Stereoselective reduction and reductive dephosphonylation of β-iminophosphonates

Article abstract of DOI:10.1016/S0040-4039(02)00521-X

Proline-like 2,4-dialkyl-5-phosphonylpyrrolidines 2 were obtained stereoselectively by reduction of the corresponding β-iminophosphonates 1 with NaBH₄. The detailed characterization of compounds 2 was accomplished by ¹H and ¹³C NMR as well as by crystal structure analysis. When 1 was reduced with LiAlH₄ the reaction gave dephosphonylated pyrrolidines 3. The latter method is suitable for providing substituted pyrrolidines regioselectively. A possible mechanism for the dephosphonylation is proposed.

Full text of DOI:10.1016/S0040-4039(02)00521-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3761–3764
Stereoselective reduction and reductive dephosphonylation of
b-iminophosphonates
Mohamed Amedjkouha,* and Jacques Grimaldib
aOrganic Chemistry, Department of Chemistry, Go¨teborg University, S-412 96 Go¨teborg, Sweden
bStructure et Re´activite´ des Espe`ces Paramagne´tiques, CNRS UMR 6517-Chimie, Biologie et Radicaux Libres, Case 521,
Universite´ Aix-Marseille I et III, Centre St-Je´roˆme, Av. Esc. Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 1 June 2001; revised 5 March 2002; accepted 15 March 2002
Abstract—Proline-like 2,4-dialkyl-5-phosphonylpyrrolidines 2 were obtained stereoselectively by reduction of the corresponding
1
b-iminophosphonates 1 with NaBH4. The detailed characterization of compounds 2 was accomplished by H and 13C NMR as
well as by crystal structure analysis. When 1 was reduced with LiAlH4 the reaction gave dephosphonylated pyrrolidines 3. The
latter method is suitable for providing substituted pyrrolidines regioselectively. A possible mechanism for the dephosphonylation
is proposed. © 2002 Elsevier Science Ltd. All rights reserved.
Pyrrolidine derivatives are attractive synthetic targets1
because they occur in numerous biological compounds2
and some are pharmaceutically important.3 Substituted
pyrrolidines have been obtained by pyrrolidine con-
struction, e.g. photocyclization of N-chloramines,4
reductive amination of 1,4-diketones5 and metal-cata-
lyzed cyclizations.6 In continuation of our concept of
using stable free radicals, extensively developed in our
laboratories, we became interested in pyrrolidine
derived b-phosphonylated nitroxides. Nitroxide radicals
are becoming more important due to the need of mate-
rials which enjoy new or improved physical and chemi-
cal properties. After being used in ESR as spin probes,7
they have also been applied as contrast-enhancing
agents for magnetic resonance imaging.8 They also
found a successful application in the field of living free
radical polymerization.9 In line with this project and
taking aim at new pyrrolidines, we recently reported the
synthesis of b-allenyl aminophosphonates and their
cyclization into b-iminophosphonates 1.10
2,5-dialkylpyrrolines gave the cis-pyrrolidines with
DIBAL-H, while the trans-isomer is favored with
LAH/Me3Al. Hydrides such NaBH4 or NaBH3CN
afford less selectivity. Likewise, cis-pyrrolidines were
obtained by treatment of 3- and 4-ethoxycarboxy-1-
pyrrolines with NaBH4.13
On the other hand, b-functionalized phosphonates
undergo dephosphonylation upon reduction. Although
various methods and reagents14 have been used to
reduce a CꢀPV bond into a CꢀH bond, the known
chemical methods for CꢀPV cleavage are of limited
generality. Moreover, there is only one literature15 ref-
erence involving the CꢀP bond reduction of b-keto-1-
phosphonato esters. It was pointed out that there is no
general method for cleavage of the CꢀP bond in b-keto
phosphonates.16 Recently, dephosphonylation of b-keto
phosphonates with LiAlH4 has been reported.17 The
phosphonate was used as a temporary activating group.
On one hand, imine and iminium salts can be readily
reduced by metallic hydrides such as LiAlH4 or NaBH4
and its derivatives.11 Another consideration which must
be addressed involves the control of stereochemistry.
Indeed, reduction of substituted cyclic imines with
hydrides displays varying stereoselectivity, depending
both on the reagent and the substrate.12 For instance,
* Corresponding author. Tel.: +46-31-7722896; fax: +46-31-7723840;
e-mail: mohamed.amedjkouh@oc.chalmers.se
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00521-X

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M. Amedjkouh, J. Grimaldi / Tetrahedron Letters 43 (2002) 3761–3764
Nevertheless, the pyrroline 1c needed 6 equiv. of
NaBH4 for reduction and a reaction at room tempera-
ture to afford 70% conversion as shown by 31P NMR.
This difference in reactivity could arise from the steric
hindrance by the cyclohexyl group.
However b-iminophosphonates have not been investi-
gated. In this paper we wish to report our preliminary
results on the stereoselective reduction of b-iminophos-
phonates 1 with NaBH4 and on their unprecedented
reductive dephosphonylation (Scheme 1).
It is worth noting that the amount of NaBH4 used and
the temperature were both important. The highest con-
version rate (80%) was reached by using 0.5 equiv. of
NaBH4 at −20°C over 4 h.19 If the reaction was run for
longer the pyrrolidine undergoes dephosphonylation,
and with a larger amount of NaBH4 this decomposition
occurs much faster.
We first observed the dephosphonylation of b-
iminophosphonate 1b when reacted with NaBH4 using
the conditions described in the literature.13,18 This led to
complicated mixtures in which no product of type 2
could be detected. Although disappointing, the experi-
ments were repeated and the reaction was monitored by
31P NMR. It was gratifying to find that reduction had
occured. The 31P NMR chemical shift of the only
product formed was at l 27 ppm. However, this peak
tended to disappear and another peak appear at l 6.3
ppm, which corresponds to the diethylphosphite 31P
NMR chemical shift. The intermediate aminophospho-
nate 2b appeared to be extremely sensitive under the
reaction conditions. After several trials, under the
mildest conditions, we were able to isolate 2b which
was crystallized from pentane. Its structure was
unequivocally confirmed by spectroscopic and X-ray
methods as the cis-isomer 2b.10b Analysis of the mother
solution did not show any trans-isomer.
31P NMR analysis showed that complete dephosphonyl-
ation is reached after 8 h leading to complicated mix-
tures. In contrast, after their crystallization, the
aminophosphonates 2 are stable in nonpolar solvents as
well as in crystalline form (Table 1).
In contrast to NaBH4, reaction with LiAlH4 did not
afford compounds 2. Although the starting materials
were completely consumed on reaction of b-iminophos-
20
phonates 1 with LiAlH4 in THF, complicated mix-
tures resulted. Purification by chromatography yielded
pyrrolidines 3 as a mixture of stereoisomers in a 1:1
ratio (Table 1), along with side products which could
not be identified. Thus, b-iminophosphonates 1 were
dephosphonylated by reaction with 3 equiv. of LiAlH4
in THF at 20°C for 1 h and then quenching with a 4N
NaOH aqueous solution (Scheme 3). Additionally, the
reaction with the nucleophilic L-Selectride (tri-sec-
butylborohydride) produced 2a as the sole product. In
the case of the electrophilic 9-BBN, 2a was obtained
along with a small amount of 3a. No significant change
was noticed upon further addition of 9-BBN. It has
Keeping in mind that NaBH4 is a small reducing
reagent, one could expect that coordination of the
sodium of the NaBH4 by the phosphonyl oxygen could
direct hydride addition to the imine and give the trans-
isomer. The stereoselectivity in the reduction of pyrroli-
nes 1 can be rationalized by assuming a steric effect
between the diethylphosphonyl and the methyl groups.
Indeed, this particular steric hindrance puts the
diethylphosphonyl group in a pseudoaxial position, and
therefore makes possible the attack from the less
shielded face (Scheme 2).
Scheme 2.
Scheme 3.
Table 1. Reduction of b-iminophosphonates 1
Substrate
R1
R2
Reagent
Time (h)
Products
Yield (%)
1a
1b
1c
1d
1a
1b
1c
1d
Me
Me
Me
-(CH2)5-
Me
Me
Me
-(CH2)5-
H
Me
Et
-(CH2)5-
H
Me
Et
-(CH2)5-
NaBH4
NaBH4
NaBH4
NaBH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
4
4
4
4
0.5
0.5
0.5
0.5
2a
2b
2c
2d
3a
3b
3c
3d
72a
64a
61a
52
70b
57b
62b
47
a The yields are for isolated material after crystallization.
b The yields are for isolated material after preparative TLC.

M. Amedjkouh, J. Grimaldi / Tetrahedron Letters 43 (2002) 3761–3764
3763
Scheme 4.
been reported that during CꢀP bond cleavage, the
hydride does not attack the carbon atom bearing the
phosphonyl group.17
led to identification of dephosphonylated compounds 3
by reaction with LiAlH4. Further studies are in pro-
gress including use of pyrrolidines 2 as nitroxide precur-
sors and development of an asymmetric route to
compounds 2.
The above results suggested that dephosphonylation
might occur via a lithium amide intermediate which
resulted from the hydride attack on the imino group as
outlined in Scheme 4.
Acknowledgements
To gain insight into possible reaction pathways, we
carried out the following experiments. Aminophospho-
nate 2a was lithiated by reaction with LDA to generate
the intermediate 4a. The latter intermediate was
expected to rearrange by dephosphonylation into 5a
and thus give diastereoisomers 3a (path A, Scheme 4).
However, this was not the case and no dephosphonyla-
tion was observed for 4a. When the reduction of 1a was
performed with LiAlD4 the reaction yielded a pyrro-
lidine 6a containing two deuteriums, as shown in
Scheme 5. This also shows that both hydrides were
transferred from LiAlH4 and not during the quenching
step,17 which is consistent with the 1:1 ratio of the
diastereomers obtained. Although there is no evidence
for a direct hydride attack on the carbon bearing the
phosphorus atom, this cannot be excluded at this time.
However, the formation of 5a could be rationalized by
assuming a concerted process according to path B
(Scheme 4) in which a hydride attack on the imine
carbon is followed immediately by the double bond
migration within the intermediate 7a and then
dephosphonylation.
We thank Professor Paul Tordo and Dr. Jacques
Hatem for fruitful discussions.
References
1. (a) Braekman, J. C.; Daloze, D. In Studies in Natural
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Chem. 1990, 55, 826; (b) Cancho, Y.; Martin, J. M.;
Martinez, M.; Liebaria, A.; Moreto, J. M.; Delgado, A.
Tetrahedron 1998, 54, 1221.
In summary, we have developed an effective methodol-
ogy for hydride reduction of the 2,4-alkyl-5-phosphonyl
pyrrolines 1 using NaBH4. This reduction has been
shown to occur stereoselectively and allowed us to
isolate cis-isomers of the resulting pyrrolidines 2 after
crystallization from pentane. A preliminary study has
7. (a) Bioactive Spin Labels I and II; Zhdanov, R. I., Ed.;
Springer-Verlag, 1992; (b) Keana, J. F. W. In Spin
Labelling in Pharmacology; Holtzman, J. L., Ed.; Aca-
demic Press: London, 1984; pp. 2–67; (c) Berliner, L. J.
Spin Labelling–Theory and Applications I and II; Aca-
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8. Kuppusamy, P.; Chzan, M.; Sweier, J. L. J. Magn.
Reson., Ser. B. 1995, 106, 122–130.
Scheme 5.

3764
M. Amedjkouh, J. Grimaldi / Tetrahedron Letters 43 (2002) 3761–3764
9. (a) Grimaldi, S.; Finet, J. P.; Zeghdaoui, A.; Tordo, P.;
over Na2SO4, filtered and concentrated under reduced
pressure to give a colorless oil which was dissolved in 10
ml of pentane to afford white crystals of the pure pyrro-
lidine 2 in 52–72% yield. Data for a representative com-
pound 2a are given below.
Benoit, D.; Gnanou, Y.; Fontanille, M.; Nicol, P.; Pier-
son, J. F. A. C. S. Polym. Prepr. 1997, 38, 651–652; (b)
Hawker, C. J. Acc. Chem. Res. 1997, 30, 373–382.
10. (a) Amedjkouh, M.; Faure, R.; Hatem, J.; Tordo, P.;
Grimaldi, J. Phosphorus Sulfur 1997, 126, 53; (b) Amed-
jkouh, M.; Grimaldi, J.; Reboul, J.-P.; Siri, D. Acta
Crystallogr. 2000, C56, e31; (c) Amedjkouh, M.;
Grimaldi, J. Phosphorus Sulfur 2002, 177, 391–398.
11. (a) Seyden-Penne, J. Re´duction par les Alumino- et Boro-
hydrures en Synthe`se Organique, Technique et Documen-
tation (Lavoisier), 1988, p. 92; (b) Hudlicky, M.
Reduction in Organic Chemistry; Wiley: New York, 1984;
p. 132; (c) Pelter, A.; Smith, K. In Comprehensive Organic
Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.; Perga-
mon Press: Oxford, 1979; Vol. 3, p. 689.
Compound
2a:
(5-Ethyl-2,3,3-trimethylpyrrolidin-2-
yl)diethylphosphonate. Yield 72%. Colorless crystalline
1
prisms, mp: 71°C. H NMR (200 MHz) l (ppm): 0.90 (t,
3H, J=7.4 Hz); 1.01 (s, 3H); 1.23 (s, 3H); 1.25 (d, 3H,
J=15.4 Hz); 1.33 and 1.34 (2t, 6H, J=7.0 Hz); 1.4–1.8
(m, 2H); 1.99 (dd, 1H, J=9.3 Hz, J=12.1 Hz); 3.20 (m,
1H, J=8.4 Hz); 4.12 (m, 2H); 4.23 (quin., 2H, J=7.1
Hz). 13C NMR (100.61 MHz) l (ppm): 11.59 (C
6
C); 16.29–16.62 (d, OCH2C
P); 24.71 and 25.06 (d, J=12.5 Hz, J=4.1 Hz (C
30.1 (s, CH3CH2-C); 43.93 (d, J=5.9 Hz (CH3)2C
and 46.38 (-C
61.02 and 63.09 (d, J=7.5 Hz, OC
J=155.9 Hz, C
-P). 1P NMR (40.53 MHz) l (ppm): 27.67.
6
H3); 19.44 (d, J=4.5, C
63
6
6
6
6
H2-); 57.12 (d, J=5.1 Hz, CH3CH2-C
H2CH3); 65.91 (d,
6
12. Hutchins, R. O.; Hutchins, M. K. In Comprehensive
Organic Chemistry; Trost, B., Ed.; Pergamon: New York,
1991; Vol. 8, p. 25.
13. Dehnel, A.; Kanabus-Kaminska, J. M.; Lavielle, G. Can.
J. Chem. 1988, 66, 310.
6
Anal. calcd for C13H28NO3P: C, 56.28; N, 5.05; H, 10.18;
found: C, 56.23; N, 4.99; H, 10.10%.
20. Typical procedure for the reduction of b-iminophospho-
nate 1 with LiAlH4: Compound 1 (275 mg, 1 mmol) in a
solution of 2 ml dry THF was added, in small portions
over 30 min, to 114 mg (3 mmol) of LiAlH4 at room
temperature. The resulting mixture was stirred for 1 h
and then quenched with a solution of NaOH (4N) and
then filtered. The remaining white cake was washed with
THF (3×10 ml) and the combined organic layers were
dried over Na2SO4, filtered and concentrated under
reduced pressure to give a colorless oil which was then
purified by preparative TLC (dichloromethane). Pyrro-
lidines 3 were isolated in 47–70% yield as 1:1 mixtures of
diastereomers. Data for a representative compound 3a
are given below.
14. (a) Bestmann, H. J.; Graf, G.; Kolewa, S.; Vilsmeier, E.
Chem. Ber. 1970, 103, 2794; (b) Kondo, K.; Negishi, A.;
Tunemoto, D. Angew. Chem., Int. Ed. Engl. 1974, 13,
407.
15. Durrant, G.; Sutherland, J. K. J. Chem. Soc., Perkin
Trans. 1 1972, 2582.
16. Denmark, S. E.; Marlin, J. E. J. Org. Chem. 1991, 56,
1003.
17. (a) Hong, J. E.; Shin, W. S.; Jang, W. B.; Oh, D. Y.; Lee,
K. J. Org. Chem. 1996, 61, 2199–2201; (b) Lee, S. Y.;
Lee, C. W.; Oh, D. Y.; Lee, K. J. Org. Chem. 1999, 64,
7017–7022.
18. Jones, T. H.; Blum, M. S.; Fales, H. M. Tetrahedron
1982, 38, 1949.
Compound 3a: 5-Ethyl-2,3,3-trimethylpyrrolidine. Yield
19. Typical procedure for the reduction of b-iminophospho-
nate 1 with NaBH4: To 1.5 g (5×10−3 moles) of pyrroline
1 in a solution of 10 ml of ethanol was added, in small
portions over 30 min, 2.5×10−3 mol of sodium borohy-
dride. The resulting mixture was stirred for 4 h then
acidified with 5% HCl solution to pH 3, and the ethanol
was evaporated under reduced pressure. The remaining
aqueous layer was neutralized with a solution of 10%
KOH and extracted three times with dichloromethane.
After washing with brine, the organic layer was dried
1
72%. Colorless oil. H NMR (400 MHz) l ppm: 0.83 (s,
3H, CH
(s, 3H, CH
(AB system, 2H, J=12.8 Hz, H
J=7.2 Hz, CH3-CH2-); 2.73 and 2.79 (m, 1H, J=6.8 Hz,
C-2); 2.94 and 3.08 (m, 1H, J=7.2 Hz, H
C-5); 13C
6
3-C-3); 0.91 (t, 3H, J=7.6 Hz, CH3
3-C-3); 0.99 (d, 3H, J=6.6 Hz, CH3
2C-4); 1.33–1.55 (m, 2H,
6
-CH2-); 0.98
6
6
-C-2); 1.45
6
6
H
6
6
NMR (100.61 MHz) l ppm: 62.70; 57.70; 48.00; 40.80;
30.50; 26.87; 22.51; 14.74; 11.67. EIMS m/z: 142 (M+1,
100%); 112 (42); 70 (30).