Double nucleophilic 1,2-addition of silylated dialkyl phosphites to 4-phosphono-1-aza-1,3-dienes: Synthesis of γ-phosphono-α- aminobisphosphonates

Article abstract of DOI:10.1021/jo701718t

(Chemical Equation Presented) γ-Phosphono-α- aminobisphosphonates were synthesized from a new class of 4-phosphono-1-aza-1,3- dienes by the addition of dialkyl trimethylsilyl phosphites to these azadienes in the presence of acid. Depending on the steric demand of the group on nitrogen, double 1,2-addition or tandem 1,4-1,2-addition occurred.

Full text of DOI:10.1021/jo701718t

Double Nucleophilic 1,2-Addition of Silylated Dialkyl Phosphites to
4-Phosphono-1-aza-1,3-dienes: Synthesis of
γ-Phosphono-r-aminobisphosphonates
Kurt G. R. Masschelein and Christian V. Stevens*
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
UniVersity, Coupure Links 653, B-9000 Ghent, Belgium
chris.steVens@ugent.be
ReceiVed August 6, 2007
γ-Phosphono-R-aminobisphosphonates were synthesized from a new class of 4-phosphono-1-aza-1,3-
dienes by the addition of dialkyl trimethylsilyl phosphites to these azadienes in the presence of acid.
Depending on the steric demand of the group on nitrogen, double 1,2-addition or tandem 1,4-1,2-addition
occurred.
Introduction
4-phosphono-1-aza-1,3-dienes and to evaluate the synthesis of
diphosphono derivatives, phosphorus nucleophiles were chosen.
The addition reactions of phosphorus nucleophiles have been
extensively described in the literature, and several reviews have
been published.3 In general, the regioselectivity is strongly
dependent on the type of phosphorus nucleophile, the substrate,
and the reaction conditions. Recently, the tandem 1,4-1,2-
addition of dialkyl trimethylsilyl phosphites and trialkyl phos-
phites to R,â-unsaturated imines derived from cinnamaldehyde
was developed in our laboratory.4
Azadienes in general are recognized as useful intermediates
in synthetic chemistry for the construction of both heterocyclic
systems as well as acyclic polyfunctionalized compounds.1 The
introduction of a phosphonate functionality on azadienes may
be very interesting in view of inverse electron demand Diels-
Alder reactions and for synthetic transformations leading to
aminophosphonate derivatives and azaheterocyclic phospho-
nates.2 Because of the lack of general methods for their
synthesis, the reactivity of 4-phosphono-1-aza-1,3-dienes has
not been described in the literature so far. Besides their potential
usefulness in pericyclic reactions, these compounds could also
serve as substrates for nucleophilic addition reactions.
In the case of 4-phosphono-1-aza-1,3-dienes 1, nucleophiles
can interact with several electrophilic centers. A 1,2- or 1,4-
addition to the R,â-unsaturated imine functionality could occur,
or a Michael addition to the vinylphosphonate could be
envisaged. To investigate the regioselectivity of the addition to
Depending on the regioselectivity of the addition of phos-
phorus nucleophiles to 4-phosphono-1-aza-1,3-dienes, the ad-
dition could lead to aminophosphonates or bisphosphonates.
Aminophosphonates are known to efficiently mimic amino acids
and to have a negligible mammalian toxicity. Although the
biological importance of these compounds was recognized over
* Corresponding author. Fax: +32-9-264 62 43.
(1) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002,
58, 379.
(2) (a) Palacios, F.; Gil, M. J.; de Marigorta, E. M.; Rodriguez, M.
Tetrahedron 2000, 56, 6319. (b) Palacios, F.; Ochoa de Retana, A. M.;
Martinez de Marigorta, E.; Rodriguez, M.; Pagalday, J. Tetrahedron 2003,
59, 2617. (c) Vanderhoydonck, B.; Stevens, C. V. Synthesis 2004, 722. (d)
Vanderhoydonck, B.; Stevens, C. V. J. Org. Chem. 2005, 70, 191. (e)
Palacios, F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org. Chem. 2007,
72, 2682. (f) For a review on azaheterocyclic phosphonates, see: Moonen,
K.; Laureyn, I.; Stevens, C. V. Chem. ReV. 2004, 104, 6177.
(3) (a) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81. (b) Enders,
D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006,
26.
(4) (a) Moonen, K.; Van Meenen, E.; Verwe´e, A.; Stevens, C. V. Angew.
Chem., Int. Ed. 2005, 44, 1. (b) Van Meenen, E.; Moonen, K.; Verwe´e, A.;
Stevens, C. V. J. Org. Chem. 2006, 71, 7903.
10.1021/jo701718t CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/31/2007
9248
J. Org. Chem. 2007, 72, 9248-9252

Synthesis of γ-Phosphono-R-aminobisphosphonates
SCHEME 3
50 years ago, they still represent a promising class of potential
drugs.5 Bisphosphonates (BPs), on the other hand, are analogues
of naturally occurring pyrophosphate (PPi) and are a major class
of drugs for the treatment of bone diseases.6 Besides their
antiresorptive properties, several bisphosphonates are also potent
growth inhibitors of some pathogenic trypanosomatids.7
Results and Discussion
TABLE 1. Synthesis of 4-Phosphono-1-aza-1,3-dienes
Synthesis of 4-Phosphono-1-aza-1,3-dienes. The precursor
of 4-phosphono-1-aza-1,3-dienes, dialkyl (1E)-3-oxoprop-1-
enylphosphonates 4, were prepared starting from epibromohy-
drin 2. An Arbuzov reaction between epibromohydrin 2 and
trialkyl phosphites resulted in dialkyl 2,3-epoxypropylphospho-
nates 3 in reasonable yields.8 After treatment of 3 with NaOMe
in MeOH, followed by the addition of Dowex resin, and
subsequent oxidation of the formed alcohol with PCC, dialkyl
(1E)-3-oxoprop-1-enylphosphonates 4 were obtained in moder-
ate yields (Scheme 1).9
R1
R2
product
yield (%)
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
t-Bu
i-Pr
sec-Bu
i-Bu
c-Hex
Bn
t-Bu
i-Pr
sec-Bu
i-Bu
c-Hex
1a
1b
1c
1d
1e
1f
1g
1h
1i
91
91
99
91
99
97a
93
99
97
99
99
1j
1k
SCHEME 1
a Only stable for a few hours.
1-enylphosphonates 4 and dimethylhydrazine in the presence
of acetic acid provided hydrazones 6 in reasonable to good yields
(Scheme 4).
SCHEME 4
Having the dialkyl (1E)-3-oxoprop-1-enylphosphonates 4 in
hand, several 4-phosphono-1-aza-1,3-dienes were prepared. The
synthesis of diethyl (1E,3E)-3-{[(4-methylphenyl)sulfinyl]-
imino}prop-1-enylphosphonate 5 was initially evaluated. Re-
cently, an attractive method for the synthesis of N-sulfonyl
aldimines and N-sulfonyl ketimines via N-sulfinyl aldimines and
N-sulfinyl ketimines has been published.10 Imination of diethyl
(1E)-3-oxoprop-1-enylphosphonate 4b with p-toluenesulfina-
mide in the presence of Ti(OEt)4 provided diethyl (1E,3E)-3-
{[(4-methylphenyl)sulfinyl]imino}prop-1-enylphosphonate 5 in
good yield (Scheme 2).
Addition of Dialkyl Trimethylsilyl Phosphite. To evaluate
the addition of phosphorus nucleophiles to 4-phosphono-1-aza-
1,3-dienes, dialkyl trimethylsilyl phosphites were chosen. Di-
alkyl trimethylsilyl phosphites were reported by Afarinkia et
al. as excellent mild phosphonylation agents because the more
nucleophilic σ3λ3 form of the dialkyl phosphite reagent could
be obtained by O-silylation with trimethylsilyl chloride (TMSCl)
in CH2Cl2 and triethylamine as a base.11 Following the research
of the one-pot tandem 1,4-1,2-addition of phosphites to R,â-
unsaturated imines,5a reaction conditions, optimized during this
research, were used. It was shown that, when mixing dialkyl
trimethylsilyl phosphites (after filtration of triethylammonium
hydrochloride salt) with an imine in dry dichloromethane, the
reaction proceeded violently upon addition of 1 equiv of
concentrated sulfuric acid and yielded the desired tandem
product after 30 min at room temperature.5a Applying these
reaction conditions to diethyl (1E,3E)-3-{[(4-methylphenyl)-
sulfinyl]imino}prop-1-enylphosphonate 5 resulted in a mixture,
which proved very difficult to transform into one end product.
Increasing the reaction time and temperature did not give better
results and had to be abandoned. Applying the same reaction
conditions to another substrate (e.g., dimethyl (1E,3E)-3-
(isopropylimino)prop-1-enylphosphonate 1b) also resulted in a
mixture, but a closer look at the 1H NMR and 31P NMR spectra
SCHEME 2
Several 4-phosphono-1-aza-1,3-dienes were prepared by
reacting dialkyl (1E)-3-oxoprop-1-enylphosphonates 4 with
amines in CH2Cl2 in the presence of MgSO4 (Scheme 3 and
Table 1).
Finally, hydrazones 6 were prepared to evaluate the reactivity
of 4-phosphono-1-aza-1,3-dienes with an electron-donating
group on the 1-position. Reaction of dialkyl (1E)-3-oxoprop-
(5) Kafarski, P.; Lejczak, B. Curr. Med. Chem. 2001, 1, 301.
(6) Graham, R.; Russell, G. Ann. N.Y. Acad. Sci. 2006, 1068, 367.
(7) Docampo, R.; Moreno, S. N. J. Curr. Drug Targets 2001, 1, 51.
(8) Griffin, C. E.; Kundu, S. K. J. Org. Chem. 1969, 34, 1532.
(9) Just, G.; Potvin, P.; Hakimelahi, G. H. Can. J. Chem. 1980, 58, 2780.
(10) Ruano, J. L.; Alema´n, J.; Bele´n Cid, M.; Parra, A. Org. Lett. 2005,
7, 179.
(11) Afarinkia, K.; Rees, C. W.; Cadogan, J. I. G. Tetrahedron 1990,
46, 7175.
J. Org. Chem, Vol. 72, No. 24, 2007 9249

Masschelein and Stevens
TABLE 2. Synthesis of γ-Phosphono-r-aminobisphosphonates
R1
R2
reagents
temperature
time (h)
product
yield (%)
Me
Me
Me
i-Pr
sec-Bu
i-Bu
DMPTMS, H2SO4, CH2Cl2
DMPTMS, H2SO4, CH2Cl2
DMPTMS, H2SO4, CH2Cl2
rt
reflux
rt
reflux
rt
rt
rt
MW (80 °C)
rt
rt
87
17
76
20
126
103
78
3
9a
9b
9c
71
77
72
69
79
44
76
73
72
74
69
Me
Me
Et
c-Hex
Bn
i-Pr
DMPTMS, H2SO4, CH2Cl2
DMPTMS, H2SO4, CH2Cl2
DEPTMS in situ, CH2Cl2
9d
9e
9f
Et
Et
sec-Bu
c-Hex
DEPTMS, H2SO4, CH2Cl2
DEPTMS, H2SO4, CH2Cl2
DEPTMS in situ, CH2Cl2
110
90
8
9g
9h
MW (80 °C)
SCHEME 6
of this mixture revealed some interesting intermediates (e.g.,
1,2-adduct 7 and enamine 8).
of R-amino-R,â-unsaturated phosphonates and R-amino-â,γ-
unsaturated phosphonates could be followed (by P-P coupling)
and allowed us to propose a possible mechanism for the double
1,2-addition. In this mechanism, the addition of acid to the
reaction seems to be a crucial step to obtain full conversion.
Besides the activation of the imine in the first step, the protons
are also utilized during the imine tautomerization. Thus, at least
1 equiv of protons has to be present in the reaction mixture.
On the other hand, an excess of protons will slow down the
reaction, due to the protonation of the intermediate enamine
and the subsequent blocking of the imine tautomerization
(Scheme 7).
The formation of enamine 8 prompted us to increase the
reaction time because tautomerism of this enamine would lead
to an imine that is susceptible to a second addition of silylated
phosphite. Analysis of the course of the reaction by 31P NMR
indicated the formation of a double 1,2-adduct that was in
contrast with the spectra observed when studying the phosphite
addition to R,â-unsaturated imines.5 However, it took several
days for the reaction to go to completion. Reducing the reaction
time was possible by refluxing the reaction mixture; however,
in most cases, side products were formed. Even under reflux,
the reaction still required 24 h to complete. Therefore, micro-
wave heating was evaluated. Under microwave conditions,
double 1,2-addition was completed after several hours. Since
in some cases side product formation was observed at higher
temperatures when using DAPTMS and H2SO4, another method
was evaluated. Substrates were added to freshly prepared
DAPTMS (without filtration of the triethylammonium hydro-
chloride salt). In this case, the formation of the double 1,2-
adduct was also observed. Unfortunately, in both cases (using
DAPTMS in the presence of H2SO4 or using in situ DAPTMS
in the presence of triethylammonium hydrochloride salts)
purification was needed. Since chromatography on silica gel
always resulted in a loss of product due to the high affinity of
the end products to silica gel, we have optimized an acid-base
extractive methodology from which the bisphosphonates could
be isolated (Scheme 5 and Table 2).
A possible reaction mechanism for the formation of 10 was
already described for the tandem 1,4-1,2-addition of phosphites
to R,â-unsaturated imines.5a The sterically demanding t-butyl
group of 1a is in favor of this tandem 1,4-1,2-addition, as the
1,2-addition should be slowed down by the steric bulk. Also, a
parallel but reversible 1,2-addition was observed (Scheme 8).
In conclusion, a convenient methodology for the synthesis
of γ-phosphono-R-aminobisphosphonates was developed in
good yield from 4-phosphono-1-aza-1,3-dienes. In the case of
the N-t-Bu derivative, a tandem 1,4-1,2-addition of silylated
phosphite was observed.
Experimental Section
SCHEME 5
Synthesis of 4-Phosphono-1-aza-1,3-dienes 1. Unless otherwise
stated, all phosphonylated R,â-unsaturated aldimines were prepared
by mixing di(m)ethyl (1E)-3-oxoprop-1-enylphosphonate 4a,b with
1 equiv of amine (1.1 equiv in case of volatile amines) and 0.5
equiv of MgSO4 in dry dichloromethane. The mixture was then
stirred overnight and shielded from moisture using a CaCl2 tube.
The imines were obtained as yellowish/brownish oils (except for
1e and 1f: white crystals after recrystallization) in high purity and
yield after filtration of the solids and evaporation of the solvent
under reduced pressure. Dimethyl (1E,3E)-3-(t-butylimino)prop-
1-enylphosphonate 1a: yellowish oil. 1H NMR (300 MHz, CDCl3)
δ: 1.24 (9H, s, 3 × CH3, t-Bu), 3.77 (6H, d, 3JHP ) 11.0 Hz, 2 ×
Applying these reaction conditions to dimethyl (1E,3E)-3-
(t-butylimino)prop-1-enylphosphonate 1a, another regioselec-
tivity was observed (Scheme 6), leading to the formation of
the 1,4-1,2-addition product 10. Finally, when adding
DAPTMS and H2SO4 to hydrazones 6, no phosphonylation was
observed.
2
P(O)OCH3), 6.18 (1H, dd, JHP ) 18.4 Hz, J ) 17.3 Hz, CHP),
3
Mechanism. Following the previously mentioned reactions
7.11 (1H, ddd, JHP ) 20.6 Hz, J ) 17.3 Hz, J ) 8.5 Hz, HCd
with 1H NMR and 31P NMR, the appearance and disappearance
CHP), 7.95 (1H, d, J ) 8.5 Hz, HCdN). 13C NMR (75 MHz,
9250 J. Org. Chem., Vol. 72, No. 24, 2007

Synthesis of γ-Phosphono-R-aminobisphosphonates
SCHEME 7
SCHEME 8
2
CDCl3) δ: 29.4 (3 × CH3, t-Bu), 52.7 (d, JCP ) 5.8 Hz, 2 ×
To a solution of 4b (0.62 g, 3.22 mmol) and p-toluenesulfinamide
(0.50 g, 3.22 mmol) in dry CH2Cl2 (50 mL) was added Ti(OEt)4
(2.94 g, 12.88 mmol). This mixture was refluxed under a N2
atmosphere over a period of 16 h. After cooling down to room
temperature, MeOH (15 mL) and a few drops of a NaHCO3 solution
(aq, saturated) (until precipitation of Ti salts) were added. The
resulting suspension was filtrated over MgSO4, and the solids were
washed with EtOAc. The combined organic fractions were dried
(MgSO4), and after filtration, the solvent was removed under
reduced pressure. As a result, 5 (0.99 g, 93%) was obtained as a
brownish oil. Diethyl (1E,3E)-3-{[(4-methylphenyl)sulfinyl]imino}-
prop-1-enyl-phosphonate 5: 1H NMR (300 MHz, CDCl3) δ: 1.35
(6H, t, J ) 7.2 Hz, 2 × P(O)OCH2CH3), 2.41 (3H, s, CH3), 4.07-
1
P(O)OCH3), 58.3 (Cquat, t-Bu), 125.2 (d, JCP ) 189.2 Hz, CHP),
2
3
147.8 (d, JCP ) 5.8 Hz, HCdCHP), 155.5 (d, JCP ) 31.2 Hz,
HCdN). 31P NMR (121 MHz, CDCl3) δ: 19.77. IR (cm-1) νmax
:
2969, 1252 (PdO), 1032 (br, P-O). MS m/z (%): (ES, Pos) 220
(M + H+, 100). Elem. anal. calcd for C9H18NO3P: C 49.31, H
8.28, N 6.39. Found: C 49.43, H 8.36, N 6.15. Yield: 91%.
Synthesis of Di(m)ethyl (1E)-3-Oxoprop-1-enylphosphonate
4a,b. Diethyl (1E)-3-oxoprop-1-enylphosphonate 4b was prepared
in several steps from epibromohydrin according to literature
procedures. For the synthesis of dimethyl (1E)-3-oxoprop-1-
enylphosphonate 4a, the same procedures were followed.9,10
Synthesis of Diethyl (1E,3E)-3-{[(4-Methylphenyl)sulfinyl]-
imino}prop-1-enylphosphonate 5. (See Ruano et al. for a general
method for the preparation of N-sulfonyl aldimines and ketimines.)10
2
4.19 (4H, m, 2 × P(O)OCH2CH3), 6.49 (1H, dd, JHP ) 17.3 Hz,
J ) 17.1 Hz, CHP), 7.22 (1H, ddd, 3JHP ) 19.8 Hz, J ) 17.1 Hz,
J. Org. Chem, Vol. 72, No. 24, 2007 9251

Masschelein and Stevens
J ) 9.1 Hz, HCdCHP), 7.32 (2H, d, J ) 8.0 Hz, 2 × CHarom),
7.57 (2H, d, J ) 8.0 Hz, 2 × CHarom), 8.41 (1H, d, J ) 9.1 Hz,
of TMSCl (1.1 equiv) was added using a syringe. After 1 h at
0 °C, a suitable 4-phosphono-1-aza-1,3-diene (5 mmol) dissolved
in 5 mL of dry dichloromethane was added to the in situ prepared
DAPTMS. The mixture was allowed to react until completion as
was determined by 31P NMR (for reaction time and temperature,
see Table 2). The workup and purification of the products were
the same as for the procedure with DAPTMS and H2SO4. Dimethyl
[1,3-bis(dimethoxyphosphoryl)-1-isopropylaminopropyl]-phospho-
nate 9a: yellowish oil. 1H NMR (300 MHz, CDCl3) δ: 1.10 (6H,
d, J ) 6.3 Hz, 2 × CH3, i-Pr), 1.57 (1H, br s, NH), 2.07-2.30
(4H, m, CH2CH2P), 3.25 (1H, sept, J ) 6.3 Hz, NCH, i-Pr), 3.75
3
HCdN). 13C NMR (75 MHz, CDCl3) δ: 16.5 (d, JCP ) 6.9 Hz,
2 × P(O)OCH2CH3), 21.5 (CH3), 62.6 (d, 2JCP ) 5.8 Hz, 2 × P(O)-
OCH2CH3), 124.7 (2 × CHarom), 130.1 (2 × CHarom), 132.5 (d, 1JCP
) 186.9 Hz, CHP), 140.6 (Cquat,arom), 142.2 (d, 2JCP ) 5.8 Hz, HCd
CHP), 142.3 (Cquat,arom), 159.7 (d, 3JCP ) 30 Hz, HCdN). 31P NMR
(121 MHz, CDCl3) δ: 15.04. IR (cm-1) νmax: 1575 (CdN), 1253
(PdO), 1096, 1051 (P-O), 1024 (P-O). MS m/z (%): (ES, Pos)
330 (M + H+, 100). Elem. anal. calcd for C7H13NO4PS: C 35.29,
H 5.50, N 5.88. Found: C 34.99, H 5.21, N 6.06.
3
Synthesis of Di(m)ethyl (1E,3E)-3-(dimethylhydrazono)prop-
1-enylphosphonate 6a,b. To a solution of 2.6 mmol of N,N-
dimethylhydrazine in CH2Cl2 (2.5 mL) was added dropwise 2.6
mmol of AcOH (1.0 equiv) with continuous stirring. After cooling
the mixture in an ice bath, 2.6 mmol of di(m)ethyl (1E)-3-oxoprop-
1-enylphosphonate 4a,b was added, and the whole mixture was
stirred for 1 h without further cooling. After CH2Cl2 was added,
the mixture was washed thoroughly with aqueous Na2CO3 and dried
over MgSO4. Removal of the solvent in vacuo afforded di(m)ethyl
(1E,3E)-3-(dimethylhydrazono)prop-1-enylphosphonate 6a,b as a
yellowish oil. Dimethyl (1E,3E)-3-(dimethylhydrazono)prop-1-
enylphosphonate 6a: 1H NMR (300 MHz, CDCl3) δ: 3.03 (6H, s,
2 × CH3), 3.73 (d, 3JHP ) 11.0 Hz, 2 × P(O)OCH3), 5.58 (1H, dd,
2JHP ) 18.4 Hz, J ) 17.1 Hz, CHP), 6.86 (1H, d, J ) 9.1 Hz,
HCdN), 7.18 (1H, ddd, 3JHP ) 20.9 Hz, J ) 17.1 Hz, J ) 9.1 Hz,
HCdCHP). 13C NMR (75 MHz, CDCl3) δ: 42.3 (2 × CH3), 52.4
(6H, d, JHP ) 10.7 Hz, 2 × P(O)OMe), 3.85 (6H, d, 3JHP ) 10.7
Hz, 2 × P(O)OMe), 3.86 (6H, d, 3JHP ) 10.7 Hz, 2 × P(O)OMe).
13C NMR (75 MHz, CDCl3) δ: 20.0 (dt, 1JCP ) 140.8 Hz, 3JCP
)
4.6 Hz, CH2P), 24.3 (CH2CH2P), 25.9 (2 × CH3, i-Pr), 44.3 (t,
2
3JCP ) 6.9 Hz, NCH, i-Pr), 52.4 (d, JCP ) 6.9 Hz, 2 × P(O)-
2
4
OMe), 54.0 (dt, JCP ) 45.0 Hz, JCP ) 3.5 Hz, 4 × P(O)OMe),
62.9 (dt, 1JCP ) 140.8 Hz, 3JCP ) 19.6 Hz, CquatP2). 31P NMR (121
MHz, CDCl3) δ: 24.47 (2 × P(O)(OMe)2), 34.72 (P(O)(OMe)2).
IR (cm-1) νmax: 3480 (NH), 2958, 1248 (PdO), 1028 (br, P-O).
MS m/z (%): (ES, Pos) 426 (M + H+, 100), 316 (M+ - P(O)-
(OMe)2, 69). Elem. anal. calcd for C12H30NO9P3: C 33.89, H 7.11,
N 3.29. Found: C 33.62, H 7.11, N 3.03. Yield: 71%.
Synthesis of Dimethyl [1-t-Butylamino-3,3-bis(dimethoxy-
phosphoryl)propyl]phosphonate 10. Dimethyl (1E,3E)-3-(t-bu-
tylimino)prop-1-enylphosphonate 1a (5 mmol) dissolved in 15 mL
of dry dichloromethane was allowed to stir at room temperature
under a nitrogen atmosphere. Then, 10.5 mmol of DAPTMS (2.1
equiv) and 2.5 mmol of sulfuric acid (0.5 equiv; 1 equiv of H+)
were added consecutively. The mixture was allowed to react until
completion as was determined by 31P NMR (see Scheme 7). The
workup and purification of the products were the same as for the
synthesis of γ-phosphono-R-aminobisphosphonates 9. Dimethyl
[1-t-butylamino-3,3-bis(dimethoxyphosphoryl)-propyl]phospho-
nate 10: 1H NMR (300 MHz, CDCl3) δ: 1.14 (9H, s, 3 × CH3,
t-Bu), 1.89-2.41 (2H, m, CH2), 3.27 (1H, ddt, J ) 24.2 Hz, J )
7.7 Hz, J ) 5.0 Hz, CHP2), 3.60 (1H, dt, J ) 7.8 Hz, J ) 7.8 Hz,
NCHP), 3.77 (3H, d, J ) 10.5 Hz, P(O)OCH3), 3.82 (3H, d, J )
11.0 Hz, P(O)OCH3), 3.82 (3H, d, J ) 10.5 Hz, P(O)OCH3), 3.83
(3H, d, J ) 11.0 Hz, P(O)OCH3), 3.83 (3H, d, J ) 11.0 Hz, P(O)-
OCH3), 3.84 (3H, d, J ) 10.5 Hz, P(O)OCH3). 13C NMR (75 MHz,
CDCl3) δ: 29.3 (br, CH2), 29.9 (t-Bu), 31.4 (dt, 1JCP ) 133.8 Hz,
3JCP ) 4.6 Hz, CHP2), 47.3 (ddd, 1JCP ) 152.3 Hz, 3JCP ) 9.2 Hz,
2
1
(d, JCP ) 5.8 Hz, 2 × P(O)OCH3), 110.6 (d, JCP ) 196.1 Hz,
2
CHP), 129.2 (d, JCP ) 31.2 Hz, HCdN), 147.8 (d, J ) 6.9 Hz,
HCdCHP). 31P NMR (121 MHz, CDCl3) δ: 23.87. IR (cm-1
)
ν
max: 1598 (CdN), 1244 (PdO), 1031 (br, P-O). MS m/z (%):
(ES, Pos) 207 (M + H+, 74). Elem. anal. calcd for C7H15N2O3P:
C 40.78, H 7.33, N 13.59. Found: C 40.65, H 7.57, N 13.67.
Yield: 65%.
Synthesis of γ-Phosphono-R-aminobisphosphonates 9. Pro-
cedure with DAPTMS and H2SO4. A suitable 4-phosphono-1-
aza-1,3-diene (5 mmol) dissolved in 15 mL of dry dichloromethane
was allowed to stir at room temperature under a nitrogen atmo-
sphere. Then, 10.5 mmol of DAPTMS (2.1 equiv) and 2.5 mmol
of sulfuric acid (0.5 equiv; 1 equiv of H+) were added consecutively.
The mixture was allowed to react until completion as was
determined by 31P NMR (for reaction time and temperature, see
Table 2). Then, the mixture was poured into 20 mL of a saturated
NaHCO3(aq) solution. The organic phase was recovered, and the
remaining aqueous phase was washed 3 times with 5 mL of
dichloromethane. The organics were dried (MgSO4) and filtered.
The solvent was removed in vacuo. Because of the excess of dialkyl
trimethylsilyl phosphite used, the products had to be purified by
an acid-base extraction. Therefore, the product was dissolved in
15 mL of ether. To this solution, 45 mL of 3 N HCl was added.
The mixture was stirred for 30 min at room temperature, followed
by three extractions with diethyl ether. The aqueous phase was
basified with 3 N NaOH followed by extraction with CH2Cl2. The
CH2Cl2 phase was dried with MgSO4. After filtration and removal
of the solvent in vacuo, the γ-phosphono-R-aminobisphosphonates
were obtained in good yield and purity as yellowish oils.
Procedure with DAPTMS in Situ. Dialkyl phosphite (10.5
mmol) was mixed with 11.5 mmol of triethylamine (1.1 equiv) in
10 mL of dry dichloromethane in an oven dry flask under a nitrogen
atmosphere. The mixture was then cooled to 0 °C, and 11.5 mmol
3
3JCP ) 4.6 Hz, NCHP), 51.6 (d, JCP ) 6.9 Hz, Cquat, t-Bu), 52.7
(d, 2JCP ) 6.9 Hz, P(O)OCH3), 53.2 (d, 2JCP ) 6.9 Hz, 2 × P(O)-
2
2
OCH3), 53.3 (d, JCP ) 6.9 Hz, P(O)OCH3), 53.5 (d, JCP ) 6.9
Hz, P(O)OCH3), 53.6 (d, JCP ) 6.9 Hz, P(O)OCH3). 31P NMR
2
(121 MHz, CDCl3) δ: 26.60, 27.15 (d, J ) 2.2 Hz), 31.12. IR
(cm-1) νmax: 3476, 3418, 1248 (PdO), 1228 (PdO), 1017 (br,
P-O). MS m/z (%): (ES, Pos) 440 (M + H+, 100). Elem. anal.
calcd for C13H32NO9P3: C 35.54, H 7.34, N 3.19. Found: C 35.53,
H 7.40, N 3.26. Yield: 54%.
Supporting Information Available: General information and
spectroscopic data of all compounds synthesized with complete peak
1
assignments. Copies of H NMR spectra and 13C NMR spectra of
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO701718T
9252 J. Org. Chem., Vol. 72, No. 24, 2007