Synthesis of sulfoximidoyl-substituted triazoles by huisgen 1,3-dipolar cycloaddition

Article abstract of DOI:10.1055/s-2007-1000837

The reaction of alkynyl sulfoximines with in situ prepared organic azides in water-dichloromethane under reflux affords sulfoximidoyl-substituted triazoles by Huisgen 1,3-dipolar cycloaddition. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000837

116
LETTER
Synthesis of Sulfoximidoyl-Substituted Triazoles by Huisgen 1,3-Dipolar
Cycloaddition
S
ynthesisof Sulf
e
r
S
ubstitut
n
ed
T
riazoles
h
by
H
uisge
n
a
1,3-Dipolar
r
Cycloa
d
a
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: Carsten.Bolm@oc.rwth-aachen.de
b
The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and The Lise Meitner-Minerva Center for
Computational Quantum Chemistry, Technion-Israel Institute of Technology, Haifa 32 000, Israel
Received 11 October 2007
Sulfoximidoyl alkynes 4 were prepared by copper-cata-
lyzed imination of the corresponding sulfoxides with
PhI=NTs.10,11 For the initial screening and optimization,
(N-tosyl)-tolylhexynyl sulfoximine (4a)12 was chosen as
starting material. Albeit in only low yield, the corre-
sponding triazole derivative 3a was obtained, when mix-
tures of 4a and benzyl azide (1.5 equiv) were heated to
100 °C for 3 hours in toluene, water, or a 3:1 mixture of
water and dichloromethane (Table 1, entries 1–3). The
molecular structure of the product was determined by
Abstract: The reaction of alkynyl sulfoximines with in situ pre-
pared organic azides in water–dichloromethane under reflux affords
sulfoximidoyl-substituted triazoles by Huisgen 1,3-dipolar cycload-
dition.
Key words: azide, cycloaddition, Huisgen, sulfoximines, triazole
Sulfoximines have been used as chiral auxiliaries,1 build-
ing blocks of pseudopeptides,2 and chiral ligands.3 For
their synthesis various approaches have been described.4
Of particular interest are heterocyclic systems, since they
might eventually be applied as bioactive compounds with
appropriate solubility properties.5 Recently, we reported
on the synthesis of N-(1H)-tetrazole derivatives 1 starting
from N-cyano sulfoximines 2.6,7 Key step was a metal-
catalyzed 1,3-dipolar cycloaddition with sodium azide in
the presence of ZnBr2. Realizing the importance of 1,2,3-
triazoles as agrochemicals, corrosion inhibitors, dyes, op-
tical brighteners, and pharmaceuticals,8 we now focused
our attention on the synthesis of sulfoximine derivatives
3, which we envisaged to be accessible by Huisgen 1,3-di-
polar cycloaddition reaction between organoazides and
sulfoximidoyl alkynes 4 (Scheme 1). The latter com-
pounds have recently been applied as starting materials in
regio- and stereoselective copper-catalyzed carbozinca-
tion reactions.9
1
NMR analysis, and H-NOESY spectroscopy confirmed
the regioselectivity of the triazole formation.13 Gratifying-
ly, a few reaction modifications allowed to significantly
Table 1 Optimization of the Reaction Conditions of the Triazole
Synthesisa
Ts
Ts
N
S
N
S
azide
Bu
Bu
O
solvent,
reflux
O
N
N
Bn
Me
Me
N
4a
3a
Entry BnBr
NaN3
Solvent
Time
(h)
Yield of 3a
(equiv) (equiv)
(%)b
1
2
BnN3 (1.5)
Toluenec
H2O
3
3
7
31
19
35
63
48
58
59
56
61
68
68
57
67
BnN3 (1.5)
d
N
N
3
BnN3 (1.5)
H2O–CH2Cl2
H2O
3
N
NC
R1
N
S
N
4
2
2
1.5
1.5
3
3
N
S
H
R2
R2
5
H2O
20
3
R1
O
O
1
2
6
3
H2O
7
6
6
H2O
3
R4
R1
R4
N
8
15
18
6
12
H2O
3
R2
N
S
S
9
18
6
H2O
3
O
R1
N
N
R3
R2
N
O
d
d
d
d
d
10
11
12
13
14
H2O–CH2Cl2
H2O–CH2Cl2
H2O–CH2Cl2
H2O–CH2Cl2
H2O–CH2Cl2
3
3
4
15
18
15
24
12
18
12
24
3
Scheme 1 Retrosynthetic approaches towards heterocycles bearing
sulfoximidoyl substituents based on 1,3-dipolar cycloadditions
3
8
SYNLETT 2008, No. 1, pp 0116–0118
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
3
DOI: 10.1055/s-2007-1000837; Art ID: G33307ST
© Georg Thieme Verlag Stuttgart · New York
a Reaction conditions: see ref. 14.
b Isolated by column chromatography.
c Performed at 100 °C.
d Ratio of H2O–CH2Cl2 = 3:1.

LETTER
Synthesis of Sulfoximidoyl-Substituted Triazoles by Huisgen 1,3-Dipolar Cycloaddition
117
increase the yield of 3a.14 Thus, finally, performing the re- tivity dependance on the substitution pattern of the sulfur
action in water–dichloromethane with benzyl azide reagent became apparent. Whereas (N-tosyl)-1-hexynyl-
formed in situ from benzyl bromide and sodium azide led methylsulfoximine (4b) and (N-tosyl)-3-methoxypropy-
to triazole 3a in 68% yield (Table 1, entry 11).
nyl-phenylsulfoximine (4c) reacted well to give the corre-
sponding triazoles 3g and 3h in 73% and 51% yield,
respectively, (N-tosyl)-2-tert-butylethynyl-phenylsulfox-
imine (4d) and (N-tosyl)-2-phenylethynyl-phenylsulfox-
imine (4e) proved unreactive. Presumably, steric as well
as electronic factors hampered their conversion.
For achieving this result, the reagent amounts had to be in-
creased to 15 and 12 equivalents (for BnBr and NaN3, re-
spectively). Using a larger excess of reagents or extending
the reaction time had no impact or even reduced the yield
of 3a (entries 12 and 13, respectively). Without the organ-
ic cosolvent (in pure water) the maximal yield of 3a In summary, we have developed the synthesis of sulfox-
reached 63% (Table 1, entry 5). Interestingly, this result imidoyl-substituted triazoles by Huisgen 1,3-dipolar cy-
was achieved with a combination of only 2 equivalents of cloaddition reactions. Starting from alkynyl sulfoximines
BnBr and 1.5 equivalents of NaN3. Entries 4 and 5 in and organoazides prepared in situ from organobromides
Table 1 reveal that an extended reaction time (20 h) was and sodium azide, the products can be obtained in yields
crucial for the high yield in this case. An increase in the up to 73% after a short reaction time (3 h). Educts bearing
reagent quantity had also benefical effects on the product various substituents are tolerated leading to triazole deriv-
yield (Table 1, entries 6–9).
atives with potential bioactivities. Our current studies are
focused on an expansion of the substrate scope combined
with further process optimizations to achieve higher prod-
uct yields.
For a successful cycloaddition reaction, it was essential to
heat the reaction mixture. The cycloaddition did not occur
at temperatures below 50 °C, and at 80 °C, the yield of 3a
was only 11% (under the reaction conditions as described
in Table 1, entry 11).
Acknowledgment
Next, the substrate scope of the cycloaddition reaction
was examined. As the data in Table 2 (entries 1–4) show,
various azides reacted with 4a analogously, providing the
corresponding triazoles (3b–e) in moderate yields (of up
to 52%). Noteworthy is the fact that also other azides than
benzyl azides were applicable. (2-Naphthyl)methyl bro-
mide could not be converted (entry 5).
This research was supported by the Fonds der Chemischen Industrie
and a grant from the G.I.F., the German-Israeli Foundation for Sci-
entific Research and Development (I-871-62.5/2005), by the Israel
Science Foundation administrated by the Israel Academy of Sci-
ences and Humanities (459/04), and by the Fund for Promotion of
Research at the Technion. I. M. is holder of the Sir Michael and
Lady Sobell Academic Chair. B. F. thanks DFG (GRK 440) for a
predoctoral fellowship.
In reactions between (in situ formed) benzyl azide and
various sulfoximines (Table 2, entries 6–9), a strong reac-
Table 2 Substrate Scope of the Cycloaddition Reactiona
Ts
Ts
N
N
R3Br, NaN3
R2
S
R1
S
R1
R2
H2O–CH2Cl2,
reflux, 3 h
O
N
N
R3
O
N
4a–e
3b–j
Entry
R1
R2
Sulfoximine
R3
Product
3b
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Me
Bu
Bu
Bu
Bu
Bu
Bu
4a
4a
4a
4a
4a
4b
4c
4d
4e
4-NO2Bn
4-MeOBn
Ph(CH2)2
Ph(CH2)3
2-Naphth-CH2
Bn
52
41
51
39
0
3c
3d
3e
3f
3g
73
51b
0
Ph
CH2OMe
t-Bu
Bn
3h
Ph
Bn
3i
Ph
Ph
Bn
3j
0
a Reaction conditions: sulfoximine 4 (1.0 equiv), NaN3 (12.0 equiv), RBr (15.0 equiv) in H2O–CH2Cl2 (3:1) at 100 °C for 3 h.
b Determined by NMR.
Synlett 2008, No. 1, 116–118 © Thieme Stuttgart · New York

118
B. Füger et al.
LETTER
(10) (a) Lacôte, E.; Amatore, M.; Fensterbank, L.; Malacria, M.
Synlett 2002, 116. (b) Leca, D.; Song, K.; Amatore, M.;
Fensterbank, L.; Lacote, E.; Malacria, M. Chem. Eur. J.
2004, 10, 906.
(11) For recently developed alternative imination protocols, see:
(a) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
(b) Cho, G. Y.; Bolm, C. Org. Lett. 2005, 7, 4983. (c) Cho,
G. Y.; Bolm, C. Tetrahedron Lett. 2005, 46, 8007. (d) Refs
6 and 7.
References and Notes
(1) For selected recent contributions, see: (a) Reggelin, M.;
Kuehl, J.; Kaiser, J. P.; Buehle, P. Synthesis 2006, 2224.
(b) Rajender, A.; Gais, H.-J. Org. Lett. 2007, 9, 579.
(c) Adrien, A.; Gais, H.-J.; Koehler, F.; Runsink, J.; Raabe,
G. Org. Lett. 2007, 9, 2155.
(2) (a) Bolm, C.; Müller, D.; Dalhoff, C.; Hackenberger, C. P.
R.; Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13, 3207.
(b) Cho, G. Y.; Okamura, H.; Bolm, C. J. Org. Chem. 2005,
70, 2346 and references therein.
(12) In the reactions reported here, racemic sulfoximines were
used.
(3) Reviews: (a) Harmata, M. Chem. Abstr. 2003, 16, 660.
(b) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482.
(4) Reviews: (a) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341.
(b) Pyne, S. G. Sulfur Rep. 1992, 12, 57. (c) Reggelin, M.;
Zur, C. Synthesis 2000, 1. (d) Bolm, C. In Asymmetric
Synthesis with Chemical and Biological Methods; Enders,
D.; Jäger, K.-E., Eds.; Wiley-VCH: Weinheim, 2007, 149.
(5) For a selection of recent patents emphasizing this point, see:
(a) Luecking, U.; Krüger, M.; Jautelat, R.; Siemeister, G.
WO 037800 A1, 2005; Schering AG. (b) Luecking, U.;
Siemeister, G.; Jautelat, R. WO 099974 A1, 2006; Schering
AG. (c) Luecking, U.; Nguyen, D.; von Bonin, A.; von
Ahsen, O.; Krueger, M.; Briem, H.; Kettschau, H.; Prien, O.;
Mengel, A.; Krolikiewicz, K.; Boemer, U.; Bothe, U.;
Hartung, I. WO 071455 A1, 2007; Schering AG.
(13) The interactions between the benzylic hydrogens and the
hydrogens of the alkyl or alkoxy chain in the 1H-NOESY
spectra also confirmed the molecular structures of triazole
derivatives 3b–e,g,h. Although present in the crude product
mixtures, the other regioisomers (triazoles 5) could never be
obtained in pure form (Figure 1).
Ts
N
S
R2
R1
O
R3
N
N
N
5
Figure 1
(d) Luecking, U. EP 1 710 246 A1, 2006; Schering AG.
(e) Luecking, U.; Bader, B.; Siemeister, G. EP 1 803 723 A1,
2007; Bayer Schering Pharma. (f) Shetty, S. J.; Patel, G. D.;
Lohray, B. B.; Lohray, V. B.; Chakrabarti, G.; Chatterjee,
A.; Jain, M. J.; Patel, P. R. WO 077574 A2, 2007; Cadila
Healthcare Limited. (g) Zhu, Y.; Rogers, R. B.; Huang, Y.
X. US 228027 A1, 2005; Dow Agroscience.
(h) Jeanguenat, A.; O’Sullivan, A. C. WO 032462 A1, 2006;
Syngenta. (i) Jeanguenat, A.; O’Sullivan, A. C. WO 061200
A1, 2006; Syngenta. (j) Plant, A.; Boehmer, J. E.; Peace, A.
L. WO 037945 A1, 2006; Syngenta. (k) Kajita, S.; Ohmura,
H.; Akashi, M.; Kojima, S.; Satoh, A.; Tomida, K. WO
052849, 2004; Nippon Soda Co., Ltd.
(14) General Procedure for the Cycloaddition Reaction
Under vigorous stirring a mixture of NaN3 (12 equiv) and the
corresponding bromide (15 equiv) was heated to reflux in
H2O (0.7 M) for 1 h. Then, a solution of sulfoximine 4 (1
equiv) in CH2Cl2 (0.08 M) was added dropwise. After 3 h at
100 °C under reflux and stirring, the product was extracted
with CH2Cl2 and purified by flash column chromatography.
As representative example, the analytical data for 1-benzyl-
5-butyl-4-(N-tosyl)-(4-methylphenylsulfonimidoyl)-1H-
1,2,3-triazole (3a) obtained from the reaction of sulfoximine
4a with benzyl azide are given. Colorless oil (68%);
chromatography: EtOAc–pentane (1:3). 1H NMR (400
MHz, CDCl3): d = 0.79 (t, J = 7.0 Hz, 3 H), 1.21–1.29 (m, 4
H), 2.37 (s, 3 H), 2.41 (s, 3 H), 2.76–2.85 (m, 1 H), 2.93–3.02
(m, 1 H), 5.44 (d, J = 15.5 Hz, 1 H), 5.49 (d, J = 15.5 Hz, 1
H), 7.14–7.18 (m, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.31–7.35
(m, 5 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.98 (d, J = 8.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.6 (CH3), 21.5 (CH3),
21.7 (CH3), 22.7 (CH2), 23.0 (CH2), 30.5 (CH2), 52.5 (CH2),
126.5 (CH), 127.2 (CH), 128.2 (CH), 128.7 (CH), 129.0
(2 × CH), 129.9 (CH), 133.5 (C), 135.2 (C), 140.4 (C), 141.4
(C), 141.9 (C), 142.6 (C), 145.4 (C). IR (CHCl3): n = 2959
(m), 1454 (m), 1318 (m), 1243 (m), 1096 (s), 1018 (m), 757
(s), 540 (m). MS (CI): m/z (relative intensity) = 523 (6) [M
+ H]+. Anal. Calcd for C27H30N4S2O3: C, 62.04; H, 5.79; N,
10.72. Found: C, 62.06; H, 5.81; N, 11.14.
(6) Garcia Mancheño, O.; Bolm, C. Org. Lett. 2006, 8, 2349.
(7) Garcia Mancheño, O.; Bistri, O.; Bolm, C. Org. Lett. 2007,
9, 3809.
(8) For regioselective syntheses and applications of triazoles,
see: (a) Butler, R. N. In Comprehensive Heterocyclic
Chemistry, Vol. 4; Katritzky, A. R.; Rees, C. W.; Scriven, E.
F. V., Eds.; Pergamon: Oxford UK, 1996, 121. (b) Yoo, E.
J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless,
K. B.; Chang, S. Angew. Chem. Int. Ed. 2007, 46, 1730.
Reviews: (c) Bock, V. D.; Hiemstra, H.; van Maarseveen, J.
H. Eur. J. Org. Chem. 2006, 51. (d) Lutz, J. F. Angew.
Chem. Int. Ed. 2007, 46, 1018.
(9) Sklute, G.; Bolm, C.; Marek, I. Org. Lett. 2007, 9, 1259.
Synlett 2008, No. 1, 116–118 © Thieme Stuttgart · New York

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