Stereoselective α-amidoalkylation of phenylglycinol-derived lactams. Synthesis of enantiopure 5,6-disubstituted 2-piperidones

Article abstract of DOI:10.1016/j.tetasy.2006.05.018

The stereochemical outcome of α-amidoalkylation reactions of chiral nonracemic bicyclic lactams 2b and 2c with indole, allyltrimethylsilane, TMSCN and Grignard reagents to gain access to enantiopure 5,6-disubstituted 2-piperidones is discussed.

Full text of DOI:10.1016/j.tetasy.2006.05.018

Tetrahedron: Asymmetry 17 (2006) 1581–1588
Stereoselective a-amidoalkylation of phenylglycinol-derived
lactams. Synthesis of enantiopure 5,6-disubstituted 2-piperidones
a
a
a
a
Mercedes Amat,a, Carmen Escolano, Arantxa Gomez-Esque, Oscar Lozano, Nuria Llor,
´
*
´
´
Rosa Griera,a Elies Molinsb and Joan Boscha
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
b
`
Institut de Ciencia de Materials de Barcelona (CSIC), Campus UAB, 08193-Cerdanyola, Spain
Received 15 May 2006; accepted 19 May 2006
Abstract—The stereochemical outcome of a-amidoalkylation reactions of chiral nonracemic bicyclic lactams 2b and 2c with indole, allyl-
trimethylsilane, TMSCN and Grignard reagents to gain access to enantiopure 5,6-disubstituted 2-piperidones is discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tion, that is, next to the electrophilic carbon of the oxazol-
idine ring.
Owing to the relevance of piperidine-containing bioactive
compounds, the development of new methodologies giving
access to diversely substituted enantiopure piperidines con-
tinues to be a subject of considerable interest.1 In previous
papers, we have reported the stereoselective synthesis of 6-
substituted 2-piperidones by a-amidoalkylation reactions
of the simple trans H3–H8a (R)-phenylglycinol-derived lac-
tam 1.2 We demonstrated that carbon nucleophiles in the
presence of Lewis acids, such as TiCl4 and BF3ÆEt2O, lead
to compounds with an inversion of configuration at the C-
8a stereocentre, whereas Grignard reagents afford 6-substi-
tuted 2-piperidones with retention of configuration
(Scheme 1).3 Moreover, we observed that the cis-epimer
of lactam 1, under the same reaction conditions, gave com-
plex mixtures or starting materials.
2. Results and discussion
2.1. Preparation of C-8 substituted bicyclic lactams
Cyclocondensation of (R)-phenylglycinol with racemic
methyl 4-formylhexanoate stereoselectively afforded the
cis H3–H8a lactam 2a, through a process that involves dy-
namic kinetic resolution of the racemic substrate. Minor
amounts of the trans H3–H8a isomer 2b and, in some cases,
its C-8a epimer 2c were also formed.4 Thus, when a toluene
solution of methyl 4-formylhexanoate and (R)-phenylgly-
cinol was heated at reflux, a 63:25:12 mixture of isomers
2a, 2b and 2c, respectively, was formed. However, when
an Et2O solution of starting materials containing anhy-
drous Na2SO4 was stirred at 0 °C and the resulting mixture
heated under vacuum (10–15 mmHg) at 70 °C, lactams 2a
and 2b were isolated in a 90:10 ratio, respectively (see
Scheme 2).
Herein we report the extension of the above methodology
from chiral lactams bearing a substituent at the C-8 posi-
C6H5
C6H5
O
C6H5
O
R
Inversion
Retention
OH
R
OH
R
3
R
C6H5
C6H5
C6H5
C6H5
[A] CH2=CHCH2SiMe3,
indole or TMSCN, TiCl4
O
OH
N
O
N
N
8a
RMgX, THF
NH2
O
H
O
O
O
O
N
O
N
O
N
[B] R2Cu(CN)Li2, BF3·Et2O
i
8a
8a
8a
1
MeO2C
Racemate
8
8
8
2a
2b
2c
Scheme 1.
Scheme 2. Reagents and conditions: (i) toluene, reflux, 18 h, 80% (2a/2b/
2c 63:25:12) or Et2O, anhyd Na2SO4, 0 °C, 1 h, then 70 °C, 10–15 mmHg,
76% (2a/2b ratio 90:10).
*
Corresponding author. Tel.: +34 93 4024540; fax: +34 93 4024539;
e-mail: amat@ub.edu
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.018

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M. Amat et al. / Tetrahedron: Asymmetry 17 (2006) 1581–1588
Table 1. Equilibration of lactam 2a
C6H5
C6H5
O
C6H5
C6H5
O
OH
OH
OH
Reagents and conditions
2a
2b
2c
O
O
N
N
O
N
N
Acid
TiCl4 (2 equiv), CH2Cl2, 7 h, reflux
TFA (10 equiv), CH2Cl2, 24 h, reflux
TFA (10 equiv), CH2Cl2, 64 h, reflux
3 N MeOH–HCl, 25 h, 25 °C
64
60
57
28
4
5
14
70
32
35
29
2
A
B
C
2a
C6H5
C6H5
O
O
O
N
O
N
As could be expected from previous observations,2c all at-
tempts to carry out a-amidoalkylation reactions from lac-
tam 2a using a variety of conditions failed. In all cases,
only starting material was recovered, thus confirming the
reluctance of cis H3–H8a phenylglycinol-derived lactams
to undergo a-amidoalkylation reactions.
2c
2b
Scheme 3.
2.2. a-Amidoalkylation reactions of lactams 2b and 2c
To gain access to trans H3–H8a bicyclic lactams, we studied
the isomerization of the major cis-isomer 2a under acidic
conditions (Table 1). Heating at reflux temperature a
CH2Cl2 solution of 2a in the presence of TiCl4 or TFA
for 7 or 24 h, respectively, brought about isomerization
of the C-8a stereocentre, affording mixtures of 2a and 2c
in a diastereomeric ratio of about 2:1, along with minor
amounts of 2b. When the solution of 2a and TFA was
heated for longer reaction times (64 h), an increase in the
ratio of the isomer 2b was observed. Finally, changing
the acidic conditions to a 3 M HCl methanolic solution
dramatically increased the ratio of isomer 2b, which be-
came the major product, and only trace amounts of 2c were
detected. This isomerization can be rationalized by taking
into account that trans H3–H8a (R)-phenylglycinol-derived
lactams, such as 2b and 2c, are more stable than the cis-iso-
mers5 and that, due to the conformational rigidity of the
bicyclic system, the ethyl substituent is pseudoaxial in iso-
mer 2c, whereas in 2b it is pseudoequatorial. Under acidic
conditions, fragmentation of the C–O bond of cis lactam 2a
takes place, leading to acyliminium cation A, which, after
closure of the oxazolidine ring, affords the trans-isomer
2c. A is in equilibrium with its epimer C through the acyl
enamine B. Closure of the oxazolidine ring from C gives
the trans-isomer 2b (Scheme 3).6
Lactam 2b proved to be more reluctant to undergo a-amid-
oalkylation than the analogous de-ethyl bicyclic lactam 1.
In fact, all attempts to carry out reactions on 2b using high-
er order cyanocuprates [R2Cu(CN)Li2] under acidic condi-
tions failed, while the other amidoalkylations studied
(Table 2) required longer reaction times or higher temper-
atures than those needed for 1.
The reaction of 2b with indole in the presence of TiCl4 led
exclusively to trans-5-ethyl-6-indolylpiperidone 3a, in
which the configuration at the C-8a position remained
unchanged (entry 1). However, the addition of allyltrimeth-
ylsilane using the same Lewis acid occurred with an inver-
sion of configuration, to afford a cis-5,6-disubstituted
piperidone 4b (entry 2). A similar stereochemical result
was observed when trimethylsilyl cyanide was used as the
nucleophile. In this case, after a longer reaction time
(22 h), cis-isomer 5b was obtained in moderate yield along
with starting material (entry 3). In contrast, a-amidoalkyl-
ation of lactam 2b using alkyl (entries 5 and 6), aryl (entry
7), vinyl (entry 8) or allyl (entry 9),7 Grignard reagents
took place with retention of the configuration at the C-8a
stereocentre, stereoselectively affording the corresponding
5,6-trans isomers a.
Table 2. Stereoselective a-amidoalkylation reactions from lactam 2b
C6H5
C6H5
O
C6H5
OH
R
OH
R
O
8a
O
N
N
O
N
Reagent
a
b
2b
Entry
Reagents
R
Yield (%)
Producta
1
2
3
4
5
6
7
8
9
Indole, TiCl4
3-In
CH2–CH@CH2
CN
77
83
37
76
63
66
74
43
33b
3a
4b
5b
6a
7a
8a
9a
10a
4a
CH2@CH–CH2SiMe3, TiCl4
TMSCN, TiCl4
CH3MgCl
EtMgBr
n-PrMgBr
C6H5MgBr
CH2@CHMgBr
CH2@CH–CH2MgBr
CH3
CH2CH3
CH2CH2CH3
C6H5
CH@CH2
CH2–CH@CH2
a a:b (or b:a for 4 and 5) ratio >95:5.
b The triallylated product 4c was isolated in 34% yield (see Section 4).

M. Amat et al. / Tetrahedron: Asymmetry 17 (2006) 1581–1588
1583
we next studied some a-amidoalkylation reactions upon
lactam 2c, the C-8 epimer of 2b.
Ti
X
R
C6H5
H
H
Mg
Retention
Inversion
O
O
H
O
H
O
H
H
RMgX
N
TiCl4
N
C6H5
N
O
C6H5
O
H8a
In accordance with the above results, the reaction of lactam
2c with either indole or allyltrimethylsilane in the presence
of TiCl4 also took place with inversion of the C-8a stereo-
centre to give the respective trans-5,6-disubstituted piperi-
dones 11b and 12b (Table 3; entries 1 and 2), whereas
phenylmagnesium bromide afforded the cis-isomer 13a (en-
try 3), with retention of the configuration.
2b
H
Nu
Scheme 4.
The stereochemical outcome of the above a-amidoalkyl-
ations can be explained by considering that, when a Lewis
acid such as TiCl4, is used (entries 2 and 3), the reaction
takes place through an acyliminium species, which under-
goes attack of the nucleophile from the less hindered face
to give cis-products b (Scheme 4). An explanation for the
opposite stereoselectivity in the reaction with indole (entry
1) is that the stereogenic centre at the 6-position in 6-(3-
indolyl)-2-piperidones is configurationally labile under
acidic conditions,2a,8 ultimately leading to the thermo-
dynamically more stable trans-5-ethyl-6-(3-indolyl) isomer.
The absolute configuration of the stereogenic centre gener-
ated in the above a-amidoalkylation reactions leading to
5,6-disubstituted piperidones 3–13 was assigned (Table 4)
by correlation of their NMR data with those reported for
their respective 5-de-ethyl derivatives.2 The configuration
of 7a was unambiguously confirmed by X-ray crystallo-
graphic analysis9 (Fig. 1).
2.3. Synthesis of enantiopure cis- and trans-5,6-disubstituted
2-piperidones
In contrast, Grignard reagents coordinate with the oxygen
atom of the oxazolidine ring, weakening the C–O bond.
The subsequent delivery of the alkyl or aryl group on the
incipient acyliminium salt takes place from the same face
of the C–O bond, affording 5,6-trans products a, with
retention of the configuration at the C-8a stereocentre.
Consequently, the pseudoequatorial ethyl substituent in
lactam 2b does not modify the stereochemical outcome al-
ready observed in the a-amidoalkylation reactions from the
de-ethyl lactam 1.
With a method in hand for the expeditious preparation of
the disubstituted lactams 3–13, we undertook the removal
of the chiral inductor to gain access to enantiopure
N-unsubstituted cis- and trans-5,6-disubstituted-2-piperid-
ones.
The chemoselective reduction of the 5,6-trans piperid-
ones 3a, 7a and 9a to the corresponding N-unsubstituted
To analyze the influence of the spatial disposition of the
ethyl substituent on the stereoselectivity of the reaction,
Table 3. Stereoselective a-amidoalkylation reactions from lactam 2c
C6H5
C6H5
O
C6H5
O
OH
R
OH
R
O
8a
O
N
N
N
Reagent
a
2c
b
Entry Reagents
R
Yield Producta
(%)
1
2
Indole, TiCl4
CH2@CH–CH2SiMe3, CH2–CH@CH2 64
3-In
45
11b
12b
TiCl4
3
C6H5MgBr
C6H5
61
13a
Figure 1. X-ray structure of (5R,6S)-5,6-diethyl-1-[(1R)-2-hydroxy-1-
phenylethyl]-2-piperidone 7a.
a b:a (or a:b for 13) ratio >95:5.
Table 4. Significant 13C NMR data of C-6 substituted 5-ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-piperidones 3–13
3a
4a
4b
5b
6a
7a
8a
9a
10a
11b
12b
13a
2
3
4
5
172.8
28.5
20.8
40.0
53.5
59.8
63.0
23.2
11.5
172.5
28.5
20.3
35.5
59.0
63.0
63.7
24.4
11.5
172.0
30.8
21.8
40.8
61.0
67.2
63.8
25.4
11.6
171.0
31.1
23.2
39.0
51.0
60.6
62.0
25.0
11.1
171.8
28.5
20.5
40.5
54.4
61.7
63.0
24.2
11.3
172.6
28.6
20.6
35.1
61.6
63.1
63.9
24.6
11.5
172.3
28.5
20.7
35.6
59.1
62.5
63.4
24.5
11.4
172.0
28.7
19.8
42.4
61.4
60.0
62.1
23.7
11.3
172.3
29.0
21.0
40.2
60.7
60.2
63.0
23.7
11.3
172.5
30.0
21.2
40.1
61.4
68.1
64.9
23.9
11.4
172.0
28.9
20.3
35.6
61.4
66.3
64.4
24.5
11.4
171.6
31.5
20.7
40.7
60.9
59.9
61.9
24.9
11.3
6
10
20
CH2
CH3

1584
M. Amat et al. / Tetrahedron: Asymmetry 17 (2006) 1581–1588
C6H5
O
column chromatography and was carried out on SiO2 (sil-
OH
R
H
ica gel 60, 230–400 mesh). Melting points were determined
in a capillary tube and are uncorrected. Unless otherwise
indicated NMR spectra were recorded in CDCl3. Only
noteworthy IR absorptions (cmꢀ1) are listed. Mass spectra
(MS) data are reported as m/z (%). High resolution mass
spectra (HMRS) were performed in Unidade de Espec-
trometria de Masas, Santiago de Compostela. Microanal-
N
R
O
N
Na/NH3
3a, R = 3-In
7a, R = Et
9a, R = C6H5
10a, R = CH=CH2
14, R = 3-In, 80%
15, R = Et, 84%
16, R = C6H5, 72%
17, R = CH=CH2, 23%
´
yses were performed by Centre d’Investigacio
Desenvolupament (CSIC), Barcelona.
i
C6H5
OH
H
O
N
O
N
Na/NH3
73%
4.2. (5R,6R)-5-Ethyl-1-[(1R-2-hydroxy-1-phenylethyl]-6-
(3-indolyl)-2-piperidone, 3a
4b
18
C6H5
O
Indole (858 mg, 7.32 mmol) and TiCl4 (0.27 mL,
2.44 mmol) were added to a solution of 2b (300 mg,
1.22 mmol) in CH2Cl2 (7 mL). The mixture was stirred at
rt for 5 h. The reaction was quenched by the addition of
saturated NaHCO3, and the mixture extracted with
CH2Cl2. The combined organic extracts were dried and
concentrated, and the resulting residue chromatographed
(SiO2, EtOAc) to give 3a (340 mg, 77%): IR (NaCl) 3288,
2957, 1607 cmꢀ1; 1H NMR (300 MHz, COSY, HETCOR):
d 0.61 (t, J = 7.2 Hz, 3H, CH3CH2), 1.12–1.29 (m, 2H,
CH3CH2), 1.43 (m, 1H, H-4), 1.70 (m, 1H, H-5), 1.98 (m,
1H, H-4), 2.54–2.59 (m, 2H, H-3), 3.46 (br s, 1H, OH),
3.81–3.94 (m, 2H, H-20), 4.56 (d, J = 1.8 Hz, 1H, H-6),
6.07 (dd, J = 9.6, 5.1 Hz, 1H, H-10), 7.05–7.33 (m, 9H,
HAr), 7.40 (d, J = 8.1 Hz, 1H, HAr), 8.79 (br s, 1H,
NH); 13C NMR (75.4 MHz): d 11.5 (CH3CH2), 20.8 (C-
4), 23.2 (CH3CH2), 28.5 (C-3), 40.0 (C-5), 53.5 (C-6),
59.8 (C-10), 63.0 (C-20), 111.6 (CHAr), 117.6 (CHAr),
117.9 (CHAr), 119.3 (CHAr), 122.0 (CHAr), 122.7
(CHAr), 124.8 (CHAr, C-3a), 128.2 (CHPh), 128.5
OH
H
N
N
C6H5
C6H5
O
Na/NH3
75%
13a
19
Scheme 5.
derivatives 14, 15 and 16 was accomplished in good yields
(72–84%) with Na/liq NH3. However, under these condi-
tions vinyl piperidone 10a furnished the expected com-
pound 17 in low yield, while the major product (73%)
(4R)-4-ethyl-5-heptenamide, was formed by radical opening
of the lactam ring. A similar debenzylation from the cis-
derivatives 4b and 13a led to the respective cis-5,6-disubsti-
tuted piperidones 18 and 19 in good yields (see Scheme 5).
3. Conclusions
In conclusion, starting from racemic methyl 4-formylhex-
anoate and (R)-phenylglycinol, diversely cis- and trans-5-
ethyl-6-substituted-2-piperidones have been stereoselec-
tively prepared in enantiopure form. The key steps are a
cyclocondensation of the chiral aminoalcohol with the
racemic aldehyde–ester and a subsequent a-amidoalkyl-
ation. By choosing the appropriate nucleophile and reaction
conditions in the latter reaction we ensured the stereocon-
trolled formation of a C–C bond at the C-6 position,
providing access to either cis- or trans-5,6-disubstituted
derivatives. The presence of the C-8 ethyl substituent has
no significant effect on the stereochemical outcome of the
a-amidoalkylation reaction.
(2CHPh), 129.1 (2CHPh), 136.3, 136.5 (C i, C-7a), 172.8
22
(NCO); mp 180–181 °C (EtOAc–Et2O–MeOH); ½aꢁD
¼
ꢀ34:8 (c 1.03, MeOH); m/z 362 (M+, 21), 344 (50), 331
(66), 226 (100). Anal. Calcd for C23H26N2O2: C, 76.21;
H, 7.23; N, 7.73. Found: C, 75.84; H, 7.32; N, 7.59.
4.3. (5R,6R)-6-Allyl-5-ethyl-1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2-piperidone, 4b
Allyltrimethylsilane (1.16 mL, 7.32 mmol) and TiCl4 (0.27
mL, 2.44 mmol) were added to a solution of 2b (300 mg,
1.22 mmol) in CH2Cl2 (10 mL). The mixture was stirred
at room temperature for 23 h. The reaction was quenched
by the addition of saturated aqueous NaHCO3, and the
mixture extracted with CH2Cl2. The combined organic ex-
tracts were dried and concentrated, and the resulting resi-
due was chromatographed (FlorisilÒ, AcOEt) to give 4b
4. Experimental
4.1. General
(291 mg, 83%): IR (NaCl) 3374, 2959, 1620 cmꢀ1 1H
;
NMR (300 MHz, COSY, HETCOR): d 0.83 (t, J =
7.8 Hz, 3H, CH3CH2), 1.21–1.33 (m, 2H, CH3CH2), 1.59
(m, 1H, H-4), 1.70 (m, 1H, H-5), 1.83 (m, 1H, H-4), 2.14
(m, 1H, CH2CH@), 2.33 (m, 1H, CH2CH@), 2.53–2.59
(m, 2H, H-3), 3.28 (dd, J = 9.6, 5.4 Hz, 1H, H-6), 4.04
(dd, J = 12.0, 3.6 Hz, 1H, H-20), 4.14 (dd, J = 12.0,
6.9 Hz, 1H, H-20), 4.71 (dd, J = 6.9, 3.6 Hz, 1H, H-10),
5.00 (br s, 1H, CH2@), 5.04 (d, J = 7.2 Hz, 1H, CH2CH@),
5.70 (m, 1H, CH2@), 7.24–7.36 (m, 5H, HAr); 13C NMR
(75.4 MHz): d 11.6 (CH3CH2), 21.8 (C-4), 25.4 (CH3CH2),
All reactions were performed under either an argon or
nitrogen atmosphere with dry, freshly distilled solvents
using standard procedures. Drying of organic extracts dur-
ing the work-up of reactions was performed over anhy-
drous Na2SO4 or MgSO4. Evaporation of solvents was
accomplished with a rotatory evaporator. Thin-layer chro-
matography was carried out on SiO2 (silica gel 60 F254) or
FlorisilÒ, and the spots were located by UV and either a 1%
KMnO4 solution or iodine. Chromatography refers to flash

M. Amat et al. / Tetrahedron: Asymmetry 17 (2006) 1581–1588
1585
30.8 (C-3), 34.3 (CH2CH@CH2), 40.8 (C-5), 61.0 (C-6),
63.8 (C-20), 67.2 (C-10), 117.3 (CH@CH2), 127.4 (CHAr),
127.5 (2CHAr), 128.3 (2CHAr), 135.1 (CH@CH2), 137.1
(C i), 172.0 (NCO); m/z 288 (M++1, 21), 246 (32), 216
(2), 168 (13), 126 (100); HRMS calcd for C18H25NO2
(M++1) 288.1963, found 288.1953.
(C-5), 54.4 (C-6), 61.7 (C-10), 63.0 (C-20), 127.4 (CHAr),
128.1 (2CHAr), 128.2 (2CHAr), 137.0 (C i), 171.8
22
(NCO); mp 109–111 °C (EtOAc–Et2O); ½aꢁD ¼ ꢀ2:9 (c
0.48, MeOH); m/z 262 (M+1, 1), 243 (12), 230 (56), 216
(5). Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N,
5.36. Found: C, 73.56; H, 8.94; N, 5.28.
4.4. (5R,6S)-6-Cyano-5-ethyl-1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2-piperidone, 5b
4.5.2.
(5R,6S)-5,6-Diethyl-1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2-piperidone, 7a. Operating as described in the gen-
eral procedure, from 2b (320 mg, 1.30 mmol) and
ethylmagnesium bromide (1 M in THF, 3.90 mL,
3.90 mmol), a residue was obtained. Purification by column
chromatography (SiO2, 7:3 EtOAc–hexane to EtOAc) gave
Trimethylsilyl cyanide (0.53 mL, 4.24 mmol) and titanium
tetrachloride (0.23 mL, 2.12 mmol) were added to a solu-
tion of 2b (260 mg, 1.06 mmol) in CH2Cl2 (10 mL). The
mixture was then refluxed for 22 h. The reaction was
quenched by the addition of saturated aqueous NaHCO3,
and the mixture extracted with CH2Cl2. The combined
organic extracts were dried and concentrated, and the
resulting residue was chromatographed (FlorisilÒ, 7:3
EtOAc–hexane to EtOAc) to give 5b (107 mg, 37%) and
2b (119 mg). Compound 5b: IR (NaCl) 3404, 2963, 1640
7a (226 mg, 63%): IR (NaCl) 3372, 2960, 1618 cmꢀ1; H
1
NMR (300 MHz, COSY, HETCOR): d 0.66 (t, J =
7.5 Hz, 3H, CH3CH2), 0.79 (t, J = 7.5 Hz, 3H, CH3CH2),
1.04 (m, 1H, CH3CH2), 1.17 (m, 1H, CH3CH2), 1.46–
1.54 (m, 2H, CH2CH3), 1.55–1.60 (m, 1H, H-5), 1.68 (m,
1H, CH2CH3), 1.96 (m, 1H, H-4), 2.40–2.45 (m, 2H, H-
3), 2.87 (app d, J = 10.8 Hz, 1H, H-6), 3.59 (br s, 1H,
OH), 4.13 (dd, J = 11.4, 4.8 Hz, 1H, H-20), 4.24 (dd,
J = 11.4, 8.4 Hz, 1H, H-20), 5.31 (dd, J = 8.4, 4.8 Hz, 1H,
H-10), 7.26–7.37 (m, 5H, HAr); 13C NMR (75.4 MHz): d
10.6 (CH3CH2), 11.5 (CH3CH2), 20.6 (C-4), 24.6
(CH3CH2), 27.5 (CH2CH3), 28.6 (C-3), 35.1 (C-5), 61.6
(C-6), 63.1 (C-10), 63.9 (C-20), 128.0 (CHAr), 128.2
1
cmꢀ1; H NMR (400 MHz, COSY, HETCOR): d 0.94 (t,
J = 7.6 Hz, 3H, CH3CH2), 1.47 (m, 2H, CH3CH2), 1.74
(m, 1H, H-4), 1.91–1.98 (m, 2H, H-4, H-5), 2.55 (m, 1H,
H-3), 2.71 (dd, J = 8.0, 1.6 Hz, 1H, H-3), 3.45 (br s, 1H,
OH), 4.12 (m, 2H, H-20), 4.31 (m, 1H, H-6), 5.56 (t,
J = 5.6 Hz, 1H, H-10), 7.33–7.40 (m, 5H, HAr). 13C
NMR (100.6 MHz): d 11.1 (CH3CH2), 23.2 (C-4), 25.0
(CH3CH2), 31.1 (C-3), 39.0 (C-5), 51.0 (C-6), 60.6 (C-10),
(2CHAr), 128.4 (2CHAr), 137.0 (C i), 172.6 (NCO); mp
22
109–110 °C (EtOAc, Et2O, MeOH); ½aꢁD ¼ ꢀ48:9 (c 0.27,
62.0 (C-20), 116.0 (CN), 128.5 (CHAr), 128.6 (2CHAr),
MeOH); m/z 257 (M+ꢀH2O), 244 (72), 228 (10), 216
(20), 200 (5), 126 (60). Anal. Calcd for C17H25NO2: C,
74.14; H, 9.15; N, 5.09. Found: C, 73.94; H, 9.18; N, 4.94.
22
128.9 (2CHAr), 135.2 (C i), 171.0 (NCO); ½aꢁD ¼ ꢀ16:0
(c 0.18, MeOH); m/z 273 (M++H, 2), 254 (38), 241 (67),
225 (23), 214 (51), 120 (44). Anal. Calcd for
C16H20N2O2Æ1/3H2O: C, 69.06; H, 7.48; N, 10.07. Found:
C, 68.80; H, 7.50; N, 9.83. HRMS calcd for C16H20N2O2
272.1525, found 272.1515.
4.5.3. (5R,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-
propyl-2-piperidone, 8a. Operating as described in the
general procedure, from 2b (300 mg, 1.22 mmol) and pro-
pylmagnesium chloride (2 M in Et2O, 3.66 mL, 7.32 mmol)
a residue was obtained. Purification by column chromato-
graphy (SiO2, 7:3 EtOAc–hexane to EtOAc) gave 8a
4.5. General procedure for the reaction of lactam 2b with
Grignard reagents
(233 mg, 66%): IR (NaCl) 3376, 2958, 1620 cmꢀ1 1H
;
The Grignard reagent (6 equiv) was added to a cooled
(0 °C) solution of 2b (1 equiv) in THF (2 mL) and the mix-
ture stirred at this temperature for 18 h. The reaction was
quenched by the addition of saturated aqueous NaCl,
and the mixture extracted with EtOAc. The combined
extracts were dried and concentrated.
NMR (300 MHz, COSY, HETCOR): d 0.64 (t, J =
7.5 Hz, 3H, CH3CH2), 0.84 (t, J = 7.5 Hz, 3H, CH3CH2),
0.97–1.35 (m, 4H, 2CH3CH2), 1.51 (m, 1H, H-5), 1.55–
1.59 (m, 3H, CHCH2CH2, H-4), 1.98 (dddd, J = 13.8,
13.8, 9.0, 4.8 Hz, 1H, H-4), 2.41 (dd, J = 8.4, 5.7 Hz, 2H,
H-3), 2.98 (m, 1H, H-6), 3.96 (br s, 1H, OH), 4.13 (dd,
J = 11.4, 5.1 Hz, 1H, H-20), 4.25 (dd, J = 11.4, 8.1 Hz,
1H, H-20), 5.35 (dd, J = 8.1, 5.1 Hz, 1H, H-10), 7.26–7.34
(m, 5H, HAr); 13C NMR (75.4 MHz): d 11.4 (CH3CH2),
13.7 (CH3CH2CH2), 19.3 (CH3CH2), 20.7 (C-4), 24.5
(CH3CH2), 28.5 (C-3), 35.6 (C-5), 36.7 (CH3CH2CH2),
59.1 (C-6), 62.5 (C-10), 63.4 (C-20), 127.5 (CHAr), 128.2
4.5.1. (5R,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-
methyl-2-piperidone, 6a. Operating as described in the
general procedure, from 2b (300 mg, 1.22 mmol) and meth-
ylmagnesium chloride (3 M in THF, 2.44 mL, 7.32 mmol) a
residue was obtained. Purification by column chromatogra-
phy (FlorisilÒ, 1:1 EtOAc–hexane to EtOAc) gave 6a
(2CHAr), 128.3 (2CHAr), 137.0 (C i), 172.3 (NCO); mp
22
(243 mg, 76%): IR (NaCl) 3380, 2960, 1618 cmꢀ1
;
1H
70–71 °C (EtOAc); ½aꢁD ¼ ꢀ34:8 (c 1.03, MeOH); m/z
NMR (300 MHz, COSY, HETCOR):
d
0.66 (t,
271 (M+ꢀH2O, 4), 258 (63), 246 (3), 216 (16), 170 (21).
Anal. Calcd for C18H27NO2: C, 74.70; H, 9.40; N, 4.84.
Found: C, 74.44; H, 9.35; N, 4.78.
J = 7.2 Hz, 3H, CH3CH2), 1.03–1.21 (m, 2H, CH3CH2),
1.22 (d, J = 6.3 Hz, 3H, CH3), 1.39 (m, 1H, H-5), 1.54
(m, 2H, H-4), 2.03 (m, 1H, H-4), 2.42–2.47 (m, 2H, H-3),
3.16 (m, 1H, H-6), 3.59 (br s, 1H, OH), 4.14 (dd,
J = 11.4, 5.1 Hz, 1H, H-20), 4.25 (dd, J = 11.4, 8.7 Hz,
1H, H-20), 5.39 (dd, J = 8.1, 5.1 Hz, 1H, H-10), 7.26–7.37
(m, 5H, HAr); 13C NMR (75.4 MHz): d 11.3 (CH3CH2),
20.5 (C-4), 22.5 (CH3), 24.2 (CH3CH2), 28.5 (C-3), 40.5
4.5.4. (5R,6R)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-
phenyl-2-piperidone, 9a. Operating as described in the
general procedure, from 2b (300 mg, 1.22 mmol) and
phenylmagnesium bromide (1 M in THF, 7.32 mL, 7.32
mmol), a residue was obtained. Purification by column

1586
M. Amat et al. / Tetrahedron: Asymmetry 17 (2006) 1581–1588
chromatography (FlorisilÒ, 1:1 EtOAc–hexane to EtOAc)
(300 MHz): d 0.81 (t, J = 7.5 Hz, 3H CH3CH2), 0.89–1.40
(m, 6H), 2.05–2.21 (m, 6H), 2.58 (ddd, J = 7.2, 7.2,
3.0 Hz, 1H, H-6), 3.50 (dd, J = 10.5, 9.0 Hz, 1H, H-20),
3.63 (dd, J = 10.5, 4.5 Hz, 1H, H-20), 3.77 (dd, J = 8.7,
4.8 Hz, 1H, H-10), 5.02–5.13 (m, 6H, CH2@CH), 5.66–
5.86 (m, CH2@CH), 7.24–7.36 (m, 5H, HAr); 13C NMR
(75.4 MHz): d 12.2 (CH3), 22.4 (CH2), 22.7 (CH2), 35.2
(CH2), 37.2 (CH2), 43.1 (CH), 43.4 (CH2), 43.6 (CH2),
56.5 (C-6), 62.6 (C-10), 66.6 (C-20), 73.3 (C), 116.7
(CH@CH2), 118.3 (CH@CH2), 118.4 (CH@CH2), 127.4
(3CHAr), 128.4 (2CHAr), 133.7 (2CH@CH2), 136.5
(CH@CH2), 141.8 (C i); HRMS calcd for C24H36NO
(M++1) 354.2791, found 354.2779.
gave 9a (292 mg, 74%): IR (NaCl) 3385, 2958, 1618
1
cmꢀ1; H NMR (300 MHz, COSY, HETCOR): d 0.58 (t,
J = 7.5 Hz, 3H, CH3CH2), 1.06–1.25 (m, 2H, CH3CH2),
1.38–1.51 (m, 2H, H-4, H-5), 1.87 (m, 1H, H-4), 2.53–
2.60 (m, 2H, H-3), 2.89 (br s, 1H, OH), 3.69 (app d,
J = 6.9 Hz, 2H, H-20), 4.10 (d, J = 3.0 Hz, 1H, H-6), 5.94
(t, J = 7.8 Hz, 1H, H-10), 7.10–7.24 (m, 3H, HAr), 7.25–
7.35 (m, 7H, HAr); 13C NMR (75.4 MHz): d 11.3
(CH3CH2), 19.8 (C-4), 23.7 (CH3CH2), 28.7 (C-3), 42.4
(C-5), 60.0 (C-10), 61.4 (C-6), 62.1 (C-20), 126.6 (2CHAr),
127.3 (CHAr), 127.9 (CHAr), 128.2 (2CHAr), 128.3
(2CHAr), 128.9 (2CHAr), 136.5 (C i), 142.5 (C i), 172.0
(NCO); m/z 305 (M+ꢀH2O, 3), 292 (10), 204 (4), 117
(27), 106 (100); HRMS calcd for C21H26NO2 324.1963,
found 324.1960.
4.5.7. (5S,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-
(3-indolyl)-2-piperidone, 11b. Indole (288 mg, 2.46 mmol)
and titanium tetrachloride (0.10 mL, 0.82 mmol) were
added to a solution of 2c (100 mg, 0.41 mmol) in CH2Cl2
(5 mL). The mixture was refluxed for 3 h, TiCl4 (0.1 mL,
0.91 mmol) then added, and the mixture refluxed for an
additional 5 h. The reaction was quenched by addition of
saturated aqueous NaHCO3, and the mixture was ex-
tracted with CH2Cl2. The combined organic extracts were
dried and concentrated, and the resulting residue chro-
matographed (FlorisilÒ, 1:9 EtOAc–hexane to EtOAc) to
4.5.5. (5R,6S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-6-
vinyl-2-piperidone, 10a. Operating as described in the gen-
eral procedure, from 2b (500 mg, 2.04 mmol) and vinyl-
magnesium bromide (1 M in THF, 12.2 mL, 12.2 mmol)
a residue was obtained. Purification by column chromato-
graphy (4:1 AcOEt–hexane to EtOAc) gave 10a (240 mg,
43%): IR (NaCl) 3383, 2931, 1616 cmꢀ1
;
1H NMR
(300 MHz): d 0.58 (t, J = 7.5 Hz, 3H, CH2CH3), 0.98–
1.23 (m, 2H, CH2CH3), 1.45 (m, 1H, H-5), 1.49 (m, 1H,
H-4), 2.00 (m, 1H, H-4), 2.45 (m, 2H, H-3), 3.52 (dm,
J = 7.2 Hz, 1H, H-6), 4.07 (dd, J = 11.0, 6.0 Hz, 1H, H-
20), 4.20 (dd, J = 11.4, 9.0 Hz, 1H, H-20), 5.10–5.17 (m,
2H, CH@CH2), 5.76 (dd, J = 9.0, 6.0 Hz, 1H, H-10), 5.87
(ddd, J = 17.4, 10.5, 7.2 Hz, 1H, CH@CH2), 7.22–7.37
(m, 5H, HAr); 13C NMR (75.4 MHz): d 11.3 (CH3), 21.0
(C-4), 23.7 (CH2CH3), 29.0 (C-3), 40.2 (C-5), 60.2 (C-10),
60.7 (C-6), 63.0 (C-20), 116.3 (CH@CH2), 127.8 (CHAr),
give 11b (55 mg, 55%): IR (NaCl) 3271, 1613 cmꢀ1
;
1H
NMR (300 MHz, COSY, HETCOR): 0.77 (t,
d
J = 7.5 Hz, 3H, CH3CH2), 1.26–1.38 (m, 2H, CH3CH2),
1.48 (dd, J = 13.5, 6.5 Hz, 1H, H-4), 1.93–2.00 (m, 2H,
H-4, H-5), 2.62 (app t, J = 6.3 Hz, 2H, H-3), 3.93 (dd,
J = 12.3, 2.7 Hz, 1H, H-20), 4.07 (dd, J = 12.3, 6.6 Hz,
1H, H-20), 4.32 (dd, J = 6.6, 2.7 Hz, 1H, H-10), 4.49 (d,
J = 3.0 Hz, 1H, H-6), 7.02–7.11 (m, 3H, HAr), 7.15–7.33
(m, 6H, HAr), 7.41 (d, J = 7.8 Hz, 1H, HAr), 9.01 (br s,
1H, NH); 13C NMR (100.6 MHz): d 11.4 (CH3CH2), 21.2
(C-4), 23.9 (CH3CH2), 30.0 (C-3), 40.1 (C-5), 61.4 (C-6),
64.9 (C-20), 68.1 (C-10), 111.8 (CHAr), 115.7 (Car), 118.2
(CHAr), 119.5 (CHAr), 122.2 (CHAr), 123.0 (CHAr),
125.3 (Car), 127.5 (CHAr), 127.7 (2CHAr), 128.4
128.4 (2CHAr), 128.7 (2CHAr), 136.6 (C i), 140.4
22
(CH@CH2), 172.3 (NCO); ½aꢁD ¼ ꢀ142:2 (c 0.18, MeOH);
m/z 274 (M+, 100), 256 (25), 242 (10), 154 (62); HRMS
calcd for C17H23NO2 (M++Na) 296.162, found 296.162.
4.5.6. (5R,6S)-6-Allyl-5-ethyl-1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2-piperidone, 4a. Operating as described in the
general procedure, from 2b (100 mg, 0.41 mmol) and allyl-
magnesium bromide (1 M in Et2O, 2.45 mL, 2.45 mmol) a
residue was obtained. Purification by column chromatogra-
phy (FlorisilÒ, 7:3 EtOAc–hexane to EtOAc) gave 4a
(38 mg, 33%) and (5R,6S)-2,2,6-triallyl-5-ethyl-1-[(1R)-2-
hydroxy-1-phenylethyl]piperidine (4c; 49 mg, 34%). Com-
(2CHAr), 136.8 (Car), 137.7 (Car), 172.5 (NCO);
22
½aꢁD ¼ ꢀ5:4 (c 0.11, MeOH); m/z 344 (M+ꢀH2O, 81),
315 (17), 225 (21), 196 (63), 183 (68), 168 (100).
4.5.8. (5S,6R)-6-Allyl-5-ethyl-1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2-piperidone, 12b. Operating as described in the
preparation of 4b, from 2c (300 mg, 1.22 mmol), allyltri-
methylsilane (1.16 mL, 7.32 mmol) and TiCl4 (0.27 mL,
2.44 mmol) in CH2Cl2 (10 mL), 12b (226 mg, 64%) and 2c
(55 mg) were obtained after purification by column chro-
matography (FlorisilÒ, 1:1 EtOAc–hexane to EtOAc).
1
pound 4a: IR (NaCl) 3355, 2932, 1619 cmꢀ1; H NMR
(200 MHz): d 0.66 (t, J = 7.5 Hz, 3H, CH3CH2), 1.02–
1.33 (m, 2H, CH3CH2), 1.50–1.70 (m, 3H, 2H-4, H-5),
1.96–2.37 (m, 2H, CH2CH@), 2.47 (app dd, J = 8.4,
5.6 Hz, 2, H-3), 3.05 (dm, J = 10.2 Hz, 1H, H-6), 4.16
(dd, J = 11.5, 4.8 Hz, 1H, H-20), 4.28 (dd, J = 11.5,
8.4 Hz, 1H, H-20), 4.98–5.14 (m, 2H, CH2@CH), 5.34
(dd, J = 8.4, 4.8 Hz, 1H, H-10), 7.26–7.40 (m, 5H, HAr);
13C NMR (50.4 MHz): d 11.5 (CH3CH2), 20.3 (C-4), 24.4
(CH3CH2), 28.5 (C-3), 35.5 (C-5), 39.3 (CH2CH@), 59.3
(C-6), 63.0 (C-10), 63.7 (C-20), 117.8 (CH@CH2), 127.6
(CHAr), 128.2 (2CHAr), 128.5 (2CHAr), 134.0
(CH@CH2), 136.8 (C i), 172.5 (NCO); m/z 269
(M+ꢀH2O, 1), 246 (11), 158 (3), 126 (100). Compound
Compound 12b: IR (NaCl) 1620, 3380 cmꢀ1 1H NMR
;
(300 MHz, COSY, HETCOR): d 0.70 (t, J = 7.5 Hz, 3H,
CH3CH2), 1.15 (m, 1H, CH3CH2), 1.27 (m, 1H, CH3CH2),
1.57 (m, 1H, H-4), 1.67 (m, 1H, H-5), 1.98 (m, 1H, H-4),
2.19–2.27 (m, 2H, CH2CH@), 2.42 (dd, J = 7.8, 4.0 Hz,
1H, H-3), 2.44 (dd, J = 6.9, 4.0 Hz, 1H, H-3), 3.09 (m,
1H, H-6), 4.03 (dd, J = 12.0, 3.9 Hz, 1H, H-20), 4.25 (dd,
J = 12.0, 7.5 Hz, 1H, H-20), 4.66 (dd, J = 7.5, 3.9 Hz, 1H,
H-10), 5.00 (dq, J = 17.0, 1.8 Hz, 1H, CH2@), 5.07 (m,
1H, CH2@), 5.59 (m, 1H, CH2CH@), 7.25–7.37 (m, 5H,
HAr); 13C NMR (75.4 MHz): d 11.4 (CH3CH2), 20.3 (C-
4), 24.5 (CH3CH2), 28.9 (C-3), 35.6 (C-5), 38.5 (CH2CH@),
4c: IR (NaCl) 3042, 2930, 1618 cmꢀ1
;
1H NMR

M. Amat et al. / Tetrahedron: Asymmetry 17 (2006) 1581–1588
1587
61.4 (C-6), 64.4 (C-20), 66.3 (C-10), 118.0 (CH@CH2), 127.8
(CHAr), 119.7 (CHAr), 122.3 (CHAr), 122.7 (CHAr),
125.4 (Car), 136.6 (Car), 172.2 (NCO); m/z 242 (76), 186
(72), 143 (100). HRMS calcd for C15H18N2O, 242.1419;
found 242.1411. Anal. Calcd for C15H18N2OÆ1/3CH2Cl2:
C, 68.11; H, 6.96; N, 10.36. Found: C, 67.85; H, 6.93; N,
10.11.
(CHAr), 128.1 (2CHAr), 128.4 (2CHAr), 134.0
22
(CH@CH2), 137.4 (C i), 172.0 (NCO); ½aꢁD ¼ ꢀ19:6 (c
10.9, MeOH). Anal. Calcd for C18H25NO2Æ1/4H2O: C,
75.22; H, 8.77; N, 4.87. Found: C, 74.46; H, 8.80; N,
4.80. HMRS calcd for C18H25NO2 (M++Na) 310.177,
found 310.178.
4.6.2. (5R,6S)-5,6-Diethyl-2-piperidone, 15. Operating as
described in the general procedure, from 7a (80 mg,
0.29 mmol) in THF (5 mL) and NH3 (15 mL), a residue
was obtained. Purification by column chromatography
(SiO2, EtOAc) afforded 15 (38 mg, 84%): IR (NaCl) 3209,
2962, 1666 cmꢀ1; 1H NMR (400 MHz, COSY, HETCOR):
d 0.92 (t, J = 7.2 Hz, 3H, CH3CH2), 0.95 (t, J = 7.6 Hz,
3H, CH3CH2), 1.24 (m, 1H, CH3CH2), 1.37–1.67 (m, 5H,
H-4, H-5, CH3CH2), 1.93 (m, 1H, H-4), 2.26 (ddd,
J = 18.0, 9.6, 6.0 Hz, 1H, H-3), 2.39 (dt, J = 18.0, 4.8 Hz,
1H, H-3), 3.06 (dd, J = 10.8, 6.4 Hz, 1H, H-6), 6.36 (br s,
1H, NH); 13C NMR (100.6 MHz): d 8.9 (CH3CH2), 11.1
4.5.9. (5S,6R)-5-Ethyl-6-phenyl-1-[(1R)-2-hydroxy-1-phen-
ylethyl]-2-piperidone, 13a. Operating as described in the
general procedure for the reaction with Grignard reagents,
from 2c (300 mg, 1.22 mmol) and phenylmagnesium bro-
mide (1 M in THF, 7.32 mL, 7.32 mmol), 13a (241 mg,
61%) was obtained after purification by column chroma-
tography (FlorisilÒ, 1:1 EtOAc–hexane to EtOAc): IR
(NaCl) 3385, 2959, 1618 cmꢀ1
;
1H NMR (300 MHz,
COSY, HETCOR): d 0.63 (m, 1H, CH3CH2), 0.72 (t,
J = 7.5 Hz, 3H, CH3CH2), 1.03 (m, 1H, CH3CH2), 1.50
(m, 1H, H-5), 1.59–1.70 (m, 2H, H-4), 2.62 (ddd,
J = 18.3, 10.5, 8.1, 1H, H-3), 2.79 (ddd, J = 18.3, 7.2,
0.9 Hz, 1H, H-3), 3.5 and 3.61 (2dd, J = 11.4, 8.4 Hz,
2H, H-20), 4.14 (dd, J = 4.2, 0.6 Hz, 1H, H-6), 5.94 (d,
J = 8.4 Hz, 1H, H-10), 7.02–7.05 (m, 2H, HAr), 7.15–7.18
(m, 2H, HAr), 7.26–7.36 (m, 8H, HAr); 13C NMR
(75.4 MHz): d 11.3 (CH3CH2), 20.7 (C-4), 24.9 (CH3CH2),
31.5 (C-3), 40.7 (C-5), 59.9 (C-10), 60.9 (C-6), 61.9 (C-20),
127.6 (CHAr), 127.7 (CHAr), 127.9 (2CHAr), 128.0
(CH3CH2), 23.9, 24.1, 27.2 (2CH3CH2, C-4), 30.1 (C-3),
22
37.5 (C-5), 58.1 (C-6), 172.7 (NCO); ½aꢁD ¼ þ5:0 (c 0.08,
MeOH).
4.6.3. (5R,6R)-5-Ethyl-6-phenyl-2-piperidone, 16. Operat-
ing as described in the general procedure, from 9a
(175 mg, 0.54 mmol) in THF (10 mL) and NH3 (25 mL),
a residue was obtained. Purification by column chromato-
graphy (EtOAc) afforded 16 (79 mg, 72%): IR (NaCl) 3216,
2960, 1655 cmꢀ1; 1H NMR (300 MHz, COSY, HETCOR):
d 0.85 (t, J = 7.2 Hz, 3H, CH3CH2), 1.14 (m, 1H,
CH3CH2), 1.38 (m, 1H, CH3CH2), 1.48–1.68 (m, 2H, H-
4, H-5), 2.02 (m, 1H, H-4), 2.43 (m, 1H, H-3), 2.53 (m,
1H, H-3), 4.12 (d, J = 8.7 Hz, 1H, H-6), 5.89 (br s, 1H,
NH), 7.25–7.28 (m, 2H, HAr), 7.30–7.39 (m, 3H, HAr);
13C NMR (75.4 MHz): d 10.9 (CH3CH2), 23.8 (CH3CH2),
24.4 (C-4), 30.7 (C-3), 42.2 (C-5), 62.9 (C-6), 127.1
(2CHAr), 128.3 (2CHAr), 128.4 (2CHAr), 136.6 (C i),
22
138.1 (C i), 171.6 (NCO); ½aꢁD ¼ ꢀ126:1 (c 0.23, MeOH);
mp 124–126 °C (EtOAc–Et2O–MeOH); m/z 324 (M+,
100), 306 (25), 292 (9), 204 (47); HMRS calcd for
C21H26NO2 324.197, found 324.196.
4.6. General procedure for Na/NH3 reaction
Into
a three-necked, 100 mL round-bottomed flask
equipped with a coldfinger condenser charged with dry
ice–acetone, was condensed NH3 at ꢀ78 °C. The tempera-
ture was raised to ꢀ33 °C, and a solution of the lactam in
THF was added, followed by the addition of sodium metal
in small portions until the blue color persisted. After the
mixture was stirred at ꢀ33 °C for 5 min, the reaction was
quenched by the addition of solid NH4Cl until the blue col-
our disappeared. The mixture was stirred at rt for 4 h,
poured into water and extracted with Et2O. The combined
organic extracts were dried and concentrated to give a res-
idue, which was chromatographed.
(2CHAr), 127.9 (CHAr), 128.5 (2CHAr), 141.4 (C i),
172.7 (NCO); ½aꢁD ¼ ꢀ10:4 (c 0.27, MeOH).
22
4.6.4. (5R,6S)-5-Ethyl-6-vinyl-2-piperidone, 17. Operating
as described in the general procedure, from 10a (85 mg,
0.31 mmol) in THF (5 mL) and NH3 (15 mL), a residue
was obtained. Purification by column chromatography
(EtOAc) afforded (4R)-4-ethyl-5-heptenamide (35 mg,
73%) and 17 (11 mg, 23%). (4R)-4-Ethyl-5-heptenamide:
1H NMR (300 MHz): d 0.85 (t, J = 7.6 Hz, 3H, CH3CH2),
1.20 (m, 1H), 1.34–1.51 (m, 2H), 1.66 (dd, J = 6.6, 1.8 Hz,
3H, CH3CH@), 1.69–1.83 (m, 2H), 2.07–2.29 (m, 2H), 5.10
(m, 1H, CH@), 5.35 (m, 1H, CH@); 13C NMR (50.3 MHz):
d 11.8 (CH3), 18.0 (CH3), 28.4 (CH2), 30.7 (CH2), 34.0
(CH2), 44.4 (CH), 125.9 (CH), 134.7 (CH), 176.0 (NCO);
m/z 155 (3), 138 (5), 126 (7), 97 (21), 59 (100). Compound
17: 1H NMR (200 MHz): d 0.94 (t, J = 7.2 Hz, 3H,
CH3CH2), 1.20–2.00 (m, 6H), 2.27–2.50 (m, 1H), 3.57 (m,
1H), 5.22 (m, 2H), 5.73 (ddd, J = 17.6, 9.8, 2.2 Hz, 1H);
13C NMR (50.3 MHz): d 11.2 (CH3CH2), 24.1 (CH2),
29.8 (CH2), 30.7 (CH2), 39.7 (C-5), 61.4 (C-6), 118.1
(CH@CH2), 138.5 (CH@CH2), 172.0 (CON); m/z 153
(11), 96 (19), 69 (28), 56 (100).
4.6.1.
(5R,6R)-5-Ethyl-6-(3-indolyl)-2-piperidone,
14.
Operating as described in the general procedure, from 3a
(80 mg, 0.22 mmol) in THF (5 mL) and NH3 (15 mL), a
residue was obtained. Purification by column chromatogra-
phy (SiO2, EtOAc) afforded 14 (43 mg, 80%): IR (NaCl)
3247, 2961, 1646 cmꢀ1 1H NMR (300 MHz): d 0.85 (t,
;
J = 7.5 Hz, 3H, CH3CH2), 1.16 (m, 1H, CH2CH3), 1.38–
1.61 (m, 2H), 1.90 (m, 1H), 2.05 (m, 1H), 2.43–2.62 (m,
2H, H-3), 4.44 (d, J = 8.7 Hz, 1H, H-6), 5.90 (br s, 1H,
NH), 7.08–7.13 (m, 2H, HAr), 7.20 (t, J = 6.9 Hz, 1H,
HAr), 7.39 (d, J = 8.1 Hz, 1H, HAr) 7.59 (t, J = 7.5 Hz,
1H, HAr), 8.72 (br s, 1H, NH); 13C NMR (75.4 MHz): d
11.1 (CH3CH2), 24.5, 24.9 (CH3CH2, C-4), 30.9 (C-3),
40.9 (C-5), 56.0 (C-6), 111.6 (CHAr), 116.2 (Car), 119.0
4.6.5. (5R,6R)-6-Allyl-5-ethyl-2-piperidone, 18. Operating
as described in the general procedure, from 4b (280 mg,

1588
M. Amat et al. / Tetrahedron: Asymmetry 17 (2006) 1581–1588
0.97 mmol) in THF (10 mL) and NH3 (30 mL), a residue
was obtained. Purification by column chromatography
(SiO2, EtOAc) afforded 18 (118 mg, 73%): IR (NaCl)
References
1. (a) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1–8; (b)
Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633–640; (c) Husson, H.-P.; Royer, J. Chem. Soc. Rev.
1999, 28, 383–394; (d) Laschat, S.; Dickner, T. Synthesis 2000,
1781–1813; (e) Groaning, M. D.; Meyers, A. I. Tetrahedron
2000, 56, 9843–9873; (f) Weintraub, P. M.; Sabol, J. S.; Kane,
J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989; (g)
Toyooka, N.; Nemoto, H. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The
Netherlands, 2003; Vol. 29, pp 419–448; (h) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701–1729.
3207, 2959, 1663 cmꢀ1 1H NMR (300 MHz): d 0.95 (t,
;
J = 7.5 Hz, 3H, CH3CH2), 1.22–1.50 (m, 2H), 1.70–1.82
(m, 3H), 2.02–2.12 (m, 1H), 2.23–2.39 (m, 3H), 3.44 (m,
1H, H-6), 5.13 (m, 1H, CH2@), 5.19 (br s, 1H, CH2@),
5.65–5.82 (m, 1H, CH2CH@), 6.11 (br s, 1H, NH); 13C
NMR (75.4 MHz): d (ppm): 11.4 (CH3CH2), 20.6 and
22.4 (C-4 and CH3CH2), 28.9 (C-3), 36.0 (CH2CH@CH2),
37.0 (C-5), 54.6 (C-6), 118.5 (CH@CH2), 133.9 (CH@CH2),
22
171.9 (NCO); mp 48–50 °C (EtOAc); ½aꢁD ¼ þ48:4 (c 1.19,
2. (a) Amat, M.; Llor, N.; Bosch, J.; Solans, X. Tetrahedron 1997,
53, 719–730; (b) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.;
Bosch, J. J. Org. Chem. 2003, 68, 1919–1928; (c) Amat, M.;
MeOH). Anal. Calcd for C10H17NO: C, 71.81; H, 10.25; N,
8.37. Found: C, 71.35; H, 10.37; N, 8.17.
´
Escolano, C.; Llor, N.; Huguet, M.; Perez, M.; Bosch, J.
4.6.6. (5S,6R)-5-Ethyl-6-phenyl-2-piperidone, 19. Operat-
ing as described in the general procedure, from 13a
(95 mg, 0.29 mmol) in THF (5 mL) and NH3 (15 mL), a
residue was obtained. Purification by column chromatogra-
phy (SiO2, EtOAc) afforded 19 (45 mg, 75%): IR (NaCl)
Tetrahedron: Asymmetry 2003, 14, 1679–1683.
3. For a related study in the oxazolopyrrolidone series, see:
Baussanne, I.; Chiraroni, A.; Royer, J. Tetrahedron: Asymme-
try 2001, 12, 1219–1224.
4. Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J. Tetrahedron:
Asymmetry 1997, 8, 2237–2240.
2926, 1661 cmꢀ1 1H NMR (300 MHz): d 0.83–0.93 (m,
;
4H, CH3CH2, CH3CH2), 1.11–1.24 (m, 1H, CH3CH2),
1.62–1.79 (m, 2H), 1.96 (m, 1H), 2.43 (m, 1H, H-3), 2.52
(dt, J = 4.5, 2.7 Hz, 1H, H-3), 4.65 (dd, J = 4.5, 2.7 Hz,
1H, H-6), 6.39 (br s, 1H, NH), 7.16–7.20 (m, 2H, HAr),
7.25–7.37 (m, 3H, HAr); 13C NMR (75.4 MHz): d 11.6
(CH3CH2), 21.5 and 22.3 (C-4, CH3CH2), 29.7 (C-3),
39.3 (C-5), 60.2 (C-6), 127.3 (2CHAr), 127.6 (CHAr),
5. For a similar equilibration in the de-ethyl series, see: (a) Amat,
´
´
M.; Bosch, J.; Hidalgo, J.; Canto, M.; Perez, M.; Llor, N.;
Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org.
Chem. 2000, 65, 3074–3084; (b) Amat, M.; Llor, N.; Escolano,
´
C.; Huguet, M.; Perez, M.; Molins, E.; Bosch, J. Tetrahedron:
Asymmetry 2003, 14, 293–295.
6. For recent reviews on the chemistry of N-acyliminium ions,
see: (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817–3856; (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J.
H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–
1628.
128.1 (CHAr), 139.4 (C i), 171.9 (NCO); mp 75–77 °C
22
(EtOAc); ½aꢁD ¼ ꢀ75:6 (c 0.53, MeOH).
7. The triallyl derivative 4c, formed by attack of the Grignard
reagent to the initially formed lactam 4a, was also isolated.
8. Amat, M.; Hadida, S.; Llor, N.; Sathyanarayana, S.; Bosch, J.
J. Org. Chem. 1996, 61, 3878–3882.
9. Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 607207. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
Financial support from the Ministry of Science and Tech-
nology (Spain)-FEDER (project BQU2003-00505) and
the DURSI, Generalitat de Catalunya (Grant 2005SGR-
0603) is gratefully acknowledged. Thanks are also due
to the Ministry of Science and Technology (Spain) for a
fellowship to O.L.