Conformational Switching and the Synthesis of Spiro[2H-indol]-3(1H)-ones by Radical Cyclization

Article abstract of DOI:10.1021/jo970105t

Radical cyclization of 1-(2-bromophenylamino)cyclohexanecarbonitriles (3, X = CH) and 4-(2-bromophenylamino)-4-piperidinecarbonitriles (3, X = N) provide spiro[2H-indole-2-cyclohexan]-3(1H)-imines (5, X = CH) and spiro[2H-indole-2,4′-piperidin]-3(1H)-imines (5, X = N), respectively, in 33-57% yields. This contradicts a recent report that 1-(2-bromophenylamino)cyclohexane-carbonitrile (3, X-R² = CH₂), treated under apparently identical conditions, led only to nitrile transfer product 6 (X-R² = CH₂). Acidic hydrolyses of the imines provide the corresponding ketones 2 in quantitative yields. Single-crystal X-ray analyses of ketone 2e and nitrile 3e indicate that the relative configuration of the aromatic nitrogen has been inverted during the cyclization. In addition, NOE NMR analyses of spiroindolepiperidine 2c and its aniline-nitrogen-methylated analogue 10a show that the relative conformation of the piperidine ring has inverted. Thus, methylation of 2c acts as a conformational "switch" for the spiroindolepiperidine ring system.

Full text of DOI:10.1021/jo970105t

5504
J . Org. Chem. 1999, 64, 5504-5510
Con for m a tion a l Sw itch in g a n d th e Syn th esis of
Sp ir o[2H-in d ol]-3(1H)-on es by Ra d ica l Cycliza tion
Richard Sulsky,*,† J ack Z. Gougoutas,‡ J ohn DiMarco,‡ and Scott A. Biller†
Bristol-Myers Squibb Pharmaceutical Research Institute Princeton, New J ersey 08543-4000
Received J anuary 22, 1997 (Revised Manuscript Received May 18, 1999)
Radical cyclization of 1-(2-bromophenylamino)cyclohexanecarbonitriles (3, X ) CH) and 4-(2-
bromophenylamino)-4-piperidinecarbonitriles (3, X ) N) provide spiro[2H-indole-2-cyclohexan]-
3(1H)-imines (5, X ) CH) and spiro[2H-indole-2,4′-piperidin]-3(1H)-imines (5, X ) N), respectively,
in 33-57% yields. This contradicts a recent report that 1-(2-bromophenylamino)cyclohexane-
carbonitrile (3, X-R2 ) CH2), treated under apparently identical conditions, led only to nitrile
transfer product 6 (X-R2 ) CH2). Acidic hydrolyses of the imines provide the corresponding ketones
2 in quantitative yields. Single-crystal X-ray analyses of ketone 2e and nitrile 3e indicate that the
relative configuration of the aromatic nitrogen has been inverted during the cyclization. In addition,
NOE NMR analyses of spiroindolepiperidine 2c and its aniline-nitrogen-methylated analogue 10a
show that the relative conformation of the piperidine ring has inverted. Thus, methylation of 2c
acts as a conformational “switch” for the spiroindolepiperidine ring system.
In tr od u ction
functionality of 2 would behave as an arylogous amide
and thus mimic the isoindolone electron density.
Isoindolylpiperidine (1) was identified by high-through-
put screening in our laboratories as an inhibitor of
microsomal triglyceride-transfer protein (MTP) function.1
As part of a structure-activity-based study of 1, we
desired to prepare spiro[2H-indole-2,4′-piperidin]-3(1H)-
ones (spiroindoxyls) of general structures 2-cis/2-tr a n s
as conformationally restricted analogues.2 The spiro-
Spiroindoxyls have been prepared previously by base-
catalyzed rearrangements of oxidized indoles (eq 1).4,5 For
our purposes, this was judged not to be an attractive
route. Preparation of the necessary indoles would be
difficult and the presence of a basic nitrogen in the
saturated ring was anticipated to lead to complications
in the oxidative rearrangement step.
We set out to design a mild synthetic route to spiro-
indoxyls that would accommodate a variety of functional-
ity in the precursors. Anilinonitrile 3 (Scheme 1) ap-
peared to be an attractive intermediate for such a
synthetic sequence. Aryl radical 4R was proposed to
undergo 5-exo-dig cyclization to 5R followed by reduction
to form imine 5. Subsequent hydrolysis of 5 would provide
the desired spiroindoxyl 2.
The feasibility of this reaction sequence was open to
question. Potential competing side reactions include the
direct reduction of radical 4R to form 4, and the cleavage
of bond b of intermediate 5R to form 6R followed by
reduction to the nitrile transfer product 6. In fact,
Beckwith6,7 had shown that a related radical precursor
indoxyls offer more structural rigidity than the lead
compound and would therefore act as probes of the
spatial requirements of the biological target. By altering
the steric bulk of R1, we hoped to orient the ring system
in one of the two possible chair conformations, 2-cis or
2-tr a n s (X ) N). Thus, we envisioned the substituent
R1 as a conformational “switch”3 for the spiroindoxyl ring
system. We also anticipated that the o-amino ketone
† Department of Metabolic Diseases Chemistry.
(3) (a) Stafford, J . A.; Veal, J . M.; Feldman, P. L.; Valvano, N. L.;
Baer, P. G.; Brackeen, M. F.; Brawley, E. S.; Connolly, K. M.;
Domanico, P. L.; Han, B.; Rose, D. A.; Rutkowske, R. D.; Sekut, L.;
Stimpson, S. A.; Strickland, A. B.; Verghese, M. W. J . Med. Chem.
1995, 38, 4972. (b) Tsai, Ya-Ching; Liou, J ing-Oing; Liao, Richard;
Cheng, Chen-Yu; Tao, Pao-Luh Bioorg. Med. Chem. Lett. 1998, 8, 1813.
(c) Elliott, J . M.; Broughton, H.; Cascieri, M. A.; Chicchi, G.; Huscroft,
I. T.; Kurtz, M.; MacLeod, A. M.; Sadowski, S.; Stevenson, G. I. Bioorg.
Med. Chem. Lett. 1998, 8, 1851.
(4) Rodriquez, J . G.; San Andre´s, A. J . Heterocycl. Chem. 1991, 28,
1293.
(5) O’Rell, P. D.; Lee, F. G. H.; Boekelheide, V. J . Am. Chem. Soc.
1972, 94, 3205.
‡ Department of Solid State Chemistry.
(1) J amil, H.; Gordon, D. A.; Eustice, D. C.; Brooks, C. M.; Dickson,
J . K., J r.; Chen, Y.; Ricci, B.; Chu, C.-H.; Harrity, T. W.; Ciosek, C. P.,
J r.; Biller, S. A.; Gregg, R. E.; Wetterau, J . R. Proc. Natl. Acad. Sci
U.S.A. 1996, 93, 11991.
(2) For some recent work involving restricted conformations of
piperidine systems and their application biological receptors, see: (a)
Tong, W.; Collantes, E. R.; Chen, Y.; Welsh, W. J . J . Med. Chem. 1996,
39, 380. (b) Dijkstra, G. D. H. Recl. Trav. Chim. Pays-Bas 1993, 112,
151. (c) DiMeglio, C. M.; Froimowitz, M.; Makriyannis, A. Pharm. Res.
1993, 10, 1200. (d) McCague, R.; Rowlands, M. G. J . Med. Chem. 1992,
35, 3699 and references therein.
10.1021/jo970105t CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/09/1999

Synthesis of Spiro[2H-indol]-3(1H)-ones
J . Org. Chem., Vol. 64, No. 15, 1999 5505
Sch em e 1a
a
Key: (a) i. Bu3SnH, AIBN/toluene, reflux; ii. satd aq KF. (b) 1 M HCl/H2O or H2O-MeOH, reflux.
Ta ble 1. Syn th esis of Nitr iles 3a -e, Sp ir oin d oleim in es
5a -e, a n d Sp ir oin d olon es 2a -e fr om Cyclic Keton es 7a -e
underwent an analogous nitrile transfer as the major
pathway (eq 2).
yield (%)
7
X
R2
3a
5b
2c
a
b
c
d
e
N
N
N
CH
CH
CO2Et
CH2Ph
CH2CH2CHPh2
H
C(CH3)3
94
69
60
97
76
33
57
57
58
45
100
100
83
100
100
a
Condensation of 2-bromoaniline and cyclic ketones 7a -e (eq
3). Radical cyclization of 3a -e to 5a -e (Scheme 1). c Hydrolysis
of 5a -e to 2a -e (Scheme 1).
b
(eq 2)
After the completion of our studies, a report8 appeared
claiming that for the type of radical cyclization under
study here (for example, substrate 3d , Scheme 1), nitrile
6 was the sole reaction product. In contrast, we demon-
strate that radical cyclization does provide the desired
spiroindoxyl imines in moderate yields. In addition, we
demonstrate that the nature of the R1 substituent can
have a dramatic effect on the conformational preference
of the spiro ring system, providing either conformer 2-cis
or 2-tr a n s as desired.
nonbasic amine. Reaction under standard Strecker condi-
tions (HOAc/KCN) led only to the undesired cyanohy-
drin.10 Piperidone 7c was prepared by alkylation of 1,4-
dioxa-8-azaspiro[4.5]decane with 3,3-diphenylpropyl-1-
tosylate11 and subsequent hydrolysis of the ketal.
Refluxing nitrile 3b in a dilute solution of toluene
(0.065 M) with 1.1 equiv of tributyltin hydride for 16 h
(catalytic AIBN as initiator) and then quenching with
half-saturated ammonium hydroxide solution gave two
minor and two major products (Scheme 1). The direct
reduction product 4b and the nitrile transfer product 6b
were isolated in 3 and 5% yields, respectively. The two
major products, however, were imine 5b, (31% yield) and
the corresponding ketone 2b (26% yield). Further experi-
mentation showed that reaction times as short as 1 h
were sufficient for complete reaction. Quenching the
reaction with aqueous potassium fluoride afforded imine
5b in 57% yield (Table 1) without formation of the ketone
2b. Changing reactant addition order or rate did not alter
product distributions or yields, nor did increasing the
relative amount of tributyltin hydride up to three equiva-
lents. The highly fluorescent polar imine, a stable com-
pound in neutral or basic solution, was readily isolated
by normal phase silica gel chromatography. For sub-
strates 3a and 3c, the yield of the cyclization products
5a and 5c were 33 and 57%, respectively, while the yields
of the reduction and transfer products 4a ,c and 6a ,c
remained low, and little of the reactant 3a or 3c was
recovered from the reaction mixture. Cyclohexanes 3d
and 3e also gave moderate yields of cyclized products 5d
and 5e (Table 1). Hydrolyses of imines 5a -e to ketones
2a -e were effected quantitatively upon brief reflux with
dilute hydrochloric acid.
Resu lts a n d Discu ssion
Preparation of the substituted aniline 3 was achieved
by a modified Strecker reaction.9 Treatment of a mixture
of 2-bromoaniline and cyclic ketones 7a -e in acetic acid
with cyanotrimethylsilane at room temperature for pro-
longed reaction times led to high yields of 3a -e (eq 3,
Table 1). This remarkable reaction provided the desired
(eq 3)
products despite a high degree of steric crowding, and
occurred even though the substrate was a relatively
(6) Beckwith, A. L. J .; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J .
Chem. Soc. Chem. Commun. 1987, 666.
(7) Beckwith, A. L. J .; O’Shea, D. M.; Westwood, S. W. J . Am. Chem.
Soc. 1988, 110, 2565.
(8) Cossy, J .; Poitevin, C.; Pardo, D. G.; Peglion, J . L. Synthesis 1995,
1368.
(9) Feldman, P. L.; Brackeen, M. F. J . Org. Chem. 1990, 55, 4207.
(10) Brine, G. A.; Stark, P. A.; Carroll, F. I.; Singh, P. J . Heterocycl.
Chem. 1994, 31, 513.
(11) Laubie, J . D. Chim. Ther. 1969, 4 (3), 183.

5506 J . Org. Chem., Vol. 64, No. 15, 1999
Sulsky et al.
Alternatively, the reaction outcome may be determined
by the stability of the radical intermediates, where the
equatorial imine radical 5eâ is the thermodynamically
favored structure.
The indoxyl nitrogen of 2 could be alkylated or acylated
(Scheme 2). For example, alkylation of 2a with iodo-
methane using sodium bis(trimethylsilyl)amide in THF
at 60 °C provided 8a in 86% yield. Similar treatment of
2a with benzyl bromide provided 8b in 70% yield. When
the sodium anion of 2b was treated with stoichiometric
allyl bromide for 48 h, compound 9 was produced in 62%
yield without any sign of quaternization of the piperidine
nitrogen. Removal of the piperidine nitrogen protecting
group of 8a , 8b, and 9 and alkylation of the resulting
piperidines with 3,3-diphenylpropyl tosylate provided
compounds 10a -c. In addition, 2c was reacted with
acetyl chloride, giving acetylated spiroindoxyl 10d .
We examined the conformational preferences of 2c and
its N-methylated analogue 10a by NMR spectroscopy.
Assignments of the chemical shifts and J values of the
1H NMR spectra for 2c and 10a indicate that they each
exist in single and distinct conformation.14 The positions
of H2 in 2c and 10a were suggestive of predominant cis
and trans conformations, respectively, as shown in Figure
3. Methylated 10a shows a 0.7-ppm downfield shift of
H2ax and a 0.2-ppm downfield shift of H2eq compared to
2c, indicative of a conformational switch. In addition,
large J 3ax/2ax coupling constants are seen for both 2c (J
) 9.7 Hz) and 10a (J ) 12.7 Hz), indicating that each
compound exists in a distinct chair conformation.
F igu r e 1. (top) The solid state conformation of 3e. The
apparent thermal ellipsoids of the axial cyano group reflect
some angular disorder which persists in the crystal structure
at -63 °C. (bottom) The solid state conformation of ketone 2e.
A recent report8 on related radical reactions described
a very different outcome from that reported here. For
example, reaction of 3d with Bu3SnH in toluene was
reported to provide only 6d in 45% yield with no cycliza-
tion products isolated. Under our reaction conditions, 3d
provided a 35% yield of a 1:24 mixture of 4d and 6d and
a 58% yield of the spiroimine 5d . We speculate that the
highly polar imine could not have been isolated under
the chromatography conditions described by the authors
and may well have been present in the unpurified
reaction mixture.
The predominant conformations of 2c and 10a shown
in Figure 3 were confirmed on the basis of 1D NOE data.
A compound in the cis conformation should exhibit 1D
nuclear Overhauser enhancements between the N-H (or
N-CH3) proton(s) and both the H3eq and H2ax protons,
whereas in the trans conformation, enhancements be-
tween the N-H (or N-CH3) proton(s) and the H3ax proton
should be observed. Irradiation of the N-H proton of 2c
led to enhancements of H3eq (2%) and H2ax (4%), consist-
ent with the cis conformer. In contrast, irradiation of the
N-CH3 protons of 10a led to enhancement of H3ax (7%).
The stereochemical assignments for structure 3e and
2e, obtained by single-crystal X-ray analysis, provided
useful insight with respect to the mechanism of cycliza-
tion.12 The X-ray structure of 3e (Figure 1), despite a
small amount of disorder in the crystal lattice, clearly
showed that the anilino nitrogen is equatorial and trans
to the tert-butyl group. The X-ray structure of ketone 2e
(Figure 1b) indicated that the anilino nitrogen is now in
the axial position. This suggests that initially formed
radical 3eR (Figure 2) closes to cyclic imine radical 5eR,
which rapidly undergoes bond scission to nitrile radical
6eR, inversion to 6eâ, reclosure to 5eâ, and finally
hydrogen abstraction to form 5e. No product identifiable
as 5f (the result of 5eR hydrogen abstraction) was
discovered in the reaction mixture. These results suggest
that the radical cyclization and ring opening reactions
leading from 5eR to 5eâ must be rapid and reversible
relative to the quenching of intermediates with Bu3SnH.
The barrier to inversion of pyramidal radicals similar to
6eR and 6eâ has been estimated at 3-6 kcal/mol13 and
thus low enough to allow a sufficient population of 5eâ
to form and quench to 5e. Molecular models suggest that
the selective trapping of 5eâ relative to 5eR is due to a
more favorable approach of Bu3SnH to the equatorial
imine radical of 5eâ where steric interference would be
minimized, rather than to the axial imine radical of 5eR.
No NOE effects were observed for protons H2ax or H2eq
,
consistent with compound 10a adopting the trans con-
formation.
We propose that 2c exists in the cis conformer so that
the carbonyl avoids the H2 axial protons to minimize 1,3-
diaxial interactions found in the trans-conformation. In
the case of 10a , the methyl group is more sterically
demanding than the carbonyl, and thus the carbonyl
group now prefers to be in proximity to the H2 axial
protons in the trans-conformation. Thus, alkylation of the
indoxyl nitrogen results in an inversion of the piperidine
chair conformation.
Su m m a r y
We have demonstrated that, despite a conflicting
report,8 aryl radical cyclizations of nitriles 3a -e do lead
to cyclized products in moderate yields. The discrepancy
between our observations and those previously reported8
may be due to the high polarity and masking fluorescence
(12) Coordinates for the X-ray determinations have been deposited
in the Cambridge Crystallographic Database and can be obtained upon
request from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, U.K.
(13) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry; Harper & Row: New York, 1981; pp 677-681.
(14) Coupling constants (free base in DMSO-d6). 2c: J 2gem ) 11.7
Hz, J 3eq/2ax < 2 Hz, J 3gem ) 12.2 Hz, J 3ax/2ax ) 9.7 Hz. 10a : J 2gem ) 11.0
Hz, J 3ax/2ax ) 12.7 Hz, J 3ax/2eq ) 4.6 Hz, J 3gem ) 11.6 Hz.

Synthesis of Spiro[2H-indol]-3(1H)-ones
J . Org. Chem., Vol. 64, No. 15, 1999 5507
F igu r e 2. Postulated reaction scheme for the formation of spiroindoxylimine 2e from nitrile 1e.
F igu r e 3. Nuclear Overhauser enhancement experiment on compounds 2c and 10a . Italicized and underlined protons were
irradiated; bold-faced protons indicate NOE enhancement.
Sch em e 2a
3-imines to be reported. In addition, both the imines
5a -c and the corresponding ketones 2a -c are the first
examples of a previously unreported spiro system.
Furthermore, unalkylated spiroketone 2a and its N-
methylated counterpart 10a have been shown to exist
in different and distinct ring conformations. The presence
or absence of substituent R1 serves as a “conformational
switch”, a phenomenon which may have broader ap-
plicability in molecular design.
Exp er im en ta l Section
Gen er a l Exp er im en ta l Deta ils. Melting points are uncor-
1
rected. 300 MHz H NMR and 75 MHz 13C NMR spectra were
recorded using CDCl3 as the solvent unless otherwise indi-
cated, and signal positions (δ values) were measured relative
to the signals for TMS (δ 0.00) and CDCl3 (δ 77.0), respectively.
Nuclear Overhauser enhancement experiments were per-
formed at 500 MHz field strength. TLC was carried out using
commercial glass-backed silica gel 60 plates. Flash chroma-
tography was performed on 230-400 mesh silica gel (E.
Merck).
a
Key: (a) NaN(TMS)2/THF; (b) CH3I; (c) PhCH2Br; (d) 1.1 equiv
CH2dCHCH2Br; (e) TMSI/CH3CN; (f) CH3CHClO2CCl/CH2Cl2; (e)
K2CO3/iPrOH, Ph2CHCH2CH2OTs; (n) CH3COCl/CH2Cl2.
All reactions were carried out under an atmosphere of dry
argon using flame-dried or oven-dried glassware.
of imines 5a -e,15 making identification and isolation
unobvious. The spiroindoxyl imines 5a -e are thermally
and chemically stable compounds, and are the first indol-
Gen er a l P r oced u r e for th e P r ep a r a tion of 4-(2-Br o-
m op h en yla m in o)-4-p ip er id in eca r bon itr ile or Cycloh ex-
a n eca r bon itr iles (3). To a stirred mixture of the 4-piperidone
or cyclohexanone (30.0 mmol) and 2-bromoaniline (5.16 g, 30.0
mmol) in HOAc (25 mL) at room temperature was added
(15) The 254-nm fluorescence of commonly used TLC plates makes
the fluorescent imine difficult to see against the background.

5508 J . Org. Chem., Vol. 64, No. 15, 1999
Sulsky et al.
TMSCN (4.20 mL, 31.5 mmol). After 24-112 h, the reaction
was poured into ice-cold 7 N NH4OH (100 mL). The resulting
solids were collected, washed with water, and dried in vacuo
at 40 °C. Purified products were obtained either by recrystal-
lization or flash column chromatography on silica gel.
was evaporated. Purification by silica gel chromatography (3:1
EtOAc/hexanes) gave 8-(3,3-diphenylpropyl)-1,4-dioxa-8-aza-
spiro[4.5]decane as a light yellow oil: 4.30 g, 85% yield; 1H
NMR δ 7.23 (m, 8 H), 7.14 (m, 2 H), 3.97 (t, 1 H, J ) 7.4 Hz),
3.89 (s, 4H), 2.47 (br s, 4 H), 2.25 (m, 4 H), 1.73 (t, 4 H, J )
5.5 Hz); 13C NMR δ 144.7, 128.3, 127.7, 126.0, 107.2, 64.0, 56.3,
51.3, 49.0, 34.8, 33.0; MS (CI) m/z 338 (M + H).
A stirred mixture of 8-(3,3-diphenylpropyl)-1,4-dioxa-8-
azaspiro[4.5]decane (4.30 g, 14.2 mmol) in 6 M HCl (48 mL)
was set to reflux for 40 min. The resulting solution was cooled,
brought to pH 10 with 1 M NaOH solution, and extracted twice
with CH2Cl2. The organic extracts were combined, dried
(Na2SO4), and evaporated to give 7c (3.40 g, 91% yield) as a
yellow solid: mp 88-90 °C; 1H NMR δ 7.28 (m, 8 H), 7.18 (m,
2 H), 4.05 (t, 1 H, J ) 7.6 Hz), 2.68 (t, 2 H, J ) 6.0 Hz), 2.42
(t, 4 H, J ) 6.0 Hz), 2.28 (t, 2 H, J ) 7.3 Hz); 13C NMR δ
209.1, 144.6, 128.4, 127.7, 126.1, 48.8, 41.1, 33.2; MS (CI) m/z
294 (M + H).
1′-(P h en ylm et h yl)-sp ir o[2H -in d ole-2,4′-p ip er id in e]-
3(1H)-im in e (5b), 1-(P h en ylm eth yl)-4-(2-cya n op h en yl)-1-
p ip er id in e (6b), a n d 1′-(P h en ylm eth yl)-sp ir o[2H-in d ole-
2,4′-p ip er id in ]-3(1H)-on e (2b). To a refluxing solution of 3b
(605 mg, 1.63 mmol) in toluene (25 mL) was added AIBN (15
mg, 0.1 mmol) and then Bu3SnH (0.480 mL, 1.79 mmol),
dropwise, over 40 min. After 2 h and again after 4 h, an
additional portion of AIBN (5 mg) was added. After 16 h of
reflux, the reaction was cooled and then vigorously stirred with
7 M NH4OH (20 mL). After 40 min, the reaction was extracted
twice with EtOAc. The organic extracts were combined, dried
(Na2SO4), and purified by silica gel chromatography. The first
fraction, eluted with 9:1 EtOAc/hexane provided 6b (35 mg,
5% yield) as a colorless oil: 1H NMR δ 7.38 (m, 9 H), 6.61 (m,
2 H), 4.43 (d, 1 H, J ) 7.0 Hz), 3.40 (m, 1 H), 2.88 (br d, 2 H,
J ) 17.0 Hz), 2.13 (m, 2 H), 2.03 (br d, 2 H, J ) 17.0 Hz) 1.62
(m, 2 H); 13C NMR δ 149.2, 138.2, 134.1, 132.9, 129.0, 128.2,
127.0, 117.9, 116.2, 111.0, 95.8, 63.0, 51.9, 49.6, 32.0; IR (thin
film) 2215 cm-1; MS (CI) m/z 292 (M + H).
Eth yl 4-(2-Br om op h en yla m in o)-4-cya n o-1-p ip er id in e-
ca r boxyla te (3a ): Reaction of ethyl 4-oxo-1-piperidinecar-
boxylate (5.00 g, 27.3 mmol, reaction time 112 h) as described
in the general procedure gave, after purification by silica gel
chromatography (1:49 Et2O/CH2Cl2), 3a (9.64 g, 94%) as a
colorless oil: 1H NMR δ 7.49 (dd, 1 H, J ) 1.4, 8.0 Hz), 7.25
(dt, 1 H, J ) 1.4, 8.2 Hz), 7.18 (dd, 1 H, J ) 1.6, 8.0 Hz), 6.77
(dt, 1 H, J ) 1.6, 7.5 Hz), 4.30 (s, 1 H), 4.15 (q, 2 H, J ) 7.1
Hz), 3.96 (br d, 2 H, J ) 13.7 Hz), 3.42 (dt, 2 H, J ) 3.8, 10.0
Hz), 2.37 (br dd, 2 H, J ) 3.2, 13.5 Hz), 1.90 (dt, 2 H, J ) 4.0,
10.0 Hz), 1.27 (t, 3 H, J ) 7.1 Hz); 13C NMR δ 155.0, 140.2,
133.0, 128.4, 121.1, 119.5, 115.7, 112.5, 61.7, 52.3, 39.7, 35.3,
14.6; IR (thin film) 2230, 1700 cm-1; MS (CI) m/z 369/371 (M
+ NH3), 351/353 (M + H), 325/327 (M - CN).
4-(2-Br om op h en yla m in o)-1-(p h en ylm et h yl)-4-p ip er i-
d in eca r b on it r ile (3b ). Reaction of 1-(phenylmethyl)-4-pi-
peridone (1.00 g, 5.28 mmol, reaction time 65 h) as described
in the general procedure gave, after purification by silica gel
chromatography (3:17 EtOAc/hexane), 3b (1.35 g, 69%) as a
1
white solid: mp 91-93 °C; H NMR δ 7.46 (dd, 1 H, J ) 1.3,
8.0 Hz), 7.3-7.1 (m, 5 H), 6.71 (dt, 1 H, J ) 1.8, 7.4 Hz), 4.40
(s, 1 H), 3.54 (s, 2 H), 2.73 (br d, 2 H, J ) 11.4 Hz), 2.50 (dt,
2 H, J ) 2.6, 9.7 Hz), 2.37 (dd, 2 H, J ) 3.0, 13.7 Hz), 1.99 (br
t, 2 H, J ) 11.8 Hz); 13C NMR δ 140.6, 137.8, 132.8, 128.9,
128.3, 127.2, 120.5, 120.3, 115.4, 112.1, 62.5, 52.0, 48.9, 35.6;
IR (thin film) 2228 cm-1; MS (CI) m/z 370/372 (M + H).
4-(2-Br om op h en yla m in o)-1-(3,3-d ip h en ylp r op yl)-4-p i-
p er id in eca r bon itr ile (3c). Reaction of 1-(3,3-diphenylpro-
pyl)-4-piperidone (2.93 g, 9.23 mmol, reaction time 24 h) as
described in the general procedure gave, after purification by
silica gel chromatography (1:4 EtOAc/hexane), 3c (2.85 g, 60%)
as a colorless oil: 1H NMR δ 7.41 (dd, 1 H, J ) 1.0, 8.5 Hz),
7.22 (m, 8 H), 7.14 (m, 4 H), 6.64 (dt, 1 H, J ) 2.9, 5.6 Hz),
4.37 (s, 1 H), 3.97 (t, 1 H, J ) 7.5), 2.62 (br d, 2 H, J ) 9.5
Hz), 2.4-2.1 (m, 8 H), 1.92 (br t, 2 H, J ) 15 Hz); 13C NMR δ
144.5, 140.4, 132.7, 128.2, 128.1, 127.6, 126.0, 120.4, 120.0,
115.3, 112.0, 55.9, 51.8, 48.8, 48.6, 35.5, 32.6; IR (thin film)
2230 cm-1; MS (CI) m/z 474/476 (M + H), 447/449 (M - CN).
Anal. Calcd for C27H28N3Br: C, 68.35; H, 5.95; N, 8.86; Br,
16.84. Found: C, 68.13; H, 5.87; N, 9.02; Br, 16.64.
Further elution with 1:4 MeOH/EtOAc provided two frac-
tions: less polar 2b (124 mg, 26% yield) as a yellow solid, mp
142-143 °C (EtOH/H2O); 1H NMR δ 7.60 (d, 1 H, J ) 7.7 Hz),
7.43 (dt, 1 H, J ) 1.0, 7.0 Hz), 7.33 (m, 5 H), 6.87 (d, 1 H, J )
8.1 Hz), 6.80 (t, 1 H, J ) 7.4 Hz), 5.20 (br s, 1 H), 3.58 (s, 1 H),
2.98 (dt, 2 H, J ) 3.5, 11.9 Hz), 2.23 (dt, 2 H, J ) 2.2,12.0 Hz),
2.08 (dt, 2 H, J ) 3.8, 11.8 Hz), 1.43 (d, 2 H, J ) 13.0 Hz); 13
C
NMR δ 204.1, 159.7, 138.0, 137.0, 128.9, 128.2, 127.0, 124.8,
120.4, 118.8, 112.6, 64.8, 63.0, 49.9, 33.0; IR (thin film) 1670,
1620 cm-1; MS (CI) m/z 293 (M + H). Anal. Calcd for
1-(2-Br om op h en yla m in o)-1-cycloh exa n eca r b on it r ile
(3d ). Reaction of cyclohexanone (2.95 g, 30.0 mmol, reaction
time 48 h) as described in the general procedure gave, after
purification by silica gel chromatography (1:4 EtOAc/hexane)
and recrystallization, 3d (8.13 g, 97%) as a white solid: mp
98-99 °C (hexane); 1H NMR δ 7.46 (dd, 1 H, J ) 1.3, 8.0 Hz),
7.19 (m, 2 H), 6.70 (dt, 1 H, J ) 2.0, 6.9 Hz), 4.40 (s, 1 H), 2.35
(m, 2 H), 1.73 (m, 6 H), 1.38 (dt, 2 H, J ) 5.2, 9.0 Hz); 13C
NMR δ 140.7, 132.7, 128.2, 120.6, 115.2, 111.8, 53.3, 36.1, 24.7,
21.8; MS (CI) m/z 278/280 (M + H). Anal. Calcd for C13H15N2-
Br: C, 55.93; H, 5.42; N, 10.03; Br, 28.62. Found: C, 55.95;
H, 5.43; N, 10.03; Br, 28.45.
tr a n s-1-(2-Br om op h en yla m in o)-4-(1,1-d im eth yleth yl)-
cycloh exa n eca r bon itr ile (3e). Reaction of 4-(1,1-dimethyl-
ethyl)cyclohexanone (4.63 g, 30.0 mmol, reaction time 48 h)
as described in the general procedure gave, after recrystalli-
zation, 3e as white needles: mp 149-150 °C (EtOAc); 1H NMR
δ 7.47 (dd, 1 H, J ) 1.4, 8.0 Hz), 7.19 (m, 2 H), 6.70 (ddd, 1 H,
J ) 0.8, 1.8, 7.1 Hz), 4.40 (s, 1 H), 2.59 (dd, 2 H, J ) 2.0, 17.8
Hz), 1.88 (m, 2 H), 1.53 (m, 2 H), 1.11 (m, 1 H), 0.91 (s, 9 H);
13C NMR δ 144.0, 132.8, 128.3, 120.3, 120.1, 115.3, 111.9, 54.4,
47.0, 37.2, 32.3, 27.4, 23.7; MS (CI) m/z 334/336 (M + H). Anal.
Calcd for C17H23N2Br: C, 60.90; H, 6.91; N, 8.36; Br, 23.83.
Found: C, 60.92; H, 6.88; N, 8.35; Br, 23.83.
C
19H20N2O‚0.17H2O: C, 77.23; H, 6.94; N, 9.48. Found: C,
77.16; H, 6.72; N, 9.55.
More polar 5b (148 mg, 31% yield) as an amorphous foam:
1H NMR δ 7.83 (br s, I H), 7.54 (d, 1 H, J ) 7.3 Hz), 7.4-7.2
(m, 6 H), 6.80 (d, 1 H, J ) 8.3 Hz), 6.79 (t, 1 H, J ) 7.2 Hz),
4.95 (br s, 1 H), 3.59 (s, 1 H), 2.98 (br d, 2 H, J ) 11.8 Hz),
2.25 (dt, 2 H, J ) 1.8,12.2 Hz), 2.01 (dt, 2 H, J ) 1.9, 5.9 Hz),
1.54 (dd, 2 H, J ) 2.0,13.3 Hz); 13C NMR δ 183.8, 154.7, 138.0,
137.9, 134.2, 128.9, 128.2, 127.1, 122.9, 121.8, 118.7, 111.8,
63.8, 63.0, 50.0, 35.5; IR (thin film) 1740, 1625 cm-1; MS (CI)
m/z 292 (M + H).
Alternatively, the crude reaction mixture was treated with
saturated KF (see procedure for 5a below) to provide the imine
5b in 57% yield.
Eth yl 1,3-Dih yd r o-3-im in o-sp ir o[2H-in d ole-2,4′-p ip er i-
d in e]-1′-ca r boxyla te (5a ). To a stirred, argon-purged solution
of 3a (7.90 g, 22.4 mmol) and AIBN (450 mg) in toluene (350
mL) was added Bu3SnH (6.7 mL, 24.6 mmol) at room temper-
ature. The solution was evacuated and purged three times with
argon and then set to reflux for 1 h. The resulting bright yellow
solution was cooled to room temperature, and the reaction was
quenched with saturated KF solution (100 mL). After 30 min
of vigorous stirring, the reaction was diluted with EtOAc and
filtered through Celite. The organic layer was separated, dried
(Na2SO4), and evaporated. Purification by silica gel chroma-
tography (1:49 MeOH/EtOAc) gave 5a as an amorphous yellow
solid (2.00 g, 33% yield): 1H NMR δ 8.35 (br s, 1 H), 7.48 (d,
1 H, J ) 7.5 Hz), 7.31 (dt, 1 H, J ) 1.2, 8.1 Hz), 6.79 (d, 1 H,
1-(3,3-Dip h en ylp r op yl)-4-p ip er id on e (7c). To a stirred
solution of 1,4-dioxa-8-azaspiro[4.5]decane (2.15 g, 15.0 mmol)
i
and 3,3-diphenylpropyl-1-tosylate (5.49 g, 15.0 mmol) in PrOH
(30 mL) under argon at room temperature was added anhy-
drous K2CO3 (3.1 g, 22.5 mmol). The mixture was refluxed for
4 h, cooled, and filtered (washing with CH2Cl2), and the filtrate

Synthesis of Spiro[2H-indol]-3(1H)-ones
J . Org. Chem., Vol. 64, No. 15, 1999 5509
J ) 7.9 Hz), 6.79 (t, 1 H, J ) 7.1 Hz), 5.39 (br s, 1 H), 4.25 (br
d, 2 H, J ) 9.5 Hz), 4.15 (q, 2 H, J ) 7.1 Hz), 3.12 (br t, 2 H,
J ) 11.9 Hz), 1.90 (dt, 2 H, J ) 4.7, 12.3 Hz), 1.55 (d, 2 H, J
) 12.6 Hz), 1.27 (t, 3 H, J ) 7.1 Hz); 13C NMR δ 183.1, 155.2,
154.4, 134.0, 122.5, 121.0, 118.5, 111.7, 63.5, 61.2, 40.1, 34.9,
14.4; IR (KBr pellet) 3360, 1616 cm-1; MS (CI) m/z 274 (M +
H). Anal. Calcd for C15H19N3O2‚0.4EtOAc: C, 64.61; H, 7.25;
N, 13.62. Found: C, 64.59; H, 7.20; N, 13.95.
1′-(3,3-Diph en ylpr opyl)-spir o[2H-in dole-2,4′-piper idin e]-
3(1H)-im in e (5c). Cyclization of 3c (2.73 g, 5.75 mmol) as for
3a above, provided, after purification by silica gel chromatog-
raphy (EtOAc, followed by 3:17 MeOH/EtOAc), 5c as an
amorphous yellow solid (1.30 g, 57% yield): 1H NMR δ 8.55
(br s, 1 H), 7.25 (m, 9 H), 7.16 (m, 2 H), 6.76 (m, 2 H), 4.91 (br
s, 1 H), 4.06 (t, 1 H, J ) 7.2 Hz), 2.92 (d, 2 H, J ) 11.1 Hz),
2.11 (t, 2 H, J ) 11.7 Hz), 2.01 (t, 2 H, J ) 11.1 Hz), 1.50 (d,
2 H, J ) 12.5 Hz); 13C NMR δ 183.6, 154.5, 144.6, 133.9, 128.2,
127.7, 125.9, 122.8, 121.8, 118.6, 111.6, 63.8, 56.5, 50.0, 48.5,
35.5, 32.6; IR (KBr pellet) 3414, 1620 cm-1; MS (CI) m/z 396
(M + H). Anal. Calcd for C27H29N3O2‚1.5H2O: C, 76.74; H, 7.63;
N, 9.94. Found: C, 76.66; H, 7.84; N, 9.90.
for C15H18N3O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.78;
H, 6.51; N, 10.08.
1′-(P h en ylm eth yl)-spir o[2H-in dole-2,4′-piper idin ]-3(1H)-
on e (2b). Hydrolysis of 5b (1.31 g, 4.49 mmol) as described in
the general procedure gave 2b (1.31 g, 100%) as a yellow solid,
mp 142-144 °C, which was identical to that which was
obtained directly from 3b as described above.
1′-(3,3-Diph en ylpr opyl)-spir o[2H-in dole-2,4′-piper idin ]-
3(1H)-on e (2c). Hydrolysis of 5c (485 mg, 1.23 mmol) as
described in the general procedure gave 2c (440 mg, 83%) as
1
a yellow solid (the monohydrochloride salt): mp >240 °C; H
NMR (free base in DMSO-d6) δ 7.70 (s, 1 H), 7.37 (m, 2 H),
7.31 (m, 8 H), 7.16 (m, 1 H), 6.85 (d, 1 H, J ) 8.2 Hz), 6.66 (t,
1 H, J ) 7.6 Hz), 4.03 (t, 1 H, J ) 6.5 Hz), 2.80 (d, 2 H, J )
11.7 Hz), 2.23 (m, 6 H), 1.75 (dt, 2 H, J ) 9.7, 12.2 Hz), 1.21
(d, 2 H, J ) 12.2 Hz); 13C NMR (in CDCl3) δ 204.0, 159.7, 144.7,
137.0, 128.4, 127.8, 124.8, 124.8, 120.4, 118.9, 112.6, 64.9, 56.6,
50.0, 48.6, 33.0, 32.6; IR (KBr pellet) 3202, 2496, 1697 cm-1
;
MS (CI) m/z 397 (M + H). Anal. Calcd for C27H28N2O‚HCl: C,
74.90; H, 6.75; N, 6.47; Cl, 8.19. Found: C, 74.68; H, 6.79; N,
6.57; Cl, 8.36.
1-(P h en yla m in o)cycloh exa n eca r bon itr ile (4d ), Sp ir o-
[2H-in d ole-2-cycloh exa n e]-3(1H)-im in e (5d ), a n d N-Cy-
cloh exyl-2-a m in oben zon itr ile (6d ). To a stirred, argon-
purged solution of 3d (1.40 g, 5.01 mmol) and AIBN (50 mg,
0.3 mmol) in toluene (80 mL) was added Bu3SnH (1.50 mL,
5.5 mmol) in one portion at room temperature. The solution
was evacuated and purged three times with argon and then
set to reflux. After 1 h, reverse-phase HPLC analysis indicated
that no 3d remained and two products had formed. After 16 h
of reflux, HPLC showed no change in the ratio of products.
The resulting bright yellow solution was cooled to room
temperature, saturated KF solution (20 mL) was added, and
the reaction was stirred rapidly for 30 min. The mixture was
diluted with EtOAc and filtered through Celite. The organic
phase was separated, dried (Na2SO4), and evaporated to give
a yellow syrup (1.32 g). Purification by silica gel chromatog-
raphy (2:3 CH2Cl2/hexanes) provided a white solid (381 mg).
NMR analysis showed this to be an inseparable 1:24 mixture
of 4d and 6d (35%). Data for 4d : 1H NMR δ 7.45 (d, 2 H),
4.40 (br s, 1 H), 2.70 (q, 1 H), 2.35 (m, 4 H); 13C NMR δ 141,
127.9, 119.9, 114.9, 53.0, 35.8, 21.6. Data for 6d : 1H NMR δ
7.32 (m, 2 H), 6.60 (m, 2 H), 4.45 (br d, 1 H, J ) 7.4 Hz), 3.31
(dt, 1 H, J ) 4.0, 9.9 Hz), 2.00 (br d, 2 H, J ) 11.0 Hz), 1.62
(m, 4 H), 1.23 (m, 6 H); 13C NMR δ 149.1, 133.8, 132.4, 117.7,
115.6, 110.7, 95.0, 50.9, 32.6, 25.3, 24.4; MS (FAB) m/z 201
(M + H). Further elution with 7:43 MeOH/EtOAc followed by
trituration with CH2Cl2/hexane provided 5d (575 mg, 58%) as
a yellow solid: mp 40-41 °C; 1H NMR δ 8.70 (br s, 1 H), 7.51
(d, 1 H, J ) 7.6 Hz), 7.28 (dt, 1 H, J ) 1.9, 8.2 Hz), 6.77 (d, 1
H, J ) 8.2 Hz), 6.76 (dd, 1 H, J ) 7.6, 8.2 Hz), 5.09 (br s, 1 H),
1.8-1.3 (m, 10 H); 13C NMR δ 184.6, 154.7, 133.8, 122.7, 121.3,
118.1, 111.5, 65.6, 35.3, 24.7, 22.4; MS (CI) m/z 201 (M + H).
Anal. Calcd for C13H16N2‚0.12CH2Cl2: C, 75.13; H, 7.62; N,
13.23. Found: C, 75.12; H, 7.70; N, 13.36.
Gen er a l P r oced u r e for th e P r ep a r a tion of Sp ir o[2H-
in d ole-2,4′-p ip er id in ]-3(1H)-on es a n d Cycloh exa n -3(1H)-
on es (2). A mixture of 5 (5.0 mmol) and 1 M HCl (10 mL) was
heated at 100 °C under argon for 1 h. The resulting solution
was cooled and adjusted to pH 8 with saturated NaHCO3
solution followed by extraction with CH2Cl2. The organic
extract was dried (MgSO4) and evaporated. Trituration with
Et2O provided 2 as a bright yellow fluorescent solid sufficiently
pure for elemental analysis.
E t h yl 1,3-Dih yd r o-3-oxo-sp ir o[2H -in d ole-2,4′-p ip er i-
d in e]-1′-ca r boxyla te (2a ). Hydrolysis of 5a (1.18 g, 4.32
mmol) as described in the general procedure gave 2a (1.18 g,
100%) as a yellow solid: mp 133-135 °C; 1H NMR δ 7.60 (dd,
1 H, J ) 0.6, 7.5 Hz), 7.46 (dt, 1 H, J ) 1.3, 7.0 Hz), 6.90 (dd,
1 H, J ) 0.6, 7.7 Hz), 6.83 (dt, 1 H, J ) 0.6, 7.4 Hz), 5.55 (br
s, 1 H), 4.16 (m, 4 H), 3.23 (br t, 2 H, J ) 11.6 Hz), 1.94 (ddd,
2 H, J ) 4.5, 6.8, 12.4 Hz), 1.48 (d, 2 H, J ) 13.4 Hz), 1.28 (t,
3 H, J ) 7.1 Hz); 13C NMR δ 203.4, 159.9, 155.4, 137.3, 124.8,
119.9, 119.0, 112.6, 64.4, 61.4, 40.1, 32.5, 14.6; IR (KBr pellet)
3304, 1694, 1678 cm-1; MS (CI) m/z 275 (M + H). Anal. Calcd
Sp ir o[2H-in d ole-2,4′-cycloh exa n ]-3(1H)-on e (2d ). Hy-
drolysis of 5d (260 mg, 1.29 mmol) was accomplished in
refluxing MeOH (5 mL) and 1 M HCl (5 mL) for 1 h under
argon. The reaction mixture was brought to pH 8 with 1 M
KOH and extracted twice with EtOAc. The combined organic
extracts were dried (MgSO4) and evaporated. Recrystallization
from CH2Cl2/hexane gave 2d (260 mg, 100%) as yellow
1
platelets: mp 133-135 °C; H NMR δ 7.59 (d, 1 H, J ) 7.7
Hz), 7.42 (dt, 1 H, J ) 1.4, 7.3 Hz), 6.89 (d, 1 H, J ) 8.6 Hz),
6.77 (dt, 1 H, J ) 2.1, 7.7 Hz), 5.53 (br s, 1 H), 1.85 (d, 2 H, J
) 7.7 Hz), 1.77 (d, 2 H, J ) 8.1), 1.46 (m, 6 H); 13C NMR δ
205.0, 160.0, 136.9, 124.7, 120.0, 118.3, 112.5, 32.7, 24.7, 22.4;
IR (KBr pellet) 3333, 1680 cm-1; MS (CI) m/z 202 (M + H).
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found:
C, 77.39; H, 7.54; N, 6.91.
tr a n s-4′-(1,1-Dim et h ylet h yl)-sp ir o[2H -in d ole-2-cyclo-
h exan e]-3(1H)-im in e (5e) an d tr a n s-4′-(1,1-Dim eth yleth yl)-
sp ir o[2H-in d ole-2-cycloh exa n e]-3(1H)-on e (2e). Cycliza-
tion of 2e (1.07 g, 3.19 mmol) as described for the synthesis of
5a gave 5e (365 mg, 45%) as a bright yellow glass: MS (CI)
m/z 257 (M+H). Hydrolysis of 150 mg (0.59 mmol) of 5e was
accomplished in refluxing MeOH (2 mL) and 3 M HCl (2 mL)
for 1 h under argon. The reaction mixture was brought to pH
8 with 1 M KOH and extracted twice with EtOAc. The
combined organic extracts were dried (MgSO4) and evaporated.
Recrystallization gave 2e (149 mg, 100% yield) as fine yellow
needles: mp 215-216 °C (CH2Cl2/hexane); 1H NMR δ 7.61 (d,
1 H, J ) 7.7 Hz), 7.44 (dt, 1 H, J ) 1.0, 7.1 Hz), 6.89 (d, 1 H,
J ) 8.5 Hz), 6.81 (t, 1 H, J ) 7.7 Hz), 5.11 (br s, 1 H), 4.06 (t,
1 H, J ) 7.0 Hz), 1.92 (d, 2 H, J ) 3.8 Hz), 1.78 (dt, 2 H, J )
4.5, 16.6 Hz), 1.51 (d, 2 H, J ) 12.1 Hz), 1.18 (m, 4 H), 0.91 (s,
9 H); 13C NMR δ 205.0, 159.9, 136.9, 124.9, 120.6, 118.7, 112.6,
66.9, 46.6, 33.4, 32.4, 27.4, 23.7; IR (KBr pellet) 3290, 1674
cm-1; MS (CI) m/z 258 (M + H). Anal. Calcd for C17H23NO: C,
79.33; H, 9.01; N, 5.44. Found: C, 79.35; H, 9.03; N, 5.33.
E t h yl 1,3-Dih yd r o-3-oxo-sp ir o[2H -in d ole-2,4′-p ip er i-
d in e]-1′-ca r boxyla te (8a ). To a stirred solution of 2a (532
mg,1.94 mmol) in THF (10 mL) at room temperature under
argon was added NaN(TMS)2 solution (2.0 mL, 2.0 mmol, 1 M
in THF) over 5 min. A deep red, nearly unstirrable slurry
formed. After 1 h, CH3I (0.15 mL, 2.4 mmol) was added in one
portion. After an additional 3 h, the resulting light yellow
solution was quenched with brine and extracted twice with
EtOAc. The organic extracts were combined, dried (MgSO4),
and evaporated. Purification by silica gel chromatography (1:
24 Et2O/CH2Cl2) provided 8a (477 mg, 86%) as a light yellow
amorphous solid: 1H NMR δ 7.55 (dd, 1 H, J ) 0.6, 7.7 Hz),
7.46 (dt, 1 H, J ) 1.3, 7.2 Hz), 6.74 (d, 1 H, J ) 8.3 Hz), 6.71
(t, 1 H, J ) 7.4 Hz), 4.15 (q, 2 H, J ) 7.0 Hz), 4.12 (br s, 2 H),
3.72 (br s, 2 H), 2.88 (s, 3 H), 1.89 (dt, 2 H, J ) 4.7, 12.7 Hz),
1.47 (d, 2 H, J ) 11.7 Hz), 1.29 (t, 2 H, J ) 7.1 Hz); 13C NMR
δ 203.6, 159.4, 155.5, 137.5, 124.6, 118.3, 117.0, 108.4, 64.9,
61.2, 38.1, 28.3, 26.7, 14.6; IR (KBr pellet) 1688 cm-1; MS (CI)

5510 J . Org. Chem., Vol. 64, No. 15, 1999
Sulsky et al.
m/z 306 (M + NH4), 289 (M + H). Anal. Calcd for C16H20N2O3:
C, 66.65; H, 6.99; N, 9.72. Found: C, 66.57; H, 6.79; N, 7.13.
1-Meth yl-1′-(3,3-d ip h en ylp r op yl)-sp ir o[2H-in d ole-2,4′-
p ip er id in ]-3(1H)-on e (10a ). To a stirred solution of 8a (359
mg, 1.25 mmol) in rigorously dried CH3CN (4 mL) at room
temperature under argon was added TMSI (190 µL, 1.33
mmol). The reaction was heated to reflux for 16 h and then
quenched with MeOH. The reaction mixture was evaporated
twice from MeOH and then twice from CH2Cl2 to provide a
yellow foam. At rt under argon, this foam was dissolved in
iPrOH (10 mL) and, with stirring, 3,3-diphenylpropyl tosylate
(460 mg, 1.26 mmol) followed by K2CO3 (430 mg, 3.1 mmol).
After 16 h of reflux, the reaction mixture was cooled and
filtered, and the filtrate was evaporated. Purification by silica
mmol) gave 9 (723 mg, 63%) as a yellow oil. The compound
was used in the next procedure without characterization.
To a stirred solution of 9 (720 mg, 2.18 mmol) in CH2Cl2
(15 mL) at 0 °C under argon was added 1-chloroethyl chloro-
formate (0.2 mL, 2.4 mmol). After 3 h, the reaction mixture
was evaporated at <30 °C, and the residue was treated with
MeOH (10 mL). After 16 h, the reaction mixture was evapo-
rated, and the residue was triturated with Et2O. Filtration
isolated a bright yellow solid, the piperidinium hydrochloride
(592 mg, 98%).
At rt under argon, this solid was dissolved in DMF (5 mL)
and, with stirring, 3,3-diphenylpropyl tosylate (770 mg, 2.1
mmol) followed by K2CO3 (670 mg, 5.0 mmol) was added. After
16 h of heating at 70 °C, the reaction was cooled, quenched
with H2O, and extracted three times with Et2O. The extracts
were combined, dried (Na2SO4), and evaporated. Purification
by preparative HPLC (YMC S-100DS column, 50 to 100%
gradient of 0.2% H3PO4 in MeOH/H2O) provided 10c (485 mg,
58% yield) as a yellow oil: 1H NMR δ 7.54 (d, 1 H, J ) 7.6
Hz), 7.38 (dd, 1 H, J ) 1.2, 7.2 Hz), 7.30-7.13 (m, 10 H), 6.67
(t, 1 H, J ) 7.4 Hz), 6.63 (d, 1 H, J ) 8.2 Hz), 5.78 (m, 1 H),
5.22 (d, 2 H, J ) 14.0 Hz), 5.16 (d, 2 H, J ) 13.7 Hz), 3.96 (m,
3 H), 2.91 (dt, 2 H, J ) 2.3, 12.0 Hz), 2.80 (d, 2 H, J ) 11.1
Hz), 2.42 (m, 2 H), 2.30 (m, 2 H), 1.98 (dt, 2 H, J ) 4.6, 12.8
Hz), 1.51 (d, 2 H, J ) 12.8 Hz); 13C NMR δ 203.7, 158.5, 144.8,
137.0, 133.8, 128.3, 127.7, 126.1, 124.6, 118.4, 116.7, 108.9,
i
gel chromatography of the residue (3:17 PrOH/hexane) pro-
vided 10a (338 mg, 66%) as a yellow fluorescent solid after
1
trituration in Et2O: mp 114-116 °C; H NMR (DMSO-d6) δ
7.46 (dd, 1 H, J ) 6.9, 8.3 Hz), 7.37 (d, 1 H, J ) 7.8 Hz), 7.3-
7.2 (m, 8 H), 7.15 (dd, 1 H, J ) 6.8, 7.8 Hz), 6.89 (d, 1 H, J )
8.3 Hz), 6.65 (dd, 1 H, J ) 6.9, 7.8 Hz), 4.02 (t, 2 H, J ) 7.8
Hz), 2.88 (s, 3 H), 2.80 (dd, 2 H, J ) 11.0, 12.7 Hz), 2.65 (ddd,
2 H, J ) 4.6, 11.0, 11.6 Hz), 2.30 (m, 2 H), 2.22 (m, 2 H), 1.93
(dt, 2 H, J ) 4.6, 11.6 Hz), 1.33 (d, 2 H, J ) 11.6 Hz); 13C
NMR (CDCl3) δ 204.0, 159.5, 144.7, 137.2, 128. 4, 127.8, 126.1,
124.7, 118.7, 116.8, 108.3, 65.2, 56.7, 49.3, 57.5, 32.8, 28.6, 26.9;
IR (KBr pellet) 1692 cm-1; MS (CI) m/z 411 (M + H). Anal.
Calcd for C28H30N2O‚0.18Et2O: C, 81.38; H, 7.56; N, 6.61.
Found: C, 81.37; H, 7.32; N, 6.78.
65.6, 56.7, 49.3, 47.4, 43.2, 32.9, 29.7; IR (thin film) 1690 cm-1
;
MS (CI) m/z 437 (M + H). Anal. Calcd for
C30H32N2O‚
1′-(3,3-Dip h en ylp r op yl)-1-(p h en ylm eth yl)-sp ir o[2H-in -
d ole-2,4′-p ip er id in ]-3(1H)-on e (10b). By the same procedure
as 8a , 2b (0.500 g, 1.82 mmol) and benzyl bromide (0.25 mL,
2.5 mmol) gave 8b (465 mg, 70%) as a yellow amorphous solid.
The compound was used in the next procedure without
characterization.
0.35H2O: C, 81.36; H, 7.44; N, 6.33. Found: C, 81.34; H, 7.40;
N, 6.65.
1-Acet yl-1′-(3,3-d ip h en ylp r op yl)-sp ir o[2H-in d ole-2,4′-
p ip er id in ]-3(1H)-on e (10d ). To a stirred solution of 2c (450
mg, 1.13 mmol) in CH2Cl2 (5 mL) at 0 °C under argon was
added freshly distilled acetyl chloride (85 µL, 1.25 mmol) over
5 min. The resulting solution was allowed to warm to room
temperature and stirred for 16 h. The reaction mixture was
partitioned between saturated NaHCO3 solution and EtOAc.
The organic extract was dried (Na2SO4) and evaporated.
Purification by silica gel chromatography (9:1 EtOAc/hexane)
To a stirred solution of 8b (445 mg,1.82 mmol) in rigorously
dried CH3CN (4 mL) at room temperature under argon was
added TMSI (280 µL, 2.0 mmol). The reaction was heated to
reflux for 16 h and then quenched with MeOH. The reaction
mixture was evaporated twice from MeOH and then twice from
CH2Cl2 to provide a yellow foam. At rt under argon, this foam
was dissolved in iPrOH (10 mL) and, with stirring, 3,3-
diphenylpropyl tosylate (450 mg,1.22 mmol) was added, fol-
lowed by K2CO3 (420 mg, 3.0 mmol). After 16 h of reflux, the
reaction mixture was cooled and filtered, and the filtrate was
evaporated. Purification by silica gel chromatography of the
1
gave 10d (315 mg, 64%) as a tan solid: mp 127-128 °C; H
NMR δ 7.87 (br s, 1 H), 7.74 (d, 1 H, J ) 7.6 Hz), 7.63 (dd, 1
H, J ) 1.2, 7.9 Hz), 7.7-7.1 (m, 11 H), 4.07 (t, 2 H, J ) 7.6
Hz), 2.91-2.77 (m, 6 H), 2.54 (s, 3 H), 2.44 (m, 3 H), 2.28 (m,
2 H), 1.53 (d, 2 H, J ) 9.4 Hz); 13C NMR δ 201.5, 168.3, 151.1,
144.8, 136.7, 128.2, 127.8, 125.9, 124.5, 123.7, 122.4, 117.0,
67.6, 55.7, 48.8, 47.7, 32.8, 28.3, 27.2; IR (thin film) 1711, 1690
cm-1; MS (CI) m/z 439 (M + H). Anal. Calcd for C29H30N2O2‚
0.14H2O: C, 78.97; H, 6.92; N, 6.35. Found: C, 78.97; H, 6.81;
N, 6.51.
i
residue (3:47 PrOH/hexane) provided 10b (325 mg, 55%) as a
yellow fluorescent solid after trituration in Et2O: mp 156-
158 °C; 1H NMR δ 7.59 (d, 1 H, J ) 7.6 Hz), 7.32-7.12 (m, 16
H), 6.68 (t, 1 H, J ) 7.4 Hz), 6.44 (d, 1 H, J ) 8.3 Hz), 4.56 (s,
2 H), 3.98 (t, 2 H, J ) 7.6 Hz), 2.92 (dt, 2 H, J ) 2.1, 11.8 Hz),
2.71 (d, 2 H, J ) 11.1 Hz), 2.42 (m, 2 H), 2.28 (m, 2 H), 2.01
(dt, 2 H, J ) 4.4, 12.8 Hz), 1.59 (d, 2 H, J ) 13.5 Hz); 13C
NMR δ 203.6, 158.9, 144.8, 138.0, 137.1, 128.6, 127.7, 127.0,
126.1, 126.0, 124.7, 118.7, 117.1, 109.2, 65.9, 56.6, 49.2, 47.4,
44.7, 32.9, 29.8; IR (KBr pellet) 1690 cm-1; MS (CI) m/z 487
(M + H). Anal. Calcd for C34H34N2O‚0.15H2O: C, 83.09; H,
7.19; N, 5.61. Found: C, 83.09; H, 7.07; N, 5.54.
Ack n ow led gm en t. We thank Ms. Yolanda Pan and
Dr. Adrienne Tymiak for their assistance in obtaining
NOE data.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of all new compounds and details of the X-ray
structural analyses of 2e and 3e. This material is available
free of charge via the Internet at http://pubs.acs.org.
1′-(3,3-Diph en ylpr opyl)-1-(2-pr open yl)-spir o[2H-in dole-
2,4′-p ip er id in ]-3(1H)-on e (10c). By the same procedure as
8a , 2b (1.012 g, 3.46 mmol) and allyl bromide (0.35 mL, 4.0
J O970105T