Synthesis and derivatisation of a novel spiro1-benzofuran-2,4′- piperidinl-3-one scaffold

Article abstract of DOI:10.1039/b507339a

The synthesis of a novel spiro[l-benzofuran-2,4′-piperidin]-3-one scaffold 6 has been achieved in five steps with an overall yield of 47%. The versatility of the spiropiperidine scaffold in the context of library synthesis is exemplified by selective and

Full text of DOI:10.1039/b507339a

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A R T I C L E
Synthesis and derivatisation of a novel
spiro[1-benzofuran-2,4ꢀ-piperidin]-3-one scaffold
Rowan A. Wilson,a Lai Chan,b Robin Woodb and Richard C. D. Brown*a
a School of Chemistry, University of Southampton, Southampton, Hants, UK SO17 1BJ.
E-mail: rcb1@soton.ac.uk; Fax: +44 (0)23 80596805; Tel: +44 (0)23 80594108
b AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire,
UK SK10 4TG
Received 24th May 2005, Accepted 13th July 2005
First published as an Advance Article on the web 3rd August 2005
The synthesis of a novel spiro[1-benzofuran-2,4ꢀ-piperidin]-3-one scaffold 6 has been achieved in five steps with an
overall yield of 47%. The versatility of the spiropiperidine scaffold in the context of library synthesis is exemplified by
selective and sequential derivatisation of the amino and aryl bromide functional groups, including the development of
multi-step telescope reaction matrices.
Introduction
Since the generalisation of high throughput screening in drug
discovery, there has been significant interest in the design of
chemical libraries with the goal of identifying new lead com-
pounds for further development.1–3 Libraries based on privileged
structures are considered by many to provide an ideal source
of new leads.4–9 The molecular framework identified is often
capable of binding to several diverse biological receptors with
good affinity, such that single libraries derived from scaffolds
containing these structures may provide promising compounds
in diverse therapeutic areas.4–6 Empirical guidelines for desirable
properties of molecular scaffolds have been formulated in order
to increase the likelihood of identifying lead compounds with
drug-like properties from their libraries.5 An attractive scaffold
should exhibit a balanced polarity profile with a molecular
weight in the range of 100–300, depending on the number of
available positions for diversification. Obviously the scaffold
should be synthetically attainable on a multi-gram scale, and
it should carry 1–3 sites with orthogonal reactivity amenable to
rapid derivatisation.5
Frameworks incorporating spiropiperidine motifs have been
labelled as privileged structures,5–7 and many important exam-
ples have been discovered including the well-known painkiller
morphine, growth hormone secretagogues (e.g. 1 and 5),10 NK-2
Fig. 1 Biologically active spiropiperidines.
antagonists (e.g. 2),11 chemokine receptor antagonists (e.g. 3),12
and antihypertensive agents (e.g. 4) (Fig. 1).13 The spirocyclic
ring system may be particularly important since its rigidity
serves to position the required functional groups appropri-
ately in 3-dimensional space, whilst minimising the number
of rotatable bonds and thus increasing the potential for oral
bioavailability.5,14 With this in mind, we reasoned that the furan-
3-one containing spiropiperidine 6 would provide an attractive
conformationally constrained scaffold possessing a capacity for
selective single, double, or triple substitution with appropriate
reagents to provide a host of derivatised spirocycles (Fig. 2).
In this paper, we describe a convenient synthesis of the
spiropiperidine scaffold 6 and go on to demonstrate its facile
elaboration by selective reactions of the amino, aryl bromide
and carbonyl functionalities.
Fig. 2 Spiro[1-benzofuran-2,4ꢀ-piperidin]-3-one scaffold.
Scheme 1 Synthetic approach to spiropiperidine scaffold.
Results and discussion
the synthesis of 6 was achieved in five steps with an overall
yield of 47% (Scheme 2). Thus 5-bromo-2-fluorobenzaldehyde
was first converted to its corresponding dithiane 10 to facilitate
formation of an acyl anion equivalent. The formation of the
dithiane anion deserves some discussion as deprotonation of
10 at −78 ◦C using LDA led to metallation of the aromatic
Our analysis of the N-protected spiropiperidine scaffold 7 led
us to consider a synthetic approach involving the use of an acyl
anion equivalent to form the benzylic C–C bond (Scheme 1).
Closure of the dihydrofuran ring could then be achieved via an
intramolecular SNAr reaction. Following this general strategy,
3 2 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 2 Reagents and conditions: a) 1,3-propanedithiol, 0.03 eq I2, CHCl3; b) LDA, −78 ◦C, cyclohexanone, THF; c) LDA, −20 ◦C, 9, THF;
d) C5H5N·HBr·Br2, pyridine, TBAB, H2O, DCM; e) tBuOK, THF, 70 ◦C, 5 min (lw); f) TFA, DCM, 140 ◦C, 20 min, (lw).
Scheme 3 Reagents and conditions: a) HNR1R2, Pd2(dba)3, BINAP, tBuOK, PhMe, 100 ◦C, 1 h, (lw); b) ArB(OH)2, Pd(PPh3)4, Na2CO3,
PhMe/EtOH/H2O (5 : 5 : 2), 110 ◦C, 10 min, (lw); c) R4CCH, Pd(PPh3)2Cl2, CuI, NEt3, 120 ◦C, 20 min (lw); d) R5CHCH2, Pd(OAc)2, P(o-tol)3,
NEt3, DMF, 100 ◦C, 18 h. a(42% Debrominated starting material recovered).
ring adjacent to the fluorine substituent.15 On warming the
reaction mixture to −20 ◦C, the aryl lithium intermediate
underwent equilibration to the thermodynamically preferred
dithiane anion. Evidence for kinetic ortho-lithiation came from
the isolation of 1-aryl-1-cyclohexanol 13 when the lithiation was
carried out at −78 ◦C prior to the addition of cyclohexanone
at the same temperature. The required lithiated dithiane anion
was ultimately reacted with N-Boc-4-piperidone (9) to afford
the tricycle 11, which on treatment with pyridinium tribromide
unmasked the carbonyl group to give ketone 12 in excellent
yield.16 The synthesis of the N-Boc protected scaffold 7 was
completed by an extremely facile intramolecular ring closure
through nucleophilic aromatic substitution of the fluoro group.
In contrast, attempted cyclisation of the protected ketone 11 in
the presence of tBuOK at elevated temperature led to expulsion
of the dithiane anion, returning compounds 9 and 10. The
deprotected scaffold 6 was obtained in good yield following
removal of the N-Boc group from 7 using TFA at 140 ◦C. The
deprotection could be carried at room temperature, but was
found to be rather sluggish.
With a scalable multi-gram synthesis of spiropiperidine 6
completed, attention turned to elaboration of the scaffold by
derivatisation at each of three functional groups (the aryl
bromide, ketone, and amine). A variety of palladium-catalysed
C–C bond-forming reactions (Suzuki, Sonogashira, Heck) of
the aryl bromide functionality were found to proceed readily
under microwave irradiation, affording substituted spirocycles
in good to excellent yield (Scheme 3).17 Palladium-catalysed
amination proved to be more challenging, but was ultimately
effective using the Pd2(dba)3/BINAP/NaOtBu system to secure
the desired anilines 14a–c, even with the problematic 2◦ amine
nBu2NH.18,19 In the latter case reduction of the aryl bromide was
observed as a significant side reaction.
Confident that the piperidine nitrogen could be acylated
without problems, we chose to combine the N-functionalisation
chemistry with a Sonogashira cross-coupling reaction in order
to develop a one-pot sequential derivatisation of the spiropiperi-
dine scaffold 6. This technique of “telescoping” would provide
quick and efficient access to a collection of potential drug
candidates, and would constitute a valuable asset to library
synthesis.
We elected to carry out three separate N-acylation reactions
first, employing a slight excess of the appropriate acid chloride
in THF (Scheme 4). After a short period N-methylpiperazine
was added, which served a dual role, acting as a scavenger
for any unreacted acylating reagent and by providing the
base for the subsequent Sonogashira reaction. It is worth
noting that N-methyl piperazine was chosen for this role in
preference to piperidine due to its extra N-methyl group, which
would ultimately facilitate removal of the polar scavenged
by-products. At this stage each of the three crude reaction
mixtures were divided into three equal portions and submitted
to Sonogashira reaction conditions with three different alkynes.
As can be seen by the results of the matrix (Table 1), a
series of sequential derivatisations were executed to give the
nine products in good overall yield (49–70% over 2 steps)
after chromatography. The nine compounds prepared in the
reaction matrix display physical characteristics consistent with
the Lipinski “rule of 5” and contain 7 or fewer rotatable
bonds,5,14,20 vindicating the use of the scaffold 6 as a starting
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5
3 2 2 9

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3 column-0.25 lm (30 m × 0.25 mm). Microwave irradiation was
carried out in a Biotage Smith SynthesiserTM
.
2-(5-Bromo-2-fluorophenyl)-[1,3]dithiane (10). To a stirred
solution of 5-bromo-2-fluorobenzaldehyde (20.0 g, 98.5 mmol)
and 1,3-propanedithiol (9.82 mL, 97.5 mmol) in CHCl3 (350 mL)
was added iodine (750 mg, 2.96 mmol). After stirring at room
temperature for 18 h the orange solution was poured into
Na2S2O3 solution (0.4 M, 180 mL) and a 40% solution of
NaOH was added (150 mL). The organic phase was separated
and the aqueous extracted with a further portion of CHCl3
(300 mL). The combined organic fractions were washed with
water (400 mL), brine (400 mL), dried (Na2SO4), filtered and
evaporated to give a yellow solid (32.1 g). Recrystallisation from
DCM–hexane afforded th◦e title compound 10 as a white solid
(26.0 g, 90%); Mp 51–53 C (DCM–hexane); IR: mmax (CDCl3
film) 1484 cm−1; NMR: dH 7.74 (1H, dd, J 6.3, 2.5, Har), 7.39
(1H, ddd, J 8.8, 4.5, 2.5, Har), 6.95 (1H, t, J 9.0, Har), 5.47 (1H, s,
S2CH), 3.10 (2H, ddd, J 14.8, 12.6, 2.5, SCHax), 2.92 (2H, ddd, J
14.8, 4.3, 3.0, SCHeq), 2.18 (1H, dtt, J 13.8, 4.3, 2.5, CHeq), 1.94
(1H, dtt, J 14.0, 12.6, 3.0, CHax); dC 158.2 (d, J 247.3, CarF),
133.0 (d, J 8.7, CarH), 132.7 (d, J 2.9, CarH), 128.6 (d, J 15.4,
Car), 117.4 (d, J 24.2, CarH), 117.3 (Car), 42.6 (d, J 4.5, CH),
Scheme 4 Reagents and conditions: a) R1COCl, NEt3, THF, RT;
b) R2CCH, Pd(PPh3)2Cl2, CuI, N-methylpiperazine, THF, 120 ◦C, (lw).
Table 1 3 × 3 Matrix for sequential derivatisation of 6 (see Scheme 4)
Yielda (compound number)
t
R2 = p-MeOC6H4
R2 = Bu
R2 = m-FC6H4
R1 = Ph
R1 = 2-furyl
66% (18)
59% (21)
59% (24)
69% (19)
70% (22)
64% (25)
53% (20)
50% (23)
49% (26)
n
R1 = Pr
a Yields are reported for isolated purified compounds.
point to synthesise libraries of compounds with sound drug-like
properties.
Derivatisation of the carbonyl group present in scaffold 6
was also explored, although it proved to be more restricted in
terms of scope due to steric congestion. Additions of small
nucleophiles (e.g. NaBH4, allylMgBr, PhCCLi) proceeded in
good to excellent yields, whereas reaction with EtMgBr gave
the desired product 29 alongside the reduction product 27
(Scheme 5). Larger nucleophiles such as iPrMgCl and PhMgCl
failed to react.
•
32.2 (2 × CH2S), 25.1 (CH2); (EI) m/z (%): 292, 294 ([M]+ , 39),
217, 219 (51), 74 (100); Elemental analysis: Found: C, 40.98; H,
3.56. C10H10BrFS2 requires: C, 40.96; H, 3.44%.
1-(5-Bromo-3-[1,3]dithian-2-yl-2-fluorophenyl)-cyclohexanol
(13). To a degassed and stirred solution of diisopropylamine
(105 lL, 0.75 mmol) in THF (2 mL) at −78 ◦C was added nBuLi
(2.31 M solution in hexanes, 325 lL, 0.75 mmol) dropwise.
The solution was then stirred at −78 ◦C for 10 min, 0 ◦C for
10 min and then cooled back to −78 ◦C. To the stirred solution
of LDA was added a solution of 10 (200 mg, 0.68 mmol) in
THF (3 mL) and the reaction stirred at −78 ◦C for 30 min.
Cyclohexanone (106 lL, 0.75 mmol) was added dropwise
and the reaction stirred at −78 ◦C for 30 min. TLC showed
incomplete conversion. A further portion of cyclohexanone
was added (106 lL, 0.75 mmol) and the reaction stirred for
a further hour, after which no further progress was observed.
The reaction was poured into sat. NH4Cl solution (10 mL)
and extracted with EtOAc (3 × 15 mL). The combined organic
fractions were washed with water (30 mL), brine (30 mL),
dried (Na2SO4), filtered and evaporated to give a yellow oil
(307 mg). This was purified by column chromatography (5%
EtOAc–hexane) to give the title compound 13 as a white solid
(91 mg, 34%); Mp 118–119 ◦C (EtOAc–hexane). Starting
material 10 was also recovered from the reaction (64 mg, 32%).
IR: mmax (CDCl3 film) 3442, 1446 cm−1; NMR: dH 7.69 (1H, dd, J
7.0, 2.8, Har), 7.64 (1H, dd, J 5.8, 2.8, Har), 5.48 (1H, s, S2CH),
3.10 (2H, ddd, J 14.3, 12.6, 2.5, SCHax), 2.93 (2H, dt, J 14.3,
3.3, SCHeq), 2.34–1.64 (12H, m, CH2 + OH), 1.35–1.28 (1H,
m, Hcyc); dC 155.5 (d, J 247.3, CarF), 138.3 (d, J 14.5, Car), 131.2
(d, J 2.9, CarH), 130.4 (d, J 4.9, CarH), 129.1 (d, J 17.5, Car),
117.5 (d, J 2.9, Car), 73.0 (d, J 3.9, COH), 43.0 (d, J 5.8, CS2),
36.6 (d, J 3.9, 2 × CH2), 32.4 (2 × CH2S), 25.3, 25.2 (CH2),
Scheme 5 Reagents and conditions: a) NaBH4, EtOH; b) RMgBr, THF;
n
a
c) PhCCH, BuLi, THF. Compound 27 (56%) was also obtained as a
major by-product.
In summary, an efficient approach has been developed to
access a novel spiropiperidine scaffold 6 that is capable of
undergoing efficient selective modification at two sites. Both
the aryl bromide and amine functional groups present in 6
can be readily built on to provide a host of novel chemical
entities for screening purposes. This has been exemplified both
in single chemoselective reactions, and later in the composition
of multi-step telescope reaction matrices. In the latter case,
the 9 compounds synthesised exhibit physical characteristics
consistent with guidelines for sound drug-like properties.
Experimental
•
21.9 (2 × CH2); (EI) m/z (%): 390, 392 ([M]+ , 47), 372, 374
General
(36), 105 (78), 45 (100); Elemental analysis: Found: C, 48.73; H,
5.20. C16H20BrFOS2 requires: C, 49.11; H, 5.15%.
Melting points were obtained using an Electrothermal melting
point apparatus and are uncorrected. IR spectra were recorded
on a Nicolet Impact 400 spectrometer. 1H-NMR and 13C-NMR
were recorded in CDCl3 solution using a Bruker DPX400 (400
and 100 MHz respectively) unless otherwise stated. Chemical
shifts are reported in d units with CHCl3 being used as an
internal standard. Coupling constants (J) are reported in Hz.
Mass spectra acquired using an electrospray technique (ES+)
were recorded on a Fisons VG platform single quadrupole mass
spectrometer in electron spray ionisation mode. Those obtained
using an electron (EIMS) or chemical ionisation technique
(CIMS) were recorded on a Thermoquest trace GC-MS with
combined EI/CI source using a Macherey-Nagel Optima Delta-
4-[2-(5-Bromo-2-fluoro-phenyl)-[1,3]dithian-2-yl]-4-hydroxy-
piperidine-1-carboxylic acid tert-butyl ester (11). Compound
10 (21.8 g, 74.4 mmol) was added to a solution of LDA (1 eq)
in THF (300 mL) following the procedure for compound 13.
The reaction mixture was then allowed to warm to −20 ◦C for
◦
30 min before being cooled back to −78 C and a solution of
N-Boc-4-piperidone (9, 15.1 g, 75.8 mmol) in THF (150 mL)
added. Work-up and purification (20–40% EtOAc–hexane) gave
the title compound 11 as a pale yellow solid (29.3 g, 80%); Mp
111–112 ◦C (hexane); IR: mmax (CDCl3 film) 3428, 1673 cm−1;
NMR: dH 8.21 (1H, dd, J 7.5, 2.5, Har), 7.44 (1H, ddd, J 8.5,
3 2 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5

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3.5, 2.5, Har), 6.99 (1H, dd, J 12.0, 8.5, Har), 3.93 (2H, br s,
CHeqN), 2.99 (2H, br t, J 11.6, CHaxN), 2.86 (2H, dt, 14.6, 4.5,
SCHeq), 2.64 (2H, ddd, J 14.6, 9.8, 5.0, SCHax), 2.46 (1H, br s,
OH), 1.92–1.85 (2H, m, CH2), 1.84–1.73 (4H, m, CH2COH),
(dec.). On a 2.62 mmol scale, this reaction was refluxed in 15 mL
of DCM for 4 h to afford 6 in 74% yield; IR: mmax (CDCl3 film)
1720, 1677 cm−1; NMR: dH 7.79 (1H, d, J 2.2, Har), 7.73 (1H,
dd, J 8.8, 2.2, Har), 7.06 (1H, d, J 8.8, Har), 6.75 (1H, br s,
NH), 3.44 (2H, dt, J 12.9, 3.9, CHeqN), 2.27 (2H, td, J 12.8, 3.2,
CHaxN), 2.17 (2H, ddd, J 13.9, 12.8, 4.6, CHaxCOAr), 1.78 (2H,
=
1.43 (9H, s, (CH3)3); dC 161.0 (d, J 252.1, CarF), 154.9 (C O),
137.6 (CarH), 133.3 (d, J 9.7 Hz, CarH), 127.4 (d, J 8.7, Car),
119.7 (d, J 28.0, CarH), 116.9 (d, J 2.9 Hz, Car), 79.6 (O–CMe3),
77.0 (COH), 69.6 (d, J 6.8, CS2), 39.7 (2 × CH2N), 32.6 (2 ×
CH2COH), 28.6 ((CH3)3), 27.84 (2 × CH2), 24.3 (CH2); (ES+)
m/z: 1005, 1007, 1009 ([2M + Na]+); Elemental analysis:
Found: C, 48.91; H, 5.69; N, 2.69. C20H27BrFOS2 requires: C,
48.78; H, 5.53; N, 2.84%.
=
d, J 13.8 Hz, CHeqCOAr); dC 200.1 (C O), 169.7 (Car), 141.2
(CarH), 127.7 (CarH), 121.7 (Car), 115.7 (CarH), 115.1 (Car), 86.4
(C–OAr), 40.8 (2 × CH2N), 30.1 (2 × CH2COAr); (EI) m/z:
•
•
281, 283 ([M+ ], 81), 238, 240 (18), 56 (100); HR(EI) m/z: [M+ ]:
281.0036. C12H12BrNO2 requires 281.0051.
tert-Butyl 5-(octylamino)-spiro[1-benzofuran-2,4ꢀ-piperidine]-
3-one-1ꢀ-carboxylate (14a). To a stirred mixture of BINAP
(9.8 mg, 15.7 lmol) in toluene (1.3 mL) was added Pd2(dba)3
(4.8 mg, 5.2 lmol) and the reaction stirred at room temperature
for 5 min. To this solution was added 7 (100 mg, 0.26 mmol),
octylamine (56 lL, 0.34 mmol), and tBuONa (35 mg, 0.37 mmol)
in that order. The orange solution was heated in the microwave
for 1 h at 100 ◦C. The reaction was then filtered, washing with
ether (15 mL), concentrated to a brown oil (113 mg) and purified
by column chromatography (1–4% EtOAc–DCM) to afford the
title compound 14a as a bright yellow oil (78 mg, 69%); IR: mmax
(CDCl3 film) 2922, 1701, 1678 cm−1; NMR: dH 6.99 (1H, dd, J
8.8, 2.2, Har), 6.95 (1H, d, J 8.8, Har), 6.73 (1H, d, J 2.0, Har),
4.13 (2H, br s, CHeqN), 3.63 (1H, br s, NH), 3.25–3.18 (2H, m,
CHaxN), 3.07 (2H, t, J 7.0, ArNHCH2), 1.42 (2H, td, J 13.6, 4.8,
CHaxCOAr), 1.61 (2H, t, J 7.0, CH2), 1.55 (2H, d, J 13.4 Hz,
CHeqCOAr), 1.48 (9H, s, C(CH3)3), 1.44–1.21 (10H, m, 5 ×
4-(5-Bromo-2-fluoro-benzoyl)-4-hydroxy-piperidine-1-carboxylic
acid tert-butyl ester (12). Following a procedure described
by Bates and O’Doherty,16 to a stirred solution of 11 (4.15 g,
8.43 mmol) and pyridine (1.02 mL, 12.6 mmol) in DCM (50 mL)
and water (10 mL) was added pyridine tribromide (4.04 g,
12.6 mmol) followed by TBAB (272 mg, 0.84 mmol). The
resulting mixture was stirred at room temperature for 24 h. The
reaction was then poured into water (120 mL) and extracted
with DCM (3 × 160 mL). The combined organic fractions were
washed with water (400 mL), brine (400 mL), dried (Na2SO4),
filtered and evaporated to give a cream residue (4.33 g). This was
absorbed onto silica and purified by column chromatography
(0–20% EtOAc–hexane) to give the title compound 12 as a pale
yellow oil (3.32 g, 98%); IR: mmax (CDCl3 film) 3413, 1664 cm−1;
NMR: dH 7.54 (1H, ddd, J 8.6, 4.5, 2.5, Har), 7.49 (1H, dd, J
5.8, 2.5, Har), 7.01 (1H, t, J 8.8, Har), 3.96 (2H, br d, J 9.4,
CHeqN), 3.47 (1H, br s, OH), 3.13 (2H, br t, J 10.6, CHaxN),
1.96 (2H, td, J 12.8, 4.8, CHaxCOH), 1.65 (2H, br d, J 13.0,
=
CH2), 0.89 (3H, t, J 7.0, CH3); dC 203.3 (Ar–C O), 164.9 (Car),
t
154.8 (CO2 Bu), 144.2 (Car), 126.9 (CarH), 120.3 (Car), 114.3,
=
CHeqCOH), 1.43 (9H, s, (CH3)3); dC 205.0 (d, J 1.9, Ar–C O),
103.3 (CarH), 87.2 (C–OAr), 79.9 (O–CMe3), 44.8 (CH2NH),
40.1 (2 × CH2N), 32.0, 32.0, 31.6, 29.5, 29.5, 29.4 (CH2), 28.6
((CH3)3), 27.3, 22.8 (CH2), 14.2 (CH3); (ES+) m/z: 883 ([2M +
Na]+), 431 ([M + H]+); HR(ES+) m/z: 431.2904. C25H39N2O4
requires 431.2901.
t
158.0 (d, J 247.3, CarF), 154.8 (CO2 Bu), 135.4 (d, J 8.7, CarH),
131.5 (d, J 3.9, CarH), 128.1 (d, J 19.3, Car), 118.1 (d, J 24.1,
CarH), 117.0 (d, J 2.9, Car), 80.0 (O–CMe3), 77.8 (COH), 39.1
(2 × CH2N), 33.3 (2 × CH2COH), 28.5 ((CH3)3); (ES+) m/z:
•
402, 404 ([M + H]+); HR(ES+) m/z: [2M + Na]+ : 825.1174.
tert-Butyl 5-(dibutylamino)-spiro[1-benzofuran-2,4ꢀ-piperidine]-
3-one-1ꢀ-carboxylate (14b). Following the procedure described
for the synthesis of 14a, 7 (100 mg, 0.26 mmol) was coupled
with dibutylamine (62 lL, 0.37 mmol). Column chromatography
of the crude product (10% EtOAc–hexane) afforded the title
compound 14b as a bright yellow oil (31 mg, 28%). The resulting
product of scaffold debromination was also recovered from the
reaction (33 mg, 42%); IR: mmax (CDCl3 film) 1696 cm−1; NMR:
dH 7.11 (1H, dd, J 9.0, 2.8, Har), 7.01 (1H, d, J 9.0, Har), 6.79 (1H,
d, J 2.8, Har), 4.15 (2H, br s, CHeqN), 3.22 (2H, br s, CHaxN), 3.22
(4H, t, J 7.5, ArN(CH2)2), 1.93 (2H, td, J 12.8, 4.8, CHaxCOAr),
1.56–1.49 (6H, m, CH2), 1.49 (9H, s, C(CH3)3), 1.33 (4H, sext,
C34H42Br2F2N2O8Na requires 825.1168.
tert-Butyl 5-bromo-spiro[1-benzofuran-2,4ꢀ-piperidine]-3-one-
1ꢀ-carboxylate (7). To a solution of 12 (190 mg, 0.47 mmol)
t
in THF (2 mL) was added BuOK (80 mg, 0.71 mmol) and
the mixture reacted in the microwave at 70 ◦C for 5 min (heating
may also be conducted thermally). The reaction was then poured
into water (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic fractions were washed with water (30 mL),
brine (30 mL), dried (Na2SO4), filtered and evaporated to give a
pale yellow oil (97 mg). Purification by column chromatography
(20% EtOAc–hexane) gave the title compound 7 as a yellow
crystalline solid (135 mg, 75%). On a 4.08 mmol scale, this
reaction was performed in 3 microwave vials (5 mL each) to
afford 7 in 72% yield; Mp 124–126 ◦C (EtOAc–hexane); IR: mmax
(CDCl3 film) 2978, 1706, 1678 cm−1; NMR: dH 7.79 (1H, dd,
J 2.3, 0.5, Har), 7.71 (1H, dd, J 8.8, 2.3, Har), 7.04 (1H, dd, J
8.8, 0.5, Har), 4.15 (2H, br s, CHeqN), 3.22 (2H, br t, J 12.1,
CHaxN), 1.94 (2H, ddd, J 13.8, 12.3, 5.0, CHaxCOAr), 1.59 (2H,
br d, J 13.6, CHeqCOAr), 1.49 (9H, s, (CH3)3); dC 201.1 (Ar–
=
J 7.3, CH2), 0.94 (6H, t, J 7.3, CH3); dC 203.6 (Ar–C O), 163.7
(Car), 154.8 (CO2 Bu), 144.5 (Car), 125.6 (CarH), 120.3 (Car),
t
114.3, 104.7 (CarH), 87.1 (C–OAr), 79.9 (O–CMe3), 51.7 (2 ×
CH2N), 40.4, 39.6 (CH2N), 31.6, 29.4 (4 × CH2), 28.6 ((CH3)3),
20.5 (2 × CH2), 14.2 (2 × CH3); (ES+) m/z: 431 ([M + H]+);
HR(ES+) m/z: 431.2899. C25H39N2O4 requires 431.2904.
tert-Butyl 5-[methyl(phenyl)amino]-spiro[1-benzofuran-2,4ꢀ -
piperidine]-3-one-1ꢀ-carboxylate (14c). Following the proce-
dure described for the synthesis of 14a, 7 (100 mg, 0.26 mmol)
was coupled with N-methylaniline (62 lL, 0.37 mmol). Column
chromatography of the crude product (10% EtOAc–hexane
afforded the title compound 14c as a bright yellow oil (67 mg,
63%); IR: mmax (CDCl3 film) 2969, 1697 cm−1; NMR: dH 7.40
(1H, dd, J 8.8, 2.5, Har), 7.30 (1H, d, J 2.5, Har), 7.26 (2H,
dd, J 8.0, 7.0, Har), 7.05 (1H, d, J 8.8, Har), 6.94 (1H, t, J
7.0, Har), 6.93 (2H, d, J 8.0, Har), 4.15 (2H, br s, CHeqN), 3.29
(3H, s, NCH3), 3.27–3.21 (2H, m, CHaxN), 1.96 (2H, td, J 13.6,
t
=
C
O), 169.8 (Car), 154.7 (CO2 Bu), 140.9, 127.6 (CarH), 122.0
(Car), 115.7 (CarH), 114.7 (Car), 88.4 (C–OAr), 80.2 (O–CMe3),
39.8 (2 × CH2N), 31.4 (2 × CH2COH), 28.6 ((CH3)3); (ES+)
m/z: 785, 787, 789 ([2M + Na]+); Elemental analysis: Found:
C, 53.47; H, 5.34; N, 3.62. C17H20BrNO4 requires: C, 53.42; H,
5.27; N, 3.66%.
5-Bromo-spiro[1-benzofuran-2,4ꢀ-piperidin]-3-one (6). To a
solution of 7 (100 mg, 0.26 mmol) in THF (1 mL) was added
TFA (0.10 mL, 1.31 mmol) dropwise and the reaction heated
◦
in the microwave for 20 min at 140 C. The reaction was then
4.8, CHaxCOAr), 1.61 (2H, d, J 13.3, CHeqCOAr), 1.50 (9H, s,
t
=
evaporated to dryness and chromatographed on silica (0–10%
MeOH–DCM, 1% NH3) to afford the title compound 6 as a
white solid (65 mg, 0.23 mmol, 88% yield); Mp 171–173 ◦C
(CH3)3); dC 202.5 (Ar–C O), 167.1 (Car), 154.8 (CO2 Bu), 149.2,
144.4 (Car), 134.0, 129.5, 129.5, 121.3 (CarH), 120.7 (Car), 119.4,
119.4, 115.7, 114.4 (CarH), 87.9 (C–OAr), 80.0 (O–CMe3), 40.9
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5
3 2 3 1

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(NCH3), 39.9 (2 × CH2N), 33.6 (2 × CH2COAr), 28.6 ((CH3)3);
(ES+) m/z: 409 ([M + H]+), 426 ([M + NH4]+); HR(ES+) m/z:
409.2127. C24H29N2O4 requires 409.2122.
(97 lL, 0.78 mmol) in NEt3 (2 mL) was added Pd(PPh3)2Cl2
(9.2 mg, 13.1 lmol) followed by CuI (2.5 mg, 13.1 lmol).
The reaction was purged with N2 before being heated in the
microwave for 15 min at 100 ◦C. The reaction was concentrated
to give an orange solid (158 mg), which was purified by
column chromatography (5% EtOAc–hexane) to afford to title
compound 16a as a pale orange solid (85 mg, 85%); Mp 51–
53 ◦C (EtOAc–hexane); IR: mmax (CDCl3 film) 1711, 1682 cm−1;
NMR: dH 7.69 (1H, d, J 1.5, Har), 7.63 (1H, dd, J 8.6, 1.7,
Har), 7.04 (1H, d, J 8.6, Har), 4.13 (2H, br s, CHeqN), 3.22
(2H, br t, J 12.0 Hz, CHaxN), 1.94 (2H, td, J 12.5, 4.8 Hz,
CHaxCO), 1.57 (2H, br d, J 13.6 Hz, CHeqCO), 1.49 (9H, s,
tert-Butyl 5-phenyl-spiro[1-benzofuran-2,4ꢀ-piperidine]-3-one-
1ꢀ-carboxylate (15a). To a stirred biphasic mixture of 7
(400 mg, 1.05 mmol) and phenyl boronic acid (191 mg,
1.57 mmol) in toluene (1 mL), ethanol (1 mL) and 2M Na2CO3
(1 mL) was added Pd(PPh3)4 (60 mg, 0.05 mmol) and the
reactions heated in the microwave for 10 min at 110 ◦C. The
reaction was poured into water (20 mL) and extracted with
EtOAc (3 × 30 mL). The combined organic fractions were
washed with water (70 mL), brine (70 mL), dried (Na2SO4),
filtered and evaporated to give a brown residue (672 mg). This
was purified by column chromatography (10% EtOAc–hexane)
to afford the t◦itle compound 15a as a white solid (337 mg, 85%);
Mp 134–135 C (EtOAc–hexane); IR: mmax (CDCl3 film) 1716,
1678 cm−1; NMR: dH 7.90 (1H, dd, J 8.3, 1.8, Har), 7.79 (1H, s,
Har), 7.56 (2H, d, J 7.5, Har), 7.45 (2H, t, J 7.3, Har), 7.37 (1H, t,
J 7.3, Har), 7.21 (1H, d, J 8.3, Har), 4.18 (2H, br s, CHeqN), 3.27
(2H, br t, J 12.8, CHaxN), 1.99 (2H, td, J 12.6, 4.8, CHaxCO),
=
OC(CH3)3), 1.49 (9H, s, CC(CH3)3); dC 201.8 (Ar–C O), 170.0
t
(Car), 154.8 (CO2 Bu), 141.5, 128.0 (2 × CarH), 120.2 (Car), 118.6
(Car), 113.7 (CarH), 98.7 (Calkyne), 88.0 (C–OAr), 80.1 (O–CMe3),
77.7 (Calkyne), 40.1 (2 × CH2N), 31.5 (2 × CH2COAr), 31.1
(OC(CH3)3), 28.6 (CC(CH3)3), 28.1 (CCMe3); (EI) m/z: 383
•
•
([M+ ], 36), 310 (57), 56 (100); HR(EI) m/z: [M+ ]: 383.2077.
C23H29NO4 requires 383.2097.
tert-Butyl 5-[(4-methoxyphenyl)ethynyl]-3-oxo-spiro[1-
benzofuran-2,4ꢀ-piperidine]-1ꢀ-carboxylate
(16b). Following
1.63 (2H, br d, J 12.0 Hz, CHeqCO), 1.51 (9H, s, (CH3)3); dC
t
=
202.6 (Ar–C O), 170.6 (Car), 154.8 (CO2 Bu), 139.8 (Car), 137.7
the procedure described for the synthesis of 16a, 7 (100 mg,
0.26 mmol) was coupled with 1-ethynyl-4-methoxybenzene
(104 mg, 0.78 mmol) in piperidine (2 mL) to afford the title
compound 16b as a pale yellow coloured solid (105 mg, 93%);
(CarH), 135.9 (Car), 129.2 (2 × Car), 127.7 (CarH), 129.2 (2 × Car),
122.9 (CarH), 120.7 (Car), 114.2 (CarH), 88.0 (C–OAr), 80.1 (O–
C(CH3)3), 39.8 (2 × CH2N) 31.5 (2 × CH2COAr) 28.6 ((CH3)3);
(ES+) m/z: 781 ([2M + Na]+); Elemental analysis: Found: C,
72.84; H, 6.68; N, 3.63. C23H25NO4 requires: C, 72.80; H, 6.64;
N, 3.69%.
◦
Mp 144–145 C (EtOAc–hexane); IR: mmax (CDCl3 film) 1725,
1682 cm−1; NMR: dH 7.81 (1H, d, J 2.0, Har), 7.76 (1H, dd, J
8.6, 2.0, Har), 7.46 (2H, d, J 8.8, Har), 7.11 (1H, d, J 8.6, Har),
6.89 (2H, d, J 9.0, Har), 4.15 (2H, br s, CHeqN), 3.84 (3H, s,
OCH3), 3.25 (2H, br t, J 12.4 Hz, CHaxN), 1.96 (2H, td, J
12.5, 4.8 Hz, CHaxCO), 1.61 (2H, br d, J 12.8, CHeqCO), 1.51
tert-Butyl 5-(3-methoxyphenyl)-spiro[1-benzofuran-2,4ꢀ -
piperidine]-3-one-1ꢀ-carboxylate (15b). Following the proce-
dure described for the synthesis of 15a, 7 (100 mg, 0.26 mmol)
was coupled with 3-methoxyphenyl boronic acid (60 mg,
0.39 mmol) to afford the title compound 15b as a pale yellow
=
(9H, s, C(CH3)3); dC 201.6 (Ar–C O), 170.3 (Car), 160.0 (Car),
154.8 (CO2 Bu), 141.3 (CarH), 133.2 (2 × CarH), 127.9 (CarH),
t
◦
120.4 (Car), 118.1, 115.2 (Car), 114.3 (2 × CarH), 114.1 (CarH),
89.6 (Calkyne), 88.2 (C–OAr), 86.7 (Calkyne), 80.1 (O–CMe3), 55.5
(OCH3), 40.2 (2 × CH2N) 31.5 (2 × CH2COAr) 28.6 (C(CH3)3);
(ES+) m/z: 378 ([M + H–C4H8]+), 334 ([M + H–C4H8OCO]+);
HR(ES+) m/z [M + H–C4H8OCO]+: 334.1454. C21H20NO3
requires 334.1443.
solid (83 mg, 77%); Mp 141–142 C (hexane); IR: mmax (CDCl3
film) 1715, 1692 cm−1; NMR: dH 7.89 (1H, dd, J 8.3, 2.0, Har),
7.88 (1H, br s, Har), 7.36 (1H, t, J 8.0, Har), 7.20 (1H, dd, J 8.3,
1.3, Har), 7.14 (1H, ddd, J 7.8, 1.5, 0.8, Har), 7.08 (1H, t, J 1.8,
Har), 6.91 (1H, ddd, J 8.3, 2.5, 0.8, Har), 4.17 (2H, br s, CHeqN),
3.87 (3H, s, OCH3), 3.27 (2H, br t, J = 13.7 Hz, CHaxN),
1.98 (2H, td, J 13.8, 4.8, CHaxCO), 1.63 (2H, br d, J 13.6 Hz,
tert-Butyl 3-oxo-5-{[4-(trifluoromethyl)phenyl]ethynyl}-spiro[1-
benzofuran-2,4ꢀ-piperidine]-1ꢀ-carboxylate (16c). Following the
procedure described for the synthesis of 16a, 7 (100 mg,
0.26 mmol) was coupled with 4-ethynyl-a,a,a-trifluorotoluene
(109 lL, 0.78 mmol) in piperidine (2 mL) to afford the title
compound 16c as a cream solid (92 mg, 75%); Mp 177–178 ◦C
(EtOAc–hexane); IR: mmax (CDCl3 film) 1721, 1682 cm−1; NMR:
dH 7.88 (1H, d, J 1.8, Har), 7.81 (1H, dd, J 8.6, 1.8, Har), 7.68–7.61
(4H, m, Har), 7.15 (1H, d, J 8.7, Har), 4.16 (2H, br s, CHeqN), 3.26
(2H, br t, J 11.8, CHaxN), 1.88 (2H, td, J 13.4, 5.0, CHaxCO),
=
CHeqCO), 1.51 (9H, s, C(CH3)3); dC 202.6 (Ar–C O), 170.6
(Car), 160.3 (Car), 154.8 (CO2 Bu), 141.2 (Car), 137.7 (CarH),
t
135.6 (Car), 130.2, 123.0 (CarH), 120.6 (Car), 119.5, 114.1, 113.2,
112.8 (CarH), 88.1 (C–OAr), 80.1 (O–CMe3), 55.5 (OCH3), 40.0
(2 × CH2N), 31.5 (2 × CH2COAr) 28.6 (C(CH3)3); (ES+) m/z:
841 ([2M + Na]+); Elemental analysis: Found: C, 69.99; H, 6.70;
N, 3.33. C24H27NO5 requires: C, 70.40; H, 6.65; N, 3.42%.
tert-Butyl 5-(3-nitrophenyl)-spiro[1-benzofuran-2,4ꢀ-piperidine]-
3-one-1ꢀ-carboxylate (15c). Following the procedure described
for the synthesis of 15a, 7 (100 mg, 0.26 mmol) was coupled
with 3-nitrophenyl boronic acid (66 mg, 0.39 mmol) to afford
the title compound 15c as a pale yellow solid (85 mg, 77%); Mp
175–176 ◦C (hexane); IR: mmax (CDCl3 film) 1720, 1692 cm−1;
NMR: dH 8.42 (1H, t, J 2.0, Har), 8.22 (1H, ddd, J 8.3, 2.3,
1.0, Har), 7.94 (1H, dd, J 9.2, 2.0, Har), 7.92 (1H, d, 2.0 Har),
7.88 (1H, ddd, J 7.8, 1.8, 1.0, Har), 7.63 (1H, t, J 8.0, Har),
7.28 (1H, t, J 9.3, Har), 4.17 (2H, br s, CHeqN), 3.27 (2H, br
t, J 11.3 Hz, CHaxN), 1.99 (2H, td, J 12.3, 5.0 Hz, CHaxCO),
1.62 (2H, br d, J 14.0, CHeqCO), 1.50 (9H, s, C(CH3)3); dC 201.4
t
=
(Ar–C O), 170.7 (Car), 154.8 (CO2 Bu), 141.4 (CarH), 132.0 (2 ×
CarH), 130.3 (q, J 32.9, CarCF3), 128.6 (CarH), 127.0 (Car), 123.1
(q, J 272.0, CF3), 125.6 (q, J 3.8, 2 × CarH), 120.6 (Car), 117.0
(Car), 114.3 (CarH), 90.4 (Calkyne), 88.4 (C–OAr), 88.1 (Calkyne),
80.2 (O–CMe3), 39.8 (2 × CH2N), 31.4 (2 × CH2COAr) 28.6
(C(CH3)3); 19F NMR (376 MHz): dF 63.2 (CF3); (ES+) m/z:
416 ([M + H–C4H8]+), 372 ([M + H–C4H8OCO]+); HR(EI)
m/z: [M + H–C4H8OCO]+: 372.1216 C21H17NO2F3 requires
372.1211.
1.64 (2H, br d, J 12.8 Hz, CHeqCO), 1.50 (9H, s, (CH3)3); dC
t
=
202.1 (Ar–C O), 171.1 (Car), 154.8 (CO2 Bu), 149.0 (Car), 141.4
tert-Butyl 3-oxo-5-[(E)-2-phenylvinyl]-spiro[1-benzofuran-2,4ꢀ-
piperidine]-1ꢀ-carboxylate (17a). To a stirred solution of
Pd(OAc)2 (1.8 mg, 7.85 lmol) and P(o-tol)3 (7.3 mg, 23.54 lmol)
in DMF (1 mL) was added 7 (100 mg, 0.26 mmol), styrene
(36 lL, 0.31 mmol), and triethylamine (55 lL, 0.39 mmol). The
reaction mixture was purged with nitrogen before being heated
(Car), 137.3 (CarH), 133.2 (Car), 132.8, 130.2, 123.4, 122.4, 121.8
(CarH), 121.0 (Car), 114.8 (CarH), 88.5 (C–OAr), 80.2 (O–CMe3),
39.8 (2 × CH2N) 31.5 (2 × CH2COAr) 28.6 ((CH3)3); (ES+) m/z:
871 ([2M + Na]+); Elemental analysis: Found: C, 64.84; H, 5.78;
N, 6.53. C23H24N2O6 requires: C, 65.08; H, 5.70; N, 6.60%.
◦
tert-Butyl 5-(3,3-dimethylbut-1-yn-1-yl)-3-oxo-spiro[1-
benzofuran-2,4ꢀ-piperidine]-1ꢀ-carboxylate (16a). To a degassed
solution of 7 (100 mg, 0.26 mmol), and 3,3-dimethylbutyne
at 100 C for 2 days. The reaction was then poured into water
(10 mL) and extracted with EtOAc (3 × 15 mL). The combined
organic fractions were washed with water (30 mL) and brine
3 2 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5

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(30 mL), dried (Na2SO4), filtered and evaporated to give an or-
ange oil (160 mg). This was purified by column chromatography
(20% EtOAc–hexane) to afford the title compound 17a as a pale
of Pd(PPh3)2Cl2 (6.2 mg, 8.7 lmol) and copper iodide (1.7 mg,
8.9 lmol). A second nitrogen purge was carried out and the
reactions then heated in the microwave at 120 ◦C for 20 minutes
(or 1 h for the 1-ethynyl-3-fluorobenzene substrates). On comple-
tion of coupling, the reaction mixtures were concentrated to give
brown residues, which were purified by column chromatography
(0–30% EtOAc–hexane) to afford the following products:
◦
yellow solid (101 mg, 95%); Mp 193–194 C (EtOAc–hexane);
IR: mmax (CDCl3 film) 1706, 1677 cm−1; NMR: dH 7.84 (1H, dd,
J 8.5, 2.0, Har), 7.79 (1H, d, J 1.8, Har), 7.50 (2H, d, J 7.5, Har),
7.38 (2H, t, J 7.5, Har), 7.29 (1H, t, J 7.4, Har), 7.14 (1H, d, J
8.5, Har), 7.10 (1H, d, J 16.3, Halkene), 7.05 (1H, d, J 16.3, Halkene),
4.17 (2H, br s, CHeqN), 3.26 (2H, br t, J 10.8, CHaxN), 1.97 (2H,
td, J 12.6, 5.0, CHaxCOAr), 1.61 (2H, br d, J 12.8, CHeqCOAr),
1ꢀ -Benzoyl-5-[(4-methoxyphenyl)ethynyl]-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (18). Yield: 51 mg, 66%. Mp 164–165 ◦C
(EtOAc–hexane); IR: mmax (CDCl3 film) 1716, 1617 cm−1; NMR
=
1.51 (9H, s, (CH3)3); dC 202.4 (Ar–C O), 170.6 (Car), 154.8
(CO2 Bu), 137.1 (Car), 136.7 (CarH), 132.3 (Car), 129.1, 128.9,
◦
t
(500 MHz, DMSO, 100 C): dH 7.85 (1H, dd, J 8.7, 1.9, Har),
128.9 (CarH), 128.0, 127.0 (Calkene), 126.7, 126.7, 122.2 (CarH),
120.6 (Car), 114.1 (CarH), 88.1 (C–OAr), 80.1 (O–CMe3), 40.0
(2 × CH2N), 31.5 (2 × CH2COAr), 28.6 ((CH3)3); (ES+) m/z:
833 ([2M + Na]+); Elemental analysis: Found: C, 73.99; H, 6.54;
N, 3.36. C25H27NO4 requires: C, 74.05; H, 6.71; N, 3.45%.
7.75 (1H, dd, J 1.8, 0.5, Har), 7.48–7.46 (7H, m, Har), 7.31 (1H,
dd, J 8.5, 0.6, Har), 6.98 (2H, dd, J 6.8, 2.1, Har), 4.07 (2H, br d,
J 12.0, CHeqN), 3.82 (3H, s, OCH3), 3.43 (2H, td, J 12.0, 3.5,
CHaxN), 1.90 (2H, td, J 11.2, 4.7, CHaxCOAr), 1.76 (2H, br
=
d, J 10.9, CHeqCOAr); dC 199.8 (Ar–C O), 169.1 (Car), 169.0
=
(N–C O), 159.3 (Car), 140.6 (CarH), 135.6 (Car), 132.3 (2 ×
tert-Butyl 5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-oxo-spiro[1-
CarH), 128.9 (CarH), 127.8 (2 × CarH), 126.3 (CarH), 126.1 (2 ×
CarH), 119.4 (Car), 116.7, 113.8 (Car), 114.0 (2 × CarH), 113.7
(CarH), 88.8 (Calkyne), 87.1 (C–OAr), 86.1 (Calkyne), 54.9 (OCH3),
39.0 (2 × CH2N) 30.5 (2 × CH2COAr); (ES+) m/z: 438 ([M +
H]+); HR(ES+) m/z: [M + H]+: 438.1725. C28H24NO4 requires
438.1705.
benzofuran-2,4ꢀ-piperidine]-1ꢀ-carboxylate
(17b). Following
the procedure described for the synthesis of 17a, 7 (100 mg,
0.26 mmol) was coupled with methyl acrylate (28 lL, 0.31 mmol)
to afford the title co◦mpound 17b as a pale yellow solid (85 mg,
77%); Mp 165–166 C (EtOAc–hexane); IR: mmax (CDCl3 film)
1711, 1678, 1616 cm−1; NMR: dH 7.83 (1H, d, J 2.0 Har), 7.82
(1H, dd, J 9.3, 2.0, Har), 7.67 (1H, d, J 16.1, Halkene), 7.16 (1H, d,
J 9.3, Har), 6.38 (1H, d, J 16.1, Halkene), 4.15 (2H, br s, CHeqN),
3.81 (3H, s, OCH3), 3.24 (2H, br t, J 12.3, CHaxN), 1.96 (2H,
td, J 13.1, 4.8, CHaxCOAr), 1.60 (2H, br d, J 13.3, CHeqCOAr),
1ꢀ-Benzoyl-5-(3,3-dimethylbut-1-yn-1-yl)-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (19). Yield: 47 mg, 69%. Mp 209–210 ◦C
(EtOAc–hexane); IR: mmax (CDCl3 film) 1715, 1616 cm−1; NMR:
dH 7.70 (1H, s, Har), 7.65 (1H, d, J 8.6, Har), 7.47–7.42 (5H,
m, Har), 7.06 (1H, d, J 8.6, Har), 4.72 (1H, br s, CHeqN), 3.86
(1H, br s, CHeqN), 3.43 (2H, br s, CHaxN), 2.02 (2H, br s,
CHaxCOAr), 1.67 (2H, br s, CHeqCOAr), 1.31 (9H, s, (CH3)3);
=
1.49 (9H, s, (CH3)3); dC 201.7 (Ar–C O), 172.0 (Car), 167.3
(CO2Me), 154.7 (CO2 Bu), 143.2 (Calkene), 137.7 (CarH), 129.1
t
(Car), 124.8 (CarH), 120.8 (Car), 117.9 (Calkene), 114.6 (CarH),
88.6 (C–OAr), 80.2 (O–CMe3), 51.9 (OCH3), 39.8 (2 × CH2N)
31.4 (2 × CH2COAr), 28.6 ((CH3)3); (ES+) m/z: 797 ([2M +
Na]+); Elemental analysis: Found: C, 64.96; H, 6.33; N, 3.41.
C21H25NO6 requires: C, 65.10; H, 6.50; N, 3.61%.
=
=
dC 201.3 (Ar–C O), 170.8 (Car), 169.9 (N–C O), 141.7 (CarH),
135.9 (Car), 130.0 (CarH), 128.8 (2 × CarH), 128.0 (CarH), 127.1
(2 × CarH), 120.1 (Car), 118.8 (Car), 113.8 (CarH), 98.9 (Calkyne),
87.7 (C–OAr), 77.6 (Calkyne), 32.0 (2 × CH2N), 31.1 ((CH3)3),
•
31.1 (2 × CH2COAr), 28.1 (CMe3); (EI) m/z: 387 ([M]+ , 42),
tert-Butyl 3-oxo-5[(E )-2-(phenylsulfonyl)vinyl]-spiro[1-
•
282 (11), 240 (85), 105 (100); HR(EI) m/z: [M+ ]: 387.1851.
benzofuran-2,4ꢀ-piperidine]-1ꢀ-carboxylate
(17c). Following
C25H25NO3 requires 387.1834.
the procedure described for the synthesis of 17a, 7 (100 mg,
0.26 mmol) was coupled with phenylvinyl sulfone (53 mg,
0.39 mmol) to afford the title compound 17c as a white solid
(95 mg, 77%); Mp 168–170 ◦C (EtOAc–hexane); IR: mmax
(CDCl3 film) 1716, 1682, 1163 cm−1; NMR: dH 7.94 (2H, d, J
7.0, Har), 7.79 (1H, d, J 2.0, Har), 7.76 (1H, dd, J 8.5, 2.0, Har),
7.66 (1H, d, J 15.3, Halkene), 7.62 (1H, t, J 7.2, Har), 7.55 (2H, t,
J 7.0, Har), 7.16 (1H, d, J 8.5, Har), 6.82 (1H, d, J 15.3, Halkene),
4.13 (2H, br s, CHeqN), 3.22 (2H, br t, J 12.5, CHaxN), 1.93 (2H,
td, J 13.8, 4.8, CHaxCOAr), 1.58 (2H, br d, J 13.6, CHeqCOAr),
1ꢀ -Benzoyl-5-[(3-fluorophenyl)ethynyl]-spiro[1-benzofuran-
xsxs2,4ꢀ-piperidin]-3-one (20). Yield: 40 mg, 53%, oil; IR: mmax
(CDCl3 film) 1717, 1604 cm−1; NMR: dH 7.81 (1H, dd, J 1.8,
0.5, Har), 7.85 (1H, dd, J 8.8, 1.8, Har), 7.48–7.42 (5H, m, Har),
7.35–7.29 (2H, m, Har), 7.21 (1H, d, J 9.2, Har), 7.15 (1H, d,
J 8.8, Har), 7.09–7.04 (1H, m, Har), 4.73 (1H, br s, CHeqN),
3.88 (1H, br s, CHeqN), 3.45 (2H, br s, CHaxN), 2.05 (2H, br s,
=
CHaxCOAr), 1.71 (2H, br s, CHeqCOAr); dC 201.0 (Ar–C O),
170.8 (Car), 170.6 (N–C O), 162.6 (d, J 245.4, CarF), 141.6
=
=
1.49 (9H, s, (CH3)3); dC 201.3 (Ar–C O), 172.3 (Car), 154.7
(CO2 Bu), 140.7 (Car), 140.6 (Calkene), 138.1, 133.6, 129.5, 129.5,
(CarH), 135.9 (Car), 130.2 (d, J 8.7, CarH), 130.1 (CarH), 128.8
(2 × CarH), 128.4 (CarH), 127.7 (CarH), 127.1 (2 × CarH),
124.9 (d, J 9.7, Car), 120.4 (Car), 118.5 (d, J 23.2, CarH), 117.5
(Car), 116.0 (d, J 21.3, CarH), 114.3 (CarH), 88.7, 88.4 (Calkyne),
88.0 (C–OAr), 38.5 (2 × CH2N), 31.8 (2 × CH2COAr); (ES+)
m/z: 448 ([M + Na]+); HR(ES+) m/z: [M + Na]+: 448.1323.
C27H20NO3Na requires 448.1319.
t
127.8, 127.8 (CarH), 127.4 (Calkene), 127.0 (Car), 125.5 (CarH),
120.9 (Car), 114.8 (CarH), 88.9 (C–OAr), 80.2 (O–CMe3), 39.7
(2 × CH2N) 31.3 (2 × CH2COAr), 28.6 ((CH3)3); (ES+) m/z:
961 ([2M + Na]+); Elemental analysis: Found: C, 63.62; H, 5.61;
N, 2.72. C25H27NO6S requires: C, 63.95; H, 5.80; N, 2.98%.
REACTION MATRIX: Compounds 18–20
Compounds 21–23
To a solution of 6 (150 mg, 0.53 mmol) and NEt3 (0.1 mL) in
THF (5.7 mL) was added benzoyl chloride (74 lL, 0.64 mmol).
A white precipitate formed immediately. The reaction was
stirred at room temperature for 5 minutes, after which LCMS
revealed complete conversion to the amide intermediate (ES+)
m/z: 388, 386 ([M + H]+). N-Methylpiperazine was added
(0.2 mL), the reaction mixture was stirred for a further 5
minutes and then separated into 3 equal portions. To the
3 reaction mixtures were added 1-ethynyl-4-methoxybenzene
(91 mg, 0.71 mmol), 3,3-dimethylbutyne (87 lL, 0.71 mmol),
and 1-ethynyl-3-fluorobenzene (82 lL, 0.71 mmol) respectively.
The reactions were then purged with nitrogen before addition
Following the procedure described for the synthesis of 18 to
20, 6 (150 mg, 0.53 mmol) was coupled with butyryl chloride
(66 lL, 0.64 mmol) to afford the required acylated intermediate
as identified by LCMS (ES+) m/z: 354, 352 ([M + H]+). Again
the reaction mixture was divided into 3 portions and the in-
termediate bromide coupled with 1-ethynyl-4-methoxybenzene
(91 mg, 0.71 mmol), 3,3-dimethylbutyne (87 lL, 0.71 mmol),
and 1-ethynyl-3-fluorobenzene (82 lL, 0.71 mmol) respectively.
The crude reaction mixtures were concentrated and purified by
column chromatography (0–30% EtOAc–hexane) to afford the
following products:
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5
3 2 3 3

View Article Online
1ꢀ -Butyryl-5-[(4-methoxyphenyl)ethynyl]-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (21). Yield: 42 mg, 59%, oil; IR: mmax
(CDCl3 film) 1720, 1620 cm−1; NMR: dH 7.81 (1H, d, J 1.8,
Har), 7.77 (1H, dd, J 8.6, 1.8, Har), 7.46 (2H, d, J 9.0, Har),
7.12 (1H, d, J 8.8, Har), 6.89 (2H, d, J 9.0, Har), 4.64 (1H, br
d, J 13.1, CHeqN), 3.94 (1H, br d, J 14.0, CHeqN), 3.84 (3H, s,
OCH3), 3.53 (1H, td, J 14.2, 3.1, CHaxN), 3.15 (1H, td, J 12.8,
2.4, CHaxN), 2.37 (2H, t, J 7.5, C(O)CH2), 1.98 (1H, td, J 13.1,
4.8, CHaxCOAr), 1.94 (1H, td, J 13.8, 5.5, CHaxCOAr), 1.71
(2H, sext, J 7.5, CH2CH3), 1.73–1.66 (2H, m, CHeqCOAr),
(1H, d, J 1.8, Har), 7.46 (2H, d, J 8.8, Har), 7.14 (1H, d, J
8.6, Har), 7.05 (1H, d, J 3.5, Har), 6.89 (2H, d, J 8.8, Har),
6.51 (1H, dd, J 3.5, 1.8, Har), 4.60 (2H, br d, J 13.2, CHeqN),
3.84 (3H, s, OCH3), 3.55–3.44 (2H, m, CHaxN), 2.10 (2H,
ddd, J 13.8, 12.3, 4.8, CHaxCOAr), 1.74 (2H, br d, J 13.6,
=
=
CHeqCOAr); dC 201.1 (Ar–C O), 170.2 (Car), 160.0 (N–C O),
159.4 (Car), 148.1 (Car), 143.9 (CarH), 141.5 (CarH), 133.2 (2 ×
CarH), 127.9 (CarH), 120.4 (Car), 118.3 (Car), 116.7 (CarH), 115.1
(Car), 114.3 (2 × CarH), 114.1, 111.6 (CarH), 89.7 (Calkyne), 88.0
(C–OAr), 86.6 (Calkyne), 55.5 (OCH3), 41.0 (2 × CH2N), 32.0
•
(2 × CH2COAr); (EI) m/z: 427 ([M]+ , 52), 290 (99), 95 (100);
=
1.01 (3H, t, J 7.5, CH3); dC 201.3 (Ar–C O), 171.7 (Car), 170.2
•
(N–C O), 160.0 (Car), 141.5 (CarH), 133.2 (2 × CarH), 127.9
HR(EI) m/z: [M+ ]: 427.1407. C26H21NO5 requires 427.1420.
=
(CarH), 120.4 (Car), 115.1, 114.3 (Car), 114.3 (2 × CarH), 114.1
(CarH), 89.7 (Calkyne), 87.9 (C–OAr), 86.6 (Calkyne), 55.5 (OCH3),
41.8, 37.7 (CH2N), 35.5, 32.2, 31.5, 18.9 (CH2), 14.2 (CH3);
5-(3,3-Dimethylbut-1-yn-1-yl)-1ꢀ-(2-furoyl)-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (25). Yield: 43 mg, 64%. Mp 120–121 ◦C
(EtOAc–hexane); IR: mmax (CDCl3 film) 1715, 1616 cm−1; NMR:
dH 7.70 (1H, d, J 1.8, Har), 7.65 (1H, dd, J 8.6, 1.8, Har), 7.49
(1H, d, J 1.8, Har), 7.07 (1H, d, J 8.8, Har), 7.04 (1H, d, J
3.5, Har), 6.50 (1H, dd, J 3.5, 1.8, Har), 4.58 (2H, br d, J 13.2,
CHeqN), 3.53–3.43 (2H, m, CHaxN), 2.07 (2H, td, J 14.1, 4.8,
CHaxCOAr), 1.70 (2H, br d, J 14.3, CHeqCOAr), 1.31 (9H, s,
•
•
(EI) m/z: 403 ([M]+ , 33), 333 (9), 290 (100); HR(EI) m/z: [M+ ]:
403.1791. C25H25NO4 requires 403.1784.
1ꢀ -Butyryl-5-(3,3-dimethylbut-1-yn-1-yl)-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (22). Yield: 44 mg, 70%. Mp 147–148 ◦C
(EtOAc–hexane); IR: mmax (CDCl3 film) 1725, 1611 cm−1. NMR:
dH 7.69 (1H, dd, J 1.8, 0.4, Har), 7.64 (1H, dd, J 8.6, 1.8, Har),
7.05 (1H, dd, J 8.6, 0.6, Har), 4.63 (1H, br d, J 13.4, CHeqN),
3.93 (1H, br d, J 13.5, CHeqN), 3.51 (1H, td, J 13.6, 2.9,
CHaxN), 3.13 (1H, td, J 13.4, 2.9, CHaxN), 2.36 (2H, t, J 7.5,
C(O)CH2), 1.96 (1H, td, J 13.4, 4.6, CHaxCOAr), 1.92 (1H, td,
J 13.6, 4.8, CHaxCOAr), 1.71 (2H, sext, J 7.5, CH2CH3), 1.66
(2H, br d, J 13.2, CHeqCOAr), 1.31 (9H, s, (CH3)3), 1.00 (3H, t,
=
=
(CH3)3); dC 201.2 (Ar–C O), 169.9 (Car), 159.4 (N–C O),
148.1 (Car), 143.9, 141.6, 128.0 (CarH), 120.1, 118.8 (Car), 116.7,
113.8, 111.5 (CarH), 98.8 (Calkyne), 87.8 (C–OAr), 77.6 (Calkyne),
40.0 (2 × CH2N), 32.0 (2 × CH2COAr), 31.1 ((CH3)3), 28.1
•
(CMe3); (EI) m/z: 377 ([M]+ , 14), 240 (52), 95 (100); HR(EI)
•
m/z: [M+ ]: 377.1619. C23H23NO4 requires 377.1627.
1ꢀ -(2-Furoyl)-5-[(3-fluorophenyl)ethynyl]-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (26). Yield: 35 mg, 49%, oil; IR: mmax
(CDCl3 film) 1713, 1603 cm−1; NMR: dH 7.86 (1H, d, J 1.8,
Har), 7.80 (1H, dd, J 8.5, 1.8, Har), 7.51 (1H, dd, J 1.8, 0.8,
Har), 7.36–7.28 (2H, m, Har), 7.22 (1 H, dd, J 9.0, 0.8, Har),
7.16 (1H, d, J 8.7, Har), 7.09–7.04 (1H, m, Har), 7.06 (1H, dd,
J 3.5, 0.8, Har), 6.51 (1H, dd, J 3.5, 1.8, Har), 4.60 (2H, br
d, J 13.0, CHeqN), 3.52 (2H, br s, CHaxN), 2.11 (2H, td, J
14.0, 4.8, CHaxCOAr), 1.75 (2H, br d, J 13.5, CHeqCOAr); dC
=
=
J 7.5, CH3); dC 201.4 (Ar–C O), 171.7 (Car), 170.0 (N–C O),
141.6 (CarH), 128.0 (CarH), 120.1 (Car), 118.8 (Car), 113.7
(CarH), 98.8 (Calkyne), 87.7 (C–OAr), 77.6 (Calkyne), 41.8, 37.7
(CH2N), 35.5, 32.1, 31.5 (CH2), 31.1 ((CH3)3), 28.1 (CMe3),
•
19.0 (CH2), 14.2 (CH3); (EI) m/z: 353 ([M]+ , 18), 283 (15),
•
240 (100); HR(EI) m/z: [M+ ]: 353.1981. C22H27NO3 requires
353.1991.
1ꢀ -Butyryl-5-[(3-fluorophenyl)ethynyl]-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (23). Yield: 35 mg, 50%, oil; IR: mmax
(CDCl3 film) 1717, 1605 cm−1; NMR: dH 7.84 (1H, d, J 1.8,
Har), 7.79 (1H, dd, J 8.5, 1.8, Har), 7.35–7.29 (2H, m, Har),
7.22 (1H, d, J 9.5, Har), 7.15 (1H, d, J 8.5, Har), 7.09–7.04
(1H, m, Har), 4.66 (1H, br d, J 12.2, CHeqN), 3.95 (1H, br d,
J 10.8, CHeqN), 3.53 (1H, t, J 11.0, CHaxN), 3.16 (1H, t, J
12.0, CHaxN), 2.37 (2H, t, J 7.7, C(O)CH2), 1.97 (2H, br s,
CHaxCOAr), 1.70 (2H, sext, J 7.6, CH2CH3), 1.72–1.66 (2H,
=
201.0 (Ar–C O), 170.6 (Car), 162.6 (d, J 245.4, CarF), 159.5
(N–C O), 148.1 (Car), 143.9, 141.6 (CarH), 130.2 (d, J 8.7,
=
CarH), 128.4 (CarH), 127.7 (CarH), 124.9 (d, J 9.7, Car), 120.5
(Car), 118.5 (d, J 23.1, CarH), 117.4 (Car), 116.8 (CarH), 116.0
(d, J 21.2, CarH), 114.2 (CarH), 111.6 (CarH), 88.8, 88.4 (Calkyne),
88.2 (C–OAr), 40.0 (2 × CH2N), 32.0 (2 × CH2COAr); (ES+)
m/z: 438 ([M + Na]+); HR(ES+) m/z: [M + Na]+: 438.1114.
C25H18NO4Na requires 438.1112.
=
m, CHeqCOAr), 1.01 (3H, t, J 7.5, CH3); dC 201.1 (Ar–C O),
171.7 (Car), 170.6 (N–C O), 162.6 (d, J 245.4, CarF), 141.6
tert-Butyl
5-bromo-3-hydroxy-spiro[1-benzofuran-2,4ꢀ -
=
piperidine]-1ꢀ-carboxylate (27). To a solution of 7 (50 mg,
0.13 mmol) in ethanol (2 mL) was added NaBH4 (6 mg,
0.15 mmol) and the reaction stirred at room temperature for 5
minutes. Acetic acid was then added (0.1 mL) and the reaction
concentrated to a white residue (80 mg). The residue was
purified by column chromatography (10–20% EtOAc–hexane)
to afford the title compound 27 as a white powder (50 mg,
0.13 mmol, 99%); Mp 142–143 ◦C (EtOAc–hexane); IR: mmax
(CDCl3 film) 3385, 1668 cm−1; NMR: dH 7.51 (1H, d, J 2.2,
(CarH), 130.2 (d, J 8.7, CarH), 128.4 (CarH), 127.7 (CarH), 124.9
(d, J 9.7, Car), 120.5 (Car), 118.5 (d, J 23.1, CarH), 117.4 (Car),
116.0 (d, J 21.3, CarH), 114.2 (CarH), 88.8, 88.4 (Calkyne), 88.1
(C–OAr), 41.8, 37.7 (CH2N), 35.5, 32.2, 31.5, 19.0, (CH2), 14.2
(CH3); (ES+) m/z: 414 ([M + Na]+); HR(ES+) m/z: [M + Na]+:
414.1482. C24H22NO3Na requires 414.1476.
Compounds 24–26
Following the procedure described for the synthesis of 18 to
20, 6 (150 mg, 0.53 mmol) was coupled with 2-furoyl chloride
(63 lL, 0.64 mmol) to afford the required acylated intermediate
as identified by LCMS (ES+) m/z: 378, 376 ([M + H]+). Again
the reaction mixture was divided into 3 portions and the in-
termediate bromide coupled with 1-ethynyl-4-methoxybenzene
(91 mg, 0.71 mmol), 3,3-dimethylbutyne (87 lL, 0.71 mmol),
and 1-ethynyl-3-fluorobenzene (82 lL, 0.71 mmol) respectively.
The crude reaction mixtures were concentrated and purified by
column chromatography (0–30% EtOAc–hexane) to afford the
following products:
Har), 7.36 (1H, dd, J 8.6, 2.2, Har), 6.73 (1H, d, J 8.6, Har),
4.79 (1H, s, J 5.3, CHOH), 3.91 (1H, br d, J 13.4, CHeqN),
3.80 (1H, br d, J 13.1, CHeqN), 3.58–3.31 (2H, m, CHaxN),
1.92–1.90 (2H, m, CHaxCOAr), 1.65–1.58 (2H, m, CHeqCOAr),
1.48 (9H, s, (CH3)3), (OH not observed); dC 157.8 (Car), 155.0
t
(CO2 Bu), 133.8 (CarH), 130.7 (Car), 129.4, 112.8 (CarH), 112.6
(Car), 89.3 (C–OAr), 80.0 (O–CMe3), 77.5 (Ar–COH), 40.7 (2 ×
CH2N) 34.5, 29.6 (CH2COAr) 28.6 ((CH3)3). (EI) m/z: 383, 385
•
([M]+ , 32), 327, 329 ([M–C4H8]+, 76), 223, 225 (78), 57 (C4H9 ,
+
•
100); HRMS (EI) m/z: [M+ ]: 383.0732. C17H22BrNO4 requires
383.0730.
1ꢀ-(2-Furoyl)-5-[(4-methoxyphenyl)ethynyl]-spiro[1-benzofuran-
2,4ꢀ-piperidin]-3-one (24). Yield: 45 mg, 59%. Mp 155–156 ◦C
(EtOAc–hexane); IR: mmax (CDCl3 film) 1715, 1616 cm−1; NMR:
dH 7.82 (1H, d, J 1.8, Har), 7.78 (1H, dd, J 8.6, 1.8, Har), 7.50
tert-Butyl 3-allyl-5-bromo-3-hydroxy-spiro[1-benzofuran-2,4ꢀ-
piperidine]-1ꢀ-carboxylate (28). To a solution of 7 (100 mg,
0.26 mmol) in THF (2 mL) at 0 ◦C was added allylMgBr
(0.39 mL, 0.39 mmol) and the reaction stirred at this temperature
3 2 3 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5

View Article Online
for 10 min. Sat. NH4Cl solution was then added (2 mL) and
the resulting biphasic mixture extracted with EtOAc (3 ×
10 mL). The combined organic fractions were washed with
water (20 mL), brine (20 mL), dried (Na2SO4), filtered and
concentrated to an orange residue (136 mg). The residue was
purified by column chromatography (5–10% EtOAc–hexane) to
afford the title compound 28 as a white solid (85 mg, 0.20 mmol,
77%); Mp 82–83 ◦C (EtOAc–hexane); IR: mmax (film) 3404,
1659 cm−1; NMR: dH 7.40 (1H, d, J 2.0, Har), 7.33 (1H, dd, J 8.3,
2.0, Har), 6.73 (1H, d, J 8.5, Har), 6.02 (1H, ddt, J 17.3, 10.0, 7.3,
7.64 (1H, d, J 2.3, Har), 7.48 (2H, dd, J 7.8, 1.8, Har), 7.39 (1H,
dd, J 8.5, 2.1, Har), 7.37–7.33 (3H, m, Har), 6.77 (1H, d, J 8.5,
Har), 4.18 (1H, br s, CHeqN), 4.07 (1H, br s, CHeqN), 3.18–3.09
(2H, br m, CHaxN), 2.59 (1H, s, OH), 2.15 (1H, dd, J 14.0, 2.3,
CHeqCOAr), 2.03 (1H, td, J 13.3, 4.3, CHaxCOAr), 1.92 (1H, td,
J 13.6, 5.0, CHaxCOAr), 1.72 (1H, dd, J 13.8, 2.0, CHeqCOAr),
t
1.48 (9H, s, (CH3)3); dC 157.2 (Car), 155.0 (CO2 Bu), 134.1
(CarH), 133.3 (Car), 132.0 (2 × CarH), 129.3 (CarH), 128.6 (2 ×
CarH), 127.9 (CarH), 111.8 (Car), 113.2 (CarH), 113.1 (Car), 92.4
(C–OAr), 88.9, 85.6 (Calkyne), 79.9 (Ar–COH), 78.1 (O–CMe3),
40.5 (2 × CH2N), 33.0 (2 × CH2COAr), 28.6 ((CH3)3); (ES−)
m/z: 482, 484 ([M–H]−); Elemental analysis: Found: C, 56.26;
H, 6.05; N, 3.16. C25H26BrNO4 requires: C, 56.61; H, 6.18; N,
3.30%.
=
=
CH2 CH), 5.29 (1H, d, Jcis 10.0, CH2 CH), 5.25 (1H, d, Jtrans
=
17.3, CH2 CH), 4.09 (2H, br s, CHeqN), 3.10 (2H, br s, CHaxN),
2.68 (1H, dd, J 14.3, 7.3, CH2 CHCH2), 2.51 (1H, dd, J 14.3,
=
=
7.3, CH2 CHCH2), 1.97 (1H, dd, J 14.0, 1.8, CHeqCOAr),
1.71 (2H, td, J 13.8, 4.8, CHaxCOAr), 1.58 (1H, dd, J 14.0,
1.8, CHeqCOAr), 1.47 (9H, s, (CH3)3), (OH not observed); dC
Acknowledgements
t
156.9 (Car), 155.0 (CO2 Bu), 134.5 (Car), 133.2 (CarH), 132.1
(CH2 CH), 127.6 (CarH), 120.5 (CH2 CH), 113.0 (CarH), 112.6
(Car), 91.6 (C–OAr), 80.9 (Ar–COH), 79.8 (O–CMe3), 40.4
We thank AstraZeneca and the EPSRC for CASE studentship
funding (RW) and The Royal Society for a University Research
Fellowship (RCDB). We also gratefully acknowledge CEM and
Biotage for the use of Explorer and Smith Synthesiser microwave
reactors respectively.
=
=
=
(2 × CH2N), 39.5 (CH2 CHCH2), 30.8, 29.8 (CH2COAr), 28.6
((CH3)3). (ES+) m/z: 424, 426 ([M + H]+); Elemental analysis:
Found: C, 56.26; H, 6.05; N, 3.16. C20H26BrNO4 requires: C,
56.61; H, 6.18; N, 3.30%.
References
tert-Butyl 5-bromo-3-ethyl-3-hydroxy-spiro[1-benzofuran-2,4ꢀ-
piperidine]-1ꢀ-carboxylate (29). To a solution of 7 (100 mg,
0.26 mmol) in THF (2 mL) at 0 ◦C was added EtMgBr (0.39 mL,
0.39 mmol) and the reaction stirred at this temperature for
30 min. Sat. NH4Cl solution was then added (2 mL) and
the resulting biphasic mixture extracted with EtOAc (3 ×
5 mL). The combined organic fractions were concentrated to an
orange residue (136 mg). The residue was purified by column
chromatography (10–20% EtOAc–hexane) to afford the title
compound 29 as a white powder (26 mg, 63 lmol, 24%). The
reduced product 27 was also recovered from the reaction (56 mg,
0.15 mmol, 56%); Mp 81–82 ◦C (EtOAc–hexane); IR: mmax (film)
3153, 1663 cm−1; NMR: dH 7.39 (1H, d, J 2.2, Har), 7.33 (1H, dd,
J 8.5, 2.2, Har), 6.72 (1H, d, J 8.3, Har), 4.08 (2H, br s, CHeqN),
3.11 (2H, br s, CHaxN), 1.97 (2H, br d, J 14.5, CHeqCOAr),
1.79 (2H, q, J 7.5, CH2CH3), 1.67–1.61 (2H, m, CHaxCOAr),
1.48 (9H, s, (CH3)3), 1.09 (3H, t, J 7.5, CH2CH3), (OH not
1 J. S. Mason, I. Morize, P. R. Menard, D. L. Cheney, C. Hulme and
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t
observed); dC 156.8 (Car), 155.0 (CO2 Bu), 135.1 (Car), 133.1,
127.4, 113.0 (CarH), 112.6 (Car), 91.7 (C–OAr), 82.0 (Ar–COH),
79.8 (O–CMe3), 40.4 (2 × CH2N), 30.7, 30.1 (CH2COH) 28.6
((CH3)3), 27.7 (CH2CH3), 7.8 (CH2CH3); (ES+) m/z: 312, 314
•
([M + H–C4H8OCO]+); HRMS (EI) m/z: [M–H2O+ ]: Found
393.0941. C19H24BrNO3 requires 393.0940.
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tert-Butyl
5-bromo-3-hydroxy-3-(2-phenylethynyl)-spiro[1-
benzofuran-2,4ꢀ-piperidine]-1ꢀ-carboxylate (30). To a solution
of phenylacetylene (30 lL, 0.27 mmol) in THF (1 mL) at
−78 ◦C was added nBuLi (2.31 M solution in hexanes, 119 lL,
0.27 mmol) and the reaction stirred at this temperature for
15 min. The anion formed was then added dropwise to a
solution of 7 (100 mg, 0.26 mmol) in THF (2 mL) at −78 ◦C and
the reaction warmed to −20 ◦C to be stirred at this temperature
for 1 h. The reaction was later poured into sat. NH4Cl solution
and extracted with EtOAc (3 × 10 mL). The combined organic
fractions were washed with water (20 mL), brine (20 mL),
dried (Na2SO4), filtered and concentrated to an orange residue
(120 mg). The residue was purified by column chromatography
(10% EtOAc–hexane) to afford the title compound 30 as
a white solid (63 mg, 0.13 mmol, 50%); Mp 217–218 ◦C
(EtOAc–hexane); IR: mmax (film) 3350, 1660 cm−1; NMR: dH
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weights of less than 500, CLog P values of less than 5, fewer than 5
H-bond donors and fewer than 10 H-bond acceptors.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 2 2 8 – 3 2 3 5
3 2 3 5