Lewis acid-mediated highly regioselective SN2-type ring-opening of 2-Aryl-N-tosylazetidines and aziridines by alcohols

Article abstract of DOI:10.1021/jo0703294

(Chemical Equation Presented) Lewis acid-mediated highly regioselective S_N2-type ring-opening of 2-aryl-N-tosylazetidines with alcohols to afford various 1,3-amino ethers in excellent yields with good enantiomeric excess is described. Similar S

Full text of DOI:10.1021/jo0703294

formation of nonracemic products.4 We anticipated LA-mediated
ring-opening of aziridines and azetidines to follow SN2 pathways
which would enable the design of enantioselective ring-opening
reactions of chiral aziridines and azetidines toward enantiopure
targets.
Lewis Acid-Mediated Highly Regioselective
SN2-Type Ring-Opening of
2-Aryl-N-tosylazetidines and Aziridines by
Alcohols
During our synthetic and mechanistic investigations on LA-
mediated ring-opening of azetidines, we have developed an
efficient strategy for nucleophilic ring-opening of 2-aryl-N-
sulfonylazetidines followed by (i) a novel rearrangement to
allylamines5a and (ii) [4 + 2] cycloaddition with carbonyl
compounds to nonracemic 1,3-oxazinanes.5b Our observations
provide convincing evidence that the rearrangement or the
cycloaddition proceeds through an SN2-type pathway, instead
of a 1,4-dipole as invoked earlier.2e-g We have also demon-
strated the ring-opening of chiral 2-phenyl-N-tosylaziridine
followed by cycloaddition with carbonyl compounds to give a
variety of nonracemic 1,3-oxazolidines Via an SN2-type pathway.5c
To rule out the SN1 pathway through the intermediacy of a stable
1,4-dipole, the nucleophilic ring-opening of 2-aryl-N-tosylaze-
tidines 1 in polar and protic alcohol (methyl, benzyl, propargyl,
etc.) medium was studied where the solvent served as the
nucleophile. We report, herein, an expedient approach for a
direct access to nonracemic 1,3-amino ethers with excellent
yields and high ee (up to 90%) by the regioselective nucleophilic
ring-opening of chiral 2-phenyl-N-tosylazetidine with alcohols.
Biologically active amino ethers of general structure 2 (Figure
1) are widely used for the treatment of anxiety and depression
and their analogues belong to a class of potent and selective
serotonin and norepinephrin reuptake inhibitors.6-9
Manas K. Ghorai,* Kalpataru Das, and Dipti Shukla
Department of Chemistry, Indian Institute of Technology,
Kanpur, 208016, India
mkghorai@iitk.ac.in
ReceiVed March 6, 2007
Lewis acid-mediated highly regioselective SN2-type ring-
opening of 2-aryl-N-tosylazetidines with alcohols to afford
various 1,3-amino ethers in excellent yields with good
enantiomeric excess is described. Similar SN2-type ring-
opening of chiral 2-phenyl-N-tosylaziridine with various
alcohols produces the corresponding nonracemic 1,2-amino
ethers in excellent yields and good ee. The mechanism of
the ring-opening of aziridines and azetidines Via an SN2
pathway is supported by the formation of nonracemic amino
ethers.
Although few reports are available in the literature for the
synthesis of 1,3-amino ethers,10 there is no report for the
synthesis of these amino ethers Via LA-mediated nucleophilic
ring-opening of 2-aryl-N-tosylazetidines with alcohols. Chiral
1,2-amino ethers as essential fragments in many glycopeptide
antibiotics11 and ether-containing peptide bond surrogate units12
are important for several biological processes. Alkoxide- or
Aziridines and azetidines are valuable building blocks in
organic synthesis because of their ability to undergo ring-
opening,1 cycloaddition,2 and fragmentation3 reactions. We have
recently reported Lewis acid (LA)-mediated nucleophilic ring-
opening and cycloaddition of 2-aryl-N-tosylazetidines and
aziridines to provide nonracemic products, and a mechanism
was proposed Via an SN2-type pathway to rationalize the
(2) For cycloaddition of aziridines: (a) Concello´n, J. M.; Riego, E.;
Sua´rez, J. R.; Garc´ıa-Granda, S.; D´ıaz, M. R. Org. Lett. 2004, 6, 4499-
4501. (b) Zhu, W.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 5545-5548. (c)
Ghorai, M. K.; Ghosh, K.; Das, K. Tetrahedron Lett. 2006, 47, 5399-
5403 and references cited therein. For cycloaddition of azetidines: (d)
Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A. Chem. Commun. 2001,
958-959. (e) Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A.
Tetrahedron Lett. 2001, 42, 6087-6091. (f) Prasad, B. A. B.; Bisai, A.;
Singh, V. K. Org. Lett. 2004, 6, 4829-4831. (g) Yadav, V. K.; Sriramurthy,
V. J. Am. Chem. Soc. 2005, 127, 16366-16367. (h) Baeg, J. O.; Bensimon,
C.; Alper, H. J. Org. Chem. 1995, 60, 253-256. (i) Baeg, J. O.; Bensimon,
C.; Alper, H. Ibid. 1995, 60, 3092-3095.
(3) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Salgado, N. R. J. Org.
Chem. 1999, 64, 9596-9604 and the referrences cited therein.
(4) (a) Ghorai, M. K.; Das, K.; Kumar, A.; Ghosh, K. Tetrahedron Lett.
2005, 46, 4103-4106. (b) Ghorai, M. K.; Das, K.; Kumar, A.; Das, A.
Tetrahedron Lett. 2006, 47, 5393-5397. (c) Ghorai, M. K.; Ghosh, K.:
Das, K. Tetrahedron Lett. 2006, 47, 5399-5403.
(5) (a) Ghorai, M. K.; Kumar, A.; Das, K. Unpublished results. (b)
Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, doi: 10.1016/
j.tetlet.2007.04.097. (c) Ghorai, M. K.; Ghosh, K. Tetrahedron Lett. 2007,
48, 3191-3195.
(6) Robertson, D. W.; Jones, N. D.; Swartzendruber, J. K.; Yang, K. S.;
Wong, D. T. J. Med. Chem. 1988, 31, 185-189 and references cited therein.
(7) Silver, H. Int. Clin. Psychopharm. 2003, 18, 305-313.
(8) Wong, D. T.; Bymaster, F. P.; Engleman, E. A. Life Sci. 1995, 57,
411-441.
(9) Chouinard, G.; Annable, L.; Bradwejn, J. Psychopharmacology 1984,
83, 126-128.
* To whom correspondence should be addressed. Tel: +91-512-2597518;
Fax: +91-512-2597436.
(1) For ring opening of aziridines: (a) Hu, X. E. Tetrahedron 2004, 60,
2701-2743 and references cited therein. (b) Minakata, S.; Okada, Y.;
Oderaotoshi, Y.; Komatsu, M. Org. Lett. 2005, 7, 3509-3512. (c) Ding,
C. H.; Dai, L. X.; Hou, X. L. Tetrahedron 2005, 61, 9586-9593. (d)
Pineschi, M.; Bertolini, F.; Haak, R. M.; Crotti, P.; Macchia, F. Chem.
Commun. 2005, 1426-1428. (e) Minakata, S.; Hotta, T.; Oderaotoshi, Y.;
Komatsu, M. J. Org. Chem. 2006, 71, 7471-7472. (f) Fukuta, Y.; Mita,
T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
6312-6313. (g) De Kimpe, N. Three- and Four-Membered Rings, With
All Fused Systems Containing Three- and Four-Membered Rings. In
ComprehensiVe Heterocyclic Chemistry II; Padwa, A., Ed.; Elsevier: Oxford
1996; Vol. 1, Chapter 1.21. For ring opening of azetidines: (h) Almena,
J.; Foubelo, F.; Yus, M. Tetrahedron 1994, 50, 5775-5782. (i) Akiyama,
T.; Daidouji, K.; Fuchibe, K. Org. Lett. 2003, 5, 3691-3693. (j) Vargas-
Sanchez, M.; Couty, F.; Evano, G.; Prim, D.; Marrot, J. Org. Lett. 2005, 7,
5861-5864. (k) Domostoj, M.; Ungureanu, I.; Schoenfelder, A.; Klotz, P.;
Mann, A. Tetrahedron Lett. 2006, 47, 2205-2208. (l) Van Brabandt, W.;
Van Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8, 1105-1108. (m)
Golding, P; Millar, R. W.; Paul, N. C.; Richards, D. H. Tetrahedron 1995,
51, 5073-5082. (n) Vanecko, J. A.; West, F. G. Org. Lett. 2005, 7, 2949-
2952.
10.1021/jo0703294 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/26/2007
J. Org. Chem. 2007, 72, 5859-5862
5859

TABLE 1. Cu(OTf)2-Mediated Regioselective Nucleophilic
Ring-Opening of 2-Phenyl-N-tosylazetidine with Alcoholsa
FIGURE 1. Representative biologically active amino ethers.
SCHEME 1. Lewis Acid-Mediated Regioselective
Nucleophilic Ring-Opening of 2-Aryl-N-tosylazetidines with
Alcohols
Bronsted acid-mediated alcoholyses of aziridines has been
reported by Stamm et al. where a borderline SN2-type mecha-
nism was mentioned.13a Similar opening of N-nosyl aziridine13b
by MeOH is reported by Maligres et al. There are few reports
known for KSF clay13c or LA-mediated13d ring-opening of
aziridines with alcohols to racemic 1,2-amino ethers without
illustrating proper mechanism of the reaction.13c,d Some amino
ethers prepared from other methods have been effectively used
as chiral ligands for asymmetric transformations.14 In this article,
we describe a direct route to nonracemic 1,2-amino ethers (up
to 92% ee) by LA-mediated regioselective nucleophilic ring-
opening of chiral 2-phenyl-N-tosylaziridine 5 with alcohols Via
an SN2 pathway.
Our study began with the ring-opening of enantiomerically
pure (S)-2-phenyl-N-tosylazetidine 1A (ee >99%)15 in polar
protic solvents, such as various alcohols. When (S)-1A was
treated with MeOH in the presence of LA, to our great pleasure,
we observed the formation of nonracemic 1,3-amino ether 3a
in good yield with excellent ee (86-90%) (Scheme 1). Ring-
opening of 1A with MeOH in the presence of Cu(OTf)2 was
a In all the cases the alcohol served as the solvent. b Yield of isolated
product after column chromatographic purification. c Determined by chiral
HPLC. d 90% ee was obtained at 40 °C. e At 0 °C reaction was completed
i
in 10 min and 76% ee was obtained. f 20% CH2Cl2 in PrOH was used as
the solvent.
found to be highly regioselective and only one regioisomer 3a
was formed as indicated by the 1H NMR of the crude reaction
mixture.
Formation of the other regioisomer 4a from the terminal
attack of 1A was not observed. To demonstrate the general value
of this strategy, ring-opening of (S)-1A was studied with a
number of alcohols (allyl, benzyl, propargyl, etc.), and the results
are summarized in Table 1. (S)-1A gave ring opened product
3c in 91% yield with 76% ee within 10 min at 0 °C when
propargyl alcohol was used in the presence of Cu(OTf)2. The
reaction time was reduced to 5 min for the same reaction
performed in CH2Cl2 as the solvent with 5 equiv of the alcohol;
however, the enantioselectivity was found to be poor (ee 44%).
A little variation of ee was observed when BF3·OEt2 or Zn-
(OTf)2 was used as the LA. 1A was found to be less reactive
with secondary alcohol (iPrOH) and a reduced yield of the
corresponding amino ether 3e was obtained at ambient temper-
ature. Under similar reaction conditions, more sterically crowded
tbutyl alcohol failed to give any ring-opening product with 1A.
The reaction did not proceed well with catalytic amount (0.3
equiv) of LA and 1 equiv of catalyst was required for completion
of the reaction. To broaden the scope of this strategy, the ring-
opening of a number of substituted N-tosylazetidines 1B-E with
various alcohols was studied, and the corresponding 1,3-amino
ethers 3f-m were obtained in excellent yields (Table 2).
Azetidines 1D,E (entries 7, 8, Table-2) reacted slowly with
propargyl alcohol in comparison with 1A-C (entry 3 Table 1
and entries 1, 5, Table 2). All azetidines reacted faster with
propargyl and benzyl alcohols compared to other alcohols.
However, 2-benzyl-N-tosylazetidine reacted slowly (10 h) with
propargyl alcohol to produce 4-phenyl-3-(prop-2-ynyloxy)-N-
tosylbutan-1-amine in 51% yield.16 The reaction was found to
be more facile in CH2Cl2 instead of alcohols serving as the
solvent. Using o-cresol in CH2Cl2, 1A furnished regioisomers
3i and 4i in a 1:1 ratio. The formation of other regioisomer 4i
can be ascribed to the steric repulsion caused by methyl group
in o-cresol during nucleophilic attack at benzylic position.
(10) (a) Li, Y.; Li, Z.; Li, F.; Wang, Q.; Tao, F. Org. Bimol. Chem.
2005, 3, 2513-2518. (b) Watanabe, M.; Murata, K.; Ikariya, T. J. Org.
Chem. 2002, 67, 1712-1715. (c) O’Brien, P.; Phillips, D. W.; Towers, T.
D. Tetrahedron Lett. 2002, 43, 7333-7335. (d) Kumar, P.; Upadhyay, R.
K.; Pandey, R. K. Tetrahedron: Asymmetry 2004, 15, 3955-3959. (e)
Kamal, A.; Khanna, G. B. R.; Ramu, R. Tetrahedron: Asymmetry 2002,
13, 2039-2051. (f) Bhandari, K.; Srivastava, S.; Shanker, G.; Nath, C.
Bioorg. Med. Chem. 2005, 13, 1739-1747.
(11) Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J. H.; Rogel, O.; Castle,
S. L.; McAtee, J. J. J. Am. Chem. Soc. 2001, 123, 1862-1871 and references
cited there in.
(12) Ho, M.; Chung, J. K. K.; Tang, N. Tetrahedron Lett. 1993, 34,
6513-6516.
(13) (a) Bucholz, B.; Stamm, H. Isr. J. Chem. 1986, 27, 17-23. (b)
Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett.
1997, 38, 5253-5256. (c) Yadav, J. S.; Reddy, B. V. S.; Balanarsaiah, E.;
Raghavendra, S. Tetrahedron Lett. 2002, 43, 5105-5107. (d) Prasad, B.
A. B.; Sanghi, R.; Singh, V, K. Tetrahedron 2002, 58, 7355-7363.
(14) (a) Hodgson, D. M.; Sˇtefane, B.; Miles, T. J.; Witherington, J.
Chem. Commun. 2004, 2234-2235. (b) Furth, P. S.; Reitman, M. S.;
Gentles, R.; Cook, A. F. Tetrahedron Lett. 1997, 38, 6643-6646. (c) Sott,
R.; Granander, J.; Hilmersson, G. J. Am. Chem. Soc. 2004, 126, 6798-
6805. (d) Ram´ırez, A.; Lobkovsky, E.; Collum, D. B.; J. Am. Chem. Soc.
2003, 125, 15376-15387. (e) Okuda, M.; Tomioka, K. Tetrahedron Lett.
1994, 35, 4585-4586. (e) Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K.
Tetrahedron: Asymmetry 1993, 4, 1603-1606. (f) Periasamy, M.; Seenivas-
aperumal, M.; Rao, V. D. Tetrahedron: Asymmetry 2004, 15, 3847-3852.
(g) Aravind, A.; Mohanty, S. K.; Pratap, T. V.; Baskaran, S. Tetrahedron
Lett. 2005, 46, 2965-2968.
(15) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48,
2471-2475.
(16) Details are provided in the Supporting Information.
5860 J. Org. Chem., Vol. 72, No. 15, 2007

TABLE 2. Cu(OTf)2-mediated Nucleophilic Ring-Opening of
TABLE 3. Cu(OTf)2-Mediated Regioselective Nucleophilic
Racemic 2-Aryl-N-tosylazetidines with Alcoholsa
Ring-Opening of 2-Phenyl-N-tosylaziridine with Alcoholsa
a In all the cases the alcohol served as the solvent. b Yield of isolated
product after column chromatographic purification. c Determined by chiral
HPLC. d Nonracemic 6b is inseparable in both AD and OD HPLC columns.
SCHEME 3. Mechanism for the LA-Mediated
Ring-Opening of 2-Phenyl-N-tosylazetidines and Aziridine
with Alcohols
a In all the cases CH2Cl2 served as the solvent. b Yield of isolated product
after column chromatographic purification. c Determined by 1H NMR.
d Additionally 30% of 4i were received.
SCHEME 2. LA-Mediated Regioselective Nucleophilic
Ring-Opening of (R)-5 with Alcohols
configuration of 1,2-amino ether 6a was ascertained.18 On the
basis of the above facts, we suggest that the ring-opening of
chiral 2-phenyl-N-tosylazetidine and aziridine with alcohols
proceeds Via an SN2 pathway as depicted in Scheme 3. LA is
coordinated to the azetidine 1 (n ) 2) or aziridine 5 (n ) 1)
nitrogen, generating a highly reactive species 8, which undergoes
nucleophilic attack by alcohols in an SN2 fashion to provide
nonracemic 3 or 6, respectively.
It is clear that the reaction does not proceed through a stable
benzylic carbocation intermediate 9 from which a racemic
product could be expected either from enantiomerically pure
(S)-1A or (R)-5. We rationalized that the reduced enantiose-
lectivity in all the cases was due to partial racemization of
starting azetidine or aziridine (through the interconversion of
1/5 and 9) before the nucleophilic ring-opening step as shown
in Scheme 3. This mechanistic proposal is supported by the
formation of racemized amino ether 4i (38-54% ee) from the
reaction of (S)-1A with varying amount of o-cresol in CH2Cl2
where enantiomerically pure 4i could be expected from enan-
tiomerically pure (S)-1A (Scheme 4). Furthermore, (S)-1A was
found to be racemized in the presence of Cu(OTf)2 without any
nucleophile.16
After successful demonstration of the strategy for the ring-
opening of azetidines, we envisaged that a straightforward
approach to nonracemic 1,2-amino ethers 6 would be realized
by the ring-opening of enantiomerically pure (R)-2-phenyl-N-
tosylaziridine 5 (ee >99%) with alcohols in the presence of
LA (Scheme 2). We have studied the ring-opening of (R)-5 with
various alcohols, and in all the cases corresponding amino ethers
6 were obtained in high yields with good to excellent ee (Table
3). When (R)-2-phenyl-N-nosylaziridine (>99% ee) was reacted
with methanol, the reaction was completed in 2.5 h to produce
the corresponding amino ether in 91% yield with 94% ee.16 The
nucleophilic ring-opening of 2-phenyl-N-tosylaziridines with
alcohols was found to be more facile compared to 2-phenyl-
N-tosylazetidines. This is probably because of more inherent
strain present in the aziridine nucleus in comparison with
azetidine.
The full mechanistic interpretations for the ring-opening of
optically active (S)-2-phenyl-N-tosylazetidine 1A and (R)-2-
phenyl-N-tosylaziridine 5 with alcohols Via SN2 pathways have
been firmly established by the generation of nonracemic amino
ethers (3a and 6a, respectively) with inverted absolute configu-
rations. In order to determine the absolute configuration of the
major enantiomer of 3a obtained from the nucleophilic ring-
opening of (S)-1A with MeOH, it was converted into (R)-3-
methoxy-N-methyl-3-phenyl-N-tosylpropan-1-amine and its ab-
solute configuration was assigned by comparing optical rotation
and chiral HPLC analysis with an authentic sample17 prepared
from (S)-mandelic acid with ee >99%. Similarly, the absolute
(17) The absolute configuration of 1,3-amino ether prepared from (S)-
mandelic acid and that obtained from (S)-2-phenyl-N-tosylazetidine is the
same. Details of the preparation of authentic compound are provided in the
Supporting Information.
(18) The absolute stereochemistry for the major enantiomer of 6a was
determined by compairing optical rotation and chiral HPLC analysis of an
authentic compound (ee 98%) prepared from (S)-mandelic acid (ee > 99%).
The absolute configuration of 1,2-amino ether prepared from (S)-mandelic
acid and that obtained from (R)-2-phenyl-N-tosylaziridine is the same.
Details of the preparation of authentic compound for (S)-6a is provided in
the Supporting Information.
J. Org. Chem, Vol. 72, No. 15, 2007 5861

SCHEME 4. LA-Mediated Ring-Opening of (S)-1A with
o-Cresol
OD-H column), hexane-2-propanol, 90:10; flow rate ) 1.0 mL/
min; TR(1): 18.12 min (major), TR(2): 23.84 min (minor). Rf 0.28
(EtOAc:petroleum ether, 3:7); IR νmax (film, cm-1) 3286, 2923,
2856, 2117, 1598, 1325, 1159, 1091, 813,702, 634; 1H NMR (400
MHz, CDCl3): δ 7.69 (d, 2H, J ) 8.0 Hz), 7.26-7.19 (m, 5H),
7.10 (dd, 2H, J ) 7.3, 1.2 Hz), 5.03 (t, 1H, J ) 5.9 Hz), 4.48 (dd,
1H, J ) 9.0, 4.4 Hz), 4.02 (dd, 1H, J ) 15.9, 2.4 Hz), 3.70 (dd,
1H, J ) 15.9, 2.2 Hz), 3.11-3.06 (m, 1H), 3.05-2.96 (m, 1H),
2.37 (s, 3H), 2.36-2.35 (m, 1H), 1.83-1.74 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 143.2, 139.9, 136.9, 129.6, 128.6, 128.2,
127.1, 126.5, 79.6, 79.1, 74.7, 55.5, 40.7, 36.8. 21.5, ESI-MS m/z
) 344 (M+ + 1); Anal. Calcd (%) for C19H21NO3S: C, 66.45; H,
6.16; N, 4.08; Found (%) C, 66.39; H, 6.29; N, 4.29.
In conclusion, we have demonstrated that the nucleophilic
ring-opening of 2-aryl-N-tosylazetidines or aziridines does
proceed through an SN2 pathway instead of a stable 1,4- or 1,3-
dipolar intermediate, respectively. We report a direct synthesis
of optically active 1,3- and 1,2-amino ethers from enantiopure
N-tosylazetidine and aziridine, respectively. Utilizing this ap-
proach, biologically active amino ether precursors could be
obtained easily. Further applications of this methodology are
under investigation in our laboratory.
(S)-2-Methoxy-2-phenyl-N-tosylethanamine (6a). The general
method A described above was followed when (R)-5 reacted with
MeOH to afford 6a as a white solid in 82% yield, mp 105 °C;
25
[R]D +89.8 (c 0.345 in CHCl3) for a 92% ee sample. Optical
purity was determined by chiral HPLC analysis (Chiralcel AD-H
column), hexane-2-propanol, 95:5; flow rate ) 1.0 mL/min; TR-
(1): 26.04 min (minor), TR(2): 28.08 min (major). Rf 0.34 (EtOAc:
petroleum ether, 3:7); IR νmax (KBr, cm-1) 3284, 2910, 2820, 1600,
Experimental Section
General Procedure for the Cu(OTf)2-Mediated Ring-Opening
of 2-Aryl-N-tosylazetidine and -aziridine with Alcohols (method
A). A solution of the azetidine (0.087 mmol, 1.0 equiv) or azirdine
(0.091 mmol, 1.0 equiv) in 1.0 mL of alcohol was added to
anhydrous Cu(OTf)2 (1.0 equiv) at an appropriate temperature under
an argon atmosphere. The mixture was stirred for an appropriate
time (Table 1/Table 3), and then the reaction was quenched with
saturated aqueous NaHCO3 solution. The aqueous layer was
extracted with CH2Cl2 (3 × 5.0 mL) and dried over anhydrous Na2-
SO4. The crude product was purified by flash column chromatog-
raphy on silica gel (230-400 mesh) using 15% ethyl acetate in
petroleum ether to provide the pure nonracemic products. Important
note: In CH2Cl2 reaction was completed in a shorter time with
better yields; however, the enantioselectivity was reduced. General
experimental method B is described in the Supporting Information.
(R)-3-Phenyl-3-(prop-2-ynyloxy)-N-tosylpropan-1-amine (3c).
The general method A described above was followed when (S)-
1A reacted with propargyl alcohol to afford 3c as a dense liquid in
91% yield; [R]D25 +67.5 (c 0.126 in CHCl3) for a 76% ee sample
(ee 82% when the reaction was performed at -25 °C for 1.5 h).
Optical purity was determined by chiral HPLC analysis (Chiralcel
1
1448, 1321, 1160, 1074, 900, 812, 761, 700, 548; H NMR (400
MHz, CDCl3): δ 7.70 (d, 2H, J ) 8.3 Hz), 7.34-7.17 (m, 7H),
4.94 (br m, 1H, NH), 4.17 (dd, 1H, J ) 9.3, 3.7 Hz), 3.21-3.16
(m, 1H), 3.15 (s, 3H), 2.95-2.89 (m, 1H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 143.4, 138.2, 136.8, 129.8, 128.6, 128.4,
127.0, 126.5, 82.4, 56.8, 49.3, 21.5; Anal. Calcd (%) for C16H19-
NO3S: C, 62.93; H, 6.27; N, 4.59; Found (%) C, 62.65; H, 6.19;
N, 4.55.
Acknowledgment. M.K.G. is grateful to IIT-Kanpur and
DST, India. K. Das and D. Shukla thank IIT-Kanpur, India, for
research fellowships.
Supporting Information Available: General experimental
1
procedures, spectroscopic data, copies of H and 13C spectra for
all new compounds and HPLC chromatograms for ee determination.
This material is available free of charge Via the Internet at
http://pubs.acs.org.
JO0703294
5862 J. Org. Chem., Vol. 72, No. 15, 2007