Synthesis of fluoroalkylated β-aminophosphonates and pyridines from primary β-enaminophosphonates

Article abstract of DOI:10.1021/jo8005667

(Chemical Equation Presented) A simple and efficient stereoselective synthesis of fluorine containing β-aminophosphonates by reduction of β-enaminophosphonates is described. Reduction with sodium cyanborohydride in the presence of zinc chloride and the catalytic hydrogenation of β-enaminophosphonates gives β-aminophosphonates. β- Enaminophosphonates are also used as intermediates for the regioselective synthesis of fluoroalkyl-substituted pyridines.

Full text of DOI:10.1021/jo8005667

Synthesis of Fluoroalkylated ꢀ-Aminophosphonates and Pyridines
from Primary ꢀ-Enaminophosphonates
Francisco Palacios,* Ana M. Ochoa de Retana, Julen Oyarzabal, Sergio Pascual, and
Guillermo Ferna´ndez de Troco´niz
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 March 12, 2008
A simple and efficient stereoselective synthesis of fluorine containing ꢀ-aminophosphonates by reduction
of ꢀ-enaminophosphonates is described. Reduction with sodium cyanborohydride in the presence of zinc
chloride and the catalytic hydrogenation of ꢀ-enaminophosphonates gives ꢀ-aminophosphonates.
ꢀ-Enaminophosphonates are also used as intermediates for the regioselective synthesis of fluoroalkyl-
substituted pyridines.
Introduction
containing molecules with biological activity and commercial
applications.4 In this context, selective fluorination of amino
acids and preparation of fluorinated analogues of amino acids
has recently been used to stabilize proteins for their application
in protein-based biotechnologies such as protein therapeutics
and biosensors.5 For these reasons, the development of new
methods for the preparation of fluorine-substituted aminophos-
phonates6 is an interesting goal in synthetic organic chemistry,
not only because of their use in medicinal chemistry as inhibitors
Organophosphorus compounds are important substrates in the
study of biochemical processes, and ꢀ-aminophosphonates,
being isosteres of ꢀ-amino acids, play an important role and
reveal interesting biological and biochemical properties as
enzyme inhibitors, agrochemicals or pharmaceuticals.1 At the
same time, in the field of bioactive molecules, fluoroorganic
compounds have received a great deal of attention since the
incorporation of a fluorine-containing group into an organic
molecule dramatically alters its physical, chemical, and biologi-
cal properties.2 These changes in properties make them suitable
for diverse applications in synthetic, agricultural, and medicinal
chemistry as well as in material science.3 Special interest has
been focused on developing synthetic methods for the prepara-
tion of fluorinated building blocks because they can be used
for the efficient and/or selective preparation of fluorine-
(4) (a) Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stere-
ochemical Challenges and Biomedical Targets; Soloshonok, V. A., Ed.; Wiley:
New York, 1999. (b) Fluorine-Containing Amino Acids: Synthesis and Applica-
tions; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: New York, 1995.
(5) For recent contributions, see: (a) Meng, H.; Kumar, K. J. Am. Chem.
Soc. 2007, 129, 15615–15622. (b) Chiu, H. P.; Suzuki, Y.; Gullickson, D.;
Ahmad, R.; Kokona, B.; Fairman, R.; Cheng, R. P. J. Am. Chem. Soc. 2006,
128, 15556–15557. (c) Lee, H. Y.; Lee, K. H.; Al-Hashimi, H. M.; Marsh,
E. N. G. J. Am. Chem. Soc. 2006, 128, 337–343.
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(7) For recent contributions, see: (a) Jakeman, D. L.; Ivory, A. J.; Blackburn,
G. M.; Wiliamson, M. P. J. Biol. Chem. 2003, 278, 10957–1962. (b) Boyle,
N. A.; Rajwanshi, V. K.; Prhavc, M.; Wang, G.; Fagan, P.; Chen, F.; Ewing,
G. J.; Brooks, J. L.; Hard, T.; Leeds, J. M.; Bruice, T. W.; Cook, P. D. J. Med.
Chem. 2005, 48, 2695–2700. (c) Dufresne, C.; Roy, P.; Wang, Z.; Asante-Appiah,
E.; Cromlish, W.; Boie, Y.; Forghani, F.; Desmarais, Q.; Wang, K.; Skorey, K.;
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Anderson, C. W. J. Biol. Chem. 2000, 275, 23199–23203. (e) Herczegh, P.;
Buxton, T. B.; McPherson, J. C.; Kova´cs-Kulyassa, A.; Brewer, P. D.; Sztaricskai,
F.; Stroebel, G. G.; Plowman, K. M.; Farcasiu, D.; Hartmann, J. F. J. Med.
Chem. 2002, 45, 2338–2341.
(1) For reviews see: (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem.
ReV. 2005, 105, 899–931. (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; pp 277-317.
(2) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim,
2004. (b) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan, S.,
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Bioorganic Chemistry; Welch, J. T., Ed.; American Chemical Society: Wash-
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4568 J. Org. Chem. 2008, 73, 4568–4574
10.1021/jo8005667 CCC: $40.75 2008 American Chemical Society
Published on Web 05/20/2008

Fluoroalkylated ꢀ-Aminophosphonates and Pyridines
of enzymes ligands for phosphoglycerate kinase,7a–c catalytic
antibodies, 7d or antibacterials7e but also for the preparation of
fluorinated peptidomimetics.8 However, only the addition of
amines7e or ammonia9 to unsaturated phosphonates, the addition
of fluorinated phosphonate carbanions to N-protected R-haloa-
mines10a or imines,10b–e or the ring opening of fluorinated
aziridines11 for the synthesis of fluorine-substituted aminophos-
phonates have been described.
SCHEME 1. Synthetic Strategy for Preparation of
ꢀ-Aminophosphonates and Pyridines from
ꢀ-Enaminophosphonates
Moreover, enamines have attracted a great deal of attention
in recent years because of their range of applications,12,13 and
especially metaloenamines,14 carbanions derived from enamines
or enolizable imines, are useful substrates for the regio- and
stereoselective carbon-carbon bond formation reaction with
electrophilic reagents.15,16 However, primary enamines, despite
their potential interest as synthons in organic synthesis for the
preparation of acyclic and cyclic derivatives, have been less
studied, given that they are unstable unless conjugated with an
electron-withdrawing group on the ꢀ-carbon atom.17 In con-
nection with our interest in the preparation of three-,18 five-,19
and six-membered20 phosphorus-substituted nitrogen hetero-
cycles, we described the synthesis of stable primary enamines
derived from phosphonates21a and carboxylates21b as well as
their synthetic use for the preparation of functionalized acyclic
compounds,22a aminophosphonate derivatives,22b and phos-
phorus-containing heterocycles.23 In this context, we reported
the first synthesis of fluorinated primary enamine phosphonates
by reaction of alkylphosphonates I with fluoroalkyl nitriles II
(see Scheme 1)24 and the synthetic application of these
intermediates as starting material for the preparation of acyclic
fluoroalkyl nitrogenated derivatives.25 However, for preparative
purposes, the use of perfluoroalkylated nitriles has two draw-
backs for the preparation of enamines III in a multigram scale:
the price (availability) of the nitriles and the fact that the low
members (C2, C3) are gases with problems for the control of
the stoichiometry of the reaction.
Phosphorus substituents could regulate important biological
functions and increase biological activity, in a way similar to
that reported for pharmaceuticals.26 Therefore, continuing with
our interest in the chemistry of amino phosphorus derivatives1
and in the design of new phosphorus scaffolds, in this case also
containing fluoroalkyl substituents, we report here new alterna-
tives for the selective synthesis of primary ꢀ-enaminophospho-
nates containing fluoroalkyl substituents in the ꢀ position III
(Scheme 1) from easily available starting materials, as well as
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Gvozdovska, N.; Belik, M.; Sorochinsky, A. Tetrahedron Lett. 2004, 45, 6665–
6667. (c) Sergeeva, N. N.; Golubev, A. S.; Henning, L.; Burger, K. Synthesis
2003, 915–919. (d) Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard, J.
Tetrahedron 1996, 52, 165–176. (e) Xiao, J.; Yuan, C. Heteroat. Chem. 2000,
11, 541–545.
(11) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem.
2006, 71, 6141–6148.
(12) For an excellent review see: Rappoport, Z. The Chemistry of Enamines.
The Chemistry of Functional Groups; Patai, S., Rappoport, Z., Eds.; J. Wiley:
Chichester, 1994.
(13) For recent reviews, see: (a) Stanovnik, B.; Svete, J. Chem. ReV. 2004,
104, 2433–2480. (b) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975–
978. (c) Elassar, A. Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463–8480.
(14) For reviews see: (a) Shatzmiller, S.; Lidor, R. In reference 12, Part 2,
1994, pp 1507-1533. (b) Martin S. F. ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 475.
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11283. (b) Stork, G. Med. Res. ReV. 1999, 19, 370–387. (c) Cuvigny, T.; Normant,
H. Synthesis 1977, 198–200. (d) Stork, G.; Brizzolarra, A.; Landesman, H.;
Szmuszkovicz, J.; Terrele, R. J. Am. Chem. Soc. 1963, 85, 207–222.
(16) (a) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E.; Ferna´ndez, A.
Tetrahedron 2001, 57, 3131–3141. (b) Palacios, F.; Aparicio, D.; Garc´ıa, J.;
Vicario, J.; Ezpeleta, J. M. Eur. J. Org. Chem. 2001, 3357–3365. (c) Palacios,
F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E. Eur. J. Org. Chem. 1998, 1413–
1423. (d) Palacios, F.; Aparicio, D.; Garc´ıa, J. Tetrahedron 1996, 52, 9609–
9628.
(20) (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.; Aparicio,
D.; Lo´pez, Y.; de los Santos, J. M.; Alonso, C. Eur. J. Org. Chem. 2005, 1142–
1147. (c) Palacios, F.; Herran, E.; Rubiales, G.; Ezpeleta, J. M. J. Org. Chem.
2002, 67, 2131. (d) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Lopez de
Munain, R. Org. Lett. 2002, 4, 2405–2508. (e) Palacios, F.; Ochoa de Retana,
A. M.; Oyarzabal, J. Tetrahedron 1999, 55, 5947–5964.
(21) (a) Palacios, F.; Oyarzabal, J.; Ochoa de Retana, A. M. Tetrahedron
Lett. 1996, 37, 4577–4580. (b) Palacios, F.; Vicario, J.; Aparicio, D. J. Org.
Chem. 2006, 71, 7690–7696.
(17) (a) Novak, B. M.; Cafmayer, J. J. Am. Chem. Soc. 2001, 123, 11083–
11084. (b) Erker, G.; Riedel, M.; Koch, S.; Jo¨edicke, T.; Wu¨rthwein, E. U. J.
Org. Chem. 1995, 60, 5284–5290.
(22) (a) Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405–5408. (b) Palacios,
F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org. Chem. 2007, 72, 2682–
2685.
(18) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem.
2005, 70, 8895–8901. (b) 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. (c) 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–
7288. (d) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta, J. M. J.
Org. Chem. 2000, 65, 3213–3217.
(23) (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Lopez de Munain,
R.; Oyarzabal, J.; Ezpeleta, J. M. Tetrahedron 2005, 61, 1087–1094. (b) Palacios,
F.; Ochoa de Retana, A. M.; Pascual, S.; Lopez de Munain, R. Tetrahedron
Lett. 2002, 43, 5917–5919. (c) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal,
J. Tetrahedron 1999, 55, 3091–3104.
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Lett. 2002, 4, 769–772.
(19) (a) de los Santos, J. M.; Aparicio, D.; Lo´pez, Y.; Palacios, F. J. Org.
Chem. 2008, 73, 550–557. (b) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos,
J. M.; Ezpeleta, J. M. Tetrahedron 2006, 62, 1095–1101. (c) Palacios, F.;
Aparicio, D.; Vicario, J. Eur. J. Org. Chem. 2005, 2843–2850. (d) Palacios, F.;
Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M. Tetrahedron 2004, 60, 8937–
8947.
(25) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J. J. Org.
Chem. 2004, 69, 8767–8774.
(26) (a) Toy, A. D. F.; Walsh, E. N. Phosphorus Chemistry in EVeryday
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Organophosphorus Chemistry; Engel, R., Ed.; M. Dekker: New York, 1992.
J. Org. Chem. Vol. 73, No. 12, 2008 4569

Palacios et al.
yield (%)a
TABLE 2. ꢀ-Enaminophosphonates 6 Obtained
SCHEME 2. Synthesis of Ketones 3 and Enamines 6
entry
compound
R1
RF
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
H
H
H
H
CF3
74
C2F5
C7F15
CHF2
CH2F
CF3
CHF2
CH2F
C2F5
71(70)b
49
72
H
61(77)b
70
CH3
CH3
CH3
CH3
6gc
6he
6i
67(51)d
67
72f
a Yield of isolated purified compounds from ketones 3 and AcONH4.
b Yield of isolated purified compounds from ketones
3 and NH3.
c Obtained as a mixture of Z/E isomers (75:25) and determined by 31P
NMR. d Yield obtained from 6d. e Obtained as a mixture of Z/E isomers
(57:43) and determined by 31P NMR. f Yield obtained from 6b.
also explored, since this process represents one of the best
alternatives for the selective construction of carbon-nitrogen
bonds and has been used for the preparation of 1-22 and
2-azadienes.20c Treatment of ꢀ-keto phosphonate 3a with
N-trimethylsilyl phosphazene 4 gave silylated enamine 5′a.
However, this compound is unstable, and after distillation or
chromatography enamine 6a (R1 ) H, RF ) CF3) was obtained.
The process can be explained by initial construction of the CdN
double bond with formation of imine 5, followed by prototropic
tautomerie and C-Si bond cleavage of enamine 5′a in the
reaction conditions.
Next we accomplished the synthesis of ꢀ-enaminophospho-
nates or ꢀ-dehydroaminophosphonates 6 by condensation of
ammonia gas with ꢀ-keto phosphonates 3. Ammonia was
bubbled through a solution of 1 mmol of ꢀ-keto phosphonates
3b (R1 ) H, RF ) C2F5) and 3e (R1 ) H, RF ) CH2F) in
toluene, and after 7-8 h this led to the formation of enamines
6b and 6e (Scheme 2, Table 2, entries 2 and 5). However, when
the reaction was extended to a multigram scale, the reaction
times were very long and a large amount of starting material
did not react. This disadvantage was overcome by using
ammonium acetate29 instead of ammonia. Heating ammonium
acetate at 80 °C with ꢀ-keto phosphonates 3 (scale 25 mmol)
in the absence of solvent gave Z-enamines 6 in moderate or
good yields (Scheme 2, Table 2, entries 1-6). However, when
ꢀ-keto phosphonates 3d,e (R1 ) CH3, RF ) CHF2, CH2F) were
used, mixtures of Z- and E-enamines 6g,h are obtained in good
yields with a higher proportion of the Z isomer (Scheme 2, Table
2, entries 7 and 8). 13C-31P coupling constant (3JPC) in the range
of 4-10 Hz showing that the fluoro-substituted alkyl group (RF)
and the phosphorus atom in enamines 6 are cis related, and
values in the range of 24-35 Hz are trans related.30
TABLE 1. ꢀ-Keto Phosphonates 3
entry
compound
R1
RF
yield (%)a
1
2
3
4
5
6
7
8
9
3ab
3bb
3c
H
H
H
H
CF3
78
75
91
82
94
73
90
90
90
C2F5
C7F15
CHF2
CH2F
CF3
C2F5
CHF2
CH2F
3d
3e
H
3fb
3g
3h
3i
CH3
CH3
CH3
CH3
a Yield of isolated purified compounds. b Reference.11
their use as versatile tools for the formation of fluoro-containing
ꢀ-aminophosphonates IV and substituted pyridines V. Retrosyn-
thetically, we envisaged obtaining primary enamines III by
condensation reaction with ammonia or its synthetic equivalent
(“NH3”, Scheme 1) of ꢀ-keto phosphonates VI, and these
phosphonates VI can be easily prepared by simple addition of
fluoroalkyl esters VII to metallated alkyl phosphonates I.11
Results and Discussion
Synthesis of (Z)-Primary ꢀ-Enaminophosphonates 6. The
ꢀ-keto phosphonates required were prepared by reaction of
diethyl methylphosphonates 1 (R1 ) H, CH3) with perfluoroalkyl
carboxylates 2 (RF ) CF3, C2F5, C7F15), ethyl 2,2-difluoromethyl
acetate 2 (RF ) CHF2), or ethyl 2-fluoromethyl acetate 2 (RF
) CH2F) in the presence of LDA or BuLi in an inert atmosphere,
which after workup gave fluorine-substituted ꢀ-keto phospho-
nates 3a-3i in a good yield (Scheme 2, Table 1, entries 1-
9).27 Therefore, the scope of the process was not restricted to
perfluoroalkyl carboxylates, given that R′,R′-difluoro- or R′-
monofluoro ꢀ-keto phosphonates 3 can also be prepared.
The synthesis of enamines by aza-Wittig reaction28 of
N-trimethylsilyl phosphazene 4 with ꢀ-keto phosphonates 3 was
This process cannot be used for the synthesis of ꢀ-enami-
nophosphonate 6i (R1 ) CH3, RF ) C2F5) by condensation of
ꢀ-keto phosphonate 3f (R1 ) CH3, RF ) C2F5) either with
ammonia or with ammonium acetate; the starting keto phos-
phonate 3f was recovered. Therefore, an alternative strategy was
developed for the preparation of R-methyl-substituted enamines
6 (R1 ) Me) by methylation reaction of metallated enamines 6
(R1 ) H). The reaction of enamines 6b,d (R1 ) H) with methyl
(28) For reviews see: (a) Palacios, F.; Aparicio, D.; Rubiales, G.; Alonso,
C.; de los Santos, J. M. Tetrahedron 2007, 3, 523–575. (b) Fresneda, M. P.;
Molina, P. Synlett 2004, 1–17. (c) Barluenga, J.; Palacios, F. Org. Prep. Proced.
Int. 1991, 23, 1–59.
(29) (a) Pe´vet, I.; Meyer, C.; Cossy, J. Synlett 2003, 663–666. (b) Baraldi,
P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902–905.
(27) Fluorinated ꢀ-keto phosphonates 3, initially formed, can undergo addition
of water to provide the hydrate form. The use of high vacuum allows one to
dehydrate the gem-diol to recover ꢀ-keto phosphonates 3.11
(30) (a) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron 1994,
50, 12727. (b) Duncan, M.; Gallager, M. J. Org. Magn. Reson. 1981, 15, 37.
4570 J. Org. Chem. Vol. 73, No. 12, 2008

Fluoroalkylated ꢀ-Aminophosphonates and Pyridines
TABLE 3. ꢀ-Aminophosphonates 7 Obtained by Reduction of
ꢀ-Enaminophosphonates 6 (R1 ) H)
SCHEME 3. Preparation of Fluorinated
ꢀ-Aminophosphonates 7 and 8
entry
compound
RF
yield (%)a
1
2
3
4
5
7ab
7b
7c
CF3
67c
68c
61c
64c
79d
CHF2
CH2F
C2F5
C7F15
76d
7db
7e
75d
87d
a Yield of isolated purified compounds from enamines 6. b References
9 and 11. c Procedure A (ZnCl2-NaBH3CN/MeOH) d Procedure B (H2
(80 psi)) and Pd/C, MeOH).
TABLE 4. ꢀ-Aminophosphonates 8 Obtained by Reduction of
ꢀ-Enaminophosphonates 6 (R1 ) CH3)
entry compound
RF
syn/anti 8 ratioa procedure yield (%)b
iodide in the presence of BuLi gave fluorine-substituted R-meth-
yl enamines 6g,i (R1 ) CH3) after workup (Scheme 2, Table 2,
entries 7 and 9).
1
2
3
4
5
6
7
8a
8a
8b
8b
8c
8d
8d
CF3
CF3
35/65
100/0
15/85
70/30
22/78
25/75
90/10
Ac
Bd
Ac
Bd
Ac
Ac
Bd
62
75
65
69
65
59
71
CHF2
CHF2
CH2F
C2F5
C2F5
Reduction of ꢀ-Enaminophosphonates or ꢀ-Dehydroamino-
phosphonates 6. Synthesis of Fluoroalkylated ꢀ-Aminophos-
phonates. Aminophosphorus derivatives31 in general, even those
containing fluorine substituents,6 and ꢀ-amino compounds in
particular1,32 have acquired increased interest in recent years
because of their application in organic and medicinal chemistry.
For this reason we tried to study the use of phosphorylated
enamines containing fluoroalkyl substituents for the preparation
of fluorinated ꢀ-aminophosphorus derivatives. Reduction of R-
and ꢀ-dehydroamino acid derivatives is an excellent tool for
the stereoselective preparation of R-22a,33 and ꢀ-amino acids.34
Therefore, we explored whether the reduction of isosteric
ꢀ-dehydroaminophosphonates 6 obtained here (vide supra) could
be used to obtain fluoroalkyl-substituted ꢀ-aminophosphonates.
For this objective, we thought that the use of hydrides for
the reduction of enaminophosphonates 6 could be appropriate.
Initially, NaBH4 in THF/H2O was used, but the starting material
was recovered. Other reagents such as LiAlH4, NaBH[OC-
(O)CF3], Na/iPrOH, and BH3-pyridine were not effective for
the reduction of enamines 6. However, when the reduction of
enamine 6a (R1 ) H, RF ) CF3) was performed using ZnCl2
and NaBH3CN in refluxing MeOH (Procedure A) the corre-
sponding trifluoromethyl-substituted ꢀ-aminophosphonate 7a
(Scheme 3, Table 3, Entry 1) was obtained. The reaction was
extended to difluoromethyl (R1 ) H, RF ) CHF2), monofluo-
romethyl (R1 ) H, RF ) CH2F), and pentafluoroethyl (R1 ) H,
RF ) C2F5) enamines 6, and the corresponding fluorinated
ꢀ-aminophosphonate 7b-d (Scheme 3, Table 3, entries 2-4)
a Determined by 31P NMR. b Yield of isolated purified compounds
from enamines. c Procedure A (ZnCl2-NaBH3CN/MeOH). d Procedure
B (H2 (80 psi) and Pd/C, MeOH).
FIGURE 1. Felkin-Anh approach. Preferred addition of hydride to
enamines 6.
were prepared. Spectroscopic data are in agreement with the
proposed structure for compounds 7.
This reduction reaction was extended to R-methyl-substituted
enamines 6 (R1 ) Me), and when these enamines 6 were treated
with ZnCl2 and NaBH3CN in refluxing MeOH (Procedure A),
the corresponding trifluoromethyl 8a (RF ) CF3), difluoromethyl
8b (RF ) CHF2), monofluoromethyl 8c (RF ) CH2F), and
pentafluoroethyl 8d (RF ) C2F5) ꢀ-aminophosphonates were
obtained as a mixture of two diastereoisomers, with a higher
proportion of the anti isomer (Scheme 3, Table 4, entries 1, 3,
5, 6). Very small vicinal coupling constants (3JHH) between 0-5
Hz are characteristic of the syn isomers, and higher values (7-12
Hz) for the anti isomers.35
The stereochemical outcome to the higher proportion of anti
isomers in this reduction reaction of R-methyl-substituted
enamines 6 (R1 ) Me) can be explained by the Felkin-Anh
approach,36 in which the ZnCl2 coordinates to the nitrogen imino
group (Figure 1).37 The hydride then attacks the imino double
bond from the face opposite to the phosphonate group.
(31) For reviews, see: (a) Berrlicki, L.; Kafarski, P. Curr. Org. Chem. 2005,
9, 1829–1850. (b) Kafarski, P.; Lejczak, B. Curr. Med. Chem. Anti-Cancer Agents
2001, 1, 301–312. (c) Aminophosphonic and Aminophosphinic Acids. Chemistry
and Biological ActiVity; Kukhar, V. P., Hudson, H. R., Eds.; Wiley: Chichester,
2000.
(32) For a review of ꢀ-phosphapeptidomimetics, see:(a) Palacios, F.; Alonso,
C.; de los Santos, J. M. Curr. Org. Chem. 2004, 8, 1491–1496.
(33) For recent contributions to hydrogenation of R-dehydroamino acid
derivatives, see: (a) Giacomina, F.; Meetsma, A.; Panella, L.; Lefort, L.; de Vries,
A. H. M.; de Vries, J. C. Angew- Chem. Int. Ed. 2007, 46, 1497–1500. (b) Zhang,
W.; Zhang, X. J. Org. Chem. 2007, 72, 31020–1030. (c) Zheng, Q. H.; Hu,
X. P.; Duan, Z. C.; Liang, X. M.; Zheng, Z. J. Org. Chem. 2006, 71, 393–396.
(34) For recent contributions to reduction of ꢀ-dehydroamino acid derivatives,
see: (a) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem.
Res. 2007, 40, 1267–1267. (b) Ikemoto, N.; Tellers, D. M.; Dreher, S. D.; Liu,
J.; Huang, A.; Rivera, N. R.; Njolito, E.; Hsiao, Y.; McWillams, J. C.; Williams,
J. M.; Armstrong, J. D.; Sun, Y.; Mathre, D. J.; Grabowski, E. J. J.; Tllyer,
R. D. J. Am. Chem. Soc. 2004, 126, 3048–3049. (c) Pen˜a, D.; Minnaard, A. J.;
de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552–14553. (d)
David, O.; Blot, J.; Bellec, C.; Fargeau-Bellassoued, M.-C.; Haviari, G.; Ce´lerier;
J. P.; Llommet, G.; Gramain, J. C.; Gardette, D. J. Org. Chem. 1999, 64, 3122–
3131.
(35) (a) Gaudemar, A.; Golfrer, M.; Mandelbaum, A.; Parthasarathy, R.
Determination of Configutration by Spectroscopic Methods; Kaganv H, B., Ed.;
G. Thieme: Stuttgart, 1977; Vol. 1, p 39. (b) Haasnoot, C. A. G.; de Leeuw,
F. A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783–2792.
(36) (a) Che´rest, M.; Felfin, H.; Prudent, N. Tetrahedron Lett. 1968, 9, 2199–
2204. (b) Anh, N. T. Top. Curr. Chem. 1980, 88, 145–162.
(37) The more favorable conformation involves the phosphonate group being
placed in a perpendicular position to the imino group while the bulky group, in
our case the methyl group, occupies the remote position from the fluorine
susbstituted group.
J. Org. Chem. Vol. 73, No. 12, 2008 4571

Palacios et al.
SCHEME 4. Synthesis of Fluorine-Containing Pyridine
To test whether the minor isomer (syn) could be obtained in
a selective fashion, we explored the catalytic hydrogenation of
these substrates 6. Better yields were obtained when the
reduction of enamines 6 was accomplished by catalytic hydro-
genation with palladium. Catalytic hydrogenation of enamines
6 (R1 ) H) with hydrogen (80 psi) and palladium on carbon in
methanol (Procedure B) gave ꢀ-aminophosphonates 7 (Scheme
3, Table 3, entries 1, 2, 4, 5). This reduction reaction was also
extended to R-methyl-substituted enamines 6 (R1 ) Me). When
enamine 6a (RF ) CF3) was treated with hydrogen (80 psi)
and palladium on carbon in methanol (Procedure B), only the
corresponding syn-trifluoromethyl ꢀ-aminophosphonates 8a (RF
) CF3) was obtained (Scheme 3, Table 4, entry 2). However,
in these reaction conditions (Procedure B) a small proportion
of anti isomer (syn/anti ratio 90/10) of pentafluoroethyl ꢀ-ami-
nophosphonate 8d (RF ) C2F5) was obtained (Scheme 3, Table
4, entry 7), whereas when a mixture of Z/E (75/25) enamine 6g
(RF ) CHF2) was used, the corresponding R-difluoromethyl
ꢀ-aminophosphonate 8b (RF ) CHF2) was obtained (Scheme
3, Table 4, entry 4), as a mixture of two diastereoisomers (syn/
anti ratio 70/30).
Derivatives 10
TABLE 5. ꢀ-Fluorinated Pyridines 10 Obtained
The suprafacial (syn) addition of hydrogen is the most
accepted mechanism for metal-catalyzed hydrogenations, in
which the reaction occurs between species that are adsorbed
onto the surface (LangmuirsHinshelwood mechanism).38 How-
ever, the presence of a small proportion of the anti isomer can
be explained by means of a carbon-carbon double bond
isomerization due to the interaction of the metal (Pd) in an
addition-elimination sequence.39,34d The preparation of some
perfluoroalkyl-substituted ꢀ-aminophosphonate derivatives such
as 7a and 7b has been reported.9,10e,11 However, as far as we
know, this strategy reports the first synthesis of ꢀ-trifluoro-
methyl- (8a), ꢀ-difluoromethyl- (7b, 8b), ꢀ-monofluoromethyl-
(7c, 8c), perfluoroethyl- (8d), and perfluorohepthyl (7e)-
substituted ꢀ-aminophosphonate derivatives. These new fluori-
nated aminophosphonates could be very interesting starting
materials for the preparation of new phosphapeptides containing
fluorine atoms.
Reaction of Enamines with r,ꢀ-Unsaturated Ketones.
Synthesis of Fluorinated Pyridines. Fluorine-containing het-
erocycles in general4a and pyridines in particular have acquired
increased interest in chemistry.40 For this reason we tried to
explore if phosphorylated enamines containing fluoroalkyl
substituents 6 could be used for the preparation of fluorinated
pyridine derivatives. Heating fluorine-containing enamines 6 (R
) H, CH3, RF ) CF3, C2F5) with fluorinated R,ꢀ-unsaturated
ketones25 9 (RF ) CF3, C2F5) at high temperature (100-130
°C) and in the absence of solvent gave only one isomer of
polysubstituted pyridines 10 containing two fluoroalkyl groups
in position 2 and 6 in a regioselective fashion and moderate
yields (Scheme 4, Table 5, entries 1-8). The formation of these
pyridines 10 could be explained through a Michael addition of
enamine phosphonate 6 to the unsaturated ketones 9 (1,4-
addition) followed by cyclization of adduct 11 and aromatization
of cyclic compound 12.
a Yield of isolated purified compounds from enamines.
Finally, we explored the reaction of metalo-enamines derived
from fluorinated enamines 6 with 1,3-diphenyl-2-propen-1-one
13, in order to test if the increase of the nucleophilic character
of enamine could modify the reactivity toward unsaturated
ketones. Reaction of primary enamines 6 with butyllithium,
followed by the addition of 1,3-diphenyl-2-propen-1-one 13,
gave fluorine-substituted pyridines 14 in a regioselective fashion
(Scheme 5, Table 5, entries 9-11). It is noteworthy that, on
the basis of spectroscopic data, the loss of a fluorine atom seems
to take place during the formation of these pyridines 14. The
regioselective synthesis of these pyridines 14 could be explained
through an addition of metallated enamine phosphonate to the
unsaturated ketone 13 (1,2-addition) followed by cyclization,
elimination of HF from heterocycles 16 with formation of 17,
followed by prototropic rearrangement to give pyridines 14.
Some methods of synthesis of fluorinated pyridines has been
reported.41 However, as far as we know, this strategy reports
(38) Smith, G. V.; Notheisz, F. Heterogeneous Catalysis in Organic
Chemistry; Academic Press: New York, 1999.
(39) Siegel, S. ComprehensiVe Organic Synthesis; Pergamon Press: Oxford,
1991; Vol. 8, p 417.
(40) For reviews, see: (a) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–
1029. (b) Bo¨hm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller,
K.; Obst-Sander, U.; Sttahl, M. ChemBioChem. 2004, 5, 637–643. (c) Jeschke,
P. ChemBioChem 2004, 5, 570–589.
4572 J. Org. Chem. Vol. 73, No. 12, 2008

Fluoroalkylated ꢀ-Aminophosphonates and Pyridines
SCHEME 5. Preparation of Pyridines 14
crude product was purified by vacuum distillation or by chroma-
tography using silica gel eluting with 2:1 hexane/ethyl acetate to
afford ꢀ-keto phosphonates 3.
the first synthesis of polysubstituted pyridines containing two
fluoroalkyl groups 10 and fluorinated pyridines 14.
Diethyl 3,3-Difluoro-2-oxopropylphosphonate 3d. Obtained as
a colorless oil as described in the general procedure (9.43 g, 82%):
Conclusion
bp 70-72 °C (10-1 Torr); IR (NaCl) νmax 1751, 1216, 1052 cm-1
;
In conclusion, this account describes a simple, mild, and
convenient strategy for the preparation of ꢀ-trifluoromethyl-,
ꢀ-difluoromethyl-, ꢀ-monofluoromethyl-, perfluoroethyl-, and
perfluorohepthyl-substituted ꢀ-aminophosphonate derivatives by
reduction of ꢀ-dehydroaminophosphonates. Reduction with
sodium cyanborohydride in the presence of zinc chloride of CR-
methyl-substituted enamines gives anti ꢀ-aminophosphonates
as major products, whereas the catalytic hydrogenation leads
mainly to the formation of syn ꢀ-aminophosphonates. These
new fluorinated aminophosphonates could be very interesting
starting materials for the preparation of new phosphapeptides
containing fluorine atoms, in which the fluoroalkyl substituents
could stabilize the corresponding biologically active peptides
or proteins.5 Likewise, the regioselective synthesis of fluorine-
containing pyridines from enaminophosphonates and unsaturated
ketones is also described. Substituted fluorinated pyridines40 as
well as ꢀ-amino phosphonate derivatives1,32 are important
building blocks in organic synthesis and in the preparation of
biologically active compounds of interest in medicinal chemistry.
1H NMR (CD3OD) δ 1.14 (m, 6H), 3.13 (d, 2JPH ) 22.6 Hz, 2H),
3.97 (m, 4H), 5.71 (t, 2JFH ) 53.7 Hz, 1H) ppm; 13C NMR (CD3OD)
1
1
δ 14.8, 35.5 (d, JPC ) 130.4 Hz), 61.7, 108.2 (t, JFC ) 250.3
Hz), 190.6 (dt, JPC ) 7.0 Hz, JFC ) 26.2 Hz) ppm; 31P NMR
2
2
2
(CDCl3) δ 17,4 ppm ; 19F NMR (CD3OD) δ -129.5 (d, JFH
)
53.4 Hz) ppm; MS (EI) m/z 230 (M+, 7). Anal. Calcd for
C7H13F2O4P: C, 36.53; H, 5.69. Found: C, 36.70; H, 5.55.
Aza-Wittig Reaction of ꢀ-Keto Phosphonate 3a with N-
Trimethylsilyl Phosphazene 4. To a solution of N-trimethylsilyl
phosphazene 4 (1.74 g, 5mmol) in THF (15 mL) was added a
solution of ꢀ-keto phosphonate 3a (1.24 g, 5 mmol) in THF (10
mL) at room temperature under nitrogen atmosphere. The mixture
was stirred for 3 h at the same temperature. After the reaction was
completed, the solvent was evaporated under vacuum to afford the
silylated enamine 5′a. However, this compound was unstable and
by distillation or by chromatography enamine 6a was obtained. Mp
63-65 °C. For spectroscopic data see ref 25.
General Procedure for the Synthesis of Fluorinated Primary
ꢀ-Enaminophosphonates 6. General Procedure A. Ammonia was
bubbled through a solution of corresponding ꢀ-keto phosphonate
3 (1 mmol) in toluene (10 mL) at 100 °C until TLC showed the
disappearance of ketone 3 (4-8 h). Then, the solvent was
evaporated under vacuum, and the crude product was purified by
chromatography using silica gel (hexane/ethyl acetate).
General Procedure B. Ammonium acetate (75 mmol) was
heated at 80 °C under vacuum, and the corresponding ꢀ-phospho-
rylated ketone 3 (25 mmol) was added. The mixture was stirred at
100 °C, under vacuum, and in the absence of solvent until TLC
showed the disappearance of the ꢀ-phosphorilated ketone 3 (1-2
h). Then, a saturated solution of NaCO3 (50 mL) was added, and
the organic layer was extracted with CH2Cl2 (3 × 50 mL). The
organic layer was dried over anhydrous MgSO4 and filtered and
the solvent was evaporated under vacuum. The crude product was
purified by chromatography using silica gel (hexane/ethyl acetate).
General Procedure C. Butyllithium (1.6 M in hexanes) (25
mmol) was added to a solution of R-unsubstituted fluorinated
enaminophosphonate 6 (R1 ) H) (25 mmol) in THF (75 mL) at 0
°C and under N2 atmosphere. The mixture was stirred for 1 h at
the same temperature. Then, methyl iodide (1.6 mL, 25 mmol) was
added, and the reaction was stirred at room temperature until TLC
Experimental Section
General Procedure for the Synthesis of ꢀ-Keto Phosphonates
3. To a solution of LDA (6 mmol) in THF (25 mL) was added a
solution of alkylphosphonate 1 (5 mmol) in THF (15 mL) cooled
at -78 °C under nitrogen atmosphere. The mixture was stirred for
1 h at -78 °C, a solution of the corresponding ester was added (6
mmol) in THF (12 mL) at the same temperature, and the mixture
was stirred for 1 h and then allowed to warm at 0 °C. After the
reaction was complete, the solvent was evaporated under vacuum.
The crude residue was treated with HCl to 10% (5 mL) during 30
min. The crude reaction was extracted three times with CH2Cl2 (3
× 15 mL). The organic layer was dried over anhydrous MgSO4
and filtered and the solvent was evaporated under vacuum. The
(41) For recent contributions, see: (a) Sosnovskikh, V. Y.; Irgashev, R. A.;
Khalymbadzha, I. A.; Slepukhin, P. A. Tetrahedron Lett. 2007, 48, 6297–6300.
(b) Nenajdenko, V. G.; Druzhinin, S. V.; Belenkova, E. S. J. Fluorine Chem.
2006, 127, 865–873. (c) Palacios, F.; Alonso, C.; Rodriguez, M.; Martinez de
Marigorta, E.; Rubiales, G. Eur. J. Org. Chem. 2005, 1795–1804. (d) Cottet, F.;
Schlosser, M. Eur. J. Org. Chem. 2002, 327–330.
J. Org. Chem. Vol. 73, No. 12, 2008 4573

Palacios et al.
31
showed the disappearance of the enaminophosphonate 6. A saturated
solution of ammonium chloride (50 mL) was added, the organic
layer was extracted with CH2Cl2 (3 × 50 mL), dried over anhydrous
MgSO4, and filtered, and the solvent was evaporated under vacuum.
The crude product was purified by chromatography using silica gel
(hexane/ethyl acetate).
Hz); P NMR (CDCl ) δ 30.7 ; 19F NMR (CDCl3) δ -76.1(d,
3
3JFH ) 3.63 Hz). anti-8a: Rf 0.15 (ethyl acetate); IR (NaCl) ν
max
3390, 2959, 1732, 1454, 1116 cm-1; 1H NMR (CDCl3) δ 1.22 (d,
3JHH ) 7.6 Hz, 3H), 1.27 (m, 6H), 1.78 (sa, 2H), 2.10 (m, 1H),
3.29 (m, 1H), 4.11 (m, 4H); 13C NMR (CDCl 3) δ 12,2, 16.2, 33.2
(d, 1J PC ) 143.0 Hz), 55.2(q, 2JFC ) 28.7 Hz), 62.0, 125.9 (dq, 1J
3
31
(Z)-Diethyl 2-Amino-3,3-difluoro-1-propenylphosphonate 6d.
Obtained as a red solid as described in the general procedure B
from diethyl 3,3-difluoro-2-oxopropylphosphonate 3d and am-
monium acetate (4.12 g, 72%): mp 70-71 °C; IR (KBr) νmax 3409,
) 282.5 Hz, JPC ) 16.6 Hz); P NMR (CDCl ) δ 29.9 ; 19F
FC
3
NMR (CDCl3) δ -74.6(d, 3JFH ) 7.63 Hz); MS (EI) m/z 264 (M+
+ 1, 2). Anal. Calcd for C8H 17F3NO3P:C, 36.51; H, 6.51; N, 5.32.
Found: C, 36.76; H, 6.42; N, 5.46.
1
3316, 1653, 1224, 1049 cm-1; H NMR (CDCl3) δ 1.27 (m, 6H),
General Procedure for the Synthesis of Fluorinated Py-
ridines 10. A mixture of the corresponding fluorinated enamino-
phosphonate 6 (2 mmol) and fluorinated R,ꢀ-unsaturated ketones25
9 (2 mmol) in the absence of solvent was stirred at 100-130 °C
under nitrogen atmosphere, until TLC showed the disappearance
of fluorinated enaminophosphonate 6. The crude product was
purified by chromatography using silica gel (hexane/ethyl acetate).
2-p-Tolyl-2,6-bis(trifluoromethyl)pyridine 10a. Obtained as a
white solid as described in the general procedure (323 mg, 53%):
Rf 0.61 (hexane/ethyl acetate, 15/1); mp 56-57 °C; IR (KBr) νmax
4.00 (m, 4H), 4.11 (d, 2JPH ) 10.1 Hz, 1H), 5.69 (sa, 2H), 5.94 (t,
2JFH ) 55.2 Hz, 1H); 13C NMR (CDCl3) δ 15.6, 60.9, 74.7 (d, 1JPC
3
1
) 193.9 Hz), 111.6 (dt, JPC ) 27.7 Hz, JFC ) 216.0 Hz), 154.0
(t, JFC ) 22.1 Hz); 31P NMR (CDCl3) δ 23.0; 19F NMR (CDCl3)
2
δ -122.0 (d, JFH ) 54.9 Hz); MS (EI) m/z 229 (M+, 20). Anal.
2
Calcd for C7H14F2NO3P: C, 36.69; H, 6.16; N, 6.11. Found: C,
36.55; H, 6.25; N, 6.00.
General Procedure for the Synthesis of Fluoroalkylated
ꢀ-Aminophosphonates 7 and 8. General Procedure A. To a
solution of ZnCl2 (1 mmol) and NaBH3CN (2 mmol) in anhydrous
methanol (3 mL) was added a solution of the corresponding
fluorinated enaminophosphonate 6 (1 mmol) in anhydrous methanol
(3 mL) at room temperature under nitrogen atmosphere. The mixture
was heated at methanol reflux until TLC showed the disappearance
of the fluorinated enaminophosphonate 6 and then was allowed at
room temperature. A solution of NaOH 1 M (10 mL) was added,
the organic layer was extracted with Et2O (3 × 15 mL), washed
with saturated solution of NaCl, dried over anhydrous MgSO4, and
filtered, and the solvent was evaporated under vacuum. The crude
product was purified by chromatography using silica gel (ethyl
acetate).
3431, 1390, 1197, 1141 cm-1; H NMR (CDCl3) δ 2.37 (s, 3H),
1
7.29 (d, 3JHH ) 7.9 Hz, 2H), 7.52 (d, 3JHH ) 7.9 Hz, 2H), 8.01 (s,
2H); 13C NMR (CDCl3) δ 21.2, 121.0 (q, 1JFC ) 275.0 Hz), 120.5,
127.0, 130.4, 132.6, 141.3, 149.3 (q, JFC ) 35.2 Hz), 152.4; 19F
2
NMR (CDCl3) δ -68.6; MS (EI) m/z 305 (M+, 100). Anal. Calcd
for C14H9F6N: C, 55.09; H, 2.97; N, 4.59. Found: C, 54.80; H,
2.93; N, 4.55.
General Procedure for the Synthesis of Fluorinated Py-
ridines 14. Butyllithium (1.6 M in hexanes) (1.25 mL, 2 mmol)
was added to a solution of fluorinated enaminophosphonate 6 (2
mmol) in anhydrous THF (6 mL) at 0 °C and under N2 atmosphere.
The mixture was stirred for 1 h at the same temperature. Then, a
solution of 1, 3-diphenyl-2-propen-1-one 13 (2 mmol) in anhydrous
THF (6 mL) was added. The reaction was stirred at room
temperature or was heated at reflux until TLC showed the
disappearance of the fluorinated enaminophosphonate 6. Then, a
saturated solution of ammonium chloride (15 mL) was added, the
organic layer was extracted with Et2O (3 × 15 mL), dried over
anhydrous MgSO4, and filtered, and the solvent was evaporated
under vacuum. The crude product was purified by chromatography
using silica gel (hexane/ethyl acetate).
General Procedure B. To a solution of fluorinated enamino-
phosphonate 6 (1 mmol) and Pd/C (0.1 mmol) in anhydrous
methanol was applied 80 psi of hydrogen, and the reaction was
stirred until TLC showed the disappearance of the enamine 6
(48-72 h). Then the reaction was filtrated through celite, and the
solvent was evaporated under vacuum. The crude product was
purified by chromatography using silica gel (ethyl acetate).
Diethyl 2-Amino-3-fluoropropylphosphonate 7c. Obtained as
a pale yellow oil as described in the general procedure A (130 mg,
61%): Rf 0.20 (ethyl acetate/ methanol, 8/2); IR (NaCl) νmax 3400,
4,6-Diphenyl-2-difluoromethylpyridine 14a. Obtained as a
1
1607, 1442, 1391, 1225, 1025 cm-1; H NMR (CDCl3) δ 1.34 (t,
colorless oil as described in the general procedure (416 mg, 74%):
2
2
3JHH ) 7.1 Hz, 6H), 1.82 (ddd, JHH ) 15.3 Hz, JPH ) 17.5 Hz,
Rf 0.96 (ethyl acetate); IR (NaCl) νmax 3038, 2957, 1605, 1126 cm-1
;
3JHH ) 8.9 Hz, 1H), 1.98 (m, 1H), 2.01 (sa, 2H), 3.47 (m, 1H),
1H NMR (CDCl3) δ 6.78 (t, JFH ) 55.6 Hz, 1H), 7.43-8.17 (m,
12H); 13 C NMR (CDCl 3) δ 114.4 (t, 1JFC ) 241.2 Hz), 116.3 (d,
3JFC ) 2.5 Hz), 119.9, 128.8-129.7, 137.7, 138.4, 150.7, 153.3 (t,
2JFC ) 25.7 Hz), 157.8; 19F NMR (CDCl3) δ -115.6; MS (EI) m/z
281 (M+, 100). Anal. Calcd for C18H 13F2N: C, 76.87; H, 4.63; N,
4.98. Found: C, 76.94; H, 4.55; N, 4.90.
2
4.13 (m, 4H), 4.34 (m, 2H); 13C NMR (CDCl ) δ 16.7, 29.9 (dd,
3
1J ) 141.5 Hz, JFC ) 5.7 Hz), 47.1 (dd, JFC ) 20.7 Hz, JPC
3
2
2
PC
) 4.1 Hz), 62.1, 87.7 (dd, 1JFC ) 172.7 Hz, 3JPC ) 18.1 Hz); 31
P
NMR (CDCl ) δ 29.3 (d, JPF ) 3.2 Hz); 19F NMR (CDCl3) δ
4
3
2
3
4
-226.1 (ddt, JFH ) 47.3 Hz, JFH ) 16.8 Hz, JPF ) 3.0 Hz);
HRMS (EI+) calcd for C7 H17FNO3P [M+] 213.0930, found M+
213.0925.
Acknowledgment. The authors thank The University of the
Basque Country (UPV, GIU 06/51) and the Direccio´n General
de Investigacio´n del Ministerio de Ciencia y Tecnolog´ıa
(MCYT, Madrid DGI, CTQ2006-09323) for supporting this
work.
syn/anti-Diethyl 2-Amino-3,3,3-trifluoro-1-methylpropylphos-
phonate 8a. Obtained as a mixture of syn/anti isomers (35:65) as
a pale yellow oil as described in the general procedure A (163 mg,
62%) or obtained as a mixture of syn/anti isomers (100:0) as a
pale yellow oil as described in the general procedure B (197 mg,
75%). Both isomers can be separated by chromatography using
silica gel. syn-8a: Rf 0.1 (ethyl acetate); IR (NaCl) νmax 3378, 3317,
Supporting Information Available: Experimental proce-
dures and characterization data (1H NMR, 13C NMR, 31P NMR,
IR, and elemental analysis) for compounds 3c-e,g-i, 6d,g-i,
7b,c,e, 8a-d, 10a-h, and 14a-c. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
3
1117, 1031 cm-1; H NMR (CDCl3) δ 1.11 (dd, JPH ) 18.8 Hz,
3
2
JHH ) 7.3 Hz, 3H), 1.20 (m, 6H), 1.57 (sa, 2H), 2.28 (ddq, JPH
) 23.6 Hz, 3JHH ) 7.3 Hz, 3JHH ) 1.8 Hz, 1H), 3.77 (ddq, 3JPH
13
)
C
3
3
11.9 Hz, JFH ) 8.2 Hz, JHH ) 1.8 Hz, 1H), 4.11 (m, 4H);
1
NMR (CDCl ) δ 6.6, 16.1, 31.1 (d, J
) 144.0 Hz), 51.8 (q,
) 282.0 Hz, JPC ) 25.7
3
PC
2JFC ) 29.0 Hz), 62.0, 126.0 (dq, J
JO8005667
1
3
FC
4574 J. Org. Chem. Vol. 73, No. 12, 2008