Diastereoselective coupling of N-(tert-Butyl)sulfinyl imines and dimethyl malonate. Synthesis of enantiomerically enriched β-amino esters and β-lactams

Article abstract of DOI:10.1002/hlca.201200303

A diastereoselective coupling of dimethyl malonate with N-(tert-butyl)sulfinyl imines under solvent-free conditions was developed, using NaHCO₃ or NaI as base promoters. The resulting dimethyl 2-(1-aminoalkyl)malonates could be easily transformed successively to β-amino esters and the corresponding β-lactams with high optical purity. Copyright

Full text of DOI:10.1002/hlca.201200303

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Helvetica Chimica Acta – Vol. 95 (2012)
Diastereoselective Coupling of N-(tert-Butyl)sulfinyl Imines and Dimethyl
Malonate. Synthesis of Enantiomerically Enriched b-Amino Esters and
b-Lactams
by Haythem K. Dema, Francisco Foubelo*, and Miguel Yus*
´
´
Departamento de Quꢀmica Organica, Facultad de Ciencias and Instituto de Sꢀntesis Organica (ISO),
Universidad de Alicante, Apdo. 99, ES-03080 Alicante
(phone: þ 34965903548; fax: þ 34965903549; e-mail: foubelo@ua.es, yus@ua.es)
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
A diastereoselective coupling of dimethyl malonate with N-(tert-butyl)sulfinyl imines under solvent-
free conditions was developed, using NaHCO3 or NaI as base promoters. The resulting dimethyl 2-(1-
aminoalkyl)malonates could be easily transformed successively to b-amino esters and the corresponding
b-lactams with high optical purity.
1. Introduction. – Chiral amines are important targets for synthetic organic chemists
because of their importance in agrochemicals, fine chemicals, and pharmaceuticals. In
addition, they have also found high applicability as chiral ligands as well as
organocatalysts in asymmetric syntheses. One of the most direct and reliable methods
for the synthesis of enantiomerically enriched amine derivatives is the stereoselective
addition of an organometallic reagent to the C¼N bond of an imine [1]. Significant
achievements have been reached in the condensation of enolyzable carbonyl
compounds and imines catalyzed by chiral organic and organometallic reagents [2].
The resulting b-aminocarbonyl compounds, the so-called Mannich adducts, are
versatile intermediates that could be easily transformed into a wide range of interesting
multifunctionalized molecules, as for instance, b-amino esters which are direct
precursors of b-lactams [3]. A different strategy, leading to the Mannich adducts in a
stereoselective fashion, consists in the use of chiral imines as electrophiles, and, among
them, N-(tert-butyl)sulfinyl imines [4] have lately emerged as the first choice for several
reasons. They are easily prepared [5] by condensation of a carbonyl compound and the
corresponding tert-butanesulfinamide (¼2-methylpropane-2-sulfinamide), which are
commercially available in enantiomerically pure form on a large scale at reasonable
prices. Nucleophilic additions of organometallic reagents used to take place in high
diastereoselectivities, because the tert-butylsulfinyl group is capable of metal coordi-
nation. Importantly, practical processes for recycling the tert-butylsulfinyl group upon
deprotection of N-(tert-butyl)sulfinyl amines have also been reported [6]. Thus, the
reaction of ester enolates with N-(tert-butyl)sulfinyl imines produced b-amino esters.
The highest yields and diastereoselectivities were achieved by using ester titanium
enolates at ꢀ 788 in THF [7]. The Reformatsky addition of unsubstituted acetate
ꢁ 2012 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 95 (2012)
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enolates allowed also access to these compounds under milder reaction conditions (08
or room temperature) [8]. Considering enolates derived from malonates, as far as we
know, there are only two examples of nucleophilic addition to chiral N-sulfinyl imines:
the reaction of allyl methyl malonate with para-toluenesulfinyl imine derived from 2-
¯
formylthiazole, which Sunazuka and Omura and co-workers used in one step of the
synthesis of antibiotic bottromycin A2 [9], and the organic base-catalyzed reaction of
(S)-N-[(tert-butyl)sulfinyl]1,1,1-trifluoroacetaldimine with dialkyl malonates [10]
(Scheme).
Scheme
Because of our interest in enolate addition to chiral N-(tert-butyl)sulfinyl imines
[11], we report here the base-mediated condensation of these imines with dimethyl
malonate under mild reaction conditions and further synthetic applications of the
resulting reaction products.
2. Results and Discussion. – Compound (R)-2c, derived from 3-phenylpropanal and
(R)-tert-butanesulfinamide, was taken as the imine model for the optimization of the
reaction conditions in the base-promoted coupling reaction of dimethyl malonate (1)
and (tert-butyl)sulfinyl imines 2. Many assays were undertaken, and the most
significant ones are compiled in Table 1. A good conversion (68%) but a relativety
poor diastereoselectivity (32 :68) were obtained in the reaction of imine (R)-2c (1m)
with 2 equiv. of dimethyl malonate (1) in the presence of 1.5 equiv. of MeONa in
MeOH (1m) in THF as solvent at 08 for 12 h (Table 1, Entry 1). A similar result was
obtained with 1.5 equiv. of NaOH as a base, but in this case, performing the reaction at
room temperature for 72 h (Table 1, Entry 2). However, conversion and diastereose-
lectivity were slightly improved, when a stronger base, such as tBuOK, was used under
the same reaction conditions (Table 1, Entry 3). The reaction with 2 equiv. of NaHCO3
in THF at room temperature led to a lower conversion (39%) but, surprisingly, to a
significantly higher and opposite diastereoselectivity (91:9; Table 1, Entry 4). It seems
that the nucleophilic addition of 1 to chiral (tert-butyl)sulfinyl imines follows different
stereochemical pathways, depending on the base. A better result (90% conversion) was
obtained, when the reaction was performed in the absence of any solvent but using

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4 equiv. of dimethyl malonate (1). Importantly, a single diastereoisomer 3c was isolated
as reaction product (Table 1, Entry 5). Switching from NaHCO3 to KHCO3 as a base
did not lead to a better result (slightly higher conversion, but poorer diastereoselec-
tivity, Table 1, Entry 6), as in the case of using Et3N (Table 1, Entry 7). NaI has recently
been used successfully as a base in the condensation of compounds with acidic H-atoms,
such as BrCH2NO2, with imines [12], and identical results were obtained, when 1 equiv.
of NaI was used instead of NaHCO3 (Table 1, compare Entries 5 and 8). In these
heterogeneous reactions, the conversion was not improved using 3 equiv. of NaI
(Table 1, Entry 9). Finally, KI was not as effective as a base as the Na salt to perform
this coupling reaction (Table 1, Entry 10).
Table 1. Reaction of Aldimine (R)-2c with Dimethyl Malonate (1)
Entry
1
Conditionsa)
Conversion [%]b)
68
3c/3’c ratioc)
1 (2 equiv.), 1m MeONa/MeOH (1.5 equiv.),
THF (2 ml), 08, 12 h
32 : 68
2
3
4
5
6
7
8
9
10
1 (2 equiv.), NaOH (1.5 equiv.), THF (2 ml), 238, 72 h
1 (2 equiv.), BuOK (1.5 equiv.), THF (2 ml), 238, 72 h
69
77
39
90
93
15
90
88
5
28 : 72
17: 83
91 : 9
99 : 1
75 : 25
–
99 : 1
99 : 1
–
t
1 (2 equiv.), NaHCO3 (2 equiv.), THF (2 ml), 238, 72 h
1 (4 equiv.), NaHCO3 (2 equiv.), 238, 72 h
1 (4 equiv.), KHCO3 (2 equiv.), 238, 72 h
1 (2 equiv.), Et3N (2 equiv.), 238, 72 h
1 (2 equiv.), NaI (1 equiv.), 238, 72 h
1 (2 equiv.), NaI (3 equiv.), 238, 72 h
1 (2 equiv.), KI (1 equiv.), 238, 72 h
a) All the reactions were carried out with 0.2 mmol of aldimine (R)-2c. b) Conversion is given based on
the disappearance of the starting (R)-2c by 1H-NMR. c) Diastereoisomer ratio was determined by
1H-NMR.
We studied next the coupling reaction of different N-(tert-butyl)sulfinyl imines 2
with dimethyl malonate (1) by applying the optimized conditions depicted in Table 1,
Entries 5 (Method A) and 8 (Method B). The expected 2-(1-aminoalkyl)malonates 3
were obtained in moderate-to-good yields as single diastereoisomers in all cases
(Table 2) except for aldimine 2d derived from PhCHO. Compound 3d was isolated in
only 7% yield with NaHCO3 as a base (Table 2, Entry 7) and was not detected when the
reaction was conducted in the presence of NaI (Table 2, Entry 8). In these two cases,
the starting aldimine (R)-2d was the major component of the reaction mixture.
Mannich coupling reaction also did not occur with aromatic aldimines derived from 4-
nitro- and 4-hydroxybenzaldehyde. It has been previously reported that N-sulfonyl
imines derived from PhCHO react with dialkyl malonates al low temperature, but

Helvetica Chimica Acta – Vol. 95 (2012)
1793
easily undergo a retro-Mannich process when standing at room temperature under
basic conditions [13] as in Methods A and B. In general, Method B led to slightly higher
yields than Method A (Table 2, Entries 1 – 6).
Table 2. Reactions of Different N-(tert-Butyl)sulfonyl Imines 2 with Dimethyl Malonate (1)
Entry
R
Imine 2
Methoda)
2-(1-Aminoalkyl)malonates 3b)
Yield [%]c)
1
2
3
4
5
6
7
8
9
10
11
12
13
Me(CH2)7
Me(CH2)7
iPr
(R)-2a
(R)-2a
(R)-2b
(R)-2b
(R)-2c
(R)-2c
(R)-2d
(R)-2d
(S)-2a
(S)-2b
(S)-2c
(R)-2e
(R)-2f
A
B
A
B
A
B
A
B
A
A
A
B
B
3a
3a
3b
3b
3c
3c
3d
3d
ent-3a
ent-3b
ent-3c
3e
74
86
43
60
77
86
7
iPr
Ph(CH2)2
Ph(CH2)2
Ph
Ph
Me(CH2)7
iPr
Ph(CH2)2
PhCH2
iBu
–
78
47
82
78
77
3f
a) Method A: 4 equiv. of 1 were used; Method B: 2 equiv. of 1 were used. b) All products were > 95%
pure (GLC and/or 300-MHz H-NMR). c) Yield of isolated product after CC (SiO2; hexane/AcOEt)
1
based on the starting aldimine 2.
To establish the utility of the obtained 2-(1-aminoalkyl)malonates 3, some of them
were transformed first to the corresponding b-amino ester 4 and then to the b-lactams 5
in high optical purity, this being the same as the starting Mannich products 3. Acidic
hydrolysis was performed with 6m HCl under reflux, and crude reaction products 4
were obtained in high purity with very good yields (Table 3), without further
purification for the next step being needed. Intramolecular cyclization of b-amino
esters 4 was achieved upon treatment with an excess of lithium diisopropylamide
(LDA) at ꢀ 788, leading to the expected b-lactam 5, but in moderate yields in all cases
(Table 3).
The configuration of the newly created stereogenic center in 2-(1-aminoalkyl)mal-
onates 3 was determined by comparing the specific rotation of 5c ([a]2D3 ¼ þ10.3 (c ¼
1.35, CHCl3)), derived from 3c, with that provided in the literature for (R)-4-(2-
phenylethyl)azetidin-2-one ([a]2D5 ¼ þ19 (c ¼ 0.21, CHCl3)) [14]. This experimental
result could be explained considering that a six-membered ring model TSI (Fig.), with
a four-membered metallacycle, in which the metal is chelated both by the O- and the N-
atoms of the imine moiety, would be involved. Thus, we assume that the nucleophilic
attack occurs to the Si-face of the imine unit for (RS)-isomers (Table 2, Entries 1 – 8, 12,

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Table 3. Transformations of Dimethyl 2-(1-Aminoaltyl)malonates 3 to b-Amino Esters 4 and b-Lactams 5
Entry
R
Starting imine 3 b-Amino ester 4 Yield [%]a) b-Lactam 5 Yield [%]b)
1
2
3
4
Me(CH2)7 3a
4a
4c
ent-4c
4e
91
82
83
81
5a
5c
ent-5c
5e
45
58
53
43
Ph(CH2)2
Ph(CH2)2
PhCH2
3c
ent-3c
3e
a) Yield of isolated product based on the starting dimethyl 2-(1-aminoalkyl)malonates 3. b) Yield of
isolated product after CC (SiO2; hexane/AcOEt) based on the starting amino ester 4.
and 13) and to the Re-face in the case of (SS)-derivatives (Table 2, Entries 9 – 11). As
previously commented, the stereochemical pathway under the solvent-free reaction
conditions in Methods A and B is the opposite to that obtained when the reaction is
performed in THF (Table 1, Entries 1 – 3). This result is consistent with an approach of
the malonate to the less-hindered Re face of C¼N in a s-cis-like conformation (the most
stable conformation according to theoretical calculations [15]) through a non-chelated
transition state model TSII (Fig.).
Figure. The six-membered-ring model TSI and non-chelated transition-state model TSII for 2-(1-amino-
alkyl)malonates 3

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3. Conclusions. – We have reported that a direct Mannich-type reaction of dimethyl
malonate and N-(tert-butyl)sulfinyl imines could be performed under solvent-free
conditions in the presence of NaHCO3 or NaI. The process is highly diastereoselective,
giving rise to a single stereoisomer. The configuration of the newly created stereogenic
center is determined by the configuration of the starting chiral imine. Enantiomerically
pure b-amino esters and b-lactams can be easily obtained from the Mannich products.
´
The authors thank the Spanish Ministerio de Ciencia e Innovacion (Grant No. CTQ2007-65218,
Consolider Ingenio 2010-CSD-2007-00006 and CTQ2011-24165), the Generalitat Valenciana (Grant No.
PROMETEO/2009/039 and FEDER), and the University of Alicante for financial support. H. K. D.
thanks to the Generalitat Valenciana for a predoctoral fellowship (programa Santiago Grisolꢀa).
Experimental Part
1. General. TLC: Silica gel 60 F254 using aluminum plates; visualization with phosphomolybdic acid
(PMA) stain. Flash chromatography (FC): handpacked columns of silica gel 60 (SiO2; 230 – 400 mesh).
M.p.: Reichert Thermovar hostage microscope; uncorrected. Optical rotations: Perkin-Elmer Model 341
polarimeter with a thermally jacketted 5-cm cell at ca. 208; concentrations (c) in g/100 ml. IR Spectra:
Nicolet Impact 400D spectrophotometer equipped with an ATR component; ˜n in cmꢀ1. 1H-NMR Spectra:
Bruker AV300 and Bruker AV400 spectrometers; at 300 or 400 MHz, with CDCl3 as the solvent and TMS
as internal standard (0.00 ppm). 13C-NMR Spectra: Bruker AV300 or Bruker AV400 spectrometers; 1H-
decoupling at 75 or 100 MHz and referenced to CDCl3 at 77.16 ppm. DEPT-135 experiments were
performed to assign CH, CH2 and CH3 (d in ppm, J in Hz). EI-MS: Agilent 5973N gas chromatographer/
mass spectrometer instrument; at 70 eV; and fragment ions in m/z with relative intensities [%] in
parentheses. HR-EI-MS: Finnigan MAT955 instrument; at 70 eV.
2. Starting Materials. (RS)-tert-Butanesulfinamide and its enantiomer were a gift of Medalchemy
(> 99% ee by chiral HPLC on a Chiracel AS column; hexane/iPrOH (90 :10) 1.2 ml/min, l 222 nm).
t
Other used reagents and solvents such as dimethyl malonate, MeOH, THF, MeONa, NaOH, BuOK,
NaHCO3, KHCO3, Et3N, NaI, KI, HCl, iPr2NH, BuLi, and AcOEt are commercially available. N-(tert-
Butyl)sulfinyl imines 2 were prepared according to known protocols [5].
3. Reaction of Dimethyl Malonate 1 with N-(tert-Butyl)sulfinyl Imines 2. Synthesis of Methyl 2-(1-
Aminoalkyl)malonates 3 (Method A). A heterogeneous mixture of dimethyl malonate (1; 1.056 g,
0.94 ml, 8.0 mmol), NaHCO3 (236 mg, 4.0 mmol), and the corresponding N-(tert-butyl)sulfinyl imine 2
(2.0 mmol) was stirred at r.t. for 72 h. The resulting mixture was hydrolyzed with H2O (10 ml), acidified
with 2m HCl (3 ml), and extracted with AcOEt (3 ꢁ 15 ml). The combined org. layer was dried
(MgSO4), the solvent was evaporated, and the residue was purified by CC (SiO2; hexane/AcOEt) to give
pure compounds 3.
Dimethyl [(1R)-1-{[(R)-(tert-Butyl)sulfinyl]amino}nonyl]propanedioate (3a). Yield: 558 mg
(74%). Colorless oil. [a]2D3 ¼ ꢀ38 (c ¼ 1.23, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.37. IR (neat): 2953,
2925, 2856, 1735, 1434, 1240, 1159, 1075. 1H-NMR: 0.88 (t, J ¼ 6.8, MeCH2); 1.22 (s, tBu); 1.24 – 1.46 (m, 6
CH2); 1.54 – 1.59 (m, CH2); 3.77 (s, Me); 3.80 (s, Me); 3.78 – 3.84 (m, CHCHN); 4.53 (d, J ¼ 9.3, NH).
13C-NMR: 14.1 (Me); 22.6 (CH2); 22.7 (Me); 26.2, 29.0, 29.2, 29.4, 31.8, 34.1 (CH2); 52.5, 52.8 (Me); 56.0
(CH); 56.2 (C); 56.9 (CH); 168.3, 168.8 (C). EI-MS: 270 (7, [M – tBuSOH2]þ), 255 (11), 225 (23), 200
(24), 187 (100), 175 (68), 143 (30), 133 (81), 101 (21), 69 (38), 55 (43). HR-EI-MS: 320.1520 ([M ꢀ
tBu]þ, C14H26NO5Sþ; calc. 320.1532).
Dimethyl [(1R)-1-{[(R)-(tert-Butyl)sulfinyl]amino}-2-methylpropyl]propanedioate (3b). Yield:
264 mg (43%). Colorless oil. [a]2D3 ¼ ꢀ30 (c ¼ 1.23, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.28. IR (neat):
2957, 2930, 1731, 1434, 1262, 1194, 1159, 1076. 1H-NMR: 0.92 (d, J ¼ 6.8, 2 Me); 1.25 (s, tBu); 1.75 (sept.,
J ¼ 6.8, Me2CH); 3.61 – 3.68 (m, CHN); 3.73 – 3.76 (m, CHCHN); 3.79 (s, Me); 3.82 (s, Me); 4.89 (d, J ¼
8.4, NH). 13C-NMR: 18.8, 20.2, 23.0 (Me); 33.3 (CH); 52.6, 53.1 (Me); 53.9 (CH); 56.5 (C); 62.6 (CH);
168.0, 169.4 (C). EI-MS: 251 (6, [M – Me2C¼CH2]þ), 231 (15), 207 (18), 163 (19), 140 (37), 55 (100).
HR-EI-MS: 251.0833 ([M – Me2C¼CH2]þ, C9H17NO5Sþ; calc. 251.0827).

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Helvetica Chimica Acta – Vol. 95 (2012)
Dimethyl [(1R)-1-{[(R)-(tert-Butyl)sulfinyl]amino}-3-phenylpropyl]propanedioate (3c). Yield:
568 mg (77%). Colorless oil. [a]2D3 ¼ ꢀ32 (c ¼ 1.43, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.29. IR (neat):
1
t
3060, 3024, 2953, 2924, 2855, 1734, 1434, 1240, 1071, 1045. H-NMR: 1.26 (s, Bu); 1.89 – 1.95 (m, CH2);
2.59 – 2.66 (m, 1 H of CH2); 2.80 – 2.87 (m, 1 H of CH2); 3.72 (s, Me); 3.78 (s, Me); 3.80 – 3.86 (m, CHN);
3.88 (d, J ¼ 4.1, CHCHN); 4.64 (d, J ¼ 9.6, NH); 7.15 – 7.21 (m, 3 arom. H); 7.26 – 7.30 (m, 2 arom. H).
13C-NMR: 22.7 (Me); 32.4, 35.8 (CH2); 52.4, 52.8 (Me); 56.0 (CH); 56.2 (C); 56.3 (CH); 126.0, 128.2,
128.3, 140.8 (arom. C); 168.0, 168.6 (C). EI-MS: 263 (4, [M – tBuSOH]þ), 247 (11), 207 (36), 175 (100),
t
143 (44), 132 (23), 115 (30), 91 (82), 77 (19), 65 (16). HR-EI-MS: 207.0204 ([M ꢀ Bu ꢀ Ph(CH2)2]þ,
C6H9NO5Sþ; calc. 207.0201).
Dimethyl [(1S)-1-{[(R)-(tert-Butyl)sulfinyl]amino}-3-phenylpropyl]propanedioate (3’c). Side prod-
uct. Colorless oil. [a]2D3 ¼ ꢀ96 (c ¼ 1.15, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.35. IR (neat): 3183, 3062,
1
t
3028, 2955, 2931, 2860, 1727, 1258, 1239, 1152, 1039, 1021. H-NMR: 1.19 (s, Bu); 1.86 – 1.95 (m, CH2);
2.14 – 2.23 (m, 1 H of CH2); 2.67 – 2.75 (m, 1 H of CH2); 2.82 – 2.90 (m, 1 H of CH2); 3.68 (d, J ¼ 5.7,
CHCHN); 3.70 (s, Me); 3.75 (s, Me); 3.83 – 3.92 (m, CHN); 4.30 (d, J ¼ 9.3, NH); 7.15 – 7.21 (m, 3 arom.
H); 7.26 – 7.30 (m, 2 arom. H). 13C-NMR: 22.6 (Me); 32.1, 36.1 (CH2); 52.5, 52.6 (Me); 56.1 (CH); 56.2
t
(C); 57.0 (CH); 126.0, 128.4, 128.5, 140.7 (arom. C); 168.0, 168.5 (C). EI-MS: 263 (1, [M ꢀ BuSOH]þ),
248 (10), 216 (21), 183 (40), 156 (17), 128 (23), 117 (12), 91 (100), 65 (18). HR-EI-MS: 263.1160
(C14H17NOþ4 ; [M ꢀ BuSOH]þ, calc. 263.1158).
t
Dimethyl [(S)-{[(R)-(tert-Butyl)sulfinyl]amino}(phenyl)methyl]propanedioate (3d). Yield: 47 mg
(7%). Colorless oil. [a]2D3 ¼ ꢀ21 (c ¼ 0.98, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.26. IR (neat): 3281, 3060,
2985, 2955, 1755, 1715, 1312, 1263, 1067, 1057. 1H-NMR: 1.19 (s, tBu); 3.67 (s, Me); 3.69 (s, Me); 4.01 (d,
J ¼ 6.7, CHCHN); 4.81 (d, J ¼ 9.4, NH); 5.09 (dd, J ¼ 9.3, 6.7, CHN); 7.30 – 7.41 (m, 5 arom. H).
13C-NMR: 22.5 (Me); 52.6, 52.7 (Me); 56.4 (C); 58.1, 60.1 (CH); 127.0, 128.1, 128.6, 138.8 (arom. C);
t
167.2, 168.2 (C). EI-MS: 235 (14, [M ꢀ BuSOH]þ), 219 (77), 164 (12), 152 (100), 132 (29), 103 (51), 77
t
(48), 69 (17), 59 (21), 51 (20). HR-EI-MS: 235.0849 ([M ꢀ BuSOH]þ, C12H13NO4þ ; calc. 235.0845).
Dimethyl [(1S)-1-{[(S)-(tert-Butyl)sulfinyl]amino}nonyl]propanedioate (ent-3a). Yield: 588 mg
(78%). Physical and spectroscopic data were found to be same as for 3a. [a]2D3 ¼ þ36 (c ¼ 1.46, CH2Cl2).
Dimethyl [(1S)-1-{[(S)-(tert-Butyl)sulfinyl]amino}-2-methylpropyl]propanedioate (ent-3b). Yield:
288 mg (47%). Physical and spectroscopic data were found to be same as for 3b. [a]2D3 ¼ þ42 (c ¼ 1.40,
CH2Cl2).
Dimethyl [(1S)-1-{[(S)-(tert-Butyl)sulfinyl]amino}-3-phenylpropyl]propanedioate (ent-3c). Yield:
738 mg (82%). Physical and spectroscopic data were found to be same as for 3c. [a]2D3 ¼ þ29 (c ¼ 0.94,
CH2Cl2).
4. Reaction of Dimethyl Malonate (1) with N-(tert-Butyl)sulfinyl Imines 2. Synthesis of Dimethyl 2-(1-
Aminoalkyl)malonates 3 (Method B). A heterogeneous mixture of 1 (0.528 g, 0.47 ml, 4.0 mmol), NaI
(0.300 g, 2.0 mmol), and the corresponding N-(tert-butyl)sulfinyl imine 2 (2.0 mmol) was stirred at r.t. for
72 h. The resulting mixture was hydrolyzed with H2O (10 ml), acidified with 2m HCl, and extracted with
AcOEt (3 ꢁ 15 ml). The combined org. layer was dried (MgSO4), the solvent was evaporated, and the
residue was purified by CC (SiO2; hexane/AcOEt) to give pure compounds 3.
Compound 3a. Yield: 649 mg (86%). Physical and spectroscopic data are given above.
Compound 3b. Yield: 368 mg (60%). Physical and spectroscopic data are given above.
Compound 3c. Yield: 635 mg (86%). Physical and spectroscopic data are given above.
Dimethyl [(1R)-1-{[(R)-(tert-Butyl)sulfinyl]amino}-2-phenylethyl]propanedioate (3e). Yield:
554 mg (78%). Colorless oil. [a]2D3 ¼ ꢀ35 (c ¼ 1.62, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.39. IR (neat):
3050, 3023, 2978, 2954, 2924, 2854, 1734, 1240, 1073, 1046. 1H-NMR: 1.07 (s, tBu); 2.92 (d, J ¼ 7.0, CH2);
3.76 – 3.78 (m, CHCHN); 3.80 (s, Me); 3.81 (s, Me); 4.11 – 4.14 (m, CHN); 4.62 (d, J ¼ 9.3, NH); 7.17 –
7.31 (m, 5 arom. H). 13C-NMR: 22.4 (Me); 40.6 (CH2); 52.6, 53.0 (Me); 55.0 (CH); 56.1 (C); 58.5 (CH);
t
126.7, 128.5, 129.4, 137.5 (arom. C); 168.2, 168.8 (C). EI-MS: 249 (15, [M ꢀ BuSOH]þ), 234 (29), 132
t
(12), 117 (22), 91 (100), 65 (13). HR-EI-MS: 249.0999 ([M ꢀ BuSOH]þ, C13H15NO4þ ; calc. 249.1001).
Dimethyl [(1R)-1-{[(R)-(tert-Butyl)sulfinyl]amino}-3-methylbutyl]propanedioate (3f). Yield:
495 mg (77%). Colorless oil. [a]2D3 ¼ ꢀ38 (c ¼ 1.59, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.51. IR (neat):
3330, 2953, 2925, 2870, 1745, 1721, 1254, 1160, 1064. 1H-NMR: 0.90 (d, J ¼ 6.5, Me); 0.92 (d, J ¼ 6.6, Me);
t
1.22 (s, Bu); 1.24 – 1.28 (m, 1 H of CH2); 1.55 – 1.65 (m, 1 H of CH2); 1.72 – 1.79 (m, Me2CH); 3.77 (s,

Helvetica Chimica Acta – Vol. 95 (2012)
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Me); 3.80 (s, Me); 3.84 – 3.92 (m, CHCHN); 4.51 (d, J ¼ 9.7, NH). 13C-NMR: 20.9, 22.6 (Me); 23.1 (CH);
42.9 (CH2); 52.3, 52.7 (Me); 55.1 (CH); 56.1 (C); 56.2 (CH); 168.1, 168.7 (C). EI-MS: 265 (4, [M ꢀ
Me2C¼CH2]þ), 133 (100), 101 (14) 69 (10), 57 (28). HR-EI-MS: 265.0981 ([M ꢀ Me2C¼CH2]þ,
C10H19NO5Sþ; calc. 265.0984).
5. Acidic Hydrolysis of Methyl 2-(1-Aminoalkyl)malonates 3. Synthesis of b-Amino Esters 4. A
mixture of 3 (1.0 mmol) and 6m HCl (4 ml) was heated under reflux for 1.5 h. The mixture was cooled to
r.t., and MeOH (16 ml) was added. The mixture was stirred for 36 h at the same temp., and the reaction
was quenched with a sat. aq. NaHCO3 soln. (10 ml), and the mixture was extracted with AcOEt (3 ꢁ
15 ml). The combined org. layer was dried (MgSO4), and the solvent was evaporated to give compounds
4 which were pure enough for the next reaction.
Methyl (3R)-3-Aminoundecanoate (4a). Yield: 228 mg (91%). Colorless oil. [a]2D3 ¼ ꢀ9 (c ¼ 1.48,
CH2Cl2). Rf (AcOEt) 0.45. IR (neat): 2953, 2923, 2854, 1735, 1436, 1165, 1017. 1H-NMR: 0.88 (t, J ¼ 7.0,
MeCH2); 1.27 – 1.43 (m, 7 CH2); 2.34 (dd, J ¼ 15.9, 8.8, 1 H of CH2); 2.52 (dd, J ¼ 15.9, 4.1, 1 H of CH2);
2.76 (br. s, NH2); 3.20 – 3.26 (m, CHN); 3.70 (s, Me). 13C-NMR: 14.1 (Me); 22.6, 26.0, 29.2, 29.5, 31.8,
36.9, 41.5 (CH2); 48.4 (CH); 51.6 (Me); 172.8 (C). EI-MS: 200 (8, [M ꢀ NH3]þ), 142 (79), 102 (100), 70
(31), 60 (24), 56 (15).
Methyl (3R)-3-Amino-5-phenylpentanoate (4c). Yield: 169 mg (82%). Colorless oil. [a]2D3 ¼ þ5 (c ¼
0.61, CH2Cl2). Rf (AcOEt) 0.37. IR (neat): 3025, 2950, 2923, 2857, 1731, 1435, 1158, 838. 1H-NMR: 1.62 –
1.82 (m, CH2, NH2); 2.33 (dd, J ¼ 15.7, 6.9, 1 H of CH2); 2.52 (dd, J ¼ 15.7, 4.0, 1 H of CH2); 2.62 – 2.81
(m, CH2); 3.15 – 3.26 (m, CHN); 3.69 (s, Me); 7.16 – 7.21 (m, 3 arom. H); 7.24 – 7.31 (m, 2 arom. H).
13C-NMR: 32.4, 39.2, 42.4 (CH2); 48.0 (CH); 51.5 (Me); 125.9, 128.3, 128.4, 141.6 (arom. C); 172.8 (C).
EI-MS: 207 (15, Mþ), 190 (22), 134 (42), 130 (29), 117 (27), 102 (100), 91 (83), 70 (30), 60 (21).
Methyl (3S)-3-Amino-5-phenylpentanoate (ent-4c). Yield: 172 mg (83%). Physical and spectro-
scopic data were found to be same as for 4c. [a]2D3 ¼ ꢀ5 (c ¼ 1.32, CH2Cl2).
Methyl (3R)-3-Amino-4-phenylbutanoate (4e). Yield: 156 mg (81%). Colorless oil. [a]2D3 ¼ þ7 (c ¼
1.54, CH2Cl2). Rf (MeOH/CH2Cl2 1:1) 0.55. IR (neat): 3060, 3026, 2950, 2922, 2853, 1731, 1454, 1436,
1258, 1195, 1160. 1H-NMR: 1.69 (br. s, NH2); 2.34 (dd, J ¼ 15.9, 8.8, 1 H of CH2); 2.52 (dd, J ¼ 15.9, 4.1,
1 H of CH2); 2.63 (dd, J ¼ 13.4, 5.7, 1 H of CH2); 3.43 – 3.51 (m, CHN); 3.68 (s, Me); 7.19 – 7.33 (m, 5
arom. H). 13C-NMR: 41.5, 43.9 (CH2); 49.6 (CH); 51.6 (Me); 126.5, 128.5, 129.3, 138.4 (arom. C); 172.8
(C). EI-MS: 120 (24, [M ꢀ CH2COOMe]þ), 102 (100), 91 (17), 70 (22), 60 (18).
i
6. Synthesis of b-Lactams 5 from b-Amino Esters 4. To a THF soln. (8 ml) of Pr2NH (0.272 mg,
0.377 ml, 2.7 mmol) was added BuLi (2.5m in hexane, 1.0 ml, 2.5 mmol) at 08. After stirring for 30 min,
the mixture was cooled to ꢀ 788. To the mixture was added a soln. of the corresponding b-amino ester 4
(0.7 mmol) in THF (3 ml). After stirring at the same temp. for 24 h, the reaction was quenched with a sat.
aq. NaHCO3 soln. (10 ml), and the mixture was extracted with AcOEt (3 ꢁ 15 ml). The combined org.
layer was dried (MgSO4), the solvent was evaporated, and the residue was purified by CC (SiO2; hexane/
AcOEt) to give pure compounds 5.
(4R)-4-Octylazetidin-2-one (5a). Yield: 57 mg (45%). White solid. M.p.: 47 – 488 (CH2Cl2/hexane).
[a]2D3 ¼ ꢀ8 (c ¼ 1.06, CH2Cl2). Rf (hexane/AcOEt 1:1) 0.57. IR (KBr): 3190 – 3130, 2955, 2918, 2849, 1779,
1
1701, 1467, 1199. H-NMR: 0.88 (t, J ¼ 7.0, MeCH2); 1.27 – 1.44 (m, 6 CH2); 1.54 – 1.67 (m, CH2); 2.52
(ddd, J ¼ 16.9, 4.6, 3.4, 1 H of CH2CO); 3.04 (ddd, J ¼ 14.8, 5.0, 2.1, 1 H of CH2CO); 3.56 – 3.63 (m,
CHN); 6.61 (br. s, NH). 13C-NMR: 13.9 (Me); 22.5, 26.1, 29.1, 29.2, 29.3, 31.7, 35.3, 43.3 (CH2); 48.1
(CH); 168.5 (C). EI-MS: 140 (31, [M – HN ¼ C¼O]þ), 111 (15), 97 (32), 83 (38), 70 (100), 69 (67), 56
(96).
(4R)-4-(2-Phenylethyl)azetidin-2-one (5c). Yield: 71 mg (58%). Colorless oil. [a]2D3 ¼ þ11 (c ¼ 1.35,
CH2Cl2). Rf (hexane/AcOEt 1:1) 0.40. IR (film): 3290 – 3220, 3060, 3025, 2925, 1736, 1495, 1454, 1373,
1182. 1H-NMR: 1.97 (t, J ¼ 7.6, CH2); 2.57 (ddd, J ¼ 14.9, 2.4, 1.3, 1 H of CH2CO); 2.63 – 2.76 (m,
CH2Ph), 3.06 (ddd, J ¼ 14.9, 5.0, 2.2, 1 H of CH2CO); 3.60 – 3.67 (m, CHN); 5.79 (br. s, NH); 7.16 – 7.33
(m, 5 arom. H). 13C-NMR: 32.9, 36.9, 43.5 (CH2); 47.8 (CH); 126.3, 128.3, 128.6, 140.5 (arom. C); 167.8
(C). EI-MS: 175 (23, Mþ), 158 (19), 133 (44), 132 (35), 91 (100), 65 (12). HR-EI-MS: 175.0999 (Mþ,
C11H13NOþ; calc. 175.0997).
(4S)-4-(2-Phenylethyl)azetidin-2-one (ent-5c). Yield: 65 mg (53%). Physical and spectroscopic data
were found to be same as for 5c. [a]2D3 ¼ ꢀ10 (c ¼ 1.31, CH2Cl2).

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Helvetica Chimica Acta – Vol. 95 (2012)
(4R)-4-Benzylazetidin-2-one (5e). Yield: 48 mg (43%). Colorless oil. [a]2D3 ¼ þ18 (c ¼ 1.44, CH2Cl2).
Rf (hexane/AcOEt 1:1) 0.36. IR (film): 3305 – 3210, 2951, 2923, 2852, 1738, 1454, 1364, 1179. 1H-NMR:
2.69 (ddd, J ¼ 14.8, 2.3, 1.2, 1 H of CH2CO); 2.85 (dd, J ¼ 13.7, 7.8, 1 H of CH2); 2.97 (dd, J ¼ 13.7, 5.9,
1 H of CH2); 3.06 (ddd, J ¼ 14.8, 4.9, 2.2, 1 H of CH2CO); 3.80 – 3.87 (m, CHN); 6.10 (br. s, NH); 7.16 –
7.37 (m, 5 arom. H). 13C-NMR: 41.8, 43.2 (CH2); 48.9 (CH); 126.8, 128.7, 128.8, 137.5 (arom. C); 167.6
(C). EI-MS: 161 (9, Mþ), 133 (11), 118 (100), 117 (42), 91 (64), 70 (39), 65 (16). HR-EI-MS: 161.0837
(Mþ, C10H11NOþ; calc. 161.0841).
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Received June 14, 2012