An efficient method for the synthesis of nitropiperidones

Article abstract of DOI:10.1021/jo702130a

(Chemical Equation Presented) A three step efficient strategy for the synthesis of substituted 5-nitropiperidones in high de, employing Michael addition of N-p-tolylsulfinyl β-nitroamines to α,β-unsaturated esters, hydrolysis of the sulfinyl group, and cyclization of the resulting free amines, has been developed. A very simple experimental procedure involving mild conditions and only one chromatographic purification are the main features of the process.

Full text of DOI:10.1021/jo702130a

SCHEME 1. Retrosynthetic Analysis of Substituted
Piperidones
An Efficient Method for the Synthesis of
Nitropiperidones
Jose´ Luis Garc´ıa Ruano,* Teresa de Haro,
Rajinder Singh, and M. Bele´n Cid*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
belen.cid@uam.es
ReceiVed October 1, 2007
of nitromethane8 with a wide variety of N-p-tolylsulfinylimines
derived from aldehydes (aliphatic and aromatic) or ketones,9
even when they had enolizable protons. We envisioned that
enantiomerically pure substituted nitropiperidones could be
obtained from the Michael addition of â-nitroamines 1, followed
by sulfoxide removal and cyclization (Scheme 1). Despite of
the low diastereoselectivity anticipated for the Michael addition
on the basis of our previous results,10 the strong acidity of the
R-proton to nitro group also made predictable an easy epimer-
ization of the final nitropiperidone favoring one diastereoisomer.
A straightforward strategy for the diastereoselective synthesis
of substituted nitropiperidones, including fluorinated derivatives,
is reported herein.
For optimization of the Michael reaction conditions, N-p-
tolylsulfinylnitroamine 1a and ethyl acrylate were utilized as
reaction partners. Reaction was attempted by using several bases
(Et3N, cinchona alkaloids, BuLi, DBU) and solvents (THF, CH2-
Cl2, MeCN) at different temperatures.11 Some representative
results are presented in the Table 1, which indicate that a fine-
tuning of the reaction conditions was necessary to minimize
A three step efficient strategy for the synthesis of substituted
5-nitropiperidones in high de, employing Michael addition
of N-p-tolylsulfinyl â-nitroamines to R,â-unsaturated esters,
hydrolysis of the sulfinyl group, and cyclization of the
resulting free amines, has been developed. A very simple
experimental procedure involving mild conditions and only
one chromatographic purification are the main features of
the process.
Piperidones are attractive synthetic targets due to their
interesting pharmacological properties.1 They are also used as
precursors to the piperidine ring,1a,2 which is a frequently
observed structural feature of many of the biologically important
alkaloids and aza sugars. As a consequence, considerable interest
is centered on the synthesis of piperidones in general, and
nitropiperidones3 in particular, because the latter are precursors
to aminopiperidines, which exhibit a wide range of interesting
biological activities.4 Moreover, in view of the increased
biological potential of the fluorinated derivatives,5 there has been
an ever increasing quest for novel routes toward the synthesis
of fluorinated piperidones6 and thus piperidines.7
(4) (a) Cox, J. M.; Edmondson, S. D.; Harper, B.; Weber, A. E. PCT
Int. Appl. WO 2006039325, 2006. (b) Edmondson, S. D.; Mastracchio, A.;
Cox, J. M. PCT Int. Appl. WO2006058064, 2006. (c) Ashwell, S.; Gero,
T.; Ioannidis, S.; Janetka, J.; Lyne, P.; Su, M.; Toader, D.; Yu, D.; Yu, Y.
PCT Int. Appl. WO 2005066163, 2005. (d) Cody, W. L.; Holsworth, D.
D.; Powell, N. A.; Jalaie, M.; Zhang, E.; Wang, W.; Samas, B.; Bryant, J.;
Ostroski, R.; Ryan, M. J.; Edmunds, J. J. Bio. Med. Chem. 2004, 13, 59.
(5) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(6) (a) Gille, S.; Ferry, A.; Billard, T.; Langlois, B. R. J. Org. Chem.
2003, 68, 8932. (b) Bariau, A.; Jatoi, W. B.; Calinaud, P.; Troin, Y.; Canet,
J.-L. Eur. J. Org. Chem. 2006, 3421.
(7) (a) Jiang, J.; DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J.; Lo, J-L.;
Ren, N.; Yudkovitz, J. B.; Cui, J.; Yang, Y. T.; Cheng, K.; Rohrer, S. P.
Bioorg. Med. Chem. Lett. 2004, 14, 1795. (b) Lee, C.-S.; Koh, J. S.; Koo,
K. D.; Kim, G. T.; Kim, K.-H.; Hong, S. Y.; Kim, S.; Kim, M.-J.; Yim, H.
J.; Lim, D.; Kim, H. J.; Han, H. O.; Bu, S. C.; Kwon, O. H.; Kim, S. H.;
Hur, G.-C.; Kim, J. Y.; Yeom, Z.-H.; Yeo, D.-J. PCT Int. Appl. WO
2006104356, 2006.
We have recently reported the highly diastereoselective
synthesis of nitroamines 1 by the asymmetric aza-Henry reaction
(1) See, for example: (a) Pei, Z.; Li, X.; von Geldern, T. W.;
Longenecker, K.; Pireh, D.; Stewart, K. D.; Backes, B. J.; Lai, C.; Libben,
T. H.; Ballaron, S. J.; Beno, D. W. A.; Kempf-Grote, A. J.; Sham, H. L.
Trevillyan, J. M. J. Med. Chem. 2007, 50, 1983. (b) Chicharro, R.; Alonso,
M.; Mazo, M. T.; Aran, V. J.; Herradon, B. Chem. Med. Chem. 2006, 1,
710. (c) Barrow, J.; Selnick, H. G.; Nanterment, P. G. PCT Int. Appl. WO
2000025782 2000. (d) Pistia-Brueggeman, G.; Hollingsworth, R. I. Tetra-
hedron 2001, 57, 8773 and references cited therein.
(2) (a) Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1984, 59,
3575. (b) Mayers, A. I.; Shawe, T. T.; Gottlieb, L. Tetrahedron Lett. 1992,
33, 867. (c) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D.
R. Tetrahedron 2003, 59, 2953. (d) For a review, see: Buffat, M. G. P.
Tetrahedron 2004, 60, 1701.
(8) Garc´ıa Ruano, J. L.; Topp, M.; Lo´pez-Cantarero, J.; Alema´n, J.;
Remuin˜a´n, M. J.; Cid, M. B. Org. Lett. 2005, 7, 4407.
(9) N-p-Tolylsulfinylimines where obtained by condensation of the
corresponding aldehydes with (S)-N-p-tolylsulfinylamide following the Ti-
(OEt)4 Davis’ protocol (a) with slight modifications in the workup (b): (a)
Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13 and
references cited therein. (b) Garc´ıa Ruano, J. L.; Alema´n, J.; Cid, M. B.;
Parra, A. Org. Lett. 2005, 7, 179.
(10) For reaction with nitroethane and transformations, see also: Garc´ıa
Ruano, J. L.; Lo´pez-Cantarero, J.; de Haro, T.; Alema´n, J.; Cid, M. B.
Tetrahedron 2006, 62, 12197.
(3) (a) Xu, F.; Corley, E.; Murry, J. A.; Tschaen, D. M. Org. Lett. 2007,
9, 2669 and references cited therein. (b) Nara, S.; Tanaka, R.; Eishima, J.;
Hara, M.; Takahashi, Y.; Otaki, S.; Foglesong, R. J.; Hughes, P. F.;
Turkington, S.; Kanda, Y. J. Med. Chem. 2003, 46, 2467.
(11) For a review article on the conjugate additions of nitroalkanes, see:
Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV.
2005, 105, 933.
10.1021/jo702130a CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/03/2008
1150
J. Org. Chem. 2008, 73, 1150-1153

TABLE 1. Optimization of the Reaction Conditions for the
Michael Addition
SCHEME 2. Synthesis of Piperidone 5a from 2a + 2a′
base (equiv),
T
conva
2a/2a′/
3a/4aa
entry equiv of acrylate solvent t (h) (°C) (%)
basis of the slightly higher selectivity observed. The low
selectivity (2a/2a′ ratio) obtained under all the conditions,
suggests an easy equilibration due to the strongly acidic
character of the R-proton to the nitro group. Differences in the
2a/2a′ ratio observed in CH2Cl2 and CH3CN indicates the
influence of the solvent polarity on the stability of the epimers.
The treatment of a purified 2a/2a′ mixture (67:33) with TFA
to remove the sulfinyl group15 resulted in a crude that after
loading on a SCX column16 directly afforded lactams 5a and
5a′ as a clean 82/18 mixture of diastereoisomers in 65% yield.17
Cyclization and further isomerization18 at C5 occurred when
the product was being eluted with MeOH/NH3 from the SCX
column (Scheme 2).19
1
2
3
4
Et3N (5), 18
quinine (5), 18
quinidine (5), 20
cinchonidine (5),
20
(DHQ)2PHAL (5), CH2Cl2 168
20
BuLi (0.5), 5
CH2Cl2 120
CH2Cl2 144
rt
rt
rt
rt
80 31:43:26:0
99 30:42:11:17
100 16:22:26:36
43 52:38:0:10
CH2Cl2
15
CH2Cl2 168
5
6
rt
0
THF
10
-78 100b 44:34:22:0
to 0
rt
7
8
9
DBU (1.1), 5
DBU (0.4), 5
DBU (0.4), 5
CH2Cl2
CH2Cl2
MeCN
1
100
92 50:36:7:7
1.5 -35 100c 55:28:17:0
0:0:0:100
1.5 -35
a Determined by 1H NMR. b 2a and 2a′ were isolated in 42% yield after
flash chromatography. c 2a and 2a′ were isolated in 75% yield after flash
chromatography.
Further, in order to increase the synthetic as well as practical
utility of this method, it was planned to eliminate the chro-
matographic purification after the Michael addition step. Toward
this end, a crude mixture of the Michael addition reaction,
obtained under conditions mentioned in Table 1 (entry 9), was
subjected to the treatment shown in Scheme 2. To our delight,
lactam 5a was isolated diastereomerically pure after only one
final chromatographic purification (5a′ was not detected by 1H
NMR) in 47% overall yield starting from 1a (Scheme 2 and
entry 1, Table 2). It is noteworthy that this protocol involves
three steps (Michael addition/desulfinilation/cyclization to one
of the epimers) in a very simple experimental procedure,
requiring only one final chromatographic separation, for obtain-
ing a diastereoismerically pure product, despite of the modest
diastereoselectivity of the Michael addition step.
With the optimized conditions for the whole process, we
examined the scope and limitations of this straightforward
approach in the reactions of N-sulfinyl nitroamines containing
aromatic and more hindered aliphatic groups with ethyl acrylate
and methyl â-trifluoromethylacrylate (Table 2). When N-sulfinyl
â-nitroamines 1b and 1c were submitted to the conditions
indicated in Table 2, lactams 5b and 5c respectively, were
obtained in excellent diastereomeric excess and reasonable yields
(Table 2, entries 2 and 3).20
the formation of the double Michael addition (3a) and the retro
aza-Henry reaction (4a) products.12,13
When Et3N was used as base (entry 1), the sluggish reaction
afforded a mixture of the mono- and double-Michael addition
products 2 and 3, with a low selectivity at the new chiral center
(2a/2a′ ) 42:58). The use of chiral bases such as cinchona
alkaloids (entries 2-5) neither increased the diastereoselectivity
nor suppressed the formation of the retro aza-Henry product
4a.14 Under cinchonidine catalysis, 3a was not formed, but the
reactivity was drastically decreased (43% conversion at rt after
168h, entry 4). No reaction was observed with (DHQ)2PHAL
(entry 5). A large excess of ethyl acrylate (18-20 equiv) and a
high equivalent of base were used in all the above-mentioned
cases. When BuLi (0.5 equiv) was used as base, 2a and 2a′
were isolated in 42% combined yield (entry 6) and compound
4a was not formed.
The best results were obtained with substoichiometric amounts
of DBU at -35 °C (entries 8 and 9). When acetonitrile was
1
used as solvent, formation of 4a could not be detected by H
NMR, and a 2:1 mixture of the Michael addition products 2a
and 2a′ in good overall yields (entry 9) along with compound
3a were obtained. When CH2Cl2 was used as solvent, a small
ratio of 4a was detected (entry 8) which became the exclusive
product when over-stoichiometric amount of DBU was used at
room temperature, as a result of the retro aza-Henry reaction
(entry 7). Variation in the temperature in these last two reactions
(entries 8 and 9) did not improve the results. Although the results
shown in entries 8 and 9 are very similar, we have chosen
conditions of the entry 9 to extend our investigations on the
The (S) configuration at C-6 has been assigned on the basis
of the well-established stereochemical course of the aza-Henry
(15) Davis, F. A. J. Org. Chem. 2006, 71, 8993.
(16) SCX (Strong cation exchange) resin to effect “catch and release”
purification.
(17) For another example of synthesis of piperidones from sylfinylimines,
see: Davis, F. A.; Chao, B. Org. Lett. 2000, 17, 2623.
(18) 5a was treated for several hours with DBU (0.4 equiv) in CHCl3
and then filtered through a sort pad of silica gel eluting with EtOAc. The
formation of a 87/13 mixture of 5a and 5a′ supports that epimerization is
taking place under these conditions.
(19) A similar strategy that also uses aza-Henry reaction and cyclization
has been described to obtained racemic 5-nitro-6-substituted lactames:
Bhagwatheeswaran, H; Gaur, S. P.; Jain, P. C. Synthesis 1976, 615.
(20) Although in most of the cases the amine has been previously passed
through a SCX column, it has been proven that the yields of the final
piperidones are similar when the reaction crudes are directly treated with
NH3 in MeOH (see note b in entry 2 of Table 2 and Scheme 3).
(12) We observed a similar behavior when the corresponding N-
sulfonylnitroamine, obtained by oxidation of the corresponding N-sulfi-
nylnitroamine 1a was subjected to Michael addition conditions.
(13) When we used nitroamine with a phenyl group (1b) as starting
material, compound obtained from retro aza-Henry reaction turned out to
be the main product under most of the conditions used.
(14) For enantioselective Michael addition of nitro derivatives with
cinchona alkaloids see for example a review article: Almas¸i, D.; Alonso,
D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 299.
J. Org. Chem, Vol. 73, No. 3, 2008 1151

TABLE 2. Preparation of Substituted Piperidones through the
Sequence Michael/Desulfuration/ Cyclization/Epimerization
SCHEME 3. Synthesis of the r-trifluoromethyl Piperidone
10
yield (%)
of 5 or 6
entry
R1
R2
step a: T (°C)/t
dea 5 or 6
1
2
3
4
5
6
Me (1a)
Ph (1b)
i-Pr (1c)
Me (1a)
Ph (1b)
i-Pr (1c)
H
H
H
CF3
CF3
CF3
-35/1h 30 min
-15/35 min
-10/3 h
-25/25 min
-15/20 min
-5/15 min
>98
>98
>98
82c
96
96
47 (5a)
49b (5b)
54 (5c)
50 (6a)
54 (6b)
44 (6c)
It is remarkable that the stereochemistry of 6b (all groups are
in a cis arrangement) is different from that observed in case of
6a and 6c, which is probably related to the thermodynamic
stability of the epimers at C-5.
a Determined by 1H NMR after flash chromatography. b 52% yield was
obtained when the crude obtained after treatment with TFA was directly
treated with NH3/MeOH without using the SCX column. c Before flash
chromatography 6a was obtained in 60% de.
Due to the electron-withdrawing properties of the CF3 group,
small changes in the strategy used to obtain the starting
nitroamine 8, required for the preparation of the disubstituted
piperidone 10, were necessary (Scheme 3). Compounds 7a or
7b were prepared as a 1:1 diastereomeric mixture by reaction
of (S)-tolylsulfinyl amide with the ethyl hemiacetal of the
trifluoroacetaldehyde.27 The aza-Henry reaction of either 7a,
7b, or a mixture of both, with nitromethane using NaOH as
base required high temperature to afford the same mixture of
nitroamines 8 and 9, which could be obtained diastereomerically
pure in 28 and 23% yield, respectively, after separation by flash
chromatography. The application of the previously developed
protocol involving three steps to compound 8, afforded R-tri-
fluormethyl piperidone 10 in an unoptimized 37% yield after
flash chromatography (Scheme 3).
In summary, we have developed an efficient three step
diastereoconvergent strategy that provides a straightforward
access to a number of enantiomerically pure substituted nitropi-
peridones from nitroamines, using a simple experimental
protocol involving only one chromatographic purification.
Structural variation can be set up in the substituent appended
at C6 including aliphatic, aromatic, and CF3 groups. Trisubsti-
tuted lactams have also been prepared in a highly stereoselective
manner with a CF3 group at C4.
reaction.8 The trans arrangement of the substituents R1 and NO2
was unequivocally established by X-ray analysis for 5b (R1 )
Ph) (see the Supporting Information). Identical configuration
was assumed for the rest of the disubstituted piperidones 5.
As the synthesis of (()-CP-99,994, a highly potent NK1 and
substance P nonpeptidic antagonist,21 has been described from
racemic 5b,22 the above-described method for preparing enan-
tiomerically pure 5b (Table 2) can be considered as an efficient
formal synthesis of (+)-CP-99,994.23
Although reactions of compounds 1a-c with â-trifluorom-
ethyl acrylate24 were expected to be much more complex
because of the formation of an additional chiral center, the
results were analogously satisfactory (Table 2, entries 4-6) by
employing the sequence used for synthesizing lactams 5. Under
very mild conditions,25 Michael reactions afforded diastereo-
meric mixtures26 that were directly transformed into γ-trifluo-
romethyl piperidones 6a-c by the sequence shown in Table 2.
Lactam 6a was obtained with 82% de (entry 4) after chromato-
graphic purification, whereas 6b and 6c were obtained in 96%
de. The stereochemistry of lactams 6a-c has been determined
by analysis of the coupling constants and NOESY experiments.26
Experimental Section
(21) (a) Watson, J. W.; Gonsalves, S. F.; Fossa, A. A.; McLea, S.; Seeger,
T.; Obach, S.; Andrews, P. L. R. Br. J. Pharmacol. 1995, 115, 84. (b)
Zaman, S.; Woods, A. J.; Watson, J. W.; Reynolds, D. J. M.; Andrews, P.
L. R. Neuropharmacology 2000, 39, 316. (c) Datar, P.; Srivastava, S.;
Coutinho, E.; Govil, G. Curr. Top. Med. Chem. 2004, 4, 75.
(22) (a) Desai, M. C.; Thadeio, P. F.; Lefkowitz, S. L. Tetrahedron Lett.
1993, 34, 5831. (b) Desai, M. C.; Lefkowitz, S. L. Bioorg. Med. Chem.
Lett. 1993, 3, 2083.
(23) For some examples of asymmetric synthesis of CP-99,994, see: (a)
Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem. Eur. J.
2006, 12, 466. (b) Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.;
Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564. (c)
Davis, F. A.; Zhang, Y.; Li, D. Tetrehedron Lett. 2007, 48, 7838.
(24) For Michael addition of other nitro derivatives on this substrate,
see: Miyake, N.; Kitazume, T. J. Fluorine Chem. 2003, 122, 243.
(25) The CF3 group increases the reactivity of the acrylate. Other
substituted acrylates like 3-phenyl acrylate and p-nitrophenyl acrylate do
not react under the optimized conditions for ethyl acrylate.
General Procedure for the Michael Reaction of (S)-N-
Sulfinylnitroamines. DBU (0.05 mmol) was added to a solution
of the corresponding N-sulfinylnitroamine (0.123 mmol) and
the R,â-unsaturated compound (0.615mmol) in acetonitrile (1
mL) at the specified temperature. The reaction mixture was
stirred at temperature and reaction time indicated in each case.
Reactions were monitored by TLC (hexane/EtOAc). After
completion, the reaction mixture was filtered through a short
pad of silica gel, and the silica gel was thoroughly washed with
excess of EtOAc. In all cases, the crude was used for the next
step without prior purification. Nevertheless, for some cases
(27) To prepare 7a and 7b, we followed the same procedure described
for the synthesis of the corresponding t-Bu (Ellman) sulfinimine-ethanol
adducts: Kuduk, S. D.; Di Marco, C. Ng.; Pitzenberger, S. M.; Tsou, N.
Tetrahedron Lett. 2006, 47, 2377.
(26) For a discussion of the stereochemical assignment as well as some
molecular modeling supporting such assignment, see the Supporting
Information.
1152 J. Org. Chem., Vol. 73, No. 3, 2008

diastereoisomers have been purified by flash chromatography
for characterization purpose.
The crude residual mass was dissolved in 1 mL of a 7 N NH3/
MeOH solution, and the mixture was stirred for 30 min. The
solvent was evaporated and the crude was purified by flash
chromatography. (B) The crude residual mass was directly
loaded onto a SCX column (Varian BondElut, 1000 mg SCX
resin/10 mL) and the impurities were eluted with MeOH (2 ×
5 mL), the product was eluted with 7 N NH3/MeOH (2 × 5
mL), and the resulting solution stirred for 30 min. After removal
of the solvent, the compounds were purified by flash chroma-
tography.
(5R,6S)-5-nitro-6-phenylpiperidin-2-one (5b). This com-
pound was obtained in 49% yield following the general method
for the hydrolysis of sulfoxide with TFA of a mixture of 2b
and 2b′ and the procedure B for the cyclization process. After
flash chromatography (Hex/EtOAc ) 1/2), compound 5b was
obtained in a de >98%. Following procedure A, diastereomeri-
cally pure 5b was obtained in 52% yield: white solid; mp
141 °C; [R]20D -56 (c 0.25, CHCl3); IR (film) 3364, 3229, 1662,
1551, 1373, 786, 462, 442 cm-1; 1H NMR (300 MHz) δ 7.45-
7.30 (m, 5H), 6.16 (bs, NH), 5.25 (dd, J ) 6.1 Hz, J ) 1.8 Hz
1H), 4.74-4.68 (m, 1H), 2.74-2.68 (m, 3H), 2.37-2.27 (m,
1H); 13C NMR (75 MHz) δ 169.7, 137.3, 129.4 (2C), 126.5,
85.1, 58.9, 27.8, 23.3; MS (EI+) m/z 220 (M+, 3), 173 (100),
77 (25); HRMS (EI+) calcd for C11H12N2O3 220.0839, found
220.0847.
(5S,4R,(S)S)- and (5S,4S,(S)S)-Ethyl-5-phenyl-5-N-(p-tolyl-
sulfinyl)amino-4-nitropentanate (2b and 2b′). These com-
pounds were obtained as a mixture of diastereoisomers (60:40)
following the general procedure for the Michael addition using
DBU from 1b at -15 °C for 35 min. The diasteroisomers were
separated by flash chromatography (Hex/EtOAc ) 3/1) to give
2b and 2b′ in >98 % de and 31% and 20% respective yields.
Data of the major diasteroisomer 2b: colorless oil; [R]20D +136
(c 0.45, CHCl3); IR (film): 3228, 3004, 2927, 1723, 1642, 1555,
1089, 1059 cm-1; 1H NMR (300 MHz) δ: 7.52 (d, J ) 8.3 Hz,
2H), 7.42-7.31 (m, 7H), 4.94-4.97 (m, 2H), 4.72 (t, J ) 7.6
Hz, 1H), 4.09 (q, J ) 7.1 Hz, 2H), 2.43 (s, 3H), 2.40-2.04 (m,
3H), 1.92-1.80 (m, 1H), 1.21 (t, J ) 7.1 Hz, 3H); 13C NMR
(75 MHz): δ 171.5, 141.9, 140.9, 136.8, 129.7, 129.3, 129.1,
127.5, 125.5, 91.4, 60.8, 59.8, 29.7, 26.2, 21.4, 14.1; MS (FAB)
m/z 405 (M + 1, 15), 154 (24), 139 (100); HRMS [M + 1]
calcd for C20H25N2O5S 405.1477, found 405.1474. Data of the
minor diasteroisomer 2b′: yellow oil; [R]20 +114 (c 0.15
D
CHCl3); IR (film) 3442, 3004, 2925, 1724, 1642, 1552, 1089,
1
1057 cm-1; H NMR (300 MHz) δ 7.57 (d, J ) 8.3 Hz, 2H),
7.42-7.32 (m, 7H), 4.89-4.77 (m, 3H), 4.10 (q, J ) 7.3 Hz,
2H), 2.43 (s, 3H), 3.37-2.04 (m, 4H), 1.23 (t, J ) 7.3 Hz,
3H); 13C NMR (75 MHz) δ 171.7, 136.6, 129.8, 129.1, 129.0,
128.3, 127.6, 127.4, 125.3, 90.9, 60.9, 59.4, 30.0, 24.8, 21.4,
14.1; MS (FAB) m/z 405 (M + 1, 46), 154 (56), 139 (100),
HRMS [M + 1] calcd for C20H25N2O5S 405.1484, found
405.1480.
Acknowledgment. We thank the Spanish Government and
Universidad Auto´noma de Madrid for financial support (Grant
Nos. CTQ2006-06741/BQU and CCG06_UAM/PPQ-0479).
R.S. thanks the Ministerio de Ciencia y Tecnolog´ıa for a
postdoctoral fellowship.
General Procedure for Removal of Sulfinyl Group, Cy-
clization, and Epimerization. TFA (trifluoroacetic acid) (0.615
mmol) was added to a solution of the corresponding crude
material, obtained from the Michael addition (using 0.123 mmol
of the â-nitroamine) in methanol (1 mL) at room temperature,
and the reaction mixture stirred for 2 h. The solvent was
evaporated under reduced pressure to get a residual mass. The
cyclization can be carried out by two different procedures. (A)
Supporting Information Available: Experimental procedures
and spectroscopic data for compounds 2a-c, 5a-c, 6a-c, 7a,b,
and 8-10 and some other intermediates as well as X-ray ORTEP
of 5b. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702130A
J. Org. Chem, Vol. 73, No. 3, 2008 1153