Facile synthesis of δ-amino-β-ketoesters and piperidinediones via a vinylogous mannich-type reaction of brassard-type diene with aldimines without catalyst

Article abstract of DOI:10.1080/00397910902730846

The vinylogous Mannich reaction of N-tosyl-aldimines with Brassard diene proceeds at room temperature under catalyst-free conditions smoothly to give δ-amino-β-ketoesters (4b-l) in good to excellent yields, which are easily converted to piperidinediones at higher temperature. The two-step reactions could be combined in a one-pot process with toluene as a solvent and without the use of any catalyst for direct synthesis of piperidinediones (5). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910902730846

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Facile Synthesis of δ-
Amino-β-ketoesters and
Piperidinediones via a
Vinylogous Mannich-Type
Reaction of Brassard-Type
Diene with Aldimines without
Catalyst
Chun-Ling Gu a , Li Liu a , Dong Wang a & Yong-Jun
Chen a
a Beijing National Laboratory for Molecular Science,
Laboratory for Chemical Biology, Institute of
Chemistry, Chinese Academy of Sciences, Beijing,
China
Published online: 14 Jul 2009.
To cite this article: Chun-Ling Gu , Li Liu , Dong Wang & Yong-Jun Chen (2009): Facile
Synthesis of δ-Amino-β-ketoesters and Piperidinediones via a Vinylogous Mannich-
Type Reaction of Brassard-Type Diene with Aldimines without Catalyst, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:16, 2989-3002
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Synthetic Communications1, 39: 2989–3002, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730846
Facile Synthesis of d-Amino-b-ketoesters
and Piperidinediones via a Vinylogous
Mannich-Type Reaction of Brassard-Type Diene
with Aldimines without Catalyst
Chun-Ling Gu, Li Liu, Dong Wang, and Yong-Jun Chen
Beijing National Laboratory for Molecular Science, Laboratory for
Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences,
Beijing, China
Abstract: The vinylogous Mannich reaction of N-tosyl-aldimines with Brassard
diene proceeds at room temperature under catalyst-free conditions smoothly to
give d-amino-b-ketoesters (4b–l) in good to excellent yields, which are easily
converted to piperidinediones at higher temperature. The two-step reactions
could be combined in a one-pot process with toluene as a solvent and without
the use of any catalyst for direct synthesis of piperidinediones (5).
Keywords: Catalyst-free, one-pot process, piperidinedione, vinylogous Mannich
INTRODUCTION
The piperidine ring system is one of the key structural subunits of many
naturally occurring compounds as well as synthetic derivatives that
exhibit interesting biological activities and in many cases have proved
to be useful chemotherapeutic agents.[1] Among them, piperidinedione
derivatives are not only structural subunits of compounds with biological
activities, such as kinase-inhibiting, teratogenic, tumor necrosis factor-a
(TNFa)-modulatory, and antiangiogenic thalidomide agents,[2] but also
Received September 8, 2008.
Address correspondence to Li Liu, Beijing National Laboratory for Molecular
Science (BNLMS), Laboratory for Chemical Biology, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China. E-mail: lliu@iccas.ac.cn
2989

2990
C.-L. Gu et al.
are useful precursors for the synthesis of several biologically active com-
pounds.[3] These reasons have prompted a rapid growth of research
focused on the development of synthetic strategies[4,5] for these com-
pounds. One synthetic method for piperidinedione derivatives was based
on vinylogous Mannich-type reaction.[6] The venerable vinylogous
Mannich reaction is widely used as a key construction step for synthesis
of alkaloids[7] and various useful intermediates in organic synthesis.
Although the vinylogous Mannich-type reactions of N-alkyl and aryl imi-
nes with activated dienes has been reported, for which the use of a proper
catalyst such as Lewis acid[8] or Brønsted acid[9] was required, there were
very few examples of the vinylogous Mannich-type reaction of aldimines
with Brassard diene reported. Recently, Kawecki[10] has reported the
addition of chiral sulfinimines to dienolates catalyzed by trimethylsilyl
trifluoromethanesulfonate (TMSOTf) for stereoselective synthesis of
piperidinediones. Herein, we disclose the vinylogous Mannich-type
reaction of N-tosyl-aldimines with Brassard dienes without the use of
any catalyst, by which the one-pot synthesis of piperidinediones is
accomplished under the same catalyst-free conditions.
RESULTS AND DISCUSSION
At first, the reaction of N-p-methoxyphenyl-imine (1a, R¼PMP) with
O-silyl dienolate (2, Brassard-type diene) derived from 2,2-dimethyl-[1,3]-
dioxin-4-ones (3) was carried out in dichloromethane (DCM) at room
temperature in the absence of any catalyst (Scheme 1). Unfortunately,
no reaction or product 4a were observed, and the starting materials were
recovered. To our delight, when the PMP group was replaced by the tosyl
group, aldimine 1b (R¼Ts) exhibited greater reactivity for the same reac-
tion under the same catalyst-free conditions, affording the vinylogous
Mannich adduct 4b in 83% yield. On the other hand, the cyclization lead-
ing to the piperidinedione structure could take place usually as a competi-
tion reaction during the Lewis acid–catalyzed reaction of Brassard diene
with imines.[11] However, for the catalyst-free reaction of Brassard diene
Scheme 1. The reaction of aldimine 1b with 2 without catalyst.

d-Amino-b-ketoesters and Piperidinediones
2991
Table 1. Reaction of aldimine 1b with 2 without catalysta
Entry
Solventb
Yield of 4b (%)c
1
2
3
4
5
6
DCM
Toluene
Et2O
CH3CN
THF
None
83
82
78
75
72
66
aThe ratio of 1b to 2 ¼ 1=2. The reactions were performed at
rt for 30 min.
bConcentration of 1b: 0.1 mmol=1 mL.
with N-tosyl-aldimine at room temperature, no subsequent cyclization
product was detected in the reaction mixture, and the vinylogous
Mannich adduct was obtained exclusively. The vinylogous Mannich-type
reactions of 1b with 2 in different solvents and under solvent-free con-
ditions were examined further (Scheme 1, Table 1). As shown in Table 1,
DCM and toluene turned out to be the best solvents (entries 1 and 2).
Although the reaction also occurred under solvent-free conditions, the
yield was less (entry 6).
The catalyst-free vinylogous Mannich-type reactions of various
N-tosyl-aldimines 1b–l with Brassard diene 2 at room temperature proved
to be remarkably general (Scheme 2, Table 2). Aromatic aldimines were
better substrates, which provided excellent yields of the products (4b–i),
and heteroaromatic, a, b-unsaturated, and aliphatic ones were also
suitable substrates for the vinylogous Mannich-type reactions, afford-
ing the products 4j–l in good yields (Table 2, entries 9–11). The
electron-withdrawing substituents at both the 2- and 4-positions in
the phenyl ring noticeably increased the reaction rate and the yield of
the Mannich adduct, while the electron-donating ones decreased them
(Table 2, entries 2–8). The less active substrates, such as aromatic
aldehydes and ketimines, gave only traces of the Mannich adduct under
the same conditions. In all cases, no subsequent cyclization product was
detected in the reaction mixture.
Scheme 2. Catalyst-free reaction of aldimines 1b–l with 2.

2992
C.-L. Gu et al.
Table 2. Catalyst-free reaction of aldimines 1b–l with 2a,b
Entry
Time (h)
Product (R)
Yield (%)c
1
2
3
4
5
6
7
8
9
2
1
2
2.5
5
2
2.5
5
7
1
24
4b, Ph
92
Quant.
90
84
85
95
94
90
81
4c, 4-NO2-Ph
4d, 4-Cl-Ph
4e, 4-Me-Ph
4f, 4-OMe-Ph
4g, 2-Cl-Ph
4h, 2-Br-Ph
4i, 2-OMe-Ph
4j, PhCH¼CH
4k, 2-furyl
4l, i-Pr
10
11
82
72
aThe ratio of 1=2 was 1=2.
bConcentration of 1:0.1 mmol in 50 mL solvent.
cIsolated yield.
Interestingly, by just increasing the reaction temperature up to the
boiling point of toluene, the cyclization of the vinylogous Mannich pro-
duct 4b can be easily performed in the absence of any catalyst to afford
the product, N-tosyl-2,4-dioxo-1-piperidine 5b, in 65% yield (Scheme 3).
Further studies indicated that the vinylogous Mannich reaction in first
step and the cyclization in second step could be combined in a one-pot
process without the use of any catalyst. Taking the reaction of
N-tosyl-aldimines (4b) with 2 as a model reaction, the reaction conditions
for the one-pot synthesis of piperidinediones were examined. To increase
the temperature for the cyclization reaction, toluene was selected as a
solvent (Scheme 4). In this case, more solvent of toluene was added to
the reaction system because of the lesser solubility of the aldimines in
toluene, and the reaction time must be prolonged for 24h to get better
conversion in the first step (Table 3). If the reaction temperature in the
second step was less than the boiling point of toluene (105ꢀC), the reduc-
tion product (6) could be obtained instead of the cyclization products
Scheme 3. Cyclization of vinylogous Mannich product under heating.

d-Amino-b-ketoesters and Piperidinediones
2993
Scheme 4. One-pot syntheses of piperidinediones.
(entries 5 and 6). The conditions listed in Table 3, entry 4, are the optimized
reaction conditions for the one-pot synthesis of the piperidinediones.
The one-pot protocol for the synthesis of piperidinediones through
the tandem reaction proved to be general (Scheme 4, Table 4). Both the
aromatic and heteroaromatic aldimines were good substrates in this
one-pot reaction system. Except for the aldimine bearing a strong
electron-withdrawing group (e.g., NO2 group) in the phenyl ring (4c)
(Table 4, entry 2), there was no big difference between substituent types
in the 4-position of the phenyl ring (Table 4). Furthermore, the aldim-
ine with the same substituent at the 2-position gave a slightly lesser yield
than the one at the 4-position provided (Table 4, entry 4 vs. 5).
In conclusion, N-tosyl aldimines showed remarkable activity for the
vinylogous Mannich-type reaction with Brassard dienes under the
catalyst-free conditions. Just by using toluene as a solvent and simply
controlling the reaction temperature, d-amino-b-ketoesters and piperidi-
nediones could be obtained in a one-pot process without any catalyst,
respectively. The new protocol was developed for the facile and selective
synthesis of d-amino-b-ketoesters and piperidinediones derivatives in
good to excellent yields.
Table 3. Reactions of 1b with 2 in a temperature-enhancing program
Entry
Ratio of 1b=2
Temp (ꢀC) time (h)
Yield (%)a
1
2
3
4
5
6
1:2
1:2
1:1.5
1:1.2
1:1.2
1:1.2
rt=1–105=2
rt=24–105=2
rt=24–105=2
rt=24–105=2
rt=24–100=2
rt=24–90=2
<10
24
38
53
28b
26b
aIsolated yield.
bCompound 6 was obtained as the major product.

2994
C.-L. Gu et al.
Table 4. One-pot syntheses of piperidinedionesa
Entry
Aldimine (R)
Product (R)
Yield of 5 (%)b
1
2
3
4
5
6
7
4b, Ph
5b, Ph
53
44
52
52
49
57
51
4c, 4-NO2-Ph
4d, 4-Cl-Ph
4f, 4-OMePh
4i, 2-OMe-Ph
4j, PhCH¼CH
4k, 2-furyl
5c, 4-NO2Ph
5d, 4-ClPh
5f, 4-OMePh
5i, 2-OMePh
5j, PhCH¼CH
5k, 2-furyl
aRatio of 1=2: 1=1.2.
bIsolated yield.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a BrukerTensor 27 IR spectro-
1
meter. H and 13C NMR spectra were measured on a Bruker AV-300
spectrometer in CDCl3 with tetramethylsilane (TMS) as an internal stan-
dard. Mass spectra (MS) were recorded on a Bruker Dallonics Apex II
FT-ICRMS Micromass spectrometer. Melting points were measured by
a Beijing-Tike X-4 apparatus and are uncorrected. Common reagents
and materials were purchased from commercial resources and purified
before used. Brassard diene (2) and N-tosyl-aldimines (1) was synthesized
according to literature procedures.[12]
General Procedure
Typical Procedure for Catalyst-Free Vinylogous Mannich Reaction
Brassard diene 2 (45 mL, 43 mg, 0.2 mmol) was added to a solution of
N-tosyl-aldimine 1b (26 mg, 0.1 mmol) in toluene (50 mL), followed by
stirring at room temperature for 2 h. The reaction mixture was concen-
trated under reduced pressure, and the residue was purified by flash
chromatography on silica gel (elution gradient: petroleum ether=ethyl
acetate, 8=1 to 6=1) to provide the product 4b (36 mg, 92%).
Typical Procedure for One-Pot Reaction
Brassard diene 2 (55 mL, 52 mg, 0.24 mmol) was added to a solution of
N-tosyl aldimine 1b (52 mg, 0.2 mmol) in toluene (2 mL), followed by

d-Amino-b-ketoesters and Piperidinediones
2995
stirring at room temperature for 24 h and at 105ꢀC (refluxing) for 2 h. The
reaction mixture was concentrated under reduced pressure, and the
residue was purified by flash chromatography on silica gel (elution
gradient: petroleum ether=ethyl acetate, 4=1 to 2=1) to the product 5b
(36 mg, 53%).
Data
N-[2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-phenylethyl]-p-
toluenesulfonamide (4b)
A white solid, mp 130–131ꢀC. n
cmꢁ1: 3267, 1712, 1636, 1330, 1204,
CH2Cl2
max
1159, 1092; 1H NMR d ¼ 7.48 (2H, d, J ¼ 8.2 Hz), 7.16–6.97 (7H, m), 5.95
(1H, d, J ¼ 8.2 Hz), 5.20 (1H, s), 4.65 (1H, dd, J ¼ 8.2, 15.3 Hz), 2.74
(1H, dd, J ¼ 8.2, 14.7 Hz), 2.61 (1H, dd, J ¼ 6.8, 14.6 Hz), 2.32 (3H, s),
1.64 (3H, s), 1.56 (3H, s). 13C NMR d ¼ 167.2, 161.2, 143.2, 138.8,
137.4, 129.3, 128.6, 127.9, 126.9, 126.5, 107.1, 95.7, 55.3, 41.4, 25.2,
24.8, 21.4. HRMS (ESI): m=z calcd. for C21H23NO5S: 402.1370
(MþH); found: 402.1362.
N-[2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-(4-nitrophenyl)
ethyl]-p-toluenesulfonamide (4c)
A white solid, mp 132–133ꢀC. n
cmꢁ1: 3258, 1714, 1635, 1348,
CH2Cl2
max
1
1204, 1160, 1092; H NMR d ¼ 7.94 (2H, d, J ¼ 8.4 Hz), 7.43 (2H, d,
J ¼ 8.0 Hz), 7.26 (2H, d, J ¼ 8.6 Hz), 7.04 (1H, d, J ¼ 7.9 Hz), 6.63
(1H, b), 5.36 (1H, s), 4.51 (1H, b), 2.75–2.55 (2H, m), 2.29 (3H, s),
1.72 (3H, s), 1.67 (3H, s); 13C NMR d ¼ 166.3, 161.2, 147.3, 146.3,
143.8, 137.2, 129.4, 127.5, 126.8, 123.7, 107.5, 96.2, 54.6, 41.1, 25.4,
24.8, 21.3. HRMS (ESI): m=z calcd. for C21H22N2O7S: 447.1220
(M þ H); found: 447.1216.
N-[1-(4-Chlorophenyl)-2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)
ethyl]-p-toluenesulfonamide (4d)
A white solid, mp 141–143ꢀC. n
cmꢁ1: 3256, 1720, 1638, 1274, 1203,
CH2Cl2
max
1150, 1082; 1H NMR d ¼ 7.44 (2H, d, J ¼ 8.3 Hz), 7.09–7.04 (4H, m), 6.95
(2H, d, J ¼ 8.5 Hz), 6.04 (1H, d, J ¼ 8.5 Hz), 5.24 (1H, s), 4.69–4.60
(1H, m), 2.69 (1H, dd, J ¼ 8.8, 14.6 Hz), 2.56 (1H, dd, J ¼ 6.4, 14.6 Hz),
2.37 (3H, s), 1.67 (3H, s), 1.61 (3H, s). 13C NMR d ¼ 166.8, 161.1,

2996
C.-L. Gu et al.
143.5, 137.3, 137.2, 133.8, 129.4, 128.7, 127.9, 126.8, 107.2, 95.9, 54.7,
41.2, 25.3, 24.8, 21.4. HRMS (ESI): m=z calcd. for C21H22NO5SCl:
436.0980 (M þ H); found: 436.0982.
N-[2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-p-tolylethyl]-p-
toluenesulfonamide (4e)
A white solid, mp 144–145ꢀC. n
cmꢁ1: 3212, 1705, 1629, 1327, 1203,
CH2Cl2
max
1160, 1092; 1H NMR d ¼ 7.51 (2H, d, J ¼ 8.2 Hz), 7.11 (2H, d,
J ¼ 8.2 Hz), 6.96–6.86 (4H, m), 5.38 (1H, d, J ¼ 7.7 Hz), 4.62–4.54
(1H, m), 2.74 (1H, dd, J ¼ 7.8, 14.6 Hz), 2.62 (1H, dd, J ¼ 7.3, 14.6 Hz),
2.43 (3H, s), 2.36 (3H, s), 1.62 (3H, s), 1.54 (3H, s). 13C NMR
d ¼ 167.0, 160.9, 143.3, 138.0, 137.3, 135.6, 129.4, 129.3, 127.0, 126.84,
107.0, 95.7, 55.1, 41.3, 25.1, 24.9, 21.4, 21.0. HRMS (ESI): m=z calcd.
for C22H25NO5S: 416.1526 (M þ H), found: 416.1513.
N-[2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-(4-
methoxyphenyl)ethyl]-p-toluenesulfonamide (4f)
A white solid, mp 119–120ꢀC. n
cmꢁ1: 3262, 1725, 1634, 1325, 1204,
CH2Cl2
max
1159, 1093; 1H NMR d ¼ 7.51 (2H, d, J ¼ 8.1 Hz), 7.12 (2H, d,
J ¼ 7.7 Hz), 6.92 (2H, d, J ¼ 8.6 Hz), 6.65 (2H, d, J ¼ 7.6 Hz), 5.47 (1H,
br), 5.15 (1H, d, J ¼ 2.0 Hz), 4.62–4.54 (1H, m), 3.73 (3H, s), 2.77 (1H,
dd, J ¼ 7.9, 14.6 Hz), 2.60 (1H, dd, J ¼ 7.4, 14.6 Hz), 2.36 (3H, s), 1.62
(3H, s), 1.54 (3H, s). 13C NMR d ¼ 166.2, 160.0, 158.4, 142.2, 136.4,
129.8, 128.4, 126.7, 126.0, 113.0, 106.0, 94.7, 54.2, 53.8, 40.3, 24.1,
23.9, 20.4. HRMS (ESI): m=z calcd. for C22H25NO6S: 431.1475
(M þ H); found: 416.1480.
N-[1-(2-Chlorophenyl)-2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)
ethyl]-p-toluenesulfonamide (4g)
A white solid, mp 136–138ꢀC. n
cmꢁ1: 3265, 1726, 1636, 1321,
CH2Cl2
max
1204, 1160, 1092; 1H NMR d ¼ 7.51 (2H, d, J ¼ 8.1 Hz), 7.15–7.11
(2H, m), 7.08–6.98 (4H, m), 6.14 (1H, d, J ¼ 8.6 Hz), 5.26 (1H, s),
5.18–5.10 (1H, m), 2.68 (2H, d, J ¼ 7.4 Hz), 2.30 (3H, s), 1.70 (3H, s),
1.62 (3H, s). 13C NMR d ¼ 166.9, 161.1, 143.3, 137.0, 136.2, 132.1,
129.8, 129.3, 129.0, 128.3, 127.2, 126.8, 107.2, 95.7, 52.6, 40.0, 25.4,
24.7, 21.4. HRMS (ESI): m=z calcd. for C21H22NO6SCl: 436.0980
(M þ H); found: 436.0984.

d-Amino-b-ketoesters and Piperidinediones
2997
N-[1-(2-Bromophenyl)-2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)
ethyl]-p-toluenesulfonamide (4h)
A white solid, mp 128–130ꢀC. n
cmꢁ1: 3263, 1711, 1635, 1326, 1204,
CH2Cl2
max
1160, 1092; 1H NMR d ¼ 7.52 (2H, d, J ¼ 7.6 Hz), 7.34 (1H, d,
J ¼ 7.6 Hz), 7.13 (1H, J ¼ 7.1 Hz), 7.14–6.95 (5H, m), 6.21 (1H, d,
J ¼ 8.6 Hz), 5.29 (1H, s), 5.17–5.14 (1H, m), 2.72–2.50 (2H, m), 2.30
(3H, s), 1.71 (3H, s), 1.64 (3H, s). 13C NMR d ¼ 166.9, 161.2, 143.3,
137.9, 137.0, 133.0, 129.3, 129.2, 128.3, 127.8, 126.9, 122.3, 107.3, 95.7,
54.6, 40.2, 25.4, 24.7, 21.4. HRMS (ESI): m=z calcd. for C21H22NO5SBr:
480.0475 (M þ H), found: 480.0475.
N-[2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-(2-
methoxyphenyl)ethyl]-p-toluenesulfonamide (4i)
A white solid, mp 149–150ꢀC. n
cmꢁ1: 3274, 1726, 1635, 1328, 1204,
CH2Cl2
max
1160, 1093; 1H NMR d ¼ 7.42 (2H, d, J ¼ 8.2 Hz), 7.11–7.04 (1H, m), 6.98
(2H, d, J ¼ 8.1 Hz,), 6.86–6.82 (1H, m), 6.70–6.67 (1H, m), 6.57 (1H, d,
J ¼ 8.2 Hz), 5.79 (1H, d, J ¼ 10.2 Hz), 5.14 (1H, s), 4.74–4.65 (1H, m),
3.71 (3H, s), 2.82 (1H, dd, J ¼ 8.5, 14.4 Hz), 2.69 (1H, dd, J ¼ 7.1,
14.4 Hz), 2.28 (3H, s), 1.67 (3H, s), 1.59 (3H, s). 13C NMR d ¼ 167.4,
161.0, 156.3, 142.9, 137.3, 129.3, 128.9, 126.7, 125.7, 120.6, 110.7,
106.9, 95.4, 55.1, 54.7, 39.6, 25.5, 24.6, 21.3. HRMS (ESI): m=z calcd.
for C22H25NO6S: 432.1475 (M þ H), found: 432.1480.
(E)-N-[1-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-4-phenylbut-3-en-
2-yl]-p-toluenesulfonamide (4j)
A white solid, mp 124–126ꢀC. n
cmꢁ1: 3261, 1726, 1634, 1330, 1204,
CH2Cl2
max
1160, 1093; 1H NMR d ¼ 7.71 (2H, d, J ¼ 8.2 Hz), 7.27–7.21 (4H, m), 7.16
(2H, d, J ¼ 8.1 Hz), 7.05–7.01 (2H, m), 6.22 (1H, d, J ¼ 15.8 Hz), 5.67
(1H, dd, J ¼ 7.7, 15.8 Hz), 5.50 (1H, d, J ¼ 8.6 Hz), 5.28 (1H, s),
4.34–4.10 (1H, m), 2.60–2.41 (2H, m), 2.24 (3H, s), 1.69 (3H, s), 1.65
(3H, s). 13C NMR d ¼ 167.1, 161.0, 143.7, 137.8, 135.6, 132.7, 129.7,
128.5, 128.1, 127.2, 126.4, 107.1, 95.8, 53.6, 40.1, 25.4, 25.1, 21.3. HRMS
(ESI): m=z calcd. for C23H25NO5S: 428.1520 (M þ H); found: 428.1510.
N-[2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-(furan-2-yl)ethyl]-p-
toluenesulfonamide (4k)
A white solid, mp 107–109ꢀC. n
cmꢁ1: 3256, 1725, 1636, 1333, 1204,
CH2Cl2
max
1160, 1093; 1H NMR d ¼ 7.60 (2H, d, J ¼ 8.3 Hz), 7.19 (2H, d,

2998
C.-L. Gu et al.
J ¼ 8.2 Hz), 7.14 (1H, J ¼ 1.6 Hz), 6.09 (1H, dd, J ¼ 1.9, 3.2 Hz), 5.94 (1H,
d, J ¼ 3.2 Hz), 5.38 (1H, d, J ¼ 9.0 Hz), 5.19 (1H, s), 4.76 (1H, dd, J ¼ 7.4,
16.3 Hz), 2.81–2.66 (2H, m), 2.38 (3H, s), 1.66 (3H, s), 1.58 (3H, s). 13C
NMR d ¼ 166.4, 160.8, 151.0, 143.4, 142.4, 137.4, 129.5, 126.9, 110.2,
107.7, 107.1, 95.8, 48.9, 39.1, 25.1, 25.0, 21.4. HRMS (ESI): m=z calcd.
for C19H21NO6S: 392.1162 (M þ H); found: 392.1164.
N-[1-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-methylbutan-2-yl]-p-
toluenesulfonamide (4l)
cmꢁ1: 3279, 2964, 1717, 1635, 1391, 1206, 1160,
CH2Cl2
max
A viscous liquid. n
1094; 1H NMR d ¼ 7.74 (2H, d, J ¼ 8.2 Hz), 7.30 (2H, d, J ¼ 8.1 Hz), 5.16
(1H, s), 4.62 (1H, d, J ¼ 8.9 Hz), 3.45–3.39 (1H, m), 2.33–2.26 (2H, m),
1.82–1.75 (1H, m), 1.64 (6H, s), 0.86–0.80 (6H, m). 13C NMR
d ¼ 167.9, 160.5, 143.7, 137.8, 129.8, 126.9, 106.7, 95.1, 56.4, 36.5, 31.2,
25.2, 24.9, 21.5, 18.3, 17.4. HRMS (ESI): m=z calcd. for C18H25NO5S:
368.1526 (M þ H), found: 368.1520.
6-Phenyl-1-tosylpiperidine-2,4-dione (5b)
1
A white solid, mp 166–167ꢀC. n
cmꢁ1: 1705, 1671, 1353, 1167; H
CH2Cl2
max
NMR d ¼ 7.84 (2H, d, J ¼ 8.3 Hz), 7.58–7.16 (5H, m), 7.10 (d,
J ¼ 10.5 Hz, 2H), 6.21–6.19 (m, 1H), 3.26 (s, 3H), 3.21 (dd, J ¼ 2.5,
17.3 Hz, 1H), 3.02 (dd, J ¼ 5.9, 17.2 Hz, 1H), 2.44 (s, 3H). 13C NMR
(75 MHz, CDCl3): d 200.2, 165.9, 145.6, 137.5, 135.1, 129.4, 129.3,
128.5, 125.7, 55.6, 49.6, 45.9, 21.7. HRMS (ESI): m=z calcd. for
C18H17NO4S (M þ H): 344.0950; found: 344.0943.
6-(4-Nitrophenyl)-1-tosylpiperidine-2,4-dione (5c)
A pale yellow crystal, mp 193–195ꢀC. n
cmꢁ1: 1710, 1522, 1348, 1265;
CH2Cl2
max
1H NMR d ¼ 8.25 (2H, d, J ¼ 8.7 Hz), 7.88 (2H, d, J¼ 8.3 Hz), 7.42 (2H,
d, J¼ 8.7 Hz), 7.34 (2H, d, J¼ 8.2 Hz), 6.27 (1H, m), 3.37–3.07 (4H, m),
2.47 (3H, s); 13C NMR d ¼ 198.6, 165.2, 148.0, 146.1, 144.8, 134.9, 129.6,
129.3, 126.8, 124.8, 55.2, 49.3, 45.7, 21.7. HRMS (ESI): m=z calcd. for
C18H16N2O6S: 389.0802 (M þ H), found: 389.0805.
6-(4-Chlorophenyl)-1-tosylpiperidine-2,4-dione (5d)
A white solid, mp 166–167ꢀC. n
cmꢁ1: 1706, 1492, 1354, 1290, 1166;
CH2Cl2
max
1H NMR d ¼ 7.86 (2H, d, J ¼ 8.4 Hz), 7.37–7.31 (4H, m), 7.14 (2H, d,

d-Amino-b-ketoesters and Piperidinediones
2999
J ¼ 8.3 Hz), 6.18–6.16 (1H, m), 3.32–2.97 (4H, m), 2.46 (3H, s). 13C NMR
d ¼ 199.5, 165.5, 145.8, 136.2, 135.2, 134.7, 129.6, 129.4, 129.3, 127.1,
55.1, 49.4, 45.8, 21.6. HRMS (ESI): m=z calcd. for C18H16NO4SCl:
378.0561 (M þ H); found: 378.0572.
6-(4-Methoxyphenyl)-1-tosylpiperidine-2,4-dione (5f)
A white solid, mp 190ꢀC (decomposed). n
cmꢁ1: 1706, 1611, 1349,
CH2Cl2
max
1297, 1163; 1H NMR d ¼ 7.85 (2H, d, J ¼ 8.1 Hz), 7.30 (2H, d, J ¼ 7.9 Hz),
7.10 (2H, d, J ¼ 8.5 Hz), 6.87 (2H, d, J ¼ 8.6 Hz), 6.16–6.14 (1H, m), 3.79
(3H, s), 3.25 (3H, s), 3.18 (1H, dd, J ¼ 2.2, 17.2 Hz), 2.98 (1H, dd,
J ¼ 5.6, 17.2 Hz), 2.44 (3H, s). 13C NMR d ¼ 200.3, 165.8, 159.8, 145.5,
135.4, 129.5, 129.3, 129.2, 127.0, 114.7, 55.3, 55.2, 49.5, 45.9, 21.6. HRMS
(ESI): m=z calcd. for C19H19NO5S: 374.1056 (M þ H); found: 374.1058.
6-(2-Methoxyphenyl)-1-tosylpiperidine-2,4-dione (5i)
1
A white solid, mp 153–155ꢀC. n
cmꢁ1: 1701, 1192, 1357, 1167; H
CH2Cl2
max
NMR d ¼ 7.55 (2H, d, J ¼ 8.4 Hz), 7.31 (1H, m), 7.15 (2H, d, J ¼ 8.2 Hz),
7.05 (1H, dd, J ¼ 1.5, 7.6 Hz), 6.92 (1H, m), 6.79 (1H, d, J ¼ 8.2 Hz), 6.10
(1H, dd, J ¼ 3.7, 5.5 Hz), 3.59 (3H, s), 3.38 (2H, dd, J ¼ 20.0, 22.4 Hz),
3.08 (2H, m), 2.38 (3H, s). 13C NMR d ¼ 199.6, 166.8, 156.3, 144.9,
135.3, 130.1, 129.4, 128.8, 128.0, 125.8, 120.8, 111.3, 54.7, 54.3, 49.0,
44.8, 21.5. HRMS (ESI): m=z calcd. for C19H19NO5S: 396.0876
(M þ Na); found: 396.0873.
(E)-6-Styryl-1-tosylpiperidine-2,4-dione (5j)
1
A white solid, mp 174–176ꢀC. n
cmꢁ1: 1704, 1352, 1165; H NMR
CH2Cl2
max
d ¼ 7.97 (d, J ¼ 7.3 Hz, 2H), 7.30–7.18 (m, 7H), 6.48 (d, J ¼ 15.8 Hz,
1H), 6.12 (dd, J ¼ 3.7, 15.8 Hz, 1H), 5.74 (m, 1H), 3.44 (d, J ¼ 20.0 Hz,
1H), 3.27 (d, J ¼ 20.0 Hz, 1H), 2.94 (s, 3H), 2.43 (s, 3H). 13C NMR
d ¼ 200.4, 165.5, 145.5, 135.5, 134.9, 133.3, 129.4, 129.3, 128.8, 126.7,
125.4, 54.1, 49.1, 44.4, 21.6. HRMS (ESI): m=z calcd. for C20H19NO4S:
392.0927 (M þ Na); found 392.0927.
6-(Furan-2-yl)-1-tosylpiperidine-2,4-dione (5k)
1
A white solid, mp 159–161ꢀC. n
cmꢁ1: 1706, 1354, 1293, 1167; H
CH2Cl2
max
NMR d ¼ 7.77 (2H, d, J ¼ 8.4 Hz), 7.32 (1H, d, J ¼ 0.7 Hz), 7.27 (2H,

3000
C.-L. Gu et al.
d, J ¼ 8.1 Hz), 6.40–6.36 (2H, m), 6.13–6.10 (1H, m), 3.60 (1H, d,
J ¼ 20.3 Hz), 3.31 (1H, d, J ¼ 20.3 Hz), 3.13–2.97 (2H, m), 2.42 (3H, s).
13C NMR d ¼ 200.1, 165.6, 150.9, 145.4, 143.4, 135.2, 129.3, 129.2,
110.8, 109.0, 49.7, 48.8, 43.5, 21.6. HRMS (ESI): m=z calcd. for
C16H15NO5S: 334.0744 (M þ H); found: 334.0749.
ACKNOWLEDGMENTS
The research was financially supported by the National Natural Science
Foundation of China and the Chinese Academy of Sciences.
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