A new method of synthesis of 6-substituted piperidine-2,4-diones from homoallylamines

Article abstract of DOI:10.1002/ejoc.201101114

Mono- and dihomoallylamines serve as convenient precursors for the preparation of 6-substituted piperidine-2,4-diones. This transformation is based, on the one hand, on a simple and well-known halocyclocarbamation reaction proceeding by the addition of a

Full text of DOI:10.1002/ejoc.201101114

FULL PAPER
DOI: 10.1002/ejoc.201101114
A New Method of Synthesis of 6-Substituted Piperidine-2,4-diones from
Homoallylamines
Nikolai Yu. Kuznetsov,*[a] Victor I. Maleev,[a] Victor N. Khrustalev,[a] Anna F. Mkrtchyan,[a]
Ivan A. Godovikov,[a] Tatyana V. Strelkova,[a] and Yuri N. Bubnov*[a]
Keywords: Allylic compounds / Boranes / Allylation / Nitrogen heterocycles / Rearrangement
Mono- and dihomoallylamines serve as convenient precur-
sors for the preparation of 6-substituted piperidine-2,4-di-
ones. This transformation is based, on the one hand, on a
simple and well-known halocyclocarbamation reaction pro-
ceeding by the addition of a source of cationic halogen to the
N-Boc-protected homoallylamines and, on the other, on a
new enolate-isocyanate rearrangement that proceeds by the
action of strong bases on bromocyclocarbamates. A set of ra-
cemic dihomoallylamines were prepared by the allylboration
of nitriles or primary amides with triallylborane and enantio-
merically enriched N-Boc-1-phenyl-3-butenylamine was
synthesized by the addition of (–)-AllB(Ipc)2 to the corre-
sponding silylimine. Chiral precursors containing a carbox-
ylic ester group were synthesized from (S)-allylglycine and
-alanine. The reactions of N-Boc derivatives with NBS
smoothly produced the corresponding bromocyclocarb-
amates either in the form of a single diastereomer or as an
isomeric mixture. All these bromourethanes were cleanly
transformed into 6-substituted piperidine-2,4-diones in good
yields via the formation of intermediate cyclic enolates,
which was confirmed by the direct synthesis of enolate 12
and its transformation into dione 8 in a series of kinetic ex-
periments. Based on the experimental results, a mechanism
for the new enolate-isocyanate rearrangement is proposed.
Introduction
Among the various heterocycles present in natural prod-
ucts, piperidine occupies a privileged place.[1] As a subset,
piperidin-2-one is a structural motif found in many alk-
aloids,[1] biologically active small synthetic molecules,[2] and
peptidomimetics.[3] A special type of piperidin-2-one mole-
cule is the piperidine-2,4-dione. These compounds are key
intermediates in the syntheses of various pharmaceutically
interesting compounds.[2f,4,6a] In addition, this skeleton also
shows biological activity, for example, as an inhibitor of
bacterial dihydroorotase[5a] with a 6-carboxylic acid group
in the cycle and as inhibitors of undecaprenyl pyrophos-
phate synthase with 3,6-diaryl(arylmethyl) groups.[5b]
Unlike the synthesis of the parent piperidines, straight-
forward methods for the construction of 6-substituted pi-
peridine-2,4-diones are limited. There are several ap-
proaches leading to piperidine-2,4-diones[6a] (racemic and
enantiomerically pure form) that are based either on the
enolate cyclization of β-amino esters (Dieckman condensa-
tion),[4a,4e,6b,6c,6j] δ-amino β-keto ester cyclization,[4d,4e,6d–6g]
Blaise cyclization,[4c] enolate-imine addition,[6h] or enolate-
cyanide cycloaddition[6i] (Scheme 1).
Scheme 1. General routes to piperidine-2,4-diones.
Piperidine-2,4-diones have been stereoselectively synthe-
sized by using chiral sulfinyl auxiliaries[6d–6f,6h] or enantio-
merically pure β-amino acids.[4a,6g] All the methods are con-
venient and reliable and they share a common feature: the
two carbonyl groups in the piperidine-2,4-dione are trans-
ferred directly from the source material. This limits to a
certain extent the planning and realization of the synthesis
because of the reactivity of the carbonyl groups. In this
work we describe a new method for the synthesis of 6-sub-
stituted piperidine-2,4-diones.[7] Our long-standing interest
in allylboranes and allylated organic compounds[8] has led
to the elaboration of a route for the conversion of the allyl
group into an acetonyl group in a series of 2,6-disubstituted
tetrahydropyridines (Scheme 2).[9]
[a] A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences,
The novelty of this methodology is related to the un-
usually effective dehydrohalogenation step upon formation
of the cyclic enolate-urethane, which proceeds for a few sec-
onds. The study of this simple transformation in a series of
homodiallylamines, in which one hydrogen atom (RЈ-NH-
Vavilov 28, 119991, Moscow, Russian Federation
E-mail: nkuznff@ineos.ac.ru
bubnov@ineos.ac.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101114.
334
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 334–344

Synthesis of Piperidine-2,4-diones from Homoallylamines
tion of a keto acetate in moderate yield[13] because of inter-
mediate enolate formation. In the case of TAB, the acidity
of the protons at the carbon atom is not important because
Lewis acid–Lewis base coordination of boron to the nitro-
gen of the nitrile group occurs, thus directing the allylbor-
ation towards the nitrile.
Scheme 2. Conversion of the allyl group into the acetonyl group by
a rapid dehydrobromination step.
Table 1. Synthesis of gem-homodiallylamines and their conversion
into 6-substituted piperidine-2,4-diones.
Boc) is left at the Boc-protected nitrogen atom, led to the
discovery of a new base-mediated rearrangement resulting
in the formation of the piperidine-2,4-dione skeleton in
which the homoallylamine moiety is totally incorporated
into the piperidine-2,4-dione. The advantages of this new
approach are the following: (a) the easy introduction of an
allyl group into a substrate, (b) the possibility of keeping
the relatively inert protected homoallylic system inside a
complex molecule until the preparation of the target dione,
and (c) due to the wide variety of highly effective asymmet-
ric methods of synthesis of homoallylamines, the most ap-
propriate one can be selected depending on the chemical
environment of the molecule.
R
1, % Yield
3, % Yield;
cis\trans
4, % Yield
The high reactivity of triallylborane (TAB) towards com-
pounds with multiple carbon–heteroatom bonds provides
an easy access to a broad spectrum of different mono- and
diallylated compounds.[8,10] TAB readily reacts with aro-
matic azaheterocycles and derivatives of carboxylic acids
such as nitriles and lactams. Two allyl groups can be intro-
duced into these substrates in one step to form 2,6-diallyl-
1,2,3,4-tetrahydropiperidines, -isoquinolines, and -pyrrol-
idine or 2,2-diallylated amines.[10] If the amino function is
protected with an acyl or preferably a Boc group, then such
products are excellent substrates for RCM with Grubbs cat-
alysts and a number of azabicyclics have been prepared by
diallylboration/metathesis.[11] The other type of reaction
known for N-Boc-protected allylic amines is halocyclization
and, in particular, the cyclobromocarbamation reaction.
The effect of cationic halogens (iodine, bromine, NBS, NIS)
on such substrates is well known and leads to the formation
of halourethanes.[12] Surprisingly, the dehydrohalogenation
of the resulting urethanes is not well studied.
Ph
1a, 94
1b, 89
1c, 92
1d, 54
1e, 48
3a, 94; 1:25
3b, 95; 16:1
3c, 78; 1:1
3d, 84; 1:1
3e, 96; 1:1
4a, 91
4b, 93
4c, 92
4d, 84
4e, 90
CH3O(CH2)2
tBuOOCCH2
FCH2
(CH3)2CHCH2
The diallylated amino ester 1c was isolated in 92% yield
after alkaline deboronation. When nitriles are less available,
amides can be used instead. The allylboration of cyclic
amides (lactams) with an NH group proceeds cleanly in
yields of up to 95%,[14] but in the case of acyclic primary
amides the isolated yields of diallylated amines do not ex-
ceed 60% because of the concurrent formation of the dial-
lylated alcohol,[15] which is separated by consecutive acid/
base extractions. Treatment of amines 1a–e with Boc anhy-
dride quantitatively gives N-Boc-amides 2a–e (Table 1).
The amides 2 react smoothly with NBS giving rise to
bromourethanes 3a–e in different isomeric ratios. In the
cases of 3a and 3b, high diastereoselectivity was observed.
The major isomer of 3a was isolated by chromatography
and its structure was determined by X-ray diffraction to be
the trans isomer (Figure 1). The structure of the major iso-
mer of 3b was determined to be the cis isomer from a
Results and Discussion
The reductive allylboration of nitriles or primary amides NOESY experiment (Figure 2).
with TAB leads to the formation of gem-homodiallylamines
Bromides 3a–e were treated with 2.2 equiv. of tBuOK. In
in preparative quantities. The most atom-effective process the temperature range of –10 to +5 °C, no changes (TLC
is the addition of TAB to nitriles because only one allyl monitoring) were observed, but when the temperature
group remains unreactive on the boron atom. TAB was reached 15–20 °C, the reaction mixture rapidly became tur-
added to benzonitrile and 3-methoxypropionitrile in ac- bid and the starting material completely disappeared over
cordance with the previously described procedure[10f] to 0.5–3.0 h. A set of bases (LDA, NaH, DBU) were tested
give the corresponding primary amines 1a,b in high yields and tBuOK was the reagent of choice.
(Table 1). Despite its high reactivity, TAB can selectively
To broaden the scope of this transformation, monoho-
allylborate the cyano group in the presence of an ester moallylamine derivatives were tested because numerous
group. To demonstrate such a possibility, the allylboration methods exist for the preparation of homoallylamines both
of tert-butyl cyanoacetate with TAB was carried out. It is in racemic and, especially important, in enantiomerically
known that the addition of organometallic reagents to the pure[16] forms. Because our group deals with organoboron
nitrile group of ethyl cyanoacetate proceeds with the forma- compounds, we used the simple reaction of 1-phenyl-N-tri-
Eur. J. Org. Chem. 2012, 334–344
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
335

N. Yu. Kuznetsov, Yu. N. Bubnov et al.
FULL PAPER
allylamide rac-6 with NBS. The major isomer crystallized
from the reaction mixture and was found by X-ray analysis
to be cis-7 (Figure 3).
Figure 1. Molecular structure of the trans isomer 3a (ellipsoids
drawn at the 50% probability level).
Figure 3. Structure of the major isomer cis-7.
The mixture of isomers 7 reacts with tBuOK cleanly to
give 6-phenylpiperidine-2,4-dione (8). From the mixture of
chiral isomers (S)-7, dione (S)-8 was obtained in 95% yield
and 98.5%ee, which corresponds to the ee of the bromoure-
thanes (S)-7, which was accidentally enriched by crystalli-
zation during isolation (confirmed by chiral HPLC analysis
of the major cis isomer).
Figure 2. Structure determination of 3b by NOE.
Other interesting chiral substrates with a homoallyla-
mine fragment are allylglycines, which have previously been
prepared in enantiomerically pure form by the allylation of
glycine and alanine.[17] Starting from (S)-allylglycine and
-alanine, N-Boc derivatives of benzyl and isopropyl esters
(9a,b) were synthesized (Scheme 4). The reactions of 9a,b
with NBS produces mixtures of isomeric bromourethanes
10a (cis/trans = 1:2) and 10b (cis/trans = 1:11), the configu-
rations of which were assigned by analogy to the formation
of iodourethanes in a similar reaction.[12f] These bromides
were also transformed into piperidine-2,4-diones 11a,b in
high yields. As we anticipated, compound 10a, due to the
presence of an acidic proton at the stereocenter, forms prod-
uct 11a in nearly racemic form (24%ee, Scheme 4) in the
strong basic media.
methylsilylmethanimine with TAB for the preparation of
rac-phenylhomoallylamine (rac-6) or (–)-B-allyl(diisopino-
campheyl)borane for the preparation of the S enantiomer
(S)-6 (Scheme 3).[16m]
We propose the following plausible mechanism for this
transformation (Scheme 5). In the first stage, tBuOK ab-
stracts the acidic N–H proton to form the potassium salt.
In the next slow stage, abstraction of HBr occurred in the
anionic substrate to give the unstable anionic enolate, which
undergoes enolate-isocyanate rearrangement in the third
Scheme 3.
TAB reacts with imine 5 with the evolution of heat and stage. The resulting enolato-isocyanate is irreversibly cy-
subsequent alkaline treatment of the reaction mixture pro- clized to piperidine-2,4-dione. To the best of our knowl-
duces the crude homoallylamine, which was treated with edge, such an enolate-isocyanate rearrangement is unprece-
Boc2O and heated at reflux in THF for 1 h to finally give dented in urethane chemistry. Although the intermolecular
rac-6 in 80% yield. Following the method[16m] of Ramach- addition of enolates to isocyanates is a common reaction,[18]
andran and Burghardt, (Ipc)2BAll was added to 5 and after its intramolecular analogue is rare. A similar cyclization of
transformation of the crude amine to the N-Boc derivative, 2-vinylphenyl isocyanates, generated in situ by radical scis-
(S)-6 was obtained in 53% yield and 94.5%ee [after sion, leads to the formation of quinolinones.[19a,19b] Similar
crystallization from n-C6H14, prior to crystallization (S)-6 rearrangements involving the formation of an enolate anion
had 91.5%ee]. Bromourethane 7 is formed as a mixture of and leading to the cyclohexane- and cyclopentane-1,3-dione
cis-7/trans-7 isomers (3:1 ratio) by the reaction of homo- skeleton have been known for a long time.[19c–19g] However,
336
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 334–344

Synthesis of Piperidine-2,4-diones from Homoallylamines
Scheme 4.
Scheme 5. Plausible mechanism for the formation of 6-substituted piperidine-2,4-diones.
Scheme 6. Synthesis of 6-methylene-4-phenyl-1,3-oxazinan-2-one (12).
the mechanism postulated for these transformations is com- in water/acetic acid (or even on a silica gel TLC plate), and
pletely different to what we have proposed for the formation the target enol 12 was isolated in 48% yield as a crystalline
of piperidine-2,4-diones.
solid. Having in hand enough 12, tests were carried out at
Stage 2 of the reaction is slow and proceeds only at room low temperature. Interestingly, the rearrangement step is a
temperature. Evidently, the formation of a dianion is an un- very fast process (Scheme 5); although a temperature of
likely process and hence HBr elimination would be a more –78 °C is too low for the reaction to take place, at –50 °C
concerted process. Indeed, we never detected the formation the rearrangement reaction was completed in 30–35 min
of an enolate in the dehydrobromination step. When (Scheme 7, Figure 4). The rate constant for the enolate-iso-
1 equiv. of tBuOK was used, a mixture was obtained that cyanate rearrangement was calculated on the basis of the
included the starting bromourethane, piperidine-2,4-dione, ratios of enol 12/dione 8 determined by 1H NMR spec-
and the dimeric product, which arises by nucleophilic sub- troscopy from a series of low-temperature experiments.
stitution of the bromide atom by the enolate form of the
dione. To support the mechanism in Scheme 5, we tried to
synthesize 6-methylene-4-phenyl-1,3-oxazinan-2-one (12),
which in fact was a difficult task (Scheme 6). Our first idea
was to protect the nitrogen atom with TMSCl or TBSCl
and 1 equiv. of base, however, only the starting material or
some dione 8 was isolated. An attempt to protect the nitro-
gen by the reaction of 7 with a powerful silylating agent
such as N,O-bis(trimethylsilyl)acetamide left 7 almost un-
changed. Thus, we used a procedure reported for the pro-
Scheme 7.
The kinetic analysis of this process reveals a first-order
tection of oxazolidine-type[20] compounds with orthofor- reaction with rate constant k = 2.85ϫ10–2 s–1 at –48 °C. A
mate in the presence of catalytic amounts of AlCl3. In our relatively big deviation from linearity at 15 and 20 min (sev-
case many byproducts were formed and (irreproducible) eral experiments were performed) could be related to the
only tiny amounts of the protected bromide.
heterogeneous character of the reaction mixture at a late
Finally, we found that 7 is readily protected with stage in the transformation because of the low solubility of
HMDSLi/TBSCl (1 equiv.) at low temperature. Upon ad- the lithium salt of dione 8. Nevertheless, this analysis pro-
dition of a second equivalent of HMDSLi, fast dehydrobro- vides a good approximation of the value of the rate con-
mination occurred, the intermediate silyl ether was cleaved stant.
Eur. J. Org. Chem. 2012, 334–344
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
337

N. Yu. Kuznetsov, Yu. N. Bubnov et al.
FULL PAPER
Figure 4. Kinetic study of the enolate–isocyanate rearrangement.
68.37, 57.88, 52.61, 44.79 (2 C), 38.59 ppm. MS (70 eV, EI): m/z
(%) = 170 (33) [M + H]+, 169(6) [M]+, 149 (16), 135 (16), 129 (10),
128 (49), 123 (18), 121 (18), 111 (26), 109 (23), 97 (43), 96 (100),
95 (31), 91 (16), 83 (24), 81 (57), 79 (47), 77 (36), 71 (30), 69 (28), 57
(33), 55 (26), 41 (24). C10H19NO (169.2): calcd. C 70.96, H 11.31, N
8.28; found C 70.81, H 11.36, N 8.31.
Conclusions
A new base-mediated enolate-isocyanate rearrangement
has been discovered and a convenient synthesis of 6-substi-
tuted piperidine-2,4-diones has been elaborated. The advan-
tages of this new approach are the following: (a) the easy
introduction of the allyl group into a substrate, (b) the pos-
sibility of keeping the relatively inert protected homoallylic
system inside a complex molecule until the preparation of
the dione, and (c) due to a wide variety of highly effective
asymmetric methods for the synthesis of homoallylamines,
the most appropriate can be selected depending on the
chemical environment of the molecule. Further extensions
of this method for preparing further relevant compounds
are underway.
tert-Butyl 3-Allyl-3-amino-5-hexenoate (1c): Triallylborane (4.8 g,
6.0 mL, 35.4 mmol) was added dropwise to a solution of tert-butyl
cyanoacetate (5.0 g, 35.4 mmol) in DCM (10 mL) at –70 °C. The
resulting solution was stirred for 15 min after which it was warmed
to 0 °C and heated at 100 °C (when DCM was distilled off) for 1 h.
This mixture was carefully treated with 20% aq. NaOH (22 mL,
0.11 mol) keeping the temperature of the mixture in a range of 100–
110 °C for 30 min. The product was extracted with hexane/Et2O
(1:1), washed with water, dried with K2CO3, and the solvents evap-
orated. The residue was distilled in vacuo at 97–98 °C (0.5 Torr) to
1
yield 7.35 g (92%) of 1c. H NMR (300 MHz, CDCl3): δ = 5.94–
5.80 (m, 2 H, CH=), 5.17–5.10 (m, 4 H, CH2=), 2.30 (s, 2 H, CH2),
2.22 (d, J = 7.5 Hz, 4 H, CH2,allyl), 1.62 (br. s, 2 H, NH2), 1.48 (s,
9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.29, 133.70 (2
C), 118.88 (2 C), 80.57, 53.30, 45.05, 44.67 (2 C), 28.11 (3C) ppm.
MS (70 eV, EI): m/z (%) = 226 (8) [M + H]+, 154 (4), 129 (8), 128
(100), 110 (65), 96 (5): 93 (4), 91 (7), 83 (5), 82 (20), 81 (6), 80 (8),
69 (8), 68 (53), 67 (33), 65 (6), 55 (5), 43 (8), 42 (5), 41 (14), 39
(11). C13H23NO2 (225.3): calcd. C 69.29, H 10.29, N 6.22; found C
69.11, H 10.41, N 6.21.
Experimental Section
General: The manipulations with triallylborane were carried out
under an inert atmosphere of dry Ar. Triallylborane was prepared
according to a previously described procedure.[21] NMR spectra
were recorded with Bruker Avance 300, 400, and 600 MHz instru-
ments. Mass spectra were recorded with a Finnigan Polaris Q Ion
Trap spectrometer. Column chromatography was carried out by
using silica gel 60–230 mesh (Merck). Compounds 1a[22] and 5[23]
were synthesized as described previously.
4-(Fluoromethyl)-1,6-heptadien-4-amine (1d): Triallylborane (26.8 g,
34.6 mL, 0.2 mol) was added to a solution of α-fluoroacetamide
(7.7 g, 0.1 mol) in THF (20 mL) and the reaction mixture was
heated at reflux for 1.5 h. MeOH (20 mL) was added and heating
was continued for 30 min before deboronation workup with 20%
NaOH (120 mL). After complete deboronation (green flame test)
the reaction mixture was diluted with hexane, cooled, and the or-
ganic layer separated and washed with water. The organic phase
was thoroughly shaken with 6 n HCl (20 mL) and separated from
the aqueous phase. The aqueous layer was extracted with hexane/
EtOAc (1:1) twice. Then the aqueous phase was made alkaline with
solid NaOH (10 g) and extracted with hexane (20 mLϫ3). The
combined extracts were dried with K2CO3, evaporated, and dis-
tilled under reduced pressure (b.p. 62–63 °C/10 Torr) to furnish 1d
(7.78 g, 54%) as a colorless liquid. 1H NMR (300 MHz, CDCl3): δ
4-(2-Methoxyethyl)-1,6-heptadien-4-amine (1b): 3-Methoxypro-
pionitrile (10 g, 0.118 mol) was added dropwise to neat triallylbor-
ane (19 g, 24 mL, 0.142 mol) after which the mixture was heated at
110 °C for 1 h. Excess triallylborane was destroyed by the addition
of MeOH (10 mL) followed by deboronation with 20% NaOH
(100 g, 0.5 mol) at 110–120 °C. The completion of the de-
boronation was verified by the green flame test as soon as the gas
evolution had ceased. After the reaction mixture had cooled, the
upper organic layer was diluted with hexane (50 mL), separated
from the aqueous phase, washed with water, dried with K2CO3, and
the solvents evaporated. The residue was distilled under reduced
pressure at 93–94 °C (5 Torr) to furnish 17.70 g (89%) of 1b as a
colorless liquid. 1H NMR (400 MHz, [D6]DMSO): δ = 5.90–5.80
(m, 2 H, CH=), 5.05–5.00 (m, 4 H, CH2=), 3.42 (t, J = 7.2 Hz, 2 = 5.88–5.74 (m, 2 H, CH=), 5.15–5.09 (m, 4 H, CH2=), 4.14 (d,
H, CH2O), 3.19 (s, 3 H, CH3O), 2.01 (d, J = 7.4 Hz, 4 H, CH2,allyl), JFH = 47.6 Hz, 2 H, CH2F), 2.17 (dd, J = 1.2, 7.5 Hz, 4 H,
1.48 (t, J = 7.2 Hz, 2 H, -CH2-), 1.31 (br. s, 2 H, NH2) ppm. 13C CH2,allyl), 1.27 (s, 2 H, NH2) ppm. 13C NMR (75 MHz, CDCl3): δ
NMR (100 MHz, [D6]DMSO): δ = 135.00 (2 C), 117.43 (2 C), = 132.83 (2 C), 119.24 (2 C), 89.35 and 87.03 (JCF = 173.9 Hz),
338
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 334–344

Synthesis of Piperidine-2,4-diones from Homoallylamines
53.96 and 53.73 (JCF = 17.1 Hz), 41.28 and 41.24 (JCF = 3.1 Hz, 2
C) ppm. 19F NMR (282 MHz, CDCl3): δ = –226.5 ppm. MS (70 eV,
EI): m/z (%) = 144 (26) [M + H]+, 124 (5), 122 (6), 102 (100), 82
(40), 80 (90), 67 (50), 60 (54), 55 (25), 42 (20), 41 (20), 39 (27).
C8H14FN (143.2): calcd. C 67.10, H 9.85, N 9.78, F 13.27; found
C 67.05, H 9.83, N 9.84, F 13.32.
(10), 91 (10), 82 (10), 80 (8), 68 (23), 67 (17), 41 (15). C18H31NO4
(325.4): calcd. C 66.43, H 9.60, N 4.30; found C 66.37, H 9.52, N
4.36.
tert-Butyl N-[1-Allyl-1-(fluoromethyl)-3-butenyl]carbamate (2d):
The procedure was the same as that used for the synthesis of 2a.
1
Yield of 2d: 4.85 g, 99%. H NMR (300 MHz, CDCl3): δ = 5.85–
4-Isobutyl-1,6-heptadien-4-amine (1e): The procedure used was the
same as that used for the synthesis of 1d. The reaction between
isovaleramide (5.0 g, 49.4 mmol) and TAB (11.9 g, 15.4 mL,
89.0 mmol) produced 1e (4.0 g, 48%) as a colorless liquid. 1H
5.71 (m, 2 H, CH=), 5.17–5.12 (m, 4 H, CH2=), 4.49 (d, JFH =
47.2 Hz, 2 H, CH2F), 4.49 (br. s, 1 H, NH), 2.50 (dd, J = 7.3,
13.9 Hz, 2 H, 2CHAHB), 2.37 (dd, J = 7.7, 13.9 Hz, 2 H, 2CHAHB),
1.42 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.35,
NMR (300 MHz, CDCl3): δ = 5.86–5.72 (m, 2 H, CH=), 5.08–5.01 132.27 (2 C), 119.51 (2 C), 85.49 and 83.16 (JCF = 174.5 Hz), 79.29,
(m, 4 H, CH2=), 2.09 (d, J = 7.5 Hz, 4 H, CH2,allyl), 1.82–1.70 (m,
1 H, CH), 1.25 (d, J = 5.5 Hz, 4 H, CH2), 1.12 (br. s, 2 H, NH2),
56.91 and 56.68 (JCF = 17.14 Hz), 37.44 (br., 2 C), 28.30 (3 C) ppm.
19F NMR (282 MHz, CDCl3): δ = –229.5 ppm. MS (70 eV, EI):
0.92 (d, J = 6.6 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): m/z (%) = 243 (3) [M]+, 204 (3), 188 (16), 146 (53), 102 (100), 82
δ = 134.33 (2 C), 118.20 (2 C), 54.14, 48.72, 45.20 (2 C), 25.18 (2
C), 23.70 ppm. MS (70 eV, EI): m/z (%) = 168 (57) [M + H]+, 152
(34), 151 (15), 136 (15), 126 (100), 110 (35), 109 (12), 95 (21), 84
(46), 70 (30), 67 (20), 57 (21), 42 (26), 41 (27). C11H21N (167.3):
calcd. C 78.97, H 12.65, N 8.37; found C 79.10, H 12.74, N 8.33.
(38), 80 (35), 57 (24), 41 (50), 39 (39). C13H22FNO2 (243.3): calcd.
C 64.17, H 9.11, N 5.76; found C 64.16, H 9.22, N 5.70.
tert-Butyl N-(1-Allyl-1-isobutyl-3-butenyl)carbamate (2e): The pro-
cedure was the same as that used for the synthesis of 2a. Yield of
1
2e: 5.41 g, 97%. H NMR (300 MHz, CDCl3): δ = 5.83–5.69 (m, 2
tert-Butyl N-(1-Allyl-1-phenyl-3-butenyl)carbamate (2a): Diallylated H, CH=), 5.12–5.06 (m, 4 H, CH2=), 4.32 (br. s, 1 H, NH), 2.45
amine 1a (3.74 g, 20 mmol) was heated at reflux with Boc2O
(4.58 g, 21 mmol) in THF (10 mL) for 1 h. When the amine 1a had
been consumed, MeOH (10 mL) was added and the solution was
heated at reflux for 30 min, after which all volatiles were removed
under reduced pressure. The residual oil was passed through the
short column of silica gel with n-C6H14/EtOAc (6:1) as eluent to
give 2a (5.63 g, 98%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ = 7.31–7.29 (m, 4 H, Ph), 7.25–7.19 (m, 1 H, Ph), 5.65–
5.51 (m, 2 H, CH=), 5.13–5.07 (m, 4 H, CH2=), 4.84 (br. s, 1 H,
NH), 2.85 (br. m, 2 H, 2CHAHB), 2.68–2.61 (m, 2 H, 2CHAHB),
1.40 (br. s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.09,
144.43, 133.34 (2 C), 128.11 (2 C), 126.54, 125.69 (2 C), 119.02 (2
C), 79.02, 59.45, 42.99 (2 C), 28.32 (3 C) ppm. MS (70 eV, EI): m/z
(%) = 287 (0.3) [M]+, 246 (4), 232 (4), 191 (8), 190 (67), 170 (4),
155 (2), 147 (11), 146 (100), 129 (30), 128 (15), 117 (4), 115 (5), 104
(26), 91 (5), 77 (8), 57 (4), 44 (6), 41 (10). C18H25NO2 (287.4): calcd.
C 75.22, H 8.77, N 4.87; found C 75.19, H 8.82, N 4.90.
(dd, J = 7.7, 13.8 Hz, 2 H, 2CHAHB), 2.33 (dd, J = 7.7, 13.5 Hz,
2 H, 2CHAHB), 1.82–1.70 (m, 1 H, CH), 1.60 (d, J = 5.5 Hz, 2 H,
CH2), 1.41 (s, 9 H, tBu), 0.95 (d, J = 6.7 Hz, 6 H, 2 CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 153.97, 133.50 (2 C), 118.49 (2
C), 78.39, 57.17, 43.48, 40.26 (2 C), 28.36 (3 C), 24.48 (2 C),
23.59 ppm. MS (70 eV, EI): m/z (%) = 268 (2) [M + H]+, 226 (3),
212 (8), 171 (12), 170 (100), 154 (16), 126 (72), 110 (26), 109 (20),
93 (13), 91 (11), 84 (25), 79 (9), 70 (28), 67 (17), 57 (16), 41 (31).
C16H29NO2 (267.4): calcd. C 71.86, H 10.93, N 5.24; found C
71.88, H 10.90, N 5.31.
(4R*,6R*)-4-Allyl-6-(bromomethyl)-4-phenyl-1,3-oxazinan-2-one
(3a): NBS (0.89 g, 5.0 mmol) was added to a solution of 2a (1.10 g,
3.85 mmol) in DCM (10 mL) and the mixture was stirred for 1.5 h.
The solvent was removed under reduced pressure, the residue dis-
solved in Et2O (10 mL), and the mixture stirred with 10% NaOH
(5 mL) for 15 min. The organic layer was separated, dried with
K2CO3, evaporated, and passed through a short column of silica
tert-Butyl N-[1-Allyl-1-(2-methoxyethyl)-3-butenyl]carbamate (2b): gel (n-C6H14/EtOAc, 1:1) to furnish 3a (1.12 g, 94%) as a white
The procedure was the same as that used for the synthesis of 2a.
Yield of 2b: 7.62 g, 96%. B.p. 116–117 °C (0.5 Torr). 1H NMR
(400 MHz, CDCl3): δ = 5.78–5.67 (m, 2 H, CH=), 5.06–5.02 (m, 4
solid. M.p. 121–122 °C. Rf = 0.23 (n-C6H14/EtOAc, 4:1). 1H NMR
(400 MHz, CDCl3): δ = 7.41–7.32 (m, 2 H, Ph), 7.29–7.26 (m, 3 H,
Ph), 6.52 (s, 1 H, NH), 5.47–5.37 (m, 1 H, CH=), 5.22–5.16 (m, 2
H, CH2=), 4.89 (br. s, 1 H, NH), 3.43 (t, J = 6.2 Hz, 2 H, CH2O), H, CH2=), 4.07–4.02 (m, 1 H, CHO), 3.43 (dd, J = 4.4, 10.8 Hz, 1
3.25 (s, 3 H, CH3O), 2.50–2.45 (m, 2 HAB), 2.39–2.34 (m, 2 HAB), H, BrCHAHB), 3.39 (dd, J = 6.0, 10.8 Hz, 1 H, BrCHAHB), 2.83
1.82 (t, J = 6.2 Hz, 2 H, CH2), 1.37 (s, 9 H, tBu) ppm. 13C NMR
(dd, J = 5.0, 13.9 Hz, 1 H, CHAHB), 2.51–2.45 (m, 2 H, CH2,allyl),
(100 MHz, CDCl3): δ = 154.21, 133.50 (2 C), 118.40 (2 C), 78.39, 2.05 (t, J = 12.0 Hz, 1 H, CHAHB) ppm. 13C NMR (100 MHz,
68.68, 58.53, 56.19, 40.52 (2 C), 35.01, 28.27 (3 C) ppm. MS (70 eV,
CDCl3): δ = 153.47, 143.28, 130.97, 129.03 (2 C), 127.74, 125.46 (2
C), 121.40, 72.83, 58.82, 47.51, 38.16, 33.00 ppm. MS (70 eV, EI):
EI): m/z (%) = 269 (2) [M]+, 216 (3), 172 (14), 154 (4), 129 (6), 128
(76), 105 (7), 97 (10), 96 (100), 94 (12), 91 (12), 81 (20), 80 (17), 79 m/z (%) = 311/309 (0.1) [M]+, 270/268 (25), 226/224 (20), 206/208
(34), 77 (22), 41 (15). C15H27NO3 (269.2): calcd. C 66.88, H 10.10, (3), 149 (20), 144 (100), 117 (7), 104 (15), 77 (10), 51 (4), 41 (3).
N 5.20; found C 66.79, H 10.02, N 5.19.
C14H16BrNO2 (310.2): calcd. C 54.21, H 5.20, Br 25.76, N 4.52;
found C 54.38, H 5.19, Br 25.49, N 4.43.
tert-Butyl 3-Allyl-3-[(tert-butoxycarbonyl)amino]-5-hexenoate (2c):
The procedure was the same as that used for the synthesis of 2a.
Yield of 2c: 4.33 g, 95%. Rf = 0.51 (n-C6H14/EtOAc, 10:1). 1H
NMR (600 MHz, CDCl3): δ = 5.81–5.74 (m, 2 H, CH=), 5.13 (br.
s, 1 H, NH), 5.11–5.09 (m, 4 H, CH2=), 2.55 (dd, J = 7.4, 13.5 Hz,
2 H, 2 CHAHB), 2.50 (s, 2 H, CH2), 2.47 (dd, J = 7.4, 13.7 Hz, 2
(4S*,6R*)-4-Allyl-6-(bromomethyl)-4-(2-methoxyethyl)-1,3-oxazi-
nan-2-one (3b): The procedure was the same as that used for the
synthesis of 3a. Yield of 3b: 0.57 g, 95%. Colorless crystals. M.p.
113–114 °C (CHCl3). Rf = 0.20 (n-C6H14/EtOAc, 4:1). 1H NMR
(400 MHz, CDCl3): δ = 6.52 (s, 1 H, NH), 5.70–5.59 (m, 1 H,
CH=), 5.17–5.10 (m, 2 H, CH2=), 4.51–4.47 (m, 1 H, CHO), 3.59
H, 2 CHAHB), 1.43 (s, 9 H, tBuester), 1.41 (s, 9 H, tBuBoc) ppm. 13
C
NMR (150 MHz, CDCl3): δ = 170.73, 154.35, 133.19 (2 C), 119.05 (td, J = 3.5, 10.1 Hz, 1 H, BrCHAHB), 3.52–3.44 (m, 2 H, CH2O),
(2 C), 80.82, 78.78, 55.92, 41.34, 40.59 (2 C), 28.38 (3 C), 28.05 (3 3.37 (dd, J = 7.0, 10.5 Hz, 1 H, BrCHAHB), 3.29 (s, 3 H, OCH3),
C) ppm. MS (70 eV, EI): m/z (%) = 327/326 (7.5/52) [M + H]+, 284
(1.5), 271 (3), 270 (14), 228 (4), 226 (4), 214 (10), 196 (27), 172 (35),
154 (8), 152 (5), 129 (8), 128 (100), 124 (5), 110 (52), 107 (11), 93
2.44 (dd, J = 6.7, 14.3 Hz, 1 H, CHAHB,allyl), 2.33 (dd, J = 7.9,
14.3 Hz, 1 H, CHAHB,allyl), 2.15 (d, J = 14.0 Hz, 1 H, CHAHB,cycle),
1.83 (ddd, J = 4.7, 10.1, 15.0 Hz, 1 H, CHAHB,chain), 1.68 (dt, J =
Eur. J. Org. Chem. 2012, 334–344
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
339

N. Yu. Kuznetsov, Yu. N. Bubnov et al.
FULL PAPER
3.8, 15.0 Hz, 1 H, CHAHB,chain), 1.58 (t, J = 13.4 Hz, 1 H,
tert-Butyl N-(1-Phenyl-3-butenyl)carbamate (rac-6): TAB (4.0 g,
CHAHB,cycle) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.91, 5.2 mL, 30.0 mmol) was added dropwise to a solution of silylimine
131.81, 120.38, 72.53, 68.81, 59.05, 55.10, 42.85, 38.66, 34.65, 5 (5.0 g, 28.2 mmol) in THF (15 mL) with cooling in a chilled water
33.05 ppm. MS (70 eV, EI): m/z (%) = 294/292 (0.3) [M + H]+, 251/
bath. The mixture was stirred for 2 h, after which MeOH (10 mL)
249 (25), 208/206 (95), 176/174 (30), 150/148 (14), 127 (20), 108 and 5 n NaOH (18 mL) were added. To complete the deboronation
(11), 94 (100), 82 (18), 67 (10), 45 (11). C11H18BrNO3 (292.1):
calcd. C 45.22, H 6.21, Br 27.35, N 4.79; found C 45.17, H 6.14,
Br 27.08, N 4.74.
the mixture was heated at reflux for 1 h. The solvents were removed
under reduced pressure and Et2O/n-C6H14 was added to the resi-
due. The organic layer was separated, washed with sat. NaCl, dried
with K2CO3, and evaporated to furnish the crude 1-phenyl-3-bu-
tenylamine (3.79 g, 91%). Boc2O (5.92 g, 27.2 mmol) was added to
a solution of the crude amine (3.79 g, 25.7 mmol) in THF (15 mL)
and the mixture was heated at reflux for 1 h. After evaporation of
the reaction mixture, the residue was washed with chilled hexane to
tert-Butyl 2-[4-Allyl-6-(bromomethyl)-2-oxo-1,3-oxazinan-4-yl]acet-
ate (3c): The procedure was the same as that used for the synthesis
of 3a. Yield of 3c: 0.84 g, 78%. Colorless oil, 1:1 mixture of
cis/trans isomers. Rf = 0.17 (n-C6H14/EtOAc, 4:1). 1H NMR
(400 MHz, CDCl3): δ = 6.67 and 6.25 (both br. s, 1 H total, NH),
5.80–5.62 (m, 1 H), 5.22–5.10 (m, 2 H), 4.51–4.46 (m, 1 H), 3.54–
3.50 (m, 1 H), 3.43–3.38 (m, 1 H), 2.54–2.31 (m, 4 H), 2.23 (dd, J
= 4.7, 14.0 Hz, 1 H), 1.70 (ddd, J = 12.0, 13.6, 21.6 Hz, 1 H), 1.42
(s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.50,
169.26, 152.98, 152.75, 131.42, 131.11, 121.20, 120.91, 82.04, 81.83,
72.65, 72.32, 53.99, 53.89, 44.76, 44.62, 44.40, 43.56, 34.59, 34.46,
32.78, 32.73, 28.02 (3 C) ppm. MS (70 eV, EI): m/z (%) = 349/347
1
give rac-6 (5.07 g, 80%) as a white solid. H NMR[16g] (300 MHz,
CDCl3): δ = 7.41–7.31 (m, 5 H, Ph), 5.80–5.67 (m, 1 H, CH=),
5.19–5.12 (m, 2 H, CH2=), 4.94 (br. s, 1 H, NH), 4.80 (br. s, 1 H,
CH), 2.57 (br. s, 2 H, CH2), 1.47 (s, 9 H, tBu) ppm.
tert-Butyl (S)-N-(1-Phenyl-3-butenyl)carbamate [(S)-6]: (S)-1-
Phenyl-3-butenylamine[16m] was synthesized by the addition of sil-
ylimine 5 (1.8 g, 10 mmol) to a solution of (–)-AllB(Ipc)2 (4.56 g,
(0.2) [M]+, 276/274 (8), 252/250 (100), 234/232 (14), 208/206 (70), 14 mmol) in THF (12 mL)/pentane (7 mL) at –78 °C followed by
190/188 (50), 149 (11), 127 (30), 126 (70), 108 (60), 83 (27), 80 (75),
the addition of a solution of H2O (0.2 mL) in THF (1 mL) at
41 (20). C14H22BrNO4 (348.2): calcd. C 48.29, H 6.37, Br 22.95, N –100 °C. After alkaline oxidative treatment with 3 n NaOH (8 mL,
4.02; found C 48.11, H 6.33, Br 22.75, N 4.11.
24 mmol) and 30% H2O2 (3 mL) with stirring overnight, the reac-
tion mixture was concentrated under reduced pressure. A 3 n HCl
(12 mL, 36 mmol) solution was added to the residue and extracted
with DCM (10 mLϫ3), after which the pH was adjusted to 14 with
NaOH and again extracted with Et2O (10 mLϫ3). The combined
extracts were dried with K2CO3 and the solvents evaporated. The
crude amine was treated with Boc2O (2.4 g, 11 mmol) in THF
(5 mL) for 1 h at reflux. Evaporation of the volatiles gave a white
solid, which was recrystallized from hexane to furnish (S)-6 (1.31 g,
53%) with 94.5%ee. [α]2D5 = –47.3 (c = 1.5, CHCl3) {ref.[24] optical
rotation of the S isomer [α]2D5 = –48.4 (c = 1, CHCl3)}.
4-Allyl-6-(bromomethyl)-4-(fluoromethyl)-1,3-oxazinan-2-one (3d):
The procedure was the same as that used for the synthesis of 3a.
Yield of 3d: 2.64 g, 84%. Oil, 1:1 mixture of cis/trans isomers. Rf
= 0.35 (n-C6H14/EtOAc, 7:3). 1H NMR (300 MHz, CDCl3): δ =
6.96 (br. s, 1 H), 5.85–5.71 (m, 1 H), 5.29–5.18 (m, 2 H), 4.58–4.54
(m, 1 H), 4.41–4.15 (dm, JFH = 47.0 Hz, 2 H), 3.61–3.53 (m, 1 H),
3.49–3.42 (m, 1 H), 2.50–2.28 (m, 2 H), 2.17 (t, J = 13.0 Hz, 1 H),
1.83–1.71 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.15,
154.00, 130.63, 130.10, 121.65, 121.30, 87.61, 87.27, 85.23, 84.87
(JCF = 178.5 Hz), 179.6, 72.93, 72.89, 72.47, 55.62, 55.38 (JCF
=
18.3 Hz), 54.95, 54.70 (JCF = 18.8 Hz), 41.71, 41.68 (JCF = 2.6 Hz), 6-(Bromomethyl)-4-phenyl-1,3-oxazinan-2-one (7): NBS (7.4 g,
41.28, 41.24 (JCF = 2.9 Hz), 32.85, 32.48, 31.33, 30.52, 30.47 (JCF 41.4 mmol) was added to a solution of rac-6 (8.2 g, 33.2 mmol) in
=
4.3 Hz) ppm. 19F NMR (282 MHz, CDCl3):
δ
=
–223.5,
DCM (60 mL) and the mixture was heated at reflux for 3 h, after
which DCM was removed under reduced pressure. EtOAc/n-C6H14
(1:2) and 10% NaOH (30 mL) were added to the residue with stir-
ring for 10 min. The precipitate was filtered and washed with a
mixture of EtOAc/n-C6H14 and water, and drying gave cis-7 (3.59 g,
40%) as a white powder. Rf = 0.21 (n-C6H14/EtOAc, 1:1). The or-
ganic phase of the filtrate was concentrated and the residue was
dissolved in EtOAc/n-C6H14 (1:1) and left to crystallize. Oxazinane
trans-7 (1.03 g, 11.4%) was obtained as colorless crystals. Rf = 0.32
(n-C6H14/EtOAc, 1:1). The remaining filtrate was purified by FC
on silica gel in EtOAc/n-C6H14 (1:1) to give additional amounts of
cis-7 (0.31 g, 3%) and trans-7 (0.36 g, 4%).
–227.8 ppm. MS (70 eV, EI): m/z (%) = 268/266 (0.7) [M + H]+,
226/224 (14), 182/180 (25), 149 (4), 108 (7), 101 (10), 100 (100), 80
(46), 68 (5). C9H13BrFNO2 (266.1): calcd. C 40.62, H 4.92, N 5.26;
found C 40.67, H 4.81, N 5.14.
4-Allyl-6-(bromomethyl)-4-isobutyl-1,3-oxazinan-2-one (3e): The
procedure was the same as that used for the synthesis of 3a. Yield
of 3e: 3.02 g, 96%. Colorless oil, 1:1 mixture of cis/trans isomers.
Rf = 0.78 (EtOAc). 1H NMR (600 MHz, CDCl3): δ = 7.26 and 6.97
(both s, 1 H total, NH), 5.79–5.69 (m, 1 H), 5.19–5.10 (m, 2 H),
4.54–4.50 (m, 1 H), 3.56 and 3.54 (both d, J = 4.6 and 4.1 Hz, 1
H total), 3.43 and 3.40 (both dd, J = 6.9, 11.0 and 6.8, 10.5 Hz, 1
H total), 2.39–2.26 (m, 2 H), 2.05 and 2.00 (both d, J = 14.2 and
13.7 Hz, 1 H total), 1.81–1.71 (m, 1 H), 1.77 and 1.67 (both dd, J
= 11.9, 13.2 and 11.9, 13.7 Hz, 1 H total), 1.52–1.40 (m, 2 H),
cis-7: M.p.[7] 180–181 °C (DCM). 1H NMR (400 MHz, [D6]-
DMSO): δ = 7.79 (s, 1 H, NH), 7.44–7.41 (m, 2 H), 7.37–7.35 (m,
3 H), 4.68–4.64 (m, 2 H), 3.78 (dd, J = 3.8, 10.8 Hz, 1 H), 3.70
0.97–0.94 (m, 6 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 154.23, (dd, J = 5.4, 10.8 Hz, 1 H), 2.25 (dm, J = 13.3 Hz, 1 H), 1.68 (dt,
154.20, 132.03, 131.88, 120.35, 120.15, 72.92, 72.71, 55.63, 55.30,
48.65, 48.07, 45.99, 44.27, 35.03, 33.64, 33.11, 33.01, 25.10, 25.07,
24.70, 24.12, 23.73, 23.60 ppm. MS (70 eV, EI): m/z (%) = 291/289
(1) [M]+, 250/248 (34), 234/232 (16), 206/204 (64), 190/188 (13), 170
(14), 164/162 (16), 150 (15), 149 (18), 148 (12), 126 (100), 124 (84),
108 (48), 107 (19), 106 (18), 97 (12), 95 (10), 84 (80), 82 (51), 80
(25), 77 (16), 70 (36), 68 (45), 57 (39), 42 (38), 41 (45).
C12H20BrNO2 (290.2): calcd. C 49.67, H 6.95, N 4.83; found C
49.74, H 6.90, N 4.79.
J = 11.4, 13.3 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 153.08, 142.26, 129.07 (2 C), 128.22, 126.62 (2 C), 74.83, 53.90,
35.77, 35.42 ppm. trans-7: M.p.[7] 155–156 °C (EtOAc/n-C6H14). 1H
NMR (600 MHz, CDCl3): δ = 7.42–7.40 (m, 2 H), 7.35–7.28 (m, 3
H), 6.70 (s, 1 H, NH), 4.80 (narrow m, 1 H), 4.38 (m, 1 H), 3.50
(dd, J = 5.0, 11.0 Hz, 1 H), 3.46 (dd, J = 6.4, 11.0 Hz, 1 H), 2.37
(ddd, J = 5.9, 10.0, 13.7 Hz, 1 H), 2.15 (dm, J = 14.2 Hz, 1 H) ppm.
13C NMR (150 MHz, CDCl3): δ = 153.73, 141.24, 129.03 (2 C),
128.13, 125.81 (2 C), 72.22, 52.01, 32.70, 32.43 ppm. In the case of
340
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 334–344

Synthesis of Piperidine-2,4-diones from Homoallylamines
(S)-6, the major isomer (S)-cis-7, which precipitates from the reac-
tion mixture during the workup has [α]2D5 = –59.8 (c = 1, MeOH).
(0.64 g, 3.58 mmol) in CHCl3 (8 mL) was stirred for 2 h at reflux.
The solvent was removed under reduced pressure and Et2O (6 mL)
and 5% aq. NaOH (8 mL) were added to the residue with vigorous
stirring for 5 min. The organic layer was separated, washed with
sat. NaCl, dried with K2CO3, evaporated, and subjected to FC in
n-C6H14/EtOAc (2:1) to give 10b (0.57 g, 81%) as a solid. Rf =
0.78 (EtOAc). A (1:11) cis/trans mixture was obtained. Major trans
Benzyl (2S)-2-[(tert-Butoxycarbonyl)amino]-4-pentenoate (9a): (S)-
Allylglycine (0.34 g, 2.95 mmol), Boc2O (0.90 g, 4.10 mmol), and
K2CO3 (0.83 g, 6.0 mmol) were dissolved in THF (3 mL)/H2O
(3 mL) and the mixture was stirred for 6 h. The solution was acidi-
fied with 6 n HCl (2.3 mL, 14 mmol) to pH 3–4, extracted with
DCM (10 mL ϫ3), washed with sat. NaCl, dried with Na2SO4,
and evaporated to give the crude protected amino acid. A solution
of (S)-N-Boc-allylglycine in DMF (7 mL) was cooled to 0-+5 °C in
an ice/water bath and Cs2CO3 (1.01 g, 3.1 mmol) was added with
stirring for 1 h. BnBr (0.58 g, 0.4 mL, 3.4 mmol) was added and
the mixture was stirred overnight at 25 °C. The mixture was poured
into water (20 mL), extracted with hexane (50 mL), washed with
water, dried with Na2SO4, evaporated, and subjected to FC on sil-
ica gel (n-C6H14/EtOAc, 9:1) to yield 9a (0.88 g, 98%) as a colorless
1
isomer: H NMR (300 MHz, CDCl3): δ = 6.93 (s, 1 H, NH), 5.03
[sept., J = 6.3 Hz, 1 H, CH(CH3)2], 4.38–4.30 (m, 1 H, CHO), 3.53
(dd, J = 4.3, 10.9 Hz, 1 H, CHACHBBr), 3.45 (dd, J = 6.3, 10.9 Hz,
1 H, CHACHBBr), 2.67 (d, J = 13.7 Hz, 1 H, CHACHB,cycle), 1.73
(dd, J = 12.1, 13.7 Hz, 1 H, CHACHB,cycle), 1.50 (s, 3 H, Me), 1.26
[dd, J = 2.1, 6.3 Hz, 6 H, CH(CH3)2] ppm. 13C NMR (75 MHz,
CDCl3): δ = 172.63, 152.72, 73.73, 70.12, 57.43, 35.00, 32.69, 26.21,
21.65, 21.60 ppm. MS (70 eV, EI): m/z (%) = 296/294 (2) [M +
H]+, 208/206 (29), 164/162 (12), 83 (11), 82 (100), 67 (9), 42 (5), 41
(4). C10H16BrNO4 (294.1): calcd. C 40.83, H 5.48, Br 27.17, N 4.76;
found C 40.77, H 5.49, Br 27.04, N 4.80.
1
oil. [α]2D5 = –7.8 (c = 1, DCM). H NMR (300 MHz, CDCl3): δ =
7.41 (narrow m, 5 H, Ph), 5.78–5.64 (m, 1 H, CH=), 5.29–5.11 (m,
5 H, CH2=, CH2O, NH), 4.78 (dd, J = 6.0, 13.5 Hz, 1 H, CHN),
2.66–2.49 (m, 2 H, CH2CHN), 1.49 (s, 9 H, tBu) ppm. The spec-
trum coincides with literature data.[25]
6-Allyl-6-phenyl-5,6-dihydro-2,4(1H,3H)-pyridinedione (4a): tBuOK
(0.25 g, 2.22 mmol) was added to a cooled solution of bromide 3a
(0.3 g, 0.96 mmol) in THF (6 mL) at 0 °C and the solution was
stirred for 2 h at room temperature (TLC control, Rf = 0.53, n-
C6H14/EtOAc, 1:1). The turbid solution was neutralized with
AcOH (0.07 g, 1.2 mmol) and passed through a pad of silica gel
on a glass filter, washed with EtOAc (8 mLϫ3), evaporated, and
subjected to FC to yield 4a (0.20 g, 91%) as an oil. 1H NMR
(400 MHz, CDCl3): δ = 7.39 (s, 1 H, NH), 7.44–7.32 (m, 5 H, Ph),
5.59–5.48 (m, 1 H, CH=), 5.30–5.26 (m, 2 H, CH2=), 3.27 (d, J
Isopropyl (2S)-2-[(tert-Butoxycarbonyl)amino]-2-methyl-4-penteno-
ate (9b): Et3N (1.52 g, 2.08 mL, 15.0 mmol) was added with stirring
to a solution of the hydrochloride of the isopropyl ester of (S)-
allylalanine (2.08 g, 10.0 mmol) and Boc2O (2.29 g, 10.5 mmol) in
iPrOH (10 mL). After 10 min the mixture was heated at reflux for
another 10 min. The solvent was removed under reduced pressure
and the residue was taken up in hexane and washed with water.
Purification by flash chromatography gave protected ester 9b
(2.57 g, 95%) as a colorless liquid. Rf = 0.64 (n-C6H14/EtOAc, 6:1).
[α]2D5 = –3.73 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
5.70–5.56 (m, 1 H, CH=), 5.20 (br. s, 1 H, NH), 5.09–5.04 (m, 2
H, CH2=), 5.01 [sept., J = 6.3 Hz, 1 H, CH(CH3)2], 2.75–2.69 (br.
m, 1 H, CH2CH=), 2.51 (dd, J = 7.3, 13.8 Hz, 1 H, CH2CH=),
1.48 (s, 3 H, Me), 1.39 (s, 9 H, tBu), 1.21 [dd, J = 1.3, 6.3 Hz, 6 H,
CH(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 173.39, 154.23,
132.42, 119.20, 79.25, 68.91, 58.82, 41.19, 28.31 (3 C), 23.16, 21.68
(2 C) ppm. MS (70 eV, EI): m/z (%) = 272 (6) [M + H]+, 271 (0.8)
[M]+, 184 (55), 174 (29), 132 (13), 130 (29), 128 (100), 110 (10), 88
(55), 85 (10), 84 (48), 57 (17), 42 (69), 41 (43). C14H25NO4 (271.4):
calcd. C 61.97, H 9.29, N 5.16; found C 61.94, H 9.33, N 5.17.
= 16.2 Hz, 1 HAB, CHAHBCON), 3.22 (d, J = 20.6 Hz, 1 HAЈBЈ
,
COCHAHB), 2.99 (d, J = 20.3 Hz, 1 HAЈBЈ, COCHAHB), 2.88 (d,
J = 15.9 Hz, 1 HAB, CHAHBCON), 2.82 (dd, J = 5.4, 14.0 Hz, 1
H, CHAHB,allyl), 2.61 (dd, J = 8.9, 14.0 Hz, 1 H, CHAHB,allyl) ppm.
13C NMR (100 MHz, CDCl3): δ = 202.61, 169.74, 142.18, 130.82,
129.22 (2 C), 128.04, 125.40 (2 C), 121.71, 58.45, 50.78, 47.65,
46.75 ppm. MS (70 eV, EI): m/z (%) = 229 (0.3) [M]+, 189 (13), 188
(100) [M – Allyl]+, 146 (10), 120 (34), 104 (31), 103 (26), 77 (13),
51 (4), 42 (3). C14H15NO2 (229.3): calcd. C 73.34, H 6.59, N 6.11;
found C 73.24, H 6.65, N 6.03.
6-Allyl-6-(2-methoxyethyl)-5,6-dihydro-2,4(1H,3H)-pyridinedione
(4b): The procedure was the same as that used for the synthesis of
4a. Yield of 4b: 0.39 g, 93%. Oil. Rf = 0.27 (n-C6H14/EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): δ = 7.62 (s, 1 H, NH), 5.70–5.62 (m,
1 H, CH=), 5.19–5.12 (m, 2 H, CH2=), 3.55 (ddd, J = 3.8, 8.9,
10.2 Hz, 1 H, CHAHBO), 3.48 (ddd, J = 4.8, 5.1, 10.2 Hz, 1 H,
CHAHBO), 3.28 (s, 3 H, CH3O), 3.16 (s, 2 H, CH2CON), 2.60 (d,
Benzyl
(4S)-6-(Bromomethyl)-2-oxo-1,3-oxazinane-4-carboxylate
(10a): A solution of 9a (0.6 g, 1.96 mmol) in DCM (2 mL) was
added dropwise to a solution of NBS (0.66 g, 3.7 mmol) in DCM
(12 mL) at reflux. After completion of the addition the heating was
continued for 1 h (TLC control, Rf = 0.51; n-C6H14/EtOAc, 4:1),
then the solvent was evaporated under reduced pressure and the
residue was dissolved in Et2O/EtOAc (2:1, 15 mL) and treated with
5% NaOH (5 mL) for 15 min. The organic layer was separated,
washed with water, dried with K2CO3, evaporated, and subjected
to FC (n-C6H14/EtOAc, 3:1) to give 10a (0.48 g, 75%) as a white
powder. Mixture of isomers cis/trans = 1:2.2 was obtained. 1H
NMR (400 MHz, CDCl3): δ = 7.39–7.38 (m, 5 H), 6.60 and 6.23
(both br. s, 1 H, NH), 5.27–5.17 (m, 2 H, CH2O), 4.50–4.43 (m, 1
H), 4.24–4.23 (m, 1 H), 3.58–3.43 (m, 2 H), 2.63 and 2.43 (both d,
J = 12.4 and 13.4 Hz, 1 H), 2.21–2.14 and 1.93–1.84 (both m, 1
H) ppm. MS (70 eV, EI): m/z (%) = 329/327 (0.2) [M]+, 302/300
(0.2), 278/276 (1), 232/230 (0.3), 194/192 (11), 150/148 (11), 105 (5),
91 (51), 79 (11), 69 (11), 68 (100), 65 (14). C13H14BrNO4 (328.2):
calcd. C 47.58, H 4.30, N 4.27; found C 47.63, H 4.39, N 4.15.
J = 15.6 Hz, 1 HAB, CH2CO), 2.54 (d, J = 15.3 Hz, 1 HAB
,
CH2CO), 2.31 (d, J = 7.3 Hz, 2 H, CH2,allyl), 1.87 (ddd, J = 4.4,
8.6, 14.9 Hz, 1 H, CH2CHAHB), 1.75 (dt, J = 4.4, 15.6 Hz, 1 H,
CH2CHAHB) ppm. 13C NMR (100 MHz, CDCl3): δ = 203.79,
169.47, 131.73, 121.92, 68.94, 59.30, 55.86, 49.08, 45.95, 45.16,
39.74 ppm. MS (70 eV, EI): m/z (%) = 211 (1) [M]+, 210 (4), 208
(6), 197 (6), 184 (20), 169 (15), 157 (32), 154 (46), 149 (16), 138 (8),
128 (9), 126 (20), 112 (42), 96 (20), 85 (57), 83 (100), 45 (28), 41
(12). C11H17NO3 (211.3): calcd. C 62.54, H 8.11, N 6.63; found C
62.17, H 8.15, N 6.59.
tert-Butyl 2-(2-Allyl-4,6-dioxo-2-piperidinyl)acetate (4c): The pro-
cedure was the same as that used for the synthesis of 4a. Yield of
4c: 0.46 g, 92%. Oil. Rf = 0.56 (EtOAc). 1H NMR (300 MHz,
CDCl3): δ = 7.39 (s, 1 H, NH), 5.77–5.63 (m, 1 H, CH=), 5.22–
5.12 (m, 2 H, CH2=), 3.24 (d, J = 20.8 Hz, 1 HAB, CHAHBCON),
Isopropyl
(4S)-6-(Bromomethyl)-4-methyl-2-oxo-1,3-oxazinane-4- 3.17 (d, J = 20.8 Hz, 1 HAB, CHAHBCON), 2.62 (s, 2 H, CH2CO),
carboxylate (10b): A mixture of 9b (0.65 g, 2.39 mmol) and NBS
2.44 (d, J = 4.3 Hz, 2 H, CH2,allyl), 2.38 (d, J = 7.3 Hz, 2 H, CH2),
Eur. J. Org. Chem. 2012, 334–344
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
341

N. Yu. Kuznetsov, Yu. N. Bubnov et al.
FULL PAPER
1.41 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 202.32,
(6), 70 (11), 65 (26), 44 (60). C13H13NO4 (247.3): calcd. C 63.15, H
169.16, 168.33, 130.75, 121.92, 82.17, 54.25, 47.95, 45.76, 44.67, 5.30, N 5.67; found C 63.02, H 5.34, N 5.48.
44.57, 28.00 (3 C) ppm. C14H21NO4 (267.3): calcd. C 62.90, H 7.92,
Isopropyl (2S)-2-Methyl-4,6-dioxohexahydro-2-pyridinecarboxylate
N 5.24; found C 62.84, H 7.83, N 5.26.
(11b): The procedure was the same as that used for the synthesis
of 4a. Yield of 11b: 0.26 g, 84%. White powder. Rf = 0.43 (n-C6H14/
EtOAc, 1:1). M.p. 78–80 °C. [α]2D5 = +53.7 (c = 1, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.67 (br. s, 1 H, NH), 4.98 (sept., J =
6.3 Hz, 1 H, CHO), 3.27 (d, J = 21.0 Hz, 1 H, NCOCHAHB), 3.18
(d, J = 21.4 Hz, 1 H, NCOCHAHB), 2.87 (d, J = 15.7 Hz, 1 H,
COCHAHB), 2.56 (d, J = 16.1 Hz, 1 H, COCHAHB), 1.55 (s, 3 H,
CH3), 1.21 (d, J = 6.3 Hz, 6 H, 2 CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 201.35, 171.52, 169.59, 70.74, 56.82, 48.26, 45.67,
25.05, 21.53, 21.45 ppm. MS (70 eV, EI): m/z (%) = 214(3) [M +
H]+, 213 (0.5), 149 (5), 126 (100), 97 (4), 84 (16), 83 (11), 69 (15), 58
(79), 43 (12), 42 (26), 41 (10). C10H15NO4 (213.2): calcd. C 56.33, H
7.09, N 6.57; found C 56.22, H 7.15, N 6.60.
6-Allyl-6-(fluoromethyl)-5,6-dihydro-2,4(1H,3H)-pyridinedione (4d):
The procedure was the same as that used for the synthesis of 4a.
Yield of 4d: 0.4 g, 84%. White powder. M.p. 94–95 °C (acetone).
Rf = 0.23 (n-C6H14/EtOAc, 7:3), 1H NMR (300 MHz, CDCl3): δ =
7.91 (br. s, 1 H, NH), 5.82–5.68 (m, 1 H, CH=), 5.30–5.20 (m, 2 H,
CH2=), 4.31 (d, JFH = 46.8 Hz, 2 H, CH2F), 3.28 (d, J = 21.0 Hz, 1
H, CHAHBCON), 3.18 (dd, J = 2.0, 21.0 Hz, 1 H, CHAHBCON),
2.61 (s, 2 H, CH2CO), 2.41 (dd, J = 6.4, 14.1 Hz, 1 H, CHAHB),
2.29 (dd, J = 8.2, 14.1 Hz, 1 H, CHAHB) ppm. 13C NMR (75 MHz,
CDCl3): δ = 202.05, 170.16, 129.54, 122.24, 89.41 and 87.04 (JCF
= 177.9 Hz), 56.39 and 56.16 (JCF = 16.8 Hz), 45.34 and 45.31 (JCF
= 2.6 Hz), 44.91 and 44.97 (JCF = 2.0 Hz), 40.50 and 40.44 (JCF
=
4.6 Hz) ppm. 19F NMR (282 MHz, CDCl3): δ = –145.58 ppm. MS
(70 eV, EI): m/z (%) = 185 (0.7), 165 (2), 150 (2), 149 (22), 144
(100), 135 (2), 124 (5), 111 (4), 102 (7), 96 (6), 85 (5), 82 (5), 81 (5),
76 (84), 69 (14), 60 (10), 56 (27), 43 (11), 41 (10). C9H12FNO2
(185.2): calcd. C 58.37, H 6.53, F 10.26, N 7.56; found C 58.40, H
6.47, F 10.24, N 7.60.
6-Methylene-4-phenyl-1,3-oxazinan-2-one (12): Half of the volume
of a solution of HMDSLi freshly prepared from HMDS (3.54 g,
4.57 mL, 22 mmol) and nBuLi (2.5 m, 9.3 mL, 23 mmol) was added
to a solution of bromide cis-7 (2.7 g, 10 mmol) in THF (50 mL) at
–60 °C and the mixture was stirred for 3 min. Then TBSCl (1.81 g,
12 mmol) was added and stirring was continued for another 15 min
to ensure silylation at this temperature. Then the rest of the
HMDSLi solution was injected by syringe and the reaction mixture
was warmed to room temperature. The resulting solution was evap-
orated under reduced pressure and a mixture of THF/AcOH/H2O
(20:10:10 mL) was added to the residue, which was stirred for
30 min at 50 °C (TLC control, Rf = 0.48, n-C6H14/EtOAc, 1:1).
The residue that was obtained after evaporation of the mixture was
dissolved in DCM (15 mL) and dried with K2CO3, again evapo-
rated and purified by flash chromatography to finally yield 0.90 g
(48%) of 12 as colorless crystals. M.p. 139–140 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H, Ph), 6.70 (s, 1 H, NH),
4.72 (s, 1 H, CHAHB=), 4.59 (m, 1 H, CH), 4.25 (s, 1 H, CHAHB=),
2.81 (dd, J = 4.4, 13.9 Hz, 1 H, CHAHB), 2.52 (dd, J = 7.9, 13.9 Hz,
1 H, CHAHB) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.77,
151.27, 139.86, 129.00 (2 C), 128.51, 126.01 (2 C), 94.77, 53.51,
34.33 ppm. MS (70 eV, EI): m/z = 189 (8) [M+], 188 (2), 174 (4),
160 (13), 147 (8), 146 (33), 145 (11), 132 (27), 131 (6), 119 (8), 118
(8), 115 (6), 106 (5), 105 (26), 104 (100), 103 (36), 102 (5), 91 (5),
78 (41), 77 (34), 51 (10), 43 (4). C11H11NO2 (189.2): calcd. C 69.83,
H 5.86, N 7.40; found C 69.86, H 5.87, N 7.36.
6-Allyl-6-isobutyl-5,6-dihydro-2,4(1H,3H)-pyridinedione (4e): The
procedure was the same as that used for the synthesis of 4a. Yield
of 4e: 0.78 g, 90%. White crystals. M.p. 117–118 °C (acetone). Rf
= 0.49 (n-C6H14/EtOAc, 1:1). 1H NMR (300 MHz, CDCl3): δ =
7.79 (s, 1 H, NH), 5.84–5.70 (m, 1 H, CH=), 5.22–5.12 (m, 2 H,
CH2=), 3.20 (s, 2 H, CH2CON), 2.57 (s, 2 H, CH2CO), 2.41 (dd, J
= 14.0, 7.0 Hz, 1 H, CHAHB,allyl), 2.31 (dd, J = 14.0, 7.8 Hz, 1 H,
CHAHB,allyl), 1.82 (m, 1 H, CH), 1.47 (dd, J = 5.8, 14.6 Hz, 2 H,
CH2), 0.99 (d, J = 6.6 Hz, 6 H, 2CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 203.64, 169.43, 131.29, 121.20, 56.16, 48.62, 48.46,
45.31, 45.00, 24.63, 24.49, 23.86 ppm. MS (70 eV, EI): m/z (%) =
209 (0.5) [M]+, 169 (9), 168 (87), 152 (35), 126 (100), 124 (14), 112
(11), 84 (17), 57 (6), 43 (7), 42 (8), 41 (9). C12H19NO2 (209.3): calcd.
C 68.87, H 9.15, N 6.69; found C 68.92, H 9.14, N 6.54.
6-Phenyl-5,6-dihydro-2,4(1H,3H)-pyridinedione [rac- and (S)-8]: The
isomeric bromides (S)-7 (0.12 g, 0.44 mmol) in THF (3 mL) was
treated with tBuOK (87 mg, 0.78 mmol) and the mixture was
stirred for 40 min at room temp. TLC control in EtOAc: Rf = 0.46.
Purification by FC in EtOAc furnished (S)-8 (79 mg, 95%) as a
1
Procedure for the Kinetic Experiments: A freshly prepared solution
of HMDSLi (0.138 mL, 0.22 mmol) [from HMDS (1 mL/0.77 g,
4.79 mmol) and nBuLi (2.5 m, 2.02 mL, 5.04 mmol)] was added to
a solution of 12 (40 mg, 0.2 mmol) in THF (5 mL) at –55 °C (to
compensate an increase in the temperature) and the mixture was
stirred for the required time (3, 5, 8, 10, 12, 15, 20, 35 min). To
terminate the reaction a solution of AcOH [0.26 mL in Et2O
(2 mL)] (0.015 mL, 0.28 mmol) was added and the solution was
warmed to room temp., then treated with water (0.3 mL), stirred
for 30 min, filtered through “Super Cel”, evaporated, and analyzed
by 1H NMR in CDCl3. The integration was performed for the
peaks at δ = 4.72 ppm (for 12) and δ = 4.86 ppm (for 8).
solid, 98.5%ee. H NMR (300 MHz, CDCl3): δ = 7.48–7.32 (m, 5
H, Ph), 7.20 (s, 1 H, NH), 4.87–4.84 (m, 1 H, CH), 3.35 (s, 2 H,
CH2CON), 2.92 (dd, J = 4.4, 16.1 Hz, 1 H, COCHAHB), 2.79 (dd,
J = 9.5, 16.1 Hz, 1 H, COCHAHB) ppm. 13C NMR (75 MHz,
CDCl3): δ = 202.46, 169.25, 139.29, 129.38 (2 C), 128.82, 126.04 (2
C), 52.81, 47.22, 46.94 ppm. The spectra coincide with the litera-
ture data.[7]
Benzyl 4,6-Dioxo-2-piperidinecarboxylate (11a): The procedure was
the same as that used for the synthesis of 4a. Yield of 11a: 0.19 g,
79%, 24%ee. White crystals. M.p. 95–96.5 °C (ref.[6g] m.p. 102–
103 °C for the pure S isomer). Rf = 0.56 (EtOAc). 1H NMR
(300 MHz, CDCl3): δ = 7.40–7.29 (m, 6 H, Ph, NH), 4.69 (s, 2 H,
CH2O), 3.69 (m, 1 H, CHCOOBn), 2.38 (d, J = 24.9 Hz, 1 H,
CHaHbC=O), 2.26 (d, J = 25.1 Hz, 1 H, CHaHbC=O), 1.82 (dd, J
X-ray Structure Determinations
Crystal Data for 3a: C14H16NO2Br, M = 310.19, triclinic, space
¯
= 6.6, 21.0 Hz, 1 H, CHaHbCH), 1.61 (dd, J = 8.2, 21.0 Hz, 1 H, group P1, T = 120 K, a = 6.4169(3), b = 8.4943(4), c =
CHaHbCH) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.88,
169.73, 168.69, 134.40, 128.99, 128.84 (2 C), 128.56 (2 C), 68.31,
50.74, 47.56, 40.74 ppm. The spectra coincide with the literature
data.[6g] MS (70 eV, EI): m/z (%) = 247 (0.5) [M]+, 221 (0.5), 149
12.5947(6) Å, α = 79.601(1), β = 82.835(1), γ = 77.719(1)°, V =
657.11(5) Å3, Z = 2, dcalcd. = 1.568 g/cm3, F(000) = 316, μ =
3.121 mm–1. A total of 7688reflections (3786 unique reflections,
Rint = 0.018) were measured with a three-circle Bruker SMART 1K
(1.5), 112 (56), 105 (2), 95 (6), 92 (12), 91 (100), 89 (5), 84 (7), 77 CCD diffractometer [λ(Mo-Kα) radiation, graphite monochroma-
342
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 334–344

Synthesis of Piperidine-2,4-diones from Homoallylamines
J. M. Pasteels, J. Nat. Prod. 1996, 59, 510–511; g) tasipeptins A
and B: P. G. Williams, W. Y. Yoshida, R. E. Moore, V. J. Paul,
J. Nat. Prod. 2003, 66, 620–624; h) micropeptins: V. Reshef, S.
Carmeli, Tetrahedron 2001, 57, 2885–2894; i) paraherquamides,
brevianamides, and asperparalines: R. M. Williams, R. J. Cox,
Acc. Chem. Res. 2003, 36, 127–139; j) strychnine: J. Bonjoch,
D. Sole, Chem. Rev. 2000, 100, 3455–3482.
tor, φ and ω scan mode, 2θmax = 60°] and corrected for absorp-
tion.[26] The structure was determined by direct methods and re-
fined by the full-matrix least-squares technique on F2 with aniso-
tropic displacement parameters for non-hydrogen atoms. The hy-
drogen atom of the NH group was localized in the difference Fou-
rier map and included in the refinement with fixed positional and
isotropic displacement parameters [Uiso(H) = 1.2Ueq(N)]. The other
hydrogen atoms were placed in calculated positions and refined
within the riding model with fixed isotropic displacement param-
eters [Uiso(H) = 1.2Ueq(C)]. The final divergence factors were R1 =
[2]
a) D. Bell, M. R. Davies, F. J. L. Finney, G. R. Geen, P. M.
Kincey, I. S. Mann, Tetrahedron Lett. 1996, 37, 3895–3898 (po-
tassium channel activator BRL 55834); b) H. G. Bull, M. Gar-
cia-Calvo, S. Andersson, W. F. Baginsky, H. K. Chan, D. E.
Ellsworth, R. R. Miller, R. A. Stearns, R. K. Bakshi, G. H.
Rasmusson, R. L. Tolman, R. W. Myers, J. W. Kozarich, G. S.
Harris, J. Am. Chem. Soc. 1996, 118, 2359–2365 (finasteride
MK-906 inhibitor of the human prostate enzyme); c) G. A.
Reichard, J. Spitler, I. Mergelsberg, A. Miller, G. Wong, R.
Raghavan, J. Jenkins, T. Gan, A. T. McPhail, Tetrahedron:
Asymmetry 2002, 13, 939–943 (SCH206272 NK1\NK2 antago-
nist); d) S. Nara, R. Tanaka, J. Eishima, M. Hara, Y. Takah-
ashi, S. Otaki, R. J. Foglesong, P. F. Hughes, S. Turkington, Y.
Kanda, J. Med. Chem. 2003, 46, 2467–2473 [anticancer drugs
Farnesyltransferase (FTase) inhibitors]; e) Z. Pei, X. Li, T. W.
von Geldern, K. Longenecker, D. Pireh, K. D. Stewart, B. J.
Backes, C. Lai, T. H. Lubben, S. J. Ballaron, D. W. A. Beno,
A. J. Kempf-Grote, H. L. Sham, J. M. Trevillyan, J. Med.
Chem. 2007, 50, 1983–1987 (dipeptidyl peptidase IV (DPP4)
inhibitors, treatment of type 2 diabetes); f) E. Vanotti, R.
Amici, A. Bargiotti, J. Berthelsen, R. Bosotti, A. Ciavolella, A.
Cirla, C. Cristiani, R. D’Alessio, B. Forte, A. Isacchi, K. Mar-
tina, M. Menichincheri, A. Molinari, A. Montagnoli, P. Orsini,
A. Pillan, F. Roletto, A. Scolaro, M. Tibolla, B. Valsasina, M.
Varasi, D. Volpi, C. Santocanale, J. Med. Chem. 2008, 51, 487–
501 (Cdc7 kinase inhibitors); g) Y. Nishimura, H. Adachi, T.
Satoh, E. Shitara, H. Nakamura, F. Kojima, T. Takeuchi, J.
Org. Chem. 2000, 65, 4871–4882 (glycosidase inhibitors).
a) L. Halab, F. Gosselin, W. D. Lubell, Biopolymers 2000, 55,
101–122; b) S. Hanessian, G. McNaughton-Smith, H.-G.
Lombart, W. D. Lubell, Tetrahedron 1997, 53, 12789–12854; c)
K. Weber, U. Ohnmacht, P. Gmeiner, J. Org. Chem. 2000, 65,
7406–7416; d) F. E. Dutton, B. H. Lee, S. S. Johnson, E. M.
Coscarelli, P. H. Lee, J. Med. Chem. 2003, 46, 2057–2073.
a) N. Leflemme, P. Dallemagne, S. Rault, Tetrahedron Lett.
2001, 42, 8997–8999; b) D. Desmaele, K. Mekouar, J. dЈAngelo,
J. Org. Chem. 1997, 62, 3890–3901; c) R. L. Beard, A. I. Mey-
ers, J. Org. Chem. 1991, 56, 2091–2096; d) Y. Xie, A. Raffo, M.
Ichise, S. Deng, P. E. Harris, D. W. Landry, Bioorg. Med. Chem.
Lett. 2008, 18, 5111–5114; e) M. Menichincheri, A. Bargiotti,
J. Berthelsen, J. A. Bertrand, R. Bossi, A. Ciavolella, A. Cirla,
C. Cristiani, V. Croci, R. DЈAlessio, M. Fasolini, F. Fiorentini,
B. Forte, A. Isacchi, K. Martina, A. Molinari, A. Montagnoli,
P. Orsini, F. Orzi, E. Pesenti, D. Pezzetta, A. Pillan, I. Poggesi,
F. Roletto, A. Scolaro, M. Tato, M. Tibolla, B. Valsasina, M.
Varasi, D. Volpi, C. Santocanale, E. Vanotti, J. Med. Chem.
2009, 52, 293–307.
0.023 for 3540 independent reflections with IϾ2σ(I) and wR2
=
0.059 for all independent reflections (S = 1.003). All calculations
were carried out by using the SHELXTL program.[27]
Crystal Data for cis-7: C11H12NO2Br, M = 270.13, monoclinic,
space group C2/c, T = 120 K, a = 17.1029(10), b = 11.9023(7), c =
11.3889(7) Å, β = 108.510(1)°, V = 2198.4(2) Å3, Z = 8, dcalcd.
=
1.632 g/cm3, F(000) = 1088, μ = 3.718 mm–1. A total 12484 reflec-
tions (3190 unique reflections, Rint = 0.032) were measured with
a three-circle Bruker SMART 1K CCD diffractometer [λ(Mo-Kα)
radiation, graphite monochromator, φ and ω scan mode, 2θmax
=
60°] and corrected for absorption.[26] The structure was determined
by direct methods and refined by the full-matrix least-squares tech-
nique on F2 with anisotropic displacement parameters for non-hy-
drogen atoms. The hydrogen atom of the NH group was localized
in the difference Fourier map and included in the refinement with
fixed positional and isotropic displacement parameters [Uiso(H) =
1.2Ueq(N)]. The other hydrogen atoms were placed in calculated
positions and refined within the riding model with fixed isotropic
displacement parameters [Uiso(H) = 1.2Ueq(C)]. The final diver-
gence factors were R1 = 0.033 for 2406 independent reflections with
IϾ2σ(I) and wR2 = 0.090 for all independent reflections (S =
1.006). All calculations were carried out by using the SHELXTL
program.[27]
[3]
[4]
CCDC-832555 (for 3a) and -832556 (for cis-7) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra, HPLC traces, and
selected crystallographic data.
Acknowledgments
This work was supported by the President of the Russian Federa-
tion (Sci. School No. 7946.2010.3), the Russian Foundation for Ba-
sic Research (grant No. 08-03-00790), and the Presidium of the
Russian Academy of Sciences (RAS) (No. 18, coordinator: V. A.
Tartakovsky). The authors are grateful to Dr. S. Lubimov for chiral
HPLC analysis.
[5]
[6]
a) Y. Li, F. M. Raushel, Bioorg. Chem. 2005, 33, 470–483; b) S.
Peukert, Y. Sun, R. Zhang, B. Hurley, M. Sabio, X. Shen, C.
Gray, J. A. Dzink-Fox, J. Tao, R. Cebula, S. Wattanasin, Bi-
oorg. Med. Chem. Lett. 2008, 18, 1840–1844.
[1] a) G. M. Strunz, J. A. Findlay in The Alkaloids (Ed.: A. Brossi),
Academic Press, Orlando, 1985, vol. 26, pp. 89–183; b) G. B.
Fodor, B. Colasanti in Alkaloids: Chemical and Biological Per-
spectives (Ed.: S. W. Pelletier), Wiley, New York, 1985, vol. 3,
pp. 1–90; c) piperidine-2-ones: T. H. Jones, M. S. Blum in Alka-
loids: Chemical and Biological Perspectives (Ed.: S. W. Pel-
letier), Wiley, New York, 1983, vol. 1, pp. 33–84; d) J. W. Daly,
J. Nat. Prod. 1998, 61, 162–172; e) ciliatamide C: Y. Nakao, S.
Kawatsu, C. Okamoto, M. Okamoto, Y. Matsumoto, S. Mat-
sunaga, R. W. M. van Soest, N. Fusetani, J. Nat. Prod. 2008,
71, 469–472; f) adalinine: G. Lognay, J. L. Hemptinne, F. Y.
Chan, C. H. Gaspar, M. Marlier, J. C. Braekman, D. Daloze,
a) For a review, see: P. M. Weintraub, J. S. Sabol, J. M. Kane,
D. R. Borcherding, Tetrahedron 2003, 59, 2953–2989; b) T. Ku-
rihara, H. Tanno, S. Takemura, S. Harusawa, R. Yoneds, J.
Heterocycl. Chem. 1993, 30, 643–652; c) H. W. Lam, G. J. Mur-
ray, J. D. Firth, Org. Lett. 2005, 7, 5743–5746; d) F. A. Davis,
T. Fang, B. Chao, D. M. Burns, Synthesis 2000, 14, 2106–2112;
e) F. A. Davis, B. Chao, T. Fang, J. M. Szewczyk, Org. Lett.
2000, 2, 1041–1043; f) F. A. Davis, B. Chao, A. Rao, Org. Lett.
2001, 3, 3169–3171; g) J. Marin, C. Didierjean, A. Aubry, J.-R.
Casimir, J.-P. Briand, G. Guichard, J. Org. Chem. 2004, 69,
130–141; h) R. Kawecki, Tetrahedron 2001, 57, 8385–8390; i)
C. K. McClure, J. S. Link, J. Org. Chem. 2003, 68, 8256–8257;
Eur. J. Org. Chem. 2012, 334–344
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
343

N. Yu. Kuznetsov, Yu. N. Bubnov et al.
FULL PAPER
j) M. J. Ashton, S. J. Hills, C. G. Newton, J. B. Taylor, S. C. D.
Tondu, Heterocycles 1989, 28, 1015–1035.
Lange, B. Kaptein, R. M. Kellogg, Q. B. Broxterman, Org.
Lett. 2001, 3, 3943–3946; f) P. V. Ramachandran, T. E. Burgh-
ardt, L. Bland-Berry, J. Org. Chem. 2005, 70, 7911–7918; g) T.
Vilaivan, C. Winotapan, V. Banphavichit, T. Shinada, Y.
Ohfune, J. Org. Chem. 2005, 70, 3464–3471; h) S. Lou, P. N.
Moquist, S. E. Schaus, J. Am. Chem. Soc. 2007, 129, 15398–
15404; i) M. Sugiura, C. Mori, S. Kobayashi, J. Am. Chem.
Soc. 2006, 128, 11038–11039; j) R. Wada, T. Shibuguchi, S.
Makino, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem.
Soc. 2006, 128, 7687–7691; k) E. Hernandez, E. Canales, E.
Gonzalez, J. A. Soderquist, Pure Appl. Chem. 2006, 78, 1389–
1395; l) M. Rueping, A. P. Antonchick, Angew. Chem. 2008,
120, 10244; Angew. Chem. Int. Ed. 2008, 47, 10090–10093; m)
P. V. Ramachandran, T. E. Burghardt, Chem. Eur. J. 2005, 11,
4387–4395.
[7] Preliminary results were presented at the BOSS XII conference
11–16th July 2010 in Namur, Belgium, and independently from
the paper: S. Magnelinckx, Y. Nural, H. A. Dondas, B. Denolf,
R. Sillanpaa, N. De Kimpe, Tetrahedron 2010, 66, 4115–4124.
[8] a) Yu. N. Bubnov, Advances in Boron Chemistry (Ed.: W. Sieb-
ert), Royal Society of Chemistry, Cambridge, 1997, pp. 123–
138; b) B. M. Mikhailov, Yu. N. Bubnov, Organoboron Com-
pounds in Organic Synthesis, Harwood, London, 1984.
[9] N. Yu. Kuznetsov, V. N. Khrustalev, I. A. Godovikov, Yu. N.
Bubnov, Eur. J. Org. Chem. 2007, 2015–2021.
[10] a) Yu. N. Bubnov, E. A. Shagova, S. V. Evchenko, A. V. Ignat-
enko, Russ. Chem. Bull. 1994, 43, 645–656; b) Yu. N. Bubnov,
E. E. Demina, A. V. Ignatenko, Russ. Chem. Bull. 1997, 46,
1361–1371; c) Yu. N. Bubnov, S. V. Evchenko, A. V. Ignatenko,
Russ. Chem. Bull. 1993, 42, 1268–1269; d) Yu. N. Bubnov, L. I.
Lavrinovich, A. Yu. Zikov, E. V. Klimkina, A. V. Ignatenko,
Russ. Chem. Bull. 1993, 42, 1269–1270; e) Yu. N. Bubnov, E. V.
Klimkina, L. I. Lavrinovich, A. Yu. Zikov, A. V. Ignatenko,
Russ. Chem. Bull. 1999, 48, 1696–1705; f) B. M. Mikhailov,
Yu. N. Bubnov, A. V. Tsyban, M. Sh. Grigoryan, J. Organomet.
Chem. 1978, 154, 131–145; g) Yu. N. Bubnov, M. A. Misharin,
A. V. Ignatenko, Tetrahedron Lett. 1997, 38, 6259–6262; h)
Yu. N. Bubnov, F. V. Pastukhov, I. V. Yampolsky, A. V. Ignat-
enko, Eur. J. Org. Chem. 2000, 1503–1505; i) Yu. N. Bubnov,
E. V. Klimkina, A. V. Ignatenko, Russ. Chem. Bull. 1998, 47,
451–458; j) Yu. N. Bubnov, E. V. Klimkina, Chem. Heterocycl.
Compd. 1999, 35, 888–899.
[11] a) N. Yu. Kuznetsov, V. N. Khrustalev, I. A. Godovikov, Yu. N.
Bubnov, Eur. J. Org. Chem. 2006, 113–120; b) N. Yu. Kuznet-
sov, K. A. Lyssenko, A. S. Peregudov, Yu. N. Bubnov, Russ.
Chem. Bull. 2007, 56, 1569–1574.
[12] a) Y. Wang, T. Izawa, S. Kobayashi, M. Ohno, J. Am. Chem.
Soc. 1982, 104, 6464–6466; b) P. A. Bartlett, D. J. Tanzella, J. F.
Barstow, Tetrahedron Lett. 1982, 23, 619–622; c) P. A. Bartlett,
Tetrahedron 1980, 36, 2–72; d) G. Puigbo, F. Diaba, J. Bonjoch,
Tetrahedron 2003, 59, 2657–2665; e) S. G. Davies, J. R. Haggitt,
O. Ichihara, R. J. Kelly, M. A. Leech, A. J. P. Mortimer, P. M.
Roberts, A. D. Smith, Org. Biomol. Chem. 2004, 2, 2630–2649;
f) M. Pattarozzi, C. Zonta, Q. B. Broxterman, B. Kaptein, R.
De Zorzi, L. Randaccio, P. Scrimin, G. Licini, Org. Lett. 2007,
9, 2365–2368.
[17]
[18]
Yu. N. Belokon, V. I. Bakhmutov, N. I. Chernoglazova, K. A.
Kochetkov, S. V. Vitt, N. S. Garbalinskaya, V. M. Belikov, J.
Chem. Soc. Perkin Trans. 1 1988, 305–312.
a) S. B. Hendi, M. S. Hendi, J. F. Wolfe, Synth. Commun. 1987,
17, 13–18; b) C. E. Augelli-Szafran, C. J. Blankley, B. D. Roth,
B. K. Trivedi, R. F. Bousley, A. D. Essenburg, K. L. Hame-
lehle, B. R. Krause, R. L. Stanfield, J. Med. Chem. 1993, 36,
2943–2949; c) P. López-Alvarado, C. Avendaño, J. C.
Menéndez, Tetrahedron Lett. 2001, 42, 4479–4482; d) T. Miya-
gawa, K. Nagai, A. Yamada, Y. Sugihara, T. Fukuda, T. Fu-
kuda, R. Uchida, H. Tomoda, S. Omura, T. Nagamitsu, Org.
Lett. 2011, 13, 1158–1161.
a) L. Benati, G. Bencivenni, R. Leardini, M. Minozzi, D.
Nanni, R. Scialpi, P. Spagnolo, G. Zanardi, J. Org. Chem. 2006,
71, 3192–3197; b) L. Luo, M. D. Bartberger, W. R. Dolbier Jr.,
J. Am. Chem. Soc. 1997, 119, 12366–12367; c) N. P. Shusherina,
T. H. Gladisheva, R. Y. Levina, Zh. Org. Khim. 1966, 2, 1801–
1804; d) E. Guntrum, W. Kuhn, W. Sponlein, V. Jager, Synthe-
sis 1986, 921–925; e) R. J. Ferrier, S. Middleton, Chem. Rev.
1993, 93, 2779–2831; f) T. Pouplin, B. Tolon, P. Nuhant, B.
Delpech, C. Marazano, Eur. J. Org. Chem. 2007, 5117–5125; g)
G. Mehta, M. K. Bera, S. Chatterjee, Tetrahedron Lett. 2008,
49, 1121–1124.
a) P. Gmeimer, B. Bollinger, Synthesis 1995, 168–170; b) W. B.
Motherwell, G. Begis, D. E. Cladingboel, L. Jerome, T. D.
Sheppard, Tetrahedron 2007, 63, 6462–6476.
L. I. Zakharkin, V. I. Stanko, Izv. Acad. Nauk SSSR, Ser.
Khim. 1960, 1896–1898 (Chem. Abstr. 1961, 55, 15337d).
Yu. N. Bubnov, V. S. Bogdanov, B. M. Mikhailov, Russ. J. Gen.
Chem. 1968, 38, 260–267.
D. J. Hart, K. Kanai, D. G. Thomas, T.-K. Yang, J. Org. Chem.
1983, 48, 289–294.
S. Laschat, H. Kunz, J. Org. Chem. 1991, 56, 5883–5889.
D. Passarella, B. Peretto, R. B. Yepes, G. Cappelletti, D. Car-
telli, C. Ronchi, J. Snaith, G. Fontana, B. Danieli, J. Borlak,
Eur. J. Med. Chem. 2010, 45, 219–226.
[19]
[20]
[21]
[22]
[23]
[13] a) L. Wu, S. Qiu, G. Liu, Org. Lett. 2009, 11, 2707–2710; b) Y.
Yamamoto, D. Matsumi, R. Hattori, K. Itoh, J. Org. Chem.
1999, 64, 3224–3229; c) F. Bennett, D. W. Knight, G. Fenton,
J. Chem. Soc. Perkin Trans. 1 1991, 133–140; d) G. W. An-
derson, I. F. Halverstadt, W. H. Miller, R. O. Roblin, J. Am.
Chem. Soc. 1945, 67, 2197–2200.
[24]
[25]
[14] P. Nieczypor, J. C. Mol, N. B. Bespalova, Y. N. Bubnov, Eur. J.
Org. Chem. 2004, 812–819.
[15] I. V. Yampolsky, diploma work, unpublished results, High
Chemical College Russian Academy of Sciences, 2002.
[16] a) For a recent review, see: H. Ding, G. K. Friestad, Synthesis
2005, 2815–2829; b) P. V. Ramachandran, D. Biswas, Org. Lett.
2007, 9, 3025–3027; c) X.-W. Sun, M.-H. Xu, G.-Q. Lin, Org.
Lett. 2006, 8, 4979–4982; d) F. Foubelo, M. Yus, Tetrahedron:
Asymmetry 2004, 15, 3823–3825; e) M. Sluis, J. Dalmolen, B.
[26]
[27]
G. M. Sheldrick, SADABS, v. 2.01, Bruker/Siemens Area De-
tector Absorption Correction Program, Bruker AXS Inc.,
Madison, WI, 1998.
G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
Received: July 29, 2011
Published Online: November 10, 2011
344
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 334–344