A convenient synthetic route to enantiopure N-tosylazetidines from α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2007.02.033

A general and convenient synthetic route to various chiral 2-substituted- and 2,4-disubstituted-N-tosylazetidines (ee >99%) is described in good overall yields starting from chiral α-amino acids using very simple chemistry.

Full text of DOI:10.1016/j.tetlet.2007.02.033

Tetrahedron Letters 48 (2007) 2471–2475
A convenient synthetic route to enantiopure N-tosylazetidines
from a-amino acids
Manas K. Ghorai,* Kalpataru Das and Amit Kumar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 25 December 2006; revised 1 February 2007; accepted 9 February 2007
Available online 13 February 2007
Abstract—A general and convenient synthetic route to various chiral 2-substituted- and 2,4-disubstituted-N-tosylazetidines (ee
>99%) is described in good overall yields starting from chiral a-amino acids using very simple chemistry.
Ó 2007 Elsevier Ltd. All rights reserved.
Over the years, biologically active nitrogen-containing
molecules including a wide variety of natural products
have attracted the attention of organic chemists in order
to develop novel, synthetically useful and elegant meth-
odologies for the synthesis of such types of compound as
targets or designs for new drugs and important inter-
mediates in organic synthesis. Azetidines are an important
class of small ring heterocyclic compounds1 found in
many naturally occurring or synthetically important
organic molecules which exhibit interesting biological
and pharmacological properties.2,3 Moreover, enantiopure
azetidines have been successfully utilized as ligands,4
catalysts in various asymmetric syntheses5 and ring
opening reactions to prepare many important nitro-
gen-containing organic compounds.6 Recently, 2-substi-
tuted-N-tosylazetidines have been utilized as masked
1,4-dipoles for the construction of nitrogen-containing
six-membered heterocycles.7 In continuation of our
research activity in azetidine chemistry, we introduced
an alternative method for stereoselective nucleophilic
ring opening of 2-aryl-N-tosylazetidines.8 In order to
continue our mechanistic investigations on the chemis-
try of N-activated azetidines, we required a variety of
enantiopure N-tosylazetidines. Although several meth-
ods for the synthesis of chiral azetidines are known in
the literature,9 we report herein, a very simple, practical,
and general synthetic route to various chiral 2-substi-
tuted- and 2,4-disubstituted-N-tosylazetidines (ee >99%),
starting from easily available a-amino acids.
The reported method involves homologation of a-amino
acids to the corresponding b-amino acids or b-amino
aldehydes which are transformed into optically active
N-tosylazetidines by intramolecular N-heterocyclization
of the corresponding c-amino alcohols in good overall
yields (Scheme 1). Our strategy was further extended
to the syntheses of enantiopure 2,4-disubstituted-
N-tosylazetidines including 2-cyano-N-tosylazetidines.
The latter could be easily transformed into the corres-
ponding azetidine-2-carboxylic acid derivatives10 and
various chiral ligands.4b
Although, the Arndt–Eistert method could be used for
homologation of enantiopure a-amino acids to b-amino
acids,11 the occurrence of side reactions12 made this
strategy less promising for our purpose. In our approach
a-amino acids 1 were reduced to the corresponding
b-amino alcohols following a literature procedure13
(the latter could also be obtained commercially). Tosyla-
tion14 of the b-amino alcohols with 2 equiv of TsCl in
excess pyridine at ꢀ30 °C followed by treatment with
NaCN in DMSO at rt gave N-tosyl b-amino nitriles 2
in excellent yields. b-Amino nitriles 2 were hydrolyzed
to the corresponding acids 3 by treatment with 40% aq
NaOH under refluxing conditions. Subsequently, c-
amino alcohols 4 were obtained by reduction of 3 with
LiAlH4 in THF at room temperature. Finally, alcohols
4 were cyclized to the corresponding 2-substituted-N-
tosylazetidines 5 in excellent yields (>99% ee) by treat-
ment with TsCl and excess KOH in THF under reflux.15
Alternatively, the nitrile group of 2 was carefully
Keywords: Chiral substituted-N-tosylazetidine; 2-Cyano-N-tosylazeti-
dine; a-Amino acid; b-Amino acid; b-Amino aldehyde; Chiral cyano-
hydrin; Enantiopure.
*
Corresponding author. Tel.: +91 512 2597518; fax: +91 512
2597436; e-mail: mkghorai@iitk.ac.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.033

2472
M. K. Ghorai et al. / Tetrahedron Letters 48 (2007) 2471–2475
R
Ts
R
R
R
v
∗
vi
R
iv
i, ii
iii
∗
N
∗
∗
CO2H
TsHN
CH2OH
TsHN
CO2H
TsHN
CN
H2N
2
1
3
4
5
50-69% (overall
starting from 1)
viii
R
a: R = Me b: R = Ph c: R = Bn
vii
∗
i
d: R = iBu e: R = Pr
TsHN
CHO
6
Scheme 1. Synthesis of enantiopure 2-substituted-N-tosylazetidines from a-amino acids. Reagents and conditions: (i) NaBH4–I2, THF, 0 °C to
reflux, 18 h, 80–94%; (ii) TsCl, Py, 0 °C to ꢀ30 °C overnight, 90–95%; (iii) NaCN, DMSO, rt, 2 h, 90–95%; (iv) 40% NaOH, 110 °C, 12–15 h, 50%
H2SO4, 80–85%; (v) LAH, THF, 0 °C–rt, 1 h, 98%; (vi) TsCl/KOH, THF, reflux, 30 min, 98%; (vii) DIBAL-H, THF, ꢀ65 °C, 30 min, 85%; (viii)
NaBH4, MeOH, 0 °C–rt, 2 h, 90%.
reduced using DIBAL-H at ꢀ65 °C in THF to give the
corresponding b-amino aldehyde 6, which was further
reduced with NaBH4 in MeOH to the same c-amino
alcohol 4 (Scheme 1). The generalization of this strategy
for the synthesis of several chiral 2-substituted-N-tosyl-
azetidines (5a–e) starting from various a-amino acids
is shown in Table 1.
Grignard reaction to aldehyde 6 produced a diastereo-
meric mixture of c-amino alcohols 7 and 8 favoring
the syn diastereomer. The diastereomers were separated
through column chromatography leading to enantio-
pure 7 and 8. Intramolecular N-heterocyclization of 7
and 8 separately, using Mitsunobu’s protocol,16 afforded
the enantiopure 2,4-disubstituted-N-tosylazetidines17
and 10, respectively, in excellent yields (Table 2).
9
Next, structural diversity in the azetidine nucleus was
introduced by exploiting N-tosyl-b-amino aldehyde 6.
We envisioned that addition of a variety of nucleophiles
to aldehyde 6 obtained from b-amino nitriles 2, would
lead to diastereomeric mixtures of secondary c-amino
alcohols. Separation of the diastereomers followed by
stereoselective N-heterocyclization, would lead to enan-
tiopure 2,4-disubstituted-N-tosylazetidines. The pro-
posed strategy was realized as delineated in Scheme 2.
We anticipated that cyanohydrin formation from alde-
hyde 6 followed by cyclization would be a straightfor-
ward route to the corresponding cyano azetidines.
These cyanohydrins could then be utilized as precursors
in organic synthesis. When aldehyde 6 was treated with
NaCN and sodium metabisulfite in water for 10 min,18
cyanohydrins 11 and 12 were obtained as a diastereo-
meric mixture in excellent yield. After column chro-
Table 1. Synthesis of enantiopure 2-substituted N-tosylazetidines from a-amino acids
25
Entry
Amino acida
Azetidineb
Overall yieldc (%)
½aꢁD
Mp (°C)
H3C
Ts
Me
CO2H
H
N
1
50
+66.6
66
H2N
5a
Ph
Ts
N
Ph
H
CO2H
NH2
N
2
3
4
61
55
58
ꢀ310.7
+126
133
5b
Ts
Ts
CO2H
Ph
Ph
H2N
86–88
49
H
5c
CO2H
H
N
+130.2
H2N
5d
Ts
CO2H
N
5
69
+105
53–55
H
H2N
5e
a ee of amino acids were >99%.
b ee’s >99% determined by chiral HPLC.
c Overall yield starting from 1, after column chromatographic purification.
Ts
R
Ts
R
R
Ts
R
Ts
N
Ts
R
ii
iii
i
NH OH
NH OH
NH
O
N
*
*
*
*
R1
R1
*
*
*
*
R1
R1
H
major
6
7
8
9
10
R = Ph, Bn; R1 = Et,
n-Pr
Scheme 2. Synthesis of enantiopure 2,4-di-substituted N-tosylazetidines from a-amino acids. Reagents and conditions: (i) R1MgBr, THF, 0 °C–rt,
2 h; (ii) chromatographic separation of both diastereomers; (iii) PPh3, DIAD, THF, 0 °C–rt, 2 h. * Relative stereochemistry is shown.

M. K. Ghorai et al. / Tetrahedron Letters 48 (2007) 2471–2475
2473
Table 2. Synthesis of enantiopure 2,4-di-substituted N-tosylazetidines from a-amino acids
25
Amino acida
7:8b (% yield)c
Azetidined,e (% yield)c
½aꢁD
Mp (°C)
Ts
NH OH
R1
R
7 and 8
Ph
Ts
Et
Ph
Et
N
ꢀ125
ꢀ144
61
NH OH
Ts
7a
9a (88)
Ph
CO2H
NH2
1.36:1.00 (88)
H
Ph
Ts
Ph
Ts
Et
N
110
NH OH
Et
10a (95)
8a
Ph
Ts
Ph
Ts
n-Pr
N
ꢀ130
ꢀ157
45
NH OH
n-Pr
7b
9b (83)
Ph
CO2H
NH2
1.67:1.00 (72)
Ph
Ts
H
Ph
Ts
n-Pr
NH OH
N
112–114
n-Pr
8b
10b (87)
Bn
Ts
Et
N
Ph
Ph
+79
+47
—
NH OH
7c
Ts
Ts
Et
9cf (89)
CO2H
Ph
H2N
1.51:1.00 (85)
H
Bn
Ts
Et
N
102–104
NH OH
8c
Et
10c (96)
a ee of amino acids were >99%.
b Ratio determined by chiral HPLC and 1H NMR of the crude reaction mixture.
c Yield after column chromatographic purification.
d Stereochemistry determined by NOE.
e ee’s >99% determined by chiral HPLC.
f Liquid at room temperature.
matographic separation, the major anti diastereomer 12
was subjected to Mitsunobu conditions to afford cyano
azetidine 13 in 38–40% yield (Scheme 3). In all cases,
the cis/trans relationships of the substituents were con-
firmed by NOE experiments (Fig. 1).
H
H
H
H
Ts
Ts
N
N
Bn
Bn
9c
10c
Figure 1. Determination of the stereochemistry of 9c and 10c by NOE.
The stereochemical outcome in both nucleophilic addi-
tion reactions with aldehyde 6 (Schemes 2 and 3) is
rationalized in Scheme 4. During Grignard addition to
aldehyde 6, the major syn diastereomer 7 resulted prob-
ably due to the formation of six-membered chelate 14.
The poor diastereoselectivity in the Grignard addition
reaction can be explained by considering the reduced
electron availability of the sulfonamide nitrogen of 6.
In contrast, cyanohydrin formation from aldehyde 6,
is sterically controlled by the b-chiral center, leading to
the major anti diastereomer 12.
R
Ts
Ts
R
Ts
R
Ts
R
NH OH
NH OH
N
NH
O
i
ii
*
*
CN
*
*
CN
CN
*
*
H
iii
major
12
6
11
13
R = Ph, 11a : 12a = 1 : 1.27, Yield of (11a+12a) = 98%, Yield of 13a = 40%
R = Bn, 11b : 12b = 1 : 1.33, Yield of (11b+12b) = 98%, Yield of 13b = 38%
In conclusion, we have developed a promising and con-
cise route toward enantiopure substituted N-tosylazeti-
dines, starting from easily available a-amino acids.
Numerous activated azetidines could be synthesized in
enantiomerically pure form starting from the appropriate
Scheme 3. Synthesis of enantiopure substituted N-tosyl-cyanoazeti-
dines from a-amino acids. (i) NaCN, Na2S2O5, 0 °C–rt, 10 min; (ii)
separation of major diastereomer 12; (iii) 12 was subjected to PPh3,
DIAD, THF, 0 °C–rt, 2 h. * Relative stereochemistry is shown,
stereochemistry of 13 was confirmed by NOE.

2474
M. K. Ghorai et al. / Tetrahedron Letters 48 (2007) 2471–2475
Br R1
Mg
Suzuki, K.; Shimada, K.; Nozoe, S.; Tanzawa, K.; Ogita,
T. J. Antibiot. 1996, 49, 1284–1285.
4. (a) Shi, M.; Jiang, J. K. Tetrahedron: Asymmetry 1999, 10,
1673–1679; (b) Keller, L.; Sanchez, M. V.; Prim, D.;
Couty, F.; Evano, G.; Marrot, J. J. Organomet. Chem.
2005, 690, 2306–2311.
Ts
R
Ts
NH OH
R1
NH
O
R1MgBr
Ts
R
N
O
R
H
H
syn (major)
6
14
7
Ts
R
Ts
5. (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998,
37, 1986–2012; (b) Rao, A. V. R.; Gurjar, M. K.; Kaiwar,
V. Tetrahedron: Asymmetry 1992, 3, 859–862; (c) Yama-
guchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996,
61, 3520–3530; (d) Starmans, W. A. J.; Thijs, L.;
Zwanenburg, B. Tetrahedron 1998, 54, 629–636; (e)
Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de
Gelder, R.; Smits, J. M. M.; Zwanenburg, B. Tetrahedron
1998, 54, 4991–5004.
NaCN
NH
O
NH OH
No Chelation
Na2S2O5
H
R CN
anti (major)
6
12
Scheme 4. Rationale for the diastereoselectivity in the addition of
nucleophiles to chiral b-amino aldehyde 6.
6. (a) Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1994,
50, 5775–5782; (b) Akiyama, T.; Daidouji, K.; Fuchibe, K.
Org. Lett. 2003, 5, 3691–3693; (c) Vargas-Sanchez, M.;
Couty, F.; Evano, G.; Prim, D.; Marrot, J. Org. Lett.
2005, 7, 5861–5864; (d) Domostoj, M.; Ungureanu, I.;
Schoenfelder, A.; Klotz, P.; Mann, A. Tetrahedron Lett.
2006, 47, 2205–2208; (e) Van Brabandt, W.; Landeghem,
R. V.; De Kimpe, N. Org. Lett. 2006, 8, 1105–1108; (f)
Golding, P.; Millar, R. W.; Paul, N. C.; Richards, D. H.
Tetrahedron 1995, 51, 5073–5082; (g) Vanecko, J. A.;
West, F. G. Org. Lett. 2005, 7, 2949–2952.
amino acid precursors. The advantages of our method
include the use of inexpensive reagents, very simple
work-up conditions and excellent yields in each step.
Further applications of this methodology to construct
poly-functionalized N-activated azetidines and other
nitrogen-containing heterocyles are under investigation
in our laboratory.
Acknowledgements
7. (a) Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A.
Chem. Commun. 2001, 958–959; (b) Ungureanu, I.; Klotz,
P.; Schoenfelder, A.; Mann, A. Tetrahedron Lett. 2001, 42,
6087–6091; (c) Prasad, B. A. B.; Bisai, A.; Singh, V. K. Org.
Lett. 2004, 6, 4829–4831; (d) Yadav, V. K.; Sriramurthy, V.
J. Am. Chem. Soc. 2005, 127, 16366–16367.
M.K.G. is grateful to IIT-Kanpur and DST, India. K.
Das and A. Kumar thank IIT-Kanpur and CSIR, India,
respectively, for research fellowships.
8. Ghorai, M. K.; Das, K.; Kumar, A.; Das, A. Tetrahedron
Lett. 2006, 47, 5393–5397.
Supplementary data
9. (a) Couty, F.; Evano, G.; Prim, D. Minirev. Org. Chem.
2004, 1, 133–148, and references cited therein; (b) Hanes-
sian, S.; Bernstein, N.; Yang, R. Y.; Maguire, R. Bioorg.
Med. Chem. Lett. 1999, 9, 1437–1442; (c) Burtoloso, A. C.
B.; Correia, C. R. D. Tetrahedron Lett. 2004, 45, 3355–
3358; (d) Sajjadi, Z.; Lubell, W. D. J. Peptide Res. 2005,
65, 298–310; (e) Dieter, E.; Jo¨rg, G. Synthesis 2005, 20,
3508–3516; (f) Couty, F.; Evano, G.; Prim, D.; Marrot, J.
Eur. J. Org. Chem. 2004, 18, 3893–3897; (g) Mangales-
waran, S.; Couty, F.; Evano, G.; Srinivas, B.; Sridhar, R.;
Rao, K. R. Synlett 2006, 781–785; (h) Dieter, E.; Jo¨rg, G.;
Zin-Sig, K. Eur. J. Org. Chem. 2004, 21, 4471–4482; (i)
Burtoloso, A. C. B.; Correia, C. R. D. Synlett 2005, 1559–
1562; (j) Morimoto, H.; Wiedemann, S. H.; Yamaguchi,
A.; Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2006, 45, 3146–3150; (k) de
Figueiredo, R. M.; Fro¨hlich, R.; Christmann, M. J. Org.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.02.033.
References and notes
1. (a) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79,
331–358; (b) Moore, J. A.; Ayers, R. S. In Chemistry of
Heterocyclic Compounds-Small Ring Heterocycles; Hass-
ner, 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.; Pergamon: Oxford, 1984;
Vol. 7, Part 5, pp 237–284; (d) De Kimpe, N. Three- and
Four-Membered Rings, With All Fused Systems Contain-
ing Three- and Four-Membered Rings. In Comprehensive
Heterocyclic Chemistry II; Padwa, A., Ed.; Elsevier:
Oxford, 1996; Vol. 1, Chapter 1.21.
´
Chem. 2006, 71, 4147–4154; (l) de Talance, V. L.; Banide,
E.; Bertin, B.; Comesse, S.; Kadouri-Puchot, C. Tetra-
hedron Lett. 2005, 46, 8023–8025.
10. Couty, F.; Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J.
Org. Chem. 2005, 70, 9028–9031, and references cited
therein.
11. (a) Cole, D. C. Tetrahedron 1994, 50, 9517–9582; (b) Ye,
T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160;
(c) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991–8035;
(d) Vasanthakumar, G. R.; Patil, B. S.; Babu, V. V. S.
J. Chem. Soc., Perkin Trans. 1 2002, 2087–2089, and
references cited therein.
2. (a) Fowden, L. Nature 1955, 176, 347–348; (b) Ohfune, Y.;
Tomita, M.; Nomoto, K. J. Am. Chem. Soc. 1981, 103,
2409–2410; (c) Kinoshita, E.; Yamakoshi, J.; Kikuchi, M.
Biosci. Biotechnol. Biochem. 1993, 57, 1107–1110; (d) Liu,
D. G.; Lin, G. Q. Tetrahedron Lett. 1999, 40, 337–340; (e)
Yoda, H.; Uemura, T.; Takabe, K. Tetrahedron Lett.
2003, 44, 977–979; (f) Cheng, Q.; Kiyota, H.; Yamaguchi,
M.; Horiguchi, T.; Oritani, T. Bioorg. Med. Chem. Lett.
2003, 13, 1075–1077; (g) Singh, S.; Crossley, G.; Ghosal,
S.; Lefievre, Y.; Pennington, M. W. Tetrahedron Lett.
2005, 46, 1419–1421.
´
12. Plucinska, K.; Liberek, B. Tetrahedron 1987, 43, 3509–
3517.
13. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M.
J. Org. Chem. 1993, 58, 3568–3571.
14. Cernerud, M.; Adolfsson, H.; Moberg, C. Tetrahedron:
Asymmetry 1997, 8, 2655–2662.
3. (a) Bannon, A. W.; Decker, M. W.; Holladay, M. W.;
Curzon, P.; Donnelly-Roberts, D.; Puttfarcken, P. S.;
Bitner, R. S.; Diaz, A.; Dickenson, A. H.; Porsolt, R. D.;
Williams, M.; Arneric, S. P. Science 1998, 279, 77–81; (b)

M. K. Ghorai et al. / Tetrahedron Letters 48 (2007) 2471–2475
2475
15. Representative procedure for the synthesis of substituted
N-tosylazetidine 5 from 4: To a suspension of powdered
KOH (21.3 mmol, 3 equiv) in 10.0 mL dry THF, a
solution of 4 (7.1 mmol, 1.0 equiv) in 25.0 mL dry THF
was added. Then TsCl (7.8 mmol, 1.1 equiv) was added
portionwise at room temperature and the reaction mixture
was refluxed for 30 min. After completion of the reaction,
cold water was added and the reaction mixture was
extracted with ethyl acetate twice. The combined organic
layer was washed with brine, dried over anhydrous sodium
sulfate and the solvent was removed under reduced
pressure. The crude azetidine was purified by column
chromatography on silica gel using ethyl acetate and
petroleum ether as the eluent.
had been consumed. Next, 0.5 mmol of aldehyde 6,
dissolved in 1.0 ml of THF, was added dropwise at 0 °C
and the reaction was continued for another 1.5 h at rt. The
reaction was quenched by dropwise addition of saturated
aq NH4Cl solution at 0 °C. The crude reaction mixture
was extracted with ethyl acetate, the organic layer washed
with brine, dried over anhydrous sodium sulfate and the
solvent removed under reduced pressure. After column
chromatographic purification, both diastereomers were
obtained in the yields reported in Table 2. Both diaste-
reomers 7 and 8 were cyclized separately under Mitsunobu
conditions (1.5 equiv DIAD, 1.5 equiv PPh3, THF, 2 h) to
afford 9 and 10, respectively, in the yields reported.
(2R,4R)-2-Benzyl-4-ethyl-1-tosylazetidine (9c): Liquid; Rf
0.39 (20% ethyl acetate in petroleum ether); 1H NMR
(400 MHz, CDCl3) d: 0.66 (t, J = 7.6 Hz, 3H), 1.35–1.43
(m, 1H), 1.66–1.73 (m, 1H); 1.86–1.97 (m, 2H), 2.37 (s,
3H), 2.70 (dd, J = 13.4, 10.5 Hz, 1H), 3.29 (dd, J = 13.4,
3.9 Hz, 1H), 4.04–4.08 (m, 1H), 4.29–4.33 (m, 1H), 7.06–
7.25 (m, 7H), 7.69 (d, J = 8.3 Hz, 2H); 13C NMR (CDCl3,
100 MHz) d: 8.3, 21.5, 26.4, 27.2, 40.2, 62.7, 63.6, 126.6,
(S)-2-Phenyl-1-tosylazetidine (5b): White solid; mp 133 °C;
Rf 0.28 (EtOAc:petroleum ether, 1:4), 1H NMR (400 MHz,
CDCl3): d 2.08–2.18 (m, 1H), 2.20–2.28 (m, 1H), 2.36 ( s,
3H); 3.64–3.75 (m, 2H), 4.80 (t, J = 8.3 Hz, 1H), 7.19–7.35
(m, 7H), 7.61 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d 21.6, 25.8, 47.2, 65.6, 126.3, 127.9, 128.4, 128.5,
129.6, 132.1, 140.5, 143.9; ESI-MS m/z = 288 (M++1).
Anal. Calcd (%) for C16H17NO2S: C, 66.87; H, 5.96; N,
127.4, 128.5, 129.3, 129.6, 136.7, 137.9, 143.2; IR (cmꢀ1
,
25
4.87. Found (%): C, 66.64; H, 5.98; N, 5.09. ½aꢁD ꢀ310.7 (c
neat) 3060, 3028, 2963, 2928, 2877, 1599, 1495, 1455, 1337,
1154, 1095, 1022, 816, 736, 704, 672, 633, 606, 549, 499;
Anal. Calcd (%) for C19H23NO2S: C, 69.27; H, 7.04; N,
0.204 g/100 mL, CHCl3), with >99% ee.
(S)-2-Isobutyl-1-tosylazetidine (5d): White solid; mp 49 °C;
Rf 0.39 (EtOAc:petroleum ether, 1:4), 1H NMR (400 MHz,
CDCl3): d 0.79 (d, J = 6.4 Hz, 3H), 0.81 (d, J = 6.4 Hz,
3H), 1.49–1.57 (m, 2H), 1.75–1.92 (m, 3H), 2.39 (s, 3H),
3.43 (q, J = 8.8 Hz, 1H), 3.58–3.63 (m, 1H), 3.77–3.84 (m,
25
4.25. Found (%): C, 69.31; H, 7.15; N, 4.32. ½aꢁD +79 (c
0.41 g/100 mL, CHCl3), with >99% ee.
(2R,4S)-2-Benzyl-4-ethyl-1-tosylazetidine (10c): White
solid; mp 102–104 °C; Rf 0.43 (20% ethyl acetate in
1H), 7.30 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H); 13
C
petroleum ether); H NMR (400 MHz, CDCl3) d: 0.70 (t,
1
NMR (100 MHz, CDCl3): d 21.5, 22.4, 22.9, 23.5, 24.6,
45.4, 47.7, 63.2, 128.3, 129.6, 131.8, 143.8; Anal. Calcd (%)
for C14H21NO2S: C, 62.89; H, 7.92; N, 5.24. Found (%): C,
J = 7.3 Hz, 3H), 1.41–1.55 (m, 2H), 1.62–1.69 (m, 1H);
1.81–1.88 (m, 1H), 2.38 (s, 3H), 2.89 (dd, J = 13.7, 9.0 Hz,
1H), 3.06 (dd, J = 13.7, 3.6 Hz, 1H), 3.45–3.52 (m, 1H),
3.73–3.80 (m, 1H), 7.09–7.31 (m, 7H), 7.67 (d, J = 8.3 Hz,
2H); 13C NMR (CDCl3, 100 MHz) d: 8.3, 21.6, 27.3, 28.6,
42.0, 60.4, 61.6, 126.5, 128.2, 128.3, 129.5, 129.7, 132.4,
136.6, 143.8; IR (cmꢀ1, neat) 3057, 3029, 2960, 2899, 2871,
1599, 1496, 1454, 1385, 1340, 1259, 1223, 1153, 1091, 1049,
1022, 941, 807, 766, 740, 699, 665, 602, 549, 500; Anal.
Calcd (%) for C19H23NO2S: C, 69.27; H, 7.04; N, 4.25.
25
62.75; H, 7.76; N, 5.41. ½aꢁD 130.2 (c 0.205 g/100 mL,
CHCl3), with >99% ee.
16. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Cyclization
with TsCl/KOH was also found to be equally efficient in
all cases except for 13a and 13b.
17. Representative procedure for the synthesis of 9 and 10: In
a
typical procedure, 2.0 mmol of bromoethane was
25
dissolved in 2.0 mL of dry THF and a quarter of this
solution was added dropwise to 2.0 mmol of Mg turnings
(suspended in 1.0 mL of THF in the presence of a crystal
of iodine) at ice-cold temperature. After disappearance of
the yellow color, the rest of the bromoethane solution was
added dropwise. Stirring was continued until all the Mg
Found (%): C, 69.33; H, 7.28; N, 4.33. ½aꢁD +47 (c 0.42 g/
100 mL, CHCl3) with >99% ee.
18. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.;
Revised by Furniss, B. S.; Hannaford, A. J.; Smith, P. W.
G.; Tatchell, A. R. Longman Group, UK Ltd., 1989; pp
729–730.