Preparation of α-acetonylpiperidines from α-allylated heterocycles by a bromocyclocarbamation reaction

Article abstract of DOI:10.1002/ejoc.200601031

2,6-Disubstituted (alkyl)(allyl)- and diallylpiperidines containing C=C bonds in different environments can be selectively transformed into α-acetonylpiperidines, including the alkaloid (±)-6-epipinidinone. The key step is the bromocyclocarbamation reaction of the N-Boc-protected α-allylheterocycle with N-bromosuccinimide. The bulky tert-butyl group on the piperidine ring can affect the diastereoselectivity of the cyclization by 1,5-asymmetric induction. The structure of one of the isolated diastereomers was established by X-ray single-crystal diffraction. The prepared bicyclic bromides were readily dehydrobrominated with tBuOK and the corresponding enols were hydrolyzed to α-acetonylpiperidine hydrochlorides. The method presented is convenient and simple to perform. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200601031

FULL PAPER
DOI: 10.1002/ejoc.200601031
Preparation of α-Acetonylpiperidines from α-Allylated Heterocycles by a
Bromocyclocarbamation Reaction
Nikolai Yu. Kuznetsov,[a] Victor N. Khrustalev,[a] Ivan A. Godovikov,[a] and
Yuri N. Bubnov*[a]
Keywords: Alkaloids / Allylic compounds / Boranes / Nitrogen heterocycles / Halocyclocarbamation
2,6-Disubstituted (alkyl)(allyl)- and diallylpiperidines con-
taining C=C bonds in different environments can be selec-
tively transformed into α-acetonylpiperidines, including the
alkaloid (Ϯ)-6-epipinidinone. The key step is the bromocy-
clocarbamation reaction of the N-Boc-protected α-allylhet-
erocycle with N-bromosuccinimide. The bulky tert-butyl
group on the piperidine ring can affect the diastereoselectiv-
ity of the cyclization by 1,5-asymmetric induction. The struc-
ture of one of the isolated diastereomers was established by
X-ray single-crystal diffraction. The prepared bicyclic bro-
mides were readily dehydrobrominated with tBuOK and the
corresponding enols were hydrolyzed to α-acetonylpiperid-
ine hydrochlorides. The method presented is convenient and
simple to perform.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
In this report we describe an approach to the preparation
of piperidine-type amino ketones, including (Ϯ)-6-epipinid-
inone. Our approach is based on a simple and practical bro-
mocyclocarbamation reaction of α-allyl-substituted hetero-
cycles.
Introduction
The piperidine ring is a ubiquitous structural motif in
many naturally occurring compounds.[1] Moreover, piperi-
dine alkaloids and their synthetic analogues are of great
interest in the pharmaceutical industry because of their
wide spectrum of biological activities.[2] For these reasons,
and because the structural diversity of these alkaloids
makes them a good vehicle for the testing of synthetic meth- Results and Discussion
odology, the stereocontrolled synthesis of piperidine deriva-
Three allylated heterocycles (1a–c) were prepared by a
tives has attracted considerable synthetic attention in the
last few years.[3] One way to obtain the piperidine ring is to
modify the corresponding pyridine or isoquinoline deriva-
tives.
previously described protocol.[9a,9b] First organolithium
(MeLi and tBuLi) was added to pyridine or isoquinoline
(Scheme 1) at –10 °C. The resulting organolithium adducts
were treated with triallylborane followed by MeOH in order
to destroy the resulting amine–borane complex. The corre-
sponding trans-6-alkyl-2-allyl-substituted heterocycles (1a–
c) were isolated by either chromatography or distillation
(for preparative experiments). The amines 1a–c were treated
with Boc2O and the Boc-protected tetrahydropyridines were
then subjected to a bromocyclocarbamation reaction with
NBS (Scheme 2). This reaction was typically carried out in
CHCl3 under reflux for 1–1.5 h. The reaction mixture was
We have previously found that pyridines,[4] isoquino-
line,[5] and pyrrole[6] undergo reductive trans-α,αЈ-dial-
lylation on treatment with allylic boranes (triallyl-, trimeth-
allyl, and tricrotylborane) and alcohol to give the corre-
sponding α,αЈ-diallylated heterocyclic compounds. Further-
more, gem-α,α-diallylation can be achieved by reaction of
triallylborane with nitriles, carboxylic acids, esters,[7] lac-
tams,[8a] and amides,[8b] producing a wide range of allylated
compounds. Successive treatment of pyridine and isoquino-
line with alkyl- or phenyllithium, triallylborane, alcohol,
and base lead to the formation of trans-α-(alkyl or phenyl)-
αЈ-allyl-substituted heterocycles.[9a] Di- and monoallylated
tetrahydropyridines thus obtained were used as starting ma-
terials for the preparation of bridged azabicycles[9c] and cer-
tain alkaloids such as epidihydropinidine, dihydropinidine,
and indolizidines 167B and 209D.[9a,9b]
[a] A. N. Nesmeyanov Institute of Organoelement Compounds
Russian Academy of Sciences,
Vavilov 28, 119991 Moscow, Russia
Scheme 1.
Eur. J. Org. Chem. 2007, 2015–2021
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2015

N. Yu. Kuznetsov, V. N. Khrustalev, I. A. Godovikov, Yu. N. Bubnov
FULL PAPER
washed with 10% NaOH, filtered, and dried to afford ana- atoms. The crystal of 2b is a racemate with space group
lytically pure compounds 2 and 3 as a mixture of dia- Pbca. The relative configurations of the asymmetric centers
stereomers.
are (2S*,4R*,8R*).
The difference in the isomeric ratio of the substituted iso-
quinoline derivative (2c/3c = 4.8:1) was more marked
(Scheme 2). The structures of isomers 2c and 3c were as-
signed by analogy with 2b. The observed diastereoselectivity
can be rationalized on the basis of the analysis of the con-
formations of the six-membered chair-like transition
state.[11]
We found that bromomethyl derivatives undergo rapid
dehydrobromination (at –20 °C in minutes) with tBuOK in
THF (Scheme 3). Cyclic enol esters obtained in this way
have high analytical purity and can be converted directly
into amino ketone hydrochlorides with HCl solution in high
yields.
Scheme 2.
Earlier, a similar transformation (with iodine) was suc-
cessfully exploited to protect the allyl group in 2,6-dial-
lylated piperidine.[10a] The iodide was formed as a mixture
of diastereomers in a 1:1 ratio. For this reason, this method
was not selective enough for the synthesis of (–)-poranterid-
ine.[10b] In the case of 1a, bromocyclocarbamation also gave
rise to an inseparable mixture of diastereomers (1:1).
It was not clear whether 1,3- or 1,5-induction was re-
sponsible for the stereoselectivity of the bromocarbamation
reaction in the case of 2,6-disubstituted piperidines. Al-
though a high level of 1,3-asymmetric induction is well
known in halocyclization reactions of acyclic substrates,[11]
the presence of an additional ring system has to be taken
into account when estimating the expected level of stereose-
lectivity. Indeed when the substituent at the 2-position was
bulky (1b, 1c), a good level of diastereoselectivity was ob-
served. We were able to separate the diastereomers (R =
tBu) and the structure of major isomer 2b was unambigu-
ously established by X-ray single-crystal crystallography
(Figure 1).
Scheme 3.
Note that a Wacker-type oxidation reaction[12] failed in
our experiments, even when using protected (Bn, Cbz) tetra-
hydropyridines, as described in refs.[10a,13] Hydrogenation of
compound 5a gave rise to alkaloid (Ϯ)-6-epipinidinone, a
racemic form of the naturally occurring (+)-6-epipinidinone
[or (2R,6S)-2-methyl-6-(2-oxopropyl)piperidine] (Scheme 4),
The X-ray diffraction study revealed that 2b is a bicyclic
compound containing two six-membered rings in an un-
symmetrical half-chair conformation with deviations of the
C2, C3 and N1, C4 atoms, respectively, from the mean
plane of the other ring atoms. Compound 2b is chiral and
has three asymmetric centers at the C2, C4, and C8 carbon Scheme 4.
Figure 1. Molecular structure of 2b. The non-hydrogen atoms are shown with the thermal ellipsoids drawn at the 50% probability level.
Hydrogen atoms have been drawn as circles of arbitrarily small radius for clarity.
2016
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Eur. J. Org. Chem. 2007, 2015–2021

α-Acetonylpiperidines from α-Allylated Heterocycles
FULL PAPER
Scheme 5.
which together with its cis isomer are trace components in the halocyclocarbamation reaction by 1,5-asymmetric in-
extracts of Picea Pungens Engelm (Colorado blue spruce);[14a] duction. Additionally, this transformation does not affect
both isomers are also the components of alkaloids isolated other double bonds in the molecule.
from coccinellid (Cryptolaemus montrouzieri).[14b] It was
noted that the trans isomer underwent spontaneous iso-
Experimental Section
merization during isolation to the cis isomer and actually
has to be the major or even sole isomer found in intact
ladybird beetles. We also observed a little isomerization of
the trans ketone to its cis isomer during isolation of its free
base (after treatment of its hydrochloride salt with K2CO3),
as detected by 1H NMR spectroscopy. The cis/trans isomer-
ization process is evidently a general process in α-acetonylp-
iperidines and also occurs in lobeline.[14c,14d]
General: The manipulations with triallylborane were carried out
under dry argon. Triallylborane[15] and compounds 1a[9a] and 6[4c]
were prepared as described previously. NMR spectra were recorded
with Bruker AMX-400 and Avance-300 instruments. Chemical
shifts δ are given in ppm and coupling constants J in Hz. Mass
spectra were recorded with a Finnigan Polaris Q Ion Trap spec-
trometer. Column chromatography was carried out using silica gel
(Merck, 60–230 mesh). Thin-layer chromatography was performed
on silica gel 60 F254 (Merck). All compounds were prepared in race-
mic form.
In
addition,
trans-2,6-diallyl-5-bromo-1,2,3,6-tetra-
hydropyridine (6) was subjected to the bromocyclocarbam-
ation reaction (Scheme 5). The protection of 6 and subse-
quent cyclization reaction were performed without isolation
of the intermediates. After dehydrohalogenation, two iso-
mers 7a and 7b were isolated by flash chromatography.
These isomers were structurally discriminated by NMR
spectroscopy (COSY and NOESY experiments). We ob-
served no selectivity in the bromocyclocarbamation reac-
tion; however, the two allyl groups were shown to have
slightly different reactivities. The composition of the cyclic
enol esters obtained after dehydrohalogenation was equal
to 1:1.8 in favor of 7a. Additionally, we detected the forma-
tion of the free base of amino ketone 7aЈ derived from 7a.
The corresponding enol ester is probably very prone to hy-
drolytic cleavage which occurs during the chromatography
or TLC monitoring steps.
(2S*,6R*)-2-Allyl-6-(tert-butyl)-1,2,3,6-tetrahydropyridine (1b): Dry
pyridine (1.22 g/1.25 mL, 15 mmol) in Et2O (1 mL) was added to a
solution of tBuLi (0.85  in pentane, 20 mL, 17 mmol) in Et2O/
THF (1:1) (12 mL) at –10 °C and the resulting solution was stirred
at –5 to 0 °C for 2 h. Then neat triallylborane (2.41 g/3.1 mL,
18 mmol) was added to the mixture at –15 °C and stirring was con-
tinued for 10 min followed by the addition of MeOH (10 mL) at
0 °C. The mixture was refluxed for 1 h and then 5  NaOH (10 mL,
50 mmol) was added to complete the deboronation process. The
organic layer was separated and the aqueous layer extracted with
hexane (20 mL). The combined organic phases were dried with
K2CO3, the solvent was evaporated, and the residue was purified
by FC (hexane/EtOAc, 2:1) on silica gel, Rf = 0.54. Yield: 1.5 g
(56%) as a reddish liquid. 1H NMR (300 MHz, CDCl3): δ = 5.80–
5.67 (m, 3 H), 5.09–5.00 (m, 2 H), 3.02–2.96 (m, 2 H), 2.20–2.10
(m, 3 H), 1.72 (m, 1 H), 0.83 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.01, 126.64, 125.40, 117.07, 59.25, 48.90, 39.00,
35.15, 30.49, 26.68 (3 CH3) ppm. MS (70 eV, EI): m/z (%) = 180.2
(2) [MH]+, 164 (7), 138 (6), 122 (20), 108 (7), 93 (9), 81 (12), 80
(100), 79 (8), 67 (8), 53 (5). C12H21N (179.3): calcd. C 80.36, H
11.81, N 7.81; found C 80.32, H 11.69, N 7.77.
After individual hydrolytic treatment of the enol esters
7a and 7b with HCl solution, both amino ketone hydro-
chlorides 8a and 8b were isolated in good yields.
(1S*,3S*)-3-Allyl-1-(tert-butyl)-1,2,3,4-tetrahydroisoquinoline (1c):
The procedure was the same as that used for the preparation of 1b,
but was carried out with isoquinoline. Isolation by FC (hexane/
EtOAc, 5:1) on silica gel, Rf = 0.56. Yield: 2.2 g (64%) as a yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.17–7.12 (m, 4 H), 5.97–
5.83 (m, 1 H), 5.18–5.13 (m, 2 H), 3.78 (s, 1 H), 3.54 (m, 1 H), 3.00
(dd, J = 5.3, 16.2 Hz, 1 H), 2.60 (dd, J = 7.8, 16.2 Hz, 1 H), 2.22
(m, 1 H), 2.11 (m, 1 H), 1.04 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.7, 135.6, 135.3, 129.03, 128.48, 126.15, 124.55,
Conclusion
A simple and fast strategy for the conversion of α,αЈ-
diallyl- and α-alkyl-αЈ-allyl-tetrahydropyridines and -isoquin-
oline into the corresponding amino ketone hydrochlorides
has been elaborated. In this way the alkaloid (Ϯ)-6-epipin-
idinone was prepared. It was found that substituents on the
piperidine ring can affect the diastereoselectivity of 117.57, 63.38, 48.07, 41.62, 37.71, 34.96, 28.63 (3 CH3) ppm. MS
Eur. J. Org. Chem. 2007, 2015–2021
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Yu. Kuznetsov, V. N. Khrustalev, I. A. Godovikov, Yu. N. Bubnov
FULL PAPER
(70 eV, EI): m/z (%) = 230.2 (6) [MH]+, 188 (5), 173 (13), 172 (94), 2c: Rf = 0.51 (hexane/EtOAc, 3:1) (major isomer). 1H NMR
155 (5), 143 (7), 131 (16), 130 (100), 117 (4), 103 (5), 91 (2), 77 (4). (400 MHz, CDCl3): δ = 7.23–7.15 (m, 3 H, Ar), 7.09 (d, J = 7.1 Hz,
C16H23N (229.4): calcd. C 83.79, H 10.11, N 6.11; found C 83.62,
H 10.18, N 6.09.
1 H, Ar), 5.34 (s, 1 H, CHtBu), 4.50 (dddd, J = 2.0, 4.6, 7.3, 8.9 Hz,
1 H, CHNCH2), 4.24 (dddd, J = 5.3, 7.1, 7.6, 10.7 Hz, 1 H, CHO),
3.57 (dd, J = 4.4, 10.5 Hz, CHaHbAr), 3.38 (dd, J = 7.3, 10.5 Hz,
CHaHbAr), 3.32 (dd, J = 7.5, 17.4 Hz, 1 H, CHaHbBr), 2.73 (dd,
J = 7.1, 17.1 Hz, 1 H, CHaHbBr), 2.57 (ddd, J = 2.1, 5.0, 13.5 Hz,
1 H, CHaHbCHO), 1.71 (ddd, J = 11.2, 11.4, 13.2 Hz, 1 H,
CHaHbCHO), 1.03 (s, 9 H, tBu) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.29, 134.41, 131.76, 128.51, 128.24, 127.21, 125.57,
73.98, 62.46, 48.16, 38.26, 35.64, 34.97, 32.60, 28.61 (3 CH3) ppm.
MS (70 eV, EI): m/z (%) = 352/354 (0.5) [MH]+, 294/296 (95), 250/
252 (98), 214/216 (15), 170 (100), 143 (12), 130 (57), 103 (12), 77
(5). C17H22BrNO2 (352.3): calcd. C 57.96, H 6.29, Br 22.68, N 3.98;
found C 57.99, H 6.15, Br 22.83, N 3.97.
General Protocol for the Protection/Bromocyclocarbamation Pro-
cess: Amines 1a–c or 6 (1 equiv.) and Boc2O (1.05 equiv.) in THF
(2 mL for 4 mmol) were refluxed for 1–2 h (TLC control). After
completion of the reaction, THF was evaporated, residual oil was
dissolved in CHCl3, NBS (1.2 equiv.) was added, and the mixture
refluxed for 1 h (TLC control). The solvent was evaporated and the
residue was treated with Et2O (10 mL for 4 mmol) and 10% NaOH
(5 mL for 4 mmol) with stirring for 15 min. The organic layer was
separated, dried with K2CO3, and the solvent evaporated.
(4aR*,8S*)-3-(Bromomethyl)-8-methyl-4,4a,5,8-tetrahydro-3H-pyr-
ido[1,2-c][1,3]oxazin-1-one (2a/3a): Yield: 2.76 g (92%). Rf = 0.43
(hexane/EtOAc, 1:1). Diastereoisomeric ratio = 1:1, estimated by
1H NMR spectroscopy. MS (70 eV, EI): m/z (%) = 260/262 (4)
[MH]+, 244/246 (27), 200/202 (25), 180 (55), 138 (19), 120 (100), 94
(44), 80 (22), 67 (16), 39 (10). C10H14BrNO2 (260.1): calcd. C 46.17,
H 5.42, Br 30.72, N 5.38; found C 46.32, H 5.56, Br 30.74, N 5.29.
3c: Rf = 0.55 (hexane/EtOAc, 3:1) (minor isomer). 1H NMR
(400 MHz, CDCl3): δ = 7.22–7.14 (m, 3 H, Ar), 7.11 (d, J = 7.4 Hz,
1 H, Ar), 5.27 (s, 1 H, CHtBu), 4.48 (m, 1 H, CHNCH2), 4.24
(ddd, J = 2.2, 8.3, 14.2 Hz, 1 H, CHO), 3.59 (dd, J = 4.3, 10.5 Hz,
1 H, CHaHbAr), 3.45 (dd, J = 7.2, 10.5 Hz, 1 H, CHaHbAr), 2.92
(d, J = 8.4 Hz, 2 H, CH2Br), 2.19 (ddd, J = 6.1, 10.4, 14.0 Hz, 1
H, CHaHbCHO), 2.14 (dt, J = 2.2, 14.0 Hz, CHaHbCHO), 1.06 (s,
9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.54, 135.09,
132.49, 128.98, 128.02, 126.93, 125.86, 71.09, 62.68, 45.99, 37.34,
34.78, 32.57, 30.66, 29.24 (3 CH3) ppm. MS (70 eV, EI): m/z (%) =
352/354 (0.5) [MH]+, 244/246 (40), 200/202 (30), 166 (70), 120
(100), 80 (42), 77 (10), 44 (10).
(3S*,4aR*,8R*)-3-(Bromomethyl)-8-(tert-butyl)-4,4a,5,8-tetrahydro-
3H-pyrido[1,2-c][1,3]oxazin-1-one (2b) and (3R*,4aR*,8R*)-3-(Bro-
momethyl)-8-(tert-butyl)-4,4a,5,8-tetrahydro-3H-pyrido[1,2-c][1,3]-
oxazin-1-one (3b): Total yield: 0.83 g (91.2%). Diastereomeric ratio
1
= 1:4, estimated by H NMR spectroscopy. The individual isomers
were isolated by FC (hexane/EtOAc, 3:1) on silica gel: 2b as white
crystals, m.p. 137–138 °C; 3b as an oil.
Typical Dehydrohalogenation with tBuOK: A mixture of dia-
stereomeric bromides 2 (1 equiv.) was dissolved in THF (6 mL for
3 mmol). The solution was kept at –25 to –20 °C and tBuOK
(1.2 equiv.) was added. The pink mixture was stirred for 5 min and
then the solution was passed through a short pad of silica gel to
remove colored organic material from the solution. The silica gel
pad was washed with a mixture of hexane/EtOAc, 2:1. Concentra-
tion of the colorless filtrate under reduced pressure afforded the
analytically pure product.
2b: Rf = 0.62 (hexane/EtOAc, 2:1) (major isomer). 1H NMR
(300 MHz, CDCl3): δ = 5.88 (ddt, J = 1.8, 5.5, 12.3 Hz, 1 H,
CH=CH2), 5.81 (m, 1 H, CH=CHN), 4.56 (m, 1 H, CHNtBu),
4.49 (m, 1 H, CHO), 3.89 (m, 1 H, CHNCH2), 3.58 (dd, J = 4.4,
10.5 Hz, 1 H, CHaHbBr), 3.42 (dd, J = 7.3, 10.5 Hz, 1 H,
CHaHbBr), 2.28–1.98 (m, 4 H), 1.02 (s, 9 H, tBu) ppm. 13C NMR
(100 MHz, CDCl3): δ = 152.55 (C=O), 126.36 (CH=), 124.89
(CH=), 71.18, 62.17, 47.34, 36.97, 32.85, 31.67, 30.06, 27.97 (3
CH3) ppm. MS (70 eV, EI): m/z (%) = 302/304 (7) [MH]+, 244/246
(32), 200/202 (26), 166 (89), 120 (100), 88 (20), 80 (50), 79 (30), 67
(5), 44 (15). C13H20BrNO2 (302.2): calcd. C 51.67, H 6.67, Br 26.4,
N 4.63; found C 51.55, H 6.76, Br 26.53, N 4.59.
(4aR*,8S*)-8-Methyl-3-methylene-4,4a,5,8-tetrahydro-3H-pyrido-
[1,2-c][1,3]oxazin-1-one (4a): Yield: 0.53 g (84%) as an oil. Rf = 0.67
1
(hexane/EtOAc, 1:1). H NMR (400 MHz, CDCl3): δ = 5.75 (ddt,
J = 1.9, 5.7, 10.2 Hz, 1 H CH=), 5.65 (dtd, J = 0.9, 2.6, 10.2 Hz,
1 H CH=), 4.72 (s, 1 H), 4.70 (m, 1 H), 4.34 (s, 1 H), 3.61 (ddd, J
= 3.7, 6.7, 14.5 Hz, 1 H), 2.79 (dd, J = 6.6, 14.4 Hz, 1 H), 2.42 (dd,
J = 3.7, 14.4 Hz, 1 H), 2.20 (dddd, J = 2.5, 4.6, 11.1, 17.0 Hz, 1
H), 2.02 (ddd, J = 3.8, 4.7, 17.0 Hz, 1 H), 1.27 (d, J = 7.0 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.24 (C=O), 129.85
(CH=), 123.27 (CH=), 94.78 (C=), 50.21 (CH), 45.23 (CH), 31.20
(CH2), 31.06 (CH2), 28.16 (CO=), 18.53 (CH3) ppm. MS (70 eV,
EI): m/z (%) = 179 (42) [M]+, 164 (100), 134 (14), 122 (19), 104
(12); 94 (30), 80 (33), 67 (22). C10H13NO2 (179.2): calcd. C 67.02,
H 7.31, N 7.82; found C 66.95, H 7.28, N 7.90.
3b: Rf = 0.71 (hexane/EtOAc, 2:1) (minor isomer). 1H NMR
(300 MHz, CDCl3): δ = 5.86 (m, 2 H, CH=), 4.68 (m, 1 H,
CHNtBu), 4.41 (dddd, J = 1.6, 4.6, 7.1, 11.4 Hz, 1 H, CH), 3.83
(dddd, J = 3.9, 7.5, 10.5, 10.5 Hz, 1 H, CH), 3.60 (dd, J = 4.6,
10.5 Hz, 1 H, CHaHbBr), 3.44 (dd, J = 7.1, 10.7 Hz, 1 H,
CHaHbBr), 2.61 (ddd, J = 3.0, 7.3, 13.7 Hz, 1 H), 2.32 (ddd, J =
3.5, 3.6, 16.4 Hz, 1 H), 1.97 (ddd, J = 2.7, 10.5, 18.0 Hz, 1 H), 1.64
(ddd, J = 10.9, 21.9, 10.5 Hz, 1 H), 1.02 (s, 9 H, tBu) ppm. 13C
NMR (75 MHz, CDCl3): δ = 154.27, 125.22, 123.70, 72.76, 59.80,
48.86, 37.78, 34.58, 33.37, 32.21, 27.76 (3 CH3) ppm. MS (70 eV,
EI): m/z (%) = 302/304 (1) [MH]+, 244/246 (25), 200/202 (23), 166
(65), 120 (100), 88(17), 80 (41), 79 (24), 53 (7), 44 (12).
C13H20BrNO2 (302.2): calcd. C 51.67, H 6.67, N 4.63; found C
51.48, H 6.83, N 4.55.
(4aR*,8R*)-8-(tert-Butyl)-3-methylene-4,4a,5,8-tetrahydro-3H-pyr-
ido[1,2-c][1,3]oxazin-1-one (4b): Yield: 0.36 g (82%) as an oil. Rf =
1
0.56 (hexane/EtOAc, 2:1). H NMR (300 MHz, CDCl3): δ = 5.91
(ddt, J = 1.8, 5.7, 10.5 Hz, 1 H CH=), 5.65 (dtd, J = 0.9, 2.5,
10.5 Hz, 1 H, CH=), 4.70 (s, 1 H, CHaHb=), 4.50 (m, 1 H,
CHNtBu), 4.29 (t, J = 1.6 Hz, 1 H, CHaHb=), 3.76 (m, 1 H, CHN),
(3S*,4aR*,10S*)-3-(Bromomethyl)-10-(tert-butyl)-4,4a,5,10-tetra-
hydro-3H-[1,3]oxazino[3,4-b]isoquinolin-1-one (2c) and
(3R*,4aR*,10S*)-3-(Bromomethyl)-10-(tert-butyl)-4,4a,5,10-tetra- 2.85 (dd, J = 6.4, 14.4 Hz, 1 H, CHaHbCO=), 2.42 (dd, J = 2.0,
hydro-3H-[1,3]oxazino[3,4-b]isoquinolin-1-one (3c): Total yield:
1.29 g (88 %). Diastereomeric ratio = 1:4.8, as estimated by 1H
NMR spectroscopy. The individual isomers were isolated by FC
(hexane/EtOAc, 3:1) on silica gel: 2c as white crystals, m.p. 147–
148 °C; 3c as an oil.
14.4 Hz, 1 H, CHaHbCO=), 2.19 (dddd, J = 2.5, 4.8, 11.4, 16.9 Hz,
1 H, CHaHbCH=), 1.96 (ddd, J = 4.1, 5.3, 17.1 Hz, CHaHbCH=),
1.03 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.89,
150.27, 125.83, 125.60, 94.29, 63.21, 47.51, 36.47, 30.28, 27.73 (3
CH3) ppm. MS (70 eV, EI): m/z (%) = 222 (40) [MH]+, 206 (10)
2018
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Eur. J. Org. Chem. 2007, 2015–2021

α-Acetonylpiperidines from α-Allylated Heterocycles
[M – CH3]+, 165 (100), 164 (62), 150 (10), 124 (17), 120 (42), 104 (2R*,6R*)-6-(tert-Butyl)-2-(2-oxopropyl)-1,2,3,6-tetrahydropyridinium
FULL PAPER
(18), 91 (26), 80 (65), 67 (10), 53 (6). C13H19NO2 (221.3): calcd. C
70.56, H 8.65, N 6.33; found C 70.58, H 8.54, N 6.28.
Hydrochloride (5b): Yield: 0.31 g (93%), m.p. 183–184 °C (dec.). 1H
NMR (300 MHz, CDCl3): δ = 10.23 (br. s, 1 H NH2), 8.39 (br. s,
1 H NH2), 5.96 (br. d, J = 10.7 Hz, 1 H, CH=CH2), 5.68 (d, J =
10.7 Hz, 1 H, CH=CHtBu), 4.12 (br. s, 1 H, CHNCH2), 3.58 (d, J
= 16.0 Hz, 1 H, CHaHbCH=), 3.49 (br. s, 1 H, CHtBu), 2.83 (dd,
J = 8.2, 17.3 Hz, 1 H, CHaHbCH=), 2.75 (d, J = 18.1 Hz, 1 H,
CHaHbCO), 2.27 (d, J = 18.1 Hz, 1 H, CHaHbCO), 2.23 (s, 3 H,
CH3), 1.17 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ =
205.86 (C=O), 125.97 (CH=CH2), 121.62 (CH=ChtBu), 59.67
(ChtBu), 47.16 (CHCH2), 43.29 (CH2CH=), 34.41 (C), 30.38
(CH3), 26.75 (3 CH3), 26.04 (CH2C=O) ppm. MS (70 eV, EI): m/z
(%) = 231 (0.1) [M]+, 196 (10), 138 (15), 122 (7), 80 (100), 78 (4),
53 (3). C12H22ClNO (231.8): calcd. C 62.19, H 9.57, Cl 15.30, N
6.04; found C 62.04, H 9.67, Cl 15.43, N 6.04.
(4aR*,10S*)-10-(tert-Butyl)-3-methylene-4,4a,5,10-tetrahydro-3H-
[1,3]oxazino[3,4-b]isoquinolin-1-one (4c): Yield: 0.69 g (88%) as an
1
oil. Rf = 0.46 (hexane/EtOAc, 2:1). H NMR (400 MHz, CDCl3):
δ = 7.17–7.14 (m, 3 H, Ar), 7.11 (d, J = 7.1 Hz, 1 H, Ar), 5.27 (s,
1 H, CHtBu), 4.71 (s, 1 H, CHaHb=), 4.29 (s, 1 H, CHaHb=), 4.16
(m, 1 H, CHN), 3.03 (dd, J = 6.4, 16.7 Hz, 1 H), 2.84 (dd, J = 8.6,
16.7 Hz, 1 H), 2.80 (dd, J = 5.2, 14.3 Hz, 1 H), 2.42 (dd, J = 5.8,
14.3 Hz, 1 H), 1.07 (s, 9 H, tBu) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.03, 150.78, 135.05, 132.43, 128.93, 128.47, 127.12,
125.83, 93.91, 63.79, 47.25, 37.69, 33.62, 32.50, 28.93 (3 CH3) ppm.
MS (70 eV, EI): m/z (%) = 272 (8) [M + H]+, 256 (5), 214 (100),
170 (28), 141 (15), 130 (34), 128 (10), 115 (5), 103 (5), 77 (4).
C17H21NO2 (271.3): calcd. C 75.25, H 7.80, N 5.16; found C 75.22,
H 7.74, N 5.18.
(1S*,3R*)-1-(tert-Butyl)-3-(2-oxopropyl)-1,2,3,4-tetrahydroisoquin-
olinium Hydrochloride (5c): Yield: 0.56 g (93%), m.p. 155–156 °C.
1H NMR (400 MHz, CDCl3): δ = 10.62 (br. s, 1 H, NH), 8.58 (br.
s, 1 H, NH), 7.27–7.23 (m, 2 H, Ar), 7.18 (dd, J = 2.1, 8.6 Hz, 1
H, Ar), 7.12 (dd, J = 1.9, 8.3 Hz, 1 H, Ar), 4.72 (br. s, 1 H, CHN),
4.33 (t, J = 4.5 Hz, 1 H, CHtBu), 3.39 (dd, J = 2.8, 18.3 Hz, 1 H),
3.25 (dd, J = 4.0, 16.6 Hz, 1 H), 2.87 (dd, J = 2.5, 16.6 Hz, 1 H),
2.30 (dd, J = 9.2, 18.3 Hz, 1 H), 2.06 (s, 3 H, CH3), 1.17 (s, 9 H,
tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 204.68 (C=O),
132.29, 129.80, 129.64, 128.72, 128.19, 126.41, 62.92, 47.48, 42.79,
36.90, 31.24, 30.37, 26.93 ppm. MS (70 eV, EI): m/z (%) = 281 (0.3)
[M]+, 188 (38), 131 (15), 130 (100), 129 (10), 103 (10), 77(5).
C16H24ClNO (281.8): calcd. C 68.19, H 8.58, Cl 12.58, N 4.97;
found C 68.08, H 8.66, Cl 12.62, N 5.02.
Typical Hydrolysis Procedure: The corresponding enol ester 4
(1 equiv.) was dissolved in THF/iPrOH (9 mL:1 mL for 2 mmol)
and then a 6  HCl solution (5 equiv.) was added. The resulting
solution was refluxed for 30 min. After completion of the reaction
(TLC control) the reaction mixture was concentrated under re-
duced pressure to dryness, diethyl ether was added to the residue,
and the mixture was stirred until complete crystallization of the
amino ketone hydrochloride. The precipitate was filtered off and
dried in vacuo.
(2R*,6S*)-6-Methyl-2-(2-oxopropyl)-1,2,3,6-tetrahydropyridinium
Hydrochloride (5a): Yield: 0.65 g (94%), m.p. 159–160 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 9.88 (br. s, 1 H, NH2), 9.29 (br. s, 1
H NH2), 5.79 (br. d, J = 10.5 Hz, 1 H), 5.68 (br. d, J = 10.5 Hz, 1
H), 3.85 (br. s, 1 H), 3.68 (br. s, 1 H), 3.15 (dd, J = 4.6, 18.0 Hz, 1
H), 2.90 (dd, J = 8.0, 18.0 Hz, 1 H), 2.38 (br. d, J = 18.3 Hz, 1 H),
2.17 (s, 3 H), 2.15–2.06 (br. m, 1 H), 1.36 (d, J = 6.8 Hz, 3 H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 205.76 (C=O), 126.54
(CH=), 124.21 (CH=), 47.20, 44.56, 44.12, 30.68, 27.29, 17.99 ppm.
MS (70 eV, EI): m/z (%) = 189 (4) [M]+, 154 (20) [M – Cl]+, 138
(6), 110 (6), 95 (25), 94 (100), 80 (83), 67 (21), 53 (10), 39 (10).
C9H16ClNO (189.7): calcd. C 56.99, H 8.50, Cl 18.69, N 7.38;
found C 56.82, H 8.56, Cl 18.74, N 7.29.
(4aS*,8S*)-8-Allyl-5-bromo-3-methylene-4,4a,7,8-tetrahydro-3H-pyr-
ido[1,2-c][1,3]oxazin-1-one (7a) and (4aR*,8S*)-8-Allyl-7-bromo-3-
methylene-4,4a,5,8-tetrahydro-3H-pyrido[1,2-c][1,3]oxazin-1-one
(7b): A mixture of four diastereoisomeric dibromides (0.72 g,
1.97 mmol) in THF (4 mL), obtained from 6 (0.5 g, 2.06 mmol) in
a total yield of 96% according to the above-mentioned protocols
was dehydrohalogenated with tBuOK (0.26 g, 2.36 mmol) at –20 °C
for 5 min. After standard treatment, the product mixture was puri-
fied by FC on silica gel (hexane/EtOAc, 4:1). Three fractions were
isolated as oils: first 7a (0.22 g), second 7b (0.16 g), and third amino
ketone 7aЈ derived from 7a (0.07 g) in a total yield of 80%.
7a: Major fraction. Rf = 0.43 (hexane/EtOAc, 4:1). 1H NMR
(400 MHz, CDCl3): δ = 6.15 (dm, J = 7.0 Hz, 1 H, CH=cycle), 5.72
(m, 1 H, CH=allyl), 5.06–5.01 (m, 2 H, CH2=), 4.71 (dd, J = 7.2,
14.4 Hz, 1 H, CHNCH2), 4.63 (m, 1 H, CHaHb=C), 4.28 (m, 1 H,
CHaHb=C), 3.94 (dm, J = 12.0 Hz, 1 H, CHNCBr=), 3.13 (dd, J
= 3.6, 14.2 Hz, 1 H, CHaHbCHN.Br), 2.45 (dddd, J = 2.2, 3.6, 6.1,
17.5 Hz, 1 H, CHaHbCH=cycle), 2.35–2.18 (m, 3 H, CHaHbCHN.Br
and CH2CHNchain), 2.06 (dddd, J = 1.0, 2.1, 7.0, 17.6 Hz, 1 H,
CHaHbCH=cycle) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.26
(C), 150.00 (C), 134.13 (CH=allyl), 127.49 (CH=cycle), 118.65
CH2=allyl), 118.32 (CBr), 93.85 (CH2=C), 52.62 (CHNCBr), 47.98
(CHNCH2), 36.05 (CH2 chain), 32.34 (CH2CHN.Br), 29.91
(CH2 in cycle) ppm. C12H14BrNO2 (284.2): calcd. C 50.72, H 4.97,
Br 28.12, N 4.93; found C 50.69, H 4.86, Br 27.95, N 4.82.
(2S*,6R*)-2-Methyl-6-(2-oxopropyl)hexahydropyridinium Hydro-
chloride [(؎)-6-Epipinidinone Hydrochloride]: A solution of 5a
(0.38 g, 2.0 mmol) in MeOH (10 mL) and palladium on carbon
(10%, 0.2 g) were successively added to a steel autoclave. The re-
sulting solution was hydrogenated at 580 psi at 40 °C with rotation
for 4 h. After filtration, the resulting clear solution was concen-
trated under reduced pressure and the residue was treated with
EtOAc containing some CHCl3. The precipitate was collected and
dried in vacuo to afford 0.32 g (85%) of (Ϯ)-6-epipinidinone hydro-
chloride, m.p. 69–70 °C. 1H NMR (400 MHz, CDCl3): δ = 9.12 (br.
s, 1 H), 8.69 (br. s, 1 H), 3.44 (br. m, 1 H), 3.14 (m, 1 H), 2.92 (dd,
J = 4.2, 18.4 Hz, 1 H), 2.57 (dd, J = 8.4, 18.4 Hz, 1 H), 1.84 (s, 3
H), 1.62–1.55 (m, 2 H), 1.35–1.24 (m, 4 H), 1.08 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 204.58, 48.04, 46.69,
43.72, 30.26, 28.13, 26.64, 17.07, 16.39 ppm. C9H18ClNO (191.7):
calcd. C 56.39, H 9.46, Cl 18.49, N 7.31; found C 56.18, H 9.44,
7b: Minor fraction. Rf = 0.31 (hexane/EtOAc, 4:1). 1H NMR
(400 MHz, CDCl3): δ = 6.07 (m, 1 H, CH=cycle), 5.84–5.73 (m, 1
H, CH=all), 5.08–5.02 (m, 2 H, CH2=all), 4.85 (dm, J = 8.1 Hz, 1
H, CHNAll), 4.70 (s, 1 H, CHaHb=C), 4.30 (m, 1 H, CHaHb=C),
3.68 (m, 1 H, CHNCH2C=), 2.79 (dm, J = 14.7 Hz, 1 H,
CHaHb in allyl), 2.70 (ddd, J = 0.9, 6.2, 14.6 Hz, 1 H, CHaHbCO=),
1
Cl 18.54, N 7.26. The H NMR spectrum of the free base of the
alkaloid is consistent with literature data.[14a] 1H NMR (400 MHz,
CDCl3): δ = 3.53 (m, 1 H), 3.12 (m, 1 H), 2.83 (dd, J = 7.8, 17.2 Hz,
1 H), 2.57 (dd, J = 5.5, 17.2 Hz, 1 H), 2.16 (s, 3 H), 1.73–1.60 (m,
2 H), 1.59–1.51 (m, 1 H), 1.39–1.27 (m, 3 H), 1.16 (d, J = 6.5 Hz, 2.40 (ddd, J = 7.5, 8.6, 14.9 Hz, 1 H, CHaHb in allyl), 2.34 (dd, J =
3 H) ppm.
2.6, 14.3 Hz, 1 H, CHaHbCO=), 2.26 (dddd, J = 2.2, 4.3, 11.4,
Eur. J. Org. Chem. 2007, 2015–2021
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2019

N. Yu. Kuznetsov, V. N. Khrustalev, I. A. Godovikov, Yu. N. Bubnov
FULL PAPER
16.8 Hz, 1 H, CHaHbCH=in cycle), 2.03 (dt, J = 4.8, 17.1 Hz, 1 H, reflections with IՆ2σ(I) and wR2 = 0.0769 for all 3233 (Rint
=
CHaHbCH=in cycle) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.79
and 149.59 (C=O and C=CH2), 133.47 (CH=all), 127.07 (CH=cycle),
0.060) independent reflections. The maximum and minimum peaks
on the final difference Fourier map corresponded to 0.536 and
121.54 (CBr=), 118.28 (CH2=all), 95.71 (CH2=C), 58.64 (CHNAll), –0.566 eÅ–3, respectively. All calculations were carried out using
44.98 (CHNCH2C=), 35.98 (CH2All), 33.13 (CH2 in cycle), 30.18 the SHELXTL (PC Version 6.12) program.[17] CCDC-628827 con-
(CH2CO) ppm. MS (70 eV, EI): m/z (%) = 283/285 (0.4) [M]+, 242/
244 (100/95), 198/200 (34), 169/171 (10), 158/160 (20), 119 (35), 118
(75), 91 (27). C12H14BrNO2 (284.2): calcd. C 50.72, H 4.97, Br
28.12, N 4.93; found C 50.66, H 4.95, Br 28.03, N 4.87.
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1-[(2S*,6S*)-6-Allyl-3-bromo-1,2,5,6-tetrahydro-2-pyridinyl]acetone
(7aЈ): Rf = 0.24 (hexane/EtOAc, 4:1). 1H NMR (300 MHz, CDCl3):
δ = 6.10 (m, 1 H, CH=cycle), 5.75 (qt, J = 7.1, 10.3, 16.7 Hz, 1 H,
CH=all), 5.11 (d, J = 6.2 Hz, 1 H, CHaHb=), 5.07 (s, 1 H,
CHaHb=), 3.96 (d, J = 10.3 Hz, 1 H, CHN), 2.96 (dd, J = 2.7,
16.9 Hz, 1 H, CHaHbC=O), 2.89 (m, 1 H, CHNAll), 2.74 (dd, J =
10.0, 16.9 Hz, 1 H, CHaHbC=O), 2.20 (s, 3 H, CH3), 2.15 (t, J =
7.3 Hz, 2 H, CH2 all), 2.06 (m, 1 H, CHaHbCH=cycle), 1.92 (ddt, J =
2.5, 9.2, 17.4 Hz, 1 H, CHaHbCH=cycle) ppm. 13C NMR (75 MHz,
CDCl3): δ = 207.59, 134.62, 128.66, 123.78, 117.73, 55.40, 45.87,
45.53, 39.77, 34.26, 30.71 ppm.
Acknowledgments
This work was supported by the Russian Foundation for Basic Re-
search (grant 05-03-33268), the Programme of the President of the
RAS (coordinator: V. A. Tartakovsy) and the President of Russian
Federation V. V. Putin (program 2878.2006.3).
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pp. 1–90.
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lished results.
(2S*,6S*)-2-Allyl-5-bromo-6-(2-oxopropyl)-1,2,3,6-tetrahydropyr-
idinium Hydrochloride (8a): Yield: 0.19 g (94%) as cream-colored
crystals, m.p. 179–182 °C (dec.). 1H NMR (300 MHz, [D6]DMSO):
δ = 10.22 and 9.43 (br. s, 1 H each, NH2+), 6.32 (m, 1 H, CH=cycle),
5.84–5.71 (m, 1 H, CH=allyl), 5.24–5.16 (m, 2 H, CH2=allyl), 4.45
(dm, J = 5.7 Hz, 1 H, CHNCBr), 3.48 (m, 1 H, CHN), 3.33 (dd, J
= 7.8, 19.0 Hz, 1 H, CHaHbCO), 3.03 (dd, J = 3.0, 19.0 Hz, 1 H,
CHaHbCO), 2.72 (dm, J = 13.7 Hz, 1 H, CHaHb allyl), 2.45–2.35
(m, 2 H, CHaHb allyl, CHaHb cycle), 2.32–2.21 (m, 1 H, CHaHb cycle),
2.25 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
204.33 (C=O), 132.74, 128.98, 119.65, 116.71, 51.87, 51.78, 47.25,
43.54, 36.18, 30.38, 29.55 ppm. MS (70 eV, EI): m/z (%) = 258/260
(9) [M – Cl]+, 216/218 (11), 198/200 (7), 158/160 (100), 120 (12), 93
(7), 78 (12), 65(6), 51 (6), 43 (6). C11H17BrClNO2 (294.6): calcd. C
44.84, H 5.82, N 4.75; found C 44.83, H 5.86, N 4.73.
(2R*,6S*)-6-Allyl-5-bromo-2-(2-oxopropyl)-1,2,3,6-tetrahydropyr-
idinium Hydrochloride (8b): Yield: 0.15 g (92%) as cream-colored
crystals, m.p. 118.5–119.5 °C. 1H NMR (400 MHz, CDCl3): δ =
10.66 and 9.12 (br. s., 1.4 H in total, NH2+), 6.23 (s, 1 H, CH=cycle),
5.95–5.84 (m, 1 H, CH=allyl), 5.43 (d, J = 16.8 Hz, 1 H, CHaHb=
allyl), 5.29 (d, J = 10.0 Hz, 1 H, CHaHb=allyl), 4.08 (br. s., 1 H,
CHNallyl), 3.89 (m, 1 H, CHNCH2CO), 3.47 (dd, J = 4.6, 18.5, Hz,
1 H, CHaHbCO), 3.01–2.90 (m, 2 H, CHaHbCO and CHaHb allyl),
2.77 (m, 1 H, CHaHb allyl), 2.49 (m, 2 H, CH2 cycle), 2.18 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 205.04 (C=O),
130.88, 128.25, 121.94, 115.91, 56.50, 45.23, 44.58, 34.96, 30.37,
29.67 ppm. C11H17BrClNO2 (294.6): calcd. C 44.84, H 5.82, N
4.75; found C 44.81, H 5.82, N 4.68.
X-ray Diffraction of 2b: C13H20BrNO2, Mr = 302.21, orthorhom-
bic, space group Pbca, T = 100.0(2) K; a = 17.608(2), b = 7.2047(9),
c = 21.431(2) Å, V = 2718.7(5) Å3, Z = 8, dcalcd. = 1.477 gcm–3,
F(000) = 1248, µ = 3.015 mm–1. Data were collected with a Bruker
three-circle diffractometer equipped with a SMART APEX-II
CCD area detector using graphite-monochromated Mo-Kα radia-
tion (λ = 0.71073 Å, φ- and ω-scan mode, 2θ = 56°) and corrected
for Lorentz, polarization and absorption effects.[16] The structure
was solved by direct methods and refined by full-matrix least-
squares refinement on F2 with anisotropic displacement parameters
for all non-hydrogen atoms. Hydrogen atoms were generated geo-
metrically and included in the refinement with fixed positions and
thermal parameters. The final R factors were R1 = 0.0314 for 2594
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2020
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Eur. J. Org. Chem. 2007, 2015–2021

α-Acetonylpiperidines from α-Allylated Heterocycles
FULL PAPER
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Published Online: February 27, 2007
Eur. J. Org. Chem. 2007, 2015–2021
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2021