An efficient synthesis of a spirocyclic oxindole analogue

Article abstract of DOI:10.3390/11090700

An efficient, scaleable synthesis approach towards the spirocyclic oxindole analogue 1′-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,4′- piperidine]-5-carboxylic acid (1) is described. The key steps are dianion alkylation and cyclization of ethyl 2-oxindoline-5-carboxylate (4) and demethylation of the resulting spirocyclic oxindole ethyl 1′-methyl-2- oxospiro[indoline-3,4′-piperidine]-5-carboxylate (5). The target compound was obtained in an overall yield of 35 % over eight steps without resorting to chromatographic purification.

Full text of DOI:10.3390/11090700

Molecules 2006, 11, 700-706
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
An Efficient Synthesis of a Spirocyclic Oxindole Analogue
Dawei Teng *, Hongxing Zhang and A. Mendonca
Department of Chemistry, ChemRoutes Corporation, Edmonton, Alberta T6E 5P8, Canada
* Author to whom correspondence should be addressed; E-mail: tengdw@yahoo.com
Received: 13 August 2006; in revised form: 6 September 2006 / Accepted: 14 September 2006 /
Published: 14 September 2006
Abstract: An efficient, scaleable synthesis approach towards the spirocyclic oxindole
analogue 1’-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,4’-piperidine]-5-carboxylic acid
(1) is described. The key steps are dianion alkylation and cyclization of ethyl 2-
oxindoline-5-carboxylate (4) and demethylation of the resulting spirocyclic oxindole
ethyl 1’-methyl-2-oxospiro[indoline-3,4’-piperidine]-5-carboxylate (5). The target
compound was obtained in an overall yield of 35 % over eight steps without resorting to
chromatographic purification.
Keywords: Spirocyclic oxindole, dianion alkylation, N-demethylation.
Introduction
Spiro compounds are becoming key building blocks for drug discovery as these templates have
been shown to exhibit a variety of interesting biological activities, such as growth hormone
secretagogues (Ibutamoren, MK-0677) [1], neurokinin antagonists [2], oxytocin antagonists [3],
monoamine transporter inhibitors [4], bradykinin antagonists [5] and cell cycle inhibitors [6]. Due to
their structure, they interact with a wide range of receptors and this activity has resulted in significant
interest in developing efficient methods to prepare spiro compounds. We report herein the efficient
synthesis of 1’-(tert-butoxycarbonyl)-2-oxospiro [indoline-3, 4’-piperidine]-5-carboxylic acid (1).

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701
Boc
N
HO2C
N
O
H
1
Results and Discussion
The synthetic plan for the synthesis of the target molecule is outlined in Scheme 1. Our first
objective was synthesis of the substituted oxindole 4. Of the reported synthetic routes to oxindoles [7],
Lewis acid catalyzed cyclization of α-haloacetanilides [8] was proposed as the most efficient route to
synthesize 4, but in practice this method gave a rather low yield (<10%), due to the strongly acidic
conditions used in the transformation. Next, the synthesis of the target oxindole via the intermediacy of
an azasulfonium salt [9] was investigated for its relatively mild conditions. Ethyl 4-aminobenzoate 2
was sequentially treated with tert-butyl hypochlorite, ethyl(methylthio) acetate and triethylamine,
followed by dilute hydrochloric acid, to give substituted 3-methylthiooxindole 3 in 75% yield.
Reductive desulfurization of 3 with Raney Ni afforded the target 4 in 85% yield.
Scheme 1
SMe
EtO2C
EtO2C
EtO2C
c
a
b
N
O
NH2
N
O
H
H
4
2
3
Boc
Boc
Me
N
N
N
EtO2C
HO2C
EtO2C
d
e
N
H
O
N
O
N
O
H
H
1
6
5
o
o
(a) (i) t-BuOCl, ethyl(methylthio) acetate, CH2Cl2, -65 C, (ii) Et3N, -65 C to rt., (iii) HCl, ether, rt.; (b)
Raney Ni, ethanol, reflux; (c) NaH, dichloroethamine hydrochloride, DMF, rt.; (d) (i) Trichloroethyl
chloroformate, Et3N, 1,2-dichloroethane, (ii) Zinc, HOAc, (iii) (Boc)2O, dioxane; (e) NaOH, MeOH, H2O
Now we turned to the key step, the synthesis of the spirocyclic oxoindole 5. Goehring and others
[5,10] have reported that treatment of a non substituted oxindole with excess sodium
hexamethyldisilazide gave an oxoindole dianion [11], which when alkylated with N-methylbis(2-
chloroethyl)amine afforded the corresponding spirocyclic oxindole. Unfortunately, in our case these
conditions gave rather low yields. We found that the alkylation is difficult with various bases such as
sodium hexamethyldisilazide, lithium hexamethyldisilazide, lithium diisopropylamide and potassium
tert-butoxide in solvents such as tetrahydrofuran and dimethylformamide [12]. The low yields are due
to the presence in 4 of the electron-withdrawing carboxylic ester group, which decreases the
nucleophilicity of the enolate anion. Eventually we found that treatment of 4 with 4.5 equivalents of

Molecules 2006, 11
702
sodium hydride and dichloroethylmine hydrochloride in dimethylformamide for 5 hours gave the
desired product 5 in 65% yield. With this intermediate in hand, we next embarked on the
demethylation of 5 [13]. It is worth noting that, in our hands, attempts to alkylate the oxindole dianion
with either N-Boc or N-benzyl dichloroethamine (to potentially shorten the synthesis) met with no
success. However, treatment of 5 with 2,2,2-trichloroethyl chloroformate (TCE-Cl), followed by zinc
reduction and subsequent Boc protection, gave a low yield (31%) of the desired protected amine 6.
After detailed investigation of the process, we found the following (Scheme 2): a) when 5 was
treated with TCE-Cl, the mono-acylated intermediate 7 is first formed quantitatively, but it cannot be
completely converted to 9, even when excess TCE-Cl is added. The acid, which was formed in situ
during the formation of 7, would most likely result in the competition between the formation of
hydrochloric salt 10, which would no longer react with TCE-Cl, and quaternary salt intermediate 8,
which will lead to the desired di-acylated intermediate 9; b) when 7 was isolated and treated with TCE-
Cl, the reaction is still reversible even under reflux conditions. This strongly indicates that the
quaternary salt intermediate 8 undergoes two competitive reactions [13d], namely nucleophilic attack
of the chloride ion on the O-alkyl portion, which has no net effect on 7, and nucleophilic attack of the
chloride ion on the methyl group, leading to 9; c) eventually we found that upon treatment of 5 with 1-
1.5 eq. triethylamine, followed by addition of TCE-Cl, the desired intermediate 9 was formed
quantitatively and the reaction was complete in less than 10 minutes. These results suggest that
triethylamine not only neutralizes the hydrochloric acid generated during the formation of 7, but also
has significant influence on the breakup of quaternary salt 8. Presumably triethylamine is chelated with
the chloride ion. The nucleophilic attack of the chelated chloride ion on the O-alkyl portion is then
disfavored due to steric hindrance. To test the hypothesis, we investigated the dealkylation of N-
ethylpiperidine, which was most often reported as the standard substrate for dealkylation [13b]. The
report yield is less than 10% when TCE-Cl was used. As we expected, when one equivalent of
triethylamine hydrochloride was added in the reaction mixture, the dealkylation was finished within 30
minutes with 95% yields. Finally, upon zinc reduction and subsequent Boc protection, the spirocyclic
oxindole 6 was obtained in 92% from 5. Saponification of 6 gave 1 in 91% yield.
Scheme 2
O
O
N
O
CCl3
Me
N+
EtO2C
O
CCl3
EtO2C
b
N
O
N
O
O
O
O
O
Cl3C
Cl3C
Me
N
Me
EtO2C
N
9
8
EtO2C
a
N
O
N
O
O
H
O
Cl3C
Me
HCl
N
5
EtO2C
7
c
N
O
O
O
10
Cl3C
(a) Trichloroethyl chloroformate, 1,2-dichloroethane, rt.; (b) and (c) Trichloroethyl chloroformate, Et3N,
1,2-dichloroethane, rt.

Molecules 2006, 11
703
Conclusions
We have described an efficient route to prepare the spirocyclic oxindole analogue 1’-(tert-
butoxycarbonyl)-2-oxospiro[indoline-3,4’-piperidine]-5-carboxylic acid 1 in eight steps with an overall
yield of 35%. This synthetic route is scaleable without chromatographic purification.
Experimental Section
General
All commercially available chemicals and reagents were used without further purification. The 1H-
and 13C-NMR spectra were recorded on Bruker DPX-300 spectrometer. Chemical shifts (δ) are
1
reported in ppm and are referenced to the deuterium solvent residual peak (for H-NMR, δ is 7.26 in
13
CDCl3 and 2.50 in DMSO-d6, respectively; for C-NMR, δ is 77.2 in CDCl3 and 39.5 in DMSO-d6,
respectively). Mass spectral analyses were performed by the Institute for Biomolecular Design of
University of Alberta using an Applied Biosystems Voyager System 6064. TLC analysis was
facilitated by the use of the following stains in addition to UV light with fluorescent-indicating plates
(silica gel on glass, Silicycle): phosphomolybdic acid, anisaldehyde/EtOH, or KMnO4/H2O.
Ethyl 3-(methylthio)-2-oxindoline-5-carboxylate (3).
To a solution of ethyl 4-aminobenzoate 2 (30.0 g, 0.182 mol) in dichloromethane (600 mL) at 0 oC
was added a solution of tert-butylhypochlorite (19.8 g, 0.182 mol) in dichloromethane (80 mL). The
reaction mixture was stirred for 10 minutes and cooled to -65 °C. A solution of ethyl (methylthio)
acetate (24.4 g, 0.182 mol) in dichloromethane (80 mL) was added dropwise and the reaction mixture
was stirred for 1 hour, then a solution of triethylamine (18.4 g, 0.182 mol) in dichloromethane (80 mL)
was added and the reaction mixture was warmed to room temperature. To this mixture was added
water (300 mL) and the phases were separated. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and concentrated. The residue was dissolved in ether (600 mL) to which 2N
HCl (80 mL) was added and the mixture was stirred for 18 hours. The solid formed was collected by
filtration, washed with a small amount of hexane and dried in a vacuum oven to afford 3 (34.3 g, 75%)
as an off white solid; 1H-NMR (CDCl3) δ 9.64 (br, 1H), 8.06 (s, 1H), 8.03 (d, 1H, J = 8.1 Hz), 6.98 (d,
1H, J = 8.1 Hz), 4.40 (dd, 2H, J = 7.1 Hz, 7.2 Hz), 2.03 (s, 3H), 1.41 (t, 3H, J = 7.1 Hz, 7.2 Hz); 13C-
NMR (CDCl3) δ 176.4, 165.4, 147.0, 130.9, 127.1, 125.5, 123.4, 109.3, 60.5, 45.0, 14.2, 11.7; LRMS:
MS (ES+) m/z = 252.3 (M+1)+
Ethyl 2-oxindoline-5-carboxylate (4)
To a solution of ethyl 3-(methylthio)-2-oxindoline-5-carboxylate 3 (60.0 g, 0.239 mol) in absolute
ethanol (1200 mL) was added Raney Nickel 2800 (60 g). The reaction mixture was heated to reflux for
4 hours and quickly filtered while it was still hot. The filtrate was concentrated to half its volume and
the product was crystallized. The solid was filtered and dried in a vacuum oven to afford 4 (41.6 g, 85
%) as a white solid; 1H-NMR (DMSO-d6) δ 10.72 (br, 1H), 7.83 (d, 1H, J = 8.1 Hz), 7.60 (s, 1H), 6.89

Molecules 2006, 11
704
(d, 1H, J = 8.1 Hz), 4.25 (dd, 2H, J = 7.1 Hz, 7.2 Hz), 3.54 (s, 2H), 1.29 (t, 3H, J = 7.1 Hz, 7.2 Hz);
13C-NMR (DMSO-d6) δ 176.7, 165.7, 148.2, 129.8, 126.1, 125.1, 122.7, 108.8, 60.3, 35.5, 14.2;
LRMS: MS (ES+) m/z = 206.2 (M+1)+
Ethyl 1’-methyl-2-oxospiro[indoline-3,4’-piperidine]-5-carboxylate (5)
To a solution of oxindole 4 (26.7 g, 0.130 mol) in dry dimethylformamide (900 mL) at 0 °C was
added sodium hydride (14.1 g, 0.585 mol). The reaction mixture was stirred for 10 minutes.
Dichloethylamine hydrochloride (25.0 g, 0.130 mol) was added in one portion. The reaction mixture
was stirred for 10 minutes and warmed to room temperature for 5 hours. The mixture was cooled to
0°C and quenched with saturated ammonium chloride solution. The resulted mixture was diluted with
water and extracted (4x) with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The
product was crystallized to afford 5 (24.4 g, 65%) as a white solid; 1H-NMR (CDCl3) δ 8.18 (br, 1H),
8.04 (s, 1H), 7.98 (d, 1H, J = 8.1 Hz), 6.93 (d, 1H, J = 8.1Hz), 4.36 (dd, 2H, J = 7.1 Hz, 7.2 Hz), 3.07
– 2.93 (m, 2H), 2.84 – 2.72 (m, 2H), 2.50 (s, 3H), 2.13-2.02 (m, 2H), 2.02 – 1.93 (m, 2H), 1.39 (t, 3H,
J = 7.1 Hz, 7.2 Hz); 13C-NMR (CDCl3) δ 182.1, 166.5, 144.2, 135.0, 130.7, 125.2, 124.9,, 109.2, 61.1,
50.5(x2), 46.4, 44.6, 33.1(x2), 14.6; LRMS: MS (ES+) m/z = 289.3 (M+1)+
1’-tert-Butyl 5-ethyl-2-oxospiro [indoline-3,4’-piperidine]-1’5-dicarboxylate (6)
To a solution of spirocyclic oxindole 5 (18.3 g, 0.0634 mol) in 1,2-dichloroethane (400 mL) was
added triethylamine (9.6 g, 0.0951 mol). 2,2,2-Trichloroethylchloroformate (28.2 g, 0.133 mol) was
then added dropwise. The reaction mixture was stirred for 15 minutes and was diluted with ether (800
mL). The mixture was washed with water and brine, dried over anhydrous sodium sulfate and
concentrated. The residue was dissolve in acetic acid (300 mL). Zinc powder (9 g) was added in
several portions and the reaction mixture was stirred for 2 hours. The solvent was evaporated under
vacuum and water was added. The mixture was basified to pH = 10 by addition of ammonium
hydroxide and then extracted with dichloromethane (3x). The organic layer was combined, dried over
anhydrous sodium sulfate and concentrated. The residue was dissolve in dioxane (150 mL). To the
solution, di-tert-butyl dicarbonate (13.8 g, 0.0634 mol) was added and the mixture was stirred for 1
hour. The solvent was evaporated and was recrystallized from 1:5 ethyl acetate/hexane to afford
compound 6 (21.7 g, 92%) as a white solid; 1H-NMR (CDCl3) δ 8.61 (br, 1H), 8.01 (d, 1H, J = 8.1 Hz),
7.99 (s, 1H), 6.96 (d, 1H, J = 8.1 Hz), 4.37 (dd, 2H, J = 7.1 Hz, 7.2 Hz), 3.86 – 3.82 (m, 4H), 1.91 –
1.84 (m, 4H), 1.52 (s, 9H), 1.42 (t, 3H, J = 7.1 Hz, 7.2 Hz); 13C-NMR (CDCl3) δ 182.8, 166.5, 155.2,
144.6, 134.4, 130.9, 125.0, 124.8, 109.8, 80.1, 61.2, 46.7, 45.7 (x2), 32.6 (x2), 28.7(x3), 14.6; LRMS:
MS (ES+) m/z = 375.4 (M+1)+
1’-(tert-Butoxycarbonyl)-2-oxospiro[indoline-3,4’-piperidine]-5-carboxylic acid (1)
To a solution of spirocyclic oxindole 6 (19.6 g, 0.0524 mol) in a mixture of methanol (450 mL) and
water (80 mL) was added 2N sodium hydroxide (40 mL). The reaction mixture was heated to 55 °C
and stirred for 8 hours. The methanol was evaporated under vacuum. The residue was cooled to 0 °C,

Molecules 2006, 11
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acidified carefully to pH = 3 and extracted with ethyl acetate (3x). The organic layer was combined,
washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallized from
ethyl acetate/hexane (2:1) to afford 1 (16.4 g, 91%) as an off white solid; 1H-NMR (DMSO-d6) δ 12.63
(br, 1H), 10.77 (s, 1H), 7.87 (s, 1H), 7.85 (d, 1H, J = 8.1 Hz), 6.93 (d, 1H, J = 8.1 Hz), 3.71 – 3.60 (m,
13
4H), 1.72 – 1.68 (m, 4H), 1.43 (s, 9H); C-NMR (DMSO-d6) δ 180.9, 167.3, 154.1, 145.5, 134.2,
130.4, 124.3, 124.1, 109.3, 78.8, 59.8, 44.6(x2), 31.9(x2), 28.1(x3); LRMS: MS (ES+) m/z = 347.4
(M+1)+
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Sample Availability: Samples of compounds 1, 3, 4 and 5 are available from the authors.
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