Lewis acid-mediated unprecedented ring-opening rearrangement of 2-Aryl-N-tosylazetidines to enantiopure (E)-allylamines

Article abstract of DOI:10.1021/ol7023218

A highly efficient strategy for Cu(OTf)₂-mediated ring-opening of 2-aryl-N-Mosylazetidines in polar and coordinating solvents followed by an unprecedented rearrangement to substituted achiral and chiral (E)-allylamines (ee >99%) is reported. Th

Full text of DOI:10.1021/ol7023218

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5441-5444
Lewis Acid-Mediated Unprecedented
Ring-Opening Rearrangement of
2-Aryl-N-tosylazetidines to Enantiopure
(E)-Allylamines
Manas K. Ghorai,* Amit Kumar, and Kalpataru Das
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
mkghorai@iitk.ac.in
Received September 24, 2007
ABSTRACT
A highly efficient strategy for Cu(OTf)2-mediated ring-opening of 2-aryl-N-tosylazetidines in polar and coordinating solvents followed by an
unprecedented rearrangement to substituted achiral and chiral (E)-allylamines (ee >99%) is reported. The methodology has been applied for
the synthesis of
γ-unsaturated-â-amino acids. A plausible mechanism for the rearrangement is also described.
Ring-opening transformations of small ring aza-heterocyles
provide excellent routes for the construction of important
synthetic targets.1 In recent years, azetidines have been
utilized in ring-opening2 or in association with ring expan-
sion,3 fragmentation,3c rearrangement,4 and cycloaddition
reactions5 to generate a wide variety of nitrogen-containing
compounds of synthetic and pharmacological importance.
Although nonactivated azetidines and azetidinium ions have
been exploited extensively,2a,b,3b,4 the chemistry of activated
azetidines has not been much explored.
Recently, Lewis acid (LA)-mediated ring-opening of
enantiopure 2-aryl-N-tosylazetidines by several nucleophiles
such as halides,6a nitriles,6a carbonyls,6b and alcohols6c to
provide nonracemic products in high enantiomeric excess
has been reported by us (Scheme 1). We have demonstrated
that the nucleophilic ring-opening of 2-aryl-N-tosylazetidines
proceeds through an SN2 pathway instead of a stable 1,4-
dipolar intermediate as invoked earlier.5a,b Similar chemistry
was observed for 2-aryl-N-tosylaziridines6c,7 as well. In
continuation of our research activities in this area to elucidate
the mechanism of nucleophilic ring-opening of 2-aryl-N-
(1) (a) Davies, D. E.; Storr, R. C. In ComprehensiVe Heterocyclic
Chemistry; Lwowski, W., Ed.; Pergamon: Oxford, UK, 1984; Vol. 7, Part
5, pp 237-284. (b) Moore, J. A.; Ayers, R. S. In Chemistry of Heterocyclic
CompoundssSmall Ring Heterocycles; Hassner, A., Ed.; Wiley: New York,
1983; Part 2, pp 1-217. (c) De Kimpe, N. In ComprehensiVe Heterocyclic
Chemistry II; Padwa, A., Ed.; Elsevier: Oxford, UK, 1996; Vol. 1, Chapter
1.21. (d) Gribble, G. W.; Joule, J. A. In Progress In Heterocyclic Chemistry;
Elsevier, Oxford, UK, 2004; Vol. 16, p 475.
(2) (a) Vargas-Sanchez, M.; Lakhdar, S.; Couty, F.; Evano, G. Org. Lett.
2006, 8, 5501. (b) Couty, F.; David, O.; Durrat, F. Tetrahedron Lett. 2007,
48, 1027. (c) Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1994, 50, 5775.
(d) Akiyama, T.; Daidouji, K.; Fuchibe, K. Org. Lett. 2003, 5, 3691. (e)
Domostoj, M.; Ungureanu, I.; Schoenfelder, A.; Klotz, P.; Mann, A.
Tetrahedron Lett. 2006, 47, 2205. (f) Dwivedi, S. K.; Gandhi, S.; Rastogi,
N.; Singh, V. K. Tetrahedron Lett. 2007, 48, 5375. (g) Golding, P.; Millar,
R. W.; Paul, N. C.; Richards, D. H. Tetrahedron 1995, 51, 5073.
(3) (a) Vanecko, J. A.; West, F. G. Org. Lett. 2005, 7, 2949. (b) Couty,
F.; Durrat, F.; Evano, G.; Marrot, J. Eur. J. Org. Chem. 2006, 18, 4214. (c)
Alcaide, B.; Almendros, P.; Aragoncillo, C.; Salgado, N. R. J. Org. Chem.
1999, 64, 9596 and references cited therein.
(5) (a) Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A. Chem.
Commun. 2001, 958. (b) Prasad, B. A. B.; Bisai, A.; Singh, V. K. Org.
Lett. 2004, 6, 4829. (c) Yadav, V. K.; Sriramurthy, V. J. Am. Chem. Soc.
2005, 127, 16366. (d) Baeg, J.-O.; Bensimon, C.; Alper, H. J. Org. Chem.
1995, 60, 253. (e) Baeg, J.-O.; Alper, H. J. Org. Chem. 1995, 60, 3092.
(6) For SN2-type ring-opening of N-tosylazetidines: (a) Ghorai, M. K.;
Das, K.; Kumar, A.; Das, A. Tetrahedron Lett. 2006, 47, 5393. (b) Ghorai,
M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48, 4373. (c) Ghorai,
M. K.; Das, K.; Shukla, D. J. Org. Chem. 2007, 72, 5859.
(4) (a) Vargas-Sanchez, M.; Couty, F.; Evano, G.; Prim, D.; Marrot, J.
Org. Lett. 2005, 7, 5861 and references cited therein. (b) De Kimpe, N.;
Tehrani, K. A.; Fonck, G. J. Org. Chem. 1996, 61, 6500. (c) Van Brabandt,
W.; Van Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8, 1105. (d)
Sulmon, P.; De Kimpe, N.; Schamp, N. Tetrahedron 1989, 45, 2937.
10.1021/ol7023218 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/17/2007

Scheme 1. SN2-Type Nucleophilic Ring-Opening of
2-Aryl-N-tosylazetidines and Aziridines
Table 1. Synthesis of Chiral Allylamines from
2,4-Disubstituted Azetidines
tosylazetidines, we studied their fate in the presence of Lewis
acid in polar solvents and discovered an unprecedented
rearrangement of azetidine 1 to allylamine 2 as shown in
Scheme 2. The synthesis of allylamines has been an area of
Scheme 2. Ring-Opening Rearrangement in
2-Phenyl-N-tosylazetidine 1
considerable research activity8,9 primarily due to their key
function as precursors or intermediates in organic synthesis,10
as well as their presence in several biologically active
compounds.11 Moreover, these allylamines could be trans-
formed into various important natural and unnatural amino
acids upon oxidative cleavage of the olefinic bond.9a Herein,
we report for the first time a highly efficient strategy for
LA-mediated nucleophilic ring-opening followed by a novel
rearrangement of 2-aryl-N-tosylazetidines to achiral and
chiral allylamines. However, the ring-opening of other types
of azetidinium intermediates toward allylamine derivatives
has been reported earlier.12 Allylamines obtained from
suitably functionalized azetidines were easily converted into
olefinic â-amino acids (Scheme 6), which are known to
exhibit reversible or irreversible enzyme inhibition activity
for a number of enzymes.13,14
a All azetidine ee values were >99% (determined by chiral HPLC).
b Stereochemistry and ee predicted based on precursor azetidine and
supported by chiral HPLC. c Yield after column chromatographic purifica-
tion.
When 2-phenyl-N-tosylazetidine 1 was treated with Cu-
(OTf)2 as the Lewis acid with DMSO as the solvent at
65 °C, (E)-allylamine 2 was obtained in almost quantitative
yield (Scheme 2). A series of Lewis acids such as ZnCl2,
ZnBr2, Zn(OTf)2, InCl3, and BF3‚OEt2 were studied for the
ring-opening of 1. Cu(OTf)2 was found to be the most
efficient catalyst, although BF3‚OEt2 and Zn(OTf)2 func-
tioned in a similar fashion. In the absence of Lewis acid, no
reaction was observed even at elevated temperatures. Solvent
dependence of the reaction was studied in other coordinating
solvents such as DMF, THF, and Et2O with use of Cu(OTf)2
as the Lewis acid. Similar reactions were observed in all
these cases except Et2O, where poor yield of 2 was obtained.
Interestingly, when THF was served as the solvent, reaction
was completed within 15 min at rt with use of 0.3 equiv of
Cu(OTf)2. With noncoordinating solvents such as CH2Cl2
or benzene, the reaction was found to be complicated and 2
was obtained in poor yield.
(7) For SN2- type ring-opening of N-tosylaziridines: (a) Ghorai, M. K.;
Das, K.; Kumar, A.; Ghosh, K. Tetrahedron Lett. 2005, 46, 4103. (b) Ghorai,
M. K.; Ghosh, K.; Das, K. Tetrahedron Lett. 2006, 47, 5399. (c) Ghorai,
M. K.; Ghosh, K. Tetrahedron Lett. 2007, 48, 3191.
(8) For reviews on Allylic amination, see: (a) Cheikh, R. B.; Chaabouni,
R.; Laurent, A.; Mison, P.; Nafti, A. Synthesis 1983, 685. (b) Johannsen,
M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689.
(9) (a) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
124, 12225. (b) Concello´n, J. M.; Sua´rez, J. R.; Del Solar, V. Org. Lett.
2006, 8, 349 and references cited therein. (c) Hodgson, D. M.; Fleming,
M. J.; Stanway, S. J. Org. Lett. 2005, 7, 3295.
(10) (a) Nagashima, H.; Isono, Y.; Iwamatsu, S. J. Org. Chem. 2001,
66, 315. (b) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2000, 17, 3007.
(c) Oppolzer, W.; Stammen, B. Tetrahedron 1997, 53, 3577. (d) Davis, F.
A.; Ramachandar, T.; Chai, J.; Skucas, E. Tetrahedron Lett. 2006, 47, 2743.
(11) (a) Magnus, P.; Lacour, J.; Coldham, I.; Mugrage, B.; Bauta, W.
B. Tetrahedron 1995, 51, 11087. (b) Trost, B. M. Angew. Chem., Int. Ed.
1989, 28, 1173.
(13) For a review on olefinic amino acids, see: Berkowitz, D. B.;
Charette, B. D.; Karukurichi, K. R.; McFadden, J. M. Tetrahedron:
Asymmetry 2006, 17, 869.
(14) (a) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 10677.
(b) Baldwin, J. E.; Moloney, M. G.; North, M. Tetrahedron 1989, 45, 6319.
(c) O’Donnell, M. E.; Sanvoisin, J.; Gani, D. J. Chem. Soc., Perkin Trans.
1 2001, 1696 and references cited therein.
(12) D’hooghe, M.; Van Brabandt, W.; De Kimpe, N. J. Org. Chem.
2004, 69, 2703.
5442
Org. Lett., Vol. 9, No. 26, 2007

After getting this fascinating reactivity pattern of 1, the
scope of the reaction was extended to the synthesis of
enantiomerically pure allylamines 14-22 from the chiral
azetidines 5-13 (Table 1). Chiral disubstituted azetidines
5-13 were synthesized from amino acid precursors.15
Azetidines 5-13 were treated with 1.0 equiv of Cu(OTf)2
in refluxing THF for 2 h leading to enantiopure allylamines
14-22 in excellent yields (Scheme 3) and the results are
Scheme 5. Proposed Mechanism for the Formation of
Allylamine and â-Aminoketone from 2-Aryl-N-tosylazetidine
Scheme 3. Synthesis of Chiral Allylamines from
2,4-Disubstituted Azetidines
shown in Table 1. In all these cases 1.0 equiv of Cu(OTf)2
and refluxing condition were necessary for complete conver-
sion, the reaction was found to be slower with a lesser
amount of Cu(OTf)2 and at lower temperatures.
To investigate the mechanism of the reaction, azetidines
26-29 with different aryl groups were subjected to the
reaction conditions mentioned in Scheme 2 and the results
are summarized in Scheme 4. All azetidines (26-29) led to
whereas it is retarded with an electron-withdrawing group
(28-29) and competitive oxidative cleavage reaction takes
place to generate â-aminoketones 34-35. We suggest that
â-aminoketones are formed by the elimination of dimethyl
sulfide, probably via a higher energetic seven-membered
transition state 40 as shown in Scheme 5. Stereoselective
formation of (E)-allylamines can be rationalized by consider-
ing the E2 elimination from the favorable conformation 41
over 42 as shown in Scheme 5.
Scheme 4. Effect of Aryl Group on the Reactivity of
Azetidine
After demonstrating an efficient route to enantiopure
allylamines, we further extended this strategy for the
synthesis of olefinic â-amino acids.13,14 Azetidines 43 and
46 (ee >99%) were conveniently prepared from (R)-
phenylglycinol.18 43 and 46 when subjected to ring-opening
rearrangement with Cu(OTf)2 in refluxing THF, correspond-
ing allylamines 44 and 47 were obtained in almost quantita-
tive yields with ee >99%. Further, the silyl ether groups
of 44 and 47 were unmasked to the corresponding alcohols
by using TBAF in quantitative yields. Finally, oxida-
tion14a of these alcohols by the Jones method produced
the formation of allylamines 30-33 along with â-aminoke-
tones 34-35 in some cases. â-Aminoketones 34-35 resulted
as the minor products from the oxidative cleavage of 28-
29 by DMSO. The probable mechanism of the ring-opening
reaction is described in Scheme 5.16 LA is coordinated to
azetidine nitrogen generating a highly reactive species 36,
which undergoes nucleophilic attack by DMSO to give 37.
Subsequently, intramolecular E2 elimination from 37 is
triggered by N-sulfoxonium ion via a six-membered transition
state17 38 to produce 24. Formation of 34-35 supports the
involvement of DMSO in the reaction. The reaction is faster
with an electron-donating substituent in aryl group (26),
(17) (a) We proposed a similar type of six-membered transition state
for oxidative cleavage of 2-phenyl-N-tosylaziridine by DMSO to R-amino
ketone as the only product (Ghorai, M. K. Unpublished result).
(b) A similar oxidative ring-opening of aziridine-1-carboxylates to R-amino
ketones by DMSO was reported earlier, see: Fujita, S.; Hiyama, T.; Nozaki,
H. Tetrahedron Lett. 1969, 21, 1677.
(18) The synthesis of azetidines 43 and 46 is described in the Supporting
Information (pp S-12).
(15) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48,
2471.
(16) A similar mechanism operates in other coordinating solvents (THF,
DMF).
Org. Lett., Vol. 9, No. 26, 2007
5443

Scheme 6. Synthesis of of γ-Unsaturated-â-amino Acids 45 and 48
N-tosyl-γ-unsaturated-â-amino acids 45 and 48 in excellent
yields (Scheme 6).
Acknowledgment. M.K.G. is grateful to IIT-Kanpur and
DST, India. A.K. and K.D. thank CSIR, India and IIT-
Kanpur, respectively, for research fellowships.
In conclusion, we have developed a direct synthetic route
to enantiopure (E)-allylamines via the ring-opening rear-
rangement of corresponding N-tosylazetidines. A plausible
mechanism for the reaction is provided. The method has been
utilized for the synthesis of important unnatural olefinic
â-amino acids. More applications of this methodology and
mechanistic exploration are under investigation in our
laboratory.
Supporting Information Available: Experimental
procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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