Synthesis of bicyclic carbamates as precursors of Sedum alkaloid derivatives

Article abstract of DOI:10.1016/j.tet.2004.08.073

Synthesis of a N-Boc-protected piperidin-2-yl phosphine oxide starting from piperidine in three steps, followed by olefination using a variety of α,β-unsaturated aldehydes resulted in tert-butyl 2-(2′- alkenylidene)piperidine-1-carboxylates in high yields

Full text of DOI:10.1016/j.tet.2004.08.073

Tetrahedron 61 (2005) 1595–1602
Synthesis of bicyclic carbamates as precursors
of Sedum alkaloid derivatives
a,b
¨ ¨
Zsolt Szakonyi, Matthias D’hooghe, Ivan Kanizsai, Ferenc Fulop and Norbert De Kimpe
a
a,b
b
a,
*
´
aDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
bInstitute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 121, Hungary
Received 2 June 2004; revised 20 August 2004; accepted 20 August 2004
Available online 6 January 2005
Abstract—Synthesis of a N-Boc-protected piperidin-2-yl phosphine oxide starting from piperidine in three steps, followed by olefination
using a variety of a,b-unsaturated aldehydes resulted in tert-butyl 2-(20-alkenylidene)piperidine-1-carboxylates in high yields. A novel type
of intramolecular cyclization of these enamides furnished a new family of 3-alkyl-4,6,7,8-tetrahydro-3H-pyrido[1,2-c][1,3]oxazin-1-ones as
useful substrates for further elaboration. Subsequent reduction of these unsaturated bicyclic carbamates using NaCNBH3 or NaBH4 afforded
the corresponding 3-alkylhexahydropyrido[1,2-c][1,3]oxazin-1-ones in a highly stereoselective way. Reductive ring opening of two
representatives furnished the corresponding Sedum alkaloid derivatives in good yields.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
cycloaddition reactions with nitrones and by other tech-
niques for construction of the heterocycle, such as
intramolecular Michael additions, metathesis reactions,
condensations (e.g., between an imine and an ester or
between an aminoalcohol and an aldehyde) and alkylations
with haloalkanes (e.g., using an a-cyanopiperidine) or
haloalkenes and epoxides (with e.g., dithiane).2
Biologically active alkaloids bearing a substituted piper-
idine ring have been the objective of considerable synthetic
efforts.1,2 Among others, the Sedum alkaloids constitute an
extensive family of 2-substituted and 2,6-disubstituted
piperidines, many of which feature the 1,3-aminoalcohol
moiety, for example, allosedridine (1 [2R-(20S)], R1ZR2Z
R3ZH), sedridine (1 [2S-(20S)], R1ZR2ZR3ZH) and
halosaline (1, R1ZEt, R2ZR3ZH) (Fig. 1).2–5 Although
the interest in the synthesis of these alkaloids has been
ongoing for nearly half a century, the synthetic derivatives
have mainly been used as a testing ground for the control of
the stereochemistry of the 1,3-aminoalcohol system.2 Only
recently the memory-enhancing properties and the potential
use as anti-Alzheimer agents have put the Sedum alkaloids
in a new perspective,6 hence the renewed interest in the
preparation of these compounds and related structures with
potential physiological activities. A large variety of
syntheses towards Sedum alkaloids are known in the
literature. Most of these strategies are based on the use of
a preformed nitrogen heterocycle onto which a side-chain is
appended. This group can be subdivided into those
involving a pyridine and those involving a piperidine
moiety.2 Sedum alkaloids have also been synthesized by
A key intermediate in many synthetic pathways towards
Sedum alkaloids is the bicyclic carbamate 2, since cleavage
of this moiety affords the desired 1,3-aminoalcohol unit and
liberates the piperidine ring (Fig. 1).2 In this report a novel
synthesis of unsaturated bicyclic carbamates as precursors
of Sedum alkaloid derivatives is described, based on the
intramolecular nucleophilic attack of a N-Boc group onto an
in situ formed iminium species. According to the retro-
synthetic pathway in Figure 1, bicyclic carbamates 2 can be
prepared by cyclization of enamides 3, which can be useful
starting materials for the synthesis of piperideine alkaloids
4, for example, nigrifactin (R1Z(2E)-butenylidene, R2ZH)
or 2-(20-propenyl)-1-piperideine (R1ZR2ZH), an alkaloid
from the leaves of Punica granatum.7–9
2. Results and discussion
The synthetic pathway leading to 2-(20-alkenylidene)piperi-
dine-1-carboxylates 3a–f and 9 is depicted in Scheme 1. The
phosphorylated carbamate 5 was readily prepared in three
steps via the formation of the 2,3,4,5-tetrahydropyridine
Keywords: Enamide; Bicyclic carbamate; Stereoselectivity; Sedum
alkaloid.
* Corresponding author. Tel.: C32-92645951; fax: C32-92646243;
e-mail: norbert.dekimpe@UGent.be
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.073

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Z. Szakonyi et al. / Tetrahedron 61 (2005) 1595–1602
Figure 1.
Scheme 1. (i) t-BuOCl, Et2O, 0 8C, then 2 N NaOMe, MeOH, 45 min reflux; 65%; (ii) 1 equiv Ph2P(O)H, toluene, 3 h reflux; 92%; (iii) 1.2 equiv Boc2O,
1 equiv triethylamine, 5 mol% DMAP, THF, 40 8C, 6 h; 78%; (iv) 1.25 equiv BuLi, THF, K78 8C, 1 equiv of R1R2C]CH–CHO, with a: R1ZR2ZH; b: R1Z
Me, R2ZH; c: R1ZPh, R2ZH; d: R1ZMe, R2ZMe; e: R1Zi-Pr, R2ZH; f: R1Z4-MeOC6H4, R2ZH; 5: 33–68% after chromatography; (v) 1.25 equiv BuLi,
1 equiv PhCHO, THF, K78 8C to rt, 2 h, 90%; (vi) 19 equiv TFA, CH2Cl2, 0 8C, 30 min, 81%.
trimer 6 from piperidine using t-BuOCl and NaOMe,10
followed by phosphorylation with 1 equiv of diphenylphos-
phine oxide in toluene and protection of the resulting amine
8 with 1.2 equiv of di-tert-butyl dicarbonate, 1 equiv of
triethylamine and 5 mol% DMAP in THF, furnishing the
Boc-protected piperidin-2-yl phosphine oxide 5 in 78%
yield.10–12 The modified Horner reaction between this
phosphorylated carbamate 5 and 1 equiv of various a,b-
unsaturated aldehydes or benzaldehyde using 1.25 equiv of
BuLi in THF at K78 8C resulted in new enamides 3a–f and
9 in good to excellent yields after 2 h at room temperature
(Scheme 1).12,13
CH2Cl2 afforded 2-benzylpiperideine 10 in 81% yield.14,15
Consequently, this method seemed suitable for the prepar-
ation of piperideine alkaloids, for example, 2-(20-propenyl)-
1-piperideine (R1ZR2ZH), an alkaloid in the pomegranate
(see 4, Fig. 1).7 Although Boc-deprotection of enamides 3
bearing a diene function was attempted using an excess of
TFA in CH2Cl2 or 1.5 equiv of trimethylsilyl iodide in
CH3CN, only a complex mixture of unknown compounds
was obtained, even though the conditions applied were very
mild (K10 to 0 8C, workup at 0 8C) (Scheme 2).
Further investigation of the literature lead to the application
of other methods for the removal of a N-Boc group, for
example, the use of Me3SiI and phenol in CH2Cl2. To the
Deprotection of enamide 9 using an excess of TFA in
Scheme 2. (i) TFA, CH2Cl2, 0 8C to rt, 30 min; (ii) 1.5 equiv TMS-I, 1.5 equiv H2O, MeCN; (iii) 1.5 equiv TMS-I, 1.5 equiv phenol, CH2Cl2, rt, 30 min; a:
R1ZR2ZH; b: R1ZMe, R2ZH; c: R1ZPh, R2ZH; d: R1ZMe, R2ZMe; e: R1Zi-Pr, R2ZH; f: R1Z4-MeOC6H4, R2ZH; 41–70% after chromatography.

Z. Szakonyi et al. / Tetrahedron 61 (2005) 1595–1602
1597
enamides 3a–f was added a mixture of 1.5 equiv of
trimethylsilyl iodide and 1.5 equiv of phenol in CH2Cl2,
resulting in the unsaturated bicyclic carbamates 11a–f in
good yields after 30 min at room temperature (Scheme 2),
which were subsequently purified by means of column
chromatography.
NOESY experiments revealed that the major component
was the cis-isomer. Reduction of carbamate 11c with
4 equiv of NaBH4 in glacial AcOH resulted selectively in
the cis compound 2c. Reduction of the saturated bicyclic
carbamates 2a and 2b with 2 equiv of LiAlH4 in THF upon
reflux for 1 h, followed by purification on silica gel, gave
rise to the known racemic Sedum alkaloids (2R*,20S*)-N-
methylallosedridine 1a and (2R*,20S*)-1-(1-methylpiperi-
din-2-yl)butan-2-ol 1b.19–21
The reactivity of the N-Boc protecting group has been well
documented in the literature.16 An important feature of the
N-Boc group is the possibility to react intramolecularly as
an electrophile or as a nucleophile, furnishing a cyclic
carbamate. The intramolecular nucleophilic reactivity
generally results from the presence of an electrophilic
carbon atom due to a carbenium ion, a halonium ion or a
good leaving group attached to the electrophilic centre. This
centre is then attacked by the substantial negative charge on
the carbonyl oxygen of the Boc-group.17 Indeed, the
combination of trimethylsilyl iodide and phenol leads to
the formation of trimethylsilyl phenoxide with the liberation
of hydrogen iodide.18 In this medium, the Boc-group of
compound 3 is cleaved upon expulsion of isobutene, and the
iminium species 13, in situ formed due to the presence of
hydrogen iodide, undergoes intramolecular trapping by the
oxygen anion furnishing carbamate 14. It should be noted
that the double bond in compound 14 shifts from its initial
position in the carbamate ring to the piperidine ring upon
isomerization in the acidic medium, resulting in the isolated
carbamates 11 (Scheme 3).
3. Conclusions
A new, efficient and straightforward synthesis of 3-alkyl-
4,6,7,8-tetrahydro-3H-pyrido[1,2-c][1,3]oxazin-1-ones has
been developed, based on the synthesis of an N-Boc-
protected piperidin-2-yl phosphine oxide in three steps from
piperidine, followed by olefination with a variety of a,b-
unsaturated aldehydes and finally a new type of intra-
molecular cyclisation of the N-Boc group onto an in situ
formed iminium species upon treatment with trimethylsilyl
iodide and phenol in dichloromethane. Subsequent
reduction of the resulting unsaturated bicyclic carbamates
with NaCNBH3 or NaBH4 in glacial AcOH and reductive
ring opening furnished the corresponding Sedum alkaloid
derivatives in good yields.
4. Experimental
When the unsaturated bicyclic carbamates 11a and 11b
were reduced with either 3 equiv of NaCNBH3 in MeOH or
with 4 equiv of NaBH4, both in glacial AcOH, a mixture of
diastereomers of the saturated carbamates 2 [2a (cis/transZ
86/14) and 2b (cis/transZ88/12)] was obtained (Scheme 4).
1H NMR spectra were recorded at 270 MHz (JEOL JNM-
EX 270) or at 300 MHz (JEOL EclipseC 300) or at
400 MHz (Bruker Avance DRX 400 spectrometer), with
CDCl3 as solvent and TMS as internal standard. 13C NMR
Scheme 3.
Scheme 4. (i) 3 equiv NaCNBH3, MeOH, reflux, 72 h or 4 equiv NaBH4, AcOH, rt, 5 h; a: RZH, cis/transZ86/14; b: RZMe, cis/transZ88/12; c: RZPh,
cis/transZ100/0 (4 equiv NaBH4, AcOH, rt, 3 h); 80%; (ii) LiAlH4, THF or Et2O, reflux; 1 h; 65–66%, then flash chromatography.

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Z. Szakonyi et al. / Tetrahedron 61 (2005) 1595–1602
spectra were recorded at 68 MHz (JEOL JNM-EX 270) or at
75 MHz (JEOL ECLIPSEC 300) in CDCl3. IR spectra were
measured with a Perkin–Elmer Spectrum One FT-IR. Mass
spectra were recorded with an Agilent 1100 (series: MS,
detector: VL, 70 eV, ES 4000 V) or with a (Varian MAT
112 (70 eV) mass spectrometer using GC–MS coupling
(RSL 200, 20 m glass capillary column, i.d. 0.53 mm, He
carrier gas). Microanalyses were determined on a Perkin–
Elmer 2400 elemental analyser. Melting points were
performed on a Kofler apparatus and are uncorrected.
Et2O and THF were dried by distillation over sodium
benzophenone ketyl. Ethanol was used as received from the
supplier. 2,3,4,5-Tetrahydropyridine trimer 6, 2-(diphenyl-
phosphinoyl)piperidine 8 and its Boc carbamate derivative 5
were prepared according to literature methods.10–12
(NC]CH); and 153.1 (C]O). MS (70 eV) m/z (%): 223
(MC, 12); 167 (90); 152 (25); 150 (11); 123 (42); 122 (69);
108 (39); 95 (12); 94 (22); 80 (17); 67 (9); 57 (100); 55 (13);
and 41 (49). Anal. calcd for C13H21NO2 (223.31): C, 69.92;
H, 9.48; N, 6.27; found C, 69.81; H, 9.56; N, 6.19.
4.1.2. tert-Butyl 2-[(20E)-20-butenylidene]piperidine-1-
carboxylate 3b. Mixture of E and Z isomers, ratio E/ZZ
86/14. Flash chromatography (petrol ether/EtOAc 9/1,
RfZ0.70). Yield: 54%, yellow oil. IR (NaCl, cmK1):
1
nC]OZ1694. Major isomer: H NMR (270 MHz, CDCl3):
d 1.26–1.79 (8H, m, CH3, (CH2)2CH2N and (HCH)N); 1.45
(9H, s, tBu); 2.14 (2H, br s, CH2(CH2)3N); 3.35–3.38 (1H,
m, (HCH)N); 5.59–5.70 (2H, m, Ha and Hc); and 5.96–6.06
(1H, m, Hb). 13C NMR (68 MHz, CDCl3): d 18.3 (CH3);
25.6 and 26.8 (NCH2(CH2)2); 28.3 ((CH3)3C); 33.1
(N(CH2)3CH2); 46.7 (CH2N); 79.5 ((CH3)3C); 123.2,
126.5 and 141.4 (CHa, CHb and CHc); 136.9 (NC]CH);
and 153.6 (C]O). MS (70 eV, direct inlet) m/z (%): 237
(MC, 14); 181 (100); 164 (21); 137 (27); 136 (78); 122 (30);
4.1. General method for the synthesis of tert-butyl 2-(20-
alkenylidene)piperidine-1-carboxylates 3a–f and 9
As a representative example, the synthesis of tert-butyl 2-
(20-propenylidene)piperidine-1-carboxylate 3a is described.
To a solution of phosphorylated piperidine derivative 5
(0.39 g, 1 mmol) in THF (5 mL), n-BuLi (0.5 mL,
1.25 mmol, 2.5 M in n-hexane) was added dropwise at
K78 8C under a N2 atmosphere. The orange mixture was
stirred for 20 min at K78 8C, followed by the addition of a
solution of acrolein (0.056 g, 1 mmol) in THF (2 mL) via a
syringe. After a further stirring period of 20 min at K78 8C,
the reaction mixture was allowed to warm up to room
temperature during stirring for 2 h. Addition of water
(10 mL), extraction with Et2O (3!10 mL), drying
(MgSO4), filtration and evaporation in vacuo afforded the
crude product 3a, which was purified by column chroma-
tography with petrol ether/ethyl acetate (90/10), yielding
pure 3a (0.105 g, 47%). All NMR data of compounds 3a–f
are derived from mixtures of the E and Z-isomers at position 2.
1
108 (28); 94 (20); 57 (55); and 41 (17). Minor isomer: H
NMR (270 MHz, CDCl3): d 1.26–1.79 (8H, m, CH3,
(CH2)2CH2N and (HCH)N); 1.45 (9H, s, tBu); 2.28–
2.30 (2H, m, CH2(CH2)3N); 3.48–3.52 (1H, m, (HCH)N);
5.39–5.55 (1H, m, Hc); 5.88 (1H, d, JZ10.9 Hz, Ha);
and 6.17–6.29 (1H, m, Hb). 13C NMR (68 MHz, CDCl3): d
18.42 (CH3); 25.8 and 27.0 (NCH2(CH2)2); 28.5 ((CH3)3C);
33.7 (N(CH2)3CH2); 46.3 (CH2N); 79.5 (CH3)3C); not
recognizable (CHa, CHb, CHc); 136.3 (NC]CH); and
153.6 (C]O). MS (70 eV) m/z (%): 237 (MC, 13); 181
(100); 164 (7); 137 (29); 136 (87); 122 (36); 108 (29); 94
(21); 57 (71); and 41 (23). Anal. calcd for C14H23NO2
(237.41): C, 70.85; H, 9.77; N, 5.90; found C, 70.98; H,
9.86; N, 5.83.
4.1.3. tert-Butyl 2-[(20E)-30-phenyl-20-propenylidene]
piperidine-1-carboxylate 3c. Mixture of E and Z isomers,
ratio E/ZZ76/24. Flash chromatography (petrol ether/
EtOAc 9/1, RfZ0.42). Yield: 68%, white crystals, mp:
106–107 8C. IR (NaCl, cmK1): nC]OZ1691. Major isomer:
1H NMR (270 MHz, CDCl3): d 1.28–1.73 (5H, m,
(CH2)2CH2N and (HCH)N); 1.47 (9H, s, tBu); 2.20–2.25
(1H, m, (HCH)(CH2)3N); 2.44 (1H, t, JZ5.9 Hz,
(HCH)(CH2)3N); 3.55 (1H, t, JZ5.5 Hz, (HCH)N); 5.92
and 6.47 (2!1H, 2!d, JZ11.2, 15.5 Hz, Ha and Hc); 6.77
(1H, dd, JZ11.2, 15.5 Hz, Hb); and 7.19–7.41 (5H, m,
C6H5). 13C NMR (68 MHz, CDCl3): d 25.4 and 25.5
(NCH2(CH2)2); 28.3 ((CH3)3C); 33.4 (N(CH2)3CH2); 46.6
(CH2N); 79.9 ((CH3)3C); 121.7, 127.3 and 130.6 (CHa, CHb
and CHc); 124.7 (HCpara); 126.3 and 128.6 (2!HCortho and
2!HCmeta); 137.64 (NC]CH); 139.6 (Carom,quat); and
153.6 (C]O). MS (70 eV, direct inlet) m/z (%): no MC;
243 (MC-isobutene, 100); 199 (63); 156 (15); 115 (17); 97
(11); 57 (31); and 41 (15). Minor isomer: 1H NMR
(270 MHz, CDCl3): d 1.28–1.73 (5H, m, (CH2)2CH2N and
(HCH)N); 1.46 (9H, s, tBu); 2.20–2.46 (2H, m,
CH2(CH2)3N); 3.34–3.40 (1H, m, (HCH)N); 6.12 and 6.51
(2!1H, 2!d, JZ11.2, 15.5 Hz, Ha and Hc); 6.98 (1H, dd,
JZ11.2, 15.5 Hz, Hb); and 7.19–7.41 (5H, m, C6H5). 13C
NMR (68 MHz, CDCl3): recognizable signal: d 28.5
((CH3)3C). Anal. calcd for C19H25NO2 (299.41): C, 76.22;
H, 8.42; N, 4.68; found C, 76.05; H, 8.25; N, 4.80.
4.1.1. tert-Butyl 2-[(20E)-20-propenylidene]piperidine-1-
carboxylate 3a. Mixture of E and Z-isomers, ratio E/ZZ67/
33. Flash chromatography (petrol ether/EtOAc 9/1, RfZ
0.58). Yield: 47%, pale-yellow oil. IR (NaCl, cmK1):
nC]OZ1712. Major isomer: 1H NMR (270 MHz, CDCl3): d
1.26–1.69 (5H, m, (CH2)2CH2N and (HCH)N); 1.45 (9H, s,
tBu);2.12–2.21(2H,m,CH2(CH2)3N);3.52(1H, t,JZ5.5 Hz,
(HCH)N); 4.99 (1H, d, JZ10.6 Hz, CH](HCH)); 5.14
(1H, d, JZ17.0 Hz, CH](HCH)); 5.77 (1H, d, JZ10.6 Hz,
NC]CH); and 6.32 (1H, dt, JZ10.6, 17.0 Hz,
NC]CHCH). 13C NMR (68 MHz, CDCl3): d 25.4 and
26.6 (NCH2(CH2)2); 28.2 ((CH3)3C); 33.0 (N(CH2)3CH2);
46.5 (CH2N); 79.7 ((CH3)3C); 115.3 (CH]CH2); 122.0 and
132.6 (NC]CHCH); 139.0 (NC]CH) and 153.1 (C]O).
MS (70 eV) m/z (%): 223 (MC, 14); 167 (100); 152 (29);
150 (24); 123 (51); 122 (65); 108 (41); 95 (12); 94 (28); 80
(20); 67 (11); 57 (69); 55 (13); and 41 (41). Minor isomer:
1H NMR (270 MHz, CDCl3): d 1.26–1.69 (5H, m,
(CH2)2CH2N and (HCH)N); 1.46 (9H, s, tBu); 2.08–2.18
(2H, m, CH2(CH2)3N); 3.35–3.38 (1H, m, (HCH)N); 5.07–
5.21 (2H, m, CH]CH2); 5.95 (1H, d, JZ10.6 Hz,
NC]CH); and 6.55 (1H, dt, JZ10.6, 10.8 Hz,
NC]CHCH). 13C NMR (68 MHz, CDCl3): d 25.3 and
26.9 (NCH2(CH2)2); 28.3 ((CH3)3C); 33.0 (N(CH2)3CH2);
46.3 (CH2N); not recognizable ((CH3)3C); 116.2
(CH]CH2); 124.1 and 131.8 (NC]CHCH); 139.1

Z. Szakonyi et al. / Tetrahedron 61 (2005) 1595–1602
1599
1
4.1.4. tert-Butyl 2-[(20E)-30-methyl-20-butenylidene]
piperidine-1-carboxylate 3d. Mixture of E and Z isomers,
ratio E/ZZ86/14. Flash chromatography (petrol ether/
EtOAc 9/1, RfZ0.67). Yield: 60%, yellow oil. IR (NaCl,
nC]OZ1677. H NMR (300 MHz, CDCl3): d 1.22–1.73
(5H, m, (CH2)2CH2N and (HCH)N); 1.38 (9H, s, tBu);
2.11–2.32 (2H, m, CH2(CH2)3N); 2.77–2.79 (1H, m,
(HCH)N); 5.89 and 6.42 (2!1H, 2!d, JZ10.6, 15.7 Hz,
Ha and Hc); 6.63 (1H, dd, JZ10.6, 15.7 Hz, Hb); 6.83 (2H,
d, JZ8.7 Hz, 2!MeOCHortho); and 7.32 (2H, d, JZ8.7 Hz,
2!MeOCHmeta). 13C NMR (75 MHz, CDCl3): d 25.6 and
26.8 (NCH2(CH2)2); 28.3 ((CH3)3C); 33.3 (N(CH2)3CH2);
46.3 (CH2N); 55.3 (CH3O); 79.7 ((CH3)3C); 114.1 (2!
MeOHCortho); 121.8 (CHa or CHc); 122.7 (CHb); 128.6 (2!
MeOHCmeta); 128.5, 130.1, 138.6 (Carom,quat; NC]CH and
CHa or CHc); 153.9 (C]O); and 159.1 (COMe). MS
(70 eV) m/z (%): 329 (MC, 23); 273 (66); 256 (10); 229
(88); 228 (100); 214 (27); 186 (12); 97 (39); and 57 (22).
Anal. calcd for C20H27NO2 (329.43): C, 72.92; H, 8.26; N,
4.25; found C, 72.81; H, 8.16; N, 4.33.
1
cmK1): nC]OZ1677. Major isomer: H NMR (270 MHz,
CDCl3): d 1.35–1.93 (5H, m, (CH2)2CH2N and (HCH)N);
1.45 (9H, s, tBu); 1.74 and 1.78 (6H, 2!s, 2!CH3); 2.12–
2.19 (2H, m, CH2(CH2)3N); 3.51 (1H, t, JZ5.3 Hz,
(HCH)N); and 5.75 and 5.89 (2!1H, 2!d, JZ10.9 Hz,
Ha and Hb). 13C NMR (68 MHz, CDCl3): d 25.6 and 26.9
(NCH2(CH2)2); 26.1 (2!CH3); 28.3 ((CH3)3C); 33.4
(N(CH2)3CH2); 46.7 (CH2N); 79.3 ((CH3)3C); 119.8 and
120.9 (CHa and CHb); 136.4, 142.6 and 154.2 (3!Cquat).
MS (70 eV) m/z (%): 251 (MC, 12); 195 (100); 178 (12);
151 (17); 150 (29); 136 (60); 122 (8); 108 (10); 57 (36); and
41 (17). Minor isomer: 1H NMR (270 MHz, CDCl3): d
1.35–1.93 (5H, m, (CH2)2CH2N and (HCH)N); 1.43 (9H, s,
tBu); 1.81 and 1.90 (2!CH3); 2.12–2.19 (2H, m,
CH2(CH2)3N); 3.35 (1H, t, JZ5.3 Hz, (HCH)N); and 5.96
and 6.10 (2!1H, 2!d, JZ11.1 Hz, Ha and Hb). 13C NMR
(68 MHz, CDCl3): d 25.8 and 27.8 (NCH2(CH2)2); 25.6
(2!CH3); 28.5 ((CH3)3C); not recognizable (N(CH2)3CH2
and CH2N); and 79.4 ((CH3)3C); not recognizable (CHa,
CHb and 3!Cquat). MS (70 eV) m/z (%): no MC; 181 (100);
164 (17); 136 (73); 122 (29); 108 (28); 94 (22); 57 (77); and
41 (35). Anal. calcd for C15H25NO2 (251.36): C, 71.67; H,
10.02; N, 5.57; found C, 71.81; H, 9.87; N, 5.66.
4.1.7. tert-Butyl 2-benzylidenepiperidine-1-carboxylate
9. Mixture of E and Z isomers, ratio E/ZZ77/23. Flash
chromatography (petrol ether/EtOAc 9/1, RfZ0.65). Yield:
90%, white crystals, mp 86–88 8C. IR (NaCl, cmK1):
nC]OZ1652. Major isomer: 1H NMR (270 MHz, CDCl3): d
1.47 (9H, s, tBu); 1.54–1.67 (4H, m, (CH2)2CH2N); 2.39–
2.43 (2H, m, CH2(CH2)3N); 3.57–3.62 (2H, m, CH2N); 6.39
(1H, s, NC]CH); and 7.15–7.36 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): 25.6 and 27.3 (NCH2(CH2)2); 28.3
((CH3)3C); 34.1 (N(CH2)3CH2); 46.6 (CH2N); 79.6
((CH3)3C); 124.2 (HCpara); 126.4 (NC]CH); 128.1 and
128.7 (2!HCortho and 2!HCmeta); 136.7 (NC]CH); 139.3
(Carom,quat); and 154.2 (C]O). MS (70 eV, direct inlet) m/z
(%): 274 (MCC1, 8); 273 (MC, 16); 217 (80); 173 (37);
and 57 (100). Minor isomer: 1H NMR (270 MHz, CDCl3): d
1.47 (9H, s, tBu); 1.54–1.67 (4H, m, (CH2)2CH2N); 2.29–
2.31 (2H, m, CH2(CH2)3N); 3.35–3.38 (2H, m, CH2N); 6.05
(1H, s, NC]CH); and 7.15–7.36 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): 25.3 and 26.9 (NCH2(CH2)2); 27.7
((CH3)3C); 34.1 (N(CH2)3CH2); 45.8 (CH2N); 79.4
((CH3)3C); 120.5 and 126.5 (HCpara and NC]CH); 127.7
and 128.3 (2!HCortho and 2!HCmeta); 136.8 (NC]CH);
138.4 (Carom,quat); and 152.8 (C]O). Anal. calcd for
C17H23NO2 (273.37): C, 74.69; H, 8.48; N, 5.12; found C,
74.51; H, 8.61; N, 5.29.
4.1.5. tert-Butyl 2-[(20E)-40-methyl-20-pentenylidene]
piperidine-1-carboxylate 3e. Mixture of E and Z isomers,
ratio E/ZZ92/8. Flash chromatography (petrol ether/EtOAc
9/1, RfZ0.65). Yield: 53%, yellow oil. IR (NaCl, cmK1):
nC]OZ1692. Major isomer: 1H NMR (270 MHz, CDCl3): d
1.00 (6H, d, JZ6.9 Hz, CH(CH3)2); 1.42–1.68 (5H, m,
(CH2)2CH2N and (HCH)N); 1.42 (9H, s, tBu); 2.02–2.24
(2H, m, CH2(CH2)3N); 2.27–2.39 (1H, m, CH(CH3)2); 3.36
(1H, t, JZ5.3 Hz, (HCH)N); 5.55–5.71 (2H, m, Ha and Hc);
and 5.87–6.01 (1H, m, Hb). 13C NMR (68 MHz, CDCl3): d
22.4 (CH(CH3)2); 25.6 and 26.7 (NCH2(CH2)2); 28.3
((CH3)3C); 31.4 (CH(CH3)2); 33.1 (N(CH2)3CH2); 46.1
(CH2N); 79.4 ((CH3)3C); 121.7 and 140.3 (CHa and CHc);
123.1 (CHb); 136.4 (NC]CH); and 153.6 (C]O). MS
(70 eV) m/z (%): 265 (MC, 16); 209 (93); 194 (51); 164
(34); 150 (100); 136 (20); 122 (27); 97 (22); 57 (51); and 41
1
(15). Minor isomer: H NMR (270 MHz, CDCl3): d 1.01
4.1.8. 6-Benzyl-2,3,4,5-tetrahydropyridine 10. To a solu-
tion of 0.19 g (0.7 mmol) of tert-butyl 2-benzylidenepiperi-
dine-1-carboxylate 9 in dry CH2Cl2 (8 mL), TFA (1 mL)
was added in one portion at 0 8C. The mixture was stirred at
0 8C for 30 min (the reaction was monitored by means of
TLC) and subsequently the solution was poured onto ice-
cold water (20 mL), basified with 10% NaOH solution and
extracted with Et2O (3!25 mL). The combined organic
phases were dried (MgSO4) and evaporated, and the crude
product obtained was purified by flash chromatography on a
silica gel column with EtOAc/Et3N (9/1), resulting in
0.098 g (81%) of the oily cyclic imine 10. The spectroscopic
data on compound 10 corresponded to those reported in the
literature.15
(6H, d, JZ6.6 Hz, CH(CH3)2); 1.42–1.68 (5H, m,
(CH2)2CH2N and (HCH)N); 1.46 (9H, s, tBu); 2.02–2.24
(2H, m, CH2(CH2)3N); 2.27–2.39 (1H, m, CH(CH3)2); 3.50
(1H, t, JZ5.4 Hz, (HCH)N); 5.40–5.71 (2H, m, Ha and Hc);
and 6.11–6.17 (1H, m, Hb). 13C NMR (68 MHz, CDCl3): d
22.4 (CH(CH3)2); 25.8 and 27.0 (NCH2(CH2)2); 28.4
((CH3)3C); 31.5 (CH(CH3)2); not recognizable (N(CH2)3CH2
and CH2N); 79.5 ((CH3)3C); 122.1 and 141.3 (CHa and
CHc); 124.0 (CHb); 136.6 (NC]CH); and 153.6 (C]O).
MS (70 eV) m/z (%): 265 (MC, 12); 209 (82); 194 (41); 164
(40); 150 (100); 136 (11); 122 (54); 97 (24); 57 (53); and 41
(21). Anal. calcd for C16H27NO2 (265.39): C, 72.41; H,
10.25; N, 5.28; found C, 72.29; H, 10.20; N, 5.40.
4.1.6. tert-Butyl (2E)-2-[(20E)-30-(4-methoxyphenyl)-20-
propenylidene)]piperidine-1-carboxylate 3f. Flash chro-
matography (petrol ether/EtOAc 9/1, RfZ0.40). Yield:
33%, white crystals, mp 138–139 8C. IR (NaCl, cmK1):
IR (NaCl, cmK1): nC]OZ3368; 2928; 1660; 1483; 1110;
and 695. 1H NMR (CDCl3): d 1.50–1.62 (m, 4H, 2!CH2);
2.02–2.07 (m, 2H, CH2); 3.47 (s, 2H, CH2); 3.60–3.64 (m,
2H, CH2); and 7.19–7.23 (m, 5H, Ph). 13C NMR (CDCl3): d

1600
Z. Szakonyi et al. / Tetrahedron 61 (2005) 1595–1602
19.4; 21.6; 28.0; 48.1; 49.3; 126.3; 128.3; 128.9; 137.7; and
169.7.
4.40–4.49 (1H, m, OCH); 4.65–4.66 (1H, m, NC]CH); and
7.20–7.39 (5H, m, C6H5). 13C NMR (75 MHz, CDCl3): 21.8
(NCH2(CH2)2); 32.2 (NCCH2); 40.8 (CH2C6H5); 42.9
(CH2N); 76.5 (OCH); 104.1 (NC]CH); 127.0 (HCpara);
128.7 and 129.6 (2!HCortho and 2!HCmeta); 131.0
(NC]CH); 136.0 (Carom,quat); and 151.3 (C]O). MS
(70 eV) m/z (%): 243 (MC, 85); 199 (12); 198 (57); 184
(5); 170 (5); 122 (18); 108 (100); 97 (14); and 91 (33). Anal.
calcd for C15H17NO2 (243.30): C, 74.05; H, 7.04; N, 5.76;
found C, 73.95; H, 7.14; N, 5.85.
4.2. Synthesis of 3-alkyl-4,6,7,8-tetrahydro-3H-pyrido
[1,2-c][1,3]oxazin-1-ones 11a–f. As a representative
example, the synthesis of 3-methyl-4,6,7,8-tetrahydro-3H-
pyrido[1,2-c][1,3]oxazin-1-one 11a is described. To a
solution of Me3SiI (3.00 g, 15 mmol) and phenol (1.41 g,
15 mmol) in CH2Cl2 (40 mL), tert-butyl (2E)-2-(2-propenyl-
idene)piperidine-1-carboxylate 3a (2.23 g, 10 mmol) in
CH2Cl2 (10 mL) was added at room temperature, and the
resulting mixture was stirred for 30 min. The reaction
mixture was then poured into 4 N NaOH solution (20 mL),
extracted with CH2Cl2 (3!20 mL), dried (MgSO4), filtered
and evaporated in vacuo, furnishing crude 3-methyl-4,6,7,8-
tetrahydro-3H-pyrido[1,2-c][1,3]oxazin-1-one 11a, which
was purified by column chromatography with petrol ether/
EtOAc (3/2), yielding pure 11a (0.69 g, 41%).
4.2.4. 3-Isopropyl-4,6,7,8-tetrahydro-3H-pyrido[1,2-
c][1,3]oxazin-1-one 11d. Flash chromatography (petrol
ether/EtOAc 3/2, RfZ0.60). Yield: 48%, yellow oil. IR
(NaCl, cmK1): nC]OZ1677. 1H NMR (300 MHz, CDCl3):
d 0.96 and 1.02 (6H, 2!d, JZ6.9 Hz, (CH3)2); 1.75–1.94
(3H, m, NCH2CH2 and CHMe2); 2.05–2.12 (2H, m,
N(CH2)2CH2); 2.33–2.53 (2H, m, NCCH2); 3.46 (1H, ddd,
JZ4.1, 8.8, 12.9 Hz, (HCH)N); 3.89–3.97 (2H, m, (HCH)N
and OCH); and 4.68–4.71 (1H, m, NC]CH). 13C NMR
(75 MHz, CDCl3): 17.7 and 17.8 ((CH3)2); 21.8
(NCH2(CH2)2); 30.3 (NCCH2); 32.8 (CHMe2); 42.8
(CH2N); 80.7 (OCH); 103.5 (NC]CH); 131.5 (NC]CH);
and 151.9 (C]O). MS (70 eV) m/z (%): 195 (MC, 42); 150
(26); 136 (100); 122 (10); 110 (12); 108 (32); 94 (10); 80
(6); 55 (10); and 54 (8). Anal. calcd for C11H17NO2
(195.26): C, 67.66; H, 8.78; N, 7.17; found C, 67.51; H,
8.85; N, 7.28.
4.2.1.
3-Methyl-4,6,7,8-tetrahydro-3H-pyrido[1,2-
c][1,3]oxazin-1-one 11a. Flash chromatography (petrol
ether/EtOAc 3/2, RfZ0.25). Yield: 41%, pale-yellow oil.
IR (NaCl, cmK1): nC]OZ1666. 1H NMR (300 MHz,
CDCl3): d 1.36 (3H, d, JZ6.1 Hz, CH3); 1.80–1.98 (2H,
m, NCH2CH2); 2.02–2.08 (2H, m, N(CH2)2CH2); 2.29–2.51
(2H, m, NCCH2); 3.52 (1H, ddd, JZ4.8, 8.1, 12.9 Hz,
(HCH)N); 3.84–3.93 (1H, m, (HCH)N); 4.34–4.44 (1H, m,
CHO); and 4.70 (1H, br s, NC]CH). 13C NMR (75 MHz,
CDCl3): 20.42 (CH3); 21.8 (NCH2(CH2)2); 34.9 (NCCH2);
42.9 (CH2N); 72.4 (OCH); 103.7 (NC]CH); 130.4
(NC]CH); and 151.2 (C]O). MS (70 eV) m/z (%): 167
(MC, 70); 122 (100); 108 (40); 95 (42); 94 (21); 82 (26); 80
(25); 67 (13); 55 (20); 54 (29); and 41 (13). Anal. calcd for
C9H13NO2 (167.21): C, 64.65; H, 7.84; N, 8.38; found C,
64.76; H, 7.95; N, 8.31.
4.2.5. 3-Isobutyl-4,6,7,8-tetrahydro-3H-pyrido[1,2-c]
[1,3]oxazin-1-one 11e. Flash chromatography (petrol
ether/EtOAc 3/2, RfZ0.62). Yield: 70%, yellow oil. IR
(NaCl, cmK1): nC]OZ1673. 1H NMR (300 MHz, CDCl3):
d 2!0.93 (6H, 2!d, JZ6.6 Hz, (CH3)2); 1.62–1.71 (2H,
m, CH2CHMe2); 1.79–1.92 (3H, m, NCH2CH2 and
CHMe2); 2.05–2.07 (2H, m, N(CH2)2CH2); 2.27–2.50
(2H, m, NCCH2); 3.51 (1H, ddd, JZ4.8, 8.1, 12.9 Hz,
(HCH)N); 3.88 (1H, ddd, JZ4.8, 5.3, 12.9 Hz, (HCH)N);
4.26–4.35 (1H, m, OCH); and 4.69 (1H, br s, NC]CH). 13C
NMR (75 MHz, CDCl3): 21.7 and 21.8 (NCH2(CH2)2); 22.1
and 22.9 (CH3)2); 23.9 (CHMe2); 33.6 (NCCH2); 42.9 and
43.5 (CH2CHMe2 and CH2N); 74.4 (OCH); 103.6
(NC]CH); 131.3 (NC]CH); and 151.7 (C]O). MS
(70 eV) m/z (%): 209 (MC, 58); 164 (15); 152 (23); 150
(55); 122 (100); 108 (19); and 97 (47). Anal. calcd for
C12H19NO2 (209.14): C, 68.87; H, 9.15; N, 6.69; found C,
68.76; H, 9.27; N, 6.80.
4.2.2. 3-Ethyl-4,6,7,8-tetrahydro-3H-pyrido[1,2-c][1,3]
oxazin-1-one 11b. Flash chromatography (petrol ether/
EtOAc 3/2, RfZ0.44). Yield: 52%, yellow oil. IR (NaCl,
1
cmK1): nC]OZ1674. H NMR (300 MHz, CDCl3): d 1.00
(3H, t, JZ7.4 Hz, CH3); 1.70–1.80 (2H, m, CH3CH2); 1.80–
1.97 (2H, m, NCH2CH2); 2.04–2.14 (2H, m, N(CH2)2CH2);
2.22–2.51 (2H, m, NCCH2); 3.50 (1H, ddd, JZ4.4, 8.5,
12.9 Hz, (HCH)N); 3.89 (1H, ddd, JZ4.4, 5.4, 12.9 Hz,
(HCH)N); 4.09–4.21 (1H, m, CHO); and 4.69 (1H, br s,
NC]CH). 13C NMR (75 MHz, CDCl3): 9.3 (CH3); 21.8
and 21.9 (NCH2(CH2)2); 27.5 (CH2CH3); 32.7 (NCCH2);
42.9 (CH2N); 77.3 (OCH); 103.6 (NC]CH); 131.4
(NC]CH); and 151.7 (C]O). MS (70 eV) m/z (%): 181
(MC, 88); 152 (8); 136 (87); 122 (100); 108 (49); 96 (17);
95 (20); 94 (32); 82 (22); 81 (16); 80 (24); 67 (13); 55 (23);
54 (22); and 41 (14). Anal. calcd for C10H15NO2 (181.23):
C, 66.27; H, 8.34; N, 7.73; found C, 66.41; H, 8.24; N, 7.61.
4.2.6. 3-(4-Methoxybenzyl)-4,6,7,8-tetrahydro-3H-pyr-
ido[1,2-c][1,3]oxazin-1-one 11f. Flash chromatography
(petrol ether/EtOAc 3/2, RfZ0.42). Yield: 46%, oil. IR
(NaCl, cmK1): nC]OZ1684. 1H NMR (300 MHz, CDCl3):
d 1.77–1.91 (2H, m, NCH2CH2); 1.99–2.12 (2H, m,
N(CH2)2CH2); 2.26–2.43 (2H, m, NCCH2); 2.79 and 3.04
(2H, 2!dd, JZ5.2, 7.7, 13.8 Hz, (HCH)C6H5); 3.51 (1H,
ddd, JZ4.3, 8.5, 12.8 Hz, (HCH)N); 3.80 (3H, s, OCH3);
3.87 (1H, ddd, JZ4.3, 5.2, 12.9 Hz, (HCH)N); 4.35–4.44
(1H, m, OCH); 4.64 (1H, br s, NC]CH); 6.83–6.86 (2H, m,
2!HCortho); and 7.11–7.15 (2H, m, 2!HCmeta). 13C NMR
(75 MHz, CDCl3): 21.8 (NCH2(CH2)2); 32.1 (NCCH2);
39.8 (CH2C6H5); 42.9 (CH2N); 55.4 (OCH3); 76.7 (OCH);
103.9 (NC]CH); 114.1 (2!HCortho); 130.6 (2!HCmeta);
127.9 and 131.1 (NC]CH and Carom,quat); and 158.7
4.2.3. 3-Benzyl-4,6,7,8-tetrahydro-3H-pyrido[1,2-c][1,3]
oxazin-1-one 11c. Flash chromatography (petrol ether/
EtOAc 3/2, RfZ0.58). Yield: 60%, white crystals, mp 186–
188 8C. IR (NaCl, cmK1): nC]OZ1673. 1H NMR
(300 MHz, CDCl3): d 1.79–1.89 (2H, m, NCH2CH2);
2.05–2.17 (2H, m, N(CH2)2CH2); 2.30–2.44 (2H, m,
NCCH2); 2.85 and 3.11 (2H, 2!dd, JZ5.4, 7.7, 13.7 Hz,
(HCH)C6H5); 3.52 (1H, ddd, JZ4.3, 8.5, 12.9 Hz,
(HCH)N); 3.87 (1H, ddd, JZ4.3, 5.9, 12.9 Hz, (HCH)N);

Z. Szakonyi et al. / Tetrahedron 61 (2005) 1595–1602
1601
(C]O). MS (70 eV) m/z (%): 273 (MC, 83); 229 (25); 228
(65); 152 (22); 134 (21); 124 (21); 122 (19); 121 (86); 108
(100); 97 (19); and 77 (12). Anal. calcd for C16H19NO2
(273.33): C, 70.31; H, 7.01; N, 5.12; found C, 70.20; H,
7.16; N, 5.23.
trans 2b (cis/transZ88/12). Yield: 80 mg (95%), semisolid.
Method B: To the ice-cooled solution of 11a (55 mg,
0.3 mmol) in 8 mL of glacial AcOH, NaBH4 (43 mg,
1.2 mmol) was added. The reaction mixture was allowed
to warm up to room temperature, stirred for 5 h at this
temperature, poured into water (15 mL) and extracted with
CHCl3 (3!30 mL). The combined organic phases were
dried (MgSO4), filtered and evaporated in vacuo. The crude
4.2.7. (3R*,5S*)- and (3R*,5R*)-3-Methylhexahydropyr-
ido[1,2-c][1,3]oxazin-1-one 2a. Method A: To an ice-
cooled solution of 3-methyl-4,6,7,8-tetrahydro-3H-pyrido
[1,2-c][1,3]oxazin-1-one 11a (170 mg, 1.0 mmol) in 20 mL
of dry MeOH, NaCNBH3 (188 mg, 3.0 mmol) and glacial
AcOH (90 mg, 1.5 mmol) were added. The reaction mixture
was stirred for 72 h under reflux, then poured into water
(30 mL) and extracted with CH2Cl2 (3!40 mL). The
combined organic phases were dried (MgSO4), filtered
and evaporated in vacuo. The crude product was purified by
flash chromatography on silica gel with hexane/EtOAc (3/2,
RfZ0.55), resulting in an inseparable mixture of cis and
trans 2a (cis/transZ86/14). The 1H NMR peaks of the two
isomers overlapped for all protons except H-8. The minor
1
product was analysed by H NMR; the cis/trans ratio and
yield were found to be the same as in Method A.
Yield (cis/transZ88/12): 80%, semisolid. IR (NaCl, cmK1):
nC]OZ1688. Major isomer: 1H NMR (300 MHz, CDCl3): d
0.99 (3H, t, JZ7.6 Hz, CH3); 1.25–1.56 (2H, m,
NCH2CH2); 1.69–1.73 (2H, m, CH2CH3); 1.77–1.90 (2H,
m, N(CH2)2CH2); 1.98 (2H, dd, JZ4.5, 13.6 Hz,
NCHCH2); 2.18–2.23 (2H, m, N(CH2)3CH2); 2.58 (1H, dt,
JZ2.5, 12.8 Hz, N(HCH)(CH2)3); 3.13–3.26 (1H, m,
CHO); 3.94–4.03 (1H, m, N(CH2)4CH); and 4.40 (1H, m,
NHCH(CH2)3). 13C NMR (68 MHz, CDCl3): 9.1 (CH3);
23.7 and 25.1 (NCH2(CH2)2); 27.9 (CH2CH3); 33.6
(NCHCH2); 35.3 (N(CH2)3CH2); 44.7 (NCH2(CH2)3);
54.0 (NCH); 76.3 (CHO); and 154.1 (C]O). MS (70 eV)
m/z (%): 184 (MCC1, 18); 183 (MC, 95); 168 (9); 154 (65);
140 (85); 138 (36); and 127 (100). Minor isomer: 1H NMR
(300 MHz, CDCl3): d 1.00 (3H, t, JZ7.4 Hz, CH3); 1.25–
1.56 (2H, m, NCH2CH2); 1.74–1.76 (2H, m, CH2CH3);
1.77–1.90 (2H, m, N(CH2)2CH2); 2.02–2.07 (2H, m,
NCHCH2); 2.28–2.31 (2H, m, N(CH2)3CH2); 2.51–2.65
(1H, m, overlapped, N(HCH)(CH2)3); 3.13–3.26 (1H, m,
N(CH2)4CH); 4.04–4.13 (1H, m, CHO); and 4.33 (1H, d,
JZ13.6 Hz, NHCH(CH2)3). 13C NMR (68 MHz, CDCl3):
9.4 (CH3); 24.6 and 25.5 (NCH2(CH2)2); 27.6 (CH2CH3);
32.7 (NCHCH2); 33.2 (N(CH2)3CH2); 45.8 (NCH2(CH2)3);
53.2 (NCH); 75.0 (CHO); and 154.1 (C]O). Anal. calcd for
C10H17NO2 (183.25): C, 65.54; H, 9.35; N, 7.64; found C,
65.45; H, 9.42; N, 7.56.
component could only be detected by GC, 1H NMR and 13
C
NMR. Method B: To an ice-cooled solution of 11a (36 mg,
0.21 mmol) in 5 mL of glacial AcOH, NaBH4 (30 mg,
0.84 mmol) was added. The reaction mixture was next
allowed to warm up to room temperature, stirred for 5 h at
this temperature, poured into water (10 mL) and extracted
with CHCl3 (3!25 mL). The organic phase was dried
(MgSO4), filtered and evaporated in vacuo. The crude
1
product was analysed by H NMR; and the cis/trans ratio
was found to be the same as in Method A.
Yield (cis/transZ86/14):136 mg(80%), semisolid. IR(NaCl,
1
cmK1): nC]OZ1691. Major isomer: H NMR (400 MHz,
CDCl3): d 1.16–2.00 (7H, m); 1.33 (3H, d, JZ6.2 Hz, CH3);
2.06 (1H, ddd, JZ2.0, 5.5, 14.1 Hz, CH2CHO); 2.66 (1H,
dt, JZ2.5, 12.6 Hz, N(HCH)(CH2)3); 3.24–3.33 (1H, m,
N(CH2)4CH); 4.24–4.43 (1H, m, CHO); and 4.44–4.50 (1H,
m, NHCH(CH2)3). 13C NMR (100.6 MHz, CDCl3): 21.5
(CH3); 24.3 and 25.6 (NCH2(CH2)2); 34.2 (NCHCH2); 38.2
(N(CH2)3CH2); 45.3 (NCH2(CH2)3); 54.6 (NCH); 72.0
(CHO); and 154.3 (C]O). MS (70 eV) m/z (%): 170
(MCC1, 14); 169 (MC, 76); 127 (100); 126 (85); 83 (64);
and 68 (18). Minor isomer: 1H NMR (400 MHz, CDCl3): d
4.24–4.41 (1H, m, NHCH(CH2)3), all the other peaks
overlapped with the peaks of the major compound. 13C
NMR (100.6 MHz, CDCl3): 21.2 (CH3); 25.2 and 26.1
(NCH2(CH2)2); 33.8 (NCHCH2); 35.5 (N(CH2)3CH2); 46.4
(NCH2(CH2)3); 53.8 (NCH); 70.5 (CHO); and 154.1
(CZO). Anal. calcd for C9H15NO2 (169.22): C, 63.88; H,
8.93; N, 8.28; found C, 63.72; H, 8.83; N, 8.41.
4.2.9. (3R*,5S*)-3-Benzylhexahydropyrido[1,2-c][1,3]
oxazin-1-one 2c. To an ice-cooled solution of 3-benzyl-
4,6,7,8-tetrahydro-3H-pyrido[1,2-c][1,3]oxazin-1-one 11c
(50 mg, 0.21 mmol) in 5 mL of glacial AcOH, NaBH4
(30 mg, 0.84 mmol) was added. The reaction mixture was
then allowed to warm up to room temperature and stirred for
3 h at this temperature, poured into water (10 mL) and
extracted with CHCl3 (3!25 mL). The combined organic
phases were dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by flash chromato-
graphy on silica gel with n-hexane/EtOAc (3/2, RfZ0.70)
resulting in 2c, as the cis isomer only. Yield: 40 mg (80%),
mp 88–89 8C.
4.2.8. (3R*,5S*)- and (3R*,5R*)-3-Ethylhexahydropyrido
[1,2-c][1,3]oxazin-1-one 2b. Method A: To an ice-cooled
solution of 3-ethyl-4,6,7,8-tetrahydro-3H-pyrido[1,2-c]
[1,3]oxazin-1-one 11b (80 mg, 0.44 mmol) in 10 mL of
dry MeOH, NaCNBH3 (90 mg, 0.13 mmol) and glacial
AcOH (42 mg, 0.66 mmol) were added. The reaction
mixture was stirred for 20 h under reflux, then poured into
water (10 mL) and extracted with CH2Cl2 (3!25 mL). The
combined organic phases were dried (MgSO4), filtered and
evaporated in vacuo. The crude product was purified by
flash chromatography on silica gel with n-hexane/EtOAc 3/
2, (RfZ0.58), resulting in an inseparable mixture of cis and
IR (NaCl, cmK1): nmaxZ3324, 1673, 1436, 1154, and 796.
1H NMR (400 MHz, CDCl3): d 1.15–1.52 (4H, m, N(CH2)
(HCH)3HC(HCH)); 1.66–1.99 (4H, m, N(CH2)(HCH)3
HC(HCH)); 2.62 (1H, dt, JZ2.7, 13.4 Hz, N(HCH)(CH2)3);
2.86 and 3.07 (2H, 2!dd, JZ5.0, 8.1, 13.6 Hz, CH2C6H5);
3.15–3.24 (1H, m, N(CH2)4CH); 4.27–4.38 (1H, m, CHO);
4.46 (1H, dt, JZ13.1 Hz, overlapped peaks, NHCH(CH2)3);
and 7.21–7.32 (5H, m, C6H5). 13C NMR (68 MHz, CDCl3):
24.3 and 25.6 (NCH2(CH2)2); 34.2 (N(CH2)3CH2); 35.6
(CH2CH(O)); 42.0 (CH2C6H5); 45.4 (NCH2(CH2)3); 76.3
(CHO); 127.5 (HCpara); 129.2, 130.2 (2!HCorthoCmeta);

1602
Z. Szakonyi et al. / Tetrahedron 61 (2005) 1595–1602
136.9 (Cqarom); and 151.3 (C]O). MS (70 eV) m/z (%): 246
(MCC1, 3); 245 (MC, 11); 201 (65); 110 (54); and 83 (100).
Anal. calcd for C15H19NO2 (245.32): C, 73.44; H, 7.81; N,
5.71; found C, 73.60; H, 7.76; N, 5.80
Acknowledgements
Financial support from the Fund for Scientific Research—
Flanders (FWO-Vlaanderen), the Bilateral Scientific
Research Cooperation between Flanders and Hungary and
from Ghent University is gratefully acknowledged. Z. S. is
indebted to the National Scientific Research Foundation,
Hungary (OTKA, F 032828).
4.2.10. (2R*,20S*)-1-(N-Methylpiperidin-2-yl)propan-2-
ol 1a. To a slurry of LiAlH4 (100 mg, 2.6 mmol) in
10 mL of dry THF, a diastereomeric mixture of cis- and
trans-3-methylhexahydropyrido[1,2-c][1,3]oxazin-1-one
2a (220 mg, 1.3 mmol) dissolved in 4 mL of dry THF was
added dropwise at room temperature. The reaction mixture
was stirred for 1 h under reflux, and the excess of LiAlH4
was then decomposed by addition of 0.20 g of water in 2 mL
of THF. The inorganic part was filtered off and washed with
THF and the organic phase was dried (MgSO4), filtered and
evaporated in vacuo to yield the crude product, as 190 mg of
a pale-yellow oil. NMR study of the crude product revealed
the presence of two isomers in a ratio of 86:14. After
purification by flash chromatography with CH2Cl2/triethyl-
amine (9/1, RfZ0.25) on silica gel, only the major isomer
was isolated in diastereomeric pure form, and identified as
References and notes
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1
N-methylallosedridine. Yield: 135 mg, 66%. The H and
13C NMR data corresponded to those of N-methylallose-
dridine in the literature.19
4. Kim, J. H.; ’t Hart, H.; Stevens, J. F. Phytochemistry 1996, 41,
1319–1324.
NMR (400 MHz, CDCl3): d 1.16 (3H, d, JZ6.3 Hz); 1.19–
1.61 (5H, m); 1.65–1.73 (2H, m); 2.42 (3H, s); 2.44–2.51
(1H, m); 2.59–2.65 (1H, m); 2.98 (1H, ddd, JZ3.0, 7.0,
9.6 Hz); and 3.97 (1H, dqd, JZ2.5, 6.1, 10.1 Hz). 13C NMR
(100.6 MHz, CDCl3): 21.3; 22.7; 24.5; 26.5; 39.4; 40.2;
52.4; 60.8; and 67.9.
5. Takahata, H.; Kubota, M.; Momose, T. Tetrahedron Lett.
1997, 38, 3451–3454.
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Cagniard, D.-H.; Renard, P., Eur. Pat., 2000, EP 1050531
A1, 08/11/2000; Chem. Abstr. 2000, 133, 350144.
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chemistry 1967, 6, 711–717.
4.2.11. (2R*,20S*)-(1-(N-Methylpiperidin-2-yl)butan-2-ol
1b. To an ice-cooled solution of a diastereomeric mixture of
cis- and trans-3-ethylhexahydropyrido[1,2-c][1,3]oxazin-1-
one 2b (50 mg, 0.28 mmol) in 10 mL of dry Et2O, LiAlH4
(26 mg, 0.7 mmol) was added. The reaction mixture was
stirred for 4 h under reflux and then poured into ice cold
water. The organic phase was separated, dried (MgSO4),
filtered and evaporated in vacuo to yield the crude product.
This product was purified by flash chromatography with
CH2Cl2/triethylamine 9/1 (RfZ0.18), resulting in 1-(N-
methylpiperidin-2-yl)butan-2-ol 1b. Only the major isomer
was identified after the purification process.19
8. Schuster, E.; Hesse, C.; Schumann, D. Synlett 1991, 916–918.
9. De Koning, H.; Mallo, G. N.; Springer-Fidder, A.; Subramanian-
Erhart, K. E. C.; Huisma, H. O. Recl. Trav. Chim. Pays-Bas
1973, 92, 683–688.
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Leonce, S.; Renard, P.; Pfeiffer, B. Bioorg. Med. Chem. 2000,
8, 2113–2125. (b) Ley, S. V.; Lygo, B.; Organ, H. M.;
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Soc. 1992, 114, 5459–5460.
Yield: 30 mg (65%). IR (NaCl, cmK1): nC–OHZ3419 cmK1
;
nmaxZ2935; 2856; 2795; 2087; 1645; 1458; 1376; 1268;
1121; 1022; and 983. H NMR (400 MHz, CDCl3): d 0.94
15. Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; Jagdmann, G. E.
J. Org. Chem. 1985, 50, 1019–1026.
1
(3H, t, JZ7.3 Hz CH2CH3); 1.16–1.45 (5H, m, N(CH2)
(HCH)3HC(CH2)); 1.47 (2H, q, JZ7.1 Hz, CH2CH3); 1.52–
1.87 (3H, m, N(CH2)(HCH)3); 2.42 (3H, s, N–CH3); 2.45–
2.55 (1H, m, N(HCH)(CH2)3); 2.56–2.75 (1H, m,
N(CH2)4CH); 2.97–3.04 (1H, m, N(HCH)(CH2)3); 3.66–
3.74 (1H, m, CH(OH)); and 4.36–4.38 (1H, d, JZ7.98 Hz,
CH(OH)). 13C NMR (68 MHz, CDCl3): 9.9 (CH3); 20.9 and
22.7 (NCH2(CH2)2); 26.3 CH2CH3); 31.2 (NCHCH2CH
(OH)); 37.1 (N(CH2)3CH2); 40.1 (N–CH3); 51.9
(NCH2(CH2)3); 60.9 (N(CH2)4CH); and 73.5 (CH(OH)).
MS (70 eV) m/z (%): 171 (MC,1); 142 (5); 112 (2); 98
(100); 84 (2); 70 (9); 57 (3); and 42 (5).
16. Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701–2724 and
references cited therein.
17. Brocherieux-Lanoy, S.; Dhimane, H.; Poupon, J.-C.; Vanucci, C.;
Lhommet, G. J. Chem. Soc., Perkin Trans. 1 1997, 2163–2165.
18. Kaiser, E.; Tam, J. P.; Kubiak, T. M.; Merrifield, R. B.
Tetrahedron Lett. 1988, 29, 303–306.
19. Takahata, H.; Kubota, M.; Ikota, N. J. Org. Chem. 1999, 64,
8594–8601.
´
20. Stevens, J. F.; ’t Hart, H.; Hendriks, H.; Malingre, T. M.
Phytochemistry 1992, 31, 3917–3924.
21. Schneider, M. J.; Brendze, S.; Montali, J. A. Phytochemistry
1995, 39, 1387–1390.