Asymmetric synthesis of α-chloro-β-amino-N-sulfinyl imidates as chiral building blocks

Article abstract of DOI:10.1021/jo200082w

New chiral α-chloro-β-amino-N-sulfinyl imidates were synthesized in high yield and excellent diastereomeric excess via highly anti-selective Mannich-type reactions of (R_S)-methyl N-tert-butanesulfinyl-2- chloroethanimidate with aromatic aldimin

Full text of DOI:10.1021/jo200082w

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of r-Chloro-β-amino-N-sulfinyl Imidates as
Chiral Building Blocks
Filip Colpaert, Sven Mangelinckx,† Stijn De Brabandere, and Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
S Supporting Information
b
ABSTRACT: New chiral R-chloro-β-amino-N-sulfinyl imidates
were synthesized in high yield and excellent diastereomeric
excess via highly anti-selective Mannich-type reactions of (RS)-
methyl N-tert-butanesulfinyl-2-chloroethanimidate with aromatic
aldimines. The R-chloro-β-amino-N-sulfinylimidates proved to
be excellent building blocks for the asymmetric synthesis of
β-amino-R-chloro amides and esters, aziridine-2-carboxylic
amides and esters, trans-2-aryl-3-chloroazetidines, and methyl
4-phenyloxazolidin-2-one-5-carboxylate. The obtained absolute
anti-diastereoselectivity is the opposite of the stereochemical
outcome observed for R-methyl-substituted imidates.
’ INTRODUCTION
Besides aziridines, azetidines are also an extraordinary class of
strained azaheterocyclic compounds with a wide range of known
biological activities.11 In particular, 3-haloazetidines form an
important subclass because of their potential physiological acti-
vities and their use as substrates toward the synthesis of 3-sub-
stituted azetidine derivatives.12 Remarkably, however, no asym-
metric synthesis of 3-haloazetidines was reported in the literature
until now.
4,5-Disubstituted 2-oxazolidinones, like (-)-cytoxazone, i.e.,
(4R,5R)-5-(hydroxymethyl)-4-(4-methoxyphenyl)oxazolidin-2-
one, and its analogues, have been the subject of numerous studies
because of their potent cytokine-modulating activity and possible
use as novel immunotherapeutic agents but also because the ring
system provides an interesting objective for various asymmetric
synthesis strategies.13 Whereas in the literature the oxazolidinone
ring is conveniently formed from amino alcohols,13a an alter-
native cyclization strategy of R-chloro-β-amino acid derivatives
will be explored.
The Mannich reaction is a classic method for the preparation
of β-amino carbonyl compounds and is therefore a very im-
portant carbon-carbon bond-forming reaction in organic syn-
thesis as a key step in natural product synthesis as well as in
medicinal chemistry.1 The unique conformational and biological
properties of β-peptides incorporating β-amino acids as mono-
mers,2 and the use of β-amino acid derivatives as building blocks
for the preparation of pharmaceutical targets and natural pro-
ducts has prompted a tremendous amount of efforts in the deve-
lopment of asymmetric Mannich reactions to this class of amino
acids.3,4 Very recently, our group elaborated the asymmetric
synthesis of new chiral β-(sulfonylamino)sulfinylimidates by
highly anti-selective Mannich-type reactions of N-sulfinyl imi-
dates across N-tosyl aldimines.5 These imidates proved to be
excellent intermediates for the synthesis of the corresponding
enantiopure β-sulfonylamino amides and esters as new chiral
β-amino acid derivatives. Therefore, we envisioned that the use
of an R-chloro N-sulfinyl imidate in the addition reaction across
aromatic aldimines would lead to the synthesis of new chiral
β-aryl-R-chloro-substituted β-amino acid derivatives as potential
building blocks of enantiopure functionalized aziridines, azeti-
dines and oxazolidinones.
Among aziridines, chiral aziridine-2-carboxylic acid deriva-
tives are of special importance because of their occurrence
in natural products and synthetic pharmaceuticals and their
versatility in the preparation of diverse chiral bioactive nitro-
gen-containing compounds, mainly via a range of regio- and
stereoselective ring-opening reactions.6-8 In contrast to oxi-
rane-2-carboxylic acid derivatives,9 the synthesis of optically
active aziridine-2-carboxylates still remains challenging to
synthetic chemists.7c,8a,10
’ RESULTS AND DISCUSSION
The synthesis of R-chloro-N-tert-butanesulfinyl imidate (RS)-
3 from 2-chloro-1,1,1-trimethoxyethane 2 was optimized by
systematically changing the reaction conditions. Using similar
conditions as applied in the synthesis of nonhalogenated
N-tert-butanesulfinyl imidates,14 the condensation of (RS)-
tert-butanesulfinamide (RS)-1 and 3 equiv of 2-chloro-1,1,1-
trimethoxyethane 2 in the presence of a catalytic amount of
p-TsOH without solvent afforded after 3 h at 100 °C a mixture of
the desired R-chloro-N-tert-butanesulfinyl imidate (RS)-3 and
Received: January 13, 2011
Published: March 07, 2011
r
2011 American Chemical Society
2204
dx.doi.org/10.1021/jo200082w J. Org. Chem. 2011, 76, 2204–2213
|

The Journal of Organic Chemistry
ARTICLE
Table 1. Synthesis of r-Chloro-N-tert-butanesulfinyl Imidate (RS)-3
entry
2 (equiv)
time (h)
conversion of (RS)-1 to 3 and 4a (%)
(RS)-3/4a
yield (RS)-3 (%)
1
2
3
4
5
3
3
3
72
89
72:28
51:49
86:14
86:14
77:23
31b, 45c
8
7
3
97
7
4
100
100
84c,d
73c
10
0.5
a Determined via GC analysis of the crude reaction mixture. b Yield after purification by distillation (74 °C/0.05 mmHg). c Yield after purification by flash
chromatography. d N-(tert-Butanesulfinyl)-tert-butanesulfinimide 4 was isolated in 10% yield.
Table 2. Addition Reaction of r-Chloro-N-tert-butanesulfinyl Imidate (RS)-3 across Aldimines 5
temp (°C)/
time (h)
conversion of 3 and
5 into 6 (%)a
(RS,R,R)-6/
minor-6a,b
entry
aldimine
(RS)-3 (equiv)
base (equiv)
yield (%)
1
2
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
1.0
1.0
1.0
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.6
1.8
1.8
1.8
DBU (cat.)c
DBU (1.1)c
DBU (2.0)c
DBU (1.6)c
LiHMDS (1.2)d
LiHMDS (1.2)d,e
KHMDS (1.2)d
NaHMDS (1.2)d
LDA (1.2)d
LiHMDS (1.2)f
LiHMDS (1.6)d
LiHMDS (1.8)d
LiHMDS (1.8)d
LiHMDS (1.8)d
0/3
0
42
-78/1
-78/2
-40/2
-78/1
-78/1
-78/1
-78/1
-78/1
-97/1
-78/1
-78/0.5
-78/0.5
-78/0.5
63:37
69:31
56:44
91:9
3
68
4
92
5
75
(RS,R,R)-6a (57)
6
71
87:13
91:9
7
72
8
70
92:8
9
26
85:15
90:10
91:9
10
11
12
13
14
66
91
100
100
100
94:6
(RS,R,R)-6a (86)
(RS,R,R)-6b (87)
(RS,R,R)-6c (71)
96:4
5c
1
92:8
a Determined via H NMR analysis of the crude reaction mixture. b minor-6 = (RS,S,S)-anti-6 þ (RS,S,R)-syn-6 þ (RS,R,S)-syn-6. DBU was added
dropwise to a solution of (RS)-3 and 5a in DMF (entry 1) or THF (entries 2-4). d Deprotonation was performed at -78 °C for 45 min in THF. e 1.2
equiv of MgBr2 was added after deprotonation at -78 °C for 15 min at -78 °C. f Deprotonation was performed at -97 °C for 45 min in THF.
c
N-(tert-butanesulfinyl)-tert-butanesulfinimide 4 in a ratio of 72:28
(Table 1, entry 1). After purification by distillation, pure R-
chloro-N-tert-butanesulfinyl imidate (RS)-3 was obtained, but in
a disappointing yield of only 31%, partly due to the incomplete
conversion (72%) of starting compound (RS)-1 into (RS)-3 and
4. Purification by flash chromatography resulted in a higher yield
of 45% of (RS)-3. In a second attempt, to obtain full conversion of
starting compound (RS)-1, the reaction time was increased to 8 h,
resulting in a better conversion of 89% but also in a more
extensive formation of the undesired sulfinimide 4 (entry 2).
Subsequently, the condensation of (RS)-tert-butanesulfinamide
(RS)-1 with 7 equiv of 2-chloro-1,1,1-trimethoxyethane 2 gave
almost full conversion (97%) after 3 h, and sulfinimide 4 was
formed in minor amounts (entry 3). Repeating the reaction with
7 equiv of 2-chloro-1,1,1-trimethoxyethane 2 for 4 h led to a full
conversion of starting compound (RS)-1 into reaction products
(RS)-3 and 4, and after flash chromatography, R-chloro-N-tert-
butanesulfinyl imidate (RS)-3 and sulfinimide 4 were obtained in
84% and 10% yield, respectively (entry 4). In order to improve
the yield of imidate (RS)-3 and to reduce the formation of
sulfinimide 4, a final reaction was performed with 10 equiv of
ortho ester 2, unfortunately providing R-chloro-N-tert-butane-
sulfinyl imidate (RS)-3 in a lower yield of 73% (entry 5). It is
assumed that the formation of N-(tert-butanesulfinyl)-tert-buta-
nesulfinimide 4 proceeds with partial inversion of stereochem-
istry at sulfur.
2205
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Synthesis of Chiral Imidate Hydrochlorides (R,R)-7, Amides (R,R)-8, Esters (R,R)-9, Aziridine-2-carboxylic Amides
(2S,3R)-10, and Esters (2S,3R)-11
a Compounds (2S,3R)-10b and (2S,3R)-11c could not be obtained in pure form due to their instability during purification with flash chromatography.
The addition reaction of imidate (RS)-3 across aldimine 5a
was optimized by systematically changing the reaction conditions
in the synthesis of R-chloro-β-(sulfonylamino)sulfinylimidates
6a (Table 2). An initial attempt using similar reaction conditions
as applied by Kobayashi and co-workers in the synthesis of
β-aminosulfonylimidates,15 namely reaction of imidate (RS)-3 with
aldimine 5a in the presence of a catalytic amount of DBU in
DMF, did not result in the formation of addition products
(Table 2, entry 1). The use of more DBU (1.1-2 equiv) resulted
in incomplete conversions to imidates 6a with poor diastereo-
selectivity (Table 2, entries 2-4). In contrast, the use of 1.2 equiv
of LiHMDS at -78 °C to deprotonate imidate (RS)-3 resulted
after addition of aldimine 5a in the formation of imidates 6a with
high diastereoselectivity, but with incomplete conversion of 75%
(Table 2, entry 5). Four diastereomers could be detected by 1H
NMR analysis of the crude reaction mixture, namely major-(RS,R,
R)-6a/minor-6a = (RS,S,S)-6a þ (RS,S,R)-6a þ (RS,R,S)-6a in a
91:9 ratio.
The use of other bases, such as LDA, KHMDS, and NaHMDS,
addition of MgBr2 as Lewis acid, or performing the reaction at -
97 °C did not result in improved diastereomeric ratios and/
or conversion (Table 2, entries 6-10). Subsequently, in order to
obtain a full conversion of (RS)-3 and 5a into 6a, more equivalents
of LiHMDS and (RS)-3 were applied (Table 2, entries 11 and 12),
and finally, the use of 1.8 equiv of LiHMDS to deprotonate 1.8
equiv of (RS)-3 was sufficient to achieve a full conversion of (RS)-3
and 5a into imidates 6a in excellent diastereomeric ratio [(RS,R,R)-
6a/minor-6a 94:6]. The optically pure (RS,R,R)-6a was isolated in
86% yield after purification via flash chromatography (entry 12).
Analogously, new (hetero)aromatic chiral imidates 6b,c were
prepared with excellent diastereoselectivity [(RS,R,R)-6/minor-6
92:8 to 96:4] and good yields (71-87%) using the latter opti-
mized reaction conditions (entries 13 and 14).
Furthermore, these hydrochlorides (R,R)-7 proved to be
excellent intermediates for an easy transformation to new chiral
R-chloro-β-sulfonylamino amides (R,R)-8 and esters (R,R)-9 in
excellent yields (94-99%), upon simple heating in chloroform
and hydrolysis, respectively (Scheme 1). It is noteworthy that the
HCl-promoted N-deprotection of imidate (R,R)-6c (Ar = furan-
2-yl, R1 = C6H5SO2) in dioxane led directly to the corresponding
amide (R,R)-8c in 95% yield, whereas ester (R,R)-9c was formed
in 89% yield via the addition of 30 equiv of 3 N HCl in MeOH to
imidate (RS,R,R)-6c (Scheme 1).
In the next step, amides (R,R)-8 and esters (R,R)-9 could be
easily cyclized to the corresponding aziridine-2-carboxylic amides
(2S,3R)-10 and esters (2S,3R)-11 via addition of K2CO3 in
CH3CN (Scheme 1). Unfortunately, the formed aziridine-2-
carboxylic amide (2S,3R)-10b and ester (2S,3R)-11c could not
be obtained in pure form because of their instability during
purification with flash chromatography.
An alternative important application of esters 9 involved
reduction with LiAlH4 to afford β-chloro-γ-sulfonylamino alco-
hols 12. Initially, when 2.8 equiv of LiAlH4 was added to ester
(R,R)-9a, a mixture of alcohol (R,R)-12a, (S)-N-(3-hydroxy-1-
phenylpropyl)-4-methylbenzenesulfonamide (S)-13, and (2S,3R)-
2-hydroxymethyl-3-phenyl-1-(p-toluenesulfonyl)aziridine (2S,3R)-
14 was obtained, which could be isolated after flash chromatography
in 42%, 25%, and 17% yield, respectively (Scheme 2).
Finally, when fewer equivalents of LiAlH4 at lower temperature,
were used in order to suppress the formation of alcohol (S)-13 and
aziridine (2S,3R)-14, β-chloro-γ-sulfonylamino alcohols (R,R)-12
were obtained in good yields (84-88%) (Scheme 3). In a final
step, these alcohols (R,R)-12 were cyclized under Mitsunobu
conditions, leading to the first asymmetric synthesis of trans-2-
aryl-3-chloroazetidines (2R,3S)-15 in good yields (Scheme 3).
Aziridine-2-carboxylic ester (2S,3R)-11a and the enantiomer
of aziridine (2S,3R)-14 are reported compounds in the literature
and thus allowed a comparison of the optical rotations ([R]D
(2S,3R)-11a -34.6 (c 0.4, CH2Cl2) vs -29.4 (c 1.0,
CH2Cl2) and (2R,3S)-11a þ33.1 (c 1.0, CH2Cl2) in ref 16;
In a next step, the chiral (RS,R,R)-anti-R-chloro-β-(sulfonylamino)
sulfinylimidates (RS,R,R)-6a,b were N-deprotected by simple treat-
ment with a 4 N solution of anhydrous HCl in dioxane to the
corresponding imidate hydrochlorides (R,R)-7a,b (Scheme 1).
2206
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
Scheme 2. Reduction of (R,R)-Methyl 2-Chloro-3-phenyl-3-(p-toluenesulfonylamino)propanoate (R,R)-9a with LiAlH4
ARTICLE
Scheme 3. Synthesis of Chiral β-Chloro-γ-sulfonylamino Alcohols (R,R)-12 and trans-2-Aryl-3-chloroazetidines (2R,3S)-15
Scheme 4. Synthesis of (RS,R,R)-6d and Further Transformation to Chiral Amide (R,R)-8d, Hydrochlorides (R,R)-17 and (R,R)-
18, and Oxazolidin-2-one (4R,5S)-19
[R]D (2S,3R)-14 -50.5 (c 0.3, CHCl3) vs (2R,3S)-14 þ48.4 (c
1.9, CHCl3, > 98% ee) in ref 17) confirming the assigned
absolute stereochemistry of all synthesized products 6-15. In
view of the strong correspondence of the optical rotations with
literature data, and with an ee of >98% for the commercially
available starting material (RS)-tert-butanesulfinamide (RS)-1, an
ee of >98% can be concluded for all synthesized products 6-15.
In order to expand the Mannich-type additions of R-chloro-
N-sulfinyl imidate (RS)-3 across aromatic N-sulfonyl aldimines
5, N-Boc-protected R-chloro-β-aminosulfinylimidate (RS,R,R)-
6d was synthesized via the Mannich-type reaction of imidate
(RS)-3 across R-amido sulfone 16 (Scheme 4).18 R-Amido sulfone
16 was prepared from benzaldehyde, sodium benzenesulfinate,
and tert-butyl carbamate according to a literature procedure.19
After flash chromatography, the major diastereomer (RS,R,R)-6d
could be obtained in 91% yield, containing still 5% of the
inseparable diastereomer (RS,S,S)-6d, leading to a diastereomer-
ic excess of 90% (Scheme 4).
amide (R,R)-8d in 57% yield and an enantiomeric ratio of 95:5
(Scheme 4). Furthermore, N-Boc-deprotected hydrochlorides
(R,R)-17 and (R,R)-18 were obtained upon treatment of amide
(R,R)-8d and imidate (RS,R,R)-6d with 50 equiv of 4 N HCl in
dioxane and 80 equiv of 3 N HCl in MeOH, respectively.
Importantly, the 4,5-disubstituted oxazolidin-2-one (4R,5S)-
19 was obtained in 96% yield when the addition of the excess of
HCl in MeOH to N-Boc-protected R-chloro-β-aminosulfinyli-
midate (RS,R,R)-6d was followed by basic extraction with
NaHCO3. Similar syntheses of oxazolidin-2-ones via the con-
densation of β-chloroamines with Na2CO3 or NaHCO3 have
been reported.20
It is noteworthy that, whereas the high relative anti-diaster-
eoselectivity of the Mannich-type reactions of R-chloro N-
sulfinyl imidate (RS)-3 across aldimines 5 and R-amido sulfone
16 is in analogy with the previously mentioned anti-selective
addition reactions of R-methyl-N-sulfinyl imidates across N-tosyl
aldimines,5 the absolute anti-diastereoselectivity is reversed. It is
speculated that the nature of the R-substituent of the imidates
influences the E/Z ratio and the coordination behavior of the
The treatment of imidate (RS,R,R)-6d with 20 equiv of 4 N HCl
in dioxane led to the selective formation of R-chloro-β-amino
2207
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
ARTICLE
Li enolates, which influences the diastereoselectivity of the
Mannich reactions.
R)-methyl 2-chloro-3-phenyl-3-(p-toluenesulfonylamino)-N-tert-butane-
sulfinyl-propanimidate (RS,R,R)-6a.
The synthesis of (RS,R,R)-methyl 2-chloro-3-phenyl-3-(tert-butoxycar-
bonylamino)-N-tert-butanesulfinyl propanimidate (RS,R,R)-6d was per-
formed via the addition reaction of (RS)-methyl N-tert-butanesulfinyl-2-
chloroethanimidate (RS)-3 with R-amido sulfone 16.
’ CONCLUSIONS
In conclusion, it was demonstrated that new chiral R-chloro-
β-aminosulfinyl imidates are formed in high yield and excellent
diastereomeric excess via highly anti-selective Mannich-type
reactions of an R-chloro sulfinylimidate across aromaticN-sulfonyl-
aldimines or R-amido sulfones. The absolute anti-diastereo-
selectivity obtained in the newly synthesized R-chloro-β-amino-
sulfinylimidates is the opposite of the stereochemical outcome
observed for R-methyl-substituted imidates. Several transforma-
tions of the R-chloro-β-aminosulfinylimidates led to the synthe-
sis of new chiral β-aryl-R-chloro-substituted β-amino acid and
aziridine-2-carboxylic acid derivatives, the first entry to enan-
tiopure trans-2-aryl-3-chloroazetidines and the cyclization to
(4R,5S)-methyl 4-phenyloxazolidin-2-one-5-carboxylate.
(RS,R,R)-Methyl 2-Chloro-3-phenyl-3-(p-toluenesulfonyl-
amino)-N-tert-butanesulfinylpropanimidate (RS,R,R)-6a. Rf
= 0.77 (petroleum ether/Et2O 3:7). White crystals, yield 86%. [R]D
-172.6 (c 0.3, CHCl3). Mp: 53.7-54.1 °C. IR (cm-1): νmax 1067, 1160,
1298, 1615, 2948, 3161. 1H NMR (300 MHz, CDCl3): δ 1.35 (9H, s),
2.28 (3H, s), 3.86 (3H, s), 4.63 (1H, t, J = 9.9 Hz), 5.38 (1H, d, J =
9.9 Hz), 6.76 (1H, d, J = 9.9 Hz), 6.95 (2H, d, J = 8.3 Hz), 7.07-7.22 (3H,
m), 7.24-7.28 (2H, m), 7.33 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz,
CDCl3): δ 21.4, 22.1, 55.6, 57.2, 58.2, 60.4, 126.9 (2C), 127.7 (2C), 128.2,
128.4 (2C), 129.1 (2C), 137.1, 137.9, 142.7, 167.4. MS (ES, pos mode)
m/z: 471/473 (M þ Hþ, 100). Anal. Calcd for C21H27ClN2O4S2: C,
53.55; H, 5.78; N, 5.95. Found: C, 53.21; H, 5.53; N, 5.59.
(RS,R,R)-Methyl 2-Chloro-3-(4-methoxyphenyl)-3-(p-
toluenesulfonylamino)-N-tert-butanesulfinylpropanimi-
date (RS,R,R)-6b. Rf = 0.57 (petroleum ether/Et2O 25:75). White
crystals, yield 87%. [R]D -202.3 (c 0.3, CHCl3). Mp: 55.7-56.0 °C. IR
(cm-1): νmax 665, 1028, 1065, 1159, 1250, 1297, 1335, 1514, 1611,
2947, 3150. 1H NMR (300 MHz, CDCl3): δ 1.34 (9H, s), 2.29 (3H, s),
3.73 (3H, s), 3.87 (3H, s), 4.60 (1H, t, J = 9.9 Hz), 5.35 (1H, d, J = 9.9
Hz), 6.63 (2H, d, J = 8.3 Hz), 6.71 (1H, d, J = 9.9 Hz), 6.98 (2H, d, J = 8.3
Hz), 7.04 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.3 Hz). 13C NMR (75
MHz, CDCl3): δ 21.3, 22.0, 55.2, 55.5, 57.4, 58.1, 59.8, 113.8 (2C),
126.9 (2C), 128.8 (2C), 129.1 (2C), 129.2, 138.1, 142.5, 159.5, 167.5.
MS (ES, pos mode) m/z: 501/503 (M þ Hþ, 100). Anal. Calcd for
C22H29ClN2O5S2: C, 52.74; H, 5.83; N, 5.59. Found: C, 53.02; H, 5.73;
N, 5.66.
’ EXPERIMENTAL SECTION
Synthesis of (RS)-Methyl N-tert-Butanesulfinyl-2-chloro-
ethanimidate (RS)-3. To a round-bottomed flask charged with
(RS)-tert-butanesulfinamide (RS)-1 (3.00 g, 24.79 mmol) were added
1-chloro-2,2,2-trimethoxyethane 2 (7 equiv, 26.80 g, 173.55 mmol) and
p-toluenesulfonic acid monohydrate (0.005 equiv, 0.02 g, 0.12 mmol).
The reaction mixture was stirred for 4 h at 100 °C, and the volatile
materials were removed in vacuo. The crude oil was purified via flash
chromatography to yield 4.40 g (20.83 mmol, 84% yield) of pure (RS)-
methyl N-tert-butanesulfinyl-2-chloroethanimidate (RS)-3 and 0.28 g
(1.24 mmol, 10% yield) N-(tert-butanesulfinyl)-tert-butanesulfinimide 4
as byproduct.
(RS,R,R)-Methyl 3-(Benzenesulfonylamino)-2-chloro-3-
furan-2-yl-N-tert-butanesulfinylpropanimidate (RS,R,R)-6c.
Rf = 0.19 (petroleum ether/Et2O 4:6). White crystals, yield 71%.
[R]D -236.2 (c 0.2, CHCl3). Mp: 54.6-54.8 °C. IR (cm-1): νmax
(RS)-Methyl N-tert-Butanesulfinyl-2-chloroethanimidate
(RS)-3. Rf = 0.11 (petroleum ether/Et2O 7:3). Yellow oil, 84%. [R]D
-247.8 (c 1.2, CHCl3). IR (cm-1): νmax 1076, 1294, 1634, 2949. H
1
1
742, 915, 1026, 1058, 1163, 1290, 1332, 1447, 1639, 2949, 3128. H
NMR (300 MHz, CDCl3): δ 1.24 (9H, s), 3.82 (3H, s), 4.30 (1H, d, J =
12.4 Hz), 4.60 (1H, d, J = 12.4 Hz). 13C NMR (75 MHz, CDCl3): δ 21.9,
37.6, 54.9, 56.0, 167.0. MS (ES, pos mode) m/z: 212/214 (M þ Hþ,
100). Anal. Calcd for C7H14ClNO2S: C, 39.71; H, 6.67; N, 6.62. Found:
C, 39.62; H, 6.74; N, 6.69.
N-(tert-Butanesulfinyl)-tert-butanesulfinimide 4. Rf = 0.61
(petroleum ether/Et2O 7:3). White crystals, yield 10%. [R]D -21.9
(c 0.6, CHCl3). Mp: 161.1-161.5 °C. IR (cm-1): νmax 884, 1124, 1296,
1362, 2979, 3233. 1H NMR (300 MHz, CDCl3): δ 1.32 (9H, s), 1.43
(9H, s), 5.44 (1H, br s). 13C NMR (75 MHz, CDCl3): δ 24.8, 28.2, 48.6,
61.3. MS (ES, neg. mode) m/z: 224 (M - Hþ, 100). Anal. Calcd for
C8H19NO2S2: C, 42.63; H, 8.50; N, 6.21. Found: C, 42.34; H, 8.73;
N, 6.37.
Synthesis of r-Chloro-β-amino-N-sulfinylimidates (RS,R,
R)-6. The synthesis of (RS,R,R)-R-chloro-β-(sulfonylamino)-N-sulfinyl-
imidate (RS,R,R)-6a is representative. A solution of (RS)-methyl N-tert-
butanesulfinyl-2-chloroethanimidate (RS)-3(1.8 equiv, 3.00 g, 14.19 mmol)
in THF (60 mL) was cooled to -78 °C. A 1 M solution of LiHMDS
(1.8 equiv, 14.19 mL, 14.19 mmol) in THF was slowly added, and the
resulting solution was stirred for 45 min at -78 °C. After deprotonation, a
solution of N-benzylidene-4-methylbenzenesulfonamide 5a (1 equiv, 2.04
g, 7.88 mmol) in THF (20 mL) was added dropwise, and the reaction
mixture was stirred at -78 °C for 0.5 h. To the reaction mixture was added
a saturated solution of NH4Cl (5 mL), followed by a 1.0 N aqueous
solution of NaOH (40 mL). The aqueous phase was extracted with Et2O
(3 ꢀ 40 mL). The combined organic phases were dried (MgSO4), filtered,
and evaporated in vacuo. The crude product was purified by flash
chromatography to yield 3.18 g (6.77 mmol, 86% yield) of pure (RS,R,
NMR (300 MHz, CDCl3): δ 1.33 (9H, s), 3.86 (3H, s), 4.79 (1H, t, J =
9.6 Hz), 5.63 (1H, d, J = 9.6 Hz), 6.04-6.06 (2H, m), 6.62 (1H, d, J =
9.6 Hz), 7.09-7.12 (1H, m), 7.24-7.35 (2H, m), 7.38-7.44 (1H, m),
7.57-7.63 (2H, m). 13C NMR (75 MHz, CDCl3): δ 22.1, 53.8, 54.0,
58.0, 110.0, 110.2, 127.0 (2C), 128.6 (2C), 132.1, 140.5, 142.7, 148.2,
166.3. MS (ES, pos mode) m/z: 447/449 (M þ Hþ, 100). Anal. Calcd
for C18H23ClN2O5S2: C, 48.37; H, 5.19; N, 6.27. Found: C, 48.22; H,
5.33; N, 5.99.
(RS,R,R)-Methyl 2-Chloro-3-phenyl-3-(tert-butoxycarbonyl-
amino)-N-tert-butanesulfinylpropanimidate (RS,R,R)-6d. Rf =
0.54 (petroleum ether/Et2O 6:4). White crystals, yield 91%. dr 95:5.
[R]D -231.7 (c 0.4, CHCl3). Mp: 107.0-107.3 °C. IR (cm-1): νmax
1
1159, 1243, 1301, 1510, 1619, 1722, 2969, 3324. H NMR (300 MHz,
CDCl3): δ 1.30 (9H, s, tBu), 1.36 (9H, s), 3.83 (3H, s), 5.01 (1H, t, J =
9.9 Hz), 5.51 (1H, d, J = 9.9 Hz), 6.29 (1H, d, J = 9.9 Hz), 7.25-7.46 (5H,
m). 13C NMR (75 MHz, CDCl3): δ 22.0, 28.3, 55.0, 56.7, 57.3, 57.7, 79.4,
127.6 (2C), 128.2, 128.6 (2C), 139.0, 154.2, 167.7. MS (ES, pos mode)
m/z: 417/419 (M þ Hþ, 20), 439/441 (M þ Naþ, 100). Anal. Calcd for
C19H29ClN2O4S: C, 54.73; H, 7.01; N, 6.72. Found: C, 54.89; H, 6.83;
N, 6.59.
Synthesis of r-Chloro-β-(sulfonylamino)midate Hydro-
chlorides (R,R)-7. The synthesis of (R,R)-methyl 2-chloro-3-phenyl-
3-(p-toluenesulfonylamino)propanimidate hydrochloride (R,R)-7a is
representative. To a solution of (RS,R,R)-methyl 2-chloro-3-phenyl-
3-(p-toluenesulfonylamino)-N-tert-butanesulfinylpropanimidate (RS,R,
R)-6a (3.00 g, 6.38 mmol) in diethyl ether (60 mL) was added a 4 N
solution of HCl in dioxane (20 equiv, 31.88 mL, 127.54 mmol) at room
2208
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
ARTICLE
temperature. The mixture was allowed to stir for 1 h at room tempera-
ture. Subsequently, the reaction mixture was concentrated in vacuo.
Precipitation in diethyl ether afforded 1.82 g (4.53 mmol, 71% yield) of
Precipitation in diethyl ether afforded 0.70 g (2.13 mmol, 95% yield) of
pure (R,R)-3-(benzenesulfonylamino)-2-chloro-3-furan-2-ylpropan-
amide (R,R)-8c.
pure
(R,R)-methyl
2-chloro-3-phenyl-3-(p-toluenesulfonylami-
(R,R)-2-Chloro-3-phenyl-3-(p-toluenesulfonylamino)pro-
panamide (R,R)-8a. White crystals, yield 99%. [R]D -38.6 (c 0.3,
DMF). Mp 214.2-214.4 °C. IR (cm-1): νmax 666, 1089, 1154, 1319,
1586, 1682, 3186, 3368, 3472. 1H NMR (300 MHz, DMSO-d6, int. ref
2.49): δ 2.23 (3H, s), 4.37 (1H, d, J = 8.3 Hz), 4.79 (1H, d, J = 8.3 Hz),
7.01-7.15 (7H, m), 7.35 (2H, d, J = 8.3 Hz), 7.45 (1H, br s), 7.68 (1H,
br s), 8.40 (1H, br s). 13C NMR (75 MHz, DMSO-d6, int. ref 40.0): δ
21.4, 60.1, 60.7, 126.9 (2C), 127.9, 128.2 (2C), 128.3 (2C), 129.4 (2C),
137.5, 138.8, 142.5, 168.8. MS (ES, pos mode) m/z (%): 353/355 (M þ
Hþ, 100). Anal. Calcd for C16H17ClN2O3S: C, 54.46; H, 4.86; N, 7.94.
Found: C, 54.57; H, 5.03; N, 7.96.
(R,R)-2-Chloro-3-(4-methoxyphenyl)-3-(p-toluenesulfo-
nylamino)propanamide (R,R)-8b. White crystals, yield 99%. [R]D
-45.3 (c 0.1, DMF). Mp: 176.8-177.0 °C. IR (cm-1): νmax 665, 1091,
1156, 1250, 1323, 1514, 1611, 1677, 3273. 1H NMR (300 MHz, DMSO-
d6, int ref 2.49): δ 2.25 (3H, s), 3.65 (3H, s), 4.33 (1H, d, J = 8.8 Hz),
4.74 (1H, t, J = 8.8 Hz), 6.62 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz),
7.07 (2H, d, J = 8.0 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.44 (1H, br s), 7.66
(1H, br s), 8.30 (1H, br s). 13C NMR (75 MHz, DMSO-d6, int ref 40.0):
δ 21.3, 55.5, 59.5, 61.0, 113.6 (2C), 126.8, 126.9 (2C), 129.4 (2C), 129.5
(2C), 138.8, 142.4, 159.1, 168.8. MS (ES, neg. mode) m/z: 381/383
(M - Hþ, 100). Anal. Calcd for C17H19ClN2O4S: C, 53.33; H, 5.00; N,
7.32. Found: C, 53.14; H, 4.93; N, 7.09.
(R,R)-3-(Benzenesulfonylamino)-2-chloro-3-furan-2-yl-
propanamide (R,R)-8c. White crystals, yield 95%. [R]D -45.5 (c 0.2,
DMF). Mp: 222.3-222.4 °C. IR (cm-1): νmax 686, 736, 1088, 1156,
1315, 1454, 1580, 1677, 3149, 3376. 1H NMR (300 MHz, DMSO-d6, int
ref 2.49): δ 4.45 (1H, d, J = 9.0 Hz), 4.89 (1H, t, J = 9.0 Hz), 6.04-6.11
(2H, m), 7.31 (1H, br s), 7.35-7.41 (2H, m), 7.43-7.53 (2H, m), 7.58
(2H, d, J = 7.2 Hz), 7.78 (1H, br s), 8.59 (1H, d, J = 9.0 Hz). 13C NMR
(75 MHz, DMSO-d6, int ref 40.0): δ 53.8, 59.0, 109.5, 110.6, 126.7 (2C),
129.1 (2C), 132.5, 141.5, 142.8, 150.0, 168.2. MS (ES, pos mode) m/z:
327/329 (M þ Hþ, 100). Anal. Calcd for C18H23ClN2O5S2: C, 48.37;
H, 5.19; N, 6.27. Found: C, 48.17; H, 5.23; N, 6.29.
no)propanimidate hydrochloride (R,R)-7a.
(R,R)-Methyl 2-Chloro-3-phenyl-3-(p-toluenesulfonylami-
no)propanimidate hydrochloride (R,R)-7a. White crystals, yield
71%. [R]D -33.6 (c 0.2, DMF). Mp: 214.9-215.2 °C. IR (cm-1): νmax
1
670, 701, 1066, 1087, 1159, 1334, 1402, 1460, 1649, 2871, 3044. H
NMR (300 MHz, CDCl3): δ 2.26 (3H, s), 4.55 (3H, s), 4.69 (1H, t, J =
10.5 Hz), 5.56 (1H, d, J = 10.5 Hz), 6.97 (2H, d, J = 7.7 Hz), 7.05-7.17
(2H, m), 7.23 (2H, d, J = 7.2 Hz), 7.43 (2H, d, J = 8.3 Hz), 8.06 (1H, d,
J = 10.5 Hz), 12.22 (1H, br s). 13C NMR (75 MHz, CDCl3): δ 21.4, 56.8,
61.1, 62.1, 126.9 (2C), 127.0, 127.9, 128.6 (2C), 129.2 (2C), 134.6,
136.9, 143.2, 175.0. MS (ES, pos mode) m/z: 367/369 (M þ Hþ
-
HCl, 100). Anal. Calcd for C17H20Cl2N2O3S: C, 50.62; H, 5.00; N, 6.95.
Found: C, 50.42; H, 5.13; N, 7.01.
(R,R)-Methyl 2-Chloro-3-(4-methoxyphenyl)-3-(p-toluene-
sulfonylamino)propanimidate Hydrochloride (R,R)-7b.
White crystals, yield 84%. [R]D -45.7 (c 0.2, DMF). Mp: 126.8-
127.0 °C. IR (cm-1): νmax 688, 814, 1060, 1166, 1260, 1346, 1655, 2845,
3126. MS (ES, pos mode) m/z: 381/383 (M þ Hþ - HCl - 16, 100).
Anal. Calcd for C18H22Cl2N2O4S: C, 49.89; H, 5.12; N, 6.46. Found: C,
49.77; H, 5.02; N, 6.57. Imidate hydrochloride (R,R)-7b proved to be
unstable in solvent leading to the formation of the corresponding amide
(R,R)-8b. In order to obtain full characterization of hydrochloride (R,R)-
7b, the salt (0.20 g, 0.46 mmol) was redissolved in CH2Cl2 (10 mL),
followed by the addition of a saturated solution of NaHCO3 (10 mL).
The organic phase was dried (MgSO4), filtered, and evaporated in vacuo
to obtain 0.18 g (0.46 mmol) of pure (R,R)-methyl 2-chloro-3-(4-
methoxyphenyl)-3-(p-toluenesulfonylamino)propanimidate.
(R,R)-Methyl 2-Chloro-3-(4-methoxyphenyl)-3-(p-toluene-
sulfonylamino)propanimidate (R,R)-7b. Colorless oil, quantita-
tive yield. [R]D -48.5 (c 0.2, CHCl3). IR (cm-1): νmax 665, 750, 1092,
1159, 1252, 1329, 1439, 1514, 1663, 3024, 3278. 1H NMR
(300 MHz, CDCl3): δ 2.34 (3H, s), 3.71 (3H, s), 3.74 (3H, s), 4.73
(1H, d, J = 4.4 Hz), 5.02 (1H, d ꢀ d, J = 9.4, 4.4 Hz), 6.09 (1H, d, J =
9.4 Hz), 6.64 (2H, d, J = 8.3 Hz), 6.93 (2H, d, J = 7.4 Hz), 7.11 (2H, d, J =
8.3 Hz), 7.57 (2H, d, J = 7.4 Hz). 13C NMR (75 MHz, CDCl3): δ 21.4,
54.1, 55.2, 58.4, 64.9, 113.5 (2C), 126.7, 127.0 (2C), 128.6 (2C), 129.4
(2C), 137.2, 143.3, 159.4, 166.0. MS (ES, pos mode) m/z: 397/399 (M
þ Hþ, 10), 290 (100). Anal. Calcd for C18H21ClN2O4S: C, 54.47; H,
5.33; N, 7.06. Found: C, 54.28; H, 5.61; N, 6.97.
Synthesis of Chiral r-Chloro-β-amino Amides (R,R)-8.
The synthesis of (R,R)-2-chloro-3-phenyl-3-(p-toluenesulfonylamino)
propanamide (R,R)-8a is representative. (R,R)-methyl 2-chloro-3-phen-
yl-3-(p-toluenesulfonylamino)propanimidate hydrochloride (R,R)-7a
(0.50 g, 1.24 mmol) was dissolved in chloroform (20 mL). The reaction
mixture was stirred for 16 h at reflux temperature and subsequently
evaporated in vacuo. Recrystallization from diethyl ether afforded 0.44 g
(1.23 mmol, 99% yield) of pure (R,R)-2-chloro-3-phenyl-3-(p-toluene-
sulfonylamino)propanamide (R,R)-8a.
(R,R)-3-(Benzenesulfonylamino)-2-chloro-3-furan-2-ylpropanamide
(R,R)-8c and (R,R)-2-chloro-3-phenyl-3-(tert-butoxycarbonylamino)
propanamide (R,R)-8d were formed directly via the addition of HCl
in the N-deprotection of the corresponding R-chloro-β-aminosulfinyli-
midates (RS,R,R)-6c and (RS,R,R)-6d. The synthesis of (R,R)-3-
(benzenesulfonylamino)-2-chloro-3-furan-2-ylpropanamide (R,R)-8c is
representative. To a solution of (RS,R,R)-methyl 3-(benzenesulfonyl-
amino)-2-chloro-3-furan-2-yl-N-tert-butanesulfinylpropanimidate (RS,
R,R)-6c (1.00 g, 2.24 mmol) in diethyl ether (20 mL) was added a 4N
solution of HCl in dioxane (20 equiv, 11.20 mL, 44.80 mmol) at room
temperature. The mixture was allowed to stir for 1 h at room tempera-
ture. Subsequently, the reaction mixture was concentrated in vacuo.
(R,R)-2-Chloro-3-phenyl-3-(tert-butoxycarbonylamino)
propanamide (R,R)-8d. White crystals, yield 57%. er 95:5. [R]D
-
48.3 (c 0.2, DMF). Mp: 196.3-196.5 °C. IR (cm-1): νmax 1165, 1522,
1644, 1675, 3195, 3356, 3398. 1H NMR (300 MHz, DMSO-d6, int ref
2.49): δ 1.33 (9H, s), 4.49 (1H, d, J = 8.8 Hz), 4.97 (1H, t, J = 8.8 Hz),
7.22-7.37 (5H, m), 7.42 (1H, br s), 7.52 (1H, d, J = 8.8 Hz), 7.70 (1H,
br s). 13C NMR (75 MHz, DMSO-d6, int ref 40.0): δ 28.6, 57.3, 59.0,
78.9, 128.0 (2C), 128.1, 128.7 (2C), 139.9, 155.0, 169.5. MS (ES, neg
mode) m/z: 297/299 (M - Hþ, 10), 187 (100). Anal. Calcd for
C14H19ClN2O3: C, 56.28; H, 6.41; N, 9.38. Found: C, 56.46; H, 6.23;
N, 9.65.
Synthesis of Chiral N-Tosyl-r-chloro-β-amino Esters (R,R)-
9a and (R,R)-9b. The synthesis of (R,R)-methyl 2-chloro-3-phenyl-
3-(p-toluenesulfonylamino)propanoate (R,R)-9a is representative.
(R,R)-Methyl 2-chloro-3-phenyl-3-(p-toluenesulfonylamino)propanimidate
hydrochloride (R,R)-7a (1.20 g, 2.98 mmol) was dissolved in H2O (50 mL).
The reaction mixture was stirred for 24 h at 50 °C and subsequently poured
into a saturated aqueous solution of NaHCO3 (50 mL) and extracted with
diethyl ether (3 ꢀ 50 mL). The combined organic phases were dried
(MgSO4), filtered, and evaporated in vacuo. The crude product was
purified by flash chromatography to yield 1.03 g (2.80 mmol, 94% yield)
of pure (R,R)-methyl 2-chloro-3-phenyl-3-(p-toluenesulfonylamino)propa-
noate (R,R)-9a.
(R,R)-Methyl 2-Chloro-3-phenyl-3-(p-toluenesulfonylami-
no)propanoate (R,R)-9a. Rf = 0.21 (petroleum ether/Et2O 5:5).
White crystals, yield 94%. [R]D -70.4 (c 0.3, CHCl3). Mp: 121.9-
1
122.0 °C. IR (cm-1): νmax 1088, 1152, 1326, 1433, 1766, 3252. H
2209
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
ARTICLE
NMR (300 MHz, CDCl3): δ 2.34 (3H, s), 3.66 (3H, s), 4.56 (1H, d, J =
5.7 Hz), 4.93 (1H, d ꢀ d, J = 9.0, 5.7 Hz), 6.07 (1H, d, J = 9.0 Hz), 7.06-
7.25 (7H, m), 7.58 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): δ
21.5, 53.2, 59.1, 59.8, 127.0 (2C), 127.1 (2C), 128.5, 128.6 (2C), 129.4
(2C), 135.6, 137.2, 143.4, 167.9. MS (ES, pos mode) m/z: 368/370 (M
þ Hþ, 100). Anal. Calcd for C17H18ClNO4S: C, 55.51; H, 4.93; N, 3.81.
Found: C, 55.24; H, 5.03; N, 3.67.
CDCl3): δ 2.42 (3H, s), 3.90 (1H, d, J = 4.4 Hz), 4.09 (1H, d, J = 4.4 Hz),
5.52 (1H, br s), 6.25 (1H, br s), 7.21-7.41 (7H, m), 7.59 (2H, d, J =
8.3 Hz). 13C NMR (75 MHz, CDCl3): δ 21.7, 44.1, 50.9, 127.7 (2C),
128.4 (2C), 129.3 (2C), 129.4, 129.7 (2C), 135.7, 144.8, 145.2, 168.0.
MS (ES, pos mode) m/z: 317 (M þ Hþ, 100). Anal. Calcd for
C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85. Found: C, 60.81; H, 5.23;
N, 9.02.
(R,R)-Methyl 2-Chloro-3-(4-methoxyphenyl)-3-(p-toluene-
sulfonylamino)propanoate (R,R)-9b. Rf = 0.13 (petroleum
ether/Et2O 5:5). Yellow oil, yield 99%. [R]D -73.2 (c 0.4, CHCl3).
IR (cm-1): νmax 663, 1029, 1158, 1251, 1329, 1438, 1514, 1747, 3274.
1H NMR (300 MHz, CDCl3): δ 2.34 (3H, s), 3.67 (3H, s), 3.73 (3H, s),
4.55 (1H, d, J = 6.3 Hz), 4.88 (1H, d ꢀ d, J = 8.8, 6.3 Hz), 6.22 (1H, d, J =
8.8 Hz), 6.68 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J =
8.0 Hz), 7.57 (2H, d, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): δ 21.5,
53.2, 55.2, 59.4, 59.5, 113.8 (2C), 127.1 (2C), 127.6, 128.4 (2C), 129.3
(2C), 137.3, 143.3, 159.5, 168.1. MS (ES, pos mode) m/z: 415/417
(M þ NH4þ, 20), 290 (90), 227/229 (100). Anal. Calcd for
C18H20ClNO5S: C, 54.34; H, 5.07; N, 3.52. Found: C, 54.32; H, 5.10;
N, 3.78.
Synthesis of (R,R)-3-(Benzenesulfonylamino)-2-chloro-3-
furan-2-ylpropanoate (R,R)-9c. To a solution of (RS,R,R)-methyl
2-chloro-3-(benzenesulfonylamino)-3-furan-2-yl-N-tert-butanesulfinyl-
propanimidate (RS,R,R)-6c (1.23 g, 2.76 mmol) in methanol (50 mL)
was added a 3 N solution of HCl in MeOH (30 equiv, 27.55 mL,
82.65 mmol) at room temperature. The mixture was stirred for 24 h at
room temperature and subsequently poured into a saturated aqueous
solution of NaHCO3 (50 mL) and extracted with dichloromethane (3 ꢀ
50 mL). The combined organic phases were dried (MgSO4), filtered,
and evaporated in vacuo. The crude product was purified by flash
chromatography to yield 0.84 g (2.45 mmol, 89% yield) of pure (R,R)-3-
(2S,3R)-1-Benzenesulfonyl-3-furan-2-ylaziridine-2-carboxylic
Amide (2S,3R)-10c. White crystals, yield 81%. [R]D þ24.3 (c 0.1,
DMF). Mp 128.7-128.9 °C. IR (cm-1): νmax 1090, 1165, 1323, 1672,
3319, 3432. 1H NMR (300 MHz, CDCl3): δ 3.66 (1H, d, J = 7.7 Hz),
4.07 (1H, d, J = 7.7 Hz), 5.73 (1H, br s), 6.17 (1H, br s), 6.27-6.31 (1H,
m), 6.33-6.38 (1H, m), 7.33 (1H, br s), 7.56-7.65 (2H, m), 7.68-7.76
(1H, m), 7.99 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): δ 40.3,
43.5, 110.7, 110.9, 128.1 (2C), 129.5 (2C), 134.5, 136.4, 143.7, 144.9,
166.3. MS (ES, pos mode) m/z: 293 (M þ Hþ, 100). Anal. Calcd for
C13H12N2O4S: C, 53.42; H, 4.14; N, 9.58. Found: C, 53.53; H, 4.29; N, 9.38.
Synthesis of Chiral N-Tosyl-3-arylaziridine-2-carboxylic
Esters (2S,3R)-11. The synthesis of (2S,3R)-methyl 3-phenyl-1-(p-
toluenesulfonyl)aziridine-2-carboxylate (2S,3R)-11a is representative.
(R,R)-Methyl 2-chloro-3-phenyl-3-(p-toluenesulfonylamino)propano-
ate (R,R)-9a (0.25 g, 0.68 mmol) was dissolved in acetonitrile (20 mL),
and K2CO3 (2 equiv, 0.188 g, 1.36 mmol) was added in one portion. The
reaction mixture was stirred for 2 h at room temperature and subse-
quently evaporated in vacuo. The reaction mixture was dissolved in
CH2Cl2 (20 mL), washed with brine (20 mL), dried (MgSO4), filtered,
and evaporated in vacuo. Purification via flash chromatography afforded
0.22 g (0.67 mmol, 98% yield) of pure (R,R)-methyl 2-chloro-3-phenyl-
3-(p-toluenesulfonylamino)propanoate (2S,3R)-11a. In the synthesis of
(2S,3R)-methyl 3-(4-methoxyphenyl)-1-(p-toluenesulfonyl)aziridine-2-
carboxylate (2S,3R)-11b 5 equiv of K2CO3 was used, and the reaction
mixture was stirred for 2 h at room temperature. (2S,3R)-Methyl 3-(4-
methoxyphenyl)-1-(p-toluenesulfonyl)aziridine-2-carboxylate (2S,3R)-
11b was obtained in analytically pure form after extraction, without the
need of purification via flash chromatography.
(benzenesulfonylamino)-2-chloro-3-furan-2-ylpropanoate
(R,R)-9c.
Rf = 0.38 (petroleum ether/Et2O 3:7). White crystals, yield 89%.
[R]D -63.6 (c 0.2, CHCl3). Mp: 99.3-99.5 °C. IR (cm-1): νmax 752,
1047, 1164, 1309, 1343, 1434, 1743, 3268. 1H NMR (300 MHz,
CDCl3): δ 3.74 (3H, s), 4.62 (1H, d, J = 5.5 Hz), 5.08 (1H, d ꢀ d, J
= 9.9, 5.5 Hz), 5.64 (1H, d, J = 9.9 Hz), 6.08 (1H, d, J = 3.3 Hz), 6.17
(1H, d ꢀ d, J = 3.3, 1.7 Hz), 7.20 (1H, d, J = 1.7 Hz), 7.40-7.47 (2H, m),
7.49-7.56 (1H, m), 7.76-7.81 (2H, m). 13C NMR (75 MHz, CDCl3):
δ 53.4, 54.3, 57.7, 109.3, 110.5, 127.0 (2C), 129.0 (2C), 132.8, 140.1,
142.8, 148.4, 167.5. MS (ES, neg. mode) m/z: 342/344 (M - Hþ, 100).
Anal. Calcd for C14H14ClNO5S: C, 48.91; H, 4.10; N, 4.07. Found: C,
48.63; H, 3.98; N, 4.26.
(2S,3R)-Methyl 3-Phenyl-1-(p-toluenesulfonyl)aziridine-
2-carboxylate (2S,3R)-11a. Rf = 0.32 (petroleum ether/EtOAc
8:2). Colorless oil, yield 98%. [R]D -34.6 (c 0.4, CH2Cl2) vs -29.4
(c 1.0, CH2Cl2) and (2R,3S)-11a þ33.1 (c 1.0, CH2Cl2) in ref 16. 1H
NMR (300 MHz, CDCl3): δ 2.41 (3H, s), 3.53 (1H, d, J = 3.9 Hz), 3.86
(3H, s), 4.44 (1H, d, J = 3.9 Hz), 7.21-7.36 (7H, m), 7.78 (2H, d, J = 8.3
Hz). Anal. Calcd for C17H17NO4S: C, 61.61; H, 5.17; N, 4.23. Found: C,
61.41; H, 4.95; N, 4.07. All spectroscopic data were in good agreement
with reported data.16
Synthesis of Chiral N-Sulfonyl 3-Arylaziridine-2-carboxylic
Amides (2S,3R)-10. The synthesis of (2S,3R)-3-phenyl-1-(p-tolue-
nesulfonyl)aziridine-2-carboxylic amide (2S,3R)-10a is representa-
tive. (R,R)-2-Chloro-3-phenyl-3-(p-toluenesulfonylamino)propan-
amide (R,R)-8a (0.25 g, 0.71 mmol) was dissolved in acetonitrile
(20 mL), and K2CO3 (2 equiv, 0.196 g, 1.42 mmol) was added in one
portion. The reaction mixture was stirred for 5 h at room temperature and
subsequently evaporated in vacuo. The reaction mixture was dissolved in
CH2Cl2 (20 mL), washed with brine (20 mL), dried (MgSO4), filtered,
and evaporated in vacuo. Purification via flash chromatography and
recrystallization from diethyl ether afforded 0.17 g (0.54 mmol, 76% yield)
of pure (2S,3R)-3-phenyl-1-(p-toluenesulfonyl)aziridine-2-carboxylic amide
(2S,3R)-10a. In the synthesis of (2S,3R)-1-benzenesulfonyl-3-furan-2-
ylaziridine-2-carboxylic amide (2S,3R)-10c, 3 equiv of K2CO3 was used,
and the reaction mixture was stirred for 20 h at room temperature. The
obtained (2S,3R)-1-benzenesulfonyl-3-furan-2-ylaziridine-2-carboxylic
amide (2S,3R)-10c was purified by recrystallization from Et2O.
(2S,3R)-3-Phenyl-1-(p-toluenesulfonyl)aziridine-2-carboxylic
amide (2S,3R)-10a. Rf = 0.23 (CH2Cl2 þ 3% MeOH). White crystals,
yield 76%. [R]D þ28.3 (c 0.2, DMF). Mp: 167.0-167.2 °C. IR (cm-1):
νmax 684, 762, 909, 1165, 1334, 1656, 3182, 3385. 1H NMR (300 MHz,
(2S,3R)-Methyl 3-(4-Methoxyphenyl)-1-(p-toluenesulfo-
nyl)aziridine-2-carboxylate (2S,3R)-11b. Rf = 0.23 (hexane/
Et2O 7:3). Colorless oil, yield 96%. [R]D -19.4 (c 0.2, CHCl3). IR
(cm-1): νmax 790, 1160, 1251, 1333, 1517, 1746, 2954. 1H NMR (300
MHz, CDCl3): δ 2.42 (3H, s), 3.60 (1H, d, J = 4.1 Hz), 3.79 (3H, s), 3.84
(3H, s), 4.35 (1H, d, J = 4.1 Hz), 6.83 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J =
8.3 Hz), 7.28 (2H, d, J = 7.7 Hz), 7.75 (2H, d, J = 8.3 Hz). 13C NMR (75
MHz, CDCl3): δ 21.6, 46.0, 48.0, 53.1, 55.3, 114.0 (2C), 123.9, 127.5
(2C), 129.0 (2C), 129.6 (2C), 137.0, 144.3, 160.1, 166.6. MS (ES, pos
mode) m/z: 362 (M þ Hþ, 100). Anal. Calcd for C18H19NO5S: C,
59.82; H, 5.30; N, 3.88. Found: C, 60.11; H, 5.02; N, 3.68.
Synthesis of Chiral β-Chloro-γ-sulfonylamino Alcohols (R,
R)-12, (S)-N-(3-Hydroxy-1-phenylpropyl)-4-methylbenzene-
sulfonamide (S)-13, and (2S,3R)-2-Hydroxymethyl-3-phen-
yl-1-(p-toluenesulfonyl)aziridine (2S,3R)-14. The synthesis
of (R,R)-N-(2-chloro-3-hydroxy-1-phenylpropyl)-4-methylbenzenesul-
fonamide (R,R)-12a is representative. Lithium aluminum hydride (2.05
equiv, 0.106 g, 2.79 mmol) was suspended in tetrahydrofuran (10 mL) at
0 °C. A solution of (R,R)-methyl 2-chloro-3-phenyl-3-(p-toluenesulfo-
nylamino)propanoate (R,R)-9a (0.50 g, 1.36 mmol) in tetrahydrofuran
2210
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
ARTICLE
(10 mL) was added dropwise to the LiAlH4 suspension under N2. The
reaction mixture was stirred for 2.5 h at 0 °C. Subsequently, the reaction
was quenched with H2O (1 mL), diluted with CH2Cl2 (40 mL), and
filtered through a short pad of Celite. The Celite pad was washed
exhaustively with excess CH2Cl2. The collected solvent was dried
(MgSO4), filtered again and evaporated in vacuo. Purification via flash
chromatography afforded 0.40 g (1.18 mmol, 87% yield) of pure
(1R,2R)-N-(2-chloro-3-hydroxy-1-phenylpropyl)-4-methylbenzenesul-
fonamide (R,R)-12a. When the reaction was performed with 2.8 equiv of
LiAlH4 at 0 °C for 2.5 h upon which the reaction was slowly warmed to
room temperature, a mixture was obtained of (1R,2R)-N-(2-chloro-3-
hydroxy-1-phenylpropyl)-4-methylbenzenesulfonamide (R,R)-12a, (S)-
N-(3-hydroxy-1-phenylpropyl)-4-methylbenzenesulfonamide (S)-13,
and (2S,3R)-2-hydroxymethyl-3-phenyl-1-(p-toluenesulfonyl)aziridine
(2S,3R)-14, which were purified and isolated via flash chromatography
in respectively 42%, 17%, and 25% yield (Scheme 2).
(R,R)-N-(2-Chloro-3-hydroxy-1-phenylpropyl)-4-methyl-
benzenesulfonamide (R,R)-12a. Rf = 0.40 (petroleum ether/Et2O
25:75). White crystals, yield 87%. [R]D -71.0 (c 0.4, CHCl3). Mp:
124.0-124.2 °C. IR (cm-1): νmax 702, 1091, 1159, 1325, 2948, 3271,
3465, 3524. 1H NMR (300 MHz, CDCl3): δ 2.34 (3H, s), 2.75 (1H, t,
J = 6.6 Hz), 3.65-3.78 and 3.88-4.02 (2H, m), 4.18-4.25 (1H, m),
4.71 (1H, d ꢀ d, J = 8.8, 6.6 Hz), 5.99 (1H, d, J = 8.8 Hz), 6.98-7.22
(7H, m), 7.54 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): δ 21.5,
59.6, 63.4, 64.4, 127.2 (2C), 127.3 (2C), 128.1, 128.4 (2C), 129.4 (2C),
136.6, 136.8, 143.5. MS (ES, neg mode) m/z: 338/340 (M - Hþ, 100).
Anal. Calcd for C16H18ClNO3S: C, 56.55; H, 5.34; N, 4.12. Found: C,
56.29; H, 5.21; N, 4.01.
(R,R)-N-[2-Chloro-3-hydroxy-1-(4-methoxyphenyl)propyl]-
4-methylbenzenesulfonamide (R,R)-12b. White crystals, yield
88%. [R]D -69.6 (c 0.3, CHCl3). Mp: 113.3-113.4 °C. IR (cm-1):
νmax 666, 752, 1031, 1156, 1250, 1321, 1514, 2934, 3278, 3496. 1H NMR
(300 MHz, CDCl3): δ 2.35 (3H, s), 2.92 (1H, d ꢀ d, J = 7.2, 6.3 Hz),
3.64-3.77 and 3.89-3.99 (2H, m), 3.73 (3H, s), 4.20 (1H, t ꢀ d, J = 6.3,
4.4 Hz), 4.66 (1H, d ꢀ d, J = 8.5, 6.3 Hz), 6.04 (1H, d, J = 8.5 Hz), 6.65
(2H, d, J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.3 Hz), 7.53
(2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): δ 21.5, 55.2, 59.0,
63.5, 64.7, 113.7 (2C), 127.1 (2C), 128.5 (2C), 128.6, 129.4 (2C),
136.9, 143.4, 159.3. MS (ES, neg. mode) m/z: 368/370 (M - Hþ, 100).
Anal. Calcd for C17H20ClNO4S: C, 55.20; H, 5.45; N, 3.79. Found: C,
54.91; H, 5.56; N, 3.69.
(R,R)-N-(2-Chloro-1-furan-2-yl-3-hydroxypropyl)-4-meth-
ylbenzenesulfonamide (R,R)-12c. White crystals, yield 84%. [R]D
-71.2 (c 0.3, CHCl3). Mp: 99.0-99.3 °C. IR (cm-1): νmax 746, 1022,
1163, 1321, 1451, 2941, 3215, 3485. 1H NMR (300 MHz, CDCl3): δ
2.56 (1H, t, J = 6.1 Hz), 3.75-3.87 and 4.01-4.12 (2H, m), 4.24 (1H, t
ꢀ d, J = 6.9, 4.4 Hz), 4.81 (1H, d ꢀ d, J = 9.4, 6.9 Hz), 5.60 (1H, d, J =
9.4 Hz), 5.90 (1H, d, J = 3.3 Hz), 6.13 (1H, d ꢀ d, J = 3.3, 1.7 Hz), 7.19
(1H, d, J = 1.7 Hz), 7.38-7.47 (2H, m), 7.49-7.56 (1H, m), 7.70-7.77
(2H, m). 13C NMR (75 MHz, CDCl3): δ 53.5, 62.7, 63.4, 109.0, 110.3,
127.0 (2C), 129.0 (2C), 132.9, 139.6, 142.5, 149.1. MS (ES, neg. mode)
m/z: 314/316 (M - Hþ, 100). Anal. Calcd for C13H14ClNO4S: C,
49.45; H, 4.47; N, 4.44. Found: C, 49.66; H, 4.26; N, 4.24.
Colorless oil, yield 17%. [R]D -50.5 (c 0.3, CHCl3) vs (2R,3S)-14
þ48.4 (c 1.9, CHCl3, > 98% ee) in ref 17. IR (cm-1): νmax 687, 696, 906,
1
1153, 1303, 1318, 2920, 3518. H NMR (300 MHz, CDCl3): δ 2.41
(3H, s), 3.12-3.23 (2H, m), 4.03 (1H, d, J = 4.4 Hz), 4.18 (1H, d ꢀ d ꢀ
d, J = 13.6, 8.5, 4.4 Hz), 4.32 (1H, d ꢀ d ꢀ d, J = 13.6, 9.9, 3.2 Hz), 7.10-
7.34 (7H, m), 7.83 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): δ
21.6, 46.3, 54.7, 60.6, 126.4 (2C), 127.1 (2C), 128.4, 128.6 (2C), 129.7
(2C), 134.5, 137.0, 144.4. MS (ES, pos mode) m/z: 304 (M þ Hþ, 100).
Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62. Found: C,
63.06; H, 5.39; N, 4.76. All spectroscopic data were in good agreement
with reported data for the (2R,3S)-enantiomer of (2S,3R)-14.17
Synthesis of Chiral N-Sulfonyl trans-2-Aryl-3-chloroazeti-
dines (2R,3S)-15. The synthesis of (2R,3S)-3-chloro-2-phenyl-1-
tosylazetidine (2R,3S)-15a is representative. (1R,2R)-N-(2-Chloro-3-
hydroxy-1-phenylpropyl)-4-methylbenzenesulfonamide (R,R)-12a (0.25 g,
0.74 mmol) and triphenylphosphine (1.5 equiv, 0.29 g, 1.11 mmol) were
dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicarboxylate
(1.5 equiv, 0.22 g, 1.11 mmol) was slowly added, and the mixture was
stirred for 24 h at room temperature. The reaction mixture was rinsed
through a pad of silica gel with diethyl ether and evaporated in vacuo.
Purification via flash chromatography afforded 0.23 g (0.71 mmol, 97%
yield) of pure (2R,3S)-3-chloro-2-phenyl-1-tosylazetidine (2R,3S)-15a.
(2R,3S)-3-Chloro-2-phenyl-1-tosylazetidine (2R,3S)-15a. Rf =
0.04 (petroleum ether/Et2O 7:3). White crystals, yield 97%. Mp: 137.4-
137.5 °C. [R]D -175.3 (c 0.4, CHCl3). IR (cm-1): νmax 656, 695, 1102,
1157, 1346, 2923. 1H NMR (300 MHz, CDCl3): δ2.43 (3H, s), 3.72-3.82
(1H, m), 4.12-4.24 (2H, m), 4.75-4.82 (1H, m), 7.23-7.45 (7H, m),
7.67 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): δ 21.6, 51.3, 57.0,
75.8, 126.3 (2C), 128.4 (2C), 128.7 (2C), 128.9, 129.8 (2C), 131.3, 136.9,
144.6. MS (ES, pos mode) m/z: 344/346 (M þ Naþ, 10), 184 (100). Anal.
Calcd for C16H16ClNO2S: C, 59.71; H, 5.01; N, 4.35. Found: C, 59.91; H,
5.19; N, 4.23.
(2R,3S)-3-Chloro-2-(4-methoxyphenyl)-1-tosylazetidine
(2R,3S)-15b. Rf = 0.34 (hexane/Et2O 5:5). White crystals, yield 70%.
Mp: 91.6-91.7 °C. [R]D -192.8 (c 0.2, CHCl3). IR (cm-1): νmax 1025,
1102, 1162, 1252, 1294, 1348, 3209, 3480. 1H NMR (300 MHz,
CDCl3): δ 2.46 (3H, s), 3.68-3.78 (1H, m), 3.81 (3H, s), 4.12-4.22
(2H, m), 4.66-4.73 (1H, m), 6.89 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J =
8.8 Hz), 7.34 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz). 13C NMR
(75 MHz, CDCl3): δ 21.7, 51.6, 55.3, 56.8, 75.7, 114.1 (2C), 127.9 (2C),
128.4 (2C), 129.1, 129.8 (2C), 131.4, 144.6, 160.1. MS (ES, pos mode) m/
z: 374/376 (M þ Naþ, 20), 184 (100). Anal. Calcd for C17H18ClNO3S: C,
58.03; H, 5.16; N, 3.98. Found: C, 57.88; H, 5.08; N, 3.97.
(2R,3S)-1-Benzenesulfonyl-3-chloro-2-furan-2-ylazetidine
(2R,3S)-15c. Rf = 0.33 (petroleum ether/Et2O 7:3). White crystals,
yield 72%. Mp: 84.9-85.1 °C. [R]D -102.6 (c 0.2, CHCl3). IR (cm-1):
νmax 738, 1020, 1090, 1160, 1341. 1H NMR (300 MHz, CDCl3): δ 3.83
(1H, t, J = 7.7 Hz), 4.18 (1H, t, J = 7.7 Hz), 4.63 (1H, t ꢀ d, J =
7.7, 6.6 Hz), 4.89 (1H, d, J = 6.6 Hz), 6.33 (1H, d ꢀ d, J = 3.3, 1.7 Hz),
6.41 (1H, d, J = 3.3 Hz), 7.39 (1H, d, J = 1.7 Hz), 7.48-7.56 (2H, m),
7.59-7.65 (1H, m), 7.75-7.80 (2H, m). 13C NMR (75 MHz, CDCl3):
δ 48.1, 56.6, 68.2, 110.7, 110.8, 128.1 (2C), 129.2 (2C), 133.5, 135.4,
143.8, 148.7. MS (ES, neg mode) m/z: 296/298 (M - Hþ, 10), 278
(100). Anal. Calcd for C13H12ClNO3S: C, 52.44; H, 4.06; N, 4.70.
Found: C, 52.24; H, 3.93; N, 4.49.
(S)-N-(3-Hydroxy-1-phenylpropyl)-4-methylbenzenesul-
fonamide (S)-13. Rf = 0.14 (petroleum ether/Et2O 25:75). White
crystals, yield 25%. [R]D -74.9 (c 0.1, CHCl3). Mp: 140.6-140.7 °C.
1H NMR (300 MHz, CDCl3): δ 1.88-2.00 (2H, m), 2.35 (3H, s), 2.47
(1H, t, J = 5.1 Hz), 3.57-3.69 and 3.74-3.85 (2H, m), 4.52 (1H, q, J =
7.4 Hz), 5.98 (1H, d, J = 7.4 Hz), 6.98-7.18 (7H, m), 7.56 (2H, d, J =
8.3 Hz). Anal. Calcd for C16H19NO3S: C, 62.93; H, 6.27; N, 4.59.
Found: C, 62.71; H, 6.11; N, 4.37. All spectroscopic data were in good
agreement with reported data.21
Synthesis of (R,R)-3-Amino-2-chloro-3-phenylpropan-
amide Hydrochloride (R,R)-17. To a solution of (R,R)-2-chloro-
3-phenyl-3-(tert-butoxycarbonylamino)propanamide (R,R)-8d (0.20 g,
0.67 mmol) in diethyl ether (6 mL) was added a 4 N solution of HCl in
dioxane (50 equiv, 11.17 mL, 33.51 mmol) at room temperature. The
mixture was allowed to stir for 3 h at room temperature. Subsequently,
the reaction mixture was concentrated in vacuo. Precipitation in diethyl
ether afforded 0.10 g (0.52 mmol, 78% yield) of pure (R,R)-3-amino-2-
chloro-3-phenylpropanamide hydrochloride (R,R)-17 (er 95:5). White
(2S,3R)-2-Hydroxymethyl-3-phenyl-1-(p-toluenesulfonyl)
aziridine (2S,3R)-14. Rf = 0.72 (petroleum ether/Et2O 25:75).
2211
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
ARTICLE
crystals, yield 78%. er 95:5. [R]D þ7.4 (c 0.2, DMF). Mp: 209.2-
209.9 °C. IR (cm-1): νmax 701, 1412, 1512, 1578, 1685, 2774, 3038,
3394. 1H NMR (300 MHz, D2O, int. ref CH3CN): δ 5.09 (1H, d, J = 4.4
Hz), 5.14 (1H, d, J = 4.4 Hz), 7.46-7.62 (5H, m). 13C NMR (75 MHz,
D2O, int ref CH3CN): δ 56.7, 57.8, 127.6 (2C), 129.3 (2C), 130.2,
131.2, 170.3. MS (ES, pos mode) m/z: 199/201 (M þ Hþ - HCl, 100).
Anal. Calcd for C9H12Cl2N2O: C, 45.98; H, 5.14; N, 11.91. Found: C,
46.19; H, 5.00; N, 11.77.
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: þ32 (0)9 264 59 51. Fax: þ32 (0)9 264 62 43. E-mail:
norbert.dekimpe@ugent.be.
Synthesis of (R,R)-Methyl 3-Amino-2-chloro-3-phenylpro-
panoate Hydrochloride (R,R)-18. To a solution of (RS,R,R)-methyl
2-chloro-3-phenyl-3-(tert-butoxycarbonylamino)-N-tert-butanesulfinyl-
propanimidate (RS,R,R)-6d (0.40 g, 0.96 mmol) in methanol (15 mL)
was added a 3 N solution of HCl in MeOH (80 equiv, 25.61 mL, 76.84
mmol) at room temperature. The mixture was stirred for 16 h at room
temperature. Subsequently, the reaction mixture was concentrated in
vacuo. Precipitation in diethyl ether afforded 0.19 g (0.76 mmol, 79%
yield) of pure (R,R)-methyl 3-amino-2-chloro-3-phenylpropanoate hy-
drochloride (R,R)-18 (er 95:5). White crystals, yield 79%. er 95:5. [R]D
þ19.0 (c 0.1, DMF). Mp: 198.4-198.9 °C. IR (cm-1): νmax 700, 1168,
1511, 1746, 2849. 1H NMR (300 MHz, D2O, int. ref CH3CN): δ 3.83
(3H, s), 5.26 (1H, d, J = 4.7 Hz), 5.36 (1H, d, J = 4.7 Hz), 7.48-7.59
(5H, m). 13C NMR (75 MHz, D2O, int. ref CH3CN): δ 54.2, 56.0, 58.7,
127.6 (2C), 129.3 (2C), 130.4, 131.0, 168.1. MS (ES, pos mode) m/z:
214/216 (M þ Hþ - HCl, 100). Anal. Calcd for C10H13Cl2NO2: C,
48.02; H, 5.24; N, 5.60. Found: C, 47.91; H, 5.23; N, 5.57.
Synthesis of (4R,5S)-Methyl 4-Phenyloxazolidin-2-one-5-
carboxylate (4R,5S)-19. To a solution of (RS,R,R)-methyl 2-chloro-
3-phenyl-3-(tert-butoxycarbonylamino)-N-tert-butanesulfinylpropani-
midate (RS,R,R)-6d (0.40 g, 0.96 mmol) in methanol (15 mL) was added
a 3N solution of HCl in MeOH (80 equiv, 25.61 mL, 76.84 mmol) at
room temperature. The mixture stirred for 16 h at room temperature and
subsequently poured in a saturated aqueous solution of NaHCO3
(40 mL) and extracted with dichloromethane (3 ꢀ 40 mL). The com-
bined organic phases were dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by recrystallization from diethyl
ether to yield 0.20 g (0.92 mmol, 96% yield) of pure (4R,5S)-methyl
4-phenyloxazolidin-2-one-5-carboxylate (4R,5S)-19 (er 95:5). White
crystals, yield 96%. er 95:5. [R]D þ47.4 (c 0.1, CHCl3). Mp: 156.6-
156.7 °C. IR (cm-1): νmax 699, 1076, 1211, 1722, 1760, 2849, 3261. 1H
NMR (300 MHz, CDCl3): δ 3.88 (3H, s), 4.78 (1H, d, J = 5.0 Hz), 4.99
(1H, d, J = 5.0 Hz), 6.14 (1H, br s), 7.35-7.48 (5H, m). 13C NMR
(75 MHz, CDCl3): δ 53.2, 59.1, 80.3, 125.9 (2C), 129.2, 129.4 (2C),
138.8, 157.7, 168.8. MS (ES, neg. mode) m/z: 220 (M - Hþ, 100). Anal.
Calcd for C11H11NO4: C, 59.73; H, 5.01; N, 6.33. Found: C, 59.52; H,
4.86; N, 6.13. All spectroscopic data were in good agreement with
reported data of the racemate of 19.22
Notes
†Postdoctoral Fellow of the Research Foundation - Vlaanderen
(FWO).
’ ACKNOWLEDGMENT
We are indebted to the Research Foundation - Flanders
(FWO - Vlaanderen) and Ghent University (BOF) for financial
support.
’ REFERENCES
(1) (a) Kleinman, E. F. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter
4.1. (b) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044.
(2) (a) F€ul€op, F.; Martinek, T. A.; Toth, G. K. Chem. Soc. Rev.
2006, 35, 323. (b) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008,
41, 1366.(c) Juaristi, E., Ed. Enantioselective Synthesis of β-Amino Acids,
1st ed.; Wiley-VCH: New York, 1997. (d) Hamuro, Y.; Schneider,
J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200. (e) Wang,
X.; Espinosa, J. F.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 4821.
(f) Appella, D. H.; Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am.
Chem. Soc. 1999, 121, 2309.
(3) For reviews on the asymmetric Mannich reaction, see: (a)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (b) Denmark, S.;
Nicaise, O. J.-C. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamomoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p 93. (c)
Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org. Chem. 2000, 4, 563. (d)
Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. (e) Verkade, J. M. M.;
van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc.
Rev. 2008, 37, 29. (f) Cordova, A. Acc. Chem. Res. 2004, 37, 102. (g)
Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541.(h) Ueno, M.;
Kobayashi, S. In EnantioselectiveSynthesis of β-AminoAcids, 2nd ed.; Juaristi,
E., Soloshonok, V. A., Eds.; Wiley: New York, 2005; pp 139-157.
(4) For representative examples, see: (a) Liu, M.; Sibi, M. P. Tetra-
hedron 2002, 58, 7991. (b) Van Nguyen, H.; Matsubara, R.; Kobayashi, S.
Angew. Chem., Int. Ed. 2009, 48, 5927. (c) Ferreira, F.; Botuha, C.; Chemla,
F.; Pꢀerez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162. (d) Schenkel, L. B.;
Ellman, J. A. Org. Lett. 2004, 6, 3621. (e) Zhao, C. -H.; Liu, L.; Wang, D.;
Chen, Y. -J. Eur. J. Org. Chem. 2006, 2977. (f) Lanter, J. C.; Chen, H. F.;
Zhang, X. Q.; Sui, Z. H. Org. Lett. 2005, 7, 5905. (g) Jacobsen, M. F.; Ionita,
L.; Skrydstrup, T. J. Org. Chem. 2004, 69, 4192. (h) Wenzel, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (i) Morton, D.;
Stockman, R. A. Tetrahedron 2006, 62, 8869. (j) Robak, M. T.; Herbage,
M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600. (k) Tiong, E. A.; Gleason,
J. L. Org. Lett. 2009, 11, 1725.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental condi-
b
tions and copies of H NMR and 13C NMR spectra for (RS)-
1
methyl N-tert-butanesulfinyl-2-chloroethanimidate (RS)-3,
N-(tert-butanesulfinyl)-tert-butanesulfinimide 4, R-chloro-β-
amino-N-sulfinylimidates (RS,R,R)-6, R-chloro-β-sulfonylamino
imidate hydrochlorides (R,R)-7, R-chloro-β-amino amides (R,
R)-8, R-chloro-β-amino esters (R,R)-9, aziridine-2-carboxylic
amides (2S,3R)-10, aziridine-2-carboxylic esters (2S,3R)-11, β-
chloro-γ-sulfonylamino alcohols (R,R)-12, (S)-N-(3-hydroxy-1-
phenylpropyl)-4-methylbenzenesulfonamide (S)-13, (2S,3R)-2-
hydroxymethyl-3-phenyl-1-(p-toluenesulfonyl)aziridine (2S,3R)-14,
trans-2-aryl-3-chloroazetidines (2R,3S)-15, hydrochlorides (R,
R)-17 and (R,R)-18, and oxazolidin-2-one (4R,5S)-19. This
(5) Colpaert, F.; Mangelinckx, S.; De Kimpe, N. Org. Lett. 2010,
12, 1904.
(6) For recent reviews on the asymmetric synthesis of aziridines, see:
(a) Hu, X. E. Tetrahedron 2004, 60, 2701. (b) Sweeney, J. B. Chem. Soc.
Rev. 2002, 31, 247. (c) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
(d) Pellissier, H. Tetrahedron 2010, 66, 1509.
(7) (a) Zhou, A. K.; Chen, B.-C.; Davis, F. A. Asymmetric synthesis
with aziridinecarboxylate and aziridinephosphonate building blocks. In
Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH:
New York, 2006; Chapter 3. (b) Ramallal, R. M.; Liz, R.; Gotor, V. J. Org.
Chem. 2010, 75, 6614. (c) Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang,
2212
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213

The Journal of Organic Chemistry
ARTICLE
Z.-T.; Wang, M.-X. J. Org. Chem. 2007, 72, 2040. (d) Wang, J.-Y.; Wang,
D.-X.; Fan, J.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2007, 72, 9391.
(e) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349.
(8) (a) Lee, W. K.; Ha, H.-J. Aldrichim. Acta 2003, 36, 57. (b)
Beresford, K. J. M.; Church, N. J.; Douglas, W. Y. Org. Biomol. Chem.
2006, 4, 2888. (c) Davis, F. A.; Ping Zhou, H. L.; Fang, T.; Reddy, G. V.;
Zhang, Y. J. Org. Chem. 1999, 64, 7559. (d) Davis, F. A.; Reddy, G. V.;
Liang, C.-H. Tetrahedron Lett. 1997, 38, 5139.
(9) Wang, M.-X.; Lin, S.-J.; Liu, C.-S.; Zheng, Q.-Y.; Li, J.-S. J. Org.
Chem. 2003, 68, 4570 and references cited therein.
(10) (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Aldrichim. Acta
2003, 36, 39 and references therein. (b) Davis, F. A.; Zhou, P.; Reddy,
G. V. J. Org. Chem. 1994, 59, 3243 and references therein.
(11) (a) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79, 331.
(b) Moore, J. A.; Ayers, R. S. In Chemistry of Heterocyclic Compounds -
Small Ring Heterocycles; Hassner, A., Ed.; Wiley: New York, 1983; Part 2,
pp 1-217. (c) Davies, D. E. ; Starr, R. C. In Comprehensive Heterocyclic
Chemistry; Lwowski, W., Ed.; Pregamon: Oxford, 1984; Vol. 7, Part 5, pp
237-284. (d) De Kimpe, N. In Comprehensive Heterocyclic Chemistry II;
Padwa, A., Ed.; Elsevier: Oxford, 1996; Vol. 1B, Chapter 1.21. (e) Singh,
G. S.; D’hooghe, M.; De Kimpe, N. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A., Ramsden, C., Scriven, E., Taylor, R., Eds.;
Elsevier: Oxford, 2008; Vol. 1, p 1. (f) Couty, F.; Evano, G. Org. Prep.
Proced. Int. 2006, 38, 427. (g) Ferraris, D.; Belyakov, S.; Li, W. X.; Oliver,
E.; Ko, Y. S.; Calvin, D.; Lautar, S.; Thomas, B.; Rojas, C. Curr. Top. Med.
Chem. 2007, 7, 597. (h) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev.
2008, 108, 3988.
(12) (a) Van Driessche, B.; Van Brabandt, W.; D’hooghe, M.;
Dejaegher, Y.; De Kimpe, N. Tetrahedron 2006, 62, 6882 and references
cited therein. (b) Van Brabandt, W.; Mangelinckx, S.; D’hooghe, M.;
Van Driessche, B.; De Kimpe, N. Curr. Org. Chem. 2009, 13, 829 and
references cited therein.
(13) (a) Kakeya, H.; Morishita, M.; Kobinata, K.; Osono, M.;
Ishizuka, M.; Osada, H. J. Antibiot. 1998, 51, 1126. (b) Matsunaga, S.;
Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8777. (c) Grajewska, A.; Rozwadowska, M. D. Tetrahedron:
Asymmetry 2007, 18, 803.
(14) Colpaert, F.; Mangelinckx, S.; Verniest, G.; De Kimpe, N. J. Org.
Chem. 2009, 74, 3792.
(15) Matsubara, R.; Berthiol, F.; Nguyen, H. V.; Kobayashi, S. Bull.
Chem. Soc. Jpn. 2009, 82, 1083.
(16) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328. (b) Davis, F. A.; Liu, H.;
Zhou, P.; Fang, T.; Reddy, V. G.; Zhang, Y. J. Org. Chem. 1999, 64, 7559.
(17) Ma, L. G.; Jiao, P.; Zhang, Q. H.; Xu, J. X. Tetrahedron:
Asymmetry 2005, 16, 3718.
(18) For some recent examples of the use of R-amido sulfones in
asymmetric Mannich-type additions, see: (a) Yin, B.; Zhang, Y.; Xu,
L.-W. Synthesis 2010, 3583. (b) Zhang, H.; Salahuddin, S.; Barbas, C. F.,
III. Org. Lett. 2010, 12, 708. (c) Momo, R. D.; Fini, F.; Bernardi, L.; Ricci,
A. Adv. Synth. & Cat. 2009, 351, 2283.
(19) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994,
59, 1238.
(20) (a) Hassner, A.; Burke, S. S. Tetrahedron 1974, 30, 2613. (b)
Gundermann, K. D.; Holtmann, G. Chem. Ber. 1958, 91, 160.
(21) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc.
2009, 131, 18028.
(22) Mishra, R. K.; Coates, C. M.; Revell, K. D.; Turos, E. Org. Lett.
2007, 9, 575.
2213
dx.doi.org/10.1021/jo200082w |J. Org. Chem. 2011, 76, 2204–2213