Synthesis of N-(1H)-tetrazole sulfoximines

Article abstract of DOI:10.1021/ol071302+

N-(1H)-Tetrazole sulfoximines are readily available by addition of sodium azide to the corresponding N-cyano derivatives in the presence of ZnBr ₂. The use of these N-(1H)-tetrazoles as intermediates in the synthesis of other N-heterocyclic sulfoximines is demonstrated.

Full text of DOI:10.1021/ol071302+

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2951-2954
Synthesis of N-(1H)-Tetrazole
Sulfoximines
Olga Garc´ıa Manchen˜o and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received June 1, 2007
ABSTRACT
N-(1H)-Tetrazole sulfoximines are readily available by addition of sodium azide to the corresponding N-cyano derivatives in the presence of
ZnBr2. The use of these N-(1H)-tetrazoles as intermediates in the synthesis of other N-heterocyclic sulfoximines is demonstrated.
Tetrazoles are appealing ligands in coordination chemistry
and important compounds in pharmaceutical and material
sciences.1 Moreover, 1H-tetrazoles proved valuable for the
preparation of substituted tetrazoles and other nitrogen-
containing heterocycles.2 The most direct and convenient
route to 5-substituted-(1H)-tetrazoles is the [2 + 3]-cycload-
dition between a nitrile and an azide.3 Various synthetic
approaches have been developed for this transformation.
Most of them rely on the in situ generation of highly toxic
and explosive hydrazoic acid through activation of the azide
by expensive and toxic metals,4 strong Lewis acids,5 or amine
salts.6 Recently, Sharpless reported an efficient and safe
procedure for the synthesis of tetrazoles using stoichiometric
amounts of nontoxic ZnBr2 in water.7,8
Encouraged by the intense research activity in the tetrazole
field and in pursuit of our continuing interest in sulfoximine
chemistry,9,10 we envisioned the combination of these at-
tractive functional groups by the synthesis of 1H-tetrazole
sulfoximines 1 (Figure 1). Here, we report the synthesis of
various N-cyano sulfoximines 2 and their conversion into
tetrazole derivatives 1.
(7) (a) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945.
(b) Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. B. J. Am. Chem.
Soc. 2002, 124, 12210. (c) Himo, F.; Demko, Z. P.; Noodleman, L.;
Sharpless, K. B. J. Am. Chem. Soc. 2003, 125, 9983.
(8) For the use of nanocrystalline ZnO and zinc hydroxyapatite as catalyst,
see: (a) Lakshmi Kantam, M.; Shiva Kumar, K. B.; Sridhar, C. AdV. Synth.
Catal. 2005, 347, 1212. (b) Lakshmi Kantam, M.; Balasubrahmanyam, V.;
Shiva Kumar, K. B. Synth. Commun. 2006, 36, 1809.
(9) For examples of sulfoximines as chiral ligands, see: (a) Bolm, C.;
Simic, O. J. Am. Chem. Soc. 2001, 123, 3830. (b) Harmata, M.; Ghosh, S.
K. Org. Lett. 2001, 3, 3321. (c) Bolm, C.; Martin, M.; Simic, O.; Verrucci,
M. Org. Lett. 2003, 5, 427. (d) Bolm, C.; Verrucci, M.; Simic, O.; Cozzi,
P. G.; Raabe, G.; Okamura, H. Chem. Commun. 2003, 2816. (e) Bolm, C.;
Martin, M.; Gescheidt, G.; Palivan, C.; Neshchadin, D.; Bertagnolli, H.;
Feth, M. P.; Schweiger, A.; Mitrikas, G.; Harmer, J. J. Am. Chem. Soc.
2003, 125, 6222. (f) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004,
43, 5984. (g) Mo¨ssner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44, 7564.
(h) Langner, M.; Re´my, P.; Bolm, C. Synlett 2005, 781. (i) Langner, M.;
Re´my, P.; Bolm, C. Chem.sEur. J. 2005, 11, 6254. (j) Reetz, M. T.;
Bondarev, O. G.; Gais, H.-J.; Bolm, C. Tetrahedron Lett. 2005, 46, 5643.
Reviews: (k) Harmata, M. Chemtracts 2003, 16, 660. (l) Okamura, H.;
Bolm, C. Chem. Lett. 2004, 33, 482.
(10) For the use of sulfoximine as building blocks for pseudopeptides,
see: (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997, 38,
1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem.sEur. J. 2001, 7,
1118. (c) Tye, H.; Skinner, C. L. HelV. Chim. Acta 2002, 85, 3272. (d)
Bolm, C.; Mu¨ller, D.; Hackenberger, C. P. R. Org. Lett. 2002, 4, 893. (e)
Bolm, C.; Mu¨ller, D.; Dalhoff, C.; Hackenberger, C. P. R.; Weinhold, E.
Bioorg. Med. Chem. Lett. 2003, 13, 3207.
(1) (a) Butler, R. N. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996;
Vol. 4. (b) Singh, H.; Chala, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R.
K. Prog. Med. Chem. 1980, 17, 151. (c) Ostrovskii, V. A.; Pevzner, M. S.;
Kofmna, T. P.; Sheherbinin, M. B.; Tselinskii, I. V. Targets Heterocycl.
Syst. 1999, 3, 467. (d) Hiskey, M.; Chavez, D. E.; Naud, D. L.; Son, S. F.;
Berghout, H. L.; Bome, C. Proc. Int. Pyrotech. Semin. 2000, 27, 3.
(2) Moderhack, D. J. Prakt. Chem. 1998, 340, 687.
(3) A review: (a) Wittenberger, S. J. Org. Prep. Proc. Int. 1994, 26,
499.
(4) (a) Dunica, J. V.; Pierce, M. E.; Santella, J. B., III. J. Org. Chem.
1991, 56, 2395. (b) Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993,
58, 4139. (c) Curran, D. P.; Hadida, S.; Kim, S.-Y. Tetrahedron 1999, 55,
8997.
(5) (a) Wiberg, V. E.; Michaud, H. Z. Naturforsch., Teil B 1954, 9, 497.
(b) Grzonka, Z.; Liberek, B. Roczniki Chemii 1971, 45, 967.
(6) (a) Koguro, K.; Ora, T.; Mitsui, S.; Orita, P. Synthesis 1998, 6, 910.
(b) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccoro, L. J.
Org. Chem. 2004, 69, 2896.
10.1021/ol071302+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/27/2007

Next, the [3 + 2]-cycloaddition reaction between N-cyano
phenyl methyl sulfoximine (2a) and sodium azide to form
the corresponding N-(1H)-tetrazole sulfoximine 1a was
studied (Table 1). Due to the poor water solubility of 2a,
Table 1. N-(1H)-Tetrazole Sulfoximine 1aa
Figure 1. Target compounds 1 and their precursors 2.
The most common approach toward sulfoximines consists
of the direct imination of sulfoxides with a suitable nitrogen
source.11 Unfortunately, all attempts to perform such trans-
formations with cyanogen amine were unsuccessful, and
sulfoximines of type 2 remained inaccessible by this route.
In contrast, diversely substituted N-cyano sulfilimines 4 could
easily be prepared from the corresponding sulfides 3 by
imination with cyanogen amine in combination with
PhI(OAc)2 (Scheme 1).12 The reaction proceeded smoothly
catalyst
(mol %)
yield
(%)b
entry
T (°C)
1
2
3
4
5
6
-
-
120
160
120
120
120
120
-
ndc
decomp
decomp
15-35
84 (82)e
aq sat NH4Cl (excess)d
Me2NH‚HCl (20)
CuI (20)
ZnBr2 (120)
Scheme 1
a Reaction conditions: sulfoximine 2a (1 equiv), NaN3 (1.2 equiv), and
catalyst in H2O-MeOH 4:1 (0.4 M) in a sealed pressure tube. b Yield after
column chromatography. c An inseparable 1:1 mixture of tetrazole 1a and
NH-sulfoximine was obtained. d Used as solvent instead of H2O. e Yield
after trituration with Et2O-pentane 1:1.
the addition of methanol (H2O-MeOH 4:1) was required to
improve its dispersion. Consequently, the reactions were
performed in sealed glass pressure tubes.
Initially, the cycloaddition was carried out in the absence
of a catalyst at 120 °C. At this temperature, no reaction
occurred after 24 h, and in order to obtain the desired
tetrazole sulfoximine 1a, it was necessary to overheat the
mixture to 160 °C. Unfortunately, under those conditions,
an inseparable 1:1 mixture of the desired tetrazole and the
corresponding NH-sulfoximine resulted (Table 1, entry 2).
In the presence of amino salts such as Me2NH‚HCl (20 mol
%) or an aqueous solution of NH4Cl, N-cyano sulfoximine
2a decomposed (entries 3 and 4).
To avoid the cleavage of the N-cyano group or the
decomposition of the sulfoximine, various metal salts were
tested as catalysts.15 Finally, the most suitable method for
the synthesis of N-(1H)-tetrazole sulfoximines 1 was found
to be the addition of sodium azide in the presence of a
stoichiometric amount of ZnBr2.7 Thus, when N-cyano
sulfoximine 2a was treated with a 1:1 mixture of NaN3 and
ZnBr2 (1.2 equiv), tetrazole sulfoximine 1a was obtained in
84% yield (Table 2, entry 7). Due to the highly crystalline
nature of 1H-tetrazoles, a simple trituration with a 1:1
mixture of Et2O-pentane permitted pure tetrazole sulfox-
imine 1a to be obtained in high yield (82%).
at 0 °C even in the absence of a metal catalyst.13 Subsequent
oxidation of sulfilimines 4 with m-CPBA and K2CO3 in
ethanol gave the desired sulfoximines 2 in moderate to good
yields (63-86%).
Following an alternative sequence, 2h and 2i were
synthesized from NH-sulfoximines 5 by N-cyanation with
BrCN.14 As demonstrated later, this approach permits the
synthesis of optically active products from enantiopure NH-
sulfoximines.
(11) For previous contributions on iminations of sulfur compounds,
see: Rh-catalyzed: (a) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
Ag-catalyzed: (b) Cho, G. Y.; Bolm, C. Org. Lett. 2005, 7, 4983.
Fe-catalyzed: (c) Garc´ıa Manchen˜o, O.; Bolm, C. Org. Lett. 2006, 8, 2349.
Metal-free: (d) Cho, G. Y.; Bolm, C. Tetrahedron Lett. 2005, 46, 8007.
(12) For previous synthesis of N-cyano sulfilimines, see: (a) Swern, D.;
Ikeda, I.; Whitfield, G. F. Tetrahedron Lett. 1972, 13, 2635. (b) Kemp, J.
E. G.; Ellis, D.; Closier, M. D. Tetrahedron Lett. 1979, 20, 3781. (c)
Hutchins, M. G. K.; Swern, D. Tetrahedron Lett. 1981, 22, 4599. (d) Zhu,
Y.; Rogers, R. B.; Huang, J. X. US Patent 20050228027 A1, 2005.
(13) When the imination of 3a was performed in the presence of Fe-
(acac)3 (10 mol %) in combination with PhIdO or PhI(OAc)2, the reaction
was faster (0.5 h vs 2 h) and the yield of 4a was about the same.
To determine the generality of this transformation, other
N-cyano sulfoximines 2b-i were applied as substrates (Table
(14) (a) Stoss, P.; Satzinger, G. Tetrahedron Lett. 1973, 14, 267. For
the synthesis and application of N-cyano sulfoximines as insecticides, see
ref 12d.
(15) The AlMe3 mediated cycloaddition between 2a and NaN3 in dry
toluene or THF at room temperature did not proceed.
2952
Org. Lett., Vol. 9, No. 15, 2007

2, 3, and 5, respectively). In contrast, cycloaddition of
2-pyridyl sulfoximine 2f did not give the desired tetrazole.
Not surprisingly, 1f was obtained by displacement of the
sulfoximidoyl group at the pyridine core with NaN3 (90%,
entry 7). The IR absorption of the azido group in 1f was
weak, indicating the presence of the more stable ring-closed
isomer, tetrazolo[1,5-R]pyridine.17
Table 2. Synthesis of N-(1H)-Tetrazole Sulfoximinesa
Next, the value of the 1H-tetrazole sulfoximines as inter-
mediates for the synthesis of N-substituted tetrazoles and
other N-heterocyclic sulfoximines was demonstrated (Scheme
2).
Initial attempts to prepare N-benzyl substituted tetrazoles
6 and/or 7 by reaction of 1a with benzyl azide or the in situ
formed organic azide (generated from NaN3 and BnBr)
failed.18 Therefore, the alkylation of 1H-tetrazole 1a in the
presence of bases, which can provide both 1N- and 2N-alkyl
substituted tetrazoles, was studied.1a The use of Et3N in
combination with a catalytic amount of DMAP in acetone
at room temperature gave a 1.1:1 mixture of the N-benzylated
regioisomers 6 and 7 (67%).19 In contrast, with Et3N alone,
an inverse regioselectivity favoring the alkylation at N(1)
was observed, leading to tetrazoles 6 and 7 in 32 and 59%
yields, respectively.
The preparation of other five-membered heterocycles was
studied next. In particular, we were interested in the well-
established reaction of tetrazoles with anhydrides, which is
of great importance for the synthesis of unsymmetrically
substituted 1,3,4-oxadiazoles. Here, the reaction of 1H-
tetrazole 1a with highly reactive trifluoroacetic anhydride
proceeded smoothly in acetonitrile at room temperature,
leading after 2 h to the corresponding oxadiazole 8 in 81%
yield.
On the other hand, treatment of 1a with acetic anhydride
under typical thermal conditions2 (120 °C, 16 h) gave a
complex product mixture, and the desired oxadiazole 9 was
only obtained in a low yield (31%). Application of micro-
wave irradiation (200 W, 120 °C), however, led to an
excellent result in this reaction,20 and after only 2 h,
oxadiazole 9 was cleanly obtained in 70% yield.
(16) In the case of tetrazole sulfoximine 1d, which was highly insoluble
in water, the low pKa of the tetrazole allowed complete precipitation by
simple acidification. For the other tetrazoles 1, this precipitation was
inefficient, and most of the ones shown in Table 2 were obtained after
trituration.
a Reaction conditions: sulfoximine 2 (1 equiv), NaN3 (1.2 equiv), and
ZnBr2 (1.2 equiv) in H2O-MeOH 4:1 (0.4 M) at 120 °C in a sealed pressure
tube. b Yield after trituration with Et2O-pentane 1:1. c Yield after acidifica-
tion and filtration. d Yield after purification by column chromatography.
(17) (a) Wentrup, C.; Winter, H.-W. J. Am. Chem. Soc. 1980, 102, 6159.
(b) Klump, S. P.; Shechter, H. Tetrahedron Lett. 2002, 43, 8421.
(18) For a recent example of cycloadditions of acylcyanides with aliphatic
azides, see: Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2113.
(19) The structures of isomers 6 and 7 were assigned based on their 1H
and 13C NMR spectra. Characteristically, the benzylic protons of the 2N-
benzylated tetrazoles resonate at lower field than those of the corresponding
1N-benzylated isomers.
2). All reactions proceeded to completion in less than 24 h,
and tetrazole sulfoximines 1 were isolated in moderate to
good yields (65-87%). The purification involved either
acidification followed by simple filtration or extraction and
subsequent trituration with Et2O-pentane mixtures.16 In
general, electronic and steric modifications had no significant
effect on the reactivity of the N-cyano sulfoximine. The best
results were obtained with nitriles 2c, 2h, and 2e containing
electron-rich substituents at sulfur (83, 86, and 87%; entries
(20) For the first example of using microwave irradiation in the
preparation of 1,3,4-oxadiazoles from tetrazoles, see: Lukyanov, S. M.;
Bliznets, I. V.; Shorshnev, S. V.; Aleksandrov, G. G.; Stepanov, A. E.;
Vasil’ev, A. A. Tetrahedron 2006, 62, 1849.
(21) Sulfoximine (S)-5a was prepared following literature procedures:
(a) Fusco, R.; Tenconi, F. Chim. Ind. (Milan) 1965, 47, 61. (b) Johnson, C.
R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418. For an improved
protocol, see: (c) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997,
8, 909.
Org. Lett., Vol. 9, No. 15, 2007
2953

Scheme 2
Finally, the stereospecificity of the Zn-mediated [2 +
3]-cycloaddition leading to N-tetrazole sulfoximines was
studied (Scheme 3).
In summary, various N-cyano sulfoximines have been
synthesized from readily available sulfides and cyanogen
amine in two synthetic steps or by direct cyanation of the
corresponding NH-sulfoximines. A [3 + 2]-cycloaddition
reaction of the N-cyano sulfoximines with NaN3 using
inexpensive and nontoxic ZnBr2 in H2O-MeOH mixtures
at 120 °C led to tetrazole sulfoximines. The reaction is
stereospecific, constituting an easy access to novel enan-
tiopure sulfoximines from the corresponding optically active
N-cyano derivatives. Finally, the transformation of these
compounds into N-benzylated tetrazole and 5-substituted
1,3,4-oxadiazole sulfoximines has been accomplished.
For this purpose, sulfoximine (S)-5a21,22 with >99% ee
was converted into (S)-2a by N-cyanation with BrCN.23
Subsequent reaction of (S)-2a under standard conditions with
NaN3 afforded N-tetrazole sulfoximine (S)-1a. Unfortunately,
all attempts to determine its enantiomer ratio by chiral HPLC
or GC techniques remained unsuccessful. Treatment of (S)-
1a with trifluoroacetic anhydride at room temperature gave
1,3,4-oxadiazole (S)-8 in 83% yield (corresponding to 61%
over three steps from sulfoximine 5a). Finally, the enantiomer
ratio determination of (S)-8 revealed that the entire reaction
sequence had proceeded without loss of enantiopurity.24
Acknowledgment. The Fonds der Chemischen Industrie
is gratefully acknowledged for financial support. O.G.M.
thanks the Spanish Ministerio de Educacio´n y Ciencia
(M.E.C.) for a postdoctoral fellowship.
Scheme 3
Supporting Information Available: Experimental pro-
cedures, full characterization of new compounds, and 1H and
13C NMR spectra. This material is available free of charge
via the Internet http://pubs.acs.org.
OL071302+
(22) The enantiomeric excess of (S)-5a was determined by HPLC using
a chiral column: Chiralcel OJ; heptane/i-PrOH ) 85:15; 0.5 mL/min; 254
nm; tR(R) ) 36.9 min, tR(S) ) 48.9 min.
(23) Since this and the subsequent transformations do not involve the
stereogenic center, we assume retention of configuration at sulfur.
(24) The enantiomeric excess of (S)-8 was determined by HPLC using
a chiral column: Chiralcel OJ; heptane/i-PrOH ) 90:10; 0.7 mL/min; 254
nm; tR(R) ) 89.8 min, tR(S) ) 101.4 min.
2954
Org. Lett., Vol. 9, No. 15, 2007