Synthesis of α-phosphorylated α,β-unsaturated imines and their selective reduction to vinylogous and saturated α-aminophosphonates

Article abstract of DOI:10.1021/jo062609+

An efficient synthesis of α,β-unsaturated imines derived from α-aminophosphonates is achieved through aza-Wittig reaction of P-trimethyl phosphazenes with β,γ-unsaturated α-ketophosphonates. Selective 1,2-reduction of such 1-azadienes affords β,γ-unsatura

Full text of DOI:10.1021/jo062609+

SCHEME 1. Strategy for Preparation of
r-Aminophosphonate Derivatives
Synthesis of r-Phosphorylated r,â-Unsaturated
Imines and Their Selective Reduction to
Vinylogous and Saturated r-Aminophosphonates
Francisco Palacios,* Javier Vicario,
Agnieszka Maliszewska, and Domitila Aparicio
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 December 19, 2006
activity4 or new activity would be expected from the phospho-
rylated isosters of R-vinylglycines.
The most common method for the synthesis of R-amino-
phosphonates involves a variant of the Strecker reaction5a
consisting of the nucleophilic addition of dialkylphosphites to
imines and was described for the first time in the early 1950s.5b
As part of research on the addition of dialkylphosphites to
imines, some regioselective additions to R,â-unsaturated imines
derived from cynnamaldehyde6a have been reported, in some
cases enantioselectively6b,c for the preparation of some specific
examples of aminophosphonates I (mainly, R ) Ph, Scheme
1). Likewise, dialkyl trimethylsilylphosphites as mild phospho-
nylation agents of R,â-unsaturated imines have also been
reported,7 and Stevens et al. recently used this process for an
elegant preparation of glutamic acid analogues through a double
addition (1,2 and 1,4) of silylphosphite to R,â-unsaturated
imines.8 On the other hand, R,â-unsaturated imines or 1-aza-
dienes are a versatile family of compounds with a wide range
of applications in preparative organic chemistry.9 Besides the
well-known aza-Diels-Alder reaction,10a 1-azadienes have also
been extensively used in the synthesis of several natural
products.10b Moreover, owing to their ambident electrophilic
character, R,â-unsaturated imines can either undergo 1,211 or
conjugate (1,4)12 nucleophilic addition processes. However,
generally, the control of the regioselectivity is difficult, and very
An efficient synthesis of R,â-unsaturated imines derived from
R-aminophosphonates is achieved through aza-Wittig reac-
tion of P-trimethyl phosphazenes with â,γ-unsaturated R-ke-
tophosphonates. Selective 1,2-reduction of such 1-azadienes
affords â,γ-unsaturated R-aminophosphonates, phosphoryl-
ated analogs of vinylglycines, which are hydrogenated to
yield saturated R-aminophosphonate derivatives.
R-Aminophosphonates1 I are structurally analogous to R-ami-
no acids II (see Scheme 1), obtained by isosteric substitution
of the carboxylic acid by a phosphonate moiety. As expected
from this analogy the single R-aminophosphonic molecules or
their phosphonic esters as well as phosphapeptides containing
R-aminophosphonic units show a variety of biological activities2
such as haptens of catalytic antibodies, peptide mimetics,
enzyme inhibitors, and antibacterial or antihypertensive agents.
Among this family of compounds, vinylogous R-aminophos-
phonates I are isosters of vinylogous R-aminoacids II, also
known as R-vinylglycines. Simple R-vinylglycine is a potent
inhibitor of several transaminase and decarboxylase enzymes,3a,b
and there are numerous natural substituted R-vinylglycines such
as rhizobitoxin,3c radiosumin,3d or (L)-trans-R-methoxyvinyl-
glycine3e that show biological activity. Moreover, it is well-
known that molecular modifications involving the introduction
of organophosphorus functionalities could increase biological
(4) Toy; A. D. F.; Walsh, E. N. In Phosphorus Chemistry in EVeryday
LiVing; American Chemical Society: Washington, DC, 1987.
(5) (a) Gro¨ger, H. Chem. ReV. 2003, 103, 2795-2827. (b) Fields, E. K.
J. Am. Chem. Soc. 1952, 74, 1528-1531.
(6) (a) Firouzabadi, H.; Iranpoor, N.; Sobhani, S. Synthesis 2004, 2692-
2696 and references therein. (b) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe,
K. Org. Lett. 2005, 7, 2583-2587. (c) Joly, G. D.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 4102-4103.
(7) Afarinkia, K.; Cadogan, J. I. G.; Rees, C. W. Synlett 1992, 123-
123.
(8) Moonen, K.; van Meenen, E.; Verwe´e, A.; Stevens, C. V. Angew.
Chem., Int. Ed 2005, 44, 7407-7411.
(1) For an excellent book see: Kukhar, V. P., Hudson, H. R., Eds.; In
Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological
ActiVity; J. Wiley: Chichester, 2000.
(9) For reviews, see: (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379-471. (b) Buonora, P.; Olsen, J. C.; Oh, T.
Tetrahedron 2001, 57, 6099-6138.
(2) For reviews, see: (a) Kafarski, P.; Lejczak, B. Curr. Med. Chem:
Anti-Cancer Agents 2001, 1, 301-312. (b) Gambecka, J.; Kafarski, P. Mini-
ReV. Med. Chem. 2001, 1, 133-144. (c) Kafarski, P.; Lejczak, B.
Phosphorus Sulfur Silicon Relat. Elem. 1991, 63, 193 -215.
(3) (a) Griffith, O. W. J. Biol. Chem. 1983, 258, 1591-1598. (b) Soper,
T. S.; Manning, J. M.; Marcotte, P. A.; Walsh, C. T. J. Biol. Chem. 1977,
252, 1571-1575. (c) Keith, D. D.; de Bernardo, S.; Weigele, M.
Tetrahedron 1975, 31, 2629-2632. (d) Coleman, J. E.; Wright, J. L. C. J.
Nat. Prod. 2001, 64, 668-670. (e) Rando, R. R. Nature 1974, 250, 586-
587.
(10) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418-8420. (b) Schnermann, M. J.; Boger, D. L. J. Am. Chem. Soc.
2005, 127, 15704-15705.
(11) Contributions to selective 1,2-addition to R,â-unsaturated imines:
(a) Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875-5878. (b)
Allin, S. M.; Button, M. A. C.; Baird, R. D. Synlett 1998, 1117-1119.
(12) Recent contributions to selective conjugate addition to R,â-unsatur-
ated imines: (a) Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405-5408.
(b) Zheng, J.-C.; Liao, W.-W.; Tang, Y.; Sun, X.-L.; Dai, L.-X. J. Am.
Chem. Soc. 2005, 127, 12222-12223.
10.1021/jo062609+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/01/2007
2682
J. Org. Chem. 2007, 72, 2682-2685

TABLE 1. Phosphazenes 1 and r,â-Unsaturated Imines Derived
from r-Aminophosphonate 5
SCHEME 2. Synthesis of r,â-Unsaturated Imines Derived
from r-Aminophosphonate 5
31P NMRa yieldb
entry compd
R1
R2
R3
(ppm)
(%)
1
2
3
4
5
6
7
8
1a
1b
1c
5a
5b
5c
5d
5e
p-Me-C6H5
p-NO2-C6H5
p-MeO-C6H5
p-Me-C6H5
2.5
9.5
1.6
10.8
10.2
10.2
5.0
Me C6H5
89
89
85
Me 2-furyl p-Me-C6H5
Me OEt
p-Me-C6H5
p-NO2-C6H5
p-MeO-C6H5
Et
Et
Me
Me
often the double nucleophilic addition products are obtained.8,13
The simplest method for the synthesis of R,â-unsaturated imines
implies condensation of R,â-unsaturated carbonyl compounds
with primary amines.14 This method is often complicated by
the Michael addition reaction, especially in the case of R,â-
unsaturated ketones.14,15 However, this preparative drawback
can be avoided either by olefination reaction of â-phosphorated
imines or enamines with aldehydes to generate the conjugated
CdC bond of 1-azadienes16 or by the aza-Wittig reaction17,18
of phosphazenes, a strategy recently applied for the construction
of 1-azadienes derived from R-aminoester derivatives IV
(Scheme 1).19
8.1
a In toluene-d8. b Isolated yield.
tives. Likewise, we have been involved in the chemistry of
azadienes,16,18 and recently we have reported both an efficient
synthesis of R,â-unsaturated imines derived from R-ami-
noesters,19 as well as the enantioselective synthesis of R-dehy-
dro-aminoesters.12a Continuing with our interest in the chemistry
of phosphazenes19 and functionalized azadienes,16,18,19 we report
here the first synthesis R,â-unsaturated imines derived from
R-aminophosphonates III (see Scheme 1) by the aza-Wittig
approach19 with the very reactive P-trialkyl phosphazenes, as
well as their selective 1,2-reduction to vinylogous R-amino-
phosphonates I and their total reduction to obtain saturated
R-aminophosphonates I.
In this context, we have used functionalized aminophosphorus
derivatives for the preparation of three-,20 five-,21 and six-
membered22 phosphorus-substituted nitrogen heterocycles,23 as
well as the synthesis of â-24 and R-aminophosphonate25 deriva-
P-Trimethyl phosphazenes 1 were readily prepared in situ
by addition of trimethylphosphine 2 to azides 326 (Scheme 2;
Table 1, entries 1-3). Phosphazenes 1 were used without
isolation, and the addition of â,γ-unsaturated R-ketophospho-
nates 4 gave the phosphorylated syn-R,â-unsaturated imines 5
in a regioselective fashion and in high yields (Scheme 2; Table
1, entries 4-8). After consumption of trimethylphosphine 1,
addition of â,γ-unsaturated R-ketophosphonates 4 showed the
disappearance of the signal corresponding to the phosphazenes
1 and appearance of the signal corresponding to trimethylphos-
phine oxide at δ ) 31.6 ppm, as well as only one signal
corresponding to the phosphorylated (E)-R,â-unsaturated imines
5 in the range of δ ) 5-10 ppm.
(13) Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2005, 34, 1456-
1457.
(14) (a) Pearson, W. H.; Jacobs, V. A. Tetrahedron Lett. 1994, 35, 7001-
7004. (b) Teng, M.; Fowler, F. W. J. Org. Chem. 1990, 55, 5646-5653.
(15) Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem. 2006,
2843-2850.
(16) (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J.
J. Org. Chem. 2004, 69, 8767-8774. (b) Palacios, F.; Ochoa de Retana,
A. M.; Pascual, S.; Oyarzabal, J. Org. Lett. 2002, 4, 769-772. (c) Palacios,
F.; Aparicio, D.; Vicario, J. Eur. J. Org. Chem. 2002, 4131-4136. (d)
Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E.; Ferna´ndez-Acebes A.
Tetrahedron 2001, 57, 3131-3141.
(17) For reviews, see: (a) Palacios, F.; Aparicio, D.; Rubiales, G.; Alonso
C.; de los Santos J. M. Tetrahedron 2007, 63, 523-575. (b) Fresneda, P.
M.; Molina, P. Synlett 2004, 1-17.
(18) For contributions of creation of the CdN double bond by means of
this process, see: (a) Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M.
Tetrahedron 2005, 61, 2779-2794. (b) Palacios, F.; Herra´n, E.; Rubiales,
G.; Ezpeleta, J. M. J. Org. Chem. 2002, 67, 2131-2135.
(19) Palacios, F.; Vicario, J.; Aparicio, D. J. Org. Chem. 2006, 71, 7690-
7696.
(20) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org.
Chem. 2006, 71, 6141-6148. (b) Palacios, F.; Ochoa de Retana, A. M.;
Gil, J. I.; Ezpeleta, J. M. J. Org. Chem. 2000, 65, 3213-3217.
(21) (a) Palacios, F.; Aparicio. D.; Lo´pez, Y.; de los Santos, J. M.;
Ezpeleta, J. M. Tetrahedron 2006, 62, 1095-1101. (b) Palacios, F.; Ochoa
de Retana, A. M.; Gil, J. I.; Alonso, J. M. Tetrahedron: Asymmetry 2002,
13, 2525-2541. (c) Palacios, F.; Aparicio. D.; de los Santos, J. M.
Tetrahedron 1996, 52, 4123-4132.
(22) (a) Palacios, F.; Herran, E.; Alonso, C.; Rubiales, G.; Lecea, B.;
Ayerbe, M.; Coss´ıo, F. P. J. Org. Chem. 2006, 71, 6020-6030. (b) Palacios,
F.; Ochoa de Retana, A. M.; Gil, J. I.; Lopez de Munain, R. Org. Lett.
2002, 4, 2405-2408. (c) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal,
J. Tetrahedron Lett. 1996, 37, 4577-4580.
(23) For an excellent review of azaheterocyclic phosphonates, see:
Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. ReV. 2004, 104, 6177-
6215.
R,â-Unsaturated imines bearing an aromatic (5a, R2 ) C6H5),
heteroaromatic (5b, R2 ) 2-furyl), or alkoxy (5c, R2 ) OEt)
substituent in the â position are stable and allowed isolation by
the conventional purification techniques, obtaining yields that
were good even after chromatography (Table 1, entries 4-6).
However, in the case of R,â-unsaturated imines derived from
crotonaldehyde (5d,e, R2 ) Me), no isolation was possible
(Table 1, entries 7 and 8). R,â-Unsaturated imines 5a-c were
fully characterized on the basis of their 1H, 13C, and 31P NMR,
IR and MS spectra, whereas only satisfactory 31P NMR for
unstable R,â-unsaturated imines 5d,e was possible due to
overlapping of toluene signals in (in situ) 1H or 13C NMR. R,â-
Unsaturated imines derived from R-phosphonates 5 were
obtained as a single isomer, obvious by the presence of a single
signal in 31P NMR. Characteristic signals in the 1H NMR
spectrum of 5a are the doublet corresponding to the CH alkene
at δ ) 7.85 ppm with a characteristic coupling constant for an
E configuration19 (3JHH ) 16.6 Hz) and coupled with the double
(24) For a recent review, see: Palacios, F.; Alonso, C.; de los Santos, J.
M. Chem. ReV. 2005, 105, 899-931.
(25) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org.
Chem. 2005, 70, 8895-8901. (b) Palacios, F.; Aparicio. D.; Lo´pez, Y.; de
los Santos, J. M. Tetrahedron Lett. 2004, 45, 4345-4348. (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, 689-700. (d) Palacios,
F.; Aparicio, D.; Ochoa de Retana, A. M.; de los Santos, J. M.; Gil, J. I.;
Alonso, J. M. J. Org. Chem. 2002, 67, 7283-7288.
(26) The formation of the phosphazenes 1 was evident from the visible
nitrogen gas formation during the addition of trimethylphosphine and was
monitored by 31P NMR using toluene-d8 as solvent. The spectra showed
the disappearance of the signal at δ ) -61.1 ppm, corresponding to
trimethylphosphine and appearance of a new signal in the range of δ )
2-10 ppm which was attributed to the phosphazenes 1
J. Org. Chem, Vol. 72, No. 7, 2007 2683

TABLE 2. Vinylogous r-Aminophosphonates 6 and Saturated
r-Aminophosphonates 7
31P NMRa
(ppm)
yieldb
(%)
entry compd R1
R2
R3
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
7a
7b
Me C6H5
Me 2-furyl p-Me-C6H5
Me OEt
p-Me-C6H5
25.9
84c, 82d
84c
p-Me-C6H5
p-NO2-C6H5
p-MeO-C6H5
p-Me-C6H5
p-MeO-C6H5
27.2
21.7
83c, 82d
88d
Et
Et
Me
Me
87d
FIGURE 1. NOE and HOE effect observed for R,â-unsaturated imine
5a.
Me C6H5
Et Me
29.2
33.0
91e, 88f
95e, 84g
a In CDCl3. b Isolated yield. c Yield from isolated R,â-unsaturated imines
5 using BH3.SMe2 (toluene, -78 °C). d Yield for one-pot procedure from
â,γ-unsaturated R-ketophosphonates 4. e Yield from vinylogous amino-
phosphonates 6 using H2, Pd-C (MeOH, 25 °C). f Yield from R,â-
unsaturated imines 5 using H2, Pd-C (MeOH, 25 °C). g Yield from in situ
prepared R,â-unsaturated imine 5d using H2, Pd-C (MeOH, 25 °C).
SCHEME 3. Selective 1,2 or Total Reduction of
r,â-Unsaturated Imines 5
SCHEME 4. Synthesis of Primary Vinylogous 8 and
Saturated r-Aminophosphonates 9
doublet corresponding to the other olefinic CH at δ ) 6.78 ppm,
which is also coupled with the phosphorus with a coupling
2
constant JPH ) 38.4 Hz. Nuclear Overhauser enhancement
spectroscopy (NOESY) and heteronuclear Overhauser enhance-
ment spectroscopy (HOESY) experiments were performed in
order to determine the configuration of the imine bond. The
NOESY spectrum of R,â-unsaturated imine 5a showed no
correlation between olefinic protons and the aromatic protons
of the p-tolyl group, whereas the HOESY spectrum showed a
correlation between the phosphorus signal at δ ) 10.8 ppm and
the doublet at δ ) 6.77 ppm corresponding to the ortho protons
of the p-tolyl substituent (see Figure 1).
of R,â-unsaturated imines 5d,e containing a methyl group (R2
) Me) in position 4.
Some specific examples of synthesis of vinylogous R-ami-
nophosphonates 6 (R2 ) Ph) either by nucleophilic addition of
dialkylphosphites to R,â-unsaturated imines derived from cyn-
namaldehyde6,7 or by the addition of trialkylphosphites to
unstable R,â-unsaturated iminium salts27 have been reported.
However, the new strategy here described can be applied to
vinylogous R-aminophosphonates 6 containing not only aromatic
(R2 ) Ph) but also heteroaromatic (R2 ) 2-furyl), alkoxi (R2 )
OEt), or alkyl (R2 ) Me) groups.
The synthesis of the saturated R-aminophosphonate 7a can
also be achieved either by hydrogenation of the vinylogous
R-aminophosphonate 6a or by total reduction of the R,â-
unsaturated imine 5a (Scheme 3; Table 2, entries 6 and 7). In
the case of R,â-unsaturated imine 5e (R2 ) Me), the hydrogena-
tion can be also carried out in a one-pot reaction from â,γ-
unsaturated R-ketophosphonate 4e to obtain the saturated
R-aminophosphonate 7b in very good yield (Scheme 3; Table
2, entry 7).
Finally, the primary vinylogous R-aminophosphonate 8 (62%)
and saturated R-aminophosphonate 9 (65%) were prepared from
p-methoxyphenyl N-substituted compounds by N-deprotection
reaction of vinylogous R-aminophosphonate 6e or saturated
R-aminophosphonate 7b with cerium ammonium nitrate (CAN)
(Scheme 4).
The very reactive phosphazene species derived from trim-
ethylphosphine 1 constitute an excellent alternative if selective
condensation (1,2-addition) with the carbonyl group of R,â-
These results suggest a syn configuration of the imine bond,
where phosphonate and aryl substituent are pointing to the same
direction. Moreover, the HOESY spectrum showed correlation
between the phosphorus signal and the doublet at δ ) 7.85 ppm
corresponding to the proton in the â position of the olefinic
bond, which may suggest a pseudo-trans conformation in the
1-azadienic system (Figure 1). As far as we known, this strategy
leads the first example of 1-azadienes derived from R-amino-
phosphonates 5.
The availability of an efficient method for the synthesis of
R,â-unsaturated imines 5 derived from R-aminophosphonate
raised the possibility of exploring their reactivity toward
reduction agents. First, the selective reduction of R,â-unsaturated
imines 5 was explored. Treatment of R,â-unsaturated imines 5
derived from R-aminophosphonates with BH3‚SMe2 in toluene
at -78 °C afforded only the 1,2-addition adducts, vinylogous
R-aminophosphonates 6 with very good yields (Scheme 3; Table
2, entries 1-3), keeping the E configuration of the carbon-
carbon double bond. It is remarkable that the 1,2-reduction can
be also carried out in a one-pot procedure starting from â,γ-
unsaturated R-ketophosphonates 4. Addition of the â,γ-unsatur-
ated R-ketophosphonates 4 to the in situ generated phosphazenes
1 (toluene, 25 °C) followed by addition of BH3‚SMe2 to the
resulting toluene solution at low temperature (-78 °C) also
afforded vinylogous R-aminophosphonates 6 with very good
yields (Scheme 3; Table 2, entries 1 and 3-5). This last aspect
is of special importance due to the unfeasibility of the isolation
(27) (a) Atmani, A.; Combret, J.-C.; Malhiac, C.; Kajima Mulkengi, J.
Tetrahedron Lett. 2000, 42, 6045-6048. (b) Stevens, C. V.; Vekemans,
W.; Moonen, K.; Rammeloo, T. Tetrahedron Lett. 2003, 44, 1619-1622.
2684 J. Org. Chem., Vol. 72, No. 7, 2007

phenyl-1-p-tolylimino-allyl)-phosphonate 5a (329 mg, 1.0 mmol),
affording 278 mg (84%) of 6a as a pale yellow oil. Rf (AcOEt):
0.60. 1H NMR (300 MHz, CDCl3): δ 2.21 (s, 3 H, CH3), 3.77 (d,
3JPH ) 10.7 Hz, 3 H, OCH3), 3.80 (d, 3JPH ) 10.5 Hz, 3 H, OCH3),
3.89 (broad s, 1H, NH), 4.44 (ddd, 4JHH ) 1.5 Hz, 3JHH ) 6.3 Hz,
2JPH ) 25.6 Hz, 1 H, CHN), 6.22 (ddd, 3JPH ) 5.2 Hz, 3JHH ) 6.3
unsaturated carbonyl compounds 4, avoiding the undesirable
Michael addition (1,4-addition), is required. This methodology
applied to â,γ-unsaturated R-ketophosphonates 4 provides access
to R,â-unsaturated imines derived from R-aminophosphonates
5, molecules that are described here for the first time. Moreover,
regioselective reduction (1,2-addition) of the imine carbon-
nitrogen double bond of R,â-unsaturated imines derived from
R-aminophosphonates 5 proves to be a general method for the
preparation of vinylogous R-aminophosphonates 6, whereas total
reduction of both double bonds (carbon-nitrogen and carbon-
carbon) of R,â-unsaturated imines 5 gives R-aminophosphonates
7. Likewise primary R-aminophosphonates 8 and 9 can be
obtained by selective N-deprotection of the amino group.
R-Amino-phosphonate derivatives are important building blocks
in organic synthesis1 and in the preparation of biologically active
compounds of interest in medicinal chemistry.2
3
3
Hz, JHH ) 15.8 Hz, 1 H, CHd), 6.60 (d, JHH ) 8.5 Hz, 2 H, 2
4
4
3
× CHar), 6.69 (ddd, JHH ) 1.5 Hz, JPH ) 4.9 Hz, JHH ) 15.8
3
Hz, 1 H, CHd), 6.97 (d, JHH ) 8.5 Hz, 2 H, 2 × CHar), 7.20-
7.35 (m, 5H, 5 × CHar). 13C NMR (75 MHz, CDCl3): δ 20.3
2
2
(CH3), 53.4 (d, JPC ) 7.6 Hz, OCH3), 53.9 (d, JPC ) 7.1 Hz,
OCH3), 54.0 (d, 1JPC ) 154.6 Hz, CHN), 113.9 (2 × CHar), 123.3
(d, 2JPC ) 4.5 Hz, CHd), 126.6 (2 × CHar), 127.8 (CHar), 127.9
3
(Cquat), 128.4 (2 × CHar), 129.7 (2 × CHar), 133.3 (d, JPC
10.0 Hz, CHd), 136.1 (d, 4JPC ) 4.0 Hz, Cquat), 143.9 (d, 3JPC
)
)
12.6 Hz, Cquat). 31P NMR (120 MHz, CDCl3): δ 25.9. FTIR (KBr)
νmax (cm-1): 3310 (N-H st), 1229 (PdO st). CIMS m/z (amu):
332 ([M+ + H], 74), 222 ([M+] - PO(OMe)2, 100). Anal. Calcd
for C18H22NO3P: C 65.25; H 6.69; N 4.23. Found: C 65.31; H
6.75; N 4.16.
Experimental Section
General Procedure. Synthesis R-Aminophosphonates 7. A
solution of R,â-unsaturated imine 5 or vinylogous R-aminophos-
phonate 6 (0.5 mmol) in EtOH (5 mL) with Pd-C (10%) (32 mg,
0.03 mmol) was stirred for 2 days under H2 atmosphere at 80 psi.
The resulting mixture was filtered through celite and concentrated
under reduced pressure. The crude residue was purified by
chromatography (SiO2, AcOEt/pentane 3:1).
General Procedure. Synthesis of R,â-Unsaturated Imines 5
Derived from R-Aminophosphonate. To a solution of the corre-
sponding azide 3 (2.0 mmol) in toluene (10 mL) at 0 °C was added
a 1.0 M solution of trimethylphosphine in toluene (2 mL). The
resulting solution was stirred 30 min until N2 evolution stopped,
which indicates the completion of the reaction and phosphazene 1
formation and can be monitored by 31P NMR. The corresponding
neat â,γ-unsaturated R-ketophosphonate 2 (2.0 mmol) was then
added, and the reaction was stirred for an additional 30 min at room
temperature. R,â-Unsaturated imines 5d,e were used without any
further workup as a toluene solution. For the workup of the reactions
corresponding to R,â-unsaturated imines 5a-c, the solution was
diluted with CH2Cl2 (40 mL), washed with water (3 × 20 mL),
dried over MgSO4 and concentrated under reduced pressure to
afford a yellow oily crude that was purified by chromatography
(SiO2, AcOEt/pentane 3:1).
Dimethyl (3-Phenyl-1-p-tolylamino-propyl)-phosphonate 7a.
Synthesized according to the general procedure from dimethyl (3-
phenyl-1-p-tolylimino-allyl)-phosphonate 5a (165 mg, 0.5 mmol),
affording 258 mg (88%) of 7a as a colorless oil. Synthesized
according to the general procedure from dimethyl (3-phenyl-1-p-
tolylamino-allyl)-phosphonate 6a (167 mg, 0.5 mmol), affording
1
0.241 mg (91%) of 7a as a colorless oil. Rf (AcOEt): 0.67. H
NMR (300 MHz, CDCl3): δ 1.97 (m, 1 H, CH2), 2.20 (m, 1 H,
CH2), 2.22 (s, 3 H, CH3), 2.72 (m, 1 H, CH2), 2.88 (m, 1 H, CH2),
Dimethyl (3-Phenyl-1-p-tolylimino-allyl)-phosphonate 5a. Syn-
thesized according to the general procedure with p-tolylazide (266
mg, 2 mmol) and diethyl (3-phenyl-acryloyl)-phosphonate (480 mg,
2 mmol), affording 407 mg (89%) of 5a as a yellow oil. Rf.
(AcOEt): 0.57. 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3 H, CH3),
3.92 (d, 3JPH ) 10.8 Hz, 6 H, 2 × OCH3), 6.77 (d, 3JHH ) 8.1 Hz,
3
3
3.67 (d, JPH ) 11.0 Hz, 3 H, OCH3), 3.71 (d, JPH ) 11.1 Hz, 3
H, OCH3), 3.80 (m, 1 H, CHN), 6.50 (d, 3JHH ) 8.4 Hz, 2 H, 2 ×
3
CHar), 6.98 (d, JHH ) 8.4 Hz, 2 H, 2 × CHar), 7.12-7.16 (m,
2H, 2 × CHar), 7.19-7.30 (m, 3H, 3 × CHar). 13C NMR (75 MHz,
3
CDCl3): δ 20.6 (CH3), 32.2 (d, JPC ) 12.1 Hz, CH2), 32.6 (d,
2JPC ) 4.5 Hz, CH2), 50.5 (d, JPC ) 155.1 Hz, CHN), 52.8 (d,
1
3
3
2 H, 2 × CHar), 6.78 (dd, JHH ) 16.6 Hz, JPH ) 38.4 Hz, 1 H,
2JPC ) 7.1 Hz, OCH3), 53.8 (d, 2JPC ) 7.1 Hz, OCH3), 113.8 (2 ×
3
CHd), 7.15 (d, JHH ) 8.1 Hz, 2 H, 2 × CHar), 7.28-7.30 (m,
CHar), 126.3 (CHar), 127.7 (Cquat), 128.7 (2 × CHar), 128.9 (2
3
2H, 2 × CHar), 7.35-7.38 (m, 3 H, 3 × CHar), 7.85 (d, JHH
)
3
× CHar), 130.0 (2 × CHar), 141.1 (Cquat), 144.8 (d, JPC ) 5.0
16.6 Hz, 1 H, CHd). 13C NMR (75 MHz, CDCl3): δ 21.2 (CH3),
Hz, Cquat). 31P NMR (120 MHz, CDCl3): δ 29.8. FTIR (KBr)
νmax (cm-1): 3297 (N-H st), 1228 (PdO st). CIMS m/z (amu):
334 ([M+ + H], 77), 224 ([M+] - PO(OMe)2, 100). Anal. Calcd
for C18H24NO3P: C 64.85; H 7.26; N 4.20. Found: C 64.95; H
7.33; N 4.15.
2
3
54.2 (d, JPC ) 7.1 Hz, 2 × OCH3), 119.7 (d, JPC ) 33.2 Hz,
CHd), 120.5 (2 × CHar), 128.1 (2 × CHar), 129.0 (2 × CHar),
129.8 (2 × CHar), 130.1 (CHar), 135.3 (Cquat), 135.8 (Cquat),
3
1
142.8 (CdH), 147.0 (d, JPC ) 31.2 Hz, Cquat), 162.9 (d, JPC
)
214.5 Hz, CdN). 31P NMR (120 MHz, CDCl3): δ 10.8. FTIR (KBr)
νmax (cm-1): 1613 (CdN st), 1255 (PdO st). CIMS m/z (amu):
330 ([M+ + H], 100), 220 ([M+] - PO(OMe)2, 78). Anal. Calcd
for C18H20NO3P: C 65.65; H 6.12; N 4.25. Found: C 65.71; H
6.05; N 4.27.
Acknowledgment. The present work has been supported by
the Direccio´n General de Investigacio´n del Ministerio de Ciencia
y Tecnolog´ıa (MCYT, Madrid DGI, CTQ2006-09323) and by
the Universidad del Pa´ıs Vasco (UPV, GIU 06/51). J.V. thanks
the Departamento de Educacio´n, Universidades e Investigacio´n
del Gobierno Vasco for a postdoctoral fellowship. Drs. J. M.
de los Santos and C. Alonso are gratefully acknowledged for
their assistance with 2D NMR experiments.
General Procedure. Selective Reduction of R,â-Unsaturated
Imines 5 with BH3.SMe2. Synthesis of Vinylogous R-Amino-
phosphonates 6. To a solution of R,â-unsaturated imine 5 (1.0
mmol) in toluene (5 mL) at -78 °C was added a 1.0 M solution of
BH3‚SMe2 in CH2Cl2 (1.5 mL, 1.5 mmol). The reaction was stirred
at -78 °C for 3 h, quenched with a saturated aqueous solution of
NaHCO3, and allowed to warm to room temperature. The resulting
mixture was diluted in CH2Cl2 (20 mL), washed with water (3 ×
20 mL), dried over MgSO4, and concentrated under reduced
pressure. The crude residue was purified by chromatography (SiO2,
AcOEt/pentane 3:1).
Supporting Information Available: Procedures and full char-
acterization for compounds 5b-e, 6b-e, 7a-c, 8, and 9. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Dimethyl (3-Phenyl-1-p-tolylamino-allyl)-phosphonate 6a.
Synthesized according to the general procedure with dimethyl (3-
JO062609+
J. Org. Chem, Vol. 72, No. 7, 2007 2685