Synthesis of 1,1-bisphosphono-2-aza-1,3-dienes, a new class of electron-deficient azadienes

Article abstract of DOI:10.1016/j.tetlet.2008.05.031

1,1-Bisphosphono-2-aza-1,3-dienes are formed by 1,4-dehydrohalogenation of the corresponding N-(bisphosphonomethyl)-α-haloimines in moderate to good yields. The precursors could be formed by condensation of bisphosphono-amines and the corresponding α-haloaldehydes.

Full text of DOI:10.1016/j.tetlet.2008.05.031

Tetrahedron Letters 49 (2008) 4336–4338
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,1-bisphosphono-2-aza-1,3-dienes, a new class
of electron-deficient azadienes
*
Kurt G. R. Masschelein, Christian V. Stevens
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
1,1-Bisphosphono-2-aza-1,3-dienes are formed by 1,4-dehydrohalogenation of the corresponding N-(bis-
phosphonomethyl)-a-haloimines in moderate to good yields. The precursors could be formed by conden-
sation of bisphosphono-amines and the corresponding a-haloaldehydes.
Received 9 April 2008
Revised 21 April 2008
Accepted 7 May 2008
Available online 10 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Phosphono-azadienes
Bisphosphonates
1,4-Dehydrohalogenation
Bisphosphonates (BPs) are analogues of naturally occurring
pyrophosphate (PPi) and are a major class of drugs for the treat-
ment of bone diseases.1 Besides their antiresorptive properties,
several bisphosphonates are also potent growth inhibitors of some
pathogenic trypanosomatids.2
2-Azadienes in general are recognized as useful intermediates
in synthetic chemistry for the construction of both heterocyclic
systems as well as acyclic polyfunctionalized compounds.3
Although the synthesis and reactivity of azadienes are well-estab-
lished, their synthesis is mainly focused on electron-rich and elec-
tronically neutral 2-azadienes (in view of the well-established
Diels–Alder methodology).4 Due to the lack of general methods
for their synthesis and their less pronounced importance for
inverse electron demand Diels–Alder methodology,5 electron-poor
azadienes have received much less attention.
Keeping in mind the importance of the bisphosphonates as
therapeutic agents and the azadienes as building blocks for a wide
variety of compounds, the synthesis of a new class of electron-defi-
cient bisphosphono-azadienes is interesting and could lead to new
synthetic methods for azaheterocycles.
Until now, only a few reports on the synthesis of phosphonyl-
ated azadienes or their precursors appeared in the literature.6
In some of these reports, 1,4-dehydrohalogenation of suitable
phosphonylated a-haloimines was used as a strategy for the syn-
thesis of 2-aza-1,3-dienes.6a The a-haloimines were formed either
by condensation of a-halo carbonyl compounds with 1-amino-
alkylphosphonates6a or by a-chlorination of phosphonylated
imines.6c
To make the new class of 1,1-bisphosphono-2-aza-1,3-dienes,
both synthetic pathways towards the halogenated imines were
evaluated. Condensation of tetraethyl aminomethylbisphospho-
nate 1 (prepared by condensation of dibenzylamine, triethyl phos-
phite and triethyl orthoformate and subsequent debenzylation)7
and appropriate aldehydes 2 gave the imines 3 in good yields
and purity (>95%). However, the subsequent a-chlorination with
NCS in CCl4 did not proceed as smoothly as expected. The reaction
mixture contained three major compounds together with 12 less
important side products. The failure of the a-chlorination is pro-
bably related to the difficult formation of the corresponding en-
amine, which is counteracted by the electron withdrawing
N-substituent. Instead, in both cases the formation of unidentified
side products was observed following the reaction by 31P NMR at
room temperature and at reflux temperature (Scheme 1).
Therefore, the halogenated imines 4 had to be synthesized using
the condensation of a-halogenated aldehydes 5 and tetraethyl
aminomethylbisphosphonate 1. The synthesis of freshly prepared
a-halogenated aldehydes 5a–e was performed by chlorination
using SO2Cl2 (Scheme 2 and Table 1).8
In case of isobutyraldehyde, chlorination with SO2Cl2 was
performed using a literature procedure.9 Also, the brominated
aldehyde 5g could be obtained in good yield (Scheme 3).10
With the halogenated aldehydes in hand, the condensation with
tetraethyl aminomethylbisphosphonate 1 was evaluated. Stirring
the reactants in dry CH2Cl2 at room temperature for a couple of
hours proved sufficient to obtain the halogenated imines 4 in good
yield and purity. However, during the evaporation of the solvent
after filtration of the drying agent, colouring of the product was
* Corresponding author. Tel.: +32 9 2645957; fax: +32 9 2646243.
E-mail address: chris.stevens@UGent.be (C. V. Stevens).
URL: http://www.synbioc.ugent.be
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.031

K. G. R. Masschelein, C. V. Stevens / Tetrahedron Letters 49 (2008) 4336–4338
4337
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
N P(O)(OEt)2
MgSO4
CH2Cl2
NCS
CCl4
O
P(O)(OEt)2
R1
N
+
R1
Cl
R1
H
H2N
P(O)(OEt)2
rt, 4 - 5 h
rt or Δ
R2
H
H
R2
R2
1
2
3
4
Scheme 1.
Table 2
Synthesis of bisphosphono-azadienes 6
O
O
SO2Cl2
rt
R1
Cl
R1
H
H
R1
R2
Product
Crude yielda (%)
Yieldb (%)
R2
R2
5a-e
Ph
Me
Ph
Ph
Ph
Cl
6a
6b
6c
6d
6e
6f
88
63
2a-e
92
58
Complex
95
16
68
Scheme 2.
(CH2)5(c-Hex)
Et
Me
Et
Me
93
56
93c/89d
63c/60d
Table 1
Synthesis of a-chlorinated aldehydes 5
a
b
c
After workup.
After column chromatography.
Using the chlorinated aldehyde.
Using the brominated aldehyde.
Entry
Compound
Reaction time (min)
R1
R2
Yielda (%)
d
2a
2b
2c
2d
2e
5a
5b
5c
5d
5e
30
30
900
30
Ph
Me
Ph
Ph
Ph
H
75
71
61
68
67
(CH2)5 (c-Hex)
Et
In conclusion, a straightforward synthesis of a new class of
30
Et
phosphono-azadienes, that is, 1,1-bisphosphono-2-aza-1,3-dienes,
was elaborated using a 1,4-dehydrohalogenation of phosphonyl-
ated a-chloroimines as a key step. The synthetic reactivity study
of this new class of electron-deficient azadienes is currently under
investigation and will be reported in due course.
a
After distillation.
O
O
a) ref. 9
Me
X
H
H
Acknowledgement
b) ref. 10
Me
Me
2f
Me
Financial support for this research from the BOF (Bijzonder
Onderzoeksfonds Universiteit Gent, Research Fund Ghent Univer-
sity) is gratefully acknowledged.
a) 5f X = Cl
b) 5g X = Br
Scheme 3.
References and notes
observed. 1,4-Dehalogenation was already occurring which could
be confirmed by 1H NMR and 31P NMR spectroscopy. When trying
to purify the halogenated imines by chromatography, only the 1,1-
bisphosphono-2-aza-1,3-dienes could be isolated.
1. Graham, R.; Russell, G. Ann. N.Y. Acad. Sci. 2006, 1068, 367.
2. Docampo, R.; Moreno, S. N. J. Curr. Drug Targets 2001, 1, 51.
3. Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379.
4. Boger, D. L. Tetrahedron 1983, 39, 2869.
Because of the ease of 1,4-dehalogenation, a one-step procedure
for the synthesis of the 1,1-bisphosphono-2-aza-1,3-dienes starting
from a-haloaldehydes 5 and tetraethyl aminomethylbisphospho-
nate 1 was evaluated. Therefore, 1.1 equiv of triethylamine was
added to the in situ formed a-halogenated imines 4. 31P NMR of
the reaction mixture showed the formation of the desired azadienes
6. After workup,11 the 1,1-bisphosphono-2-aza-1,3-dienes were ob-
tained as yellowish oils. In case of 6c, a complex mixture was
formed after workup. Following the reaction, 31P NMR revealed that
condensation of 5c and 1 immediately led to a lot of side products.
In general, in order to obtain the azadienes analytically pure,
column chromatography was performed, however this resulted
in a significant drop of the yields (Scheme 4 and Table 2).
5. (a) Boger, D. L. Chem. Rev. 1986, 86, 781; (b) Boger, D. L.; Patel, M. Prog.
Heterocycl. Chem. 1989, 1, 30.
6. (a) Onys’ko, P. P.; Maidanovich, N. K.; Kim, T. V.; Kiseleva, E. I.; Sinitsa, A. D. Zh.
Obshch. Khim. 1989, 68, 573; (b) Palacios, F.; Gil, M. J.; Martinez de Marigorta,
E.; Rodriguez, M. Tetrahedron Lett. 1999, 40, 2411; (c) Stevens, C.; Gallant, M.;
De Kimpe, N. Tetrahedron Lett. 1999, 40, 3457; (d) Palacios, F.; Gil, M. J.;
Martinez de Marigorta, E.; Rodriguez, M. Tetrahedron 2000, 56, 6319; (e)
Palacios, F.; Ochoa de Retana, A. M.; Martinez de Marigorta, E.; Rodriguez, M.;
Pagalday, J. Tetrahedron 2003, 59, 2617; (f) Vanderhoydonck, B.; Stevens, C. V.
Synthesis 2004, 722; (g) Palacios, F.; Herrán, E.; Alonso, C.; Rubiales, G. Arkivoc
2007, iv, 397–407; (h) Masschelein, K. G. R.; Stevens, C. V. J. Org. Chem. 2007, 72,
9248.
7. Kantoci, D.; Denike, J. K.; Wechter, W. J. Synth. Commun. 1996, 26, 2037. The
debenzylation of tetraethyl dibenzylaminomethylbisphosphonate was
performed with Pd–C (20%) in MeOH at room temperature under
atmosphere (stirring for 16 h).
a H2-
8. Typical procedure for the synthesis of a-chloroaldehydes 5: to the aldehyde in a
flask equipped with an air cooler was added carefully 1.05 equiv of SO2Cl2 at
P(O)(OEt)2
MgSO4
O
P(O)(OEt)2
Et3N
CH2Cl2
rt, 4 h
P(O)(OEt)2
P(O)(OEt)2
N
P(O)(OEt)2
R1
R2
N
X
R1
+
H
P(O)(OEt)2
X
R1
H2N
rt, 30'
H
R2
H
R2
6
4
1
5
Scheme 4.

4338
K. G. R. Masschelein, C. V. Stevens / Tetrahedron Letters 49 (2008) 4336–4338
0 °C (in case of 5c 2.1 equiv of SO2Cl2 was necessary and stirring was continued
of the solvent, the residue was dissolved in diethyl ether. The solids (MgSO4 and
triethylammonium salts) were removed by filtration and the solvent was
evaporated in vacuo. If necessary, the residue was again dissolved in diethyl
ether to remove the remaining triethylammonium salts. The crude product was
purified by column chromatography on silica gel (100% EtOAc). Spectral data of
diethyl [(diethoxyphosphoryl)-(2-methylpropenylimino)methyl]phosphonate
6f: 1H NMR (300 MHz, CDCl3): d 1.36 (6H, t, J = 7.2 Hz, 2 Â P(O)OCH2CH3),
1.37 (6H, t, J = 7.2 Hz, 2 Â P(O)OCH2CH3), 1.98 (3H, s, CH3), 2.10 (3H, s, CH3), 4.20
(4H, q, J = 7.2 Hz, 2 Â P(O)OCH2CH3), 4.25 (4H, q, J = 7.2 Hz, 2 Â P(O)OCH2CH3),
for 15 h). After stirring for 30 min at room temperature, the resulting mixture
was poured into water. The water phase was extracted with CH2Cl2. The
combined organic fractions were washed with a saturated NaHCO3-solution
and dried (MgSO4). After filtration and evaporation, the crude chlorinated
aldehydes 5 were obtained. To use the aldehydes in the following imination
step, distillation was performed.
9. Stevens, C. L.; Gillis, B. T. J. Am. Chem. Soc. 1957, 79, 3448.
10. Tisdale, E. J.; Vong, B. G.; Li, H.; Kim, S. H.; Chowdhury, C.; Theodorakis, E. A.
Tetrahedron 2003, 59, 6873.
3
7.73 (1H, br s, NCH). 13C NMR (75 MHz, CDCl3): d 16.37 (d, JCP = 5.8 Hz,
11. Typical procedure for the synthesis of 1,1-bisphosphono-2-aza-1,3-dienes 6:
2 Â P(O)OCH2CH3), 16.43 (d, 3JCP = 5.8 Hz, 2 Â P(O)OCH2CH3), 18.45 (CH3), 23.90
2
2
tetraethyl aminomethylbisphosphonate
1
(5.0 mmol) and an appropriate
(CH3), 63.08 (d, JCP = 6.9 Hz, 2 Â P(O)OCH2CH3), 63.46 (d, JCP = 6.9 Hz,
3
3
a-chloroaldehyde (5.0 mmol) were dissolved in 15 mL of dichloromethane. To
this solution, anhydrous magnesium sulfate (2.5 mmol) was added. The
reaction mixture was protected from moisture by a calcium chloride tube and
was stirred for 4 h at room temperature. Triethylamine (5.5 mmol) was added
to the mixture and the reaction was further stirred for 30 min. After evaporation
2 Â P(O)OCH2CH3), 134.88 (dd, JCP = 34.6 Hz, JCP = 19.6 Hz, NCH), 151.56
1 1
(C=CHN), 153.06 (dd, JCP = 212.3 Hz, JCP = 129.2 Hz, C@N). 31P NMR
2
2
(121 MHz, CDCl3):
d 0.50 (d, JPP = 155.6 Hz), 8.77 (d, JPP = 155.6 Hz). IR
(cmÀ1) mmax: 1248 (P@O), 1014 (P–O). MS m/z (%): (ES, Pos) 356 (M+H+, 100).
Chromatography: EtOAc (100%) Rf = 0.18.