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J. Chern. SOC.(C), 1970
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2510
Sequential Attack by a Diketone on a Polyhydrazine; the Reaction of
Triaminoguanidine with Acetylacetone
By R. N. Butler,t F. L. Scott,* and R. D. Scott, Department of Chemistry, University College, Cork, Ireland
The reaction of triaminoguanidine with acetylacetone involves a sequential attack of the diketone on the hydrazine
groupings of the triaminoguanidine. The reaction provides a new route to substituted tetrazines and dipyrazolyl
ketone hydrazones, but it cannot be used to provide a hydrazidinating reagent comparable with the amidinating
agents obtained from similar reactions of diketones with monoacylhydrazines.
WE examined, some time ago, the mechanistic patterns
of cleavage of l-acylpyrazoles and evolved from these
studies a variety of useful synthetical procedures.1.2
The acyl groups we used were principally nitrogencontaining such as carbamoyl, thiocarbamoyl, amidino,
etc., and the deacylation processes proved to be efficient
means of transacylation. In particular, the l-amidinopyrazoles proved t o be useful amidinating agents for
both organic synthesis l y 3 and biochemical purpose^.^
Because of this latter use especially, we considered the
possibility of synthesising a l-acylpyrazole containing a
hydrazidino-group [C(:N*NH,)-NH*NH,] so that its use
in novel modification of amino-acids might be examined.
A ready synthesis of our l-amidinopyrazolesinvolved the
reaction of p-diketones with monoacylhydrazines. A
similar reaction with the polyhydrazine triaminoguanidine would give the desired hydrazidino-transferring agent (I). Hence we investigated the reaction of
triaminoguanidine with acetylacetone as a means of
preparing materials such as compounds (I).
On treatment of triaminoguanidine nitrate with
acetylacetone a complex reaction occurred giving rise
to a number of products, the proportions of which varied
t Present address: sligo Regional Technical College, SligO,
Ireland.
F. L. Scott, D. O’Donovan, and J. Reilly, J . Anzer. Chern.
SOG.,1953, 75, 4053.
F. L. Scott, J . Org. Chem.,, 1957, 22, 1568.
Reagents for Organic Synthesis,’
Wiley, New York, 1967, p. 738.
* A. F. S. A. Habeeb, Biochinz. Biophys. A d a , 1959, 34, 294;
Canad. J . Biochenz. Physiol., 1960, 38, 493.
2
3 L. F. Fieser and M. Fieser,
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2511
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Org.
with the conditions of the reaction (Table). I n the
presence of sufficient acetylacetone, a t ambient temperatures the dipyrazolylmethylenehydrazono-derivative
(111) was the main product, whereas under reflux conditions considerable decomposition occurred and a pale
yellow compound with the dihydrotetrazine structure
(IV) was isolated in highest yield. Small quantities of
3,5-dimethylpyrazole were also isolated from these reactions. Hence this procedure provides a new route to
substituted tetrazines. By using two, or less, molar
proportions of acetylacetone, the product (111)could be
excluded from the reaction entirely. Under these
conditions, prolonged stirring of the reactants a t ambient
temperatures or gentle heating of the solutions favoured
formation of the product (IV). It was also noted that a
stoicheiometry of 2 : 1 (acetylacetone to triaminoguanidine) appeared to be operating in the reaction,
since when less than two molar proportions of acetylacetone were used, a quantity close to the expected
both as its benzylidene derivative (V) and as its acetylacetone derivative (111). Treatment of the material (11)
with dilute nitric acid or hydrochloric acid yielded the
dihydrotetrazine (IV) (30-50~0) and 3,5-dimethylpyrazole (90%); thus the origin of these materials is
explained. Hence the overall reaction can be represented as a coherent process involving sequential
attack of the diketone at the hydrazine-groupings of the
substrate (Scheme). Attack of acetylacetone on each
hydrazine grouping, followed by elimination of a
molecule of water (cf. ref. 5) leads to the material (11),
probably via the hydrazidinopyrazole derivative (I).*
This latter material, however, if present a t all, is apparently extremely reactive and is rapidly converted into
the material (11)and hence cannot be used as an effective
hydrazidinating agent. Subsequent reaction of the
material (11) with acid or excess of acetylacetone
accounts for the other products observed.
EXPERIMENTAL
Me
NHiNH-C-N H-NH,,HNO,
II
N
o=c(
t
CH2
o=c /
I
NH2
PY
\
,C=N-NH2
PY
N-N
(Nl
‘Me
-
( A c ) ~ G H ~ Py-C-NH*
II
NH2
I
IY
I
R’
Pv
1
2
(ml R=Me,R=CH2Ac
1
(Y) R = H , R2=Ph
P y = 3,5-dimethylpyrazol-l-yl
SCHEME
quantity of triarninoguanidine nitrate was recovered
unchanged in each case. This suggested the presence of
an intermediate, a possible precursor of compound (IV),
and this was subsequently isolated in yields up to 50:/,
by a brief stirring of the reactants (15 min.) at ambient
temperatures followed by immediate work-up, thereby
intercepting it prior to its conversion into compound
(IV)*
This intermediate was identified as the novel dipyrazolyl ketone hydrazone (11). It was characterised
5 The reactions of diketones with monsubstituted hydrazines
t o give substituted pyrazoles are well documented: F. Kurzer
and K. Douraghi-Zadeh, J . Chem. SOC.( C ) , 1966, 6 ; H. Beyer
and K. Pommerening, Chern. Bey., 1966, 99, 2937; H. Beyer,
E. Bulka, W. Dietz, and H.-G. Potzwaldt, ibid., 1963, 96, 1996;
D. T. Manning and H. A. Coleman, J . Oyg. Chern., 1969,34, 2747.
M.p.s are corrected. Molecular weights were determined
by cryoscopic methods. 1.r. spectra were measured with a
Perkin-Elmer Infracord (model 137E) spectrophotometer
with sodium chloride optics. Solids were examined as discs
with potassium bromide. U.V. spectra were measured with
a Perkin-Elmer (model 137) spectrophotometer with 95%
ethanol as solvent.
Reaction of Triaminoguanidine Nitrate with A cetylacetone.
-The following is a typical example. A solution of triaminoguanidine nitrate (2.25 g.) in slightly warmed water
(60 ml.) was cooled to ambient temperature and treated
with acetylacetone (1.75 ml.) in 95% ethanol (15 ml.).
The mixture was stirred for 1 hr. and set aside for 3 days,
during which time successive crops of pale yellow crystals
of 1,2-dihydro-3,6-bis-(3,5-dimethyl~yrazol-l-yZ)tetrazine
(IV)
(total yield 593 mg., 32.5%) separated, m.p. 147-149’
(from aqueous ethanol) (Found: C, 53.05; H , 5.95; N,
41.75%; M ,269. C,,H,,N, requires C, 52.9; H, 5.9; N,
41.15%; M , 272). A solution of the material in 95%
ethanol developed a red colour and showed a characteristic
tetrazine U.V. absorptions a t 528 nm. resulting from
oxidation of the compound. The fully oxidised tetrazine
was obtained as described later. Also in accord with
structure (IV) was a strong N-H i.r. absorption a t 3320
cm.-l.
The filtrate from this material was treated with water
(50 ml.) and extracted with ether (4 x 70 ml.). The
yellow extracts were separated from the aqueous portion
[solution (A)], combined, dried, and evaporated. The
residue, a white crystalline solid with a sticky yellow gum
was repeatedly shaken with small portions of cold ether to
remove the gum. The white solid (521 mg., 28%) was
bis- (3,5-dimethylpyrazol1-yZ) ketone hydrazone (11), m.p.
119-121’ [from light petroleum (b.p. 40-60°)] (Found:
C, 56.75; H , 6.7; N, 35-85. C1lH,,N, requires C, 56.9;
H, 6.9; N, 36.2%). The i.r. spectrum of the material
showed characteristic primary amine bands, vmaX. 3300 and
3410 (NH stretching) and 1630 cm.-l (NH, deformation).
* Attempts t o isolate this material b y using excess of triaminoguanidine were unsuccessful (see Table).
6 C. H. Lin, E. Lieber, and J. P. Hotwitz, J . Amer. Chem.
SOC.,1954, 76, 427.
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2512
J. Chem. SOC. (C), 1970
The aqueous solution (A) was brought to pH 6 with Nsodium hydroxide and slowly evaporated a t 40" under
vacuum. Successive crops of triaminoguanidine nitrate
separated (total recovery 615 mg., 27%). The solution was
finally evaporated to dryness and the brown sticky residue
was dissolved in water (10ml.). The solution was extracted
with ether (10 x 20 ml.). Work up of the extracts yielded
white plates (51 mg., 9%) of 3,5-dimethylpyrazole (m.p.
107-109").
The results of a number of such reactions are summarised
in the Table.
Conditions
Molar ratio
(triaminoguanidine to
acetylacetone)
1 : 1.1la
Temp.
Products (%)
(reaction
time)
(11)
(1111
(IV~
Ambient
28
<1
32.5
(3 days)
1:2b
50
<1
1.5
Ambient
(15 min.)
2.5
<1
<1
Ambient
4: 1 c
(15 min.)
<1
64-70
4
Ambient
(30 min.)
Reflux
<1
11
13
(30 rnin.)
a Triaminoguanidine nitrate recovered, 28%.
3,5-dimethylpyrazole was isolated in 9% yield. A sticky reddish yellow
oil was also obtained. 6 No triaminoguanidine nitrate
recovered. A reddish yellow oil was obtained. 0 Triaminoguanidine nitrate recovered, 75-80%.
Sticky yellow gums
again formed. d No triaminoguanidine nitrate recovered.
3,5-Dimethylpyrazole isolated, 5% . 6 Considerable quantities
of resinous decomposition products were encountered. A
previous report (cf. F. L. Scott, M. F. Cashman and J. Reilly,
J . Amer. Clzem. SOL, 1953, 75, 1510) of a 58% yield of compound (IV) under these conditions is in error. The figure
should probably have been 5.8.
A
Reactions of t h Hydrazone (11).-(a) With aldehydes.
Benzaldehyde (0.057 ml.) was added to a solution of compound (11) (100 mg.) in 95% ethanol and the mixture was
heated a t 70" for 15 min., treated with a few drops of water,
and stirred for 3 hr. a t ambient temperature. The solution
was then heated to boiling, treated with water until cloudiness appeared, and set aside for 24 hr. White crystals
(106 mg., 77%) of bis-(3,5-divtzethylpyrazol-l-y1) ketone
benzylidenehydrazone (V) separated, m.p. 102-103" (from
aqueous ethanol) (Found: C, 67.1; H, 6.5; N, 26.2.
C18H2,,N, requires C, 67-5; H, 6-25; N, 26.25%).
A similar reaction with acetylacetone yielded bis-(3,5dimethylfiyrazol-l-yl) ketone (l-methyl-3-oxobutylidene)hydrazone (111),m.p. 103-104" (from aqueous ethanol),identical
(mixed m.p. and i.r. spectra) with that obtained from the
reaction of triaminoguanidine with acetylacetone (Found :
C, 60.95; H, 7.3; N, 26.7. C1,H2ZN,0 requires C, 61.1;
H, 7.0; N, 26.75%).
(b) With acids. A solution of compound (11) (200 mg.)
in 95% ethanol was treated with water (3 ml.) followed by
hydrochloric acid ( 0 . 0 1 ~ ;0.5 ml.), and the mixture was
stirred a t ambient temperature for 2 hr. It was then
heated to boiling and treated with water until crystals
began to appear. On cooling the solution, pale yellow
crystals (35 mg., 30-6y0)of compound (IV) separated, m.p.
144-147', identical (mixed m.p. and i.r. spectra) with that
obtained previously.
The filtrate from this material was extracted with ether
but the ethereal solution yielded only an intractable brown
gum. The aqueous solution remaining was evaporated to
dryness ; i t deposited white crystalline 3,5-dimethylpyrazole
hydrochloride (103 mg., go%), m.p. 236-240" (shrinks and
turns brown), identical (mixed m.p. and i.r. spectra) with a
sample prepared by dissolving a small quantity of 3,5dimethylpyrazole in a few ml. of dilute hydrochloric acid
and evaporating the solution (Found: C, 45.2; H, 7.15;
C1, 26.55; N, 20.85. Calc. for C,H,C1N2: C, 45.3; H, 6-8;
C1, 26.8; N, 21.15%).
A similar reaction with nitric acid yielded compound
(IV) (51yo)and 3,5-dimethylpyrazole (40%).
Oxidation of the Dihydrotetrazine (IV).-A solution of the
diliydrotetrazine (IV) (340 mg.) in acetic acid (15 ml.) was
treated with hydrogen peroxide (20 vol.; 1-5ml.) and the
mixture was heated a t 70" for 1.75 hr. The dark red
solution was cooled, treated with water (10 ml.) and set
aside for 18 hr.; red crystals (20 mg., 6%) of 3,6-bis-(3,5dimethylpyrazol-l-y I) tetrazine separated, m.p . 223-225"
(from aqueous alcohol) (Found: C, 53.5; H, 5.15; N, 40.9% ;
M , 269. C1,Hl,N, requires C, 53.35; H, 5.2; N, 41.5%;
N , 270), hmxs (95% ethanol) 528 nm. (c 390). Further
work-up of the reaction mixture yielded only decomposition
products and some 3,5-dimethylpyrazole, A similar decomposition was found to occur when compound (IV) was
heated similarly in acetic acid; this explains the low yield
of the tetrazine.
A cleaner but more tedious dehydrogenation of compound (IV) was effected by oxidation with air in toluene.
A solution of compound (IV) (2-4g.) in dry toluene (40ml.)
was set aside for 20 weeks in an air-filled stoppered vessel.
It gradually turned red and long red needles (300 mg.,
12.5%) of the tetrazine separated.
We thank the Irish Government for a research fellowship
(to R. N. B.).
[0/701 Received, April 30th, 19701