A convenient synthetic route to spiro[indole-3,4'-piperidin]-2-ones

Article abstract of DOI:10.1002/1522-2675(20000607)83:6<1247::AID-HLCA1247>3.0.CO;2-1

Starting from 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid and 2-bromoaniline, the spiro[indole-3,4'-piperidin]-2-one system was obtained in three high-yielding steps: anilide formation, N(1)-protection, and intramolecular cyclization under Pd catalysis as the key reaction. The preparation of the corresponding 2-bromoanilide was studied. In extension, the same sequence was developed with 4-methyl- and 4-nitro-2-bromoaniline. In the key step, the NO₂ group led to a rather diminished yield. The transformation of the protected spiro[indole-3,4'-piperidin]-2'one to the corresponding unprotected dihydroindoles is discussed.

Full text of DOI:10.1002/1522-2675(20000607)83:6<1247::AID-HLCA1247>3.0.CO;2-1

Helvetica Chimica Acta ± Vol. 83 (2000)
1247
A Convenient Synthetic Route to Spiro[indole-3,4'-piperidin]-2-ones
by Ralf Freund*
Institut für Organische Chemie, Universität Hannover, Schneiderberg 1b, D-30167 Hannover
(Fax: ‡495117623011; e-mail: R.Freund@mbox.oci.uni-hannover.de)
and Werner W.K.R.Mederski
Merck KGaA, Preclinical Pharmaceutical Research, Frankfurter Str. 250, D-64271 Darmstadt
(Fax: ‡496151723129; e-mail: mederski@merck.de)
Starting from 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid and 2-bromoaniline, the spiro[indole-
3,4'-piperidin]-2-one system was obtained in three high-yielding steps: anilide formation, N(1)-protection, and
intramolecular cyclization under Pd catalysis as the key reaction. The preparation of the corresponding 2-
bromoanilide was studied. In extension, the same sequence was developed with 4-methyl- and 4-nitro-2-
bromoaniline. In the key step, the NO2 group led to a rather diminished yield. The transformation of the
protected spiro[indole-3,4'-piperidin]-2-one to the corresponding unprotected dihydroindoles is discussed.
Introduction. ± 1,2-Dihydrospiro[indole-3,4'-piperidines] and 1,2-dihydro[indole-
3,4'-piperidin]-2-ones are key moieties of a variety of biologically active compounds,
such as growth hormone secretagogues (Ibutamoren, MK-0677) [1], neurokinin
antagonists [2], oxytocin antagonists [3], monoamine transporter inhibitors [4], and
bradykinin antagonists [5]. For the ability of certain molecular units to interact with
certain receptors, the term ꢀprivileged structuresꢁ has been coined [6]. This has led to a
significant interest in developing efficient methods for their preparation.
The reduction of the CˆO group of the 3,3-disubstituted dihydroindol-2-ones,
leading to the corresponding dihydroindoles is a well-investigated literature procedure
[7]. With sodium bis(2-methoxyethoxy)aluminium hydride as the reducing agent, this
transformation is carried out with an excellent yield [7]. Therefore, the 1,2-
dihydrospiro[3H-indole-3,4'-piperidin]-2-ones are appropriate targets for a general
and flexible synthesis of different phenyl substituted derivatives.
The most straightforward route to 1,2-dihydrospiro[3H-indole-3,4'-piperidin]-2-
ones involves the conversion of indolone I with the highly toxic and carcinogenic 2,2'-
dichloro-N-methyldiethylamine hydrochloride to give the spirocyclic compound II [5]
(Scheme 1). The N-Me group should be removed in a two-step procedure involving
demethylation with 2,2,2-trichloroethyl chloroformate and cleavage of the correspond-
ing carbamate with Zn. However, treatment of I with N-[(tert-butoxy)carbonyl]-2,2'-
dichloro-N-methyldiethylamine to prepare the corresponding II was unsuccessful [5].
The preparation of indol-2-ones of general structure IV by means of a Pd-catalyzed
intramolecular amide arylation of a variety of 2'-bromoanilides III has recently been
described [8] (Scheme 1), stating that both electron-withdrawing (i.e., X ˆ 4'-CN) and
electron-donating (i.e., X ˆ 4'-OMe) substituents on the aromatic ring of the

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Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme 1. Synthetic Routes to 1,2-Dihydrospiro[3H-indole-3,4'-piperidin]-2-ones
2'-bromoanilide substrate are tolerated. To our knowledge, the application of this
intramolecular a-arylation of amides for the synthesis of 1,2-dihydrospiro[3H-indole-
3,4'-piperidin]-2-ones has not been described.
To realize this concept, the preparation of these spiropiperidines from commercially
available 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (2, N-Boc-isonipecotic
acid) is reported in the present communication.
Results and Discussion. ± For this purpose, the 2'-bromoanilides 3a ± c had to be
prepared from N-Boc-isonipecotic acid (2) and the selected 2-bromoanilines 1a ± c,
which, in turn, had to be protected by N-benzylation to give 4a ± c, representing the key
intermediates for the cyclization step to the target compounds 5a ± c (Scheme 2).
Initial attempts, however, to prepare the 2'-bromoanilide 3a from 2-bromoaniline
1a and the acid-sensitive starting compound 2 by means of several peptide-coupling
techniques (e.g., DCC, DMF; EDC, HOBt, NMM, THF or DMF; 2,4-dinitrobenze-
nesulfonyl chloride, Et3N, DMAP, MeCN; POCl3, Et3N, CH2Cl2) gave only a low yield
or failed completely.
At this stage, the low reactivity of 2-bromoaniline 1a was studied briefly in a test
system (Scheme 3). Thus, the imidazolide 8 was prepared from the acid 2. After
addition of 1a to a solution of 8 and stirring the mixture for 24 h, not even a trace of
product was formed, whereas after addition of aniline to the same reaction mixture,
conversion was almost complete within 40minutes to give anilide 9. On the other hand,
the less nucleophilic pyridin-2-amine 10 reacted smoothly with the imidazolide 8 to give
the N-(pyridin-2-yl)carboxamido compound 11. These experiments clearly demon-
strate the drastic o-bromo effect of these anilines due to steric hindrance.
Finally, it was found that the only method to obtain the 2'-bromoanilides 3a ± c in
high yield involves formation of the acid chloride of 2 under non-acidic conditions
(SOCl2, pyridine, CH2Cl2) and subsequent in situ reaction with the anilides 1a ± c in the

Helvetica Chimica Acta ± Vol. 83 (2000)
1249
Scheme 2
a) 1. SOCl2, pyridine, CH2Cl2, r.t.; 2. Et3N, 4-(dimethylamino)pyridine (DMAP), CH2Cl2; 3a, 71%, 3b: 84%,
3c: 67%, 4a: 86%. b) BnCl, KF-Al2O3, MeCN/1,2-dimethoxyethane (DME), r.t.; 4a: 80%, 4b, 95%, 4c: 86%.
c) 1. Toluene, reflux; 2. NaBH4, MeOH, r.t.; 54% (as HCl salt). d) t-BuONa, [Pd(dba)2], 2,2'-bis(diphenyl-
phosphanyl)-1,1'-binaphthalene (BINAP), dioxane, 95 ± 1108; 5a: 80%, 5b: 78%, 5c: 22%. e) 5b, HCl in
dioxane, Et2O; 86%.

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Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme 3
a) 1,1'-Carbonyldiimidazole (CDI), CH2Cl2, r.t., 87%. b) THF, r.t.; 3a: no reaction, 9: fast reaction, 11: 73%
(crude).
presence of Et3N and 4-(dimethylamino)pyridine (DMAP). Even the least nucleo-
philic aniline 1c could be converted easily under severer conditions.
To protect the anilide N-atom, benzylation was performed with BnCl, KF-Al2O3
[9]. Very clean reactions did actually occur, and the N-Bn anilides 4a ± c could be
isolated in very high yield, but very long reaction times were usually required for
complete conversion.
Additionally, an alternative route was developed, exemplified by the preparation of
4a (Scheme 2). Thus, reductive amination of benzaldehyde with 1a to N-benzyl-2-
bromoaniline 6 and subsequent anilide formation with acid 2 in the usual way
proceeded without any complications.
With the key intermediates 4a ± c in hand, their Pd-mediated cyclizations were
performed under the conditions described in [8] (t-BuONa, [Pd(dba)2], rac-BINAP,
(2,2'-bis(diphenylphosphanyl)-1,1'-binaphthalene), dioxane, 1008, 3 ± 4.5 h). As ex-
pected, the unsubstituted anilide 4a and the more electron-rich derivative 4b reacted
smoothly (ca. 80% yield) to yield the spirocycles 5a and 5b. The cyclization of the
electron-deficient anilide 4c represented a particular challenge, as it is well-known [10]
that aromatic NO2 compounds are rapidly affected, undergoing side reactions under

Helvetica Chimica Acta ± Vol. 83 (2000)
1251
these harsh conditions. Nevertheless, as in the other cases, the cyclization took place
and the nitro derivative 5c could easily be isolated in pure state ± albeit in low yield ±
after 3 h. No further attempts at optimization to enhance the yield were undertaken.
In addition, the N-Boc protecting group was removed in the case of 5b to yield the
spiropiperidine hydrochloride 7b.
Conclusions and Perspectives. ± An easy and efficient preparative route to 1,2-
dihydrospiro[3H-indole-3,4'-piperidin]-2-ones is presented. The readily prepared 2'-
bromoanilides 4a ± c were cyclized by Pd catalysis to afford the spiro compounds 5a,b in
high yield. An aromatic NO2 substituent, however, limited the applicability.
Furthermore, overall conversion to the 1,2-dihydrospiro[3H-indole-3,4'-piperi-
dines] 12 should be possible following literature procedures for similar compounds:
reduction of the CˆO group of 1,2-dihydroindol-2-ones as mentioned before (Red-Al,
toluene [7] or LiAlH4, Et2O [11]) and subsequent N-debenzylation (H2, Pd/C [12], or
irradiation [13]) or, vice versa, N-debenzylation (Na, liq. NH3 [14]) prior to reduction
of the CˆO group [7].
Proceeding from the commercially available isomeric piperidine- and pyrrolidine-
carboxylic acids, investigations of the syntheses of the corresponding unprotected ±
hitherto unknown ± 1,2-dihydrospiro[indole-piperidines] and 1,2-dihydrospiro[indole-
pyrrolidines] are in progress.
R.F. wishes to thank Prof. Dr. Dr. h.c. E. Winterfeldt for laboratory space and equipment.
Experimental Part
General. 1-[(tert-Butoxy)carbonyl]piperidine-4-carboxylic acid was purchased from Chess and KF-Al2O3
from Fluka. TLC: Merck 60 F-254 silica-gel plates. Flash-column chromatography (FC): silica gel (Baker, 30 ±
60 mm). The portions of solvents in solvent mixtures are given in parts by volume. M.p.: HWS Labortechnik
SGV 500 Plus melting-point apparatus; uncorrected. IR Spectra: Bruker 85 IFS 48 IR or Perkin-Elmer FT 1710
spectrophotometer. 1H-NMR Spectra: Bruker AC 200, Avance 200, WM 250, or Avance 400 spectrometer;
chemical shifts (d) in ppm relative to TMS. MS: electron impact (EI or fast atom bombardement, with a
Micromass VG 70-70E or 70-250SE, or with a Finigan MAT 312 at 70eV, respectively; m/z, relative intensity in
%). High-resolution (HR) mass spectra (peak matching method): Autospec M or VG-Autospec from
Micromass. Elemental microanalyses: Elementar vario EL (Hanau, Germany) CHNOS elemental analyzer.
Syntheses. tert-Butyl 4-{[(2-Bromophenyl)amino]carbonyl}piperidine-1-carboxylate (3a). SOCl2 (0.80 ml,
11.01 mmol) was added, under N2 and at r.t., to a mixture of N-[(tert-butoxy)carbonyl]piperidine-4-carboxylic
acid (2; 2.115 g, 9.22 mmol), pyridine (1.90ml, 23.56 mmol), and CH 2Cl2 (13 ml) while stirring. After 25 min, a
soln. of 2-bromoaniline (1.748 g, 10.16 mmol), Et3N (4.50ml, 32.33 mmol), and DMAP (113 mg, 0.92 mmol) in
CH2Cl2 (16 ml) was added dropwise, and stirring was continued for 14 h. (TLC control: t-BuOMe/petroleum
ether 1:1). The mixture was added to 2n HCl (100 ml), followed by extraction with t-BuOMe (100 ml). The org.
phase was washed with 2n HCl (2 Â 100 ml) and then with sat. Na2CO3 soln. (100 ml), and dried (Na2SO4).
After inoculation, the product was crystallized from Et2O to yield 2.514 g (71.1%) of 3a. White solid. M.p. 137 ±
1398. IR (KBr): 3294, 2926, 1693, 1668, 1581, 1527, 1173. 1H-NMR ((D6)DMSO): 9.41 (br. s, 1 H); 7.65 (dd, J ˆ
1.5, 8.0, 1 H); 7.54 (dd, J ˆ 1.7, 8.0, 1 H); 7.36 (ddd, J ˆ 1.5, 7.6, 7.8, 1 H); 7.14 (ddd, J ˆ 1.7, 7.7, 7.7, 1 H); 3.98
(d, J ˆ 13.2, 2 H); 2.85 ± 2.75 (m, 2 H); 2.69 ± 2.57 (m, 1 H); 1.82 (dd, J ˆ 3.2, 13.2, 2 H); 1.57 ± 1.42 (m, J ˆ 4.3,
.
‡
12.7, 2 H); 1.41 (s, 9 H). FAB-MS: 385 (19), 383 (20, M ), 329 (68), 327 (73), 249 (40), 112 (100). Anal. calc. for
C17H23BrN2O3 (383.29): C 53.26, H 6.06, N 7.31, O 12.52; found: C 53.40, H 6.10, N 7.40, O 12.60.
tert-Butyl 4-{[(2-Bromo-4-methylphenyl)amino]carbonyl}piperidine-1-carboxylate (3b). In a flask with a
reflux condenser, SOCl2 (6.10ml, 83.92 mmol) was added, under N 2 and at r.t., to a mixture of 2 (16.496 g,
71.95 mmol), pyridine (14.5 ml, 179.83 mmol), and CH2Cl2 (100 ml) while stirring vigorously. After 25 min, a
soln. of 2-bromo-4-methylaniline (14.722 g, 79.13 mmol), Et3N (35.0ml, 251.46 mmol), DMAP (0.894 g,

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Helvetica Chimica Acta ± Vol. 83 (2000)
7.32 mmol) in CH2Cl2 (120ml) was added dropwise within 25 min, and stirring was continued for 14 h (TLC
control: Et2O/petroleum ether 1 :2). The mixture was concentrated, added to 2n HCl (200 ml), and extracted
with t-BuOMe (150ml). The org. phase was washed with 2 n HCl (2 Â 200 ml), then with sat. Na2CO3 soln.
(200 ml), and dried (Na2SO4). The crude product was crystallized from Et2O/petroleum ether to yield 23.873 g
(83.5%) of 3b. White solid. M.p. 143 ± 1448. IR (KBr): 3259, 2977, 1700, 1653, 1519, 1425, 1176. 1H-NMR
((D6)DMSO): 9.34 (br. s, 1 H); 7.47 (d, J ˆ 1.9, 1 H); 7.37 (d, J ˆ 8.2, 1 H); 7.16 (dd, J ˆ 1.9, 8.2, 1 H); 3.96
(d, J ˆ 13.3, 2 H); 2.85 ± 2.70( m, 2 H); 2.65 ± 2.57 (m, 1 H); 2.27 (s, 3 H); 1.80( dd, J ˆ 2.9, 13.2, 2 H); 1.55 ± 1.42
.
‡
(m, 2 H); 1.40( s, 9 H). EI-MS: 398 (4), 396 (5, M ), 341 (7), 339 (8), 297 (26), 295 (27), 57 (100). Anal. calc.
for C18H25BrN2O3 (397.32): C 54.41, H 6.35, Br 20.11, N 7.05, O 12.08; found: C 53.90, H 6.30, Br 19.80, N 7.00,
O 12.20.
tert-Butyl 4-{[(2-Bromo-4-nitrophenyl)amino]carbonyl}piperidine-1-carboxylate (3c). While stirring vig-
orously at r.t., SOCl2 (1.90ml, 26.14 mmol) was slowly added dropwise, under N 2, to a soln. of 2 (5.152 g,
22.47 mmol) and pyridine (4.50ml, 55.81 mmol) in CH 2Cl2 (30ml). Stirring was continued for 20min.
Subsequently, 2-bromo-4-nitroaniline (5.361 g, 24.70mmol) and DMAP (4.121 g, 33.73 mmol) in CH 2Cl2
(40ml) were added dropwise within 15 min. The mixture was stirred at r.t. for 16 h; then Et 3N (6.0ml,
43.1 mmol) was added. The mixture was then refluxed for 4.5 h and stirred at r.t. for a further 14 h (TLC control:
Et2O/petroleum ether 3 :1). The mixture was added to 2n HCl (150ml) and extracted with Et 2O (150ml). The
org. phase was washed first with 4n HCl (2 Â 150ml) and then sat. Na 2CO3 soln. (150ml). The Na 2CO3 soln. was
extracted twice with Et2O (100 and 50 ml), the combined Et2O phases were dried (Na2SO4), and the solvent was
removed. A total of 6.49 g (67.4%) of pure 3c was obtained by crystallization from CH2Cl2/Et2O. M.p. 162 ± 1648.
1
IR (KBr): 3341, 2991, 1716, 1669, 1584, 1530, 1502, 1342, 1153. H-NMR ((D6)DMSO): 9.69 (br. s, 1 H); 8.47
(d, J ˆ 2.6, 1 H); 8.23 (dd, J ˆ 2.6, 9.0, 1 H); 8.04 (d, J ˆ 9.0, 1 H); 3.99 (d, J ˆ 13.2, 2 H); 2.88 ± 2.70( m, 3 H);
.
‡
1.85 (dd, J ˆ 3.2, 13.4, 2 H); 1.66 ± 1.42 (m, 2 H); 1.41 (s, 9 H). FAB-MS: 430(11), 428 (12, M ), 374 (17), 372
(18), 217 (45), 91 (100). Anal. calc. for C17H22BrN3O5 (428.29): C 47.67, H 5.19, Br 18.65, N 9.81, O 18.68; found:
C 47.60, H 5.20, Br 18.40, N 9.90, O 18.70.
tert-Butyl 4-{[(Benzyl)(2-bromophenyl)amino]carbonyl}piperidine-1-carboxylate (4a). Method A: The
anilide 3a (2.981 g, 7.78 mmol) was dissolved in MeCN (35 ml), and BnCl (1.20ml, 10.42 mmol) as well as KF-
Al2O3 (3.56 g, ca. 19.6 mmol) were added. The mixture was stirred at r.t. for 72 h (TLC control: t-BuOMe/
petroleum ether 1 :1). The solid substance was filtered by suction, and the solvent was removed. Crystallization
from Et2O yielded 2.933 g (79.7%) of pure 4c. M.p. 120± 122 8.
Method B: A mixture of PhCHO (4.75 g, 44.8 mmol) and 2-bromoaniline (1a) (7.07 g, 41.1 mmol) in
toluene (40ml) was refluxed on a water separator for 110min, and the toluene (30ml) was thereafter distilled
off. After removal of the remaining solvent on a rotary evaporator, the residue was dissolved in dry MeOH
(75 ml). While cooling in a water bath, NaBH4 (7.0g, 185.0mmol) was added in portions during 48 h. After
removal of the solvent, 0.1n NaOH (80ml) was added, followed by extraction with CH 2Cl2 (3 Â 80ml). The org.
phase was dried (Na2SO4) and completely freed from solvent, yielding the known N-benzyl-2-bromoaniline (6)
[15] as a raw product (8.35 g), the spectroscopic data of which conform with those given in the literature. This
raw product (3.203 g) was taken up in Et2O (20ml), mixed with 4.0 m HCl in dioxane (3.2 ml, 12.8 mmol), and
left to stand for 14 h. It was decanted from the precipitate, which was then dissolved in boiling MeOH (5 ml).
After cooling, the product was crystallized by slowly adding Et2O (15 ml). Crystallization was completed at 08,
and the crystals were, after decantation of the solvent, washed with Et2O: N-Benzyl-2-bromoaniline
hydrochloride (6 ´ HCl; 2.544 g, 69.7%; total yield, calculated on 2-bromoaniline: 54.0%). IR (KBr): 2880,
2846, 2608, 2576, 1474, 754. 1H-NMR ((D6)DMSO): 7.40( dd, J ˆ 1.5, 7.8, 1 H); 7.33 ± 7.19 (m, 5 H); 7.06
(ddd, J ˆ 1.5, 7.3, 8.3, 1 H); 6.52 (dd, J ˆ 1.5, 8.3, 1 H); 6.48 (ddd, J ˆ 1.5, 7.3, 7.8, 1 H); 6.37 (br. s, 2 H); 4.41
.
‡
(s, 2 H). EI-MS: 263 (2), 261 (2, [M À 1] ), 173 (100), 171 (99), 92 (34). HR-MS: 261.0155 (calc. for C13H12BrN
.
‡
[M À H] : 261.0153).
To a stirred soln. of 2 (5.372 g, 23.43 mmol) and pyridine (4.60ml, 57.17 mmol) in CH 2Cl2 (30ml), SOCl 2
(2.14 ml, 29.44 mmol) was slowly added dropwise under N2 and at r.t., and stirring was continued for 75 min.
Subsequently, a soln. of 6 (raw product; 4.818 g of 69.7% purity, 12.82 mmol), Et3N (6.30ml, 45.26 mmol), and
DMAP (159 mg, 1.30mmol) in CH 2Cl2 (30ml) was swiftly added dropwise, and the mixture was stirred for a
further 20h (TLC control: t-BuOMe/petroleum ether 1:1). The mixture was concentrated and poured into 2n
HCl (100 ml), followed by extraction with t-BuOMe (100 ml). The org. phase was washed with 2n HCl (100 ml)
and then with sat. Na2CO3 soln. (100 ml), and dried (Na2SO4). Crystallization from Et2O/petroleum ether
yielded 5.220g (86.0%) of 4a. IR (KBr): 1691, 1651, 1475, 1433, 1403, 1229, 1168. 1H-NMR ((D6)DMSO): 7.82 ±
7.77 (m, 1 H); 7.36 ± 7.23 (m, 5 H); 7.16 (dd, J ˆ 2.2, 7.8, 2 H); 7.06 ± 7.01 (m, 1 H); 5.35 (d, J ˆ 14.6, 1 H); 4.11
(d, J ˆ 14.6, 1 H); 3.94 ± 3.79 (m, 2 H); 2.45 ± 2.39 (m, 1 H); 2.15 ± 2.04 (m, 1 H); 1.64 ± 1.54 (m, 3 H); 1.47 ± 1.39

Helvetica Chimica Acta ± Vol. 83 (2000)
1253
.
‡
(m, 2 H); 1.38 (s, 9 H). FAB-MS: 475 (17), 473 (18, M ), 419 (47), 317 (48), 91 (100). Anal. calc. for
C24H29BrN2O3 (473.41): C 60.88, H 6.19, Br 16.88, N 5.92, O 10.14; found: C 60.90, H 6.30, Br 16.40, N 5.90,
O 10.20.
tert-Butyl 4-{[(Benzyl)(2-bromo-4-methylphenyl)amino]carbonyl}piperidine-1-carboxylate (4b). BnCl
(9.00 ml, 78.17 mmol) and KF-Al2O3 (27.11 g, ca. 149.1 mmol) were added to a soln. of 3b (23.706 g, 59.66 mmol)
in 1,2-dimethoxyethane (110ml) and stirred at r.t. for 9 days (TLC control: t-BuOMe/petroleum ether 1:1). The
solid substance was filtered by suction over Celite, the solvent was removed, and the residue was dried in vacuo
at an increased temp. A non-crystallizable, highly viscous mass (30.487 g) resulted. A portion thereof (1.242 g)
was purified by FC (silica gel; t-BuOMe/petroleum ether 3 :4): semi-solid, sticky mass of 4b (1.130g), resulting
in a 95.4% yield of the reaction. IR (KBr): 1695, 1662, 1493, 1401, 1365, 1231, 1168. 1H-NMR ((D6)DMSO): 7.68
(d, J ˆ 1.8, 1 H); 7.31 ± 7.21 (m, 4 H); 7.16 ± 7.11 (m, 3 H); 6.89 (d, J ˆ 8.0, 1 H); 5.35 (d, J ˆ 14.6, 1 H); 4.05
(d, J ˆ 14.6, 1 H); 3.93 ± 3.79 (m, 2 H); 2.45 ± 2.35 (m, 1 H); 2.30( s, 3 H); 2.18 ± 2.06 (m, 1 H); 1.64 ± 1.53
.
‡
(m, 3 H); 1.46 ± 1.40( m, 1 H); 1.38 (s, 9 H). FAB-MS: 489 (6), 487 (7, M ), 433 (34), 431 (35), 91 (100). Anal.
calc. for C25H31BrN2O3 (487.44): C 61.59, H 6.42, N 5.75, O 9.85; found: C 61.50, H 6.60, N 5.60, O 10.10.
tert-Butyl 4-{[(Benzyl)(2-bromo-4-nitrophenyl)amino]carbonyl}piperidine-1-carboxylate (4c). BnCl
(3.00 ml, 26.06 mmol) and KF-Al2O3 (9.09 g, ca. 50.0 mmol) was added to a soln. of 3c (8.530g, 19.92 mmol)
in MeCN (60ml) and DME (75 ml), and stirred at r.t. for 13 days. After 9 days, additional BnCl (1.00ml,
8.69 mmol), and, after 10.3 days, additional KF-Al2O3 (3.02 g, ca. 16.6 mmol) were added (TLC control: Et2O/
petroleum ether 3 :1). The carrier was filtered by suction over Celite, the solvent was removed, and the product
was purified by FC (silica gel; t-BuOMe/petroleum ether 1 :1): 8.878 g, (86.0%) of 4c. Colorless foam. M.p. 60±
638. IR (KBr): 1691, 1672, 1581, 1527, 1476, 1346, 1168. 1H-NMR ((D6)DMSO): 8.61 (d, J ˆ 2.6, 1 H); 8.20
(dd, J ˆ 2.6, 8.7, 1 H); 7.36 (d, J ˆ 8.7, 1 H); 7.31 ± 7.24 (m, 4 H); 7.17 (d, J ˆ 8.0, 1 H); 5.29 (d, J ˆ 14.7, 1 H); 4.26
(d, J ˆ 14.7, 1 H); 3.88 (d, J ˆ 13.0, 2 H); 3.81 (d, J ˆ 12.3, 1 H); 2.51 ± 2.45 (m, 1 H); 2.15 ± 2.08 (m, 1 H); 1.64 ±
.
‡
1.55 (m, 2 H); 1.41 ± 1.38 (m, 2 H); 1.37 (s, 9 H). FAB-MS: 520(12), 518 (13, M ), 464 (14), 462 (15), 91 (100).
Anal. calc. for C24H28BrN3O5 (518.41): C 55.60, H 5.45, N 8.11, O 15.43; found: C 55.90, H 5.60, N 7.90, O 15.20.
tert-Butyl 1-Benzyl-1,2-dihydro-2-oxospiro[(3H-indole-3,4'-piperidine]-1'-carboxylate (5a). t-BuONa
(2.713 g, 28.23 mmol), [Pd(dba)2] (0.542 g, 0.94 mmol), and rac-BINAP (0.876 g, 1.41 mmol) were added to a
soln. of 4a (8.887 g, 18.77 mmol) in dry dioxane (1.65 ml). The mixture was stirred in a closed flask under N2 at
100 ± 1108 for 4.5 h. 0.5n Citric acid (150ml) was added, the soln. was diluted with H 2O (50ml) and extracted
with CH2Cl2 (1 Â 100 and 2 Â 50ml). The org. phase was dried (Na 2SO4) and liberated from solvent. A
crystalline raw product was obtained from Et2O/petroleum ether. FC of the raw product over silica gel with
Et2O/petroleum ether 14 :13 and of the mother liquor with t-BuOMe/petroleum ether 5 :9 produced 5.874 g
(79.7%) of 5a. Colorless crystals. M.p. 118 ± 1198. IR (KBr): 1712, 1686, 1609, 1487, 1452, 1433, 1366, 1248.
1H-NMR ((D6)DMSO): 7.51 (d, J ˆ 6.8, 1 H); 7.36 ± 7.16 (m, 6 H); 7.15 (t, J ˆ 7.4, 1 H); 6.89 (d, J ˆ 7.7, 1 H); 4.90
.
‡
(s, 2 H); 3.80± 3.65 ( m, 4 H); 1.75 (t, J ˆ 6.0, 4 H); 1.45 (s, 9 H). FAB-MS: 393 (10, M ), 337 (25), 217 (61), 91
(100). Anal. calc. for C24H28N2O3 (392.50): C 73.43, H 7.20, N 7.14, O 12.23; found: C 73.30, H 7.20, N 7.20,
O 12.20.
tert-Butyl 1-Benzyl-1,2-dihydro-5-methyl-2-oxospiro[3H-indole-3,4'-piperidine]-1'-carboxylate (5b). In a
closed flask, a soln. of 4b (916 mg, 1.88 mmol), t-BuONa (273 mg, 2.84 mmol), rac-BINAP (88 mg, 0.14 mmol),
and [Pd(dba)2] (57 mg, 0.10 mmol) in dry dioxane (17 ml) was stirred under N2 at 95 ± 1058 for 4.5 h. The
mixture was added to 0.5n citric acid (80ml) and extracted with CH 2Cl2 (1 Â 100 and 2 Â 50ml). The org. phase
was dried (Na2SO4) and liberated from solvent. The product 5b was obtained pure (598 mg, 78.3%) by FC (silica
gel; t-BuOMe/petroleum ether 5 :1). Compound 5b was crystallizable from Et2O/petroleum ether. M.p. 151 ±
1528. IR (KBr): 1712, 1681, 1617, 1498, 1418, 1366, 1347, 1244, 1154, 1121. 1H-NMR ((D6)DMSO): 7.35 ± 7.21
(m, 6 H); 6.99 (d, J ˆ 7.7, 1 H); 6.76 (d, J ˆ 8.0, 1 H); 4.86 (s, 2 H); 3.81 ± 3.64 (m, 4 H); 2.26 (s, 3 H); 1.80± 1.65
.
‡
(m, 4 H); 1.45 (s, 9 H). FAB-MS: 407 (30, M ), 351 (100), 333 (50), 306 (34), 91 (95). Anal. calc. for
C25H30N2O3 (406.53): C 73.85, H 7.45, N 6.89, O 11.81; found: C 73.30, H 7.50, N 6.80, O 11.70.
tert-Butyl 1-Benzyl-1,2-dihydro-5-nitro-2-oxospiro[3H-indole-3,4'-piperidine]-1'-carboxylate (5c). The ani-
lide 4c (8.757 g, 16.89 mmol) was dissolved in dry dioxane (150ml), followed by addition of t-BuONa (2.443 g,
25.42 mmol), [Pd(dba)2] (0.492 g, 0.856 mmol), and rac-BINAP (0.790 g, 1.27 mmol). The mixture was stirred
in a closed flask under N2, at 95 ± 1108 for 3 h, concentrated, and introduced into sat. NaHCO3 soln. (150ml).
Extraction was performed with CH2Cl2 (1 Â 100 and 2 Â 50ml), the extract was dried (Na 2SO4) and freed from
solvent. FC (silica gel; t-BuOMe/petroleum ether 3 :4) afforded 1.599 g (21.6%) of 5c. Yellowish foam. M.p. of
66 ± 678. IR (KBr): 1717, 1692, 1606, 1527, 1491, 1448, 1424, 1346, 1164. 1H-NMR ((D6)DMSO): 7.92 (dd, J ˆ 2.1,
8.2, 1 H); 7.84 (d, J ˆ 8.2, 1 H); 7.69 (d, J ˆ 2.1, 1 H); 7.39 ± 7.25 (m, 5 H); 5.03 (s, 2 H); 3.81 ± 3.65 (m, 4 H);

1254
Helvetica Chimica Acta ± Vol. 83 (2000)
.
‡
1.91 ± 1.75 (m, 4 H); 1.45 (s, 9 H). FAB-MS: 438 (13, M ), 382 (40), 364 (39), 91 (100). Anal. calc. for
C24H27N3O5 (437.50): C 65.88, H 6.23, N 9.61, O 18.28; found: C 65.80, H 6.40, N 9.20, O 17.90.
1-Benzyl-1,2-dihydro-5-methyl-2-oxospiro[3H-indole-3,4'-piperidin]-1'-ium Hydrochloride (7b). Com-
pound 5b (458 mg, 1.127 mmol) was taken up in dry dioxane (2.0ml) and mixed at r.t. with 4.0 m HCl in
dioxane (4.0ml) while stirring. Stirring was continued for 1 h, and Et 2O (10ml) was then swiftly added dropwise
while stirring vigorously. Crystallization then started and was completed at 08. After having been sucked off, 7b
was washed with Et2O and dried: 358 mg (86.4%). M.p. >2608 (dec.). IR (KBr): 2965, 2922, 2718, 2612, 1711,
1602, 1501, 1461, 1351. 1H-NMR ((D6)DMSO): 9.20(br. s, 2 H); 7.36 ± 7.21 (m, 5 H); 7.18 (d, J ˆ 1.7, 1 H); 7.04
(ddd, J ˆ 0.8, 1.7, 8.0, 1 H); 6.80 (d, J ˆ 8.0, 1 H); 4.89 (s, 2 H); 3.61 ± 3.47 (m, 2 H); 3.36 ± 3.26 (m, 2 H); 2.29
.
‡
(s, 3 H); 2.25 ± 2.11 (m, 2 H); 1.99 ± 1.88 (m, 2 H). EI-MS: 306 (69, [M À 1] ), 250(53), 91 (100). HR-MS:
.
‡
306.1731 (calc. for C20H22N2O [M À H] ): 306.1732). Anal. calc. for C20H23ClN2O ´ 1/3 Et2O (367.58): C 69.71,
H 7.22, N 7.62, O 5.80; found: C 69.20, H 7.00, N 7.90, O 5.70.
tert-Butyl 4-(1H-Imidazole-1-carbonyl)piperidine-1-carboxylate (8). To a stirred soln. of 1,1'-carbon-
yldiimidazole (1.162 g, 7.17 mmol) in dry CH2Cl2 (11 ml), 2 (1.22 g, 5.32 mmol) was added in portions at r.t. The
mixture was stored at 08 for 4.5 h, diluted with Et2O (22 ml), washed with ice-water and subsequently with ice-
cold sat. NaHCO3 soln., and dried (Na2SO4). After evaporation of the solvents, 8 (1.291 g, 86.9%) was obtained.
Colorless solid. IR (CHCl3): 2981, 1736, 1686, 1475, 1427, 1319, 1166. 1H-NMR (CDCl3): 8.19 (s, 1 H); 7.48
(s, 1 H); 7.13 (s, 1 H); 4.18 (m, 2 H); 3.06 (tt, J ˆ 4.0, 10.9, 1 H); 2.92 (br. t, J ˆ 11.6, 2 H); 1.93 (br. d, J ˆ 11.0,
.
‡
2 H); 1.90± 1.79 ( m, J ˆ 4.2, 11.2, 2 H); 1.47 (s, 9 H). EI-MS: 279 (18, M ), 222 (63), 206 (62), 179 (28), 156
(49), 128 (39), 112 (98), 84 (36), 82 (36), 69 (100). HR-MS: 279.1581 (calc. for C14H21N3O3: 279.1583).
tert-Butyl 4-[(Phenylamino)carbonyl]piperidine-1-carboxylate (9). To 8 (397 mg, 1.34 mmol) in dry THF
(1.5 ml), a soln. of 2-bromoaniline (218 mg, 1.27 mmol) in dry THF (1.5 ml) was added under stirring at r.t. TLC
Control (t-BuOMe/petroleum ether 1 :1) revealed that not even a trace of product was formed after more than
24 h. Aniline (119 mg, 1.28 mmol) was now added to the same mixture. This time, product formation was almost
complete within 40min at r.t. (TLC). To identify the product 9, a sample was purified by FC (silica gel; t-
BuOMe/petroleum ether 3 :1). M.p. 136 ± 1378. IR (KBr): 3317, 2931, 1697, 1665, 1602, 1546, 1441, 1238, 1167.
1H-NMR (CD3OD): 7.54 (dd, J ˆ 1.2, 8.7, 2 H); 7.29 (dd, J ˆ 7.4, 8.7, 2 H); 7.07 (tt, J ˆ 1.2, 7.4, 1 H); 4.14
(br. d, J ˆ 13.2, 2 H); 2.83 (br. t, J ˆ 12.1, 2 H); 2.55 (tt, J ˆ 4.0, 11.5, 1 H); 1.83 (dd, J ˆ 2.9, 13.3, 2 H); 1.75 ± 1.54
.
‡
(m, J ˆ 4.3, 12.0, 2 H); 1.47 (s, 9 H). EI-MS: 304 (6, M ), 247 (51), 203 (98), 147 (100). Anal. calc. for
C17H24N2O3 (304.49): C 67.08, H 7.95, N 9.20, O 15.77; found: C 67.20, H 8.20, N 8.90, O 15.60.
tert-Butyl 4-{[(6-Methylpyridin-2-yl)amino]carbonyl}piperidine-1-carboxylate (11). A soln. of 2-amino-6-
methylpyridine (10; 281 mg, 2.60mmol) in dry THF (3 ml) was added to 8 (858 mg, 3.07 mmol) in dry THF
(5 ml) at r.t., and the mixture was stirred for 45 h. After dilution with t-BuOMe (25 ml), the mixture was washed
with sat. NH4Cl soln. (2 Â 25 ml) and subsequently with sat. Na2CO3 soln. (25 ml). After drying (Na2SO4) and
removing of the solvents, a solid raw product (898 mg) was obtained. According to 1H-NMR analysis, this
material consisted of 11 (610mg, 73%), 8 (221 mg), and imidazole (67 mg). The desired product was isolated as
follows: the solid was taken up in MeCN (10 ml), and 10% aq. NaOH soln. (0.5 ml) was added. After stirring for
15 min at r.t., the mixture was diluted with t-BuOMe (50ml), washed with 10% aq. AcONa/AcOH buffer soln.
(2 Â 50ml), sat. Na 2CO3 soln. (50ml), and dried (Na 2SO4). Evaporation of the solvents afforded pure 11
(395 mg, 47.6%), which solidified on standing. M.p. 150± 152 8. IR (CHCl3): 3416, 2979, 1685, 1520, 1454, 1427,
1237, 1158. 1H-NMR (CDCl3): 8.02 (br. s, 1 H); 8.01 (d, J ˆ 8.3, 1 H); 7.60( dd, J ˆ 7.4, 8.3, 1 H); 6.91 (d, J ˆ 7.4,
1 H); 4.17 (m, 2 H); 2.79 (br. t, J ˆ 11.5, 2 H); 2.45 (s, 3 H); 2.40( tt, J ˆ 3.8, 11.5, 1 H); 1.91 (br. d, J ˆ 11.7, 2 H);
.
‡
1.79 ± 1.68 (m, J ˆ 4.3, 11.9, 2 H); 1.47 (s, 9 H). EI-MS: 319 (13, M ), 262 (11), 218 (21), 163 (100). Anal. calc.
for C17H25N3O3 (319.41): C 63.93, H 7.89, N 13.16, O 15.03; found: C 63.60, H 8.20, N 12.90, O 15.40.
REFERENCES
[1] A. A. Patchett, R. P. Nargund, J. R. Tata, M.-H. Chen, K. J. Barakat, D. B. R. Johnston, K. Cheng, W. W.-S.
Chan, B. Butler, Hickey, T. Jacks, K. Schleim, S.-S. Pong, L.-Y. P. Chaung, H. Y. Chen, E. Frazier, K. H.
Leung, S.-H. L. Chiu, R. G. Smith, Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 70 0 1.
[2] S. K. Shah, J. J. Hale, H. Qi, D. J. Miller, C. P. Dorn Jr., S. G. Mills, S. J. Sadowski, M. A. Cascieri, J. M.
Metzger, G. J. Eiermann, M. J. Forrest, D. E. MacIntyre, M. MacCoss, ꢀAbstracts of Papersꢁ, 211th Am.
Chem. Soc. Natl. Mtg., New Orleans, March 24 ± 29, 1996, MEDI 136.

Helvetica Chimica Acta ± Vol. 83 (2000)
1255
[3] B. E. Evans, J. L. Leighton, K. E. Rittle, K. F. Gilbert, G. F. Lundell, N. P. Gould, D. W. Hobbs, R. M.
DiPardo, D. F. Veber, D. J. Pettibone, B. V. Clineschmidt, P. S. Anderson, R. M. Freidinger, J. Med. Chem.
1992, 35, 3919.
[4] S. M. N. Efange, A. P. Kamath, A. B. Khare, M.-P. Kung, R. H. Mach, S. M. Parsons, J. Med. Chem. 1997, 40,
3905.
[5] R. R. Goehring, Org. Prep. Proced. Int. 1995, 27, 691.
[6] B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F.
Veber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P.
Springer, J. Hirshfield, J. Med. Chem. 1988, 31, 2235.
[7] A. Kucerovy, J. S. Hathaway, P. G. Mattner, O. Repic, Synth. Commun. 1992, 22, 729.
[8] K. H. Shaughnessy, B. C. Hamann, J. F. Hartwig, J. Org. Chem. 1998, 63, 6546.
[9] J. Yamawaki, T. Ando, T. Hanafusa, Chem. Lett. 1981, 1143.
[10] R. D. Guthrie, D. E. Nutter, J. Am. Chem. Soc. 1982, 104, 7478, and refs. cit. therein; R. D. Guthrie, C.
Hartmann, R. Neill, D. E. Nutter, J. Org. Chem. 1987, 52, 736.
[11] T. Nishio, N. Okuda, C. Kashima, Helv. Chim. Acta 1990, 73, 1719.
[12] F. Knefeli, K. K. Mayer, W. Wiegrebe, U. P. Schlunegger, R. Lauber, Arch. Pharm. (Weinheim Ger.) 1990,
323, 145; K. Jones, J. M. D. Storey, Tetrahedron 1993, 49, 4901.
[13] M. Ibrahim-Ouali, M.-E. Sinibaldi, Y. Troin, A. Cuer, G. Dauphin, J.-C. Gramain, Heterocycles 1995, 41,
1939.
[14] W. v. d. Saal, J.-P. Hölck, W. Kampe, A. Mertens, B. Müller-Beckmann, J. Med. Chem. 1989, 32, 1481;
J. M. D. Storey, C. McCarthy, K. Jones, J. Chem. Soc., Chem. Commun. 1991, 892.
[15] Y.-T. Park, I.-H. Lee, Y.-H. Kim, J. Heterocycl. Chem. 1994, 31, 1625.
Received February7, 2000