Conjugate addition of amines to an α,β-unsaturated imine derived from α-aminophosphonate. Synthesis of γ-amino-α- dehydroaminophosphonates

Article abstract of DOI:10.1021/jo8022022

(Chemical Equation Presented) Aza-Michael reaction of ammonia, aliphatic, aromatic and optically active amines to an α,β-unsaturated imine derived from α-aminophosphonate affords α-dehydroaminophosphonates with a γ-stereogenic center bearing an amino group. Resulting γ-amino α-dehydroaminophosphonates can be used for the preparation of phosphorylated pyrimidine derivatives.

Full text of DOI:10.1021/jo8022022

is well documented in the literature, to the best of our knowledge
there are no examples reported about conjugate addition of
amines to R,ꢀ-unsaturated imines. Moreover, the presence of a
phosphonate group in the imine increases the synthetic interest
of these substrates due to the applications of functionalized
aminophosphonates in organic and medicinal chemistry.7-10
We have been involved in the chemistry of azabutadienes,11
and we recently reported an efficient synthesis of R,ꢀ-unsatur-
ated imines derived from R-aminoesters12a and R-amino-
phosphonates.12b These 1-azadienes have shown very assorted
reactivity, and they have proved to be very useful intermediates
for the synthesis of several heterocycles13 as well as for the
preparation of R-amino acid or R-aminophosphonic acid deriva-
tives,12 in some cases enantioselectively.14 Following our interest
in the chemistry of R-aminophosphonates15 and 1-azabuta-
dienes11,12 and specifically in the reactivity of R,ꢀ-unsaturated
imines derived from R-aminophosphonates, we report here the
first example of a conjugate addition of amine nucleophiles to
the ꢀ-carbon vinylogously attached to an imine group.
Conjugate Addition of Amines to an
r,ꢀ-Unsaturated Imine Derived from
r-Aminophosphonate. Synthesis of
γ-Amino-r-dehydroaminophosphonates
Javier Vicario, Domitila Aparicio, and Francisco Palacios*
Departamento de Qu´ımica Orga´nica I, Facultad de
Farmacia, UniVersidad del Pa´ıs Vasco,
Apartado 450, 01080 Vitoria, Spain
francisco.palacios@ehu.es
ReceiVed October 2, 2008
Conjugate addition of ammonia 2a (R1 ) R2 ) H) to R,ꢀ-
unsaturated imine 1 derived from R-aminophosphonate does not
require any additional activation and can be performed in CH2Cl2
under mild conditions (procedure A, see the Experimental
Section), affording exclusively the E isomer of γ-amino-R-
dehydroaminophosphonate 3a (R1 ) R2 ) H), in a stereose-
Aza-Michael reaction of ammonia, aliphatic, aromatic and
optically active amines to an R,ꢀ-unsaturated imine derived
from R-aminophosphonate affords R-dehydroaminophos-
phonates with a γ-stereogenic center bearing an amino group.
Resulting γ-amino R-dehydroaminophosphonates can be used
for the preparation of phosphorylated pyrimidine derivatives.
(6) For some recent examples of organocatalytic aza-Michael reactions, see:
(a) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. J. Am. Chem. Soc. 2006, 128,
9328. (b) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 1983. (c) Liu, B. K.; Wu, Q.; Qian, X. Q.; Lv, D. S.; Lin,
X. F. Synthesis 2007, 2653. (d) Han, X. Tetrahedron Lett. 2007, 48, 2845. (e)
Yeom, C.-E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63, 904. (f) Uria, U.;
Vicario, J. L.; Badia, D.; Carrillo, L. Chem. Commun. 2007, 2509.
(7) For an excellent book, see: Kukhar, V. P., Hadson, H. R., Eds. In
Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological ActiVity;
J. Wiley: Chichester, 2000.
(8) For reviews on R-aminophosphonates, see: (a) Kafarski, P.; Lejczak, B.
Curr. Med. Chem: Anti-Cancer Agents. 2001, 1, 301. (b) Gambecka, J.; Kafarski,
P. Mini-ReV. Med. Chem. 2001, 1, 133.
(9) For reviews on ꢀ-aminophosphonates, see: (a) Palacios, F.; Alonso, C.;
de los Santos, J. M. Chem. ReV. 2005, 105, 899. (b) Palacios, F.; Alonso, C.; de
los Santos, J. M. In EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd ed.; Juaristi,
E., Soloshonok, V. A., Eds.; Wiley: New York, 2005; p 277.
(10) For some recent contributions on γ-aminophosphonates, see: (a)
Fernandez, M. C.; Diaz, A.; Guillin, J. J.; Blanco, O.; Ruiz, M.; Ojea, V. J.
Org. Chem. 2006, 71, 6958. (b) Chowdhury, S.; Muni, N. J.; Greenwood, N. P.;
Pepperberg, D. R.; Standaert, R. F. Bioorg. Med. Chem Lett. 2007, 17, 3745.
(c) Hakogi, T.; Monden, Y.; Taichi, M.; Iwama, S.; Fujii, S.; Ikeda, K.;
Katsumura, S. J. Org. Chem. 2002, 67, 4839.
(11) (a) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E.; Ferna´ndez-
Acebes, A. Tetrahedron 2001, 57, 3131. (b) Palacios, F.; Ochoa de Retana, A. M.;
Pascual, S.; Oyarzabal, J. Org. Lett. 2002, 4, 769. (c) Palacios, F.; Aparicio, D.;
Vicario, J. Eur. J. Org. Chem. 2002, 4131. (d) Palacios, F.; Herra´n, E.; Rubiales,
G.; Ezpeleta, J. M. J. Org. Chem. 2002, 67, 2131. (e) Palacios, F.; Ochoa de
Retana, A. M.; Pascual, S.; Oyarzabal, J. J. Org. Chem. 2004, 69, 8767.
(12) (a) Palacios, F.; Vicario, J.; Aparicio, D. J. Org. Chem. 2006, 71, 7690.
(b) Palacios, F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org. Chem. 2007,
72, 2682.
(13) (a) Palacios, F.; Vicario, J.; Aparicio, D. Tetrahedron Lett. 2007, 48,
6747. (b) Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem. 2006, 2843.
(14) (a) Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405. (b) Palacios, F.;
Vicario, J. Synthesis 2007, 3923.
(15) (a) de los Santos, J. M.; Ignacio, R.; Aparicio, D.; Palacios, F. J. Org.
Chem. 2007, 72, 5202. (b) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M.
J. Org. Chem. 2005, 70, 8895. (c) Palacios, F.; Aparicio, D.; Ochoa de Retana,
A. M.; de los Santos, J. M.; Gil, J. I.; Lopez de Munain, R. Tetrahedron:
Asymmetry. 2003, 14, 689. (d) Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.;
de los Santos, J. M.; Gil, J. I.; Lopez de Munain, R. J. Org. Chem. 2002, 67,
7283.
The aza-Michael reaction is one of the most powerful
reactions in organic chemistry for the formation of C-N bonds.1
Its simplicity makes it the most appropriate alternative for the
preparation of functionalized γ-amino compounds. Conjugate
addition of nitrogen nucleophiles to Michael acceptors can
sometimes proceed without catalyst,2 but, very often, deproto-
nation of the amine,3 or activation of the conjugated system by
the presence of Bro¨nsted4 or Lewis5 acids or organocatalysts6
is required, especially in the case of the addition of weakly
nucleophilic aromatic amines. Despite the fact that conjugate
addition of amines to R,ꢀ-unsaturated carbonylic compounds
(1) (a) For reviews, see: Perlmutter, P. Conjugate Addition Reactions in
Organic Synthesis; Pergamon: Oxford, 1992. (b) Xu, L.-W.; Xia, C.-G. Eur. J.
Org. Chem. 2005, 633. (c) Vicario, J. L.; Bad´ıa, D.; Carrillo, L.; Etxebarria, J.;
Reyes, E.; Ruiz, N. Org. Prep. Proc. Int. 2005, 37, 513.
(2) Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141. (b) Kumar,
R.; Chaudhary, P.; Nimesh, S.; Chandra, R. Green Chem. 2006, 356.
(3) (a) Some recent examples of aza-Michael using lithium amides: Sakai,
T.; Doi, H.; Kawamoto, Y.; Yamada, K.-I.; Tomioka, K. Tetrahedron Lett. 2004,
45, 926. (b) Etxebarria, J.; Vicario, J. L.; Badia, D.; Carrillo, L.; Ruiz, N. J.
Org. Chem. 2005, 70, 8790. (c) Davies, S. G.; Garner, A. C.; Goddard, E. C.;
Kruchinin, D.; Roberts, P. M.; Rodriguez-Solla, H.; Smith, A. D. Chem. Commun.
2006, 2664. (d) Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71,
4706.
(4) (a) Um, I.-H.; Lee, E.-J.; Min, J.-S. Tetrahedron 2001, 57, 9585. (b)
Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484.
(5) For some recent examples of Lewis acid catalyzed aza-Michael reactions,
see: (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319. (b)
Varala, R.; Alam, M. M.; Adapai, S. R. Synlett 2003, 720. (c) Azizi, N.; Saidi,
R. M. Tetrahedron 2004, 60, 383. (d) Narsaiah, A. V. Lett. Org. Chem. 2007,
4, 462. (e) Bhanushali, M. J.; Nandurkar, N. S.; Jagtap, S. R.; Bhanage, B. M.
Catal. Commun. 2008, 9, 1189.
452 J. Org. Chem. 2009, 74, 452–455
10.1021/jo8022022 CCC: $40.75 2009 American Chemical Society
Published on Web 11/19/2008

SCHEME 1. Nucleophilic Addition of Ammonia and
Amines to r,ꢀ-Unsaturated Imine 1
SCHEME 2. Pathway for the Formation of E- and
Z-Enamines by Addition of Amines to Imine 1
TABLE 1. (E)-γ-Amino r-Dehydroaminophosphonates 3
Synthesized by Aza-Michael Reaction of Ammonia and Amines 2 to
Imine 1
(Scheme 1, Table 1, entries 2 and 3). Likewise, the process
was extended to methylamine 2d (R1 ) H, R2 ) Me) (Table 1,
entry 4), a secondary cyclic amine such as pyrrolidine (R1R2 )
(CH2)4) (Table 1, entry 5) and optically active ꢀ-amino alcohol
derivatives such as (S)-methoxymethylpyrrolidine or (S)-pseu-
doephedrine (Table 1, entries 6 and 7) with the formation the
(E)-γ-amino-R-dehydroaminophosphonates 3d-g.
entry compd
R1
R2
E/Za
% yieldb
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
H
H
H
H
H
100/0
100/0
100/0
100/0
100/0
100/0
100/0
82, 80d
83, 81d
81, 80d
88
p-CH3-C6H4
p-NO2-C6H4
CH3
(CH2)4
79, 77d
86
(S)-methoxymethylpyrrolidinec
(S)-pseudoephedrinec
The formation of the E-enamines could be explained taking
into account a pseudo-trans conformation17 of imine 1. Nu-
cleophilic addition of the amine could initially take place to
afford the ionic intermediate I, with a Z configuration of the
carbon-carbon double bond. If the γ-amine substituent is
adequate, the zwitterionic (Z)-enamine I could evolve to the
thermodynamically more stable zwiterionic E-enamine III18 and
the corresponding (E)-enamines can be obtained (Scheme 2).
A different behavior was observed by the conjugate addition
of benzylamine 4a (R1 ) C6H5), allylamine 4b (R1 ) CHdCH2),
and propargylamine 4c (R1 ) Ct CH) to R,ꢀ-unsaturated imine
1 in CH2Cl2 to give (Z)-γ-amino-R-dehydroaminophospho-
nates19 5a-c in a stereoselective manner (Scheme 1, Table 2
3g
81
a Determined by integration of 31P NMR signals of the crude. b Yield
after chromatography. c er ) 1:1. d Yield using the multicomponent
reaction, starting from but-2-(E)-enoylphosphonic acid diethyl ester 10
(procedure B).
lective fashion, with good yield (Scheme 1, Table 1, entry 1).
γ-Amino-R-dehydroaminophosphonate 3a was characterized on
the basis of its 1H, 31P, and 13C NMR, IR, and MS spectra. For
1
example, the H NMR spectrum of (E)-enamine 3a presents a
representative double doublet for the enaminic CH at δH ) 6.46
ppm, which shows coupling constants 3JHH ) 8.6 Hz, with the
adjacent methyne, and 3JPH ) 13.4 Hz, typical for a cis relative
configuration P-H in olefins.16 13C NMR spectrum of (E)-
enamine 3a shows two doublets for the methyne and the
quaternary carbon of the enamine double bond at δC ) 145.9
1
entries 1-3). H NMR spectrum of enamine 5a shows the
double doublet for the enaminic CH at δH ) 6.11 ppm with
3
coupling constant values JHH ) 10.3 Hz with the adjacent
methyne and 3JPH ) 41.9 ppm with the phosphonate, representa-
tive for a trans relative configuration P-H in the double bond.
The 13C NMR spectrum of enamine 5a presents doublets at δC
) 137.8 ppm and δC ) 127.2 ppm, with coupling constants
2
ppm, with a coupling constant JPC ) 23.7 Hz, and at δC )
1
128.2 ppm, with a coupling constant JPC ) 208.0 Hz,
respectively, and another doublet for the methyne at 44.1 ppm
1
2JPC ) 20.3 Hz and JPC ) 200.3 Hz, the first one for the
3
with a coupling constant JPC ) 15.1 Hz typical for the trans
relative configuration P-C in alkenes.16
methyne and the second one for the quaternary carbon of the
enamine double bond as well as another doublet for the
Aromatic amines showed a similar behavior, and conjugate
addition of p-toluidine 2b (R1 ) H, R2 ) p-Me-C6H4) and
electron-deficient p-nitrophenylamine 2c (R1 ) H, R2 ) p-NO2-
C6H4) to R,ꢀ-unsaturated imine 1 in CH2Cl2 gave only (E)-γ-
amino-R-dehydroaminophosphonates 3b,c with very good yields
(17) The configuration and conformation in solution of R,ꢀ-unsaturated imine
1 was established on the basis of 2D NMR experiments. For the nuclear
Overhauser enhancement spectroscopy (NOESY) spectrum, see the Supporting
Information.
(18) Unlike enamine species I, in the iminic structures II there is free rotation
around the C-C single bond, and if the energy barrier is small enough, the
zwiterionic imine II can be converted into E-enamines III.
(19) Z Isomers compared to E-enamines showed a downfield shift of the
signal corresponding to enaminic CH and an upfield shift of the signal assigned
to the CH in the ꢀ-position.
(16) (a) Palacios, F.; Ochoa de Retana, A. M., D.; Oyarzabal, J.; Pascual,
S.; Ferna´ndez de Troconiz, G. J. Org. Chem. 2008, 73, 4568. (b) Palacios, F.;
Aparicio, D.; de los Santos, J. M. Tetrahedron 1994, 50, 12727. (c) Duncan,
M.; Gallager, M. J. Org. Magn. Reson. 1981, 15, 37.
J. Org. Chem. Vol. 74, No. 1, 2009 453

TABLE 2. γ-Amino r-Dehydroaminophosphonates 5 and 7
Synthesized
TABLE 3. Isomerization of Z-Enamines 5a-c and Mixtures of E-
and Z-Enamines 7a,b to E-Enamines 3h-k
entry
compd
starting enamine
R1
C6H5
CHdCH2
Ct CH
CH2CH3
CH(CH3)2
yielda (%)
entry
compd
R1
C6H5
CHdCH2
Ct CH
CH2CH3
CH(CH3)2
E/Za
% yieldb
79, 78c
85
91
86
1
2
3
4
5
3h
3i
3j
3k
3l
5a
95
95
94
93
91
1
2
3
4
5
5a
5b
5c
7a
7b
0/100
0/100
0/100
62/38
63/37
5b
5c
7ab
7bb
89
a Yield after chromatography b Mixtures of E- and Z-enamines.
a Determined by integration of 31P NMR signals of the crude. b Yield
after chromatography c Yield using the multicomponent procedure,
starting from but-2-(E)-enoylphosphonic acid diethyl ester 10 (procedure
B).
SCHEME 4. Multicomponent Synthesis of
(E)-γ-Amino-r-dehydroaminophosphonates 3
SCHEME 3. Base-Mediated Isomerization of Z-Enamines 5
and 7 to E-Enamines 3
SCHEME 5. Synthesis of 4,5-Dihydro-2-pyrimidones 11a,b
ꢀ-methyne at δC ) 51.4 ppm and that shows a coupling constant
3JPC ) 3.6 Hz representative for a cis relative configuration P-C
in the alkene bond.16
The formation of the Z-enamines could be explained by
nucleophilic addition of the amine to afford the ionic intermedi-
ate I, with a Z configuration of the carbon-carbon double bond
(Scheme 2). However, when a primary amine with sp2 (benzyl
or allyl amine) or sp (propargyl amine) ꢀ-carbon was used, this
zwitterionic species I would undergo fast intermolecular inter-
change of the proton to afford the thermodynamically less
favored Z-enamines.
On the other hand, when aliphatic amines such as n-
propylamine 6a (R1 ) CH2CH3) or isobutylamine 6b (R1 )
CH(CH3)2) were treated with R,ꢀ-unsaturated imine 1, mixtures
of E and Z-enamines 7a,b were obtained (Scheme 1, Table 2,
entries 4 and 5). In these cases, n-propyl and isobutyl groups
linked to the amino seems to favor the formation of mixtures
of E and Z isomers.
With these results, we wanted to explore if the isomerization
between Z- and E-enamines could be performed. In fact, heating
Z-enamines 5a-c in CH2Cl2 and in the presence of triethylamine
afforded exclusively E-enamines 3h-j in very good yields
(Scheme 3, Table 3, entries 1-3).
In a similar way, heating mixtures of E- and Z-enamines 7a,b
in CH2Cl2 in the presence of triethylamine gave exclusively
E-enamines 3k,l (Scheme 3, Table 3, entries 4 and 5). This
thermal isomerization is consistent with the higher stability of
E-enamines toward the corresponding Z-enamines. It should be
mentioned that the nucleophilic addition of amines to R,ꢀ-
unsaturated imine 1 does not require the use of the isolated
starting material, since the synthesis of enamines 3 can also be
performed in very good yields in a multicomponent reaction
(Scheme 4, Table 1, entries 1-3 and 5, Table 2, entry 1) by
addition to R-ketophosphonate 10 of phosphazene 9, generated
“in situ” by addition of trimethylphosphine to p-nitrophenylazide
8, with formation of ꢀ,γ-unsaturated iminophosphonate 1 and
subsequent addition of the corresponding amine to the reaction
mixture (procedure B, see the Experimental Section).
Finally, given both the interest of azaheterocyclic phospho-
nates20 and that it is well-known that molecular modifications
involving the introduction of organophosphorus functionalities
could increase biological activity,21 enamines 3 were used as
synthetic intermediates for the synthesis of 6-membered-ring
phosphonylated heterocycles. Treatment of enamines 3h,i at
room temperature with triphosgene in the presence of 2 equiv
of triethylamine afforded the phosphonylated 4,5-dihydro-2-
pyrimidones 11a,b in very good yield (87-90%) (Scheme 5).
As far as we know, this strategy represents the first synthesis
of 4,5-dihydropyrimidin-2-one-containing phosphorus substituents.
(20) For an excellent review of azaheterocyclic phosphonates, see: Moonen,
K.; Laureyn, I.; Stevens, C. V. Chem. ReV. 2004, 104, 6177.
(21) Toy, A. D. F.; Walsh, E. N. In Phosphorus Chemistry in EVeryday
LiVing; American Chemical Society: Washington DC., 1987.
454 J. Org. Chem. Vol. 74, No. 1, 2009

added, and the reaction mixture was stirred for 30 min. The resulting
solution was concentrated under reduced pressure, and the resulting
yellow oily crude was purified by chromatography (SiO2, AcOEt)
to afford 175 mg (81%) of 3b as a pale yellow oil. Rf (AcOEt/
MeOH 95:5): 0.08. 1H NMR (300 MHz, CDCl3): δ 1.11-1.29 (m,
In conclusion, we have shown here the first example of an
aza-Michael reaction to R,ꢀ-unsaturated imines 1 to afford
functionalized enamines 3. The fact that a R,ꢀ-unsaturated imine
derived from R-aminophosphonate is used as Michael acceptors
makes this example of aza-Michael a suitable method for the
preparation of chiral γ-amino R-dehydro aminophosphonates
3. R-7,8 and γ-aminophosphonate derivatives10 as well as
phosphapeptides containing R-aminophosphonic units show a
variety of biological activities with interest in medicinal
chemistry. Moreover, an application of γ-amino R-dehydro
aminophosphonates 3 for the first synthesis of phosphorylated
pyrimidone derivatives20 is reported.
3
6H, 2 × CH3), 1.35 (d, JHH ) 6.8 Hz, 3H, CH3), 3.98-4.09 (m,
4H, 2 × CH2O), 2.21 (s, 3H, CH3), 4.22 (m, 1H, CHN), 6.18 (s,
3
3
1H, NH), 6.38 (dd, JPH ) 14.2 Hz, JHH ) 8.9 Hz, 1H, CH)),
3
3
6.77 (d, JHH ) 9.0 Hz, 2 × CHar), 6.47 (d, JHH ) 8.6 Hz, 2H, 2
3
3
× CHar), 6.93 (d, JHH ) 8.6 Hz, 2H, 2 × CHar), 8.07 (d, JHH
)
9.0 Hz, 2H, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ 16.1 (d,3JPC
) 5.5 Hz, 2 × CH3), 19.6 (CH3), 20.2 (CH3), 47.2 (d, 3JPC ) 15.1
Hz, CHN), 62.5 (d,2JPC ) 6.4 Hz, CH2O), 62.6 (d,2JPC ) 6.1 Hz,
CH2O), 113.3 (2 × CHar), 114.5 (2 × CHar), 125.8 (2 × CHar),
126.2 (Cquat), 127.4 (d, 1JPC ) 212.0 Hz), 129.6 (2 × CHar), 139.6
(Cquat), 143.6 (Cquat), 146.8 (d, 2JPC ) 23.1 Hz, CH)), 151.7 (Cquat).
31P NMR (120 MHz, CDCl3): δ 13.0. FTIR (KBr) νmax (cm-1):
Experimental Section
Representative Example for the Aza-Michael Reaction of
Amines 3 with the r,ꢀ-Unsaturated Imine-Derived from r-Ami-
nophosphonate 4. Synthesis of [1-(4-Nitrophenylamino)-3-p-
tolylaminobut-1-enyl]phosphonic Acid Diethyl Ester 3b. Pro-
cedure A: To a solution of R,ꢀ-unsaturated imine 1 (163 mg, 0.5
mmol) in CH2Cl2 (2 mL) was added p-toluidine (64 mg, 0.6 mmol).
The solution was stirred for 30 min, and the resulting mixture was
concentrated under reduced pressure. The crude residue was purified
by chromatography (SiO2, AcOEt/MeOH 95:5) to afford 178 mg
(83%) of 3b as a pale yellow oil. Procedure B: multicomponent
reaction procedure starting from but-2-(E)-enoylphosphonic acid
diethyl ester 10. To a solution of p-nitrophenyl azide 8 (82 mg,
0.5 mmol) in CH2Cl2 (3 mL) at 0 °C was added a 1.0 M solution
of trimethylphosphine in toluene (0.5 mL). The resulting solution
was stirred for 30 min until N2 evolution stopped, which indicates
the completion of the reaction and phosphazene 9 formation. But-
2-(E)-enoylphosphonic acid diethyl ester 10 (2.06 g, 10 mmol) was
then added, and the reaction was stirred for an additional 30 min
at rt. Neat p-toluidine (64 mg, 0.6 mmol) (0.6 mmol) was then
3343 (N-H st), 1239 (P ) O st). CIMS m/z (amu): 433 ([M+
+
H], 87), 296 ([M+]
- PO(OEt)2, 100). Anal. Calcd for
C21H28N3O5P: C, 58.19; H, 6.51; N, 9.69. Found: C, 58.25; H, 6.47;
N, 9.73.
Acknowledgment. The present work was supported by the
Direccio´n General de Investigacio´n del Ministerio de Ciencia
y Tecnolog´ıa (MCYT, Madrid DGI, CTQ2006-09323) and by
the Departamento de Educación Universidades e Investigación
del Gobierno Vasco (IT-277-07). J.V. thanks the Ministerio de
Ciencia e Innovacio´n for a Ramo´n y Cajal contract.
Supporting Information Available: Procedures and full
characterization for compounds 3, 5, and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8022022
J. Org. Chem. Vol. 74, No. 1, 2009 455