Synthesis and chemistry of 3-tert-butyl-1,5-diaminopyrazole

Article abstract of DOI:10.1039/b306058f

N-Amination of 3-amino-5-tert-butylpyrazole 11 with hydroxylamine-O-sulfonic acid gave the 1,5-diaminopyrazole 12 with good regiochemical control. The reactions of 12 with certain electrophiles (e.g. acetic anhydride, DMF acetal, aromatic aldehydes, methoxymethylene Meldrum's acid) took place at one (or both) of the amino groups and no cyclised products were obtained. Reaction of 12 with carbon disulfide followed by alkylation under basic conditions provided the pyrazolo[1,5-b]1,2,4-triazole 26 which is a useful photographic magenta coupler. Reactions of 12 with 1,2- and 1,3-dicarbonyl compounds (diketones and ketoesters) provided new pyrazolo[1,5-b]1,2,4-triazines 29, 30, 42 and 43 and the first derivatives of the pyrazolo[1,5-b]1,2,4-triazepine system 31 and 35-36. The X-ray crystal structure of the pyrazolotriazepine 33 is reported.

Full text of DOI:10.1039/b306058f

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Synthesis and chemistry of 3-tert-butyl-1,5-diaminopyrazole†
Alexander J. Blake,a David Clarke,b Richard W. Maresc and Hamish McNab*c
a School of Chemistry, The University of Nottingham, University Park, Nottingham,
UK NG7 2RD
b Kodak European Research and Development, Headstone Drive, Harrow, Middlesex,
UK HA1 4TY
c School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh,
UK EH9 3JJ
Received 2nd June 2003, Accepted 3rd September 2003
First published as an Advance Article on the web 21st October 2003
N-Amination of 3-amino-5-tert-butylpyrazole 11 with hydroxylamine-O-sulfonic acid gave the 1,5-diaminopyrazole
12 with good regiochemical control. The reactions of 12 with certain electrophiles (e.g. acetic anhydride, DMF acetal,
aromatic aldehydes, methoxymethylene Meldrum’s acid) took place at one (or both) of the amino groups and no
cyclised products were obtained. Reaction of 12 with carbon disulfide followed by alkylation under basic conditions
provided the pyrazolo[1,5-b]1,2,4-triazole 26 which is a useful photographic magenta coupler. Reactions of 12 with
1,2- and 1,3-dicarbonyl compounds (diketones and ketoesters) provided new pyrazolo[1,5-b]1,2,4-triazines 29, 30,
42 and 43 and the first derivatives of the pyrazolo[1,5-b]1,2,4-triazepine system 31 and 35–36. The X-ray crystal
structure of the pyrazolotriazepine 33 is reported.
Although vicinal diamines are important intermediates in the
synthesis of heterocycles, very little work has been published on
the 1,5-diaminopyrazole system 2. The problem is that N-amin-
(δH 5.21) was the major product (57%) together with unreacted
starting material 11 (δH 5.40) (40%) and only a small peak at
δH 5.30 (ca. 3%) which was assigned to the 1,3-diamino isomer
13. The tert-butyl group clearly had the desired effect in control-
ling the regiochemistry of the N-amination process. In one
other example of a 5-substituent directing the nucleophilic
reactivity towards the 2-heteroatom in 3-aminopyrazole
systems, a bulky tert-butyl group is apparently unnecessary.4
ation of most 3-aminopyrazoles
1 proceeds with little
regioselectivity under standard conditions and mixtures of 1,5-
diamino- and 1,3-diamino- pyrazole isomers 2 and 3 respect-
ively are obtained which are separable only with difficulty
(Scheme 1).1,2 The aim of the present work was to find condi-
tions of reagent or substrate which might improve the regio-
selectivity of this amination reaction so that the properties – in
particular heterocyclisation reactions – of the 1,5-diamino-
pyrazole unit 2 could be explored in detail. Only one type of
heterocyclisation reaction is known in this series; Sliskovic et al.
reported condensation of 2 (R = H) with 1,2-dialdehydes,
1,2-diketones and 2-ketoaldehydes to give derivatives of the
pyrazolo[1,5-b]1,2,4-triazine ring system 4.1,3
Scheme 1
Next, it was important to develop conditions which would
allow the N-amination process to be driven to completion, since
separation of 11–13 by Kugelrohr distillation was ineffective
and chromatography proved time-consuming and low-yielding.
Use of two equivalents of aminating agent gave an increased
amount of products but starting material was still present; the
situation was not improved by use of three or four equivalents
of reagent which led to the presence of impurities in the final
product. The optimum method, reported in detail in the
Experimental section, involved treatment of 11 with a two-fold
excess of hydroxylamine-O-sulfonic acid in DMF, followed by
work-up and repeat reaction with a further two equivalents
of aminating agent. Yields of 60–70% of 12 and its 4-chloro
derivative 15 could be routinely achieved. However, attempted
amination of the imine 16 was unsuccessful and only the amine
11 and anisaldehyde were recovered.
As found by the previous workers,1 reaction of 3-amino-
pyrazole 5 with hydroxylamine-O-sulfonic acid gave a 1 : 1 mix-
ture of amination products 6 and 7. The H NMR chemical
1
shifts of 4-position resonances of the amination products
appeared at lower frequencies (by 0.2–0.3 ppm) than that of the
starting material 5. Attempted in situ cyclisation reactions of 6
were unsuccessful. The regioselectivity was only marginally
improved by amination of 3-amino-5-methylpyrazole 8; in this
case 9 and 10 were obtained in a 60 : 40 ratio. However, reaction
of 3-amino-5-tert-butylpyrazole 11 with hydroxylamine-O-
sulfonic acid under the standard conditions showed much
greater selectivity. Although three signals were present in the
1
region of the 4-proton resonances in the H NMR spectrum
of the product mixture, the required 1,5-aminopyrazole 12
The reactivities of the amino groups of 12 were then probed
by reaction of the diamine with a range of mono-functionalised
electrophiles, by analogy with the chemistry of o-phenylene-
diamine 17. Thus treatment of 12 with an excess of DMF acetal
† CCDC reference number 211651. See http://www.rsc.org/suppdata/
ob/b3/b306058f/ for crystallographic data in .cif or other electronic
format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 6 8 – 4 2 7 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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gave a product in almost quantitative yield which showed the
molecular mass expected of the bis-amidine 18. In agreement
with this, the product showed two methine singlets (δH 8.27 and
7.74) and broad signals in the N-methyl region of the 13C NMR
spectrum (δC 34.1–40.1) consistent with restricted rotation
around the N–C bonds. No clearly defined products could be
obtained by reaction of 12 with triethyl orthoformate. Under
comparable conditions, reaction of o-phenylenediamine either
with DMF acetal5 or with trimethyl orthoformate6 gives benz-
imidazole. These results establish that the reactivity of 12 is
fundamentally different to that of a simple aromatic diamine,
probably because of the additional strain in fused 5–5 ring
systems compared with that in fused 6–5 systems.
Scheme 2 Reagents and conditions: i, CS2, base, ii, Mel, base.
spectroscopy which showed a signal at δH 5.61 due to the ring
proton at the electron rich 7-position.
These reactions of the diamine 12 therefore provide a novel
route to the pyrazolo[1,5-b]1,2,4-triazole system, which is an
important magenta coupler in colour photography.10 The
2-methylthio compound 26 is a new derivative of this system
and its properties as a coupler were therefore investigated.11
Treatment of 26 with the developer 27 in the presence of potas-
sium persulfate provided the azomethine dye 28 (81% isolated
Reaction of 12 with an excess of acetic anhydride gave a
triacetyl derivative (25%), thought to be 19 by analogy with
results quoted below. Other acylated products were present but
were not characterised, though it was clear that no cyclisation
reactions had occurred.
Other electrophiles were more selective and reacted only at
one of the amino groups of 12. Thus benzaldehyde gave a single
monoimine (72%) (which could either be 20 or 21), character-
ised by the imine resonance at δH 8.88 and a pyrazole ring signal
at δH 5.41. The pyrazole ring resonance of the N-unsubstituted
imine 16 (δH 6.10) is significantly deshielded relative to this
value, which suggests that the structure of the product is 20,
i.e. the N-amino function is the more reactive of the two
amines. This conclusion was confirmed by spraying a TLC
spot of the imine product (20/21), with the developer 22 in the
presence of an oxidising agent (potassium persulfate).7 This
produced a coloured spot (cyan), which would be expected only
if the 5-amino group was available for electron donation into
the pyrazole ring.
Similarly, reaction of 12 with methoxymethylene Meldrum’s
acid in acetonitrile solution gave a single mono-‘Meldrumsated’
product (37%) which was assigned the structure 23 by analogy
with the work described in the previous paragraph. In addition,
the pyrazole methine signal (at δC 87.11) is significantly shielded
relative to the signal due to the corresponding position of 248
(δC 93.49) which provides further evidence for ‘Meldrumsation’
at the 1-position of 12. The presence of a methine signal at
δC 152.21 in the 13C NMR spectrum of 23 confirms that an
unsaturated 5-methylene moiety is still present in the product
and hence that cyclisation of the remaining NH2 group at the
methylene position has not taken place.
yield) [λmax (EtOAc) 546 nm, ε 5.8 × 10Ϫ4, w 66 nm], which
½
shows none of the secondary blue absorptions found in certain
other magenta coupler series. The absorption maximum is
strongly solvent dependent; changing the solvent from cyclo-
hexane to methanol causes a bathochromic shift of 34 nm. The
2-methylthio group causes a bathochromic shift of 16 nm in the
absorption maximum by comparison with the effect of a methyl
group at the same position.12
The diamine 12 was also reacted with a range of 1,2- and
1,3-dicarbonyl compounds which provided a good route to
fused 5–6 and 5–7 heterocyclic systems with a consecutive array
of three nitrogen atoms. As found by Sliskovic and co-workers
for the parent 1,5-diaminopyrazole,1 reaction of 12 with
butanedione or with benzil in acetic acid gave the pyrazolo-
[1,5-b]1,2,4-triazines 29 (54%) and 30 (27%) respectively.
In contrast to the above results, a cyclised product was suc-
cessfully obtained when 12 was reacted with carbon disulfide in
the presence of base (Scheme 2). There is some precedent for
this reaction, even in the 5–5 fused ring series.9 On work-up
of the thione 25 a semi-solid was obtained which showed
many spots by TLC, but the mixture was directly alkylated
(iodomethane, base) and the pyrazolo[1,5-b]1,2,4-triazole 26
was isolated as a yellow solid after column chromatography in
5.5% (unoptimised) yield. The product was characterised by
mass spectrometry (m/z 210, Mϩ, 81%) and by 1H NMR
Reaction of 12 with acetylacetone in refluxing acetic acid
provided the first example of the pyrazolo[1,5-b]1,2,4-tri-
azepine system 31. The product was obtained as an oil (39%
yield) after chromatography on alumina. Compound 31 adopts
the 3H tautomer exclusively, even in hydrogen bond acceptor
solvents such as [2H6]acetone. By analogy with the 1,5-benzo-
diazepine system, which adopts an analogous tautomer, the
seven membered ring of 31 is likely to be non-planar and inter-
conversion between two equivalent forms may be reflected in
the coalescence behaviour of the methylene protons. For
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example, these signals of the 1,5-benzodiazepine 32 show a
coalescence temperature of Ϫ50 ЊC corresponding to an
activation energy barrier to ring inversion of 49.8 kJ molϪ1 13
.
However, the methylene protons of the pyrazolo[1,5-b]1,2,4-tri-
1
azepine 31 (H-3) occur as a singlet in the H NMR spectrum
([2H6]acetone solvent) at δH 3.18 at temperatures as low as
Ϫ100 ЊC, indicating that the fused 5–7 pyrazolo[1,5-b]1,2,4-tri-
azepine system is much more flexible than the fused 6–7 1,5-
benzodiazepine (see also below).
1-aminopyrazole;15 even the N(5)–N(6) distance [1.389(4) Å] is
coincidentally close to the corresponding exocyclic N–N bond
length in 1-aminopyrazole [1.403(2) Å]. Except for the bond
angles at the pyrazole ring, which are close to typical values, the
other angles at the ring junctions of 33 are distorted. In particu-
lar the endocyclic angle C(9a)–N(6)–N(5) [131.9(3)Њ] and the
exocyclic angle N(1)–C(9a)–C(9) [128.8(3)Њ] are much larger
than expected. Intermolecular contacts include an N–H ؒ ؒ ؒ O
hydrogen bond linking a-glide related molecules into chains
running along the [100] direction. As with the dimethyl deriv-
ative 31, the 3-methylene group of 33 appears as a singlet
1
(δH 3.36) in the H NMR spectrum at temperatures as low as
Ϫ80 ЊC, so that ring inversion is fast on the NMR time scale.
The corresponding benzodiazepin-2-one 37 shows coalescence
at Ϫ60 ЊC (∆G# 39.8 kJ molϪ1).12 It appears, therefore, that
pyrazolo[1,5-b]1,2,4-triazepines are consistently much more
flexible than the corresponding benzodiazepines.
Elguero and co-workers have reported that analogous tri-
azolo[4,3-b]1,2,4-triazepin-2-ones 39 can undergo an unusual
ring contraction on heating in acetic anhydride to give 1-acyl-
ated pyrazolo[5,1-c]1,2,4-triazoles 40, by formal loss of
HCNO.16 The reaction is thought to involve initial N-acylation
at the 1-position.17 However, reaction of 33 with acetic
anhydride under these conditions gave no useful products,
possibly owing to the tert-butyl group hindering the acylation at
position 7 which would be required as the first step of the
mechanism.
β-Ketoesters also react with the diaminopyrazoles 12 and 15
in refluxing acetic acid (1–1.5 h) to give pyrazolo[1,5-b]1,2,4-
triazepin-2-ones 33–36. Compounds 33–35 were prepared in
42–55% yield using the appropriate ketoesters, though ethyl
benzoylacetate and ethyl pivaloylacetate failed to react, pre-
sumably for electronic and steric reasons respectively. When the
chloropyrazole 15 was employed, the yield of 36 was almost
doubled relative to its unsubstituted analogues (see also below),
though the reason for this effect is not clear. The products were
characterised by their spectra (see Experimental section) and
the regiochemistry of the reaction and tautomeric form of the
products were established by an X-ray crystal structure of the
4-methyl derivative 33 (Fig. 1). The observed regiochemistry
suggests that the cyclisation mode is determined by reaction of
the more reactive N-amino function of the diaminopyrazole
with the ketonic carbonyl group of the ketoester. A similar
tautomeric form to 33 is adopted by the related 1,5-benzo-
diazepine derivative 37, though the dihydrodiazepine 38 is
instead an enamine in solution and in the solid state.14 The
crystal structure of 33 additionally shows the planarity of the
5-membered ring (to within 0.007 Å) and the boat-shape
adopted by the 7-membered ring (Fig. 1).
Reaction of 12 with diethyl malonate under comparable
conditions gave no cyclised products.
The geometric parameters of 33 are generally unexceptional.
For example, those of the 5-membered ring are close to those of
Finally, treatment of 12 with methyl (or ethyl) pyruvate in
refluxing acetic acid for 1.5 h gave a single solid product whose
mass spectrum was consistent with the formation of one of the
regioisomers 41 or 42 (32%). Poorer yields were obtained when
either longer or shorter reaction times were used, but again the
yield was doubled when the chloropyrazole 15 was used as the
starting material. The cyclised products proved to be weakly
active towards the oxidised coupler 22 which suggests that their
structures must be the pyrazolo[1,5-b]1,2,4-triazin-2-one (42
and 43) since the alternative isomer (e.g. 41) is not activated
towards coupling at the 8-position. As found for the β-ketoester
condensations described above, the regiochemistry is therefore
controlled by reaction of the N-amino function with the ketonic
carbonyl group.
Fig. 1 A view of the crystal structure of the pyrazolotriazepinone 33.
Displacement ellipsoids are drawn at the 50% probability level. Selected
bond lengths/Å: N(1)–C(2) 1.360(5), N(1)–C(9a) 1.386(5), C(2)–O(2)
1.210(5), C(2)–C(3) 1.500(6), C(3)–C(4) 1.490(6), C(4)–N(5) 1.283(5),
N(5)–N(6) 1.389(4), N(6)–C(9a) 1.358(5), N(6)–N(7) 1.363(4), N(7)–
C(8) 1.331(4), C(8)–C(9) 1.402(5), C(9)–C(9a) 1.354(5); selected bond
angles/Њ: C(2)–N(1)–C(9a) 127.1(3), N(1)–C(2)–C(3) 115.2(4), C(4)–
C(3)–C(2) 114.3(4), N(5)–C(4)–C(3) 124.8(4), C(4)–N(5)–N(6)
116.5(3), C(9a)–N(6)–N(7) 111.6(3), C(9a)–N(6)–N(5) 131.9(3), N(7)–
N(6)–N(5) 114.3(3), C(8)–N(7)–N(6) 104.8(3), N(7)–C(8)–C(9)
110.8(3), C(9a)–C(9)–C(8) 106.1(3), C(9)–C(9a)–N(6) 106.7(3), N(1)–
C(9a)–C(9) 128.8(3), N(6)–C(9a)–N(1) 124.3(3).
In conclusion, we have shown that the simple strategy of
increasing the steric bulk at the 5-position of a 3-amino-
pyrazole dramatically increases the regioselectivity of
N-amination reactions so that appropriate 1,5-diaminopyrazole
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 6 8 – 4 2 7 4
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derivatives are now readily available. We have shown that the
reactivities of the two amino functions are substantially differ-
ent, with the N-amino group being the more reactive. Balancing
the disparate reactivities of these two groups can cause prob-
lems with cyclisation reactions particularly when the product
consists of two fused 5-membered rings. Nevertheless, a
new pyrazolo[1,5-b]1,2,4-triazole has been synthesised and its
application as a photographic magenta coupler examined.
Cyclisation reactions with 1,2- and 1,3-dicarbonyl compounds
(diketones and ketoesters) were successful giving access to
new pyrazolo[1,5-b]1,2,4-triazines and pyrazolo[1,5-b]1,2,4-tri-
azepines.
were generally used after distillation. Two diamines were syn-
thesised by this method:
1,5-Diamino-3-tert-butylpyrazole 12. (0.92–1.07 g, 60–70%),
bp 128–129 ЊC (0.1 Torr). (Found: Mϩ 154.1214. C7H14N4
requires M 154.1218); δH 5.20 (1H, s), 4.50 (4H, br, s) and 1.19
(9H, s); δC 158.10 (quat), 144.43 (quat), 83.35, 31.87 (quat) and
31.10 (CH3); m/z 154 (Mϩ, 44%), 139 (81), 124 (100), 122 (16),
112 (22), 109 (97), 95 (12) and 94 (18).
1,5-Diamino-3-tert-butyl-4-chloropyrazole 15. (1.15 g, 61%),
bp 156–158 ЊC/0.1 Torr. (Found: Mϩ 188.0830. C7H1335ClN4
requires M 188.0829); δH 5.08 (2H, br, s), 4.08 (2H, br, s) and
1.26 (9H, s); δC 151.52 (quat), 141.84 (quat), 86.62 (quat), 32.62
(quat) and 28.37 (CH3); m/z 190 (Mϩ, 8%), 188 (Mϩ, 26%), 175
(24), 173 (79), 160 (33), 158 (100), 139 (31) and 124 (43).
As reported by Sliskovic,1 3-aminopyrazole 5 gave a 1 : 1
mixture of 1,5-diaminopyrazole 6 and 1,3-diaminopyrazole 7
upon amination under standard conditions. Efforts to separate
the mixture were unsuccessful.
Experimental
1H And 13C NMR spectra were recorded at 250 (or 200) and 63
(or 50) MHz respectively for solutions in [2H]chloroform unless
otherwise stated. Coupling constants are quoted in Hz. 13C
NMR signals refer to CH resonances unless otherwise stated; in
most cases assignments were confirmed by appropriate DEPT
experiments. Mass spectra were obtained under electron impact
conditions.
Amination of 3-amino-5-methylpyrazole 8 gave a 60 : 40
mixture of 1,5-diamino-3-methylpyrazole 9 and 1,3-diamino-5-
methylpyrazole 10. This mixture was also inseparable by stand-
ard methods.
3-Amino-5-tert-butylpyrazole 1118
This product was made by the standard method18 from hydra-
zine hydrate (15 g, 15 cm3, 0.28 mol) and 4,4-dimethyl-3-oxo-
pentanenitrile (18.5 g, 0.15 mol) heated under reflux in ethanol
(200 cm3) for 1 h. After work-up, the crude compound was
recrystallised as reported.18 The yield of the pyrazole was
16.80 g (74%), mp 78–79 ЊC (lit.,18 80 ЊC). δH 5.31 (1H, s), 3.89
(2H, br, s) and 1.19 (9H, s); δC 155.18 (quat), 153.62 (quat),
88.93, 30.86 (quat) and 29.88 (CH3).
1-Aza-1-(5-tert-butylpyrazol-3-yl)-2-(4-methoxyphenyl)ethene
16
3-Amino-5-tert-butylpyrazole 11 (1.39 g, 10 mmol) was dissol-
ved in absolute ethanol (150 cm3) and treated with piperidine
(1 cm3) and p-anisaldehyde (1.36 g, 1.21 cm3, 10 mmol). The
mixture was heated to reflux for 3 h. On removal of solvent
a gummy product was obtained. This was redissolved in ether
and removal of solvent gave a solid product identified as
1-aza-1-(5-tert-butylpyrazol-3-yl)-2-(4-methoxyphenyl)ethene
16 (1.67 g, 65%), mp 138–139 ЊC (from cyclohexane). (Found:
C, 67.85; H, 7.1; N, 15.9. C15H19N3O. 0.5 H2O requires C, 67.65;
H, 7.1; N, 15.8%); δH 8.67 (1H, s), 7.80 (2H, d, 3J 8.7), 6.89 (2H,
d, 3J 8.7), 6.10 (1H, s), 3.78 (3H, s) and 1.32 (9H, s); δC 161.88
(quat), 159.14, 157.31 (quat), 156.08 (quat), 130.24, 128.84
(quat), 113.79, 91.20, 55.04 (CH3), 31.16 (quat) and 29.91
(CH3); m/z 257 (Mϩ, 100%), 256 (31), 241 (62), 215 (36), 200
(12) and 134 (52).
3-Amino-5-tert-butyl-4-chloropyrazole 1419
3-Amino-5-tert-butylpyrazole 11 (1.39 g, 10 mmol) was dissol-
ved in dichloromethane (30 cm3) and cooled to 0 ЊC. N-Chloro-
succinimide (1.34 g, 10 mmol) was added slowly in small
portions and the mixture was stirred at room temperature for
1 h. The reaction mixture was washed with saturated sodium
bicarbonate solution (3 × 50 cm3). The organic phase was
separated and dried over anhydrous magnesium sulfate. The
solvent was removed in vacuo to give a dark coloured solid,
which was recrystallised from cyclohexane to give 3-amino-5-
tert-butyl-4-chloropyrazole 14 as orange–red crystals, 1.25 g
(72%), mp 122–123 ЊC (from cyclohexane). δH 6.10 (2H, br, s)
and 1.31 (9H, s); δC 151.11 (quat), 147.54 (quat), 93.13
(quat), 31.72 (quat) and 27.80 (CH3); m/z 175 (Mϩ, 13%), 173
(Mϩ, 40%), 160 (33), 158 (100), 130 (15) and 123 (10).
This compound has been previously reported in a Japanese
patent.19
Reaction of 1-aza-1-(5-tert-butylpyrazol-3-yl)-2-(4-methoxy-
phenyl)ethene 16 with hydroxylamine-O-sulfonic acid
1-Aza-1-(5-tert-butylpyrazol-3-yl)-2-(4-methoxyphenyl)ethene
16 (0.257 g, 1 mmol) was dissolved in DMF (2 cm
3). Potassium
hydroxide (0.416 g, 7.4 mmol) and hydroxylamine-O-sulfonic
acid (0.226 g, 2 mmol) were added using the same conditions
mentioned previously. The mixture was left stirring for 2 h
and DMF was removed in vacuo. After further work up with
dichloromethane products were isolated which were found
to be 5-tert-butyl-3-aminopyrazole 11 and anisaldehyde,
i.e. hydrolysis of the imine had occurred.
N-Amination of 3-aminopyrazoles: general method
The aminopyrazole (10 mmol) was dissolved in dry dimethyl-
formamide (15 cm3) and cooled to Ϫ10 ЊC. Crushed potassium
hydroxide (4.16 g) was added and the solution was left to stir for
20 min at Ϫ10 ЊC. Hydroxylamine-O-sulfonic acid (2.26 g,
20 mmol) was added cautiously in small portions. The resulting
mixture was allowed to warm to room temperature and stirred
for 2 h. The mixture was then filtered and the solvent was
removed under reduced pressure. The resulting semi-solid was
re-dissolved in dichloromethane, filtered, and dried over
anhydrous magnesium sulfate. On removal of the solvent at
reduced pressure an oily product was obtained which was found
to be a mixture of diamines and starting materials. The mixture
was re-dissolved in dimethylformamide and the whole reaction
sequence was repeated. The resulting products were distilled
under vacuum (Kugelrohr); they could be further purified by
dry flash chromatography (50 : 50 ethyl acetate–hexane), but
1,5-Bis(3,3-dimethyl-1,3-diazapropenyl)-3-tert-butylpyrazole 18
1,5-Diamino-3-tert-butylpyrazole 12 (0.154 g, 1 mmol) was
heated on a steam bath with dimethylformamide dimethylacetal
(2 cm3) for 1 h. On removal of solvent under reduced pressure
a white solid was obtained which was identified as the bis-
amidine, 1,5-bis-(3,3-dimethyl-1,3-diazapropenyl)-3-tert-butyl-
pyrazole 18 (0.254 g, 96%), which could not be purified, mp
ca. 92 ЊC; (Found: Mϩ 264.2068. C13H24N6 requires M
264.2062); δH 8.27 (1H, s), 7.74 (1H, s), 5.52 (1H, s), 2.94–2.90
(12H, m) and 1.21 (9H, s); δC 155.88 (quat), 154.54, 154.10,
144.87 (quat), 84.42, 40.11 (CH3), 37.96 (2CH3), 34.19 (CH3),
32.05 (quat) and 30.39 (CH3); m/z 264 (Mϩ, 100%), 249 (10),
194 (21), 193 (12), 179 (26), 152 (14) and 138 (24).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 6 8 – 4 2 7 4
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Reaction of 1,5-diamino-3-tert-butylpyrazole with triethyl
orthoformate
scopy showed a peak at δH 5.45 which was attributable to 6-tert-
butylpyrazolo[1,5-b]1,2,4-triazole-2-thione 25 which was used
without further purification.
1,5-Diamino-3-tert-butylpyrazole 12 (0.154 g, 1 mmol) was
heated in a Kugelrohr oven to 80 ЊC with triethyl orthoformate
(0.25 cm3). The by-product ethanol was distilled off, collected
and identified by its 1H NMR spectrum. The mixture was
heated until ethanol ceased to evolve. A glassy solid was
obtained which appeared to be polymeric.
The solid mixture was dissolved in methanol (10 cm3), iodo-
methane (0.22 cm3, 3.53 mmol) was added followed by potas-
sium hydroxide (0.2 g, 3.57 mmol). The mixture was stirred at
room temperature for 2 h, evaporated to dryness and par-
titioned between hydrochloric acid (5%) and ethyl acetate. The
organic layer was dried over magnesium sulfate to give an oily
product. TLC showed the presence of product as a purple spot
on spraying with developer 22 and aqueous potassium per-
sulfate. The mixture was purified by column chromatography
(silica), [ethyl acetate–light petroleum (bp 60–80 ЊC) (50 : 50)
eluents] to give a yellow solid, 6-tert-butyl-2-(methylthio)-
pyrazolo[1,5-b]1,2,4-triazole 26 (0.045 g, 5.5%), mp 226–227 ЊC
(from ethyl acetate). (Found: C, 50.05; H, 6.6; N, 25.6.
C9H14N4S 0.33 H2O requires C, 50.0; H, 6.8; N, 25.9%);
δH (2[H]6DMSO) 12.77 (1H, br, s), 5.61 (1H, s), 2.61 (3H, s) and
1.26 (9H, s); δC (2[H]6DMSO) 161.43 (quat), 147.64 (quat),
138.01 (quat), 74.81, 32.49 (quat), 30.54 (CH3) and 14.84
(CH3); m/z 210 (Mϩ, 81%), 195 (100), 168 (20), 148 (32) and 127
(23).
5-Acetamido-1-(N,N-diacetylamino)-3-tert-butylpyrazole 19
1,5-Diamino-3-tert-butylpyrazole 12 (0.308 g, 2 mmol) was
heated under reflux in acetic anhydride (10 cm3) for 2 h. On
cooling a white precipitate was recovered and this was identified
as 5-acetamido-1-(N,N-diacetylamino)-3-tert-butylpyrazole 19
(0.140 g, 25%), mp 220–221 ЊC (from ethanol). (Found: Mϩ
280.1540. C13H20N4O3 requires M 280.1535); δH (2[H]6DMSO)
6.43 (1H, s), 2.18 (6H, s), 2.06 (3H, s) and 1.21 (9H, s);
δC (2[H]6DMSO) 170.47 (quat), 167.33 (quat), 159.81 (quat),
137.85 (quat), 92.00, 32.21 (quat), 30.01 (CH3), 24.56 (CH3) and
23.29 (CH3); m/z 280 (Mϩ, 20%), 238 (93), 196 (100), 154 (33)
and 125 (40). Removal of solvent in vacuo yielded a yellow
oil which was found to be a mixture of triacetylated and
diacetylated products.
6-tert-Butyl-2-methylthio-7-(4-diethylamino-2-methylphenyl-
imino)pyrazolo[1,5-b]1,2,4-triazole 28
1-Aza-1-(5-amino-3-tert-butylpyrazol-1-yl)-2-phenylethene 20
6-tert-Butyl-2-(methylthio)pyrazolo[1,5-b]1,2,4-triazole
26
(0.052 g, 0.25 mmol) was dissolved in a mixture of 5% aqueous
sodium carbonate solution (5 cm3) and methanol (2.5 cm3). The
developer, 4-(N,N-diethylamino)-3-methylaminobenzene hydro-
chloride 27 (0.062 g, 0.29 mmol) was added, followed by potas-
sium persulfate (0.15 g, 0.55 mmol). The solution became
intense purple and the resulting dye, 6-tert-butyl-2-methylthio-
7-(4-diethylamino-2-methylphenylimino)-7H-pyrazolo[1,5-b]-
1,2,4-triazole 28 was formed as a purple precipitate, (0.077 g,
81%), mp 133–134 ЊC (crude). (Found: Mϩ 384.2097. C20H28-
N6S requires M 384.2096); λmax (MeOH), 558 nm, λmax (EtOAc),
546 nm, λmax (cyclohexane), 524 nm; ε(EtOH) 58400; δH 9.02
1,5-Diamino-3-tert-butylpyrazole (0.167 g, 1.08 mmol) was
condensed with benzaldehyde (0.115 g, 0.110 cm3) in the pres-
ence of toluene-p-sulfonic acid (cat.) in methanol (3 cm3). The
mixture was maintained at reflux temperature for 3 h. Removal
of solvent gave a brown solid, 1-aza-1-(5-amino-3-tert-butyl-
pyrazol-1-yl)-2-phenylethene 20 (0.188 g, 72%), mp ca. 136 ЊC.
(Found Mϩ 242.1527. C14H18N4 requires M 242.1531); δH 8.88
(1H, s), 7.79 (2H, m), 7.39 (3H, m), 5.41 (1H, s), 4.24 (2H, br, s)
and 1.31 (9H, s); δC 160.55 (quat), 144.82, 144.04 (quat), 133.9
(quat), 129.59, 128.53, 127.55, 84.85, 32.44 (quat) and 29.99
(CH3); m/z 242 (Mϩ, 20%), 227 (7), 210 (7), 138 (4) and 124(9).
3
3
4
(1H, d, J 9.4), 6.73 (1H, d, d, J 9.4 and J 2.9), 6.59 (1H, d,
4J 2.9), 3.49 (4H, q, 3J 7.1), 2.66 (3H, s), 2.53 (3H, s), 1.53 (9H,
s) and 1.25 (6H, t, 3J 7.1); δC 170.23 (quat), 162.30 (quat),
151.84 (quat), 146.70 (quat), 143.09 (quat), 135.21 (quat),
131.12 (quat), 127.10, 112.54, 110.39, 44.92, 35.38 (quat), 29.43,
20.42, 14.98 and 12.73; m/z 384 (Mϩ, 100%), 369 (33) and 258
(24).
5-(3-tert-Butyl-5-aminopyrazol-1-ylamino)methylene-2,2-di-
methyl-1,3-dioxane-4,6-dione 23
5-Methoxymethylene-2,2-dimethyl-1,3-dioxane-4,6-dione
(0.165 g, 0.89 mmol) was added to a solution of 1,5-diamino-3-
tert-butylpyrazole 12 (0.154 g, 1 mmol) in acetonitrile (2 cm3).
The mixture was left stirring overnight. A white precipitate was
isolated and was identified as 5-(3-tert-butyl-5-aminopyr-
azol-1-ylamino)methylene-2,2-dimethyl-1,3-dioxane-4,6-dione
23 (0.115 g, 37%), mp 230–231 ЊC (from acetonitrile). (Found:
C, 54.25; H, 6.45; N, 17.9. C14H20N4O4 requires C, 54.55; H, 6.5;
7-tert-Butyl-2,3-dimethylpyrazolo[1,5-b]1,2,4-triazine 29
1,5-Diamino-3-tert-butylpyrazole 12 (0.154 g, 1 mmol) was dis-
solved in acetic acid (5 cm3). Butanedione (0.086 g, 1 mmol) was
added and the mixture was heated under reflux for 1 h. The
solvent was removed in vacuo and the residue was partitioned
between hexane (25 cm3) and aqueous sodium bicarbonate
(25 cm3). The organic layer was dried (MgSO4) and the solvent
was removed at reduced pressure to give 7-tert-butyl-2,3-di-
methylpyrazolo[1,5-b]-1,2,4-triazine 29 (0.110 g, 54%), mp 144–
145 ЊC (from ethanol–cyclohexane). (Found: Mϩ 204.1367.
C11H16N4 requires M 204.1375); δH 6.37 (1H, s), 2.50 (3H, s),
2.48 (3H, s) and 1.34 (9H, s); δC 164.32 (quat), 150.62 (quat),
144.42 (quat), 140.57 (quat), 91.37, 32.60 (quat), 30.12 (CH3),
22.52 (CH3) and 19.44 (CH3); m/z 204 (Mϩ, 51%), 189 (100),
162 (28), 148 (67), 109 (11) and 77 (13).
3
N, 18.2%); δH (2[H]6DMSO) 11.45 (1H, br d, JH,NH 14.6) 8.57
3
(1H, d, JH,NH 14.6), 6.55 (1H, s), 6.37 (2H, br s), 1.70 (6H, s)
and 1.25 (9H, s); δC (2[H]6DMSO) 164.58 (quat), 162.27 (quat),
156.83 (quat), 152.21, 136.99 (quat), 104.69 (quat), 87.51
(quat), 87.11, 32.16 (quat), 30.21 (CH3) and 26.57 (CH3); m/z
308 (Mϩ, 18%), 251 (20), 250 (100), 217 (16), 205 (15), 204 (79),
191 (20) and 123 (11).
6-tert-Butyl-2-(methylthio)pyrazolo[1,5-b]1,2,4-triazole 26
1,5-Diamino-3-tert-butylpyrazole 12 (0.60 g, 3.9 mmol) was
dissolved in methanol (10 cm3). Water (0.3 cm3) was then added
followed by potassium hydroxide (0.27 g, 4.82 mmol) and
carbon disulfide (2.55 cm3). The mixture was heated to reflux
for 2–3 h during which time the solution became yellow and
evolution of hydrogen sulfide was noted. The mixture was then
neutralised with hydrochloric acid (5%), poured into water and
extracted with ethyl acetate (2 × 25 cm3). The organic layer was
separated and dried over anhydrous magnesium sulfate. On
removal of solvent in vacuo a semi-solid product was obtained.
TLC showed many products had formed but NMR spectro-
7-tert-Butyl-2,3-diphenylpyrazolo[1,5-b]1,2,4-triazine 30
1,5-Diamino-3-tert-butylpyrazole 12 (0.15 g, 1 mmol) was
reacted with benzil (0.50 g, 4.2 mmol) in acetic acid (5 cm3). The
resulting solution was heated to reflux for 4 h. The solvent was
removed and the residue was purified by column chromato-
graphy on silica (toluene eluent), to give a yellow solid, 7-tert-
butyl-2,3-diphenylpyrazolo[1,5-b]1,2,4-triazine 30 (0.090 g,
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27%), mp 135–136 ЊC (from hexane–ethanol). (Found: Mϩ
328.1678. C21H20N4 requires M 328.1688); δH 7.43–7.25 (10H,
m), 6.67 (1H, s) and 1.46 (9H, s); δC 166.59 (quat), 149.98
(quat), 145.69 (quat), 140.67 (quat), 136.76 (quat), 134.67
(quat), 129.59, 129.42, 129.33, 129.11, 128.10 (2C), 92.93, 32.94
(quat) and 30.17 (CH3); m/z 328 (Mϩ, 100%), 313 (65), 286 (26),
211 (12), 210 (78), 178 (12), 105 (11) and 77(55).
δC 165.84 (quat), 160.39 (quat), 160.16 (quat), 132.79 (quat),
90.52, 40.68, 40.05, 32.17 (quat), 29.93, 18.84, and 13.42; m/z
248 (Mϩ, 46%), 233 (100), 220 (18), 206 (10), 164 (14) and 124
(14).
1H-8-tert-Butyl-9-chloro-4-methylpyrazolo[1,5-b]1,2,4-
triazepin-2(3H)-one 36
A solution of 1,5-diamino-3-tert-butyl-4-chloropyrazole 15
(0.212 g, 1.12 mmol) and ethyl acetoacetate (0.146 g, 1.12
mmol) in acetic acid (8 cm3) was heated under reflux for 1 h.
Removal of solvent gave an oil which crystallised on cooling in
a salt–ice bath. The solid was washed with light petroleum
(bp 60–80 ЊC) and was identified as 1H-8-tert-butyl-9-chloro-4-
methylpyrazolo[1,5-b]1,2,4-triazepin-2(3H)-one 36 (0.232 g,
81%), mp 224–225 ЊC (from cyclohexane–ethanol). (Found: Mϩ
254.0939. C11H1535ClN4O requires M 254.0934); δH 3.36 (2H, s),
2.31 (3H, s) and 1.35 (9H, s); δC 164.71 (quat), 158.72 (quat),
153.65 (quat), 130.03 (quat), 94.20 (quat), 42.02, 33.00 (quat),
28.17 and 24.52; m/z 256 (Mϩ, 20%), 254 (Mϩ, 60%), 241 (32),
239 (100), 214 (10), 212 (30), 177 (10) and 158 (10).
1H-8-tert-Butyl-2,4-dimethylpyrazolo[1,5-b]1,2,4-triazepine 31
A solution of 1,5-diamino-3-tert-butylpyrazole 12 (0.20 g,
1.3 mmol) and acetylacetone (0.13 g, 1.3 mmol) in acetic acid
(4 cm3) was heated under reflux for 2 h. The solvent was
removed in vacuo to yield a semi-solid product. This was
washed with aqueous sodium carbonate to remove the last
traces of acetic acid. The mixture was purified by column
chromatography (alumina) using a 30 : 70 mixture of ethyl
acetate–hexane as eluant. The dark red oily product obtained
was identified as 1H-8-tert-butyl-2,4-dimethylpyrazolo[1,5-b]-
1,2,4-triazepine 31 (0.11 g, 39%), bp 120–122 ЊC (0.2 Torr).
(Found: Mϩ 218.1529. C12H18N4 requires M 218.1531); δH 6.12
(1H, s), 3.18 (2H, s), 2.30 (3H, s), 2.26 (3H, s) and 1.31 (9H, s);
δC 161.23 (quat), 160.07 (quat), 154.46 (quat), 135.70 (quat),
97.62, 42.33, 32.74 (quat), 30.76, 28.56 and 24.70; m/z 218 (Mϩ,
57%), 217 (17), 203 (100), 189 (6), 176 (13), 164 (14), 163 (10),
162 (13) and 148 (14).
Reaction of 1,5-diamino-3-tert-butylpyrazole with other
ꢀ-dicarbonyl compounds
Reaction of solutions of 1,5-diamino-3-tert-butylpyrazole
(1 mmol) in acetic acid (3 cm3) with ethyl benzoylacetate
(1 mmol), with ethyl pivaloylacetate (1 mmol) or with diethyl
malonate (1 mmol) at reflux for 1.5–2 h gave oils which were
identified as starting material, though with some decom-
position.
1H-8-tert-Butyl-4-methylpyrazolo[1,5-b]1,2,4-triazepin-2(3H)-
one 33
A solution of 1,5-diamino-3-tert-butylpyrazole 12 (0.82 g,
5.33 mmol) and ethyl acetoacetate (0.70 g, 5.40 mmol) in acetic
acid (8 cm3) was heated under reflux for 1 h. The solvent was
removed in vacuo and the residue was washed with ether to yield
a pale buff coloured solid, 1H-8-tert-butyl-4-methylpyrazolo-
[1,5-b]1,2,4-triazepin-2(3H)-one 33 (0.51 g, 44%), mp 221–222
ЊC (from ethyl acetate). (Found: C, 59.6; H, 7.15; N, 24.85.
C11H16N4Oؒ0.1H2O requires C, 59.5; H, 7.3; N, 25.25%); δH 9.96
(1H, br, s), 5.80 (1H, s), 3.36 (2H, s), 2.32 (3H, s) and 1.28 (9H,
s); δC 165.66 (quat), 160.12 (quat), 157.53 (quat), 132.61 (quat),
90.56, 41.73, 32.17 (quat), 29.92 and 24.44; m/z 220 (Mϩ, 51%),
205 (100), 178 (15) and 164 (11).
7-tert-Butyl-3-methylpyrazolo[1,5-b]1,2,4-triazin-2-one 42
A solution of 1,5-diamino-3-tert-butylpyrazole 12 (1.0 g,
6.5 mmol) and ethyl (or methyl) pyruvate (1.5 g, 13 mmol) was
heated under reflux in acetic acid solution (10 cm3) for 1.5 h.
The solvent was then removed under reduced pressure. The
residue was washed with ether and filtered to obtain 7-tert-
butyl-3-methylpyrazolo[1,5-b]1,2,4-triazin-2-one 42 as a white
solid, (0.42 g, 32%), mp 233–234 ЊC (from ethanol–cyclo-
hexane). (Found: C, 58.2; H, 6.85; N, 27.2. C10H14N4O requires
C, 58.25; H, 6.85; N, 27.2%); δH 5.86 (1H, s), 2.41 (3H, s) and
1.33 (9H, s); δC 162.87 (quat), 154.29 (quat), 145.95 (quat),
132.98 (quat), 84.17, 32.57 (quat), 29.89 (CH3) and 16.92 (CH3);
m/z 206 (Mϩ, 47%), 191 (100), 164 (26) and 150 (53).
1H-8-tert-Butyl-3,4-dimethylpyrazolo[1,5-b]1,2,4-triazepin-
2(3H)-one 34
A solution of 1,5-diamino-3-tert-butylpyrazole 12 (0.171 g,
1.11 mmol) and ethyl 2-methylacetoacetate (0.160 g, 1.11
mmol) in acetic acid (3 cm3) was heated under reflux for 1.5 h.
The solvent was removed in vacuo to yield initially an oil. Tri-
turation with ether gave a buff solid, 1H-8-tert-butyl-3,4-di-
methylpyrazolo[1,5-b]1,2,4-triazepin-2(3H)-one 34 (0.144 g,
55%), mp 204–205 ЊC (from ethanol–cyclohexane). (Found: Mϩ
234.1487. C12H18N4O requires M 234.1480); δH 5.80 (1H, s),
3.45 (1H, q, J 6.9), 2.21 (3H, s), 1.42 (3H, d, J 6.9) and 1.30
(9H, s); δC 167.28 (quat), 162.00 (quat), 160.34 (quat), 132.91
(quat), 90.04, 42.49, 32.20 (quat), 29.95, 19.79, and 10.53; m/z
234 (Mϩ, 42%), 219 (100), 178 (9) and 96 (11).
7-tert-Butyl-8-chloro-3-methylpyrazolo[1,5-b]1,2,4-triazin-2-one
43
A solution of 1,5-diamino-3-tert-butyl-4-chloropyrazole 15
(0.8 g, 4.25 mmol) and ethyl pyruvate (0.5 g, 4.30 mmol) was
heated under reflux in acetic acid solution (7 cm3) for 1.5 h. The
solvent was then removed in vacuo, the residue was washed with
light petroleum (bp 60–80 ЊC) to yield a white solid 7-tert-butyl-
8-chloro-3-methylpyrazolo[1,5-b]1,2,4-triazin-2-one 43 (0.74 g,
72%), mp 174–175 ЊC (from ethanol–cyclohexane). (Found: Mϩ
240.0770. C10H1335ClN4O requires Mϩ 240.0778); δH 7.66 (1H,
br, s), 2.40 (3H, s) and 1.14 (9H, s); δC 156.42 (quat), 153.35
(quat), 147.24 (quat), 130.60 (quat), 88.01 (quat), 33.40 (quat),
33.40 (CH3) and 16.82 (CH3); m/z 242 (Mϩ, 20%), 240 (Mϩ,
60%), 227 (33), 225 (100), 215 (5), 200 (15), 198 (45), 186 (25),
184 (76), 163 (25) and 156 (40).
3
3
1H-8-tert-Butyl-4-propylpyrazolo[1,5-b]1,2,4-triazepin-2(3H)-
one 35
A solution of 1,5-diamino-3-tert-butylpyrazole 12 (0.184 g,
1.2 mmol) and ethyl butyrylacetate (0.189 g, 1.2 mmol) in acetic
acid (5 cm3) was heated under reflux for 1.5 h. Removal of
solvent in vacuo yielded a yellow oil which crystallised over a
period of 2 days. The solid was washed with cyclohexane to give
1H-8-tert-butyl-4-propylpyrazolo[1,5-b]1,2,4-triazepin-2(3H)-
one 35 (0.125 g, 42%), mp 155–156 ЊC (from ethanol–cyclo-
Crystal data for 33
C11H16N4O, M = 220.28, monoclinic, a = 10.483(5), b = 9.356(4),
c = 12.297(3) Å, β = 101.14(3)Њ, U = 1183.4(8) Å3, T = 298(2) K,
space group P21/a (Alt. P21/c, No. 14), Z = 4, Dc = 1.237 g cmϪ3
,
hexane). (Found: Mϩ 248.1648. C13H20N4O requires
M
µ(Mo–Kα) = 0.084 mmϪ1, 1554 unique reflections measured and
used in all calculations. Final R1 [869 F > 4σ(F)] = 0.0570 and
wR(all F 2) was 0.171.
248.1637); δH 5.80 (1H, s), 3.34 (2H, s), 2.59–2.51 (2H, m),
1.76–1.65 (2H, m), 1.28 (9H, s) and 0.98–0.91 (3H, m);
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 6 8 – 4 2 7 4
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8 D. Clarke, R. W. Mares and H. McNab, J. Chem. Soc., Perkin Trans.
1, 1997, 1799–1804.
Acknowledgements
9 K. Pilgram and G. E. Pollard, J. Heterocycl. Chem., 1976, 13, 1225–
We are grateful to the EPSRC and to Kodak Ltd. for a CASE
award (to RWM) and to Lonza Ltd. for a generous gift of
Meldrum’s acid. We also thank the EPSRC for the award
of a diffractometer. This paper is dedicated to the memory of
Dr N. E. (Sam) Milner.
1228.
10 T. Kawagishi and N. Furutachi, European Patent, 119,860; Chem.
Abstr., 1985, 102, 36637b.
11 D. Clarke, H. McNab and R. W. Mares, US Patent 5,723,623; Chem.
Abstr., 1997, 127, 121724p.
12 T. Sato, Nippon Shashin Gakkaishi, 1989, 52, 162–166; Chem. Abstr.,
1989, 111, R205129f.
13 A. Mannschreck, G. Rissmann, F. Vögtle and D. Wild, Chem. Ber.,
1967, 100, 335–346.
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