[4+2] Cycloaddition of 1-phosphono-1,3-butadiene with azo- and nitroso-heterodienophiles

Article abstract of DOI:10.1016/j.tetlet.2008.01.050

Under microwave activation, diethyl 1-phosphono-1,3-butadiene (1) reacted with t-butyl azodicarboxylate (2) and o-nitrosotoluene (5) to furnish quantitatively [4+2] cycloadducts, 3-phosphono-3,6-dihydro-1,2-pyridazine (3) and 6-phosphono-3,6-dihydro-1,2-o

Full text of DOI:10.1016/j.tetlet.2008.01.050

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1839–1842
[4+2] Cycloaddition of 1-phosphono-1,3-butadiene with
azo- and nitroso-heterodienophiles
Jean-Christophe Monbaliu, Jacqueline Marchand-Brynaert *
ˆ
Unite´ de Chimie Organique et Me´dicinale, De´partement de Chimie, Universite´ Catholique de Louvain, Batiment Lavoisier,
Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
Received 4 December 2007; revised 22 December 2007; accepted 9 January 2008
Available online 15 January 2008
Abstract
Under microwave activation, diethyl 1-phosphono-1,3-butadiene (1) reacted with t-butyl azodicarboxylate (2) and o-nitrosotoluene
(5) to furnish quantitatively [4+2] cycloadducts, 3-phosphono-3,6-dihydro-1,2-pyridazine (3) and 6-phosphono-3,6-dihydro-1,2-oxazine
(6), respectively. Selective oxidation and/or reduction of 6 led to functionalized d-aminophosphonic derivatives in cyclic (7, 8) and
aliphatic series (9, 10). Intermediate 10 may be cyclized into 2-phosphono-2,5-dihydro-1-pyrrole (12).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Hetero Diels–Alder reaction; 1-Phosphono-1,3-butadiene; Azo dienophile; Nitroso dienophile; Microwave activation; Aminophosphonic
derivatives
With its well-known potential of forming highly func-
tionalized molecules, in a convergent way compatible with
a wide range of substituents, the Diels–Alder (DA) reaction
(i.e., [4+2] cycloaddition) is a versatile synthetic tool that
can be used for the synthesis of aminophosphonic deriva-
tives.1 These compounds are recognized as an important
class of pharmacologically active molecules effective in
several diseases.2 Surprisingly, aminophosphonic deriva-
tives other than the a-ones have been obtained only via
punctual methods. This stimulates the development of
novel synthetic routes towards such compounds.2,3 Our
interest in cycloaddition reactions leads us to investigate
HDA (hetero-Diels–Alder) reaction4 as a valuable strategy
towards d-aminophosphonic derivatives of potential
interest in medicinal chemistry.5,6 In this Letter, we
describe the [4+2] reaction of phosphono-butadiene (1)
with t-butyl azodicarboxylate (2) and 2-nitrosotoluene (5)
as heterodienophile model compounds (Scheme 1). We
further demonstrate that cycloadduct 6 is a versatile inter-
mediate leading to various aminophosphonic derivatives
both in cyclic and aliphatic series.
1-(Diethylphosphono)-1,3-butadiene (1) could be read-
ily obtained in two steps from 1,4-trans-dichlorobutene.7
The DA reactivity of 1 was initially studied in 1963 by
Pudovik et al.8 Cycloadditions occurred with acrylonitrile,
PO3Et2
PO3Et2
PO3Et2
E
E
N
N
a.
b.
N
NH
NH
+
N
E
E
1
2
3
4
E = CO2tBu
Ar
PO3Et2
PO3Et2
PO3Et2
Ar
a.
O
N
O
N
N
O
+
+
Ar
1
5
proximal
distal
(very minor)
6
(major)
Ar = o-Tolyl
*
Corresponding author. Tel.: +32 (0)10 472740; fax: +32 (0)10 474168.
Scheme 1. Reagents and conditions: (a) (CH2Cl)2, 95 °C or MW
activation; (b) TFA, DCM, rt, 15 h.
E-mail address: Jacqueline.Marchand@uclouvain.be (J. Marchand-
Brynaert).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.050

1840
J.-C. Monbaliu, J. Marchand-Brynaert / Tetrahedron Letters 49 (2008) 1839–1842
Table 1
acroleine, ethyl methacrylate and dimethylmaleate, at high
temperature in an autoclave, but in poor yields because
dimerization of the diene was the major process. Similar
observations were reported later by Griffin and co-work-
ers,9 opposing 1 to other electron-poor dienophiles such
as diethyl vinylphosphonate and dimethyl acetylenedi-
carboxylate. In the case of electron-rich dienophiles,
namely enamines, the cycloadditions of 1 were even more
sluggish according to Darling and Subramanian.10
Microwave activation of diene 1 in HDA reactions
Entry Reagent Conditions
Conv.a Regioselectivity
(%)
proximal/
distala
1
2
3
4
2
2
5
5
DCE, 95 °C, 7 d
lW, 650 W, 120 °C, 1 h
DCE, 95 °C, 15 h
55
>99
>99
—
—
10:1
Proximal
DCE, lW, 500 W, 100 °C, >99
1 h
a
From 500 MHz 1HNMR on the crude mixture.
We found that 1 reacted smoothly with t-butyl azodicar-
boxylate (2) under classical thermal conditions to furnish
1,2-(di-t-butyloxycarbonyl)-3-diethoxyphosphono-3,6-di-
hydro-1,2-pyridazine (3) (Scheme 1), while microwave
activation11 provided a significant increase in yields and
reaction rate (Table 1). The cycloadduct was easily purified
by column chromatography on silica gel and characterized
by the usual spectroscopies.12 Deprotection of the Boc
groups with trifluoroacetic acid (TFA) gave the corre-
sponding hydrazine derivative 4 in 95% yield.13
Next, we found that diene 1 reacted more easily with
2-nitrosotoluene14 in refluxing dichloroethane (DCE) to
afford dihydro-1,2-oxazine cycloadducts 6 (Scheme 1) as
a 10:1 mixture of proximal and distal regioisomers, which
were easily separated by column chromatography on silica
gel.15 Interestingly, when microwave activation was
applied, the regioselectivity became complete in favour of
the proximal isomer and the reaction time was shortened
(Table 1). This can be explained by the greater synchronic-
ity of the distal transition state versus the proximal one.16
Oxidation of 6 without cleavage of the C–C double bond
was investigated (Scheme 2). Treatment with K2OsO2(OH)4
and N-methyl morpholine oxide (NMO)17 to effect cis-
dihydroxylation of the double bond gave the syn-diol 7 in
high yield (92%).18 1H, 13C and 31P NMR data are consis-
tent with the formation of one stereoisomer, suggesting a
control of the relative stereochemistry by the bulky phos-
phonate. Esterification of 7 with benzoyl chloride afforded
PO3Et2
O
PO3Et2
R3
R4
O
N
O
N
a.
O
6
7, R3 = R4 = H
b.
8, R3 = R4 = COPh
d.
c.
PO3Et2
PO3Et2
PO3Et2
HO
HO
a.
OH
c.
OH
OH
HN
HN
11
9
10
e.
PO3Et2
N
12
Scheme 2. Reagents and conditions: (a) K2OsO2(OH)4, acetone–water, rt, 24 h, 92%; (b) benzoyl chloride, DMAP, pyridine, DCM, rt, 2 h, >95%; (c) H2,
Pd–C, EtOH, rt, 12 h, >99%; (d) Zn, AcOH, water, 70 °C, 15 h, >99%; (e) CBr4, Imidazole, Et3N, PPh3, DCM, rt, 15 h, 75%.

J.-C. Monbaliu, J. Marchand-Brynaert / Tetrahedron Letters 49 (2008) 1839–1842
1841
diester 8 that smoothly crystallized from a benzene–ether
References and notes
5:1 mixture. X-ray diffraction analysis of a monocrystal
confirmed that the phosphonate group is in anti relation-
ship regarding the two syn hydroxyl groups.19
Reductive cleavage of the 1,2-oxazine motif of 7 under
catalytic hydrogenation conditions (Scheme 2) led quanti-
tatively to diethyl 4-(o-tolylamino)-1,2,3-trihydroxybutyl-
phosphonate (9).20
1. (a) Monbaliu, J.-C.; Tinant, B.; Marchand-Brynaert, J. J. Mol. Struct.
2007. doi:10.1016/j.molstruc.2007.08.018; (b) Robiette, R.; Defacqz,
N.; Peeters, D.; Marchand-Brynaert, J. Curr. Org. Synth. 2005, 2,
453–477; (c) Robiette, R.; Cheboub-Benchaba, K.; Peeters, D.;
Marchand-Brynaert, J. J. Org. Chem. 2003, 68, 9809–9812 and
references cited therein.
2. Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Aminophosphinic
Acids, Chemistry and Biological Activity; J. Wiley & Sons Ltd: New
York, 2000.
A useful synthetic application of 3,6-dihydro-1,2-
oxazine 6 could be the selective reductive cleavage of the
N–O bond to generate 1,4-difunctional 2-butene deriva-
tives with preserved (Z)-configuration. The currently most
popular way of oxazine cleavage uses freshly prepared
Mo(CO)3(CH3CN)3.21 But in our case the reductive cleav-
age with Zn in AcOH22 was the most efficient method for
preparing (Z)-diethyl 4-(o-tolylamino)-1-hydroxybut-2-
enylphosphonate (10) in quantitative yield.23 The (Z)-rela-
tionship of olefinic protons was confirmed by the observa-
3. Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177–
6215.
4. (a) Streith, J.; Defoin, A. Synthesis 1994, 1107–1117; (b) Vogt, P. F.;
Miller, M. J. Tetrahedron 1998, 54, 1317–1348; (c) Yamamoto, Y.;
Yamamoto, H. Eur. J. Org. Chem. 2006, 2031–2043; (d) Comins, D.
L.; Kuethe, J. T.; Miller, T. M.; Fevrier, F. C.; Brooks, C. A. J. Org.
Chem. 2005, 70, 5221–5234.
5. Kaname, M.; Yoshinaga, K.; Arakawa, Y.; Yoshifuji, S. Tetrahedron
Lett. 1999, 40, 7993–7994.
´
6. Wroblewski, A. E.; Glowacka, I. Tetrahedron 2005, 61, 11930–11938.
3
7. Pudovik, A. N.; Konovalova, I. V. J. Gen. Chem. USSR 1961, 31,
1580.
tion of a JH–H value of 6 Hz. Oxidation of 10 by using
K2OsO2(OH)4 as previously described led to 9 in low
yields. Thus, the best route to synthesize 9 from 6 is
C@C dihydroxylation followed by O–N cleavage (91%
yield) and not the reversed reaction sequence (42% yield).
Treatment of 10 by hydrogen in the presence of Pd cat-
alyst reduced the C@C double bond and simultaneously
cleaved the o-tolylamine group. This unexpected reaction
furnished the known diethyl 1-hydroxybutylphosphonate
(11).24 Lastly, ring closure of 10 into pyrrolidine-2-phos-
phonic derivative was possible by using PPh3/CBr4 activa-
tion.25 The reactive intermediate (not isolated) underwent
an intramolecular nucleophilic substitution by the aniline
moiety, in the presence of imidazole, leading to diethyl
2,5-dihydro-1-o-tolyl-1-pyrrol-2-yl-2-phosphonate (14)26
(Scheme 2).
In conclusion, we have demonstrated that under micro-
wave activation, HDA reaction of 1-phosphono-butadiene
could be readily performed. This is most probably due to
the high polarizability of reagent 1.27 Reaction with azo
partner 2 followed by N-deprotection represents the best
way to prepare 3-phosphono-1,2,3,6-tetrahydropyridazine
(4), an already known biologically active molecule.5 Reac-
tion with nitroso partner 3 followed by either oxidation or
reduction illustrates the versatility of our strategy towards
d-aminophosphonic derivatives, in particular poly-hydrox-
ylated compounds such as 9. Also, a novel entry into the 2-
phosphono-pyrrolidine (12) family28 has been shown.
8. Pudovik, A. N.; Konovalova, I. V.; Ishmaevan, E. A. Zh. Obshch.
Khim. 1963, 33, 2509.
9. Claibourne, E.; Griffin, C. E.; Daniewski, W. M. J. Org. Chem. 1970,
35, 1691–1693.
10. Darling, S. D.; Subramanian, N. J. Org. Chem. 1975, 40, 2851–2852.
11. (a) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225; (b) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43,
6250–6284; (c) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–
9223.
12. Procedure for 1,2-(di-t-butyloxycarbonyl)-3-diethoxyphosphono-3,
6-dihydro-1,2-pyridazine 3: A mixture of t-butyl azodicarboxylate
(5.3 mmol) and 1 (5.3 mmol) with a few drops of toluene was stirred
in a microwave oven under 650 W irradiation at 120 °C for 1 h. The
reaction mixture was concentrated in vacuo and purified by column
chromatography on silica gel to give 3 as a yellow oil (>99%). Rf
(ethyl acetate) = 0.6; 1H NMR (500 MHz; 50 °C, CDCl3) d: 5.94 (br s,
2H), 5.04 (br d, 1H, J = 19.6 Hz), 4.41 (dd, 1H, J = 7 and 7.7 Hz),
4.27–4.15 (m, 4H), 3.76–3.63 (m, 1H), 1.47 (br s, 18H), 1.31 (t, 3H,
J = 7.2 Hz), 1.25 (t, 3H, J = 7.2 Hz); 13C NMR (125 MHz; CDCl3,
major rotamer) d: 154.17, 152.68, 126.07, (d, JC–P = 7.7 Hz) 121.25,
81.02, 63.58 (d, JC–P = 6.5 Hz), 62.77 (d, JC–P = 6.1 Hz), 51.3 (d,
JC–P = 162.3 Hz), 41.55 (d, JC–P = 2.1 Hz), 28.58 (m), 16.71 (m); 31P
NMR (121 MHz; CDCl3, H3PO4) d: 21.23; IR (NaCl, m, cmÀ1) 2984,
2934, 1734, 1420, 1284, 1015, 952; ESI HRMS m/z for
C
18H33N2O7PNa [M+Na+]: calcd 443.1918; found 443.1921.
13. Procedure for diethyl 1,2,3,6-tetrahydropyridazin-3-yl-3-phosphonate 4:
To a solution of 3 (0.34 mmol) in chloroform (2.5 cm3) at room
temperature was added TFA (2.72 mmol). After 15 h, the reaction
mixture was concentrated in vacuo affording 4 as a yellow oil (95%).
Rf [ethyl acetate/iPrOH 95:5] = 0.25; 1H NMR (300 MHz; CDCl3) d:
6.06 (br s, 2H), 4.21 (m, 5H), 3.91–3.81 (m, 2H), 1.35 (t, 6H,
J = 6.3 Hz); 13C NMR (75 MHz; CDCl3) d: 122.81 (d, JC–P = 9.5 Hz),
121.19, 65.44 (d, JC–P = 155.4 Hz); 42.79, 16.56; 31P NMR (121 MHz;
CDCl3, H3PO4) d: 19.99; IR (NaCl, m, cmÀ1) 3325, 1280, 1023; ESI
HRMS m/z for C8H17N2O3PNa [M+Na+]: calcd 243.0875; found
243.0878.
Acknowledgements
This work was supported by the F.N.R.S. (Fonds
National de la Recherche Scientifique, Belgium) and the
14. 2-Nitrosotoluene 5 was purchased from commercial source (Aldrich)
as a dimeric form (colourless). In dichloroethane solution, the
dissociation towards monomeric form was instantaneous (deep green
solution). See: Lee, J.; Chen, L.; West, A. H.; Richter-Addo, G. B.
Chem. Rev. 2002, 102, 1019–1065.
15. Procedure for diethyl 3,6-dihydro-2-o-tolyl-1,2-oxazin-6-yl-6-phos-
phonate 6: A solution of 1 (6.58 mmol) in dichloroethane (10 cm3)
and 2-nitrosotoluene (6.58 mmol) was stirred in a microwave oven
`
F.R.I.A. (Fonds pour la Formation a la Recherche dans
l’Industrie et dans l’Agriculture, Belgium). Pr. B. Tinant
is acknowledged for X-ray diffraction analysis. J.M.-B is
a senior research associate of F.N.R.S. and J.-C.M is
F.R.I.A. fellow.

1842
J.-C. Monbaliu, J. Marchand-Brynaert / Tetrahedron Letters 49 (2008) 1839–1842
under 500 W irradiation at 100 °C for 1 h. The reaction mixture was
concentrated in vacuo and purified by column chromatography on
22. Lepore, S. D.; Schacht, A.; Wiley, M. R. Tetrahedron Lett. 2002, 43,
8777–8779.
silica gel to give 6 as a brown oil (>99%). Rf (ethyl acetate) = 0.6; 1H
NMR (500 MHz; CDCl3) d: 7.16 (m, 4H), 6.13 (m, 2H), 5.1 (ddd, 1H,
J = 7.6, 5.3 and 3 Hz), 4.14 (m, 4H), 3.88 (m, 1H), 3.57 (tdd, 1H,
J = 7, 4.1 and 1.9 Hz), 2.33 (s, 3H), 1.28 (m, 6H); 13C NMR
(125 MHz; CDCl3) d: 147.76, 133.1, 130.99, 126.47, 126.34 (d,
JC–P = 10 Hz), 125.85, 122.87 (d, JC–P = 5 Hz), 118.57, 75.68 (d,
JC–P = 160 Hz), 63.49 (d, JC–P = 6.2 Hz), 62.86 (d, JC–P = 6.2 Hz),
52.15 (d, JC–P = 2.8 Hz), 18.33, 16.61 (dd, JC–P = 5.7 Hz); 31P NMR
(121 MHz; CDCl3, H3PO4) d: 18.2; IR (NaCl, m, cmÀ1) 2935, 1495,
1454, 1209, 1068; ESI HRMS m/z for C15H22NO4PNa, [M+Na+]:
calcd 334.1184; found 334.1171.
23. Procedure for (Z)-diethyl 4-(o-tolylamino)-1-hydroxybut-2-enyl-phos-
phonate 10: To a solution of 6 (6.4 mmol) in a AcOH/water 1:2
mixture (90 cm3) was added zinc dust (10.2 mmol). The reaction
mixture was heated at 70 °C for 12 h with vigorous stirring. The
mixture was cooled down (20 °C) and solid K2CO3 was added
portionwise to pH 7, and then 3 N aqueous KOH to pH 9. The
mixture was then extracted with ethyl acetate (3 Â 50 cm3). The
organic phase was dried over MgSO4 and concentrated in vacuo,
affording 10 as a brown solid (>99%). Rf (ethyl acetate) = 0.32; mp
72–73 °C; 1H NMR (500 MHz; CDCl3): 7.15–7.07 (m, 2H), 6.73–6.64
(m, 2H), 5.89 (td, 1H, J = 10.1 and 6.1 Hz), 5.73 (m, 1H), 4.83 (t, 1H,
J = 10 and 7.5 Hz), 4.23–4.19 (m, 4H), 3.94–3.85 (m, 2H), 2.18 (s,
3H), 1.36 (t, 6H, J = 7.1 Hz); 13C NMR (125 MHz; CDCl3) d: 145.97,
132.32 (d, JC–P = 12.6 Hz), 130.52, 127.53 (d, JC–P = 3.8 Hz), 123.20,
118.14, 110.75, 66.13 (d, JC–P = 160.9 Hz), 63.52 (t, JC–P = 7.9 Hz),
41.12, 17.89, 16.86 (d, JC–P = 5.5 Hz); 31P NMR (121 MHz; CDCl3,
H3PO4) d: 23.05; IR (NaCl, m, cmÀ1) 3323, 1605, 1514, 1238, 1051; ESI
HRMS m/z for C15H24NO4PNa [M+Na+]: calcd 336.1341; found
336.1342.
24. (a) Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8, 4911–4914;
(b) Blazeswka, K.; Paneth, P.; Gajda, T. J. Org. Chem. 2007, 72,
878–887.
25. Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876–
2883.
26. Procedure for diethyl 2,5-dihydro-1-o-tolyl-1-pyrrol-2-yl-2-phosphonate
12: To a solution of 10 (0.91 mmol), imidazole (0.91 mmol), triethyl-
amine (0.91 mmol) and freshly recrystallized CBr4 (0.91 mmol) in
dry dichloromethane (5 cm3) was added portionwise PPh3
(0.91 mmol) at 20 °C for 10 min. After 15 h, the reaction mixture
was concentrated in vacuo, diluted with AcOEt, washed with 10%
aqueous NH4Cl (1Â), brine (1Â) and water (2Â). The organic layer
was dried over MgSO4, filtered and concentrated in vacuo. The oily
residue was purified by column chromatography on silica gel to give
16. Leach, A. G.; Houk, K. N. J. Org. Chem. 2001, 66, 5192–5200.
17. Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818–7824.
18. Procedure for diethyl syn-4,5-dihydroxy-2-o-tolyl-3,4,5,6-tetrahydro-
1,2-oxazin-6-yl-6-phosphonate 7: A solution of 6 (9.4 mmol) in acetone
(30 cm3) was treated successively by water (20 cm3), NMO
(20.68 mmol) and K2OsO2(OH)4 (0.47 mmol) at room temperature.
After 24 h, toluene (30 cm3) was added and concentrated in vacuo.
The resulting dark oil was directly purified by column chromatogra-
phy on silica gel to give 7 as a slightly yellow oil (>95%). Rf (ethyl
acetate/iPrOH 95:5) = 0.43; 1H NMR (500 MHz; CD3CN) d: 7.54 (m,
4H), 4.55 (dd, 1H, J = 10.3 and 9.6 Hz), 4.12 (m, 5H), 3.97 (ddd, 1H,
J = 12.9, 8.4 and 4.4 Hz), 3.86 (large s, 1H), 3.55 (large s, 1H), 3.4 (dd,
2H, J = 7.1 and 2.8 Hz), 2.36 (s, 3H), 1.30 (t, 3H, J = 6.9 Hz), 1.26 (t,
3H, J = 7.1 Hz); 13C NMR (125 MHz; CD3CN) d: 148.28, 134.28,
131.54, 127.17, 126.8, 119.22, 76.41 (d, JC–P = 158.1 Hz), 67.76 (d,
JC–P = 13.8 Hz), 66.9 (d, JC–P = 11.3 Hz), 63.81 (d, JC–P = 6.7 Hz),
63.44 (d, JC–P = 6.3 Hz), 58.54, 18.04, 16.65 (d, JC–P = 5.8 Hz); 31P
NMR (121 MHz; CDCN, H3PO4) d: 20.37; IR (NaCl, m, cmÀ1) 3389,
2982, 1489, 1230, 1047, 976; ESI HRMS m/z for C15H24NO6PNa
[M+Na+]: calcd 368.1239; found 368.1245.
19. This structure has been deposited at the Cambridge Crystallographic
Data Centre with the number 666038.
20. Procedure for diethyl 4-(o-tolylamino)-1,2,3-trihydroxybutylphospho-
nate 9: A solution of 7 (1.6 mmol) in ethanol (25 cm3) was stirred for
15 h at room temperature under H2 atmosphere in the presence of
Pd–C as catalyst (5 mol %). Afterwards, the reaction mixture was
concentrated in vacuo and purified by column chromatography on
silica gel to give 7 as a white solid (>99%). Rf (ethyl acetate/iPrOH
95:5) = 0.6; mp 105–106 °C; 1H NMR (500 MHz; CDCl3) d: 7.04 (m,
2H), 6.65 (m, 2H), 4.39 (br s, 3H), 4.14 (m, 6H), 3.96 (m, 1H), 3.47
(dd, 1H J = 12.6 and 4.2 Hz), 3.22 (dd, 1H, J = 12.6 and 6.5 Hz), 2.12
(s, 3H), 1.28 (dt, 6H, J = 7.1 and 3.9 Hz); 13C NMR (125 MHz;
CDCl3) d: 146.23, 130.33, 127.29, 123.49, 118.17, 111.23, 73.77, 71.19,
71.12, 69.54 (d, JC–P = 158.3 Hz), 63.70 (d, JC–P = 6.9 Hz), 63.31 (d,
JC–P = 6.9 Hz), 46.56, 17.73, 16.62 (t, JC–P = 6.1 Hz); 31P NMR
(121 MHz; CDCl3, H3PO4) d: 24.62; IR (NaCl, m, cmÀ1) 3366, 1608,
1514, 1213, 1028; ESI HRMS m/z for C15H27NO6P [M+H+]: calcd
348.1576; found 348.1577.
12 as a yellow oil (75%). Rf (dichloromethane/ethyl acetate
3:1) = 0.33; 1H NMR (500 MHz; CDCl3): d 7.09 (ddd, 2H, J = 12,
9.9 and 4.7 Hz), 6.91 (dt, 2H, J = 7.2 and 1.9 Hz), 5.99 (tq, 1H,
J = 6.1 and 3.1 Hz), 5.99–5.95 (m, 1H), 5.02 (dq, 1H, J = 5.9, 5.8 and
2.3 Hz), 4.58–4.41 (m, 1H), 3.92 (m, 4H), 3.70 (tddd, 1H, J = 19.5,
14.1, 3.7, and 2 Hz), 2.33 (s, 3H), 1.13 (dt, 6H, J = 7.1 and 5.5 Hz);
13C NMR (125 MHz; CDCl3) d: 149.02 (d, JC–P = 2.7 Hz), 133.52,
131.40, 129.87 (d, JC–P = 11.3 Hz), 126.70, 124.46 (d, JC–P = 5.6 Hz),
123.33, 120.71, 66.18 (d, JC–P = 168.3 Hz), 62.65 (d, JC–P = 7.1 Hz),
62.65 (d, JC–P = 7.3 Hz), 61.87, 19.54, 16.50 (dd, JC–P = 11.7 and
5.7 Hz); 31P NMR (121 MHz; CDCl3, H3PO4) d: 21.98; IR (NaCl, m,
cmÀ1) 3446, 2249, 1493, 1240, 1055, 1026; ESI MS m/z (%) for
C
15H23NO3P [M+H+]: 296.12 (10), 279.27 (100).
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