Synthesis of new substituted 4,5-dihydro-3H-spiro[1,5]-benzoxazepine-2, 4′-piperidine and biological properties

Article abstract of DOI:10.1071/CH06318

The reduction of substituted spiro-piperidinyl chromanone oximes with DIBAH reagents has been known to afford the corresponding substituted 4,5-dihydro-3H-spiro[1,5]-benzoxazepine-2,4?-piperidine. The position and electronic effects of the substituents on

Full text of DOI:10.1071/CH06318

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2006, 59, 812–818
www.publish.csiro.au/journals/ajc
Synthesis of New Substituted 4,5-Dihydro-3H-spiro[1,5]-
benzoxazepine-2,4ꢀ-piperidine and Biological Properties
Younes Laras,A Nicolas Pietrancosta,A Vincent Moret,A Sylvain Marc,A Cédrik Garino,A
Amandine Rolland,A Valérie Monnier,B and Jean-Louis KrausA,C
A Laboratoire de Chimie Biomoléculaire, IBDML Faculté des Sciences de Luminy,
Université de la Méditerranée, 13288 Marseille Cedex 9, France.
B Spectropole-Service de Spectrométrie de Masse, Faculté de St Jérôme,
Avenue Escadrille Normandie Niémen, 13397 Marseille Cedex 20, France.
C Corresponding author. Email: kraus@luminy.univ-mrs.fr
The reduction of substituted spiro-piperidinyl chromanone oximes with DIBAH reagents has been known to afford
the corresponding substituted 4,5-dihydro-3H-spiro[1,5]-benzoxazepine-2,4ꢀ-piperidine. The position and elec-
tronic effects of the substituents on the aryl moiety control the observed rearrangement. Spiro-benzoxazepine
analogue 5j represents a key intermediate for the creation of a library of diverse potential bioactive drugs. With
three functional groups that could be selectively and orthogonally protected, many different substituents can be
introduced. The obtained analogues were assayed as the possible aspartyl protease inhibitors HIV protease (HIV-1),
and β-secretase (BACE-1).
Manuscript received: 30 August 2006.
Final version: 9 October 2006.
R4
Introduction
R1
R2
N
Certain privileged structures can provide useful ligands for
more than one receptor, and judicious modifications of such
structures might provide viable alternatives in the search for
either new receptor agonists or antagonists, as well as protein
active sites.[1] The selection and derivatization of scaffolds
that recur in classes of bioactive compounds has become a
strategy to complement diversity in the generation of chemi-
cal libraries for lead discovery. Among privileged structures,
which are believed to be important for biological activity,
spiro-piperidines[2] have been identified as a relevant scaf-
fold for the design of bioactive compounds. More recently, it
has been shown[3] that some criteria (the number of rotatable
bonds and numbers of hydrogen bond acceptors and donors)
appear to be determinative for a drug to have an acceptable
oral bioavailability. Moreover, structure rigidity as well as
the functional groups introduced on the different positions
of a scaffold are essential for receptor or enzyme active-site
affinity.
Taking into account these considerations, we selected
the motive 4,5-dihydro-3H-spiro[1,5]-benzoxazepine-2,4ꢀ-
piperidine as a privileged structure for the creation of a
focussed library of bioactive drugs (Fig. 1).
New analogues of this focussed library will be tested
for their inhibitory properties on two representative aspartyl
proteases: HIV protease involved in the HIV viral repli-
cation cycle of infected cells,[4] and β-secretase (BACE-1)
O
N
R3
Fig. 1. General structure of spiro-benzoxazepine-piperidine.
involved in the formation of senile plaque in Alzheimer’s
disease.[5–8] To reach this goal, an efficient method is needed
for the synthesis of such scaffolds starting from spiro-
piperidine chromanone oximes. The synthesis of this latter
scaffold has been published,[9] but the described structures
bear no substituents on the aryl moiety. Introduction of var-
ious substituents on this part of the structure presents two
main interests: first to increase the structural diversity of
the resulting analogues; and second to study substituent
effects on the reductive rearrangement process (Beckmann
rearrangement).
Results and Discussion
As a preliminary objective, we developed a synthetic
route which allowed the synthesis of a diversity of
spiro-benzoxazepine bearing various substituents as shown
in Scheme 1.[9,10] Some compounds 3a, 3d, 3f, 3g, 4f, and 5f
of this scheme have been recently described.[9,11,12]
© CSIRO 2006
10.1071/CH06318
0004-9425/06/110812

Spiro-benzoxazepine-piperidine and Biological Properties
813
O
Table 1. Reduction of aryl-substituted chromanone oximes
OH
O
N
H
N
O
1
1
2
1
R
R
R
1
2
(i)
R
R
i-Bu AlH
2
N
ϩ
2
N
R
O
2
R
O
R
OH
NBn
O
N
1
2
3
Oximes
R1
R2
Products
Yield [%]
4a
4b
4c
4d
4e
4f
OMe
Me
OBn
Cl
F
H
H
H
H
H
H
H
OMe
H
5a
5b
5c
5d
5e
5f
61
16
52
32
40
52
(ii)
OH
H
N
N
O
1
R
1
2
R
R
(iii)
A
4g
4h
H
NO2
5g
5h
—
2
R
O
A
—
NBn
NBn
A Not detected.
5
4
Scheme 1. Reagents and conditions: (i) pyrrolidine, MeOH, reflux;
(ii) HCl·H2N-OH, pyridine, EtOH, reflux; (iii) reductive rearrangement
step (Beckmann rearrangement).
secondary amines through diisobutylaluminium hydride
(DIBAH) reduction.[10]
Introduction of specific substituents on the aryl moiety
was considered as an important aspect to build a diver-
sified focussed library of aryl-substituted 4,5-dihydro-3H-
spiro[1,5]-benzoxazepine-2,4ꢀ-piperidine. We also synthe-
sized a large variety of compounds starting directly from
chromanone oximes. Then, we explored the effect of sub-
stituents R1 and R2 on the reductive rearrangement products
using DIBAH in CH2Cl2 as a reducing agent. Results are
reported in Table 1.
H
R1
N
R1
R2
N
NH2
R1
R2
R2
O
O
N
O
N
R3
N
R3
R3
5
6
7
Fig. 2. Possible compounds obtained after reduction step (Beckman
rearrangement).
From these results it can observed that:
• When oximes (4a–4f) have been reduced by DIBAH, the
only products obtained were the corresponding anilines
(5a–5f) in various yields, without detection of either imine
6 or primary amines 7 (Fig. 2) in the reaction mixture. Only
starting oxime derivatives were recovered.
• The electronic effects (donating or withdrawing) of
the substituents on the aryl moiety greatly influence
the progression of this reductive step. Strong electron-
withdrawing substituents such as the nitro group (NO2) at
position 6 of the aromatic moiety are clearly unfavourable
to the rearrangement since no reaction occurred under the
experimental conditions. In contrast, either electron donat-
ing substituents, or less electron-withdrawing substituents
than NO2 (H, Cl, OCH3), led to the expected secondary
aniline 5 as major rearrangement product.
Some of final spiro-benzoxyazepines, after selective
deprotection, could be considered as possible starting build-
ing blocks for the construction of a chemical library.
Introduction of substituents for R3 and R4 (Fig. 1) was
standard chemistry. In contrast, introduction of various sub-
stituents on the aromatic ring appears more difficult since
the reductive rearrangement (Beckmann rearrangement) step
could lead to at least three possible products as shown
in Fig. 2.
The yield of the primary aryl alkyl amines 7 with respect
to the formation of secondary amine 5, and imine 6 depends
on the following parameters:
• The position and electronic effect of substituents R1 and
R2 on the aryl nucleus.
• The protection or not of the oxime function by tosyl or
other substituted silyl groups.[13,14]
• The size of the ring bearing the oxime function and the
substituent on the heterocyclic ring fused to the aromatic
ring (e.g. spiro-piperidine ring).
• Considering compounds 4a and 4g with a methoxy group
at position 6 and 7 of the aromatic ring, respectively, it
can be observed (Table 1) that the reductive rearrangement
step is greatly influenced by the substitution position on
this moiety. No reaction was observed with the oxime 4g,
and 95% of the starting oxime was recovered. Using mass
spectrum and NMR analyses of the obtained side products,
only the corresponding intracyclic 4-ene-benzoxazepine
6g analogue was identified in 2% yield.
• The nature of the reductive agent used for the rearrange-
ment of the oxime and the reaction conditions.
Catalytic reduction of aromatic oximes alkyl and aryl ethers
withboraneandorganoboronreagentsaffordseitherhydroxyl
amine, or amines that mainly depend on the structure of
the starting oximes and the reaction conditions.[15,16] Free
oximes have been reported to be converted into rearranged
In contrast, for the oxime 4a only the expected secondary
aniline 5a was obtained in 61% yield. These observations are
in agreement with the proposedYamamoto mechanism[10] for

814
Y. Laras et al.
(BF3–Et2O/BH3–DMSO) takes place only when the chro-
manone oximes were silylated, analogue 4g bearing a
methoxy substituent at position 7 was first silylated and
then submitted to the reductive step using BF3–Et2O/BH3–
DMSO. Under these conditions, 95% of starting oxime was
recovered, and among the isolated formed products, ana-
logues 6g and 7g were isolated in less than 2% yield but
clearly identified (Scheme 2).
Al
Al
Al
Al
O
O
N
O
N
Ϫ
ϩ
N
ϩ
O
O
Ϫ
N
O
ϩ
N
O
ϩ
Fig. 3. Stabilizing effect on the cationic center by aryl substituents
6-NO2 and 7-OMe.
These results show that, whatever the reagents used for this
reductive step, this reductive process is mainly determined by
the position and nature of the substituent (electronic effect)
on the aryl moiety of the chromanone oxime.
Table 2. Catalyst effects on aryl-substituted chromanone oximes
Oximes
Reduction conditions
Yield 5A [%]
Yield 6 [%]
Finally, in order to introduce a function suitable to link
various side chains on the aryl moiety, we deprotected the
methoxy and amine functions of compound 5a into its corre-
sponding compound 5j (Scheme 3).The 5j analogue has three
positions which could be selectively protected or deprotected
(two amino groups and one hydroxyl group), and which allow
the introduction of diverse substituents. This analogue repre-
sents a versatile basic scaffold on which a library of potential
bioactive analogues may be built.
B
4a
4g
4a
4g
4a
4g
4a
DIBAH·CH2Cl2/0◦C/3 h
DIBAH·CH2Cl2/0◦C/3 h
Red-Al·THF/ꢀ/18 h
Red-Al·THF/ꢀ/18 h
LiAlH4·ether/rt/18 h
LiAlH4·ether/rt/18 h
BMS·THF/rt/18 h
61
2.5
—
—
B
No reaction
No reaction
B
B
B
5
5
5
—
—
—
A For each experiment the starting oximes were entirely recovered.
B Not isolated and not detected.
The whole synthesized compounds were assayed for
inhibitory activity against HIV protease and BACE-1
(β-secretase). These evaluations were performed accord-
ing standard procedures: BACE-1 inhibition measurements
using the FRET Kit assay methodology[18] (PanVera Corp.,
Madison, WI), and recombinant HIV protease according
to Bihel and Kraus.[19] However, neither whole derivative
showed inhibitory activity, even at 10 µM concentration, for
any enzymes tested under our assay conditions.
the reduction of oximes using DIBAH leading to rearrange-
ment.Addition of DIBAH on the oxime substrate coordinates
to nitrogen and oxygen lone pairs, leading to a complex
in which the nitrogen positive charge is stabilized through
resonance. A reaction mechanism different from classical
Beckmann rearrangement has also been suggested.[17] In this
case, first the reduction of the oxime double bond occurred,
then the rearrangement proceeded.
When a methoxy substituent, which has a lower field effect
than resonance effect, is introduced at position 7 of the aro-
matic ring 4g, a direct resonance interaction with the cationic
center occurs. This interaction stabilizes the reactive cationic
center and impedes the reductive rearrangement. In contrast,
introduction of this methoxy substituent at position 6 abol-
ished direct interaction with the cationic center, which is
thus less stabilized, and reductive rearrangement could occur.
Similarly, when the strong electron-withdrawing NO2 sub-
stituent is introduced at the 6 position on the aromatic ring,
its high field withdrawing effect conjugated with its reso-
nance effect destabilizes the cationic center, and therefore,
prevents the reductive rearrangement as shown in Fig. 3.
We next performed the same reductive rearrangement
reaction on free chromanone oxime 4a as representative
substrate, but using various aluminium containing catalysts
(DIBAH, Red-Al, LiAlH4) and non-aluminum reagents such
as borane dimethyl sulfide (BMS). Results are reported in
Table 2.
Conclusion
We have succeeded to elaborate a focussed library
of 4,5-dihydro-3H-spiro[1,5]-benzoxazepine-2,4ꢀ-piperidine
derivatives with various substituents on the aryl moiety, start-
ing directly from free oxime chromanones by a reductive
Beckmann rearrangement. Compound 5j with three func-
tional groups will be used as a versatile intermediate for the
construction of a diverse library of bioactive analogues. Our
results bring evidence that the position and electronic effects
of the substituents on the aryl moiety greatly influence the
formation of the spiro-benzoxazepine products.These results
are also in agreement with reported studies that suggest
a cationic rearrangement mechanism during the reductive
rearrangement step of OH-free oxime chromanones using
an aluminated catalyst. After biological evaluation of the
inhibitory properties of the new analogues on two aspartyl
protease enzymatic models, no significant inhibitory activity
was found for these new analogues.
As shown, only DIBAH in CH2Cl2 leads to the secondary
amine in satisfactory yield. Other aluminium catalysts either
failed or gave very low yield, probably by forming a cationic
complex, and thus confirming the electrophilic nature of the
rearrangement. Strengthening this hypothesis, when BMS
reductive reagent in THF was used, reduction of analogue
4a did not proceed.
Experimental
Unless otherwise noted, starting materials and reagents were obtained
from commercial suppliers and were used without purification.
Tetrahydrofuran (THF) was distilled over sodium benzophenone ketyl
immediately before use. Methylene dichloride (CH2Cl2) was distilled
over P2O5 just before use. Nuclear magnetic resonance spectra were
recorded at 250 MHz for 1H and 62.9 MHz for 13C on a Bruker AC-250
spectrometer. Chemical shifts are expressed as ppm downfield from
TMS (tetramethylsilane). Electrospray mass spectra were obtained on a
Following the results of Ortiz-Marciales et al.[15]
that oxime rearrangement with borane reductive catalyst

Spiro-benzoxazepine-piperidine and Biological Properties
815
N
O
MeO
OH
N
OTBDMS
N
NBn
NBn
6g
ϩ
(i)
(ii)
NBn
NBn
MeO
O
MeO
O
NH
2
4g
4i
O
MeO
7g
Scheme 2. (i) TBDMS-Cl, CH2Cl2, rt; (ii) (a) BF3-Et2O, (b) BH3-S(CH3)2, THF, rt.
1ꢀ-Benzyl-6-(benzyloxy)spiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3c
H
N
H
N
MeO
HO
Yellow solid (90%), mp 133–134◦C. (Found: C 78.26, H 6.32, N 3.47,
Calc. forC27H27NO3:C78.42, H6.58, N3.39%). δH (CDCl3, 250 MHz)
1.69 (2H, ddd, J 13.5, 9.6, 4.6), 2.04–2.10 (2H, m), 2.44 (2H, td, J 11.4,
2.5), 2.61–2.70 (2H, m), 2.73 (2H, s), 3.57 (2H, s), 5.06 (2H, s), 6.93
(1H, d, J9.0), 7.17(1H, dd, J9.0, 3.1), 7.23–7.45(11H, m). m/z (ES–MS)
414 [M + 1]+.
(i), (ii)
O
O
N
NH
5a
5j
Scheme 3. (i) BBr3, CH2Cl2, rt; (ii) H2, Pd(OH)2 (10%), MeOH, rt.
1ꢀ-Benzyl-6-chlorospiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3d
Yellowish oil (95%). (Found: C 70.34, H 5.96, N 3.85. Calc. for
C20H20ClNO2: C 70.27, H 5.90, N 4.10%). δH (CDCl3, 250 MHz) 1.69
(2H, ddd, J 13.5, 9.6, 4.6), 1.93–2.00 (2H, m), 2.38 (2H, td, J 11.4, 2.5),
2.53–2.61 (2H, m), 2.65 (2H, s), 3.48 (2H, s), 6.90 (1H, d, J 8.8), 7.19–
7.27 (5H, m), 7.36 (1H, dd, J 2.6, 8.8), 7.75 (1H, d, J 2.7). m/z (ES–MS)
342 [M + 1]+.
Waters Micromass ZMD spectrometer by direct injection of the sample
solubilizedinacetonitrile. MicroanalyseswerecarriedoutbytheService
Central d’Analyses du CNRS (Venaison, France) and were within 0.4%
of theoretical values. Analytical thin layer chromatography (TLC) and
preparative thin layers chromatography (PLC) were performed using sil-
ica gel plates 0.2 mm thick and 1 mm thick respectively (60F254 Merck).
Preparative flash column chromatography was carried out on silica gel
(230–240 mesh, G60 Merck).
1ꢀ-Benzyl-6-fluorospiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3e
Yellow solid (38%), mp 88–89◦C. (Found: C 73.85, H 6.14, N 4.42. Calc.
for C20H20FNO2: C 73.83, H 6.20, N 4.30%). δH (CDCl3, 250 MHz)
1.70 (2H, ddd, J 13.5, 9.6, 4.6), 1.92–2.04 (2H, m), 2.46 (2H, td,
J 11.4, 2.5), 2.52–2.59 (2H, m), 2.69 (2H, s), 3.47 (2H, s), 7.13 (2H,
m), 7.21–7.29 (5H, m), 7.41 (1H, dd, J 8.8, 2.6). m/z (ES–MS) 326
[M + 1]+.
Typical Procedure for Synthesis of 2,3-Dihydrochromanone:
1ꢀ-Benzylspiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3f
Compound 3f was obtained by refluxing 2ꢀ-hydroxyacetophenone 1f
(2 g, 14.6 mmol) with N-benzyl-piperidone 2 (3.3 mL, 14.6 mmol) in
methanol (20 mL), in the presence of a catalytic amount of pyrroli-
dine (0.6 mL, 7.3 mmol). The resulting mixture was extracted with ethyl
acetate (3 × 50 mL). The organic layer was dried (MgSO4) and con-
centrated to give a yellow oil. Purification was carried out by flash
silica gel chromatography using cyclohexane/ethyl acetate (3:1, v/v) as
eluent to give product 3f as yellow solid (4.1 g, 91%), mp 99–101◦C.
(Found: C 78.32, H 6.97, N 4.43. Calc. for C20H21NO2: C 78.15, H 6.89,
N 4.56%). δH (CDCl3, 250 MHz) 1.75 (2H, ddd, J 13.5, 9.6, 4.6), 2.02–
2.07 (2H, m), 2.46 (2H, td, J 11.4, 2.5), 2.61–2.66 (2H, m), 2.72 (2H, s),
3.56 (2H, s), 6.96–7.03 (2H, m), 7.26–7.38 (5H, m), 7.46–7.52 (1H, m),
7.86–7.90 (1H, m). m/z (ES) 308 [M + H]+.
1ꢀ-Benzyl-7-methoxyspiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3g
Yellow oil (86%). (Found: C 74.55, H 6.72, N 4.23. Calc. for
C21H23NO3: C 74.75, H 6.87, N 4.15%). δH (CDCl3, 250 MHz) 1.75
(2H, ddd, J 13.5, 9.6, 4.6), 2.00–2.05 (2H, m), 2.46 (2H, td, J 11.4, 2.5),
2.58–2.61 (2H, m), 2.65 (2H, s), 3.54 (2H, s), 3.85 (3H, s), 6.45 (1H, d,
J 2.4), 6.54 (1H, dd, J 8.6, 2.4), 7.25–7.32 (5H, m), 7.79 (1H, d, J 8.8).
m/z (ES–MS) 338 [M + 1]+.
1ꢀ-Benzyl-6-nitrospiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3h
Yellow oil (85%). (Found: C 68.01, H 5.94, N 8.19. Calc. for
C22H20N2O4: C 68.17, H 5.72, N 7.95%). δH (CDCl3, 250 MHz) 1.84
(2H, ddd, J 13.5, 9.6, 4.6), 2.03–2.09 (2H, m), 2.48 (2H, td, J 11.4, 2.5),
2.64–2.71 (2H, m), 2.81 (2H, s), 3.57 (2H, s), 7.12 (1H, dd, J 8.9, 3.1),
7.25–7.35 (5H, m), 8.36 (1H, dd, J 9.1, 2.8), 8.75 (1H, d, J 2.8). m/z
(ES–MS) 353 [M + 1]+.
1ꢀ-Benzyl-6-methoxyspiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3a
Yellowish oil (60%). (Found: C 74.55, H 6.72, N 4.23. Calc. for
C21H23NO3: C 74.75, H 6.87, N 4.15%). δH (CDCl3, 250 MHz) 1.75
(2H, ddd, J 13.5, 9.6, 4.6), 2.02–2.07 (2H, m), 2.46 (2H, td, J 11.4, 2.5),
2.63 (2H, dt, J 11.6, 3.8), 2.72 (2H, s), 3.56 (2H, s), 3.82 (3H, s), 6.94
(1H, d, J 9.0), 7.12 (1H, dd, J 8.9, 3.1), 7.29–7.36 (6H, m). m/z (ES–MS)
338 [M + 1]+.
Typical Procedure for the Synthesis of Oximes:
1ꢀ-Benzylspiro[chromene-2,4ꢀ-piperidin]-4(3H)-one Oxime 4f
Compound 3f (3.1 g, 10 mmol) was refluxed for 3 h with hydroxylamine
hydrochloride (1.4 g, 20 mmol), anhydrous ethanol (50 mL), and pyri-
dine (1.6 mL, 20 mmol). After cooling, the reaction mixture was poured
into water; the precipitate was then recrystallized from dilute ethanol to
give the oxime almost quantitatively, mp 229–231◦C. (Found: C 74.56,
H 6.95, N 8.44. Calc. for C20H22N2O2: C 74.51, H 6.88, N 8.69%).
δH ([D6]DMSO, 250 MHz) 1.99–2.16 (4H, m), 2.78 (2H, s), 3.12–3.14
(4H, m), 4.31–4.35 (2H, m), 6.93–6.98 (2H, m), 7.24–7.33 (6H, m),
7.74 (1H, d, J 8.7), 11.16 (1H, s). m/z (ES–MS) 323 [M + 1]+.
1ꢀ-Benzyl-6-methylspiro[chromene-2,4ꢀ-piperidin]-4(3H)-one 3b
Yellow solid (65%), mp 96–97◦C. (Found: C 78.32, H 7.17, N 4.26. Calc.
for C21H23NO2: C 78.47, H 7.21, N 4.36%). δH (CDCl3, 250 MHz)
1.69 (2H, ddd, J 13.5, 9.6, 4.6), 1.94 (2H, m), 2.22 (3H, s), 2.43 (2H, td,
J 11.4, 2.5), 2.57–2.60 (2H, m), 2.69 (2H, s), 3.45 (2H, s), 6.81 (1H, d,
J 8.4), 7.19–7.32 (5H, m), 7.68 (1H, d, J 8.7), 7.56 (1H, d, J 1.55). m/z
(ES–MS) 322 [M + 1]+.

816
Y. Laras et al.
1ꢀ-Benzyl-6-methoxyspiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4a
cyclohexane/ethyl acetate (3:1, v/v) as eluent to give product 1ꢀ-
benzyl-7-methoxyspiro[chromene-2,4ꢀ-piperidin]- 4(3H)-one-O-[tert-
butyl(dimethyl)silyl] oxime 4i as yellow oil (0.4 g, 80%). (Found: C
69.76, H 8.44, N 5.68. Calc. for C27H38N2O3Si: C 69.49, H 8.21, N
6.00%). δH (CDCl3, 250 MHz) 0.26 (6H, s), 1.00 (9H, m), 1.68–1.79
(2H, m), 1.88–2.04 (2H, m), 2.40–2.45 (2H, m), 2.61–2.68 (2H, m),
2.87 (2H, s), 3.59 (2H, s), 3.84 (3H, s), 6.46 (1H, d, J 2.2), 6.55 (1H, dd,
J 8.7, 2.3), 7.26–7.38 (5H, m), 7.83 (1H, d, J 8.8). m/z (ES–MS) 467
[M + 1]+.
White solid (72%), mp 279–280◦C. (Found: C 71.61, H 6.92, N 8.05.
Calc. for C21H24N2O3: C 71.57, H 6.86, N 7.95%). δH ([D6]DMSO,
250 MHz) 1.93–2.13 (4H, m), 2.75 (2H, s), 3.02–3.16 (4H, m), 3.71
(3H, s), 4.39–4.42 (2H, m), 6.92–6.94 (2H, m), 7.22–7.26 (2H, m), 7.44
(3H, m), 7.70 (1H, m), 11.47 (1H, s). m/z (ES–MS) 353 [M + 1]+.
1ꢀ-Benzyl-6-methylspiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4b
Typical Procedure for the Synthesis of Secondary Anilines:
White solid (93%), mp 268–269◦C. (Found: C 75.23, H 7.17, N 8.61.
Calc. for C21H24N2O2: C 74.97, H 7.19, N 8.33%). δH ([D6]DMSO,
250 MHz) 1.95–2.07 (4H, m), 2.15 (3H, s), 2.39–2.43 (2H, m), 6.86
(2H, s), 2.97–3.10 (4H, m), 6.79 (1H, d, J 8.3), 7.01 (1H, dd, J 8.5, 1.9),
7.29–7.41 (3H, m), 7.48–7.50 (1H, m), 7.58 (2H, m), 12.03 (1H, s). m/z
(ES–MS) 337 [M + 1]+.
1ꢀ-Benzyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4ꢀ-piperidine] 5f
Oxime4f (3 g, 9.3 mmol)wassolubilizedinanhydrousdichloromethane
(20 mL). The mixture was stirred at 0◦C for 30 min, and diisobutylalu-
minium hydride in dichloromethane (54 mL, 1 M, 54 mmol) was added
dropwise during 1 h. The mixture was stirred for 3 h under nitrogen at
0◦C. The reaction was quenched by slowly adding MeOH (9 mL), fol-
lowed by distilled water (9 mL) and 20% sulfuric acid (50 mL). The
solution was stirred for a further 20 min. The solution was basified to
pH 9 using 30% sodium hydroxide solution. The resulting mixture was
extracted with ethyl acetate (2 × 100 mL). The organic layer was dried
(MgSO4) and concentrated to give a yellow oil.The residue was purified
by chromatography on alumina with cyclohexane/ethyl acetate (1:1, v/v)
to give product 5f as yellow oil (1.5 g, 52%). (Found: C 78.04, H 7.88,
N 9.25. Calc. for C20H24N2O: C 77.89, H 7.84, N 9.08%). δH (CDCl3,
250 MHz) 1.69 (2H, ddd, J 13.5, 9.6, 4.6), 1.96 (2H, t, J 5.4), 2.06–2.11
(2H, m), 2.55 (2H, td, J 11.4, 2.5), 2.65 (2H, dt, J 11.6, 3.8), 3.30 (2H,
t, J 5.4), 3.62 (2H, s), 6.65 (1H, dd, J 1.5, 7.8), 6.78 (1H, td, J 7.8, 1.5),
6.91 (1H, td, J 7.8, 1.5), 7.20 (1H, dd, J 7.8, 1.5), 7.28–7.40 (5H, m).
m/z (ES–MS) 309 [M + 1]+.
1ꢀ-Benzyl-6-(benzyloxy)spiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4c
White solid (95%), mp 245–254◦C. (Found: C 75.71, H 6.54, N 6.25.
Calc. for C27H28N2O3: C 75.68, H 6.59, N 6.54%). δH ([D6]DMSO,
250 MHz) 2.02–2.07 (2H, m), 2.39–2.50 (2H, m), 2.95 (2H, s), 2.99–
3.13 (2H, m), 3.27–3.32 (2H, m), 4.20–4.21 (2H, m), 4.98 (2H, s),
6.74–6.77 (1H, m), 6.88–6.89 (1H, m), 7.29–7.52 (9H, m), 7.65–7.74
(2H, m), 12.03 (1H, s). m/z (ES–MS) 429 [M + 1]+.
1ꢀ-Benzyl-6-chlorospiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4d
White solid (76%), mp 259–260◦C. (Found: C 67.07, H 5.66, N 7.98.
Calc. for C20H21ClN2O2: C 67.32, H 5.93, N 7.85%). δH ([D6]DMSO,
250 MHz) 1.94–2.08 (4H, m), 2.78 (2H, s), 3.10–3.17 (4H, m), 4.31–
4.36 (2H, m), 7.00–7.04 (1H, m), 7.36–7.45 (4H, m), 7.64–7.69 (3H,
m), 11.67 (1H, s). m/z (ES–MS) 357 [M + 1]+.
1ꢀ-Benzyl-7-methoxy-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5a
Yellow oil (61%). (Found: C 74.68, H 7.57, N 8.41. Calc. for
C21H26N2O2: C 74.52, H 7.74, N 8.28%). δH (CDCl3, 250 MHz) 1.52
(2H, ddd, J 13.5, 9.6, 4.6), 1.81 (2H, t, J 5.4), 1.86–1.91 (2H, m), 2.40
(2H, td, J 11.4, 2.5), 2.50–2.55 (2H, m), 3.21 (2H, t, J 5.4), 3.47 (2H,
s), 3.64 (3H, s), 6.08 (1H, d, J 2.8), 6.16 (1H, dd, J 8.7, 2.9), 6.76 (1H,
d, J 8.7), 7.16–7.25 (5H, m). m/z (ES–MS) 339 [M + 1]+.
1ꢀ-Benzyl-6-fluorospiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4e
White solid (29%), mp 212–214◦C. (Found: C 70.71, H 6.18, N 8.17.
Calc. for C20H21FN2O2: C 70.57, H 6.22, N 8.23%). δH ([D6]DMSO,
250 MHz) 1.91–2.08 (4H, m), 2.37 (2H, m), 2.64 (4H, m), 3.46 (2H, s),
7.12–7.57 (8H, m), 11.56 (1H, s). m/z (ES–MS) 341 [M + 1]+.
1ꢀ-Benzyl-7-methyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5b
1ꢀ-Benzyl-7-methoxyspiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4g
Yellow solid (16%), mp 64–65◦C. (Found: C 78.32, H 8.38, N 8.77. Calc.
for C21H26N2O: C 78.22, H 8.13, N 8.69%). δH (CDCl3, 250 MHz) 1.52
(2H, ddd, J 13.5, 9.6, 4.6), 1.81 (2H, t, J 5.4), 1.86–1.91 (2H, m), 2.16
(2H, s), 2.40 (2H, td, J 11.4, 2.5), 2.51–2.56 (2H, m), 3.21 (2H, t, J 5.4),
3.47 (2H, s), 6.10–6.18 (2H, m), 6.76–6.78 (1H, m), 7.24–7.32 (5H, m).
m/z (ES–MS) 323 [M + 1]+.
White solid (88%), mp 279–280◦C. (Found: C 71.49, H 6.76, N 8.23.
Calc. for C21H24N2O3: C 71.57, H 6.86, N 7.95%). δH ([D6]DMSO,
250 MHz) 1.93–2.14 (4H, m), 2.74 (2H, s), 3.10–3.25 (4H, m), 3.76 (3H,
s), 4.33–4.43 (2H, m), 6.48–6.61 (2H, m), 7.43–7.47 (3H, m), 7.64–7.67
(3H, m), 11.16 (1H, s). m/z (ES–MS) 353 [M + 1]+.
1ꢀ-Benzyl-7-(benzyloxy)-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5c
1ꢀ-Benzyl-6-nitrospiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4h
Yellow solid (52%), mp 101–103◦C. (Found: C 78.14, H 7.11,
N 6.54. Calc. for C27H30N2O2: C 78.23, H 7.29, N 6.76%). δH (CDCl3,
250 MHz) 1.66 (2H, ddd, J 13.5, 9.6, 4.6), 1.93 (2H, t, J 5.4), 2.02–2.06
(2H, m), 2.50–2.70 (2H, m), 2.29–2.39 (2H, m), 3.28 (2H, t, J 5.4), 3.61
(2H, s), 4.98 (2H, s), 6.29–2.30 (1H, d, J 2.8), 6.39 (1H, dd, J 8.5, 2.8),
6.91 (1H, d, J 8.7), 7.29–7.49 (10H, m). m/z (ES–MS) 415 [M + 1]+.
White solid (81%), mp 230–231◦C. (Found: C 65.57, H 5.69, N 11.62.
Calc. for C20H21N3O4: C 65.38, H 5.76, N 11.44%). δH ([D6]DMSO,
250 MHz) 2.00–2.25 (4H, m), 3.13–3.58 (8H, m), 7.25 (1H, d, J 9.1),
7.44–7.47 (3H, m), 7.65–7.74 (2H, m), 8.25 (1H, dd, J 9.1, 2.8), 8.56
(1H, d, J 2.7), 11.90 (1H, s). m/z (ES–MS) 368 [M + 1]+.
Typical Procedure for the Silylation of Oximes: 1ꢀ-Benzyl-
7-methoxyspiro[chromene-2,4ꢀ-piperidin]-4(3H)-one-
O-[tert-butyl(dimethyl)silyl] Oxime 4i
1ꢀ-Benzyl-7-chloro-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5d
Yellow oil (32%). (Found: C 70.19, H 6.82, N 8.37. Calc. for
C20H23ClN2O: C 70.06, H 6.76, N 8.17%). δH (CDCl3, 250 MHz) 1.66
(2H, ddd, J 13.5, 9.6, 4.6), 1.92 (2H, t, J 5.4), 1.97–2.02 (2H, m), 2.50
(2H, td, J 11.4, 2.5), 2.63–2.68 (2H, m), 3.28 (2H, t, J 5.4), 3.60 (2H,
s), 6.60 (1H, d, J 2.6), 6.68 (1H, dd, J 8.4, 2.4), 6.89 (1H, d, J 6.5),
7.30–7.39 (5H, m). m/z (ES–MS) 343 [M + 1]+.
To a stirred solution of 4g (0.40 g, 1.1 mmol) and tert-butyldimethylsilyl
chloride (TBDMS-Cl) (0.17 g, 1.1 mmol) in CH2Cl2 (10 mL) was
added dropwise a solution of imidazole (0.15 g, 2.2 mmol) in CH2Cl2
at room temperature. The reaction was left overnight with stirring.
Purification was carried out by flash silica gel chromatography using

Spiro-benzoxazepine-piperidine and Biological Properties
817
1ꢀ-Benzyl-7-fluoro-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5e
slowly added, and the reaction mixture was refluxed at 70◦C for 1 h.
The reaction mixture was extracted with CH2Cl2 (3 × 10 mL), and the
aqueous phase was basified with aqueous NaOH (2 N), extracted with
CH2Cl2 (3 × 10 mL), washed with brine (7 mL), and dried with anhy-
drous MgSO4.The solution was filtered and concentrated under reduced
pressure. The crude product was analyzed by MS and purified by flash
chromatography (CH2Cl2/MeOH 95:5) to give the compounds 6g, 7g
in less than 2% yield. For 6g, m/z (ESI–MS) 337 [M + H]+, and 7g, m/z
(ESI–MS) 339 [M + H]+.
Yellow oil (40%). (Found: C 73.42, H 6.89, N 8.22. Calc. for
C20H23FN2O: C 73.59, H 7.10, N 8.58%). δH (CDCl3, 250 MHz) 1.68
(2H, ddd, J 13.5, 9.6, 4.6), 1.95 (2H, t, J 5.4), 1.99–2.07 (2H, m), 2.35
(2H, td, J 11.4, 2.5), 2.63–2.68 (2H, m), 3.28 (2H, t, J 5.4), 3.46 (2H,
s), 6.95 (1H, dd, J 8.6, 4.8), 7.15 (1H, m), 7.22–7.31 (5H, m), 7.42 (1H,
dd, J 9.6, 2.8), 11.64 (1H, s). m/z (ES–MS) 327 [M + 1]+.
1ꢀ-Benzyl-8-methoxy-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5g
Procedure for Inhibition Assay
HIV-1 Aspartate Protease Assay
Yellow oil (2.5%). (Found: C 74.63, H 7.41, N 8.34. Calc. for
C21H26N2O2: C 74.52, H 7.74, N 8.28%). δH (CDCl3, 250 MHz) 1.63–
1.75 (2H, m), 1.88–2.04 (4H, m), 2.44–2.57 (2H, m), 2.59–2.73 (2H,
m), 3.15 (2H, t, J 5.4), 3.62 (2H, s), 3.72 (3H, s), 6.45 (1H, dd, J 9.6,
2.8), 6.53 (1H, d, J 2.6), 6.60 (1H, d, J 8.6), 7.24–7.37 (5H, m). m/z
(ES–MS) 339 [M + 1]+.
In the assay for HIV-protease inhibition, the enzyme was preincu-
bated for 10 min at 37◦C with inhibitor by adding an aliquot (10 µL)
of the inhibitor in DMSO to the enzyme (20 µL of a 0.294-µM solu-
tion) in buffer (370 µL, 0.05 M NaOAc, pH 4.9, 0.2 M NaCl, 0.005 M
DTT, 10% v/v glycerol). Percentage of inhibition was spectrophotomet-
rically measured (λ 300 nm) on a Uvikon 930 spectrophotometer by
adding an aliquot of the substrate solution (20 µL of a 573-µM solution
of H–His–Lys–Ala–Arg–Val–Leu–pNO2Phe–Glu–Ala–Nle–Ser–NH2)
to the enzyme-inhibitor solution in a cuvette. Amprenavir was used as
reference inhibitor.
Typical Procedure for Lithium Aluminum Hydride Reduction
To a swirling suspension of 0.20 mg of LiAlH4 in 10 mL of ether, a
solutionofoximes(4a, 4g)(0.2 g, 0.5 mmol)in10 mLofetherwasadded
dropwise at room temperature. The solution was then allowed to stand
overnight at room temperature. The reaction mixture was decomposed
with water under cooling with ice. The ether layer was washed with 1 N
sodium hydroxide and water, then dried (MgSO4) and concentrated to
give oil. The residue was purified by chromatography on alumina with
cyclohexane/ethyl acetate (1:1, v/v) to give product 5a, 5g as yellow oil
(5a, 5%; 5g, 5%).
BACE-1 Enzymatic Assay
These experiments were performed using a BACE-1 (β-secretase)
FRET Kit assay (PanVera Corp.), according to the described protocol
and using a multiwell spectrofluorometer with 530–545 nm excita-
tion and 570–590 nm emission wavelengths (Victor2 1420, Wallac
Perkin Elmer). The procedure was as follows: substrate and enzyme
were diluted into the provided assay buffer (50 × 10−3 M Tris, pH
7.5, 10% glycerol) according to the described protocol. Each inhibitor
was diluted in DMSO at the desired concentration. The substrate
(Rh-EVNLDAEFK-Quencher, 10 µL of the main solution) and each
inhibitor (1 µL of the corresponding solution) were introduced in a
96-well flat bottom black polystyrene plate (Corning). The resulting
mixtures were gently mixed and 10 µL of the enzyme solution was
then added to each well to start the reaction. The reaction mixtures
were incubated at 25◦C for 90 min and the fluorescence was moni-
tored at 530–545 nm (excitation wavelength) and 570–590 nm (emis-
sion wavelength). The kinetic assays were performed in duplicate for
each inhibitor, using BACE-1 inhibitor (H–Lys–Thr–Glu–Glu–Ile–Ser–
Glu–Val–Asn–3S,4S–Stat–Val–Ala–Glu–Phe–OH, IC50 30 × 10−9 M,
Calbiochem) as reference (positive control, 100% inhibition at 1 µM),
DMSO alone as negative control (no inhibition). The provided BACE-1
product standard (Rh-EVNL) was used as control for the enzyme cleav-
age, 15% cleavage of the substrate was obtained after 90 min of reaction
at 37◦C.
4,5-Dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidin]-7-ol 5j
To a suspension of 5a (0.62 mg, 1.8 mmol) in 15 mL of CH2Cl2 and
cooled to 0◦C a 1 M solution of BBr3 in dichloromethane (5.5 mL) was
slowly added dropwise, and the solution was stirred at room temperature
for 48 h. The organic layer was washed successively by H2O (10 mL),
brine (10 mL), 5% aqueous NaHCO3 (2 × 10 mL), then brine (10 mL),
and was dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(CH2Cl2/MeOH 95:5) to give the intermediate compound as white oil
(204 mg, 34%). (Found: C 73.82, H 7.76, N 8.53. Calc. for C20H24N2O2:
C 74.04, H 7.46, N 8.64%). δH (CDCl3, 250 MHz) 1.64 (2H, ddd, J 13.5,
9.6, 4.6), 1.87 (2H, t, J 5.4), 1.93–2.03 (2H, m), 2.53 (2H, td, J 11.4,
2.5), 2.56–2.68 (2H, m), 3.17 (2H, t, J 5.4), 3.62 (2H, s), 6.13 (1H, dd,
J 8.5, 2.8), 6.21 (1H, d, J 2.9), 6.66 (1H, d, J 8.6), 7.28–7.36 (5H, m).
m/z (ES–MS) 325 [M + 1]+.
To a stirred suspension of the previous N-benzyl compound (0.1 g,
0.42 mmol) in dry methanol (10 mL), was added an equal weight of
10% Pd(OH)2 under H2. The resulting mixture was stirred at room
temperature, and the reaction was monitored by TLC. After comple-
tion, the catalyst was removed by filtration through Celite and washed
with methylene chloride (10 mL). The residue was purified by flash
chromatography (CH2Cl2/MeOH 95:5) to give the desired compound
5j in quantitative yield. (Found: C 66.82, H 7.61, N 12.07%. Calc. for
C13H18N2O2: C 66.64, H 7.74, N 11.96%). δH (CD3OD, 250 MHz) 1.51
(2H, ddd, J 4.5, 11.5, 13.5), 1.87–1.94 (4H, m), 2.80 (2H, m), 3.05 (2H,
ddd, J 2.8, 11.5, 12.3), 3.19 (2H, t, J 5.4), 6.14 (1H, dd, J 2.8, 8.5), 6.21
(1H, d, J 2.9), 6.72 (1H, d, J 8.6). m/z (ES–MS) 235 [M + H]+.
Acknowledgment
Professor K. Dudley is greatly acknowledged for assistance
with manuscript preparation.
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