Properties and Reactions of Substituted 1,2-Thiazetidine 1,1-Dioxides: Chiral Mono- and Bicyclic 1,2-Thiazetidine 1,1-Dioxides from α-Amino Acids

Article abstract of DOI:10.1002/hlca.200490021

New chiral mono- and bicyclic β-sultams, valuable building blocks for drug synthesis, have been prepared from L-Ala, L-Val, L-Leu, L-Ile, L-Phe, L-Cys, L-Ser, L-Thr, and D-penicillamine by transformation of the COOH group into a methylsulfonyl chloride function, followed by cyclization under basic conditions. Selected properties, derivatives, and reactions of the β-sultams are described.

Full text of DOI:10.1002/hlca.200490021

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Properties and Reactions of Substituted 1,2-Thiazetidine 1,1-Dioxides:
Chiral Mono- and Bicyclic 1,2-Thiazetidine 1,1-Dioxides from a-Amino Acids
by Alexandra Meinzer, Andrea Breckel, Bassam Abu Thaher, Nico Manicone, and Hans-Hartwig Otto*
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald,
Friedrich-Ludwig-Jahn-Str. 17, D-17487 Greifswald
(phone: ‡‡ 49-3834-864876; fax ‡‡ 49-3834-864874; e-mail: ottohh@pharmazie.uni-greifswald.de)
New chiral mono- and bicyclic b-sultams, valuable building blocks for drug synthesis, have been prepared
from l-Ala, l-Val, l-Leu, l-Ile, l-Phe, l-Cys, l-Ser, l-Thr, and d-penicillamine by transformation of the
COOH group into a methylsulfonyl chloride function, followed by cyclization under basic conditions. Selected
properties, derivatives, and reactions of the b-sultams are described.
Introduction. 1,2-Thiazetidine 1,1-dioxide (b-sultam) is a sulfone analogue (bio-
isoster) of the b-lactam moiety found in many important drugs [1]. It is known that the
sultam ring is much more reactive than the b-lactam ring [2], and that b-sultams can
interact with serine proteases such as elastase [3]. Therefore, b-sultams might be useful
building blocks for new synthetic drugs and, therefore, should be available not only as
racemic or diastereoisomeric mixtures, but as pure isomers [4]. Here, we report the
synthesis and properties of chiral, stereochemically pure mono and bicyclic 3-
substituted 1,2-thiazetidine 1,1-dioxides and their substitution products.
A few examples of chiral b-sultams have been described in the literature [5]. For
example, (R)-1,2-thiazetidine-3-carboxylic acid was obtained from l-Cys, and (R)-1,2-
thiazetidine-3-methanol from l-Ser. In both cases, compounds from the natural −chiral
pool× were used as starting materials, a general approach that has also been followed in
the present paper.
Results and Discussion. To obtain the 3-alkyl-substituted 1,2-thiazetidine 1,1-
dioxides 7a e, the amino acids l-Ala, l-Val, l-Leu, l-Ile, and l-Phe (1a e) were
reduced with LiAlH4 in THF, forming the parent 2-aminoethanols 2a e [6], which
were then transformed into the Br compounds 3, either by reaction with HBr (48%)
[7], with a mixture of HBr and PBr3 [8], or by reaction with thionylbromide
(Scheme 1).
Compounds 3 were isolated as their crystalline hydrobromides. These salts were
transformed into the thiols 4 by reaction with thiourea and tetraethylenepentamine [9]
in ca. 40% yield, or they were transformed into the disulfides 5. Compounds 4 were
purified by sublimation; their high air sensitivity afforded immediate oxidation to the
stable sulfonyl chloride hydrochlorides 6 with Cl2/HCl in a mixture of EtOH and CCl4.
Finally, compounds 6 were cyclized with NH3 in CHCl3 at 08, whereby the thiazetidine
1,1-dioxides 7a e were obtained in crystalline form. In the a-series of compounds, we
isolated not the sulfonylchloride, but the sulfonic acid 6a (X ˆ CH), which was

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91
Scheme 1
a) LiAlH4, THF. b) HBr, Ph3P or SOBr2. c) Thiourea, EtOH. d) Na2S2O3, I2, EtOH. e) I2, EtOH. f) HCl, Cl2,
CCl4, EtOH. g) NH3, CHCl3, CCl4, THF.
transformed into the b-sultam 7a in a one-pot reaction. Alternatively, 7a was prepared
from the disulfide 5a.
l-Cystine dialkyl ester hydrochlorides 8, obtained from l-Cys, were transformed
into the parent b-sultams 9a and 9b [10] by oxidative chlorination (Scheme 2). By
Scheme 2
a) 1. HCl, Cl2, CCl4, EtOH; 2. NH3, CHCl3, CCl4, THF. b) LiBH4, THF. c) BuLi, R3SiCl, THF, À788. d) RNH2,
CHCl3, 08. e) Ac2O, 08. f) BuLi, R3SiCl, THF, À788. g) BuLi, AcCl, THF, HMPA, À788.

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silylation of 9b, we obtained the N-protected b-sultams 11a and 11b. Compounds 9 also
allow simple modifications of the ester group. By reduction with LiBH4, we obtained
the free alcohol 10 [5]. Finally, by aminolysis of 9, the amides 12 were obtained.
Remarkably, 12a is soluble only in DMSO or DMF/MeOH. Next, the acetate 13 was
first transformed into the diprotected b-sultam 14, which was then acetylated to 15,
which was obtained as a colorless liquid, and, as established by 1H-NMR spectroscopy,
present as the trans isomer only. Synthons 14 and 15 allow further reactions, such as
cyclization to different bicyclic b-sultams [11].
N-Substituted b-sultams may be synthesized by deprotonation (Et3N, NaOH, or
NaNH2) at low temperature, followed by alkylation or acylation [2]. An example is the
synthesis of (RS)-16 from (RS)-7e. However, since deprotonation may lead to (partial)
racemization, it seems more appropriate to introduce the N-substituent into the starting
material. Hence, we used N-benzoyl-l-Leu (17a) as the starting material for the
synthesis of (S)-24a. Reduction with LiAlH4 in THF yielded the N-benzylated
derivative (S)-18a, which was reacted with Ph3P in MeCN to yield the optically active
aziridine derivative 19 in 71% yield. When 19 was reacted with PhCH2SH, the mixed
sulfide 21 was obtained. Oxidative chlorination and cyclization yielded (S)-23a and,
finally, (S)-24a. By a similar sequence, the racemic (RS)-17b was reduced to (RS)-18b,
then transformed into the bromo compound 20, from which, in the presence of
Na2S2O3, the disulfide 22 and then the sulfonyl chloride (RS)-23b were obtained.
Cyclization yielded the racemic (RS)-24b in 81% yield.
The 4,4-disubstituted 1,2-thiazetidine-3-carboxylate 27 was synthesized stereo-
specifically from the hydrochloride of d-penicillamine benzyl ester (25) [12]. As
reported [13] for similar compounds, the oxidative chlorination of 25 was not possible.
Therefore, 25 was oxidized with Br2 in dilute AcOH to the sulfonic acid 26, a taurine
derivative, which, after chlorination with Cl3PO in MeCN/sulfolane was cyclized by
treatment with Et3N to afford 27 as a yellow, viscous liquid in ca. 40% yield. The (S)-
1
configuration of 27 was confirmed by H- and 13C-NMR experiments, including a
1
1
H-NMR dilution study with Pr(hfc)3 ), and by its circular-dichroism spectrum, giving
rise to a minimum at l ˆ 227 nm, while the (R)-enantiomer of 27 has a maximum at this
wavelength [14].
The bicyclic b-sultams 37a and 37b were prepared from N-benzylated l-Thr (28a)
and l-Ser (28b) resp. By reaction with chloroacetyl chloride, they were transformed
into the crystalline morpholine derivatives 29a and 29b, which, after esterification to
30a and 30b, were reduced with LiAlH4 to the methanol derivatives 31a and 31b. The
latter were transformed via the bromo compounds 32a and 32b into the benzyl sulfides
33a and 33b. Then, the N-Bn group was replaced by the (2,2,2-trichloroethoxy)carbonyl
group. The resulting compounds 34a and 34b were transformed with Zn in glacial
AcOH to the morpholine derivatives 35a and 35b. Oxidative chlorination gave the
sulfonyl chlorides 36a and 36b. Cyclization with NH3 in CHCl3 finally resulted in the
bicyclic b-sultams 37a and 37b. By an alternative route, the Bn group of 31a was
removed by hydrogenolysis in the presence of Pd/C to afford 38. Furthermore, we
transformed 31a via the methanesulfonate 39 and the acetylthio derivative 40 into the
1
)
Chiral shift reagent −tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]prasedymium(III)×.

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Scheme 3
a) PhCOBr, Et3N, THF. b) LiAlH4, THF. c) Ph3P, Et3N, CCl4, MeCN. d) HBr, PBr3. e) Na/EtOH, PhCH2SH.
f) Na2S2O3, I2. g) HCl, Cl2, CHCl3, CCl4, 08. h) NH3, CHCl3, THF, CCl4.
thiol 41. However, the analogous transformation of the N-unprotected 38, via the
bromo- or mercapto analogs into a bicyclic sultam, failed.
Finally, we prepared the spirotype-b-sultam 47 from 1-aminocyclohexanecarboxylic
acid (42). Reduction with LiAlH4 yielded the parent alcohol 43, which was transformed
to the bromide 44 [9], which, by reaction with Na2S2O3 and I2, gave the disulfide 45. The
latter was immediately transformed by oxidative chlorination into the stable

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Scheme 4
a) Br2, H2O, AcOH, 508. b) 1. Cl3PO, sulfolane, MeCN; 2. NH3, CHCl3.
Scheme 5
a) CH2ClCOCl, NaOH. b) SOCl2, EtOH. c) LiAlH4, THF. d) Ph3P, CBr4, MeCN. e) NaOH, PhCH2SH, EtOH.
f) Cl3CCH2OCOCl, K2CO3. g) Zn, AcOH. h) HCl, Cl2, CHCl3, CCl4. i) NH3, CHCl3. j) H2, Pd/C, EtOH. k)
1. MeSO2Cl, NH3; 2. MeCOSK, DMF, CHCl3. l) NH3, EtOH.

Helvetica Chimica Acta Vol. 87 (2004)
95
Scheme 6
a) LiAlH4. b) HBr, PBr3. c) Na2S2O3, I2, H2O. d) HCl, Cl2, CCl4, EtOH. e) NH3, CHCl3.
chlorosulfonyl derivative 46. Cyclization in the usual manner yielded 47 in more than
80% yield, demonstrating the general utility of our synthetic route towards b-sultams.
In conclusion, we have demonstrated that differently substituted b-sultams, either
optically active or racemic, can be synthesized from a-amino acids. Many of these
compounds, which are often stable products, should be useful synthons, especially for
drug synthesis.
Financial support provided by the Fonds der Chemischen Industrie, Frankfurt/M., and Novartis, Basel, is
gratefully appreciated. B. A. T. thanks the DAAD, Bonn, for a Ph.D. grant. We thank Volker Brecht, Freiburg,
for recording NMR spectra, and Ursula Predoiu, Freiburg, for experimental help.
Experimental Part
General. THF was stored over KOH, refluxed over Na/benzophenone, and distilled prior to use. Other
solvents were dried and purified according to literature procedures. Lithium diisopropylamide (LDA) was
freshly prepared by mixing equimolar amounts of (i-Pr)2NH and BuLi (15% in hexane) in THF at À788. TL C:
silica-gel 60-F254 plates; Merck. Column and flash chromatography (CC, FC): silica gel 60, 0.063 0.200 mm;
Merck. M.p.: Linstrˆm apparatus, uncorrected. IR Spectra (KBr; cmÀ1): Perkin-Elmer 1310. 1H- and 13C-NMR
Spectra: Varian T-60 (1H, 60 MHz), Bruker WP-80 (1H, 80 MHz), and Varian Unity-300 (300/75.43 MHz for 1H
and 13C, resp.); d in ppm rel. to SiMe4 (d ˆ 0 ppm), J in Hz; in CDCl3, if not otherwise noted. MS: Finnigan
MAT-312, MAT-44S. Elemental analyses: Institute of Pharmacy or Chemisches Laboratorium of the Universit‰t
Freiburg (Germany), or Institute of Pharmacy, University of Basel (Switzerland). All compounds gave
satisfactory elemental analyses or were analyzed by MS and/or HR-MS; in m/z (rel. %).
Syntheses of 2-Amino Alcohols 2. (S)-2-Aminopropan-1-ol (2a), (S)-2-amino-4-methylpentan-1-ol (2c),
and (S)-2-amino-3-phenylpropan-1-ol (2e) were prepared according to [6]. General Procedure for the synthesis
of 2b and 2d. LiAlH4 (11.1 g, 0.29 mol) was suspended in THF (500 ml). The amino acid (200 mmol) was added
in small portions at 08. The mixture was refluxed for 4 h, then cooled to r.t. Then, an aq. soln. of KOH (10%,
12 ml) and H2O (10 ml) were added dropwise. The precipitate was separated, washed with THF (50 ml), and
extracted with boiling THF (250 ml) for 2 h. The combined org. filtrates (if necessary, CH2Cl2 was added to
obtain a clear soln.) were dried (Na2SO4) and concentrated in vacuo. The residue was purified by distillation.
(S)-2-Amino-3-methylbutan-1-ol (2b) [6]. From l-Val (23.4 g, 0.2 mol): 17.0 g (83%). Yellow liquid. B.p.
1008 (10 mbar). 1H-NMR: 0.88, 0.89 (2d, J ˆ 2.7, each 2 Me); 1.54 (m, HÀC(3)); 2.51 (m, ABM, JAM ˆ 3.7, JBM
ˆ
8.4, HÀC(2)); 2.66 (s, NH2, OH); 3.25 (dd, ABM, JAB ˆ 10.6, JBM ˆ 8.5, HÀC(1)); 3.57 (dd, ABM, JAB ˆ 10.6,
JAM ˆ 3.7, H'ÀC(1)). [a]2D0 ˆ ‡16.7 (c ˆ 1, EtOH).
(S)-2-Amino-3-methylpentan-1-ol (2d). From l-Ile (26.2 g, 0.2 mol): 18.9 g (81%). Yellow liquid. B.p. 1108
(10 mbar). [a]2D0 ˆ ‡4.8 (c ˆ 1, EtOH). 1H-NMR: 0.84 (m, 2 Me); 1.10 (m, CH); 1.33, 1.45 (2m, CH2); 2.66 (m,

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HÀC(2), NH2, OH); 3.28 (dd, ABM, JAB ˆ 10.4, JBM ˆ 8.4, 1 H of CH2OH); 3.58 (dd, ABM, JAB ˆ 10.4, JAM
3.4, 1 H of CH2OH).
ˆ
General Procedures for the Synthesis of Bromoalkanamine Hydrobromides of Type 3. Method A [8]: A
mixture of 2 (0.1 mol) and HBr (48%, 50 ml) was refluxed at 170 1758 for 5 h. The mixture was diluted with
H2O (100 ml), charcoal was added, and the filtrate was evaporated. The residue was recrystallized from AcOEt/
EtOH.
Method B [8]: With cooling, HBr (48%, 10 ml) was added to 2 (0.1 mol). The mixture was evaporated in
vacuo at r.t., and PBr3 (10 ml) was added to the residue. When the reaction was complete, all volatile compounds
were evaporated. The residue was precipitated by adding Et2O and recrystallized from AcOEt/EtOH.
Method C [9]: To a cooled soln. of 2 (0.1 mol) in MeOH (20 ml), HBr (48%, 12 ml) was added. Volatile
parts were evaporated, the residue was recrystallized from AcOEt and carefully added to hot PBr3 (10 ml). This
mixture was heated to 708 with vigorous stirring for 1.5 h. After cooling to 358, Et2O (50 ml) was slowly added.
The supernatant was decanted, and the residue was recrystallized from a 1:1 mixture of AcOEt/Et2O or AcOEt/
EtOH.
Method D: SOBr2 (15.6 g) in CH2Cl2 (20 ml) was added to 2 (66 mmol) in CH2Cl2 (50 ml) at 08. The mixture
was carefully warmed, until no more gas was produced. The residue was concentrated and dissolved in EtOH.
Charcoal was added, and after heating, the charcoal was filtered off, the filtrate was concentrated, and the
residue was recrystallized from EtOH/acetone.
(S)-1-(Bromo(methyl)ethylammonium Bromide (3a). From a) 2a (8 g, 106 mmol) in MeOH (30 ml) with
HBr (48%, 18 g, 110 mmol), Method B; or b) from 2a (5 g, 66 mmol) in CH2Cl2 (50 ml), Method D: a) 8 g
‡
‡
(34%); b) 6 g (44%). Yellow crystals. M.p. 1178 (EtOH/acetone). IR: 3280 2200 (NH3 ), 1570 (NH3 ), 680
(CÀBr).
(S)-1-(Bromomethyl)-2-methylpropylammonium Bromide (3b). From 2b (7.5 g, 0.1 mol): 12.3 g (50%).
‡
‡
Colorless crystals. M.p. 1778. [a]2D0 ˆ ‡4.49 (c ˆ 1, EtOH). IR: 3200 2800 (NH3 ), 2970 (CH), 1590 (NH3 ).
1H-NMR: 1.12, 1.20 (2d, J ˆ 6.8, each 2 Me); 2.32 (m, HÀC(2)); 3.36, 3.72, 3.87 (ABM, JAM ˆ 4.3, JBM ˆ 5.4,
‡
JAB ˆ 11.6, HÀC(1), CH2Br); 8.30 (br. s, NH3 ). Anal. calc. for C5H13Br2N (246.98): C 24.32, H 5.30, Br 64.71, N
5.30; found: C 24.20, H 5.34, Br 64.24, N 5.59.
(S)-1-(Bromomethyl)-3-methylbutylammonium Bromide (3c) [15]. From 2c (11.8 g, 0.1 mol), Method C:
16.0 g (61%). Colorless crystals. M.p. 1818 (AcOEt/Et2O; lit. 1808 [15]). [a]2D0 ˆ ‡3.56 (c ˆ 1, EtOH). IR: 3160
‡
2700, 1600 (NH3 ), 2950 (CH). 1H-NMR: 0.86, 0.88 (2d, J ˆ 3.5 each, 2 Me); 1.45 (t, J ˆ 7.1, CH2); 1.67 (m,
‡
HÀC(4)); 3.48, 3.68, 3.75 (ABM, JAM ˆ 3.75, JBM ˆ 4.4, JAB ˆ 11.4, HÀC(2), BrCH2); 8.15 (br. s, NH3 ).
(RS)-1-(Bromomethyl)-3-methylbutylammonium Bromide ((RS)-3c). From (RS)-2c, Method C: 15.6 g
(60%). Colorless crystals. M.p. 1828.
(S)-1-(Bromomethyl)-2-methylbutylammonium Bromide (3d). From 2d (11.8 g, 0.1 mol): 15.2 g (57%).
‡
Colorless crystals. M.p. 1878. [a]2D0 ˆ ‡7.69 (c ˆ 1, EtOH). IR: 3200 2700, 1590 (NH3 ), 2960 (CH). 1H-NMR:
0.98 (t, J ˆ 7.3, Me); 1.07 (d, J ˆ 6.8, Me); 1.39, 1.68 (2m, 2 CH2); 2.12 (m, HÀC(3)); 3.46, 3.71, 3.83 (ABM,
‡
JAM ˆ 3.8, JBM ˆ 6.1, JAB ˆ 11.5, HÀC(2), BrCH2); 8.40 (br. s, NH3 ). Anal. calc. for C6H15Br2N (261.01): C 27.61,
H 5.79, Br 61.23, N 5.37; found: C 27.27, H 5.70, Br 61.04, N 5.46.
(S)-1-(Bromomethyl)-2-phenylethylammonium Bromide (3e). From a) 2e (15.1 g, 0.1 mol), Method C; or
b) 2e (5 g, 0.33 mol), Method D: a) 18.0 g (61%), b) 5 g (51%). Colorless crystals. M.p. 1688. IR: 3000 2800,
‡
1500 (NH3 ), 2925 (CH), 745, 700 (arom.). 1H-NMR ((D6)DMSO): 2.86, 2.99 (ABM, JAM ˆ 8.6, JBM ˆ 5.8, JAB
ˆ
13.7, HÀC(3), H'ÀC(3)); 3.44, 3.67 (ABM, JAM ˆ 4.5, JBM ˆ 3.4, JAB ˆ 11.5, HÀC(1), H'ÀC(1)); 3.77 (m
(ABM), HÀC(2)); 7.3 (m, 5 arom. H); 8.2 (br. s, NH3 ). [a]2D0 ˆ À3.9 (c ˆ 1, EtOH). MS (70 eV): 214 (8.8, [M À
‡
‡
HBr] ), 162 (24.6); 91 (39).
Synthesis of Amino Thiols 4. General Procedure [16]. A soln. of 3 (0.05 mol) and thiourea (4.2 g, 0.05 mol)
in EtOH (80 100 ml) was refluxed for 15 h. Then, tetraethylenepentamine (7.5 g) was added, and the mixture
was refluxed for 1 h. The solvent was removed in vacuo, and the residue was purified by sublimation and
recrystallization from EtOH. Alternatively, the sublimate was dissolved in a few milliliters of CCl4 and
immediately used for the next reaction.
(S)-2-Amino-3-methylbutane-1-thiol (4b). From 3b (12.3 g, 0.05 mol): 1.9 g (32%). Colorless crystals. M.p.
468. [a]2D0 ˆ ‡4.24 (c ˆ 1, EtOH). IR: 2995 (CH), 2535 (SH), 1585 (NH). 1H-NMR: 0.90, 0.92 (2d, J ˆ 2.2 each,
2 Me); 1.48 (br. s, NH2, SH); 1.69 (m, HÀC(3)); 2.38, 2.69, 2.85 (ABM, JAB ˆ 12.8, JAM ˆ 8.7, JBM ˆ 3.4, HÀC(2),
HÀC(1), H'ÀC(1)).
(S)-2-Amino-4-methylpentane-1-thiol (4c). From 3c (13.0 g, 0.05 mol): 2.5 g (38%). Colorless crystals. M.p.
488. [a]2D0 ˆ ‡6.23 (c ˆ 1, EtOH). IR: 3000 (CH), 2530 (SH), 1587 (NH). 1H-NMR: 0.9 (m, 2 Me); 1.25 (t,

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J ˆ 7.2, HÀC(3), H'ÀC(3)); 1.68 (m, HÀC(4), NH2, SH); 2.36, 2.65, 2.85 (ABM, JAB ˆ 13.4, JAM ˆ 7.6, JBM ˆ 3.9,
HÀC(2), HÀC(1), H'ÀC(1)).
(RS)-2-Amino-4-methylpentane-1-thiol ((RS)-4c). From (RS)-3c (13.0 g, 0.05 mol): 2.7 g (41%). Colorless
crystals. M.p. 488.
(S)-2-Amino-3-methylpentane-1-thiol (4d). From 3d (13.0 g, 0.05 mol): 2.3 g (35%). Colorless crystals. M.p.
528. [a]2D0 ˆ ‡7.2 (c ˆ 1, EtOH). IR: 2995 (CH), 2530 (SH), 1585 (NH). 1H-NMR: 1.02 (m, 2 Me); 1.61 (s, CH2);
1.68 (m, HÀC(3), NH2, SH); 2.34, 2.64, 2.85 (ABM, JAB ˆ 13.2, JAM ˆ 7.1, JBM ˆ 3.7, HÀC(2), HÀC(1),
H'ÀC(1)).
(S)-2-Amino-3-phenylpropane-1-thiol (4e). From 3e (14.7 g, 0.05 mol): 3.2 g (38.4%). Colorless crystals.
M.p. 568. [a]2D0 ˆ À5.2 (c ˆ 1, EtOH). IR: 3350 (NH), 3030, 2920 (CH), 900, 730, 700 (Ar). 1H-NMR: 2.54, 2.59
(ABM, JAB ˆ 13.43, JAM ˆ 8.4, JBM ˆ 6.83, HÀC(3), H'ÀC(3)); 2.76, 2.78 (ABM, JAB ˆ 13.30, JAM ˆ 7.1, JBM ˆ 4.4,
HÀC(1), H'ÀC(1)); 2.96 (br. s, NH2, SH); 3.29 (m (ABM), HÀC(2)); 7.2 (m, 5 arom. H).
Synthesis of Disulfides 5. General Procedure [16]. To a soln. of 3 (25 mmol) in H2O (80 ml), Na2S2O3 ¥ 5
H2O (6.3 g, 25 mmol) was added. The soln. was refluxed for 1 h, and to the hot soln., a soln. of I2 in EtOH was
added dropwise, until the reaction was complete. The mixture was cooled, an aq. soln. of NaOH (20%) was
added dropwise, until a pH of ca. 10 was reached. Then, the mixture was extracted 3 4 times with CH2Cl2, the
combined org. layers were washed with sat. NaCl soln., dried (Na2SO4), and evaporated in vacuo. The residue
was immediately used for the next reaction without further purification.
(2S)-1-[((2S)-2-Aminopropyl)disulfanyl]propan-2-amine (5a). From 3a (5 g) and I2 (3.2 g): 2.9 g (71%).
(2S)-1-[((2S)-2-Amino-4-methylpentyl)disulfanyl]-4-methylpentan-2-amine (5c). From 3c (10 g, 38 mmol),
Na2S2O3 ¥ 5 H2O (8.7 g, 38 mmol), and I2 (4.6 g): 3.5 g (70%).
(2S)-1-[((2S)-2-Amino-3-phenylpropyl)disulfanyl]-3-phenylpropan-2-amine (5e). From 3e (3 g, 10 mmol),
Na2S2O3 ¥ 5 H2O (2.5 g, 10 mmol), and I2 (1.2 g): 2 g (60%). Yellow viscous liquid.
(S)-2-Aminopropane-1-sulfonic Acid (6a). A refluxing soln. of 3a (8 g, 37 mmol) in EtOH (95%, 20 ml)
and H2O (8 ml) was slowly treated with a soln. of Na2SO3 ¥ 5 H2O (5 g) in H2O (10 ml), and reflux was continued
for 2 h. The solvents were evaporated, the inorg. salts were filtered off, and the product was extracted with
boiling EtOH (95%, 40 ml). On cooling, 6a crystallized: 3.2 g (54%). Colorless crystals. M.p. 3028 (dec).
Synthesis of 2-(Aminoalkyl)sulfonylchloride Hydrochlorides 6b 6e. General Procedure. A soln. of
4
(20 mmol) in CCl4 (100 ml) was saturated with HCl. EtOH (50 ml) was added, and Cl2 gas was bubbled through
the soln. below 108. When the reaction was complete (yellow soln.), N2 was blown through the mixture, and the
solvent was evaporated. A few milliliters of Et2O were added to the residue, which was recrystallized from
acetone.
(S)-2-Amino-3-methylbutane-1-sulfonyl Chloride Hydrochloride (6b). From 4b (2.4 g, 20 mmol): 3.2 g
‡
(72%). Colorless crystals. M.p. 1858. [a]2D0 ˆ ‡25.5 (c ˆ 1, EtOH). IR: 3300 2700 (CH, NH3 ), 2895 (CH), 1570,
‡
1470 (NH3 ), 1380, 1170 (SO2). 1H-NMR ((D6)DMSO): 0.85 (m, 2 Me); 1.67 (m, HÀC(3)); 2.55, 2.75, 3.38
‡
(ABM, JAB ˆ 14.2, JAM ˆ 10.2, JBM ˆ 2.4, HÀC(2), HÀC(1), H'ÀC(1)); 7.9 (br. s, NH3 ). Anal. calc. for
C5H13Cl2NO2S (222.13): C 27.04, H 5.90, N 6.30, S 14.43; found: C 27.21, H 5.87, N 6.16, S 14.38.
(S)-2-Amino-4-methylpentane-1-sulfonyl Chloride Hydrochloride (6c). From 4c (2.6 g, 20 mmol): 3.2 g
‡
‡
(69%). Colorless crystals. M.p. 1978. [a]D20 ˆ ‡11.74 (c ˆ 1, EtOH). IR: 3200 2800 (CH, NH3 ), 1595 (NH3 ),
1
1380, 1170 (SO2). H-NMR ((D6)DMSO): 0.87 (m, 2 Me); 1.46 (m, HÀC(3), H'ÀC(3)); 1.67 (m, HÀC(4));
‡
2.59, 2.74, 3.34 (ABM, JAB ˆ 14.3, JAM ˆ 10.1, JBM ˆ 2.7, HÀC(2), HÀC(1), H'ÀC(1)); 7.95 (br. s, NH3 ). Anal.
calc. for C6H15Cl2NO2S (236.16): C 30.52, H 6.40. N 5.93, S 13.58; found: C 30.31, H 6.31, N 5.91, S 13.67.
(RS)-2-Amino-4-methylpentane-1-sulfonyl Chloride Hydrochloride ((RS)-6c). From (RS)-4c (2.6 g,
20 mmol): 2.9 g (63%). Colorless crystals. M.p. 1978.
(S)-2-Amino-3-methylpentane-1-sulfonyl Chloride Hydrochloride (6d). From 4d (2.6 g, 20 mmol): 3.0 g
‡
‡
(65%). Colorless crystals. M.p. 1958. [a]D20 ˆ ‡13.5 (c ˆ 1, EtOH). IR: 3200 2800 (CH, NH3 ), 1500 (NH3 ),
1375, 1165 (SO2). 1H-NMR ((D6)DMSO): 0.82 (m, 2 Me); 1.16, 1.32 (2m, HÀC(4), H'ÀC(4)); 1.74 (m,
HÀC(3)); 2.56, 2.68, 3.31 (ABM, JAB ˆ 14.2, JAM ˆ 10.8, JBM ˆ 1.9, HÀC(2), HÀC(1), H'ÀC(1)); 7.89 (br. s,
‡
NH3 ). Anal. calc. for C6H15Cl2NO2S (236.16): C 30.52, H 6.40, N 5.93, S 13.58; found: C 30.30, H 6.35, N 5.89, S
13.65.
(S)-2-Amino-3-phenylpropane-1-sulfonyl Chloride Hydrochloride (6e). From 4e (3.3 g, 20 mmol): 4.1 g
‡
(77%). Colorless crystals. M.p. 1848 (dec.). [a]2D0 ˆ À12.0 (c ˆ 1, MeOH). IR: 3000 2800 (CH, NH3 ), 1495
‡
1
(NH3 ), 1370, 1160 (SO2), 760, 745, 700. H-NMR ((D6)DMSO): 2.57, 2.66 (dd (ABM), JAB ˆ 14.2, JAM ˆ 3.2,
JBM ˆ 9.6, HÀC(3), H'ÀC(3)); 2.80, 3.08 (ABM, JAB ˆ 13.3, JAM ˆ 9.4, JBM ˆ 5.1, HÀC(1), H'ÀC(1)); 3.5 (m
‡
‡
(ABM), HÀC(2)); 7.2 (m, 5 arom. H); 8.1 (br. s, NH3 ). MS (70 eV): 274 (17, M ). Formula: C9H13Cl2NO2S
(270.17 g molÀ1).

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Helvetica Chimica Acta Vol. 87 (2004)
(S)-3-Methyl-1,2-thiazetidine 1,1-Dioxide (7a). Method A: To a soln. of 6a (3.2 g, 20 mmol) in Cl3PO
(60 ml), H2O (4 ml) was added at 608. Then, PCl5 (27 g) was added, and the mixture was evaporated in vacuo.
The residue was dissolved in CHCl3 (20 ml) and neutralized with 8n KOH at 08. The org. layer was washed with
ice-cold H2O, dried (Na2SO4), and concentrated in vacuo: 0.8 g (33%).
Method B: 5a (1 g, 11 mmol) was dissolved in a mixture of CHCl3 (20 ml) and CCl4 (20 ml). Then, HCl gas
was passed at 08 through the mixture for a few minutes. EtOH (98%, 10 ml) was added, and the mixture was
saturated with Cl2 gas. After evaporation in vacuo, the residue was dissolved in anh. (!) CHCl3 (30 ml), and
NH3-sat. CHCl3 (50 ml) was added. After 24 h at r.t., NH4Cl salts were separated by filtration over Kieselgur,
and the filtrate was evaporated in vacuo: 0.8 g (61%). Colorless oily liquid. IR (film): 3290 (NH), 3040, 2870,
2930 (CH), 1300, 1155 (SO2). 1H-NMR: 1.48 (d, J ˆ 6.0, Me); 3.83 (m, HÀC(3)); 3.83 (dd, J ˆ 14.0, 5.0,
HÀC(4)); 4.39 (dd, J ˆ 14.0, 9.0, H'ÀC(4)); 5.95 (br. s, NH). Anal. calc. for C3H7NO2S (121.16): C 29.74, H 5.82,
N 11.56; found: C 29.70, H 5.89, N 11.45.
Synthesis of 3-Alkyl-1,2-thiazetidine 1,1-Dioxides 7b e. General Procedure. To a cooled suspension of 6
(20 mmol) in THF (100 ml), a sat. soln. of NH3 in CHCl3 was added, until the mixture was pH-neutral. After a
few hours, the precipitate was separated, and the solvent was evaporated in vacuo. A few milliliters of CCl4 were
added to the residue, and, after a short period of heating, the product crystallized on cooling.
(S)-3-Isopropyl-1,2-thiazetidine 1,1-Dioxide (7b). From 6b (4.4 g, 20 mmol): 1.8 g (61%). Colorless crystals.
M.p. 538. [a]2D0 ˆ ‡9.73 (c ˆ 1, EtOH). IR: 3335 (NH), 3047 (CH), 1340, 1150 (SO2). 1H-NMR: 0.92, 0.95 (2d,
J ˆ 6.7 each, 2 Me); 1.89 (m, CH); 3.29 (m (ABM), HÀC(3)); 3.89, 4.18 (ABM, JAB ˆ 12.6, JAM ˆ 11.6, JBM ˆ 6.1,
HÀC(4), H'ÀC(4)); 5.4 (s, NH). 13C-NMR: 17.86, 18.35 (2 Me); 33.55 (CH); 46.56 (C(3)); 63.03 (C(4)). Anal.
calc. for C5H11NO2S (149.21): C 40.25, H 7.43, N 9.39, O 21.45; found: C 40.08, H 7.35, N 9.36, O 21.47.
(S)-3-(2-Methylpropyl)-1,2-thiazetidine 1,1-Dioxide (7c). Method A: From 6c (4.7 g, 20 mmol): 1.2 g
(37%). Method B: from 5c (3.5 g, 26.5 mmol), as described for 7a: 2.9 g (86%). Colorless crystals. M.p. 568
(CHCl3/pentane). A) [a]2D0 ˆ ‡11.5 (c ˆ 1, EtOH); B) [a]D23 ˆ ‡3.57 (c ˆ 2.41, CHCl3). IR: 3290 (NH), 3030
1
(CH), 1370, 1160 (SO2). H-NMR: 0.89, 0.93 (2d, J ˆ 5.3 each, 2 Me); 1.58 (m, CH2); 1.69 (m, CH); 3.69 (m
(ABM), HÀC(3)); 3.83, 4.28 (ABM, JAB ˆ 12.5, JAM ˆ 10.8, JBM ˆ 5.7, HÀC(4), H'ÀC(4)); 5.3 (br. s, NH).
13C-NMR: 21.94, 22.59 (2 Me); 25.80 (CH); 44.95 (CH2); 39.50 (C(3)); 65.18 (C(4)). Anal. calc. for C6H13NO2S
(163.24): C 44.15, H 8.03, N 8.58, S 19.64; found: C 44.03, H 8.09, N 8.52, S 19.74.
(RS)-3-(2-Methylpropyl)-1,2-thiazetidine 1,1-Dioxide ((RS)-7c). From (RS)-6c (4.4 g, 20 mmol): 1.4 g
(43%). Colorless crystals. M.p. 568.
(S)-3-(1-Methylpropyl)-1,2-thiazetidine 1,1-Dioxide (7d). From 6d (4.7 g, 20 mmol): 1.2 g (37%). Colorless
1
crystals. M.p. 588. [a]2D0 ˆ ‡12.54 (c ˆ 1, EtOH). IR: 3330 (NH), 3048 (CH), 1385, 1165 (SO2). H-NMR: 0.9
(m, 2 Me); 1.1 (m, CH); 1.49, 1.65 (2m, 2 CH2); 3.35 (m (ABM), HÀC(3)); 3.89, 4.17 (ABM, JAB ˆ 12.6, JAM
ˆ
4.0, JBM ˆ 6.1, HÀC(4), H'ÀC(4)); 5.40 (s, NH). 13C-NMR: 10.78, 14.02 (2 Me); 25.49 (CH2); 39.83 (CH); 45.39
(C(3)); 63.03 (C(4)). Anal. calc. for C6H13NO2S (163.23): C 44.15, H 8.03, N 8.58; found: C 43.71, H 7.83, N 8.52.
(S)-3-(Phenylmethyl)-1,2-thiazetidine 1,1-Dioxide (7e). From 6e (3.0 g, 11 mmol): 1.9 g (87%). Light
yellow crystals. M.p. 68 708. [a]2D3 ˆ À19.96 (c ˆ 2.43, CHCl3); [a]2D0 ˆ À34.7 (c ˆ 1, EtOH). IR: 3270 (NH),
1
1385, 1165 (SO2), 780, 740, 700. H-NMR: 3.02 (d, CH2); 3.85 (m (ABM), HÀC(3)); 3.95, 4.26 (ABM, JAB
ˆ
12.5, JAM ˆ 7.6, JBM ˆ 5.3, HÀC(4), H'ÀC(4)); 5.21 (br. s, NH); 7.2 (m, 5 arom. H). 13C-NMR: 41.79 (CH2); 41.98
(C(3)); 64.31 (C(4)); 127.39, 128.86, 129.01, 136.04 (6 arom. C). Anal. calc. for C9H11NO2S (197.26): C 54.80, H
5.62, N 7.10, S 16.25; found: C 54.61, H 5.69, N 7.16, S 16.20.
(RS)-3-(Phenylmethyl)-1,2-thiazetidine 1,1-Dioxide ((RS)-7e) was prepared from d,l-Phe via the disulfide
(RS)-5e. M.p. 698.
Methyl (R)-1,2-Thiazetidine-3-carboxylate 1,1-Dioxide (9a). From l-cystine dimethyl ester hydrochloride
(8; 5 g, 14.7 mmol)), as described for 9b [10]: 2.3 g (50%). Colorless crystals. M.p. 72 738. [a]2D3 ˆ À58.15 (c ˆ
1.26, CHCl3).
Ethyl (R)-1,2-Thiazetidine-3-carboxylate 1,1-Dioxide (9b): see [10].
(R)-1,2-Thiazetidine-3-methanol 1,1-Dioxide (10) [10]. From 9b (1.8 g, 10 mmol) in THF (40 ml), and
LiBH4 (0.2 g, 10 mmol): 0.5 g (36%). Colorless crystals. M.p. 708 (CH2Cl2; lit. 70 718 [10]). 1H-NMR (CDCl3/
(D6)DMSO): 3.58 (m, CH2OH, HÀC(3), NH); 3.88 4.50 (m, HÀC(4), H'ÀC(4)). Formula: C3H7NO3S
(137.16 g molÀ1).
Ethyl (R)-2-[(tert-Butyl)dimethylsilyl]-1,2-thiazetidine-3-carboxylate 1,1-Dioxide (11a). Under N2 at À788,
BuLi (7.5 ml, 12 mmol) was added to 9b (2.15 g, 12 mmol) dissolved in THF (100 ml). After stirring for 10 min,
(t-Bu)Me2SiCl (1.96 g, 13 mmol) was added. After stirring for 30 min at À788, the mixture was warmed to r.t.,
and hydrolyzed with a sat. NaCl soln. The org. layer was dried (Na2SO4), concentrated in vacuo, and the residue
was purified by CC (cyclohexane/AcOEt 5 :7): 2.5 g (71%). Light yellow liquid. [a]2D3 ˆ À64.22 (c ˆ 2.2,

Helvetica Chimica Acta Vol. 87 (2004)
99
CHCl3). IR (film): 3030, 2950, 2920, 2850 (CH), 1745 (CˆO), 1320, 1310, 1195, 1150 (SO2). 1H-NMR: 0.25, 0.31
(2s, Si(Me)2); 1.00 (s, t-Bu); 1.35 (t, J ˆ 7.0, Me); 4.15 (dd, J ˆ 4.0, 8.0, HÀC(3)); 4.25 (q, J ˆ 7.0, OCH2); 4.3 (dd,
J ˆ 12.0, 4.0, HÀC(4)); 4.55 (dd, J ˆ 12.0, 8.0, H'ÀC(4)). Anal. calc. for C11H23NO4SSi (293.46): C 45.02, H 7.90,
N 4.77; found: C 44.74, H 7.71, N 4.91.
Ethyl (R)-2-[(tert-Butyl)diphenylsilyl]-1,2-thiazetidine-3-carboxylate 1,1-Dioxide (11b). From 9b (1.1 g,
6 mmol), BuLi (3.8 ml, 6 mmol), and (t-Bu)Ph2SiCl (1.6 ml, 6 mmol), as described for 11a. CC (cyclohexane/
AcOEt 1:1): 1.6 g (65%). Colorless crystals. M.p. 80 828 (CCl4/pentane). [a]2D3 ˆ À49.3 (c ˆ 1.1, CHCl3). IR:
3080, 3050, 2980, 2950, 2900, 2860 (CH), 1750 (CˆO), 1320, 1310, 1200, 1150 (SO2). 1H-NMR: 0.83 (t, Me); 1.15
(s, t-Bu); 3.35 3.8 (m, OCH2); 3.88 (dd, J ˆ 4.0, 8.0, HÀC(3)); 4.21 (dd, J ˆ 13.0, 4.0, HÀC(4)); 4.48 (dd, J ˆ
13.0, 8.0, H'ÀC(4)); 7.25 7.96 (m, 10 arom. H). Anal. calc. for C21H27NO4SSi (417.60): C 60.40, H 6.52, N 3.35;
found: C 60.13, H 6.48, N 3.47.
(R)-1,2-Thiazetidine-3-carboxamide 1,1-Dioxide (12a). Compound 9b (3 g, 16.7 mmol) was dissolved in an
NH2-sat. CHCl3 soln. At 08, NH3 was passed through the soln. for 30 min. After 2 d, the crystals that had formed
were separated: 1.5 g (60%). Colorless crystals. M.p. 1478 (dec.). IR: 3430, 3340 (NH), 3080, 2980 (CH), 1660,
1600 (amide), 1305, 1155, 1140 (SO2). 1H-NMR (CDCl3/(D6)DMSO): 3.0 4.75 (br. s, NH2); 3.98 (dd, J ˆ 8.0,
5.0, HÀC(3)); 4.2 (dd, J ˆ 12.0, 5.0, HÀC(4)); 4.54 (dd, J ˆ 12.0, 8.0, H'ÀC(4)); 7.41 (d, NH). Anal. calc. for
C3H6N2O3S (150.16): C 22.64, H 4.44, N 17.60, S 20.14; found: C 22.50, H 4.47, N 17.35, S 20.02.
(R)-N-(Phenylmethyl)-1,2-thiazetidine-3-carboxamide 1,1-Dioxide (12b). Method A: 11a (2.3 g, 7.8 mmol)
was dissolved in Et2O, benzylamine (1 ml, 9 mmol) was added, and the mixture was refluxed for 8 h. After
evaporation, a few drops of CCl4 were added to the residue: 1.1 g (60%).
Method B: 9b (1.9 g, 10.6 mmol), and benzylamine (1.13 g, 10.6 mmol) in CH2Cl2 (20 ml) were refluxed for
10 h. After evaporation, a few drops of CCl4 were added to the residue: 1.4 g (55%). Colorless crystals. M.p. 1408
(dec.). IR: 3350, 3100 (NH), 1650, 1530 (amide), 1315, 1185, 1150 (SO2). 1H-NMR (CDCl3/(D6)DMSO): 2.75
3.63 (br. s, NH); 4.05 (dd, J ˆ 6.0, 8.0, HÀC(3)); 4.25 4.49 (m, HÀC(4), PhCH2); 4.55 (dd, J ˆ 12.0, 8.0,
H'ÀC(4)); 7.26 (m, 5 arom. H); 8.2 (br. s, NH). Anal. calc. for C10H12N2O3S (240.28): C 49.99, H 5.03, N 11.66, S
13.34; found: C 49.97, H 5.12, N 11.76, S 13.36.
(R)-(1,2-Thiazetidine-3-yl)methyl Acetate 1,1-Dioxide (13) [10]. From 10 (5 g, 18.1 mmol), FC (AcOEt/
cyclohexane 1 :2 ! 1:1): 1.45 g (45%). Colorless crystals. M.p. 498. [a]2D5 ˆ ‡7.9 (c ˆ 3.3, EtOH). Formula:
C5H9NO4S (179.20 g molÀ1).
(R)-2-[(tert-Butyl)dimethylsilyl]-3-({[(tert-butyl)dimethylsilyl]oxy}methyl)-1,2-thiazetidine 1,1-Dioxide
(14). Under N2 at À788, BuLi (5.6 ml, 8.96 mmol) was added to 13 (0.5 g, 2.79 mmol) in THF (20 ml), and
after stirring for 15 min, (t-Bu)Me2SiCl (1.5 g, 9.95 mmol) in THF (5 ml) was added. Stirring was continued at
r.t. for 90 min, the mixture was hydrolyzed with sat. NH4Cl soln. (50 ml). AcOEt (50 ml) was added, and the org.
layer was dried (MgSO4) and evaporated in vacuo. The residue was purified by FC (AcOEt/cyclohexane 1:9):
0.5 g (49%). Colorless needles. M.p. 258. Rf 0.30 (AcOEt/cyclohexane 1:9). [a]2D3:2 ˆ À31.5 (c ˆ 1.1, Et2O). IR
(film): 2975, 2935, 2863 (CH), 1470 (Me), 1312, 1199, 1153, (SO2), 1257 (MeSi). 1H-NMR: 0.07, 0.08, 0.27, 0.28
(4s, 4 MeSi); 0.90, 0.99 (2s, 2 t-Bu); 3.60 3.69 (m, 1 H of CH2, HÀC(3)); 3.86 (dd, J ˆ 8.0, 11.0, 1 H of CH2); 3.97
(dd, J ˆ 1.0, 13.0, HÀC(4)); 4.30 (dd, J ˆ 7.0, 14.0, H'ÀC(4)). 13C-NMR: À5.6, À5.4, À4.3 (SiMe); 18.1, 18.3,
25.8, 26.1 (t-Bu); 43.7 (C(3)); 63.2 (C(4)); 65.6 (CH2O). Anal. calc. for C15H35NO3SSi2 (365.69): C 49.27, H 9.65,
N 3.83; found: C 49.43, H 9.47, N 3.56.
(3R,4S)-4-Acetyl-2-[(tert-Butyl)dimethylsilyl]-3({[(tert-butyl)dimethylsilyl]oxy}methyl)-1,2-thiazetidine
1,1-Dioxide (15). Under N2 at À788, BuLi (1.03 ml, 1.65 mmol) was added to a soln. of 14 (0.4 g, 1.1 mmol) in a
mixture of THF (5 ml) and HMPA (1 ml). After 10 min, acetyl chloride (0.15 ml, 2.2 mmol) was added with
stirring, the mixture was warmed to r.t., AcOEt (50 ml) was added, and the mixture was washed with sat. NH4Cl
soln. (3 Â 50 ml). The org. layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by FC
(AcOEt/cyclohexane 1:9): 42 mg (9.3%). Colorless liquid. Rf 0.3 (AcOEt/cyclohexane 1:9). [a]2D5 ˆ À8.3 (c ˆ
0.3, acetone). 1H-NMR: 0.15, 0.257 (2s, 2 SiMe); 0.263 (s, 2 MeSi); 0.94, 0.97 (s and mc, 2 t-Bu); 2.07 (s, Ac); 3.60
(ddd, J ˆ 4.0, 5.0, 6.0, HÀC(3)); 3.86 (d, J ˆ 4.0, HÀC(4)); 4.16 (dd, J ˆ 6.0, 12.0, 1 H, C(3)CH2); 4.31 (dd, J ˆ
5.0, 12.0, 1 H, C(3)CH2). Anal. calc. for C16H37NO4SSi2 (407.72): C 50.08, H 9.15, N 3.44; found: C 50.50, H 9.39,
N 2.99.
(RS)-2-Benzoyl-3-(phenylmethyl)-1,2-thiazetidine 1,1-Dioxide ((RS)-16). To a soln. of (RS)-7e (1.2 g,
6 mmol) in THF (40 ml), Et3N (0.6 g, 6.1 mmol) was added at 08, followed dropwise by PhCOBr (1.0 g,
5.8 mmol) in THF (10 ml). The mixture was stirred for 1.5 h at 58, the precipitate was filtered off, and the filtrate
was concentrated in vacuo. The residue solidified, when stored for 3 d at À208: 1.3 g (74%). Colorless crystals.
M.p. 898 (98% EtOH). IR: 3060, 3020, 2960, 2920 (CH), 1670 (CˆO), 1600, 1580, 1490, 1445 (arom.), 1345,
1320, 1195, 1160 (SO2). 1H-NMR: 3.0 (dd, J ˆ 14.4, 8.0, 1 H of PhCH2); 3.5 (dd, J ˆ 14.4, 4.0, 1 H of PhCH2); 3.88

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Helvetica Chimica Acta Vol. 87 (2004)
(dd, J ˆ 13.0, 6.0, HÀC(4)); 4.15 (dd, J ˆ 13.0, 8.0, H'ÀC(4)); 4.38 4.8 (m, HÀC(3)); 7.05 8.15 (m, 10 arom.
H). Anal. calc. for C16H15NO3S (301.36): C 63.77, H 5.02, N 4.64, S 10.64; found: C 63.76, H 5.11, N 5.11, S 10.72.
N-Benzoyl-l-leucine ((S)-17a) [15]. From l-Leu (13.1 g, 100 mmol) and benzoyl chloride (11 ml,
100 mmol): 23 g (98%).
N-(Phenylmethyl)-d,l-alanine ((RS)-17b). See [18].
(S)-4-Methyl-2-[(phenylmethyl)amino]pentan-1-ol ((S)-18a). From (S)-17a (23 g, 98 mmol), and LiAlH4
(20 g, 540 mmol), as described for 2, after 3 h of heating. The residue solidified on cooling: 19.8 g (97%).
Colorless crystals. M.p. 708 (toluene). [a]2D3 ˆ À22.4 (c ˆ 3.6, EtOH). IR: 3280 (NH), 3200 2500 (OH, CH).
1H-NMR (60 MHz): 0.97 (d, 2 Me); 1.1 1.8 (m, CHCH2); 1.93 2.3 (m, OH, NH); 2.5 3.07 (m, CHN); 3.8 (s,
PhCH2); 3.17 3.9 (m, CH2O); 7.33 (m, 5 arom. H). Anal. calc. for C13H21NO (207.32): C 75.32, H 10.21, N 6.76;
found: 75.09, H 10.10, N 6.68.
ꢀRS)-2-[(Phenylmethyl)amino]propan-1-ol ((RS)-18b). From (RS)-17b (11.1 g, 62 mmol), and LiAlH4
(5 g) in THF (200 ml), as described for 2, after 5 h of heating. The residue solidified on cooling: 7.9 g (77%).
1
Colorless crystals. M.p. 648 (Et2O). IR: 3280 (NH), 3260 2500 (OH, CH). H-NMR: 1.08 (d, Me); 2.5 (br. s,
OH, NH); 2.83 (m, HÀC(2)); 3.28 (dd, J ˆ 11.0, 6.0, HÀC(1)); 3.55 (dd, J ˆ 11.0, 4.0, H'ÀC(1)); 3.75 (AB, CH2);
7.26 (m, 5 arom. H). Formula: C10H15NO (165.24 g molÀ1).
(S)-2-(2-Methylpropyl)-1-(phenylmethyl)aziridine (19). Ph3P (15.5 g, 59 mmol), Et3N (5.2 g, 52 mmol),
and CCl4 (8 g, 2 mmol) were added to a soln. of (S)-18a (10.8 g, 52 mmol) in MeCN (40 ml). The mixture was
stirred for 4 h at ca. 88, and was then stored at 5 88 for 12 24 h. The precipitate (Et3N ¥ HCl) was filtered off,
the filtrate was concentrated in vacuo, and the residue was extracted with petroleum ether (4 Â 50 ml). The
combined org. extracts were stored for 12 24 h at À188. The precipitate (Ph3PO) was separated, the solvent
was concentrated, and the residue was purified by bulb-to-bulb distillation: 7 g (71%). Colorless liquid. B.p. 708
(0.8 mbar), 1358 (15 mbar). [a]2D3 ˆ ‡12.1 (c ˆ 2.98, CHCl3). IR (film): 3080, 3060, 3015, 2950, 2860 (CH), 1490,
1460, 1450, 730, 695 (arom.). 1H-NMR: 0.75, 0.80 (2d, 2 Me); 1.02 1.9 (m, CH, CH2, HÀC(2), HÀC(3),
H'ÀC(3)); 3.38 (s, PhCH2). Anal. calc. for C13H19N (189.30): C 82.48, H 10.12, N 7.40; found: C 82.20, H 10.01, N
7.27.
(RS)-N-Benzyl-2-bromo-1-methylethylammonium Bromide (20). From (RS)-18b (7.9 g, 48 mmol), HBr
(48%, 7.8 g), and PBr3 (6.8 g), as described for 3, Method B: 9 g (60%). Yellowish crystals. M.p. 1158 (EtOH/
Et2O).
(S)-N-Benzyl-1-[(benzylsulfanyl)methyl]-3-methylbutanamine (21). Under N2, PhCH2SH (4 g, 32 mmol)
and Na (50 mg) were dissolved in EtOH (20 ml), and warmed to 408. 19 (6 g, 32 mmol) was added, the mixture
was stirred for 3 h at 408, then for 2 d at r.t. The solvent was evaporated, and the residue was purified by CC
(CHCl3/acetone 9 :1): 3 g (31%). Colorless viscous liquid. 1H-NMR: 0.78 (d, 2 Me); 1.09 1.75 (m, CHCH2,
NH); 2.3 2.8 (m, CHCH2S); 3.53 (s, CH2N); 3.58 (s, CH2S); 7.19 (m, 10 arom. H). Anal. calc. for C20H27NS
(313.51): C 76.62, H 8.68, N 4.47; found: 76.40, H 8.35, N 4.21.
(RS)-2,2'-Dithiobis(N-benzyl-1-methylethanamine) (22). From 20 (9 g, 29 mmol), Na2S2O3 ¥ 5 H2O (7.2 g,
29 mmol), and I2 (3.8 g), as described for 5: 2.5 g (48%). Yellow viscous liquid, which was immediately used for
the next reaction without further purification.
(S)-N-Benzyl-2-[(chlorosulfonyl)methyl]-3-methylbutylammonium Chloride ((S)-23a). A soln. of 21 (3 g,
10 mmol) in a mixture of CHCl3 (20 ml) and CCl4 (40 ml) was saturated at 08 with HCl, EtOH (96%, 20 ml) was
added, the mixture was saturated with Cl2 gas, and then evaporated in vacuo. A few milliliters of an acetone/
Et2O 1:1 mixture were added to the residue: 2.3 g (70%). Colorless crystals. M.p. 2028 (dec.; acetone/Et2O). IR:
3100 2300 (NH2‡), 1570 (NH2‡), 1380, 1165 (SO2). Formula: C13H21Cl2NO2S (326.29 g molÀ1).
(RS)-N-Benzyl-2-(chlorosulfonyl)-1-methylethylammonium Chloride ((RS)-23b). From 22 (2 g) by
oxidative chlorination, as described for 6 (General Procedure). The product was precipitated by adding
‡
Et2O: 2.2 g (79%). Colorless crystals. M.p. 1488 (acetone/Et2O). IR: 3100 2300 (NH2 ), 1370, 1170, 1140
(SO2Cl). Formula: C10H15Cl2NO2S (284.21 g molÀ1).
(S)-3-(2-Methylpropyl)-2-(phenylmethyl)-1,2-thiazetidine 1,1-Dioxide ((S)-24a). From (S)-23a (2 g,
6 mmol), as described for 7 (General Procedure): 0.5 g (29%). Colorless crystals. M.p. 508. [a]2D3 ˆ ‡59.87
1
(c ˆ 2.22, CHCl3). IR: 3030, 2950, 2920, 2860 (CH), 1310, 1295, 1160, 1145 (SO2). H-NMR: 0.75, 0.78 (2 d, 2
Me); 1.2 1.7 (m, CHCH2); 3.08 3.5 (m, HÀC(3)); 3.7 (dd, J ˆ 12.0, 6.0, HÀC(4)); 3.9, 4.3 (2d, J ˆ 15.0,
PhCH2); 4.1 (dd, J ˆ 12.0, 8.0, H'ÀC(4)); 7.3 (m, 5 arom. H). Anal. calc. for C13H19NO2S (253.37): C 61.63, H
7.56, N 5.53, S 12.65; found: C 61.78, H 7.50, N 5.50, S 12.79.
(RS)-3-Methyl-2-(phenylmethyl)-1,2-thiazetidine 1,1-Dioxide (24b). From (RS)-23b (2.1 g, 8.3 mmol), as
described for 7 (General Procedure). Yield: 1.5 g (81%). Colorless crystals. M.p. 358 (CHCl3/pentane). IR: 3080,

Helvetica Chimica Acta Vol. 87 (2004)
101
3060, 3030, 2970, 2920, 1310, 1165, 1145 (SO2). Anal. calc. for C10H13NO2S (211.28): C 56.85, H 6.20, N 6.63, S
15.18; found: C 56.81, H 6.20, N 6.70, S 15.06.
d-Penicillamine Benzyl Ester Hydrochloride (ˆ Phenylmethyl (S)-2-Amino-3-methyl-3-sulfanylbutanoate
Hydrochloride; 25) [19]. From d-penicillamine (13 g, 87 mmol), polyphosphoric acid (32.5 g), and BnOH
‡
(160 ml, 1.42 mol): 10.2 g (43%). Colorless solid. M.p. 140 1448 (Et2O/MeOH). IR: 3100 2750 (NH3 , CH),
‡
1743 (CˆO), 1584 (NH3 ), 1230 (CÀO). 1H-NMR ((D6)DMSO, 80 MHz): 1.45, 1.50 (2s, 2 Me); 4.15 (s,
‡
HÀC(2)); 5.25 (s, CH2); 7.40 (s, 5 arom. H); 7.30 8.30 (br. s, NH3 ).
(S)-1-Amino-1-[(benzyloxy)carbonyl]-2-methylpropane-2-sulfonic Acid (26). To a soln. of 25 (2 g,
7.25 mmol) in H2O/AcOH 1:1 (20 ml) at 508, Br2 (5 g, 31.3 mmol) was added dropwise. The mixture was
stirred for 45 min, the solvent was evaporated, the residue was dried (KOH), and washed with acetone (20 ml):
1.6 g (77%). Colorless crystals. M.p. 235 2408 (96% i-PrOH). [a]2D5 ˆ À9.0 (c ˆ 0.1, 1n HCl). IR: 3300 2700
‡
‡
(NH3 , CH), 1744 (CˆO), 1597 (NH3 ), 1465, 1203, 1104 (SO2). 1H-NMR ((D6)DMSO): 1.20, 1.22 (2s, 2 Me);
‡
‡
4.05 (s, HÀC(3)); 5.10 (s, CH2); 7.33 7.45 (m, 5 arom. H); 8.20 (s, NH3 ). FAB-MS: 575 (36, [2M ‡ 1] ), 380
(75), 288 (100, [M ‡ 1] ), 277 (84), 206 (82), 185 (100). Formula: C12H17NO5S (287.34 g molÀ1).
‡
Phenylmethyl (S)-4,4-Dimethyl-1,2-thiazetidine-3-carboxylate 1,1-Dioxide (27). To a suspension of 26 (1 g,
3.48 mmol) in a mixture of MeCN (2 ml) and sulfolane (2 ml), Cl3PO (1.5 ml, 5.9 mmol) was added, and the
mixture was heated to 658 for ca. 1 h. The solvent was evaporated at 508, the residue was dissolved in CHCl3
(50 ml) and alkalized with a soln. of Et3N in CHCl3. After stirring for 2 h, the solvent was evaporated, the
residue was dissolved in AcOEt, and washed with sat. aq. NH4Cl soln. The org. layer was dried (Na2SO4),
evaporated, and the residue was purified by FC (AcOEt/cyclohexane 1:1): 0.35 g (37%). Yellow viscous liquid.
Rf 0.4 (AcOEt/cyclohexane 1:1). [a]2D5:6 ˆ ‡39.3 (c ˆ 3.5, AcOEt). IR (film): 3288 (NH), 1753 (CÀO), 1320,
1168, 1129 (SO2). 1H-NMR: 1.46, 1.76 (2s, 2 Me); 3.90 (s, HÀC(3)); 5.20 (AB, J ˆ 9.0, CH2); 5.72 (br. s, NH);
7.35 (s, 5 arom. H). 13C-NMR: 18.9, 23.3 (2 Me); 54.3 (CH2); 68.3 (C(3)); 80.4 (C(4)); 128.8, 128.9, 129.0, 134.4 (6
‡
arom. C); 167.9 (CˆO). CI-MS (isobutane): 413 (4), 270 (6, [M ‡ 1] ), 262 (4), 207 (14), 206 (100.0). Anal.
calc. for C12H15NO4S (269.32): C 53.52, H 5.61, N 5.20; found: C 53.47, H 5.74, N 5.02.
N-Benzyl-l-threonine (ˆ(2S,3R)-3-Hydroxy-2-[(phenylmethyl)amino]butanoic Acid; 28a). From l-Thr
(16.7 g, 140 mmol), as described for 28b [20]: 21 g (72%). Colorless crystals. M.p. 2388 (dec.; H2O). IR: 3200
‡
(OH), 3100 2500 (CH, COOH), 1625 (CˆO), 1590, 1550 (NH2 ).
N-Benzyl-l-serine (ˆ(S)-3-Hydroxy-2-[(phenylmethyl)amino]propanoic Acid; 28b) [20]. From l-Ser
(14.7 g, 140 mmol): 19 g (69%). Colorless crystals. M.p. 2358 (dec.; lit. 2198 [20]).
(2R,3S)-2-Methyl-5-oxo-4-(phenylmethyl)morpholine-3-carboxylic Acid (29a). To a cooled soln. of 28a
(20 g, 91 mmol) in 2n aq. NaOH soln. (100 ml), ClCH2COCl (9.5 ml, 109 mmol) was added dropwise. The
mixture was stirred for 30 min, an aq. soln. of NaOH (30 ml, 30%) was added, and stirring was continued for 2 h.
After acidifying with conc. HCl to pH 1, the precipitate was dissolved in boiling i-PrOH, and filtered hot. The
solvent was evaporated in vacuo, the residue was dissolved in CHCl3, the soln. was dried (Na2SO4), and
evaporated: 9.6 g (40%). Colorless crystals. M.p. 1368. [a]2D9 ˆ ‡268 (c ˆ 2, EtOH). IR: 3200 2400 (OH), 1725,
1600 (CˆO), 1110 (CÀO). 1H-NMR: 1.2 (d, Me); 3.6 (d, J ˆ 4.0, HÀC(3)); 3.7 (d, J ˆ 15.0, HÀC(6)); 4.26 (s,
PhCH2); 4.26 (m, HÀC(2)); 5.6 (d, J ˆ 15.0, H'ÀC(6)); 7.28 (m, 5 arom. H); 10.8 (s, COOH). Anal. calc. for
C13H15NO4 (249.27): C 62.64, H 6.07, N 5.62; found: C 62.49, H 6.01, N 5.66.
(S)-5-Oxo-4-(phenylmethyl)morpholine-3-carboxylic Acid (29b) [20]. From 28b (17.8 g, 91 mmol) in 2n aq.
NaOH soln. (100 ml) and ClCH2COCl (8.7 g, 109 mmol), as described for 29a: 8.6 g (40%). Colorless crystals.
M.p. 1568 (lit. 143 1458 [20]). IR: 3100 2300 (OH), 1720, 1600 (CˆO), 1485, 1450, 730, 700 (arom.).
Ethyl (2R,3S)-2-Methyl-5-oxo-4-(phenylmethyl)morpholine-3-carboxylate (30a). From 29a (7 g, 28 mmol)
in EtOH (150 ml), and SOCl2 (2.2 ml, 30 mmol), as described for 30b: 7.7 g (97%). Light yellow crystals. M.p.
39 408. [a]2D3 ˆ À34.18 (c ˆ 4.11, AcOEt). IR: 1730, 1650 (CˆO); 1110 (CÀO). 1H-NMR: 1.23 (d, Me); 1.25 (t,
Me); 3.65 (d, HÀC(3)); 3.75 (d, J ˆ 15.0, HÀC(6)); 4.18 (q, OCH2); 4.24 (s, PhCH2); 4.05 4.36 (m, HÀC(2));
5.48 (d, J ˆ 15.0, H'ÀC(6)); 7.26 (m, 5 arom. H). Anal. calc. for C15H19NO4 (277.32): C 64.97, H 6.91, N 5.05;
found: C 64.70, H 6.80, N 5.18.
Ethyl (S)-5-Oxo-4-(phenylmethyl)morpholine-3-carboxylate (30b). To an ice-cold soln. of 29b (8 g,
33.9 mmol) in EtOH (200 ml) was added dropwise under stirring SOCl2 (4.3 g, 36 mmol). Stirring was continued
at r.t. for 1 h. The mixture was evaporated in vacuo: 8.4 g (94%). Colorless crystals. M.p. 62 648 (AcOEt). IR:
3080, 3060, 3020, 2980, 2920, 2870 (CH); 1735, 1635 (CˆO). 1H-NMR: 1.2 (t, Me); 3.6 3.95 (m, HÀC(2),
HÀC(3)); 3.8 (d, J ˆ 15.0, HÀC(6)); 4.0 4.45 (m, OCH2, H'ÀC(2)); 4.25 (s, PhCH2); 5.5 (d, J ˆ 15.0,
HÀC(6)); 7.3 (m, 5 arom. H).
(2R,3R)-2-Methyl-3-(phenylmethyl)morpholine-3-methanol (31a). From 30a (8 g, 28 mmol) in THF
(30 ml) and LiAlH4 (5 g) in THF (100 ml), as described for 31b: 5 g (80%). Colorless, air-sensitive crystals.

102
Helvetica Chimica Acta Vol. 87 (2004)
M.p. 648. [a]2D3 ˆ À57.75 (c ˆ 2, EtOH). IR: 3600 3100 (OH), 3060, 3020, 2970, 2940, 2870, 2810 (CH), 1115
(CÀO); 745, 695 (arom.). 1H-NMR: 1.25 (d, Me); 1.95 2.8 (m, OH, HÀC(3); HÀC(5), H'ÀC(5)); 3.13 (d, J ˆ
13.0, 1 H, PhCH2); 3.3 4.13 (m, HÀC(2), CH2, HÀC(6), H'ÀC(6)); 4.15 (d, J ˆ 13.0, 1 H, PhCH2); 7.29 (s, 5
arom. H). Anal. calc. for C13H19NO2 (221.30): C 70.56, H 8.65, N 6.33; found: C 70.28, H 8.52, N 6.54.
(R)-3-(Phenylmethyl)morpholine-3-methanol (31b). An ice-cold soln. of 30b (10.5 g, 40 mmol) in THF
(50 ml) was slowly added to a suspension of LiAlH4 (3 g, 80 mmol) in THF (150 ml). The mixture was refluxed
for 6 h, before being slowly (!) hydrolyzed by adding wet Et2O (100 ml), and then H2O (10 ml). After cooling,
the precipitate was separated, and the filtrate was dried (Na2SO4) and evaporated. The precipitate was extracted
with EtOH (50 ml), which was filtered, and the filtrate was combined with the first residue. The soln. was
concentrated to 20 ml, Et2O (100 ml) was added, the soln. was filtered (Kieselgur) and evaporated in vacuo. The
product solidified on cooling: 7.5 g (90%). Colorless, air-sensitive crystals. M.p. 358. IR: 3600 3200 (OH), 3070,
3040, 2950, 2900, 2860, 2820 (CH), 1125 (CÀO), 745, 705 (arom.). 1H-NMR: 2.13 2.87 (m, HÀC(3), HÀC(5),
H'ÀC(5), OH); 3.25 (d, J ˆ 14.0, 1 H, PhCH2); 3.38 4.0 (m, HÀC(2), H'ÀC(2), HÀC(6), H'ÀC(6), CH2); 4.1
(d, J ˆ 14.0, 1 H, PhCH2); 7.25 (m, 5 arom. H).
(2R,3S)-3-(bromomethyl)-2-methyl-4-(phenylmethyl)morpholine (32a). Under N2, Ph3P (3.9 g, 15 mmol)
was added to a soln. of 31a (3 g, 13.5 mmol) in MeCN (50 ml). After cooling to 58, a soln. of CBr4 (5 g, 15 mmol)
in MeCN (15 ml) was added. The clear soln. was stirred under N2 at r.t. for 16 h. The solvent was evaporated in
vacuo, and the residue was dissolved with stirring in a mixture of 0.5n HBr (100 ml), and hexane (100 ml). The
precipitate (Ph3PO) was separated, and the aq. (!) layer was alkalized with dil. aq. NaOH soln., and extracted
with Et2O/petroleum ether 1 :1 (3 Â 50 ml). The org. layer was dried (Na2SO4), cooled for 12 h to À188, filtered,
and evaporated in vacuo: 2.6 g (68%). Yellow viscous liquid. IR (film): 3100, 3080, 3040, 2990, 2970, 2870, 2820
(CH), 1605, 1490, 1450, 745, 700 (arom.). 1H-NMR: 1.29 (d, Me); 2.00 2.85 (m, HÀC(3), HÀC(5), H'ÀC(5));
3.13 (d, J ˆ 13.0, 1 H, PhCH2); 3.30 4.28 (m, HÀC(2), HÀC(6), H'ÀC(6), BrCH2); 4.1 (d, J ˆ 13.0, 1 H,
PhCH2); 7.25 (m, 5 arom. H). Anal. calc. for C13H18BrNO (284.20): C 54.94, H 6.38, N 4.93; found: C 55.07, H
6.42, N 4.84.
(S)-3-(Bromomethyl)-4-(phenylmethyl)morpholine (32b). From 31b (8.8 g, 42 mmol), Ph3P (13.9 g,
53 mmol), and CBr4 (17.6 g, 53 mmol), as described for 32a: 6.8 g (60%). Yellow viscous liquid. [a]2D3 ˆ À48.5
(c ˆ 1.4, CHCl3). IR (film): 3080, 3060, 3020, 2960, 2910, 2860, 2810 (CH), 1490, 1450, 1120 (CÀO), 740, 700
1
(arom.). H-NMR: 2.08 2.88 (m, HÀC(3), HÀC(5), H'ÀC(5)); 3.28 4.0 (m, HÀC(2), H'ÀC(2), HÀC(6),
H'ÀC(6), CH2); 3.75 (s, PhCH2); 7.23 (m, 5 arom. H). Anal. calc. for C12H16BrNO (270.18): C 53.35, H 5.97, N
5.19; found: C 53.26, H 5.90, N 5.05.
(2R,3S)-2-Methyl-4-(phenylmethyl)-3-{[(phenylmethyl)sulfanyl]methyl}morpholine (33a). Under N2 ,
phenylmethanethiol (1.4 g, 11 mmol), dissolved in a soln. of Na (250 mg) in EtOH (10 ml), was added to a
soln. of 32a (3.1 g, 11 mmol) in EtOH (30 ml). The mixture was refluxed for 4 5 h, and stirred at r.t. for 12 h.
The precipitate (NaBr) was filtered off, and the filtrate was evaporated in vacuo. The residue was dissolved in a
mixture of Et2O and H2O, and extracted with Et2O (4Â). The combined org. layers were dried (Na2SO4),
evaporated in vacuo, and the residue was purified by CC (CHCl3/AcOEt 7:3): 1.6 g (44%). Yellow viscous
liquid. IR (film): 3080, 3060, 3020, 2940, 2900, 2860 (CH), 1600, 1490, 1450, 745, 700 (arom.). 1H-NMR: 1.0 (d,
Me); 1.89 À2.65 (m, HÀC(5), H'ÀC(5), C(3)ÀCH2); 2.73 3.08 (m, HÀC(3)); 2.93 (d, J ˆ 13.0, 1 H,
PhCH2N); 3.3 3.85 (m, HÀC(2), HÀC(6), H'ÀC(6)); 3.63 (s, PhCH2S); 4.08 (d, J ˆ 13.0, 1 H, PhCH2N); 7.26
(m, 10 arom. H). Anal. calc. for C20H25NOS (327.49): C 73.35, H 7.69, N 4.28, S 9.79; found: C 73.08, H 7.60, N
4.34, S 9.50.
(S)-4-(Phenylmethyl)-3-{[(phenylmethyl)sulfanyl]methyl}morpholine (33b). From 32b (4.45 g,
16.5 mmol), Na (0.4 g), and phenylmethanethiol (2.1 g, 16.5 mmol), as described for 33a: 3.2 g (62%). Yellow
viscous liquid. 1H-NMR: 2.13 (m, HÀC(3)); 2.35 2.73 (m, HÀC(5), H'ÀC(5), C(3)CH2); 3.13 (d, J ˆ 13.0,
1 H, PhCH2); 3.34 4.0 (m, HÀC(2), H'ÀC(2), HÀC(6), H'ÀC(6), PhCH2S); 3.83 (d, J ˆ 13.0, 1 H, PhCH2N);
7.21 (m, 10 arom. H). Anal. calc. for C19H23NOS (313.46): C 72.80, H 7.40, N 4.47; found: C 71.55, H 7.29, N 4.40.
2,2,2-Trichloroethyl (2R,3S)-2-Methyl-3-{[(phenylmethyl)sulfanyl]methyl}morpholine-4-carboxylate
(34a). Compound 33a (1.5 g, 4.5 mmol), 2,2,2-trichloroethyl chloroformate (1.06 g, 5 mmol), and K2CO3
(0.5 g) in toluene (20 ml) were refluxed for 10 12 h. The mixture was filtered, and the solvent was evaporated.
The residue was dissolved in Et2O (50 ml) and washed with 3n aq. HCl soln. (50 ml) and H2O (100 ml). The org.
layer was dried (Na2SO4), evaporated, and the residue was purified by CC (CHCl3/CCl4 2 :3): 1.2 g (64%).
Yellow viscous liquid. IR (film): 3090, 3060, 3020, 2970, 2920, 2870 (CH), 1710 (CO), 1125 (CÀO), 750, 715
(arom.). 1H-NMR (60 MHz): 1.33 (d, Me); 2.83 (d, C(3)ÀCH2); 3.05 4.3 (m, HÀC(2), HÀC(3), HÀC(5),
H'ÀC(5), HÀC(6), H'ÀC(6)); 3.8 (s, PhCH2S); 4.87 (s, Cl3CCH2); 7.3 (s, 5 arom. H). Anal. calc. for
C16H20Cl3NOS (412.77): C 46.56, H 4.88, Cl 25.77, N 3.39, S 7.77; found: C 46.55, H 4.98, Cl 25.55, N 3.30, S 7.64.

Helvetica Chimica Acta Vol. 87 (2004)
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2,2,2-Trichloroethyl (S)-3-{[(phenylmethyl)sulfanyl]methyl}morpholine-4-carboxylate (34b). From 33b
(5 g, 16 mmol), and 2,2,2-trichloroethyl chloroformate (3.4 g, 16 mmol), as described for 34a: 4 g (63%). Light-
brown, viscous liquid. IR (film): 3060, 3020, 2950, 2910, 2850 (CH), 1710 (CˆO), 1490, 1450, 715, 700 (arom.),
1120 (CÀO).
(2R,3S)-2-Methyl-3-{[(phenylmethyl)sulfanyl]methyl}morpholine (35a). Compound 34a (3 g, 7.3 mmol)
was dissolved in MeOH (20 ml). Glacial AcOH (10 ml), and Zn powder (1.6 g) were added, and the mixture
was refluxed for 5 h. After cooling and filtration, the soln. was alkalized with aq. NaOH soln. (10%), and
extracted with CH2Cl2 (2 Â 50 ml). The org. layer was washed with a sat. aq. soln. of NaCl, dried (Na2SO4), and
evaporated in vacuo. The residue was immediately transformed into 36a.
(S)-3-{[(Phenylmethyl)sulfanyl]methyl}morpholine (35b). From 34b (6 g, 15 mmol), glacial AcOH (3 ml),
and Zn powder (3 g) in MeOH (30 ml), as described for 35a: 2.2 g (67%). Yellow, viscous liquid. 1H-NMR: 2.04
(m, NH); 2.29 (m, HÀC(3)); 2.44 2.95 (m, C(3) À CH2S, HÀC(5)); 3.0 3.95 (m, HÀC(2), H'ÀC(2),
H'ÀC(5), HÀC(6), H'ÀC(6)); 3.65 (s, PhCH2S); 7.26 (m, 5 arom. H).
((2R,3S)-2-Methylmorpholine-3-methanesulfonyl Chloride Hydrochloride (36a). A soln. of 35a (1.4 g,
5.9 mmol) in CHCl3 (20 ml), and CCl4 (10 ml) was cooled and saturated with gaseous HCl. Then, EtOH (96%,
10 ml) was added, and the mixture was saturated with Cl2 gas (temp. < 108). The excess of Cl2 was removed by
bubbling N2 through the soln. The mixture was evaporated in vacuo, and a few milliliters of an acetone/Et2O
‡
mixture were added to the residue: 1.1 g (75%). Colorless crystals. M.p. 100 1018 (dec.). IR: 3200 2300 (NH2 ,
‡
CH), 1580 (NH2 ), 1380, 1170 (SO2), 1120 (CÀO).
(S)-Morpholine-3-methanesulfonyl Chloride Hydrochloride (36b). From 35b (2 g, 10 mmol), as described
‡
for 36a: 2 g (80%). Colorless crystals. M.p. 1278 (dec.). IR: 3100 2500 (NH2 , CH), 1370, 1170 (SO2), 1115
(CÀO). Anal. calc. for C5H11Cl2NO3S (236.12): C 25.43, H 4.70, Cl 30.03, N 5.93; found: C 25.28, H 4.60, Cl
30.24, N 5.85.
(5R,6S)-5-Methyl-4-oxa-8-thia-1-azabicyclo[4.2.0]octane 8,8-Dioxide (37a). To a suspension of 36a (1 g,
4 mmol) in anh. CHCl3 (20 ml), a sat. soln. of NH3 in CHCl3 was added, until the mixture was alkalized. After
24 h at r.t., the mixture was filtered (Kieselgur), and the filtrate was evaporated in vacuo: 0.5 g (70%). Colorless,
viscous liquid. [a]D23 ˆ ‡24.74 (c ˆ 1.17, CHCl3). IR (film): 3040, 2970, 2930, 2870 (CH), 1310, 1180, 1150 (SO2),
1105 (CÀO). 1H-NMR (400 MHz): 1.20 (d, J ˆ 6.0, Me); 3.15 (ddd, J ˆ 15.0, 12.0, 4.5, HÀC(2)); 3.33 (ddd, J ˆ
10.0, 7.5, 2.3, HÀC(6)); 3.40 (dd-like, J ˆ 15.0, 3.4, H'ÀC(2)); 3.63 (dd, J ˆ 12.0, 2.3, HÀC(7)); 3.70 (dq, J ˆ 10.0,
6.0, HÀC(5)); 3.76 (dd-like, J ˆ 12.0, 4.5, HÀC(3)); 3.91 (dt-like, J ˆ 12.0, 12.0, 3.4, H'ÀC(3)); 4.25 (dd, J ˆ
12.0, 7.5, H'ÀC(7)). Anal. calc. for C6H11NO3S (177.22): C 40.66, H 6.26, N 7.90, S 18.09; found: C 40.89, H 6.34,
N 7.75, S 18.00.
(S)-4-Oxa-8-thia-1-azabicyclo[4.2.0]octane 8,8-Dioxide (37b). From 36b (2 g, 8 mmol), as described for
37a: 1.1 g (85%). Colorless crystals. M.p. 91 928. [a]2D3 ˆ ‡13.1 (c ˆ 1.32, CHCl3). IR: 3030, 2980, 2960, 2920,
2860 (CH), 1300, 1190, 1170 (SO2), 1090 (CÀO). 1H-NMR (400 MHz): 3.24 (ddd, J ˆ 15.0, 12.0, 4.5, HÀC(2));
3.46 (dd, J ˆ 15.0, 3.0, H'ÀC(2)); 3.6 (dd, J ˆ 12.0, 2.3, HÀC(7)); 3.63 (dd-like, J ˆ 12.0, 12.0, H'ÀC(5)); 3.72
(dd, J ˆ 12.0, 4.5, HÀC(3)); 3.78 (ddd-like, J ˆ 12.0, 12.0, 3.0, H'ÀC(3)); 3.81 (m, HÀC(6)); 4.12 (ddd, J ˆ 12.0,
5.0, 1.5, HÀC(5)); 4.28 (dd, J ˆ 12.0, 7.5, H'ÀC(7)). Anal. calc. for C5H9NO3S (163.20): C 36.80, H 5.56, N 8.58, S
19.65; found: C 36.99, H 5.52, N 8.47, S 19.51.
(2R,3R)-3-(Hydroxymethyl)-2-methylmorpholine Hydrochloride (38). To a soln. of 31a (4 g, 18 mmol) in
anh. EtOH (80 ml), 10% Pd/C (1 g) was added, and the mixture was hydrogenated for ca. 3.5 h (1 atm of H2).
The catalyst was filtered off, the solvent was evaporated in vacuo, and the residue was dissolved in a mixture of
EtOH (20 ml) and Et2O (100 ml). The cooled soln. was saturated with gaseous HCl to complete precipitation:
‡
2.4 g (78%). Colorless crystals. M.p. 176 1798. [a]2D3 ˆ ‡18.4. IR: 3400 (OH), 3100 2400, 1580 (NH2 , CH),
1115 (CÀO). 1H-NMR: 1.13 (d, Me); 2.68 3.30 (m, HÀC(3), HÀC(5), H'ÀC(5)); 3.43 4.13 (m, CH2O,
‡
HÀC(2), HÀC(6), H'ÀC(6)); 5.46 (s, OH); 9.25 (s, NH2 ). Anal. calc. for C6H14ClNO2 (167.64): C 40.80, H 8.56,
Cl 20.07, N 7.93; found: C 40.62, H 8.65, Cl 20.17, N 7.96.
[(2R,3S)-2-Methyl-4-(phenylmethyl)morpholin-3-yl]methyl Methanesulfonate (39). To a cooled soln. of
31a (7.5 g, 34 mmol) in THF (50 ml), Et3N (3.4 g, 34 mmol) was added. Over a period of 30 min,
methanesulfonyl chloride (4 g, 35 mmol) was added dropwise with stirring. Stirring was continued for 16 h at
r.t., the precipitate was separated, the filtrate was washed with a sat. aq. soln. of NaCl, the org. layer was dried
(Na2SO4), and evaporated in vacuo: 2.7 g (26%). Colorless needles (turning red fast). M.p. 83 848 (EtOH).
[a]2D3 ˆ À34.52 (c ˆ 1.99, CHCl3). IR: 3080, 3060, 3020, 3000, 2960, 2880, 2850, 2820 (CH), 1345, 1165 (OSO2),
1125 (CÀO), 750, 740, 700 (arom.). 1H-NMR: 1.30 (d, Me); 2.05 2.85 (m, HÀC(3), HÀC(5), H'ÀC(5)); 2.96
(s, MeO2S); 3.30 (d, J ˆ 14.0, 1 H, PhCH2); 3.40 3.95 (m, HÀC(2), HÀC(6), H'ÀC(6)); 4.12 (d, J ˆ 14.0, 1 H,

104
Helvetica Chimica Acta Vol. 87 (2004)
PhCH2); 4.20 4.69 (dd, SOCH2); 7.28 (m, 5 arom. H). Anal. calc. for C14H21NO4S (299.39): C 56.17, H 7.07, N
4.68, S 10.71; found: C 56.01, H 7.00, N 4.60, S 10.83.
S-[(2R,3S)-2-Methyl-4-(phenylmethyl)morphinan-3-yl] Ethanethioate (40). Under N2, potassium thioace-
tate (0.9 g, 7.9 mmol) in DMF (10 ml) was added to a soln. of 39 (2.2 g, 7.3 mmol) in CHCl3 (20 ml) at r.t., and
the mixture was stirred for 20 h. Then, the DMF was removed by washing with H2O, the org. layer was dried
(Na2SO4), and the solvent was evaporated in vacuo. The residue was purified by CC (CHCl3/AcOEt 8 :1): 1.4 g
(69%). Light yellow, viscous liquid. [a]2D3 ˆ 54.45 (c ˆ 2.67, CHCl3). IR (film): 3080, 3060, 3020, 2960, 2850, 2800
(CH), 1680 (CˆO), 1120, 1100 (CÀO), 740, 700 (arom.). 1H-NMR: 1.23 (d, Me); 2.0 2.75 (m, HÀC(3),
HÀC(5), H'ÀC(5)); 2.3 (s, Ac); 3.05 (d, J ˆ 13.0, 1 H, PhCH2); 3.2 3.88 (m, HÀC(2), HÀC(6), H'ÀC(6),
SCH2); 4.06 (d, J ˆ 13.0, 1 H, PhCH2); 7.3 (m, 5 arom. H). Anal. calc. for C15H21NO2S (279.40): C 64.48, H 7.57, N
5.01; found: C 64.37, H 7.55, N 5.10.
(2R,3S)-2-Methyl-4-(phenylmethyl)morpholine-3-methanethiol (41). Under N2, 40 (1.2 g, 4.3 mmol) was
dissolved in EtOH, sat. with NH3. After stirring for 3 h at r.t., the mixture was evaporated in vacuo, and the
residue was purified by CC (CHCl3/AcOEt 8 :1): 0.8 g (79%). Light-yellow, viscous liquid. [a]2D3 ˆ À46.2 (c ˆ
2.26, AcOEt). IR (film): 3090, 3060, 3020, 2960, 2860, 2800 (CH), 2550 (SH), 1125, 1105 (CÀO), 1600, 1490,
1450, 740, 700 (arom.). 1H-NMR: 1.21 (d, Me); 2.5 2.78 (m, HÀC(3), HÀC(5), H'ÀC(5), 1 H of CH2S); 3.0
(d, J ˆ 13.0, 1 H, PhCH2); 2.94 3.31 (m, 1 H of CH2S); 3.38 4.05 (m, HÀC(2), HÀC(6), H'ÀC(6)); 4.08 (d,
J ˆ 13.0, 1 H, PhCH2); 7.3 (m, 5 arom. H). Anal. calc. for C13H19NOS (237.37): C 65.78, H 8.07, N 5.90; found: C
65.99, H 8.00, N 5.80.
1-Aminocyclohexane-1-methanol (43). From 1-aminocyclohexane carboxylic acid (42) (14.3 g, 100 mmol)
and LiAlH4 (10 g, 270 mmol), as described for 2, reflux for 5 h: 9 g (70%). B.p. 1178 (15 mbar) (lit. 68 698
(1 mbar)). IR (film): 3600 2400 (OH, NH2), 1590 (NH2), 1060 (CÀO).
1-(Bromomethyl)cyclohexylammonium Bromide (44). HBr (48%, 11.4 g) was added to 43 (9 g, 70 mmol)
in MeOH (40 ml) at 58. The soln. was concentrated in vacuo, the aminium salt of 43 was precipitated by addition
of acetone/Et2O 1:1 , and then added to PBr3 (14 g) at r.t. After heating for 1 h, all volatile compounds were
evaporated, Et2O was added, and the solid residue was recrystallized from AcOEt/Et2O: 3 g (16%). Colorless
crystals. M.p. 2128 (AcOEt/Et2O; lit. 214 2168 [9]).
1,1'-Bis(dithiomethyl)cyclohexanamine (45). A mixture of 44 (3 g, 11 mmol) in H2O (40 ml) and Na2S2O3 ¥
5 H2O (2.7 g, 11 mmol) was refluxed for 1.5 h. At ca. 908, I2 (1.3 g) was added within 30 min. Workup as
described for 5 (extraction with toluene (3 Â 50 ml)): 1.7 g (47%). The crude product was used without further
purification for the synthesis of 46.
1-[(Chlorosulfonyl)methyl]cyclohexylammonium Chloride (46). Chlorination of 47 (1.7 g) in CHCl3
(30 ml) and EtOH (96%, 10 ml) was carried out as described for 6: 1.8 g (66%). Colorless crystals. M.p. 2358
(dec.). Formula: C7H15Cl2NO2S (248.18 g molÀ1).
2-Thia-1-azaspiro[3.5]nonane 2,2-Dioxide (47). According to the General Procedure described for 7, 46
(1.8 g, 7 mmol), suspended in CHCl3 (30 ml), was cyclized. The viscous residue was carefully dried, and
crystallization started after some days: 1 g (81%). Colorless crystals. M.p. 528. IR: 3270 (NH), 3020, 2930, 2860
(CH), 1320, 1290, 1165, 1140 (SO2). 1H-NMR (80 MHz): 1.25 2.0 (m, (CH2)5); 3.93 (s, HÀC(4), H'ÀC(4)); 5.4
(br. s, NH). Anal. calc. for C7H13NO2S (175.25): C 47.97, H 7.48, N 7.99, S 18.29; found: C 47.71, H 7.52, N 7.89, S
18.44.
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Received May 14, 2003