Reactions of azovinylphosphonates with nucleophilic alkenes and heterocycles: Synthesis of tetrahydropyridazine-3-phosphonate and 2-substituted-1-hydrazonoethylphosphonate derivatives

Article abstract of DOI:10.1080/10426500802028393

Transient azovinylphosphonates, generated in situ by base induced dehydrohalogenation of the corresponding 2-bromo- and 2-chloro- acetylphosphonate- tertbutoxycarbonyl hydrazones are intercepted by electron rich alkenes and heterocycles in hetero Diels-Al

Full text of DOI:10.1080/10426500802028393

Phosphorus, Sulfur, and Silicon, 183:2882–2890, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802028393
Reactions of Azovinylphosphonates with Nucleophilic
Alkenes and Heterocycles: Synthesis of
Tetrahydropyridazine-3-phosphonate and
2-Substituted-1-hydrazonoethylphosphonate Derivatives
´
Americo Lemos and Marta Lopes
CIQA, Departamento de Qu´ımica, Bioqu´ımica e Farma´cia, Faculdade de
Cieˆncias e Tecnologia, Universidade do Algarve, Campus de Gambelas,
Faro, Portugal
Transient azovinylphosphonates, generated in situ by base induced dehydrohalo-
genation of the corresponding 2-bromo- and 2-chloro-acetylphosphonate- tert-
butoxycarbonyl hydrazones are intercepted by electron rich alkenes and heterocycles
in hetero Diels-Alder reactions, producing tetrahydopyridazine-3-phosphonates or
open chain α-hydrazono phosphonates.
Keywords
α-hydrazonophosphonates;
3-phosphono-1,2-diaza-1,3-butadienes;
azovinylphosphonates; addition-elimination; cycloaddition; tetrahydropyridazine-
3-phosphonates
INTRODUCTION
α-Aminophosphonic compounds are useful and important analogues of
α-amino acids and exhibit biological activity.1 Also α-hydrazino phos-
phonic acids and phosphonates are analogues of α-aminophosphonic
acids and are effective protectors of crops from the phytoxic action of
herbicides.2
Over the last decades a large number of heterocyclic systems
have been obtained with great success using electron deficient 1,2-
diaza-1,3-butadienes, either as Michael acceptors3 or as heterodi-
enes in inverse electron demand cycloaddition reactions,4 with a vast
range of nucleophilic olefins and heterocycles. However, literature
reports of 1,2-diaza-1,3-butadienes carrying phosphorus substituents
Received 29 February 2008; accepted 3 March 2008.
Thanks are due to Dr. T. L. Gilchrist for helpful discussions and Fundac¸a˜o Cieˆncia e
Tecnologia, UID 272/94, for financial support.
Address correspondence to Ame´rico Lemos, CIQA, Departamento de Qu´ımica,
Bioqu´ımica e Farma´cia, Faculdade de Cieˆncias e Tecnologia, Universidade do Algarve,
Campus de Gambelas, Faro 8005-139, Portugal. E-mail: alemos@ualg.pt
2882

Reactions of Azovinylphosphonates
2883
are scarce.3g,4a,5 To the best of our knowledge, there is only one re-
port describing the use of 4-phosphonyl- or 4-phosphinyl-1,2-diaza-
1,3-butadienes in [4+2] cycloaddition reactions with alkenes and
dihydrofuran.4a
We have recently described the first examples of cycloaddition
reactions of nitrosovinyl-3-phosphonates, generated from the corre-
sponding 2-chloro-1-hydroxyiminophosphonates.6 As a continuation of
our work we have extended this methodology to the synthesis of
tetrahydopyridazine-3-phosphonates or open chain α-hydrazono phos-
phonates via the interception of transient 3-phosphono-1,2-diaza-1,3-
butadienes, obtained from halogenated hydrazones, with electron rich
heterocycles and olefins.
RESULTS AND DISCUSSION
The acylphosphonates 1a, b were obtained by the Arbuzov re-
action of the respective haloacetyl halides and the corresponding
alkylphosphite.7 Further treatment with tert-butyl carbazate in ethyl
ether, afforded the hydrazones 2a, b in good yields (Scheme 1).
O
EtO
CO CMe
2
3
Br
+
P
OEt
HN
N
O
EtO
Br
OR
OR
H NNHCO CMe
3
2
2
OR
OR
P
P
ethyl ether
X
O
O
X
O
i
Pr O
i
i
i
1 a R = Pr ; X = Cl
b R = Et ; X = Br
Cl
2 a R = Pr ; X = Cl 89%
b R = Et ; X = Br 66%
+
P
OPr
i
Pr O
Cl
SCHEME 1
When treated with sodium carbonate in dichloromethane at room
temperature, the hydrazones 2a, b were converted into the transient
azovinylphosphonates 3a, b. These transient species were trapped in
situ by alkenes or heterocycles (Scheme 2), producing new 3-phosphonyl
tetrahydropyridazines 4–7 or α-hydrazono phosphonates 8, 9 (Table I).
With alkenes, cycloadducts were produced. The efficiency of the re-
action was directly associated with the properties of the dienophile,
becoming less efficient with decreasing electron rich character of the
dienophile. With heterocycles possessing lower aromatic or non aro-
matic character, such furan and 2,3-dihydrofuran, cycloadducts were
isolated. With pyrrole and indole the open chain hydrazones were
obtained, possibly, as a result of rearomatization of the primarily

2884
A. Lemos and M. Lopes
CO CMe
CO CMe
2
3
2
3
HN
N
N
N
i)
alkene or
OR
OR
OR
OR
Products
P
P
- HX
heterocycle
X
O
O
3 a,b
i
2 a,b
i) Na CO ; CH Cl ; rt; 3-6h.
R = Et ; Pr X = Cl ; Br
2
3
2
2
SCHEME 2
formed cycloadducts.8 The yields were, in general, somewhat bet-
ter than those obtained in similar reactions with nitrosovinyl-3-
phosphonates,6 but lower than those obtained with 4-phosphonyl-1,2-
diaza-1,3-butadienes4a and also with azoalkenes carrying the same
alkoxycarbonylazo substituent, but having an ethoxycarbonyl group
at the 3-position.9 Although a direct comparative analysis of isolated
product yields may be defective, these results may point out that the
ethoxycarbonyl group may be a more effective electron withdrawing
group than the phosphonate moiety; the phosphonate functionality may
be more efficient at position 4 than at the position 3; azovinylphospho-
nates may be more electrophilic, and so more efficient, than nitroso-
vinylphosphonates.
We also explored the possibility to use the hydrazone 2a as an
alkylating agent for other azoles, thus attempting the synthesis of
functionalised α-hydrazono phosphonates. Since it is known that 1-
methylpyrazole is basic enough to promote the dehydrohalogenation
of α-halogenated oximes,10 this was used in the absence of base. The
adduct 10 was isolated in 49% yield (Scheme 3).
SCHEME 3
In summary, we have developed
new tetrahydopyridazine-3-phosphonate
hydrazonoethylphosphonate derivatives in moderate to good yields,
a
synthetic route to
and 2-substituted-1-

Reactions of Azovinylphosphonates
2885
either based on hetero Diels-Alder reactions of azovinylphosphonates
derived from 2-halo-1-hydrazono phosphonates, or by elimination-
addition reactions of one of these hydrazones. Established methods
of reductive transformations at the C=N bond,11 combined with
the expected ease of removal of the tert-butoxycarbonyl group, will
allow the access to a wide range of α-hydrazino and/or α−amino
phosphonates.
TABLE I Isolated Adducts and Cycloadducts
Hydrazone
Alkene or Heterocycle
Product
Yield (%)
61
67
22
44
33

2886
A. Lemos and M. Lopes
TABLE I Isolated Adducts and Cycloadducts (Continued)
Hydrazone Alkene or Heterocycle Product
Yield (%)
38
36
EXPERIMENTAL
NMR and mass spectra were obtained at RIAIDT at Santiago de Com-
postela. 1H NMR, 13C NMR (75.47 MHz) and 31P NMR spectra (121.47
MHz) were recorded with a Varian Unity Plus 300 (300 MHz) spectrom-
eter or with a Bruker WM AMX spectrometer using CDCl3 (except oth-
erwise reported) as solvent and TMS (1H and 13C) or 85% phosphoric
acid (31P) as internal and external standards, respectively (chemical
shifts (δ) in ppm, Jin Hz). IR spectra were recorded with a Brucker
FT-IR Tensor 27 instrument. Melting points were measured on a SRS
MAP120 EZ-Melt melting point apparatus and are uncorrected.
Synthesis of the Hydrazono Phosphonates 2a,b—General
Procedure
To the acylphosphonate 1a or 1b (12 mmol) in diethyl ether (30 mL) was
added tert-butyl carbazate (12 mmol) and two drops of glacial acetic acid
and the mixture was stirred at room temperature for 24 h. The insoluble
material was then filtered and H2O (30 mL) was added. The organic
layer was separated, dried (Na2SO4) and the solvent was evaporated
under reduced pressure. The residue was triturated with n-hexane and
kept in the refrigerator. The hydrazono phosphonates separated as a
solid (2a) or thick yellow oil (2b).

Reactions of Azovinylphosphonates
2887
Diisopropyl 2-Chloro-1-(tert-butoxycarbonylhydrazono)
ethylphosphonate (2a)
Yield 3.81 g (89%), white solid, mp 114.8−116.4 ◦C (from
hexane/CH2Cl2). IR (KBr) νmax = 3209, 2981, 1756, 1249, 997 cm–1. 1H
NMR: δ = 1.35−1.38 (m, 12H), 1.52 (s, 9H), 3.87 (d, 3 J = 8.7 Hz, 2H,
PH
CH2), 4.61–4.82 (m, 2H, OCH), 11.42 (br, 1H). 13C NMR: δ = 24.5 (Me of
iPr), 24.6 (Me of iPr), 28.7 (Me of tBu), 34.1 (d, 2 JPC = 19.5 Hz, CH2Cl),
73.1 (OCH), 83.4 (OCMe3), 141.4 (C=N), 151.6 (C=O). 31P NMR: δ =
4.4. HRMS (ESI) [M+Na]+ calculated for C13H3256ClN2NaO5P 379.1160,
found 379.1155.
Diethyl 2-Bromo-1-(tert-butoxycarbonylhydrazono)
ethylphosphonate (2b)
Yield 2.96 g (66%), yellow oil. IR (KBr) νmax = 3120, 2983, 1732, 1253,
1022 cm–1. 1H NMR: δ = 1.34−1.36 (m, 3H), 1.38−1.41 (m, 12H), 3.94
(d, 2 J = 11.4 Hz, 2H, -CH2Br), 4,39−4.78 (m, 2H, OCH), 11.38 (br,
PH
1H).
Reactions of the Hydrazono Phosphonates 2a,b—General
Procedure
A mixture of the hydrazone 2a or 2b (2.2 mmol), Na2CO3 (11 mmol)
and the alkene or heterocycle (22 mmol) in CH2Cl2 (30 mL) was stirred
at room temperature until the disappearance (TLC) of the hydrazone
(3 to 6 h). Filtration of the insoluble material and evaporation of the
solvent followed by dry-flash chromatography gave the phosphonates
4–9.
1-tert-Butoxycarbonyl-3-diethylphosphono-6-ethoxy-
5,6-dihydro-4H-pyridazine (4a)
From 2b and ethyl vinyl ether, yield 0.49 g, (61%), oil. IR (neat) νmax
=
2979, 2929, 1732, 1249, 1151, 1014 cm–1. 1H NMR: δ = 1.18 (t, J = 7.0
Hz, 3H), 1.35−1.44 (m, 15H), 1.84−2.06 (m, 2H, 5’ and 5-H), 2.26−2.49
(m, 2H, 4ꢀ and 4-H), 3.46 (dq,J = 8.0, 3.0 Hz, 1H, MeCHHO), 3.83 (dq,
J = 8.0, 2.7 Hz, 1H, MeCHHO), 4.74−4.82 (m, 2H, OCH), 5.18 (dt, J =
3.0, 2.7 Hz, 1H, 6-H).
1-tert-Butoxycarbonyl-3-diisopropylphosphono-6-ethoxy-5,6-
dihydro-4H-pyridazine (4b)
From 2a and ethyl vinyl ether, yield 0.58 g, (67%), oil. IR (neat) νmax
=
2980, 2933, 1738, 1389, 1248, 115, 999 cm–1. 1H NMR: δ = 1.16 (t, J =
7.0 Hz, 3H), 1.32−1.38 (m, 12H), 1.43 (s, 9H), 1.80−2.10 (m, 2H, 5ꢀ

2888
A. Lemos and M. Lopes
and 5-H), 2.42 - 2.49 (m, 2H, 4ꢀ and 4-H), 3.51−3.57 (m, 1H, MeCHHO),
3.79−3.85 (m, 1H, MeCHHO), 4.41−4.75 (m, 2H, OCH), 5.22 (bs, 1H, 6-
H). MS (CI): m/z(%) = 393 [M+H]+ (62), 374 (34), 337 (54), 247 (61), 163
(100), 155 (57), 117 (46), 57 (46). HRMS: calculated for C17H34N2O6P,
393.21545; found 393.21457.
1-tert-Butoxycarbonyl-3-diisopropylphosphono-6-methyl-6-
phenyl-5,6-dihydro-4H-pyridazine (5)
From 2a and α-methylstyrene, yield 0.21 g, (22%), oil. IR (neat)
νmax = 2979, 2933, 1726, 1372, 1250, 1000 cm–1. 1H NMR: δ = 1.32−1.42
(m, 21H), 1.51 (s, 3H), 1.61−1.93 (m, 2H, 5’ and 5-H), 2.12−2.37 (m,
2H, 4’ and 4-H), 4.71−4.84 (m, 2H, OCH), 7.19−7.34 (m, 5H). MS (CI):
m/z(%) = 439 [M+H]+ (100%). HRMS: calculated for C22H36N2O5P
[M+1], 439.23564; found 439.23619.
1-tert-Butoxycarbonyl-3-diisopropylphosphono-1,4,4a,7a-
tetrahydrofuro[3,2-c]-pyridazine (6)
From 2a and furan, yield 0.38 g, (44%), oil. IR (neat) νmax = 2981,
1
2935, 1755, 1369, 1249, 998 cm−1. H NMR: δ = 1.31−1.39 (m, 12H),
1.49 (s, 9H), 2.32 (dd, J = 14.0, 4.2 Hz, 1H, H-4), 3.36 (m, 1H, H-4’),
4.69−4.78 (m, 2H, OCH), 5.02−5.13 (m, 3H, H-4a, H-7, H-7a), 6.33
(d, J = 6.0 Hz, 1H, H-6). HRMS (FAB): calculated for C17H30N2O6P,
389.18360 [M+1]; found 389.18291.
1-tert-Butoxycarbonyl-3-diisopropylphosphono-1,4,4a,6,7,7a-
hexahydrofuro[3,2-c]-pyridazine (7)
From 2a and 2,3-dihydrofuran, yield 0.28 g, (33%), colorless oil, IR
(neat) νmax = 2981, 2935, 1722, 1252, 999 cm−1. 1H NMR: δ = 1.22−1.40
(m, 12H), 1.51 (s, 9H), 1.82−2.56 (m, 4H, H-4, H-4ꢀ, H-7, H-7ꢀ), 3.83−4.26
(m, 4H, H-4a, H-6, H-6ꢀ, H-7a), 4.68−4.81 (m, 2H, OCH). MS (CI):
m/z(%) = 391 [M+H]+ (100%). HRMS: calculated for C17H32N2O6P,
391.1998 [M+1]+; found 389.1989.
Diisopropyl 1-tert-butoxycarbonylhydrazono-2-
(1H-pyrrol-2-yl)ethylphosphonate (8)
From 2a and pyrrole, yield 0.32 g (38%), oil. IR (neat) νmax = 3219,
2980, 1728, 1371, 1250, 1143, 1001. 1H NMR: δ = 1.32−1.53 (m, 21H),
3.99 (d, J = 13,8 Hz, 2H), 4.61−4.66 (m, 2H, OCH), 6.08−6.15 (m,
PH
2H, H-3, H-4), 6.60−6.71 (m, 1H, H-5), 9.65 (br, 1H), 11.19 (br, 1H). MS
(CI): m/z(%) = 388 (100) [M++1]. HRMS: calculated for C17H30N3O5P,
388.19925; found 288.19966.

Reactions of Azovinylphosphonates
2889
Diisopropyl 1-tert-butoxycarbonylhydrazono-2-
(1H-indol-3-yl)ethylphosphonate (9)
From 2a and indole, yield 0.35 g, (36%), light yellow oil. IR (neat)
νmax = 3.381, 2981, 2935, 1722, 1252, 997 cm−1. 1H NMR: δ = 1.32−1.38
(m, 12H), 1.49 (s, 9H), 4.08 (d, 3 J = 13.5 Hz, 2H, CH2), 4.49–4.60 (m,
PH
2H, OCH), 7.05−7.71 (m, 5H, arom-H), 8.39 (br, 1H, NH-indole), 11.38
(br, 1H, NH-hydrazone). 13C NMR: δ = 23.2 (Me of iPr), 23.9 (Me of
iPr), 28.2 (Me of tBu), 32.1 (d, 2 JPC = 19.7 Hz, CH2), 64.2 (OCH), 82.4
(OCMe3), 119.4, 110.1, 116.6, 117.1, 119.7, 121.2, 125.8, 134.9, 143.2 (d,
1 JPC = 37 Hz, C=N), 152.5 (C=O). 31P NMR: δ = 6.5. MS (CI): m/z(%)
= 438 (15) [M+1]+, 392 (100). HRMS: calculated for C21H33N3O5P,
438.21576; found 438.21635.
3-((2-tert-Butoxycarbonylhydrazono)-2-
diisopropylphosphonoethyl)-1-
methylimidazo-lium Chloride (10)
To 2a (0.78 g, 2.2 mmol) in CH2Cl2 (20 mL) was added dropwise 1-
methylimidazole (0.36 g, 4.4 mmol). After the addition was complete
the mixture was stirred for further 15 min. Evaporation of the solvent
followed by addition of hexane resulted in the formation of a very hy-
groscopic yellow solid 0.47 g (49%). IR (neat) νmax = 3155, 2979, 1728,
1
1371, 1273, 1252, 1159, 988 cm−1. H NMR (DMSO-d6): δ = 1.11 (d,
J = 6.7 Hz, 6H), 1.17 (d, J = 6.7 Hz, 6H), 1.51 (s, 9H), 4.60 (s, 3H),
2
4.62−4.69 (m, 2H), 5.02 (d, J = 11.0 Hz, 2H), 7.37 (dd, J = 6.7, 3.3
PH
Hz, 2H), 8.71 (s, 1H), 11.40 (bs, 1H).
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