Ag(I)-catalyzed regioselective ring-opening of N -tosylaziridine and N -tosylazetidine with S -, O -, and N -nucleophiles and tethered dinucleophiles

Article abstract of DOI:10.1021/jo102285z

[Ag(COD)₂]PF₆ catalyzes the ring-opening of N-tosylaziridines and -azetidines with alcohols, amines, thiols, and related tethered 1,2-ethane dinucleophiles. Initial rate studies and DFT-based evaluation of stepwise energetics suggest

Full text of DOI:10.1021/jo102285z

pubs.acs.org/joc
diverse range of organic architecture can be generated by the
Ag(I)-Catalyzed Regioselective Ring-Opening of N-
Tosylaziridine and N-Tosylazetidine with S-, O-, and
N-Nucleophiles and Tethered Dinucleophiles
regioselective ring-opening of aziridines and azetidines with
various nucleophiles.3-6 In particular, for ring-opening using
heteroatom centered O-, N-, and S-nucleophiles, chiefly alco-
hol, amine, and thiol, various catalytic routes have been devised
employing an array of homogeneous and heterogeneous cat-
alysts with varying degrees of efficiency and functional group
selectivity. Compounds containing 1,2-diamine, amino ether,
and amino thioether functionality find many synthetic uses.7
Vicinal amino thioethers have also found utility as medicinal
agents and bioactive compounds. Compounds containing
the 1,2-diamino moiety have been used in cancer chemother-
apy as oxaliplatin, NDDP, and NK121 drugs. Amino ethers
Milan Bera,† Sanjay Pratihar,† and Sujit Roy*,†,‡
†Organometallics & Catalysis Laboratory, Chemistry
Department, Indian Institute of Technology, Kharagpur
721302, India, and ‡School of Basic Science, Indian Institute
of Technology, Bhubaneswar 751013, India
royiitkgp@gmail.com
Received November 17, 2010
(3) (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247. (b) Padwa, A.;
Murphree, S. S. ARKIVOC 2006, 6. (c) Lu, P. Tetrahedron. 2010, 66, 2549.
(e) Bergmeier, S. C., Lapinsky, D. J. Prog. Heterocycl. Chem. 2009, 20, 47;
2009, 21, 69.
(4) Selected examples: (a) Prasad, B. A. B.; Sekar, G.; Singh, V. K.
Tetrahedron Lett. 2000, 41, 4677. (b) Li, P.; Forbeck, E. M.; Evans, C. D.;
Joullie, M. M. Org. Lett. 2006, 22, 5105. (c) Prasad, B. A. B.; Sanghi, R.;
Singh, V. K. Tetrahedron. 2002, 58, 7355. (d) Yadav, J. S.; Reddy, B. V. S.;
Balanarsaiah, E.; Raghavendra, S. Tetrahedron Lett. 2002, 43, 5105.
(e) Bodenan, J; Chanet-Ray, J; Vessiere, R. Synthesis 1992, 3, 288. (f) Ghorai,
M. K.; Das, K.; Shukla, D. J. Org. Chem. 2007, 72, 5859. (g) Watanabe, M.;
Murata, K.; Ikariya, T. J. Org. Chem. 2002, 67, 1712. (h) Li, Y.; Li, Z.; Li, F.;
Wang, Q.; Tao, F.; et al. Biomol. Chem. 2005, 3, 2513. (i) Ottenson, L. K.;
Jaroszewski, J. W.; Franzyk, H. J. Org. Chem. 2010, 75, 4983. (j) Baktharaman,
S.; Afagh, N.; Vandersteen, A.; Yudin, A. K. Org. Lett. 2010, 12, 240.
(k) Lorpitthaya, R.; Liu, X.-W.; Xie, Z.-Z.; Sophy, K. B.; Kuo, J.-L. Chem.;
Eur. J. 2010, 16, 588. (l) Catak, S.; Waroquier, M.; Van Speybroeck, V.;
D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2010, 75, 885.
(5) Selected examples: (a) Masaki, M.; Naokl, A.; Yamamoto, Y.
Tetrahedron Lett. 1994, 35, 7395. (b) Sekar, G.; Singh, V. K. J. Org. Chem.
1999, 64, 2537. (c) Crestey, F.; Witt, M.; Frydenvang, K.; Stærk, D.;
Jaroszewski, J. W.; Franzyk, H. J. Org. Chem. 2008, 73, 3566. (d) Swamy,
N. R.; Venkateswarlu, Y. Synth. Commun. 2003, 33, 547. (e) Chandrasekhar,
S.; Jaya Prakash, S.; Shyamsunder, T.; Ramachandar, T. Synth. Commun.
2004, 34, 3865. (f) Bisai, A.; Prasad, B. A. B.; Singh, V. K. ARKIVOC 2007, 5,
20. (g) Wu, J.; Sun, X.; Li, Y. Eur. J. Org. Chem. 2005, 20, 4271. (h) Nadir,
U. K.; Singh, A. Tetrahedron Lett. 2005, 46, 2083. (i) Scheuermann, J. E. W.;
Ilyashenko, G.; Griffiths; Vaughan, D.; Watkinson, M. Tetrahedron: Asym-
metry 2002, 13, 269. (j) Kelly, B. T.; Joullie, M. M. Org. Lett. 2010, 12, 4244.
(k) Seki, K.; Yu, R.; Yamazaki, Y.; Yamashita, Y.; Kobayashi, S. Chem.
Commun. 2009, 5722. (l) Das, B.; Reddy, V. S.; Tehseen, F.; Krishnaiah, M.
Synthesis 2007, 5, 666. (m) Wang, J.-Y.; Wang, D.-X.; Pan, J.; Huang, Z.-T.;
Wang, M.-X. J. Org. Chem. 2007, 72, 9391. (n) Goujon, J.-Y.; Gueyrard, D.;
Compain, P.; Martin, O. R.; Asano, N. Tetrahedron: Assymmetry 2003, 14,
1969.
(6) Selected examples: (a) Bae, J. H.; Shin, S.-H.; Park, C. S.; Lee, W. K.
Tetrahedron 1999, 55, 10041. (b) Peruncheralathan, S.; Henze, M.; Schneider, C.
Tetrahedron Lett. 2007, 48, 6743. (c) Wu, J.; Suna, X.; Suna, W. Org. Biomol.
Chem. 2006, 4, 4231. (d) Concellon, J. M.; Bernad, P. L.; Suarez, J. R.;
Santiago, G.-G.; Dıaz, M. R. J. Org. Chem. 2005, 70, 9411. (e) Das, B.;
Reddy, V. S.; Ramu, R. J. Mol. Catal A: Chem. 2007, 266, 40. (f) Yadav, J. S.;
Reddy, B. V. S.; Baishya, G.; Reddy, V. P.; Narsaiah, A. V. Catal. Commun.
2006, 7, 807. (g) Larson, S. E.; Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett.
2009, 11, 5186. (h) Ingebrigtsen, T.; Lejon, T. Tetrahedron Lett. 2006, 47,
3949. (i) Larson, S. E.; Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett. 2009, 11,
5186. (j) Jadav, J. S.; Satheesh, G.; Murthy; Changalvala, V. S. R. Org. Lett.
2010, 12, 2544. (k) Ottesen, L. K.; Jaroszewski, J. W.; Franzyk, H. J. Org.
Chem. 2010, 75, 4983. (l) Craig, D.; Lu, P.; Mathie, T.; Tholen, Niels T. H.
Tetrahedron. 2010, 66, 6376.
[Ag(COD)2]PF6 catalyzes the ring-opening of N-tosyla-
ziridines and -azetidines with alcohols, amines, thiols, and
related tethered 1,2-ethane dinucleophiles. Initial rate stud-
ies and DFT-based evaluation of stepwise energetics suggest
an inverse relationship between the nucleophilic reactiv-
ity of a heteroatom donor and its binding affinity to
cationic Ag(I).
The strained N-heterocycles aziridines and azetidines are
widely utilized as synthetic intermediates in organic synthe-
sis, more importantly in the design of nitrogen-containing
natural products and biologically active compounds.1,2
A
(1) (a) Cox, J. D. Thermochemistry of Organic and Organometallic
Compounds; New York University Press: London, 1970; p 643. (b) Tanner,
D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (c) Pearson, W. H.; Lian,
B. W.; Bergmeier, S. C. In Comprehensive Heterocyclic Chemistry II; Padwa,
A., Ed.; Pergamon: New York, 1996; Vol. 1A, p 1. (d) Osborn, H. M. I.;
Sweeney, J. B. Tetrahedron: Asymmetry 1997, 8, 1693. (e) McCoull, W.;
Davis, F. A. Synthesis 2000, 1347. (f) Zwanenburg, B.; ten Holte, P. In
Stereoselective Heterocyclic Chemistry III; Metz, P., Ed.; Springer: Berlin,
2001; p 93. (g) Oppolzer, W.; Flaskamp, E. Helv. Chim. Acta 1977, 60, 204.
(h) Oppolzer, W.; Flaskamp, E.; Bieber, L. W. Helv. Chim. Acta 2001, 84,
141. (i) Martens, J.; Scheunemann, M. Tetrahedron Lett. 1991, 32, 1417.
(j) Hu, X. E. Tetrahedron 2004, 60, 2701 and references cited therein. (k) Saha, B.;
Nandy, J. P.; Shukla, S.; Siddiqui, I.; Iqbal, J. J. Org. Chem. 2002, 67, 7858.
(l) Nishikawa, T.; Ishikawa, M.; Wada, K.; Isobe, M. Synlett 2001, 945.
(2) (a) Ghorai, M. K.; Kumar, A.; Tiwari, D. P. J. Org. Chem. 2010, 75,
137. (b) Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013.
(c) Ghorai, M. K.; Kumar, A.; Das, K. Org. Lett. 2007, 9, 5441. (d) Ghorai,
M. K.; Das, K.; Kumar, A.; Ghosh, K. Tetrahedron Lett. 2005, 46, 4103.
(7) (a) Ingenitio, R.; Bianchi, E.; Fattori, D.; Pessi, A. J. Am. Chem. Soc.
1999, 121, 11369–11374. (b) Adams, B.; Beresford, K. J. M.; Whyte, S. M.;
Young, D. W. J. Chem. Soc., Chem. Commun. 2000, 619–620. (c) Khokhar,
A. R.; Salaam, A.-B.; Brown, T.; Roman, P.-S. J. Med. Chem. 1991, 34, 325.
(d) Kelland, L. R.; Clarke, S. J.; Mckeage, M. J. Platinum Metals Rev. 1992,
36, 178 and references cited therein. (e) 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 therein. (f) Ho, M.; Chung, J. K. K.;
Tang, N. Tetrahedron Lett. 1993, 34, 6513. (g) Ager, D. J.; Prakash, I.;
Schaad, D. R. Chem. Rev. 1996, 96, 835. (h) Studer, A. Synthesis 1996, 793.
(i) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30, 3.
DOI: 10.1021/jo102285z
r
Published on Web 02/03/2011
J. Org. Chem. 2011, 76, 1475–1478 1475
2011 American Chemical Society

Bera et al.
JOCNote
SCHEME 1. Ring-Opening of N-Tosylaziridine and N-Tosyla-
zetidine with N-, O-, and S-Nucleophiles
and ether-containing peptide surrogates are popular as anti-
biotics for the treatment of anxiety and depression. Enantio-
merically pure chiral vicinal compounds are also used in
asymmetric catalysis as ligands and auxiliaries.
FIGURE 1. Pseudo-first-order rate constant (log k) in[Ag(COD)2]PF6-
catalyzed ring-opening of N-tosylaziridine with N-, O-, and
S-nucleophile.
Within the ambit of our ongoing program on Tm catalysis
for fine chemicals,8 we have recently reported Ag(I)-
catalyzed ring-opening of N-tosylaziridines and azetidines by a
C-nucleophile.9 By using propargyl alcohol as a O-nucleo-
phile, we could also execute tandem ring-opening and ring-
closing resulting in the formation of N,O-heterocycles, namely
oxazines, oxazepines, and oxazocines.10 In this paper, we re-
port Ag(I)-catalyzed ring-opening of N-tosyl aziridines and
azetidines with alcohols, amines, thiols, and tethered dinu-
cleophiles, relative rate studies, and DFT-based evaluation
of the binding ability of the tethered nucleophiles to cationic Ag(I).
The air-stable but light-sensitive complex [Ag(COD)2]PF6
was easily synthesized from AgPF6 and 1,5-cyclooctadiene in
methanol.10 Control studies on ring-opening were performed at
ambient temperature using N-tosyl-2-phenylaziridine as the
representative aziridine and diphenylmethanol, p-toluidine,
and tert-butylthiol as the representative O-, N-, and S-nucleo-
phile, respectively (Supporting Information). Among the cat-
alysts screened, AgNO3, Ag3PO4, and AgOAc showed neg-
ligible activity. On the other hand, Ag(COD)2PF6, AgPF6,
AgBF4, and Ag[(COD)2]BF4 showed good to excellent cat-
alytic efficiency in dichloroethane as solvent and at an
optimum loading of 2 mol %. Using Ag(COD)2PF6 as cata-
lyst, the ring-opening of substituted aziridines and N-tosy-
lazetidine with alcohols, phenols, aliphatic, and aromatic
amines and thiols have been accomplished giving rise to
corresponding 1,2-amino ethers, diamines, amino thioethers,
and 1,3-amino ethers in good yields (Scheme 1, please see later
for substrate scope).
SCHEME 2. Attempted Ring-Opening of 4-Chlorophenyl-N-
tosylaziridine with Tethered Dinucleophiles (Donor = N/S, N/N,
N/O, O/O)
To further augment the reactivity order, we conducted the
reaction of 4-chlorophenyl aziridine and cyclohexylaziridine
with tethered ethane 1,2-dinucleophiles bearing -NH2, -OH,
and -SH groups (Schemes 2-4). The following results are
particularly noteworthy: (1) Among the tethered homo dinu-
cleophiles, only 1,2-ethanedithiol accomplished the ring-open-
ing of 4-chlorophenylaziridine leading to 38 as the sole
product. (2) Among the hetero-dinucleophiles, only 2-
mercaptoethanol reacted with 4-chlorophenylaziridine giving
rise to 39 (from S-attack) as the major and 40 (from O-
attack) as the minor product. (3) 2-Mercaptoethanol also
reacted with cyclohexylaziridine leading to 41 (from S-attack)
as the exclusive product, while other hetero-dinucleophiles re-
mained unreactive. (4) 4-Aminothiophenol reacted with
4-chlorophenylaziridine leading to 42 (from S-attack) as
the sole product.
In an effort to understand the observed reactivity pattern
of the tethered 1,2-ethane dinucleophiles, we looked into the
simplest paradigm of stability versus reactivity. The O-, N-,
and S-tethered dinucleophiles are ideally poised to bind to
Ag(I) in 1:1 and 1:2 stoichiometry leading to the correspond-
ing chelates. It is expected that the coordination strength of a
donor atom could influence the nucleophilic reactivity in an
inverse sense. To probe further, the energetics of the step-
wise displacement of COD by dinucleophile L leading to the
complexes [Ag(COD)(L)]PF6 C1-C6 (step 1) and [AgL2]PF6
C7-C12 (step 2) have been evaluated at the B3LYP/SDD,
What is the relative reactivity of N-, O-, and S-nucleo-
philes in the ring-opening of N-tosylaziridine? To look for
the answer, a kinetic study was attempted with 2-phenyl-
N-tosylaziridine as the electrophile and phenol, aniline,
and thiophenol as the representative nucleophile from each
group. As shown in Figure 1, the pseudo-first-order rate data
(vide 1H NMR) indicate the reactivity order as -SH >
-OH > -NH2.
(8) (a) Choudhury, J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127,
6162. (b) Podder, S.; Choudhury, J.; Roy, S. J. Org. Chem. 2007, 72, 3129.
(c) Podder, S.; Choudhury, J.; Roy, U. K.; Roy, S. J. Org. Chem. 2007, 72,
3100. (d) Podder, S.; Roy, S. Tetrahedron. 2007, 63, 9146. (e) Roy, U. K.;
Roy, S. Chem. Rev. 2010, 110, 2472. (f) Chatterjee, N. P.; Roy, S. J. Org.
Chem. 2010, 75, 4413.
(9) (a) Bera, M.; Roy, S. Tetrahedron Lett. 2007, 48, 7144. (b) Bera, M.;
Roy, S. J. Org. Chem. 2010, 75, 4402.
(10) Bera, M.; Roy, S. J. Org. Chem. 2009, 74, 8814.
(11) (a) The structures of 12 complexes resulting from step 1 and step 2
were optimized at the B3LYP/SDD, 6-31G* level of theory. From the energy
difference of product and reactant, complex formation energy was calculated
without correction for zero-point energy differences. It was observed from
the data that step 1 involving formation of complexes C1-C6 is energetically
more favorable than step 2 involving the formation of complex C7-C12.
(b) For a perspective article on DFT-based studies of LA-catalyzed organic
transformation, see: Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
1476 J. Org. Chem. Vol. 76, No. 5, 2011

Bera et al.
JOCNote
SCHEME 3. Ring-Opening of 4-Chlorophenyl-N-tosylaziridine with Tethered dinucleophiles (donor = S/S, S/O, S/N)a
aYield refers to isolated yield of product(s).
FIGURE 2. Relative complex formation energy for the stepwise displacement of COD by dinucleophile. Diagram drawn with reference to the
formation energy of (i) C4 (-67.8 kJ mol-1) as zero in step 1 (left) and (ii) C10 (-8.8 kJmol-1) as zero in step 2 (right). Details in the Supporting
Information.
SCHEME 4. Attempted Reaction of Cyclohexyl-N-tosylaziridine and 1,2-Ethane Dinucleophiles (Donor = N/S, N/N, N/O, O/O)
6-31G* level of theory (Figure 2).11 Figure 2 represents the
relative complex formation energy data for both step 1 and
step 2 by taking the complex formation energy of C4 and C10
as zero. One may note that in both the cases, the complex
formation energy decreases in the order L1 > L2 > L3 >
L4 > L5 > L6, suggesting higher binding affinity of cationic
Ag(I) toward N-donor ligands than O- and S-donors.12 We
may therefore conclude that by virtue of their poor binding
affinity to cationic Ag(I), the S-donor ligands L5 and L6
promote facile ring-opening of N-tosylaziridines; in contrast,
J. Org. Chem. Vol. 76, No. 5, 2011 1477

Bera et al.
JOCNote
As pointed out previously, we have successfully tested
the substrate scope in the present Ag(COD)2PF6-catalyzed
ring-opening of aziridines and N-tosylazetidine with N-, O-,
and S-nucleophiles (Figure 3). In all cases, the products were
isolated at good to excellent yields. In 2-arylaziridines, the
nucleophiles always attacked the benzylic position. How-
ever, cyclohexyl-N-tosylaziridine did not react with aliphatic
or aromatic amines even after increasing the catalyst loading
and temperature. Attempted reaction of N-benzyl-2-pheny-
laziridine (as the electrophile) and ethanol (as the nucle-
ophile) led to unidentified complex mixture, and the desired
coupling product was not observed.
In summary, we have demonstrated in this note a facile
[Ag(COD)2]PF6-catalyzed ring-opening of N-tosylaziridines
and -azetidines with N-, O-, and S-nucleophiles including
tethered 1,2-ethane dinucleophiles. Initial rate studies and
DFT-based evaluation of stepwise energetics suggests that
there exists an inverse relationship between the nucleophilic
reactivity of a heteroatom donor and its binding affinity to
cationic Ag(I). Further studies are warranted to arrive at the
mechanistic description.
Experimental Section
All reactions were carried out under an argon atmosphere in
flame-dried glassware using Schlenk techniques. Chromato-
graphic purifications were done with either 60-120 or
100-200 mesh silica gel. For monitoring the reaction, precoated
silica gel 60 F254 TLC sheets were used. Petroleum ether refers to
the fraction boiling in the range 60-80 °C. Dichloroethane was
dried and distilled prior to use.
Typical Procedure for the Ring-Opening of N-Tosylaziridine
and Azetidine with S-, O-, and N-Nucleophile. A mixture N-
tosylaziridine or azetidine (0.5 mmol), the nucleophile (0.5 mmol),
and [Ag(COD)2]PF6 (2 mol %) in 3 mL of dry dichloroethane
was stirred at room temperature. Following completion (via
TLC), the reaction mixture was diluted with water (5 mL) and
extracted with dichloromethane. The combined organic layer
were dried over anhydrous sodium sulfate and concentrated in
vacuum, and the resulting product was purified by column
chromatography on silica gel (100-200 mesh, ethyl acetate-
petroleum ether, gradient elution) to afford pure amino thio-
ether, amino ether, or diamine derivatives.
FIGURE 3. Substrate scope for Ag(I)-catalyzed regioselective ring-
opening of N-tosylaziridine and N-tosylazetidine with N-, O-, and
S-nucleophiles. Yield refers to isolated yields of pure products.
Acknowledgment. Financial support from DST (to S.R.)
and CSIR (to M.B. and S.P.) is acknowledged. S.R. is most
thankful to Prof. M. Bhattacharjee for continuing encour-
agement and support.
tethered dinucleophiles L1, L2, L3, and L4 show no reactiv-
ity. It will be interesting to explore whether similar correla-
tion between binding affinity and nucleophilic reactivity
exists in the case of other nucleophilic reactions involving
heteroatoms which are catalyzed by cationic d8/d10 metals.
Supporting Information Available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra
for all new compounds; computational methodology, optimized
structures with coordinates, and all the results in detail. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(12) Selected examples of DFT-based calculations on cationic silver(I)
complexes: (a) Shoeib, T.; Aribi, E. H.; Michael, S. W. K.; Hopkinson, C. A.
J. Phys. Chem. A 2001, 105, 710. (b) Kim, K. C.; Kim, K. C.; Lee, S. B.; Won,
J.; Kim, S. H.; Kang, S. Y. J. Phys. Chem. A 2001, 105, 9024. (c) Shoeib, T.;
Hopkinson, C. A.; Michael, S. W. K. J. Phys. Chem. B 2001, 105, 12399.
1478 J. Org. Chem. Vol. 76, No. 5, 2011