A New Synthesis of Diazenes (Azoalkanes) Using 4-(S,S-Dimethylsulfoximino)- 1,2,4-triazoline-3,5-dione. the Construction of Diazenes from Amino Nitrenes via Base-Induced Sulfoximine Cleavage

Full text of DOI:10.1021/jo970011j

J . Org. Chem. 1997, 62, 3779-3781
3779
Sch em e 1. P r op osed P a th w a y for Dia zen e
F or m a tion
A New Syn th esis of Dia zen es (Azoa lk a n es)
Usin g 4-(S,S-Dim eth ylsu lfoxim in o)-
1,2,4-tr ia zolin e-3,5-d ion e. Th e Con str u ction
of Dia zen es fr om Am in o Nitr en es via
Ba se-In d u ced Su lfoxim in e Clea va ge
Scott Meehan and R. Daniel Little*
Department of Chemistry, University of California, Santa
Barbara, Santa Barbara, California 93106
Received J anuary 2, 1997
Diazenes are well known, valuable precursors of reac-
tive intermediates.1 They are most commonly prepared
by the hydrolysis of either a biscarbamate or a urazole,
followed by oxidation of the intermediate hydrazine or
semicarbazide, respectively.2 We describe the first syn-
thesis and exploration of the chemistry of 4-(S,S-di-
methylsulfoximino)-1,2,4-triazoline-3,5-dione (S-TAD, 1).
This material undergoes cycloaddition with conjugated
dienes to afford urazoles in high yield and provides a
useful and novel method for the construction of diazenes.
The latter process is highlighted by a new, base-induced
sulfoximine cleavage (13 f 15) that allows the direct
conversion of urazole to diazene via the intermediacy of
an aminonitrene (15), as illustrated in Scheme 1. With-
out isolation, the latter fragments to afford the diazene
linkage, bypassing the oxidation step entirely.
depending, as illustrated in eqs 2 and 3, upon the
reactivity of the cycloaddition partner.
S-TAD (1) is easily synthesized from N-aminourazole
(2, “p-urazine”),3,4 a substance that can be prepared on a
large scale via the self-condensation of semicarbazide
hydrochloride. Thus, treatment of 2 with 2 equiv of
iodobenzene diacetate (IBD, 3) in DMSO converts the
aminourazole to S-TAD (1). One equivalent of IBD (3)
oxidizes the 1,2-hydrazide and the other oxidizes the
resulting 1,1-hydrazide to the aminonitrene, which is
subsequently intercepted by DMSO to form the sulfox-
imine.5,6 S-TAD (1) is not isolated but is conveniently
used as a solution in DMSO or acetonitrile.
Once formed, the S-TAD adduct can be converted to
the desired diazene by treatment with any of a variety
of bases, aqueous potassium carbonate being particularly
convenient; those bases found useful in the conversion
of 8 to anthracene are illustrative.
The cycloadditions are generally carried out at tem-
peratures ranging from -78 °C to room temperature,
(1) (a) Adam, W.; De Lucchi, O. Angew. Chem., Int. Ed. Engl. 1980,
19, 762. (b) Dougherty, D. A. Acc. Chem. Res. 1991, 24, 88. (c) Engel,
P. S. Chem Rev. 1980, 99.
(2) (a) Barton, D. H. R.; Shioiri, T.; Widdowson, D. A. J . Chem. Soc.,
C 1971, 1968. (b) Semmelhack, M. F.; Foos, J . S.; Katz, S. J . Am.
Chem. Soc. 1973, 95, 7325. (c) Squillacote, M.; De Felippis, J . J . Org.
Chem. 1994, 59, 3564. (d) The diazenes illustrated in the table are
known and their preparation is recorded in Little, R. D.; Carroll, G. L.
J . Org. Chem. 1979, 44, 4720.
Highlighting the utility of the methodology is its
application to the synthesis of bicyclic diazenes that serve
as precursors to the trimethylenemethane diradicals used
in diyl trapping reactions (see Table 1).2d,7 These materi-
als are prepared via the reaction of S-TAD (1) with a
fulvene such as 9a -c, followed by reduction of the ∆-5,6
(3) Lenoir, J . A.; Colebrook, L. D.; Williams, D. F. Can. J . Chem.
1972, 50, 2661.
(6) The mechanism of hydrazine oxidation is not known. There is
considerable evidence that a “free” amino-nitrene is not involved. The
sulfoximine can be formed by the reaction of DMSO with another
electrophilic nitrogen intermediates. See: (a) Atkinson, R. S.; J ones,
D. W.; Kelly, B. J . J . Chem. Soc., Perkin Trans. 1 1991, 1344. (b)
Atkinson, R. S.; Grimshire, M. J .; Kelly, B. J . Tetrahedron 1989, 43,
2873.
(4) N-Aminourazole was first synthesized by the Thiele and Curtius
groups over a century ago. (a) Thiele, J .; Stange, O. Liebigs Ann. Chem.
1894, 283, 1. (b) Curtius, T.; Heidenreich, K. Chem. Ber. 1894, 2684.
(5) (a) Cambell, C. D.; Rees, C. W. Chem. Commun. 1965, 10, 193.
(b) Gilchrist, T. L.; Rees, C. W.; Stanton, E. Chem. Commun. 1971,
801. (c) Anderson, D. J .; Horwell, D. C.; Stanton, E.; Gilchrist, T. L.;
Rees, C. W. J . Chem. Soc., Perkin Trans. 1 1972, 1317.
(7) Little, R. D. Chem. Rev. 1996, 96, 93.
S0022-3263(97)00011-X CCC: $14.00 © 1997 American Chemical Society

3780 J . Org. Chem., Vol. 62, No. 11, 1997
Notes
Ta ble 1. Dia zen e F or m a tion fr om S-TAD Ur a zoles
rapidly exchanged with deuterium when the process is
conducted in the presence of D2O and potassium carbon-
ate. It is important to point out that the corresponding
diphenylsulfoximine, i.e., a system devoid of an ab-
stractable proton, was not converted to diazene. Thus,
it is reasonable to postulate a pathway involving depro-
tonation of 13, followed by elimination of dimsylate to
afford aminonitrene 15, and its subsequent fragmenta-
tion with the extrusion of carbon monoxide and nitrogen
to afford the diazene. In a sense, the process is remi-
niscent of the conversion of 1,1-disubstituted-2-arene-
sulfonohydrazides to aminonitrenes in the presence of
base.11
In short, we have designed, synthesized, and examined
the cycloaddition chemistry of a new triazolinedione,
S-TAD (1). This material is particularly useful in its role
as a precursor to diazenes. Of particular note is the fact
that, under mildly basic conditions, S-TAD-derived ura-
zoles undergo base-induced fragmentation, leading di-
rectly to the diazene unit.
yield
%, 10)
yield
(%, 11)
R
R′
condns (10 to 11)
a
b
c
CH3 CH3
93
90
80
0.1 N K2CO3, 75 °C, 1.5 h
0.1 N K3PO4, 85 °C, 5 h
1 N K2CO3, 75 °C, 5 h
80
83
77
H
C6H4OMe-p
C6H5 C6H5
Exp er im en ta l Section
4-(S,S-Dim eth ylsu lfoxim in o)-1,2,4-tr iazolin e-3,5-dion e (S-
TAD, 1). Meth od A. Powdered N-aminourazole3 (2, 0.116 g,
1.0 mmol) was dissolved in 5 mL of dry (3 Å mol sieves) DMSO
and placed in a 25 mL flask cooled in a room-temperature water
bath. Iodobenzene diacetate (IBD, 3, 0.650 g, 2.0 mmol) was
added in portions over 1 h. The slow addition of IBD prevented
the decomposition of S-TAD (1) caused by overheating. The
resulting deep violet colored solution of S-TAD (1; ca. 0.2 M)
was used for cycloadditions: 1H NMR (200 MHz, DMSO-d6) δ
3.28 (s, 6 H, Me); 13C NMR (200 MHz, DMSO-d6) δ 222.59, 39.39;
UV (DMSO) λmax 310, 554 nm.
π bond of the resulting Diels-Alder adduct using diimide
at low temperature.8 The resulting highly polar products
are readily characterized by the sulfoximine methyl
singlet appearing at ca. 3.2 ppm of the 1H NMR spectrum
and the distinctive urazole signals found at 1715 and
1780 cm-1 in the IR.
Conversion of these materials to the corresponding
diazene is a simple matter. For example, diazene 11a
was isolated in an 82% yield after stirring compound 10a
(200 mg, 0.66 mmol) dissolved in 40 mL of 1 N aqueous
potassium phosphate at room temperature for 3 days.2d
The reaction time was reduced, and a comparable yield
(80%) was obtained when a 0.5 M solution of 10a (100
mg, 0.33 mmol) was heated at 75 °C for 1.5 h in the
presence of 0.1 N aqueous potassium carbonate. Because
cis-diazenes are stabilized in water,9 they can be gener-
ated at temperatures exceeding that required for extru-
sion of nitrogen in a nonaqueous solvent. This factor can
prove advantageous in the synthesis of thermally labile
diazenes. For example, while the diphenyl diazene 11c
has an estimated half-life of roughly 2 min at 75 °C in
acetonitrile,2d,10 it can be isolated in a 77% yield after
treatment of urazole 10c with aqueous potassium car-
bonate at that temperature for 5 h.
Meth od B. Powdered N-aminourazole3 (2, 1.16 g, 10 mmol)
was suspended in 10 mL of dry (3 Å mol sieves) DMSO. IBD
(3, 3.22 g, 10 mmol) was added over 4 h to the ice-cooled
suspension. The suspension was stirred at room temperature
for 2 h. The solution remained violet throughout the reaction,
slowly fading as S-TAD (1) was consumed. The reaction was
considered complete when the solution was colorless and gave
a negative test to starch-iodide paper; this indicated consump-
tion of 3. The suspension was triturated twice with 75 mL of
ether to give 1.80 g (9.3 mmol, 93%) of dihydro-S-TAD: mp 220-
221 °C (recrystallized from water); 1H NMR (200 MHz, DMSO-
d6) δ 9.86 (s, 2 H), 3.19 (s, 6 H, Me); 13C NMR (200 MHz, DMSO-
d6) δ 154.89, 40.35; IR (Nujol) 3245, 3010, 2938, 2900, 2851,
1687, 1432, 1374, 1328, 1218, 1189, 1043 cm-1; MS (CI, CH4)
79 (DMSO - H+), 63, 44; MS (CI, NH3) 193, 134, 96, 79; MS
(CI, APCI) 193, 79 (100); HRMS (CI) calcd for C4H9N4O3S
193.0395, found 193.0395 (MH+).
The mechanism for the conversion to diazene deserves
comment. While the present reaction conditions call for
the use of water as solvent, a hydrolytic pathway involv-
ing the attack of water or hydroxide on the carbonyl unit
is not operable. Were that so, a stable semicarbazide
intermediate would have formed; none could be detected.
Instead, we favor the process portrayed in Scheme 1, one
initiated by the removal of a proton from the dimethyl-
sulfoximine unit of 13. The feasibility of this pathway
was demonstrated by showing that these protons are
Powdered dihydro-S-TAD (0.192 g, 1.0 mmol) and IBD (3,
0.330 g, 1.01 mmol) were suspended in 10 mL of MeCN. The
suspension was stirred in the dark for 1 h to give a 0.1 M solution
of S-TAD (1). No cooling bath was needed as the insolubility of
both reactants moderated the reaction temperature. The reac-
tion was judged to be complete when the solids had dissolved.
This solution was used for the cycloaddition reactions.
Gen er a l P r oced u r e for th e Diels-Ald er Rea ction s of
S-TAD (1) w ith F u lven es. F or m a tion of 10a -c. A solution
of S-TAD (1) prepared via method B was added to 1 mmol of
fulvene dissolved in 200 mL of CH2Cl2 precooled to -78 °C. The
violet color of S-TAD (1) disappeared instantly upon addition.
The reaction was complete when the solution remained faintly
violet or when TLC indicated consumption of fulvene. Dipotas-
sium azodicarboxylate (2.0 g, 10 mmol, 10 equiv) and glacial
acetic acid (1.3 g, 20 mmol, 20 equiv) were added, and the
solution was maintained at -78 °C for 4 h. The crude mixture
was added to a 2.5 × 2.5 cm plug of silica and eluted with ether;
organic byproducts elute first. Further elution with 10% MeOH
(8) Fulvene adducts with STAD (1) must be hydrogenated at low
temperature using diimide to avoid rearrangements. Attempts to
convert the initially formed adduct to diazene without first reducing
the ∆-5,6 π bond would afford an unstable material that would lose
nitrogen and regenerate the fulvene. (a) Adam, W.; Erden, I. Angew.
Chem., Int. Ed. Engl. 1978, 17, 210. (b) Olsen, H. Angew. Chem. Suppl.
1982, 893. (c) Zhang, X.; Khan, S. I.; Foote, C. S. J . Org. Chem. 1995,
60, 4102. Adducts that do not rearrange can be conveniently hydro-
genated over Pd/C.
(9) Little, R. D.; Brown, L. M. J . Am. Chem. Soc. 1992, 114, 3071
and references therein.
(10) Little, R. D.; Billera, C. B. Tetrahedron Lett. 1988, 29, 5711.
(11) See also, (a) Carpino, L. A. J . Am. Chem. Soc. 1957, 79, 4427.
(b) Carpino, L. A.; Go¨wecke, S. J . Org. Chem. 1964, 29, 2824. (c)
Carpino, L. A. J . Org. Chem. 1965, 30, 737.

Notes
J . Org. Chem., Vol. 62, No. 11, 1997 3781
in CH2Cl2 and concentration in vacuo afforded the hydrogenated
cycloadduct 10. Spectral data for compounds 10a -c follow.
4-(S,S-Dim et h ylsu lfoxim in o)-10-(isop r op ylid in e)-2,4,6-
tr ia za [5.2.2.02,6]-tr icyclod eca n e-3, 5-d ion e (10a ): 80% yield;
mp 190-194 °C (recrystallized from CH2Cl2/pentane); TLC (10%
MeOH/CH2Cl2) Rf 0.35, stains blue with p-anisaldehyde; 1H
NMR (200 MHz, CDCl3) δ 4.70 (s, 2 H), 3.16 (s, 6 H, Me), 1.88
(m, 4 H), 1.64 (s, 6 H, Me); 13C NMR (200 MHz, CDCl3) δ 159.4,
131.8, 124.0, 59.5, 40.6, 27.7, 20.9; IR (CDCl3) 3027, 2982, 2935,
2862, 1771, 1719, 1383, 1229, 1184, 909, 728 cm-1; MS (EI) 298,
220, 192, 134, 107, 93, 79 (100), 63; MS (CI, NH4) 299 (100),
221, 208, 193, 107, 96, 79; MS (APCI) 299 (100), 221, 193, 107,
79; HRMS (EI) calcd for C12H18N4O3S 298.1099, found 298.1096.
4-(S,S-Dim eth ylsu lfoxim in o)-10-(4-m eth oxyben zyliden e)-
2,4,6-tr ia za [5.2.2.02,6]tr icyclod eca n e-3, 5-d ion e (10b): 83%
yield; mp 146-150 °C; TLC (10% MeOH/CH2Cl2) Rf 0.4, stains
blue with p-anisaldehyde; 1H NMR (200 MHz, CDCl3) δ 7.11 (d,
8.7 Hz, 2 H), 6.81 (d, 8.7 Hz, 2H), 6.36 (s, 1 H), 5.1 (s, 1 H), 4.58
(s, 1 H), 3.72 (s, 3 H, Me), 3.12 (s, 3 H, Me), 3.06 (s, 3 H, Me),
2.0 (m, 4 H); 13C NMR (200 MHz, CDCl3) δ 159.5, 159.4, 136.6,
129, 127, 120, 119, 114, 77.2, 63.7, 58.7, 55.1, 40.4, 40.2, 27.4;
IR (CDCl3) 3013, 2358, 1769, 1714, 1604, 1509, 1382, 1218, 1029
cm-1; MS (CI, NH3) 377, 286, 185, 79 (100); HRMS (CI) calcd
for C17H21N4O4S 377.1283, found 377.1270 (MH+).
230-234 °C (recrystallized from MeOH); TLC (10% MeOH/
CH2Cl2) Rf 0.45, stains brown with p-anisaldehyde; 1H NMR (200
MHz, CDCl3) δ 7.45 (m, 4H), 7.26 (m, 4H), 6.23 (s, 2 H), 2.95 (s,
6H); 13C-NMR (DMSO-d6) δ 157, 136.5, 127.9, 124.0, 59.4, 39.0;
IR (CDCl3) 3014, 2919, 2256, 1760, 1706, 1455, 1380, 1199, 1124,
1025, 904, 734 cm-1; UV (MeCN) λmax 212, 262 nm; MS (CI, CH4)
207 (protonated diazenium cation), 179, 178 (anthracene, 100),
79 (DMSO - H+), 44; HRMS (CI) calcd for C18H15N4O3S
369.1021, found 369.1028 (MH+).
Ba se-In d u ced Su lfoxim in e Clea va ge of Ad d u ct 8. Usin g
P ota ssiu m Ca r bon a te. Adduct 8 (220 mg, 0.59 mmol) was
suspended in 300 mL of 0.1 N K2CO3 and heated to 90 °C for 1
h. The fluorescence of anthracene could be seen in the flask
(long wavelength UV) immediately after heat was applied. The
reaction mixture was added to 20 mL of brine and extracted
twice with 20 mL of CH2Cl2. The organic layer was dried over
Na2SO4, concentrated, and chromatographed on silica gel, elut-
ing with ether. Removal of the solvent afforded 97 mg (0.54
mmol, 92%) of anthracene.
Usin g P yr r olid in e. Adduct 8 (20 mg, 0.05 mmol) was
suspended in 4 mL of H2O and 1 mL of pyrrolidine and heated
at 90 °C for 3 h. The reaction mixture was cooled, quenched
with 20 mL of 0.1 N HCl, and worked up as described above to
give 9.4 mg (0.047 mmol, 97%) of anthracene.
4-(S,S-Dim eth ylsu lfoxim in o)-10-(d ip h en ylm eth ylid en e)-
2,4,6-tr ia za [5.2.2.02,6]tr icyclod eca n e-3, 5-d ion e (10c): 77%
yield; mp 214-216 °C (recrystallized from MeOH); TLC (10%
MeOH/CH2Cl2) Rf 0.35, stains blue with p-anisaldehyde; 1H
NMR (200 MHz, CDCl3) δ 7.35 (m, 3 H, 7.15 (m, 2 H), 4.89 (s, 2
H), 3.23 (s, 6 H, Me) 2.11 (m, 4 H); 13C NMR (200 MHz, CDCl3)
δ 158.9, 136.5, 134.5, 129.3, 128.4, 128.2, 61.0, 41.0, 27.9; IR
(CDCl3) 3018, 1773, 1708, 1380, 1210, 1033 cm-1; MS (CI, NH3)
423, 274, 231 (100), 193, 96, 79; HRMS (EI) calcd for C22H23N4O3S
423.1490, found 422.1424.
Gen er a l P r oced u r e for th e Diels-Ald er Rea ction s of
S-TAD (1) w ith Un r ea ctive Dien es: An th r a cen e a n d 1,4-
Dip h en ylbu ta d ien e (4). P r ep a r a tion of 5 a n d 8. A 1 mmol
solution of S-TAD (1), prepared by method B, was added to 1
mmol of diene dissolved in 50 mL of CH2Cl2 at room tempera-
ture. When the solution was no longer violet, the crude mixture
was added to a 2.5 × 2.5 cm plug of silica and washed with ether
(100 mL) to remove organic byproducts. Further elution with
50 mL of 10% MeOH/CH2Cl2 and concentration in vacuo afforded
the adduct in 90-100% purity, as determined by 1H NMR. The
adducts were recrystallized from MeOH. Spectral data and
melting points for 5 and 8 are presented below.
Usin g p H 10 Bu ffer . Adduct 8 (20 mg, 0.05 mmol) was
suspended in 3 mL of Fisherbrand pH 10 buffer and heated at
90 °C for 3 h. After standard workup (see above), 9-9.2 mg
(0.045-0.046 mmol, 93-95%) of anthracene was obtained.
Usin g Na 3BO3. Adduct 8 (20 mg, 0.05 mmol) was dissolved
in 3 mL of 0.1 N Na3BO3 and heated at 90 °C for 24 h. After
standard workup (see above), 9 mg (0.045 mmol, 90%) of
anthracene was obtained.
Dir a d ica l P r ecu r sor s 11a -c. These materials are known.2d
Adduct 10a (100 mg, 0.33 mmol) was dissolved in 500 mL of 0.1
N K2CO3 and heated at 75 °C for 1.5 h. The aqueous layer was
extracted with CH2Cl2 and the organic layer dried over Na2SO4
and concentrated in vacuo to afford 73 mg (82%) of diazene 11a .
Adduct 10b (50 mg, 0.13 mmol) was heated in 50 mL of 0.1 M
aqueous K3PO4 at 85 °C for 3 h. Workup as previously described
afforded 25 mg of diazene 11b (0.1 mmol, 83%). Adduct 11c
(50 mg, 0.12 mmol) was heated in 80 mL of 1.0 M aqueous K2CO3
at 75 °C for 5 h. Workup as previously described afforded 23
mg of diazene 11c (0.9 mmol, 77%).
Ack n ow led gm en t. We are grateful to the National
Science Foundation and the National Institutes of
Health for their support of our research programs.
2,5-Dip h en yl-8-(S,S-d im et h ylsu lfoxim in o)-1,6,8-t r ia za -
[4.3.0]bicyclon on -3-en e-7,9-d ion e (5): mp 224-226 °C (re-
crystallized from MeOH); TLC (10% MeOH/CH2Cl2) Rf 0.35,
1
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
data for dihydro-S-TAD and S-TAD (1) in DMSO-d6, as well
as for compounds 5, 8, and 10a -c (8 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
stains blue with p-anisaldehyde; H NMR (200 MHz, CDCl3) δ
7.47 (m, 4 H), 7.36 (m, 6H), 5.96 (s, 2 H), 5.47 (s, 2 H), 3.10 (s,
6 H); 13C NMR (200 MHz, CDCl3) δ 154, 137.1, 128.7, 128.5,
127.8, 125.2, 58.1, 40.8; IR (CDCl3) 3013, 2356, 1773, 1710, 1602,
1411, 1210, 1085 cm-1; MS (CI, NH3) 397, 321, 306, 235
(diazenium cation), 206, 79 (100); HRMS (EI) calcd for
C
20H21N4O3S 396.1256, found 396.1258.
8,9:10,11-Dib e n zo-4-(S ,S -d im e t h ylsu lfoxim in o)-2,4,6-
tr iaza[5.2.2.02,6]tr icyclou n deca-8,10-dien e-3,5-dion e (8): mp
J O970011J