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-
1,3-Dicarbonyl dianions have been used extensively in or- carbonyl dianions, it was envisaged that dianions derived
ganic synthesis for building ring systems. The anion on the from suitable precursors could be regioselectively added to
terminal carbon of the dianion can be regioselectively reacted aldimines to give an easy access to d-amino-b-keto esters18
with 1 equiv of an electrophile resulting in an enolate ion, and their diketone analogues. These compounds could easily
which can be trapped by the addition of a second electrophile be converted into various piperidine and azetidine deriva-
or quenched by a proton source.1 Comprehensive studies of tives.
1,3-dicarbonyl dianions employing a variety of electrophiles
to produce useful and synthetically important cyclic com- Substituted d-amino-b-keto esters are important polyfunc-
pounds, especially heterocycles, are well documented tionalized building blocks for the synthesis of important
in the literature.2 These electrophiles include N,N1-di- alkaloids, e.g., (R)-(+)-2-phenylpiperidine, ()-SS20846A,
methoxy-N,N1-dimethylethanediamide,3 1,2-diketones,4 1,2- (+)-241D, and its C-4 epimer, 4-hydroxypipecolic acid.19
dibromo or 1,2-diiodoethane,5 1-bromo-2-chloroethane,6 Similarly, d-amino-b-diketone derivatives could be utilized
1,4-dibromo-2-butene,7 oxalic acid-bis(imidoyl)chlorides,8 as important intermediates for direct synthesis of some of
a-chloroacetic esters,9 esters and amides,9 aldehydes,10 a- these alkaloids. Davis et al. reported the synthesis of
azidoketones,11 cyclic sulfate esters,12 epoxides,13 N-tosyl d-amino-b-keto ester derivatives by a sequential addition of
aziridines,14 and nitro-olefins.15 Six-membered nitrogen 2 equiv of methyl acetate enolate to N-sulfinyl aldimine.19b,20
heterocycles are one of the widely found structural units in They utilized those d-amino-b-keto esters as the key interme-
various natural products and are very important intermediates diates for elegant syntheses of the aforesaid alkaloids.19 We
in organic synthesis. In particular, the piperidine alkaloids report herein, a new strategy for the regioselective addition
and their synthetic analogues are the focus of great interest of 1,3-dicarbonyl dianions to N-sulfonyl aldimines as a con-
in the pharmaceutical industry because of their wide range venient and new route to substituted d-amino-b-keto esters
of biological activities.16 Azetidines are another important and d-amino-b-diketones in good to excellent yields. These
class of heterocyclic compounds found in many naturally oc- d-amino-b-keto esters were further transformed to N-sulfo-
curring or important organic molecules, which exhibit inter- nyl piperidines and N-sulfonyl azetidines using simple
esting biological and pharmacological properties.17 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. To test our methodology, we selected ethyl acetoacetate 1 as
* Corresponding author. Tel.: +91 512 2597518; fax: +91 512 2597436; a precursor of 1,3-dicarbonyl dianion 2. We anticipated that
e-mail: mkghorai@iitk.ac.in 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

aldimines would provide the corresponding d-amino-b-keto Table 1. Regioselective addition of 1,3-dianion of ethyl acetoacetate to
esters 3 in a single step (Scheme 1). Dianion 2 was generated N-sulfonyl aldimines
from 1 by the treatment of LDA at 50  C. When 1.0 equiv Entry Ar Ar1 Yielda of 3 (%)
of N-sulfonyl aldimine was added to 1.0 equiv of 2 (entry 1,
Table 1), a complex mixture was obtained from which only 1 3a, 77 (35)
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- 2 3b, 87
Cl
creased the yield of 3a to 77%. In order to generalize this
approach, reaction of 2 with a number of N-sulfonyl aldi- 3 Cl 3c, 83
mines (entries 2–8) was studied. In all cases, the reaction
went smoothly to produce d-amino-b-keto esters 3a–h in Br
excellent yields (Table 1). Similarly, 1,3-dianion 5 was 4 3d, 88
generated from acetyl acetone 4 by the treatment of LDA
at 50  C. When 2.5 equiv of 5 was allowed to react with
5 MeO 3e, 90
1.0 equiv of N-sulfonyl aldimines, the corresponding
d-amino-b-diketones 6a–e were obtained in very good yield
(Scheme 2). 6 MeO 3f, 72

O O
O O OLi OLi 7 3g, 75 (30)
2 eq LDA Ar N SO2Ar1 OEt
OEt −50 °C, THF OEt SO2Ar1
−50 °C, THF Ar N
1h 2-2.5 h H
1 2 3 upto 90% 8 3h, 85
O
1 1
a: Ar = Ph, Ar = 4-Me-C6H4 e: Ar = 4-MeO-C6H4, Ar = 4-Me-C6H4
b: Ar = 2-Cl-C6H4, Ar1 = 4-Me-C6H4 f: Ar = 4-MeO-C6H4, Ar1 = Ph a
Yields of isolated products after column chromatographic purification.
c: Ar = 4-Cl-C6H4, Ar1 = 4-Me-C6H4 g: Ar = Ph, Ar1 = Ph Yield mentioned in the parenthesis is obtained by using 1:1 ratio of di-
d: Ar = 3-Br-C6H4, Ar1 = 4-Me-C6H4 h: Ar = furfuryl, Ar1 = 4-Me-C6H4 anion and the aldimine.
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
To explore the synthetic potential of this strategy, we further in Table 2.
converted 3a–d into the corresponding substituted piperi-
dines 9a–d using simple and known chemistry (Scheme 3). After successful utilization of 3 for the syntheses of six-
The keto group of 3a was first protected as a cyclic ketal membered N-heterocycles 9, we were interested in the
7a using 1,2-ethane diol in the presence of p-toluenesulfonic synthesis of four-membered N-heterocycles (azetidines).
acid. The ester functionality of 7a was further reduced to the Our initial attempt toward the synthesis of azetidine 10 is
corresponding primary alcohol 8a by treatment with LiAlH4. shown in Scheme 4. At first the keto group of 3a was reduced
Treatment of 8a with TsCl and excess KOH in refluxing THF to the corresponding alcohol by treatment with NaBH4 in

O O
O O OLi OLi
2 equiv. LDA Ar N Ts (0.4 equiv.)
Ts
−50 °C, THF −50 °C, THF Ar N
1h 2-2.5 h H
4 5 6
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, HO OH OEt LAH, THF OH
Ar NH Benzene, Ar NH 0 °C-R.T., 1 h Ar NH
Ts Reflux, 5-8 h
Ts Ts
3 7 8

O O
KOH, TsCl
up to 77%
THF, Reflux from 3 Ar = a: Ph, b: 2-Cl-C6H4, c: 4-Cl-C6H4, d: 3-Br-C6H4
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 4781

Table 2. Synthesis of substituted N-sulfonyl piperidines 9 from d-amino-b-keto esters 3

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
Ar NH Ar NH Ts Ar N
Ar N
Ts Ts H Ts

1 a: Ar¼Ph 78 95 98 72
2 b: Ar¼2-Cl–C6H4 88 90 90 71
3 c: Ar¼4-Cl–C6H4 85 93 98 77
4 d: Ar¼3-Br–C6H4 80 96 92 70
a
Yields of isolated products after column chromatography.

Ph Ts
N
O O OH O
CO2Et
OEt OEt 10
NaBH4 TsCl, KOH
O
Ph NH MeOH Ph NH THF, Reflux
Ts Ts OEt
3a Ph NH
Ts
11

Scheme 4. Attempt toward the synthesis of substituted azetidine from d-amino-b-keto ester 3a.

methanol. When the alcohol was treated with TsCl and ex- Table 3. Synthesis of N-sulfonyl azetidines 14 from d-amino-b-keto esters 3
cess KOH in refluxing THF, homoallyl amine 11 was formed 3 Yieldb (%) of Yieldb (%) of Yieldb,c
instead of 10. 12 (syn/anti)a,d 13x+13y (syn/anti)a,c,d,e (%) of 14
3a 12a, 65 (1:1.2) 13xa+13ya, 98 (1:1.2) 14xa, 98
However, 3 was converted into the corresponding N-sulfonyl 14ya, 95
azetidine 14 by a different strategy as shown in Scheme 5.
3b 12b, 65 (1:2) 13xb+13yb, 98 (1:2) 14xb, 97
Both the keto and ester groups of d-amino-b-keto ester 3a 14yb, 92
were reduced by treating with LiAlH4 to give the corre-
3e 12e, 55 (1:2) 13xe+13ye, 95 (1:2) 14xe, 85
sponding amino diol 12a as a mixture of diastereomers (dr 14ye, 70
1.2:1) (Table 3). Primary alcohol group of 12a was selec-
tively protected as TBDMS ether 13 as a mixture of diaste- a
Ratio determined by 1H NMR of crude reaction mixture.
b
reomers (dr 1.2:1) by using TBDMSCl and Et3N in the Yield of isolated product after column chromatography.
c
The relative stereochemistry is shown.
presence of catalytic DMAP in DMF.21 Both the diastereo- d
syn/anti Stereochemistry was decided considering the SN2 cyclization of
mers 13xa and 13ya were isolated in pure forms by silica 13 leading to 14 (stereochemistry of 14 was determined by NOE experi-
gel column chromatography. Subsequently, each of the ment).
e
pure diastereomers 13xa and 13ya was treated separately Compounds 13x and 13y were separated by column chromatography
before cyclization to 14.
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- 12b,e as TBDMS ethers, both the diastereomers 13xb,e
tion of 3b,e furnished 12b,e as a mixture of diastereomers and 13yb,e were separated by column chromatography to
(dr 2:1). After protection of the primary alcohol group of afford diastereomerically pure products. In a similar fashion,

O OH
CO2Et
OH
LAH, THF TBDMSCl Ar Ar
2 OTBDMS 2 OTBDMS
Ar NH Ar NH +
0 °C-R.T. Et3N, DMAP NHTs OH NHTs OH
Ts Ts
1h DMF, 0 °C-R.T., 1 h
3 12 13x 13 y
1. Separation through 2. TsCl, KOH, THF, reflux, 1 h
a: Ar = Ph column chromatography
b: Ar = 2-Cl-C6H4
Ar Ts Ar Ts
e: Ar = 4-MeO-C6H4 N N
OTBDMS OTBDMS
2 2
14 x 14 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

OTBDMS 2.9 mmol) at 50  C and stirred for 30 min. The color of
H OTBDMS the solution changed to yellow, to which ethyl acetoacetate
H
H (0.18 mL, 1.45 mmol) was added slowly. Then stirring was
Ts H
N Ts
N continued for 1 h to allow the formation of 1,3-dianion. N-
Cl Sulfonyl imine (0.58 mmol) dissolved in 3 mL dry THF
Cl
was added to the reaction mixture and allowed to stir for ad-
14xb (cis) 14yb (trans) ditional 2–2.5 h at the same temperature. After the comple-
tion of the reaction (monitored by TLC), it was quenched
Figure 1. Determination of stereochemistry of 14b by NOE experiment. with saturated aqueous ammonium chloride solution, and
extracted with 20 mL ethyl acetate in two portions. The
13xb,e and 13yb,e when treated with TsCl and excess KOH in
combined organic extract was dried over anhydrous
refluxing THF, the corresponding N-tosyl-azetidines 14xb,e
Na2SO4 and the solvent was evaporated under vacuum.
and 14yb,e were obtained in diastereomerically pure forms
Silica gel column chromatographic purification of the crude
in excellent yields. Interestingly, in all the above cases the
mixture, using 20% ethyl acetate in petroleum ether as the
major diastereomer 14x was obtained with 2,4-cis stereo-
eluant, afforded the pure products 3a–h.
chemistry. The cis-geometry was determined by NOE mea-
surements between the protons at C-2 and C-4 positions
4.2.1. 3-Oxo-5-phenyl-5-(toluene-4-sulfonylamino)-
(Fig. 1).
pentanoic acid ethyl ester (3a). The general procedure de-
scribed in Section 4.2 was followed to afford 3a (173.9 mg,
When the free amino diol 12b was treated with TsCl and ex-
77%) as a yellow liquid. [Found: C, 61.78; H, 5.90; N,
cess KOH in refluxing THF, the reaction was found to be
3.65. C20H23NO5S requires: C, 61.68; H, 5.95; N, 3.60%.] Rf
complicated as indicated by the 1H NMR of the crude reac-
(40% ethyl acetate/petroleum ether) 0.39; nmax (neat) 3278,
tion mixture.
2981, 2925, 1737, 1713, 1649, 1411, 1386, 1323, 1157, 1091,
1025, 965, 813, 754, 701, 667 cm1; dH (400 MHz, CDCl3)
3. Conclusion 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-
In conclusion, we have developed a new strategy for the CO2Et), 4.1 (2H, q, J 7.1 Hz, OCH2CH3), 4.62–4.75 (1H,
regioselective addition of 1,3-dicarbonyl dianions derived m, NCHPh), 5.38 (1H, d, J 7.0 Hz, NH), 6.93–7.13 (6H, m,
from ethyl acetoacetate or acetyl acetone to N-sulfonyl ArH), 7.51 (2H, d, J 8.3 Hz, ArH); dC (100 MHz, CDCl3)
aldimines to produce d-amino-b-keto esters or d-amino-b-di- 14.1, 21.5, 49.0, 49.6, 53.8, 61.6, 126.5, 127.1, 127.7,
ketones, respectively. The synthetic potential of this method- 128.5, 129.4, 137.0, 139.5, 143.1, 166.8, 200.5; FAB Mass:
ology is further demonstrated by the syntheses of various m/z 390 (M++1).
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
4. Experimental (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;
4.1. General N, 3.30%.] Rf (40% ethyl acetate/petroleum ether) 0.37;
nmax (neat) 3280, 3064, 2982, 2925, 1739, 1717, 1653,
All commercial reagents were used as received. 1H and 13C 1598, 1473, 1443, 1414, 1367, 1323, 1237, 1187, 1159,
NMR spectra were recorded on JEOL JNM-LA400 instru- 1091, 1030, 813, 757, 729, 704, 666, 589 cm1; dH
ment at 20–25  C in CDCl3 as the solvent and using TMS (400 MHz, CDCl3) 1.16 (3H, t, J 7.1 Hz, OCH2CH3), 2.27
as the internal standard. IR spectra were recorded on (3H, s, ArCH3), 2.93–3.13 (2H, m, CH2CO), 3.21–3.30
BRUKER VERTEX 70 instrument. Elemental analysis data (2H, m, COCH2CO2Et), 4.12 (2H, q, J 7.1 Hz, OCH2CH3),
were obtained from THERMO QUEST CE Instrument (EA 5.02–5.07 (1H, m, NCHPh), 5.86 (1H, d, J 8.0 Hz, NH),
1110, CHNS-O). TLC was carried out with 0.2 mm thick 6.93–7.25 (6H, m, ArH), 7.50 (2H, d, J 8.3 Hz, ArH); dC
pre-coated silica gel plates (Merck, silica gel 60 F254) using (100 MHz, CDCl3) 14.1, 21.5, 42.4, 48.9, 53.2, 61.6,
ethyl acetate/petroleum ether as the mobile phase. Visualiza- 122.4, 125.3, 126.9, 129.4, 129.7, 129.9, 130.6, 136.8,
tion of spots was accomplished by UV light and iodine. Col- 141.5, 143.5, 166.7, 200.2; FAB Mass: m/z 424 (M++1),
umn chromatography was performed using Acme’s (India) 426 (M++3).
silica gel (100–200 mesh size) and Spectrochem (India) silica
gel (230–400 mesh size). All solvents used in reactions were 4.2.3. 5-(4-Chloro-phenyl)-3-oxo-5-(toluene-4-sulfonyl-
anhydrous and purified according to standard procedures. All amino)-pentanoic acid ethyl ester (3c). The general proce-
air- or moisture-sensitive reactions were performed under dure described in Section 4.2 was followed to afford 3c
argon atmosphere. Glassware was oven-dried (130  C) and (204.1 mg, 83%) as a yellow liquid. [Found: C, 56.77; H,
purged with argon. 5.30; N, 3.42. C20H22ClNO5S requires: C, 56.67; H, 5.23;
N, 3.30%.] Rf (40% ethyl acetate/petroleum ether) 0.39;
4.2. General procedure for the preparation of d-amino- nmax (neat) 3278, 2980, 1737, 1713, 1649, 1411, 1386,
b-keto esters (3a–h) 1323, 1157, 1091, 1029, 965 cm1; dH (400 MHz, CDCl3)
1.17 (3H, t, J 7.1 Hz, OCH2CH3), 2.33 (3H, s, ArCH3),
To a solution of diisopropylamine (0.41 mL, 2.9 mmol) 2.89–3.12 (2H, m, CH2CO), 3.22–3.30 (2H, m, COCH2-
in 5 mL dry THF was added 2.3 M n-BuLi (1.26 mL, CO2Et), 4.08 (2H, q, J 7.1 Hz, OCH2CH3), 4.62–4.64 (1H,
 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, in Section 4.2 was followed to afford 3g (163.3 mg, 75%) as
ArH), 7.48 (2H, d, J 8.2 Hz, ArH); dC (100 MHz, CDCl3) a yellow liquid. [Found: C, 60.98; H, 5.72; N, 3.69.
14.1, 21.5, 49.0, 49.6, 53.8, 61.6, 126.5, 127.1, 127.7, C19H21NO5S requires: C, 60.78; H, 5.64; N, 3.73%.] Rf
128.5, 129.4, 137.0, 139.5, 143.1, 166.8, 200.5; FAB (40% ethyl acetate/petroleum ether) 0.28; nmax (neat)
Mass: m/z 424 (M++1), 426 (M++3). 3281, 3064, 2982, 2933, 1738, 1716, 1625, 1447, 1410,
1370, 1323, 1262, 1161, 1094, 1068, 1029, 941, 859, 807,
4.2.4. 5-(3-Bromo-phenyl)-3-oxo-5-(toluene-4-sulfonyl- 756, 721, 691, 644 cm1; dH (400 MHz, CDCl3) 1.17 (3H,
amino)-pentanoic acid ethyl ester (3d). The general proce- t, J 7.1 Hz, OCH2CH3), 2.93–3.16 (2H, m, CH2CO), 3.21–
dure described in Section 4.2 was followed to afford 3d 3.43 (2H, m, COCH2CO2Et), 4.01 (2H, q, J 7.1 Hz,
(238.7 mg, 88%) as a yellow liquid. [Found: C, 51.35; H, OCH2CH3), 4.66–4.77 (1H, m, NCHPh), 5.60 (1H, d,
4.82; N, 3.12. C20H22BrNO5S requires: C, 51.29; H, 4.73; J 3.3 Hz, NH), 6.99–7.45 (8H, m, ArH), 7.62 (2H, d,
N, 2.99%.] Rf (40% ethyl acetate/petroleum ether) 0.38; J 7.8 Hz, ArH); dC (100 MHz, CDCl3) 14.1, 49.0, 49.6,
nmax (neat): 3272, 3061, 2981, 2928, 1738, 1714, 1649, 53.8, 61.6, 126.5, 127.1, 127.7, 128.5, 129.4, 137.0, 139.5,
1596, 1569, 1439, 1409, 1367, 1327, 1189, 1159, 1092, 143.1, 166.8, 200.5; FAB Mass: m/z 376 (M++1).
1026, 963, 895, 813, 787, 736, 699 cm1; dH (400 MHz,
CDCl3) 1.16 (3H, t, J 7.1 Hz, OCH2CH3), 2.32 (3H, s, 4.2.8. 5-Furan-2-yl-3-oxo-5-(toluene-4-sulfonylamino)-
ArCH3), 2.90–3.11 (2H, m, CH2CO), 3.28–3.30 (2H, m, pentanoic acid ethyl ester (3h). The general procedure de-
COCH2CO2Et), 4.07 (2H, q, J 7.1 Hz, OCH2CH3), 4.64– scribed in Section 4.2 was followed to afford 3h (187.1 mg,
4.70 (1H, m, NCHPh), 5.73 (1H, d, J 6.6 Hz, NH), 6.98– 85%) as a yellow solid, mp 50  C. [Found: C, 56.76; H,
7.26 (6H, m, ArH), 7.47 (2H, d, J 8.2 Hz, ArH); dC 5.43; N, 3.35. C18H21NO6S requires: C, 56.98; H, 5.58; N,
(100 MHz, CDCl3) 14.1, 21.4, 47.2, 49.3, 51.2, 53.2, 61.6, 3.69%.] Rf (40% ethyl acetate/petroleum ether) 0.37; nmax
126.8, 127.1, 128.7, 129.0, 129.3, 129.6, 131.8, 136.4, (neat) 3277, 3122, 2984, 1746, 1719, 1599, 1501, 1443,
136.7, 143.3, 166.6, 200.5; FAB Mass: m/z 468 (M++1), 1410, 1327, 1156, 1090, 968, 918, 812, 752, 709, 678,
470 (M++3). 598 cm1; dH (400 MHz, CDCl3) 1.16 (3H, t, J 7.1 Hz,
OCH2CH3), 2.33 (3H, s, ArCH3), 2.96–3.19 (2H, m,
4.2.5. 5-(4-Methoxy-phenyl)-3-oxo-5-(toluene-4-sulfonyl- CH2CO), 3.32–3.40 (2H, m, COCH2CO2Et), 4.12 (2H, q,
amino)-pentanoic acid ethyl ester (3e). The general proce- J 7.1 Hz, OCH2CH3), 4.73–4.83 (1H, m, NCHPh), 5.47
dure described in Section 4.2 was followed to afford 3e (1H, d, J 8.2 Hz, NH), 5.91–6.10 (2H, m, Ar–H), 7.07–7.25
(219 mg, 90%) as a yellow liquid. [Found: C, 60.35; H, (3H, m, Ar–H), 7.59 (2H, d, J 8.3 Hz, Ar–H); dC
6.12; N, 3.29. C21H25NO6S requires: C, 60.13; H, 6.01; N, (100 MHz, CDCl3) 14.0, 21.5, 46.4, 47.7, 49.5, 61.6, 107.4,
3.34%] Rf (40% ethyl acetate/petroleum ether) 0.30; nmax 110.4, 127.0, 129.7, 139.1, 141.9, 143.5, 151.6, 166.7, 200.2.
(neat) 3280, 2980, 2929, 1739, 1714, 1647, 1612, 1514,
1444, 1410, 1367, 1323, 1249, 1158, 1092, 1030, 814, 736, 4.3. General procedure for the preparation of d-amino-
666 cm1; dH (400 MHz, CDCl3) 1.16 (3H, t, J 7.1 Hz, b-diketones (6a–e)
OCH2CH3), 2.34 (3H, s, ArCH3), 2.92–3.16 (2H, m,
CH2CO), 3.20–3.29 (2H, m, COCH2CO2Et), 3.67 (3H, s, To a solution of diisopropylamine (0.24 mL, 1.7 mmol)
OCH3), 4.04 (2H, q, J 7.1 Hz, OCH2CH3), 4.57–4.75 (1H, in 5 mL dry THF was added 2.3 M n-BuLi (0.74 mL,
m, NCHPh), 5.26 (1H, s, NH), 6.63–7.29 (6H, m, ArH), 1.7 mmol) at 50  C and stirred for 30 min. The color of
7.52 (2H, d, J 8.3 Hz, ArH); dC (100 MHz, CDCl3) 14.1, the solution changed to yellow, to which acetyl acetone
21.5, 44.7, 49.2, 53.8, 55.2, 61.6, 113.8, 127.1, 127.8, (0.087 mL, 0.85 mmol) was added slowly. Then stirring
129.4, 131.4, 136.9, 143.2, 159.0, 166.8, 200.7; FAB was continued for 1 h to allow the formation of 1,3-dianion.
Mass: m/z 420 (M++1). N-Sulfonyl imine (0.34 mmol), dissolved in 2 mL dry THF
was added to the reaction mixture and allowed to stir for ad-
4.2.6. 5-Benzenesulfonylamino-5-(4-methoxy-phenyl)-3- ditional 2–2.5 h at the same temperature. After the comple-
oxo-pentanoic acid ethyl ester (3f). The general procedure tion of the reaction (monitored by TLC), it was quenched
described in Section 4.2 was followed to afford 3f with saturated aqueous ammonium chloride solution and ex-
(169.3 mg, 72%) as a yellow liquid. [Found: C, 59.54; H, tracted with 20 mL ethyl acetate in two portions. The com-
5.82; N, 3.41. C20H23NO6S requires: C, 59.24; H, 5.72; N, bined organic extract was dried over anhydrous Na2SO4
3.45%.] Rf (40% ethyl acetate/petroleum ether) 0.25; nmax and the solvent was evaporated under vacuum. Silica gel col-
(neat) 3278, 3064, 2980, 2934, 1739, 1716, 1612, 1513, umn chromatographic purification of the crude mixture using
1446, 1411, 1369, 1321, 1250, 1160, 1093, 1029, 833, 20% ethyl acetate in petroleum ether as the eluant afforded
756, 721, 690, 597 cm1; dH (400 MHz, CDCl3) 1.15 (3H, the pure products 6a–e. All these compounds exist mostly
t, J 7.3 Hz, OCH2CH3), 2.90–3.12 (2H, m, CH2CO), 3.21– in enol form in CDCl3 as indicated by the 1H NMR spectra.
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), 4.3.1. N-(3,5-Dioxo-1-phenyl-hexyl)-4-methyl-benzene-
5.68 (1H, d, J 3.3 Hz, NH), 6.58–7.42 (7H, m, ArH), 7.60 sulfonamide (6a). The general procedure described in Sec-
(2H, d, J 7.1 Hz, ArH); dC (100 MHz, CDCl3) 14.1, 42.8, tion 4.3 was followed to afford 6a (95.3 mg, 78%) as
49.2, 49.5, 55.3, 61.6, 113.8, 126.9, 127.4, 127.7, 128.7, a yellow solid, mp 82  C. [Found: C, 63.47; H, 5.79; N,
131.3, 132.3, 140.1, 158.9, 166.7, 200.5; FAB Mass: m/z 3.95. C19H21NO4S requires: C, 63.49; H, 5.89; N, 3.90%.]
405 (M+). Rf (40% ethyl acetate/petroleum ether) 0.39; nmax (neat)
3173, 3065, 2960, 2883, 2746, 1744, 1697, 1601, 1571,
4.2.7. 5-Benzenesulfonylamino-3-oxo-5-phenyl-penta- 1497, 1460, 1423, 1322, 1294, 1254, 1232, 1203, 1152,
noic acid ethyl ester (3g). The general procedure described 1092, 1066, 1030, 1009, 965, 911, 845, 804, 751, 699,
4784 M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787

668, 629, 582, 553, 510, 493 cm1; dH (400 MHz, CDCl3) (40% ethyl acetate/petroleum ether) 0.35; nmax (neat)
1.87 (3H, s, COCH3), 2.29 (3H, s, ArCH3), 2.55–2.66 (2H, 3358, 3266, 3061, 2921, 1702, 1598, 1528, 1493, 1473,
m, CH2), 4.59–4.64 (1H, m, ArCHN), 5.25 (1H, s, ]CH 1414, 1336, 1305, 1253, 1207, 1156, 1091, 1055, 1018,
of enol), 5.74 (1H, d, J 7.1 Hz, NH), 7.03–7.11 (7H, m, 998, 940, 905, 842, 813, 788, 698, 672, 592, 563, 544,
ArH), 7.50 (2H, d, J 8.3 Hz, ArH); dC (100 MHz, CDCl3) 505, 427 cm1; dH (400 MHz, CDCl3) 1.90 (3H, s,
21.4, 24.3, 45.2, 55.1, 101.0, 126.4, 127.0, 127.5, 128.4, COCH3), 2.31 (3H, s, ArCH3), 2.57–2.59 (2H, m, CH2),
129.3, 137.1, 139.7, 143.1, 190.4, 190.8; FAB Mass: m/z 4.57–4.63 (1H, m, ArCHN), 5.27 (1H, s, ]CH of enol),
360 (M++1). 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
4.3.2. N-[1-(2-Chloro-phenyl)-3,5-dioxo-hexyl]-4-methyl- (100 MHz, CDCl3) 21.4, 24.3, 43.4, 57.7, 100.8, 126.9,
benzenesulfonamide (6b). The general procedure described 127.1, 128.6, 128.7, 129.3, 129.5, 131.7, 136.7, 137.1,
in Section 4.3 was followed to afford 6b (95.1 mg, 71%) as 143.2, 190.5, 191.0.
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 4.4. General procedure for the synthesis of N-sulfonyl
(40% ethyl acetate/petroleum ether) 0.35; nmax (neat) piperidines (9a–d) starting from d-amino-b-keto ester 3
3235, 3062, 2916, 1711, 1606, 1319, 1159, 1090, 1012,
947 cm1; dH (400 MHz, CDCl3) 1.87 (3H, s, COCH3), In a typical procedure, d-amino-b-keto ester 3 (1.32 mmol)
2.28 (3H, s, ArCH3), 2.49–2.67 (2H, m, CH2), 4.92–4.97 and 1,2-ethane diol (0.088 mL, 1.58 mmol) were dissolved
(1H, m, ArCHN), 5.22 (1H, m, ]CH of enol), 5.84 (1H, in 10 mL dry benzene in the presence of catalytic PTSA.
d, J 7.1 Hz, NH), 7.02–7.26 (6H, m ArH), 7.52 (2H, d, J The mixture was refluxed for 5–8 h using Dean–Stark appa-
7.3 Hz ArH); dC (100 MHz, CDCl3) 21.4, 24.3, 43.4, 57.7, ratus. After the completion of the reaction, the crude mixture
100.8, 126.9, 127.1, 128.6, 128.7, 129.3, 129.5, 131.7, was washed with aq NaHCO3 solution and extracted with
136.7, 137.1, 143.2, 190.5, 191.0; FAB Mass: m/z 394 ethyl acetate. Silica gel column chromatographic purifica-
(M++1), 396 (M++3). tion of the crude mixture afforded the pure cyclic ketal 7.
To a suspension of LiAlH4 (13.3 mg, 0.35 mmol) in
4.3.3. N-[1-(4-Methoxy-phenyl)-3,5-dioxo-hexyl]-4- 1.0 mL dry THF was added 0.23 mmol of 7 (dissolved in
methyl-benzenesulfonamide (6c). The general procedure 1.0 mL dry THF) at 0  C and the reaction was allowed to
described in Section 4.3 was followed to afford 6c stir at room temperature for 1 h. After quenching the reac-
(72.8 mg, 55%) as a yellow solid, mp 77–80  C. [Found: C, tion with drop wise addition of ethyl acetate at 0  C, the re-
61.88; H, 5.90; N, 3.50. C20H23NO5S requires: C, 61.68; H, action mixture was filtered through a sintered funnel. The
5.95; N, 3.60%.] Rf (40% ethyl acetate/petroleum ether) filtrate was washed with brine and concentrated under vac-
0.28; nmax (neat) 3276, 2923, 2844, 1705, 1611, 1513, 1445, uum to afford 8. The crude product was sufficiently pure
1323, 1250, 1157, 1092, 1030, 958, 815, 737, 667, 453 cm1; as indicated by 1H NMR to proceed for the next reaction.
dH (400 MHz, CDCl3) 1.87 (3H, s, COCH3), 2.30 (3H, s, Finally, 8 (0.25 mmol) was treated with TsCl (57.2 mg,
ArCH3), 2.53–2.67 (2H, m, CH2), 3.67 (3H, s, OCH3), 0.30 mmol) and excess KOH (42 mg, 0.75 mmol) in reflux-
4.54–4.59 (1H, m, ArCHN), 5.26 (1H, s, ]CH of enol), ing THF for 30 min. After the completion of the reaction
5.72 (1H, d, J 6.5 Hz, NH), 6.62 (2H, d, J 8.5 Hz, ArH), 6.95 (monitored by TLC), it was quenched with water and ex-
(2H, d, J 8.5, ArH), 7.08 (2H, d, J 8.0 Hz, ArH), 7.49 (2H, d, J tracted with 10 mL ethyl acetate in two portions. The com-
8.3 Hz, ArH); dC (100 MHz, CDCl3) 21.4, 24.4, 45.2, 54.6, bined organic extract was dried over anhydrous Na2SO4
55.2, 100.9, 113.7, 127.0, 127.6, 129.3, 131.8, 137.2, and the solvent was evaporated under vacuum. Silica gel
143.1, 158.9, 190.4, 191.2; FAB Mass: m/z 390 (M++1). column chromatographic purification of the crude mixture
using 15% ethyl acetate in petroleum ether as the eluant
4.3.4. N-[1-(4-Chloro-phenyl)-3,5-dioxo-hexyl]-4-methyl- afforded the pure products 9a–d.
benzenesulfonamide (6d). The general procedure described
in Section 4.3 was followed to afford 6d (104.5 mg, 78%) as 4.4.1. 7-Phenyl-8-(toluene-4-sulfonyl)-1,4-dioxa-8-aza-
a yellow solid, mp 73  C. [Found: C, 57.82; H, 5.24; N, 3.65. spiro[4.5]decane (9a). The general procedure described in
C19H20ClNO4S requires: C, 57.94; H, 5.12; N, 3.56%.] Rf Section 4.4 was followed to afford 9a (354.9 mg, 72% over-
(40% ethyl acetate/petroleum ether) 0.37; nmax (neat) 3235, all starting from 3a) as a yellow liquid. [Found: C, 64.35; H,
1712, 1606, 1492, 1453, 1422, 1321, 1249, 1160, 1090, 6.35; N, 3.80. C20H23NO4S requires: C, 64.32; H, 6.21; N,
1061, 1013, 948, 842, 815, 694, 660, 593, 566, 535, 3.75%.] Rf (30% ethyl acetate/petroleum ether) 0.36; nmax
450 cm1; dH (400 MHz, CDCl3) 1.94 (3H, s, COCH3), (neat) 2929, 1601, 1493, 1451, 1345, 1226, 1158, 1095,
2.36 (3H, s, ArCH3), 2.61–2.64 (2H, m, CH2), 4.63–4.65 1035, 948, 861, 813, 728, 651, 472 cm1; dH (400 MHz,
(1H, m, ArCHN), 5.28 (1H, s, ]CH of enol), 5.97 (1H, d, CDCl3) 1.49–1.52 (2H, m, CH2), 1.78 (1H, dd, J 6.4,
J 7.0 Hz, NH), 7.02–7.29 (6H, m, ArH), 7.51 (2H, d, J 14.2 Hz, CHaHb), 2.25 (1H, dd, J 3.6, 14.2 Hz, CHaHb),
8.2 Hz, ArH); dC (100 MHz, CDCl3) 21.4, 24.3, 45.2, 55.1, 2.30 (3H, s, ArCH3), 3.37–3.44 (1H, m, CHaHbN), 3.63–
101.0, 126.4, 127.0, 127.5, 128.4, 129.3, 137.1, 139.7, 3.83 (5H, m, CHaHbN, OCH2CH2O), 5.12 (1H, m, PhCH),
143.1, 190.4, 190.8. 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,
4.3.5. N-[1-(3-Bromo-phenyl)-3,5-dioxo-hexyl]-4-methyl- 106.2, 126.5, 126.7, 127.0, 128.0, 129.6, 137.7, 139.4,
benzenesulfonamide (6e). The general procedure described 143.2; FAB Mass: m/z 374 (M++1).
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. 4.4.2. 7-(2-Chloro-phenyl)-8-(toluene-4-sulfonyl)-1,4-di-
C19H20BrNO4S requires: C, 52.06; H, 4.60; N, 3.20%]; Rf 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 4.4 was followed to afford 9b (382.3 mg, evaporation to afford crude 12, which was purified through
71% overall starting from 3b) as a white solid, mp 100  C. a flash column chromatography (230–400 mesh size) using
[Found: C, 58.79; H, 5.35; N, 3.48. C20H22ClNO4S requires: 30% acetone in petroleum ether as the eluant. To a solution
C, 58.89; H, 5.44; N, 3.43%.] Rf (30% ethyl acetate/petro- of DMAP (6.1 mg, 0.05 mmol), 12 (0.5 mmol), and triethyl
leum ether) 0.35; nmax (neat) 2976, 2937, 2894, 1596, amine (0.1 mL, 0.75 mmol) in 2.0 mL dry DMF was added
1466, 1440, 1349, 1310, 1216, 1155, 1121, 1089, 1033, drop wise a solution of TBDMSCl (90.4 mg, 0.6 mmol) in
943, 851, 818, 774, 749, 714, 688, 652, 618, 559, 503, 1.0 mL dry DMF at 0  C over a period of 1 h. The reaction
477 cm1; dH (400 MHz, CDCl3) 1.62–1.69 (1H, m, CHaHb), mixture was stirred for additional 1 h at room temperature
1.76–1.84 (2H, m, CHaHbCHcHd), 2.2 (1H, dd, J 8.0, and monitored by TLC. The reaction was quenched with
13.9 Hz, CHcHd), 2.30 (3H, s, ArCH3), 3.53–3.59 (1H, m, cold water and crude product was extracted with ethyl ace-
CHaHbN), 3.63–3.91 (5H, m, CHaHbN, OCH2CH2O), tate. Silica gel column chromatographic purification of the
5.02–5.05 (1H, m, ArCH), 7.02–7.12 (6H, m, ArH), 7.35– crude mixture furnished the pure diastereomers 13x and
7.44 (2H, m, ArH); dC (100 MHz, CDCl3) 21.4, 34.4, 38.8, 13y. To a solution of 13x or 13y (0.25 mmol) and KOH
44.1, 55.3, 64.1, 64.3, 106.3, 126.4, 127.3, 128.3, 129.2, (42 mg, 0.75 mmol) in 1.0 mL dry THF was added TsCl
129.3, 132.1, 136.2, 138.1, 143.0; FAB Mass: m/z 408 (57.2 mg, 0.30 mmol) in portions at room temperature,
(M++1), 410 (M++3). then the reaction was refluxed for 1 h. After the completion
of the reaction (monitored by TLC), it was quenched with
4.4.3. 7-(4-Chloro-phenyl)-8-(toluene-4-sulfonyl)-1,4-di- water and extracted with ethyl acetate. The organic extract
oxa-8-aza-spiro[4.5]decane (9c). The general procedure was dried over anhydrous Na2SO4 and the solvent was
described in Section 4.4 was followed to afford 9c evaporated under vacuum to give the crude product. Both
(414.6 mg, 77% overall starting from 3c) as a yellow liquid. diastereomers were purified through silica gel column chro-
[Found: C, 58.95, H, 5.54, N, 3.45. C20H22NO4S requires: C, matography to provide the pure products 14x and 14y.
58.89; H, 5.44; N, 3.43%.] Rf (30% ethyl acetate/petroleum
ether) 0.28; nmax (neat) 2964, 2931, 2885, 1650, 1596, 1491, 4.5.1. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-
1448, 1401, 1348, 1304, 1263, 1233, 1160, 1093, 1037, 984, phenylpentyl)-4-methyl benzenesulfonamide (13xa). The
948, 870, 817, 748, 714, 656, 601, 553 cm1; dH (400 MHz, general procedure described in Section 4.5 was followed
CDCl3) 1.35–1.53 (2H, m, CH2), 1.77 (1H, dd, J 6.1, to afford 13xa (103.2 mg, 44.5% from 12a) as colorless liq-
14.2 Hz, CHaHb), 2.18 (1H, dd, J 3.4, 14.1 Hz, CHaHb), uid. Rf (35% ethyl acetate/petroleum ether) 0.50; nmax (neat)
2.35 (3H, s, ArCH3), 3.32–3.40 (1H, m, CHaHbN), 3.66– 3504, 3278, 3063, 3030, 2952, 2928, 2883, 2856, 1717,
3.83 (5H, m, CHaHbN, OCH2CH2O), 5.07–5.11 (1H, m, 1599, 1495, 1471, 1458, 1421, 1360, 1323, 1305, 1288,
ArCH), 7.16–7.21 (6H, m, ArH), 7.58 (2H, d, J 8.3 Hz, 1255, 1214, 1184, 1159, 1092, 1020, 1005, 938, 837, 812,
ArH); dC (100 MHz, CDCl3) 21.3, 33.7, 37.1, 41.2, 56.0, 778, 701, 667, 564, 547 cm1; dH (400 MHz, CDCl3) 0.05
64.0, 64.3, 106.1, 126.9, 127.0, 127.9, 128.3, 129.8, 137.6, (3H, s, CH3Si), 0.07 (3H, s, CH3Si), 0.89 (9H, s, t-BuSi),
138.0, 143.5; FAB Mass: m/z 408 (M++1), 410 (M++3). 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,
4.4.4. 7-(3-Bromo-phenyl)-8-(toluene-4-sulfonyl)-1,4-di- CHOH, OH), 4.61–4.66 (1H, m, ArCHN), 6.44 (1H, d,
oxa-8-aza-spiro[4.5]decane (9d). The general procedure J 7.32 Hz, NH), 7.09–7.20 (7H, m, ArH), 7.58 (2H, d,
described in Section 4.4 was followed to afford 9d J 8.0 Hz, ArH).
(418 mg, 70% overall starting from 3d) as a yellow liquid.
[Found: C, 53.25; H, 5.17; N, 3.15. C20H22BrNO4S requires: 4.5.2. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-
C, 53.10; H, 4.90; N, 3.10%.] Rf (30% ethyl acetate/petro- phenylpentyl)-4-methyl benzenesulfonamide (13ya). The
leum ether) 0.30; nmax (neat) 2962, 2928, 2886, 1655, general procedure described in Section 4.5 was followed
1596, 1568, 1449, 1425, 1350, 1303, 1262, 1233, 1160, to afford 13ya (124 mg, 53.5% from 12a) as a white solid,
1092, 1037, 987, 950, 900, 858, 812, 741, 696, 660, 624, mp 98–100  C. Rf (35% ethyl acetate/petroleum ether)
549, 472, 432 cm1; dH (400 MHz, CDCl3) 1.50–1.55 (2H, 0.43; nmax (neat) 3487, 3273, 2952, 2929, 2857, 1599,
m, CH2), 1.78 (1H, dd, J 6.4 Hz, J 14.2 Hz, CHaHb), 2.18 1494, 1461, 1430, 1325, 1254, 1158, 1089, 937, 835, 812,
(1H, dd, J 3.6, 14.2 Hz, CHaHb), 2.35 (3H, s, ArCH3), 779, 701, 667, 549, 427 cm1; dH (400 MHz, CDCl3) 0.07
3.33–3.40 (1H, m, CHaHbN), 3.66–3.83 (5 H m, CHaHbN, (6H, s, CH3Si), 0.90 (9H, s, t-BuSi), 1.41–1.68 (3H, m,
OCH2CH2O), 5.08–5.11 (1H, m, ArCH), 7.01–7.28 (6H, CHaCHb, CHcHd), 1.87–1.96 (1H, m, CHcHd), 2.37 (3H, s,
m, ArH), 7.57 (2H, d, J 8.32 Hz, ArH); dC (100 MHz, ArCH3), 3.70–3.76 (2H, m, OCH2), 3.81–3.86 (1H, m,
CDCl3) 21.6, 33.8, 37.1, 41.3, 53.3, 56.4, 64.0, 74.1, CHOH), 4.00 (1H, s, OH), 4.32–4.36 (m, 1H, ArCHN),
106.1, 126.5, 126.9, 127.3, 128.0, 129.8, 137.5, 139.4, 6.44 (1H, d, J 2.4 Hz, NH), 7.13–7.20 (7H, m, ArH), 7.55
143.0; Mass: m/z 452 (M++1), 454 (M++3). (2H, d, J 8.3 Hz, ArH).

4.5. General procedure for the synthesis of N-sulfonyl 4.5.3. N-(5-(tert-Butyldimethylsilyloxy)-1-(2-chloro-

azetidines starting from d-amino-b-keto ester 3 phenyl)-3-hydroxypentyl)-4-methyl benzenesulfonamide
(13xb). The general procedure described in Section 4.5
To a suspension of LiAlH4 (190 mg, 5.0 mmol) in 15 mL dry was followed to afford 13xb (81.4 mg, 32.7% from 12b) as
THF was added 3 (1.0 mmol dissolved in 5 mL dry THF) at a white solid, mp 101–103  C. Rf (35% ethyl acetate/petro-
0  C and the reaction was stirred at room temperature for leum ether) 0.51; nmax (neat) 3491, 3283, 2952, 2930,
1 h. After quenching the reaction with drop wise addition 2885, 2857, 1598, 1469, 1444, 1329, 1255, 1214, 1160,
of ethyl acetate at 0  C, the reaction mixture was filtered 1091, 1040, 939, 836, 813, 780, 755, 731, 704, 666, 549,
through a sintered funnel. The filtrate was concentrated by 461, 418 cm1; dH (400 MHz, CDCl3) 0.00 (3H, s,
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 CHaHb), 3.61–3.71 (2H, m, OCH2), 3.92–4.00 (1H, m,
(4H, m, (CH2)a, (CH2)b), 2.31 (3H, s, ArCH3), 3.60–3.76 NCH), 4.58 (1H, t, J 8.3 Hz, ArCHN), 7.17–7.35 (7H, m,
(3H, m, OCH2, CHOH), 4.94–4.95 (1H, m, ArCHN), ArH), 7.62 (2H, d, J 8.0 Hz, ArH); dC (100 MHz, CDCl3)
6.78–6.79 (1H, m, ArH), 7.05–7.40 (7H, m, ArH), 7.59 5.5, 5.4, 18.1, 21.6, 25.8, 33.2, 39.1, 58.5, 59.3, 62.9,
(2H, d, J 8.3 Hz, ArH). 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- 4.5.8. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-phenyl-1-

phenyl)-3-hydroxypentyl)-4-methyl benzenesulfonamide tosylazetidine (14ya). The general procedure described in
(13yb). The general procedure described in Section 4.5 Section 4.5 was followed to afford 14ya (105.8 mg, 95%
was followed to afford 13yb (162.7 mg, 65.3% from 12b) from 13ya) as colorless liquid. [Found: C, 64.79; H, 7.75;
as a white solid, mp 103–108  C. Rf (35% ethyl acetate/pe- N, 3.27. C24H35NO3SSi requires: C, 64.68; H, 7.92; N,
troleum ether) 0.44; nmax (neat): 3450, 3269, 2952, 2929, 3.14%.] Rf (10% ethyl acetate/petroleum ether) 0.34; nmax
2557, 1596, 1468, 1442, 1332, 1255, 1160, 1088, 941, (neat) 3063, 3031, 2954, 2927, 2884, 2856, 1598, 1494,
836, 814, 779, 756, 729, 666, 559, 460, 425 cm1; 1471, 1460, 1388, 1343, 1304, 1287, 1255, 1158, 1094,
dH (400 MHz, CDCl3) 0.00 (6H, s, CH3Si), 0.84 (9H, s, 1028, 1006, 972, 939, 911, 882, 835, 813, 777, 735, 698,
t-BuSi), 1.41–1.62 (4H, m, (CH2)a, (CH2)b), 2.33 (3H, s, 673, 609, 547, 520 cm1; dH (400 MHz, CDCl3) 0.06 (6H,
ArCH3), 3.59–3.79 (3H, m, OCH2, CHOH), 4.62–4.65 s, CH3Si), 0.87 (9H, s, t-BuSi), 1.98–2.06 (1H, m, CHaHb),
(1H, m, ArCHN), 7.03–7.22 (5H, m, ArH), 7.45 (1H, d, 2.32–2.40 (4H, m, ArCH3CHaHb), 2.47–2.55 (2H, m,
J 7.3 Hz, ArH), 7.61 (2H, d, J 8.3 Hz, ArH). 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
4.5.5. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-(4- (9H, m, ArH); dC (100 MHz, CDCl3) 5.5, 5.4, 18.1,
methoxyphenyl)pentyl)-4-methyl benzenesulfonamide 21.4, 25.8, 31.9, 36.9, 59.7, 62.2, 65.2, 127.1, 127.6,
(13xe). The general procedure described in Section 4.5 was 127.9, 128.2, 128.9, 136.8, 138.5, 142.5.
followed to afford 13xe (78.2 mg, 31.7% from 12e) as color-
less liquid. Rf (35% ethyl acetate/petroleum ether) 0.38; nmax 4.5.9. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(2-chloro-
(neat) 3482, 3278, 3054, 2953, 2929, 2856, 1733, 1653, 1612, phenyl)-1-tosylazetidine (14xb). The general procedure
1558, 1540, 1513, 1463, 1440, 1361, 1321, 1304, 1265, 1250, described in Section 4.5 was followed to afford 14xb
1177, 1158, 1091, 1036, 938, 836, 812, 779, 738, 704, 666, (116.4 mg, 97% from 13xb) as a white solid, mp 92–
565, 454, 417 cm1; dH (400 MHz, CDCl3): dH (400 MHz, 94  C. [Found: C, 60.21; H, 7.18; N, 3.10. C24H34ClNO3SSi
CDCl3) 0.05 (3H, s, CH3Si), 0.06 (3H, s, CH3Si), 0.89 (9H, requires: C, 60.04; H, 7.14; N, 2.92%.] Rf (10% ethyl ace-
s, t-BuSi), 1.41–1.80 (4H, m, (CH2)a, (CH2)b), 2.36 (3H, s, tate/petroleum ether) 0.46; nmax (neat) 2953, 2928, 2857,
ArCH3), 3.68–3.92 (6H, m, OCH2, OCH3), 4.56–4.57 (1H, 1596, 1467, 1439, 1379, 1349, 1255, 1163, 1085, 1026,
m, ArCHN), 6.35 (1H, d, J 6.8 Hz, NH), 6.69 (2H, d, 942, 885, 832, 754, 662, 603, 553, 465 cm1; dH
J 8.0 Hz, ArH), 7.03 (2H, d, J 8.2 Hz, ArH), 7.13 (2H, d, (400 MHz, CDCl3) 0.03 (3H, s, CH3Si), 0.00 (3H, s,
J 8.0 Hz, ArH), 7.57 (2H, d, J 8.0 Hz, ArH). 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),
4.5.6. N-(5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-(4- 2.44 (3H, s, ArCH3), 2.52–2.59 (1H, m, CHaHb), 3.60–
methoxyphenyl)pentyl)-4-methyl benzenesulfonamide 3.66 (1H, m, OCHaHb), 3.69–3.74 (1H, m, OCHaHb),
(13ye). The general procedure described in Section 4.5 was 3.93–4.00 (1H, m, NCH), 4.93 (1H, t, J 8.3 Hz, ArCHN),
followed to afford 13ye (156.3 mg, 63.3% from 12e) as 7.16–7.35 (5H, m, ArH), 7.69 (2H, d, J 8.3 Hz, ArH), 7.87
a white solid, mp 105–107  C. Rf (35% ethyl acetate/petro- (1H, d, J 7.6 Hz, ArH); dC (100 MHz, CDCl3) 5.5, 5.4,
leum ether) 0.31; nmax (neat) 3490, 3273, 2952, 2929, 18.1, 21.6, 25.8, 32.1, 39.3, 58.7, 59.0, 60.0, 127.0, 128.0,
2856, 1612, 1513, 1463, 1441, 1360, 1323, 1305, 1249, 128.6, 128.7, 128.9, 129.7, 131.0, 131.3, 138.7, 144.1.
1177, 1158, 1091, 1036, 939, 835, 812, 778, 735, 806,
666, 548, 464, 419 cm1; dH (400 MHz, CDCl3) 0.07 (6H, 4.5.10. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(2-
s, CH3Si), 0.90 (9H, s, t-BuSi), 1.47–1.95 (4H, m, (CH2)a, chlorophenyl)-1-tosylazetidine (14yb). The general proce-
(CH2)b), 2.38 (3H, s, ArCH3), 3.71–3.86 (6H, m, OCH2, dure described in Section 4.5 was followed to afford 14yb
OCH3), 4.29 (1H, dd, J 4.8, 9.7 Hz, ArCHN), 6.70 (2H, d, (110.4 mg, 92% from 13yb) as colorless liquid. [Found: C,
J 8.5 Hz, ArH), 7.05 (2H, d, J 8.5 Hz, ArH), 7.14 (2H, d, 60.18; H, 7.21; N, 2.95. C24H34ClNO3SSi requires: C,
J 8.0 Hz, ArH), 7.55 (2H, d, J 8.0 Hz, ArH). 60.04; H, 7.14; N, 2.92%.] Rf (10% ethyl acetate/petroleum
ether) 0.38; nmax (neat) 2955, 2929, 2856, 1597, 1470, 1441,
4.5.7. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-phenyl-1- 1346, 1257, 1158, 1092, 1035, 834, 778, 755, 668, 607, 546,
tosylazetidine (14xa). The general procedure described in 462, 416 cm1; dH (400 MHz, CDCl3) 0.06 (6H, s, CH3Si),
Section 4.5 was followed to afford 14xa (109.2 mg, 98% 0.89 (9H, s, t-BuSi), 1.83–1.91 (1H, m, CHaHb), 2.19–2.26
from 13xa) as a white solid, mp 125–130  C. [Found: C, (1H, m, CHaHb), 2.37–2.63 (5H, m, ArCH3 CH2), 3.65–
64.61; H, 7.85; N, 3.20. C24H35NO3SSi requires: C, 64.68; 3.71 (2H, m, OCH2), 4.58–4.64 (1H, m, NCH), 5.66 (1H,
H, 7.92; N, 3.14%.] Rf (10% ethyl acetate/petroleum ether) dd, J 6.8, 9.2 Hz, ArCHN), 7.19–7.42 (5H, m, ArH), 7.63–
0.41; nmax (neat) 3030, 2953, 2927, 2884, 2855, 1598, 1494, 7.69 (3H, m, ArH); dC (100 MHz, CDCl3) 5.6, 18.1,
1471, 1386, 1346, 1304, 1289, 1256, 1161, 1092, 1018, 939, 21.5, 25.8, 32.0, 35.2, 59.7, 61.2, 62.4, 126.9, 127.6,
885, 834, 812, 775, 742, 698, 665, 614, 599, 550, 527 cm1; 128.0, 128.7, 129.1, 129.4, 131.8, 136.8, 137.8, 143.3.
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), 4.5.11. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(4-
2.10–2.19 (1H, m, CHaHb), 2.35–2.43 (4H, m, ArCH3, methoxyphenyl)-1-tosylazetidine (14xe). The general
 M. K. Ghorai et al. / Tetrahedron 63 (2007) 4779–4787 4787

procedure described in Section 4.5 was followed to afford 3. (a) Langer, P.; Stoll, M. Angew. Chem., Int. Ed. 1999, 38, 1803;
14xe (101.1 mg, 85% from 13xe) as a white solid, mp 93– (b) Sibi, M. P.; Marvin, M.; Sharma, R. J. Org. Chem. 1995, 60,
96  C. [Found: C, 63.23; H, 7.89; N, 2.96. C25H37NO4SSi re- 5016.
quires: C, 63.12; H, 7.84; N, 2.94%.] Rf (10% ethyl acetate/ 4. Gawish, A.; Mitschka, R.; Cook, J. M. Tetrahedron Lett. 1981,
petroleum ether) 0.26; nmax (neat) 2953, 2928, 2894, 2856, 22, 211.
1613, 1558, 1514, 1463, 1386, 1347, 1303, 1250, 1162, 5. Hampton, K. G.; Christie, J. J. J. Org. Chem. 1976, 41, 2772.
1091, 1034, 940, 887, 833, 776, 712, 680, 661, 604, 550, 6. (a) Langer, P.; Bellur, E. J. Org. Chem. 2003, 68, 9742; (b)
470 cm1; dH (400 MHz, CDCl3) 0.00 (6H, s, CH3Si), Langer, P.; Holtz, E.; Karime, I.; Saleh, N. N. R. J. Org.
0.85 (9H, s, t-BuSi), 1.87–1.95 (2H, m, CH2), 2.16–2.19 Chem. 2001, 66, 6057.
(1H, m, CHaHb), 2.36–2.42 (4H, m, ArCH3, CHaHb), 7. (a) Langer, P.; Holtz, E. Angew. Chem. 2000, 112, 3208; (b)
3.68–3.79 (5H, m, OCH3, OCH2), 3.93–3.97 (1H, m, Langer, P.; Holtz, E. Angew. Chem., Int. Ed. 2000, 39, 3086.
NCH), 4.55 (1H, t, J 8.3 Hz, ArCHN), 6.82–6.85 (2H, m, 8. Langer, P.; D€oring, M. Synlett 2001, 1437.
ArH), 7.28–7.33 (4H, m, ArH), 7.64 (2H, d, J 8.1 Hz, 9. Shibato, K.; Yamaguchi, M.; Nakashima, H.; Minami, T.
ArH); dC (100 MHz, CDCl3) 5.4, 18.1, 21.5, 25.8, 33.3, Tetrahedron 1988, 44, 4767.
39.1, 55.2, 58.2, 59.3, 62.6, 113.8, 127.8, 128.4, 129.5, 10. Kraus, G. A.; Gottschalk, P. J. Org. Chem. 1983, 48, 2111.
132.4, 133.0, 143.7, 159.2. 11. Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668.
12. Pound, M. K.; Davies, D. L.; Pilkington, M.; Pina Vaz Sousa,
4.5.12. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-(4-me- M. M.; Wallis, J. D. Tetrahedron Lett. 2002, 43, 1915.
thoxyphenyl)-1-tosylazetidine (14ye). The general proce- 13. (a) Hoffman, R. V.; Patonay, T.; Nayyar, N. K.; Tao, J.
dure described in Section 4.5 was followed to afford 14ye Tetrahedron Lett. 1996, 37, 2381; (b) Bryson, T. A. J. Org.
(83.2 mg, 70% from 13ye) as colorless liquid. [Found: C, Chem. 1973, 38, 3428; (c) Langer, P.; Freifeld, I.; Holtz, E.
63.15; H, 7.74; N, 2.86. C25H37NO4SSi requires: C, 63.12; Synlett 2000, 501.
H, 7.84; N, 2.94%.] Rf (10% ethyl acetate/petroleum ether) 14. Lygo, B. Synlett 1993, 764.
0.22; nmax (neat) 2954, 2928, 2856, 1699, 1684, 1653, 15. (a) Seebach, D.; Ehrig, V. Angew. Chem. 1974, 86, 446; (b)
1611, 1559, 1541, 1514, 1496, 1463, 1388, 1342, 1304, Seebach, D.; Ehrig, V. Angew. Chem., Int. Ed. Engl. 1974,
1291, 1251, 1177, 1157, 1095, 1034, 971, 883, 833, 812, 13, 401.
777, 709, 674, 609, 548, 440 cm1; dH (400 MHz, CDCl3): 16. (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure,
0.06 (6H, s, CH3Si), 0.89 (9H, s, t-BuSi), 1.96–2.04 (1H, Preparation and Synthetic Applications of Piperidine and its
m, CHaHb), 2.30–2.52 (6H, m, CHaHb, CH2, ArCH3), Derivatives; Elsevier: Amsterdam, 1991; (b) Bailey, P. D.
3.74–3.81 (5H, m, OCH3, OCH2), 4.49–4.57 (1H, m, Chem. Commun. 1998, 633.
NCH), 5.17 (1H, dd, J 5.4, 8.5 Hz, ArCHN), 6.66–6.69 17. (a) Fowden. Nature 1955, 176, 347; (b) Bannon, A. W.; Decker,
(2H, m, ArH), 6.99–7.26 (7H, m, ArH); dC (100 MHz, M. W.; Holladay, M. W.; Curzon, P.; Donnelly-Roberts, D.;
CDCl3) 5.4, 18.1, 21.4, 25.8, 31.8, 37.2, 55.2, 59.7, 61.9, Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.; Dickenson, A. H.;
64.9, 113.5, 127.1, 128.9, 129.0, 130.5, 136.9, 142.3, 159.4. 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,
Acknowledgements R. M. d; Fr€ ohlich, R.; Christmann, M. J. Org. Chem. 2006,
71, 4147; (e) Ghorai, M. K.; Das, K.; Kumar, A.; Das, A.
M.K.G. is grateful to IIT-Kanpur and DST, India. A.K. Tetrahedron Lett. 2006, 47, 5393 and reference cited therein.
thanks CSIR and S.H. thanks DST for research fellowships. 18. Li, B.; Franck, R. W. Bioorg. Med. Chem. Lett. 1999, 9, 2629.
We are grateful to Nirupam Purkaystha for initial experi- 19. (a) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169; (b)
ments. 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.;
Supplementary data Zhang, J.; Li, Y.; Xu, H.; DeBrosse, C. J. Org. Chem. 2005,
70, 5413.
Supplementary data associated with this article can be found 20. From the experimental procedure19b,c provided by Davis et al.
in the online version, at doi:10.1016/j.tet.2007.03.081. 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-
References and notes late to aldimine produces b-amino ester, which subsequently
reacts with one more equivalent of the ester enolate to give
1. Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702. d-amino-b-keto esters probably via a Claisen type ester con-
2. (a) Langer, P.; Freiberg, W. Chem. Rev. 2004, 104, 4125; (b) densation reaction.
Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33, 2159. 21. Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20, 99.