β-Tosylhydrazono phosphonates in organic synthesis. An unambiguous entry to polysubstituted pyrazoles

Article abstract of DOI:10.1055/s-1999-2608

β-Tosylhydrazono phosphonates are novel, bifunctional reagents which were used for a concise approach to a wide range of polysubstituted pyrazoles in a single operation from aromatic and aliphatic aldehydes.

Full text of DOI:10.1055/s-1999-2608

LETTER
299
b-Tosylhydrazono Phosphonates in Organic Synthesis. An Unambiguous
Entry to Polysubstituted Pyrazoles
N. Almirante, A. Benicchio, A. Cerri, G. Fedrizzi, G. Marazzi and M. Santagostino*
Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese, (MI), Italy.
Fax +39 (0233) 500388, E-mail: pstchem@tin.it
Received 16 December 1998
tone hydrazones with aromatic esters followed by acidic
dehydration to pyrazole.2
Abstract: b-Tosylhydrazono phosphonates are novel, bifunctional
reagents which were used for a concise approach to a wide range of
polysubstituted pyrazoles in a single operation from aromatic and
aliphatic aldehydes.
Diethoxyphosphorylacetaldehyde tosylhydrazone, 1a (R1,
R2 = H), the simplest member of the series, was recently
Key words: b-tosylhydrazono phosphonate, aldehyde, a,b-unsatur- employed for the one-pot synthesis of 3(5)-aryl, alkenyl
and alkyl monosubstituted pyrazoles.3 The generality,
ated tosylhydrazone, pyrazole
conciseness and wide functional groups compatibility
(e.g. COOH, AcO, TBSO, NMe2, CH(OEt)2, OH) of the
procedure, made it attractive enough to justify efforts to
its extension to the convergent synthesis of polysubstitut-
ed pyrazoles from substituted b-tosylhydrazono phospho-
nates 1b-h (R1 and/or R2 π H) and aldehydes.
While the relative inability of Nature in dealing with the
N-N bond renders pyrazole containing natural products a
real rarity, such heterocycles are indeed abundantly fea-
tured in agricultural, material and pharmaceutical chemi-
cals. Among the many excellent methods available for
pyrazoles synthesis, the condensation of hydrazine with
1,3-difunctional compounds or 1,3-dipolar cycloadditions
to triple bond often emerge as the standard methods for
their recognised versatility.1 Although appealingly gener-
al, these procedures sometimes suffer from the need of
multistep sequence to secure the starting material and the
not so obvious regiocontrol of substitution in the final
products. In the pursuit of synthetic efficiency, we have
been exploring a new [1+4] approach which addresses the
mentioned limits by combining aliphatic or aromatic alde-
hydes, as readily available C1 synthons, with novel b-tos-
ylhydrazono phosphonates 1a-h as the CCNN counterpart
in a Horner-Emmons condensation / cyclative dispropor-
tionation fashion (Scheme 1).
As indicated in Scheme 2, preparation of 1b-h could be
efficaciously approached on a substituent basis by ex-
ploiting one of the numerous procedures available4 for the
preparation of parent b-keto phosphonates:5 primarily the
Arbuzov reaction6 (method a), the acylation of alkylphos-
phonate anion7 (method b) or the methodologies based on
the reaction of ketone enolates with electrophilic phos-
phorus reagents8 (method c). Acidic condensation of the
appropriate ketones with tosylhydrazide then gave the de-
sired b-tosylhydrazono phosphonates 1b-h as easily puri-
fied, highly crystalline, stable compounds (see Table 1).
Scheme 2
To further extend the flexibility of the synthesis, we sur-
veyed the alkylation of b-tosylhydrazono phosphonates
dianions, which could allow direct modification of b-tos-
ylhydrazono phosphonates at the carbon next to phospho-
rous (method d). Reactive halides (e.g. 4-bromobenzyl-
bromide) and lithium countercation were found to be
essential for a clean transformation [n-BuLi 2.2 equiv, 15
min -50 to -70°C, then RX 2.8 equiv, 90 min, -78°C,
THF]. On the other hand, unactivated primary iodide, e.g.
n-BuI, reacted only partially, even at 0°C, providing low
yields of mono- and dialkylated derivatives 1i and 2 (23
Scheme1
These features distinguish the present methodology from
the important precedent of Beam and co-workers, who re-
ported the [1+4] coupling of strongly basic dianions of ke-
Synlett 1999, No. 3, 299–302 ISSN 0936-5214 © Thieme Stuttgart · New York

300
N. Almirante et al.
LETTER
room temperature thus preventing complete consumption
of the aldehyde in the subsequent Horner-Emmons con-
densation.
Although with non base-sensitive substrate trapping of in
situ generated dianion [NaH 2 equiv, 50°C, THF] with al-
dehyde proved to be fruitful, in most cases, deprotonation
of 1d-h, was best accomplished with KH [2 equiv, 0°C to
r.t., THF] or NaH/n-BuLi [1 equiv at 0°C then 1 equiv at
-78°C or at 0°C, THF] (see Table 1).
Aldehyde was then added to the dianion solution and the
temperature was adjusted to allow complete formation of
a,b-unsaturated tosylhydrazone salts. While in some cas-
es (aromatic aldehydes), eventual cyclization to pyrazole
took place even at room temperature over long times, the
cyclization process was greatly accelerated upon working
at higher temperature and these conditions were routinely
employed (see Table 2).
Scheme 3
and 7% respectively), while sodium countercation and po-
lar aprotic solvents (DMF) favoured dianion
decomposition9 over alkylation as demonstrated by the
isolation of the vinylazobenzyl derivative 3 (Scheme 3).
The substitution pattern influences the ease of deproton-
ation of b-tosylhydrazono phosphonates and the stability
of the corresponding dianions. Thus, NaH [2 equiv, 0°C
to r.t., THF] readily deprotonates a-unsubstituted phos-
phonates, 1a-c (R1 = H), giving thermally stable dianions.
On the contrary, a-alkylation depresses both the acidity of
the a-carbon and the stability of the dianions (see Table
1), probably by increasing steric hindrance and electronic
density at the a position. In these cases, 1d-h (R1 π H),
stronger bases and/or lower temperatures ought to be
used. Shapiro-like decomposition processes, which begin
with the extrusion of p-tolylsulphinate, occurred fast at
As apparent from the examples, the method is versatile,
allowing for structural variations in both the aldehyde (see
also ref. 3) and the phosphonate components. Substituents
position on the heterocyclic nucleus is unambiguously de-
termined by an a priori choice of the substitution pattern
on the parent b-keto phosphonates, which is in turn easily
predictable through a selection of the appropriate synthet-
ic route. This can be especially useful for the synthesis of
polyalkylsubstituted pyrazoles for which neither the hy-
drazine or dipolar approaches are expected to allow facile
substitution regiocontrol. Moderate to low yields are
sometimes observed in the synthesis of 3-alkyl-4-sub-
Synlett 1999, No. 3, 299–302 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
b-Tosylhydrazono Phosphonates in Organic Synthesis
301
stituted pyrazoles (compounds 4, 5, 7, 9). In these cases,
Experimental procedure for alkylation of diethoxy-
increase of steric hindrance at the a-position of b-tosyl- phosphoryl acetaldehyde tosylhydrazone (1a).
hydrazono phosphonates is expected to favour the forma-
To a solution of 1a (2.50g, 7.18 mmol) in dry THF (40
tion of undesired (Z)-a,b-unsaturated tosylhydrazone at
mL) at -50°C n-BuLi (1.6 M in hexane, 5 mL, 8.0 mmol)
the expense of the (E) isomer required for the cycliza-
was added. The slightly yellow solution was cooled to
tion.10 This is not especially a problem with aromatic al-
-70°C and treated with n-BuLi (1.6 M in hexane, 5 ml, 8.0
dehydes where the (E)/(Z) ratio is thermodynamically
mmol) to give an intensely yellow solution. After 15 min
controlled, but causes serious yield decrease with aliphat-
a solution of the electrophile (2.8 equiv) in dry THF (20
ic aldehydes for which the initial step of Horner-Emmons
mL) was added and the stirring was continued for 90 min
condensation in essentially irreversible.11 On the contrary,
at -78°C. The reaction was then quenched with sat. aq.
substitution at the b-position (i.e. R2 π H) is easily predict-
NH4Cl and extracted with EtOAc. The solvent was re-
ed to revert this trend and formation of pyrazoles proceeds
moved under reduced pressure to give a crude product
in better yield with aromatic as well as aliphatic substrates
which was purified by crystallization (EtOAc/iPr2O,
(compounds 17-20).
2.10 g of 1d, 80%; hexane/EtOAc, 2.42 g of 1e, 65%).
In conclusion, the use of b-tosylhydrazono phosphonates
could be extended to the convergent synthesis of a wide
Typical procedure for pyrazoles formation.
array of polysubstituted pyrazoles.12 Remarkably, hetero-
cycle construction is possible in a single experimental op-
eration, from readily accessible starting materials, under
conditions which have been shown to respect a number of
functional groups and with complete control of substitu-
ents position.
A solution (or suspension) of b-tosylhydrazono phos-
phonates 1b-h dianion in THF (0.1 M, 1.5 equiv) was gen-
erated as described in Table 1. The aldehyde in THF (0.7
M, 1.0 equiv) was added and the mixture was stirred at the
indicated temperature until completion of the Horner-Em-
mons step (see Table 2, 1st step). The mixture was then re-
fluxed for the time specified in Table 2 (2nd step) to allow
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N. Almirante et al.
LETTER
Diethyl 1-formylethylphosphonate tosylhydrazone (1d)
pyrazole formation. After quenching with 5% aq.
NaH2PO4 and extraction with EtOAc, the residue was pu-
rified by chromatography on silica gel.
1H-NMR (300 MHz, MeOD): d 1.24 (3H, t, J = 7.0 Hz ); 1.25
(3H, t, J = 7.0 Hz ); 1.28 (3H, dd, JHP = 18.6 and J = 7.8 Hz);
2.42 (3H, s); 2.91 (1H, ddq, JHP = 23.4 and J = 6.0 , 7.8 Hz);
3.97 (4H, m); 7.17 (1H, dd, JHP = 4.0 and J = 6.0 Hz); 7.39
(2H, d, J = 7.5 Hz); 7.77 (2H, d, J = 7.5 Hz). 13C-NMR (75
MHz, MeOD): d 11.8 (dq, JCP = 6.2 Hz); 17.0 (dq, JCP = 5.7
Hz); 21.9 (q); 37.6 (dd, JCP = 138.9 Hz); 64.3 (dt, JCP = 6.8
Acknowledgement
Appreciation is expressed to Dr. Piero Melloni for critical reading
of this manuscript and supporting this work.
Hz); 129.2 (d); 131.0 (d); 137.8 (s); 145.6 (s); 148.0 (dd, JCP
=
7.7 Hz). Anal. Calcd for C14H23N2O5PS: C 46.40, H 6.35, N
7.73, S 8.83. Found 46.21, H 6.38, N 7.68, S 8.81.
Diethyl 1-formyl-2-(4’-bromophenyl)ethylphosphonate
tosyl hydrazone (1e)
References and Notes
(1) Elguero J. Comprehensive Heterocyclic Chemistry Katritzky
A. R., Rees C. W. Eds.; Pergamon Press: Oxford, 1984; Vol.
5, pp 167-303.
(2) Beam C.F., Sandifer RM., Foote R.S., Hauser C.R. Synth.
Comm. 1976, 6, 5-10 and references therein.
(3) Almirante N., Cerri A., Fedrizzi G., Marazzi G. and M.
Santagostino Tetrahedron Lett. 1998, 39, 3287.
(4) Several distinct routes to b-keto phosphonates have been iden-
tified: Delamarche I. and Mosset P. J. Org. Chem. 1994, 59,
5453.
(5) b-keto phosphonates precursors of b-tosylhydrazono phos-
phonates are commercially available (for 1a-c) or can be pre-
pared according to published procedures: Aboujaoude E.E.,
Collignon N. and Savignac P. J. Organomet. Chem. 1984,
264, 9 (for 1f), Clark R.D., Kozar L.G. and Heathcock C.H.
Synthesis, 1975, 635 (for 1g), Calogeropoulou T., Hammond
G.B. and Wiemer D.F. J. Org. Chem. 1987, 52, 4185 (for 1h).
(6) Arbuzov B.A. Pure Appl. Chem. 1964, 9, 307.
(7) Hulme A.N., Howells G.E. and Walker R.H. Synlett 1998, 828
and references quoted.
(8) Baker T.J. and Wiemer D.F. J. Org. Chem. 1998, 63, 2613 and
references quoted.
(9) Shapiro R.H., Heath M. J. Am. Chem. Soc. 1967, 89, 5734.
(10) Only the (E)-isomer of b-monosubstituted a,b-unsaturated
tosylhydrazones cyclize to pyrazole under the described
conditions. See ref. 3.
1H-NMR (300 MHz, MeOD): d 1.24 (3H, t, J = 7.0 Hz); 1.25
(3H, t, J = 7.0 Hz); 2.48 (3H, s); 2.90-3.25 (3H, m); 4.03 (4H,
m); 6.96 (2H, d, J = 7.8 Hz); 7.06 (1H, dd, JHP = 3.7 and J =
6.5 Hz); 7.26 (2H, d, J = 7.8 Hz); 7.34 (2H, d, J = 7.5 Hz); 7.65
(2H, d, J = 7.5 Hz). 13C-NMR (75 MHz, MeOD): d 16.6 (dq,
J
CP = 5.8 Hz); 21.7 (q); 32.5 (dt, JCP = 3.9 Hz); 44.3 (dd, JCP =
135.9 Hz); 64.2 (dt, JCP = 7.1 Hz); 121.2 (s); 128.7 (d); 130.7
(d); 131.9 (d); 132.4 (d); 137.6 (s); 138.7 (d, JCP = 15.5 Hz);
145.2 (s), 145.8 (dd, JCP = 8.6 Hz). Anal. Calcd for
C20H26N2O5PSBr: C 46.43, H 5.07, N 5.41, S 6.20, Br 15.44.
Found C 46.75, H 5.06, N 5.47, S 6.23, Br 15.25.
Diethyl 1-formylbenzylphosphonate tosylhydrazone (1f)
1H-NMR (300 MHz, MeOD): d 1.07 (3H, t, J = 7.1 Hz); 1.16
(3H, t, J = 7.1 Hz); 2.42 (3H, s); 3.70-4.05 (4H, m); 4.15 (1H,
dd, JHP = 24.2 and J = 7.2 Hz); 7.30 (5H, m); 7.41 (1H, t, JHP
= 7.2 Hz); 7.36 (2H, d, J = 8.2 Hz ); 7.75 (2H, d, J = 8.2 Hz).
13C-NMR (75 MHz, MeOD): d 16.4 (dq, JCP = 5.8 Hz); 16.6
(dq, JCP = 5.9 Hz); 21.5 (q); 49.7 (dt, JCP = 137.8 Hz); 64.4 (dt,
JCP = 7.4 Hz); 64.5 (dt, JCP = 7.6 Hz); 128.9 (s); 128.9 (d) 129.
8 (dd, JCP = 2.3 Hz); 130.4 (dd, JCP = 6.7 Hz); 130.7 (d); 134.1
(d, JCP = 7.7 Hz); 137.4 (s); 145.3 (s); 146.6 (d, JCP = 7.2 Hz).
Anal. Calcd for C19H25N2O5PS: C 53.77, H 5.94, N 6.60, S
7.55. Found C 52.77, H 5.83, N 6.50, S 7.35.
Diethyl 1-methyl-2-oxopropylphosphonate tosylhydra-
zone (1g)
1H-NMR (300 MHz, MeOD): d 1.16 (3H, t, J = 7.0 Hz); 1.18
(3H, t, J = 7.0 Hz); 1.89 (3H, d, JHP = 2.7 Hz); 2.43 (3H, s);
2.92 (3H, dq, JHP = 21.0 Hz and J = 6.5 Hz); 3.93 (4H, m); 7.30
(2H, d, J = 7.5 Hz); 7.85 (2H, d, J = 7.5 Hz). 13C-NMR (75
MHz, CDCl3): d 11.5 (dq, JCP = 6.0 Hz); 15.0 (q); 15.56 (dq,
JCP = 2.4 Hz); 15.64 (dq, JCP = 2.4 Hz); 20.4 (q); 41.4 (dt, JCP
= 136.4 Hz); 62.8 (dt, JCP = 4.7 Hz); 62.9 (dt, JCP = 4.5 Hz);
128.2 (d); 129.4 (d); 136.7 (s); 144.2 (s); 155.1 (d, JCP = 7.3
Hz). Anal. Calcd for C15H25N2O5PS: C 47.86, H 6.69, N 7.44,
S 8.50. Found C 47.55, H 6.81, N 7.47, S 8.39.
(11) For a review of the effects of structural changes in the phos-
phoryl and carbonyl components on the (E)/(Z) ratio see
Organic Reactions Vol. 25 Wadsworth W.S. pp 81-85.
All new compounds gave spectroscopic data and elemental
analysis in agreement with the assigned structures. Spectral
and fisical data for b-tosylhydrazono phosphonates 1b-h fol-
low:
Diethyl 2-oxopropylphosphonate tosylhydrazone (1b)
1H-NMR (300 MHz, CDCl3): d 1.18 (6H, t, J = 7.0 Hz); 1.93
(3H, d, JHP = 2.7 Hz); 2.43 (3H, s); 2.82 (2H, d, JHP = 22.0 Hz);
3.95 (4H, m); 7.30 (2H, d, J = 7.5 Hz); 7.85 (2H, d, J = 7.5 Hz);
9.60 (1H, s) 13C-NMR (75 MHz, CDCl3): d 16.2 (dq, JCP = 5.3
Hz); 16.6 (q); 21.5 (q); 37.1 (dt, JCP = 135.9 Hz); 62.2 (dt, JCP
= 7.5 Hz); 128.1 (d); 129.4 (d); 135.7 (s); 143.9 (s); 150.2 (d,
2-Diethoxyphosphoryl-1-oxo-1,2,3,4-tetrahydronaphtale-
ne tosyl hydrazone (1h)
1H-NMR (300 MHz, CDCl3): d 0.71 (3H, J = 7.1 Hz); 1.37
(3H, J = 7.1 Hz); 1.90-2.30 (2H, m); 2.41 (3H, s); 2.67 (1H, dt,
J = 16.6, 4.4 Hz); 3.04 (1H, ddd, J = 16.6, 11.9, 4.7 Hz); 3.39
- 3.65 (2H, m); 3.68 (1H, ddd, JHP = 24.3 Hz and J = 3.3, 5.8
Hz); 4.17 (2H, m); 7.08 (1H, d, J = 7.5 Hz); 7.16 (1H, t, J = 7.5
Hz); 7.25 (1H, t, J = 7.5 Hz); 7.31 (2H, d, J = 8.2 Hz); 7.92
(1H, d, J = 7.5 Hz); 7.98 (2H, d, J = 8.2 Hz); 10.38 (1H, s). 13C-
NMR (75 MHz, CDCl3): d 15.7 (dq, JCP = 5.4 Hz); 16.3 (dq,
JCP = 9.4 Hz). Anal. Calcd for C14H23N2O5PS: C 46.40, H
6.35, N 7.73, S 8.83. Found 46.47, H 6.33, N 7.64, S 9.19.
Diethyl 2-oxo-2-phenylethylphosphonate tosylhydrazone
(1c)
1H-NMR (300 MHz, CDCl3): d 1.14 (6H, t, J = 7.0 Hz); 2.40
(3H, s); 3.34 (2H, d, JHP = 22.9 Hz); 3.95 (4H, m); 7.28 (2H,
d, J = 7.5 Hz); 7.35 (3H, m); 7.67 (2H, m); 7.95 (2H, d, J = 7.5
Hz); 10.1 (1H, s). 13C-NMR (75 MHz, MeOD): d 16.7 (dq, JCP
JCP = 5.8 Hz); 21.5 (q); 23.0 (dt, JCP = 6.4 Hz); 26.2 (dt, JCP
=
4.0 Hz); 36.0 (dd, JCP = 134.3 Hz); 62.7 (dt, JCP = 6.8 Hz); 63.8
(dt, JCP = 6.9 Hz); 125.5 (d), 126.5 (d), 128.3 (d), 128.4 (d),
129.2 (d), 129.8 (d); 131.0 (d, JCP = 2.7 Hz);136.2 (s); 138.6
(d, JCP = 1.6 Hz), 143.4 (s), 147.4 (d, JCP = 7.5 Hz). Anal. Cal-
cd for C21H27N2O5PS: C 55.99, H 6.09, N 6.22, S 7.12. Found
C 55.99, H 6.00, N 6.21, S 7.15.
= 6.1 Hz); 21.8 (q); 28.3 (dt, JCP = 135.1 Hz); 64.9 (dt, JCP
6.9 Hz); 128.1 (d); 129.7 (d); 129.6 (d); 130.9 (d); 131.3 (d);
137.5 (s); 138.1 (d,JCP = 3.2 Hz); 145.9 (s); 149.0 (d, JCP
10.0 Hz). Anal. Calcd for C19H25N2O5PS: C 53.77, H 5.94, N
6.60, S 7.55. Found C 53.74, H 5.92, N 6.71, S 7.87.
=
=
Synlett 1999, No. 3, 299–302 ISSN 0936-5214 © Thieme Stuttgart · New York