Synthesis of 3-phenyl-4-piperidones from acetophenone by shapiro and azamichael reactions and their further derivatization

Article abstract of DOI:10.1002/ejoc.200700325

The Shapiro reaction of acetophenone is the key in a convenient three-step access to a divinyl ketone which is further transformed by double aza-Michael reactions with primary amines into N-substituted 3-phenyl-4-piperidones. In the case of N-benzyl and N

Full text of DOI:10.1002/ejoc.200700325

FULL PAPER
DOI: 10.1002/ejoc.200700325
Synthesis of 3-Phenyl-4-piperidones from Acetophenone by Shapiro and Aza-
Michael Reactions and Their Further Derivatization
Anna Rosiak,[a][‡] Christoph Hoenke,[b] and Jens Christoffers*[a]
Keywords: Piperidines / Heterocycles / Ketones / Protecting groups / Shapiro reaction / Hydrazones
The Shapiro reaction of acetophenone is the key in a conve-
nient three-step access to a divinyl ketone which is further
transformed by double aza-Michael reactions with primary
amines into N-substituted 3-phenyl-4-piperidones. In the
case of N-benzyl and N-allyl derivatives, the piperidine ni-
trogen atom can be deprotected and further functionalized,
for example, by carboxamide, carbamate, or urea formation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
bromo olefins like 4 with various residues in the aromatic
moiety are not routinely accessible. In contrast to α-bromo-
styrenes, a broad variety of acetylbenzene derivatives and
acetylated heteroaromatic compounds are readily available.
Therefore, we report herein on an alternative route to
ketone 3 which starts from acetophenone (6) and has a Sha-
piro reaction as the key step. Moreover, we will report on
the utilization of building block 3 for the preparation of
3-phenyl-4-piperidones 1 with various N-substituents R by
double aza-Michael reaction.
Introduction
Successful drug development is dependent on the avail-
ability of functionalized heterocyclic building blocks with a
broad variety of aromatic and heteroaromatic substituents.
For example, 4-piperidinones 1 with an aromatic substitu-
ent in the 3-position are of enormous importance for the
preparation of biologically active compounds, mostly with
applications in medicinal chemistry.[1] Whereas the synthe-
sis of 4-piperidone derivatives with various other substitu-
tion patterns is highly developed,[2] the preparation of con-
geners 1 (Scheme 1) with an aryl substituent in particular
at the 3-position is almost unknown. Reliable procedures
are so far only found in the patent literature.[3] The most
prominent of these routes to N-substituted 3-aryl-4-piperid-
ones 1 starts from 2-arylacetic acids and proceeds in several
steps by α-methylenation, aza-Michael reaction, Dieck-
mann condensation, ester saponification and decarboxyl-
ation.[4] Since established methods for a direct α-arylation
of cyclohexanones failed, largely due to E1cb eliminations
in this heterocyclic series, we envisioned a double hetero-
Michael reaction of divinyl ketone 3 to access these target
compounds.[5] This idea is actually related to our recent Scheme 1. Divinyl ketone 3 is accessed via α-lithiostyrene (5) from
either α-bromostyrene (4) or more conveniently from acetophenone
work on tetrahydro-4-pyranones and -thiopyranones 2
(6), the latter by Shapiro reaction. Compound 3 is the key building
which we have prepared by ring closure of divinyl ketone 3
with water or H2S. In this context we have developed a
block for the preparation of 3-aryl-substituted heterocyclic ketones
1 and 2.
short and scalable access to divinyl ketone 3 with an aryl
substituent in the α-position which starts from α-bromo-
styrene (4) and proceeds via α-lithiostyrene (5).[6] However,
Results and Discussion
[a] Institut für Reine und Angewandte Chemie der Universität
Oldenburg,
Shapiro Reaction of Acetophenone
Carl von Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
Fax: +49-441-798-3873
E-mail: jens.christoffers@uni-oldenburg.de
The transformation of phenylsulfonylhydrazones with at
least 2 equiv. of n-butyllithium into lithiated alkenes is a
convenient and reliable method for the synthesis of olefins
from ketones.[7] When intermediate lithioalkenes such as 5
are converted with ketones or aldehydes, highly substituted
[b] Boehringer Ingelheim Pharma GmbH & Co. KG, Abteilung
Chemische Forschung,
Birkendorfer Str. 65, 88397 Biberach an der Riß, Germany
[‡] New address: Degussa GmbH,
Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany
4376
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4376–4382

3-Phenyl-4-piperidones from Acetophenone
FULL PAPER
allylic alcohols are obtained.[8] However, conversions with Table 1. Conditions and yields for the Shapiro reaction of hydraz-
ones 7a–7c giving allylic alcohol 8.
acrolein as a very reactive and, thus, problematic electro-
phile have, to the best of our knowledge, not been reported
so far. And indeed, conversion of the common acetophen-
one p-tosylhydrazone (7a)[9] with acrolein yielded only 17%
of allylic alcohol 8 after tedious optimization of the reac-
tion conditions (Scheme 2). In the literature the utilization
of mesitylsulfonylhydrazones is often recommended to give
superior results. Therefore, we converted the corresponding
hydrazone 7b,[10] but again the results were not satisfying
(33% yield) although the temperature at which N2 evol-
ution started was lower (5 °C instead of 23 °C). One of the
major problems in Shapiro reactions is reported to be the
ortho-lithiation of a phenylsulfonyl group or the α-lithiation
of a mesitylsulfonyl moiety. To overcome this drawback it
was suggested to use 2,4,6-triisopropylphenylsulfonylhydraz-
ones (“trisylhydrazones”) which are neither capable of α-
lithiation nor ortho-lithiation.[11] The preparation of tri-
sylhydrazine[12] and the corresponding hydrazone 7c[13] of
acetophenone are known and were well reproducible in our
hands. To our delight, deprotonation of trisylhydrazone 7c
with 2.2 equiv. of nBuLi, subsequent nitrogen elimination
and conversion with acrolein gave allylic alcohol 8 in 82%
yield. Again, the temperature at which N2 evolution started
was lower (0 °C). The yield and the purity of the crude
product after chromatography was better than that achieved
in the preparation of alcohol 8 from α-bromostyrene 4
(78%).[6] Careful control of reaction temperatures and times
is crucial for the success of these conversions which can
be conveniently monitored by gas evolution upon nitrogen
elimination. Optimal reaction conditions are listed in
Table 1.
Hydrazone
Ar
Conditions[a]
Yield of 8
7a
4-MeC6H4
1. –78 °C, 20 min
2. 23 °C, 20 min
3. –78 °C, 2 h
17%
7b
7c
2,4,6-Me3C6H2 1. –78 °C, 30 min
2. 5 °C, 30 min
33%
82%
3. 23 °C, 2 h
2,4,6-iPr3C6H2 1. –78 °C, 30 min
2. 0 °C, 15 min
3. –78 °C, 1 h
[a] Steps: 1. addition of nBuLi; 2. nitrogen elimination; 3. addition
and reaction with acrolein.
excess MnO2 is simply removed by filtration through SiO2
yielding about 90% of the crude divinyl ketone 3 which was
used directly to yield piperidones without storage or purifi-
cation.
Double Aza-Michael Reaction
Divinyl ketone 3 can be cyclized with a small excess of
primary amines 10a–10d as well as ammonia (10e) to afford
the racemic 3-aryl-4-piperidones 1a–1e (Scheme 3). Reac-
tion conditions (solvent, temperature and time) were first
optimized with benzylamine (10a). With MeCN as solvent
and at 80 °C the yield of compound 1a was 68% after a
reaction time of 1.5 h (Table 2). Comparable yields were ob-
tained with allylamine (10b) (73% of 1b), aniline (10c) (55%
of 1c) and optically active α-phenylethylamine (10d) (62%
of 1d). The latter product was obtained as a mixture of two
diastereoisomers (dr 1:1) which were not separated. Appli-
cation of aqueous ammonia (10e) gave the N-unsubstituted
product 1e, however, in low yield, which could not be im-
Further oxidation of alcohol 8 to ketone 3, our key inter-
mediate for heterocycle synthesis, was reported by us ear-
lier.[6] A key feature of this step is the high reactivity and
instability of compound 3. It can neither be stored under
ambient conditions nor at low temperatures and it cannot
be purified by chromatography without loss of material and
must therefore be directly converted after its preparation.
For this reason, we utilized an excess of MnO2 as a hetero-
geneous reagent which gives rapid conversion of alcohol 8
without the formation of any other soluble byproduct. The
progress of the reaction is conveniently monitored by TLC
Scheme 3. Ring closure of divinyl ketone 3 with amines 10 forming
3-aryl-4-piperidones 1. For substituents R, conditions and yields
and after full conversion has been achieved (10–60 min), the see Table 2.
Scheme 2. Preparation of allylic alcohol 8 by Shapiro reaction and oxidation to divinyl ketone 3. For residues Ar, the conditions and
yields of the first step see Table 1.
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4377

A. Rosiak, C. Hoenke, J. Christoffers
FULL PAPER
proved in our hands. In order to have direct access to the N-Deprotection
N-Boc-protected compound 1f we tried to perform the cy-
Since the direct preparation of unsubstituted piperidone
1e with ammonia 10e was not satisfying at all, we decided
to access this important intermediate by N-deprotection of
the N-benzyl and N-allyl compounds 1a and 1b. The latter
was achieved with catalytic amounts of RhCl3 hydrate in
EtOH/H2O at an elevated temperature,[15] however, the
yield (56%) was not entirely satisfying. More successful was
the hydrogenolytic cleavage of the N-benzyl group of com-
pound 1a with Pd/C and a drop of hydrochloric acid, which
proceeded smoothly with 97% yield. Use of 2-propanol in-
stead of ethanol as the solvent prevents ketal formation at
the carbonyl group.[16] Finally, we showed that the N-Boc
protective group installed in compound 1f can be readily
removed by a standard protocol[17] and in good yield (77%)
(Scheme 5, Table 4).
clization with tert-butyl carbamate, which unfortunately
failed completely.
Table 2. Conditions, products, and yields of double aza-Michael
reactions of 3 with primary amines.
Product
Conditions
Yield
1a, R = Bn
1b, R = Allyl
1c, R = Ph
80 °C, 1.5 h
80 °C, 1.5 h
80 °C, 3 h; then 23 °C, 16 h
68%
73%
55%
1d, R = (R)-PhCH(CH3)- 80 °C, 3 h; then 23 °C, 16 h 62% (dr 1:1)
1e, R = H
80 °C, 4 h
27%
N-Functionalization
We were interested in whether the cyclic β-aminocar-
bonyl moiety in parent compound 1e is stable under condi-
tions of N-functionalization, namely, in carbamate, amide
and urea formation. Conversion with Boc2O under stan-
dard conditions furnished the N-Boc-protected compound
1f in almost quantitative yield (Scheme 4, Table 3). DCC-
mediated amide formation with diphenylacetic acid pro-
ceeded smoothly, however, the yield was somewhat lowered
by chromatographic separation of the product 1g (76%)
from the dicyclohexylurea. Reaction of 1e with PhNCO[14]
gave urea 1h in 84% yield after chromatographic purifica-
tion. When treated with base and a solution of phosgene,
“dimeric” urea 1i was formed in 66% yield and as a mixture
of two diastereoisomers (dr 1:1).
Scheme 5. N-Deprotection yielding compound 1e. For reagents and
conditions see Table 4.
Conclusions
3-Aryl-substituted 4-piperidone derivatives 1 can be con-
veniently accessed by cyclization of divinyl ketone 3 with
primary amines 10. The N-unsubstituted compound 1e is
best prepared by hydrogenolysis of the benzyl derivative 1a
which proceeds in two steps and in 66% yield from 3. N-
Functionalization at the piperidine nitrogen atom as the
carbamate, carboxamide or urea can be achieved without
significant problems.
The Shapiro reaction of acetophenone is the method of
choice for a convenient three-step access to key intermedi-
ate divinyl ketone 3. This reaction proceeds with optimal
results when the trisylhydrazone of acetophenone is uti-
Scheme 4. N-Functionalization of piperidone 1e. For reagents and
conditions see Table 3.
Table 3. Products, reaction conditions and yields for the N-functionalization of piperidone 1e.
Product
Reagents and conditions
Yield
1f, X = OtBu
1g, X = CHPh2
a) Boc2O, cat. DMAP, MeOH, 23 °C, 30 min
b) Ph2CHCO2H, DCC, CH2Cl2, 23 °C, 20 h
c) PhNCO, toluene, 23 °C, 1 h
98%
76%
84%
1h, X = NHPh
1i, X = 4-oxo-3-phenyl-1-piperidyl
d) COCl2, NEt3, cat. DMAP, CH2Cl2, 0–10 °C, 3 h
66% (dr 1:1)
Table 4. Starting materials, reaction conditions and yields for the formation of piperidone 1e by deprotection.
Starting material
Reagents and conditions
Yield of 1e
1a, R = Bn
1b, R = Allyl
1f, R = Boc
a) 1 atm H2, cat. Pd/C, cat. HCl, iPrOH, 23 °C, 16 h
b) cat. RhCl3 hydrate, EtOH, H2O, 90 °C, 5 h
c) TFA, CH2Cl2, 23 °C, 16 h
97%
56%
77%
4378
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Eur. J. Org. Chem. 2007, 4376–4382

3-Phenyl-4-piperidones from Acetophenone
FULL PAPER
(PE/EA = 2:1, Rf = 0.25) to yield the title compound 1a (454 mg,
1.71 mmol, 68%) as a light yellow solid, m.p. 56–58 °C. H NMR
lized. This method is superior with respect to purity
and yield to a procedure published earlier starting from α-
bromostyrene.
1
(500 MHz, CDCl3): δ = 2.48–2.53 (m, 1 H), 2.61–2.69 (m, 2 H),
2.77 (dd, J = 11.5, J = 10.1 Hz, 1 H), 3.05–3.08 (m, 1 H), 3.17
(ddd, J = 11.5, J = 5.7, J = 2.4 Hz, 1 H), 3.65 (s, 2 H), 3.80 (dd, J
= 9.8, J = 5.7 Hz, 1 H), 7.20–7.37 (m, 10 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 40.76 (CH2), 53.50 (CH2), 56.40 (CH),
59.78 (CH2), 61.98 (CH2), 127.20 (CH), 127.40 (CH), 128.41 (2
CH), 128.43 (2 CH), 128.93 (2 CH), 128.96 (2 CH), 136.76 (C),
Experimental Section
General Methods: Preparative column chromatography was carried
out using Merck SiO2 (0.035–0.070 mm, type 60 A) with hexanes
(PE, b.p. 40–60 °C) and ethyl acetate (EA) as eluents. TLC was
performed on Merck SiO2 F254 plates on aluminium sheets; we rec-
ommend use of molybdophosphoric acid reagent to visualize spots.
1H and 13C NMR spectra were recorded with Bruker Avance DRX
500, Avance DPX 300, and AC 250 spectrometers. Multiplicities
were determined with DEPT experiments. EI-MS and HRMS data
were obtained with a Finnigan MAT 95 spectrometer. IR spectra
were recorded with a Bruker Tensor 27 spectrometer equipped with
a “GoldenGate” diamond-ATR unit. Elemental analyses were per-
formed with an EA 1108 from Fisons Instruments. All starting ma-
terials were commercially available except for hydrazones 7a,[9]
7b,[10] and 7c[13] which were prepared according to literature pro-
cedures. Experimental data for compounds 3 and 8 were reported
by us earlier.[6] Procedures using nBuLi (2 moldm–3 solution in pen-
tane, Aldrich) were performed in flame-dried glassware and with
absolute solvents under nitrogen. Acrolein was freshly distilled
prior to use. MnO2 (active) was used as obtained from Fluka.
137.93 (C), 208.10 (C=O) ppm. IR (ATR): ν = 3060 (w), 3028 (w),
˜
2904 (w), 2804 (w, br.), 1717 (vs), 1602 (w), 1494 (m), 1453 (m),
1353 (m), 1183 (w), 1126 (w), 736 (w), 699 (m) cm–1. MS (EI,
70 eV): m/z (%) = 265 (93) [M]+, 174 (9), 146 (12), 118 (10), 104
(29), 91 (100), 65 (9), 42 (14). C18H19NO (265.35): calcd. C 81.48,
H 7.22, N 5.27; found C 81.08, H 7.25, N 5.28.
1-Allyl-3-phenyl-4-piperidone (1b): Allylamine (10b) (160 mg,
2.80 mmol) was added to a solution of divinyl ketone 3 (300 mg,
1.89 mmol) in MeCN (4 mL). The mixture was stirred in a tightly
closed reaction flask at 80 °C for 1.5 h, then water (20 mL) and EA
(20 mL) were added, the layers were separated and the aqueous
phase was extracted (EA, 20 mL). The combined organic layers
were dried (MgSO4). After filtration, the solvent was evaporated
and the residue purified by chromatography on SiO2 (PE/EA = 1:2,
Rf = 0.31) to yield the title compound 1b (297 mg, 1.38 mmol,
1
73%) as a yellow oil. H NMR (500 MHz, CDCl3): δ = 2.48–2.76
(m, 4 H), 3.09–3.24 (m, 4 H), 3.80 (dd, J = 10.4, J = 5.7 Hz, 1 H),
5.19 (dm, J = 10.1 Hz, 1 H), 5.22 (dq, J = 17.1, J = 1.6 Hz, 1 H),
5.92 (ddt, J = 17.1, J = 10.6, J = 6.1 Hz, 1 H), 7.19–7.36 (m, 5 H)
ppm. 13C{1H} NMR (62 MHz, CDCl3): δ = 40.78 (CH2), 53.54
(CH2), 56.38 (CH), 59.83 (CH2), 60.57 (CH2), 118.45 (CH2), 127.24
(CH), 128.44 (2 CH), 128.94 (2 CH), 134.72 (CH), 136.66 (C),
2-Phenyl-1,4-pentadien-3-ol (8): Under the exclusion of moisture
and air, a solution of nBuLi (2.8 mL, 5.6 mmol, c = 2 moldm–3 in
pentane) was at –78 °C added dropwise to a solution of trisylhydraz-
one 7c (1.00 g, 2.50 mmol) in abs. THF (8 mL). The resulting mix-
ture was further stirred at –78 °C for 30 min, then warmed to 0 °C
and stirred for 15 min at this temperature (rapid nitrogen evol-
ution), and again cooled to –78 °C. Freshly distilled acrolein
(520 mg, 9.3 mmol) was added and the resulting mixture sub-
sequently stirred at –78 °C for 1 h. Finally, NaHCO3 (15 mL sat.
aqueous solution) was added and the mixture extracted with EA
(3ϫ20 mL). The combined organic layers were washed with brine
(25 mL) and dried (MgSO4). After filtration and evaporation of the
solvent, the residual oil was purified by chromatography on SiO2
[PE/EA, gradient elution from 5:1 to 2:1, Rf(5:1) = 0.35] to give
the title compound 8 (327 mg, 2.04 mmol, 82%) as a colourless oil.
All spectroscopic and analytical data are in accordance with the
literature.[6]
207.89 (C=O) ppm. IR (ATR): ν = 3028 (w), 2906 (w), 2793 (m),
˜
1717 (vs), 1642 (w), 1602 (w), 1495 (w), 1453 (w), 1418 (w), 1345
(w), 1188 (m, br.), 1124 (m), 993 (w), 923 (w), 699 (m) cm–1. MS
(EI, 70 eV): m/z (%) = 215 (100) [M]+, 118 (13), 104 (63), 96 (20),
91 (13), 82 (27), 42 (21). HRMS (EI, 70 eV): calcd. for C14H17NO
[M]+ 215.1310; found 215.1310.
1,3-Diphenyl-4-piperidone (1c): Aniline (10c) (106 mg, 1.14 mmol)
was added to a solution of divinyl ketone 3 (150 mg, 0.95 mmol)
in MeCN (2 mL). The mixture was stirred in a tightly closed reac-
tion flask at 80 °C for 3 h and at 23 °C for 16 h, then water (10 mL)
and EA (15 mL) were added, the layers were separated and the
aqueous phase was extracted (EA, 10 mL). The combined organic
layers were dried (MgSO4). After filtration, the solvent was evapo-
rated and the residue purified by chromatography on SiO2 (PE/EA
= 5:1, Rf = 0.21) to yield the title compound 1c (131 mg,
2-Phenyl-1,4-pentadien-3-one (3): Active MnO2 (3.41 g, 39.3 mmol)
was added portionwise to a solution of 8 (300 mg, 1.87 mmol) in
CH2Cl2 (10 mL) at ambient temperature. The progress of the reac-
tion was monitored by TLC [product 3: Rf(SiO2, PE/EA = 5:1) =
0.44]. After being stirred for 20 min at 23 °C, the reaction mixture
was filtered under vacuum through SiO2 to separate MnO2 and the
residue was washed several times with acetone (total ca. 100 mL).
The filtrate was concentrated under vacuum to give 3 as a yellow
oil (280 mg, 1.77 mmol, 90%), which decomposes under ambient
conditions. It can not even be stored at –5 °C. All spectroscopic
and analytical data are in accordance with the literature.[6]
1
0.52 mmol, 55%) as a yellow oil. H NMR (500 MHz, CDCl3): δ
= 2.58 (dt, J = 14.5, J = 4.4 Hz, 1 H), 2.67–2.74 (m, 1 H), 3.44
(ddd, J = 13.0, J = 10.9, J = 4.3 Hz, 1 H), 3.50 (dd, J = 13.7, J =
10.9 Hz, 1 H), 3.82 (dd, J = 10.5, J = 6.2 Hz, 1 H), 3.94–4.22 (m,
2 H), 6.87–6.90 (m, 1 H), 6.98–7.00 (m, 2 H), 7.17–7.22 (m, 2 H),
7.27–7.36 (m, 5 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
40.14 (CH2), 49.24 (CH2), 55.60 (CH2), 55.74 (CH), 115.69 (2 CH),
119.88 (CH), 127.43 (CH), 128.59 (2 CH), 128.81 (2 CH), 129.52
(2 CH), 136.07 (C), 148.70 (C), 207.02 (C=O) ppm. IR (ATR): ν
˜
1-Benzyl-3-phenyl-4-piperidone (1a): BnNH2 (10a) (400 mg,
3.73 mmol) was added to a solution of divinyl ketone 3 (400 mg,
2.53 mmol) in MeCN (3 mL). The mixture was stirred in a tightly
closed reaction flask at 80 °C for 1.5 h, then water (20 mL) and
CH2Cl2 (20 mL) were added, the layers were separated and the
aqueous phase was extracted (CH2Cl2, 2ϫ15 mL). The combined
organic layers were dried (MgSO4). After filtration, the solvent was
evaporated and the residue purified by chromatography on SiO2
= 3027 (w), 2821 (w, br.), 1714 (vs), 1599 (vs), 1498 (vs), 1453 (w),
1383 (w), 1283 (w), 1214 (m), 1032 (w), 994 (w), 753 (m), 698 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 251 (100) [M]+, 147 (19), 132 (16),
118 (13), 105 (63), 77 (15). HRMS (EI, 70 eV): calcd. for
C17H17NO [M]+ 251.1310; found 251.1308.
3-Phenyl-1-[(R)-1-phenylethyl]-4-piperidone (1d): (+)-[(R)-1-Phen-
ylethyl]amine (10d) (230 mg, 1.90 mmol) was added to a solution
Eur. J. Org. Chem. 2007, 4376–4382
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A. Rosiak, C. Hoenke, J. Christoffers
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of divinyl ketone 3 (200 mg, 1.26 mmol) in MeCN (2 mL). The
mixture was stirred in a tightly closed reaction flask at 80 °C for
3 h and at 23 °C for 16 h, then water (15 mL) and EA (15 mL) were
added, the layers were separated and the aqueous phase extracted
(EA, 10 mL). The combined organic layers were dried (MgSO4).
After filtration, the solvent was evaporated and the residue purified
by chromatography on SiO2 (PE/EA = 2:1, Rf = 0.38) to yield the
title compound 1d (217 mg, 0.78 mmol, 62%) as a yellow oil, which
was a mixture of two optically active diastereoisomers (dr 1:1 ac-
(d) By Boc Cleavage of 1f: A mixture of N-Boc-piperidone 1f
(35 mg, 0.13 mmol), CH2Cl2 (1 mL) and TFA (0.2 mL) was stirred
at 23 °C for 16 h, then CH2Cl2 (5 mL) and NaHCO3 (20 mL satd.
aqueous solution) were added. The layers were separated and the
aqueous phase was extracted with CH2Cl2 (20 mL). After drying
(MgSO4) and filtration, the combined organic layers were concen-
trated to yield the product 1e (18 mg, 0.10 mmol, 77%) as a light
yellow solid which was pure according to 1H NMR and did not
need further purification. 1H NMR (250 MHz, CDCl3): δ = 1.84
(br. s, 1 H,), 2.50–2.58 (m, 2 H), 3.15–3.18 (m, 1 H), 3.18 (dd, J =
1
1
cording to H NMR). H NMR (500 MHz, CDCl3): δ = 1.43 (d,
J = 6.7 Hz, 3 H), 1.44 (d, J = 6.5 Hz, 3 H), 2.43–2.52 (m, 2 H), 12.4, J = 10.2 Hz, 1 H), 3.40–3.55 (m, 2 H), 3.67 (dd, J = 10.9, J
2.55–2.66 (m, 4 H), 2.71 (t, J = 10.4 Hz, 1 H), 2.76 (t, J = 10.4 Hz, = 5.8 Hz, 1 H), 7.16–7.19 (m, 2 H), 7.23–7.38 (m, 3 H) ppm.
1 H), 3.04–3.08 (m, 1 H), 3.11–3.14 (m, 1 H), 3.17 (ddd, J = 11.6,
J = 5.5, J = 2.7 Hz, 1 H), 3.27 (ddd, J = 11.6, J = 5.5, J = 2.7 Hz,
13C{1H} NMR (62 MHz, CDCl3): δ = 43.38 (CH2), 47.92 (CH2),
54.31 (CH2), 59.33 (CH), 127.24 (CH), 128.51 (2 CH), 128.81 (2
1 H), 3.67 (q, J = 6.9 Hz, 1 H), 3.68 (q, J = 6.9 Hz, 1 H), 3.74 (dd, CH), 136.38 (C), 207.87 (C=O) ppm. IR (ATR): ν = 3332 (m),
˜
J = 10.0, J = 5.6 Hz, 1 H), 3.79 (dd, J = 10.0, J = 5.7 Hz, 1 H), 2956 (w), 2899 (w), 2801 (m), 1700 (vs), 1601 (w), 1452 (m), 1355
7.19–7.36 (m, 20 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = (w), 1322 (w), 1221 (m), 1161 (m), 1143 (m), 1070 (w), 920 (m),
19.12 (CH3), 19.30 (CH3), 40.92 (CH2), 41.04 (CH2), 50.41 (CH2), 833 (m), 766 (vs), 741 (m), 701 (vs) cm–1. MS (EI, 70 eV): m/z (%)
50.71 (CH2), 56.60 (CH), 56.74 (CH), 56.89 (CH2), 57.06 (CH2), = 175 (69) [M]+, 118 (7), 104 (100), 84 (13), 77 (6), 56 (11), 42 (42).
63.34 (CH), 63.44 (CH), 127.11 (CH), 127.15 (CH), 127.17 (CH),
C11H13NO (175.23): calcd. C 75.39, H 7.48, N 7.99; found C 75.10,
127.19 (CH), 127.32 (2 CH), 127.40 (2 CH), 128.35 (4 CH), 128.36 H 7.58, N 7.71.
(4 CH), 128.91 (2 CH), 128.98 (2 CH), 136.93 (C), 136.96 (C),
tert-Butyl 4-Oxo-3-phenylpiperidine-1-carboxylate (1f): A solution
142.99 (C), 143.11 (C), 208.27 (C=O), 208.30 (C=O) ppm. IR
of Boc2O (90 mg, 0.41 mmol) in MeOH (0.7 mL) was added drop-
wise to a solution of piperidone 1e (70 mg, 0.40 mmol) and DMAP
(2 mg, 16 μmol) in MeOH (1 mL). After stirring the mixture at
ambient temperature for 30 min, the solvent was evaporated and
the residue purified by chromatography on SiO2 (PE/EA = 2:1, Rf
= 0.38) to yield the title compound 1f (107 mg, 0.39 mmol, 98%)
(ATR): ν = 3027 (w), 2970 (w), 2802 (w), 1714 (vs), 1601 (w), 1492
˜
(m), 1451 (m), 1414 (w), 1207 (m), 1127 (m), 1080 (w), 1031 (w),
763 (m), 698 (s) cm–1. MS (EI, 70 eV): m/z (%) = 279 (87) [M]+,
264 (26), 175 (17), 105 (100), 91 (6), 77 (8). HRMS (EI, 70 eV):
calcd. for C19H21NO [M]+ 279.1623; found 279.1623.
1
as a colourless solid, m.p. 93–94 °C. H NMR (500 MHz, CDCl3):
3-Phenyl-4-piperidone (1e)
δ = 1.50 (s, 9 H), 2.51–2.61 (m, 2 H), 3.48–3.55 (m, 1 H), 3.50–3.66
(br. s, 1 H), 3.67–3.74 (m, 1 H), 4.12–4.20 (m, 1 H), 4.15–4.39 (br.
s, 1 H), 7.17–7.21 (m, 2 H), 7.28–7.39 (m, 3 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 28.37 (3 CH3), 40.60 (CH2), 43.49
(br., CH2), 49.23 (br., CH2), 56.31 (CH), 80.63 (C), 127.52 (CH),
128.56 (2 CH), 128.64 (2 CH), 135.52 (C), 154.39 (C=O), 206.99
(a) By Ring Closure with Ammonia: Ammonia (10e) (10 mmol,
680 mg of a 25% aqueous solution) was added to a solution of
divinyl ketone 3 (680 mg, 4.30 mmol) in MeCN (4.5 mL). The mix-
ture was stirred in a tightly closed reaction flask at 80 °C for 4 h,
then water (10 mL) and CH2Cl2 (15 mL) were added, the layers
were separated and the aqueous phase was extracted (CH2Cl2,
3ϫ10 mL). The combined organic layers were dried (MgSO4). Af-
ter filtration, the solvent was evaporated and the residue purified
by chromatography on SiO2 (MeOH/EA = 9:1, Rf = 0.25) to yield
the title compound 1e (202 mg, 1.15 mmol, 27%) as a light yellow
solid, m.p. 97–98 °C.
(C=O) ppm. IR (ATR): ν = 2979 (w), 1714 (m), 1683 (s), 1477 (m),
˜
1458 (w), 1421 (m), 1365 (m), 1309 (m), 1279 (w), 1161 (s, br.),
1123 (m), 1047 (m), 974 (w), 869 (m), 701 (s) cm–1. MS (EI, 70 eV):
m/z (%) = 275 (21) [M]+, 202 (13), 175 (37), 104 (87), 84 (10), 57
(100), 41 (14). C16H21NO3 (275.35): calcd. C 69.79, H 7.69, N 5.09;
found C 69.50, H 7.89, N 4.96.
(b) By Hydrogenation of 1a: A mixture of benzylpiperidone 1a
(100 mg, 0.38 mmol), Pd/C (5% Pd, 40 mg), concd. hydrochloric
acid (ca. 0.02 mL) and iPrOH (5 mL) was degassed (three cycles of
freeze, pump and thaw) and then stirred at 23 °C under 1 atm of
H2 for 16 h. After filtering off the catalyst (washing with MeOH)
and evaporation of the solvent, the residue was suspended in
CH2Cl2 (20 mL) and washed with NaHCO3 (20 mL satd. aqueous
solution). The aqueous phase was extracted with CH2Cl2
(3ϫ20 mL). The combined organic layers were dried (MgSO4). Af-
ter filtration, the solvent was evaporated to yield the title com-
pound 1e (65 mg, 0.37 mmol, 97%) as a light yellow solid.
1-(Diphenylacetyl)-3-phenyl-4-piperidone (1g): DCC (60 mg,
0.29 mmol) and diphenylacetic acid (62 mg, 0.29 mmol) were added
to a solution of piperidone 1e (50 mg, 0.29 mmol) in CH2Cl2
(2.5 mL). The mixture was stirred at ambient temperature for 20 h,
then the solvent was evaporated and the residue purified by
chromatography twice on SiO2 (PE/EA = 1:1, Rf = 0.46) to yield
the title compound 1g (81 mg, 0.22 mmol, 76%) as a colourless oil.
A doubled signal set is observed in the NMR spectra which is due
1
to two rotamers (A/B = 1:0.7 according to H NMR integration).
1H NMR (500 MHz, CDCl3); isomer A: δ = 2.54–2.57 (m, 2 H),
2.86 (dd, J = 11.2, J = 6.0 Hz, 1 H), 3.19–3.28 (m, 1 H), 3.53 (dd,
(c) By N-Deallylation of 1b: RhCl3·2.3H2O (18 mg, 72 μmol) was J = 13.6, J = 11.3 Hz, 1 H), 4.22 (ddd, J = 13.7, J = 6.0, J =
added to a solution of allylpiperidone 1b (100 mg, 0.46 mmol) in
EtOH/H2O (2 mL/1.5 mL). The mixture was stirred in a tightly
closed reaction flask at 90 °C for 5 h, then water (5 mL), NaHCO3
(10 mL satd. aqueous solution) and CH2Cl2 (15 mL) were added,
the layers were separated and the aqueous phase was extracted
(CH2Cl2, 3ϫ10 mL). The combined organic layers were dried
(MgSO4). After filtration, the solvent was evaporated and the resi-
due purified by chromatography on SiO2 (MeOH/EA = 9:1, Rf =
0.25) to yield the title compound 1e (45 mg, 0.26 mmol, 56%) as a
yellow solid.
2.7 Hz, 1 H), 4.84–4.89 (m, 1 H), 5.27 (s, 1 H), 6.71–6.74 (m, 2 H),
7.15–7.44 (m, 13 H) ppm; isomer B: δ = 2.04 (ddd, J = 15.0, J =
9.7, J = 5.8 Hz, 1 H), 2.26 (dt, J = 15.0, J = 4.7 Hz, 1 H), 3.62
(ddd, J = 13.6, J = 9.7, J = 4.2 Hz, 1 H), 3.67–3.73 (m, 2 H), 4.02
(ddt, J = 13.5, J = 2.0, J = 5.5 Hz, 1 H), 4.57–4.64 (m, 1 H),
5.30 (s, 1 H), 7.15–7.44 (m, 15 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3); isomer A: δ = 40.64 (CH2), 42.23 (CH2), 51.71 (CH2),
55.11 (CH), 56.60 (CH), 127.12 (CH), 127.70 (2 CH), 128.38 (2
CH), 128.59 (2 CH), 128.72 (2 CH), 128.81 (2 CH), 129.10 (2 CH),
129.38 (2 CH), 134.82 (C), 138.56 (C), 139.13 (C), 170.47 (C=O),
4380
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4376–4382

3-Phenyl-4-piperidones from Acetophenone
FULL PAPER
205.85 (C=O) ppm; isomer B: δ = 40.11 (CH2), 45.15 (CH2), 47.07
(CH2), 55.13 (CH), 55.86 (CH), 127.21 (CH), 127.44 (CH), 127.60
(CH), 128.44 (2 CH), 128.62 (2 CH), 128.69 (2 CH), 128.86 (2 CH),
128.87 (2 CH), 128.92 (2 CH), 134.96 (C), 138.78 (C), 138.91 (C),
[1]
a) K. Hohenlohe-Oehringen, Monatsh. Chem. 1965, 96, 262–
265; b) H. Ott, R. Süess, German Patent, DE 2123328, 1971
[Chem. Abstr. 1972, 76, 72495]; c) H. Ott, R. Süess, German
Patent, DE 2352909, 1974 [Chem. Abstr. 1974, 81, 25645]; d)
D. Flockerzi, K. Klemm, H. Amschler, V. Figala, R. Beume,
D. Häfner, G. Hanauer, M. Eltze, C. Schudt, U. Kilian, World
Patent, WO 9117991 A1, 1991 [Chem. Abstr. 1992, 116,
151742]; e) R. Engelstätter, R. Beume, U. Kilian, C. Schudt,
R. Riedel, H. Amschler, D. Flockerzi, German Patent, DE
4310050 A1, 1993; [Chem. Abstr. 1994, 120, 45952].
170.64 (C=O), 206.25 (C=O) ppm. IR (ATR): ν = 3027 (w), 2871
˜
(w), 1714 (s), 1639 (vs), 1600 (m), 1494 (m), 1451 (m), 1427 (m,
br.), 1366 (m), 1210 (m), 1125 (w), 1080 (w), 1057 (w), 1002 (w),
827 (m), 743 (m), 694 (vs), 610 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 369 (38) [M]+, 202 (62), 167 (100), 104 (12), 28 (29). HRMS (EI,
70 eV): calcd. for C25H23NO2 [M]+ 369.1729; found 369.1727.
[2]
a) S. Cicchi, J. Revuelta, A. Zanobini, M. Betti, A. Brandi,
Synlett 2003, 2305–2308; b) R. Shintani, N. Tokunaga, H. Doi,
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Patent, DE 4217401 A1, 1993 [Chem. Abstr. 1993, 118, 254760].
3-Phenyl-1-(phenylaminocarbonyl)-4-piperidone
(1h):
PhNCO
(68 mg, 0.65 mL, 0.57 mmol) was added to a solution of piperidone
1e (100 mg, 0.57 mmol) in toluene (1 mL). The resulting mixture
was stirred at 23 °C for 1 h, then water (5 mL) was added and the
mixture extracted with EA (2ϫ10 mL). The combined organic lay-
ers were dried (MgSO4) and the solvent was evaporated after fil-
tration. The residue was purified by chromatography on SiO2 [PE/
EA, gradient elution from 5:1 to 2:1, Rf(2:1) = 0.17] to give the
title compound 1h (140 mg, 0.48 mmol, 84%) as a colourless oil.
1H NMR (500 MHz, CDCl3): δ = 2.64–2.74 (m, 2 H), 3.63–3.68
(m, 2 H), 3.80–3.83 (m, 1 H), 4.16–4.18 (m, 1 H), 4.26 (dd, J =
13.0, J = 5.4 Hz, 1 H), 6.54 (s, 1 H), 7.07 (t, J = 7.1 Hz, 1 H), 7.18
(d, J = 7.4 Hz, 1 H), 7.29–7.38 (m, 8 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 40.45 (CH2), 43.59 (CH2), 49.52 (CH2),
56.04 (CH), 120.17 (2 CH), 123.63 (CH), 127.80 (CH), 128.60 (2
CH), 128.81 (2 CH), 128.99 (2 CH), 135.16 (C), 138.50 (C), 154.68
[3]
[4]
[5]
a) A. Lindenmann, R. Süess, French Patent, FR 1542649, 1968
[Chem. Abstr. 1969, 71, 124400]; b) A. Lindenmann, R. Süess,
French Patent, FR 6827, 1969 [Chem. Abstr. 1971, 74, 53760].
(C=O), 206.27 (C=O) ppm. IR (ATR): ν = 3314 (w, br.), 3031 (w),
˜
2873 (w), 1713 (s), 1637 (s), 1595 (s), 1530 (vs), 1498 (m), 1442 (s),
1384 (m, br.), 1310 (m), 1236 (s), 1156 (w), 1133 (m), 1076 (m),
1024 (m), 998 (m), 966 (m), 922 (m), 750 (s), 693 (vs) cm–1. MS
(EI, 70 eV): m/z (%) = 294 (14) [M]+, 175 (100), 119 (14), 104 (91),
84 (12). HRMS (EI, 70 eV): calcd. for C18H18N2O2 [M]+ 294.1368;
found 294.1368.
a) B. B. Snider, T. C. Harvey, Tetrahedron Lett. 1995, 36, 4587–
4590; b) F. Hughes, R. B. Grossman, Org. Lett. 2001, 3, 2911–
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Org. Lett. 2003, 5, 2141–2144; e) T. C. Wabnitz, J.-Q. Yu, J. B.
Spencer, Chem. Eur. J. 2004, 10, 484–493; f) M. J. Lee,
K. Y. Lee, J. N. Kim, Bull. Korean Chem. Soc. 2005, 26, 477–
480; g) S. Dörrenbacher, U. Kazmaier, S. Ruf, Synlett 2006,
547–550.
1,1Ј-Carbonylbis(4-oxo-3-phenylpiperidine) (1i): Under nitrogen a
solution of COCl2 (0.28 mL, 0.55 mmol, c = 2.0 moldm–3 in tolu-
ene), NEt3 (111 mg, 1.1 mmol) and DMAP (1 mg, 8 μmol) were
added to a cooled (ice/water bath) solution of piperidone 1e
(180 mg, 1.0 mmol) in abs. CH2Cl2 (3.5 mL). After stirring at 23 °C
for 3 h, the mixture was poured into water (15 mL) and extracted
with CH2Cl2 (4ϫ10 mL). After drying (MgSO4) and filtration, the
solvent was evaporated and the residue purified by chromatography
(SiO2, PE/EA = 1:2, Rf = 0.67) to give the title compound 1i
(123 mg, 0.33 mmol, 66%) as a yellow oil, which consisted of two
racemic diastereoisomers (1:1 according to 1H NMR). 1H NMR
(300 MHz, CDCl3): δ = 2.61 (t, J = 5.6 Hz, 4 H), 3.52–3.78 (m, 6
H), 4.27–4.43 (m, 4 H), 7.07–7.10 (m, 4 H), 7.25–7.35 (m, 6 H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 39.82 (CH2), 40.11
(CH2), 44.97 (CH2), 47.45 (CH2), 50.03 (CH2), 52.80 (CH2), 55.40
(CH), 55.92 (CH), 127.98 (2 CH), 128.42 (2 CH), 128.86 (6 CH),
[6]
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a) A. Rosiak, W. Frey, J. Christoffers, Eur. J. Org. Chem. 2006,
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a) P. Grammaticakis, C. R. Seances Acad. Sci., Ser. C 1967,
264, 2067–2070 [Chem. Abstr. 1967, 67, 108368]; b) R. J. Crem-
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1978, 43, 147–154; b) A. S. Kende, L. N. Jungheim, Tetrahedron
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[8]
[9]
134.20 (2 C), 148.60 (C=O), 204.58 (2 C=O) ppm. IR (ATR): ν =
˜
3031 (w), 2888 (w, br.), 1717 (vs), 1644 (w), 1498 (w), 1467 (w),
1453 (w), 1408 (m), 1383 (m), 1269 (w), 1222 (m), 1204 (m), 1178
(m), 1082 (w), 1049 (m), 854 (w), 764 (w), 701 (m), 662 (m), 631
(s) cm–1. MS (EI, 70 eV): m/z (%) = 376 (22) [M]+, 272 (6), 202
(68), 175 (21), 146 (16), 104 (100), 77 (34). HRMS (EI, 70 eV):
calcd. for C23H24N2O3 [M]+ 376.1787; found 376.1787.
[10]
[11]
Acknowledgments
[12]
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N. J. Cusack, C. B. Reese, A. C. Risius, B. Roozpeikar, Tetrahe-
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432.
This work was supported by the Fonds der Chemischen Industrie.
Thanks are due to Dr. Patrick Tielmann for helpful comments.
Eur. J. Org. Chem. 2007, 4376–4382
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4381

A. Rosiak, C. Hoenke, J. Christoffers
FULL PAPER
[14] a) J. Habermann, S. V. Ley, J. S. Scott, J. Chem. Soc. Perkin
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Schnider, World Patent, WO 062784 A1, 2002 [Chem. Abstr.
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Received: April 12, 2007
Published Online: July 5, 2007
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Chem. 2004, 2701–2706; b) S. Kolczewski, S. Roever, P.
4382
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4376–4382