl)acetate (3e). The product was
obtained as a pale yellow oil; Rf = 0.4 (hexanes/EtOAc, 7:3); υmax
(thin film, cmÀ1): 1721, 1625, 1473, 1441, 1394, 1380, 1379,
1328, 1299, 1255, 1252, 1175, 1055, 1027, 904; dH (400 MHz,
CDCl3): 7.03 (1H, d, J 7.6), 6.70 (1H, d, J 7.6), 6.59 (1H, s),
5.70 (1H, br s, NH), 4.21–4.30 (1H, m), 3.65 (3H, s), 3.30
(1H, dd, J 8.5, 15.0), 2.73–2.68 (3H, m); dC (100 MHz, CDCl3):
172.1, 143.5, 133.2, 124.7, 122.5, 121.5, 113.5, 56.2, 52.3, 41.2,
36.9; MS m/z (EI): calcd for C11H12BrNO2 269.0051, found
269.0058. Anal. Calcd for C11H12BrNO2: C, 48.91%; H, 4.48%;
N, 5.19%. Found: C, 48.95%; H, 4.49%; N, 5.21%.
Methyl 2-(5,6-dimethylindolin-2-yl)acetate (3f). The product was
obtained as a pale yellow oil; Rf = 0.37 (hexanes/EtOAc, 7:3); υmax
(thin film, cmÀ1): 3080, 2979, 2939, 2885, 2861, 1653, 1619,
1150, 1045; dH (400 MHz, CDCl3): 7.24 (1H, s), 6.90 (1H, s),
4.96 (1H, br s, NH), 4.25–4.29 (1H, m), 3.67 (3H, s), 3.32
(1H, dd, J 8.5, 15.0), 2.77–2.65 (3H, m), 2,22 (3H, s), 2.17
(3H, s); dC (100 MHz, CDCl3): 171.0, 137.3, 135.2, 131.9,
127.6, 126.5, 115.4, 55.5, 51.1, 40.0, 34.5, 20.2, 19.4; MS m/z
(EI): calcd for C13H17NO2 219.1259, found 219.1255. Anal.
Calcd for C13H17NO2: C, 71.21%: H, 7.81%: N, 6.39%. Found:
C, 71.20%: H, 7.84%: N, 6.32%.
REFERENCES AND NOTES
[1] Naito, T. Chem Pharm Bull 2008, 56, 1367.
[2] Michael, J. P. J. Nat Prod Rep 1996, 13, 73.
[3] Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem 2010, 3975.
[4] Kozlov, N. G.; Gusak, K. N.; Kadutskii, A. P. Chem.
Heterocycl. Compd 2010, 46, 505.
[5] Motohashi1, K.; Nagai, A.; Takagi, M.; Shin-ya, K. J Antibiot
2011, 64, 281.
[6] Wyler, H.; Meuer, U.; Bauer, J.; Stravs-Mombelli, L.
Helvetica Chimica Acta 1984, 67, 1348.
[7] Knouzi, N.; Vaultier, M.; Toupet, L.; Carrie, R. Tetrahedron
Lett 1987, 28, 1757–1760.
[8] Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Rodriguez, E.;
Barrio, P. Org Lett 2010, 12, 5494.
[9] Gärtner, M.; Weihofen, R.; Helmchen, G. Chem Eur J 2011,
17, 7605.
[10] Enkisch, C.; Schneider, C. Eur. J. Org. Chem 2009, 5549.
[11] Wipf, P.; Kim, Y. Tetrahedron Lett 1992, 33, 5477.
[12] Bland, D.; Chambournier, G.; Dragan, V.; Hart, D. J. Tetrahedron
1999, 55, 8953.
Methyl 2-(1,2,3,4-tetrahydroquinolin-2-yl)acetate (5). Rf = 0.3
(hexanes/EtOAc, 4:1); υmax (thin film, cmÀ1): 3396, 2981, 2934,
2846, 1726, 1607, 1586, 1485, 1445, 1351, 1275, 1188, 1114,
1028, 931, 853, 810, 749; dH (400MHz, CDCl3): 7.04–7.09 (2H,
m), 6.69 (1H, t, J 6.4), 6.56 (1H, d, J 8.0), 4.54 (1H, br s, NH),
3.77–3.80 (1H, m), 3.69 (3H, s), 2.89–2.91 (1H, m), 2.69–2.83
(1H, m), 2.52 (2H, d, J 6.0), 1.99–2.02 (1H, m), 1.71–1.80 (1H,
m); dC (100 MHz, CDCl3): 172.3, 144.1, 129.3, 126.9, 120.9,
117.4, 114.6, 57.6, 47.8, 41.0, 28.1, 25.7; MS m/z (EI): calcd for
C12H15NO2 205.1103, found 205.1110. Anal. Calcd for
C12H15NO2: C, 70.22%; H, 7.37%; N, 6.82%. Found: C,
70.20%; H, 7.34%; N, 6.87%.
(E)-Methyl 6-(2-aminophenyl)hex-2-enoate (6). The product
was obtained as a pale yellow oil (161 mg, 73%); Rf = 0.5
(hexanes/EtOAc, 7:3); υmax (thin film, cmÀ1): 3375, 2890, 2862,
1711, 1651, 1624, 1497, 1457, 1368, 1273, 1186, 1154, 1093,
1039, 978, 860, 750; dH (400 MHz, CDCl3): 7.04–7.11 (3H, m),
6.78 (1H, t, J 7.6), 6.71 (1H, d, J 7.6), 5.90 (1H, dt, J 1.4,
15.6), 3.65 (3H, s), 3.62 (2H, br s, NH2), 2.56 (2H, t, J 7.6),
2.33 (2H, q, J 7.6), 1.86 (2H, quintet, J 7.6); dC (100 MHz,
CDCl3): 166.6, 148.6, 144.1, 129.5, 127.2, 125.7, 121.8, 118.8,
115.7, 57.2, 31.9, 30.6, 26.9; MS m/z (EI): calcd for
C13H17NO2 219.1259, found 219.1253. Anal. Calcd for
C13H17NO2: C, 71.21%: H, 7.81%: N, 6.39%. Found: C,
71.25%: H, 7.89%: N, 6.37%.
[13] Bunce, R. A.; Herron, D. M.; Ackerman, M. L. J Org Chem
2000, 65, 2847.
[14] Labadie, S. S.; Parmer, C. Synth. Commun 2011, 41, 1752.
[15] Moreira, N. D. F.; de Oliveira, T. T.; Nagem, T. J.; Taylor,
J. G. Heterocycl. Commun 2011, 17 (5–6), 203.
[16] Concellón, J. M.; Concellón, C. J Org Chem 2006, 71, 1728.
[17] Concellon, J. M.; Concellon, C.; Mejica, C. J Org Chem 2005,
70, 6111.
[18] Concellon, J. M.; Rodriguez-Solla, H.; Concellon, C.; Simal, C.;
Alvaredo, N. J Org Chem 2010, 75, 3451.
[19] Yu, C.; Liu, B.; Hu, L. J Org Chem 2001, 66, 919.
[20] Gilchrist, T. L.; Rahmam, A. J Chem Soc Perkin Trans 1
1998, 1203.
[21] Wierenga, W.; Harrison, A. W.; Evans, B. R.; Chidester,
C. G. J Org Chem 1984, 49, 438.
[22] Fielden, R.; Meth-Cohn, O.; Price, D.; Suschitzky, H. J Chem
Soc Perkin Trans 1 1973, 696.
[23] Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. J Org Chem 2006, 71, 4255.
[24] Laboratórios Serono as, Patent: WO2008/101979 A1, 2008.
[25] Meiji Seika Kaisha Ltd. Patent: EP2151447 A1, 2010.
[26] Yamane, Y.; Liu, X.; Hamasaki, A.; Ishida, T.; Haruta, M.;
Yokoyama, T.; Tokunaga, M. Org Lett 2009, 11, 5162.
[27] Raucher, S.; Koolpe, G. A. J Org Chem 1983, 48, 2066.
[28] McIntosh, M. L.; Johnston, R. C.; Pattwong, O.; Ashburn, B. O.;
Naffziger, M. R.; Cheong P. H.; Carter, R. G. J Org Chem 2012, 77, 1101.
[29] Chernyak, N.; Buchwald, S. L. J Am Chem Soc 2012,
134, 12466.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet