Synthesis of new β- and γ-aminopyrrolidinephosphonates via 1,3-dipolar cycloaddition of substituted vinylphosphonates

Article abstract of DOI:10.1016/j.tetlet.2009.10.087

Synthesis of α- and β-(aminomethyl)vinylphosphonates was achieved from vinyl bromide via a cross-coupling reaction with triethyl phosphite and by cross-metathesis of allyl bromide and vinylphosphonate, respectively. The 1,3-dipolar cycloaddition of these

Full text of DOI:10.1016/j.tetlet.2009.10.087

Tetrahedron Letters 51 (2010) 60–63
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new b- and c-aminopyrrolidinephosphonates via 1,3-dipolar
cycloaddition of substituted vinylphosphonates
*
Nicolas Rabasso, Antoine Fadel
Laboratoire de Synthèse Organique et Méthodologie, ICMMO (UMR 8182-CNRS), Bât. 420, Université Paris-Sud 11, 91405 Orsay, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of
a- and b-(aminomethyl)vinylphosphonates was achieved from vinyl bromide via a cross-
Received 15 September 2009
Revised 13 October 2009
Accepted 16 October 2009
Available online 22 October 2009
coupling reaction with triethyl phosphite and by cross-metathesis of allyl bromide and vinylphospho-
nate, respectively. The 1,3-dipolar cycloaddition of these vinylphosphonates with a dipole in the presence
of trifluoroacetic acid afforded selectively the b-aminopyrrolidinephosphonates. Syntheses of cis- and
trans-c-aminopyrrolidinephosphonates are also described.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
b-Aminophosphonic Acids
Vinylphosphonates
1,3-Dipolar cycloaddition
Cross-metathesis
Pyrrolidines
1. Introduction
In this Letter, we report the synthesis of the first members of a
new class of b- and -aminophosphoryl pyrrolidines.
c
Vinylphosphonates have been known for several decades1 and
constitute a very important class of building blocks for the synthe-
sis of complex structures,2 including biologically active molecules.3
The b-aminovinylphosphonates, although rarely described,4 have
been used for the synthesis of b-aminophosphonic acid
derivatives5 that display interesting biological properties such as
antibiotics,6 enzyme inhibitors,7and anti-HIV agents.8 However,
synthesis of heterocyclic b-aminophosphonates, in particular
pyrrolidine analogues, remains a challenge.
Syntheses of substituted pyrrolidines are largely reported by
cycloaddition of a 1,3-dipole with vinyl derivatives.9 To the best
of our knowledge, only one 1,3-dipolar cycloaddition reaction has
been reported between a 1,3-dipole and an unsubstituted vinyl-
phosphonate to provide a heterocyclopentylphosphonate.10 On
the contrary, the 1,3-dipolar cycloaddition reaction with substi-
tuted vinylphosphonate is still unknown.
2. Results and discussion
Synthesis of b-aminovinylphosphonates 1 was achieved by the
SN2 displacement of the allylic bromide 2 by oxazolidinone or
amide 3 in the presence of a base (Cs2CO3 or NaH). Then, vinyl
bromide 4 was coupled with triethyl phosphite at 150 °C in the
presence of a catalytic amount of nickel bromide.13 The resulting
vinylphosphonates 1 were obtained in good yields (Scheme 1,
Table 1).14
O
R'RN
O
P(OEt)2
P(OEt)2
N
Bn
N
Bn
R'RN
In continuation of our work on the development of new meth-
odology for the synthesis of heterocyclic aminophosphonic acids,11
and considering the importance of heterocyclic aminophospho-
nates in synthetic, agrochemical, and medicinal chemistry,12 we
Figure 1. b- and
c
-Aminopyrrolidinephosphonates.
decided to investigate the 1,3-dipolar cycloaddition of
a- and
RR'NH
3
b-substituted vinylphosphonates with azomethine ylides to access
a range of pyrrolidines, for phosphonopeptide construction (Fig. 1).
O
P
OEt
OEt
c) P(OEt)3
Br
Br
R'
R'
Br
N
R
N
R
a or b
NiBr2,1 h
150 °C
4
1
2
* Corresponding author. Tel.: +33 1 6915 3239; fax: +33 1 6915 6278.
E-mail address: antfadel@icmo.u-psud.fr (A. Fadel).
Scheme 1. Synthesis of b-aminovinylphosphonates: see Table 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.087

N. Rabasso, A. Fadel / Tetrahedron Letters 51 (2010) 60–63
61
Table 1
Formation of vinylphosphonates 1a–c produced via Scheme 1
Table 2
Formation of b-aminophosphonates 7a–c produced via Scheme 3
Entry
R-NH-R0
3
4 (Yield %)
1c (Yield %)
Vinylphosphonate 1a–c
Entry
R-NH-R0
1
7 (Yield %)
b-Aminophosphonates 7a–c
O
O
OEt
O
O
OEt
OEt
P OEt
O
P
1
4a (78)a
1a (74)
O
NH
O
O
N
1
1a
7a (80)
N
O
3a
N
Bn
O
O
O
P
OEt
OEt
OEt
O
O
NH
Ph
N
P
OEt
N
O
2
4
4b (61)a
4c (76)b
( )-1b (89)
1c (82)
2
4
( )-1b
( )-7b (99)a
Ph
O
N
Bn
( )-3b
Ph
O
P
Ts
OEt
OEt
NH
OEt
P OEt
Ts
O
N
Bn
Bn
3c
Ts
1c
7c (91)
N
a
b
c
Bn
N
Bn
Reaction conditions: NaH, DMF, rt, 12 h.
Cs2CO3, CH3CN, reflux, 2 h.
Solvent-free reaction of 4 with P(OEt)3 5 equiv, NiBr2 20 mol %, 150 °C, 1 h.
a
Diastereoisomeric excess de = 8%.
O
O
O
O
H2,
Lindlar Ts
OEt
OEt
1)
Br
O
P
a
b, c
P
OEt
OEt
Ts
Cl
O
N
O
NH
Ph
O
N
Cs2CO3, 97%
N
Bn
3c
N
Bn
90%
30%
OEt
OEt
AcOEt,
3 h, 68%
P
O
2) LDA, 51%
ClP(O)(OEt)2
Ph
Ph
( )-1b
8c
9c
( )-3b
5
Scheme 2. Reagents and conditions: (a) (CH2O)n, TMSCl excess, reflux, 2 h; (b) NaH,
CH2[P(O)(OEt)2]2, THF, 0 °C; (c) NaH, (CH2O)n 5 equiv, THF, rt.
O
P
Ts
O
P
Grubbs II
Ts
OEt
OEt
OEt
OEt
N
Bn
N
Bn
CH2Cl2, reflux
20 h, 61%
10
11
12c
It is noteworthy that the preparation of 1b from oxazolidinone
( )-3b by chloromethylation [(CH2O)n/TMSCl] to afford oxazolidi-
none 5, and subsequent alkylation [CH2(P(O)(OEt)2)2] and vinylation
[NaH/(CH2O)n]4d gave only a poor yield of the vinylphosphonate ( )-
1b (Scheme 2).
For this study, the 1,3-dipole derived from 6 (an expensive com-
mercial product) was prepared from benzylamine by following a
well-known procedure.9 With vinylphosphonates 1a–c in hand, we
submitted them to a 1,3-dipolar cycloaddition with amine 6 in the
presenceof trifluoroacetic acid(TFA)intolueneat roomtemperature
(Scheme 3). Under these conditions the desired b-aminophospho-
nates 7a–c were produced in excellent yields (Table 2).15
In order to expand the scope of our method, we decided to pre-
pare the heterocyclic aminophosphonates via the cycloaddition of
Scheme 4. Synthesis of c-aminovinylphosphonates.
for 9c and (3JPHcis = 22.0 Hz) for 12c are in agreement with the
literature.4c,d
The 1,3-dipolar cycloaddition of cis- and trans-amin-
ovinylphosphonates 9c and 12c was achieved under the same con-
ditions as noted above. Amine 6 and aminovinylphosphonates 9c
and 12c were treated with TFA in toluene at room temperature
to produce, with complete stereoselectivity, the heterocyclic
c-
aminophosphonates cis-13c and trans-14c in good yields (Scheme
5).19 The relative stereochemistry of cis-13c and trans-14c was
supported by coupling constants in 13C NMR spectra between P
and CH2–C-4. The observed values (3JPCcis = 7.2 Hz) for 13c and
(3JPCtrans = 0 Hz) for 14c were in agreement with our reported data
in a related system.20
Selective deprotection of N,N-dibenzylaminophosphonate 7c by
hydrogenolysis with a catalytic amount of 20% Pd(OH)2/C in AcOH/
HCl under hydrogen (1 atm, 20 h), gave aminophosphonate 15c21
in good yield (Scheme 6).22
dipole derived from 6 with the cis- and trans-c-aminophospho-
nates 9c and 12c, respectively. The preparation of cis-vinylphosph-
onate 9c was achieved by alkylation of N-tosyl amine 6c followed
by phosphorylation to provide aminoalkynephosphonate 8c. Sub-
sequent Lindlar hydrogenation (5 wt % Pd on CaCO3) of the latter
afforded the cis-c
-aminophosphonate 9c in good yield.16
trans-Aminovinylphosphonate 12c was prepared selectively by
cross-metathesis of allyl amide 10 and vinylphosphonate 11 using
Grubbs II catalyst (5 mol %)17 in dichloromethane at reflux for 20 h
(Scheme 4).18 Assignment of the stereochemistry of 9c and 12c was
confirmed by the analysis of 3J coupling constants between H-3
and the phosphorus atom. The observed values (3JPHtrans = 51.7 Hz)
O
OEt
OEt
OMe
P
P
Me3Si
Ts
TFA, 0.4 eq
N
Bn
4 3
9c
N
Toluene,rt, 2 h
80%
N
Bn
Bn
6
( )-cis-13c
O
O
OEt
OEt
OEt
O
P
OMe
TMS
OEt
OEt
OEt
Ts
N
TFA, 0.4 eq
TFA, 0.4 eq
P
R'
R
4 3
12c
N
R
N
R'
N
6
Toluene,rt, 2 h
80–99%
Bn
Toluene,rt, 2 h
82%
N
Bn
N
Bn
Bn
1a-c
6
7a-c
( )-trans-14c
Scheme 3. b-Aminophosphonates by 1,3-dipolar cycloaddition.
Scheme 5. Synthesis of cis- and trans-c-aminophosphonates.

62
N. Rabasso, A. Fadel / Tetrahedron Letters 51 (2010) 60–63
3
1H, H-1). 13C NMR (CDCl3, 90.56 Hz) d = 16.2 (d, JPC = 6.2 Hz, CH3), 16.4 (d,
O
N
OEt
OEt
O
OEt
OEt
3JPC = 6.1 Hz, CH3), 44.3 (C-40), 45.8 (d, JPC = 14.6 Hz, C-3), 61.8 (C-50), 62.2 (d,
2
P
P
2JPC = 5.9 Hz, CH2OP), 131.4 (d, 2JPC = 8.6 Hz, C-1), 134,5 (d, 1JPC = 177.1 Hz, C-2),
158.1 (C-20). 31P NMR (CDCl3, 101.25 MHz) d = 16.44. Data for 1b: 1H NMR
(CDCl3, 360 MHz) d = 1.25 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 3.41 (dd,
J = 14.5, 15.4 Hz, 1H, H-3), 3.96–4.16 (m, 4H), 4.15 (dd, J = 6.1, 8.6 Hz, 1H, H-50),
4.37 (dd, J = 9.0, 15.8 Hz, 1H, H-3), 4.63 (dd, J = 8.6, 9.0 Hz, 1H, H-50), 4.85 (dd,
H2, Pd(OH)2/C
Ts
Ts
N
Bn
N
H
AcOH/2N HCl, rt
81%
N
H
Bn
7c
15c
3
J = 6.1, 9.0 Hz, 1H, H-40), 5.77 (d, JPHtrans = 45.7 Hz, 1H, H-1), 6.17 (d,
3JPHcis = 21.6 Hz, 1H, H-1), 7.22–7.31 (m, 2H), 7.34–7.45 (m, 3H). 13C NMR
(CDCl3, 90.56 Hz) d = 16.2 (d, 3JPC = 2.6 Hz, CH3), 16.3 (d, 3JPC = 3.3 Hz, CH3), 43.6
Scheme 6. Selective deprotection of amine by hydrogenolysis.
2
2
(d, JPC = 13.9 Hz, C-3), 59.0 (C-40), 62.2 (d, JPC = 2.6 Hz, CH2OP), 62.3 (d,
2JPC = 2.6 Hz, CH2OP), 69.9 (C-50), [6 arom C: 127.1 (2CH), 129.1 (CH), 129.3
3. Conclusion
2
1
(2CH), 137.7 (Cq)], 132.4 (d, JPC = 7.9 Hz, C-1), 133.9 (d, JPC = 176.0 Hz, C-2),
157.8 (C-20). 31P NMR (CDCl3, 145.78 MHz) d = 16.52. Data for 1c: 1H NMR
(CDCl3, 250 MHz) d = 1.27 (t, J = 7.0 Hz, 6H), 2.47 (s, 3H), 3.88–4.10 (m, 6H,
2CH2O and 2H-3), 4.39 (s, 2H, benzyl), 5.93 (d, 3JPHtrans = 46.8 Hz, 1H, H-1), 6.09
In summary, an easy and efficient synthesis of new b- and
-aminopyrrolidinephosphonates involving a 1,3-dipolar cycload-
dition of the corresponding vinyl phosphonates with a dipole in
the presence of TFA has been described. Furthermore, new synthetic
routes to vinylphosphonates have been developed via a cross-cou-
pling reaction of vinyl bromide with triethyl phosphite to afford
-(amino-methyl)vinylphosphonates and via a cross-metathesis to
provide a trans-b-(aminomethyl) analogue, in good yields. Further
studies directed toward the asymmetric synthesis of b- and c-amin-
opyrrolidinephosphonates are currently underway.
c
3
(d, JPHcis = 22.7 Hz, 1H, H-1), 7.08–7.20 (m, 2H), 7.20–7.38 (m, 5H), 7.75 (d,
J = 8.2 Hz, 2H). 13C NMR (CDCl3, 62.9 Hz) d = 16.2 (CH3), 16.3 (CH3), 21.6 (CH3,
2
2
Ts), 47.7 (d, JPC = 19.9 Hz, C-3), 51.8 (CH2 benzyl), 62.0 (d, JPC = 5.5 Hz, CH2OP),
[12 arom C: 127.3 (2CH), 128.0 (CH), 128.6 (2CH), 128.9 (2CH), 129.8 (2CH),
2
135.3 (Cq), 137.1 (Cq), 143.6 (Cq)], 130.6 (d, JPC = 7.1 Hz, C-1), 130.6 (d,
1JPC = 171.6 Hz, C-2). 31P NMR (CDCl3, 101.25 MHz) d = 17.00.
a
15. Data for 7a: 1H NMR (CDCl3, 250 MHz) d = 1.29 (t, J = 7.0 Hz, 6H, CH3), 1.75–
1.98 (m, 1H, H-4), 2.06–2.30 (m, 1H, H-4), 2.30–2.52 (m, 1H, H-5), 2.52–2.78
(m, 2H, CH2N), 2.78–2.90 (m, 1H, H-5), 3.34–3.82 (m, 6H, 2H-2, 2H-40 and
2Hbenzyl), 4.00 –4.40 (m, 6H, 2H-50 and 4H, CH2OP), 7.05–7.40 (m, 5H). 13C NMR
1
(CDCl3, 62.9 Hz) d = 16.6 (2 CH3), 30.7 (C-4), 45.3 (d, JPC = 147.2 Hz, C-3), 46.5
(C-40), 50.4 (C-2), 53.7 (d, 3JPC = 3.6 Hz, C-5), 58.6 (CH2N), 59.6 (CH2 benzyl), 61.9
2
2
(C-50), 62.2 (d, JPC = 7.4 Hz, CH2OP), 62.5 (d, JPC = 7.0 Hz, CH2OP), [6 arom C:
127.0 (CH), 128.2 (2CH), 128.6 (2CH), 138.8 (Cq)], 159.6 (C-20). 31P NMR (CDCl3,
101.25 MHz) d = 31.77. Data for 7b: 1H NMR (CDCl3, 250 MHz) two
diastereoisomers (a/b, 54:46) d = 1.23 (t, J = 6.9 Hz, 3H, a), 1.27 (t, J = 6.9 Hz,
3H, a), 1.32 (t, J = 7.2 Hz, 3H, b), 1.35 (t, J = 7.2 Hz, 3H, b), 1.68–2.06 (m, 1H, H-4,
a/b), 2.06–2.30 (m, 1H, H-4, a/b), 2.30–3.00 (m, 5H, 2H-5, 1H-2 and 2H-7, a/b),
3.40–3.80 (m, 2Hbenzyl, a/b), 3.80–4.25 (m, 6H, 1H-2, 4H CH2OP, and 1H-50, a/b),
4.50–4.66 (m, 1H, H-50, a/b), 5.08 (dd, J = 3.7, 8.7 Hz, 1 H-40, b), 5.28 (dd, J = 3.5,
8.7 Hz, 1H, H-40, a), 6.83–6.92 (m, 2H, b), 7.12–7.23 (m, 2H, a), 7.23–7.46 (m,
8H, a/b). 31P NMR (CDCl3, 101.25 MHz) d = 31.85 a/b not separable. Data for 7c:
1H NMR (CDCl3, 360 MHz) d = 1.28 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H),
1.96–2.15 (m, 2H, H-4), 2.30–2.50 (m, 1H, H-5), 2.44 (s, 3H, Ts), 2.64 (dd,
JAB = 10.1 Hz, 3JPH = 17.3 Hz, 1H, CH2–C–P), 2.76 (dd, JAB = 10.1 Hz, 3JPH = 8.3 Hz,
Acknowledgments
The authors thank Mr. M. Decoux and R. Blareau for technical
assistance and Dr. Jason Martin for proofreading the manuscript.
References and notes
1. Edmunson, R. F.; Hartley, F. R.. In The Chemistry of Organophosphorus
Compounds; John Wiley and Sons: Chichester, 1996; Vol. 4.
2. For recent reviews, see: (a) Coudray, L.; Montchamp, J.-L. Eur. J. Org. Chem.
2008, 3601–3613; (b) Janecki, T.; Kedzia, J.; Wasek, T. Synthesis 2009, 1227–
1254; (c) Ananikov, V. P.; Khemchyan, L. L.; Beletskaya, I. P. Synlett 2009, 2375–
2381.
3. For recent examples, see: (a) Whitteck, J. T.; Ni, W.; Griffin, B. M.; Eliot, A. C.;
Thomas, P. M.; Kelleher, N. L.; Metcalf, W. W.; van der Donk, W. A. Angew.
Chem., Int. Ed. 2007, 46, 9089–9092; (b) Quntar, A. A. A.; Gallily, R.; Katzavian,
G.; Srebnik, M. Eur. J. Pharmacol. 2007, 556, 9–13; (c) Doddridge, Z. A.; Bertram,
R. D.; Hayes, C. J.; Soultanas, P. Biochemistry 2003, 42, 3239–3246.
4. (a) Krawczyk, H. Phosphorus, Sulfur Silicon 1995, 101, 221–224; (b) Krawczyk, H.
Synth. Commun. 1994, 24, 2263–2271; (c) Loreto, M. A.; Pompili, C.; Tardella, P.
A. Tetrahedron 2001, 57, 4423–4427; (d) Gajda, A.; Gajda, T. Tetrahedron 2008,
64, 1233–1241.
5. For a synthesis of b-aminophosphonates and their biological activities, see: (a)
Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899–991; (b)
Mikolajczyk, M., Drabowicz, J., Lyzwa, P. In Enantioselective Synthesis of b-Amino
Acids; Juaristi, E., Soloshonok, V. A., Eds.; John Wiley and Sons: New York, 2005;
Chapter 12, p 261.
6. Allen, J. G.; Arthenton, F. R.; Hall, M. J.; Hassal, C. H.; Holmes, S. W.; Lambert, R.
W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 373, 56–58.
7. (a) Smith, W. W.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4622–4628; (b)
Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1998, 32,
1652–1661.
8. Alonso, E.; Alonso, E.; Solis, A.; del Poso, C. Synlett 2000, 698–700.
9. For the preparation of azomethine ylide precursors and their
[3+2]cycloaddition reaction with vinylsulfones, vinylcarboxylates and other
dipolarophiles, see: (a) Padwa, A.; Dent, W. Org. Synth. 1988, 67, 133–140; (b)
Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235–244; (c) Padwa, A.. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 4, pp 1090–1109.
10. Yan, L.; Hale, J. J.; Lynch, C. L.; Badhu, R.; Gentry, A.; Mills, S. G.; Hadju, R.;
Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.; Shei, G.-J.; Chrebet, G.;
Bergstrom, J.; Card, D.; Rosen, H.; Mandala, S. M. Bioorg. Med. Chem. Lett. 2004,
14, 4861–4866.
3
1H, CH2-C-P), 2.80–2.92 (m, 1H, H-5), 3.47 (dd, JAB = 15.3 Hz, JPH = 9.0 Hz, 1H,
H-2), 3.58 (AB system, JAB = 13.0 Hz,
system, JAB = 15.3 Hz, AB = 11.5 Hz, 1H, H-2), 4.00–4.20 (m, 4H, CH2OP), 4.76
(AB system, JAB = 16.6 Hz, AB = 37.8 Hz, 2H, Hbenzyl), 6.84–6.94 (m, 2H), 7.08–
7.20 (m, 2H), 7.20–7.40 (m, 8H), 7.74 (d, J = 7.9 Hz, 2H). 13C NMR (CDCl3,
DmAB = 29.9 Hz, 2H, PhCH2N), 3.82 (AB
D
m
Dm
3
3
90.56 Hz) d = 16.4 (d, JPC = 7.2 Hz, CH3), 16.5 (d, JPC = 5.8 Hz, CH3), 21.5 (CH3,
2
1
Ts), 29.4 (d, JPC = 2.5 Hz, C-4), 45.6 (d, JPC = 143.3 Hz, C-3), 49.95 (d,
2JPC = 5.5 Hz, C-2), 51.6 (TsNCH2 benzyl), 54.1 (d, JPC = 3.8 Hz, C-5), 58.9 (CH2-
3
2
2
NTs), 60.0 (NCH2Ph), 62.1 (d, JPC = 7.4 Hz, CH2OP), 62.6 (d, JPC = 7.2 Hz,
CH2OP), [18 arom C: 127.1 (CH), 127.3 (CH), 127.4 (2CH), 128.2 (2CH), 128.3
(2CH), 128.4 (2CH), 129.0 (2CH), 129.6 (2CH), 136.0 (Cq), 138.1 (Cq), 139.1
(Cq), 143.1 (Cq)]. 31P NMR (CDCl3, 101.25 MHz) d = 32.70.
16. Data for 9c: 1H NMR (CDCl3, 250 MHz) d = 1.27 (t, J = 7.0 Hz, 6H), 2.46 (s, 3H, CH3,
Ts), 3.85–4.10 (m, 4H, CH2OP), 4.24–4.35 (m, 2H, H-3), 4.32 (s, 2H, CH2 benzyl), 5.45
2
3
(ddt, JPH = 15.0 Hz, J = 13.2, 2.0 Hz, 1H, H-1), 6.33 (ddt, JPHtrans = 51.7 Hz,
J = 13.2, 6.0 Hz, 1H, H-2), 7.26–7.39 (m, 7H), 7.75 (d, J = 8.5 Hz, 2H). 13C NMR
(CDCl3, 62.9 Hz) d = 16.3 (CH3), 16.4 (CH3), 21.6 (CH3, Ts), 47.8 (d, 2JPC = 8.3 Hz,
CH2OP), 53.2 (CH2 benzyl), 61.6 (d, 3JPC = 5.5 Hz, C-3), 117.3 (d, 1JPC = 182.1 Hz, C-
1), [12 arom C: 127.4 (2CH), 127.8 (CH), 128.5 (2CH), 128.6 (2CH), 129.9 (2CH),
136.0 (Cq), 136.1 (Cq), 143.6 (Cq)], 150.0 (d, 2JPC = 2.8 Hz, C-2).31P NMR (CDCl3,
101.25 MHz) d = 15.56.
17. For a preparation of allylic phosphonates with a cross metathesis, see: He, A.;
Yan, B.; Thanaravo, A.; Spilling, C. D.; Rath, N. P. J. Org. Chem. 2004, 69, 8643–
8651.
18. Data for12c:1HNMR (CDCl3, 250 MHz)d = 1.27 (t, J = 7.0 Hz, 6H), 2.43 (s, 3H, CH3,
Ts), 3.80–3.88 (m, 2H, H-3), 3.88–4.05 (m, 4H, CH2OP), 4.32 (s, 2H, CH2 benzyl), 5.63
2
3
(dd, JPH = 19.0 Hz, Jtrans = 17.2 Hz, 1H, H-1), 6.39 (ddt, JPHcis = 22.0 Hz,
Jtrans = 17.0 Hz, J = 5.2 Hz, 1H, H-2), 7.17–7.36 (m, 5H), 7.33 (d, J = 8.2 Hz, 2H),
7.73 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 62.9 Hz) d = 16.3 (CH3), 16.4 (CH3), 21.6
(CH3, Ts), 49.1 (CH2OP), 49.5 (CH2OP), 51.7 (CH2 benzyl), 61.8 (d, 3JPC = 5.5 Hz, C-3),
120.2 (d, 1JPC = 187.2 Hz, C-1), [12 arom C: 127.2 (2CH), 128.1 (CH), 128.5 (2CH),
128.7 (2CH), 130.0 (2CH), 135.3 (Cq), 136.7 (Cq), 143.7 (Cq)], 146.1 (d,
2JPC = 5.2 Hz, C-2).31P NMR (CDCl3, 101.25 MHz) d = 16.52.
11. (a) Rabasso, N.; Louaisil, N.; Fadel, A. Tetrahedron 2006, 62, 7445–7454; (b)
Louaisil, N.; Rabasso, N.; Fadel, A. Synthesis 2007, 289–293; (c) Rabasso, N.;
Fadel, A. Synthesis 2008, 2353–2362; (d) Louaisil, N.; Rabasso, N.; Fadel, A.
Tetrahedron 2009, 65, 8587–8595.
19. Data for 13c: 1H NMR (CDCl3, 300 MHz) d = 1.25 (t, J = 7.0 Hz, 3H), 1.27 (t,
J = 7.2 Hz, 3H), 2.13 (dd, J = 9.3, J = 7.2 Hz, 1H, H-5), 2.36–2.65 (m, 3H, H-3, H-2
and H-4), 2.45 (s, 3H, Ts), 2.695 (dd, J = 9.3, 7.2 Hz, 1H, H-5), 2.80–2.94 (m, 1H,
H-2), 3.37 (dd, J = 13.5, 3.0 Hz, 1H, CH2-NTs), 3.40–3.55 (m like AB system, 2H,
Bn-N), 3.62 (dd, J = 13.5, 12.0 Hz, 1H, CH2-NTs), 3.93–4.08 (m, 4H, CH2OP), 4.13
(d, J = 15.0 Hz, 1H, Bn-NTs), 4.32 (d, J = 15.0 Hz, 1H, Bn-NTs), 7.15–7.44 (m,
12H), 7.74 (d, J = 8.4 Hz, 2H). 13C NMR (CDCl3, 90.56 Hz) d = 16.4 (CH3), 16.5
12. Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological Activities;
Kukhar, V. P., Hudson, H. R., Eds.; Wiley & Sons: New York, 2000.
13. (a) Tavs, P.; Weitkamp, H. Tetrahedron 1970, 26, 5529–5534; (b) Kazankova, M.
A.; Trostyanskaya, I. G.; Lutsenko, S. V.; Beletskaya, I. P. Tetrahedron Lett. 1999,
40, 569–572.
1
(CH3), 21.5 (CH3, Ts), 36.9 (d, JPC = 145.3 Hz, C-3), 38.3 (C-4), 50.5 (d,
3
3JPC = 7.2 Hz, CH2-NTs), 53.9 (C-2), 54.0 (TsNCH2Ph), 58.5 (d, JPC = 5.6 Hz, C-
2
2
14. Data for 1a: 1H NMR (CDCl3, 360 MHz) d = 1.27 (t, J = 7.0 Hz, 6H), 3.52 (dd,
J = 8.5, 7.5 Hz, 2H, H-40), 3.90–4.10 (m, 6H, 4H-6 and 2H–3), 4.27 (dd, J = 8.5,
5), 59.8 (NCH2Ph), 61.5 (d, JPC = 6.8 Hz, CH2OP), 61.8 (d, JPC = 6.7 Hz, CH2OP),
[18 arom C: 127.0 (CH), 127.4 (2CH), 127.8 (CH), 128.2 (2CH), 128.6 (4CH),
128.7 (2CH), 129.7 (2CH), 136.3 (Cq), 136.7 (Cq), 138.8 (Cq), 143.3 (Cq)]. 31P
2
2
7.3 Hz, 2H, H-50), 5.88 (d, JPHtrans = 45.8 Hz, 1H, H-1), 6.13 (d, JPHcis = 22.0 Hz,

N. Rabasso, A. Fadel / Tetrahedron Letters 51 (2010) 60–63
63
NMR (CDCl3, 121.49 MHz) d = 29.46. Data for 14c: 1H NMR (CDCl3, 250 MHz)
d = 1.24 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H), 1.88 (dddd, JPH = 16.5 Hz,
20. (a) Fadel, A.; Tesson, N. Eur. J. Org. Chem. 2000, 2153–2159; (b) Fadel, A.;
Tesson, N. Tetrahedron: Asymmetry 2000, 11, 2023–2031.
2
J = 8.2, 8.2, 6.2 Hz, 1H, H-3) 2.17–2.66 (m, 4H, 2H-5, H-2 and H-4), 2.44 (s, 3H,
Ts), 2.70–2.95 (m, 1H, H-2), 3.10 (dd, J = 4.8, 13.8 Hz, 1H, CH2-NTs), 3.35 (dd,
J = 10.2, 13.8 Hz, 1H, CH2-NTs), 3.38–3.57 (m like AB system, 2H, Bn-N), 3.90–
4.18 (m, 4H, CH2OP), 4.16 (d, J = 15.2 Hz, 1H, Bn-NTs), 4.51 (d, J = 15.2 Hz, 1H,
Bn-NTs), 7.20–7.50 (m, 12H), 7.74 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 62.9 Hz)
d = 16.5 (CH3), 16.6 (CH3), 21.6 (CH3, Ts), 38.1 (C-4), 38.2 (d, 1JPC = 148.6 Hz, C-
3), 52.8 (TsNCH2), 53.0 (PhCH2-NTs), 53.9 (C-2), 57.4 (d, 3JPC = 5.9 Hz, C-5), 59.4
(NCH2Ph), 61.8 (d, 2JPC = 6.6 Hz, CH2OP), 62.1 (d, 2JPC = 6.6 Hz, CH2OP), [18 arom
C: 127.0 (CH), 127.4 (2CH), 127.8 (CH), 128.3 (2CH), 128.5 (2CH), 128.6 (4CH),
129.8 (2CH), 136.6 (2Cq), 138.8 (Cq), 143.4 (Cq)]. 31P NMR (CDCl3, 101.25 MHz)
d = 30.94.
21. Data for 15c: 1H NMR (CDCl3, 360 MHz) d = 1.26 (t, J = 7.0 Hz, 6H), 1.85–2.00
(m, 1H-4), 2.06–2.50 (m, 1H-4), 2.41 (s, 3H, Ts), 3.00–3.18 (m, 5H, 2H-5, 1H-2
and 2H, CH2NTs), 3.82 (dd, JAB = 14.4 Hz, 3JPH = 12.6 Hz, 1H, H-2), 4.00–4.15 (m,
4H, CH2OP), 5.18 (br s, 2H, NH), 7.29 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H).
3
13C NMR (CDCl3, 90.56 Hz) d = 16.5 (d, JPC = 5.4 Hz, 2CH3), 21.6 (CH3, Ts), 31.6
1
3
(C-4), 45.5 (d, JPC = 147.1 Hz, C-3), 46.7 (C-2), 46.9 (d, JPC = 6.9 Hz, C-5), 52.0
(CH2NTs), 62.9 (d, 2JPC = 7.2 Hz, 2CH2OP), [6 arom C: 127.2 (2CH), 129.8 (2CH),
137.1 (Cq), 143.4 (Cq)]. 31P NMR (CDCl3, 101.25 MHz) d = 31.41.
22. For other possible deprotections of amine or hydrolysis of phosphonate
function, see Refs. 11,20.