Preparation of highly substituted 7-oxa-1-azabicyclo[2.2.1]heptanes from 4-nitro-1-butene derivatives. Route to polysubstituted piperidines

Article abstract of DOI:10.1016/S0040-4020(01)00021-7

4-Nitro-1-butene derivatives 2 readily available from the palladium(0)-catalyzed C-allylation of nitroalkanes were converted into highly substituted 7-oxa-1-azabicyclo[2.2.1]heptane derivatives 6 in three steps including an intramolecular 1,3-dipolar cycloaddition reaction. Catalytic hydrogenolysis of the N-O bond in 6 afforded polysubstituted 4-hydroxypiperidines.

Full text of DOI:10.1016/S0040-4020(01)00021-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2021±2030
Preparation of highly substituted
7-oxa-1-azabicyclo[2.2.1]heptanes from 4-nitro-1-butene
derivatives. Route to polysubstituted piperidines
p
Â
Anna Budzinska and Wojciech Sas
Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland
Received 4 September 2000; revised 6 December 2000; accepted 21 December 2000
AbstractÐ4-Nitro-1-butene derivatives 2 readily available from the palladium(0)-catalyzed C-allylation of nitroalkanes were converted
into highly substituted 7-oxa-1-azabicyclo[2.2.1]heptane derivatives 6 in three steps including an intramolecular 1,3-dipolar cycloaddition
reaction. Catalytic hydrogenolysis of the N±O bond in 6 afforded polysubstituted 4-hydroxypiperidines. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
dine.13 The idea of applying 4-nitrobut-1-enes for the
synthesis of piperidine derivatives seemed to be very
attractive due to its simplicity and the fact that these nitro
compounds, aside from Tufariello's approach,13 could be
conveniently prepared with vast structural diversity from
palladium(0)-catalyzed C-allylation of nitroalkanes.15±20 In
a preliminary communication we reported the utility of this
strategy for the synthesis of highly substituted piperidine
derivatives, e.g. cis-2,2-bis(hydroxymethyl)-4-hydroxy-2-
phenylpiperidine.21 Herein we describe details of this
methodology. Polyhydroxylated piperidines are potent
inhibitors of various glycosidases,22 and in order to obtain
structurally similar compounds we utilized 5-allylic deriva-
tives of 5-nitro-1,3-dioxane as the basic starting materials.
N-(3-alkenyl)nitrones readily undergo intramolecular 1,3-
dipolar cycloaddition to give 7-oxa-1-azabicyclo[2.2.1]hep-
tane derivatives in high yield and stereoselectivity.1±12 Since
these adducts are smoothly converted into piperidine
derivatives via reductive cleavage of the N±O bond, access
to the N-(3-alkenyl)nitrones or hydroxylamines opens the
route to piperidine derivatives.1,4±6,8,10 There are a few
useful methods for preparation of these unsaturated
nitrones. Usually nitrones are obtained from N-substituted
hydroxylamines and carbonyl derivatives. However, the key
problem in the application of this approach for preparation
of the unsaturated nitrones is the synthesis of the corre-
sponding N-homoallylhydroxylamines, which may be
prepared from a sodium cyanoborohydride reduction of
oximes of b,g-unsaturated aldehydes2,3 which are not
readily available, or from the addition of allylic boronates
to aldoximes.4±6 Some N-(3-alkenyl)nitrones may be
obtained from N-homoallylation of salts of Z-aldoximes1,9,11
and Michael addition of oximes to 1,3-butadienes substi-
tuted at the 2 and 3 positions with electron-withdrawing
groups.7±10 Allylation of the salts of acidic nitrones has
also been used for preparation of N-(3-alkenyl)nitrones.12
2. Results and discussion
The allylation of sodium salt of 5-nitro-2,2-pentamethylene-
1,3-dioxane23 1 and 2-nitropropane was carried out in the
presence of palladium(0) catalyst, generated in situ from
bis(triphenylphosphine)palladium(II) chloride and tri-
phenylphosphine
15
(Scheme 1, Table 1) or 1,2-bis-
(diphenylphosphino)ethane. The latter phosphine only
appeared to be better than the former for the preparation
of 3c, giving more pure product. Allyl acetate was used
for the preparation of 3a and 3e while to obtain derivatives
3b±3d, substituted at the double bond, the corresponding
commercial allylic chlorides were employed.17 For cin-
namylation of 1, both cinnamyl chloride and acetate were
used, furnishing 3d in 52 and 76% yield, respectively.
Crotylation of 1 with crotyl chloride (mixture of E/Z
isomers) afforded 3b as the inseparable E/Z mixture in an
85:15 ratio.
Tufariello and Trybulski have shown that N-homoallyl-
hydroxylamines may be prepared from the unsaturated
nitro derivatives, in which the 4-nitrobut-1-ene moiety
may be found. These authors reduced 7,7-dimethoxy-4-
nitrohept-1-ene to 7,7-dimethoxyhept-1-en-4-hydroxyl-
amine, which was converted into pseudotropine via the
cyclic unsaturated nitrone followed by tricyclic isoxazoli-
Keywords: nitrocompounds; nitrones; cycloaddition; piperidines.
Corresponding author. Fax: 148-22-628-2741; e-mail: sas@ch.pw.edu.pl
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00021-7

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2022
Scheme 1.
Table 1. Yields of allylic derivatives 3
(Table 3, entries 1 and 2), compared to the yield of 6ab,
were somewhat lower. However, in the case of 6bb the
decrease in yield might be partially caused by the con-
tamination of (E)-3b with the Z isomer. In contrast to
other compounds 4, the reaction of 4d with benzaldehyde
and paraformaldehyde gave the mixture of regioisomers 6d
and 7d in a 3:1 ratio (Table 3, entries 3 and 4).§ However,
heating 4d with formaldehyde (obtained from the triethyl-
amine-catalyzed depolymerization of paraformaldehyde) in
boiling n-propanol furnished the 6da/7da mixture in a 1:1
ratio. This result showed that the selectivity of the cyclo-
addition depends upon the substitution type of double bond
but not of the nitrone part. Oppolzer and co-workers also
reported a decrease in the selectivity of the intramolecular
cycloaddition of N-(4-phenyl-3-butenyl)nitrone, which
heated in boiling toluene gave a 7:1 mixture of the less
substituted analogues of 6da and 7da, respectively.2,3
Entry
Allylating agent
3
R1
R2
Yield (%)
1
2
3
4
5
Allyl acetate
a
b
c
d
d
H
Me
H
Ph
Ph
H
H
Me
H
H
75
75b
65c
52
Crotyl chloridea
Methallyl chloride
Cinnamyl acetate
Cinnamyl chloride
76
a
Mixture of E and Z isomers.
(E)-3b and (Z)-3b in ratio 85:15, respectively.
Obtained in the presence of 1,2-bis(diphenylphosphino)ethane.
b
c
Initially, we reduced 3a using the zinc±acetic acid system in
methanol, and crude 4a was converted to the corresponding
nitrone 5, which without any puri®cation was transformed
into the bicyclic adduct 6 by heating in boiling toluene.21
However, we later discovered that the yields of 6 were not
reproducible and the reduction of 3 was responsible for
these results. In addition, the zinc reduction failed to give
4d. All reduction problems disappeared when we employed
aluminum amalgam in wet THF24 for the preparation of 4.
Next we examined whether isolation of the nitrone 5 was
necessary. In order to test this, we prepared 6ab in two
ways. Firstly, crude 4a was heated with benzaldehyde in
boiling toluene to afford 6ab in 61% (for comparison the
best yield of 6ab was 43% when zinc was utilized for the
reduction). After that, 6ab was prepared from the nitrone
5ab, which was obtained as single isomer, presumably Z, in
75% yield calculated on 3a. Heating of 5ab in boiling
toluene furnished 6ab in 85% yield (overall yield was
62%). Since both procedures gave 6ab in almost identical
yields (calculated on 3a), we therefore used the simpler one-
pot protocol to prepare 6 throughout this work.
The structures of the cycloadducts 6 and 7 were derived
from their H NMR spectra, which are generally similar to
1
the spectra of 7-oxa- and 2-oxa-1-azabicyclo[2.2.1]heptane
derivatives, respectively, described in literature.1,3,5,8 Thus
all 6a (R1ˆR2ˆH), as well as 5-substituted derivatives
(6bb, 6da and 6db), display the H-4 proton as a `triplet'
and doublet, respectively, at dˆ4.80±4.95 ppm. All 6a
(R1ˆR2ˆH) and 6cb show long range coupling (ca.
2.5 Hz) between H-3ex and H-5ex, being in the planar
`W' arrangement. In contrast, both 7da and 7db show a
singlet for H-3 at low ®eld. All these ®ndings indicate that
R1 substituents occupy the exo position in 6 as well as 7. The
exo position of R3 in all 6a is evident from the fact that the
coupling constant J6,5ex (4.0±4.8 Hz) is smaller than J6,5en
(7.6±8.4 Hz). For both 6bb and 6db the coupling constants
between protons H-6 and H-5 (J6,5ˆ8.2 Hz) fall in the range
of values characteristic for an endo±endo interaction, there-
fore both R1 and R3 occupy the exo position.
²
Thus, heating of crude 4 with various aldehydes (0.8 equiv.
with respect to 3) in boiling toluene usually gave the
bicyclic isoxazolidines 6 and very occasionally the 6/7
mixtures in satisfactory yields (Scheme 2, Tables 2 and
3). The reaction of 4a±c and 4e afforded only 7-oxa-1-
azabicyclo [2.2.1]heptanes 6, in which R3 occupied the
The observed regio- and stereoselectivity of the 1,3-dipolar
cycloadditions of N-(3-alkenyl)-nitrones 5 are consistent
with literature ®ndings.3,8 Thus, for the intramolecular 1,3-
dipolar cycloaddition of 5, two transition states TS-A and
TS-B (Scheme 3) leading to regioisomers 6 and 7, respec-
tively, are feasible.
³
exo position. This new procedure appeared to be bene®cial
for the preparation of 6aa (Table 2, entry 1), which could
not be obtained when zinc was used for the reduction of 3a.
We reasoned that in this case the pollution of crude 5aa with
acetic acid might be responsible for this failure. Indeed, the
reaction of 4a, obtained from the aluminum reduction, with
formaldehyde, conducted in the presence of acetic acid,
afforded a mixture of products. The yields of 6bb and 6cb
It has been shown that due to angle strain TS-B is much
higher in energy than TS-A, therefore 7-oxa-1-azabicyclo-
[2.2.1]heptane derivatives are formed as the sole or the
major products.3,8 Deviations from complete selectivity
are fortunately rare and have been observed only by the
Oppolzer group and by us for the reaction of the nitrones
of the type 5d. We assume that the decrease of selectivity
²
Ketones did not react with 4a.21
³
In one experiment the reaction of `aluminum'-4a with 2-thiophenecar-
boxaldehyde gave mixture of exo/endo stereoisomers of 6ak (R3ˆ2-thie-
nyl). Our attempts to repeat this result failed and in all other experiments
only exo 6ak was isolated.
§
The 6db/7db mixture was inseparable by chromatography.

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2023
Scheme 2.
Table 2. Yields of 7-oxa-1-azabicylo[2.2.1]heptanes 6a (R1ˆR2ˆH)
with the fact that only the (Z)-nitrones undergo the cyclo-
addition.3 The exo position of the R1group in both cyclo-
adducts 6 and 7 is a consequence of E-con®guration of
double bond.
Entry
R3
No
Yielda (%)
1
2
3
4
5
6
7
8
H
C6H5
p-FC6H4
p-CF3C6H4
2-CH3OC6H4
3,4-(CH3O)2C6H3
(E)-C6H5CHvCH
C6H5CH2
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
56b
61
36
56
33
35
55
42
51
63
67
Having secured access to the bicyclic isoxazolidines 6 we
examined their conversion into piperidine derivatives
(Scheme 4, Table 4). Since the N±O bond in 7-oxa-1-azabi-
cyclo[2.2.1]heptanes 6 is in a more crowded environment
than the N±O bond in the analogous compounds described
in literature, transformation of 6 into piperidines appeared to
be more dif®cult than we might have expected based on
reported data. We have already discovered21 that the N±O
bond could not be cleaved by zinc in an acidic medium4±6 or
by molybdenum hexacarbonyl.27 Thus the best method of
converting 6 into piperidine derivatives was catalytic hydro-
genolysis carried out in the presence of 10% palladium on
charcoal 1,4±6,8 or Raney nickel. The latter catalyst was used
when the palladium-catalyzed reduction was very slow or
failed.
9
10
11
3-Pyridyl
2-Pyridyl
2-Thienyl
6aj
6ak
a
Calculated on 3a.
The reaction was carried out in n-propanol.
b
Table 3. Yields of isoxazolidines 6 and 7 (R1±R2)
Entry
No
R1
R2
R3
Yield (%)
1
2
3
6bb
6cb
6da
7da
6db
7db
CH3
H
C6H5
H
CH3
H
C6H5
C6H5
H
42
49
44a
15a
50b
17b
The 6-alkyl derivatives 6 underwent the N±O bond cleavage
slower than the corresponding 6-aryl derivatives. However,
for 6-phenyl derivatives 6 the hydrogenolysis of the N±O
bond competes with the benzylic cleavage of the N±C bond.
The benzylic cleavage problem was overcome by the addi-
tion of sodium borohydride to the palladium-catalyzed
hydrogenation.¶ In this way all the 6-phenyl derivatives 8
were obtained. The isoxazolidine 6ag (R3ˆ2-phenylethe-
nyl) could be transformed only into piperidine 8ag (R3ˆ2-
phenylethyl) since the hydrogenation of the double bond
was much easier than the N±O cleavage. Thus, to obtain
8ag the reduction of 6ag was carried out in the presence of
Raney nickel at elevated temperature and under 8 bar
pressure. We also failed to split the N±O bond in 6ag by
lithium aluminum hydride in boiling THF. The derivative
6aj underwent reduction sluggishly and the piperidine 9aj
was obtained, after deprotection (see below), in only 37%
4
C6H5
H
C6H5
a
The 6da/7da ratio was 1:1 for the reaction carried out in propanol.
Ratio 6/7 determined from H NMR spectra.
b
1
for 5da and 5db is caused by unfavorable substitution
pattern of the double bond. In both 5da and 5db the
dipolarophile part might be regarded as a 1-alkyl-2-pheny-
lethylene, where the dipolarophile±dipole connection is
considered as an alkyl substituent. This type of alkene
undergoes the intramolecular 1,3-dipolar cycloaddition to
nitrones, to afford 4-alkyl-5-phenylisoxazolidines as the
major product.25 So, the substitution effect favoring, in
contrast to the strain factor, the formation of 7da and 7db,
possessing the 4-alkyl-5-phenylisoxazolidine subunit,
lowers the selectivity of the cycloaddition. Luckily for
other nitrones 5 (except 5bb)k the substitution26 and strain
effect cooperate and only derivatives 6 arise. In the case of
5bb the substitution effect are `neutral' from the selectivity
point of view and strain factor means that also only 6bb is
formed. The formation of 6 having exo R3 as well as 7db
possessing the structure shown in Scheme 2 is consistent
¶
We discovered the in¯uence of sodium borohydride on the selectivity of
hydrogenolysis of 6ab by accident. Inspired by referee we performed
additional experiments to explain how sodium borohydride acts. So
based on literature data28 we assumed that sodium borohydride might
work just as a base, increasing pH of the reaction mixture. Indeed, the
hdrogenolysis of 6ab carried out in the presence of 10% palladium on
charcoal in methanol is also selective if pH of the reaction mixture was
increased up to 9 with the addition of sodium hydroxide. In addition we
found out that the rise of the pH to 10 impedes both N±O and the benzylic
hydrogenolysis.
k
The dipolarophile-dipole bridge in nitrones 5a, 5bb and 5cb is also trea-
ted as an alkyl substituent.

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2024
Scheme 3.
Scheme 4.
Table 4. Yield of the piperidines 8 and 9
triplets' with a large axial±axial coupling constant
(Jˆ11.1±12.0 Hz) and a smaller one (Jˆ4.2±4.5 Hz) for
the axial±equatorial couplings. Proton H-6 is coupled with
protons H-5e and H-5a by 2.2±2.8 and 11.5±12.3 Hz,
respectively. In addition, the H-3e and H-5e protons being
in a planar `W' arrangement are coupled by 4Jˆ2.0±2.5 Hz.
The all-cis con®guration of the piperidine 9bb requires that
in the chair conformation the methyl group has an axial
Entry No R1
R2
R3
Catalyst
Yield (%)a
1
2
3
4
5
6
7
8
9aa
9ab
8ag
9ah
9aj
8ak
9bb CH3
9cb
H
H
H
H
H
H
H
H
Ph
10% Pd±C
10% Pd±C±NaBH4
87
74b
87
H
H
H
H
H
H
PhCH2CH2 Raney-Ni
PhCH2
10% Pd±C
10% Pd±C
2-Thienyl Raney-Ni±DMSO
81
2-Pyridyl
37c
73
1
Ph
10% Pd±C±NaBH4
10% Pd±NaBH4
73
87
orientation. The H NMR spectrum con®rms this fact; the
H
CH3 Ph
H-4 signal is doublet of triplets with coupling constant
J43aˆ12.3 Hz (doublet) and J4±3e<J4±5eˆ4.5±4.8 Hz,
respectively, while the resonance for H-6 is a doublet with
a coupling constant characteristic (J6±5eˆ2.5 Hz) of the
a
b
c
Based on 6.
Yield of intermediate 8ab was 85%.
Yield of intermediate 8aj was 49%.
Figure 1.
overall yield (Table 4, entry 5). To convert 2-thienyl
derivative 6ak into the piperidine 8ak it was necessary to
use Raney nickel. The reaction conditions depended on the
quality of the catalyst used; when old catalyst was employed
for the reduction of 6ak the piperidine 8ak was obtained
selectively at room temperature and under 8±9 bar pressure.
Freshly prepared catalyst (W2) was so active, however, that
to obtain 8ak, its activity had to be moderated by the
addition of DMSO.
axial±equatorial interaction. Long range coupling between
H-3e and H-5e is not observed for this derivative. The H
1
NMR spectrum of 9cb suggests that also this compound
exists in a chair conformation. Indeed, values of vicinal
coupling constants J6±5aˆ12.1 Hz and J6±5eˆ2.2 Hz are
characteristic for such a conformation. However, the deter-
mination of the 9cb conformation was based only on two
vicinal coupling constants. So it is possible that 9cb might
exist in a twist-boat conformation.pp In order to clarify this
ambiguity we measured NOE-diff spectra of 9cb (Fig. 1b).
Irradiation of the methyl group resulted in an enhancement
of the intensities of signals H-6 (1.8%), one hydroxymethyl
group (1.6%) and H-3e and H-5e protons (2.2%). Such a
NOE-diff spectrum is only possible when the chair confor-
mation is the dominating one.
Hydroxymethyl groups were readily deprotected by 5%
hydrochloric acid in methanol to afford the derivatives of
2,2-bis(hydroxymethyl)-4-hydroxypiperidine 9.
1H NMR spectra of the piperidines 8 and 9 were very similar
to the spectra described in literature for related piperidine
derivatives5±7 and the structures derived from these spectra
were consistent with the structures of the corresponding 6.
Thus 8 and 9 of the series `a' (R1ˆR2ˆH) have the cis
con®guration and in the chair conformation both the 4-OH
group and R3 occupy equatorial positions (Fig. 1a). Indeed,
the signal of the H-4 proton is nearly a regular `triplet of
In conclusion, we have demonstrated that 4-nitrobut-1-ene
derivatives prepared from the palladium(0) catalyzed
C-allylation of nitroalkanes are useful starting materials
ppMolecular modeling of 9cb by MM1 and AM1 calculation showed that
such twist-boat conformation is quite probable.

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2025
for the preparation of highly substituted piperidines via
intramolecular 1,3-dipolar cycloaddition reaction of N-(3-
alkenyl)nitrones.
99.14, 121.44, 128.52 (2). IR (neat): 3084, 2940, 1640,
1548, 1360, 1160, 1136 cm21; Anal. calcd for C12H19NO4:
C 59.73, H 7.94, N 5.81; found: C 59.90, H 7.90, N 5.72.
3.1.2. 2,2-Pentamethylene-5-(2-butenyl)-5-nitro-1,3-di-
oxane (3b). Yield 75%, oil, the E/Z mixture in 85:15
ratio, respectively. (E)-3b: dH 1.41±1.81 (m, 10H, C6H10),
1.66 (bd, Jˆ6.5 Hz, 3H, CH3), 2.47 (bd, Jˆ7.4 Hz, 2H,
CH2), 3.93 (d, Jˆ12.9 Hz, 2H, 2£CH-O), 4.43 (d,
Jˆ12.9 Hz, 2H, 2£CH-O), 5.22 (dtq, Jˆ15.1, 7.4, 1.6 Hz,
1H, vCHCH2), 5.57 (dqt, Jˆ15.1, 1.2, 6.5 Hz, 1H,
vCHCH3). dC (APT) 17.93 (2), 22.37, 22.51, 25.40,
29.52, 34.71, 37.42, 62.89, 86.28, 99.01, 120.85 (2),
3. Experimental
1H NMR spectra were measured with a Varian GEMINI
2000 or with a Bruker AMX-500 spectrometers. 13C NMR
spectra were recorded only on the former apparatus at
50 MHz. In APT spectra resonances corresponding to CH
and CH3 are indicated by `-'. TMS and DSS were used as
internal standards for CDCl3 and D2O solution, respectively.
Coupling constants (J) are in Hz and chemical shifts (d) in
ppm. IR spectra were recorded with a Specord M80 (Carl-
Ziess Jena) spectrometer. Mass spectra (electron impact or
LSIMS) were obtained from an AMD 604 instrument.
Merck precoated TLC plates (Kieselgel 60 F254, 0.2 mm)
were used for TLC and column chromatography was
performed on Marchery Nagel MN-Kieselgel 60 (200±300
mesh).
132.33 (2). IR (neat): 2940, 1644, 1546, 1148 cm21
.
HRMS (EI) m/z calcd for C13H21NO4 (M1) 255.1471,
found 255.1479.
3.1.3. 2,2-Pentamethylene-5-(2-methyl-2-propenyl)-5-
nitro-1,3-dioxane (3c). Yield 65%, white crystals after
chromatography, mp 87±888C (hexane). dH 1.35±1.85 (m,
10H, C6H10), 1.68 (dd, Jˆ1.0, 1.4 Hz, 3H, CH3), 2.52 (bs,
2H, CH2), 3.97 (d, Jˆ12.8 Hz, 2£CH-O), 4.47 (d,
Jˆ12.8 Hz, 2£CH-O), 4.74 (p, Jˆ1.5 Hz, 1H, CHv) 4.94
(m, 1H, CHv). dC (APT) 22.37, 22.52, 23.30 (2), 25.41,
29.46, 34.81, 42.06, 63.35, 85.83, 99.01, 117.37, 137.37: IR
3.1. General procedure for a preparation of the allylic 5-
nitro-1,3-dioxanes 3
(KBr): 3076, 2924, 1638, 1548, 1460, 1292, 1156 cm21
.
Nitro derivative (1 or 2-nitropropane, 0.019 mol) and a solu-
tion of sodium methoxide, prepared from Na (0.625 g,
0.025 mol) and MeOH (15 mL), were stirred for 0.5 h
under argon. To this mixture, PPh3 (0.5 g, 1.9 mmol) or
1,2-bis(diphenylphosphino)ethane (0.38 g, 0.95 mmol; for
preparation of 3c) followed by bis(triphenylphosphine)di-
chloropalladium (0.67 g, 0.95 mmol) was added. After
0.5 h, allylating reagent (0.025 mol) was introduced drop-
wise with stirring. Additionally, THF (30 mL) was added to
the reaction in which allylic chlorides were used. The reac-
tion with allyl acetate was carried out at 50±558C for
ca.15 h and with allylic chlorides at room temperature for
20±25 h. The reaction was followed by TLC (except the
preparation of 3e) with hexane±ethyl acetate (3:1, v/v)
mixture as eluent. At the end of the reaction, black
palladium separated frequently. The reaction mixture was
passed through a short pad of Celitew and the ®ltrate was
diluted with cold water and the resulting mixture was
extracted three times with CH2Cl2. The organic solution
was successively washed with 20% aqueous sodium
hydroxide, then water until washings were neutral, and
®nally with brine. After drying over anhydrous magnesium
sulfate the solvent was removed under reduced pressure and
the residue was dissolved in methylene chloride and passed
through short pad of silica gel and then puri®ed by column
chromatography on silica gel (10±25% of ethyl acetate in
hexane) and/or by crystallization from hexane (3a and 3c) or
methanol (3d). The yields of 3a±3d are listed in Table 1. 1H
(200 MHz) and 13C NMR spectra of 3 were measured in
CDCl3 solution.
Anal. calcd for C13H21NO4: C 61.16, H 8.29, N 5.48;
found C 61.30, H 8.38, N 5.51.
3.1.4. 2,2-Pentamethylene-5-nitro-5-(3-phenyl-2-propen-
yl)-1,3-dioxane (3d). White crystals, mp 106±1078C
(methanol). dH 1.35±1.85 (m, 10H, C6H10), 2.74 (dd,
Jˆ7.6, 1.2 Hz, 2H, CH2), 4.01 (d, Jˆ12.9 Hz, 2H, 2£CH-
O), 4.49 (d, Jˆ12.9 Hz, 2H, 2£CH-O), 5.94 (dd, Jˆ15.6,
7.6 Hz, 1H, CH2CHv), 6.48 (dt, Jˆ15.6, 1.2 Hz, 1H,
PhCHv), 7.30 (m, 5H, C6H5). dC (APT) 22.37, 22.52,
25.38, 30.05, 34.14, 37.70, 62.89, 86.11, 99.18, 119.50
(2), 126.41 (2), 128.01 (2), 128.59 (2), 136.03 (2),
136.11. IR (KBr): 3032, 2948, 1664, 1542, 1272,
1140 cm21. Anal. calcd for C18H24NO4: C 68.12, H 7.30,
N 4.41; found C 68.28, H 7.29, N 4.42.
3.1.5. 5-Methyl-5-nitropent-1-ene (3e). Colorless liquid,
bp 608C/16 mmHg (lit.14 bp 738C/30 mmHg).
3.2. General procedure for preparation of 6 and 7 (the
one-pot procedure)
Aluminum foil cut in small pieces (0.55 g, 20.0 mmol) was
added to a solution of mercury(II) chloride (0.2 g,
0.75 mmol) in THF (30 mL) and water (1.0 mL). The result-
ing mixture was stirred at room temperature for 10 min, then
3 (10 mmol) in THF (15 mL) was added dropwise. When
TLC (ethyl acetate±hexane 3:1 v/v) showed that the reac-
tion was complete (usually after 3 h; reduction to 1±5 mmol
scale required shorter reaction time) the mixture was passed
through short pad of Celite and washed with THF. The
solvent was distilled off under reduced pressure and crude
4 was combined with aldehyde (8.5 mmol) and toluene
(30 mL) unless otherwise stated. The mixture was re¯uxed
under argon for 10±20 h until TLC (10±20% ethyl acetate
in hexane) showed that the reaction was complete. Toluene
was removed under reduced pressure and the residue was
3.1.1. 2,2-Pentamethylene-5-nitro-5-(2-propenyl)-1,3-di-
oxane (3a). Yield 75%, white crystals; mp 37±398C
(hexane). dH 1.35±1.80 (m, 10H, C6H10), 2.55 (bd,
Jˆ7.3 Hz, 2H, CH2), 3.92 (d, Jˆ12.9 Hz, 2£CH-O), 4.43
(d, Jˆ12.9 Hz, 2H, 2£CH-O), 5.21±5.23 (m, 2H, CH2v),
5.60 (ddt, Jˆ16.6, 10.4, 7.3 Hz, 1H, CHv). dC (APT)
22.39, 22.52, 25.41, 29.76, 34.49, 38.45, 62.87, 85.99,

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2026
taken into methylene chloride and the solution was passed
through a short column of silica gel. The solvent was
distilled off and the residue was puri®ed by chromatography
134.77. IR (KBr): 3080, 2936, 1640, 1584, 1160,
1118 cm21. HRMS (EI) m/z calcd for C19H25NO3 (M1)
315.1834, found 315.1832. 5ab (0.235 g, 0.745 mmol)
was re¯uxed in toluene (5 mL) under argon for 18 h to
afford after chromatographic puri®cation (15% ethyl acetate
in hexane) 0.20 g (85%) of 6ab, mp 113±1158C.
1
and/or by crystallization as it is speci®ed for each 6. H
(500 MHz) and 13C NMR spectra of 6 and 7 were measured
for CDCl3 solution.
3.2.1. 7-Oxa-1-azabicyclo[2.2.1]heptane-2-spiro-50-(10,30-
dioxan)-20-spiro-100-cyclohexane (6aa). Paraformaldehyde
(0.132 g, 4.4 mmol), triethylamine (48 mL) and n-propanol
(24 mL) were re¯uxed to obtain a clear solution, then 4a
(prepared from 1 mmol of 3a) was added and heating was
continued for 1.5 h. Propanol was removed and crystalliza-
tion from hexane afforded 0.132 g (56%) of 6aa (white
crystals); mp 80±818C. dH (COSY) 1.37 (d, Jˆ11.9 Hz,
1H, H-3en), 1.41 (m, 2H, C6H10), 1.45±1.56 (m, 5H,
H-5en, 4H of C6H10), 1.67±1.85 (m, 4H, C6H10), 1.90 (ddd,
Jˆ11.9, 5.3, 2.6 Hz, 1H, H-3ex), 1.96 (m, 1H, H-5ex), 2.99
(ddd, Jˆ12.3, 10.7, 5.6 Hz, 1H, 6-ex), 3.07 (ddd, Jˆ12.3, 8.3,
3.9 Hz, 1H, H-6en), 3.53 (dd, Jˆ11.5, 1.3 Hz, CH-O), 3.66
(dd, Jˆ11.6, 1.3 Hz, 1H, CH-O), 3.90 (d, Jˆ11.6 Hz, 1H,
CH-O), 3.94 (d, Jˆ11.5 Hz, 1H, CH-O), 4.86 (t, Jˆ5.3 Hz,
1H, H-4). dC (APT) 22.48, 22.62, 25.57, 30.95, 32.61, 33.61,
42.57, 49.11, 63.73, 65.47, 67.70, 80.00 (2), 98.03. IR
(KBr): 2940, 1288, 1276, 1118 cm21. Anal. calcd for
C13H21NO3: C 65.24, H 8.84, N 5.85; found C 64.93, H
8.77, N 5.88.
3.2.4. 6-exo-(4-Fluorophenyl)-7-oxa-1-azabicyclo[2.2.1]-
heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6ac). Yield 36%, white crystals, mp 80±818C (hexane). dH
1.38±1.58 (m, 6H, C6H10), 1.56 (d, Jˆ12.0 Hz, 1H, H-3en),
1.64±1.86 (m, 4H, C6H10), 2.04 (dddd, Jˆ11.8, 5.2, 4.5,
2.5 Hz, 1H, H-5ex), 2.12 (ddd, Jˆ12.0, 5.2, 2.5 Hz, 1H,
H-3ex), 2.12 (dd, Jˆ11.8, 8.2 Hz, 1H, H-5en), 3.58 (dd,
Jˆ11.4, 1.8 Hz, CH-O), 3.74 (dd, Jˆ11.1, 1.8 Hz, 1H,
CH-O), 4.02 (d, Jˆ11.4 Hz, 1H, CH-O), 4.08 (d,
Jˆ11.1 Hz, 1H, CH-O), 4.10 (dd, Jˆ8.2, 4.5 Hz, 1H,
H-6), 4.98 (t, Jˆ5.2 Hz, 1H, H-4), 6.98 (m, 2H of C6H4),
7.35 (m, 2H of C6H4). dC (APT) 22.50, 22.69, 25.59, 29.21,
35.45, 42.25, 42.66, 61.76 (2), 63.93, 65.27, 67.96, 80.65
(2), 98.14, 115.12 (2) (d, JC±Fˆ21.1 Hz), 128.51 (2) (d,
JC±Fˆ1.8 Hz), 139.36 (d, JC±Fˆ2.8 Hz), 161.8 (d,
JC±Fˆ243.7 Hz). IR (KBr): 2952, 1450, 1254, 1224,
1114 cm21. Anal. calcd for C19H24NFO3: C 68.45, H 7.26,
N 4.20; found C 68.68, H 7.26, N 4.13.
3.2.5. 6-exo-(4-Tri¯uoromethylphenyl)-7-oxa-1-azabicy-
clo[2.2.1]heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-
cyclohexane (6ad). Yield 56%, white crystals, mp 125±
1268C (hexane). dH 1.39±1.58 (m, 6H, C6H10), 1.57 (d,
Jˆ12.1 Hz, 1H, H-3en), 1.65±1.86 (m, 4H, C6H10), 2.03
(dddd, Jˆ11.7, 5.1, 4.6, 2.5 Hz, 1H, H-5ex), 2.11 (ddd,
Jˆ12.1, 5.3, 2.5 Hz, 1H, H-3ex), 2.16 (dd, Jˆ11.7,
8.3 Hz, 1H, H-5en), 3.60 (dd, Jˆ11.4, 1.7 Hz, 1H, CH-O),
3.76 (dd, Jˆ11.1, 1.7 Hz, 1H, CH-O), 4.03 (d, Jˆ11.4 Hz,
CH-O), 4.08 (d, Jˆ11.1 Hz, 1H, CH-O), 4.19 (dd, Jˆ8.3,
4.6 Hz, 1H, H-6), 4.99 (dd, Jˆ5.3, 5.1 Hz, 1H, H-4), 7.52
(m, 2H of C6H4), 7.55 (m, 2H of C6H4). dC (APT) 22.51,
22.69, 25.58, 29.43, 35.20, 42.22, 42.57, 61.90 (2), 63.88,
65.35, 67.90, 80.71 (2), 98.21, 125.35 (2) (q,
JC±Fˆ3.8 Hz), 127.20 (2), 147.48. IR (KBr): 2944, 1448,
1288, 1256, 1112 cm21. HRMS (EI) m/z calcd for
C20H24NF3O3 (M1) 383.1708, found 383.1696.
3.2.2. 6-exo-Phenyl-7-oxa-1-azabicyclo[2.2.1]heptane-2-
spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6ab).
Yield 61%, white crystals, mp 114±1158C (hexane). dH
(COSY) 1.38±1.60 (m, 6H, C6H10), 1.45 (d, Jˆ11.9 Hz,
1H, H-3en), 1.63±1.87 (m, 4H, C6H10), 2.08 (dddd,
Jˆ12.0, 4.9, 5.0, 2.5 Hz, 1H, H-5ex), 2.12 (dd, Jˆ12.0,
8.0 Hz, 1H, H-5en), 2.14 (ddd, Jˆ12.0, 5.0, 2.5 Hz, 1H,
H-3ex), 3.59 (dd, Jˆ11.4, 1.9 Hz, CH-O), 3.74 (dd,
Jˆ11.2, 1.9 Hz, 1H, CH-O), 4.04 (d, Jˆ11.4 Hz, 1H,
CH-O), 4.08 (d, Jˆ11.2 Hz, 1H, CH-O), 4.11 (dd, Jˆ8.0,
4.9 Hz, 1H, H-6), 4.98 (t, Jˆ5.0 Hz, 1H, H-4), 7.30 (m,
5H, C6H5). dC (APT) 22.52, 22.73, 25.62, 28.92, 35.80,
42.39, 42.61, 62.35 (2), 64.04, 65.24, 68.06, 80.71 (2),
98.12, 127.08 (2), 128.45 (2), 143.52. IR (KBr):
2940, 1456, 1274, 1252, 1118 cm21. Anal. calcd for
C19H25NO3: C 72.35, H 7.99, N 4.44; found C 72.50, H
8.00, N 4.33.
3.2.6. 6-exo-(2-Methoxyphenyl)-7-oxa-1-azabicyclo[2.2.1]-
heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6ae). Yield 33%, yellowish oil after chromatography
(hexane±ethyl acetate, 5:1, v/v). dH 1.39±1.60 (m, 6H,
C6H10), 1.60 (d, Jˆ12.0 Hz, 1H, H-3en), 1.62±1.86 (m,
4H, C6H10), 1.86 (dddd, Jˆ11.9, 5.2, 4.6, 2.6 Hz, 1H,
H-5ex), 2.12 (dd, Jˆ11.9, 8.2 Hz, 1H, H-5en), 2.13 (ddd,
Jˆ12.0, 5.2, 2.6 Hz, 1H, H-3ex), 3.59 (dd, Jˆ11.4, 1.9 Hz,
CH-O), 3.76 (dd, Jˆ11.1, 1.9 Hz, 1H, CH-O), 3.80 (s, 3H,
OCH3), 4.04 (d, Jˆ11.4 Hz, 1H, CH-O), 4.09 (d,
Jˆ11.1 Hz, 1H, CH-O), 4.47 (dd, Jˆ8.2, 4.6 Hz, 1H,
H-6), 4.91 (t, Jˆ5.2 Hz, 1H, H-4), 6.81 (m, 1H, C6H4),
6.93 (m, 1H, C6H4), 7.18 (m, 1H, C6H4), 7.61 (m, 1H,
C6H4). dC (APT) 22.47, 22.68, 25.58, 28.72, 35.90, 42.24,
42.60, 55.22 (2), 56.18 (2), 63.93, 65.19, 68.12, 80.57 (2),
97.96, 109.83 (2), 120.58 (2), 126.98 (2), 127.58 (2),
131.73, 155.94. IR (KBr): 2948, 1464, 1268, 1244,
1100 cm21. HRMS (EI) m/z calcd for C20H27NO4 (M1)
345.1940, found 345.1935.
3.2.3. The preparation of 6ab from 5ab. The mixture of
crude 4a, prepared from 3a (1 mmol), THF (3 mL), benzal-
dehyde (0.091 mL, 0.9 mmol) and acetic acid (0.057 mL)
was stirred overnight under argon at room temperature then
heated at 608C for 6 h. THF was removed under reduced
pressure and the residue was dissolved in methylene
chloride and successively washed with water, aqueous
sodium bicarbonate, water, brine and dried with anhydrous
magnesium sulfate. The residue was puri®ed by chromato-
graphy (10±20% of ethyl acetate in hexane) to give 0.24 g
(75%) of 5ab as pale yellow syrup. dH (200 MHz, CDCl3)
1.49 (m, 10H, C6H10), 2.58 (d, Jˆ7.3 Hz, 2H, CH2), 4.01 (d,
Jˆ12.9 Hz, 2H, 2£CH-O), 4.34 (d, Jˆ12.9 Hz, 2H, 2£CH-
O), 5.11 (m, 2H, vCH2), 5.62 (m, 1H, vCH), 7.40 (m, 3H,
C6H5), 7.74 (s, 1H, NvCH), 8.32 (m, 2H, C6H5). dC
(CDCl3) 22.33, 22.42, 25.41, 28.57, 35.95, 37.26, 63.51,
70.27, 98.86, 119.94, 128.29, 129.18, 130.28, 130.61,

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2027
3.2.7. 6-exo-(3,4-Dimethoxyphenyl)-7-oxa-1-azabicyclo-
[2.2.1]heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclo-
hexane (6af). Yield 35%, yellowish oil after chromato-
graphy (hexane±ethyl acetate, 4:1, v/v). dH 1.40±1.57 (m,
6H, C6H10), 1.58 (d, Jˆ12.0 Hz, 1H, H-3en), 1.64±1.87 (m,
4, C6H10), 2.06 (dddd, Jˆ11.9, 4.8, 5.0, 2.4 Hz, 1H, H-5ex),
2.10 (dd, Jˆ11.9, 8.1 Hz, 1H, H-5en), 2.15 (ddd, Jˆ12.0,
5.3, 2.4 Hz, 1H, H-3ex), 3.59 (dd, Jˆ11.4, 2.0 Hz, CH-O),
3.73 (dd, Jˆ11.0, 2.0 Hz, 1H, CH-O), 3.85 (s, 3H, CH3),
3.89 (s, 3H, OCH3), 4.04 (d, Jˆ11.4 Hz, 1H, CH-O), 4.04
(dd, Jˆ8.1, 5.0 Hz, 1H, H-6), 4.11 (d, Jˆ11.0 Hz, 1H, CH-
O), 4.99 (dd, Jˆ5.3, 4.8 Hz, 1H, H-4), 6.79 (d, Jˆ8.3 Hz,
1H of C6H3), 6.87 (dd, Jˆ8.3, 2.0 Hz, 1H of C6H3), 6.97 (d,
Jˆ2.0 Hz, 1H of C6H3). dC (APT) 22.45, 22.65, 25.48,
28.73, 35.87, 42.26, 42.72, 55.82 (2), 62.15 (2), 63.97,
65.12, 68.00, 80.54 (2), 98.02, 110.14 (2), 110.88 (2),
119.09 (2), 136.27, 148.00, 148.96. IR (KBr): 2936,
1464, 1252, 1236, 1110 cm21. HRMS (EI) m/z calcd for
C21H29NO5 (M1) 375.2046, found 375.2047.
chloroform). dH 1.40±1.56 (m, 6H, C6H10), 1.56 (d,
Jˆ12.1 Hz, 1H, H-3en), 1.66±1.85 (m, 4H, C6H10), 2.05
(dddd, Jˆ11.7, 5.0, 4.3, 2.5 Hz, 1H, H-5ex), 2.08 (ddd,
Jˆ12.1, 5.3, 2.5 Hz, 1H, H-3ex), 2.17 (dd, Jˆ11.7,
8.3 Hz, 1H, H-5en), 3.59 (dd, Jˆ11.5, 1.5 Hz, CH-O),
3.79 (dd, Jˆ11.3, 1.5 Hz, 1H, CH-O), 4.01 (d, Jˆ11.5 Hz,
1H, CH-O), 4.08 (d, Jˆ11.3 Hz, 1H, CH-O), 4.20 (dd,
Jˆ8.3, 4.3 Hz, 1H, H-6), 5.00 (dd, tl, Jˆ5.3, 5.0 Hz, 1H,
H-4), 7.25 (dd, Jˆ7.9, 4.8 Hz, 1H, H-5pyr), 7.83 (dt, Jˆ7.9,
1.8 Hz, 1H, H-4pyr.), 8.47 (dd, Jˆ4.8, 1.2 Hz, 1H, H-6pyr.),
8.56 (d, Jˆ1.8 Hz, 1H, H-2pyr). dC (APT) 22.51, 22.68,
25.57, 29.74, 34.90, 42.15, 42,37, 60.32 (2), 63.82, 65.55,
67.63, 80.69 (2), 98.26, 123.58 (2), 135.01 (2), 139.23,
148.03 (2), 2148.43 (2). IR (KBr): 2940, 1576, 1456,
1288, 1258, 1110 cm21. HRMS (EI) m/z calcd for
C18H24N2O3 (M1) 316.1787, found 316.1795.
3.2.11. 6-exo-(2-Pyridyl)-7-oxa-1-azabicyclo[2.2.1]hep-
tane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6aj). Yield 63%, light brown powder; analytical sample
was puri®ed by chromatography (ethyl acetate±hexane,
5:1,v/v), crystals, mp 106±1088C. dH 1.4±1.59 (m, 6H,
C6H10), 1.61 (d, Jˆ12.1 Hz, 1H, H-3en), 1.67±1.86 (m,
4H, C6H10), 2.10 (ddd, Jˆ12.1, 5.3, 2.6 Hz, 1H, H-3ex),
2.18 (dd, Jˆ11.9, 8.5 Hz, 1H, H-5en), 2.26 (dddd,
Jˆ11.9, 5.0, 4.4, 2.6 Hz, 1H, H-5ex), 3.62 (dd, Jˆ11.4,
1.8 Hz, CH-O), 3.78 (dd, Jˆ11.3, 1.8 Hz, 1H, CH-O),
4.06 (d, Jˆ11.4 Hz, 1H, CH-O), 4.09 (d, Jˆ11.3 Hz, 1H,
CH-O), 4.34 (dd, Jˆ8.5, 4.4 Hz, 1H, H-6), 4.96 (dd, tl,
Jˆ5.3, 5.0 Hz, 1H, H-4), 7.13 (m, 1H, pyr), 7.66 (m, 1H,
pyr), 7.73 (m, 1H, pyr), 8.49 (m, 1H, pyr). dC (APT) 22.52,
22.71, 25.61, 29.53, 35.18, 40.90, 42.45, 63.89 (2), 63.96,
65.29, 67.99, 80.80 (2), 98.18, 121.23 (2), 121.89 (2),
136.80 (2), 148.67 (2), 162.33. IR (KBr):2956, 1592,
1468, 1284, 1258, 1106 cm21. HRMS (EI) m/z calcd for
C18H24N2O3 (M1) 316.1787, found 316.1795.
3.2.8. 6-exo-[(E)-2-Phenylethenyl)]-7-oxa-1-azabicyclo-
[2.2.1]heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclo-
hexane (6ag). Yield 55%, white needles, mp 129±1308C
(hexane). dH 1.41 (m, 2H, C6H10), 1.49 (d, Jˆ12.0 Hz,
1H, H-3en), 1.50±1.68 (m, 6H, C6H10), 1.85 (m, 3H, 2H
of C6H10, H-5ex), 1.89 (dd, Jˆ11.7, 7.8 Hz, 1H, H-5en),
2.04 (ddd, Jˆ12.0, 5.3, 2.3 Hz, 1H, H-3ex), 3.56 (dd,
Jˆ11.4, 1.5 Hz, CH-O), 3.70 (dd, Jˆ11.3, 1.5 Hz, 1H,
CH-O), 3.76 (ddd, Jˆ7.8, 7.5, 4.2 Hz, 1H, H-6), 4.00 (d,
Jˆ11.4 Hz, 1H, CH-O), 4.06 (d, Jˆ11.3 Hz, 1H, CH-O),
4.92 (dd, Jˆ5.3, 4.7 Hz, 1H, H-4), 6.21 (dd, Jˆ16.0,
7.5 Hz, 1H, CHv), 6.44 (d, Jˆ16.0 Hz, 1H, PhCHv),
7.18±7.36 (m, 5H, C6H5). dC (APT) 22.52, 22.70, 25.61,
29.52, 35,16, 40.69, 42.38, 61.70 (2), 63.87, 65.24, 67.90,
80.57 (2), 98.16, 126.39 (2), 127.45 (2), 128.42 (2),
130.09 (2), 131.40 (2), 136.71. IR (KBr): 2936, 1660,
1448, 1288,1256,1110 cm21. Anal. calcd for C21H27NO3:
C 73.87, H 7.97, N 4.10; found C 73.63, H 8.0, N 4.14.
3.2.12. 6-exo-(2-Thienyl)-7-oxa-1-azabicyclo[2.2.1]hep-
tane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6ak). Yield 67%, white crystals, mp 149.5±1508C
(hexane). dH 1.40±1.56 (m, 6H, C6H10), 1.57 (d,
Jˆ12.0 Hz, 1H, H-3en), 1.62±188 (m, 4H, C6H10), 2.11
(dd, Jˆ11.7, 8.0 Hz, 1H, H-5en) 2.11±2.19 (m, 2H,
H-3ex, H-5ex), 3.58 (dd, Jˆ11.4, 2.0 Hz, CH-O), 3.69
(dd, Jˆ11.0, 2.0 Hz, 1H, CH-O), 4.03 (d, Jˆ11.4 Hz, 1H,
CH-O), 4.11 (d, Jˆ11.0 Hz, 1H, CH-O), 4.39 (dd, Jˆ8.0,
4.2 Hz, 1H, H-6), 5.02 (t, Jˆ5.2 Hz, 1H, H-4), 6.91 (m, 2H,
C4H3S), 7.19 (m, 1H, C4H3S). dC (APT) 22.50, 22.68, 25.59,
28.79, 35.87, 42.22, 43.11, 59.26 (2), 63.93, 65.02, 67.96,
80.73 (2), 98.12, 124.04 (2), 125.05 (2), 126.28 (2),
3.2.9. 6-exo-(Phenylmethyl)-7-oxa-1-azabicyclo[2.2.1]-
heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6ah). Yield 42%, yellow oil after chromatography
(hexane±ethyl acetate, 6:1, v/v). dH (COSY) 1.34 (d,
Jˆ12.0 Hz, 1H, H-3en), 1.39±1.56 (m, 6H, C6H10), 1.55
(dd, Jˆ12.0, 7.6 Hz, 1H, H-5en), 1,62±1.72 (m, 3H,
H-5ex, 2H, C6H10), 1.81 (m, 2H, C6H10), 1.93 (ddd,
Jˆ12.0, 5.3, 2.5 Hz, 1H, H-3ex), 2.54 (dd, Jˆ13.9,
8.1 Hz, 1H, CHPh), 3.11 (dd, Jˆ13.9, 6.4 Hz, 1H, CHPh),
3.35 (dddd, Jˆ8.1, 7.6, 6.4, 4.0 Hz, 1H, H-6), 3.54 (dd,
Jˆ11.4, 1.4 Hz, CH-O), 3.65 (dd, Jˆ11.4, 1.4 Hz, 1H,
CH-O), 3.92 (d, Jˆ11.4 Hz, 1H, CH-O), 3.95 (d,
Jˆ11.4 Hz, 1H, CH-O), 4.85 (dd, Jˆ5.3, 5.0 Hz, 1H,
H-4), 7.25 (m, 5H, C6H5). dC (APT) 22.49, 22.63, 25.57,
30.34, 34.25, 39.08, 41.82, 42.13, 60.73 (2), 63.71, 65.22,
67.80, 80.66 (2), 98.01, 126.11 (2), 128.27 (2), 129.19
(2), 138.86. IR (KBr): 2936, 1448, 1286, 1264,
1108 cm21. HRMS (EI) m/z calcd for C20H27NO3 (M1)
329.1991, found 329.1983.
147.31. IR (KBr): 2936, 1444, 1270, 1252, 1120 cm21
.
Anal. calcd for C17H23NO3S: C 63.52, H 7.21, N 4.36;
found C 63.79, H 7.27, N 4.37.
3.2.13. 6-exo-2,2-Dimethyl-6-phenyl-7-oxa-1-azabicyclo-
[2.2.1]heptane (6eb). Yield 58%, white crystals, mp 38±
398C (hexane). dH 1.31 (s, 3H, CH3), 1.35, (d, Jˆ11.3 Hz,
1H H-3en), 1.36 (s, 3H, CH3), 1.84 (ddd, Jˆ11.3, 5.4,
2.3 Hz, 1H, H-3ex), 2.00 (dddd, Jˆ11.5, 5.0, 4.6, 2.3 Hz,
1H, H-5ex), 2.05 (dd, Jˆ11.5, 8.3 Hz, 1H, H-5en), 4.44 (dd,
Jˆ8.3, 4.6 Hz, 1H, H-6), 4.90 (dd, Jˆ5.4, 5.0 Hz, 1H, H-4),
7.177.42 (m, 5H, C6H5). dC 24.62, 31.48, 42.24, 46.59,
62.71, 65.70, 81.34, 126.60, 127.02, 128.35, 144.58. IR
3.2.10. 6-exo-(3-Pyridyl)-7-oxa-1-azabicyclo[2.2.1]hep-
tane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6ai). Yield 51%, yellow oil (solidifying during standing in
a refrigerator) after chromatography (5% methanol in

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2028
(KBr): 2964, 1456, 1282, 1260 cm21. HRMS (EI) m/z calcd
1H, H-7), 2.92 (bd, Jˆ4.1 Hz, 1H, H-4), 2.96 (bdd, Jˆ10.8,
2.0 Hz, 1H, H-7), 3.39 (dd, Jˆ11.7, 1.4 Hz, 1H, CH-O),
3.74 (dd, Jˆ11.9, 1.4 Hz, 1H, CH-O), 3.82 (d, Jˆ11.7 Hz,
1H, CH-O), 4.25 (d, Jˆ11.9 Hz, 1H, CH-O), 4.55 (bs, 1H,
H-3), 7.22±7.35 (m, 5H, C6H5). dC 22.56, 22.70, 25.62,
30.56, 34.12, 37.99, 48.09, 55.47, 64.69, 66.75, 67.14,
83.21, 98.16, 125.52, 127.35, 128.26, 140.93. IR (KBr):
2940, 1436, 1272, 1224, 1102 cm21. Anal. calcd for
C19H25NO3: C 72.35, H 7.99, N 4.44; found C 72.39, H
7.99, N 4.45.
for C13H17NO (M1) 203.1310, found 203.1302.
3.2.14. 5-exo-Methyl-6-exo-phenyl-7-oxa-1-azabicyclo-
[2.2.1]heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclo-
hexane (6bb). Yield 42%, white crystals, mp 123±1248C
(hexane). dH 0.55 (d, Jˆ7.2 Hz, 3H, CH3), 1.38±1.64 (m,
8H, C6H10), 1.69 (d, Jˆ12.2 Hz, 1H, H-3en), 1.83 (m, 2H,
C6H10), 2.22 (dd, Jˆ12.2 Hz, 5.4, H-3ex), 2.35 (qd, Jˆ7.2,
8.2 Hz, 1H, H-5en), 3.62 (dd, Jˆ11.3, 2.0 Hz, 1H, CH-O),
3.71 (dd, Jˆ11.0, 2.0 Hz, 1H, CH-O), 4.06 (d, Jˆ11.3 Hz,
CH-O), 4.08 (d, Jˆ11.0 Hz, 1H, CH-O), 4.17 (d, Jˆ8.2 Hz,
1H, H-6), 4.48 (d, Jˆ5.4 Hz, 1H, H-4), 7.17±7.34 (m, 5H,
C6H5). dC (APT) 16.52 (2), 22.48, 22.73, 25.60, 28.36,
36.30, 42.76, 46.06 (2), 64.01, 65.01, 66.27 (2), 68.09,
86.72 (2), 98.08, 126.61 (2), 127.83 (2), 128.04 (2),
Method (b) From formaldehyde. Hydroxylamine 4d
(obtained from 1 mol of 3d) was added to solution of form-
aldehyde (prepared from paraformaldehyde (0.033 g,
1.1 mmol), propanol (5 mL) and NEt3 (4 mL) as described
for compound 6aa) and resulting mixture was re¯uxed
under argon for 1 h. The product was separated as described
in general procedure for preparation of 6. Chromatography
separation afforded 6da (0.08 g, 25.5%, mp 156±1578C)
and 7da (0.08 g, 25.5%, mp 142±1458C).
138.96. IR (KBr): 2936, 1452, 1286, 1256, 1112 cm21
.
Anal. calcd for C20H27NO3: C 72.92, H 8.26, N 4.25;
found C 72.69, H 8.33, N 4.21.
3.2.15. 4-Methyl-6-exo-phenyl-7-oxa-1-azabicyclo[2.2.1]-
heptane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(6cb). Yield 49%, white crystals, after chromatography
(hexane±ethyl acetate, 6:1, v/v) followed by crystallization,
mp 85±868C (hexane). dH (COSY) 1.38±1.51 (m, 4H,
C6H10), 1.56 (m, 2H, C6H10), 1.60 (s, 3H, CH3), 1.64 (m,
2H, C6H10), 1.77 (d, Jˆ12.1 Hz, 1H, H-3en), 1.87 (m, 3H,
H-5ex, 2H, C6H10), 1.98 (dd, Jˆ12.1, 2.9 Hz, H-3ex), 2.26
(dd, Jˆ11.7, 8.4 Hz, 1H, H-5en), 3.65 (dd, Jˆ11.4, 2.0 Hz,
1H, CH-O), 3.74 (dd, Jˆ11.0, 2.0 Hz, 1H, CH-O), 4.06 (d,
Jˆ11.4 Hz, 1H, CH-O), 4.07 (d, Jˆ11.0 Hz, 1H, CH-O),
4.15 (dd, Jˆ8.4, 4.7 Hz, 1H, H-6), 7.19±7.40 (m, 5H,
C6H5). dC 18.24, 22.50, 22.72, 25.61, 28.47, 36.24, 48.03,
48.14, 64.05, 64.20 66.42, 68.19, 89.91, 98.07, 126.89,
128.43, 143.76. IR (KBr): 2944, 1452, 1288, 1258,
1108 cm21. HRMS (EI) m/z calcd for C20H27NO3 (M1)
329.1991, found 329.1986.
3.2.17. 5,6-exo-Diphenyl-7-oxa-1-azabicyclo[2.2.1]hep-
tane-2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
6db and (^)(5Sp,7Rp)-5,7-diphenyl-2-oxa-1-azabicy-
clo[2.2.1]heptane-6-spiro-50-(10,30-dioxan)-20-spiro-100-
cyclohexane (7db). Yield 67%, the 6db/7db mixture, white
crystals, mp 135±1448C (hexane). The major isomer 6db
(75%) dH 1.40±1.73 (m, 2H, C6H10, 6db17db), 1.84 (d,
Jˆ12.4 Hz, 0.75H, H-3en), 2.32 (dd, Jˆ12.4, 5.4 Hz,
0.75H, H-3ex), 3.48 (d, Jˆ8.6 Hz, 0.75H, H-5en), 3.70
(dd, Jˆ11.3, 2.0 Hz, 0.75H, CH-O), 3.83 (dd, Jˆ11.0,
2.0 Hz, 0.75H, CH-O), 4.14 (d, Jˆ11.3 Hz, 0.75H, CH-
O), 4.15 (d, Jˆ11.0, 2.0 Hz, 0.75H, CH-O), 4.63 (d,
Jˆ8.6 Hz, 0.75H, H-6), 4.98 (d, Jˆ5.4 Hz, 0.75H, H-4),
6.74±7.17 (m, 10H, 2 C6H5, 6db17db) dC (APT) 22.53,
22.75, 25.63, 28.68, 36.08, 43.48, 58.55 (2), 64.07 65.34,
68.24, 68.34 (2), 87.26 (2), 98.21, 125.91 (2), 126.01 (2),
127.24 (2), 127.52 (2), 127.87 (2), 128.76 (2), 138.48,
139.65. 7db (minor isomer, 25%) dH 1.84±1.90 (m, 0.25H,
H-5en, 1.5H, C6H10, 6db17db), 1.94 (m, 0.5H, C6H10), 2.05
(dd, Jˆ12.4, 3.8 Hz, 0.25H, H-5ex), 3.49 (dd, Jˆ11.6,
1.8 Hz, 0.25H, CH-O), 3.59 (bd, Jˆ3.8 Hz, 0.25H, H-4),
3.78 (dd, Jˆ11.8, 1.8 Hz, 0.25H, CH-O), 4.04 (d,
Jˆ11.6 Hz, 0.25H, CH-O), 4.22 (bs, 0.25H, H-7), 4.37 (d,
Jˆ11.8 Hz, 0.25H, CH-O), 4.62 (s, 0.25H, H-3). dC (APT)
22.62, 29.56, 35,28, 40.96, 50.96 (2), 65.27, 67.54, 71.28
(2), 82.92 (2), 124.79 (2), 125.74 (2), 126.45 (2), 127.14
(2), 127.36 (2), 127.44 (2). IR (KBr): 2936, 1448, 1272,
1256, 1104 cm21. HRMS (EI) m/z calcd for C25H29NO3
(M1) 391.2147, found 391.2142.
3.2.16. 5-exo-Phenyl-7-oxa-1-azabicyclo[2.2.1]heptane-
2-spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane (6da)
and 3-exo-phenyl-2-oxa-1-azabicyclo[2.2.1]heptane-6-
spiro-50-(10,30-dioxan)-20-spiro-100-cyclohexane
(7da).
Method (a) The one-pot procedure. 4d and paraformalde-
hyde was heated in boiling toluene as described in general
procedure for preparation of 6. The mixture of 6da and 7da
was separated by column chromatography (15±20% ethyl
acetate in hexane). 6da was obtained in 44% yield as white
crystals, mp 156±1578C); dH 1.42 (m, 2H, C6H10), 1.54 (d,
Jˆ12.2 Hz, 1H, H-3en), 1.49±1.87 1.97 (dd, Jˆ12.2,
5.3 Hz, 1H, H-3ex), 2.89 (dd, Jˆ8.1, 5.6 Hz, 1H, H-5en),
3.04 (dd, Jˆ12.7, 5.6 Hz, 1H, H-6ex), 3.59 (m, 2H, H-6en,
CH-O), 3.75 (dd, Jˆ11.8, 1.4 Hz, 1H, CH-0), 3.97 (d,
Jˆ11.2 Hz, 1H, CH-O), 3.99 (d, Jˆ11.2 Hz, 1H, CH-O),
4.73 (d, Jˆ5.3 Hz, 1H, H-4), 7.19±7.30 (m, 5H, C6H5). dC
22.52, 22.65, 25.59, 31.09, 33.53, 42.46, 51.70, 59.85,
63.54, 65.42, 67.63, 86.99, 98.18, 126.78, 127.25, 128.61,
3.3. General procedure for preparation of 8 and 9
Compound 6 (1 mmol) in methanol (15±20 mL) was hydro-
genated in the presence of catalyst and under conditions
speci®ed for each 6. When TLC showed disappearance of
6 the catalyst was removed by ®ltration through a short pad
of Celitew and the solvent was distilled off. The residue (8)
was puri®ed by chromatography or when crude 8 was
chromatographically homogeneous it was deprotected with-
out puri®cation. (Only 8ab, 8ag, 8ak and 8eb were fully
characterized.). 8 was treated with 5% HCl aq (5 mL) in
boiling methanol (17 mL) for 1±3 h. The ®ltration rate
143.53. IR (KBr): 2988, 1456, 1284, 1220, 1120 cm21
.
Anal. calcd for C19H25NO3: C 72.35, H 7.99, N 4.44;
found C 71.79, H 7.98, N 4.25. 7da was obtained in 15%
as white crystals, mp 142±1438C. dH (COSY) 1.41±1.57
(m, 6H, C6H10), 1.58 (dd, Jˆ12.6, 2.0 Hz, 1H, H-5en),
1.70 (m, 2H, C6H10), 1.74 (dd, Jˆ12.6, 4.1 Hz, 1H,
H-5ex), 1.87 (m, 2H, C6H10), 2.66 (dd, Jˆ10.8, ca. 1 Hz,

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2029
was neutralized by solid sodium bicarbonate then inorganic
materials were ®ltered off. Methanol was removed and resi-
due was taken into acetone or into a mixture of acetone and
methanol. Residual inorganic material was ®ltered off then
crude 9 was chromatographically puri®ed (chloroform±
3.81 (tt, Jˆ11.5, 4.5 Hz, 1H, H-4), 3.94 (dd, Jˆ1.9,
2.3 Hz, CH-O), 4.24 (dd, Jˆ11.5, 2.5 Hz, 1H, H-6), 6.94
(dd, Jˆ5.0, 3.5 Hz, 1H, C4H3S), 6.98, (bd, Jˆ3 Hz, 1H of
C4H3S), 7.19 (dd, Jˆ5.0, 1.2 Hz, 1H of C4H3S). dC (APT)
22.42, 25.50, 28.20, 36.22, 38.55, 45.56, 49.46 (2), 51.18,
62.40, 65.27 (2), 69.86, 99,45, 123.03 (2), 123.68 (2),
126.17 (2), 148.42. IR (neat): 3412, 3324, 2936, 1664,
1448, 1156, 1108 cm21. HRMS (EI) m/z calcd for
C17H25NO3S (M1) 323.1555, found 323.1562.
1
methanol, 2:1,v/v). H (500 MHz) and 13C NMR spectra
of 8 and 9 were recorded for CDCl3 and D2O solution,
respectively.
3.3.1. cis-4-Hydroxy-6-phenylpiperidine-2-spiro-50-(10,30-
dioxan)-20spiro-100-cyclohexane (8ab). 6ab (0.41 g,
1.3 mmol) was hydrogenated in the presence of 10% Pd±
C (0.117 g) and sodium borohydride (0.06 g) under ambient
pressure for 3 h. Chromatographic puri®cation (ethyl
acetate±methanol, 9:1, v/v) afforded 8ab (0.35 g, 85%) as
a colorless glass. dH 1.15 (dd, Jˆ12.4, 11.7 Hz, 1H, H-3a),
1.41 (m, 2H, C6H10), 1.46±1.55 (m, 5H, 4H of C6H10, H-5a),
1.60 (m, 2H, C6H10), 1.80 (ddd, Jˆ12.4, 4.6, 1.9 Hz, 1H,
H-3e), 1.86 (m, 2H, C6H10), 2.09 (dddd, Jˆ11.9, 4.4, 2.4,
1.9 Hz, 1H, H-5e), 2.17 (bs, 2H, NH, OH), 3.49 (dd, Jˆ11.3,
2.3 Hz, 1H, CH-O), 3.77 (d, Jˆ11.9 Hz, 1H, CH-O), 3.79
(d, Jˆ11.3 Hz, CH-O), 3.84 (dddd, Jˆ11.7, 11.1, 4.4,
4.6 Hz, 1H, H-4), 3.92 (dd, Jˆ11.6, 2.4 Hz, 1H, H-6),
4.00(dd, Jˆ11.9, 2.3 Hz, 1H, CH-O), 7.24±7.44 (m, 5H,
C6H5); dC 22.52, 25.61, 28.14, 36.50, 38.73, 44.71, 50.99,
53.57, 62.49, 65.81, 70.30, 77.20, 98.51, 126.87, 127.27,
3.3.4.
cis-2,2-Dimethyl-4-hydroxy-6-phenylpiperidine
(8eb). 6eb was hydrogenated for 24 h under conditions
described for the reduction of 6ab. Chromatographic puri-
®cation afforded 8eb in 82% yield as a colorless glass. dH
1.20 (s, 6H, 2£CH3), 1.32 (dd, Jˆ12.1, 11.3 Hz, 1H, H-3a),
1.33 (ddd, Jˆ11.9, 11.2, 11.9 Hz, 1H, H-5a), 1.87 (ddd,
Jˆ12.1, 4.5, 2.0 Hz, 1H, H-3e), 2.12 (dddd, Jˆ11.9, 4.5,
2.6, 2.0 Hz, 1H, H-5e), 3.89 (dd, Jˆ11.8, 2.6 Hz, 1H, H-6),
3.97 (tt, Jˆ11.2, 4.5 Hz, 1H, H-4), 7.22±27.37 (m, 5H,
C6H5). dC (APT) 24.78 (2), 32.82 (2), 43.57, 46.66,
54.57 (2), 66.77 (2), 126.69 (2), 127.23 (2), 128.45
(2), 143.77. IR (neat); 3456, 2936, 1674, 1448,
1158 cm21. HRMS (EI) m/z calcd for C13H19NO (M1)
205.1467, found 205.1462.
3.3.5. 2,2-Bis(hydroxymethyl)-4-hydroxypiperidine (9aa).
6aa (0.25 g, 1 mmol) was hydrogenated in the presence of
10%-Pd±C (0.075 g) under ambient pressure for 20 h. Depro-
tection of crude 8aa afforded after chromatographic puri®ca-
tion 9aa (0.14 g, 87%) as a colorless glass. dH 1.21 (dd,
Jˆ13.0, 10.9 Hz, 1H, H-3a), 1.34 (dddd, Jˆ12.5, 12.3,
10.9, 4.5 Hz, 1H, H-5a), 1.88 (ddd, Jˆ13.0, 4.5, 1.6 Hz,
1H, H-3e), 1.95 (m, 1H, H-5e), 2.78 (ddd, Jˆ13.0, 12.3,
2.8 Hz, 1H, H-6a), 2.92 (dt, Jˆ13.0, 3.9 Hz, 1H, H-6e),
3.48 (AB, Dˆ0.07, Jˆ11.3 Hz, 2H, CH2OH), 3.62 (AB,
Dˆ0.05, Jˆ11.9 Hz, CH2OH), 3.92 (tt, Jˆ10.9, 4.5 Hz,
1H, H-4). dC 36,09, 38.35, 40.73, 60.01, 62.32, 67.48,
68.88. IR (nujol): 3392, 2948, 1636, 1444, 1148 cm21.
HRMS (LSIMS) m/z calcd for C7H16NO3 (M1H1)
162.1130, found 162.1127.
128.38, 144.14. IR (KBr): 3332, 2936, 1448, 1108 cm21
.
HRMS (EI) m/z calcd for C19H27NO3 (M1) 317.1991,
found 317.2012.
3.3.2. cis-4-Hydroxy-6-(2-phenylethyl)piperidine-2-spiro-
50-(10,30-dioxan)-20spiro-100-cyclohexane
(8ag).
6ag
(0.102 g, 0.3 mmol) was hydrogenated in the presence of
Raney Nickel slurry (ca. 0.3 g under of 10 bar at 608C for
3 h). Chromatographic puri®cation (chloroform±methanol,
5:1, v/v) gave 8ag (0.09 g, 87%) as colorless glass. dH
(COSY) 1.06 (t, Jˆ12.0 Hz, 1H, H-3a), 1.11 (q,
Jˆ11.5 Hz, 1H, H-5a), 1.41 (m, 2H, C6H10), 1.43 (m, 2H,
C6H10), 1.58 (m, 2H, C6H10), 1.67 (m, 2H, C6H10), 1.71±
1.78 (m, 3H, H-3e, CH2CH2Ph), 1.85 (m, 2H, C6H10), 1.98
(m, 1H, H-5e), 2.02 (bs, 2H, OH, NH), 2.69 (m, 2H, CH2Ph),
2.79 (m, 1H, H-6), 3.46 (dd, Jˆ11.3, 2.3 Hz, 1H, CH-O),
3.68 (d, Jˆ11.8 Hz, 1H, CH-O), 3.70 (m, 1H, H-4 overlap
with CH-O) 3.73 (d, Jˆ11.3 Hz, 1H, CH-O), 3.83 (dd,
Jˆ11.8, 2.2 Hz, 1H, CH-O), 7.17±7.29 (m, 5H, C6H5). dC
(APT) 22.52, 25.58, 28.15, 32.04, 36.56, 38.52, 38.98,
42.10, 48.00 (2), 50.88, 62.49, 65.43 (2), 70.01, 98.50,
125.82 (2), 128.35 (2), 128.40 (2), 141.702. IR (neat):
3332, 2936, 1664, 1448, 1156, 1108 cm21. HRMS (EI)
m/z calcd for C21H21NO3 (M1) 345.2304, found 345.2292.
3.3.6. cis-2,2-Bis(hydroxymethyl)-4-hydroxy-6-phenyl-
piperidine (9ab). Deprotection of 8ab (0.2 g, 0.63 mmol)
gave 9ab (0.13 g, 87%; the overall yield was 74%) as a
colorless glass. dH 1.27 (dd, Jˆ12.8, 11.8 Hz, 1H, H-3a),
1.51 (ddd, Jˆ12.0, 12.1, 11.3 Hz, 1H, H-5a), 2.00 (ddd,
Jˆ12.8, 4.5, 1.7 Hz, 1H, H-3e), 2.16 (dddd, Jˆ12.0, 4.5,
2.3, 1.7 Hz, 1H, H-5), 3.50 (AB, Dˆ0.05, Jˆ11.3 Hz, 2H,
CH2OH), 3.75 (AB, Dˆ0.4, Jˆ12.0 Hz, 2H, CH2OH), 3.99
(dd, Jˆ12.1, Jˆ2.3 Hz, 1H, H-6), 4.09 (dddd, Jˆ11.8, 11.3,
4.5, 4.5 Hz, 1H, H-4). dC (APT) 38.05, 43.22, 51.51 (2),
60.96, 62.15, 68.02 (2), 69.145, 129.47 (2), 130.45 (2),
131.48 (2), 144.70. IR (KBr): 3336, 2948, 1448,
1108 cm21. HRMS (LSIMS) m/z calcd for C13H20NO3
(M1H1) 238.1443, found 238.1445.
3.3.3. cis-4-Hydroxy-6-(2-thienyl)piperidine-2-spiro-50-
(10,30-dioxan)-2-0spiro-100-cyclohexane
(8ak).
6ak
(0.115 g, 0.36 mmol) was hydrogenated in the presence of
Raney Nickel (0.3 g) and DMSO (0.3 mL) under 10 bar for
29 h. at 908C. 8ak was puri®ed as 8ag to yield a colorless
glass (0.085 g, 73%). dH 1.15 (dd, Jˆ12.4, 11.4 Hz, 1H,
H-3a), 1.40 (m, 2H, C6H10), 1.45±1.56 (m, 5H, H-5a,
C6H10), 1.61 (m, 2H, C6H10), 1.79 (ddd, Jˆ11.9, 4.6,
1.9 Hz, 1H, H-3e), 1.84 (m, 2H, C6H10), 2.19 (dddd,
Jˆ11.9, 4.5, 2.5, 1.9 Hz, 1H, H-5e), 2.38 (bs, 2H, NH,
OH), 3.52 (dd, Jˆ11.4, 2.3 Hz, 1H, CH-O), 3.75 (d,
Jˆ11.4 Hz, 1H, CH-O), 3.76 (d, Jˆ11.9 Hz, 1H, CH-O),
3.3.7. cis-2,2-Bis(hydroxymethyl)-4-hydroxy-6-(phenyl-
methyl)piperidine (9ah). 6ah (0.235 g, 0.71 mmol) was
hydrogenated in the presence of 10% Pd±C (0.15 g) under
8 bar for 23 h. Deprotection of crude 8ah yielded 9ah
(0.145 g, 81%) as a colorless glass. dH 1.08 (ddd, Jˆ12.3,
11.5, 11.5 Hz, 1H, H-5a), 1.13 (dd, Jˆ12.8, 11.5 Hz, 1H,
H-3a), 1.89 (ddd, Jˆ12.8, 4.65, 1.3 Hz, 1H, H-3e), 1.98 (m,

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A. Budzinska, W. Sas / Tetrahedron 57 (2001) 2021±2030
2030
1H, H-5e), 2.72 (dd, Jˆ13.4, 7.4 Hz, 1H, CH2Ph), 2.76 (dd,
Jˆ13.4, 6.5 Hz, 1H, CH2Ph), 3.10 (m, 1H, H-6), 3.40 (AB,
Dˆ0.02, Jˆ11.3 Hz, CH2OH), 3.56 (AB, Dˆ0.02,
Jˆ11.9 Hz, CH2OH), 3.92 (Jˆ11.5, 4.6 Hz, 1H, H-4),
7.27±7.41 (m, 5H, C6H5). dC 38.60, 42.27, 44.51, 52.61,
60.03, 61.76, 67.80, 69.35, 129.34, 131.39, 132.03,
Research (KBN) for ®nancial support of this workÐGrant
3T09A 012 013.
References
141.19. IR (KBr): 3416, 1632, 1496 cm21
. HRMS
1. Lumma, Jr., W. C. J. Am. Chem. Soc. 1969, 91, 2820±2821.
2. Oppolzer, W.; Siles, S.; Snowden, R. L.; Bakker, B. H.;
Petrzilka, M. Tetrahedron Lett. 1979, 4391±4394.
3. Oppolzer, W.; Siles, S.; Snowden, R. L.; Bakker, B. H.;
Petrzilka, M. Tetrahedron 1985, 41, 3497±3509.
4. Hoffmann, R. W.; Endesfeldr, A. Liebigs Ann. Chem. 1986,
1823±1836.
(LSIMS) m/z calcd for C14H22NO3 (M1H1) 252.1600
found 252.1591.
3.3.8. cis-2,2-Bis(hydroxymethyl)-4-hydroxy-6-(2-pyri-
dyl)piperidine (9aj). Crude 6aj (0.316 g, 1 mmol) was
hydrogenated in the presence of 10% Pd±C (0.15 g) under
9 bar for 21 h. Chromatographic puri®cation (chloroform±
methanol, 9:1,v/v) afforded 0.155 g (49%) of 8aj. This
(0.1 g, 0.31 mmol) was deprotected to give 9aj (0.056 g,
76%; the summary yield 37%) as a as a colorless glass.
dH 1.44 (dd, Jˆ13.2, 11.5 Hz, 1H, H-3a), 1.58 (ql,
Jˆ12.1 Hz, 1H, H-5a), 2.07 (ddd, Jˆ13.2, 4.5, ca. 1.5 Hz,
1H, H-3e), 2.36 (m, 1H, H-5e), 3.62 (bs, 2H, CH2OH), 3.81
(AB, Dˆ0.09, Jˆ12.2 Hz, 2H, CH2OH), 4.21 (tt, Jˆ11.5,
4.5 Hz, 1H, H-4), 4.30 (bd, Jˆ11.4 Hz, 1H, H-6), 7.42 (dd,
Jˆ7.0, 5.2 Hz, 1H, C5H4N), 7.51 (d, Jˆ7.9 Hz, 1H, C5H4N),
7.91 (ddd Jˆ7.9, 7.0, 1.4 Hz, 1H of C5H4N), 8.54 (db,
Jˆ4.6 Hz, 1H, C5H4N), dC 36.79, 40.49, 57.15, 61.44,
64.44, 66.13, 67.01, 124.88, 126.92, 141.32, 151.79,
158.27. IR (KBr): 3412, 1620, 1452, 1032 cm21. HRMS
(LSIMS) m/z calcd for C12H18N2NaO3 (M1Na1)
261.1215 found 261.1223.
5. Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957±1965.
6. Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 5989±
5994.
7. Padwa, A.; Norman, B. H. Tetrahedron Lett. 1988, 29, 2417±
2420.
8. Norman, B. H.; Gareau, Y.; Padwa, A. J. Org. Chem. 1991, 56,
2154±2161.
9. Grigg, R.; Markandu, J.; Surendrakumar, S. Tetrahedron Lett.
1990, 31, 2417±2420.
10. Grigg, R.; Dorrity, M. J.; Heaney, F.; Malone, J. F.;
Rajviroongit, S.; Sridharan, V.; Surendrakumar, S. Tetrahedron
1991, 47, 8297±8322.
11. Chen, Q.; Yu, X.; Zhang, T.; Jia, X. Acta Chim. Sin. (Engl.
Ed.) 1989, 176 (Chem. Abstr., 1990, 112, 158107f).
È
12. Lau, H. H.; Scholkopf, U. Liebigs Ann. Chem. 1981, 1378±
1387.
13. Tufariello, J. J.; Trybulski, E. J. J. Chem. Soc., Chem.
Commun. 1973, 720.
3.3.9.
(^)(4Sp,5Sp,6Sp)-2,2-bis(hydroxymethyl)-4-hy-
14. Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Tetrahedron
1982, 38, 1321±1327.
droxy-5-methyl-6-phenylpiperidine (9bb). The adduct
6bb (0.33 g, 1 mmol) was hydrogenated for 20 h as it was
described for 6ab. Crude 8bb was deprotected to give after
chromatographic puri®cation 9bb (0.185 g, 73%) as a color-
less glass. dH 0.60 (d, Jˆ7.1 Hz, 3H, CH3), 1.58 (dd,
Jˆ13.3, 12.3 Hz, 1H, H-3a), 1.68 (dd, Jˆ13.3, 4.8 Hz,
1H, H-3e), 2.21 (m, 1H, H-5a), 3.59 (AB, Dˆ0.04,
Jˆ11.3 Hz, 2H, CH2OH), 3.68 (AB, Dˆ0.03, Jˆ12.0 Hz,
CH2OH), 4.19 (d, Jˆ2.5 Hz, 1H, H-6), 4.27 (ddd, Jˆ12.3,
4.8, 4.6 Hz, 1H, H-4), 7.31±7.44 (m, 5H, C6H5). dC 6.07,
30.89, 42.55, 58.59, 60.75, 62.98, 69.18, 70.94, 129.09,
129.66, 131.08, 143.90. IR (neat): 3352, 2940, 1656,
15. Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Polish J. Chem.
1981, 55, 1469±1472.
16. Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Monatsh 1982,
113, 1221±1224.
17. Ferroud, D.; Genet, J. P.; Muzart, J. Tetrahedron Lett. 1984,
25, 4379±4382.
18. Genet, J. P.; Ferroud, D. Tetrahedron Lett. 1984, 25, 3579±3582.
19. Genet, J. P.; Grisoni, S. Tetrahedron Lett. 1986, 4165, 00 (see
also 1988, 29 4543±4546).
20. Chittari, P.; Jadhav, V. R.; Gansh, K. N.; Rajappa, S. J. Chem.
Soc., Perkin Trans. 1 1998, 1319±1324.
Â
21. Budzinska, A.; Bukowska, M.; Sas, W. Tetrahedron Lett.
1452, 1152 cm21
. HRMS (LSIMS) m/z calcd for
C14H22NO3 (M1H1) 252.1600 found 252.1596.
1999, 40, 565±568.
22. Sinnott, M. L. Chem. Rev. 1990, 90, 1171±1202.
 Â
23. Koszytkowska-Stawinska, M.; Sas, W.; Sowinska, A.
3.3.10. (^)(4Sp,6Sp)-2,2-bis(hydroxymethyl)-4-hydroxy-
4-methyl-6-phenylpiperidine (9cb). 9cb (87%) was
obtained as a colorless glass in the way described for 9bb.
dH 1.46 (s, 3H, CH3), 1.54 (d, Jˆ13.9 Hz, 1H, H-3a), 1.72
(dd, Jˆ12.8, 12.1 Hz, 1H, H-5a), 1.92 (dd, Jˆ13.9, ca. 1 Hz,
1H, H-3e), 1.92 (ddd, Jˆ12.8, 2.2, ca. 1 Hz, 1H, H-5e), 3.50
(AB, Dˆ0.05, Jˆ11.3 Hz, CH2OH), 3.75 (s, 2H, CH2OH),
3.95 (dd, Jˆ12.1, 2.2 Hz, 1H, H-6), 7.35±7.45 (m, 5H,
C6H5). dC 30.91, 42.21, 48.65, 55.31, 60.44, 63.06, 70.09,
72.92, 129.45, 130.40,131.53, 145.29. IR (KBr): 3392,
1630, 1436, 1132 cm21. HRMS (LSIMS) m/z calcd for
C14H22NO3 (M1H1) 252.1600 found 252.1612.
J. Chem. Res., Synop. 1996, 162±163.
24. Calder, A.; Forrester, A. R.; Hepburn, S. P. Organic Synth-
eses; Collect. Vol. 6; Wiley: New York, 1988; pp 804±806.
25. Bianchi, G.; DeMicheli, C.; Gandol®, R. J. Chem. Soc., Perkin
Trans. 1 1976, 1518±1523.
26. Nitrile oxides, Nitrones and Nitronates in Organic Synthesis,
Novel Strategies in Organic Synthesis, Torssell, K. B. G., Ed.;
VCH: New York, 1988; Chapter 1.7.
27. Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351±3354.
28. Rylander, P. N. Hydrogenation Methods; Academic: London,
1985; pp 157±165.
Acknowledgements
We are grateful to the Polish State Committee for Scienti®c