Regioselective addition of 1,3-dicarbonyl dianion to N-sulfonyl aldimines: an expedient route to N-sulfonyl piperidines and N-sulfonyl azetidines

Article abstract of DOI:10.1016/j.tet.2007.03.081

A simple route for the synthesis of δ-amino-β-keto esters and δ-amino-β-diketones is reported. This involves regioselective addition of 1,3-dianions derived from ethyl acetoacetate and acetyl acetone to N-sulfonyl aldimines. The δ-amino-β-keto ester deriv

Full text of DOI:10.1016/j.tet.2007.03.081

Tetrahedron 63 (2007) 4779–4787
Regioselective addition of 1,3-dicarbonyl dianion to N-sulfonyl
aldimines: an expedient route to N-sulfonyl piperidines
and N-sulfonyl azetidines
*
Manas K. Ghorai, Amit Kumar and Sandipan Halder
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 26 June 2006; revised 23 February 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—A simple route for the synthesis of d-amino-b-keto esters and d-amino-b-diketones is reported. This involves regioselective
addition of 1,3-dianions derived from ethyl acetoacetate and acetyl acetone to N-sulfonyl aldimines. The d-amino-b-keto ester derivatives
were further converted into the corresponding N-sulfonyl piperidines and N-sulfonyl azetidines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In continuation of our research on enolate chemistry and also
supported by the related literature on the reactivity of 1,3-di-
carbonyl dianions, it was envisaged that dianions derived
from suitable precursors could be regioselectively added to
aldimines to give an easy access to d-amino-b-keto esters18
and their diketone analogues. These compounds could easily
be converted into various piperidine and azetidine deriva-
tives.
1,3-Dicarbonyl dianions have been used extensively in or-
ganic synthesis for building ring systems. The anion on the
terminal carbon of the dianion can be regioselectivelyreacted
with 1 equiv of an electrophile resulting in an enolate ion,
which can be trapped by the addition of a second electrophile
or quenched by a proton source.1 Comprehensive studies of
1,3-dicarbonyl dianions employing a variety of electrophiles
to produce useful and synthetically important cyclic com-
pounds, especially heterocycles, are well documented
in the literature.2 These electrophiles include N,N1-di-
methoxy-N,N1-dimethylethanediamide,3 1,2-diketones,4 1,2-
dibromo or 1,2-diiodoethane,5 1-bromo-2-chloroethane,6
1,4-dibromo-2-butene,7 oxalic acid-bis(imidoyl)chlorides,8
a-chloroacetic esters,9 esters and amides,9 aldehydes,10 a-
azidoketones,11 cyclic sulfate esters,12 epoxides,13 N-tosyl
aziridines,14 and nitro-olefins.15 Six-membered nitrogen
heterocycles are one of the widely found structural units in
variousnatural productsand areveryimportant intermediates
in organic synthesis. In particular, the piperidine alkaloids
and their synthetic analogues are the focus of great interest
in the pharmaceutical industry because of their wide range
of biological activities.16 Azetidines are another important
class of heterocyclic compounds found in many naturally oc-
curring or important organic molecules, which exhibit inter-
esting biological and pharmacological properties.17
Substituted d-amino-b-keto esters are important polyfunc-
tionalized building blocks for the synthesis of important
alkaloids, e.g., (R)-(+)-2-phenylpiperidine, (ꢀ)-SS20846A,
(+)-241D, and its C-4 epimer, 4-hydroxypipecolic acid.19
Similarly, d-amino-b-diketone derivatives could be utilized
as important intermediates for direct synthesis of some of
these alkaloids. Davis et al. reported the synthesis of
d-amino-b-keto ester derivatives by a sequential addition of
2 equivof methyl acetate enolate to N-sulfinylaldimine.19b,20
They utilized those d-amino-b-keto esters as the key interme-
diates for elegant syntheses of the aforesaid alkaloids.19 We
report herein, a new strategy for the regioselective addition
of 1,3-dicarbonyl dianions to N-sulfonyl aldimines as a con-
venient and new route to substituted d-amino-b-keto esters
and d-amino-b-diketones in good to excellent yields. These
d-amino-b-keto esters were further transformed to N-sulfo-
nyl piperidines and N-sulfonyl azetidines using simple
chemistry.
2. Results and discussion
Keywords: 1,3-Dianion; b-Keto ester; b-Dicarbonyl; d-Amino-b-keto ester;
d-Amino-b-diketone; Piperidine; Azetidine.
* Corresponding author. Tel.: +91 512 2597518; fax: +91 512 2597436;
e-mail: mkghorai@iitk.ac.in
To test our methodology, we selected ethyl acetoacetate 1 as
a precursor of 1,3-dicarbonyl dianion 2. We anticipated that
addition of the terminal carbanion of 2 to N-sulfonyl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.081

4780
M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
Table 1. Regioselective addition of 1,3-dianion of ethyl acetoacetate to
N-sulfonyl aldimines
aldimines would provide the corresponding d-amino-b-keto
esters 3 in a single step (Scheme 1). Dianion 2 was generated
from 1 by the treatment of LDA at ꢀ50 ꢁC. When 1.0 equiv
of N-sulfonyl aldimine was added to 1.0 equiv of 2 (entry 1,
Table 1), a complex mixture was obtained from which only
35% of the addition product 3a was isolated. To optimize the
yield of this reaction we studied the concentration depen-
dence of the dianion 2 and observed that 2.5 equiv of 2 in-
creased the yield of 3a to 77%. In order to generalize this
approach, reaction of 2 with a number of N-sulfonyl aldi-
mines (entries 2–8) was studied. In all cases, the reaction
went smoothly to produce d-amino-b-keto esters 3a–h in
excellent yields (Table 1). Similarly, 1,3-dianion 5 was
generated from acetyl acetone 4 by the treatment of LDA
at ꢀ50 ꢁC. When 2.5 equiv of 5 was allowed to react with
1.0 equiv of N-sulfonyl aldimines, the corresponding
d-amino-b-diketones 6a–e were obtained in very good yield
(Scheme 2).
Entry
1
Ar
Ar1
Yielda of 3 (%)
3a, 77 (35)
2
3
4
3b, 87
3c, 83
3d, 88
Cl
Cl
Br
5
6
3e, 90
3f, 72
MeO
MeO
O
O
7
3g, 75 (30)
3h, 85
O
O
OLi OLi
OEt
N
SO2Ar1
OEt
Ar
2 eq LDA
SO2Ar1
OEt
−50 °C, THF
−50 °C, THF
Ar
N
H
1 h
2-2.5 h
8
upto 90%
1
2
3
O
a: Ar = Ph, Ar1 = 4-Me-C6H4
e: Ar = 4-MeO-C6H4, Ar1 = 4-Me-C6H4
f: Ar = 4-MeO-C6H4, Ar1 = Ph
g: Ar = Ph, Ar1 = Ph
a
b: Ar = 2-Cl-C6H4, Ar1 = 4-Me-C6H4
c: Ar = 4-Cl-C6H4, Ar1 = 4-Me-C6H4
d: Ar = 3-Br-C6H4, Ar1 = 4-Me-C6H4
Yields of isolated products after column chromatographic purification.
Yield mentioned in the parenthesis is obtained by using 1:1 ratio of di-
anion and the aldimine.
h: Ar = furfuryl, Ar1 = 4-Me-C6H4
Scheme 1. Regioselective addition of 1,3-dianion of ethyl acetoacetate to
N-sulfonyl aldimines.
afforded N-sulfonyl piperidine 9a in excellent overall yield
starting from 3a. Generalization of this approach is shown
in Table 2.
To explore the synthetic potential of this strategy, we further
converted 3a–d into the corresponding substituted piperi-
dines 9a–d using simple and known chemistry (Scheme 3).
The keto group of 3a was first protected as a cyclic ketal
7a using 1,2-ethane diol in the presence of p-toluenesulfonic
acid. The ester functionality of 7a was further reduced to the
corresponding primary alcohol 8a by treatment with LiAlH4.
Treatment of 8a with TsCl and excess KOH in refluxing THF
After successful utilization of 3 for the syntheses of six-
membered N-heterocycles 9, we were interested in the
synthesis of four-membered N-heterocycles (azetidines).
Our initial attempt toward the synthesis of azetidine 10 is
shown in Scheme 4. At first the keto group of 3a was reduced
to the corresponding alcohol by treatment with NaBH4 in
O
O
O
O
OLi OLi
(0.4 equiv.)
N Ts
2 equiv. LDA
Ar
Ts
−50 °C, THF
−50 °C, THF
Ar
N
H
6
1 h
2-2.5 h
4
5
6a: Ar = Ph, 78%; 6b: Ar = 2-Cl-C6H4, 71%; 6c: Ar = 4-MeO-C6H4, 55%; 6d: Ar = 4-Cl-C6H4, 78%;
6e Ar = 3-Br-C6H4, 81%.
Scheme 2. Regioselective addition of 1,3-dianion of acetyl acetone to N-sulfonyl aldimines.
O
O
O
O
O
O
O
OEt
PTSA,
OEt
OH
HO
OH
LAH, THF
Benzene,
Reflux, 5-8 h
0 °C-R.T., 1 h
Ar
NH
Ts
Ar
NH
Ts
Ar
NH
Ts
3
7
8
O
O
KOH, TsCl
up to 77%
from 3
Ar = a: Ph, b: 2-Cl-C6H4, c: 4-Cl-C6H4, d: 3-Br-C6H4
THF, Reflux
30 mins
Ar
N
Ts
9
Scheme 3. Synthesis of substituted N-sulfonyl piperidines 9 from d-amino-b-keto esters 3.

M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
Table 2. Synthesis of substituted N-sulfonyl piperidines 9 from d-amino-b-keto esters 3
4781
Entry
3
Yielda of 7 (%)
Yielda of 8 (%)
Yielda of 9 (%)
Overall yield
of 9 (%)
O
O
O
O
O
O
O
O
O
OEt
OEt
OH
Ts
Ar
NH
Ts
Ar
NH
Ts
Ar
N
Ts
Ar
N
H
1
2
3
4
a: Ar¼Ph
78
95
98
90
98
92
72
71
77
70
b: Ar¼2-Cl–C6H4
c: Ar¼4-Cl–C6H4
d: Ar¼3-Br–C6H4
88
85
80
90
93
96
a
Yields of isolated products after column chromatography.
Ph
Ph
Ts
N
O
O
OH
O
CO2Et
OEt
10
OEt
NaBH4
MeOH
TsCl, KOH
THF, Reflux
O
NH
Ts
Ph
Ph
NH
Ts
OEt
3a
NH
Ts
11
Scheme 4. Attempt toward the synthesis of substituted azetidine from d-amino-b-keto ester 3a.
Table 3. Synthesis of N-sulfonyl azetidines 14 from d-amino-b-keto esters 3
methanol. When the alcohol was treated with TsCl and ex-
cess KOH in refluxing THF, homoallyl amine 11 was formed
instead of 10.
3
Yieldb (%) of
Yieldb (%) of
Yieldb,c
(%) of 14
12 (syn/anti)a,d
13x+13y (syn/anti)a,c,d,e
3a
3b
12a, 65 (1:1.2)
12b, 65 (1:2)
12e, 55 (1:2)
13xa+13ya, 98 (1:1.2)
13xb+13yb, 98 (1:2)
13xe+13ye, 95 (1:2)
14xa, 98
14ya, 95
However, 3 was converted into the corresponding N-sulfonyl
azetidine 14 by a different strategy as shown in Scheme 5.
Both the keto and ester groups of d-amino-b-keto ester 3a
were reduced by treating with LiAlH4 to give the corre-
sponding amino diol 12a as a mixture of diastereomers (dr
1.2:1) (Table 3). Primary alcohol group of 12a was selec-
tively protected as TBDMS ether 13 as a mixture of diaste-
reomers (dr 1.2:1) by using TBDMSCl and Et3N in the
presence of catalytic DMAP in DMF.21 Both the diastereo-
mers 13xa and 13ya were isolated in pure forms by silica
gel column chromatography. Subsequently, each of the
pure diastereomers 13xa and 13ya was treated separately
with TsCl and excess KOH in refluxing THF to afford the
corresponding N-sulfonyl azetidines 14xa and 14ya, respec-
tively, in almost quantitative yields. Similar LiAlH4 reduc-
tion of 3b,e furnished 12b,e as a mixture of diastereomers
(dr 2:1). After protection of the primary alcohol group of
14xb, 97
14yb, 92
3e
14xe, 85
14ye, 70
Ratio determined by 1H NMR of crude reaction mixture.
Yield of isolated product after column chromatography.
The relative stereochemistry is shown.
syn/anti Stereochemistry was decided considering the SN2 cyclization of
13 leading to 14 (stereochemistry of 14 was determined by NOE experi-
ment).
a
b
c
d
e
Compounds 13x and 13y were separated by column chromatography
before cyclization to 14.
12b,e as TBDMS ethers, both the diastereomers 13xb,e
and 13yb,e were separated by column chromatography to
afford diastereomerically pure products. In a similar fashion,
OH
O
CO2Et
LAH, THF
OH
Ar
TBDMSCl
Ar
2OTBDMS
2 OTBDMS
NH
Ts
Ar
NH
Ts
3
Ar
+
Et3N, DMAP
0 °C-R.T.
1 h
NHTs
OH
OH
NHTs
13
DMF, 0 °C-R.T., 1 h
13
12
x
y
1. Separation through
column chromatography
2. TsCl, KOH, THF, reflux, 1 h
a: Ar = Ph
b: Ar = 2-Cl-C6H4
e: Ar = 4-MeO-C6H4
Ar
Ar
Ts
Ts
N
N
OTBDMS
OTBDMS
2
2
14
14
x
y
Scheme 5. Synthesis of substituted azetidines 14 from d-amino-b-keto esters 3.

4782
M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
2.9 mmol) at ꢀ50 ꢁC and stirred for 30 min. The color of
OTBDMS
H
the solution changed to yellow, to which ethyl acetoacetate
(0.18 mL, 1.45 mmol) was added slowly. Then stirring was
continued for 1 h to allow the formation of 1,3-dianion. N-
Sulfonyl imine (0.58 mmol) dissolved in 3 mL dry THF
was added to the reaction mixture and allowed to stir for ad-
ditional 2–2.5 h at the same temperature. After the comple-
tion of the reaction (monitored by TLC), it was quenched
with saturated aqueous ammonium chloride solution, and
extracted with 20 mL ethyl acetate in two portions. The
combined organic extract was dried over anhydrous
Na2SO4 and the solvent was evaporated under vacuum.
Silica gel column chromatographic purification of the crude
mixture, using 20% ethyl acetate in petroleum ether as the
eluant, afforded the pure products 3a–h.
OTBDMS
Ts
H
H
H
Ts
N
N
Cl
Cl
14yb (trans)
14xb (cis)
Figure 1. Determination of stereochemistry of 14b by NOE experiment.
13xb,e and 13yb,e when treated with TsCl and excess KOH in
refluxing THF, the corresponding N-tosyl-azetidines 14xb,e
and 14yb,e were obtained in diastereomerically pure forms
in excellent yields. Interestingly, in all the above cases the
major diastereomer 14x was obtained with 2,4-cis stereo-
chemistry. The cis-geometry was determined by NOE mea-
surements between the protons at C-2 and C-4 positions
(Fig. 1).
4.2.1. 3-Oxo-5-phenyl-5-(toluene-4-sulfonylamino)-
pentanoic acid ethyl ester (3a). The general procedure de-
scribed in Section 4.2 was followed to afford 3a (173.9 mg,
77%) as a yellow liquid. [Found: C, 61.78; H, 5.90; N,
3.65. C20H23NO5S requires: C, 61.68; H, 5.95; N, 3.60%.] Rf
(40% ethyl acetate/petroleum ether) 0.39; nmax (neat) 3278,
2981, 2925, 1737, 1713, 1649, 1411, 1386, 1323, 1157, 1091,
1025, 965, 813, 754, 701, 667 cmꢀ1; dH (400 MHz, CDCl3)
1.16 (3H, t, J 7.1 Hz, OCH2CH3), 2.31 (3H, s, ArCH3),
2.92–3.13 (2H, m, CH2CO), 3.20–3.39 (2H, m, COCH2-
CO2Et), 4.1 (2H, q, J 7.1 Hz, OCH2CH3), 4.62–4.75 (1H,
m, NCHPh), 5.38 (1H, d, J 7.0 Hz, NH), 6.93–7.13 (6H, m,
ArH), 7.51 (2H, d, J 8.3 Hz, ArH); dC (100 MHz, CDCl3)
14.1, 21.5, 49.0, 49.6, 53.8, 61.6, 126.5, 127.1, 127.7,
128.5, 129.4, 137.0, 139.5, 143.1, 166.8, 200.5; FAB Mass:
m/z 390 (M++1).
When the free amino diol 12b was treated with TsCl and ex-
cess KOH in refluxing THF, the reaction was found to be
complicated as indicated by the 1H NMR of the crude reac-
tion mixture.
3. Conclusion
In conclusion, we have developed a new strategy for the
regioselective addition of 1,3-dicarbonyl dianions derived
from ethyl acetoacetate or acetyl acetone to N-sulfonyl
aldimines to produce d-amino-b-keto esters or d-amino-b-di-
ketones, respectively. The synthetic potential of this method-
ology is further demonstrated by the syntheses of various
N-sulfonyl piperidines and azetidines. Further research in
this area is under progress.
4.2.2. 5-(2-Chloro-phenyl)-3-oxo-5-(toluene-4-sulfonyl-
amino)-pentanoic acid ethyl ester (3b). The general proce-
dure described in Section 4.2 was followed to afford 3b
(213.9 mg, 87%) as a yellow liquid. [Found: C, 56.79; H,
5.25; N, 3.36. C20H22ClNO5S requires: C, 56.67; H, 5.23;
N, 3.30%.] Rf (40% ethyl acetate/petroleum ether) 0.37;
nmax (neat) 3280, 3064, 2982, 2925, 1739, 1717, 1653,
1598, 1473, 1443, 1414, 1367, 1323, 1237, 1187, 1159,
1091, 1030, 813, 757, 729, 704, 666, 589 cmꢀ1; dH
(400 MHz, CDCl3) 1.16 (3H, t, J 7.1 Hz, OCH2CH3), 2.27
(3H, s, ArCH3), 2.93–3.13 (2H, m, CH2CO), 3.21–3.30
(2H, m, COCH2CO2Et), 4.12 (2H, q, J 7.1 Hz, OCH2CH3),
5.02–5.07 (1H, m, NCHPh), 5.86 (1H, d, J 8.0 Hz, NH),
6.93–7.25 (6H, m, ArH), 7.50 (2H, d, J 8.3 Hz, ArH); dC
(100 MHz, CDCl3) 14.1, 21.5, 42.4, 48.9, 53.2, 61.6,
122.4, 125.3, 126.9, 129.4, 129.7, 129.9, 130.6, 136.8,
141.5, 143.5, 166.7, 200.2; FAB Mass: m/z 424 (M++1),
426 (M++3).
4. Experimental
4.1. General
All commercial reagents were used as received. 1H and 13
C
NMR spectra were recorded on JEOL JNM-LA400 instru-
ment at 20–25 ꢁC in CDCl3 as the solvent and using TMS
as the internal standard. IR spectra were recorded on
BRUKER VERTEX 70 instrument. Elemental analysis data
were obtained from THERMO QUEST CE Instrument (EA
1110, CHNS-O). TLC was carried out with 0.2 mm thick
pre-coated silica gel plates (Merck, silica gel 60 F254) using
ethyl acetate/petroleum ether as the mobile phase. Visualiza-
tion of spots was accomplished by UV light and iodine. Col-
umn chromatography was performed using Acme’s (India)
silicagel (100–200 mesh size) and Spectrochem (India) silica
gel (230–400 mesh size). All solvents used in reactions were
anhydrous and purified according to standard procedures. All
air- or moisture-sensitive reactions were performed under
argon atmosphere. Glassware was oven-dried (130 ꢁC) and
purged with argon.
4.2.3. 5-(4-Chloro-phenyl)-3-oxo-5-(toluene-4-sulfonyl-
amino)-pentanoic acid ethyl ester (3c). The general proce-
dure described in Section 4.2 was followed to afford 3c
(204.1 mg, 83%) as a yellow liquid. [Found: C, 56.77; H,
5.30; N, 3.42. C20H22ClNO5S requires: C, 56.67; H, 5.23;
N, 3.30%.] Rf (40% ethyl acetate/petroleum ether) 0.39;
nmax (neat) 3278, 2980, 1737, 1713, 1649, 1411, 1386,
1323, 1157, 1091, 1029, 965 cmꢀ1; dH (400 MHz, CDCl3)
1.17 (3H, t, J 7.1 Hz, OCH2CH3), 2.33 (3H, s, ArCH3),
2.89–3.12 (2H, m, CH2CO), 3.22–3.30 (2H, m, COCH2-
CO2Et), 4.08 (2H, q, J 7.1 Hz, OCH2CH3), 4.62–4.64 (1H,
4.2. General procedure for the preparation of d-amino-
b-keto esters (3a–h)
To a solution of diisopropylamine (0.41 mL, 2.9 mmol)
in 5 mL dry THF was added 2.3 M n-BuLi (1.26 mL,

M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
4783
m, NCHPh), 5.62 (1H, d, J 6.3 Hz, NH), 6.95–7.12 (6H, m,
ArH), 7.48 (2H, d, J 8.2 Hz, ArH); dC (100 MHz, CDCl3)
14.1, 21.5, 49.0, 49.6, 53.8, 61.6, 126.5, 127.1, 127.7,
128.5, 129.4, 137.0, 139.5, 143.1, 166.8, 200.5; FAB
Mass: m/z 424 (M++1), 426 (M++3).
in Section 4.2 was followed to afford 3g (163.3 mg, 75%) as
a yellow liquid. [Found: C, 60.98; H, 5.72; N, 3.69.
C19H21NO5S requires: C, 60.78; H, 5.64; N, 3.73%.] Rf
(40% ethyl acetate/petroleum ether) 0.28; nmax (neat)
3281, 3064, 2982, 2933, 1738, 1716, 1625, 1447, 1410,
1370, 1323, 1262, 1161, 1094, 1068, 1029, 941, 859, 807,
756, 721, 691, 644 cmꢀ1; dH (400 MHz, CDCl3) 1.17 (3H,
t, J 7.1 Hz, OCH2CH3), 2.93–3.16 (2H, m, CH2CO), 3.21–
3.43 (2H, m, COCH2CO2Et), 4.01 (2H, q, J 7.1 Hz,
OCH2CH3), 4.66–4.77 (1H, m, NCHPh), 5.60 (1H, d,
J 3.3 Hz, NH), 6.99–7.45 (8H, m, ArH), 7.62 (2H, d,
J 7.8 Hz, ArH); dC (100 MHz, CDCl3) 14.1, 49.0, 49.6,
53.8, 61.6, 126.5, 127.1, 127.7, 128.5, 129.4, 137.0, 139.5,
143.1, 166.8, 200.5; FAB Mass: m/z 376 (M++1).
4.2.4. 5-(3-Bromo-phenyl)-3-oxo-5-(toluene-4-sulfonyl-
amino)-pentanoic acid ethyl ester (3d). The general proce-
dure described in Section 4.2 was followed to afford 3d
(238.7 mg, 88%) as a yellow liquid. [Found: C, 51.35; H,
4.82; N, 3.12. C20H22BrNO5S requires: C, 51.29; H, 4.73;
N, 2.99%.] Rf (40% ethyl acetate/petroleum ether) 0.38;
nmax (neat): 3272, 3061, 2981, 2928, 1738, 1714, 1649,
1596, 1569, 1439, 1409, 1367, 1327, 1189, 1159, 1092,
1026, 963, 895, 813, 787, 736, 699 cmꢀ1; dH (400 MHz,
CDCl3) 1.16 (3H, t, J 7.1 Hz, OCH2CH3), 2.32 (3H, s,
ArCH3), 2.90–3.11 (2H, m, CH2CO), 3.28–3.30 (2H, m,
COCH2CO2Et), 4.07 (2H, q, J 7.1 Hz, OCH2CH3), 4.64–
4.70 (1H, m, NCHPh), 5.73 (1H, d, J 6.6 Hz, NH), 6.98–
7.26 (6H, m, ArH), 7.47 (2H, d, J 8.2 Hz, ArH); dC
(100 MHz, CDCl3) 14.1, 21.4, 47.2, 49.3, 51.2, 53.2, 61.6,
126.8, 127.1, 128.7, 129.0, 129.3, 129.6, 131.8, 136.4,
136.7, 143.3, 166.6, 200.5; FAB Mass: m/z 468 (M++1),
470 (M++3).
4.2.8. 5-Furan-2-yl-3-oxo-5-(toluene-4-sulfonylamino)-
pentanoic acid ethyl ester (3h). The general procedure de-
scribed in Section 4.2 was followed to afford 3h (187.1 mg,
85%) as a yellow solid, mp 50 ꢁC. [Found: C, 56.76; H,
5.43; N, 3.35. C18H21NO6S requires: C, 56.98; H, 5.58; N,
3.69%.] Rf (40% ethyl acetate/petroleum ether) 0.37; nmax
(neat) 3277, 3122, 2984, 1746, 1719, 1599, 1501, 1443,
1410, 1327, 1156, 1090, 968, 918, 812, 752, 709, 678,
598 cmꢀ1; dH (400 MHz, CDCl3) 1.16 (3H, t, J 7.1 Hz,
OCH2CH3), 2.33 (3H, s, ArCH3), 2.96–3.19 (2H, m,
CH2CO), 3.32–3.40 (2H, m, COCH2CO2Et), 4.12 (2H, q,
J 7.1 Hz, OCH2CH3), 4.73–4.83 (1H, m, NCHPh), 5.47
(1H, d, J 8.2 Hz, NH), 5.91–6.10 (2H, m, Ar–H), 7.07–7.25
(3H, m, Ar–H), 7.59 (2H, d, J 8.3 Hz, Ar–H); dC
(100 MHz, CDCl3) 14.0, 21.5, 46.4, 47.7, 49.5, 61.6, 107.4,
110.4, 127.0, 129.7, 139.1, 141.9, 143.5, 151.6, 166.7, 200.2.
4.2.5. 5-(4-Methoxy-phenyl)-3-oxo-5-(toluene-4-sulfonyl-
amino)-pentanoic acid ethyl ester (3e). The general proce-
dure described in Section 4.2 was followed to afford 3e
(219 mg, 90%) as a yellow liquid. [Found: C, 60.35; H,
6.12; N, 3.29. C21H25NO6S requires: C, 60.13; H, 6.01; N,
3.34%] Rf (40% ethyl acetate/petroleum ether) 0.30; nmax
(neat) 3280, 2980, 2929, 1739, 1714, 1647, 1612, 1514,
1444, 1410, 1367, 1323, 1249, 1158, 1092, 1030, 814, 736,
666 cmꢀ1; dH (400 MHz, CDCl3) 1.16 (3H, t, J 7.1 Hz,
OCH2CH3), 2.34 (3H, s, ArCH3), 2.92–3.16 (2H, m,
CH2CO), 3.20–3.29 (2H, m, COCH2CO2Et), 3.67 (3H, s,
OCH3), 4.04 (2H, q, J 7.1 Hz, OCH2CH3), 4.57–4.75 (1H,
m, NCHPh), 5.26 (1H, s, NH), 6.63–7.29 (6H, m, ArH),
7.52 (2H, d, J 8.3 Hz, ArH); dC (100 MHz, CDCl3) 14.1,
21.5, 44.7, 49.2, 53.8, 55.2, 61.6, 113.8, 127.1, 127.8,
129.4, 131.4, 136.9, 143.2, 159.0, 166.8, 200.7; FAB
Mass: m/z 420 (M++1).
4.3. General procedure for the preparation of d-amino-
b-diketones (6a–e)
To a solution of diisopropylamine (0.24 mL, 1.7 mmol)
in 5 mL dry THF was added 2.3 M n-BuLi (0.74 mL,
1.7 mmol) at ꢀ50 ꢁC and stirred for 30 min. The color of
the solution changed to yellow, to which acetyl acetone
(0.087 mL, 0.85 mmol) was added slowly. Then stirring
was continued for 1 h to allow the formation of 1,3-dianion.
N-Sulfonyl imine (0.34 mmol), dissolved in 2 mL dry THF
was added to the reaction mixture and allowed to stir for ad-
ditional 2–2.5 h at the same temperature. After the comple-
tion of the reaction (monitored by TLC), it was quenched
with saturated aqueous ammonium chloride solution and ex-
tracted with 20 mL ethyl acetate in two portions. The com-
bined organic extract was dried over anhydrous Na2SO4
and the solvent was evaporated under vacuum. Silica gel col-
umn chromatographic purification of the crude mixture using
20% ethyl acetate in petroleum ether as the eluant afforded
the pure products 6a–e. All these compounds exist mostly
in enol form in CDCl3 as indicated by the 1H NMR spectra.
4.2.6. 5-Benzenesulfonylamino-5-(4-methoxy-phenyl)-3-
oxo-pentanoic acid ethyl ester (3f). The general procedure
described in Section 4.2 was followed to afford 3f
(169.3 mg, 72%) as a yellow liquid. [Found: C, 59.54; H,
5.82; N, 3.41. C20H23NO6S requires: C, 59.24; H, 5.72; N,
3.45%.] Rf (40% ethyl acetate/petroleum ether) 0.25; nmax
(neat) 3278, 3064, 2980, 2934, 1739, 1716, 1612, 1513,
1446, 1411, 1369, 1321, 1250, 1160, 1093, 1029, 833,
756, 721, 690, 597 cmꢀ1; dH (400 MHz, CDCl3) 1.15 (3H,
t, J 7.3 Hz, OCH2CH3), 2.90–3.12 (2H, m, CH2CO), 3.21–
3.30 (2H, m, COCH2CO2Et), 3.65 (3H, s, OCH3), 4.05
(2H, q, J 7.3 Hz, OCH2CH3), 4.63–4.77 (1H, m, NCHPh),
5.68 (1H, d, J 3.3 Hz, NH), 6.58–7.42 (7H, m, ArH), 7.60
(2H, d, J 7.1 Hz, ArH); dC (100 MHz, CDCl3) 14.1, 42.8,
49.2, 49.5, 55.3, 61.6, 113.8, 126.9, 127.4, 127.7, 128.7,
131.3, 132.3, 140.1, 158.9, 166.7, 200.5; FAB Mass: m/z
405 (M+).
4.3.1. N-(3,5-Dioxo-1-phenyl-hexyl)-4-methyl-benzene-
sulfonamide (6a). The general procedure described in Sec-
tion 4.3 was followed to afford 6a (95.3 mg, 78%) as
a yellow solid, mp 82 ꢁC. [Found: C, 63.47; H, 5.79; N,
3.95. C19H21NO4S requires: C, 63.49; H, 5.89; N, 3.90%.]
Rf (40% ethyl acetate/petroleum ether) 0.39; nmax (neat)
3173, 3065, 2960, 2883, 2746, 1744, 1697, 1601, 1571,
1497, 1460, 1423, 1322, 1294, 1254, 1232, 1203, 1152,
1092, 1066, 1030, 1009, 965, 911, 845, 804, 751, 699,
4.2.7. 5-Benzenesulfonylamino-3-oxo-5-phenyl-penta-
noic acid ethyl ester (3g). The general procedure described

4784
M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
668, 629, 582, 553, 510, 493 cmꢀ1; dH (400 MHz, CDCl3)
1.87 (3H, s, COCH3), 2.29 (3H, s, ArCH3), 2.55–2.66 (2H,
m, CH2), 4.59–4.64 (1H, m, ArCHN), 5.25 (1H, s, ]CH
of enol), 5.74 (1H, d, J 7.1 Hz, NH), 7.03–7.11 (7H, m,
ArH), 7.50 (2H, d, J 8.3 Hz, ArH); dC (100 MHz, CDCl3)
21.4, 24.3, 45.2, 55.1, 101.0, 126.4, 127.0, 127.5, 128.4,
129.3, 137.1, 139.7, 143.1, 190.4, 190.8; FAB Mass: m/z
360 (M++1).
(40% ethyl acetate/petroleum ether) 0.35; nmax (neat)
3358, 3266, 3061, 2921, 1702, 1598, 1528, 1493, 1473,
1414, 1336, 1305, 1253, 1207, 1156, 1091, 1055, 1018,
998, 940, 905, 842, 813, 788, 698, 672, 592, 563, 544,
505, 427 cmꢀ1; dH (400 MHz, CDCl3) 1.90 (3H, s,
COCH3), 2.31 (3H, s, ArCH3), 2.57–2.59 (2H, m, CH2),
4.57–4.63 (1H, m, ArCHN), 5.27 (1H, s, ]CH of enol),
5.86 (1H, d, J 7.1 Hz, NH), 6.97–7.25 (5H, m, ArH), 7.46
(2H, d, J 8.3 Hz, ArH), 7.74 (1H, d, J 8.0 Hz, ArH); dC
(100 MHz, CDCl3) 21.4, 24.3, 43.4, 57.7, 100.8, 126.9,
127.1, 128.6, 128.7, 129.3, 129.5, 131.7, 136.7, 137.1,
143.2, 190.5, 191.0.
4.3.2. N-[1-(2-Chloro-phenyl)-3,5-dioxo-hexyl]-4-methyl-
benzenesulfonamide (6b). The general procedure described
in Section 4.3 was followed to afford 6b (95.1 mg, 71%) as
a yellow solid, mp 75 ꢁC. [Found: C, 57.60; H, 5.14; N, 3.50.
C19H20ClNO4S requires: C, 57.94; H, 5.12; N, 3.56%.] Rf
(40% ethyl acetate/petroleum ether) 0.35; nmax (neat)
3235, 3062, 2916, 1711, 1606, 1319, 1159, 1090, 1012,
947 cmꢀ1; dH (400 MHz, CDCl3) 1.87 (3H, s, COCH3),
2.28 (3H, s, ArCH3), 2.49–2.67 (2H, m, CH2), 4.92–4.97
(1H, m, ArCHN), 5.22 (1H, m, ]CH of enol), 5.84 (1H,
d, J 7.1 Hz, NH), 7.02–7.26 (6H, m ArH), 7.52 (2H, d, J
7.3 Hz ArH); dC (100 MHz, CDCl3) 21.4, 24.3, 43.4, 57.7,
100.8, 126.9, 127.1, 128.6, 128.7, 129.3, 129.5, 131.7,
136.7, 137.1, 143.2, 190.5, 191.0; FAB Mass: m/z 394
(M++1), 396 (M++3).
4.4. General procedure for the synthesis of N-sulfonyl
piperidines (9a–d) starting from d-amino-b-keto ester 3
In a typical procedure, d-amino-b-keto ester 3 (1.32 mmol)
and 1,2-ethane diol (0.088 mL, 1.58 mmol) were dissolved
in 10 mL dry benzene in the presence of catalytic PTSA.
The mixture was refluxed for 5–8 h using Dean–Stark appa-
ratus. After the completion of the reaction, the crude mixture
was washed with aq NaHCO3 solution and extracted with
ethyl acetate. Silica gel column chromatographic purifica-
tion of the crude mixture afforded the pure cyclic ketal 7.
To a suspension of LiAlH4 (13.3 mg, 0.35 mmol) in
1.0 mL dry THF was added 0.23 mmol of 7 (dissolved in
1.0 mL dry THF) at 0 ꢁC and the reaction was allowed to
stir at room temperature for 1 h. After quenching the reac-
tion with drop wise addition of ethyl acetate at 0 ꢁC, the re-
action mixture was filtered through a sintered funnel. The
filtrate was washed with brine and concentrated under vac-
uum to afford 8. The crude product was sufficiently pure
4.3.3. N-[1-(4-Methoxy-phenyl)-3,5-dioxo-hexyl]-4-
methyl-benzenesulfonamide (6c). The general procedure
described in Section 4.3 was followed to afford 6c
(72.8 mg, 55%) as a yellow solid, mp 77–80 ꢁC. [Found: C,
61.88; H, 5.90; N, 3.50. C20H23NO5S requires: C, 61.68; H,
5.95; N, 3.60%.] Rf (40% ethyl acetate/petroleum ether)
0.28; nmax (neat) 3276, 2923, 2844, 1705, 1611, 1513, 1445,
1323, 1250, 1157, 1092, 1030, 958, 815, 737, 667, 453 cmꢀ1
;
as indicated by H NMR to proceed for the next reaction.
1
dH (400 MHz, CDCl3) 1.87 (3H, s, COCH3), 2.30 (3H, s,
ArCH3), 2.53–2.67 (2H, m, CH2), 3.67 (3H, s, OCH3),
4.54–4.59 (1H, m, ArCHN), 5.26 (1H, s, ]CH of enol),
5.72 (1H, d, J 6.5 Hz, NH), 6.62 (2H, d, J 8.5 Hz, ArH), 6.95
(2H, d, J 8.5, ArH), 7.08 (2H, d, J 8.0 Hz, ArH), 7.49 (2H, d, J
8.3 Hz, ArH); dC (100 MHz, CDCl3) 21.4, 24.4, 45.2, 54.6,
55.2, 100.9, 113.7, 127.0, 127.6, 129.3, 131.8, 137.2,
143.1, 158.9, 190.4, 191.2; FAB Mass: m/z 390 (M++1).
Finally, 8 (0.25 mmol) was treated with TsCl (57.2 mg,
0.30 mmol) and excess KOH (42 mg, 0.75 mmol) in reflux-
ing THF for 30 min. After the completion of the reaction
(monitored by TLC), it was quenched with water and ex-
tracted with 10 mL ethyl acetate in two portions. The com-
bined organic extract was dried over anhydrous Na2SO4
and the solvent was evaporated under vacuum. Silica gel
column chromatographic purification of the crude mixture
using 15% ethyl acetate in petroleum ether as the eluant
afforded the pure products 9a–d.
4.3.4. N-[1-(4-Chloro-phenyl)-3,5-dioxo-hexyl]-4-methyl-
benzenesulfonamide (6d). The general procedure described
in Section 4.3 was followed to afford 6d (104.5 mg, 78%) as
a yellow solid, mp 73 ꢁC. [Found: C, 57.82; H, 5.24; N, 3.65.
C19H20ClNO4S requires: C, 57.94; H, 5.12; N, 3.56%.] Rf
(40% ethyl acetate/petroleum ether) 0.37; nmax (neat) 3235,
1712, 1606, 1492, 1453, 1422, 1321, 1249, 1160, 1090,
1061, 1013, 948, 842, 815, 694, 660, 593, 566, 535,
450 cmꢀ1; dH (400 MHz, CDCl3) 1.94 (3H, s, COCH3),
2.36 (3H, s, ArCH3), 2.61–2.64 (2H, m, CH2), 4.63–4.65
(1H, m, ArCHN), 5.28 (1H, s, ]CH of enol), 5.97 (1H, d,
J 7.0 Hz, NH), 7.02–7.29 (6H, m, ArH), 7.51 (2H, d, J
8.2 Hz, ArH); dC (100 MHz, CDCl3) 21.4, 24.3, 45.2, 55.1,
101.0, 126.4, 127.0, 127.5, 128.4, 129.3, 137.1, 139.7,
143.1, 190.4, 190.8.
4.4.1. 7-Phenyl-8-(toluene-4-sulfonyl)-1,4-dioxa-8-aza-
spiro[4.5]decane (9a). The general procedure described in
Section 4.4 was followed to afford 9a (354.9 mg, 72% over-
all starting from 3a) as a yellow liquid. [Found: C, 64.35; H,
6.35; N, 3.80. C20H23NO4S requires: C, 64.32; H, 6.21; N,
3.75%.] Rf (30% ethyl acetate/petroleum ether) 0.36; nmax
(neat) 2929, 1601, 1493, 1451, 1345, 1226, 1158, 1095,
1035, 948, 861, 813, 728, 651, 472 cmꢀ1; dH (400 MHz,
CDCl3) 1.49–1.52 (2H, m, CH2), 1.78 (1H, dd, J 6.4,
14.2 Hz, CHaHb), 2.25 (1H, dd, J 3.6, 14.2 Hz, CHaHb),
2.30 (3H, s, ArCH3), 3.37–3.44 (1H, m, CHaHbN), 3.63–
3.83 (5H, m, CHaHbN, OCH2CH2O), 5.12 (1H, m, PhCH),
7.11–7.24 (7H, m, ArH), 7.59 (2H, d, J 8.3 Hz, ArH); dC
(100 MHz, CDCl3) 21.5, 33.8, 37.1, 41.2, 56.4, 64.0, 64.3,
106.2, 126.5, 126.7, 127.0, 128.0, 129.6, 137.7, 139.4,
143.2; FAB Mass: m/z 374 (M++1).
4.3.5. N-[1-(3-Bromo-phenyl)-3,5-dioxo-hexyl]-4-methyl-
benzenesulfonamide (6e). The general procedure described
in Section 4.3 was followed to afford 6e (120.7 mg, 81%) as
a yellow solid, mp 75 ꢁC. [Found: C, 52.16; H, 4.72; N, 3.10.
C19H20BrNO4S requires: C, 52.06; H, 4.60; N, 3.20%]; Rf
4.4.2. 7-(2-Chloro-phenyl)-8-(toluene-4-sulfonyl)-1,4-di-
oxa-8-aza-spiro[4.5]decane (9b). The general procedure

M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
4785
described in Section 4.4was followed to afford9b(382.3 mg,
71% overall starting from 3b) as a white solid, mp 100 ꢁC.
[Found: C, 58.79; H, 5.35; N, 3.48. C20H22ClNO4S requires:
C, 58.89; H, 5.44; N, 3.43%.] Rf (30% ethyl acetate/petro-
leum ether) 0.35; nmax (neat) 2976, 2937, 2894, 1596,
1466, 1440, 1349, 1310, 1216, 1155, 1121, 1089, 1033,
943, 851, 818, 774, 749, 714, 688, 652, 618, 559, 503,
477 cmꢀ1; dH (400 MHz, CDCl3) 1.62–1.69 (1H, m, CHaHb),
1.76–1.84 (2H, m, CHaHbCHcHd), 2.2 (1H, dd, J 8.0,
13.9 Hz, CHcHd), 2.30 (3H, s, ArCH3), 3.53–3.59 (1H, m,
CHaHbN), 3.63–3.91 (5H, m, CHaHbN, OCH2CH2O),
5.02–5.05 (1H, m, ArCH), 7.02–7.12 (6H, m, ArH), 7.35–
7.44 (2H, m, ArH); dC (100 MHz, CDCl3) 21.4, 34.4, 38.8,
44.1, 55.3, 64.1, 64.3, 106.3, 126.4, 127.3, 128.3, 129.2,
129.3, 132.1, 136.2, 138.1, 143.0; FAB Mass: m/z 408
(M++1), 410 (M++3).
evaporation to afford crude 12, which was purified through
a flash column chromatography (230–400 mesh size) using
30% acetone in petroleum ether as the eluant. To a solution
of DMAP (6.1 mg, 0.05 mmol), 12 (0.5 mmol), and triethyl
amine (0.1 mL, 0.75 mmol) in 2.0 mL dry DMF was added
drop wise a solution of TBDMSCl (90.4 mg, 0.6 mmol) in
1.0 mL dry DMF at 0 ꢁC over a period of 1 h. The reaction
mixture was stirred for additional 1 h at room temperature
and monitored by TLC. The reaction was quenched with
cold water and crude product was extracted with ethyl ace-
tate. Silica gel column chromatographic purification of the
crude mixture furnished the pure diastereomers 13x and
13y. To a solution of 13x or 13y (0.25 mmol) and KOH
(42 mg, 0.75 mmol) in 1.0 mL dry THF was added TsCl
(57.2 mg, 0.30 mmol) in portions at room temperature,
then the reaction was refluxed for 1 h. After the completion
of the reaction (monitored by TLC), it was quenched with
water and extracted with ethyl acetate. The organic extract
was dried over anhydrous Na2SO4 and the solvent was
evaporated under vacuum to give the crude product. Both
diastereomers were purified through silica gel column chro-
matography to provide the pure products 14x and 14y.
4.4.3. 7-(4-Chloro-phenyl)-8-(toluene-4-sulfonyl)-1,4-di-
oxa-8-aza-spiro[4.5]decane (9c). The general procedure
described in Section 4.4 was followed to afford 9c
(414.6 mg, 77% overall starting from 3c) as a yellow liquid.
[Found: C, 58.95, H, 5.54, N, 3.45. C20H22NO4S requires: C,
58.89; H, 5.44; N, 3.43%.] Rf (30% ethyl acetate/petroleum
ether) 0.28; nmax (neat) 2964, 2931, 2885, 1650, 1596, 1491,
1448, 1401, 1348, 1304, 1263, 1233, 1160, 1093, 1037, 984,
948, 870, 817, 748, 714, 656, 601, 553 cmꢀ1; dH (400 MHz,
CDCl3) 1.35–1.53 (2H, m, CH2), 1.77 (1H, dd, J 6.1,
14.2 Hz, CHaHb), 2.18 (1H, dd, J 3.4, 14.1 Hz, CHaHb),
2.35 (3H, s, ArCH3), 3.32–3.40 (1H, m, CHaHbN), 3.66–
3.83 (5H, m, CHaHbN, OCH2CH2O), 5.07–5.11 (1H, m,
ArCH), 7.16–7.21 (6H, m, ArH), 7.58 (2H, d, J 8.3 Hz,
ArH); dC (100 MHz, CDCl3) 21.3, 33.7, 37.1, 41.2, 56.0,
64.0, 64.3, 106.1, 126.9, 127.0, 127.9, 128.3, 129.8, 137.6,
138.0, 143.5; FAB Mass: m/z 408 (M++1), 410 (M++3).
4.5.1. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-
phenylpentyl)-4-methyl benzenesulfonamide (13xa). The
general procedure described in Section 4.5 was followed
to afford 13xa (103.2 mg, 44.5% from 12a) as colorless liq-
uid. Rf (35% ethyl acetate/petroleum ether) 0.50; nmax (neat)
3504, 3278, 3063, 3030, 2952, 2928, 2883, 2856, 1717,
1599, 1495, 1471, 1458, 1421, 1360, 1323, 1305, 1288,
1255, 1214, 1184, 1159, 1092, 1020, 1005, 938, 837, 812,
778, 701, 667, 564, 547 cmꢀ1; dH (400 MHz, CDCl3) 0.05
(3H, s, CH3Si), 0.07 (3H, s, CH3Si), 0.89 (9H, s, t-BuSi),
1.41–1.44 (1H, m, CHaHb), 1.57–1.83 (3H, m, CHaHb,
CHcHd), 2.36 (3H, s, ArCH3), 3.67–3.89 (4H, m, OCH2,
CHOH, OH), 4.61–4.66 (1H, m, ArCHN), 6.44 (1H, d,
J 7.32 Hz, NH), 7.09–7.20 (7H, m, ArH), 7.58 (2H, d,
J 8.0 Hz, ArH).
4.4.4. 7-(3-Bromo-phenyl)-8-(toluene-4-sulfonyl)-1,4-di-
oxa-8-aza-spiro[4.5]decane (9d). The general procedure
described in Section 4.4 was followed to afford 9d
(418 mg, 70% overall starting from 3d) as a yellow liquid.
[Found: C, 53.25; H, 5.17; N, 3.15. C20H22BrNO4S requires:
C, 53.10; H, 4.90; N, 3.10%.] Rf (30% ethyl acetate/petro-
leum ether) 0.30; nmax (neat) 2962, 2928, 2886, 1655,
1596, 1568, 1449, 1425, 1350, 1303, 1262, 1233, 1160,
1092, 1037, 987, 950, 900, 858, 812, 741, 696, 660, 624,
549, 472, 432 cmꢀ1; dH (400 MHz, CDCl3) 1.50–1.55 (2H,
m, CH2), 1.78 (1H, dd, J 6.4 Hz, J 14.2 Hz, CHaHb), 2.18
(1H, dd, J 3.6, 14.2 Hz, CHaHb), 2.35 (3H, s, ArCH3),
3.33–3.40 (1H, m, CHaHbN), 3.66–3.83 (5 H m, CHaHbN,
OCH2CH2O), 5.08–5.11 (1H, m, ArCH), 7.01–7.28 (6H,
m, ArH), 7.57 (2H, d, J 8.32 Hz, ArH); dC (100 MHz,
CDCl3) 21.6, 33.8, 37.1, 41.3, 53.3, 56.4, 64.0, 74.1,
106.1, 126.5, 126.9, 127.3, 128.0, 129.8, 137.5, 139.4,
143.0; Mass: m/z 452 (M++1), 454 (M++3).
4.5.2. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-
phenylpentyl)-4-methyl benzenesulfonamide (13ya). The
general procedure described in Section 4.5 was followed
to afford 13ya (124 mg, 53.5% from 12a) as a white solid,
mp 98–100 ꢁC. Rf (35% ethyl acetate/petroleum ether)
0.43; nmax (neat) 3487, 3273, 2952, 2929, 2857, 1599,
1494, 1461, 1430, 1325, 1254, 1158, 1089, 937, 835, 812,
779, 701, 667, 549, 427 cmꢀ1; dH (400 MHz, CDCl3) 0.07
(6H, s, CH3Si), 0.90 (9H, s, t-BuSi), 1.41–1.68 (3H, m,
CHaCHb, CHcHd), 1.87–1.96 (1H, m, CHcHd), 2.37 (3H, s,
ArCH3), 3.70–3.76 (2H, m, OCH2), 3.81–3.86 (1H, m,
CHOH), 4.00 (1H, s, OH), 4.32–4.36 (m, 1H, ArCHN),
6.44 (1H, d, J 2.4 Hz, NH), 7.13–7.20 (7H, m, ArH), 7.55
(2H, d, J 8.3 Hz, ArH).
4.5. General procedure for the synthesis of N-sulfonyl
azetidines starting from d-amino-b-keto ester 3
4.5.3. N-(5-(tert-Butyldimethylsilyloxy)-1-(2-chloro-
phenyl)-3-hydroxypentyl)-4-methyl benzenesulfonamide
(13xb). The general procedure described in Section 4.5
was followed to afford 13xb (81.4 mg, 32.7% from 12b) as
a white solid, mp 101–103 ꢁC. Rf (35% ethyl acetate/petro-
leum ether) 0.51; nmax (neat) 3491, 3283, 2952, 2930,
2885, 2857, 1598, 1469, 1444, 1329, 1255, 1214, 1160,
1091, 1040, 939, 836, 813, 780, 755, 731, 704, 666, 549,
461, 418 cmꢀ1; dH (400 MHz, CDCl3) 0.00 (3H, s,
To a suspension of LiAlH4 (190 mg, 5.0 mmol) in 15 mL dry
THF was added 3 (1.0 mmol dissolved in 5 mL dry THF) at
0 ꢁC and the reaction was stirred at room temperature for
1 h. After quenching the reaction with drop wise addition
of ethyl acetate at 0 ꢁC, the reaction mixture was filtered
through a sintered funnel. The filtrate was concentrated by

4786
M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
CH3Si), 0.02 (3H, s, CH3Si), 0.85 (9H, s, t-BuSi), 1.32–1.77
(4H, m, (CH2)a, (CH2)b), 2.31 (3H, s, ArCH3), 3.60–3.76
(3H, m, OCH2, CHOH), 4.94–4.95 (1H, m, ArCHN),
6.78–6.79 (1H, m, ArH), 7.05–7.40 (7H, m, ArH), 7.59
(2H, d, J 8.3 Hz, ArH).
CHaHb), 3.61–3.71 (2H, m, OCH2), 3.92–4.00 (1H, m,
NCH), 4.58 (1H, t, J 8.3 Hz, ArCHN), 7.17–7.35 (7H, m,
ArH), 7.62 (2H, d, J 8.0 Hz, ArH); dC (100 MHz, CDCl3)
ꢀ5.5, ꢀ5.4, 18.1, 21.6, 25.8, 33.2, 39.1, 58.5, 59.3, 62.9,
126.3, 127.8, 128.4, 128.5, 129.6, 132.2, 140.8, 143.8.
4.5.4. N-(5-(tert-Butyldimethylsilyloxy)-1-(2-chloro-
phenyl)-3-hydroxypentyl)-4-methyl benzenesulfonamide
(13yb). The general procedure described in Section 4.5
was followed to afford 13yb (162.7 mg, 65.3% from 12b)
as a white solid, mp 103–108 ꢁC. Rf (35% ethyl acetate/pe-
troleum ether) 0.44; nmax (neat): 3450, 3269, 2952, 2929,
2557, 1596, 1468, 1442, 1332, 1255, 1160, 1088, 941,
4.5.8. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-phenyl-1-
tosylazetidine (14ya). The general procedure described in
Section 4.5 was followed to afford 14ya (105.8 mg, 95%
from 13ya) as colorless liquid. [Found: C, 64.79; H, 7.75;
N, 3.27. C24H35NO3SSi requires: C, 64.68; H, 7.92; N,
3.14%.] Rf (10% ethyl acetate/petroleum ether) 0.34; nmax
(neat) 3063, 3031, 2954, 2927, 2884, 2856, 1598, 1494,
1471, 1460, 1388, 1343, 1304, 1287, 1255, 1158, 1094,
1028, 1006, 972, 939, 911, 882, 835, 813, 777, 735, 698,
673, 609, 547, 520 cmꢀ1; dH (400 MHz, CDCl3) 0.06 (6H,
s, CH3Si), 0.87 (9H, s, t-BuSi), 1.98–2.06 (1H, m, CHaHb),
2.32–2.40 (4H, m, ArCH3CHaHb), 2.47–2.55 (2H, m,
CH2), 3.76 (2H, t, J 5.9 Hz, OCH2), 4.53–4.59 (1H, m,
NCH), 5.21 (1H, dd, J 5.6, 8.8 Hz, ArCHN), 7.02–7.41
(9H, m, ArH); dC (100 MHz, CDCl3) ꢀ5.5, ꢀ5.4, 18.1,
21.4, 25.8, 31.9, 36.9, 59.7, 62.2, 65.2, 127.1, 127.6,
127.9, 128.2, 128.9, 136.8, 138.5, 142.5.
836, 814, 779, 756, 729, 666, 559, 460, 425 cmꢀ1
;
dH (400 MHz, CDCl3) 0.00 (6H, s, CH3Si), 0.84 (9H, s,
t-BuSi), 1.41–1.62 (4H, m, (CH2)a, (CH2)b), 2.33 (3H, s,
ArCH3), 3.59–3.79 (3H, m, OCH2, CHOH), 4.62–4.65
(1H, m, ArCHN), 7.03–7.22 (5H, m, ArH), 7.45 (1H, d,
J 7.3 Hz, ArH), 7.61 (2H, d, J 8.3 Hz, ArH).
4.5.5. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-(4-
methoxyphenyl)pentyl)-4-methyl benzenesulfonamide
(13xe). The general procedure described in Section 4.5 was
followed to afford 13xe (78.2 mg, 31.7% from 12e) as color-
less liquid. Rf (35% ethyl acetate/petroleum ether) 0.38; nmax
(neat)3482, 3278, 3054, 2953, 2929, 2856, 1733, 1653, 1612,
1558, 1540, 1513, 1463, 1440, 1361, 1321, 1304, 1265, 1250,
1177, 1158, 1091, 1036, 938, 836, 812, 779, 738, 704, 666,
565, 454, 417 cmꢀ1; dH (400 MHz, CDCl3): dH (400 MHz,
CDCl3) 0.05 (3H, s, CH3Si), 0.06 (3H, s, CH3Si), 0.89 (9H,
s, t-BuSi), 1.41–1.80 (4H, m, (CH2)a, (CH2)b), 2.36 (3H, s,
ArCH3), 3.68–3.92 (6H, m, OCH2, OCH3), 4.56–4.57 (1H,
m, ArCHN), 6.35 (1H, d, J 6.8 Hz, NH), 6.69 (2H, d,
J 8.0 Hz, ArH), 7.03 (2H, d, J 8.2 Hz, ArH), 7.13 (2H, d,
J 8.0 Hz, ArH), 7.57 (2H, d, J 8.0 Hz, ArH).
4.5.9. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(2-chloro-
phenyl)-1-tosylazetidine (14xb). The general procedure
described in Section 4.5 was followed to afford 14xb
(116.4 mg, 97% from 13xb) as a white solid, mp 92–
94 ꢁC. [Found: C, 60.21; H, 7.18; N, 3.10. C24H34ClNO3SSi
requires: C, 60.04; H, 7.14; N, 2.92%.] Rf (10% ethyl ace-
tate/petroleum ether) 0.46; nmax (neat) 2953, 2928, 2857,
1596, 1467, 1439, 1379, 1349, 1255, 1163, 1085, 1026,
942, 885, 832, 754, 662, 603, 553, 465 cmꢀ1; dH
(400 MHz, CDCl3) ꢀ0.03 (3H, s, CH3Si), 0.00 (3H, s,
CH3Si), 0.83 (9H, s, t-BuSi), 1.68–1.75 (1H, m, CHaHb),
1.84–1.90 (1H, m, CHaHb), 2.15–2.22 (1H, m, CHaHb),
2.44 (3H, s, ArCH3), 2.52–2.59 (1H, m, CHaHb), 3.60–
3.66 (1H, m, OCHaHb), 3.69–3.74 (1H, m, OCHaHb),
3.93–4.00 (1H, m, NCH), 4.93 (1H, t, J 8.3 Hz, ArCHN),
7.16–7.35 (5H, m, ArH), 7.69 (2H, d, J 8.3 Hz, ArH), 7.87
(1H, d, J 7.6 Hz, ArH); dC (100 MHz, CDCl3) ꢀ5.5, ꢀ5.4,
18.1, 21.6, 25.8, 32.1, 39.3, 58.7, 59.0, 60.0, 127.0, 128.0,
128.6, 128.7, 128.9, 129.7, 131.0, 131.3, 138.7, 144.1.
4.5.6. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-(4-
methoxyphenyl)pentyl)-4-methyl benzenesulfonamide
(13ye). The general procedure described in Section 4.5 was
followed to afford 13ye (156.3 mg, 63.3% from 12e) as
a white solid, mp 105–107 ꢁC. Rf (35% ethyl acetate/petro-
leum ether) 0.31; nmax (neat) 3490, 3273, 2952, 2929,
2856, 1612, 1513, 1463, 1441, 1360, 1323, 1305, 1249,
1177, 1158, 1091, 1036, 939, 835, 812, 778, 735, 806,
666, 548, 464, 419 cmꢀ1; dH (400 MHz, CDCl3) 0.07 (6H,
s, CH3Si), 0.90 (9H, s, t-BuSi), 1.47–1.95 (4H, m, (CH2)a,
(CH2)b), 2.38 (3H, s, ArCH3), 3.71–3.86 (6H, m, OCH2,
OCH3), 4.29 (1H, dd, J 4.8, 9.7 Hz, ArCHN), 6.70 (2H, d,
J 8.5 Hz, ArH), 7.05 (2H, d, J 8.5 Hz, ArH), 7.14 (2H, d,
J 8.0 Hz, ArH), 7.55 (2H, d, J 8.0 Hz, ArH).
4.5.10. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(2-
chlorophenyl)-1-tosylazetidine (14yb). The general proce-
dure described in Section 4.5 was followed to afford 14yb
(110.4 mg, 92% from 13yb) as colorless liquid. [Found: C,
60.18; H, 7.21; N, 2.95. C24H34ClNO3SSi requires: C,
60.04; H, 7.14; N, 2.92%.] Rf (10% ethyl acetate/petroleum
ether) 0.38; nmax (neat) 2955, 2929, 2856, 1597, 1470, 1441,
1346, 1257, 1158, 1092, 1035, 834, 778, 755, 668, 607, 546,
462, 416 cmꢀ1; dH (400 MHz, CDCl3) 0.06 (6H, s, CH3Si),
0.89 (9H, s, t-BuSi), 1.83–1.91 (1H, m, CHaHb), 2.19–2.26
(1H, m, CHaHb), 2.37–2.63 (5H, m, ArCH3 CH2), 3.65–
3.71 (2H, m, OCH2), 4.58–4.64 (1H, m, NCH), 5.66 (1H,
dd, J 6.8, 9.2 Hz, ArCHN), 7.19–7.42 (5H, m, ArH), 7.63–
7.69 (3H, m, ArH); dC (100 MHz, CDCl3) ꢀ5.6, 18.1,
21.5, 25.8, 32.0, 35.2, 59.7, 61.2, 62.4, 126.9, 127.6,
128.0, 128.7, 129.1, 129.4, 131.8, 136.8, 137.8, 143.3.
4.5.7. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-phenyl-1-
tosylazetidine (14xa). The general procedure described in
Section 4.5 was followed to afford 14xa (109.2 mg, 98%
from 13xa) as a white solid, mp 125–130 ꢁC. [Found: C,
64.61; H, 7.85; N, 3.20. C24H35NO3SSi requires: C, 64.68;
H, 7.92; N, 3.14%.] Rf (10% ethyl acetate/petroleum ether)
0.41; nmax (neat) 3030, 2953, 2927, 2884, 2855, 1598, 1494,
1471, 1386, 1346, 1304, 1289, 1256, 1161, 1092, 1018, 939,
885, 834, 812, 775, 742, 698, 665, 614, 599, 550, 527 cmꢀ1
;
dH (400 MHz, CDCl3) ꢀ0.02 (3H, s, CH3Si), ꢀ0.01 (3H, s,
CH3Si), 0.83 (9H, s, t-BuSi), 1.83–1.93 (2H, m, CH2),
2.10–2.19 (1H, m, CHaHb), 2.35–2.43 (4H, m, ArCH3,
4.5.11. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(4-
methoxyphenyl)-1-tosylazetidine (14xe). The general

M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787
4787
3. (a) Langer, P.; Stoll, M. Angew. Chem., Int. Ed. 1999, 38, 1803;
(b) Sibi, M. P.; Marvin, M.; Sharma, R. J. Org. Chem. 1995, 60,
5016.
4. Gawish, A.; Mitschka, R.; Cook, J. M. Tetrahedron Lett. 1981,
22, 211.
5. Hampton, K. G.; Christie, J. J. J. Org. Chem. 1976, 41, 2772.
6. (a) Langer, P.; Bellur, E. J. Org. Chem. 2003, 68, 9742; (b)
Langer, P.; Holtz, E.; Karime, I.; Saleh, N. N. R. J. Org.
Chem. 2001, 66, 6057.
7. (a) Langer, P.; Holtz, E. Angew. Chem. 2000, 112, 3208; (b)
Langer, P.; Holtz, E. Angew. Chem., Int. Ed. 2000, 39, 3086.
procedure described in Section 4.5 was followed to afford
14xe (101.1 mg, 85% from 13xe) as a white solid, mp 93–
96 ꢁC. [Found: C, 63.23; H, 7.89; N, 2.96. C25H37NO4SSi re-
quires: C, 63.12; H, 7.84; N, 2.94%.] Rf (10% ethyl acetate/
petroleum ether) 0.26; nmax (neat) 2953, 2928, 2894, 2856,
1613, 1558, 1514, 1463, 1386, 1347, 1303, 1250, 1162,
1091, 1034, 940, 887, 833, 776, 712, 680, 661, 604, 550,
470 cmꢀ1; dH (400 MHz, CDCl3) 0.00 (6H, s, CH3Si),
0.85 (9H, s, t-BuSi), 1.87–1.95 (2H, m, CH2), 2.16–2.19
(1H, m, CHaHb), 2.36–2.42 (4H, m, ArCH3, CHaHb),
3.68–3.79 (5H, m, OCH3, OCH2), 3.93–3.97 (1H, m,
NCH), 4.55 (1H, t, J 8.3 Hz, ArCHN), 6.82–6.85 (2H, m,
ArH), 7.28–7.33 (4H, m, ArH), 7.64 (2H, d, J 8.1 Hz,
ArH); dC (100 MHz, CDCl3) ꢀ5.4, 18.1, 21.5, 25.8, 33.3,
39.1, 55.2, 58.2, 59.3, 62.6, 113.8, 127.8, 128.4, 129.5,
132.4, 133.0, 143.7, 159.2.
€
8. Langer, P.; Doring, M. Synlett 2001, 1437.
9. Shibato, K.; Yamaguchi, M.; Nakashima, H.; Minami, T.
Tetrahedron 1988, 44, 4767.
10. Kraus, G. A.; Gottschalk, P. J. Org. Chem. 1983, 48, 2111.
11. Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668.
12. Pound, M. K.; Davies, D. L.; Pilkington, M.; Pina Vaz Sousa,
M. M.; Wallis, J. D. Tetrahedron Lett. 2002, 43, 1915.
13. (a) Hoffman, R. V.; Patonay, T.; Nayyar, N. K.; Tao, J.
Tetrahedron Lett. 1996, 37, 2381; (b) Bryson, T. A. J. Org.
Chem. 1973, 38, 3428; (c) Langer, P.; Freifeld, I.; Holtz, E.
Synlett 2000, 501.
4.5.12. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(4-me-
thoxyphenyl)-1-tosylazetidine (14ye). The general proce-
dure described in Section 4.5 was followed to afford 14ye
(83.2 mg, 70% from 13ye) as colorless liquid. [Found: C,
63.15; H, 7.74; N, 2.86. C25H37NO4SSi requires: C, 63.12;
H, 7.84; N, 2.94%.] Rf (10% ethyl acetate/petroleum ether)
0.22; nmax (neat) 2954, 2928, 2856, 1699, 1684, 1653,
1611, 1559, 1541, 1514, 1496, 1463, 1388, 1342, 1304,
1291, 1251, 1177, 1157, 1095, 1034, 971, 883, 833, 812,
777, 709, 674, 609, 548, 440 cmꢀ1; dH (400 MHz, CDCl3):
0.06 (6H, s, CH3Si), 0.89 (9H, s, t-BuSi), 1.96–2.04 (1H,
m, CHaHb), 2.30–2.52 (6H, m, CHaHb, CH2, ArCH3),
3.74–3.81 (5H, m, OCH3, OCH2), 4.49–4.57 (1H, m,
NCH), 5.17 (1H, dd, J 5.4, 8.5 Hz, ArCHN), 6.66–6.69
(2H, m, ArH), 6.99–7.26 (7H, m, ArH); dC (100 MHz,
CDCl3) ꢀ5.4, 18.1, 21.4, 25.8, 31.8, 37.2, 55.2, 59.7, 61.9,
64.9, 113.5, 127.1, 128.9, 129.0, 130.5, 136.9, 142.3, 159.4.
14. Lygo, B. Synlett 1993, 764.
15. (a) Seebach, D.; Ehrig, V. Angew. Chem. 1974, 86, 446; (b)
Seebach, D.; Ehrig, V. Angew. Chem., Int. Ed. Engl. 1974,
13, 401.
16. (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure,
Preparation and Synthetic Applications of Piperidine and its
Derivatives; Elsevier: Amsterdam, 1991; (b) Bailey, P. D.
Chem. Commun. 1998, 633.
17. (a) Fowden. Nature 1955, 176, 347; (b) Bannon, A. W.; Decker,
M. W.; Holladay, M. W.; Curzon, P.; Donnelly-Roberts, D.;
Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.; Dickenson, A. H.;
Porsolt, R. D.; Williams, M.; Arneric, S. P. Science 1998, 279,
77; (c) Suzuki, K.; Shimada, K.; Nozoe, S.; Tanzawa, K.;
Ogita, T. J. Antibiot. (Tokyo) 1996, 49, 1284; (d) Figueiredo,
€
R. M. d; Frohlich, R.; Christmann, M. J. Org. Chem. 2006,
Acknowledgements
71, 4147; (e) Ghorai, M. K.; Das, K.; Kumar, A.; Das, A.
Tetrahedron Lett. 2006, 47, 5393 and reference cited therein.
18. Li, B.; Franck, R. W. Bioorg. Med. Chem. Lett. 1999, 9, 2629.
19. (a) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169; (b)
Davis, F. A.; Chao, B.; Fang, T. Org. Lett. 2000, 2, 1041; (c)
Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623; (d) Davis,
F. A.; Fang, T. Synthesis 2000, 4, 2106; (e) Davis, F. A.;
Zhang, J.; Li, Y.; Xu, H.; DeBrosse, C. J. Org. Chem. 2005,
70, 5413.
M.K.G. is grateful to IIT-Kanpur and DST, India. A.K.
thanks CSIR and S.H. thanks DST for research fellowships.
We are grateful to Nirupam Purkaystha for initial experi-
ments.
Supplementary data
20. From the experimental procedure19b,c provided by Davis et al.
where methyl acetate was added slowly to a solution of excess
NaHMDS at ꢀ78 ꢁC, it is clear that their reaction proceeds by
the following mechanism. The addition of methyl acetate eno-
late to aldimine produces b-amino ester, which subsequently
reacts with one more equivalent of the ester enolate to give
d-amino-b-keto esters probably via a Claisen type ester con-
densation reaction.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.03.081.
References and notes
1. Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702.
2. (a) Langer, P.; Freiberg, W. Chem. Rev. 2004, 104, 4125; (b)
Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33, 2159.
21. Chaudhary, S. K.; Hernandez, O. TetrahedronLett. 1979, 20, 99.