One-pot tandem 1,4- and 1,2-addition of phosphites to α,β- unsaturated hydrazones

Article abstract of DOI:10.1055/s-2007-986654

The 1,4- and 1,2-addition of phosphites to α,β-unsaturated hydrazones was investigated. When silylated phosphites and trialkyl phosphites were compared, trialkyl phosphites gave better conversions and subsequently higher yields. A variety of hydrazones we

Full text of DOI:10.1055/s-2007-986654

LETTER
2549
One-Pot Tandem 1,4- and 1,2-Addition of Phosphites to a,b-Unsaturated
Hydrazones
D
ouble Phosphite
h
A
ddition to
r
H
ydrazo
i
nes stian V. Stevens,*a Ellen Van Meenen,a Kurt G. R. Masschelein,a Kristof Moonen,a Ann De Blieck,a
Jozef Drabowiczb
a
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: chris.stevens@UGent.be
b
Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland
Received 25 June 2007
tion than 1,2-addition, where a reverse reactivity is
noticed with silylated phosphites. To evaluate the scope of
these reactions, hydrazones 2, which were anticipated to
be much less reactive compared to imines, have now been
Abstract: The 1,4- and 1,2-addition of phosphites to a,b-unsaturat-
ed hydrazones was investigated. When silylated phosphites and tri-
alkyl phosphites were compared, trialkyl phosphites gave better
conversions and subsequently higher yields. A variety of hydra-
zones were evaluated as substrate in this reaction, which yield 3- evaluated as possible substrates.
phosphonyl-1-hydrazinoalkyl phosphonates.
Key words: phosphorylations, tandem addition, hydrazones, ami-
no acids, Michael additions
R3
N
R3
O
N
R4
R2
N
R4
(RO)2P
R1
HN
P nucleophile
acid
R1
H
P(OR)2
O
R2
a-Hydrazinoalkyl phosphonic acids 1 (Figure 1) and their
derivatives have been found to have an interesting pro-
tecting effect against the phytotoxic action of chloroacet-
anilide herbicides.1 Limited research was performed to
establish a general route to this type of compounds.2
Among the specific methods, the lithium perchlorate/di-
ethyl ether catalyzed multicomponent reaction of an alde-
hyde, a hydrazine, and silylated phosphite2e or the binary
reagent (MeO)3P/Me3SiCl2f seems to be the most straight-
forward. However, this method is only applicable to ali-
phatic aldehydes.
2
3
Scheme 1 Synthesis of 3-phosphonyl-1-hydrazinophosphonates 3
To synthesize the substrates 2, an a,b-unsaturated alde-
hyde was dissolved in methanol in the presence of one
equivalent of the hydrazine or hydrazide. After one hour
at 0 °C, the solvent was evaporated in vacuo and the
products were recovered in excellent yields (95–99%).
The first part of the research comprised the evaluation of
silylated phosphite as a phosphorus nucleophile and was
based on the work of Afarinkia and co-workers for the
synthesis of a-aminophosphonates.6 O-Silylation of di-
alkyl phosphite provided the more nucleophilic s3l3 re-
agent.7 In these experiments the hydrazone 2 was
dissolved in dry dichloromethane, and 5 equivalents of si-
lylated phosphite were added. This mixture was heated to
reflux temperature after which 0.5 equivalents of sulfuric
acid were added.
Follow-up of the reaction by 31P NMR (whenever possi-
ble, conversions were calculated from integrations in the
31P NMR) had shown a very slow and incomplete conver-
sion.8 Imines, on the other hand, showed vigorous reac-
tion upon addition of sulfuric acid (the solvent starts to
boil) and the reactions were complete after one hour at
room temperature.4 As seen in Table 1, the results were
not really satisfying and only two derivatives 3b,d
showed an acceptable yield (the conversion was not deter-
mined for 3a and 3b). Next to the incomplete conversion,
the low yields can also be explained by the work-up. An
acid–base extraction was required to remove the excess of
phosphite. However, a lot of side products remained in the
crude reaction mixture, which made flash chromatogra-
phy inevitable for further purification.9 These phosphono
O
H2N NH
R
OH
OH
P
1
Figure 1 a-Hydrazinoalkyl phosphonic acid
As a continuation of our studies on the behavior of differ-
ent phosphorus nucleophiles and the chemistry of aza-
heterocyclic phosphonates,3 the addition of silylated
phosphites and trialkyl phosphites to a,b-unsaturated hy-
drazones 2 is presented in this paper (Scheme 1). In this
reaction, two phosphonate moieties are introduced in one
single reaction to form 3-phosphonyl-1-hydrazinoalkyl
phosphonates 3. Our previous research showed that both
reagents are able to perform a tandem 1,4–1,2-addition to
a,b-unsaturated imines.4,5 A mechanistic study proved a
different reactivity of both phosphorus reagents. Trialkyl
phosphites show a higher tendency to perform 1,4-addi-
SYNLETT 2007, No. 16, pp 2549–2552
0
1
.1
0
.2
0
0
7
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986654; Art ID: G16607ST
© Georg Thieme Verlag Stuttgart · New York

2550
C. V. Stevens et al.
LETTER
Table 2 Reaction of Hydrazones 2 with Triethyl Phosphite in
Acidic Medium
Table 1 Reaction of Hydrazones 2 with Dimethyl Trimethyl-
silylphosphite in Acidic Medium
Product
Time
(d)
Conv. Isolated yield
Product
Conversion (%) Isolated yield (%)
(%)
(%)
O
N
O
(MeO)2P
HN
HN
N
3a
3b
–
–
18
55
(EtO)2P
HN
HN
3f
1
1
–
52
Ph
P(OMe)2
O
Ph
P(OEt)2
O
O
N
O
(MeO)2P
N
(EtO)2P
3g
70
21
57
P(OMe)2
P(OEt)2
O
O
O
Ph
O
Ph
O
NH
O
3c
46
90
32
75
(MeO)2P
HN
NH
3h
3i
2
1
7
–
(EtO)2P
HN
Ph
P(OMe)2
Ph
P(OEt)2
O
O
O
Ph
O
Ph
O
NH
O
3d
(MeO)2P
HN
NH
98
76
78
53
(EtO)2P
HN
P(OMe)2
P(OEt)2
O
O
O
Ph
O
Ph
O
NH
O
(MeO)2P
HN
NH
3e
35
19
3j
3k
3l
(EtO)2P
HN
P(OMe)2
O
P(OEt)2
O
O
Ph
O
NH
hydrazino phosphonates 3, however, were to a great
extent retained on the column, leading to the low yields
listed in Table 1.
4
5
2
7
8
89
86
91
81
21
64
64
76
47
18
(EtO)2P
HN
P(OEt)2
O
Because of these unsatisfactory results, another method
was evaluated before further optimization of the reaction
conditions. In this case, a trialkyl phosphite was used as
the phosphorus nucleophile. Literature showed that this
reagent can perform a 1,4-addition to a,b-unsaturated imi-
nes.10 Furthermore, our own research showed that for this
methodology, the combination triethyl phosphite in etha-
nol was preferred over trimethyl phosphite in methanol.5
Therefore, the starting hydrazone 2 was dissolved in abso- 3m
lute ethanol, and 5 equivalents of triethyl phosphite were
added (when less phosphite was used, say 2 equivalents,
the yield was <5% so that the 1,2-to-1,4-addition ratio
could not be easily determined). After the reaction was
N
O
N
(EtO)2P
HN
HN
Ph
P(OEt)2
O
N
O
N
(EtO)2P
P(OEt)2
O
N
O
N
brought to reflux temperature, 5 equivalents of formic
3n
(EtO)2P
HN
HN
acid were added to the mixture.11 A sufficient amount of
formic acid is crucial to obtain a good conversion in this
reaction. Also here, the reaction was monitored by 31P
NMR, which showed a slow reaction (several days).8 The
conversion, however, was higher than in the first case.
3o
P(OEt)2
O
N
O
N
(EtO)2P
P(OEt)2
O
Synlett 2007, No. 16, 2549–2552 © Thieme Stuttgart · New York

LETTER
Double Phosphite Addition to Hydrazones
2551
Table 2 Reaction of Hydrazones 2 with Triethyl Phosphite in
Acidic Medium (continued)
Acknowledgment
We thank the Fund for Scientific Research-Flanders and the Gent
University Research Fund for financial support of this research.
Product
Time
(d)
Conv. Isolated yield
(%)
(%)
References and Notes
O
O
(1) Diel, P.; Maier, L. EP 143078, 1985; Chem. Abstr. 1985,
103, 215544m.
NH
3p
3q
3r
3
1
6
84
55
(EtO)2P
HN
(2) (a) Baraldi, P. G.; Guarneri, M.; Moroder, F.; Pollini, G. P.;
Simoni, D. Synthesis 1982, 653. (b) Yuan, C.; Chen, S.; Xie,
R.; Feng, H. Phosphorus, Sulfur Silicon Relat. Elem. 1995,
106, 115. (c) Yuan, C.; Li, C. Synthesis 1996, 507.
(d) Kaname, M.; Yoshinaga, K.; Arakawa, Y.; Youshifuji, S.
Tetrahedron Lett. 1999, 40, 7993. (e) Heydari, A.; Jadivan,
A.; Schaffie, M. Tetrahedron Lett. 2001, 42, 8071.
(f) Heydari, A.; Mehrdad, M.; Schaffie, M.; Abdoirezaie, M.
S.; Hajinassirei, R. Chem. Lett. 2002, 11, 1146.
(3) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004,
104, 6177.
Ph
P(OEt)2
O
O
O
NH
–
62
58
(EtO)2P
HN
P(OEt)2
O
O
O
(4) Moonen, K.; Van Meenen, E.; Verwée, A.; Stevens, C. V.
Angew. Chem. Int. Ed. 2005, 44, 7401.
NH
89
(EtO)2P
HN
(5) Van Meenen, E.; Moonen, K.; Verwée, A.; Stevens, C. V.
J. Org. Chem. 2006, 71, 7903.
(6) (a) Afarinkia, K.; Rees, C. W.; Cadogan, J. I. G. Tetrahedron
1990, 46, 7175. (b) The silylated diethyl phosphite was
prepared in a separate reaction. Triethylammonium salts
were removed from the reagent.
P(OEt)2
O
O
O
NH
(EtO)2P
HN
3s
4
66
42
(7) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; J.
Wiley and Sons: New York, 2000, Chap. 2, 394.
(b) Wozniak, L.; Chojnowski, J. Tetrahedron 1989, 45,
2465.
P(OEt)2
O
(8) The phosphonylated adduct appears in the 31P NMR
spectrum as a major and minor diastereomeric pair. One
gives two singlets and the other two doublets (31P coupling).
(9) A suitable solvent mixture for flash chromatography is
MeCN–CH2Cl2–MeOH (81:17:3).
An acid–base extraction was used to obtain the pure prod-
ucts. The excess of phosphite was removed during the
acidic extraction. It was, however, necessary to use dieth-
yl ether at this stage, and not dichloromethane, in order to
prevent excessive loss of the product in the organic phase.
In most cases, no further chromatographic purification
was necessary, which avoided additional losses.
(10) Teulade, M.-P.; Savignac, P. Synth. Commun. 1987, 19,
1037.
(11) Detailed Description of the Procedure
In an oven-dry flask, hydrazone 2 (2 mmol) is dissolved in
abs. EtOH. To this solution, triethyl phosphite (10 mmol, 5
equiv) is added. This mixture is brought to reflux tem-
perature under an N2 atmosphere and formic acid (5 equiv)
As can be seen from Table 2 (3f–j) the yields are generally
higher than with the first method (Table 1). Therefore the
scope of this reaction was investigated by making a series
of derivatives (Table 2; the conversion was not deter-
mined for 3f and 3h). From these results some conclusions
can be drawn concerning the steric influence of the b-sub-
stituents. In general, the reaction proceeds slower when
the substituents become more sterically demanding. The
unexpected behavior of the cinnamaldehyde-derived sub-
strates in this respect can be caused by the extended con-
jugated system. The lower reactivity of hydrazones
compared to imines can be explained by the less electro-
philic C=N double bond. Using acyl-substituted hydra-
zones, the electrophilicity of the C=N bond is again
increased. However, not in all the cases a significant
effect could be noticed.
is added by a syringe. The reaction is followed with 31
P
NMR. When no changes are observed anymore (after several
days) the reaction is stopped. The solvent is evaporated and
the residue redissolved in Et2O (20 mL). After pouring into
3 N HCl (30 mL) this system is extracted 3 times with Et2O
(20 mL). The aqueous phase is made basic with 3 N NaOH
and extracted three times with CH2Cl2 (20 mL). The
combined organic layers are dried over MgSO4. After
filtration, the solvent is evaporated in vacuo. 1H NMR, 13
C
NMR, IR, and MS spectra were entirely consistent with the
assigned structures. Selected example: [1-(N¢-Benzoyl-
hydrazino)-3-(diethoxyphosphoryl)but-yl]phosphonic acid
diethyl ester (3i): Ratio A:B = 47:53 (31P NMR). 1H NMR
(300 MHz, CDCl3): d = 1.19–1.41 [15 H (A) + 15 H (B), m,
CHCH3 (A + B), P(O)OCH2CH3 (A + B)], 1.67–1.87 [2 H
(A), m, CHCH2CH], 2.10–2.29 [2 H (B), m, CHCH2CH],
2.32–2.55 [1 H (A) + 1 H (B), m, CHP], 3.27–3.36 [1 H (B),
m, NCHP], 3.58–3.67 (1 H (A), m, NCHP], 4.02–4.30 [8 H
(A) + 8 H (B), m, P(O)OCH2CH3], 7.40–7.53 [6 H, m,
CH(Ph) (A + B)], 7.80–7.86 [4 H, m, CH(Ph) (A + B)], 8.77
(1 H, br s, NH (B)], 8.79 [1 H, br s, NH (B)], 9.22 [1 H, br s,
NH (A)], 9.24 [1 H, br s, NH (A)] ppm. 13C NMR (75 MHz,
CDCl3): d = 13.16 [d, 2JCP = 4.6 Hz, CHCH3 (B)], 15.36 [d,
In summary we have broadened the scope of the previous-
ly described tandem 1,4- and 1,2-addition of phosphites.4,5
Hydrazones 2 (derived from hydrazines or hydrazides)
are, despite the lower reactivity in comparison to imines,
appropriate substrates for the synthesis of 3-phosphonyl-
1-hydrazinophosphonates 3 in one step.
Synlett 2007, No. 16, 2549–2552 © Thieme Stuttgart · New York

2552
C. V. Stevens et al.
LETTER
2JCP = 4.6 Hz, CHCH3 (A)], 16.38, 16.46, 16.54, 16.61
[P(O)OCH2CH3 (A + B)], 26.61 [dd, 1JCP = 140.8 Hz,
3JCP = 9.2 Hz, CHP (A)], 27.02 [dd, 1JCP = 143.1 Hz,
3JCP = 13.9 Hz, CHP (B)], 28.00 [CHCH2CH (B)], 28.78 [d,
2JCP = 2.3 Hz, CHCH2CH (A)], 55.58 [dd, 1JCP = 155.8 Hz,
3JCP = 6.9 Hz, NCHP (A)], 55.65 [dd, 1JCP = 161.5 Hz,
3JCP = 13.9 Hz, NCHP (B)], 61.79 [d, 2JCP = 6.9 Hz,
P(O)OCH2CH3], 61.88 [d, 2JCP = 6.9 Hz, P(O)OCH2CH3],
62.52 [d, 2JCP = 6.9 Hz, P(O)OCH2CH3], 62.71 [d, 2JCP = 6.9
Hz, P(O)OCH2CH3] 62.83 [d, 2JCP = 6.9 Hz,
P(O)OCH2CH3], 63.13 [d, 2JCP = 6.9 Hz, P(O)OCH2CH3],
126.97, 128.63, 131.70, 131.81 [CH(Ph) (A + B)], 132.53
[Cq(Ph) (A)], 132.57 [Cq(Ph) (B)], 165.64 [C=O (A)],
165.98 [C=O (B)] ppm. 31P NMR (121 MHz, CDCl3): d =
25.72 [d, JPP = 1.5 Hz (A)], 26.16 [d, JPP = 7.4 Hz (B)],
34.47 [d, JPP = 7.4 Hz (B)], 35.11 [d, JPP = 1.5 Hz (A)] ppm.
IR: 3413 (NH), 1648 (C=O), 1229 (P=O), 1052, 1027 (P–O)
cm–1. MS: m/z (%) = 465 (100) [M + H]+.
Synlett 2007, No. 16, 2549–2552 © Thieme Stuttgart · New York