A convenient synthesis of indole-substituted 2-pyrrolidones and their cyclized derivatives

Article abstract of DOI:10.1002/1099-0690(200009)2000:17<3051::AID-EJOC3051>3.0.CO;2-3

Condensation between indole, Meldrum's acid, and benzyloxycarbonylacetaldehyde or aminoacetaldehyde derivatives yielded trimolecular adducts 7a-c. The latter were cyclized to indole-substituted 2-pyrrolidones 15a-b or 3-aminopyrrolid-2-ones 18a-b, dependi

Full text of DOI:10.1002/1099-0690(200009)2000:17<3051::AID-EJOC3051>3.0.CO;2-3

FULL PAPER
A Convenient Synthesis of Indole-Substituted 2-Pyrrolidones and Their
Cyclized Derivatives
¨
Michel Boisbrun,[a] Laurent Jeannin,[a] Loıc Toupet,[b] and Jean-Yves Laronze*[a]
Keywords: Cyclizations / Drug research / Meldrum’s acid derivatives / Nitrogen heterocycles / Pyrrolopyridoindoles
Condensation between indole, Meldrum’s acid, and
benzyloxycarbonylacetaldehyde or aminoacetaldehyde
derivatives yielded trimolecular adducts 7a−c. The latter
were cyclized to indole-substituted 2-pyrrolidones 15a−b or
3-aminopyrrolid-2-ones 18a−b, depending on the starting
material. Derivative 18a was transformed into pyrrolo-
[3Ј,4Ј:5,6]pyrido[3,4-b]indol-3(2H)-ones 19a and 20a by a
Pictet−Spengler condensation with benzaldehyde.
Introduction
ary results concerning their conversion into pyrrolo[3Ј,4Ј:5,-
6]pyrido[3,4-b]indol-3-ones 4.
4-Arylpyrrolidin-2-one derivatives 1 (Scheme 1) are cyclic
analogs of 3-aryl-γ-aminobutyric acids (3-aryl-GABA) 2,
which are effective medicines (e.g. Baclofen ) for the treat-
ment of neurological disorders. Surprisingly, their indolic
derivatives (Ar ϭ indole) are not common, and to the best
of our knowledge, compounds like 3 (Scheme 1), bearing a
primary amino group at position 3, were unknown until
now. These latter compounds, furthermore, can serve as
useful building blocks for the synthesis of pharmacolo-
gically active molecules. Among these, compounds of
general structure 4 are potent tyrosine-kinase inhibitors,[1]
and compound 5 is very close to synthetic analogs of stau-
rosporine.[2,3]
Results and Discussion
Two routes, both based on the opening of the dioxane
ring of a Meldrum’s acid derivative (Scheme 2), were
envisaged for the synthesis of 3. In Route 1, intramolecular
cyclization of A would lead to mixed anhydride AЈ, which,
after submission to a double nitrogen insertion (by means
of a Curtius reaction), would give the target compound 3.
In a less ambitious scheme (Route 2), the starting material
is amine derivative B. In this case, intramolecular cycliza-
tion would give acid BЈ, further transformation of which by
Curtius reaction would afford 3. Decarboxylation of AЈ or
BЈ would give 1 (Ar ϭ Indole) as a side product.
Scheme 1
In this paper, we report an efficient synthesis of indole-
substituted 2-pyrrolidone derivatives 3, as well as prelimin-
[a]
UPRES A CNRS 6013 ‘‘Isolement, Structure, Transformations
`
´
et Synthese de Produits Naturels’’, IFR 53 Biomolecules,
´
´
Faculte de Pharmacie, Universite de Reims-Champagne-
Ardenne,
51 rue Cognacq-Jay, F-51096 Reims Cedex, France
Fax: (internat.) ϩ 33-3/26898029
Scheme 2
E-mail: jy.laronze@univ-reims.fr
`
´
´
[b]
Groupe Matiere Condensee et Materiaux, UMR CNRS 6626,
´
Synthesis of type A or B derivatives could be achieved
Universite de Rennes I,
ˆ
Bat 11A, Campus de Beaulieu, F-35042 Rennes Cedex, France using a protocol that was developed in our laboratory,[4]
Eur. J. Org. Chem. 2000, 3051Ϫ3057
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0917Ϫ3051 $ 17.50ϩ.50/0
3051

M. Boisbrun, L. Jeannin, L. Toupet, J.-Y. Laronze
FULL PAPER
based on results reported by Yonemitsu.[5] It involved the
Route 1 (Scheme 5) starts with the debenzylation of 7a
trimolecular condensation between indole, Meldrum’s acid, by hydrogenolysis to give 12 in 79% yield. This, in the
and aldehyde 6a؊c, in the presence of ,-proline as cata- presence of Hünig’s base, presumably gave the unstable an-
lyst (Scheme 3), giving compounds 7a؊c in good yields hydride 13 (IR absorption bands of the crude solution at
(64Ϫ76%).
1881, 1763, and 1730 cmϪ1). The crude mixture containing
13 was treated with diazomethane, affording diester 14 in
87% yield, presumably through ring opening followed by
decarboxylation. This decarboxylation also occurred when
the same mixture was allowed to react with diphenylphos-
phoryl azide (DPPA), giving lactam 15a in moderate yield
(22%). This route might indeed lead to 4-(1H-indol-3-yl)-
pyrrolidin-2-one, but decarboxylation prevented access to
its 3-amino derivative.
Scheme 3
For this purpose, we needed to synthesize aldehydes
6a؊c. Dibenzylation of trans-3-hexenedioic acid with
benzyl chloroformate, triethylamine and a catalytic amount
of 4-(dimethylamino)pyridine,[6] giving 8 in 66% yield, and
subsequent ozonolysis of the dibenzyl intermediate gave al-
dehyde 6a (Scheme 4). This two-step procedure is a more
convenient method than the one previously reported.[7] Al-
dehydes 6b and 6c were obtained by hydrolysis of acetals 9
and 11. The synthesis of 6b has already been described,[8,9]
but 6c is a new synthon, in which both N-protecting groups
show different sensitivity to hydrogenolysis (see below). Be-
cause of their instability, aldehydes 6a؊c were used immedi-
ately in the crude state for the trimolecular condensation
(see Experimental Section).
Scheme 5
As has been reported,[10] an amide nitrogen atom can re-
act with a Meldrum’s acid derivative to give an imide.
Therefore, we could envisage the intramolecular reaction of
a carbamate nitrogen atom with a Meldrum’s acid moiety.
Indeed, an ethanolic solution of compound 7b was refluxed
to afford 15b in fair yield (63%), but unfortunately again
with the loss of the carboxylic group.
Route 2 potentially led to the same type of compound
as did Route 1, but in a more convenient way; although
decarboxylation still remained a problematic side reaction.
Taking account of the fact that the rigid structure of the γ-
lactam could enhance the rate of decarboxylation, we de-
cided to perform the nitrogen insertion (through Curtius
reaction) before the formation of the lactam ring. This re-
quired the opening of the Meldrum’s acid moiety with an
external nucleophile, such as ethanol.
Scheme 4
3052
Eur. J. Org. Chem. 2000, 3051Ϫ3057

A Convenient Synthesis of Indole-Substituted 2-Pyrrolidones
FULL PAPER
Figure 1. Molecular structure of compound 18b as determined by
X-ray diffraction; the numbering does not correspond to the sys-
tematic name
Scheme 6
Further transformations could be carried out by a
PictetϪSpengler reaction following Bailey’s procedure,[13]
affording
2-benzylhexahydropyrrolo[3Ј,4Ј:5,6]pyrido[3,4-
b]indol-3(2H)-one (19a) (less polar diastereomer) and 20a
(more polar diastereomer) in a 1:1 ratio (58% overall yield).
As expected, this reaction did not take place when the trans
diastereomer 18b was used as starting material, presumably
because of tension resulting from a trans ring junction. Ac-
cording to TLC, a new compound was formed (presumably
the intermediate imine 19b), but it decomposed during col-
umn chromatography and the starting amine was reco-
vered completely.
The relative configuration at the new chiral center of
compounds 19a and 20a could be assigned by measuring
nOes between 5-H and 3a-H (Scheme 6). We also noticed
that, in the case of compound 19a, the 13C NMR signals of
C-5 and C-3a appear downfield compared to those of 20a
(see Experimental Section). This is in accordance with Co-
ok’s results[14,15] concerning 1,3-disubstituted tetrahydro-β-
carbolines.
This was achieved by using compound 7c (Scheme 6). Re-
fluxing an ethanolic solution of 7c yielded 16 as a 1:1 mix-
ture of diastereomers in 90% yield. Yamada’s modified Cur-
tius reaction[11] was applied to 16, affording 17 as a mixture
of diastereomers in the same ratio, in 63% yield. Cleavage
of both carbamate functions, followed by cyclization, pro-
ceeded smoothly by hydrogenolysis in a one-pot reaction.
Both diastereomers could be isolated by column chromato-
graphy, giving 18a (less polar diastereomer) and 18b (more
polar diastereomer) in 38% and 37% yield, respectively.
Since J3-H/4-H coupling constant values in 18a and 18b
are very close together (8.0 Hz and 9.0 Hz, respectively), cis/
trans stereochemistry was assigned with the aid of nuclear
Overhauser enhancements (nOe) (Scheme 6). From a pre-
cedent concerning the relative stereochemistry of 5-mem-
bered cycles,[12] we studied interactions between a proton
belonging to the 5-membered ring and protons belonging
to the substituent located at the adjacent carbon atom of
the ring. The distance between these protons is shorter in
trans isomers than in cis isomers. For compound 18b we
indeed measured a strong (6%) nOe between the proton
located next to the carbonyl group of the lactam ring and
Conclusion
In conclusion, an efficient synthesis of new 3-amino-4-
protons located at positions 2 and 4 of the indole moiety, (1H-indol-3-yl)pyrrolidin-2-one derivatives was achieved.
which was not the case for compound 18a. X-ray analysis Compound 18a was readily converted into new hexahy-
confirmed the relative stereochemistry (Figure 1).
dropyrrolo[3Ј,4Ј:5,6]pyrido[3,4-b]indol-3(2H)-one derivat-
Eur. J. Org. Chem. 2000, 3051Ϫ3057
3053

M. Boisbrun, L. Jeannin, L. Toupet, J.-Y. Laronze
FULL PAPER
(CDCl3): δ ϭ 1.18 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 3.82 (m, 1 H,
CH2NH), 3.92 (d, J ϭ 3.0 Hz, 1 H, Meldrum CH), 4.01 (m, 1 H,
CH2NH), 4.41 (br t, 1 H, CH), 5.10 (m, 2 H, CH2Ph), 5.22 (br t,
1 H, carbamate NH), 7.05Ϫ7.40 (m, 9 H, Harom), 7.68 (d, J ϭ
8.0 Hz, 1 H, indole 4-H), 8.49 (s, 1 H, indole NH). Ϫ 13C NMR
(CDCl3): δ ϭ 27.7 (CH3), 27.9 (CH3), 37.0 (CH), 44.0 (CH2NH),
48.4 (Meldrum CH), 66.8 (CH2Ph), 105.3 (Meldrum acetonide car-
bon), 111.1 (indole C-7), 111.9 (indole C-3), 119.2, 119.5, 122.3,
123.5 (indole C-2), 126.9 (indole C-3a), 128.0, 128.3, 128.4, 135.5,
136.2, 156.6 (carbamate CϭO), 165.5 (Meldrum CϭO), 165.6
(Meldrum CϭO). Ϫ C24H24N2O6 (436.45). Ϫ MS (EI); m/z (%):
334 (10) [Mϩ Ϫ CH3COCH3 Ϫ CO2], 203 (12), 143 (20), 117 (100).
ives. Extension of this approach to the synthesis of analogs
of natural products is under way in our laboratory.
Experimental Section
General: Melting points were determined with a Reichert Thermo-
var hot-stage apparatus and are uncorrected. Ϫ IR (film) spectra
were measured with a Bomem FTIR instrument. Ϫ UV spectra
were measured in MeOH, using a UNICAM 8700 UV/Vis spectro-
photometer. Ϫ 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were measured with a Bruker AC 300 spectrometer. Ϫ Mass
spectra were recorded with a VG Autospec apparatus. Ϫ All solv-
ents were purified by following standard literature methods. Ϫ
Chromatography was performed on silica gel 60 (Merck). Reac-
tions were monitored using Merck TLC aluminium sheets (Kiesel-
gel 60F254).
Benzyl (Benzyl){2-[2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl]-2-(1H-
indol-3-yl)ethyl}carbamate (7c): Deprotection of the acetal: To a
stirred solution of 11 (27.65 g, 84.06 mmol) in CH3CN (310 mL)
was added 10% HCl solution (310 mL). The reaction mixture was
stirred at room temperature for 12 h. The organic solvent was evap-
orated, and the aqueous residue was extracted with Et2O (3 ϫ
100 mL). The combined organic extracts were washed with brine
(3 ϫ 100 mL), dried (Na2SO4), and concentrated to a 10 mL vol-
ume. Ϫ Condensation of the aldehyde with indole and Meldrum’s
acid: The residue was dissolved in CH3CN (200 mL) and to this
solution were added indole (4.92 g, 42.00 mmol), Meldrum’s acid
(6.05 g, 42.00 mmol), and ,-proline (242 mg, 2.10 mmol), under
nitrogen. The reaction mixture was stirred for 20 h at room temper-
ature. The solvent was evaporated and column chromatography
(eluent: EtOAc/hexane, 3:7) afforded 15.46 g (29.40 mmol, 70%
Benzyl 3-[2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl]-3-(1H-indol-3-yl)-
propanoate (7a): Ozonolysis of the alkene: A stirred solution of 8
(2.65 g, 8.18 mmol) in CH2Cl2 (150 mL) was cooled to Ϫ78 °C. O3
was bubbled through the solution for ca. 2 h, until it became blue.
Excess Me2S was added to the mixture, until the blue color disap-
peared. The solution was concentrated to a volume of 10 mL. Ϫ
Condensation with indole and Meldrum’s acid: The residue was
dissolved in CH3CN (100 mL) and to this solution were added in-
dole (957 mg, 8.18 mmol), Meldrum’s acid (1.18 g, 8.18 mmol), and
,-proline (47 mg, 0.41 mmol) under nitrogen. The reaction mix-
ture was stirred for 2 d at room temperature. The solvent was evap-
orated and column chromatography (eluent: acetone/hexane, 5:9)
yield) of a light brown solid. Ϫ M.p. 116 °C. Ϫ UV: λmax ϭ 206 nm,
˜
272, 289. Ϫ IR (film): ν ϭ 3424, 2949, 1778, 1742, 1690, 1296,
1234, 1013, 743. Ϫ 1H NMR (CDCl3): δ ϭ 1.25 (s, 3 H, CH3), 1.55
(s, 3 H, CH3), 3.78 (m, 2 H), 4.22 (m, 1 H), 4.45 (d, J ϭ 15.6 Hz,
1 H, NCH2Ph), 4.60 (t, J ϭ 3.0 Hz, 1 H), 4.61 (d, J ϭ 15.6 Hz, 1
H, NCH2Ph), 5.17 (d, J ϭ 12.8 Hz, 1 H, COOCH2Ph), 5.23 (d,
J ϭ 12.8 Hz, 1 H, COOCH2Ph), 7.00Ϫ7.40 (m, 14 H, Harom), 7.55
(d, J ϭ 8.0 Hz, 1 H, indole 4-H), 8.10 (s, 1 H, NH). Ϫ 13C NMR
(CDCl3): δ ϭ 27.7 (CH3), 28.1 (CH3), 35.4 (CH), 48.6 (Meldrum
CH), 50.5 (CH2N), 51.4 (CH2N), 67.7 (OCH2Ph), 105.0 (Meldrum
acetonide carbon), 111.0 (indole C-7), 112.9 (indole C-3), 119.2,
120.0, 122.4, 123.9 (indole C-2), 127.1 (indole C-3a), 127.4, 127.5,
128.1, 128.2, 128.4, 128.5, 135.5, 136.6, 137.7, 157.1 (carbamate
yielded 2.60 g of pale green solid (6.18 mmol, 76% yield). Ϫ M.p.
˜
46 °C. Ϫ UV: λmax ϭ 205 nm, 224, 270. Ϫ IR (film): ν ϭ 3412
1
cmϪ1, 1778, 1741, 1298, 1205, 1165, 1101, 1013, 745. Ϫ H NMR
(CDCl3): δ ϭ 1.31 (s, 3 H, CH3), 1.61 (s, 3 H, CH3), 3.08 (dd, J ϭ
6.7, 17.0 Hz, 1 H, CH2CO), 3.51 (dd, J ϭ 9.5, 17.0 Hz, 1 H,
CH2CO), 4.15 (d, J ϭ 3.0 Hz, 1 H, Meldrum CH), 4.70 (m, 1 H,
CH), 5.08 (d, J ϭ 4.0 Hz, 2 H, CH2Ph), 7.08Ϫ7.40 (m, 9 H, Harom),
7.72 (d, J ϭ 8.0 Hz, 1 H, indole 4-H), 8.28 (s, 1 H, indole NH). Ϫ
13C NMR (CDCl3): δ ϭ 27.5 (CH3), 28.0 (CH3), 31.8 (CH), 37.2
(CH2CO), 49.5 (Meldrum CH), 66.4 (CH2Ph), 105.1 (Meldrum
acetonide carbon), 111.1 (indole C-7), 114.3 (indole C-3), 119.1,
119.9, 122.3, 123.6 (indole C-2), 126.3 (indole C-3a), 128.0 (Ph),
128.1 (Ph), 128.4 (Ph), 135.5, 135.6, 165.0 (Meldrum CϭO), 165.6
(Meldrum CϭO), 172.2 (ester CϭO). Ϫ C24H23N1O6 (421.43). Ϫ
MS (EI); m/z (%): 373 (15), 277 (92) [Mϩ Ϫ Meldrum], 181 (25),
170 (58), 143 (100), 115 (60).
CϭO), 165.3 (Meldrum CϭO), 165.5 (Meldrum CϭO).
Ϫ
C31H30N2O6 (526.57). Ϫ MS (EI): m/z (%) ϭ 442 (17), 382 (13)
[Mϩ Ϫ Meldrum], 325 (18), 300 (10), 290 (45) [Mϩ Ϫ Meldrum Ϫ
Bn], 247 (13), 156 (15), 143 (100), 115 (20).
Dibenzyl (E)-Hex-3-enedioate (8): A stirred solution of (E)-3-hex-
enedioic acid (1.80 g, 12.50 mmol) and triethylamine (3.83 mL,
27.50 mmol) in CH2Cl2 (100 mL) was cooled to 0 °C with an ice
bath. To this solution was added benzyl chloroformate (3.57 mL,
Benzyl {2-[2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl]-2-(1H-indol-3-
yl)ethyl}carbamate (7b): Deprotection of the acetal: To a stirred
solution of acetal 9 (3.50 g, 14.60 mmol) in THF (80 mL) was ad- 25.00 mmol), and 4-(dimethylamino)pyridine (153 mg, 1.25 mmol).
ded 10% HCl solution (80 mL). The reaction mixture was stirred
at room temperature for 12 h. The organic solvent was evaporated,
and the aqueous residue was extracted with Et2O (3 ϫ 80 mL).
The combined extracts were washed with brine (3 ϫ 80 mL), dried
(Na2SO4), and concentrated to a volume of 10 mL. Ϫ Condensa-
tion with indole and Meldrum’s acid: The residue was dissolved in
CH3CN (100 mL) and to this solution were added indole (854 mg,
After warming the mixture to room temperature, it was stirred for
12 h, then washed with 5% NaHCO3 solution (2 ϫ 50 mL), 5%
citric acid solution (2 ϫ 50 mL), and brine (2 ϫ 50 mL), dried
(Na2SO4), and the solvent was then removed. The residue was puri-
fied by column chromatography (eluent: EtOAc/hexane, 2:8) to give
2.69 g (8.30 mmol, 66% yield) of white crystals. Ϫ M.p. 40 °C. Ϫ
˜
UV: λmax ϭ 207 nm. Ϫ IR (film): ν ϭ 3026 cmϪ1, 2944, 1726, 1383,
1
7.30 mmol), Meldrum’s acid (1.05 g, 7.30 mmol), and ,-proline 1302, 1184, 970, 741, 698. Ϫ H NMR (CDCl3): δ ϭ 3.12 (d, J ϭ
(42 mg, 0.36 mmol), under nitrogen. The reaction mixture was
stirred for 20 h at room temperature. The solvent was evaporated
and column chromatography (eluent: acetone/hexane, 5:9) yielded
5.4 Hz, 4 H, CH2CO), 5.12 (s, 4 H, CH2Ph), 5.72 (m, 2 H, CH),
7.34 (s, 10 H, Ph). Ϫ 13C NMR (CDCl3): δ ϭ 37.4 (CH2CO), 66.1
(CH2Ph), 125.6 (CH), 127.9 (Ph), 128.1 (Ph), 128.3 (Ph), 135.5
(Ph), 171.0 (CϭO). Ϫ C20H20O4. Ϫ MS (EI); m/z (%): 325 (53)
[Mϩ ϩ H], 307 (10), 271 (30), 233 (55), 181 (100), 145 (40), 127
(95), 107 (77). Ϫ HRMS: calcd. 325.1439; found 325.1434.
2.04 g of a light brown solid (4.68 mmol, 64% yield). Ϫ M.p. 62
˜
°C. Ϫ UV: λmax ϭ 206 nm, 272, 289. Ϫ IR (film): ν ϭ 3343 cmϪ1
,
1
3065, 2949, 1778, 1740, 1701, 1528, 1296, 1258, 743. Ϫ H NMR
3054
Eur. J. Org. Chem. 2000, 3051Ϫ3057

A Convenient Synthesis of Indole-Substituted 2-Pyrrolidones
FULL PAPER
Benzyl (2,2-Dimethoxyethyl)carbamate (9): To a stirred solution of
(2,2-dimethoxyethyl)amine (1.63 mL, 14.96 mmol) in Et2O (75 mL)
ture was stirred under H2 at atmospheric pressure at room temper-
ature for 20 h. The suspension was filtered through Celite , and
were added H2O (75 mL) and K2CO3 (6.20 g, 44.86 mmol). The the solvent was evaporated to give 525 mg (1.59 mmol, 79% yield)
reaction mixture was cooled to 0 °C and benzyl chloroformate
(2.14 mL, 14.96 mmol) was added dropwise. The mixture was al-
lowed to warm to room temperature and was stirred for 12 h. The 1101, 1017, 746. Ϫ 1H NMR ([D6]DMSO): δ ϭ 1.32 (s, 3 H, CH3),
of a clear orange solid. Ϫ M.p. 44 °C. Ϫ UV: λmax ϭ 205 nm, 272,
˜
289. Ϫ IR (film): ν ϭ 3410 cmϪ1, 2980, 1175, 1740, 1304, 1206,
phases were separated and the aqueous layer was extracted with
Et2O (2 ϫ 50 mL). The combined organic extracts were washed
with 5% citric acid solution (3 ϫ 75 mL) and brine (2 ϫ 75 mL),
dried (Na2SO4), and the solvent was then removed to give 3.50 g
1.72 (s, 3 H, CH3), 3.10 (m, 2 H, CH2), 4.51 (br t, J ϭ 9.0 Hz, 1
H, CH), 4.68 (d, J ϭ 2.0 Hz, 1 H, Meldrum CH), 7.01 (t, J ϭ
8.0 Hz, 1 H, indole 5-H), 7.08 (t, J ϭ 8.0 Hz, 1 H, indole 6-H),
7.34 (d, J ϭ 8.0 Hz, 1 H, indole 7-H), 7.62 (d, J ϭ 8.0 Hz, 1 H,
indole 4-H), 10.98 (s, 1 H, NH), 12.22 (br s, 1 H, COOH). Ϫ 13C
NMR ([D6]DMSO): δ ϭ 27.1 (CH3), 27.8 (CH3), 31.9 (CH), 38.7
(CH2), 50.6 (Meldrum CH), 105.1 (Meldrum acetonide carbon),
(14.60 mmol, 97% yield) of colorless oil. Ϫ UV: λmax ϭ 207 nm. Ϫ
˜
IR (film): ν ϭ 3337 cmϪ1, 2944, 2835, 1722, 1535, 1254, 1130, 1065,
970, 698. Ϫ 1H NMR (CDCl3): δ ϭ 3.32 (t, J ϭ 6.0 Hz, 2 H,
CH2NH), 3.38 (s, 6 H, OCH3), 4.39 (t, J ϭ 6.0 Hz, 1 H, CH), 5.02 111.5 (indole C-7), 113.8 (indole C-3), 118.7, 119.2, 121.2, 123.9
(br t, 1 H, NH), 5.11 (s, 2 H, CH2Ph), 7.35 (m, 5 H, Ph). Ϫ 13C
NMR (CDCl3): δ ϭ 42.5 (CH2NH), 54.3 (CH3), 66.8 (OCH2),
(indole C-2), 126.8 (indole C-3a), 135.7 (indole C-7a), 165.8 (Meld-
rum CϭO), 165.9 (Meldrum CϭO), 173.3 (acid CϭO).
C17H17N1O6: Mr ϭ 331.32. Ϫ MS (EI); m/z (%): 229 (59) [Mϩ
Ϫ
Ϫ
102.8 (CH), 128.0, 128.1, 128.5, 136.4, 156.4 (CϭO).
Ϫ
C12H17N1O4. Ϫ MS (EI); m/z (%): 239 (5) [Mϩ], 207 (30), 164 CH3COCH3 Ϫ CO2], 201 (10), 170 (15), 143 (100), 115 (26).
(100). Ϫ HRMS: calcd. 239.1157; found 239.1120.
Dimethyl 3-(1H-Indol-3-yl)pentanedioate (14): To a solution of 12
(100 mg, 0.30 mmol) in CH3CN (50 mL) was added ethyldiisoprop-
ylamine (0.53 mL, 3.02 mmol). The solution was stirred at 50 °C
for 3 d. The solvent was evaporated and Et2O (50 mL) was added
to the residue. To the suspension was added an excess of diazo-
methane. Dissolution gradually occurred on vigorous stirring. The
mixture was stirred for 10 h at room temperature, then concen-
trated under reduced pressure to give a brown residue which, after
crystallization in MeOH, gave 72 mg (0.26 mmol, 87% yield) of
Benzyl(2,2-dimethoxyethyl)amine (10): To a solution of (2,2-dime-
thoxyethyl)amine (10.67 mL, 98.11 mmol) in dry toluene (150 mL)
was added benzaldehyde (10.00 mL, 98.11 mmol). The mixture was
heated to 80 °C and stirred at this temperature for 12 h. The solvent
was then removed in vacuo, and the residue was dissolved in meth-
anol (120 mL). The mixture was stirred, cooled in an ice bath and
sodium tetrahydroborate (3.78 g, 100.00 mmol) was added por-
tionwise. After completion of the addition, the mixture was stirred
at room temperature for 24 h. The methanol was removed in vacuo,
and the white residue was dissolved in EtOAc (150 mL), washed
with water (3 ϫ 120 mL), dried (Na2SO4), and the solvent was then
white crystals. Ϫ M.p. 124 °C. Ϫ UV: λmax ϭ 203 nm, 221, 274,
˜
281, 291. Ϫ IR (KBr): ν ϭ 3403 cmϪ1, 2953, 1732, 1458, 1435,
1340, 1279, 1175, 1011, 745. Ϫ 1H NMR (CDCl3): δ ϭ 2.82 (d,
J ϭ 6.5 Hz, 4 H, CH2), 3.60 (s, 6 H, OCH3), 3.99 (t, J ϭ 6.5 Hz,
1 H, CH), 6.98 (d, J ϭ 2.0 Hz, 1 H, indole 2-H), 7.09 (t, J ϭ
8.0 Hz, 1 H, indole 5-H), 7.15 (t, J ϭ 8.0 Hz, 1 H, indole 6-H),
7.30 (d, J ϭ 8.0 Hz, 1 H, indole 7-H), 7.62 (d, J ϭ 8.0 Hz, 1 H,
indole 4-H), 8.50 (br s, 1 H, indole NH). Ϫ 13C NMR (CDCl3):
δ ϭ 29.9 (CH), 39.8 (CH2), 51.4 (OCH3), 111.3 (indole C-7), 117.1
(indole C-3), 118.7, 119.2, 121.2 (indole C-2), 121.7, 126.0 (indole
C-3a), 136.3 (indole C-7a), 172.6 (ester CϭO). Ϫ C15H17N1O4. Ϫ
MS (EI); m/z (%): 275 (43) [Mϩ], 244 (10), 215 (20), 202 (100),
170 (20), 160 (70), 143 (55), 115 (30). Ϫ HRMS: calcd. 275.1154;
found 275.1163.
removed to give 17.79 g of 10 as a colorless oil (91.23 mmol, 93%
˜
yield). Ϫ UV: λmax ϭ 203 nm. Ϫ IR (film): ν ϭ 2934 cmϪ1, 2905,
2832, 1495, 1452, 1194, 1130, 1067, 739, 698. Ϫ 1H NMR (CDCl3):
δ ϭ 1.59 (s, 1 H, NH), 2.76 (d, J ϭ 5.4 Hz, 2 H, CH2CH), 3.38 (s,
6 H, OCH3), 3.81 (s, 2 H, CH2NH), 4.49 (t, J ϭ 5.4 Hz, 1 H, CH),
7.31 (m, 5 H, Harom). Ϫ 13C NMR (CDCl3): δ ϭ 50.5, 53.8, 53.9
(CH3), 103.9 (CH), 126.9, 128.1, 128.4, 140.1. Ϫ C11H17N1O2. Ϫ
MS (EI); m/z (%): 195 (3) [Mϩ], 164 (25), 120 (100), 106 (13). Ϫ
HRMS: calcd. 195.1259; found 195.1258.
Benzyl (Benzyl)(2,2-dimethoxyethyl)carbamate (11): To a solution
of 10 (16.91 g, 86.74 mmol) in Et2O (150 mL) was added K2CO3
(35.96 g, 260.20 mmol) and water (150 mL). After cooling the reac-
tion mixture with an ice bath, benzyl chloroformate (12.38 mL,
86.74 mmol) was added dropwise. After 2 h, the layers were separ-
ated, and the aqueous layer was extracted with Et2O (2 ϫ 100 mL).
The combined organic extracts were washed with water (3 ϫ
100 mL) and dried (Na2SO4). The solvent was then removed to give
4-(1H-Indol-3-yl)pyrrolidin-2-one (15a): To
a solution of 12
(550 mg, 1.66 mmol) in CH3CN (50 mL) was added ethyldiisoprop-
ylamine (2.89 mL, 16.60 mmol). The solution was stirred at 50 °C
for 3 d. The solvent was evaporated and the residue was dissolved
in tBuOH (50 mL). The solution was heated to 50 °C, and di-
phenylphosphoryl azide (0.36 mL, 1.66 mmol) was added. The
mixture was stirred at this temperature for 2 d. The solvent was
evaporated and column chromatography (eluent: EtOAc/MeOH,
27.82 g of 11 as a yellowish oil (84.56 mmol, 97% yield). Ϫ UV:
˜
λmax ϭ 208 nm. Ϫ IR (film): ν ϭ 2947 cmϪ1, 1703, 1418, 1242,
1
1122. Ϫ H NMR ([D5]pyridine): δ ϭ 3.28 (s, 1.5 H, OCH3), 3.32
100:2) gave 73 mg (0.37 mmol, 22% yield) of white crystals. Ϫ M.p.
(s, 1.5 H, OCH3), 3.51 (d, J ϭ 4.0 Hz, 1 H, CHCH2), 3.63 (d, J ϭ
4.0 Hz, 1 H, CHCH2), 4.64 (t, J ϭ 4.0 Hz, 0.5 H, CH), 4.74 (s, 1
H, NCH2), 4.79 (t, J ϭ 4.0 Hz, 0.5 H, CH), 4.84 (s, 1 H, NCH2),
5.34 (s, 1 H, OCH2), 5.38 (s, 1 H, OCH2), 7.20Ϫ7.55 (m, 10 H,
Harom). Ϫ 13C NMR (CDCl3): δ ϭ 47.7, 48.7, 51.4, 54.5 (OCH3),
67.3 (OCH2), 103.4 (CH), 103.9 (CH), 127.2, 127.8, 127.9, 128.4,
136.6, 137.7, 156.4 (CϭO). Ϫ C19H23N1O4: Mr ϭ 329.38. Ϫ MS
(EI); m/z (%): 298 (100) [Mϩ Ϫ OCH3], 254 (54), 222 (49), 181 (39),
162 (29), 118 (31). Ϫ HRMS: calcd. 298.1443; found 298.1437.
˜
163 °C. Ϫ UV: λmax ϭ 221 nm, 281, 290. Ϫ IR (KBr): ν ϭ 3406
cmϪ1, 3260, 1680, 1431, 1339, 1267, 1103, 743. Ϫ 1H NMR
([D6]DMSO): δ ϭ 2.40 (dd, J ϭ 9.0, 17.0 Hz, 1 H, CH2CO), 2.60
(dd, J ϭ 9.0, 17.0 Hz, 1 H, CH2CO), 3.32 (t, J ϭ 8.0 Hz, 1 H,
CH2NH), 3.73 (t, J ϭ 8.0 Hz, 1 H, CH2NH), 3.85 (m, 1 H, CH),
7.01 (t, J ϭ 8.0 Hz, 1 H, indole 5-H), 7.11 (t, J ϭ 8.0 Hz, 1 H,
indole 6-H), 7.24 (d, J ϭ 2.0 Hz, 1 H, indole 2-H), 7.38 (d, J ϭ
8.0 Hz, 1 H, indole 7-H), 7.58 (d, J ϭ 8.0 Hz, 1 H, indole 4-H),
7.71 (s, 1 H, lactam NH), 10.92 (s, 1 H, indole NH). Ϫ 13C NMR
([D6]DMSO): δ ϭ 31.9 (CH), 37.4, 48.2, 111.7 (indole C-7), 116.1
(indole C-3), 118.6, 118.7, 121.3, 121.7, 126.4 (indole C-3a), 136.8
(indole C-7a), 176.6 (CϭO). Ϫ C12H12N2O1. Ϫ MS (EI); m/z (%):
3-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-(1H-indol-3-yl)-
propionic Acid (12): To a solution of 7a (850 mg, 2.02 mmol) in
absolute ethanol (50 mL) was added 10% Pd/C (127 mg). The mix-
Eur. J. Org. Chem. 2000, 3051Ϫ3057
3055

M. Boisbrun, L. Jeannin, L. Toupet, J.-Y. Laronze
FULL PAPER
200 (70) [Mϩ], 170 (10), 143 (100), 115 (35). Ϫ HRMS: calcd.
200.0949; found 200.0996.
741. Ϫ 1H NMR (CDCl3): δ ϭ 1.05 (t, J ϭ 7.0 Hz, 3 H, CH3),
3.30Ϫ5.20 (m, 12 H), 6.80Ϫ7.55 (m, 21 H), 8.12 (s, 0.5 H, indole
NH), 8.25 (s, 0.5 H, indole NH). Ϫ 13C NMR (CDCl3): δ ϭ 13.8,
13.9, 36.3, 37.1, 38.2, 38.8, 47.0, 48.2, 48.6, 49.5, 50.4, 51.1, 55.2,
56.4, 61.5, 61.7, 66.7, 67.0, 67.2, 67.7, 110.5, 110.6, 113.0, 111.3,
118.3, 118.7, 119.5, 122.1, 127.2, 127.4, 127.6, 127.8, 128.0, 128.1,
128.4, 128.5, 136.0, 136.1, 136.8, 137.4, 156.4 (carbamate CϭO),
156.7 (carbamate CϭO), 171.5 (ester CϭO). Ϫ C37H37N3O6. Ϫ MS
(EI): m/z (%) ϭ 619 (2) [Mϩ], 511 (45), 383 (100). Ϫ HRMS: calcd.
619.2682; found 619.2665.
Benzyl 4-(1H-Indol-3-yl)-2-oxopyrrolidine-1-carbamate (15b): A so-
lution of 7b (0.50 g, 1.15 mmol) in absolute ethanol was refluxed
for 1.5 h. The mixture was concentrated to dryness and purified
twice by column chromatography on silica gel (eluent: CH2Cl2/
MeOH, 9.5:0.5) to give 240 mg (0.62 mmol, 63% yield) of a color-
less solid. Ϫ M.p. 163 °C. Ϫ UV: λmax ϭ216 nm, 281, 290. Ϫ IR
˜
(KBr): ν ϭ 3345 cmϪ1, 2927, 1780, 1709, 1456, 1281, 1103, 1028,
1
745. Ϫ H NMR ([D6]DMSO): δ ϭ 2.80 (dd, J ϭ 8.9, 16.9 Hz, 1
H, CH2CO), 2.95 (dd, J ϭ 7.7, 16.9 Hz, 1 H, CH2CO), 3.80 (m, 2
H, CH & CH2N), 4.25 (t, J ϭ 6.6 Hz, 1 H, CH2N), 5.25 (s, 2 H,
CH2Ph), 7.01 (t, J ϭ 8.0 Hz, 1 H, indole 5-H), 7.11 (t, J ϭ 8.0 Hz,
1 H, indole 6-H), 7.28 (d, J ϭ 2.0 Hz, 1 H, indole 2-H), 7.30Ϫ7.50
(m, 6 H, Harom), 7.62 (d, J ϭ 8.0 Hz, 1 H, indole 4-H), 10.98 (br
s, 1 H, NH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 28.2 (CH), 39.3, 52.2,
67.1 (CH2Ph), 111.8 (indole C-7), 114.4 (indole C-3), 118.7, 118.8,
121.5, 121.9, 126.3 (indole C-3a), 127.9 (Ph), 128.2 (Ph), 128.6 (Ph),
136.0, 136.7, 151.1 (carbamate CϭO), 173.2 (lactam CϭO). Ϫ
C20H18N2O3. Ϫ MS (EI); m/z (%): 334 (45) [Mϩ], 200 (18), 143
(100), 130 (10), 115 (15). Ϫ HRMS: calcd. 334.1317; found
334.1304.
(؎)-cis-3-Amino-1-benzyl-4-(1H-indol-3-yl)pyrrolidin-2-one
(18a)
and (؎)-trans-3-Amino-1-benzyl-4-(1H-indol-3-yl)pyrrolidin-2-one
(18b): To a solution of 17 (3.07 g, 4.96 mmol) in absolute ethanol
(80 mL) was added 10% Pd/C (400 mg). The mixture was stirred
under H2 at atmospheric pressure at room temperature for 48 h.
The suspension was filtered through Celite , and the solvent was
evaporated. The residue was purified twice by column chromato-
graphy on silica gel (eluent: CH2Cl2/MeOH/AcOH, 180:10:5) to
give 0.57 g of 18a as a light brown solid (1.87 mmol, 38% yield,
less polar compound) and 0.56 g of 18b as
a white solid
(1.84 mmol, 37% yield, more polar compound). Both were crystal-
lized from MeOH to give analytically pure samples.
Ethyl Hydrogen 2-{2-[(Benzyl)(benzyloxycarbonyl)amino]-1-(1H-in-
dol-3-yl)ethyl}malonate (16): A solution of 7c (4.15 g, 7.89 mmol)
in EtOH (40 mL) was stirred under nitrogen for 48 h at 60 °C. The
solvent was evaporated, the residue was dissolved in Et2O (75 mL)
and extracted with 5% NaHCO3 solution (4 ϫ 50 mL). The com-
bined aqueous extracts were carefully acidified with 10% HCl solu-
tion, and the resulting suspension was extracted with EtOAc (3 ϫ
100 mL). The combined organic extracts were washed with brine
(2 ϫ 100 mL), dried, and concentrated to give 3.61 g of 16 as a
Compound 18a: M.p. 155 °C. Ϫ UV: λmax ϭ 207 nm, 218, 273, 283,
˜
290. Ϫ IR (KBr): ν ϭ 3235 cmϪ1, 2934, 2874, 1684, 1495, 1456,
1
1261, 745. Ϫ H NMR ([D6]DMSO): δ ϭ 1.31 (br s, 2 H, NH2),
3.45 (dd, J ϭ 5.0, 9.0 Hz, 1 H, CH2NCH2Ph), 3.59 (dd, J ϭ 7.0,
9.0 Hz, 1 H, CH2NCH2Ph), 3.76 (d, J ϭ 8.0 Hz, 1 H, CHNH2),
3.88 (m, 1 H, CH), 4.48 (d, J ϭ 12.0 Hz, 1 H, CH2Ph), 4.58 (d,
J ϭ 12.0 Hz, 1 H, CH2Ph), 6.98 (t, J ϭ 8.0 Hz, 1 H, indole 5-H),
7.08 (s, 1 H, indole 2-H), 7.10 (t, J ϭ 8.0 Hz, 1 H, indole 6-H),
7.25Ϫ7.40 (m, 6 H, Harom), 7.53 (d, J ϭ 8.0 Hz, 1 H, indole 4-H),
11.0 (s, 1 H, NH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 35.3 (CH),
46.0 (CH2Ph), 50.0 (CH2), 55.6 (CHNH2), 111.4 (indole C-3), 111.6
(indole C-7), 118, 7 (indole C-5), 118.9 (indole C-4), 121.3 (indole
C-6), 123.2 (indole C-2), 127.3 (indole C-3a), 127.5 (Ph), 128.1
(Ph), 128.8 (Ph), 136.3 (indole C-7a), 137.1 (Ph), 175.3 (CϭO). Ϫ
C19H19N3O1. Ϫ MS (EI): m/z (%) ϭ 305 (45) [Mϩ], 288 (3) [Mϩ
Ϫ NH3], 248 (5), 171 (10), 158 (23), 143 (100), 130 (25), 115 (10).
Ϫ HRMS: calcd. 305.1528; found 305.1497.
brown solid (7.02 mmol, 90% yield). Ϫ M.p. 136 °C. Ϫ UV: λmax ϭ
˜
203 nm, 217, 282, 292. Ϫ IR (film): ν ϭ 3389 cmϪ1, 3061, 3034,
2982, 1730, 1694, 1456, 1427, 1227, 1177, 741. Ϫ 1H NMR
(CDCl3): δ ϭ 0.80 (t, J ϭ 7.0, 1.5 H, CH3), 1.18 (t, J ϭ 7.0, 1.5
H, CH3), 3.65Ϫ3.95 (m, 4 H), 4.05Ϫ4.40 (m, 4 H), 4.90Ϫ5.12 (m,
2 H, OCH2), 6.80Ϫ7.55 (m, 15 H, Harom), 8.08 (s, 0.5 H, NH), 8.12
(s, 0.5 H, NH), 9.30 (br s, 1H, CO2H). Ϫ 13C NMR (CDCl3): δ ϭ
13.4 (CH3), 13.9 (CH3), 49.0, 50.6, 50.7, 54.8 (CH), 55.4 (CH),
61.5 (COOCH2CH3), 61.9 (COOCH2CH3), 67.5 (CO2CH2Ph), 67.6
(CO2CH2Ph), 111.2 (indole C-7), 111.3 (indole C-7), 112.7 (indole
C-3), 112.8 (indole C-3), 118.9, 119.0, 119.6, 122.1, 123.3, 127.2,
127.4, 127.5, 127.6, 127.7, 128.0, 128.4, 136.1, 136.2, 136.5, 137.4,
137.6, 156.9 (carbamate CϭO), 168.3 (ester CϭO), 169.0 (ester Cϭ
O), 171.1 (acid CϭO), 171.3 (acid CϭO). Ϫ C30H30N2O6: Mr ϭ
514.56. Ϫ MS (EI): m/z (%) ϭ 470 (55) [Mϩ Ϫ CO2], 229 (45), 216
(100), 143 (90). Ϫ HRMS: calcd. 470.2202; found 470.2205.
Compound 18b: M.p. 185 °C. Ϫ UV: λmax ϭ 207 nm, 218, 273, 283,
˜
290. Ϫ IR (KBr): ν ϭ 3293 cmϪ1, 2930, 2878, 1686, 1495, 1447,
1
1261, 741. Ϫ H NMR ([D5]pyridine): δ ϭ 2.40 (br s, 2 H, NH2),
3.45 (t, J ϭ 8.5 Hz, 1 H, CH2NCH2Ph), 3.61 (t, J ϭ 8.5 Hz, 1 H,
CH2NCH2Ph), 3.69 (m, 1 H, CH), 4.10 (d, J ϭ 9.0 Hz, 1 H,
CHNH2), 4.62 (d, J ϭ 14.5 Hz, 1 H, CH2Ph), 4.70 (d, J ϭ 14.5 Hz,
1 H, CH2Ph), 7.15Ϫ7.40 (m, 7 H, Harom), 7.42 (d, J ϭ 2.0 Hz, 1
H, indole 2-H), 7.58 (d, J ϭ 8.0 Hz, 1 H, indole 7-H), 7.83 (d,
J ϭ 8.0 Hz, 1 H, indole 4-H), 12.03 (s, 1 H, NH). Ϫ 13C NMR
([D6]DMSO): δ ϭ 40.2 (CH), 46.0 (CH2Ph), 49.5 (CH2), 58.8
(CHNH2), 111.7 (indole C-7), 113.6 (indole C-3), 118.5 (indole C-
5), 119.0 (indole C-4), 121.2 (indole C-6), 122.4 (indole C-2), 126.8
(indole C-3a), 127.4 (Ph), 127.8 (Ph), 128.8 (Ph), 136.7, 137.0, 175.2
(CϭO). Ϫ C19H19N3O1. Ϫ MS (EI): m/z (%) ϭ 305 (40) [Mϩ], 288
(2) [Mϩ Ϫ NH3], 248 (5), 171 (10), 158 (20), 143 (100), 130 (25),
115 (10). Ϫ HRMS: calcd. 305.1528; found 305.1513.
Ethyl 4-[(Benzyl)(benzyloxycarbonyl)amino]-2-[(benzyloxycarbonyl)-
amino]-3-(1H-indol-3-yl)butyrate (17): To a solution of 16 (3.59 g,
6.98 mmol) in dry toluene (49 mL) was added triethylamine
(1.46 mL, 10.47 mmol) and diphenylphosphoryl azide (2.26 mL,
10.47 mmol), under nitrogen. The reaction mixture was stirred for
1 h at 50 °C, then refluxed for 0.5 h. Benzyl alcohol (1.08 mL,
10.47 mmol) was added, and the mixture was refluxed for 12 h. The
solvent was evaporated, and the residue was dissolved in EtOAc
(150 mL). The solution was washed with 5% NaHCO3 solution (3
ϫ 100 mL), 5% citric acid solution (3 ϫ 100 mL), and brine (2 ϫ
(؎)-(3aR*,5R*,10cR*)-2-Benzyl-5-phenyl-1,3a,4,5,6,10c-hexa-
100 mL), then dried (Na2SO4), and concentrated. The residue was hydropyrrolo[3Ј,4Ј:5,6]pyrido[3,4-b]indol-3(2H)-one (19a) and (؎)-
purified by column chromatography on silica gel (eluent: EtOAc/ (3aR*,5S*,10cR*)-2-benzyl-5-phenyl-1,3a,4,5,6,10c-hexahydro-
hexane, 2:8) to give 2.78 g (4.49 mmol, 63% yield) of a light yellow pyrrolo[3Ј,4Ј:5,6]pyrido[3,4-b]indol-3(2H)-one (20a): To a suspen-
solid. Ϫ M.p. 50 °C. Ϫ UV: λmax ϭ 224 nm, 276, 281, 290. Ϫ IR
sion of 18a (100 mg, 0.32 mmol) in CH2Cl2 (15 mL), containing
activated molecular sieves (4 A), was added benzaldehyde (50 µL,
˚
˜
(film): ν ϭ 3325 cmϪ1, 3063, 3034, 1722, 1699, 1497, 1234, 1062,
3056
Eur. J. Org. Chem. 2000, 3051Ϫ3057

A Convenient Synthesis of Indole-Substituted 2-Pyrrolidones
FULL PAPER
0.49 mmol). The mixture was stirred at room temperature under
nitrogen for 24 h. Trifluoroacetic acid (50 µL, 0.66 mmol) was ad-
(0.04Fo2)2]Ϫ1/2} with the resulting R ϭ 0.043, Rw ϭ 0.042 and Sw ϭ
˚
0.724 (residual ∆ρ Յ 0.17 e AϪ3). Atomic scattering factors from
ded and the mixture was stirred for 3 h, then washed with 5% International Tables for X-ray Crystallography, 1974. The calcula-
NaHCO3 solution (2 ϫ 20 mL), and brine (2 ϫ 20 mL), dried tions were performed with a Silicon Graphics Indy R4600 com-
(Na2SO4), and concentrated to dryness. Column chromatography puter with the MOLEN package (EnrafϪNonius, 1990) and
(eluent: EtOAc/hexane, 5:5) gave 37 mg (0.09 mmol, 29% yield) of
white crystals of 19a (less polar compound) and 37 mg (0.09 mmol,
29% yield) of white crystals of 20a (more polar compound).
SHELXS-86 (Sheldrick, 1985).
Acknowledgments
Compound 19a: M.p. 201 °C. Ϫ UV: λmax ϭ 206 nm, 220, 281, 290.
˜
Ϫ IR (KBr): ν ϭ 3281 cmϪ1, 2924, 1682, 1454, 1258, 698. Ϫ 1H
This work was financed by the ADIR Company (Laboratoires
Servier) and by the CNRS (Centre National de la Recherche Scien-
tifique), to which our gratitude is expressed. Special thanks are
due to Dr. Csaba Nemes for helpful discussions and to Christelle
Berteaux for her collaboration.
NMR (CDCl3): δ ϭ 2.40 (br s, 1 H, NH), 3.48 (t, J ϭ 8.6 Hz, 1
H, CH2NCH2Ph), 3.61 (m, 1 H, CHCHNH), 3.79 (t, J ϭ 7.9 Hz,
1 H, CH2NCH2Ph), 3.95 (d, J ϭ 6.1 Hz, 1 H, CHCHNH), 4.41 (d,
J ϭ 14.9 Hz, 1 H, CH2Ph), 4.60 (d, J ϭ 14.9 Hz, 1 H, CH2Ph),
5.15 (s, 1 H, CHPh), 7.00Ϫ7.40 (m, 14 H, Harom), 7.55 (s, 1 H,
indole NH). Ϫ 13C NMR (CDCl3): δ ϭ 31.0 (CH2CH), 46.5
(NCH2Ph), 52.1 (CH2CH), 57.4 (NHCHPh), 58.5 (COCHNH),
107.6 (indole C-3), 111.1 (indole C-7), 118.0, 119.7, 121.9, 126.7
(indole C-3a), 127.5, 127.9, 128.5, 128.6, 128.7, 128.8, 135.7, 135.8,
136.2, 140.5, 173.6 (CϭO). Ϫ C26H23N3O1. Ϫ MS (EI): m/z (%) ϭ
393 (100) [Mϩ], 316 (60), 245 (55), 219 (55), 169 (95). Ϫ HRMS:
calcd. 393.1841; found 393.1838.
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A. Terpin, C. Winklhofer, S. Schumann, W. Steglich, Tetra-
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Y. Oikawa, H. Hirasawa, O. Yonemitsu, Tetrahedron Lett.
1978, 1759.
S. Kim, J. I. Lee, Y. C. Kim, J. Org. Chem. 1985, 50, 560Ϫ565.
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[3]
[4]
[5]
Compound 20a: M.p. 195 °C. Ϫ UV: λmax ϭ 205 nm, 220, 283, 290.
˜
Ϫ IR (KBr): ν ϭ 3297 cmϪ1, 2928, 2861, 1688, 1454, 1285, 1117,
[6]
1
743, 700. Ϫ H NMR (CDCl3): δ ϭ 2.70 (br s, 1 H, NH), 3.51 (d,
[7]
J ϭ 9.6 Hz, 1 H, CH2NCH2Ph), 3.63 (dd, J ϭ 6.0, 9.6 Hz, 1 H,
CH2NCH2Ph), 3.99 (t, J ϭ 6.6 Hz, 1 H, CHCHNH), 4.13 (d, J ϭ
7.0 Hz, 1 H, CHCHNH), 4.16 (d, J ϭ 14.9 Hz, 1 H, CH2Ph), 4.61
(d, J ϭ 14.9 Hz, 1 H, CH2Ph), 5.28 (s, 1 H, CHPh), 6.95Ϫ7.40 (m,
14 H, Harom), 7.60 (s, 1 H, indole NH). Ϫ 13C NMR (CDCl3): δ ϭ
30.4 (CH2CH), 46.7 (NCH2Ph), 49.6 (CH2CH), 53.8 (NHCHPh),
57.9 (COCHNH), 108.0 (indole C-3), 111.2 (indole C-7), 118.0,
119.6, 121.8, 126.2 (indole C-3a), 127.3, 127.6, 128.4, 128.5, 128.7,
128.9, 135.7, 136.1, 136.5, 140.7, 173.1 (CϭO). Ϫ C26H23N3O1. Ϫ
MS (EI): m/z (%) ϭ 393 (100) [Mϩ], 376 (30), 302 (30), 285 (25),
245 (80), 219 (20), 169 (85). Ϫ HRMS: calcd. 393.1841; found
393.1820.
[8]
[9]
[10] A. S. Verdini, S. Silvestri, C. Becherucci, M. G. Longobardi,
L. Parente, S. Peppoloni, M. Perretti, P. Pileri, M. Pinori, G.
C. Viscomi, L. Nencioni, J. Med. Chem. 1991, 34, 3372Ϫ3379.
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26, 2343Ϫ2346.
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60, 3700Ϫ3706.
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Palmer, S. N. Prince, C. D. Reynolds, S. D. Wood, J. Chem.
Soc., Perkin Trans. 1 1993, 431Ϫ439.
[14] J. Sandrin, D. Soerens, J. M. Cook, Heterocycles 1976, 4, 1249.
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102, 6976.
X-ray Analysis of 18b:[16,17] C19H19ON3 (Mr ϭ 305.38), orthorhom-
˚
bic, P212121, a ϭ 8.490(2), b ϭ 9.358(2), c ϭ 20.262(4) A, V ϭ
˚
1609.7(6) AϪ3, Z ϭ 4, Dx ϭ 1.260 Mg·mϪ3, λ(Mo-Kα) ϭ 0.71073
[16] Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-137717. A copy of the data can be ob-
tained free of charge on application to the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/
336-033; E-mail: deposit@ccdc.cam.ac.uk].
˚
A, µ ϭ 0.746 cmϪ1, F(000) ϭ 648, T ϭ 294 K. The sample (0.30
ϫ 0.30 ϫ 0.35 mm) was studied with an automatic diffractometer
CAD4 - with graphite-monochromatized Mo-Kα radi-
ation. The cell parameters were obtained by fitting a set of 25 high-
theta reflections. The data collection [2θmax ϭ 50°, scan ω/2θ ϭ 1,
[17] [17a] C. K. Fair, in An interactive Intelligent System for Crystal
t
max ϭ 60 s, hkl range: h 0,10, k 0,11, l 0,25 intensity controls with-
out appreciable decay (0.3%)] gave 1922 reflections, of which 1375
independent with I Ͼ 2σ(I). After Lorentz and polarization correc-
tions, the structure was solved using SHELXS-86, which revealed
the non-hydrogen atoms of the molecule. After anisotropic refine-
Structure analysis, EnrafϪNonius, Delft, The Netherlands,
[17b]
1990. Ϫ
International Tables for X-ray Crystallography,
Birmingham, Kynoch Press (present distributor: D. Reidel,
Dordrecht), 1974, vol. IV. Ϫ
[17c]
C. K. Johnson, ORTEP, Re-
port ORNL-3794, Oak Ridge National Laboratory, Tennessee,
USA, 1965. Ϫ [17d] G. M. Sheldrick, in Crystallographic Com-
puting 3: Data Collection, Structure Determination, Proteins
and Databases (Ed.: G. M. Sheldrick, C. Krüger, R. Goddard),
Oxford, Clarendron Press, 1985.
ment, the hydrogen atoms were found with a difference Fourier
˚
analysis (between 0.40 and 0.25 e AϪ3). The whole structure was
refined by full-matrix, least-squares techniques {use of F magni-
tude; x, y, z, βij for C, O and N atoms and x, y, z for H atoms; 266
Received March 8, 2000
variables and 1375 observations; w ϭ 1/σ(Fo)2 ϭ [σ2(I)
ϩ
[O00119]
Eur. J. Org. Chem. 2000, 3051Ϫ3057
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