Intramolecular Mannich reaction of 2-oxotryptamine and homologues with oxo reagents yielding spiro compounds. Part II

Article abstract of DOI:10.1135/cccc20021669

2-Oxotryptamine and its homo derivative undergo intramolecular Mannich-type cyclization with acetone and other ketones to give spiro[indole-3,3′-pyrrolidin]-2-ones and spiro[indole-3,3′-piperidin]-2-ones. A similar reaction with the bis-homologue of 2-oxotryptamine to yield spiro[azepane-3,3′-indol]-2′-ones was unsuccessful.

Full text of DOI:10.1135/cccc20021669

Mannich Reaction Yielding Spiro Compounds
1669
INTRAMOLECULAR MANNICH REACTION OF 2-OXOTRYPTAMINE
AND HOMOLOGUES WITH OXO REAGENTS YIELDING SPIRO
COMPOUNDS. PART II+
1,
2
Gábor DÖRNYEI *, Mária INCZE, Mária KAJTÁR-PEREDY and Csaba SZÁNTAY
Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
1
H-1025 Budapest II, Pusztaszeri út 59–67, Hungary; e-mail: gdornyei@chemres.hu,
2
szantay@mail.bme.hu
Received May 28, 2002
Accepted October 29, 2002
2-Oxotryptam in e an d its h om o derivative un dergo in tram olecular Man n ich -type cycli-
zation with aceton e an d oth er keton es to give spiro[in dole-3,3′-pyrrolidin ]-2-on es an d
spiro[in dole-3,3′-piperidin ]-2-on es. A sim ilar reaction with th e bis-h om ologue of 2-oxo-
tryptam in e to yield spiro[azepan e-3,3′-in dol]-2′-on es was un successful.
Keyw ord s: In tram olecular Man n ich reaction ; Spirocyclic com poun ds; Oxin doles;
Pyrrolidin es; Piperidin es; Cyclization s; Alkaloids; Keton es; In doles.
In our previous publication 1, we reported an un expected in tram olecular
Man n ich cyclization , wh ich occurred wh en 2-oxotryptam in e an d 2-oxo-
5-m eth oxytryptam in e were treated with aceton e in th e presen ce of K2CO3
an d alkyl h alides. In th is way, a series of 1′-substituted 2′,2′-dim eth ylspiro-
[in dole-3,3′-pyrrolidin ]-2-on e derivatives h as been syn th esized (Sch em e 1).
NR1
R
NH3 Cl
R
R1X/K2CO3
acetone
N
H
O
N
H
O
R = H or CH3O; R1 = alkyl, aralkyl
SCHEME 1
3-Substituted in dolin -2-on es are con sidered ph ysiologically active com -
poun ds, with poten tial selectivity to various receptor tyrosin e kin ases2 an d
seroton in es; sim ilarly, 2-oxospiroin doles sh ow im portan t biological ef-
+ Part I, see ref.1
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021669

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Dörnyei et al.:
fects3. On e of th ese com poun ds is a selective an tagon ist of vasopressin V2
receptor, an d h en ce a can didate for con trollin g th e clin ically debilitatin g
con dition of h ypon atrem ia an d associated syn drom es4.
Because of th e in creasin g in terest, th e scope an d lim itation of th is in tra-
m olecular Man n ich -type rin g closure h ave been in vestigated. In th e course
of th is research , th e reaction of 2-oxotryptam in e (1) with bulkier keton es
was studied first. Wh en eth yl m eth yl keton e was used as th e reagen t in -
stead of aceton e, th e reaction slowed down an d th e correspon din g 2′-eth yl-
2′-m eth yl-2-oxospiropyrrolidin e diastereom ers (2 an d 3) could be isolated
as a m ixture of h ydroch lorides (Sch em e 2). Th e actual stereoch em istry at
ch iral cen ter C2′ of th is on e an d sim ilar diastereom etric pairs was assign ed
on th e basis of th e m easured NOE effects between th e H4 arom atic proton
an d on e of th e C2′ substituen ts. In th e case of diastereom eric m ixture 2 + 3,
1H NMR sh owed th at th e ratio of th e two com poun ds was about 10:1 in
favour of th e sterically less h in dered isom er 2. After repeated recrystal-
lization , th e m ore stable isom er 2 was isolated in a pure form .
H
N
H
N
NH3 Cl
CH3COC2H5
+
:
O
O
N
H
O
K2CO3
51%
N
H
N
H
2
3
1
10
1
SCHEME 2
A sim ilar result was expected wh en th e reaction was carried out with
m eth yl vin yl keton e; h owever a great n um ber of products was observed by
TLC in th e reaction m ixture as a con sequen ce of am bivalen t reactivity of
α,β-un saturated carbon yl com poun ds.
Th e reaction with bulkier keton es (pen tan -3-on e, acetoph en on e, ben zo-
ph en on e) proved un successful. Wh ile th e form ation of a n ew com poun d,
presum ably 2′,2′-dieth yl spiro com poun d 4, could be observed in th e reac-
tion of 2-oxotryptam in e with pen tan -3-on e, th is com poun d turn ed out to
be extrem ely un stable, an d durin g even a careful work-up a reverse process
took place, an d on ly th e startin g m aterial could be isolated (Sch em e 3). No
reaction was observed (TLC) with acetoph en on e an d ben zoph en on e.
Surprisin gly, cyclic keton es (cycloh exan on e an d 1-ben zyl-4-piperidon e)
gave good yields of bis-spiro com poun ds 5 an d 6 (Sch em e 4).
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Mannich Reaction Yielding Spiro Compounds
1671
H
N
NH3 Cl
CH3COC2H5
K2CO3
O
N
H
O
N
H
4
1
SCHEME 3
H
N
Z
NH3 Cl
Z
O
O
N
H
O
K2CO3
N
H
1
Z
CH2
NCH2Ph
yield
65%
72%
5
6
SCHEME 4
With cycloh exan e-1,3-dion e, h owever, n o cyclization was observed. Th e
Sch iff base 7, th e form ation of wh ich is assum ed to be th e in itial step of all
in tram olecular Man n ich -type reaction s, is stabilized in th is case as a con ju-
gated en am in e (vin ylogous am ide 8) (Sch em e 5).
O
N
O
NH3 Cl
O
N
H
O
N
H
O
7
1
H
N
O
79%
N
H
O
8
SCHEME 5
An oth er in terestin g poin t was to in vestigate th e reactivity of 3-am in o-
alkylin dol-2-on es. Th e h om ologues of 2-oxotryptam in e seem to be excitin g
startin g m aterials for an in tram olecular Pictet–Spen gler cyclization , n ot
on ly from th e viewpoin t of determ in in g th e scope an d lim itation , but also
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1672
Dörnyei et al.:
because of th e possibility of preparin g n ew, so far un described spiro com -
poun ds. For th is reason , 2-oxoh om otryptam in e [3-(3-am in opropyl)in dolin -
2-on e; 17], an d th e bis-h om o derivative [3-(4-am in obutyl)in dolin -2-on e;
18] were syn th esized from in dole-3-propan oic acid (9) an d in dole-3-
butan oic acid (11), respectively, as depicted in Sch em e 6.
CO2R
CONH2
n
n
NH3
N
H
N
H
n
2
3
n
R
H
Me
H
13
14
9
2
2
3
3
10
11
12
LiAlH4
Me
NH3 Cl
NH3 Cl
m
m
DMSO/HCl
N
H
O
N
H
m
3
4
yield
75%
62%
m
3
4
17
18
15
16
SCHEME 6
Carboxylic acids 9 an d 11 were first esterified with MeOH/HCl, an d
am in olysis of esters 10 an d 12 furn ish ed th e correspon din g am ides 13 an d
14. LiAlH4 reduction of 13 an d 14 in THF produced tryptam in e h om o-
logues 15 an d 16 as HCl salts; fin ally, 2-oxotryptam in e h om ologues 17 an d
18 were obtain ed by DMSO/HCl oxidation 1,5. Wh ile in vestigatin g th e reac-
tivity of th e two h om ologues, we foun d th at com poun d 17 basically gives
all th e studied in tram olecular Man n ich -type reaction s with aldeh ydes an d
keton es resultin g in th e form ation of spiro[in dole-3,3′-piperidin ]-2-on es
(19–27). Som e represen tative reaction s are sh own in Sch em e 7.
Interestingly enough, these spiro[indole-3,3′-piperidin]-2-ones are som ewhat
less stable th an th e correspon din g spiro[in dole-3,3′-pyrrolidin ]-2-on es; th ey
can be stored as th e correspon din g HCl salts, but th e free bases slowly de-
com pose in a reverse process (TLC an d NMR evaluation ).
Startin g with com poun d 18, n o in tram olecular Man n ich reaction leadin g
to spiro[azepan e-3,3′-in dole]-2′-on es could be effected with an y keton e.
In sum m ary, our presen t an d earlier1 fin din gs sh ow th at in tram olecular
Man n ich -type cyclization of 2-oxotryptam in e (1) an d 2-oxoh om otrypt-
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Mannich Reaction Yielding Spiro Compounds
1673
HN
Ph
HN
H
NR
H
Ph
+
O
O
N
H
O
N
H
N
H
acetone + RX
22 (54%)
23 (28%)
PhCHO
R
H
yield
70%
74%
72%
19
20
21
CH3
CH2CO2Et
NH3 Cl
N
H
O
Z
O
CH3COC2H5
68%
17
NH
Z
HN
HN
O
N
H
+
:
O
O
N
H
N
H
Z
CH2
yield
66%
72%
26
27
NCH2Ph
24
1
1
25
SCHEME 7
am in e [3-(3-am in opropyl)in dolin -2-on e; 17] could be effected n ot on ly
with aldeh ydes, but also with som e keton es. Th e scope an d lim itation con -
cern in g both reactan ts (keton es an d am in es) were in vestigated. Wh ile th e
5 + 5 spiro com poun ds from 2-oxotryptam in e turn ed out to be m ore stable
th an th e 5 + 6 on es from th e correspon din g h om ologue, on ly aceton e an d
cyclic keton es could be em ployed as partn ers in th e reaction . Bulkier ke-
ton es failed to react. As a result of our presen t fin din gs, a n ew rin g system
(spiro[in dole-3,3′-piperidin ]-2-on es) was syn th esized an d described. No sim -
ilar reaction leadin g to spiro[azepan e-3,3′-in dol]-2′-on es from th e bis-
h om ologue of 2-oxotryptam in e [3-(4-am in obutyl)in dolin -2-on e; 18] was
observed.
EXPERIMENTAL
Meltin g poin ts were m easured on a Boetius h ot-stage apparatus an d are un corrected. IR spec-
tra (waven um bers in cm –1) were recorded on a Nicolet 205 FT spectroph otom eter. 1H an d
13C NMR spectra were m easured on a Varian Un ity In ova-400 spectrom eter, ch em ical sh ifts
(δ, ppm ) are reported relative to TMS; couplin g con stan ts (J) are given in Hz. Mutual
1
in terproton couplin gs are given on ly on ce, at th eir first occurren ce. Selective 1H-{ H} NOE
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1674
Dörnyei et al.:
m easurem en ts were perform ed in th e differen ce m ode. Two-dim en sion al h eteron uclear
sin gle-quan tum correlation (HSQC) experim en ts were used to correlate th e proton s an d th e
proton ated carbon s. 2D h eteron uclear m ultiple bon d correlation (HMBC) experim en t was
used for th e assign m en t of quatern ary carbon reson an ces in 19. Mass spectra were recorded
on a VG ZAB2-SEQ tan dem m ass spectrom eter usin g electron im pact ion ization . For TLC
an alyses MN Polygram SIL G/UV254 sh eets were used. Preparative separation s were per-
form ed by colum n ch rom atograph y on Merck Kieselgel 60 (0.063–0.200). Elem en tal an alyses
(C, H, N) were carried out on a Vario EL III (Elem en tar An alysen System e Gm bH) autom atic
m icroan alyzer, ion ic h alide con ten t was m easured by th e titration with m ercuric perch lorate.
Gen eral Meth ods for In tram olecular Man n ich -Type Cyclization
Method A 6. To
a suspen sion of 2-oxotryptam in e h ydroch loride (1) or 3-(3-am in o-
propyl)in dolin -2-on e h ydroch loride (15; 2 m m ol) in eth an ol (10 m l), keton e or aldeh yde
(2–5 m m ol) an d a solution of NaOAc·3H2O (0.56 g, 4 m m ol) in water (2 m l) were added.
Th e m ixture was stirred at room tem perature or at reflux for several h ours. Th e reaction
tim e depen ded on th e progress of th e cyclization ; th e reaction was followed by TLC
(dich lorom eth an e–m eth an ol 4:1 or dich lorom eth an e–m eth an ol–aqueous NH4OH 10:1:0.1;
th e RF of th e product was always h igh er th an th at of th e startin g m aterial 1 or 17). After
com pletion , th e solven t was rem oved, th e residue dissolved in water (10 m l), an d th e solu-
tion acidified with HCl (pH 2–3). Th e excess keton e was rem oved by extraction with dieth yl
eth er, an d th e aqueous ph ase evaporated to dryn ess. Th e fin al product was dissolved by th e
digestion of th e m ixture with ch loroform (3 × 20 m l). Th e CHCl3 ph ase was evaporated, an d
th e residue crystallized. In som e cases, purification by colum n ch rom atograph y was n eces-
sary to obtain a pure product.
Method B. In case of lower reactivity or to accom plish parallel alkylation , an h ydrous con -
dition s an d argon gas protection were em ployed as follows: To a suspen sion of 2-oxotrypt-
am in e h ydroch loride (1) or 3-(3-am in opropyl)in dolin -2-on e h ydroch loride (17; 2 m m ol) in a
keton e reactan t (30–60 m m ol), dried K2CO3 (0.2 g) an d NaI (0.1 g) were added. Th e suspen -
sion was stirred at room tem perature or at 60–70 °C for several h ours. Th e reaction tim e de-
pen ded on th e progress of th e cyclization , wh ich was followed by TLC (see m eth od A). After
com pletion , th e m ixture was diluted with water (10 m l), acidified with HCl (pH 2–3), an d
th e excess keton e rem oved by extraction with dieth yl eth er. If th e product turn ed out to be
sufficien tly stable in an alkalin e m edium , th e aqueous ph ase was n eutralized with am m on ia
(pH 8), an d extracted with CH2Cl2. After evaporation , th e residue was crystallized. If th e
product was un stable in an alkalin e m edium , th e acidic aqueous ph ase was evaporated
to dryn ess, an d th e product separated by digestin g th e organ ic product with ch loroform
(3 × 20 m l). Th e CHCl3 solution was evaporated, an d th e residue crystallized. In som e cases,
purification by colum n ch rom atograph y was n ecessary to obtain a pure product.
2′-Ethyl-2′-methylspiro[indoline-3,3′-pyrrolidin]-2-one diastereomers (2 and 3). Meth od A, reac-
tan ts: 2-oxotryptam in e h ydroch loride (1; 2 m m ol) an d eth yl m eth yl keton e (20 equiv.).
Tem perature/tim e: 80 °C, 20 h . Th e h ydroch loride salt obtain ed (0.34 g, 62%) was a 10:1
m ixture of th e exo (2) an d endo (3) diastereom ers (1H NMR spectroscopy, NOE m easurem en t).
Recrystallization of th is m ixture from dich lorom eth an e/eth yl acetate furn ish ed pure 2. Yield:
0.28 g (51%), m .p. 199–201 °C. IR (KBr): 1705 (5-m em bered lactam ). 1H NMR (DMSO-d6
+
CDCl3): 0.81 t, Jvic = 7.5, 3 H (CH2-CH3); 1.46 + 1.86 2 × dq, Jgem = 14.4, 2 × 1 H (CH2-CH3);
1.56 s, 3 H (CH3); 2.30 + 2.70 2 × ddd, Jgem = 13.8, J4′,5′ = 7.6 + 4.4 an d 10.0 + 9.0, 2 × 1 H
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Mannich Reaction Yielding Spiro Compounds
1675
(H4′); 3.66 m , 2 H (H5′); 6.98 d, 1 H (H7); 7.02 dd, 1 H (H5); 7.24 dd, 1 H (H6); 7.34 d, 1 H
(H4); 8.60 + 10.20 2 × brs, 2 × 1 H (NH2+); 10.90 s, 1 H (CONH). NOE: 1.56 (CH3) → 7.34
(H4). 13C NMR (DMSO-d6 + CDCl3): 8.35 (CH2-CH3), 18.51 (CH3), 27.18 (CH2-CH3), 31.96
(C4′), 40.48 (C5′), 59.45 (C3), 70.15 (C2′), 110.53 (C7), 122.07 (C5), 125.60 (C4), 126.16
(C3a), 129.33 (C6), 143.03 (C7a), 179.77 (CONH). MS, m/z (%): 230 (M+, 49), 160 (10), 146
(14), 132 (15), 98 (17), 85 (100), 56 (33). For C14H19ClN2O (266.8) calculated: 63.13% C,
7.18% H, 13.29% Cl, 10.50% N; foun d: 62.97% C, 7.08% H, 13.41% Cl, 10.37% N.
Dispiro[cyclohexane-1,2′-pyrrolidine-3′,3′′-indolin]-2′′-one (5). Meth od A, reactan ts: 2-oxo-
tryptam in e h ydroch loride (1; 2 m m ol) an d cycloh exan on e (8 m m ol). Tem perature/tim e: 25 °C,
24 h . Th e bis-spiro product 5 was isolated as a base in th e form of colourless crystals
(dich lorom eth an e/dieth yl eth er). Yield: 0.35 g (65%), m .p. 166–170 °C. IR (KBr): 1690
(5-m em bered lactam ), 3250 (NH). 1H NMR (CDCl3): 0.90–1.80 m , 10 H (5 × cycloh exyl
CH2); 2.27 t, J4′,5′ = 7.4, 2 H (H4′); 2.50 brs, 1 H (H1′); 3.18 an d 3.29 2 × dt, Jgem = 12.1, 2 ×
1 H (H5′); 6.90 d, 1 H (H7′′); 7.02 dd, 1 H (H5′′); 7.20 dd, 1 H (H6′′); 7.22 d, 1 H (H4′′);
8.70 brs, 1 H (CONH). 13C NMR (CDCl3): 21.80 an d 23.15 (C3 an d C5), 25.68 (C4), 30.45
an d 31.44 (C2 an d C6), 35.29 (C4′), 43.27 (C5′), 62.91 (C3′), 69.72 (C2′), 109.60 (C7′′),
121.53 (C5′′), 125.45 (C4′′), 127.68 (C6′′), 130.06 (C3′′a), 141.78 (C7′′a), 183.30 (CO). MS,
m/z (%): 256 (M+, 70), 213 (6), 144 (5), 130 (8), 111 (100), 110 (38), 96 (10), 83 (37). For
C
16H20N2O (256.4) calculated: 74.97% C, 7.86% H, 10.93% N; foun d: 74.90% C, 7.98% H,
10.77% N.
1′′-Benzyldispiro[indoline-3,3′-pyrrolidine-2′,4′′-piperidin]-2-one (6). Meth od A, reactan ts:
2-oxotryptam in e h ydroch loride (1; 2 m m ol) an d 1-ben zylpiperidin e (2.5 m m ol). Tem pera-
ture/tim e: 25 °C, 48 h . Th e bis-spiro product 6 was isolated as a base in th e form of colour-
less crystals (dieth yl eth er/h exan e). Yield: 0.51 g (72%), m .p. 183–185 °C. IR (KBr): 1685
(5-m em bered lactam ), 3180 an d 3400 (NH). 1H NMR (CDCl3): 1.30–1.85 m , 4 H (H3′′ +
H5′′); 1.72 m , 2 H (Hax2′′ + Hax6′′); 2.10–2.90 m , 5 H (Heq2′′ + Heq6′′ + H4′ + H1′); 3.23 m ,
2 H (H5′); 3.46 s, 2 H (N-CH2-Ph ); 6.81 d, 1 H (H7); 6.96 dd, 1 H (H5); 7.14 dd, 1 H (H6);
7.20 d, 1 H (H4); 7.22 m , 5 H (ben zylic rin g proton s); 9.21 brs, 1 H (N1-H). 13C NMR
(CDCl3): 30.01 + 31.21 (C3′′ an d C5′′), 35.17 (C4′), 43.18 (C5′), 49.08 an d 50.61 (C2′′ an d
C6′′), 62.18 (C3), 63.08 (N-CH2-Ph ), 67.62 (C2′), 109.60 (C7), 121.73 (C5), 125.45 (C4),
127.71 (C6), 129.51 (C3a), 141.62 (C7a), 182.73 (CO), ben zylic rin g carbon s: 126.90 (C4′′′),
128.08 (C3′′′ an d C5′′′), 129.28 (C2′′′ an d C6′′′), 138.05 (C1′′′). MS, m/z (%): 347 (M+, 93),
256 (M+ – ben zyl, 18), 228 (57), 201 (12), 187 (10), 172 (53), 146 (17), 134 (33), 120 (11), 91
(Bn +, 100), 83 (33), 42 (31). For C22H25N3O (347.5) calculated: 76.05% C, 7.25% H,
12.09% N; foun d: 75.91% C, 7.20% H, 12.01% N.
3-{2[(3-Oxocyclohex-1-en-1-yl)amino]ethyl}indolin-2-one (8). Meth od A, reactan ts: 2-oxotrypt-
am in e h ydroch loride (1; 2 m m ol) an d cycloh exan e-1,3-dion e (3 m m ol). Tem perature/tim e:
25 °C, 24 h . Th e en am in o keton e 8 was isolated as a base in th e form of yellow crystals
(m eth an ol/dieth yl eth er). Yield: 0.43 g (79%), m .p. 215–217 °C. IR (KBr): 1680 (5-m em bered
lactam an d con jugated keton e C=O), 3280 an d 3400 (NH). 1H NMR (CDCl3 + DMSO-d6):
1.87 m , 2 H (H5′); 2.12 m , 2 H (CH2-CH2-NH); 2.17 t, J = 6.2, 2 H (H4′); 2.32 t, J = 6.1, 2 H
(H6′); 3.16 m , 2 H (NH-CH2); 3.47 t, J = 6.3, 1 H (H3); 4.90 s, 1 H (H2′); 6.85 d, 1 H (H7);
6.95 dd, 1 H (H5); 6.96 brt, J = 6.0, 1 H (NH); 7.15 dd, 1 H (H6); 7.20 d, 1 H (H4); 10.30 s,
1 H (CONH). 13C NMR (CDCl3 + DMSO-d6): 21.96 (C5′), 28.98 (C4′ an d C6′), 36.64
(CH2-CH2-NH), 39.50 (CH2-CH2-NH), 43.57 (C3), 95.30 (C2′), 109.67 (C7), 121.56 (C5),
123.86 (C4), 127.85 (C6), 129.13 (C3a), 142.78 (C7a), 164.96 (C1′), 179.03 (CONH), 195.58
(CO). MS, m/z (%): 270 (M+, 41), 146 (7), 133 (13), 125 (100), 110 (7), 97 (25), 77 (6), 55 (12).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1676
Dörnyei et al.:
For C16H18N2O2 (270.3) calculated: 71.09% C, 6.71% H, 10.36% N; foun d: 70.95% C,
6.55% H, 10.50% N.
Syn th esis of 3-(3-Am in opropyl)in dolin -2-on e (17) an d 3-(4-Am in obutyl)in dolin -2-on e (18)
1. Esterification
A solution of carboxylic acid (0.1 m ol) in m eth an ol (100 m l) an d 1 M HCl/MeOH (20 m l)
was left to stan d at am bien t tem perature for 48 h . Th e solven t was th en evaporated, an d th e
residue dissolved in CH2Cl2 (100 m l). Th e solution was wash ed with 10% aqueous Na2CO3
solution (2 × 20 m l), water (20 m l) an d brin e (20 m l), dried over an h ydrous Na2SO4 an d
evaporated in vacuo. Th e residue was crystallized from eth er/h exan e to furn ish colourless
crystals.
Methyl indole-3-propanoate (10). Yield: 18.1 g (88%), m .p. 78–79 °C (ref.7 gives m .p. 79–80 °C).
IR (KBr): 1710 (C=O), 3380 (NH).
Methyl indole-3-butanoate (12). Yield: 19.8 g (93 %), m .p. 70–72 °C (ref.8 gives m .p. 71–72 °C).
IR (KBr): 1710 (C=O), 3380 (NH).
2. Aminolysis
Th e solution s of m eth yl esters 10 an d 12 (40 m m ol) in CH3OH (100 m l) were saturated with
am m on ia gas at –70 °C. Th e resultan t solution s were left to stan d at room tem perature for
48 h . Th e solven ts were th en evaporated an d th e residues treated with dieth yl eth er. Th e
colourless crystals were filtered off. With th e residues obtain ed by evaporatin g th e m oth er li-
quors, repeated am in olyses were perform ed. Th e crystals obtain ed in th ree con secutive pro-
cedures were com bin ed.
Indole-3-propanamide (13). Yield: 6.77 g (90%), m .p. 133–135 °C (ref.9 gives m .p. 131.5–
133 °C). IR (KBr): 1645 (C=O am ide), 3380 (NH).
Indole-3-butanamide (14). Yield: 6.72 g (83%), m .p. 117–118 °C (ref.9 gives m .p. 117–118 °C).
IR (KBr): 1645 (C=O am ide), 3380 (NH).
3. Reduction
To a vigorously stirred suspen sion of LiAlH4 (15.2 g, 0.4 m ol) in dry THF (500 m l), a solu-
tion of am ide 13 or 14 (50 m m ol) in dry THF (250 m l) was added dropwise at room tem per-
ature durin g ca 30 m in . Th e suspen sion was stirred un der argon at room tem perature for
about 24 h . W h en th e reduction was com plete (TLC, CH2Cl2–MeOH–NH4OH 5:1:0.1;
RF am in e < RF am ide), th e m ixture was cooled an d th e excess reagen t decom posed by care-
ful addition of water (15 m l), 15% NaOH solution (15 m l) an d water (45 m l) again . After
12 h , th e wh ite precipitate was filtered off an d wash ed with ch loroform (3 × 100 m l). Th e
aqueous ph ase was separated, th e organ ic ph ase was dried (an h ydrous Na2SO4), acidified
with 1 M HCl/MeOH, an d th e solven t evaporated. On treatin g th e residue with dieth yl eth er,
th e h ydroch lorides of th e tryptam in e h om ologues were obtain ed as colourless crystals.
3-(Indol-3-yl)propan-1-amine hydrochloride (15). Yield: 9.5 g (90%), m .p. 166–169 °C (ref.10
gives m .p. 169–170 °C). IR (KBr): 2500–3000 (salt), 3360 (NH). For C11H15ClN2 (210.7) calcu-
lated: 62.70% C, 7.18% H, 16.83% Cl, 13.29% N; foun d: 62.54% C, 7.28% H, 16.69% Cl,
12.99% N.
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Mannich Reaction Yielding Spiro Compounds
1677
4-(Indol-3-yl)butan-1-amine hydrochloride (16). Yield: 9.55 g (85%), m .p. 217–219 °C (ref.10
gives m .p. 217–218 °C). IR (KBr): 2500–3000 (salt), 3370 (NH). For C12H17ClN2 (224.7) calcu-
lated: 64.14% C, 7.62% H, 15.78% Cl, 12.47% N; foun d: 64.02% C, 7.53% H, 15.59% Cl,
12.71% N.
4. Oxidation
A solution of th e am in e h ydroch loride 15 or 16 (30 m m ol) in DMSO (6.5 m l, 7.08 g, 90 m m ol)
was cooled in an ice bath an d con cen trated HCl (3.8 m l, ca 42 m m ol) was added dropwise.
Th e m ixture was th en stirred at room tem perature overn igh t. Th e crystallin e m ass obtain ed
was diluted with eth an ol (50 m l), stirred for an oth er 1 h , an d th en left to stan d in a refriger-
ator for several h ours. Th e crystals were filtered off an d wash ed with eth an ol an d dieth yl
eth er.
3-(3-Aminopropyl)indolin-2-one hydrochloride (17). Yield: 5.18 g (75%), m .p. 179–181 °C.
IR (KBr): 1670 (C=O; 5-m em bered lactam ). 1H NMR (CDCl3 + DMSO-d6): 1.64 m , 2 H
(CH2-CH2-NH3+); 1.92 m , 2 H (CH2-CH2-CH2-NH3+); 2.79 t, J = 7.5, 2 H (CH2-NH3+); 3.44 t,
J = 6.0, 1 H (H3); 6.86 d, 1 H (H7); 6.95 dd, 1 H (H5); 7.17 dd, 1 H (H6); 7.26 d, 1 H (H4);
8.04 brs,
3 H 1 H + CDCl3): 23.75
(NH3+); 10.40 s, (CONH). 13C NMR (DMSO-d6
(CH2-CH2-NH3+), 27.24 (CH2-CH2-CH2-NH3+), 39.23 (CH2-NH3+), 44.98 (C3), 109.70 (C7),
121.61 (C5), 124.25 (C4), 127.96 (C6), 129.45 (C3a), 142.13 (C7a), 178.91 (CONH). MS, m/z
(%): 190 (M+, 72), 173 (100), 145 (93), 133 (94), 117 (30), 104 (17), 91 (6), 77 (22), 56 (18),
45 (47). For C11H15ClN2O (226.7) calculated: 58.28% C, 6.67% H, 15.64% Cl, 12.36% N;
foun d: 58.11% C, 6.80% H, 15.71% Cl, 12.48% N.
3-(4-Aminobutyl)indolin-2-one hydrochloride (18). Towards th e en d of th e reaction , th e m ix-
ture was stirred at 50 °C for 3–4 h . Yield: 4.48 g (62%), m .p. 232–233 °C. IR (KBr): 1670
(C=O; 5-m em bered lactam ). 1H NMR (CDCl3 + DMSO-d6): 1.40 m , 2 H (CH2-CH2-CH2-NH3+);
1.68 m , 2 H (CH2-CH2-NH3+); 1.89 m , 2 H (CH2-CH2-CH2-CH2-NH3+); 2.79 t, J = 7.5, 2 H
(CH2-NH3+); 3.37 t, J = 6.0, 1 H (H3); 6.87 d, 1 H (H7); 6.95 dd, 1 H (H5); 7.14 dd, 1 H (H6);
7.21 d, 1 H (H4); 8.20 brs, 3 H (NH3+); 10.26 s, 1 H (CONH). 13C NMR (DMSO-d6 + CDCl3):
22.78 (CH2-CH2-CH2-NH3+), 27.30* (CH2-CH2-NH3+), 29.83* (CH2-CH2-CH2-CH2-NH3+),
39.26 (CH2-NH3+), 45.44 (C3), 109.64 (C7), 121.50 (C5), 123.93 (C4), 127.69 (C6), 129.44
(C3a), 142.87 (C7a), 179.21 (CONH). MS, m/z (%): 204 (M+, 67), 187 (16), 146 (100), 133
(32), 117 (11), 104 (8), 91 (6), 77 (12), 59 (34), 47 (7). For C12H17ClN2O (240.7) calculated:
59.87% C, 7.12% H, 14.73% Cl, 11.64% N; foun d: 59.70% C, 7.02% H, 14.85% Cl,
11.49% N.
2′,2′-Dimethylspiro[indoline-3,3′-piperidin]-2-one (19). Meth od A, reactan ts: 3-(3-am in o-
propyl)in dolin -2-on e h ydroch loride (17; 2 m m ol) an d aceton e as a solven t. Tem perature/
tim e: 60 °C, 3 h . Th e spiro com poun d 19 was isolated in th e form of a base as colourless
crystals (0.33 g, 70%), m .p. 189–191 °C (eth yl acetate). IR (KBr): 1690 (5-m em bered lactam ),
3040 an d 3250 (NH), 3400 (am ide NH). 1H NMR (CDCl3 + DMSO-d6): 0.84 s, 3 H (CH3
directed towards th e C=O group); 1.30 s, 3 H (CH3 directed towards th e arom atic rin g);
1.48 m , 1 H (Heq5′); 1.65 m , 1 H (Heq4′); 2.11 m , 1 H (Hax4′); 2.14 m , 1 H (Hax5′); 2.93 m ,
2 H (H6′); 3.20 brs, 1 H (N1′-H); 6.84 d, 1 H (H7); 6.93 dd, 1 H (H5); 7.13 dd, 1 H (H6);
7.24 d, 1 H (H4); 10.19 brs, 1 H (CONH). NOE: 7.24 (H4) → 1.30 (CH3). 13C NMR (CDCl3
+
DMSO-d6): 20.46 (C5′), 22.70 (CH3 directed towards th e arom atic rin g), 25.88 (CH3 directed
towards th e C=O group), 28.68 (C4′), 40.44 (C6′), 52.57 (C3), 53.88 (C2′), 109.31 (C7),
121.00 (C5), 124.72 (C4), 127.29 (C6), 133.54 (C3a), 142.04 (C7a), 181.19 (CONH). MS, m/z
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1678
Dörnyei et al.:
(%): 230 (M+, 70), 173 (9), 145 (8), 117 (7), 85 (100), 70 (32), 57 (17), 42 (25). For
14H18N2O (230.3) calculated: 73.01% C, 7.88% H, 12.16% N; foun d: 73.14% C, 7.95% H,
C
12.08% N.
1′,2′,2′-Trimethylspiro[indoline-3,3′-piperidin]-2-one (20). Meth od B, reactan ts: 3-(3-am in o-
propyl)in dolin -2-on e h ydroch loride (17; 2 m m ol), m eth yl iodide (0.18 m l, 0.414 g,
2.9 m m ol) an d aceton e (30 m l) as a solven t. Tem perature/tim e: 25 °C, overn igh t. Th e spiro
com poun d 20 was isolated in th e form of a base as colourless crystals (0.36 g, 74%), m .p.
176–178 °C (eth yl acetate/h exan e). IR (KBr): 1690 (5-m em bered lactam ), 3050 an d 3180
(NH), 3400 (am ide NH). 1H NMR (CDCl3): 0.76 s, 3 H (CH3 directed towards th e arom atic
rin g); 1.27 s, 3 H (CH3 directed towards th e C=O group); 1.46 + 2.24 2 × ddd, Jgem = 13.3,
J4′,5′ = 4.5 + 3.5 an d 12.7 + 4.7, 2 × 1 H (H4′); 1.70 + 2.06 2 × m , 2 × 1 H (H5′); 2.23 s, 3 H
(N-CH3); 2.69 + 2.77 2 × ddd, Jgem = 12.5, J5′,6′ = 5.3 + 5.1 an d 11.3 + 3.7, 2 × 1 H (H6′);
6.88 d, 1 H (H7); 6.98 dd, 1 H (H5); 7.18 dd, 1 H (H6); 7.94 d, 1 H (H4); 8.59 brs, 1 H
(CONH). NOE: 0.76 (CH3) → 7.94 (H4). 13C NMR (CDCl3): 11.37 + 23.84 [C2′-(CH3)2], 20.80
(C5′), 29.42 (C4′), 37.45 (N-CH3), 49.75 (C6′), 55.86* (C3), 57.65* (C2′), 109.07 (C7), 121.22
(C5), 127.22+ (C6), 128.13+ (C4), 133.70 (C3a), 140.45 (C7a), 181.26 (C=O). Peaks with th e
sam e sign als are in terch an geable. MS, m/z (%): 244 (M+, 100), 229 (12), 173 (18), 145 (13),
112 (15), 99 (54), 84 (27), 71 (79), 56 (74), 42 (10). For C15H20N2O (244.3) calculated:
73.74% C, 8.25% H, 11.47% N; foun d: 73.58% C, 8.14% H, 11.61% N.
Ethyl 2′,2′-dimethyl-2-oxospiro[indoline-3,3′-piperidine]-1′-acetate (21). Meth od B, reactan ts:
3-(3-am in opropyl)in dolin -2-on e h ydroch loride (17; 2 m m ol), eth yl brom oacetate (0.30 m l,
0.45 g, 2.7 m m ol) an d aceton e (30 m l) as a solven t. Tem perature/tim e: 25 °C, 3 h . Th e spiro
com poun d 21 was isolated in th e form of th e h ydroch loride salt as colourless crystals
(0.51 g, 72%), m .p. 168–170 °C (eth an ol/dieth yl eth er). IR (KBr): 1695 (5-m em bered lactam ),
1740 (C=O ester), 3040 an d 3110 (NH+), 3380 (am ide NH). 1H NMR (CDCl3 + DMSO-d6):
1.23 s, 3 H (CH3 directed towards th e C=O group); 1.34 t, Jvic = 7.2, 3 H (CH3-CH2O); 1.68 +
2.49 2 × ddd, Jgem = 14.2, J4′,5′ = 3.5 + 1.0 an d 13.8 + 4.3, 2 × 1 H (H4′); 1.90 s, 3 H (CH3 di-
rected towards th e arom atic rin g); 1.95 + 2.63 2 × m , 2 × 1 H (H5′); 3.59 ddd, Jgem = 12.5,
J5′,6′ = 4.5 + 1.0, 1 H (Heq6′); 4.05 m , 1 H (Hax6′); 4.35 q, 2 H (CH3-CH2O); 4.41 d + 4.68 2 ×
dd, Jgem = 17.5, JCH
= 1.0 an d 6.5, 2 × 1 H (+N-CH2-CO); 7.07 dd, 1 H (H5); 7.20 d, 1 H
NH
2
(H7); 7.23 d, 1 H (H4); 7.29 dd, 1 H (H6); 9.74 brs, 1 H (NH+); 11.63 s, 1 H (CONH). NOE:
1.90 (CH3) → 7.23 (H4). 13C NMR (CDCl3 + DMSO-d6): 13.88 (CH2-CH3), 16.77 + 21.61
[C2′-(CH3)2], 17.89 (C5′), 26.91 (C4′), 51.31 (C6′), 51.40* (C3), 52.94* (C2′), 63.40
(CO2-CH2-CH3); 67.48 (+N-CH2-CO), 111.85 (C7), 122.88 (C5), 124.11 (C4), 129.40 (C6),
129.01 (C3a), 141.67 (C7a), 166.90 (C=O ester), 180.46 (C=O am ide). MS, m/z (%): 316 (M+,
100), 301 (7), 243 (26), 184 (14), 173 (40), 158 (10), 144 (16), 117 (7), 98 (70), 84 (15), 56
(6), 42 (9). For C18H25ClN2O3 (352.9) calculated: 61.27% C, 7.14% H, 10.05% Cl, 7.94% N;
foun d: 61.08% C, 7.11% H, 9.97% Cl, 7.82% N.
2′-Phenylspiro[indoline-3,3′-piperidin]-2-one isomers (22 and 23). Meth od A, reactan ts:
3-(3-am in opropyl)in dolin -2-on e h ydroch loride (17; 2 m m ol) an d ben zaldeh yde (0.30 m l,
0.31 g, 3 m m ol). Tem perature/tim e: 25 °C, 24 h . Th e m ixture of th e spiro diastereom ers 22
an d 23 (about 2:1) was isolated in th e form of a base as pale tan crystals (0.49 g, 88%).
Separation of th e two isom ers was perform ed by colum n ch rom atograph y (CHCl3–MeOH
9:1, th e reten tion tim e of 22 was h igh er th an th at of 23).
Isom er 22. Yield: 0.30 g (54%), m .p. 151–153 °C. IR (KBr): 1690 (5-m em bered lactam ), 3040
an d 3200 (NH), 3400 (am ide NH). 1H NMR (CDCl3): 1.62 m , 1 H (Heq5′); 2.02 m , 1 H
(Heq4′); 2.12 m , 1 H (Hax4′); 2.38 brs, 1 H (NH); 2.46 m , 1 H (Hax5′); 2.94 m , 1 H (Hax6′);
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Mannich Reaction Yielding Spiro Compounds
1679
3.47 m , 1 H (Heq6′); 4.08 s, 1 H (H2′); 6.51 m , 1 H (H7); 6.92–7.07 m , 7 H (5 × ph en yl CH +
H5 + H6); 7.29 m , 1 H (H4); 7.90 brs, 1 H (CONH). NOE: 4.08 (H2′) → 7.29 (H4). 13C NMR
(CDCl3): 21.08 (C5′), 33.41 (C4′), 47.23 (C6′), 51.30 (C3), 67.71 (C2′), 109.21 (C7), 121.92*
(C5), 122.60* (C4), 127.16 (C6), 127.35 + 127.48 (C2′′ + C6′′ an d C3′′ + C5′′), 127.57 (C4′′),
133.22 (C3a), 138.81 (C1′′), 140.07 (C7a), 180.26 (CO). MS, m/z (%): 278 (M+, 100), 173 (9),
145 (11), 132 (55), 118 (17), 104 (67), 91 (16), 69 (9), 41 (6). For C18H18N2O (278.4) calcu-
lated: 77.67% C, 6.52% H, 10.06% N; foun d: 77.48% C, 6.64% H, 9.88% N.
Isom er 23: Yield: 0.16 g (28%), m .p. 153–155 °C. IR (KBr): 1700 (5-m em bered lactam ), 3050
an d 3200 (NH), 3400 (am ide NH). 1H NMR (CDCl3): 1.72–1.80 m , 3 H (Heq4′ + Heq5′ + NH);
2.10–2.26 m , 2 H (Hax4′ + Hax5′); 3.07 m , 1 H (Hax6′); 3.42 m , 1 H (Heq6′); 4.20 s, 1 H (H2′);
6.61 d, 1 H (H7); 6.92–7.06 m , 6 H (5 × ph en yl CH + H5); 7.11 dd, 1 H (H6); 7.96 brs, 1 H
(CONH); 8.07 d, 1 H (H4). 13C NMR (CDCl3): 21.24 (C5′), 33.08 (C4′), 47.60 (C6′), 54.10
(C3), 66.64 (C2′), 109.16 (C7), 121.46 (C5), 127.20 + 127.34 (C4 + C6), 127.38 (C3′′ + C5′′),
127.49 (C4′), 127.75 (C2′′ + C6′′), 131.48 (C3a), 139.67 (C1′′), 140.21 (C7a), 180.46 (CONH).
MS, m/z (%): 278 (M+, 100), 173 (9), 145 (10), 132 (56), 118 (19), 104 (76), 91 (17), 77 (8).
For C18H18N2O (278.4) calculated: 77.67% C, 6.52% H, 10.06% N; foun d: 77.55% C,
6.49% H, 10.10% N.
2(-Ethyl-2(-methylspiro[indoline-3,3′-piperidin]-2-one isomers (24) and (25). Meth od B, reac-
tan ts: 3-(3-am in opropyl)in dolin -2-on e h ydroch loride (17; 2 m m ol) an d eth yl m eth yl keton e
(10 m l, 8.04 g, 112 m m ol). Tem perature/tim e: 25 °C, 4 h . Th e m ixture of th e spiro dia-
stereom ers 24 an d 25 (ca 1:1) was isolated in th e form of th e h ydroch loride salt as pale tan
crystals (0.38 g, 68%). Th e two diastereom ers could n ot be separated eith er by crystallization
or by ch rom atograph y, but th eir ratio could be calculated: from th e 1H NMR spectrum .
IR (KBr): 1695 (5-m em bered lactam ), 3060 an d 3280 (NH2+), 3420 (am ide NH). 1H NMR
(CDCl3 + DMSO-d6): 0.78 t + 0.97 t, Jvic = 7.3, 3 H (CH3-CH2); 1.18 s + 1.65 s, 3 H (CH3);
1.20–3.40 m , 8 H (CH3-CH2 + H4′ + H5′ + H6′); 6.92–7.06 m , 2 H (H5 + H6); 7.20–7.48 m ,
2 H (H4 + H7); 7.75 brt + 8.27 br an d 9.18 br + 9.35 brd, 2 × 1 H (H1′); 11.00 s + 11.07 s,
1 H (CONH). MS, m/z (%): 244 (M+, 100), 173 (12), 145 (10), 132 (23), 117 (8), 99 (86), 84
(53), 70 (16), 56 (13). For C15H21ClN2O (280.8) calculated: 64.16% C, 7.54% H, 12.63% Cl,
9.98% N; foun d: 64.08% C, 7.70% H, 12.54% Cl, 9.86% N.
Dispiro(cyclohexane-1,2′-piperidine-3′,3′′-indolin)-2′′-one (26). Meth od B, reactan ts: 3-(3-
am in opropyl)in dolin -2-on e h ydroch loride (17; 2 m m ol) an d cycloh exan on e (8 m m ol).
Tem perature/tim e: 60 °C, 24 h . Th e bis-spiro product 26 was isolated as th e h ydroch loride
salt in th e form of colourless crystals (dich lorom eth an e/dieth yl eth er). Yield: 0.41 g (66%),
m .p. 231–233 °C. IR (KBr): 1690 (5-m em bered lactam ), 3250 (NH). 1H NMR (base, CDCl3):
0.96 m , 1 H (Hax4); 1.03 ddd, 1 H (Hax2); 1.24–1.76 m , 9 H (Heq4′ + Hax5′ + Heq2 + H3 +
H
eq4 + H5 + HA6); 1.98 brs, 1 H (H1′); 2.10–2.30 m , 3 H (Hax4′ + Heq5′ + HB6); 2.87 + 2.98
2 × m , 2 × 1 H (H6′); 6.86 d, 1 H (H7); 7.00 dd, 1 H (H5); 7.19 dd, 1 H (H6); 7.31 d, 1 H
(H4); 8.30 brs, 1 H (CONH). 13C NMR (CDCl3): 20.53 (C5′), 20.61 (C3 + C5), 25.87 (C4),
27.81 an d 32.21 (C2 + C6), 28.17 (C4′), 39.13 (C6′), 54.60* (C3′′), 56.50* (C2′), 109.17 (C7′′),
121.56 (C5′′), 125.82 (C4′′), 127.39 (C6′′), 133.54 (C3′′a), 140.95 (C7′′a), 181.69 (CONH).
MS, m/z (%): 270 (M+, 100), 173 (11), 145 (12), 132 (17), 125 (76), 117 (15), 110 (37), 97
(33), 82 (24), 54 (22), 36 (15). For C17H23ClN2O (306.8) calculated: 66.55% C, 7.56% H,
11.55% Cl, 9.13% N; foun d: 66.39% C, 7.70% H, 11.65% Cl, 9.05% N.
1′′-Benzyldispiro[indoline-3,3′-piperidine-2′,4′′-piperidin]-2-one (27). Meth od A, reactan ts:
3-(3-am in opropyl)in dolin -2-on e h ydroch loride (17; 2 m m ol) an d 1-ben zyl-4-piperidon e
(2.5 m m ol). Tem perature/tim e: 25 °C, 24 h . Crystallin e product was precipitated from th e
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1680
Dörnyei et al.:
reaction m ixture. After dilutin g with water (4 m l), pH was adjusted to
am m on ia, an d th e product was filtered off. C2o7mwpaosunodbtain ed as base (colou
crystals). Yield: 0.52 (72%), m .p. 199–200 °2C7;·HCml.p.21o1–f 212 °C. IR (KBr):
(5-m em bered lactam ), 3050, 3080, 3150 an d 3240H (NNMH)R. (CDC+l DMSOd- ):
8
b
a
g
1
3
6
1.36 m, 2 H (H3′′); 1.47 , m1 H (Heq5′); 1.65 , m1 H (Heq4′); 1.82 , m1 H (Hax5′′); 2.10–
2.20 m, 3 H (Hax4′ + Hax5′ + Heq5′′); 2.36–2.62 m , ′H′ + H(H62′′ + H1′); 2.84 m ,
(Hax6′); 2.95 , m1 H (Heq6′); 3.42 , s2 (N-PChH); 6.82 , d1 (H7); 6,.941 ddH (H5
7.12 dd, (H6); 7.15–7.25 m , (ben zylic rin g proton s); 7.23 d,
(CONH). 13C NMR (CDC+l DMSOd- ): 20.46 (′C), 5 27.19 (′C′),5 28.20 (′C), 4 32.16 (′C′),3
5
1
H
H
2
1
H
5
H
1
3
6
38.82 (C′6), 47.99 an d 48.13′′ +(CC26′′), 53.55* (C3), 54.82*′), (C622.95 (N-2C-HPh ),
109.24 (C7), 121.12 (C5), 125.52 (C4), 127.22 (C6), 132.98 (C3a), 141.75
(CONH), ben zyl: 126.63 ′′′()C, 4 127.92 (′C′′ 3+ C5′′′), 129.00 (′C′′ 2+ C6′′′), 138.65 (′C′′)1.
+
MS, m/z (%): 361 (,M 93), 270 + –(M ben zyl, 16), 242 (82), 215 (25), 187 (11), 17
(7), 134 (16), 120 (12), 91 (Bz, 100), 82 (17), 56 (273)H, 27N42O (2(13)6. 1.5F)or caC-lcu
3
lated: 76.42% C, 7.53% H, 11.62% N; foun d: 76.37% C, 7.72% H, 11.55%
The authors wish to thank Ms. Á. Gömöry for MS measurements, Ms M. Roczko
for technical assistance. Support of this research (grant No.
T
029743, the Natio
search Foundation
–
OTKA) is gratefully acknowledged.
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3653.
5. Szabó-Pusztay K., Szabó L.: Synthesis 1979, 276.
6. Intramolecular cyclization of 2-oxotryptamine with aldehydes resulting in a diastereo-
meric mixture of 2′-substituted spiro[indoline-3,3′-pyrrolidin]-2-ones via method A is
widely used; the method was frequently utilized for the synthesis of various oxindole
alkaloids (e.g. in the aspidosperma and strichnos series) published in the following
references: a) Harley-Mason J., Ingleby R. F. J.: J. Chem. Soc. 1958, 3639; b) Hendrickson
J. B., Silva R. A.: J. Am. Chem. Soc. 1963, 84, 643; c) Jansen A. B. A., Richards C. G.:
Tetrahedron 1965, 21, 1327; d) Oishi T., Nagai M., Ban Y.: Tetrahedron Lett. 1968, 491;
e) Ban Y., Seto M., Oishi T.: Tetrahedron Lett. 1972, 2113; f) Ban Y., Taga N., Oishi T.:
Tetrahedron Lett. 1974, 187; g) Döé De Mandreville M., Lévy J.: Bull. Soc. Chim. Fr. 1981,
2, 179; h) Bascop S.-I., Sapi J., Laronze J.-Y., Lévy J.: Heterocycles 1994, 38, 725;
i) Mirand C., Papa M., Cartier D., Levy J.: Tetrahedron Lett. 1997, 38, 2263.
7. Iqbal Z., Jackson A. H., Nagaraja Rao K. R.: Tetrahedron Lett. 1988, 29, 2577.
8. Jackson A. H., Naidoo B., Smith P.: Tetrahedron 1968, 24, 6119.
9. Crosby D. G., Boyd J. B., Johnson H. E.: J. Org. Chem. 1960, 25, 1826.
10. Avramenko V. G., Suvorov N. N., Mashkovskii M. D., Mushulov P. I., Eryshev B. Ya.,
Fedorova V. S., Orlova I. A., Trubitsyna T. K.: Khim.-Farm. Zh. 1970, 4, 10.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)