Synthesis of 2,5-difunctionalised-3,3-dimethylpiperidines via ω-halogenated imines

Article abstract of DOI:10.1016/S0040-4020(01)00762-1

2,5-Difunctionalised-3,3-dimethylpiperidines were prepared by addition of nucleophiles to piperideinium salts, formed by electrophile-induced cyclisation of γ,δ-unsaturated imines with N-bromosuccinimide in alcoholic medium.

Full text of DOI:10.1016/S0040-4020(01)00762-1

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 7865±7870
Synthesis of 2,5-difunctionalised-3,3-dimethylpiperidines
via v-halogenated imines
Christian V. Stevens,p Maria Peristeropoulou and Norbert De Kimpep
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 2 May 2001; revised 4 July 2001; accepted 24 July 2001
AbstractÐ2,5-Difunctionalised-3,3-dimethylpiperidines were prepared by addition of nucleophiles to piperideinium salts, formed by
electrophile-induced cyclisation of g,d-unsaturated imines with N-bromosuccinimide in alcoholic medium. q 2001Elsevier Science Ltd.
All rights reserved.
The synthesis of piperidines and piperideines has always
been an important topic in synthetic organic chemistry
because of their importance as substrates for alkaloid syn-
theses, as biologically active substances, etc.1 Also, the
3-oxygenated piperidine nucleus2 is found in natural
products, such as canavalline,3 leptophyllins,3 pseudo-
conhydrine,4±6 deoxocassine7 and in some interesting
therapeutic compounds, such as zamifenacin8 and melato-
nergic agents.9 Although many synthetic methodologies are
known for the preparation of piperidines, the electrophile-
induced cyclisation of alkenylimines was only described for
the synthesis of pyrrolidines via pyrrolinium salts 3,10,11 for
selenenylated pyrrolidines and for piperidines by ring
expansion.12
of intermediate stable salts and because of their broad
range of reactivity towards different nucleophiles.
During the systematic study of the chemistry of v-halo-
genated imines13 and their applications,14,15 the convenient
preparation of piperideinium salts came to our attention, and
their reactivity towards nucleophiles, i.e. oxygenated
nucleophiles, was extensively studied.
The required 4-alkenylimines 1 were prepared in two ways.
A ®rst route consisted of the alkylation of N-7isobutyl-
idene)amines 4 7prepared by condensation of isobutyr-
aldehyde and a primary amine) with allylbromide after
deprotonation with LDA at 08C 7Scheme 2).
No direct electrophile-induced cyclisation towards piperi-
dines from piperideinium salts 2 has been elaborated
7Scheme 1).
A second method consisted of the condensation of isobutyr-
aldehyde with allyl alcohol in p-cymene under re¯ux in the
presence of p-toluenesulfonic acid with formation of 2,2-
dimethyl-4-pentenal 7 under Dean±Stark conditions,16
followed by imination in the presence of magnesium sulfate.
The preparation of pentenal 7 via the latter route, however,
was sometimes problematic because of the fact that the
reaction was not always reproducible and the end product
7 was not always obtained in pure form. Therefore, the ®rst
In this paper, the electrophile-induced cyclisation of alkenyl-
imines 1 was developed for the synthesis of 2,5-di-
functionalised piperidines from piperideinium salts 2 via
in situ formed v-halogenated imines. This cyclisation is
especially attractive because of the convenient synthesis
Scheme 1.
Keywords: piperidines; halogenated imines; piperideinium salts.
Corresponding authors. Tel.: 1-32-09-264-5957; fax: 1-32-09-264-6243; e-mail: chris.stevens@rug.ac.be; norbert.dekimpe@rug.ac.be
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00762-1

7866
C. V. Stevens et al. / Tetrahedron 57 .2001) 7865±7870
easily by evaporation of the solvent giving a solid which
contains the salt and succinimide 7Scheme 3).
Succinimide can be removed completely by one or more
crystallisations of the salt from a dichloromethane/diethyl
ether mixture 7the salts are dissolved completely in a mini-
mum amount of dichloromethane followed by the addition
of diethyl ether until slightly cloudy), in order to obtain the
pure piperideinium salts 2. The recrystallisations, however,
lead mostly to an important loss of the piperideinium salts
and in some cases to substantial losses 7e.g. for R0ˆEt).
However, the use of the crude mixture of the piperideinium
salts 2 does not give any problem for the following reactions
since succinimide can be removed during the aqueous
workup after the next reaction.
Scheme 2.
route is more reliable although the second one is more
suitable for larger scale preparations 7e.g. 1mole scale).
The piperideinium salts 2 were reacted with a range of
benzyl alcoholates in the corresponding alcohol to give
the 2,5-dialkoxypiperidines 10 in good to excellent yields.
However, these derivatives could not be puri®ed by ¯ash
chromatography due to the lability of the products during
the chromatography. Although the purity of the products in
the reaction mixtures was quite high 7.95%), it was tried to
prepare solid piperidine derivatives which could then be
puri®ed by recrystallisation. Unfortunately, none of the
products synthesised was obtained as a solid 7so, the
reported yields refer to the crude yields). The derivative
10e, however, was not obtained with a purity of .95%,
but was contaminated with benzyl alcohol 7purity: 70%).
Another derivative, e.g. the 4-phenylbenzyl derivative
10d, was not stable since the a-alkoxypiperidine decom-
posed again at room temperature to the alcohol and the
piperideinium salt 2 after a couple of hours. The other
benzyl alcohol adducts were stable and could be isolated
without problems 7Scheme 4).
Reaction of imines 1 with N-bromosuccinimide in an
alcoholic solvent at room temperature during 16 h gave
rise to the formation of the iminium salt 2 via the inter-
mediate g-alkoxy-d-bromoimine 9. The electrophilic
addition of NBS to the non-activated double bond occurs
according to the Markovnikoff rule with the solvent acting
as nucleophile and leads to the reactive d-bromoimine 9
which spontaneously cyclises to the stable piperideinium
salt 2. On the contrary, in less polar and non-nucleophilic
solvents, e.g. dichloromethane, the electrophile-induced
ring closure using bromine or phenylselenenyl bromide as
electrophile leads regiospeci®cally to the formation of the
corresponding pyrrolinium salts 3.17 Accordingly, the
cyclisation process of compounds 1 is now handled in a
regiospeci®c way so as to give rise either to pyrrolinium
salts 3 or to piperideinium salts 2, depending on the reaction
conditions and the electrophile.
Concerning the stereochemistry, the adducts 10 were
obtained as trans isomers 7considering the 2- and
5-position) due to steric interactions during the addition
The reactions for the formation of the piperideinium salts
are almost quantitative. The piperideinium salts are isolated
p
p
p
pp
Scheme 3. 2a R1 ˆ t-Bu, R2 ˆ Me ꢀ95%† ꢀ76%†pp; 2b R1 ˆ t-Bu, R2 ˆ Et ꢀ90%† ꢀ20%†pp; 2c R1 ˆ i-Pr, R2 ˆ Me ꢀ78%† ꢀ15%†
pp Yields after recrystallisation.
.
p The yields correspond to the crude products after evaporation of the solvent and taking into account the amount of succinimide 7estimated by 1H NMR).
Scheme 4. 10a R1 ˆ t-Bu, R2 ˆ Me, R3 ˆ H, R4 ˆ H ꢀ98%†; 10b R1 ˆ t-Bu, R2 ˆ Me, R3 ˆ Br, R4 ˆ H ꢀ97%†; 10c R1 ˆ t-Bu, R2 ˆ Me, R3 ˆ R4 ˆ OMe
ꢀ98%†; 10d R1 ˆ t-Bu, R2 ˆ Me, R3 ˆ Ph, R4 ˆ H; 10e R1 ˆ i-Pr, R2 ˆ Me, R3 ˆ H, R4 ˆ H ꢀ68%†; 10f R1 ˆ i-Pr, R2 ˆ Me, R3 ˆ OMe, R4 ˆ H 746%,
t/c; ,4/1).

C. V. Stevens et al. / Tetrahedron 57 .2001) 7865±7870
7867
Scheme 5.
and due to the favourable 2,5-diequatorial substitution of the
piperidine ring after addition as in 13. However, for
compound 10f, a mixture of trans and cis isomers are
obtained in about a 4:1ratio 7Scheme 5).
gate this entry to 2-functionalised-5-alkoxypiperidines, the
reaction was performed with hydride 7e.g. lithium alu-
miniumhydride 71mole equivalent in diethyl ether, re¯ux
2 h), sodium cyanide 73 equiv. in methanol, re¯ux 3 h),
sodium ethylthiolate 72 equiv. in tetrahydrofuran, re¯ux
2 h) and sodium methoxide 72 equiv. in methanol, re¯ux
2 h)).
The reaction of the piperideinium salt 2 with sodium
phenolates did not result in the adducts but led to complete
decomposition.
These reactions gave the adducts 16 in good yields 769±
98%) without competing reactions. The derivatives with a
low molecular weight could be puri®ed by high vacuum
distillation 7e.g. 16a bp: 144±145/14 mmHg, yield: 95%;
16b bp: 55±58/14 mmHg, yield: 76%). The N-isopropyl
derivatives 16e±f could not be puri®ed by ¯ash chroma-
tography due to decomposition of these compounds on the
silica gel column 7Scheme 6).
Although the reaction did not succeed with phenolates, the
addition of other nucleophiles to the 2-position of the piperi-
deinium salts was general, as expected. In order to investi-
Also for the adducts 16, the same stereochemical considera-
tions can be formulated as for the adducts 10 7Scheme 7).
Scheme 6. 16a R1ˆt-Bu, R2ˆMe, NuˆCN 790%, t1c); 16b R1ˆt-Bu,
R2ˆMe, NuˆOMe 776%); 16c R1ˆt-Bu, R2ˆMe, NuˆSEt 786%); 16d
R1ˆt-Bu, R2ˆMe, NuˆH 795%); 16e R1ˆi-Pr, R2ˆMe, NuˆCN 758%,
t1c); 16f R1ˆi-Pr, R2ˆMe, NuˆH 771%).
One peculiar reaction was observed during the puri®cation
of 2,5-dimethoxypiperidine 16b and 2-ethylthio-5-methoxy-
piperidine 16c. Preparative isolation during gas chromato-
graphic analysis of the samples resulted in the formation of
5-methoxy-1,2,3,4-tetrahydropyridine 17. This reaction was
also observed when 16b was synthesised from the corre-
sponding pyrrolinium salt.17 In order to prove the substi-
tution pattern on the piperidine ring and in order to
explain this remarkable elimination, double irradiation
NMR experiments were conducted to assign the methoxy
group to the 2-position in the starting material. Irradiating
the proton at the 5-position of the piperidine ring of 16b
resulted in a simpli®cation of the coupling systems for the
protons at positions 4 and 6 of the piperidine ring. The
signals became both AB-systems with Jˆ12.9 Hz and
Jˆ11.4 Hz, respectively. This measurement proved that
the second methoxy substituent was located at the 2-position
and also proved this remarkable elimination.17
The same rearrangement was also observed during the
analysis of the 2-ethylthio derivative 16c.
In this paper, the electrophile-induced cyclisation of
4-alkenyl imines was developed and proved to be a
Scheme 7.

7868
C. V. Stevens et al. / Tetrahedron 57 .2001) 7865±7870
convenient way to synthesise a broad range of 2,5-difunc-
tionalised piperidines in a directed way.
cm21) 1 71 2n7CvN). White solid, tentative mp 1788C
7due to traces of succinimide). Yield: 90% 7crude yield).
Anal. Calcd for C13H26BrNO: C, 53.43%; H, 8.97%.
Found: C, 53.60%; H, 8.84%.
1. Experimental
1.1.3.
1-Isopropyl-3,3-dimethyl-5-methoxy-1-piperi-
deinium bromide 2c. 1H NMR 7CDCl3, 270 MHz) d:
1.44 73H, s, Me); 1.55 76H, m, i-Pr); 1.56 73H, s, Me);
2.00 72H, m, CH2); 3.37 73H, s, OMe); 3.74 and 4.29 72H,
2x d, AB, JABˆ15 Hz, CH2N); 3.96 71H, br s, CHOMe);
4.80 71H, sept, Jˆ6.9 Hz, CHMe2); 9.3171H, s, CHvN).
13C NMR 7CDCl3) d: 19.87 7q, Me), 20.70 7q, Me), 26.85
7t, Me); 27.98 7Me), 33.60 7t, CH2), 36.39 7s, CMe2), 50.37
7t, CH2N), 56.60 7q, OMe), 64.40 7s, NCHMe2), 70.64 7d,
CHOMe), 181.52 7d, CvN). IR 7KBr, cm21) 1678 7n
CvN). Beige solid, mp 157±1598C. Yield: 78% 7crude
yield). Anal. Calcd for C11H22BrNO: C, 50.01%; H,
8.39%. Found: C, 49.78%; H, 8.76%.
1H NMR spectra were recorded at 60 MHz 7Jeol PMX 60
SI), at 270 MHz 7Jeol JNM EX 270) or at 500 MHz 7BruÈker
500) with CDCl3 as solvent. 13C NMR spectra were
recorded at 20 MHz 7Varian FT-80) with CDCl3 as solvent.
Mass spectra were obtained on a mass spectrometer 770 eV)
using direct inlet or GC±MS coupling 7RSL 200, 20 m
capillary column, i.d. 0.53 mm, He carrier gas). Diethyl
ether and tetrahydrofuran were distilled from sodium/
benzophenone ketyl.
1.1. General procedure for the synthesis of
piperideinium salts 2
To 0.02 M of alkenylimine 1 in 40 ml of absolute alcohol
7methanol or ethanol), 0.021M 71.05 equiv.) of N-bromo-
succinimide was added. The mixture was stirred for 16 h at
room temperature and the mixture was protected from
humidity in the air by a calcium chloride tube. The solvent
was then evaporated leaving a sticky mixture. Dry diethyl
ether was added and the product was well scratched and
stirred with a glass rod in order to obtain a crystalline
product mixture. The ether was removed by ®ltration and
the whole procedure was repeated another time. After a
second ®ltration the product was dried under vacuum. The
piperideinium salt 7in the presence of succinimide) can be
used as such in the next reaction step. In order to purify the
piperideinium salt from the succinimide, the piperideinium
salt was dissolved in a minimum amount of boiling
dichloromethane, and diethyl ether was added untill the
mixture got slightly cloudy. The mixture was then placed
in a refrigerator for the piperideinium salt to recrystallise.
The piperideinium salt 2 was obtained pure after ®ltration
and drying in vacuo.
1.2. General procedure for the synthesis of the adducts
10 and 16
To 4 mmol of piperideinium salt 2 in 20 ml of dry tetra-
hydrofuran, 4 mmol of nucleophile 7sodium alcoholate,
prepared from the corresponding alcohol and sodium
hydride, sodium metal or sodium methoxide) in 10 ml of
tetrahydrofuran was added dropwise. The reaction mixture
was stirred at room temperature for 3 h and then poured into
30 ml of NaOH 71M). The mixture was extracted three
times with diethyl ether 73£20 ml) and the combined
organic layers were dried over magnesium sulfate. After
®ltration of the drying agent, the solvent was evaporated
in vacuo yielding the 2-substituted-5-alkoxypiperidines 10.
A similar procedure was used for the preparation of the
adducts 16. For 16a, 16e the reaction was performed in
dry methanol with 3 equiv. of KCN and the reaction mixture
was re¯uxed for 3 h. For 16b, 16c 2 equiv. of sodium
alkoxide and sodium thiolate 7prepared from sodium
methoxide and ethylthiol) were used during 2 h of re¯ux.
The reactions using lithium aluminium hydride 71mole
equiv.) were performed in dry diethyl ether and the mixture
was re¯uxed during 2 h for the preparation of 16d and 16f.
1.1.1. 1-t-Butyl-3,3-dimethyl-5-methoxy-1-piperideinium
bromide 2a. H NMR 7CDCl3, 500 MHz) d: 1.39 73H, s,
1
Me); 1.51 73H, s, Me); 1.59 79H, s, t-Bu); 1.93 and 1.99 72H,
2x br d, AB, JABˆ14.5 Hz, J,1Hz, CH 2); 3.28 73H, s,
OMe); 3.92 71H, br s, CHOMe); 3.91and 4.37 72H, 2x br
d, AB, JABˆ12.6, J,1Hz, CH 2N); 8.77 71H, br s, CHvN).
13C NMR 7CDCl3) d: 27.25 7q, Me3), 27.99 7q, Me3), 33.67
7t, CH2CHOMe); 37.05 7s, CMe2), 50.96 7t, CH2N), 56.64
7q, OMe), 69.70 7s, CMe3), 71.10 7d, CHOMe), 179.96 7d,
CvN). IR 7KBr, cm21) 1705 7n CvN). White solid, mp
1828C. Yield 95% 7crude yield). Anal. Calcd for
C12H24BrNO: C, 51.80%; H, 8.69%. Found: C, 51.72%;
H, 8.78%.
1.2.1.
2-Benzyloxy-1-t-butyl-3,3-dimethyl-5-methoxy-
1
piperidine 10a. H NMR 7CDCl3) d: 1.00 73H, s, Me);
1.13 73H, s, Me), 1.13 79H, s, t-Bu); 1.5±1.9 72H, m,
CH2); 2.6±3.0 72H, m, CH2N); 3.1±3.5 71H, m, CHOMe),
3.36 73H, s, OMe); 4.13 71H, s, OCHN), 4.60 and 4.72 72H,
2xd, AB, JABˆ12 Hz, CH2O), 7.36 75H, s, Ph). 13C NMR
7CDCl3) d: 26.79 7q, Me), 27.917q, Me), 28.57 7q, Me3),
37.75 7s, CMe2), 38.99 7t, CH2CMe2), 43.08 7t, CH2N),
53.28 7s, CMe3), 55.57 7q, OMe), 71.13 7t, OCH2), 75.00
7d, CHOMe), 92.72 7d, OCHN), 126.68 7d, CH), 126.85 7d,
CH), 128.07 7d, CH), 139.64 7s, Cquat). IR 7NaCl) nmax
7cm21): 2975, 1455, 1360, 1105. MS 7m/z) direct inlet:
305 7M1, 13); 290 713); 250 713); 199 756); 191 713); 184
76); 182 76); 158 719); 142 744); 126 731); 108 731); 107
738); 102 744); 91 7100); 79 738); 77 725); 57 756); 41 756).
Yellowish oil; Yield: 98%.
1.1.2. 1-t-Butyl-3,3-dimethyl-5-ethoxy-1-piperideinium
1
bromide 2b. H NMR 7CDCl3) d: 1.16 73H, t, Jˆ7 Hz,
Me); 1.53 73H, s, Me), 1.61 73H, s, Me), 1.73 79H, s,
t-Bu); 1.9±2.1 72H, m, CH2CMe2); 3.6172H, q, Jˆ7 Hz,
OCH2CH3); 4.0±4.5 72H, m, CH2N); 9.10 71H, br s,
CHvN). 13C NMR 7CDCl3) d: 15.25 7q, MeCH2), 27.31
7q, Me), 27.83 7q, Me3), 29.78 7q, Me), 34.50 7t, CH2);
37.04 7s, CMe2), 51.24 7t, CH2N), 64.42 7t, OCH2), 69.24
7d, OCH), 69.28 7s, CMe3), 178.36 7d, CvN). IR 7KBr,
1.2.2. 2-)4-Bromobenzyloxy)-1-t-butyl-3,3-dimethyl-5-
methoxypiperidine 10b. H NMR 7CDCl3) d: 0.98 73H,
1

C. V. Stevens et al. / Tetrahedron 57 .2001) 7865±7870
7869
s, Me); 1.15 712H, s, Me, t-Bu); 1.3±1.8 72H, m, CH2); 2.3±
2.9 72H, m, CH2N); 2.9±3.6 71H, m, CHOMe), 3.35 73H, s,
OMe); 4.08 71H, s, OCHN), 4.49 and 4.63 72H, 2xd, AB,
JABˆ12 Hz, CH2O), 7.14 72H, d, Jˆ9 Hz, 2£ CH), 7.39
72H, d, Jˆ9 Hz, 2£CH). 13C NMR 7CDCl3) d: 26.75 7q,
Me), 27.88 7q, Me), 28.56 7q, Me3), 37.717s, CMe2),
38.97 7t, CH2CMe2), 43.06 7t, CH2N), 53.27 7s, CMe3),
55.62 7q, OMe), 70.27 7t, OCH2), 74.88 7d, CHOMe),
92.917d, O CHN), 120.59 7s, CCH2), 128.40 7d, CH),
131.19 7d, CH), 138.72 7s, Cquat). IR 7NaCl) nmax 7cm21):
2920, 1592, 1485, 1385, 1360. MS 7m/z) direct inlet: 198
7M12BrC6H4CH2O, 13); 185/87 746); 183/85 722); 157
717); 142 711); 126 723); 106 789); 90 711); 89 713); 86
713); 79 789); 78 744); 777100); 76 713); 75 717); 57 789);
51729); 50 727). Yellowish oil; Yield: 97%.
7Me); 27.26 727.55) 7Me); 36.84 737.72) 7CMe2); 38.28
738.51) 7CH2CMe2); 43.49 743.86) 7CH2N); 53.03 750.00)
7CH); 54.65 755.31) 7OMe); 63.81 765.39) 7ArOMe); 71.48
770.96) 7ArCH2O); 74.27 774.54) 7CHOMe); 96.71797.34)
7OCHN); 113.26 7113.15); 128.05 7128.05); 133.15
7131.18); 158.47 7158.76). IR 7NaCl) nmax 7cm21): 1610,
1510, 1460. MS 7m/z) direct inlet: 3217M 1, 0.2); 137
7100) 136 766); 121 748); 109 770); 107 724); 105 713); 94
725); 79 713); 77740); 78 711); 65 711). Yellowish oil; Yield:
98%.
1.2.7. 1-t-Butyl-2-cyano-3,3-dimethyl-5-methoxypiperi-
dine 16a. Mixture of stereoisomers, major17minor); ratio
1
,4:1. H NMR 7CDCl3) d: 1.13 76H, s, Me2); 1.18 79H, s,
t-Bu); 1.5±2.0 72H, m, CH2); 2.0±2.7 72H, m, CH2N); 3.33
73H, s, OMe); 3.0±3.5 71H, m, CHOMe); 3.56 71H, br s,
CHCN). 13C NMR 7CDCl3): major17minor) d: 25.54 7q,
Me), 27.09 7q, Me3), 28.18 728.71) 7q, Me), 34.82 733.81)
7s, CMe2), 40.34 736.75) 7t, CH2), 46.46 743.93) 7t, CH2N),
54.46 754.25) 7s, CMe3), 55.83 7q, OMe), 56.98 757.79) 7d,
CHCN), 73.96 774.71) 7d, CHOMe), 118.15 7118.37) 7s,
CN). IR 7NaCl) n 7cm21): 2820 7OMe), 2220 7CN). MS
7m/z): 224 7M1, 7); 209 7100); 182 78); 177 74); 14174);
126 710); 111 74); 99 74); 96 74); 83 711); 82 715); 71 78);
68 78); 58 723); 57 720); 56 723); 55 720); 41757); 40 730);
39717). Colorless oil; Yield: 90%, bp 144±1458C/
14 mmHg. Anal. Calcd for C13H24N2O: C, 69.60%; H,
10.78%. Found: C, 69.43%; H, 10.64%.
1.2.3. 2-)3,4-Dimethoxybenzyloxy)-1-t-butyl-3,3-dimethyl-
5-methoxypiperidine 10c. 1H NMR 7CDCl3) d: 1.00 73H, s,
Me); 1.13 73H, s, Me); 1.16 79H, s, t-Bu); 1.58 72H, m,
CH2CHOMe); 2.4±3.3 73H, m, CH2N, CHOMe); 3.36
73H, s, OMe); 3.86 73H, s, OMe); 3.88 73H, s, OMe); 4.11
71H, s, OCH); 4.52 and 4.67 72H, 2xd, AB, JABˆ11.2 Hz,
CH2O), 6.8±7.0 73H, m, C6H3). 13C NMR 7CDCl3) d: 26.82
7q, Me), 28.00 7q, Me), 28.58 7q, Me3), 37.75 7s,CMe2),
39.02 7t, CH2), 43.08 7t, CH2N), 53.317s, CMe3), 55.68
7q, OMe), 55.82 7q, OMe), 55.94 7q, OMe), 70.97 7t,
OCH2), 75.017d, C HOMe), 92.70 7d, OCHN), 110.86
7d,CH), 111.48 7d,CH), 119.11 7d,CH), 132.55 7s, CCH2),
148.34 7s, COMe), 149.12 7s, COMe). IR 7NaCl) nmax
7cm21): 1592, 1515, 1465, 1265. MS 7m/z) direct inlet:
213 7M127MeO)2C6H3CH2, 3); 198 747); 197 720); 182
747); 168 740); 151 747); 142 727); 138 713); 134 710);
126 7100); 94 716); 57 740). Yellowish oil; Yield: 98%.
1.2.8. 1-t-Butyl-3,3-dimethyl-2,5-dimethoxypiperidine
16b. H NMR 7CDCl3, 270 MHz) d: 0.95 73H, s, Me);
1
0.96 73H, s, Me), 1.13 79H, s, t-Bu); 1.2±1.8 72H, m,
CH2); 2.5171H, dxd, Jˆ12.9, 9.5 Hz, NCHCHOMe); 2.95
71H, dxd, Jˆ11.4, 4.9 Hz, NCHCHOMe); 3.3±3.4 71H, m,
CHOMe), 3.34 73H, s, OMe); 3.4173H, s, OMe); 3.80 71H,
s, OCHN). 13C NMR 7CDCl3) d: 26.83 7q, Me), 27.74 7q,
Me), 28.36 7q, Me3), 37.66 7s, CMe2), 38.74 7t, CH2CMe2),
43.00 7t, CH2N), 53.29 7s, CMe3), 55.74 7q, OMe), 58.04 7q,
OMe), 74.89 7d, CHOMe), 95.13 7d, MeOCHN). IR 7NaCl)
nmax 7cm21): 2820 7OMe). MS 7m/z): an appropriate mass
spectrum could not be obtained due to spontaneous loss of
methanol. Colorless oil; Yield: 76%, bp 552588C/
0.05 mmHg. Anal. Calcd for C13H27NO2: C, 68.08%; H,
11.87%. Found: C, 67.93%; H, 11.98%.
1.2.4. 1-t-Butyl-2-)4-phenylbenzyloxy)-3,3-dimethyl-5-
methoxypiperidine 10d. No structural assignment could
be performed due to the fast decomposition of the
compound after synthesis.
1.2.5. 2-Benzyloxy-3,3-dimethyl-1-isopropyl-5-methoxy-
piperidine 10e. H NMR 7CDCl3, 270 MHz) d: 0.99 73H,
1
s, Me); 1.01 73H, s, Me); 1.05 73H, d, Jˆ6.6 Hz, i-Pr); 1.09
73H, d, Jˆ6.6 Hz, i-Pr); 1.58 72H, m, CH2); 2.65 71H, m,
CH2); 2.83 71H, m, CHOMe), 3.05 71H, sept., Jˆ6.6 Hz,
CHMe2); 3.35 73H, s, OMe); 4.5±4.7 72H, m,
OCH2C6H5); 7.3±7.36 75H, m, Ph). 13C NMR 7CDCl3) d:
19.19, 21.65, 26.31, 27.35, 37.00, 38.38, 43.68, 53.15,
55.45, 71.80, 74.41, 96.89, 126.59, 128.03, 139.15,
140.93. IR 7NaCl) nmax 7cm21): 1496, 1206, 1382, 1361.
MS 7m/z) direct inlet: 292 7M111, 12); 185 782); 173
713); 169 724); 145 728); 108 7100); 107 782); 91 760); 86
719); 84 730); 79 786); 77 756); 51 729); 49 729). Yellowish
oil. Yield: 68%.
1.2.9.
1-t-Butyl-3,3-dimethyl-2-ethylthio-5-methoxy-
1
piperidine 16c. H NMR 7CDCl3) d: 1.10 73H, s, Me);
1.11 73H, s, Me), 1.18 79H, s, t-Bu); 1.2±1.8 72H, m,
CH2); 1.26 73H, t, Jˆ7.3 Hz, CH2CH3); 2.66 72H, q, Jˆ
7.3 Hz, CH2CH3); 3.2±3.5 73H, m, CHOMe, CH2N); 3.38
73H, s, OMe); 4.00 71H, brs, CHSEt). 13C NMR 7CDCl3,
68 MHz) d: 15.77 7q,Me), 27.83 7q, Me3), 27.83 7t, MeCH2),
29.05 7q, Me), 38.94 7s, CMe2), 39.517t, CH2CMe2), 46.11
7t, CH2N), 54.34 7s, CMe3), 55.72 7q, OMe), 74.78 7d,
CHOMe), 79.13 7d, CHS). IR 7NaCl) nmax 7cm21): 2970,
1960, 1455, 1380. MS 7m/z): an appropriate spectrum
could not be obtained due to spontaneous loss of ethane-
thiol. Brown oil; Yield: 86%.
1.2.6. 2-)4-Methoxybenzyloxy)-3,3-dimethyl-1-isopropyl-
5-methoxypiperidine 10f. H NMR 7CDCl3, 270 MHz) d:
1
0.98 73H, s, Me); 1.00 73H, s, Me); 1.05 73H, d, Jˆ6.6 Hz,
i-Pr); 1.09 73H, d, Jˆ6.6 Hz, i-Pr); 1.55 71H, m, CH2); 2.69
71H, t, Jˆ10.6 Hz, CH); 2.80 71H, m, CHOMe), 3.02 71H,
m, CHMe2); 3.34 73H, s, OMe); 3.35 72H, m, CH2), 3.78 7s,
3H, PhOMe), 4.47 and 4.58 72H, d, AB, JABˆ12.2 Hz); 6.86
and 7.25 74H, m, C6H4). 13C NMR 7CDCl3) major17minor)
d: 19.71 720.43) 7i-Pr); 21.56 725.36) 7i-Pr); 26.20 726.97)
1.2.10. 1-t-Butyl-3,3-dimethyl-5-methoxypiperidine18 16d.
1H NMR 7CDCl3; 500 MHz) d: 0.86 73H, s, Me); 0.93 73H,
s, Me); 1.00 79H, s, t-Bu); 1.5±1.9 72H, m, CH2); 2.3±2.7
74H, m, CH2NCH2); 3.30 73H, s, OMe); 3.1±3.3 71H, m,

7870
C. V. Stevens et al. / Tetrahedron 57 .2001) 7865±7870
CHOMe). 13C NMR 7CDCl3) d: 26.317q, Me), 26.46 7q,
Me3), 29.83 7q, Me), 31.50 7s, CMe2), 44.04 7t, CH2), 51.53
7t, CH2N), 53.18 7s, CMe3), 55.87 7q, OMe), 58.44 7t,
CH2N), 75.57 7d, CHOMe). IR 7NaCl) nmax 7cm21): 2985,
2790, 1105, 738. MS 7m/z): 199 7M1, 10); 184 7100); 152
710); 144 75); 96 75); 95 710); 70 710); 58 714); 57 724); 56
714); 55 719); 44 714); 43 75); 42 714); 41 733); 40 757); 39
710). Yield: 95%.
138 712); 71 710); 58 714); 56 729); 44 713); 43 716); 41 722).
Puri®ed by ¯ash chromatography 7Hexanes/EtOAc: 95:5)
Rfˆ0.17. Yield: 71%. Yellowish oil. Anal. Calcd for
C11H23NO; C, 71.30%; H, 12.51%. Found: C, 71.04%; H,
12.65%.
References
1. Rubiralta, M.; Giralt, E.; Diez, A. Piperidine, Structure,
Preparation, Reactivity and Synthetic Applications of
Piperidine and its Derivatives; Elsevier: Amsterdam, 1991.
2. Pinder, A. Nat. Prod. Rep. 1992, 9, 491±504.
3. Bolzani, V. da S.; Gunatilaka, A. A. L.; Kingston, D. G. I.
Tetrahedron 1995, 51, 5929±5934.
1.2.11.
2-Cyano-3,3-dimethyl-1-isopopyl-5-methoxy-
1
piperidine 16e. H NMR 7CDCl3): mixture of 2-stereo-
isomers: major17minor); ratio ,4:1; d: 1.11 70.90) 76H,
s, Me2); 1.11 73H, d, Jˆ6.9 Hz, Me); 1.13 73H, d, Jˆ
6.3 Hz, Me); 1.2±1.4 71.4±1.5) 72H, m, CH2); 1.6±1.8
71.6±1.7) 71H, m); 2.24 72.5±2.6) 71H, t, Jˆ10.9 Hz),
2.817sept., 1H, Jˆ6.6 Hz, NCHMe2), 3.12±3.18 73.0±3.1)
71H, m, CHOMe); 3.32 71H, s, CHCN), 3.36 73H, s, OMe).
13C NMR 7CDCl3) major17minor); ratio ,4:1; d: 19.44
716.74) 7q, Me), 19.82 720.22) 7q, Me), 25.18 726.10) 7q,
Me), 28.02 727.05) 7q, Me), 34.22 733.73) 7s, CMe2),
39.82 738.67) 7t, CH2), 48.86 747.64) 7t, CH2N), 53.50
752.71) 7s, CMe3), 55.78 755.78) 7q, OMe), 59.64 761.06)
7d, CHCN), 73.10 773.68) 7d, CHOMe), 117.00 7117.25) 7s,
CN). IR 7NaCl) nmax 7cm21): 2220 7CN), 1464, 1388, 1367.
MS 7m/z): 211 7M111, 7); 196 7100); 167 710); 164 713); 59
749); 57 710); 43 717). Yellowish oil; Puri®ed by ¯ash
chromatography 7Hexanes/EtOAc:70/30) Rfˆ0.56. Yield:
69%. Anal. Calcd for C12H22N2O: C, 68.53%; H, 10.54%.
Found: C, 68.62%; H, 10.39%.
4. Tadano, K.; Iimura, Y.; Suami, T. J. Carbohydr. Chem. 1985,
129±139.
5. Dockner, M.; Sasaki, A.; Riche, C.; Potier, P. Liebigs Ann./
Recueil 1997, 1267±1272.
6. Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. J. Org. Chem.
1997, 62, 746±748.
7. Harding, K.; Jones, W. Heterocycles 1989, 28, 663±668.
8. Cossy, J.; Dumas, C.; Pardo, D. G. Biorg. Med. Chem. Lett.
1997, 7, 1343±1344.
9. Mattson, R. J.; Keavy, D. J.; Catt, J. Eur. Pat. Appl. EP
718,286 7Cl. C07D211/22), 26 June 1996, 15pp; Chem.
Abstr. 1996, 125, 142653j.
10. De Kimpe, N.; Boelens, M.; Piqueur, J.; Baele, J. Tetrahedron
Lett. 1994, 35, 1925±1928.
11. De Smaele, D.; De Kimpe, N. J. Chem. Soc., Chem. Commun.
1995, 2029±2030.
1.2.12. 3,3-Dimethyl-1-isopropyl-5-methoxypiperidine
16f. H NMR 7270 MHz, CDCl3) d: 0.9173H, s, Me);
1
12. De Kimpe, N.; Boelens, M. J. Chem. Soc., Chem. Commun.
1993, 916±918.
0.98 73H, s, Me); 0.97 73H, d, Jˆ6.6 Hz, Me); 1.00 73H,
d, Jˆ6.6 Hz, Me); 1.08±1.16 71H, m, HCHCHOMe); 1.75
71H, ddt, Jˆ12.5, 4.62, 1.65 Hz, HCHCHOMe); 1.85 71H,
d, Jˆ10.9 Hz, CMe2HCHN); 1.86 71H, d, Jˆ9.9 Hz,
NHCHCH); 2.26 71H, dt, Jˆ10.9, 1.65 Hz); 2.76 71H,
sept., Jˆ6.6 Hz, CHMe2); 3.03 71H, ddt, Jˆ9.9, 4.62,
1.65 Hz, NCHCH); 3.35 73H, s, OMe); 3.36±3.45 71H, m,
CHOMe). 13C NMR 7CDCl3) d: 17.12 7q, Me),18.74 7q,
Me), 25.88 7q, Me), 29.78 7q, Me), 31.37 7s, CMe2), 43.99
7t, CH2), 54.37 7t, CH2N), 54.64 7s, CMe2), 56.12 7q, OMe),
59.64 7t, CH2N), 75.22 7d, CHOMe). IR 7NaCl) nmax 7cm21):
2940, 1460, 1360, 1050. MS 7m/z): 185 7M1, 8); 170 7100);
13. De Kimpe, N.; Stevens, C. Bull. Soc. Chim. Belg. 1992, 101,
569±578.
14. Stevens, C.; De Kimpe, N. Synlett 1991, 351±352.
15. Stevens, C.; De Kimpe, N. J. Org. Chem. 1993, 58, 132±134.
16. Salomon, R. G.; Ghosh, S. Org. Synth. 1984, 62, 125.
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1996, 37, 3171±3174.
18. Abbaspour Tehrani, K.; Van Syngel, K.; Boelens, M.;
Contreras, J.; De Kimpe, N.; Knight, D. W. Tetrahedron
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